Long COVID, formally known as Post-Acute Sequelae of SARS-CoV-2 infection (PASC), is a complex, multi-system chronic condition that can affect individuals regardless of the severity of their initial illness. Defined as symptoms persisting for at least three months after the initial infection, Long COVID presents a wide array of debilitating issues, including extreme fatigue, cognitive dysfunction (often called “brain fog”), and cardiorespiratory problems. Research is rapidly advancing to understand the underlying biology and develop effective treatments for the millions of people affected worldwide. Current developments focus on identifying objective biomarkers, testing repurposed and novel therapies, and integrating the condition into public health systems for better management.
Current Understanding of Biological Drivers
The scientific consensus suggests that Long COVID is caused by a combination of persistent issues stemming from the initial infection, not a single factor. One leading theory involves viral persistence, where fragments or whole SARS-CoV-2 virus particles remain in “reservoirs” within the body’s tissues, such as the gut or brain. Research has detected viral RNA in the gastrointestinal tissue of some patients many months following the initial infection. This persistence may continuously provoke the immune system and lead to chronic inflammation.
The body’s misdirected immune response, known as autoimmunity, is another driver of persistent symptoms. Following the infection, some individuals develop autoantibodies, which are proteins that mistakenly target and attack the body’s own cells and tissues. These autoantibodies can interfere with the nervous system. This interference potentially contributes to conditions like Postural Orthostatic Tachycardia Syndrome (POTS), a form of autonomic nervous system dysfunction common in Long COVID patients.
Investigation also focuses on blood abnormalities, specifically the presence of microclots and endothelial dysfunction. Microclots are tiny, fibrin-based clots that resist the body’s natural process for breaking them down, potentially impairing oxygen delivery to tissues throughout the body. The formation of these clots is often linked to damage to the endothelial cells that line blood vessels, a condition called endotheliitis. This damage contributes to poor blood flow and inflammation.
Underlying all these mechanisms is chronic, low-grade inflammation that persists long after the virus has been cleared from most systems. Studies have identified distinct patterns of sustained immune activation, including the overactivation of the complement system and inflammation of myeloid cells. This ongoing inflammatory process can affect the central nervous system. It is thought to be the common pathway resulting in the diverse range of symptoms, such as fatigue and pain, experienced by patients.
Advances in Diagnosis and Biomarkers
Currently, a diagnosis of Long COVID relies primarily on the presence of persistent symptoms and is often a clinical diagnosis of exclusion, meaning other conditions must be ruled out first. Researchers are working to move beyond this symptom-based approach by identifying objective biological markers, or biomarkers. These biomarkers can confirm the condition and potentially differentiate between its various subtypes, which is necessary to accurately diagnose and tailor treatments.
Recent studies use advanced techniques like proteomic and immune profiling to compare the blood of Long COVID patients with that of fully recovered individuals. One analysis found a distinct signature in patients with breathlessness, including elevated plasma markers related to inflammation, cell death, and platelet activation. Research is also investigating specific immune cell profiles. Restrained memory CD8+ T cell responses appear to be a more reliable indicator than traditional viral antigen detection methods.
The use of “omics” technologies, including metabolomics, proteomics, and lipidomics, is instrumental in mapping the molecular changes associated with the condition. This molecular scrutiny aims to reveal specific metabolic alterations and immune dysregulations that could serve as measurable diagnostic tools. Although no single, widely accepted biomarker test is available yet, identifying these distinct molecular signatures is paving the way for future blood-based diagnostics.
Emerging Therapies and Clinical Trials
The search for effective interventions focuses on addressing the underlying biological drivers of Long COVID through pharmacological and non-pharmacological approaches. A major effort is underway to test repurposed drugs that target proposed mechanisms, such as viral persistence and chronic inflammation. For instance, the antiviral drug nirmatrelvir/ritonavir, used for acute infection, is being studied for its potential to reduce Long COVID symptoms by clearing persistent viral reservoirs.
Immunomodulatory agents are also a focus, including drugs like baricitinib, which is being tested in patients exhibiting immune dysregulation and chronic inflammation. For neurological and cognitive symptoms, several drugs originally used for other conditions are showing promise in smaller studies. These include low-dose naltrexone, which possesses anti-inflammatory properties, and low-dose aripiprazole (Abilify), suggested to help with cognitive issues like brain fog.
The National Institutes of Health (NIH) launched the RECOVER-TLC initiative, shifting toward conducting numerous clinical trials for potential treatments. These trials investigate treatments for burdensome symptoms, such as sleep disturbances and the extreme worsening of symptoms after physical or mental effort, known as Post-Exertional Malaise (PEM). Non-pharmacological strategies are also a significant part of the treatment landscape, with specialized rehabilitation programs focusing on pacing strategies to manage PEM.
Global and Policy Updates on Management
Long COVID represents a substantial global health burden, with an estimated pooled worldwide prevalence of 36% among COVID-19 survivors. The condition poses a significant challenge to public health systems and economies globally. The number of affected individuals has necessitated a systemic response from governments and international bodies.
The National Academies of Sciences, Engineering, and Medicine in the US developed a clearer definition of Long COVID in 2024 to aid clinicians and researchers. Globally, a survey of healthcare professionals from 110 countries revealed that approximately half of the institutions surveyed had established dedicated Long COVID clinics. However, the study highlighted considerable variation in management practices, diagnostic tests, and access to multidisciplinary care based on geographic region and national income levels.
Public health recommendations emphasize the protective effect of vaccination, which has been shown to reduce the likelihood of developing Long COVID. Policies are being developed to address the societal impact, particularly concerning disability recognition and employment accommodations. These efforts reflect the understanding that managing Long COVID requires not just medical treatment but also robust societal and institutional support.