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

Chapter: 3 Common Mechanistic Factors of Infection-Associated Chronic Illnesses

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Suggested Citation:"3 Common Mechanistic Factors 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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3

Common Mechanistic Factors of Infection-Associated Chronic Illnesses

Key Points from Individual Speakers and Participants1

  • Latent viral infections interact in complex ways in those who get sick with other infections, but this is still not well understood. Additionally, there is growing evidence that these infections associate with long COVID. (Peluso)
  • Data support that early in acute COVID-19 infection there is a viremic phase where tissues throughout the body become seeded with the virus that then replicate and evolve in the different anatomic compartments of the body. (Chertow)
  • The SARS-CoV-2 viral RNA can persist in multiple anatomic compartments for an extended interval, and in multiple cell types, and in various phases of COVID-19 illness. (Chertow)
  • In animal model studies, Lyme disease bacteria can persist following conventional single antibiotic treatments, and combination treatments were more effective in clearing infection in some models. (Embers)
  • The brain can choose to shut down certain activities when ill, leading to fatigue, slowed cognitive processing, and lack of motivation. There is a role in this space for more psychiatric research and the education of physicians and researchers across different fields to integrate their expertise. (Miller)

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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:"3 Common Mechanistic Factors 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.
×

With the surge in research in this area since 2020, much of which attributed to the high prevalence of long COVID, it is increasingly recognized that there are many common symptoms and potential mechanisms linking different types of infection-associated chronic illnesses. Consequently, attention has turned to learning more about the common factors that may exist across multiple conditions. This chapter begins with discussion of host-mediated factors of illnesses, such as immune dysfunction, autonomic dysfunction, neuroinflammation, and the microbiome. It then reviews pathogen-mediated factors and the role of pathogen persistence, including lessons from research with Epstein-Barr virus (EBV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and animal studies.

HOST-MEDIATED FACTORS

Speakers in this section presented their research on mechanisms behind the cause and symptoms of infection-associated chronic illnesses that are affected by host-mediated factors, such as immune dysregulation and autoimmunity, reactivation of—or interactions with—latent viruses, dysfunction of the autonomic nervous system, and neuroinflammation.

Immune Dysfunction

Carmen Scheibenbogen, Charité University, presented on immune dysregulation and autoimmunity from her work based on long COVID and myalgic encephalitis/chronic fatigue syndrome (ME/CFS). Presenting an overview of post-COVID conditions, she acknowledged the increased incidence of well-defined diseases such as new onset diabetes, autoimmunity, and cardiovascular conditions, but she focused on long COVID symptoms (e.g., fatigue, exertion intolerance, cognitive symptoms, and pain) as a major problem in younger patients. Echoing comments from Anthony Komaroff, Harvard Medical School, on the overlap between diseases, she found through a prospective observational study that about 50 percent of long COVID patients fit the diagnostic criteria for ME/CFS (Kedor et al., 2022). ME/CFS is a complex illness that has been neglected and poorly studied over the past few decades, Scheibenbogen said, noting that patients often report aggravated symptoms following everyday activities. There is significant overlap between symptoms experienced by long COVID and ME/CFS patients.2 One potential common mechanism behind these symptoms may be viral persistence or reactivation of latent viruses from an earlier infection (e.g., EBV) that lead to inflammation and autoimmunity,

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2 For a comparison of common symptoms reported by patients with ME/CFS and long COVID, see Figure 2-2.

Suggested Citation:"3 Common Mechanistic Factors 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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which eventually results in endothelial disease, hypoperfusion, or microclots (Davis et al., 2023).

Scheibenbogen also shared evidence for the role of autoimmunity in infection-triggered ME/CFS and post-COVID conditions. In patients who develop these chronic illnesses, there is often family history and/or comorbidity of autoimmune disease, coinfection with EBV, qualitative alterations in the memory B cell population (such as B cell receptor skewing), other autoimmune risk factors, or correlation of autoantibody levels with symptom severity. For example, levels of autoantibodies to the autonomic nervous system correlate with symptom severity and level of fatigue in patients with infection-triggered ME/CFS (Freitag et al., 2021), as well as patients who fit the diagnostic criteria for both long COVID and ME/CFS (Sotzny et al., 2022). However, correlation was not seen in ME/CFS patients without a known infection trigger or in post-COVID patients who did not fit the criteria for ME/CFS. In summary, Scheibenbogen showed that a subset of long COVID patients have ME/CFS, and there is evidence for autoantibodies as a mediating factor of long COVID and ME/CFS, so studies to examine treatments that target autoantibodies are needed.

Latent Viruses as Drivers of Chronic Illness

Michael Peluso, University of California, San Francisco, reviewed the Long-term Impact of Infection with Novel Coronavirus (LIINC) study conducted at University of California, San Francisco, which has enrolled more than 800 participants and banked more than 50,000 biospecimens. Acknowledging that there are many proposed mechanisms of long COVID, as other speakers have noted, Peluso presented data on the role of viral reactivation with a focus on EBV (see Figure 3-1).

While most infections are successfully cleared, some infectious agents can establish latency or persist in the human body. This is often associated with herpesviruses, said Peluso, including EBV and cytomegalovirus (CMV). EBV is a ubiquitous herpesvirus that can infect B cells and establish latency in memory B cells, where it associates with the host genome and relies on normal host cell division to passively propagate into new cells. But under certain conditions, EBV can reactivate and enter a lytic cycle, where the virus expresses all its genes to produce infectious viral particles, leading to cell death and viral propagation. The immune response to EBV is complex, but Peluso highlighted that antibody levels can be measured as a proxy for viral activity, with some antibodies persisting over time and others peaking and waning after a period of months.

EBV has been implicated in a variety of conditions, often autoimmune diseases, but most associations are correlations and not causational. One recent finding is the association between EBV and the increased risk of

Suggested Citation:"3 Common Mechanistic Factors 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.
×
Six mechanisms of long COVID that can manifest between acute COVID-19 infection and recovery are depicted. At the top of the figure, a horizontal arrow connects an image of a coughing man to an image of a healthy man to show the path from acute COVID-19 to full recovery. A curved arrow connects the coughing man to an image of a fatigued man to signify long COVID interrupting the path to recovery. Six mechanisms of long COVID are depicted and connected to the long COVID man with arrows.
FIGURE 3-1 Proposed mechanisms of long COVID.
NOTES: Figure 3-1 was originally published in Trends in Immunology in 2022. A modified version was included in Peluso’s presentation.
SOURCE: Michael Peluso presentation, June 29, 2023; Peluso and Deeks, 2022.

developing multiple sclerosis (MS), Peluso stated.3 Other herpesviruses have been frequently associated with ME/CFS, but the current evidence in literature is insufficient to firmly establish whether EBV infection is associated with developing ME/CFS, or whether the chronic illness is creating an environment where EBV can reactivate. Though some benefits of antiviral treatment against EBV were shown for people who were suffering from ME/CFS and have high viral loads, there are a limited number of these studies, Peluso explained. Based on this prior knowledge from ME/CFS, he investigated whether EBV is associated with developing long COVID. Indeed, higher EBV titers were associated with more symptomatic long COVID phenotypes (Gold et al., 2021), and EBV viremia during early infection was associated with subsequent development of long COVID symptoms (Su et al., 2022).

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3 See Bjornevik et al. (2022). https://www.science.org/doi/10.1126/science.abj8222 (accessed January 19, 2024).

Suggested Citation:"3 Common Mechanistic Factors 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.
×

With these two studies in mind, Peluso examined chronic viral coinfections and their effect on the likelihood of developing long COVID through the LIINC study. Initial serologic evidence suggested that patients with recent EBV reactivation had 2.5 times higher odds of reporting long COVID fatigue, and those with evidence of elevated serologic responses to EBV had two times higher odds of experiencing neurologic symptoms of long COVID such as brain fog (Peluso et al., 2023a). While the initial data did not show a clear relationship with cardiopulmonary or gastrointestinal symptoms, a follow-up study did demonstrate a strong association between EBV reactivation, cardiopulmonary symptoms, and abnormal performance on exercise testing (Durstenfeld et al., 2023).

CMV, a herpesvirus similar to EBV, infects 60 percent of adults in high income countries; it can also cause a mononucleosis-like illness and can reactivate in immunocompromised hosts. Initial observations found that CMV seropositivity was associated with nearly two times higher odds of hospitalization during acute COVID-19 infection (Peluso et al., 2023b). However, in the study on chronic viral infections and the differential likelihood of long COVID, Peluso and colleagues found that CMV seropositivity was associated with decreased odds of having long COVID. This was an unexpected finding that was opposite of their data on EBV, but it was consistent with previously reported results that CMV-infected young adults mounted better immune responses to the flu vaccine (Furman et al., 2015). There is a protective correlation between CMV and MS, with one study reporting 30 percent decreased odds of developing MS for CMV-seropositive individuals (Grut et al., 2021).

Peluso posited that one explanation could be that EBV acts via the inflammatory and autoimmune pathways and is compartmentalized differently than CMV in the immune system (Peluso et al., 2023a). Another potential explanation could point to the immunoregulatory effects that CMV exerts on its host that alter immune responses that would otherwise drive development of long COVID. These different effects from EBV and CMV on acute COVID-19 infection are outlined in Figure 3-2.

Going forward, Peluso plans to further explore the role of CMV and EBV in long COVID through characterizing tissue samples in the LIINC biobank, examining linkages between EBV and autoimmunity, and testing whether EBV antiviral treatment provides clinical benefit. It is also unclear whether there is active viral replication in patients with long COVID, so an opportunity for future research could include probing tissue samples to understand this possible mechanism. There are also knowledge gaps in understanding whether other types of EBV treatment (e.g., host-targeted therapeutics) will have any clinical benefit compared with traditional antiviral drugs. Finally, he reiterated that there is growing evidence linking these latent viral infections with long COVID, and that research advancements

Suggested Citation:"3 Common Mechanistic Factors 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 map of images and arrows depicts the interconnectedness between COVID-19, Epstein-Barr virus, cytomegalovirus, and long COVID. Clockwise from top left, small graphics depict acute COVID-19, EBV reactivation, autoreactivity, long COVID, and CMV-induced immune regulation. In the approximate center of these images is a sixth that depicts inflammation and is linked to all others in the map.
FIGURE 3-2 Differential effects of Epstein-Barr virus (EBV) and cytomegalovirus (CMV) in long COVID.
SOURCE: Michael Peluso presentation, June 29, 2023, created with BioRender.com.

for long COVID may help determine the role that these viruses play in other infection-associated chronic illnesses.

Autonomic Dysfunction

Satish Raj, University of Calgary, spoke about the cardiovascular aspects of autonomic dysfunction and its downstream effects, including postural orthostatic tachycardia syndrome (POTS) and orthostatic intolerance. One early observation in the emergence of long COVID was the common presentation of tachycardia in patients, he said. Raj observed that many symptoms experienced by patients with long COVID were historically seen in patients with POTS.4

Reviewing POTS in more detail, Raj said it is a clinical syndrome that is diagnosed based on abnormal physiology, particularly excessive orthostatic tachycardia,5 but patients also experience symptoms that get worse

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4 The Canadian Cardiovascular Society released a position paper on the need to define the ecosystem of orthostatic intolerance beyond just POTS, see https://doi.org/10.1016/j.cjca.2019.12.024 (accessed December 10, 2023). Challenges remain in diagnosing conditions featuring orthostatic intolerance, as patients experiencing different ranges of symptoms may receive differing diagnoses. Further, the range of symptoms associated with ME/CFS overlaps with other diagnoses.

5 Excessive orthostatic tachycardia is characterized by an increase in heart rate of greater than 30 beats per minute in adults when transitioning from lying down to standing up. The diagnosis of POTS requires an exaggerated increase in heart rate over the course of 10 minutes upright compared to supine values. The heart rate increment must be at least 30 beats per

Suggested Citation:"3 Common Mechanistic Factors 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.
×

positionally and last for more than 3 to 6 months. POTS may be the most well-known orthostatic intolerance condition, he noted, but there are other similar disorders. For example, patients with inappropriate sinus tachycardia have abnormally high heart rates all the time, even while lying down. There are also several different types of orthostatic hypotension (drop in blood pressure related to position) disorders, all of which occur within a short time of standing, he explained. Raj and colleagues looked for autonomic abnormalities in patients with long COVID and found that nearly 75 percent of patients had some symptom in common with POTS, 30 percent of patients met the diagnostic criteria for POTS, and most met the criteria for at least one cardiovascular autonomic abnormalities (Hira et al., 2023).

These results also revealed a sex difference in both symptom presentation and in frequency of the specific disorders. Overall, more female patients were found to have symptoms and accounted for the majority of POTS patients in the study, though there was no significant difference in initial presentation of orthostatic hypotension (Hira et al., 2023). In summary, Raj found that these autonomic hemodynamic disorders were common in patients with long COVID and cautioned that these disorders are often overlooked in routine care if care providers do not specifically look for the associated symptoms.

Treatment options for POTS often target the hallmark symptom of excessive tachycardia, and can be categorized into pharmacological and nonpharmacological treatment approaches. Pharmacological treatments include medications to reduce heart rate or regulate blood pressure, such as propranolol, ivabradine, pyridostigmine, and desmopressin. Nonpharmaceutical approaches can include increased dietary salt intake, diet changes, compression garments, and exercise as tolerated. A recent study found that a high salt diet increased blood volume, decreased norepinephrine levels, and decreased the patient’s heart rate (Garland et al., 2021). Compression garments were also recently found to decrease heart rate and partially alleviate other symptoms (Bourne et al., 2021). Raj emphasized that the primary motivation for patients to seek care is their quality of life. Raj reiterated it is important to keep in mind that these chronic disorders are associated with significant disability, and while a cure is not readily available right now, there are some interventions that can provide some relief to patients.

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minute for adults (20 years of age and older), or at least 40 beats per minute for adolescents (12–19 years of age) in the absence of orthostatic hypotension during the first 3 minutes upright. The diagnosis also requires the presence of chronic orthostatic symptoms such as fatigue, lightheadedness, blurry vision, weakness, cognitive difficulties, and nausea. See https://link.springer.com/article/10.1007/s10286-011-0119-5 (accessed November 21, 2023).

Suggested Citation:"3 Common Mechanistic Factors 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.
×

Common Underlying Mechanisms of Chronic Illnesses

Mitchell Miglis, Stanford University, spoke about the overlap between numerous autonomic disorders such as POTS, ME/CFS, and long COVID. Long COVID symptoms, including fatigue, brain fog, nausea, gastrointestinal issues, insomnia, anxiety, allergy issues, and others are familiar to patients with other autonomic disorders. Involvement of autonomic dysfunction in ME/CFS has been long known, with reduced cerebral blood flow and hypocapnia detected in ME/CFS patients upon orthostatic challenge (van Campen et al., 2020). While POTS is the most commonly diagnosed autonomic condition, present in up to 50 percent of patients (Hoad et al., 2008), these physiological abnormalities were measured regardless of whether the patients met the diagnostic criteria for POTS. Furthermore, levels of reduction in cerebral blood flow were also demonstrated in patients with long COVID and found to be comparable to patients with ME/CFS (not associated with SARS-CoV-2 infection) (van Campen and Visser, 2022).

Regarding autonomic dysfunction and long COVID, Miglis reported that POTS has been the most common primary diagnosis in long COVID patients. A review of several studies found that patients were often predominately female (<70 percent), and chief complaints included prominent cognitive impairment, headaches, fatigue, orthostatic intolerance, pain, and symptoms consistent with hyperadrenergic state and mast cell activation (Larsen et al., 2021). Many patients also had a history of mild preexisting or self-limiting autonomic symptoms, Miglis added, suggesting possible individual susceptibility (Larsen et al., 2021). Trying to understand the severity of autonomic dysfunction in long COVID, Larsen et al. (2022) found that while most of the long COVID patients in their study were not hospitalized for their acute illnesses, nearly two-thirds of long COVID patients scored in the moderate to severe range on COMPASS-31, a widely used screening tool for autonomic dysfunction,6 suggesting that the likelihood of developing long COVID is independent of the initial infection severity.

The study also noted a correlation of several preexisting conditions that may predispose patients to develop post-COVID autonomic dysfunction, including asthma, obesity, vitamin D deficiency, and a history of autoimmune disease, anxiety, depression, allergies, or smoking. Congruous with other published works, a small retrospective study that compared the phenotypes of long COVID patients with age- and sex-matched cohorts of patients diagnosed with POTS and healthy controls found that all of the

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6 COMPASS-31 was developed as a patient questionnaire to provide standardized, quantitative assessment of autonomic dysfunction symptoms and has been widely used since 2012, see https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3541923/ (accessed October 8, 2023).

Suggested Citation:"3 Common Mechanistic Factors 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.
×

long COVID patients had a wide range of abnormalities spanning from autonomic reflexes to sudomotor, parasympathetic, and adrenergic dysfunctions (Novak et al., 2021).

In addition, this study recognized and adjusted the measured cerebral blood flow based on the extent of hypocapnia in the study population to reveal a greater severity in cerebral blood flow reduction for the long COVID cohort compared with the POTS group.7 Miglis contended that inclusion of cerebral blood flow and end-tidal CO2 measurements are an important protocol adjustment that could be included in future studies, as screening for only blood pressure and heart rate may underdiagnose or overlook infection-associated dysautonomia disorders.

Miglis also shared ongoing work in elucidating the underlying phenotypes of these autonomic symptoms across the cerebrovascular, respiratory, small fiber, and autonomic systems in patients diagnosed with POTS in association with long COVID. While observations of reduced cerebral blood flow and tachycardia on orthostatic challenge were consistent with previous studies, Miglis also reported an unusual finding of phosphorylated alpha-synuclein, a biomarker commonly associated with Parkinson’s disease, from skin biopsies of his study cohort (Miglis et al., 2022).

Miglis speculated on potential mechanisms that could underlie infection-associated chronic illnesses such as long COVID, POTS, and ME/CFS. His team is formulating hypotheses around immune dysregulation, given that many POTS patients have a history of autoimmune disease and long COVID has been associated with elevated inflammatory markers, vagal nerve damage, and elevated levels of autoantibodies. Another common theory is viral persistence, as many studies have shown SARS-CoV-2 detected in the body months after recovery. Current findings suggest systemic dissemination of the pathogen, even crossing the blood–brain barrier, regardless of the symptom severity during the initial acute COVID-19 infection.

A third potential mechanism is mast cell activation, as mast cells also express angiotensin-converting enzyme 2 (ACE-2),8 many patients with POTS or similar disorders have elevated mast cell activation, and mast cell degranulation may also explain the cytokine storm seen in acute respiratory distress syndrome for patients with severe COVID-19 infections, he added. Additionally, the blood pressure fluctuations experienced by many long COVID patients could be evidence that the virus might invade the central

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7 The exclusion criteria for the long COVID patient group included history of dysautonomia, but the authors did not specifically indicate whether concurrent diagnosis of POTS was considered an exclusion criterion for the cohort.

8 Angiotensin-converting enzyme 2 (ACE-2) is a membrane protein that also serves as the receptor for the SARS-CoV and SARS-CoV-2 spike protein and mediates cellular entry of the viruses. For a review of the role of ACE-2 in COVID-19 pathogenesis, see https://ccforum.biomedcentral.com/articles/10.1186/s13054-020-03120-0 (accessed October 8, 2023).

Suggested Citation:"3 Common Mechanistic Factors 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.
×

nervous system and affect the brain stem. Lastly, sex physiology likely has a role given the average lower skeletal muscle mass, increased pelvic venous pooling, and higher propensity for autoimmune diseases in females compared with males. Sex hormones may also play a role, Miglis added, as many female patients report worse symptoms during their menstrual cycle.

In closing, Miglis acknowledged that the first approach that comes to mind for an autonomic disorder specialist is to treat the autonomic symptoms. However, the discipline has also started using anti-inflammatory medications for long COVID and sees promise in using vagal nerve stimulators. In his view, future progress in addressing these infection-associated chronic illnesses will include defining the diagnostic criteria for these types of illnesses, standardizing definitions, and establishing patient registries with open access to deidentified data. In particular, Miglis pointed to a lack of large-scale clinical trials for new treatments at 3 years after the emergence of the pandemic and said there are opportunities to accelerate the initiation of new treatment trials.

Inflammation in the Brain

Andrew Miller, Emory University, discussed common mechanisms of behavioral changes that may be involved in many chronic illnesses and their manifestations. This work began with observations made by oncologists in the early 2000s, he explained, when they began treating cancer patients with the inflammatory cytokine interferon alpha (IFNα). Many patients reported adverse effects of depression, anxiety, problems with memory and concentrations, and a variety of neurovegetative symptoms including fatigue and appetite alterations. IFNα plays many roles in infectious diseases, such as inducing antiviral defense, enhancing innate immune response, facilitating adaptive immune response, and regulating physiological processes. Interestingly, said Miller, IFNα has been implicated in several infection-associated illnesses such as ME/CFS (Vojdani et al., 1998). It has also been associated with behavioral changes during human immunodeficiency virus (HIV) infection (Anderson et al., 2017), and persistent symptoms of fatigue and cognitive deficits in Lyme disease (Jacek et al., 2013).

A systematic review of published research on the mechanisms by which inflammatory cytokines affect the brain revealed a critical role of the basal ganglia in psychiatric and behavioral symptoms (Lucido et al., 2021). Cytokines’ effects in different areas of the basal ganglia can lead to anhedonia, said Miller, a core symptom of depression, as well as fatigue, psychomotor slowing, decreased processing speed, and cognitive dysfunction. It appears that the underlying mechanism of these effects is cytokine-mediated disruption in the metabolism

Suggested Citation:"3 Common Mechanistic Factors 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 neurotransmitters like dopamine and glutamate—which ultimately disrupts the neurocircuitry in the brain and leads to the observed symptoms.

Miller shared a study that documented an IFNα-induced decrease in ventral striatal activation in healthy study participants as detected by functional magnetic resonance imaging (fMRI), which is associated with reduced motivation and increased mental and physical fatigue (Capuron et al., 2012). This effect was replicated across different laboratories with two other, different inflammatory stimuli, he said (Eisenberger et al., 2010; Harrison et al., 2016). These findings translated to ME/CFS patients. Using the same experimental setup, Miller described the finding that fMRI detected reduced neural activation in the basal ganglia that correlated with higher fatigue levels in ME/CFS patients. He explained that, based on data from animal studies where treatment with IFNα suppressed dopamine release, dopamine dysregulation is a likely mechanism underlying the symptoms in humans.

Miller also discussed endogenous inflammation, noting its difference from exogenously stimulated inflammation in patients. Viral reactivation and other consequences from viral infections often involve endogenous inflammation, so his team studied whether this disrupts connectivity in motivational and motor circuits in patients with major depression, using C-reactive protein as a marker for inflammation. The study found the greatest change in connectivity among different regions of the brain was a decrease in connectivity between the ventromedial prefrontal cortex and the ventral striatum (the motivational circuits) (Felger et al., 2016), and similar results were seen with decreased connectivity in motor circuits in the brain. These changes in circuits also mapped to the behavior of decreased motivation, cognitive slowing, and fatigue.

Shifting to peripheral inflammation, Miller said that though the reasons are unclear, there appear to be breaches in the blood–brain barrier in the context of stress and inflammation that seem to occur selectively in the same region of the brain that controls motor and motivational circuits. Overall, Miller summarized, antiviral and inflammatory cytokines lead to chronic changes in neurocircuits and neurotransmitter systems that contribute to neurovegetative symptoms including anhedonia, fatigue, and cognitive dysfunction. He offered the following research priorities:

  1. Determining the common behaviors affected in infection-associated chronic illnesses,
  2. Determining the common central nervous system circuits affected in infection-associated chronic illnesses,
  3. Determining the effects of infection and infection-related immune changes on neuronal and microglial function with a focus on neurotransmitter metabolism, and
Suggested Citation:"3 Common Mechanistic Factors 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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  1. Testing pharmacologic agents targeting antiviral and inflammatory cytokines and their signaling pathways as treatments for infection-associated chronic illnesses.

The Role of the Microbiome in ME/CFS

Julia Oh, Jackson Laboratory, began by stating that the role of microbes in our health extends far beyond infections. The human microbiome plays an overwhelmingly positive role in regard to health and maintaining the immune system, she explained, and there are now a range of diseases linked to broader changes in the microbiome as a whole. She shared a graphic on homeostasis of the microbiome, which can be tipped into disease upon the introduction of pathogens, leading away from regulation and toward inflammation in a process called dysbiosis (see Figure 3-3).

Oh shared some of her laboratory’s research looking at mediators of the host–microbiome interactions to see how these interactions might

A set of images depicts the increase in inflammation that occurs during immunological disequilibrium as a result of a pathogen. The top image is of a balanced scale, with equal measurements of “symbionts” on the left, “commensals” in the middle, and “pathobionts” on the right. Below the scale are boxes depicting “regulation” and “inflammation” in balance. The bottom image shows a tipped scale, with “regulation” lighter and “inflammation” heavier, signifying disequilibrium caused by pathogens.
FIGURE 3-3 Dysbiotic microbiome-immune interactions.
NOTES: Figure 7-1 was originally published in Nature Reviews Immunology in 2009. A modified version was included in Oh’s presentation.
SOURCE: Julia Oh presentation, June 29, 2023; Round and Mazmanian, 2009.
Suggested Citation:"3 Common Mechanistic Factors 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.
×

be altered in ME/CFS patients. Ample prior research has shown that the microbiome can contribute to disease severity in ME/CFS. Acute infection can trigger ME/CFS symptoms, she said, which has been seen following Lyme disease and HIV. Additionally, prior research has also shown metabolomic irregularities and immune dysregulation in ME/CFS, and there has been anecdotal success with fecal microbiota transplantation for ME/CFS patients. There is collective precedent for integrating various “omics” approaches to generate new hypotheses for ME/CFS.9 Her team is seeking to generate high-resolution datasets for the gut microbiome; examine details such as species composition, community structures, and coding capacity of the microbiome for different metabolites; and associate it with targeted plasma metabolomics and immune profiling. Data on the manifestation of disease are then collected via detailed surveys and clinical measurements and integrated into the dataset.

Oh’s team studied patients who have short- versus long-term disease, matched with healthy controls, who were all followed longitudinally. Using state-of-the-art machine learning classifiers, they identified features that are characteristic of the disease stage. A major finding from this work is that short-term patients show the most significant microbial dysbiosis, even though long-term patients have the most severe disease. But long-term patients have the most major metabolic dysbiosis despite their reestablished healthy control lookalike microbiome, said Oh, which was surprising. For example, they were able to examine microbial diversity and pinpoint different species to see which are more dominant in various stages of disease. In late-stage patients, they saw the greatest change in blood metabolites compared to short-term disease patients or health controls. Summarizing these initial findings, Oh said that while they do not know why there is such a difference between short- and long-term disease, especially when the long-term disease patients appear to have a healthy microbiome while exhibiting the most changes in metabolic dysbiosis.

Oh also described the integration of clinical and -omics data into a machine learning model to develop a classification of cohorts. Their multiomics model was used to accurately predict ME/CFS patients and identify biomarkers such as the butyrate pathway. Butyrates are one of the microbe-produced short-chain fatty acids (SCFAs) and are linked to the function of a healthy gut, Oh explained. The microbes that produce butyrate were significantly depleted in both short- and long-term ME/CFS patients.

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9 In biology, “omics” refers to the study of “the entire complement of a specific type of biomolecule or the totality of a molecular process within an organism,” particularly under a defined condition or time point; see https://www.britannica.com/science/omics (accessed December 10, 2023). Branches of these studies include genomics, metagenomics, transcriptomics, proteomics, metabolomics, and phenomics.

Suggested Citation:"3 Common Mechanistic Factors 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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Oh concluded by offering potential research opportunities to address the current knowledge gaps. She pointed out that a major limitation in the study of ME/CFS and other similar chronic diseases is the lack of good animal models that can reflect the heterogeneity of symptoms. There is a need for human clinical studies paired with high-resolution -omics data to identify causal links, such as immunotherapy studies. She also suggested studying whether supplementation of butyrate producing microbes, direct supplementation of butyrate or SCFAs, or dietary modulation to enhance the presence of these butyrate producers in ME/CFS cohorts can lead to changes in the clinical phenotype or -omics profile toward a healthier state.

PATHOGEN-MEDIATED FACTORS AND PATHOGEN PERSISTENCE

In addition to host-specific factors, pathogens and their mechanisms are also considered alongside potential persistence within the body. This section highlights lessons from EBV, SARS-CoV-2, and animal models to better understand common factors across syndromes.

Lessons from Epstein-Barr Virus

Bill Robinson, Stanford University, talked about the role of EBV and molecular mimicry in MS. Robinson’s lab is interested in the contribution of EBV reactivation in driving autoimmunity. Building from previous discussions, Robinson posed an overarching question of whether EBV is a causal contributor to these autoimmune diseases or whether it is just an epidemiological phenomenon. A recent longitudinal analysis reveals a high prevalence of EBV associated with MS, where 801 patients developed MS and 800 of them had prior EBV infection (Bjornevik et al., 2022). To further define whether EBV was a causal factor of MS, Robinson’s lab studied B cells from the spinal fluid of MS patients and found that there was a limited number of large clonal families of B cells. This is very different from what is found in typical blood samples, which contain a diverse repertoire of B cells.

After many years of studying the EBV-specific antibody repertoire of these B cells, Robinson’s team honed in on an antibody, MS39, that binds to the Epstein-Barr virus nuclear antigen 1 (EBNA1).10 Essentially, anti-EBNA1 B cells are activated during EBV infection, and the repeated activation that is necessary to promote affinity maturation inadvertently results in these cells targeting and binding to the myelin sheath in the brain. To see whether this reactivity was pathogenic or not, additional studies conducted

___________________

10 For a review of EBV infection pathogenesis, including the role of EBNA1, see https://www.nature.com/articles/nrc1452 (accessed December 10, 2023).

Suggested Citation:"3 Common Mechanistic Factors 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.
×

by Robinson’s team found that the cross-reactivity between antibodies to EBNA1 and GlialCAM (glial cell adhesion molecule, a central nervous system protein) can contribute to demyelinating disease in mice. Looking at larger cohorts of human MS patients and comparator groups, Robinson noted that the MS patients had high titers of anti-EBNA1 antibodies. This demonstrates that EBV can induce activation of anti-EBNA1 B cells, said Robinson, and that repeated EBV reactivation can cause a chain of events that mediate central nervous system and myelin tissue destruction, resulting in symptoms of MS.

To summarize the data, Robinson said that this research demonstrates a critical role for EBNA-1-mediated molecular mimicry in driving the autoimmune response that potentially underlies the pathogenesis in approximately one-quarter of human MS patients. It is likely there are additional pathways through which activation of B cell and other immune cells contribute to molecular mimicry and other mechanisms that play a role in the pathogenesis of autoimmune diseases associated with EBV infection.

Learning from SARS-CoV-2

Dan Chertow, National Institutes of Health (NIH), shared his team’s findings on the pathogen distribution and persistence of SARS-CoV-2 based on autopsy studies of COVID-19 cases from three Maryland regions. The initial study goal was to describe the SARS-CoV-2 burden within and outside of the respiratory tract, as evidence from SARS-CoV-1 suggests that the virus can establish outside of the respiratory tract and even translocate to the brain. Investigators also wanted to determine whether the virus persists in different tissues, and hoped to establish whether the virus is capable of replicating in tissues outside of the respiratory tract and how it might evolve in those areas of the body.

Between March 2020 and March 2021, the first year of the study (also the first year of the pandemic), Chertow and his team performed 44 autopsies and collected over 10,000 tissue samples from various places throughout the body. None of the individuals who were autopsied or provided tissue donations had been vaccinated, and most were severely ill from their acute infection of COVID-19. The cohort averaged 59 years of age, and was mixed across sex, race, and ethnicity. On average, Chertow said, 77 percent of the cohort had two or more comorbidities, such as cardiovascular disease, diabetes, obesity, or hypertension. Summarizing their overall findings, Chertow said that they found the most viral RNA among early cases in respiratory and cardiovascular tissues. Importantly, though, they found viral RNA across all tissue types and in all phases of COVID-19 patients—early, mid, and late cases of disease. One notable case was an individual who had a relatively mild course of illness from COVID-19,

Suggested Citation:"3 Common Mechanistic Factors 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.
×

recovered, and then returned to the hospital months later with hepatitis A and died from an associated complication. When the autopsy was performed, 230 days after the initial illness onset, researchers were able to find viral RNA across multiple tissue compartments in his body. In the majority of the 11 autopsies from which brain samples were collected, there was evidence of viral RNA in multiple brain regions.

Viral culture is often viewed as the gold standard for demonstrating viral persistence. Chertow shared that they successfully recovered replicative virus from multiple tissues including eye, jejunum, lymph node, heart, adrenals, and brain. Examining site-associated viral RNA burden, Chertow found evidence of more viral RNA in respiratory versus nonrespiratory tissues. However, the burden of viral RNA decreased more rapidly from early- to late-stage of the infection in respiratory tissues while viral RNA clearance was slower throughout the course of infection in non-respiratory sites (Stein et al., 2022).

To address viral evolution, Chertow showed sequencing results from a single patient that harbored minor but distinct variants in the gene encoding the spike protein in viral isolates from the brain that were not seen in isolates from lung tissue. This supported their hypothesis that there is a viremic phase early in the infection where tissues throughout the body become seeded by viral dissemination, where the virus then undergo replications and evolution in the different anatomic compartments. Overall, his team was able to detect viral RNA in more than 30 cell types across 35 tissues, although they found a lack of inflammation—in this case, a lack of infiltration of immune cells—outside of the lungs, and a paucity of direct cytopathology in non-respiratory tissues. Chertow summarized by noting that SARS-CoV-2 RNA can persist in multiple anatomic compartments for an extended interval and that SARS-CoV-2 can infect and replicate in multiple cell types outside of the respiratory tract.

Lessons from Animal Studies

Monica Embers, Tulane University, shared her work on Lyme disease. Posttreatment Lyme disease syndrome (PTLDS) has existed for a long time, she said, but only came under extensive study in the past decade. Most Lyme disease patients can be successfully treated with timely administration of antibiotics, but some experience treatment failures and continue to suffer long-term debilitating symptoms. A study in 2020 estimated the cumulative number of PTLDS cases at nearly 2 million, so she hypothesized the case number is even higher in 2023. As a result of various metanalyses and clinical case definitions, Embers explained, the pattern of symptoms for PTLDS appears to be different from those seen in fibromyalgia, depression, and ME/CFS.

Suggested Citation:"3 Common Mechanistic Factors 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.
×

Embers shared that potential causes for PTLDS include induction of inflammatory responses by persistence of non-living spirochete bacteria or their antigens, the continuation of active infection, and irreversible sequelae from a previous active infection—otherwise thought of as autoimmune components. Furthermore, she added, all three of these causes can occur simultaneously. Doxycycline is typically used to treat the acute infection, working together with host immune clearance of the bacteria. But Borrelia burgdorferi, the causative agent of Lyme disease, can evade the immune response and may persist even in healthy hosts. Embers added that B. burgdorferi can survive for months inside ticks without nourishment and that metabolically dormant or persistent bacteria can be more tolerant to antibiotics. The efficacy and accepted regimen of antibiotic treatment for human borreliosis has been a contentious issue, she explained, with different professional organizations suggesting different regimens of treatment. Additionally, in vitro efficacy tests of antibiotics to inhibit and kill bacteria, which is what many treatment determinations are based on, can be different from in vivo effectiveness. Embers highlighted studies that show antibiotic tolerance is not a heritable trait (e.g., a genetic mutation that confers antibiotic resistance) but is mainly driven by the slow growth of the bacteria. Host adaptation can also contribute to antibiotic tolerance.

A recent study using nonhuman primates showed bacterial persistence and mild to moderate inflammation in the brain, peripheral nerves, spinal cord, joints, skeletal muscle, and heart following B. burgdorferi infection. Embers drew a parallel to a case study of a 69-year-old woman who first contracted Lyme disease at age 54 and was treated with the standard doxycycline regimen, which led to symptom resolution (Gadila et al., 2021). However, the patient later developed a sleep and cognitive disorder years after the original Lyme disease infection. Her serological tests (C6 ELISA and IgG Western blot) were positive, but polymerase chain reaction (PCR) for Bartonella, Babesia, and B. burgdorferi were negative.11 Despite extended retreatment with antibiotics, the patient’s neurocognitive and behavioral symptoms worsened and she eventually died 15 years after her initial Lyme disease diagnosis.

Imaging studies for this patient before her passing showed results consistent with Alzheimer’s disease, and analysis of this patient’s brain tissue revealed evidence of Lewy bodies, amyloid plaques, and Borrelia cells,

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11 Both ELISA and IgG Western blot detect the presence of circulating antibodies against bacterial antigens. For early-stage Lyme disease, the sensitivity of C6 ELISA is around 50–60% with specificity around 98.4%. Diagnostic performance may differ beyond early-stage disease. For more background on diagnosis of Lyme disease, see https://www.columbia-lyme.org/diagnosis and https://wwwnc.cdc.gov/eid/article/22/7/15-1694_article (accessed December 10, 2023).

Suggested Citation:"3 Common Mechanistic Factors 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.
×

Embers said. She concluded that this case study, along with supporting evidence from animal models, supports the hypothesis that B. burgdorferi can persist after conventional antibiotic treatment. She added that borreliosis may play a role in the development of dementia.12 Future strategies for treatment could be similar to the approach for tuberculosis, with combination antibiotics given to eliminate the development of bacterial persisters.13

In conclusion, Embers highlighted there are three primary similarities between long COVID and PTLDS: fatigue, brain fog and cognitive impairment, and musculoskeletal pain. Given the prevalence of both Lyme disease and COVID-19 in the United States and Europe, Embers suggested the possibility of these interacting as a syndemic.

Discussion

Several questions during the discussion were related to pathogen persistence in the human body. Responding to a question about the specificity of EBV-mediated autoimmunity in his studies, Robinson pointed out that in MS, as in many other autoimmune diseases, only specific regions of tissue are attacked and involved. For example, with type I diabetes, one islet of Langerhans in the pancreas might be wiped out while the one next to it would remain perfectly intact even though both carry the targets of the autoimmune response. Therefore, Robinson favors leveraging general tolerance mechanisms that prevent the broad autoimmune attacks in these diseases, though the best therapeutic options continue to elude researchers. Embers said they are pursuing the hypothesis that Bartonella and Borrelia co-infection allows Bartonella to cause more disease and persist longer, which may create a scenario where people are asymptomatic for a long time, making it difficult to detect. While Lyme disease may be at the core of the issue because of its ability to evade and suppress the immune system so effectively, other coinfections should also be considered, she added.

Another participant asked about age differences associated with persistence—mainly noticeable differences between children and adults in long COVID, and whether there are clues from other diseases. Embers said the mechanisms involved in PTLDS based on age are unknown, but it is well established that immune systems decline with advanced age, so children and young adults typically have better outcomes across types of infections, unless the infections lead to runaway inflammatory responses. A participant

___________________

12 Note that the case study was not presented to demonstrate causation and that the speaker stated the possibility of other contributing factors to the patient’s chronic symptoms.

13 Persisters describe a phenotypic subpopulation of bacterial cells that are non-dividing, metabolically dormant, and tolerant to bactericidal effects of antimicrobial compounds. See https://www.nature.com/articles/nrmicro1557 (accessed December 10, 2023).

Suggested Citation:"3 Common Mechanistic Factors 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.
×

added that it is true that children have a lower incidence of these postviral or postpathogenic syndromes, but the symptoms are just as severe in those who do develop the chronic syndromes.

Chertow said that while the mechanism behind the different rates of viral clearance of various body tissues remain unclear, his team has observed a massive inflammatory response in the lungs of severe COVID-19 cases. Even in mild or moderate cases, there is likely a meaningful inflammatory response, he said. The mechanisms of pathogen persistence and evasion of adaptive immune response is not well defined, said Chertow, calling for more research on mechanisms of persistence and immune evasion.

Other questions revolved around therapeutics for these chronic illnesses, such as the efficacy of intravenous immunoglobulin for encephalitis and related symptoms. Miller highlighted the central nervous system consequences of these infections, noting that activation of the immune system will affect the brain and likely result in behavioral changes. Even though there is still much to learn about immunology, Miller noted that psychiatric approaches that address neurotransmitter systems and neurocircuits can relieve symptoms and improve patients’ quality of life. He reiterated the downstream consequences of an activated immune response: the immune response comes with a high energy demand, so the brain shuts down other activities to conserve overall energy use, leading to fatigue, slowed processing, and lack of motivation. He argued that there is a role in this space for more psychiatrists and investments in psychiatric research to support development of potential treatments.

Related, another participant highlighted the importance of integrating immunology and psychiatry when treating MS patients, saying that the two fields have historically been fairly siloed, making it challenging to get MS patients to see a psychiatrist. Miller agreed, but emphasized that psychiatrists are important not because symptoms are “in the patient’s head,” but because biological processes in the brain are affected by the infection, which is then influencing their behavior—and this aspect of treatment need is being missed. He called for the education of physicians and researchers to integrate these fields and recommended funding these types of cross-disciplinary efforts.

Similarly, Miller also responded to another question on therapeutics to mitigate symptoms affecting the brain, saying he tends to prescribe drugs that facilitate dopamine release and temper glutamate levels. The problem is there are so few physicians and psychiatrists working in this area, and so many things have not been tried yet, he explained. He added that what is really needed is more time for doctors to sit with patients and learn from their experiences and what they have researched themselves. Adding to this point, Rowe noted that his team also prescribes stimulants to their patients with orthostatic intolerance, which potentially could be helping

Suggested Citation:"3 Common Mechanistic Factors 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.
×

blood flow and oxygen delivery in the brain, improving symptoms from a different angle.

Peter Daszak, president of EcoHealth Alliance, asked about a vaccine for EBV given it likely plays a significant role in the development of MS. Robinson replied that there is an EBV vaccine advancing through Phase 2 trials at NIH, and Moderna just initiated a set of trials as well, but both are focused on prevention of EBV infection, which may differ from the type of clearance of already infected cells that many are hoping for.

Suggested Citation:"3 Common Mechanistic Factors 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:"3 Common Mechanistic Factors 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:"3 Common Mechanistic Factors 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:"3 Common Mechanistic Factors 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:"3 Common Mechanistic Factors 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:"3 Common Mechanistic Factors 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:"3 Common Mechanistic Factors 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:"3 Common Mechanistic Factors 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:"3 Common Mechanistic Factors 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:"3 Common Mechanistic Factors 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:"3 Common Mechanistic Factors 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:"3 Common Mechanistic Factors 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:"3 Common Mechanistic Factors 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:"3 Common Mechanistic Factors 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:"3 Common Mechanistic Factors 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.
×
Page 31
Suggested Citation:"3 Common Mechanistic Factors 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:"3 Common Mechanistic Factors 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:"3 Common Mechanistic Factors 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:"3 Common Mechanistic Factors 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:"3 Common Mechanistic Factors 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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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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