Lung infections with Mycobacterium abscessus, a species of multidrug resistant nontuberculous mycobacteria, are emerging as an important global threat to individuals with cystic fibrosis (CF) where they accelerate inflammatory lung damage leading to increased morbidity and mortality. Previously, M. abscessus was thought to be independently acquired by susceptible individuals from the environment. However, using whole genome analysis of a global collection of clinical isolates, we show that the majority of M. abscessus infections are acquired through transmission, potentially via fomites and aerosols, of recently emerged dominant circulating clones that have spread globally. We demonstrate that these clones are associated with worse clinical outcomes, show increased virulence in cell-based and mouse infection models, and thus represent an urgent international infection challenge.Nontuberculous mycobacteria (NTM; referring to mycobacterial species other than M. tuberculosis complex and M. leprae) are ubiquitous environmental organisms that can cause chronic pulmonary infections in susceptible individuals [1,2], particularly those with preexisting inflammatory lung diseases such as cystic fibrosis (CF) [3]. The major NTM infecting CF individuals around the world is Mycobacterium abscessus; a rapidly growing, intrinsically multidrug-resistant species, which can be impossible to treat despite prolonged combination antibiotic therapy [1,[3][4][5], leads to accelerated decline in lung function [6,7], and remains a contraindication to lung transplantation in many centers [3,8,9].Until recently, NTM infections were thought to be independently acquired by individuals through exposure to soil or water [10][11][12]. As expected, previous analyses from the 1990s and 2000s [13][14][15][16] showed that CF patients were infected with unique, genetically diverse strains of M. abscessus, presumably from environmental sources. We used whole genome sequencing at a single UK CF center and identified two clusters of patients (11 individuals in total) infected with identical or near-identical M. abscessus isolates, which social network analysis suggested were acquired within hospital via indirect transmission between patients Phylogenetic analysis of these sequences (using one isolate per patient), supplemented by published genomes from US, France, Brazil, Malaysia, China, and South Korea (Table S1), was performed and analysed in the context of the geographical provenance of isolates ( Figure 1; Figure S1). Within each subspecies, we found multiple examples of deep branches (indicating large genetic differences) between isolates from different individuals, consistent with independent acquisition of unrelated environmental bacteria. However, we also identified multiple clades of near-identical isolates from geographically diverse locations (Figure 1), suggesting widespread transmission of circulating clones within the global CF patient community.To investigate further the relatedness of isolates from different individuals, we a...

Chronic pulmonary infection with Pseudomonas aeruginosa is responsible for most of the morbidity and mortality in cystic fibrosis (CF). Once established as a biofilm, chronic P. aeruginosa infection caused by the mucoid phenotype cannot be eradicated. However, a period of intermittent colonization with P. aeruginosa precedes the establishment of the chronic infection. This window of opportunity can be utilized to eradicate P. aeruginosa from the respiratory tract of CF patients by means of oral ciprofloxacin in combination with nebulized colistin for 3 weeks or, even better, for 3 months or by means of inhaled tobramycin as monotherapy for 4 weeks or longer. This early, aggressive eradication therapy has now been used for 15 years without giving rise to resistance to the antibiotics and without serious side effects. The therapeutic results have been very successful and have completely changed the epidemiology in the Danish Cystic Fibrosis Center and a few other centers which have used this strategy for several years. The chronic P. aeruginosa lung infection is not seen in CF infants and children anymore due to the aggressive therapy, and no other bacteria have replaced P. aeruginosa in these young patients. The aggressive therapy has been shown to very cost-effective, and a European Consensus report recommends this approach.

We have shown that P. aeruginosa form biofilm in the sinuses, which constitute an important bacterial reservoir for subsequent lung infection. The high amount of IgA in the upper airways probably protects P. aeruginosa from the inflammatory immune system, and they can proceed unnoticed into a permanent infectious focus that cannot be eradicated with antibiotics.

BackgroundNontuberculous mycobacteria (NTM) are an emerging threat to cystic fibrosis (CF) patients but their epidemiology is not well described.MethodsIn 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.ResultsDuring 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.ConclusionNTM 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.

BackgroundForced expiratory volume in 1 s as a percentage of predicted (%FEV1) is a key outcome in cystic fibrosis (CF) and other lung diseases. As people with CF survive for longer periods, new methods are required to understand the way %FEV1 changes over time. An up to date approach for longitudinal modelling of %FEV1 is presented and applied to a unique CF dataset to demonstrate its utility at the clinical and population level.Methods and findingsThe Danish CF register contains 70 448 %FEV1 measures on 479 patients seen monthly between 1969 and 2010. The variability in the data is partitioned into three components (between patient, within patient and measurement error) using the empirical variogram. Then a linear mixed effects model is developed to explore factors influencing %FEV1 in this population. Lung function measures are correlated for over 15 years. A baseline %FEV1 value explains 63% of the variability in %FEV1 at 1 year, 40% at 3 years, and about 30% at 5 years. The model output smooths out the short-term variability in %FEV1 (SD 6.3%), aiding clinical interpretation of changes in %FEV1. At the population level significant effects of birth cohort, pancreatic status and Pseudomonas aeruginosa infection status on %FEV1 are shown over time.ConclusionsThis approach provides a more realistic estimate of the %FEV1 trajectory of people with chronic lung disease by acknowledging the imprecision in individual measurements and the correlation structure of repeated measurements on the same individual over time. This method has applications for clinicians in assessing prognosis and the need for treatment intensification, and for use in clinical trials.