ABSTRACT
Background: COVID19 and its etiological agent SARS-COV2 may cause a wide spectrum of clinical disease ranging from asymptomatic infection to severe disease and death. Clinical severity of disease has been linked to the variable immune responses to the virus. Identification of markers that distinguish clinically mild from severe disease may be of benefit in predicting disease severity. Design: Analysis of T cells (CD3), three subsets of macrophages (CD11b, CD163, and CD206), PDL1 and viral load in nasopharyngeal swabs of 20 people that were reverse transcriptase polymerase chain reaction positive with mild disease and 20 reverse transcriptase polymerase chain reaction negative controls versus the same variables in 20 lungs from people who died with COVID-19 versus normal aged matched controls was performed. The fatal COVID-19 lung data were stratified into the lung sections with high viral load versus lung sections, often from the same person, where viral involvement was not evident by in situ hybridization. Results: There was a 20X fold increase in the percentage of CD3+ cells in the viral positive nasopharyngeal swabs versus the controls whereas no change was noted in the CD3 count in the lungs of fatal COVID-19 with high viral load. The percentage of cells positive for the macrophage marker CD163 and for PDL1 were equivalent in the mild versus fatal disease samples. There was a significant increase in the number of cells expressing CD11b and CD206 in the fatal lungs with virus compared to the normal lungs;however, these increases were significantly higher in the nasopharyngeal swabs with mild infection. In the fatal COVID-19 lungs without detectable virus, the PDL1, CD11b and CD206 counts were very low, indicating that even in fatal disease the virus was inducing this immune response. Surprisingly, viral load was equivalent in mild versus fatal disease. Conclusions: It is concluded that markedly increased counts of CD3 T cells as well as CD11b and CD206 macrophages can differentiate mild versus fatal COVID-19 which may provide a way to predict clinical outcome by analyzing viral nasopharyngeal swabs for the T cell and macrophage response.
ABSTRACT
BACKGROUND: There are two distinctive acral manifestations of COVID-19 embodying disparate clinical phenotypes. One is perniosis occurring in mildly symptomatic patients, typically children and young adults; the second is the thrombotic retiform purpura of critically ill adults with COVID-19. OBJECTIVES: To compare the clinical and pathological profiles of these two different cutaneous manifestations of COVID-19. METHODS: We compared the light microscopic, phenotypic, cytokine and SARS-CoV-2 protein and RNA profiles of COVID-19-associated perniosis with that of thrombotic retiform purpura in critical patients with COVID-19. RESULTS: Biopsies of COVID-19-associated perniosis exhibited vasocentric and eccrinotropic T-cell- and monocyte-derived CD11c+ , CD14+ and CD123+ dendritic cell infiltrates. Both COVID-associated and idiopathic perniosis showed striking expression of the type I interferon-inducible myxovirus resistance protein A (MXA), an established marker for type I interferon signalling in tissue. SARS-CoV-2 RNA, interleukin-6 and caspase 3 were minimally expressed and confined to mononuclear inflammatory cells. The biopsies from livedo/retiform purpura showed pauci-inflammatory vascular thrombosis without any MXA decoration. Blood vessels exhibited extensive complement deposition with endothelial cell localization of SARS-CoV-2 protein, interleukin-6 and caspase 3; SARS-CoV-2 RNA was not seen. CONCLUSIONS: COVID-19-associated perniosis represents a virally triggered exaggerated immune reaction with significant type I interferon signaling. This is important to SARS-CoV-2 eradication and has implications in regards to a more generalized highly inflammatory response. We hypothesize that in the thrombotic retiform purpura of critically ill patients with COVID-19, the vascular thrombosis in the skin and other organ systems is associated with a minimal interferon response. This allows excessive viral replication with release of viral proteins that localize to extrapulmonary endothelium and trigger extensive complement activation.