A pathophysiological model of long COVID based on the persistence of the SARS-CoV-2 virus

WHO defines long COVID as: “the continuation or development of new symptoms 3 months after the initial SARS-CoV-2 infection, with these symptoms lasting for at least 2 months with no other explanation”. Despite the extensive research on long COVID, its pathogenesis remains unclear. In a theoretical article, the authors from Canada presented a pathophysiological model of long COVID based on the persistence of the SARS-CoV-2 virus.

Long COVID or post-COVID-19 condition can affect anyone exposed to SARS-CoV-2, regardless of age or severity of the original symptoms. Long-term health problems can persist or appear after the typical recovery period of COVID-19.

About the study

The authors discussed evidence that the duration of SARS-CoV-2 infection in patients may last significantly longer than PCR-negative tests on nasopharyngeal swabs or bronchoalveolar lavage fluids would suggest. The authors suggested that persistent multisystem injury in both adults and children may be a consequence of an infection-associated chronic disease.

Researchers from the National Institutes of Health studied the replication competence, persistence, and evolution of SARS-CoV-2 in human cells and looked for histopathological features in infected tissues by performing autopsies of 44 COVID-19 cases. They found that SARS-CoV-2 RNA was widely distributed in 84 distinct anatomical locations up to 230 days after infection.

Although the virus was not found in plasma, high-sensitivity droplet digital PCR detected viral persistence in multiple tissue samples from all decedents. These results suggest that the viral load in biospecimens from patients after acute SARS-CoV-2 infection might be low but still detectable. In addition, the detection of subgenomic RNA, a marker of recent viral replication, and the isolation of replication-competent viruses from respiratory and nonrespiratory tissues, suggest that viral replication may continue for several months after initial infection.

Researchers in Singapore also found residual viral protein and RNA in the appendix, skin, and breast tissue of two patients who developed long COVID symptoms 163 and 426 days after the onset of symptoms, respectively. The findings of Spanish researchers indicate that the SARS-CoV-2 was still present in surgically resected intestinal specimens 6 months after COVID-19, even though nasopharyngeal PCR results were negative. Researchers from the USA and Austria found viral RNA in the stool of COVID-19 patients 7 months after diagnosis.

These findings indicate that the virus persists in gastrointestinal tract in people with long COVID, and that the gut of people with long COVID might be a viral reservoir.

Slovakian scientists found the presence of SARS-CoV-2 in the cerebrospinal fluid of patients with long COVID. The US investigation found that patients with long COVID had circulating SARS-CoV-2 spike antigen within 12 months of being diagnosed.

A consortium of scientists led by scientists from South Africa demonstrated that adding of the spike protein to whole blood and platelet-poor plasma samples of healthy individuals resulted in the formation of large, dense and anomalous amyloid masses, and structural changes in β and γ fibrin(ogen), complement 3, and prothrombin

These findings show that the persistence of SARS-CoV-2 triggers a dysregulation of the immune system, followed by increased release of inflammatory cytokines and abnormal endothelial damage, leading to the development of chronic inflammation, vascular damage, hypercoagulability, microthrombosis, and multiorgan symptoms.

Image from the original article of Yang C et al.

The authors, therefore, proposed a pathophysiological model of long COVID based on the persistence of SARS-CoV-2 virus. It apears that long COVID is an infection-associated chronic disease that affects every single organ system, and results in multisystem injury in both adults and children. The authors concluded that the rapid elimination of the SARS-CoV-2 virus in patients with persistent infection is of crucial importance.

This article was published in Lancet Respiratory Medicine.

Journal Reference

Yang C et al. Association of SARS-CoV-2 infection and persistence with long COVID. Lancet Respir Med 2023 Published Online May 10, 2023 (Open Access)