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

Chapter: 2 Overview of Infection-Associated Chronic Illnesses

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Suggested Citation:"2 Overview of 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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2

Overview of Infection-Associated Chronic Illnesses

Key Points from Individual Speakers and Participants1

  • There is overlap between postinfectious syndromes and chronic viral infections, and the scientific field is now beginning to appreciate the potential for this persistence of acute infections resulting in documented clinical morbidity. (Henrich, Komaroff)
  • Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long COVID share a similar set of symptoms and underlying pathophysiology. Ongoing symptoms may be attributable in part to an evolutionary protection mechanism known as the sickness behavior response. (Komaroff)
  • A coordination partnership in research can have numerous benefits, making studies more efficient and relevant, connecting researchers with patients, improving equity, and accelerating discovery. (Krumholz)
  • The time of illness needs to be accounted for, as conditions can look immunologically different at different time points. Research on these conditions should also involve several com-

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1 This 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:"2 Overview of 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.
×
  • parator groups, including patients with diagnoses ranging from ME/CFS to Lyme disease to dysautonomia. (Davis)
  • There is an opportunity to use rigor and knowledge to help serve people living with these conditions while the answers in research are still in development. This should include public education for providers, medical students, and the media on the legitimacy of these conditions. (O’Rourke)
  • To advance progress in infection-associated chronic illness, patients need to be centered in research efforts, listened to, made active participants, and have their conditions and challenges more visible in the public agenda and arena. (Obregón)

This chapter summarizes speaker talks that provided background information on the overlap between the underlying biological abnormalities in patients and shared pathophysiology across conditions. Speakers in this session shared perspectives from different stakeholders affected by these diseases, while providing suggestions on what is needed to advance the knowledge generation in this area and help patients.

SPONSOR REMARKS

The workshop was supported in part by the Division of Vector-Borne Diseases and the Division of High-Consequence Pathogens and Pathology of the Centers for Disease Control and Prevention (CDC) and the Steven & Alexandra Cohen Foundation. Speakers affiliated with each sponsor shared their perspectives as part of setting the context for the workshop. Lyle Petersen, director of the Division of Vector-Borne Diseases, CDC, shared his personal experience from being infected with West Nile virus several years prior. He found he was not getting better following the acute infection and that it took him nearly 6 months to fully recover. During this time, he was unable to work a full day and often struggled to even walk up short sets of stairs despite having previously run several marathons. Petersen noted that the causes of many of the chronic illnesses following infection are unknown.

Other knowledge gaps across diseases include the pathogenic mechanisms of why these symptoms occur, and how to help patients improve, Petersen said; however, the broad reach of the COVID pandemic and the large number of people suffering from long COVID has reenergized efforts to address these gaps in knowledge. Speaking on behalf of CDC, Petersen said that it is critical to better understand the epidemiology and pathogenesis of these chronic symptoms and identify more effective approaches to manage, treat, and potentially cure these debilitating illnesses. Mul-

Suggested Citation:"2 Overview of 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.
×

tiple treatment trials over the past decades have failed to resolve chronic symptoms that stem from various infectious disease triggers, he said, so it is necessary to continue active research that can advance treatments for symptoms and improve diagnostic capabilities.

Ben Nemser, chief program officer at the Steven & Alexandra Cohen Foundation, underscored that while most people survive and recover from initial infection by a pathogen, a substantial portion cannot regain their full health. Millions of Americans face debilitating symptoms of infection-associated chronic illnesses every day, Nemser said, placing untold strain on their families and communities. He shared his hope to collectively forge a legacy of scientific achievement where people can not only survive these infections but also thrive afterwards in recovery.

COMMON GROUND ACROSS INFECTION-ASSOCIATED CHRONIC ILLNESSES

Tim Henrich, University of California, San Francisco, reviewed the common ground observed across disease conditions, with a specific focus on pathogen persistence, immune dysregulation, and ongoing inflammation following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other infection-associated chronic illnesses. He pointed out that in early 2020, many leaders considered the emergence of a novel coronavirus in China to pose little risk to the United States. However, researchers at University of California, San Francisco, suspecting there may be longer-term effects outside the usual acute viral infection symptoms, began studying the long-term immunological effect of COVID-19 infections even before there were any documented cases in the area. Over time, more news stories emerged of people who recovered from COVID-19 but were still unable to return to normal activities in their life. Eventually these patients adopted the name of long COVID or long haulers, as their symptoms persisted for months to years.

Persistent symptoms are not unique to long COVID, Henrich continued. Many RNA viruses have now been found to result in chronic sequelae, including Ebola virus, respiratory syncytial virus, Zika virus, West Nile virus, and others. For example, Henrich said, Ebola is known as a severe acute infection that can have extremely high mortality. But even for those who recover from the acute infection, many suffer from tiredness, headaches, muscle and joint pain, weight gain, and other symptoms for months afterward (CDC, 2023a). Studies have found increased levels of biomarkers showing inflammation, intestinal tissue damage, and T and B cell activation and exhaustion in these patients up to 2 years after making a full recovery from the acute infection (Wiedemann et al., 2020). An additional study demonstrated that some people who recovered from Ebola can continue to carry the virus after initial convalescence and again exhibit symptoms

Suggested Citation:"2 Overview of 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.
×

of acute disease without evidence of reexposure to the virus from other sources. This has even resulted in instances of a person becoming sick again months after initial recovery and then transmitting the virus to another individual (Mbala-Kingebeni et al., 2021).

While Ebola spread has been more geographically confined, Henrich said, there are many other viruses widely distributed around the world that are responsible for a large burden of chronic viral infection in humans. For example, even though people can now be on fully suppressive antiretroviral therapy for human immunodeficiency virus (HIV), there can still be persistent infection by the virus, leading to depletion of the gut microbiota and alteration of the gut mucosa regardless of the antiviral treatment, he explained. This can lead to persistent inflammation, immune activation, immune exhaustion, and even immune senescence.

If there is a similar inflammatory biomarker profile across diseases, one could argue that multiple exposures to these pathogens could have an additive effect, he said. For example, if someone is already living with HIV and becomes infected with COVID, they may be at greater risk of acquiring long COVID. Recent studies provided evidence supporting this hypothesis. One study found that people living with HIV are 1.75 times as likely to have persistent COVID-19 symptoms compared to people who are HIV negative (Kingery et al., 2022). Another small case control study found that people living with HIV were four times as likely to have long COVID (Peluso et al., 2022).

Looking beyond HIV, Henrich also highlighted the role that Epstein-Barr virus (EBV) plays in chronic infections, in addition to the serious illness that it can cause in acute stages of infection. He pointed to a large study that tracked 10 million active military individuals over several years and found that the risk of being diagnosed with multiple sclerosis (MS) increased 32-fold after EBV infection, but not after cytomegalovirus (CMV) infection (Bjornevik et al., 2022). Further analysis of these data by Horwitz et al. (2022) did reveal elevated levels of MS diagnosis associated with CMV, though the risk was not as high compared with that associated with EBV. So while there is clearly a viral trigger, Henrich noted, it seems there are often environmental conditions, which can include the factors from the physical environment or host immune responses, that can increase the risk of the chronic sequelae. There are also clear overlaps and triggers between infections, with some evidence showing reactivation of EBV following acute COVID-19 infection: 67 percent of people with long COVID had evidence of EBV reactivation during acute SARS-CoV-2 infection, compared to just 10 percent of those who fully recovered from COVID infection without suffering from chronic symptoms (Gold et al., 2021).

There is clear overlap between postinfectious syndromes and chronic viral infections, said Henrich, and the scientific community is beginning to

Suggested Citation:"2 Overview of 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.
×

appreciate the potential for acute infections to persist and potentially lead to documented clinical morbidity. Reactivation of existing chronic viral infections in the setting of another acute microbial illness may also play a role, he added. The majority of these pathogens and infections are localized to the affected tissues, so researchers and clinicians need to account for tissue-specific alterations in addition to biomarkers in the peripheral blood. Finally, he said, researchers need to keep in mind that patients may have new immune or inflammatory baseline set points as a result of COVID-19 that need to be accounted for in prospective research and clinical diagnostics. There may be an additional longer-term effect of COVID-19 on human health, but the severity of this remains to be seen.

A HISTORICAL PERSPECTIVE

Anthony Komaroff, Harvard Medical School and Brigham and Women’s Hospital, reviewed the similarity of symptoms suffered by people with postinfection syndromes and the emerging evidence around a shared underlying pathophysiology—especially for ME/CFS and long COVID. As Henrich mentioned, viruses, bacteria, and other microbial pathogens can produce lingering symptoms after acute infection. In a systematic review of 21 studies, these lingering symptoms were rigorously characterized in patients with ME/CFS and long COVID and concluded that most of the symptoms are shared between both conditions (Wong and Weitzer, 2021). However, said Komaroff, the question remains of whether either syndrome has underlying objective biological abnormalities.

Komaroff went on to share additional evidence from a comparison of underlying pathophysiology between the two conditions and discussed the findings of significant overlap between ME/CFS and long COVID related to the nervous system, metabolism, cardiovascular and pulmonary systems, and gut microbiome (Komaroff and Lipkin, 2023). Regarding the gut microbiome, there is now established evidence of low-grade chronic gut inflammation attributed in part to reduced numbers of symbiotic bacteria producing anti-inflammatory molecules such as butyrate and acetate, which also correlated strongly with the severity of fatigue (Guo et al., 2023). This inflammation allows bacterial products and organisms to “leak” into systemic circulation, possibly causing systemic inflammation and secondarily leading to neuroinflammation. This has been replicated in multiple cohorts of people with ME/CFS, he added.

Another remaining question is what triggers the pathophysiology of both syndromes. In both cases there is evidence of mitochondrial dysfunction, oxidative stress, cellular aging, and chronic inflammation. This becomes a vicious cycle, he explained, as one initial abnormality can lead to a series of abnormalities even if the triggering events are different (see Figure 2-1).

Suggested Citation:"2 Overview of 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 graph shows the connections between various abnormalities through a series of connecting blue lines and symptom descriptions between abnormalities. Clockwise, the abnormalities are oxidative and nitrosative stress, mitochondrial dysfunction, and chronic inflammation. The chart shows that cellular senescence, NLRP3 inflammasome activation, and viral replication/reactivation can trigger more abnormalities.
FIGURE 2-1 Relationship between abnormalities.
NOTE: Nicotinamide adenine dinucleotide (NAD+); nitric oxide (NO); hydrogen sulfide (H2S); reactive oxygen species (ROS); reactive nitrogen species (RNS); tricarboxylic acid (TCA); oxidative phosphorylation (OXPHOS); NOD-like receptor protein-3 (NLRP3).
SOURCE: Anthony Komaroff presentation, June 29, 2023; Paul et al., 2021.

To understand how this pathophysiology leads to the symptoms of ME/CFS and long COVID, Komaroff shared the sickness behavior hypothesis, which can be difficult to characterize in humans but is well documented in other animals. Sickness symptoms are a hardwired protective response that lead to behavioral changes such as less physical and mental activity, less eating and digestion, less energy-consuming behaviors overall—all to preserve adenosine triphosphate (ATP) to fight the infection. Usually this is transient for an infection like the flu because the infection is promptly eradicated, said Komaroff, but this response seems to persist for chronic conditions such as long COVID and ME/CFS. This could be because the inflammation persists, or because a protective response that is meant to be temporary gets “stuck” because the neurochemical mechanism meant to turn it off becomes defective. Symptoms are experienced in the brain. If sickness behavior has been preserved by evolution, that behavior is likely orchestrated by a group of neurons dedicated to that task. This was hypothetical until the last 3 years, he noted, when a series of publications in Nature identified a cluster of neurons located in the hypothalamus and the brain stem of mice that orchestrates this sickness behavior (Bains and Sharkey, 2022; Hrvatin et al., 2020; Ilanges et al., 2022; Takahashi et al., 2020). Anything that causes inflammation in the brain can trigger these neurons, whether it is reactivation of latent viruses, systemic inflammation, or a proinflammatory gut microbiome.

Suggested Citation:"2 Overview of 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.
×

Effects on Society

Taking a broader look at the effects on society in the United States, Komaroff shared the disease burden of ME/CFS and long COVID in both prevalence and cost. As many as 2.5 million people may be living with ME/CFS, with direct and indirect costs totaling $17–24 billion per year (IOM, 2015). An estimated 16 million people are experiencing long COVID illnesses nationwide (Bach, 2022b), which will cost the country $544 billion each year, totaling $2.7 trillion over the next 5 years (Cutler and Summers, 2020).

These two examples of postinfection illnesses share a similar set of symptoms, and it has now been well documented that they also share underlying pathophysiology, Komaroff stated. What is still unknown is whether the same underlying pathophysiology for ME/CFS and long COVID is also shared by other postinfection syndromes. In both ME/CFS and long COVID, he posited, the symptoms may be due in large part to the expression of an ancient, evolutionarily preserved, orchestrated response meant to be protective—the sickness behavior response—the final common pathway that involves activation of neurons dedicated to generating sickness symptoms. An understanding of this underlying biology will ultimately lead to good diagnostic tests and effective treatments, he concluded.

STAKEHOLDER PERSPECTIVES

Several stakeholders provided their perspectives on research and lived experience of infection-associated chronic illnesses, including scientists, community-based researchers, and personal accounts from patients living with infection-associated chronic illnesses.

Research to Better Understand Long COVID

Joseph Breen, National Institutes of Health (NIH), described his team’s efforts as part of the Researching COVID to Enhance Recovery (RECOVER) program at NIH, and how it might interface with the efforts to address infection-associated chronic illnesses more broadly.2 The goal of the program is to understand, predict, treat, and prevent postacute sequelae of COVID, he explained, including long COVID and multisystem inflammatory syndrome in children (MIS-C). This program is guided by a principle of patient-centered research on a national scale and aims to cover

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2 For more on the RECOVER study at NIH, see https://recovercovid.org/ (accessed July 19, 2023).

Suggested Citation:"2 Overview of 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.
×

large swaths of the U.S. population to include people typically underrepresented in research.

RECOVER is using platform protocols to understand what is happening in communities while also trying to adapt to the numerous changes that have happened throughout the last few years of the pandemic, shared Breen. The initiative so far has enrolled more than 20,000 adults and children in research cohorts and incorporated 60 million electronic health records (EHRs), he noted. The eventual goal is to try and merge the data from EHRs with data from RECOVER’s observational cohort studies across the country, he explained. In 2020–2021 alone, there were 42 different studies directed toward understanding the mechanisms of the various pathologies of long COVID symptoms. Another goal at the initiative is to leverage these findings from the large RECOVER cohort to benefit not only the long COVID patient community but also patients with overlapping symptoms such as people suffering from ME/CFS, posttreatment Lyme disease syndrome, or other similar conditions.

Community-Based Participatory Research

Harlan Krumholz, Yale School of Medicine, discussed the beginning of his work in community-based participatory research approximately 15 years ago. Krumholz stated that he initially struggled with the concept, which diverges from the traditional research model in which researchers alone determine the terms of studies and do not prioritize partnerships with patients. However, he realized that there were many areas for improvement within the traditional model, as patients were often alienated, recruitment was slow, and many participants dropped out of studies. Additionally, implementation and dissemination of study outcomes were typically neglected, lessening the effect of these findings. Over time, community members and patients became his teachers as they worked together to utilize the wisdom of people living with these symptoms.

His team at Yale began a study called LISTEN for people living with long COVID and vaccine-related injuries, with the hypothesis that insights from this study could benefit people living with other postinfectious conditions.3 His team studied social media, read stories, held patient-led meetings and town halls, recognized the gaps in knowledge, worked across traditional boundaries, and used new methods and tools. The idea, he said, was to disrupt norms and reject the status quo to embrace interdisciplinarity.

If democratizing research is about representation, Krumholz asked, who is really speaking for the patients and patient researchers? He outlined

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3 For more on the LISTEN study, see https://medicine.yale.edu/ycci/listen-study/ (accessed July 19, 2023).

Suggested Citation:"2 Overview of 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.
×

some of the challenges they encountered related to cognitive biases and encouraging academic and clinical researchers to think more creatively. Crowdsourcing can also lead to so many ideas that it is difficult to sort through in a systematic and actionable way. While bringing in patients to the research process can encourage more out-of-the-box thinking, they may lack the scientific knowledge to balance new ideas with technical feasibility. Conversely, communication and coordination are skills that are not well taught in traditional research, he noted.

There are ample rewards for the partnership between researchers and study participants, as studies can be more efficient and relevant by tapping into both groups’ expertise. The connection between researchers and participants can become quite strong, which fuels momentum and creates a positive process and competitive advantage for researchers. In the LISTEN study, Krumholz said, his team would have never thought of certain questions to ask in surveys without first talking to the patients with lived experiences. Krumholz shared that using this model builds platforms and processes that allow researchers and patients to move together and advance as a team, promote acceptance, improve equity, and accelerate discovery. He also argued that models must be propelled by high-quality science and can be applied to many areas beyond long COVID where people are motivated to find answers.

Considering Critical Research Needs

Hannah Davis, Patient-Led Research Collaborative, introduced herself as a long COVID patient also diagnosed with ME/CFS, dysautonomia, cognitive impairment, and blood clots from COVID. Her organization was borne out of the Body Politic support group in April 2020, she explained, when multiple advocates for chronic illness conditions reached out to support each other and efforts began to build upon the knowledge from existing patients and researchers.

Currently, approximately 1 in 18 American adults are living with long COVID, she said (Ford et al., 2023). Long COVID not only overlaps with biological symptoms from other conditions, the infectious origins of these chronic illnesses can also interact. Many patients with long COVID have reactivated latent viruses, she explained, and the reactivation of EBV in the acute phase of COVID-19 infection has been hypothesized to be involved in ME/CFS development as well. Some infections’ initial onset may progress from the initial immune overactivation to immune system exhaustion over the years, she said. Therefore, research efforts need to account for time of illness and be aware that conditions such as ME/CFS can look immunologically different at different time points; there is also a need for standardizing and unifying outcome measures across research trials for better learning,

Suggested Citation:"2 Overview of 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.
×

said Davis. She also called for research on these conditions to involve several comparator groups, including patients with diagnoses ranging from ME/CFS to posttreatment Lyme disease syndrome to dysautonomia, among others. Davis stated that there is a need for dynamic, strategic designs of multiarm trials where therapeutic agents can be quickly added or removed depending on discovery or performance, as patients cannot afford to wait years for treatments that do not show a clear benefit.

Almost every infection-associated chronic illness has faced major stigmatization, Davis highlighted, and the field needs a massive increase of medical provider and researcher education. Finally, with a note on equity, she called for any research agenda to prioritize the most affected populations, including low-income workers, Black and Latino populations, and transgender individuals. Research should involve people with lived experience of long COVID, said Davis, and improved funding opportunities for disabled and chronically ill researchers is necessary.

Designing a Long Overdue Paradigm Shift

Meghan O’Rourke, Yale University, opened her remarks by stating that while some people spend their 20s and 30s dreaming about buying a home or planning their wedding, she spent hers dreaming about this conference. Elaborating on her personal journey through chronic illness, she explained how her family spent a celebratory weekend in Connecticut after her college graduation. Shortly after that, she started experiencing symptoms such as debilitating fatigue, night sweats, and cognitive problems. Despite many doctors and clinic visits, no one thought she was actually sick, and she was routinely told her symptoms were caused by anxiety. She expressed feeling stuck by the limitations imposed on her by illness, despite having a wonderful partner and a dream job at the time. Eventually, nearly 10 years later, she finally received a diagnosis of Lyme disease, along with other coinfections. She shared that while the suffering and physical pain was extreme, the hardest thing to bear was the invisibility of the illness. Living with a stigmatized or dismissed illness is very difficult, O’Rourke shared, noting that she recently heard from someone with a similar chronic illness who could not even go to the emergency room for help due to a lack of understanding and belief of these conditions.

O’Rourke shared that the long time frame of her own illness has helped her remain aware of new and changing science and findings, become more comfortable with uncertainty, and identify her own cognitive biases and areas of entrenched thinking. She outlined the critical need for science to study symptom manifestations as overlapping conditions and not individual illnesses, the need to break down silos to accelerate progress, and the need to turn knowledge into action for many patients that are still suffering. In

Suggested Citation:"2 Overview of 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.
×

conclusion, she shared three key questions to consider when advancing research in this area:

  1. How will any research help patients?
  2. How can change happen faster so that new information reaches frontline doctors promptly?
  3. How can new doctors be trained to understand the long-term sequelae of infections and understand the reality of infection-associated chronic illnesses?

She concluded by invoking a broad idea from historian Thomas Kuhn. He argued that paradigm shifts in medicine do not happen by slow and steady incremental change. They happen when a change in perception allows us to see anew what was already there, O’Rourke said, and that happens when people new to the field come in with fresh eyes and ask questions. She was hopeful that the attention and interest of long COVID can help propel the advancement of research into Lyme disease and other tickborne illnesses, and the paradigm shift could result in building a deeper scientific understanding of all chronic illness triggered by infection.

DISCUSSION

Rafael Obregón, UNICEF, moderated a discussion with the session’s panelists that centered around the value of additional research in determining whether the similar underlying biology (immune, neurologic, metabolic, cardiovascular and pulmonary, and microbiome-based) that is being identified in long COVID and ME/CFS should also be examined in other post-acute infection syndromes. Henrich agreed that the immune system and overall host response is critical, and that many are now studying this with the goal of understanding the immune response associated with these chronic illnesses, and whether there are therapeutics opportunities through modifying these immune responses. In addition, children clearly have a different immune response compared to adults, he said, and there is a need to look more carefully at age and sex differences in the immune response.

O’Rourke added that, in her experience, each successive insult to her immune system from additional infections felt like she was “slowly wading into deeper water.” She agreed there is a critical need to understand more about the immune system. But importantly, she remarked, in an age when medicine is based on evidence: what can be done for people who live at the edge of medical knowledge? How can scientific rigor and knowledge be translated to help people living with these conditions while the answers being researched are still in development? While we wait for science to uncover the answers, she said, there are many people whose experience and

Suggested Citation:"2 Overview of 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.
×

symptoms are reflexively rejected by those around them. She advocated for the research field to develop ways to support public education for doctors, medical students, and the media to understand that while there may not be a clear understanding of the mechanisms yet, these conditions, symptoms, and complaints are legitimate, and those living with these challenges should have their lived experiences supported.

In discussing the confounding effects of overlapping biomarkers and illnesses, Henrich said that COVID-19 has brought recognition and legitimacy to these persistent chronic conditions and shone a new light on all of these overlaps. On the clinical side, he added, “We’ve also learned that if you don’t understand something, that doesn’t mean the patient isn’t right.” He agreed there is a need to better understand what is happening instead of just dismissing patients’ symptoms as fabricated or exaggerated.

Komaroff introduced a note of caution: while multiple biological correlates have been identified in these syndromes, correlation and causation are not the same. He noted that some of the underlying biological abnormalities may, in fact, help cause the symptoms while others may just be epiphenomena. He called for more efforts to follow patients longitudinally and have them remain in close contact with researchers on good and bad days in order to identify biomarkers that change when symptoms worsen compared to baseline, which may help point to causation. This kind of study looking at illness cycles can be very instructive.

Krumholz added that every day people are going in to see their doctors and being dismissed. The critical output of this meeting is legitimizing these symptoms and conditions, he said. He called for accelerating research through the knowledge pipeline and streamlining innovation across the full spectrum of these chronic illnesses, while pointing to the fundamental need for more resources. When thinking about pandemic preparedness, he continued, prevention and response is important, but this long tail of recovery around the world demands a plan to augment efforts and get more answers, and more attention and investments, commensurate with the size of the problem. Davis and O’Rourke agreed, with Davis commenting there should be a $3 billion annual commitment to infectious-onset illness, to include public education campaigns so people realize their risks, even if they have recovered from a prior infection.

Obregón summarized the comments and emphasized the need of placing people at the center of these efforts, listening to patients, treating patients as participants rather than subjects, and making these conditions and challenges more visible by bringing them to the public agenda and arena. Collectively, there is a chance to make a difference, he concluded.

Suggested Citation:"2 Overview of 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:"2 Overview of 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:"2 Overview of 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:"2 Overview of 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:"2 Overview of 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:"2 Overview of 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:"2 Overview of 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:"2 Overview of 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:"2 Overview of 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:"2 Overview of 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:"2 Overview of 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:"2 Overview of 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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 Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop
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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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