Frequencies of pathogenic CFTR variants in Greek cystic fibrosis patients with allergic bronchopulmonary aspergillosis and Aspergillus fumigatus chronic colonization: A retrospective cohort study.

INTRODUCTION: The clinical spectrum of Aspergillus fumigatus diseases in cystic fibrosis (CF) patients, including allergic bronchopulmonary aspergillosis (ABPA) and Aspergillus fumigatus chronic colonization, has recently gained attention due to its association with the progression of lung disease. Our aim was to examine whether there is a difference on pathogenic variant frequencies of the CFTR gene between CF patients with ABPA and those with A. fumigatus chronic colonization. MATERIAL AND METHODS: Greek CF patients diagnosed with ABPA and/or A. fumigatus chronic colonization were grouped according to their CFTR genotype. Patients with "minimal" CFTR function were defined as carrying a combination of class I or II pathogenic variants, while patients with "residual" function as carrying at least one class III, IV, V or VI pathogenic variant. RESULTS: Fifty-four CF patients were included and all except one were defined as having "minimal" CFTR function. Among the 108 CFTR alleles, 69 (63.9%) of pathogenic variants belonged to class II, and 32 (29.6%) to class I. Five patients had a history of both ABPA and A. fumigatus chronic colonization. No significant difference was detected among patients diagnosed only with ABPA (n = 29) and those who had only a positive history of A. fumigatus chronic colonization (n = 20). The median age of ABPA diagnosis was significantly lower than the median age of A. fumigatus chronic colonization (P = 0.011), while no significant difference was detected on median FEV1% predicted. DISCUSSION: No significant differences were detected in the type of CFTR pathogenic variants among patients with ABPA and those with A. fumigatus colonization. Similar studies should be performed in larger CF populations of different ethnic origin to further confirm our results.

Scedosporium apiospermum complex in cystic fibrosis; should we treat?

Species of the Scedosporium apiospermum complex are the second most frequent filamentous fungi after Aspergillus fumigatus that can be found in cystic fibrosis (CF). Mixed colonisation by S. apiospermum complex and A. fumigatus is also quite common. In this study we summarise all CF patients who were colonised by S. apiospermum complex during their childhood and we present two CF patients who were treated as fungal bronchitis due to S. apiospermum complex. The medical records of 400 CF patients were reviewed in order to identify those with positive respiratory cultures for S. apiospermum complex. Scedosporium apiospermum complex was isolated in 10 CF patients and six of them had more than two positive sputum cultures during the study period. By the time of first isolation, the median age was 14.5 years, the median BMI was 19.41 kg/m2 , the median predicted FEV1 % was 78.65% and six patients had a history of A. fumigatus isolation. Two patients presented symptoms of infection while they were colonised by S. apiospermum complex. A rapid remission of their symptoms was observed only when antifungal therapy was administered. Antifungal treatment should be considered in CF patients who present symptoms of infection not responding to antibacterial therapy and S. apiospermum complex is persistently growing in sputum cultures.

The role of basophil activation test in allergic bronchopulmonary aspergillosis and Aspergillus fumigatus sensitization in cystic fibrosis patients.

BACKGROUND: Allergic bronchopulmonary aspergillosis (ABPA) and Aspergillus fumigatus sensitization (AFS) are quite often observed in cystic fibrosis (CF) patients. The aim of this study was to evaluate the use of basophil activation test (BAT) in these manifestations of hypersensitivity reactions. METHODS: BAT (CD63 and CD203c) was performed for 56 CF patients (17 ABPA, 24 AFS and 15 non-AFS). A receiver operating characteristic (ROC) curve analysis and a survival analysis were performed. RESULTS: Both markers significantly contributed in ABPA diagnosis (P value<0.001 for both). Twelve AFS patients fulfilled the criteria for ABPA diagnosis during the follow-up period. The median time to ABPA diagnosis was 9months for patients whose values were over the best cutoffs (P value<0.001 for both). CONCLUSIONS: BAT could be considered as an additional criterion for ABPA diagnosis in CF as well as a potential marker for the monitoring of patients with AFS.

Candida albicans chronic colonisation in cystic fibrosis may be associated with inhaled antibiotics.

Candida albicans is increasingly recognised as a coloniser of the respiratory tract in cystic fibrosis (CF) patients. Yet, the potential role, if any, of the micro-organism in the progress of the disease remains unclear. In this study, we investigated the association between inhaled antibiotics and C. albicans chronic colonisation in patients with CF. A cohort of 121 CF patients born from 1988 to 1996 was, respectively, studied. The medical records of each patient were reviewed from the first time they attended the CF Centre until the occurrence of C. albicans chronic colonisation or their last visit for the year 2010. Chronic colonisation was defined as the presence of C. albicans in more than 50% of cultures in a given year. A number of possible confounders were included in the multivariate logistic regression analysis to identify an independent association between inhaled antibiotics and C. albicans chronic colonisation. Fifty-four (44.6%) of the 121 patients enrolled in the study developed chronic colonisation by the micro-organism. Multivariate logistic regression analysis determined the independent effect of inhaled antibiotic treatment on the odds of chronic colonisation (OR 1.112, 95% CI [1.007-1.229], P = 0.036). Candida albicans chronic colonisation may be associated with the duration of inhaled antibiotic treatment.

Time constant of inspiratory muscle relaxation in cystic fibrosis.

BACKGROUND: Patients with cystic fibrosis (CF) are at increased risk of inspiratory muscle fatigue and respiratory failure. The time constant (τ) of the inspiratory muscle relaxation is a simple bedside test of muscle fatigue. We have compared patients with CF and healthy controls regarding τ and hypothesized that it is negatively associated with severity of lower airway obstruction. METHODS: For this cross-sectional study, τ after maximal inspiration and spirometric indices (forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC)) were measured. RESULTS: Fifty-three CF patients (median age 14 y (interquartile range: 11-19.5)) and 53 age- and sex-matched healthy control subjects (14 y (11-19.5)) were recruited. Application of a general linear model revealed that health status (CF vs. non-CF) had a significant effect on τ (P < 0.001), but age group and the interaction of age group with health status did not have significant effects on τ (P = 0.10 and P = 0.71, respectively). Participants with CF had significantly higher τ (253 (188-406)) than control subjects (117 (81-185)) (P < 0.001) and τ was negatively related to FEV1 (r = -0.205; P = 0.031) and FVC (r = -0.294; P = 0.002). CONCLUSION: Patients with CF have higher τ than healthy controls but the correlation of τ with expiratory flow function is modest.

Inhaled corticosteroids and Aspergillus fumigatus isolation in cystic fibrosis.

Aspergillus fumigatus isolation in cultures from respiratory specimens of patients with cystic fibrosis (CF) is quite common; however, the role of A. fumigatus as a pathogen and whether its presence is associated with progression of pulmonary disease remain unclear. We investigated the association between inhaled corticosteroids and the recovery of A. fumigatus by performing a retrospective cohort study of CF patients born between 1988 and 1996. The patients' medical records from their first visit to the CF Center until December 2010 were reviewed. Outcomes were the occurrence of A. fumigatus first isolation, chronic colonization, or the last visit at the CF Center. A number of possible confounders were included in the multivariate logistic regression analysis in order to identify an independent association between inhaled corticosteroids and colonization status. A total of 121 patients were included in the study. Thirty-nine patients (32.2%) had at least one positive culture and 14 (11.6%) developed chronic colonization. Multivariate logistic regression analysis was used to determine the independent effect of inhaled corticosteroids on the odds of first isolation (odds ratio [OR], 1.165; 95% confidence interval [CI], 1.015-1.337; P = 0.029) and chronic colonization (OR, 1.180; 95% CI, 1.029-1.353; P = 0.018). In conclusion, A. fumigatus first isolation and chronic colonization are associated with the duration of inhaled corticosteroid treatment.

Chronic Pseudomonas aeruginosa infection and respiratory muscle impairment in cystic fibrosis.

BACKGROUND: Chronic infection with Pseudomonas aeruginosa in patients with cystic fibrosis (CF) is associated with increased morbidity. Chronic infection can cause limb and respiratory muscle compromise. Respiratory muscle function can be assessed via maximal inspiratory pressure (PImax), maximal expiratory pressure (PEmax), and the pressure-time index of the respiratory muscles (PTImus). We studied the effect of chronic P. aeruginosa infection on respiratory muscle function in patients with CF. METHODS: This cross-sectional study assessed PImax, PEmax, PTImus, FEV1, FVC, maximum expiratory flow during the middle half of the FVC maneuver, body mass index, and upper arm muscle area in 122 subjects with CF, in 4 subgroups matched for age and sex at different stages of P. aeruginosa infection, according to the Leeds criteria. We compared respiratory muscle function in the subgroups according to P. aeruginosa infection state. RESULTS: Median PImax was significantly lower in CF subjects with chronic P. aeruginosa infection (PImax = 62 cm H2O), compared to subjects who were never infected (PImax = 86 cm H2O, P = .02), free of infection (PImax = 74 cm H2O, P = .01), or intermittently infected (PImax = 72 cm H2O, P = .02). Median PTImus was significantly increased in CF subjects with chronic P. aeruginosa infection (PTImus = .142), compared to subjects who were free of infection (PTImus = .102, P = .006). Median upper-arm muscle area was significantly lower in CF subjects with chronic P. aeruginosa infection (upper-arm muscle area = 2,219 mm(2)), compared to subjects who were never infected (2,754 mm(2), P = .03), free of infection (2,678 mm(2), P = .01), or intermittently infected (2,603 mm(2), P = .04). Multivariate logistic regression revealed P. aeruginosa state of infection as a significant determinant of PTImus (P = .03) independently of sex, upper-arm muscle area, and FEV1. CONCLUSIONS: CF subjects with chronic P. aeruginosa infection exhibited impaired respiratory muscle function and decreased inspiratory muscle strength, and chronic P. aeruginosa infection independently impacts respiratory muscle function in subjects with CF.

Aerobic exercise and respiratory muscle strength in patients with cystic fibrosis.

BACKGROUND: The beneficial role of exercise in maintaining health in patients with cystic fibrosis (CF) is well described. Few data exist on the effect of exercise on respiratory muscle function in patients with CF. Our objective was to compare respiratory muscle function indices in CF patients that regularly exercise with those CF patients that do not. METHODS: This cross-sectional study assessed nutrition, pulmonary function and respiratory muscle function in 37 CF patients that undertook regular aerobic exercise and in a control group matched for age and gender which consisted of 44 CF patients that did not undertake regular exercise. Respiratory muscle function in CF was assessed by maximal inspiratory pressure (Pimax), maximal expiratory pressure (Pemax) and pressure-time index of the respiratory muscles (PTImus). RESULTS: Median Pimax and Pemax were significantly higher in the exercise group compared to the control group (92 vs. 63 cm H2O and 94 vs. 64 cm H2O respectively). PTImus was significantly lower in the exercise group compared to the control group (0.089 vs. 0.121). Upper arm muscle area (UAMA) and mid-arm muscle circumference were significantly increased in the exercise group compared to the control group (2608 vs. 2178 mm2 and 23 vs. 21 cm respectively). UAMA was significantly related to Pimax in the exercising group. CONCLUSIONS: These results suggest that CF patients that undertake regular aerobic exercise maintain higher indices of respiratory muscle strength and lower PTImus values, while increased UAMA values in exercising patients highlight the importance of muscular competence in respiratory muscle function in this population.

Respiratory muscle function in patients with cystic fibrosis.

Respiratory muscle function in patients with cystic fibrosis (CF) can be assessed by measurement of maximal inspiratory pressure (Pimax ), maximal expiratory pressure (Pemax ), and pressure-time index of the respiratory muscles (PTImus ). We investigated the differences in maximal respiratory pressures and PTImus between CF patients with no gross hyperinflation and healthy controls and described the effects of pulmonary function and nutrition impairment on respiratory muscle function in this group of CF patients. Forced expiratory volume in 1 sec (FEV1 ), forced vital capacity (FVC) and maximal expiratory flow between 25% and 75% of VC (MEF25-75 ), body mass index (BMI), upper arm muscle area (UAMA), Pimax , Pemax , and PTImus were assessed in 140 CF patients and in a control group of 140 healthy subjects matched for age and gender. Median Pimax and Pemax were significantly lower in CF patients compared to the controls [Pimax = 74 (57-94) in CF vs. 84 (66-102) in controls, P = 0.009], [Pemax = 71 (50-95) in CF vs. 84 (66-102) in controls, P < 0.001]. Median PTImus in CF patients compared to controls was significantly increased [PTImus = 0.110 (0.076-0.160) in CF vs. 0.094 (0.070-0.137) in controls, P = 0.049] and it was significantly higher in CF patients with impaired pulmonary function. In CF patients, PTImus was significantly negatively related to upper arm muscle area (r = 0.184, P = 0.031). These findings suggest that CF patients with no severe lung disease compared to healthy subjects exhibit impaired respiratory muscle function, while CF patients with impaired pulmonary function and nutrition indices exhibit higher PTImus values.

Voriconazole pharmacokinetics and photosensitivity in children with cystic fibrosis.

BACKGROUND: A high incidence of adverse skin reactions following long-term oral administration of voriconazole in children with cystic fibrosis and allergic bronchopulmonary aspergillosis (ABPA). The aim was to study the pharmacokinetics of voriconazole in these patients and to determine a possible association between drug levels and adverse effects. METHODS: Multiple venous blood samples were collected for HPLC determination of voriconazole concentrations and routine blood tests. Adverse events were recorded. RESULTS: No significant correlation was found between incidence of photosensitivity and voriconazole serum levels in 6 of 8 children with ABPA. 80% of patients had trough voriconazole concentrations<1000 ng/mL and were highly variable. CONCLUSIONS: Long-term voriconazole therapy and greater sun exposure in Greece appear to play a major role in the occurrence of photosensitivity. Steady-state plasma drug concentrations were found to be highly variable and below the recommended therapeutic range in most patients, without any apparent negative influence on outcome.