key: cord-1011405-jswt37wu
authors: Komaroff, Anthony L.; Lipkin, W. Ian
title: Insights from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome May Help Unravel the Pathogenesis of Post-Acute COVID-19 Syndrome
date: 2021-06-07
journal: Trends Mol Med
DOI: 10.1016/j.molmed.2021.06.002
sha: 897dcf86478fe5406a3cafcc989479306d556274
doc_id: 1011405
cord_uid: jswt37wu

SARS-CoV-2 can cause chronic and acute disease. Post-Acute Sequelae of SARS-CoV-2 infection (PASC) include injury to the lungs, heart, kidneys and brain, that may produce a variety of symptoms. PASC also includes a post-COVID-19 syndrome (“long COVID”) with features that can follow other acute infectious diseases as well as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Here we summarize what is known about the pathogenesis of ME/CFS and of acute COVID-19, and speculate that the pathogenesis of post-COVID-19 syndrome in some people may be similar to that of ME/CFS. We propose molecular mechanisms that might explain the fatigue and related symptoms in both illnesses, and suggest a research agenda for both ME/CFS and post-COVID-19 syndrome.

causing the chronic symptoms following severe acute COVID-19 is different from the pathophysiology causing symptoms following moderate acute illness, it also is possible that the pathophysiology following severe and moderate illness is similar. In either case, it is likely that the pathophysiology of post-COVID-19 syndrome overlaps with that of acute COVID-19, other post-infectious fatigue syndromes, and ME/CFS.

An illness consistent with ME/CFS (Box 1) has been described in the medical literature for over 200 years. Many people with ME/CFS report that the illness began with an "infectious-like" prodrome-typically, respiratory and gastrointestinal symptoms, fever, lymphadenopathy, and myalgias. In most instances an infectious agent is neither sought nor identified. However, post-infectious fatigue syndromes that resemble or meet criteria for ME/CFS have been reported following well-documented infections. The precipitating infectious agents include herpesviruses -Epstein-Barr virus [7] , human cytomegalovirus [8] , and human herpesviruses 6A and 6B [9] -SARS-COV-1 (the cause of Severe Acute Respiratory Disease, SARS) [10] , Ebola virus [11] , West Nile virus [12] , dengue virus [13] , Ross river virus [14] , Borrelia burgdorferi [15] , enteroviruses [16] , human parvovirus B19 [17] , Mycoplasma pneumoniae [18] , Giardia lamblia [19] , Coxiella [14] , and Candida sp [20] . Claims that murine leukemia viruses, including a laboratory recombinant virus (XMRV), cause ME/CFS have been refuted [21, 22] , as have similar claims for Borna disease virus [23] . Post-infectious fatigue syndromes can follow both sporadic and apparently epidemic infections [24] . The observation that such a wide variety of infectious agents are associated with ME/CFS suggests that an abnormal host response to infection may be implicated. ME/CFS has been linked not only to exogenous infectious agents, but also to endogenous agents. Intestinal dysbiosis has been reported by several groups. Proinflammatory Proteobacteria species tend to be increased in number, and antiinflammatory Faecalibacteria and Bifidobacteria species and other species that produce the anti-inflammatory compound butyrate are decreased in number [25, 26] . Whether the dysbiosis is a cause of the disease or an epiphenomenon secondary to metabolic or immunologic changes, or to reduced activity levels, is unclear. However, these studies have also found: 1) evidence of increased gut wall permeability with bacterial products entering the circulation; 2) that the abundance of various bacterial taxa correlate significantly with the severity of pain and fatigue [25, 26] ; and 3) that some metabolomic findings (discussed below) appear to reflect the expression of bacterial rather than human genes [25] . These findings suggest a linkage between the microbiome, gut inflammation and the symptoms of the illness, in at least some people.

A variety of abnormal phenotypic and functional immune responses in blood and cerebrospinal fluid (CSF), involving several arms of the immune system, have been independently reported by several research groups. The abnormalities reported by a preponderance of studies, when people with ME/CFS are compared to matched healthy control subjects, are summarized in Box 2. Several of the abnormalities appear to be affected by the duration of the illness, with more pronounced abnormalities seen in the first three years followed by a tendency for the abnormalities to subside-a

The majority of patients recover from COVID-19 and resume normal activities.

Nonetheless, many report persistent symptoms at least 6 months after acute infection [40] . Over 70,000 COVID-19 patients who remained alive 30 days after the onset of symptoms were compared to nearly 5 million matched non-COVID control subjects.

Four months later, patients with COVID-19 had persistent respiratory, cardiovascular, nervous system, metabolic, and gastrointestinal system disorders significantly more often than the control subjects. The same was true when hospitalized COVID-19

patients were compared to hospitalized influenza patients [41] .

Reports of neurological signs and symptoms in in-patients with acute COVID-19 vary:

36% of patients in Wuhan; 57% of inpatients in Spain; and 82% of patients in Chicago [42] [43] [44] . The most commonly reported manifestations are myalgia, headache, dysgeusia, anosmia, encephalopathy, and neuropsychiatric disorders. Seizures and movement disorders are uncommon. Acute ischemic events and intracranial hemorrhage have been reported in 1-4% of patients, including young adults without known vascular disease [45, 46] . Although controversial, some observers have reported neurogenic respiratory failure ("Ondine's curse"). Demyelinating events involving the brain and spinal cord have been reported, as have Guillain-Barré syndrome and leukoencephalopathies [47, 48] .

Autopsy reports of COVID-19 patients with neurologic disease may vary in findings in accordance with signs and symptoms of disease. Some report low levels of SARS-CoV-2 RNA and protein in brain as well as astrogliosis and microglial activation [49] [50] [51] . In others the primary pathology may reflect ischemia. One study found viral RNA, protein and particles in olfactory epithelial cells, dendritic projections of olfactory neurons that extended into the mucosa, and the brainstem, as well as microthrombi and infarcts [52] .

The distribution of virus in olfactory mucosa and neural processes that extend into the nasopharynx provides a mechanism for understanding anosmia and dysgeusia, and for J o u r n a l P r e -p r o o f Journal Pre-proof invasion of the CNS. However, in another study, single cell sequencing of the olfactory epithelium indicated that whereas the requisite viral receptor, the angiotensinconverting enzyme-2 (ACE2) receptor, is expressed in support cells, stem cells, and perivascular cells, it is not present in olfactory sensory neurons [53] . It is unclear therefore, whether COVID-associated anosmia reflects direct neuronal damage due to infection, loss of some factor that is essential to olfactory signal transduction or transmission, or a deleterious inflammatory response. [54] . In another study of 58 patients, 81% with encephalopathy, the presence of virus RNA in CSF was also infrequent (7%); however, 40% had elevated CSF albumin, a finding interpreted to represent trafficking of proteins from the systemic circulation to the CSF due to a breakdown of the blood brain barrier. Seven of 17 (41%) had elevated CSF levels of the interleukin-6 (IL-6) cytokine [55] .

Taken in concert, autopsy and CSF studies suggest that at least some of the neuropathology of COVID-19 is more likely to represent a host response to the virus and microvascular damage, rather than a direct cytopathic effect of SARS-CoV-2 [50] .

Indeed, the vascular pathology-pro-coagulant, pro-aggregatory, anti-fibrinolytic, proinflammatory, vasoconstrictive, pro-oxidant-seen in the lungs, heart, brain, and other organs may all indicate that primary endothelial dysfunction is central to the pathology of both acute COVID-19 and its long term consequences [56] . There is ample precedent for infarcts resulting in dementia and cognitive dysfunction in the elderly [57] . The wide distribution of microinfarcts in COVID-19 suggests they may be one cause of cognitive dysfunction. Magnetic resonance imaging of brain in 37 individuals with severe disease revealed multifocal white matter hemorrhages [58] .

The primary persistent symptoms following COVID-19 include chronic fatigue, impaired smell (anosmia) and taste (ageusia), cognitive problems (e.g., difficulty with J o u r n a l P r e -p r o o f Journal Pre-proof concentration and attention, and possibly memory), and breathlessness. These symptoms may occur in people who have had only mild or no respiratory disease. A post COVID-19 clinic reported that even patients never hospitalized for pneumonia or hypoxemia reported neurologic complaints persisting for more than six weeks that included cognitive dysfunction described as "brain fog" (81%), headache (68%), paresthesias (60%), dysgeusia (59%), anosmia (55%) and myalgias (55%) [59] .

Surveys from the US, Europe and Scandinavia [40, [60] [61] [62] [63] [64] [65] [66] report very different frequencies of persisting symptoms at 6 months out from acute illness. This may be due to differences in methods for ascertainment, differing patient populations (hospitalized vs. not-hospitalized), different definitions of COVID-19 (confirmed by nucleic acid, antigen or antibody testing, or not), and different methods for collecting symptoms (medical records, patient self-report, formal surveys).

The frequency of an infectious prodrome in patients with ME/CFS suggests that, in many cases, infection triggers host responses that culminate in disease. It is plausible that SARS-CoV-2 infection might induce a similar syndrome and that insights from ME/CFS research may be helpful in developing a research agenda for post-acute COVID-19 syndrome. Conversely, because ME/CFS by definition cannot be diagnosed until six months after symptom onset, studies of PASC may yield insights into early manifestations and biomarkers for ME/CFS.

Several studies have reported widespread activation of both astrocytes and microglia in people with ME/CFS [67, 68] . Cognitive dysfunction ("brain fog") may reflect cytokines produced by immune activation (either peripherally, or in the CNS) that are known to cause fatigue, cognitive and mood disorders. For example, elevated peripheral levels of proinflammatory cytokines such as IL-6 can have profound effects on mood, cognition and behavior in humans and animal models [69] . Since this has been well documented for cytokines detected in the circulation, it is at least as likely when cytokines are generated in the brain by neuroinflammation.

The sensation of fatigue experienced by people with ME/CFS is not relieved by rest, and becomes more pronounced hours to days after physical or cognitive exertion. ME/CFS is characterized by a generalized impairment in energy production, a general hypometabolic state and redox imbalance (Box 3) that may contribute to the pathogenesis of fatigue.

Many patients report postural hypotension and tachycardia. Dysautonomia and cerebral hypoperfusion have been documented in ME/CFS patients by various autonomic nervous system tests [70] .

Many ME/CFS patients have autoantibodies that target adrenergic and muscarinic cholinergic receptors [30, [71] [72] [73] . Autoantibodies against neural targets may contribute to cognitive dysfunction, depression, weakness, and autonomic instability.

ME/CFS may represent the unchecked persistence of a response that occurs when various stressors (e.g., infection, injury, cold temperatures, lack of sufficient nutrients) threaten the viability of a cell or of an organism. At the cellular level it is called the cell danger response (CDR) [74] . At the level of the organism, such as in the extreme case of a hibernating animal, it has been called the integrated stress response (ISR) [75] . In both the CDR and ISR, non-essential energy-consuming processes are throttled down, allowing the available energy molecules to be used for processes essential to maintaining viability. A hypothalamic "torpor" nucleus (a group of neurons dedicated to a particular function) has been identified in rodents [76] ; we speculate that such a nucleus also may mediate the ISR. We speculate that a similar nucleus of neurons may be implicated in human sickness symptoms and associated physiologic phenomena, like fever. The nucleus may be triggered by neuroinflammation. Neuroinflammation can J o u r n a l P r e -p r o o f occur directly through injury to or infection of the brain. It also can occur indirectly, in response to humoral and retrograde neural signals generated by inflammation elsewhere in the body [77] or by autoantibodies against specific neural or immune system targets. The redox imbalance that is a central feature of ME/CFS [78] may be a marker for systemic inflammation in response to infection or injury.

Studies are underway to identify the type and frequency of permanent organ injury caused by COVID-19, and to assess the impact of organ injury on symptoms and functional status of that injury, as well as to identify the frequency and underlying pathogenesis of post-COVID-19 syndrome. Viruses can cause damage directly and indirectly [79] . They can invade and kill cells by diverting resources and processes required for viability. They can also compromise cells without killing them and reduce their capacity to express products like hormones, neurotransmitters, and other factors that are essential for function of the infected organism [80] . Infection can also induce immune responses that result in damage or dysfunction, even at sites where the virus may not be replicating. Infection-induced cytokine expression can have profound effects on energy metabolism and cognition [81, 82] . Adaptive immune responses may result in damage to adjacent, uninfected cells or a break in tolerance to self that culminates in autoimmunity [83] .

There is evidence that, as in ME/CFS, autoantibodies may be contributing to post-COVID illness symptoms. Investigators looked for autoantibodies against 2,770 extracellular and secreted proteins in 194 acute COVID-19 patients. They found autoantibodies against cytokines, chemokines, lymphocyte receptors, endothelial targets and multiple CNS targets, including the orexin receptor (important in fatigue and sleep)-autoantibody profiles that correlated with the severity of illness [84] .

There also is evidence that autonomic dysfunction may contribute to post-COVID illness [85] , as it does in ME/CFS [70, 86, 87] . Given the emotional, social and financial trauma suffered by many people with COVID-19, in some people it is possible that mood J o u r n a l P r e -p r o o f disorders also contribute to the symptoms of post-COVID-19 syndrome. Much remains unknown about its pathogenesis.

In this review we have summarized the preponderance of evidence, as reflected by multiple prospective, controlled studies conducted by multiple laboratories. As is often true in the literature on most topics, some studies involve fewer patients than one would like. Whereas peer reviewed studies of ME/CFS patients typically include matched healthy control subjects, very few also include comparison groups with other fatiguing illnesses. Despite this weakness in the literature, inconsistencies in findings most commonly entail differences in the details, rather than in general conclusions.

For example, while virtually all reported studies find impairment in energy metabolism, they differ as to which mechanisms of energy production are most impaired, and which metabolites have the most aberrant levels. This is neither surprising nor disturbing: metabolomics measures dynamic processes rather than fixed defects, such as polymorphic change in gene structure. The moment in a dynamic process when a blood sample is obtained affects the results of any measurement. The first movement and the third movement of the same symphony do not sound the same.

In summary, while the findings we have summarized regarding the underlying pathology of ME/CFS are robust, they also raise questions that require further investigation, as outlined below in Outstanding Questions.

In addition to defining individual components in the pathogenesis of ME/CFS-chronic inflammation, redox imbalance, defective energy metabolism-we also need to understand how these components interact. Several are bidirectionally related. 

Lingering symptoms after acute COVID-19 may be due in some patients to chronic damage to the lungs, heart and kidneys, and in other patients to the psychosocial trauma of the illness and the impact of the pandemic on family, friends and workplace.

In other patients, without evidence of such chronic organ damage-those with post-COVID-19 syndrome-it seems likely that the underlying biology is similar to that of other post-infectious fatigue syndromes, to post-critical illness syndrome and to that of ME/CFS. It also is likely that the underlying pathology involves the central and autonomic nervous system, and a persistent, dysregulated immune and metabolic response to any of multiple infectious agents.

The COVID-19 pandemic is likely to greatly increase the number of people who suffer from ME/CFS or a similar illness, as well as other post-COVID illnesses (e.g., chronic hypoxia from impaired lung function, congestive heart failure from post-COVID cardiomyopathy) [88] . Before the pandemic, ME/CFS was estimated to impact 836,000 to 2,500,000 Americans and to cost as much as $24 billion annually [89] . An estimated J o u r n a l P r e -p r o o f 10 million people may be affected worldwide [88] . It is too early to know the ultimate health impact of post-COVID chronic illnesses; however, senior economists have estimated that the cumulative future costs in the United States may be as high as $4.2 trillion [90] .

These human and economic costs underscore the importance of investing in rigorous research into the epidemiology and pathogenesis of ME/CFS and post-COVID chronic illnesses (see Outstanding Questions and Clinicians Corner). The National Institutes of Health announced in early 2021 that it would invest $1.15 billion in studies of these illnesses. In addition, an NIH-supported biorepository of plasma, serum and cells from well-characterized patients, with detailed clinical information on each patient, is available to investigators (https://searchmecfs.org/). We anticipate that this investment will lead to fundamental answers about the underlying biology of both post-COVID-19 syndrome and ME/CFS, diagnostic and prognostic tests, and new strategies for intervention that reduce the morbidity, social, and economic costs of these diseases. 

Increased production of pro-inflammatory cytokines (e.g., interleukin-1A, interleukin-17a, tumor necrosis factor-α) and "anti-inflammatory" cytokines (e.g., interleukin-1 receptor antagonist, interleukin-4, and interleukin-13) [28, 29, 91] , particularly in the first 3 years of illness [28] .

Levels of multiple cytokines correlate significantly with severity of symptoms [29] .

Decreased cytotoxicity of natural killer cells, with diminished expression of cytolytic proteins and production of cytokines [92, 93] .

Increased numbers of CD8 + cytotoxic T cells bearing activation antigens (CD38+, Human Leucocyte Antigen-DR isotype) [93] .

T cell exhaustion [27, 28] , typically in illness of longer duration.

Decreased and increased numbers of regulatory T cells have been reported [93, 94] although the studies did not consider the current stage of the illness (e.g., flare vs. relative remission).

Increased production of multiple autoantibodies, particularly against central and autonomic nervous system targets [71] .

Antigen-driven clonal B cell expansion (proteomic studies) [95] .

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 Glucose via the TCA cycle [96] , reduced levels of fatty acids and of acyl-carnitine [97] and reduced levels of amino acids, via urea cycle [96, 98]  Impaired oxidative phosphorylation [99, 100]  Glycolysis: either a compensatory increase [101] or decreased [98] Hypometabolic state: reduced levels of many molecules [102] Redox imbalance [78, 103] :

 Increased levels of pro-oxidants: Peroxides and superoxides, correlating with severity of symptoms [104] ; isoprostanes, both at rest and after exercise [105]  Decreased levels of antioxidants: Decreased levels of α-tocopherol [106] ; thiobarbituric acid reactive substances, or TBARS, that correlate with severity of symptoms [107]  Increased nitrosative stress: Increased levels of inducible nitric oxide synthase (iNOS), possibly secondary to increased production of NFκB [108] ; increased nitric oxide (NO), peroxynitrite and nitrate, particularly following exercise [109]  Brain magnetic resonance imaging (MRI) has shown elevated levels of ventricular lactic acid consistent with oxidative stress [110, 111] .

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Cognitive deficits, primarily in attention and reaction time [112] Increased pain in response to various stimuli [113] [114] [115] White matter abnormalities on magnetic resonance imaging (MRI) [116, 117] Impaired response to cognitive, motor, visual and auditory challenges on functional MRI testing [118] Single photon emission computed tomography (SPECT), positron emission tomography (PET) and magnetic resonance spectroscopy reveal hypoperfusion and/or metabolic dysfunction of glial cells [119] , neuroinflammation characterized by widespread activation of both astrocytes and microglia [67, 68] Down-regulation of the hypothalamic-pituitary-adrenal (HPA) axis [120] Impaired connectivity (response of one region of the brain to signals from another region) [121, 122] , also seen in other fatigue states [123] Disordered sympathetic and parasympathetic activity with reduced cerebral perfusion [70, 124] Proteomic studies of spinal fluid employing mass spectrometry, liquid chromatography and peptide sequencing found increased levels of proteins (e.g., α2-macroglobulin, keratin 16, orsomucoid) indicating tissue injury and repair [125] Autoantibodies targeting adrenergic, muscarinic and cholinergic receptors [30, [71] [72] [73] Post-exertion neuromuscular studies reveal reduced anaerobic threshold and peak work, particularly after a second exercise challenge 24 hours later [126] as well as increased lactic acid in muscle [127] and the need to recruit additional brain regions to respond to cognitive challenges (as demonstrated by functional MRI), particularly following exertion [128] J o u r n a l P r e -p r o o f

Although many subjects with ME/CFS report a prodrome consistent with infection, no single agent is consistently implicated. A diagnosis of ME/CFS is based on symptoms; no diagnostic test with adequate sensitivity and specificity has yet been developed, although a number are being tested. Even though the diagnosis is based just on symptoms, multiple underlying biological abnormalities have been identified, as summarized in this article.

There is no specific therapy for ME/CFS and few if any therapies have yet been studied with large, randomized controlled trials.

Although respiratory tract infection may be considered the sine qua non of acute COVID-19, SARS-CoV-2 can also cause injury to multiple organs, including the heart, kidney and brain through parenchymal infection as well as the immune response and vascular damage.

Following COVID-19, some individuals have lingering illness with features of ME/CFS that may not be explained by obvious organ pathology: post-COVID-19 syndrome.

J o u r n a l P r e -p r o o f Post-infectious fatigue syndromes: lingering and debilitating symptoms following a variety of well-documented, specific viral, bacterial, fungal and protozoal infections.

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Will multi-center studies of people with ME/CFS in different geographic areas, including people with both early and late disease, consistently confirm the previously-described immunologic, neurologic, and metabolomic/redox abnormalities?

Do the molecular, proteomic, and metabolomic tests that discriminate people with ME/CFS from healthy controls also discriminate ME/CFS from comparison groups of people with other fatiguing illnesses, such as post-COVID-19 syndrome, MS, systemic lupus erythematosus, and major depression?

Will abnormalities that distinguish people with ME/CFS and post-COVID-19 syndrome at baseline become worse after physical, cognitive and emotional stressors that typically worsen symptoms-and thereby suggest that they may be directly connected to the disease process that generates the symptoms?

Will larger studies using noninvasive imaging techniques confirm the presence of neuroinflammation in people with ME/CFS and post-COVID-19 syndrome?

Will newer anti-inflammatory therapies targeting neuroinflammation, specifically, such as therapies to suppress inflammasome activation in glial cells, ameliorate symptoms in people with both ME/CFS and post-COVID-19 syndrome?

Since a redox imbalance has been consistently documented in people with ME/CFS, will trials of therapies to restore redox balance ameliorate symptoms in people with both ME/CFS and post-COVID-19 syndrome?

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Hyperintense sensorimotor T1 spin echo MRI is associated with brainstem abnormality in chronic fatigue syndrome

Functional neuroimaging correlates of mental fatigue induced by cognition among chronic fatigue syndrome patients and controls

SPECT imaging of the brain: comparison of findings in patients with chronic fatigue syndrome, AIDS dementia complex, and major unipolar depression

Meta-analysis and meta-regression of hypothalamicpituitary-adrenal axis activity in functional somatic disorders

Aberrant Resting-State Functional Connectivity in the Salience Network of Adolescent Chronic Fatigue Syndrome

Abnormal Resting-State Functional Connectivity in Patients with Chronic Fatigue Syndrome: Results of Seed and Data-Driven Analyses

Using functional connectivity changes associated with cognitive fatigue to delineate a fatigue network

Cerebral blood flow is reduced in chronic fatigue syndrome as assessed by arterial spin labeling

A Chronic Fatigue Syndrome -related proteome in human cerebrospinal fluid

Properties of measurements obtained during cardiopulmonary exercise testing in individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Loss of capacity to recover from acidosis on repeat exercise in chronic fatigue syndrome: a case-control study

Neural consequences of post-exertion malaise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

The authors thank Kelly Magnus for assistance with manuscript preparation, and Jill