Sweat Test Values Research Articles

Анализ эффективности и безопасности применения CFTR-модулятора лумакафтор/ивакафтор у пациентов с муковисцидозом в разных возрастных группах

Russia’s first registered CFTR-modulator lumacaftor/ivacaftor was developed for patients with cystic fibrosis (CF) with the F508del/F508del genotype. The purpose of this research was to study the efficacy and safety of lumacaftor/ivacaftor therapy in different age groups. Materials and methods used: the data of homozygotes for F508del aged 2 to 18 y/o in the Russian CF Patient Registry who had been treated with lumacaftor/ivacaftor were analyzed. The effectiveness of therapy was evaluated in 3 age groups based on examination data, nutritional status, spirometry, sweat test at the start of therapy and after 12 months. In order to assess the safety, examination data, assessment of adverse events (AE), blood biochemical parameters, blood pressure and lens condition were taken into account in 334 pediatric patients in the first month of therapy and in 180 after 12 months. Results: decrease in sweat conductivity was noted in three age groups (p<0.001), only in the 2 to 6 y/o age group were negative values obtained in 6.8%. An increase in BMI was observed in the 6 to 12 y/o and 12 to 18 y/o age groups (р<0.001) whilst an improvement in FVC was observed only in the 12 to 18 y/o age group (p=0.015). Changes in biochemical parameters were statistically significant, both downward and upward, only in the age groups of 6 to 12 y/o and 12 to 18 y/o, changing not significantly. Withdrawal of the drug was required in only a single patient with a persistent increase in transaminase level. Fluctuations in blood pressure occurred within the normal age limits. Frequency of AE was comparable with the results of other studies, it was noted at the start in all groups and after 12 months more often in the age group of 12 to 18 y/o. The best tolerance was noted in the age group of 2 to 6 y/o. Conclusion: for the first time, the efficacy and tolerability of lumacaftor/ivacaftor in patients with CF in Russia was studied against the age aspect according to the 2022-2024 Registry. In the 2 to 6 y/o age group, the achievement of normal sweat test values and the lowest number of adverse reactions were noted, while in the 12 to 18 y/o age group, the positive dynamics were noted for a greater number of indicators, incl. an increase in FVC.

The Investigation of the Effect of Electrolyte Disorder on Sweat Test in Newborns with Positive Cystic Fibrosis Screening

Background and objectives: The aim of this study is to investigate the effect of the electrolyte and acid-base status present at the time of admission to the hospital on the sweat test (ST) of the patients who were found to have a positive newborn screening test (NST) for Cystic Fibrosis (CF). Methods: The patients who referred to pediatric pulmonology clinic for ST with positive NST for CF and diagnosed as CF were analyzed retrospectively. From the medical records acid-base status measured simultaneously with the ST and with serum sodium, potassium, and chloride levels were included in the study. Results: The study completed with 37 patients who met the inclusion criteria. At the time of ST, the mean sodium, potassium and chlorine values were 134.83±4.25 (122.0-141.0), 4.94±0.95 (2.9-7.6) and 97.72±12.40 (64.0-116.0) mEq/L, respectively. Patients whose electrolytes were measured at the time of diagnosis, 27.0% (n=10) had hyponatremia, 8.1% (n=3) had hypokalemia, and 4.8% (n=1) had hypochloremia. There was a significant difference between serum chloride and bicarbonate levels according to the negative, borderline, positive ST groups (p=0,036). In addition, no significance detected between the sweat test values of patients with Pseudo-Bartter Syndrome (PBS) (38.7%) and without. Conclusion: The chloride level during ST is lower in patients with borderline and negative ST results. The mean potassium and chloride values of the patients with PBS are lower while the mean bicarbonate value is higher. This may cause false negative results in ST. So, it is important to check the serum electrolyte levels before the ST is performed in the newborn screening positive baby.

P080 Impact of elexacaftor/tezacaftor/ivacaftor on sweat test values in cystic fibrosis patients in North Macedonia

P080 Impact of elexacaftor/tezacaftor/ivacaftor on sweat test values in cystic fibrosis patients in North Macedonia

The first described pathogenic variant c.2617G>T of the CFTR gene

Cystic fibrosis (CF) is a disease caused by pathogenic variants in the CFTR gene. The greatest difficulty at the moment is assessing the contribution to the development of the disease of rare and previously unidentified genetic variants (mutations), mutations of uncertain clinical significance, as well as determining the genotype-phenotype relationship. Additional diagnostic methods are needed due to the large number of patients with borderline sweat test values. Purpose of the study: to study the pathogenicity of a newly identified variant of the nucleotide sequence of the CFTR gene based on assessing the functional activity of epithelial ion channels (ENaC, CFTR, CaCCs). Materials and methods: medical history data, method intestinal current measurement (ICM). Results: the patient had a severe course of the disease. Positive sweat test results, low fecal pancreatic elastase. The ICM method showed the absence of chlorine channel function. Conclusion: For the first time, the clinical features of a patient with the c.2617G>T genetic variant in the genotype have been described. The results of the examination and the clinical course of the disease correspond to the severe course of the disease. Additional use of the ICM method confirmed the absence of CFTR channel function in a patient carrier of this variant of the CFTR gene.

Результаты таргетной терапии муковисцидоза у детей в Оренбургской области в 2022 году

Aim. To evaluate tolerability, safety and efficacy of target products used in the treatment of cystic fibrosis (CF) in children. Design. Retrospective and prospective comparative study. Materials and methods. The study included 12 patients aged 3 to 18 years old with complete genetic analysis of CF, which can be treated with target therapy (TT), and a chronic bronchopulmonary process. Seven children were treated with a two-component drug and five children — with a three-component drug. A control group included 12 patients with CF, but not treated with TT; the groups were similar in age and sex and had mutations of respective classes. All subjects underwent clinical, laboratory and instrumental tests and assessments. Condition was monitored at baseline, in 2 weeks, 1, 3, 6 months. Results. At baseline, the majority of patients had minor complaints which resolved without any intervention. Adverse effects, which required drug discontinuation, were recorded in one patient treated with the two-component drug. Patients, who received the three-component therapy, had significant improvement in nutritional status, marked and stable reduction in sweat test values. Conclusion. Modern TT for CF is well-tolerated, quickly improves patients' state, especially when a three-component drug is used. Subjective perception of improved breathing function, reported by patients, was not confirmed with pulmonary function test results and requires monitoring in a larger population. Keywords: cystic fibrosis, target therapy, children.

Experience of using lumacaftor/ivacaftor in children with cystic fibrosis in the Astrakhan region

Background. Targeted therapy in patients with cystic fibrosis, which aims to restore the function of the cystic fibrosis transmembrane conductance regulator protein, is currently revolutionary in the treatment of the disease. The first drug available in Russia for the treatment of patients with this genetic disease is lumacaftor/ivacaftor (Orkambi®), which was registered on December 2, 2020.The aim. To study the efficacy of lumacaftor/ivacaftor during 12 weeks of administration in children in Astrakhan region.Materials and methods. This article presents the clinical experience of Orkambi medicine use in 3 children with F508del/F508del genotype and a severe course of cystic fibrosis for 12 weeks. According to the study design, such indices as body mass index, indexes of external respiratory function, character of respiratory tract microbiota, level of chloride in sweat fluid and pancreatic elastase in feces, dynamics of biochemical blood indexes were evaluated. The study was performed within the time periods specified in the study protocol, namely, before the start of therapy, 2, 4, and 12 weeks of treatment.Results. Two patients had a decrease in sweat test values by 11 and 19 mmol/l from the baseline, a significant increase in forced vital capacity of lungs. One patient had an adverse event in the form of hepatobiliary disorders manifested by increased liver transaminase activity, which was the reason for discontinuing the drug.Conclusions. The short-term experience of using pathogenetic therapy with lumacaftor/ ivacaftor in children in the Astrakhan region demonstrated both the expected effect on chlorine channel function and the possibility of side effects, including severe ones, that can lead to withdrawal of the drug.

Health Characteristics of Patients with Cystic Fibrosis whose Genotype Includes a Variant of the Nucleotide Sequence c.3140-16T>A and Functional Analysis of this Variant.

Cystic fibrosis (CF) is the most common monogenic autosomal recessive disease, associated with pathogenic variants in the CFTR gene. The splicing variant c.3140-16T>A (3272-16T>A) has been described previously and, according to the Russian CF Patients Registry, occurs with a frequency of 0.34%. The phenotypic features of CF patients with the c.3140-16T>A variant were compared with those of patients with the genotype F508del/F508del. Patients with the allele c.3140-16T>A had higher average age and age at diagnosis, and the allele was present in a greater proportion of adults. Patients carrying the c.3140-16T>A allele were characterised by better physical development indicators, both in adults and in children, had preserved pancreatic function, as well as the absence of a number of complications, and required pancreatic enzyme replacement therapy less often than patients with the F508del/F508del genotype. Sweat test values also were lower in patients with the c.3140-16T>A genotype. According to the results of clinical and laboratory studies, the phenotype of patients with the genetic variant c.3140-16T>A can be considered “mild”. Functional CFTR protein activity in the presence of c.3140-16T>A was evaluated using intestinal current measurements (ICM) and the forskolin-induced swelling assay on organoids obtained from patients’ rectal biopsies. c.3140-16T>A had high residual CFTR channel activity and was amenable to effective pharmacological correction with thea VX-770 potentiator. To evaluate the effect of the variant on CFTR pre-mRNA splicing we performed a minigene assay, as well as RT-PCR analysis of RNA isolated from the nasal epithelium and rectal biopsy of patients. We showed that the c.3140-16T>A variant creates a novel acceptor AG dinucleotide within CFTR intron 19, resulting in a 14-nucleotide extension of exon 20. This frameshift produces a premature termination codon and triggers mRNA degradation by the nonsense-mediated decay (NMD) mechanism. Moreover, we observed that the c.3140-16T>A allele could produce a residual amount of normally spliced transcript, thus explaining the patient’s mild phenotype.

Intra-individual biological variation in sweat chloride concentrations in CF, CFTR dysfunction, and healthy pediatric subjects.

The sweat test is one of the main diagnostic tools used in newborn screening programs and as a confirmatory test, in case of suspect of Cystic Fibrosis (CF). Since sweat chloride (Cl) concentration is also considered an appropriate parameter to explore the efficacy of CFTR modulators in clinical trials, it is crucial to evaluate the biological variability of this test in healthy and pathological conditions. The aim of this pilot study was to determine the intra-individual biological variability of sweat Cl, both in healthy individuals and CF patients and to assess its correlation with diet, season, and menstrual cycle. Thirty-five out of 36 selected subjects (6-18 years) were enrolled by 2 CF care centers and assigned to 3 cohorts: CF, CFTR-related disorder (CFTR-RD) and healthy volunteers. Each participant was subjected to eight sweat tests in different conditions and time of the year. Data were analyzed using linear mixed effects models for repeated measures, taking also into account intra-individual correlations. We observed a high intra-individual variability of sweat Cl, with the lowest mean CV% values among CF patients (20.21 in CF, 29.74 in CFTR-RD, and 31.15 in healthy subjects). Gender and diet had no influence on sweat Cl variability, nor had pubertal age and menstrual phase. Results of this pilot study confirmed that sweat Cl variability is high in CF patients, although non-CF individuals displayed even higher mean CV% values. Season significantly influenced sweat test values only in CF patients, likely due to changes in their hydration status.

Newborn cystic fibrosis screening in southeastern Mexico: Birth prevalence and novel CFTR gene variants.

To use the results of the first five years of a cystic fibrosis newborn screening program to estimate the cystic fibrosis birth prevalence and spectrum of cystic fibrosis transmembrane conductance regulator ( CFTR) gene variants in Yucatan, Mexico. Screening was performed from 2010 to 2015, using two-tier immunoreactive trypsinogen testing, followed by a sweat test. When sweat test values were >30 mmol/L, the CFTR gene was analyzed. Of 96,071 newborns screened, a second sample was requested in 119 cases. A sweat test was performed in 30 newborns, and 9 possible cases were detected (seven confirmed cystic fibrosis and two inconclusive). The most frequently detected CFTR pathogenic variant (5/14 cystic fibrosis alleles, 35.7%) was p.(Phe508del); novel p.(Ala559Pro) and p.(Thr1299Hisfs*29) pathogenic variants were found. Cystic fibrosis birth prevalence in southeastern Mexico is 1:13,724 newborns. Immunoreactive trypsinogen blood concentration is influenced by gestational age and by the time of sampling. The spectrum of CFTR gene variants in Yucatan is heterogeneous.

Variability of sweat chloride concentration in subjects with cystic fibrosis and G551D mutations

IntroductionSweat chloride concentration, a biomarker of CFTR function, is an appropriate outcome parameter in clinical trials aimed at correcting the basic CF defect. Although there is consensus on a cut-off value to diagnose CF, we have only limited information on the within subject variability of sweat chloride over time. Such information would be useful for sample size calculations in clinical trials. Therefore, we retrospectively analyzed repeated sweat chloride values obtained in patients with G551D mutation(s) assigned to placebo in an ivacaftor interventional trial. MethodsIn subjects with G551D at least 12years of age, a pilocarpine sweat test using Macroduct collector was taken on both arms at 8 time points over 48weeks. We explored 1062 pilocarpine sweat test values obtained in 78 placebo patients of the VX08-770-102 trial. ResultsMean overall sweat chloride value (all patients, all tests, n=1062) was 100.8mmol/L (SD 12.7mmol/L). Using a multilevel mixed model, the between-subject standard deviation (SD) for sweat chloride was 8.9mmol/L (95% CI 7.4–10.6) and within-subject SD was 8.1mmol/L (95% CI 7.5–8.7). Limits of repeatability for repeat measurements were −19.7 to +21.6mmol/L using values from one arm, and −13.3 to 11.8mmol/L using mean of values obtained at 4 test occasions. Sample size calculations showed that the minimal treatment effect on sweat chloride concentration that can be demonstrated for a group of 5 patients is around 15mmol/L, using a cross-over design and combinations of 4 tests for each phase of the trial. ConclusionAlthough the sweat test is considered a robust measure, sweat chloride measurements in patients with CF and a G551D mutation had an inherent biological variability that is higher than commonly considered. Further analyses of placebo group data are crucial to learn more about the natural variability of this outcome parameter.

WS20.2 Intra-patient variability of sweat chloride concentrations in patients with cystic fibrosis (CF)

Introduction Sweat chloride concentration, a biomarker of CFTR function, is an appropriate outcome parameter in clinical trials aimed at correcting the basic CF defect. Although we agree on a cut-of value to diagnose CF, we have only limited information on the natural variability of sweat chloride over time. Still, this information is useful for power calculations in clinical trials. Therefore, we analyzed sweat test results obtained in patients with G551D mutation(s) assigned to placebo in an ivacaftor interventional trial. Methods In subjects with G551D at least 12 years of age, a pilocarpine sweat test using Macroduct collector was taken on both arms at 8 time points over 48 weeks. We explored 1062 pilocarpine sweat test values obtained in 78 patients. Results Mean overall sweat chloride value (all patients, all tests) was 100.1 mmol/L (95% CI 96.4–103.7). Using a random coefficient model, the within-subject standard deviation(SD) for sweat chloride was 8.5 mmol/L (95% CI 8.1–8.9) and between-subject SD was 9.8 mmol/L (95% CI 8.1–11.9). Standard deviations were similar with results from the left and from the right arm. Taking the mean measure of both arms rather than the result of one arm decreased within-subject SD by only 0.3 mmol/L. Conclusion Although the sweat test is considered a robust measure, sweat chloride measurements in patients with CF had an inherent biological variability that is higher than commonly considered. Further analyses of placebo arm data are crucial to learn more about the natural variability of outcome parameters.

17 Cystic fibrosis newborn screening (CF NBS): 4 year experience of the Prague Centre with the IRT/DNA/IRT protocol

Background: Cystic Fibrosis Newborn screening (CFNBS) as a pilot study started at the Institute of Mother and Child (IMC) Centre in 1999 and 444 063 newborns were examined until 2003. Current CFNBS has started gradually in Poland in 2006, covering the whole country in 2009 and is ongoing. 582 693 children were screened until the end of 2011. During CFNBS different protocol’s strategies were used. Aim: Impact of the implementation of NBS on the age of CF diagnosis. Methods: The study involved children diagnosed and treated only in IMC CF Centre (from 1999 until the end of 2011). Three groups were formed: 1. Pilot group (p-NBS) − 56 children, according to protocol strategy IRT/IRT and IRT/IRT/DNA, only F508del mutation was assessed; 2. Current group (c-NBS) − 92 children, IRT/IRT/DNA and IRT/DNA protocol, with expanded DNA analysis panel; 3. Patient diagnosed clinically (non-NBS) − 56 children. Moreover, DNA analysis in c-NBS group contains also frequent mutation in Polish population: 3849+10kbC>T, which is combined with low sweat test values. All patients underwent sweat tests. Results: The age of diagnosis was significantly lower (both p T than p-NBS and non-NBS group (both 0.9%). Conclusion: IRT/DNA strategy with extended DNA analysis provides an opportunity of earlier CF diagnosis even in children with normal sweat test values.

16 Influence of newborn screening on the age of diagnosis in cystic fibrosis patients

Background: Cystic Fibrosis Newborn screening (CFNBS) as a pilot study started at the Institute of Mother and Child (IMC) Centre in 1999 and 444 063 newborns were examined until 2003. Current CFNBS has started gradually in Poland in 2006, covering the whole country in 2009 and is ongoing. 582 693 children were screened until the end of 2011. During CFNBS different protocol’s strategies were used. Aim: Impact of the implementation of NBS on the age of CF diagnosis. Methods: The study involved children diagnosed and treated only in IMC CF Centre (from 1999 until the end of 2011). Three groups were formed: 1. Pilot group (p-NBS) − 56 children, according to protocol strategy IRT/IRT and IRT/IRT/DNA, only F508del mutation was assessed; 2. Current group (c-NBS) − 92 children, IRT/IRT/DNA and IRT/DNA protocol, with expanded DNA analysis panel; 3. Patient diagnosed clinically (non-NBS) − 56 children. Moreover, DNA analysis in c-NBS group contains also frequent mutation in Polish population: 3849+10kbC>T, which is combined with low sweat test values. All patients underwent sweat tests. Results: The age of diagnosis was significantly lower (both p T than p-NBS and non-NBS group (both 0.9%). Conclusion: IRT/DNA strategy with extended DNA analysis provides an opportunity of earlier CF diagnosis even in children with normal sweat test values.

Cystic Fibrosis and Non-Cystic Fibrosis Bronchiectasis

Cystic fibrosis (CF) is an autosomal recessive disease characterized by an elevated sweat chloride level, diffuse bronchiectasis, and pancreatic exocrine deficiency. It is the most common lethal inherited disease in whites. Most patients present at birth or early childhood, although later diagnoses are not infrequent. Once CF was uniformly fatal at an early age, but advances in nutrition, airway clearance, and infection management have led to an average survival of 37 years. The newest aspect of care is the advent of protein modulators, which may increase life expectancy even further. This chapter discusses the epidemiology, genetics, pathophysiology and pathogenesis, diagnosis, differential diagnosis, and treatment of CF. The definition, epidemiology, etiology, pathogenesis, diagnosis, management, and prognosis of non-CF bronchiectasis are also covered. Figures illustrate normal and abnormal CF transmembrane conductance regulators, the vicious cycle hypothesis of lung injury, rates of respiratory germs by age, the diagnosis of CF, the therapeutics pipeline for CF, forced expiratory volume in 1 second lung function percent predicted versus body mass index, and the median predicted survival age of patients with CF. A chest x-ray and chest computed tomographic scan of CF are also provided. Tables outline the most common CF mutations in 2011, class mutations of CF, a mnemonic for acute exacerbations of CF, the diagnosis of CF-related diabetes in a stable patient, sweat test values, and the differential diagnosis of bronchiectasis.This chapter contains 9 highly rendered figures, 6 tables, 143 references, 1 teaching slide set, and 5 MCQs.

Cystic Fibrosis and Non-Cystic Fibrosis Bronchiectasis

Cystic fibrosis (CF) is an autosomal recessive disease characterized by an elevated sweat chloride level, diffuse bronchiectasis, and pancreatic exocrine deficiency. It is the most common lethal inherited disease in whites. Most patients present at birth or early childhood, although later diagnoses are not infrequent. Once CF was uniformly fatal at an early age, but advances in nutrition, airway clearance, and infection management have led to an average survival of 37 years. The newest aspect of care is the advent of protein modulators, which may increase life expectancy even further. This chapter discusses the epidemiology, genetics, pathophysiology and pathogenesis, diagnosis, differential diagnosis, and treatment of CF. The definition, epidemiology, etiology, pathogenesis, diagnosis, management, and prognosis of non-CF bronchiectasis are also covered. Figures illustrate normal and abnormal CF transmembrane conductance regulators, the vicious cycle hypothesis of lung injury, rates of respiratory germs by age, the diagnosis of CF, the therapeutics pipeline for CF, forced expiratory volume in 1 second lung function percent predicted versus body mass index, and the median predicted survival age of patients with CF. A chest x-ray and chest computed tomographic scan of CF are also provided. Tables outline the most common CF mutations in 2011, class mutations of CF, a mnemonic for acute exacerbations of CF, the diagnosis of CF-related diabetes in a stable patient, sweat test values, and the differential diagnosis of bronchiectasis.This chapter contains 9 highly rendered figures, 6 tables, 143 references, 1 teaching slide set, and 5 MCQs.

Phenotypic expression of the p.Leu1077Pro CFTR mutation in Sicilian cystic fibrosis patients

BackgroundThe p.Leu1077Pro CFTR mutation was firstly described in 1992 as a mild allele that confers a pancreatic sufficiency phenotype but the information collected in database CFTR2 lead to consider p.Leu1077Pro as a severe CF mutation. Although it is typical of Southern Italy, p.Leu1077Pro is not included in the mutation panel firstly tested in individuals originated from this area. The aim of our study was to describe prevalence and clinical features in patients bearing this mutation followed in our Cystic Fibrosis Centre to demonstrate that this mutation should be included in the mutation panel firstly tested in patients originated from Southern Italy.FindingsWe reviewed data from a cohort of 111 cystic fibrosis patients. 4 patients who were heterozygous for the p.Leu1077Pro mutation were included in the study.In our Cystic Fibrosis Centre, the prevalence of p.Leu1077Pro is 3.6% among all mutations. All patients had positive sweat test values, pancreatic insufficiency and pulmonary exacerbations. One out of four patients even showed both FEV1 and FVC values significantly below the normal range, the presence of bronchiectasis and chronic Pseudomonas aeruginosa colonization.ConclusionsWe found that the p.Leu1077Pro CFTR mutation is associated with a classic CF phenotype confirming what is reported in CFTR2 database. The relatively high prevalence of p.Leu1077Pro associated with the severe clinical course of the disease in patients bearing this mutation is of interest for genetic counselling purposes, as it should be part of mutation panel to be tested in individuals originated from Southern Italy.

Pulmonologists and lung cancer: pivotal role in multidisciplinary approach

Introduction: CFTR p.Leu206Trp mutation is associated with residual transmembrane transport of chloride and mild CF. Objective: to analyze the clinical differences between adults and paediatric CF patients who are compound heterozygous for p.Leu206Trp. Methods: Clinical retrospective data of 13 paediatric patients (group A: 6 males ranging 3 months to 12 y) and 10 adults (group B: 6 males, 27-51 y) harbouring p.Leu206Trp were analyzed. Sweat test (ST), clinical symptoms, pancreatic sufficiency (PS), pulmonary function (PF), air trapping (AT)/bronchiectasis (BC) on CT scan and colonization with Staphylococcus aureus (SA) or Pseudomonas aeruginosa (PA) or were examined. Results: Patients in group A were diagnosed by newborn screening (NS) and adults at mean age of: 30 y. 8 adults were diagnosed by respiratory symptoms and had BC on CT compared with only AT in 5 paediatric patients. ST values were borderline at NS period (except in one case) but became positive with increasing age. In adults, ST values were positive. FEV1 predicted values were normal in group A but in 60% of adults values were abnormal. PA and SA were isolated occasionally in paediatric patients but all adults were chronic colonized. All the patients except one were PS in both groups. Conclusions: In childhood p.Leu206Trp is associated with mild disease but patients diagnosed in adulthood have lung disease, chronic colonization with PA/SA and diffuse BC, showed clear differences between paediatric and adults patients heterozygous for this mutation. Identification at NS of the p.Leu206Trp in patients with other identified mutation and borderline ST values allows early treatment to delay lung disease in adulthood.

Evaluation of Demographic and Clinical Characteristics of Patients with Cystic Fibrosis

Objective: This study was performed to examine the demographic characteristics, clinical features and diagnostic tests of children with the diagnosis of cystic fibrosis. Material and Methods: Presenting symptoms, complaints on admission, clinical features, and diagnostic tests for 41 children with cystic fibrosis between the age of 2 days and 4 months diagnosed at the Pediatrics clinic of Dr. Sami Ulus Maternity, Children Health and Diseases Training and Research Hospital between January 2005 and June 2012 were examined. Results: The mean age at diagnosis was 5.2 months. There was a history of consanguinity in 61.1% of cystic fibrosis patients. Mutation analysis revealed that 75% of the children had a cystic fibrosis mutation. Gastrointestinal complaints were the most common presenting complaint (43.9%). There was no statistically significant difference between demographic characteristics, age at diagnosis, duration of complaints, hospitalization frequency, sweat test values, and mutation analysis between children presenting with gastrointestinal symptoms, respiratory tract symptoms (31.7%) and the Pseudo-Bartter clinical syndrome (24.4%). Conclusion: Cystic fibrosis is a multisystemic disease with findings related to the respiratory system and gastrointestinal system, and patients might present with the Pseudo-Bartter syndrome as well. It should be noted that cystic fibrosis can present with different clinical presentations due to the different genotypic features in our country.

Elevated levels of miR-145 correlate with SMAD3 down-regulation in Cystic Fibrosis patients

MicroRNAs (miRNAs) have recently emerged as important gene regulators in Cystic Fibrosis (CF), a common monogenic disease characterized by severe infection and inflammation, especially in the airway compartments. In the current study, we show that both miR-145 and miR-494 are significantly up-regulated in nasal epithelial tissues from CF patients compared with healthy controls (p<0.001 and p<0.01, respectively) by Quantitative Real-Time PCR. Only miR-494 levels showed a trend of correlation with reduced CFTR mRNA expression and positive sweat test values, supporting the negative regulatory role of this miRNA on CFTR synthesis. Using computational prediction algorithms and luciferase reporter assays, SMAD family member 3 (SMAD3), a key element of the TGF-β1 inflammatory pathway, was identified as a target of miR-145. Indeed, miR-145 synthetic mimics suppressed by approximately 40% the expression of a reporter construct containing the SMAD3 3'-UTR. Moreover, we observed an inverse correlation between SMAD3 mRNA expression and miR-145 in CF nasal tissues (r=-0.68, p=0.0018, Pearson's correlation). Taken together, these results confirm the pivotal role of miRNAs in the CF physio-pathogenesis and suggest that miRNA deregulation play a role in the airway disease severity by modulating CFTR levels as well as the expression of important molecules involved in the inflammatory response. miR-494 and miR-145 may, therefore, be potential biomarker and therapeutic target to specific CF clinical manifestations.

20 Cystic fibrosis newborn screening in Italy: survey for assessment of technical-scientific and organizational issues

Aim: Evaluation of patients with pancreatic sufficiency (PS) and insufficiency (PI) diagnosed in CF NBS. Methods: Groups of 17 PS and PI patients diagnosed in CF NBS with the similar CFTR mutations and confirmed elastaze-1 status were analyzed. Patients with Meconium ileus were excluded. Birth weight and length, age at diagnosis, IRT, sweat test values, evaluation of SD body weight and height at the end of the 1st year of life as well as Pseudomonas aeruginosa (PA) infection were collected. Results: From Sept. 2006 to the end of Dec. 2010 CF was confirmed in 84 newborns screened. In PS group were 41% females and 53% respectively. Both groups consisted of 10 F508del heterozygotes and 7 non-F508del heterozygotes. Average age of diagnosis in PS group was similar to PI patients (55 v 45 days). The mean birth weight (3697.35±472.45 v 3122.12±368.52; p< 0.001) and length (55.82±2.83 v 53.76±2.49; p = 0.031) were significantly higher in PS patients. The mean IRT for the group PS was significantly lower (455.07±342.88 v 676.72±353.22; p = 0.036). At the end of 1st year of life, mean SD body weight and IWH% was in the normal range without differences between group. However, SD height (0.36±0.81 v −0.26±0.89; p = 0.033 were significantly reduced in PI patients. Iontophoresis sweat test was significantly lower in PS group (54.48±20.55 v 81.31±22.77; p = 0.001). 3 patients in both groups had infection with PA in assessed period. Conclusion: CF newborns with PS were characterized by lower sweat test and IRT results but higher birth weight and length than PI children. Although there were no differences in weight at the end of 1st year of life between the groups, children with PI were taller.