Factors Associated with Worse Lung Function in Cystic Fibrosis Patients with Persistent Staphylococcus aureus

Abstract

Background: Staphylococcus aureus is an important pathogen in cystic fibrosis (CF). However, it is not clear which factors are associated with worse lung function in patients with persistent S. aureus airway cultures. Our main hypothesis was that patients with high S. aureus density in their respiratory specimens would more likely experience worsening of their lung disease than patients with low bacterial loads.

Methods: Therefore, we conducted an observational prospective longitudinal multi-center study and assessed the association between lung function and S. aureus bacterial density in respiratory samples, co-infection with other CF-pathogens, nasal S. aureus carriage, clinical status, antibiotic therapy, IL-6- and IgG-levels against S. aureus virulence factors.

Results: 195 patients from 17 centers were followed; each patient had an average of 7 visits. Data were analyzed using descriptive statistics and generalized linear mixed models. Our main hypothesis was only supported for patients providing throat specimens indicating that patients with higher density experienced a steeper lung function decline (p<0.001). Patients with exacerbations (n = 60), S. aureus small-colony variants (SCVs, n = 84) and co-infection with Stenotrophomonas maltophilia (n = 44) had worse lung function (p = 0.0068; p = 0.0011; p = 0.0103). Patients with SCVs were older (p = 0.0066) and more often treated with trimethoprim/sulfamethoxazole (p = 0.0078). IL-6 levels positively correlated with decreased lung function (p<0.001), S. aureus density in sputa (p = 0.0016), SCVs (p = 0.0209), exacerbations (p = 0.0041) and co-infections with S. maltophilia (p = 0.0195) or A. fumigatus (p = 0.0496).

Conclusions: In CF-patients with chronic S. aureus cultures, independent risk factors for worse lung function are high bacterial density in throat cultures, exacerbations, elevated IL-6 levels, presence of S. aureus SCVs and co-infection with S. maltophilia.

Trial registration: ClinicalTrials.gov NCT00669760.

Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1. Patients with throat cultures with high bacterial density experience a more rapid lung function decline.

Patients with high bacterial density in throat specimens are indicated by red squares, patients with low bacterial density in throat specimens by blue circles, the fitted model prediction is coloured accordingly.

Fig 2. Patients with exacerbations have worse lung function.

Patients with exacerbation are indicated by red squares, patients without exacerbation by blue circles, the fitted model prediction is coloured accordingly.

Fig 3. Patients with S. aureus nasal carriage have better lung function.

S. aureus nasal carriers are indicated by blue squares, non-nasal carriers by red circles, fitted model prediction is coloured accordingly.

Fig 4. Patients with SCVs have worse lung function.

Patients with SCVs are indicated by red squares, patients without SCVs by blue circles, fitted model prediction is coloured accordingly.

Fig 5. Patients with culture of S. maltophilia have worse lung function.

Patients with S. maltophilia are indicated by red squares, patients without S. maltophilia by blue circles, fitted model prediction is coloured accordingly.

Fig 6. Higher IL-6 is associated with lower FEV1% predicted.

Scatterplot of baseline measurements (n = 88) of all patients with blood samples provided at the first visit. The fit line shows the results of a non-linear regression model. Dark shaded areas show 95% confidence band, lighter shaded area shows 95% prediction band.