National Academies Press: OpenBook
« Previous: 4 Global Functioning in Long COVID
Suggested Citation:"5 Chronic Conditions Similar to Long COVID." National Academies of Sciences, Engineering, and Medicine. 2024. Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection. Washington, DC: The National Academies Press. doi: 10.17226/27756.
×
Page 183
Suggested Citation:"5 Chronic Conditions Similar to Long COVID." National Academies of Sciences, Engineering, and Medicine. 2024. Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection. Washington, DC: The National Academies Press. doi: 10.17226/27756.
×
Page 184
Suggested Citation:"5 Chronic Conditions Similar to Long COVID." National Academies of Sciences, Engineering, and Medicine. 2024. Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection. Washington, DC: The National Academies Press. doi: 10.17226/27756.
×
Page 185
Suggested Citation:"5 Chronic Conditions Similar to Long COVID." National Academies of Sciences, Engineering, and Medicine. 2024. Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection. Washington, DC: The National Academies Press. doi: 10.17226/27756.
×
Page 186
Suggested Citation:"5 Chronic Conditions Similar to Long COVID." National Academies of Sciences, Engineering, and Medicine. 2024. Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection. Washington, DC: The National Academies Press. doi: 10.17226/27756.
×
Page 187
Suggested Citation:"5 Chronic Conditions Similar to Long COVID." National Academies of Sciences, Engineering, and Medicine. 2024. Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection. Washington, DC: The National Academies Press. doi: 10.17226/27756.
×
Page 188
Suggested Citation:"5 Chronic Conditions Similar to Long COVID." National Academies of Sciences, Engineering, and Medicine. 2024. Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection. Washington, DC: The National Academies Press. doi: 10.17226/27756.
×
Page 189
Suggested Citation:"5 Chronic Conditions Similar to Long COVID." National Academies of Sciences, Engineering, and Medicine. 2024. Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection. Washington, DC: The National Academies Press. doi: 10.17226/27756.
×
Page 190
Suggested Citation:"5 Chronic Conditions Similar to Long COVID." National Academies of Sciences, Engineering, and Medicine. 2024. Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection. Washington, DC: The National Academies Press. doi: 10.17226/27756.
×
Page 191
Suggested Citation:"5 Chronic Conditions Similar to Long COVID." National Academies of Sciences, Engineering, and Medicine. 2024. Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection. Washington, DC: The National Academies Press. doi: 10.17226/27756.
×
Page 192
Suggested Citation:"5 Chronic Conditions Similar to Long COVID." National Academies of Sciences, Engineering, and Medicine. 2024. Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection. Washington, DC: The National Academies Press. doi: 10.17226/27756.
×
Page 193
Suggested Citation:"5 Chronic Conditions Similar to Long COVID." National Academies of Sciences, Engineering, and Medicine. 2024. Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection. Washington, DC: The National Academies Press. doi: 10.17226/27756.
×
Page 194
Suggested Citation:"5 Chronic Conditions Similar to Long COVID." National Academies of Sciences, Engineering, and Medicine. 2024. Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection. Washington, DC: The National Academies Press. doi: 10.17226/27756.
×
Page 195
Suggested Citation:"5 Chronic Conditions Similar to Long COVID." National Academies of Sciences, Engineering, and Medicine. 2024. Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection. Washington, DC: The National Academies Press. doi: 10.17226/27756.
×
Page 196
Suggested Citation:"5 Chronic Conditions Similar to Long COVID." National Academies of Sciences, Engineering, and Medicine. 2024. Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection. Washington, DC: The National Academies Press. doi: 10.17226/27756.
×
Page 197
Suggested Citation:"5 Chronic Conditions Similar to Long COVID." National Academies of Sciences, Engineering, and Medicine. 2024. Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection. Washington, DC: The National Academies Press. doi: 10.17226/27756.
×
Page 198
Suggested Citation:"5 Chronic Conditions Similar to Long COVID." National Academies of Sciences, Engineering, and Medicine. 2024. Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection. Washington, DC: The National Academies Press. doi: 10.17226/27756.
×
Page 199
Suggested Citation:"5 Chronic Conditions Similar to Long COVID." National Academies of Sciences, Engineering, and Medicine. 2024. Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection. Washington, DC: The National Academies Press. doi: 10.17226/27756.
×
Page 200
Suggested Citation:"5 Chronic Conditions Similar to Long COVID." National Academies of Sciences, Engineering, and Medicine. 2024. Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection. Washington, DC: The National Academies Press. doi: 10.17226/27756.
×
Page 201
Suggested Citation:"5 Chronic Conditions Similar to Long COVID." National Academies of Sciences, Engineering, and Medicine. 2024. Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection. Washington, DC: The National Academies Press. doi: 10.17226/27756.
×
Page 202
Suggested Citation:"5 Chronic Conditions Similar to Long COVID." National Academies of Sciences, Engineering, and Medicine. 2024. Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection. Washington, DC: The National Academies Press. doi: 10.17226/27756.
×
Page 203
Suggested Citation:"5 Chronic Conditions Similar to Long COVID." National Academies of Sciences, Engineering, and Medicine. 2024. Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection. Washington, DC: The National Academies Press. doi: 10.17226/27756.
×
Page 204
Suggested Citation:"5 Chronic Conditions Similar to Long COVID." National Academies of Sciences, Engineering, and Medicine. 2024. Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection. Washington, DC: The National Academies Press. doi: 10.17226/27756.
×
Page 205
Suggested Citation:"5 Chronic Conditions Similar to Long COVID." National Academies of Sciences, Engineering, and Medicine. 2024. Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection. Washington, DC: The National Academies Press. doi: 10.17226/27756.
×
Page 206
Suggested Citation:"5 Chronic Conditions Similar to Long COVID." National Academies of Sciences, Engineering, and Medicine. 2024. Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection. Washington, DC: The National Academies Press. doi: 10.17226/27756.
×
Page 207
Suggested Citation:"5 Chronic Conditions Similar to Long COVID." National Academies of Sciences, Engineering, and Medicine. 2024. Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection. Washington, DC: The National Academies Press. doi: 10.17226/27756.
×
Page 208
Suggested Citation:"5 Chronic Conditions Similar to Long COVID." National Academies of Sciences, Engineering, and Medicine. 2024. Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection. Washington, DC: The National Academies Press. doi: 10.17226/27756.
×
Page 209
Suggested Citation:"5 Chronic Conditions Similar to Long COVID." National Academies of Sciences, Engineering, and Medicine. 2024. Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection. Washington, DC: The National Academies Press. doi: 10.17226/27756.
×
Page 210
Suggested Citation:"5 Chronic Conditions Similar to Long COVID." National Academies of Sciences, Engineering, and Medicine. 2024. Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection. Washington, DC: The National Academies Press. doi: 10.17226/27756.
×
Page 211
Suggested Citation:"5 Chronic Conditions Similar to Long COVID." National Academies of Sciences, Engineering, and Medicine. 2024. Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection. Washington, DC: The National Academies Press. doi: 10.17226/27756.
×
Page 212
Suggested Citation:"5 Chronic Conditions Similar to Long COVID." National Academies of Sciences, Engineering, and Medicine. 2024. Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection. Washington, DC: The National Academies Press. doi: 10.17226/27756.
×
Page 213
Suggested Citation:"5 Chronic Conditions Similar to Long COVID." National Academies of Sciences, Engineering, and Medicine. 2024. Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection. Washington, DC: The National Academies Press. doi: 10.17226/27756.
×
Page 214

Below is the uncorrected machine-read text of this chapter, intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text of each book. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

5 Chronic Conditions Similar to Long COVID While Long COVID has recently garnered significant attention because of its wide-ranging effects on a considerable portion of the global population, infection-associated chronic conditions (IACCs) are not a new phenomenon. Additionally, Long COVID shares many features with other complex mul- tisystem chronic conditions, including myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and fibromyalgia (FM). This chapter focuses on Long COVID’s similarities with those two conditions, which are requested in the committee’s statement of task. The committee also reviewed Long COVID’s similarities with other conditions, including postural orthostatic tachycardia syndrome (POTS), posttreatment Lyme disease, and hypermo- bile Ehlers-Danlos syndrome, and data on those similarities are included where available; however, the research here is limited. A discussion of auto- nomic dysfunction, including POTS, is provided in Chapter 3. SARS-CoV-2 is the viral trigger for Long COVID. It is also hypothesized to be one potential viral trigger for ME/CFS and FM. Other mechanistic links have been suggested among these conditions, including abnormalities involving the immune system, central and autonomic nervous systems, car- diopulmonary system, gut microbiome, and energy metabolism. Addition- ally, given their common symptoms, treatments for ME/CFS and FM can help inform treatment for Long COVID. Beginning with a review of ME/ CFS and FM and their shared symptoms with Long COVID, this chapter explores the parallels among those disorders, including a review of the common potential mechanisms of action, testing procedures, prognosis and progression, and management and treatment. 183 PREPUBLICATION COPY—Uncorrected Proofs A02506-Long-Term_Health_Effects_of_COVID-19_Ch05.indd 183 5/21/24 11:25 AM

184 LONG-TERM HEALTH EFFECTS OF COVID-19 CASE DEFINITIONS AND EPIDEMIOLOGY Myalgic Encephalomyelitis/Chronic Fatigue Syndrome ME/CFS is a severe systemic illness with symptoms based predominantly on neurological, immunological, and endocrinological dysfunction (Carruthers et al., 2011). The Institute of Medicine’s (IOM’s) diagnostic criteria for adults and children with ME/CFS are the most widely used (IOM, 2015). According to the IOM, ME/CFS is diagnosed when a patient meets the following criteria: a new-onset substantial activity impairment lasting at least 6 months, post- exertional malaise, and unrefreshing sleep, in addition to cognitive impairment or orthostatic intolerance. In addition to the IOM criteria, there exist more than 20 clinical case definitions for ME/CFS (Brurberg et al., 2014), presenting a challenge in standardization and comparison across research studies. It is estimated that 17–24 million people globally have ME/CFS (Lim et al., 2020a). Prevalence estimates for the United States range from 0.2 percent to 1.3 percent (Lim et al., 2020a; Vahratian et al., 2023). ME/CFS is more prevalent among women than men (Wessely, 1995), and peak ages of onset are during adolescence and ages 30–50 years (Bakken et al., 2014). Data on ME/CFS in children and adolescents are sparse; however, pediatric popu- lations are generally considered to have a better recovery prognosis than adults (Moore et al., 2021; Rowe et al., 2017). Diagnosis of ME/CFS is difficult due to limited knowledge about the pathomechanism of ME/CFS and lack of a consensus biomarker. In addi- tion to being an obstacle to accurate diagnosis, poor knowledge of ME/CFS is detrimental to efficient patient care. In an early publication, estimates of misdiagnosis are reported to be as high as 84–91 percent as a result of physician misinformation (Solomon and Reeves, 2004), while other authors have reported that 71 percent of patients needed to see four or more physi- cians to receive a diagnosis (Tidmore et al., 2015). The percentage of patients with Long COVID that meet criteria for ME/ CFS varies in the literature. An overview of the literature shows that on aver- age, 40–70 percent of Long COVID patients meet the criteria for ME/CFS (Bonilla et al., 2023; Jason and Islam, 2022; Kedor et al., 2022; Mancini et al., 2021; Twomey et al., 2022). In contrast, González-Hermosillo and colleagues (2021) found that only 13 percent of Long COVID patients met the criteria for ME/CFS, and AlMuhaissen and colleagues (2023) found an overlap of 8.1 percent. These differences could be due to the varied case definitions for both Long COVID and ME/CFS. Fibromyalgia FM is characterized by chronic and widespread musculoskeletal pain, accompanied by fatigue and sleep disturbances (Bhargava and Hurley, 2023; PREPUBLICATION COPY—Uncorrected Proofs A02506-Long-Term_Health_Effects_of_COVID-19_Ch05.indd 184 5/21/24 11:25 AM

CHRONIC CONDITIONS SIMILAR TO LONG COVID 185 Häuser et al., 2015; Sarzi-Puttini et al., 2020). Patients with FM present with a range of other clinical symptoms, including cognitive dysfunction, anxiety or mood disturbances, and variable gastrointestinal symptoms (Fialho et al., 2023). Pain and stiffness are usually found in the muscles of the neck, shoul- ders, back, hips, arms, and legs. In addition to fatigue and sleep disturbances, other signs and symptoms include headaches, and fatigue (Bhargava and Hurley, 2023). FM impacts approximately 2 percent of the U.S. adult popu- lation (CDC, 2022). The rates of FM increase with age between 20 and 55, with dominance in middle-aged and older women, although the condition can occur in anyone, including children (Brill et al., 2012; Lindell et al., 2000). Diagnoses of FM may involve dynamic evoked pain assessments with neuroimaging (Boquete et al., 2022; de la Coba et al., 2022; Mosch et al., 2023). Several of the features leading to diagnosis of FM are also present in other rheumatologic diseases, such as connective tissue disorders, ankylosing spondylitis, and spondylarthritis. Other researchers have investigated the differentiation of FM from other chronic pain disorders or ME/CFS. The dis- tinct symptoms of FM are persistent deep aching within the body, poor bal- ance, environmental sensitivity, tenderness to touch, and pain after exercise (Bennett et al., 2022). Studies show that up to 39 percent of people with Long COVID also meet the 2011 criteria for FM (Plaut, 2023; Ursini et al., 2021). SHARED SYMPTOMS AND FUNCTIONAL IMPLICATIONS Shared Symptoms Systemic postinfectious syndromes share several symptom profiles, includ- ing post-exertional malaise, chronic fatigue, impaired concentration and memory, pain, and sleep disturbances (Jason et al., 2023). Interestingly, the IOM (2015) core criteria for ME/CFS noted above are also core symptoms of Long COVID, as described in Chapter 3 of this report. One key differ- ence is that for an ME/CFS diagnosis, symptoms must be present for at least 6 months, whereas for Long COVID, the timeframe varies in the literature from 2 to 6 months. A systematic review comparing clinical presentation and symptoms for ME/CFS and Long COVID found that only 3 of 21 Long COVID studies assessed patients who had had symptoms for at least 6 months (Wong and Weitzer, 2021). The authors compared the 21 selected studies with ME/CFS case definitions and found that of 29 ME/CFS symptoms, 25 were reported in at least one Long COVID study. Fatigue, reduced daily activity, and post-exertional malaise were reported in multiple studies, with fatigue appear- ing in 12 of the 21 reviewed. Komaroff and Lipkin (2023) provide a helpful table summarizing the overlap in clinical presentation between Long COVID and ME/CFS, based on the work of Wong and Weitzer (2021). The committee adapted this table to include symptoms of FM (Table 5-1). PREPUBLICATION COPY—Uncorrected Proofs A02506-Long-Term_Health_Effects_of_COVID-19_Ch05.indd 185 5/21/24 11:25 AM

186 LONG-TERM HEALTH EFFECTS OF COVID-19 TABLE 5-1  Overlap in Common Symptoms among Long COVID, ME/CFS, and Fibromyalgia Long COVID ME/CFS Fibromyalgia Common Symptoms Post-exertional malaise ✓ ✓ Chronic fatigue ✓ ✓ ✓ Orthostatic intolerance ✓ ✓ Cognitive impairment ✓ ✓ ✓ Pain/Lower Threshold for Pain ✓ ✓ ✓ Sleep disturbances ✓ ✓ ✓ Neurosensory, perceptual, and motor disturbances ✓ ✓ Muscle abnormalities ✓ ✓ ✓ Sensitivity to food, medications, and odors ✓ ✓ Altered smell/taste ✓ Palpitations or cardiovascular conditions ✓ ✓ Breathlessness ✓ ✓ Gastrointestinal and genitourinary issues ✓ ✓ ✓ Loss of thermostatic stability ✓ ✓ Anxiety and depression ✓ ✓ ✓ Hair loss ✓ NOTE: This is a list of common symptoms and is not intended to be a diagnostic tool. Not all people with Long COVID, ME/CFS, and fibromyalgia will have the checked symptoms. Ad- ditionally, the symptoms listed may present in individuals who do not have those conditions. SOURCES: AMA, 2023; American College of Rheumatology, 2024; Bhargava and Hurley, 2023; Cabrera Martimbianco et al., 2021; Carruthers et al., 2011; Komaroff and Lipkin, 2023; Raveendran et al., 2021; Sukocheva et al., 2021; WHO, 2020; Wong and Weitzer, 2021. Functional Implications People with Long COVID, ME/CFS, and FM have decreased quality of life, including reduced physical and cognitive capacity, impairment in work performance, and reduced participation in society. In a study by Haider and colleagues (2023), individuals with Long COVID, ME/CFS, and FM reported a similar impact on physical and cognitive function; however, individuals with Long COVID versus those with the other two conditions reported lower pain and fatigue. Other studies suggest that the functional impairment in people with ME/CFS may be greater than in those with Long COVID (Komaroff and Lipkin, 2023). A comorbid diagnosis of Long COVID with ME/CFS and/or FM further exacerbated pain, fatigue, and psy- chological domains compared with Long COVID alone (Haider et al., 2023). PREPUBLICATION COPY—Uncorrected Proofs A02506-Long-Term_Health_Effects_of_COVID-19_Ch05.indd 186 5/21/24 11:25 AM

CHRONIC CONDITIONS SIMILAR TO LONG COVID 187 FIGURE 5-1  36-Item Short Form Survey (SF-36) and World Health Organization Disability Assessment Schedule (WHODAS) scores among ME/CFS, Long COVID and control populations NOTES: (A) Line graph representing median and 95% confidence interval (CI) of SF-36v2 domains. (B) Line graph representing median and 95% CI of WHODAS 2.0 domains. Abbreviations: BP = bodily pain; CO = cognition; GA = getting along; GH = general health perceptions; HC = healthy control; LA1 = life activities 1; ME/CFS = myalgic encephalomyelitis/chronic fatigue syndrome; MH = general mental health; MO = mobility; PA = participation; PCC = post-COVID-19 condi- tion; PF = physical functioning; RE = role limitations due to personal or emotional problems; RP = role limitations due to physical health Problems; SC = self-care; SF = social functioning; SF-36v2 = 36-Item Short-Form Health Survey (version 2); VIT = vitality; WHODAS = 2.0 World Health Organization Disability Assessment Schedule (version 2). ***p<0.001 ****p<0.0001 SOURCE: Based on data published in Weigel et al., 2023. Data currently under review show that ME/CFS and Long COVID cohorts do not differ significantly in any domain of quality of life using either the 36-Item Short Form Survey (SF-36) or the World Health Organization Dis- ability Assessment Schedule (WHODAS) (Figure 5-1), the Hospital Anxiety and Depression Scale (HADS), or the Modified Fatigue Impact Scale (MFIS). For all three chronic conditions, symptoms are cyclic, with some relatively “good” days and frequent “bad” days. Some people with the conditions are able to perform their responsibilities at home and work, while others are bedridden and unable to work (Komaroff and Lipkin, 2023). COMMON MECHANISMS OF ACTION The COVID-19 pandemic has generated interest in virally associated fatigue syndromes, though not all fatigue syndromes result from viral pandemics. The Epstein-Barr virus (EBV) is the most common cause of infectious mononucleosis and has been the most researched source of post- viral fatigue. There is evidence indicating the onset of ME/CFS following viral infections such as EBV, Q fever, influenza, and other coronaviruses (Sasso et al., 2022). In 2003, 4 years following an outbreak of severe acute PREPUBLICATION COPY—Uncorrected Proofs

188 LONG-TERM HEALTH EFFECTS OF COVID-19 respiratory syndrome (SARS) caused by SARS-CoV-1, one study found that 40.3 percent of patients reported persistent chronic fatigue, 27.1 percent of whom qualified for a diagnosis of ME/CFS (Lam et al., 2009). Although SARS-CoV-2 infection has received attention as a potential infectious trig- ger for ME/CFS (Sasso et al., 2022), additional research is needed to con- firm this hypothesis. Indeed, the underlying pathomechanism of ME/CFS also remains unknown because of the multitude of symptoms, including cognitive, endocrine, gastrointestinal, and cardiovascular dysfunction. FM is a complex disease with uncertain etiology and pathophysiology; however, symptom worsening has been reported following infectious trig- gers, including SARS-CoV-2 (Attal et al., 2021; Clauw et al., 2020; Fialho et al., 2023). Approximately 30 percent of individuals with FM report physical or psychological triggers prior to disease onset (Fitzcharles et al., 2021). Viral infections linked with FM include hepatitis C virus, HIV, par- vovirus, and EBV (Buskila et al., 2008). Lyme disease also has overlapping features with FM, contributing to diagnostic confusion. The significant overlap in clinical presentation between Long COVID and ME/CFS and FM raises the question of common mechanisms that could be involved in the pathogenesis of these conditions and offers the potential to use past clinical and biomedical research to accelerate the understand- ing of pathomechanisms specific to Long COVID. This section provides an overview of the potential overlapping pathomechanisms for which there is published evidence, summarized in Table 5-2. It should be noted that the discussion here focuses on biological mechanisms of action, given the available literature. As described in Chapter 1, the Internal Classification of Functioning, Disability, and Health (ICF) framework developed by the World Health Organization provides a comprehensive perspective that includes not only biological conditions but also the impact of these condi- tions on an individual’s functioning in various aspects of life. In addition to biological mechanisms, illness and disability are mediated by stress and stress response, behaviors and social forces, and environmental factors. Immune Dysregulation The underlying pathomechanism of Long COVID is not yet clear. How- ever, varying degrees of immune dysregulation have been reported in Long COVID patients (Gottschalk et al., 2023). Similarly, immune dysregulation is commonly reported in ME/CFS and FM (Brenu et al., 2011; Hardcastle et al., 2015a; Klimas and Koneru, 2007; Klimas et al., 1990; Ojo-Amaize et al., 1994), with noted abnormalities in cytokines (Broderick et al., 2010; Corbitt et al., 2019; Fletcher et al., 2009), lymphocyte subsets (Curriu et al., 2013; Huth et al., 2014; Rivas et al., 2018), and cytotoxic function (Brenu et al., 2011; Hardcastle et al., 2015b; Huth et al., 2016; Klimas et al., 1990; PREPUBLICATION COPY—Uncorrected Proofs A02506-Long-Term_Health_Effects_of_COVID-19_Ch05.indd 188 5/21/24 11:25 AM

CHRONIC CONDITIONS SIMILAR TO LONG COVID 189 TABLE 5-2  Summary of Potential Biological Mechanisms of Long COVID, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), and Fibromyalgia (FM) Long Postinfectious onset COVID ME/CFS FM Immune Innate immune exhaustion ✓ ✓ dysregulation Cytokine dysregulation ✓ ✓ ✓ Autoantibodies ✓ ✓ Neurological Neuroinflammation ✓ ✓ disturbances Reduced cerebral blood flow ✓ ✓ Impaired functional connectivity ✓ ✓ Abnormal brain metabolites ✓ ✓ ✓ Changes in brain region volumes ✓ ✓ Cardiovascular Orthostatic intolerance ✓ ✓ disturbances Endothelial dysfunction ✓ ✓ Coagulopathies ✓ Gastrointestinal Dysbiosis ✓ ✓ ✓ disturbances Gut–immune–brain axis ✓ ✓ Metabolic and Mitochondrial dysfunction ✓ ✓ mitochondrial Mitochondrial metabolite abnormalities ✓ ✓ dysfunction Down-regulation of the hypothalamic- pituitary-adrenal axis SOURCES: Augustin et al., 2021; Bakken et al., 2014; Bhargava and Hurley, 2023; Cao, 2020; Carruthers et al., 2011; Cervia et al., 2022; de Miranda et al., 2022; Demitrack et al., 1991; Farhadian et al., 2023; Garg et al., 2021b; Guasp et al., 2022; Jason et al., 2009; Komaroff and Lipkin, 2023; Lindell et al., 2000; NICE, 2020; Ram-Mohan et al., 2022; Raveendran et al., 2021; Srikanth et al., 2023; Su et al., 2022; Sukocheva et al., 2021; Tay et al., 2020; Urhan et al., 2022; Wessely, 1995; Yelin et al., 2022. Ojo-Amaize et al., 1994; Whiteside and Friberg, 1998), with the caveat that many of those markers are not very specific, and proper measurement of some poses technical challenges. Dysregulation of innate immune responses has been reported in some patients with Long COVID, ME/CFS, and FM, as well as hypermobile Ehlers-Danlos Syndrome (Bagga and Bouchard, 2014; Jukema et al., 2022; Mohandas et al., 2023; Wirth and Löhn, 2023). Immune dysregulation tends to pair closely with cytokine dysregulation (Freidin et al., 2023; Prompetchara et al., 2020). Indeed, severe acute SARS- CoV-2 infection is associated with a well-described cytokine storm, charac- terized by elevated levels of proinflammatory cytokines (McGonagle et al., 2020; Prompetchara et al., 2020). In a similar fashion, multisystem inflam- matory syndrome in children (MIS-C) can be seen 2–8 weeks after acute PREPUBLICATION COPY—Uncorrected Proofs A02506-Long-Term_Health_Effects_of_COVID-19_Ch05.indd 189 5/21/24 11:25 AM

190 LONG-TERM HEALTH EFFECTS OF COVID-19 SARS-CoV-2 infection, requiring anti-inflammatory agents for treatment (CDC, 2023; Consiglio et al., 2020; Gruber et al., 2023; Vella et al., 2021). Notably, aberrations in cytokines reported in ME/CFS and FM are equivo- cal (Corbitt et al., 2019). Finally, while autoantibodies have been reported in acute COVID-19, ME/CFS, and FM, the underlying autoimmunity pri- mary pathomechanism does not currently meet the classification criteria for autoimmune diseases, although it does open a theoretical field of potential therapeutic options if proven to have a relevant role in the pathophysiology of those entities (Akbari et al., 2023; Arthur et al., 2021; Casciola-Rosen et al., 2022; Freitag et al., 2021; Hallmann et al., 2023; Malkova and Shoenfeld, 2023; Marshall-Gradisnik et al., 2015; Rodriguez-Perez et al., 2021; Vojdani et al., 2023; Wallukat et al., 2021). Neurological Disturbances Neurological and cognitive disturbances are reported in individuals with Long COVID, ME/CFS, and FM. Neuroinflammation has been sug- gested in Long COVID and ME/CFS (Tate et al., 2022). Supporting this hypothesis, microglial activation has been reported in Long COVID and ME/CFS (Fernández-Castañeda et al., 2022; Nakatomi et al., 2020; Tomo et al., 2022). Other neurological mechanisms include reduced cerebral blood flow (Barnden et al., 2016, 2019; Campen et al., 2022; Davis et al., 2023; Gay et al., 2015; Monje and Iwasaki, 2022; Shungu et al., 2012; Thapaliya et al., 2020, 2022) and anatomical and/or connectivity changes (Douaud et al., 2022; Monje and Iwasaki, 2022; Morris and Maes, 2013); however, findings are inconsistent, and there is no overlap in anatomical brain region changes between the two disorders. Changes in brain metabo- lites have been reported in Long COVID, ME/CFS, and FM (Baraniuk et al., 2004; Deters et al., 2023; Martínez-Lavín and Miguel-Álvarez, 2023; Martini et al., 2022; Mueller et al., 2020; Puri et al., 2002; Russell et al., 1992). Overall, there are inconsistencies in research findings across various measures, and further comprehensive studies are required to elucidate the role of neurological disturbances in the pathomechanism of Long COVID. Cardiovascular Damage Cardiovascular disturbances, including endothelial dysfunction (Scherbakov et al., 2020; Xu et al., 2023b), coagulation issues (Nunes et al., 2023; Patell et al., 2020; Roberts et al., 2020), and orthostatic intolerance, are reported in Long COVID, ME/CFS, and FM (Gyöngyösi et al., 2023), and are quoted globally in the majority of chronic inflammatory diseases. Indi- viduals with ME/CFS have reduced total blood volume, plasma volume, and red blood cell volume compared with control groups (Hurwitz et al., 2009). PREPUBLICATION COPY—Uncorrected Proofs A02506-Long-Term_Health_Effects_of_COVID-19_Ch05.indd 190 5/21/24 11:25 AM

CHRONIC CONDITIONS SIMILAR TO LONG COVID 191 Similarly, patients with ME/CFS and FM and some patients with Long COVID have impaired autonomic and cardiovascular responses to pos- tural challenges that reduce autonomic flexibility and adaptability to situational demands. Gastrointestinal Manifestations Gastrointestinal manifestations are commonly reported in Long COVID and ME/CFS, and FM is associated with concurrent diagnosis of irritable bowel disorders. Changes resulting in gut dysbiosis, defined by an imbal- ance in the gut microbiome, are associated with recovery from COVID-19 (D’Amico et al., 2020; Tian et al., 2021). A pro-inflammatory gut micro- biome has been documented in some patients with Long COVID and ME/ CFS. This is hypothesized to allow microbial antigens (including endotox- ins) to breach the gut-blood barrier, potentially contributing to inflamma- tion at different systemic levels (Giloteaux et al., 2016; Guo et al., 2023; Haran et al., 2021; Liu et al., 2022; Nagy-Szakal et al., 2017; Xiong et al., 2023; Yeoh et al., 2021). Metabolic Energy insufficiency increased reactive oxygen species (ROS), and mito- chondrial dysfunction are features that may be shared in patients with Long COVID, ME/CFS, and FM. Identified phenomena also include the down- regulation of the hypothalamic-pituitary-adrenal axis (Urhan et al., 2022; Demitrack et al., 1991). While mitochondrial dysfunction may correlate with severity of SARS-CoV-2 infection (Ganji and Reddy, 2021; Holder and Reddy, 2021), findings in Long COVID and ME/CFS are equivocal and require further investigation to confirm commonalities and differences (Domingo et al., 2021; Fukuda et al., 2016; Guarnieri et al., 2023; Holden et al., 2020; Missailidis et al., 2020; Sweetman et al., 2020). Studies have shown increased risk of diabetes mellitus, hyperlipidemia, and kidney dis- ease in the post-acute phase of SARS-CoV-2 infection (Bowe et al., 2021; Xie and Al-Aly, 2022; Xu et al., 2023a). Although the evidence base is less well developed, similar metabolic abnormalities have also been reported in ME/CFS and FM. Gene Structure and Expression Variations in gene structure and gene expression have been reported in Long COVID, ME/CFS and FM. Thus far, published genome-wide associa- tion studies (GWAS) have involved small numbers of patients; predictably, given the sample sizes, no risk loci have been identified or validated for PREPUBLICATION COPY—Uncorrected Proofs A02506-Long-Term_Health_Effects_of_COVID-19_Ch05.indd 191 5/21/24 11:25 AM

192 LONG-TERM HEALTH EFFECTS OF COVID-19 either ME/CFS or Long COVID (Lammi at al., 2023; Li et al, 2021; Pairo- Castineira et al, 2021; Thibord et al, 2022). However, in both ME/CFS and FM, a recent publication employing combinatorial analysis reported potentially significant associations involving genes involved in the response to infection, mitochondrial function, and autoimmunity (Das et al., 2022). Attempts to replicate this potentially important result in different and larger groups of patients are underway. Studies of gene expression have primarily analyzed levels of microRNAs (miRNAs). Different studies involving different tissues have identified dif- ferent miRNAs that distinguish people with ME/CFS and Long COVID from healthy control subjects. One would not expect the same miRNAs to be identified in every study. Instead, one would expect the miRNAs identi- fied by different studies to act on genes involved in the same underlying physiological processes. Indeed, a recent published pathway analysis finds that the different miRNAs identified in these different studies, in fact, control the expression of genes involved in the same physiologic processes (Kaczmarek, 2023). Other epigenetic phenomena, like DNA methylation, that have been postulated as having impact in acute COVID infection may also have an impact in the pathophysiology of Long COVID or other post- viral syndromes, and research is ongoing (Balnis et al., 2022). There currently is no specific diagnostic test for Long COVID, ME/ CFS, or FM. Diagnosis can involve the following laboratory tests and self- report questionnaires, as well as elimination of other potential causes of the patient’s symptoms. Initial Laboratory Tests Clinical criteria for ME/CFS can be used as a guide for laboratory testing in patients presenting with suspected Long COVID, which then can be used to exclude other diagnoses that are similar or that may copresent. The 2021 National Institute for Health and Care Excellence (NICE) guidelines for ME/CFS suggest testing for white blood cell count, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), presence of human immunodeficiency virus (HIV), blood urea nitrogen (BUN), creatine and electrolytes, blood glucose, calcium and phosphorus, thyroid- stimulating hormone (TSH), alkaline phosphatase, and aspartate and alanine aminotransferases, as well as total protein, albumin, and globulin (NICE, 2021). Elevated ferritin levels have been reported in female par- ticipants meeting criteria for ME/CFS compared with female participants not meeting those criteria, while ferritin levels are often low in individu- als with Long COVID with or without true anemia (Dignass et al., 2018; Lechuga et al., 2023; Ruscitti et al., 2023; Yamamoto et al., 2023). Addi- tionally, iron deficiency and anemia of chronic disease are very common PREPUBLICATION COPY—Uncorrected Proofs A02506-Long-Term_Health_Effects_of_COVID-19_Ch05.indd 192 5/21/24 11:25 AM

CHRONIC CONDITIONS SIMILAR TO LONG COVID 193 in people with fatigue-related illnesses. Emerging evidence requires further validation with objective analysis of study limitations (Dignass et al., 2018; Lechuga et al., 2023). Additional testing such as sleep studies and exercise testing (including VO2max) may be needed to address specific symptoms, often performed in consultation with a specialist (CDC, 2021; Lim et al., 2020b). Symptom Inventory Questionnaires Jason and colleagues (2023) suggest that one of the challenges in diag- nosing ME/CFS accurately and reliably is the use of ambiguous questions or psychometrically invalid questionnaires. The NICE guidelines recom- mend the use of a screening questionnaire during the initial consultation to capture the patient’s symptoms, in addition to clinical assessment. Con- current with laboratory-based testing, a symptom inventory questionnaire can be used to determine the severity and frequency of a symptom, as well as whether a symptom is preexisting (same vs. worsened), new since acute COVID-19 infection and stable/improving, or new since acute infection and worsening. Symptom inventory questionnaires are used to diagnose and research ME/CFS. For example, the DePaul Symptom Questionnaire (DSQ), consisting of 54 questions assessing key symptoms of ME/CFS (such as fatigue; post-exertional malaise; sleep, pain, and cognitive distur- bances; autonomic dysfunction; and immune dysregulation) (Bedree et al., 2019; Jason and Sunnquist, 2018). Indeed, the DSQ has since been used for research on Long COVID (Jason et al., 2021; Oliveira et al., 2023), although it does not incorporate all symptoms of Long COVID because of minimal differences in symptomology between ME/CFS and Long COVID (for example, hair loss). Other symptom inventory questionnaires used to evaluate health effects of these chronic conditions include the 31-question Composite Autonomic Symptom Score (COMPASS 31) for autonomic dys- function and the Patient-Reported Outcomes Measurement Information System (PROMIS) for cognitive function (Larsen et al., 2022; Weerahandi et al., 2021). Symptom inventory questionnaires for cognitive concerns are an inte- gral part of a comprehensive cognitive assessment, as they capture the impact of cognitive symptoms on patients’ daily functioning. While such symptom inventories have not been validated specifically for patients with Long COVID, measures such as the Patient’s Assessment of Own Func- tioning Inventory (PAOFI), Cognitive Failures Questionnaire (CFQ), and Everyday Cognition Scale (ECog) have excellent psychometric properties and are known as reliable tools for the detection of self-reported cogni- tive impairment in a variety of conditions and with diverse populations (Broadbent et al., 1982; Tomaszewski Farias et al., 2011). PREPUBLICATION COPY—Uncorrected Proofs A02506-Long-Term_Health_Effects_of_COVID-19_Ch05.indd 193 5/21/24 11:25 AM

194 LONG-TERM HEALTH EFFECTS OF COVID-19 PROGNOSIS AND PROGRESSION ME/CFS is a chronic debilitating multisystem condition with poor prognosis for complete recovery. Recovery trajectories vary widely across studies, although most conclude that the prognosis is unfavorable. Studies have found that 0–8 percent of patients recover fully, while 17–64 percent experience some improvement (Ghali et al., 2022). There is a severity spectrum for ME/CFS, which is relative to the patient’s premorbid activ- ity level. Patients with mild ME/CFS report a reduction from preillness activity of approximately 50 percent, including reduced ability to maintain employment and interpersonal relationships (Pendergrast et al., 2016). A moderate case of ME/CFS is associated with a significant reduction in activity, restricted mobility, and inability to perform activities of daily living consistently. Generally, patients classified as having moderate ME/CFS are restricted to home (Pendergrast et al., 2016). A person with a severe case of ME/CFS is typically bedbound and will be dependent on mobility aids and a caregiver (Pendergrast et al., 2016). Approximately 25 percent of ME/CFS cases are considered severe (Pendergrast et al., 2016). Studies have identified a worse prognosis in ME/CFS patients with comorbid Long COVID or FM (Ghali et al., 2022; Komaroff and Lipkin, 2023). Limited research on FM outcomes has suggested that patients rarely achieve remission, although some may experience improvement or waxing and waning of symptoms over time (Schaefer et al., 2016). In general, it can be said that FM is a chronic condition that does not significantly improve or worsen, although longitudinal data are sparse and heterogeneous. One study on established FM patients (median disease duration of 7.8 years at the beginning of the study) found that functional disability worsened over the 7-year study period, while pain, fatigue, sleep disturbances, anxi- ety, and depression remained unchanged (Wolfe et al., 1997). In another study conducted in the United States that followed patients for 10 years, two-thirds of patients indicated that their symptoms were a little to a lot better, 10 percent reported no change, and a quarter reported they were a little or a lot worse at the end of the study period (Kennedy and Felson, 1996). Another study in the United States followed FM patients for 2 years and found that patients reported high levels of burden at both time points, with few significant changes over time. Outcomes varied among patients and were better among those whose pain improved (Schaefer et al., 2016). As discussed in Chapter 4 of this report, preliminary studies suggest that many people with persistent Long COVID symptoms improve over time, and recovery can plateau 6–12 months after acute infection. Disease severity, functional disability, and duration vary, with severity of acute COVID-19 being a major risk factor for poor functional outcomes, although such out- comes can be experienced even by those with mild initial illness. PREPUBLICATION COPY—Uncorrected Proofs A02506-Long-Term_Health_Effects_of_COVID-19_Ch05.indd 194 5/21/24 11:25 AM

CHRONIC CONDITIONS SIMILAR TO LONG COVID 195 Some studies have compared the prognosis and progression of Long COVID and ME/CFS. In general, it appears that Long COVID (especially Long COVID that does not meet criteria for ME/CFS) has a better prognosis than ME/CFS (Oliveira et al., 2023). Like ME/CFS, Long COVID appears to be a chronic illness, with few patients achieving full remission (Wong and Weitzer, 2021), though the chronicity and duration of full recovery for patients with Long COVID are currently unknown (Oliveira et al., 2023). Studies comparing Long COVID and ME/CFS have several limitations, however. First, Long COVID is a new disease, so that study participants are usually newly diagnosed, while ME/CFS study participants often have had the condition for a longer time and so are less likely to improve. Additionally, to qualify for a diagnosis of ME/CFS, symptoms need to be ongoing for 6 months or more, whereas the criteria for Long COVID vary in the literature from 2 to 6 months. Thus, the two conditions are difficult to compare. At this time, the committee did not identify any studies comparing the prognosis and progres- sion of Long COVID and FM. For all three conditions, comorbid medical illnesses tend to worsen the overall course of the condition as it progresses. Additionally, Long COVID may be a trigger for ME/CFS and FM, and it may exacerbate the symptoms of people already living with fatigue or chronic pain (Fialho et al., 2023). TREATMENT AND MANAGEMENT The CDC “Post-COVID Conditions: Information for Healthcare Pro- viders” page suggests symptom management approaches for Long COVID that have been helpful for disorders such as ME/CFS, FM, posttreatment Lyme disease, dysautonomia, and mast cell activation syndrome (CDC, 2024). Indeed, the goal of treatment and management for Long COVID and similar infection-associated chronic conditions is to optimize function and quality of life. These conditions represent many potentially overlapping entities, with different biological causes, risk factors, and outcomes. Different treatment approaches are needed for different individuals depending on their symptoms. This section provides an overview of nonpharmacological management and pharmacological treatments in clinical trial. Nonpharmacological Management and Treatments Pacing Pacing refers to a self-management strategy whereby individuals alternate activities with small, interspersed rest intervals. Successful pacing is believed to be a beneficial treatment for ME/CFS according to NICE, the CDC and the National Institutes of Health (NIH). Pacing is accompanied by the concept PREPUBLICATION COPY—Uncorrected Proofs A02506-Long-Term_Health_Effects_of_COVID-19_Ch05.indd 195 5/21/24 11:25 AM

196 LONG-TERM HEALTH EFFECTS OF COVID-19 of an energy envelope. In the case of ME/CFS, an energy envelope provides people with a strategy for managing their exertional tolerance, especially in activities of daily living. The size of the energy envelope is defined by the varying day-to-day tolerance and resources of patients; exceeding the energy envelope may result in worsening or exacerbation of symptoms. Pacing provides an approach to reduce the burden of fatigue and post-exertional malaise when accompanied by assistive devices and flexibility in approaching activities of daily living or employment/school (Friedberg et al., 2020; NICE, 2021; Smith et al., 2015). Wearable technologies may be used to provide just-in-time assessments of physiological exertion (Clague-Baker et al., 2023). Environmental Control Patients who report sensitivities to light, noise, odors, are often diag- nosed with comorbid multiple chemical sensitivities. Therefore, it is perti- nent to limit the impact of these sensory triggers by (1) removing perfume and chemicals from the environment, and (2) using eye masks and ear plugs. Environmental control provides an effective technique for improving sleep hygiene and lessening the burden of sleep disturbances. Mobility Support Depending on the severity of illness, occupation therapy referrals for home adaption may be essential to incorporate the use of aids that can improve quality of life. Such aids may include (1) disability parking permits, (2) wheelchairs or motorized scooters and appropriate home modifications, and (3) shower chairs and handrails. Additionally, alternative forms of pain management accompanied by physical therapy (within the energy envelope of the patient) may support patient mobility. Multidisciplinary Care and Rehabilitation Multidisciplinary care comprises the primary physician, appropriate medical and surgical and allied health professionals, and the patient advo- cacy community. A systematic review of nonpharmacological treatments in post-viral syndromes (including Long COVID) suggested interventions using Pilates exercises, resistance exercise, telerehabilitation, neuromodula- tion, and music therapy (Chandan et al., 2023). According to the NICE guidelines, recommendations for health care planning include the following: • Self-management advice – Self-management and monitoring of symptoms – Support groups and forums – Housing, employment, financial, and other supports PREPUBLICATION COPY—Uncorrected Proofs A02506-Long-Term_Health_Effects_of_COVID-19_Ch05.indd 196 5/21/24 11:25 AM

CHRONIC CONDITIONS SIMILAR TO LONG COVID 197 • Support from integrated coordinated primary care, community, rehabilitation, and mental health services • Multidisciplinary assessment Patients with neuromuscular weakness can benefit from physical reha- bilitation. It has been hypothesized that standardized exercise testing for cardiorespiratory fitness after recovery from acute COVID-19 can be used to improve the understanding of Long COVID. However, the use of graded exer- cise therapy (GET) requires caution in the treatment of ME/CFS because of the potential for iatrogenic harm. There is widespread and valid concern that exercise programs, even graded, may result in deterioration of the patient’s condition given the underlying pathology of disease and the potential to trigger post-exertional malaise and exacerbate symptoms following activity (Tuller and Vink, 2023). It is important at this time to highlight the lessons that can be learned from ME/CFS regarding this need for caution in the use of GET (Torjesen, 2020; Tuller and Vink, 2023; Twisk and Maes, 2009). Psychosocial Support Chronic conditions pose a significant burden with respect to psycho- logical health. Protocols for cognitive-behavioral therapy (CBT) or mindful- ness are not standardized for the treatment of Long COVID, ME/CFS, or FM (Friedberg, 2016; O’Dowd et al., 2006; Worm-Smeitink et al., 2016). CBT and mindfulness are the most widely studied psychological interven- tions for managing pain. Changes in different brain regions observed after CBT include grey matter volume, activation/deactivation, and intrinsic con- nectivity. CBT involves cognitive and emotional regulation, with the dorso- lateral prefrontal cortex, orbitofrontal cortex, right ventrolateral prefrontal cortex, posterior cingulate cortex, and amygdala being key regions. After CBT, the brain shows stronger top-down pain control, cognitive reassessment, and altered perception of stimulus signals (Arroyo-Fernández et al., 2022). Research is currently ongoing on the effectiveness of CBT (NCT05676047, NCT05597722, NCT05731570) or forms of cognitive rehabilitation in Long COVID, including behavioral amygdala-insula retraining (NCT05851846), sound mindfulness strategies (NCT05848401), mind–body reprocessing ther- apy (NCT05703074 & NCT05422924), behavioral and coping coaching (NCT05752331 & NCT05453201), and mindfulness (NCT05566379 & NCT05422924). Diet Modulation Symptoms akin to food intolerances and irritable bowel syndrome are reported in people with Long COVID, ME/CFS, and FM (Weigel et al., 2022). PREPUBLICATION COPY—Uncorrected Proofs A02506-Long-Term_Health_Effects_of_COVID-19_Ch05.indd 197 5/21/24 11:25 AM

198 LONG-TERM HEALTH EFFECTS OF COVID-19 The NICE guidelines encourage referral for dietic assessment and creation of a management plan by a dietitian (NICE, 2020, 2021). Lifestyle interven- tions and dietary supplementation in Long COVID are to be investigated (NCT05836402 & NCT05705648). Endothelial Modulation Both Long COVID and ME/CFS have demonstrated and been charac- terized by endothelial dysfunction (Haffke et al., 2022; McLaughlin et al., 2023; Varga et al., 2020). Enhanced external counterpulsation (EECP) is a Food and Drug Administration (FDA)–approved, noninvasive treatment for refractory angina and ischemic heart failure that has been effective for symptoms associated with heart disease such as chest pain, shortness of breath, and fatigue. A handful of studies have been published showing the benefit of EECP in Long COVID (Dayrit et al., 2021; Sathyamoorthy et al., 2022; Wu et al., 2023). ClinicalTrials.gov also reports an EECP study under way (NCT05668039). Pharmacological Treatments Currently, no standardized FDA-approved treatments are available for Long COVID, ME/CFS, or FM (Jason et al., 2023). Recently updated NICE guidelines for ME/CFS highlight that agents currently prescribed to treat cognitive impairment, fatigue, and sleep disturbances are of low qual- ity and efficacy. Those treatments include, for cognitive disturbances and fatigue, modafinil, amantadine, and methylphenidate (Garg et al., 2021a; Pliszka, 2022; Randall et al., 2005), and for sleep disturbances, trazadone, low-dose tricyclic antidepressants, and cyclobenzaprine (Calandre et al., 2011; Clemons et al., 2011; Morillas-Arques et al., 2010). Treatment of chronic pain in ME/CFS follows the guidelines for the treatment of FM, and includes duloxetine, pregabalin, amitriptyline. ClinicalTrials.gov lists clinical trials evaluating the efficacy of various treatments for Long COVID, ME/CFS, and FM aimed at addressing the underlying disease and disease- associated manifestations. As of December 2023, the database included a total of 18 completed and ongoing clinical trials in Phase III or IV for ME/ CFS, 124 for FM, and 30 for Long COVID. The limited overlap in treatment trials among the three conditions is discussed in this section. Rintatolimod, also known as ampligen, has received attention as a potential treatment for ME/CFS and Long COVID because of its immuno- modulatory and antiviral activities as a toll-like receptor 3 (TLR-3) agonist (Mitchell, 2016; Strayer et al., 2020). Trials have shown that it increases exercise tolerance and decreases drug dependence in patients with ME/CFS (Mitchell, 2016; Strayer et al., 2020). Given concerns about toxicity, how- ever, rintatolimod is approved only for the treatment of severe ME/CFS in PREPUBLICATION COPY—Uncorrected Proofs A02506-Long-Term_Health_Effects_of_COVID-19_Ch05.indd 198 5/21/24 11:25 AM

CHRONIC CONDITIONS SIMILAR TO LONG COVID 199 Argentina. It is included within the AMP-511 Expanded Access Program in the United States, but of note was rejected for approval by the FDA in 2009 for an indication of ME/CFS. The reason it was not approved, according to the FDA, was that the two randomized controlled trials “did not provide credible evidence of efficacy,” and there were “clinical, statistical, clinical pharmacology, nonclinical, product quality, and facilities inspections defi- ciencies” (Castro-Marrero et al., 2017). Given the overlap with ME/CFS, including similar potential mechanisms of action, the efficacy of rintatolimod is under investigation in people with Long COVID (NCT05592418). Metformin, an insulin response enhancer, is being investigated for use in Long COVID, ME/CFS, and FM (NCT06147050, NCT06128967, NCT05900466). Bramante and colleagues found that the incidence of Long COVID was reduced by 42 percent with metformin treatment (Bramante et al., 2022). Previous research has suggested the potential benefit of metfor- min in improving bioenergetic profiles in patients with FM (Alcocer-Gómez et al., 2015). Immunomodulation is a treatment trial target for Long COVID, ME/ CFS, and FM, and given their shared potential mechanism of action. Intravenous administration of immunoglobin shows efficacy in some auto- immune conditions and is used at a higher dose for anti-inflammatory effects (which also leads to increased side effect potential). It has been inves- tigated for use in ME/CFS; however, it is no longer recommended for ME/ CFS under the NICE guidelines published in 2021 because of inconsistent findings (NICE, 2021). In general, pharmacological treatments for Long COVID, ME/CFS, and FM are not yet effective, and management of these conditions involves pri- marily the symptom management and functional improvement techniques described in the previous section. SUMMARY AND CONCLUSIONS Long COVID shares many features with other complex multisystem conditions. This review focused on similarities with ME/CFS and FM. Other less researched similar conditions include, but are not limited to, POTS, posttreatment Lyme disease, and hypermobile Ehlers-Danlos syn- drome. More research is needed to understand infection-associated chronic illnesses. The mechanism of action for these conditions remains unclear, and fur- ther investigation is needed. Current theories for potential shared mechanisms of action supported by published literature include immune dysregulation (including dysregulation of innate immune responses, cytokine dysregula- tion, or mast cell activation); neurological disturbances (neuroinflammation has been suggested in ME/CFS and Long COVID); cardiovascular damage (endothelial dysfunction, coagulation issues, and orthostatic intolerance have PREPUBLICATION COPY—Uncorrected Proofs A02506-Long-Term_Health_Effects_of_COVID-19_Ch05.indd 199 5/21/24 11:25 AM

200 LONG-TERM HEALTH EFFECTS OF COVID-19 been reported in some patients with Long COVID, ME/CFS, and FM); gas- trointestinal symptoms (due to gut microbiome dysbiosis); metabolic issues (energy insufficiency, reactive oxygen species production, and mitochondrial dysfunction are shared features in Long COVID, ME/CFS, and FM); and genetic variations. There is currently no specific laboratory-based diagnostic test for Long COVID or ME/CFS. Rather, diagnosis is a process of exclusion and con- sideration of other potential causes of the patient’s symptoms. Secondary testing should be at the discretion of the attending physician. The NICE guidelines recommend the use of a screening questionnaire during the ini- tial consultation to capture the patient’s symptoms, in addition to clinical assessment. Concurrent with laboratory-based testing, a symptom inventory questionnaire can be used to determine the severity and frequency of a symptom, as well as to determine whether a symptom is preexisting (same vs. worsened), new since acute SARS-CoV-2 infection and stable/improving, or new since acute infection and worsening. Symptom inventory question- naires are used to diagnose and research ME/CFS. Studies have compared the prognosis and progression of Long COVID and ME/CFS. It appears that in general, Long COVID (especially for Long COVID that does not meet ME/CFS criteria) has a better prognosis than ME/CFS, with some manifestations of Long COVID being similar to those of ME/CFS. Like ME/CFS, Long COVID appears to be a chronic illness, with few patients achieving full remission. Studies comparing Long COVID and ME/CFS have several limitations, however. First, Long COVID is a new disease, so that Long COVID study participants are usually newly diagnosed, while ME/CFS study participants often have had the condition for a longer time and so are less likely to improve. Additionally, to qualify for a diagnosis of ME/CFS, symptoms need to be ongoing for 6 months or more, whereas the criteria for Long COVID vary in the literature from 2 to 6 months. Thus, the two conditions are difficult to compare. The full recovery duration for Long COVID patients remains uncertain, but early diagnosis and treatment may help prevent progression to chronic conditions such as ME/CFS and FM. Currently there are no FDA approved drugs or evidence-based treatments for Long COVID, ME/CFS, or FM. The primary approach to managing the three conditions involves the use of techniques, such as pacing and rehabili- tation, to manage symptoms and improve functional ability. However, this approach is complicated by multisystem clinical presentation, and treatment approaches may need to be tailored to the individual. Numerous random- ized controlled trials are currently under way to determine the efficacy of a number of identified pharmacological agents; however, limited data have been published, and these trials have yet to be finalized. Moreover, the use of some pharmacological agents is not supported by current research because of the limited understanding of the pathomechanism of Long COVID. PREPUBLICATION COPY—Uncorrected Proofs A02506-Long-Term_Health_Effects_of_COVID-19_Ch05.indd 200 5/21/24 11:25 AM

CHRONIC CONDITIONS SIMILAR TO LONG COVID 201 REFERENCES Akbari, A., A. Hadizadeh, M. Islampanah, E. Salavati Nik, S. L. Atkin, and A. Sahebkar. 2023. COVID-19, G protein-coupled receptor, and renin-angiotensin system autoantibodies: Systematic review and meta-analysis. Autoimmunity Reviews 22(9):103402. Alcocer-Gómez, E., J. Garrido-Maraver, P. Bullón, F. Marín-Aguilar, D. Cotán, A. M. Carrión, J. M. Alvarez-Suarez, F. Giampieri, J. A. Sánchez-Alcazar, M. Battino, and M. D. Cordero. 2015. Metformin and caloric restriction induce an AMPK-dependent restoration of mito- chondrial dysfunction in fibroblasts from fibromyalgia patients. Biochimica et Biophysica Acta 1852(7):1257–1267. AlMuhaissen, S., A. Abu Libdeh, Y. ElKhatib, R. Alshayeb, A. Jaara, and S. K. Bardaweel. 2023. Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and COVID-19: Is there a connection? Current Medical Research and Opinion 39(8):1119–1126. AMA (American Medical Association). 2023. Long COVID and the brain: Neurological symptoms may persist. https://www.ama-assn.org/delivering-care/public-health/long- covid-and-brain-neurological-symptoms-may-persist (accessed February 26, 2024). American College of Rheumatology. 2024. Fibromyalgia. https://rheumatology.org/patients/ fibromyalgia (accessed February 26, 2024). Arroyo-Fernández, R., J. Avendaño-Coy, R. Velasco-Velasco, R. Palomo-Carrión, E. Bravo- Esteban, and A. Ferri-Morales. 2022. Effectiveness of transcranial direct current stimula- tion combined with exercising in people with fibromyalgia: A randomized sham-controlled clinical trial. Archives of Physical Medicine and Rehabilitation 103(8):1524–1532. Arthur, J. M., J. C. Forrest, K. W. Boehme, J. L. Kennedy, S. Owens, C. Herzog, J. Liu, and T. O. Harville. 2021. Development of ACE2 autoantibodies after SARS-CoV-2 infection. PLoS ONE 16(9):e0257016. Attal, N., V. Martinez, and D. Bouhassira. 2021. Potential for increased prevalence of neuro- pathic pain after the COVID-19 pandemic. Pain Reports 6(1):e884. Augustin, M., P. Schommers, M. Stecher, F. Dewald, L. Gieselmann, H. Gruell, C. Horn, K. Vanshylla, V. D. Cristanziano, L. Osebold, M. Roventa, T. Riaz, N. Tschernoster, J. Altmueller, L. Rose, S. Salomon, V. Priesner, J. C. Luers, C. Albus, S. Rosenkranz, B. Gathof, G. Fatkenheuer, M. Hallek, F. Klein, I. Suarez, and C. Lehmann. 2021. Post- COVID syndrome in non-hospitalised patients with COVID-19: A longitudinal prospec- tive cohort study. The Lancet Regional Health. Europe 6:100122. Bagga, S., and M. J. Bouchard. 2014. Cell cycle regulation during viral infection. Cell Cycle Control 1170:165–227. Bakken, I. J., K. Tveito, N. Gunnes, S. Ghaderi, C. Stoltenberg, L. Trogstad, S. E. Håberg, and P. Magnus. 2014. Two age peaks in the incidence of chronic fatigue syndrome/myalgic encephalomyelitis: A population-based registry study from Norway 2008-2012. BMC Medicine 12:167. Balnis, J., A. Madrid, K. J. Hogan, L. A. Drake, A. Adhikari, R. Vancavage, H. A. Singer, R. S. Alisch, and A. Jaitovich. 2022. Persistent blood DNA methylation changes one year after SARS-COV-2 infection. Clinical Epigenetics 14(1):94. Baraniuk, J. N., G. Whalen, J. Cunningham, and D. J. Clauw. 2004. Cerebrospinal fluid levels of opioid peptides in fibromyalgia and chronic low back pain. BMC Musculoskeletal Disorders 5(1):48. Barnden, L. R., R. Kwiatek, B. Crouch, R. Burnet, and P. Del Fante. 2016. Autonomic cor- relations with MRI are abnormal in the brainstem vasomotor centre in chronic fatigue syndrome. NeuroImage: Clinical 11:530–537. Barnden, L. R., Z. Y. Shan, D. R. Staines, S. Marshall-Gradisnik, K. Finegan, T. Ireland, and S. Bhuta. 2019. Intra-brainstem connectivity is impaired in chronic fatigue syndrome. NeuroImage: Clinical 24:102045. Bedree, H., M. Sunnquist, and L. A. Jason. 2019. The DePaul Symptom Questionnaire-2: A validation study. Fatigue: Biomedicine, Health & Behavior 7(3):166–179. PREPUBLICATION COPY—Uncorrected Proofs A02506-Long-Term_Health_Effects_of_COVID-19_Ch05.indd 201 5/21/24 11:25 AM

202 LONG-TERM HEALTH EFFECTS OF COVID-19 Bennett, R. M., K.D. Jones, J. H. Aebischer, A. W. St John, and R. Friend. 2022. Which symp- toms best distinguish fibromyalgia patients from those with other chronic pain disorders? Journal of Evaluation in Clinical Practice 28(2):225–234. Bhargava, J., and J. A. Hurley. 2023. Fibromyalgia. In Statpearls. Treasure Island (FL): StatPearls Publishing. Bonilla, H., T. C. Quach, A. Tiwari, A. E. Bonilla, M. Miglis, P. C. Yang, L. E. Eggert, H. Sharifi, A. Horomanski, A. Subramanian, L. Smirnoff, N. Simpson, H. Halawi, O. Sum-Ping, A. Kalinowski, Z. M. Patel, R. W. Shafer, and L. N. Geng. 2023. Myalgic encephalomyelitis/chronic fatigue syndrome is common in post-acute sequelae of SARS- CoV-2 infection (PASC) Results from a post-COVID-19 multidisciplinary clinic. Frontiers in Neurology 14:1090747. Boquete, L., M.-J. Vicente, J.-M. Miguel-Jiménez, E.-M. Sánchez-Morla, M. Ortiz, M. Satue, and E. Garcia-Martin. 2022. Objective diagnosis of fibromyalgia using neuroretinal eval- uation and artificial intelligence. International Journal of Clinical and Health Psychology 22(2):100294. Bowe, B., Y. Xie, E. Xu, and Z. Al-Aly. 2021. Kidney outcomes in long COVID. Journal of the American Society of Nephrology 32(11):2851–2862. Bramante, C. T., J. B. Buse, D. Liebovitz, J. Nicklas, M. A. Puskarich, K. Cohen, H. Belani, B. Anderson, J. D. Huling, C. Tignanelli, J. Thompson, M. Pullen, L. Siegel, J. Proper, D. J. Odde, N. Klatt, N. Sherwood, S. Lindberg, E. L. Wirtz, A. Karger, K. Beckman, S. Erickson, S. Fenno, K. Hartman, M. Rose, B. Patel, G. Griffiths, N. Bhat, T. A. Murray, and D. R. Boulware. 2022. Outpatient treatment of COVID-19 with metformin, iver- mectin, and fluvoxamine and the development of long COVID over 10-month follow-up. medRxiv [Preprint]. 2022 Dec 23:2022. Brenu, E. W., M. L. van Driel, D. R. Staines, K. J. Ashton, S. B. Ramos, J. Keane, N. G. Klimas, and S. M. Marshall-Gradisnik. 2011. Immunological abnormalities as potential biomarkers in chronic fatigue syndrome/myalgic encephalomyelitis. Journal of Translational Medicine 9(1):81. Broadbent, D. E., P. F. Cooper, P. Fitzgerald, and K. R. Parkes. 1982. The Cognitive Fail- ures Questionnaire (CFQ) and its correlates. British Journal of Clinical Psychology 21(1):1–16. Broderick, G., J. Fuite, A. Kreitz, S. D. Vernon, N. Klimas, and M. A. Fletcher. 2010. A formal analysis of cytokine networks in chronic fatigue syndrome. Brain, Behavior, and Immunity 24(7):1209–1217. Brurberg, K. G., M. S. Fønhus, L. Larun, S. Flottorp, and K. Malterud. 2014. Case definitions for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME): A systematic review. BMJ Open 4(2):e003973. Buskila, D., F. Atzeni, and P. Sarzi-Puttini. 2008. Etiology of fibromyalgia: The possible role of infection and vaccination. Autoimmunity Reviews 8(1):41–43. Cabrera Martimbianco, A. L., R. L. Pacheco, Â. M. Bagattini, and R. Riera. 2021. Frequency, signs and symptoms, and criteria adopted for long COVID-19: A systematic review. International Journal of Clinical Practice 75(10):e14357. Calandre, E. P., P. Morillas-Arques, R. Molina-Barea, C. M. Rodriguez-Lopez, and F. Rico- Villademoros. 2011. Trazodone plus pregabalin combination in the treatment of fibro- myalgia: A two-phase, 24-week, open-label uncontrolled study. BMC Musculoskeletal Disorders 12:95. Campen, C. L. M. C. v., P. C. Rowe, and F. C. Visser. 2022. Orthostatic symptoms and reduc- tions in cerebral blood flow in long-haul COVID-19 patients: Similarities with myalgic encephalomyelitis/chronic fatigue syndrome. Medicina 58(1):28. Cao, X. 2020. COVID-19: Immunopathology and its implications for therapy. Nature Reviews Immunology 20(5):269–270. PREPUBLICATION COPY—Uncorrected Proofs A02506-Long-Term_Health_Effects_of_COVID-19_Ch05.indd 202 5/21/24 11:25 AM

CHRONIC CONDITIONS SIMILAR TO LONG COVID 203 Carruthers, B. M., M. I. van de Sande, K. L. D. Meirleir, N. G. Klimas, G. Broderick, T. Mitchell, D. Staines, A. C. P. Powles, N. Speight, R. Vallings, L. Bateman, B. Baumgarten-Austrheim, D. S. Bell, N. Carlo-Stella, J. Chia, A. Darragh, D. Jo, D. Lewis, A. R. Light, S. Marshall- Gradisbik, I. Mena, J. A. Mikovits, K. Miwa, M. Murovska, M. L. Pall, and S. Stevens. 2011. Myalgic encephalomyelitis: International consensus criteria. Journal of Internal Medicine 270(4):327–338. Casciola-Rosen, L., D. R. Thiemann, F. Andrade, M. I. Trejo Zambrano, J. E. Hooper, E. K. Leonard, J. B. Spangler, A. L. Cox, C. E. Machamer, L. Sauer, O. Laeyendecker, B. T. Garibaldi, S. C. Ray, C. A. Mecoli, L. Christopher-Stine, L. Gutierrez-Alamillo, Q. Yang, D. Hines, W. A. Clarke, R. Rothman, A. Pekosz, K. J. Fenstermacher, Z. Wang, S. L. Zeger, and A. Rosen. 2022. IgM anti-ACE2 autoantibodies in severe COVID-19 activate complement and perturb vascular endothelial function. JCI Insight 7(9):e158362. Castro-Marrero, J., N. Sáez-Francàs, D. Santillo, and J. Alegre. 2017. Treatment and manage- ment of chronic fatigue syndrome/myalgic encephalomyelitis: All roads lead to Rome. British Journal of Pharmacology 174(5):345–369. CDC (Centers for Disease Control and Prevention). 2021. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Evaluation. https://www.cdc.gov/me-cfs/healthcare-providers/diagnosis/ evaluation.html (accessed March 12, 2024). CDC. 2022. Fibromyalgia. https://www.cdc.gov/arthritis/types/fibromyalgia.htm (accessed February 26, 2024). CDC. 2023. For parents: Multisystem inflammatory syndrome in children (MIS-C) associ- ated with COVID-19. https://www.cdc.gov/mis/mis-c.html#print (accessed February 26, 2024). CDC. 2024. Post-COVID Conditions: Information for healthcare providers. https://www.cdc. gov/coronavirus/2019-ncov/hcp/clinical-care/post-covid-conditions.html (accessed February 26, 2024). Cervia, C., Y. Zurbuchen, P. Taeschler, T. Ballouz, D. Menges, S. Hasler, S. Adamo, M. E. Raeber, E. Bachli, A. Rudiger, M. Stussi-Helbling, L. C. Huber, J. Nilsson, U. Held, M. A. Puhan, and O. Boyman. 2022. Immunoglobulin signature predicts risk of post-acute COVID-19 syndrome. Nature Communications 13(1):446. Chandan, J. S., K. R. Brown, N. Simms-Williams, N. Z. Bashir, J. Camaradou, D. Heining, G. M. Turner, S. C. Rivera, R. Hotham, S. Minhas, K. Nirantharakumar, M. Sivan, K. Khunti, D. Raindi, S. Marwaha, S. E. Hughes, C. McMullan, T. Marshall, M. J. Calvert, S. Haroon, and O. L. Aiyegbusi. 2023. Non-pharmacological therapies for post-viral syndromes, including long COVID: A systematic review. International Journal of Environmental Research and Public Health 20(4):3477. Clague-Baker, N., T. E.Davenport, M. Madi, K. Dickinson, K. Leslie, M.Bull, and N. Hilliard. 2023. An international survey of experiences and attitudes towards pacing using a heart rate monitor for people with myalgic encephalomyelitis/chronic fatigue syndrome. Work 74(4):1225–1234. Clauw, D. J., W. Häuser, S. P. Cohen, and M.-A. Fitzcharles. 2020. Considering the potential for an increase in chronic pain after the COVID-19 pandemic. Pain 161(8):1694–1697. Clemons, A., M. Vasiadi, D. Kempuraj, T. Kourelis, G. Vandoros, and T. C. Theoharides. 2011. Amitriptyline and prochlorperazine inhibit pro-inflammatory mediator release from human mast cells–Possible relevance to chronic fatigue syndrome. Journal of Clinical Psychopharmacology 31(3):385–387. Consiglio, C. R., N. Cotugno, F. Sardh, C. Pou, D. Amodio, L. Rodriguez, Z. Tan, S. Zicari, A. Ruggiero, G. R. Pascucci, V. Santilli, T. Campbell, Y. Bryceson, D. Eriksson, J. Wang, A. Marchesi, T. Lakshmikanth, A. Campana, A. Villani, P. Rossi, CACTUS Study Team, N. Landegren, P. Palma, and P. Brodin. 2020. The immunology of multisystem inflamma- tory syndrome in children with COVID-19. Cell 183(4):968–981. PREPUBLICATION COPY—Uncorrected Proofs A02506-Long-Term_Health_Effects_of_COVID-19_Ch05.indd 203 5/21/24 11:25 AM

204 LONG-TERM HEALTH EFFECTS OF COVID-19 Corbitt, M., N. Eaton-Fitch, D. Staines, H. Cabanas, and S. Marshall-Gradisnik. 2019. A systematic review of cytokines in chronic fatigue syndrome/myalgic encephalomyelitis/ systemic exertion intolerance disease (CFS/ME/SEID). BMC Neurology 19(1):207. Curriu, M., J. Carrillo, M. Massanella, J. Rigau, J. Alegre, J. Puig, A. M. Garcia-Quintana, J. Castro-Marrero, E. Negredo, B. Clotet, C. Cabrera, and J. Blanco. 2013. Screening NK-, B- and T-cell phenotype and function in patients suffering from chronic fatigue syndrome. Journal of Translational Medicine 11:68. D’Amico, F., D. C. Baumgart, S. Danese, and L. Peyrin-Biroulet. 2020. Diarrhea during COVID-19 infection: Pathogenesis, epidemiology, prevention, and management. Clinical Gastroenterol- ogy and Hepatology 18(8):1663–1672. Das, S., K. Taylor, J. Kozubek, J. Sardell, and S. Gardner. 2022. Genetic risk factors for ME/ CFS identified using combinatorial analysis. Journal of Translational Medicine 20(1):598. Davis, H. E., L. McCorkell, J. M. Vogel, and E. J. Topol. 2023. Long COVID: Major findings, mechanisms and recommendations. Nature Reviews Microbiology 21(3):133–146. Dayrit, J. K., M. Verduzco-Gutierrez, A. Teal, and S. A. Shah. 2021. Enhanced external counter- pulsation as a novel treatment for post-acute COVID-19 sequelae. Cureus 13(4):e14358. de la Coba, P., C. I. Montoro, G. A. Reyes Del Paso, and C. M. Galvez-Sánchez. 2022. Algometry for the assessment of central sensitisation to pain in fibromyalgia patients: A systematic review. Annals of Medicine 54(1):1403–1422. de Miranda, D. A. P., S. V. C. Gomes, P. S. Filgueiras, C. A. Corsini, N. B. F. Almeida, R. A. Silva, M. I. V. A. R. C. Medeiros, R. V. R. Vilela, G. R. Fernandes, and R. F. Q. Grenfell. 2022. Long COVID-19 syndrome: A 14-months longitudinal study during the two first epidemic peaks in southeast Brazil. Transactions of the Royal Society of Tropical Medi- cine and Hygiene 116(11):1007–1014. Demitrack, M. A., J. K. Dale, S. E. Straus, L. Laue, S. J. Listwak, M. J. Kruesi, G. P. Chrousos, and P. W. Gold. 1991. Evidence for impaired activation of the hypothalamic-pituitary-adrenal axis in patients with chronic fatigue syndrome. Journal of Clinical Endocrinology and Metabolism 73(6):1224–1234. Deters, J. R., A. C. Fietsam, P. E. Gander, L. L. Boles Ponto, and T. Rudroff. 2023. Effect of post-COVID-19 on brain volume and glucose metabolism: Influence of time since infection and fatigue status. Brain Sciences 13(4):675. Dignass, A., K. Farrag, and J. Stein. 2018. Limitations of serum ferritin in diagnosing iron defi- ciency in inflammatory conditions. International Journal of Chronic Diseases 2018:1–11. Domingo, J. C., B. Cordobilla, R. Ferrer, M. Giralt, J. Alegre-Martín, and J. Castro-Marrero. 2021. Are circulating fibroblast growth factor 21 and N-terminal prohormone of brain natriuretic peptide promising novel biomarkers in myalgic encephalomyelitis/chronic fatigue syndrome? Antioxidants & Redox Signaling 34(18):1420–1427. Douaud, G., S. Lee, F. Alfaro-Almagro, C. Arthofer, C. Wang, P. McCarthy, F. Lange, J. L. R. Andersson, L. Griffanti, E. Duff, S. Jbabdi, B. Taschler, P. Keating, A. M. Winkler, R. Collins, P. M. Matthews, N. Allen, K. L. Miller, T. E. Nichols, and S. M. Smith. 2022. SARS-CoV-2 is associated with changes in brain structure in UK Biobank. Nature 604(7907):697–707. Farhadian, S. F., H. D. Reisert, L. McAlpine, J. Chiarella, P. Kosana, J. Yoon, and S. Spudich. 2023. Self-reported neuropsychiatric post-COVID-19 condition and CSF markers of neuroinflammation. JAMA Network Open 6(11):e2342741. Fernández-Castañeda, A., P. Lu, A. C. Geraghty, E. Song, M.-H. Lee, J. Wood, M. R. O’Dea, S. Dutton, K. Shamardani, K. Nwangwu, R. Mancusi, B. Yalçın, K. R. Taylor, L. Acosta- Alvarez, K. Malacon, M. B. Keough, L. Ni, P. J. Woo, D. Contreras-Esquivel, A. M. S. Toland, J. R. Gehlhausen, J. Klein, T. Takahashi, J. Silva, B. Israelow, C. Lucas, T. Mao, M. A. Peña-Hernández, A. Tabachnikova, R. J. Homer, L. Tabacof, J. Tosto-Mancuso, E. Breyman, A. Kontorovich, D. McCarthy, M. Quezado, H. Vogel, M. M. Hefti, D. P. Perl, S. Liddelow, R. Folkerth, D. Putrino, A. Nath, A. Iwasaki, and M. Monje. 2022. Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation. Cell 185(14):2452–2468.e2416. PREPUBLICATION COPY—Uncorrected Proofs A02506-Long-Term_Health_Effects_of_COVID-19_Ch05.indd 204 5/21/24 11:25 AM

CHRONIC CONDITIONS SIMILAR TO LONG COVID 205 Fialho, M. F. P., E. S. Brum, and S. M. Oliveira. 2023. Could the fibromyalgia syndrome be triggered or enhanced by COVID-19? Inflammopharmacology 31(2):633–651. Fitzcharles, M.-A., S. P. Cohen, D. J. Clauw, G. Littlejohn, C. Usui, and W. Häuser. 2021. Nociplastic pain: Towards an understanding of prevalent pain conditions. The Lancet 397(10289):2098–2110. Fletcher, M. A., X. R. Zeng, Z. Barnes, S. Levis, and N. G. Klimas. 2009. Plasma cytokines in women with chronic fatigue syndrome. Journal of Translational Medicine 7:96. Freidin, M. B., N. Cheetham, E. L. Duncan, C. J. Steves, K. J. Doores, M. H. Malim, N. Rossi, J. M. Lord, P. W. Franks, A. Borsini, I. Granville Smith, M. Falchi, C. Pariante, and F. M. K. Williams. 2023. Long-COVID fatigue is not predicted by pre-pandemic plasma IL-6 levels in mild COVID-19. Inflammation Research 72(5):947–953. Freitag, H., M. Szklarski, S. Lorenz, F. Sotzny, S. Bauer, A. Philippe, C. Kedor, P. Grabowski, T. Lange, G. Riemekasten, H. Heidecke, and C. Scheibenbogen. 2021. Autoantibodies to vasoregulative G-protein-coupled receptors correlate with symptom severity, auto- nomic dysfunction and disability in myalgic encephalomyelitis/chronic fatigue syndrome. Journal of Clinical Medicine 10(16):3675. Friedberg, F. 2016. Cognitive-behavior therapy: Why is it so vilified in the chronic fatigue syndrome community? Fatigue: Biomedicine, Health & Behavior 4(3):127–131. Friedberg, F., M. Sunnquist, and L. Nacul. 2020. Rethinking the standard of care for myal- gic encephalomyelitis/chronic fatigue syndrome. Journal of General Internal Medicine 35(3):906–909. Fukuda, S., J. Nojima, Y. Motoki, K. Yamaguti, Y. Nakatomi, N. Okawa, K. Fujiwara, Y. Watanabe, and H. Kuratsune. 2016. A potential biomarker for fatigue: Oxidative stress and anti-oxidative activity. Biological Psychology 118:88–93. Ganji, R., and P. H. Reddy. 2021. Impact of COVID-19 on mitochondrial-based immunity in aging and age-related diseases. Frontiers in Aging Neuroscience 12:614650. Garg, H., M. Douglas, G. D. Turkington, and D. Turkington. 2021a. Recovery from refractory chronic fatigue syndrome with CBT and modafinil. BMJ Case Reports 14(3):e240283. Garg, P., U. Arora, A. Kumar, and N. Wig. 2021b. The “post-COVID” syndrome: How deep is the damage? Journal of Medical Virology 93(2):673–674. Gay, C., A. O’Shea, M. Robinson, J. Craggs, and R. Staud. 2015. Default mode network con- nectivity in chronic fatigue syndrome patients. Journal of Pain 16(4):S54. Ghali, A., C. Lacout, J.-O. Fortrat, K. Depres, M. Ghali, and C. Lavigne. 2022. Factors influenc- ing the prognosis of patients with myalgic encephalomyelitis/chronic fatigue syndrome. Diagnostics 12(10):2540. Giloteaux, L., J. K. Goodrich, W. A. Walters, S. M. Levine, R. E. Ley, and M. R. Hanson. 2016. Reduced diversity and altered composition of the gut microbiome in individuals with myalgic encephalomyelitis/chronic fatigue syndrome. Microbiome 4(1):30. González-Hermosillo, J. A., J. P. Martínez-López, S. A. Carrillo-Lampón, D. Ruiz-Ojeda, S. Herrera-Ramírez, L. M. Amezcua-Guerra, and M. D. R. Martínez-Alvarado. 2021. Post-acute COVID-19 symptoms, a potential link with myalgic encephalomyelitis/chronic fatigue syndrome: A 6-month survey in a Mexican cohort. Brain Sciences 11(6):760. Gottschalk, C. G., D. Peterson, J. Armstrong, K. Knox, and A. Roy. 2023. Potential molecular mechanisms of chronic fatigue in long haul COVID and other viral diseases. Infectious Agents and Cancer 18(1):7. Gruber, C. N., R. S. Patel, R. Trachtman, L. Lepow, F. Amanat, F. Krammer, K. M. Wilson, K. Onel, D. Geanon, K. Tuballes, M. Patel, K. Mouskas, T. O’Donnell, E. Merritt, N. W. Simons, V. Barcessat, D. M. Del Valle, S. Udondem, G. Kang, C. Agashe, N. Karekar, J. Grabowska, K. Nie, J. Le Berichel, H. Xie, N. Beckmann, S. Gangadharan, G. Ofori-Amanfo, U. Laserson, A. Rahman, S. Kim-Schulze, A. W. Charney, S. Gnjatic, B. D. Gelb, M. Merad, and D. Bogunovic. 2023. Mapping systemic inflammation and antibody responses in multisystem inflammatory syndrome in children (MIS-C). Cell 186(15):3325. PREPUBLICATION COPY—Uncorrected Proofs A02506-Long-Term_Health_Effects_of_COVID-19_Ch05.indd 205 5/21/24 11:25 AM

206 LONG-TERM HEALTH EFFECTS OF COVID-19 Guarnieri, J. W., J. M. Dybas, H. Fazelinia, M. S. Kim, J. Frere, Y. Zhang, Y. Soto Albrecht, D. G. Murdock, A. Angelin, L. N. Singh, S. L. Weiss, S. M. Best, M. T. Lott, S. Zhang, H. Cope, V. Zaksas, A. Saravia-Butler, C. Meydan, J. Foox, C. Mozsary, Y. Bram, Y. Kidane, W. Priebe, M. R. Emmett, R. Meller, S. Demharter, V. Stentoft-Hansen, M. Salvatore, D. Galeano, F. J. Enguita, P. Grabham, N. S. Trovao, U. Singh, J. Haltom, M. T. Heise, N. J. Moorman, V. K. Baxter, E. A. Madden, S. A. Taft-Benz, E. J. Anderson, W. A. Sanders, R. J. Dickmander, S. B. Baylin, E. S. Wurtele, P. M. Moraes-Vieira, D. Taylor, C. E. Mason, J. C. Schisler, R. E. Schwartz, A. Beheshti, and D. C. Wallace. 2023. Core mitochondrial genes are down-regulated during SARS-CoV-2 infection of rodent and human hosts. Science Translational Medicine 15(708):eabq1533. Guasp, M., G. Muñoz-Sánchez, E. Martínez-Hernández, D. Santana, Á. Carbayo, L. Naranjo, U. Bolós, M. Framil, A. Saiz, M. Balasa, R. Ruiz-García, R. Sánchez-Valle, and Barcelona Neuro-COVID Study Group. 2022. CSF biomarkers in COVID-19 associated encepha- lopathy and encephalitis predict long-term outcome. Frontiers in Immunology 13:866153. Guo, C., X. Che, T. Briese, A. Ranjan, O. Allicock, R. A. Yates, A. Cheng, D. March, M. Hornig, A. L. Komaroff, S. Levine, L. Bateman, S. D. Vernon, N. G. Klimas, J. G. Montoya, D. L. Peterson, W. I. Lipkin, and B. L. Williams. 2023. Deficient butyrate-producing capac- ity in the gut microbiome is associated with bacterial network disturbances and fatigue symptoms in ME/CFS. Cell Host Microbe 31(2):288–304.e8. Gyöngyösi, M., P. Alcaide, F. W. Asselbergs, B. J. J. M. Brundel, G. G. Camici, P. d. C. Martins, P. Ferdinandy, M. Fontana, H. Girao, M. Gnecchi, C. Gollmann-Tepeköylü, P. Kleinbongard, T. Krieg, R. Madonna, M. Paillard, A. Pantazis, C. Perrino, M. Pesce, G. G. Schiattarella, J. P. G. Sluijter, S. Steffens, C. Tschöpe, S. Van Linthout, and S. M. Davidson. 2023. Long COVID and the cardiovascular system- elucidating causes and cellular mechanisms in order to develop targeted diagnostic and therapeutic strategies: A joint scientific state- ment of the ESC working groups on cellular biology of the heart and myocardial and pericardial diseases. Cardiovascular Research 119(2):336–356. Haffke, M., H. Freitag, G. Rudolf, M. Seifert, W. Doehner, N. Scherbakov, L. Hanitsch, K. Wittke, S. Bauer, F. Konietschke, F. Paul, J. Bellmann-Strobl, C. Kedor, C. Scheibenbogen, and F. Sotzny. 2022. Endothelial dysfunction and altered endothelial biomarkers in pa- tients with post-COVID-19 syndrome and chronic fatigue syndrome (ME/CFS). Journal of Translational Medicine 20(1):138. Haider, S., A. J. Janowski, J. B. Lesnak, K. Hayashi, D. L. Dailey, R. Chimenti, L. A. Frey-Law, K. A. Sluka, and G. Berardi. 2023. A comparison of pain, fatigue, and function between post-COVID-19 condition, fibromyalgia, and chronic fatigue syndrome: A survey study. Pain 164(2):385–401. Hallmann, E., D. Sikora, B. Poniedziałek, K. Szyman´ski, K. Kondratiuk, J. Z˙urawski, L. Brydak, and P. Rzymski. 2023. IgG autoantibodies against ACE2 in SARS-CoV-2 infected patients. Journal of Medical Virology 95(1):e28273. Haran, J. P., E. Bradley, A. L. Zeamer, L. Cincotta, M. C. Salive, P. Dutta, S. Mutaawe, O. Anya, M. Meza-Segura, A. M. Moormann, D. V. Ward, B. A. McCormick, and V. Bucci. 2021. Inflammation-type dysbiosis of the oral microbiome associates with the duration of COVID-19 symptoms and long COVID. JCI Insight 6(19):e152346. Hardcastle, S. L., E. W. Brenu, S. Johnston, T. Nguyen, T. Huth, S. Ramos, D. Staines, and S. Marshall-Gradisnik. 2015a. Longitudinal analysis of immune abnormalities in varying severities of chronic fatigue syndrome/myalgic encephalomyelitis patients. Journal of Translational Medicine 13:299. Hardcastle, S. L., E. W. Brenu, S. Johnston, T. Nguyen, T. Huth, N. Wong, S. Ramos, D. Staines, and S. Marshall-Gradisnik. 2015b. Characterisation of cell functions and receptors in chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). BMC Immunology 16:35. PREPUBLICATION COPY—Uncorrected Proofs A02506-Long-Term_Health_Effects_of_COVID-19_Ch05.indd 206 5/21/24 11:25 AM

CHRONIC CONDITIONS SIMILAR TO LONG COVID 207 Häuser, W., J. Ablin, M.-A. Fitzcharles, G. Littlejohn, J. V. Luciano, C. Usui, and B. Walitt. 2015. Fibromyalgia. Nature Reviews. Disease Primers 1:15022. Holden, S., R. Maksoud, N. Eaton-Fitch, H. Cabanas, D. Staines, and S. Marshall-Gradisnik. 2020. A systematic review of mitochondrial abnormalities in myalgic encephalomyelitis/ chronic fatigue syndrome/systemic exertion intolerance disease. Journal of Translational Medicine 18:290. Holder, K., and P. H. Reddy. 2021. The COVID-19 effect on the immune system and mito- chondrial dynamics in diabetes, obesity, and dementia. Neuroscientist 27(4):331–339. Hurwitz, B. E., V. T. Coryell, M. Parker, P. Martin, A. Laperriere, N. G. Klimas, G. N. Sfakianakis, and M. S. Bilsker. 2009. Chronic fatigue syndrome: Illness severity, sedentary lifestyle, blood volume and evidence of diminished cardiac function. Clinical Science (London, England: 1979) 118(2):125–135. Huth, T. K., E. W. Brenu, T. Nguyen, S. L. Hardcastle, S. Johnston, S. Ramos, D. Staines, and Marshall-Gradisnik. 2014. Characterization of natural killer cell phenotypes in chronic fa- tigue syndrome/myalgic encephalomyelitis. Journal of Clinical & Cellular Immunology 5(3). Huth, T. K., E. W. Brenu, S. Ramos, T. Nguyen, S. Broadley, D. Staines, and S. Marshall-Gradisnik. 2016. Pilot study of natural killer cells in chronic fatigue syndrome/myalgic encephalomy- elitis and multiple sclerosis. Scandinavian Journal of Immunology 83(1):44–51. IOM (Institute of Medicine). 2015. Beyond myalgic encephalomyelitis/chronic fatigue syndrome: Redefining an illness. Washington, DC: The National Academies Press. Jason, L. A., and M. F. Islam. 2022. A classification system for post-acute sequelae of SARS-CoV-2 infection. Central Asian Journal of Medical Hypotheses and Ethics 3(1):38–51. Jason, L. A., and M. Sunnquist. 2018. The development of the DePaul Symptom Questionnaire: Original, expanded, brief, and pediatric versions. Frontiers in Pediatrics 6:330. Jason, L. A., N. Porter, M. Brown, V. Anderson, A. Brown, J. Hunnell, and A. Lerch. 2009. CFS: A review of epidemiology and natural history studies. Bulletin of the IACFS/ME 17(3):88–106. Jason, L. A., M. Islam, K. Conroy, J. Cotler, C. Torres, M. Johnson, and B. Mabie. 2021. COVID-19 symptoms over time: Comparing long-haulers to ME/CFS. Fatigue: Biomedicine, Health & Behavior 9(2):59–68. Jason, L.A., B. H. Natelson, H. Bonilla, Z. A. Sherif, S. D. Vernon, M. Verduzco-Gutierrez, L. O’Brien, E. Taylor. 2023. What Long COVID investigators can learn from four decades of ME/CFS research. Brain Behavior and Immunity Integrative, Volume 4:100022. Jukema, B. N., K. Smit, M. T. E. Hopman, C. C. W. G. Bongers, T. C. Pelgrim, M. H. Rijk, T. N. Platteel, R. P. Venekamp, D. L. M. Zwart, F. H. Rutten, and L. Koenderman. 2022. Neutrophil and eosinophil responses remain abnormal for several months in primary care patients with COVID-19 disease. Frontiers in Allergy 3:942699. Kaczmarek, M. P. 2023. Heterogenous circulating mirna changes in ME/CFS converge on a unified cluster of target genes: A computational analysis. PLoS ONE 18(12):e0296060. Kedor, C., H. Freitag, L. Meyer-Arndt, K. Wittke, L. G. Hanitsch, T. Zoller, F. Steinbeis, M. Haffke, G. Rudolf, B. Heidecker, T. Bobbert, J. Spranger, H. D. Volk, C. Skurk, F. Konietschke, F. Paul, U. Behrends, J. Bellmann-Strobl, and C. Scheibenbogen. 2022. A prospective observational study of post-COVID-19 chronic fatigue syndrome following the first pandemic wave in Germany and biomarkers associated with symptom severity. Nature Communications 13(1):5104. Kennedy, M., and D. T. Felson. 1996. A prospective long-term study of fibromyalgia syndrome. Arthritis & Rheumatism 39(4):682–685. Klimas, N. G., and A. O. B. Koneru. 2007. Chronic fatigue syndrome: Inflammation, immune function, and neuroendocrine interactions. Current Rheumatology Reports 9(6):482–487. Klimas, N. G., F. R. Salvato, R. Morgan, and M. A. Fletcher. 1990. Immunologic abnormalities in chronic fatigue syndrome. Journal of Clinical Microbiology 28(6):1403–1410. PREPUBLICATION COPY—Uncorrected Proofs A02506-Long-Term_Health_Effects_of_COVID-19_Ch05.indd 207 5/21/24 11:25 AM

208 LONG-TERM HEALTH EFFECTS OF COVID-19 Komaroff, A. L., and W. I. Lipkin. 2023. ME/CFS and long COVID share similar symptoms and biological abnormalities: Road map to the literature. Frontiers in Medicine (Lausanne) 10:1187163. Lam, M. H.-B., Y.-K. Wing, M. W.-M. Yu, C.-M. Leung, R. C. W. Ma, A. P. S. Kong, W. Y. So, S. Y.-Y. Fong, and S.-P. Lam. 2009. Mental morbidities and chronic fatigue in severe acute respiratory syndrome survivors: Long-term follow-up. Archives of Internal Medicine 169(22):2142–2147. Lammi, V., T. Nakanishi, S. E. Jones, S. J. Andrews, J. Karjalainen, B. Cortés, H. E. O’Brien, B. E. Fulton-Howard, H. H. Haapaniemi, A. Schmidt, R. E. Mitchell, A. Mousas, M. Mangino, A. Huerta-Chagoya, N. Sinnott-Armstrong, E. T. Cirulli, M. Vaudel, A. S. F. Kwong, A. K. Maiti, M. Marttila, C. Batini, F. Minnai, A. R. Dearman, C. A. R. Warmerdam, C. B. Sequeros, T. W. Winkler, D. M. Jordan, L. Guare, E. Vergasova, E. Marouli, P. Striano, U. A. Zainulabid, A. Kumar, H. F. Ahmad, R. Edahiro, S. Azekawa, Long COVID Host Genetics Initiative, FinnGen, DBDS Genomic Consortium, GEN-COVID Multicenter Study, J. J. Grzymski, M. Ishii, Y. Okada, N. D. Beckmann, M. Kumari, R. Wagner, I. M. Heid, C. John, P. J. Short, P. Magnus, K. Banasik, F. Geller, L. H. Franke, A. Rakitko, E. L. Duncan, A. Renieri, K. K. Tsilidis, R. d. Cid, A. Niavarani, T. Tusié-Luna, S. S. Verma, G. D. Smith, N. J. Timpson, M. J. Daly, A. Ganna, E. C. Schulte, J. B. Richards, K. U. Ludwig, M. Hultström, H. Zeberg, and H. M. Ollila. 2023. Genome-wide association study of Long COVID. medRxiv The Preprint Server for Health Sciences. https://www.medrxiv.org/content/10.1101/2023.06.29.23292056v1 (accessed February 26, 2024). Larsen, N. W., L. E. Stiles, R. Shaik, L. Schneider, S. Muppidi, C. T. Tsui, L. N. Geng, H. Bonilla, and M. G. Miglis. 2022. Characterization of autonomic symptom burden in long COVID: A global survey of 2,314 adults. Frontiers in Neurology 13:1012668. Lechuga, G. C., C. M. Morel, and S. G. De-Simone. 2023. Hematological alterations associated with long COVID-19. Frontiers in Physiology 14:1203472. Li, Y., Y. Ke, X. Xia, Y. Wang, F. Cheng, X. Liu, X. Jin, B. Li, C. Xie, S. Liu, W. Chen, C. Yang, Y. Niu, R. Jia, Y. Chen, X. Liu, Z. Wang, F. Zheng, Y. Jin, Z. Li, N. Yang, P. Cao, H. Chen, J. Ping, F. He, C. Wang, and G. Zhou. 2021. Genome-wide association study of COVID-19 severity among the Chinese population. Cell Discovery 7:76. Lim, E.-J., Y.-C. Ahn, E.-S. Jang, S.-W. Lee, S.-H. Lee, and C.-G. Son. 2020a. Systematic review and meta-analysis of the prevalence of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). Journal of Translational Medicine 18(1). Lim, E.-J., E.-B. Kang, E.-S. Jang, and C.-G. Son. 2020b. The prospects of the two-day cardio- pulmonary exercise test (CPET) in ME/CFS patients: A meta-analysis. Journal of Clinical Medicine 9(12):4040. Lindell, L., S. Bergman, I. F. Petersson, L. T. H. Jacobsson, and P. Herrström. 2000. Prevalence of fibromyalgia and chronic widespread pain. Scandinavian Journal of Primary Health Care 18(3):149–153. Liu, Q., J. W. Y. Mak, Q. Su, Y. K. Yeoh, G. C. Lui, S. S. S. Ng, F. Zhang, A. Y. L. Li, W. Lu, D. S. Hui, P. K. Chan, F. K. L. Chan, and S. C. Ng. 2022. Gut microbiota dynamics in a prospective cohort of patients with post-acute COVID-19 syndrome. Gut 71(3):544–552. Malkova, A. M., and Y. Shoenfeld. 2023. Autoimmune autonomic nervous system imbalance and conditions: Chronic fatigue syndrome, fibromyalgia, silicone breast implants, COVID and post-COVID syndrome, sick building syndrome, post-orthostatic tachycardia syndrome, autoimmune diseases and autoimmune/inflammatory syndrome induced by adjuvants. Autoimmunity Reviews 22(1):103230. Mancini, D. M., D. L. Brunjes, A. Lala, M. G. Trivieri, J. P. Contreras, and B. H. Natelson. 2021. Use of cardiopulmonary stress testing for patients with unexplained dyspnea post- coronavirus disease. JACC: Heart Failure 9(12):927–937. Marshall-Gradisnik, S., P. Smith, B. Nilius, and D. R. Staines. 2015. Examination of single nucleotide polymorphisms in acetylcholine receptors in chronic fatigue syndrome patients. Immunology and Immunogenetics Insights 7:III.S25105. PREPUBLICATION COPY—Uncorrected Proofs A02506-Long-Term_Health_Effects_of_COVID-19_Ch05.indd 208 5/21/24 11:25 AM

CHRONIC CONDITIONS SIMILAR TO LONG COVID 209 Martínez-Lavín, M., and A. Miguel-Álvarez. 2023. Hypothetical framework for post- COVID 19 condition based on a fibromyalgia pathogenetic model. Clinical Rheumatology 42(11):3167–3171. Martini, A. L., G. Carli, L. Kiferle, P. Piersanti, P. Palumbo, S. Morbelli, M. L. Calcagni, D. Perani, and S. Sestini. 2022. Time-dependent recovery of brain hypometabolism in neuro-COVID-19 patients. European Journal of Nuclear Medicine and Molecular Imaging 50(1):90–102. McGonagle, D., K. Sharif, A. O’Regan, and C. Bridgewood. 2020. The role of cytokines including interleukin-6 in COVID-19 induced pneumonia and macrophage activation syndrome-like disease. Autoimmunity Reviews 19(6):102537. McLaughlin, M., N. E. M. Sanal-Hayes, L. D. Hayes, E. C. Berry, and N. F. Sculthorpe. 2023. People with long COVID and myalgic encephalomyelitis/chronic fatigue syndrome exhibit similarly impaired vascular function. American Journal of Medicine October 12:S0002-9343(23):00609-5. Advance online publication. Missailidis, D., O. Sanislav, C. Y. Allan, S. J. Annesley, and P. R. Fisher. 2020. Cell-based blood biomarkers for myalgic encephalomyelitis/chronic fatigue syndrome. International Journal of Molecular Sciences 21(3):1142. Mitchell, W. M. 2016. Efficacy of rintatolimod in the treatment of chronic fatigue syndrome/ myalgic encephalomyelitis (CFS/ME). Expert Review of Clinical Pharmacology 9(6): 755–770. Mohandas, S., P. Jagannathan, T. J. Henrich, Z. A. Sherif, C. Bime, E. Quinlan, M. A. Portman, M. Gennaro, J. Rehman, and RECOVER Mechanistic Pathways Task Force. 2023. Immune mechanisms underlying COVID-19 pathology and post-acute sequelae of SARS-CoV-2 infection (PASC). eLife 12:e86014. Monje, M., and A. Iwasaki. 2022. The neurobiology of long COVID. Neuron 110(21): 3484–3496. Moore, Y., T. Serafimova, N. Anderson, H. King, A. Richards, A. Brigden, P. Sinai, J. Higgins, C. Ascough, P. Clery, and E. M. Crawley. 2021. Recovery from chronic fatigue syndrome: A systematic review-heterogeneity of definition limits study comparison. Archives of Disease in Childhood 106(11):1087–1094. Morillas-Arques, P., C. M. Rodriguez-Lopez, R. Molina-Barea, F. Rico-Villademoros, and E. P. Calandre. 2010. Trazodone for the treatment of fibromyalgia: An open-label, 12-week study. BMC Musculoskeletal Disorders 11:204. Morris, G., and M. Maes. 2013. A neuro-immune model of myalgic encephalomyelitis/chronic fatigue syndrome. Metabolic Brain Disease 28(4):523–540. Mosch, B., V. Hagena, S. Herpertz, and M. Diers. 2023. Brain morphometric changes in fibro- myalgia and the impact of psychometric and clinical factors: A volumetric and diffusion- tensor imaging study. Arthritis Research & Therapy 25(1):81. Mueller, C., J. C. Lin, S. Sheriff, A. A. Maudsley, and J. W. Younger. 2020. Evidence of wide- spread metabolite abnormalities in myalgic encephalomyelitis/chronic fatigue syndrome: Assessment with whole-brain magnetic resonance spectroscopy. Brain Imaging and Behavior 14(2):562–572. Nagy-Szakal, D., B. L. Williams, N. Mishra, X. Che, B. Lee, L. Bateman, N. G. Klimas, A. L. Komaroff, S. Levine, J. G. Montoya, D. L. Peterson, D. Ramanan, K. Jain, M. L. Eddy, M. Hornig, and W. I. Lipkin. 2017. Fecal metagenomic profiles in subgroups of patients with myalgic encephalomyelitis/chronic fatigue syndrome. Microbiome 5(1):44. Nakatomi, Y., K. Mizuno, A. Ishii, Y. Wada, M. Tanaka, S. Tazawa, K. Onoe, S. Fukuda, J. Kawabe, K. Takahashi, Y. Kataoka, S. Shiomi, K. Yamaguti, M. Inaba, H. Kuratsune, and Y. Watanabe. 2014. Neuroinflammation in patients with chronic fatigue syndrome/ myalgic encephalomyelitis: An 11C-(R)-PK11195 PET study. Journal of Nuclear Medicine 55(6):945–950. NICE (National Institute for Health and Care Excellence). 2020. COVID-19 rapid guideline: Managing the long-term effects of COVID-19. London, UK: NICE. PREPUBLICATION COPY—Uncorrected Proofs A02506-Long-Term_Health_Effects_of_COVID-19_Ch05.indd 209 5/21/24 11:25 AM

210 LONG-TERM HEALTH EFFECTS OF COVID-19 NICE. 2021. Myalgic encephalomyelitis (or encephalopathy)/chronic fatigue syndrome: Diagnosis and management. London, UK: NICE. Nunes, J. M., D. B. Kell, and E. Pretorius. 2023. Cardiovascular and haematological pathol- ogy in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): A role for viruses. Blood Reviews 60:101075. O’Dowd, H., P. Gladwell, C. A. Rogers, S. Hollinghurst, and A. Gregory. 2006. Cognitive behav- ioural therapy in chronic fatigue syndrome: A randomised controlled trial of an outpatient group programme. Health Technology Assessment (Winchester, England) 10(37): 1–121. Ojo-Amaize, E. A., E. J. Conley, and J. B. Peter. 1994. Decreased natural killer cell activity is associated with severity of chronic fatigue immune dysfunction syndrome. Clinical Infectious Diseases 18 (Suppl 1):S157–S159. Oliveira, C. R., L. A. Jason, D. Unutmaz, L. Bateman, and S. D. Vernon. 2023. Improvement of long COVID symptoms over one year. Frontiers in Medicine 9:1065620. Pairo-Castineira, E., S. Clohisey, L. Klaric, A. D. Bretherick, K. Rawlik, D. Pasko, S. Walker, N. Parkinson, M. H. Fourman, C. D. Russell, J. Furniss, A. Richmond, E. Gountouna, N. Wrobel, D. Harrison, B. Wang, Y. Wu, A. Meynert, F. Griffiths, W. Oosthuyzen, A. Kousathanas, L. Moutsianas, Z. Yang, R. Zhai, C. Zheng, G. Grimes, R. Beale, J. Millar, B. Shih, S. Keating, M. Zechner, C. Haley, D. J. Porteous, C. Hayward, J. Yang, J. Knight, C. Summers, M. Shankar-Hari, P. Klenerman, L. Turtle, A. Ho, S. C. Moore, C. Hinds, P. Horby, A. Nichol, D. Maslove, L. Ling, D. McAuley, H. Montgomery, T. Walsh, A. C. Pereira, A. Renieri, X. Shen, C. P. Ponting, A. Fawkes, A. Tenesa, M. Caulfield, R. Scott, K. Rowan, L. Murphy, P. J. M. Openshaw, M. G. Semple, A. Law, V. Vitart, J. F. Wilson, and J. K. Baillie. 2021. Genetic mechanisms of critical illness in COVID-19. Nature 591(7848):92–98. Patell, R., T. Bogue, A. Koshy, P. Bindal, M. Merrill, W. C. Aird, K. A. Bauer, and J. I. Zwicker. 2020. Postdischarge thrombosis and hemorrhage in patients with COVID-19. Blood 136(11):1342–1346. Pendergrast, T., A. Brown, M. Sunnquist, R. Jantke, J. L. Newton, E. B. Strand, and L. A. Jason. 2016. Housebound versus nonhousebound patients with myalgic encephalomyelitis and chronic fatigue syndrome. Chronic Illness 12(4):292–307. Plaut, S. 2023. “Long COVID-19” and viral “fibromyalgia-ness”: Suggesting a mechanistic role for fascial myofibroblasts (Nineveh, the shadow is in the fascia). Frontiers Medicine (Lausanne) 10:952278. Pliszka, A. G. 2022. Modafinil: A review and its potential use in the treatment of long COVID fatigue and neurocognitive deficits. American Journal of Psychiatry Residents’ Journal 17(4):5–7. Prompetchara, E., C. Ketloy, and T. Palaga. 2020. Immune responses in COVID-19 and po- tential vaccines: Lessons learned from SARS and MERS epidemic. Asian Pacific Journal of Allergy and Immunology 38(1):1–9. Puri, B. K., S. J. Counsell, R. Zaman, J. Main, A. G. Collins, J. V. Hajnal, and N. J. Davey. 2002. Relative increase in choline in the occipital cortex in chronic fatigue syndrome. Acta Psychiatrica Scandinavica 106(3):224–226. Ram-Mohan, N., D. Kim, A. J. Rogers, C. A. Blish, K. C. Nadeau, A. L. Blomkalns, and S. Yang. 2022. Association between SARS-CoV-2 RNAemia and postacute sequelae of COVID-19. Open Forum Infectious Diseases 9(2):ofab646. Randall, D. C., F. H. Cafferty, J. M. Shneerson, I. E. Smith, M. B. Llewelyn, and S. E. File. 2005. Chronic treatment with modafinil may not be beneficial in patients with chronic fatigue syndrome. Journal of Psychopharmacology (Oxford, England) 19(6):647–660. Raveendran, A. V., R. Jayadevan, and S. Sashidharan. 2021. Long COVID: An overview. Diabetes & Metabolic Syndrome 15(3):869–875. Rivas, J. L., T. Palencia, G. Fernández, and M. García. 2018. Association of T and NK cell phenotype with the diagnosis of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Frontiers in Immunology 9:1028. PREPUBLICATION COPY—Uncorrected Proofs A02506-Long-Term_Health_Effects_of_COVID-19_Ch05.indd 210 5/21/24 11:25 AM

CHRONIC CONDITIONS SIMILAR TO LONG COVID 211 Roberts, L. N., M. B. Whyte, L. Georgiou, G. Giron, J. Czuprynska, C. Rea, B. Vadher, R. K. Patel, E. Gee, and R. Arya. 2020. Postdischarge venous thromboembolism following hospital admission with COVID-19. Blood 136(11):1347–1350. Rodriguez-Perez, A. I., C. M. Labandeira, M. A. Pedrosa, R. Valenzuela, J. A. Suarez-Quintanilla, M. Cortes-Ayaso, P. Mayán-Conesa, and J. L. Labandeira-Garcia. 2021. Autoantibodies against ACE2 and angiotensin type-1 receptors increase severity of COVID-19. Journal of Autoimmunity 122:102683. Rowe, P. C., R. A. Underhill, K. J. Friedman, A. Gurwitt, M. S. Medow, M. S. Schwartz, N. Speight, J. M. Stewart, R. Vallings, and K. S. Rowe. 2017. Myalgic encephalomyelitis/ chronic fatigue syndrome diagnosis and management in young people: A primer. Frontiers in Pediatrics 5:121. Ruscitti, P., F. Ursini, and Y. Shoenfeld. 2023. Ferritin and myalgic encephalomyelitis/chronic fa- tigue syndrome in post COVID-19, an unexpected facet of the hyperferritinemic syndrome? Journal of Psychosomatic Research 169:111231. Russell, I. J., H. Vaeroy, M. Javors, and F. Nyberg. 1992. Cerebrospinal fluid biogenic amine metabolites in fibromyalgia/fibrositis syndrome and rheumatoid arthritis. Arthritis & Rheumatology 35(5):550–556. Sarzi-Puttini, P., V. Giorgi, D. Marotto, and F. Atzeni. 2020. Fibromyalgia: An update on clinical characteristics, aetiopathogenesis and treatment. Nature Reviews Rheumatology 16(11):645–660. Sasso, E.M., K. Muraki, N. Eaton-Fitch,P. Smith, O. L. Lesslar, G. Deed, and S. Marshall- Gradisnik. 2022. Transient receptor potential melastatin 3 dysfunction in post COVID-19 condition and myalgic encephalomyelitis/chronic fatigue syndrome patients. Molecular Medicine 28(98). Sathyamoorthy, M., M. Verduzco-Gutierrez, S. Varanasi, R. Ward, J. Spertus, and S. Shah. 2022. Enhanced external counterpulsation for management of symptoms associated with long COVID. American Heart Journal Plus: Cardiology Research and Practice 13:100105. Schaefer, C. P., E. H. Adams, M. Udall, E. T. Masters, R. M. Mann, S. R. Daniel, H. J. McElroy, J. C. Cappelleri, A. G. Clair, M. Hopps, R. Staud, P. Mease, and S. L. Silverman. 2016. Fibromyalgia outcomes over time: Results from a prospective observational study in the United States. Open Rheumatology Journal 10(1):109–121. Scherbakov, N., M. Szklarski, J. Hartwig, F. Sotzny, S. Lorenz, A. Meyer, P. Grabowski, W. Doehner, and C. Scheibenbogen. 2020. Peripheral endothelial dysfunction in myalgic encephalomyelitis/chronic fatigue syndrome. ESC Heart Failure 7(3):1064–1071. Shungu, D. C., N. Weiduschat, J. W. Murrough, X. Mao, S. Pillemer, J. P. Dyke, M. S. Medow, B. H. Natelson, J. M. Stewart, and S. J. Mathew. 2012. Increased ventricular lactate in chronic fatigue syndrome. III. Relationships to cortical glutathione and clinical symp- toms implicate oxidative stress in disorder pathophysiology. NMR in Biomedicine 25(9):1073–1087. Smith, M. E. B., E. Haney, M. McDonagh, M. Pappas, M. Daeges, N. Wasson, R. Fu, and H. D. Nelson. 2015. Treatment of myalgic encephalomyelitis/chronic fatigue syndrome: A systematic review for a national institutes of health pathways to prevention workshop. Annals of Internal Medicine 162(12):841–850. Solomon, L., and W. C. Reeves. 2004. Factors influencing the diagnosis of chronic fatigue syndrome. Archives of Internal Medicine 164(20):2241–2245. Srikanth, S., J. R. Boulos, T. Dover, L. Boccuto, and D. Dean. 2023. Identification and diagno- sis of long COVID-19: A scoping review. Progress in Biophysics and Molecular Biology 182:1–7. Strayer, D. R., D. Young, and W. M. Mitchell. 2020. Effect of disease duration in a random- ized phase III trial of rintatolimod, an immune modulator for myalgic encephalomyelitis/ chronic fatigue syndrome. PLoS ONE 15(10):e0240403. PREPUBLICATION COPY—Uncorrected Proofs A02506-Long-Term_Health_Effects_of_COVID-19_Ch05.indd 211 5/21/24 11:25 AM

212 LONG-TERM HEALTH EFFECTS OF COVID-19 Su, Y., D. Yuan, D. G. Chen, R. H. Ng, K. Wang, J. Choi, S. Li, S. Hong, R. Zhang, J. Xie, S. A. Kornilov, K. Scherler, A. J. Pavlovitch-Bedzyk, S. Dong, C. Lausted, I. Lee, S. Fallen, C. L. Dai, P. Baloni, B. Smith, V. R. Duvvuri, K. G. Anderson, J. Li, F. Yang, C. J. Duncombe, D. J. McCulloch, C. Rostomily, P. Troisch, J. Zhou, S. Mackay, Q. DeGottardi, D. H. May, R. Taniguchi, R. M. Gittelman, M. Klinger, T. M. Snyder, R. Roper, G. Wojciechowska, K. Murray, R. Edmark, S. Evans, L. Jones, Y. Zhou, L. Rowen, R. Liu, W. Chour, H. A. Algren, W. R. Berrington, J. A. Wallick, R. A. Cochran, M. E. Micikas, the ISB-Swedish COVID-19 Biobanking Unit, T. Wrin, C. J. Petropoulos, H. R. Cole, T. D. Fischer, W. Wei, D. S. B. Hoon, N. D. Price, N. Subramanian, J. A. Hill, J. Hadlock, A. T. Magis, A. Ribas, L. L. Lanier, S. D. Boyd, J. A. Bluestone, H. Chu, L. Hood, R. Gottardo, P. D. Greenberg, M. M. Davis, J. D. Goldman, and J. R. Heath. 2022. Multiple early factors anticipate post-acute COVID-19 sequelae. Cell 185(5):881–895.e20. Sukocheva, O. A., R. Maksoud, N. M. Beeraka, S. V. Madhunapantula, M. Sinelnikov, V. N. Nikolenko, M. E. Neganova, S. G. Klochkov, M. Amjad Kamal, D. R. Staines, and S. Marshall-Gradisnik. 2021. Analysis of post COVID-19 condition and its overlap with myalgic encephalomyelitis/chronic fatigue syndrome. Journal of Advanced Research 40:179–196. Sweetman, E., T. Kleffmann, C. Edgar, M. de Lange, R. Vallings, and W. Tate. 2020. A SWATH-MS analysis of myalgic encephalomyelitis/chronic fatigue syndrome peripheral blood mono- nuclear cell proteomes reveals mitochondrial dysfunction. Journal of Translational Medicine 18(1):365. Tate, W., M. Walker, E. Sweetman, A. Helliwell, K. Peppercorn, C. Edgar, A. Blair, and A. Chatterjee. 2022. Molecular mechanisms of neuroinflammation in ME/CFS and long COVID to sustain disease and promote relapses. Frontiers in Neurology 13:877772. Tay, M. Z., C. M. Poh, L. Rénia, P. A. MacAry, and L. F. P. Ng. 2020. The trinity of COVID-19: Immunity, inflammation and intervention. Nature Reviews Immunology 20(6):363–374. Thapaliya, K., S. Marshall-Gradisnik, D. Staines, and L. Barnden. 2020. Mapping of pathologi- cal change in chronic fatigue syndrome using the ratio of T1- and T2-weighted MRI scans. NeuroImage: Clinical 28:102366. Thapaliya, K., S. Marshall-Gradisnik, D. Staines, J. Su, and L. Barnden. 2022. Alteration of cortical volume and thickness in myalgic encephalomyelitis/chronic fatigue syndrome. Frontiers in Neuroscience 16:848730. Thibord, F., M. V. Chan, M.-H. Chen, and A. D. Johnson. 2022. A year of COVID-19 GWAS results from the GRASP portal reveals potential genetic risk factors. Human Genetics and Genomics Advances 3(2):100095. Tian, Y., K.-Y. Sun, T.-Q. Meng, Z. Ye, S.-M. Guo, Z.-M. Li, C.-L. Xiong, Y. Yin, H.-G. Li, and L.-Q. Zhou. 2021. Gut microbiota may not be fully restored in recovered COVID-19 patients after 3-month recovery. Frontiers in Nutrition 8:638825. Tidmore, T., L. Jason, L. Chapo-Kroger, S. So, A. Brown, and M. Silverman. 2015. Lack of knowledgeable healthcare access for patients with neuro-endocrine-immune diseases. Frontiers in Clinical Medicine 2:46–54. Tomaszewski Farias, S., D. Mungas, D. J. Harvey, A. Simmons, B. R. Reed, and C. Decarli. 2011. The measurement of everyday cognition: Development and validation of a short form of the everyday cognition scales. Alzheimer’s & Dementia 7(6):593–601. Tomo, S., M. Banerjee, S. Karli, P. Purohit, P. Mitra, P. Sharma, M. K. Garg, and B. Kumar. 2022. Assessment of DHEAS, cortisol, and DHEAS/cortisol ratio in patients with COVID-19: A pilot study. Hormones (Athens, Greece) 21(3):515–518. Torjesen, I. 2020. NICE cautions against using graded exercise therapy for patients recovering from COVID-19. BMJ (Clinical Research Edition) 370:m2912. Tuller, D., and M. Vink. 2023. Graded exercise therapy and cognitive behavior therapy do not improve employment outcomes in ME/CFS. Work 74(4):1235–1239. PREPUBLICATION COPY—Uncorrected Proofs A02506-Long-Term_Health_Effects_of_COVID-19_Ch05.indd 212 5/21/24 11:25 AM

CHRONIC CONDITIONS SIMILAR TO LONG COVID 213 Twisk, F. N. M., and M. Maes. 2009. A review on cognitive behavorial therapy (CBT) and graded exercise therapy (GET) in myalgic encephalomyelitis (ME)/chronic fatigue syn- drome (CFS): CBT/GET is not only ineffective and not evidence-based, but also potentially harmful for many patients with ME/CFS. Neuroendocrinology Letters 30(3):284–299. Twomey, R., J. DeMars, K. Franklin, S. N. Culos-Reed, J. Weatherald, and J. G. Wrightson. 2022. Chronic fatigue and postexertional malaise in people living with long COVID: An observational study. Physical Therapy 102(4):pzac005. Urhan, E., Z. Karaca, G. K. Unuvar, K. Gundogan, and K. Unluhizarci. 2022. Investiga- tion of pituitary functions after acute coronavirus disease 2019. Endocrine Journal 69(6):649–658. Ursini, F., J. Ciaffi, L. Mancarella, L. Lisi, V. Brusi, C. Cavallari, M. D’Onghia, A. Mari, E. Borlandelli, J. F. Cordella, M. L. Regina, P. Viola, P. Ruscitti, M. Miceli, R. D. Giorgio, N. Baldini, C. Borghi, A. Gasbarrini, A. Iagnocco, R. Giacomelli, C. Faldini, M. P. Landini, and R. Meliconi. 2021. Fibromyalgia: A new facet of the post-COVID-19 syndrome spectrum? Results from a web-based survey. RMD Open 7(3):e001735. Vahratian, A., J.-M. S. Lin, J. Bertolli, and E. R. Unger. 2023. Myalgic encephalomyelitis/ chronic fatigue syndrome in adults: United States, 2021-2022. NCHS Data Briefs 488:1–8. Varga, Z., A. J. Flammer, P. Steiger, M. Haberecker, R. Andermatt, A. S. Zinkernagel, M. R. Mehra, R. A. Schuepbach, F. Ruschitzka, and H. Moch. 2020. Endothelial cell infection and endotheliitis in COVID-19. The Lancet 395(10234):1417–1418. Vella, L. A., J. R. Giles, A. E. Baxter, D. A. Oldridge, C. Diorio, L. Kuri-Cervantes, C. Alanio, M. B. Pampena, J. E. Wu, Z. Chen, Y. J. Huang, E. M. Anderson, S. Gouma, K. O. McNerney, J. Chase, C. Burudpakdee, J. H. Lee, S. A. Apostolidis, A. C. Huang, D. Mathew, O. Kuthuru, E. C. Goodwin, M. E. Weirick, M. J. Bolton, C. P. Arevalo, A. Ramos, C. J. Jasen, P. E. Conrey, S. Sayed, H. M. Giannini, K. D’Andrea, the UPenn COVID Processing Unit, N. J. Meyer, E. M. Behrens, H. Bassiri, S. E. Hensley, S. E. Henrickson, D. T. Teachey, M. R. Betts, and E. J. Wherry. 2021. Deep immune profiling of MIS-C demonstrates marked but transient immune activation compared with adult and pediatric COVID-19. Science Immunology 6(57):eabf7570. Vojdani, A., E. Vojdani, E. Saidara, and M. Maes. 2023. Persistent SARS-CoV-2 infection, EBV, HHV-6 and other factors may contribute to inflammation and autoimmunity in long COVID. Viruses 15(2):400. Wallukat, G., B. Hohberger, K. Wenzel, J. Fürst, S. Schulze-Rothe, A. Wallukat, A.-S. Hönicke, and J. Müller. 2021. Functional autoantibodies against G-protein coupled receptors in pa- tients with persistent long-COVID-19 symptoms. Journal of Translational Autoimmunity 4:100100. Weerahandi, H., K. A. Hochman, E. Simon, C. Blaum, J. Chodosh, E. Duan, K. Garry, T. Kahan, S. L. Karmen-Tuohy, H. C. Karpel, F. Mendoza, A. M. Prete, L. Quintana, J. Rutishauser, L. Santos Martinez, K. Shah, S. Sharma, E. Simon, A. Z. Stirniman, and L. I. Horwitz. 2021. Post-discharge health status and symptoms in patients with severe COVID-19. Journal of General Internal Medicine 36(3):738–745. Weigel, B., N. Eaton-Fitch, R. Passmore, H. Cabanas, D. Staines, and S. Marshall-Gradisnik. 2022 Gastrointestinal symptoms, dietary habits, and the effect on health-related quality of life among Australian myalgic encephalomyelitis/chronic fatigue syndrome patients: A cross-sectional study. Quality of Life Research 29(6):1521–1531. Weigel, B., N. Eaton-Fitch, K. Thapaliya, S. Marshall-Gradisnik. 2023. Symptom presenta- tion and quality of life are comparable in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and post COVID-19 condition. Population Medicine 5(Supplement):A372 Wessely, S. 1995. The epidemiology of chronic fatigue syndrome. Epidemiologic Reviews 17(1):139–151. PREPUBLICATION COPY—Uncorrected Proofs A02506-Long-Term_Health_Effects_of_COVID-19_Ch05.indd 213 5/21/24 11:25 AM

214 LONG-TERM HEALTH EFFECTS OF COVID-19 Whiteside, T. L., and D. Friberg. 1998. Natural killer cells and natural killer cell activity in chronic fatigue syndrome. American Journal of Medicine 105(3A):27S-34S. WHO (World Health Organization). 2020. Clinical management of COVID-19. https://www.who. int/teams/health-care-readiness/covid-19 (accessed February 26, 2024). Wirth, K. J., and M. Löhn. 2023. Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and comorbidities: Linked by vascular pathomechanisms and vasoactive mediators? Medicina 59(5):978. Wolfe, F., J. Anderson, D. Harkness, R. M. Bennett, X. J. Caro, D. L. Goldenberg, I. J. Russell, and M. B. Yunus. 1997. Health status and disease severity in fibromyalgia. Results of a six-center longitudinal study. Arthritis & Rheumatology 40(9):1571–1579. Wong, T. L., and D. J. Weitzer. 2021. Long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)—A systemic review and comparison of clinical presentation and symptomatology. Medicina 57(5):418. Worm-Smeitink, M., S. Nikolaus, K. Goldsmith, J. Wiborg, S. Ali, H. Knoop, and T. Chalder. 2016. Cognitive behaviour therapy for chronic fatigue syndrome: Differences in treatment outcome between a tertiary treatment centre in the United Kingdom and the Netherlands. Journal of Psychosomatic Research 87:43–49. Wu, E., A. Mahdi, J. Nickander, J. Bruchfeld, L. Mellbin, K. Haugaa, M. Ståhlberg, and L. Desta. 2023. Enhanced external counterpulsation for management of postacute sequelae of SARS-CoV-2 associated microvascular angina and fatigue: An interventional pilot study. Cardiology Research and Practice 2023:6687803. Xie, Y., and Z. Al-Aly. 2022. Risks and burdens of incident diabetes in long COVID: A cohort study. The Lancet Diabetes & Endocrinology 10(5):311–321. Xiong, R., C. Gunter, E. Fleming, S. D. Vernon, L. Bateman, D. Unutmaz, and J. Oh. 2023. Multi-’omics of gut microbiome-host interactions in short- and long-term myalgic encephalomyelitis/chronic fatigue syndrome patients. Cell Host Microbe 31(2):273–287. e275. Xu, E., Y. Xie, and Z. Al-Aly. 2023a. Risks and burdens of incident dyslipidaemia in long COVID: A cohort study. The Lancet Diabetes & Endocrinology 11(2):120-128. Xu, S.-W., I. Ilyas, and J.-P. Weng. 2023b. Endothelial dysfunction in COVID-19: An overview of evidence, biomarkers, mechanisms and potential therapies. Acta Pharmacologica Sinica 44(4):695-709. Yamamoto, Y., Y. Otsuka, K. Tokumasu, N. Sunada, Y. Nakano, H. Honda, Y. Sakurada, T. Hasegawa, H. Hagiya, and F. Otsuka. 2023. Utility of serum ferritin for predicting my- algic encephalomyelitis/chronic fatigue syndrome in patients with long COVID. Journal of Clinical Medicine 12(14):4737. Yelin, D., C. D. Moschopoulos, I. Margalit, E. Gkrania-Klotsas, F. Landi, J.-P. Stahl, and D. Yahav. 2022. ESCMID rapid guidelines for assessment and management of long COVID. Clinical Microbiology and Infection 28(7):955-972. Yeoh, Y. K., T. Zuo, G. C.-Y. Lui, F. Zhang, Q. Liu, A. Y. Li, A. C. Chung, C. P. Cheung, E. Y. Tso, K. S. Fung, V. Chan, L. Ling, G. Joynt, D. S.-C. Hui, K. M. Chow, S. S. S. Ng, T. C.-M. Li, R. W. Ng, T. C. Yip, G. L.-H. Wong, F. K. Chan, C. K. Wong, P. K. Chan, and S. C. Ng. 2021. Gut microbiota composition reflects disease severity and dysfunctional immune responses in patients with COVID-19. Gut 70(4):698-706. PREPUBLICATION COPY—Uncorrected Proofs A02506-Long-Term_Health_Effects_of_COVID-19_Ch05.indd 214 5/21/24 11:25 AM

Next: 6 Overall Conclusions »
Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection Get This Book
×
 Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection
Buy Prepub | $61.00 Buy Paperback | $52.00
MyNAP members save 10% online.
Login or Register to save!
Download Free PDF

Since the onset of the coronavirus disease 2019 (COVID-19) pandemic in early 2020, many individuals infected with the virus that causes COVID-19, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), have continued to experience lingering symptoms for months or even years following infection. Some symptoms can affect a person's ability to work or attend school for an extended period of time. Consequently, in 2022, the Social Security Administration requested that the National Academies convene a committee of relevant experts to investigate and provide an overview of the current status of diagnosis, treatment, and prognosis of long-term health effects related to Long COVID. This report presents the committee conclusions.

READ FREE ONLINE

  1. ×

    Welcome to OpenBook!

    You're looking at OpenBook, NAP.edu's online reading room since 1999. Based on feedback from you, our users, we've made some improvements that make it easier than ever to read thousands of publications on our website.

    Do you want to take a quick tour of the OpenBook's features?

    No Thanks Take a Tour »
  2. ×

    Show this book's table of contents, where you can jump to any chapter by name.

    « Back Next »
  3. ×

    ...or use these buttons to go back to the previous chapter or skip to the next one.

    « Back Next »
  4. ×

    Jump up to the previous page or down to the next one. Also, you can type in a page number and press Enter to go directly to that page in the book.

    « Back Next »
  5. ×

    To search the entire text of this book, type in your search term here and press Enter.

    « Back Next »
  6. ×

    Share a link to this book page on your preferred social network or via email.

    « Back Next »
  7. ×

    View our suggested citation for this chapter.

    « Back Next »
  8. ×

    Ready to take your reading offline? Click here to buy this book in print or download it as a free PDF, if available.

    « Back Next »
Stay Connected!