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. 2021 Nov 18;59(12):e0122921.
doi: 10.1128/JCM.01229-21. Epub 2021 Sep 8.

Aspergillus Test Profiles and Mortality in Critically Ill COVID-19 Patients

Mehmet Ergün  1   2 , Roger J M Brüggemann  1   3 , Alexandre Alanio  4   5 , Sarah Dellière  4   5 , Andreas van Arkel  6 , Robbert G Bentvelsen  6   7 , Tom Rijpstra  8 , Simone van der Sar-van der Brugge  9 , Katrien Lagrou  10   11 , Nico A F Janssen  1   12 , Jochem B Buil  1   2 , Karin van Dijk  13 , Willem J G Melchers  1   2 , Monique H E Reijers  1   14 , Jeroen A Schouten  15   16 , Joost Wauters  17 , Alan Cordey  18 , Shuchita Soni  18 , P Lewis White  18 , Frank L van de Veerdonk  1   12 , Paul E Verweij  1   2
Affiliations

Aspergillus Test Profiles and Mortality in Critically Ill COVID-19 Patients

Mehmet Ergün et al. J Clin Microbiol. .

Abstract

The literature regarding COVID-19-associated pulmonary aspergillosis (CAPA) has shown conflicting observations, including survival of CAPA patients not receiving antifungal therapy and discrepancy between CAPA diagnosis and autopsy findings. To gain insight into the pathophysiology of CAPA, we performed a case-control study in which we compared Aspergillus test profiles in CAPA patients and controls in relation to intensive care unit (ICU) mortality. This was a multinational case-control study in which Aspergillus test results, use of antifungal therapy, and mortality were collected from critically ill COVID-19 patients. Patients were classified using the 2020 European Confederation for Medical Mycology and the International Society for Human and Animal Mycology (ECMM/ISHAM) consensus case definitions. We analyzed 219 critically ill COVID-19 cases, including 1 proven, 38 probable, 19 possible CAPA cases, 21 Aspergillus-colonized patients, 7 patients only positive for serum (1,3)-β-d-glucan (BDG), and 133 cases with no evidence of CAPA. Mortality was 53.8% in CAPA patients compared to 24.1% in patients without CAPA (P = 0.001). Positive serum galactomannan (GM) and BDG were associated with increased mortality compared to serum biomarker-negative CAPA patients (87.5% versus 41.7%, P = 0.046; 90.0% versus 42.1%, P = 0.029, respectively). For each point increase in GM or 10-point BDG serum concentration, the odds of death increased (GM, odds ratio [OR] 10.208, 95% confidence interval [CI], 1.621 to 64.291, P = 0.013; BDG, OR, 1.247, 95% CI, 1.029 to 1.511, P = 0.024). CAPA is a complex disease, probably involving a continuum of respiratory colonization, tissue invasion, and angioinvasion. Serum biomarkers are useful for staging CAPA disease progression and, if positive, indicate angioinvasion and a high probability of mortality. There is need for a biomarker that distinguishes between respiratory tract colonization and tissue-invasive CAPA disease.

Keywords: COVID-19; critically ill; invasive pulmonary aspergillosis; mortality; mycology.

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Conflict of interest statement

R.J.M.B. reports grants and other from Pfizer, MSD, and Gilead, and other from Mundipharma, Astellas, F2G, Amplyx, and Cidara outside the submitted work. A.A. reports personal fees from Gilead and Pfizer and nonfinancial support from Astellas outside the submitted work. K.L. reports personal fees from SMB Laboratoires, Gilead, FUJIFILM Wako, and Thermo Fisher Scientific and nonfinancial support from Pfizer outside the submitted work. J.B.B. reports grants from Gilead Sciences, F2G Ltd, and Thermo Fisher Scientific outside the submitted work. J.W. reports research grants and speakers’ fees from Pfizer, MSD, and Gilead outside the submitted work. P.L.W. reports personal fees from Gilead, Pfizer, F2G, IMMY, and MSD and other from Bruker, Launch, and Associates of Cape Cod outside the submitted work. F.L.V.D.V. reports personal fees from Gilead and Sobi and grants from VIDI outside the submitted work. P.E.V. reports research grants from Gilead Sciences, Astellas, MSD, F2G, and Bio-Rad; he is a speaker for Gilead Sciences and MSD and is on the advisory boards for Pfizer, MundiPharma, Cidara, MSD, and F2G. M.E., S.D., A.V.A., R.G.B., T.R., S.V.D.S.-V.D.B., N.A.F.J., K.V.D., W.J.G.M., M.H.E.R., J.A.S., A.C., and S.S. declare no conflicting interests.

Figures

FIG 1
FIG 1
Kaplan-Meier survival curve and table of number at risk per CAPA classification. Comparing proven/probable CAPA cases with controls where no evidence of CAPA was found was significant (P = 0.000) and nonsignificant in all other comparisons. BDG, (1,3)-β-d-glucan; CAPA, COVID-19-associated pulmonary aspergillosis.
FIG 2
FIG 2
Predicted probability of 30-day mortality for initial BAL GM concentration measured (top left), highest BAL GM concentration measured (top right), highest serum GM concentration measured (bottom left), and highest serum BDG concentration measured (bottom right). BAL, bronchoalveolar lavage; BDG, (1,3)-β-d-glucan; CAPA, COVID-19-associated pulmonary aspergillosis; GM, galactomannan.
FIG 3
FIG 3
Schematic representation of 30-day mortality, CAPA classification, and possible role of Aspergillus tissue and angioinvasion. BDG, (1,3)-β-d-glucan; CAPA, COVID-19-associated pulmonary aspergillosis; GM, galactomannan.
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