In this study, we present a large cohort of critically ill patients with COVID-19 from a medical center located in the midwestern USA. We found that CAPA was uncommon and occurred in only 1% of patients. Our findings contrast with data from several European studies, which have noted an alarming number of CAPA cases complicating critically ill patients with COVID-19, with rates of 19–33% [6,7,8,9, 11]. Outside of Europe, a study from Pakistan noted a cumulative incidence of CAPA of 22% in mechanically ventilated patients . Similar to our findings, one Swiss study reported only three cases of CAPA (2.5%) among 118 critically ill patients with COVID-19 .
The exact incidence and risk factors for CAPA in critically ill patients with COVID-19 are not well understood. Other respiratory viral infections, particularly influenza, have been shown to be independent risk factors for IPA and increase mortality [4, 5]. Patients with influenza-associated aspergillosis (IAPA) typically do not have classic risk factors like neutropenia or T-cell immunosuppression [1, 14, 15]. Rather, influenza infection itself leads to disruption of the respiratory epithelium and destruction of mucociliary clearance [4, 15]. This allows for easier invasion by fungal organisms that are already colonizing the respiratory tree. Influenza may also impair the local immune response by impairing phagocytosis and reducing natural killer cell function via cytokine imbalance.  As the pathophysiology of IAPA is different than traditional IPA, which relies heavily on underlying immunocompromise, patients with IAPA are more likely to have atypical findings on imaging and, since angioinvasion is uncommon, may not present with positive biomarkers like β-D-glucan or GM [14,15,16].
As critically ill patients with COVID-19 may have similar clinical and radiological presentations as patients with severe influenza, it is possible that a similar process may be at play regarding susceptibility to fungal disease. Indeed, recognition of the similarities between influenza and COVID-19 related lung disease may have led to rapid recognition of aspergillosis in patients with COVID-19 early in the SARS-CoV-2 pandemic . Autopsies of patients with the closely related epidemic coronavirus SARS-CoV-1 have demonstrated lung findings consistent with aspergillosis, albeit in the setting of high dose steroid administration [18, 19]. Patients with COVID-19 have been shown to have activation of the innate immune system in the lungs, leading to localized inflammation and presumably similar damage to the respiratory epithelium similar to that seen in IAPA [14, 20]. Patients with severe COVID-19 also have lymphopenia and altered cytokine levels, likely leading to impaired immune cell function as is seen in IAPA . Based on its similarity to IAPA, patients with CAPA may also present atypically, as did all three patients in our study (Table 2).
As the pathophysiology of severe COVID-19 pneumonia is universal and does not differ based on geographic location, one wonders why multiple European centers have much higher rates than our center located in the USA. Rates of Aspergillus infection vary around the world, and rates of Aspergillus infection may be lower in North America as compared to Europe; this has been specifically demonstrated for IAPA in a large Canadian series . The reason for this difference in incidence is unknown, but speculation is that both genetic and environmental factors (including the local Aspergillus spore composition and distribution) are at play . In addition, European centers may have higher rates than our center due to increased detection of IPA in patients with COVID-19. European centers have demonstrated awareness of and experience with secondary Aspergillus infections, as evidenced by the bulk of literature on IAPA, as well as the early reports of COVID-associated secondary aspergillosis [6,7,8,9, 11, 22]. Several European centers have established screening protocols for CAPA in patients with severe COVID-19 [11, 13, 22]. This strategy may have led to early identification of a larger number of patients with CAPA. Our center did not standardize screening for CAPA in patients with severe COVID-19, but providers often obtained tracheal aspirate cultures, serum GM, and beta-D-glucan assay when clinically indicated. Similar to practice in other institutions, BAL fluid was uncommonly obtained as bronchoscopies were often deferred in patients with COVID-19 to minimize aerosol-generating procedures [13, 20].
The use of tocilizumab, which inhibits interleukin-6 (IL-6) and presumably halts the cytokine cascade, has been proposed as a predisposing factor for CAPA. IL-6 plays an important role in the immune system response to Aspergillus, and animal models suggest that decreased IL-6 levels increase susceptibility for Aspergillus infection [20, 23]. As per our institutional guidelines, 94 of our patients received tocilizumab for the treatment of COVID 19; only three of them developed CAPA . In a retrospective review from our institution, tocilizumab use was associated with an increase in bacterial pneumonia but not with fungal infections .
Another proposed risk factor for CAPA is the widespread use of negative pressure rooms in patients with COVID-19. Data from observational studies support the use of positive pressure in the immunocompromised to prevent IPA; under normal circumstances, positive air pressure is used in ICU rooms . However, during the height of the COVID-19 pandemic, a large portion of our ICU rooms were converted to negative air pressure rooms as recommended to protect patients and health care workers [26, 27]. In this setting, air could have been pulled from the outside environment, increasing the risk of fungal infection through the spread of aerosols, even in the setting of HEPA filtration [25, 28, 29]. Outbreaks of IPA have been linked to the use of negative pressure rooms for COVID-19 patients and switching to neutral or positive pressure ameliorated the outbreak in one instance .
Our study was limited by its retrospective and single-center nature. Importantly, the use of corticosteroids in the management of COVID-19 was not standardized at our center. In the early pandemic, steroid use was not recommended under our institutional guidelines. A subsequent large multi-center study demonstrated a survival benefit of dexamethasone in patients with severe COVID-19, and guidelines were later changed to recommend steroid use; this occurred after the completion of our study period . Our patients were followed for 30 days from the time of their ICU admission for COVID-19 and thus, cases of CAPA occurring beyond that period were not captured.
Our findings contrast with previous reports and highlight the significant variability in the rates of CAPA at different centers. Collaborative efforts are needed to further understand the specific geographic and environmental factors that may determine the risk of CAPA in critically ill patients with COVID-19.