Influenza-associated invasive aspergillosis in the ICU: a prospective, multicentre cohort study

Background: Influenza-associated pulmonary aspergillosis (IAPA) can develop in critically ill patients with influenza in the intensive care unit (ICU), even in absence of classical risk factors. Thus far, most studies have been retrospective and the reported incidence has varied. Therefore, we set out to prospectively investigate IAPA incidence, potential risk factors and impact on patient outcomes. Methods: A prospective, multicentre observational cohort study was performed in the Netherlands and Belgium during three influenza seasons (2017–2020). Adult patients with PCR confirmed influenza or non-influenza community-acquired pneumonia (niCAP; control group) admitted to ICU with respiratory distress were included. Diagnosis of niCAP and mycological diagnostic work-up was at the treating physicians’ discretion. IAPA was defined according to the 2020 expert opinion case definition. Results: Invasive aspergillosis occurred in 24% (34/140) of patients with influenza, compared to 13% (10/76) of patients with niCAP (p = 0.054) undergoing mycological diagnostic work-up and radiological imaging. IAPA was diagnosed at a median of 4 days after ICU admission. Patients with IAPA did not differ from those with influenza alone regarding presence of European Organization for Research and Treatment of Cancer/Mycosis Study Group Education and Research Consortium (EORTC/MSGERC) host factors (9/32 [28%] versus 22/85 [26%], respectively; p = 0.82). They more frequently required invasive ventilatory support (26/29 [90%] versus 50/88 [57%], respectively; p = 0.001) and renal replacement therapy (15/33 [45%] versus 13/103 [13%], respectively; p < 0.001) in ICU. IAPA ICU mortality was significantly higher with 44% (15/34) compared to 14% (15/106) for influenza without aspergillosis (p < 0.001) and 17% (13/76) for niCAP. Non-survivors with IAPA were predominantly male (13/15 [87%] versus 9/19 [47%] survivors; p = 0.030) and more frequently received systemic corticosteroids in ICU (14/15 [93%] versus 10/19 [53%] survivors; p = 0.020). IAPA was an independent predictor of ICU mortality in patients with influenza (adjusted hazard ratio 1.99 [95% confidence interval 1.05 – 3.76]; p = 0.035). Conclusions: We demonstrate prospectively that IAPA is a frequent complication in critically ill patients with influenza and that it is associated with high mortality and an adverse clinical course, rendering increased awareness among treating physicians imperative.