key: cord-0944720-nz6e4s87
authors: Meijer, Eelco F. J.; Dofferhoff, Anton S. M.; Hoiting, Oscar; Meis, Jacques F.
title: COVID‐19–associated pulmonary aspergillosis: a prospective single‐center dual case series
date: 2021-02-16
journal: Mycoses
DOI: 10.1111/myc.13254
sha: 8272032b18226c0d1f08564c6dcdeaf94ea0401f
doc_id: 944720
cord_uid: nz6e4s87

BACKGROUND: COVID‐19–associated pulmonary aspergillosis (CAPA) has emerged as an invasive fungal disease, often affecting previously immunocompetent, mechanically ventilated, intensive care unit (ICU) patients. Incidence rates of 3.8%–33.3% have been reported depending on the geographic area, with high (47%) mortality. OBJECTIVES: Here, we describe a single‐centre prospective case series with CAPA cases from both the first (March‐May, n = 5/33) and second (mid‐September through mid‐December, n = 8/33) COVID‐19 wave at a 500‐bed teaching hospital in the Netherlands. PATIENTS/METHODS: In the first COVID‐19 wave, a total of 265 SARS‐CoV‐2 PCR‐positive patients were admitted to our hospital of whom 33 needed intubation and mechanical ventilation. In the second wave, 508 SARS‐CoV‐2 PCR‐positive patients were admitted of whom 33 needed mechanical ventilation. Data were prospectively collected. RESULTS: We found a significant decrease in COVID‐19 patients needing mechanical ventilation in the ICU in the second wave (p < .01). From these patients, however, a higher percentage were diagnosed with CAPA (24.2% vs 15.2%), although not significant (p = .36). All CAPA patients encountered in the second wave received dexamethasone. Mortality between both groups was similarly high (40%–50%). Moreover, we found environmental TR(34)/L98H azole‐resistant Aspergillus fumigatus isolates in two separate patients. CONCLUSIONS: In this series, 19.7% (n = 13/66) of mechanically ventilated SARS‐CoV‐2 patients were diagnosed with CAPA. In addition, we found a significant reduction in COVID‐19 patients needing mechanical ventilation on the ICU in the second wave. Numbers are too small to determine whether there is a true difference in CAPA incidence in mechanically ventilated patients between the two waves, and whether it could be attributed to dexamethasone SARS‐CoV‐2 therapy.

COVID-19-associated pulmonary aspergillosis (CAPA) is a recently described disease entity being mainly reported in the Intensive Care Unit (ICU), also affecting immunocompetent patients.

Recently published small case series describe an overall high incidence of CAPA in SARS-CoV-2-positive patients admitted to the ICU with acute respiratory distress syndrome requiring mechanical ventilation. The United Kingdom, 1, 2 The Netherlands, 3, 4 Belgium, 5 Germany, 6 Italy 7 and France 8,9 report incidences of 12.3%-33.3%.

In Denmark, 10 a 25% (n = 2/8) incidence of invasive aspergillosis in COVID-19 patients undergoing extracorporeal membrane oxygenation (ECMO) was described, totalling 7.4% when adding the non-ECMO ICU population (n = 19). China, 11 Mexico 12 and Switzerland 13 report incidences of 8%, 9.7% and 3.8% in mechanically ventilated patients, respectively. In addition, Spain 14 

Pakistan 15 reported CAPA incidences of 3.3% and 21.7% in single studies, respectively, although patient data describing the use of mechanical ventilation were incomplete. Altogether, CAPA is associated with a high mortality of approximately 50% in these series, underscoring the importance of global awareness and early diagnosis.

The above-mentioned percentages of CAPA are alarming, keeping in mind that novel and mixed existing definitions [16] [17] [18] [19] are used in diagnosing cases, often not confirmed by histopathology. The higher percentages are comparable with observations made in influenza, which is an independent risk factor for invasive pulmonary aspergillosis in the ICU setting. 20, 21 However, clinically and mechanistically, influenza-associated pulmonary aspergillosis (IAPA) and CAPA are clearly distinct clinical entities. 16, 22 More published data are needed to delineate the true incidence of CAPA in the ICU setting. Fortunately, the recently published CAPA 2020 ECMM/ISHAM consensus criteria 23 should provide clinical guidance and uniformity in classifying patients. Here, we report prospective findings from CAPA patients admitted to the ICU of a 500-bed teaching hospital in the Netherlands during the first and second waves of the COVID-19 pandemic during the year 2020.

In the first COVID-19 wave during a 2-month-period from March until May 1 2020, a total of 265 SARS-CoV-2 PCR-positive patients were admitted to our hospital of whom 33 needed intubation and mechanical ventilation. In the second wave, a 3-month-period from mid-September through mid-December 2020, 508 SARS-CoV-2 PCR-positive patients were admitted of whom 33 needed mechanical ventilation due to respiratory insufficiency. Data were prospectively collected in a study named 'Clinical course and prognostic factors for COVID-19', approved March 2020 by the Canisius Wilhelmina hospital medical ethics committee CWZ-nr 027-2020.

CAPA classification (possible/probable) was performed by using the 2020 ECMM/ISHAM consensus criteria, 23 using a combination of microbiology, imaging and clinical factors. Statistical analyses were performed with SPSS statistics (IBM version 25). For the unpaired two-tailed t tests, a p-value of less than .05 was considered statistically significant.

SARS-CoV-2 PCR was performed by in-house PCR or by Cepheids GeneXpert Xpress SARS-CoV-2 PCR as described by Wolters et al. 24 Triazole susceptibility screening was done using VIPcheck™ (Mediaproducts BV). MICs of Aspergillus fumigatus isolates were determined with broth microdilution using CLSI standards. 25 Fungal PCR targeting the Cyp51A gene was done using AsperGenius™ (PathoNostics). 1-3 β-d-glucan (BDG) testing was done using the Fungitell assay (Associates of Cape Cod Inc). Galactomannan (GM) testing was done using Platelia Aspergillus (Bio-Rad) and/or Aspergillus lateral flow device (AspLFD, OLM Diagnostics).

Case characteristics and diagnostics performed are presented in Table 1 

In this series, we found a significant reduction in COVID-19 patients needing mechanical ventilation on the ICU in the second wave. This reduction is probably partly attributable 26 to the 10-day 6 mg intravenous dexamethasone SARS-CoV-2 therapy 27 introduced after the first wave, indicated for patients with severe COVID-19 and associated symptoms longer than 7 days. From these patients, however, a larger percentage were diagnosed with CAPA in the second wave (24.2% vs 15.2%), although not significant. Prolonged use of corticosteroids is known to be a risk factor for invasive fungal disease. 17 However, numbers are too small to determine whether there is a true difference in CAPA incidence in mechanically ventilated patients between the two waves, and whether it could be attributed to dexamethasone SARS-CoV-2 therapy. None of the CAPA patients in this case series had prior immuno-compromising conditions, and diabetes mellitus was not overrepresented in either group. Table 2 ). The 47% (n = 62/132) mortality found in these case series is comparable to a recent study who report 52.5% mortality including both case series and case reports. 31 Not all patients were discharged from the hospital in several studies, possibly underestimating mortality. In IAPA, a similar overall mortality has been described (51%), 21 with a subset of IAPA tracheobronchitis patients having a reported mortality of over 90%. 32 To our knowledge, invasive tracheobronchitis has not been reported in CAPA patients, underscoring how IAPA and CAPA are mechanistically distinct clinical entities.

In diagnosing CAPA, little was known on the performance of serum GM and the 'panfungal' marker BDG. Serum GM testing in neutropenic non-CAPA patients with proven invasive aspergillosis has been shown to have a sensitivity of around 70%, and 25%

in the non-neutropenic host. 33 CAPA patients are generally nonneutropenic and sensitivity of serum GM reported in these patients are similarly low (15.6%-21%). 30, 31 Whilst BDG testing is nonspecific, its sensitivity in the ICU population for invasive fungal disease has been shown to be high (88%). 34 Combining the case series reported, we found that only 20.9% had a positive serum GM ( 20 This mutation has also been identified in CAPA patients in Ireland, 38 France 39 and the UK 2 underscoring the challenges faced in patient management, the importance of early diagnostics and (inter)national surveillance programs.

The authors declare no conflict of interest. Abbreviations: BDG, 1-3 β-d-glucan; CAPA, COVID-19-associated pulmonary aspergillosis; GM, Galactomannan. a Novel criteria are discussed in these publications.

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