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Long COVID or post-COVID-19 syndrome: putative pathophysiology, risk factors, and treatments

Updated: Feb 1, 2022


Long COVID or post-COVID-19 syndrome first gained widespread recognition among social support groups and later in scientific and medical communities. This illness is poorly understood as it affects COVID-19 survivors at all levels of disease severity, even younger adults, children, and those not hospitalized. While the precise definition of long COVID may be lacking, the most common symptoms reported in many studies are fatigue and dyspnoea that last for months after acute COVID-19. Other persistent symptoms may include cognitive and mental impairments, chest and joint pains, palpitations, myalgia, smell and taste dysfunctions, cough, headache, and gastrointestinal and cardiac issues. Presently, there is limited literature discussing the possible pathophysiology, risk factors, and treatments in long COVID, which the current review aims to address. In brief, long COVID may be driven by long-term tissue damage (e.g. lung, brain, and heart) and pathological inflammation (e.g. from viral persistence, immune dysregulation, and autoimmunity). The associated risk factors may include female sex, more than five early symptoms, early dyspnoea, prior psychiatric disorders, and specific biomarkers (e.g. D-dimer, CRP, and lymphocyte count), although more research is required to substantiate such risk factors. While preliminary evidence suggests that personalized rehabilitation training may help certain long COVID cases, therapeutic drugs repurposed from other similar conditions, such as myalgic encephalomyelitis or chronic fatigue syndrome, postural orthostatic tachycardia syndrome, and mast cell activation syndrome, also hold potential. In sum, this review hopes to provide the current understanding of what is known about long COVID.

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Concluding remarks

This review presents the current understanding of long COVID, a relatively new and puzzling condition that may affect COVID-19 survivors, regardless of initial disease severity or age. The symptoms, putative pathophysiology, associated risk factors, and potential treatments have been discussed. However, much remains ambiguous about long COVID, particularly its risk factors with inconsistent data thus far. This may be due to its multiple symptomatic presentations and pathophysiologies, ranging from long-term damage of multiple organ systems to unresolved inflammation from multiple sources. Hence, future research might be interested in phenotyping subtypes of long COVID [49]. Presently, only rehabilitation has been found as possibly effective in improving symptoms of long COVID, whereas the potential pharmaceutical drugs repurposed from ME/CFS, POTS, and MCAS still require future research to validate.

Evidently, the pandemic has brought us a wave of a new chronic, disabling condition called long COVID that deserves serious attention among the scientific and medical communities to resolve. Assuming at least 10% of COVID-19 survivors develop long COVID, which is likely underestimated (Table 2), it is estimated that 5 million people are facing long COVID globally [5]. The information presented in this review, which has not been communicated extensively elsewhere in the literature, may serve as a starting point for further exploration on long COVID

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