2024 US National Academy of Medicine Long COVID Definition: What is it? How might it impact ME/CFS care and research?

By Lily Chu, MD, MSHS

In 2023,  I was invited by the US National Academy of Medicine (NAM) to be part of a Committee updating and harmonizing the different existing Long COVID (LC) definitions for the US government. In 2014, I had been part of another NAM Committee which created a new, evidence-based ME/CFS criteria for the US. Because LC shares many characteristics with ME/CFS - including a post-infectious onset, similar symptoms, absence of a validated diagnostic test, and skepticism from medical providers / society – I was asked to contribute my insights and experience. The Committee consisted of 16 experts from a variety of backgrounds, including several people personally affected by LC. Six NAM staff members and several consultants assisted us in gathering information, drafting the report, and disseminating the results.

How was the NASEM LC definition created?

For 15 months, the Committee reviewed scientific literature, heard expert testimony, and gathered input from people and families affected by LC. The goal was to create a definition based on the most current science while also incorporating clinical and lived experiences. The definition was intended for clinical, research, and public health surveillance purposes.

 What is the NASEM LC definition? What is different about this definition compared to others? How will the NASEM LC definition help those affected by LC?

On June 11, 2024, the Committee published the new definition accompanied by a full report, a 1-page summary sheet, and article highlighting aspects of the report. We defined LC as

“an infection-associated chronic condition (IACC) that occurs after SARSCoV-2 infection and is present for at least 3 months as a continuous, relapsing and remitting, or progressive disease state that affects one or more organ systems.”

The figure above summarizes the definition and its key features.

The definition includes several key features to help people currently affected by LC but not yet formally diagnosed receive a diagnosis. Other LC definitions had not explicitly included or highlighted these features, potentially leading to ignorance and misconceptions about LC among clinicians. Without a documented medical condition (an issue the ME/CFS community is very familiar with), affected individuals cannot receive appropriate medical care, social support, or disability benefits.

1)     An abnormal SARS-CoV-2 test is not needed to be diagnosed with LC. Instead, a person’s history – for example, distinctive symptoms during acute infection or exposure to a person infected by SARS-CoV-2 – can suggest prior infection. Availability, accessibility, and varying sensitivities of testing over time meant that many people were not able to be tested when they were acutely ill. Many LC clinics and research studies, however, require laboratory evidence of infection, leading to a substantial percentage of people being excluded from them.

2)     LC can occur weeks to months after full or substantial recovery from an acute infection. Longitudinal studies and patient narratives showed that symptoms of LC do not necessarily start during or immediately after SARS-CoV-2 infection and persist unabated. Some patients report temporary remission of symptoms only to suffer symptoms returning or starting later. Thus, we do not include a specific interval after acute SARS-CoV-2 infection that symptoms must start within for them to be considered LC. 

3)     A list of the fourteen most common symptoms, such as fatigue, post-exertional malaise, cognitive difficulties, and sleep disturbances, is provided to help clinicians assess the possibility of LC. Although this list is non-exhaustive – over 200+ symptoms have been associated with LC – and no one symptom is required for LC diagnosis, absence of these symptoms would decrease the chances of a person’s illness being LC. Conversely, if a patient reports multiple symptoms on this list occurring together, their likelihood of LC increases.

4)     Symptoms must have lasted at least 3 months in total. Note that symptoms need not be present daily for the whole 3 months (see point 5). This time period allows acute SARS-CoV-2 and temporary symptoms unrelated to SARS-CoV-2 to subside (e.g., sleep issues from shift work, migraine headache episodes). Clinicians can also check for alternative diagnoses and attempt trials of treatments for these diagnoses. If a patient’s symptoms resolve completely or substantially improve with these trials, it is less likely LC is the cause.

5)     Disease trajectories can vary. Besides persisting, improving, and worsening, LC symptoms can also fluctuate, waxing and waning without going away entirely, or remit and relapse, with periods where symptoms are absent only to recur after a while.

6)     Twenty-two medical conditions commonly detected in LC patients are also listed. This list educates clinicians about the diverse ways LC patients can present so that patients affected by them can be identified as potential LC patients or, conversely, prompt clinicians to consider these diagnoses (some of which have specific, effective treatments) for their LC patients. In either case, the presence of these conditions does not necessarily exclude an LC diagnosis.

How does the NASEM LC definition impact ME/CFS care, research, and public health surveillance?

The new LC definition does not change the current NAM or other ME/CFS definitions being used in the United States for clinical care, research, public health surveillance, or assessment of accommodations/ benefits. The few sections in the report which mention ME/CFS stress that the two diagnoses are not mutually exclusive and indeed, up to 40% of LC patients may be affected by ME/CFS. Patients with LC also told the Committee some clinicians would drop their LC diagnosis once they were diagnosed with ME/CFS or other conditions like postural orthostatic tachycardia syndrome (POTS) or mast cell activation syndrome (MCAS), even if those conditions were triggered by SARS-CoV-2 infection. The non-exclusionary clause also means ME/CFS patients who developed new or experienced worsening symptoms after SARS-CoV-2 infection can qualify for a LC diagnosis.

Some people have asked me whether all ME/CFS patients diagnosed after 2019, the start of the pandemic, would be considered to have LC. My answer to that is NO. First, although a post-infectious onset is common in ME/CFS, 10 – 50% of patients experience another event directly before their onset. Some examples are pregnancy, surgery, and vaccination. Second, even with post-infectious onsets, some patients have clinical or laboratory evidence of a specific infection (e.g., oral herpes lesions, giardia stool test) that is not SARS-CoV-2.  Finally, an individual’s pre-onset symptoms or circumstances may not indicate prior SARS-CoV-2 infection.

Of course, there will be a percentage of individuals for which it is unclear if they in fact have SARS-CoV-2-triggered ME/CFS. Ideally, we will have tests or biomarkers soon that can help distinguish people suffering from LC (no matter their symptoms or conditions) from everyone else. Currently, since there are no disease-modifying treatments for LC, people with LC and ME/CFS are treated similarly as people affected by ME/CFS. Treatment involves patient education, energy conservation/ activity management techniques, alleviation of symptoms as possible, and identification of/ specific therapies for co-morbid conditions.

For research, the definition allows scientists plenty of leeway to design appropriate inclusion and exclusion criteria for their specific study. I hope that this flexibility will permit more LC patients to participate in studies, even if – for example - they do not have documentation of an acute SARS-CoV-2 infection or are affected by other medical conditions. While understandable that initial studies focused on those with laboratory documentation of infection, several studies have since indicated that those without documentation suffer similar symptoms and prognoses. One study even found that 40% of patients with chronic neurologic symptoms but without evidence of SARS-CoV-2 infection on commercial testing demonstrated infection when they were tested with more sophisticated research-based assays. This group of LC patients has been overlooked. The Committee does not control who is accepted or rejected from a study. Ultimately, it is up to a study’s investigators to devise study protocols that can best test their ideas.

How is the NASEM LC definition currently being used?

After creating the definition, the NASEM LC Committee encouraged the federal government to adopt it and made suggestions for how to go about applying the definition in clinical care, medical research, and public health activities. These recommendations are not binding, and it is up to the US government to decide whether and how to follow the recommendations. Presently, the US Centers for Disease Control and Prevention have adopted the definition for its activities and have included it on their website. Furthermore, the USA’s Long COVID Coordination Council has proclaimed its support of  the definition and in the upcoming months will be analyzing and adapting it for use in clinical settings.

What does the future hold for the NASEM LC definition?

The definition’s official name is the “2024 NASEM LC Definition”, in recognition that it is based on currently available evidence and that our knowledge of LC is evolving daily. Some people have asked why the Committee did not create a more specific definition. The answer is we could not. To do so would have resulted in a definition based on non-existent/ sparse evidence or on mere speculation. A narrow definition would result in many people not being able to receive appropriate care and might even block research progress if investigators are confined to examining only a slice of those affected.

The full report includes a section of questions/ issues which – if answered – could assist in refining the definition. Furthermore, the Committee recommended the government re-visit and possibly revise the definition in either 3 years or when new, significant findings emerge, whichever time arrives first.

YOUR TURN: What do you think of the 2024 NASEM LC definition? Are there specific features you wish had been included or excluded? Do you plan to use it? If so, how will you apply it?

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