Staphylococcus aureus ventilator-associated pneumonia in patients with COVID-19: clinical features and potential inference with lung dysbiosis

Abstract

Background: Hospitalized patients with COVID-19 admitted to the intensive care unit (ICU) and requiring mechanical ventilation are at risk of ventilator-associated bacterial infections secondary to SARS-CoV-2 infection. Our study aimed to investigate clinical features of Staphylococcus aureus ventilator-associated pneumonia (SA-VAP) and, if bronchoalveolar lavage samples were available, lung bacterial community features in ICU patients with or without COVID-19.

Methods: We prospectively included hospitalized patients with COVID-19 across two medical ICUs of the Fondazione Policlinico Universitario A. Gemelli IRCCS (Rome, Italy), who developed SA-VAP between 20 March 2020 and 30 October 2020 (thereafter referred to as cases). After 1:2 matching based on the simplified acute physiology score II (SAPS II) and the sequential organ failure assessment (SOFA) score, cases were compared with SA-VAP patients without COVID-19 (controls). Clinical, microbiological, and lung microbiota data were analyzed.

Results: We studied two groups of patients (40 COVID-19 and 80 non-COVID-19). COVID-19 patients had a higher rate of late-onset (87.5% versus 63.8%; p = 0.01), methicillin-resistant (65.0% vs 27.5%; p < 0.01) or bacteremic (47.5% vs 6.3%; p < 0.01) infections compared with non-COVID-19 patients. No statistically significant differences between the patient groups were observed in ICU mortality (p = 0.12), clinical cure (p = 0.20) and microbiological eradication (p = 0.31). On multivariable logistic regression analysis, SAPS II and initial inappropriate antimicrobial therapy were independently associated with ICU mortality. Then, lung microbiota characterization in 10 COVID-19 and 16 non-COVID-19 patients revealed that the overall microbial community composition was significantly different between the patient groups (unweighted UniFrac distance, R² 0.15349; p < 0.01). Species diversity was lower in COVID-19 than in non COVID-19 patients (94.4 ± 44.9 vs 152.5 ± 41.8; p < 0.01). Interestingly, we found that S. aureus (log₂ fold change, 29.5), Streptococcus anginosus subspecies anginosus (log₂ fold change, 24.9), and Olsenella (log₂ fold change, 25.7) were significantly enriched in the COVID-19 group compared to the non-COVID-19 group of SA-VAP patients.

Conclusions: In our study population, COVID-19 seemed to significantly affect microbiological and clinical features of SA-VAP as well as to be associated with a peculiar lung microbiota composition.

Keywords: Bronchoalveolar lavage; COVID-19; Lung microbiota; Staphylococcus aureus; Ventilator-associated pneumonia.

Fig. 1

a Microbiological and clinical features of SA VAP in COVID-19 patients and controls. b Kaplan–Meier curve showing the impact of IIAT (black line) on ICU mortality. SA: Staphylococcus aureus; BSI: bloodstream infection; MRSA: methicillin-resistant Staphylococcus aureus; Micro: microbiological; VAP: ventilator-associated pneumonia; IIAT: initial inadequate antibiotic therapy; IAAT: initial adequate antibiotic therapy

Fig. 2

Lung microbiota composition and diversity indices in patients with S. aureus respiratory infection. Alpha diversity (a) and Unweighted Unifrac Beta diversity (b) were analysed on the basis of the dataset normalized to 105,851 reads per sample. The two groups compared were defined by SARS-CoV-2 positive infection. The differences between groups were assessed by Wilcoxon nonparametric test showing a lower alpha diversity in COVID-19 group compared to patients from the non-COVID-19 group (Observed index: 94.4 ± 44.9 vs. 152.5 ± 41.8; P = 0.001). No significant differences were observed in the Shannon (P = 0.421), Simpson’s inverse (P = 0.979), or Pielou's evenness (P = 0.938) indices. Permutational multivariate analysis of variance (PERMANOVA) showed significant differences between the microbial communities of the two groups (R² 0.15349, P = 0.004). Panel C shows the mean of the relative abundances of the 30 more represented genera within the six major phyla that compose the lung bacterial community of COVID-19 and non-COVID-19 groups

Fig. 3

Differential abundances between patients with concomitant SARS-CoV-2 and S. aureus respiratory infection and SARS-CoV-2-negative patients with S. aureus infection. The analysis of differentially abundant taxa was assessed using the DESeq2 package. In all analyses, a P value < 0.05 was set as the statistical significance threshold. Positive values of log2 Fold change represent genera significantly more abundant in Covid-19 group