Tania Pressler

Understanding the natural progression in %FEV1 decline in patients with cystic fibrosis: a longitudinal study

Background Forced 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 findings The 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. Conclusions This 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.

Colonisation and infection of the paranasal sinuses in cystic fibrosis patients is accompanied by a reduced PMN response

BACKGROUND We studied whether the sinuses might be foci for Pseudomonas aeruginosa lung infection. METHODS Endoscopic Sinus Surgery was performed in 78 CF patients; PFGE was used for bacterial genotyping. Material from sinuses and lungs were Gram-stained to detect biofilms. Immunoglobulins were measured in serum and saliva. RESULTS When P. aeruginosa was cultured simultaneously from the sinuses and the lungs they were genetically identical in 38 of the 40 patients (95%). In the sinuses, P. aeruginosa formed biofilms with minimal cellular inflammation, probably because of a significantly higher local production of secretory IgA compared with IgG (p<0.001). CONCLUSIONS 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.

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.

Shifting paradigms of nontuberculous mycobacteria in cystic fibrosis

Important paradigms of pulmonary disease with nontuberculous mycobacteria (NTM) are currently shifting based on an increasing attention within the field of cystic fibrosis (CF). These shifts are likely to benefit the management of all patients with pulmonary NTM, regardless of underlying pathology. Currently several key areas are being revised: The first outbreak of human NTM transmission has been proven and new evidence of biofilm growth in vivo has been demonstrated. A better understanding of the clinical impact of NTM infection has led to increased diagnostic vigilance and new recommendations for lung transplantation are under way. While recent changes have reinvigorated the interest in NTM disease, the challenge remains, whether such advances can be successfully translated into improved management and care.

Chronic pulmonary infection with Stenotrophomonas maltophilia and lung function in patients with cystic fibrosis

BACKGROUND The clinical consequences of chronic Stenotrophomonas maltophilia infection in cystic fibrosis (CF) patient are still unclear. METHOD All patients treated in the Copenhagen CF centre (N=278) from 1 January 2008 to 31 December 2009 were included. Each patient chronically infected with S. maltophilia for at least 2 years without any other chronic Gram-negative infection were matched to two non-infected CF controls. RESULTS Twenty-one patients were chronically infected with S. maltophilia during the 2-year study period. Fifteen were infected for at least 2 years. The patients in the S. maltophilia group had a steeper decline (-3.2%/year vs. -0.3%/year) in FEV(1) compared to the non-infected CF controls (P=0.03). The rate of decline was the same as observed 3 years before the patients became chronically infected. DISCUSSIONS Chronic infection with S. maltophilia does not lead to a steeper decline in lung function when compared to the period before chronic infection.

Comparing the harmful effects of nontuberculous mycobacteria and Gram negative bacteria on lung function in patients with cystic fibrosis

Background To better understand the relative effects of infection with nontuberculous mycobacteria and Gram negative bacteria on lung function decline in cystic fibrosis, we assessed the impact of each infection in a Danish setting. Methods Longitudinal registry study of 432 patients with cystic fibrosis contributing 53,771 lung function measures between 1974 and 2014. We used a mixed effects model with longitudinally structured correlation, while adjusting for clinically important covariates. Results Infections with a significant impact on rate of decline in %FEV1 were Mycobacterium abscessus complex with − 2.22% points per year (95% CI − 3.21 to − 1.23), Burkholderia cepacia complex − 1.95% (95% CI − 2.51 to − 1.39), Achromobacterxylosoxidans − 1.55% (95% CI − 2.21 to − 0.90), and Pseudomonas aeruginosa − 0.95% (95% CI − 1.24 to − 0.66). Clearing M. abscessus complex was associated with a change to a slower decline, similar in magnitude to the pre-infection slope. Conclusions In a national population we have demonstrated the impact on lung function of each chronic CF pathogen. M. abscessus complex was associated with the worst impact on lung function. Eradication of M. abscessus complex may significantly improve lung function.

Co-morbidity of cystic fibrosis and celiac disease in Scandinavian cystic fibrosis patients

BACKGROUND The co-morbidity of cystic fibrosis (CF) and celiac disease (CD) has been reported sporadically since the 1960s. To our knowledge, this is the first time a systematic screening is performed in a large cohort of CF patients. METHODS Transglutaminase-IgA (TGA), endomysium-IgA (EMA) and total IgA in serum were measured in 790 CF patients (48% females, 86% with pancreatic insufficiency). Six patients were diagnosed with CD prior to the study, all receiving a gluten-free diet. Patients with elevated TGA (>50 Units/mL) and a positive EMA test were offered a gastroscopy obtaining mucosal biopsies from the duodenum. RESULTS Four new cases of CD were diagnosed. Two additional patients had positive serological tests, but normal biopsies. In total, 10 cases of CD (1.2%, 1:83) indicate a prevalence rate about three times higher than the general prevalence of CD in Norway and Sweden. No CD patients were detected in the Danish CF cohort. Patients diagnosed with untreated CD reported symptoms typical of both CF and CD (poor weight gain, loose and/or fatty stools, fatigue, irritability, abdominal pain). They improved after introduction of a gluten-free diet. CONCLUSIONS Systematic screening for CD in a Scandinavian cohort of CF patients revealed a higher prevalence of CD than in the general population. Clinical signs of CD are difficult to differentiate from CF with malabsorption, and patients may go undiagnosed for a long time. In a population where CD is common we recommend screening for CD in patients with CF.

Clinical effects of sinus surgery and adjuvant therapy in cystic fibrosis patients - can chronic lung infections be postponed?

BACKGROUND The paranasal sinuses can be a bacterial reservoir for pulmonary infections in patients with cystic fibrosis (CF) METHODOLOGY: In this prospective, non-randomised, uncontrolled, intervention cohort study, the clinical effect of sinus surgery followed by two weeks` intravenous antibiotics, 6 months` antibiotic nasal irrigations was assessed in 106 CF patients. RESULTS One year after sinus surgery, the prevalence of intermittently colonised patients had decreased by 38%, while the prevalence of non-colonised patients had increased by 150%. The frequency of pulmonary samples with CF pathogens was reduced after surgery. Specific IgG against P. aeruginosa decreased after six months. Additionally, the self reported symptoms of chronic rhinosinusitis and quality of life improved. CONCLUSION Combined sinus surgery and postoperative systemic and topical antibiotic treatment significantly reduced the frequency of pulmonary samples positive for CF pathogens in the first year after sinus surgery.

Quantitative analysis of the IgG and IgG subclass immune responses to chromosomal Pseudomonas aeruginosa beta-lactamase in serum from patients with cystic fibrosis by western blotting and laser scanning densitometry.

BACKGROUND: Antibodies against chromosomal beta-lactamase of Pseudomonas aeruginosa (a beta ab) are markers of the development of resistance of P aeruginosa to beta-lactam antibiotics in patients with cystic fibrosis and chronic lung infection. The role of these antibodies in patients with chronic lung infection with P aeruginosa was further investigated by correlating the a beta ab IgG subclasses with pulmonary function in patients with cystic fibrosis. METHODS: Immunoglobulin G (IgG) and IgG subclass a beta ab were investigated by western blotting and quantified by laser scanning densitometry. A longitudinal study on 43 consecutive patients with cystic fibrosis who developed chronic lung infection with P aeruginosa was performed. RESULTS: IgG subclass a beta ab appeared in all patients with chronic infection with P aeruginosa. Eleven years after the onset of infection all the patients had IgG1, 79% had IgG4, 56% IgG2, and only 16% of the patients had IgG3 a beta ab. The IgG1 and IgG4 a beta ab appeared first, and more than 50% of the patients were IgG1 and IgG4 a beta ab positive within 2-3 years of the onset of infection, but IgG2 positivity only appeared after seven years and IgG3 remained absent from most of the patients. The median a beta ab levels increased during chronic infection: 100-fold for IgG1, 22-fold for IgG2, and 45-fold for IgG4. A 16-fold increase in the IgG3 a beta ab levels was detected in the six patients who developed IgG3 a beta ab. In the first four years of the chronic infection the a beta ab titres were higher in patients with good lung function than in those with poor lung function. CONCLUSIONS: The association of a weak IgG3 and a strong IgG4 a beta ab response suggests that the contribution of a beta ab antibodies to lung diseases mediated by immune complexes might be less important than other antipseudomonal antibodies. A beneficial neutralising effect of the a beta ab antibodies on the antibiotic destroying enzymes may be an additional factor.

Sinus surgery postpones chronic Gram-negative lung infection: cohort study of 106 patients with cystic fibrosis.

BACKGROUND In patients with cystic fibrosis (CF) the sinuses are a bacterial reservoir for Gram-negative bacteria (GNB). From the sinuses the GNB can repeatedly migrate to the lungs. In a one-year follow-up study, endoscopic sinus surgery (ESS) with adjuvant therapy reduced the frequency of pulmonary samples positive for GNB. We investigated whether the effect is sustained. METHODOLOGY We report the effect of ESS and adjuvant therapy three years postoperatively in a CF cohort participating in this prospective clinical follow-up study. The primary endpoint was the lung infection status defined by Leeds criteria. RESULTS One hundred and six CF patients underwent ESS; 27 had improved lung infection status after three years. The prevalence of patients free of lung colonization with GNB significantly increased from 16/106 patients (15%) preoperatively to 35/106 patients (33%) after three years. The total cohort had decreasing lung function during follow-up; however, in 27 patients with improved lung infection status lung function was stable. Revision surgery was performed in 31 patients (28%). CONCLUSION ESS with adjuvant therapy significantly improves the lung infection status for at least three years in our cohort of patients with CF and may postpone chronic lung infection with GNB and thus stabilize lung function.