Case Report: Maintenance of Desensitization to Nebulized Colomycin Over 10 Years.

Drug desensitization can be achieved successfully by gradual drug dose increases in different protocols. Most protocols are designed to obtain temporal tolerance. The data on long-term maintenance of drug tolerance is scarce. Based on an IgE-mediated colomycin allergy we describe the maintenance of drug tolerance to nebulized drug for the period of 10 years in a 15-year-old cystic fibrosis patient, proceeded by successful rush intravenous desensitization protocol. The mechanism of drug tolerance is largely speculative; however, long-term maintenance of it seems achievable by continuous local drug application.

Cystic Fibrosis Newborn Screening in Austria Using PAP and the Numeric Product of PAP and IRT Concentrations as Second-Tier Parameters.

In Austria, newborns have been screened for cystic fibrosis (CF) by analyzing immunoreactive trypsinogen (IRT) from dried blood spots (DBS)s for nearly 20 years. Recently, pancreatitis-associated protein (PAP) analysis was introduced as a second-tier test with the aim of reducing recalls for second DBS cards while keeping sensitivity high. For 28 months, when IRT was elevated (65-130 ng/mL), PAP was measured from the first DBS (n = 198,927) with a two-step cut-off applied. For the last 12 months of the observation period (n = 85,421), an additional IRT×PAP cut-off was introduced. If PAP or IRT×PAP were above cut-off, a second card was analyzed for IRT and in case of elevated values identified as screen-positive. Above 130 ng/mL IRT in the first DBS, newborns were classified as screen-positive. IRT analysis of first DBS resulted in 1961 (1%) tests for PAP. In the first 16 months, 26 of 93 screen-positive were confirmed to have CF. Two false-negatives have been reported (sensitivity = 92.8%). Importantly, less than 30% of families compared to the previous IRT-IRT screening scheme had to be contacted causing distress. Adding IRT×PAP caused a marginally increased number of second cards and sweat tests to be requested during this period (15 and 3, respectively) compared to the initial IRT-PAP scheme. One case of confirmed CF was found due to IRT×PAP, demonstrating an increase in sensitivity. Thus, the relatively simple and economical algorithm presented here performs effectively and may be a useful model for inclusion of CF into NBS panels or modification of existing schemes.

Update on Respiratory Fungal Infections in Cystic Fibrosis Lung Disease and after Lung Transplantation.

Cystic fibrosis is the most common autosomal-recessive metabolic disease in the Western world. Impaired trans-membrane chloride transport via the cystic fibrosis transmembrane conductance regulator (CFTR) protein causes thickened body fluids. In the respiratory system, this leads to chronic suppurative cough and recurrent pulmonary infective exacerbations, resulting in progressive lung damage and respiratory failure. Whilst the impact of bacterial infections on CF lung disease has long been recognized, our understanding of pulmonary mycosis is less clear. The range and detection rates of fungal taxa isolated from CF airway samples are expanding, however, in the absence of consensus criteria and univocal treatment protocols for most respiratory fungal conditions, interpretation of laboratory reports and the decision to treat remain challenging. In this review, we give an overview on fungal airway infections in CF and CF-lung transplant recipients and focus on the most common fungal taxa detected in CF, Aspergillus fumigatus, Candida spp., Scedosporium apiospermum complex, Lomentospora species, and Exophiala dermatitidis, their clinical presentations, common treatments and prophylactic strategies, and clinical challenges from a physician's point of view.

Estimating the age of p.(Phe508del) with family studies of geographically distinct European populations and the early spread of cystic fibrosis.

The high incidence of cystic fibrosis (CF) is due to the frequency of the c.1521_1523delCTT variant in the cystic fibrosis transmembrane conductance regulator (CFTR), but its age and origin are uncertain. This gap limits attempts to shed light on the presumed heterozygote selective advantage that accounts for the variant's high prevalence among Caucasian Europeans and Europe-derived populations. In addition, explaining the nature of heterozygosity to screened individuals with one c.1521_1523delCTT variant is challenging when families raise questions about these issues. To address this gap, we obtained DNA samples from 190 patients bearing c.1521_1523delCTT and their parents residing in geographically distinct European populations plus a Germany-derived population in the USA. We identified microsatellites spanning CFTR and reconstructed haplotypes at 10 loci to estimate the time/age of the most recent common ancestor (tMRCA) with the Estiage program. We found that the age estimates differ between northwestern populations, where the mean tMRCA values vary between 4600 and 4725 years, and the southeastern populations where c.1521_1523delCTT seems to have been introduced only about 1000 years ago. The tMRCA values of Central Europeans were intermediate. Thus, our data resolve a controversy by establishing an early Bronze Age origin of the c.1521_1523delCTT allele and demonstrating its likely spread from northwest to southeast during ancient migrations. Moreover, taking the archeological record into account, our results introduce a novel concept by suggesting that Bell Beaker folk were the probable migrating population responsible for the early dissemination of c.1521_1523delCTT in prehistoric Europe.

Aspergillus fumigatus-specific immunoglobulin levels in BALF of CF patients.

IgE responses to Aspergillus fumigatus in cystic fibrosis lungs http://ow.ly/XXwv30furqs.

Early detection of lung function decrements in children and adolescents with cystic fibrosis using new reference values.

Interpretation of lung function values in children with cystic fibrosis (CF) depends on the applied reference values. We hypothesize that differences between the new global lung function initiative (GLI) values and the formerly used Zapletal et al. values produce significantly different clinical results. We analyzed 3719 lung function measurements of 108 children and adolescents (n = 54 male; aged 6-18 years) with CF treated between September 1991 and July 2009. Data were analyzed in milliliters (ml) and % predicted (pred.) and interpreted using Zapletal and GLI reference values. Applying GLI compared to Zapletal resulted in significantly lower mean forced expiratory volume in 1s (FEV1)% pred. VALUES: Zapletal 86.6% (SD 20.6), GLI 79.9% (SD 20.3) and 32% (n = 497/1543) were misclassified as normal when using Zapletal. Despite showing no overall differences in FEV1 and forced vital capacity (FVC) between concomitant Pseudomonas detection (PA+) in n = 938 and Pseudomonas negative (PA-) (n = 2781) using either reference PA+ resulted in lower FEV1 and FVC values with increasing age; however, measurement of small airway obstruction with forced expiratory flow at 75% of FVC (FEF75) values - available for Zapletal -showed significant differences. Reassurance regarding lung function when using old reference values may occur with potential clinical significance. Discrepancies in lung function interpretation underline the importance of using uniform and best available reference values.

Cystic fibrosis in Austria.

Registry data for patients with cystic fibrosis (CF) are increasingly used to evaluate the natural history, for benchmarking of therapy and in order to identify eligible patients for clinical studies. So far, no data on frequency and clinical status of CF patients have been available for Austria on a national level. We collected data of CF patients treated 2014 in Austrian CF outpatient clinics by means of a European CF registry and on an individual search basis. A total of 773 CF patients with a median age of 18.9 years (SD 11.8 years) were seen in 13 centers (18-151 patients/center). Homozygous F508del mutation being the most common genotype was observed in 48.8% of patients. Mean age at diagnosis was 27 days. In 59% of all patients FEV1% predicted (Forced Exspiratory Volume in 1 second) was <80% and in 20% <50%. An average FEV1 predicted decline per year of 1.9% was observed between 6-18 years of age. Colonisation with Pseudomonas aeruginosa ranged between 12% and 69% in adult patients and in 0-16% in children with CF. Burkholderia cepacia complex species were present in a total of 29 samples (3.8%). Insulin therapy for diabetes was given in 14.5%. Liver involvement was reported in 36.3%. A wide variation of prescribed CF therapy was observed between centers. Data on CF patients living in Austria are now available and form a basis for clinical benchmarking as well as analyses from a public health perspective.

[New international reference values for spirometry: implications for clinical issues using a comparative analysis of a paediatric population]. / Neue internationale Referenzwerte für die Spirometrie--Implikation für die Praxis anhand einer vergleichenden Analyse eines pädiatrischen Patientenkollektivs.

BACKGROUND: The new lung function reference values of the global lung initiative (GLI) are recommended by most health societies. The aim of this study was to analyze FEV1- and FEV1/FVC-values from a German and Austrian patient group applying old and new reference values. RESULTS: A total of 215 Caucasian children (aged 5-17 years) were included. FEV1-values were significantly lower applying GLI reference values compared to Zapletal values (median 96.9 % pred. (87.3-105.2) versus 100.6 % pred. (quartile 91.5-111.4), p = 0.000), the median difference was 4.9 % (range -12.9 to 27.5) % pred. Differences correlated significantly with age and FEV1 in % predicted (Zapletal), p = 0.000 17/70 (24 %) patients with cystic fibrosis had FEV1-values <80% pred. applying Zapletal, in 25 (36 %) patients FEV1 was abnormal (z-score <1645) using GLI values; 3/145 asthmatics (2 %) had FEV1-Werte <80 % d.S. (Zapletal), 7/145 (5 %) z-scores <1645 (GLI). CONCLUSION: Differences between GLI-and Zapletal-reference values were considerable in pediatric asthma and CF-patients.

Successful implementation of infection control strategies prevents P. aeruginosa transmission among cystic fibrosis patients inside the hospital.

BACKGROUND: The aim of this study was to characterise the epidemiology of P. aeruginosa isolated from cystic fibrosis (CF) patients at the Vienna General Hospital (VGH) by molecular genetic fingerprinting in order to understand transmission ways and to evaluate the established infection control protocols. METHODS: The outpatient clinic for CF patients at the VGH cares for children and adolescents up to the age of 18 years. Among an average of 139 patients cared for at the clinic, 41 were tested positive for P. aeruginosa during the study period. Fifty P. aeruginosa isolates, obtained between August 2010 and March 2012 from routine examinations of CF patients, were subject to molecular characterization using the DiversiLab(®) method. RESULTS: 42 distinguishable molecular-biological patterns were identified, 7 of which were found multiple times. 40 out of 42 genotypes were retrieved from single patients only, while two patterns were present in two patients each. Nine patients presented with two or more phenotypically diverse P. aeruginosa isolates. In five of these cases the retrieved isolates belonged to the same genotype. CONCLUSION: The broad genetic heterogeneity of P. aeruginosa in the studied patient population suggests that the majority of CF patients cared for at the VGH acquire P. aeruginosa from environmental sources. It may be concluded that implemented infection control guidelines have been successful in preventing nosocomial transmission of P. aeruginosa among CF patients within the VGH and patient-to-patient transmission outside the hospital. Chronic polyclonal infection/colonization was rare in the study population.

A Th17- and Th2-skewed cytokine profile in cystic fibrosis lungs represents a potential risk factor for Pseudomonas aeruginosa infection.

RATIONALE: Cystic fibrosis (CF) is characterized by progressive pulmonary inflammation that is infection-triggered. Pseudomonas aeruginosa represents a risk factor for deterioration of lung function and reduced life expectancy. OBJECTIVES: To assess T-cell cytokine/chemokine production in clinically stable children with CF and evaluate the association between T-cell subtypes and susceptibility for infection with P. aeruginosa. METHODS: T-cell cytokine/chemokine profiles were measured in bronchoalveolar lavage fluid (BALF) from children with CF (n = 57; 6.1 ± 5.9 yr) and non-CF control subjects (n = 18; 5.9 ± 4.3 yr). Memory responses to Aspergillus fumigatus and P. aeruginosa were monitored. High-resolution computed tomography-based Helbich score was assessed. In a prospective observational trial the association between BALF cytokine/chemokine profiles and subsequent infection with P. aeruginosa was studied. MEASUREMENTS AND MAIN RESULTS: Th1- (INF-γ), Th2- (IL-5, IL-13), Th17- (IL-17A), and Th17-related cytokines (IL-1ß, IL-6) were significantly up-regulated in airways of patients with CF. IL-17A, IL-13, and IL-5 were significantly higher in BALF of symptomatic as compared with clinically asymptomatic patients with CF. IL-17A and IL-5 correlated with the percentage of neutrophils in BALF (r = 0.41, P < 0.05 and r = 0.46, P < 0.05, respectively). Th17- (IL-17A, IL-6, IL-1ß, IL-8) and Th2-associated cytokines and chemokines (IL-5, IL-13, TARC/CCL17), but not IFN-γ levels, significantly correlated with high-resolution computed tomography changes (Helbich score; P < 0.05). P. aeruginosa- and A. fumigatus-specific T cells from patients with CF displayed significantly higher IL-5 and IL-17A mRNA expression. IL-17A and TARC/CCL17 were significantly augmented in patients that developed P. aeruginosa infection within 24 months. CONCLUSIONS: We propose a role for Th17 and Th2 T cells in chronic inflammation in lungs of patients with CF. High concentrations of these cytokines/chemokines in CF airways precede infection with P. aeruginosa.