Impact of lumacaftor/ivacaftor on the bacterial and fungal respiratory pathogens in cystic fibrosis: a prospective multicenter cohort study in Sweden.

BACKGROUND: A significant decline in pulmonary exacerbation rates has been reported in CF patients homozygous for F508del treated with lumacaftor/ivacaftor. However, it is still unclear whether this reduction reflects a diminished microbiological burden. OBJECTIVES: The aim of this study was to determine the impact of lumacaftor/ivacaftor on the bacterial and fungal burden. DESIGN: The study is a prospective multicenter cohort study including 132 CF patients homozygous for F508del treated with lumacaftor/ivacaftor. METHODS: Clinical parameters as well as bacterial and fungal outcomes 1 year after initiation of lumacaftor/ivacaftor were compared to data from 2 years prior to initiation of the treatment. Changes in the slope of the outcomes before and after the onset of treatment were assessed. RESULTS: Lung function measured as ppFEV1 (p < 0.001), body mass index (BMI) in adults (p < 0.001), and BMI z-score in children (p = 0.007) were improved after initiation of lumacaftor/ivacaftor. In addition, the slope of the prevalence of Streptococcus pneumoniae (p = 0.007) and Stenotrophomonas maltophilia (p < 0.001) shifted from positive to negative, that is, became less prevalent, 1 year after treatment, while the slope for Candida albicans (p = 0.009), Penicillium spp (p = 0.026), and Scedosporium apiospermum (p < 0.001) shifted from negative to positive. CONCLUSION: The current study showed a significant improvement in clinical parameters and a reduction of some of CF respiratory microorganisms 1 year after starting with lumacaftor/ivacaftor. However, no significant changes were observed for Pseudomonas aeruginosa, Staphylococcus aureus, or Aspergillus fumigatus, key pathogens in the CF context.

Coxsackievirus B infections are common in Cystic Fibrosis and experimental evidence supports protection by vaccination.

Viral respiratory tract infections exacerbate airway disease and facilitate life-threatening bacterial colonization in cystic fibrosis (CF). Annual influenza vaccination is recommended and vaccines against other common respiratory viruses may further reduce pulmonary morbidity risk. Enteroviruses have been found in nasopharyngeal samples from CF patients experiencing pulmonary exacerbations. Using serology tests, we found that infections by a group of enteroviruses, Coxsackievirus Bs (CVBs), are prevalent in CF. We next showed that a CVB vaccine, currently undergoing clinical development, prevents infection and CVB-instigated lung damage in a murine model of CF. Finally, we demonstrate that individuals with CF have normal vaccine responses to a similar, commonly used enterovirus vaccine (inactivated poliovirus vaccine). Our study demonstrates that CVB infections are common in CF and provides experimental evidence indicating that CVB vaccines could be efficacious in the CF population. The role of CVB infections in contributing to pulmonary exacerbations in CF should be further studied.

MAIT cell counts are associated with the risk of hospitalization in COPD.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by persistent airflow limitation associated with chronic inflammation in the airways. Mucosal-associated invariant T (MAIT) cells are unconventional, innate-like T cells highly abundant in mucosal tissues including the lung. We hypothesized that the characteristics of MAIT cells in circulation may be prospectively associated with COPD morbidity. METHODS: COPD subjects (n = 61) from the Tools for Identifying Exacerbations (TIE) study were recruited when in stable condition. At study entry, forced expiratory volume in 1 s (FEV1) was measured and peripheral blood mononuclear cells were cryopreserved for later analysis by flow cytometry. Patients were followed for 3 years to record clinically meaningful outcomes. RESULTS: Patients who required hospitalization at one or more occasions during the 3-year follow-up (n = 21) had lower MAIT cell counts in peripheral blood at study inclusion, compared with patients who did not get hospitalized (p = 0.036). In contrast, hospitalized and never hospitalized patients did not differ in CD8 or CD4 T cell counts (p = 0.482 and p = 0.221, respectively). Moreover, MAIT cells in hospitalized subjects showed a more activated phenotype with higher CD38 expression (p = 0.014), and there was a trend towards higher LAG-3 expression (p = 0.052). Conventional CD4 and CD8 T cells were similar between the groups. Next we performed multi-variable logistic regression analysis with hospitalizations as dependent variable, and FEV1, GOLD 2017 group, and quantity or activation of MAIT and conventional T cells as independent variables. MAIT cell count, CD38 expression on MAIT cells, and LAG-3 expression on both MAIT and CD8 T cells were all independently associated with the risk of hospitalization. CONCLUSIONS: These findings suggest that MAIT cells might reflect a novel, FEV1-independent immunological dimension in the complexity of COPD. The potential implication of MAIT cells in COPD pathogenesis and MAIT cells' prognostic potential deserve further investigation.

The Effects of Aspergillus fumigatus Colonization on Lung Function in Patients with Cystic Fibrosis.

Aspergillus fumigatus is commonly isolated from CF airways. However, the impact on CF lung progression is not completely understood. In this study, using a 16-year retrospective observational cohort study (2000-2015) that included 132 patients, we determined the annual lung function, measured as percent predicted forced expiratory volume in the first second (ppFEV1), decline before and after the first colonization with A. fumigatus. Further, in the same individual, the ratios of lung function when patients were colonized with A. fumigatus and when they were not were calculated. The impact of eradication, with antifungal treatment or spontaneously, was assessed. The annual ppFEV1 was significantly lower after the first colonization with A. fumigatus. Furthermore, within the same individual, colonization with A. fumigatus for two and three years in a row was associated with 4.3% and 7.9% lower ppFEV1, respectively, compared to when not colonized. Finally, patients who eradicated A. fumigatus the following two years after colonization exhibited 9.9% and 14.5% higher ppFEV1 compared to patients who continued to produce cultures with A. fumigatus for two and three years. Our study demonstrated that A. fumigatus colonization was associated with a negative impact on lung function in the long term and eradication, spontaneously or with treatment, was associated with a better pulmonary outcome.

A 16-year retrospective study on fungal prevalence and diversity in patients with cystic fibrosis: Candida dubliniensis was associated with a decline in lung function.

OBJECTIVES: To study the prevalence of fungal species in cystic fibrosis (CF) patients over a 16 years period. To examine the impact of Candida albicans (C. albicans), Candida dubliniensis (C. dubliniensis) and Aspergillus fumigatus (A. fumigatus) on lung function. METHODS: Observational single-center cohort study (2000-2015) including 133 CF patients (ages 6-66 years). Linear mixed models with autoregressive covariance matrix were used. RESULTS: The most common fungus was C. albicans (prevalence 62%) followed by A. fumigatus (22%) and C. dubliniensis (11%). In the initial year of detection, there was no impact of C. albicans, C. dubliniensis or A. fumigatus on lung function. However, one and two years after detection of C. dubliniensis a reduction in percent predicted forced expiratory volume in the first second (ppFEV1) was observed of 3.8% (p = 0.022) and 4.1% (p = 0.017), respectively, compared with CF patients without these findings. Furthermore, patients with positive cultures for any of these fungal species for three consecutive years exhibited a decline in lung function: C. dubliniensis, 7.6% reduction in ppFEV1 (p = 0.001); A. fumigatus, 4.9% (p = 0.007); C. albicans, 2.6% (p = 0.014). The results were adjusted for age, CFTR genotype, chronic and intermittent P. aeruginosa colonization, and numbers of intravenous antibiotic treatments per year. Persistence of C. dubliniensis for three consecutive years was positively correlated to age and erythrocyte sedimentation rate (ESR) (both p = 0.001). CONCLUSIONS: Cystic fibrosis patients who were cultured positive for C. dubliniensis, C. albicans or A. fumigatus in sputum exhibited a decline in ppFEV1 over time. The effect was most pronounced for C. dubliniensis.

Severely Impaired Control of Bacterial Infections in a Patient With Cystic Fibrosis Defective in Mucosal-Associated Invariant T Cells.

Here we report a unique case of a patient with cystic fibrosis characterized by severely impaired control of bacterial respiratory infections. This patient's susceptibility to such infections was much worse than expected from a cystic fibrosis clinical perspective, and he died at age 22 years despite extensive efforts and massive use of antibiotics. We found that this severe condition was associated with a near-complete deficiency in circulating mucosal-associated invariant T (MAIT) cells as measured at several time points. MAIT cells are a large, recently described subset of T cells that recognize microbial riboflavin metabolites presented by the highly evolutionarily conserved MR1 molecules. The MAIT cell deficiency was specific; other T-cell subsets were intact. Even though this is only one unique case, the findings lend significant support to the emerging role of MAIT cells in mucosal immune defense and suggest that MAIT cells may significantly modify the clinical phenotype of respiratory diseases.

A Link Between a Common Mutation in CFTR and Impaired Innate and Adaptive Viral Defense.

Acute respiratory virus infections predispose the cystic fibrosis (CF) lung to chronic bacterial colonization, which contributes to high mortality. For reasons unknown, respiratory virus infections have a prolonged duration in CF. Here, we demonstrate that mice carrying the most frequent cystic fibrosis transmembrane conductance regulator (CFTR) mutation in humans, ΔF508, show increased morbidity and mortality following infection with a common human enterovirus. ΔF508 mice demonstrated impaired viral clearance, a slower type I interferon response and delayed production of virus-neutralizing antibodies. While the ΔF508 mice had a normal immune cell repertoire, unchanged serum immunoglobulin concentrations and an intact immune response to a T-cell-independent antigen, their response to a T-cell-dependent antigen was significantly delayed. Our studies reveal a novel function for CFTR in antiviral immunity and demonstrate that the ΔF508 mutation in cftr is coupled to an impaired adaptive immune response. This important insight could open up new approaches for patient care and treatment.

Non-invasive Ventilation as Airway Clearance Technique in Cystic Fibrosis.

BACKGROUND AND PURPOSE: For patients with cystic fibrosis, chest physiotherapy is crucial for evacuating airway secretions. Because chest physiotherapy increases energy expenditure, fatigue and dyspnoea, non-invasive ventilation (NIV) could be beneficial for severely ill patients during airway clearance. The aim of the study is to evaluate and compare the effects between NIV and positive expiratory pressure (PEP) on airway clearance. METHODS: Prospective, randomized trial compares PEP to NIV. Thirty-two subjects, mean age 31 years, mean forced expiratory volume in 1 second 47% (±14) and mean forced vital capacity 69% (±13), completed a 3-month randomized trial comparing NIV with standard PEP treatment as airway clearance technique. Lung functions testing, 6-minute walk test, blood gases, sputum culture and inflammatory parameters were measured before and after the treatment period. RESULTS: There was a significant reduction in lung clearance index (LCI) following NIV compared with PEP (p = 0.01). LCI is performed within the lung function testing. DISCUSSION: Non-invasive ventilation was shown to be a good alternative to PEP in chest physiotherapy for patients with cystic fibrosis who are severely ill.

Psychometric evaluation of the Swedish translation of the revised Cystic Fibrosis Questionnaire in adults.

AIM: The CFQ-R is one of the most established disease-specific, health-related quality of life (HRQOL) measurements for patients with cystic fibrosis (CF). The aim was to evaluate the psychometric properties of the Swedish translation of CFQ-R in adults. METHOD: A total of 173 CF patients answered the CFQ-R. The CFQ-R was evaluated with regard to: (1) distributional properties; (2) reliability; and (3) construct validity. RESULTS: The majority of scales were negatively skewed with ceiling effects. Eight of the 12 scales had satisfactory homogeneity; 10 of the 12 scales had satisfactory test-retest reliability. On many of the CFQ-R scales expected differences were observed when patients were divided regarding disease severity, nutritional status, age, and gender. CONCLUSION: Some weaknesses were detected, but overall the instrument has satisfactory psychometric properties.

Associations between genetics, medical status, physical exercise and psychological well-being in adults with cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF) is the most common autosomal recessive, life-shortening disease among people of European origin. Type of genetic mutation and regular physical exercise has an impact on clinical outcome. This cross-sectional study explores the associations between genetics, medical status, physical exercise and psychological well-being in adult patients with CF. METHODS: Adult patients with CF (N=68; mean age: 32.2; range 18-67 years; 46% women) completed the Cystic Fibrosis Questionnaire-Revised and Hospital Anxiety Depression Scale. Measures about lung function/forced expiratory volume in 1 s per cent predicted, body mass index, physical working capacity, immunoglobulin G, CF Transmembrane Conductance Regulator (CFTR) mutations, and physical exercise were obtained. structural equation modelling was used to fit models to data. RESULTS: A cftr gene mutation×age interaction effect indicates a psychological disadvantage increasing with age of having more severe CFTR mutations; >65% of the effect is mediated by medical status. Physical exercise has a positive effect on psychological well-being, but >75% of the effect is mediated by medical status. CONCLUSIONS: Psychological well-being decreases with age in patients with more severe cftr mutations, to a large extent due to a parallel deterioration of medical status. Physical exercise has a positive effect on psychological well-being if resulting in better health only. To manage the complexity of these patients' needs, the CF-care should emphasise a holistic approach and offer individualised exercise/treatment programmes and psychological competence.

Anxiety and depression in adults with cystic fibrosis: a comparison between patients and the general population in Sweden and three other European countries.

BACKGROUND: Cystic fibrosis (CF) is the most common autosomal recessive life-shortening disease among Caucasians. Studies exploring the prevalence of anxiety and depression in adult CF patients are few, show inconsistent findings and rarely include comparisons with general populations. Prevalence and degree of anxiety and depression were investigated in adult CF patients in Sweden, Belgium, Germany and the UK, and compared to corresponding general population data. METHODS: Adult non-transplanted CF patients from the three largest CF-centres (out of four) in Sweden (N = 129; Age range 18-70 years; 50 % women) completed the Hospital Anxiety and Depression Scale (HADS). Studies using HADS in adult CF populations in the UK, Germany, and Belgium were included, as well as HADS normative data from the corresponding general populations. RESULTS: No elevated risk for anxiety and depression was found among the CF patients. However, a Country x Group interaction effect emerged; CF patients experienced a higher degree of anxiety than the general population in Sweden, but not in the other countries, though this finding did not remain significant in a logistic regression analysis. In Sweden the effect was limited to women. A Country x Group interaction effect was also found for Depression; CF patients experienced lower degree of depression than the general population in Sweden, Germany and the UK, but not in Belgium/Netherlands. CONCLUSIONS: Contrary to earlier outcomes, the present results do not indicate any general elevated risk for anxiety and depression among CF patients. Anxiety was slightly higher in the Swedish CF population, compared to the general population; this finding was not seen in the other countries. Depression among CF patients was lower than or similar to that in the general populations in the studied countries.

Time point to perform lung function tests evaluating the effects of an airway clearance therapy session in cystic fibrosis.

BACKGROUND: Lung function parameters are used as end points in most clinical and therapeutic trials in cystic fibrosis (CF) and to evaluate the effects of airway clearance techniques. The aim of the study was to identify at what time point after a physiotherapy session spirometry (FEV1 and FVC) should be performed to obtain the highest result compared to baseline and to determine whether there are inter-individual and intra-individual differences in children and adults with CF. METHODS: This was a prospective study. Twenty-four subjects with CF and mean FVC 70 ± 30% and FEV1 61 ± 30% of predicted were included. Each subject performed spirometry before their airway clearance session and then immediately after, 30 min after, and 1, 2, and 3 h after their physiotherapy session for 2 consecutive days. RESULTS: In adult subjects, mean FEV1 improved 30 min (P < .001), 1 h (P < .002), and 2 h (P < .006) after physiotherapy compared to baseline. In pediatric subjects, it improved immediately after the session but was not statistically significant for recommendation. There were no intra-individual variations, but there were inter-individual variations (not statistically significant). CONCLUSIONS: Performing spirometry 30 min (adults) and immediately (children) after a session might be optimal if individual peak time values cannot be used.

Nasal potential difference measurements in diagnosis of cystic fibrosis: an international survey.

BACKGROUND: The role of nasal potential difference (NPD) measurement as a diagnostic test for cystic fibrosis (CF) is a subject of global controversy because of the lack of validation studies, clear reference values, and standardized protocols for diagnostic NPD. METHODS: To determine diagnostic NPD frequency, protocols, interpretation, and rater agreement, we surveyed the 18 NPD centres of the European Cystic Fibrosis Society Diagnostic Network Working Group. RESULTS: Fifteen centres reported performing 373 diagnostic NPDs in 2012. Most use the CFF-TDN-SOP (67%) and the chloride-free + isoproterenol response of the side with the largest response (47%) as diagnostic criteria and use centre-specific reference ranges. Rater agreement for five NPD tracings - in general - was good, but poor in tracings with different responses between the two nostrils. CONCLUSIONS: NPD is frequently used as a diagnostic and research tool for CF. Performance is highly standardized, centre-specific reference ranges are established, and rater agreement - in general - is good. Centre-independent diagnostic criteria and reference ranges must be defined by multicentre validation studies to improve standardized interpretation for diagnostic use.

Dietary intake and nutritional status in a Scandinavian adult cystic fibrosis-population compared with recommendations.

BACKGROUND: Malnutrition is a well-known complication in cystic fibrosis (CF). There is good evidence that maintaining a normal body-weight correlates well with improved survival in CF. Energy intake in excess of 120% of the estimated average requirement (EAR) has been advised since 1980s. OBJECTIVES: To investigate the nutritional intake and status in the adult Scandinavian CF-population. SUBJECTS/METHODS: A cross-sectional multi-centre study was used to investigate the nutritional status of 456 adult CF-patients (2003 2006). Height and weight were measured and body mass index (BMI) and z-scores were calculated. Pulmonary function was examined by dynamic spirometry. A 7-day pre-coded food record (FR) obtained energy and nutrient intake data in 180 patients. RESULTS: The mean energy intake was 114 (SD 30.0)% of EAR and thus significantly lower than the target of 120% EAR (p< 0.001) for patients with pancreatic insufficiency (PI) (n=136). Mean BMI was 22.0 (SD 2.9), the prevalence of BMI <18 was 13% and the prevalence of BMI ≥25 was 15% (n=136). Mean BMI was 20.8 (SD 2.4) in PI-patients with FEV(1) <70% and 23.2% (SD 3.0), in PI-patients with FEV(1) ≥70%, mean difference 2.4, (95% CI: 1.5, 3.3) (p<0.001), but there was no difference in energy intake. BMI ≥18.5 and a reported energy intake <120% were revealed in 54% of the PI-patients. CONCLUSIONS: The energy intake did not reach the recommended 120% EAR, but the prevalence of underweight was lower than reported in other studies. The recommendation may exceed the requirement for a number of CF-patients. The nutritional status must still be closely monitored and nutritional advice and intervention should be individualised and adjusted to actual needs.

Age at diagnosis and disease progression of cystic fibrosis in an area without newborn screening.

We studied age at diagnosis and disease progression of cystic fibrosis (CF) patients with a new study design, using data of 119 patients extracted from Stockholm CF Centre registry. Risk factors for overall morbidity and for lung, liver and nutritional morbidity were investigated separately using time to event methodology (Kaplan-Meier curves, proportional hazards regression). The patients were followed from: (i) healthy at diagnosis to morbidity, (ii) diagnosis with symptoms of morbidity to being free of morbidity, and (iii) free of morbidity to relapse of morbidity. Median age at diagnosis was 5.0 months. Of the patients with overall morbidity at diagnosis 50% became free of morbidity after 4.8 years; however, the patients above the age of 24 months at diagnosis had a reduced chance of becoming free of morbidity (crude hazard ratio 0.14 [95 % confidence interval 0.04, 0.45]) compared with those with diagnosis between the ages of 2 and 12 months (P<0.01). Of the healthy at diagnosis, 50% experienced overall morbidity after 1.4 years. They had a slow decline to the endpoint of the specific morbidities; 50% experienced lung morbidity after 3.4 years and liver morbidity after 4.8 years, while 50% never reached nutritional morbidity during the 10 years follow-up. We conclude that there was a disadvantage for the CF patients diagnosed after the age of 24 months with symptoms of overall morbidity at diagnosis in an area without newborn screening.

Parental support for newborn screening for cystic fibrosis.

AIM: To describe the attitudes among parents towards including cystic fibrosis (CF) in the newborn screening programme and towards the potential knowledge of their own carrier status. METHODS: A questionnaire with three to five response categories and an information leaflet was posted to 143 CF parents, 3 matched diabetes and 3 matched population parents, the response rate being 85%, 74% and 70%, respectively. Comparisons between groups were made with statistical tests for independent groups. RESULTS: Eighty-six percent of CF, 70% of diabetes and 77% of population parents were in favour of newborn screening for CF, 47%, 45% and 50%, respectively, wished to know their CF carrier status. The parental attitude was independent of the age of the child, as well as delay of diagnosis and well-being of the CF child at the time of diagnosis. Sixty percent of the CF parents experienced the diagnosis as delayed. CONCLUSION: Parents in Sweden support CF newborn screening. Half of the parents wanted to know their CF carrier status.

The effect of S-nitrosoglutathione and L-cysteine on chloride efflux from cystic fibrosis airway epithelial cells.

The endogenous bronchodilator, S-nitrosoglutathione (GSNO), has been proposed as a possible pharmacological remedy that reverses the ΔF508-CFTR (cystic fibrosis transmembrane conductance regulator) maturation defect and increases CFTR-mediated chloride efflux in cultured cystic fibrosis airway epithelial cells (CFBE41o(-)). It has also been reported that L-cysteine enhanced S-nitrosothiol uptake and increased the intracellular S-nitrosothiol levels, likely through transnitrosation chemistry. The present study investigated whether L-cysteine augmented the effect of GSNO on chloride efflux from CF airway epithelial cells. Treatment with 10 µM GSNO combined with 20 µM L-cysteine resulted in increased chloride efflux from CFBE41o(-) cells after 5 minutes exposure compared to the control efflux rate and to the efflux rate in the presence of L-cysteine alone as measured using the fluorescent dye N-(ethoxycarbonylmethyl)-6-methoxyquinolinium bromide (MQAE). Chloride efflux rates from these cells after 4h exposure to GSNO and L-cysteine were not different from control. Treatment with 10 µM GSNO alone increased chloride efflux from CFBE41o(-) cells after 4h but not at shorter incubation times. GSNO with or without L-cysteine did not alter epithelial tight junction integrity. In conclusion, a combination of GSNO with L-cysteine led to significant increase in chloride efflux in CFBE41o(-) cells but the effect was transient and not sustained beyond minutes.

Mental health and sense of coherence among Swedish adults with cystic fibrosis.

The purpose of this study was to describe mental health among adult Swedish patients with cystic fibrosis (CF) and to study if mental health and the salutogene factor sense of coherence (SOC) intercorrelate with good medical status. Women and men were compared. The patient group (n=59) attended the Stockholm CF Center. Mental health was measured with the General Health Questionnaire (GHQ-28) and the salutogenesis by SOC-3. Medical status included forced vital capacity and forced expiratory volume in 1 second in per cent of predicted as well as Body Mass Index. The differences within and between groups were tested with t-tests and the relations between the variables were described by Spearman's correlation coefficient. The patients had on the whole good mental health, but the group with a risk of mental ill-health (n=19) experienced life as difficult to manage, meaningless and hard to understand compared to the group with a small risk of mental ill-health (n=40). Women at risk of mental ill-health (n=10) experienced difficulties in managing life to a greater extent than women with a small risk of mental ill-health (n=16). Men at risk of mental ill-health (n=9) found life hard to understand. Mental health and SOC did not correlate significantly with the medical status of the CF patients. The conclusion was that there were comparably few problems of mental health among the patients with CF. The problems that were found were not related to the seriousness of their CF. Women had a more complex pattern of problems in mental health and SOC than men had.