Long COVID Research Update: Causes, Treatments, and NIH RECOVER Trial 2026

What Causes Long COVID?

Research into the pathophysiology of long COVID has identified several leading hypotheses, which are not mutually exclusive and likely contribute to the heterogeneous clinical presentation of the condition. Viral persistence — the continued presence of SARS-CoV-2 RNA or spike protein in tissue reservoirs such as the gut, lymph nodes, brain, and other organs — has been documented in multiple studies. A 2022 study in Nature found SARS-CoV-2 RNA in intestinal tissue biopsies of patients months after acute infection, and spike protein has been detected in blood monocytes up to 15 months post-infection. This persistent viral antigen may drive ongoing immune activation and tissue inflammation.

Immune dysregulation is another key mechanism. Studies have documented elevated levels of pro-inflammatory cytokines (including IL-6, TNF-alpha, and interferon-gamma), exhausted T cells, and autoantibody formation in long COVID patients. A landmark study published in Science in 2022 identified reduced cortisol levels and elevated levels of exhausted T cells as distinguishing features of long COVID. Reactivation of latent herpesviruses, particularly Epstein-Barr virus (EBV) and human herpesvirus 6 (HHV-6), has been observed in a significant proportion of long COVID patients and may contribute to fatigue and neurological symptoms.

Microvascular dysfunction and microclot formation represent a third major pathway. Research led by Resia Pretorius at Stellenbosch University identified anomalous amyloid fibrinogen microclots in blood samples from long COVID patients that are resistant to fibrinolysis (the body's normal clot-dissolving process). These microclots can impair oxygen delivery to tissues and may underlie symptoms such as exercise intolerance, brain fog, and fatigue. Endothelial dysfunction — damage to the cells lining blood vessels — has also been consistently documented and may contribute to the multi-organ nature of long COVID symptoms. Complement activation and serotonin depletion have been identified in more recent studies as additional contributing mechanisms.

What Is the NIH RECOVER Initiative?

The Researching COVID to Enhance Recovery (RECOVER) Initiative, launched by the National Institutes of Health in 2021 with $1.15 billion in funding from Congress, is the largest and most comprehensive study of long COVID in the United States. The initiative spans more than 200 research sites across the country and has enrolled over 24,000 adult, pediatric, and pregnant participants in both observational cohorts and randomized clinical trials. RECOVER aims to understand who develops long COVID, the underlying biological mechanisms, and which treatments are effective.

The RECOVER observational study, published in JAMA in May 2023, used data from over 9,700 participants to develop a scoring system identifying 12 symptoms most strongly associated with long COVID: post-exertional malaise, fatigue, brain fog, dizziness, gastrointestinal symptoms, heart palpitations, changes in sexual desire or capacity, loss of or change in smell or taste, thirst, chronic cough, chest pain, and abnormal movements. The study identified four distinct symptom clusters, suggesting that long COVID may represent multiple sub-conditions requiring different treatment approaches.

RECOVER's platform clinical trials, which began enrolling participants in 2023, are testing multiple interventions simultaneously. The RECOVER-VITAL trial is evaluating Paxlovid (nirmatrelvir/ritonavir) for 25 days as an antiviral approach targeting potential viral persistence. The RECOVER-NEURO trial is testing cognitive behavioral approaches and brain training for neurological symptoms. The RECOVER-SLEEP trial is evaluating interventions for sleep disturbances. Additional trials are investigating exercise protocols, metformin, and other interventions. While RECOVER has faced criticism for its pace — with some patient advocates noting that results have been slow to emerge relative to the urgency of the problem — the initiative represents the most systematic effort to date to identify evidence-based treatments for long COVID.

What Treatments Are Being Studied for Long COVID?

Paxlovid (nirmatrelvir/ritonavir), Pfizer's oral antiviral treatment for acute COVID-19, is being investigated as a potential long COVID treatment based on the viral persistence hypothesis. The rationale is that if residual virus in tissue reservoirs drives ongoing symptoms, an extended course of antiviral therapy might clear the reservoir and resolve symptoms. The RECOVER-VITAL trial is testing a 25-day course of Paxlovid in long COVID patients. Preliminary results from the STOP-PASC trial at Stanford (a smaller, independent study) suggested modest but not statistically significant benefits, and the larger RECOVER trial results are anticipated to provide more definitive evidence.

Metformin, the widely used diabetes medication, has shown promise as a preventive measure. A randomized controlled trial published in The Lancet Infectious Diseases in 2023 (the COVID-OUT trial, led by Carolyn Bramante at the University of Minnesota) found that a 14-day course of metformin started within the first few days of acute COVID-19 reduced the incidence of long COVID by approximately 41% over 10 months of follow-up. The mechanism may involve metformin's anti-inflammatory effects, its ability to reduce viral replication (demonstrated in vitro), or its metabolic benefits. Studies evaluating metformin as a treatment (rather than prevention) for established long COVID are underway.

Other investigational approaches include low-dose naltrexone (LDN), which has shown preliminary benefit for fatigue and pain in small studies, likely through modulation of neuroinflammation and the innate immune system. Anticoagulant and antiplatelet therapies are being explored based on the microclot hypothesis, though these carry bleeding risks and require careful evaluation in clinical trials. For specific symptom management, structured pacing and rehabilitation programs remain the cornerstone of care, particularly for patients with post-exertional malaise. Autonomic dysfunction (including postural orthostatic tachycardia syndrome, or POTS, which affects many long COVID patients) is managed with standard POTS therapies including increased fluid and salt intake, compression garments, and medications such as fludrocortisone or midodrine.