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Multicenter Study
. 2023 Aug:76:154272.
doi: 10.1016/j.jcrc.2023.154272. Epub 2023 Feb 16.

Incidence, risk factors and pre-emptive screening for COVID-19 associated pulmonary aspergillosis in an era of immunomodulant therapy

Rebecca van Grootveld  1 , Martha T van der Beek  2 , Nico A F Janssen  3 , Mehmet Ergün  4 , Karin van Dijk  5 , Carina Bethlehem  6 , Susanne Stads  7 , Judith van Paassen  2 , Leo M A Heunks  8 , Catherine S C Bouman  5 , Monique H E Reijers  4 , Roger J Brüggeman  4 , Frank L van de Veerdonk  4 , Sjoerd H W van Bree  9 , Charlotte H S B van den Berg  10 , Marnix Kuindersma  11 , Joost Wauters  12 , Albertus Beishuizen  13 , Paul E Verweij  14 , Jeroen A Schouten  4 ; CAPA2.0 study group  15
Affiliations
Multicenter Study

Incidence, risk factors and pre-emptive screening for COVID-19 associated pulmonary aspergillosis in an era of immunomodulant therapy

Rebecca van Grootveld et al. J Crit Care. 2023 Aug.

Abstract

Purpose: COVID-19 associated pulmonary aspergillosis (CAPA) is associated with increased morbidity and mortality in ICU patients. We investigated the incidence of, risk factors for and potential benefit of a pre-emptive screening strategy for CAPA in ICUs in the Netherlands/Belgium during immunosuppressive COVID-19 treatment.

Materials and methods: A retrospective, observational, multicentre study was performed from September 2020-April 2021 including patients admitted to the ICU who had undergone diagnostics for CAPA. Patients were classified based on 2020 ECMM/ISHAM consensus criteria.

Results: CAPA was diagnosed in 295/1977 (14.9%) patients. Corticosteroids were administered to 97.1% of patients and interleukin-6 inhibitors (anti-IL-6) to 23.5%. EORTC/MSGERC host factors or treatment with anti-IL-6 with or without corticosteroids were not risk factors for CAPA. Ninety-day mortality was 65.3% (145/222) in patients with CAPA compared to 53.7% (176/328) without CAPA (p = 0.008). Median time from ICU admission to CAPA diagnosis was 12 days. Pre-emptive screening for CAPA was not associated with earlier diagnosis or reduced mortality compared to a reactive diagnostic strategy.

Conclusions: CAPA is an indicator of a protracted course of a COVID-19 infection. No benefit of pre-emptive screening was observed, but prospective studies comparing pre-defined strategies would be required to confirm this observation.

Keywords: Aspergillus fumigatus; CAPA; COVID-19; Intensive care unit; Invasive fungal infections; Invasive pulmonary aspergillosis; SARS-CoV-2.

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Conflict of interest statement

Declaration of Competing Interest Paul Verweij: Institution contracted for research grant: F2G and Gilead Sciences; Honoraria for lectures paid to institution: F2G, Gilead Sciences, Pfizer; Participation on a Data Safety Monitoring Board or Advisory Board paid to institution: F2G, Mundipharma. Roger Brüggeman: Institution contracted for research grant: Astellas Pharma, Inc., Gilead Sciences, Merck Sharp & Dohme Corp., Pfizer; Consulting fees paid to institution: Astellas Pharma, Inc., F2G, Amplyx, Gilead Sciences, Merck Sharp & Dohme Corp., Mundipharma, Pfizer. Joost Wauters: Investigator-initiated grants: Gilead, MSD, Pfizer; Consulting fees: Investigator-initiated grants from Gilead, Pfizer; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Speakers fees from Gilead, Pfizer; Support for attending meetings and/or travel: travel grants from Gilead and Pfizer. No potential financial or non-financial competing interest was reported by any of the other authors.

Figures

Fig. 1
Fig. 1
Total number of patients with COVID-19 admitted to the ICU in the study period (total cohort) and patients undergoing CAPA diagnostics (diagnostic cohort). CAPA classification according to 2020 ECMM/ISHAM consensus criteria (proven, probable or possible CAPA) [12]. Patients with positive Aspergillus test results who did not fulfil CAPA criteria were classified as colonised. Patients who did not have any positive Aspergillus test results were classified as no CAPA. CAPA: COVID-19 associated pulmonary aspergillosis, ICU: intensive care unit.
Fig. 2
Fig. 2
First positive NBL or BAL GM sample after ICU admission in days. Screening: medical centres that screened for CAPA systematically (pre-emptive screening strategy). No screening: medical centres that performed diagnostics for Aspergillus spp. on clinical suspicion of CAPA (reactive diagnostic strategy). BAL: bronchoscopic alveolar lavage, CAPA: COVID-19 associated pulmonary aspergillosis, GM: galactomannan, ICU: intensive care unit, ICUA: ICU admission, NBL: non-bronchoscopic lavage.
Fig. 3
Fig. 3
a. Kaplan-Meier survival curve of patients with and without CAPA. Log-rank test: p = 0.020. b. Kaplan-Meier survival curve of patients classified as proven, probable/possible or no CAPA. Log-rank test: p = 0.006.
Fig. 4
Fig. 4
Flow chart depicting the different CAPA protocols of centres that screened for CAPA pre-emptively. Pre-emptive screening strategy: centres in which Aspergillus diagnostics were routinely performed in all patients with COVID-19 admitted to the ICU, Reactive diagnostic strategy: centres in which Aspergillus diagnostics were only performed when there was suspicion of CAPA. BA: bronchial aspirate, BAL: bronchoalveolar lavage, CAPA: COVID-19 associated pulmonary aspergillosis, GM: galactomannan, ICU: intensive care unit, NBL: non-bronchoscopic lavage, TA: tracheal aspirate.
Fig. 5
Fig. 5
30- and 90-day mortality in patients with positive test results ranked on the basis of positive test results theoretically indicative of Aspergillus invasiveness or load. The estimated probability of death at day 30 (5a) or 90 (5b) with corresponding 95% confidence interval (95%-CI), calculated with the Wilson score interval. Patients with probable or possible CAPA according to 2020 ECMM/ISHAM consensus criteria [12], colonised (patients with positive Aspergillus test results who did not fulfil CAPA criteria) or no CAPA. Ranking: serum GM/PCR blood > microscopy: BAL/NBL microscopy > culture: BAL/NBL culture > PCR: BAL PCR > GM: BAL/NBL GM*†‡ > colonised > negative test results. BAL: bronchoscopic alveolar lavage, GM: galactomannan, NBL: non-bronchoscopic lavage. * NBL GM positivity according to 2020 ECMM/ISHAM consensus criteria [12]. † 30- and 90-day mortality and estimated probability of death with 95%-CI of patients with a positive BAL GM: day 30: 29.7% (31.6%; 95%-CI: 17.5–45.9); day 90: 56.7% (55.9%; 95%-CI: 39.2–72.6). ‡ 30- and 90-day mortality and estimated probability of death with 95%-CI of patients with a positive NBL GM: day 30: 14.3% (22%; 95%-CI: 4–39.9); day 90: 55.6% (53.9%; 95%-CI: 26.7–81.1).
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