Higher risk for influenza‐associated pulmonary aspergillosis (IAPA) in asthmatic patients: A Swiss multicenter cohort study on IAPA in critically ill influenza patients

Abstract Background Influenza‐associated pulmonary aspergillosis (IAPA) is an important complication of severe influenza with high morbidity and mortality. Methods We conducted a retrospective multicenter study in tertiary hospitals in Switzerland during 2017/2018 and 2019/2020 influenza seasons. All adults with PCR‐confirmed influenza infection and treatment on intensive‐care unit (ICU) for >24 h were included. IAPA was diagnosed according to previously published clinical, radiological, and microbiological criteria. We assessed risk factors for IAPA and predictors for poor outcome, which was a composite of in‐hospital mortality, ICU length of stay ≥7 days, mechanical ventilation ≥7 days, or extracorporeal membrane oxygenation. Results One hundred fifty‐eight patients (median age 64 years, 45% females) with influenza were included, of which 17 (10.8%) had IAPA. Asthma was more common in IAPA patients (17% vs. 4% in non‐IAPA, P = 0.05). Asthma (OR 12.0 [95% CI 2.1–67.2]) and days of mechanical ventilation (OR 1.1 [1.1–1.2]) were associated with IAPA. IAPA patients frequently required organ supportive therapies including mechanical ventilation (88% in IAPA vs. 53% in non‐IAPA, P = 0.001) and vasoactive support (75% vs. 45%, P = 0.03) and had more complications including ARDS (53% vs. 26%, P = 0.04), respiratory bacterial infections (65% vs. 37%, P = 0.04), and higher ICU‐mortality (35% vs. 16.4%, P = 0.05). IAPA (OR 28.8 [3.3–253.4]), influenza A (OR 3.3 [1.4–7.8]), and higher SAPS II score (OR 1.07 [1.05–1.10]) were independent predictors of poor outcome. Interpretation High clinical suspicion, early diagnostics, and therapy are indicated in IAPA because of high morbidity and mortality. Asthma is likely an underappreciated risk factor for IAPA.


| INTRODUCTION
Influenza is a known risk factor for invasive pulmonary aspergillosis, 1 as are other viral respiratory infections including SARS-Cov-2 (COVID-19), 2 parainfluenza, and respiratory syncytial virus. 3 Since its first case description in 1952, 4 influenza-associated pulmonary aspergillosis (IAPA) is increasingly recognized as a severe complication in critically ill influenza patients. [5][6][7][8] IAPA incidence ranges from 10% to 32% of influenza patients admitted to ICU. 1,9,10 Differences in prevalence might be related to different awareness and screening practices. 11 Risk factors for developing IAPA include male sex, smoking, chronic lung disease, influenza A, solid organ transplant, hematologic malignancy, and treatment with corticosteroids within 28 days prior to influenza infection but are otherwise poorly defined. 1,26 IAPA carries a high mortality of 30-60% 1,5,6,12,13 and commonly results in need of organ supportive therapies. 14 Optimal diagnostic and preventive strategies are unclear. 15 During the 2017/2018 season, we identified IAPA in 11% of critically ill influenza patients in two Swiss centers, which was associated with high risk of complications and mortality. 14 In the current study, we aimed to analyze the epidemiology and clinical outcome of IAPA in a multicenter study of Swiss ICUs combining our 2017/2018 data with new data from 2019/2020.

| STUDY DESIGN AND METHODS
We performed a multicenter cohort study in ICUs of seven tertiary Our inclusion criteria and definitions were reported previously. 14 We combined data on influenza patients from seven ICUs    F I G U R E 1 Screening algorithm for IAPA in critically ill patients with influenza on the ICU. *If critically ill and unstable patient with suitable clinical presentation of IAPA start preemptive therapy before microbiological results are obtained. Determine GM before starting antifungal treatment because of rapid decrease under therapy. Determine voriconazole trough level after 5-7 days (aim at 1-5 mg/L). Alternative treatment: liposomal amphotericin B. IAPA = influenza-associated pulmonary aspergillosis, BAL = bronchoalveolar lavage, TS = tracheal secretion

| Diagnostics
Despite our proposed algorithm, GM was more often measured (overall: 94% vs. 40%, P < 0.001) in patients with IAPA than those without IAPA (Table 2). GM was positive in serum in 57% versus 3% and in BAL in 42% versus 0% (P < 0.001) of patients with IAPA and without IAPA. Cultural growth of Aspergillus spp. was observed in 88% of patients with IAPA and in one non-IAPA patient in whom BAL was performed (P < 0.001). All patients with IAPA had radiological infiltrates on chest x-ray or computer tomography (CT)-scan T A B L E 1 Baseline characteristics compared with 83% of non-IAPA patients (P = 0.08). IAPA was proven in one patient with histopathological evidence of invasive aspergillosis, and all other patients were classified as probable IAPA (94%).

| DISCUSSION
This study on critically ill influenza patients in seven tertiary care hospitals in Switzerland found an IAPA prevalence of 10.8% over two influenza seasons. IAPA was independently associated with asthma and duration of mechanical ventilation and was an independent risk factor for poor outcome. Other independent predictors of poor outcome were influenza A and higher SAPS II. Prednisone treatment within 28 days prior to influenza infection has been recognized as a risk factor for developing IAPA 1 and corticosteroid treatment is a risk factor for invasive fungal infection in lung disease. 22 Corticosteroid treatment was also shown to cause a higher fungal burden in the lung. 23 Therefore, application of inhaled and/or systemic corticosteroids in asthma patients could explain the higher risk for IAPA. Our data also show more frequent corticosteroid treatment in asthma patients during hospitalization. In addition, asthma patients have altered mucociliar clearance of the lung that explains higher rates of fungal growth and colonization in these patients. 24 High clinical suspicion, early and regular screening for IAPA are therefore warranted in asthma patients. Similarly, this underlines the importance of influenza vaccination for patients with asthma as recommended in Swiss guidelines. 25 The colonization with Aspergillus spp.-a prerequisite for the development of IAPA-likely occurs prior to ICU admission as suggested by the POSA-flu trial, where posaconazole prophylaxis started on ICU admission had failed to prevent IAPA or lower mortality in influenza patients. 15 The authors therefore concluded that development of invasive fungal disease occurs early after influenza infection as 71% of IAPA cases were diagnosed within 24 h of ICU admission. This seems plausible since colonization with Aspergillus spp. is a known risk factor for developing invasive aspergillosis. 26 Identification of asthma as a risk factor for IAPA further strengthens this pathophysiologic hypothesis since asthma patients are frequently colonized with Aspergillus spp. 24,27 This study identified IAPA, high SAPS II, and infection with influenza A as predictors for poor outcome in critically ill patients with influenza. High mortality in patients with IAPA has been reported by us and others. 1,14 Interestingly, influenza A was associated with poor outcome that was also shown in a recent metaanalysis of 14 studies of IAPA. 28 An association of influenza A with an increased risk of bacterial respiratory infections and mortality has been previously suggested, 29

PEER REVIEW
The peer review history for this article is available at https://publons. com/publon/10.1111/irv.13059.

DATA AVAILABILITY STATEMENT
Data are available upon request.