key: cord-1008967-er68j9r4
authors: Brüggemann, Roger J; van de Veerdonk, Frank L; Verweij, Paul E
title: The challenge of managing COVID-19 associated pulmonary aspergillosis
date: 2020-08-18
journal: Clin Infect Dis
DOI: 10.1093/cid/ciaa1211
sha: a4795c8baf4e42b6f48d427c46cf1f253daf7b93
doc_id: 1008967
cord_uid: er68j9r4

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M a n u s c r i p t Dr. Bartoletti and colleagues are the first to perform a prospective study to determine the incidence and mortality of COVID-19 associated pulmonary aspergillosis (CAPA) by systematic bronchoalveolar lavage (BAL) sampling in 108 mechanically ventilated patients with proven COVID-19 and acute respiratory distress syndrome (ARDS). The results show a very high incidence of 27.7% of CAPA and a 25% lower survival in patients compared to those not fulfilling the criteria for aspergillosis (44% vs 19%, p= 0.002) [Bartoletti et al, CID accepted for publication]. The authors indicate that CAPA has similarities to influenza associated pulmonary aspergillosis (IAPA) including the high prevalence of aspergillosis cases, comparable timing of CAPA and IAPA following ICU-admission, and the presence of lymphopenia.

Diagnosing patients with CAPA has been subject of much debate (1, 2). Recent case series indicate that well known host factors for invasive pulmonary aspergillosis (IPA) are commonly absent in COVID-19 patients in the ICU, and that radiology is seldom specific for invasive fungal disease (3) (4) (5) (6) . Due to limited use of bronchoscopy, CAPA diagnosis commonly relies on detection of Aspergillus in upper respiratory tract specimens such as sputum or tracheal aspirates, which may represent airway colonization rather than IPA. Diagnostic uncertainty is further increased by frequent negative serum galactomannan (GM), even in patients with proven CAPA (4) as well as the observation of survival of Aspergillus positive patients who did not receive antifungal therapy (5) . Although histopathology would be required to prove angio-invasive disease, the study of Bartoletti et al. provides important evidence that detection of Aspergillus in critically-ill COVID-19 patients should be taken seriously. Through systematic bronchoscopy with BAL in COVID-19 patients with ARDS admitted to the ICU, a significant association was observed between CAPA diagnosis and mortality. A possible causal relation is supported by the correlation between initial BAL GM-index and odds of death and the trend towards lower mortality and GM index reduction in CAPA-patients receiving voriconazole.

Despite the observed similarities between IAPA and CAPA and the independent association between CAPA and mortality, it remains unclear if COVID-19 infection itself predisposes for IPA.

A c c e p t e d M a n u s c r i p t

The pathophysiology of SARS-CoV-2 infection is different to that of influenza, including viral tropism as well as the effects on the host defense. Thus, additional risk factors may be required to develop IPA in COVID-19 patients. In the cohort of Dr Bartoletti and colleagues, two immunosuppressant agents, corticosteroids and tocilizumab, were widely used. Three quarters of the patients received anti-IL-6 treatment with tocilizumab. IL-6 is an important inducer of STAT3 which in turn is essential for protective Th17 responses (7) . Patients who are deficient in STAT3 are specifically susceptible for IPA (8) . Therefore, the blockade of IL-6 might be a very specific risk factor for the development of CAPA. In addition, it is known that corticosteroids can impair a specific form of phagocytosis called LC3-associated phagocytosis (LAP), which is essential for host defense against aspergillosis (9) . Chronic steroid treatment was significantly more frequent in CAPA patients, while corticosteroid use was more frequent in non-survivors. The authors argue that reluctance to initiate antifungal therapy was due to the microbiology results being interpreted as respiratory colonization. The observed excess mortality in CAPApatients underscores the need for therapeutic interventions.

As many centers may not have rapid access to diagnostics test such as GM and beta-D-glucan, and bronchoscopy may not be performed due to the associated contamination risk, antifungal prophylaxis might be a feasible approach. The question remains, with which drug as currently no antifungal agent is licensed for prophylactic use in the ICU.

A prophylactic strategy has been proposed for the management of IAPA (10) , and a pilot study with intravenous posaconazole is currently being conducted in patients admitted to the ICU with influenza (the POSAFLU trial; NCT03378479). Results from this study might help to further explore the feasibility and benefits of a prophylactic strategy in CAPA.

Regardless of the strategic choice made, all efforts should be put into improving our ability to reliably identify patients that may benefit from therapeutic interventions, which include host and risk factors, clinical factors and CAPA disease markers. The WHO recently published a minimal common outcome measure set for COVID-19 clinical research, aimed to routinely collect specific data elements of COVID-19 patients in order to facilitate pooling of data across M a n u s c r i p t cohort studies and clinical trials (11) . The initiative may help to gain better insights in the dilemmas surrounding CAPA diagnosis and management if fungal infections are added to the secondary infection outcome set (Verweij and Alanio, accepted for publication Lancet Infect Dis 2020). In the meantime the study from Bartoletti et al alerts the clinical audience to be aware of CAPA and take appropriate (and where needed repetitive) actions that fits their clinical setting.

A c c e p t e d M a n u s c r i p t NOTES

Late histopathologic characteristics of critically ill COVID-19 patients: Different phenotypes without evidence of invasive aspergillosis, a case series

COVID-19-associated Pulmonary Aspergillosis

COVID-19-associated invasive pulmonary aspergillosis

Prevalence of putative invasive pulmonary aspergillosis in critically ill patients with COVID-19

COVID-19 associated pulmonary aspergillosis

Interleukins 1beta and 6 but not transforming growth factor-beta are essential for the differentiation of interleukin 17-producing human T helper cells

Autosomal dominant STAT3 deficiency and hyper-IgE syndrome: molecular, cellular, and clinical features from a French national survey

Corticosteroids block autophagy protein recruitment in Aspergillus fumigatus phagosomes via targeting dectin-1/Syk kinase signaling

Review of influenza-associated pulmonary aspergillosis in ICU patients and proposal for a case definition: an expert opinion

Characterisation WHOWGotC, Management of C-i. A minimal common outcome measure set for COVID-19 clinical research

Conflicts of interest: Roger Brüggemann has served as a consultant to Astellas Pharma, F2G, Amplyx, Gilead Sciences, MSD and Pfizer and has received unrestricted and research grants from Astellas Pharma, Gilead Sciences, MSD and Pfizer. All contracts were through Radboudumc and all payments were invoiced by Radboudumc. Frank van de Veerdonk reports personal fees from Gilead and Sobi, outside the submitted work. Paul Verweij reports grants from Mundipharma, F2G, Pfizer, Thermofisher, Gilead Sciences, and Cidara; advisory board fees from F2G and Cidara, and non-financial support from IMMY, outside the submitted work.

A c c e p t e d M a n u s c r i p t