key: cord-0685691-8jgl15cx
authors: Koehler, Philipp; von Stillfried, Saskia; Garcia Borrega, Jorge; Fuchs, Frieder; Salmanton-García, Jon; Pult, Fabian; Böll, Boris; Eichenauer, Dennis A.; Shimabukuro-Vornhagen, Alexander; Kurzai, Oliver; Boor, Peter; Kochanek, Matthias; Cornely, Oliver A.
title: Aspergillus tracheobronchitis in COVID-19 patients with acute respiratory distress syndrome: a cohort study
date: 2022-05-05
journal: Eur Respir J
DOI: 10.1183/13993003.03142-2021
sha: 251ebf2523cc7868df7792959024cc8e04e1af7b
doc_id: 685691
cord_uid: 8jgl15cx

Comprehensive work-up is needed for COVID-19 ARDS patients, especially when suspecting invasive fungal infections. Aspergillus tracheobronchitis has a substantial prevalence in patients with CAPA accounting for an overall mortality of 75% in this study. https://bit.ly/3uF3FZU

therapy during the stay on ICU. Of those, 53 patients were treated with more than one antibiotic. Median treatment duration was 14 days (IQR 9.25-17.75, range 2-49 days) for the total cohort. In CAPA patients, median duration was 15.5 days (IQR 12.25-24, range 5-49 days) versus non-CAPA patients 14 days (IQR 8.75-17, range 2-48 days).A proportion of 13.5% of non-CAPA patients (8/52) showed an immunocompromising underlying disease, versus 11.8% (2/17) in the CAPA cohort. Upon admission, a median arterial oxygen tension (P aO 2 )/inspired oxygen fraction (F IO 2 ) index of 150.5 (IQR 108-205, range 37.6-453) was documented for non-CAPA patients in comparison to 97.3 (IQR 81.4-173, range 42.9-314) for CAPA patients. Bronchoscopy was performed in 40 (76.9%) of the non-CAPA and all (n=17) CAPA patients. White-coloured plaques were reported in 41.2% of CAPA cases (n=7). Pseudomembranes were reported in 41.2% CAPA patients and the clinical diagnosis of tracheobronchitis was established in 47.1% of CAPA patients (figure 1a).

We observed 8/17 (47.1%) CAPA patients with clinical diagnosis of ATB during bronchoscopy. Non-ATB CAPA patients had longer ICU stays with a median of 21 days (IQR 19-28, range 4-255 days), in contrast to CAPA ATB patients with 14.5 days in the ICU (IQR 11-21, range 6-64 days). This is mirrored in a higher day-30 mortality in ATB patients (ATB day-30 mortality: n=5, 62.5%; overall mortality: n=6, 75%; versus non-ATB day-30 mortality: n=2, 22.2%; overall mortality: n=3, 33.3%; overall mortality in all CAPA patients: 52.9%). Bronchoscopy revealed tracheal plaques in all ATB patients, with seven (87.6%) of white and one (12.5%) of dark colour. Additionally, pseudomembranes (n=7), thrombi (n=4) and a vulnerable or bloody trachea (n=7) were reported in 87.5%, 50% and 87.5%, respectively. In 6/8 (75%) tracheobronchitis patients, BAL samples were tested positive for galactomannan-antigen index of >0.5. Seven cultures (87.5%), as well as eight PCR tests from patients with tracheobronchitis were positive for Aspergillus (n=8, 100%). Conversely, half of the non-tracheobronchitis group yielded a positive culture (n=5, 55.6%) or PCR (n=5, 55.6%) result. The dominant species identified was Aspergillus fumigatus (tracheobronchitis: n=7, 87.5%; non-tracheobronchitis: n=3, 33.3%). Serum galactomannan showed significant limitations since only one ATB patient and two without tracheobronchitis tested positive. In contrast, 6/8 ATB patients had positive BAL galactomannan and all had a positive culture (no azole resistance detected). Applying the ECMM/ ISHAM definitions, all CAPA patients had probable disease. Antifungal drugs used were voriconazole (ATB: n=6, 75%; non-tracheobronchitits n=6, 66.7%) and isavuconazole (ATB n=4, 50%; non-tracheobronchitis: isavuconazole n=2, 22.2%).

During the first wave of the COVID-19 pandemic, bronchoscopy has played a limited role. By lack of tracheal examination, local ulcerations, pseudomembranes and lesions are not diagnosed (figure 1). Samples obtained by TA or non-bronchoscopic lavages show reduced diagnostic quality. Our cohort presents insights about ATB in CAPA patients. Our results suggest that identifying the presence of plaques and ulceration are crucial for diagnosis (figure 1) [6] . The use of computed tomography scans can hardly differentiate ATB from non-ATB patients. In particular, Aspergillus-PCR and culture support ATB diagnosis. On the contrary serum galactomannan showed low diagnostic value, possibly due to its lack of accuracy in non-haematological patients [10] . Nevertheless, identification through biomarkers may be limited in their diagnostic accuracy due to CAPA stage specificity, so that in case of persistence or progression of tracheobronchitis or space-consuming lesions, a sampling by brush or even biopsy should be considered [6] . The day-30 mortality as well as the overall mortality rate of patients with ATB was significantly higher, emphasising the importance of early diagnosis and targeted treatment. This single-centre study has several limitations. The data reflect a real-life scenario of critically ill COVID-19 patients, that did not undergo a pre-defined bronchoscopy protocol. The indication for bronchoscopy was adjusted to the clinical and respiratory status of the patient, triggered by positive results from tracheal aspirates and persisting fever or high volume of mucous, blood or other fluids. Tracheobronchitis in our cohort was a clinical and visual diagnosis that has been combined with the respective microbiological results taken during the procedure and not by biopsy to avoid severe injury and subsequent deterioration.

This study reveals the importance of predefined diagnostic strategies, such as indications for bronchoscopy, to identify ATB patients. ATB produces tracheal plaques, pseudomembranes and increased tracheal bleeding and is observed in a very ill patient subpopulation (P aO 2 /F IO 2 index median 84.6). The combination of severely impaired respiratory function and aspergillosis leads to higher mortality. Key challenges for future research comprise identifying predisposing factors, also with regard to immunosuppressive treatments, such as IL-6, JAK and IL-1 inhibitors, and strategies to reduce CAPA prevalence. Prophylaxis and treatment of CAPA and ATB should be evaluated in prospective trials; especially the use of inhaled antimycotics could play a major role in patients with ATB.

Philipp Koehler 1,2 , Saskia von Stillfried 3 , Jorge Garcia Borrega 1 , Frieder Fuchs 4 , Jon Salmanton-García 1,2 , Fabian Pult 1,2 , Boris Böll 1 , Dennis A. Eichenauer 1 , Alexander Shimabukuro-Vornhagen 1 , Oliver Kurzai 5,6 , Peter Boor 3,7 , Matthias Kochanek 1,10 and Oliver A. Cornely 1, 2, 8, 9, 10 

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received honoraria from Sanofi and Takeda outside the submitted work. A. Shimabukuro-Vornhagen reports travel grants from Gilead Sciences outside the submitted work. O. Kurzai reports payment or honoraria for lectures, presentations or speakers' bureaus by Gilead and Pfizer, and receipt of equipment, materials, drugs, medical writing, gifts or other services by Pfizer, MSD, Basilea, Gilead, Virotech and Wako Fujifilm outside the submitted work. P. Boor has nothing to disclose. M. Kochanek reports payment or honoraria for lectures, presentations or speakers' bureaus by Gilead, MSD and Pfizer outside the submitted work. O.A. Cornely reports grants or contracts from Amplyx, Basilea, BMBF, Cidara, DZIF, EU-DG RTD (101037867)