Pulmonary Aspergillosis in Critically Ill COVID-19 Patients Admitted to the Intensive Care Unit: A Retrospective Cohort Study
Abstract
:1. Introduction
2. Methods
2.1. Study Design and Setting
2.2. Study Population
2.3. Definition of Pulmonary Aspergillosis
2.4. Outcome Parameters
2.5. Statistical Analysis
3. Results
3.1. Study Population
3.2. Mortality
3.3. Pathogen Distribution
3.4. Antifungal Therapy
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Raffaelli, F.; Tanzarella, E.S.; de Pascale, G.; Tumbarello, M. Invasive Respiratory Fungal Infections in COVID-19 Critically Ill Patients. J. Fungi 2022, 8, 415. [Google Scholar] [CrossRef] [PubMed]
- Maes, M.; Higginson, E.; Pereira-Dias, J.; Curran, M.D.; Parmar, S.; Khokhar, F.; Cuchet-Lourenço, D.; Lux, J.; Sharma-Hajela, S.; Ravenhill, B.; et al. Ventilator-Associated Pneumonia in Critically Ill Patients with COVID-19. Crit. Care 2021, 25, 25. [Google Scholar] [CrossRef]
- Gabelloni, M.; Faggioni, L.; Cioni, D.; Mendola, V.; Falaschi, Z.; Coppola, S.; Corradi, F.; Isirdi, A.; Brandi, N.; Coppola, F.; et al. Extracorporeal Membrane Oxygenation (ECMO) in COVID-19 Patients: A Pocket Guide for Radiologists. Radiol. Med. 2022, 127, 369–382. [Google Scholar] [CrossRef]
- Brandi, N.; Ciccarese, F.; Rimondi, M.R.; Balacchi, C.; Modolon, C.; Sportoletti, C.; Renzulli, M.; Coppola, F.; Golfieri, R. An Imaging Overview of COVID-19 ARDS in ICU Patients and Its Complications: A Pictorial Review. Diagnostics 2022, 12, 846. [Google Scholar] [CrossRef]
- Bartoletti, M.; Pascale, R.; Cricca, M.; Rinaldi, M.; Maccaro, A.; Bussini, L.; Fornaro, G.; Tonetti, T.; Pizzilli, G.; Francalanci, E.; et al. Epidemiology of Invasive Pulmonary Aspergillosis among Intubated Patients with COVID-19: A Prospective Study. Clin. Infect. Dis. 2021, 73, E3606–E3614. [Google Scholar] [CrossRef]
- Bardi, T.; Pintado, V.; Gomez-Rojo, M.; Escudero-Sanchez, R.; Azzam Lopez, A.; Diez-Remesal, Y.; Castro, N.M.; Ruiz-Garbajosa, P.; Pestaña, D. Nosocomial Infections Associated to COVID-19 in the Intensive Care Unit: Clinical Characteristics and Outcome. Eur. J. Clin. Microbiol. Infect. Dis. 2021, 40, 495–502. [Google Scholar] [CrossRef] [PubMed]
- Brandi, N.; Ciccarese, F.; Balacchi, C.; Rimondi, M.R.; Modolon, C.; Sportoletti, C.; Capozzi, C.; Renzulli, M.; Paccapelo, A.; Castelli, A.; et al. Co-Infections and Superinfections in COVID-19 Critically Ill Patients Are Associated with CT Imaging Abnormalities and the Worst Outcomes. Diagnostics 2022, 12, 1617. [Google Scholar] [CrossRef] [PubMed]
- Rouzé, A.; Martin-Loeches, I.; Povoa, P.; Metzelard, M.; du Cheyron, D.; Lambiotte, F.; Tamion, F.; Labruyere, M.; Geronimi, C.B.; Nieszkowska, A.; et al. Early Bacterial Identification among Intubated Patients with COVID-19 or Influenza Pneumonia: A European Multicenter Comparative Clinical Trial. Am. J. Respir. Crit. Care Med. 2021, 204, 546–556. [Google Scholar] [CrossRef]
- Pandey, M.; May, A.; Tan, L.; Hughes, H.; Jones, J.P.; Harrison, W.; Bradburn, S.; Tyrrel, S.; Muthuswamy, B.; Berry, N.; et al. Comparative Incidence of Early and Late Bloodstream and Respiratory Tract Co-Infection in Patients Admitted to ICU with COVID-19 Pneumonia versus Influenza A or B Pneumonia versus No Viral Pneumonia: Wales Multicentre ICU Cohort Study. Crit. Care 2022, 26, 158. [Google Scholar] [CrossRef]
- Dimopoulos, G.; Almyroudi, M.P.; Myrianthefs, P.; Rello, J. COVID-19-Associated Pulmonary Aspergillosis (CAPA). J. Intensive Med. 2021, 1, 71–80. [Google Scholar] [CrossRef]
- Kim, S.H.; Hong, J.Y.; Bae, S.; Lee, H.; Wi, Y.M.; Ko, J.H.; Kim, B.; Joo, E.J.; Seok, H.; Shi, H.J.; et al. Risk Factors for Coronavirus Disease 2019 (COVID-19)-Associated Pulmonary Aspergillosis in Critically Ill Patients: A Nationwide, Multicenter, Retrospective Cohort Study. J. Korean Med. Sci. 2022, 37, e134. [Google Scholar] [CrossRef]
- Leistner, R.; Schroeter, L.; Adam, T.; Poddubnyy, D.; Stegemann, M.; Siegmund, B.; Maechler, F.; Geffers, C.; Schwab, F.; Gastmeier, P.; et al. Corticosteroids as Risk Factor for COVID-19-Associated Pulmonary Aspergillosis in Intensive Care Patients. Crit. Care 2022, 26, 30. [Google Scholar] [CrossRef]
- Lamoth, F.; Lewis, R.E.; Walsh, T.J.; Kontoyiannis, D.P. Navigating the Uncertainties of COVID-19-Associated Aspergillosis: A Comparison With Influenza-Associated Aspergillosis. J. Infect. Dis. 2021, 224, 1631–1640. [Google Scholar] [CrossRef] [PubMed]
- Townsend, L.; Martin-Loeches, I. Invasive Aspergillosis in the Intensive Care Unit. Diagnostics 2022, 12, 2712. [Google Scholar] [CrossRef] [PubMed]
- Pfeiffer, C.D.; Fine, J.P.; Safdar, N. Diagnosis of Invasive Aspergillosis Using a Galactomannan Assay: A Meta-Analysis. Clin. Infect. Dis. 2006, 42, 1417–1427. [Google Scholar] [CrossRef]
- Vandenbroucke, J.P.; von Elm, E.; Altman, D.G.; Gøtzsche, P.C.; Mulrow, C.D.; Pocock, S.J.; Poole, C.; Schlesselman, J.J.; Egger, M. Strengthening the Reporting of Observational Studies in Epidemiology (STROBE): Explanation and Elaboration. PLoS Med. 2007, 4, 1628–1654. [Google Scholar] [CrossRef] [Green Version]
- Blot, S.I.; Taccone, F.S.; van den Abeele, A.M.; Bulpa, P.; Meersseman, W.; Brusselaers, N.; Dimopoulos, G.; Paiva, J.A.; Misset, B.; Rello, J.; et al. A Clinical Algorithm to Diagnose Invasive Pulmonary Aspergillosis in Critically Ill Patients. Am. J. Respir. Crit. Care Med. 2012, 186, 56–64. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Verweij, P.E.; van de Veerdonk, F.L. Managing Secondary Fungal Infections in Severe COVID-19: How to Move Forward? Lancet Respir. Med. 2022, 10, 127–128. [Google Scholar] [CrossRef]
- Rouzé, A.; Lemaitre, E.; Martin-Loeches, I.; Povoa, P.; Diaz, E.; Nyga, R.; Torres, A.; Metzelard, M.; du Cheyron, D.; Lambiotte, F.; et al. Invasive Pulmonary Aspergillosis among Intubated Patients with SARS-CoV-2 or Influenza Pneumonia: A European Multicenter Comparative Cohort Study. Crit. Care 2022, 26, 11. [Google Scholar] [CrossRef]
- Gangneux, J.P.; Dannaoui, E.; Fekkar, A.; Luyt, C.E.; Botterel, F.; de Prost, N.; Tadié, J.M.; Reizine, F.; Houzé, S.; Timsit, J.F.; et al. Fungal Infections in Mechanically Ventilated Patients with COVID-19 during the First Wave: The French Multicentre MYCOVID Study. Lancet Respir. Med. 2022, 10, 180–190. [Google Scholar] [CrossRef]
- Dupont, D.; Menotti, J.; Turc, J.; Miossec, C.; Wallet, F.; Richard, J.C.; Argaud, L.; Paulus, S.; Wallon, M.; Ader, F.; et al. Pulmonary Aspergillosis in Critically Ill Patients with Coronavirus Disease 2019 (COVID-19). Med. Mycol. 2021, 59, 110–114. [Google Scholar] [CrossRef] [PubMed]
- Fekkar, A.; Lampros, A.; Mayaux, J.; Poignon, C.; Demeret, S.; Constantin, J.M.; Marcelin, A.G.; Monsel, A.; Luyt, C.E.; Blaize, M. Occurrence of Invasive Pulmonary Fungal Infections in Patients with Severe COVID-19 Admitted to the ICU. Am. J. Respir. Crit. Care Med. 2021, 203, 307–317. [Google Scholar] [CrossRef] [PubMed]
- Janssen, N.A.F.; Nyga, R.; Vanderbeke, L.; Jacobs, C.; Ergün, M.; Buil, J.B.; van Dijk, K.; Altenburg, J.; Bouman, C.S.C.; van der Spoel, H.I.; et al. Multinational Observational Cohort Study of COVID-19-Associated Pulmonary Aspergillosis. Emerg. Infect. Dis. 2021, 27, 2892–2898. [Google Scholar] [CrossRef] [PubMed]
- Koukaki, E.; Rovina, N.; Tzannis, K.; Sotiropoulou, Z.; Loverdos, K.; Koutsoukou, A.; Dimopoulos, G. Fungal Infections in the ICU during the COVID-19 Era: Descriptive and Comparative Analysis of 178 Patients. J. Fungi 2022, 8, 881. [Google Scholar] [CrossRef]
- Koehler, P.; Bassetti, M.; Chakrabarti, A.; Chen, S.C.A.; Colombo, A.L.; Hoenigl, M.; Klimko, N.; Lass-Flörl, C.; Oladele, R.O.; Vinh, D.C.; et al. 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–e162. [Google Scholar] [CrossRef] [PubMed]
- Peter Donnelly, J.; Chen, S.C.; Kauffman, C.A.; Steinbach, W.J.; Baddley, J.W.; Verweij, P.E.; Clancy, C.J.; Wingard, J.R.; Lockhart, S.R.; Groll, A.H.; 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. Clin. Infect. Dis. 2020, 71, 1367–1376. [Google Scholar] [CrossRef] [Green Version]
- Winters, B.; Custer, J.; Galvagno, S.M.; Colantuoni, E.; Kapoor, S.G.; Lee, H.W.; Goode, V.; Robinson, K.; Nakhasi, A.; Pronovost, P.; et al. Diagnostic Errors in the Intensive Care Unit: A Systematic Review of Autopsy Studies. BMJ Qual. Saf. 2012, 21, 894–902. [Google Scholar] [CrossRef] [Green Version]
- Kula, B.E.; Clancy, C.J.; Hong Nguyen, M.; Schwartz, I.S. Invasive Mould Disease in Fatal COVID-19: A Systematic Review of Autopsies. Lancet Microbe 2021, 2, e405–e414. [Google Scholar] [CrossRef]
- Feys, S.; Almyroudi, M.P.; Braspenning, R.; Lagrou, K.; Spriet, I.; Dimopoulos, G.; Wauters, J. A Visual and Comprehensive Review on COVID-19-Associated Pulmonary Aspergillosis (Capa). J. Fungi 2021, 7, 1067. [Google Scholar] [CrossRef]
- Hatzl, S.; Reisinger, A.C.; Posch, F.; Prattes, J.; Stradner, M.; Pilz, S.; Eller, P.; Schoerghuber, M.; Toller, W.; Gorkiewicz, G.; et al. Antifungal Prophylaxis for Prevention of COVID-19-Associated Pulmonary Aspergillosis in Critically Ill Patients: An Observational Study. Crit. Care 2021, 25, 335. [Google Scholar] [CrossRef]
- The RECOVERY Collaborative Group. Dexamethasone in Hospitalized Patients with COVID-19. N. Engl. J. Med. 2021, 384, 693–704. [Google Scholar] [CrossRef] [PubMed]
- van de Veerdonk, F.L.; Brüggemann, R.J.M.; Vos, S.; de Hertogh, G.; Wauters, J.; Reijers, M.H.E.; Netea, M.G.; Schouten, J.A.; Verweij, P.E. COVID-19-Associated Aspergillus Tracheobronchitis: The Interplay between Viral Tropism, Host Defence, and Fungal Invasion. Lancet Respir. Med. 2021, 9, 795–802. [Google Scholar] [CrossRef] [PubMed]
Overall (n = 181) | No CAPA (n = 146) | Putative CAPA (n = 35) | p-Value | |
---|---|---|---|---|
Demographic characteristics | ||||
Female sex, n (%) | 54 (29.8) | 45 (30.8) | 9 (25.7) | 0.698 |
Age, mean (SD) | 54.46 (13.03) | 54.08 (13.56) | 56.06 (10.58) | 0.422 |
BMI, mean (SD) | 30.73 (7.13) | 30.86 (7.52) | 30.17 (5.24) | 0.609 |
Length of hospital stay (days), mean (SD) | 36.73 (25.53) | 35.92 (25.41) | 43.28 (26.30) | 0.250 |
Antigen assays a | ||||
Galactomannan index, median (IQR) | 0.10 (0.06–0.23) | 0.08 (0.06–0.15) | 3.69 (0.16–7.04) | 0.0001 |
Positive galactomannan index, n (%) | 22 (16.4) | 4 (3.7) | 18 (66.67) | 0.0001 |
β-D-Glucan (pg/mL), median (IQR) | 74.83 (0.00–194.2) | 72.59 (0.00–169.6) | 142.2 (51.47–365.1) | 0.02 |
Positive β-D-Glucan, n (%) | 66 (47.1) | 49 (43) | 17 (65.4) | 0.039 |
Bacterial infection b | 46 (25.4) | 39 (26.7) | 7 (20) | 0.52 |
Baseline comorbidities, n (%) | ||||
Diabetes | 24 (13.3) | 16 (11.0) | 8 (22.9) | 0.113 |
Obesity | 84 (46.4) | 74 (49.3) | 10 (28.6) | 0.03 |
Coronary artery disease | 13 (7.2) | 13 (8.9) | 0 (0.0) | 0.142 |
Chronic heart failure | 4 (2.2) | 2 (1.4) | 2 (5.7) | 0.352 |
Asthma | 5 (2.8) | 4 (2.7) | 1 (2.9) | 1.000 |
Chronic obstructive pulmonary disease | 9 (5.0) | 8 (5.5) | 1 (2.9) | 0.835 |
Hypertension | 42 (23.2) | 32 (21.9) | 10 (28.6) | 0.539 |
Chronic kidney disease | 15 (8.3) | 12 (8.2) | 3 (8.6) | 1.000 |
Skin disorder | 16 (8.8) | 15 (10.3) | 1 (2.9) | 0.291 |
Mental disorder | 33 (18.2) | 31 (21.2) | 2 (5.7) | 0.059 |
Neurologic disorder | 20 (11.0) | 19 (13.0) | 1 (2.9) | 0.155 |
Neoplasm | 26 (14.4) | 19 (13.0) | 7 (20.0) | 0.429 |
Immunosuppressants at ICU admission | 133 (73.5) | 110 (75.3) | 22 (62.9) | 0.135 |
SARS-CoV-2 variant | 0.213 | |||
Wildtype | 34 (18.8) | 28 (19.2) | 6 (17.1) | |
B.1.1.7 (Alpha) | 80 (44.2) | 66 (45.2) | 14 (40.0) | |
B.1.617.2 (Delta) | 54 (29.8) | 39 (26.7) | 15 (42.9) | |
Unknown | 13 (7.2) | 13 (8.9) | 0 (0.0) |
Patient | Sex | Age (Years) | Immunosuppressants at ICU Admission | Aspergillus spp. | Time to Infection from ICU Admission (Days) | Initial Antifungal Therapy at Time of Infection | Second-Line Antifungal Therapy | Outcome |
---|---|---|---|---|---|---|---|---|
1 | M | 49 | Dexamethasone 12 mg | Fumigatus | 11 | Voriconazole 200 mg | Voriconazole 400 mg | Recovered |
2 | M | 35 | Prednisolone 100 mg | Fumigatus | 1 | Caspofungin 70 mg | Voriconazole 400 mg | Recovered |
3 | F | 46 | Hydrocortisone 200 mg | Fumigatus | 10 | Voriconazole 300 mg | [-] | Recovered |
4 | M | 50 | None | Fumigatus | 1 | Micafungin 100 mg | Voriconazole 400 mg | Death |
5 | M | 50 | Dexamethasone 4 mg | Fumigatus | 2 | Voriconazole 400 mg | [-] | Death |
6 | M | 49 | None | Flavus | 3 | Voriconazole 200 mg | [-] | Recovered |
7 | M | 59 | None | Fumigatus | 4 | Voriconazole 200 mg | [-] | Death |
8 | M | 46 | Prednisolone 50 mg | Fumigatus | 29 | Fluconazole 800 mg | [-] | Recovered |
9 | M | 27 | Dexamethasone 40 mg | Flavus | 1 | Voriconazole 400 mg | [-] | Death |
Fumigatus | 1 | |||||||
Niger | 1 | |||||||
10 | M | 64 | Prednisolone 50 mg | Fumigatus | 10 | n/a | n/a | Death |
11 | M | 45 | None | Fumigatus | 18 | n/a | n/a | Death |
12 | M | 56 | Dexamethasone 10 mg | Fumigatus | 4 | Voriconazole 400 mg | [-] | Death |
13 | M | 63 | None | Fumigatus | 1 | Voriconazole 200 mg | [-] | Death |
14 | M | 51 | Dexamethasone 6 mg | Fumigatus | 1 | Voriconazole 400 mg | [-] | Death |
15 | M | 67 | Dexamethasone 8 mg | Fumigatus | 4 | Nystatin 1 mL | [-] | Recovered |
16 | F | 55 | Prednisolone 25 mg | Fumigatus | 5 | Voriconazole 300 mg | [-] | Recovered |
17 | F | 61 | None | Terreus | 18 | Voriconazole 400 mg | [-] | Recovered |
18 | M | 57 | Dexamethasone 8 mg | Fumigatus | 1 | Voriconazole 200 mg | [-] | Death |
19 | M | 56 | Dexamethasone 6 mg | Fumigatus | 5 | Fluconazole 600 mg | Voriconazole 200 mg | Death |
20 | M | 61 | None | Fumigatus | 3 | Isavuconazole 200 mg | [-] | Death |
21 | F | 69 | None | Fumigatus | 13 | n/a | n/a | Death |
22 | M | 70 | Dexamethasone 10 mg | Fumiigatiiaffinis | 12 | Micafungin 100 mg | Voriconazole 400 mg | Death |
23 | M | 70 | Dexamethasone 6 mg | Nidulans | 10 | n/a | n/a | Death |
24 | M | 48 | Dexamethasone 6 mg | Fumigatus | 1 | Voriconazole 200 mg | Voriconazole 300 mg | Recovered |
25 | F | 62 | None | Fumigatus | 1 | Voriconazole 200 mg | Voriconazole 200 mg Nystatin 0.5 mL | Recovered |
26 | M | 60 | None | Flavus | 27 | n/a | n/a | Recovered |
27 | M | 54 | Dexamethasone 10 mg Anakinra 600 mg | Fumigatus | 7 | Fluconazole 800 mg | Voriconazole 200 mg | Death |
28 | M | 58 | Hydrocortisone 200 mg | Fumigatus | 6 | Caspofungin 70 mg | Amphotericin B 600 mg | Recovered |
29 | F | 69 | None | Fumigatus | 16 | Caspofungin 50 mg | n/a | Death |
30 | F | 79 | Dexamethasone 4 mg | Fumigatus | 5 | n/a | n/a | Death |
31 | F | 51 | Dexamethasone 4 mg | Fumigatus | 3 | Voriconazole 200 mg | Voriconazole 400 mg | Recovered |
32 | M | 54 | None | Fumigatus | 4 | Micafungin 100 mg | n/a | Recovered |
33 | M | 63 | Prednisolone 250 mg | Fumigatus | 25 | n/a | n/a | Death |
34 | M | 43 | None | Fumigatus | 14 | Micafungin 100 mg | Micafungin 100 mg Amphotericin B 10 mg inhal. | Recovered |
35 | F | 65 | Prednisolone 500 mg | Fumigatus | 7 | Voriconazole 300 mg | [-] | Death |
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Bergmann, F.; Jorda, A.; Blaschke, A.; Gabler, C.; Bohdan, S.; Nussbaumer-Pröll, A.; Radtke, C.; Zeitlinger, M. Pulmonary Aspergillosis in Critically Ill COVID-19 Patients Admitted to the Intensive Care Unit: A Retrospective Cohort Study. J. Fungi 2023, 9, 315. https://doi.org/10.3390/jof9030315
Bergmann F, Jorda A, Blaschke A, Gabler C, Bohdan S, Nussbaumer-Pröll A, Radtke C, Zeitlinger M. Pulmonary Aspergillosis in Critically Ill COVID-19 Patients Admitted to the Intensive Care Unit: A Retrospective Cohort Study. Journal of Fungi. 2023; 9(3):315. https://doi.org/10.3390/jof9030315
Chicago/Turabian StyleBergmann, Felix, Anselm Jorda, Amelie Blaschke, Cornelia Gabler, Serhii Bohdan, Alina Nussbaumer-Pröll, Christine Radtke, and Markus Zeitlinger. 2023. "Pulmonary Aspergillosis in Critically Ill COVID-19 Patients Admitted to the Intensive Care Unit: A Retrospective Cohort Study" Journal of Fungi 9, no. 3: 315. https://doi.org/10.3390/jof9030315