Long COVID may be fueled by inflammation and tiny clots
Long COVID affects an estimated 65 million people worldwide and can damage the brain, heart, blood vessels, and immune system long after infection. Researchers now link symptoms to lingering virus, inflammation, micro-clots, and disrupted energy metabolism. While structured rehab and pacing can improve quality of life, a growing list of experimental treatments—from antivirals and metformin to microbiome therapies and biologics—shows early promise. Clear answers, however, are still limited by small studies and the lack of large, definitive trials.
Long COVID is defined as symptoms that last at least two months after an initial SARS-CoV-2 infection, with no other clear medical explanation. An estimated 65 million people worldwide are now affected, yet there are still no approved, evidence-based treatments. Researchers are working to better understand what drives the condition and to test a wide range of possible therapies, from structured rehabilitation programs to antivirals, blood thinners, anti-inflammatory drugs, supplements, and new biologic treatments.
Scientists believe long COVID is fueled by several overlapping biological problems. These include lingering virus in the body, ongoing low-level inflammation marked by elevated IL-1β, IL-6, and TNF-α, and the formation of tiny blood clots caused by interactions between the viral spike protein and fibrinogen. Other contributing factors include auto-immunity, disruptions in gut bacteria, and impaired mitochondrial function. Together, these processes can damage multiple organs, leading to blood vessel dysfunction, heart inflammation, neuro-inflammation, small-fiber neuropathy, ME/CFS-like fatigue, menstrual changes, problems with blood sugar regulation, and kidney or liver injury.
Rehabilitation and Non-Drug Approaches
For people with mild symptoms in the early stages, non-drug treatments remain the first option. Clinical trials show that online, group-based physical and mental rehabilitation programs can improve quality of life. Breathing exercises and inspiratory-muscle training have also been shown to boost heart and lung fitness.
Additional strategies may include pacing daily activities, cognitive and speech therapy, smell retraining, and dietary counseling. However, exercise that is not carefully supervised can worsen inflammation. For this reason, activity programs need to be gradual and adjusted based on symptoms.
Antivirals and Early Treatment Effects
Antiviral drugs taken during the initial COVID-19 infection appear to slightly reduce the risk of developing long COVID. In Japan, ensitrelvir lowered long-COVID rates by 25% among out-patients. In high-risk individuals, nirmatrelvir/ritonavir and molnupiravir were linked to about a 25% reduction in risk, while favipiravir showed little benefit. Researchers are also studying monoclonal antibodies that target the spike protein for possible effects on neuro-toxicity, although phase-3 trial results are not yet available.
Medications Targeting Specific Symptoms
Some treatments focus on particular complications such as clotting, autonomic nervous system problems, and immune imbalance. Low-dose naltrexone has been shown to reduce fatigue and lower platelet aggregation. Apheresis can remove micro-clots and auto-antibodies from the blood, but it is expensive and its benefits tend to be short-lived.
Other medications are being tested for symptom relief. β-blockers are used to treat postural-tachycardia syndrome. Famotidine, intravenous immunoglobulin, SGLT-2 inhibitors, and GLP-1 agonists are under investigation for neurological, immune-related, heart, and kidney symptoms.