Introduction
Influenza is a known risk factor for invasive pulmonary
aspergillosis1, as are other viral respiratory
infections including SARS-Cov-2 (COVID-19)2,
parainfluenza and respiratory syncytial virus3. Since
its first case description in 19524influenza-associated pulmonary aspergillosis (IAPA) is increasingly
recognized as a severe complication in critically ill influenza
patients5-8. IAPA incidence ranges from 10-32% of
influenza patients admitted to ICU 1, 9,10. Differences in prevalence might be related to
different awareness and screening practices11. Risk
factors for developing IAPA include male sex, smoking, chronic lung
disease, influenza A, solid organ transplant, haematologic malignancy
and treatment with corticosteroids within 28 days prior to influenza
infection but are otherwise poorly defined1,26. IAPA
carries a high mortality of 30-60% 1, 5, 6,12, 13 and commonly results in need of organ
supportive therapies14. Optimal diagnostic and
preventive strategies are unclear15.
During the 2017/18 season we identified IAPA in 11% of critically ill
influenza patients in two Swiss centers which was associated with high
risk of complications and mortality14. In the current
study we aimed to analyze the epidemiology and clinical outcome of IAPA
in a multicenter study of Swiss ICUs combining our 2017/18 data with new
data from 2019/20.
Study design and methods
We performed a multicenter cohort study in ICUs of seven tertiary care
hospitals in Switzerland during the 2019/20 influenza season.
Participating ICUs received an educational training on influenza and
IAPA in fall 2019 and a screening algorithm for IAPA was implemented
(figure 1) in order to increase awareness of this entity and homogenize
diagnostics and treatment strategies. We proposed to screen all patients
with influenza infection systematically for IAPA on admission to the ICU
using fungal cultures from bronchoalveolar lavage (BAL) or tracheal
secretion (TS), if BAL was not possible, and galactomannan (GM) from BAL
or serum. A positive GM was defined as >0.5 in serum and
>1.0 in BAL. Patients were assessed daily for new clinical
signs of IAPA, which triggered microbiological sampling for
aspergillosis from BAL (or TS) and serum. IAPA was diagnosed according
to diagnostic criteria by Schauwvlieghe et al. and Blot et
al1, 16. Anti-mold treatment was initiated as soon as
criteria of IAPA were fulfilled or pre-emptively if patients were
unstable and had suspicion of IAPA (figure 1). All data were
retrospectively collected from electronic medical records. Our inclusion
criteria and definitions were reported previously 14.
We combined data on influenza patients from seven ICUs during the
2019/20 influenza season with those from the 2017/18 influenza season of
two tertiary care hospitals (University Hospital Geneva, Cantonal
Hospital St. Gallen). The primary outcome was to find risk factors for
IAPA and secondary outcomes were to define predictors for poor outcome,
which was a composite of in-hospital mortality, ICU length of stay (LOS)
≥ 7d, mechanical ventilation ≥ 7d or extracorporeal membrane oxygenation
(ECMO).
The study was approved by the local ethics committees (EKOS 2018-01994
and 2019-02173). Funding was provided by the research funding of the
Cantonal Hospital of St. Gallen and the Swiss network on fungal diseases
(FUNGINOS).
Statistical analysis
No missing data were observed in 158 data sets. Continuous variables
were not categorized. Continuous variables were assessed by Wilcoxon
ranksum test, categorical values by Fisher’s exact test. Multivariable
logistic regression was performed to assess risk factors for IAPA and
the composite poor outcome. To prevent multicollinearity, we first
removed variables which were obviously (per definition, or clinically)
related to the relevant outcomes (antifungal therapy for IAA, and
intubation, renal replacement therapy, ARDS, bacterial superinfection
and delirium for bad outcome). The last two variables e.g. are known to
be associated with ICU-LOS.
Variables with very low numbers were also removed from the model (i.e.
neutropenia, solid organ transplantation). Restricted cubic splines were
used for modelling continuous variables. We performed a stepwise
backward elimination procedure. Collinearity was tested with variance
inflation factor and variables that were highly collinear were
eliminated. Bootstrapping procedures were used to check validation and
calibration of the model. Kaplan Meier curves were analyzed for
assessment of duration of ICU stay. Univariate analysis of LOS-ICU was
performed by the logrank test. All statistical analyses were performed
by R 4.0.2 (2017, R foundation for statistical computing, Vienna,
Austria).
Results
We included 158 influenza patients (81 [51%] from the 2017/18 and
77 [49%] from the 2019/20 influenza season). 17 patients (10.8%)
were diagnosed with IAPA. We did not observe a different proportion of
IAPA over the two influenza seasons (2017/18: 9 cases [11.1%],
2019/20: 8 cases [10.3%], p=1.0). Baseline characteristics were
similar in patients with and without IAPA, except for a significantly
higher prevalence of asthma among patients with IAPA (p=0.05, table 1).
Patients with and without asthma received corticosteroids in 3/8
(37.5%) vs. 27/150 (18%, p=0.2) before influenza diagnosis and in 7/8
(87.5%) vs. 76/150 (50.7%, p=0.05) during hospitalization.