Hepatitis C, Antimicrobial Stewardship, HIV Treatment
Congress Features:
Respiratory Viral Infections and Emerging Global Threats
Foreword
Congress Highlights
12 Congress Review: Review of IDWeek 2024
Congress Features
21 HIV Treatment at IDWeek 2024
Maurice Policar
25 Respiratory Viral Infections: Highlights from IDWeek 2024
Karen C. Bloch
28 A Case for Caution: Breaking Down Antimicrobial Resistance
Aleksandra Zurowska
32 A Global Approach to Tackling Emerging Infectious Diseases
Ada Enesco
Poster Reviews
36 Ibalizumab’s Role in Multidrug-Resistant HIV
40 Reducing Cardiovascular Risk in HIV: The Unseen Impact of Visceral Fat
Abstract Reviews
48 Gender Differences in Hepatitis C Treatment in the New York City Jail System, 2019–2023
Simonson et al.
51 Breast Cancer and Colorectal Cancer Screenings Among Persons with HIV: The Role of Individual and System-Level Factors on Screening Completion
Bredehoeft et al.
55 Assessing Hepatitis A Virus and Hepatitis B Virus Screening, Immunity, and Vaccination in People Living with HIV in the Illinois Department of Corrections
Truong et al.
57 Evaluation of Microbiology and Antibiotic Prescribing Behavior of Foot Puncture Wound Infection: an Opportunity for Antimicrobial Stewardship
Kim et al.
59 Cardiac MRI Identifies Heart Disease Risk in Individuals with Hepatitis C Regardless of Myocardial Damage Markers or Fibrosis Stage
D'Amore et al.
62 Assumptions and Realities: Unraveling Varicella Zoster Virus Immunity in Unvaccinated Populations
Jordão et al.
63 Rabies Encephalitis: Spectrum of MRI Findings and Predicted Probability of Abnormality Detection Based on Symptom Duration
Mohata et al.
66 Immunological Profile of Human T-Lymphotropic Virus Type 1 in Pediatric Patients
Donneys et al.
69 Prospective Study on the Clinico-epidemiological Characteristics, Diagnostic Approaches, and Correlation with Autopsy Findings of Rabies Encephalitis
Mohata et al.
Congress Interview
74 Jacqueline Toia and Kathleen Murtagh Interviews
77 Battling Pediatric Mold Infections: Invasive Aspergillosis and Invasive Mucormycosis
84 Gail J Demler–Harrison
88 Lisa Armitige Article
93 Melioidosis in Patients with Cancer, A Cloaked Menace: A Case Series
Jayakrishnan et al.
Editorial Board
Editor-in-Chief
Dr. Shira Doron
Tufts Medical Center, Boston, Massachusetts
Dr. Shira Doron is the Chief Infection Control Officer for the Tufts Medicine Health System and the Hospital Epidemiologist for Tufts Medical Center, where she is an Infectious Disease physician. She is Professor of Medicine at Tufts University School of Medicine, a member of the Infectious Diseases Society of America’s (IDSA) Practice and Quality Committee, and the immediate past Chair of the society’s Antimicrobial Stewardship Centers of Excellence subcommittee. She is a long-time consultant to the Massachusetts Department of Public Health in the area of antimicrobial resistance prevention, focusing on long-term care facilities. She was a member of Governor Charlie Baker’s Medical Advisory Board during the COVID-19 pandemic. She is also an elected member of the Wellesley Board of Health.
Dr. Lisa Akhtar
Ann & Robert H. Lurie
Children’s Hospital of Chicago, Illinois
Dr. Michael Angarone
Northwestern University Feinberg School of Medicine, Chicago, Illinois
Dr. Shweta Anjan
University of Miami Miller School of Medicine, Florida
Dr. Karen C. Bloch
Vanderbilt University Medical Center, Nashville, Tennessee
Dr. Syra Madad
New York City Health and Hospitals, New York
Dr. L. Silvia Munoz Price
Emerald Coast Infectious Diseases, Fort Walton Beach, Florida
Dr. Sandhya Nagarakanti
Mayo Clinic-Arizona, Phoenix, Arizona
Dr. Maurice Policar
New York City Health and Hospitals/Elmhurst, New York
Aims and Scope
AMJ Microbiology & Infectious Diseases is an open-access, peer-reviewed eJournal committed to helping elevate the quality of healthcare by publishing high quality content on all aspects of microbiology and infectious diseases.
The journal is published annually, 6 weeks after the IDWeek 2024, and features highlights from this congress, alongside interviews with experts in the field, reviews of abstracts presented at the congress, as well as in-depth features on congress sessions. Additionally, this journal covers advances within the clinical and pharmaceutical arenas by publishing sponsored content from congress symposia, which is of high educational value for healthcare professionals. This undergoes rigorous quality control checks by independent experts and the in-house editorial team. AMJ Microbiology & Infectious Diseases also publishes peerreviewed research papers, review articles, and case reports in the field. In addition, the journal welcomes the submission of features and opinion pieces intended to create a discussion around key topics in the field and broaden readers’ professional interests. AMJ Microbiology & Infectious Diseases is managed by a dedicated editorial team that adheres to a rigorous double-blind peer-review process, maintains high standards of copy editing, and ensures timely publication.
Our focus is on research that is relevant to all healthcare professionals in microbiology and infectious diseases. We do not publish veterinary science papers or laboratory studies not linked to patient outcomes. We have a particular interest in topical studies that advance research and inform of coming trends affecting clinical practice in the respiratory field. is an open access, peer-reviewed eJournal committed to helping elevate the quality of practices in microbiology and infectious diseases globally by informing healthcare professionals on the latest research in the field.
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This Publication
Launch Date: November 2023
Frequency: Annually Online ISSN: 2977-4055
All information obtained by AMJ and each of the contributions from various sources is as current and accurate as possible. However, due to human or mechanical errors, AMJ 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 2024) and the use of the organisations does not constitute endorsement or media partnership in any form whatsoever. The cover photo is of Los Angeles, California, USA, the location of IDWeek 2024.
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Welcome
Dear Readers,
To you, I extend the warmest of welcomes to our publication, AMJ Microbiology & Infectious Diseases. This journal publication comes after an indescribable quarter of launching AMJ and moving operations Stateside to better understand the needs, nuances, practices, and healthcare landscape here in the US. Since moving AMJ to Miami, Florida in October, it has been a whirlwind, to say the least.
One of the major highlights was our trip to Los Angeles, California for IDWeek 2024. IDWeek had a touch of LA glamour. It was exhilarating to walk among “celebrities”: erudite experts with a rich history of work and much to celebrate. I decided this was a selfless community; a community who have dedicated their lives to protect the world from cataclysmic events, such as the anticipation of the next pandemic. To the time-poor healthcare provider with limited access to new research, researcher who missed the developments in clinical practice, and administrator protecting patients from harm, I present our review of IDWeek 2024.
I’m excited to feature so many meeting abstracts in the journal; they represent the diversity and depth of research from microcosms across the globe, from community hospitals to renowned research institutions and academic medical centers. Yet, these are just a snapshot of today’s landscape. Many thanks to the peer reviewers, authors, interviewees, and Editorial team for their contributions to this journal.
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Foreword
Welcome to the November issue of AMJ Microbiology and Infectious Diseases, in which we feature highlights from IDWeek 2024, held from October 16th–19th in Los Angeles, California. The opening plenary included honest assessments of our nation’s pandemic preparedness, both past and future, and what needs to be done before the next pandemic.
This was expertly presented by Jennifer Nuzzo, Brown University School of Public Health, Providence, Rhode Island; Paul Friedrichs, Office of Pandemic Preparedness and Response, Washington, D.C.; and Nichole Lurie, Coalition for Epidemic Preparedness Innovations, Washington, D.C. Always one of my favorites, the SHEA lectureship was presented by Louise Dembry of Yale School of Medicine and Yale School of Public Health, New Haven, Connecticut, and titled "Musings on Growing the Next Generation of Healthcare Epidemiologists". I appreciated that she emphasized the importance of creating dedicated training tracks for ID fellows interested in learning healthcare epidemiology, something I am passionate about. Recurring topics at the meeting this year included the social determinants of health and AI. I hope to see all of you at next year’s IDWeek, which will be held October 19th–22nd , 2025 in Atlanta, Georgia.
Hot topics in infectious diseases these days include the ongoing outbreaks of highly pathogenic avian influenza affecting
poultry, cattle, other mammals, and a growing number of humans; Marburg virus in Rwanda; and mpox in the Democratic Republic of the Congo and neighbouring countries. But perhaps the biggest news in our field in a long time has been the results of the PURPOSE-1 trial in which none of the participants who received the longacting injectable HIV drug lenacapavir, who were women in South Africa and Uganda, developed HIV, compared to 2% of those who took oral pre-exposure prophylaxis.
The opening plenary included honest assessments of our nation’s pandemic preparedness, both past and future
In this year's issue of AMJ Microbiology and Infectious Diseases, you will find a fascinating case series of melioidosis in patients with cancer. We feature a wide selection of abstracts presented at IDWeek 2024 to provide a snapshot of emerging research. Other highlights include indepth congress features authored by our esteemed editorial board members, providing their expert insights into acute respiratory infections and the latest advancements in HIV treatments as presented at the meeting. We strive to enhance patient outcomes by sharing knowledge with the microbiology and infectious diseases community. We hope you find this issue both insightful and inspiring.
Shira Doron
Chief Infection Control Officer, Tufts Medicine; Professor of Medicine, Tufts University School of Medicine, Boston, Massachusetts
hospitalizations among working and the potential benefit of recombinant USA, 2012-13 through 2022-23
1 2
Suboptimal vaccination rates among working age adults (18-64 years) despite the universal influenza vaccine recommendation
Influenza vaccination rates in 2022-231
among 18-49 years
Adults 18-64 years of age account for >60% of the US population2 48% among 50-64 years
3
Modeling data suggests a switch to recombinant hospitalizations
+47% of averted influenza hospitalizations based upon 30% relative vaccine e The full use of recombinant vaccine in adults 50-64 years hospitalizations each season6
Consideration of vaccination programs tailored to working
REFERENCES
1. CDC. Influenza vaccination coverage. Data extracted in March 2024 from https://www.cdc.gov/fluvaxview/interactive/general-population-coverage.html. https://staticweb.usafacts.org/media/documents/USAFacts_2024_DIGITAL_Population.pdf. Accessed October 02, 2024. 3. CDC. Accessed September 24, 2024; 4. Clark A, et al. Lancet Glob Heal. 2020;8:1003–1017; 5. Coleman BL, et al. Influenza Other Respi
Substantive burden of severe influenza in working age adults (18-64 years), particularly 50-64 years and at risk* 18-49 years over the past 10 years
From 37,000 to 204,000 influenza hospitalizations per season among 18-64 years old†
18-64 years contributed from 21 to 47% of all-age influenza hospitalization, with higher percentages during seasons dominated by H1N1pdm09†
*At-risk: people having ≥1 chronic medical condition
123
Average annual influenza hospitalization rates per 100,000 population 50-64 years†
82 At-risk* 18-49 years‡
†Based on retrospective descriptive analysis of US CDC influenza burden data from 2012-13 through 2022-23 (excluding 2020-21 season)3
‡Estimated influenza hospitalization applying US prevalence4 and relative risk5 among at-risk 18-49 years
recombinant influenza vaccine may reduce influenza
ectiveness of recombinant vaccine compared to standard dose years and at-risk 18-49 years of age could have averted >10,000 influenza
working age adults may support improved public health in the US
https://www.cdc.gov/fluvaxview/interactive/general-population-coverage.html. Accessed September 24, 2024; 2. USA Facts. America in facts. 2024. Available from: CDC. About estimated flu burden. Data extracted in March 2024 from https://www.cdc.gov/flu-burden/php/about/index.html. Respi Viruses. 2018;12:22-29; 6. Torcel-Pagnon L, et al. IDWEEK congress 2024. Poster_P-35.
THE VIBRANT city of Los Angeles, California welcomed over 12,000 clinicians, scientists, epidemiologists, researchers, advanced practice providers, and teachers in microbiology and infectious diseases at IDWeek 2024. This unique community met to explore new opportunities, forge connections with peers, and inspire the next generation of thought leaders.
Emily Erbelding, Director of the Division of Microbiology and Infectious Diseases (DMID), National Institute of Allergy and Infectious Diseases (NIAID), Maryland, kicked off the Opening Plenary. She likened The City of Angels, which hosted IDWeek for the first time, to the community of microbiology and infectious diseases: embodying ambition, diversity, and limitless possibilities.
The condensed, 4-day meeting was packed with a breadth of forums for discourse, boasting workshops, lectures, interactive and debate sessions, symposia, and "Meet The Professor" talks. The fantastic "BugHub Stage” was front and center in the main foyer, with a constant stream of tidbits presented throughout the week with a packed audience.
The commitment to excellence was evident throughout the week, not least by hundreds of late-breaking science posters and abstracts presented that showcased the hard work and new discoveries at the forefront of the field. The IDWeek 2024 Program Committee must be highly commended for curating a schedule designed to engage
students and trainees to enter careers in this field, with a variety of interactive sessions, mentorship opportunities, hands-on experience, and a Careers Fair guaranteed to inspire and support the next generation.
A plethora of awards were bestowed upon outstanding investigators for celebrated abstracts. Awardees included Angelica Kottkamp, New York University (NYU); Shruti Gohil, University of California, Irvine (UCI); Rebecca Reece, West Virginia University, Morgantown; and Judith Martin, University of Pittsburgh, Pennsylvania. Next, we heard from those who had nominated their colleagues who transformed the frontiers of infectious diseases in research, patient care, and education.
Lisa Dumko, Trinity Health Saint Mary's Grand Rapids, Michigan, accepted an award for SIDP Outstanding Clinician Award. In her acceptance speech, she spoke to the importance of recognising providers from community hospitals versus academic medical centers. Recipients of this specific award tend to hail from academic medical
centers. She shared a story with the audience, where she was advised to prepare infectious disease pharmacy residents for less desirable positions where they will have fewer opportunities in community hospitals compared to large academic medical centers. Dumko opposed this statement, affirming that she has had more opportunities over the last 12 years than she could dream possible. “Under-resourced and not funded, but the most rewarding work in the world. You can change prescribing culture, build robust teaching services, and maintain strong research practices in the community space,” Dumkow shared. She, therefore, warmly encouraged young people to consider community hospital positions where, given the infectious diseases specialist shortage, the needs of the hospitals are just as great, if not greater, and the opportunities and rewards are just as fulfilling. She concluded with a heartfelt thanks to those working on solutions in antimicrobial resistance as her family are touched by it so deeply.
Accepting his award, David Norman Gilbert, Oregon Health & Sciences University, Portland, shared a tale of the inimitable Alexander Fleming. Today, it is estimated that Fleming has saved over 200 million people’s lives worldwide, shared Gilbert. Gilbert even brought in a vial of penicillin from the first commercial availability of penicillin. “Dr Fleming would be excited and enthused about where the next breakthrough was going to come. If I was a young trainee I would be really excited. We’ve got new diagnostic tools, new treatments, tremendous insights. I can’t think of another specialty that is as exciting, dynamic, and never boring”, shared Gilbert.
It is admirable that the community of specialists in microbiology and infectious diseases take their shared responsibility for building and commitment to the future community very seriously. Another commitment, how we prepare for the next pandemic, took center stage. The keynote session, “Navigating The Next Pandemic: Policy and Practice Integration” explored both policy and practice solutions to better equip the community to respond to these challenges.
Jennifer Nuzzo, Brown University School of Public Health, Providence, Rhode Island, USA, opened the plenary by reflecting on one, but not sole, under-represented mistake in our response to COVID-19, which was to brand it as a “once in a century pandemic”. There are noticeable comparisons with the 1918 influenza pandemic; both events had profound damages. The 1918 influenza pandemic was estimated to have caused 675,000 US deaths, this is at a time that the US population was one-third of what it is today. The COVID-19 pandemic resulted in over 1.2 million deaths. As a head-to-head comparison, the 1918 pandemic was more fatal. Of course, COVID-19 caused a historic loss of life expectancy, eroding a decade worth of progress, Nuzzo solemnly stated. To Nuzzo’s primary point, just because an event happened in 1918 and another event happened 100 years later, does not mean it will be another 100 years until the next deathly event happens. The timing of two independent events do not affect each other.
The steady stream of infectious diseases being carefully monitored by the community since COVID-19 speaks to this.
Three months ago, the WHO declared a public health emergency of international concern due to a rise in cases of mpox virus. This was the second mpox global emergency declared in a year. Currently, the US is experiencing some deeply concerning outbreaks of highly pathogenic avian influenza A in animals and people.
This virus has been on the list of potential pandemic threats since it was identified in the late 1990s. So far, this animal virus has not gained the ability to easily infect and spread between people, but if it does gain stability, we would be in another pandemic. Ultimately, the frequency of outbreaks of new infectious diseases is increasing.
Ultimately, the frequency of outbreaks of new infectious diseases is increasing
Changes in our environment and our behaviour are giving rise to new disease threats and resurrecting old ones.
At the same time as these hazards are increasing, so too are our vulnerabilities to infectious diseases. “We are living in age of infectious disease threats. We need to stop treating COVID-19 like it’s a one-off,” warned Nuzzo, “We need to start preparing for infectious diseases like the recurring hazards they are”.
There remains work to be done, but this era could usher in new progress. And who else but the microbiology and infectious disease community to progress this work, patient care, and advocacy? “Building on this, we can transform the age of infectious disease threats into the age of infectious disease discoveries!”
One disease threat of global concern, a virus known to be one of the most dangerous in the world, is the Marburg outbreak virus in Rwanda. Rwanda’s Minister of Health, Sabin Nsanzimana, shared a video message with the IDWeek audience.
Continue reading for an in-depth look at the latest research updates from this year's IDWeek.
The Impact of Changing Healthcare Policies on HIV Prophylaxis in Newborns
NEW research presented at IDWeek 2024 revealed that there has been a significant decline in the use of zidovudine single prophylaxis among infants receiving postnatal antiretroviral treatment, due to a shift towards more effective treatment strategies. Yet, a substantial number of infants diagnosed with HIV still did not receive any form of perinatal prophylaxis.
Despite changes in national policy surrounding perinatal HIV transmission and postnatal antiretroviral prophylaxis, there is a lack of real-life data to understand the impact of these policies. Therefore, researchers conducted a population-based retrospective study using the MarketScan Multi-State Medicaid Database from 2009–2021, to assess prophylactic antiretroviral drug use (in particular, use of the zidovudine single prophylaxis) among newborns. The study included 3,147,318 infants, of which 2,304 received postnatal antiretroviral prophylaxis, and the analysis included a linear regression model to identify temporal trends in zidovudine single prophylaxis use.
The results revealed that among the 2,304 infants, 2,123 received zidovudine single prophylaxis in 2009; however, the rate dropped to 71.7% by 2021, correlating with the introduction of dual and triple prophylactic regimens (p for trend <0.001). Additionally, the data showed that triple prophylaxis became more commonly used than double prophylaxis by 2018. Despite the shift towards more effective treatment strategies, 52 infants were diagnosed with HIV within their first year of life, and among them, 27 (51.9%) infants did not receive perinatal prophylaxis, suggesting missed maternal infections.
Whilst postnatal HIV prophylaxis strategies have evolved over time, there is still a need for continuous assessment and improvement
The findings highlight that whilst postnatal HIV prophylaxis strategies have evolved over time, there is still a need for continuous assessment and improvement of postnatal HIV prophylaxis strategies in clinical practice. Future initiatives should focus on enhancing screening and treatment protocols for pregnant individuals living with HIV to ensure that infants receive appropriate prophylactic care. Additionally, ongoing monitoring of HIV transmission rates and treatment efficacy will be essential to inform and refine clinical guidelines, ultimately aiming to eliminate perinatal HIV transmission.
Safety of Mpox Vaccination in Adolescents
A RECENT Phase II clinical trial presented at IDWeek 2024 indicated that the MVA-BN vaccine, currently licensed for smallpox and mpox prevention in adults, is safe and effective in adolescents aged 12–17 years.
This study was conducted as a response to the rising mpox cases among children in the Democratic Republic of Congo, who represent 70% of infections and 88% of fatalities. The study aimed to explore the potential of extending vaccine coverage to younger age groups in mpox-endemic regions.
The study was conducted at multiple sites and compared two doses of the MVA-BN vaccine administered to 315 adolescents and 211 adults. The two doses were given 28 days apart, with safety monitored through Day 210 and immune responses assessed 14 days after the second dose. Side effects were generally mild and similar in both groups, with dizziness reported slightly more often in adolescents (3%) but at rates comparable to other vaccines commonly given to teenagers.
Immunogenicity results revealed that adolescents developed strong antibody responses to the vaccine, with antibody titers non-inferior to those seen in adults. Specifically, geometric mean titers in adolescents reached 470.3, compared to 293.2 in adults.
This suggests that the vaccine performs well in both age groups, providing adolescents with a robust immune response.
The interim findings support MVA-BN as a safe and effective vaccination option for adolescents, which could be pivotal in controlling mpox spread in high-risk regions. Further studies are planned to evaluate its efficacy in younger children, aiming to expand protection to the most vulnerable populations.
This study was conducted as a response to the rising mpox cases among children in the Democratic Republic of Congo who represent 70% of infections and 88% of fatalities
Quality Improvement Initiative Reduces Antibiotic Duration for Pediatric Ear Infections
A RECENT study from the University of Colorado, presented at IDWeek 2024, has shown promising results in reducing the duration of antibiotics prescribed for children with acute otitis media, a common ear infection.
The study, which analyzed the effectiveness of a quality improvement intervention at local emergency and urgent care centers, found that implementing a new clinical pathway and a streamlined electronic health record order set led to shorter antibiotic treatments in many cases.
The retrospective review, including data from 34,324 pediatric patients between January 2019–September 2023, revealed that while the overall rate of antibiotic prescribing remained high (88–93%), compliance with recommended treatment durations increased dramatically. Prior to the intervention, only 3% of children aged 24 months and older were prescribed antibiotics for 5 days or less. After the electronic health record order set was implemented, this figure increased to 83%. Interestingly, the study also found a decline in the use of amoxicillin, the most commonly prescribed first-line antibiotic for acute otitis media. The rate of amoxicillin prescriptions dropped from 77% to 74%.
The rate of amoxicillin prescriptions dropped from 77% to 74%
Despite these positive changes, the study found that overall antibiotic prescribing rates remained high, pointing to the need for further efforts to curb unnecessary antibiotic use. The authors suggest that broader dissemination of the new care pathway and continued efforts to phase out outdated prescribing practices are needed to make more substantial progress in reducing antibiotic overuse.
An Interactive Map to Assess Initial Clostridioides difficile Infection Outcomes
HIGH vulnerability scores across multiple social determinants of health are associated with increased severity and mortality in patients with Clostridioides difficile infection (CDI), according to new research presented at IDWeek 2024.
Inequities in social determinants of health, including factors such as socioeconomic status (SES), housing, access to healthcare, and racial/ethnic disparities, have been hypothesised to impact CDI outcomes. The Centers for Disease Control’s (CDC) Social Vulnerability Index (SVI), a composite tool assessing neighborhood vulnerabilities based on SES, housing characteristics (H&C), race/ethnicity (REM), and housing and transportation (H&T), provides a way to quantify these social risks.
Researchers aimed to examine how each SVI theme impacts the severity of initial CDI episodes and all-cause mortality, with the intention of guiding more precise, sociallyinformed clinical interventions for CDI.
Researchers analyzed data from adult patients admitted to Loma Linda University Medical Center (LLUMC), California, for initial CDI episodes between January 2020–June 2021. Each patient's address was inputted into the CDC/Agency for Toxic Substances and Disease Registry (ATSDR) SVI Interactive Map, and used to map their neighborhood SVI score, which grouped patients into low vulnerability (SVI scores below 0.4999), and high vulnerability (scores at or above 0.5). A total of 206 patients were included, and outcomes were evaluated against their SVI scores to assess CDI severity and mortality rates.
The findings revealed that patients with high vulnerability scores had significantly worse outcomes. Specifically, initial severe CDI cases were three times more frequent in high vulnerability groups for SES and H&C (29.61%
versus 9.22%) compared to low vulnerability patients. For H&T, patients with HV scores had elevated risks of severe CDI (26.21% versus 12.62%) and fulminant CDI (13.11% versus 5.34%) compared to those in the low vulnerability group. REM showed the most pronounced disparity, with a 37-fold increase in initial fulminant CDI (17.96% versus 0.49%) and a ninefold increase in mortality (8.74% versus 0.97%) for high vulnerability patients versus low vulnerability patients.
In conclusion, the study suggests that high social vulnerability, as measured by SES, H&C, REM, and H&T SVI themes, correlates with more severe CDI cases and higher mortality. These findings highlight the importance of addressing social determinants within clinical practice. By integrating SVI data into patient assessments, healthcare providers may better identify at-risk patients and develop targeted interventions that address the specific SDoH impacting CDI outcomes.
For REM, high vulnerability patients versus low vulnerability patients showed
increase in initial fulminant CDI (17.96% versus 0.49%) increase in mortality (8.74% versus 0.97%) x x
High Mortality Rates Linked to NDM-Positive Infections in Hospitals
A RECENT study, led by Northwell Health in New York and presented at IDWeek 2024, has revealed a concerning rise in infections caused by carbapenemaseproducing organisms (CPO), particularly those harboring the blaNDM resistance gene, which encodes New Delhi metallo-beta-lactamase (NDM). These infections, often associated with significant morbidity and mortality, pose a substantial challenge in healthcare settings due to their resistance to a wide spectrum of antibiotics.
Conducted across 10 hospitals, this retrospective, multicentre study analyzed positive CPO blood cultures from 2021–2023 and urine cultures from 2023. CPO infections were identified using PCR testing for blood cultures, while urine specimens underwent a lateral flow immunoassay for phenotypic carbapenemase detection. The study assessed clinical outcomes including time to appropriate therapy, hospital stay duration, 30day readmission rates, and mortality.
The findings indicated that Klebsiella pneumoniae was the predominant organism isolated from both blood and urine samples, with urinary tract infections being the main source of CPO bacteremia. Of the carbapenemase genes identified, blaNDM was notably prevalent, representing 39% of CPOs in blood samples and 46% in urine samples, underscoring the increasing threat of NDM-harboring organisms within healthcare settings.
Observed clinical outcomes included median times for appropriate therapy for both blood and urine infections that were 3.9 hours and 16 hours, respectively. Hospital stays were prolonged, averaging 20 days for bloodstream infections and 13 days for urine infections.
Thirty-day readmission rates were 16% for blood infections and 50% for urine infections, indicating a high likelihood of recurrent infections. Mortality rates were 39% for bloodstream infections and 6% for urine infections, with NDM-related bloodstream infections reaching even higher mortality, 54% in 2022 and 50% in 2023.
These results underscore the urgency of timely CPO detection and identification of specific resistance genes to inform effective treatment adjustments. Despite prompt interventions, NDM-harboring CPOs continue to drive high mortality rates, pointing to a critical need for improved infection control measures and novel treatment strategies to aid in reducing the spread of these pathogens.
Despite prompt interventions, NDM-harboring CPOs continue to drive high mortality rates, pointing to a critical need for improved infection control measures
HIV Treatment at IDWeek 2024
Author: Maurice Policar1
1. New York City Health and Hospitals/Elmhurst, New York, USA
AT IDWeek 2024, held in Los Angeles, California, researchers converged from across the world to discuss the latest research surrounding HIV prevention and the most effective treatment for people with HIV (PWH).
LONG-ACTING INJECTABLE MEDICATION
The use of long-acting injectable medication (LAI) for the treatment of HIV infection was featured in many abstracts and presentation discussions at the event. Some addressed the (off label) use of bimonthly injectable cabotegravir/rilpivirine (CAB/RPV) for patients who were not virally suppressed. Although these agents have proven to be effective, original studies and FDA approval support their use only in people who have achieved viral suppression with oral agents.
Tara Vijayan, UCLA Health, Los Angeles, California, suggested the use of LAI as a possible intervention to help re-engage struggling patients, while at the same time emphasizing that this should ideally be coupled with intensive case management and addressing mental health, substance use, and other social issues.1
Elizabeth Hastie, University of California, San Diego, reviewed the interim results of the ongoing LATITUDE study, which showed that LAI in patients with adherence issues achieved a 14% lower failure rate compared with oral regimens. She also presented the results of a study from her clinic (Abstract 157), which showed a >80% suppression
rate at 24 and 48 weeks for viremic patients with adherence issues who were treated with CAB/RPV.2
These and other recent series suggest that CAB/RPV may be used for select people who are not virally suppressed, as a means of overcoming adherence issues seen with daily oral treatments. This has helped to balance some of the concerns about possible resistance that can occur with missed doses of long-acting agents. It is extremely important to note that positive outcomes have been demonstrated only in settings which provide intensive medical case management and extensive support for social issues. It is also unclear if similar outcomes can be achieved with patients who have higher baseline viral loads. In Hastie’s cohort, patients with viral loads over 10,000 were also treated with additional agents at the time of CAB/RPV initiation, some with lenacapavir (LEN). In the LATITUDE study, participants were offered financial incentives as motivation to complete an oral induction phase leading to viral suppression, before starting CAB/RPV.
>80% suppression rate at 24 and 48 weeks for viremic patients with adherence issues who were treated with CAB/RPV.
Poster 558, presented by James Brock, University of Mississippi Medical Center, Jackson, described nine patients with viremia, and with resistance-associated mutations to CAB or RPV, who were treated with LEN injection every 6 months along with bimonthly CAB/RPV. From a mean baseline viral load of >36,000, all patients maintained a viral load <200 for at least 26 weeks.3
Susan Koletar, Ohio State University, Columbus, reviewed results of a trial by Eron et al. evaluating the efficacy of LEN plus two different broadly neutralizing antibody preparations, all administered parenterally twice yearly. At least 90% maintained viral suppression at 6 months.4
Since many patients we treat today are older and have one or more comorbidities, reducing the pill burden by one tablet may not be much incentive to take bimonthly injections. Extending the interval to every 6 months may sway some patients to opt for LAI administered at the time of routine clinic visits.
HIV PREVENTION (PrEP)
Colleen Kelley, Emory University, Atlanta, Georgia, presented an updated analysis of studies examining the use of twice-yearly LEN injections as pre-exposure prophylaxis
LAI PrEP is an incredibly effective tool for HIV prevention, but one that is costly and requires additional staff resources
(PrEP), in cisgender women (PURPOSE 1) and in men who have sex with men, transgender individuals, and non-binary individuals (PURPOSE 2). Impressive results suggested 100% and 96% efficacy, respectively.5
Koletar reported on the pharmacokinetics of a new formulation of ultra long-acting cabotegravir/rilpivirine, which suggests effectiveness with extended dosing intervals of every 4 months.4
Raphael J. Landovitz, University of California, Los Angeles, warned of the rare Longacting Early Viral Inhibition (LEVI) Syndrome; a masking of the symptoms of acute HIV infection and possible suppression of HIV RNA and HIV Ab in persons with undiagnosed HIV infection using CAB for PrEP. Appearance of HIV Ab may be delayed up to 24 months.6
LAI PrEP is an incredibly effective tool for HIV prevention, but one that is costly and requires additional staff resources. It will be challenging to overcome disparities in access to LAI PrEP that exist in the US and globally.
TWO DRUG ANTIRETROVIRAL REGIMENS
The longstanding dogma of needing at least three drugs to effectively treat HIV infection is slowly giving way to a new paradigm. The inclusion of more potent integrase inhibitors has permitted the successful use of two-drug regimens to achieve viral suppression in many PWH.
In an interesting session formatted as a debate, speakers defended their position for or against switching virally suppressed PWH to two-drug regimens. Amesika Nyaku, Rutgers New Jersey Medical School, Newark, argued that we should routinely consider switching to two drugs in selected patients (who are not infected with the hepatitis B virus and who have no viral resistance to these agents), recounting a great many studies that revealed non-inferiority of dolutegravir + lamivudine, dolutegravir + rilpivirine, and CAB/RPV when compared with three-drug regimens.7 Arguing against this approach was Darcy Wooten, Washington University in St. Louis, Missouri, maintaining that you don’t want to “rock the boat”; and by doing so, you run the risk that something could go wrong: adverse events, insurance issues, new drug-drug interactions. She suggested that real-world results may not have the same outcomes seen in these clinical trials and that we have decades of experience with three-drug regimens.8
When switching from three to two drug regimens, we are usually removing tenofovir, which has been associated with renal and bone toxicity. Some would argue that using tenofovir alafenamide is safe and results in less tenofovir exposure than tenofovir
The longstanding dogma of needing at least three drugs to effectively treat HIV infection is slowly giving way to a new paradigm
dipivoxil fumarate. For PWH treated with abacavir + dolutegravir + lamivudine, a decision to change to a two-drug regimen may be a less complicated choice given that abacavir has at times been associated with an increased risk of cardiac events.
CARDIOVASCULAR DISEASE RISK CALCULATORS FOR PEOPLE WITH HIV
Poster 434 was presented by Caitlin Bettger, Brooke Army Medical Center, Fort Sam Houston, Texas, whose team compared several atherosclerotic cardiovascular disease (ASCVD) risk calculators in a population of 134 PWH seen between 2006–2019 who had known ASCVD events. They applied four risk calculators, including a newly published HIV-CARDIO-PREDICT, at 10, 5, and 2 years prior to the ASCVD event. HIV-CARDIO-PREDICT had the highest percentage of high-risk participants at any given time interval (>90%), performing significantly better than the other 3 more commonly used risk calculators.9
The REPRIEVE trial suggested benefits from statin use in lowering the risk of major cardiovascular events in PWH between ages 40–75 years
Evidence from the REPRIEVE trial suggested benefits from statin use in lowering the risk of major cardiovascular events in PWH between ages 40–75 years, and resulted in updated recommendations for statin use in this group. The treatment group had a 35% lower rate of events over 5 years in comparison with placebo, despite a median 10-year ASCVD risk score of only 4.5%. The availability of a more accurate risk calculator for PWH might allow us to better stratify risk for individuals within this group. More evaluation is needed to clarify the predictive ability of these calculators.
TREATMENT OF PNEUMOCYSTIS JIROVECII PNEUMONIA
Amy Bethel Peralta-Prado, Research Centre of Infectious Diseases, Instituto Nacional de Enfermedades Respiratorias, Mexico City, Mexico, described a randomized open-label trial in PWH and Pneumocystis jirovecii pneumonia (PCP). This compared the conventional 21-day steroid regimen with a shortened steroid regimen of 8 days for moderate and 14 days for severe PCP. There was no difference between the two groups in the incidence of immune reconstitution
References
1. Vijayan, T. Peace of mind: optimizing mental health in the HIV clinic. Utilizing clinic-based interventions to re-engage the struggling patient. [Presentation]. ID Week 2024, Los Angeles, California, USA, October 16-19, 2024.
2. Hastie E et al. Long-acting injectable HIV treatment in individuals with adherence challenges: real-world insights from southern California. Abstract 157. ID Week 2024, Los Angeles, California, USA, October 16-19, 2024.
3. Brock J et al. Long-acting injectable cabotegravir/rilpivirine plus subcutaneous lenacapavir effective in people with HIV and viremia and cabotegravir or rilpivirine resistanceassociated mutations. Poster 558. ID Week 2024, Los Angeles, California, USA, October 16-19, 2024.
4. Koletar S. State-of-the-Art HIV care and
inflammatory syndrome, mechanical ventilation, mortality, respiratory function testing, baseline and 90-day viral load, and CD4. The shortened steroid regimen group had a shorter hospital stay (12 versus 18 days).10
Although this was a small study of only 44 participants, it suggested non-inferiority for a shorter regimen of steroids, a meaningful change in the approach to PCP treatment for the first time since the early HIV epidemic. Given the advances made in the treatment of HIV since that time, using shorter courses of steroids is logical.
prevention. Treatment and prevention pipeline: what’s coming? [Presentation]. ID Week 2024, Los Angeles, California, USA, October 16-19, 2024.
5. Kelley C. Update on lenacapavir for PrEP: results from the interim analysis of PUPPOSE 1 and PURPOSE 2. Stateof-the-art HIV care and prevention. [Presentation]. ID Week 2024, Los Angeles, California, USA, October 16-19, 2024.
6. Landovitz R. What’s the latest data and experience on LAI treatment and prevention? State-of-the-Art HIV Care and Prevention. [Presentation]. ID Week 2024, Los Angeles, California, USA, October 16-19, 2024.
7. Nyaku A. Should we prioritize switching suppressed PWH to two drugs? – Pro. Status neutral squabbles: should we prioritize switching suppressed PWH to two drugs? And should we ramp up PrEP initiation in pharmacies? [Presentation].
ID Week 2024, Los Angeles, California, USA, October 16-19, 2024.
8. Wooten D. Should we prioritize switching suppressed PWH to two drugs? – Cro. Status neutral squabbles: should we prioritize switching suppressed PWH to two drugs? And should we ramp up PrEP initiation in pharmacies? [Presentation]. ID Week 2024, Los Angeles, California, USA, October 16-19, 2024.
9. Bettger C et al. Comparison of cardiovascular disease risk calculators in people with HIV in the US military natural history study. Abstract P-434. ID Week 2024, Los Angeles, California, USA, October 16-19, 2024.
10. Peralta-Prado A et al. Shortened steroid regimen in people living with HIV/AIDS with associated moderate and severe P. jirovecii pneumonia. Abstract P-440. ID Week 2024, Los Angeles, California, USA, October 16-19, 2024.
Respiratory Viral Infections: Highlights from IDWeek 2024
Author: Karen C Bloch1
1. Vanderbilt University Medical Center, Nashville, Tennessee, USA
IDWEEK 2024, held in Los Angeles, California, October 16th–19th, was an opportunity for the >12,000 attendees to hear about state-of-the-art scientific updates in infectious diseases. Respiratory viral infections were prominently featured, with myriad presentations on the epidemiology, prevention, and management of several important and emerging pathogens. Highlights of the program are listed below.
GLOBAL BURDEN OF VIRAL LOWER RESPIRATORY TRACT DISEASE
There are limited data on the healthcare burden of lower respiratory tract disease (LRTD), particularly outside the United States. Pratik Sinha (Washington University School of Medicine, St. Louis, Missouri) presented an elegant study1 using Bayesian modeling to estimate the global incidence of viral LRTD worldwide between 2010–2021. Not surprisingly, data from 2020–2021 reflected the tremendous impact of COVID-19, with total hospitalizations rising from 123 per 100,000 person years pre-pandemic to 388 per 100,000 person years. Yet even before the pandemic, annual increases in viral LRTDrelated hospitalizations were documented, with 90 million hospitalizations cumulatively between 2010–2019. The healthcare burden of viral LRTD, many of which are vaccine preventable, underscores the importance of global surveillance for early detection, implementation of preventive strategies, and expedited administration of antiviral therapy.
Another multi-national study analyzed seasonality of influenza and COVID-19 in
the United States, United Kingdom, and European Union in the post-pandemic era.2 This study, performed during the 2022–2023 and 2023–2024 seasons, found that influenza virus hospitalizations, which had diminished significantly during the pandemic, have returned to pre-pandemic levels. While influenza-related hospitalizations peak during winter months, there is less seasonality with SARS-CoV-2 hospitalizations. These findings highlight the need for maximizing coverage for both vaccine-preventable diseases.
THE EMERGING THREAT OF HIGHLY PATHOGENIC AVIAN INFLUENZA VIRUSES
The looming threat of highly pathogenic avian influenza (H5N1) was a hot topic, with H5N1 dominating the Opening Plenary Session on Navigating the Next Pandemic.3 The John Enders Lecture, presented by Tim Uyeki from the Centers for Disease Control and Prevention, National Center for Immunization and Respiratory Diseases focused on this emerging pathogen.4 While human cases of H5N1 have been recognized
since 1997, primarily in Asia and Africa, the current Clade 2.3.4.4b H5N1 virus is displaying several unique features that raise the threat level of an evolving pandemic.
So far in 2024, there have been 25 human cases of H5N1 in the United States, in contrast to a solitary case in the preceding 2 years. In all but one of these cases, there was an epidemiologic link to an animal reservoir. While infection in poultry has been well documented, a novel feature in the US is the association of human cases with infected dairy cattle. Clade 2.3.4.4b H5N1 virus has also been detected in other zoonotic hosts and is a cause of significant mortality to livestock and wild animals. Reassuringly, there are no documented cases of human-to-human transmission among US cases, although in a single patient no zoonotic exposure was documented, and the source of infection remains unknown.
The clinical presentation of the Clade 2.3.4.4b H5N1 virus also appears to be unique from that seen in previous years. Historically, H5N1 presents as a respiratory illness, with manifestations ranging from mild disease to severe pneumonia. The case fatality of H5N1 infections between 1997–2024 approached 50%. In contrast, hemorrhagic conjunctivitis has been the presenting symptom in all but one of the 2024 US cases, and there have been no fatalities. Yet the fact that human cases in
Data from 2020–2021 reflected the tremendous impact of COVID-19, with total hospitalizations rising from:
Compared to per 100,000 person years pre-pandemic
per 100,000 person year post-pandemic
the US have been relatively mild should not be met with complacency. Viral mutations have the potential to allow human-to-human transmission, which in a non-immune population could have catastrophic consequences.
Virologic and disease surveillance are key measures to monitor H5N1 activity. Alessandro Zulli (Stanford University, Stanford, California) presented a timely oral abstract5 outlining the utility of wastewater surveillance for identifying disease outbreaks. He and his colleagues reported on an investigation following detection of an out-of-season increase in influenza A concentrations in wastewater in Amarillo, Texas. Sequencing confirmed that this was
due to H5N1 virus, and the authors were able to localize the source to a specific dairy processing plant. Notably, viral detection in wastewater predated confirmed bovine and human cases by approximately 1 month, suggesting that testing of material from sewage treatment facilities may serve as a sentinel surveillance system for zoonotic infections and community transmission.
Testing of material from sewage treatment facilities may serve as a sentinel surveillance system for zoonotic infections and community transmission
RESPIRATORY SYNCYTIAL VIRUS IMMUNIZATION IN ADULTS
Respiratory syncytial virus (RSV), long known to be a pathogen in young children, is now increasingly recognized to cause serious disease in older adults and those with medical comorbidities. This led the CDC Advisory Committee on Immunization Practices (ACIP) to recommend universal RSV vaccination among adults 60 years and older in June 2023 (later revised in June 2024 to age 75 and older).
A year into the approval of two RSV vaccines (RSV vaccine bivalent and RSV vaccine adjuvanted) for use in adults, post-marketing data was presented at IDWeek. Heidi Ransohoff (Los Angeles Department
References
1. Sinha P et al. Global Incidence of Viral Lower Respiratory Tract Disease (LRTD) episodes and hospitalizations (2010–2021), IDWeek 2024, October 16-19, 2024, Los Angeles, CA.
2. Shaikh N et al. Revealing seasonal patterns in the post-pandemic era: a comparative analysis of burden and seasonality of influenza and COVID-19 in Europe and the US, IDWeek 2024, October 16-19, 2024, Los Angeles, CA.
of Public Health, Los Angeles, California) reported a study6 by the Los Angeles County Department of Public Health evaluating the real-world efficacy of vaccination in elderly adults. During the study period, they identified almost 2,300 incident cases of RSV in adults aged 60 and older. Crosslinking these cases with the vaccine registry, the authors reported that the risk of RSV infection among unvaccinated individuals in the target population was 5.1 times higher than among the vaccinated cohort, providing compelling data supporting vaccine efficacy.
H. Keipp Talbot (Vanderbilt University, Nashville, Tennessee) presented data on FDA post-licensure adverse event monitoring for these two vaccines.7 Among the more than 2 million adults who had received the RSV vaccine, there were 24 cases of Guillain-Barré syndrome. Using positive predictive value adjusted analysis, this translated to a risk of 10–25 cases per million doses. While elevated incidence of Guillain-Barré syndrome was only statistically significant for one of the vaccines, Talbot urged caution in directly comparing the side effect profile due to the small numbers of patients affected.
Among the more than 2 million adults who had received the RSV vaccine, there were 24 cases of Guillain-Barré syndrome. Using positive predictive value adjusted analysis, this translated to a risk of 10–25 cases per million doses.
3. Nuzzo J et al. Opening plenary: navigating the next pandemic: policy and practice integration, IDWeek 2024, October 16-19, 2024, Los Angeles, CA.
4. Uyeki TM. John F. Enders Lecture. Human infections with highly pathogenic avian influenza A (H5N1) viruses and pandemic influenza threats, IDWeek 2024, October 16-19, 2024, Los Angeles, CA.
5. Zulli A et al. Detection of hemagglutinin H5 influenza A virus sequence in municipal waterwater solids during an outbreak of avian influenza. IDWeek
2024, Abstract 309, October 16-19, 2024, Los Angeles, CA.
6. Ransohoff H et al. Respiratory syncytial virus (RSV) infections among persons aged 60 years and older, by vaccination status, reported via electronic laboratory reporting (ELR) – Los Angeles County (LAC), California, IDWeek 2024, October 16-19, 2024, Los Angeles, CA.
7. H. Keipp Talbot. RSV prevention at 1 year, IDWeek 2024, October 16-19, 2024, Los Angeles, CA.
A Case for Caution: Breaking Down Antimicrobial Resistance
AS ANTIMICROBIAL resistance grows into a global crisis, effective treatment strategies for drug-resistant infections are more essential than ever. Robert Bonomo, Case Western Reserve University School of Medicine, Cleveland, Ohio, recently shared his expert recommendations on navigating these complex cases. Using a real-world example of a young medical student with a highly resistant Pseudomonas aeruginosa infection, Bonomo explored key approaches to managing some of the most challenging pathogens encountered in clinical practice today. Bonomo’s recommendations offer a roadmap for clinicians facing infections caused by multidrug-resistant organisms, emphasizing tailored, evidence-based strategies for tackling resistant gram-negative pathogens.
A PECULIAR CASE
Bonomo began his talk by describing an interesting real-world case of a 24-year-old medical student who was run over with his own car and sustained burn injuries on his back as a result of being trapped under the manifold. After a few days in the hospital, the medical student developed fever and chills, indicating that the wound had become infected. Blood cultures indicated P. aeruginosa, susceptible only to gentamicin. That raises the question for physicians: What is the best course of action in this case?
TREATMENT STRATEGIES IN DIFFERENT PATHOGENS
Bonomo continued describing the most common and problematic gramnegative pathogens physicians are likely to encounter in cases such as this. This included extended-spectrum β-lactamaseproducing organisms (ESBL), AmpC β-lactamase (AmpC), carbapenem-resistant
Enterobacteriaceae (CRE), difficult-to-treat (DTR) P. aeruginosa, Carbapenem-Resistant Acinetobacter baumannii (CRAb), and Stenotrophomonas maltophilia (Steno).
EXTENDED-SPECTRUM β-LACTAMASE
In cases of ESBL infections, ceftriaxone and other cephalosporins are commonly used for infections where ESBL-producing Enterobacteriaceae (ESBL-E) are not yet suspected, such as uncomplicated urinary tract infections (UTIs). Uncomplicated cystitis caused by ESBL-E can be effectively managed with nitrofurantoin and trimethoprim-sulfamethoxazole (TMPSMX), with ciprofloxacin, levofloxacin, and carbapenems serving as alternatives. However, Bomono stressed that the use of these alternatives is discouraged when nitrofurantoin and TMP-SMX are effective, as higher generation antibiotics should be reserved for more severe cases to maintain their effectiveness.
Bonomo’s recommendations offer a roadmap for clinicians facing infections caused by multidrug-resistant organisms
In cases of pyelonephritis and complicated UTIs (cUTIs) caused by ESBL-E, the recommended antibiotics are TMPSMX, ciprofloxacin, or levofloxacin, while ertapenem, meropenem, and imipenemcilastatin are preferred when resistance or toxicities preclude the use of TMP-SMX or fluoroquinolones. Bonomo also mentioned that aminoglycosides can be an option for an alternative treatment of pyelonephritis and cUTI; however, it is best to avoid if possible, as in renal infections. These do act well in the kidneys and sterilizing the urine.
For ESBL-E infections outside of the urinary tract, the recommended antibiotics are meropenem, imipenem-cilastatin, or ertapenem. In patients who are critically ill or experiencing hypoalbuminemia, meropenem or imipenem-cilastatin are the preferred carbapenem. Bonomo recommended administering oral TMP-SMX, ciprofloxacin, or levofloxacin after clinical responsiveness, if achieved, provided that the susceptibility to these antibiotic agents is demonstrated.
Additionally, it is recommended that the administration of piperacillin-tazobactum be avoided in ESBL-E infection outside the urinary tract, even if susceptibility to the drug is demonstrated. However, if the drug is initiated as an empiric therapy before the organism is identified as ESBL-E, and the patient demonstrates clinical improvement, no change or extension of antibiotic therapy is necessary.
The avoidance of piperacillin-tazobactum stemmed from the MERINO trial, as Bonomo described, which showed evidence that meropenem is preferable to piperacillintazobactam for ESBL infections due to better clinical outcomes.1 Bonomo also mentioned that cefepanime is not recommended for treatment of ESBL-E infections, pyelonephritis, and complicated UTIs, as ESBLs can break down cefapime. However, similar to piperacillin-tazobactum, if it is administered as empiric therapy, it should not be changed or extended.
Bonomo speculated that the results of this trial will challenge the recommendations that were implemented as a result of the MERINO trial.
On the other hand, Bonomo explained that the PeterPen trial, currently underway in Europe, will make different assumptions about using β-lactamase inhibitors than the MERINO trial. In short, the article by Bitterman et al.2 reported on the design of the PeterPen trial, where the rationale for further replication of randomized controlled trials was the threefold difference in mortality rates between the two arms in the MERINO trial. Such striking difference was never previously observed in a randomized comparison between antibiotics.2 Bonomo speculated that the results of this trial will challenge the recommendations that were implemented as a result of the MERINO trial.
AMPC β-LACTAMASE
Moving to AmpC β-lactamase (AmpC), Bomono explained that AmpC-producing organisms, such as the Enterobacter species, present unique challenges. He went on to explain why ceftriaxone is not advisable for these infections, as it can induce AmpC production, rendering the drug ineffective. However, cefepime can be an option for strains with lower AmpC production. While carbapenems are safer for higher AmpC production due to their resistance to AmpC enzyme degradation.
CARBAPENEM-RESISTANT ENTEROBACTERIACEAE
Moving to CREs, Bomono explained that for infections caused by Enterobacterales isolates that exhibit susceptibility to meropenem and imipenem-cilastatin, but are not susceptible to ertapenem, the preferred treatment approach is the use of extendedinfusion meropenem, or imipenem-cilastatin, if no carbapenemase gene has been identified.
For UTIs caused by CRE, agents such as nitrofurantoin, TMP-SMX, ciprofloaxin, or levofloaxin are preferred when possible. Additionally, a single dose of an aminoglycoside is an alternative option
for uncomplicated cystitis caused by CRE. For more systemic infections, newer agents such as ceftazidime-avibactam and meropenem-vaborbactam are available, with cefiderocol as an additional option in some cases. However, fosfomycin use should be limited to uncomplicated CRE cystitis caused by Escherichia coli, as the fosA gene can hydrolyze Fosfomycin and may lead to clinical failure.
In cases of pyelonephritis and cUTIs caused by CRE, TMP-SMX, ciprofloxacin, or levofloxacin are the preferred treatment options, as well as ceftazidime-avibactam, meropenem-vaboractam, imipenemcilastatin-relebactam, and cefiderocol.
MULTIDRUG-RESISTANT AND DIFFICULT-TO-TREAT PSEUDOMONAS AERUGINOSA
Bonomo explained that physicians who encounter multidrug-resistant and DTR P. aeruginosa should use traditional noncarbapenem β-lactam agents, such as piperacillin-tazovactam, ceftazidime, and cefepime, when susceptibility is demonstrated. In resistant cases, the recommended agents are ceftolozanetazobactam, ceftazidime-avibactam, imipenem-cilastatin-relebactam, and cefiderocol. These agents are also recommended for pyelonephritis and cUTIs, and infections outside of the urinary tract caused by DTR P. aeruginosa.
A PECULIAR CASE: CONTINUED
Circling back to the medical student, molecular analysis revealed blaVIM-2, a gene that encodes the metallo-β-lactamase enzyme, and can break down a wide range of β-lactam antibiotics such as carbapenems. The analysis also revealed resistance to ceftolozane-avibactam, meropenem-vaborbactam, imipenemcliastain-relebactam, and cefepimeenmerazobactam. However, susceptibility
to cefiderocol was revealed and the patient recovered after a 14-day therapy with cefiderocol and gentamicin.
CARBAPENEM-RESISTANT ACINETOBACTER
In discussing CRAb, Bonomo emphasized that cefiderocol has become a key treatment option. However, he cautioned against using cefiderocol as a monotherapy for CRAb infections, advising instead to combine it with another antibiotic to improve effectiveness. This approach, he explained, may help prevent the rapid development of resistance, a significant risk when cefiderocol is used alone against highly resistant strains.
STENOTROPHOMONAS MALTOPHILIA
Turning to Steno, Bonomo noted its inherent resistance to many antibiotics, making it especially challenging to treat. He highlighted TMP-SMX as the standard treatment but acknowledged that some resistant strains might require alternative options. In such cases, high-dose minocycline in combination
14 Days
References
The patient recovered after a 14-day therapy with cefiderocol and gentamicin
1. Harris PNA et al. MERINO Trial Investigators and the Australasian Society for Infectious Disease Clinical Research Network (ASID-CRN). Effect of piperacillin-tazobactam vs meropenem on 30-day mortality for patients with E coli or Klebsiella pneumoniae bloodstream infection and ceftriaxone resistance: a randomized clinical trial. JAMA. 2018;320(10):984-94. Erratum in: JAMA. 2019;321(23):2370.
Bonomo stressed the importance of antibiotic stewardship as a cornerstone of modern medicine
with TMP-SMX or levofloxacin can be effective. Additionally, he mentioned that the combination of ceftazidime-avibactam and aztreonam could bypass some resistance mechanisms in Stenotrophomonas, making it a useful strategy for treating more complicated infections.
CONCLUSION
In his closing remarks, Bonomo stressed the importance of antibiotic stewardship as a cornerstone of modern medicine. He highlighted that while novel treatments and tailored approaches are essential for combating resistant infections, preserving the effectiveness of existing antibiotics is equally crucial. Thoughtful stewardship, using antibiotics judiciously, and avoiding broad-spectrum agents when narrowspectrum drugs suffice, help curb the emergence of resistance. Bonomo reminded clinicians that every treatment decision contributes to the global fight against antimicrobial resistance, emphasizing that with careful management, the medical community can continue to protect the efficacy of antibiotics for future generations.
2. Bitterman R et al. Piperacillintazobactam versus meropenem for treatment of bloodstream infections caused by thirdgeneration cephalosporin-resistant Enterobacteriaceae: a study protocol for a non-inferiority open-label randomised controlled trial (PeterPen). BMJ Open. 2021;11(2):e040210.
A Global Approach to Tackling Emerging Infectious Diseases
THE PAST two decades have been marked by the accelerated emergence and re-emergence of infectious diseases worldwide, challenging the optimistic belief that humans had infectious diseases under control. In an enlightening session presented at IDWeek 2024, held in Los Angeles, California, from October 16th–19th, three experts offered a global approach to identifying and responding to emerging infectious diseases, providing multi-disciplinary perspectives that encompassed ecology, healthcare, and diagnostics.
AN ECOLOGICAL PERSPECTIVE ON DISEASE EMERGENCE
Current ongoing disease threats, such as influenza, Marburg virus, mpox, and Oropouche virus, serve as a reminder that the global issue of emerging diseases is here to stay, opened Marion Koopmans, Erasmus Medical Center, Rotterdam, the Netherlands.
In the era of the Anthropocene, where health is increasingly affected by the impact of humans on the planet, changes in demographics, climate, land use, and technology are key drivers of zoonotic disease emergence. The global footprint of human presence, including large scale deforestation, biodiversity loss, and animal farming with low biosecurity, increases the
Changes in demographics, climate, land use, and technology are key drivers of zoonotic disease emergence
probability of a spillover event, where a species-specific pathogen is transmitted to a new host. This was recently observed with the highly pathogenic avian influenza A virus, which spilled over from wild birds to mammals. The transition from low pathogenic to highly pathogenic avian influenza A can be considered a man-made problem, said Koopmans, as the accumulation of mutations and genetic reassortment that drive changes in pathogenicity mainly occur on large density poultry farms.
These spillovers can be linked to ecotones, “where normally distinct ecosystems converge, leading to novel interactions and risks,” explained Koopmans. A 2010 study by Rimoin et al.1 examined mpox spillover events in Democratic Republic of Congo, finding that the risk of mpox infection in humans was significantly higher in ecotones spanning deforested areas. This should have warned us of the current fast-expanding, multi-country mpox outbreak, stated Koopmans. She added that different mpox clades are derived from repeated zoonotic spillovers and require very different types of action, complicating control of disease spread.
Furthermore, the dissemination of a pathogen between humans is amplified by global travel and trade, as well as poor infrastructure in densely populated areas, continued Koopmans. This was seen with Ebola, which remained a localized outbreak until major urban slums in West Africa became hotspots for viral dispersal from 2014–2016.
Finally, changes in human demographics can also alter disease impact: an ageing population with increased comorbidities is at higher risk for severe illness from emerging diseases. This was observed during the COVID-19 pandemic, where SARS-CoV-2 disproportionately affected vulnerable populations.
Planetary Health, which addresses the impacts of human disruptions on life on Earth, and One Health, which aims to sustainably balance the health of people, animals, and ecosystems, both focus on understanding the root causes of disease emergence, integrating new solutions from a transdisciplinary perspective. This holistic approach to disease prevention will be crucial to get ahead of ongoing and future disease outbreaks, concluded Koopmans.
The transition from low pathogenic to highly pathogenic avian influenza can be considered a man-made problem
A CLINICAL APPROACH TO EMERGING INFECTIOUS DISEASES
Peter Rabinowitz, University of Washington, USA, transitioned from an ecological to a clinical perspective on emerging infectious diseases, presenting a series of informative clinical cases related to environmental changes.
The first case was a 55-year-old male complaining of abundant tick bites, fever, and abdominal pain during a summer in Massachusetts. Despite no rash and negative Lyme disease test, a physical exam revealed splenomegaly, and complete blood count test showed anemia and thrombocytopenia. A diagnosis of babesiosis was made. Rabinowitz emphasized that global warming is having profound effects on vector-borne disease transmission. For instance, Aedes aegypti
mosquitos are extending their range, driving dengue spread. “The population at risk of dengue is going to continue to increase,” warned Rabinowitz. As reflected in this case, temporal changes in tick-borne disease are also being observed.
The second case was of construction workers on a solar power installation site in the Southwest, who were seen in primary care complaining of fatigue, night sweats, weakness, difficulty breathing, fever, cough, joint/muscle pain, and weight loss. They noted that, around the construction site, recent drought had been followed by heavy rain. After serology, a diagnosis of coccidioidomycosis was made. Rabinowitz explained that an increase in droughts can alter potential vector breeding sites, leading to a heightened risk of coccidioidomycosis concentrated within a specific calendar period, related to periods of precipitation following droughts.
The third case was a 44-year old female returning from a recent trip to East Africa, where she was in contact with flooded areas. She complained of fever, nausea, and abdominal discomfort without diarrhea, and a physical exam revealed conjunctival reddening and abdominal tenderness. Blood tests showed elevated white count, low platelets, and elevated liver function tests. The patient was hospitalized for acute hepatitis, and a diagnosis of leptospirosis was made. An increase in floods, said Rabinowitz, heightens the prevalence of waterborne pathogens like Leptospira bacteria, as well as Vibrio vulnificus, a bacterium causing life-threatening septicemia and severe wound infections,
and Vibrio cholerae, responsible for cholera. Floods also create a water habitat for breeding of vector-borne diseases.
“How can we be astute clinicians?” asked Rabinowitz. Taking medical history is crucial, including collecting data on animal contacts and environmental exposures that could point to vector-borne or zoonotic diseases. Specific weather events, like heat, drought, or flooding, should also be considered. He added that risk maps are available online to evaluate flood risks or arbovirus detection, and efforts should be made to integrate these into electronic health records. Furthermore, these environmental determinants should be combined with social determinants to assess patient vulnerability.
While performing a physical examination, it is important to remember the pathognomonic signs of different infectious diseases, such as reddening of the eye in leptospirosis. Rabinowitz added that key findings, like rashes, jaundice, or lymphadenopathy, should give hints to clinicians that a disease is “different from the usual”.
With diagnostic tests, Rabinowitz emphasized the value of coming up with a pre-test probability to inform testing strategies and allow for a more judicious use of molecular tools. He also urged clinicians to be aware of the limitations of serology, such as cross-reactivity and time lag.
“An astute clinician is like Sherlock Holmes,” concluded Rabinowitz. By having a wide differential and thinking broadly to develop
targeted diagnostic strategies, clinicians can be the first to detect an emerging infection. Keeping up to date with the patient is essential, as well as communicating with other healthcare providers and veterinarians. Finally, alerting public health authorities when new cases are detected will be crucial for effective infection prevention and control.
NOVEL DIAGNOSTICS FOR EMERGING INFECTIOUS DISEASES
Paul Eder, National Institute of Allergy and Infectious Diseases (NIAID), Maryland, gave a comprehensive overview of current challenges and solutions in the development of diagnostics for emerging infectious diseases, with a focus on work conducted by the NIAID to tackle high-priority issues, including zoonotic viral infections, resistant fungal infections, nosocomial antimicrobial resistant (AR) bacterial infections, and community AR sexually transmitted infections.
Among the numerous NIAID clinical research networks, Eder drew attention to the Centers for Research on Emerging Infectious Diseases (CREID), a global network of multidisciplinary investigations into how and where viral pathogens emerge and cause disease outbreaks. Now active for 5 years, the CREID funds research programs across the globe, reaching over 30 countries and 47 research sites beyond the USA and across South America, Central Africa, and Southeast Asia. The studies focus on developing diagnostic solutions, such as monoclonal antibodies and novel antigens for antigendetection tests, for emerging pathogens like Ebola, Marburg virus, and mpox.
NIAID is seeing the expansion of diagnostic product development programs to maximise public health readiness ahead of emerging infectious diseases. Eder presented three powerful, innovative in vitro diagnostic systems for identification and classification of emerging pathogens. First, the fully automated ESKAPE+ detection system (Clear Labs, San Francisco, California) uses
Now active for 5 years, the CREID funds research programs across the globe, reaching over 30 countries and 47 research sites beyond the USA and across South America, Central Africa, and Southeast Asia
next generation sequencing to identify AR bacteria directly from the blood, including Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp. (ESKAPE pathogens). Second, a semi-automated bacterial and fungal detection system (Siemens Healthineers, Erlangen, Germany) can identify and sequence pathogen DNA directly from the blood, and identify its antimicrobial resistance marker from a large number of primer sets in under 6 hours. Finally, the most recently funded product, a singlecell RNA response profiling system (GE HealthCare, Chicago, Illinois) for antimicrobial susceptibility testing can identify small changes in growth of microbial RNA in the presence or absence of antibiotics, generating an antimicrobial susceptibility testing phenotype in less than 2 hours
Eder emphasized key challenges to overcome in future diagnostic systems, including broader pathogen identification capabilities, and faster and better characterization of antimicrobial resistance. He added that faster, simpler, and more sensitive antigen detection tests are also needed for earlier intervention in community settings. As emerging infectious agents evolve, the development of diagnostic tools needs to co-evolve to keep pace, concluded Eder.
References
1. Rimoin AW et al. Major increase in human monkeypox incidence 30 years after smallpox vaccination campaigns cease in the Democratic Republic of Congo. Proc Natl Acad Sci USA. 2010;107(37):16262-16267.
Ibalizumab’s Role in Multidrug-Resistant HIV
This poster was presented at IDWeek 2024, held in Los Angeles, California, USA, October 16th−19th .
Poster author: Princy Kumar1
1. MedStar Georgetown University Hospital, Washington DC, USA
Disclosure: Kumar has received institutional research funding from ViiV Healthcare/GSK, Gilead Sciences, Inc., Merck, and Theratechnologies Inc.; consultancy/advisory board fees from ViiV Healthcare/GSK, Gilead Sciences, Inc., and Merck; and publicly owned stock in Merck, Pfizer, Gilead Sciences, Inc., Johnson & Johnson, GSK, and Moderna.
Acknowledgements: Medical writing assistance was provided by Eleanor Roberts, Beeline Science Communications, Ltd, UK.
Disclaimer The article content and views expressed herein are those of the presenter and Theratechnologies.
Support: The poster presentations and publication of this article were supported by Theratechnologies, Inc.
Meeting Summary
PARTNERSHIP
Although treatment for HIV has advanced considerably over the decades, there are still people with HIV that is resistant to multiple antiretroviral therapies (ART). Ibalizumab, a humanized IgG4 monoclonal antibody that gained orphan status in 2018, is a post-attachment inhibitor whose efficacy for people with multidrugresistant (MDR) HIV has been demonstrated in Phase II and III trials. The Prospective and Retrospective Observational Study of Multidrug-Resistant Patient Outcomes with and without Ibalizumab in a Real-World Setting: United States (PROMISE-US) is an ongoing study that will investigate long-term efficacy and durability of ibalizumab plus an optimized background regimen (OBR). In the poster discussed here, presented at IDWeek 2024, examination of baseline demographics showed that individuals prescribed ibalizumab (IBA group) had similar mean age, sex, race, and duration since diagnosis of HIV to those on regimens that did not include ibalizumab (non-IBA group). However, mean baseline HIV RNA copies/mL were much higher and CD4+ T cells/mm3 lower in the IBA group compared with the non-IBA group, and highest/lowest at baseline in a subset of IBA group patients who were also prescribed the capsid inhibitor lenacapavir. OBR also differed between groups. These results highlight the HIV-related characteristics of individuals who are more likely to be prescribed ibalizumab.
PHARMA
Introduction
In the USA, around 1.1 million people are currently diagnosed with HIV.1 While treatment has advanced greatly,1 a recent analysis including nearly 24,000 individuals found that 9.1% had limited and/or exhausted treatment options.2 Typically, this cohort has multiple ART class exposure, which may be due to HIV with drug resistance,2,3 decreased sequential regimen potency,2,4 adverse effects,2,5 and/ or suboptimal treatment adherence.6 As treatment choice becomes limited, maintaining virologic control can be challenging and may lead to grave clinical outcomes.1
The humanized IgG4 monoclonal antibody ibalizumab binds CD4 extracellular domain 2, preventing CD4-HIV envelope glycoprotein 120-induced conformational changes and inhibiting viral entry.7 Ibalizumab lacks cross-resistance with other ARTs, including entry inhibitors.8 Ibalizumab’s efficacy in combination with an OBR has been demonstrated in Phase II and III trials where administration led to large decreases in viral load, including in people with MDR HIV.7,9,10
PROMISE-US Real World Study of Ibalizumab
While ibalizumab gained orphan drug status in 2018,11 clinical trial study numbers were relatively low and administration time was relatively short (up to 48 weeks).4,7,9,10
PROMISE-US is an ongoing, Phase IV, multicenter, retrospective and prospective, observational, non-interventional, registry study in adults with MDR HIV.12 This 3-year, real-world study will investigate long-term efficacy and durability of ibalizumab plus an OBR (IBA group), compared to matched patients not receiving IBA (non-IBA group). The first patient visit was in May 2022, with retrospective data collected from May 2018. Data presented in this poster at IDWeek 2024, collected up to November 8th 2023, provided an insight into the HIV-related status of adults with MDR HIV.
At baseline (latest treatment change event), non-IBA (n=70) and IBA (n=42) group participants had similar mean (standard deviation [SD]) ages of 58.5 (9.71) and 53.8 (10.89) years. Participants were predominantly assigned male at birth (71.4% and 81.0%, respectively), were White (48.6% and 47.6%, respectively) or Black or African American (48.6% and 45.2%, respectively), and were non-Hispanic (84.3% and 78.6%, respectively).
Notable was that mean (SD) duration since HIV+ diagnosis was long and was similar between groups: 26.4 (8.87) years for non-IBA group and 27.7 (8.73) years for IBA group. While respective medians were also similar (28.3 and 30.9 years, respectively), examination of interquartile ranges (IQR; 4.68, 42.42 years and 5.29, 38.84 years, respectively) revealed that some individuals had only been diagnosed for relatively few years while others had lived with HIV for several decades.
As can be seen in Figure 1, at enrollment, mean HIV RNA copies/mL were lowest in the non-IBA group, though still indicative of some virologic failure (>200 copies/mL).13 Viral load was highest in a subset of 12 IBA group participants who, due to more limited ART choices, additionally received the first-in-class capsid inhibitor lenacapavir (IBA/LEN group), a parenteral agent recently approved for people with MDR HIV.14 Of note, SDs in all groups were high, and along with medians (IQR) of 19 (0, 148,000) copies/mL in the non-IBA group, 44 (0, 1,200,000) copies/ mL in the IBA group, and 108 (19, 1,200,000) copies/mL in the IBA/LEN group, highlighted between and within group heterogeneity.
Figure 1 shows how mean and median CD4+ T cells/mm3 were highest in the non-IBA group (571 and 579 cells/mm3, respectively) and were within the healthy range of 500−1500 cells/mm3,15 However, both SD (302 cells/mm3) and IQRs (34, 1,436 cells/mm3) indicated some individuals not receiving ibalizumab were below this range. Respective mean CD4+ T cells/mm3 (Figure 1; SD: 279 and
†Subgroup
211 cells/mm3, respectively) and medians [IQR] (283 [13, 1,231] cells/mm3 and 311 [32, 609] cells/mm3, respectively) were similar in the IBA and IBA/LEN groups and indicated that many participants had low counts, with some into the immunocompromised range (<200 cells/mm3).15
The OBR at enrollment for each group is reported in Table 1. For both non-IBA and IBA groups, this primarily included an integrase strand transfer inhibitor, a non-nucleotide reverse transcriptase inhibitor, and/or a protease inhibitor. Two participants in the non-IBA group also received lenacapavir.
Mean [SD] combined genotypic sensitivity score, a measure of ART resistance,16 was lowest in the non-IBA group (2.2 [0.75]), compared with the IBA (2.7 [0.96]) and IBA/LEN (2.9 [1.4]) groups. Commercial resistance testing is not available for ibalizumab, fostemsavir, or lenacapavir, so they are considered fully active and
were not included in this score. As such, the authors postulated that “this measure may overestimate regimen sensitivity in IBA group participants who were more likely to have these in their regimens.”
At the time of data collection, around 80% in the IBA group had been taking ibalizumab for >12 months, and around 60% for >24 months. Ibalizumab was well-tolerated with no infusion reactions.
In conclusion, even though IBA group participants had higher viral loads and lower CD4 cell counts at baseline than the non-IBA group, ibalizumab (with or without lenacapavir) demonstrated good durability, with many remaining on this therapy for ≥2 years. PROMISE-US will add to clinical trial results, help further characterize the efficacy and safety profile of ibalizumab plus OBR, and help guide treatment selection for a population with a high unmet need to maintain virological control.
of IBA cohort. IBA: ibalizumab; LEN: lenacapavir.
Figure 1: Mean (standard deviation) HIV-1 RNA copies/mL and CD4+ T cells/mm3 at enrolment.
Table 1: Optimized background regimen by group.
Ibalizumab and lenacapavir, n (%)
*Due to missing data, optimized background regimen is only reported for the subset of participants with complete data entry.
1. Centers for Disease Control and Prevention (CDC). HIV Surveillance Report: Diagnoses, Deaths, and Prevalence of HIV in the United States and 6 Territories and Freely Associated States, 2022. 2024. Available at: https:// stacks.cdc.gov/view/cdc/156509. Last accessed: 24 October 2024.
2. Mocroft A et al. Heavy antiretroviral exposure and exhausted/limited antiretroviral options: predictors and clinical outcomes. AIDS. 2024;38(4):497-508.
3. Wensing AM et al. 2022 update of the drug resistance mutations in HIV-1. Top Antivir Med. 2022;30(4):559-74.
4. Gathe JC et al. Efficacy, pharmacokinetics, and safety over 48 weeks with ibalizumab-based therapy in treatment-experienced adults infected with HIV-1: A phase 2a study. J Acquir Immune Defic Syndr. 2021;86(4):482-9.
5. Li H et al. The role of ARV associated adverse drug reactions in influencing adherence among HIV-infected individuals: a systematic review and qualitative meta-synthesis. AIDS Behav. 2017;21(2):341-51.
6. Abdulrahman SA et al. HIV treatment adherence - a shared burden for patients, health-care providers, and other stakeholders. AIDS Rev. 2019;21(1):28-39.
7. Emu B et al. Phase 3 study of ibalizumab for multidrug-resistant HIV-1. N Engl J Med. 2018;379(7):645-54.
8. Rose R et al. Clinical evidence for a lack of cross-resistance between temsavir and ibalizumab or maraviroc. AIDS. 2022;36(1):11-18.
9. TaiMed Biologics Inc. Ibalizumab plus optimized background regimen in treatment-experienced patients with multi-drug resistant HIV-1 (TMB-311). NCT02707861. https://clinicaltrials.gov/ study/NCT02707861?term=TMB311%20&rank=1.
10. DeJesus E et al. Efficacy and safety of two fixed doses of ibalizumab plus optimized background regimen in treatment-experienced HIVpositive individuals. J Acquir Immune Defic Syndr. 2024;DOI:10.1097/ QAI.0000000000003524.
11. U.S. Food and Drug Administration. FDA approves new HIV treatment for patients who have limited treatment options. 2018. Available at: https:// www.fda.gov/news-events/pressannouncements/fda-approves-new-hivtreatment-patients-who-have-limitedtreatment-options.
Last accessed: 24 October 2024.
12. Theratechnologies. A prospective and retrospective observational study of multidrug-resistant patient outcomes with and without ibalizumab (PROMISEUS). NCT05388474. https://clinicaltrials. gov/study/
Reducing Cardiovascular Risk in HIV: The Unseen Impact of Visceral Fat
The posters were presented at IDWeek 2024, held in Los Angeles, California, USA, October 16th−19th .
Presenters: Karam Mounzer,1 Colleen McGary2
1. Philadelphia FIGHT Community Health Centers, Philadelphia, Pennsylvania, USA
2. Theratechnologies, Montreal, Canada
Disclosure: Mounzer is an advisor for, and has received research funding from, Theratechnologies; is a consultant for Epividian, Triohealth, Gilead Sciences, ViiV Healthcare, and Merck; and part of Speaker's Bureau for Gilead Sciences, ViiV Healthcare, and Merck. Mounzer's institution has received grants for Trials Support from Gilead Sciences, ViiV Healthcare, and Merck. McGary is an employee of Theratechnologies.
Acknowledgements: Medical writing assistance was provided by Eleanor Roberts, Beeline Science Communications, Ltd, UK.
Disclaimer The article content and views expressed herein are those of the presenters and Theratechnologies.
Keywords: Antiretroviral therapy (ART), cardiovascular disease (CVD), comorbidities, excess visceral abdominal fat (EVAF), growth hormone, people with HIV (PWH).
Support: The poster presentations and publication of this article were supported by Theratechnologies, Inc.
Meeting Summary
While modern antiretroviral therapy (ART) for people with HIV (PWH) increases life expectancy, there is still an increased risk of developing cardiovascular disease (CVD) in this population. As one factor associated with this increased risk is excess visceral abdominal fat (EVAF), the Visceral Adiposity Measurement and Observations Study (VAMOS) aimed to assess the impact of EVAF on CVD risk in PWH taking modern ART. Participants were grouped according to visceral adipose tissue (VAT) surface area <130 cm2 (non-EVAF group) or ≥130 cm2 (EVAF group), quantified by CT scan. Findings presented at IDWeek 2024 revealed significant differences between EVAF and non-EVAF groups in 10-year atherosclerotic CVD (ASCVD) risk score, as well as many of their individual components. VAMOS also showed correlations between increasing VAT surface area and increasing 10-year ASCVD risk score and insulin resistance measures.
PHARMA PARTNERSHIP
Accordingly, VAT may represent a targetable factor to reduce ASCVD risk. Also shown was an inverse relationship between growth hormone (GH) levels and VAT surface area. As GH reductions related to obesity are associated with elevated CVD risk, increasing GH levels may consequently reduce ASCVD risk score. Analysis of two Phase III trials of the GH-releasing hormone (GHRH) analogue tesamorelin, which can significantly reduce VAT in PWH, was also presented at IDWeek 2024. A significant overall trend in 10-year ASCVD risk score reduction was shown in tesamorelin-treated participants, around half of which were already taking lipid lowering therapies. This suggests a benefit of targeting and reducing EVAF to further impact ASCVD risk.
Introduction
The advent and increased availability of ART has led to dramatic reductions in HIV-related deaths for PWH,1,2 leading to significantly greater life expectancy.3 Modern ART is more potent, has lower adverse event profiles, and is easier to take than early treatments.4,5 However, despite these advances promoting increased rates of viral suppression, PWH have an increased risk of cardiovascular (CV)-related diseases compared with the general population, even after excluding traditional risk factors such as age, BMI, diabetes, substance abuse, and hypertension.6 For example, in PWH, increased incidences have been shown of subclinical coronary plaques,7 coronary artery disease,8 myocardial infarction,9 and heart failure.10,11
EVAF, a key characteristic of central adiposity, has been independently associated with increased CVD risk in men with HIV.12,13 While CV status may be partly attributable to HIVassociated factors,10,14 there is also evidence that links CVD risk to several classes of ART, including protease inhibitors, integrase strand transfer inhibitors, and some nucleoside analogue reverse transcriptase inhibitors.14-18 As such, 2022 International Antiviral Society (IAS)-USA Panel guidelines highlighted the need to regularly assess weight and anthropometric measurements, including waist circumference, and screen for diabetes and CVD risk in PWH taking ART, as well as to encourage CVD-targeting lifestyle changes.19
The Visceral Adiposity Measurement and Observations Study
VAMOS was a cross-sectional, multi-center, observational study that included PWH who were virologically suppressed with ART for at least 1 year and had a BMI of 20−40 kg/m2. In the analysis presented in a poster at IDWeek 2024, the investigators examined whether EVAF impacted traditional CVD risk factors and overall CVD risk in PWH in the modern ART era.20
EVAF, defined here as a VAT surface area ≥130 cm2, was quantified via an abdominal CT scan at the L4−5 vertebrae. Percentage Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), triglyceride (TG) to high density lipoprotein (HDL) ratio (TG:HDL; an alternative measure of insulin resistance), and GH levels were also analyzed. Participants completed study visits, assessments, and CT scans following overnight fasting.20
At the time of analysis, 170 participants had paired CT scans and laboratory measurements. Overall, the mean (standard deviation [SD]) VAT surface area was 229.0 (83.50) cm2 for the EVAF group (n=98) and 82.7 (28.99) cm2 in the non-EVAF group (n=72). Significant differences were shown between the EVAF group and the non-EVAF group in respective mean (SD) age (57 [9.3] versus 49 [11.4] years; p<0.0001), sex (93.9% versus 83.3% male; p=0.027), and race (79.4% White, 16.5% Black versus 59.2% White, 32.3% Black; p=0.017).
Most notably in this analysis, significant differences were shown between the EVAF and non-EVAF groups in mean (SD) 10-year ASCVD risk (20% [17.8] versus 12% [13.5], respectively; p=0.0001; Figure 1A), as well as lifetime ASCVD risk (51% [15.1] versus 43% [16.8], respectively; p=0.0166). As can be seen from Figure 1B, where the participants were analyzed as a whole, there was significant positive correlation between percentage 10-year ASCVD risk and VAT surface area.20
The 10-year ASCVD risk score is based on several components, one of which is HDL, with an optimal level (for calculation of this score) of ≥50 mg/dL.21 Here, mean (SD) HDL in both groups was below this optimum and significantly lower in the EVAF group (46 [16.5] mg/dL) compared with the non-EVAF group (49 [13.0] mg/dL; p=0.015). Though not a direct component of the ASCVD risk score, mean (SD) TG levels were also significantly different between these groups, at 145 (68.4) mg/DL in the EVAF group versus 115 (52.1) mg/DL in the non-EVAF group (p=0.0008).20
As shown in Figure 1C, TG:HDL ratio, a marker of insulin resistance, was significantly higher in participants with EVAF and was positively correlated with VAT surface area (Figure 1D).20 These results reflect similar findings from a 2023 study of PWH, where VAT correlated with TG and HDL levels. It was also higher in PWH with detectable coronary artery calcium and presence of any coronary plaque, compared to those without such findings.22
Significant differences were also shown between participants in regard to insulin resistance measured via HOMA-IR (Figure 1E), again with a positive correlation to VAT surface area (Figure 1F). The TG:HDL and HOMA-IR findings are reflected in another ASCVD risk factor component, diabetes history, which was shown in 6.9% of the nonEVAF group but a significantly higher 19.4% of the EVAF group (p=0.021).20 These findings are of interest as there is a known association between insulin resistance and VAT in PWH,23 which may due to HIV itself,16 metabolic syndrome, and some classes of ART.24
A further ASCVD risk score component is total cholesterol (TC), with an optimum level ≤170 mg/dL.21 While this optimum was seen in the non-EVAF group (mean 167 [41.7] mg/dL), levels were elevated in the EVAF group (mean 182 [38.2] mg/dL), with a significant difference between groups (p=0.017).20 While another component that impacts ASCVD risk is current smoking status,21 in this cohort, although smoking rates were higher in the EVAF group, they were not significantly different than the non-EVAF group.20
Systolic blood pressure also contributes to ASCVD risk score, where the optimal untreated level is ≤110 mmHg.21 Both groups were above this optimal level, at 125 [14.6] mmHg in the EVAF group versus 120 [14.0] mmHg in the non-EVAF group, and it was significantly higher in the former (p=0.014).
Reflecting this, while 52.0% of the EVAF group were being treated for hypertension, this was only seen in 34.7% of the non-EVAF group (p=0.025).20
The study also found significantly lower GH levels in the EVAF group (Figure 1G) with this measure inversely correlating with increasing VAT surface area (Figure 1H). The relevance of this is discussed below.20
Overall, the authors concluded that these data demonstrate how EVAF and associated factors contribute to a heightened risk of CVD in PWH on modern ART regimens.20
The Impact of Tesamorelin on Cardiovascular Risk Prediction Scores
Normally GH works to regulate vascular health, body fat distribution, and lipid metabolism. However, GH deficiency is associated with increased central adiposity, higher TG levels and hypertension rates, and lower HDL levels. Further, reductions in GH related to obesity are significantly associated with CVD risk.25
Figure 1: A) Mean (circle) and median (line) percentage 10-year ASCVD risk, C) TG:HDL ratio, E) percentage HOMA-IR, G) and growth hormone levels in participants with or without excess visceral abdominal fat; visceral adipose tissue surface area (denoted visceral fat area) correlation with B) percentage 10-year ASCVD risk, D) TG:HDL ratio, F) percentage HOMA-IR, and H) growth hormone levels.
With EVAF
p=0.0001 Without EVAF
Fat Area (cm2)
With EVAF Without EVAF
Visceral Fat Area (cm2)
= 0.43
With EVAF
Visceral Fat Area (cm2)
Visceral Fat Area (cm2)
Wilcoxon Two-Sample tests were performed for dichotomous EVAF (EVAF as Visceral Fat Area ≥130 cm2 (1A,1C, 1E, 1G). Spearman correlations were performed to determine the associations between Visceral Fat Area measurements and 10-year ASCVD risk (1B), measures of insulin resistance (1D, 1F), and GH (1H).
ASCVD: atherosclerotic cardiovascular disease; EVAF: excess visceral abdominal fat; GH: growth hormone; HOMA-IR: Homeostatic Model Assessment for Insulin Resistance; TG-HDL: triglyceride-high density lipoprotein.
In the VAMOS findings reported above, GH levels were decreased in PWH with EVAF.20 These results bring relevance to the findings from a 2001 study in males with HIV that showed that mean GH concentrations were significantly lower, and mean VAT significantly higher, in individuals with HIV-associated lipodystrophy compared to controls and to individuals with HIV but without HIV-associated lipodystrophy. VAT was a significant predictor of mean GH concentration.26
GHRH is a hypothalamic peptide that increases pituitary GH secretion. Administration of GHRH in a study of males with HIV and lipodystrophy was shown to decrease trunk fat and improve the ratio of abdominal visceral fat to abdominal subcutaneous fat.27 Tesamorelin is a GHRH analogue that has been shown to significantly reduce VAT in PWH compared to placebo in randomized controlled trials.28-30 Significant reductions were also shown in TC and TG levels, with little effect on glucose levels or subcutaneous or limb fat.28-31
A sub-analysis of two Phase III trials of tesamorelin was presented at IDWeek 2024. This aimed to determine the impact of tesamorelin on 10-year ASCVD risk scores.32
Key inclusion criteria for trial participants were PWH with CD4 cell counts >100 cells/mm3; viral load <10,000 copies/mL; in receipt of ART for ≥8 weeks; and presence of excessive accumulation of abdominal fat (measured as waist circumference >95 cm in males and >94 cm in females, and waist to hip ratio >0.94 in males and >0.88 in females). Key exclusion criteria included fasting glucose >150 mg/dl (8.33 mmol/L), fasting TG >0.99 g/dl (11.3 mmol/L), Type 1 or Type 2 diabetes requiring medication, and untreated hypertension (systolic pressure >140 mmHg, diastolic pressure >90 mmHg).28,30,31 Participants were 85% male, 76% White, and 13% Black, with a median age of 47 years. Median BMI was 28.4 kg/m2, VAT was 168 cm2, TC was 188 mg/dL, and HDL was 43 mg/dL. Lipid-lowering medication was being taken
by 44% of participants, 36% were taking blood pressure medication, and 17% had impaired glucose tolerance or diet-controlled diabetes. Baseline characteristics were similar between participants randomized to either 2 mg/day tesamorelin (n=543) or placebo (n=263) for 26 weeks.32
Baseline calculation of 10-year ASCVD risk using American College of Cardiology (ACC)/ American Heart Association (AHA) criteria21 revealed that, while overall 57% of participants had low CV risk classification, almost 28% had intermediate or high risk. Similar classifications were seen using Framingham criteria, where overall 53% had low risk, with 47% having moderate or high risk (Figure 2).32
An effects analysis was conducted to characterize the significance of treatment impact via intermediate variables that factor into ASCVD risk prediction changes. Modifiable variables included systolic and diastolic blood pressure, TC, HDL, and lowdensity lipoprotein.32 Following 26 weeks’ treatment, tesamorelin was associated with an estimated decrease in ASCVD risk score of −0.40% (95% CI: −0.89%, 0.05%). The reduction was significantly higher among participants with higher CVD risk at baseline (p=0.038 for overall trend among all group participants; Figure 3).32
Administration of lipid lowering therapies to PWH with low to moderate CVD risk can reduce noncalcified plaque volume and progression and potentially reduce occurrence of a major adverse CV event.33 In this analysis, 44% in the tesamorelin group and 43% in the placebo group were taking lipid-lowering therapies at baseline and remained stable through the duration of study. Of note, ASCVD risk reduction was independent of lipid lowering therapies, and it was postulated that this risk reduction was driven predominantly by reductions in TC levels, which were significant compared to placebo (p=0.061).32
Figure 2: Cardiovascular risk classifications of study participants at baseline.
ACC/AHA: American College of Cardiology/American Heart Association; CVD: cardiovascular disease.
The authors concluded that “this analysis provides evidence that reductions in EVAF with tesamorelin lead to a significant reduction in forecasted CVD risk in PWH even among a group heavily treated with lipid-lowering therapy.”32
Conclusion
As PWH have an increased lifetime CVD risk compared with the general population,6 addressing factors associated with this risk is key in such individuals. With VAMOS findings highlighting how EVAF may contribute to heightened CVD risk in PWH,20 attention should be given to targeting EVAF when considering CVD risk management. Therapeutic tools, such as tesamorelin, have been shown to significantly reduce EVAF in PWH and may also be associated with decreased ASCVD risk scores.2
Figure 3: Estimates of the effect of tesamorelin on average cardiovascular risk score, calculated using 10-year atherosclerosis cardiovascular disease risk score.
Estimated effect shown as a function of baseline 10-year ASCVD risk score. Pointwise 95% CIs are displayed, along with a rug plot showing the distribution of the baseline risk score.
ACC/AHA: American College of Cardiology/American Heart Association; ASCVD: atherosclerotic cardiovascular disease.
References
1. Joint United Nation Programme on HIV/ AIDS (UNAIDS). The urgency of now: AIDS at a crossroads. 2024. Available at: https://crossroads.unaids.org/wpcontent/uploads/2024/09/GAU-2024Full-report_En.pdf. Last accessed: 30 October 2024.
2. GBD 2021 Diseases and Injuries
Collaborators. Global incidence, prevalence, years lived with disability (YLDs), disability-adjusted life-years (DALYs), and healthy life expectancy (HALE) for 371 diseases and injuries in 204 countries and territories and 811 subnational locations, 1990-2021: a systematic analysis for the Global Burden of Disease Study 2021. Lancet. 2024;403(10440):2133-61.
3. Teeraananchai S et al. Life expectancy of HIV-positive people after starting combination antiretroviral therapy: a meta-analysis. HIV Med. 2017;18(4):256-66.
4. Fauci AS, Lane HC. Four decades of HIV/AIDS - much accomplished, much to do. N Engl J Med. 2020;383(1):1-4.
5. Tanushree et al. Human immunodeficiency virus infection challenges: Current therapeutic limitations and strategies for improved management through long-acting injectable formulation. Rev Med Virol. 2024;34(4):e2563.
6. Shah ASV et al. Global burden of atherosclerotic cardiovascular disease in people living with HIV: systematic review and meta-analysis. Circulation. 2018;138(11):1100-12.
7. deFilippi C et al. Association of cardiac troponin T with coronary atherosclerosis in asymptomatic primary prevention people With HIV. JACC: Advances. 2024;3(9):101206.
8. Hoffmann U et al. Assessment of coronary artery disease with computed tomography angiography and inflammatory and immune activation biomarkers among adults with HIV eligible for primary cardiovascular prevention. JAMA Network Open. 2021;4(6):e2114923.
9. Freiberg MS et al. HIV infection and the risk of acute myocardial infarction. JAMA Intern Med. 2013;173(8):614-22.
10. Feinstein MJ et al. Adjudicated heart failure in HIV-infected and uninfected men and women. J Am Heart Assoc. 2018;7(21):e009985.
11. Freiberg MS et al. Association between HIV infection and the risk of heart failure with reduced ejection fraction and preserved ejection fraction in the antiretroviral therapy era: results from the Veterans Aging Cohort Study. JAMA Cardiol. 2017;2(5):536-46.
12. Lake JE et al. Regional fat deposition and cardiovascular risk in HIV infection: the FRAM study. AIDS Care. 2011;23(8):929-38.
13. Orlando G et al. Ectopic fat is linked to prior cardiovascular events in men with HIV. J Acquir Immune Defic Syndr. 2012;59(5):494-7.
14. Hudson JA et al. HIV-associated cardiovascular disease pathogenesis: an emerging understanding through imaging and immunology. Circ Res. 2024;134(11):1546-65.
15. Seplowe M et al. Atherosclerosis and HIV: exploring cardiovascular risks and management. Cardiol Rev. 2024;DOI:10.1097/ CRD.0000000000000747.
16. Paternò Raddusa MS et al. Atherosclerosis and cardiovascular complications in people living with HIV: a focused review. Infect Dis Rep. 2024;16(5):846-63.
17. Capeau J et al. HIV and adipose tissue: a long history linked to therapeutic classes of antiretrovirals. Ann Endocrinol (Paris). 2024;85(3):255-8.
18. Corti N et al. Risk of cardiovascular events in people with HIV (PWH) treated with integrase strand-transfer inhibitors: the debate is not over; results of the SCOLTA study. Viruses. 2024;16(4):613.
19. Gandhi RT et al. Antiretroviral drugs for treatment and prevention of HIV infection in adults: 2022
recommendations of the International Antiviral Society-USA Panel. JAMA. 2023;329(1):63-84.
20. Mounzer K et al. Cardiovascular risk scores and insulin resistance are higher with excess visceral abdominal fat in people with HIV in the modern antiretroviral era. Poster 453. ID Week, 16-19 October, 2024.
21. American College of Cardiology. ASCVD risk estimator plus. Resources. Understanding cardiovascular risk. Available at: https://tools.acc.org/ascvdrisk-estimator-plus/#!/content/cliniciansplit-layout/clinical_understanding. Last accessed: 30 October 2024.
22. Thomas TS et al. Visceral adiposity index as a measure of cardiovascular disease in persons with human immunodeficiency virus. Open Forum Infect Dis. 2023;10(8):ofad398.
23. Grunfeld C et al. Association of upper trunk and visceral adipose tissue volume with insulin resistance in control and HIV-infected subjects in the FRAM study. J Acquir Immune Defic Syndr. 2007;46(3):283-90.
24. Masenga SK et al. Hypertension and metabolic syndrome in persons with HIV. Current Hypertension Reports. 2020;22(10):78.
25. Stanley TL, Grinspoon SK. Effects of growth hormone-releasing hormone on visceral fat, metabolic, and cardiovascular indices in human studies. Growth Horm IGF Res. 2015;25(2):59-65.
26. Rietschel P et al. Assessment of growth hormone dynamics in human immunodeficiency virus-related lipodystrophy. J Clin Endocrinol Metab. 2001;86(2):504-10.
27. Koutkia P et al. Growth hormonereleasing hormone in HIV-infected men with lipodystrophy: a randomized controlled trial. JAMA. 2004;292(2):210-18.
28. Falutz J et al. Long-term safety and effects of tesamorelin, a growth hormone-releasing factor analogue, in HIV patients with abdominal fat accumulation. AIDS. 2008;22(14):1719-28.
29. Falutz J et al. Metabolic effects of a growth hormone-releasing factor in patients with HIV. N Engl J Med. 2007;357(23):2359-70.
30. Falutz J et al. Effects of tesamorelin (TH9507), a growth hormonereleasing factor analog, in human immunodeficiency virus-infected patients with excess abdominal fat: a pooled analysis of two multicenter, double-blind placebo-controlled phase 3 trials with safety extension data. J Clin Endocrinol Metab. 2010;95(9):4291-304.
31. Falutz J et al. Effects of tesamorelin, a growth hormone-releasing factor, in HIV-infected patients with abdominal fat accumulation: a randomized placebo-controlled trial with a safety extension. J Acquir Immune Defic Syndr. 2010;53(3):311-22.
32. Grinspoon S et al. Impact of tesamorelin on cardiovascular disease risk prediction scores in Phase 3 studies treatment arms: subanalysis. Poster 433. IDWeek, 16-19 October, 2024.
33. Lu MT et al. Effects of pitavastatin on coronary artery disease and inflammatory biomarkers in HIV: mechanistic substudy of the REPRIEVE randomized clinical trial. JAMA Cardiology. 2024;9(4):323-34.
Abstract Reviews
This collection of abstracts showcases the cutting-edge research presented at IDWeek 2024. Written by the presenters themselves, this rich collection offers a taste of the current developments nationally and internationally to impact patient outcomes.
Gender Differences in Hepatitis C Treatment in the New York City Jail System, 2019–2023
Authors: Raphael Simonson,1 Batya Koenigsberg,1 Natalia Gonzalez Varela,1 Jacqueline LaPene,1 Richard Figueroa,1 Janet Wiersema,1 *Chibuzo U Enemchukwu1
1. New York City Health and Hospitals/Correctional Health Services, New York, USA *Correspondence to enemchuc1@nychhc.org
Disclosure: The authors have declared no conflicts of interest.
Acknowledgements: The authors would like to thank Wendy McGahee, Rodrigue Joseph, and Matthew J. Akiyama for their contributions to the Hepatitis C program and patient care. They thank Monica Katyal for critical data review.
Keywords: Hepatitis C virus (HCV), health equity, gender, incarceration.
Hepatitis C virus (HCV) care among women experiencing incarceration is rarely addressed in the literature. Although women comprise a minority of persons experiencing incarceration in the USA,1 studies have shown higher HCV seroprevalence among women in this population compared with men.2-4 In the New York City (NYC) jail system, women make up 7% of the population but represent 18% of individuals diagnosed with active HCV.
This study describes the HCV care cascade for women and men in the NYC jail system and examines potential gender-related factors in outcomes.
METHODS
Persons admitted to the NYC jail system and who completed a medical intake between October 2019–December 2023 were included in this retrospective cohort analysis.
The authors constructed a care cascade including:
1. HCV screening (HCV rapid test through universal opt-out testing, HCV RNA or genotype test, or HCV self-report)
2. Confirmatory HCV testing (HCV RNA or genotype test)
3. Diagnosis (detectable confirmatory test result)
4. Linkage to jail-based clinical HCV care
5. Jail-based HCV treatment initiation
6. On-site completion of HCV treatment
7. On-site SVR12 test ≥64 days after treatment completion
8. On-site undetectable SVR12 test
Descriptive statistics, Chi-Square analysis, and Mann–Whitney U tests were used to examine differences between men and women in demographic characteristics,
medical history, and rates of progress through the HCV care cascade.
RESULTS
The study included 71,130 people, and 5,085 (7.1%) were women (Table 1). Compared to men, women had higher rates of screening (88.7% versus 28.1%; p<0.0001) and lower rates of confirmatory testing (9.6% versus 11.2%; p=0.002) (Table 2). Both groups had similar rates of active HCV (51.2% versus 47.8%; p=0.22) and linkage to on-site HCV care (55.4% versus 59.6%; p=0.32).
Women initiated HCV treatment at nearly half the rate of men (15.3% versus 30.3%; p<0.0001). Women and men completed HCV treatment, SVR12 testing, and on-site cure confirmation at similar rates.
Women in the NYC jails had significantly higher rates of homelessness (23.5% versus 19.5%), HIV (3.7% versus 2.7%), mental health needs (53.7% versus 30.8%), and history of select substance use disorders (58.6% versus 45.8%) when compared to men (p<0.0001) (Table 3). Women had significantly shorter median length of stay in jail than men (18 days versus 27 days; p<0.0001).
Table 1: Population demographics, stratified by documented gender.
*Analysis is at the incarceration, not person level.
† Chi-Square testing was used for categorical variables, and Mann-Whitney U testing was used for continuous variables. Comparison was between gender groups.
‡Patient indicated being homeless prior to incarceration through self-report during medical intake.
§Each date was counted as a separate day.
**Does not include individuals currently incarcerated with no discharge date (n=3734).
No: number; IQR: interquartile range.
Percentages for each step were based on prior step, except where otherwise noted.
*HCV screening was defined as having an HCV antibody, RNA, or genotype test, or self-reporting HCV.
†HCV confirmatory test was defined as having an HCV RNA or genotype test.
‡Among patients with a length of stay ≥6 days.
§Percentage was based on patients with a detectable confirmatory test.
**SVR12 tests to confirm cure were defined as an HCV RNA test ≥64 days and ≤6 months after treatment completion.
††Analysis is at the incarceration, not person level.
‡‡Chi-square testing was used for categorical variables and Mann-Whitney U testing was used for continuous variables. The comparison was between gender groups.
Table 2: Hepatitis C care cascade outcomes, stratified by documented gender. Total††
Table 3: Population health characteristics, stratified by documented gender. Total§
Table 3: Continued.
*Patient was enrolled in mental health services during incarceration.
†Patient has serious mental illness diagnosis during incarceration. CHS defines SMI to include (a) schizophrenia spectrum and other psychotic disorders, (b) bipolar and related disorders, (c) depressive disorders, or (d) post-traumatic stress disorder, as defined by the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5), or individuals who do not meet the above diagnostic criteria but experience severe functional impairment or clinical distress as a result of a DSM-5 diagnosis. These exclude diagnoses resulting from substance use or medical condition.
‡Defined as any one or multiple of alcohol use disorder, opioid use disorder, and cocaine use disorder.
§Analysis is at the incarceration, not personal, level.
**Chi-square testing was used for categorical variables and Mann-Whitney U testing was used for continuous variables. The comparison was between gender groups.
CONCLUSION
Large HCV treatment gaps exist between women and men experiencing incarceration. Disproportionally higher rates of medical, mental health, and history of substance use disorders, as well as shorter lengths of stay, are associated with treatment differences among women. Further work is needed to elucidate the individual impacts of these factors on HCV care outcomes among women.
Gender-specific strategies centered on the needs of women with justice involvement are required to improve the uptake of jailbased HCV treatment. In light of notably short lengths of stay in municipal jail systems, optimizing treatment access for all persons with justice involvement is critical for HCV elimination efforts.
Breast
References
1. Buehler ED, Kluckow R. Correctional populations in the United States, 2022 – Statistical Tables. 2024. Available at: https://bjs.ojp.gov/library/publications/ correctional-populations-united-states-2022statistical-tables. Last accessed: 12 September 2024.
2. Hoff E et al. Hepatitis C epidemiology in a large urban jail: a changing demographic. Public Health Rep. 2023;138(2):248-58.
3. Wenger PJ et al. Assessment of hepatitis C risk factors and infection prevalence in a jail population. Am J Public Health. 2014;104(9):1722-7.
4. Stockman LJ et al. Performance of risk-based and birth-cohort strategies for identifying hepatitis C virus infection among people entering prison, Wisconsin, 2014. Public Health Rep. 2016;131(4):544-51.
Cancer and Colorectal Cancer Screenings
Among People with HIV: The Role of Individual and System-Level Factors on Screening Completion
Authors: *Cole T. Bredehoeft,1 Jing Peng,2 Ashley Lipps,1 Mohammad Mahdee Sobhanie,1 Carlos Malvestutto,1 Susan L. Koletar,1 Yesha S. Patel1
1. Division of Infectious Diseases, The Ohio State University, Columbus, Ohio, USA
2. Center for Biostatistics, The Ohio State University, Columbus, USA
*Correspondence to Cole.Bredehoeft@osumc.edu
Disclosure: Bredehoeft received IDWeek Travel Awards to present at IDWeek 2024. Otherwise, the authors declare no relevant or material financial
interests that relate to the research described in this paper.
Keywords: AIDS, breast cancer (BC), colorectal cancer (CRC), HIV, non-AIDS-defining cancers (NADC), obesity-related cancers.
As persons with HIV (PWH) age, non-AIDSdefining cancers (NADC) are emerging as a leading cause of morbidity and mortality.1 Simultaneously, BMI among PWH is increasing, with a growing proportion of individuals being categorized as overweight or obese at the time of ART initiation and while on ART.2,3 Breast cancer (BC) and colorectal cancer (CRC) are the most common obesity-related cancers among females and males, respectively, and have increased cancer-specific mortality in PWH compared to individuals without HIV.4,5 Strategies to optimize screening practices for early detection while maintaining equitable access is essential in managing the care of this aging population. With healthcare digitalization, evolving HIV care models, and anticipated AI integration, the authors investigated BC and CRC screening rates, along with individual and system-level factors associated with screening completion.
METHODS
This single center, retrospective cohort study took place between 1 July 2022–1 July 2023, among PWH aged 40–75 years at the Ohio State University Wexner Medical Center Infectious Diseases Clinic (OSUWMC IDC), Columbus, Ohio. Established PWH (≥3 appointments between 1 July 2020–1 July 2023 with ≥1 within the study period) were included. The primary outcome was ordering and completion of BC and CRC screenings
based on the United States Preventative Services Taskforce guidelines. Demographics were summarized as frequencies and percentages across groups with different screening status. Associations between factors and outcomes were assessed using Chi-square or Fisher’s exact tests. Descriptive statistics and p values were considered for evaluating associations between characteristics and screening status.
RESULTS
A total of 178 PWH were eligible for BC screening. Of these, 62.9% (112/178) had BC screening ordered and 52.8% (94/178) had BC screening completed. One hundred and thirteen (63.5%) were of Black or African American race, 151 (84.8%) had a primary care physician (PCP), and 138 (77.5%) were enrolled in an electronic medical record application (MyChart®, Epic Systems Corporation, Verona, Wisconsin). There was a statistically significant association between having a PCP (90.2% versus 75.8%; p=0.018) and ordering of BC screening. Additionally, PWH who completed BC screening were less likely to have obesity (39.4% versus 56.0%; p=0.039) and were more likely to be established with a PCP (91.5% versus 77.4%; p=0.012).
Of those enrolled, 739 PWH were eligible for CRC screening, of whom 64.8% (479/739) had CRC screening ordered and 47.2% (349/739) had CRC screening completed. Five hundred and ninety-one (80.0%) were assigned male at birth, 634 (85.8%) had a PCP, and 601 (81.3%) were enrolled in MyChart. Significant associations were observed between having a PCP (90.8% versus 81.3%; p<0.001), higher median income (79.6% versus 69.9%; p=0.003), and MyChart enrolment (88.0% versus 75.4%; p<0.001) and CRC screening completion. Other notable variables are listed in Table 1
Table 1: Notable characteristics by differing screening status for breast and colorectal cancer.
Breast cancer screening (n=178)
Established
MyChart® enrollment†
Colorectal cancer screening (n=739)
Table 1: Continued.
Colorectal cancer screening (n=739)
Established with PCP
MyChart® enrollment†
Viral load (copies/mL)
*p<0.05 is considered significant.
†MyChart® is an electronic medical record application.
‡Government insurance represents: Medicare, Medicaid, and Ryan White coverage.
§Median income was estimated by zip code.
PCP: primary care provider.
CONCLUSION
Improving BC and CRC screening rates is essential for reducing morbidity, mortality, and disparities of these cancers among PWH. The authors’ study highlights opportunities for large-scale integration of electronic interventions to improve screening rates. It also identifies marginalized populations that may benefit from additional resource allocation and targeted interventions to ensure equitable access and delivery of preventative care services. This framework may be considered for expansion to other preventative care measures to improve overall health of aging PWH.
References
1. Weber MSR et al.; Swiss HIV Cohort Study. Time trends in causes of death in people with HIV: insights from the Swiss HIV Cohort Study. Clin Infect Dis. 2024;79(1):177-88.
2. Koethe JR et al.; North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD). Rising obesity prevalence and weight gain among adults starting antiretroviral therapy in the United States and Canada. AIDS Res Hum Retroviruses. 2016;32(1):50-8.
3. Hasse B et al. Obesity trends and body mass index changes after starting antiretroviral treatment: the Swiss HIV Cohort Study. Open Forum Infect Dis. 2014;1(2):ofu040.
4. U.S. Centers for Disease Control and Prevention (CDC). Obesity and Cancer. 2023. Available at: https:// www.cdc.gov/cancer/risk-factors/obesity.html?CDC_ AAref_Val=https://www.cdc.gov/cancer/obesity/ index.htm. Last accessed: 14 September 2023.
5. Coghill AE et al. Elevated cancer-specific mortality among HIV-infected patients in the United States. J Clin Oncol. 2015;33(21):2376-83.
Assessing Hepatitis A Virus and Hepatitis B Virus Screening, Immunity, and Vaccination in People Living with HIV in the Illinois Department of Corrections
Authors: Nicholas T. Truong,1 Alex Dang,1 Hillary Debs,1 Jennifer Morrow,1 Huda Kalota,1 Mahesh Patel,2 Scott Borgetti,2 Emily N. Drwiega,1 *Melissa E. Badowski1
1. University of Illinois Chicago, Retzky College of Pharmacy, USA
2. University of Illinois, College of Medicine, Chicago, USA *Correspondence to badowski@uic.edu
Disclosure: The authors of this research have no financial relationships to disclose.
Keywords: Corrections, hepatitis A virus (HAV), hepatitis B virus (HBV), HIV, vaccine.
Individuals in custody face higher risks of vaccine-preventable diseases due to overcrowding, high turnover, high-risk behaviors, and inadequate healthcare access.1 Low immunization rates among individuals in custody are partly due to social marginalization and distrust in healthcare personnel, despite the opportunity for health interventions during incarceration.2 Organizations such as World Health Organization (WHO) and Centers for Disease Control and Prevention (CDC) recommend vaccinating individuals in custody, but implementation varies by facility, especially in resource-limited settings.3 A 2001 survey found that only two states routinely vaccinate for hepatitis B virus (HBV), with cost and funding being major barriers to widespread vaccination in prisons.4 The prevalence of HBV among incarcerated individuals is
significantly higher than in the general USA population, with 30% of acute HBV cases having a history of incarceration.5 Enhanced vaccination efforts, routine screenings, and close follow-up by multidisciplinary healthcare teams are needed to improve hepatitis A virus (HAV) and HBV immunity in incarcerated populations.6 The primary objective was to compare the rates of vaccination and immunity to HAV and/or HBV among individuals in custody living with HIV in 2022, to prior data in 2019, where standardized recommendations for serologic screening and vaccination were not routinely performed.
METHODS
The study was a retrospective cohort pre-post design that involved adults living with HIV who were followed in the Illinois Department of Corrections (IDOC) HIV Telemedicine Clinic during two distinct periods: from January 1 2019–December 31 2019, and from January 1 2022–December 31 2022. A follow-up period of 9 months was included to incorporate recommendations regarding screening and vaccinations. The statistical analysis for this study incorporated descriptive statistics, the Chi-squared test, and the Student’s t-test.
RESULTS
A total of 436 patients were included in the 2019 cohort, which served as historical control data. Of 341 patients screened for inclusion in the 2022 cohort, 300 were included. The majority of patients in either cohort were male (p=0.93) and Black (p=0.53). Overall, baseline demographics were similar between groups. In terms of baseline characteristics, the proportion of patients with an undetectable HIV-1 viral load was similar between groups, with 85% in 2019 and 84% in 2022 (p=0.80). Similarly, 95% of patients in 2019 and 94% in 2022 had a CD4 count above 200 cells/mm³ (p=0.96). In 2019, 79% of patients were immune to HAV compared to 70% in 2022 (p=0.02). For
HBV, 65% of patients in 2019 were immune compared to 71% in 2022 (p=0.12). Overall, 52% of patients in 2019 and 53% in 2022 were immune to both HAV and HBV (p=0.89), while 8% in 2019 and 12% in 2022 had no immunity to either HAV or HBV (p=0.08).
A majority of patients were screened for both HAV (60%) and HBV (63%) during initial intake. Among individuals in custody who were not immune at initial intake, 23% received HAV screening and 28% received HBV screening during follow-up appointments. Thirty-six patients were released before follow-up. Of the 24 and 22 patients offered HAV and HBV vaccines, respectively, nine (38%) accepted the HAV vaccine, and 13 (59%) accepted the HBV vaccine.
CONCLUSION
The results indicated that there was no significant increase in overall immunity to both HAV and HBV in the post-intervention cohort. Among patients who initially lacked immunity to HAV and/or HBV, many did not undergo follow-up serologic screening after vaccination. The primary barrier to increasing vaccination rates among individuals in custody appears to be patient refusal. However, screening individuals in custody upon intake presents a valuable public health opportunity to recommend vaccination to those who are non-immune.
References
1. Vicente-Alcalde N et al. Vaccination coverage among prisoners: a systematic review. Int J Environ Res Public Health. 2020;17(20):7589.
2. Vandergrift LA, Christopher PP. Do prisoners trust the healthcare system? Health Justice. 2021;9:15.
3. Charuvastra A et al. Hepatitis B vaccination practices in state and federal prisons. Public Health Rep. 2001;116(3):203-9.
4. Centers for Disease Control and Prevention. Clinical testing and diagnosis for Hepatitis B. 2024. Available at: https://www.cdc.gov/hepatitis-b/hcp/diagnosistesting/?CDC_AAref_Val=https://www.cdc.gov/ hepatitis/hbv/testingchronic.htm. Last accessed: November 1, 2024.
5. Gough E et al. HIV and hepatitis B and C incidence rates in US correctional populations and high risk groups: a systematic review and meta-analysis. BMC Public Health. 2010;10:777.
6. Poondi N et al. Assessing immunity to hepatitis A and hepatitis B among individuals in custody living with HIV. J Correct Health Care. 2024;30(2):107-12.
Evaluation of Microbiology and Antibiotic Prescribing Behavior of Foot Puncture Wound Infection: An Opportunity for Antimicrobial Stewardship
Authors: *Brian Kim,1,2 Niki Arab,1,2 Arthur Jeng2,3
1. Department of Pharmacy, Olive View-UCLA Medical Center, Sylmar, California, USA
2. Division of Infectious Diseases, Department of Medicine, Olive View-UCLA Medical Center, Sylmar, California, USA
3. University of California, Los Angeles David Geffen School of Medicine, California, USA *Correspondence to bkim2@dhs.lacounty.gov
Disclosure: The authors have declared no conflicts of interest.
The primary pathogens of soft tissue infections, including those of the foot, are beta-haemolytic Streptococci and Staphylococcus aureus. 1 However, Pseudomonas aeruginosa has been implicated as a cause of foot infections in patients after they have sustained a nail puncture wound through a sneaker, historically leading to recommendations for prescribing empiric antipseudomonal antibiotics.2,3 At Olive ViewUCLA Medical Center, Sylmar, California, the authors evaluated empiric antibiotic prescribing behaviour and microbiology of foot puncture wound infections.
METHODS
A retrospective chart review was conducted on adults (aged ≥18 years) admitted with an ICD-10 code for puncture wounds from January 1 2017–December 31 2023. Inclusion criteria included foot infection after sustaining nail, screw, staple, thumbtack, or razorblade puncture. Non-foot puncture wounds and punctures from an object other than those listed in the inclusion criteria were excluded. Antipseudomonal antibiotic was defined as either piperacillin-tazobactam, cefepime, ceftazidime, or ciprofloxacin.
RESULTS
Fifty-eight cases were reviewed, and 45 met the inclusion criteria. The majority of puncture wounds were due to nails (n=34; 76%), followed by screws (n=6; 13%). Puncture occurred through the shoe in 38/45 cases (84%), barefoot in 2/45 (5%), and not described in 5/45 (11%). An empiric antipseudomonal antibiotic was prescribed in the emergency department in 41/45 cases (91%), whereas an empiric antipseudomonal antibiotic was prescribed or continued upon admission in 19/45 (42%). The average days of therapy on antipseudomonal antibiotics was 2 days (interquartile range: 2–3 days). Wound culture was obtained in 44 cases, with no isolation of P. aeruginosa. The majority of identified pathogens consisted of methicillin-susceptible S. aureus (n=26; 59%) and Streptococcus agalactiae (n=19; 43%); infection involving both S. aureus and Streptococcus spp. was seen in 15 cases
(34%; Figure 1). Subsequent foot infection with P. aeruginosa within 30 days of puncture wound infection did not occur in any cases.
Figure 1: Organisms isolated in wound culture.
CONCLUSION
P. aeruginosa was not isolated in any cases of foot puncture wound infection, including puncture occurring through a shoe,
Methicillin-Susceptible Staphylococcus aureus
Methicillin-Resistant Staphylococcus aureus
Streptococcus agalactiae
Streptococcus mitis
Viridans Streptococcus
Gram Negative Rods (non Pseudomonas)
No growth Organism
MSSA: methicillin-susceptible S. aureus; MRSA: methicillin-resistant S. aureus; GNR: Gram-negative rods; non-PsA: non-Pseudomonas.
documented in 84% of the authors’ cases, the majority of which had diabetes (95.5%).
Given the historical perception of the role that P. aeruginosa plays in this infection, the majority of cases were started on an empiric antipseudomonal antibiotic. This finding provides insight into antibiotic prescribing behaviour for foot puncture infection, whether the puncture occurred through a shoe or not. The primary pathogens consisted of S. aureus and/or Streptococcus spp., especially S. agalactiae, a virulent pathogen in individuals with diabetes.
Foot puncture wound infections present an opportunity for antimicrobial stewardship to prioritise empiric, narrower antibiotic treatment selection against S. aureus and Streptococcus spp., and not against P. aeruginosa, as is commonly practised.
References
1. Stevens DL et al. Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the Infectious Diseases Society of America. Clin Infect Dis. 2014;59(2):e10-52.
2. Inaba AS et al. An update on the evaluation and
management of plantar puncture wounds and pseudomonas osteomyelitis. Pediatr Emerg Care. 1992;8(1):38-44.
3. Jacobs RF, et al. Pseudomonas osteochondritis complicating puncture wounds of the foot in children: a 10-year evaluation. J Infect Dis. 1989;160(4):657-61.
Cardiac MRI Identifies Heart Disease Risk
in Individuals with Hepatitis
C
Regardless of Myocardial Damage Markers or Fibrosis Stage
1. Harvard Affiliated Emergency Medicine Residency, Mass General Brigham, Boston, Massachusetts, USA
2. Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland, USA
3. National Institutes of Health (NIH), Bethesda, Maryland, USA
*Correspondence to adamore1@mgb.org
Disclosure: D’Amore disclosed provision of a PRISM grant to their institution to fund this project. Mathur disclosed payment from the Merck Investigator Studies Program to their institution and hepatitis C medications for this abstract review. Sirajuddin, George, and Gharib have declared no conflicts of interest.
Infection with hepatitis C virus (HCV) increases the risk of extrahepatic manifestations, including cardiovascular disease (CVD).1 Cardiac magnetic resonance (CMR) remains the gold standard test for non-invasive structural and functional assessment of the heart, and can be used to detect CVD. Using CMR, the authors sought to determine the CVD risk in patients with HCV prior to therapy.2
METHODS
Individuals with chronic HCV infection were prospectively enrolled in the CHROME study (NCT03823911).3 A subset of 10 individuals infected with HCV were enrolled in the MRI sub-study from March–September 2019. HCV antibody assays, HCV RNA levels, liver fibrosis scores, and markers of inflammation and myocardial damage were obtained.
CMR was performed prior to the initiation of direct-acting antiviral treatment. Extracellular volume (ECV) fraction was calculated using the equation: ECV=100% x (1-hematocrit) x [(1/T1myocardium post-contrast) – (1/ T1myocardium pre-contrast)]/[(1/T1blood post-contrast) – (1/T1 blood pre-contrast)]. An ECV fraction >30% was considered abnormally increased. Ten age-matched, HCV-negative volunteers were included in the analysis so that T-test was used to compare ECV fraction in both groups.
RESULTS
Demographics are shown in Table 1. CMR showed that 8/10 individuals infected with HCV had an abnormal ECV fraction (>30%;4 average=0.30; range 29–38%). When compared with age-matched healthy volunteers, ECV fraction in the individuals infected with HCV was significantly increased (0.30±0.03 versus 0.26±0.03; p=0.0036; Figure 1). Three of the 10 individuals infected with HCV had non-ischemic patterns of gadolinium enhancement on the late gadolinium enhancement images (Figure 2). For individuals infected with HCV, markers of
Table 1: Baseline demographic features of hepatitis C virus cardiac magnetic resonance cohort.
1: Extracellular volume of individuals infected with hepatitis C virus and healthy volunteers.
Figure
A B C
A) Short axis late gadolinium enhancement image shows a midwall pattern of enhancement within the basal septal wall (arrow), compatible with an area of midwall fibrosis. B) Native T1 map, and C) Post-contrast T1 map show a corresponding area of abnormal T1 measurements within the basal septum (arrows).
inflammation and myocardial damage were within laboratory reference ranges for all subjects in the CMR cohort, and ECV fraction was elevated regardless of myocardial damage markers or liver fibrosis stage.
CONCLUSIONS
The findings suggest that myocardial changes secondary to HCV infection can occur without measurable changes in inflammatory or myocardial biomarkers, and that ECV fraction via CMR may be a sensitive screening tool to detect these changes. This has important implications for the necessity of early HCV treatment, since cardiovascular changes can precede the development of advanced liver fibrosis in individuals infected with HCV.
References
1. Revuelto Artigas T et al. Antiviral treatment does not improve subclinical atheromatosis in patients with chronic hepatitis caused by hepatitis C virus. Gastroenterol Hepatol. 2019;42(6):362-71.
2. Kramer CM. Role of cardiac MR imaging in cardiomyopathies. J Nucl Med. 2015;56 (Suppl 4):39S-45S.
3. University of Maryland, Baltimore. Cardiovascular Disease in HIV and hepatitis C: risk outcomes after hepatitis C eradication (CHROME). NCT03823911. https://www.clinicaltrials.gov/study/ NCT03823911?term=NCT03823911&rank=1.
4. Marques MD et al. Myocardial fibrosis by T1 mapping magnetic resonance imaging predicts incident cardiovascular events and all-cause mortality: the Multi-Ethnic Study of Atherosclerosis. Eur Heart J Cardiovasc Imaging. 2022;23(10):1407-16.
Figure 2: Inflammatory changes seen on cardiac magnetic resonance in patient with hepatitis C.
Assumptions and Realities: Unraveling Varicella Zoster Virus Immunity in Unvaccinated Populations
Authors: *Sofia Jordão,1 Eduarda Pena,1 Maria João Gonçalves,1 Clara Batista,1 Susana Oliveira,1 Constança Azeredo,1 Sara Araújo,1 Fábio Reis,1 Cristina Soeiro,1 Ricardo Correia Abreu1
1. Infectious Diseases Department, Unidade Local de Saúde de Matosinhos, Hospital Pedro Hispano, Portugal *Correspondence to sofjordao@gmail.com
Disclosure: The authors declare no conflicts of interest.
In countries without universal vaccination for chickenpox in childhood, a very high seroprevalence for varicella zoster virus
(VZV) IgG in adults is often assumed. Consequently, some suggest vaccinating at-risk adults against herpes zoster, even if they lack a documented history of chickenpox, under the assumption of immunity.1,2 However, this presumption may not accurately reflect today's epidemiological landscape.3,4 Neglecting the risk of primary infection post-childhood could lead to severe outcomes in vulnerable adults,5 pregnant patients,6 and increase the likelihood of exposure for caregivers, potentially resulting in secondary transmission.7
METHODS
A retrospective study was conducted on VZV serology among individuals aged 11 years and above, from February 2014–March 2024, who were unvaccinated and lacked known chickenpox history, within a Portuguese hospital.
Figure 1: Varicella zoster virus IgG seroprevalence by gender and age group.
RESULTS
Analysis of 613 patients (68% women; median age: 39 years) with high VZV infection risk due to comorbidities or immunosuppression revealed an 83.6% VZV IgG positivity rate, increasing with age (Figure 1). Among workingage individuals aged 21–60 years, 12% were seronegative for VZV, and 19.2% of women aged 16–40 years showed no immunity.
CONCLUSION
Although common, the presence of antibodies against VZV is not universal after childhood in unvaccinated populations. Vaccination for herpes zoster is not indicated for the prevention of primary infection, so assuming immunity may fail to prevent it in a population at risk.
Prevention of chickenpox relies on specific vaccination, or the use of immunoglobulin when the former is contraindicated, which implies recognition of this susceptibility. Serology remains a useful tool, especially for at-risk individuals and caregivers.
References
1. Australian Government (2023). Zoster (herpes zoster). The Australian Immunisation Handbook. 2024. Available at: https://immunisationhandbook. health.gov.au/contents/vaccine-preventablediseases/zoster-herpes-zoster. Last accessed: 13 October 2024.
2. Centers for Disease Control and Prevention (CDC). Shingles vaccine recommendations, Centers for Disease Control and Prevention. 2024. Available at: https://www.cdc.gov/shingles/hcp/vaccineconsiderations/index.html. Last accessed: 13 October 2024.
3. Yun JH et al. Seroprevalence of varicella-zoster virus and measles among healthcare workers in a tertiary medical center in Korea. Vaccines (Basel). 2022;10(11):1956.
4. Chong CH et al. Seroprevalence of varicella-zoster virus antibody and immunogenicity of live attenuated varicella vaccine in healthcare workers in Taiwan. J Microbiol Immunol Infect. 2023;56(2):274-81.
5. Ho BCH, Tai DYH. Severe adult chickenpox infection requiring intensive care. Ann Acad Med Singap. 2004;33(1):84-8.
6. Lamont RF et al. Varicella-zoster virus (chickenpox) infection in pregnancy. BJOG. 2011;118(10):1155-62.
7. Yang J et al. Nosocomial transmission of chickenpox and varicella zoster virus seroprevalence rate amongst healthcare workers in a teaching hospital in China. BMC Infect Dis. 2019;19(1):582.
Rabies Encephalitis: Spectrum of MRI Findings and Predicted Probability of Abnormality Detection Based on Symptom Duration
To explore the spectrum of MRI abnormalities in patients with rabies encephalitis.
BACKGROUND
Rabies is a highly lethal infectious disease and is equivalent to a death sentence for patients. The ante-mortem diagnostic sensitivity is only approximately 40% with currently available tests. Currently, there are only isolated case reports1 or small case series exploring the MRI features in rabies encephalitis.
METHODS
A prospective observational study was designed to explore the patterns of MRI abnormalities in rabies patients. A total of 31 patients were enrolled in the study, out of which 21 underwent contrast enhancedMRI of the brain and spinal cord.
RESULTS
Overall, MRI was normal in 10 (47.6%) patients, whereas 11 (52.4%) patients showed abnormalities. It was observed that those with abnormal MRI tended to have longer time to MRI from symptom onset as compared to those whose MRIs were normal (mean number of days: 4.5 days versus 2.9 days; Figure 1). In addition, univariate logistic regression analysis revealed that the likelihood of picking up abnormalities on MRI increases with the duration from the symptom onset, approaching approximately 80% at Day 6 and >90% at Day 8. Abnormalities were detected in various brain regions, with brainstem, spinal cord and basal ganglia being the most affected regions (Figure 2 and 3). Other regions such as the cortex, sub-cortical white matter, limbic system, internal capsule, corona radiata, thalamus, and sub-thalamic region were also involved to varying degrees.
Predicted probability of MRI being abnormal based on number of days elapsed from 1st cardinal symptom
Figure 1: Predicted probability of MRI being abnormal based on the number of days elapsed from the onset of first cardinal symptom.
Figure 2: T2 turbo spin echo showing hyperintensities in bilateral basal ganglia (caudate nucleus, putamen, and globus pallidus) and thalamus and corresponding diffusion-weighted imaging and apparent diffusion coefficient images showing true diffusion restriction.
Figure 3: Fluid-attenuated inversion recovery/T2 hyperintensities in dorsal brainstem and cervical spinal cord of two different patients.
Diffusion-weighted-imaging showed a typical pattern of diffusion restriction in six cases (28.5%). No gadolinium contrast enhancement was observed in any patient in the affected brain areas; however, some patients demonstrated contrast enhancement in the spinal nerve roots. Overall, no significant difference in neuroimaging findings were observed between encephalitic and paralytic forms of rabies.
CONCLUSION
To date this is the largest prospective study (21 cases) exploring the MRI findings
patients with rabies encephalitis. The study demonstrated certain patterns of brain imaging in rabies that, in the appropriate clinical context, could significantly aid in establishing the ante-mortem diagnosis of rabies encephalitis. At the same time, the study also highlighted the fact that a normal MRI brain does not rule out the diagnosis and that the probability of finding specific abnormalities on MRI increases as the disease progresses.
Reference
1. Awasthi M et al. Imaging findings in rabies encephalitis. AJNR Am J Neuroradiol. 2001;22(4):677-80.
Immunological Profile of Human T-Lymphotropic Virus Type 1 in Pediatric Patients
Authors: Diana MC Donneys,1,2 Ingara C James,1,2 Herney Garcia,3 *Juan P Rojas1,2,4-7
1. Department of Pediatrics, Universidad Libre Cali, Colombia
2. Member of the Pediatric Research Group (GRINPED)
3. Division of Urology/Urooncology, Department of Surgery, School of Medicine Universidad del Valle, Cali, Colombia
4. Hospital Universitario del Valle Evaristo García, Cali, Colombia
5. Epidemiology, Universidad Libre, Cali, Colombia
6. Fundación Universitaria San Martín, Cali, Colombia
7. Pontificia Universidad Javeriana, Cali, Colombia *Correspondence to juan.rojas.hernandez@correounivalle.edu.co
Disclosure: The authors declare no conflicts of interest.
Keywords: Cellular immunity, human T lymphotropic virus type 1 (HTLV-1), humoral immunity, retroviridae.
Human T-lymphotropic virus type 1 (HTLV-1) is a retrovirus associated with significant immunological dysregulation and oncogenesis.1 It is highly endemic in South America, notably in Brazil, Peru, and Colombia, affecting primarily individuals of indigenous and African descent.2 In children, HTLV-1 often presents with dermatologic manifestations, respiratory diseases, opportunistic co-infections, and autoimmune disorders.3 The virus primarily targets CD4+ T lymphocytes but can also infect CD8+ T cells, B cells, and other immune cell types.4 Transmission occurs mainly through prolonged breastfeeding, sexual contact, blood transfusions, and needle sharing.5 This study aims to describe the immunological profile of pediatric patients diagnosed with HTLV-1 in Cali, Colombia, focusing on cellular and humoral responses.
METHODS
This observational, descriptive, and retrospective cross-sectional study was conducted at a pediatric referral center from January 2017–March 2021. Nineteen pediatric patients with confirmed HTLV-1 infection
and immunological
were included. The median age at diagnosis was 94 months, with school-age children representing the largest group (52.6%). The analysis involved lymphocyte subpopulations (CD4+, CD8+, CD19+, CD3+) and serum immunoglobulin levels (IgA, IgG, IgM, IgE), interpreted according to age-specific
Case 1 14 M Pulmonary aspergillosis No
Case 2 8 F Pulmonary aspergillosis No
Case 3 10 F Pulmonary tuberculosis Yes, scabies
Case 4 8 M Pulmonary tuberculosis No
Case 5 16 M
Case 6 6 F
Case 7 6 M
Case 8 7 F Pulmonary aspergillosis
Case 9 16 M Pulmonary aspergillosis
Case 10 1 M
Case 11 12 F
Case 12 1 M
Case 13 11 F Toxoplasmosis, leptospirosis, dengue, and malaria
infective dermatitis
infective dermatitis
infective dermatitis
infective dermatitis
IgE
IgA
IgG
IgA
IgG
IgA
IgE
IgG
IgA
IgE
IgA
Hyper IgG
IgA
IgE Hyper IgM
Hyper IgG
IgA
IgE
IgM
IgG
IgA
IgE
IgG
IgE
IgG
PanuveitisVogt-KayanagiHadara syndrome Not available Not available
IgG
IgE
Table 1: Clinical characteristics
profile of patients with HTLV-1 in the present study.
Table 1: Continued.
Case 14 1 M
Case 15 5 F
Case 16 3 M
Case 17 1 M
Case 18 10 M
Case 19 9F
Intestinal parasitosis by Ascaris lumbricoides, Trichuris trichiura Soft tissue infection by S. pyogenes
F: female; M: male.
reference values. Data were collected from medical records and analyzed using IBM® SPSS® Statistics 22 (Armonk, New York).
RESULTS
Of the 19 patients, 57.9% were male, and 84.2% were affiliated with the subsidized health insurance system. Malnutrition was observed in 52.6% of the cases, suggesting a potential risk factor for immune dysfunction. No cases of HIV co-infection were found. Cellular immunity analysis in six patients revealed that 50% had elevated B lymphocytes (CD19), while CD4+ and CD8+ T cell counts were within normal ranges for most patients. Regarding humoral immunity, 16 patients were evaluated, with elevated IgA, IgG, and IgE levels in over half of the patients, while IgM was normal in 81.3% of cases (Table 1). The increase in immunoglobulin levels, particularly IgE and IgA, was associated with elevated CD19+ B lymphocytes, suggesting a link between B cell activation and polyclonal
hypergammaglobulinemia.
DISCUSSION
The findings indicate that immunosuppression in pediatric HTLV-1 patients is not related to reduced lymphocyte subpopulations but may be mediated by cytokine dysregulation and viral regulatory proteins that interfere with immune signaling.4 This immune dysregulation contributes to increased susceptibility to opportunistic infections such as Strongyloides stercoralis, Aspergillus fumigatus, and Mycobacterium tuberculosis 6 Pulmonary infections, including tuberculosis and aspergillosis, along with dermatological conditions like infective dermatitis, were common opportunistic manifestations.7 The male predominance observed contrasts with studies reporting a higher prevalence in females.8 Consistent with prior research, this study identified polyclonal hypergammaglobulinemia rather than
lymphopenia, reflecting an aberrant but functional immune response.9 Additionally, the elevated immunoglobulin levels and B lymphocytes suggest a possible link to immune system overstimulation rather than depletion.10
CONCLUSION
Pediatric patients with HTLV-1 infection exhibit elevated B lymphocytes and immunoglobulin levels, indicating immune dysregulation driven by cytokine alterations rather than lymphocyte depletion.2 Enhanced monitoring for opportunistic infections and regular immunological assessments are recommended to improve outcomes. Future studies should focus on understanding immune activation mechanisms and developing therapeutic interventions that address pediatric HTLV-1 infection.5
References
1. Vásquez P. HTLV-I (Human T- cell lymphotropic virus), algo que decir? Rev Chil Infect. 2003;20 (Suppl 1):S34-7.
2. Kannagi M et al. Impact of host immunity on HTLV-1 pathogenesis: potential of Tax-targeted immunotherapy against ATL. Retrovirology. 2019;16(1):23.
3. Futsch N et al. HTLV-1, the other pathogenic yet neglected human retrovirus: from transmission to therapeutic treatment. Viruses. 2017;10(1):1.
4. Sanchez-Palacios C et al. Seroprevalence and risk factors for human T-cell lymphotropic virus (HTLV-I) infection among ethnically and geographically diverse Peruvian women. Int J Infect Dis. 2003;7(2):132-7.
5. Mosquera Herrera CE et al. Infección por el Virus Linfotrópico de Células T Humano HTLV1 y Paraparesia Espástica Tropical en Ecuador: Paradigma de Enfermedad Tropical Desatendida. Rev Ecuat Neurol. 2019;28(2):71-4.
6. Fuzii HT et al. Immunopathogenesis of HTLV-1assoaciated myelopathy/tropical spastic paraparesis (HAM/TSP). Life Sci. 2014;104(1-2):9-14.
7. Gotuzzo Herencia E et al. Veinte años de investigación sobre HTLV-1 y sus complicaciones médicas en el Perú: perspectivas generales. Acta Med Per. 2010;27(3):196.
8. Paiva AM et al. Risk factors associated with HTLV-1 vertical transmission in Brazil: longer breastfeeding, higher maternal proviral load and previous HTLV1-infected offspring. Sci Rep. 2018;DOI:10.1038/ s41598-018-25939-y.
9. Mejía-Mertel J et al. Clinical profile of human T-lymphotropic virus type I: a forgotten infection in pediatrics. Revista Infectio. 2021;25(1):28-32.
10. James IC et al. Case series: pediatric human T-lymphotropic virus type 1 and its clinical expression. Front Trop Dis. 2022;DOI:10.3389/ fitd.2021.824067.
Prospective Study on the Clinico-epidemiological Characteristics, Diagnostic Approaches, and Correlation with Autopsy Findings of Rabies Encephalitis
1. Department of Internal Medicine, Post Graduate Institute of Medical Education and Research, Chandigarh, India
2. Department of Radiodiagnosis, Post Graduate Institute of Medical Education and Research, Chandigarh, India
3. Department of Virology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
4. Department of Histopathology, Post Graduate Institute of Medical Education and Research, Chandigarh, India *Correspondence to surivikas9479@gmail.com
Disclosure: The authors declare no conflicts of interest.
Acknowledgements: The authors would like to thank Dr Vignesh for
Rabies is the deadliest infectious disease, with a nearly 100% fatality.1 Due to this fear, it is often an overlooked disease, resulting in a scarcity of comprehensive knowledge, most of which is derived from retrospective studies.2,3 This prospective study is aimed to narrow this knowledge gap.
METHODS
This prospective observational study included 31 participants. Detailed clinical history and clinical examination were performed, and the Milwaukee protocol was used for patient management. For diagnostics, CEMRI Brain was performed, and samples of cerebrospinal fluid, saliva, serum, skin, and brain biopsies were collected for various diagnostic tests. An autopsy was done for eight patients.
RESULTS
The study unearthed numerous intriguing aspects of the disease. Despite the presence of adequate infrastructure, only 48% initiated post-exposure prophylaxis, and a mere 13% received Rabies immunoglobulin. Adherence to the vaccination schedule was subpar, with only 13.3% completing the full course. The median incubation period in the authors' study was 29 days, with variations depending on the type of rabies, site of the bite, and the application of red chilli on the wound (Table 1). Facial bites were associated with significantly shorter incubation periods as compared to upper limb (p=0.083) and lower limb bites (p=0.0003). Upper limb bites were associated with significantly shorter incubation periods as compared to lower limb bites (p=0.0325). Application of red chilli was associated with a significant shortening of the incubation period (p=0.0478). Clinical features of hydrophobia and aerophobia were consistently reported in this study as in other studies (Table 2).
This study also identified spontaneous ejaculation as one of the consistent manifestations of encephalitic rabies. Autonomic dysfunction emerged as a prominent manifestation, with variations in heart rate (90%), blood pressure (90%), and temperature (81%); hypersalivation (61%),
Table 1: Frequency of clinical features in rabies at presentation.
Table 1: Continued.
Table 2: Table representing various incubation periods in median (interquartile range), and the respective p-values between the two groups.
Incubation Period
Overall IP (n=31)
Median (IQR) IP
29 (21–90)
Min IP 13 days
Max IP 30 years
IP based on the type of rabies
Encephalitic rabies (n=24)
Paralytic rabies (n=4)
34 (21–123)
24 (19–29)
P value 0.506
IP based on the site of bite (considering first bite if bites at multiple time intervals and considering the most proximal bite if bites at multiple sites present)
HNF (n=4) 15 (14–16)
UL (n=12)
22 (21–44)
LL (n=12) 84 (43–246.5)
P value of comparison between site of bite (p value by Dunn test with post-hoc Sidac correction)
hyperhidrosis, spontaneous ejaculations (29%), and neurogenic pulmonary edema (19%) being the common features. Antemortem diagnosis showed the following positivity rates: nape of neck skin biopsy immunohistochemistry (40%), salivaPCR (23.8%), skin biopsy PCR (20%), and cerebrospinal fluid PCR (4.3%). Postmortem brain biopsy PCR demonstrated 100% positivity. Autopsy findings revealed the characteristic Negri bodies (100%) with perivascular lymphocytic infiltrate (75%), microglial proliferation and/or nodule formation (75%), and neuronophagia (37%) in almost all areas of the brain, with maximum concentration in hippocampus, cortex, brainstem, and basal ganglia.
CONCLUSION
This is the first prospective study of its kind which studies the clinical-epidemiological and autopsy features and the performance of various diagnostic tests in rabies. The unique features highlighted in the study include its prospective nature, prominent clinical features of dysautonomia and spontaneous ejaculations, positivity rates of various diagnoses, and their correlation with autopsy findings.
References
1. Fooks AR et al. Current status of rabies and prospects for elimination. Lancet. 2024;384(9951):1389-99.
2. Hampson K et al. Estimating the global burden of endemic canine Rabies. PLOS Negl Trop Dis. 2015;9(4):e0003709.
3. Rahman SA, Isloor S. Rabies on the Indian subcontinent. Rev Sci Tech. 2018;37(2):529-42.
Congress Interviews
Advanced Practice Registered Nurses Jacqueline Toia and Kathleen Murtagh underpin the critical role of Advanced Practice Providers as frontline care in multi-disciplinary teams, and share the importance of the Advanced Practice Providers voice at large meetings such as IDWeek 2024.
Jacqueline Toia1 and Kathleen Murtagh2
1. Pediatric Nurse Practitioner, Infectious Diseases Ann & Robert H. Lurie Children's Hospital of Chicago, Illinois, USA
2. Family Nurse Practitioner, Infectious Diseases Ann & Robert H. Lurie Children's Hospital of Chicago, Illinois, USA
What does a typical day as an Advanced Practice Registered Nurse (APRN) look like?
Typical? Every day is different, that is part of the Infectious Diseases (ID) magic. We tend to start each day by individually completing a thorough review of each patient’s chart. We then come together to discuss each patient as a team. This is followed by service rounds; we have two separate ID services at Ann & Robert H. Lurie Children’s Hospital (LCH) in Chicago, Illinois. Our service teams consist of the General ID team and the Transplant ID team. There are slight nuances for each team. Ultimately, the teams round on the wards, examining our patients and engaging with the families and the primary team for updated and ongoing communication. Often, we will participate in multi-disciplinary rounds, this is especially valuable for the most critically ill patients, ensuring all stakeholders are
informed and engaged in a planned approach to care provisions. Of course, the documentation of our work takes priority, usually in the afternoon. There is additional coordination of care (labs, discussion about antimicrobial changes, follow up appointments, coordinating clinic visits with other sub-specialities) for many of our patients that is accomplished as needs arise throughout the day. We manage new consults as they are requested and prioritize education, formally and informally, for ID team members and our partners on collaborating teams. The Advanced Practice Providers (APP) provide continuity for the ID services. We are the frontline for all of our partners on the collaborating teams Monday–Friday. We cover assigned inpatient and outpatient responsibilities, some of us have assigned outpatient clinics; but, most importantly, we are prepared to pivot, on any typical day, as we are needed.
Q2 What is the most rewarding and most challenging part of your work?
At the risk of sounding trite, it’s all rewarding! ID is a unique subspeciality that has a wide breadth of knowledge, experience, and encounters. Not one day resembles another, which can be challenging, but it is also rewarding. Couple that with the privilege of working with children and their families and you have the perfect recipe for a beautifully fulfilling career. That is not to say there are not difficult times, there are. The best and worst of times are experienced. There are cases that will stay with you forever, some outcomes will make you rejoice, other outcomes will darken your soul. Working hard to make a difference is the best part, a bad outcome for a child and their family can be devastating. Learning to navigate the differences is crucial.
Q3 How do you cross-collaborate with other healthcare professionals to deliver patient care?
Collaboration is the key to every medical success. Be it among our own team members or between the multi-disciplinary services. As a consultation service, our success depends on collaboration. We work hard every day to foster the relationships we have in place with our partnering teams. Our aim is to be available for coordination of clinical care, we focus on efficiency, and improved outcomes. When we formulate a plan of care we close the loop by directly communicating our recommendations with the main stakeholders. This is often accomplished during multidisciplinary rounds, or via direct contact after completion of our consultation. We make every effort to discuss our thoughts face-to-face as soon as our determinations have been made; if that is not an available option, we call and speak directly with one of the partnering team members.
Q4 What is the importance of large meetings, such as IDWeek 2024, to provide a platform for APPs to discuss their issues related to practice?
Meetings are paramount to the future success of APPs within the speciality of ID. Professional meetings are designed to be devoted to the professional development of its members, promoting, and improving the profession with which they are associated. This is a bit of a fragile question because, after many years, APPs are just now gaining a little traction into having a voice within Infectious Diseases Society of America (IDSA), which is our professional society. Continuing to grow our involvement is critical. APPs are a growing part of the ID workforce. As the landscape of ID continues to change, preparedness is essential to the future. APPs can be especially useful in many areas of ID including clinical care, clinical research, antimicrobial stewardship, and infection control. IDSA can provide unique opportunities for APP learning, The Advanced Practice Providers (APP) provide continuity for the ID services. We are the frontline for all of our partners on the collaborating teams
career advancement, networking, and enhanced outcomes within ID. That said, leadership needs to continue to recognize our presence and provide directed opportunities and resources aimed at APP job responsibilities and practice.
Q5
What were your most surprising or valuable takeaways from IDWeek 2024?
Knowledge, it is all about the knowledge. During IDWeek we are given the opportunity to attend sessions presented by national and international leaders. We are exposed to experts within the field. It is a time to listen and consider new trends or learn how to adapt them to your clinical practice. It is a place and time to develop problem solving and decision-making skills. IDWeek is also a venue to present some of your own work, be it a poster presentation or an oral presentation. Meeting colleagues and building relationships that can be enduring throughout one’s career is invaluable. We always make it a point to spend time with other APPs at IDWeek, which has led to a working group of APPs that meet regularly throughout the year.
Q6
What is the most recent activity of your IDSA Working Group, and what are your hopes for the future?
We started as an informal “working group” for many years. With our commitment to caring for children within the subspeciality of Infectious Diseases, and to each other, we never wavered on the importance of becoming recognized within the IDSA/ Pediatric Infectious Disease Society (PIDS) society. Hence our persistence on moving forward with a dedicated place on the organizational chart, knowing there is much work ahead of us to define this place and the commitment to our work.
For many years now (since 2019), pediatric ID APPs have been working with one another and supporting one another parallel to the organization. In 2022 we were
We are excited to have a place at the table and work to grow our involvement and contributions as APPs within our professional society
recognized as a "Working Group" by the PIDS, and since, we have continued to try to gain support and buy-in to become an APP committee. In May, we submitted a proposal to the PIDS Board of Directors and in August we were granted status as a sub-committee. It is our strong belief that there will be direct and significant benefits from having an APP presence in place within PIDS. It will enhance our professional engagement and allow us to contribute in meaningful ways, including professional development, advocacy, research and quality improvement, and patient and family education. We further emphasized the need for embracing APPs as critical members of the pediatric ID workforce in a paper we published earlier this year, entitled 'Advanced Practice Providers in Pediatric Infectious Diseases'.1 We are excited to have a place at the table and work to grow our involvement and contributions as APPs within our professional society.
References
1. Toia J et al. Advanced practice providers in pediatric infectious diseases. JPIDS. 2024;13(3):228-31.
Battling Pediatric Mold Infections:
Invasive Aspergillosis and Invasive Mucormycosis
Interviewee: Surabhi Vora1
1. Division of Pediatric Infectious Diseases, Seattle Children’s Hospital, Washington, USA
Disclosure: Vora has acted as a consultant for Astellas.
Acknowledgements: Writing assistance was provided by Eleanor Roberts, Beeline Science Communications Ltd, London, UK.
Disclaimer: This content is intended for health care professionals only. The opinions expressed in this article belong solely to the interviewee.
Support: The publication of this article was funded by Astellas.
Interview Summary
Mold species are inhaled by people every day and, typically, infection is locally curtailed by the immune system. However, in people who are immunocompromised, invasive aspergillosis (IA) or invasive mucormycosis (IM) can lead to great morbidity and even mortality. Although many studies have been conducted in adults regarding diagnosis and treatment of IA and IM, infections in children have been investigated to a much lower extent. Surabhi Vora is a pediatrician based in Seattle who specializes in treating immunocompromised children with fungal infections. Here, she discusses several issues around IA and IM in these populations, including the importance of detecting and treating these infections early. Diagnosis of IA and IM may be problematic in children as symptoms can be non-specific, such as repeated bouts of fever; chest CTs and laboratory tests may not be as accurate as needed; and accessing tissue for biopsy can be difficult. Treatment of IA and IM can depend on a number of factors, such as the specific pathogen, drug–drug interactions, and a child’s age and ability to consume a medication. Education is needed for both patients and caregivers, especially with regard to the need to take medication for extended periods of time and be on guard for both further IA or IM symptoms and for medication side effects.
PHARMA
INTRODUCTION
The genus Aspergillus includes several pathogenic mold species, including the most common invasive species A. fumigatus. 1 Genera under the order Mucorales include Rhizopus, the most common to cause IM.2 Sources of both of these include soil and decaying vegetation,1,2 with reports of Aspergillus also being air- or water-borne.1 Following inhalation of Aspergillus1 or Mucorales2 spores, local colonization can occur, with subsequent invasion of the vascular system and widespread dissemination, leading to IA1 or IM.2 Morbidity and mortality associated with these infections can be high in people who are immunocompromised.1,2 As such, awareness regarding infection signs and symptoms, as well as of suitable treatment, is paramount, especially considering that incidence/prevalence of both IA3 and IM4 is increasing.
Treatment for IA and IM has predominantly been studied in adults, with only a few studies conducted in pediatric populations.5-10 To discuss these infections in children, the AMJ sat down with Surabhi Vora, a pediatric infectious diseases specialist with a particular interest in fungal infections in immunocompromised patients.
Invasive fungal infections such as IA and IM are most commonly seen in children with hematologic malignancies, especially acute myeloid leukemia5,7,8,10 and relapsed/refractory acute lymphoblastic leukemia,5-8,10 which may involve stem cell transplantation.5-8,10 IA and IM may also develop in children undergoing solid organ transplant.5,7,10 However, Vora explained, “most of our pediatric organ transplant patients are not significantly immunocompromised in the pre-transplant period. At the time of transplant, they are immunosuppressed intensely and continue on immune suppression, but not at the levels we sometimes see with stem cell transplants. Here, they may have had a fungal infection even before their transplant because they’ve had prolonged periods of profound neutropenia and immune suppression due to their underlying condition.”
IA and IM may particularly occur in children with prolonged neutropenia or high steroid doses.5,7,10 For example, in an IA study including 139 children, neutropenia was present for ≥3 days in 59% of patients and lasted for ≥30 days in ~30%. Corticosteroid therapy for the period prior to detection of IA was administered to 69% of patients and immunosuppressive therapies to 43%.5
PRESENTATION AND PROGRESSION OF INVASIVE ASPERGILLUS OR INVASIVE MUCORMYCOSIS
The spectrum of clinical manifestations of IA and IM is highly dependent on the individuals’ risk factors, including immune system status. Greater immune suppression is associated with increased risk for invasive disease.1,2 Infection with Aspergillus most commonly leads to invasive pulmonary aspergillosis (IPA), with symptoms including pulmonary infiltrates, pleural effusion, dyspnea, progressive cough, hemoptysis, pneumothorax, fever, and pleuritic chest pain. Other syndromes associated with IA include tracheobronchitis and sinusitis, and disseminated disease to other organs, bone, skin, and the central nervous system.1 Clinical forms of IM include pulmonary, cutaneous, gastrointestinal, and rhinocerebral infections, and/or it can also be disseminated. Symptoms are site dependent; for example, symptoms of rhinocerebral mucormycosis can include facial pain, edema, and headache, whereas patients with pulmonary mucormycosis may experience chest pain, dyspnea, cough, and fever.2
Based on Vora’s experience, a typical presentation in a pediatric patient with IA or IM “is a child who has been neutropenic for an extended period of time and then has fevers that do not go away despite antibiotic therapy. Depending on the infection site, they can also have skin lesions, sinus symptoms, sinus or face pain, headaches, respiratory symptoms, cough, shortness of breath, or chest pain.” In her clinical experience, Vora
explained, the rate of progression of IA or IM “really depends on the individual and their immune system. Some can be fine one day and the next can have rapid progression, especially with IM. Others, more commonly, progress over weeks to months.” She continued: “Even with early diagnosis, there’s a risk of mortality.1,2 It’s pretty rare because we have more options for treatment and we’re vigilant about progression and spread, but we still have to be very careful.”
DIAGNOSING INVASIVE ASPERGILLUS OR INVASIVE MUCORMYCOSIS
Vora explained how immunocompromised children “are generally at risk for bacterial and viral infections,11 not just fungal infections, so we look holistically at what could be causing symptoms. If it’s just a fever, it can be very non-specific. We tend to start with treatment for bacterial infections, because we see those more commonly. If symptoms persist or are very severe, we look for other things, including viruses and fungal infections.”
When discussing pulmonary manifestations of IM and IA, Vora explained how “one of our first diagnostic strategies is to image the lungs with a chest CT, because a regular X-ray doesn’t usually pick up the subtle findings of a mold infection.”1,2 In IPA, such scans may reveal multiple, diffuse, nodules; focal consolidation; isolated masses; wedge-shaped densities or cavitary lesions; and pleural effusions.1 In IM, findings may be similar including multiple nodules, consolidation nodules, cavities, abscesses, micronodules, and pleural effusions.2 A chest CT may be able to distinguish pulmonary symptoms of IA from IM, with the former showing a halo sign1 and the latter showing a reversed halo sign.2 However, discussed Vora, “in reality we don’t always see those things; the imaging findings really may be quite nonspecific in children, but a nodular or cavitary lesion would certainly raise our suspicion for fungal infection.”
Diagnosis of IA or IM may be challenging as there are no simple blood tests available,1 with definitive diagnosis necessitating a bronchoscopy or biopsy.1,2 Of note though, emphasized Vora from her clinical experience, “getting a bronchoscopy is a big deal in pediatric patients because they require sedation and may not tolerate the procedure.1,2 They’re already sick and have a lot of other things going on and they’re fragile. There may be a lot of risk associated.” Not being able to obtain a sample can be problematic, noted Vora, because “we’re often in a situation where we think there’s a probable or a presumed fungal infection, but we haven’t been able to confirm it because of diagnostic limitations.” It may also be the case that there is no absolute diagnosis even after an invasive procedure, explained Vora.
If a sample is collected, advanced techniques may be used to examine specimens, such as fungal PCR testing and metagenomic next-generation sequencing.1,2,6 “However,” said Vora regarding the latter, “it’s relatively new and very expensive so it remains to be seen how useful it will be in this setting.”
TREATMENT
There are various antifungal agents for treatment of IA and IM.1,2 “Using [an agent with] the appropriate spectrum of activity is very important,” remarked Vora. However, she also explained that there are only a few clinical studies investigating the efficacy and safety of treatments for pediatric patients with invasive molds.8,9,12
One trial that examined the pharmacokinetics and safety of an antifungal agent in this population was a Phase I, open-label, multicenter study of isavuconazonium sulfate including 46 immunocompromised pediatric patients. Participants were stratified by age to receive intravenous (aged 1−17 years) or oral (aged 6−17 years) formulations. At the studied dose, these formulations were well tolerated and resulted in exposure in pediatric patients that was similar to adults.8
In a subsequent open-label, noncomparative, Phase II study, 31 pediatric patients were administered oral (aged 6−17 years, weighing ≥12 kg) or intravenous (aged 1−17 years) formulations of isavuconazonium sulfate for treatment of at least possible IM or IA. Overall response rate at the end of treatment was 54.8%. Isavuconazole was well tolerated, with adverse events and exposure consistent with adult studies.13 In these studies, the most frequently reported adverse reactions were diarrhea (26%), abdominal pain (23%), vomiting (21%), elevated liver chemistry tests (18%), rash (14%), nausea (13%), pruritus (13%), and headache (12%).12
Vora discussed how there are other factors to consider with regard to treatment choice, such as drug–drug interactions.1 Additionally, “the site of infection can make a difference. If we have an infection in the brain, for instance, we want to make sure we have a drug that penetrates the CNS.” Also of consideration, Vora discussed, is “what we think the patient can tolerate and their underlying renal or liver status. We also look at the age of the patient and whether we have dosing we’re comfortable with.” Another consideration Vora described is whether the drug of choice has an age-appropriate formulation. “If it’s a young child, then we’re limited by what they can take orally.”
It was noted by Vora that, “if you suspect a mold infection, you really have to treat immediately and aggressively even when diagnosis is not confirmed.”2,14 She explained that “this means that sometimes we’re treating a bit blindly because we don’t know if it’s IA or IM or a different organism.” Specimens for fungal culture and other relevant laboratory studies (including histopathology) to isolate and identify causative organism(s) should be obtained prior to initiating antifungal therapy, though it may be instituted before results of cultures and other laboratory studies are known. Once results are available, antifungal therapy should be adjusted accordingly.14
When prescribing a medication, Vora discussed how consideration needs to be given regarding treatment duration. She described how there is potential for using an intravenous drug initially, but then switching to an oral medication when the child has to take it at home for an extended period of time. Such time spans were evidenced by a pediatric study of treatment for invasive fungal infections where isavuconazonium sulfate was administered for a median 81 days, with a range of 15–356 days.9
Treatment for IM or IA can also include surgery, growth factors, or granulocyte transfusions.1,2 “Surgery is a really important part of treatment in some of these infections, especially when they’re focal and very aggressive. For IM especially, surgery is a critical part of reducing mortality. When there is something we can debride, we do that urgently to try and decrease the load of infection we need to treat,” Vora said.2
EDUCATIONAL NEEDS FOR PATIENTS AND CARERS
Vora also discussed patient and family education regarding fungal infections in pediatric patients. “These infections can be very scary and it’s tricky, because there’s such a range of presentations and outcomes. You can be pretty convinced that a patient will be fine if they take their treatment for a very long time, or you can be very worried for a patient’s life on Day 1. What the conversation is going to be like really depends on the situation.”
Vora explained how “there’s a lot of very specific education around diagnostics” when suspicious for IA or IM. Conversations may be challenging, she said, “especially when you’ve convinced someone to have a bronchoscopy then you don’t have a diagnosis, but you’re still going to treat them as if they have a fungal infection, because it would be too dangerous not to treat them.” Once a treatment regimen has been established, Vora explained that education then centers around the importance of taking antifungals every day for a long time,
as well as regarding potential side effects and symptoms to look out for at home.
A final aspect of IA and IM Vora discussed was professional networks that, she explained, “are often all we have in pediatrics.” She highlighted the International Pediatric Fungal Network15 who “work together to do studies on fungal infections in children, trying to answer questions that no single site can answer alone because these are relatively rare infections.” For example, they are currently undertaking a study looking at better strategies to diagnose IA and IM in the lungs.15,16
References
1. Thompson GR, Patterson TF. “Aspergillus Species,” Bennett JE et al. (eds.), Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases (2009) 9th Edition, Philadelphia: Elsevier, pp.3103-16.
2. Wattier RL, Steinbach WJ. “Mucormycosis and entomophthoramycosis,” Cherry JD et al. (eds.), Feigin and Cherry’s Textbook of Pediatric Infectious Diseases (2013), Philadelphia: Elsevier Saunders, pp.2094-102.
3. Lass-Flörl C, Steixner S. The changing epidemiology of fungal infections. Mol Aspects Med. 2023;94:101215.
4. Alqarihi A et al. Mucormycosis in 2023: an update on pathogenesis and management. Front Cell Infect Microbiol. 2023;13:1254919.
5. Burgos A et al. Pediatric invasive aspergillosis: a multicenter retrospective analysis of 139 contemporary cases. Pediatrics. 2008;121(5):e1286-94.
6. Zhang Y et al. Clinical features of pediatric mucormycosis: role
CONCLUSION
Vora concluded by reminding people that “there’s a lot of morbidity and mortality associated with both IA and IM,1,2 so we have to be very vigilant about looking for them in high-risk patients. Even with the limitations of diagnostics, we have to treat aggressively if there’s even suspicion that that’s what’s going on. The more antifungal treatment options we have, the more chance we have of achieving better outcomes.”
of metagenomic next generation sequencing in diagnosis. Front Cell Infect Microbiol. 2024;14:1368165.
7. Al Dhaheri F et al. Epidemiology and outcomes of invasive aspergillosis among pediatric immunocompromised patients: a 12-year singlecenter experience. Med Mycol. 2022;60(4):myac014.
8. Arrieta AC et al. Safety, tolerability, and population pharmacokinetics of intravenous and oral isavuconazonium sulfate in pediatric patients. Antimicrob Agents Chemother. 2021;65(8):e0029021.
9. Zimmermann P et al. Isavuconazole treatment for invasive fungal infections in pediatric patients. Pharmaceuticals (Basel). 2022;15(3):375.
10. Wattier RL et al. A prospective, international cohort study of invasive mold infections in children. J Pediatric Infect Dis Soc. 2015;4(4):313-22.
11. Torres JP, Santolaya ME. Respiratory viral infections in children with cancer and febrile neutropenia and children undergoing hematopoietic stem cell transplantation. Curr Opin Infect Dis.
2024;37(5):407-12.
12. Astellas Pharma US, Inc. Cresemba (isavuconazonium sulfate). Highlights of prescribing information. Available at: https://www.astellas.us/docs/cresemba. pdf. Last accessed: Nov 13 2024.
13. Segers H et al. Safety, outcomes, and pharmacokinetics of isavuconazole as a treatment for invasive fungal diseases in pediatric patients: a noncomparative phase 2 trial. Antimicrob Agents Chemother. 2024; DOI: 10.1128/ aac.00484-24.
14. Patterson TF et al. Practice guidelines for the diagnosis and management of aspergillosis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis. 2016;63(4):e1-e60.
15. International Pediatric Fungal Network. Available at: https://www.ipfn.org. Last accessed: 13 November 2024.
16. Arkansas Children's Hospital Research Institute. Non-invasive diagnosis of pediatric pulmonary invasive mold infections (DOMINIC). NCT03827694. https://clinicaltrials.gov/study/ NCT03827694
IMPORTANT SAFETY INFORMATION AND INDICATIONS AND USAGE OF CRESEMBA (isavuconazonium sulfate)
CONTRAINDICATIONS
• CRESEMBA is contraindicated in persons with known hypersensitivity to isavuconazole
• Coadministration of strong CYP3A4 inhibitors, such as ketoconazole or high-dose ritonavir (400 mg every 12 hours), with CRESEMBA is contraindicated because strong CYP3A4 inhibitors can significantly increase the plasma concentration of isavuconazole
• Coadministration of strong CYP3A4 inducers, such as rifampin, carbamazepine, St. John’s wort, or long acting barbiturates with CRESEMBA is contraindicated because strong CYP3A4 inducers can significantly decrease the plasma concentration of isavuconazole
• CRESEMBA shortened the QTc interval in a concentration-related manner. CRESEMBA is contraindicated in patients with familial short QT syndrome
WARNINGS AND PRECAUTIONS
Hepatic Adverse Drug Reactions (e.g., elevations in ALT, AST, alkaline phosphatase, total bilirubin) have been reported in clinical trials and were generally reversible and did not require discontinuation of CRESEMBA. Cases of severe hepatic adverse drug reactions including hepatitis, cholestasis or hepatic failure including death have been reported in patients with serious underlying medical conditions (e.g., hematologic malignancy) during treatment with azole antifungal agents, including CRESEMBA. Evaluate liver tests at the start and during therapy. Monitor patients who develop liver abnormalities during CRESEMBA therapy for severe hepatic injury. Discontinue if clinical signs and symptoms consistent with liver disease develop that may be attributable to CRESEMBA.
Infusion-Related Reactions including hypotension, dyspnea, chills, dizziness, paresthesia, and hypoesthesia were reported during intravenous administration of CRESEMBA. Discontinue the infusion if these reactions occur.
Hypersensitivity Reactions: Anaphylactic reactions, with fatal outcome, have been reported during treatment with CRESEMBA. Serious skin reactions, such as Stevens Johnson syndrome, have been reported during treatment with other azole antifungal agents. Discontinue CRESEMBA if anaphylactic or serious skin reactions occur, and initiate supportive treatment as needed.
Embryo-Fetal Toxicity: During pregnancy, CRESEMBA may cause fetal harm when administered, and CRESEMBA should only be used if the potential benefit to the patient outweighs the risk to the fetus. Women who become pregnant while receiving CRESEMBA are encouraged to contact their physician.
Drug Interactions: Coadministration of CRESEMBA with strong CYP3A4 inhibitors such as ketoconazole or high-dose ritonavir and strong CYP3A4 inducers such as rifampin, carbamazepine, St. John’s Wort, or long acting barbiturates is contraindicated.
Drug Particulates: Following dilution, CRESEMBA intravenous formulation may form precipitate from the insoluble isavuconazole. Administer CRESEMBA through an in-line filter.
ADVERSE REACTIONS
In adult patients, the most frequently reported adverse reactions among CRESEMBA-treated patients were nausea (26%), vomiting (25%), diarrhea (22%), headache (17%), elevated liver chemistry tests (16%), hypokalemia (14%), constipation (13%), dyspnea (12%), cough (12%), peripheral edema (11%), and back pain (10%).
In adult patients, the adverse reactions which most often led to permanent discontinuation of CRESEMBA therapy during the clinical trials were confusional state (0.7%), acute renal failure (0.7%), increased blood bilirubin (0.5%), convulsion (0.5%), dyspnea (0.5%), epilepsy (0.5%), respiratory failure (0.5%), and vomiting (0.5%).
In pediatric patients, the most frequently reported adverse reactions were diarrhea (26%), abdominal pain (23%), vomiting (21%), elevated liver chemistry tests (18%), rash (14%), nausea (13%), pruritus (13%), and headache (12%).
In general, adverse reactions in pediatric patients (including serious adverse reactions and adverse reactions leading to permanent discontinuation of CRESEMBA) were similar to those reported in adults.
INDICATIONS AND USAGE
CRESEMBA (isavuconazonium sulfate) is an azole antifungal indicated for the treatment of invasive aspergillosis and invasive mucormycosis as follows:
• CRESEMBA for injection: adults and pediatric patients 1 year of age and older
• CRESEMBA capsules: adults and pediatric patients 6 years of age and older who weigh 16 kg and greater
Specimens for fungal culture and other relevant laboratory studies (including histopathology) to isolate and identify causative organism(s) should be obtained prior to initiating antifungal therapy. Therapy may be instituted before the results of the cultures and other laboratory studies are known. However, once these results become available, antifungal therapy should be adjusted accordingly.
Please see full Prescribing Information for CRESEMBA (isavuconazonium sulfate).
AMJ had the pleasure of interviewing Gail J Demler–Harrison and Lisa Armitige, two leading experts in infectious diseases. Demler–Harrison raises awareness of congenital cytomegalovirus infections and discusses the importance of fetal and neonatal antiviral therapy. Lisa Armitige speaks about challenges in adult and pediatric tuberculosis, highlighting the need for improved education and prevention strategies globally.
Gail J Demler–Harrison
Professor, Department of Pediatrics and Pathology & Immunology, Baylor College of Medicine, Houston, Texas; Texas Children’s Hospital, USA
Citation:
CMV is the most common virus most people have never heard of
First of all, what originally sparked your interest in the field of pediatric viral infections, and cytomegalovirus (CMV) in particular?
As an undergraduate student at the University of Texas in Austin, USA studying pre-med and microbiology, I gravitated towards the virology classes, so from early on I felt comfortable with viruses, in general. Their simplistic elegance fascinated me, and their ability to influence not just the machinery of a single cell, but an entire organism, body, human, was remarkable; and, taking experience from contemporary times and global pandemics, viruses can influence the machinery of an entire country or continent, and that is downright amazing to contemplate.
My specific interest in cytomegalovirus or CMV began when I was a first-year postdoctoral fellow in pediatric infectious diseases at Baylor
College of Medicine and Texas Children’s Hospital. My mentor was Martha Yow, who was a legendary trailblazer in the field of pediatric infectious diseases, clinical virology, and congenital infections, and the author of a very inspiring book ‘Balancing Act: A Memoir of a Southern Woman Doctor’. Early in my fellowship, Yow and I were walking together in the halls of the medical school, and she put her arm around me and said: “I have a new project, a funded grant, on CMV, and I need a fellow to help me do to the work. Would you like to be that fellow?” I immediately said yes, but she immediately said: “Do not ever make such an important personal or professional decision that quickly. Take this grant project home, read it, and see if it is something you want to commit to. If you do, then we can discuss it further tomorrow.” That was my first ‘mentoring moment’ from my mentor Yow, and how I entered the world of CMV. I chose CMV not because it was easy, but because it was hard.
In her book, Yow writes something like: “Why did I feel that the study of congenital CMV was so important? Few people had ever heard of it and most doctors didn’t understand it, but it was the leading infectious cause of disabilities and deafness. This was a major public health dilemma, and preventive measures were urgently needed.”
These words were true when I started my CMV journey. These words are still true today.
Q2
Your research primarily focuses on congenital CMV infections. How common is CMV infection in pregnant women, and are there any warning symptoms during pregnancy?
CMV is the most common virus most people have never heard of, including pregnant people. However, they should know about it. CMV is very common, most of us will be infected with this virus in our lifetime. The prevalence of CMV antibodies, indicating a prior infection with CMV, in individuals
of childbearing age is between 45–75% in the USA, depending on a variety of demographics.
The annual seroconversion rate of CMV antibody-negative individuals who are pregnant is between 1–4%. So, between 1–4 % of pregnant people will contract CMV for the first time during their pregnancy, and about 40% of them will transmit CMV to their fetus after their primary infection. CMV can also cause recurrent infections, through reactivation or re-infection, in individuals who have already been infected with CMV, but the transmission rate to the fetus is much less, probably 1% or so.
Most CMV infections are asymptomatic, making them very difficult to detect and monitor. If CMV had a common rash to go with it, like chicken pox or rubella, it may be easier to follow and study. But it doesn’t. Some pregnant people will experience CMV symptoms, such as fever, malaise, hepatitis, sore throat, or mononucleosis-like symptoms. Sometimes, the first
indication a pregnant person has had CMV is that the fetal anatomy ultrasound scan may be abnormal, showing poor fetal growth, echogenic bowel, microcephaly, brain malformations, enlarged liver or spleen, fetal ascites, or other anomalies of the fetus.
CMV is not routinely screened or tested for in pregnancy in the USA, so many CMV infections in pregnancy go unnoticed and undiagnosed.
Q3
What are some of the long-term effects of CMV on the growth, development, vision, and hearing of fetuses and newborns?
Most congenital infections with CMV in the fetus and newborn are also asymptomatic, inapparent, or ‘silent’. It is a ‘stealth virus’. About 90% of live newborns who have congenital CMV diagnosed are asymptomatic at birth with normal exams. The 10% that do have symptoms at birth may have a wide variety of signs and symptoms.
infection may have mild symptoms, such as isolated low platelets, growth restriction, mild lab abnormalities of the liver, or mild abnormalities on their brain imaging such as vasculopathy or cysts.
Moderate to severe congenital CMV infection may include severe growth restriction; abnormalities of platelets with low platelet counts, which can cause bleeding; significantly abnormal liver enzymes or cholestasis with elevated bilirubin; sightthreatening ocular eye diseases, such as retinitis or optic nerve atrophy, or even cortical vision impairment if their brain is malformed; hearing loss that is sensorineural (i.e. permanent nerve deafness), bilateral, or unilateral; and brain involvement that may include microcephaly, intra cranial calcifications, ventriculomegaly, or cortical dysplasia such as poly microgyria or lissencephaly.
Long-term effects of congenital CMV include progressive hearing loss, permanent vision loss, growth and developmental disorders,
associated with congenital CMV infection. Congenital CMV is a lifelong condition, not just a condition for the fetus or newborn or infant. CMV also is a cause of fetal loss, stillbirths, and neonatal death. About 8% of newborns with severe symptomatic congenital CMV will die despite antiviral treatments and neonatal intensive care.
Q4
What are the benefits of fetal and neonatal antiviral therapy for CMV infection?
Antiviral treatment, administered as ganciclovir intravenously or valganciclovir given orally, to newborns with symptomatic congenital CMV, has been shown in multicenter, randomized clinical trials to improve general growth, improve head circumference growth (and therefore likely brain growth), improve hearing outcomes by reducing the risk of hearing loss progressing or later onset hearing loss occurring, and improve neurodevelopmental milestones including speech and language acquisition, in those infants treated with antivirals.
important, because the early years are periods of language acquisition, and if hearing can be preserved during this important period it can be of benefit. However, some studies are showing that antiviral treatment may not benefit long term. In one study we published, we found that when we follow these children longer, up to age 18 years, the hearing benefits do not seem to be enduring through childhood and adolescence, and they continue to lose their hearing after the antiviral is stopped. This antiviral treatment is still not an FDA-approved indication for the treatment of congenital CMV, despite it being in use for decades, but it is a treatment endorsed by expert opinion and consensus guidelines in the USA and Europe.
Fetal treatment is still experimental and emerging. Some studies have shown CMV transmission to the fetus in pregnant people experiencing a primary or first CMV infection can be reduced using oral high-dose valacyclovir during pregnancy. This is an area of active research as well.
Q5
In terms of prevention, what role does professional education and community awareness play in reducing the risk of congenital CMV infections? What strategies have you found to be the most effective
The first step in CMV prevention is awareness. We need to make CMV a household word and we need to ‘normalize’ CMV, so we are comfortable talking about it. It is still under-appreciated, and knowledge about CMV is limited, both among healthcare workers and the general public. An ounce of CMV awareness plus three simple behavioral precautions may reduce the risk of CMV transmission to the pregnant person. I call this the ‘CMV Knowledge Vaccine’ or the ‘CMV Information Immunization’. For example, toddlers are virtual ‘hot zones’ for CMV as they actively shed CMV in their saliva and urine for about a year once they acquire it, usually from other toddlers and in daycare or group care settings. So, avoidance of kissing toddlers around the mouth, sharing food or drinks with them, and washing hands well after wiping runny noses, drool, and doing diaper changes are important to reduce transmission.
Q6
Your work also focuses on other neonatal infections, such as herpes simplex virus (HSV), influenza, and respiratory syncytial virus (RSV). Can you tell us more about your work in developing new diagnostic tests and antiviral treatments for these viral infections in newborns?
When I directed the Diagnostic Virology Laboratory at Texas Children’s Hospital for 25 years,
I helped raise awareness about the importance of viral infections in children and develop rapid diagnostic tests and PCR-based tests to detect viruses in a variety of body fluids to aid rapid and confirmatory diagnosis of a variety of viral illness important to neonates and children. To say “It’s just a virus” was never enough for me. I felt then, and I still feel, that it is very important to name the virus causing an illness, so appropriate management decisions can be made for the patient, and also for us to track epidemiologically, viruses by seasons, and how they change over the years.
Most recently, I am working to develop point-of-care tests for CMV detection in urine, saliva, and newborn dried blood spots, to facilitate the accurate and rapid detection of CMV in newborns, and to facilitate universal screening and targeted newborn testing for CMV. Many viruses, such as influenza and RSV, are seasonal; however, many viruses that affect newborns, such as CMV and HSV, are endemic and non-seasonal, and also deserve our attention.
Q7How do you see the field of antivirals for infants evolving in the next few years, especially in response to emerging/ re-emerging viral threats like influenza and RSV?
We need more antivirals, more options for treatment, more creative and equitable approaches, and more approaches that can be globalized, so that all individuals have access to viral diagnosis, viral treatments, and viral preventive measures. We also need more awareness that we can
diagnose and treat viruses. Like I said earlier, viruses not only take over and shut down the machinery of a single cell, but they can shut down an entire country or continent if enough individuals get infected. So, they deserve our attention and respect. We should be more proactive rather than reactive, and develop timely strategies for monitoring, diagnosis, treatment, and prevention.
We also need more prevention measures, such as vaccines. The most recent news around newly licensed RSV vaccines for senior adults, pregnant people, and infants is very exciting. It is quite possible we may not see ‘RSV seasons’ in the future, which currently fill our hospitals and ICUs in the fall and winter months, with infants and adults with bronchiolitis, pneumonia, and other illnesses! More options for influenza vaccines also are very important.
A CMV vaccine is not yet licensed or available, but work has been ongoing since the 1970s on CMV vaccines. In fact, a CMV vaccine, in addition to a better influenza vaccine, was put as a vital vaccine priority for 21st century by the Institute of Medicine in a report published in 2000. Work continues on a CMV vaccine, by many companies around the world in the vaccine industry arena, and Phase III multicenter trials are underway and close to being completed that appear very promising. So, maybe in the near future, congenital CMV will no longer be waiting its turn for prevention by a vaccine.
Lisa Armitige
Heartland National TB Center, San Antonio, Texas, USA
Q1With your extensive background in infectious diseases, particularly tuberculosis (TB), what drew you to focus on TB in adults and pediatric patients?
My mom was a nurse; so, when I was about 3 years old, I decided I was going to be a nurse just like her. I think she sensed that I was a little bit hardheaded and not good at taking orders. So, she asked me why I didn't want to be a doctor. From then on, I wanted to grow up to be a pediatrician. That was my life's goal. However, the first year I applied I did not get in. The second year that I applied, I got in on Thursday and school started on the next Monday. In my first year, I met Terry Satterwhite, who I still keep in touch with. He gave the TB lectures. Micro just kind of caught me; there's a bug, and they are extraordinary, they're smart, and they are the enemy trying to kill my patient. They are a formidable foe.
together, it was TB in adults and children, just the whole spectrum, from the womb to the tomb.
That’s the backstory, but it’s always in the persistence. I'd tell young folk: ‘Don't ever let somebody tell you that you can't do something. You tell them what you can't do. They're not you. They don't know you like you know you. So, hang in there.’
Q2Could you share some of the most significant findings from your work on TB, and their potential impact on TB treatment and prevention?
Don't ever let somebody tell you that you can't do something. You tell them what you can't do
We had a lot of basic science professors, and they were pulling me to the field, but Dr Satterwhite gave more clinical talks as he was an infectious disease doctor. It just sucked me in. I loved pediatrics, it was what I wanted to do but older patients can have 40 years of drinking, smoking, and chicken fried steak in themselves, and being able to pull them out and have them feel better than they've ever felt is very gratifying. It sounds funny, but as a pediatrician, I don't like sick kids. I really like to make sure that, if they're sick, we're getting them back to right as quickly as possible. Once I pulled it all
Understanding the stigma patients go through, and really walking with them, is crucial. We have set up a directly observed therapy (DOT) to make sure that there is somebody watching them take their meds. For me, it's making sure that they're okay and that the medications go in and there's no toxicity, and that I know about any problems they experience on the day that it happens. So, it’s about getting them to a point where they understand that we're taking care of them, that we're less about dictating over them, and more so about making sure that they're okay, and walking the journey with them the entire way.
We've met patients in parking lots. My favorite story was about a gentleman who was at his work site every day. He would go around the corner to the fast-food place and get his lunch. So, the DOT worker would just meet him in the parking lot, and he would pop in the car,
We're trying to meet people where they are
take his meds, make sure his toxicity screens were all negative, and then he would run inside, get his lunch, and go back to work as usual.
We're trying to meet people where they are, getting them more regular with their meds. We have people with substance use problems, and I tell them, I'm not here to judge you, I'm just here to make you better. It’s about the patient.
From a clinical standpoint, the thing that we've been able to impact is patients who are newly diagnosed with HIV, who have not really been consistent with their meds. We offer for them to take their HIV meds when the DOT worker comes, and from this we’ve been able to help them see consistency with their meds, and they feel better. I remind them: ‘You've been every
day with your HIV meds. Look how much weight you've gained. Look how well you're doing. Look how good you feel. Don't give that back. Keep taking that med.’
With patients who are diabetic, it’s about helping them with their diet. Every month, we have one little lesson about diabetic diets and about the medication, working with their physicians. So, when we step away from the TB, we want to leave them with well controlled diabetes. I think being able clinically to step in is something that we give to the patient.
I would say that from the research standpoint, we are one of the few sites of the Tuberculosis Trials Consortium (TBTC) that is enrolling adolescents. Children often get left out. We just assume that if it works in adults, it's going to work well in children. But adolescents are not adults. They have different concerns, and if you belittle their concerns, it just does harm, and it doesn't help them get to where they need to be. They don't want
to take the meds. They don't want to be different.
I had a 9-year-old child who told me that they would call him to take his meds, and because he sat in the front of the room he would have to walk all the way past his peers. He felt like everybody was looking at him leaving the room, and then again when he'd come back in. So, we called the school nurse and aligned his schedule with lunch. This meant he could line up toward the back, and she would just swoop out, snatch him up, give him his meds, and launch him back into the cafeteria. The kids were so busy that they didn't even notice that he was gone.
I would say that being able to have an impact on people at one of the worst times of their lives is so important. From a research standpoint, being able to look at gearing the studies toward our adolescents, and then campaigning for studies involving younger children, and then, in the future, women who are pregnant.
Q3
You’ve participated in clinical studies focusing on treatment-shortening regimens for latent TB infection. How close are we to making these shorter regimens standard practice, and what challenges remain?
We’re seeing impact. We were one of the sites that studied 3HP, we looked at the 3-month rifapentinecontaining regimen. We saw it work, and that was really exciting. But next to that, we’ve incorporated it into our practice. Unless you have a contraindication, that's the one that we use. We're seeing completion rates like we have never seen before. We're pulling out data from 9 months of isoniazid, where we lost patient after patient to that. Then we went to 3 months of rifapentine, and we saw an improvement. But with the 3HP, it's just 12 doses, and we're seeing real impact. We're able to give that to children once a week at school. We're able to have adults come in once a week and receive their dosing. I would say that we're very close if we can keep the supply chains for the medications open. We went through a rifapentine shortage right when we got very excited after the regimen came out, and that seems to have loosened up again. Very recently, here in the USA, we also had an isoniazid shortage, and that really impacted almost everything we did. We have now been able to very aggressively incorporate that back in.
I would say that I think we're very close to the newest regimen, with the TBTC, that is shortening even further down to 6 weeks. I think it's looking good so far. From a patient tolerability standpoint, we won't know outcomes until we've had a further chance to follow.
I really think that we're getting there. I always tell this story that in 9 months, you start with a single ovum, and you get a whole baby. So 9 months of isoniazid, it's a pill every single day. Nobody wants to do that for 9 months, and if you're not even sick, you don't see the benefit. It's hard.
Q4
You lecture both nationally and internationally on TB. In your view, how does the level of TB awareness and treatment approach differ between countries, and what lessons can be learned from these global differences?
In the USA, as part of public health, we always joke that we do things that nobody knows. I tell them that we're ninjas. We go in and take care of what needs to be taken care of, and we come back out without breaking any furniture, and nobody ever knows. That's great for your patients, less stigma, but it's not so great for you getting the messaging out there. When you tell people they have TB they're like: ‘I heard my grandma had TB in the 50s. What is that?’ Getting education in the lower incidence countries is very different. The stigma in the higher incidence countries is a problem; that's really the difference between talking in the two areas, having to remind people that it's very stigmatizing, and be careful with your words and the things that you say.
In low incidence countries, when things hit the media, everybody's first question is: ‘Who is it?’ That's the double-edged sword of alerting the public that things are happening, but knowing that we do not want the patient punished, in any way, for just having a disease.
Q5 What is the current prevalence of TB in low versus high incidence countries?
High incidence country is considered 20 cases of TB per 100,000 people. In the USA, we're close to three; we were down as low as 2.2 I think, COVID-19 just did a number on everybody. The world numbers dropped, but the African continent did not have that hard drop like everybody else, and the European region is still trying to recover. Here in the North American region, we're rebounding pretty well, but we're still behind. We haven't caught up the numbers that we lost to people being isolated for COVID-19 and taking our eyes off of the problem.
Q6 Your research work also extends into HIV. How do treatment challenges of HIV and TB overlap? Has your experience in HIV care informed your approach to treating tuberculosis, or vice versa?
I started off as an assistant professor, junior faculty in HIV. I was, till this day, fiercely protective of my patients, of their information. Now there are commercials for HIV medication, and people are stepping out of the shadows and are a little more vocal about being treated appropriately. That has gotten better, but there is still a lot of stigma. I learned early the importance of the ways you phrase things, who you speak to, who you know, just being careful about what you disclose. In the same way as with our TB patients, the first thing we do with an HIV clinic is set up a safe space. When the patient walks in and they have TB, we know their first name, we know their children, we have a
conversation. They know they are welcome here, and that nobody's going to judge them.
With HIV co-infected patients, the challenge is that TB medications sometimes compete with their HIV medications. We’re making sure that we're working with the patient and their HIV provider so that all needs are being met. I think that's the more specific thing, but the stigma always runs in the background for both diseases. We're always trying to be careful if we come to screen patients at that establishment where they work.
What I learned in HIV has served me well when coming into TB. It's much easier to be very careful about disclosing people's personal information, ways that you can skirt around the answer to what the problem is, how you word your paperwork for them to be off work for a while. We're just very careful in our wording.
Treat people how you want to be treated. I think I got a lot of that from my mom. She used to tell us, when we're growing up, that nobody's better than you, and you're not better than anybody. If there's a meeting, you respect everybody, from the person who runs that meeting to the person who cleans up after. As a physician, I have a lot of patients who speak Spanish, and I always apologize that my Spanish is not as good as it could be. We have someone who speaks Spanish better than I do, but I'll kind of muddle through sometimes until my translator gets there. I’ll let them know that everything is not their problem or their fault, make them feel a little bit more empowered because a lot of control is taken from you when
you have TB. You have to isolate; you have to take these pills. Trying to give back some of that control to the patient, engaging them, is important. And okay, we have to take the pills, but where would you like to take them? When would you like to take them? Does it work better in the evenings? Never discount someone's side effects. No one should be expected to get up and feel sick every day.
Q7
As the world continues to grapple with emerging infectious diseases, what do you think are the key public health strategies we should focus on for controlling TB, especially in high-burden settings?
It's going to have to be education; educating people without scaring them. Educating folks on how to protect themselves, how to protect their children. Asking who the most important person is to them, and how we’re going to protect them. It’s about bringing it to a place where it's impactful for them. We learned a lot about COVID-19; like here in the US, you could isolate everyone, but there were people who still had to go to work. We had a disproportionate number of people who drove buses, who worked in areas where we couldn't shut down the public transit, because the people who were working in healthcare had to get to work. We had to look at how we could better protect some of the folks who make our world work. This is not unique. We have bus drivers in London. We have people who run petrol stations there. It’s the same learning on how to protect those individuals all the way down to that level. But education is crucial. I really feel like the infectious diseases are going
to keep coming, we're just seeing the beginnings. There'll be smaller ones, and there were smaller, less impactful waves. But this one hit us hard, and I think the waves are going to keep coming. The only way we're going to get there is by being honest in the education.
Q8With the rising concern about multidrug-resistant TB (MDR-TB), what advancements or innovations in treatment do you find most promising?
The last free-standing hospital in the USA is here in San Antonio, and I can peep out my office window and see it. But we had people who actually lived here for 2 years taking the MDR-TB medications because they were so toxic and they were so few that you could use. We now have the BPaLM regimen (bedaquiline, pretomanid, linezolid, and moxifloxacin), and bedaquiline has been a game changer. We have a regimen that has shortened to 6 months and is almost less toxic than our drugs for susceptible disease, but we're already starting to see some resistance emerge, and that is the most frightening thing, because we don't have a backup. There are other drugs coming down the pipeline, but they're not close. We don't have one that we can switch to. So, we're back close to where we started, we're going backwards. Like I said, the bugs are smart. They wait. If you're not paying attention, they're always waiting.
I attended the Union meeting that is this month, so I'm really excited. That's usually where we get the innovations. I think there was some impetus, once we got bedaquiline and we saw how impactful that was, to try to get more options, because
we knew what was going to happen. The baseline resistance to bedaquiline is around 2.2–3%. That's low enough that we're still able to get a lot of good things done. But if you look at all of the regimens that are being studied, they're all bedaquiline based. We haven't come up with that backup drug, but now that alarm has been sounded.
I think we'll start seeing some additional drugs that are coming along. There are some that are there. There's one, TBAJ-876, that is 10 times as effective as bedaquiline, and maybe without the cardiac toxicity. There are some things that are coming, and we're hoping that they will come fast enough that we don't have patients suffering. I think the part that people always forget is that if you don't have good drugs, you're giving somebody a whole lot of medications, and the chances that they're going to have toxicity is very high and you're going to be treating them for a long time. It's not something that's going to kill you quick, it’s something that's going to linger. That's always in
the back of my head, some patient is suffering because we don't have anything to offer them.
I try to explain to patients that they should get treated before they become infectious. I tell them that if you break down with disease, you're not going to infect that co-worker you don't like, because you're avoiding those people. It's the people that are closest to you, that you care about the most, who are most likely to get sick. The one, I would say, blemish on what's happening right now in TB is the emerging bedaquiline resistance, because that's going to most impact the forward motions we're making. However, there's a lot of effort in treatment shortening of drug susceptible TB, shortening of drugresistant TB. We need all the tools that we have, but it's an exciting time in TB compared to just 5 years ago. I'm very encouraged, but also very aware that the bug is very smart.
I think back to the standard RIPE regimen (rifampin, isoniazid, pyrazinamide, ethambutol) that was developed by the British Royal
Army Medical Corps and only really started being clinically used in the 80s. I was in high school or middle school at that time, and I was a child when they were first doing the studies. We’re only about 40 years after that. That was so impactful back then, but we’ve still got high numbers of TB. We put a dent in it, but we’re still chugging along, we're not getting things to where they need to be. We're not getting the regimens as aggressively to the folks who need to benefit from it. Worldwide, the DOT short course had an incredible impact. I saw that with the BPaLM regimen in MDRTB, and I think we'll still see the benefits, but our numbers are still high. That bug is not dumb.
We're already starting to see some resistance emerge, and that is the most frightening thing, because we don't have a backup
Melioidosis in Patients with Cancer, A Cloaked Menace: A Case Series
Melioidosis is an infection caused by the gram-negative bacteria Burkholderia pseudomallei The infection is endemic in South Asia and Australia, and several risk factors have been described for acquiring the infection, the most prominent among them being diabetes. Active malignancy is not a recognized common predisposing condition for this infection, but there have been several case reports of patients with underlying malignancies who have been diagnosed with concomitant melioidosis. But the increasing use of corticosteroids along with chemotherapy-induced immunosuppression could be factors that could lead to a possible rise of the infection in this patient population. The recognition of the infection is challenging due to nonspecific clinical features, but arriving at the diagnosis is crucial in view of the protracted course of antibiotics needed to treat the acute infection, while also giving eradication therapy to prevent recurrences. The authors describe a series of three cases of melioidosis in patients with active malignancy, each highlighting a different aspect of treatment of the infection.
Key Points
1. This article describes a series of cases of infection with Burkholderia pseudomallei in patients who had an underlying malignancy. While melioidosis is an infection that is endemic to South Asia and Australia, its incidence is underreported in several countries where it is endemic.
2. Melioidosis has not historically been associated with malignancies, but with the concomitant use of corticosteroids increasing, melioidosis could be a potential infection in this population of patients.
3. The diagnosis of melioidosis is challenging, and treatment requires a protracted course of antibiotic therapy, which could potentially add to the cost of cancer care, and inadvertent delays in the continuation of antineoplastic therapy.
INTRODUCTION
Melioidosis is an infection encountered in tropical climates, endemic to South Asia and Northern Australia. Burkholderia pseudomallei, a gram-negative bacillus found in soil and water, is the causative organism. Transcutaneous inoculation, inhalation, or ingestion have all been described as modes of transmission.1 Person-to-person mode of transmission is rare, and transmission of melioidosis via sexual contact remains unproven.2 Several risk factors have been described for the occurrence of infection, prominent among them being diabetes. Chronic renal disease, alcohol use, thalassemia, and occupational exposure have all been described as risk factors in literature.3,4 There have been sparse reports of the infection occurring in patients with active malignancy and receiving chemotherapy. This case series describes the authors’ experience in treating three cases of melioidosis in patients with active malignancies, all of whom were residents of southern India.
CASE REPORTS
Case 1
A 76-year-old male, who was on secondline therapy for relapsed multiple myeloma with lenalidomide, presented with a history of fever, decreased appetite, and bilateral lower limb edema. There was a history of intermittent fever spikes over a 2-week period. The patient was evaluated after admission. On initial examination, the patient was drowsy but arousable. There were no focal neurological deficits, and respiratory examination did not reveal any significant findings. A chest X-ray was performed for source identification, which showed lung infiltrates (Figure 1). Initial blood investigations revealed an elevated C reactive protein level (134.6 mg/L), and a complete blood count showed a total leucocyte count of 11.6x109 /L with a neutrophilic predominance. Empirical
antibiotics were started (cefoperazone + sulbactam). Blood cultures drawn on the day of admission were reported on Day 5 as positive for Burkholderia pseudomallei. Antibiotics were changed as per sensitivity pattern, and he received 14 days of intravenous (IV) meropenem. The patient improved symptomatically with defervescence of fever spikes and improvement in sensorium. Three days after discharge, the patient presented with worsening fever spikes and altered sensorium. Repeat blood cultures showed further growth of Burkholderia pseudomallei. The patient was started on parenteral antibiotic therapy with IV ceftazidime, which was again administered for a period of 14 days. The patient was counseled regarding the need for long-term oral antibiotic therapy and started on eradication therapy with oral cotrimoxazole for 3 months. The patient completed the course of eradication therapy, and while on the same he was restarted on anti-myeloma therapy with a rechallenge of the combination of cyclophosphamide, bortezomib, and dexona. The patient is currently on follow-up receiving maintenance bortezomib.
Case 2
A 54-year-old female patient, who had been diagnosed with multiple myeloma and was on first-line treatment with a bortezomibbased regimen, presented with a history of progressively worsening dyspnea. It was also known that the patient had Type 2 diabetes. Later it was also found that the patient had hyperglycemia, which was initially managed with intravenous insulin and later switched to subcutaneous basal bolus insulin. The patient underwent a high-resolution CT thorax because of persistent dyspnea, which showed lobar consolidation in the right lower lobe with associated minimal pleural effusion (Figure 2). Because of reduced IgG levels, suggestive of immune paresis, the patient received a dose of intravenous immunoglobulin. Empirical antibiotic therapy with IV cefaperazone + sulbactam was started and continued till Day 4 of admission, when blood cultures were found
Figure 1: Initial chest X-ray in Case 1 showing lung infiltrates.
Figure 2: CT Thorax of Case 2 showing right lower lobe consolidation with associated pleural effusion. associated scattered soft tissue densities in bilateral lung fields.
to be positive for Burkholderia pseudomallei. The patient was started on ceftazidime injection and received the same for a duration of 3 weeks, followed by eradication therapy with cotrimoxazole, for a total of 3 months. The patient continued antimyeloma treatment with bortezomib, lenalidomide, and dexona. One month after the initial acute episode, the patient developed a persistent cough with dyspnea on exertion; imaging showed a recurrent right-sided pleural effusion, which was drained, and cultures were sterile. The patient underwent a successful autologous stem cell transplantation after the completion of eradication therapy and obtaining clearance from the pulmonologist in view of a mildly restrictive pattern on pulmonary function tests, and is currently on regular follow-up.
Case 3
A 33-year-old patient, a diagnosed case of metastatic pancreatic neuroendocrine carcinoma with liver metastases, who was receiving chemotherapy with the combination of cisplatin and etoposide, presented with a high-grade fever for 2 days. The patient was febrile on examination (104 °F), but clinical examination did not reveal any focus of infection. Broad-spectrum antibiotics (cefaperazone + sulbactam) and other supportive measures were started. Blood cultures drawn on the day of admission were positive for Burkholderia pseudomallei. Antibiotics were changed to IV ceftazidime, in consultation with the infectious disease specialist. Ceftazidime was given at a dose of 2 gm IV every 8 hours for a duration of 14 days, the same was administered on an outpatient basis from the day care facility. Eradication therapy with trimethoprimsulfamethoxazole was started, but in view of poor tolerance to the drug, eradication therapy was changed to oral levofloxacin at a dose of 750 mg for a duration of 3 months. The patient continued his scheduled chemotherapy, after a delay of 1 week during the acute febrile period of the infection.
DISCUSSION
Melioidosis is an infectious agent that is endemic to tropical climates, with South Asia predicted to bear 44% of all cases.1 There have been suggestions that the incidence of melioidosis has been underreported in approximately 45 countries where it is considered endemic. The past decade has seen a sharp rise in the reporting of cases from several south Asian and southeast Asian countries, including India.1,5 The diagnosis of the infection remains challenging due to several factors, the signs and symptoms of the disease are nonspecific, and there is considerable overlap with other diseases endemic to these regions, such as tuberculosis. Melioidosis can affect any organ in the body, and clinical manifestations can include pneumonia, skin, and soft tissue infections. Neurological infections, abscess formation, and septic arthritis are also known manifestations of the infection. The occurrence of fulminant sepsis without an obvious focus of infection has also been reported. Pneumonia is the most common manifestation, and the majority of patients are bacteremic. The presence of bacteremia is associated with a more fulminant clinical course.2,6 Several risk factors have been attributed to the development of the infection. In a case-control study, Suputtamongkol et al.7 tried to identify the risk factors associated with acquiring the infection. Diabetes, renal impairment, and occupational exposure to contaminated soil and water were all demonstrated to be significant risk factors. Diabetes, in addition, was the sole factor found to have a significant association with the occurrence of bacteremic melioidosis. In this study, 60.9% of the patients had underlying diabetes as a risk factor, while only 4.2% had underlying hematological malignancies or solid tumors.7
There have only been a few reported cases of melioidosis in patients with underlying malignancies (Table 1). McIntosh et al.8 reported the case of a patient with nonsmall cell lung cancer receiving cytotoxic chemotherapy who developed melioidosis
Table 1: Previously reported cases of melioidosis in patients with active malignancy.
Report of Case Number of cases
McIntosh et al.,8 1999. One
Rossi et al.,9 2013. Two (Patient 2 had been previously treated and presented with recurrent infection)
Small cell carcinoma lung
Hairy cell leukemia
Laplertsakul et al.,10 2020. One
Mukhopadhyay et al.,11 2010. Two
Sukauichai,4 2020 One
Non-small cell carcinoma lung
Carcinoma ovary with febrile neutropenia (Patient 1)
Carcinoma stomach post gastrectomy with febrile neutropenia (Patient 2)
Carcinoma breast on neoadjuvant chemotherapy with febrile neutropenia
but completed the planned chemotherapy without interruption.8 Sukauichai et al.4 reported on a patient with Stage III carcinoma of the breast receiving neoadjuvant chemotherapy who developed neutropenic sepsis secondary to melioidosis bacteremia. Two cases were reported by Mukhopadhyay et al.11 on fatal pulmonary melioidosis in patients with febrile neutropenia following chemotherapy; both patients were nondiabetic.4,11 Melioidosis has also been reported to be mistaken for a diagnosis of malignancy. Baker et al.12 reported on a series of seven cases of melioidosis, which were initially presumed to be malignancies based on imaging and clinical findings. One of these cases was a patient with known lymphoma,
(acute + eradication)
Outcome
Ceftazidime + doxycycline Patient recovered and continued chemotherapy
Ceftazidime + cotrimoxazole+ docycline for acute infection and cotrimoxazole + doxycycline for eradication in Patient 1
Cotrimoxazole + doxycycline + ceftazidime for acute infection and 6 months of cotrimoxazole and doxycycline for eradication in Patient 2
Ceftazidime for 3 weeks + cotrimoxazole for eradication (20 weeks)
Teicoplanin and cefipime (Patient 1)
Piperacillin/tazobactam and cotrimoxazole for eradication (Patient 2)
Both patients recovered from their infectious episode
Ceftazidime + cotrimixazole for 20 weeks for eradication
Recovered from the infectious episode
Patient 1 had a rapid deterioration of her condition and succumbed to death (Burkholderia was isolated during post mortem)
Patient 2 recovered from the acute infectious episode
Recovered from the infectious episode and completed treatment of carcinoma breast
and the infectious process was initially suspected to be a progressive disease.12 In larger epidemiological studies, there have been considerable variations in the reported incidence of melioidosis in patients with underlying malignancies. Suputtamongkol et al.7 suggested that patients with hematological and/or solid malignancies were not more likely to develop melioidosis, and the immune impairment secondary to neutropenia did not possibly contribute to any enhanced risk for melioidosis. Currie et al.13 showed malignancy to be an underlying risk factor in 6% of their patients but led to mortality in 26% of those patients, yet this was not statistically significant.7,13
All three of the patients described here had a diagnosis of active malignancy, and only one patient had a history of underlying diabetes, while none of the three patients had a history of febrile neutropenia. All patients had received corticosteroids as part of the management of the malignancy, which has been postulated to increase the severity of the infection due to its immunosuppressive effects.14 Impairment of host immunity has been found to play a major role in the pathogenesis of the disease. Immune suppression secondary to the use of corticosteroids and cytotoxic chemotherapy are factors that mediate the risk of melioidosis in patients with active malignancies. Studies looking at the clinical outcomes following discharge from the hospital have been limited, with limited evidence showing that a quarter of patients required re-admissions, and a quarter of these patients required multiple re-admissions.11,14 In this case series, Patient 2 had to be readmitted as described, and residual restriction in pulmonary function tests was a concern while the patient was taken up for autologous stem cell transplantation.
The treatment of melioidosis consists of two phases, of which the acute phase is aimed at preventing mortality with high dose intravenous antibiotics. A minimum 14-day course is currently recommended, with the use of either a cephalosporin (ceftazidime) or a carbapenem (meropenem). Carbapenem is often reserved for the more critically ill patients.15 Eradication therapy is aimed at eliminating any residual lesion that might relapse and is recommended for an extended duration. Relapses have been recorded in 13–23% of patients from Thailand and up to 6% of patients from the Darwin study in Australia, but with the initiation of eradication therapy recurrences have now become rarer.16 Oral eradication therapy with cotrimoxazole should be given for a minimum of 12 weeks, which can be further extended to 24 weeks.17 Other approaches for eradication therapy have been studied, combination therapy with doxycycline did not have any additional benefit compared to cotrimoxazole alone. Levofloxacin is another
option but is not generally recommended due to its high degree of resistance. Rifampicin has also demonstrated strong bactericidal activity but is associated with a high degree of resistance.18
There was a significant delay in the commencement of definitive therapy for malignancy in Case 1, while poor initial compliance with eradication therapy led to rapid recurrence of the infection in the same patient. All three patients had prolonged hospitalization, with a median duration of approximately 15 days. Nevertheless, all three patients recovered from the infectious episode and were able to continue with further lines of management for their underlying malignancy (Table 2).
Melioidosis is a relatively uncommon cause of infection in patients with cancer, but the increasing use of corticosteroids and the immunosuppression associated with chemotherapy can predispose patients with active malignancies to the infection. The requirement of a protracted course of antibiotic therapy makes its recognition crucial, as in the absence of adequate eradication therapy there is a significant risk of recurrence. The residual sequelae of the disease can also complicate further treatment of the underlying malignancy, as in Case 2, where there was an added risk for autologous stem cell transplantation because of a mild restriction in lung function.
CONCLUSION
Melioidosis is an uncommon infection but is underreported in regions where it is endemic (South Asia, Australia). The association of malignancy with the risk of acquiring melioidosis has not been as strong as that with other risk factors like diabetes, as shown in several studies. The increased use of corticosteroids in combination with cytotoxic chemotherapy has been suggested as a factor that could increase the incidence of melioidosis in patients with active malignancies in several studies. Of the three
patients described here, all had an underlying diagnosis of active malignancy, and only one patient had previously been diagnosed with diabetes. All patients had received extended courses of antibiotics and prolonged hospitalization, including re-admission in
1 Multiple myeloma 76
2 Multiple myeloma 54
3 Neuroendocrine carcinoma pancreas 33
I: intermediate sensitivity; S: sensitive.
References
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2. Prinsloo C et al. The epidemiological, clinical, and microbiological features of patients with Burkholderia pseudomallei Bacteraemia—implications for clinical management. Trop Med Int Health. 2023;8(11):481.
one of the patients, leading to delays in commencing definitive treatment of the underlying malignancies. Thus, in the patients described, melioidosis added significantly to the burden of cancer care.
Male
Female
Male
3. Yadav V et al. Melioidosis as a mystique infection: a study from central india. Cureus. 2023;15(8):e43439.
4. Sukauichai S, Pattarowas C. Melioidosis with septic shock and disseminated infection in a neutropenic patient receiving chemotherapy. Case Rep Infect Dis. 2020;2020:8976180.
5. Limmathurotsakul D et al. Predicted global distribution of Burkholderia pseudomallei and burden of melioidosis. Nat Microbiol. 2016;1(1):1-5.
Amoxicillin/ clavulanic Acid (S)
Ceftazidime (S)
Cotrimoxazole (S)
Doxycycline (S)
Imipenem (S)
Meropenem (S)
Levofloxacin (S)
Amoxicillin/ clavulanic Acid (S)
Ceftazidime (S)
Cotrimoxazole (S)
Doxycycline (S)
Imipenem (S)
Meropenem (S)
Levofloxacin (I)
Amoxicillin/ clavulanic acid (S)
Ceftazidime (S)
Cotrimoxazole (S)
Doxycycline (S)
Imipenem (S)
Meropenem (S)
Levofloxacin (S)
First admission: 17 days
Second admission: 17 days
Total duration: 34 days
First admission: 23 days
Second admission: 5 days
Total duration: 28 days
Total duration: 10 days (received IV antibiotics on outpatient basis)
6. Chang CY et al. Disseminated melioidosis in early pregnancy-an unproven cause of foetal loss. BMC infect dis. 2020;20:1-4.
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8. McIntosh R, Norton R. Safe completion of planned combination chemotherapy despite septicaemic presentation of melioidosis. Aust N Z J med. 1999;29(1):91-2.
Table 2: Antibiotic sensitivity pattern and duration of hospital stay due to melioidosis.
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10. Laplertsakul G et al. Non-small cell lung carcinoma with concomitant localized pulmonary melioidosis: a rare coexisting disease. Infect Drug Resist. 2020:2957-61.
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for clinical management. Acta Trop. 2024;254:107209.
13. Currie BJ et al. The epidemiology and clinical spectrum of melioidosis: 540 cases from the 20 year Darwin prospective study. PLoS Negl Trop Dis. 2010;4(11):e900.
14. Chantratita N et al. Characteristics and one year outcomes of melioidosis patients in Northeastern Thailand: a prospective, multicenter cohort study. Lancet Reg Health Southeast Asia. 2023;9:100118.
15. Gee JE et al. Multistate outbreak of melioidosis associated with imported aromatherapy spray.NEJM.
2022;386(9):861-8.
16. Sarovich DS et al. Recurrent melioidosis in the darwin prospective melioidosis study: improving therapies mean that relapse cases are now rare. J Clin Microbiol. 2014;52(2):650-3.
17. Lim YM et al. Effective therapeutic options for melioidosis: Antibiotics versus phage therapy. Pathogens. 2022;12(1):11.
18. Ross BN et al. Evaluating new compounds to treat Burkholderia pseudomallei infections. Front Cell Infect Microbiol. 2018;8:210.
