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

Abstract

BackgroundStaphylococcus 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.MethodsTherefore, 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.Results195 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).ConclusionsIn 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 RegistrationClinicalTrials.gov NCT00669760

Stenotrophomonas maltophilia: A marker of lung disease severity

“…We also observed in this pediatric cohort that only the cases were colonized by P. aeruginosa and MRSA, two pathogens known to be associated with an accelerated lung function decline in CF patients . Moreover, Junge et al recently showed that S. maltophila co‐infection was a risk factor of a worse lung function in CF patients with persistent S. aureus airway colonization . Besides, Waters et al showed that chronic S. maltophilia infection was associated with an almost three‐fold increased risk of death or lung transplant in CF patients .…”

Phenazine Antibiotic‐Inspired Discovery of Bacterial Biofilm‐Eradicating Agents

“…Young CF patients are often afflicted with persistent S. aureus lung infections . We believe these infections to be biofilm‐associated, as CF patients endure lung infections that persist for years.…”

“…Young CF patients are often afflictedw ith persistent S. aureus lung infections. [114][115][116] We believe these infections to be biofilm-associated, as CF patientse ndure lung infections that persist for years. As these CF patients age, P. aeruginosa co-infects their lungs and eradicates the established S. aureus infection using ad iversea rray of redox-active phenazine antibiotic com-poundst hat demonstrate antimicrobial activities.…”

Importance of superoxide dismutases A and M for protection ofStaphylococcus aureusin the oxidative stressful environment of cystic fibrosis airways

“…Staphylococcus aureus is the most common and one of the first pathogens that can be isolated from the airways of CF patients (Cystic Fibrosis Foundation Patient Registry, ). Despite antistaphylococcal treatment, S. aureus is able to persist over several years (Kahl et al, ; Schwerdt et al, ), causing inflammation (Sagel et al, ) and a decline in lung function (Junge et al, ). The long‐term persistence of S. aureus might be facilitated by its ability to enter, replicate, and reside in professional phagocytes like macrophages (Li et al, ) and neutrophils (Gresham et al, ) and non‐professional phagocytes as keratinocytes, fibroblasts, endothelial, and epithelial cells (Strobel et al, ), including also CF cells (Jarry & Cheung, ; Kahl et al, ).…”