Microbiology and Infectious Diseases The American Medical Journal 1.1 2023

An EMJ Publication

Volume 1.1 / November 2023

Microbiology & Infectious Diseases The American Medical Journal

Review of

IDWeek 2023 Interview

Shweta Anjan discusses the applications of antimicrobial stewardship to transplant infectious diseases

Feature The 2022–2023 USA Respiratory Viral ‘Tripledemic’: Healthcare Lessons Learned

emjreviews.com

Contents 4

Editorial Board

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Welcome

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Congress Review Review of IDWeek 2023, October 11th-15th 2023

Congress Features Under the Microscope: Artificial Intelligence in Healthcare Darcy Richards

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Disease X: Preparing for the Next Pandemic

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A Preview of Clinical Practice Guideline Updates

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Evan Kimber

Abigail Craig

Abstract Review Evaluation of Bacteremia in Febrile Neutropenia and Implications on Antimicrobial Stewardship Kalava et al.

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Abstract Highlights Interview Shweta Anjan

Feature The 2022–2023 USA Respiratory Viral ‘Tripledemic’: Healthcare Lessons Learned Madad et al.

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Articles Vaccine Candidates for Arboviruses with Pandemic Potential: A Mini Review Adekola et al.

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A Retrospective Study in Patients With Varying Prescription Coverage With Ursodeoxycholic Acid and Association With Incidence of COVID-19 Diagnosis in Primary Care Ming et al.

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Editorial Board Shweta Anjan Associate Program Director, Transplant Infectious Disease Fellowship; Assistant Professor of Clinical Medicine; Division of Infectious Diseases; Transplant and Immunocompromised Host Service; Miami Transplant Institute; Jackson Memorial Hospital, Miami; University of Miami Miller School of Medicine, Florida, USA.

Syra Madad Senior Director of the System-wide Special Pathogens Program, New York City Health + Hospitals, USA; Co-Principal Investigator of NYC Health + Hospitals Institute of Diseases and Disaster Management; Core Faculty Member, National Emerging Special Pathogens Training and Education Center, USA; Affiliate Faculty Member, Center for Emerging Infectious Disease Policy & Research, Boston University, Massachusetts, USA.

Sandhya Nagarakanti Senior Associate Consultant; Assistant Professor; Section Education Co-ordinator, Internal Medicine Residency Program; Program Director, Infectious Diseases Fellowship Program; Vice Chair, Education, Division of Infectious Diseases Mayo Clinic, Phoenix, Arizona, USA.

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Aims and Scope

We are always keen to hear from healthcare professionals wishing to discuss potential submissions, please email: editorial.assistant@emjreviews.com

EMJ is an online only, peer-reviewed, open access general journal, targeted towards readers in the medical sciences.

We aim to make all our articles accessible to readers from any medical discipline.

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Submission details can be found through our website: www.emjreviews.com/contributors/authors

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The editorial policy is designed to encourage discussion among this peer group.

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EMJ is published quarterly and comprises review articles, case reports, practice guides, theoretical discussions, and original research.

Distribution and Readership

EMJ also publishes 18 therapeutic area journals, which provide concise coverage of salient developments at the leading European congresses. These are published annually, approximately 6 weeks after the relevant congress.

Further details can be found on our website: www.emjreviews.com

EMJ is distributed through controlled circulation to healthcare professionals in the relevant fields.

Indexing and Availability EMJ is indexed on DOAJ, the Royal Society of Medicine, and Google Scholar®; selected articles are indexed in PubMed Central®.

Editorial Expertise EMJ is supported by various levels of expertise: • • • •

EMJ is available through the websites of our leading partners and collaborating societies.

Guidance from an Editorial Board consisting of leading authorities from a wide variety of disciplines.

Invited contributors are recognized authorities from their respective fields.

Peer review, which is conducted by EMJ’s Peer Review Panel as well as other experts appointed due to their knowledge of a specific topic.

An experienced team of editors and technical editors.

EMJ journals are all available via our website: www.emjreviews.com Open Access This is an open-access journal in accordance with the Creative Commons Attribution-Non Commercial 4.0 (CC BY-NC 4.0) license.

Peer Review

Congress Notice

On submission, all articles are assessed by the editorial team to determine their suitability for the journal and appropriateness for peer review.

Staff members attend medical congresses as reporters when required.

Editorial staff, following consultation with either a member of the Editorial Board or the author(s) if necessary, identify three appropriate reviewers, who are selected based on their specialist knowledge in the relevant area.

This Publication ISSN 2977-4055 Microbiology & Infectious Diseases AMJ is published once a year. For subscription details please visit: www.emjreviews.com

All peer review is double blind.

Following review, papers are either accepted without modification, returned to the author(s) to incorporate required changes, or rejected.

We welcome contributions from professionals, consultants, academics, and industry leaders on relevant and topical subjects.

All information obtained by EMJ and each of the contributions from various sources is as current and accurate as possible.

However, due to human or mechanical errors, EMJ and the contributors cannot guarantee the accuracy, adequacy, or completeness of any information, and cannot be held responsible for any errors or omissions. EMJ is completely independent of the review event (IDWeek 2023) and the use of the organizations does not constitute endorsement or media partnership in any form whatsoever.

We seek papers with the most current, interesting, and relevant information in each therapeutic area and accept original research, review articles, case reports, and features.

Front cover and contents photograph: Boston, Massachusetts home of the IDWeek 2023 © romanslavik.com / stock.adobe.com

Editorial staff have final discretion over any proposed amendments.

Submissions

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Stay up to date with new advancements across healthcare Visit EMJ for our comprehensive collection of peerreviewed research articles, latest interviews, and features across a range of therapeutic disciplines.

Visit EMJ

www.emjreviews.com

Welcome letter Editor Evgenia Koutsouki Editorial Manager Anaya Malik Copy Editors Noémie Fouarge, Kirsty Hewitt

Evgenia Koutsouki Editor

Editorial Co-ordinator Natasha Meunier-McVey Editorial Assistants Lucy Anderson, Victoria Antoniou, Abigail Craig, Ada Enesco, Evan Kimber, Darcy Richards Design Manager Stacey Rivers Senior Designer Roy Ikoroha Designer Steven Paul Junior Designers Dillon Benn Grove, Shanjok Gurung Head of Sales Robert Hancox Senior Project Manager Michael Stevenson Director of Performance Keith Moule Chief Operating Officer Dan Scott Chief Commercial Officer Dan Healy Founder and Chief Executive Officer Spencer Gore

Dear Readers, It is with great pleasure that I welcome you to this inaugural issue of Microbiology and Infectious Diseases – The American Medical Journal.

This new journal brings key updates from IDWeek 2023, which took place in Boston, Massachusetts, USA, in October. We are committed to bringing you a publication that spotlights the main themes from IDWeek, alongside peer-reviewed content. The prevailing themes in this year’s meeting were the ever-relevant topics of artificial intelligence and climate change, nicely balanced with comprehensive coverage of key topics in adult and pediatric infectious diseases.

I would like to extend a warm welcome to our inaugural Editorial Board members, who have helped bring this issue to fruition. The EMJ team is looking forward to working with them on building a strong and reputable journal, and disseminating relevant, high-impact content. I do hope you enjoy the interview with one of our Editorial Board members, Shweta Anjan, University of Miami Miller School of Medicine, Florida, USA, where she discusses the applications of antimicrobial stewardship to transplant infectious diseases, and offers valuable advice for young clinicians.

Among our selection of peer-reviewed content, you will find an excellent mini-review on vaccine candidates for arboviruses with pandemic potential. Additionally, a retrospective study on the relationship between ursodeoxycholic acid prescription and positive primary care coding for COVID-19 is included in this issue.

I would like to close by thanking our Editorial Board, contributors, and peer reviewers for upholding high-quality standards for this issue. We are looking forward to welcoming your article submissions over the next year, leading up to the publication of the 2024 journal.

Contact us Editorial enquiries: editor@emjreviews.com Sales opportunities: salesadmin@emjreviews.com Permissions and copyright: accountsreceivable@emjreviews.com

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Reprints: info@emjreviews.com Media enquiries: marketing@emjreviews.com

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Congress Review

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IDWeek 2023 Review of IDWeek 2023 Location:

Boston, Massachusetts, USA

Date:

October 11th–15th 2023

Citation:

Microbiol Infect Dis AMJ. 2023;1[1]:8-13.

DOI/10.33590/microbiolinfectdisamj/10302553. https://doi.org/10.33590/microbiolinfectdisamj/10302553.

This year’s IDWeek, the joint annual meeting of the Infectious Diseases Society of America (IDSA), the Society for Healthcare Epidemiology of America (SHEA), the HIV Medicine Association (HIVMA), the Pediatric Infectious Diseases Society (PIDS), and the Society of Infectious Diseases Pharmacists (SIDP), took place in the capital of Massachusetts, USA. Boston is well known as a hub for art, history, culture, and education, famously housing the globally renowned institution of Harvard University. With this strong background in learning and education, Boston provided a fantastic setting for the wealth of basic, translational, and clinical science presented over the course of IDWeek 2023.

This year’s event, which surpassed previous records for attendance, saw 3,019 speakers from across the globe deliver a total of 285 sessions, including 39 oral abstract sessions, and over 2,000 poster abstracts.

Whilst artificial intelligence and climate change emerged as key themes throughout the sessions, the program covered a plethora of topics, including adult and pediatric infectious diseases, COVID-19, epidemiology and infection control, global infectious diseases, HIV, sexually transmitted diseases, tuberculosis, and investigative infectious diseases.

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IDWeek Program Chair, Heather Yun, Brooke Army Medical Center, San Antonio, Texas, USA, opened the event by reflecting on the very first IDSA meeting she attended and presented at, which, by happenstance, also took place in Boston. Yun discussed the pride she felt in being part of a team who helped advance science to solve a critical problem for patients, and the awe she felt at both the prospective possibilities the future held, and the support amongst the infectious diseases community. Referring to the present, Yun stated: “IDWeek connects our science with our humanity as we come together from across the world to better our own communities of practice, and solve real challenges for our patients.” Yun further emphasized the importance of community and collaboration, commenting: “The stories we share, the research we present, and the new connections we make will shape the field of ID in the years ahead.”

Multiple awards were presented during the opening session, including the IDWeek Program Committee Choice Awards. Benjamin Johnson, Johns Hopkins School of Medicine, Baltimore, Maryland, USA, was recipient of this award from the IDSA, for research called ‘Reporting of SARSCoV-2 testing results among PEPFAR and nonPEPFAR countries in Sub-Saharan Africa during the first year of the COVID-19 pandemic’; Jennie H. Kwon, Washington University School of Medicine, Saint Louis, Missouri, USA, received this award from the SHEA, her research on ‘The Impact of

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Race and Rurality on Healthcare-Associated Infections and Downstream Adverse Outcomes’; Lewis Musoke, Veterans Affairs Northeast Ohio Healthcare System, Cleveland, Ohio, USA, received this award from the HIVMA for research called ‘PrEP Inequity Across Geographic, Racial and Sex Groups in a Nationwide US Veteran Cohort’; and Anne-Marie Rick, University of Pittsburgh, Pennsylvania, USA, received this award from PIDS for her research into ‘Protective Effects of Maternal Influenza Vaccine during Pregnancy and Breastfeeding on Risk of Infant Influenza’.

Additionally, five prestigious awards were bestowed by the five societies of IDWeek to colleagues who have “transformed the frontiers of infectious diseases in research, patient care, and education.” The IDSA Alexander Fleming award for lifetime achievement was presented by Carlos del Rio, Emory University School of Medicine, Decatur, Georgia, USA, to Susan Swindells, University of Nebraska Medical Center, Omaha, USA, in recognition of her contributions to the acquisition and dissemination of knowledge in infectious diseases. Del Rio highlighted Swindells as a “trailblazer in HIV research,” whose groundbreaking research has influenced clinical practice, with work spanning optimal antiretroviral treatment 10

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strategies, treatment for opportunistic infections, and HIV prevention through antiretroviral therapy.

The HIVMA Transformative Leader Award was presented to Judith Feinberg, West Virginia University, Morgantown, USA, by the HIVMA Chair, Michelle Cespedes. The award recognizes HIVMA members who have transformed the field through significant achievement in HIV clinical care, provider education, research, or advocacy.

The SHEA Senior Scholar Award was presented to Victoria Fraser, Washington University School of Medicine, by SHEA President, Deborah Yokoe, in recognition of her work in improving patient safety through infection prevention.

The PIDS Walter T. Hughes Distinguished Physician Award was delivered to Patricia M. Flynn, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA, by PIDS President Buddy Creech, for her globally-recognized contributions to pediatric and adolescent HIV care.

The SIDP Outstanding Clinician Award was given to Julie Ann Justo, University of South Carolina College of Pharmacy, Columbia, USA, by SIDP President, Melissa Johnson, for exemplary skills as

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a practitioner with expertise in infectious diseases pharmacy practice.

Congress Review

and prioritized in the future, and concluded her message with a poignant statement: “I look forward to working together to support healthy people, healthy families, a healthy nation, and a healthy world.”

The session then saw del Rio rejoin the stage, where he spotlighted the President’s Emergency Plan for AIDS relief (PEPFAR), a flagship US Global Health Program that has saved more than 25 million lives, as the topic for IDWeek 2023’s closing plenary.

Following this address, del Rio introduced the opening session’s keynote speaker, Isaac Kohane, Harvard Medical School, Boston, Massachusetts, USA, who delivered a fascinating plenary on the intersection between infectious diseases and artificial intelligence. At the end of this insightful presentation, Yun invited attendees to join the Bug Bash reception, and wished everyone a great IDWeek.

In recognition of the work involved in delivering the IDWeek program, del Rio gave thanks to the event’s four female co-chairs for putting together a superb meeting. He also gave recognition to IDWeek Meeting Secretariat, Sandra Vura Harwood, for her contributions to IDSA and IDWeek, stating that her work has helped grow IDWeek into a leading infectious diseases meeting in the world through innovative thinking and fostering international collaboration.

EMJ was thrilled to attend this fantastic and engaging meeting for the first time, and we look forward to participating in IDWeek 2024, which will take place in Los Angeles, California, USA, between October 16th–20th. For now, we hope you enjoy reading the scientific highlights from IDWeek 2023. ●

A special video message saw Mandy Cohen, Director of the Centers for Disease Control and Prevention (CDC) give thanks to the delegates for their work in protecting the public from health threats, including their efforts during the COVID-19 pandemic, and collaboration on the Mpox response. Cohen emphasized that the collaborative approaches should be continued

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Role of Healthcare System Barriers in Inappropriate Antibiotic Use RESEARCH presented at IDWeek 2023 suggests that personal beliefs and healthcare system barriers are two of the primary reasons for which patients report using antibiotics without a prescription. The overuse and misuse of antibiotics is a contributing factor in antimicrobial resistance; however, many patients find it a cheaper and more convenient option. Therefore, the researchers emphasized the need for antibiotic stewardship education, and increased access efforts.

This study, presented by Lindsey Laytner, Department of Family and Community Medicine, Baylor College of Medicine, Houston, Texas, USA, involved in-depth, semi-structured interviews with patients who had reported non-prescription antibiotic use on a previous survey in public and private healthcare systems. The interviews were carried out from May 2020–October 2021.

Non-prescription antibiotic use includes using antibiotics leftover from a previously prescribed course, obtained from social networks, and purchased over the counter in other countries or illegally in USA-based stores.

Of the 86 patients interviewed, over 70% were female, Hispanic, or African American, educated (high school or above), and attended publicly funded clinics.

The interviewees reported using antibiotics primarily for symptoms of COVID-19, the flu, and the common cold, in addition to pain management, allergies, and wound treatment.

Patients stated that they used antibiotics because they understood their illness and what medications would treat it, or because they perceived over-the-counter medications as ineffective.

These participants commented that they faced barriers to healthcare and treatment access, struggling with long wait times to schedule appointments, as well as difficulties getting transportation to and from appointments, and the costs associated with seeing a doctor. They then choose to use non-prescription antibiotics, as they are more convenient and more affordable.

Laytner highlighted the need for increased education efforts in safe antibiotic use and alternative treatment options for common symptoms, as well as improved access to healthcare, in order to combat antimicrobial resistance. “Improper use of antibiotics contributes to the growing threat of antimicrobial resistance, where bacteria and viruses evolve genetically to counter drugs,” Laytner concluded, adding that a patient-provider communication tool is already in development at the Baylor College of Medicine, aiming to increase safe antibiotic use. ●

"Interviewees reported using antibiotics primarily for symptoms of COVID-19, the flu, and the common cold."

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Wastewater-Based Surveillance Reveals Seasonal Respiratory Viral Infections WASTEWATER-based surveillance of severe acute respiratory syndrome coronavirus 2 is an established method for monitoring the COVID-19 pandemic, and for providing an indicator of cases and hospitalizations. However, its potential application to monitoring endemic respiratory viruses has not been elucidated. Therefore, a research team based at the University of Calgary, Canada, sought to assess the occurrence of Influenza A, Influenza B, and respiratory syncytial virus (RSV) RNA in wastewater treatment plants in Calgary, and its correlation with clinical disease.

They reported their research at IDWeek 2023.

2022, Influenza B peaked between February– April 2023, and RSV peaked between November 2022–February 2023. Importantly, the composite signals for Influenza A and Influenza B correlated with clinical cases across the entire province (p<0.0001), while composite signals of RSV correlated with clinical cases and test positivity rates across Alberta (p=0.0070).

The researchers suggest the results provide a novel surveillance approach that can exist independently of, and complementary to, clinical testing. Overall, it could enable the detection of common seasonal respiratory viruses, with an understanding of community level viral trends permitting the identification of hotspots. This, in turn, could inform local public health decisionmaking, and prepare clinicians for potential outbreaks. “Just one flush can hold a lot of information. Wastewater surveillance equips public health experts, clinicians, policymakers, and the public with community-based, objective data to inform health and safety decisions against the flu and RSV,” said Kristine Du, Cumming School of Medicine, University of Calgary. ●

Twenty-four-hour composite wastewater samples were collected weekly from three wastewater treatment plants in Calgary between March 2022– April 2023. RNA was extracted from concentrated wastewater and then quantified. The wastewater values were compared with clinical data reported

by Alberta Health Services (AHS).

Analysis showed that viral signals of Calgary’s wastewater correlated with confirmed weekly cases for all three included viruses. Specifically, Influenza A peaked between November–December

"Twenty-four-hour composite wastewater samples were collected weekly from three wastewater treatment plants."

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Under the Microscope: Artificial Intelligence in Healthcare Authors:

Darcy Richards, EMJ, London, UK

Citation:

Microbiol Infect Dis AMJ. 2023;1[1]:14-16.

DOI/10.33590/microbiolinfectdisamj/10307187. https://doi.org/10.33590/microbiolinfectdisamj/10307187.

ARTIFICIAL INTELLIGENCE (AI) was a theme embedded throughout the program of IDWeek 2023, which was held in Boston, Massachusetts, USA, between the 11th–15th October. The opening session saw Isaac Kohane, Harvard Medical School, Boston, Massachusetts, USA, deliver a fascinating presentation spotlighting the rapid progression of AI algorithms in healthcare, the potential pitfalls associated with its use, and its future implications in clinical practice.

INTRODUCTION AI in healthcare is emerging and continually evolving, with seemingly infinite potential, including improving screening and diagnosis, identifying novel therapeutic targets, and streamlining workflows. However, whilst these possibilities are exciting and encouraging, implementation and rollout of AI in healthcare will not be straightforward. During his presentation, Kohane explored the rapidly progressing field, and gave insight into its impact on healthcare.

THE RAPID EVOLUTION OF ARTIFICIAL INTELLIGENCE Kohane discussed the pace of change in AI, highlighting that what was considered state-ofthe-art in 2021, is now considered ‘old-school’ AI. Spotlighting an example of ‘old-school’ AI used in 2021, Kohane reflected on his personal experience with the evolution of AI. He compared AI used as part of work performed with an undiagnosed

disease network, comprising 12 clinical sites in the USA, to more recent work utilizing GPT-4 in 2022.

The work in 2021 involved genome sequencing from patients with undiagnosed diseases, and then utilizing AI algorithms to determine which identified mutations were most likely to be responsible for the patient phenotype, followed by evaluation from a corresponding clinical expert to put everything together, and determine the diagnosis.

Comparatively in 2022, Kohane discussed the use of GPT-4 to diagnose a rare disease. He detailed a case and highlighted that, after being fed information pertaining to five genes that displayed severe loss of function on wholeexome sequencing, the GPT-4 algorithm was able to identify and give expert level insights into a rare disease diagnosis. The algorithm was able to rationalize the likelihood of these genes contributing to the patient phenotype, and its selection was confirmed using CRISPR technology.

In the space of just 2 years, AI technology has matured, and it is anticipated this trajectory of evolution will continue over the coming years.

"The algorithm relayed the information and potential analyses that could be performed from the data."

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PITFALLS AND IMPLICATIONS

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A potential solution to overcome this is the use of reinforcement learning, but again, this has its limitations. Reinforcement learning works well when the material being learned is deterministic and fully observed, the action space is discrete, there is access to a perfect simulator, the episode is short, the evaluation is clear and fast, and there is a large dataset. Human physiology and medicine, drug response, surgery, and disease course, however, do not follow these rules. Kohane did comment that an area in medicine that does fulfill these criteria is reimbursement and billing, and suggested that AI in this space could be transformative.

Whilst AI undoubtedly has the potential to effect significant benefits to healthcare systems, professionals, and patients, it is not without its challenges. Kohane explained that temporal and financial investment is required to train AI models, and that even when trained, they can make mistakes and require regular updates, which can be costly. Challenges with globalization were also noted as a concern.

Kohane also explored the issue surrounding AI software quality, emphasizing that the U.S. Food & Drug Administration (FDA) evaluates AI as a medical device using a standard trial framework with a specified outcome, conditions, and population. However, Kohane stressed that this type of evaluation only works well for a narrow spectrum task, and works less well for larger, general purpose, generative AI models. This creates a challenge, as these large generative models exist in the public domain, and lend themselves to self-diagnosis. This, in turn, could result in misdiagnosis and perpetuation or deterioration of health conditions.

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Alongside implications for the business of healthcare, Kohane explored the potential AI may have in bridging gaps in physician shortages. For example, in the USA, there were fewer applicants than there were slots available to pediatric infectious disease posts. Physician shortages pose a significant problem for the future, and are not limited to the USA. This problem gives rise to the discussion exploring whether combining the knowledge and skills of other healthcare professionals, such as nurse practitioners

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and physician assistants, with AI, can result in performance close to, or better than, that of the average physician. Kohane discussed evidence from a study showing that usage of AI to report on echocardiograms leads to less inter-observer variance than that seen with standard cardiologist reporting. This AI technology could therefore reduce the need for echocardiogram technicians to consult cardiologists, and therefore reduce physician workload.

An important caveat to consider with the implementation of AI models in healthcare is the need for quality and accurate data. Alongside this, there are challenges regarding data ownership, and the ever-changing nature of medicine and medical practice. This means that different institutions will require devices that need to be customized to different populations and different medical practices, and require continual updates, which will pose a challenge for FDA approval.

POTENTIAL IMPACT FOR INFECTIOUS DISEASES PRACTICE Kohane displayed a video example, where he utilized an AI algorithm to review a Centers for Disease Control and Prevention (CDC) document.

The algorithm relayed the information and potential

analyses that could be performed from the data.

He displayed how he was able to ask the algorithm a series of questions, which culminated in the algorithm’s ability to provide visual representation in the form of a video displaying antibiotic resistance distribution across the USA over time.

Following this demonstration, Kohane stated: “This should give you courage to go into data, and you have the world’s best programmer at your fingertips to do your analyses.”

CONCLUSION In the concluding remarks of the presentation, Kohane explained that the change in AI is happening at a much faster rate than its regulation and education on the subject matter, noting that there is a gap in medical education, and the inclusion of AI into medical training is needed.

He also highlighted the need for implementation of appropriate computational resources, as this will be crucial in training AI models in healthcare settings. Kohane further stressed that for public health and practice, it is important that experts in quantitative data analysis perform the analyses of the data, to limit the dangers of non-quantitative data exploration. Kohane ended by urging the audience to start exploring AI algorithms to be able to keep pace with this rapidly advancing field. ●

"An important caveat to consider with the implementation of AI models in healthcare is the need for quality and accurate data."

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Disease X: Preparing for the Next Pandemic Authors:

Evan Kimber, EMJ, London, UK

Citation:

Microbiol Infect Dis AMJ. 2023;1[1]:17-18.

DOI/10.33590/microbiolinfectdisamj/10307350. https://doi.org/10.33590/microbiolinfectdisamj/10307350.

LOOKING ahead, experts at IDWeek 2023 delivered a thought-provoking session on emerging pathogens with pandemic potential. Historically, a symposium such as this might not have attracted a sell-out crowd, but recent global events have brought this topic to the forefront of medicine, and in Boston, Massachusetts, USA, this series of presentations was one of the highlights from IDWeek. Ruth Lynfield, Minnesota Department of Health, Saint Paul, USA, and Emily Erbelding, National Institutes of Health (NIH), Bethesda, Maryland, USA, co-chaired this session that discussed how to avoid, track, and prepare for ‘disease X’, our next pandemic-causing infection.

PRIMARY PREVENTION OF ZOONOTIC DISEASE EMERGENCE

antimicrobial resistance. According to Bernstein, greater health equity and vaccination access across lower-income countries will reduce outbreaks and future disease emergence. He gave four avenues for altering activity in order to prevent pandemics at source: land use change, wildlife consumption, wildlife trade, and livestock biosecurity. He concluded his section with the encompassing statement: “We live on a world in which our infectious disease risks are completely tied in with the welfare of other living things.”

The idea of preventing diseases before they start was integral to the first presentation, delivered by Aaron Bernstein, National Center for Environmental Health, Agency for Toxic Substances and Disease Registry (ATSDR), Centers for Disease Control and Prevention (CDC), Atlanta, Georgia, USA. Citing a recent study, and listing multiple species with which humans share a common germ pool, Bernstein stressed that up to 75% of emerging infections have zoonotic origins. The concept of spillover was discussed in depth, referencing the movement of pathogens from animals into humans, either through insect vectors or largely by domesticated animals. Bernstein highlighted the need for improved preparedness to prevent human amplification and global spread of these diseases, especially when considering that climate change is creating conditions for increased encounters with animals, in turn facilitating the spread of zoonotic infections and spillover events.

SURVEILLANCE FOR DISEASE X In her presentation, Christine Johnson, University of California (UC) Davis, USA, built on the themes raised by Bernstein to provide a global view of emerging disease during the period of accelerated change we are experiencing. Given the impact of the biodiversity crisis and climate instability in the world today, she emphasized that disease emergence is a consequence, and repeated the statistic that “over 75% of recently emerging infectious diseases have come from wildlife origins.” Johnson went on to stress the irreversible nature of spillover events, and the permanent changes which are brought about as a result.

Viral spillover has historically caused the greatest problems globally. Referencing the Spanish flu and COVID-19, Bernstein spotlighted this as a focal point for primary prevention, alongside Creative Commons Attribution-Non Commercial 4.0

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Her work focuses on investigating and documenting the animal–human interface between outbreaks, to promote readiness in dealing with a pandemic in the future.

Throughout her talk, Johnson described the circular nature of zoonotic disease transmission, “which really adds a layer of complexity with our ability to trace back emerging infectious diseases.”

Using coronaviruses as an example, she described detection windows and the extreme difficulty in tracing a disease back to its origins. Part of her talk presented data ranking the zoonotic transmission of viruses. Domesticated mammals linked to agricultural production provided the most significant sources of transmission, in the form of pigs, cattle, and horses. She also explained the links of spillover through mice and rats with urbanization.

Johnson emphasized the challenges with tracking zoonotic disease transmission effectively in at-risk populations who have less access to healthcare.

Surveillance and improved provision in these populations should be a key focus.

Johnson concluded by urging her fellow infectious disease experts to report and publish both their cases and wider research, acknowledging that there are currently large gaps in literature relating to how people are being exposed and infected, labelling these “epidemiologic puzzle pieces.”

Using large bat populations that live in American road overpasses close to cities as a reference, she finished by reminding attendees that habitat loss, and exploitation of wildlife through hunting and trade, are driving spillover events by facilitating inter-species contact and viral transmission in particular. International collaboration and community engagement have never been more important to supporting pathogen surveillance.

PREPARING FOR DISEASE X Henry Walke, CDC, USA, highlighted the importance of the content in this session by sharing how the CDC is preparing for future disease outbreaks.

Categorizing threats, he provided the USA government classifications of ‘natural’, ‘accidental’, and ‘deliberate’ that make up the national biosecurity strategy, which aims to lower the risk of nationwide and international incidents. Integral to this section was the inevitability of an eventual emergence of ‘disease X’ and how we are going to deal with this.

Efforts to translate research into practice, in a way that is understandable to the public, are imperative to the future initiatives of the CDC. Walke described how funding must be flexible, sustained, and co-ordinated to ensure systems are working together efficiently, complementing themes to do with equality from the previous speakers. He also highlighted the significant investment the CDC is providing to public health infrastructure and readiness in the USA, reporting over 10 billion USD invested in 2022.

Walke emphasized that early detection, characterization of a disease, mitigating impacts, and providing protection are the four pillars that make up the CDC’s response to ‘disease X’. “The goal is to create scalable, flexible systems that will last beyond a current crisis and work for any disease or condition,” is how he described this vision. An example of this ethos being translated into tangible infrastructure is the new Center for Forecasting and Analytics (CFA), which has been set up to enable rapid response to future pathogenic threats with timely and effective decision-making. The CDC is really leading by example by implementing protective initiatives, paving the way for other public health departments to follow suit.

CONCLUSION Common themes that prevailed in this session included an emphasis on the importance of international co-operation, and improved equality in access to public health infrastructure, which will prove essential to rolling out a robust response to ‘disease X’. ●

"We live on a world in which our infectious disease risks are completely tied in with the welfare of other living things."

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Congress Feature

A Preview of Clinical Practice Guideline Updates Authors:

Abigail Craig, EMJ, London, UK

Citation:

Microbiol Infect Dis AMJ. 2023;1[1]:19-21.

DOI/10.33590/microbiolinfectdisamj/10301824. https://doi.org/10.33590/microbiolinfectdisamj/10301824.

IN a highly attended session at IDWeek 2023 in Boston, Massachusetts, USA, speakers provided a sneak preview of the eagerly anticipated updates to clinical practice guidelines in infectious diseases. Chaired by Sara Rogers, Infectious Diseases and International Medicine Associates, Albuquerque, New Mexico, USA, and Kirthana Beaulac, Emerson Hospital, Concord, Massachusetts, USA, the session specifically focused on updates to the clinical management of complicated urinary tract infections (UTI), intravascular catheter-related infections, and communityacquired pneumonia in infants and children. It is important to note that the guidelines are yet to be published, and are therefore subject to change.

COMPLICATED URINARY TRACT INFECTIONS

without a urinary catheter was presented. The patient was admitted with a week of suprapubic pain and urinary frequency that had progressed over the past 48 hours to include fever, chills, and altered mentation. She previously received ceftriaxone for levofloxacin-R Escherichia coli pyelonephritis, and was allergic to penicillin. Her vital signs were a temperature of 38 °C, blood pressure of 110/60, respiratory rate of 22, and pulse rate of 110. Urine microscopy showed pyuria and bacteriuria.

Barbara Trautner, Baylor College of Medicine, Houston, Texas, USA, presented the inaugural clinical practice guidelines for treating complicated urinary tract infections (cUTI). Following a literature search focusing on patient-important outcomes, authors gathered evidence from publications between 2008–2023.

The previous definition of uncomplicated UTI and acute pyelonephritis was limited to include only healthy, non-pregnant, afebrile females, with no diabetes or urologic abnormalities. Everything else was considered ‘complicated’. However, this did not accurately reflect clinical practice, as factors like tissue invasion outside the bladder were excluded. Thus, the new definition of cUTI includes all infection beyond the bladder, encompassing pyelonephritis, catheter-associated UTI, and febrile bacteremic UTI, with everything else categorized as an uncomplicated UTI.

The guidelines dictate that the patient must first be assessed clinically to identify the presence of sepsis, as this diagnosis dictates all subsequent decisions due to a higher mortality in a septic patient, with a smaller margin for error when selecting the empiric therapy. The patient was diagnosed with cUTI and sepsis, due to a Sequential Organ Failure Assessment (SOFA) score of greater than 2. Step two of the guidelines involves the identification of risk factors for uropathogens resistant to specific antimicrobial agents. Prior cultures will aid in this, along with the knowledge of fluoroquinolone exposure in the last 12 months. Step three considers patientspecific factors: whether the patient has any allergies, a risk of a Clostridium difficile infection,

The purpose of these guidelines is to aid all practitioners in choosing an empiric agent for the treatment of cUTIs at the point of care. To illustrate this, the case of a 68-year-old female Creative Commons Attribution-Non Commercial 4.0

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drug–drug interactions, contraindications, or a preferred route of delivery. Again, referring to the case presented, previous exposure to fluoroquinolone and a penicillin allergy ruled out piperacillin-tazobactam and fluoroquinolones as treatment options, leaving cephalosporins and carbapenems. Step four considers the antibiogram, a step only relevant to patients with sepsis. Despite limited evidence, the guideline development team decided that antibiogram use was appropriate as an additional safety measure in patients with sepsis, as the potential damage caused by inappropriate therapy is only modest. The patient had E. coli most recently, and therefore, this is the focus of step four. Fortunately, more than 80% of the E. coli are susceptible to the available drugs in this antibiogram. Ceftriaxone or ertapenem would be appropriate in this case based on patient history and allergies, and the patient received empiric therapy of intravenous ceftriaxone 2 g daily. On Day 3, she was afebrile, with normal vitals, labs, and mentation.

Nicolas Cortes-Penfield, University of Nebraska Medical Center, Omaha, USA, continued, discussing the appropriate duration and route of further treatment. Cortes-Penfield stressed that reduced treatment duration is recommended if clinical improvement is observed. In the presented case, the patient was stable, afebrile, and did not demonstrate evidence of abscess or obstruction needing source control. The patient was therefore ready for oral switch to an appropriate oral agent.

Regarding the duration of therapy, evidence suggests 7 days is appropriate for pyelonephritis and Gram-negative bacteremia that has promptly resolved, rather than longer courses. As such, per os trimethoprim-sulfamethoxazole was advised for a further 4 days in this case, resulting in a total of 7 days of treatment. Cortes-Penfield concluded by stressing that the algorithm is not a substitute for your clinical judgement, due to several limitations in the data available, and the need for an individualized plan for some patient groups.

INTRAVASCULAR CATHETERRELATED INFECTIONS Nasia Safdar, University of Wisconsin–Madison School of Medicine and Public Health, USA, presented the case of a 50-year-old male with a history of short bowel syndrome, and a longterm triple lumen venous catheter in place for the last 3 months. He presented with fever, chills, lack of appetite, and general malaise. His vital signs were a temperature of 38.9 °C, blood pressure of 102/64, a respiratory rate of 18, and a pulse rate of 110, while a physical assessment suggested the catheter site looked okay, with no rash. This case spotlighted the workflow of the draft clinical practice guidelines for the diagnosis and management of intravascular catheterrelated infections, with the rationale behind each recommendation discussed.

Using the Population, Intervention, Control, and Outcomes (PICO) framework, clinical questions were explored and linked to each stage of the draft recommendations. The first clinical question explores the impact on the patient of drawing blood through an intravascular catheter (IVC) filter alone, compared with a central venous catheter and percutaneously drawn blood. Based on the draft recommendations, peripheral and IVC blood cultures should be obtained simultaneously, so this patient underwent further lab testing, and blood cultures were considered from all lumens of the multi-lumen catheter. After 24 hours, blood cultures were growing coagulase-negative Staphylococcus, while peripheral cultures were negative at that timepoint, and thus systemic antibacterial therapy would commonly be started.

However, when considering patient-important outcomes and the draft recommendations, in patients with positive blood cultures with coagulase-negative Staphylococcus spp. and no evidence of sepsis or hemodynamic instability, monitoring without systemic antimicrobials is recommended. Starting therapy of systemic antimicrobials is only recommended in patients with retained IVC and known pathogens.

"The algorithm is not a substitute for your clinical judgement, due to several limitations in the data available."

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IDWeek 2023 In the discussed case, due to hemodynamic instability, vancomycin was started, and the IVC was removed. The patient responded well, but contrary to the UTI guidelines, there is no tangible evidence regarding the recommended duration of therapy. Based on weak evidence, systemic antibiotics are recommended for 2 weeks in patients with uncomplicated catheterrelated bloodstream infections who have had the IVC removed. However, there is more substantial evidence regarding guidewire exchange, with the draft recommendations suggesting guidewire exchange for an antimicrobial-impregnated catheter if available, and this recommendation is made irrespective of device type.

Congress Feature

The draft recommendation in this case is to obtain a chest/lung ultrasound as a first-line diagnostic modality, to be substituted with a CT when this is not available. In the discussed case, a chest ultrasound was performed, identifying multiple septations and loculations. To relieve the patient of chest pain, chest tube drainage and intrapleural fibrinolytics (CTF), rather than video-assisted thoracoscopic surgery, is recommended as a firstline therapy in children with pneumonia-associated empyema. Despite evidence showing similar outcomes following each type of intervention, video-assisted thoracoscopic surgery is a major surgical procedure, while CTF is a bedside procedure, which is less invasive and less costly.

Regarding tube size, the Infectious Diseases Society of America (IDSA) panel suggests the use of small-bore chest tubes over large-bore test tubes in children with parapneumonic effusion or empyema, based on the evidence of a small number of comparative studies. It is also recommended that tissue plasminogen activator be used alone, rather than in combination with dornase alfa (DNase) in children with pneumoniaassociated empyema. In the discussed case, the patient underwent pleural fluid drainage by CTF, with a 12-gauge catheter draining 1.5 L of purulent fluid, and tissue plasminogen activator was instilled in pleural space via a catheter for 3 days.

COMMUNITY-ACQUIRED PNEUMONIA IN INFANTS AND CHILDREN Complicated pneumonia is defined as a pulmonary parenchymal infection complicated by a range of comorbidities, with the final presentation focusing on parapneumonic effusions and empyema.

Kwabena Ampofo, University of Utah School of Medicine, Salt Lake City, USA, presented an update to the 2011 guidelines, focusing on radiographic evaluation of pleural effusion, drainage, and intrapleural fibrinolytics.

Continuing the theme of case-based learning, a 3-year-old boy with no medical history was presented. The patient developed an upper respiratory infection 10 days before admission, that lasted 3 days. Five days later, he developed a fever of 40 °C, before developing a cough and chest pain after another 2 days. On the day of admission, he developed labored breathing, and was evaluated in the emergency department. His vitals were concerning, and indicative of fever. A chest X-ray revealed left lower lobe pneumonia, associated with large pleural effusion, and patchy opacity in the right perihilar region, which could represent infection or atelectasis.

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CONCLUDING REMARKS The session concluded with thought-provoking questions for the panel. While the draft guidelines outlined during the session specifically focus on the clinical management of patients with cUTI, catheter-related bloodstream infections, and community-acquired pneumonia in infants and children, the experts hope the scope of the guidelines is widened in future to include guidelines for diagnosis. ●

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Abstract Review Featuring insightful research presented at IDWeek 2023, exploring empiric anti-pseudomonal antimicrobial stewardship in patients with cancer and febrile neutropenia at Olive View-University of California, Los Angeles (UCLA) Medical Center, Sylmar, USA.

Evaluation of Bacteremia in Febrile Neutropenia and Implications on Antimicrobial Stewardship Authors: *Sowmya Kalava,1 Niki Arab,2,3 Rolando Zamora Gonzalez,1 Brian Kim,2,3 Arthur Jeng3 1. Division of Infectious Disease, David Geffen School of Medicine, Los Angeles, California, USA 2. Department of Pharmacy, Olive View-University of California, Los Angeles (UCLA) Medical Center, Sylmar, USA 3. Department of Medicine, Division of Infectious Disease, Olive View-UCLA Medical Center, Sylmar, USA *Correspondence to skalava@mednet.ucla.edu Disclosure: Kalava and Zamora Gonzalez received travel grants to present at IDweek 2023. Jeng has received grants from bioMérieux. Arab and Kim have declared no conflicts of interest.

Keywords: Antimicrobial stewardship, bacteremia, febrile neutropenia (FN), pseudomonal infections.

Citation: Microbiol Infect Dis AMJ. 2023;1[1]:22-25.

DOI/10.33590/microbiolinfectdisamj/10300041. https://doi.org/10.33590/microbiolinfectdisamj/10300041.

BACKGROUND Febrile neutropenia (FN) is a common complication in patients with cancer, and historically, pseudomonal infections have been attributed to significant morbidity and mortality in this group 22

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of patients.1,2 Infectious Diseases Society of America (IDSA) guidelines for FN in patients with cancer recommend the initiation of an empiric anti-pseudomonal (PsA) antibiotic (abx), based on patient risk factors, with recommendation for modification of initial regimen based on microbiologic data obtained throughout the course.3 At Olive View-University of California, Los Angeles (UCLA) Medical Center, Sylmar, USA, the authors reviewed FN cases to determine the prevalence of PsA bacteremia and assess the necessity of anti-PsA abx.

MATERIALS AND METHODS Single center retrospective chart review on all positive blood cultures (Bcx) from January 1, 2017– December 30, 2022. Positive Bcx were matched with ICD-10 codes for neutropenia on inpatient encounter (Table 1). Exclusion criteria consisted of absolute neutrophil count >500, FN not related to malignancy, and untreated suspected contamination (Figure 1). Charts were reviewed for Bcx results, source of bacteremia, antibiotic prescribing, 30-day all-cause mortality, and risk factors for PsA infection.

RESULTS Of 1,303 neutropenia encounters and 3,775 positive Bcx, 92 were matched, and 48 met inclusion criteria. The most common source of bacteremia was intra-abdominal (n=17; 35.4%), followed by line-associated infection (n=9; 18.8%).

Gram-negative bacteremia was slightly more common than gram-positive, with Enterobacterales

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Table 1: Baseline characteristics.

Age (mean)

52 (IQR: 42–63)

Male sex no. (%)

31 (62.5)

Maximum temperature °C (mean±SD)

38.6±0.8

Average ANC (mean)

114 (IQR: 0–200)

Type of malignancy Solid Oncology: no. of patients (%) 14 (29.1) Liquid Oncology: no. of patients (%) 29 (70.8) Length of stay in days (mean)

19.8 (IQR: 5–26)

Antipseudomonal coverage: no. of patients (%) Started empiric 48 (100) Continued despite negative Bcx 37 (77.1) Transitioned to culture directed 11 (22.9) Required ICU admission: no. of patients (%)

20 (41.7)

30-day all cause mortality: no. of patients (%) Yes 11 (22.9) No 35 (72.9) Unknown 2 (0.5)

Three patients with >1 encounter for neutropenic fever.

ANC: absolute neutrophil count; Bcx: blood cultures; ICU: intensive care unit; IQR: interquartile range; no.: number; SD: standard deviation.

Figure 1: Methods.

1,303 neutropenia encounters

3,775 positive blood cultures

92 matched Exclusion criteria: - ANC>500 - Unrelated to malignancy - Untreated suspected contamination 48 isolates met inclusion criteria ANC: absolute neutrophil count.

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found in 28 (58.3%) and PsA found in five (10.4%; Figure 2). All 48 cases were started on empiric anti-PsA abx, and 31 (64.6%) were continued on anti-PsA abx for an average of 11 days (interquartile range: 5–14) despite no isolated PsA in the blood. Thirty-day all-cause mortality was not significantly different between those who

continued on anti-PsA abx versus those in whom anti-PsA abx were stopped when PsA was not isolated (5 out of 31 versus 3 out of 13; p=0.5; Figure 3). All cases of PsA bacteremia had at least one risk factor for nosocomial acquisition, e.g., hospitalization and/or abx exposure within prior 30 days.

Figure 2: Prevalence of bacteremia based on organism.

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Escherichia coli

Streptococcus spp.

Klebsiella spp.

Enterococcus spp.

Other Enterobacterales

Staphylococcus aureus

Pseudomonas aeruginosa

Coagulase-negative staphylococci

Number Isolates

Micrococcus Candida spp.

10

Other

5

0

Figure 3: Prevalence and outcomes of Pseudomonas bacteremia.

48 isolates met inclusion criteria 43 (89.5%) blood cultures negative for Pseudomonas 12 (28.0%) discontinued antipseudomonal coverage

5 (10.5%) blood cultures positive for Pseudomonas

31 (72.0%) continued antipseudomonal coverage

No difference in 30-day all cause mortality (5/31 versus 3/13; p=0.5)

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CONCLUSION

IDWeek 2023

PsA as part of an antibiotic de-escalation strategy, and further stewardship efforts can be focused on de-escalating anti-PsA antibiotics, especially when not isolated from cultures. ●

The most common organism causing bacteremia in FN was Enterobacterales. The prevalence of PsA bacteremia was low, yet most were continued on anti-PsA abx despite Bcx showing a different organism. Continuation of anti-PsA abx did not make a difference in 30 day all-cause mortality when PsA was not isolated. When it occurred, the most common risk factor for having PsA bacteremia was hospitalization within the prior 30 days, with exposure to broad-spectrum antibiotics.

This suggests that although anti-PsA antibiotics are routinely given empirically to this patient population, the need is low if the patient is from the community/home and has had no healthcare exposure. PsA is not felt to be normal bowel/body flora in a non-hospitalized or antibiotic-exposed patient. Thus, patients may be risk stratified for

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References

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1.

Zhu J et al. Bacterial pathogens differed between neutropenic and non-neutropenic patients in the same hematological ward: an 8-year survey. Clin Infect Dis. 2018;67(Suppl 2):S174-8.

2.

Kang C-I et al. Pseudomonas aeruginosa bacteremia: risk factors for mortality and influence of delayed receipt of effective antimicrobial therapy on clinical outcome. Clin Infect Dis. 2003;67(6):745-51.

3.

Freifeld AG et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America.

Clin Infect Dis. 2011;52(4):e56-93.

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Abstract Highlights The following highlights explore selected abstracts presented at IDWeek 2023, held in Boston, Massachusetts, USA. They cover key topics, including disparities in sepsis management, methicillin-resistant Staphylococcus aureus decolonization in neonatal intensive care, algorithms for the appropriate collection of blood cultures, and respiratory syncytial virus outcomes in adults.

Microbiol Infect Dis AMJ. 2023;1[1]:26-30.

DOI/10.33590/microbiolinfectdisamj/10303598. https://doi.org/10.33590/microbiolinfectdisamj/10303598.

Citation:

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Blood Culture Algorithms in Emergency Care: Impact on Safety INAPPROPRIATE blood culture collection can increase the number of false positive results that, in turn, can lead to excess antibiotic use, unnecessary diagnostic procedures, and increased length of hospital stay. In an era focusing on antimicrobial stewardship, strategies to reduce excess antibiotic use will be crucial. Algorithms for appropriate blood culture collection could be one such strategy.

culture positivity rate, days of antibiotic therapy, indication, and 30-day hospital readmission rates were evaluated.

Overall, the researchers found that of the 2,168 blood cultures, the majority adhered to the algorithm. In cases where non-adherence did occur, isolated fever or leukocytosis (29%), non-severe community-acquired pneumonia or healthcare-associated pneumonia (6.9%), and nonsevere cellulitis (4%) were the most common reasons.

Novel research presented at IDWeek 2023 explored this further. Researchers from Duke University Hospital, Durham, North Carolina, USA, performed a prospective cohort study between December 2022–March 2023 to evaluate whether introduction of an appropriate blood culture algorithm to their emergency department impacted clinical, operational, and safety metrics. Historical controls from December 2020–November 2022 were used for comparison. Exclusion criteria included: patients <18 years of age, heart and lung transplant recipients, and an absolute neutrophil count of <500*109 /L.

Implementation of the algorithm resulted in a decrease in the average monthly blood culture volume from 1,387 prior to the algorithm to 1,226 afterwards (p=0.046), and culture positivity increased from 11.23% to 13.90%. Additionally, no changes in 30-day hospital readmissions pre- and post-intervention (21.1% versus 19.6%; p=0.300) or days of antibiotic therapy (786 versus 783 days per 1,000 patient days; p=0.850) were noted.

The team concluded that, in an academic tertiary care emergency department, introduction of a blood culture algorithm resulted in increased culture positivity rates, decreased blood culture order volume, and had no impact on 30-day hospital readmission or days of antibiotic therapy. ●

Following electronic, in-person, and online dissemination of the blood culture algorithm, seven emergency department clinicians reviewed algorithm adherence for eligible patients each week, and provided monthly feedback to all emergency department providers. Algorithm adherence, blood culture order volume, blood

"Implementation of the algorithm resulted in a decrease in the average monthly blood culture volume."

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MRSA Infection in Neonatal Intensive Care Units RESEARCHERS presented a comparison of decolonization methods, and their impact upon methicillin-resistant Staphylococcus aureus (MRSA) infection, within the setting of a neonatal intensive care unit, at IDWeek 2023. MRSA and methicillin-susceptible S. aureus are both highly infectious diseases, which can quickly overrun hospital wards filled with vulnerable patients.

Neonates are particularly vulnerable to developing MRSA infections, which can be life-threatening.

Surveillance and decolonization have the aim of impeding both transmission and infection of MRSA and methicillin-susceptible S. aureus, and current clinical practices use the likes of topical mupirocin and chlorhexidine (CHG) wipes to do so. The ultimate aim of this study was to compare whether a combination of topical mupirocin and CHG is more effective than mupirocin alone in preventing MRSA infection in the neonatal population.

Nahid Hiermandi, Pediatric Infectious Diseases Fellow, Baylor College of Medicine, Houston, Texas, USA, and colleagues, performed a retrospective study of MRSA infections in the neonatal intensive care unit of the Texas Children’s Hospital Pavilion for Women in Houston, between January 2014– December 2020. The center receives around 900 admissions per year, most of which are in-born.

Prior to 2017, the center utilized a surveillance culture method, swapping this for a surveillance PCR test (Xpert MRSA NxG, Cepheid, Sunnyvale, California, USA) from 2017.

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In this period, of the 7,890 patients admitted to the neonatal intensive care unit, 128 (1.6%) were found to be MRSA-colonized, and 19 (0.2%) of these had an MRSA infection, defined as the isolation of MRSA from a particular specimen (body fluid, urine, blood, trachea, or cerebrospinal fluid). In the subgroup of 128 MRSA-colonized neonates, patients were assigned to three groups: mupirocin and CHG (18 patients), only mupirocin (76), or neither (34). The mupirocin and CHG treatment eradicated all incidence of MRSA infection; in the mupirocin treatment, 12 patients (15.8%) developed MRSA infection; and receiving neither treatment caused seven infants (20.6%) to develop MRSA infection.

"The mupirocin and CHG treatment eradicated all incidence of MRSA infection."

Limitations of this study included the odds ratio not reaching statistical significance, with a low rate of MRSA colonization; exclusion of infants who were ineligible for CHG treatment due to their age; instances of missing outcomes in infants who were discharged before the onset of their infection; and confounders, such as duration of hospitalization and medical condition, which were not accounted for. ●

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Sepsis: Sex and Race Disparities in Time-to-Antibiotics SEPSIS treatment disparities based on sex and race have been identified in new research presented at IDWeek 2023. Theodore R. Pak, Massachusetts General Hospital, Boston, USA, and colleagues, sought to clarify previous findings from observational studies, suggestive that compared with White males, females and people of color experience worse sepsis outcomes.

septic shock, median time-to-antibiotics was higher in females than males at 159 minutes versus 141 minutes (aOR: 1.09; 95% CI: 1.01–1.17).

Furthermore, females with septic shock displayed higher in-hospital mortality (aOR: 1.15; 95% CI: 1.05–1.27), and this persisted after adjusting for time-to-antibiotics (aOR: 1.17; 95% CI: 1.03–1.32).

However, no association between sex/race/ ethnicity and in-hospital mortality was seen for sepsis without shock.

The team performed a retrospective analysis of all adults admitted with suspected sepsis or septic shock across five Massachusetts hospitals between 2015–2022 to review, using multivariable logistic regression, whether any associations between sex/race/ethnicity, time-to-antibiotics (3–6 hours versus 0–3 hours), and in-hospital mortality existed.

"Females with septic shock displayed higher in-hospital mortality."

A diagnosis of suspected sepsis was defined as blood cultures drawn, intravenous antibiotics administered within 24 hours of arrival, and evidence of organ dysfunction. Septic shock was defined as sepsis and hypotension or a lactate of ≥4.0 mmol/L.

Additionally, disparities in the median time-toantibiotics for sepsis and septic shock were noted amongst race/ethnicity categories. The greatest disparity was seen between Black and White patients. Median time-to-antibiotics for sepsis was 212 minutes for Black patients compared with 193 minutes for White patients (aOR: 1.23; 95% CI: 1.06–1.43), and 157 minutes for Black patients and 147 minutes for White patients (aOR: 1.27; 95% CI: 1.08–1.48) in septic shock.

In total, 48,263 patients were included. The regression analysis adjusted for allergies, comorbidities, infection source, laboratory findings, language, other demographics, and vital signs.

From these findings, the authors concluded that females and Black patients were more likely to receive antibiotics later, and females experienced higher mortality in septic shock in a large cohort of patients with sepsis. ●

The evaluation highlighted that median timeto-antibiotics for sepsis was higher in females than males at 202 minutes versus 188 minutes, respectively (adjusted odds ratio [aOR]: 1.15; 95% confidence interval [CI]: 1.07–1.25). Similarly, for Creative Commons Attribution-Non Commercial 4.0

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Clinical Outcomes in Adults with Respiratory Syncytial Virus RESPIRATORY illness and hospitalization in older adults and those with certain underlying medical conditions is often caused by respiratory syncytial virus (RSV). Research presented by Michael Melgar, Centers for Disease Control and Prevention (CDC), Atlanta, Georgia, USA, at IDWeek 2023, emphasizes the importance of identifying adults with an increased risk of severe illness as novel RSV vaccines are being developed.

Melgar and team used population-based surveillance conducted through the RSV Hospitalization Surveillance Network (RSV-NET) from 2014–2022, across 75 counties in 12 states in the USA. The analysis included non-pregnant adults (≥18 years) who had been hospitalized with laboratory-confirmed RSV infection during each of the eight seasons, spanning October– April, except 2020–2021, which spanned October 2020–September 2021. Percentages of adults with intensive care unit admission were calculated, as well as mechanical ventilation and in-hospital death, stratified by demographic characteristics.

The team also calculated age-adjusted percentages with these outcomes, stratified by underlying conditions.

Results showed that there were 13,080 RSVassociated hospitalizations amongst the participants, 61.9% of which were aged ≥65 years.

Admission to the intensive care unit was recorded in 18.6% of patients, mechanical ventilation in 7.2%, and in-hospital death in 4.2%, the majority of which occurred in adults aged 75 years or older.

Patients with non-asthma chronic lung disease and with cardiovascular diseases had the highest age-adjusted percentages of in-hospital death.

Immunocompromise and asthma were the most commonly occurring underlying conditions in patients aged 18–49 years (34.8% and 29.8%, respectively).

The researchers concluded that older age and cardiopulmonary conditions were associated with severe illness in adults hospitalized with RSVassociated infections. They added that, as a result, “older adults and adults with cardiopulmonary and immune compromising conditions may benefit from RSV vaccination when licensed products become available.” ●

"There were 13,080 RSV-associated hospitalizations amongst the participants, 61.9% of which were aged ≥65 years."

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Interview

Interview We spoke with Shweta Anjan about advice for younger clinicians, applying antimicrobial stewardship to transplant infectious diseases, her research, and highlights from IDWeek 2023.

Shweta Anjan Associate Program Director, Transplant Infectious Disease Fellowship; Division of Infectious Diseases; Transplant and Immunocompromised Host Service; Jackson Memorial Hospital; Miami Transplant Institute; University of Miami Miller School of Medicine, Florida, USA

Citation:

Microbiol Infect Dis AMJ. 2023;1[1]:31-33.

DOI/10.33590/microbiolinfectdisamj/10305325. https://doi.org/10.33590/microbiolinfectdisamj/10305325.

Q1

Have there been any specific challenges associated with embarking on your career path to subspecialise in transplant infectious diseases (TID), and do you have any advice for younger clinicians starting their journey into the field?

from an ‘I want to learn and do it all’ mindset, to a mindset of identifying and developing a niche within TID. I had help from mentors at my own university and outside, who shared their experiences, and guided me through this process.

My advice for younger clinicians would be to maximize opportunities, however small; keep an open mind; and find your network of peers and mentors to learn from and collaborate with.

TID is an exciting and rapidly expanding field. I began my career as a medical student at Kasturba Medical College in Manipal, India, and moved to the USA to learn and practice evidence-based medicine. My interest in TID began during my internal medicine residency at the University of Pittsburgh Medical Center, Pennsylvania, USA, while on a TID elective as a second-year resident.

I remember having to look up every diagnosis and antibiotic on my first day. I completed 2 years of infectious disease (ID) fellowship training, and an additional year of TID fellowship at the University of Miami Miller School of Medicine (UM) - Jackson Memorial Hospital (JMH), Florida, USA. One of the challenges I faced as an ID fellow was going Creative Commons Attribution-Non Commercial 4.0

Q2

Antimicrobial stewardship is a global focus. How does this apply to TID?

Antimicrobial stewardship programs are crucial in the prevention of antimicrobial resistance.

Interestingly, transplant patients are hosts for multidrug resistant bacteria, arising from the use of prolonged prophylactic antibiotics, frequent hospitalizations, contact with healthcare settings leading up to transplant, invasive procedures, and weak immune systems.

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Interview

Thus, for an antibiotic stewardship program to be successful, it must consider this vulnerable patient population. Antibiotic stewardship in transplant patients is more complex than stopping antibiotics for cost-savings. It involves using rapid diagnostics, like molecular testing; genome sequencing for early accurate diagnostics; diligent infection prevention measures; and, at times, escalation, or even combination antibiotic use, for synergy. None of these decisions are made in a vacuum; rather, it needs a cohesive multidisciplinary team discussion. Communication and teamwork are key to successful antimicrobial stewardship in transplant infectious disease.

"Antibiotic stewardship in transplant patients is more complex than stopping antibiotics for cost-savings."

Q3

Alongside your clinical role, you have been active in research. In 2023, the Clinical Research Forum bestowed you with one of their Top 10 Clinical Research Achievement Awards. Could you tell us about the research you received this award for?

The Clinical Research Forum is a non-profit organization dedicated to providing leadership to the national clinical and translational research enterprise, promoting understanding and support for clinical research, and its impact on health and healthcare. The Top 10 Clinical Research Achievement Awards program identifies major advances resulting from the nation’s investment in research, to benefit the health and welfare of its citizens. The study that was nominated and received an award was ‘Early Outpatient Treatment for Covid-19 with Convalescent Plasma’, led by David Sullivan at the Johns Hopkins University, Baltimore, Maryland, USA. I was the principal investigator for this multicenter randomized controlled trial in Miami. The study proved that COVID-19 convalescent plasma, when given early in the outpatient setting, reduced the risk of disease progression and hospitalization.

With emerging COVID-19 variants, convalescent plasma remains a great treatment option, especially in immunocompromised patients, and resource-limited settings.

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Q4

Earlier this year you co-authored a paper entitled ‘Difference between SARS-CoV-2, seasonal coronavirus, influenza, and respiratory syncytial virus infection in solid organ transplant recipients’. What were the main findings and clinical implications from this research?

Seasonal respiratory viruses like influenza, respiratory syncytial virus, and now COVID-19, are associated with increased morbidity and mortality in organ transplant recipients. The differences in severity of illness and outcomes of each were not studied before. We found that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections were associated with higher incidence of intensive care admission, mechanical ventilation, and mortality. The older age group was at greater risk of viral pneumonia.

Our cohort included patients from early 2020, when COVID-19 vaccines and treatments were unavailable. In 2023, I am certain a comparison study would yield different results.

Q5

What does your position as a member of the American Society of Transplantation (AST) involve?

I am a member on several committees and working groups within the AST. My most impactful work, however, is through the Community Education Committee, and the Executive Committee of the Trainee and Young Faculty Community of Practice. As part of the Trainee and Young Faculty Community of Practice, we empower early career transplant physicians and students interested in pursuing a career in transplantation, by providing a community and opportunities to participate in AST initiatives. As a community education committee member, I work with a diverse group of multidisciplinary transplant clinicians and patients to create and share resources for transplant candidates, recipients, living donors, caregivers, community partners, and the public, to advance their knowledge of transplantation and organ donation. This work resonates deeply with me, and inspires a profound sense of purpose and connection.

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Q6

In 2022, you were involved with the Infectious Diseases Society of America (IDSA) Foundation Mentorship Advisory Committee. Why is this program important?

(AI) and healthcare, sessions on climate changeassociated infections, and xenotransplantation.

The IDSA Foundation Mentorship Program is a yearround program, connecting the future generation of ID trainees with seasoned mentors, as they begin to navigate their careers in the field. It started with the goal to increase the number and diversity of medical students and residents choosing ID as a career path, but the program now provides a community to mentors and mentees alike. I was a mentee on this program not too long ago, and I have been fortunate to have found inspiration and support from incredible clinician-mentors. The committee also provides ongoing training and support for mentors, the development of group education activities, and implementation of Inclusion, Diversity, Equity and Access (IDEA) best practices that increase the impact of program activities. The Mentorship Program is important because it helps maintain and build the ID workforce. With increasing antimicrobial resistance, emerging infections, and the possibility of future pandemics, the world needs a larger ID workforce.

Q7

What sessions for this year’s IDWeek, held in Boston, Massachusetts, do you feel were highlights from the event, and what were their key take-home messages?

The key points were consistent and clear: AI in healthcare is still developing, and it is prone to errors. There is a lot of work to be done until we can utilize this technology safely. Global warming, the acute and long-term changes in environmental conditions, natural disasters, and urbanization are altering vector ecology, and changing the epidemiology of infections as we know it.

Xenotransplantation, using organs from another species, most often pigs, has its challenges.

The immunological hurdles are being overcome by genetic engineering, and use of alternative immunosuppressants. There is a risk of transmission of animal infections to humans, but this can be predicted with active surveillance with cultures, serologies, and molecular tests. There are knowledge gaps to be addressed on the availability of effective therapies for which we need human data.

Q8

Looking towards the future, are you currently working on any exciting projects, or are you intrigued by any emerging innovations in the field?

My current projects are focused on emerging fungal infections in solid organ transplant recipients, and the role of anti-fungal stewardship. I have been seeing an increase in fungal infections in my clinical practice lately, which piqued my interest.

What truly intrigues me is new technology (AI), and incorporating it into clinical ID practice. So, I remain curious as to how AI will be an ally to infectious disease physicians. ●

Every session at IDWeek is so unique and knowledge-packed that it is hard to highlight just one. In my opinion, the highlights from the event were the opening plenary on artificial intelligence

"With increasing antimicrobial resistance, emerging infections, and the possibility of future pandemics, the world needs a larger ID workforce."

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EMJ Podcasts The EMJ Podcast aims to provoke conversations around the latest trends and innovations in healthcare, provide engaging and educational content for healthcare professionals, and hosts conversations with physician entrepreneur, Jonathan Sackier.

Listen today www.emjreviews.com

Feature

The 2022–2023 USA Respiratory Viral ‘Tripledemic’: Healthcare Lessons Learned Authors:

*Syra Madad,1 Richard James Salway,1 Jason Raggi,1 David Silvestri,1 Tom Cotter,2 Courtney Romolt2 1. NYC Health + Hospitals, New York, USA 2. Healthcare Ready, Washington, D.C., USA *Correspondence to syra.madad@nychhc.org

Disclosure:

The authors have declared no conflicts of interest.

Received:

08.07.23

Accepted:

10.25.23

Keywords:

COVID-19, influenza, respiratory syncytial virus (RSV), tripledemic, viral respiratory season.

Citation:

Microbiol Infect Dis AMJ. 2023;1[1]:35-39.

DOI/10.33590/microbiolinfectdisamj/10306548. https://doi.org/10.33590/microbiolinfectdisamj/10306548.

The convergence of three viral epidemics, respiratory syncytial virus (RSV), COVID-19, and influenza, during 2022–2023, placed a significant burden on healthcare systems nationally. While there was regional variation in timing and intensity of disease spread, as well as severity of illness, by early November 2022, an estimated 80% of USA regions had already neared their expected seasonal peak levels in RSV, several months ahead of its typical peak in early February.1 Nearly 50% of USA regions reported high or very high levels of influenza activity,2 months ahead of expected seasonal peaks.3 Meanwhile, COVID-19 continued to circulate in the background, with 2% of USA counties, districts, or territories reporting high COVID-19 community level, and 20% reporting medium community level during the same period.4

way they approach preparedness and response for more common respiratory diseases in the wake of the COVID-19 pandemic and an era of climate volatility. Here the authors describe the emergency preparedness and response experiences of NYC Health + Hospitals, New York, USA, during the 2022–2023 ‘tripledemic’, as it was popularly dubbed, and further call attention to critical equity considerations in how hospitals and health systems prepare for and respond to such events.

THE ‘TRIPLEDEMIC’ IN NEW YORK CITY At NYC Health + Hospitals, New York City’s public healthcare system, and the nation's largest municipal healthcare system, the unanticipated simultaneous surge in three respiratory viruses created need for time-sensitive coordination, principally targeting three goals: first, to improve comprehensive situational awareness to support efficient local and systemwide response needs; second, to decrease demands on acute care resources that were created by the patient surge;

The co-circulation of these three respiratory viruses is not new, and indeed, all three viruses circulate year-round, and experience peaks during winter months. However, the prematurity, rapidity, and simultaneity of their surges in 2022–2023 uniquely taxed health systems, and challenged the Creative Commons Attribution-Non Commercial 4.0

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Feature and third, to increase those resources to care for surging demand, particularly in areas of staff and supplies.

Improving Situational Awareness

Real-time situational awareness, meaning information about the current or anticipated extent of emergency, including resources and operations necessary for response, is critical to any response coordination. At NYC Health + Hospitals, situational awareness was provided to central and local response teams through two primary approaches: co-ordination groups and analytic tools.

NYC Health + Hospitals’ Central Emergency Management team activated a number of coordination groups to provide regular, subjective real-time information. A ‘Pediatric Action Team’ (PAT) was activated, consisting of selected pediatric clinical subject matter experts from a variety of fields (pediatric emergency medicine, pediatric intensive care unit [PICU], general pediatrics, etc.) from several of the NYC Health + Hospitals facilities, and provided both on-theground feedback regarding patient volumes, acuities, resource availability; and response operations and needs. A separate co-ordination group brought together broad hospital pediatrics and facility executive representation to identify challenges from departmental and facility perspectives, and to share response strategies and progress for further dissemination to frontline staff.

Finally, the system’s Multi-Office Coordination (MOC) Group brought together system clinical, operational, public affairs, and intergovernmental leadership, and teams to co-ordinate response actions leveraging systemwide, and external resources, informed by needs at other levels. To ensure alignment of all groups, Central Office Emergency Management led co-ordination of all three groups.

Beyond co-ordination groups, situational awareness was gleaned from a number of real-time analytic tools. While NYC Health + Hospitals had existing reporting tools available to provide realtime awareness of patient trends, including as part of their electronic health record, not all of these tools were available to all response participants, especially those without appropriate electronic health record access. Moreover, additional 36

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response metrics were required beyond those in production, and thus, new tools were necessitated.

NYC Health + Hospitals’ Data & Analytics team, building on experiences in COVID-19 and mpox outbreaks, developed tools to measure percentage of patients admitted with viral syndromes, trends of positive test cases (Figure 1), volumes in pediatric emergency departments, and outpatient clinic volumes. As Figure 1 shows, the peak timings of all three respiratory viruses varied, with RSV peaking around mid-November 2022, influenza peaking around late November and into December 2022, and COVID-19 peaking around early November 2022. The information gleaned from these dashboards supplemented and informed subjective reports provided in co-ordination groups, and helped response leadership better understand the points of strain, and anticipate where energy and resources should be focused on clinical operations.

Decreasing Demand on Acute Care Resources

As case counts regionally increased, so too did media attention on the tripledemic, as well as public fear. Patients began to pour into the pediatric emergency departments and outpatient pediatric clinics. While the overwhelming majority of these patients had mild illness, the sheer volume of them threatened to overwhelm resources, and limit their availability for those most in need. As a result, NYC Health + Hospitals instituted several strategies aimed at reducing overall demand for acute care resources.

To address and assuage the mounting public uncertainty and fear motivating acute care demand, NYC Health + Hospitals instituted a communications strategy designed to engage all NYC Health + Hospitals patients. Communication provided lay guidance on the signs and symptoms of these respiratory viral infections, what to expect, and when and where to seek care. Communications referred patients to the system’s 24/7 virtual urgent care service, Virtual ExpressCare (VEC), where clinical evaluation could be delivered without burden on acute care registration, nursing, or clinical staff or resources, and often in a far shorter timeframe. VEC clinical teams, comfortable in the provision of COVID19-related care for adults, were simultaneously

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Figure 1: Trends in case counts of three respiratory viruses, September 2022–January 2023, NYC Health + Hospitals, New York, USA.

equipped with educational materials regarding the prevalent pediatric respiratory illnesses, including the three present in the tripledemic, and a series of pediatric protocols were developed with pediatricians and physician associates with pediatric experience. The same VEC service was also offered on after-visit summaries for patients seeking care in acute care settings, as a means of short-term follow-up re-evaluation, should clinical status change or concerns develop after discharge, to avoid recurrent acute care use. In these ways, the public was equipped with an easily accessible and rapid alternative to acute care evaluation, which leveraged system subject matter expertise in a scalable fashion, to ensure comparable quality as in-person evaluation.

and opening ICU bed capacity. A systemwide risk stratification tool and set of admission criteria were developed, to standardize admission decision-making for patients with RSV or viral syndromes. When patients did not meet such criteria, to help empower parents and caretakers to feel comfortable caring for infected children at home, discharge instructions were augmented to provide specific discrete instructions for patient and caretaker education. Collectively, these tactics helped ensure that all patients were able to receive the level of care needed, while optimizing and coordinating use of acute care resources for patients most in need.

Increasing and Safeguarding Supply of Critical Resources

Although most children with respiratory illness were stable enough to remain at home with supportive care, some required admission.

Several children with respiratory viral illness during this time required non-invasive positive pressure ventilation. As such, as the volume of patients rose, so too did intensive care unit (ICU) admissions, placing strain on system- and citywide pediatric critical care resources. In response, the PAT created several clinical guidance to help optimize ICU resources. Protocols were developed to support weaning of non-invasive positive pressure ventilation on pediatric floors, helping expedite clinical transfers from ICUs to floor units, Creative Commons Attribution-Non Commercial 4.0

Notwithstanding efforts to reduce demand on acute care resources, the system also implemented several strategies to increase the supply or capacity of critical response resources.

Some resources were in short supply regionally or nationally, including amoxicillin to treat pneumonia co-infection, albuterol for patients with co-existing reactive airway disease, ventilators and highflow nasal cannula units, and cribs for admitted infants. In some cases, resource shortages were significantly ameliorated through development and implementation of protocols (developed by the PAT) to promote use of clinical alternatives.

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Feature For example, a reference guide helped clinicians systemwide adopt alternative antibiotics in lieu of amoxicillin, helping preserve resource availability, and maintain clinical quality when amoxicillin was in short supply nationally. Elsewhere, NYC Health + Hospitals leveraged stockpiles of resources to bridge supply chain gaps. With surges in inpatients, flex units were rapidly opened to accommodate additional volume, though experienced challenges fully operationalizing, given concurrent challenges in staffing them adequately. Regional surges in demand for pediatrics, and PICU-trained nursing staff, limited the availability of temporary staff traditionally used in such surge settings, and required innovative, but ultimately logisticallycomplicated methods, to identify existing nurses working in other clinical areas across the system (including adult service lines), whose relevant prior pediatrics or PICU experience and credentials enabled their reassignment to support pediatric services. Finally, in order to balance demand across a system with specialized resources concentrated in some facilities more than others, NYC Health + Hospitals transferred a small number of patients within its system from facilities with less to those with relatively greater resource capacity.

LESSONS LEARNED FROM THE TRIPLEDEMIC RESPONSE Value of Pre-Developed Plans

While the tactics employed above were effective in helping minimize demand, and maximize resources to support all clinical care needs, many of these operations were developed in a just-intime fashion. Specific co-ordination structures, plans, protocols, and clinical operations had to be developed in real-time, often limiting their implementation for days at minimum. Although the system had robust and prolonged recent experience with COVID-19 response, especially in an adult population, the tripledemic’s impact on the largely pediatric population underscored the importance of hazard non-specific clinical and operational emergency preparedness planning, as well as exercising among diverse types of clinical, operational, and administrative staff.

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Value of Telehealth

The system’s response demonstrated, as it had during COVID-19, the invaluable use of operationally-centralized, on-demand, urgent care in responding to large surges in demand, and newly highlighted the feasibility of such virtual remote clinical services in addressing pediatric respiratory illness, including through use of just-intime staff training and clinical protocols. Telehealth services provided a low-cost and highly accessible way for patients to access care in lieu of acute care and, in many cases, helped parents or caretakers comfortably care for their children at home, even as public and media attention toward the tripledemic threated to create alarm. The utilization of, and comfort shown toward, telehealth services during this surge showed that it can be a routine option for pediatric evaluation in the community, especially underserved ones.

Health Equity Considerations

As is true with most disasters, the burden of the tripledemic likely fell heaviest on historically underserved and marginalized communities. At the national level, prior research has shown that pediatric patients of color, and those from lowincome or limited English proficiency families are more likely to experience worse hospital outcomes compared to other children.5 The same socioeconomic factors increase likelihood for hospitalization due to RSV. Children in these demographic groups are at increased risk for severe illness and complications from RSV and influenza, and may face additional barriers to accessing testing, treatment, and vaccination.

Moreover, systemic racism impacts the quality of care that people of color receive, as well as reducing their likelihood to seek care for fear of mistreatment.6 Based on available data, RSVrelated hospitalization rates for Hispanic patients of all ages were consistently higher than nonHispanic patients throughout the respiratory illness surge.7 In responding to the tripledemic, NYC Health + Hospitals, as the largest provider of healthcare services to lower-income communities in New York City, took into consideration the health equity implications of the triple surge event.

Communications were developed across multiple languages, telehealth services adapted to limited

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Feature Internet capabilities, and resource capacity optimized to maintain care delivery capabilities, regardless of patients’ ability to pay.

in mitigating impacts of the unanticipated threevirus surge, considerable co-ordination resources were used to develop, execute, and sustain system response. With such respiratory surges of RSV, influenza, and COVID-19 expected to continue and overlap in the future, exacerbating existing societal health care inequities, greater attention is needed to strengthen the robustness of health care infrastructure, resources, and preparedness measures in a manner that addresses all three threats effectively, with a focus on strengthening systems caring for historically marginalized populations.

CONCLUSION The 2022–2023 tripledemic presented a challenge to health systems in New York City, including NYC Health + Hospitals. Response priorities focused on strengthening co-ordination across clinical and operational disciplines, across facilities, and at varying levels; reducing demand for services; and sustaining critical resources. While successful

References 1.

2.

American Academy of Pediatrics (AAP). Interim guidance for use of palivizumab prophylaxis to prevent hospitalization. 2023.

Available at: https://www.aap. org/en/pages/2019-novelcoronavirus-covid-19-infections/ clinical-guidance/interim-guidancefor-use-of-palivizumab-prophylaxisto-prevent-hospitalization/. Last accessed: 17 July 2023.

Centers for Disease Control and Prevention (CDC). Weekly US map: influenza summary update. 2023.

Available at: https://www.cdc.

gov/flu/weekly/usmap.htm. Last accessed: 17 July 2023.

3.

4.

Centers for Disease Control and Prevention (CDC). Key facts about seasonal flu vaccine. 2022. Available at: https://www.cdc.gov/flu/about/ season/index.html. Last accessed: 17 July 2023.

Centers for Disease Control and Prevention (CDC). COVID-19 by County. 2023. Available at: https:// www.cdc.gov/coronavirus/2019ncov/your-health/covid-by-county. html. Last accessed: 6 November 2023.

5.

Lion KC et al. Identifying modifiable health care barriers to improve health equity for hospitalized children. Hosp Pediatr. 2020;10(1):111.

6.

Powell W et al. Medical mistrust, racism, and delays in preventive health screening among AfricanAmerican men. Behav Med. 2019;45(2):102-17.

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Centers for Disease Control and Prevention (CDC). RSV-Net interactive dashboard. 2023.

Available at: https://www.cdc.gov/ rsv/research/rsv-net/dashboard. html. Last accessed: 17 July 2023.

FOR REPRINT QUERIES PLEASE CONTACT: INFO@EMJREVIEWS.COM

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Article

Vaccine Candidates for Arboviruses with Pandemic Potential: A Mini Review Authors:

*Hafeez A. Adekola,1 Ismail B. Onajobi,1 Haneefat O. Egberongbe,1 Oyindamola J. Samson,1 Wahab A. Kareem,1 Gbenga O. Osipitan,1 Rukayat A. Adekola1 1. Department of Microbiology, Olabisi Onabanjo University, Ago-Iwoye, Nigeria *Correspondence to haderinsayor@gmail.com

Disclosure:

The authors have declared no conflicts of interest.

Received:

07.25.22

Accepted:

06.08.23

Keywords:

Arboviral diseases, arbovirus, vaccines.

Citation:

Microbiol Infect Dis AMJ. 2023; DOI/10.33590/microbiolinfectdisamj/10305126. https://doi.org/10.33590/microbiolinfectdisamj/10305126.

Abstract The increasing prevalence of arboviral diseases, driven by urbanization and travel, coupled with the absence of specific treatments or vaccinations, has led to a growing burden on global health. Despite the implementation of vector control programs, outbreaks continue to occur. While vaccines are considered the ultimate solution, progress in the development of vaccines for dengue virus, Zika virus, Chikungunya virus, and West Nile virus has been limited, due to factors such as limited access to target populations, lack of funding, and concerns about safety and efficacy across all age groups. Furthermore, the growing trend of vaccine hesitancy presents a significant barrier to future vaccine adoption. This review provides a subtle overview of current progress in the development of vaccine candidates for these prevalent arboviral diseases.

Key Points 1. Arboviruses have shown pandemic potential due to their ability to rapidly spread across different regions and cause significant morbidity and mortality. With increasing globalization and climate change, the risk of arboviral outbreaks and pandemics is a growing concern for global health security.

2. This manuscript focuses on the latest progress in the development of vaccines against arboviruses, shedding light on preclinical and clinical investigations aimed at evaluating the safety, immunogenicity, and efficacy of these vaccine candidates. Additionally, the manuscript delves into the challenges of vaccine production and potential impact on vaccine hesitancy for arboviral prevention.

3. The progress in vaccine technology has accelerated the development of novel arbovirus vaccines.

Some vaccine candidates have shown promising results, but further research is necessary to guarantee their safety and efficacy. Collaborative efforts involving researchers, policymakers, and public health agencies play a crucial role in accelerating vaccine development, obtaining regulatory approval, and facilitating global vaccine distribution.

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INTRODUCTION

Dengue Virus

DENV, a Flaviviridae family member, has four serotypes, and is responsible for the majority of arboviral infections each year.1 DENV infection has spread over the Americas, Africa, Europe, Southeast Asia, the Eastern Mediterranean, and the West Pacific. Annually, approximately 390 million cases are reported, with a quarter of these instances presenting with a mild, severe, or deadly disease.

According to research, over 4 billion people in 129 countries are at risk of DENV infection.8,9

The importance of vaccines in the fight against infectious diseases cannot be emphasized enough.

Vaccine technological improvements in recent decades have led to the production of a variety of effective vaccines against infectious diseases.1 Unfortunately, vaccinations for many diseases, such as arboviral infections, are still unavailable.1 Arboviruses account for roughly 17% of the worldwide burden of infectious disease, with a mortality rate of 700,000 deaths per year.2 These infectious diseases, caused by viruses such as dengue virus (DENV), Zika virus (ZIKV), West Nile virus (WNV), and Chikungunya virus (CHIKV), have no specific treatment, and only a few vaccines are available to prevent them.1,3

DENV infections can result in mild illness or an asymptomatic clinical course. A large proportion of people infected with DENV experience a vague, generally benign, and self-limited course, with up to half of them remaining asymptomatic.10 DENV is rarely detected in individuals without diagnostic testing. Individuals under the age of 15 years, or those who have DENV for the first time, are more likely to show mild symptoms. These individuals fully recover without requiring hospital care. After 2–7 days of a high fever of up to 40 °C (104 °F), and at least two other symptoms, adults and children over the age of 15 are frequently diagnosed with classic dengue fever.10

Arboviruses are spread by arthropod vectors (mosquitoes and ticks), and have recently risen from obscurity to a public health emergency of international concern.4 Recent arbovirus epidemics have been closely connected to urbanization, international travel, and climate change.5 Because therapeutic alternatives have not been supportive or specific, the attention has mostly been on techniques that aid in the removal of arbovirus vectors, such as insecticide-based strategies, which reduce disease burden. To cope with arboviruses and lessen the overall burden of arboviral diseases, technologies concentrating on diagnostic tools, serological testing, antivirals, and vaccines are now being developed. This review intends to investigate promising vaccine options for selected arboviral diseases, while also addressing vaccine production obstacles.

Severe headache, diffuse maculopapular erythematous rash, retro-orbital eye pain, myalgia, arthralgia, and mild hemorrhagic signs are common symptoms. A high fever caused by dengue can be especially dangerous because of the individual's increased risk of seizures and other neurological impairments. Subconjunctival mucosa, buccal mucosa, soft and hard palate, and easy bruising of the lower limbs are common hemorrhagic symptoms.11 Epistaxis, gingival bleeding, gastrointestinal bleeding, and urogenital bleeding are possible complications of dengue fever.

Laboratory tests frequently reveal leukopenia with lymphocyte predominance and thrombocytopenia to varying degrees. These individuals may also suffer from severe nausea and vomiting, which can lead to dehydration.11,12

ARBOVIRAL DISEASES AS A GLOBAL HEALTH PROBLEM Arboviruses of global significance are endemic in certain areas, particularly in the tropics, and the majority of infections caused by these viruses demonstrate asymptomatic or non-pathognomonic symptoms, such as fever, malaise, and headache.6 Some of the most noteworthy arboviruses of worldwide significance in the tropical region include ZIKV, DENV, CHIKV, and WNV.7

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Zika Virus

Before its initial epidemic in 2007 on Yap Island in the Federated States of Micronesia, ZIKV, another member of the Flaviviridae family, had only produced occasional cases in Africa and Asia.1 By 2013, the virus had spread to French Polynesia and other Pacific countries and territories, causing a

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Article large-scale pandemic in Brazil 2 years later.13,14 Over the years, at least 86 countries and territories in the Americas, Africa, Asia, Oceania, and Europe have reported over 3,500 cases of ZIKV infection.15,16 Infection with ZIKV has been associated with congenital malformations and immunological diseases.17 ZIKV is frequently self-limiting, with an estimated incubation time of only a few days after being bitten by an infected mosquito.18 The majority of the initial cases were documented in people between the ages of 20–40 years, but there were a few outliers in people as young as 4 months, and as old as 98 years.19 The primary symptom of this condition is maculopapular erythematous exanthema, which begins on the face or trunk and spreads to the limbs, palms, and soles. The rash caused by CHKV infection was very similar to this one. Lowgrade fever, exudative conjunctivitis, myalgia, arthralgia, headaches, and other symptoms like those of DENV and CHKV infections may occur. Individuals who test positive for ZIKV have also been linked to a variety of neurological disorders, including Guillain–Barré syndrome and meningoencephalitis.20,21

Chikungunya Virus

CHIKV, an Alphavirus of the Togaviridae family, was first identified in Tanzania in 1952.22 CHIKV virus has spread to at least 60 nations and territories throughout the world since 2004.

Although the majority of patients recover well, outbreaks of this disease can be spontaneous.23 Symptoms of the disease can last for months, become chronic, and even result in death.

One of the most recent outbreaks occurred in the Republic of Chad, where the World Health Organization (WHO) received reports of around 27,540 cases from July–September 2020.24 Incubation time for CHKV infection ranges from 1–12 days, with an average of 2–4 days.25 The term ‘chikungunya’ was first used to describe the illness, which is derived from the acute onset of bilateral migrating arthralgia, which commonly affects the tiny joints of the fingers, wrists, toes, and knees, and ranges in severity from mild irritation to complete incapacitation. Arthralgia and arthritis usually affect multiple joints in a 42

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symmetrical pattern.26 The clinical course is usually mild and self-limiting, lasting 7–10 days; however, the arthralgia that follows can last for years. In addition to arthralgia and arthritis, infection can cause fever, myalgia, headaches, and, on rare occasions, a maculopapular, pruritic rash.26 Furthermore, CHKV can cause arthritis and has a quicker onset than DENV. This aids in differentiating the disease from DENV and ZIKV, particularly when it affects hands and feet.27 DENV and ZIKV have slower onset times, and cause more severe arthralgia. Given that children typically have a more self-limiting infection, these more severe symptoms are more commonly seen in older adults.27 Death from CHKV infection is uncommon, but likely, and it most commonly affects older adults due to cardiopulmonary failure or neuroinvasive illness.

West Nile Virus

WNV is another Flaviviridae family member that infects birds, mosquitoes, horses, humans, and other mammals.28 Incidences have been documented on all seven continents. Over 30,000 instances of human infections were documented in the first 5 years of the pandemic in North America.29 Although most of those infected are asymptomatic, the virus infection can proceed to cause neurological problems, which can result in death.30 Most individuals who are infected develop a mild illness, and less than 1% develop neurological symptoms, such as encephalitis, meningitis, meningoencephalitis, acute flaccid paralysis, ataxia, extrapyramidal signs, polyradiculitis, seizures, and eye nephritis.31 WNV is the most common cause of pandemic neuroinvasive illness in humans, and accounts for 1.4% of all central nervous system infections.32 WNV has spread throughout North America as a seasonal endemic infection since its discovery in 1999 in New York, USA. Between 1999–2017, the Centers for Disease Control and Prevention (CDC) reported 48,183 cases of WNV infection, including 22,999 cases of neuroinvasive illness.33,34 The mortality rate of individuals with neuroinvasive illnesses ranges from 8–12%.35

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VACCINE DEVELOPMENT FOR ARBOVIRUS DISEASES

developments in vaccines against dengue, and the only licensed DENV vaccine.41,44,45 The vaccine efficacy studies varied by age, serostatus, and serotype.46,47 Phase I and II trials to evaluate safety, immunogenicity, and reactogenicity were conducted in several countries in healthy adults ranging in age from 18–45 years. More than 30,000 people participated in Phase III trials, including children aged 2–16 years.48 Although it was deemed safe and well tolerated in a three-dose regimen, with no vaccine adverse effects, the absence of dengue virus non-structural proteins in the vaccine mix, however, predisposes seronegative persons to a higher risk of severe dengue infection.46

Arboviruses are medically important viruses that cause widespread infection around the world, especially in areas where their vectors are endemic, such as the tropics, subtropics, and Gulf Coast region.36,37 Several arbovirus vaccines are now being researched and tested in clinical trials, but only a few are commercially available.38,39 For example, a DENV vaccine in Phase III trials has shown varied vaccination efficacy against different serotypes, age, and previous exposure, and has been recommended for humans in epidemic areas.38 Arboviral infections have reportedly spread widely due to the current trend of rapid urbanization and increased worldwide commerce travels. As a result, there is an increasing demand for safe and effective arboviral vaccines. However, choosing the right vaccine vector is critical for successful vaccine development.38,40 Because there are currently no particular antiviral treatments for arboviruses, as well as limitations in vector control, vaccine development remains the most efficient means of protection.39

In recent years, studies have shown an increased frequency of hospitalization and severe dengue in vaccinated seronegative persons. This is because the vaccination resembles the underlying infection, and reinfection manifests as severe dengue.46,49 Additional vaccine risk studies demonstrated that the vaccine follows a distinct path that results in immunity in individuals who are seropositive at the time of inoculation.42 As recommended by the WHO, vaccination should involve a preimmunization screening technique, in which only patients who are dengue seropositive are chosen for vaccination.46

Dengue Virus Vaccines

DENV vaccines are now being developed worldwide, with live virus-vectored vaccines, live attenuated vaccines, nucleic acid vaccines, recombinant protein vaccines, and pure formalin-inactivated vaccines among the current development platforms.41 Complex disease etiology, resulting in varying levels of disease severity, lack of established correlates of protection, continually changing virus landscape, and lack of dependable animal model are all challenges impacting development platforms.42

However, Dengvaxia was also reportedly approved by the U.S. Food and Drug Administration (FDA) for use in children aged 9–16 years who live in dengue endemic areas, and have a prior laboratory-confirmed infection.50 In the midst of Dengvaxia complications caused by the potential for severe disease in dengue naïve individuals, good vaccination risk management could aid in the prevention of antibody-dependent enhancement induced severe vascular leakage.51 Dengvaxia administration could also help prevent transmission during epidemics, lowering the likelihood of severe disease.51

Primary infection usually confers sole immunity against the infecting serotype, but infection by other serotypes is still a possibility, and it can be fatal.43 As a result, DENV vaccine development is solely focused on providing simultaneous protection against all serotypes of the virus.43 Even though several different DENV vaccines are in various phases of clinical development, Dengvaxia (Sanofi Pasteur, Lyon, France), a chimeric virus with the backbone of the yellow fever vaccine, strain YF-17D, is one of the most advanced Creative Commons Attribution-Non Commercial 4.0

TAK-003 (Takeda Pharmaceuticals, Osaka, Japan) is one of the few vaccines that has recently completed Phase III trials.47 A live attenuated DENV-2 strain and three chimeric viruses with membrane and envelope protein genes from DENV-1, DENV-3, and DENV-4 strains expressed on the backbone of the DENV-2 genome make up the vaccine.47 Immunogenicity was found to be

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Article lower in seronegative people who got one primary dosage compared with those who received multiple doses in Phase II trials.46 The TAK-003 vaccine proved less serostatus dependent than Dengvaxia after two doses in Phase III studies, with more promising vaccination efficacy. However, the vaccine's potential utility and safety are still being debated due to complex nuances for DENV-3 and DENV-4 strains.46 Another DENV vaccine that has completed Phase III trials is the National Institute of Health's (NIH; Bethesda, Maryland, USA) live attenuated tetravalent DENV vaccine TV003/TV005.52 The vaccine consists of DENV-1, DENV-3, and DENV-4 that have been genetically attenuated, as well as a chimeric fourth component made up of structural genes from DENV-2 inserted into DENV-4.47 The vaccine's immunogenicity is identical to that seen in populations with natural immunity, and a single dosage was found to be 100% effective in a human challenge study.46 However, despite the vaccine's more optimistic concept than Dengvaxia and TAK003, data on the full analysis of Phase III trials are yet to be published (Table 1).

Evidently, since a tetravalent immune response is required for immunity from all serotypes, individuals who are dengue naïve remain

susceptible to infection due to antibody dependent enhancement; thus, the immunological interaction between four serotypes remains the most significant barrier to dengue vaccination.54 In the search for solutions to DENV vaccine challenges, two promising strategies have been proposed: sequential immunization and heterologous prime-boost strategy.46 According to reports, sequential immunization is significantly more immunogenic, and induces higher levels of neutralizing antibodies to all serotypes of DENV than tetravalent vaccine.55 Animal data from a study involving Singapore mice showed that sequential immunization demonstrates a diverse immunological profile, and could be offered as an alternative solution for the viral interference challenge of DENV vaccine.55 Nonetheless, a heterologous prime-boost strategy involving vaccine combination could provide another option.46 Dengvaxia significantly induces higher levels of protection against DENV serotypes 3 and 4 compared with serotypes 1 and 2, whereas TAK003 significantly induces higher levels of protection against DENV serotypes 1 and 2.56 The varying serostatus dependence of both vaccines could also be factored. Since Dengvaxia's dominant serotypes

Table 1: Dengue vaccine candidates.

Vaccine/ commercial name

Developer

Platform

Immunogenicity

Clinical trial phase

Dengvaxia

Sanofi Pasteur (Lyon, France)41,44,45

Yellow fever vaccine virus backbone vector that expresses envelope proteins of DENVs Types 1–4

Very High

Complete

TAK-003

Takeda Pharmaceuticals (Osaka, Japan)47,53

Live attenuated dengue serotype 2 virus, with genetic ‘backbone’ for DENVs Types 1–4

High

III

TV003/TV005

NIH (Bethesda, Maryland, USA)52

Tetravalent live attenuated vaccine

High

II

DENV: dengue virus; NIH: National Institute of Health.

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Article are the weakest for TAK-003 and vice versa, a prime-boost strategy involving administration of TAK-003, which is dominant against serotypes 1 and 2, followed by Dengvaxia, which is dominant against serotypes 3 and 4, is theoretically possible to counter viral interference, and offer broader immune responses against all serotypes.54

two doses of the vaccine were given, there were significant levels of serum neutralizing antibodies, a strong innate response, and undetectable viremia, albeit no human phase trials to replicate these results have been conducted yet.63 The CRM-EDIII-PM vaccine, developed by He et al.,57 is another intriguing contender. The vaccine could generate a substantial humoral and cellular immune response without causing major organ damage, although no human phase trials have been conducted so far.57

Zika Virus Vaccines

A significant number of ZIKV vaccine candidates are being developed, and are currently being tested in clinical trials. This includes a messenger RNA vaccine, as well as a DNA vaccine that encodes the ZIKV precursor membrane (prM) and E genes, and is currently being tested in Phase IIb trials in the USA, Brazil, Puerto Rico, Mexico, Panama, Peru, and Columbia. There have been several efforts to develop ZIKV vaccines that are both safe and effective.57

Currently, nine ZIKV vaccines are identifiably in clinical trial phases. There are three for purified inactivated viruses: ZPIV, developed by the Walter Reed Army Institute of Research (WRAIR; Silver Spring, Maryland, USA); PIZV, developed

by Takeda Pharmaceuticals; and VLA-1601, developed by Valneva (Saint-Herblain, France).

There are also three DNA vaccines: GLS-5700, developed by GeneOne/Inovio (Seoul, South Korea, and Plymouth Meeting, Pennsylvania, USA, respectively); and ZKADNA085-00-VP (1 and 2), developed by the Vaccine Research Center (VRC; Bethesda, Maryland, USA). There are two messenger RNA vaccines: mRNA-1325, developed

by Moderna (Cambridge, Massachusetts, USA), and measles vectored MV-Zika, developed by Themis (Mumbai, India).58 Except for ZKADNA08500-VP-2, which has progressed to Phase II, all of these vaccines are in Phase I. According to reports, all DNA vaccines have been approved for human testing.58

Purified inactivated viruses, live attenuated viruses, virus-like particles, recombinant viral vectors, DNA, messenger RNA, and viral proteins have all been the focus of these efforts.57,58 Some vaccines based on DNA and messenger RNA technologies that express prM/E protein, or purified inactivated viruses are currently undergoing clinical trials as ZIKV immunogens.59 DNA vaccines may be quickly developed using genetic engineering, and several targets on the viral structure that can be used as epitopes for eliciting immune responses.59 However, because of its history with clinical trials and effectiveness with yellow fever virus vaccines, the pure inactivated vaccine platform is regarded as the most effective.60 A lot of the vaccines were assessed using animal models utilizing non-human primates or immunosuppressed mice.58 A purified inactivated vaccine adjuvanted with alum was shown to be immunogenic after two doses by the intramuscular route in Phase I clinical trial, and a chimeric measles virus vaccine expresses the prM and E genes of ZIKV.61

There are still a few obstacles to overcome before a safe and effective ZIKV vaccine can be licensed. Although most of these vaccination studies are still in the early phases, ZIKV transmission has decreased to the point where a Phase III efficacy study will be challenging to conduct (Table 2). A typical vaccine efficacy study would necessitate a large number of participants to account for confirmed cases in both symptomatic and asymptomatic individuals, as well as control groups.71 Although, the efficacy endpoints for a ZIKV vaccine in clinical trials are not well defined; one would wonder if a vaccine would have to prevent infection to prevent microcephaly, which is a very high bar for any vaccine.72 Nonetheless, the clear purpose of vaccines should be the prevention of congenital disease caused by the virus. As with previous

Stephenson et al.62 demonstrated that ZIKV purified inactivated vaccines are safe and well tolerated by humans, but further clarity on the dosage required for adequate immunogenicity is still needed. When tested on mice, the GMZ-002 purified inactivated virus vaccine developed by Oh et al.63 also showed significant promise. When Creative Commons Attribution-Non Commercial 4.0

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Table 2: Zika virus vaccine candidates.

Vaccine/ commercial name

Developer

Platform

Immunogenicity

Clinical trial phase

GMZ-002

Oh et al.63

Purified inactivated virus

Very high

None

CRM-EDIII-PM

He et al.57

Recombinant E protein

Moderate

None

ZPIV

WRAIR (Silver Spring, Maryland, USA)62

Purified inactivated virus

Moderate

I

PIZV

Takeda Pharmaceuticals (Osaka, Japan)64

Purified inactivated virus

Unknown

I

VLA-1601

Valneva (SaintHerblain, France)65,66

Purified inactivated virus

Unknown

I

GLS-5700

GeneOne/Inovio (Seoul, South Korea, and Plymouth Meeting, Pennsylvania, USA, respectively)67

Synthetic DNA plasmid vaccine

Unknown

I

ZKADNA085-00-VP VRC (Bethesda, (1 and 2) Maryland, USA)68

DNA-based vaccine

Unknown

II

mRNA-1325

Moderna (Cambridge, Massachusetts, USA)69

mRNA based vaccine

Unknown

I

Measles vectored MV-Zika

Themis (Mumbai, India)70

Recombinant Schwarz strain MV that encodes ZIKV prM and soluble E proteins

Unknown

I

mRNA: messenger RNA; MV: measles-vectored; prM: precursor membrane; VRC: Vaccine Research Center; WRAIR: Walter Reed Army Institute of Research; ZIKV: Zika virus.

outbreaks, efforts to develop vaccines diminish as the epidemic recedes.71 Another impediment is the possibility of vaccinemediated antibody dependent enhancement.

Immunity to the ZIKV via vaccines may increase the risk of severe dengue due to cross-reactive antibodies from both viral diseases. It is critical that vaccine candidates elicit cross-reactive antibodies that are strong enough to provide protection, while avoiding vaccine-mediated antibody-dependent enhancement effects.71 Other challenges for ZIKV vaccine development include the lack of wellcharacterized animal models relevant to human 46

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disease, an incomplete understanding of immune responses required to prevent fetal infection, and the risk that immune responses from vaccines will induce Guillain–Barré and ZIKV-related pregnancy complications.73

Chikungunya Virus Vaccines

Diverse CHIKV vaccine candidates are being developed using various technologies, but the search for the best balance of safety and immunogenicity is still ongoing.74 There are currently no licensed CHIKV vaccinations; however, it is anticipated that one vaccine will

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Article protect against all CHIKV strains.75 When the formalin-inactivated vaccine was stopped due to production costs and safety concerns in the twentieth century, the USA military produced a live attenuated vaccine. Despite the latter's encouraging results, further research was halted due to the USA military's low priority.75

Given that the CHIKV appears to be linked to big epidemics every 10–30 years, a return on investment is not guaranteed, and so the pharmaceutical sector has little incentive to produce the vaccines.61 These difficulties are exacerbated by policymakers' difficulty in selecting how to roll out CHIKV vaccination during and between epidemics, as well as the difficulty of finding a good location for clinical efficacy studies during interepidemic periods. The unpredictable nature of viral epidemics further complicates the collection of human efficacy data.79 Randomized controlled trials, the gold standard, are not feasible during interepidemic periods due to the low expected cases. Similarly, the development of herd immunity, as well as the focal and episodic nature of CHIKV epidemics, have made Phase III clinical trials focusing on vaccine efficacy and safety logistically difficult.86

Research on CHIKV vaccines has been slow in recent years; however, a few replication-defective and attenuated vaccine candidates have shown promise in Phase I/II trials, and others have demonstrated safe and immunogenic in mouse and non-human primate models. Rossi et al.76 evaluated the immunogenicity and efficacy of a measles virus-vectored CHIKV vaccination in macaques, finding that all macaques tolerated the vaccine well with promising seroconversion rates. The study's findings back up earlier Phase I and II clinical trial results.76 Reisinger et al.77 and Ramsauer et al.78 conducted a similar study with human participants, with the results confirming the vaccine's outstanding safety and tolerability, as well as good immunogenicity.

Antibody-dependent enhancement is another concern for CHIKV vaccine candidates. The risk of antibody-dependent enhancement potentially exacerbating viral symptoms cannot be completely dismissed, especially given the possibility of the emergence of new quasi-species harboring mutations or co-infection/re-infection with genetically related viruses, such as DENV, Ross River virus, or ZIKV, which can lead to more severe disease complications.87 Due to low levels of maternal-acquired anti-CHIKV antibody, escape mutants could infect infants due to the infection of pregnant females. Immune senescence in elderly patients may also have an impact on vaccine efficacy, and should be taken into account during vaccine development.83

Virus-like particles vaccines are also being developed, and are in clinical trials. These vaccines elicit neutralising antibodies against envelope proteins from various CHIKV strains and immunized non-human primates produced high titer neutralizing antibodies that protected immunodeficient mice from lethal infection.79 Nucleic acid-based vaccines are also showing promise in terms of production, safety, and the ability to produce humoral and cellmediated immunity. Despite this, the majority of vaccines created have demonstrated minimal immunogenicity.79 Currently, eight CHIKV vaccines are in late pre-clinical or clinical development: TSI-GSD-218 (181/clone25), developed by the United States Armed Forces; VRC-CHKVLP05900-VP (PXVX0317 CHIKV-VLP), developed by the NIH; MV-CHIK, developed by the Pasteur Institute (Paris, France); VLA1553, developed by Valneva; VAL-181388, developed by Moderna; pMCE321, developed by the University of Pennsylvania (Philadelphia, USA); CHIKV/IRES, developed

by Takeda Pharmaceuticals; and EILV/CHIKV, developed by the University of Texas Medical Branch (Galveston, USA; Table 3).79

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West Nile Virus Vaccines

Several WNV vaccines have been proven to have high efficacy in animals, yet only a few of these vaccine candidates have been studied in humans.

Unfortunately, the majority of them have only got to Phase I trial, and no human WNV vaccines have been authorized as of yet.88,89 Vaccine candidates for WNV include nucleic acids, virus-like particles, subunit elements, and recombinant viruses, as well as platforms based on pure inactivated and live attenuated viruses.89 A vaccine candidate using plasmid DNA expressing WNV prM/E was studied in the Phase

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Table 3: Chikungunya virus vaccine candidates.

Vaccine/ commercial name

Developer

TSI-GSD-218 (181/ clone25)

Platform

Immunogenicity

Clinical trial phase

United States Armed Live attenuated Forces80 vaccine

High

II

VRC-CHKVLP05900-VP (PXVX0317 CHIKV-VLP)

NIH (Bethesda, Maryland, USA)81

CHIKV-like particle composed of E1, E2, and capsid proteins of the CHIKV (strain 37997)

Moderate

II

MV-CHIK

Pasteur Institute (Paris, France)76

Live attenuated, measles-vectored CHIKV vaccine

Moderate

II

VAL-181388

Moderna (Cambridge, Massachusetts, USA)82

mRNA-based vaccine

Moderate

I

pMCE321

University of A single consensus Pennsylvania envelope DNA (Philadelphia, USA)83 vaccine construct expressing all three envelope proteins

Moderate

None

CHIKV/IRES

Takeda Pharmaceuticals (Osaka, Japan)79,84

Live attenuated vaccine

High

II

EILV/CHIKV

University of Texas Medical Branch (Galveston, USA)79,85

EILV-based chimeric vaccine

Moderate

None

CHIKV; Chikungunya virus; EILV: Eilat virus; mRNA: messenger RNA; NIH: National Institute of Health.

I trial. The initial candidate, VRC-302 (Vical, San Diego, California, USA), and the later VRC-303 (Vical) utilize Cytomegalovirus promoter and a Cytomegalovirus promoter with an additional R region, respectively, to enhance gene expression.90 Although these vaccines, notably the VRC-303, produced a significant immune response and have high efficacy, the progress of these vaccines' clinical trials has not been disclosed.90 The recombinant E protein vaccine (WNV-80E [Hawaii Biotech, Honolulu, USA]), which was also tested in Phase I clinical trials, showed promising results, but there are no reports on long-term antibody titers or vaccine efficacy in those over 45. HydroVax-001 (Oregon National Primate Research Center [ONPRC], Hillsboro, USA), the most promising WNV candidate evaluated in 48

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Phase I clinical trials, was recently revealed to have significant immunogenicity: however, the vaccine's antigenic integrity would likely need to be improved.90 The formalin-inactivated WNV vaccine, and the most thoroughly investigated ChimeriVax-WN02 (Sanofi Pasteur) vaccine were the only candidates studied in Phase II clinical trials. The former lacks plausible immunogenicity evidence, but the latter has been claimed to be safe and efficacious, with better seroconversion rates. Even though none of the vaccine candidates revealed any safety problems or side effects that could jeopardise future clinical trials, the ChimeriVax-WN02 is thought to be the closest to licensure of all the vaccine candidates evaluated (Table 4).90,91

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Table 4: West Nile vaccine candidates.

Vaccine/ commercial name

Developer

Platform

Immunogenicity

Clinical trial phase

VRC-303

Vical (San Diego, California, USA)88,90

Plasmid DNA vaccine expressing PrM/E

High

I

WNV-80E

Hawaii Biotech (Honolulu, USA)90

Soluble E lacking the trans membrane domain

High

I

HydroVax-001

ONPRC (Hillsboro, USA)90,92

Hydrogen peroxide inactivated, whole virion (WNV–KUNV strain) vaccine adjuvanted with aluminum hydroxide

High

I

WN-VAX

Fort Dodge Animal Formalin-inactivated Health (Overland WNV vaccine Park, Kansas, USA)93

Low

II

ChimeriVax-WN02

Sanofi Pasteur (Lyon, France)90,91

Very high

II

Chimeric YF17D backbone expressing WNV PrM/E

KUNV: Kunjin virus; ONPRC: Oregon National Primate Research Center; prM: precursor membrane; WNV: West Nile virus; YF17D: yellow fever virus 17D.

Several issues, such as the relatively short WNV season (May/June–September/October), and the sporadic occurrence of outbreaks, particularly in areas where there is co-circulation with other cross-reactive flaviviruses, make clinical trials difficult.89,90 Other factors influencing vaccine development are safety concerns, significant immunogenicity after a single dose, and the ability to distinguish between infected and vaccinated individuals.89

severity would necessitate targeted vaccination approaches, which would undoubtedly impact production costs.91

CHALLENGES OF VACCINE PRODUCTION Despite the identification of several potential candidates, vaccine development against arboviruses has had mixed success. One of the major limitations is a lack of detailed understanding of the vaccine's inherent characteristics, which has a significant impact on the development of adaptive immunity against arboviral infection.94 For an optimal arbovirus vaccine, certain criteria must be met, including a single dose, long-lasting protection, a wide range of administration options, safety, and storage logistics.95 The significance of antigen selection for the production of subunit vaccines cannot be overstated; vaccine candidates' important functions during the viral replication process substantially influence their

The cost per vaccine dosage is also expensive due to low case numbers, making vaccine production unnecessary. Although targeted immunization boosts cost-effectiveness, the population would still be less than that of other vaccines.91 More targeted vaccination efforts would be encouraged as the endemic area, case numbers, and evidence of genetic variants associated with severe types of viral infection grow.91 Nonetheless, the emergence of new antigenic variants as a result of mutations could be detrimental to vaccine development efforts.89 WNV genetic variants associated with Creative Commons Attribution-Non Commercial 4.0

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Article immunogenicity and overall protective immunity.59 Three major elements drive the development of arboviral disease vaccines: necessity, availability, and cost. The number of documented acute or chronic cases can be used to determine the level of need, either worldwide or locally. Availability is determined by a suitable arrangement for commercial manufacture on a large enough scale to produce a sufficient and inexpensive supply that covers production costs and generates a profit.

The question of whether activities are more likely to be pursued by industry or subsumed within the global public health structure is inextricably linked to the cost of development and the return on investment.96 Since arboviruses primarily affect developing countries, developing and manufacturing vaccines for emerging diseases is generally much more difficult from a financial and business standpoint than developing and manufacturing vaccines for diseases that are currently prevalent in developed countries.58 As we lack effective preventive and therapeutic options for these arboviruses, it is expected that we develop a reactionary approach that would accelerate the production of effective vaccines.97 The disinclination towards vaccine development until there is an outbreak could have a devastating impact, and production of an epidemic rushed vaccine could even have a disastrous impact due to a lack of rigorous evaluation and quality control.97

POTENTIAL IMPACT ON VACCINE HESITANCY FOR ARBOVIRAL PREVENTION Nearly one-third of the 500 arboviruses discovered are linked to human diseases.98 Over the years, arbovirus vector control using insecticide-based methods had been the most common way of preventing arboviral diseases. Although, the alarming rates of insecticide resistance among mosquito populations stimulated new approaches through increasing understanding of insect biology and insect-pathogen interactions.99 Vector control strategies are now focusing on interference of arbovirus development in vectors and impacting insect survival, such as using enhancing vector immune system, manipulating vector microbiome, or editing vector genomes using clustered 50

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regularly interspaced short palindromic repeatsCas systems.99 Despite the success of the old strategies and the prospects of the recent developments, failure of the vector control methods is still prominent in several countries; therefore, vaccination remains the most effective means of prevention.100 While vaccines may be the greatest way to prevent arboviral infections, vaccine hesitancy is a major barrier to infectious diseases like arboviral diseases around the world.100-102 Vaccine hesitancy has been impacting vaccine perception and acceptability in recent years.101 This could be due to some factors, including social media misinformation, mistrust of government or policymakers, religious convictions, and negative parenting.103,104 In some parts of the world, the emergence of anti-vaccine movements capable of aggressively influencing state legislatures has also been reported.36 Interestingly, vaccine hesitancy is significant in low- and middleincome nations, where many vaccine-preventable diseases continue to kill people every year, particularly children, who account for 1.5 million deaths.103,105-109 These countries include those with a high burden of arboviral diseases in recent times, such as Brazil, Indonesia, Mexico, India, Bangladesh, and Pakistan, with cases of severe morbidities and mortalities.110,111. This implies that the introduction of arboviral disease vaccines will suffer the same fate, limiting the influence of vaccination on arboviral disease incidence in those communities.103,112 As with other vaccinepreventable diseases, including measles, poliomyelitis, rubella, and mumps, vaccine-hesitant communities that remain under-vaccinated or non-vaccinated are susceptible to outbreaks of arboviral diseases.113 Furthermore, compared with other communities with high vaccination rates, vaccine-hesitant communities would have higher morbidity and fatality rates due to the unchanged prevalence of arboviral infections.114

CONCLUSION Vaccine development would undoubtedly reduce the prevalence of arboviral infections and avoid epidemics in the future. Vaccines should, however, be highly efficacious, immunogenic, safe, and effective in all age groups, and offer long-term

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Article protection, as expected. Even though vaccine development has been successful thus far, the expanding geographic range of virus activity has undeniably increased the global burden of arboviral infections, as well as global case reports and the prevalence of severe cases. Even though vaccine development acceleration technologies are available, and have been proven to be safe and effective, there are still certain obstacles, such as funding and an unreachable target population.

Bringing together global public health institutions,

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97. Manning JE et al. Mosquito saliva: the hope for a universal arbovirus vaccine? J Infect Dis. 2018;218(1):715.

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95. Poland GA et al. Zika vaccine development: current status. Mayo Clin Proc. 2019;94(12):2572-86.

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Article

A Retrospective Study in Patients With Varying Prescription Coverage With Ursodeoxycholic Acid and Association With Incidence of COVID-19 Diagnosis in Primary Care Authors:

Simon Wan Yau Ming,1 Mike Smith,1 Yi Zhou2 1. CorEvitas, Waltham, Massachusetts, USA 2. Ionscope, Cambridge, UK *Correspondence to swanyauming@corevitas.com

Disclosure:

The authors have declared no conflicts of interest.

Received:

08.23.23

Accepted:

10.02.23

Keywords:

COVID, COVID prophylaxis, ursodeoxycholic acid (UDCA).

Citation:

Microbiol Infect Dis AMJ. 2023; DOI/10.33590/microbiolinfectdisamj/10304488. https://doi.org/10.33590/microbiolinfectdisamj/10304488.

Abstract Background: The 2019 novel coronavirus (COVID-19) pandemic resulted in significant mortality and morbidity. Ursodeoxycholic acid (UDCA) is reportedly widely in demand in some countries, such as China, to protect individuals from the effects of infection, as there is evidence that it is effective in preventing viral replication in some in vitro studies. UDCA is commonly prescribed in patients with primary biliary cirrhosis and gallbladder calculi. By evaluating a set of patients prescribed UDCA, whether or not the risk of COVID-19 infection is attenuated by adherence to UDCA can be determined.

Method: This is a retrospective database study using the Clinical Practice Research Datalink (CPRD Aurum). Patients who received a prescription of UDCA in the study timeframe of March 1, 2020–May 30, 2021 were characterized, and their primary care electronic medical records analyzed for presence of COVID-19 infection. The proportion of days covered for each patient was used as a proxy for adherence.

A comparison was made between categorized high- and low-adherence, and adherence as a continuous variable. Inverse probability weighting was used to adjust for confounding.

Results: Higher categorized adherence (≥80%) to UDCA was associated with a statistically significant lower incidence of COVID-19 (odds ratio [OR]: 0.864; 95% confidence interval [CI]: 0.759–0.984; p=0.027). This contrasted to adherence as a continuous variable, which was not statistically significant. Obesity and hematological malignancy were also associated with a higher incidence of COVID-19 infection.

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Article Conclusion: There is evidence to suggest that the regular use of UDCA is associated with a lower risk of COVID-19 infection when compared to irregular or sporadic usage.

Key Points 1. A high medication adherence to ursodeoxycholic acid appears to confer protection against COVID-19 infection, as reported by primary care coding from the start of the COVID-19 pandemic to the second quarter of 2021, which supports existing literature from prospective and in vitro studies.

2. The relationship between ursodeoxycholic acid prescription and positive primary care coding for COVID-19 infection appears to be non-linear, indicating that little protection is conferred by intermittent or sporadic prescription/dosing.

3. The possibility of an easily tolerated and inexpensive prophylactic medication could provide an alternative treatment for those who do not qualify for existing prophylactic treatments, or who do not tolerate vaccination, but still have a higher risk of morbidity from COVID-19.

INTRODUCTION The 2019 novel coronavirus (COVID-19) pandemic has resulted in significant mortality and morbidity worldwide. Around the world, around 650 million cases of infection, and around 6.6 million related deaths had been reported by the World Health Organization (WHO) by December 23, 2022.

During the pandemic, governments throughout the world instituted lockdowns of varying length and strictness, widespread testing and, eventually, mass vaccination programs.1 A significant number of therapies were adapted or purposefully created for the prophylaxis and treatment of patients suffering from COVID-19.2 Tixagevimab and cilgavimab, a combination of two monoclonal antibodies, were recommended in the UK in 2022 for the prevention of COVID-19 in those who had weakened immune systems and were unable to have a vaccination, or who were unlikely to mount an immune response to vaccination.3 In addition, four antiviral medications (nirmatrelvir, ritonavir, remdesivir, and molnupiravir) are available to those with COVID-19 who are at the highest risk of becoming ill. Other medications, such as hydrochloroquine4 and favipiravir,5 have also been explored, but evidence is lacking for efficacy.

Ursodeoxycholic acid (UDCA) has been investigated as a drug with the potential to treat COVID-19.6 UDCA is prescribed for dissolution 56

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of small gallbladder calculi in patients with asymptomatic cholelithiasis, or those with primary biliary cirrhosis.7,8 It is generally safe and well tolerated.9,10 UDCA has potential as a low-cost prophylactic and treatment for COVID-19. It is prescribed in secondary and primary care, and has a half-life of 3–6 days. Typical dose ranges from 300–900 mg/day, dependent on bodyweight.11 The protective mechanism of UDCA for COVID-19 has been attributed to the interaction with angiotensin-converting enzyme 2 (ACE2) receptor.

Research has indicated that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) gains entry into target cells by binding its spike protein to the ACE2 receptor. ACE2 maintains a strong affinity for COVID-19, and its expression remains unaltered despite viral mutations. A recent investigation has highlighted the potential of UDCA, a medication primarily employed to treat liver conditions, in thwarting COVID-19 infection by diminishing ACE2 expression.12 Subsequent validation of this discovery has been achieved through both in vitro and in vivo experiments.13 The current arsenal of antibodies generated by vaccination struggles to effectively neutralize the virus, due to its adept immune evasion tactics. Additionally, the concentration of antibodies declines notably over time, a phenomenon exacerbated in older adults and high-risk populations, such as patients who

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Article are immunocompromised, who exhibit reduced responsiveness to vaccines.14 In light of these challenges, the development of novel therapeutic agents targeting alternative aspects of the disease becomes imperative. This approach holds promise in mitigating both the risk and severity of the illness, offering particular benefits to individuals ineligible for monoclonal antibody treatment, those lacking access to vaccination, and individuals with underlying health conditions who share close quarters with individuals infected with COVID-19.

drug is not approved for COVID-19 prophylaxis or treatment, the population that has been examined in this study have been prescribed UDCA for indications such as asymptomatic cholelithiasis or primary biliary cirrhosis. This study took place from the first corresponding, to the creation and notification to primary care physicians of COVID-19 specific codes, the lifting of the first lockdown, to the reopening of indoor venues in the UK.20 The start of the period was limited by the provision of codes to record a positive COVID-19 diagnosis.

As of writing, public concern about COVID-19 has waned,15 with COVID-19 restrictions lifted in the UK in February 2022.16 As a contrast, China has had a zero COVID-19 policy in place since the pandemic emerged in 2020, with restrictions only recently lifted at the end of 2022.17 There has been a reported scramble over the counter for UCDA in China, due to less effective vaccines, lower than ideal vaccination in the elderly population, and significantly fewer intensive care beds per head of population than the USA.18 In a recent study published at a single center, the Beijing Ditan Hospital in China, UDCA was associated with fewer and milder COVID-19 infections based on self-reporting in patients with chronic liver disease during 2022.19 This study aimed to determine whether dosages of UDCA are associated with the risk of COVID-19 infection in the UK, in a select population of patients prescribed UDCA.

As this was a real-world retrospective study, a surrogate for the dosage of UDCA was required.

The proportion of days covered (PDC) is frequently used as measure of adherence to medications in real-world databases.21 The comorbidities and cofactors were based on comorbidities listed by the UK’s National Health Service (NHS) as increasing the risk of COVID-19 infection.22 In this study, the authors utilized the PDC as a surrogate for the dosage of UDCA over the study period.

UDCA prescriptions are presumed to not expire during the study period; hence, two prescriptions lasting 30 days will result in 60 days medication coverage. The patient is also assumed to have used the medication as directed. As patients with long-term prescriptions are likely to have coverage from prior to the study period, the prior prescription will also be considered in the calculation of PDC.

METHOD

Data Source

The authors’ retrospective cohort study used Clinical Practice Research Datalink (CPRD Aurum), an ongoing primary care database of anonymized medical records from general practitioners, which comprises over 40 million research-acceptable patient records (permanently registered with sufficient data quality).23,24 The database covers over 20% of the UK population. The CPRD primary care database is therefore a rich source of health data for research, including data on demographics, symptoms, tests, diagnoses, therapies, healthrelated behaviors, and referrals to secondary care. Each year, CPRD must obtain Section 251 regulatory support through the Health Research Authority (HRA) Confidentiality Advisory Group (CAG). All requests from researchers to gain access to linked data must be approved via the CPRD Research Data Governance (RDG) Process.

The authors initiated a retrospective database study, broadly covering the first reports of COVID-19 being transmitted in the UK, around March 1, 2020, to the reopening after the second lockdown in the UK, May 30, 2021.

A single cohort of patients was followed from the index date (the start of the study period) to the end of the study period. A baseline period prior to the index date was utilized to evaluate comorbidities of a patient, and to evaluate the length of the previous UDCA prescription.

Two populations were examined: patients with documented chronic liver disease, and patients without, who have been presumed to be prescribed UDCA for gallbladder calculi. As the Creative Commons Attribution-Non Commercial 4.0

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Article

Exposure Studied

The exposure studied was the adherence, as measured by the PDC for UDCA. Prescription duration for a single prescription of UDCA was calculated by the prescription length in days entered by the physician. Where prescription length was recorded as 0 days, the median prescription duration was imputed by the associated prescription instructions in the dosage text, or if unavailable, the mean length in days for that particular prescription. Medication supplied from prescriptions filled before the end of the previous supplies was also carried forward to after the end of the previous days supplied.

Population

The population of the study included patients who fit the eligibility criteria at the index date (March 1, 2020). Patients who were only prescribed UDCA after the index date were not included.

Inclusion Criteria

Eligible patients included those who had a prescription issued for UDCA in the 6 months prior to the study period. Patients exited the study when they were recorded as having a date of death, or were unregistered from a CPRD-participating practice.

Outcome Assessments

Presence of code for COVID-19 infection, either through a clinical diagnostic code, or a test result indicating a positive COVID-19 infection.25

Patient Demographics

After applying the inclusion and exclusion criteria, 8,964 patients were identified. The mean age of the low-adherence group was lower than the highadherence group (57 versus 68; p<0.001). The proportion of the low-adherence group who were male was lower than the high-adherence group (69% versus 73%; p<0.001).

Power Study

With a proportional outcome and using a type I error rate of 0.05 and a power of 70%, with a higher number of low-adherence patients to 58

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adherent patients (a ratio of 1.3), event rate of 0.059 in the low-adherence group, and event rate in the high-adherence cohort of 0.047. The required sample size was 3,837 in the highadherence group, and 4,989 in the low-adherence group. Within the data fitting the eligibility criteria, there were 3,904 patients in the high-adherence group, and 5,060 in the low-adherence group, indicating that there were enough patients to sufficiently power the study.

Statistical Analysis

Descriptive statistics are presented as proportions and means with standard deviation or, where categorical, median with interquartile ranges.

Adherence was considered as a categorical variable for descriptive purposes where poor adherence included patients with a PDC of <80%26 and high-adherence as PDC ≥80%. Adherence was also considered as both a continuous variable and a categorical variable for the outcome analysis.

The objectives of comparing risk of COVID-19 documented infection will be modeled through binary logistic regression. The odds of COVID-19 diagnosis or test/diagnosis versus no diagnosis or test/diagnosis in patients who were adherent (high-adherence, or PDC >80%) were compared to patients who were non-adherent (low-adherence, or PDC <80%). To account for confounding between the subcohort of patients with highadherence and low-adherence, inverse propensity weighting was used to enable balance. This method was chosen because of the relatively low number of COVID-19 infections recorded, and the unwillingness of the authors to discard patients.

COVID-19 vaccination was considered as a time dependent variable. The significance level was set to 5%.

All statistical analysis was performed using R Statistical Software (version 4.1.1; R Foundation for Statistical Computing, Vienna, Austria). In the study population, 482 patients had a record of COVID-19 infection within primary care. There were 3,904 patients with low-adherence <80%, and 5,060 with higher adherence. There were a total of 1,657,469 follow-up days in the highadherence subcohort, with a mean follow-up of 425 days. For the low-adherence subcohort, there were a total of 2,162,435 follow-up days, with a mean follow-up of 427 days. The median

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Article time of follow up was 426 days. Within the two groups there were significant differences, shown in Table 1. Statistically significant differences were seen in age, sex, use of immune suppressants in the baseline year, solid tumor, hemato-oncology conditions, chronic obstructive pulmonary disease, smoking status, serious liver disease, chronic renal failure, and rheumatological condition. There were

no statistically significant differences in the proportion with BMI ≥30 kg/m2, asthma, or chronic kidney disease between the two groups.

It is worth noting that the proportion of COVID-19 was slightly higher in unmatched patients who had a higher adherence compared to those with a low adherence.

Table 1: Clinical characteristics of patients prescribed ursodeoxycholic acid.

Low UDCA adherence group N=5,060

High UDCA adherence group N=3,904

Statistical test (Mann– Whitney or Wilcoxon ranked test)

Age (median [Q1, Q3])

57 (38, 71)

68 (56, 77)

<0.001

Sex (male)

3,489 (69%)

2,864 (73%)

<0.001

BMI (median [Q1, Q3])

28 (24, 35)

28 (25, 33)

0.018

Missing BMI

270

88

N/A

Obesity (n, %)

2,003 (40%)

1,515 (39%)

0.500

Immune suppressive medication (n, %)

438 (8.7%)

471 (12%)

<0.001

Solid cancer (n, %)

940 (19%)

940 (24%)

<0.001

Hemo-oncology cancer (n, %)

121 (2.4%)

65 (1.7%)

0.017

COPD (n, %)

387 (7.6%)

463 (12%)

<0.001

Asthma (n, %)

891 (18%)

679 (17%)

0.800

Current/former smoker (n, %)

2,142 (42%)

1,817 (46%)

<0.001

Chronic liver disease (n, %)

2,393 (47%)

2,703 (69%)

<0.001

Chronic kidney disease, Stage 21 (0.4%) 4 or 5 (n, %)

21 (0.5%)

0.400

Rheumatological condition (n, %)

366 (7.2%)

334 (8.6%)

0.021

At least one COVID-19 vaccination during study period (n, %)

3,455 (68%)

3,209 (82%)

<0.001

COPD: chronic obstructive pulmonary disease; N/A: not applicable; UDCA: ursodeoxycholic acid.

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Article Seventy-four percent of the study population had a code for COVID-19 vaccination by the end of the study period. There were 561 deaths and 723 people lost to follow-up, including to death.

Within the low adherence group, the number of patients with a COVID-19 code was 297, which equates to 5.9% of the subcohort. Within the high adherence group, the number of patients with a COVID-19 code was 185, which included 4.7% of the group. In a non-weighted, non-adjusted comparison, the odds ratio (OR) was 0.81.

After weighting each of the patients according to their demographics and comorbidities, the analysis was repeated with results shown in Table 2. Adherence as a continuous variable was not a statistically significant explanatory variable affecting COVID-19 coding in the multivariable model (p=0.55). The OR of a positive COVID-19 code was 0.998 (95% CI: 0.997–1.000; p=0.244).

After appropriate weighting, adherence as a categorized variable consistent of <80% adherence and ≥80% adherence was significant, with an OR of 0.864 (95% CI: 0.759–0.984; p=0.027). The direction of effect is in favour of persons in the higher adherence group being at lower risk of receiving a code for COVID-19 in primary care. Additionally, a multivariable model examining other candidate variables that may influence the number of COVID-19 codes was analyzed. From demographics and comorbidities, only obesity (p<0.001) and hematological malignancy (p=0.041) were significant, as shown in Table 3.

DISCUSSION In the authors’ limited study population, categorized higher adherence to UDCA was associated with a lower incidence of COVID-19 infection. Of note, no patients were identified with a diagnosis of sickle cell anemia, despite an increased association with gallstone formation.26 This would be consistent with speculation that high adherence to UDCA has the potential to be protective to COVID-19 infection. The conclusions drawn from this retrospective study are consistent with Li et al.’s19 2023 prospective study, and the lower incidence of COVID-19 as assessed by telephone reporting. The groups reported in Li et al.’s19 study were patients who had reported 1 or more months of UDCA prescription, and those who were not receiving UDCA. The lack of significant association with adherence as a continuous variable may initially appear to counter the hypothesis that UDCA is protective; however, the lack of significance may show that protective effects only occur with patients who were highly adherent. Since the cut-off between low- and high-adherence groups was 80% coverage, there was a significant difference between the two groups, with the median adherence of >100% in the high group, compared to 30% in the low-adherence group. Again, this was consistent with Li et al.’s19 study, where patients not receiving UDCA were compared to those who were. There are many confounding factors that may contribute to this protective effect that could contribute to patients being more adherent, including various psychosocial factors,

Table 2: Adherence and COVID outcomes (note: adherence was capped at 100%).

Low UDCA adherence group N=5,060

High UDCA adherence group N=3,804

Statistical test (Mann– Whitney or Wilcoxon ranked test)

Adherence % (median [Q1, Q3])

30 (7, 53)

100 (94, 100)

<0.001

Patients with record of COVID-19 infection

297 (5.9%)

185 (4.7%)

0.019

UDCA: ursodeoxycholic acid.

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Table 3: Multivariable regression for covariates associated with the outcome of COVID-19 infection code in primary care.

Variable

Significance (p)

Vaccination

0.475

Sex

0.811

Obesity

<0.001

Autoimmune condition

0.186

Current or ex-smoker

0.090

Asthma

0.701

COPD

0.640

Hematological malignancy

0.041

COPD: chronic obstructive pulmonary disease.

adaptive strategies, and personal difficulty in life situations.27 Other confounding factors that are known to affect both COVID-19 infection and adherence, such as social deprivation, education, financial status, and partnership, are also not accounted for in this study.28,29 Issues around access to medication were magnified during this period, and included mandatory self-isolation, changes to the way prescriptions were ordered and collected, and worries around contact with COVID-19.30 During this period, there were significant COVID-19 precautions, including three national lockdowns in England, regional lockdowns, mask wearing in public, and a program of vaccination with vaccines with different effectiveness. Although some relevant risk factors are included in the analysis, many of these factors are not taken into account. Patients who have a better prescription coverage have better organization and planning,31 which may help adherence to social distancing, and isolation methods that may reduce risk of infection. Patients who adhere to their medication tend to be patients who suffer from more severe disease,32 and may be more likely to self-isolate.

prescriptions to take them as directed. There can be situations where physicians issue prescriptions, but there are barriers to collection. During the pandemic, there were significant changes in how primary care was accessed, which may have resulted in lower prescription pick-up. The reduction in face-to-face consultations over this period could have also resulted in a lower actual adherence compared to prescription rate, as it has been shown that face-to-face consultations are beneficial to promote medication coverage.33 There are, however, limitations to this consideration, since patients can be prescribed medication, but do not collect it from the pharmacy. Additionally, patients can receive medication from a pharmacy, but do not take their prescription as prescribed.

Stockpiling pharmaceutical medications was observed during the pandemic, and thus many people requesting or collecting medications may have demonstrated this behaviour.34 Despite these limitations, records of prescription are widely used as a surrogate for adherence in chronic disease.35 Structural limitations exist within the study design, including the limitation of only collecting data within primary care. Many medication codes were only implemented into electronic medical record systems in June 2020, and thus do not record cases of COVID-19 prior to this timeframe. The adoption of the use of the codes by users of electronic medical record systems is

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Article unknown. COVID-19 recorded by home testing kits and not reported to the GP, COVID-19 recorded in secondary care, and testing centers are not recorded. COVID-19 vaccinations are likely to be incompletely recorded in primary care, given that many vaccinations took place in vaccination centers. The type of vaccination was also inconsistently recorded, and was not considered as a variable. There may be variation in the effectiveness of monovalent and bivalent vaccinations, and in the number of different vaccinations patients receive.36 This study only measures occurrences of COVID-19, and does not measure severity, or the presence or absence of any protective effect to severe disease. Hospital attendances and deaths due to COVID-19 are not recorded.

Future avenues for research include utilisation of hospital records to augment primary care

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CONCLUSION Although it is acknowledged that there are significant limitations to a retrospective data into a restricted population treated with UDCA, there is potential that it could be protective if patients are strongly adherent.

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