The condition known as Long COVID, or Post-Acute Sequelae of COVID-19 (PASC), affects many individuals weeks or months after the initial SARS-CoV-2 infection has cleared. This multi-system condition involves persistent symptoms, including profound fatigue, cognitive impairment (“brain fog”), and shortness of breath. Evidence points toward sustained, chronic inflammation as the primary biological mechanism driving these long-term effects. Research suggests that rather than an active, replicating infection, an ongoing, aberrant immune response sustains the pathology, transforming the acute viral illness into a protracted syndrome.
Defining Chronic Immune Dysregulation in Long COVID
The immune system’s response to infection typically follows a pattern of acute activation, defense, and then a return to homeostasis. In Long COVID, this process is interrupted, leading to chronic immune dysregulation where the inflammatory response fails to fully switch off. This chronic state is characterized by persistent, low-grade activation that slowly damages tissues throughout the body.
This dysregulation involves the continuous abnormal signaling of small proteins called cytokines, which function as immune system messengers. Pro-inflammatory cytokines like Interleukin-6 (IL-6) and Tumor Necrosis Factor-alpha (TNF-α) remain elevated for months in Long COVID, perpetuating a systemic inflammatory state. This continued release keeps various immune cells activated, contributing to the widespread systemic issues that define the syndrome.
Persistent activation is also marked by an uncoordinated adaptive immune response, including T-cell dysfunction and exhaustion. T-cells, responsible for long-term immune memory, show signs of abnormal behavior and depletion. The failure to restore proper balance allows inflammation to persist. Furthermore, sustained activation can lead to inappropriate activation of the complement system, which contributes to tissue damage when overactive.
Underlying Biological Drivers of Persistent Inflammation
The question of why inflammation continues after the virus is largely gone centers on three biological hypotheses. One theory involves the presence of a viral reservoir or persistence of viral remnants in certain tissues. Low levels of SARS-CoV-2 genetic material or proteins, particularly the Spike protein, have been detected in sites like the gut mucosa or lymph nodes months after recovery. This persistent presence provides a continuous, low-level stimulus to the immune system, preventing the inflammatory response from fully resolving.
A second driver is the development of autoimmunity, where the immune system mistakenly attacks its own tissues. SARS-CoV-2 infection can trigger the production of autoantibodies that target the host’s own proteins and cells, including components of the nervous system or blood vessels. This erroneous attack is often initiated through molecular mimicry, where a viral protein closely resembles a human protein, causing the immune system to turn its attack inward.
The third factor involves the reactivation of common latent viruses, most notably the Epstein-Barr Virus (EBV). The strain placed on the immune system during the initial SARS-CoV-2 infection can lead to temporary dysregulation. This allows previously quiescent viruses like EBV or Varicella Zoster Virus (VZV) to reactivate, adding a secondary source of inflammation. EBV reactivation has been associated with the development of fatigue and neurocognitive dysfunction, suggesting the initial viral insult perpetuates the inflammatory cycle.
Measuring Inflammation and Systemic Manifestations
The presence of chronic inflammation in Long COVID is measurable through specific biomarkers found in the blood. Acute-phase reactants, such as C-Reactive Protein (CRP), are often elevated, indicating generalized systemic inflammation, though these elevations can sometimes be subtle. More specific evidence comes from the persistent elevation of pro-inflammatory cytokines, which sustain the inflammatory cascade.
Chronic inflammation also manifests as an increase in specific autoantibodies and markers of endothelial damage. Activation of the complement system is frequently observed, suggesting an ongoing attack on the body’s own structures. Patients with neurological symptoms often exhibit elevated levels of neurofilament light chain (NFL) and glial fibrillary acidic protein (GFAP), which are markers of neuronal and glial cell damage. These measurable biological signals provide objective evidence of the underlying disease process.
The systemic nature of this inflammation explains the diverse symptoms experienced by patients. Neuroinflammation, or inflammation within the central nervous system, is linked to the cognitive issues, fatigue, and “brain fog.” This inflammation can disrupt normal neural communication and impair brain function.
Endothelial inflammation affects the inner lining of blood vessels, leading to vascular dysfunction. This can result in the formation of microclots, which impede oxygen delivery and contribute to organ issues. Inflammation affecting the autonomic nervous system can result in symptoms similar to Postural Orthostatic Tachycardia Syndrome (POTS), characterized by lightheadedness and rapid heart rate.
Current Anti-Inflammatory and Immunomodulatory Strategies
Current research focuses on therapeutic strategies that aim to interrupt this persistent inflammatory cycle. Targeted anti-inflammatory drugs are being explored by repurposing existing medications with immune-modulating effects. Low-dose naltrexone (LDN) is used in some cases to reduce the activity of pro-inflammatory immune cells and alleviate symptoms like fatigue and pain. Mast cell stabilizers are also under investigation, as mast cells, which release inflammatory mediators, may be overly active in Long COVID.
Other medications are being studied for their anti-inflammatory properties, such as statins, which reduce systemic inflammation beyond cholesterol-lowering effects. Repurposed antiviral medications, such as metformin, have shown promise in reducing the risk of developing Long COVID symptoms when administered early. Clinical trials are assessing the efficacy of these agents, including JAK inhibitors and IL-6 blockers, which target specific cytokine signaling pathways to dampen the immune response.
More intensive immunomodulatory treatments are used for severe cases, including therapies that filter the blood. Procedures like therapeutic plasma exchange or apheresis aim to remove circulating inflammatory molecules, autoantibodies, and microclots from the bloodstream. Intravenous immunoglobulin (IVIG) is also being investigated for its potential to neutralize pathogenic autoantibodies and modulate the dysfunctional immune system. Supportive strategies like activity pacing and dietary interventions rich in anti-inflammatory components are utilized to help reduce the overall burden of systemic inflammation.