COVID-19-associated pulmonary aspergillosis in mechanically ventilated patients: a prospective, multicentre UK study

Abstract

Background: Invasive pulmonary aspergillosis is a complication of severe COVID-19, with regional variation in reported incidence and mortality. We describe the incidence, risk factors and mortality associated with COVID-19-associated pulmonary aspergillosis (CAPA) in a prospective, multicentre UK cohort.

Methods: From March 2020 to March 2021, 266 mechanically ventilated adults with COVID-19 were enrolled across 5 UK hospital intensive care units (ICUs). CAPA was defined using European Confederation for Medical Mycology and the International Society for Human and Animal Mycology criteria and fungal diagnostics performed on respiratory and serum samples.

Results: Twenty-nine of 266 patients (10.9%) had probable CAPA, 14 (5.2%) possible CAPA and none proven CAPA. Probable CAPA was diagnosed a median of 9 (IQR 7-16) days after ICU admission. Factors associated with probable CAPA after multivariable logistic regression were cumulative steroid dose given within 28 days prior to ICU admission (adjusted OR (aOR) 1.16; 95% CI 1.01 to 1.43 per 100 mg prednisolone-equivalent), receipt of an interleukin (IL)-6 inhibitor (aOR 2.79; 95% CI 1.22 to 6.48) and chronic obstructive pulmonary disease (COPD) (aOR 4.78; 95% CI 1.13 to 18.13). Mortality in patients with probable CAPA was 55%, vs 46% in those without. After adjustment for immortal time bias, CAPA was associated with an increased risk of 90-day mortality (HR 1.85; 95% CI 1.07 to 3.19); however, this association did not remain statistically significant after further adjustment for confounders (adjusted HR 1.57; 95% CI 0.88 to 2.80). There was no difference in mortality between patients with CAPA prescribed antifungals (9 of 17; 53%) and those who were not (7 of 12; 58%) (p=0.77).

Interpretation: In this first prospective UK study, probable CAPA was associated with corticosteroid use, receipt of IL-6 inhibitors and pre-existing COPD. CAPA did not impact mortality following adjustment for prognostic variables.

Keywords: COVID-19; aspergillus lung disease; critical care; viral infection.

Figure 1

Factors associated with the development of probable CAPA. Multivariable logistic regression model. All coefficients exponentiated. APACHE II, Acute Physiology and Chronic Health Evaluation II, CAPA, COVID-19-associated pulmonary aspergillosis; COPD, chronic obstructive pulmonary disease; ICU, intensive care unit; IL, interleukin; pred-eq, prednisolone equivalent.

Figure 2

Simon-Makuch plot displaying time-adjusted survival probability over time in patients with a diagnosis of probable CAPA versus those without. Probability curves and p value calculated using an unadjusted time-dependent Cox proportional hazards model. CAPA, COVID-19-associated pulmonary aspergillosis.

Figure 3

Risk of death according to published CAPA definitions. Point estimates and HRs calculated using a time-dependent Cox hazards regression model adjusted for age, APACHE II score, receipt of ECMO and COPD. All coefficients exponentiated. APACHE II, Acute Physiology and Chronic Health Evaluation II; CAPA, COVID-19-associated pulmonary aspergillosis; COPD, chronic obstructive pulmonary disease; ECMM/ISHAM, European Confederation for Medical Mycology and the International Society for Human and Animal Mycology; ECMO, extracorporeal membrane oxygenation.

Figure 4

Kaplan-Meier survival analysis comparing 90-day mortality in patients with probable CAPA according to mycological test positivity. Tests included in analysis: serum β-D-glucan >80 (not part of ECMM/ISHAM criteria), serum GM >0.5, serum Aspergillus PCR CT <36, BAL culture, BAL-GM >1.0, BAL Aspergillus PCR CT <36. Probability curves and p value calculated using Cox proportional hazards model. BAL, bronchoalveolar lavage; CAPA, COVID-19-associated pulmonary aspergillosis; CT, cycle threshold; ECMM/ISHAM, European Confederation for Medical Mycology and the International Society for Human and Animal Mycology; GM, galactomannan.

Figure 5

Kaplan-Meier survival analysis comparing 90-day mortality in patients without any positive mycology tests with those with one positive test and those with two or more positive tests (all patients in cohort included). Tests included: serum β-D-glucan >80 (not part of ECMM/ISHAM criteria), serum GM >0.5, serum Aspergillus PCR CT <36, BAL culture, BAL-GM >1.0, BAL Aspergillus PCR CT <36. Probability curves and p value calculated using Cox proportional hazards model. BAL, bronchoalveolar lavage; CAPA, COVID-19-associated pulmonary aspergillosis; CT, cycle threshold; ECMM/ISHAM, European Confederation for Medical Mycology and the International Society for Human and Animal Mycology; GM, galactomannan.

Figure 6

UpSet diagram displaying positive test modalities in patients classified as probable CAPA. This diagram shows the number of diagnoses of probable CAPA made according to diagnostic test or combination of diagnostic tests. BAL, bronchoalveolar lavage; CAPA, COVID-19-associated pulmonary aspergillosis; GM, galactomannan.