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COVID Impacts: Pathophysiology of Long COVID

Detailed information and resources on the long-term health consequences of COVID-19 infection and the broad social impacts of the COVID-19 pandemic

Biological Factors

Despite nearly four years into the COVID-19 pandemic, scientists and clinicians still don't fully understand what Long Covid is, what causes it, and how to treat it. There are several biological factors that have emerged as possible drivers of post-acute sequelae of COVID-19 (PASC), the wide range of new onset or worsening symptoms that last for weeks or months after an acute COVID-19 infection.

Viral Reservoirs

Some individuals with PASC may not fully clear the coronavirus SARS-CoV-2 after acute infection. Instead, replicating virus and/or viral RNA—potentially capable of being translated to produce viral proteins—persist in tissue as a ‘reservoir’. This reservoir could modulate host immune responses or release viral proteins into the circulation.

SARS-CoV-2 is a single-stranded RNA virus, and there are other single-stranded RNA viruses that  have been found to persist in human tissue for months or years after acute infection, including Zika Virus, Ebolavirus, Measles, and enteroviruses. In multiple instances, these viral reservoirs have been shown to be capable of driving chronic disease, and new outbreaks of both Ebolavirus and Zika Virus have been sparked by individuals carrying persistent virus.

Autopsy and tissue biopsy studies have identified SARS-CoV-2 RNA and protein in a wide range of tissue types collected weeks or months after acute COVID-19. SARS-CoV-2 RNA or protein has been identified in tissue months after initial illness despite negative results via standard nasopharyngeal PCR testing and/or a lack of detection in peripheral blood from the same individual. These observations suggest that SARS-CoV-2 persistence occurs largely in tissues. A similar pattern has been documented with other RNA viruses associated with chronic sequelae in a subset of survivors.

A major gap in the field is the absence of PASC-specific autopsy data. Thus, most evidence for SARS-CoV-2 reservoir in individuals with PASC comes from:

  1. tissue biopsy studies
  2. studies of SARS-CoV-2 proteins in plasma
  3. studies using features of the adaptive immune response to infer the presence of a SARS-CoV-2 reservoir in tissues

Viral RNA and protein persistence were unrelated to the severity of acute COVID-19 or immunosuppressive therapy but were associated with PASC symptoms.

The identification of SARS-CoV-2 protein in PASC plasma up to 16 months after COVID-19 suggests that some patients with PASC may harbor replicating virus. However, thus far, levels of protein detected differ widely among studies, suggesting that the size and/or activity of any SARS-CoV-2 reservoirs may vary among patients with PASC. Failure to detect SARS-CoV-2 protein in the plasma of some patients with PASC could be interpreted to mean absence of a SARS-CoV-2 reservoir. However, such a result could also indicate a reservoir in tissues or sites where viral protein may be less likely to reach the circulation at the level of detection of current assays. In addition, protein could be bound by antibodies, preventing recognition by some assays. Moreover, SARS-CoV-2 protein might also be captured and potentially persist inside neutrophil extracellular traps (NETs) or host immune cells such as macrophages and thus also fail to be detected via analyses of plasma alone.

Patholophysiology of Long COVID