ME/CFS and Long COVID: Q&A With the CDC's Dr Jennifer Cope

Jennifer Cope, MD, MPH


November 17, 2022

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The growing number of individuals experiencing Long COVID — now estimated to be as high as 1 in 5 adults who have had COVID-19 — has brought greater attention to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The two conditions share many symptoms, but their causes are still unknown. Lucy Hicks of Medscape Medical News spoke with Jennifer Cope, MD, MPH, a medical officer with the Centers for Disease Control and Prevention (CDC) Chronic Viral Diseases Branch, to answer questions on what providers should know about Long COVID and ME/CFS, how to diagnose and treat these conditions, and ongoing areas of research.

Why should healthcare providers care about ME/CFS?

ME/CFS, which stands for myalgic encephalomyelitis/chronic fatigue syndrome, is a debilitating and complex illness that affects a significant number of people. The estimated prevalence of ME/CFS is between 836,000 and 2.5 million Americans. We do think that because of the COVID-19 pandemic, we could start to see increasing numbers of ME/CFS cases.

Do we know what causes ME/CFS?

The cause — or causes — of ME/CFS are not known, and that is one of the more perplexing and frustrating aspects of this illness. Postinfectious etiology has long been suspected, but environmental toxins and immune system changes, chronic stress, mitochondrial defects as well genetic links could also be involved.

How is ME/CFS diagnosed?

There is no specific diagnostic test for ME/CFS; we rely on the Institute of Medicine 2015 case definition for ME/CFS. Symptoms include (1) significant limitations in the ability to participate in routine activities associated with profound fatigue lasting at least 6 months and (2) postexertional malaise (PEM), which is worsening of symptoms after physical, mental, or emotional exertion that would not have caused a problem before the illness. PEM is considered the hallmark symptom of ME/CFS. The third symptom is unrefreshing sleep. Additionally, you need at least one of the following: cognitive impairment and/or orthostatic intolerance.

What is Long COVID, and is it similar to ME/CFS?

Long COVID is currently being used as a broad, umbrella-like term: there are different subgroups of Long COVID that fall under that that title. It's not one entity, and that has certainly contributed to some of the complexities around studying it.

At one end of the spectrum, there are conditions and symptoms that are likely due to direct organ damage by the SARS-CoV-2 virus that causes COVID-19, and these include lung fibrosis, myocarditis, or kidney damage. Routine imaging and laboratory tests can identify these types of issues. Then, at the other end of the spectrum, we have syndromes that are similar to ME/CFS that include disabling symptoms like PEM, fatigue, brain fog, unrefreshing sleep, headaches, dysautonomia, mast cell activation, and orthostatic intolerance. These are often in the absence of abnormalities that are detectable through routine laboratory tests or imaging. The clinical approach for both conditions is directed toward supportive care and symptom management.

Are there notable differences between patients with Long COVID vs ME/CFS?

Long COVID does encompass a number of different subtypes, and the organ system damage we see in a subtype of people previously infected with SARS-CoV-2 is not something that is usually seen in ME/CFS. An example is someone who has lung damage from having acute COVID, and they continue to have shortness of breath and reduced pulmonary function. That's different from what we see with ME/CFS. Another difference would be people with COVID who have had disturbances to their sense of smell and taste. That was something novel that we saw with both acute COVID and in some people who are suffering with Long COVID.

What do we know about what may be causing ME/CFS-like symptoms in patients with Long COVID?

This is an area of active investigation, with the National Institute of Health's REsearching COVID to Enhance Recovery (RECOVER) Initiative being one of the largest efforts around this topic in the United States. Current mechanisms that are being postulated and investigated include persistence of SARS-CoV-2 antigens, abnormal inflammatory reactions, reactivation of latent herpes viruses, gut dysbiosis, microvascular dysfunction, and then viral-induced autoantibodies. It's a pretty lengthy list.

When would a clinician diagnose ME/CFS, and when would they diagnose Long COVID?

Starting with ME/CFS, that diagnosis is going to be made when the patient meets those Institute of Medicine case definition criteria. As of October 1, 2022, we now have a new ICD-10 diagnostic code that is specific for myalgic encephalomyelitis and chronic fatigue syndrome: G93.32. This is an advance, because previously, there was no specific code for ME/CFS. Providers had to use less specific codes like "chronic fatigue, unspecified" or "benign encephalomyelitis." We're excited because ICD-10 codes are used in so many ways, including in analyses where we try to establish the prevalence and burden of illness. If someone meets criteria for ME/CFS and it's occurring after having COVID, the clinician would use both the ME/CFS code and use it in conjunction with the post-COVID condition code, which is U09.9.

While ME/CFS has criteria outlined for diagnosis, we're not there yet with Long COVID. This is really a clinical diagnosis, where certain symptoms are occurring after having COVID. One thing to note is that a positive COVID test is not necessarily required. It obviously supports the diagnosis, but a clinician can make a Long COVID diagnosis based on the clinical symptoms that the patient might have had or if they had an exposure to someone with COVID.

What are the current treatments available for ME/CFS and Long COVID?

For both conditions, it's really focused on targeting the most troublesome symptoms. Clinicians can turn to what is already known about what works for some of the symptoms of ME/CFS and apply that to patients with Long COVID who have similar symptoms. The American Academy of Physical Medicine and Rehabilitation has put out consensus statements that are focusing on the common types of symptoms of Long COVID: the fatigue, cognitive impairment, and some of the breathing difficulties. They're drawing from strategies that have worked for ME/CFS and other conditions for those symptoms.

How can growing research in Long COVID contribute to our understanding of ME/CFS?

There are notable similarities among the presentation and the symptoms of both conditions. ME/CFS might have an infectious trigger, and we know that's the case for Long COVID as well. Findings from studies on Long COVID on the causes and therapies that might work can then be potentially investigated and applied to patients living with ME/CFS. If there have been any positives to this pandemic, one is that Long COVID has shone a light on ME/CFS and raised the awareness of the condition.

Are there any promising areas of research in ME/CFS?

Given how little we know about the causes, there are really a lot of avenues worth investigating. Studies on mitochondrial dysfunction, neuroinflammation, glial activation, endothelial dysfunction, and immune dysregulation are all being pursued. Another crucial area to highlight is identifying biomarkers for diagnosis and monitoring the impact of therapy, as well as studies characterizing the mechanism of PEM. PEM continues to be a hallmark of ME/CFS, and it's one of the most baffling and disabling symptoms that patients face.

One area that is a bit different, but also really important, is researching models of clinical care that will allow healthcare providers the time and support necessary to provide the comprehensive care that patients with complex chronic illnesses like ME/CFS and Long COVID really need.

Have there been any areas of ME/CFS research that have been blind alleys?

We wouldn't say that there's truly any research that hasn't been useful, because even negative studies contribute to the overall knowledge of the illness. Sometimes, there are problems that occur when there are exciting findings that might be overinterpreted. One example is research that detected the virus XMRV in patients with ME/CFS. This was very exciting, because we thought we had identified one thing that we thought caused ME/CFS. Then, it ended up being determined through comprehensive collaborative study that XRMV was a laboratory contaminant and not the etiology of ME/CFS. But overall, you know, even these detours have had the advantage of raising awareness about ME/CFS and enlisting more investigators to study the condition.

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