Severe Adaptive Immune Suppression May be Why Patients with Severe COVID-19 Cannot be Discharged From the ICU Even After Negative Viral Tests (preprint)

ABSTRACT

Background: During the COVID-19 pandemic, a phenomenon emerged in which some patients with severe disease were critically ill and could not be discharged from the ICU even though they exhibited negative viral tests. In general, continuous negative viral tests are thought to indicate that the virus has been cleared from the body and that the patients can be considered "recovered". However, because these patients were still critically ill, they obviously had not truly recovered from the disease. We sought to investigate why these patients were still critically ill even though they exhibited negative viral tests by analyzing the gene expression profiles of their peripheral immune cells using transcriptome sequencing. Methods: Fourteen severe COVID-19 patients with at least 3 negative virus tests but were still in critical ill and could not be discharged from the ICU were enrolled. Blood samples from 14 patients and 5 healthy donors were collected. Total RNA was extracted from nucleated cells for RNA-Sequencing. FeatureCounts v1.5.0-p3 was used to count the reads numbers mapped to each gene. Results: All enrolled patients, regardless of changes in genes related to different symptoms and inflammatory responses, showed universally and severely decreased expression of adaptive immunity-related genes, especially those related to T/B cell arms and HLA molecules, and that these patients exhibited long-term secondary infections. This adaptive immune suppression is unlikely due to classic immune checkpoint molecules such as PD-1 or long-term use of glucocorticoids but may be caused by an unknown mechanism that has not yet been discovered. Conclusions: Our findings strongly suggest that an initial recovery of these severe COVID-19 patients, as indicated by negative viral tests, may not indicate actual recovery. They still suffer from secondary infections for a long period of time because of severe adaptive immunosuppression and need to receive a variety of antibiotics, antifungal drugs, or combination therapies. Appropriate methods should be used to detect their adaptive immune function, and appropriate immunotherapy that can activate the adaptive immune response should be developed. Trial registration Not applicable (this study does not involve intervention on human participants).