New research reveals how lingering viral activity and immune disruption contribute to long COVID, highlighting novel therapeutic strategies that could change the course of treatment for millions.

Proposed framework for defining PASC. Review: Mechanisms of long COVID and the path toward therapeutics

A recent study published in the journal Cell reviewed the current state of knowledge on the pathophysiology and biology of long COVID.

Coronavirus disease 2019 (COVID-19) can affect health over the long term. Although it is self-limited in most individuals, some infected individuals experience post-acute sequelae, including fatigue, cognitive dysfunction, and muscle weakness, among others. While more common after severe COVID-19, individuals with a history of mild or moderate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have the highest burden.

The World Health Organization (WHO) defines post-COVID-19 condition as unexplained symptoms persisting ≥ two months that manifest ≥ three months after SARS-CoV-2 infection. Further, while many countries have adopted this definition, several have formulated their own definitions. The patient community that first identified the condition prefers the term long COVID.

Overall, the definitions vary in the time scale on which the condition is defined and whether the condition is restricted to unexplained patient-reported symptoms or inclusive of incident medical diagnoses/laboratory abnormalities. The present study reviewed the epidemiology of long COVID, with emphasis on how the underlying mechanisms explain the physiology. Additionally, the study highlights how symptom clusters, identified through techniques like cluster analysis in electronic health records (EHR), could improve long COVID diagnosis by linking specific biological drivers to clinical endotypes.

Epidemiology and clinical features of long COVID

There are variations in epidemiological estimates of long COVID across variants, populations, and regions. Some studies suggest a prevalence of 30% or higher but define the syndrome as new unexplained symptoms, which might lead to misclassification. Not all symptoms may be related to SARS-CoV-2; as such, other conditions must be ruled out. Determining what is new after infection and what might be unmasking of sub- or pre-clinical conditions is a significant challenge.

Further, SARS-CoV-2 is not the only virus associated with protracted symptoms. Studies have estimated that 18 million adults in the United States (US) might suffer from long COVID. The WHO and the Institute for Health Metrics and Evaluation estimated that one in 30 European individuals had long COVID in the first three years of the COVID-19 pandemic. Globally, an estimated 65 million individuals have long COVID.

Notably, the epidemiology of severe, disabling long COVID-19 is unknown. Long COVID can manifest during or weeks after the acute infection. Cognitive problems, fatigue, and post-exertional symptoms are the most common. In addition, symptom clustering based on organ systems, such as autonomic dysfunction, neurocognitive impairment, and exercise intolerance, offers a more precise understanding of long COVID phenotypes. Further, many symptoms of long COVID overlap with those of other infection-associated chronic conditions (IACCs), such as chronic Lyme disease, post-Ebola disease, post-Giardiasis, and myalgic encephalitis/chronic fatigue syndrome, among others.

Biological drivers of long COVID

The biological drivers of long COVID are upstream processes, such as perturbations of the coagulation system and immunity, which do not directly cause disease but instead drive one another, leading to downstream physiological changes that manifest as symptoms. Some of these biological processes, like clotting and immune dysfunction, may interact, creating a cycle of chronic inflammation and tissue damage. Microclots, resistant to fibrinolysis, have been detected in long COVID patients and may contribute to tissue hypoxia and organ dysfunction. There are also associations between viral activity levels during infection and long COVID risk, with higher viral replication linked to more severe illness.

Long COVID risk appears to be lower with Omicron variants. The protective effect of antiviral therapy and vaccination suggests that viral replication and transmission during the acute phase is a significant determinant of long-term outcomes. Therefore, early COVID-19 interventions could mitigate long COVID and support pursuing robust preventive agenda.

Early in the pandemic, it was commonly assumed that SARS-CoV-2 infection would be transient; however, this was challenged by reports that viral proteins and nucleic acids could be detected months after infection. Although the precise anatomic site of viral persistence is unclear, there is consensus that persistence is tissue-backed. Various studies have linked immune dysfunction and inflammation with long COVID.

Many studies have focused on the role of inflammatory macrophages and monocytes in long COVID. Mast cell activation might also contribute to long COVID. Although not infected by SARS-CoV-2, external triggers can activate mast cells. Severe COVID-19 is also associated with autoimmunity. COVID-19 is also associated with a higher incidence of autoimmune conditions, such as lupus, Sjogren’s syndrome, inflammatory bowel disease, and rheumatoid arthritis.

Acute SARS-CoV-2 infection can lead to a hypercoagulable state and elevate the risk of thromboembolic events. Interactions between the spike protein and fibrinogen may result in abnormal clots that can trigger microglia activation in the brain, potentially contributing to neurocognitive symptoms of long COVID.  Clotting has been implicated as a long COVID mechanism, with aggregates of platelets and clotting proteins detected in affected individuals.

Clinical physiology of long COVID

The most efficient explanation for long COVID is tissue damage mediated by SARS-CoV-2 that was initiated during (initial) infection. Pancreatic infection by SARS-CoV-2 has been implicated in post-COVID-19 diabetes, another form of the post-acute sequelae, offering proof of principle. Endothelial dysfunction has been suggested to be involved in long COVID.

Various mechanisms might lead to endothelitis and macrovascular diseases, and their end-organ consequences could result in long COVID. Additionally, the study suggests that microclots and endothelial dysfunction could impair tissue perfusion, leading to organ damage and contributing to persistent symptoms such as fatigue and cognitive issues. Disruption of the gut-brain axis enables a direct connection between post-COVID-19 processes and disruption of normal physiology, including brain fog, autonomic dysfunction, and abnormal stress responses.

Brain fog, i.e., problems with memory, concentration, and attention, is among the most debilitating manifestations of long COVID. It has been a prominent symptom among non-hospitalized patients since the early pandemic. Some people, especially those with diabetes, learning and attention disorders, and substance, have a predisposition for developing brain fog. Individuals with brain fog are more likely to have abnormal cerebrospinal fluid measures.

Concluding remarks

The COVID-19 pandemic has been described as a once-in-a-century challenge, with long COVID representing a challenge of similar scale. Although long COVID is not the first known IACC, it is the first time that such a condition has manifested in a substantially large number of people following a shared, known exposure. Emerging therapies, including antivirals like nirmatrelvir/ritonavir and immunomodulators targeting inflammatory pathways, are currently being explored in clinical trials as potential treatments for long COVID. As such, there is an urgent need for all types of research (basic, epidemiological, translational, and clinical and implementation sciences) into the natural history, biology, and treatment for long COVID.