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Emerging evidence is shedding light on the common underlying mechanisms contributing to the overlapping clinical phenomena of “long COVID,” myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and dysautonomia.
At the virtual annual meeting of the International Association for Chronic Fatigue Syndrome / Myalgic Encephalomyelitis (IACFSME), speakers presented data showing similar pathophysiologic abnormalities in people with systemic symptoms associated with ME/CFS who had a prior SARS-CoV-2 infection and those who did not, including individuals whose illness preceded the COVID-19 pandemic.
Core clinical diagnostic criteria for ME/CFS established by the Institute of Medicine in 2015 include substantial decrement in functioning for 6 months or longer, post-exertional malaise, or a worsening of symptoms following even minor exertion (often described by patients as “crashes”), unrefreshing sleep, and cognitive dysfunction and/or orthostatic intolerance that are frequent and severe.
Long COVID has been defined in several different ways using different terminology. The US Centers for Disease Control and Prevention, for example, defines “post-COVID conditions” as those continuing four or more weeks beyond first symptoms. The World Health Organization’s clinical case definition of “post COVID-19 condition” includes otherwise unexplained symptoms 3 months from COVID-19 onset and lasting longer than 2 months.
Both ME/CFS and long COVID commonly involve numerous symptoms beyond the defining ones, affecting nearly every organ system in the body, including systemic, neurocognitive, endocrine, cardiovascular, pulmonary, musculoskeletal, and gastrointestinal, with wide variation among individuals. Autonomic dysfunction is common to both conditions, particularly postural orthostatic tachycardia syndrome (POTS).
“My way of understanding these illnesses is that they’re not just multisystem illnesses, but all these interactive systems that lean on each other are dysregulated…I would say that a very common underlying mediator of both ME/CFS and long COVID is autonomic dysfunction, and it presents as POTS,” Nancy Klimas, MD, director of the Institute for Neuro-Immune Medicine at Nova Southeastern University, Fort Lauderdale, Florida, told Medscape Medical News.
Klimas, who is also director of Clinical Immunology Research at the Miami Veterans Affairs Medical Center, added that “if basic bioenergetics are disrupted and in an oxidative-stress state [then] they have downregulated energy production at the cellular level, which seems to be the case in ME/CFS and now in long COVID.”
New ICD-10 Codes Better Characterize the Syndromes
New ICD-10 codes for 2023, being implemented on October 1, will enable clinicians to better document all of these interrelated conditions.
Under the existing G93.3, “Postviral and related fatigue syndromes,” there will now be:
G93.31 – “Postviral fatigue syndrome”
G93.32 – “Myalgic encephalomyelitis / chronic fatigue syndrome” (and the separate terms)
G93.39 – “Other post infection and related fatigue syndromes”
The old R53.82, “Chronic fatigue, unspecified” code now excludes all of the above conditions.
The additional code U09.9 for “post COVID-19 condition, unspecified,” may also be used if applicable.
In addition, a new code for POTS, G90.A, which wasn’t previously mentioned in ICD-10, may also be used starting October 1.
Lucinda Bateman, MD, founder and director of the Bateman Horne Center, Salt Lake City, Utah, advises using all applicable codes for a given patient. “If a patient came into my office with long COVID and met criteria for ME/CFS, we would code both, and also any other syndrome criteria that they may meet, such as POTS or fibromyalgia.
“If people use the codes appropriately, then you can understand the overlap better. It increases the likelihood of reimbursement, creates a more accurate medical record for the patient, and provides them with a better tool should they require disability benefits.”
Bateman advises in-office orthostatic evaluation for all patients with this symptom constellation, using a passive standing evaluation such as the 10-minute NASA Lean test.
“Clinicians should take the time to do orthostatic testing in these patients because it provides objective markers and will help lead us to potential interventions to help improve people’s function.”
The Bateman Horne center offers clinician resources on management of ME/CFS and related conditions.
How Common is ME/CFS After COVID-19?
According to one published meta-analysis, the global prevalence of “post-acute sequelae of SARS-CoV-2,” defined by any symptom, is about 43% of patients overall following infection, and 49% at 120 days. Fatigue was the most commonly reported symptom, followed by memory problems. As of March 22, the World Health Organization estimated that there have been more than 470 million COVID-19 cases, which would give a figure of about 200 million people who are experiencing a wide range of long COVID symptoms.
On the final day of the IACFSME conference, Luis Nacul, MD, clinical associate professor at the University of British Columbia, Vancouver, Canada, presented several sets of data from his group and others aiming to determine the proportion of individuals who develop symptoms suggestive of ME/CFS following a COVID-19 infection.
Among a cohort of 88 adults hospitalized with confirmed SARS-CoV-2 infections during the first pandemic wave in 2020 and followed up in the respiratory clinic, rates of reported generalized fatigue were 67% at 3 months and 59.5% at 6 months. Substantial fatigue (ie, present most days and affecting activity levels) were reported by 16% at 3 months and 7% at 6 months. “This should represent in principle the maximum prevalence of cases who would meet the criteria for ME/CFS,” Nacul said.
Baseline age was indirectly associated with fatigue at 3 and 6 months, while the number of comorbidities a patient had was directly associated. Comorbidities also predicted severe fatigue at 3 months, but the numbers were too small for assessment at 6 months.
Studies involving nonhospitalized patients suggested lower rates. One meta-analysis showed 1-year rates of fatigue in 32% and cognitive impairment in 22%. Another showed very similar rates, reporting fatigue in 28%, and memory/concentration difficulties in 18%-19%.
Nacul cautioned that these figures are likely overestimates since many of the study populations are taken from respiratory or long COVID clinics. “The evidence on ‘post-COVID fatigue syndrome’ or ME/CFS following COVID is still evolving. There is a huge need for studies looking more closely at cases meeting well-defined ME/CFS criteria. This unfortunately hasn’t been done for most studies.”
Immune System Dysfunction Appears to Underlie Many Cases
In a keynote address during the conference, Akiko Iwasaki, PhD, of Yale University, New Haven, Connecticut, pointed out that long COVID and ME/CFS are among many unexplained post-acute infection syndromes associated with a long list of viral pathogens, including Ebola, the prior SARS viruses, Epstein-Barr virus, and Dengue, as well as non-viral pathogens such as Coxiella burnetii (Q fever syndrome) and Borrelia (post-treatment Lyme disease syndrome).
Iwasaki cited a recent Nature Medicine review article that she co-authored on this topic with an ME/CFS patient, noting: “We really need to understand why some people are failing to recover from these types of diseases.”
Emerging evidence supports four different hypotheses regarding pathogenesis:
“Right now, it’s too early to exclude or make any conclusions about these. We need to have an open mind to dissect these various possibilities,” she said.
Two speakers reported findings of immune dysregulation in both ME/CFS and long COVID. Wakiro Sato, MD, PhD, of the National Center of Neurology and Psychiatry, Tokyo, Japan, reported that anti-G-protein coupled receptor antibodies were found in 33 (55%) of 60 patients with long COVID, and more than 40% had peripheral immune cell profile abnormalities. These findings were similar to those found in patients with ME/CFS, published by Sato’s team and other researchers in Germany.
Liisa K. Selin, MD, PhD, professor of pathology at the University of Massachusetts Chan Medical School, Worcester, presented data for an analysis of peripheral blood mononuclear cells from 26 donors with ME/CFS (8 with long COVID) and 24 healthy controls. In both patient groups, they found altered expression of inflammatory markers and decreases in CD8 T-cell number and function. The patients with long COVID showed evidence of sustained activation of both T-cell populations with increased CD38 and HLA-DR, associated with a compensatory increased frequency of activated CD4+CD8+ T cells.
“These results are consistent with immune dysregulation associated with overactivation and exhaustion of CD8 T cells, as observed in chronic viral infections and tumor environments,” Selin said.
ME/CFS and Long COVID “Frighteningly Similar, if Not Identical”
Data for a different system derangement in long COVID and ME/CFS, the pathophysiology of exercise intolerance, were presented in another keynote talk by David M. Systrom, MD, a pulmonary and critical care medicine specialist at Brigham and Women’s Hospital and director of the Massachusetts General Hospital Cardiopulmonary Laboratory, Boston. He has conducted invasive cardiopulmonary exercise testing in patients with ME/CFS and patients with long COVID.
Previously, Systrom and his team found that patients with ME/CFS have distinct defects in both ventricular filling pressure and oxygen extraction from the muscles. Neither of those are features of deconditioning, which is often blamed for exercise intolerance in people with ME/CFS. Rather, the major defect in deconditioning is decreased stroke volume and cardiac output. In ME/CFS patients, he found supranormal pulmonary blood flow compared with VO2 max, suggesting peripheral left-to-right shunting.
In addition, Systrom and colleagues found that a large proportion of ME/CFS patients with these peripheral vascular defects also have biopsy-demonstrated small-fiber neuropathy, suggesting that acute exercise intolerance is related to underlying autonomic nervous system dysfunction.
In Systrom and colleagues’ long COVID study, invasive cardiopulmonary exercise testing in 10 patients who had recovered from COVID-19 at least 6 months prior and did not have cardiopulmonary disease had significantly revealed reduced peak exercise aerobic capacity (VO2 max), compared with 10 age- and sex-matched controls. The reduction in peak VO2 was associated with impaired systemic oxygen extraction, compared with the controls, despite a preserved peak cardiac index.
The long COVID patients also showed greater ventilatory inefficiency, which “is entirely related to hyperventilation, not intrinsic lung disease,” Systrom said, adding that while there may be subsets of patients with interstitial lung disease after acute respiratory distress syndrome, these patients didn’t have that. “This for all the world looks like ME/CFS. We think they are frighteningly similar, if not identical,” Systrom said.
In a third study for which Systrom was a co-author, published in Annals of Neurology last December, multisystem involvement was found in nine patients following mild COVID-19 infection, using standardized autonomic assessments including Valsalva maneuver, sudomotor and tilt tests, and skin biopsies for small-fiber neuropathy. The findings included cerebrovascular dysregulation with persistent cerebral arteriolar vasoconstriction, small-fiber neuropathy and related dysautonomia, respiratory dysregulation, and chronic inflammation.
Systrom’s conclusion: “Dyspnea and hyperventilation are common in ME/CFS and long COVID and there is significant overlap with POTS.”
Bateman disclosed that she is conducting research for Terra Biological LLC. Systrom said he is conducting research for Astellas.
International Association for Chronic Fatigue Syndrome / Myalgic Encephalomyelitis 2022 Annual Meeting. Presentations given July 28-30, 2022.