Volume 6 | Issue 2
Delaware Journal of
Public Health A publication of the Delaware Academy of Medicine / Delaware Public Health Association
FROM CELLS TO SOCIETY: RESEARCH IN THE TIME OF COVID-19
www.delamed.org | www.delawarepha.org
Delaware Journal of
Delaware Academy of Medicine
Board of Directors: OFFICERS Omar A. Khan, M.D., M.H.S. President S. John Swanson, M.D. President Elect
A publication of the Delaware Academy of Medicine / Delaware Public Health Association
Lynn Jones Secretary David M. Bercaw, M.D. Treasurer Daniel J. Meara, M.D., D.M.D. Immediate Past President Timothy E. Gibbs, M.P.H. Executive Director, Ex-officio DIRECTORS Stephen C. Eppes, M.D. Eric T. Johnson, M.D. Joseph F. Kestner, Jr., M.D. Professor Rita Landgraf Brian W. Little, M.D., Ph.D. Arun V. Malhotra, M.D. John P. Piper, M.D. EMERITUS Robert B. Flinn, M.D. Barry S. Kayne, D.D.S.
Delaware Public Health Association
Omar Khan, M.D., M.H.S. President Timothy E. Gibbs, M.P.H. Executive Director Louis E. Bartoshesky, M.D., M.P.H. Gerard Gallucci, M.D., M.H.S. Richard E. Killingsworth, M.P.H. Erin K. Knight, Ph.D., M.P.H. Melissa K. Melby, Ph.D. Mia A. Papas, Ph.D. Karyl T. Rattay, M.D., M.S. William J. Swiatek, M.A., A.I.C.P.
Delaware Journal of Public Health Timothy E. Gibbs, M.P.H. Publisher Omar Khan, M.D., M.H.S. Editor-in-Chief Mia A. Papas, Ph.D. and Steven Stanhope, Ph.D. Guest Editors Liz Healy, M.P.H. Managing Editor Kate Smith, M.D., M.P.H. Copy Editor Suzanne Fields Image Director ISSN 2639-6378
Volume 6 | Issue 2
www.djph.org 3 | In this Issue
32 | Engineering Preclinical Tools and Therapeutics to Understand and Treat COVID-19
Omar A. Khan, M.D., M.H.S. Timothy E. Gibbs, M.P.H.
4 | Guest Editor
Catherine A. Fromen, Jason P. Gleghorn
Mia A. Papas, Ph.D. Steven Stanhope, Ph.D.
6 | Coronavirus through Delaware’s Computational Microscope
Carolina Pérez Segura, Nidhi Katyal, Ph.D., Fabio González-Arias, Alexander J. Bryer, Juan R. Perilla, Ph.D., Jodi A. Hadden-Perilla, Ph.D.
10 | Rapid Development and Validation of a Novel Laboratory-derived Test for the Detection of SARS-CoV-2
James Saylor, Jennifer Mantle, Leila H. Choe, Alana Szkodny, Vipsa Mehta, Alaina Meadows, Cynthia Flynn, Leslie Taylor, Abraham Joseph, Brewster Kingham, Kelvin H. Lee
16 | Validation and Use of Point-of-Care Lateral Flow Chromatographic Immunoassays for Early Diagnostic Support During the COVID-19 Pandemic
Richard M. Pescatore, D.O., Lisa M.G. Henry, M.H.S.A., Rebecca D. Walker, Ph.D., J.D., M.S.N., William Chasanov, D.O., M.B.A., Christopher M. Gaeta, Crystal Mintzer Webb, M.P.A., Camille Moreno-Gorrin, M.S., Paula Eggers, Frederick P. Franze, M.T. (A.S.C.P.), Sergio Huerta, M.D., Christina Pleasanton, M.S. Molly Magarik, Karyl T. Rattay, M.D., M.S., Kara Odom Walker, M.D., M.P.H., M.S.H.S., Rick Hong, M.D.
18 | The Importance of Research in Addressing the COVID-19 Pandemic: Focus on the Use of Serology Testing Vicky L. Funanage, Ph.D.
20 | Perspectives on molecular diagnostic testing for the COVID-19 pandemic in Delaware Erin L. Crowgey, Mary M. Lee, Brett Sansbury, Eric B. Kmiec
26 | Rapid COVID-19 Prognostic Blood Test for Disease Severity Using Epigenetic Immune System Biomarkers
36 | Multisystem Inflammatory Syndrome in Children (MIS-C): an emerging immune mediated syndrome in children associated with COVID-19 Deepika Thacker, M.D.
40 | Assessing the Impact of COVID-19 on Children and Youth
Lee M. Pachter, D.O., Cynthia Garcia Coll, Ph.D., Norma J. Perez-Brena, Ph.D., Lisa M. Lopez, Ph.D., Linda C. Halgunseth, Ph.D., Rashmita S. Mistry, Ph.D., Gabriela Livas Stein, Ph.D., Gustavo Carlo, Ph.D.
42 | Epidemic Meets Pandemic: Treating Opioid Use Disorder in the Age of COVID-19
Kimberly D. Williams, M.P.H., Lee M. Pachter, D.O., Scott D. Siegel, Ph.D., M.H.C..D.S.
44 | Mental Health Crisis: Depression, Anxiety, and COVID-19
Bernard Shalit, Marina Gettas, Dr.P.H., M.P.H.
48 | Courage, Cancer and COVID Carol Kerrigan Moore, M.S.
50 | Design of Clinical Trials Evaluating Ruxolitinib, a JAK1/ JAK2 Inhibitor, for Treatment of COVID-19–Associated Cytokine Storm
Peter Langmuir, M.D., Swamy Yeleswaram, Ph.D., Paul Smith, Ph.D., Barbara Knorr, M.D., Peg Squier, M.D., Ph.D.
60 | The Power of Public Health Surveillance
Rick Hong, M.D., Rebecca Walker, Ph.D., J.D., M.S.N., Gregory Hovan, Lisa Henry, M.H.S.A., Rick Pescatore, D.O.
64 | A Need for Contact Tracing Research Stephanie Shell, M.S.S.
66 | Mapping the ChristianaCare response to COVID-19: Clinical insights from the Value Institute’s Geospatial Analytics Core Madeline Brooks, M.P.H., Chenesia Brown, M.A., Ph.D.(c), Wei Liu, Ph.D., Scott D. Siegel, Ph.D., M.H.C.D.S.
72 | Social Determinants of Health, From Assessment to Action: A Review of 3 Studies from the Value Institute at ChristianaCare
Cecelia Harrison, M.P.H., Madeline Brooks, M.P.H., Jennifer N. Goldstein, M.D., M.Sc.
80 | Race as a Social Determinant of Health: Lessons from the Coronavirus Pandemic in Delaware
Daniel G. Atkins, J.D., David P. Donohue, M.D., F.A.C.P., Robert L. Hayman, Jr., Leland Ware, J.D., Maija Woodruff
88 | Addressing COVID-19 Health Disparities Through Community Engagement Marshala Lee, M.D., M.P.H., Jacqueline Ortiz, M.Phil., Jacqueline Washington, Ed.D.
92 | Engaging Community Health Workers and Social Care Staff as Social First Responders during the COVID-19 Crisis
Alicia L. Salvatore, Dr.P.H., M.P.H., Jacqueline Ortiz, M.Phil., Erin Booker, L.P.C., Nora Katurakes, M.S.N., R.N., O.C.N., Christopher C. Moore, Carla P. Aponte Johnson, M.S., Alexandra M. Mapp, M.P.H., Alex Waad, M.A., Michelle L. Axe, M.S., C.H.E.S.
96 | Delaware COVID-19 Homeless Community Outreach Partnership 2020 Rita Landgraf, Susan Holloway, Renee Beaman, Ray Fitzgerald
102 | Global Health Matters Fogarty International Center
114 | Delaware COVID - Lexicon 115 | Delaware COVID - Resources 122 | Index of Advertisers
Adam G. Marsh, G. Mark Anderson, Erich J. Izdepski
COVER On February 11, 2020 the World Health Organization announced an official name for the disease that is causing the 2019 novel coronavirus outbreak. The new name of this disease is coronavirus disease 2019, abbreviated as COVID-19. Globally, nationally, and locally, one of the most effective prevention measures is to wear a mask.
The Delaware Journal of Public Health (DJPH), first published in 2015, is the official journal of the Delaware Academy of Medicine / Delaware Public Health Association (Academy/DPHA).
only the opinions of the authors and do not necessarily reflect the official policy of the Delaware Public Health Association or the institution with which the author(s) is (are) affiliated, unless so specified.
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I N T H I S I S SU E The schedule of themed issues for the Delaware Journal of Public Health is set to close up to a year in advance of the publication date. Like many others, the Journal was impacted by COVID-19, and we utilized the opportunity to publish this two part issue on “Current Research,” with a focus on the groundbreaking research in our community.” Soon after the COVID-19 pandemic started, we convened with this issue’s Guest Co-Editors Mia Papas, Ph.D. and Steven Stanhope, Ph.D. to focus on research- of all sorts- specific to the novel coronavirus. They did a masterful and comprehensive review of Delaware research that covers the depth and breadth of public health, population health, clinical research, and interventions - and we thank them for their effort. The final title of this two part issue dynamically captures what it is all about:
“FROM CELLS TO SOCIETY: RESEARCH IN THE TIME OF COVID-19” We still included other research articles submitted to us - a validation that while COVID-19 is the big news, other work continues. You’ll read about that work in part 2 of this issue. To provide context to this issue, consider the 10 Essential Public Health Services which describe the public health activities that all communities should undertake: 1. M onitor health status to identify and solve community health problems 2. D iagnose and investigate health problems and health hazards in the community 3. I nform, educate, and empower people about health issues 4. M obilize community partnerships and action to identify and solve health problems 5. D evelop policies and plans that support individual and community health efforts 6. E nforce laws and regulations that protect health and ensure safety 7. L ink people to needed personal health services and assure the provision of health care when otherwise unavailable 8. A ssure competent public and personal health care workforce 9. E valuate effectiveness, accessibility, and quality of personal and population- based health services 10. R esearch for new insights and innovative solutions to health problems There is much anticipation and hopefulness around a vaccine. We wish to point out that community spread has been driven to nearly zero in several settings around the globe with existing technologies (masks, hand hygiene, physical distancing, testing & contact tracing). It is worth mentioning that if the numbers in the U.S. were like Delaware’s, we would have cause for optimism. This is not schadenfreude; just an observation that individuals committed to behavior change, with strong leadership from health systems, the state, and numerous partners can make a difference, even against a seemingly intractable pandemic. COVID-19 has truly activated and tested all 10 essential services above, on a global and local level. We hope this two part issue will illuminate work in Delaware and our neighboring states- a major part of what we hope will be a national success in achieving better health for all. Your feedback is welcome!
Omar A. Khan, M.D., M.H.S. President
Timothy E. Gibbs, M.P.H. Executive Director 3
From cells to communities: Addressing COVID-19 in Delaware through scientific research
Mia A. Papas, Ph.D. and Steven Stanhope, Ph.D.
“Ingenuity, knowledge, and organization alter but cannot cancel humanity’s vulnerability to invasion by parasitic forms of life. Infectious disease which antedated the emergence of humankind will last as long as humanity itself, and will surely remain, as it has been hitherto, one of the fundamental parameters and determinants of human history.” - William H. McNeill, in Plagues and Peoples, 19761 In December of 2019, reports of an outbreak of a new pneumonialike virus originated from Wuhan, China.2 The identified infectious agent, a novel coronavirus, known as SARS-CoV-2, spread rapidly and by mid-January cases were identified beyond China in Japan, Thailand, and South Korea.3 The first case in the United States occurred in a man in his 30s who resided in Washington State and was diagnosed on January 21, 2020.4 By the end of the month, the World Health Organization declared the outbreak a global public health emergency with 9,000 cases worldwide.5 Over the next two months, we witnessed the destabilization of the world economic markets and watched in disbelief as overrun hospitals and soaring death rates in Italy, Spain, and New York City became warning sentinels for the rest of the world. SARS-CoV-2 causes a respiratory illness we now commonly refer to as COVID-19.6 In the seven months since the first case reports, the world has been engulfed in a pandemic totaling over 10 million confirmed cases and 500,000 deaths with 2.65 million cases and 125,000 deaths in the United States as of June 21, 2020.7 Although some countries have successfully slowed the rate of transmission through public health practices, other countries, such as Brazil and the United States, are continuing to report new case rates that are rising exponentially. To understand the challenges the United States has faced in dealing with this pandemic, we need to look to the past. As early as the 1990s, the Centers for Disease Control and Prevention (CDC) as well as many other public health professionals had argued for strengthening the public health infrastructures of our nation in order to protect against novel infectious diseases.8 Central to the strategy of prevention is the concept that it is less costly to anticipate and prevent infectious disease threats than to react to widespread illnesses with expensive treatment and radical containment measures. Unfortunately, in the years prior to the COVID-19 pandemic, the United States has de-funded its public health infrastructure and missed opportunities to anticipate infectious disease threats.9 We are now reacting to this pandemic after repeated underinvestment in essential prevention activities including surveillance, laboratory research and training, epidemiologic investigation, and infection control efforts. This has resulted in both human suffering and widespread economic losses over the past six months that are many times greater than the savings accrued by budget cuts. Without a coordinated national response to provide guidance on a plan to halt the spread of this disease, local city, county, and state governmental agencies, as well as businesses and organizations, have been developing and implementing independent mitigation efforts. This piecemeal response to the pandemic has broadly resulted in uneven assistance to states, funding and supply delays 4 Delaware Journal of Public Health – July 2020
for healthcare providers, inconsistent public health messaging, and insufficient testing capabilities.10 It has also resulted in the continued spread of this disease throughout the United States despite the closure of schools and businesses throughout March and April. In Delaware, the first case of COVID-19 was identified on March 11, 2020.11 Prior to that first case, Delaware state and local government agencies, its healthcare systems, and our academic and technology and research partners had begun preparing for the outbreak. Having watched the toll this virus was taking on our neighbors in New York, New Jersey, and Pennsylvania, swift action by the Governor led to the transition of all schools to virtual learning platforms as well as a general shelter in place order within days after the first case was announced. In addition to the swift action of our state and local government agencies, the scientific, healthcare and business institutions of Delaware came together to develop strategies that allowed for a deeper understanding of the potential impact of COVID-19 on our community in order to develop efforts to mitigate the devastating effects of this disease. As just one example of these efforts, ChristianaCare established a drive through testing site less than 24 hours from the first diagnosed case.12 Since then, additional healthcare systems along with the Delaware Division of Public Health and New Castle County government have expanded diagnostic testing.13 In this edition of the Delaware Journal of Public Health, we have gathered a collection of innovative science occurring throughout our State as we all continue to flatten the curve. We provide a view of public health and medical activities across the continuum of clinical and translational research led by Delaware scientists. Over the past decade, several large research infrastructure programs such as the Idea Network for Biomedical Research Excellence (INBRE) and ACCEL: Delaware Center for Translational Research (DE-CTR) programs have worked to establish a network of education, healthcare, business, technology, research, and public health partners. These partners are a catalyst for connecting various research practices to improve the health of all Delawareans. Investments in this network have allowed for multidisciplinary teams to quickly come together in the face of this pandemic in order to understand disease dynamics, improve diagnosis and treatment, care for the caregivers on the frontlines, and contribute to technological advances that enhance prevention and treatment of COVID-19. The overwhelming response to our call for COVID-19 related research necessitated two volumes of the current edition. In volume 1, we start on the bench by providing insight into the virus itself. The first series of articles describe work to understand the basic virology of this novel virus and to develop methods to enhance diagnostic testing through laboratory-based methods,
serology tests, and molecular diagnostics. The next group of articles move to the bedside, highlighting the importance of developing novel treatments and therapeutics for COVID-19, testing the efficacy of existing pharmaceuticals through rapidly implemented clinical trials, and describing the need for clinical care to address important subpopulations including children, persons with mental health issues, and those with substance abuse use disorders. We then move to public health, and deal with the science of protecting and improving the health of the community. As a science, public health operates in the background of our everyday lives; it is only when disaster strikes that we realize its importance for keeping our communities healthy and safe from harm. In this section, you will read about local research on COVID-19 surveillance, contact tracing, and testing activities. Finally, our healthcare and prevention efforts must focus on the most vulnerable amongst us. Early data from across the nation, including Delaware, has brought a voice to the members of medically underserved communities who are also disproportionately more likely to contract COVID-19.14 We have gathered several examples of the focused efforts occurring throughout the State to examine the impact of the social determinants of health, racial injustice, and homelessness that cause greater divides in the health equity of our communities. You will read about research and actions addressing those disparities through community engagement and frontline social first responders. Volume 2 starts with our frontline healthcare workers. We bring you several articles describing first-hand the experience of the front-line health care workers who have been addressing this pandemic. We focus on their emotional resources and well-being and provide an editorial on the need for humility in practice and in research. In volume 2, you will also read about innovative technologies being manufactured right here in Delaware that expand the supply of personal protective equipment and engineer solutions for resource optimization. In the United States, an anti-science sentiment has been increasing over the past several years.15 COVID-19 has reminded us of the importance of scientifically based health research and practice. Science is our guide to navigate our way out of the havoc created by this devastating virus. Health professionals will continue to work intensely across the State of Delaware and throughout the nation to understand COVID-19 in order to protect the health of the population and minimize the negative impact of this and future diseases. And the rate at which we recover will be directly impacted by the universal empathetic concern we have for each other. Delaware has benefited from the strong commitment of its leaders in government, healthcare, education, business, and technology to improve lives through science and research. These efforts have established a medical and public health network that has come together toward one common human goal: our continued ability to protect and improve the health of the individuals in our community.
REFERENCES 1. McNeill, W. (1976). Plagues and peoples. Garden City, New York: Doubleday/Anchor. 2. Zhu, N., Zhang, D., Wang, W., Li, X., Yang, B., Song, J., . . . Tan, W., & the China Novel Coronavirus Investigating and Research Team. (2020, February 20). A novel coronavirus from patients with pneumonia in China, 2019. The New England Journal of Medicine, 382(8), 727–733. https://doi.org/10.1056/NEJMoa2001017
3. Mallapaty, S. (2020). Scientists fear coronavirus spread in vulnerable nations. Nature, 578, 348. Retrieved from: https://www.nature.com/articles/d41586-020-00405-w https://doi.org/10.1038/d41586-020-00405-w 4. Omer, S. B., Malani, P., & Del Rio, C. (2020, April 6). The COVID-19 pandemic in the US: A clinical update. JAMA, 323(18), 1767–1768. 5. World Health Organization. (2020, Mar 11). Director-General’s opening remarks at the media briefing on COVID-19. Retrieved from: https://www.who.int/dg/speeches/detail/whodirector-general-s-opening-remarks-at-the-media-briefing-on-covid19---11-march-2020 6. Coronaviridae Study Group of the International Committee on Taxonomy of Viruses. (2020, April). The species Severe acute respiratory syndrome-related coronavirus: Classifying 2019nCoV and naming it SARS-CoV-2. Nature Microbiology, 5(4), 536–544. Retrieved from: https://doi.org/10.1038/s41564-020-0695-z 7. Johns Hopkins University and Medicine. (n.d.). Coronavirus resource center: COVID-19 case tracker. Available at: https://coronavirus.jhu.edu/map.html 8. Centers for Disease Control and Prevention. (1994). Addressing emerging infectious disease threats: A prevention strategy for the United States. Atlanta, GA: U.S. Department of Health and Human Services, Public Health Service. Retrieved from: https://www.cdc.gov/mmwr/preview/mmwrhtml/00031393.htm 9. Maani, N., & Galea, S. (2020, June). COVID-19 and underinvestment in the public health infrastructure of the United States. The Milbank Quarterly, 98(2), 250–259. Retrieved from https://www.milbank.org/quarterly/articles/covid19-and-underinvestment-in-the-public-health-infrastructure-of-theunited-states/ https://doi.org/10.1111/1468-0009.12463 10. Barry, E. (2020, Mar 15). ‘It’s totally ad hoc’: why America’s Virus response looks like a patchwork. The New York Times. Retrieved from: www.nytimes.com/2020/03/15/us/united-statescoronavirus-response.amp.html 11. Delaware News. (2020, Mar 11). Public health announces first presumptive positive case of coronavirus in Delaware resident. Retrieved from: https://news.delaware.gov/2020/03/11/publichealth-announces-first-presumptive-positive-case-of-coronavirus-indelaware-resident/ 12. Drees, M., Papas, M., Corbo, T., Williams, K., & Kurfuerst, S. (2020). (in press). Identifying community spread of COVID-19 via a free drive-through screening event. Infection Control and Hospital Epidemiology. 13. Delaware News. (2020, May 8). Governor Carney announces significant expansion of statewide testing program for COVID-19. May 8, 2020. Retrieved from: https://news.delaware. gov/2020/05/08/governor-carney-announces-significant-expansionof-statewide-testing-program-for-covid-19/ 14. Williams, D. R., & Cooper, L. A. (2020, May 11). COVID-19 and health equity – a new kind of “herd immunity”. JAMA, 323(24), 2478–2480. https://doi.org/10.1001/jama.2020.8051 15. Otto, S. L. (2012, November). America’s science problem. Scientific American, 307(5), 62–71. https://doi.org/10.1038/scientificamerican1112-62 5
Bench: Virology, Detection and Diagnosis
Coronavirus through Delaware’s Computational Microscope Carolina Pérez Segura, Nidhi Katyal, Ph.D., Fabio González-Arias, Alexander J. Bryer, Juan R. Perilla, Ph.D., and Jodi A. Hadden-Perilla, Ph.D. Department of Chemistry and Biochemistry, University of Delaware
ABSTRACT The Perilla/Hadden-Perilla research team at the University of Delaware presents an overview of computational structural biology, their efforts to model the SARS-CoV-2 viral particle, and their perspective on how their work and training endeavors can contribute to public health.
THE COMPUTATIONAL MICROSCOPE
Since the beginning of the current global pandemic, COVID-19, the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, Figure 1, left), has infected over eight million people worldwide,1 and more than 10,000 in the state of Delaware.2 The rapid spread and severity of SARS-CoV-2 has placed significant strain on our public health infrastructure and exerted pressure on our STEM workforce to quickly develop strategies to combat the virus.
While most people are familiar with biomedical research that takes place at the laboratory benchtop or in a clinical setting, health-related research can also take place in silico or entirely within a computer. Computer-based investigations of viral diseases include epidemiological modeling to predict infection risk or spread in the population, sequencing studies to characterize similarities between pathogens or trace their evolution, data science initiatives to extract statistics and trends from accumulated public health information, and highthroughput screening of drug compounds to identify potential antiviral treatments. Within computational structural virology, investigations also include modeling to develop virtual replicas of viruses or their components and simulations to investigate the dynamics of virus structures, as well as how the structures interact with each other, drugs, or the host cell during infection.3–5 Our SARS-CoV-2 project involves modeling and simulation of the atomistic viral particle.
We are constituents of that STEM workforce at the University of Delaware. Our team, including members of two research laboratories in the Department of Chemistry and Biochemistry, have received funding from the National Science Foundation (NSF) and the Delaware Established Program to Stimulate Competitive Research (EPSCoR) to develop a new model of SARS-CoV-2. The model, a structure of the SARS-CoV-2 viral particle that encompasses all its constituent atoms, will provide an important basis for understanding the virus that causes COVID-19 from the bottom up. The approaches we are employing to develop the model are derived from a field of research referred to as computational structural virology and utilize an instrument we call the “computational microscope” (Figure 1, right). In this article, we invite our fellow Delawareans to learn more about computational structural virology, how we are leveraging it to characterize SARS-CoV-2, and how this basic science approach can ultimately impact public health. We also underscore the role of academic research in recruiting and training our nextgeneration STEM workforce to combat future viral outbreaks and introduce members of our highly diverse computational team at the University of Delaware.
For scientists like us, the computer is a research instrument. By combining theory from chemistry, physics, and biology to accurately describe the behavior of biomolecules, the computer transforms into a “computational microscope” (Figure 1, right), allowing us to examine realistic virtual virus structures and their dynamics at a level of detail that is unattainable by even the most powerful material microscopes.6 Importantly, the work we perform with our “computational microscope” integrates experimental data and is validated against experimental results to ensure that our models and simulations are representative of reality.7,8 The experimental data we incorporate comes from a variety of sources, including biochemical assays, X-ray
Figure 1. Virus models via supercomputers. Schematic of the SARS-CoV-2 viral particle, left. Conceptual diagram of the “computational microscope,” right.
6 Delaware Journal of Public Health – July 2020
crystallography, cryo-electron microscopy, and nuclear magnetic resonance spectroscopy. Some of the experimentalists that we collaborate with to obtain this data have their laboratories right here in the State of Delaware. Since the accuracy of the “computational microscope” depends on the availability and quality of experimental data, our SARS-CoV-2 project will benefit from the plethora of structural information that has already been collected for the virus, as well as other related coronaviruses. Importantly, the models that we construct and study with the “computational microscope” describe the structures of biomolecular systems down to the individual atoms that they are composed of. The simulations that we run include every atom in the model, as well as the atoms of water molecules and salt ions that surround the system and mimic its native physiological environment. When we model and simulate virus structures, the atoms that we must consider can number in the millions, and we require high-performance supercomputing resources to carry out the work. While studying the smaller structural components of SARS-CoV-2 (Figure 2) is amenable to local resources, such as the Delaware Advanced Research Workforce and Innovation Network (DARWIN) supercomputer, our model of the SARS-CoV-2 viral particle requires partnering with national resources, namely the leadership-class Frontera supercomputer at the Texas Advanced Computing Center, which is ranked fifth in the world.9
MODELING THE SARS-COV-2 VIRAL PARTICLE Developing a model of the SARS-CoV-2 viral particle is a monumental task. Fortunately, our groups have many years
of combined experience in computational structural virology and have worked on viruses like HIV-1 and hepatitis B in the past.10–13 To model an entire virus, we begin with modeling the individual structural components of SARS-CoV-2 (Figure 2), integrating as much experimental data as we have available and using computational approaches to fill in the gaps. Structures we are working on include the spike (S) protein, which mediates adhesion and entry of the virus, the membrane (M) protein, which plays an essential role in assembly of new viral particles, the envelope (E) protein, which forms a pentameric ion channel, and the helical nucleocapsid (N) protein, which encases the viral RNA (Figure 2).14–19 While the genome-containing nucleocapsid is packed into the core of the virus, numerous copies of the S, M, and E proteins are embedded in its surface, which is composed of a lipid bilayer envelope (Figure 2). The SARS-CoV-2 envelope encompasses a complex combination of lipid species, and the composition may be unique to the virus. We are separately developing a model of the envelope, including the realistic lipid composition, which will ultimately allow us to bring all the structural components together to produce a cohesive model of the viral particle. When completed, the SARS-CoV-2 model will incorporate the envelope, its surface-embedded proteins, the glycans that decorate those proteins, the viral RNA encased by the helical nucleocapsid packed within the particle core, as well as other non-structural and accessory proteins known to be packaged by the virus. While not the first atomistic model of a viral particle produced by our field,20–22 our final SARS-CoV-2 model aims to be the most comprehensive virtual representation of a virus ever constructed.
Figure 2. Structural components of the SARS-CoV-2 viral particle. Lipid bilayer envelope, left. Structural proteins, right, including the spike (S) protein, membrane (M) protein, envelope (E) protein, and N-terminal and C-terminal domains of the nucleocapsid (N) protein.
Bench: Virology, Detection and Diagnosis
SUPPORTING PUBLIC HEALTH WITH BASIC SCIENCE
TRAINING RESEARCHERS FOR FUTURE PANDEMICS
Computational structural virology is a field of basic science research. Its objective is ultimately to further our fundamental understanding of viruses. Generally, we are interested in elucidating structure-function relationships, or discovering how the details of viral architecture drive the biological processes involved in successful infection, replication, and propagation. Once we establish the mechanisms by which the structural components operate and work together to form the functional whole, then we can devise interventions that disrupt those operations to thwart the virus. For example, by characterizing a component known to play an essential role in particle assembly or mediate a key interaction with the host cell, our model can guide rational design or optimization of antiviral drugs that inhibit these events; by characterizing a component known to elicit a host immune response during infection, our model can facilitate the mapping of antigenic sites and support the development of vaccines. Further, by investigating the SARS-CoV-2 viral particle in aggregate, we can analyze emergent properties of the system that may be related to host-level factors such as infectivity, pathogenicity, and virulence.
Our project to model the SARS-CoV-2 viral particle is NSFfunded. In keeping with NSF’s strategic plan to develop a highquality, diverse national STEM workforce,23 we are actively training new researchers in the state-of-the-art computational skills they need to participate in addressing the current pandemic, as well as any that may arise in the future. Remarkably, a significant portion of our SARS-CoV-2 work is being carried out by students and postdoctoral researchers at the University of Delaware. Being engaged in biomedical research with the potential to impact an ongoing global health emergency has empowered these trainees at critical stages of their scholarly careers. As academics, we must always prioritize the recruitment and training of capable individuals who will become our next generation of scientists. Importantly, we should also aim to diversify the STEM workforce going forward.
Overall, basic science builds a foundation of knowledge for applied science to stand upon. Cultivating an understanding of SARS-CoV-2 from the bottom up will provide a powerful advantage over the virus. A model of an intact, atomistic virus particle will equip researchers with a detailed structural map of the pathogen and a depth of insight into its inner workings that will enhance biomedical research across other STEM fields, guiding new experiments and data interpretation. By promoting the development of prophylactic and therapeutic interventions, basic science translates into disease control and patient care; by expanding our fundamental understanding of the virus, basic science can lead to improved public health recommendations, education, policy, and outcomes. Moreover, the more we learn about viruses in general, the more prepared we become to combat and contain future outbreaks. Supporting basic science research is ultimately essential to maintaining the welfare of our population long-term, in Delaware and beyond.
Our research laboratories actively seek to attract diverse individuals to the field of computational structural virology. Notably, our team (Figure 3) is currently 50% male and 50% female, made up of domestic and international scholars, and includes members who identify as White, Black, Asian, Hispanic or Latino, LGTBQ, disabled, first-generation college student, first-generation immigrant, and Delaware native. Figure 3 shows a picture of our team during a recent video conference meeting. To support social distancing on the University of Delaware campus, the team has been working remotely since March 2020.
ACKNOWLEDGEMENTS This work is supported by NSF award MCB-2027096, funded in part by Delaware EPSCoR. Undergraduate student support is provided by the XSEDE Expert Mentoring Producing Opportunities for Work, Education, and Research (EMPOWER) program, funded by NSF award ACI-1548562, and the University of Delaware Summer Scholars Program. This research is part of the Frontera computing project at the Texas Advanced Computing Center. Frontera is made possible by NSF award OAC-1818253. The DARWIN computing project at the University of Delaware is made possible by NSF award OAC-1919839.
Figure 3. Members of the Perilla/Hadden-Perilla research team. A. Olivia Shaw, undergraduate student (Hadden Lab); B. Dr. Jodi Hadden-Perilla, Assistant Professor; C. Dante Freeman, postbaccalaureate researcher (Hadden Lab); D. Dr. Nidhi Katyal, postdoctoral researcher (Perilla Lab); E. Chaoyi Xu, graduate student (Perilla Lab); F. Tanya Nesterova, undergraduate student (Perilla Lab); G. Hagan Beatson, undergraduate student (Perilla Lab); H. Dr. Juan Perilla, Assistant Professor; I. Oluwatoni AkinAdenekan, undergraduate student (Perilla Lab); J. Alexander Bryer, graduate student (Perilla Lab); K. Fabio González, graduate student (Perilla Lab); L. Carolina Pérez Segura, graduate student (Hadden Lab).
8 Delaware Journal of Public Health – July 2020
REFERENCES 1. World Health Organization. (2020, June 20). Coronavirus disease (COVID-19) pandemic. Retrieved from: https://www.who.int/emergencies/diseases/novelcoronavirus-2019 2. State of Delaware. (2020, June 20). Delaware’s Response to Coronavirus Disease (COVID-19). Retrieved from: https://coronavirus.delaware.gov 3. Hadden, J. A., & Perilla, J. R. (2018, August). All-atom virus simulations. Current Opinion in Virology, 31, 82–91. https://doi.org/10.1016/j.coviro.2018.08.007 4. Reddy, T. & Sansom, M. S. P. (2016). Computational virology: From the inside out. Biochim. Biophys. Acta - Biomembr, 1858(7PtB), 1610-1618. https://doi.org/10.1016/j.bbamem.2016.02.007 5. Marzinek, J. K., Huber, R. G., & Bond, P. J. (2020, April). Multiscale modelling and simulation of viruses. Current Opinion in Structural Biology, 61, 146–152. https://doi.org/10.1016/j.sbi.2019.12.019 6. Perilla, J. R., Goh, B. C., Cassidy, C. K., Liu, B., Bernardi, R. C., Rudack, T., . . . Schulten, K. (2015, April). Molecular dynamics simulations of large macromolecular complexes. Current Opinion in Structural Biology, 31, 64–74. https://doi.org/10.1016/j.sbi.2015.03.007 7. Goh, B. C., Hadden, J. A., Bernardi, R. C., Singharoy, A., McGreevy, R., Rudack, T., . . . Schulten, K. (2016, July 5). Computational methodologies for real-space structural refinement of large macromolecular complexes. Annual Review of Biophysics, 45, 253–278. https://doi.org/10.1146/annurev-biophys-062215-011113 8. Pak, A. J., & Voth, G. A. (2018, October). Advances in coarsegrained modeling of macromolecular complexes. Current Opinion in Structural Biology, 52, 119–126. https://doi.org/10.1016/j.sbi.2018.11.005 9. The TOP500 List. (2020, June 20). Top-ranked systems as of November 2019. Retrieved from: https://www.top500.org/lists/2019/11 10. Perilla, J. R., Hadden, J. A., Goh, B. C., Mayne, C. G., & Schulten, K. (2016, May 19). All-atom molecular dynamics of virus capsids as drug targets. The Journal of Physical Chemistry Letters, 7(10), 1836–1844. https://doi.org/10.1021/acs.jpclett.6b00517 11. Zhao, G., Perilla, J. R., Yufenyuy, E. L., Meng, X., Chen, B., Ning, J., . . . Zhang, P. (2013, May 30). Mature HIV-1 capsid structure by cryo-electron microscopy and all-atom molecular dynamics. Nature, 497(7451), 643–646. https://doi.org/10.1038/nature12162 12. Perilla, J. R., & Schulten, K. (2017, July 19). Physical properties of the HIV-1 capsid from all-atom molecular dynamics simulations. Nature Communications, 8, 15959. https://doi.org/10.1038/ncomms15959
13. Hadden, J. A., Perilla, J. R., Schlicksup, C. J., Venkatakrishnan, B., Zlotnick, A., & Schulten, K. (2018, April 27). All-atom molecular dynamics of the HBV capsid reveals insights into biological function and cryo-EM resolution limits. eLife, 7, e32478. https://doi.org/10.7554/eLife.32478 14. Wrapp, D., Wang, N., Corbett, K. S., Goldsmith, J. A., Hsieh, C. L., Abiona, O., . . . McLellan, J. S. (2020, March 13). Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science, 367(6483), 1260–1263. https://doi.org/10.1126/science.abb2507 15. Walls, A. C., Park, Y. J., Tortorici, M. A., Wall, A., McGuire, A. T., & Veesler, D. (2020, April 16). Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein. Cell, 181(2), 281–292.e6. https://doi.org/10.1016/j.cell.2020.02.058 16. Liu, J., Sun, Y., Qi, J., Chu, F., Wu, H., Gao, F., . . . Gao, G. F. (2010, October 15). The membrane protein of severe acute respiratory syndrome coronavirus acts as a dominant immunogen revealed by a clustering region of novel functionally and structurally defined cytotoxic T-lymphocyte epitopes. The Journal of Infectious Diseases, 202(8), 1171– 1180. https://doi.org/10.1086/656315 17. Surya, W., Li, Y., & Torres, J. (2018, June). Structural model of the SARS coronavirus E channel in LMPG micelles. Biochimica et Biophysica Acta. Biomembranes, 1860(6), 1309–1317. https://doi.org/10.1016/j.bbamem.2018.02.017 18. Kang, S., Yang, M., Hong, Z., Zhang, L., Huang, Z., Chen, X., . . . Chen, S. (2020, April 20). Crystal structure of SARS-CoV-2 nucleocapsid protein RNA binding domain reveals potential unique drug targeting sites. Acta Pharmaceutica Sinica. B. https://doi.org/10.1016/j.apsb.2020.04.009 19. Chen, C. Y., Chang, C. K., Chang, Y. W., Sue, S. C., Bai, H. I., Riang, L., . . . Huang, T. H. (2007, May 11). Structure of the SARS coronavirus nucleocapsid protein RNA-binding dimerization domain suggests a mechanism for helical packaging of viral RNA. Journal of Molecular Biology, 368(4), 1075–1086. https://doi.org/10.1016/j.jmb.2007.02.069 20. Freddolino, P. L., Arkhipov, A. S., Larson, S. B., McPherson, A., & Schulten, K. (2006, March). Molecular dynamics simulations of the complete satellite tobacco mosaic virus. Structure, 14(3), 437–449. https://doi.org/10.1016/j.str.2005.11.014 21. Zeng, Y., Larson, S. B., Heitsch, C. E., McPherson, A., & Harvey, S. C. (2012, October). A model for the structure of satellite tobacco mosaic virus. Journal of Structural Biology, 180(1), 110–116. https://doi.org/10.1016/j.jsb.2012.06.008 22. Durrant, J. D., Kochanek, S. E., Casalino, L., Ieong, P. U., Dommer, A. C., & Amaro, R. E. (2020, February 26). Mesoscale all-atom influenza virus simulations suggest new substrate binding mechanism. ACS Central Science, 6(2), 189–196. https://doi.org/10.1021/acscentsci.9b01071 23. National Science Foundation. (2020, June 20). Building the future: Investing in discovery and innovation - NSF Strategic Plan for Fiscal Years (FY) 2018 - 2022. Retrieved from: https://www.nsf.gov/pubs/2018/nsf18045/nsf18045.pdf 9
Bench: Virology, Detection and Diagnosis
Rapid development and validation of a novel laboratory-derived test for the detection of SARS-CoV-2 James Saylor and Jennifer Mantle National Institute for Innovation in Manufacturing Biopharmaceuticals, University of Delaware Leila H. Choe and Alana Szkodny, Department of Chemical and Biomolecular Engineering, University of Delaware Vipsa Mehta, Alaina Meadows, Cynthia Flynn, Leslie Taylor and Abraham Joseph ChristianaCare Health System, Molecular Diagnostics Laboratory
Brewster Kingham Delaware Biotechnology Institute, University of Delaware Kelvin H. Lee National Institute for Innovation in Manufacturing Biopharmaceuticals, University of Delaware; ChristianaCare Health System, Molecular Diagnostics Laboratory
ABSTRACT Objectives: To increase testing capability for SARS-CoV-2 during a rapidly evolving public health emergency, we aimed to deploy a validated laboratory-developed real-time reverse transcription polymerase chain reaction (RT-PCR) diagnostic test for SARS-CoV-2 on an accelerated timeline and using reagent supply chains that were not constrained. Methods: A real-time RT-PCR assay that detects the structural envelope (E) gene of SARS-CoV-2 was developed and validated on the Roche cobas 6800 instrument platform with the omni Utility channel reagents, which performs automated nucleic acid extraction and purification, PCR amplification, and detection. In silico analysis was performed for both inclusivity of all SARS-CoV-2 variants and cross reactivity with other pathogenic organisms. Positive control material was used to determine the Limit of Detection (LOD) and patient samples (positive and negative) confirmed by another authorized assay were used for clinical validation. Experiments were carried out at the Christiana Care Health System’s Molecular Diagnostics Laboratory (Newark, DE) between April 1 and April 4, 2020. Results: A real-time RT-PCR assay for SARS-Cov-2 was developed and validated in just two weeks. For all oligonucleotides, 100% homology to the available SARS-CoV-2 sequences was observed. Greater than 80% homology between one or more oligonucleotides was observed for SARS-Cov (Urbani strain) and Influenza A, however risk of cross reactivity was deemed to be low. The limit of detection (LOD) of the assay was 250 copies/ mL. The assay identified 100% of positive patient samples (30/30) and 100% of negative patient samples (29/29 patient negatives and 1/1 saline). Up to 92 samples can be run on a single plate and analysis takes approximately 3.5 hours. Conclusions: In this work, we demonstrate the development and validation of a single target laboratorydeveloped test for SARS-CoV-2 in two weeks. Key considerations for complementary supply chains enabled development on an accelerated timeline and an increase in testing capability.
INTRODUCTION The outbreak of a novel coronavirus strain (SARS-CoV-2) first reported in December 2019 has escalated to a worldwide pandemic and rapidly evolving public health emergency. Genetic analysis shows that the SARS-CoV-2 strain belongs to the genus Betacoronavirus, which contains severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV), both of which have caused severe respiratory disease in humans.1 Due to a lack of innate immunity to SARS-CoV-2 in humans, rapid diagnosis of SARS-CoV-2 infection is a critical step in developing effective containment protocols to curb the virus’s rapid spread across the globe. Early diagnostic tests for SARS-CoV-2 developed in Germany,2 Hong Kong,3 and the USA4 have all used a qualitative real-time reverse transcription polymerase chain reaction (RT-PCR) approach to detect the presence of SARS-CoV-2 genomic RNA in patient samples. Each assay uses a different combination of genomic regions for detection (Germany: RdRp and E genes, 10 Delaware Journal of Public Health – July 2020
Hong Kong: ORF1b and N genes, USA: two targets on the N gene) and requires the detection of two distinct regions on the virus genome to confirm infection. The rapid development and deployment of these assays has been key in limiting the outbreak to the extent it has been limited; yet, achieving widespread testing capability for a public health emergency of this size and scale has been hindered by assay throughput and the availability of reagents, supplies, and equipment. These initial assays require combinations of commercially-available reagent kits and specific equipment for testing. During a public health emergency of this size and severity, establishing widespread and robust testing infrastructure is critical for monitoring community spread. Diagnostic companies have developed and marketed their own proprietary PCR-based assays as kits specifically designed for their respective in vitro diagnostic testing platforms; however, implementation is limited to testing facilities with access to these instruments and the availability of the corresponding kits. As the demand for testing increases, many labs experience supply chain issues and reagent
shortages, which limits the scale-up of widespread testing. The supply of reagents required by these PCR-based protocols cannot keep up with rapidly increasing demand, ultimately impacting the ability to effectively diagnose and contain SARS-CoV-2. On March 31, 2020, due to the rapidly evolving pandemic and shortages of commercial in vitro diagnostic tests, the US Food and Drug Administration (FDA) determined that molecularbased laboratory developed tests are justified to protect the public health5 and issued guidelines for developing and validating these assays6 under Emergency Use Authorization (EUA). Under such guidance, assays should at least establish a limit of detection, include inclusivity and cross-reactivity analyses, as well as perform clinical assessment with a number of known patientpositive as well as non-reactive samples. Laboratory-developed tests play an important role in helping healthcare systems care for their patients when commercial tests are difficult to obtain7 however developing such a test has historically required timelines on the order of months during previous viral outbreaks. In response to the first SARS outbreak in early 2003, the World Health Organization (WHO) international working group identified the novel coronavirus strain in April 2003, but early diagnostic tests developed were either unreliable or did not detect the virus until late in the illness’s course.8,9 It took nearly six months before a reliable assay could be established.10 During the Ebola outbreak of 2014-2015, the US Department of Defense obtained an EUA for their RT-PCR diagnostic in early August 2014, however, this was the only test to gain FDA authorization until BioFire Defense gained approval nearly three months later in late October 2014.11 Similarly, after the WHO declared Zika a public health emergency of international concern in February 2016,12 testing in the US was initially limited to the Centers for Disease Control and Prevention (CDC). Distribution of tests to authorized laboratories was controlled and managed by the CDC and the limitation in distribution of early CDC assays resulted in a backlog of nearly 1,000 samples in the Miami area at one point during the outbreak.7 The first commercial laboratory was issued an EUA in late April 201613 and to date, the only laboratory-developed test EUA was issued to Columbia University’s Center for Infection and Immunity in August 2017,13 a year and a half after the CDC test was authorized. During the early phases of a viral outbreak, the ability to rapidly determine which patients are positive or negative for the virus is critical. It is important for treatment of the patient as well as for developing an understanding of the spread of the disease in the community. An inability to rapidly diagnose patients can also strain healthcare systems. For example, patients that present with symptoms, but for which a diagnosis must wait several days, are treated as if they may be positive, requiring the use of a significant amount of personal protective equipment by healthcare providers and requiring special isolation. If a patient tests negative, a significant amount of equipment and resources can be allocated to those in need. The current SARS-CoV-2 situation also opens the opportunity to circumvent, or at least alleviate, certain bottlenecks in testing supplies with in-house laboratory-developed assays. Laboratories may need to strategize their choice of instruments, reagents, supplies, protocols, and sources for each, to quickly develop
tests that are rigorous enough to gain regulatory acceptance, and that can be adopted for sustained use during an outbreak of unknown duration. Some issues to consider are speed to regulatory acceptance and risk of non-acceptance, the benefits and drawbacks of using less common targets and/or reagents, compatibility with commercial platforms, and the availability of custom and commercially available reagents. One possible approach is to apply laboratory-developed tests customized for SARS-CoV-2 to commercially available automated platforms that are already designed for in vitro diagnostics. Such an approach can increase throughput by relying on an automated platform that would require less staff resources and can test numerous samples at once, as well as by using reagents and supplies that are less limited by supply chain issues. This approach can also supplement the use of proprietary diagnostic tests to maximize instrument use time and decrease turnaround time. It also can help provide a rapid clinical diagnosis to patients. Here, we report on the rapid development of a clinically validated laboratory-developed test for SARS-CoV-2 detection in just two weeks. The method relies on a commercially available platform for automated extraction, amplification, and detection, and has the benefit of being on a platform for which reagents were not limited by supply chain constraints. In the interest of accelerated development and the use of extraction and amplification kits that are not limiting during the outbreak, the assay relies on a single target in the E gene previously reported in the literature,2,14 and other publicly available information. We present observations with this clinically validated assay, which was established in two weeks, with the goal of enabling other laboratories with similar instrument platforms to rapidly develop and validate an assay for SARS-CoV-2 detection. This method is described in a manner intended to facilitate broad adoption and the ability to secure an authorization to use this assay from the appropriate health authority.
MATERIALS AND METHODS Materials The SARS-CoV-2 E-gene Forward Primer (5’-ACAGGTACGTTAATAGTTAATAGCmGT-3’) and the SARS-CoV-2 E-gene Reverse Primer (5’-ATATTGCAGCAGTACGCACAmCA-3’) were obtained from Integrated DNA Technologies (IDT; Coralville, Iowa; m = 2’-O-methyl base in penultimate to prevent primer dimer). The SARS-CoV-2 E-gene Probe (5´-Fam-ACACTAGCC/ ZEN/ATCCTTACTGCGCTTCG-Iowa Black FQ-3’) was also purchased from IDT. The positive control was purchased from SeraCare (#0505-0126, AccuPlexTM SARS-CoV-2 Reference Material Kit). Other reagents for use on the Roche cobas 6800 instrument platform included: omni Utility Channel Reagent Kit (#06645348190), buffer negative control (#07002238190), MGP reagent (#06997546190), specimen diluent (#06997511190), lysis reagent (#06997538190), wash reagent (#06997503190), processing plate (#05534917001), amplification plate (#05534941001), pipette tips (#05534925001), liquid waste container (#07094388001), solid waste bag and containers (#07435967001, #07094361001, #08030073001 and #08387281001), and secondary tubes (#06438776001). 11
Bench: Virology, Detection and Diagnosis
For clinical validation, 13 positive and 18 negative COVID-19 patient samples were donated by the Delaware Public Health Laboratory. Patient COVID-19 status was determined using the CDC assay. An additional 11 positive and 11 negative patient samples were donated to this effort by Christiana Care Health System. Patient COVID-19 status was determined using the Cepheid Xpert Xpress SARS-CoV-2 test (EUA granted March 20, 2020). All patient samples were deidentified prior to use and blinded to the laboratory technician carrying out the assay. Use of deidentified leftover patient samples was consistent with FDA Guidance.15
Oligo, Controls, and Reagent Preparation
The software automatically calls whether a batch is valid or invalid and accordingly assigns a result to each sample. A batch is valid if no flags appear for the negative control or the positive control. Invalidation of results is performed by the software based on negative control failures, while invalidation of results due to positive control failures must be determined by the user. A valid batch may include both valid and invalid sample results. A positive result for the SARS-CoV-2 E-gene indicates that the target-specific nucleic acid has been detected while a negative result for the SARS-CoV-2 E-gene indicates that the targetspecific nucleic acid has not been detected. An invalid result for a particular sample indicates that testing for that sample is invalid and should be repeated for that sample only.
Oligo sequences for detection of the SARS-CoV-2 envelope (E) gene were obtained from published literature.2,14 Sequences were verified against the available RefSeq genome (NCBI Accession Number: NC_045512, accessed March 27, 2020).16 Oligos were resuspended in molecular biology grade water to 1000µM and then further diluted and aliquoted into 100µM working stocks. Probes were diluted directly to 100µM. Positive control standard (SeraCare) containing non-replicating SARS-CoV-2 RNA sequence segments encapsulated in a viral protein coat was used. Roche Master Mix 2 (MMx-R2) was prepared as previously described.14 Briefly, 6mL of MMx-R2 was transferred into a light-protected polypropylene tube. 84 µL each of the forward and reverse primers (100 µM working stock), 10.5 µL of the probe (100 µM working stock), plus 303 µL of molecular biology grade water were added to MMx-R2 to reach a final volume of 6.48 mL. Six mL of the prepared MMx-R2 was loaded into the reagent cassette according to the manufacturer’s protocol.
Sample Preparation Positive control was diluted 1:20 in appropriate media (E-swab, Viral Transfer Media (VTM), or saline) to a final concentration of 250 genome copies / mL (cp/mL) and transferred to a secondary tube. Samples for limit of detection (LOD) determination were created by diluting positive control in appropriate media per the experimental design. To run the samples on the instrument, 0.6 mL of sample material was transferred to a barcoded secondary tube with instrument parameters as previously described.14 An RNA Internal Control (RNA IC) was included and serves as both an extraction and amplification control. Nucleic acid from patient samples and an RNA IC is simultaneously extracted. Selective amplification of the RNA IC is achieved by the use of non-competitive sequence specific forward and reverse primers, which have no homology with the SARS-CoV-2 genome.
In silico Inclusivity and Cross-Reactivity Analysis In silico inclusivity and cross-reactivity analyses were performed using NCBI BLAST (accessed March 31, 2020) to align the selected primer and probe sequences to sequences of interest. Default parameters were used for the alignments and scoring. To assess inclusivity of the assay, alignment was done against all published SARS-CoV-2 sequences available in the NCBI database (Tax ID 2697049). Potential cross-reactivity of the primer and probe sequences with the genomes of other respiratory flora and viral pathogens was assessed by aligning oligonucleotide sequences against 28 microorganisms and determining if significant primer homology existed (defined as greater than 80% homology to published sequence). 12 Delaware Journal of Public Health – July 2020
The developed assay is a real-time RT-PCR test that uses a single primer and probe set to detect the structural envelope (E) gene of the SARS-CoV-2 virus in a clinical sample. The assay was developed and performed on the Roche cobas 6800 instrument platform with the omni Utility Channel that allows one to create and run custom laboratory-developed tests. After sample and control preparation, the instrument performs fully automated nucleic acid extraction and purification, PCR amplification, and detection, in approximately 3.5 hours. Up to 92 samples can be run on a single plate.
In silico Inclusivity and Cross-Reactivity Inclusivity analysis was performed by aligning the forward primer, reverse primer, and probe to the 401 published SARSCoV-2 sequences deposited in the NCBI database as of March 31, 2020. For all oligonucleotides, 100% homology to the available SARS-CoV-2 sequences was observed (Table 1). In silico crossreactivity analysis only showed significant primer homology (homology exceeding 80%) to SARS-coronavirus (Urbani strain), SARS-CoV-2, and Influenza A. Significant homology (100%) to the SARS-CoV genome was observed for the forward primer, reverse primer, and probe. Based on sequence analysis alone, cross-reactivity of this assay for SARS-CoV-2 with SARScoronavirus (Urbani) cannot be ruled out. However, SARScoronavirus (Urbani) has not circulated broadly in the human population since 20049 sand therefore cross-reactivity during the COVID-19 outbreak is statistically unlikely and not clinicallyrelevant at this time (the early phases of the SARS-CoV-2 outbreak). An alignment with 82% homology was found between the E-gene reverse primer and Influenza A, with one mismatch (18 of 19 base pairs). No significant alignment was found between Influenza A and the forward primer or probe. Despite the in silico prediction of potential cross-reactivity, experimental observations with seven Influenza A-positive patient samples and six Influenza A (H1N1)-positive patient samples revealed no cross-reactivity.14 In addition, the lack of homology between the forward primer and probe suggests that no amplification will occur even if the reverse primer were to bind to a portion of the Influenza A genome. Therefore, the risk that this assay detects Influenza A was deemed to be low. Experimental observations with other respiratory pathogens from clinical samples were consistent with these in silico observations.14
Limit of Detection (LOD) Study The intent of this clinical LOD study was to establish the LOD as quickly as possible as part of clinical assay validation (as would be required to use this test as part of a clinical diagnosis) and not to perform a detailed series of studies to quantitatively establish the
true analytical limit. We selected a target of 250 cp/mL to test and designed the LOD study to document that the assay could detect this level. The experiments were performed to simultaneously determine the feasibility of the proposed assay and determine this LOD by spiking positive control material into three different sample matrices at levels spanning two orders of magnitude (5,000 cp/mL – 250 cp/mL). FDA guidance specifies that the LOD of the assay is the lowest detectable concentration of SARS-CoV-2 (cp/mL) at which greater than or equal to 95% of all replicates test positive, and this limit must be verified with at least 20 replicates at the claimed concentration.6 To fulfill this requirement, three concentrations of SARS-CoV-2 standard were evaluated across three sample matrices, including 20 replicates in VTM. All samples in the LOD experiment tested positive (Ct < 40 cycles) regardless of concentration or clinical matrix (Table 2). Based on this data, the assay’s LOD of 250 cp/mL was established. Organism SwARS-CoV-2 Human coronavirus 229E
Clinical Evaluation Clinical evaluation of the assay was performed with 30 patientderived, positive samples and 30 non-reactive samples, as required by the FDA.6 Twenty-four confirmed-positive patient swabs were used to generate the 30 positive samples. Thirteen of these 24 samples were previously confirmed positive using the CDC’s assay and 11 of the 24 samples were confirmed positive using an alternate technology approved under an FDA EUA (Cepheid Xpert Xpress SARS-CoV-2 test, EUA on March 20, 202017). The remaining six samples required for clinical evaluation were created by diluting samples as show in Table 3. We also tested 29 previously confirmed non-reactive patient samples (18 samples tested by CDC assay and 11 by Cepheid assay) as well as one blank media sample. All confirmed-positive samples tested positive (Ct < 40) using the proposed assay, and all non-reactive samples were confirmed negative (Ct > 40) (Table 3).
Taxonomy ID 2697049 11137
Homology E-gene Forward Primer – 100% E-gene Reverse Primer – 100% E-gene Detection Probe – 100% No significant alignment was found
Human coronavirus OC43
No significant alignment was found
Human coronavirus HKU1
No significant alignment was found
Human coronavirus NL63
SARS-coronavirus (Urbani strain)
No significant alignment was found E-gene Forward Primer – 100% E-gene Reverse Primer – 100% E-gene Detection Probe – 100% No significant alignment was found
MERS-coronavirus Adenovirus (C1 Ad. 71) Human Metapneumovirus (hMPV) Parainfluenza virus 1-4 Influenza A
1335626 129875 108098 129951 130310 130308 162145 12730 1979160 11216 1979161 11320
No significant alignment was found No significant alignment was found No significant alignment was found E-gene Reverse Primer – 82%
No significant alignment was found
No significant alignment was found
Respiratory syncytial virus Rhinovirus Chlamydia pneumoniae
No significant alignment was found
No significant alignment was found
No significant alignment was found
No significant alignment was found
No significant alignment was found
No significant alignment was found
No significant alignment was found
No significant alignment was found
Bordetella pertussis Mycoplasma pneumoniae Pneumocystis jirovecii (PJP) Candida albicans Pseudomonas aeruginosa
No significant alignment was found
No significant alignment was found
No significant alignment was found
No significant alignment was found
No significant alignment was found
No significant alignment was found
No significant alignment was found
Table 1: Results of in silico inclusivity and cross-reactivity analysis. Assay oligonucleotides were aligned to the listed microorganisms and any significant alignment (greater than 80% homology) was noted.
Bench: Virology, Detection and Diagnosis
RNA Concentration (cp/mL)
VTM + Control E-Swab + Control
Saline + Control
Number of Samples
% Positive Samples
Table 2: Results of LOD testing. All samples containing positive control material (SeraCare) tested positive for SARS-CoV-2 (Ct < 40 cycles). Four blank saline samples were run in parallel as non-reactive controls and 100% of those samples tested negative.
13/13 Positive (100%)
11/11 Positive (100%)
5/5 Positive (100%)
1/1 Positive (100%)
TOTAL POSITIVE SAMPLES Negative
Number of Samples Results
30/30 Positive (100%)
18/18 Negative (100%)
11/11 Negative (100%)
TOTAL NEGATIVE SAMPLES
1/1 Negative (100%) 30/30 Negative (100%)
Table 3: Results of the clinical evaluation. All samples previously confirmed to contain SARS-CoV-2 RNA tested positive using the proposed assay, and all negative samples tested negative using the proposed assay. All internal and negative controls were valid.
DISCUSSION The experimental development and clinical validation of a singletarget molecular diagnostic assay to detect the E-gene of SARSCoV-2 was completed in two weeks including the validation with confirmed patient-positive SARS-CoV-2 samples. This two week window included a six calendar day delay waiting for custom primers and probes as well as an additional two day delay to troubleshoot a reagent that was not performing as expected. We believe that if supply chains had not been limiting and if reagents performed as expected, this assay could have been developed and validated in less than one week. During the early phases of an outbreak, there is a significant demand for key reagents and supplies as testing capability expands globally, and these supply chain limitations can impact timelines. To circumvent limited availability of PCR extraction kits, this assay takes advantage of cobas reagents that are not specific to SARS-CoV-2 testing and which are not in limiting supply. Our experience was that to rapidly advance assay development, it was helpful to find multiple vendors and product listings to source critical reagents. While manufacturers of custom oligonucleotides, for example, can quickly ship primers and probes used by existing PCR tests established by the CDC, the production of alternate custom reagents was subject to some manufacturing delays. Our assay development effort benefited from sourcing primers, probes, controls, and other reagents from multiple vendors, as well as acquisition of different types of reagents from a given vendor (for example, lyophilized primers 14 Delaware Journal of Public Health – July 2020
as well as ready to use primers). This approach saved time during method troubleshooting; however, it did increase the financial investment needed to launch the effort. However, during the early phases of this outbreak when healthcare systems are unable to keep up with demands, each day matters. The usefulness of alternative sourcing strategies was observed when early test runs, using certain reagent lots from a vendor, were invalidated by low level amplification signals observed in negative control materials (39<Ct<40). After an initial experiment to verify that the finding was reproducible, a different lot of the same reagent from the same vendor which was already in our possession was used and did not result in the same behavior. Experiments performed separately on different instrumentation in a different laboratory also were consistent with the possibility of a concern with that specific lot of reagent from that vendor. It is important to consider failure modes early and prepare for rapid troubleshooting. While it is admittedly difficult, if not impossible, to foresee all possible issues, having a team consider failure modes early in the process helped prepare and develop mitigations. Even the smallest issues can impact the ability to validate an assay. For example, the reagent cassette used in this study must be vented with a pipette tip during loading of the prepared MMx-R2; however, the only tips available in the laboratory during early experiments were barrier tips which prevented air flow. The barrier tips made it difficult to pipette precise volumes into the reagent cassette during practice runs.
This unforeseen issue was initially overcome by using a needle to break the barrier seal on the tip for practice runs by allowing venting of the cartridge and precise pipetting. Ultimately, the issue was addressed by acquiring non-barriered tips for this purpose. Here, we presented the rapid development and clinical validation of a PCR-based assay for the detection of SARS-CoV-2 during the COVID-19 outbreak. We developed a laboratory-developed test using a widely available commercial instrument platform on an accelerated timeline. The assay was validated within two weeks of the launch of this study, with at least one week of that time dedicated to waiting for custom reagents and troubleshooting. This work suggests the possibility of rapidly validating a laboratory-developed test to support clinical diagnosis when used under appropriate authorization from a relevant health authority.
PUBLIC HEALTH IMPLICATIONS The outbreak of a novel coronavirus strain (SARS-CoV-2) first reported in December 2019 has escalated to a worldwide pandemic and rapidly evolving public health emergency. The ability to quickly develop testing capability is critical to establishing an understanding and response to such a threat. Public health laboratories have moved to rapidly develop polymerase chain reaction (PCR)-based tests and commercial diagnostics companies in the in vitro diagnostics business also develop proprietary kits. However, the demand for testing has far exceeded the supply of such tests (reagents and kits). Here we share an approach to rapidly validating a laboratory-developed test for SARS-CoV-2 on a widely available commercial instrument to increase local testing capability.
ACKNOWLEDGEMENTS The authors would like to acknowledge Steven Cages (Roche Diagnostics) for critical discussions and support on the cobas 6800 omni Utility Channel platform. The authors also thank the Delaware Department of Health for sharing samples used in the clinical evaluation of the assay. JS, JM, and KHL are supported in part by award 70NANB17H002 from U.S. Department of Commerce, National Institute of Standards and Technology.
REFERENCES 1. Lu, R., Zhao, X., Li, J., Niu, P., Yang, B., Wu, H., . . . Tan, W. (2020, February 22). Genomic characterisation and epidemiology of 2019 novel coronavirus: Implications for virus origins and receptor binding. Lancet, 395(10224), 565–574. https://doi.org/10.1016/S0140-6736(20)30251-8 2. Corman, V. M., Landt, O., Kaiser, M., Molenkamp, R., Meijer, A., Chu, D. K. W., . . . Drosten, C. (2020, January). Detection of 2019 novel coronavirus (2019-nCoV) by real-time RT-PCR. Euro Surveil, 25(3), 2000045. https://doi.org/10.2807/1560-7917.ES.2020.25.3.2000045 3. Chu, D. K. W., Pan, Y., Cheng, S. M. S., Hui, K. P. Y., Krishnan, P., Liu, Y., . . . Poon, L. L. M. (2020, April 1). Molecular diagnosis of a novel coronavirus (2019-ncov) causing an outbreak of pneumonia. Clinical Chemistry, 66(4), 549–555. https://doi.org/10.1093/clinchem/hvaa029 4. Food and Drug Administration. (n.d.). CDC 2019-Novel Coronavirus (2019-nCoV) Real-Time RT-PCR Diagnostic Panel Instructions for Use. (2020). Atlanta, GA. Retrieved from: www.fda.gov/media/134922/download
5. Hinton, D. M. (2020). Molecular LDT COVID-19 authorized tests. Retrieved from: www.fda.gov/media/136598/download 6. Food and Drug Administration. (n.d.). Policy for diagnostic tests for coronavirus disease-2019 during the public health emergency immediately in effect guidance for clinical laboratories, commercial manufacturers, and Food and Drug Administration staff. (2020). Retrieved from: www.fda.gov/regulatory-information/search-fda-guidancedocuments/policy-coronavirus-disease-2019-tests-duringpublic-health-emergency-revised 7. Kaul, K. L., Sabatini, L. M., Tsongalis, G. J., Caliendo, A. M., Olsen, R. J., Ashwood, E. R., . . . Thomson, R. B. (2017, July 16). The case for laboratory developed procedures: Quality and positive impact on patient care. Academic Pathology., 4, 2374289517708309. https://doi.org/10.1177/2374289517708309 8. Drosten, C., Günther, S., Preiser, W., van der Werf, S., Brodt, H. R., Becker, S., . . . Doerr, H. W. (2003, May 15). Identification of a novel coronavirus in patients with severe acute respiratory syndrome. The New England Journal of Medicine, 348(20), 1967–1976. https://doi.org/10.1056/NEJMoa030747 9. World Health Organization. (2003). Severe Acute Respiratory Syndrome (SARS) - multi-country outbreak - Update 27. Retrieved from: www.who.int/csr/don/2003_04_11/en/ 10. Sheridan, C. (2020, April). Coronavirus and the race to distribute reliable diagnostics. Nature Biotechnology, 38(4), 382–384. https://doi.org/10.1038/d41587-020-00002-2 11. Food and Drug Administration. (n.d.). 2014 Ebola Virus Emergency Use Authorizations. Retrieved from: www.fda. gov/medical-devices/emergency-situations-medical-devices/ emergency-use-authorizations#ebola 12. Theel, E. S., & Hata, D. J. (2018, March 26). Diagnostic testing for Zika virus: A postoutbreak update. Journal of Clinical Microbiology, 56(4), e01972-17. https://doi.org/10.1128/JCM.01972-17 13. Food and Drug Administration. (n.d.). Zika virus emergency use authorization. Retrieved from: www.fda.gov/medicaldevices/emergency-situations-medical-devices/emergencyuse-authorizations#zika 14. Pfefferle, S., Reucher, S., Nörz, D., & Lütgehetmann, M. (2020, March). Evaluation of a quantitative RT-PCR assay for the detection of the emerging coronavirus SARS-CoV-2 using a high throughput system. Euro Surveil, 25(9), 1–5. https://doi.org/10.2807/1560-7917.ES.2020.25.9.2000152 15. Food and Drug Administration. (2006). Guidance on informed consent for in vitro diagnostic device studies using leftover human specimens that are not individually identifiable. Retrieved from: www.fda.gov/media/122648/download 16. Wu, F., Zhao, S., Yu, B., Chen, Y. M., Wang, W., Song, Z. G., . . . Zhang, Y. Z. (2020, March). A new coronavirus associated with human respiratory disease in China. Nature, 579(7798), 265–269. https://doi.org/10.1038/s41586-020-2008-3 17. Food and Drug Administration. (n.d.). Xpert Xpress SARSCoV-2 test. Retrieved from: www.fda.gov/media/136316/download 15
Bench: Virology, Detection and Diagnosis
Validation and Use of Point-of-Care Lateral Flow Chromatographic Immunoassays for Early Diagnostic Support During the COVID-19 Pandemic Richard M. Pescatore, D.O. Lisa M.G. Henry, M.H.S.A. Rebecca D. Walker, Ph.D., J.D., M.S.N. William Chasanov, D.O., M.B.A. Christopher M. Gaeta Delaware Department of Health and Social Services
Crystal Mintzer Webb, M.P.A. Camille Moreno-Gorrin, M.S. Paula Eggers Frederick P. Franze, M.T. (A.S.C.P.) Sergio Huerta, M.D.
In Delaware, the first case of coronavirus disease 2019 (COVID-19) was identified on March 11, 2020 and the first death attributed to COVID-19 occurred on March 26, 2020. The Delaware Public Health Laboratory (DPHL) was the only laboratory in the state that had testing capability for COVID-19. As of May 28, 2020, 9,171 cases were diagnosed and 345 Delawareans died due to complications associated with COVID-19. Since the first case was announced, Delaware moved rapidly to institute statewide mitigation and suppression strategies to limit effects on the populace and health infrastructure. However, the need for testing quickly overwhelmed supply chains and laboratory capacity for molecular testing with reverse transcriptase polymerase chain reaction (rt-PCR).1 Consistent with FDA guidance, docket FDA-2020-D-0987, the Delaware Department of Health and Social Services, Division of Public Health (DPH) identified point-of-care lateral flow chromatographic immunoassays (“rapid tests”) as useful diagnostic adjuncts in a “PCR-sparing” testing strategy, given initial limitations in molecular testing capacity.2 In an effort to identify reliable rapid tests for implementation, DPH performed verification studies of point-of-care devices by various manufacturers. Extensive validation of the Pinnacle Biolabs COVID-19 Novel Coronavirus IgM/IgG Rapid Test was subsequently performed by the Delaware Public Health Laboratory. The Pinnacle Biolabs COVID-19 Novel Coronavirus IgM/IgG Rapid Test is a lateral flow chromatographic immunoassay. The test cassette consists of: 1) a burgundy-colored conjugate pad containing recombinant COVID-19 antigen conjugated with colloid gold (COVID-19 conjugates) and quality control antibody gold conjugates; 2) a nitrocellulose membrane strip containing two test bands (T1 and T2 bands); and 3) a control band (C band). The T1 band is pre-coated with monoclonal anti-human IgG for the detection of anti-COVID-19 IgG, the T2 band is pre-coated with reagents for the detection of anti-COVID-19 IgM, and the C band is pre-coated with quality control antibody. When an adequate volume of specimen (blood) is dispensed into the sample well of the cassette, the specimen migrates by capillary action across the cassette. Anti-COVID-19 Ig antibodies—if present in the specimen—will bind to the COVID-19 conjugates. The immunocomplex is then captured on the membrane that is pre-coated with anti-human Ig antibodies. When a burgundy T1 or T2 band appears, it indicates an anti-COVID-19 IgG or IgM 16 Delaware Journal of Public Health – July 2020
Christina Pleasanton, M.S. Molly Magarik Kara Odom Walker, M.D., M.P.H., M.S.H.S. Karyl T. Rattay, M.D., M.S. Rick Hong, M.D.
positive test result. Absence of both test bands suggests a negative result. Regardless of the presence of or absence of a detection band, the red quality control band C should appear; if it does not appear, the test result is invalid.
RESULTS CROSS REACTIVITY/ANALYTICAL SPECIFICITY A panel of 101 negative specimens was obtained, including 80 serum samples (frozen serum samples stored pre-pandemic), one sample (EDTA whole blood) from an individual confirmed to be negative for SARS-CoV-2 via rt-PCR, and 10 fresh fingerstick samples (capillary blood) from individuals confirmed to be negative for SARS-CoV-2 via rt-PCR. All samples were drawn from a population with a high prevalence of vaccination against influenza, hepatitis B virus, Haemophilus influenzae, and paramyxoviridae. In addition, five stored serum samples known to contain anti-RSV IgM and IgG as well as five stored serum samples known to contain anti-nuclear antibody (ANA) from individuals were tested.3 Testing of the samples was performed in accordance with the manufacturer-supplied package insert. Of these samples, 100/101 showed no T1 or T2 bands, indicating a negative result (99% overall specificity), and 1/101 showed a T1 band only, indicating a negative result for IgM and positive result for IgG. Sample 1/101 was compared against chemiluminescent microparticle immunoassay, verifying a false positive for SARS-CoV-2 IgG.4
ANALYTICAL SENSITIVITY A total of 46 known-positive specimens (whole blood, EDTA) were obtained from consenting hospitalized patients confirmed to be infected with SARS-CoV-2 via rt-PCR. Immune status of the individuals or length of active infection was not known or collected. Testing of the samples was performed in accordance with the manufacturer-supplied package insert. Of the 45 specimens, 35 demonstrated a positive IgM and IgG band on rapid test, with one additional specimen demonstrating a positive IgM without IgG (80% sensitivity).
SMALL-SCALE IMPLEMENTATION AND PROSPECTIVE VERIFICATION Following validation, DPH deployed rapid tests as part of outbreak investigations in areas with suspected or documented high prevalence of COVID-19 disease, principally within
post-acute care facilities. Serological surveys can aid investigation of an ongoing outbreak and extent of an outbreak.5 Tests were administered by licensed registered nurses or physicians, following training performed in-person or via instructional video. Specimens were collected in accordance with the manufacturer-supplied package insert. Specimens were collected simultaneously with nasopharyngeal swabs and compared to rt-PCR results. DPH monitored samples as part of a prospective observational effort to ensure satisfactory performance of rapid tests in a real-world setting. Institutional Review Board approval was not required, as testing was performed under executive authority consistent with the Eleventh Modification of the Declaration of a State of Emergency for the State of Delaware due to a Public Health Threat. Of these specimens, high specificity was maintained with no false positives identified by rt-PCR. Most specimens were identified to manifest both IgM and IgG, with some specimens showing IgM only and few showing IgG only. Multiple patients known to have remote infection with SARS-CoV-2 via positive rt-PCR testing manifested both IgM and IgG and were found to have repeat rtPCR threshold cycle values ranging from low (17) to high (34).
LARGE-SCALE IMPLEMENTATION Having gained confidence in the high specificity and strong negative predictive value of rapid tests, DPH opted to utilize these assays as part of a PCR-sparing strategy in a universal, community-wide outbreak investigation.6 In late April of 2020, epidemiologic surveillance data and hospital indicators sparked concern for a high level of community prevalence of COVID-19 within sub-populations in Sussex County, Delaware. Focused molecular testing efforts consistently returned high rates of positive rt-PCR tests, with 40-50% of tests positive even among asymptomatic individuals. Subsequently, DPH partnered with hospital systems and community organizations in a directed effort to expand testing and provide education, social services, and wrap-around health services within affected communities. Partners implemented a multi-modal testing strategy harnessing the high specificity of rapid tests. In late April and throughout May 2020, approximately 10,000 total tests (using both rapid and PCR tests) for COVID-19 were performed through community-based testing sites in Sussex County, including walk-up, drive-through, and test-in-place evolutions throughout Milford, Georgetown, Seaford, and the surrounding areas. Testing schema included progression to empiric isolation for those identified to have a positive IgM with rapid tests, out of concerns for a high-risk of SARS-CoV-2 infection, as well as secondary rt-PCR screening for those with negative antibody testing, effectively exploiting the high specificity of rapid tests while buttressing sensitivity via rt-PCR. Recognizing the inherent lag time of antibody response in the setting of acute infection, symptomatic individuals were referred directly to rt-PCR. rt-PCR and serology results were concordant across all testing evolutions. Side-by-side ongoing validation and random quality assurance comparing serology and PCR results on individuals
indicated continued high specificity of serology. DPH monitored disease incidence within communities and witnessed steady decline associated with intensity of testing and increase in social services. As COVID-19 incidence fell and molecular testing availability increased, serology was discontinued. By the conclusion of May 2020, COVID-19 incidence fell from a high of 60% to less than 5% at community testing sites.
CONCLUSION Following extensive validation and ongoing verification, DPH successfully deployed rapid antibody testing in a PCR-sparing strategy to greatly increase access to testing within highprevalence communities. During early phases of the COVID-19 pandemic, identification of IgM served as a reasonable surrogate to identify high probability of infection with COVID-19, sparing the need for follow-up rt-PCR and permitting recommendations for empiric isolation. Falling COVID-19 incidence (and thus lower pre-test probability) coincided with significant improvements in molecular testing availability, allowing the discontinuation of rapid testing. Concentrated testing within Sussex County – facilitated by a PCR-sparing strategy utilizing rapid antibody testing and partnered with social services, community education, and wrap-around health services – was associated with a significant decrease in COVID-19 incidence.
REFERENCES 1. Vogels, C. B. F., Anderson, F. B., Wyllie, A. L., Fauver, J. R., Ott, I. M., & Kalinich, C. C. … Grubaugh, N.D (2020). Analytical sensitivity and efficiency comparisons of SARS-COV-2 qRTPCR assays. medRxiv Retrieved from: https://www.medrxiv.org/content/10.1101/2020.03.30.20048108v3 2. Kontou, P. I., Braliou, G. G., Dimou, N. L., Nikolopoulos, G., & Bagos, P. G. (2020). Antibody tests in detecting SARS-CoV-2 infection: a meta-analysis. medRxiv. Retrieved from: https://www.medrxiv.org/content/10.1101/2020.04.22.20074914v1 3. Wan, W. Y., Lim, S. H., & Seng, E. H. (2020). Cross-reaction of sera from COVID-19 patients with SARS-CoV assays. medRxiv. Retrieved from: https://www.medrxiv.org/content/10.1101/2020.03.17.20034454v1 4. Bryan, A., Pepper, G., Wener, M. H., Fink, S. L., Morishima, C., Chaudhary, A., . . . Greninger, A. L. (2020, May 7). Performance characteristics of the Abbott Architect SARSCoV-2 IgG assay and seroprevalence in Boise, Idaho. Journal of Clinical Microbiology, JCM.00941-20. https://doi.org/10.1128/JCM.00941-20 5. World Health Organization. (2020). Laboratory testing for coronavirus disease 2019 (COVID-19) in suspected human cases: interim guidance, 2 March. World Health Organization. Retrieved from https://apps.who.int/iris/handle/10665/331329 6. Lee, C. Y. P., Lin, R. T. P., Renia, L., & Ng, L. F. P. (2020, April 24). Serological approaches for COVID-19: Epidemiologic perspective on surveillance and control. Frontiers in Immunology, 11, 879. https://doi.org/10.3389/fimmu.2020.00879 17
Bench: Virology, Detection and Diagnosis
The Importance of Research in Addressing the COVID-19 Pandemic: Focus on the Use of Serology Testing Vicky L. Funanage, Ph.D. Operational VP, Research, Nemours Children’s Health
ABSTRACT The Coronavirus disease 2019 (COVID-19) pandemic caused by SARS-CoV-2 has resulted in a global health emergency with major social and economic disruption. With no effective treatment or vaccine available, and given the ease of transmission, it becomes critical to develop rapid diagnostic and tracer methodologies, while working to understand how the virus causes critically severe disease in about 5% of those affected. Clinical and translational research of patients impacted by COVID-19 is essential, and in this commentary, the focus is on the use of serology testing as a proxy for infection to better understand risk for health complications, and tailor treatment and vaccine immunization to high-risk groups. The rationale for studying pediatric patients is that there is a paucity of research in this vulnerable population and children have fewer co-morbidities, but similar health disparities and disease complications as compared to adults. Asymptomatic children could also transmit the virus to others within their households and communities; thus, knowledge of their rate of infection is important to help mitigate spread and a possible second wave of infection.
INTRODUCTION Coronavirus disease 2019 (COVID-19), caused by the novel SARS-CoV-2, was declared a pandemic on March, 12, 2020, and to date has infected over eight million people worldwide with over two million confirmed cases in the United States. Compared to adults, the percentage of children with COVID-19 is lower,1 as are the level of severity and mortality rate.2–4 However, in both children and adults, COVID-19 disproportionally affects minority communities of low socioeconomic status, and certain co-morbidities increase the severity of disease in the elderly.
BACKGROUND Various studies in children have shown viral infection rates of 1-5%, with fever being the most commonly presenting symptom.3 It is not known if children are more resistant to infection or mount a more rapid or different immune response. In addition, are pediatric patients with chronic disease more susceptible to infection and increased severity of disease? Finally, do both asymptomatic and symptomatic children transmit the disease to others? The answers to these questions and others are emerging through numerous clinical and translational research studies conducted across the globe, and which depend on both viral and serology testing for accurate diagnosis to better understand the complexity of COVID-19. Antibody response (IgG and IgM levels) against SARS-CoV-2 usually appears for most adult and pediatric patients at ten days or later after symptom onset, and Long et al.5 have shown 100% seroconversion 19 days after symptom onset. Serology testing is especially important in the design of vaccine studies and use of convalescent plasma or therapeutic monoclonal antibodies, and antibody status will be pivotal in guiding epidemiological 18 Delaware Journal of Public Health – July 2020
measures to determine at risk populations. Serology testing is also key to answering many questions regarding how infected individuals and populations respond to the virus, as well as serving as a proxy for viral infection. Several examples of the role serology testing has played in identifying and understanding the spectrum of new clinical morbidities associated with COVID-19 in pediatric patients are described below.
SEROLOGY TESTING DeBiasi et al.6 have shown that the youngest (<1 year) and oldest (adolescents/young adults) infected with SARS-CoV-2 were more likely to be hospitalized, and the oldest required critical intensive care. Their work also suggests that African American and Hispanic populations are more severely affected by COVID-19 and that children have multi-symptom involvement. Henry et al.7 confirmed elevated levels of C-reactive protein, procalcitonin, and lactate dehydrogenase in both mild and severely affected children. Elevation of creatine kinase MB in mild pediatric cases also indicates that there is cardiac involvement in this disease. An unusual presentation of overlapping symptoms of Kawasaki disease and toxic shock syndrome occurred in previously healthy children first in Italy,8 followed by England9 and the U.S.10 in April 2020. Studies of children in France demonstrate that this disease, named multisystem inflammatory syndrome (MIS-C) associated with COVID-19, occurs at higher frequency in children of African descent and that symptoms also include gastrointestinal disorders, hemodynamic instability, myocarditis, and acute heart failure.11–13 This multisystem condition presented itself several weeks after the peak of COVID-19 infection in each country. Interestingly, although many of these children tested negative for the virus, they were seropositive, indicating prior infection by SARS-CoV-2.
Dermatological conditions also seem to be a later stage reaction to SARS-CoV-2 infection. A delayed cutaneous manifestation of COVID-19 was described recently in a 7-year old child.13 These chilblains-like lesions were documented by telehealth visits to a general pediatric outpatient clinic and confirmed by pediatric dermatology. The patient tested negative for the virus, but positive for SARS-CoV-2 IgG antibodies, indicating prior infection. What the above studies in the pediatric population have shown is to expect the unexpected with COVID-19. Without serology testing, the association between COVID-19 and MIS-C, as well as the unusual dermatological manifestations of this disease, may have been missed. Serology testing allows the ascertainment of prior infection and often is a quicker, more reliable proxy of infection than viral testing. As the transmission of the virus decreases and individuals recover, it becomes important to know who has been infected and to know short- and long-term clinical outcomes. Research is critical to prepare for a possible second wave of infection or for a different viral pandemic. One of the unifying themes of these research studies is that a preexisting proinflammatory state seems to contribute to COVID-19 disease severity in both pediatric and adult populations. This raises the interesting question as to whether children, who have not developed many of the co-morbidities of the adult population, can serve as models to understand disease susceptibility and morbidity associated with SARS-CoV-2, paving the way to better understanding of disease etiology and more effective therapies. Clinical and translational research into COVID-19 promises to provide some of these answers in addition to generating other clinical questions to drive further research efforts into understanding this complex disease.
REFERENCES 1. Cai, J., Xu, J., Lin, D., Yang, Z., Xu, L., Qu, Z., . . . Zeng, M. (2020, February 28). A Case Series of children with 2019 novel coronavirus infection: Clinical and epidemiological features. Clin Infect Dis, ciaa198; Advance online publication. https://doi.org/10.1093/cid/ciaa198 2. Tagarro, A., Epalza, C., Santos, M., Sanz-Santaeufemia, F. J., Otheo, E., Moraleda, C., & Calvo, C. (2020, April 8). Screening and severity of coronavirus disease 2019 (COVID-19) in children in Madrid, Spain. JAMA Pediatrics, 201346; Advance online publication. https://doi.org/10.1001/jamapediatrics.2020.1346 3. Dong, Y., Mo, X., Hu, Y., Qi, X., Jiang, F., Jiang, Z., & Tong, S. (2020, June). Epidemiology of COVID-19 among children in China. Pediatrics, 145(6), e20200702. https://doi.org/10.1542/peds.2020-0702 4. Lu, X., Zhang, L., Du, H., Zhang, J., Li, Y. Y., Qu, J., . . . Wong, G. W. K., & the Chinese Pediatric Novel Coronavirus Study Team. (2020, April 23). SARS-CoV-2 infection in children. The New England Journal of Medicine, 382(17), 1663–1665. https://doi.org/10.1056/NEJMc2005073
5. Long, Q. X., Liu, B. Z., Deng, H. J., Wu, G. C., Deng, K., Chen, Y. K., . . . Huang, A. L. (2020, June). Antibody responses to SARS-CoV-2 in patients with COVID-19. Nature Medicine, 26(6), 845–848; Advance online publication. https://doi.org/10.1038/s41591-020-0897-1 6. DeBiasi, R. L., Song, X., Delaney, M., Bell, M., Smith, K., Pershad, J., . . . Wessel, D. (2020, May 13). Severe COVID-19 in children and young adults in the Washington, DC metropolitan region. The Journal of Pediatrics; Advance online publication. https://doi.org/10.1016/j.jpeds.2020.05.007 7. Henry, B. M., Benoit, S. W., de Oliveira, M. H. S., Hsieh, W. C., Benoit, J., Ballout, R. A., . . . Lippi, G. (2020, July). Laboratory abnormalities in children with mild and severe coronavirus disease 2019 (COVID-19): A pooled analysis and review. Clinical Biochemistry, 81, 1–8; Advance online publication. https://doi.org/10.1016/j.clinbiochem.2020.05.012 8. Verdoni, L., Mazza, A., Gervasoni, A., Martelli, L., Ruggeri, M., Ciuffreda, M., . . . D’Antiga, L. (2020, June 6). An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: An observational cohort study. Lancet, 395(10239), 1771–1778. https://doi.org/10.1016/S0140-6736(20)31103-X 9. Alert, U. K. (2020, Apr 27). Retrieved from: www.hsj.co.uk/ acute-care/exclusive-national-alertas-coronavirus-relatedcondition-may-be-emerging-in-children/7027496.article 10. Riphagen, S., Gomez, X., Gonzalez-Martinez, C., Wilkinson, N., & Theocharis, P. (2020, May 23). Hyperinflammatory shock in children during COVID-19 pandemic. Lancet, 395(10237), 1607–1608. https://doi.org/10.1016/S0140-6736(20)31094-1 11. Toubiana, J., Poirault, C., Corsia, A., Bajolle, F., Fourgeaud, J., Angoulvant, F., . . . Allali, S. (2020, June 3). Kawasakilike multisystem inflammatory syndrome in children during the covid-19 pandemic in Paris, France: Prospective observational study. BMJ (Clinical Research Ed.), 369, m2094. https://doi.org/10.1136/bmj.m2094 12. Belhadjer, Z., Méot, M., Bajolle, F., Khraiche, D., Legendre, A., Abakka, S., . . . Bonnet, D. (2020, May 17). Acute heart failure in multisystem inflammatory syndrome in children (MIS-C) in the context of global SARS-CoV-2 pandemic. Circulation; Advance online publication. https://doi.org/10.1161/CIRCULATIONAHA.120.048360 13. Grimaud, M., Starck, J., Levy, M., Marais, C., Chareyre, J., Khraiche, D., . . . Oualha, M. (2020, June 1). Acute myocarditis and multisystem inflammatory emerging disease following SARS-CoV-2 infection in critically ill children. Annals of Intensive Care, 10(1), 69. https://doi.org/10.1186/s13613-020-00690-8 19
Bench: Virology, Detection and Diagnosis
Perspectives on molecular diagnostic testing for the COVID-19 pandemic in Delaware Erin L. Crowgey, Nemours/Alfred I. duPont Hospital for Children Mary M. Lee, Nemours/Alfred I. duPont Hospital for Children
Brett Sansbury, ChristianaCare Christiana Hospital Eric B. Kmiec, ChristianaCare Christiana Hospital
ABSTRACT The United States has quickly transitioned into one of the epicenters for the coronavirus pandemic. Limitations for rapid testing for the virus responsible for the pandemic, severe acute respiratory syndrome coronavirus 2 (SARSCoV-2), is the single most important barrier for early detection and prevention of future outbreaks. Combining innovative molecular biology techniques, such as clustered regularly interspaced short palindromic repeats (CRISPR)/Cas nuclease systems and next generation sequencing (NGS) may prove to be an effective solution to establish a high-throughput diagnostic and genomic surveillance workflow for COVID-19 in the State of Delaware. Integrating key expertise across the medical institutions in Delaware, including ChristianaCare and Nemours/ Alfred I. duPont Hospital for Children, is one potential solution for overcoming current barriers and driving a successful implementation of these techniques.
A PUBLIC HEALTH CRISIS As of June 15, 2020, there were over 7.8 million confirmed cases of COVID-19, across 213 countries with over 430,000 confirmed deaths. The virus responsible for causing COVID-19 is severe acute respiratory syndrome coronavirus 2, referred to as SARSCoV-2. In February of 2020, the United States Secretary of Health and Human Services (HHS) determined that there was a public health emergency related to COVID-19 and authorized the Emergency Use Authorization (EUA) for diagnostic tests for COVID-19. Unfortunately, several of the approved tests have had poor specificity or sensitivity,1 availability of supplies/reagents is limited,2 and pipelines for implementing high-throughput workflows for these assays has been challenging. The impact of insufficient diagnostic capacity has been devastating for the healthcare industry and economic infrastructure and the United States has unfortunately transitioned into one of the epicenters for COVID-19. Over 2 million cases and approximately 115,000 deaths have been reported in the United States, with a case mortality rate of 6%.3 Of concern, over 40 million Americans have filed for unemployment during this pandemic, highlighting the significant financial crisis unfolding. Currently, individual states are trying to grapple with measures needed to permit safe reopening and to lessen the stay at home orders to help prevent further economic hardship and the growing unease of the general population. It remains to be seen how effective these public health safety measures will be to avoid a second wave of viral infections, as predicted following the relaxation of social distancing guidance. In the State of Delaware – which has a population of over 900,000 – there have been over 10,000 cases with more than 500 deaths as of June 22, 2020. The majority of cases have been reported in Sussex and New Castle County, followed by Kent County. 20 Delaware Journal of Public Health – July 2020
OVERVIEW OF CURRENT DIAGNOSTIC TECHNIQUES Currently, there are a number of rapid real time quantitative polymerase chain reaction (RT-qPCR) assays available to enable a rapid diagnosis; however, these assays detect the presence of viral particles and are unable to track transmission patterns or virus evolution. Moreover, reagents for the various RT-PCR assays and the assay kits are in high demand, creating a supply chain limitation. The inability to conduct rapid and wide-spread testing for COVID-19 is a critical barrier for early detection in order to appropriately quarantine and implement contact tracing as public health measures to prevent further transmission and future outbreaks. Over the last decade there have been several advancements in molecular biology techniques that facilitate rapid diagnostics and genomic analysis of viruses, including SARS-CoV-2. Next generation sequencing (NGS) is a molecular biology technique that enables scalable, massively parallel DNA/cDNA sequencing. The ability to sequence cDNA molecules and the entire genome of a small virus enables the precise identification and order of nucleotides.4 NGS enables this process using a method that simultaneously sequences millions of fragments of cDNA at once, which is a significant improvement compared to the gold standard of Sanger sequencing.4 Recently, a team of scientists developed an NGS pipeline for studying COVID-19,5 now termed the ARTIC pipeline. This technique coupled with advanced translational bioinformatics enables the precise analysis of genomic differences of COVID-19 strains, which enables scientists to study transmission patterns and viral evolution.6 Furthermore, this technique ensures that the diagnostic test primers are sensitive (region of the genome are not mutating) and can be used to monitor the environmental warning system via metagenomics, which is being shown to be a useful indicator of community transmission.7 In addition to novel sequencing-based testing, breakthroughs in gene editing technology, specifically clustered regularly
interspaced short palindromic repeats (CRISPR)/Cas nuclease systems, have been adapted for numerous assays.8 CRISPR/Cas has been shown to be effective in almost every animal species tested and its molecular activities go far beyond site-specific DNA cleavage in the activation of the DNA damage response pathway in mammalian cells.8–12 CRISPR’s unique ability to target RNA and DNA sequences, in a precise fashion, has given rise to an important and exciting application of the fundamental technology. CRISPR/Cas can now be used to determine if someone is infected with a novel coronavirus13; the basis of this diagnostic application lies in the alignment of the central piece of the CRISPR with the target site on the genome. Interesting applications of CRISPR/Cas for viral detection of SARS-CoV-2 have begun to emerge including the trans reporter (DETECTR) platform.13,14 Currently, research and development studies have begun to determine if CRISPR is a more reliable and sensitive alternative to the traditional RT-qPCR assay for detection of SARS-CoV-2. Antibody screening is useful in limited clinical situations and is being used as a public health screening tool to assess prior COVID-19 infection.15 Antibody tests for SARS-CoV-2 include many that are not yet approved by the Food and Drug Administration (FDA) and have variable sensitivity and specificity.16 Some cross-react with other types of Coronavirus, not just SARS-CoV-2. With COVID-19 infections, the antibody response is delayed and may not be produced until 2-3 weeks after the onset of symptoms, thus an elevated IgM antibody is not a reliable indicator of acute infection and must be confirmed with a RT-PCR test. A detectable IgG antibody is consistent with prior COVID-19 infection,15 although it may detect other coronaviruses and may not be protective against COVID-19. Antibody testing may be useful in cases that may have been potentially missed, for screening of plasma donors, or for diagnosis in patient with multi-system inflammatory syndrome associated with COVID-19 (MIS-C). An effective response to a pandemic such as COVID-19 will need to leverage all of these techniques to have an efficient and robust outcome. The RT-qPCR assay is fast and inexpensive but does not provide enough data for studying transmission patterns or identify viral variants to assess response to targeted treatments or host interactions (see Table 1). The NGS approach enables a robust analysis of the viral genome to enable analysis, such as genomic surveillance and viral variant analysis, but is slower and more costly than RT-qPCR and there are still several hurdles for scaling this assay for high-throughput efforts – although companies like Illumina are actively working on these barriers. The CRISPR technique is also a fast and inexpensive assay but the limit of detection is not well established, and it doesn’t provide the ability to analyze the viral genome. Technique
SCREENING FOR COVID-19 IN THE STATE OF DELAWARE: ACUTE DIAGNOSIS AND LONG TERM SURVEILLANCE An analysis of the current state of molecular testing and diagnostics reveals both good intentions and unwanted consequences. While a rush to produce rapid testing assays is a meritorious response to a pandemic, it is now becoming clear that many of the early screening methodologies have suboptimal test parameters. If we are to respond in a more efficacious fashion to future public health challenges of a viral pandemic, a more comprehensive and systematic approach is needed. Currently the most common forms of sample collection for COVID-19, regardless of the down-stream diagnostic assay, involves a nasopharyngeal or oropharyngeal swab (see Figure 1). These methods have several shortcomings including potential cross-contamination with other viral material, operator dependent variability in quality of the sample, and pediatric subjects may not cooperate well.17 Improving alternative collection methods and nucleic acid extraction techniques will enhance the ability to provide high-throughput rapid diagnostic pipelines for the COVID-19 pandemic. The sample collection method and sample processing should be considered an essential aspect of developing any diagnostic assay, as this is a major bottleneck in the workflow. Regardless of the acute diagnostic test for the antigen, CRISPR or RT-qPCR, a robust workflow for COVID-19 long term should include NGS as a follow up for a positive diagnostic test or a suspected false negative. NGS is proving to be essential for understanding transmission patterns and potential host / viral interactions.6 As mentioned previously, these analyses cannot be conducted using the RT-qPCR or CRISPR technique. It is therefore possible that combining the potential for point-of-care diagnosis using the CRISPR technique outlined above with NGS could lead to a more comprehensive diagnostic and screening system for the current pandemic and could serve as a foundation for subsequent public health challenges. The combined skill sets of the ChristianaCare Gene Editing Institute (Director Dr. Kmiec) and Nemours/Alfred I. duPont Research Laboratories, including the Computational Medicine team (Director Dr. Crowgey) and the Nemours Biobank (Director Dr. Corao), enable an opportunity to carefully and precisely evaluate the capacity of enhancing viral nucleic acid preparation and combinatorial testing in an unbiased and unimpeded fashion. We are doing just that by optimizing novel viral RNA collection and extraction methods that are agnostic to downstream approaches. It is important to note that collection methods for COVID-19 samples involves the collection of a
Diagnosis acute Detect previous exposure/not infection (< 7 days) currently shedding virus
Fast Turnaround (hours)
Genomic Surveillance and Transmission Patterns
Table 1. Characteristics of each of the diagnostic tests currently active in Covid 19 detection. 21
Bench: Virology, Detection and Diagnosis Figure 1. Overview of a comprehensive diagnostic and screening workflow for COVID-19. Workflow and processing activities from collection through detection is presented highlighting the three phases of diagnostic analyses.
diverse metagenome, which is a community of bacteria, phages, viruses, and host cells, regardless if it is a nasopharyngeal or oropharyngeal swab or saliva sample. This is a key consideration when considering limit of detection for downstream assays.
grant U54-GM104941) has efficiently positioned research funding for COVID-19 in Delaware to help the scientists at Nemours and ChristianaCare drive these new types of molecular biology approaches.
Currently, the gold standard for extracting high-quality RNA from a nasopharyngeal swab involves a manual preparation using a vacuum manifold. This process does not scale well as it requires laboratory technicians working multiple shifts to extract large numbers of samples and lacks automation. Additionally, there are limitations for automating high-throughput methods for extracting viral RNA specific for COVID-19 from samples, as these methods do not yield enough viral RNA for appropriate limit of detection for downstream assays, regardless of the method of collection. The teams at ChristianaCare and Nemours/Alfred I. duPont Hospital for Children are teaming up to conquer these issues using advanced robotics, to offer a scalable and robust workflow for implementing a high-throughput workflow for the state of Delaware.
CRISPR-based technologies, classic SHERLOCK, STOP (One-step SHERLOCK), and DETECTR must be validated for sensitivity and lower limits of detection of SARS-CoV-2 (see Figure 2) using synthetic RNA templates, in order to model the reaction safely. Scientists do not fully understand the lower limits of detection in patient derived samples using either SHERLOCK or DETECTR. Thus, it is important to evaluate each of these technologies to determine which provides the most sensitive and accurate outcome, which assay is the easiest to use at point-ofcare, and which can instill the highest degree of confidence in the validity of the test. The key to any point of care acute testing process is to ensure that it is not only reproducible, but robust. Key elements of the CRISPR-based approaches must involve a full assessment of scalability and applications to enable high throughput NGS population surveillance for statewide screening.
The Gene Editing Institute at ChristianaCare is uniquely positioned in the state of Delaware to lead the efforts in adapting and implementing a CRISPR diagnostic test for COVID-19. These applications have begun to emerge across the country, including the specific high-sensitivity enzymatic reporter unlocking (SHERLOCK)18 and trans reporter (DETECTR) platforms. It is important to leverage translational research efforts to determine if CRISPR technology is a more reliable and sensitive alternative to traditional RT-qPCR assay for detection of SARSCov2 virus. The Delaware ACCEL program (PI Binder-Macleod, 22 Delaware Journal of Public Health – July 2020
The rapid diagnostic tests, such as the CRISPR technique described above, are only focused on the detection of the virus and do not yield any information on the actual sequence of the viral genome (see Table 1). As seen with other viruses, slight modifications of a viral genome can make vaccinations more or less effective, can be linked to disease outcome/severity, and can be used to trace transmission patterns. A team of scientists have developed a PCR-based NGS assay that enables the rapid sequencing of the COVID-19 viral genome.5,6 This technique was
Figure 2. Overview of CRISPR-based Technologies for COVID-19 Detection. A comparison is shown of reaction steps, reaction components, end readout, limit of detection and assay duration between three current CRISPR-based COVID-19 detection technologies Classic SHERLOCK, DETECTR, and STOP (One-step SHERLOCK).
originally established for the Illumina MiSeq platform, which is one of the lowest throughput sequencing platforms (in terms of number of reads/samples sequenced) offered by Illumina. A need to scale this platform to larger sequencing instruments, such as the NextSeq or NovaSeq are still needed, and the research teams at Nemours are in a position to help drive these efforts in the state of Delaware. Collectively these efforts will enable Delaware to generate viral genomic data that can and help drive national collaborative research efforts. NGS techniques are essential in a robust response to the COVID-19 pandemic, as acute testing methodologies provide a snapshot of the penetration of any viral or bacterial infection, none are conclusive enough to predict outcomes or establish surveillance. One way to address this issue is to implement NGS protocols to analyze for COVID-19 specific variants through linkage to transmission patterns, outcomes and scalability. Such a procedure is based on the collection of positive test samples – in this case, by the Nemours Immunology diagnostic lab – followed by a PCR NGS library preparation and sequencing using a high-throughput Illumina platform, such as the NextSeq. Of interest, this type of sequencing platform can also be leveraged to sequence the coding regions of the infects host, called whole exome sequencing, which has the potential of providing even more clues regarding pathogen-host interactions. Bioinformatics, a multi-disciplinary field focused on creating and implementing computer algorithms for analyzing complex biological data, is proving to be essential aspect to this workflow. A variety of software programs capable of analyzing COVID-19 genomic data should then be employed; for example, the database https://nextstrain.org, an open-source project that enables the comparisons of COVID-19 for genomic surveillance and outbreak response. But, importantly, it will be crucial to follow the transmission of the viral load through the population by utilizing the Nemours Biobank system to continue to screen healthcare workers and community members. This approach will also allow us to determine the presence of Delaware specific variants within the virus and link variants to transmission patterns that have been previously reported. Taken together, our efforts will contribute to the national efforts to understand how such strain mutations correlate with disease outcome and responsiveness to therapy.
REFERENCES 1. Abbott. (n.d.). Id NowTM Covid-19. Retrieved from: www.alere.com/en/home/product-details/id-now-covid-19.html 2. Soucheray, S. (2020, Apr). Experts question practicality of testing in COVID-19 response. Center for Infectious Disease Research and Policy. Retrieved from: www.cidrap.umn.edu/news-perspective/2020/04/experts-questionpracticality-testing-covid-19-response 3. Centers for Disease Control and Prevention. (n.d.). Coronavirus disease (COVID-19). Cases in the U.S. Retrieved from: www.cdc.gov/coronavirus/2019-ncov/cases-updates/cases-in-us.html 4. Crowgey, E. L., & Mahajan, N. (2019). Advancements in nextgeneration sequencing for detecting minimal residual disease. In: Minimal Residual Disease Testing. Cham, ed. Springer International Publishing, p. 159–92. 5. Quick, J., Grubaugh, N. D., Pullan, S. T., Claro, I. M., Smith, A. D., Gangavarapu, K., . . . Loman, N. J. (2017, June). Multiplex PCR method for MinION and Illumina sequencing of Zika and other virus genomes directly from clinical samples. Nature Protocols, 12(6), 1261–1276. https://https://doi.org/10.1038/nprot.2017.066 6. Grubaugh, N. D., Gangavarapu, K., Quick, J., Matteson, N. L., De Jesus, J. G., Main, B. J., . . . Andersen, K. G. (2019, January 8). An amplicon-based sequencing framework for accurately measuring intrahost virus diversity using PrimalSeq and iVar. Genome Biology, 20(1), 8. https://doi.org/10.1186/s13059-018-1618-7 7. Lodder, W., & de Roda Husman, A. M. (2020, June). SARSCoV-2 in wastewater: Potential health risk, but also data source. The Lancet. Gastroenterology & Hepatology, 5(6), 533–534. https://doi.org/10.1016/S2468-1253(20)30087-X 8. Barrangou, R., & Doudna, J. A. (2016). Applications of CRISPR technologies in research and beyond. Nature Biotechnology, 34(9), 933–941. https://doi.org/10.1038/nbt.3659 23
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9. Prakash, V., Moore, M., & Yáñez-Muñoz, R. J. (2016, March). Current progress in therapeutic gene editing for monogenic diseases. Mol Ther, 24(3), 465–474. https://doi.org/10.1038/mt.2016.5 10. Carroll, D. (2016). Genome editing: Progress and challenges for medical applications. Genome Medicine, 8, •••. Retrieved from: https://genomemedicine.biomedcentral.com/ articles/10.1186/s13073-016-0378-9 11. Doudna, J. A. (2015, February 24). Genomic engineering and the future of medicine. JAMA, 313(8), 791–792. https://doi.org/10.1001/jama.2015.287 12. Sansbury, B. M., Hewes, A. M., & Kmiec, E. B. (2019, December 6). Understanding the diversity of genetic outcomes from CRISPR-Cas generated homology-directed repair. Communications Biology, 2(1), 458. https://doi.org/10.1038/s42003-019-0705-y 13. Xiang, X., Qian, K., Zhang, Z., Lin, F., Xie, Y., Liu, Y., & Yang, Z. (2020, May 26). CRISPR-cas systems based molecular diagnostic tool for infectious diseases and emerging 2019 novel coronavirus (COVID-19) pneumonia. Journal of Drug Targeting, (May): 1–5. https://doi.org/10.1080/1061186X.2020.1769637
14. Zhang, F., Abudayyeh, O. O., Gootenberg, J. S., Sciences, C., & Mathers, L. A protocol for detection of COVID-19 using CRISPR diagnostics. Bioarchive. 2020;1–8. 15. Sethuraman, N., Jeremiah, S. S., & Ryo, A. (2020, May 6). Interpreting diagnostic tests for SARS-CoV-2. JAMA, 323(22), 2249. https://doi.org/10.1001/jama.2020.8259 16. Woloshin, S., Patel, N., & Kesselheim, A. S. (2020, June 5). False negative tests for SARS-CoV-2 infection— Challenges and implications. The New England Journal of Medicine. https://doi.org/10.1056/NEJMp2015897 17. Qian, Y., Zeng, T., Wang, H., Xu, M., Chen, J., Hu, N., . . . Liu, Y. (2020, April 4). Safety management of nasopharyngeal specimen collection from suspected cases of coronavirus disease 2019. International Journal of Nursing Sciences, 7(2), 153–156. https://doi.org/10.1016/j.ijnss.2020.03.012 18. Gootenberg, J. S., Abudayyeh, O. O., Lee, J. W., Essletzbichler, P., Dy, A. J., Joung, J., . . . Zhang, F. (2017, April 28). Nucleic acid detection with CRISPR-Cas13a/C2c2. Science, 356(6336), 438–442. https://doi.org/10.1126/science.aam9321
A Message of Gratitude COVID-19 has, and continues, to challenge us all. The impacts are precedent setting, and we want to thank and stand in solidarity with our colleagues who are first responders, healthcare providers, healthcare institutions, long-term care facilities, and public health professionals. From the highest levels of State leadership, to those providing direct care and service, the Delaware response is evidence-based and evolving based on the experience, expertise and planning of front-line health care institutions and professionals, our state partners, new data, and directives from the CDC and other components of the Federal Government. Please join us in taking a moment to thank those who are working tirelessly on behalf of the well-being of all Delawareans.
#thanksdelawarehealthcare 24 Delaware Journal of Public Health – July 2020
Registration is now open for APHA’s 2020 Virtual Annual Meeting and Expo! We’re entirely virtual this year, so join us online, Oct. 24-28, to network and learn with thousands of your peers. View rates and register now and check out the Online Program for a list of sessions and events.
The Virtual Event is New, Not Less APHA 2020 will be our first-ever Virtual Annual Meeting and Expo, so we’re working hard to make it into an unforgettable experience. The meeting will be equal parts educational, engaging and fun. As always, we’ll give you inspiration, tools and skills to make a difference in your community and advocate for evidence-based programs. Attendees can choose from 700+ live scientific sessions to watch during the meeting and continue to watch recordings on-demand after the meeting. We know networking is a top reason why public health professionals choose our meeting. We’re scheduling unique activities and creating spaces to bring people together, so you can catch up with old friends, make new ones, chat with presenters about their research and build your network with leaders in the field and exhibiting companies. More to look forward to: • Hear from influential leaders from across the country. Speaker announcements coming soon! • Be a part of the conversation about COVID-19 and “Creating the Healthiest Nation: Preventing Violence.” • Earn free CE credits: Choose from hundreds of CE accredited sessions to maintain your licensure! The first CE discipline is on us ($60 value). • Gain a fresh perspective on physical and mental wellness. Participate in fun workouts like yoga and dance, guided meditation sessions and engaging discussions. • Attend social events like the APHA Dance Party, Sunset Tweetup, Awards Ceremony and more. It’s more important now than ever to come together and share stories, challenges and research. By going all-virtual, this year’s Virtual Annual Meeting and Expo [ https://www.apha.org/events-and-meetings/annual ] will prove that public health breaks barriers and continues to find solutions to problems at every level. We hope you will join us and share the news with your colleagues! 25
Bench: Virology, Detection and Diagnosis
Rapid COVID-19 Prognostic Blood Test for Disease Severity Using Epigenetic Immune System Biomarkers Adam G. Marsh, University of Delaware, Center for Bioinformatics and Computational Biology; Genome Profiling, LLC G. Mark Anderson, Genome Profiling, LLC Erich J. Izdepski, BTS Software Solutions
ABSTRACT Objective: To develop a novel whole-blood epigenetic biomarker of immune system status, or EpiMarker, that would indicate whether a person with a recent COVID-19 diagnosis is at risk for severe symptoms including Acute Respiratory Distress Syndrome. Methods: Using a novel methyl-sensitive restriction endonuclease approach to measure site-specific DNA methylation profiles, immune system phentoype EpiMarkers are identified using a machine-learning computational bioinformatics platform. The result is a diagnostic network of 20 to 40 immuno DNA methylation sites having the greatest predictive power for identifying patients whose COVID-19 disease will likely progress to ARDS requiring ICU/intubation care. Results: Immune system status in peripheral whole blood provides a sensitive and responsive sentinel signal reflecting how different functional pathways are currently being regulated in a subject. Deciphering this signal status of how immune cells are set to respond provides deep functional information regarding patient health and potential disease phenotypes resulting from a cytokine storm characteristic of a hyper immune inflammatory response to COVID-19 infection. Conclusions: The ability to identify future potential changes in patient health using this novel EpiMarker technology opens new avenues for defending populations from severe disease risks of Acute Respiratory Distress Syndrome. Policy Implications: A successful EpiMarker Assay for COVID-19 disease severity risk would allow for two important applications: (1) patients could be triaged early in the course of infection to allow for critical decisions for allocating resources, both in terms of hospital infrastructure (ICU beds, ventilators) and therapeutic drug treatments; and (2) pre-infection, individuals could be screened to identify personnel at low-risk for mission critical assignments (first responders, doctors, nurses, military personnel, etc.) during future pandemics and ongoing battles with viral pathogens like influenza.
INTRODUCTION The COVID-19 pandemic is causing enormous patient suffering and death, and unprecedented economic and operational disruptions. A key challenge to managing the pandemic is not knowing which patients will experience severe disease and which will experience no symptoms or only mild disease. Consequently, limited medical resources cannot be focused on the approximately 20% of COVID-19 infected patients whose lives will be most threatened by the infection. This is a critical issue now, and with no anti-viral therapeutic or vaccine availability projected until 2021 or later, it will continue to be a critical issue going forward. Although it is early in the medical field’s understanding of COVID-19 disease etiology, one pattern has emerged: the leading cause of mortality in patients with COVID-19 is hypoxic respiratory failure from acute respiratory distress syndrome (ARDS).1,2 We know that the lung epithelium is a primary site of infection with a complex histopathology. Complications generally present as an immune system overreaction and dysfunction with severe inflammation and leukocyte infiltration.3 In these cases there is likely a malfunction in the patient’s ability to appropriately regulate their immune response to the viral challenge. Severe 26 Delaware Journal of Public Health – July 2020
tissue inflammation arises from a “cytokine storm” of signaling pathways that disintermediate normal controls on immune system function.4 Cytokine signaling pathways are an important molecular regulator of the human adaptive immune system but can produce deleterious side effects when unbalanced (e.g., autoimmune diseases). To fight COVID-19, we need a better understanding of immune system response to this infection. It is likely that an immune system pre-disposition contributes to the ability of some people to easily fight the infection while others experience a dysfunctional viral infection response that leads to ARDS. Recent work has shown the importance of epigenetic control mechanisms in response to viral antigen vaccines.5 The adaptive antigen production response involves many pathways in circulating white blood cells and DNA methylation is an important epigenetic mechanism that is involved in determining vaccine efficacy in subjects. Thus, specific pre-infection pathway structures or regulatory controls (embodied by epigenetic DNA methylation patterns) may exist in patients that ultimately suffer ARDS that can serve as early biomarkers of mortality and morbidity risks in response to COVID-19 infection.
solid tumor cancer patients in clinical trials of IO checkpoint inhibitor therapies. Here, EpiMarker assays for immune system pathway status can identify patients that are more likely to respond to an IO therapy, increasing the response rate in a stratified cohort by 50% to 60% above the unstratified response rate. These results are robust even with patient cohorts in late stage trials with extensive prior treatments and different tumor histology types. The EpiMarker is a collection of CpG sites (dinucleotide sequence of cytosine and guanosine) and the algorithmic models that connect or define their associations and synergistic predictive power (see Figure 1). The representation in Figure 1 shows the EpiMarker as a network with the CpG sites as the nodes and the model equations relating them together as the edges. Conceptually, the collection of both CpG sites and equations can be thought of as a network, yet the physical embodiment of the EpiMarker is more like a high-dimensional database where over 500,000 model equations and results derived from the set of CpG sites is stored for retrieval when classification calls are needed for new, unknown samples. Figure 1. EpiMarker Network-like Topolgy. From a methylome profile of 2 million CpG sites, a predictive set of 20 to 40 CpG sites is identified by the EpiMarker Discovery platform. In this representation, the CpG sites comprise the nodes (circles) and the algorithmic, numerical relationships among CpG node combinations are the red and green edges (lines). The structure is high-dimensional with over 500,000 equations described by the connecting lines.
TECHNOLOGY DNA methylation is an important epigenetic mechanism used by cells to control gene expression. Exogenous stressors, such as disease intrusion or immune system changes, trigger unique and specific DNA methylation responses, or signatures, that are encoded across the 28 million genomic methylation sites in every cell’s DNA. The GenPro EpiMarker Platform measures genome-wide DNA methylation from which it discovers complex patterns of methylation in genomic DNA that can distinguish between two functional phenotypes such as the presence or absence of disease or likelihood of responding to a particular drug. In this proposed use, pattern analyses of CpG methylation would be focused on identifying putative prognostic biomarkers of immune-system status and provide functional information for genes and pathways associated with COVID-19 disease progression in different patients. Genome Profiling’s technology for identifying epigenetic biomarkers (EpiMarkers) in peripheral blood immune cells has been effective in diagnostic applications for cerebral palsy,6 early breast cancer risk assessment, Parkinson’s disease,7 leukemia and immuno-oncology (IO) applications to stratify clinical trial subjects. The nature of IO drugs provides an ideal confirmation of the predictive power of Genome Profiling’s EpiMarker platform. Recently completed retrospective studies with a top ten biopharma immuno-oncology translational research team has resulted in the discovery and blind validation of a novel EpiMarker that successfully stratifies responder vs non-responder
Genome Profiling’s novel application of immuno-methylome profiles holds promise for discovering why some patients are much more susceptible to adverse outcomes arising from COVID-19 infection. The greater accuracy with Genome Profiling’s methyl-sensitive restriction endonuclease metrics provides unparalleled analytical power in discriminating subtle methylome EpiMarker patterns that are diagnostic of disease and health among different patients.6 Further, the machine-learning discovery platform delivers methylome profiles that are incredibly rich in information for assessing the status and activities of a patient’s immune system. Combining this level of immunophenotypic data with the platform’s statistical pattern analysis and machine-learning capabilities to derive novel diagnostic/ prediction models, opens new frontiers for research and discovery in clinical epigenetic applications.
APPROACH For COVID-19 disease progression and the onset of medical complications, it is likely that patients who resist infection and experience only mild symptoms do so because of an immune system reaction that is predisposed or preconditioned to combating coronaviruses. Such pre-disposition could also involve greater regulatory controls over innate and/or adaptive immune responses to prevent tissue inflammation in lung epithelia. By comparing patients with different disease symptoms (mild vs severe), the functional state differences in their pre-symptomatic immune systems will likely identify an EpiMarker signature in peripheral blood. In addition, the EpiMarker discovery process will illuminate biological information (e.g. genes, pathways) that are sensitive to the infection microenvironment and early pathology in the lung, as well as possible markers for the potential for immune cells to drive harmful overproduction of cytokines. The development of a diagnostic assay would be executed in two stages. First, a retrospective clinical trial for Discovery & Blind Validation of the EpiMarker. Here, the EpiMarker Platform will be used to profile the immune system status of subjects who 27
Bench: Virology, Detection and Diagnosis
are known to have experienced either: mild disease symptoms requiring minimal hospital care, or severe disease symptoms requiring advanced, specialized hospital care and ventilator intubation. The initial work is based on whole genome sequencing using Genome Profiling’s novel approach to measure DNA methylation via NGS. Once quantified, a Training Set of 50 vs 50 (mild:severe) patients will be used for the machine learning platform to identify the EpiMarker set of 20 to 40 CpG sites that has the most predictive power to identify the symptom group-type of a blind Validation Set of samples (100 total, 50:50 mild:severe). The first working components of the EpiMarker bioinformatic predictive algorithms are produced at this stage and assembled into a structure for easy retrieval and execution. The second stage would focus on translating the NGS derived EpiMarker into a targeted, high-throughput plate assay that can be executed at a fraction of the cost of whole-genome sequencing per patient. Once the EpiMarker set is identified, then a targeted sequencing panel-capture assay is designed and developed for each of the CpG sites in the EpiMarker. Off-the-shelf technology using Thermo Fisher’s AmpliSeq platform can allow for the rapid development of the specific molecular reagents required to measure CpG methylation at each of the target sites. The AmpliSeq technology allows for the multiplexing of hundreds of target sites if needed and is well suited for a rapid, highthroughput assay format. In addition, this assay platform is well-suited for CLIA approvals and rapid clinical implementation as Laboratory Developed Test (LDT). During development, 200 initial samples would serve as the material that would guide and test each of the CpG assays. Assay development would be executed in a CLIA certified laboratory. Once completed, assay reagents can be ordered directly from Thermo Fisher including the AmpliSeq plate format sample holders that would be required to execute the assay. The assay development plan would meet all regulatory and quality requirements described in the FDA Emergency Use Authorization guidance document. As soon as a clinical partner and funding source are identified, we would schedule a discussion with the FDA regarding Test and Criteria for Emergency Use Authorization Issuance. A prognostic assay for COVID-19 infection and associated ARDS clearly meets the criterion of a serious or life-threatening disease. Evidence of effectiveness will be obtained by applying the final assay format to approximately 200 blood samples from COVID-19 patients with known clinical outcome in a fully blinded validation round to demonstrate and confirm the accuracy and performance of the test. In terms of risk and benefit to the patient this analysis poses minimal direct risks because only a small, standard blood sample draw is required to perform the test. More importantly, at present there are no alternatives to the proposed prognostic assay to triage patients for COVID-19 risk for ARDS or other severe outcomes. Patients falling into broad categories based on age or comorbidities such as obesity or diabetes seem to be at higher risk, but the majority of patients in these classes still do not experience severe COVID-19 symptoms. 28 Delaware Journal of Public Health – July 2020
PUBLIC HEALTH IMPLICATIONS Establishing a link between an immune system status EpiMarker and the functional ability of patients to successfully fight a COVID-19 infection would have large ramifications for pursuing new therapeutic agents and diagnostic/prognostic strategies. This is critical not just for better management of the COVID-19 threat but also in preparing global health systems for future pandemics, as well as aiding in our current battles against non-pandemic but ever-present viral pathogen diseases, like seasonal influenza. If an EpiMarker assay can demonstrate that there is a defined immuno-methylome imprint that predisposes patients to fight viremia infections, then this assay could be a game changer in terms of opening new options for how we as a society respond to infectious diseases. Diagnostic immuno-methylome EpiMarker assays hold promise for identifying subjects at risk. The most immediate would be in health care triage. Aggressive treatment options could be pursued earlier in patients at high risk. This likely has the most promise for decreasing the COVID-19 mortality rate at the source. By not treating patients at low risk of severe disease in hospitals, precious resources of beds, equipment, medications would be saved, as well as reducing the overall exposure risk to doctors and nurses by only hospitalizing those patients that are likely to need such acute care. In addition to health care resource triage and planning, this EpiMarker assay has a large potential impact in terms of the ability of local and city governments to pre-screen police and first-responders for disease severity risks. Screened low-risk personnel can be dispatched to public-facing, mission critical jobs knowing that the mortality and morbidity risks from performing these jobs and concomitant exposure to COVID-19 may be ameliorated for them. In addition, hospital intensive care staffing decisions for doctors, nurses, orderlies could also be informed by each individual’s personal risk to severe disease symptoms. And by extension, if successful, every large business could have employees screened, allowing formulation of a pandemic criticalmission personnel plan for continuity of economic activities without having to shut-down operations to the extent experienced in the spring of 2020. Importantly, the EpiMarker Platform is not disease or application specific. It can be trained to provide severity prognostics on other infectious diseases. Adding support for analyzing case severity of a new disease follows the same process; namely, collecting data from new patients with varying demographics and disease response severity, training a new machine learning model, and deploying the model. The resulting panel assay is based on a standard blood draw and analyzed using standard laboratory equipment. Novel EpiMarker-enabled blood tests will reduce death rates and are much faster to develop and deploy than either a new vaccine or immunity test. Moreover, if there are vaccine or anti-viral drugs, these tests will efficiently prioritize which patients should be treated first. Within a military context, availability of advanced medical care requires special planning in deployed or other extremis military situations. Prognostic testing such as this can help avoid mission compromise by identifying at risk subjects a priori. Further expansion and development of this diagnostic platform strategy could become a frontline defense for future pandemics, current battles with viral pathogens like influenza, and be extended to other biological threats where early assessment of patient risk
will lead to more effective allocation of scarce medical care and resources. A simple EpiMarker blood-based assay has significant potential for the Army, other military branches and the civilian contractors that support their missions. Military operations and unit effectiveness can be compromised by disease, natural or weaponized. Knowing which individuals would be most susceptible to serious, incapacitating illness and which individuals would be moderately inconvenienced by an illness provides a powerful planning and operational tool. Imagine if you knew in advance which personnel would be more susceptible to a serious, life threatening disease than others? They could be assigned accordingly, perhaps in closer proximity to medical facilities, rather than deployed to areas of high disease risk or into remote areas without medical facilities.
COMPETING INTERESTS AGM is the inventor of the EpiMarker technology and a CoFounder of Genome Profiling LLC. He holds an equity position in this company and is a member of the Board of Directors. GMA is VP for EpiMarker Solutions to Genome Profiling. EJI is Senior VP for Research and Development at BTS Software Solutions.
REFERENCES 1. Teuwen, L. A., Geldhof, V., Pasut, A., & Carmeliet, P. (2020, July). COVID-19: The vasculature unleashed. Nature Reviews. Immunology, 20(7), 389–391. https://doi.org/10.1038/s41577-020-0343-0 2. Wu, Z., & McGoogan, J. M. (2020, February 24). Characteristics of and important lessons from the coronavirus disease 2019
(COVID-19) outbreak in China: Summary of a report of 72314 cases from the Chinese Center for Disease Control and Prevention. JAMA, 323(13), 1239–2142. https://doi.org/10.1001/jama.2020.2648 3. Fung, S. Y., Yuen, K. S., Ye, Z. W., Chan, C. P., & Jin, D. Y. (2020, March 14). A tug-of-war between severe acute respiratory syndrome coronavirus 2 and host antiviral defence: Lessons from other pathogenic viruses. Emerging Microbes & Infections, 9(1), 558–570. https://doi.org/10.1080/22221751.2020.1736644 4. Matacic, C. (2020, Jun 2), Blood vessel attack could trigger coronavirus’ fatal ‘second phase’. Science. Retrieved from: https://doi.org/doi:10.1126/science.abd1296 5. Arts, R. J. W., Moorlag, S. J. C. F. M., Novakovic, B., Li, Y., Wang, S. Y., Oosting, M., . . . Netea, M. G. (2018, January 10). BCG vaccination protects against experimental viral infection in humans through the induction of cytokines associated with trained immunity. Cell Host & Microbe, 23(1), 89–100.e5. https://doi.org/10.1016/j.chom.2017.12.010 6. Crowgey, E. L., Marsh, A. G., Robinson, K. G., Yeager, S. K., & Akins, R. E. (2018, June 21). Epigenetic machine learning: Utilizing DNA methylation patterns to predict spastic cerebral palsy. BMC Bioinformatics, 19(1), 225. https://doi.org/10.1186/s12859-018-2224-0 7. Marsh, A. G., Cottrell, M. T., & Goldman, M. F. (2016, November 2). Epigenetic DNA methylation profiling with MSRE: A quantitative NGS approach using a Parkinson’s Disease test case. Frontiers in Genetics, 7, 191. https://doi.org/10.3389/fgene.2016.00191
The DPH Bulletin
From the Delaware Division of Public Health
June 2020 Men: follow these health tips
• Wear a face covering in public. • Social distance (Keep at least 6 feet
away from others.)
• Wash hands often. • Cough or sneeze into your elbow. • Clean frequently used surfaces,
doorknobs, shared keyboards, and TV remotes every day.
• Limit your time in public. • Stay home if you are sick. • Call your doctor about testing if you
are experiencing symptoms.
Help us trace the virus. If DPH calls - please answer.
To slow the spread of COVID-19, contact tracers calling on behalf of the Division of Public Health (DPH) inform the close contacts of COVID-positive persons that they may have been exposed to the virus. Close contacts are anyone you have been within 6 feet of for 10 minutes or more, including: people in the same house, intimate partners, and/or COVID-19 positive persons for whom you are providing care without using recommended protective equipment. DPH’s contact tracers ask close contacts to stay at home and self-quarantine. They may also recommend the close contact be tested. DPHs contact tracers will reach out through phone calls or visits to the home if a phone number is not available for the person. They confirm a person's identity and ask questions about any symptoms, underlying health conditions, and their ability to quarantine at home safely. DPH contact tracers in the community wear a shirt, identification, and a mask, face shield, and gloves. DPH will NOT collect social security numbers, bank account information, credit card information, or immigration status. DPH does not share information with any person or other organizations (including immigration or family services). For more information about contact tracing, visit https://coronavirus.delaware.gov/.
30 Delaware Journal of Public Health – July 2020
Men can reduce their chance of illness and early death by following these tips: ■ Regularly visit your health care provider for checkups and recommended vaccinations. ■ Be sun smart to prevent skin cancer. Delaware males accounted for 60 percent of malignant melanoma cases in 2010-2014, according to the Division of Public Health (DPH). To prevent skin cancer, avoid the sun between 10:00 a.m. and 4:00 p.m. when it is hottest. When outdoors, wear longsleeved shirts, pants, and a wide-brimmed hat. Apply sunscreen with SPF15 or higher on exposed skin, especially the ears, neck, and exposed arms. Do not delay seeing a dermatologist for unusual moles, rashes, or other changes to the skin. ■ Get recommended cancer screenings. Visit www.healthydelaware.org/Individuals/Cancer to learn when you should be screened for colorectal, prostate, and lung cancers. ■ Do not smoke or vape and avoid breathing in secondhand smoke because cigarette smoking causes lung and other cancers. Delawareans age 18 and older who smoke can get free help quitting from the Delaware Quitline (toll-free: 1-866-409-1858). ■ Get tested for chronic diseases: diabetes, high blood pressure, and high cholesterol. An early diagnosis and treatment can help you avoid health complications, including heart attack and stroke. ■ Achieve and maintain a healthy weight with healthy eating, regular physical activity, and balancing consumed calories with used calories. ■ Visit the dentist twice a year for dental cleanings. ■ Seek help for mental health or addiction issues. Visit https://www.helpisherede.com/ or call 1-833-9-HOPEDE (467333).
Be pet-prepared for emergencies
June is National Pet Preparedness Month, an observance that reminds pet owners that their emergency plans need to include their pets. In case of an evacuation, take pets with you. Never leave pets behind because they can be injured, become lost, or die without your care. First responders are put in danger when trying to rescue abandoned pets.
Include pandemic considerations when preparing for hurricanes Hurricane season began June 1. Delawareans should review their emergency preparedness efforts with the new coronavirus (COVID-19) in mind. Since the pandemic may impact shelters, determine which local shelters will be used this year. Print evacuation route maps from the Delaware Department of Transportation. Everyone in the household should understand your evacuation plan. Download the Federal Emergency Management Agency (FEMA) app now so that during an emergency, you will have maps of open shelters and recovery centers, disaster survival tips, and weather alerts from the National Weather Service. The app is available in English and Spanish. Each household should have an emergency supply kit with enough non-perishable food, drinking water, and other supplies for every household member to last at least three days. Kits should also include a battery-powered or hand-crank powered radio or a NOAA weather radio, flashlights, phone chargers, extra batteries, paper products, a can opener, essential medications, and pet food. FEMA recommends including two cloth face coverings per family member and soap, hand sanitizer, disinfecting wipes, and general household cleaning supplies to disinfect surfaces. After a hurricane, you may not have access to these supplies for days or weeks. The FEMA app provides a customizable emergency supply checklist. For those on a limited budget, click here to assemble a kit in small steps. It is critical to gather and back up financial information to recover from disasters faster. FEMA’s Emergency Financial First Aid Kit simplifies that overwhelming task. For more readiness tips, visit PrepareDE.gov, Ready.gov, and https://www.redcross.org/gethelp/how-to-prepare-for-emergencies.html.
The DPH Bulletin – June 2020
Be pet-prepared by following this advice: • Have pets wear a collar with ID tag containing updated contact information. • Microchip your pet and register your current contact information with the chip company. • Have a pet carrier, leash, and “pet go kit” ready. Pet go kits are a backpack filled with three days’ worth of pet food and water, food and water bowls, litter and disposable litter trays, crate, toys, blankets, and any pet medications. Also include copies of your pet’s license and vaccination papers, especially for rabies; and medical records. Be sure to include proof of pet ownership such as several printed photos of you and your pet together. Back up these documents on smartphones and your home computer. • Determine which family, friends, or neighbors can care for your pet in case a disaster or emergency occurs when you are not at home. • Make a list of pet-friendly accommodations, boarding facilities, veterinarian offices, and clinics outside your immediate area. Not all emergency shelters accept companion animals. For more information on pet preparedness, visit http://djph.delamed.org/V5_I4/DP017.pdf to read “Being pet prepared saves human and animal lives,” an article that appeared in the October 2019 issue of the Delaware Journal of Public Health. Visit the American Society for the Prevention of Cruelty to Animals at https://www.aspca.org/pet-care/general-petcare/disaster-preparedness and https://www.ready.gov/pets.
Page 2 of 2
Bedside: Clinical Treatment in the time of COVID-19
Engineering Preclinical Tools and Therapeutics to Understand and Treat COVID-19 Catherine A. Fromen, Department of Chemical and Biomolecular Engineering, University of Delaware Jason P. Gleghorn, Department of Biomedical Engineering, University of Delaware
INTRODUCTION The novel respiratory coronavirus SARS-CoV-2, which causes the disease COVID-19, has caused a significant impact on humanity worldwide.1 Among the many challenges to containing SARS-CoV-2 has been its high degree of spread by asymptomatic individuals and the lack of effective therapeutics capable of either preventing viral transmission or halting adverse host immune responses.1,2 Indeed, many initial therapeutic candidates have been found to be ineffective at fighting COVID-19,3 with only recently a report of dexamethasone demonstrating some therapeutic efficacy. To combat the lack of treatment options, our team at the University of Delaware is actively working to test a novel prophylactic, post-exposure approach as a platform inhalable technology for fighting inhaled respiratory pathogens (see Figure 1).
Figure 1. Microparticles decorated with ACE2 peptide can be delivered via oral or nasal inhalation to at-risk populations.
DESIGNING INHALABLE THERAPIES AS A PROPHYLACTIC PLATFORM TECHNOLOGY FOR COVID-19 AND FUTURE RESPIRATORY PATHOGENS SARS-CoV-2 enters vulnerable cells by binding to angiotensin converting enzyme (ACE) 2 protein via spike protein on the surface of the virus.4,5 Recent studies have implicated cells within the nasal passageway as the first site of viral entry, which gradually descends through the lung as the infection progresses.6 To ultimately clear the virus, the adaptive immune system responds by producing neutralizing antibodies to the virus to block viral function.7 Many of these antibodies, isolated from 32 Delaware Journal of Public Health – July 2020
clinical samples, are specific against the viral spike protein, further showing that prevention of the initial binding interaction between the virus and the host ACE2 is an important step in halting the viral life cycle.7 However, host antibodies that neutralize the virus requires anywhere from 14-30 days from the initial time of infection to be generated by the adaptive immune system.1,8,9 This lag time from infection to neutralization allows SARS-CoV-2 with ample opportunity to continue replicating, spread to other organ systems, dysregulate the host innate immune system, and wreak havoc on the body.9 A prophylactic treatment that stops viral particles from entering cells, thus mimicking the function of neutralizing antibodies produced later in the infection, would be useful in combatting COVID-19. Applied early in the infection, immediately after known exposure, or as a prophylactic treatment to high risk populations life front line healthcare workers, this strategy could act at the site of infection and be applied via nasal spray or inhaler (Figure 1). An effective post-exposure therapy would not only lessen the viral load and asymptomatic spread, but also reduce the burden of infection. SARS-CoV-2 is particularly infectious, with reports of infected people displaying no or only mild symptoms, resulting in high degree of asymptomatic spread that is further exacerbated by limited testing. So far, no postexposure treatment regimens have proven effective in preventing the ultimate disease onset. Delivering ACE2 to an infected individual, thus acting as a decoy for SARS-CoV-2 binding, has been suggested as a possible treatment for COVID-19. Soluble ACE2 has been shown to reduce SARS-CoV-1 and CoV-2 transduction efficiency in vitro, and two ongoing phase I/II clinical trials are underway to treat acute respiratory distress syndrome and COVID-19 (NCT04335136) with recombinant ACE2.10–12 However, these clinical trials both use an intravenous route of administration as opposed to an inhalation route. Since the virus is primarily transmitted through inhalation and initial viral shedding from infected cells occurs through the epithelial apical surface into the airway lumen,4,9 a treatment that can sequester virus from the pulmonary airspace would be able to directly limit the viral load at the primary site of infection. While this could be achieved by inhaled therapeutics, pulmonary delivery is accompanied by many delivery challenges. The complex lung mucosal microenvironment and airway anatomy, combined with lowefficiency inhalers and heterogeneity in aerosol formulations, has limited commercial inhaled therapies to a few small molecule drugs.13–16 Significant innovation in both the formulation of inhaled therapeutic as well as the preclinical testing paradigm are needed to successfully create new inhaled medicines. Our current research efforts are focused on designing an inhalable microparticle to deliver SARS-CoV-2 binding domains capable of sequestering virus at the site of infection (see Figure 2). The microparticles are comprised of poly(ethylene glycol) diacrylate [PEGDA], an inert material that has been previously
studied in our group and shown to have high biocompatibility in the lung with tunable degradation profiles.17–19 By modulating the base particle formulation and the attachment of SARS-CoV-2 binding fragments that mimic ACE2, we can modulate where the particle will deposit in the lung, how much virus will be sequestered, and how the medicine will be cleared from the lung. Aerosols with aerodynamic diameters around 10 μm are known to deposit in the upper respiratory tract (mouth, pharynx and trachea) and aerosols approximately 5 μm in diameter deposit efficiently in the conducting airways.20 Our synthetic approach allows us to precisely modulate the amount of ACE binding peptide to control how well the microparticle can entrap the Figure 2. Microparticles comprised of PEGDA will block SARS-CoV-2 binding to host cells in virus and also the degradation rate in the an analogous manner to neutralizing antibodies. lung. While research is actively on-going, our overall goal is to demonstrate this Accordingly, the current paradigm of preclinical aerosol testing approach can actively sequester free virus is only capable of roughly estimating deposition location and is in the lung airspace, decrease viral load, and maintain a robust permanently decoupled from downstream biological response. safety profile. Because of this, accurate dosing needs are poorly realized.24 Initially designed for the current SARS-CoV-2 pandemic, we In collaboration, our two labs have contributed significantly believe this can be considered a platform technology to combat in this area to develop models that can represent the complete a wide range of current and future respiratory pathogens. Viral structure of the human lung. Here, we describe our on-going infections and lower respiratory diseases continue to represent engineering efforts to validate new preclinical models capable of a significant global health care burden, responsible for over two effectively evaluating our proposed inhaled PEGDA microparticle million global deaths annually.21 Development of safe and effective treatment. post-exposure and prophylactic treatments remain a high priority. Our inhalable PEGDA microparticle platform (Figure 2) is GLEGHORN LAB: MURINE EX VIVO highly modular, with a plug-and-play approach for the specific LUNG EXPLANTS. binding sequence. By simply replacing the ACE2 binding peptide The Gleghorn lab has recently demonstrated the first viable ex with a binding domain that is specific for a different pathogen, vivo culture heart-lung en bloc for neonatal mice (see Figure 3). we can create a whole new line of inhalable treatments with By culturing ex vivo, this model allows for a duration and level of similar method of preventing infection through viral decoys. By accessibility impractical with existing in vivo models and tunable pursuing development of this approach for the current COVID19 breathing control. Through active perfusion of the vasculature, pandemic, we aim to create a highly modular platform that can be this system allows for tissue nutrient delivery and waste removal, rapidly deployed in future outbreaks to prevent the occurrence of while providing critical mechanical cues to the pulmonary any subsequent viral airborne pandemics. vasculature. This is in contrast to bath culture methods that avoid necrosis by cutting the lung into blocks, preventing studies of LAB-SCALE MODELS OF THE LUNG FOR organ-scale structure and biology. Our model allows for separate ADVANCED TESTING control of the mechanics acting on airway epithelium and pulmonary vascular endothelium by independently regulating One of the critical aspects in the development of inhalable ventilation parameters and vascular perfusion. This separation therapeutics is the ability to test their efficacy in relevant can be used to decouple signaling factors that are induced by preclinical environments. Unfortunately, current ability to different mechanical disruptions that are often clinically copredict how well an inhaled therapy will work in humans is incident; e.g., the effects of mechanical ventilation and pulmonary quite limited. Despite understanding that efficacy of inhaled hypertension. We accomplish this control through airway medications depends on many factors ranging from device used, intubation through the trachea and perfusion via the heart. This airway dynamics, disease state, and local microenvironment,22,23 allows for tunable tidal volumes, breathing rates, and vascular there are currently no preclinical tools or models capable of perfusion. Using this approach, we can administer inhaled assessing these a priori, leading to generally poor in vitro/in vivo formulations directly to the airspace under highly modular and correlations (IVIVC) of inhaled therapeutics.15 Current preclinical well controlled breathing conditions. Furthermore, this approach assays, whether experimental or computational, are stationary enables us to decouple the response of the lung tissue from any approaches that fail to incorporate aspects of breathing or the lung recruited cell components and identify new mechanisms in microenvironment to assess drug efficacy following deposition. COVID-19 host response. 33
Bedside: Clinical Treatment in the time of COVID-19
Figure 4. 3D-printed breathing lung model design and features.
ON-GOING BIOENGINEERING OPPORTUNITIES
Figure 3. Ex vivo whole lung culture platform.
FROMEN LAB: DYNAMIC LUNG MODELS. The Fromen lab has developed the first breathing whole lung model to assess regional aerosol deposition in varying states of health and disease (Figure 4). Our approach leverages advances in additive manufacturing and consists of a patient-derived upper airway connected to anatomically-scaled deformable lobe units. Each lobe is independently actuated by mechanical deformation for a tunable, realistic breathing profile, with an overall breathing capability matching human tidal and forced breathing metrics, as well as spatial aerosol deposition. The full range of human airways are approximated based on Weibel’s Model A geometry,25 mimicking the cross-sectional area and total volume for each airway generation in a series of frustums (Figure 4). This firstin-kind approximation resembles a cone or bell and recreates the increasing volume available with increasing lung generation. Internal structures within the lobe enable collection of spatially distributed aerosols to mimic human deposition during breathing maneuvers. Lobes are connected to a microcontroller-driven motor that generates airflow by expansion/contraction. Not only does this approach provide advantages by approximating the full range of human airways (volume, surface area) and dynamic breathing profiles, but it also boasts ease of fabrication, with entirely interchangeable parts for disease and patient-specific modeling. This device is the first model that incorporates realistic breathing capability to enable lobe- and generation- level deposition measurements. Using this approach, we can develop personalized formulations and/or inhaler devices that will deliver optimized doses of inhaled therapeutics, as well as assess the efficacy of new therapies, such as our prophylactic PEGDA microparticle treatment. 34 Delaware Journal of Public Health – July 2020
Given the tremendous global challenge of SARS-CoV-2, novel treatment paradigms are desperately needed. Challenges in developing effective treatments for respiratory infection fall hand-in-hand with an on-going need for new preclinical assays that allow for rapid screening and successful clinical translation. Bioengineers have a considerable role to play in tackling these needs and others that have surfaced during the COVID-19 pandemic. As reported by our team in a recent report [CMBE review], on-going bioengineering efforts include the application of new preclinical tools toward the study of host immune response, viral transmission and replication, renin angiotensin system contributions, host factors and exacerbates, and drug transport in the lung. Similarly, there are many on-going bioengineering efforts to design new therapeutics capable of modulating viral dynamics, host immune response, and vaccine delivery. Together, the contribution of bioengineers in this space is significant in providing tools to learn new aspects of COVID-19 disease progression and in developing novel approaches towards the mitigation and elimination of the disease. Our on-going efforts of the Gleghorn and Fromen labs at the University of Delaware are creating platform technologies for preclinical respiratory assessment and prophylactic post-exposure antiviral treatment that will be essential components of combatting COVID-19 and future airborne respiratory pathogens.
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3. Li, G., & De Clercq, E. (2020, March). Therapeutic options for the 2019 novel coronavirus (2019-nCoV). Nature Reviews. Drug Discovery, 19(3), 149–150. https://doi.org/10.1038/d41573-020-00016-0
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4. Hoffmann, M., Kleine-Weber, H., Schroeder, S., Krüger, N., Herrler, T., Erichsen, S., . . . Pöhlmann, S. (2020, April 16). SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell, 181(2), 271–280.e8. https://doi.org/10.1016/j.cell.2020.02.052
16. Weers, J. G., Bell, J., Chan, H. K., Cipolla, D., Dunbar, C., Hickey, A. J., & Smith, I. J. (2010, December). Pulmonary formulations: What remains to be done? Journal of Aerosol Medicine and Pulmonary Drug Delivery, 23(Suppl 2), S5–S23. https://doi.org/10.1089/jamp.2010.0838
5. Du, L., He, Y., Zhou, Y., Liu, S., Zheng, B.-J., & Jiang, S. (2009, March). The spike protein of SARS-CoV—A target for vaccine and therapeutic development. Nature Reviews. Microbiology, 7(3), 226–236. https://doi.org/10.1038/nrmicro2090 6. Hou, Y. J., Okuda, K., Edwards, C. E., Martinez, D. R., Asakura, T., Dinnon, K. H., III, . . . Baric, R. S. (2020, May 27). SARS-CoV-2 reverse genetics reveals a variable infection gradient in the respiratory tract. Cell, S0092-8674(20)30675-9. https://doi.org/10.1016/j.cell.2020.05.042 7. Zohar, T., & Alter, G. (2020, July). Dissecting antibodymediated protection against SARS-CoV-2. Nature Reviews. Immunology, 20(7), 392–394. https://doi.org/10.1038/s41577-020-0359-5 8. Lauer, S. A., Grantz, K. H., Bi, Q., Jones, F. K., Zheng, Q., Meredith, H. R., . . . Lessler, J. (2020, May 5). The incubation period of coronavirus disease 2019 (COVID-19) from publicly reported confirmed cases: Estimation and application. Annals of Internal Medicine, 172(9), 577–582. https://doi.org/10.7326/M20-0504 9. Tay, M. Z., Poh, C. M., Rénia, L., MacAry, P. A., & Ng, L. F. P. (2020, June). The trinity of COVID-19: Immunity, inflammation and intervention. Nature Reviews. Immunology, 20(6), 363–374. https://doi.org/10.1038/s41577-020-0311-8 10. Jia, H. P., Look, D. C., Tan, P., Shi, L., Hickey, M., Gakhar, L., . . . McCray, P. B., Jr. (2009, July). Ectodomain shedding of angiotensin converting enzyme 2 in human airway epithelia. American Journal of Physiology. Lung Cellular and Molecular Physiology, 297(1), L84–L96. https://doi.org/10.1152/ajplung.00071.2009 11. Monteil, V., Kwon, H., Prado, P., Hagelkrüys, A., Wimmer, R. A., Stahl, M., . . . Penninger, J. M. (2020, May 14). Inhibition of SARS-CoV-2 infections in engineered human tissues using clinical-grade soluble human ACE2. Cell, 181(4), 905–913.e7. https://doi.org/10.1016/j.cell.2020.04.004 12. Khan, A., Benthin, C., Zeno, B., Albertson, T. E., Boyd, J., Christie, J. D., . . . Lazaar, A. L. (2017, September 7). A pilot clinical trial of recombinant human angiotensin-converting enzyme 2 in acute respiratory distress syndrome. Critical Care (London, England), 21(1), 234. https://doi.org/10.1186/s13054-017-1823-x 13. Smaldone, G., Berkland, C., Gonda, I., Mitchell, J., Usmani, O. S., & Clark, A. (2013, August). Ask the experts: The benefits and challenges of pulmonary drug delivery. Therapeutic Delivery, 4(8), 905–913. https://doi.org/10.4155/tde.13.76 14. Fernandes, C. A., & Vanbever, R. (2009, November). Preclinical models for pulmonary drug delivery. Expert Opinion on Drug Delivery, 6(11), 1231–1245. https://doi.org/10.1517/17425240903241788
17. Fromen, C. A., Rahhal, T. B., Robbins, G. R., Kai, M. P., Shen, T. W., Luft, J. C., & DeSimone, J. M. (2016, April). Nanoparticle surface charge impacts distribution, uptake and lymph node trafficking by pulmonary antigen-presenting cells. Nanomedicine, 12(3), 677–687. https://doi.org/10.1016/j.nano.2015.11.002 18. Shen, T. W., Fromen, C. A., Kai, M. P., Luft, J. C., Rahhal, T. B., Robbins, G. R., & DeSimone, J. M. (2015, October). Distribution and cellular uptake of PEGylated polymeric particles in the lung towards cell-specific targeted delivery. Pharmaceutical Research, 32(10), 3248–3260. https://doi.org/10.1007/s11095-015-1701-7 19. Stillman, Z., Jarai, B. M., Raman, N., Patel, P., & Fromen, C. A. (2020). Degradation profiles of poly(ethylene glycol)diacrylate (PEGDA)-based hydrogel nanoparticles. Polymer Chemistry, 11(2), 568–580. https://doi.org/10.1039/C9PY01206K 20. Chan, J. G., Wong, J., Zhou, Q. T., Leung, S. S., & Chan, H. K. (2014, August). Advances in device and formulation technologies for pulmonary drug delivery. AAPS PharmSciTech, 15(4), 882–897. https://doi.org/10.1208/s12249-014-0114-y 21. Roth, G. A., Abate, D., Abate, K. H., Abay, S. M., Abbafati, C., Abbasi, N., . . . Murray, C. J. L., & the GBD 2017 Causes of Death Collaborators. (2018, November 10). Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980-2017: A systematic analysis for the Global Burden of Disease Study 2017. Lancet, 392(10159), 1736–1788. https://doi.org/10.1016/S0140-6736(18)32203-7 22. Patton, J. S., & Byron, P. R. (2007, January). Inhaling medicines: Delivering drugs to the body through the lungs. Nature Reviews. Drug Discovery, 6(1), 67–74. https://doi.org/10.1038/nrd2153 23. Darquenne, C., Fleming, J. S., Katz, I., Martin, A. R., Schroeter, J., Usmani, O. S., . . . Schmid, O. (2016, April). Bridging the gap between science and clinical efficacy: Physiology, imaging, and modeling of aerosols in the lung. Journal of Aerosol Medicine and Pulmonary Drug Delivery, 29(2), 107–126. https://doi.org/10.1089/jamp.2015.1270 24. Carrigy, N. B., Ruzycki, C. A., Golshahi, L., & Finlay, W. H. (2014, June). Pediatric in vitro and in silico models of deposition via oral and nasal inhalation. Journal of Aerosol Medicine and Pulmonary Drug Delivery, 27(3), 149–169. https://doi.org/10.1089/jamp.2013.1075 25. Weibel, E. R. (1963). Morphometry of the human lung: Academic Press. 35
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Multisystem Inflammatory Syndrome in Children (MIS-C): an emerging immune mediated syndrome in children associated with COVID-19 Deepika Thacker, M.D., Nemours Cardiac Center, Nemours/Alfred I. duPont Hospital for Children
ABSTRACT As the world came to terms with the current COVID-19 pandemic, children were initially thought to have milder disease than adults with significantly lower morbidity and mortality. The emergence of a multi-system inflammatory syndrome in children (MIS-C) associated with the SARS-CoV-2 virus was first recognized in Europe, and then across centers in the United States. Early and widespread data sharing among centers across the world was extremely helpful in early identification and treatment of these children, with a good prognosis in a majority of cases. Significant research is required to answer several questions that have been raised, including susceptibility, long-term effects, and pathogenesis and treatment options to name a few.
INITIAL CASE On April 12th, 2020, in the midst of the COVID-19 pandemic, a 14-year old multiracial (Caucasian and Hispanic) male presented to the emergency department with a four day history of fever, fatigue, and abdominal pain and subsequently developed fever, diarrhea and a rash. Polymerase Chain Reaction (PCR) for the Severe Acute Respiratory Syndrome Coronavirus 2 (SARSCOV-2) was negative on admission. He was initially thought to have appendicitis, but work up for that was negative. On laboratory evaluation, he had very high levels of inflammatory markers including C-Reactive Protein and Erythrocyte Sedimentation rate. Brain Natriuretic Peptide, an indirect marker of cardiac function, was also elevated. Echocardiogram confirmed severely decreased heart function and mildly dilated coronary arteries. His clinical presentation had some overlapping features of Rheumatic Fever, Kawasaki Disease and Toxic Shock Syndrome, without meeting criteria for any one of them.1,2 His exact diagnosis was somewhat of a puzzle even to the multispecialty team treating him, including the intensivist, cardiologist, rheumatologist and infectious disease doctors. He received intravenous fluids, vasopressors to support blood pressure, and milrinone and diuretics to support cardiac function. He was intubated and placed on mechanical ventilation. Due to the mild dilation of the coronary arteries, he was treated with intravenous immunoglobulin for possible Kawasaki disease, though he did not meet criteria even for the incomplete form.2 He responded well to treatment, with resolution of presenting symptoms and markers of inflammation; and normalization of his cardiac function. He was discharged after 12 days in the hospital. On April 24th, the National Health Service in the United Kingdom circulated a memo to health care providers, alerting them of an emerging Kawasaki-like syndrome in older children, with a predominance of gastrointestinal symptoms. On receiving that memo as a forward, on a social media app called WhatsApp, we sent antibody testing for the SARS-COV-2 immunoglobulin (SARS-COV-2 IgG) for our patient and he was confirmed to have what was initially known as the pediatric multisystem 36 Delaware Journal of Public Health – July 2020
inflammatory syndrome in children possibly associated with COVID-19 (PIMS), the first reported case in Delaware and one of the first in the United States.
COVID-19 IN CHILDREN In December 2019, an outbreak of a severe respiratory illness caused by a novel strain of coronavirus, SARS-CoV-2, was first identified in Wuhan, China.3 The World Health Organization (WHO) declared the outbreak a Public Health Emergency of International Concern on 30 January 2020, and a pandemic on 11 March.3 As the disease progressed through China, followed by Europe, the United States, and then the rest of the world, some solace was obtained from the data suggesting that severe illness in children was far less frequent than adults.4 A systematic review published in March 2020 came to the conclusion that COVID-19 was either rare in children or it had not been diagnosed that often because this age group remained asymptomatic.5 Children represented only approximately 1.2 to 5% of diagnosed cases.5 These low figures were consistent with the data from the Severe Acute Respiratory Syndrome (SARS) epidemic in 2003, when very few of the positive cases were children and none died.6 Several suggestions were put forward to explain the milder disease in children. Overall it seemed that children had a different immune system when compared to adults, and somehow that protected them from severe symptoms in this is disease.
EVOLUTION OF THE MULTISYSTEM INFLAMMATORY SYNDROME IN CHILDREN (MIS-C): In April, 2020, reports from the United Kingdom noted a number of children of all ages presenting with a multisystem inflammatory state requiring intensive care, presenting with abdominal complaints and cardiac inflammation. A possible correlation with COVID-19 was suggested with some of these children testing positive for SARS-COV-2 PCR, and some for related antibody tests. An international web-based meeting was hosted via Zoom, a cloud based online service, on May 2, 2020, including experts from Europe and the United States. They reported data from 38
cases identified between March 25 and April 1, ranging in age 1-15 years presenting with features of this syndrome. On May 4, 2020, the New York City Health Department issued an alert to health care providers in the United States after identifying 15 patients aged 2-15 years, who had been hospitalized from April 17 to May 1, 2020 with illnesses compatible with a multisystem inflammatory syndrome.7 Then on May 14, the Centers for Disease Control (CDC) put out a health advisory outlining diagnostic criteria for this syndrome, now called Multisystem Inflammation Syndrome in Children (MIS-C, Table 1).8 CDC required reporting of identified cases to state, local or territorial health departments. While the CDC did not provide guidance on treatment, intravenous immunoglobulin and supportive care were noted as common approaches to management. WHO followed on May 15, with a similar case definition (Table 2).9 CDC: Center for Disease Control; MIS-C: Multisystem Inflammatory Syndrome in Children; CRP: C-reactive
protein; ESR: Erythrocyte Sedimentation Rate; LDH: lactic acid dehydrogenase; IL-6: Interleukin-6; RT-PCR: real time polymerase chain reaction; COVID-19: coronavirus disease 2019; WHO: World Health Organization; MIS-C: multisystem inflammatory syndrome in children; ECHO: echocardiogram; PT: prothrombin time; PTT: partial prothrombin time; ESR: erythrocyte sedimentation rate; CRP: C-reactive protein; NTproBNP: N-Terminal prohormone brain natriuretic peptide; RT-PCR: real-time polymerase chain reaction; COVID-19: Coronavirus disease 2019 More cases were reported from Europe and Eastern states in the United States, with highest numbers from New York. As of early June, more than 250 cases were reported from more than 25 states in the United States, of which approximately six were from Delaware. A surge of cases was also noted from more than twelve countries in Europe. Interestingly, no definitive cases of MIS-C were identified in China. Castagnoli’s et al. systematic review
Age < 21 years Fever > 38ºC or subjective fever > 24 hours Clinically severe illness requiring hospitalization with >2 organ involvement: cardiac, renal, respiratory, hematologic, gastrointestinal, dermatologic or neurological Laboratory evidence of inflammation: Elevated CRP, ESR, fibrinogen, procalcitonin, d-dimer, ferritin, LDH, IL-6, elevated neutrophils, reduced lymphocytes and low albumin No alternative plausible diagnoses Positive for current or recent SARS-CoV-2 infection by RT-PCR, serology or antigen test; or COVID-19 exposure within the 4 weeks prior to the onset of symptoms Table 1: CDC Case Definition for MIS-C 8
Age 0-19 years Fever > 3 days AND 2 of the following: 1) Rash or bilateral non-purulent conjunctivitis or muco-cutaneous inflammation signs (oral, hands or feet) 2) Hypotension or shock 3) Features of myocardial dysfunction, pericarditis, valvulitis, or coronary abnormalities (including ECHO findings or elevated Troponin/NT-proBNP) 4) Evidence of coagulopathy (by PT, PTT, elevated d-Dimers) 5) Acute gastrointestinal problems (diarrhea, vomiting, or abdominal pain). AND Elevated markers of inflammation such as ESR, CRP, or procalcitonin AND No other obvious microbial cause of inflammation, including bacterial sepsis, staphylococcal or streptococcal shock syndromes. AND Evidence of COVID-19 (RT-PCR, antigen test or serology positive), or likely contact with patients with COVID-19 Table 2: WHO Preliminary case definition for MIS-C9 37
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included data from 1065 children with COVID-19 infection in China with 444 cases in children aged younger than 10 years, and 553 children aged between 10 and 19 years.10 The authors reported that the children presented with symptoms similar to the presentations in adult populations e.g. fever, dry cough, fatigue, sore throat, headache, loss of taste and smell, and/or shaking chills. Chest x-ray findings reported bronchial thickening, ground-glass opacities, as well as inflammatory lung lesions. None fit the criteria for an inflammatory post infectious syndrome. It has been speculated that there are different circulating strains of the SARS-CoV-2 virus, and that the Italian strain is more likely to result in MIS-C as opposed to the Wuhan strain. This would also explain the greater incidence of this syndrome on the Eastern coast of the United States which is in closer proximity to Europe, as opposed to the Western coast where the virus first originated from a traveler from China.
ROLE OF SOCIAL MEDIA AND INTERNET BASED MEETING PLATFORMS In this age, even prior to the current pandemic, social media platforms such as Twitter, Facebook, Instagram and WhatsApp have become primary sources of information for a vast majority of the population. They are also however vehicles for fake news and misinformation. Data shared on these sites is not required to be peer-reviewed or back by valid research. The strength of these platforms however lies in those very deficiencies. They are widely used and news can be shared even as the situation evolves, in realtime and from multiple sources. Initial knowledge of this syndrome was distributed via Whatsapp and Facebook. The widespread availability and ease of setting up meetings using Zoom and WebEx allowed very early interchange of information between countries in Europe such as Italy, Spain and United Kingdom with several centers in the United States and around the world. Medical professionals were able to share data quickly, avoid the time lag and hurdles to publication, thus enabling early identification of these cases, and expedited development of management protocols.
CORRELATION WITH KAWASAKI DISEASE Due to the cardiac, especially coronary involvement in MIS-C, several comparisons were drawn to Kawasaki Disease. This mysterious illness was first described by Dr. Tomisaku Kawasaki of Japan who recently passed away on June 5, 2020 at the age of 95 (unrelated to COVID-19 related causes). In 1967, he published his full description of a child he encountered in 1961 with fever, rash and oral changes.11 Kawasaki Disease was also independently recognized as a new and distinct condition in the early 1970s by pediatricians Marian Melish and Raquel Hicks at the University of Hawaii.11 Several theories were put forth to explain the basis for near simultaneous recognition of this condition in distant parts of the world. Since that time Kawasaki Disease has become the leading cause of acquired heart disease among young children in North America, Japan and several other countries. The exact cause of this condition has remained an enigma, and baffled scientists and physicians around the world for the past 50 years. Some studies have suggested an infectious or post infectious etiology in a genetically susceptible population although a definite culprit has not yet been identified.12 There is no specific diagnostic test for Kawasaki Disease, and diagnosis is made by a combination of clinical and laboratory findings.2 38 Delaware Journal of Public Health – July 2020
The suggested association of Kawasaki Disease with coronavirus infection is not a new one. Between 2002 and 2004, SARS was identified as a viral respiratory disease of zoonotic origin caused by severe acute respiratory syndrome coronavirus (SARS-CoV or SARS-CoV-1), the first-identified strain of the SARS coronavirus species. Fortunately, it was not as widespread as the current COVID-19 pandemic. Prior to that the human coronavirus was thought to only cause mild, self-limited respiratory illness. Then, in 2005, a small case-control study was published from New Haven Connecticut, suggesting an association between a novel coronavirus from New Haven (HCoV-NH) and KD.13 Subsequent studies, however, failed to identify an association of Kawasaki Disease with HCoV-NL63, a coronavirus thought to be highly similar to the previously described HCoV-NH, thus contradicting previous claims by Esper and colleagues.14 The many controversies of Kawasaki Disease and mysteries of its etiology thus continued. In the case of MIS-C and current COVID-19 pandemic, it is noteworthy that these cases were recognized four weeks after the initial surge in COVID-19 infection in the region in Europe and United States. These children were typically older than children presenting with Kawasaki Disease, with a median age of eight years. There was a slight male preponderance and a slight increased prevalence in the black and Hispanic populations in the United States. Prevalence in the Asian population was low, in stark contrast with previous data on Kawasaki Disease. Abdominal complaints were a very prominent feature. The heart was involved in approximately one third of these patients with the extent of myocardial dysfunction being much more than what is typically seen in patients with Kawasaki Disease. Vast majority of these children responded well to treatment with anti-inflammatory medications such as steroids, supportive therapy using medications to improve blood pressure, such as norepinephrine as well as intravenous immunoglobulin.
NEED FOR FURTHER RESEARCH AND GAPS IN CURRENT KNOWLEDGE A pandemic of this nature has not been seen by anyone living at this time. The new emergence of a potentially severe inflammatory syndrome in children, contradicting previously noted mild nature of disease in this subpopulation has been unsettling. So how do we make sense of all this? Which children are most susceptible to MIS-C and which ones are protected? Many of these children noted to have MIS-C have antibody levels suggesting prior infection, but the primary infection itself was asymptomatic. What does the prevalence of MIS-C in Europe and Eastern United States, but absence of cases in China where the disease originated mean? Why the increased incidence in certain demographic groups? While thankfully, the number of cases worldwide remain small, how does MIS-C play into the discussion of reopening summer camps, daycare centers and schools? Several national and international registries and databases have been formed for descriptive observational studies to further understand the basic clinical, epidemiological and genetic parameters associated with this emerging condition. CDC, European Center for Disease Control, and WHO are partnering with institutions to analyze some of the data. Further studies—such as prospective cohort studies, seroepidemiological investigations, and investigations of inflamed tissue for the
presence of virus—are required to determine the precise role played by SARS-COV-2 virus in the pathogenesis of MIS-C and to determine underlying predisposing factors. Biobanks are being created for blood and respiratory specimens to investigate a variety of parameters including antibody levels, other indicators of immune response, markers of inflammation, viral shedding and the effects of various treatments used for COVID-19; as well as conduct genetic studies looking for variations in DNA that either protect children from COVID-19 and/or MIS-C or make them more susceptible. There is also a lack of understanding with regard to the SARS-CoV-2-induced humoral and cellular immune responses; more details are needed, especially on the duration of those immune responses and how they may relate to MIS-C. Many hope for a vaccine as the only reliable means of controlling the spread of COVID-19 infection. However considering that MIS-C is mediated by an immunological response to the virus, is it possible that it may be replicated by immune response to a vaccine? How long is long enough to ensure vaccine safety in children? This current pandemic has completely changed the way we do things, from the mundane events of daily life, to national and international travel and meetings. Lessons that we learn today will define the new normal of tomorrow, for generations to come. It is a big responsibility, and not one to be taken lightly, for our sake and for the sake of our children!
REFERENCES 1. Gewitz, M. H., Baltimore, R. S., Tani, L. Y., Sable, C. A., Shulman, S. T., Carapetis, J., . . . Kaplan, E. L., & the American Heart Association Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease of the Council on Cardiovascular Disease in the Young. (2015, May 19). Revision of the Jones Criteria for the diagnosis of acute rheumatic fever in the era of Doppler echocardiography: A scientific statement from the American Heart Association. Circulation, 131(20), 1806–1818. https://doi.org/10.1161/CIR.0000000000000205 2. McCrindle, B. W., Rowley, A. H., Newburger, J. W., Burns, J. C., Bolger, A. F., Gewitz, M., . . . Pahl, E., & the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee of the Council on Cardiovascular Disease in the Young; Council on Cardiovascular and Stroke Nursing; Council on Cardiovascular Surgery and Anesthesia; and Council on Epidemiology and Prevention. (2017, April 25). Diagnosis, treatment, and long-term management of Kawasaki Disease: A scientific statement for health professionals from the American Heart Association. Circulation, 135(17), e927–e999. https://doi.org/10.1161/CIR.0000000000000484 3. World Health Organization. (2005). Statement on the second meeting of the International Health Regulations (2005) Emergency Committee regarding the outbreak of novel coronavirus (2019-nCoV). Retrieved from: https://www.who.int/ news-room/detail/30-01-2020-statement-on-the-second-meeting-ofthe-international-health-regulations-(2005)-emergency-committeeregarding-the-outbreak-of-novel-coronavirus-(2019-ncov)
4. Shekerdemian, L. S., Mahmood, N. R., Wolfe, K. K., Riggs, B. J., Ross, C. E., McKiernan, C. A., . . . Burns, J. P., & the International COVID-19 PICU Collaborative. (2020, May 11). Characteristics and outcomes of children with coronavirus disease 2019 (COVID-19) infection admitted to US and Canadian pediatric intensive care units. JAMA Pediatrics. https://doi.org/10.1001/jamapediatrics.2020.1948 5. Ludvigsson, J. F. (2020, June). Systematic review of COVID-19 in children shows milder cases and a better prognosis than adults. Acta Paediatr, 109(6), 1088–1095. https://doi.org/10.1111/apa.15270 6. Stockman, L. J., Massoudi, M. S., Helfand, R., Erdman, D., Siwek, A. M., Anderson, L. J., & Parashar, U. D. (2007, January). Severe acute respiratory syndrome in children. The Pediatric Infectious Disease Journal, 26(1), 68–74. https://doi.org/10.1097/01.inf.0000247136.28950.41 7. New York City Department of Health. (2020). Health Alert #13: Pediatric multi-system inflammatory syndrome potentially associated with COVID-19. New York City Department of Health. Retrieved from: https://www1.nyc.gov/site/doh/providers/resources/health-alertnetwork.page 8. Centers for Disease Control and Prevention. (2020). Health advisory: multisystem inflammatory syndrome in children (MIS-C) associated with coronavirus disease 2019 (COVID-19). Centers for Disease Control and Prevention. Retrieved from: https://emergency.cdc.gov/han/2020/han00432.asp 9. World Health Organization. (2020). Scientific Brief: Multisystem inflammatory syndrome in children and adolescents with COVID-19. Retrieved from: https://www. who.int/publications-detail/multisystem-inflammatory-syndrome-inchildren-and-adolescents-with-covid-19 10. Castagnoli, R., Votto, M., Licari, A., Brambilla, I., Bruno, R., Perlini, S., . . . Marseglia, G. L. (2020, April 22). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children and adolescents: A systematic review. JAMA Pediatrics. https://doi.org/10.1001/jamapediatrics.2020.1467 11. Burns, J. C., Kushner, H. I., Bastian, J. F., Shike, H., Shimizu, C., Matsubara, T., & Turner, C. L. (2000, August). Kawasaki disease: A brief history. Pediatrics, 106(2), e27. https://doi.org/10.1542/peds.106.2.e27 12. Rowley, A. H. (2011). Kawasaki disease: Novel insights into etiology and genetic susceptibility. Annual Review of Medicine, 62, 69–77. https://doi.org/10.1146/annurev-med-042409-151944 13. Esper, F., Shapiro, E. D., Weibel, C., Ferguson, D., Landry, M. L., & Kahn, J. S. (2005, February 15). Association between a novel human coronavirus and Kawasaki disease. The Journal of Infectious Diseases, 191(4), 499–502. https://doi.org/10.1086/428291 14. Ebihara, T., Endo, R., Ma, X., Ishiguro, N., & Kikuta, H. (2005, July 15). Lack of association between New Haven coronavirus and Kawasaki disease. The Journal of Infectious Diseases, 192(2), 351–352. https://doi.org/10.1086/430797 39
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Assessing the Impact of COVID-19 on Children and Youth Lee M. Pachter, D.O. Value Institute, ChristianaCare, Newark, DE; Colleges of Medicine & Population Health, Thomas Jefferson University Cynthia Garcia Coll, Ph.D. Department of Pediatrics and Maternal Infant Study Center, University of Puerto Rico, Medical Sciences Campus Norma J. Perez-Brena, Ph.D. Department of Human Development & Family Sciences, Texas State University Lisa M. Lopez, Ph.D. Department of Educational & Psychological Studies, University of South Florida
Linda C. Halgunseth, Ph.D. Department of Human Development and Family Science, University of Connecticut Rashmita S. Mistry, Ph.D. Department of Education, University of California Los Angeles Gabriela Livas Stein, Ph.D. Department of Psychology, University of North Carolina, Greensboro Gustavo Carlo, Ph.D. Department of Human Development and Family Science, University of Missouri, Columbia
As the COVID-19 pandemic continues to change the landscape of life, little attention has been given to children and youth. While most have been saved from the extreme medical consequences of the disease, COVID-19 is still having profound effects on children and youth. Regardless of age, they face family illness, death, loss of income and support, and the closing of schools, childcare centers, and after-school programs. The disruption of daily routines and social distancing leads to loss of contact with relatives, friends, peers, and important adult role-models including teachers, coaches, and counselors. The cumulative effect of these losses are significant. They are not mentioned in the news briefings or public health statistics that have become our daily reference points. We would like to bring attention to some of the ways that the pandemic—while not directly causing significant child morbidity and mortality—is profoundly influencing the health, development, and well-being of our children.
EDUCATION Children are experiencing wide disparities in access and quality of education, depending on administrative and teacher resources, availability of learning tools, and support at home. Some children are expected to spend up to seven hours of screen time per day in learning applications. The short- and long-term effects of this amount of screen time on children’s brain development is unclear, although evidence suggests increased anxiety, behavior problems, and executive functioning deficits. Other children are not engaging in any educational experiences, preventing them from meeting necessary learning standards. The inequity in access to technology has never been so obvious, and has never had such significant consequences.
FAMILY ECONOMICS AND FUNCTIONING A major impact of this pandemic is the effect on family economics. Families’ basic needs are jeopardized. While this effects all families, increased burden has been seen in poor families. A recent poll by the Pew Research Center finds that more than half of low-income households report unemployment or underemployment.1 Over 60% of Hispanics and 44% of African Americans face this predicament. The economic fallout has resulted in surges in housing and food insecurity,2 and suboptimal nutritional choices. Besides health care workers, those most at risk for infection are millions of ‘essential’ and low-wage workers; a disproportionate number of whom are persons of color and parents. Lacking job protections and unable to work remotely, these workers are forced 40 Delaware Journal of Public Health – July 2020
to pick the lesser of two evils – go to work and risk infection (and possibly passing it on to their families) or risk losing their job. For many immigrant families, the combination of lost wages and ineligibility for unemployment increase their vulnerability. The economic and pandemic-specific factors described above lead to increases in parents’ stress. Parents whose emotional health is taxed daily may not have psychological resources to attend to their children’s demands or the capacity to play, talk, and engage with them in cognitively stimulating activities, or help with school-work. And data suggests that one of the best predictors of children’s stress and anxiety is their parents’ level of stress and anxiety. Parental stress can also result in more conflictual adult relationships and in harsher, more punitive, and less responsive parenting. Increased family stress levels have significant consequences. There have been reports of upticks in child abuse cases seen in hospitals during the first months of the pandemic. In times of past social stress like natural disasters and economic recessions, the incidence of child maltreatment rose.3 Recent anecdotal reports of increases in extreme cases (such as head injuries) ending up in hospital emergency departments are just the tip of the iceberg; most child maltreatment concerns are reported by third party individuals outside of the household (teachers, guidance counselors, neighbors, daycare staff, etc.). Lack of outfacing contact due to social distancing likely results in under-reporting of most cases of child abuse and neglect occurring during the pandemic. Aside from its effect on child abuse reporting, social distancing results in children who are in sub-optimal home environments not having the “pop-off valve” of peers, mentors, and community to buffer the toxic stress they are experiencing at home.
ACCESS TO HEALTH CARE AND MENTAL HEALTH SERVICES While children suffer less morbidity and mortality from COVID-19, the pandemic can have indirect effects that put children at greater risk of poor health. Lockdown and social distancing result in decreases in physical activity. Limited opportunities for families to shop and family financial strain can lead to sub-optimal nutritional choices. Limitations in “outside time” may put children at higher exposure to secondhand smoke. As schools move to virtual classrooms, the deleterious effects of increased screen time (e.g., headaches, visual strain, and poor sleep) may occur.
Limited use of preventive health care during the pandemic may also have consequences. There are concerns that decreases in well child visits may result in lowered immunization rates. While herd immunity in the United States will likely lessen the impact of delayed immunization, other areas of the world where baseline immunization rates are lower may see disease increases in the future. While access to health services is challenged during this pandemic, some have advocated for expansion of telehealth services as a potential fix that allows for increased access. While the potential for telehealth remains great and might work towards decreasing health care disparities, the fact remains that access to the technology required for telehealth is unequally distributed and may become a new source of health inequity. Perhaps the greatest health risk that the pandemic presents to children and youth is in mental health. A recent study showed that parents are reporting worse anxiety symptoms and youth are exhibiting a 42% increase in externalizing behaviors. As youth start experiencing negative mental health symptoms due to isolation, increased stress exposure, and trauma, there are few places to go for support. Children have lost access to critical support systems in schools, religious communities, and clinics. For youth who already have mental health diagnoses or special needs, and require these supports to thrive, this risk is even greater. Many chronic conditions are not being attended to as outpatient services are limited. Even when open, families might not seek out services for fear of catching the virus. Children with special needs such as autism, developmental delays, ADHD and physical disabilities rely on daily structured routines and specialized therapies that may not be available.
REFERENCES 1. Pew Research Center. (2020, Apr). About half of lowerincome Americans report household job or wage loss due to COVID-19. Washington, DC. Retrieved from: https://www.pewsocialtrends.org/2020/04/21/about-half-oflower-income-americans-report-household-job-or-wage-lossdue-to-covid-19/ 2. Dunn, C. G., Kenney, E., Fleischhacker, S. E., & Bleich, S. N. (2020, Mar). Feeding low-income children during the Covid-19 pandemic. N Eng J Med, 282, e40. Retrieved from: https://www.nejm.org/doi/full/10.1056/NEJMp2005638 3. Human Rights Watch. (2020). COVID-19’s devastating impact on children. Retrieved from: https://www.hrw.org/news/2020/04/09/covid-19s-devastatingimpact-children 4. Masten, A. S., & Narayan, A. J. (2012). Child development in the context of disaster, war, and terrorism: Pathways of risk and resilience. Annual Review of Psychology, 63, 227–257. https://doi.org/10.1146/annurev-psych-120710-100356 5. National Academies of Sciences, Engineering, and Medicine. (2019). Vibrant and Healthy Kids: Aligning Science, Practice, and Policy to Advance Health Equity. National Academies Press. Retrieved from: https://www.nap.edu/catalog/25466/vibrant-and-healthy-kidsaligning-science-practice-and-policy-to
These accumulative stressful experiences, and lack of access to important health and social service buffers can negatively impact children’s neurocognitive and physical development, with cascading effects in self-regulation, self-concept, social cognition, academics and health.4 These negative effects might be heightened as a result of the duration and dosage of the stress, as well as it occurring during key sensitive developmental periods (e.g., prenatal development, infancy, puberty) or social transition periods (e.g., transition into school, transition into adulthood).
KEEP CHILDREN’S HEALTH IN THE PICTURE In these unprecedented times in our lives, we cannot forget that COVID-19 poses significant threats to children’s health, even if they are not at the highest risk for direct morbidity and mortality. The indirect and secondary consequences of this pandemic are profoundly affecting children through economic hardship, educational barriers, family stress and dysfunction, limited access to preventive health care, and increased mental health concerns. While these issues are affecting all children, those who are poor and of color are disproportionately affected.5 This pandemic is putting a magnifying glass on the root social and behavioral determinants of health disparities. Children–one of the most vulnerable groups in our society–are suffering severely. The effects will be seen now as well as into the future, as these toxic stressful experiences become embedded into the psychological and physiological matrix of the development of a generation of children. 41
Bedside: Clinical Treatment in the time of COVID-19
Epidemic Meets Pandemic: Treating Opioid Use Disorder in the Age of COVID-19 Kimberly D. Williams, M.P.H. Lee M. Pachter, D.O. Scott D. Siegel, Ph.D., M.H.C..D.S.
REGULATORY BARRIERS TO CARE FOR OPIOID USE DISORDER
CHANGES IN OUD TREATMENT POLICY DURING THE COVID-19 PANDEMIC
Years before the COVID-19 pandemic consumed the world’s attention, the opioid epidemic ravaged communities across the US. In response to the exponential rise in fatal opioid overdoses, researchers sought to develop and implement treatment strategies for individuals with opioid use disorder (OUD). Unlike COVID-19 where our treatment options are currently limited, we have evidence-based treatments for OUD that are proven to be safe and effective. Unfortunately, access to treatment for OUD remains an issue and reducing barriers to care, including current regulatory hurdles, is seen as one of the key strategies to improve health outcomes.
Though its global impact has been devastating, the COVID-19 pandemic may help us improve access to care for OUD while reducing stigma. Amid calls for social (physical) distancing to reduce disease transmission, the federal government temporarily lifted restrictions on prescribing medications to treat OUD as of March 16, 2020.5 Specifically, states may request blanket exemptions for practices to prescribe up to 28 doses of takehome medications for “clinically stable patients” and up to 14 doses of take-home medication for “less stable” patients. The status of “clinically stable” is not defined and is to be left to the provider’s clinical judgment.
Two of the pharmacological therapies that have been approved by the Food and Drug Administration (FDA) for treating OUD are methadone and buprenorphine. Methadone is a synthetic opioid agonist and buprenorphine is a partial opioid agonist. Both medications can reduce withdrawal symptoms and cravings by activating the opioid receptors in the brain. However, there is some risk of diversion (illicit use of a legally prescribed controlled substance) with these two medications. Though long-acting depot injections of buprenorphine in addition to a combination buprenorphine-naloxone (also known by the brand name, Suboxone) treatment have since been created that substantially reduce diversion risk.1 Moreover, limitations in access to treatment is actually associated with a higher likelihood of diversion.2 Methadone and buprenorphine are each classified as controlled substances and, as such, federal regulations tightly control their prescribing by providers. Methadone can only be prescribed as a daily dose that must be administered in person at a federally registered opioid treatment program facility. The Drug Addiction Treatment Act of 2000 permitted providers to treat OUD with buprenorphine in office-based settings. However, eligible providers must first complete requisite training and apply for a Drug Enforcement Administration (DEA) waiver (also known as the “X-waiver”) to obtain buprenorphine prescribing privileges which are then limited to 30, 100, or 275 patients at a given time depending on the application. These regulations not only create barriers to care in accessing methadone3 and buprenorphine,1 but they also directly contribute to the persistent stigma associated with seeking help for addiction.4 While some argue that such regulations are necessary to prevent diversion of these substances and encourage providers to prescribe responsibly, it should be noted that regulations for prescribing medications used to treat opioid addiction are in fact more restrictive than the regulations for prescribing opioids themselves. 42 Delaware Journal of Public Health – July 2020
Additionally, temporary policies have been put in place for providers to treat existing patients with OUD through telemedicine services.6 This allows for providers to remotely administer and monitor their patient’s treatment with special temporary exemptions for buprenorphine prescribing (including the initiation of treatment for both new and existing patients), thereby reducing the risk of exposure to the novel coronavirus for both patients and practitioners.7 In their letter announcing the changes in telemedicine regulations, the DEA noted that these exemptions will only be in effect during the current COVID-19 public health emergency and may be discontinued at any point prior to the end of this pandemic. But what if we learn that the benefits of fewer regulations vastly outweigh the risks of diversion? If that proves to be the case, should we not at least consider permanently lifting these restrictions? The only way to know for sure is to systematically measure the impact of loosening these regulations on treatment access and outcomes including rates of diversion and sustained recovery. This presents a prime opportunity for scientists to play a key role in the development of data-driven policy decisions.
OPPORTUNITIES TO INCREASE ACCESS TO CARE Researchers will not be able to successfully bridge the gap between evidence and practice if they attempt to seek solutions in a vacuum. Therefore, we call on research scientists to partner with key stakeholders including policymakers, public health practitioners, health care administrators, medical and behavioral health care providers, and consumers who possess personal experience with addiction treatment. Such partnerships can help ensure that we conduct a robust evaluation of these temporary measures and that our findings are more effectively translated into policy and practice. In addition, it is imperative
that a consumer-centered approach informs these efforts. By including the perspectives of individuals with lived experience with addiction treatment, we can better assure that any proposed solutions address issues and outcomes that matter most to consumers and their communities. We recommend that research evaluations explore both provider and patient experiences and outcomes with telemedicine services during the COVID-19 pandemic. Such evaluations could include: • The impact of providing naloxone (an opioid overdose reversal agent) to all patients who receive treatment for OUD through telemedicine services; • Educating providers and creating clinical decision support tools addressing the temporary regulations, including additional guidance on defining the “clinical stability” of their patients and evaluating how this may affect provider concerns regarding liability; and • The impact of supplemental social support interventions including group and other talk therapy options for individuals receiving OUD treatment through telemedicine. There are growing concerns that the COVID-19 pandemic will result in a surge in substance use including opioid use, leading to an increase in overdoses and death. While we wait and hope for the development of an effective treatment for COVID-19, let us use this time to gather the necessary data to rigorously evaluate the recent clinical and policy changes and determine if they improve access to established treatments for OUD. In doing so, we can demonstrate how policies based in evidence rather than fear and stigma can measurably improve the health and wellbeing of individuals and thus, better prepare society for the next public health crisis.
REFERENCES 1. Rosenthal, R. N., & Goradia, V. V. (2017, August 28). Advances in the delivery of buprenorphine for opioid dependence. Drug Design, Development and Therapy, 11, 2493–2505. https://doi.org/10.2147/DDDT.S72543 2. Mattick, R. P., Breen, C., Kimber, J., & Davoli, M. (2014, February 6). Buprenorphine maintenance versus placebo or methadone maintenance for opioid dependence. Cochrane Database Syst Rev, (2): CD002207. https://doi.org/10.1002/14651858.CD002207.pub4 3. McBournie, A., Duncan, A., Connolly, E., & Rising, J. (2019). Methadone barriers persist, despite decades of evidence. Health Affairs Blog. Retrieved from https://doi.org/10.1377/hblog20190920.981503 4. Wakeman, S. E., & Rich, J. D. (2018, January 28). Barriers to medications for addiction treatment: How stigma kills. Substance Use & Misuse, 53(2), 330–333. https://doi.org/10.1080/10826084.2017.1363238 5. Substance Abuse and Mental Health Services Administration. (2020). Opioid treatment program (OTP) guidance 3/16/2020 (Updated 3/19/2010). Retrieved from https://www.samhsa.gov/sites/default/files/otp-guidance-20200316.PDF 6. Drug Enforcement Administration. (2020). DEA information on telemedicine. Retrieved from https://www.samhsa.gov/sites/default/files/programs_campaigns/ medication_assisted/dea-information-telemedicine.pdf 7. Drug Enforcement Administration, & U.S. Department of Justice. (n.d.). Use of telephone evaluations to initiate buprenorphine prescribing, March 31, 2020. Retrieved from https://www.deadiversion.usdoj.gov/GDP/(DEA-DC-022) (DEA068)%20DEA%20SAMHSA%20buprenorphine%20 telemedicine%20%20(Final)%20+Esign.pdf
Bedside: Clinical Treatment in the time of COVID-19
Mental Health Crisis: Depression, Anxiety, and COVID-19 Bernard Shalit Marina Gettas, Dr.P.H., M.P.H.
In December 2019, the world began facing a threat quite unlike anything seen before. An outbreak of a novel coronavirus occurred, originating in the Wuhan district of China, caused by severe acute respiratory syndrome coronavirus 2 (SARSCoV-2).1 To date, more than 188 countries and territories have been impacted, few worse than the United States (U.S.).2 More than 2.07 million COVID-19 cases have been diagnosed in the U.S., with roughly 116,000 fatalities and 622,000 recoveries.3 The urgency associated with this pandemic has prompted a national public health response, including stay-at-home orders, mandatory quarantining, employment restrictions, and travel bans. These measures have been enforced at both the local and national levels. People are facing greater restrictions on their normal livelihood than ever before. The social and economic consequences of these measures are unparalleled in the level of disruption caused at the individual and family level.4 One of the biggest impacts that the U.S. is facing due to COVID-19 is an increase in mental illness, particularly of depression and anxiety.5 Major depressive disorder (MDD) is a mood disorder, typically episodic, characterized by symptoms of depressed mood and anhedonia lasting for at least two weeks, with specific criteria as outlined in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). Anxiety is a term that encompasses a broad range of disorders that share features such as excessive and persistent fear, worry, and/or the presence of avoidance behaviors. The DSM-5 categorizes these illnesses as broadly as generalized anxiety disorder or as precisely as specific phobias or social anxiety. Both MDD and anxiety are widely accepted to have multifactorial etiologies, with contributions from developmental, environmental, genetic, neurobiological, and psychosocial factors.6 In 2017, roughly 7.1% of U.S. adults were living with MDD and 10% described having some degree of depression every year.7 Almost 18.1% of the population, about 40 million people, live with some degree of anxiety every year.8 Depression alone costs the economy an estimated $210.5 billion annually in direct and indirect costs.9 Further data suggests that anxiety costs over $42 billion a year in direct and indirect costs.10 We expect these values to be grossly underreported, likely related to stigmatization and variable access to care, causing many to refrain from seeking help.11 A recent poll performed after the start of the COVID-19 crisis indicates as many as 50% of U.S. adults may be suffering from mental illness, particularly depression and anxiety.12 People respond to stress and change in numerous ways, which can translate into unhealthy reactions or behaviors, such as psychiatric illness, excessive substance use, and even blatant noncompliance with public health directives.13 At its worst we have seen this reflected in xenophobic behaviors and outright paranoia about the reality of coronavirus and its consequences, leading some groups to be scapegoated and inequalities more magnified than pre-coronavirus.14 44 Delaware Journal of Public Health – July 2020
The consequences of the pandemic on employment and financial stability of American households are pronounced. In a sample representative of roughly 35% of U.S. adults, nearly 26% noted having lost their job, 21% of U.S. adults have had their hours reduced, 13% have taken a pay cut, and 7% were furloughed since policies such as the quarantine and stay-at-home order were put in place.15 The combined impact of both financial and psychological destabilization, especially for low-income families or those whose households consist of individuals diagnosed with a mental disorder, will likely persist beyond the resolution of the coronavirus pandemic. These factors only serve to increase the relative risk of being diagnosed with a mental disorder such as depression or anxiety. Roughly 40% of U.S. adults have said that someone within their household has lost a job and 30% of reported having barriers to afford basic needs.15 In May 2020, the U.S. experienced a 13.3% unemployment rate, with approximately 30 million workers collecting some form of unemployment benefits.16 Due to an explosion of mental health crises, health leaders are finding an increase in risky behavior to help with coping. These issues create a concomitant rise in substance abuse, ranging from increased alcohol consumption to a dramatic rise in overdose of “hard” drugs like heroin and cocaine. Stay-at-home orders, unemployment, social isolation, and multiple other stressors can contribute to the temptation for substance users and even addicts in treatment. It was reported that alcohol sales have risen 55% since the COVID-19 lockdown began and 33% of adults were drinking while working from home. Also, there has been a 30% increase in vaping and marijuana sales since the COVID-19 lockdown.17 These behaviors generate serious risk because studies have shown that smoking, regardless of substance, significantly increases the risk of acquiring COVID-19 and reduces overall health outcomes both from COVID-19 and other diseases.5 This problem can be amplified in the homeless, a particularly vulnerable group. Approximately 500,000 people in the last decade were estimated to be homeless, living in either a formal shelter-type facility or abandoned buildings and informal encampments.18 There is up to a 50% increase in family violence since COVID-19 began because some individuals are coping with their frustration and stress by engaging in violent acts.19 Between financial difficulty, household stress, and worsening of risky coping behaviors, the mental health community has experienced a significant growth in patient population. The advantage of public health is that it draws upon the expertise of multiple healthcare disciplines and uses them to produce comprehensive recommendations that create the most benefit for communities. Dispersing recommendations across multiple modalities from health experts and ensuring their accessibility will be a major driving force in combatting these negative activities. The U.S. mental health crisis, as well as an increase in risky behavior, will leave both economic and social consequences
for the foreseeable future. This highlights the importance of the interdisciplinary and collaborative efforts of the public health workforce, prevention, and education. As public health professionals, we must be ever-vigilant about new obstacles to achieving community-wide health goals. It is difficult to imagine, but for a significant proportion of our population, access to resources like food and medication, education, and psychosocial needs are increasingly unavailable. This is partially due to excessive “hoarding” of essential household supplies.20 It is the responsibility of health experts and public health leaders to advocate for preventative policies and practice anticipating these fear-driven reactions. Tangible consequences such as rampant unemployment and poverty have destabilized normal life for many people, creating desperation and fear. Many households are already primed for this change, such as those who suffer from physical or emotional abuse, the elderly, and even young children and adolescents who cannot make sense of this dramatic social upset. Teenagers unable to attend their graduation and children unable to see their friends and engage in normal playground socialization are facing higher levels of anxiety and depression. Among our nation’s youth, particularly those who are confronted with challenges to their emotional and physical safety, the disparities in health care access, education, and learning opportunities are only further exacerbated.21 A sample of over 1200 adults indicates that, regardless of age group, at least 33% of adults felt lonelier and more isolated than before the pandemic and men were more likely to indicate loneliness than women.22 The Substance Abuse and Mental Health Services Administration’s National Helpline for people in emotional distress has received a 1,000% increase in the volume of calls during April 2020 compared to April 2019.23 While the nation’s priority is undoubtedly the wellbeing of its citizens, there is no denying the widespread uncertainty and distress associated with the sudden change in lifestyle that many are experiencing. The threat caused by this novel virus is not constricted to physical effects but extends to the social and psychological sphere as well. Although this is not the first outbreak of serious disease, the advances in social media and technology in general have contributed to the intensification of feeling “distanced” from our friends, family, and peers.24 Some groups are more at risk than others. It is clear that not only the financial stability of millions of families is jeopardized, but those who suffer from chronic disease, are afflicted with poverty, and even the geriatric age groups are all at greater risk from the secondary consequences of isolation. Many of the elderly are at higher risk for certain health problems like stroke and coronary artery disease, and the social isolation is associated with increased visits to the emergency department and more hospitalizations for non-COVID-19 related problems.25 Coordination of mental health professionals, including social workers, therapists, and psychiatrists can be used to directly interact with those affected most severely. While public health specialists in epidemiology, social science, and policy have contributed immense knowledge and analysis regarding COVID-19, there needs to be collaborative and interdisciplinary effort to identify and address the difficulties facing the population as a consequence of the disease. Although some groups may be more susceptible to the psychological changes that result from a pandemic, it is important to remember that no one is immune. Everyone has the risk of constant threat to social, economic, and physical and mental wellbeing.
As such, there are several recommendations we can make for those whose mental health has been impacted by this crisis and can have positive effects even in healthy individuals: 1. Take breaks from watching, reading, or listening to news about COVID-19.5 2. Take care of your body5: a. Eat healthy and well-balanced meals. b. Exercise regularly. Although gyms have not opened, many states are opening parks, beaches, and trails. c. Get plenty of sleep. This may require adjusting schedules to make the time to unwind and find the best ways to relax for you such as mediation or reading a book. 3. Talk to someone whether that be a professional or a confidant. Find someone you trust and talk about how you feel.5 4. Connect with others. Although social distancing protocols are in place, there are a number of ways to connect with others: telephone, video-platforms, and email.26 5. Reduce caffeine, alcohol, and substance use.5 All these things have been shown to cause more depression and anxiety.27 6. Learn how to set boundaries for yourself by saying no, pausing, and taking breaks. Understand that taking care of yourself and your mental health needs is a priority.5 Resources for COVID -19: 1. Substance Abuse and Mental Health Services Administration Emergency Helpline. Services for emotional distress, substance abuse and addiction.28 a. Text or Call: 1-800- 662- HELP (4357). Available 24 hours/ 7 days a week/ 365 days a year. 2. National Domestic Violence Hotline.29 a. Call: 1-800- 799-7233 or text “loveis” to 1866-3319474. Available 24 hours/ 7 days a week/ 365 days a year. 3. Contact your local health department for community support. a. Many health departments have social service support programs that are being funded to help relieve stress due to COVID-19.5
REFERENCES 1. World Health Organization. (2020). Naming the coronavirus disease (COVID-19) and the virus that causes it. Retrieved from World Health Organization: https://www.who.int/emergencies/diseases/novel-coronavirus-2019/ technical-guidance/naming-the-coronavirus-disease-(covid-2019)and-the-virus-that-causes-it 2. Dong, E., Du, H., & Gardner, L. (2020, May). An interactive web-based dashboard to track COVID-19 in real time. The Lancet. Infectious Diseases, 20(5), 533–534. https://doi.org/10.1016/S1473-3099(20)30120-1 45
3. Johns Hopkins University & Medicine. (2020). COVID-19 dashboard by the center for systems science and engineering (CSSE) at Johns Hopkins. Retrieved from: https://coronavirus.jhu.edu/map.html 4. The New York Times. (2020, February 29). Here comes the coronavirus pandemic. Retrieved from: https://www.nytimes.com/2020/02/29/opinion/sunday/corona-virususa.html
16. Department of Labor. U.S. Bureau of Labor Statistics. (2020, May). The employment situation-May 2020. Retrieved from: https://www.bls.gov/news.release/empsit.nr0.htm 17. Hoffman, J. (2020). Smokers and vapers may be at greater risk for COVID-19. New York: The New York Times. Retrieved from https://www.nytimes.com/2020/04/09/health/coronavirussmoking-vaping-risks.html
5. Centers for Disease Control and Prevention. (2020, April 30). Coronavirus disease 2019: Coping with stress. Retrieved from: https://www.cdc.gov/coronavirus/2019-ncov/daily-life-coping/ managing-stress-anxiety.html
18. Executive Office Of The President. The Council of Economic Advisers. (2019). The State of Homelessness in America. Washington, D.C.: Executive Office Of The President. Retrieved from https://www.whitehouse.gov/wp-content/ uploads/2019/09/The-State-of-Homelessness-in-America.pdf
6. American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.). Arlington, VA: American Psychiatric Publishing. https://doi.org/10.1176/appi.books.9780890425596
19. Campbell, A. (2020). An increasking risk of family violence during the COVID-19 pandemic: strengthening community collaborations to save lives. Forensic Science International: Reports(2), 100089. https://doi.org/10.1016/j.fsir.2020.100089
7. National Institute of Mental Health. (2019). Major depressive disorder. Retrieved from: https://www.nimh.nih.gov/health/statistics/major-depression.shtml
20. Oosterhoff, B., & Palmer, C. (2020). Psychological correlates of news monitoring, social distancing, disinfecting, and hoarding behaviors among U.S. adolescents during the COVID-19 pandemic. PsyArXiv. https://doi.org/10.31234/osf.io/rpcy4
8. Anxiety and Depression Association of America. (2019). Anxiety and depression: facts & statistics. Retrieved from: https://www.nimh.nih.gov/health/statistics/mental-illness.shtml 9. Greenberg, P. E., Fournier, A.-A., Sisitsky, T., Pike, C. T., & Kessler, R. C. (2015, February). The economic burden of adults with major depressive disorder in the United States (2005 and 2010). The Journal of Clinical Psychiatry, 76(02), 155–162. https://doi.org/10.4088/JCP.14m09298 10. Konnopka, A., & König, H. (2020, January). Economic burden of anxiety disorders: A systematic review and meta-analaysis. PharmacoEconomics, 38(1), 25–37. https://doi.org/10.1007/s40273-019-00849-7 11. National Institute of Mental Health. (2019, February). Mental illness. Retrieved from: https://www.nimh.nih.gov/health/statistics/mental-illness.shtml 12. Hamel, L., Kearney, A., Kirzinger, A., Lopes, L., Muñana, C., & Brodie, M. (2020). KFF health tracking poll- May 2020. Washington, D.C.: Kaiser Family Foundation. Retrieved from: https://www.kff.org/coronavirus-covid-19/report/kff-healthtracking-poll-may-2020/ 13. Pfefferbaum, B., & North, C. (2020). Mental health and the COVID-19 pandemic. The New England Jounral of Medicine. https://doi:10.1056/NEJMp2008017 14. Devakumar, D., Shannon, G., Bhopal, S., & Abubakar, I. (2020). Racisim and discrimination in COVID-19 Responses. Lancet, 395(10231), 1194. https://doi.org/10.1016/S0140-6736(20)30792-3 15. Kirzinger, A., Hamel, L., Cailey Muñana, A. K., & Brodie, M. (2020). KFF health tracking poll- late April 2020: Coronavirus, social distancing and contact tracing. Washington, D.C.: Kaiser Family Foundation. Retrieved from: https://www.kff.org/report-section/kff-health-tracking-poll-lateapril-2020-economic-and-mental-health-impacts-of-coronavirus/ 46 Delaware Journal of Public Health – July 2020
21. Klass, P. (2020, June 5). What’s scaring the pediatricians. Retrieved from: https://www.nytimes.com/2020/05/04/well/family/ coronavirus-pediatricians-worries-children.html 22. SocialPro. (2020). Report: Loneliness and anxiety during lockdown. New York: SocialPro. Retrieved from: https://socialpronow.com/loneliness-corona/ 23. Wan, W. (2020). The coronavirus pandemic is pushing America into a mental health crisis. Washington, D.C.: The Washington Post. Retrieved from: https://www.washingtonpost. com/health/2020/05/04/mental-health-coronavirus/ 24. Banerjee, D., & Rai, M. (2020, April 29). Social isolation in Covid-19: The impact of loneliness. The International Journal of Social Psychiatry, 20764020922269, 20764020922269. https://doi.org/10.1177/0020764020922269 25. Call, G. (2020). COVID-19 and social isolation puts elderly at risk for loneliness. Retrieved from: https://journal.ahima.org/ covid-19-and-social-isolation-puts-elderly-at-risk-for-loneliness/ 26. American Psychological Association. (2017). Stress in America: coping with change. Washington, D.C.: American Psychological Association. Retrieved from: https://www.apa.org/ news/press/releases/stress/2016/coping-with-change.pdf 27. Gorka, S. M., & Phan, K. L. (2017, August). Impact of anxiety symptoms and problematic alcohol use on error-related brain activity. Int J Psychophysiol, 118(118), 32–39. https://https://doi.org/10.1016/j.ijpsycho.2017.05.011 28. Substance Abuse and Mental Health Services Administration. (2020, April 30). National helpline: SAMHSA’s national helpline. Retrieved from: https://www.samhsa.gov/find-help/national-helpline 29. National Domestic Violence Hotline. (2020). National domestic violence hotline: get help. Retrieved from: https://www.thehotline.org/
Bedside: Clinical Treatment in the time of COVID-19
Courage, Cancer and COVID Carol Kerrigan Moore, M.S.
“Although the world is full of suffering, it is also full of the overcoming of it.” — Helen Keller So here we are, in the midst of the most accelerated, far reaching pandemic of my lifetime, COVID-19. A global public health crisis, and a time of collective anxiety for a whole assortment of different reasons. At the time of this writing, the SARS CoV-2 virus has resulted in nearly 7 million confirmed infections and 400,225 deaths worldwide. U.S. fatalities passed the 100,000 mark in May, 2020, while laboratory confirmed total cases numbered 1,891,690 as of June 6, 2020.1 The U.S. death toll remains the highest in the world. And here in Delaware, we have a reported 9,845 confirmed cases and 390 deaths.2 Each one of these “cases,” each one of these deaths, was a person, not just a number. This latest crisis comes on the heels of my own two year tumble into Cancerland. Like Alice in Wonderland’s trip down the rabbit hole. Or Dorothy’s journey from Kansas to Oz. Unfamiliar places accompanied by fear of the unknown, uncertain treatments, unexpected complications, life altering side effects, and a host of unanticipated life changes. And just when things were getting back to “normal,” following my own expedition into Cancerland, the novel coronavirus arrived. I read an article recently that talked about cancer patients now facing COVID-19 – and how a cancer diagnosis is a solitary experience of grief, at least at first – as opposed to the collective experience of a worldwide pandemic. It’s like the whole world just got cancer... I am worried, but not for myself, despite my potential status as an at-risk individual. I have concern for the world, and for those who have and will experience the worst this virus has to offer, and I feel for all those experiencing the significant sacrifices that are being made to try to “flatten the curve’ to avoid overwhelming our health systems with more patients than there are beds and staff to take care of those affected. I am concerned about those who are following directives to “shelter at home” while self-monitoring their worrisome symptoms, or waiting for COVID test results. This is a patient population that can be categorized as at-risk, since we know that respiratory status can decline insidiously and precipitously – without the usual warning signs – in patients who have the virus. I am currently sheltered from the direct impact of seeing the suffering first hand since I am no longer working in the health system and witnessing what is happening to the sickest patients inside those hospital walls. But I have seen the profound effects of previously undiagnosed COVID-19 outside the hospital setting, when I witnessed a person who was actively engaged in exercise and talking normally go into severe respiratory distress in seconds, requiring emergent care and hospital transport. 48 Delaware Journal of Public Health – July 2020
I understand the varying degrees of anxiety that health professionals and patients and the entire population may be experiencing. The fear of the unknown, and the lack of a clear roadmap to recovery, coupled with less than optimal resources, collectively exacerbate the challenges of treating a virus that we still do not fully understand. Testing availability in the U.S. lagged at the outset in comparison to many other countries, hampering our initial ability to assess who and where the outbreaks were highest. Due to the limited availability, tests were used only if patients met specific key criteria. The U.S. response to the pandemic became a patchwork quilt of each state attempting to assess the problem, plan, and compete for scarce resources. COVID-19 upended health care delivery and life as we know it. Sudden, massive, reactive change. With the resulting grief reactions. The necessary “stay at home” strategy and cancellation of elective procedures and messaging about COVID had the unintended consequences of delaying other needed care as people became fearful of going to practices or hospitals for other urgent or emergent needs. Cancer care is just one area that has been deeply affected by delays, and/or other changes in treatment plans necessitated by the pandemic response. But a cancer diagnosis offers its own adventures into confronting one’s mortality, and that, for me at least, paved the way for a different perspective when faced with another (albeit worldwide) crisis. I am not living in fear. I am living in hope. Hope that as in all crises, the helpers continue to emerge. Hope that our collective scientific wisdom and humane determination prevails. Hope that we leverage the learning from the first waves of this pandemic to foster innovations to overcome the many barriers to keeping infected patients and their caregivers and community members safe. Hope that more accessible testing, better turnaround times for results, and more effective medications and treatments will be available to help in the next waves of illness. Hope that an elevated focus on the most vulnerable populations stays at the forefront of planning and action. Hope that a safe, effective vaccine becomes a reality. Hope that the tremendous economic impact and polarizing turmoil will lessen over time. And, hope that, in the midst of it all, we are reminded of the truly important things in life. Each other. We will move through the grief and loss of life, and of life as we knew it, together. Don Berwick, M.D., a founding member of the Institute for Healthcare Improvement, and President Emeritus, has a famous saying: “Hope is not a plan.” Fortunately, we each have an unusual personal opportunity to turn hope into action in this crisis. We can follow and stay abreast of the recommended precautions, and help our family members and friends follow them too. We can wear masks, to protect each other from asymptomatic or presymptomatic spread in the community. We can practice physical distancing. We can empathize with and support those on the front
“The power we discover inside ourselves as we survive a life-threatening experience can be utilized equally well outside of crisis, too. I am, in every moment, capable of mustering the strength to survive again — or of tapping that strength in other good, productive, healthy ways.” — Michele Rosenthal lines who are testing and treating and caring for patients, with the attendant fatigue and distress that occurs due to the unending demands of an infectious disease that has spread fast enough and far enough to be a pandemic. We can be sensitive to those who have been unable to work from home due to the essential “in person” nature of their jobs, and those whose workplaces have experienced significant interruptions and, for some, closures. We can advocate for the proper equipment and resources, and work with or donate to organizations supporting marginalized and underserved individuals. We can check on friends and family and our neighbors. As a state, we can continue to identify our most vulnerable populations, and use that knowledge to guide our efforts to address the ongoing health disparities and inequities that have been magnified in this crisis. Leaders need to fully identify and engage early and often with key stakeholders during planning processes to proactively identify and resolve potential barriers, and engage in shared decision-making when implementing change.
So I’m letting go of what I cannot control, and spending time writing, researching, listening, and problem solving with friends locally and across the globe. I’m practicing self-care. I’m witnessing unprecedented levels of teamwork here in Delaware as public health officials and staff, policy makers, community members, health professionals, and concerned citizens work together to save lives. And I’m filled with gratitude that I’m still here to be able to do all of these things.
REFERENCES 1. Centers for Disease Control and Prevention. (2020). Coronavirus Disease 2019 (COVID-19). Retrieved from: https://www.cdc.gov/coronavirus/2019-ncov/cases-updates/ cases-in-us.html 2. Delaware.gov. (2020). Delaware’s Response to Coronavirus Disease (COVID-19). Retrieved from: https://coronavirus.delaware.gov/
“In every crisis, doubt or confusion, take the higher path – the path of compassion, courage, understanding and love.”
— Amit Ray
We can all listen, and fully acknowledge the social injustices that have been brought to the forefront on the backdrop of this pandemic, with their own longstanding impacts on public health. We can be agents of change. We can ACT. We can help. I am grateful to be a sounding board for my former colleagues and friends and family members as they face unprecedented change amidst the other inevitable challenges. These challenges include the collateral damage of families often not being able to be present with their hospitalized loved ones or residents of assisted living, long term care facilities, and hospices, even when they are dying. Residents of all types of communal living facilities have endured months of limited social interaction with fellow residents, family and friends—losing precious time with their loved ones, time that can never be recovered. And for months, we have lost the ability to gather together in person to mourn the many losses we are enduring…or to celebrate the major milestones in life—graduations, weddings, new babies…and the little things, like sharing a hug and an evening with friends. Everything that I have learned (often the hard way) about facing and allowing and processing the emotions and challenges that a cancer diagnosis brings, has ironically helped to prepare me for what we are now collectively facing. This novel virus has, in its own way, demonstrated with brutal clarity how interconnected we all really are: locally, nationally, and globally. 49
Bedside: Clinical Treatment in the time of COVID-19
Design of Clinical Trials Evaluating Ruxolitinib, a JAK1/JAK2 Inhibitor, for Treatment of COVID-19–Associated Cytokine Storm Peter Langmuir, M.D. Incyte Corporation Swamy Yeleswaram, Ph.D. Incyte Research Institute, Incyte Corporation Paul Smith, Ph.D. Incyte Research Institute, Incyte Corporation
Barbara Knorr, M.D. Novartis Pharmaceuticals Corporation Peg Squier, M.D., Ph.D. Incyte Corporation
ABSTRACT Recent insight into the pathophysiology of severe coronavirus disease 2019 (COVID-19) has implicated hyperactivation of the immune response, resulting in a “cytokine storm,” which can lead to excessive immune-cell infiltration of the lungs, alveolar damage, decreased lung function, and death. Several cytokines implicated in the COVID-19–associated cytokine storm predominantly signal through the Janus kinase (JAK)/signal transducer and activator of transcription pathway. Ruxolitinib is a selective inhibitor of JAK1 and JAK2 that has been explored in small studies of patients with COVID-19–associated cytokine storm. Early clinical data from these trials, combined with a body of preclinical and clinical evidence in other inflammatory conditions, support exploration of the efficacy and safety of ruxolitinib in these patients in larger, well-controlled trials. Here we describe the designs of three such ongoing clinical trials. RUXCOVID is a phase 3 randomized, double-blind, multicenter study of ruxolitinib 5 mg twice daily (BID) vs placebo (both plus standard of care) in patients with COVID-19–associated cytokine storm. 369-DEVENT is a phase 3, randomized, double-blind, placebo-controlled, multicenter study of ruxolitinib 5 or 15 mg BID vs placebo (all plus standard of care) in patients with COVID-19–associated acute respiratory distress syndrome who require mechanical ventilation. Patients with severe COVID-19–associated cytokine storm who are ineligible for these trials can receive ruxolitinib through an Expanded Access Program (EAP) in the United States and similar programs outside of the United States. RUXCOVID and 369-DEVENT will provide insight into the efficacy and safety of ruxolitinib in hospitalized patients prior to or during ventilator use. If these trials are successful, ruxolitinib could improve outcomes for patients with COVID-19 as well as lessen the overall burden on the health care system.
INTRODUCTION Coronavirus disease 2019 (COVID-19), caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has emerged as a global health crisis. Approximately 15% of patients with COVID-19 will progress to severe pneumonia, and 5% will develop acute respiratory distress syndrome (ARDS), septic shock, and/or multiple organ failure, resulting in rapid progression to death.1 Recent insight into the pathophysiology of severe infection has implicated hyperactivation of the immune response, resulting in a “cytokine storm.”2 The overproduction of pro-inflammatory cytokines leads to excessive infiltration of the lungs by immune cells, resulting in alveolar damage, decreased lung function, and, ultimately, death (Figure 1A).2,3 Several cytokines implicated in the COVID-19–associated cytokine storm signal predominantly through a key cellular pathway, the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway. Interleukin (IL)-2, IL-6, IL-7, IL-10, interferon gamma (IFN-γ), granulocyte colony-stimulating factor (G-CSF), and granulocyte-macrophage colony-stimulating factor (GM-CSF) are dependent on JAK1, JAK2, or both.5,6 Additionally, IFN-γ–induced protein 10 (IP-10/CXCL10), monocyte chemotactic protein-1 (MCP-1), and macrophage inflammatory protein (MIP)-1α are dependent on IFN-γ. The convergence of signaling of multiple pro-inflammatory cytokines 50 Delaware Journal of Public Health – July 2020
on the JAK/STAT pathway suggests that its inhibition could mitigate the hyperinflammatory state associated with severe COVID-19 (Figure 1B). Ruxolitinib (INCB018424, INC424) is a selective inhibitor of JAK1 and JAK2 approved globally for the treatment of select patients with myelofibrosis (MF), polycythemia vera (PV), and steroid-refractory acute graft-versus-host disease (SR-aGVHD).7,8 Evidence from preclinical models as well as clinical data in these and other disease states (e.g., cytokine release syndrome, hemophagocytic lymphohistiocytosis [HLH]) has shown that ruxolitinib treatment results in reduction in pro-inflammatory cytokine levels and improvement in related symptoms.9–11 Mechanistic and evidentiary support for the effect of ruxolitinib on the hyperinflammatory state led a number of independent teams across the world to test its use in patients with COVID-19– associated cytokine storm. In a small randomized trial of 43 patients in Wuhan, China, 22 patients were assigned to receive ruxolitinib plus standard of care (SoC), and 21 to placebo plus SoC.12 The primary endpoint was time to clinical improvement (2-point improvement), as measured on a 7-point ordinal scale. Although not statistically significant, patients treated with ruxolitinib had a numerically shorter time to clinical improvement compared with controls (median 12 vs 15 days). At day 14, 90% of evaluable patients treated with ruxolitinib
Adapted from Autoimmunity Reviews, 19(6), McGonagle D et al, The Role of Cytokines including Interleukin-6 in COVID-19 induced Pneumonia and Macrophage Activation SyndromeLike Disease, 102537, Crown Copyright © 2020 Published by Elsevier B.V.4
Figure 1A and Figure 1B. Pathophysiology of impact of severe COVID-19 infection on lung alveoli. A. Activation of immune response to SARSCoV-2 infection of lung cells leads to hyperproliferation of cytokines (cytokine storm); massive infiltration by immune cells follows, resulting in tissue injury and decreased lung function. B. Implicated cytokines are dependent on JAK signaling; ruxolitinib is a potent and selective inhibitor of JAK1 and JAK2 and could mitigate the hyperinflammatory state. COVID-19, coronavirus disease 2019; CSF, colony stimulating factor; GM, granulocyte-macrophage; IFN, interferon; IL, interleukin; IP, interferon-gamma induced protein; JAK, Janus kinase; MCP, monocyte chemotactic protein; MIP, microphage inflammatory protein; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; TNF, tumor necrosis factor.
showed significant improvement in chest computed tomography (CT) scans compared with 62% of patients in the placebo group (P = 0.0495). In addition, cytokine levels decreased more in the ruxolitinib group than in the control group. Among patients with fever, more rapid fever reduction (within two days) was observed with ruxolitinib than placebo (four to five days). Furthermore, no patient receiving ruxolitinib deteriorated or died, whereas four patients in the placebo group experienced clinical deterioration, and three died due to respiratory failure. The median time to virus clearance was similar between patients receiving ruxolitinib and those in the placebo group (13 vs 12 days), and there was no significant difference in viral load between treatment groups at discharge (P = 0.6). Although the patient populations are small, findings from the Wuhan study, combined with favorable outcomes in a retrospective chart review and case reports,6,13 provide early clinical support for ruxolitinib as treatment for COVID-19– associated cytokine storm. Larger, well-controlled trials are needed to fully elucidate the efficacy and safety of ruxolitinib in these patients. Here we describe the designs of three ongoing clinical trials to assess ruxolitinib in patients with COVID-19– associated cytokine storm.
METHODS Ruxolitinib is being explored for treatment of COVID-19– associated cytokine storm in two phase 3 clinical trials (RUXCOVID and 369-DEVENT) and provided to patients ineligible for these trials through an Expanded Access Program (EAP) in the United States. Each of these three studies was designed and will be implemented, executed, and reported in accordance with the International Council for Harmonisation Guidelines for Good Clinical Practice, with applicable local regulations and with the ethical principles outlined in the Declaration of Helsinki. Eligible patients may be included in a study only after providing Institutional Review Board/ Independent Ethics Committee–approved informed consent.
Patient or guardian/health proxy must provide informed consent prior to any study assessment; in the case of health proxy consent, the patient must be informed to the extent possible given their understanding.
RUXCOVID RUXCOVID is a phase 3 randomized, double-blind, placebocontrolled, multicenter study to assess the efficacy and safety of ruxolitinib in patients with COVID-19 pneumonia. Eligible patients are aged ≥12 years with confirmed SARS-CoV-2 infection and hospitalized or to be hospitalized with COVID-19 disease. Eligible patients must also meet ≥1 of the following criteria: pulmonary infiltrates (chest X-ray or CT scan), respiratory frequency ≥30/minutes, requiring supplemental oxygen, oxygen saturation ≤94% on room air, or arterial oxygen partial pressure (PaO2)/fraction of inspired oxygen (FiO2) <300 mmHg. Patients will be excluded if they have severely impaired renal function, other uncontrolled infections, current or history of active tuberculosis infection; are intubated or in an intensive care unit (ICU) for COVID-19 prior to screening; are currently intubated or intubated between screening and randomization; are in ICU at time of randomization; have evidence of liver cirrhosis; or have platelet count <50 × 109/L at screening. Approximately 402 patients will be randomized (2:1, stratified by region) to receive oral ruxolitinib 5 mg twice daily (BID) or oral matching-image placebo for 14 days (or via nasogastric tube in patients unable to ingest tablets). Dose reductions/interruptions are permitted. An additional 14 days of randomized study treatment may be given at the discretion of the investigator if the patient has not experienced clinical improvement and the potential benefit outweighs the potential risk. SoC treatment will be allowed according to investigator’s clinical judgement (e.g., supportive care, antiviral treatments, systemic corticosteroids, anticoagulants). Prohibited concomitant medications include other JAK inhibitors, aspirin doses >150 mg/day, and fluconazole >200 mg/day. Patients may discontinue treatment due to 51
Bedside: Clinical Treatment in the time of COVID-19
unacceptable toxicity or disease progression, or at the discretion of the investigator or patient. The overall study period is 29 days. The primary study endpoint, clinical failure, is a composite efficacy endpoint defined as death, respiratory failure requiring mechanical ventilation, or ICU care by day 29. Secondary endpoints, assessed on day 15 and/or day 29, include clinical status (assessed on a nine-point ordinal scale); mortality rate; proportion of patients requiring mechanical ventilation; duration of hospitalization; time either to first of discharge or to a National Early Warning Score 2 (NEWS2) score of ≤2 (uninfected or not in hospital or ready for hospital discharge) maintained for 24 hours; change from baseline in SpO2/FiO2 ratio; proportion of patients with no oxygen therapy; and treatment-related adverse events (TRAEs), serious adverse events (SAEs), and changes in laboratory parameters and vital signs. Exploratory study endpoints include time to independence from noninvasive ventilation; time to independence from oxygen therapy; duration of ICU stay; duration of supplemental oxygen; duration of invasive mechanical ventilation; proportion of patients requiring treatment with tocilizumab, canakinumab, sarilumab, or anakinra; changes in serum ferritin, CRP, D-dimer, procalcitonin, and IL-6; and change in circulating inflammatory biomarkers or other molecular signatures related to COVID-19 disease biology. This trial is a global collaboration between Incyte and Novartis, with sites recruiting in the United States, Germany, Italy, Russia, Spain, and the United Kingdom at the time of this writing. The estimated primary completion date is October 12, 2020.
369-DEVENT 369-DEVENT is a phase 3, randomized, double-blind, placebocontrolled, multicenter study to assess the efficacy and safety of ruxolitinib in patients with COVID-19–associated ARDS who require mechanical ventilation. Eligible patients are aged ≥12 years with confirmed SARS-CoV-2 infection (within two weeks of randomization), and are intubated and receiving mechanical ventilation due to COVID-19–associated ARDS. Patients must have a PaO2/FiO2 of ≤300 mmHg within 6 hours of randomization and have lung imaging (chest X-ray or CT scan) showing bilateral or diffuse pulmonary infiltrates. Patients will be excluded if they have severely impaired renal function; have other active uncontrolled infection including known active tuberculosis infection; are unlikely to survive for >24 hours from randomization; are currently receiving extracorporeal membrane oxygenation; are sharing a ventilator or coventilating with another patient; have evidence of liver cirrhosis; or have platelet count <50 × 109/L at screening. Patients are not permitted to have received treatment with anti–IL-6, IL-6R, IL-1RA, IL-1β, or GMCSF antagonists, or a Bruton’s tyrosine kinase (BTK) inhibitor, within seven days of randomization or treatment with a JAK inhibitor within 30 days of randomization. Approximately 500 patients will be randomized 2:2:1 (stratified by ARDS severity) to receive ruxolitinib 5 mg BID, ruxolitinib 15 mg BID, or matching placebo for 14 days. Dose reductions/ interruptions are permitted. Study treatment can continue for an additional 14 days at the investigator’s discretion. Medication will be provided through an enteric feeding tube after suspension in water. Patients who are extubated during the study may receive oral study treatment. All patients are eligible for SoC therapy according to the investigator’s clinical judgement (e.g., supportive 52 Delaware Journal of Public Health – July 2020
care, antiviral treatments). Treatment with concomitant JAK inhibitor or IL-6, IL-6R, IL-1RA, IL-1β, or GM-CSF antibodies; any investigational medication except antivirals being used to treat SARS-CoV-2 infection or ARDS; or aspirin >150 mg/ day is not permitted. Patients may be discontinued early from treatment due to unacceptable toxicity, progression/worsening of COVID-19 ARDS, resolution/improvement of COVID-19 symptoms, and/or at the discretion of the investigator or patient. The overall study period is 29 days. The primary study endpoint is the proportion of patients who die from any cause through day 29. Secondary endpoints include the number of ventilator-free days, ICU-free days, supplemental oxygen–free days, vasopressor-free days, and hospital-free days by day 29; clinical status (assessed on a nine-point ordinal scale) on days 15 and 29; change from baseline to days 3, 5, 8, 11, 15, and 29 in sequential organ failure assessment score; and TRAEs and SAEs, including clinically significant changes in laboratory parameters and vital signs. Exploratory study endpoints include proportion of patients requiring treatment with IL-6, IL-6R, IL-1RA, IL-1β, GM-CSF, and BTK- or JAK-directed therapies by days 15 and 29; change from baseline to days 15 and 29 in serum ferritin, CRP, D-dimer, procalcitonin, and IL-6; and change from baseline to days 15 and 29 in viral load and anti–SARS-CoV-2 antibody titer. This US-only trial is open to recruitment and has an estimated primary completion date of July 29, 2020.
EXPANDED ACCESS PROGRAM In addition to the phase 3 clinical studies, an open-label EAP has been initiated in the United States to provide ruxolitinib for the emergency treatment of cytokine storm due to COVID-19. The protocol allows eligible patients with severe COVID-19– associated cytokine storm to receive ruxolitinib while it is being investigated for this indication. To qualify for this EAP, patients must be aged ≥12 years with confirmed SARS-CoV-2 infection or clinical diagnosis of COVID-19 if testing is not available, and must be unable to participate in other clinical trials of ruxolitinib in COVID-19. Patients must have disease severity making them eligible for hospitalization, with physician-determined evidence of cytokine storm, manifesting as respiratory rate >24 breaths/ minute, SpO2 <90% on ambient air, need for medical ventilation, ARDS, and/or multiple organ failure. Patients will be excluded if they have platelet counts <50 × 109/L or inadequate liver function (alanine aminotransferase >4 × upper limit of normal [ULN] or direct bilirubin 4 × ULN and considered to be due to underlying liver dysfunction). Ruxolitinib is recommended for oral use, but can be administered through a nasogastric tube for patients unable to ingest tablets. The recommended dose of ruxolitinib is 5 mg BID in most patients. Dose reductions/interruptions are permitted. For patients with moderate renal impairment or any degree of hepatic impairment and platelet counts between 50 and 100 × 109/L, the recommended dose is 5 mg once daily. For patients on dialysis, ruxolitinib should be administered after the dialysis session. Treatment will be given for seven days, and can be extended to a maximum of 14 days if the treating physician believes that clinical benefit is observed and treatment withdrawal criteria have not been met. Patients can receive or continue any concomitant medication (except aspirin >125 mg/day or any other JAK
inhibitor), including anti-infective medications for COVID-19. Patients who require concomitant treatment with strong CYP3A inhibitors or anticoagulant/antiplatelet medications should be closely monitored. The primary objective of this program is to provide ruxolitinib for the treatment of cytokine storm due to COVID-19 in the United States. The secondary objective is to monitor the safety (SAEs) in this setting. The total number of patients and investigational sites is not prospectively defined.
DISCUSSION Encouraging results have been observed in small, single-site studies of ruxolitinib for COVID-19–associated cytokine storm. These initial positive results with ruxolitinib, coupled with the biologic rationale of JAK inhibition to ameliorate the hyperinflammatory response in this condition, led to the initiation of these large phase 3 trials, the EAP in the United States and similar Managed Access Programs globally. It is anticipated that the phase 3 trials will reach their primary completion dates this summer/fall. Based on the data from >10,000 patients treated with ruxolitinib in clinical programs for other conditions that exhibit a hyperinflammatory state similar to COVID-19 (i.e., MF, SR-aGVHD, and HLH), the primary clinical risk has been myelosuppression, which can result in anemia, thrombocytopenia, and increased infection. Cytopenias observed in patients with MF treated with ruxolitinib were dose-dependent and reversible. As COVID-19 is not a disease of the bone marrow, it is hypothesized that the myelosuppressive effects will be less pronounced in these patients. In support of this, low levels of hematologic toxicity were noted in the randomized trial conducted in Wuhan, China with a ruxolitinib dose of 5 mg BID; grade 3–4 lymphopenia occurred in one patient in each treatment group, and there were no grade 3–4 anemia, neutropenia, or thrombocytopenia events in the ruxolitinib group.12 In patients with MF and PV, ruxolitinib treatment has been associated with reactivation of herpes zoster virus, and increases in hepatitis B viral load in patients with chronic hepatitis B infections. This has led to discussion of the possibility that ruxolitinib could lead to an increase in COVID-19 viral load or decrease virus clearance. Given the low dose (≤5 mg BID in all but the most severe ventilated patients) and short course of therapy in these COVID-19 trials (seven to 14 days, with possible extension of 14 days), the anticipated risk of viral titer increase or reactivation of COVID-19 is considered to be minimal. In line with this expectation, patients in the Wuhan study who received ruxolitinib had a similar median time of virus clearance as the patients in the control group and a similar viral load at discharge. Interestingly, the mean peak level of SARS-CoV-2–specific IgM antibodies was higher in the ruxolitinib group than in the control group, while there was no between-group difference in IgG antibodies.
PUBLIC HEALTH IMPLICATIONS Ruxolitinib is not approved by the US Food and Drug Administration for use in patients with COVID-19. Insights gained from the large trials described herein may inform the optimal timing of treatment initiation and clinical characteristics
of patients most likely to respond. A recently proposed staging system of COVID-19 includes three escalating stages of infection: stage I, early infection; stage II, pulmonary phase without (IIA) and with (IIB) hypoxia; and stage III, hyperinflammation phase.14 Treatment of the first stage is primarily for symptomatic relief; however, an antiviral agent that demonstrates efficacy could provide some benefit during this early infection phase marked by mild symptoms and leukopenia. During the second stage, patients develop a viral pneumonia and bilateral infiltrates or ground glass opacities on imaging, while the immune response begins to switch from primarily viral response to primarily host inflammatory response. Patients in the second stage may experience hypoxia (PaO2/FiO2 ≤300 mmHg), which may serve as a warning sign of impending deterioration and need for ventilation; during stage II, most patients would need to be hospitalized. Patients may still be treated with antiviral therapies, and could also begin careful use of corticosteroids or immunosuppressive agents upon development of hypoxia. The third stage is marked by extrapulmonary systemic hyperinflammation syndrome, with elevated markers of systemic inflammation. Multiorgan failure would manifest during this stage, and treatment with immunomodulatory agents to reduce inflammation would be appropriate. As prognosis is poor in patients with stage III disease, limiting progression from stage IIB or rapidly recognizing and treating the systemic inflammation in stage III disease could help to reduce mortality. Importantly, RUXCOVID, 369-DEVENT, and the EAP described herein are investigating ruxolitinib in patients with stage IIB or III COVID-19 infection. Hopefully, these trials will provide insights into which clinical markers will be most useful in determining the ideal timing of treatment initiation to control the host inflammatory response while minimizing adverse events. RUXCOVID and 369-DEVENT will provide insight into the efficacy and safety of ruxolitinib in hospitalized patients prior to or during ventilator use. In these studies, ruxolitinib can be administered orally or via nasogastric tube, as required given the patient’s ventilator status. If the phase 3 trials are successful, ruxolitinib may improve outcomes for patients—fewer or shorter intubations, more rapid recovery, and/or fewer deaths—and also lessen the burden on the health care system by reducing the number of patients requiring the most resource-intensive inpatient treatments.
ABOUT INCYTE Incyte is a Wilmington, Delaware-based, global biopharmaceutical company focused on finding solutions for serious unmet medical needs through the discovery, development, and commercialization of novel medicines. Since 2002, Incyte has remained committed to the relentless pursuit of science that can improve the lives of patients and make a difference in health care. Incyte is advancing a diversified portfolio of clinical candidates across indications in Oncology and Inflammation & Autoimmunity. For additional information on Incyte, please visit Incyte.com and follow @Incyte. Incyte is providing ruxolitinib cost-free to patients with COVID-19. Questions or inquiries regarding RUXCOVID, 369-DEVENT, or the EAP should be made to U.S. Medical Information, 1-888-4MED-INFO (1-855-463-3463); email@example.com. 53
Bedside: Clinical Treatment in the time of COVID-19
ACKNOWLEDGMENTS: Medical writing assistance was provided by Beth Burke, Ph.D., CMPP, of Envision Pharma Group, and funded by Incyte Corporation.
DECLARATION OF INTERESTS: PBL, SY, PAS, and PKS are employed by and hold stock/shares in Incyte Corporation. BAK is employed by and holds stock/shares in Novartis Pharmaceuticals Corporation.
CONTRIBUTORS: All authors have made substantial contributions to the drafting the article or revising it critically for important intellectual content, and provided final approval of the version to be submitted.
REFERENCES 1. Guan, W. J., Ni, Z. Y., Hu, Y., Liang, W. H., Ou, C. Q., He, J. X., . . . Zhong, N. S., & the China Medical Treatment Expert Group for Covid-19. (2020, April 30). Clinical characteristics of coronavirus disease 2019 in China. The New England Journal of Medicine, 382(18), 1708–1720. https://doi.org/10.1056/NEJMoa2002032 2. Huang, C., Wang, Y., Li, X., Ren, L., Zhao, J., Hu, Y., . . . Cao, B. (2020, February 15). Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet, 395(10223), 497–506. https://doi.org/10.1016/S0140-6736(20)30183-5 3. Xu, Z., Shi, L., Wang, Y., Zhang, J., Huang, L., Zhang, C., . . . Wang, F. S. (2020, April). Pathological findings of COVID-19 associated with acute respiratory distress syndrome. The Lancet. Respiratory Medicine, 8(4), 420–422. https://doi.org/10.1016/S2213-2600(20)30076-X 4. McGonagle, D., Sharif, K., O’Regan, A., & Bridgewood, C. (2020, June). The role of cytokines including interleukin-6 in COVID-19 induced pneumonia and macrophage activation syndrome-like disease. Autoimmunity Reviews, 19(6), 102537. https://doi.org/10.1016/j.autrev.2020.102537 5. Stark, G. R., Cheon, H., & Wang, Y. (2018, January 2). Responses to cytokines and interferons that depend upon JAKs and STATs. Cold Spring Harbor Perspectives in Biology, 10(1), a028555. https://doi.org/10.1101/cshperspect.a028555 6. Won, C., Damsky, W., Singh, I., Joseph, P., Chichra, A., Oakland, H., . . . Chun, H. (2020, May 20). HiJAKing the SARS-CoV-2 cytokinopathy: Janus kinase inhibitors for moderate to severe COVID-19. Retrieved from https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3606658 7. Incyte Corporation. (2019, May). Jakafi (ruxolitinib) [package insert]. Wilmington, DE. 8. Novartis Pharma AG. (2019, May). Jakavi (ruxolitinib) tablets [EU summary of product characteristics]. Basel, Switzerland.
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9. Ahmed, A., Merrill, S. A., Alsawah, F., Bockenstedt, P., Campagnaro, E., Devata, S., . . . Wilcox, R. A. (2019, December). Ruxolitinib in adult patients with secondary haemophagocytic lymphohistiocytosis: An open-label, singlecentre, pilot trial. The Lancet. Haematology, 6(12), e630–e637. https://doi.org/10.1016/S2352-3026(19)30156-5 10. Quintás-Cardama, A., Vaddi, K., Liu, P., Manshouri, T., Li, J., Scherle, P. A., . . . Verstovsek, S. (2010, April 15). Preclinical characterization of the selective JAK1/2 inhibitor INCB018424: Therapeutic implications for the treatment of myeloproliferative neoplasms. Blood, 115(15), 3109–3117. https://doi.org/10.1182/blood-2009-04-214957 11. Verstovsek, S., Kantarjian, H., Mesa, R. A., Pardanani, A. D., Cortes-Franco, J., Thomas, D. A., . . . Tefferi, A. (2010, September 16). Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis. The New England Journal of Medicine, 363(12), 1117–1127. https://doi.org/10.1056/NEJMoa1002028 12. Cao, Y., Wei, J., Zou, L., Jiang, T., Wang, G., Chen, L., . . . Zhou, J. (2020, July). Ruxolitinib in treatment of severe coronavirus disease 2019 (COVID-19): A multicenter, single-blind, randomized controlled trial. The Journal of Allergy and Clinical Immunology, 146(1), 137–146.e3. https://doi.org/10.1016/j.jaci.2020.05.019 13. La Rosée, F., Bremer, H. C., Gehrke, I., Kehr, A., Hochhaus, A., Birndt, S., . . . La Rosée, P. (2020, July). The Janus kinase 1/2 inhibitor ruxolitinib in COVID-19 with severe systemic hyperinflammation. Leukemia, 34(7), 1805–1815. https://doi.org/10.1038/s41375-020-0891-0 14. Siddiqi, H. K., & Mehra, M. R. (2020, May). COVID-19 illness in native and immunosuppressed states: A clinical-therapeutic staging proposal. J Heart Lung Transplant, 39(5), 405–407. https://doi.org/10.1016/j.healun.2020.03.012
Is it COVID-19, cold, flu, or meningitis? How do you tell the difference on campus? Teens and young adults are at increased risk for meningococcal disease. Meningococcal disease is a very serious illness where death can occur in as little as a few hours. Symptoms of meningitis can be confused with other widely spread illnesses.
Take some of the guesswork out of the equation. Update your school’s vaccine policies to include a requirement for meningitis immunizations.
Sources: Centers for Disease Control and Prevention, World Health Organization
Vaccines are the most effective way to protect against certain types of bacterial meningitis. There are two types of meningococcal vaccines licensed in the United States: meningococcal conjugate vaccines (MenACWY) + Serogroup B meningococcal vaccines (MenB). For more information, visit meningitisbactionproject.org or contact us at firstname.lastname@example.org.
June 11, 2020 Subject: Request for review of student immunization requirements Dear College Health Administrator, As COVID-19 continues to have an immense public health impact in our communities, and as colleges and universities determine their plans for re-opening safely in the fall, we are writing to request that you consider reviewing and revising your institution’s immunization requirements to ensure that students are fully vaccinated against critical vaccine-preventable diseases affecting young adults. As mothers who each lost our own daughters to a vaccine-preventable disease – Meningitis B – this is an issue we know very well. Emily, 19, a college sophomore, died just 36 hours after her first symptoms. Kimberly, 17, died one week before her high school graduation. While both Emily and Kimberly had received the MenACWY vaccine, the MenB vaccine was not yet available to help protect them. It is today, and we are committed to ensuring that no other young life is unnecessarily lost to a vaccine-preventable disease. The situation: significant drop in immunization rates In a recent letter to the U.S. Department of Health and Human Services, the American Academy of Pediatrics stated their concern over reports that immunization rates among children have fallen by 60-80% during this pandemic. This decline has been attributed to the reduction in patients going to see their doctor during the COVID-19 pandemic, and not vaccine hesitancy. Why does this matter to colleges and universities? Colleges and universities should be concerned that fewer students may be returning to college with their vaccines completed on schedule – leaving students, campuses and communities vulnerable to vaccine-preventable diseases such as meningitis, measles or mumps. Additionally, given the potential for future waves of COVID-19 and the unlikelihood of a COVID19 vaccine being available this fall, ensuring that students are on schedule with all other agerelevant vaccines, including the annual seasonal influenza vaccine, can help provide herd immunity and minimize the burden on local health systems. Furthermore, symptoms of meningitis, flu, cold and COVID-19 can often be similar. See attached PDF. Requiring select vaccines on campus can help take some of the guesswork out of the equation. To address the above concerns, we strongly encourage you to review your current vaccination policies. Specifically:
56 Delaware Journal of Public Health – July 2020
1. Require MMR, Tdap, MenACWY and MenB, Influenza, Hepatitis B, HPV, Varicella and COVID-19 (when available) vaccines for all students on campus and provide relevant educational materials on prevention. Meningitis B education materials can be found here. 2. Require a comprehensive, completed immunization record for all students on campus. For those schools that already require a completed record, we encourage you to verify the forms for completion. A recent study from Brown University demonstrated that requiring a completed record of vaccination and educating on the requirement before coming to school had a positive impact on immunization rates. 3. Create/update your school’s Emergency Action Plan in the event of an outbreak. We recognize the incredible work colleges and universities are currently doing to determine how to open campuses safely and appropriately for students. It is our position that comprehensive immunizations policies are an integral part of that discussion and it is an essential time to review immunization requirements to ensure the health and wellness of students. The Emily Stillman Foundation and The Kimberly Coffey Foundation, along with our partners and supporters, are dedicated to educating about and promoting the value of strong, proactive immunization policies to support community health. We thank you in advance for your consideration and welcome the opportunity to discuss these requested measures further at your convenience. Should you have any questions, please don’t hesitate to contact us via email at email@example.com. Sincerely,
Alicia Stillman, MBA, MPH Candidate Executive Director, Emily Stillman Foundation Co-Founder, Meningitis B Action Project Farmington Hills, Michigan
Patti Wukovits, BSN, RN Executive Director, Kimberly Coffey Foundation Co-Founder, Meningitis B Action Project Massapequa Park, NY
+++ The Emily Stillman Foundation is a 501(c)3 non-profit Foundation, founded in 2014 to preserve the memory of Emily Stillman. Emily passed away in 2013 from Meningitis B before a vaccine was licensed and available in the United States. The Foundation has a trifold mission. We work to raise awareness for and encourage organ and tissue donation, educate the public and engage in policy reform about meningococcal disease as well as all vaccine-preventable diseases and we also advocate globally for health and wellness issues in underserved communities. The Kimberly Coffey Foundation, a 501(c)3 non-profit organization, was created in memory and honor of Kimberly Coffey, who tragically died from Meningitis B in 2012 before a MenB vaccine had been available in the United States to protect her. Our mission is to inform the public and healthcare professionals about meningococcal disease, including its symptoms, transmission of disease, and the importance of prevention with two types of meningococcal vaccines – MenACWY and MenB. The Meningitis B Action Project is a joint initiative by two mothers, Patti Wukovits and Alicia Stillman, who each lost their young, healthy daughters too soon to a now vaccine-preventable disease, Meningitis B. The Project works to empower young adults with information to talk to their healthcare provider about Meningitis B and the vaccine that can help prevent it, encourage healthcare providers to proactively discuss Meningitis B and the MenB vaccine with their patients and to increase awareness of Meningitis B on high school, college and university campuses.
Know.Act.Prevent | MeningitisBActionProject.org | firstname.lastname@example.org
AMERICAN ACADEMY OF PEDIATRICS (AAP) SUPPORTERS
Know.Act.Prevent | MeningitisBActionProject.org | email@example.com
58 Delaware Journal of Public Health – July 2020
Know.Act.Prevent | MeningitisBActionProject.org | firstname.lastname@example.org
Public Health: Surveillance, Mapping, and Special Populations
The Power of Public Health Surveillance Rick Hong, M.D. Rebecca Walker, Ph.D., J.D., M.S.N. Gregory Hovan Lisa Henry, M.H.S.A. Rick Pescatore, D.O. Delaware Division of Public Health
Never has an emergency battered Delaware to such public health, economic, social, and emotional extremes like the one presented by coronavirus disease 2019 (COVID-19). Strict disease mitigation strategies were led by Governor John Carney’s March 22, 2020 State of Emergency declaration that closed non-essential businesses and schools, and included a Stay-at-Home order. As of June 11, 2020, the state is experiencing fewer hospitalizations and deaths due to COVID-19. The decreasing trends in the percentage of positive COVID-19 cases and hospitalizations1 were the result of many statewide infection control measures such as closures of non-essential businesses, use of face coverings, social distancing, general hand hygiene, and community testing. As Delaware reopens in phases, the Delaware Department of Health and Social Services, Division of Public Health (DPH) – the state’s lead health agency – is conducting public health surveillance. Case investigations and contact tracing have impacted disease transmission rates by identifying those needing isolation or quarantine. These measures will continue as our society moves towards normalcy.
PUBLIC HEALTH APPROACH Public health issues are diverse and dynamic, involving many significant public health threats such as infectious diseases, chronic diseases, emergencies, injuries, and environmental health problems.2 A public health concern should be addressed by one consistent approach, similar to an all-hazards response in disaster management regardless of the type of event (Figure 1). A potential public health problem can be identified using surveillance systems to monitor health events and behaviors within communities and populations. Once identified, risk
factors leading to the problem – human behaviors, environmental factors, medical conditions, and social determinants – are evaluated. Interventions are then considered to address directly the problem or to focus indirectly on risk factors associated with the concern. For example, during COVID-19, risk factors for increased transmission and complications from disease include unknown personal status of infection or exposure, non-compliance with isolation or quarantine, inability to social distance in the home environment, chronic medical conditions, and access barriers to testing. Interventions include near real time notification of positive cases, identification and outreach to their close contacts, active monitoring of those isolated or quarantined, hotel accommodations for those who cannot comply with social distancing at home, focused public messaging for those with chronic medical conditions to follow stay-at-home orders, and community testing sites to accommodate vulnerable populations. The final step is to implement interventions and evaluate their effectiveness.
PUBLIC HEALTH CORE SCIENCES Public health requires expertise and resources to address successfully public health problems using scientific methods. Public health surveillance methods monitor a public health situation. Epidemiology is the study of distribution and determinants of health-related states among specified populations and the application of that study to the control of health problems. Epidemiologists work closely with laboratories to assist with the identification of cases through testing. Given the vast amount of data in public health surveillance and investigations, public health informatics is critical beyond timely data management to include the conceptualization, design, development, deployment, refinement, maintenance, and evaluation of communication, surveillance, information, and learning systems relevant to public health.3 Prevention effectiveness studies provide information to allow for decisionmaking regarding intervention options. The following five elements collaboratively guide DPH in its approaches to address public health issues.
PUBLIC HEALTH SURVEILLANCE Public health surveillance is the ongoing systematic collection, analysis, and interpretation of health-related data essential to planning, implementation, and evaluation of public health practice, closely integrated with the timely dissemination of these data to those responsible for prevention and control. The effectiveness of surveillance has been documented back in 1854, Figure 1. A Public Health Approach2
60 Delaware Journal of Public Health – July 2020
when Dr. John Snow, referred by many as the “father of field epidemiology,” collected information from hospital and public records to determine that contaminated water from the Broad Street pump was the cause of the cholera outbreak in Soho, London. The goal of public health surveillance is to provide information for public health personnel, government leaders, and the public to guide public health policy and programs. Uses of public health surveillance include identifying patients and their contacts for treatment and intervention of infectious diseases; detecting epidemics, health problems, and changes in health behaviors; estimating the magnitude and scope of health problems; measuring trends and characterizing disease; monitoring changes in infectious and environmental agents; assessing the effectiveness of programs and control measures; developing hypotheses; and stimulating research. The Delaware Electronic Reporting and Surveillance System is the state-based electronic surveillance system that receives information of significant public health concerns from various community partners such as hospitals, health care providers, and laboratories. DPH is directly responsible for all case investigation and contact tracing for infectious disease cases of significant public health concern. Although public health surveillance may conflict with individual liberties, public welfare must be balanced with individual needs with laws and regulations that allow the state health officer to mandate the reporting of specific diseases or conditions. It is important that the surveillance system be effective with attributes such as usefulness, data quality, timeliness, flexibility, simplicity, stability, sensitivity, predictive value positive, representativeness, and acceptability. There are two main categories of surveillance: passive and active. Passive surveillance relies on health care partners to report diseases and conditions to DPH. Although this method is simple and inexpensive, it can be limited by incompleteness of reporting based on participation and variability in data quality. Active surveillance ensures more complete reporting of diseases and conditions, as DPH directly contacts health care providers and/or patients for case information. This method is used in conjunction with specific epidemiologic investigations for an identified disease or event. To target a specific geographic area or population, DPH partners with specific health professionals to conduct sentinel surveillance. This type of public health surveillance collects data from a smaller selected group of health care providers, known as sentinel providers. Data collected and reported by sentinel providers are used to identify and quantify health events that may occur among high risk populations and provide situational awareness regarding a health event in the larger population or geographic area.4 Delaware’s COVID-19 sentinel surveillance serves as a tool to describe and monitor the spread of the virus in vulnerable populations across the state with an emphasis on mitigating the spread of the virus by identifying individuals with mild or asymptomatic infection. Sentinel surveillance of COVID-19 is an integral component of Delaware’s Reopening
Plan. The COVID-19 sentinel provider network consists primarily of Federally Qualified Health Centers and other health care providers serving vulnerable populations, as well as Long Term Care facilities. Surveillance may monitor for symptoms rather than providerdiagnosed or laboratory-confirmed cases for more timely data collection to detect, understand, and monitor health events. Known as syndromic surveillance, an example of this approach is using the Influenza-like Illness Surveillance Network (ILINet) to track cases of influenza-like illness to guide public health activity. Delaware’s COVID-19 sentinel surveillance builds on ILINet, a program conducted by the U.S. Centers for Disease Control and Prevention (CDC) and state health departments to collect influenza surveillance data from volunteer sentinel health care providers. Providers who participate in the ILINet program collect and report information about the level of influenza-like illness (ILI) currently seen in their practices. Data reported by ILINet providers, in combination with other influenza surveillance data, provide a national picture of influenza and ILI activity in the U.S.5 There are more than 2,900 ILINet sentinel providers in all 50 states, Puerto Rico, the District of Columbia, and the U.S. Virgin Islands. The advantages of using syndromic surveillance are reduced reporting burden, more timely and complete information, consistently applied criteria (e.g., CDC case definition), and year-round monitoring.6 Using symptoms for early detection allows DPH to initiate quickly public health investigations and infection control measures. For example, certain diseases such as influenza or those associated with bioterrorism may not require a laboratory-confirmed diagnosis for initial treatment. Overall, the surveillance process involves data collection, data analysis, data interpretation, data dissemination, and link to action. However, before committing to data collection, the surveillance goal must be determined. There are many data sources for public health surveillance, including provider reports of laboratory-confirmed cases or suspected syndromic cases, electronic health records such as the DHIN health information exchange platform, vital statistics records such as death certificates, health registries such as the Delaware Immunization Registry (DelVAX), and surveys. Data analysis and interpretation are closely linked; interpreting investigative information such as the person, place, and time of the case can more easily determine how and why the health event happened. Data dissemination is directed by the target audiences. For instance, health alerts inform clinicians and other health care providers, whereas press releases and social media are for the general public. Surveillance efforts must lead to an action or response, including a description of the disease burden or potential; the monitoring of trends and patterns in disease, risk factors, and agents; the detection of sudden changes in disease occurrence and distribution; the provision of data for programs, policies, and priorities; and an evaluation of prevention and control efforts. Data without a plan of action do not justify the resources invested into the initial data collection. 61
Public Health: Surveillance, Mapping, and Special Populations
PUBLIC HEALTH LABORATORY ROLE IN SURVEILLANCE DPH’s Delaware Public Health Laboratory (DPHL) has a critical role in disease surveillance programs that focus on identifying diseases in state populations. DPHL tests collected samples to identify newly emerging or recurring disease outbreaks, delivering results through shared networks used by the CDC and other state public health laboratories. Historically, DPHL has developed and implemented systems that can be quickly activated in response to critical needs related to public health surveillance. Generally, this is done by facilitating data production (test results) to assess high risk groups without causing laboratory system overloads. Scientific analysis takes anywhere from a few weeks to over 12 months, depending on the complexity and level of testing needed, to develop testing methods, validate methodology for reliability, and set up sensitive laboratory instrumentation. Once the methodology is validated and determined reliable, efforts turn to the automation of results and the production of data.
The ability to optimize turn-around times (TAT) and produce accurate data is critical to public health community response efforts. Throughout the COVID-19 pandemic, DPHL has served as a primary testing laboratory for hospitals and clinics that identified COVID-19 patients. Once DPHL developed methods and established reliability, it achieved a turnaround time for results within 24 hours of receiving the specimen. DPHL was the first laboratory in Delaware to verify CDC’s diagnostic method for detecting SARS-CoV-2 (SC2), the virus that causes COVID-19. To expand on this scientific method, it should be noted that this test calls for the performance of a high complex polymerase chain reaction (PCR) test that can only be performed by federally certified laboratorians. This high sensitivity process involves amplifying (making copies of) targeted viral RNA strands to identify SC2. The amplification process is continuously repeated until enough sample is produced to allow for a detectable fluorescent response. Once the response is detectable, laboratory instruments measure the intensity of fluorescence to produce the final test results.
Image source: John Hopkins University Source: Eisenberg, J. (2020 March 17). R0: How scientists quantify the intensity of an outbreak like coronavirus and predict the pandemic’s spread. The Conversation US. Accessed May 4, 2020 Figure 2. A Public Health Approach8 62 Delaware Journal of Public Health – July 2020
Over the last few months, the need for high-throughput automated systems became more apparent based on the projected demand for testing. Also, DPHL’s ability to re-designate instrumentation to alternative methods when needed was critical to the surveillance response as the demand for testing increased. Within this year, DPHL plans to transition to data production using sophisticated instrumentation such as the Illumina MiSeqs for “Next Generation Sequencing” to provide for more comprehensive and retrospective data centered on the identity and behavior of epidemic and pandemic organisms. The goal of this initiative is to provide information that can be utilized to better target epidemiological surveillance investigations.
CONTACT TRACING Case investigation and contract tracing are critical components to prevent further spread of infectious diseases such as COVID-19. These methods support patients with suspected or confirmed infection and potential contacts, those who have been exposed to a case or a case’s environment such that they had an opportunity to acquire the infection. Certain high-risk subpopulations, segments of the population with characteristics that increase the risk of infection or severe disease, need to be identified quickly to prevent further spread of disease. As part of the case investigation, contact tracing identifies those with close contact to positive individuals during the infectious period, the period of time during which a case is able to transmit a disease to others, as they are at higher risk of being infected, becoming infected, and potentially infecting others.7 Since those exposed may not present with evidence of infection due to the incubation period between the time of invasion by an infectious agent and appearance of the first sign or symptoms of the disease, quarantine is an effective option to limit spread of disease when implemented prior to the infectious period. DPH’s contact tracers give close contacts of COVID-19 positive persons information about the disease, education about risks and transmission, and recommendations to reduce further spread of disease, including separation from others, self-monitoring of symptoms, and other infection control measures. Identifying contacts early so they do not expose others is vital to limiting community spread, especially with the concern for asymptomatic or pre-symptomatic spread. By decreasing the reproduction number (R0), the average number of people who will contract a disease from one infected case, the disease will burn out when the each infected case causes fewer than one new infection (see Figure 2). The contact tracing process should also include monitoring for symptoms throughout the quarantine period (14 days for COVID-19).
DPH remains vigilant for any resurgence of cases that could lead to the re-implementation of strict mitigation strategies to contain the infection once again, including the closure of businesses.9 All efforts ultimately depend on how well Delawareans follow the COVID-19 guidance to prevent disease transmission.
REFERENCES 1. Delaware Department of Health and Social Services (DHSS). (n.d.). My Healthy Community. Available at: https://myhealthycommunity.dhss.delaware.gov/locations/state 2. Centers for Disease Control and Prevention. (2014). Introduction to public health. In: Public Health 101 Series. Atlanta, GA: U.S. Department of Health and Human Services, CDC; 2014. Available at: https://www.cdc.gov/publichealth101/surveillance.html 3. Magnuson, J. A., & Fu, P. C. (Eds.). (2014). Public health informatics and information systems, 2nd ed. Springer, New York, NY. 4. World Health Organization. (n.d.). Sentinel surveillance. Available at: https://www.who.int/immunization/monitoring_surveillance/burden/ vpd/surveillance_type/sentinel/en/ 5. Centers for Disease Control and Prevention. (n.d.). Influenza. Available at: https://www.cdc.gov/flu/weekly/overview.html 6. Centers for Disease Control and Prevention. (n.d.). National syndromic surveillance program. Available at: https://www.cdc.gov/nssp/partners/ilinet-collaboration.html 7. World Health Organization. (n.d.). Contact tracing. Available at: https://www.who.int/news-room/q-a-detail/contact-tracing 8. Eisenberg, J. (2020, Mar 17). R0: How scientists quantify the intensity of an outbreak like coronavirus and predict the pandemic’s spread. The Conversation. Retrieved from: https://theconversation.com/r0-how-scientists-quantify-the-intensityof-an-outbreak-like-coronavirus-and-predict-the-pandemicsspread-130777 9. Centers for Disease Control and Prevention. (n.d.). Contact tracing. Available at: https://www.cdc.gov/coronavirus/2019-ncov/php/open-america/ contact-tracing-resources.html
CONCLUSION As Delaware progresses through its reopening phases, DPH’s surveillance ensures that the public remains safe and healthy. Surveillance allows DPH to provide informed recommendations around a phased re-opening approach to best mitigate risk for re-introducing spread of the virus throughout the community. 63
Public Health: Surveillance, Mapping, and Special Populations
A Need for Contact Tracing Research Stephanie Shell, M.S.S. Senior Director, Strategy Development, Public Health Management Corporation
It has now been four months since the first known case of COVID-19 was detected in the US and we have reached a tipping point. Behind us is the initial panic, depletion of resources, and surge in case numbers, ahead of us is a long road to recovery, one for which we do not have a road map. As public health experts and state officials in Delaware work through a plan for the state to safely reopen, weighing considerations of health against those of economics, it has become clear that contact tracing will play an insurmountable role in ensuring public safety and disease mitigation during the reopening phase. Contact tracing is a process that involves identifying and seeking out individuals who may have been exposed to a disease through contact with an infected person.1 Initially, a newly confirmed case will be contacted by a public health official, a ‘contact tracer,’ who will ask for a list of individuals with whom that person might have come into close contact during their contagious phase. Contact tracers then reach out to exposed individuals and ask them to self-quarantine and monitor their own symptoms for, in the case of COVID-19, two weeks following the date of exposure. This ensures that those exposed persons are aware of the risks their exposure presents and that they will not go on to spread the disease if they did indeed contract it from the infected individual. Contact tracing is an essential practice when trying to flatten the curve of a disease outbreak and can help hugely in bringing down the R0 value (the number of people to whom each infected person goes on to spread the disease).1 It is practiced routinely when dealing with several other diseases, including sexually transmitted infections and the Ebola Virus Disease (EVD).2,3 While models of contact tracing vary based on the mode of transmission and the contagiousness of the disease in question, their study is useful, allowing us to construct policies and determine best practices for future disease outbreaks. For the purposes of COVID-19, the best model we can look to is that which is used to combat EVD. The EVD contact tracing framework, developed by the World Health Organization (WHO) and implemented in West Africa at the epicenter of the outbreak, utilized health professionals who were trusted in the community to identify, trace, and isolate potential EVD contacts.2 The model lays out clear criteria to classify exposure and ensures follow-up with contacts for 21 days following a potential exposure, working efficiently to halt the spread of disease. EVD, unlike COVID-19, is spread through the transfer of bodily fluids and can take several days, sometimes up to 3 weeks, for symptoms to onset. Moreover, EVD’s high morbidity and mortality rates made contact tracing imperative to curb the spread of disease.4 Where the contact tracing approach for the novel coronavirus must differ results from the sheer number of cases to be tracked, as well as the presentation of the disease itself. Delaware alone has seen over 10,000 confirmed cases to date, a number we know to be an underestimate due to a lack of testing available in the initial stages of the disease spread.5 Moreover, because of the number of people who are either asymptomatic or experience only mild symptoms, it is significantly harder to identify cases of COVID-19 than EVD.6 Indeed, studies conducted in Wuhan, China and on an Australian cruise ship showed the percentage of asymptomatic 64 Delaware Journal of Public Health – July 2020
cases to be 42% and 81% of all cases respectively.7,8 Thus, in order to effectively tackle these hurdles, we must disperse contact tracing teams throughout the state. Contact tracing teams are made up of contact tracers, disease intervention specialists (DIS), and epidemiologists. Contact tracers may be laypeople and participate in the brunt of the contact tracing labor; that is, identifying and contacting exposed persons.1 DIS oversee contact tracers in clustered geographic locations, and epidemiologists oversee DIS, taking a highlevel view of the disease spread. In the case of COVID-19, the number of contact tracers, disease intervention specialists, and epidemiologists needed to effectively perform contact tracing across the country is unprecedented. According to a recent report from Johns Hopkins University, Wuhan, China, employed 9,000 contact tracers for a city of 11 million — that’s one contact tracer for roughly every 1,222 people.9 Applying that same ratio to Delaware, with upwards of 973,000 residents, would mean hiring and training a team of nearly 800 contact tracers. The reality we are seeing is job postings for upwards of 200 contact tracers across the state. While this is certainly a large undertaking, it comes at a time when many Delaware residents are unemployed; ready and willing to rise to the task. Primary purpose aside, COVID-19 contact tracing also presents Delaware with rare research opportunities. Contact tracing on this magnitude has never been attempted and as a result we are entering this process with limited knowledge on best policies and practices. Knowledge from small-scale contact tracing efforts has Vcertainly been important as a basis for our primary response in this field, however, as time moves on, it will become imperative that we have research conducted on contact tracing in the COVID-19 pandemic itself. This will allow public health officials to make empirically sound recommendations for the distribution of funds and resources throughout the state. This research will inevitably take many forms, and will hopefully lead to new and strengthened partnerships between research institutions and local government. Research into contact tracing will allow Delaware, and the rest of the US, to determine how to best reach potentially exposed persons, share information about the pandemic and risks incurred through exposure without inciting excess fear, and enforce self-quarantine and self-isolation to halt the spread of disease. This information will be especially necessary when looking at low-income and hard to reach populations who might not have stable phone access or permanent addresses. In addition, the pandemic presents a unique opportunity for contact tracers and researchers to address other aspects of social determinants of health. With thousands of people’s health data being tracked over time, we will have the chance to view public health trends on an unprecedented scale. While in the past it has been difficult to obtain and utilize comprehensive health data due to regulations and closed data agreements, COVID-19 contact tracing may present an opportunity for this field to open. If contact tracers were to ask a short series of questions relating to people’s general health at the end of each outreach call, they would not only be able to link those callers to necessary services
but, with consent, pass that data back to public health researchers. This would allow for study of the pandemic’s impact on mental health, its effects on people accessing basic needs, and other social determinants of health research. It would be remiss to not examine the positive impacts that comprehensive public health data sets gathered through contact tracing efforts could have on our communities. The future effects of the COVID-19 pandemic on the Delaware community tie closely with our ability to mobilize a large-scale contact tracing effort across the state. It is up to us, public health professionals, to make the most of this opportunity and learn more about the populations we serve. We have the chance to not only halt the spread of disease, but to better understand where public health practices are falling short. It is time for us to open the world of data and loosen regulations, so that we can fully utilize the wealth of information gained from the pandemic to help improve the health and happiness of all Delaware communities.
REFERENCES 1. Centers for Disease Control and Prevention. (n.d.). Contact tracing. Retrieved from https://www.cdc.gov/coronavirus/2019ncov/php/principles-contact-tracing.html 2. World Health Organization. (2015, Sep). Implementation and management of contact tracing for Ebola virus disease. Retrieved from: https://apps.who.int/iris/bitstream/handle/10665/185258/WHO_EVD_Guidance_Contact_15.1_eng.pdf;jsessionid=D46A3D57DDB1EE086612E2CC9790B8CD?sequence=1
3. National Coalition of STD Directors. (n.d.). Sexually transmitted disease contact tracing. Retrieved from: https://www.ncsddc.org/wp-content/uploads/2017/08/infographic_5-26-16.pdf 4. Swanson, K. C., Altare, C., Wesseh, C. S., Nyenswah, T., Ahmed, T., Eyal, N., . . . Altmann, M. (2018, September 12). Contact tracing performance during the Ebola epidemic in Liberia, 2014-2015. PLoS Neglected Tropical Diseases, 12(9), e0006762. PubMed https://doi.org/10.1371/journal.pntd.0006762 5. My Healthy Community. (n.d.). Number of Positive COVID-19 Cases. Retrieved from: https://myhealthycommunity.dhss.delaware.gov/locations/state#cases 6. Van Beusekom, M. (2020, Apr 27). Study: many asymptomatic COVID-19 cases undetected. Center for Infectious Disease Research and Policy. Retrieved from: https://www.cidrap.umn. edu/news-perspective/2020/04/study-many-asymptomatic-covid-19cases-undetected 7. Yang, R., Gui, X., & Xiong, Y. (2020, May 1). Comparison of clinical characteristics of patients with asymptomatic vs symptomatic coronavirus disease 2019 in Wuhan, China. JAMA Network Open, 3(5), e2010182–e2010182. https://doi.org/10.1001/jamanetworkopen.2020.10182 8. Ing, A. J., Cocks, C., & Green, J. P. (2020). COVID-19: in the footsteps of Ernest Shackleton. Thorax. 9. Watson, C., Cicero, A., Blumenstock, J., & Fraser, M. (2020). A national plan to enable comprehensive COVID-19 case finding and contact tracing in the US. Johns Hopkins Center for Health Security. Retrieved from: https://www.centerforhealthsecurity.org/ our-work/pubs_archive/pubs-pdfs/2020/200410-national-plan-to-contact-tracing.pdf
Public Health: Surveillance, Mapping, and Special Populations
Mapping the ChristianaCare response to COVID-19: Clinical insights from the Value Institute’s Geospatial Analytics Core Madeline Brooks, M.P.H. Chenesia Brown, M.A., Ph.D.(c) Wei Liu, Ph.D. Scott D. Siegel, Ph.D., M.H.C.D.S.
ABSTRACT Introduction: COVID-19 exemplifies the spatial nature of infectious disease in both its mechanism of transmission and the community-level conditions that facilitate its spread. With a long history of use for infectious disease applications, maps and geographic information systems (GIS) have been widely used in recent months for surveillance and risk prediction mapping. The Value Institute’s Geospatial Analytics Core applied spatial methodologies to inform ChristianaCare’s pandemic response around telehealth, testing disparities, and test site prioritization. Methods: Descriptive data related to disparities in telehealth utilization were mapped to identify areas in which intervention is needed to increase telehealth access. Cluster detection methodology was used to identify “hot” and “cold” spots for COVID-19 testing by place and race across New Castle County, DE. A composite risk score was created to prioritize communities for testing sites. All analyses took place in Delaware from March-June 2020, with particular emphasis on New Castle County. Results: Parts of northeastern New Castle County and western Sussex County were highlighted for intervention to increase broadband internet access for telehealth utilization. “Cold” spots for COVID-19 testing were found in New Castle County, indicating neighborhoods in which testing levels were significantly lower than expected. Data for testing levels, disease positivity, and socioeconomic risk factors were used to identify communities in northeastern New Castle County that warranted new test sites to mitigate disease spread. Public Health Implications: Geospatial methodologies can be used to combine electronic health record data and population-level spatial data for pandemic response efforts. This allows health systems to confidently identify areas of need while mitigating disparities in resource allocation.
BACKGROUND COVID-19 exemplifies the spatial nature of infectious disease in both its mechanism of transmission and the communitylevel conditions that facilitate its spread. Among individuals, COVID-19 is transmitted via respiratory droplets spread in close contact to others and through aerosolized transport.1 Across neighborhoods and counties, the disease has spread more rapidly where high residential density, large proportions of residents who work in essential service occupations, and low socioeconomic status (SES) undermine people’s capacity to practice social distancing.2,3 Data from across the U.S. show that Black and Hispanic/Latino/a populations have borne the brunt of the pandemic.4 Although further research is needed to understand this disparity, the emerging evidence strongly points to structural inequalities that place these racial and ethnic groups at greater health, economic, and social risk than their White counterparts.5 That is, longstanding racist and other discriminatory policies have contributed to inadequate health care access, poor housing and occupational conditions, and a general lack of financial safety nets for racial and ethnic minority groups,6–8 which is today manifesting as higher rates of COVID-19 morbidity and mortality.9,10 66 Delaware Journal of Public Health – July 2020
The spatial nature of COVID-19 can be understood by utilizing geographic information systems (GIS) to create maps and inform tracking and response efforts. With a long history of use for infectious disease applications, GIS have been used in recent months for COVID-19 surveillance, risk prediction mapping, and analyses of mobility data to track social distancing.3,11 The Value Institute’s Geospatial Analytics Core has applied spatial methodologies to inform ChristianaCare’s response to the current pandemic. Established in 2017, the Geospatial Analytics Core uses GIS and inferential spatial statistics to not only create maps, but to ‘go beyond the map’ and estimate relationships between exposures that vary spatially and important health outcomes. Within health care, these methods can be used to segment patient populations by geography, measure proximity to health care providers, and study environmental determinants of health such as air quality or access to healthy food. Before the pandemic, the Geospatial Analytics Core at ChristianaCare was developed primarily to study noncommunicable chronic conditions. However, during this “all hands on deck” moment, we quickly pivoted to apply spatial methodologies to three chief priorities during the early months of the COVID pandemic. First, as providers adopt telehealth to ensure continuation of care delivery while allowing patients to social distance, additional resources may be needed to serve
areas with limited broadband internet access. Second, there was a need to examine potential spatial or racial disparities in testing by examining “cold spots,” or areas where testing is significantly lower than expected, particularly in predominant minority neighborhoods. Finally, ChristianaCare and New Castle County (NCC) were tasked with identifying communities for immediate prioritization during an expanded COVID-19 testing effort that commenced in June 2020.
METHODS Telehealth Descriptive data related to disparities in telehealth access were obtained for Delaware census tracts from the U.S. Census Bureau and the Centers for Disease Control and Prevention (CDC). These included the percentage of households lacking broadband internet access,12 the percentage racial minority population,12 and the CDC’s socioeconomic vulnerability ranking. The socioeconomic vulnerability ranking is a domain within the CDC’s Social Vulnerability Index that ranks census tracts within states for vulnerability based on poverty, unemployment, income, and education.13 These three measures were depicted as choropleth maps using natural breaks classification, a method that minimizes variation within each class. The maps were compared side-by-side to identify geographic trends suggesting barriers to telehealth services.
Disparities in Testing Access We used cluster detection methodology to identify potential racial disparities in testing levels by census tract for New Castle County adults. Areas with testing levels significantly higher or lower than the rest of the county were considered “hot” and “cold” spots, respectively. A hot or cold spot, known as a cluster, is a set of contiguous geographic units in which their combined rates represent a large departure from the average across the map area. SaTScanTM, a common cluster detection software, was used to determine if testing was spread evenly across New Castle County after accounting for underlying population size.14 These analyses were also adjusted for the race of tested individuals, meaning that any clusters were assessed relative to countywide testing levels by race. SaTScan methodology assumes that test counts by race are distributed by census tract proportional to each tract’s share of the county population by racial group. The program uses a likelihood ratio statistic to gauge the discrepancy between observed and expected test counts and generates a p-value using Monte Carlo simulations. We performed cluster detection to identify hot or cold spots for testing using a dataset of people who received COVID-19 testing from ChristianaCare between March 16thApril 16th (N=5421).
Identifying Areas for Testing Prioritization In order to consider multiple indicators of COVID-19 morbidity and mortality that reflect greater need for testing, we calculated a census tract-level prioritization score that incorporated (1) testing levels, (2) positivity rates, and (3) socioeconomic risk factors using data from ChristianaCare, the U.S. Census Bureau, and the CDC.
Testing Levels We calculated the proportion of tested adults at the census tract level using a dataset of adult New Castle County, DE residents who received COVID-19 testing from ChristianaCare between March 16th and May 6th (N=9,111). Duplicate records were
removed so that unique patients were represented only once in the testing dataset. Records were geocoded according to their home address (i.e., represented as a point on a map) and aggregated to the census tracts in which they reside. Testing levels were calculated as the number of tests per 100,000 adult residents. The population denominator data were obtained from 2018 U.S. Census Bureau estimates.12
Positivity Levels Positivity levels by census tract were calculated using the same dataset of adult New Castle County residents tested by ChristianaCare from March 16th-May 6th. Positivity levels were calculated as the percentage of positive test results among all tested adults for each census tract.
Socioeconomic Risk Factors A social risk composite score was calculated using demographic and socioeconomic variables to assess risk of rapid transmission. Our risk score components included percentage racial or ethnic minority population12; percentage of people employed in service occupations, such as health care support, protective services, and food preparation12; percentage of households with more than one person per room (a common measure of overcrowding)12; and the CDC’s socioeconomic vulnerability ranking referenced above. The distributions of each variable were examined and used to assign a score of 2 (high risk), 1 (moderate risk), or 0 (low risk) based on census tracts’ values for each. We weighted our score to reflect greater risk for census tracts that had both high racial/ ethnic minority populations and socioeconomic vulnerability. The final social risk score ranged from 0-11, with higher scores indicating greater risk.
Prioritization Criteria Census tracts were prioritized for testing by first flagging those with positivity rates >15% based on World Health Organization (WHO) guidance stating that positivity rates >10% suggest undertesting.15 Next, these tracts to were filtered to include only those with social risk scores >=5 (above the median value). The final list of census tracts was rank-ordered from lowest to highest testing levels to identify the top 30 tracts for prioritization, based on the NCC capacity to conduct testing in June 2020.
RESULTS Telehealth Figure 1 depicts choropleth maps of broadband internet access, racial minority populations, and socioeconomic vulnerability for New Castle County. The percentage of households lacking access to broadband internet was elevated in northeastern New Castle County, stretching from Claymont to southeastern Newark. In some eastern and south-central Wilmington neighborhoods, 37-65% of households lacked broadband access. Kent and Sussex counties had lower levels of broadband access compared to northwestern and southern New Castle County. Broadband access was relatively even across Kent County, but lack of broadband was more pronounced in southwestern Sussex County. These trends generally overlapped with data for racial minority populations and socioeconomic vulnerability, most prominently in northeastern New Castle County. This suggests inequities in telehealth access that could create and widen health disparities during the COVID-19 pandemic unless interventions are developed to increase access to broadband internet and technology. 67
Public Health: Surveillance, Mapping, and Special Populations Figure 1. Choropleth maps of broadband internet access, racial minority populations, and socioeconomic vulnerability for New Castle County.
Disparities in Testing Access Using geocoded data for unique tested adults in New Castle County, 5,421 tests were conducted from March 16-April 16. Cluster detection found four statistically significant testing cold spots in southern Newark, north Wilmington/Claymont, east Wilmington’s Riverside neighborhood, and northeastern Smyrna (p-values <0.001) (see Figure 2). Special attention was paid to Riverside and northeast Smyrna because they have large minority communities. The adult populations of Riverside and northeast Smyrna are 70% and 44% African American, respectively.12 Overall adult testing rates in Riverside and northeast Smyrna were 44% and 11%, respectively, of what would expected if testing was distributed proportionally by population and adjusting for race. In Riverside, the overall testing levels were slightly more than half (7/1000 adults) of what were observed for New Castle County (12.5/1000 adults).
Identifying Areas for Testing Prioritization We identified six census tracts for first priority testing in early June and another 24 for second priority testing in mid-June (Figure 3). The first priority group included neighborhoods in north-central New Castle County that ranged from southeastern Newark to northeast Wilmington. Three of the first priority census tracts were concentrated around Elsmere. The second priority census tracts covered the northeastern part of the county, primarily around southern Newark and the Route 9 corridor in New Castle. All three risk indicators used to prioritize testing – testing levels, positivity rates, and social risk scores – were positively correlated with each other (testing and positivity, r=0.18; testing and social risk, r=0.55; positivity and social risk, r=0.24; all p-values <0.05). 68 Delaware Journal of Public Health – July 2020
Figure 2. Testing Cold Spots
DISCUSSION These results demonstrate but only a few of the many possible ways GIS can be used to inform health system responses to the COVID-19 pandemic. First, public data sources were mapped to identify areas which may face barriers to telehealth access. These data were used in support of an application for a $714,00 grant from the Federal Communications Commission (FCC), which ChristianaCare will use to expand its telehealth program by providing patients with broadband internet subscriptions and devices.16 This has the potential to narrow geographic disparities in telehealth utilization during a prolonged period of social distancing,17 which can be subsequently evaluated with GIS methods. Next, the cluster detection and testing prioritization strategy show how different criteria can be used to examine testing levels over time and inform resource allocation. The March-April cluster detection results showed hot and cold spots in which testing levels significantly differed from the county average. While cold spots were detected in northeastern New Castle County and around Newark, these represent generally affluent and predominantly White communities, and neither were considered high-priority areas for testing in the ranking that incorporated positivity levels and social risk scores. In contrast, the Riverside cold spot was identified as a “priority 1” site for testing, which warrants additional concern. In response to these results, ChristianaCare began offering COVID screening appointments at Riverside’s Kingswood Community Center in late April.18
The Riverside and Smyrna cold spots were each comprised of single census tracts adjacent to testing hot spots. The existence of these small cold spots in larger areas which had adequate or high levels of testing suggests unique barriers for their residents in accessing testing. Riverside is a geographically isolated neighborhood, bordered by Route 13, the Brandywine creek, and the Amtrak railroad. Northeast Smyrna is more rural and located at the bottom of New Castle County. Its close proximity to the county border suggests that its residents may have had more spatially accessible testing from Kent County providers. The cluster detection analyses will be repeated at a later date to determine if increased provision of testing reduced or eliminated New Castle County cold spots. The strategy of prioritizing communities for testing provides an example of how health systems can make informed decisions using patient-level electronic health record data as well as population data from public sources like the Census Bureau. This allowed ChristianaCare to more confidently triangulate highrisk areas for COVID transmission and make recommendations for effective and equitable use of testing resources by placing them where the need is greatest. The correlations between testing levels, positivity rates, and social risk scores suggests that our prioritization criteria identified similar areas of need while providing unique information. These analyses must considered in light of a few key limitations. The telehealth maps relied on publicly available data that do not include individual-level indicators of telehealth usage.
Testing Prioity Groups
Tract 003002 (Wilmington – Landlith/Riverside)
Tract 012300 (Elsmere – Lancaster Village/Silverbrook Gardens) Tract 012000 (Wilmington – Alberson Park) Tract 012600 (Wilmington – Bestfield/Gordey Estates)
Tract 013700 (Newark – Delaplane Manor/Roseville Park)
Tract 013904 (Newark – Christiana/Varlano)
Figure 3. Census Tracts for Priority Testing 69
Public Health: Surveillance, Mapping, and Special Populations
Investigators should avoid making inferences about an individual’s access to telehealth services based solely on where they live. The cluster detection analyses used testing data from only one health care provider over a one-month period and do not reflect testing conducted by other providers, which may spatially differ from those administered by ChristianaCare. Similarly, only ChristianaCare data were used in determining areas in which to prioritize additional testing, and may fail to identify areas in which other providers have delivered sufficient levels of testing. The consideration of positivity levels reflects only those who have been tested, and the social risk score may not account for all variables associated with rapid spread of COVID-19. Despite these limitations, the use of multiple spatial methodologies allows us to identify broad trends in access to care that can mitigate the transmission and negative sequelae of COVID-19. Together, these findings demonstrate the value of spatial methodologies not only for traditional disease surveillance, but also to inform resource allocation and narrow racial and economic health disparities by ensuring equitable access to care.
PUBLIC HEALTH IMPLICATIONS Geospatial methodologies can be used to combine electronic health record data and population-level spatial data for pandemic response efforts. This allows health systems to more confidently identify areas of need while mitigating disparities in resource allocation.
ACKNOWLEDGEMENTS The authors would like to thank Frank Curriero, Ph.D. for consulting on the development of the Geospatial Analytics Core and for his contributions to this manuscript. We also thank Matthew Meyer; Erin Booker, LPC; Jacqueline Ortiz, MPhil; LeRoi Hicks, M.D., M.P.H.; Mia Papas, Ph.D., M.S.; and Rose Kakoza, M.D., M.P.H. for their service to New Castle County residents by working to create equitable access to testing. Geospatial Analytics Core activities were supported by the Delaware INBRE program, with a grant from the National Institute of General Medical Sciences – NIGMS (P20 GM103446) from the National Institutes of Health and the State of Delaware.
6. Edelman, E. J., Aoun-Barakat, L., Villanueva, M., & Friedland, G. (2020, July). Confronting another pandemic: Lessons from: HIV can inform our COVID-19 response. AIDS and Behavior, 24(7), 1977–1979. https://doi.org/10.1007/s10461-020-02908-z 7. Kalabikhina, I. (2020). Demographic and social issues of the pandemic. Population and Economics, 4(2), 103. https://doi.org/10.3897/popecon.4.e53891 8. Souch, J. M., & Cossman, J. S. (2020, April 13). A commentary on rural-urban disparities in COVID-19 testing rates per 100,000 and risk factors. J Rural Health, 9, 1–6. https://doi.org/10.1111/jrh.12450 9. Kim, S. J., & Bostwick, W. (2020, August). Social vulnerability and racial inequality in COVID-19 deaths in Chicago. Health Educ Behav, 47(4), 509–513. https://doi.org/10.1177/1090198120929677 10. Yu, Q., Salvador, C. E., Melani, I., Berg, M. K., & Kitayama, S. (2020). The lethal spiral: Racial segregation and economic disparity jointly exacerbate the COVID-19 fatality in large American cities. PsyArXiv. https://doi.org/10.31234/osf.io/xgbpy 11. Kamel Boulos, M. N., & Geraghty, E. M. (2020, March 11). Geographical tracking and mapping of coronavirus disease COVID-19/severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) epidemic and associated events around the world: How 21st century GIS technologies are supporting the global fight against outbreaks and epidemics. International Journal of Health Geographics, 19(1), 8. https://doi.org/10.1186/s12942-020-00202-8 12. U.S. Census Bureau. (2018). 2014-2018 American community survey 5-year estimates. Retrieved from: https://data.census.gov/cedsci/ 13. Centers for Disease Control and Prevention. (2018). Social Vulnerability Index 2018 database. Retrieved from: https://svi.cdc.gov/data-and-tools-download.html 14. Kulldorf, M. and Information Management Services, I. (2009). SaTScan v8.0: Software for the spatial and space-time scan statistics. Retrieved from: https://www.satscan.org/
1. Anderson, E. L., Turnham, P., Griffin, J. R., & Clarke, C. C. (2020, May). Consideration of the aerosol transmission for COVID-19 and public health. Risk Anal, 40(5), 902–907. https://doi.org/10.1111/risa.13500
15. Aubrey, A. (2020). Which states are doing enough testing? This benchmark helps settle the debate. NPR. Retrieved from: https://www.npr.org/sections/health-shots/2020/04/22/840526338/ is-the-u-s-testing-enough-for-covid-19-as-debate-rages-on-hereshow-to-know
2. Carrion, D., Colicino, E., Foppa Pedretti, N., Rush, J., DeFelice, N., & Just, A. C. (2020). Assessing capacity to social distance and neighborhood-level health disparities during the COVID-19 pandemic. MedRxiv. https://doi.org/https://doi.org/10.1101/2020.06.02.20120790
16. ChristianaCare. (2020). ChristianaCare awarded FCC grant to expand COVID-19 telemedicine program. Retrieved from: ChristianaCare News website: https://news.christianacare. org/2020/04/christianacare-awarded-fcc-grant-to-expand-covid-19telemedicine-program/
3. Henry-Nickie, M., & Hudak, J. (2020). Social distancing in Black and white neighborhoods in Detroit: A data-driven look at vulnerable communities. 1–10.
17. Velasquez, D., & Mehrotra, A. (2020). Ensuring the growth of telehealth during COVID-19 does not exacerbate disparities in care. Retrieved from Health Affairs Blog website: https://www. healthaffairs.org/do/10.1377/hblog20200505.591306/full/
4. Yancy, C. W. (2020, April 15). COVID-19 and African Americans. JAMA, 60611, 11–12. https://doi.org/10.1001/jama.2020.6548 5. Artiga, S., Garfield, R., & Orgera, K. (2020). Communities of color at higher risk for health and economic challenges due to COVID-19. 1–13. 70 Delaware Journal of Public Health – July 2020
18. Schmitt, B. (2020). ChristianaCare expands COVID-19 testing for communities in City of Wilmington. Retrieved from ChristianaCare News website: https://news.christianacare. org/pressrelease/christianacare-expands-covid-19-testing-forcommunities-in-city-of-wilmington/
NATION’S HEALTH A P U B L I C AT I O N O F T H E A M E R I C A N P U B L I C H E A LT H A S S O C I AT I O N
July 2020 The Association recognizes the hard work of public health professionals everywhere, especially during this incredibly trying and painful time for our nation. We encourage you to share APHA’s most up-to-date COVID-19 resources and information, read our statement on racism and use our racism and health info as you join in the chorus for justice and ring an alarm to all Americans. Among many current resources, we’re pleased to offer our Advancing Racial Equity webinar series [ this summer and to continue our COVID-19 Conversations webinar series. Check out these highlights for the July 2020 issue: How will COVID-19 reshape future of US public health? As awareness of public health grows during the pandemic, U.S. health leaders hope it will translate into appreciation for the field and more federal funding. Experts fear suicide, deaths of despair will rise in wake of COVID-19. If public health measures are not put in place, an estimated 75,000 additional U.S. deaths of despair will be associated with the COVID-19 pandemic over the next decade. Local, state agencies using contact tracing to halt coronavirus spread. Local and state governments have taken the lead in hiring people to do COVID-19 contact tracing in the U.S. About 100,000 additional tracers are needed nationwide to meet the demand. Improving the health of American Indians and Alaska Natives: Q&A with new IHS director. Though health improvements have been made in American Indian and Alaska Native populations, deaths of despair and coronavirus remain issues in some regions. Virtual health care escalates during pandemic. As telehealth grows, health care professionals explore how virtual visits can be balanced with in-person visits and examine whether telehealth is increasing inequity. Report: Underfunding public health leaves many gaps in preventive care. Gaps in the U.S. public health infrastructure because of chronic federal underfunding have been cited as one of the reasons for the spread of COVID-19 in the nation this year. Healthy You: Get the most out of food by composting your waste. Food scraps make up a third of all things we throw away. But instead of sending them to rot in a landfill, there’s a better option: recycling and reusing them through composting. Read Healthy You online. Study: Decriminalizing marijuana lowers arrests of Blacks. Arrests for low-level offenses can create a pipeline to jail or prison for Blacks, impinging on their future earning potential, health and well-being. Study: Delaying school start time can reduce sleep deprivation among teens. By pushing back when classes start in the morning at schools, teens get more sleep. Sleep deprivation can harm physical health and mental health, including learning and memory.
Public Health: Surveillance, Mapping, and Special Populations
Social Determinants of Health, From Assessment to Action: A Review of 3 Studies from the Value Institute at ChristianaCare Cecelia Harrison, M.P.H. Madeline Brooks, M.P.H. Jennifer N. Goldstein, M.D., M.Sc., The Value Institute, ChristianaCare
ABSTRACT Introduction: The COVID-19 crisis highlights the importance of screening for and managing adverse social determinants of health (SDoH). Many of the same SDoH items that put individuals at increased risk of COVID-19 infection have increased dramatically due to the economic repercussions of slowing the viral spread. Methods: This is a review of 3 studies conducted by the Health Services Research Core in the Value Institute at ChristianaCare. The studies had 3 overarching goals: 1) to conduct a survey of primary care providers in Delaware to determine their current methods for collection of social determinants data, 2) to validate a 2-item screening tool for food insecurity, and 3) to assess the geographic distribution of patients with food insecurity. Results: Our studies have demonstrated the importance of screening for SDoH by highlighting the inconsistent data collection of SDoH items, examining the prevalence of food insecurity and validating a standardized instrument for rapid data collection, as well as displaying geospatial differences in food insecurity prevalence across New Castle County, DE. Public Health Implications: The COVID-19 pandemic has increased the prevalence of these social determinants in our communities. Therefore, it is imperative to employ screening and geospatial strategies to address the SDoH implications of the novel coronavirus.
INTRODUCTION Social determinants of health (SDoH), defined as the socioeconomic, environmental, and health care conditions which impact health, have been associated with adverse health outcomes for many chronic and acute health conditions.1 Increasingly, health systems have sought to identify and address SDoH with the goal of improving health outcomes of communities and larger populations. The novel Coronavirus 19 (COVID-19) pandemic has provided a critical demonstration of the importance of screening for and managing adverse SDOH. In the state of Delaware and nationally, those with low income and/or minority race and ethnicity have demonstrated higher rates of COVID-19 infection and mortality.2,3 Though the reasons for this are multifactorial, these populations may disproportionately experience higher burdens of chronic disease, housing insecurity, crowded living arrangements, and employment in service occupations that impede their ability to adhere to social distancing recommendations.4,5 In addition, the financial implications of the COVID-19 pandemic, including loss of employment and employer sponsored health insurance has exacerbated adverse SDoH for many. Data have demonstrated a dramatic increase in food insecurity and housing insecurity since the beginning of the pandemic.6 Researchers in the Value Institute at ChristianaCare have recognized the importance of social determinants of health on outcomes in Delaware and have laid a foundation for assessing SDoH among patients to best support their needs. This paper will summarize three studies focused on assessment and management of SDoH. These studies were conducted prior to the pandemic 72 Delaware Journal of Public Health – July 2020
but relate to the present situation. All studies were conducted by principal investigators from the Value Institute and all received approval from the ChristianaCare Institutional Review Board. The studies had three overarching goals: 1) to determine the current methods for collection of social determinants data in primary care clinics in Delaware, 2) to validate a 2-item screening tool for food insecurity among general medicine patients, and 3) to assess the geographic distribution of patients with food insecurity in Delaware. Combined, these studies have generated data that will help to assess, support, and predict the social needs of our neighbors and community partners in Delaware.
DESCRIPTION OF THREE PROJECTS “Assessment Of Social Determinants Of Health (Sdoh) Among Medical Practices In Delaware” Team members: Jennifer N. Goldstein, M.D., M.Sc.; Alexandra Mapp, M.P.H.; Robie Zent, R.N.; Ginger Huros, M.A.; Deborah Moore, R.N.; Zugui Zhang, Ph.D.
Methods The goal of this study was to assess how medical practices in Delaware collect and use SDoH data. To collect this information, a survey instrument was developed and distributed by email to a sample of primary care practices (Internal Medicine, Family Medicine) including private, multispecialty, and hospital-affiliated practices, as well as a Federally Qualified Health Center. The survey defined “Social Determinants of Health” based on the five categories put forth by HealthyPeople2020, which include economic stability, education, social and community context,
health and health care, and neighborhood and built environment.1 The survey included closed-ended questions that assessed whether practices collected data on specific SDoH, how the SDoH were assessed, and whether practices addressed the social needs of patients. The survey questions were assessed for readability and clarity by three internists prior to the distribution of the survey. The surveys were intended to be completed by medical directors or practice managers who were instructed to obtain all necessary information by consulting with other members of the practice (administrative staff, medical assistants, nurses, physicians) as needed. Survey respondents were compensated with a gift card. Descriptive statistics were calculated to determine the proportion of practices that collected data on SDoH, the most common SDoH assessed, mode of collection (administrative form vs. Electronic Health Record (EHR) form vs. EHR free text) and referral patterns for SDoH (in-house social worker or community-based organization). Chi-square tests were used to compare frequencies of SDoH collected between practices.
Results To date, there have been 57 respondents with 39 (68.4%) total completed surveys. Practice types were categorized as Internal Medicine (n=14), Family Medicine (n=18), and Other (n=7) (multispecialty/geriatrics/hospice/medicine-pediatrics). Of those that completed surveys, all reported that they collected data on at least one SDoH item and 38/39 (97%) of respondents reported that they collect data on more than one SDoH item. Internal Medicine practices recorded data for a median of five SDoH items, compared to a median of eight items asked by Family Medicine and Other practices. Across all practice types insurance status and employment status were collected at the highest frequency. There was variability regarding the collection of other SDoH by practice. Overall, Family Medicine practices and practices classified as “Other” collected SDoH data more frequently than Internal Medicine practices. However, there
were no significant differences in the frequency of collection of SDoH data between practices (see Figure 1). The method by which different SDoH were collected varied according to the category of SDoH. However, EHR forms and free text were the most commonly used methods compared to paper versions of administrative forms (see Figure 2). Among respondents that provided referrals to social work or community-based organizations for SDoH needs, between 90-100% reported that they referred for housing insecurity, transportation needs, and food insecurity. Greater than 80% provided referrals for patients who reported financial strain and those with inadequate prescription drug coverage. Average referral rates were lower for the remainder of SDoH categories (see Figure 3).
Public Health Implications Our study demonstrated that among a sample of primary care and mixed primary care/specialty practices in Delaware, all collected data on at least one SDoH, and the vast majority collected data on more than one SDoH. Overall, we found that practices that identified as Internal Medicine had lower rates of SDoH collection than other practices. The reason for this is not clear. These practices may perceive that they serve patients who generally do not have or may not present obviously with SDoH needs. Alternatively, the practices may lack resources to evaluate and reliably refer patients based on their social needs. Our survey demonstrated that while some practices use electronic forms to capture SDoH, many also rely on capturing SDoH data through the medical history as free text in the EHR. Prior work has demonstrated that systematic screening approaches capture SDoH more predictably and reliably than free text formats.7,8 Therefore, this finding presents an opportunity to develop and incorporate systematic tools for SDoH screening in primary care practices in Delaware. Lastly, the findings demonstrate that there was discontinuity between patterns of SDoH collection
Figure 1. Individual SDoH Items Collected by Practice Type (Total N=39) 73
Public Health: Surveillance, Mapping, and Special Populations
Figure 2. Individual SDoH Items by Collection Method (Total N=39)
Figure 3. Individual SDoH Items by Referral or No Referral (Total N=39)
versus SDoH referral. For example, although assessment of transportation needs, food insecurity, and housing insecurity was not performed consistently across practices, these three social risk factors received almost universal referrals to social work and community-based organizations. This demonstrates that when specific social risk factors are presented in the health care setting, there is considerable response from health care providers. Opportunities to increase and improve SDoH screening practices across Delaware could therefore, potentially improve referrals for social support and downstream health outcomes. 74 Delaware Journal of Public Health – July 2020
“Validation of a 2-item Food Insecurity Screen among Adult General Medicine Outpatients” Team members: Cecelia Harrison, M.P.H.; Jennifer N. Goldstein, M.D. Msc.; Adebayo Gbadebo, M.B.A.; Mia Papas, Ph.D. M.S.
The first study demonstrated that when specific SDoH such as food insecurity are identified in health care settings, providers often deliver actionable support by referring patients to social workers, community health workers, and community-based organizations. This demonstrates that increased identification
of specific SDoH such as food insecurity could lead to improved support via referral to resources. The following study focuses specifically on rapid identification of patients with food insecurity at the point of care.
Methods The goal of this study was to validate a 2-item screening tool for food insecurity in a sample of adults in the primary care setting. The gold standard instrument to assess food insecurity is the 18-item UDSA Household Food Security Scale.9 Although reliable, this instrument is lengthy and may not be suitable for all environments such as outpatient visits where time with providers may be limited. There have been several studies which have examined the validity of the 2-item version of the USDA Household Food Security Scale in a variety of populations but not among adult general medicine outpatients.10–12 It is reasonable to hypothesize that the prevalence of food insecurity would be greater among general medicine patients compared to the general population due to older age and more comorbidities, factors which have both been associated with food insecurity.13,14 Therefore, we examined the validity of the 2-item screening instrument in adult general medicine outpatients in four primary care practices in New Castle County, Delaware. Patients were approached by trained research assistants in the patient rooms of designated primary care offices. Informed consent was obtained and patients were administered a survey that consisted of social and demographic questions, as well as the 18-item UDSA Household Food Security Scale. We assessed whether responses to the first two items in the 18-item instrument reliably predicted food insecurity among the respondents by assessing sensitivity, specificity, and convergent validity of the 2-item screen compared to the 18-item gold standard instrument. The 2-item screen tested in this population was comprised of the first two questions of the 18-item USDA Household Food Security Scale: • “We worried whether our food would run out before we got money to buy more. Was that often true, sometimes true, or never true for your household in the last 12 months?” • “The food we bought just didn’t last and we didn’t have money to get more. Was that often true, sometimes true, or never true for your household in the last 12 months?”9
Results We found that 17.6% (52/295) of patients surveyed were food insecure as defined by the 18-item instrument. The proportion of food insecure patients in the general medicine sample was higher than the state and national averages, 11.9% and 12.3% respectively.15,16 Lastly, the 2-item version of the gold standard tool was found to be valid in this sample of the population.
Public Health Implications Our findings build upon previous studies which have validated this tool in families, children, adolescents, elderly populations, and other high-risk groups; and our findings serve an important role in supporting the use of the 2-item food insecurity screening
instrument in the adult general medicine population.10,11,17 This work also provides support to alleviate known barriers to screening such as time constraints and burdening the clinical workflow.18 Thus, a very brief and simple screening for this social need has the potential to impact a variety of comorbidities and provide actionable interventions for food insecurity without impeding workflows.
“Geographic Distribution of Food Insecure Patients at ChristianaCare Primary Care Clinics in Delaware” Team members: Cecelia Harrison, M.P.H.; Madeline Brooks, M.P.H.; Jennifer Goldstein, M.D. Msc.; Mia Papas, Ph.D. M.S.
As health systems screen patients for social needs, there is value in determining if and where these needs vary geographically so they can identify neighborhood determinants of health amenable to intervention. There are limitations, however, in using patient data from a single health system to infer geographic trends in SDoH. First, patient populations may lack complete screening coverage. Second, patients may not demographically or spatially represent the general population. Finally, providers risk making the reductionist fallacy by equating individual needs to community needs. Health systems can supplement patient screening data with external data sources to more confidently track geographic trends in SDoH. We sought to identify geographic areas in which ChristianaCare primary care patients experience high levels of food insecurity and compare these findings with ChristianaCare’s Community Health Needs Assessment (CHNA) and other arealevel data sources related to socioeconomic status.19
Methods Adult patients from four ChristianaCare primary care clinics were screened for food insecurity and geocoded to their respective New Castle County zip codes. A zip code-level ratio of food-insecure to food-secure patients was created to control for geographic variation in where ChristianaCare patients reside. We obtained zip code-level data from the Census Bureau to assess household poverty and receipt of food stamps/SNAP benefits. A directory of county food pantries was created and mapped to consider the spatial distribution of food resources. These measures were mapped and compared to ChristianaCare’s CHNA to identify zip codes with overlapping social needs.
Results Nearly 300 (N=291) adult primary care patients were screened for food insecurity at the time of this analysis. Of these, 52 (17.8%) were identified as food insecure. The zip codes 19802, 19805, 19702, 19801, and 19804, which represent the City of Wilmington and southern Newark, had some of the highest ratios of foodinsecure to non-food-insecure patients across the county. These zip codes included more than half of all county food pantries (57%, 39/69) and were identified as having higher levels of household poverty and food stamp/SNAP participation according to Census Bureau data (see Figure 4). ChristianaCare’s CHNA previously identified a “community 1” area consisting of five lower-income zip codes which accounted for 27% of discharges in 2018.19 This area includes zip codes 19801, 19802, 19804, 19805, and 19720, which cover the City of Wilmington and New Castle. The CHNA also identified 19801 and 19802 as “high-need” zip codes based on measures of socioeconomic status.19 75
Public Health: Surveillance, Mapping, and Special Populations Figure 4: Food Insecurity, Socioeconomic Status, and Food Pantries by New Castle County, DE Zip Codes 76 Delaware Journal of Public Health – July 2020
Public Health Implications In comparing these findings, the CHNA identified a broad segment of northeastern New Castle County that appears to have greater social needs confirmed by the screening and Census Bureau data. Reliance on the CHNA findings, however, may not direct attention to zip codes in southern Newark such as 19702 that have relatively high burdens of food insecurity and poverty. Furthermore, county food pantries were concentrated in Wilmington and New Castle. It remains unknown whether and how often ChristianaCare patients with food insecurity can access these food pantries, and whether such resources are sufficient to meet heightened need during the COVID-19 pandemic. The mapping of social needs data can be used to cross-reference their spatial trends while examining the locations of resources to meet those needs. This study demonstrates the value in using multiple data sources to confidently triangulate areas that warrant intervention for SDoH.
CONCLUSION The social determinants of health have shown to be powerful influencers of health outcomes. Through this research, we have shown how inconsistent data collection of SDoH items across different clinic settings suggests a need for standardized survey instruments. The first study suggested that food insecurity is under-screened yet actionable for resource referrals, making it an ideal case study for SDoH efforts. We continued this work by examining the prevalence of food insecurity and validating a standardized instrument for routine and rapid data collection in clinical settings. Lastly, we examined food insecurity prevalence geospatially in our community while highlighting methodology with potential for broad application to a variety of health and social needs. The COVID-19 crisis has increased the prevalence of these social determinants in our communities. Therefore, it is imperative to employ screening, geospatial techniques, and triangulation of data to address the SDoH implications of the novel coronavirus.
REFERENCES 1. US Department of Health and Human Services. (2014). Social Determinants of Health. Healthy People 2020. Retrieved from https://www.healthypeople.gov/2020/topics-objectives/topic/socialdeterminants-of-health 2. ACLU-DE. (2020). If COVID-19 doesn’t discriminate, then why are Black people dying at higher rates? Retrieved from https://www.aclu-de.org/en/news/if-covid-19-doesnt-discriminatethen-why-are-black-people-dying-higher-rates 3. Yancy, C. W. (2020, April 15). COVID-19 and African Americans. JAMA, 60611, 6–7. https://doi.org10.1001/jama.2020.6548 4. Makada, H. N., & Hudak, J. (2020). Social distancing in Black and white neighborhoods in Detroit: A data-driven look at vulnerable communities. Retrieved from: https://www.brookings.edu/blog/fixgov/2020/05/19/social-distancingin-black-and-white-neighborhoods-in-detroit-a-data-driven-look-atvulnerable-communities/ 5. Artiga, S., Garfield, R., & Orgera, K. (2020). Communities of Color at Higher Risk for Health and Economic Challenges due to COVID-19. Retrieved from: https://www.kff.org/coronavirus-covid-19/issue-brief/communities-ofcolor-at-higher-risk-for-health-and-economic-challenges-due-to-covid-19/
6. Washington University St. Louis. (2020). Update: High-poverty ZIP codes and COVID social needs in 31 states. Health Communication Research Laboratory. Retrieved from https://hcrl.wustl.edu/items/update-high-poverty-zip-codes-andcovid-social-needs-in-31-states/ 7. Gibson, D. M. (2012, September). Screening for household food insecurity in primary care settings: A commentary. Preventive Medicine, 55(3), 223. https://doi.org/10.1016/j.ypmed.2012.07.001 8. Venzon, A., Le, T. B., & Kim, K. (2019, February). Capturing social health data in electronic systems: A systematic review. CIN -. Comput Inform Nurs, 37(2), 90–98. https://doi.org/10.1097/CIN.0000000000000481 9. US Department of Agriculture. (2012). U.S. household food security survey module: three-stage design, with screeners. Retrieved from: https://www.ers.usda.gov/media/8271/hh2012.pdf 10. Gundersen, C., Engelhard, E., Crumbaugh, A., & Seligman, H. (2017). brief assessment of food insecurity accurately indentifies high-risk US adults. Public Health Nutrition, 20(8), 1367–1371. https://doi.org/10.1017/S1368980017000180 11. Hager, E. R., Quigg, A. M., Black, M. M., Coleman, S. M., Heeren, T., Rose-Jacobs, R., . . . Frank, D. A. (2010, July). Development and validity of a 2-item screen to identify families at risk for food insecurity. Pediatrics, 126(1), e26–e32. https://doi.org/10.1542/peds.2009-3146 12. Young, J., Jeganathan, S., Houtzager, L., Di Guilmi, A., & Purnomo, J. (2009, November). A valid two-item food security questionnaire for screening HIV-1 infected patients in a clinical setting. Public Health Nutrition, 12(11), 2129–2132. https://doi.org/10.1017/S1368980009005795 13. Gundersen, C., & Ziliak, J. P. (2015, November). Food insecurity and health outcomes. Health affairs (Project Hope), 34(11), 1830–1839. https://doi.org/10.1377/hlthaff.2015.0645 14. Seligman, H. K., Laraia, B. A., & Kushel, M. B. (2010, February). Food insecurity is associated with chronic disease among low-income NHANES participants. The Journal of Nutrition, 140(2), 304–310. https://doi.org/10.3945/jn.109.112573 15. US Department of Health and Human Services. (2014). Healthy People 2020. Food Insecurity. Retrieved from: https://www.healthypeople.gov/2020/topics-objectives/topic/socialdeterminants-health/interventions-resources/food-insecurity 16. Coleman-Jensen, A., Rabbitt, M. P., & Gregory, C. A. (2016). Household food security in the United States in 2015. U.S. Department of Agriculture. Economic Research Service, ERR, 215(September), 1–44. 17. Bishop, N. J., & Wang, K. (2018, September). Food insecurity, comorbidity, and mobility limitations among older U.S. adults: Findings from the Health and Retirement Study and Health Care and Nutrition Study. Preventive Medicine, 114(July), 180–187. https://doi.org/10.1016/j.ypmed.2018.07.001 18. Essel, K., Floyd, B. D., & Klein, M. (2018). Impacting food insecurity through the use of screening tools and training. In Identifying and Addressing Childhood Food Insecurity in Healthcare and Community Setting (pp. 23–41). Springer US. 19. ChristianaCare. (2019). Community Health Needs Assessment. Retrieved from: https://christianacare.org/about/whoweare/communitybenefit/ community-health-needs-assessment/ 77
FAQ: Coronavirus & Domestic Animals How should I prepare for COVID-19 if I have a pet? Designate a trusted pet caregiver (family, friend, neighbor, colleague), who has a set of keys to your home, is familiar with your home and pet, knows your emergency plan, and has your contact information. Prepare pet care instruction documents for each of your pets with information on feeding, watering, health conditions, medications, etc. Make sure your pet is microchipped, the microchip is registered, and information is up to date. Your pet should always be wearing a collar or harness with identification. Make sure your pet’s veterinary care and vaccines are up to date. Organize your veterinary records so they are readily accessible. In addition to making sure you have a supply of your own medication, be certain you have at least 2-4 weeks of your pet’s medication. Ensure you have an adequate supply of pet food, litter, and other consumable supplies. Have leashes and crates/carriers available in case your pets need to be transported.
Additional Resources CDC: https://www.cdc.gov/coronavirus/2019-ncov/index.html OIE (World Organisation for Animal Health): https://www.oie.int/scientific-expertise/specificinformation-and-recommendations/questions-and-answers-on-2019novel-coronavirus/
Questions? Contact us.
Those who are deaf and hard of hearing can call
8:00am-9:00pm Monday – Friday 9:00am-5:00pm Saturday – Sunday or email DPHCall@delaware.gov
Visit de.gov/coronavirus for more information and updates 78 Delaware Journal of Public Health – July 2020
+ JFS DELAWARE MERGES WITH CANCER CARE CONNECTION
Psycho-social Support for Delaware's Cancer Patients Starting July 1, 2020, Jewish Family Services (JFS) will be merging with another Delaware non-profit, Cancer Care Connection; specifically, Cancer Care Connection (CCC) will be combined into JFS. With this mutually-beneficial partnership, JFS will increase community awareness of CCC and ensure the continuation of its important work, while CCC fills a gap in JFS’ current services by providing their oncology-specific, psycho-social expertise. Having assessed the organizational, philosophical, and cultural fit of each organization with the other, the complementary nature of CCC and JFS services affords opportunities to strengthen, expand, and—in the long term—create new programs to better serve their joined client base and grow a service that is desperately needed in the region. Recent cancer statistics show that Delaware has the second highest cancer incidence—and Pennsylvania is close behind at third highest— despite all ongoing efforts to reduce the rate of cancer; additionally, Delaware ranks 15th highest in cancer mortality, followed by Pennsylvania at 16th highest. These statistics indicate that there are many individuals in the region who could benefit from oncology-specific support services. For JFS, this partnership is a natural extension of the agency’s mission to provide counseling and support services to vulnerable individuals and families to navigate life’s challenges.
About JFS Delaware: JFS Delaware (JFS) strengthens individuals, families, and the community by providing counseling & support services. JFS supports people of all backgrounds.
www.jfsdelaware.org 302-478-9411 Read More About the Merger
“This level of specialty and efficiency can change the entire trajectory for a cancer patient and their family.” —Erica Griffiths, Patient Advocate About Cancer Care Connection: Cancer Care Connection helps people affected by cancer to navigate the full range of the issues they face, make informed decisions, and take action on their own behalf. Oncology Social Workers help cancer patients and their caring circle obtain the best possible outcome. www.cancercareconnection.org 302-266-8050 79
Public Health: Surveillance, Mapping, and Special Populations
Race as a Social Determinant of Health: Lessons from the Coronavirus Pandemic in Delaware Daniel G. Atkins, J.D. Executive Director, Community Legal Aid Society, Inc.
Leland Ware, J.D. Louis L. Redding Chair of Law and Public Policy, University of Delaware
David P. Donohue, M.D., F.A.C.P Chief Medical Officer, Progressive Health of Delaware
Maija Woodruff Franklin & Marshall College; Intern, Community Legal Aid Society, Inc.
Robert L. Hayman, Jr. Emeritus Professor of Law, Widener University Delaware Law School
ABSTRACT As the coronavirus spread across the United States early in 2020, a trend seemed to emerge: Black Americans were getting sick, and were dying, in disproportionate numbers. In early April, Michigan and Wisconsin reported infection rates among Black Americans over twice as high as their proportion of the population.1 By mid-April, The Lancet was reporting that deaths due to COVID were disproportionately high among Black Americans across the country.2 On April 23, Congress, as part of the Paycheck Protection Program and Health Care Enhancement Act, required the federal government to include race and ethnicity among other demographic data in its COVID analyses, and while the data subsequently reported by the Centers for Diseases Control and Prevention (CDC) was limited, it clearly confirmed the trend: the pandemic was having an especially lethal impact on Black Americans. Delaware began reporting racial and ethnic breakdowns on April 24, and the first numbers were consistent with the national trend: among lab-confirmed positive cases for which race was reported, more were Black than white, even though there were three times as many white Delawareans.3 The trend was, on the surface, incommensurate with our understanding of viruses, which, after all, do not select their victims, on account of race or otherwise. But of course, it is completely consistent with our understanding of health conditions–and of health risks–in Delaware, and in the nation: they are riddled with inequalities, and the inequalities have a distinct racial cast.
THE COVID-19 DATA At this writing, the CDC reports that of the confirmed cases for which racial data were available, 34.9% are white, roughly half that demographic’s proportion of the U.S. population, while 22.0% are Black, roughly double that demographic’s proportion of the population, yielding an incident rate roughly four times as high.4 Delaware is one of 47 states that now reports racial data for confirmed cases; one of 43 states that reports that data for deaths; and one of just four states that reports racial data for testing. The State reports both raw data and, for tests and cases, rates per 10,000. At this writing, Delaware reports a testing rate (per 10,000) of 797.0 for Black residents and 470.8 for white residents, a 1.7:1 ratio; it also reports a positive case rate of 128.9 for Black residents and 45.1 for white residents, a 2.9:1 ratio. Of the 414 total deaths, 61% were white, and 27% were Black; the State reports that 69.1% of its population is white, and 21.9% of its population is Black.5 We believe two fundamental lessons emerge from the data. First, the unequal suffering depicted by the data reflects unequal vulnerabilities: Black Delawareans are more likely to be exposed to the coronavirus, and are more likely to be disadvantaged by factors that increase their risks of morbidity and mortality. Second, those inequalities reveal the critical role that race plays as 80 Delaware Journal of Public Health – July 2020
a determinant of health: COVID disparities in Delaware, that is to say, are the predictable results of the lived experience of race, of segregation, disproportionate poverty, and racial injustice.
COVID RISKS AND DISPARATE VULNERABILITIES The racial disparities in COVID cases and COVID mortality reflect racial disparities in vulnerability: Black Delawareans are at greater risk of exposure and infection, and are more likely to be disadvantaged by the comorbidities and other risk factors that portend poor outcomes in COVID cases.
Infection Risk Multiple modes of transmission for the novel coronavirus are possible, including fomite and other mediated modes of transmission, but the dominant mode of transmission is thought to be through direct person-to-person contact.6,7 Absent immunity to infection, then, the persons most at risk of infection are those most likely to be exposed to other people. Race is a key determinant of that risk, and Black Delawareans are at special risk. Residential population density is likely to mediate person-toperson contact, especially during periods of lockdown, and this density varies according to race. The CDC measures density in its “Social Vulnerability Index” (SVI) partly by reference to the presence of multiple unit residential structures, i.e., structures
with ten or more units, and at least one study of residential tracts confirms the expected positive correlation between COVID incidence and the percentage of such structures.8 Our own examination of 2018 SVI data for Delaware reveals a positive correlation between the percentage of multiple unit structures and the percentage of minority residents (see Table 1). Data from the 2010 census is consistent with this finding: 6.5% white households and 19.3% of Black households were in structures with ten or more units. Meanwhile, 68.2% of white households, but just 35.7% of Black households, were in single unit detached structures.9 Different occupations also present different risks of transmission, either because they involve more interpersonal contact, or because they are deemed “essential” and are thus exempted from stay-at-home mandates. Here too there are significant racial disparities. According to the federal Bureau of Labor Statistics, in 2017-2018, 29.9% of white workers had jobs that allowed them to work at home, and 25.6% did; by contrast, just 19.7% of Black workers could work at home, and 17.6% did.10 This disparity has been compounded by racial disparities in jobs deemed “essential” either by the federal Cybersecurity and Infrastructure Security Agency or by the State of Delaware (see Table 2). Significantly, a study of COVID incidence across New York City neighborhoods suggested that occupational disparities like these in fact accounted for much of the racial disparity in COVID cases.11 Finally, Black workers are also more likely to use public transportation: although Black Delawareans are 21.3% of the commuting population, according to the 2018 American Community Survey (ACS), they are 54.5% of those using public transportation to get to work.12
Morbidity and Mortality Risk Some biological risk factors for COVID morbidity and mortality are now fairly well-established. These include age (older persons are at greater risk), sex (men are at greater risk), and a variety of comorbidities. Among comorbidities, diabetes,13–16 kidney disease,17,18 hypertension,14,16,18 cardiovascular disease,1516,18 obesity,16 and pulmonary disease18 are most consistently found to be associated with COVID morbidity and mortality. Most of these unequally burden Black Delawareans. Nationally, the prevalence of Type 2 diabetes among Black Americans is significantly higher than it is among white Americans19; based on self-reports through the 2018 Behavioral Risk Factor Surveillance System (BRFSS), it is also higher among Black Delawareans (see Table 3). Research indicates a threefold greater incidence of end-stage kidney disease among Black Americans as compared to white Americans,20 and it too is higher among Black Delawareans. Deaths attributable to hypertension occur at roughly three times the rate for Black Americans as compared to white Americans21; hypertension is more prevalent among Black Delawareans. Cardiovascular disease disproportionately impacts Black Americans: across “nearly every metric,” the American Heart Association reports, “African Americans have poorer overall cardiovascular health than
non-Hispanic whites, and CVD mortality is higher in African Americans than whites.”22 For Black Delawareans, diagnosed coronary heart disease is less prevalent than it is among white Delawareans, but stroke is more prevalent. Nationally, research shows a consistent racial disparity in obesity,23 though that disparity is correlated with social factors, and may disappear when Black and white subjects are matched by social context and income.24 Nonetheless, calculations of Body Mass Index based on the BRFSS suggest that obesity is more common among Black Delawareans.25 Finally, self-reported COPD is estimated to be slightly lower among Black Americans, a trend that also holds in Delaware; research suggests, however, that COPD may be underdiagnosed, particularly among racial minorities.26 Importantly, research confirms the intuitive proposition that multiple comorbidities are correlated with higher mortality rates: the more comorbidities a patient presents, the higher the risk of mortality.27 While some biological features increase vulnerability to COVID morbidity and mortality, others might afford protection: nutrition,28 sleep,29 and exercise30 enhance general health and immunity, and it can be plausibly theorized that this might include some immunity from COVID. But the BRFSS suggests that sleep and exercise may be more problematic for Black Delawareans. So too is nutrition: according to the 2018 ACS, 8.1% of white Americans report some degree of food insecurity, but over twice that percentage–21.2%–of Black Americans report the same. Insecurity was greater for households with children, a special concern with schools closed during the pandemic. Access to health care is the final COVID risk factor, and Black Delawareans are more likely to have no health insurance or health care coverage. They are also likely to be disproportionately harmed by COVID triage schemes that ration resources based on comorbidities.31
RACE AS A DETERMINANT OF HEALTH: RACE IN DELAWARE The roots of these racial disparities–in housing, occupations, health and health care, and more–run deep and wide. What follows is a severely truncated effort to trace them, and to describe some small portions of their astounding breadth today: a short history of race in Delaware, and an overview of its living legacies–of segregation, disproportionate poverty, and racial injustice–as they bear on the question of Black Delawareans’ health.
A Short History of Race in Delaware Delaware was a slave state, and as such, bears all the scars that follow from that original sin. But it was a singular curiosity, a slave state with almost no slaves–by 1860, over 90% of “colored” Delawareans were free–and the result was that “race” assumed a political significance unattached to slavery. “White Supremacy” in Delaware would thus prove especially durable, and especially pernicious. A quick glance at the schools might be instructive. At the dawn of the twentieth century, “Black education” in Delaware was very nearly an oxymoron. Since 1821, the state 81
Public Health: Surveillance, Mapping, and Special Populations
Majority-Minority (50 Tracts w/ Largest Minority %)
Predominately White (50 Tracts w/ Smallest Minority %)
51.7 - 98.2
2.2 - 17.8
1.9 - 50.2
.4 - 15.9
$9181 - $44,665
$23,284 - $193,461
Per Capita Income (Tract Average)
Multiple Units % (Tract Range)
0 - 53.8
0 - 29.9
Minority % (Tract Range) Minority % (Tract Average) Poverty % (Tract Range) Poverty % (Tract Average) Per Capita Income (Tract Range)
Multiple Units % (Tract Average)
Table 1. COVID-19 Risk Factors: Delaware Disparities by Census Tract, Data from 2018 CDC Social Vulnerability Index
Total (Thousands) Total Labor Force
Home health aides
Occupational therapy aides
Personal care aides
Postal service clerks
Postal service mail carriers
Taxi drivers and chauffeurs
Table 2. COVID-19 Risk Factors: Racial Disparities in Selected “Essential” Jobs, Data from BLS Report “Labor force characteristics by race and ethnicity 2018”
Black % Diabetes
Coronary Heart Disease
Exercise in Past Month
Optimal Sleep (7-9 hours)
Hypertension (2017) COPD Obesity No Health Care Coverage
Table 3. COVID-19 Risk Factors: Delaware Disparities by Race and Income, Data from 2018 Behavioral Risk Factor Surveillance System (BRFSS) Delaware Core Variables Report 82 Delaware Journal of Public Health – July 2020
had refused to fund schools for Black Delawareans, even while collecting taxes from the Black community; the education law of 1875 finally provided funding, but only through revenues raised by taxing the property of Black citizens. In 1897, segregated schools were made a state constitutional imperative, essentially memorializing the standing practice. Spurred by Pierre S. du Pont’s reform efforts, the education law of 1921 finally created a genuine public school system. But disparities persisted between Black and white schools, so thoroughly and so blatantly that in 1952, Chancellor Collins Seitz ordered the desegregation of two of Delaware’s public schools, finding the segregated schools too unequal to be maintained separately; that order was eventually affirmed by the U.S. Supreme Court as a part of Brown v. Board of Education. The schools affected by the order did in fact desegregate, and did so largely without incident. It was, however, merely the beginning, not the end, of the ongoing struggle to desegregate: the complete desegregation of the state’s schools would take another forty years. The state legislature heralded the end of desegregation with the Neighborhood Schools Act of 2000, and in its wake, the schools of New Castle County have now resegregated, along both racial and economic lines.32 We have traveled a great distance, it seems, to get not very far.
Race and Segregation.
tracts revealed a correlation between COVID incidence and per capita income: as income increased, the rate of incidence went down.8 There is also now increasing evidence of a link between COVID infection and air pollution.34 A county-level analysis of COVID incidence determined that counties with higher proportions of Black residents have both higher rates of comorbidities and greater air pollution.35 And Black Americans generally are disproportionately burdened by air pollution: while white Americans experience 17% less air pollution exposure than is caused by their consumption, Black Americans experience 56% more exposure than is caused by their consumption.36
Race and Disproportionate Poverty Poverty is significantly correlated with race in Delaware: according to the 2018 ACS, 9.1% of white Delawareans live in poverty, while for Black Delawareans, the rate more than doubles, to 20.2%. And wealth and poverty impact health in many ways. COVID comorbidities are significantly correlated with poverty, and this alone could account for of many of the COVID racial disparities. Nationally, socio-economic status is strongly associated both with chronic kidney disease and with end stage renal disease progression37; with risk of diabetes38; with an increased risk of hypertension39; and with COPD.40 The BRFSS confirms these trends for Delaware: each morbidity is much more prevalent among low-income Delawareans. Meanwhile, general health and immunity boosters–nutrition, rest, and exercise–are unequally distributed based on wealth. According to the 2018 ACS, just 5.4% of households with an income-to-poverty ratio of 1.85 or greater are food insecure, but for households with a ratio under that, the percentage soars to 29.1%. And, according to the BRFSS, low-income Delawareans are less likely to get adequate sleep and exercise.
Residential segregation is one legacy of Delaware’s history. In Delaware, as elsewhere, racially segregated neighborhoods have been created and perpetuated by a variety of public and private schemes: by federal mortgage insurance programs, which explicitly “redlined” Black and white neighborhoods; by racially restrictive covenants in deeds, enforced by state courts; by zoning policies that excluded affordable housing from some residential zones, while permitting industrial uses near others; by the racially discriminatory practices of realtors and mortgage lenders; by public works projects, including the construction of the interstate highway system, which fostered economic growth in some neighborhoods, while fragmenting or isolating others; by educational policies, which, through a variety of devices, created racially identifiable schools, to serve racially distinct neighborhoods; and more. The results are segregated neighborhoods with very different economic and employment opportunities; very different housing options; food options that differ both in quality and quantity; very different access to recreational spaces and very different exposures to environmental allergens, irritants, and hazards; and with neighborhood schools financed by very different tax bases.33
Poverty also affects the quality and availability of housing, with obvious implications for health. Substandard housing is a direct and immediate threat to health; so too is homelessness.42 The threat is particularly great during the pandemic: put simply, it is difficult to wash your hands regularly if you don’t have running water or a sink.
Our analysis of Delaware’s census tracts as described by the CDC’s 2018 Social Vulnerability Index confirms both the extent of segregation and some of these features. The fifty tracts with the smallest percentages of racial minorities are overwhelmingly white, and have a much lower average poverty rate, and much higher average per capita income; the fifty tracts with the largest percentages of racial minorities are in fact all majority-minority, and have a much higher average poverty rate and much lower per capita income. Significantly, an analysis of Colorado’s census
Poverty and wealth also differentially affect access to the justice systems which can address–individually or systematically– inequities among the social determinants of health.43 Delaware’s eviction moratorium put in place at the start of the pandemic might soon be lifted; the law will still protect against wrongful evictions, but the vast majority of people who are poor will not have attorneys to represent them.44 The predictable result is a flood of evictions, and many more Delawareans will be homeless and unsafe.
Timely access to quality health care also varies with poverty and wealth, as low-income Delawareans are much more likely to be without health insurance or other health care coverage. For this and other reasons, low socio-economic status is associated with delays in seeking medical care, and, as a consequence, with worse outcomes.41
Public Health: Surveillance, Mapping, and Special Populations
Racial Injustice In at least three ways, racial injustice also directly impairs the health of Black Delawareans. Racial bias in health care treatment is one way. A recent review concluded that “across virtually every type of diagnostic and treatment intervention Blacks and other minorities receive fewer procedures and poorer-quality medical care than do whites.”45 For older Delawareans, especially vulnerable during the pandemic, the bias may be compounded by well-chronicled racial disparities in the access to, and the quality of, long term services and supports.46 Racial bias in state-sanctioned violence is a second way. Mass incarceration is a social determinant of–a social detriment to–the health of Black Delawareans. So too is police violence.47 And so too is official indifference to the suffering of Black Delawareans, whatever may be that suffering’s source. The stress of living with racial injustice is a third way. Exposure to racial injustice, and the persistent threat of exposure to racial injustice, are stressors with a variety of health impacts. The stress induced by racism-related vigilance, for example, is an important determinate of hypertension in Black Americans and of sleep difficulties.21,48 Recent research suggests that the experience of racial discrimination may adversely affect the mental and physical health of children, and that the impacts may extend into adulthood.45 A final reminder seems in order, about racial injustice and more: outside the contours of controlled studies, the various impacts of racial injustice really cannot be disaggregated, nor can they be separated from the impacts of segregation, or of poverty, or from the risks that inhere in comorbidities. This may be the real lesson from the findings of the U.S. Centers for Medicare and Medicaid Services, that through mid-May 2020, Black Medicare recipients were twice as likely to be infected with COVID-19 as white recipients, and four times as likely to be hospitalized.49 As with life, so too the virus: it takes us as it finds us, each one whole person, with all our aggregated vulnerabilities, accumulated over the years. And it is to our lasting shame–or for some of us, much worse–that we are burdened by all these so unequally.
RECOMMENDATIONS AND CONCLUSION
- Eliminate food deserts through the redirection of food waste and the enhancement of nutritious food assistance, because nutrition is vital to health. - Provide redress for the unequal harms caused by pollution through a system of taxes and rebates,50 because it is necessary to compensate those people, disproportionately poor and minorities, whose health has been endangered by environmental injustice. - Guarantee to all persons a right to an attorney in eviction cases, because shelter is vital to health, especially during a pandemic, and legal representation is vital to justice. - Repeal the Neighborhood Schools Act, because schools segregated by race and class remain inherently unequal, and education remains the key to our future. These reforms, we believe, are necessary, but they are also, we recognize, not sufficient, not quite enough to meet the moment. As the disparities driving health inequity are systemic and widespread, so too the responses must be systemic and widespread. Segregation results from deep and broad structural problems; discriminatory treatment results from conscious but also unconscious bias. True remedies must be structural; for some of us, they must be restorative; and for some of us, they must be rehabilitative. It was, after all, fully a century ago, that W.E.B. Du Bois posed the question, still in need of answering: “Ask your own soul what it would say, if the next census were to report that half of Black America was dead and the other half dying.”51
REFERENCES 1. Chowkwanyun, M., & Reed, A. M. (2020, May 6). Racial health disparities and COVID-19 – caution and context. New England Journal of Medicine. Retrieved from: https://www.nejm.org/doi/full/10.1056/NEJMp2012910 2. Dorn, A. V., Cooney, R. E., & Sabin, M. L. (2020, April 18). COVID-19 exacerbating inequalities in the US. Lancet, 395(10232), 1243–1244. https://doi.org/10.1016/S0140-6736(20)30893-X 3. Newman, M., & Horn, B. (2020, April 24). Black, Hispanic residents are being infected with coronavirus at drastically higher rate. News Journal. Retrieved from: https://www.delawareonline.com/story/news/health/2020/04/24/ coronavirus-affecting-more-Black-hispanic-delawareresidents/3022058001/
The pandemic is an illustrative microcosm, highlighting racial inequities that endanger the health and lives of Black Delawareans. Some specific, concrete measures can provide some redress, and we offer the following as examples: - Guarantee health care for all Black Delawareans, because despite the Affordable Care Act and the Medicaid expansion, nearly one in ten Black Delawareans still does not have health care coverage.
4. National Center for Immunization and Respiratory Diseases. (2020). Coronavirus disease 2019 (COVID-19): Cases in the U.S. Retrieved from: https://www.cdc.gov/coronavirus/2019-ncov/cases-updates/cases-in-us.html
- Expand health education and follow-up access to health care for all Delawareans, because every Delawarean should know that chronic diseases are preventable and even reversible with a healthy lifestyle.
5. Delaware Department of Health and Social Services. (n.d.). Coronavirus (COVID-19) data dashboard. State of Delaware. Retrieved from: https://myhealthycommunity.dhss.delaware.gov/locations/state
84 Delaware Journal of Public Health – July 2020
6. Chan, J. F., Yuan, S., Kok, K. H., To, K. K., Chu, H., Yang, J., . . . Yuen, K. Y. (2020, February 15). A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: A study of a family cluster. Lancet, 395(10223), 514–523. https://doi.org/10.1016/S0140-6736(20)30154-9 7. World Health Organization. (2020, March 27). Modes of transmission of virus causing COVID-19: implications for IPC precaution recommendations. Retrieved from: https://www.who.int/news-room/commentaries/detail/modesof-transmission-of-virus-causing-covid-19-implications-for-ipcprecaution-recommendations 8. Ramírez, I. J., & Lee, J. (2020, May 29). COVID-19 emergence and social and health determinants in Colorado: A rapid spatial analysis. International Journal of Environmental Research and Public Health, 17(11), 3856. https://doi.org/10.3390/ijerph17113856 9. U.S. Census Bureau. (2012). 2010 census of population and housing. Retrieved from https://www2.census.gov/library/ publications/decennial/2010/cph-2/cph-2-9.pdf 10. Bureau of Labor Statistics. (2019). BLS job flexibilities and work schedules—2017-2018 data from the American Time Use Survey. United States Department of Labor. Retrieved from: https://www.bls.gov/news.release/pdf/flex2.pdf 11. Almagro, M. & Hutchinson, A.O. (2020, Apr). The determinants of the differential exposure to COVID-19 in New York City and their evolution over time. Retrieved from: http://dx.doi.org/10.2139/ssrn.3573619 12. U.S. Census Bureau. (2018). 2018 American community survey: Delaware. Retrieved from: https://www.census.gov/acs/www/data/data-tables-and-tools/data-profiles/ 13. Roncon, L., Zuin, M., Rigatelli, G., & Zuliani, G. (2020, June). Diabetic patients with COVID-19 infection are at higher risk of ICU admission and poor short-term outcome. J Clin Virol, 127, 104354. https://doi.org/10.1016/j.jcv.2020.104354 14. Yang, J., Zheng, Y., Gou, X., Pu, K., Chen, Z., Guo, Q., . . . Zhou, Y. (2020, May). Prevalence of comorbidities and its effects in patients infected with SARS-CoV-2: A systematic review and meta-analysis. Int J Infect Dis, 94, 91–95. https://doi.org/10.1016/j.ijid.2020.03.017 15. Li, B., Yang, J., Zhao, F., Zhi, L., Wang, X., Liu, L., . . . Zhao, Y. (2020, May). Prevalence and impact of cardiovascular metabolic diseases on COVID-19 in China. Clin Res Cardiol, 109(5), 531–538. https://doi.org/10.1007/s00392-020-01626-9 16. Richardson, S., Hirsch, J. S., Narasimhan, M., Crawford, J. M., McGinn, T., Davidson, K. W., . . . Zanos, T. P., & the and the Northwell COVID-19 Research Consortium. (2020, April 22). Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City Area. JAMA, 323(20), 2052–2059. https://doi.org/10.1001/jama.2020.6775 17. Emami, A., Javanmardi, F., Pirbonyeh, N., & Akbari, A. (2020, March 24). Prevalence of underlying diseases in hospitalized patients with COVID-19: A systematic review and metaanalysis. Archives of Academic Emergency Medicine, 8(1), e35.
18. Nikpouraghdam, M., Jalali Farahani, A., Alishiri, G., Heydari, S., Ebrahimnia, M., Samadinia, H., . . . Bagheri, M. (2020, June). Epidemiological characteristics of coronavirus disease 2019 (COVID-19) patients in IRAN: A single center study. J Clin Virol, 127, 104378. https://doi.org/10.1016/j.jcv.2020.104378 19. Marshall, M. C., Jr. (2005, December). Diabetes in African Americans. Postgraduate Medical Journal, 81(962), 734–740. https://doi.org/10.1136/pgmj.2004.028274 20. Laster, M., Shen, J. I., & Norris, K. C. (2018, November). Kidney disease among African Americans: A population perspective. Am J Kidney Dis, 72(5, Suppl 1), S3–S7. https://doi.org/10.1053/j.ajkd.2018.06.021 21. Hicken, M. T., Lee, H., Morenoff, J., House, J. S., & Williams, D. R. (2014, January). Racial/ethnic disparities in hypertension prevalence: Reconsidering the role of chronic stress. American Journal of Public Health, 104(1), 117–123. https://doi.org/10.2105/AJPH.2013.301395 22. Carnethon, M. R., Pu, J., Howard, G., Albert, M. A., Anderson, C. A. M., Bertoni, A. G., . . . Yancy, C. W., & the American Heart Association Council on Epidemiology and Prevention; Council on Cardiovascular Disease in the Young; Council on Cardiovascular and Stroke Nursing; Council on Clinical Cardiology; Council on Functional Genomics and Translational Biology; and Stroke Council. (2017, November 21). Cardiovascular health in African Americans: A scientific statement from the American Heart Association. Circulation, 136(21), e393–e423. https://doi.org/10.1161/CIR.0000000000000534 23. Yu, Q., Scribner, R. A., Leonardi, C., Zhang, L., Park, C., Chen, L., & Simonsen, N. R. (2017, June). Exploring racial disparity in obesity: A mediation analysis considering geocoded environmental factors. Spatial and Spatio-temporal Epidemiology, 21, 13–23. https://doi.org/10.1016/j.sste.2017.02.001 24. Bleich, S. N., Thorpe, R. J., Jr., Sharif-Harris, H., Fesahazion, R., & Laveist, T. A. (2010, May). Social context explains race disparities in obesity among women. Journal of Epidemiology and Community Health, 64(5), 465–469. https://doi.org/10.1136/jech.2009.096297 25. Division of Public Health. (n.d.). One in Three Delaware Adults Reports Being Obese. Delaware Health and Social Services. Retrieved from: https://www.dhss.delaware.gov/dhss/dph/dpc/obesitypreventionupdate.html 26. Ejike, C. O., Dransfield, M. T., Hansel, N. N., Putcha, N., Raju, S., Martinez, C. H., & Han, M. K. (2019, August 15). Chronic obstructive pulmonary disease in America’s Black population. American Journal of Respiratory and Critical Care Medicine, 200(4), 423–430. https://doi.org/10.1164/rccm.201810-1909PP 27. Onder, G., Rezza, G., & Brusaferro, S. (2020, March 23). Case-Fatality rate and characteristics of patients dying in relation to COVID-19 in Italy. JAMA, 323(18), 1775–1776. https://doi.org/10.1001/jama.2020.4683 85
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28. Jayawardena, R., Sooriyaarachchi, P., Chourdakis, M., Jeewandara, C., & Ranasinghe, P. (2020, April 16). Enhancing immunity in viral infections, with special emphasis on COVID-19: A review. Diabetes & Metabolic Syndrome, 14(4), 367–382. https://doi.org/10.1016/j.dsx.2020.04.015 29. Shneider, A., Kudriavtsev, A., & Vakhrusheva, A. (2020, April 29). Can melatonin reduce the severity of COVID-19 pandemic? International Reviews of Immunology, 1–10. https://doi.org/10.1080/08830185.2020.1756284 30. Simpson, R. J., & Katsanis, E. (2020, July). The immunological case for staying active during the COVID-19 pandemic. Brain, Behavior, and Immunity, 87, 6–7. https://doi.org/10.1016/j.bbi.2020.04.041
40. Gershon, A. S., Dolmage, T. E., Stephenson, A., & Jackson, B. (2012, June). Chronic obstructive pulmonary disease and socioeconomic status: A systematic review. COPD, 9(3), 216–226. https://doi.org/10.3109/15412555.2011.648030 41. Patel, J. A., Nielsen, F. B. H., Badiani, A. A., Assi, S., Unadkat, V. A., Patel, B., . . . Wardle, H. (2020, June). Poverty, inequality and COVID-19: The forgotten vulnerable. Public Health, 183, 110–111. https://doi.org/10.1016/j.puhe.2020.05.006 42. Taylor, L. A. (2018, June 7). Housing and health: an overview of the literature. Health Affairs Health Policy Brief. Retrieved from: https://www.healthaffairs.org/do/10.1377/hpb20180313.396577/full/
31. Raifman, M. A., & Raifman, J. R. (2020, July). Disparities in the population at risk of severe illness from COVID-19 by race/ethnicity and income. American Journal of Preventive Medicine, 59(1), 137–139. https://doi.org/10.1016/j.amepre.2020.04.003
43. Legal Services Corporation. (2017). The justice gap: measuring the unmet civil legal needs of low-income Americans. Retrieved from: https://www.lsc.gov/sites/default/files/images/TheJusticeGap-FullReport.pdf
32. Hayman, R. L. (2009). A history of race in Delaware: 16391950. In R. L. Hayman & L. Ware (Eds.), Choosing Equality: Essays and Narratives on the Desegregation Experience (pp. 21-73). University Park, PA: Penn State University Press.
44. Center for Community Research and Service. (2020). Eviction and Legal Representation in Delaware-An Overview. Biden School of Public Policy & Administration, University of Delaware. Retrieved from: http://udspace.udel.edu/handle/19716/26352
33. Ware, L. (2002). The geography of discrimination: The Seattle and Lousiville cases and the legacy of Brown v. Board of Education. In R. L. Hayman & L. Ware (Eds.), Choosing Equality: Essays and Narratives on the Desegregation Experience (pp. 312-355). University Park, PA: Penn State University Press. 34. Brandt, E. B., Beck, A. F., & Mersha, T. B. (2020). Air pollution, racial disparities and COVID-19 mortality. J Allergy Clin Immunol, https://doi:10.1016/j.jaci.2020.04.035 Retrieved from: https://pubmed.ncbi.nlm.nih.gov/32389591/ 35. Millett, G. A., Jones, A. T., Benkeser, D., Baral, S., Mercer, L., Beyrer, C., . . . Sullivan, P. (2020, May 14). Assessing differential impacts of COVID-19 on Black communities. Annals of Epidemiology. https://doi.org/10.1016/j.annepidem.2020.05.003 36. Tessum, C. W., Apte, J. S., Goodkind, A. L., Muller, N. Z., Mullins, K. A., Paolella, D. A., . . . Hill, J. D. (2019, March 26). Inequity in consumption of goods and services adds to racialethnic disparities in air pollution exposure. Proceedings of the National Academy of Sciences of the United States of America, 116(13), 6001–6006. https://doi.org/10.1073/pnas.1818859116 37. Nicholas, S. B., Kalantar-Zadeh, K., & Norris, K. C. (2015, January). Socioeconomic disparities in chronic kidney disease. Advances in Chronic Kidney Disease, 22(1), 6–15. https://doi.org/10.1053/j.ackd.2014.07.002 38. Robbins, J. M., Vaccarino, V., Zhang, H., & Kasl, S. V. (2005, June). Socioeconomic status and diagnosed diabetes incidence. Diabetes Research and Clinical Practice, 68(3), 230–236. https://doi.org/10.1016/j.diabres.2004.09.007 39. Cuevas, A. G., Williams, D. R., & Albert, M. A. (2017, May). Psychosocial factors and hypertension: A review of the literature. Cardiology Clinics, 35(2), 223–230. https://doi.org/10.1016/j.ccl.2016.12.004 86 Delaware Journal of Public Health – July 2020
45. Williams, D. R., Lawrence, J. A., & Davis, B. A. (2019, April 1). Racism and health: Evidence and needed research. Annual Review of Public Health, 40(1), 105–125. https://doi.org/10.1146/annurev-publhealth-040218-043750 46. Shippee, T. P., Akosionu, O., Ng, W., Woodhouse, M., Duan, Y., Thao, M. S., & Bowblis, J. R. (2020, July-October). COVID-19 pandemic: Exacerbating racial/ethnic disparities in long-term services and supports. Journal of Aging & Social Policy, 32(4-5), 323–333. https://doi.org/10.1080/08959420.2020.1772004 47. Ehrenfeld, J., & Harris, P. (2020, May 29). Police brutality must stop. Retrieved from: https://www.ama-assn.org/about/leadership/police-brutality-must-stop
48. Hicken, M. T., Lee, H., Ailshire, J., Burgard, S. A., & Williams, D. R. (2013, June 1). “Every shut eye, ain’t sleep”: The role of racism-related vigilance in racial/ethnic disparities in sleep difficulty. Race and Social Problems, 5(2), 100–112. https://doi.org/10.1007/s12552-013-9095-9 49. Centers for Medicare & Medicaid Services. (2020). Preliminary Medicare COVID-19 Data Snapshot. U.S. Department of Health and Human Services. Retrieved from: https://www.cms.gov/research-statistics-data-systems/preliminarymedicare-covid-19-data-snapshot 50. Climate Action Rebate Act of 2019, S.2284, 116th Congress (2019-2020). Retrieved from: https://www.congress.gov/bill/116th-congress/senate-bill/2284 51. Du Bois, W. E. B. (1986). The Souls of White Folks. In Writings 923, 926. New York, N.Y.: Literary Classics of the United States.
AstraZeneca’s response to the COVID-19 pandemic AstraZeneca across the world is responding to the COVID-19 pandemic consistent with its values to follow the science, put patients first and do the right thing. The Company has progressed a number of initiatives to ensure the continued supply of our medicines to patients, to safeguard the health and wellbeing of all our employees and communities, and to make available a potential vaccine or treatment options for the virus. • T o help contain the spread of the virus, AstraZeneca has donated nine million face masks to support healthcare workers around the world, and partnered with the World Economic Forum’s COVID Action Platform to identify the countries in greatest need. In the US, AstraZeneca donated to the CDC Foundation to expand US testing and data capabilities and deploy emergency staffing on the front lines at the state and local level. • I n late April, AstraZeneca and the University of Oxford announced an agreement for the global development and distribution of the University’s potential recombinant adenovirus vaccine aimed at preventing COVID-19 infection from SARS-CoV-2. Under the agreement, AstraZeneca is responsible for development and worldwide manufacturing and distribution of the vaccine if the clinical trials prove successful in showing the vaccine is effective. • A month later, on May 21, AstraZeneca announced an agreement with the US Government for the development, production and delivery of 300 million doses of the potential new vaccine. AstraZeneca will deliver the first doses as early as October 2020 and additional doses in 2021. The development program includes a Phase III clinical trial with 30,000 participants and a pediatric trial. • I n early June, AstraZeneca announced agreements with CEPI, Gavi and the Serum Institute of India (SII) that will bring the vaccine to low-and-middle income countries and beyond. The agreements with CEPI and Gavi are for the manufacturing, procurement and distribution of 300 million doses of the vaccine. The agreement with SII is to manufacture and supply one billion doses to low-and middle-income countries. • M ost recently, on June 13, AstraZeneca reached an agreement with Europe’s Inclusive Vaccines Alliance (IVA), spearheaded by Germany, France, Italy and the Netherlands, to supply up to 400 million doses of the potential COVID-19 vaccine. • A straZeneca has secured global supply capacity to exceed two billion doses. Other agreements are continuing to be secured to deliver AstraZeneca’s commitment to ensure global access. These agreements are happening in parallel to ensure broad and equitable supply of the vaccine throughout the world at no profit during the pandemic. • A straZeneca has also quickly mobilized global research efforts to discover novel coronavirus-neutralizing antibodies to prevent and treat progression of the COVID-19 disease, with the aim of reaching clinical trials in the next three to five months. Additionally, the Company has moved into testing of new and existing medicines across multiple therapy areas (CVRM, Oncology) to treat the infection. • F urthering the advancement towards the discovery of novel coronavirus-neutralizing antibodies to prevent and treat the progression of COVID-19, AstraZeneca has signed new agreements with academia and US government agencies and confirms plans to progress a combination approach consisting of a pair of monoclonal antibodies (mAbs). Communicating Author: AstraZeneca Spokesperson Phone: 1-302-885-2677 email: USMediateam@astrazeneca.com
Public Health: Surveillance, Mapping, and Special Populations
Addressing COVID-19 Health Disparities Through Community Engagement Marshala Lee, M.D., M.P.H. ChristianaCare, Director of the Harrington Value Institute Community Partnership Fund Jacqueline Ortiz, M.Phil. ChristianaCare, Director of Health Equity and Cultural Competence Jacqueline Washington, Ed.D. ChristianaCare, Program Manager of the Harrington Value Institute Community Partnership Fund
The COVID-19 pandemic has disproportionately affected racial and ethnic minority communities across the world. Early in the pandemic, many minority communities were receiving conflicting messaging regarding COVID-19, which contributed to much uncertainty regarding effective COVID-19 preventative strategies and risk factors for contracting the disease.1 Despite initial efforts to decrease the spread of COVID-19, many health professionals began anecdotally reporting that they were caring for a larger than representative number of minority patients who had contracted COVID-19. This was largely supported by early data showing a high incidence of comorbid conditions such as diabetes and hypertension among COVID-19 hospitalized patients.2 Once COVID-19 demographic data became more readily available, clear trends emerged which proved that certain populations were indeed contracting COVID-19 at higher rates and accounted for a disproportionate share of COVID-19 deaths. More specifically, African Americans and other racial and ethnic minorities were accounting for a disproportionate share of COVID-19 cases and deaths in the United States.3,4 A similar trend also emerged in Delaware which revealed that African Americans and Latinos were not only comprising a disproportionate share of COVID-19 cases but also had a lower rate of testing.
In order to better inform their COVID-19 community engagement plan, we obtained feedback from many of the previously existing partnerships that had been established in the African American community prior to the COVID-19 pandemic. Prior to COVID-19, the Value Institute team members were meeting regularly with a community advisory board (Frank Hawkins, Darryl Chambers, and Richard Parson) and local barbers to develop and launch the BarbeRshop Outreach (BRO) Project which is a community embedded initiative geared towards addressing hypertension disparities in African American men in Wilmington, Delaware. Earlier in the year, the Value Institute team members had also strengthened their relationship with local churches with predominantly African American congregants when they partnered to increase the response rate for the Voices of Community Survey. The survey was the health system’s attempt to better understand the healthcare access barriers that local underserved communities faced. The Office of Health Equity team members had also previously partnered with many of the same community organizations in the past to develop effective community outreach programming.
On April 24, 2020, the Delaware Department of Public Health (DPH) released COVID-19 infection rates and demographic data stratified by race. The rate of COVID-19 cases among Hispanic and Black Delawareans was 60.1 per 10,000 people and 46.1 per 10,000 people, respectively, while the infection rate among white Delawareans was 13.9 per 10,000.5 In addition to the impacts of structural racism and other social determinant of health inequities, other factors – such as challenges adhering to social distancing guidelines, testing access disparities, lack of trust, and the need for tailored messaging and interventions – were thought to largely contribute to these COVID-19 disparities.6,7 Thus emerged the need for non-traditional outreach programs to more effectively reach large segments of COVID-19 high-risk populations who less regularly engage with the healthcare system. In efforts to combat COVID-19 health disparities in Delaware, the ChristianaCare Value Institute’s team of public health researchers and community health educators and the Office of Health Equity partnered to develop an effective community engagement plan to reach local African American communities who were at higher risk for contracting COVID-19. This plan involved targeted outreach to trusted institutions in the community that could act as network-based sources for trusted information and social support, accelerating the transmission of accurate information on strategies to lower contagion. Two of these traditionally important institutions are the network of African American churches and the multiple barbershops and hair salons located throughout lower income, underserved neighborhoods. 88 Delaware Journal of Public Health – July 2020
Figure 1. ChristianaCare’s Barbershop and Salon Safety Kit
Figure 2. ChristianaCare’s Kit Distribution held on June 16, 2020 in Wilmington, DE
There was a consensus among stakeholders about the need for more accurate and culturally tailored COVID-19 educational materials, access to testing, and access to safety supplies. With this knowledge in mind, our team developed a 2-pronged strategy for addressing COVID-19 health disparities within African American communities which focused on outreach to barbershops, salons, and church in New Castle County, Delaware. This strategy was based upon the proven effectiveness of church and barbershop/salon-based health initiatives with addressing health disparities among the African American communities.8,9 Faith leaders, barbers, and stylists are popular opinion leaders who have the ability to influence their networks to adopt healthy behaviors.10,11 With adequate training and support, faith leaders and shop owners can serve as effective frontline public health workers similar to community health workers. Their trusting relationships enable them to serve as a liaison between health/social services and the community to facilitate access to services and improve the quality and cultural responsiveness of health care. In addition to conducting specialized COVID-19 training webinars for the faith leaders, barbers, and stylists, our team also provided them with educational resources and print materials which included images and content that was culturally relevant and appropriate for a broad array of health literacy levels to share with their networks. The Barbershop and Salon Conversations training webinar series provided barbers and stylist with detailed information regarding COVID-19 symptoms, transmission routes, risk factors, community testing sites, and actionable steps that the community could take in order to prevent transmission. Executive level African American physician leaders presented the information, adding a personal framework to make the health information both more relatable and more relevant to the Wilmington community. A similar webinar series was conducted for faith leaders. In efforts to reach a larger number
of people, webinar participants were also provided with resources and messaging to share with their congregants and clients. A collateral benefit of the webinar series was to expand and strengthen the relationship between the physician leaders and members of the community. As the State of Delaware reopens, our team has continued its community engagement efforts to reduce health disparities among African American communities. Most recently, our team conducted a new safety workshop for barbers and stylists and provided them with additional guidance for steps that they can take to reduce the spread of COVID-19 in their shops. In light of significant financial burdens facing shop owners secondary to recent shop closures, our team distributed fifty COVID-19 safety kits which contain many of the items such as masks, face shields, sanitizer, screening forms, and educational posters which were recommended in the safety workshop. The goal of the barbershop and salon COVID-19 safety workshop and kits which was sponsored by ChristianaCare’s Harrington Value Institute Community Partnership Fund were to provide local barbershops and salons with tools and resources necessary to safely reopen and minimize the communal spread of COVID-19 and reduce the burden on local health systems in New Castle County Delaware. Without these supplies, some of these shops may have been forced to provide services without the ability to adhere to recommended safety guidelines. This could have potentially worsened the COVID-19 disparities in our local communities. In order to obtain a kit (Figure 1), shops were required to attend a safety training conducted by ChristianaCare Infection Prevention nursing educators (Figure 2) and complete a survey to assess their understanding of COVID-19 disease transmission and safety precautions (Figure 3). The impact of COVID-19 to mental health is becoming increasingly more evident.12 Despite the lack of statistics regarding COVID-19 related mental health effects, African 89
Public Health: Surveillance, Mapping, and Special Populations
the Northwell COVID-19 Research Consortium. (2020, April 22). Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City area. JAMA. https://doi.org/10.1001/jama.2020.6775 3. Laurencin, C. T., & McClinton, A. (2020, June). The COVID-19 pandemic: A call to action to identify and address racial and ethnic disparities. Journal of Racial and Ethnic Health Disparities, 7(3), 398–402. https://doi.org/10.1007/s40615-020-00756-0 4. Owen, W. F., Jr., Carmona, R., & Pomeroy, C. (2020, April 15). Failing another national stress test on health disparities. JAMA. https://doi.org/10.1001/jama.2020.6547 Figure 3. Completion of the Safety Training
American communities are facing unique COVID-19 and societal stressors that will have lasting effects if not addressed effectively. During the second half of June, the team partnered with Dr. Rayvann Kee, a licensed clinical psychologist who works actively with the African American faith community in Philadelphia, to address the stigma of applying evidence-based strategies for mental health within faith-based organizations. This month-long educational series provides faith leaders with education on advancing a psychological approach to mental health that is compatible with faith, improving self-care to better serve in times of heightened stress and evidence-based approaches to leading congregants to better coping mechanisms. The series also covers handling crisis scenarios involving suicidality and reportable abuse with a discussion of behavioral health resources in Delaware. Our team understands the importance of community engagement and is committed to continuing sustainable partnerships with community members to develop effective initiatives geared towards addressing COVID-19 and other health disparities. Only time will tell us if our safety kits, training webinars, and educational resources were effective in reducing the transmission of COVID-19 and the burden that the disease has had among African American communities in Delaware. We are confident that these efforts are enhancing our relationship with community partners and, therefore, our ability to advance improved health outcomes. Our team is hopeful that we have laid the groundwork for an effective strategy that will allow us to minimize the disparities and negative effects of the 2nd wave of the COVID-19 pandemic.
REFERENCES 1. Karamouzian, M., Johnson, C., & Kerr, T. (2020, May). Public health messaging and harm reduction in the time of COVID-19. The Lancet. Psychiatry, 7(5), 390–391. https://doi.org/10.1016/S2215-0366(20)30144-9 2. Richardson, S., Hirsch, J. S., Narasimhan, M., Crawford, J. M., McGinn, T., Davidson, K. W., . . . Zanos, T. P., & the and 90 Delaware Journal of Public Health – July 2020
5. Coronavirus (COVID-19) Data Dashboard State of Delaware. (n.d.). [Data Dashboard]. My Healthy Community: Delaware Environmental Public Health Tracking Network. Retrieved June 12, 2020, from: https://myhealthycommunity.dhss.delaware.gov/locations/state 6. Raifman, M. A., & Raifman, J. R. (2020, July). Disparities in the population at risk of severe illness from covid-19 by race/ethnicity and income. American Journal of Preventive Medicine, 59(1), 137–139. https://doi.org/10.1016/j.amepre.2020.04.003 7. Guha, A., Bonsu, J., Dey, A., & Addison, D. (2020). Community and Socioeconomic Factors Associated with COVID-19 in the United States: Zip code level cross sectional analysis. medRxiv. Retrieved from: https://www.medrxiv.org/content/10.1101/2020.04.19.20071944v1 8. Victor, R. G., Ravenell, J. E., Freeman, A., Leonard, D., Bhat, D. G., Shafiq, M., . . . Haley, R. W. (2011, February 28). Effectiveness of a barber-based intervention for improving hypertension control in black men: the BARBER-1 study: a cluster randomized trial. Archives of Internal Medicine, 171(4), 342–350. https://doi.org/10.1001/archinternmed.2010.390 9. Shaya, F. T., Gu, A., & Saunders, E. (2006, Winter). Addressing cardiovascular disparities through community interventions. Ethnicity & Disease, 16(1), 138–144. 10. Kelly, J. A. (2004, February). Popular opinion leaders and HIV prevention peer education: Resolving discrepant findings, and implications for the development of effective community programmes. AIDS Care, 16(2), 139–150. https://doi.org/10.1080/09540120410001640986 11. Valente, T. W. (2010). Social networks and health: Models, methods, and applications. Oxford University Press. 12. Galea, S., Merchant, R. M., & Lurie, N. (2020, April 10). The mental health consequences of COVID-19 and physical distancing: The need for prevention and early intervention. JAMA Internal Medicine. https://doi.org/10.1001/jamainternmed.2020.1562
Public Health: Surveillance, Mapping, and Special Populations
Engaging Community Health Workers and Social Care Staff as Social First Responders during the COVID-19 Crisis Alicia L. Salvatore, Dr.P.H., M.P.H. Director of Community-Engaged Research, Value Institute, ChristianaCare
Christopher C. Moore Manager, Community Health, Office of Health Equity, ChristianaCare
Jacqueline Ortiz, M.Phil. Director of Health Equity and Cultural Competence, Office of Health Equity, ChristianaCare
Carla P. Aponte Johnson, M.S. Manager, Community Health Operations, Office of Health Equity, ChristianaCare
Erin Booker, L.P.C. Vice President of Community Health and Engagement, Office of Health Equity, ChristianaCare Nora Katurakes, M.S.N., R.N., O.C.N. Manager, Community Health Outreach and Education, Helen F. Graham Cancer Center and Research Institute, ChristianaCare
Alexandra M. Mapp, M.P.H. Biostatistician, Value Institute, Office of Health Equity, ChristianaCare Alex Waad, M.A. Cultural Competence Specialist, Office of Health Equity, ChristianaCare Michelle L. Axe, M.S., C.H.E.S. Research Coordinator, Community Health, Office of Health Equity, ChristianaCare
ABSTRACT In this public health practice vignette, we describe an ongoing community and system intervention to identify and address social determinants of health and related needs experienced by ChristianaCare patients and the greater community during the Coronavirus pandemic. This intervention, being conducted by the ChristianaCare Office of Health Equity, in partnership with ChristianaCare’s embedded research institute, the Value Institute, and the Community Outreach and Education division of the Helen F. Graham Cancer Center and Research Institute, engages more than 25 community health workers, health Guides, Latinx health promoters and other social care staff as social first responders during the COVID-19 crisis. These experienced front-line social care staff screen patients and community members for social needs; make referrals to agencies and organizations for needed assistance (e.g., food, housing, financial assistance); assess people’s understanding of COVID-19 and preventive measures; provide education about COVID-19; and, connect patients and community members to COVID-19 testing and any relevant clinical services. While this ongoing intervention is under evaluation, we share here some preliminary lessons-learned and discuss the critical role that social first responders can play in reducing the growing adverse social and health impacts of COVID-19 across the state of Delaware.
INTRODUCTION The social and health impacts of COVID-19 have been unprecedented and continue to unfold. This pandemic has increased stress and social adversity across all communities. However, where the impact is felt greatest is amongst underserved and vulnerable populations.1 Prior to the COVID-19 crisis, these communities faced a myriad of challenges in meeting basic needs, accessing health services, obtaining reliable and understandable, culturally and linguistically appropriate health information from trusted individuals and sources, as well as safeguarding the health and well-being of their families. As has been noted by many, the COVID-19 crisis has elucidated, underscored and exacerbated existing societal inequities and vulnerabilities here in Delaware, as well as nationwide and globally.2 To support our patients and community members during the COVID-19 crisis, ChristianaCare’s Office of Healthy Equity, in partnership with the Value Institute and The Helen F. Graham Cancer Center and Research Institute at ChristianaCare developed and initiated a responsive intervention to address COVID-19 related social and health care needs as well as access to COVID-19 information, testing and resources. This intervention, which was implemented in March 2020 and is currently ongoing, engages over 25 of ChristianaCare’s frontline social care staff, including community health workers (CHWs), health guides, health promotors (promotoras) and others. These staff act as social first responders both for the ChristianaCare patients already enrolled in these programs as 92 Delaware Journal of Public Health – July 2020
well as for community members identified through community outreach and community-based COVID-19 testing conducted by ChristianaCare. In this public health practice vignette, we describe our ongoing intervention and the ChristianaCare social first responder teams, and share some early findings and lessons learned from this work. We conclude with observations about the public health significance of this work and the importance of social first responders for mitigating, and addressing, the disparate social and health impacts the COVID-19 crisis in Delaware.
INTERVENTION GOALS AND OBJECTIVES The overall goal of this social care intervention is to contribute to the reduction of inequitable impacts of the COVID-19 crisis on our patients and communities. To these ends we are engaging ChristianaCare social care teams in identifying and meeting social, informational and health care needs brought about by the COVID-19 crisis. The objectives of this intervention are to: 1) Identify social needs of enrolled patients and community members with social determinants of health (SDoH) screening; 2) Refer enrolled patients and community members to resources to address identified SDoH needs via the UniteDE platform3 and other programs; 3) Assess levels of understanding of COVID-19 and recommended strategies for staying safe;
4) Provide instructional materials and guidance to families about COVID-19 and recommended strategies; 5) Identify patients and community members who may need to be referred to available resources for health care consults, testing, and additional services.
INTERVENTION TEAMS Several existing ChristianaCare social care programs are engaged in this intervention. These social care staff, which include Community Health Workers, Health Guides, health promoters (promotoras), are well positioned to participate in this intervention as its activities are an extension of and/or wellaligned with their standard workflow and program of work.
Community Health Workers ChristianaCare has seventeen CHWs, or “natural helpers” who work closely with patients and care teams in Primary Care, Women’s Health, CareVio Community (a network of care coordination support services) and in school-based health centers. While the work that CHWs do with patients in each of these settings differs somewhat, key areas of CHW support include assessment of SDoH and referrals to necessary resources and services; support of patient-centered goal setting and achievement; and connection to care teams and services to meet additional medical and non-medical needs. CHWs provide ongoing support for enrolled patients who may work with them for a period of a couple months up to nine months, depending on the care program.
Health Guides ChristianaCare’s four health guides function as collaborative members of ChristianaCare primary care practices and primarily support uninsured, underinsured and vulnerable patients, including undocumented patients. They provide immediate supportive services related to referrals or assistance with health insurance, financial assistance, prescription assistance, medical and wellness appointments, and community resources. They also coordinate with CHWs, clinicians, and social workers to ensure delivery of care and that health and identified SDoH related needs are met.
Healthy Latinx Families Program Promoters
ChristianaCare patients and the wider community. Patients served include those already enrolled in our social care programs (e.g., patients enrolled in our Primary Care or Women’s Health CHW programs) and also patients newly referred to our teams. Starting in March, social first responders contacted their enrolled patients to assess emerging and changing needs and to provide them with education and materials about COVID-19. The intervention also serves community members. We employ two main outreach strategies to identify and recruit community members who may benefit from our intervention: 1) screening for SDoH during registration at ChristianaCare COVID-19 testing events and 2) establishing and advertising a bilingual hotline number for COVID-related assistance.
Screening for Social Determinants of Health at COVID-19 Testing Events During the registration process at ChristianaCare COVID-19 testing events, people are screened for SDoH-related needs using the following single-item yes or no question: “We would like to help you during this difficult time. During the last two months have you had difficulties meeting your basic needs, including paying for food, paying for the place you live, getting transportation or paying for medical care?” (In Spanish: “Nos gustaría ayudarlo en este momento difícil. Durante los últimos 2 meses, ¿ha tenido dificultades para satisfacer sus necesidades básicas, como comprar comida, pagar por su vivienda, conseguir transporte o pagar por atención médica?”) Those indicating “yes” to the social need question are asked if they would like someone from ChristianaCare to assist them with their needs. Those who do are contacted to coordinate a followup from a CHW.
Bilingual Assistance Hotline During the first month of the crisis, the Office of Health Equity established a bilingual hotline for people to call for information and support. A flyer promoting this hotline (see Figure 1) was created and is circulated at food distribution events and via social media and community partners. People who call the hotline are screened for needs and then routed to either a social first responder or to appropriate testing or health care resources.
(Promotoras del Programa de Familias Latinas Saludables).
This program is administered through the Community Health Outreach and Education Program at the Helen F Graham Cancer and Research Institute and serves Delaware Latinx families. Three health promoters (promotoras) work with enrolled families to improve knowledge of healthy behaviors, screen for social and health needs and make connections to appropriate services and programs. The promotoras working with this program are bicultural and bilingual in Spanish and English.
Once connected with a patient or community member, our social first responder teams use an 11-item social determinant of health screener to assess individual and family needs. The screener includes questions about financial insecurity, food insecurity, interpersonal safety, difficulties with transportation, and other related issues. Time permitting, they also asked followup questions that assessed whether the stated needs started or were made worse since the COVID-19 crisis. Depending on their program, social first responders enter this information into either a REDCap database and/or directly into the SDoH screening form in UniteDE.2 UniteDE is a coordinated care network of health and social care providers, sponsored by ChristianaCare, that are connected through a shared technology platform that enables them to send and receive electronic referrals. In the UniteDE platform, each SDoH need entered is met with an additional form that refers the person to one or more suggested resources.
TIME, PLACE AND POPULATION This intervention was initiated in March 2020, just after the COVID-19 crisis commenced and is ongoing. While the majority of people supported by this intervention reside primarily in New Castle and Kent Counties, some reside elsewhere in Delaware, northwestern Maryland, southeastern Pennsylvania and south western New Jersey. The population served includes both
Public Health: Surveillance, Mapping, and Special Populations
early testing events in Wilmington screened for a social need and requested assistance from our program. Stories shared by our social first responder teams indicate not only extensive and increasing social needs but also reveal a great need for supportive and emotional care. In debriefs with our intervention teams, they have shared that calls can often last more than 45 minutes as people want and need to talk not only about the things we ask about but about their experiences, feelings and fears about the COVID-19 pandemic. Additional programs and interventions are needed to meet the growing social and behavioral needs and provide culturally and linguistically appropriate care in these areas, especially to communities with limited health care access. 2) While not always easy to use SDoH screening, it is valuable for documenting and identifying growing needs. While the use of our SDoH tool has proven challenging at times for social care teams balancing high volumes of calls and urgent needs, we have found this tool to be useful in systematically capturing and helping us to target referrals that meet people’s needs. These questions are assisting us to document not only the spectrum of issues that have been impacted but also the increases in these needs that have occurred during even during the initial months of the COVID-19 crisis. For example, in just a two month period, the SDoH data from only one of our social first responder teams reveal great need associated with the COVID-19 crisis. Sixty-three percent of those seen reported that they were worried about or unable to pay their bills prior to Figure 1. Flyer for ChristianaCare COVID-19 Intervention Hotline
For example, if a person screens positive for food insecurity, a form to refer him or her to the food bank, a food pantry or other food assistance resource is provided. UniteDE uses the person’s address to provide the most locally-relevant resources. Social first responders select the appropriate resource that is then, upon receipt, accepted or returned by the selected agency or organization. Based on the decision made, social first responders either make an additional referral or the agency or organization (who has accepted the referral) directly follows up with the individual. To date, over 50 community-based organizations and programs throughout the state participate in the UniteDE platform and additional organizations are being recruited to join the UniteDE network and platform. All patients and community members served by our social first responders also are asked additional questions that assess their level of understanding of COVID-19 modes of transmission, preventive behaviors and similar topics. Each person is provided with “real time” educational and educational materials, in English and Spanish, to use themselves and/or share with others (see Figure 2 for one example).
EVALUATION AND LESSONS LEARNED The evaluation of this intervention is ongoing. We have, however, several notable key lessons to share: 1) Social Needs are Vast. Our experiences to date indicate immediate and extensive needs both among our patient population and the community members we have served. For example, 19% of the 300 people tested at one of our 94 Delaware Journal of Public Health – July 2020
Figure 2. Example of Educational Materials shared in Intervention
COVID-19; 84% of whom stated these needs started or were made worse during the crisis. Similarly, 63% also reported that they worried about their food running out prior to COVID-19; 77% of whom indicated that this need started or was made worse since the crisis began. More than half (55%) indicated that the food that they bought didn’t last and they couldn’t buy more; 88% of whom indicated this started or was made worse by the crisis. Almost 20% of those screened indicated that they had an urgent need. Nonetheless, more brief ways of assessing SDoH and other needs may allow intervention teams to better balance the needs of documentation and serving more patients and community members. We are currently in discussions about how we may adapt our questions to these ends. 3) Understanding of COVID-19 and recommended behaviors has increased. More information about testing results and ongoing preventive behaviors is vital. Early in our intervention, general understanding about COVID-19 and preventive behaviors was limited, especially among underserved and limited English proficiency populations. Recently, we have observed that knowledge of COVID-19 and recommended practices has increased. Now, however, there is a need to improve understanding about testing procedures and what different types of testing and results mean. Further, there is a need to return testing results in a linguistically and culturally appropriate manner and to provide people with clear recommendations about how they should proceed given a positive or a negative result. Social first responders may be valuable as a source of support to those who test positive and may serve as a valuable source of information about recommended practices for those with a positive test and subsequent case investigation that may follow. Social first responder teams like ours can be critical sources of trusted and culturally appropriate information as well as excellent resources for better understanding which strategies are currently working and where there are opportunities to improve our COVID-19 interventions.
ADVERSE EFFECTS To our knowledge, this intervention has not had any adverse or unintended consequences. However, despite best efforts of our teams, this intervention alone is not enough to satisfy the enormous needs of many of our patients and community members. In order to meet the growing needs of patients and community members, in an equitable manner, additional investment in social first responders, in communities across the state are needed. Additionally, policies and programs to address the underlying issues of inequity that render some communities more vulnerable not only to COVID-19 but also to its ongoing adverse social and health sequelae will be critical for promoting and safeguarding public health.
SUSTAINABILITY The costs of this intervention continue to be supported by ChristianaCare. Additional support mechanisms and resources are needed beyond these to further scale-up, support and maximize the positive public health impact statewide. CHWs and social care workers from other health systems as well as
lay health workers and natural helpers serving in communitybased organizations and in communities at large will be critical to building a broader social first responder workforce across the state and to meeting current and longer-term social care and health needs.
PUBLIC HEALTH SIGNIFICANCE In this public health practice vignette, we have described a responsive intervention raised up by ChristianaCare in order to meet patient and community needs and mitigate potentially ongoing and inequitable impacts on individuals, families and communities. While this intervention and the use of social first responder teams have likely helped to meet some social, informational, and health needs of our patients and communities, in many ways, our lessons learned, and the stories shared by these teams point to an enormity of need beyond what our teams can support. While these teams have worked tirelessly – supporting needs and providing listening ears – to our patients and community members, they are not enough. Our experiences, as well as a robust public health literature demonstrate that natural helpers such as CHWs acting as social first responder teams are critical to the reduction of health disparities and meeting emergent community needs during pandemics. We encourage public health and health leadership, insurers, philanthropists and policy makers to support the expansion of social first responder teams across the state.4 ChristinaCare’s Office of Health Equity has already started to expand UniteDE, a critical platform for making and tracking “real time” referrals to SDoH and other related services, throughout the state. This tool, as well as the experiences and lessons learned from this intervention and other similar programs, may be critical elements of a successful statewide social first responder initiative. Although social first responder interventions are valuable, they are only one of many required elements of a robust and equitable response to the COVID-19 crisis. Programs and policies that address and reverse the adverse sequelae of the COVID-19 crisis across the spectrum of SDoH – housing, jobs, food insecurity, to name a few – as well as address the root causes of the inequity that render some communities more vulnerable in the first place are fundamental to safeguarding and promoting public health and healthcare equity for all of Delaware.
REFERENCES 1. Webb Hooper, M., Nápoles, A. M., & Pérez-Stable, E. J. (2020, May 11). COVID-19 and racial/ethnic disparities. JAMA, 323(24), 2466–2467. https://doi.org/10.1001/jama.2020.8598 2. Laurencin, C. T., & McClinton, A. (2020, June). The COVID-19 pandemic: A call to action to identify and address racial and ethnic disparities. Journal of Racial and Ethnic Health Disparities, 7(3), 398–402. https://doi.org/10.1007/s40615-020-00756-0 3. Unite Delaware. (n.d.). Retrieved from: https://delaware.uniteus.com/ 4. Smith, D. O., & Wennerstrom, A. (2020, May 6). To strengthen the public health response to COVID-19, we need Community Health Workers. Health Affairs Blog. Retrieved from: https://www.healthaffairs.org/do/10.1377/hblog20200504.336184/full/ 95
Public Health: Surveillance, Mapping, and Special Populations
Delaware COVID-19 Homeless Community Outreach Partnership 2020 Rita Landgraf, Director, University of Delaware Partnership for Health Communities Susan Holloway, Associate Deputy Director, Delaware Division of Substance Abuse and Mental Health
Renee Beaman, Division Director, Delaware State Service Centers Ray Fitzgerald, Division Director, Delaware Social Services
Specifically, the outreach team engaged homeless individuals, conducted 2,528 screenings for COVID-19 symptoms, and other concerning vital signs. Our approach evolved as the availability of testing increased and we were thankful to many of the health care providers and the Division of Public Health for donating testing supplies to our teams. In addition, all on the ground team members were in full Personal Protection Equipment (PPE), which was also donated. Since this was primarily a COVID-19 outreach activation, centralized housing to safely isolate and/ or self-quarantine is a critical component of a holistic outreach model to mitigate the spread of COVID-19 among vulnerable individuals, particularly those who screen presumptive positive during outreach. It is important to note that regardless of whether the individual was COVID-19 positive or negative, the addition of this essential housing resource for protection and self-quarantine for vulnerable populations statewide was strategically established early in the activation to help mitigate viral spread and positively impact health outcomes for all Delawareans.
The disproportionate impact of the COVID-19 pandemic on individuals in poverty, individuals with substance use and mental health diagnoses and communities of color has been well documented.1 A recent report from Johns Hopkins Bloomberg School of Public Health illustrated the relationship between health disparities among vulnerable populations and the spread of COVID-19.2 The following factors play an important role in COVID-19 disparities among individuals experiencing poverty, individuals suffering from substance use and mental health disorders and communities of color: 1) Higher rates of underlying health conditions and decreased access to medical care; 2) Employment in essential jobs with high levels of public interaction; 3) Structural issues such as concentrated poverty, living conditions and lack of paid sick leave; 4) Cultural beliefs and values. In addition, the Centers for Disease Control and Prevention (CDC) identified early on that persons experiencing homelessness are at high risk for COVID 19.3 Homeless services are often provided in congregate settings, which could facilitate the spread of infection. Because many people who are homeless are older adults or have underlying medical conditions, they may also be at higher risk for severe disease. The CDC emphasized that health departments and healthcare facilities should be aware that people who are homeless are a particularly vulnerable group and recommended that if possible, identifying non-congregate settings where those at highest risk can stay may help protect them from COVID-19.4
DELAWARE ACTIVATION On March 24, 2020 the COVID-19 Homeless Community Outreach Partnership was established by Delaware Department of Health and Social Services (DHSS) and charged with identifying and engaging individuals experiencing homeless to 1) Identify if COVID-19 viral activity was present among the homeless, especially in night shelters remaining open, and those living on the streets, many of whom would continue to congregate outside of day shelters that were closed in light of the State’s restrictions. 2) Triage and place in shelter (largely motels and hotels throughout the state) those homeless who were extremely vulnerable to the acuity of COVID-19 if exposed to the virus. The triage was largely implemented based on CDC guidelines, and included those testing positive for COVID-19 and or exposed to someone positive, those 65 and older, and those with chronic medical conditions 96 Delaware Journal of Public Health – July 2020
CORE STRATEGIC ENTITIES The University of Delaware, Partnership for Healthy Communities (PHC) was invited by DHSS to lead the strategic operational plan for this specialized outreach activation. The mission of the PHC is to align and strengthen University of Delaware research, educational, and service capabilities to improve the health and well-being of Delaware communities and beyond through effective partnerships. The PHC is engaged in over 40 strategic initiatives with various degrees of involvement, ranging from alignment via board and committee memberships, to engagement in campus-community partnerships around multisector, coordinated efforts to impact social and environmental factors that promote optimal health and well-being and advance equity. Rita Landgraf as the Director of the PHC and as former Cabinet Secretary of DHSS was requested to be the lead managerial partner. DHSS/Division of Substance Abuse and Mental Health (DSAMH) was invited to join as the co-lead in strategic management as well as developing the social support teams to be integrated with a medical team in the field. DSAMH is committed to managing the impact of COVID-19 across the behavioral health system, by continuing to monitor the well-being of its population in order to reduce future incidents and deaths of despair. Prior to COVID-19, the percentage of DSAMH clients who rated themselves as “suffering” in a standardized Well-Being Assessment was greater than that of the general population and in other populations with mental health and addictions disorders (15% vs. 3%). Additionally, since the onset of the COVID-19 pandemic, DSAMH has monitored weekly DTRN data and noted increased rates of alcohol use, overdose and homelessness. Susan Holloway, associate deputy director of health, integration and social determinants serves as co-lead.
DHSS/Division of State Service Centers (DSSC) and DHSS/ Division of Social Services (DSS) are committed to assisting Delawareans during the COVID-19 pandemic by providing Emergency Assistance funds for hotel vouchers, rent, utilities and emergency shelter for eligible low-income persons in order to help to maintain self-sufficiency and to prevent homelessness. The purpose of Emergency Assistance is to avoid, eliminate or alleviate an emergency condition caused by an unforeseen circumstance resulting in a situation that calls for immediate action. To be eligible, an individual or family must be able to maintain after the crisis is alleviated; an individual or family must receive or be eligible for Cash Assistance (Temporary Assistance for Needy Families [TANF], General Assistance [GA], Social Security Insurance [SSI]) or certain Medicaid programs; or the emergency must have been the result of an unforeseen circumstance or a combination of circumstances that are beyond the recipients’ control. Renee Beaman, DSSC Division Director and Ray Fitzgerald, DSS Division Director served as leads on this integration. Lieutenant Governor Bethany Hall Long served as an advisor to the managerial strategic team and provided hands on support as a public health nurse and professor to the medical team.
SERVICE FUNCTIONS In advancing the integrated delivery model, all services delivered were in accordance with all applicable Federal, State, and Local laws, regulations, and DHSS approved program guidelines and certifications. Services included the following: 1. Intensive infection prevention efforts on those most likely to develop severe complications from COVID-19, including people who are currently in shelters and people who are currently unsheltered. A commitment to expand the category of those receiving intensive infection prevention efforts as resources permitted. The primary strategy for intensive infection prevention efforts was to provide single occupancy housing, while separating people with symptoms quickly, creating isolation units (i.e. hotels, motels) for persons under investigation (PUI), and bringing into shelter those must vulnerable to acuity if impacted by viral activity. The COVID 19 Homeless Community Outreach Partnership co-leads created clear lines of communication relative to the importance of the process, so that homeless service providers and health (physical and behavioral) systems had easy access to appropriate isolation and/or quarantine resources to decrease the chance that potentially COVID + individuals spend extended time among the general population experiencing homelessness. 2. Screening and referral were conducted by a team approach consisting of a medical team integrated with a social service team, inclusive of behavioral health specialists. Two teams were established to support the statewide activation. Dr. Sandy Gibney was the medical lead and established the medical protocols initiated inclusive of screening for symptoms. When testing became more readily available, Dr. GIbney administered the PCR test and was responsible for the follow up
and monitoring of those housed in hotels. Dr. Gibney established a medical team to assist her in the activations for New Castle and Kent Counties. Dr. Rama Peri was recruited to lead the Sussex County medical team and was trained and provided initial guidance by Dr. Gibney, following the same established recognized protocols inclusive of follow up relative to testing results and recruiting additional medical team members. Both teams continue to recirculate with the homeless as the state restrictions continue to be lifted. The Social Service Teams were integrated with Medical teams and consisted of DSS, DSSC, and DSAMH personnel, some on the ground and some behind the scenes coordinating appropriate hotel/motel referrals. In addition, behavioral health providers from Aquila, RI International, and Peace by Piece supported teams. These teams provided food at the screening sites, personal hygiene items, clothing and naloxone. When individuals were deemed eligible for placement in hotel/motel based on the CDC guideline criteria, the social service team would provide the transport and representatives from the team would support providing meals or securing support from organizations for meal and medication distribution dependent upon placements.
SCREENING AND DIAGNOSES • If an individual was presumed positive, the medical team referred that individual to the social service team for placement and medical follow up relative to isolation and or quarantine in a COVID-19 + hotel. • If an individual screened negative and is at high risk for medical complications, social service teams would arrange for placement in non Covid-19 +hotel/motel/shelter. • an individual screened negative and was at low risk of medical complications, the individual remained in the shelter or nonsheltered with appropriate social distancing, cleaning and rescreening. The CDC recommended that individuals not be forcibly “swept” from their current location. It is appropriate to provide the individual with an option to remain where they are, if appropriate social distancing and hygiene needs can be addressed, or to enter an appropriate shelter opportunity where appropriate social distancing, cleaning and screening measures can be met, if available. Individuals meeting the DSAMH criteria of serious persistent mental illness and/or substance use disorder, along with the COVID-19 triage criteria, were supported by the behavioral health provider in one of three designated sites throughout the state, with the intent to establish a behavioral health discharge plan and connect these individuals to appropriate level of care when restrictions are lifted and safely transition individuals into care.
FUNDING REQUIREMENTS Table 1 provides information regarding the managing agency, eligibility criteria, program details and funding sources related to hotel/motel placements for each identified vulnerable population. 97
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Substance Use To be deemed eligible for this transitional housing hotel placement program, the client and Mental must have a SPMI / SUD or Co-Occurring Health diagnosis and at least one of the following qualifying conditions:
Individuals are also enrolled into a DSAMH program where the participants receive treatment for substance use, mental health or cooccurring disorders.
• Over the age of 60
Connected to a community-based treatment/ service provider
• Have an underlying health condition such as: diabetes, cardiovascular disease, autoimmune disease or a physical disability
Continue to receive the appropriate level of long-term treatment after being discharged from the hotel-based program.
• Be enrolled in existing treatment services or willing to immediately enroll in a treatment program
Food, clothing and medication are provided as appropriate.
Housing emergency must have resulted from an unforeseen circumstance or combination of circumstances that are beyond the recipient’s control. Medicaid individuals and families cannot have resources immediately accessible to meet their needs. Individuals or families must meet technical and financial eligibility criteria. Client must be a participant of
The Division usually authorizes the maximum time and amount allowed for temporary emergency shelter unless free emergency shelter is available through our partnership with Centralized Intake.
1. Temporary Assistance for Needy Families (TANF) 2. General Assistance (GA) 3. Supplemental Security Income (SSI) 4. An Eligible Medicaid Qualifying Medicaid. The recipients must be homeless or in jeopardy of losing their home, cannot be more than 60 days behind in making payments on rent or mortgage or property taxes. A maximum of $1,200 is allowed to provide a homeless recipient with up to 90 consecutive days of temporary emergency shelter in a DHSS certified shelter. General Population
To be deemed eligible for a hotel placement, an individual must meet one or more of the following qualifications: • Referred by Public Health under a quarantine mandate
To be deemed eligible for housing subsidies, an individual must: • Be identified as moderate to high risk for recidivism as determined by the DOC assessment tool;
• DSAMH – PATH Grant**
Federal Funds • DSSC & DSS - TANF Grant
Once placed clients must actively seek permanent housing and cooperate with DHSS in monitoring progress of the housing search. We refer applicants to appropriate agencies for assistance in obtaining permanent living arrangements appropriate to the client and his/ her dependents after they leave a temporary shelter. Food, clothing and medication are provided as appropriate.
Individuals placed under this program are housed until they are no longer COVID-19 positive. Food, clothing and medication are provided as appropriate.
Federal Funds • DPH – FEMA/ CARES Grant The Coronavirus Aid, Relief, and Economic Security (CARES) Act
• Being discharged from an acute care hospital after a COVID-19 treatment episode Corrections
• DSAMH – SOR Grant*
Limited funding is available to pay up to one month’s rent for those needing assistance (this is usually Oxford House, sober living housing, or other housing providers).
General Funds Federal Funds
These funds cannot be used to support eligible • Be on community supervision (sentenced, not housing providers (apartments not in FSF or living with family members). pre-trial); and • Utilize a housing provider in FSF (must have TIN number).
Exceptions may be made for paid 2-week hotel stays. FSF eligible hotels are limited to New Castle County, at this time. Usually, this exception is applied to individuals who require chronic medical care and has not yet been approved for long term care or hospice. These individuals can apply for GA to get further assistance through state service centers.
Table 1. Managing agency, eligibility criteria, program details, and funding sources for hotel/motel placement. * The Delaware State Opioid Response (SOR) Grant addresses gaps in Delaware’s system and increase access to quality treatment, refine transitions to care, and complement existing efforts. This funding allows Delaware to engage vulnerable individuals, build sustainable capacity and infrastructure for treatment, housing and other social determinants of health. ** The purpose of the Projects for Assistance in the Transition from Homelessness (PATH) Formula Grant, administered by the U.S. Department of Health and Human Services, Center for Mental Health Services, is to provide federal funds to support outreach and mainstream service linkage to persons with serious mental illness who are experiencing homelessness or at imminent risk for homelessness. The target population also includes persons experiencing homelessness who have co-occurring diagnoses of mental illness and substance use disorder. 98 Delaware Journal of Public Health – July 2020
The outcomes of this effort were to build upon the systems that have been established to meet the needs of individuals, especially during the COVID 19 activation timeline (March 24 – June 15, 2020). This activation was not a solution for homelessness, but has highlighted processes that can be extended into the work many continue to advance in ending homelessness. In addition, the intersection between clinical support and social support provides a holistic approach in enhancing stability and overall wellbeing. The three hotels that DSAMH supported were considered temporary behavioral health programs during the restrictions of short-term lodging enacted by the Governor. The hotel/motel restrictions were phased out beginning June 1 and efforts were underway to connect the 332 individuals placed into the next level of care, inclusive of housing supports. All of the 332 individuals placed during the COVID-19 activation timeline were included in a planning process to support them to the next level of care, 185 accepted the plan and have moved into the next level of care. The total number of individuals refusing services was 114; however, efforts remain underway to continue to engage with these individuals in hopes of advancing treatment in the future. During this timeframe, two individuals died and cause of death appears to be of natural causes. Unfortunately, 31 individuals are currently lost to the system due to the transient nature of the population but outreach efforts remain.
TRANSITIONAL HOUSING STRATEGY The transitional housing strategy includes several types of housing (see Table 2). DSAMH is committed to increasing access to care and treatment for individuals living with substance use disorder (SUD) and opioid use disorder (OUD). This effort further supports the START Initiative, a system-wide, quality improvement process that will increase connectivity, improve referral and data sharing, and ensure wrap-around services across the State of Delaware through the implementation of evidence-based programs and practices. The system includes stakeholders from public safety, education, criminal justice, social service, transportation, public health, hospitals, and primary care providers, as well as other providers and entities.
DSAMH LONG TERM HOUSING STRATEGY DSAMH will utilize a coordinated approach to enable individuals to move from transitional housing to a long-term housing option. Further, the client will be afforded the option to remain with their current provider of choice and the flexibility to transition to a different level of care when needs dictate a change in services. The approach is also intended to allow individuals to access coordinated services from providers that may be funded by different state agencies that occupy a role in the life of the consumer. DSAMH will address the long term housing needs of individuals through various programs inclusive of the • State Rental Assistance Program. Affordable voucher-based program in partnership with Delaware State Housing Authority (DSHA). The Delaware State Rental Assistance Program is designed to assist low-income households who are eligible to receive continuing supportive services and require affordable housing to live safely in the community. The program will utilize SRAP vouchers administered by the DSHA for households referred by the Department of Health and Social Services (DHSS) and the Department of Services for Children, Youth, and their Families (DSCYF). DHSS and DSCYF will leverage existing funds to provide supportive services to SRAP applicants during the program application, screening, and housing selection processes. After a SRAP applicant is approved and moves into the SRAPassisted unit, DHSS, DSCYF, or an approved service provider will continue to make appropriate supportive services available to the participant throughout their participation in the Program. Participation in supportive services is voluntary and is not a condition of participation in SRAP. • The Section 811 Program. The Section 811 program allows persons with disabilities to live as independently as possible in the community by subsidizing rental-housing opportunities, which provide access to appropriate supportive services. • Tax Credit Properties. Apartment complexes that participate in the federal low-income housing credit program.
Single occupancy housing in a hotel/motel setting for individuals experiencing behavioral health distress; identified as homeless, high risk, and assessed as Covid +, Covid-, or Person under investigation who could be safely isolated.
Provide a healthy living environment for individuals to initiate and sustain recovery, defined as abstinence from alcohol and other non-prescribed drug use and to gain improvement in their physical, mental, spiritual, and social wellbeing. In addition, these residences act as transitional housing according to NAAR Level IV standards that provides a setting for individuals awaiting inpatient treatment post withdrawal management from residential treatment in a recovery-oriented, safe, drug and alcohol-free environment.
A statewide apartment program for persons working toward the goal to live independently and who need some additional daytime, evening, overnight and weekend supervision.
Provide a transition for those individuals who have no permanent residence and have needs that require short-term stabilization beyond traditional housing programs after exiting the hospital or If they have any ongoing psychiatric care need.
Cost-effective, community-based housing alternatives for adults living with severe psychiatric disorders, who are unable to live fully independently and can benefit from intensive supportive and rehabilitative services in the home.
Supported Vision Living Residences
A housing program for adults with serious and persistent mental illness (SPMI) who can benefit from roundthe-clock oversight and low-intensity support from onsite, unlicensed staff members. Its goal is to increase resident stability, promote hope, wellness and resiliency, and foster greater independence through providing rehabilitative services in a home-like environment.
Table 2. Transitional housing types in the traditional housing strategy 99
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DSSC – LONG TERM HOUSING STRATEGY
The individuals sheltered in DSSC/DSS monitored hotels/ motels are on a different timeline since this program has been in existence prior to COVID-19 and, due to COVID-19, the time allowed for motel/hotel shelter has been extended. In partnership with New Castle County, DHSA, Delaware Housing Alliance, and Family Promise, a pilot program has been initiated to focus on families with children placed in motels/hotels and transitioning these families utilizing programs such as rapid rehousing, housing first and/or supportive housing or some level of permanent housing through the leveraging of a variety of federal funds. The focus is to extend this statewide to achieve housing stability opportunities for homeless families.
The effort of this activation was supported by many throughout our state, inclusive of a variety of elected officials, state personnel, individuals, advocates and organizations. This work could never have been accomplished without this level of engagement. We are extremely grateful to all who provided guidance and support during this activation.
The unduplicated number of individuals placed in motels/hotels during this timeframe (ending June 11) is 1,427. The total number of households with children is 260 and the total number of children is 476. In addition, 28 individuals placed are over the age of 65.
2. Thomas, K. K. (2020, April.) How health disparities are shaping the impact of COVID-19. Retrieved from: https://www.jhsph.edu/covid-19/articles/how-health-disparities-areshaping-the-impact-of-covid-19.html
In closing, this ongoing effort, relative to homelessness, will be strengthened by focusing on cultural competence to ensure effective interaction with priority populations. By continuing to build on a framework that was developed through stakeholder feedback, statewide consortiums, and national experts, Delaware can ensure a systematic approach to addressing gaps, streamlining and leveraging resources and applying data-driven practices to improve housing access, treatment, and wraparound supports that are essential to the long-term success.
100 Delaware Journal of Public Health – July 2020
REFERENCES 1. Dorn, A. V., Cooney, R. E., & Sabin, M. L. (2020, April 18). COVID-19 exacerbating inequalities in the US. Lancet, 395(10232), 1243–1244. https://doi.org/10.1016/S0140-6736(20)30893-X
3. Centers for Disease Control and Prevention. (n.d.). People who are at higher risk for severe illness. Retrieved from: https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/ people-at-higher-risk.html 4. Center for Disease Control. (n.d.). Interim guidance on unsheltered and coronavirus disease 2019 (COVID19) for homeless providers and local officials. Retrieved from: https://www.cdc.gov/coronavirus/2019-ncov/community/homelessshelters/unsheltered-homelessness.html
www.fic.nih.gov www.fic.nih.gov www.fic.nih.gov
GLOBAL GLOBAL HEALTH GLOBAL HEALTH M AT TERS HEALTH M AT TERS M AT TERS
Inside this issue Inside this issue Former Fogarty grantee Inside this issue Former Fogarty grantee leads genomics research Former Fogarty grantee leads genomics projects in Africaresearch . . . p. 5 leads genomics projects in Africaresearch . . . p. 5
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projects in Africa . . . p. 106 5
FOGARTY INTERNATIONAL CENTER • NATIONAL INSTITUTES OF HEALTH • DEPARTMENT OF HEALTH AND HUMAN SERVICES
NIH to invest $58M to catalyze data science in Africa NIH to invest $58M to catalyze data science in Africa NIH to invest $58M to catalyze data science in Africa
FOGARTY INTERNATIONAL CENTER • NATIONAL INSTITUTES OF HEALTH • DEPARTMENT OF HEALTH AND HUMAN SERVICES
Notices of intent to publish four funding opportunity
announcements (FOAs) for DS-I Africa were recently issued by NIH. The FOAs will be issued this summer announcements (FOAs) for DS-I Africa were recently and will provide more details regarding the initiative. issued by NIH. The FOAs be Africa issuedwere this recently summer announcements forwill Applications are (FOAs) expected toDS-I be due in late 2020 with and will provide more details regarding the initiative. issued byslated NIH. to The FOAs issued this projects begin inwill the be second half of summer 2021. Applications are more expected to be due in late with and will provide details regarding the 2020 initiative. projects slated to begin in the second half of 2021. Applications are expected to be due in latesymposium 2020 with NIH is hosting a virtual projects slated to begin in the second half of platform in late summer to 2021. communiNIH is hosting a virtual symposium cate the program’s key priorities and platform in lateasummer to communiNIH is hosting virtual symposium engage participants in robust scientific cate the program’s key priorities and platform in late summer to data communidiscussions on the state of science engage in robust scientific cate theparticipants program’s key priorities and in Africa. The platform is designed discussions on the state of data science engage participants in robust scientific to encourage networking across in Africa. The isof designed discussions onplatform the state data science disciplines, sectors and geographies to encourage networking across in Africa. The platform is designed to foster collaborations that will disciplines, sectors and geographies to encourage across produce high networking quality applications. More to foster collaborations that will disciplines, sectors and geographies information is available at https:// produce quality applications. More to foster high collaborations that will commonfund.nih.gov/AfricaData. information is available at https:// produce high quality applications. More commonfund.nih.gov/AfricaData. information available at https:// DS-I Africa isisan NIH Common Fund program guided bycommonfund.nih.gov/AfricaData. a working group led by the Office of DS-I Africa is an NIH Common Fund the Director, Fogarty, the National Institute of Biomedical program guided byDS-I a working group led Common by the Office of Africa the is an NIH Fund Imaging and Bioengineering, National Institute of the Director, Fogarty, the National Institute of Biomedical program guidedand by the a working group led of by Medicine. the Office of Mental Health National Library Imaging and Bioengineering, the National Institute of the Director, Fogarty, the National Institute of Biomedical Mental Health and the National Library of Medicine. Imaging and Bioengineering, the National Institute of Mental Health and the National Library of Medicine.
NIH has announced new guidance for grantees that addresses reported gaps in its policies against sexual NIH has announced new guidance for grantees that harassment. NIH grant recipients will now be expected addresses reported gaps in its policies against sexual NIH has announced new guidance for grantees that to promptly inform the agency of changes in investigaharassment. NIH grant recipients will now be expected addresses reported gaps in its policies against sexual tors or movement of a grant to a new recipient to promptly inform the agency of changes in harassment. NIH grant willare now beinvestigaexpected institution, specifying ifrecipients the changes related to tors or movement of a grant to a new recipient to promptly inform theretaliation agency of changes investigaharassment, bullying, or hostileinworking institution, specifying the changes are related to tors or movement of a if grant to a newwhere recipient conditions. This includes situations a senior harassment, bullying, retaliation or hostile working institution, is specifying the achanges are related to researcher removed iffrom grant during investigation conditions. This includes situations where a senior harassment, bullying, retaliation or hostile working of a serious allegation. researcher removed from a grant during investigation conditions. is This includes situations where a senior of a serious allegation. researcher is removed from a grant during investigation of a serious allegation.
“The reason is clear—NIH does not tolerate sexual harassment. Period,” according to a blog post from “The reason is clear—NIH does not tolerate sexual the Office of Extramural Research that explained the harassment. Period,” according to atolerate blog post from “The reason clear—NIH does not sexual changes. Theisnew guidance builds on previous steps NIH the Office of Extramural Research that explained the harassment. Period,” according to of a blog post from has taken to strengthen reporting sexual harassment changes. The new guidance builds on previous steps NIH the Extramuraland Research that explained and Office other of misconduct, is intended to prevent the has takenThe to strengthen reporting sexual harassment changes. new guidance buildsof on NIH instances of “passing the harasser,” inprevious which a steps scientist and other misconduct, and is intended to prevent has taken to strengthen of sexual harassment who changes institutionsreporting could evade the consequences instances of “passing the harasser,” in which a scientist and otherharassment misconduct, and is intended prevent of sexual findings. For moretoinformation, who changes institutions could evade the consequences instances of “passing the harasser,” in which a scientist visit: https://bit.ly/NIH-harassment-reporting. of sexual harassment findings. more who changes institutions could For evade theinformation, consequences visit: https://bit.ly/NIH-harassment-reporting. of sexual harassment findings. For more information, visit: https://bit.ly/NIH-harassment-reporting.
Image by Image iStock Image by iStock by iStock
The NIH has announced it plans to provide $58 million over five years for a new initiative, Harnessing Data The NIH has announced it plans to provide $58 million Science for Health Discovery and Innovation in Africa over five has years for a new initiative, The NIH it is plans toHarnessing provide $58Data million (DS-I Africa). announced The program intended to explore how Science for Health Discovery and Innovation in Africa over five years forscience a new initiative, advances in data applied inHarnessing the AfricanData context (DS-I Africa). The program is and intended to explore how Science Health Discovery can spurfor health discoveries and Innovation in Africa advances in data science applied in thetoAfrican (DS-I Africa). The program is intended explorecontext how catalyze innovation. can spur health discoveries and advances in data science applied in the African context catalyze innovation. can health discoveries and data DS-Ispur Africa will leverage existing catalyze innovation. and technologies to develop solutions DS-I Africa will leverage existing data for the continent’s most pressing and to develop solutions DS-Itechnologies Africa leverage data clinical andwill public healthexisting problems. for the continent’s most pressing and technologies to develop Awards will be supported in solutions four clinical and public most healthpressing problems. for the an continent’s areas: open data science platform Awards will be supported in four clinical and public health problems. and coordinating center, research areas: an open data science platform Awards will be supported in four hubs, research training programs, and coordinating center, research areas: an open data science and ethical, legal and social platform hubs, research training programs, and coordinating center, research implications research. The program is and ethical, legal and social hubs, research training programs, targeting African academic and other implications research. The program is and ethical, legal and social non-profit organizations to apply in targeting African academic and otheris implications with research. The program partnership private sector, government and other non-profit organizations to apply in targeting partners. African academic and other research partnership with private sector, government and other non-profit organizations to apply in research partners. partnership with to private sector, and other Notices of intent publish four government funding opportunity research partners. Notices of intent to publish four funding opportunity
NIH closes harassment loopholes governing grantees NIH closes harassment loopholes governing grantees NIH closes harassment loopholes governing grantees
Fogarty community engaged in combatting COVID-19
FOCUS FOCUS FOCUS 102 Delaware Journal of Public Health – July 2020
• Grantees lead country responses coronavirus COVID-19 Fogarty community engaged intocombatting • Fellows find novel ways to contribute • Grantees lead country responses coronavirus COVID-19 Fogarty community engaged intocombatting • Pandemic poses mental health, bioethics issues • Fellows find novel ways to contribute • Grantees lead country responses to coronavirus More Read more on pages pages 107 6 – -9110 • poses bioethics issues • Pandemic Fellows find novelmental ways health, to contribute Read more on pages 6 – 9 • Pandemic poses mental health, bioethics issues Read more on pages 6 – 9
Fogarty adds search function to funding directory Image courtesy of CDC
COVID research, diagnostics projects gear up at NIH To help speed development and commercialization of COVID-19 testing technologies needed to ensure a safe reopening of society, the NIH has announced a $1.5 billion initiative, called the Rapid Acceleration of Diagnostics (RADx). The NIH will also seek opportunities to move diagnostic technologies swiftly through the development pipeline toward commercialization and broad availability. Applicants with rapid testing technologies will compete in a rapid, three-phase selection process. Finalists will be matched with technical, business and manufacturing experts to increase the odds of success. The goal is to produce millions of accurate and easy-to-use tests by the end of this summer. “We need all innovators, from the basement to the boardroom, to come together to advance diagnostic technologies, no matter where they are in development,” said NIH Director Dr. Francis S. Collins. “Now is the time for that unmatched American ingenuity to bring the best and most innovative technologies forward to make testing for COVID-19 widely available.” The NIH also continues to ramp up clinical studies of COVID-19, including two that will examine pregnant women and children. In a multipronged effort, researchers will analyze the medical records of up to 21,000 women to evaluate whether changes to healthcare delivery that were implemented as a result of the pandemic have led to higher rates of pregnancy-related complications and cesarean delivery. They also seek to establish the risk of pregnant women with COVID-19 infection transmitting the virus to their fetus. Newborns will be monitored and assessed until they are discharged from the hospital. In addition, the study will track more than 1,500 pregnant women confirmed with COVID-19 infection, monitoring their health for six weeks after childbirth.
Securing biomedical and behavioral research funding can be challenging for global health researchers. To help connect scientists across career stages with organizations offering grants, fellowships, scholarships and awards, Fogarty has for several decades maintained a directory of Non-NIH Funding Opportunities. Originally a print publication, the online version now includes a search function that allows users to find entries by keyword, funding category or career level. The collection includes listings from U.S. government departments and agencies, foreign governments, nongovernmental organizations and academic institutions.
Other NIH-funded researchers are evaluating drugs prescribed to treat COVID-19 in infants, children and adolescents. They will analyze blood samples collected from routine medical procedures to understand how the drugs move through the bodies of children, from newborns to adolescents under 21 years of age. The goal is to gather information to refine dosing and improve safety.
Fogarty welcomes directory submissions from organizations seeking candidates for their global health programs, particularly those focused on supporting research or research training in low- and middleincome countries.
Both studies are supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development.
MAY/JUNE 2020 MAY/JUNE 2020
Photo courtesy of GHESKIO
An An HIVHIV research training on HIV HIV research traininggrant grantininHaiti Haitiwill willtrain train scientists scientists focused on prevention and treatment prevention and treatmentamong amongadolescents. adolescents.
$18Mawarded awarded for $18M HIVresearch research training training HIV continuetotostrengthen strengthenresearch research capacity capacity to ToTo continue to address address the the evolving HIV epidemic in lowand middle-income evolving HIV epidemic in low- and middle-income countries countries (LMICs), Fogarty intends to award $18.3 million over the (LMICs), Fogarty intends to award $18.3 million over the next five years through 14 grants. next five years through 14 grants. One of eight new projects, a grant in Zimbabwe will build One of eight new projects, a grant in Zimbabwe will build new capacity for molecular epidemiology and genomics new capacity for molecular epidemiology and genomics with funding to the Biomedical Research and Training with funding to the Biomedical Research and Training Institute to provide doctoral and postdoctoral training Institute to provide doctoral and postdoctoral in lab research skills, bioinformatics, modelingtraining and data in science, lab research skills, bioinformatics, and in collaboration with Stanfordmodeling University. Indata science, in collaboration Stanford University. Haiti, GHESKIO Center with and Weill Cornell Medicine In will Haiti, GHESKIO Centerhealth and Weill Cornell Medicine will jointly provide public research training to Haitian jointly provide public research training toand Haitian scientists focused onhealth adolescent HIV prevention scientists focused on tuberculosis adolescent HIV prevention and treatment, HIV and co-infection, and HIV treatment, HIV and tuberculosis and HIV for and noncommunicable diseases.co-infection, Georgia’s Partnership Research and Action for Health isGeorgia’s collaborating with Tbilisi and noncommunicable diseases. Partnership for State University and the State University of New York to Research and Action for Health is collaborating with Tbilisi build implementation science capacity State University and the State research University of Newaddressing York to gaps in HIV prevention and care. build implementation science research capacity addressing gaps in HIV prevention and care. Additionally, a grant to the University of California, San Francisco aims to to the instruct candidates at Maseno Additionally, a grant University of California, University and the Kenya Medical Research San Francisco aims to instruct candidates atInstitute Maseno on food security and poverty alleviation interventions to University and the Kenya Medical Research Institute improve HIV outcomes. A program led by Washington on food security and poverty alleviation interventions to University will provide methods training, mentoring, and improve HIV outcomes. A program led by Washington University will provide methods training, mentoring, and
hands-on experience to Ugandan researchers devoted hands-on experience to Ugandan researchers devoted to children’s mental health in HIV-impacted settings. to children’s mental health in HIV-impacted settings. Vanderbilt University plans to build Nigerian research Vanderbilt University plans to build Nigerian research capacityand andenable enable clinical trials HIV-associated capacity clinical trials in in HIV-associated noncommunicable diseases through mentored projects noncommunicable diseases through mentored projects at at AminuKano KanoTeaching Teaching Hospital. Meanwhile, Yale University Aminu Hospital. Meanwhile, Yale University partneringwith withthe the University Malaya to provide isispartnering University of of Malaya to provide implementationscience science training produce researchers implementation training to to produce researchers withthe theskills skillstotoaddress address HIV prevention treatment. with HIV prevention andand treatment. AnotherYale-based Yale-based program will strengthen biomedical Another program will strengthen biomedical research to to HIV-associated comorbidities researchcapacity capacityrelated related HIV-associated comorbidities in the University of Ghana. inpartnership partnershipwith with the University of Ghana. Fogarty’s training program is also renewing Fogarty’sHIV HIVresearch research training program is also renewing funding for four existing projects. Vanderbilt University will will funding for four existing projects. Vanderbilt University continue working with the University Eduardo Mondale continue working with the University Eduardo Mondale to scientists in in HIV implementation totrain trainMozambique Mozambique scientists HIV implementation science research, while also supporting twotwo institutional science research, while also supporting institutional field sites. An existing partnership between the University field sites. An existing partnership between the University of Washington (UW) and the Kenya Medical Research of Washington (UW) and the Kenya Medical Research Institute will build additional research capacity and focus Institute will build additional research capacity and focus on prevention of new HIV infections among women and on prevention of new HIV infections among women and teen girls. The collaboration between University of North teen girls. The collaboration between University of North Carolina and University of Malawi will continue to provide Carolina andthe University of Malawi will continuefunded to provide training with goal of producing independently training with the goal of producing independently Malawian investigators capable of multidisciplinary funded MalawianTraining investigators capable ofPeruana multidisciplinary research. at Universidad Cayetano research. at Universidad Heredia willTraining help researchers achieve Peruana autonomyCayetano on Herediaaddressing will help researchers achieve autonomy projects HIV as a chronic condition, in on projects addressing HIV the as aUniversity chronic condition, in partnership with UW and of Alabama. partnership with UW and the University of Alabama. Finally, Fogarty awarded a planning grant to Makerere University to develop a training program for Ugandan Finally, Fogarty awarded a planning grant to Makerere researchers concentrated on HIV, noncommunicable University to develop a training program for Ugandan diseases and aging. And George Washington University researchers concentrated on HIV, noncommunicable received a planning grant to strengthen ethical diseases and aging. And George Washington review University capacity trials at Kinshasa University in thereview receivedofa HIV planning grant to strengthen ethical Democratic of at Congo. capacity ofRepublic HIV trials Kinshasa University in the Democratic Republic of Congo. The NIH’s National Institute on Alcohol Abuse and Alcoholism, National Institute of Child Health and Human The NIH’s National Institute on Alcohol Abuse and Development, National Institute on Drug Abuse and National Alcoholism, National Institute of Child Health and Human Institute of Mental Health are also providing support. Development, National Institute on Drug Abuse and National Institute of Mental Health are also providing support.
Fogarty awards $5M for bioethics research training Fogarty awards $5M for bioethics research training A critical mass of bioethics scholars is needed to address challenging health research issues in low- and middleA income critical countries mass of bioethics is needed to address (LMICs). scholars To help build that capacity, challenging health research inthat low-will andsupport middleFogarty has announced fourissues awards income countries (LMICs).with To help build that capacity, research ethics training nearly $5 million over the Fogarty has announced four awards that will support next five years. research ethics training with nearly $5 million over the Fogarty is funding doctoral and postdoctoral-level next five years. bioethics research training through a grant to Loyola University Chicago, for a collaboration with Ukrainian Fogarty is funding doctoral and postdoctoral-level Catholic University that will train 12 Ukrainian research bioethics research training through a grant to Loyola
University a collaboration with Ukrainian 104 DelawareChicago, Journal of for Public Health – July 2020 Catholic University that will train 12 Ukrainian research
fellows. Under the same funding scheme, Fogarty also has committed to the South African Research Ethics fellows. Initiative Under the same funding scheme, also Training Leadership Program at theFogarty University has committed to the South African Research Ethics of KwaZulu-Natal. In addition, Fogarty is supporting two Traininglevel Initiative Leadership at the University master’s bioethics research Program training programs with of KwaZulu-Natal. In addition, Fogarty is supporting two a new award to George Washington University for training in Mali andlevel continuation fundingtraining for a program at with master’s bioethics of research programs Makerere University in Uganda. a new award to George Washington University for training in Mali and continuation of funding for a program at The NIH’s National Institute of Allergy and Infectious Makerere University in Uganda. Diseases is helping to fund the awards.
The NIH’s National Institute of Allergy and Infectious Diseases is helping to fund the awards.
PPPRRROOOFFFIIILLL EEE Former Fogarty Scholar helps Former FormerFogarty Fogarty Scholar Scholar helps helps Cambodia respond to COVID Cambodia Cambodiarespond respond to to COVID COVID By Susan Scutti
ByBy Susan Scutti Susan Scutti When Cambodia identified its first patient with COVID-19 in late January,identified former Fogarty Scholar Dr. Jessica When Cambodia its patient with COVID-19 When Cambodia identified itsfirst first patient with COVID-19 Manning leapt into action. Newly trained to use a small, late January,former formerFogarty FogartyScholar ScholarDr. Dr.Jessica Jessica in in late January, technological device, she was able to quickly sequence the Manning leaptinto intoaction. action.Newly Newlytrained trainedto touse use aa small, small, Manning leapt genome of a virus sample and post it on Nextstrain, the technological device,she shewas wasable abletotoquickly quickly sequence sequence the the technological device, global collaboration database. It was among the firstthe 20 genome virussample sample andpost post onNextstrain, Nextstrain, genome of of aa virus and ititon the to be shared on the site, whichItnow thousands global collaboration database. wasincludes amongthe the first 20 20 global collaboration database. It was among first of SARS-CoV-2 genomes. “That was a really big step to be shared on the site, which now includes thousands to be shared on the site, which now includes thousands forSARS-CoV-2 us—to be thegenomes. first lab “That from awas developing country reallybig big step step to of of SARS-CoV-2 genomes. “That was aareally contribute to the global knowledge base.” The collective us—to thefirst firstlab labfrom fromaadeveloping developingcountry country to to forfor us—to bebe the effort provides insights for vaccine development and helps contribute to the global knowledge base.” The collective contribute to the global knowledge base.” The collective track the transmission, mutation spread of the effort provides insightsfor for vaccineand development andnovel helps effort provides insights vaccine development and helps coronavirus. track the transmission, mutation and spread of the novel
track the transmission, mutation and spread of the novel coronavirus. coronavirus. Manning’s pandemic-related duties did not end there.
As Science pandemic-related Attaché at the U.S. Embassy in Phnom Penh, Manning’s duties did not end there. Manning’s pandemic-related duties did for notpotential end there. she helped develop clinical algorithms As Science Attaché at the U.S. Embassy in Phnom Penh, Aspositive Sciencecases Attaché at the Embassy in Phnom Penh, among theU.S. diplomatic corps stationed she helped develop clinical algorithms for potential she helped develop clinical algorithms for potential in Cambodia. She also is setting up a sero-prevalence positive cases among the diplomatic corps stationed positive cases among the diplomatic corps stationed study and expanding capabilities there with in Cambodia. She alsosequencing is setting up a sero-prevalence in the Cambodia. She also isshe setting up afrom sero-prevalence additional funding received her employer, study and expanding sequencing capabilities there with NIH’s National Institute of Allergy and Infectious Diseases study and expanding sequencing capabilities with the additional funding she received from her there employer, (NIAID). the additional funding she received from her employer, NIH’s National Institute of Allergy and Infectious Diseases NIH’s National Institute of Allergy and Infectious Diseases (NIAID). Last year, Manning’s NIAID lab had acquired the new (NIAID). sequencer and research funding for acquired a project the supported Last year, Manning’s NIAID lab had new by the Bill & Melinda Gates Foundation and the Chan Last year, Manning’s NIAID lab had acquired the new sequencer and research funding for a project supported Zuckerberg Given the for growing global incidence sequencer and researchGates funding a project supported by the Bill &Initiative. Melinda Foundation and the Chan of mosquito-borne diseases such as malaria and dengue, byZuckerberg the Bill & Melinda Gates theincidence Chan Initiative. GivenFoundation the growingand global Manning’s study aims to use genomic sequencing to Zuckerberg Initiative.diseases Given the growing global incidence of mosquito-borne such as malaria and dengue, identify pathogens in samples collected from people of Manning’s mosquito-borne diseases such as malaria and dengue, study aims to use genomic sequencing to suffering from fevers. She intends to gather to Manning’s study aims use genomic sequencing tomap identify pathogens in to samples collected fromdata people vector-borne incidence, model transmission risk suffering fromdisease fevers. She intends to gather to map identify pathogens in samples collected from data people and identify target areas for interventions—important vector-borne diseaseShe incidence, transmission risk suffering from fevers. intendsmodel to gather data to map for withareas limited for insecticide andauthorities identifydisease target forresources interventions—important vector-borne incidence, model transmission risk spraying and other measures. But herfor main research foridentify authorities with limited resources insecticide and target areas for interventions—important focus is investigating the potential for a universal vaccine and with otherlimited measures. But her research forspraying authorities resources formain insecticide for diseases transmitted by mosquitos, created from focus isand investigating the potential for main a universal vaccine spraying other measures. But her research the insects’ spit. “We know that saliva actually worsens for diseases transmitted by mosquitos, created from focus is investigating the potential for a universal vaccine disease, so ifspit. we can the body mount a protective insects’ “We have know that saliva actually worsens forthe diseases transmitted by mosquitos, created from response against saliva, we may be able to attenuate the disease, so if we can have the body mount a protective the insects’ spit. “Weeffects—be know thatitsaliva actually worsens actual pathogen’s dengue, zika, malaria— response saliva, we may bemount able toaattenuate disease, so against if we can have body protectivethe whatever is carried by thethe mosquito,” she said. actual pathogen’s effects—be it dengue, zika, malaria— response against saliva, we may be able to attenuate the whatever is carried by the mosquito,” she said. actual pathogen’s effects—be it dengue, zika, malaria— whatever is carried by the mosquito,” she said.
Jessica Manning, MD, MSc Fogarty Scholar: 2008-09 Jessica Manning, MD,MSc MSc Jessica Manning, MD, US Institution: Fogarty Scholar: Fogarty Scholar:
University 2008-09 2008-09 of Maryland Center for Vaccine Development
Foreign Institution: US US Institution: Institution:
University Mali Maryland Center forfor Vaccine Development UniversityofofBamako, Maryland Center Vaccine Development
Research area: Gene expression in immune Foreign University ofofBamako, Mali Foreign Institution: Institution: University Bamako, Maliresponse to malaria Research Research area: area:
Gene to to malaria Geneexpression expressionininimmune immuneresponse response malaria
Manning has just published results of what may be the first clinical trial of a mosquito spit vaccine in Manning has just results ofofwhat may Manning has just published published results what maybe be The Lancet. Conducted at the NIH Clinical Center in the first clinical trial of aamosquito spit vaccine inin the first clinical trial of mosquito spit vaccine 2017, the study tested for safety and side effects in 49 The Lancet. Conducted at the Clinical Center inin The Lancet. Conducted at theNIH NIH Clinical Center healthy volunteers, who received one of two versions of 2017, the tested safety and side 49 2017, the study study testedfor for safety andwere sideeffects effectsinin 49 the vaccine or a placebo. The results promising healthy volunteers, who received one of two versions of healthy volunteers, who received one of two versions of but further research is needed to determine the the vaccine or a placebo. The results were promising the vaccine or a placebo. The results were promising effectiveness of a mosquito saliva vaccine. the but further research is needed to determine but further research is needed to determine the effectiveness of a mosquito saliva vaccine. effectiveness of ainmosquito Manning’s work Cambodiasaliva grew vaccine. out of her 2008 Fogarty fellowship Mali, where how to Manning’s work in in Cambodia grewshe outlearned of her 2008 Manning’s work in Cambodia grew first out of her 2008 a operationalize a malaria study after establishing Fogarty fellowship in Mali, where she learned how to Fogarty fellowship in Mali, where she learned how to genomics lab in to process gathered operationalize a Bamako malaria study after samples first establishing a across the resource-scarce nation. operationalize a malaria study after first establishing genomics lab in Bamako to process samples gathered a genomics in Bamako tonation. process samples gathered across thelab resource-scarce “Fogartythe changed my life,” she recounted. “I had across resource-scarce nation. never lived in the developing world and it was a “Fogarty changed my life,” she recounted. “I had character-building experience in ways that I had “Fogarty changed my life,” she recounted. “I had never lived in the developing world and it was a never considered. was eye-opening, impactful never lived in the It developing world and it was character-building experience in ways that I hadaand meaningful and I knew then that this was going to be character-building in ways that I had never considered. It experience was eye-opening, impactful and my career.” never considered. It was eye-opening, impactful meaningful and I knew then that this was going toand be
meaningful my career.” and I knew then that this was going to be Thatcareer.” fellowship helped her understand what she would my need to succeed,helped whichher led understand her to complete master’s That fellowship whata she would in epidemiology to deepen her quantitative skills. She need to succeed,helped which led to complete a master’s That fellowship her her understand what she would also learned patience. in epidemiology deepen her quantitative skills. She need to succeed,towhich led her to complete a master’s also learned patience. in epidemiology to deepen her quantitative skills. She “Fogarty taught me that everywhere you go, you have also learned patience. to drink the tea. me Youthat have to just sit you there and talk “Fogarty taught everywhere go, younot have and understand what’s happening so that ultimately to drink the tea. me Youthat haveeverywhere to just sit there andyou nothave talk “Fogarty taught you go, you can begin to what’s achievehappening the scientific objectives you and understand so that ultimately to drink the tea. You have to just sit there and not talk came with,” she “Cultural fluency is the key. you can begin tonoted. achieve the scientific youIt’s and understand what’s happening so objectives that ultimately the number one thing that has to happen and I think camecan with,” shetonoted. “Cultural fluencyobjectives is the key.you It’s you begin achieve the scientific it’s the hardest to learn.” the number one thing that has to happen and I think came with,” she noted. “Cultural fluency is the key. It’s it’s the hardest to learn.” the number one thing that has to happen and I think it’s the hardest to learn.” RESOURCES https://bit.ly/ManningCOVID RESOURCES https://bit.ly/ManningCOVID RE SO U RC E S
CHRIS TIAN HAPPI, MSC, PHD
Dr. Christian Happi is director of the African Centre of Excellence for the Genomics of Infectious Disease, and professor of molecular biology and genomics at Redeemer's University in Nigeria. A leading genomic sequencing expert, Happi is also a visiting scientist at Harvard University. His first NIH grant was a Fogarty International Research Collaboration Award (FIRCA) and he is now a Principal Investigator on the NIH’s Human Heredity and Health in Africa (H3Africa) project. He has won numerous honors for his accomplishments, including the 2019 African Prize from the Human Genome Organization.
How did Fogarty help advance your career? Being named collaborator on the Fogarty grant in 2004 was the most critical step on my career path and laid the groundwork for my research achievements so far. My mentor, Dr. Dyann F. Wirth at Harvard, gave me responsibility to manage the whole project and report to her if there were challenges. Her words still ring in my ears like yesterday: “If you are successful with this, it will be the beginning of a brilliant career. The ball is in your court and you cannot afford to fail me.” In 2008, I was promoted to Principal Investigator when the grant was renewed. This experience helped me become an independent investigator and further strengthened my capacity and abilities to manage research projects.
You initially studied malaria. Why was that? It was a childhood dream for me to solve malaria, since I had multiple malaria episodes growing up. I made significant breakthroughs—from unravelling molecular markers of resistance to many antimalarial drugs, to using my genomics data to influence evidencebased antimalaria drug policy change in Nigeria. More importantly, building capacity on the African continent in the field of malaria molecular biology was most rewarding, because I can see today that many of the young African scientists that we trained are now among the leaders of malaria research across the continent.
How did you become engaged with Ebola? In 2013, I received an NIH grant that was critical for the establishment of the first infectious disease genomics platform in West Africa, the African Center of Excellence for Genomics of Infectious Disease (ACEGID), at Redeemer's University in Nigeria. While we were doing our work on Lassa fever in 2014, we were faced with the largest Ebola outbreak in West Africa. We soon diagnosed the first case of Ebola in Sierra Leone and started working with government officials, offering diagnostic support. More importantly we quickly sequenced 99 genomes and made them available to the international research community for the development of various 106 Delaware Journal of Public Health – July 2020
countermeasures. We pioneered open data access for outbreak response and are happy that has now become the standard. We have established sequencing facilities in Nigeria, Sierra-Leone, Senegal and Liberia that have been used to respond to many outbreaks of diseases such as Lassa fever, monkeypox and yellow fever. We also have over the years built a critical mass of over one thousand well-trained African genomics scientists that are currently leveraging the skills acquired and the facilities we have established.
How did that prepare you for COVID-19? Our work on Ebola gave us the confidence that we could sequence any organism, including the human genome. We had established a very robust metagenomic platform that enabled us to sequence the whole genome of the first SARS-CoV-2 in Africa from the first index case in Nigeria within 48 hours of receiving the samples. We realized that the whole genome sequencing and analytical pipelines that we set up for Ebola work seamlessly for SARS-CoV-2. The sequence provided us with the origin of the virus and enabled us to have better insight into the virus structure. The significance of our work is that through what we are doing, we have put Africa on the map, by contributing knowledge and information to global sequencing data repositories. We have changed the narrative by shifting our status from genomics knowledge consumers to genomics knowledge producers.
How has H3Africa advanced genomics capacity? Genomics has become a critical component of infectious disease research, control and eradication. It provides both the researchers and policymakers with the type of insight and scientific evidence that they will not ordinarily have for public health interventions. It is important for Africa to have its own biobanks and genomics capabilities because with these, we will be able to adequately address health issues that are important to Africa. H3Africa has been a catalytic force for the successful establishment of stateof-the-art laboratories and biobanking facilities on the continent.
Fogarty community responds to COVID-19 in many ways GHESKIO is “facing the monster in Haiti”
With the number of Haitians testing positive for COVID-19 doubling each week, the country is struggling to mount a response, with little international help, said Dr. Vanessa Rouzier and GHESKIO colleagues in an article in the NEJM. Misinformation is rampant and stigmatization is impeding care, Rouzier reported. The NIH-funded GHESKIO clinic suffered a fire in early June that Dr. Vanessa Rouzier compounded its difficulites. Rouzier said shutting down commercial activity is not feasible in Haiti, given the extreme poverty, and presented guidance for others working in low-resource settings. “Haiti is susceptible to natural disasters and epidemics,” noted Rouzier. “But we are also resilient, creative, and relentless when faced with overwhelming challenges. We have overcome worse, and we will overcome COVID-19.”
Africa CDC: global response needed to end COVID-19
Africa’s investments in preparedness and response efforts to address Ebola, Lassa fever and HIV/AIDS have produced technical know-how that has been swiftly adapted to COVID-19, according to a recent article published in Nature Medicine. However, senior author Dr. John N. Nkengasong, director of Africa CDC, and his colleagues said the continent cannot conquer Dr. John Nkengasong coronavirus on its own. “Failure to cooperate globally and to act decisively in Africa will translate into sustained transmission and pose a risk to all. As acknowledged by world leaders: only victory in Africa can end the pandemic everywhere.”
Former Fogarty trainee at heart of China’s response
As chief epidemiologist of China’s CDC, Dr. Zunyou Wu has been actively involved in the COVID-19 response in his country since the outset. “My primary responsibility is to monitor the epidemic of COVID-19 as it changes over time, assess the epidemic’s magnitude and predict future trends,” said Wu, a former Fogarty trainee. “We give Dr. Zunyou Wu guidance on analyzing data and preparing daily reports for understanding the epidemic.” In February, Wu participated in the WHO-China joint assessment of the pandemic and published a paper in JAMA providing the early epidemiology of the outbreak, including a breakdown by gender, age, symptoms and fatality rate.
AAS promotes African involvement in COVID trials
The African Academy of Sciences (AAS) has coordinated COVID-19 response activities across the continent, including launching an online platform to increase visibility of African clinical trial sites and investigators with the potential to participate in COVID-19 clinical trials. In a recent article in the Dr. Jerome Singh Journal of Infectious Diseases, AAS bioethics advisor and Fogarty grantee Dr. Jerome Singh made the case that African involvement in COVID-19 research is essential. “As dozens of COVID-19 vaccine trials commence in the weeks and months ahead, African sites should be central to COVID-19 vaccine trial site mapping. Such an approach is in the interests of public health, scientifically responsible, and realizes key ethics values. Without such an approach, Africa risks being left behind in our response to the COVID-19 pandemic. This would be unconscionable.”
Peru struggles to socially distance
Peru confirmed its first COVID-19 patient on March 6 and 10 days later the government issued a complete lockdown, recalled Fogarty grantee and researcher at Cayetano Heredia University, Dr. Patty Garcia. The restrictions were difficult for the country to take, she said, given their tradition of warm greetings and large gatherings. The authorities imposed a curfew to try to Dr. Patty Garcia slow the pandemic’s spread. In an interview with Harvard’s public health school, Garcia described her role in the response. “I'm chairing a commission that has to do with innovations in technology for the response to COVID. So, in this commission, I work with about 16 scientists, and molecular biologists, engineers, et cetera. And we're trying to advise on how to do things better.”
AFREhealth shares best practices
As the COVID-19 pandemic took hold globally, the African Forum for Research and Education in Health (AFREhealth) began convening a monthly video conference to share information and experiences among its collaborators. Topics have included updates on the virus, tips for addressing it in low-resource settings and country response case studies. Dr. Jean Dr. Jean Nachega Nachega, an AFREhealth principal investigator, has also led COVID-related publications on mitigation strategies tailored for Africa, caution regarding use of chloroquine and hydroxychloroquine, the potential for mobile health solutions and relevant lessons learned from combatting Ebola.
Resources: https://bit.ly/FogartyCOVID19 107
FOCUS ON FOGARTY COMMUNITY’S RESPONSE TO COVID-19 In pandemic real-time, Fogarty Fellow Andrew Kim, a Ph.D. candidate based at the Health Economics and Epidemiology Research Office in South Africa, is examining the mental health impacts, perceptions and experiences of COVID-19 among families in Soweto. Kim and his research team are also conducting virtual ethnographic research to understand how people are responding to the effects of the pandemic on their daily lives. In addition, an impromptu surveillance system created by Kim’s group can identify mental health needs and then make appropriate referrals with help from South Africa’s largest mental health organization.
Current and former Fogarty Fellows Drs. Sarah Lofgren, Matt Pullen and Caleb Skipper teamed up with their mentor Dr. David Boulware to conduct a hydroxychloroquine clinical trial at the University of Minnesota. The researchers studied post-exposure
prophylaxis, preemptive treatment and pre-exposure prophylaxis of hydroxychloroquine. Published results proved the antimalarial drug did not prevent development of COVID-19 better than a placebo. News release: https://bit.ly/UM_COVID
Dr. Keymanthri Moodley Fogarty bioethics program grantee at Stellenbosch University, co-authored an article with Former Fogarty trainee Dr. Jerome Singh of the University of KwaZuluNatal for the South African Medical Journal on the ethical considerations surrounding critical care triaging during the pandemic. Article: https://bit.ly/COVID_triage
Fogarty Fellow Dr. Alliya Qazi of Stanford University is collaborating with clinicians and researchers at Addis Ababa University, Ethiopia, to develop guidelines for use of low-cost personal protective equipment in resource-limited settings during the COVID-19 pandemic. Specifically, the group is focusing on development and assessment of locally available protective equipment and locally appropriate recommendations for conservation of equipment. Pennsylvania State University’s Dr. Steven Schiff has redirected
his research to focus on neonatal infections. “It is clear to us that we know little of this new virus with respect to the spectrum of primary disease that it can generate in the infant,” according to the Fogarty brain disorders program grantee. Explorations of co-infections must now expand to include the SARS-CoV-2 virus, he said. Schiff’s team is also collaborating with African and Asian colleagues to design mapping tools to track the evolving pandemic.
Fogarty Fellow Dr. Ashley Styczynski has partnered with the CDC and the International Centre for Diarrhoeal Disease Research
in Bangladesh to train hospital staff for triage and infection prevention and control during the coronavirus pandemic. Styczynski, a postdoctoral fellow at Stanford University, has also designed a survey of risk behaviors for coronavirus transmission in mosques, developed hand sanitizer holsters for healthcare workers and explored strategies for medical staff protection in resource-limited settings with limited personal protective equipment.
Dr. Malinee Neelamegam has partnered with the infectious diseases team at University of Malaya (UM) to set up a COVID-19 hospital patient registry. The Fogarty Fellow is also planning a
Working with the Centre for Rural Health, Dr. Ruwayda Petrus, a senior lecturer at the University of KwaZulu-Natal, created a video that highlights healthy ways of dealing with fears and anxieties provoked by COVID-19. The Fogarty MEPI Junior Faculty Fellow also contributed to an educational leaflet promoting psychological self-care that was created by University of Cape Town scientists. With Petrus’ help, this same team also developed two videos, one that trains frontline medical providers to cope with stress caused by the pandemic, the other showing health care managers new ways to support and debrief their staff based on psychodynamic principles. Video: https://bit.ly/covid_vid
clinical trial aimed at reducing use of ventilation for coronavirus patients admitted to the UM Medical Centre.
Dr. Zachary Porterfield, a Fogarty Fellow at the University of Kentucky, has developed four global collaboration projects to
Dr. Kingsley Preko vice president of the Ghana Red Cross Society, donated food, sanitizers, masks and other supplies to the Ankaful prison to assist Ghana in the fight against COVID-19. Preko, a former Fogarty bioethics program fellow and a senior lecturer at the University of Cape Coast, said the humanitarian society also offered the government help with contact tracing. Article: https://bit.ly/COVID_donation
108 Delaware Journal of Public Health – July 2020
Courtesy of UKZN
examine and translate COVID-related treatments. Acting as co-principal investigator, Porterfield has begun a clinical trial of a Japanese antiviral drug, camostat, at sites supervised by his own university and the University of KwaZulu-Natal, in South Africa. Camostat, a serine inhibitor, has been shown to prevent cleavage of the spike protein in SARS-CoV-2, which is necessary for the virus to infect cells. News release: https://bit.ly/COVID_UK
FOCUS ON FOGARTY COMMUNITY’S RESPONSE TO COVID-19
Fogarty grantee studies COVID impact on pregnant teens By Susan Scutti
Image courtesy of Dr. Manasi Kumar
was finally ready to tackle group psychotherapy for the hen her Fogarty research project studying depresspregnant teens. “The pandemic lockdown was announced ion in pregnant teens was disrupted by the coronaon the very day I was supposed to start.” virus outbreak, Kenyan scientist Dr. Manasi Kumar Kumar believes the began examining how the HIV epidemic provided pandemic was impactKenya and similar ing that population. Her countries with a findings were sobering. wealth of experience Teens were hungry and they relevant to COVID-19, or their parents or partners while emphasizing the had lost jobs. Gender-based importance of prevention violence had increased, and mitigation strategies. while transportation and But translating past essential services had been practices to fight new severely disrupted. “Food and future health crises insecurity is what has requires research. Kumar remained striking in my is gathering relevant mind—going hungry for days studies for a special when you are pregnant,” journal issue she is coKumar said. Compelled to editing that is focused on act, she is helping Nairobi successes and challenges county establish a mental of policies and behavioral health help-line based on responses to COVID-19 interventions she’d developed Dr. Manasi Kumar has developed an animated video intervention as part of her in low- and middlefor her original project. Fogarty project in Kenya studying depression among pregnant teens, who have experienced additional stress due to the pandemic. income countries. The University of Nairobi It’s important to consolidate the evidence around senior lecturer had hoped to build capacity by empowering COVID-19 to inform policymakers, especially regarding health facility staff to implement parts of her Fogarty psychological research, which is often neglected, she work but learned they first needed self-care guidance and said. “I hope this pandemic conveys to global actors and sensitization training. “In fragile settings you have to do a leaders in low- and middle- income countries that mental lot of investment in the health care providers themselves,” health is a key component during a crisis.” said Kumar. After 18 months of staff development, Kumar
Fellow addresses COVID mental health needs in Vietnam By Dr. Dang Hoang Minh, Fogarty Fellow at Vietnam National University
The COVID-19 pandemic is posing serious psychological families cope with the mental health effects of the issues, especially for children and adolescents who COVID-19 pandemic and lockdown—including a often suffer more profoundly from disasters. possible second wave of coronavirus in the fall— This vulnerable age group has little control as well as future public health emergencies or over their family situation, little experience natural disasters. The project includes training coping with major events and less ability to social workers and teachers how to use the put events in perspective. Kids and teens are materials. also particularly sensitive to the stress that their parents experience and express. To help My project wouldn’t be possible without the address this need, I am collaborating with various Fogarty-related programs developed UNICEF-Vietnam to develop a set of pandemic- Dr. Dang Hoang Minh in Vietnam over the past two decades and the related mental health and psychosocial informal network of former Fogarty trainees who support materials focused on children and adolescents. maintain professional mental health and research The materials we are developing are designed to help positions around the country.
is clearly long gone in most HIV treatment and is clearly long gone in most HIV treatment and prevention research, and is probably not going prevention research, and is probably not going to be acceptable in COVID research,” he said. to be acceptable in COVID research,” he said. South Africa’s research ethics community South Africa’s research ethics community responded quickly quickly to to the theglobal globalcrisis crisisand and responded began preparing for a possible surge in urgent began preparing for a possible surge in urgent research. When the virus first crossed distant research. When the virus first crossed distant borders, Wassenaar Wassenaar and and aahandful handfulofofcolleagues colleagues borders, spontaneously formed an informal network spontaneously formed an informal network toto quickly share share relevant relevant COVID-19 COVID-19information information quickly among research research ethics ethics committee committeemembers members among across the the country. country. across
Photo by Rodger Bosch/AFP via Getty Images Photo by Rodger Bosch/AFP via Getty Images
ScientistsininSouth SouthAfrica Africaand andelsewhere elsewhereare aregrappling grapplingwith with ethical ethical dilemmas dilemmas Scientists theybegin beginclinical clinicaltrials trialsofoftherapies therapiesand andvaccines vaccinestotocombat combat COVID-19. COVID-19. asasthey
Conducting research research Conducting in aa pandemic pandemic raises raises in thorny bioethics bioethics issues issues thorny By Susan Scutti By Susan Scutti
Is it ethical to shelve studies of priority conditions to Is it ethical to shelve studies of priority conditions to conduct COVID-related research instead? How do you conduct COVID-related research instead? How do you ensure informed consent among trial participants who are ensure informed consent among trial participants who are extremely ill? Many low- and middle-income countries have extremely ill? Many and middle-income countries have been grappling withlowthese issues. In South Africa, scientists been grappling with these issues. In South Africa, scientists have already developed a large portfolio of coronavirus have already developed a large simple portfolio of coronavirus pandemic research, including observational studies pandemic research, including simple observational as well as multinational, multi-site clinical trials of studies vaccines asand welltherapies. as multinational, multi-site clinical of vaccines In all cases, research ethicstrials committees and therapies. Inaddress all cases, research ethicsbefore committees need to quickly thorny questions granting need to quickly address thorny questions before granting permission to researchers, according to Dr. Douglas permission to Dr. professor Douglas and Wassenaar,toaresearchers, University ofaccording KwaZulu-Natal Wassenaar, a University of KwaZulu-Natal professor and longtime Fogarty bioethics grantee. longtime Fogarty bioethics grantee. Informed consent remains an “ongoing debate” among researchconsent ethics committees nation’s equivalent Informed remains an(RECs)—his “ongoing debate” among of institutional review boards, explainednation’s Wassenaar. “Most research ethics committees (RECs)—his equivalent of us worry about the extent to which people comprehend of institutional review boards, explained Wassenaar. “Most they’re consenting to.” to Study protocols that compare ofwhat us worry about the extent which people comprehend a standard of care control arm versus a study intervention what they’re consenting to.” Study protocols that compare group also prove morally “tricky” because, currently, there a standard of care control arm versus a study intervention is only palliative care for COVID-19. group also prove morally “tricky” because, currently, there
is only palliative care for COVID-19. “HIV has prepared us quite well to review complicated trials,” said Wassenaar. Some South African committees “HIV has prepared us quite well to review complicated have been reviewing HIV research for the past 10 to 15 trials,” said Wassenaar. Some South African committees years and so are accustomed to “applications where the have been reviewing HIV research for the past 10 to 15 standard of care or prevention arm is quite complicated years and so are accustomed to “applications where the with a whole armamentarium of biomedical, social and standard of care or prevention arm is quite complicated behavioral things that should be considered. Placebo alone with a whole armamentarium of biomedical, social and behavioral things that should be considered. Placebo alone 110 Delaware Journal of Public Health – July 2020
Next, they they reviewed reviewed existing existingnational nationalguidance, guidance, last revised in 2015, 2015, and and found found an an enabling enablingclause clausethat that anticipated the need need for for accelerated accelerated research researchduring during an emergency. A committee committee subgroup subgroupthen thendeveloped developed procedures to facilitate rapid review of protocols. procedures to facilitate rapid review of protocols.“It “It basically recommends basically recommends full-committee full-committeereview reviewfor foraaclinical clinical trial or or research trial research that that is is more more than than minimal minimalrisk, risk,but butwe we also encourage encourage RECs also RECs to to find find faster faster ways waysof ofreviewing reviewingand and prioritizing studies prioritizing studies in in the the national national and andglobal globalinterest,” interest,” said Wassenaar. Wassenaar. There said There must must also also be be careful carefultargeting targetingofof stakeholders and opinion leaders, he said, so that everyone stakeholders and opinion leaders, he said, so that everyone is satisfied there has been sufficient engagement with is satisfied there has been sufficient engagement with affected populations. affected populations. Finally, the COVID committee endorsed an informal peerFinally, the COVID committee endorsed an informal peersupport system to empower individual REC chairs to support system to empower individual REC chairs to confidentially share a protocol and receive comments from confidentially share a protocol and“We’re receiveenriching comments other committees within 24 hours. thefrom other committees within 24 hours. “We’re enriching the review process to make sure urgency doesn’t compromise review process to make sure urgency doesn’t compromise quality and rigor,” said Wassenaar. These new measures quality saidsome Wassenaar. These measures seem toand haverigor,” enabled researchers to new receive full seem to have enabled some researchers to receive ethics approval of pandemic-related studies within full 10 to ethics approval of pandemic-related studies within almost 10 to 20 days. Importantly, South Africa’s drug regulator 20 days. Importantly, Africa’s drug regulator almost simultaneously issuedSouth assurance to swiftly review COVIDsimultaneously issuedWassenaar assurancenoted. to swiftly review COVIDrelated clinical trials, related clinical trials, Wassenaar noted. He said he and his research partners have begun to consider pandemic-related changes to have their begun Fogartyto He said he and his research partners bioethics pandemic-related research training program. “We’re to do consider changes to theirgoing Fogarty some retooling to look at lessons learned from COVID bioethics research training program. “We’re going to do and make sure our graduates and leaders on the some retooling to look at lessons learned from COVID continent inour a position to give advice and make are sure graduates andgood leaders on on thehow to respond appropriately in an emergency situation.” An continent are in a position to give good advice on how ethics committee is always both “the good guy and the to respond appropriately in an emergency situation.” An bad guy,” he suggested. Researchers committees ethics committee is always both “the think good guy and the are too bureaucratic, while committee members believe bad guy,” he suggested. Researchers think committees they’re protecting the public. “But if you are too slow and are too bureaucratic, while committee members believe inappropriately difficult—and you delay products getting they’re protecting the public. “But if you are too slow and into the public health system—then you are not on the inappropriately difficult—and you delay products getting side of the public,” said Wassenaar. “Through our program, into the public health system—then you are not on the we want to train people who consider this middle ground side of the public,” said Wassenaar. “Through our program, very seriously and can make the best possible decisions in we want to train people who consider this middle ground difficult circumstances.” very seriously and can make the best possible decisions in difficult circumstances.” 9
OPINION OPINION OPINION
ByBy Dr.Dr. Roger Roger I. I. Glass, Glass, Director, Director, Fogarty Fogarty International International Center Center By Dr. Roger I. Glass, Director, Fogarty International Center
We Wemust mustwork worktogether togethertotoend endracism, racism,promote promoteequality equality We must work together to end racism, promote equality “Human “Humanprogress progressisisneither neitherautomatic automatic “Human progress is neither automatic nor norinevitable inevitable. .. .. Every . Everystep steptoward towardthe the nor inevitable . . . Every step toward the goal goalofofjustice justicerequires requiressacrifice, sacrifice, goal of justice requires sacrifice, suffering, suffering,and andstruggle; struggle;the thetireless tireless suffering, and struggle; the tireless exertions exertionsand andpassionate passionateconcern concernofof exertions and passionate concern of dedicated dedicatedindividuals.” individuals.” dedicated— —individuals.” MARTIN MARTINLUTHER LUTHERKING, KING,JR., JR.,1961 1961 — MARTIN LUTHER KING, JR., 1961 WeWe have have seen seen painful painful reminders reminders inin the the past past few few weeks weeks that that the the fight fight against against racism racism and and the the struggle struggle forfor equality equality We have seen painful reminders in the past few weeks are are farfar from from over, over, either either here here atat home home oror inin many many other other that the fight against racism and the struggle for equality parts parts of of the the world. world. WeWe must must use use this this time time of of heightened heightened are far from over, either here at home or in many other awareness awareness toto consider consider how how toto make make meaningful meaningful progress progress parts of the world. We must use this time of heightened and and wewe must must not not stop stop until until allall people people have have equal equal rights, rights, awareness to consider how to make meaningful progress social social justice justice and and access access toto medical medical care. care. and we must not stop until all people have equal rights, social justice and access to medical care. WeWe atat Fogarty Fogarty condemn condemn racism racism and and bigotry bigotry inin allall itsits forms forms and and remain remain committed committed toto our our mission mission toto work work We at Fogarty condemn racism and bigotry in all its toward toward achieving achieving equity equity forfor allall the the world’s world’s people. people. The The forms and remain committed to our mission to work continuing continuing issues issues of of social social justice, justice, the the importance importance of of toward achieving equity for all the world’s people. The diversity, diversity, alongside alongside the the racism racism and and police police brutality brutality that that continuing issues of social justice, the importance of persist persist inin our our society society have have again again come come toto the the fore fore and and diversity, alongside the racism and police brutality that been been heightened heightened byby the the COVID-19 COVID-19 pandemic, pandemic, which which has has persist in our society have again come to the fore and impacted impacted minorities minorities and and vulnerable vulnerable groups groups farfar more more been heightened by the COVID-19 pandemic, which has than than others. others. impacted minorities and vulnerable groups far more than others. This This is is a time a time forfor allall of of usus toto reflect reflect onon what what more more wewe can can dodo toto address address these these continuing continuing problems, problems, toto determine determine This is a time for all of us to reflect on what more we can how how wewe can can contribute contribute toto meaningful meaningful solutions, solutions, do to address these continuing problems, to determine individually individually and and through through our our collective collective efforts, efforts, soso that that how we can contribute to meaningful solutions, one one day day allall people people will will live live inin a just a just and and equitable equitable world. world. individually and through our collective efforts, so that WeWe must must channel channel our our outrage, outrage, grief grief and and frustration frustration into into one day all people will live in a just and equitable world. positive positive change. change. We must channel our outrage, grief and frustration into positive change. AtAt NIH, NIH, I was I was encouraged encouraged toto see see our our director director Dr. Dr. Francis Francis S.S. Collins Collins issue issue a statement a statement calling calling onon our our community community toto At NIH, I was encouraged to see our director Dr. Francis S. Collins issue a statement calling on our community to
foster foster a culture a culture of of inclusion, inclusion, equity equity and and respect respect forfor one one foster a culture of inclusion, another, another, including including working working equity and respect for one toto enhance enhance and and nurture nurture the the another, including working diversity diversity of of our our workforce workforce to enhance and nurture the and and fighting fighting toto end end health health diversity of our workforce disparities. disparities. AsAs hehe sagely sagely noted, noted, and fighting to end health our our different different perspectives, perspectives, disparities. As he sagely noted, backgrounds backgrounds and and cultures cultures are are our different perspectives, what what fuel fuel our our creativity creativity and and backgrounds and cultures are drive drive innovation. innovation. what fuel our creativity and drive innovation. The The NIH NIH leadership leadership is is also also continuing continuing itsits efforts efforts toto end end sexual sexual harassment, harassment, including including The NIH leadership is also closing closing loopholes loopholes that that had had allowed allowed some some grantees grantees toto escape escape continuing its efforts to end sexual harassment, including repercussions repercussions forfor their their egregious egregious actions actions byby changing changing closing loopholes that had allowed some grantees to escape institutions. institutions. repercussions for their egregious actions by changing institutions. WeWe know know there there is is much much more more toto bebe done done before before there there is is truly truly a level a level playing playing field field inin science science but but wewe are are making making We know there is much more to be done before there is progress. progress. Because Because some some of of our our grantee grantee institutions institutions inin lowlowtruly a level playing field in science but we are making resource resource settings settings dodo not not have have regulations regulations and and processes processes inin progress. Because some of our grantee institutions in lowplace place toto deal deal with with harassment harassment oror bullying, bullying, wewe are are making making resource settings do not have regulations and processes in some some resources resources available available forfor that that purpose. purpose. place to deal with harassment or bullying, we are making some resources available for that purpose. For For usus atat Fogarty, Fogarty, wewe will will not not rest rest until until allall scientists scientists are are able able toto fully fully participate participate inin biomedical biomedical research research asas equal equal For us at Fogarty, we will not rest until all scientists are partners partners and and allall the the world’s world’s people people are are equal equal beneficiaries beneficiaries able to fully participate in biomedical research as equal of of research research discoveries. discoveries. This This has has been been the the overarching overarching partners and all the world’s people are equal beneficiaries principle principle that that has has guided guided the the Fogarty Fogarty International International Center Center of research discoveries. This has been the overarching and and itsits staff staff forfor more more than than 5050 years. years. It It has has never never resonated resonated principle that has guided the Fogarty International Center more more strongly strongly than than today. today. and its staff for more than 50 years. It has never resonated more strongly than today. I call I call onon you, you, our our partners partners inin these these endeavors, endeavors, toto join join usus inin our our quest quest forfor peace, peace, equality equality and and social social justice. justice. This This is is I call on you, our partners in these endeavors, to join us a time a time when when wewe must must band band together, together, toto help help each each other, other, in our quest for peace, equality and social justice. This is toto repair repair and and remake remake our our society society forfor the the next next generation, generation, a time when we must band together, to help each other, even even asas wewe address address the the physical physical and and economic economic devastation devastation to repair and remake our society for the next generation, wrought wrought byby the the COVID-19 COVID-19 pandemic. pandemic. WeWe cannot, cannot, wewe must must even as we address the physical and economic devastation not, not, fail. fail. wrought by the COVID-19 pandemic. We cannot, we must not, fail. WeWe have have indeed indeed seen seen that that progress progress is is not not automatic automatic oror inevitable. inevitable. It It falls falls onon allall of of usus toto shoulder shoulder the the burden burden We have indeed seen that progress is not automatic or together, together, soso that that real real and and enduring enduring progress progress can can bebe inevitable. It falls on all of us to shoulder the burden achieved. achieved. together, so that real and enduring progress can be achieved. RESOURCES RESOURCES
https://bit.ly/GlassEquality https://bit.ly/GlassEquality RESOURCES
PEOPLE NIH Director receives prestigious appointments The Royal Society, the United Kingdom's national academy of sciences, has elected NIH Director Dr. Francis S. Collins as one of 10 exceptional scientists worldwide to be added as Foreign Members. Collins was recognized for his human genetics contributions. In addition, the Trump Administration has added Collins to the U.S. coronavirus task force.
Former Fogarty advisory board member dies Dr. Charles Carpenter, who for several decades collaborated on Brown University’s Fogarty HIV/AIDS research training grant, died in March. Carpenter had chaired the treatment subcommittee to evaluate the President's Emergency Plan for AIDS Relief (PEPFAR). He also served as a Fogarty advisory board member and received the 2003 Fogarty Award for International Health.
Fogarty grantees recognized for contributions Fogarty grantees Drs. Quarraisha Abdool Karim and Salim S. Abdool Karim are the recipients of the 2020 John Dirks Canada Gairdner Global Health Award. The pair was recognized for their discovery that antiretrovirals prevent HIV from being sexually transmitted, which led to pre-exposure prophylaxis (PrEP) and a reduction in HIV infections in Africa and around the world. In addition, Dr. Quarraisha Abdool Karim, whose research showed a topical gel could prevent HIV transmission among women, has been awarded one of France's top science prizes. Karim will receive the 2020 Christophe Merieux Prize for her work at the Centre for the AIDS Programme of Research in South Africa (CAPRISA), which she heads.
AIDS researcher, NIH grantee dies of COVID-19 Longtime NIH grantee and pioneering AIDS researcher Dr. Gita Ramjee died of COVID-19 in April. A South African scientist renowned for her work to expand women’s access to HIV treatment and prevention, Ramjee was the chief scientific officer of the Aurum Institute, a nonprofit organization based in Johannesburg.
Barsa selected as Acting USAID Administrator John Barsa became Acting USAID Administrator in April, following the departure of Administrator Mark Green. Barsa was previously USAID’s Assistant Administrator for Latin America and the Caribbean. The son of a Cuban refugee, he has a bachelor’s degree in international affairs from Florida International University.
112 Delaware Journal of Public Health – July 2020
Global HEALTH Briefs NIH releases nutrition research plan
To spur discovery and innovation, NIH has launched the first agency-wide strategic plan for nutrition research. The cross-cutting scientific agenda— supported by nearly $2 billion each year—includes a proposed focus on diet, behavior patterns, nutrition across the lifespan and food as medicine. Full Strategic Plan: https://bit.ly/NIHnutrition
Mental health strategy developed by NIH
NIH’s National Institute of Mental Health has released a strategic plan to guide its research. Its four stated goals are: defining brain mechanisms underlying complex behaviors, examining mental illness across the lifespan, striving for prevention and cures, and strengthening the public health impact of its research. Full Strategic Plan: https://bit.ly/NIMH_SP
NIH launches PhenX Toolkit
NIH has developed a new resource—the PhenX Toolkit—to provide standardized measures for phenotypes and exposures in biomedical research involving the social determinants of health. The open-access collection of 19 protocols was supported by the NIH’s National Institute on Minority Health and Health Disparities. Website: www.phenxtoolkit.org
WHO creates COVID-19 tech access pool
Thirty countries and multiple international organizations are partnering to support the COVID-19 Technology Access Pool (C-TAP), a WHO initiative aimed at speeding progress and ensuring vaccines, tests, treatments and other health technologies to fight coronavirus are freely accessible to all. News release: https://bit.ly/WHO_CTAP
COVID-19 guide for youth is published
The Smithsonian has collaborated with the WHO and others to develop a rapid-response COVID-19 guide for youth. Published in more than 15 languages, it aims to help young people understand the science of coronavirus as well as help them take actions to keep themselves, their families and communities safe. Books: https://ssec.si.edu/covid-19
Funding Opportunity Announcement
International Bioethics Training R25 Clinical Trial Not Allowed D43 Clinical Trial Optional
Aug 4, 2020
Global Infectious Disease (GID) Research Training Program D43 Clinical Trials Optional
Aug 14, 2020
Fogarty HIV Research Training for LMIC Institutions D43 Clinical Trial Optional D71 Clinical Trial Not Allowed G11 Clinical Trial Not Allowed
Aug 20, 2020
Mobile Health: Technology and Outcomes in LMICs R21/R33 Clinical Trial Optional - non-AIDS applications
Sep 24, 2020
Japan Society for the Promotion of Science (JSPS) Short-term Fellowships for U.S. Postdoctoral Scientists in Japan
Oct 1, 2020
Global Infectious Disease (GID) Research Training Program D71 Clinical Trials Not Allowed
Oct 28, 2020
Emerging Global Leader Award K43 Independent Clinical Trial Required K43 Independent Clinical Trial Not Allowed
Nov 4, 2020
Global Brain and Nervous System Disorders Research Across the Lifespan R21 Clinical Trial Optional R01 Clinical Trial Optional
Nov 6, 2020
Reducing Stigma to Improve HIV/AIDS Prevention, Treatment and Care in LMICs R21 Clinical Trial Optional
Nov 12, 2020
For more information, visit www.fic.nih.gov/funding
Global Health Matters May/June 2020 Volume 19, No. 3 ISSN: 1938-5935 Fogarty International Center National Institutes of Health Department of Health and Human Services Managing editor: Ann Puderbaugh Ann.Puderbaugh@nih.gov Web manager: Anna Pruett Ellis Anna.Ellis@nih.gov Writer/editor: January W. Payne January.Payne@nih.gov Writer/editor: Susan Scutti Susan.Scutti@nih.gov Designer: Carla Conway All text produced in Global Health Matters is in the public domain and may be reprinted. Please credit Fogarty International Center. Images must be cleared for use with the individual source, as indicated.
Commemorative stamp issued to mark 40th anniversary of smallpox eradication On May 8, 1980, the 33rd World Health Assembly officially declared, “The world and all its peoples have won freedom from smallpox.” The announcement marked the end of a disease that had plagued humanity for at least 3,000 years, killing 300 million people in the 20th century alone. It was ended through a 10-year global effort, spearheaded by the WHO, that involved thousands of health workers around the world who administered half a billion vaccinations to stamp out smallpox. To mark the 40th anniversary of eradication, the UN and WHO have unveiled a commemorative stamp. At its launch, WHO Director-General Dr. Tedros Adhanom Ghebreyesus said, “As the world confronts the COVID-19 pandemic, humanity’s victory over smallpox is a reminder of what is possible when nations come together to fight a common health threat.” R ESOURCES News release: https://bit.ly/SmallpoxStamp 113
DELAWARE COVID – RESOURCES Centers for Disease Control and Prevention COVIDView: https://www.cdc.gov/coronavirus/2019-ncov/covid-data/covidview/index.html General Guidance: https://www.cdc.gov/coronavirus/2019-nCoV/index.html
Centers for Medicare and Medicaid www.cms.gov/About-CMS/Agency-Information/Emergency/EPRO/Current-Emergencies/CurrentEmergencies-page Delaware Coronavirus Dashboard https://coronavirus.delaware.gov/
Frontiers Coronavirus Funding Monitor https://coronavirus.frontiersin.org/covid-19-research-funding-monitor
Johns Hopkins, Coronavirus Resource Center: https://coronavirus.jhu.edu/ Massachusetts General Fast Literature Updates: www.massgeneral.org/news/coronavirus/treatment-guidance/fast-literature-updates
National Academy of Medicine Resources: https://nam.edu/coronavirus-resources/
114 Delaware Journal of Public Health – July 2020
DELAWARE COVID – LEXICON A priori Relating to or denoting reasoning or knowledge which proceeds from theoretical deduction rather than from observation or experience.
ACE-2 Protein An enzyme attached to the cell membranes of cells in the lungs, arteries, heart, kidney, and intestines
ADHD Attention Deficit Hyperactivity Disorder
Adaptive Immune System Subsystem of the immune system that is composed of specialized, systemic cells and processes that eliminates pathogens by preventing their growth.
Aerosolization The process or act of converting some physical substance into the form of particles small and light enough to be carried on the air i.e. into an aerosol.
Aggregate A whole formed by combining several (typically disparate) elements.
Agnostic Denoting or relating to hardware or software that is compatible with many types of platforms or operating systems.
Aliquot A portion of a larger whole, especially a sample taken for chemical analysis or other treatment.
Anhedonia Inability to feel pleasure.
Antibodies Antibodies are substances made by the body’s immune system in response to bacteria, viruses, fungus, animal dander, or cancer cells. Antibodies attach to the foreign substances so the immune system can destroy them. IgG: found in all bodily fluids, and are an indication of previous infection. IgM: found in blood and lymph fluid and are the first type of antibody made in response to an infection.
Antigen A toxin or other foreign substance which induces an immune response in the body, especially the production of antibodies.
Apical surface Surface of an epithelial cell that faces the body surface, a body cavity, the lumen of an internal organ or a tubular duct that receives cell secretions.
Assay An assay is an investigative (analytic) procedure in laboratory medicine, pharmacology, environmental biology and molecular biology for qualitatively assessing or quantitatively measuring the presence, amount, or functional activity of a target entity.
Atomistic Viral Particle The atomic parts (neutrons, electrons, protons) of a virus.
Bioinformatics Combination biology, computer science, information engineering, mathematics and statistics to analyze and interpret the biological data.
Bimodal A probability distribution with two different modes. These appear as distinct peaks in the probability density function.
Biomarker A measurable substance in an organism whose presence is indicative of some phenomenon such as disease, infection, or environmental exposure.
Blind Validation Information that may influence the researchers validating the process is withheld. 115
cDNA DNA that is complementary to a given RNA strand, which serves as a template for synthesis of DNA in the presence of reverse transcriptase.
Comorbid The simultaneous presence of two chronic diseases or conditions in a patient. Computational Structural Virology Computer simulations focusing on the structure of a virus.
Concordant In agreement, consistent.
Conjugate Coupled, connected, related.
Convalescent plasma The liquid part of blood that is collected from patients who have recovered from a disease, that contains antibodies to that disease.
Cross-Reactivity Analyses A process of determining if two particles react with one another.
Cryo-electron Microscopy An electron microscopy technique applied on samples cooled to cryogenic temperatures and embedded in an environment of vitreous water.
Cytokine Storm A severe immune reaction in which the body releases too many cytokines into the blood too quickly.
DNA Methylation A biological process by which methyl groups are added to the DNA molecule.
Disintermediate Reduce or eliminate the role of (an intermediary).
Efficacy The ability to produce a desired or intended result.
En bloc All together or all at the same time.
Enteric Feeding Tube A tube surgically placed in the stomach, to be used for nutrition.
Epidemiological Modeling A model of disease transmission in a geographical area.
Epigenetic Relating to or arising from nongenetic influences on gene expression.
Equipoise A balance of forces or interests.
Etiology The cause, set of causes, or manner of causation of a disease or condition.
Exogenous Relating to or developing from external factors.
Frustum The portion of a cone or pyramid which remains after its upper part has been cut off by a plane parallel to its base, or which is intercepted between two such planes.
Genome The set of chromosomes in a gamete or microorganism, or in each cell of a multicellular organism.
116 Delaware Journal of Public Health – July 2020
Genomic Surveillance The ongoing systematic collection of data relating to the genome.
Glycan Another term for polysaccharide.
Hematologic Toxicity Decreased counts of blood cells: neutropenia (neutrophils), anemia (red blood cells), leukopenia (white blood cells), lymphopenia (lymphocytes), and/or thrombocytopenia (platelets).
Heterogeneity The quality or state of being diverse in character or content.
Histopathology The study of changes in tissues caused by disease.
Hyperinflammatory Overactivation of the inflammatory pathways.
Hypoxic Low oxygen
Immunocomplex The complex formed between an antigen and an antibody.
Immunomodulator A chemical agent (as methotrexate or azathioprine) that modifies the immune response or the functioning of the immune system.
Immunophenotype The proteins expressed by cells.
In silico Conducted or produced by means of computer modeling or computer simulation.
In vitro Performed or taking place in a test tube, culture dish, or elsewhere outside a living organism.
In vivo Performed or taking place in a living organism.
Incidence The probability of occurrence of a given medical condition in a population within a specified period of time.
Lateral Flow Chromatographic Immunoassays Simple devices intended to detect the presence of a target substance in a liquid sample without the need for specialized and costly equipment.
Leukocyte White blood cell.
Limit of detection The lowest quantity of a substance that can be distinguished from the absence of that substance with a stated confidence level.
Lipid bilayer A thin polar membrane made of two layers of lipid molecules. These membranes are flat sheets that form a continuous barrier around all cells.
Lumen The inside space of a tubular structure, such as an artery or trachea.
Lyophilized Primer Freeze-dried molecule that serves as a starting material.
MERS Middle Eastern Respiratory Syndrome 117
Metagenomics The study of genetic material recovered directly from environmental samples.
Monoclonal antibodies An antibody produced by a single clone of cells or cell line and consisting of identical antibody molecules.
Nasogastric Tube A tube inserted in the nose, leading to the stomach, and used for nutrition.
Nasopharyngeal The upper part of the pharynx, including the nose and throat.
Negative Predictive Value The probability that subjects with a negative screening test truly do not have the disease.
Neurocognitive Denoting or relating to the neural processes and structures involved in cognition (thinking).
Nuclear Magnetic Resonance Spectroscopy A technique to observe local magnetic fields around atomic nuclei.
Nucleocapsid The capsid of a virus with the enclosed nucleic acid.
Oligo Sequence/Oligonucleotide Oligonucleotides are short DNA or RNA molecules, oligomers, that have a wide range of applications in genetic testing, research, and forensics
Oropharyngeal Relating to the part of the pharynx that lies between the soft palate and the hyoid bone (the mouth and throat).
Pathogens A bacterium, virus, or other microorganism that can cause disease.
Pathophysiology The disordered physiological processes associated with disease or injury.
Pentameric Ion Channel A transmembrane ion channel which open to allow ions to pass through a cell membrane.
Phenotype The set of observable characteristics of an individual resulting from the interaction of its genotype with the environment.
Polymerase Chain Reaction A method widely used to rapidly make millions to billions of copies of a specific DNA sample, allowing scientists to take a very small sample of DNA and amplify it to a large enough amount to study in detail.
Predictive Power The ability of a scientific theory to generate testable predictions.
Prevalence The proportion of a particular population found to be affected by a medical condition at a specific time.
Proinflammatory State The state of the body when mediators, factors or substances that support or exacerbate inflammation are present.
Prophylaxis/Prophylactic Action taken or substance used to prevent disease.
Quantitative Relating to, measuring, or measured by the number of something rather than its quality.
Reagent A substance or mixture for use in chemical analysis or other reactions.
Restriction endonuclease An enzyme that cleaves DNA into fragments at or near specific recognition sites within molecules known as restriction sites. 118 Delaware Journal of Public Health – July 2020
Retrospective Looking back on, or dealing with past events or situations.
Reverse Transcriptase An enzyme used to generate complementary DNA from an RNA template, a process termed reverse transcription
SARS Severe Acute Respiratory Syndrome
Sensitivity The ability of a test to correctly identify those with the disease (true positive rate).
Seroconversion The time period during which a specific antibody develops and becomes detectable in the blood.
Seroepidemiological Investigation Epidemiological investigations involving the identification of antibodies to specific antigens in populations of individuals
Serological Survey A survey to quantify the proportion of people positive for a specific antibody.
Serology Testing Blood tests to look for antibodies.
Specificity The ability of the test to correctly identify those without the disease (true negative rate).
STEM Science, Technology, Engineering, and Math
Stochastic Randomly determined.
Thromboembolism The obstruction of a blood vessel by a blood clot that has become dislodged from another site in the circulation.
Throughput The amount of material or items passing through a system or process.
Tidal Volume The lung volume representing the normal volume of air displaced between normal inhalation and exhalation when extra effort is not applied. For healthy, young, adults, this amount is approximately 500 mL per inspiration, or 7 mL/kg body mass.
Translational Research The process of applying knowledge from basic biology and clinical trials to techniques and tools that address critical medical needs.
Vacuum Manifold A simple way to process multiple samples using pressure control to assure samples are processed with high reproducibility.
Validation The action of checking or proving the validity or accuracy of something.
Vascular Perfusion The passage of fluid through the circulatory system to an organ or a tissue, usually referring to the delivery of blood to a capillary bed in tissue.
Verification Studies A study to check that the product, service, or system meets requirements and specifications, as well as fulfilling its purpose.
Viral Variant Analysis A study to determine the different parts of a virus, and to determine the similarities and differences of the viruses studied.
Viremia A viral infection of the blood.
X-Ray Crystallography The experimental science determining the atomic and molecular structure of a crystal, in which the crystalline structure causes a beam of incident X-rays to diffract into many specific directions. 119
Delaware Journal of
updated April, 2020
About the Journal Established in 2015, The Delaware Journal of Public Health is a bi-monthly, peer-reviewed electronic publication, created by the Delaware Academy of Medicine/Delaware Public Health Association. The publication acts as a repository of news for the medical, dental, and public health communities, and is comprised of upcoming event announcements, past conference synopses, local resources, peer-reviewed content ranging from manuscripts and research papers to opinion editorials and personal interest pieces, relating to the public health sector. Each issue is largely devoted to an overarching theme or current issue in public health. The content in the Journal is informed by the interest of our readers and contributors. If you have an event coming up, would like to contribute an Op-Ed, would like to share a job posting, or have a topic in public health you would like to see covered in an upcoming issue, please let us know. If you are interested in submitting an article to the Delaware Journal of Public Health, or have any additional inquiries regarding the publication, please contact DJPH Deputy Editor Elizabeth Healy at email@example.com, or the Executive Director of The Delaware Academy of Medicine and Delaware Public Health Association, Timothy Gibbs, at firstname.lastname@example.org
Information for Authors Submission Requirements The DJPH accepts a wide variety of submission formats including brief essays, opinion editorials pieces, research articles and findings, analytic essays, news pieces, historical pieces, images, advertisements pertaining to relevant, upcoming public health events, and presentation reviews. If there is an additional type of submission not previously mentioned that you would like to submit, please contact a staff member.
Cover Letters must address the following four article requirements: 1. A description of what the paper adds to current knowledge, in particular with respect to material previously published in DJPH, and if systematic reviews exist on the topic. 2. The public health importance of the paper. 3. One sentence summarizing the main message(s) of the paper, which may be used to disseminate the paper on social media.
The initial submission should be clean and complete, without edits or markups, and contain both the title and author(s) fulls name(s). Submissions should be 1.5 or 4. For individual or group randomized trials, provide the double spaced with a font size of 12. Initial submissions date of trial registration and the NCT number from must also contain a cover letter with concise text www.Clinicaltrials.gov or other approved registry. (maximum 150 words). Once completed, articles In the cover letter only, not in the paper. Do NOT should be submitted via email to Elizabeth Healy at include the trial registration or NCT number in the email@example.com as an attachment. Graphics, images, abstract or the body of the manuscript during the info-graphics, tables, and charts, are welcome and initial submission. encouraged to be included in articles. Please ensure that all pieces are in their final format, and all edits and track All manuscripts must be submitted via email to Elizabeth Healy at firstname.lastname@example.org. changes have been implemented prior to submission. 120 Delaware Journal of Public Health – July 2020
To view additional information for online submission requirements, please refer to the website for the Delaware Journal of Public Health: https://djph.org/sample-page/submit-an-article/. Submission Length While there is no prescribed word length, full articles will generally be in the 2500-4000-word range, and editorials or brief reports will be in the 1500-2500-word range. If you have any questions regarding the length of a submission, or APA guidelines, please contact a staff member. Copyright Opinions expressed by contributors and authors do not necessarily reflect the opinions of the DJPH or affiliated institutions of authors. Copying for uses other than personal reference or interest without the consent of the DJPH is prohibited. All material submitted alongside written work, including graphics, charts, tables, diagrams, etc., must be referenced properly in accordance with APA formatting. Conflicts of Interest Any conflicts of interest, including political, financial, personal, or academic conflicts, must be declared prior to the submission of the article, or in conjunction with a submission. Conflicts of interest are any competing interests that may leave readers feeling misled or deceived, and/or alter their perception of subject matter. Declared conflicts of interest may be published alongside articles in the final electronic publication.
Additional Documents and Information for Authors Please Note: All authors and contributors are asked to submit a brief personal biography (3 sentences maximum) and a headshot along submissions. These will be published alongside final submissions in the final electronic publication. For pieces with multiple authors, these additional documents are requested for all contributors. Abstracts Authors must submit a structured or unstructured abstract along with their article. The word limit is 200 words, including headings. A title page should be submitted with this abstract as well. Structured abstracts should employ 4-5 headings: Objectives (begins with “To…”) Methods Results Conclusions A fifth heading, Policy Implications, may be used if relevant to the article. Trial Registration information is required for clinical trials and must be included in the final version abstract All abstracts should provide the dates(s) and location(s) of the study is applicable. Note: There is no Background heading.
Nondiscriminatory Language Use of nondiscriminatory language is required in all DJPH submissions. The DJPH reserves the right to reject any submission found to be using sexist, racist, or heterosexist language, as well as unethical or defamatory statements.
Index of Advertisers A Message of Gratitude . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 Delaware Journal of Public Health APHA 2020 Annual Meeting and Expo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 APHA The DPH Bulletin June 2020 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 Division of Public Health, Department of Health and Social Services Delaware Public Health Series. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47 Quality Insights Student Immunization Requirements. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55 MeningitisB Action Project The Nation’s Health - July 2020. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71 American Public Health Association JFS Merges with Cancer Care Connection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79 JFS and Cancer Care Connection AstraZeneca Response to the COVID-19 Pandemic. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87 AstraZeneca Office of the Governor, Support COVID-19 Response. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91 Office of the Governor, John Carney, Press Release Top Global Health Research Stories of 2020. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102 Fogarty International Center DJPH Submission Information. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120 Delaware Journal of Public Health
122 Delaware Journal of Public Health – July 2020
Delaware Academy of Medicine / DPHA 4765 Ogletown-Stanton Road Suite L10 Newark, DE 19713
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The Delaware Academy of Medicine is a private, nonprofit organization founded in 1930. Our mission is to enhance the well being of our community through medical education and the promotion ofpublic health. Our educational initiatives span the spectrum from consumer health education tocontinuing medical education conferences and symposia. The Delaware Public Health Association was officially reborn at the 141st Annual Meeting of the American Public Health Association (AHPA) held in Boston, MA in November, 2013. At this meeting, affiliation of the DPHA was transferred to the Delaware Academy of Medicine officially on November 5, 2013 by action of the APHA Governing Council. The Delaware Academy of Medicine, who’s mission statement is “to promote the well-being of our community through education and the promotion of public health,” is honored to take on this responsibility in the First State.