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Multinational Observational Cohort Study of COVID-19–Associated Pulmonary Aspergillosis1

Nico A.F. Janssen, Rémy Nyga, Lore Vanderbeke, Cato Jacobs, Mehmet Ergün, Jochem B. Buil, Karin van Dijk, Josje Altenburg, Catherine S.C. Bouman, Hans I. van der Spoel, Bart J.A. Rijnders, Albert Dunbar, Jeroen A. Schouten, Katrien Lagrou, Marc Bourgeois, Marijke Reynders, Niels van Regenmortel, Lynn Rutsaert, Piet Lormans, Simon Feys, Yves Debavaye, Fabienne Tamion, Damien Costa, Julien Maizel, Hervé Dupont, Taieb Chouaki, Saad Nseir, Boualem Sendid, Roger J.M. Brüggemann, Frank L. van de Veerdonk, Joost Wauters2, and Paul E. Verweij2Comments to Author 

Author affiliations: Radboud University Medical Center, Nijmegen, the Netherlands (N.A.F Janssen, M. Ergün, J.B. Buil, J.A. Schouten, R.J.M. Brüggemann, F.L. van de Veerdonk, P.E. Verweij); Amiens University Hospital, Amiens, France (R. Nyga, J. Maizel, H. Dupont, T. Chouaki); University Hospitals Leuven, Leuven, Belgium (L. Vanderbeke, C. Jacobs, K. Lagrou, Y. Debavaye, J. Wauters); Katholieke Universiteit Leuven, Leuven (L. Vanderbeke, K. Lagrou, J. Wauters); Amsterdam University Medical Centers, Amsterdam, the Netherlands (K. van Dijk, J. Altenburg, C.S.C. Bouman, H. van der Spoel); Erasmus Medical Center, Rotterdam, the Netherlands (B.J.A. Rijnders, A. Dunbar); AZ Sint-Jan Brugge-Oostende, Brugge, Belgium (M. Bourgeois, M. Reynders); ZNA Campus Stuivenberg, Antwerpen, Belgium (N. van Regenmortel, L. Rutsaert); AZ Delta Hospital, Roeselare, Belgium (P. Lormans, S. Feys); Rouen University Hospital, Rouen, France (F. Tamion, D. Costa); Lille University Hospital, Lille, France (S. Nseir, B. Sendid); University of Lille, Lille (S. Nseir, B. Sendid)

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Abstract

We performed an observational study to investigate intensive care unit incidence, risk factors, and outcomes of coronavirus disease–associated pulmonary aspergillosis (CAPA). We found 10%–15% CAPA incidence among 823 patients in 2 cohorts. Several factors were independently associated with CAPA in 1 cohort and mortality rates were 43%–52%.

Incidence of coronavirus disease (COVID-19)–associated pulmonary aspergillosis (CAPA) in hospital intensive care units (ICUs) is 3.8%–33.3% (19). Variations might be explained by differences in patient populations and CAPA definitions used, complicating direct comparisons between studies.

Diagnosing CAPA is complex because cases frequently lack typical radiologic features and European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium (EORTC/MSGERC) host factors (10) and because mycologic evidence is difficult to obtain. Serum galactomannan (GM) detection has low sensitivity in CAPA (7,10).

The European Confederation of Medical Mycology and International Society for Human and Animal Mycology (ECMM/ISHAM) published consensus criteria for a CAPA definition (11). We used these criteria to perform an observational cohort study to assess CAPA incidence in patients with COVID-19 admitted to ICUs during the first wave of the COVID-19 pandemic.

The Study

We collected partially prospective and partially retrospective data for 823 patients in 2 cohorts. The discovery cohort comprised patients with PCR-confirmed or clinically presumed COVID-19 admitted to 4 ICUs in the Netherlands and 4 ICUs in Belgium during February 28–May 27, 2020. The validation cohort comprised patients with PCR-confirmed COVID-19 admitted because of respiratory insufficiency to 3 participating ICUs in France during April 7–May 31, 2020 (Appendix Methods, Table 1).

Figure 1

1 negative mycological test according to 2020 ECMM/ISHAM classification consensus criteria (11). Patients who did not undergo any of the mycological tests were designated to the CAPA not classifiable group. *Value includes 6 patients in whom CAPA was excluded at the time of obduction. CAPA, COVID-19–associated pulmonary aspergillosis; COVID-19, coronavirus disease; ECMM/ISHAM, European Confederation for Medical Mycology/International Society for Human and Animal Mycology; ICU, intensive care unit.”>

Figure 1. Flowchart of the study inclusion process for a multinational observational study of CAPA in 3 countries in Europe, 2020. A) Discovery cohort; B) validation cohort. For further analyses, patients with…

We applied ECMM/ISHAM classification criteria for CAPA (11). We considered bronchial lavage (BL) equivalent to bronchoalveolar lavage (BAL). We assumed all CAPA classified patients demonstrated clinical factors and radiographic abnormalities. We defined 3 patient groups: CAPA, CAPA-excluded, and CAPA not classifiable (Figure 1; Appendix).

We included 519 patients in the discovery cohort; median age was 64 years, 73% were male, and 82% required invasive mechanical ventilation during ICU admission (Table 1; Appendix Table 2, 3, 4). Among patients in the discovery cohort, 279 (54%) were classifiable: 6 (2%) as CAPA proven, 32 (12%) as probable CAPA, and 4 (1%) as possible CAPA (Figure 1, panel A; Appendix Results, Tables 5, 6). CAPA incidence among classifiable patients was 15% (42/279); 85% were CAPA-excluded. Among patients in the discovery cohort, 46% (240/519) were not classifiable, including 3 who did not fulfill the criteria for possible CAPA (Figure 1, panel A). In patients with any EORTC/MSGERC host factor, CAPA incidence was 30% (13/44), compared with 16% (26/161) in patients with no host factors (p = 0.053).

Chronic obstructive pulmonary disease (COPD; p = 0.04) and HIV/AIDS (p = 0.01) were more prevalent in CAPA patients (Table 1; Appendix Table 2). Among CAPA patients, 33% had >1 EORTC/MSGERC host factor, compared with 19% of CAPA-excluded patients (p = 0.053). Corticosteroid use was not more prevalent in the CAPA group (p = 0.14), in contrast to other immunosuppressant drugs (p = 0.01). In logistic regression analysis, corticosteroid use at any dose before or during ICU admission was not independently associated with CAPA development. However, COPD, HIV/AIDS, and use of other immunosuppressant drugs before ICU admission were associated with CAPA (Appendix Figure 1, panel A).

Among CAPA patients who underwent BAL or BL, Aspergillus culture was positive in 42%, GM was positive (optical density [OD] >1.0) in 78%, and Aspergillus PCR was positive in 17%. Among CAPA patients who underwent nonbronchoscopic lavage, 67% had positive cultures. Serum GM was positive in 11% of tested CAPA patients. Median time between ICU admission and first positive mycologic test was 6 (interquartile range [IQR] 3–9) days (Table 1; Appendix Table 7).

Figure 2

Kaplan-Meier survival curves comparing patients with CAPA and those classified as CAPA excluded in a multinational observational study. A) Discovery cohort; B) validation cohort. Survival analysis performed by using Mantel-Cox log rank test. Survival over time differs significantly in the discovery cohort (n = 279); median estimated survival in the CAPA group is 42.0 days (p = 0.015 by log rank test). In the validation cohort (n = 209), survival over time is not significantly different between the 2 groups (p = 0.065 by log rank test). CAPA, COVID-19–associated pulmonary aspergillosis; COVID-19, coronavirus disease; ICU, intensive care unit.

Figure 2. Kaplan-Meier survival curves comparing patients with CAPA and those classified as CAPA excluded in a multinational observational study. A) Discovery cohort; B) validation cohort. Survival analysis performed by using Mantel-Cox…

The proportion of patients receiving systematic corticosteroid treatment in ICUs was not significantly different between CAPA and CAPA-excluded groups (p = 0.40), nor was corticosteroid dose (p = 0.88) (Table 1; Appendix Table 4). Antifungal treatment was administered to 16% (83/519) of patients, 88% of CAPA patients, and 15% of CAPA-excluded patients (Appendix Table 8). ICU mortality rates were significantly higher in CAPA patients (52%) than in CAPA-excluded patients (34%) (p = 0.04; Table 1; Appendix Table 4); mortality rates were 67% for patients with positive serum GM. CAPA patients demonstrated reduced survival (p = 0.02) (Figure 2, panel A); estimated median survival was 42 days after ICU admission. When correcting for covariates, CAPA was not independently associated with ICU mortality rates, but older age and acute kidney injury (AKI) during ICU stay were (Appendix Figure 1, panel B).

We included 304 patients in the validation cohort (Figure 1, panel B); median age was 63 years, 25% were male, and 76% required invasive mechanical ventilation (Table 2; Appendix Tables 9, 10). Ultimately, 209/304 (69%) patients were classifiable for CAPA: 21 (10%) probable CAPA and 188 (90%) CAPA excluded (Figure 1, panel B; Appendix Results, Tables 5, 11). Among patients with EORTC/MSGERC host factors, CAPA incidence was 13% (3/23), compared with 10% (18/186) among patients without host factors (p = 0.71).

All 21 probable CAPA patients were female; cardiovascular disease, excluding hypertension (p = 0.02), and bronchiectasis (p = 0.03) were more prevalent in this group (Table 2; Appendix Table 9). Use of corticosteroids before or during ICU admission or other immunosuppressant drugs before ICU admission were not independently associated with CAPA (Appendix Figure 1, panel C). In the validation cohort, 19% received antifungal treatment; 57% of the CAPA group received antifungal treatment (Appendix Table 8).

Corticosteroid use during ICU stay was not significantly different between the CAPA and CAPA-excluded groups (p = 0.82) in the validation cohort. ICU mortality rates were higher in the CAPA group than the CAPA-excluded group (43% vs. 25%; p = 0.12) (Table 2; Figure 2, panel B; Appendix Table 10). The ICU mortality rate was 50% in patients with positive serum GM. CAPA was not independently associated with ICU death, but older age and AKI during ICU admission were (Appendix Table 10, Figure 1, panel D).

Conclusions

We found CAPA incidence was 10%–15%, corresponding to the 14%–19% reported in other studies (8,9). Discovery cohort CAPA incidence was similar to influenza-associated pulmonary aspergillosis (IAPA) incidence in ICUs (12,13). CAPA seems to develop later after ICU admission than IAPA. Median time to first positive mycologic test in our study was 6 days after ICU admission, similar to other studies reporting 4–8 days (79) but in contrast to the median 3 days reported for IAPA (12,14).

Corticosteroids were not associated with CAPA in our study, consistent with previous reports (79), but contrasting associations seen with invasive pulmonary aspergillosis (IPA) and IAPA (12). This finding might be explained by possible dual effects of corticosteroids in COVID-19, impairing anti-Aspergillus immunity while simultaneously ameliorating the hyperinflammatory immune dysregulation and associated tissue damage conducive to IPA.

We found CAPA ICU mortality rates were 43%–52%, in line with previous reports (79) and comparable to those for IAPA (12). We could not assess antifungal treatment effects on mortality rates, but CAPA patients in the validation cohort who received antifungal treatment demonstrated a trend toward improved survival (Appendix Figure 2).

The first limitation of our study is that assuming clinical and imaging factors were available for all patients classified with CAPA possibly led to overreporting of CAPA. Excluding CAPA based on 1 negative mycologic test might have led to underreporting. Another limitation was that patients undergoing mycologic workup were likely more severely ill, which becomes apparent when comparing baseline and outcome data of the CAPA not classifiable group to the other 2 groups (Appendix Tables 5–12). Several classifications have been published or updated after we initiated this study; therefore, not all diagnostic modalities were evaluated, and we used some terms, such as BAL and BL, interchangeably (11,15).

In conclusion, we report CAPA incidence of 10%–15% in COVID-19 patients admitted to ICUs, CAPA ICU mortality rates of 43%–52%, and decreased survival over time. Clinicians should be aware of CAPA and that underlying factors, including COPD, immunosuppressant drugs other than corticosteroids, and HIV/AIDS, can increase the risk for CAPA.

Dr. Janssen is an infectious disease clinician and PhD candidate at the Radboud University Medical Center, Nijmegen, the Netherlands. His primary research interests are fungal diseases, including viral pneumonitis-associated invasive aspergillosis and chronic pulmonary aspergillosis.

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Acknowledgments

We sincerely thank all the patients included in this study. We thank all colleagues in the participating centers for submitting their data. We thank Maeve van den Aakster, Burak Atasever, Aleid Breuning, Elena Decat, Joke Denolf, Ruben De Rouck, Laura De Velder, Willemijn van der Kleij, Gideon Saelman, Evi Smeyers, Manon Vanbellinghen, and Lauren Van der Sloten for their support in data entry.

L.V. reports grants from the Research Foundation Flanders during the study period and nonfinancial support from Gilead Sciences and Pfizer for work outside the submitted study. J.B.B. reports grants from F2G, Gilead Sciences, and Thermo Fisher Scientific for work outside the submitted study. B.J.A.R. reports grants from Gilead Sciences for work outside the submitted study. K.L. reports nonfinancial support from Pfizer and personal fees from SMB Laboratoires, Gilead Sciences, FUJIFILM Wako, Thermo Fisher Scientific, and MSD for work outside the submitted study. S.N. reports personal fees from MSD, Pfizer, Gilead, bioMérieux, and Bio-Rad for work outside the submitted study. K.L. received consultancy fees from MSD, SMB Laboratoires Brussels, and Gilead; nonfinancial support from Pfizer and MSD, speaker fees from Gilead Sciences, FUJIFILM WAKO, and Pfizer; and a grant from Thermo Fisher Scientific, for work outside the submitted study. R.J.M.B. has served as a consultant to Astellas Pharma, Inc., F2G, Amplyx, Gilead Sciences, Merck Sharp & Dohme Corp., Mundipharma, and Pfizer, Inc., and has received unrestricted and research grants from Astellas Pharma, Inc., Gilead Sciences, Merck Sharp & Dohme Corp., and Pfizer, Inc., for work outside the submitted study; all contracts were through Radboudumc, and all payments were invoiced by Radboudumc. J.W. reports grants from Gilead during the study period, grants and nonfinancial support from MSD, and grants from Pfizer for work outside the submitted study. P.E.V. reports grants from Mundipharma, F2G, Pfizer, Thermofisher, Gilead Sciences, and Cidara and nonfinancial support from IMMY for work outside the submitted study.

F.L.v.d.V. is supported by a Vidi grant of the Netherlands Association for Scientific Research.

Authors’ contributions: N.A.F.J., R.N., F.T., J.M., H.D., S.N., R.J.M.B., F.L.v.d.V., J.W., and P.E.V. came up with study concept and design. N.A.F.J., R.N., L.V., C.J., M.E., J.B.B., K.v.D., J.A., C.S.C.B., H.I.v.d.S., B.J.A.R., A.D., J.A.S., K.L., M.B., M.R., N.v.R., L.R., P.L., S.F., Y.D., F.T., D.C., J.M., H.D., T.C., S.N., B.S., R.J.M.B., F.L.v.d.V., J.W., and P.E.V. acquired data. N.A.F.J., R.J.M.B., F.L.v.d.V., J.W., and P.E.V. analyzed and interpreted data. N.A.F.J., R.J.M.B., F.L.v.d.V., J.W., and P.E.V. drafted the manuscript. R.N., L.V., C.J., M.E., J.B.B., K.v.D., J.A., C.S.C.B., H.I.v.d.S., B.J.A.R., A.D., J.A.S., K.L., M.B., M.R., N.v.R., L.R., P.L., S.F., Y.D., F.T., D.C., J.M., H.D., T.C., S.N., and B.S. provided critical revision of manuscript.

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Figures
Tables

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Suggested citation for this article: Janssen NAF, Nyga R, Vanderbeke L, Jacobs C, Ergün M, Buil JB, et al. Multinational observational cohort study of COVID-19–associated pulmonary aspergillosis. Emerg Infect Dis. 2021 Nov [date cited]. https://doi.org/10.3201/eid2711.211174

DOI: 10.3201/eid2711.211174

Original Publication Date: September 14, 2021

Table of Contents – Volume 27, Number 11—November 2021

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Page created: August 24, 2021

Page updated: September 14, 2021

Page reviewed: September 14, 2021

The conclusions, findings, and opinions expressed by authors contributing to this journal do not necessarily reflect the official position of the U.S. Department of Health and Human Services, the Public Health Service, the Centers for Disease Control and Prevention, or the authors’ affiliated institutions. Use of trade names is for identification only and does not imply endorsement by any of the groups named above.

Source : CDC Emerging Infectious Diseases Journal

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