PMC:7306567 / 26144-32058 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/7306567","sourcedb":"PMC","sourceid":"7306567","source_url":"https://www.ncbi.nlm.nih.gov/pmc/7306567","text":"Conclusion\nIAPA has emerged as a severe complication of influenza, especially in ICU patients, and this secondary infection may occur in any patient, including those considered to be at low risk of developing IPA. The global epidemiology of IAPA may be variable, which might be partly due to underdiagnosis [24]. The clinical presentation of IAPA includes invasive Aspergillus tracheobronchitis, which requires bronchoscopic visualization of plaques in the airways to make a diagnosis. Aspergillus culture and BAL GM are positive in \u003e 80% of IAPA cases, and ordering such tests is recommended in influenza cases in the ICU. The proposed case definition relies on an entry criterion based on an influenza-like illness and the detection of influenza virus. The case definition distinguishes between invasive tracheobronchitis and other pulmonary forms of IAPA, with demonstration of invasive fungal hyphae with positive mycology qualifying as proven infection. Detection of GM or positive Aspergillus culture in BAL is the main mycological criteria in probable case definition.\nThe expert group acknowledges that to date still limited data exist to support a definitive approach regarding definitions, diagnosis and treatment of IAPA, but the proposed case definition will facilitate clinical research, will enable valid study comparisons and is essential for surveillance. Awareness of IAPA and early antifungal therapy based on high clinical suspicion and Aspergillus diagnostics remains critical to improve the outcome of IAPA.\n\nCan the IAPA definitions be applied to COVID-19-associated pulmonary aspergillosis?\nRecent reports of IPA cases in coronavirus disease 2019 (COVID-19) patients in the ICU raise the question of whether these IAPA definitions can be applied to COVID-19-associated pulmonary aspergillosis (CAPA) [58–60]. Although the number of CAPA cases that have been reported is still limited, two recent studies reported putative CAPA cases in 9 of 27 (33%) and 5 of 19 (26%) COVID-19 patients admitted to the ICU [59, 60]. Although the high number of cases suggests a high risk of developing IPA in COVID-19 patients, there are a number of differences regarding the pathogenesis of SARS-CoV-2 infection compared with influenza (Table 2). In influenza patients, there are several factors that are thought to contribute to the risk of IAPA, including the local tissue damage caused by influenza, an immune modulatory effect by suppression of the NADPH oxidase complex and possible effect of treatment with neuraminidase inhibitors, such as oseltamivir. In SARS-CoV-2 infection, another receptor is used by the virus to enter human cells, which are not commonly found in the large airways (Table 2). Thus, the risk of invasive Aspergillus tracheobronchitis may be lower in CAPA compared with IAPA. In addition, there is no known direct immune modulatory effect of SARS-CoV-2, which suggests no virus infection-related increased risk of IPA. While IAPA is characterized by rapidly fatal infections with high fungal burden, such course of disease progression has not been reported for CAPA. On the contrary, eight of nine CAPA cases reported from a French cohort did not receive antifungal therapy, with a mortality rate similar to COVID-19 cases without IPA [59]. As, in contrast to IAPA cases, virtually all CAPA cases reported to date are serum GM negative, the question remains if COVID-19 patients develop invasive disease or just become colonized with Aspergillus. It is possible that COVID-19 is in itself not a risk factor for IPA, but that the risk is associated with other risk factors related to treatment such as administration of corticosteroids or underlying host factors. Nevertheless, the high rate of Aspergillus recovered from COVID-19 patients suggests that there might be conditions that favor growth of the fungus in the lung. We think that the proposed IAPA case definitions may be considered for classification of CAPA patients, while awaiting further histopathological studies that provide more insight into the interaction between Aspergillus and the SARS-CoV-2-infected lung.\nTable 2 Comparison between characteristics of IAPA and CAPA\nFactor IAPA CAPA\nHost/Risk 57% EORTC/MSGERC host factor negative [9] 85% EORTC/MSGERC host factor negative [59, 60]\nIAPA associated with corticosteroid use [7] IPA developed in SARS-2003-infected patients receiving corticosteroids [61]\nLymphopenia and chemokine-producing monocyte-derived FCN1 + macrophages causing hyperinflammation [62]\nVirus Cell entry through sialic acids-2,6Gal: epithelial layer in lung including larger airways [63] Cell entry through ACE2: type 2 pneumocytes and ciliated cells [64]\nImmune modulation by suppression of the NADPH oxidase complex [65] No evidence for immunomodulatory effect on known antifungal host defense mechanisms, although this has not been extensively studied yet\nFungal infection Invasive Aspergillus tracheobronchitis in up to 55% of patients [7–9] Invasive Aspergillus tracheobronchitis not yet reported [59, 60]\nMedian time between ICU admission and IAPA diagnosis 2–3 days [7–9] Median time between ICU admission and CAPA diagnosis 6 days [59]\nAspergillus diagnostics BAL GM positive in \u003e 88% [7–9] BAL GM commonly positive, diagnostic performance currently unknown [59, 60]\nSerum GM positive in 65% [7–9] Serum GM positive in 3 of 14 (21%) COVID-19 patients [59, 60]\nSecondary infections In 80 of 342 (23.4%) ICU patients, most frequent pathogens S. pneumoniae, Pseudomonas aeruginosa and S. aureus [66] In four of 13 (31%) ICU patients, pathogens not specified [67]\nICU mortality 45% in IAPA compared with 20% in influenza without IAPA (p \u003c 0.0001) [9] 33% in CAPA cases compared with 17% in COVID-19 without CAPA (p = 0.4) [59] (although mortality rates due to COVID-19 without CAPA vary enormous between countries and we have no clear data yet on the true mortality in ICU of 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