Factors associated with worse lung function in cystic fibrosis patients with persistent staphylococcus aureus

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

ZMYND10 Is Mutated in Primary Ciliary Dyskinesia and Interacts with LRRC6

Defects of motile cilia cause primary ciliary dyskinesia (PCD), characterized by recurrent respiratory infections and male infertility. Using whole-exome resequencing and high-throughput mutation analysis, we identified recessive biallelic mutations in ZMYND10 in 14 families and mutations in the recently identified LRRC6 in 13 families. We show that ZMYND10 and LRRC6 interact and that certain ZMYND10 and LRRC6 mutations abrogate the interaction between the LRRC6 CS domain and the ZMYND10 C-terminal domain. Additionally, ZMYND10 and LRRC6 colocalize with the centriole markers SAS6 and PCM1. Mutations in ZMYND10 result in the absence of the axonemal protein components DNAH5 and DNALI1 from respiratory cilia. Animal models support the association between ZMYND10 and human PCD, given that zmynd10 knockdown in zebrafish caused ciliary paralysis leading to cystic kidneys and otolith defects and that knockdown in Xenopus interfered with ciliogenesis. Our findings suggest that a cytoplasmic protein complex containing ZMYND10 and LRRC6 is necessary for motile ciliary function

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

Patients with culture of <i>S</i>. <i>maltophilia</i> have worse lung function.

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

Significant specific IgG levels against <i>S</i>. <i>aureus</i> antigens in CF patients compared to healthy controls.

<p>Significant specific IgG levels against <i>S</i>. <i>aureus</i> antigens in CF patients compared to healthy controls.</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

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

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

Characteristics of study patients compared to the German CF population.

<p>Characteristics of study patients compared to the German CF population.</p