Association of COVID-19-Associated Pulmonary Aspergillosis with Cytomegalovirus Replication: A Case-Control Study

Abstract

Introduction: Cytomegalovirus (CMV) infection is a well-known factor associated with invasive aspergillosis in immunocompromised hosts. However, its association with COVID-19-associated pulmonary aspergillosis (CAPA) has not been described. We aimed to examine the possible link between CMV replication and CAPA occurrence. Methods: A single-center, retrospective case-control study was conducted. A case was defined as a patient diagnosed with CAPA according to 2020 ECMM/ISHAM consensus criteria. Two controls were selected for each case among critically ill COVID-19 patients. Results: In total, 24 CAPA cases were included, comprising 14 possible CAPA and 10 probable CAPA. Additionally, 48 matched controls were selected. CMV replication was detected more frequently in CAPA than in controls (75.0% vs. 35.4%, p = 0.002). Probable CMV end-organ disease was more prevalent in CAPA (20.8% vs. 4.2%, p = 0.037). After adjusting for possible confounding factors, CMV replication persisted strongly associated with CAPA (OR 8.28 95% CI 1.90-36.13, p = 0.005). Among 11 CAPA cases with CMV PCR available prior to CAPA, in 9 (81.8%) cases, CMV replication was observed prior to CAPA diagnosis. Conclusions: Among critically ill COVID-19 patients, CMV replication was associated with CAPA and could potentially be considered a harbinger of CAPA. Further studies are needed to confirm this association.

Keywords: CAPA; COVID-associated pulmonary aspergillosis; cytomegalovirus infection; prevalence; risk factors.

Figure 1

Peak CMV-DNA viral load among patients with CMV replication according to the diagnosis of pulmonary aspergillosis. Viral load is expressed in UI/mL (0.91 UI/mL equals 1 copy/mL). and represented in a linear scale. CMV: cytomegalovirus.

Figure 2

CMV-DNA viral load in patients with CMV replication according to 2020 ECMM/ISHAM consensus criteria classification of COVID-associated pulmonary aspergillosis and controls. Viral load is expressed in UI/mL (0.91 UI/mL equals 1 copy/mL) and represented in in a linear scale. CMV: cytomegalovirus. * represents an individual patient with a unusual high CMV-DNA viral load within controls.