COVID-19 Associated Pulmonary Aspergillosis isolates are genomically diverse but similar to each other in their responses to infection-relevant stresses

Secondary infections caused by the pulmonary fungal pathogen Aspergillus fumigatus are a significant cause of mortality in patients with severe Coronavirus Disease 19 (COVID-19). Even though epithelial cell damage and aberrant cytokine responses have been linked with susceptibility to COVID-19 associated pulmonary aspergillosis (CAPA), little is known about the mechanisms underpinning co-pathogenicity. Here, we analysed the genomes of 11 A. fumigatus isolates from patients with CAPA in three centres from different European countries. CAPA isolates did not cluster based on geographic origin in a genome-scale phylogeny of representative A. fumigatus isolates. Phenotypically, CAPA isolates were more similar to the A. fumigatus A1160 reference strain than to the Af293 strain when grown in infection-relevant stresses; except for interactions with human immune cells wherein macrophage responses were similar to those induced by the Af293 reference strain. Collectively, our data indicates that CAPA isolates are genomically diverse but are more similar to each other in their responses to infection-relevant stresses. A larger number of isolates from CAPA patients should be studied to identify genetic drivers of co-pathogenicity in patients with COVID-19. ImportanceCoronavirus disease 2019 (COVID-19)-associated pulmonary aspergillosis (CAPA) has been globally reported as a life-threatening complication in some patients with severe COVID-19. Most of these infections are caused by the environmental mould Aspergillus fumigatus which ranks third in the fungal pathogen priority list of the WHO. However, little is known about the molecular epidemiology of Aspergillus fumigatus CAPA strains. Here, we analysed the genomes of 11 A. fumigatus isolates from patients with CAPA in three centres from different European countries and, carried out phenotypic analyses with a view to understand the pathophysiology of the disease. Our data indicates that A. fumigatus CAPA isolates are genomically diverse but are more similar to each other in their responses to infection-relevant stresses.

The competing risk between in-hospital mortality and recovery: A pitfall in COVID-19 survival analysis research

BackgroundA plethora of studies on COVID-19 investigating mortality and recovery have used the Cox Proportional Hazards (Cox PH) model without taking into account the presence of competing risks. We investigate, through extensive simulations, the bias in estimating the hazard ratio (HR) and the absolute risk reduction (ARR) of death when competing risks are ignored, and suggest an alternative method. MethodsWe simulated a fictive clinical trial on COVID-19 mimicking studies investigating interventions such as Hydroxychloroquine, Remdesivir, or convalescent plasma. The outcome is time from randomization until death. Six scenarios for the effect of treatment on death and recovery were considered. The HR and the 28-day ARR of death were estimated using the Cox PH and the Fine and Gray (FG) models. Estimates were then compared with the true values, and the magnitude of misestimation was quantified. ResultsThe Cox PH model misestimated the true HR and the 28-day ARR of death in the majority of scenarios. The magnitude of misestimation increased when recovery was faster and/or chance of recovery was higher. In some scenarios, this model has shown harmful treatment effect when it was beneficial. Estimates obtained from FG model were all consistent and showed no misestimation or changes in direction. ConclusionThere is a substantial risk of misleading results in COVID-19 research if recovery and death due to COVID-19 are not considered as competing risk events. We strongly recommend the use of a competing risk approach to re-analyze relevant published data that have used the Cox PH model.