3. Risk Factors Implicated in CAPA Development
Importantly, the pathogenesis of IPA differs between neutropenic and non-neutropenic patients, including those with COVID-19, impacting clinical presentation, radiological findings and diagnostic test results in the mycology laboratory [41,42]. Despite these important differences, revised European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) definitions [43] focus primarily on neutropenic patients with underlying hematological malignancies and “typical” presentation of IPA and have been shown to have limited applicability and inferior performance in non-neutropenic patients who frequently do not fulfil radiological and host criteria, including patients with COVID-19 [41,44]. This has resulted in the creation of an alternative clinical algorithm for diagnosing IPA in the ICU setting in 2012 [41], which defines putative IPA and is now the standard of care for defining IPA in the ICU [4,45], where highly reliable definitions of IA are still missing (work on improved definitions is currently in progress [45,46]).
Rapid development of CAPA few days following ICU admission [47] resembles the observation made for influenza-associated pulmonary aspergillosis [4,5]. Risk factors predisposing COVID-19 patients to develop secondary pulmonary aspergillosis are similar to those identified for influenza-IPA superinfections [4,5]. The most important risk factors include severe lung damage during the course of COVID-19 [48], the use of corticosteroids in those with ARDS, the widespread use of broad-spectrum antibiotics in intensive care units [49], and the presence of comorbidities such as structural lung defects [47,50,51,52].
There are some reports revealing that pulmonary fibrosis can be triggered by the cytokine storm activated by the viral antigens, toxicity posed by drugs, high airway pressure and hypoxia-induced acute lung injury secondary to mechanical ventilation [53]. While interstitial pulmonary fibrosis per se does not predispose to development of IPA, a small subset of these COVID-19 survivors may require long term corticosteroid treatment, which may predispose them to CAPA years after the acute phase of the viral infection. Overall, 29% of the CAPA cases published to date (10/35) had received systemic corticosteroids (Table 1). In those with ARDS, systemic corticosteroids are used to alleviate the immune responses and prevent cytokine storm [6,54,55,56], but may at the same time increase vulnerability for developing secondary infections [4,5].
Although detailed case series have not reported on antibiotic use among patients, broad-spectrum antibiotics are presumed to be used in 75% of COVID-19 patients admitted to ICU [49]. Since the human gut microbiome is a highly complicated structure of bacteria and fungi, although bacteria are the most diverse constituents, the administration of antibiotics results in perturbation of microbiome steady-state composition, which allows fungi to thrive, and may predispose the host to invasive fungal infections once the immune system becomes impaired [65,66].
Underlying medical conditions may also predispose COVID-19 patients to develop CAPA. Among the 35 CAPA cases published to date (Table 1), hypertension (17/35; 49%), diabetes (9/35; 26%), obesity (8/35; 23%), COPD (5/35; 14%), heart diseases (5/35; 14%), hypercholesterinemia (4/35; 11%), and asthma (3/35; 9%) were among the most prevalent comorbidities observed. While hypertension, coronary heart diseases, and diabetes increase the risk of infection overall [67,68,69], structural lung damage caused by COPD or asthma may particularly predispose patients to develop IPA [70].