Analyses of 1,236 genotyped primary ciliary dyskinesia individuals identify regional clusters of distinct DNA variants and significant genotype-phenotype correlations.

BACKGROUND: Primary ciliary dyskinesia (PCD) represents a group of rare hereditary disorders characterized by deficient ciliary airway clearance that can be associated with laterality defects. We aimed to describe the underlying gene defects, geographical differences in genotypes and their relationship to diagnostic findings and clinical phenotypes. METHODS: Genetic variants and clinical findings (age, sex, body mass index, laterality defects, FEV1) were collected from 19 countries using the ERN LUNG International PCD Registry. Genetic data were evaluated according to ACMG guidelines. We assessed regional distribution of implicated genes and genetic variants as well as genotype correlations with laterality defects and FEV1. RESULTS: 1236 individuals carried 908 distinct pathogenic DNA variants in 46 PCD genes. We found considerable variation in the distribution of PCD genotypes across countries due to the presence of distinct founder variants. The prevalence of PCD genotypes associated with pathognomonic ultrastructural defects (mean 72%; 47-100%) and laterality defects (mean 42%; 28-69%) varied widely among the countries. The prevalence of laterality defects was significantly lower in PCD individuals without pathognomonic ciliary ultrastructure defects (18%). The PCD cohort had a reduced median FEV1 z-score (-1.66). In the group of individuals with CCNO (-3.26), CCDC39 (-2.49), and CCDC40 (-2.96) variants, FEV1 z-scores were significantly lower, while the group of DNAH11 (-0.83) and ODAD1 (-0.85) variant individuals had significantly milder FEV1 z-score reductions compared to the whole PCD cohort. CONCLUSION: This unprecedented multinational dataset of DNA variants and information on their distribution across countries facilitates interpretation of genetic epidemiology of PCD and provides prediction of diagnostic and phenotypic features such as the course of lung function.

Epidemiology of nontuberculous mycobacteria among patients with cystic fibrosis in Scandinavia.

BACKGROUND: Nontuberculous mycobacteria (NTM) are an emerging threat to cystic fibrosis (CF) patients but their epidemiology is not well described. METHODS: In this retrospective observational study we identified all Scandinavian CF patients with a positive NTM culture from airway secretions from 2000 to the end of 2012 and used national CF databases to describe microbiological and clinical characteristics. RESULTS: During the 13-year period 157 (11%) CF patients were culture positive for NTM at least once. Mycobacterium abscessus complex (MABSC) (45%) and Mycobacterium avium complex (MAC) (32%) were the predominant species with geographical differences in distribution. Younger patients were more prone to MABSC (p<0.01). Despite treatment, less than one-third of MABSC patients with repeated positive cultures cleared their infection and a quarter had a lung transplant or died. CONCLUSION: NTM are significant CF pathogens and are becoming more prevalent in Scandinavia. MABSC and MAC appear to target distinct patient groups. Having multiple positive cultures despite treatment conveys a poor outcome.

Respiratory bacterial infections in cystic fibrosis.

PURPOSE OF REVIEW: Bacterial respiratory infections are the main cause of morbidity and mortality in patients with cystic fibrosis (CF). Pseudomonas aeruginosa remains the main pathogen in adults, but other Gram-negative bacteria such as Achromobacter xylosoxidans and Stenotrophomonas maltophilia as well as nontuberculous mycobacteria have been shown to play an important role in the lung disease. The purpose of this review is to summarize the knowledge on disease and treatment of infection with CF-related pathogens. RECENT FINDINGS: The role of the paranasal sinuses as a source of infection and site of bacterial adaptation has been recognized. This review will focus on the different conditions encountered by the bacteria in sinuses and lung, as well as the principles of treatment in the different infection sites. SUMMARY: Chronic, pulmonary infections remain the single most prominent cause of the increased morbidity and mortality in CF. After the increasing efficiency of anti-P. aeruginosa treatment, newer pathogens have been identified, with individual clinical characteristics. Microbiological surveillance is very important in keeping the patients stable. Samples from both the lower and upper respiratory tract (nasal sampling) should be investigated and both infection sites should be treated.

Stenotrophomonas maltophilia: to be or not to be a cystic fibrosis pathogen.

PURPOSE OF REVIEW: Stenotrophomonas maltophilia can cause persistent airway colonization and chronic infection in cystic fibrosis (CF) patients. The clinical effect of chronic S. maltophilia infection is still a matter of debate. The purpose of the review is to summarize studies published during the last 1.5 years with a focus on whether S. maltophilia should be regarded as a 'true' CF pathogen. RECENT FINDINGS: Studies concerning the microbiological characteristics of this microorganism with special focus on identification, virulence factors, cross-infection and resistance pattern, and studies on clinical effects of chronic infection, specifically serological responses to this infection, negative effects on the clinical status and possible effects of antibiotic treatment have been reviewed. SUMMARY: S. maltophilia can be identified with certainty, has well-described virulence factors, is capable of cross-infection and often shows multiresistance. Although CF patients with chronic S. maltophilia infection have lower lung function parameters compared with other CF patients and experience more exacerbations, chronic S. maltophilia infection in itself was not associated with a worse clinical outcome. True, pathogenic effects of S. maltophilia could not be found, but the presence of chronic S. maltophilia could be a marker of more pronounced lung disease in affected patients.