Pathophysiology and mechanism of long COVID: a comprehensive review, 2022, Castanares-Zapatero et al

[Sly Saint]

Abstract
Background
After almost 2 years of fighting against SARS-CoV-2 pandemic, the number of patients enduring persistent symptoms long after acute infection is a matter of concern. This set of symptoms was referred to as “long COVID”, and it was defined more recently as “Post COVID-19 condition” by the World health Organization (WHO). Although studies have revealed that long COVID can manifest whatever the severity of inaugural illness, the underlying pathophysiology is still enigmatic.

Aim
To conduct a comprehensive review to address the putative pathophysiology underlying the persisting symptoms of long COVID.

Method
We searched 11 bibliographic databases (Cochrane Library, JBI EBP Database, Medline, Embase, PsycInfo, CINHAL, Ovid Nursing Database, Journals@Ovid, SciLit, EuropePMC, and CoronaCentral). We selected studies that put forward hypotheses on the pathophysiology, as well as those that encompassed long COVID patients in their research investigation.

Results
A total of 98 articles were included in the systematic review, 54 of which exclusively addressed hypotheses on pathophysiology, while 44 involved COVID patients. Studies that included patients displayed heterogeneity with respect to the severity of initial illness, timing of analysis, or presence of a control group. Although long COVID likely results from long-term organ damage due to acute-phase infection, specific mechanisms following the initial illness could contribute to the later symptoms possibly affecting many organs. As such, autonomic nervous system damage could account for many symptoms without clear evidence of organ damage. Immune dysregulation, auto-immunity, endothelial dysfunction, occult viral persistence, as well as coagulation activation are the main underlying pathophysiological mechanisms so far.

Conclusion
Evidence on why persistent symptoms occur is still limited, and available studies are heterogeneous. Apart from long-term organ damage, many hints suggest that specific mechanisms following acute illness could be involved in long COVID symptoms.

https://www.tandfonline.com/doi/full/10.1080/07853890.2022.2076901

Likewise, symptoms such as fatigue are often difficult to assess, given that its causes are complex and multifactorial in nature. In this setting, long COVID could share some similar elements of post-infectious fatigue, which is observed after viruses like Influenza or other coronaviruses [111] or with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). In a large cross survey, Davis et al. reported that typical ME/CFS symptoms like post-exertional malaise were experienced following COVID-19. On the other hand, a recent systematic review including 21 studies noticed that major criteria symptoms of ME/CFS, including fatigue, post-exertional malaise, and reduced daily activity, were reported by the majority of patients included in long COVID studies [112]. Despite the possible overlap between both conditions [107,112], notable differences exist. A recent study compared ME/CFS symptoms and their duration through a survey using the Depaul Symptom Questionnaire with a list of COVID-19 symptoms [113]. Long COVID patients were initially more symptomatic than MCE-CF patients with respect to the immune (respiratory symptoms, fever and lymph nodes) and orthostatic domains, whereas ME/CFS patients displayed more gastrointestinal and neurocognitive symptoms.