COVID-19–Associated Pulmonary Aspergillosis, March–August 2020

Jon Salmanton-García; Rosanne Sprute; Jannik Stemler; Michele Bartoletti; Damien Dupont; Maricela Valerio; Carolina Garcia-Vidal; Iker Falces-Romero; Marina Machado; Sofía de la Villa; Maria Schroeder; Irma Hoyo; Frank Hanses; Kennio Ferreira-Paim; Daniele Roberto Giacobbe; Jacques F. Meis; Jean-Pierre Gangneux; Azucena Rodríguez-Guardado; Spinello Antinori; Ertan Sal; Xhorxha Malaj; Danila Seidel; Oliver A. Cornely; Philipp Koehler

Disclosures

Emerging Infectious Diseases. 2021;27(4):1077-1086.

Abstract and Introduction

Abstract

Pneumonia caused by severe acute respiratory syndrome coronavirus 2 emerged in China at the end of 2019. Because of the severe immunomodulation and lymphocyte depletion caused by this virus and the subsequent administration of drugs directed at the immune system, we anticipated that patients might experience fungal superinfection. We collected data from 186 patients who had coronavirus disease–associated pulmonary aspergillosis (CAPA) worldwide during March–August 2020. Overall, 182 patients were admitted to the intensive care unit (ICU), including 180 with acute respiratory distress syndrome and 175 who received mechanical ventilation. CAPA was diagnosed a median of 10 days after coronavirus disease diagnosis. Aspergillus fumigatus was identified in 80.3% of patient cultures, 4 of which were azole-resistant. Most (52.7%) patients received voriconazole. In total, 52.2% of patients died; of the deaths, 33.0% were attributed to CAPA. We found that the cumulative incidence of CAPA in the ICU ranged from 1.0% to 39.1%.

Introduction

Cases of pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were first described in Wuhan, China, at the end of December 2019.^[1] The infection rapidly spread, causing the coronavirus disease (COVID-19) pandemic.^[2]

Because SARS-CoV-2 and treatments such as dexamethasone or tocilizumab can impair the immune system, some researchers anticipated the possibility of fungal superinfection among COVID-19 patients.^[3–6] As of August 2020, researchers have documented COVID-19–associated pulmonary aspergillosis (CAPA),^[7–9] invasive candidiasis,^[10] coccidioidomycosis,^[11] fusariosis,^[12] histoplasmosis,^[13] mucormycosis,^[14] pneumocystosis,^[15] and saccharomycosis.^[16] Varying cumulative rates of CAPA have been described, including rates of 0.7%–7.7% among COVID-19 patients,^[17,18] 2.5%–39.1% among ICU patients with COVID-19,^[19,20] and 3.2%–29.6% among COVID-19 patients on mechanical ventilation.^[7,17] Many of these patients lack the concurrent conditions usually associated with invasive pulmonary aspergillosis (IPA) such as malignancies, neutropenia, or history of allogeneic stem cell or solid organ transplantation.^[21] Admission to the ICU or severe influenza are also risk factors for IPA in nonneutropenic patients.^[22–25] Reports of CAPA have been mostly limited to a few single-center studies; therefore, a comprehensive analysis of international distribution currently is lacking.^[4]

We analyzed reports in the literature (;^[26–50] references 51–54 in Appendix https://wwwnc.cdc.gov/EID/article/27/4/20-4895-App1.pdf) and the FungiScope registry (reference 55 in Appendix) to describe baseline conditions, clinical management, and associated deaths in CAPA patients. This analysis also contextualizes the available cumulative incidences.

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Next Section

Abstract and Introduction
Methods
Results
Discussion
References

Table 1. Pathogens of 186 patients with coronavirus disease–associated pulmonary aspergillosis, March–August 2020*
Characteristic	No. (%)
Pathogens†
Aspergillus fumigatus	122 (65.6)
A. niger	13 (7.0)
A. flavus	10 (5.4)
A. terreus	6 (3.2)
A. calidoustus	1 (0.5)
A. lentulus	1 (0.5)
A. nidulans	1 (0.5)
A. penicillioides	1 (0.5)
A. versicolor	1 (0.5)
A. tubingensis	1 (0.5)
Aspergillus spp. (culture)‡	1 (0.5)
Aspergillus spp. (serologic techniques)	34 (18.3)
Other pathogens§	40 (21.5)
Case definition
EORTC/MSG criteria (21)
Proven	7 (3.8)
Probable	10 (5.4)
Nonclassifiable	169 (90.9)
AspICU algorithm (23)¶
Proven	7 (3.8)
Putative	142 (76.3)
Colonization	34 (18.3)
Nonclassifiable	3 (1.6)
Consensus definition (reference 57 in Appendix)
Proven	7 (3.8)
Probable	82 (44.1)
Possible	19 (10.2)
Nonclassifiable¶#	78 (41.9)
Mycologic evidence
Culture**	152 (81.7)
Microscopy††	3 (1.6)
Histologic techniques‡‡	7 (3.8)
PCR§§	43 (23.1)
Galactomannan test¶¶	113 (60.8)

*Some patients had ≥1 pathogen or form of mycologic evidence. BAL, bronchoalveolar lavage; EORTC/MSG, European Organization for Research and Treatment of Cancer/Mycoses Study Group (21).
†A total of 2 patients had A. fumigatus and A. niger coinfection, 1 patient had A. flavus and A. fumigatus coninfection, 1 patient had A. flavus and A. niger coinfection, 1 patient had A. fumigatus and A. terreus coinfection, and 1 patient had A. fumigatus and A. versicolor coinfection.
‡One patient had an Aspergillus spp. infection diagnosed by culture. No species determination was provided. Other patient samples were diagnosed as Aspergillus spp, using serologic techniques.
§Small numbers of other pathogens were also retrieved from patient samples (Appendix Table 6).
¶AspICU method uses algorithm described by Blot et al. (23) for determining proven or putative aspergillosis in patients with influenza.
#Up to 78 cases (41.9%) were considered nonclassifiable according to the definition (reference 56 in Appendix) because of lack of specific details about the type of aspiration performed. Of these, 75 (96.2%) were classified as putative according to the Blot et al. algorithm (23) and 3 (3.8%) as probable according to EORTC/MSG criteria (21).
**Culture was used to analyze 50 BAL, 47 tracheal aspirate, 34 bronchial aspirate, 17 nondirected bronchial lavage, 3 sputum, 2 nonspecified lower respiratory tract, and 1 BAL and tracheal aspirate sample.
††Microscopy was used to analyze 1 BAL, 1 bronchial aspirate, and 1 tracheal aspirate sample.
‡‡Histologic techniques were used to analyze 7 lung tissue samples.
§§PCR was used to analyze 16 BAL, 12 tracheal aspirate, 10 nondirected bronchial lavage, 3 bronchial aspirate, 1 lung tissue, and 1 serum sample.
¶¶Galactomannan tests were used to analyze 63 BAL, 30 serum or plasma, 22 nondirected bronchial lavage, 9 tracheal aspirate, 3 bronchial aspirate, and 1 sputum sample.

Table 2. Characteristics of 186 patients with coronavirus disease–associated pulmonary aspergillosis, March–August 2020*
Patient characteristic	No. (%)
Sex
F	51 (27.4)
M	135 (72.6)
Median age, y (IQR)	68 (58–73)
COVID-19†	186 (100.0)
Median length of treatment, d (IQR)	7 (6–11)
Median time from COVID-19 diagnosis to CAPA, d (IQR)	10 (5–16)
Intensive care unit stay	182 (97.8)
Median length of stay before CAPA diagnosis, d (IQR)	8 (3–14)
Acute respiratory distress syndrome	180 (96.8)
Mechanical ventilation	175 (94.1)
Median time on ventilation before CAPA diagnosis, d (IQR)	7 (3–13)
Corticosteroid use	98 (52.7)
Concurrent conditions
Chronic cardiovascular disease	94 (50.5)
Renal failure‡	74 (39.8)
Diabetes mellitus	64 (34.4)
Obesity	47 (25.3)
Chronic pulmonary disease	40 (21.5)
Hematologic or oncologic disease§	21 (11.3)
Hematologic malignancy	10 (5.4)
Solid tumor	9 (4.8)
Hematologic disease	2 (1.1)
Solid organ transplantation¶	4 (2.2)
Neutropenia	2 (1.1)
Other baseline conditions and characteristics#	70 (37.6)
Lung infection	186 (100.0)
Image abnormalities of the lungs	182 (97.8)
Computed tomography scan	134 (72.0)
Radiograph	88 (47.3)
Antifungal treatment	137 (73.7)
Median length of treatment, d (IQR)	16 (10–33)
Amphotericin B	36 (19.4)
Liposomal	23 (12.4)
Deoxycholate	11 (5.9)
Lipid complex	2 (1.1)
Echinocandins	24 (12.9)
Anidulafungin	10 (5.4)
Caspofungin	13 (7.0)
Micafungin	1 (0.5)
Ibrexafungerp	1 (0.5)
Triazoles	117 (62.9)
Voriconazole	98 (52.7)
Isavuconazole	23 (12.4)
Posaconazole	4 (2.2)
Fluconazole	1 (0.5)
Overall mortality	97 (52.2)
≤6 wks	89 (47.8)
≤12 wks	93 (50.0)
Median time to death, d (IQR)	9 (3–18)
Cause of death**
CAPA	32 (17.2)
COVID-19	51 (27.4)
Other	36 (19.4)
Median length of observation from CAPA diagnosis, d (IQR)	22 (7–42)

*Values are no. (%), except as indicated. Some patients had ≥1 baseline condition or characteristic, image abnormality, or antifungal drug. CAPA, COVID-19–associated pulmonary aspergillosis; COVID-19, coronavirus disease.
†By definition, all CAPA patients had COVID-19 (Appendix Table 3).
‡In total, 54 patients had acute renal failure, 18 had chronic renal failure, and 2 had nonspecified renal failure.
§In total, 9 patients had hematologic malignancy: 3 had chronic leukemia, 3 had lymphoma, 2 had myelodysplastic syndrome, and 1 had acute leukemia. Eight patients had a solid tumor: 1 had breast cancer, 1 had carcinoma, 1 had cervical/uterine cancer, 1 had lung cancer, 1 had esophageal carcinoma, 1 had prostate cancer, 1 had testicular cancer, and 1 had urothelial carcinoma. Two patients had hematologic disease: 1 had acquired hemophilia type A and 1 had hemophagocytic lymphohistiocytosis.
¶In total, 3 patients had a kidney transplant, 1 had a liver transplant, and 1 had a lung transplant.
#Small numbers of patients had other concurrent conditions and characteristics (Appendix Table 7).
**In total, 32 patients died of CAPA or CAPA/COVID-19: 7 died of CAPA only; 25 died of CAPA and COVID-19. In addition, 26 died of COVID-19 only.

Table 3. Cumulative incidences of CAPA in 19 facilities, March–August 2020*
Country, site no.	CAPA cases, no.	Denominator, no. (% CAPA)			Timeframe
Country, site no.	CAPA cases, no.	COVID-19 patients	COVID-19 patients in ICU	COVID-19 patients on mechanical ventilation	Timeframe
Argentina, I	2	673 (0.3)	163 (1.2)	69 (2.9)	Mar–Aug
Belgium, I	4	274 (1.5)	46 (8.7)	32 (12.5)	Mar–Aug
Belgium, II	4	NA	34 (11.8)	20 (20.0)	Mar–Apr
France, I	2	519 (0.4)	113 (1.8)	45 (4.4)	Mar–Aug
Germany, I	1	83 (1.2)	18 (5.6)	15 (6.7)	Mar–Aug
Germany, II	11	231 (4.8)	64 (17.2)	56 (19.6)	Mar–Aug
Germany, III	9	93 (9.7)	38 (23.7)	27 (33.3)	Mar–Aug
Germany, IV	7	123 (5.7)	76 (9.2)	57 (12.3)	Mar–Aug
Ireland, I	3	181 (1.7)	15 (20.0)	14 (21.4)	Mar–Aug
Italy, I	2	1,279 (0.2)	196 (1.0)	188 (1.1)	Mar–Aug
Italy, II	8	1,055 (0.8)	144 (5.6)	142 (5.6)	Mar–Aug
Mexico, I	6	312 (1.9)	131 (4.6)	115 (5.2)	Mar–Aug
Netherlands, I	9	NA	NA	53 (17.0)	Apr
Netherlands, II	6	483 (1.2)	118 (5.1)	NA	Mar–Aug
Pakistan, I	9	147 (6.1)	23 (39.1)	19 (47.4)	Mar–Apr
Spain, I	8	1,543 (0.5)	348 (2.3)	146 (5.5)	Mar–Aug
Spain, II	8	7,880 (0.1)	NA	NA	Mar–Aug
Spain, III	10	5,890 (0.2)	NA	NA	Mar–Aug
Switzerland, I	3	NA	118 (2.5)	80 (3.8)	Mar–May
United Kingdom, I	19	14,615 (0.1)	257 (7.4)	200 (9.5)	Mar–May
Total	131	35,381 (0.4)	1,902 (6.9)	1,278 (10.3)	Mar–Aug

*CAPA, COVID-19–associated pulmonary aspergillosis; COVID-19, coronavirus disease; ICU, intensive care unit; NA, not available.

Authors and Disclosures

Jon Salmanton-García, Rosanne Sprute, Jannik Stemler, Michele Bartoletti, Damien Dupont, Maricela Valerio, Carolina Garcia-Vidal, Iker Falces-Romero, Marina Machado, Sofía de la Villa, Maria Schroeder, Irma Hoyo, Frank Hanses, Kennio Ferreira-Paim, Daniele Roberto Giacobbe, Jacques F. Meis, Jean-Pierre Gangneux, Azucena Rodríguez-Guardado, Spinello Antinori, Ertan Sal, Xhorxha Malaj, Danila Seidel, Oliver A. Cornely¹ and Philipp Koehler¹, The FungiScope European Confederation of Medical Mycology/The International Society for Human and Animal Mycology Working Group²

University of Cologne, Cologne, Germany (J. Salmanton-García, R. Sprute, J. Stemler, E. Sal, X. Malaj, D. Seidel, O.A. Cornely, P. Koehler); L'Azienda Ospedaliero-Universitaria di Bologna Policlinico S. Orsola, Bologna, Italy (M. Bartoletti); Alma Mater Studiorum University of Bologna, Bologna (M. Bartoletti); Hospices Civils de Lyon, Lyon, France (D. Dupont); Université Claude Bernard Lyon 1, Lyon (D. Dupont); Centre de Recherche en Neurosciences de Lyon, Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifi que, Lyon (D. Dupont); Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain (M. Valerio, M. Machado, S. de la Villa); Hospital Clinic, Institute of Biomedical Research August Pi i Sunyer, Barcelona, Spain (C. Garcia-Vidal); Hospital Universitario La Paz, Madrid (I. Falces-Romero); University Medical Center Hamburg-Eppendorf, Hamburg, Germany (M. Schroeder); Centro Médico ABC, Mexico City, Mexico (I. Hoyo); University Hospital Regensburg, Regensburg, Germany (F. Hanses); Federal University of Triângulo Mineiro, Uberaba, Brazil (K. Ferreira-Paim); Istituto di Ricovero e Cura a Carattere Scientifi co San Martino Polyclinic Hospital, Genoa, Italy (D.R. Giacobbe); Canisius Wilhelmina Hospital, Nijmegen, the Netherlands (J.F. Meis); Federal University of Paraná, Curitiba, Brazil (J.F. Meis); University of Rennes I, Institut National de la Santé et de la Recherche Médicale, École des Hautes Études en Santé Publique, Institut de Recherche en Santé, Environnement et Travail, Rennes, France (J.-P. Gangneux); Hospital de Cabueñes, Gijón, Spain (A. Rodríguez-Guardado); Instituto de Investigación Sanitaria del Principado de Asturias, Oviedo, Spain (A. Rodríguez-Guardado); University of Milan, Milan, Italy (S. Antinori); German Centre for Infection Research, Cologne (O.A. Cornely)

¹These senior authors contributed equally to this article.

²Members of this group are listed at the end of this article.

Dr. Salmanton-García is an epidemiologist at University Hospital Cologne, Cologne. His primary research interests are invasive fungal infections, infectious diseases, epidemiology, and database management.

Address for correspondence
Jon Salmanton-García, University of Cologne, Herderstrasse 52–54, Cologne 50931, Germany; email: jon.salmanton-garcia@uk-koeln.de

J.S. has received research grants from Basilea Pharmaceuticals International Ltd. and travel grants from the Meta-Alexander Foundation and German Society for Infectious Diseases, outside the context of the submitted work. C.G.V. has received grants and speaker fees from Gilead Sciences, Inc. and Merck Sharp & Dohme Corp., and speaker fees from Janssen Pharmaceuticals, Lilly, Novartis, and Pfizer Inc., outside the context of the submitted work. M.S. receives funding from the Medical Faculty of the University of Hamburg, Hamburg, Germany for clinical leave. F.H. received lecture and other honoraria from Correvio Pharma Corp., InfectoPharm Arzneimittel und Consilium GmbH, and Novartis, outside the context of the submitted work. K.F.P. is financially supported by the Coordination for the Improvement of Higher Education Personnel Foundation and Ministry of Education of Brazil (proposal no. 09/2020) and a nonfinancial scientific grant from IMMY, outside the context of the submitted work. D.R.G. has received honoraria from Stepstone Pharma GmbH and unconditional grants from MSD Italia Srl and Correvio Pharma Corp. J.F.M. reports grants from F2G Ltd. and Pulmocide, consultancy fees from Scynexis, Inc., and speaker fees from Gilead Sciences Inc., United Medical, and Teva Pharmaceutical Industries Ltd., outside the context of the submitted work. J.P.G. has participated in advisory boards and received speaker honoraria from Pfizer Inc. and Gilead Sciences Inc., outside the context of the submitted work. E.S. has received grants from the Philipp Schwartz Initiative of the Alexander von Humboldt Foundation. O.A.C. is financially supported by the German Federal Ministry of Research and Education; is funded by the Deutsche Forschungsgemeinschaft under Germany's Excellence Strategy (CECAD, EXC 2030 – 390661388); has received research grants from Actelion Pharmaceuticals Global, Amplyx Pharmaceuticals, Inc., Astellas Pharma Inc., Basilea Pharmaceutica International Ltd., Cidara Therapeutics, Inc., Da Volterra, F2G Ltd., Gilead Sciences Inc., Janssen Pharmaceuticals, The Medicines Company, Melinta Therapeutics, Merck Sharp & Dohme Corp., Octapharma AG, Pfizer Inc., and Scynexis, Inc.; is a consultant to Actelion Pharmaceuticals Global, Allecra Therapeutics GmbH, Amplyx Pharmaceuticals, Inc., Astellas Pharma Inc., Basilea Pharmaceutica International Ltd., BIOSYS USA LLC, Cidara Therapeutics, Inc., Da Volterra, Entasis Therapeutics, F2G Ltd., Gilead Sciences Inc., Matinas BioPharma Holdings, Inc., MedPace, Inc., The Menarini Group, Merck Sharp & Dohme Corp., Mylan Inc., Nabriva Therapeutics plc, NOXXON Pharma, Octapharma AG, Paratek Pharmaceuticals, Inc., Pfizer Inc., Pharmaceutical Solutions Industry, Roche Diagnostics, Scynexis, Inc., and Shionogi Inc.; and received lecture honoraria from Al-Jazeera Pharmaceutical Industries, Astellas Pharma Inc., Basilea Pharmaceutica International Ltd., Gilead Sciences Inc., Grupo Biotoscana, Merck Sharp & Dohme Corp., and Pfizer Inc., outside the context of the submitted work. P.K. has received nonfinancial scientific grants from Miltenyi Biotec GmbH and the Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, and lecture honoraria from or is advisor to Akademie für Infektionsmedizin e.V., Ambu GmbH, Astellas Pharma Inc., European Confederation of Medical Mycology, Gilead Sciences Inc., Gesundheits und Pflegezentrum Rüsselsheim gemeinnützige GmbH, Merck Sharp & Dohme Corp., and University Hospital, Ludwig Maximilian University of Munich, and is advisor to Gilead Sciences Inc. and NOXXON N.V. outside the context of the submitted work.