Volume 27, Number 11—November 2021
Multinational Observational Cohort Study of COVID-19–Associated Pulmonary Aspergillosis1
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% (1–9). 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.
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).
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).
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).
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 (7–9) 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 (7–9), 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 (7–9) 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.
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.
- Koehler P, Cornely OA, Böttiger BW, Dusse F, Eichenauer DA, Fuchs F, et al. COVID-19 associated pulmonary aspergillosis. Mycoses. 2020;63:528–34.
- van Arkel ALE, Rijpstra TA, Belderbos HNA, van Wijngaarden P, Verweij PE, Bentvelsen RG. COVID-19–associated pulmonary aspergillosis. Am J Respir Crit Care Med. 2020;202:132–5.
- Rutsaert L, Steinfort N, Van Hunsel T, Bomans P, Naesens R, Mertes H, et al. COVID-19-associated invasive pulmonary aspergillosis. Ann Intensive Care. 2020;10:71.
- Wang J, Yang Q, Zhang P, Sheng J, Zhou J, Qu T. Clinical characteristics of invasive pulmonary aspergillosis in patients with COVID-19 in Zhejiang, China: a retrospective case series. Crit Care. 2020;24:299.
- Alanio A, Dellière S, Fodil S, Bretagne S, Mégarbane B. Prevalence of putative invasive pulmonary aspergillosis in critically ill patients with COVID-19. Lancet Respir Med. 2020;8:e48–9.
- Lamoth F, Glampedakis E, Boillat-Blanco N, Oddo M, Pagani JL. Incidence of invasive pulmonary aspergillosis among critically ill COVID-19 patients. Clin Microbiol Infect. 2020;26:1706–8.
- Bartoletti M, Pascale R, Cricca M, Rinaldi M, Maccaro A, Bussini L, et al.; PREDICO study group. Epidemiology of invasive pulmonary aspergillosis among COVID-19 intubated patients: a prospective study. Clin Infect Dis. 2020;
ciaa1065; Epub ahead of print.
- White PL, Dhillon R, Cordey A, Hughes H, Faggian F, Soni S, et al. A national strategy to diagnose COVID-19–associated invasive fungal disease in the intensive care unit. [Epub ahead of print]. Clin Infect Dis. 2020.
- Dellière S, Dudoignon E, Fodil S, Voicu S, Collet M, Oillic PA, et al. Risk factors associated with COVID-19-associated pulmonary aspergillosis in ICU patients: a French multicentric retrospective cohort. Clin Microbiol Infect. 2020;27:790.e1–5.
- Verweij PE, Gangneux JP, Bassetti M, Brüggemann RJM, Cornely OA, Koehler P, et al.; European Confederation of Medical Mycology; International Society for Human and Animal Mycology; European Society for Clinical Microbiology and Infectious Diseases Fungal Infection Study Group; ESCMID Study Group for Infections in Critically Ill Patients. Diagnosing COVID-19-associated pulmonary aspergillosis. Lancet Microbe. 2020;1:e53–5.
- Koehler P, Bassetti M, Chakrabarti A, Chen SCA, Colombo AL, Hoenigl M, et al.; European Confederation of Medical Mycology; International Society for Human Animal Mycology; Asia Fungal Working Group; INFOCUS LATAM/ISHAM Working Group; ISHAM Pan Africa Mycology Working Group; European Society for Clinical Microbiology; Infectious Diseases Fungal Infection Study Group; ESCMID Study Group for Infections in Critically Ill Patients; Interregional Association of Clinical Microbiology and Antimicrobial Chemotherapy; Medical Mycology Society of Nigeria; Medical Mycology Society of China Medicine Education Association; Infectious Diseases Working Party of the German Society for Haematology and Medical Oncology; Association of Medical Microbiology; Infectious Disease Canada. Defining and managing COVID-19-associated pulmonary aspergillosis: the 2020 ECMM/ISHAM consensus criteria for research and clinical guidance. Lancet Infect Dis. 2021;21:e149–62.
- Schauwvlieghe AFAD, Rijnders BJA, Philips N, Verwijs R, Vanderbeke L, Van Tienen C, et al.; Dutch-Belgian Mycosis study group. Invasive aspergillosis in patients admitted to the intensive care unit with severe influenza: a retrospective cohort study. Lancet Respir Med. 2018;6:782–92.
- van de Veerdonk FL, Kolwijck E, Lestrade PP, Hodiamont CJ, Rijnders BJ, van Paassen J, et al.; Dutch Mycoses Study Group. Influenza-associated aspergillosis in critically ill patients. Am J Respir Crit Care Med. 2017;196:524–7.
- Wauters J, Baar I, Meersseman P, Meersseman W, Dams K, De Paep R, et al. Invasive pulmonary aspergillosis is a frequent complication of critically ill H1N1 patients: a retrospective study. Intensive Care Med. 2012;38:1761–8.
- Donnelly JP, Chen SC, Kauffman CA, Steinbach WJ, Baddley JW, Verweij PE, et al.; Revision and Update of the Consensus Definitions of Invasive Fungal Disease from the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium. Revision and Update of the Consensus Definitions of Invasive Fungal Disease From the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium. Clin Infect Dis. 2020;71:1367–76.
TablesCite This Article
Original Publication Date: September 14, 2021
1The results of this study were presented at the Scientific Spring Meeting of the Dutch Society of Medical Microbiology (NVMM) and the Royal Dutch Society of Microbiology (KNVM), held online March 30–31, 2021; and at the 31st European Congress of Clinical Microbiology & Infectious Diseases (ECCMID), held online from July 9–12, 2021.
2These authors were co–principal investigators.