Long COVID is Heterogeneous and Difficult To Treat

The term “long COVID” refers to long-lasting illness that can occur after infection with the SARS-CoV-2 virus, which causes COVID-19.[1] The illness is perplexing, variable in presentation and difficult to treat.

Symptom counts range from one to many, and their duration and severity vary. Common associated symptoms are post-exertional malaise, fatigue, cognitive challenges, headaches, lightheadedness, sleep disturbances, lung ailments, problems with taste and smell, and gastrointestinal issues. More than one organ system may be affected.

For diagnosis, there is no definitive blood or biomarker test. Long COVID may develop regardless of the severity of the initial illness and even in some people who had no COVID-19 symptoms.

Despite more than $1.7 billion of federal research commitments, there are no drug treatments. A few drugs approved for other indications are being formally evaluated for long COVID.

Defining long COVID

In July 2024 an expert committee convened by the National Academies of Sciences, Engineering, and Medicine (NASEM) defined long COVID as “an infection-associated chronic condition that occurs after SARS-CoV-2 infection and is present for at least three months as a continuous, relapsing and remitting, or progressive disease state that affects one or more organ systems.”[2]

This definition was developed after review of six previous definitions dating back to 2020 from organizations including the Centers for Disease Control and Prevention, the National Institutes of Health (NIH) and the World Health Organization. More than 1,300 individuals engaged with the NASEM committee, including patients, caregivers, researchers, clinicians and policy professionals. The definition, meant by the committee to be “intentionally inclusive” to avoid neglecting any relevant cases, may sometimes lead to overdiagnosis.

A diagnosis of long COVID does not require laboratory-confirmed proof of prior COVID-19 infection; such test results are often unavailable or unreliable. Instead, a thorough clinical assessment may be sufficient.

The NASEM definition of long COVID allows for diagnosis concurrently with other conditions. Such coexisting conditions may intensify long COVID symptoms or may be a related consequence of the COVID-19 infection. For example, case reports suggest that long COVID may be associated with progressive brain dysfunction beyond mild cognitive impairment or temporary “brain fog.”

Additionally, at least four cohort studies found that underlying autoimmune disease (for example, rheumatoid arthritis, inflammatory bowel disease, lupus and type 1 diabetes) increased the risk of long COVID or that people were more likely to develop such autoimmune diseases after recovering from COVID-19.

In addition to cognitive and autoimmune disorders, the NASEM definition lists many conditions as potential manifestations of long COVID: lung illness (shortness of breath, cough), cardiovascular disease (arrythmias, stroke), mood and anxiety disorders, kidney disease, postural orthostatic tachycardia syndrome (fast heart rate, dizziness, fatigue when standing from a lying position), chronic fatigue syndrome and fibromyalgia (widespread, chronic pain).

The NASEM committee also noted that long COVID shares many attributes with other forms of post-infection illness, such as from viruses, bacteria, and fungal and parasitic infections.

Prevalence and trajectory of long COVID

Because of the uncertain definition of long COVID, it is difficult to estimate its prevalence. Estimates from the United States made in mid-2024 indicate that 7% of adults and 1% of children have experienced long COVID (15 to 20 million people).

A November 2025 study in Nature Communications quantified the variability in symptoms after COVID-19 infection with a focus on the prevalence and severity of long COVID.[3] Study authors reviewed data from 3,659 adults participating in NIH’s Research COVID to Enhance Recovery (RECOVER) cohort study. These participants were a subset of more than 15,000 people enrolled in RECOVER as of September 2024.

The 3,659 participants were selected for the long COVID study because they were assessed three months after infection and were also assessed at least one time 6-15 months after infection. The assessment included calculation of the Long COVID Research Index (LCRI) score. The LCRI score is based on 11 symptom responses that are weighted then summed to yield a score ranging from 0 to 30, with a threshold score of 11 or more indicating long COVID.

Statistical modeling classified post-COVID patients into groupings based on the 3-15-month trajectory of their LCRI scores. Most of the participants had few and declining symptoms. For example, 49% of those assessed had limited or no symptoms, 12% had persistent symptoms but were below the threshold score for long COVID, and 5% had persistent symptoms and remained over the threshold score.

Progress in treating long COVID

At present, there are no specific treatments for long COVID.[4] In September 2025 the NIH RECOVER-Treating Long COVID (TLC) project convened experts to discuss four leading candidate drugs.[5] The candidate therapeutics were selected based on intensive, systematic prioritization initiated by more than 572 drug and nondrug treatment ideas that were crowdsourced (from patients, caregivers and scientists) from October 2024 to August 2025.

The four candidates are 1) obesity and type 2 diabetes drugs in the glucagon-like peptide-1 (GLP-1) receptor agonist class (for example, semaglutide [OZEMPIC, RYBELSUS, WEGOVY]), 2) the opioid antagonist naltrexone (VIVITROL and generics), 3) local nerve-blocking agents (for example, injectable lidocaine) and 4) the rheumatoid arthritis drug baricitinib (OLUMIANT and generics). Although these drugs are FDA approved for other indications, they are not approved for long COVID.

Despite federal investments in long COVID research of more than $1.7 billion, some patient advocates have asserted that progress developing therapies has been too slow. Leaders of the RECOVER-TLC project have said that finding treatments for long COVID is complicated because the underlying causes of the condition remain uncertain.

What You Can Do

If you have had COVID-19 and are experiencing any symptoms you think might be long COVID, consult with your clinician to see if a diagnostic workup is warranted to rule out other causes of your illness and to consider approaches to your symptoms and any related illnesses. In some cases, a multi-disciplinary approach involving more than one medical specialist may be needed. Keep in mind that the FDA has not approved any pharmaceutical treatments for long COVID; all of the proposed treatments are investigational.[6]

Prevention of COVID-19 with vaccination, social distancing and taking precautions against respiratory virus infections are important means to guarding against long COVID. For example, vaccination against COVID-19 reduces the risk of developing long COVID even if a breakthrough infection occurs, according to an observational study published in the New England Journal of Medicine in 2024.[7]
 

References

[1] Ely EW, Brown LM, Fineberg HV; National Academies of Sciences, Engineering, and Medicine Committee on Examining the Working Definition for Long Covid. Long covid defined. N Engl J Med. 2024;391(18):1746-1753.

[2] Ibid.

[3] Thaweethai T, Donohue SE, Martin JN, et al. Long COVID trajectories in the prospectively followed RECOVER-Adult US cohort. Nat Commun. 2025;16(1):9557.

[4] Boden S. Long-covid patients are frustrated that federal research hasn’t found new treatments. KFF Health News. January 22, 2025.

[5] Geerling E. Beigel J. RECOVER-TLC agent prioritization. ROVER-treating long covid (TLC), 2nd annual workshop – pathways to treatment. September 9-10, 2025. https://www.youtube.com/watch?v=kN0JbcUSL5c&list=PLqByiC0rX0ZPNYnGnFgBQzaR71VcOkys_&index=8. Accessed November 28, 2025.

[6] Mikkelsen ME, Abramoff B. COVID-19: management of adults with persistent symptoms following acute illness (“long COVID”). UpToDate. August 8, 2025.

[7] Xie Y, Choi T, Al-Aly Z. Postacute Sequelae of SARS-CoV-2 Infection in the Pre-Delta, Delta, and Omicron Eras. N Engl J Med. 2024 Aug 8;391(6):515-525.