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Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop (2024)

Chapter: 6 Advancing Research for Infection-Associated Chronic Illnesses

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Suggested Citation:"6 Advancing Research for Infection-Associated Chronic Illnesses." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
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6

Advancing Research for Infection-Associated Chronic Illnesses

Key Points from Individual Speakers and Participants1

  • There is an opportunity for the Food and Drug Administration (FDA) to spur patient engagement, explore innovation in clinical trials to provide feedback to researchers, facilitate considerations of viable endpoints, and support collection of additional types of data, such as real-world evidence. (Marston)
  • The ability to generalize Lyme disease research can be significantly affected by applying too narrow of inclusion criteria. Using real-world evidence such as patient registry data can help predict the effects of exclusion criteria on elements of studies. (Johnson)
  • Research led by patients or that meaningfully engages patients is more relevant to the patients’ lives, more effective, and leads to faster results. (McCorkell)
  • There are opportunities to further democratize research and include more people by using technologies to collect samples from home, centralizing tools, and removing barriers that prevent people from participating. (Amitay, Marston)

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1This list is the rapporteurs’ summary of points made by the individual speakers identified, and the statements have not been endorsed or verified by the National Academies of Sciences, Engineering, and Medicine. They are not intended to reflect a consensus among workshop participants.

Suggested Citation:"6 Advancing Research for Infection-Associated Chronic Illnesses." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
×
  • Barriers prolonging patient journeys include patient and provider lack of awareness, limited access to care, complex care navigation and poorly defined conditions, lack of proven treatments, and stigma. (Geng)
  • Studies of diagnostic assays demonstrated that there must be a persistent viral infection or viral reservoir that is continually producing the spike protein. (Walt)
  • Multiple infections result in chronic illnesses that are remarkably consistent, which suggests a universal mechanism. (Deeks, Fallon)

This chapter begins with an overview from FDA on its role in this field of research, and what it has been doing to speed the discovery and testing of potential diagnostics and treatments. This chapter also reviews current patient-driven research efforts and the infrastructure and innovation needed to close gaps in this area and promote progress for patients.

PERSPECTIVE FROM THE FOOD AND DRUG ADMINISTRATION

Hilary Marston, chief medical officer, FDA, reviewed the challenge for researchers in translating the growing recognition of infection-associated illness into advances in understanding and treatment. This increased awareness is counteracted by a lack of treatment options, barriers to diagnosis, and inadequate patient care, she said, and there is a lack of understanding of the cause and effect and linkages between infections and long-term symptoms. While biomedical science and technology is rapidly advancing, these advantages are not resulting in superior health and outcomes for most of the U.S. population, she added.

Using long COVID as an example, she said there has been a good amount of work just to create an interim federal working definition of the chronic condition. While it is broadly defined as signs, symptoms, and conditions that continue or develop after initial infection, she noted that it is likely not just one condition. Long COVID represents many potentially overlapping entities that may have different biological causes and sets of risk factors and outcomes. Even estimating the prevalence of long COVID has been challenging, with estimates ranging from 5 to 30 percent of people infected with severe acute respiratory syndrome coronavirus 2 (CDC, 2023b). Marston outlined several possible causes that are being explored by many researchers, including autoimmune response, persistent virus, organ damage, or microclots. Looking at the range of signs and symptoms will be essential in moving product development forward and getting some

Suggested Citation:"6 Advancing Research for Infection-Associated Chronic Illnesses." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
×

kind of consensus on key priority symptoms, while also addressing specific symptoms and the needs of the pediatric population, she said.

Marston reiterated that currently there are no drugs approved by FDA for the treatment of long COVID, and for most patients the goal of medical management right now is to improve and optimize their quality of life. She reviewed several challenges to drug development in this area, one being that long COVID is a new entity with many features, making it difficult to assess the effects of a single intervention. Additionally, because of the heterogeneity of symptoms, different treatment approaches may be needed for patients with different symptoms, including pediatric populations. Since so many of the chief complaints relate to how patients feel and function, there is also a lack of reliable tools to assess and evaluate how treatments might affect those factors for long COVID patients. She acknowledged that these same challenges in diagnostics and treatment of long COVID also apply to posttreatment Lyme disease syndrome (PTLDS). On the treatment side, no solutions have been proven effective so far, she said.

Marston stated that the role of FDA is to spur patient engagement, explore innovation in clinical trials and provide feedback to researchers, facilitate considerations of viable endpoints, and support the collection of additional types of data, such as real-world evidence. Elaborating on patient engagement, she emphasized that patients are experts in their conditions, and their input is needed early in the drug development process. She described a patient-focused drug development team meeting for long COVID and working to understand the most significant symptoms of the condition and the current approaches to treatment. FDA worked with other agencies such as the Office of the Assistant Secretary for Health, the National Institutes of Health, and the Centers for Disease Control and Prevention to plan the patient-focused drug development meeting for long COVID. FDA also collected many patient perspectives on symptoms and daily effects as well as treatment approaches. In the absence of effective treatments, patients reported use of over-the-counter products, diet modifications, and acupuncture, but they wanted treatment that targeted the root cause of long COVID instead of just their various symptoms.

Marston shared several challenges with clinical trials for these types of conditions. Access is a main barrier, whether because of the debilitating symptoms or the rural location of many patients, so a virtual, decentralized trial platform is essential. As researchers consider clinical outcome assessments that reflect how an individual might feel or function, she emphasized reviewing FDA’s guidance on selecting, developing, or modifying fit-for-purpose clinical outcome assessments (FDA, 2022). For next steps, she said FDA will continue to strengthen efforts to advocate for innovative clinical trials, advance methods of data collection, and increase coordination throughout the agency for addressing these types of infection-associated illnesses.

Suggested Citation:"6 Advancing Research for Infection-Associated Chronic Illnesses." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
×

A participant asked about whether a platform of clinical trials with multiple arms and a single placebo is a viable option for these diseases. She replied that FDA often and repeatedly encourages platform trials, which help to assess comparable treatments in different conditions. It can also be a very efficient use of government resources, especially in the case of an outbreak or scenario where time is of the essence, and she would encourage this approach. Specifically considering children with long COVID, she said FDA hosted a workshop in Fall 2022 on pediatric long COVID. Part of the reason it is poorly understood is because of the variable study methods used to examine its natural history. Some studies captured more immediate sequelae, and others looked further down the line in population-based surveys, she said. It is still understudied in the pediatric population, but what is lacking is a coalescing of methods on how to best study it compared to the adult population. FDA, she continued, is engaging in conversations, convening a research community, and ensuring that its efforts reflect the pediatric patient population in discussions and projects. Whenever projects are brought to FDA for the adult population, there also needs to be some dedication to the pediatric population.

PATIENT-DRIVEN RESEARCH

A panel of speakers provided remarks on the importance and successes of patient-driven research across diseases areas, and considered how these successes may be translated to address infection-associated chronic illnesses. Perspectives include long COVID, myalgic encephalitis/chronic fatigue syndrome (ME/CFS), and PTLDS.

Patient-Led Research Collaborative

Lisa McCorkell, Patient-Led Research Collaborative (PLRC), introduced herself as a person living with long COVID since March 2020 who has been fighting for the advancement of infection-associated chronic conditions research and long COVID research over the last 3 years. She shared some of the work and recent findings from PLRC and a vision of what a patient-driven research agenda might look like. PLRC began when the cofounders got sick in March 2020 and now has more than 45 members across four continents, she said. While the cofounders initially had fairly mild infections, they never recovered to gain full health. Following an op-ed in the New York Times describing the experience of not recovering from the initial COVID-19 infection (Lowenstein, 2020), the Body Politic COVID-19 support group was formed and many people immediately joined to share their symptoms and experiences. Soon after, the members of that group developed a survey to identify trends in symptoms, and that led to the first research on long COVID, McCorkell explained. They identified 62 symptoms, including neurological symptoms, which at the time was

Suggested Citation:"6 Advancing Research for Infection-Associated Chronic Illnesses." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
×

unexpected since COVID-19 was still seen as a purely respiratory illness. At that time it was also difficult to access tests, she added, and many of the members were being denied care because they did not have a positive COVID-19 test, yet the symptoms of those patients aligned very well with those who did test positive.

As time went on, more people became infected with COVID-19, but many of these patients with persistent symptoms were not getting better, she shared. PLRC continued gathering evidence from the growing patient community and demonstrated that many people develop long COVID even after a mild initial infection. Because many patients felt dismissed by health care workers and researchers, they developed another survey that resulted in a paper published in the Lancet (Davis et al., 2021). At this point, she said, PLRC leaders had begun connecting with people who had ME/CFS and mast cell activation syndrome and were able to identify numerous overlapping symptoms. They have now documented more than 200 symptoms that come and go over time and found that two-thirds of people with long COVID had to either reduce their work schedules or stop working completely because of their illnesses. McCorkell highlighted another paper published in Nature Reviews Microbiology focusing on the mechanisms of long COVID and their overlap with other conditions (Davis et al., 2023).

Overall, McCorkell said, her team has published several papers on long COVID and different aspects of health, including a focus on pediatric populations, psychiatric outcomes, and reproductive health effects. Though this last effect is understudied, she said many patients experienced reproductive health problems with long COVID, overlapping with such conditions as ME/CFS, postural orthostatic tachycardia syndrome (POTS), and Ehlers-Danlos syndrome (see Figure 6-1).

The variety of overlapping female reproductive conditions that have been observed in patients with long COVID, ME/CFS, POTS, and EDS are outlined. Four horizontal rectangles moving from pink on the left to lavender on the right list symptoms by category. From left to right the categories are “menstrual”, “gynepathologies”, “fertility and pregnancy”, and “menopause”, with a drop of blood, the female reproductive system, a pregnant woman, and a grey drop representing each category.
FIGURE 6-1 Female reproductive conditions in long COVID (LC), myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), postural orthostatic tachycardia syndrome (POTS), and Ehlers-Danlos syndrome (EDS).
SOURCE: Lisa McCorkell presentation, June 30, 2023; Pollack et al., 2023.
Suggested Citation:"6 Advancing Research for Infection-Associated Chronic Illnesses." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
×

McCorkell highlighted some other work she and collaborators have produced, including a survey on the effect of reinfections on people with long COVID, patient-generated hypotheses for further research, and using the data and patient experience available to advocate for better research, guidelines, and policy. When the research incorporates the patient’s perspective, even when not led by patients, said McCorkell, it leads to better research and better outcomes. It is often more relevant to the patient’s lives, more effective, and leads to faster results. For example, postexertional malaise was a top symptom in the PLRC study only because the patient-researchers knew to ask about it since they were experiencing this symptom, she said. This symptom does not have its own International Classification of Diseases (ICD) code and many providers are not familiar with it, so it is often only through incorporating patient involvement and understanding that researchers are aware of the need to include this symptom.

Touching on incentives, McCorkell said much of this work was done out of desperation because these researchers were also patients and needed answers, so they took more risks than other biomedical researchers under normal conditions. She added that this demonstrates how critical it is for funders to recognize the value of this type of research and support it. PLRC’s priority is for the research to be impact driven and disseminate results widely and quickly. In academia, she said it can take over a decade to translate research into clinical practice, and for patients living with a debilitating disease that is far too long. McCorkell described a patient scorecard that PLRC members developed to help researchers evaluate their patient collaboration throughout the research process. Thinking about what a patient-driven agenda might look like, she shared some important considerations for developing effective and inclusive patient-led research:

  1. Ensuring the meaningful engagement of patients and caregivers in all stages of the research process, integrating new and existing evidence across infection-associated chronic conditions.
  2. Accelerating the clinical trials of therapeutics that are most important for the patient community.
  3. Improving coordination so research does not exist in siloes, such as establishing an office for infection-associated chronic illnesses within the National Institutes of Health (NIH) director’s office.

Solve ME/CFS

The field of chronic illness research is in the middle of a paradigm shift, said Oved Amitay of Solve ME/CFS, largely because of the COVID-19 pandemic. Solve ME/CFS was established in 1987 as a result of a number of viral outbreaks in the United States and United Kingdom from which

Suggested Citation:"6 Advancing Research for Infection-Associated Chronic Illnesses." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
×

many patients developed chronic illnesses. The ME/CFS community has long recognized that this chronic condition is often associated with an onset of acute infection, so Solve ME/CFS saw the potential for extended effects of illness from COVID-19. Recognizing the importance of gaining funding to research this issue, Solve ME/CFS worked to develop a House resolution introduced by Representative Jamie Raskin called the Understanding COVID-19 Subsets and ME/CFS Act, requiring NIH to support research looking at ME/CFS as part of long COVID. This was before evidence of the overlap was identified, he said, but they requested the Department of Health and Human Services to carry out a public awareness campaign about these types of postviral chronic neuroimmune diseases.

Amitay said that patient-driven data platforms are an important tool to provide patients with the opportunity to participate and advance the understanding of their condition. Historically, patients had to be physically present at the study sites to participate in clinical studies, meaning they had to allocate time to travel and sometimes risk exacerbating their conditions. Democratizing research requires a change in the system, he said, such as using technological tools to help collect samples from home, centralizing tools, and removing barriers preventing people from participating. Patient organizations play a unique role in providing insights into the conditions and can also add value to participation in research, helping to recruit patients for clinical trials and ensuring they are well represented.

Using ME/CFS as an example, Amitay explained that, historically, not a lot of longitudinal data about the disease have been collected. To address this, Solve ME/CFS developed a patient registry and started a study, approved by an institutional review board, that collected data directly from patients with no intermediary. After the May 2020 launch, Solve ME/CFS also opened a cohort of people with COVID-19, some of whom developed long COVID.2 Solve ME/CFS is now working to migrate this dataset to a different platform, removing some of the data collection burden from patients, and making it open and available to everyone. Solve ME/CFS hopes to accelerate recruitment into clinical trials and run nested studies within the platform to accelerate diagnostic and therapeutic development.

Sharing some of his team’s findings, Amitay highlighted that the majority of participants in the ME/CFS cohort are female, which is also seen in the long COVID group. About 22 percent of patients in the long COVID cohort reported disabling symptoms, compared to 31 percent in the ME/CFS cohort. In summary, Amitay shared that half of people who have

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2A cohort generally refers to a group of individuals participating in a biomedical study, who are followed longitudinally for data collection (e.g., biological samples, surveys) in order to glean the development of disease condition outcomes. This cohort stood up by ME/CFS may provide data for future retrospective or prospective studies and analyses.

Suggested Citation:"6 Advancing Research for Infection-Associated Chronic Illnesses." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
×

been living with long COVID for more than 1 year meet diagnostic criteria for ME/CFS, which indicates a looming crisis. He also suggested that a complementary NIH structure would benefit from being guided by a common research agenda.

MyLymeData

Lorraine Johnson, LymeDisease.org and MyLymeData, shared information on her organization, discussing inclusion and exclusion criteria in clinical trials and how her organizations’ patient registry data can help in determining generalizability of potential therapeutics. Her teams have enrolled more than 17,000 patients since 2015, with the primary goal to increase scientific knowledge in Lyme disease and use its data to influence public policy. Unlike randomized control trials (RCTs), she said, patient registries use broad enrollment criteria and collect a wide array of information, including data on diagnostic validation. This results in a database that has both breadth of enrolled patients and depth for potential details needed, including data that only patients know, as 50 percent of Lyme patients receive care outside the insurance system, said Johnson. She shared a list of alternative treatments patients had tried and how they rated the effectiveness, demonstrating patient innovation in using alternative treatments. This information is likely to be unavailable in electronic health records or insurance databases.

Johnson also discussed patient subgroups and evaluating enrollment criteria, saying that patient registries like MyLymeData excel at describing patient populations because of the amount of information they collect from a broad group of patients. Johnson and colleagues have been able to explore symptom subgroups and identify antibiotic treatment responders and nonresponders, as well as sex-based differences in Lyme disease. Assessing the effect of exclusion criteria in studies, her teams examined four common research enrollment criteria: positive Western blot, history of rash, expression of characteristic symptoms and severity, and no diagnosis of ME/CFS or fibromyalgia. They looked at the attrition rate on the sample from each individual indicator and the cumulative effect on the sample and found that when they required patients to have a history of the rash or positive Western blot, 35 percent of patients were eliminated. When all four criteria are applied, just 39 percent of the original sample remain. Johnson contended that this substantially compromises the generalizability of the study results and increases the time and cost of the study to recruit enough patients. While researchers are trying to apply rigorous definitions to eliminate potential confounding factors, many of these RCTs end up eliminating between 89 and 99 percent of people who sought to enroll, she believed.

Suggested Citation:"6 Advancing Research for Infection-Associated Chronic Illnesses." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
×

She highlighted recent calls to relax some of these criteria and noted a 2018 FDA report that called attention to the tension between balancing the merits of stringent inclusion criteria for targeted studies and broadened inclusion criteria for generalizability (FDA, 2018). She called for researchers to think through the implications of different inclusion/exclusion criteria and make sure that what they are using is necessary for the trade-off in generalizability and sample attrition to determine cause and effect. As a final statement, Johnson suggested that when determining enrollment criteria, researchers should consider the effect that various criteria will have on recruitment, time, cost, statistical power, and generalizability. She added that one potential way of doing this is using real-world evidence such as patient registry data to predict the effects of each criterion on the enrollment for any given study.

Lyme Disease Biobank

Liz Horn, Lyme Disease Biobank, continued the conversation discussing well-characterized samples. She explained that Lyme Disease Biobank includes three distinct cohorts: early Lyme disease samples, persistent Lyme cohort, and a tissue bank that includes post-mortem3 samples. While well-characterized samples are key to advancing research, they require time, human resources, and funding to collect. She shared important questions to consider, such as which patient populations are needed, whether existing samples can be used or whether there is a need to prospectively collect them, strategies for collection, and what administrative, legal, and regulatory steps are needed. Well-characterized samples are essential, Horn said, but researchers need standardized protocols, chain of custody, laboratory or diagnostic test results, and possibly imaging pieces or additional data sources. Horn stated her support for centralized collections as they reduce costs and redundant infrastructure, increase efficiencies, support multiple projects with each blood draw, and are designed to be shared and bring new people in the field.

Horn said Lyme Disease Biobank has more than 1,200 participants enrolled across the country, and that each donated sample can support approximately 50 research projects. The biobank supports more than 85 projects in academia and industry with samples. Its collection of early Lyme disease samples targets symptoms of early Lyme in endemic areas. The biobank’s researchers recognize the variability in how the traditional bull’s-eye rash (erythema migrans) presents, which Horn called attention to because it may often be an inclusion criterion for a trial. Biobank researchers collect whole blood, serum, and urine samples, and they collect from places

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3For more information about the Lyme Disease Biobank, see https://journals.asm.org/doi/10.1128/jcm.00032-20 (accessed December 10, 2023).

Suggested Citation:"6 Advancing Research for Infection-Associated Chronic Illnesses." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
×

that are usually outside of research avenues such as family practices and urgent care centers. This collection will be used to inform the development and validation of new diagnostics. Horn shared that biobank researchers also collect samples from people with persistent Lyme, and this cohort is supporting 15 projects for novel diagnostics and biomarker exploration. Having these resources available to the research community is important, Horn added, and her teams also require researchers to provide data back to the biobank so they can share the findings with other researchers.

Lastly, it is critical to go beyond blood and also look at tissue, Horn said. The biobank holds tissue samples from 14 postmortem donations, which are linked to robust clinical information, including anonymized medical records. These tissues represent complicated cases that included neurocognitive and neurodegenerative conditions. With permission, these samples can also be linked to MyLymeData profiles. The biobank is working to develop a tissue analysis pipeline to characterize tissue while looking for evidence of infection or inflammation, conducting a comprehensive neuropathologic evaluation, and testing for a variety of pathogens, including Borrelia spp. All of this information is also being fed back to the biobank, she said, which will only make it stronger. Finally, she highlighted a call to action to standardize the evaluation of microbes in tissue. She noted that this can be crucial as researchers continue to learn from other disease areas and incorporate any lessons from the disease overlap.

Discussion

The discussion that followed included topics such as standardizing sample collection, using appropriate language in research, the role of patient-driven research, and recognizing the lived experience of patients in workplace settings. Regarding sample standards, Johnson said, so many tools are available today that were not available years ago, and there is even greater opportunity to develop sample standards using big data and real-world evidence. More complete data will help ground researchers in the validity of their findings, she added. Johnson added that it is important to continue analyzing existing data to identify additional use cases.

Using long COVID studies as an example, McCorkell pointed out that documented positive polymerase chain reaction (PCR) test is often used as inclusion criteria. Perhaps this should be reserved for narrow-scope clinical trials, she suggested. This would allow a subgroup of patients without documented PCR evidence to provide samples for analysis and potential use for more general trials. Amitay agreed, saying that it is important to remember that diseases are human constructs. Biology does not listen to how things are labeled, he noted. We need to go beyond these constructs, he said, especially when looking at samples with a renewed broader lens.

Suggested Citation:"6 Advancing Research for Infection-Associated Chronic Illnesses." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
×

In terms of appropriate language when working with patients, Johnson said language can become contentious and divisive in instances when it does not have to be. She supports the use of the broad term infection-associated diseases. McCorkell added that long COVID is a patient-created term, and it took researchers awhile to adopt because they wanted something more scientific. There are journals that still refuse to use the long COVID term but patients continue to use and socialize it. Having researchers and clinicians open to using terminology that patients want is helpful, she said, emphasizing the importance of listening to patients.

Amitay said there has been a profound change in how long COVID has increased the inclusion of patients in research. Many of these communities have been neglected for several years, he said. Long COVID has made a big impact and provided an opportunity to look at all of these conditions with a broader lens. Incorporating this research together into collaborative efforts now can ultimately create a larger body of knowledge and help all communities. Horn added that while it is unfortunate long COVID affects so many people, it has legitimized other similar conditions and brought them more to the forefront of research.

A participant highlighted the importance of lived experience of patients who are trying to continue working, as many patients with unseen disabilities are stigmatized and often sent to counseling instead of having their conditions recognized. This is very important, replied Johnson, as surveys on stigma and marginalization related to unseen disabilities have shown that around 75 percent of respondents have felt dismissed by a health care provider. People fear stigma at work and are afraid to lose their jobs. Johnson reported that people with chronic illnesses or unseen disabilities rarely tell people outside of their innermost circle of immediate family and close friends about their conditions, which can be socially isolating. McCorkell added that all of these conditions are covered under the Americans with Disabilities Act, so employers are required to provide accommodations but often do not. She added that academia is another area that needs a paradigm shift in how employees are treated. Nearly 4 million people are out of work because of long COVID, she said, and it is just going to get worse; academia needs researchers to continue this important work.

RESEARCH INNOVATION AND REQUIRED INFRASTRUCTURE

To complement the benefits of including patients in research, coordination, and collaboration across research in different disease areas also provides opportunities to learn from past successes in other underresearched conditions. This section highlights long COVID patient journeys and diagnostic tools in development, and lessons from human immunodeficiency virus (HIV) and Lyme disease networks.

Suggested Citation:"6 Advancing Research for Infection-Associated Chronic Illnesses." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
×

Understanding the Patient Journey in Long COVID

“She went to one doctor, then another, then another,” said Linda Geng, Stanford University, quoting a news headline (Cha, 2022) that resonates with many clinicians in this field who have patients bouncing around the health care system. Geng described her field of consultative medicine, which focuses on patients with puzzling conditions who get lost in fragmented systems while seeking diagnosis and treatment. Postinfectious syndromes are commonly seen in this context, she said. A study of patients seeking second opinions for puzzling symptoms at Geng’s clinic revealed that nearly one-fifth of patients had an infection, she said, and postviral syndrome was among the top of diagnostic outcomes when looking at the 10 most common symptoms that present to a clinic like hers (Chao et al., 2022). While the ideal journey for a care-seeking long COVID patient would be straightforward and linear, the reality is anything but, she said. Many patients have seen dozens of doctors and multiple specialists, meeting lots of roadblocks and dead-ends along the way.

Geng highlighted the lack of patient and clinician awareness as a significant barrier that prolongs these journeys. People often do not realize these types of chronic conditions exist, which is particularly important for vulnerable populations with low health literacy and language barriers. This highlights the importance of equity and care provision for vulnerable communities who have been disproportionately affected by the pandemic. Another factor contributing to long patient journeys is limited access to health care, with long months of waiting lists, complex care navigation, misdiagnosis, and poorly defined conditions.

Geng noted that it is important to take a broader lens and also look at other postinfection-associated diseases, and even postvaccine conditions. She shared that her clinic has seen many patients who develop long COVID symptoms after the vaccine but may or may not have had prior infection, underscoring the need to understand the intersection or common pathways of immune dysregulation. Adding to these challenges, she highlighted a study that found symptoms similar to long COVID can also occur after an influenza infection, though less frequently (Taquet et al., 2021). This highlights the difficulty of the evolving definition of long COVID and thinking about the inclusiveness for access to care. Geng shared that clinicians should apply the term as broadly as possible when considering access to care. When considering precision for research, researchers need to know the conclusions drawn are applicable to the right populations to accurately develop targeted therapy, she explained.

The lack of treatment is another significant barrier. Treatment can help support accurate diagnoses, resulting in a positive feedback loop. Stigma that comes with infection-associated chronic illnesses is a barrier to care for this population, she said. In her own work, she has often heard patients say that no one believes them, and they are dismissed by friends, family members, and employers. The lack of mechanistic understanding is a chal-

Suggested Citation:"6 Advancing Research for Infection-Associated Chronic Illnesses." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
×

lenge for providers in legitimizing the conditions, so she pushed for being able to better understand the mechanisms.

Geng cautioned about erroneous leaps to conclusions where there are gaps of knowledge that need to be filled—which is the case for long COVID as well as other postinfectious syndromes. Instead, she is encouraged that many researchers are helping to build the knowledge base of potential mechanisms, which can lead to better treatments, better care, and improved lives. She offered future directions to improve care for these types of conditions:

  • Building multidisciplinary teams, and harnessing collective intellect.
  • Engaging patients, family, and advocates.
  • Studying models of care.
  • Incorporating reimbursement and finance factors.
  • Considering equity and community.
  • Integrating education and training.
  • Advancing knowledge and research.
  • Synergizing knowledge across syndromes through intersections and broad applications.

Diagnostic Assays

David Walt, Harvard University and Brigham and Women’s Hospital, described development of ultrasensitive assays. His team developed single molecule arrays that can quantify immune complexes in the samples and enhance assay sensitivity by three to four orders of magnitude compared to the conventional enzyme-linked immunosorbent assay (ELISA), he explained. These arrays are a digital tool that can be used to make ultrasensitive measurements. Applying his team’s method to a number of assays for COVID-19 patients at different time points after the initial acute infection, Walt and colleagues found that the full viral spike protein was detectable in 60 percent of patients with long COVID in this cohort even though they were producing viral neutralizing antibodies (Swank et al., 2022). Walt’s team believed there is a persistent viral infection or viral reservoir that is continually producing the spike protein.

Lastly, he briefly touched on a new RECOVER-VITAL study, looking at therapeutic intervention (in this case, an antiviral drug) to see whether it improves outcomes in long COVID patients. He predicted a launch in Summer 2023, with goals of 100 sites and 900 adults enrolled.4 Researchers in

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4The RECOVER-VITAL study, intended to examine whether the antiviral Paxlovid (nirmatrelvir and ritonavir) improves symptoms for people who have long COVID, enrolled its first participant in July 2023. For more information on the RECOVER-VITAL study, see https://

Suggested Citation:"6 Advancing Research for Infection-Associated Chronic Illnesses." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
×

the study are hoping that individuals with the spike protein and persistent viral infection will find their symptoms ameliorated with the drug.

Drug Repurposing for Translating Infection-Associated Chronic Illness Research

Similar to several other speakers, Steven Deeks, University of California, San Francisco, explained that he is new to this field and was in fact working on HIV/AIDS before 2020, but has since applied this experience to studying long COVID. While the concept of long HIV has never really been established, he wondered whether some patients may suffer from it, as he has seen people in clinics that have ongoing issues affecting their quality of life. The assumption that these effects are caused by drug toxicity needs to be revisited, he said. Thanks to committed and sustained investment from the National Institute of Allergy and Infectious Disease in HIV biology, scientists have revealed some mechanisms enabling HIV to cause some of the comorbidities, and they are quite similar to those associated with long COVID.

He described his team’s decades of work in using existing drugs and repurposing them for experimental medicine to address the potential root causes and resulting symptoms of inflammation. Collectively, throughout many studies over the years, researchers were able to understand the pathogenesis mechanism of HIV. Experimental medicine is a potential way to identify disease mechanisms while bridging engagement from industry partners to develop products for these mechanistic pathways. With knowledge of these disease pathways, it is possible to measure the effect of the proposed treatment to see whether outcomes improve.

There are several pathways being explored in developing therapeutics for long COVID, and they are similar to the approaches taken for HIV. What is still needed are proof-of-concept studies, he explained, that can allow for more investment and encourage involvement from companies that know how to develop therapeutics. As an example, he said one leading cause of potential issues is acute viral infection with irreversible tissue damage, and much of the discussion in the workshop has been related to pathogen persistence in tissues. A possible therapy for this pathway is intervention with antiviral drugs, particularly monoclonal antibodies, he said, because they can block the virus from spreading and potentially clear out the dead virus reservoirs as well. Other potential treatments include anti-inflammatory drugs, intravenous immunoglobulin, B cell directed therapeutics, antiplatelet drugs (e.g., aspirin), anticoagulants, or fibrinolytics. Deeks noted a clinical trials agenda led by Michael Peluso in which multiple interventions will be examined in a common platform across studies. Their team at the University of California,

___________________

trials.recovercovid.org/vital (accessed December 7, 2023).

Suggested Citation:"6 Advancing Research for Infection-Associated Chronic Illnesses." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
×

San Francisco will begin with examining the effects of a monoclonal antibody that can inhibit viral replication and clear viral reservoirs. They are also seeking funding to apply a novel drug that is in development to treat a range of diseases from rheumatological disorders to long COVID, he said.

As another parallel to HIV, Deeks referenced the 1990s phenomenon of the Dallas Buyers Club, a major motion picture documenting the story of a number of HIV patients who, out of desperation, looked outside the health care system for any available treatment that might be effective to alleviate their conditions. This is happening now with long COVID, he said, as people and physicians are desperate for treatment options. No one can wait for 5 years for things to be studied and proven, and many treatments are being administered offline and off-label, Deeks said, sharing that he follows this movement very closely as even anecdotal information can be helpful to see what is working or not. What would be really helpful is a biomarker, he added, noting the transformative shift that occurred in therapeutics development when viral RNA was identified as a biomarker for HIV. Identifying surrogate markers validated by FDA could lead to a lot of investment and progress in the field. However, breaking down the silos between disease areas will be a key part of realizing greater progress, he noted, as the similarity between diseases following different infections suggests a universal mechanism.

To summarize, Deeks said that there are multiple pathways and factors involved in the emergence of infection-associated chronic illnesses, suggesting a need for combination approaches. There is a massive repository from 2020 that can be used to test different mechanistic hypotheses, and clinical trials to uncover the mechanisms are needed so industry partners are incentivized to get involved and bring their expertise to develop the necessary drugs and treatments. There are many people working on these issues, he noted, but some of the work can be redundant because researchers have limited interactions with each other. He called for more meetings such as this workshop where people can come together, understand roles, and figure out how to best collaborate and optimize outcomes.

Posttreatment Lyme and New Clinical Trials Network

Brian Fallon, Columbia University, presented on the off-label use of medications for Lyme disease, as well as symptoms of PTLDS, underlying mechanisms, prior clinical trials, and the Clinical Trials Network Coordinating Center for Lyme and other Tick-borne Diseases at Columbia University. He referenced the overlap between PTLDS and long COVID syndromes, reiterating that there may be common mechanisms underlying both syndromes. Speaking of PTLDS specifically, Fallon discussed the common cognitive deficits experienced, with up to 90 percent of PTLDS patients reporting cognitive difficulties, and up to 30 percent having objec-

Suggested Citation:"6 Advancing Research for Infection-Associated Chronic Illnesses." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
×

tive, measurable problems affecting short-term memory and processing speed (Touradji et al., 2018). On rare occasions, Lyme disease can even cause encephalitis leading to severe psychiatric disorders, but patients often make a full recovery once this is recognized and treated with antibiotics. Also related to mental health, Fallon noted that suicidal ideation is common in patients that he sees at research clinics, with one in five reporting suicidal thoughts (Doshi et al., 2018). In patients with mild to severe depression, this number increases to two-thirds.

Because he is a psychiatrist, Fallon wanted to ensure he was not drawing conclusions on psychiatric symptoms of Lyme disease from a biased sample population. Fallon collaborated with researchers in Denmark using a registry of nearly 7 million people over 22 years to study the connection between Lyme borreliosis and mental disorders and suicide. Of the 7 million entries in the registry, more than 12,000 had a hospital-based diagnosis of Lyme disease (inpatient, outpatient, or emergency room); among these individuals there was a 28 percent increased rate of a subsequent mental disorder compared to all others who had never had a hospital-based diagnosis of Lyme disease (Fallon et al., 2021). There was also a 40 percent increase of subsequent depression, a two-fold increase in suicide attempts, and a 75 percent increased rate of suicide among those with hospital-based diagnoses of Lyme disease.

There are several potential mechanisms for these ongoing symptoms, Fallon explained, including persistence of infection, immune dysregulation, neurologic dysfunction, and other possibilities such as formation of microclots, altered gastrointestinal microbiome, or mitochondrial dysfunction. There are also physiologic similarities with other diseases, as other speakers have noted, as well as distinctions. He shared one study using cerebrospinal fluid (CSF) and found that PTLDS encephalopathy was associated with a distinct CSF protein profile compared with ME/CFS and control group samples, but both disorders were associated with distinct proteins in the CSF compared to the control group (Schutzer et al., 2011).

Fallon reviewed prior clinical trials of PTLDS treatments, with four of them specifically focused on the antibiotic ceftriaxone. Two studies showed no improvement (Klempner et al., 2001), one study showed non-sustained improvement in cognition (Fallon et al., 2008), and one study showed long-term improvement in fatigue (Krupp et al., 2003); each study noted the serious risks associated with intravenous ceftriaxone therapy, particularly due to indwelling lines. None of the studies recommended the use of it therapeutically. Moving forward, he shared that Columbia is the coordinating center of a new clinical trials network for Lyme and other tick-borne diseases. There have not been any clinical trials on PTLDS in more than 10 years, he said, so there is a need for well-designed treatment studies to improve guidelines internationally. The clinical trials network will be able

Suggested Citation:"6 Advancing Research for Infection-Associated Chronic Illnesses." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
×

to harness strengths across academic centers and have larger sample sizes and faster recruitment by conducting multisite trials.

To start, the network will include Columbia University in New York City, Johns Hopkins University in Baltimore, and Children’s National Hospital in Washington, DC. He shared a few pilot studies they are launching that will examine vagus nerve stimulation (VNS) to address fatigue, transcranial direct current stimulation to address brain fog, and intravenous ketamine and cognitive retraining for depression. Highlighting VNS, Fallon explained that the vagus nerve modulates both inflammation and neural function with an extensive innervation of internal organs, thereby impacting multiple organ systems. Because VNS is already FDA approved for epilepsy, depression, migraines, and rehabilitation after ischemic stroke, there is growing interest in assessing the efficacy of VNS for those with PTLDS and other infection-associated multisystem conditions. The underlying premise of these studies is that effective treatments have to modify the underlying mechanism of disease, he said, whether that is persistent infection, autoimmune reactions, neural network dysregulation, or a combination.

In conclusion, Fallon shared some lessons from Lyme disease and a vision of a research agenda for the future. While he acknowledged that there is considerable suffering associated with these conditions, and that sometimes providers exacerbate the problem by invalidating the patient’s experience, he shared a message of hope by saying that in his work with patients with persistent Lyme encephalopathy, he has learned that there is always the possibility of improvement even for very sick patients. He shared suggested priorities for future research (Box 6-1).

BOX 6-1
Suggestions for Future Research Priorities

  • Conducting research studies targeting different mechanisms of disease to identify most effective treatment approaches for Lyme and other diseases.
    • Collecting biological samples for biomarker studies.
    • Enrolling patients who meet severity criteria for primary clinical outcomes.
  • Expanding the research study populations to include those with probable and possible Lyme/other tick-borne disease, as these patients make up a large portion of those with chronic symptoms and have been neglected by research.
  • Educating health care providers about the multiple presentations, including the neuropsychiatric ones and the need to screen for suicidal thoughts/behaviors.
  • Encouraging the creation of “infection-associated multisystem illness clinics” in major medical centers that include clinicians from multiple disciplines so as to best help these patients with chronic illness.

SOURCE: Adapted from Brian Fallon presentation, June 30, 2023.

Suggested Citation:"6 Advancing Research for Infection-Associated Chronic Illnesses." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
×

Discussion

Speakers in this session discussed developing a common research agenda, creating a specific long COVID “endotype” of patients, and accelerating approval pathways for new treatments. One participant noted the rarity of patients receiving just one diagnosis, asking for the establishment of an office at NIH on infection-associated chronic illnesses for more research on the multiple types of conditions plaguing patients. Fallon agreed this would be a great idea, and Deeks noted the power of advocacy groups to influence Congress. Given the way government works, he said, scientists will not be able to make these types of big changes rapidly, so they will need strong support from patient communities.

To engage industry to become involved in clinical trials for these chronic illnesses, Walt and Deeks agreed that the COVID-19 spike protein may be an excellent biomarker for long COVID, but Deeks said there is also a need for other surrogate markers for clinical outcomes. That would let researchers measure a biomarker, administer interventions, and then observe the changes in levels (i.e., spike protein) to predict the change in clinical outcomes, he explained. This may be more appealing to industry, as drugs may be approved based on impact on the biomarker, and there would not be a need to measure all the other diagnostics or clinical outcomes, making the trial and regulatory process more straightforward.

Geng called for learning from other disease conditions such as fibromyalgia, migraines, or others as models of how to advance therapeutics without well-established biomarkers. She emphasized the importance of not slowing down the process for treatment advances and approvals even without the perfect marker. Similarly, Deeks said currently there are available drug candidates, an informed patient community, outcomes that can be measured, and public pressure to move forward, but what is lacking is industry engagement. There is a need for funding, and assets from industry could be used to perform early probe studies, he said. Foundations are also critical in raising funds to support clinical trials, but without industry engagement it would take significant NIH funding to expand these trials, he stated.

Suggested Citation:"6 Advancing Research for Infection-Associated Chronic Illnesses." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
×
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Suggested Citation:"6 Advancing Research for Infection-Associated Chronic Illnesses." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
×
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Suggested Citation:"6 Advancing Research for Infection-Associated Chronic Illnesses." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
×
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Suggested Citation:"6 Advancing Research for Infection-Associated Chronic Illnesses." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
×
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Suggested Citation:"6 Advancing Research for Infection-Associated Chronic Illnesses." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
×
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Suggested Citation:"6 Advancing Research for Infection-Associated Chronic Illnesses." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
×
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Suggested Citation:"6 Advancing Research for Infection-Associated Chronic Illnesses." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
×
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Suggested Citation:"6 Advancing Research for Infection-Associated Chronic Illnesses." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
×
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Suggested Citation:"6 Advancing Research for Infection-Associated Chronic Illnesses." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
×
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Suggested Citation:"6 Advancing Research for Infection-Associated Chronic Illnesses." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
×
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Suggested Citation:"6 Advancing Research for Infection-Associated Chronic Illnesses." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
×
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Suggested Citation:"6 Advancing Research for Infection-Associated Chronic Illnesses." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
×
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Suggested Citation:"6 Advancing Research for Infection-Associated Chronic Illnesses." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
×
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Suggested Citation:"6 Advancing Research for Infection-Associated Chronic Illnesses." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
×
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Suggested Citation:"6 Advancing Research for Infection-Associated Chronic Illnesses." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
×
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Suggested Citation:"6 Advancing Research for Infection-Associated Chronic Illnesses." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
×
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Suggested Citation:"6 Advancing Research for Infection-Associated Chronic Illnesses." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
×
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Suggested Citation:"6 Advancing Research for Infection-Associated Chronic Illnesses." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
×
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The National Academies Forum on Microbial Threats and Forum on Neuroscience and Nervous System Disorders hosted a hybrid public workshop in June 2023 to explore opportunities to advance research and treatment of infection-associated chronic illnesses. The illnesses discussed in this workshop, including COVID-19, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), persistent or posttreatment Lyme disease syndrome (PTLDS), and multiple sclerosis (MS), share overlapping mechanisms and symptoms and have been inadequately researched. Recognizing these commonalities, speakers identified the need to advance research more comprehensively, translating to improved diagnostic and treatment options for patients across multiple conditions.

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