Buonsenso reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.

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The excessive production of proinflammatory cytokines may drive the symptoms of long COVID due to a genetic predisposition toward an inability to completely clear the virus, according to a review published in Allergy and Asthma Proceedings.

This model could be used to improve diagnostic and therapeutic procedures, Danilo Buonsenso, MD, of the department of woman and child health and public health at Fondazione Policlinico Universitaro A. Gemelli Istituti di Ricovero e Cura a Carattere Scientifico in Rome, and colleagues wrote.

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Long-term effects of COVID-19

The researchers reviewed literature about long COVID published in public databases between 2019 and 2022, identifying more than 50 long-term effects from SARS-CoV-2 infection.

The most common effect was fatigue. Shortness of breath, cough and joint and chest pain in addition to problems with thought processes, difficulty concentrating, forgetfulness, depression, muscle pain, headache, rapid heartbeat and fever also were reported.

These symptoms can last from weeks to months after COVID-19, according to the researchers, with as many as 30% of patients experiencing at least one symptom and lingering effects after 3 months. Frequency ranged from 10% to 87% of COVID-19 cases.

There was a strong female prevalence which, according to the researchers, may be due to the greater type I interferon production among women with viral infections compared with men, which may benefit women early in infections but later lead to a more persistent deleterious inflammatory state common to long COVID.

The researchers also noted more than five early symptoms among the risk factors for long COVID, including early dyspnea, previous psychiatric disorders and specific biomarkers. The researchers also associated increased BMI, asthma and advanced age with persistent inflammation.

Hypothesis-driven model of viral persistence

According to the hypothesis-driven model developed by the researchers, instead of a typical immune response, some patients experience a dysfunctional response where virus persistence leads to an excessive release of proinflammatory cytokines in a phenomenon known as a cytokine storm, causing local and systemic tissue injury. This failure to eliminate the pathogen followed by its persistence results in the immunopathologic sequelae of chronic microbial infection and the pathogenesis of long COVID.

When the virus evades the immune system’s response, it continues to stimulate the innate and adaptive immune systems, which results in deleterious expressions that are responsible for the development of long COVID, the researchers wrote.

This inflammation and immune dysregulation are related to diffuse endothelial damage and microthrombosis with consequent continuing organ damage, the researchers added. Damage in specific cortical structures can lead to altered taste and smell. Persistent myocardial inflammation may lead to arrhythmias and other cardiac issues as well.

Among children, neuroinflammatory processes related to lymphoproliferative responses and the subsequent toxic buildup of inflammatory cytokines in the central nervous system may be associated with neuropsychological symptomatology.

The researchers also found intestinal dysbiosis could have a pathogenetic role considering the relationships between the gut-brain axis in the control of inflammatory conditions in the central nervous system.

More than half of patients with long COVID experience a reactivation of latent Epstein-Barr virus infection, the researchers found, which has been associated with skin, cardiovascular, hematologic and neurologic complications that also may occur with long COVID.

Inflammation due to viral persistence could induce long COVID via long-term damage in the lungs, brain, kidneys and heart in adults and children as well, the researchers continued.

Diets poor in anti-inflammatory and/or antioxidant substances that have potential immune-modulating and antiviral activity also could play a role in the development of persistent long symptoms after the acute phase of COVID-19, according to the researchers.

Finally, the researchers cited the role of the nuclear factor kappa B and p38 mitogen-activated protein kinase signaling pathways, which regulate cytokine production, in the pathogenesis of uncontrolled inflammatory responses, acute respiratory symptoms and many manifestations of long COVID. An understanding of these signaling mechanisms, the researchers wrote, would be critical to new diagnostic and therapeutic procedures.

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