Exercise Pathophysiology in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Postacute Sequelae of SARS-CoV-2

Abstract

Topic Importance

Postacute sequelae of SARS-CoV-2 (PASC) is a long-term consequence of acute infection from COVID-19. Clinical overlap between PASC and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) has been observed, with shared symptoms including intractable fatigue, postexertional malaise, and orthostatic intolerance. The mechanistic underpinnings of such symptoms are poorly understood.

Review Findings

Early studies suggest deconditioning as the primary explanation for exertional intolerance in PASC. Cardiopulmonary exercise testing reveals perturbations related to systemic blood flow and ventilatory control associated with acute exercise intolerance in PASC, which are not typical of simple detraining. Hemodynamic and gas exchange derangements in PASC have substantial overlap with those observed with ME/CFS, suggestive of shared mechanisms.

Summary

This review illustrates exercise pathophysiologic commonalities between PASC and ME/CFS that will help guide future diagnostics and treatment.

Since the onset of the COVID-19 global pandemic, > 550 million cases of infection with SARS-CoV-2 have been recorded. A substantial subset of survivors experience long-term complications following initial infection, labeled with the all-encompassing term of postacute sequelae of SARS-CoV-2 (PASC) or colloquially referred to as “long COVID.” Diagnostic criteria for PASC are not clearly defined, and prevalence estimates range from 20% to 50% of survivors. Afflicted patients are often young and have a history of mild acute disease. Given the new and substantial global burden related to PASC, elucidating mechanisms underlying PASC that inform its diagnosis and treatment is critical.¹

PASC is recognized as a multisystem syndrome with a broad range of symptoms, including fatigue, chest pain, exertional dyspnea, postexertional malaise (PEM), headache, cognitive impairment or “brain fog,” myalgias, and depression.¹ Although the etiology of PASC is unknown, proposed mechanisms include, but are not limited to, autoimmune and hyperinflammatory states following acute infection.² Extensive overlap between PASC and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) has been increasingly recognized.³ The National Academy of Medicine requires three major criteria for diagnosis of ME/CFS (ie, substantial impairment from fatigue for > 6 months, PEM, and unrefreshing sleep), plus either cognitive impairment or orthostatic intolerance.⁴ Given the substantial overlap in symptoms, a common underlying pathophysiology has been suggested.

Noninvasive cardiopulmonary exercise tests (niCPETs), with continuous measurement of pulmonary gas exchange, ventilation, and cardiac monitoring during incremental exercise on a cycle ergometer, offer a diagnostic modality capable of quantifying and explaining the exertional intolerance of PASC and ME/CFS. Up to one-third of patients undergoing CPET after recovery from their acute illness from COVID-19 display a reduction in oxygen uptake (Vo₂).^5,6

Invasive cardiopulmonary exercise test (iCPET) data suggest that similar exercise pathophysiology underlies both PASC and ME/CFS and argue against deconditioning as the sole explanation for exertional intolerance.^7,8 Such studies suggest that systemic vascular abnormalities, including decreased venous return and peripheral left-to-right shunting, underlie acute exercise intolerance. Combining iCPETs with skin biopsy results showing decreased small neurite density further suggests that dysautonomia underlies vascular dysregulation.⁷ Although niCPETs can reveal abnormalities related to aerobic capacity, stroke volume, and ventilatory efficiency,⁹ iCPETs elucidate mechanistic underpinnings using direct measurements of pulmonary gas exchange, hemodynamics, oxygen delivery, and utilization.

The aim of the current review was to show the following: (1) niCPET assessment of PASC and ME/CFS; (2) iCPET assessment of PASC and ME/CFS; (3) commonalities underlying both syndromes, including peripheral vascular dysregulation, hyperventilation, and mitochondrial dysfunction; (4) pediatric considerations; and (5) future directions.

Literature Search

Relevant literature was identified via PubMed and was reviewed by the authors for inclusion. The search strategy included the following terms: “myalgic encephalomyelitis/chronic fatigue syndrome,” “post-acute sequelae of SARS-CoV-2,” “PASC,” “cardiopulmonary exercise test,” “dyspnea,” “post-exertional malaise,” “small fiber neuropathy,” and “mitochondrial dysfunction.” Abstracts were reviewed for relevance. Whenever possible, case series were avoided, and larger prospective trials and meta-analyses were preferentially used.

Initial Evaluation

Diagnostics performed on the patient at rest, including pulmonary function tests, chest imaging, ECG, orthostatic testing, and echocardiogram, are frequently nondiagnostic in both ME/CFS and PASC. Dyspnea on exertion after COVID-19 has a wide differential diagnosis, such as resolving or persistent interstitial lung abnormalities, pulmonary hypertension, chronic thromboembolic disease/pulmonary hypertension, tracheal stenosis from prior intubation, heart failure, neuromuscular weakness, post-ICU syndrome, and deconditioning.¹⁰ Acute cardiovascular complications related to PASC include myocarditis and pericarditis, with cardiac MRI showing persistent myocardial inflammation months following acute illness.¹¹ The focus of this review, however, was on patients with ME/CFS and PASC who do not have intrinsic cardiopulmonary abnormalities and present with unexplained exertional intolerance.

Noninvasive CPET

niCPETs are a valuable tool for assessing exercise-related symptoms in ME/CFS and PASC. Patients with ME/CFS experience an elevated perception of effort and have a reduced peak Vo₂ compared with control subjects.¹² Mildly reduced peak Vo₂ has been described in ME/CFS with early anaerobic thresholds (ATs) compared with control subjects. Overall, peak Vo₂ in ME/CFS is believed to be 5.2 to 6.5 mL/kg per min lower compared with control subjects.¹³ Related niCPET findings include inefficient breathing and hyperventilation.⁸ Inefficient ventilation is characterized by an increased value of minute ventilation (V_E)/carbon dioxide production (VCo₂), which physiologically is related to either hyperventilation or failure to normally decrease physiological dead space to tidal volume fraction (V_D/V_T) during exercise.

Another niCPET variable found in ME/CFS and PASC is chronotropic incompetence. This is of interest given emerging evidence suggesting autonomic dysfunction in patients with ME/CFS.¹⁴ However, chronotropic incompetence has not been reproduced in more recent and larger studies.¹³

Serial niCPETs in ME/CFS 24 h apart assess the ability of patients to recover and replicate physiologic performance over time.¹⁵ The rationale for such an approach relies on the fact that patients with ME/CFS experience exercise intolerance along with prolonged recovery from exercise and postexertional aggravation of symptoms, also known as PEM.⁴ Two-day niCPET protocols have found that patients with ME/CFS have significantly lower peak Vo₂, earlier onset of the AT, and lower work rate parameters on day 2 compared with day 1.^15,16 A meta-analysis identified that: (1) patients with ME/CFS have lower exercise tolerance levels of all parameters on the second CPET compared with control subjects; (2) the difference between patients and control subjects was more pronounced at the AT in relation to peak; and (3) the workload at the AT was different in patients with ME/CFS compared with control subjects.¹⁷

The biological mechanisms that underlie PEM are not well understood, although CPET has proven useful in terms of mechanistic exploration. Both maximal and submaximal exercise protocols have been used to determine behavioral and physiologic consequences of acute exercise challenge. These studies have shown symptom exacerbation of variable intensity, type, and duration,¹⁸ impaired pain regulation,¹⁹ altered immune function markers (eg, cytokines, complement levels, natural killer cells),²⁰ changes in gut microbiome interactions,²¹ disruption of metabolites,²² and altered brain function.²³ Abnormalities in the skeletal muscle exist in patients with ME/CFS related to impaired oxygen delivery during exercise and the inability to recover from exercise-induced pH reductions.²⁴

It is clear from these studies that exercise influences multiple physiologic systems. However, few studies have directly tested the associations between the physiologic and behavioral manifestations of PEM. One recent study reported that neither symptoms nor cardiopulmonary responses to acute exercise were predictive of PEM in veterans with Gulf War illness, a disease that overlaps significantly with ME/CFS.²⁵ Furthermore, given the overlap between ME/CFS and PASC along with the observation of PEM in PASC,²⁶ further research into underlying mechanisms is needed.

Invasive CPET

Protocols for iCPET, hemodynamic measurements, and pulmonary gas exchange measurements have been described previously (Fig. 1).²⁷ Briefly, the pulmonary and radial arteries are catheterized with ultrasound and fluoroscopic guidance, and then a standard right heart catheterization is performed with oxygen saturation measurements to assess for intracardiac left-to-right shunting. Patients then perform a maximum, incremental, upright exercise on a cycle ergometer as ventilation and pulmonary gas exchange are continuously measured. Hemodynamics, including right atrial pressure (RAP), mean pulmonary artery pressure, and mean arterial pressure, are continuously recorded and averaged throughout the respiratory cycle.²⁸ Pulmonary arterial wedge pressure (PAWP) and arterial and mixed-venous blood gases and pH are measured every minute. RAP and PAWP are measured as the mean of the “a” wave. Cardiac output (Q_c) is calculated by using the direct Fick principle. Predicted peak values for Q_c assume a normal hemoglobin concentration of 14 g/dL, arterial saturation of 100%, and peak mixed venous oxygen saturation of 25%. To correct for anemia, the peak arterial-venous oxygen content difference should approximate the hemoglobin concentration.²⁹

Figure 1.

Invasive cardiopulmonary exercise test.

Following elimination of pulmonary mechanical limitations to exercise, the iCPET can differentiate central cardiac and peripheral limitations to acute exercise. Central cardiac limitations are due to left-sided heart disease, right-sided heart disease/pulmonary vascular disease, or inadequate cardiac preload, with age-related upper limits of normal defined in the upright position during cycle ergometry vs using flow or Q_c-corrected pressure slopes (ie, mean pulmonary artery pressure/Q_c or PAWP/Q_c slopes).30, 31, 32 Peripheral limitations, characterized by impaired systemic oxygen extraction, may be due to mitochondrial myopathy or microcirculatory left-to-right shunts (Fig. 2).29, 30, 31^,33,34

Figure 2.

Evaluation of undifferentiated exertional intolerance. ^aBreathing Reserve Index.^{33 b}Peripheral limitation.^{29 c}Age-defined upper limits of normal.^{30 d}The mPAP/Qc slope is age-dependent whereas the TPG/Qc slope is age-independent.^31ePreload failure.³⁴ Cao₂ = arterial oxygen content; Cvo₂ = venous oxygen content; Hb = hemoglobin; mPAP = mean pulmonary artery pressure; MVV = maximum voluntary ventilation; PAWP = pulmonary artery wedge pressure; PVR = pulmonary vascular resistance; RAP = right atrial pressure; Q_c = cardiac output; TPG = transpulmonary gradient; ULN = upper limit of normal; V_E = minute ventilation; Vo₂ = oxygen uptake.

Inadequate Biventricular Preload

The normal central exercise response consists of an increase in Q_c and stroke volume to support the increased demand of skeletal muscle metabolism. Q_c rises as a function of both mechanical mechanisms (ie, skeletal-muscle and respiratory pumps) and neural mechanisms from parasympathetic withdrawal and sympathetic activation. In response, biventricular filling pressures normally increase from splanchnic vasoconstriction and peripheral venoconstriction, resulting in increased blood volume in the central circulation to support the increase in Q_c and stroke volume.³⁵

Using iCPETs, systemic vascular dysregulation seems to be similar in ME/CFS and PASC. In a heterogeneous population referred for iCPET investigation of unexplained exertional intolerance, low biventricular filling pressures (ie, “preload failure”) explains depressed aerobic capacity in approximately 20% of patients.³⁴ In studies enriched with PASC⁸ and ME/CFS,⁷ preload failure seems to be ubiquitous.

The prevalence of small fiber neuropathy (SFN) seems to be high in PASC and ME/CFS. In one small study, SFN was observed in nearly 90% of patients with PASC.³⁶ One-third of patients with ME/CFS are definitively diagnosed with SFN according to results of protein gene product 9.5-immunolabeled lower-leg epidermal biopsy,⁷ a prevalence similar to that observed in fibromyalgia and postural orthostatic tachycardia syndrome (POTS).³⁷ The prevalence described in ME/CFS may be underestimated due to the use of distal skin biopsies, which may not capture non-length-dependent SFN and are age dependent.³⁸ Small fibers regulate microvascular tone through sympathetic and parasympathetic cholinergic synapses on perivascular myocytes.³⁹ SFN and distal axonopathy can reduce venoconstriction, as seen with abnormal lower extremity venous pooling upon standing and low norepinephrine release following sympathetic nervous system stimulation in POTS.⁴⁰

Impaired Systemic Oxygen Extraction

Normally, during intense exercise, sympathetic tone is elevated, but “endogenous sympatholysis” due to local vasodilatory substances such as nitric oxide, adenosine, histamine, and prostacyclin decreases systemic vascular resistance and allows for preferential perfusion of the exercising muscle. Acid changes in the muscle capillary right-shift the oxygen-hemoglobin dissociation curve and facilitate oxygen offloading to the muscle capillary.⁴¹

A high-flow state, suggested by an elevated Q_c/Vo₂ slope throughout incremental exercise and elevated mixed venous oxygen saturation at peak exercise, has been observed in both ME/CFS and PASC.^7,8 Systemic microcirculatory dysfunction may explain this through peripheral left-to-right shunts. Left-to-right shunts may be explained by dysautonomia, which include distal or proximal SFN or a co-existing ganglionopathy, sometimes associated with autoantibodies to the acetylcholine receptor.⁴² Results of skin biopsies of patients with SFN and fibromyalgia reveal dysregulated arteriovenous blood flow due to abnormal innervation of arteriovenous shunts, enabling oxygenated blood to bypass capillary beds and return unextracted to the venous circulation.⁴³ Recent studies have suggested that RBC deformability and endothelial dysfunction may compromise microcirculatory oxygen delivery during exercise.^44,45

Mitochondrial myopathy has been implicated in both ME/CFS⁴⁶ and PASC⁴⁷ as an explanation of exertional intolerance and can also present with impaired systemic oxygen extraction during iCPETs. Although Q_c/Vo₂ slopes are elevated in both peripheral left-to-right shunts and mitochondrial dysfunction,⁴⁸ the latter’s normal peak exercise Q_c can help differentiate the two (Table 1).

Table 1.

Differential Diagnosis of Changes in Peak Exercise Vo₂ and Q_c

Exercise State	Vo2 Peak	Peak Qc	Diagnosis
Athletic heart			Commensurate increases in Vo2 and Qc at peak exercise is characteristic of endurance trained athletes
Preload failure			Depressed Vo2 and Qc at peak exercise in the absence of a pulmonary mechanical limit suggests preload failure
Left-to-right shunt			Depressed Vo2 peak and supranormal Qc peak is a hallmark of left-to-right shunting
Mitochondrial dysfunction			Depressed Vo2 peak and normal Qc peak suggests mitochondrial dysfunction without cardiac involvement

Q_c = cardiac output; Vo₂ = oxygen uptake.

Dyspnea on Exertion

Dyspnea on exertion generally results from ventilatory demand that exceeds capacity.⁴⁹ In ME/CFS and PASC without intrinsic lung disease, pulmonary mechanics are not limiting. As noted earlier, niCPETs suggest an association between breathlessness and inefficient ventilation (ie, elevated V_E/VCo₂), which by the alveolar ventilation equation is due to hyperventilation and/or increased V_D/V_T. The iCPET allows direct measurements of both, with radial arterial blood gases allowing minute-to-minute assessment of acid-base status and mixed expired CO₂ from the metabolic cart, with calculation of V_D/V_T by using the Bohr equation.

In patients with PASC and ME/CFS without intrinsic cardiopulmonary disease, ventilatory inefficiency and an erratic breathing pattern⁵⁰ are frequently observed and associated with dyspnea. Interestingly, the aberrant increase in V_E/VCo₂ is entirely due to hyperventilation and not due to the failure of the V_D/V_T to fall normally.^8,51 This is in contradistinction to heart failure⁵² and pulmonary arterial hypertension,⁵³ in which ventilatory inefficiency is driven by both elevated V_D/V_T and hyperventilation. In patients with heart failure, skeletal muscle group III/IV afferents play an important role in the exaggerated hyperventilatory response seen during exercise.⁵² These metaboreceptors detect byproducts of muscle metabolism and stimulate group III/IV afferents of the spinal cord to the medullary respiratory centers to stimulate ventilation.⁵³ It is possible that in PASC and ME/CFS, similar to patients with heart failure, an exaggerated skeletal muscle metaboreflex drives hyperventilation. This heightened ventilatory response is associated with exertional dyspnea. Respiratory alkalemia causes a leftward shift of the oxygen dissociation curve, increasing hemoglobin-oxygen affinity and inhibiting systemic capillary oxygen offloading, contributing to the reduction in peak exercise Vo₂.^41,51

Deconditioning

Deconditioning has been implicated as an explanation for exertional intolerance in ME/CFS and PASC.^5,6 iCPETs offer objective evidence arguing against simple deconditioning as an explanation for these symptoms. Low peak exercise Q_c and higher intracardiac filling pressures are observed in detrained individuals due to cardiac atrophy and decreased ventricular compliance,^54,55 diametrically opposed to the previously discussed preload failure hemodynamic phenotype. In a similar fashion, peripheral oxygen extraction is little affected by deconditioning.⁵⁴

Hypovolemia has been offered as an explanation for low intracardiac filling pressures in POTS, ME/CFS, and PASC. The lack of nothing by mouth status for iCPETs; absence of diuretic and venodilator drugs; and increased peak exercise RAP, Q_c, and Vo₂ in a recent randomized placebo-controlled iCPET study of pyridostigmine in ME/CFS suggest that neurovascular dysregulation underlies preload failure, rather than hypovolemia.^7,8,56

Special Consideration in Pediatrics

Children with SARS-Cov-2 often have asymptomatic or mild disease. However, a minority of pediatric patients have a more severe course, either acutely manifesting as ARDS and/or myocarditis or 4 to 6 weeks later as a postinflammatory disorder known as multisystem inflammatory syndrome in children (MIS-C). For those with MIS-C, illness is severe, with approximately 80% of patients requiring intensive care, approximately 50% exhibiting features of left ventricular systolic dysfunction and myocarditis, 10% to 20% developing acute coronary artery aneurysms, 20% with ECG abnormalities/arrythmias, and 4% requiring extracorporeal membrane oxygenation.^57,58

Although many surviving patients return to their baseline health within 8 weeks of their illness, a proportion of children experience chronic health impairments.⁵⁹ Meta-analyses of observational studies including > 80,000 children report long COVID symptoms in 25% of children following SARS-CoV-2 infection.⁶⁰ Prominent symptoms include exercise intolerance, shortness of breath, and orthostatic intolerance. Such impairments may be secondary to the severity of illness, post-ICU syndrome, critical illness myopathy, residual cardiac dysfunction, or deconditioning. However, these symptoms also occur in outpatients with mild SARS-CoV-2 illness, which would be more suggestive of a pathophysiology similar to ME/CFS. Fatigue and PEM are among the most common symptoms reported in children with long COVID. A recent prospective multicenter study identified persistent symptoms and activity intolerance at 2 to 4 months following hospitalization for 26.9% of children hospitalized with acute COVID-19 and 30% of those hospitalized with MIS-C.⁶¹ Meta-analysis also showed that these symptoms were among the most commonly reported in children who were not hospitalized.⁶⁰ PASC symptoms in children may be independent of the severity of the initial infection and occur despite resolution of laboratory and echocardiographic abnormalities.^61,62

There are limited data regarding formal exercise testing in patients with PASC or MIS-C. In a group of 40 children followed up after hospitalization for MIS-C, 45% had 6-min walk test performances below the third percentile for their age and sex at 6 months’ postdischarge.⁶³ In addition, abnormal cardiorespiratory responses during exercise were shown in a small number of patients after hospitalization for MIS-C. In this sample, all patients had lower peak Vo₂, impaired oxidative metabolism (lower aerobic capacity at the anaerobic threshold and oxygen uptake efficiency slope), and ventilatory inefficiency (higher V_E/VCo₂) compared with normal values for the cohort.⁶⁴

Although possibly connected to residual cardiac disease, both impaired 6-min walk test performance and low peak Vo₂ occurred in some patients who had normal inflammatory markers and normal ventricular systolic function on echocardiogram. It is unclear whether the persistent symptoms of PASC in children may have some contribution from deconditioning, as suggested from these healthy control studies, or are entirely from the pathobiology of the illness itself.⁶⁵

Shortness of breath has also been reported as a frequent symptom in children with long COVID. A single-center study comparing pulmonary function testing in 73 children and adolescents following SARS-CoV-2 seroconversion showed lack of impairment except in those with severe infection and no difference in follow-up pulmonary function testing compared with a group of healthy control subjects.⁶⁶ The mechanisms underlying the discrepancy between subjective persistent respiratory report of symptoms and normal pulmonary function in children with long COVID are unclear, but this finding is similar to what has been reported in ME/CFS.

Orthostatic intolerance, described in most patients with ME/CSF, is a common finding in adolescents with PASC with reported orthostatic symptoms as well as descriptions of palpitations, dizziness, and lightheadedness.^59,62 In some instances following COVID-19 infection, adolescents may be diagnosed with POTS in the setting of excessive heart rate increase without hypotension while upright or other forms of dysautonomia, reinforcing the importance of orthostatic testing in the evaluation of PASC symptoms in young patients.⁵⁹

In addition to obtaining a careful history of SARS-CoV-2 illness, complications, and comorbidities, testing in children and adolescents with PASC (severe illness as well as mild) should include laboratory analysis, echocardiogram with and without cardiac MRI, pulmonary function tests, 6-min walk test, CPET, and orthostatic testing. Ongoing large prospective multicenter trials such as the National Institutes of Health-sponsored Long-term Outcomes after the Multisystem Inflammatory Syndrome in Children (MUSIC) study and the National Institutes of Health Researching COVID to Enhance Recovery (RECOVER) program, studying post-acute sequelae of COVID-19, will be crucial to our understanding of this disease, allowing for more definitive clinical guidelines for management and treatment of children with PASC.

Knowledge Gaps and Future Directions

Given the significant global burden of ME/CFS and the suspected societal costs of PASC, further research into underlying mechanisms and treatment is needed. iCPETs offer insights into the underlying pathophysiology of ME/CFS and PASC that cannot be derived from testing of the patient in the resting state or noninvasively. Future directions using niCPETs in conjunction with plasma multiomic signatures may be useful. Metabolomics reveal exercise perturbations in lipid- and energy-related pathways, with commonality observed with glutamate metabolism.²² Metabolic profiles of PASC show elevated ferritin, D-dimer, erythrocyte sedimentation rate, and C-reactive protein, suggestive of a chronic inflammatory state.⁶⁷ Targeting these pathways may offer benefit related to symptom burden.

There are no US Food and Drug Administration-approved treatments for ME/CFS and PASC. Nonpharmacologic therapies can be offered, although the data are based on treating patients with POTS. These include increased dietary salt and fluid intake, activity modification such as leg crossing and squatting, and the use of compression stockings and abdominal binders.⁶⁸ Although graded exercise has been recommended for POTS, PEM makes exercise recommendations difficult in ME/CFS and PASC, supporting the role of CPET-guided exercise prescriptions in rehabilitation efforts. Prior studies have evaluated cognitive behavioral therapy, graded exercise,⁶⁹ IV immunoglobulin,⁷⁰ and B-cell depletion.⁷¹ Robust evidence exists for treating autoantibody-mediated disease such as myasthenia gravis; however, limited data support the use of immunosuppression in autoantibody-associated ME/CFS.⁷² Increasing recognition of mitochondrial dysfunction underlying PASC has led to clinical trials evaluating compounds to improve muscle metabolism.⁷³ However, limited efficacy and data exist for the use of mitochondrial supplements such as ubiquinol, alpha-lipoic acid, L-carnitine, oxaloacetate, and B vitamins, although little harm results from their use.^74,75 Finally, a double-blind randomized placebo-controlled trial of a single dose of pyridostigmine in patients with ME/CFS undergoing iCPETs showed improvement in Vo₂ by increasing Q_c and right ventricular filling pressures.⁵⁶ Long-term placebo-controlled studies are needed to assess for improvements in PEM and exercise tolerance.

Summary

PASC and ME/CFS overlap in both symptom burden and exercise derangements. niCPETs are useful in characterizing aerobic capacity and evaluating ventilatory inefficiency, the latter caused by hyperventilation. Two-day niCPET protocols may provide a diagnostic tool by showing a decrement in peak Vo₂ on day 2, potentially due to PEM. Neurovascular dysregulation observed with iCPETs further explains exercise intolerance in PASC and ME/CFS through impaired cardiac preload and peripheral oxygen extraction, associated with autonomic dysfunction, SFN, ganglionopathy, and mitochondrial dysfunction. Future studies targeting these pathways are needed to reduce the substantial global burden of PASC and ME/CFS.

Funding/Support

D. M. S. received funding from the Solve ME/CFS Initiative, Department of Defense, and Open Medicine Foundation.

Financial/Nonfinancial Disclosures

None declared.