Fatal cases after Omicron BA.1 and BA.2 infection: Diffuse alveolar damage occurs only in a minority - results of an autopsy study

Compared with previously prevalent variants of SARS-CoV-2, the Omicron lineages BA.1 and BA.2 are known to be associated with mild clinical courses. In addition, well-established animal models do not develop severe diseases. To address whether the supposedly fatal cases after Omicron-BA.1/2 infection show the known COVID-19 organ alterations, especially in the lungs, 23 full and 3 partial autopsies in the deceased with known Omicron BA.1/2 infections have been consecutively performed. Viral RNA was determined by RT-qPCR and RNA-in situ hybridization. The lineages were analyzed by whole genome sequencing or S-gene analysis. Despite high viral loads in almost all nasopharyngeal swabs and in 13 lung tissue samples, death caused by COVID-19-associated diffuse alveolar damage (DAD) in the acute and organizing stages was found in only eight cases (31%). This rate is significantly lower compared to previous studies, including non-Omicron variants, where rates of 92% and 69% for non-vaccinated and fully vaccinated vaccines were observed. It is of special interest that neither vaccination status nor known risk factors (i.e., age, comorbidities, obesity, immuno-suppression) were significantly associated with a direct cause of death by COVID-19. Only the reason for the hospital admission of the patients due to COVID-19-related symptoms showed a significant correlation with directly COVID-19-caused deaths (P < 0.001). DAD still occurred in the Omicron BA.1/BA.2 era of the SARS-CoV-2 pandemic but at a considerably lower frequency than seen with previous variants of concern. In our study, none of the known risk factors discriminated the cases with COVID-19-caused death from those that had COVID-19 infections but died due to a different disease. Therefore, the hosts genomics might play a key role in this regard. Further studies are urgently needed to elucidate the existence of a genomic mechanism as a risk factor for a fatal course.