4  DISCUSSION
Reports of pulmonary aspergillosis complicating severe COVID‐19 required mechanical ventilation are emerging. 5 ,  6  Most patients did not have underlying immunocompromising conditions, as observed in patients with ARDS due to influenza. 2  Detailed data from patients who presented in the first waves of COVID‐19 pandemic are needed to define the incidence and clinical features of COVID‐19‐associated pulmonary aspergillosis (CAPA). 8  We herein describe the clinical characteristics of four cases of critically ill COVID‐19 complicated by putative IPA.
Early diagnosis of IPA is critical but challenging in mechanically ventilated patients with COVID‐19. Bronchoscopy and transbronchial biopsy are rarely performed given the risk of complications and transmission of the virus. Further, pneumonia due to SARS‐CoV‐2 may obscure the radiological findings of IPA. Consolidation is commonly seen in both COVID‐19 and superimposing pulmonary aspergillosis, and any new radiological signs could be obscured by background bilateral ground‐glass opacities. Systemic inflammatory markers are almost always elevated with severe COVID‐19, which make them less useful to diagnose secondary fungal infection. While it has been suggested that a low procalcitonin level may indicate a high likelihood for invasive fungal infection in critically ill patients with clinical signs of sepsis, 9  the procalcitonin level was elevated in only two patients with putative IPA.
At our institution, fungal cultures are routinely performed on bronchoscopy specimens and other respiratory specimens as clinically indicated; consequently, it is plausible there were instances of Aspergillus respiratory infection that were not identified. Aspergillus infection can be seen in construction‐related clusters. 10  While there was some construction at our institution during the first wave of COVID‐19, it was physically remote from the units where all of the cases were identified. Further, there were no instances of isolating Aspergillus from any patients without the diagnosis of COVID‐19 within or around the study period.
For research purposes, EORTC/MSG Consensus Group have proposed definitions of proven, probable and possible invasive fungal disease. 11  However, these consensus definitions are much less useful for immunocompetent patients in the ICU, as the diagnosis of probable or possible IPA requires the presence of classic host factors. We used the AspICU criteria, which is an algorithm for diagnosing IPA in the ICU patients with positive Aspergillus endotracheal aspirate cultures, 7  to distinguish putative IPA from colonisation. However, the performance characteristics of the algorithm for COVID‐19 patients have not been validated with autopsy or postmortem biopsy data.
Serum galactomannan was positive in only one patient in our case series. Serum galactomannan is more specific for invasive aspergillosis than beta‐D‐glucan but has poor sensitivity in non‐neutropenic patients. 12  Combining three case series of CAPA, only three (13%) out of 23 patients had positive serum galactomannan level. 5 ,  6 ,  13  The less frequently elevated serum galactomannan levels might simply reflect colonisation rather than infection or suggest that angioinvasive pulmonary infection is a rare phenomenon in CAPA. In any case, the diagnostic value of serum galactomannan for CAPA seems less promising.
All the patients with putative IPA died in our consecutive cases, suggesting the grave prognosis of critically ill patients with CAPA. On the other hand, Alanio et al reported no significant difference in mortality between IPA and non‐IPA patients in a report of eight COVID‐19‐infected patients with putative IPA. 6  Further data from multi‐institutional series are needed to clearly characterise the potential impact on mortality of CAPA. Although dexamethasone was recently shown to decrease 28‐day mortality in mechanically ventilated patients with COVID‐19, 14  the majority of our cases received much higher doses of glucocorticoids than what was proven beneficial. Since one of the potential sequelae of COVID‐19 is secondary fungal infections as our cases demonstrated, vigilance for secondary infections will be needed to reduce adverse outcomes. Clinicians should have a high index of suspicion for CAPA when a critically ill patient with COVID‐19 in the ICU develops further respiratory decompensation, fevers or new or worsening radiographic abnormalities of the lungs, particularly if there is no response to empiric antibacterial therapy. It is important to obtain a respiratory culture for fungal pathogens and a serum galactomannan level in these settings to attempt to identify this ominous complication of COVID‐19.