Diffuse alveolar damage patterns reflect the immunological and molecular heterogeneity in fatal COVID-19

Jonas S. Erjefält, Natália de Souza Xavier Costa, Jimmie Jönsson, Olga Cozzolino, Katia Cristina Dantas, Carl Magnus Clausson, Premkumar Siddhuraj, Caroline Lindö, Manar Alyamani, Suzete Cleusa Ferreira Spina Lombardi, Alfredo Mendroni Júnior, Leila Antonangelo, Caroline Silvério Faria, Amaro Nunes Duarte-Neto, Renata Aparecida de Almeida Monteiro, João Renato Rebello Pinho, Michele Soares Gomes-Gouvêa, Roberta Verciano Pereira, Jhonatas Sirino Monteiro, João Carlos SetubalEllen Pierre de Oliveira, Jair Theodoro Filho, Caroline Sanden, Jamie M. Orengo, Matthew A. Sleeman, Luiz Fernando Ferraz da Silva, Paulo Hilário Nascimento Saldiva, Marisa Dolhnikoff, Thais Mauad

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskriftPeer review


Background: Severe COVID-19 lung disease exhibits a high degree of spatial and temporal heterogeneity, with different histological features coexisting within a single individual. It is important to capture the disease complexity to support patient management and treatment strategies. We provide spatially decoded analyses on the immunopathology of diffuse alveolar damage (DAD) patterns and factors that modulate immune and structural changes in fatal COVID-19. Methods: We spatially quantified the immune and structural cells in exudative, intermediate, and advanced DAD through multiplex immunohistochemistry in autopsy lung tissue of 18 COVID-19 patients. Cytokine profiling, viral, bacteria, and fungi detection, and transcriptome analyses were performed. Findings: Spatial DAD progression was associated with expansion of immune cells, macrophages, CD8+ T cells, fibroblasts, and (lymph)angiogenesis. Viral load correlated positively with exudative DAD and negatively with disease/hospital length. In all cases, enteric bacteria were isolated, and Candida parapsilosis in eight cases. Cytokines correlated mainly with macrophages and CD8+T cells. Pro-coagulation and acute repair were enriched pathways in exudative DAD whereas intermediate/advanced DAD had a molecular profile of elevated humoral and innate immune responses and extracellular matrix production. Interpretation: Unraveling the spatial and molecular immunopathology of COVID-19 cases exposes the responses to SARS-CoV-2-induced exudative DAD and subsequent immune-modulatory and remodeling changes in proliferative/advanced DAD that occur side-by-side together with secondary infections in the lungs. These complex features have important implications for disease management and the development of novel treatments. Funding: CNPq, Bill and Melinda Gates Foundation, HC-Convida, FAPESP, Regeneron Pharmaceuticals, and the Swedish Heart & Lung Foundation.

StatusPublished - 2022 sep.

Ämnesklassifikation (UKÄ)

  • Immunologi


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