Factors Associated with Worse Lung Function in Cystic Fibrosis Patients with Persistent <i>Staphylococcus aureus</i>

<div><p>Background</p><p><i>Staphylococcus aureus</i> 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 <i>S</i>. <i>aureus</i> airway cultures. Our main hypothesis was that patients with high <i>S</i>. <i>aureus</i> density in their respiratory specimens would more likely experience worsening of their lung disease than patients with low bacterial loads.</p><p>Methods</p><p>Therefore, we conducted an observational prospective longitudinal multi-center study and assessed the association between lung function and <i>S</i>. <i>aureus</i> bacterial density in respiratory samples, co-infection with other CF-pathogens, nasal <i>S</i>. <i>aureus</i> carriage, clinical status, antibiotic therapy, IL-6- and IgG-levels against <i>S</i>. <i>aureus</i> virulence factors.</p><p>Results</p><p>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), <i>S</i>. <i>aureus</i> small-colony variants (SCVs, n = 84) and co-infection with <i>Stenotrophomonas maltophilia</i> (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), <i>S</i>. <i>aureus</i> density in sputa (p = 0.0016), SCVs (p = 0.0209), exacerbations (p = 0.0041) and co-infections with <i>S</i>. <i>maltophilia</i> (p = 0.0195) or <i>A</i>. <i>fumigatus</i> (p = 0.0496).</p><p>Conclusions</p><p>In CF-patients with chronic <i>S</i>. <i>aureus</i> cultures, independent risk factors for worse lung function are high bacterial density in throat cultures, exacerbations, elevated IL-6 levels, presence of <i>S</i>. <i>aureus</i> SCVs and co-infection with <i>S</i>. <i>maltophilia</i>.</p><p>Trial Registration</p><p>ClinicalTrials.gov <a href="https://clinicaltrials.gov/ct2/show/NCT00669760" target="_blank">NCT00669760</a></p></div

Patients with <i>S</i>. <i>aureus</i> nasal carriage have better lung function.

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

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

<p>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.</p

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

<p>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.</p

Patients with exacerbations have worse lung function.

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