Understanding of Long COVID rapidly evolves as research sheds new light on this complex condition. Initially recognized by persistent symptoms, Long COVID is now the subject of deeper scientific inquiry into its underlying mechanisms. This dynamic field integrates new findings to refine diagnosis, treatment, and public health responses.
Evolving Understanding of Symptoms and Causes
Initial observations of Long COVID identified broad symptom clusters, including profound fatigue, cognitive dysfunction often described as “brain fog,” and persistent respiratory issues like shortness of breath. Recent research is refining this understanding, revealing distinct symptom patterns in different age groups. For instance, a RECOVER study published in JAMA Pediatrics in June 2025 found that Long COVID symptoms in young children (0-5 years old) differ significantly from those in older children and adults. Infants and toddlers with Long COVID were more likely to experience trouble sleeping, fussiness, poor appetite, stuffy nose, and cough, while preschoolers commonly presented with a dry cough and daytime tiredness.
Scientists are investigating several hypotheses regarding Long COVID’s root causes. One theory centers on persistent viral reservoirs, where SARS-CoV-2 fragments or proteins linger in tissues, driving inflammation and symptoms.
Another focus is immune system dysregulation, including potential autoimmunity. This involves the immune system mistakenly attacking its own healthy cells and tissues, observed in some patients.
Microclot formation in small blood vessels is also gaining attention. These tiny clots can impair blood flow and oxygen delivery to tissues, contributing to widespread symptoms like fatigue and organ dysfunction. Nervous system disruption, including neuroinflammation and autonomic nervous system dysfunction, is explored as a cause for neurological symptoms like brain fog, headaches, and heart rate regulation issues. These interwoven mechanisms highlight Long COVID as a multisystem disorder, rather than a single disease.
Advances in Diagnostics and Treatment
The absence of a definitive diagnostic test for Long COVID has historically complicated diagnosis, often relying on symptom-based criteria. However, progress is being made in identifying reliable biomarkers for objective diagnostic tools.
Researchers at Lawson Health Research Institute identified unique biomarkers in the blood of Long COVID patients, specifically 14 elevated markers associated with blood vessel changes. Two of these, ANG-1 and P-SEL, showed high accuracy (96%) in classifying Long COVID, paving the way for a potential blood test. Similarly, Karolinska Institutet researchers identified blood proteins linked to severe respiratory problems in Long COVID patients, suggesting a biomarker pattern tied to inflammatory pathways and lung damage. These discoveries aim to provide precise diagnosis and potentially monitor treatment effectiveness.
Treatment strategies are evolving based on these insights into Long COVID’s underlying causes. Therapeutic approaches are categorized and tested in clinical trials. Antivirals like nirmatrelvir-ritonavir (Paxlovid) are investigated to address persistent viral reservoirs, with some studies showing promising results in reducing neurodamage markers and predicting clinical recovery. Immune-modulating drugs are also under evaluation to correct immune dysregulation or autoimmune responses.
For microclot formation, anticoagulants and antiplatelet therapies are explored, with some small studies suggesting symptom improvement and a decrease in microclots. Specialized rehabilitation programs remain a cornerstone of management, particularly for symptoms like post-exertional malaise (PEM), where pacing activities help manage energy levels. Other rehabilitative efforts include pulmonary rehabilitation for breathing difficulties and cognitive therapies, such as Constraint-Induced Cognitive Therapy, which has shown improvements in brain fog.
Recent Clinical Trial and Research Highlights
Large-scale research efforts are providing important insights into Long COVID. The National Institutes of Health (NIH) RECOVER (Researching COVID to Enhance Recovery) Initiative coordinates comprehensive studies to understand, treat, and prevent the condition. This initiative has enrolled nearly 90,000 adults and children in observational studies and initiated multiple clinical trials. One notable finding from RECOVER’s observational studies indicated that adults who had COVID-19 were significantly more likely to develop Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) compared to those who did not. Approximately 4.5% of study participants with a history of COVID-19 later developed ME/CFS, compared to 0.6% in the non-COVID group.
The RECOVER Initiative launched phase 2 clinical trials in 2023, evaluating multiple potential treatments simultaneously. These trials focus on some of the most burdensome symptoms reported by patients, including sleep pattern changes and excessive daytime sleepiness, with studies testing wakefulness-promoting drugs and other interventions to improve sleep quality. These efforts underscore a shift towards targeted interventions based on emerging scientific understanding.
Public Health and Policy Updates
Governments and public health bodies increasingly recognize Long COVID as a long-term public health challenge, leading to significant policy developments. In the United States, the Department of Health and Human Services (HHS) launched its “Long COVID as a Disability” webpage in March 2024, providing information on civil rights protections for individuals whose Long COVID substantially limits major life activities. This was reinforced by technical guidance issued by the Social Security Administration in June 2023 for healthcare providers evaluating disability claims related to Long COVID.
The U.S. government established the Office of Long COVID Research and Practice within HHS in July 2023, aiming to enhance coordinated efforts across federal agencies to improve the lives of affected individuals. This office supports research and outlines federally funded services available for those experiencing long-term effects of COVID-19. Globally, countries like New Zealand have established dedicated Long COVID programs to develop clinical guidance and fund research, with a focus on ensuring equitable access to services. Concerns remain, however, regarding the sustainability and quality of specialized Long COVID clinics, with reports from the UK indicating closures despite allocated funding, highlighting the ongoing need for comprehensive national strategies.