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

Abstract

<b>Background:</b> The key impact of SARS-CoV-2 is its ability to cause a life-threatening infection in the lung. <b>Aims:</b> Using spatially resolved multiplex imaging the present study decodes the immunopathological complexity of severe COVID-19. <b>Methods:</b> 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. <b>Results:</b> 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. <b>Conclusion:</b> 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.