Dynamics and Heterogeneity of the Lung Immunopathology in Severe COVID-19

Background: The key impact of SARS-CoV-2 is its ability to cause a life-threatening infection in the lung. Aims: Using spatially resolved multiplex imaging the present study decodes the immunopathological complexity of severe COVID-19. Methods: Autopsy lung tissue from 18 COVID-19 patients was used to map immune and structural cells in acute/exudative, intermediate and advanced diffuse alveolar damage (DAD) through multiplex immunohistochemistry and spatial statistical analyses. Cytokine profiling, viral, bacteria and fungi detection and transcriptome analyses were also performed. Results: All cases displayed concomitant patterns of DAD. The spatially resolved multiplex data revealed intricate patchworks of mm2-size microenvironments representing distinct immunological niches. In-depth analysis of DAD areas revealed that the temporal/spatial DAD progression is associated with expansion of adaptive immune cells, macrophages, CD8+ T cells, fibroblasts, angiogenesis and lymphangiogenesis. Viral load correlated positively with acute DAD and negatively with disease/hospital length. Cytokines correlated mainly with macrophages and CD8+T cells. Pro-coagulation and acute repair markers were enriched in acute DAD whereas intermediate/advanced DAD had a molecular profile of elevated humoral and innate immune responses and extracellular matrix production. Conclusion: Our unraveling of the spatio-temporal immunopathology in COVID-19 cases exposes the heterogeneous dynamics of acute viral infection and subsequent responses that occur side-by-side in the lungs. This complex disease feature has important implications for disease management and development of novel immune-modulatory treatments.