Long COVID: Clinical Findings, Pathology, and Endothelial Molecular Mechanisms

Prevalence and Definition: A review and meta-analysis of published results of long COVID studies suggest a global prevalence of the post COVID-19 condition of approximately 43% with a wide range of 9-81%.¹ Using a population-representative survey epidemiologists have estimated the prevalence of long COVID in the United States to be 7.3%.² In an effort to standardize the definition of long COVID the World Health Organization (WHO) established a Clinical Case Definition Working Group on the Post-COVID-19 Condition.³

Symptoms: The symptoms of long COVID are similar to those observed in patients following chronic critical illness and hospitalization in intensive care units.⁴ In the United Kingdom a retrospective matched cohort study was undertaken to determine symptoms beyond 12 weeks in non-hospitalized SARS-CoV-2 infected patients compared with uninfected patients.⁵ A cohort of 486,149 non-hospitalized adults with confirmed SARS-CoV-2 infection was compared to 1,944,580 propensity score-matched adults with no record

Evaluation and Testing: The previously referenced study of COVID patients 6 months after discharge from hospital in Wuhan, China enrolled patients in radiographic, pulmonary function, and blood testing.⁷ High resolution computerized tomography (HRCT) was performed on 390 patients and was abnormal in 52% not requiring supplemental oxygen and 54% of patients requiring supplemental oxygen. Lung diffusion impairment was noted in 22% of patients not requiring oxygen and up to 56% of patients requiring supplemental oxygen

Pathology and Histopathology: Autopsy data has contributed considerable information to our understanding of SARS-CoV-2 infection. A review of the histopathological findings in coronavirus disease 2019 reported diffuse alveolar damage (DAD), multiple organ microvasculitis, and lymphocytic infiltration with changes in immune organs and emphasized the observance of microthrombosis in numerous studies.¹⁸ An autopsy study from New York Presbyterian Hospital revealed macroscopic and/or microscopic thrombi in 84% patients.¹⁹

Complement, von Willebrand factor, and Endotheliopathy: A prospective study in the Netherlands was conducted to examine the role of complement as a component of the innate immune response to SARS-CoV-2 infection.²⁹ Investigators found that complement factors C3a, C3c, and the terminal complement complex or membrane attack complex (MAC) were increased in COVID-19 patients compared to healthy controls. Furthermore, these complement factors were more increased in patients who were admitted to intensive care units, died, or experienced thromboembolic

Discussion: Long COVID or post acute sequelae of COVID-19 (PASC) is a frequent occurrence in patients recovering from acute SARS-CoV-2 infection. Estimates of the incidence vary widely with the more recent estimates trending below 10% in the United States. Changes in definition, increasing population immunity, treatment with antivirals and monoclonal antibodies, and newer variants may all play a role in the downward trend. The symptoms of long COVID are numerous and reflect the multi-organ nature of both…

Conclusion: The pathology and histopathology of COVID-19 patients has demonstrated the presence of widespread multi-organ microthrombi as a central feature of SARS-CoV-2 infection. Elevated levels of complement factors and von Willebrand factor have been found in COVID-19 patients and the degree of increases are directly related to the severity of disease and persistent high levels correlate with long COVID symptoms.³⁹ Persisting symptoms following acute COVID-19 occur more often and are more debilitating