How virus persistence and immune deficiency lead to long COVID disease

New research shows how persistent viral activity and immune dysfunction contribute to long COVID infection and suggests novel therapeutic strategies that could change the course of treatment for millions of people.

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

A study recently 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 have long-term health effects. Although self-limiting in most people, some infected individuals experience post-acute sequelae, including fatigue, cognitive dysfunction, and muscle weakness, among others. People with a history of mild or moderate infection with acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are more likely to have severe COVID-19 disease, but have the highest burden.

The World Health Organization (WHO) defines a post-COVID-19 condition as unexplained symptoms lasting ≥ two months and manifesting ≥ three months after SARS-CoV-2 infection. While many countries have adopted this definition, some have formulated their own definitions. The patient community that first identified the disease prefers the term “long COVID.”

Overall, definitions vary in the time scale at which the disease is defined and whether the disease is limited to unexplained patient-reported symptoms or includes medical events/laboratory abnormalities. The present study examined the epidemiology of long-COVID, with a focus on how the underlying mechanisms explain the physiology. Additionally, the study highlights how symptom clusters identified through techniques such as cluster analysis in electronic health records (EHR) could improve long-term COVID diagnosis by linking specific biological drivers to clinical endotypes.

Epidemiology and clinical features of long COVID

There are differences in epidemiological estimates of long COVID depending on variant, population and region. Some studies suggest a prevalence of 30% or more, but define the syndrome as new unexplained symptoms that could lead to misclassification. Not all symptoms may be related to SARS-CoV-2; other conditions must therefore be excluded. Determining what is new after infection and what could lead to the discovery of subclinical or preclinical disease is a major challenge.

In addition, SARS-CoV-2 is not the only virus that is associated with long-term symptoms. Studies have estimated that 18 million adults in the United States (US) may have long COVID. The WHO and the Institute for Health Metrics and Evaluation estimated that one in 30 Europeans had long-COVID in the first three years of the COVID-19 pandemic. An estimated 65 million people worldwide suffer from Long COVID.

In particular, the epidemiology of severe, disabling long-term COVID-19 disease is unknown. Long COVID can manifest during or weeks after the acute infection. Cognitive problems, fatigue and post-exertional symptoms are the most common. Additionally, clustering symptoms based on organ systems, such as: B. autonomic dysfunction, neurocognitive impairment and exercise intolerance, a more precise understanding of the long COVID phenotypes. Additionally, many symptoms of Long COVID overlap with those of other infection-associated chronic diseases (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 disruptions in the coagulation system and immunity, which do not directly cause disease but rather drive each other, leading to downstream physiological changes that manifest as symptoms. Some of these biological processes, such as blood clotting and immune deficiency, can interact to create a cycle of chronic inflammation and tissue damage. Microclots resistant to fibrinolysis have been demonstrated in Long COVID patients and may contribute to tissue hypoxia and organ dysfunction. There are also links between viral activity during infection and the risk of long COVID infection, with higher viral replication associated with more severe disease.

The long COVID risk appears to be lower with Omicron variants. The protective effects of antiviral therapy and vaccination suggest that viral replication and transmission during the acute phase is a major determinant of long-term outcomes. Therefore, early COVID-19 interventions could mitigate long COVID-19 infection and support the pursuit of a robust prevention agenda.

At the beginning of the pandemic, it was generally assumed that the SARS-CoV-2 infection would be temporary; However, this has been called into question by reports that viral proteins and nucleic acids could be detected months after infection. Although the exact anatomical site of viral persistence is unclear, there is consensus that persistence is tissue-related. Various studies have linked immune deficiency and inflammation to long COVID.

Many studies have focused on the role of inflammatory macrophages and monocytes in long COVID. Mast cell activation could also contribute to long COVID. Although not infected with 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 diseases such as lupus, Sjögren's syndrome, inflammatory bowel disease and rheumatoid arthritis.

Acute SARS-CoV-2 infection can lead to a hypercoagulable state and increase the risk of thromboembolic events. Interactions between the spike protein and fibrinogen can lead to abnormal blood clots, which can trigger microglial activation in the brain and potentially contribute to neurocognitive symptoms of long-COVID. Clotting is 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 triggered during the (initial) infection. Pancreatic infection by SARS-CoV-2 has been associated with post-COVID-19 diabetes, another form of post-acute sequelae, providing proof of principle. Endothelial dysfunction has been suggested to play a role in long-COVID.

Different mechanisms could lead to endotheliitis and macrovascular diseases, and their end-organ consequences could lead to long-COVID. Additionally, the study suggests that microclots and endothelial dysfunction may impair tissue perfusion, lead to organ damage, and contribute to persistent symptoms such as fatigue and cognitive problems. Disruption of the gut-brain axis allows for a direct link between post-COVID-19 processes and disruption of normal physiology, including brain fog, autonomic dysfunction, and abnormal stress responses.

brain fog, ieMemory, concentration and attention problems are among the most debilitating manifestations of long COVID. It has been a noticeable symptom in non-hospitalized patients since the beginning of the pandemic. Some people, particularly those with diabetes, learning and attention disorders, and substance use disorders, are predisposed to developing brain fog. People with brain fog are more likely to have abnormal cerebrospinal fluid levels.

Concluding remarks

The COVID-19 pandemic has been described as a once-in-a-century challenge, with Long-COVID posing a challenge of similar magnitude. Although Long-COVID is not the first known IACC, it is the first time such a disease has manifested itself in a significantly large number of people following a common, known exposure. New therapies, including antiviral drugs such as nirmatrelvir/ritonavir and immunomodulators that target inflammatory pathways, are currently being investigated in clinical trials as potential treatments for long-COVID. Therefore, there is an urgent need for all types of research (basic, epidemiological, translational, and clinical and implementation sciences) on the natural history, biology, and treatment of long-COVID.