In this first prospective study investigating the incidence of IAPA using a targeted screening protocol, we found an incidence of 9%, confirming an increased risk of invasive pulmonary aspergillosis among influenza patients admitted to the ICU. The study included 12 Swedish intensive care units and spanned four influenza seasons. Until now, all published studies have been retrospective, presenting a significant risk of bias as the diagnosis of IAPA depends on specific diagnostic tests. Since the initial report by Wauters et al. in 2012 raised awareness about a potential association between influenza and invasive pulmonary aspergillosis [14], several retrospective studies have replicated this association. The first major study was published in 2019 by Schauwvlieghe et al. [1] and found the IAPA incidence to be as high as 19% in a retrospective cohort of 432 influenza patients admitted to ICUs in Belgium and the Netherlands. The finding prompted studies from many other regions, studies which generally have reported significantly lower incidences [15]. The most recent major study, published in 2021, found an IAPA incidence of 5.3% in a retrospective cohort of 524 ICU patients in France [6].
There are several possible explanations for the significant regional variations, such as differences in the patients' underlying health conditions, concurrent use of corticosteroids, and exposure to Aspergillus due to environmental factors. Other important explanations are the limitations inherent to a retrospective study design, and until recently, lack of accepted criteria for diagnosing IAPA. The problem with using criteria not explicitly tailored to the target population was recently addressed in a study by Schroeder et al. [16], revealing that the concordance among four earlier classification systems for invasive pulmonary aspergillosis was as low as 4%.
In the present study, these limitations were addressed by a prospective design and application of the IAPA classification proposed by Verweij et al. The IAPA incidence of 9% found in the study aligns with the results from a recent meta-analysis [15], which included a large set of retrospective cohorts. In the metanalysis, the IAPA incidence varied considerably from 2–31%, but with an overall estimated IAPA incidence of 10%.
An important finding from the study was that screening with non-invasive test, i.e. serum BDG and GM and upper respiratory cultures, had limited sensitivity and specificity both for identifying and establishing IAPA cases. Serum GM had a very limited sensitivity of 20%, but with a 100% specificity it could prove valuable in situations where a BAL is not feasible. The utility of BDG appeared limited, with a 40% sensitivity for IAPA, and a specificity of 90%, it will generate an excessive number of false positives in a population with low IAPA prevalence. This outcome was predictable given that the test is not Aspergillus-specific. The very limited sensitivity of non-invasive tests for identifying IAPA cases strongly indicates that BAL is necessary in most cases for idenfying IAPA, and thus should be performed in all severely ill patients if possible.
Our study has several limitations, one of which is the small cohort size, which hampered our ability to determine the incidence of IAPA in Sweden with high accuracy (9%, 95% CI 3.82% − 20.4%). The lower-than-expected enrolment rate was primarily due to the COVID-19 pandemic, which significantly reduced the incidence of influenza. Nevertheless, we managed to include the majority of influenza patients admitted to the study centres during this period, thus maintaining the validity of our results. Despite promoting BAL in the screening protocol, it was only performed for 45% of the patients, probably due to concerns of respiratory failure. This could have led to underestimating the true prevalence, as only one IAPA patient would have been diagnosed without a BAL. However, BAL was predominantly not performed in less ill patients. In fact, none of the patients who did not receive mechanical ventilation underwent BAL. Despite this, all patients not mechanically ventilated were successfully discharged alive from the ICU, which could suggest that IAPA was not missed.
The ICU mortality rate of 13% in our cohort was low compared to previous cohorts, ranging from 19–29% [1, 2, 6]. The severity of the disease, measured by the SAPS 3 and SOFA, was also lower. These factors may influence the incidence of IAPA, as illness severity has been reported to be associated with an increased risk of IAPA [1].
In conclusion, this is the first-ever prospective study to investigate the incidence of IAPA. Additionally, it is the only report on the incidence of IAPA in the Nordic region, providing regional data that were previously lacking. We observed a high mortality among IAPA patients, underlining the urgency to raise awareness about this often-fatal superinfection. Most patients diagnosed with IAPA lacked traditional risk factors, underscoring the importance of routine testing for aspergillosis in influenza patients in the ICU. Non-invasive testing has a low sensitivity, and BAL with fungal culture and GM testing should be considered in all mechanically ventilated influenza patients.