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“[Even though] post-viral syndromes …. have a major effect on quality of life and daily functioning, effective treatments are not available”

Post-viral syndromes arise in a subset of individuals with acute viral infections and can persist for months to years after disease onset. Even though the accompanying symptoms have a major effect on quality of life and daily functioning, effective treatments are not available. Symptoms of affected patients are diverse and often include fatigue, post- exertional malaise, memory loss, and other neurocognitive impairments. Similar symptoms have been reported by patients after Epstein Barr virus infection and in patients with a diagnosis of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), both long-term illnesses that affects many body systems and greatly impair patients’ ability to perform their usual activities. Chronic, maladaptive engagement of the brain’s immune cells have been implicated as pathophysiological mechanism in this group of disorders even though unequivocal evidence from human studies for this mechanism is not available.

“Even though acute COVID-19 infections are no longer a major health problem, the emergence of Long Covid poses a global health challenge.”

Long COVID is a major post-viral syndrome which is presenting in a subset of patients after acute SARS-CoV-2 infection. Even though acute COVID-19 infections are no longer a major health problem, the emergence of Long Covid poses a global health challenge. The pathophysiology of post-viral syndromes, including Long Covid remains poorly understood, leaving medical systems across the world unprepared for the large number of individuals developing unexplained cardiorespiratory, neurocognitive, gastrointestinal, and musculoskeletal symptoms in the months and years following the acute infection.

“The molecular etiology of most post-viral syndromes, including Long COVID and ME/CFS or EB virus, remains unclear.”

The molecular etiology of most post-viral syndromes, including Long COVID and ME/CFS or EB virus, remains unclear. Several hypotheses have been proposed to explain the persistence of symptoms, including the persistence of the virus in the body that is not cleared after the initial infection, chronic brain inflammation, auto-antibody development, and tissue damage as a result of non-resolving anti-viral responses by the immune system. Another common feature that has been associated with post-viral syndromes is platelet dysfunction and hypercoagulability.

To address these potential mechanisms in Long Covid patients, investigators from the University of Pennsylvania under the leadership of Andrea Wong performed extensive studies in a large number of human samples and in different mouse models, and their results were published in the journal Cell in October 2023. In their study, the investigators first identified serotonin levels in the blood of different patient cohorts as a possible discriminator between recovered individuals without residual symptoms and Long COVID patients. Using a combination of analyses in several human studies, animal models of viral infection, and cultures of tissues (so called organoid cultures), they found that the presence of viral RNA and downstream immune responses (including the cytokine interferon) cause a consistent decrease in serotonin blood levels. Based on their findings they propose that several mechanisms account for this phenomenon, including diminished absorption of the serotonin precursor, the essential amino acid tryptophan in the gut, reduced uptake and storage by a reduced number of platelets (the main storage site in the blood for serotonin), and enhanced turnover by serotonin-metabolizing enzymes. Finally they provide evidence for a reduction in serotonin-mediated vagal signaling to the brain, specifically the hippocampus.

“…the study results support a possible role for the sensory vagus nerve in mediating the impact of peripheral serotonin reduction on the brain.”

These findings have several important possible implications. First, they highlight the profound consequences that persistent viral reservoirs in body tissues can have. Their findings indicate that the presence of viral components and resultant cytokine responses might be a causative factor in the development of Long COVID-associated symptoms. Second, the study highlights a mechanism by which viral infection can alter amino acid absorption in the gut, including the serotonin precursor tryptophan. Third, the study results support a possible role for the sensory vagus nerve in mediating the impact of peripheral serotonin reduction on the brain. Neurological symptoms are widespread in patients with both acute and Long COVID-19. Since unequivocal evidence for SARS-CoV-2 replication in the brain is lacking, recent studies have focused on the cognitive consequences of peripheral immune activation as well as neuroinflammation, mechanisms that have also been implicated the neurological symptoms of patients with ME/CFS and EB virus.

Based on their results, the authors suggest that sensory vagal neurons may play a critical role in the neurocognitive manifestations of both acute and post-acute viral infections. It has long been known that the sensory branches of the vagus nerve when stimulated by peripheral cytokines are an important mediator of sickness behavior. Sickness behavior is a coordinated set of behavioral changes that occur in physically ill animals and humans during the course of an infection. These behaviors include lethargy, depressed mood, reduced social exploration, loss of appetite, sleepiness, hyperalgesia, and, at times, confusion. Activation of vagal sensory nerve fibers by cytokines released by the infection have been identified as a major mechanism. Sickness behavior and the underlying mechanisms have been implicated in the pathophysiology of chronic fatigue syndrome and depression.

The sensory portion of the vagus nerve makes up 90% of all vagal fibers, and is made up of multiple components responding to a variety of different stimuli from the gut and other organs. While the precise circuit by which the vagus nerve may be involved in the development of Long COVID symptoms the specific fibers involved in this gut to brain communication remains unclear.

“Alterations in serotonin blood levels have been studied extensively in patients with Irritable Bowel Syndrome, with Major Depressive Disorder and with Autism Spectrum Disorder but have not translated into effective therapies”

Even though the findings are intriguing, there are several limitations to the study, in particular to the authors’ quick extrapolation from correlational human studies (which don’t prove causation) and studies performed in mouse models to potential human therapies. The interactions of the gut-based serotonin system (95% of the body’s serotonin is localized in specialized enterochromaffin cells in the small intestine) with the vagus nerve and with the gut microbiome are complex and incompletely understood. Alterations in serotonin blood levels have been studied extensively in patients with Irritable Bowel Syndrome, with Major Depressive Disorder and with Autism Spectrum Disorder but have not translated into effective therapies. Most importantly, blood levels of serotonin are different from serotonin concentration in synaptic connections between enterochromaffin cells and vagal sensory nerve terminals, the main signaling pathway to the brain. Finally, the authors did not address the possible role of the gut microbiome. Based on studies in mice, gut microbial metabolites such as short chain fatty acids and secondary bile acids play an important role in stimulating serotonin production in the gut. Alterations in gut microbial composition has previously been reported in patients with Long COVID-19 and may play a crucial role in solving the mystery of Long COVID.

The renewed research interest in the pathophysiology and treatment of post viral syndromes has the potential to help millions of patients around the world suffering from debilitating symptoms, which are often dismissed as psychological or “functional” problems. The study by Andrea Wong and Team is an excellent example of how to address this challenging problem.