Infection-associated chronic conditions: why long COVID is our best chance to untangle Osler’s Web

Abstract

The recognition of long COVID has renewed efforts to understand other infection-associated chronic conditions (IACCs). Here, we describe how studies of long COVID and other IACCs might inform one another. We argue for the importance of a coordinated research agenda addressing these debilitating illnesses.

One sentence summary:

A research agenda that studies long COVID in the context of related conditions could transform our understanding of these disabling illnesses.

Introduction

For nearly a century, individuals with medically unexplained chronic conditions, particularly those thought to be attributable to presumably transient infectious pathogens, have faced bewilderment, skepticism, or outright dismissal from the medical establishment. Debilitating symptoms lasting for years have been reported following acute infections with viruses [enterovirus, Epstein-Barr virus (EBV), influenza virus, Ebola virus, dengue virus, chikungunya virus, West Nile virus, and severe acute respiratory syndrome coronavirus 1 (SARS-CoV], bacteria (Borrelia, Anaplasma), and protozoa (Giardia).¹ Myalgic encephalomyelitis (ME), sometimes referred to as chronic fatigue syndrome (CFS), is perhaps the best example of a disabling syndrome that many experts believe follows an acute, often undiagnosed viral infection. Several names have been applied to these syndromes, including post-acute infection syndromes (PAIS), infection-associated chronic illnesses, and infection-associated chronic conditions (IACC). Here, we will use IACC.

Despite consistent reports regarding these conditions dating back nearly 100 years,^2-4 the biomedical establishment has made limited progress in defining the epidemiology, natural history, and pathogenesis of most IACCs. No diagnostic tests are available, no widely accepted treatments exist, and industry engagement on finding a cure has been limited. In her 1996 book “Osler’s Web,” investigative journalist Hillary Johnson catalogued the challenges facing ME/CFS research,⁵ which can be applied to many IACCs. Barriers to progress included the inability to fit ME/CFS into existing disease paradigms, variability and inconsistency in case ascertainment, skepticism on the part of many clinicians and scientists, and intense stigma that kept many of those affected from seeking medical care. Sir William Osler, the “Father of Modern Medicine,” emphasized the importance of listening to patients to discern important features of their condition. However, contemporary medical practice relies heavily on diagnostic tests, which are currently inadequate to confirm the presence of an IACC. This results in people being neglected or misdiagnosed and prevents them from receiving appropriate care and support.

The year 2020 has the potential to be a turning point in this story. Shortly after the coronavirus disease 2019 (COVID-19) pandemic began, reports of individuals with prolonged COVID-attributed symptoms emerged, a condition now often referred to as Long COVID. The synchronicity of the inciting infection, universality of the exposure, and visibility, aided by social, popular, and scientific media,⁶ resulted in the ideal environment for a coordinated effort to understand this new IACC. Substantial investment in scientific effort is starting to pay off, with real progress in defining the epidemiology, natural history, and biology of Long COVID now emerging. Following a Congressional appropriation, the U.S. National Institutes of Health rapidly launched the Researching COVID to Enhance Recovery (RECOVER) initiative, which is the first large-scale program aimed at tackling an IACC. The progress to date has been hard-won, however, in part because there is no widely accepted clinical definition, biomarker, or diagnostic test for Long COVID. But clinical trials, slow to start, are now being pursued in earnest. Although there is no guarantee that this momentum will be sustained without dedicated scientific and financial commitments,⁷ there is reason to believe that efforts to understand Long COVID have the potential to draw attention to, reframe, and revitalize the efforts to study other IACCs.

High-quality academic reviews of Long COVID are multiplying rapidly.^8-10 Our goal in this Viewpoint is not to provide a comprehensive overview of the field, but rather to place efforts to study Long COVID in the context of other IACCs. In doing so, we hope to outline several areas that we believe will require consideration as the field attempts to make progress in navigating what has been described as a “labyrinth.”⁵

Challenges in the study of infection-associated chronic conditions

For decades, chronic conditions following clear infectious triggers have been recognized.¹ Many survivors of the 2014-2016 Ebola outbreak in West Africa reported symptoms persisting for years.¹¹ Similar outcomes were documented among survivors of the first SARS-CoV pandemic,¹² foretelling the far more massive burden of disease that has emerged in the wake of COVID-19. Although viruses are the pathogens most implicated in IACCs, chronic and post-treatment Lyme Disease are examples of chronic conditions triggered by a bacterial infection.^13,14 Similarly, a 2004 Norwegian outbreak of the waterborne parasite Giardia duodenalis resulted in a high proportion of post-acute fatigue and abdominal symptoms.¹⁵ Many individuals with ME/CFS attribute their symptom onset to mononucleosis or an unknown viral-like illness.¹⁶ Some outbreaks of ME/CFS have occurred concurrently with known virus epidemics, including poliovirus outbreaks.² During the 1980s, multiple outbreaks of ME/CFS resulted in a major increase in public awareness of the condition,^2,3,5,17 but without identification of the pathogen responsible, skeptical medical professionals and negative popular media portrayals of those affected resulted in dismissal of the illness as unimportant and its infectious nature doubted. The Centers for Disease Control (CDC) investigation of an outbreak affecting several hundred people in Incline Village, Nevada is now seen as a missed opportunity to identify the inciting pathogen for ME/CFS.⁵ Even now, with the virus that incites Long COVID actually known, patients are often unable to access medical care due to skepticism of some healthcare professionals confronted with an unfamiliar syndrome, as well as insufficient specialty clinics to meet the demand.^18,19 Although the inciting pathogens must differ, the clinical presentations of ME/CFS, certain other IACCs, and some phenotypes of Long COVID are remarkably similar, suggesting that there could be at least some overlapping biological pathways (Fig. 1).

Figure 1. Shared and pathogen-specific mechanistic pathways may both drive infection-associated chronic conditions.

An intervention that disrupts a shared pathway would be expected to benefit both non-COVID and COVID-specific conditions, but other pathways might be unique to a specific IACC. Created with Biorender.com.

Inherent in the study of all IACCs are several key challenges. In the absence of a large-scale outbreak or a severe disease in the acute phase, many patients and clinicians may assume a person with a mild viral-like illness will recover. As a result, tests to identify the pathogen are unlikely to be sought or performed. By the time it is recognized that an IACC has developed, it is likely to be long after the acute phase of illness, when routine tests might have identified a pathogen. Thus, most individuals are unable to attribute their illness onset to a specific infectious trigger. In contrast, Long COVID emerged in the context of a pandemic virus. Many of the SARS-CoV-2 infections to which Long COVID is attributed were clearly documented, and the reduction in other circulating pathogens (e.g., influenza, rhinovirus, other common cold coronaviruses) in the first years of the pandemic makes the attribution less murky. Indeed, the single greatest distinction between Long COVID and most other IACCs is the scale, specificity, and immunologic novelty of the responsible organism, making case ascertainment in the early COVID-19 pandemic era of frequent testing and high-quality public health surveillance relatively straightforward.

Asymptomatic infection is also a major challenge. Given the high prevalence of asymptomatic SARS-CoV-2 infection and recent reductions in testing, the ability to trace any “long” syndrome to a prior SARS-CoV-2 infection will become difficult, hindering both care and research. Serologic tests that would only be positive in those previously infected with SARS-CoV-2 could be helpful in this regard; for example, infection but not vaccination will induce a positive nucleocapsid antibody response, although variability in the magnitude and durability of such responses limit the utility of currently available tests;^20-22 interferon-γ release assays could play a role, but their availability is currently limited.²³ In addition, with the re-emergence of other culprit viruses, some people who develop a condition consistent with Long COVID may actually have an IACC caused by a different pathogen, even if they have evidence of prior SARS-CoV-2 infection. A similar challenge exists with Lyme Disease, especially in areas where tick-borne illness is endemic. Although the identities of the pathogens that incited the 1980s ME/CFS outbreaks were never determined, abundant evidence from earlier outbreaks as well as sporadic cases strongly implicates members of the enterovirus family.³ This large and diverse family of viruses is cited by the CDC as the cause of as many as 15 million infections each year in the U.S., with many of them asymptomatic.²⁴ Given that SARS-CoV-2 is now likely to circulate indefinitely, and surges associated with new variants will be common but perhaps not confirmed by testing given limited investment in case ascertainment, the emergence of “sporadic” Long COVID will make it challenging to distinguish it from other IACCs.

Although people with Long COVID still face skepticism, the fact that this syndrome emerged in the context of a recognized pandemic with high morbidity and mortality provided the possibility of avoiding many of the obstacles faced by people with other IACCs. Imagine that instead of a novel coronavirus spreading globally in 2020, one of the four common cold coronaviruses mutated and resulted in an illness with chronic post-acute symptoms. Given the unmemorable nature of the acute phase illness, those who months later experienced chronic symptoms might be unable to recall the inciting infection, potentially leading medical professionals and others to incorrectly diagnose a psychological illness or even accuse the person of malingering to avoid work and other responsibilities, a fate that has befallen many with IACCs, especially ME/CFS. Instead, Long COVID emerged from an extraordinary worldwide pandemic, when everyone was paying attention to the inciting virus and patients were able to join together to draw attention to the issue.²⁵ It therefore represents the best opportunity to figure out the natural history, pathogenesis, and management of an IACC.

What can Long COVID researchers learn from 40 years of IACC studies?

Despite serious underfunding, important information has emerged from the many years of studying ME/CFS and other IACCs that is relevant to efforts to understand Long COVID. The first is the importance of defining the syndrome under study. The diagnostic criteria for ME/CFS have evolved over time, and, in the absence of definitive molecular or biochemical assays, a set of particular symptoms must be used to define the illness.²⁶ Criteria that are too general will result in inclusion of individuals whose underlying abnormalities are not shared, making it difficult to identify biomarkers and draw conclusions. Although still controversial, the criteria that have achieved the most acceptance include a requirement for post-exertional malaise (PEM) – such as the Institute of Medicine diagnostic criteria,²⁶ the Canadian Consensus Criteria,²⁷ and the International Consensus Criteria.²⁸

A similar exercise now needs to be done for Long COVID (several are underway, including one recently completed by the National Academies of Sciences, Engineering, and Medicine). Many individuals with severe cases of COVID-19 have verifiable organ damage that results in well-recognized and easy-to-define complications, such as lung damage causing dyspnea, or endothelial inflammation leading to cardiovascular events.²⁹ These outcomes are an important part of the research agenda but in many cases are distinct and largely unrelated to the syndrome that is Long COVID. Lumping individuals who, for example, have sequelae from ventilator-induced lung injury, with those who had mild illness followed by unexplained symptoms, could confound understanding of the biological basis of the continued symptoms.

Just as there are distinct endotypes of ME/CFS and other IACCs, individuals with Long COVID may need to be separated into distinct symptom clusters,³⁰ despite all cases being driven by SARS-CoV-2 infection. The reasons for these diverse symptom manifestations are unknown. Although this heterogeneity could be driven by different variants, pre-existing immunity, or treatment approaches, it is important to note that distinct endotypes of Long COVID emerged in 2020, long before any of these confounders. Likewise, in ME/CFS, it is likely that different members of the enterovirus family were responsible for different outbreaks, given the rapid evolution of enteroviruses and the temporal and geographical separation of the outbreaks. Nevertheless, there are many other sources of variation in presentation that need to be studied, including which latent herpesviruses a patient may be carrying, their environmental exposures, their microbiomes, and especially their genetics and epigenetics.

A major source of variation between cases, which is common to most IACCs, is biologic sex. Biological females experience many of these illnesses at least two or three times as frequently as males. Elucidating the role of sex will go a long way to addressing stigma and might lead to sex-specific strategies for prevention and treatment of IACCs. Also, it seems highly likely that the sex effect is providing a clue regarding some fundamental pathway common to most or all IACCs. Given the role of sex as a contributing factor to autoimmunity and inflammation-associated diseases (e.g., systemic lupus erythematosus, multiple sclerosis), it seems likely that immune dysfunction will prove to be a key part of the answer. The sex-based dichotomy in Long COVID and other IACCs should be a major area of research focus in the coming years.

Should Long COVID and other IACCs be studied together?

Many symptoms overlap between Long COVID after 2020 and ME/CFS cases prior to 2020.³¹ These similarities have led some to propose that the two conditions be considered one and the same, and some people with Long COVID who fulfill at least some ME/CFS diagnostic criteria are being told they have ME/CFS. Early efforts have suggested that a high proportion of those with Long COVID meet ME/CFS criteria,³² but many of these studies are limited by non-representative cohorts, lack of pre-COVID symptom data, and incomplete case definitions applied post-hoc. Together, these factors make most prevalence estimates to date uninterpretable. Fully addressing this question will require well-characterized participants, clear attribution of symptoms to a SARS-CoV-2 infection, and prospective assessment beginning in the acute phase. Such efforts are now underway through large studies like the RECOVER initiative.

Although there may be overlap between Long COVID and other IACCs, assuming that all Long COVID is ME/CFS (or that all Long COVID is driven by postural orthostatic tachycardia or mast cell activation, for example) is also scientifically problematic, as it dismisses what is perhaps the most important lead in our efforts to understand Long COVID: that we can often identify the culprit virus. The distinction will be critical in research studies that aim to include both groups, allowing for the assessment of whether any mechanistic pathways are shared or whether they might be specific to either SARS-CoV-2 or ME/CFS or other conditions (Fig. 1). The risks of conflating Long COVID and ME/CFS goes both ways; although there is hope that Long COVID research will provide some of the answers needed to fully understand ME/CFS, this should not come at the expense of investment in efforts to study pre-2020 ME/CFS, which may still be driven by distinct biology.

Thus, it is important to both study IACCs separately and to study their overlap. Though symptomatic overlap suggests that some of the same molecular, biochemical, or physiologic pathways are affected in these syndromes, mixing study participants whose underlying disruption differs could result make a complex, highly variable syndrome even more heterogenous.³³ The ultimate goal of much of this research, finding molecular biomarkers, will be made more difficult when multiple IACCs are combined. Although breaking down silos across the IACCs will undoubtedly accelerate progress, studying all IACCs as one condition is premature, as at least some mechanisms for each condition may prove to be unique. Until we know more about the underlying causes of the persistent symptoms of IACCs, we cannot be certain that a treatment for one will be beneficial for another (Figure 1).

While recognizing the risks of considering all IACCs to be a single disease, we must also acknowledge that shared mechanisms are not only possible, but in our opinion, likely.³¹ Beyond the role of an inciting infection, there appear to be many notable mechanistic similarities among these syndromes. For example, the identification of coagulation disturbances in individuals with Long COVID has been accompanied by similar observations in ME/CFS, although to a lesser degree.^34,35 Chronic inflammation and immune dysfunction is a common theme in nearly every IACC.³⁶ To truly investigate similarities and differences between IACCs, direct comparisons must be made in the same study, using the same assays. Incorporating pre-pandemic ME/CFS cohorts into the studies that will be funded by NIH’s ongoing RECOVER initiative, for example, would reveal which mechanisms are shared and whether some elements of pathophysiology differ.

Reactivation of latent human herpesviruses, such as EBV and HHV-6, has been associated with many of these syndromes.^17,37 Although it is unclear whether they are directly responsible for these conditions on their own, herpesviruses could interact through indirect mechanisms by altering a person’s susceptibility to another virus, the known ability of these viruses to persist, or more direct mechanisms in the setting of loss of herpesvirus control. Recently, a large study of college students demonstrated that among a subset of those who experienced new mononucleosis and later met criteria for ME/CFS, different metabolite and cytokine profiles could be identified prior to their illness.^38,39 These studies also revealed that GI symptoms preceding EBV infection, which potentially could be due to an a preceding exposure to another pathogen,– were strongly associated with the development of ME/CFS. Herpesvirus reactivation has often been seen following other viral infections, physical trauma, or toxic environmental exposures.⁴⁰ Whether herpesviruses play a causative role in failure to recover from COVID-19 requires further exploration.

Antigen Persistence as a Driver of IACCs

By definition, every IACC was caused by an inciting infection. Many of these are assumed to be transient, begging the question: how might exposure to an infection for days to weeks lead to life-long disability? Theoretically, an acute transient infection could cause irreversible tissue damage, or might induce immunologic mayhem, leading to loss of regulation and autoimmunity. Molecular mimicry between the infection and a host protein could also lead to autoimmunity. Recent evidence linking virus burden during acute SARS-CoV-2 infection to Long COVID is generally supportive of these possible mechanisms.^41-43 If true, more aggressive management with antimicrobials during acute infections could reduce the risk of IACCs.

It is easier, however, to build a case for an infection causing a chronic condition if the pathogen persists indefinitely. Whereas the persistence of DNA viruses is well-understood, infections with RNA viruses are generally thought to be transient. However, there is evidence that RNA and protein from these viruses can persist beyond the acute phase of illness.⁴⁴ The evidence that SARS-CoV-2 protein or nucleic acid persists indefinitely in some people continues to grow.^10,45-48 We and others have consistently found spike protein or RNA in plasma for months or even years after the acute infection.^10,45 It is even easier to find protein and nucleic acid in tissues.^10,46,48 Whether this reflects ongoing cycles of viral replication and spread is not known, but the finding that virus can evolve over months in immunocompromised people provides proof that this is at least possible.⁴⁹

To rule out false positives, we recently performed a large survey for the SARS-CoV-2 spike protein in samples from prior to the pandemic and in samples from people who were weeks to months out after a well-documented SARS-CoV-2 infection. In samples that were collected before SARS-CoV-2 vaccines became available and before re-exposures and re-infections became common, we found higher prevalence of antigen detection in the post-COVID group for up to a year following infection.⁴⁵ Although there are still many caveats, we feel that this can no longer be summarily ignored simply because it does not fit an existing paradigm. Importantly, although the evidence that SARS-CoV-2 can persist is now nearly definitive,^10,45-47 the links between persistent virus and Long COVID are weaker. Efforts to make this connection remain one of the most important parts of the research agenda.

Although the pathogen associated with a preceding illness was not identified in most cases of ME/CFS, enteroviruses are most commonly implicated.^2-4,50 Enterovirus capsid protein and RNA were found in a large proportion of stomach biopsies from patients with ME/CFS.⁵¹ Although screening for viruses in easily accessible biospecimens (e.g., blood, saliva) from pre-2020 ME/CFS samples has been negative,⁵² recent experience with SARS-CoV-2 suggests that ultrasensitive methods (e.g., single-molecule assays, peptide arrays, bacteriophage display) and the use of tissue samples will be needed to definitively assess the possible presence of persistent antigens.⁴ For example, studies which have identified post-acute SARS-CoV-2 antigen have shown that its detection is inconsistent,^45,53 and that detection in tissue might be more reliable.⁵⁴

The Emerging Clinical Trials Agenda and Experimental Medicine for IACCs

Unfortunately, there is not yet a solid animal model for studying IACCs; it remains to be seen whether development of such a model is even possible given the subjective nature of these conditions. For this reason, the best scientific strategy for defining the mechanism of each IACC may be the conduct of prospective clinical trials in which well-understood interventions in highly characterized participants are used to disrupt specific pathways of interest. We hence advocate for the financing of an experimental medicine agenda that is designed both to uncover mechanisms and identify potential interventions that might prove to be curative in Long COVID, ME/CFS, chronic Lyme disease, and other IACCs. For ME/CFS, NIH has recently sponsored production of a roadmap to guide research that will help identify promising interventions to be tested in clinical trials.⁵⁵

The first order of business should be to determine whether pathogen persistence is required for the development and maintenance of disease. Notably, randomized clinical trials of antibiotics targeting Borrelia burgdorferi (presumably the cause of chronic Lyme disease) demonstrated promising results in some but not all studies;^56,57 use of these agents remains controversial in clinical care. Uncontrolled case series of small molecule antivirals have suggested some promise in Long COVID,^58,59 and randomized studies of nirmatrelvir/ritonavir (Paxlovid) in people with established Long COVID are ongoing. This includes a large phase II/III study sponsored by RECOVER (VITAL, NCT05595369). Similar studies might be considered in other IACCs, but the lack of effective antimicrobials for most of the inciting pathogens makes such studies impossible to conduct. Biologically, there are also challenges. These approaches require active replication of the pathogen and the administration of an antimicrobial agent which penetrates relevant reservoirs/tissues in a sustained manner. Active replication may not be required, however, as instead it could be that persistent “debris” from the pathogen is inducing a harmful host response. An approach we favor is to target an exposed antigen with pathogen-specific monoclonal antibodies, which have the capacity through the Fc receptor to induce a potent host immune response, thus potentially leading to removal of a stubborn reservoir. Monoclonal antibodies have favorable pharmacokinetic profiles that make sustained administration of the antimicrobial more feasible. Case report data suggest potential benefit.⁶⁰ Two of us are now conducting a proof-of-concept study of an anti-SARS-CoV-2 monoclonal antibody in people with Long COVID (NCT05877508); more studies of this approach are needed. If anti-SARS-CoV-2 drugs can restore to health even a subset of individuals suffering from Long COVID, investigating whether a persistent virus underlies pre-pandemic ME/CFS becomes even more urgent, as development of treatment could potentially end decades of suffering for many patients.

Given the consistent finding of immune dysregulation in both ME/CFS and Long COVID, we also believe that immune-modifying strategies should be a priority. For Long COVID, the NIH is funding a large randomized clinical trial of a JAK/STAT inhibitor (baricitinib, NCT05858515), which has the potential to modify several pathways implicated in Long COVID. Funding to support early, proof-of-concept studies targeting other aspects of the immune system (e.g., the innate immune system), as well as coagulation abnormalities, autoimmunity, and coinfections such as EBV, should also be a priority. Eventually, trials of combinations of therapeutics targeting both upstream biology (e.g., virus persistence, immune dysfunction) as well as downstream pathophysiology (e.g., autonomic dysfunction, endothelial damage) may be needed.

Conclusions

Despite waning public concern about COVID-19, Long COVID has remained squarely in the spotlight. The field is moving rapidly, with studies posted or published on a near-weekly basis. Still, new funding opportunities and investment in clinical infrastructure to provide care to patients are limited. Industry engagement also remains limited and will likely remain so until progress on defining the mechanism is made. Progress in the management of HIV was only made because of a sustained, decades-long, commitment by the NIH and others. We welcome the recent news that there will be ongoing investment in RECOVER,⁶¹ but to meet the scope and scale of the challenge of IACCs will require coordinated, sustained funding beyond this one program. In the absence of such a long-term deep commitment, our current progress in the understanding of Long COVID (and all IACCs) remains under threat.⁷ Still, there is at present optimism that the energy around Long COVID will translate into breakthroughs for other IACCs. The key questions and research strategies that need to be pursued now are similar across the IACCs (Table 1). With deep engagement from those most directly affected by these conditions, now is the time to bring all the IACC stakeholders together, even as the deep dives into mechanisms and treatments remain condition-specific.

Table 1: Cross-cutting research priorities across the spectrum of IACCs.

Epidemiology
Develop clear case definitions for each IACC for use in clinical care and research, recognizing that these will not be the same
Develop population-based surveillance programs designed to characterize the global incidence and prevalence of each IACC, with an additional focus on low- and middle-income settings in which these conditions are incompletely described
Enhance population-based surveillance programs in the U.S. and similar countries to better understand health care disparities in IACCs in the settings in which they have most commonly been reported to date
Improve efforts to understand IACCs in children and adolescents
Support rigorous, prospective natural history studies of IACCs, including comparative natural history studies
Pathobiology
Definitively determine whether pathogen persistence is the central mechanism for each IACC
Implement prospective, biologically-oriented, linked cohorts designed to conduct cross-disciplinary studies of IACCs
Study proposed biological pathways, including but not limited to pathogen persistence, inflammation, coagulation, autoimmunity, and herpesvirus reactivation, across multiple IACCs to identify both shared and unique pathways
Determine why biologic sex is a consistent predictor for the incidence of IACCs
Determine the role of age across the lifespan, focusing on why IACC epidemiology appear to differ in the pediatric versus adult populations
Determine the impact of IACCs and the pathogens associated with IACCs on maternal-fetal health
Diagnostics
Develop new technologies for the study of IACCs, especially high-throughput methodologies to assess the presence and timing of prior infections
Develop methods that can determine the identity of the IACC that is causing an individual’s symptoms
Develop measures to monitor the clinical status of those experiencing an IACC over time
Develop measures for use in clinical trials to assess efficacy of treatments, being mindful that limitations experienced by some individuals with IACCs may preclude participation in certain assessments
Therapeutics and Clinical Care
Invest in proof-of-concept experimental medicine trials to probe biological pathways for specific IACCs
Develop antimicrobial drugs that can treat acute or chronic infections that result in IACCs
Determine the role of acute treatment of the inciting pathogen in preventing each IACC
Develop vaccines or other prophylactic measures to prevent infections with pathogens that lead to IACCs
Invest in the rigorous assessment of the role rehabilitation medicine, appropriate physical therapy, and other disease management approaches within and across the IACCs, being mindful that such treatments may be unhelpful or even harmful in some individuals
Study different care approaches to IACCs, including monitoring, pharmacologic, rehabilitation, behavioral, complementary medicine, and social support components of care, to define optimal models for these conditions, with a focus on patient-centered, holistic care
Continue investment in centers of excellence for the care of patients with IACCs, linking care with research
Resources
Enhance the role of community advocates and those with lived experience spanning all arenas related to IACCs, from study of basic mechanisms, to implementation of therapies, to public policy
Provide a unified set of validated, broadly accessible, centrally housed instruments for use in IACC research
Implement and promote a series of straightforward diagnostic codes to better understand the burden of IACCs using medical records data
Maintain infrastructure to rapidly implement epidemiologic investigation of IACC outbreaks, including rapid implementation of biospecimen banking
Support infrastructure for people who are homebound due to an IACC to be able to participate in research and receive clinical care
Develop well-characterized IACC cohorts and biorepositories that can be used for cross-IACC research
Provide resources for national or international meetings to bring IACC researchers together
Provide funding mechanisms to support IACC-focused multidisciplinary resource and cross-IACC research efforts

The late Paul Cheney, one of the two physicians in Incline Village who presided over its famous outbreak, was quoted as saying that “bench researchers are going to take us out of Osler’s web.”⁵ He saw the web as a “kind of diffuse feeling that this disease is real, even though we can’t find the objective measures.”⁵ Today, many underlying objective abnormalities have been identified in both ME/CFS and Long COVID.³¹ More importantly, the scientific community now has far more tools at its disposal, some that could not even have been imagined 40 years ago. Using these tools to study the full spectrum of IACCs should clear away the web of disbelief and denial, identify those objective measures, and finally provide the knowledge that can lead to beneficial treatments for long-suffering people with infection-associated chronic conditions.