Mycobiome analyses of critically ill COVID-19 patients suggests antifungal prophylaxis may be protective against A. fumigatus-associated mortality (preprint)

Rationale: Covid-associated pulmonary aspergillosis (CAPA) is a life-threatening complication in patients with severe COVID -19. Previously, acute respiratory distress syndrome in patients with COVID-19 has been associated with lung fungal dysbiosis, evidenced by reduced microbial diversity and Candida colonisation. Increased fungal burden in the lungs of critically ill COVID-19 patients is linked to prolonged mechanical ventilation and increased mortality. However, specific mycobiome signatures associated with severe COVID-19 in the context of survival and antifungal drug prophylaxis have not yet been determined and such knowledge could have an important impact on treatment. Objectives: To understand the composition of the respiratory mycobiome in critically ill COVID -19 patients with and without CAPA, the impact of antifungal use and its role in patient outcome. Methods: We performed a multi-national study of 39 COVID-19 patients in intensive care units (ICU) with and without CAPA. Respiratory mycobiome was profiled using ITS1 sequencing and Aspergillus fumigatus burden was further validated using qPCR. Fungal communities were investigated using alpha diversity, beta diversity, taxa prevalence and taxa abundances. Measurements and Main Results: Respiratory mycobiomes were dominated by Candida and Aspergillus. There was no significant association with corticosteroid use or CAPA diagnosis and respiratory fungal communities. Increased A. fumigatus burden was associated with mortality. The use of antifungals at ICU admission was associated with an absence of A. fumigatus. Conclusions: Our findings suggest that systemic antifungal treatment at ICU admission may be protective against A. fumigatus-associated mortality in CAPA.

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

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.

COVID-19 in adult acute myeloid leukemia patients: a long-term follow-up study from the European Hematology Association survey (EPICOVIDEHA) (preprint)

Patients with acute myeloid leukemia (AML) are at high risk of mortality from coronavirus disease 2019 (COVID-19). The optimal management of AML patients with COVID-19 has not been established. Our multicenter study included 388 adult AML patients with COVID-19 diagnosis between February 2020 and October 2021. The vast majority were receiving or had received AML treatment in the prior 3 months. COVID-19 was severe in 41.2% and critical in 21.1% of cases. The chemotherapeutic schedule was modified in 174 patients (44.8%), delayed in 68 and permanently discontinued in 106. After a median follow-up of 325 days, 180 patients (46.4%) had died. Death was attributed to COVID-19 (43.3%), AML (26.1%) or to a combination of both (26.7%). Active disease, older age, and treatment discontinuation were associated with death, whereas AML treatment delay was protective. Seventy-nine patients had a simultaneous AML and COVID-19 diagnosis, with an improved survival when AML treatment could be delayed. Patients with COVID-19 diagnosis between January and August 2020 had a significantly lower survival. COVID-19 in AML patients was associated with a high mortality rate and modifications of therapeutic algorithms. The best approach to improve survival was to delay AML treatment.

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

Background A 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. Methods We 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. Results The 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 a harmful treatment effect when it was beneficial. Estimates obtained from the FG model were all consistent and showed no misestimation or changes in direction. Conclusion There 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. Keywords COVID-19, competing risk, in-hospital mortality, survival analysis, recovery