Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can persistently progress to a fatal condition even after clinical resolution of severe infection suggested by negative polymerase chain reaction (PCR) test results.
In a study published in Pathology JournalIn this study, the scientists described the infection dynamics and clinical features of PCR-negative patients who ultimately died from an exacerbation of COVID-19.
COVID-19 is a highly heterogeneous disease, with clinical manifestations ranging from mild or asymptomatic infection to fatal infection. Fatal SARS-CoV-2 infection is characterized by severe lung damage, micro- and macrovascular thrombosis, and persistent infection of pulmonary and endothelial cells.
A significant proportion of COVID-19 patients remain symptomatic for several months, even after clinical resolution of acute infection. This condition is medically called long COVID. Some patients with negative PCR test results show signs of disease progression and eventually die.
In the current study, scientists conducted postmortem analyzes of a cohort of COVID-19 patients who eventually died due to gradual deterioration of clinical conditions, despite having had negative SARS-CoV-2 tests up to 300 days after acute infection. .
Postmortem analyzes were performed on a total of 27 patients with COVID-19. Three of them remained PCR-negative for more than nine months, and the rest were PCR-negative for 11-300 consecutive days. In most patients, death occurred due to pneumonia.
Lung tissue samples collected from these patients were subjected to histological and immunohistochemical analysis. RNA samples extracted from the tissues were analyzed by PCR to detect viral RNA.
Postmortem analysis of lung tissue samples showed that about 81% of patients had interstitial pneumonia. In 48% of the patients, the pneumonia was severe and caused death. The most notable features of pneumonia in these patients were severe alveolar damage, immune cell infiltration, and extensive fibrillar replacement.
Micro and macro vascular thrombosis was observed in 67% of patients. This is the most common feature of acute SARS-CoV-2 infection. Other clinical features observed in the tested specimens include vasculitis, squamous metaplasia of the respiratory epithelium, cytological and congenital abnormalities, and bronchial cartilage atrophy.
Overall, these observations indicate that the pathological changes observed in these patients are not significantly different from those observed in acutely infected patients. In other words, although SARS-CoV-2 RNA has not been consistently present in respiratory samples for a long time, these patients present clinical features similar to acute infection with detectable viral RNA.
Persistent viral infection
The study also explored whether an undetectable but persistent viral infection was responsible for the pathological changes observed in the deceased patients. Immunohistochemistry analysis was performed using spike antibody and nucleocapsid antibody to detect the presence of SARS-CoV-1 infected cells in the lung.
Immunohistochemistry results revealed a complete absence of virus-infected cells in the epithelium of the respiratory tract. This justifies the PCR results for the persistent absence of detectable viral RNA in nasopharyngeal samples.
Interestingly, about 70% of the patients showed detectable virus-infected cells in specific areas of the lung. Specifically, SARS-CoV-2 infection has been detected in chondrocytes, bronchiolar-like cells, syncytial cells and, to some extent, in perirenal endothelial cells.
The study describes the lung pathologic features of COVID-19 patients who died of progressively worsening disease, despite prolonged negative PCR results for the virus. The pulmonary pathologic features of these deceased patients are similar to those observed in a patient with acute SARS-CoV-2 infection.
Interestingly, virus-infected cells were detected in specific areas of the lung of these patients, including the para-bronchial glands and cartilages. As reported by the scientists, the long-term presence of certain virus-infected cells can cause pathological changes in the lung by maintaining a pro-inflammatory, immunomodulatory and anticoagulant state. More studies are needed to determine the relationship between persistently infected cells and the development of long-term COVID.