Fungal infection-related conditions and outcomes in severe COVID-19: a nationwide case-control study

Abstract

Background: Fungal infections are significant complications of severe coronavirus disease 2019 (COVID-19). Although various risk factors for poor outcomes in patients with COVID-19 have been identified, clinical and treatment factors associated with fungal infections in patients with severe COVID-19 remain unclear. This study aimed to elucidate clinical factors associated with fungal infections during severe COVID-19 treatment.

Methods: This was a post hoc analysis of the J-RECOVER study, a multicenter retrospective observational study involving patients with COVID-19 who required admission at 66 hospitals between January and September 2020. Inclusion criteria were ages ≥ 18 years, COVID-19 diagnosis with reverse-transcription polymerase chain reaction, and treatment with mechanical ventilation (MV). Patients who received antifungal drugs before MV were excluded. Potential predictors were identified through univariate analysis of patient and treatment characteristics between patients with- and those without fungal infection, which was defined as antifungal agent use for ≥ 5 days. To account for facility-specific data clustering, generalized estimating equations (GEE) were employed as adjusted analyses to calculate the relative risks of potentially associated factors. Two sensitivity analyses were performed with modified definitions for the two groups: patients who received antifungal drugs for ≤ 4 days were excluded, and fungal infection was re-defined as antifungal drug use for ≥ 14 days.

Results: Among 4,915 patients in the J-RECOVER study, 559 adults with COVID-19 who required MV were included. Fungal infections occurred in 57 (10.2%) patients. Univariate analyses identified age, age ≥ 65 years, D-dimer level, remdesivir use, steroid use, and duration of steroid therapy as potential predictors of fungal infections. Multivariate analysis using GEE on these six factors revealed that only the duration of steroid use was significantly associated with an increased risk of fungal infection (odds ratio [OR] for a day increase: 1.01; 95% confidence interval [CI]: 1.00-1.01; p < 0.001). The two sensitivity analyses similarly showed that the duration of steroid use was associated with fungal infection (odds ratio for a day increase: 1.01; 95% CI: 1.00-1.01; p < 0.001 for both).

Conclusions: In patients with severe COVID-19 requiring MV, each additional day of steroid use was associated with prolonged use of antifungal medications for ≥ 5 days.

Keywords: COVID-19; Fungal infection; Mechanical ventilation; Risk factors; Steroid therapy.

Fig. 1

Patient flow diagram. A total of 4,915 patients with coronavirus disease 2019 (COVID-19) were included in the J-RECOVER database. A total of 559 patients met the inclusion criteria. Of these patients, 57 fulfilled the definition of fungal infection and 502 were classified as having non-fungal infections

Fig. 2

Duration of antifungal drug administration in patients with fungal infection. Histograms show the number of cases that met the definition of fungal infection for each period of antifungal drug administration. Most treatments were administered for 1–3 weeks, with 2 weeks being the most common