Objective: To determine the effects that mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) gene and deletion of the glutathione S-transferase (GST) genes mu-1 (GSTM1) and theta-1 (GSTT1) have on the clinical course of cystic fibrosis (CF) in patients residing in the southeastern region of Brazil. Methods: The study sample consisted of all consecutive CF patients treated at the Hospital de Clínicas School of Medical Sciences of the State University at Campinas between March of 2002 and March of 2005. We included 66 CF patients. Genomic DNA was analyzed by polymerase chain reaction and restriction endonuclease digestion for the identification of the genotypes. Results: The F508 mutation of the CFTR gene was found in 44 patients (66.7%). The null genotypes GSTM1, GSTT1 and GSTM1/GSTT1 were found in 40.9%, 15.2%, and 3.0% of the patients, respectively. The F508 CFTR mutation was more common in patients diagnosed with CF before 2.5 years of age than in those diagnosed later (75.5% vs. 41.2%; p = 0.008). The frequency of the F508 CFTR mutation, as well as of the GSTM1 and GSTT1 genotypes, was not found to be associated with gender, ethnicity, pulmonary disease status, or pancreatic disease status. Conclusions: When the patients were stratified by clinical and epidemiological features, the frequencies of the GSTM1 and GSTT1 null genotypes were similar, suggesting that the inherited absence of these enzymatic pathways does not alter the course of CF. However, the high frequency of the F508 CFTR mutation found in younger children suggests that it influences the age at diagnosis of CF in this region of Brazil.

Keywords: : Cystic fibrosis; Cystic fibrosis transmembrane conductance regulator; Glutathione transferase.

Objective: To determine the frequency of six mutations (F508del, G542X, G551D, R553X, R1162X, and N1303K) in patients with cystic fibrosis (CF) diagnosed, at a referral center, on the basis of abnormal results in two determinations of sweat sodium and chloride concentrations. Methods: This was a cross-sectional study involving 70 patients with CF. The mean age of the patients was 12.38 ± 9.00 years, 51.43% were female, and 94.29% were White. Mutation screening was performed with polymerase chain reaction (for F508del), followed by enzymatic digestion (for other mutations). Clinical analysis was performed on the basis of gender, age, ethnicity, pulmonary/gastrointestinal symptoms, and Shwachman-Kulczycki (SK) score. Results: All of the patients showed pulmonary symptoms, and 8 had no gastrointestinal symptoms. On the basis of the SK scores, CF was determined to be mild, moderate, and severe in 22 (42.3%), 17 (32.7%), and 13 (25.0%) of the patients, respectively. There was no association between F508del mutation and disease severity by SK score. Of the 140 alleles analyzed, F508del mutation was identified in 70 (50%). Other mutations (G542X, G551D, R553X, R1162X, and N1303K) were identified in 12 (7.93%) of the alleles studied. In F508del homozygous patients with severe disease, the OR was 0.124 (95% CI: 0.005-0.826). Conclusions: In 50% of the alleles studied, the molecular diagnosis of CF was confirmed by identifying a single mutation (F508del). If we consider the analysis of the six most common mutations in the Brazilian population (including F508del), the molecular diagnosis was confirmed in 58.57% of the alleles studied.

Objective: To determine the relevance of screening for the F508del mutation of the cystic fibrosis transmembrane conductance regulator gene as a first step in the genetic diagnosis of cystic fibrosis (CF) by associating the genotype with various clinical variables. Methods: We evaluated 180 CF patients regarding the F508del mutation. The clinical data were obtained from the medical records of the patients and from interviews with their parents or legal guardians. Results: Of the 180 patients studied, 65 (36.1%) did not carry the F508del mutation (group 0 [G0]), 67 (37.2%) were F508del heterozygous (G1), and 48 (26.7%) were F508del homozygous (G2). All three groups showed associations with the clinical variables. Homozygosis was associated with younger patients, younger age at CF diagnosis, and younger age at the first isolation of Pseudomonas aeruginosa (PA), as well as with higher prevalence of pancreatic insufficiency (PI) and non-mucoid PA (NMPA) colonization. In comparison with G1+G2 patients, G0 patients were older; first experienced clinical symptoms, digestive disease, and pulmonary disease at an older age; were older at CF diagnosis and at first PA isolation; and had a lower prevalence of PI and meconium ileus, as well as of colonization by NMPA, mucoid PA, and Burkholderia cepacia. In G1 patients, values were intermediate for age at CF diagnosis; age at first PA isolation, first pulmonary symptoms, and first clinical manifestations; MPA colonization; and OR for PI. Conclusions: The identification of F508del in 63.9% of the patients studied showed that this can be a useful tool as a first step in the genetic diagnosis of CF. The F508del genotype was associated with clinical severity of the disease, especially with the variables related to CF onset.

Keywords: Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Genotype; Mutation.

Objective: To evaluate the diagnostic contribution of molecular analysis of the cystic fibrosis transmembrane conductance regulator (CFTR) gene in patients suspected of having mild or atypical cystic fibrosis (CF). Methods: This was a cross-sectional study involving adolescents and adults aged ≥ 14 years. Volunteers underwent clinical, laboratory, and radiological evaluation, as well as spirometry, sputum microbiology, liver ultrasound, sweat tests, and molecular analysis of the CFTR gene. We then divided the patients into three groups by the number of mutations identified (none, one, and two or more) and compared those groups in terms of their characteristics. Results: We evaluated 37 patients with phenotypic findings of CF, with or without sweat test confirmation. The mean age of the patients was 32.5 ± 13.6 years, and females predominated (75.7%). The molecular analysis contributed to the definitive diagnosis of CF in 3 patients (8.1%), all of whom had at least two mutations. There were 7 patients (18.9%) with only one mutation and 26 patients (70.3%) with no mutations. None of the clinical characteristics evaluated was found to be associated with the genetic diagnosis. The most common mutation was p.F508del, which was found in 5 patients. The combination of p.V232D and p.F508del was found in 2 patients. Other mutations identified were p.A559T, p.D1152H, p.T1057A, p.I148T, p.V754M, p.P1290P, p.R1066H, and p.T351S. Conclusions: The molecular analysis of the CFTR gene coding region showed a limited contribution to the diagnostic investigation of patients suspected of having mild or atypical CF. In addition, there were no associations between the clinical characteristics and the genetic diagnosis.

Cystic fibrosis-related diabetes (CFRD) is the principal extra-pulmonary complication of cystic fibrosis, occurring in 15-30% of adult cystic fibrosis patients. The number of cystic fibrosis patients who develop diabetes is increasing in parallel with increases in life expectancy. The aim of this study was to review the physiopathology, clinical presentation, diagnosis and treatment of CFRD. A bibliographic search of the Medline and Latin American and Caribbean Health Sciences Literature databases was made. Articles were selected from among those published in the last twenty years. Insulin deficiency, caused by reduced β-cell mass, is the main etiologic mechanism, although insulin resistance also plays a role. Presenting features of type 1 and type 2 diabetes, CFRD typically affects individuals of approximately 20 years of age. It can also be accompanied by fasting, non-fasting or intermittent hyperglycemia. Glucose intolerance is associated with worsening of nutritional status, increased morbidity, decreased survival and reduced pulmonary function. Microvascular complications are always present, although macrovascular complications are rarely seen. An oral glucose tolerance test is recommended annually for patients ≥ 10 years of age and for any patients presenting unexplained weight loss or symptoms of diabetes. Patients hospitalized with severe diseases should also be screened. If fasting hyperglycemia persists for more than 48 h, insulin therapy is recommended. Insulin administration remains the treatment of choice for diabetes and fasting hyperglycemia. Calories should not be restricted, and patients with CFRD should be managed by a multidisciplinary team.

Keywords: Cystic fibrosis; Diabetes mellitus.

Objective: To test the hypothesis that disease severity in patients with cystic fibrosis (CF) is correlated with an increased risk of sleep apnea. Methods: A total of 34 CF patients underwent clinical and functional evaluation, as well as portable polysomnography, spirometry, and determination of IL-1β levels. Results: Mean apnea-hypopnea index (AHI), SpO2 on room air, and Epworth Sleepiness Scale score were 4.8 ± 2.6, 95.9 ± 1.9%, and 7.6 ± 3.8 points, respectively. Of the 34 patients, 19 were well-nourished, 6 were at nutritional risk, and 9 were malnourished. In the multivariate model to predict the AHI, the following variables remained significant: nutritional status (β = −0.386; p = 0.014); SpO2 (β = −0.453; p = 0.005), and the Epworth Sleepiness Scale score (β = 0.429; p = 0.006). The model explained 51% of the variation in the AHI. Conclusions: The major determinants of sleep apnea were nutritional status, SpO2, and daytime sleepiness. This knowledge not only provides an opportunity to define the clinical risk of having sleep apnea but also creates an avenue for the treatment and prevention of the disease.

Keywords: Cystic fibrosis; Oxygenation; Sleep apnea, obstructive.

Objective: To determine whether nebulizers are a source of microbial contamination in patients with cystic fibrosis, as well as whether the technique and frequency of disinfection of these devices is appropriate. Methods: This was a cross-sectional, uncontrolled observational study. Samples were collected from 28 patients with cystic fibrosis. Samples were collected at the homes of the patients, who were not previously informed of the purpose of the visit. Three samples were collected from each patient: one from the nebulizer chamber, one from the mask/mouthpiece, and one from the patient (oropharyngeal swab/sputum). The samples were properly stored and taken for analyses. The patients, their parents, or their legal guardians completed a questionnaire regarding nebulizer cleaning and disinfecting methods. Results: We collected 84 samples from the 28 patients. Of those 28 patients, 15 (53.5%) were male. The median age of the patients was 11 years (range, 1-27 years). Of the 28 patients, 15 presented with positive oropharyngeal swab/sputum sample cultures. The most common bacterial isolates were Staphylococcus aureus (in 8 patients) and Pseudomonas aeruginosa (in 4 patients). Although the samples obtained from the nebulizers presented with various pathogens in culture, no specific species predominated. In 27 cases (96.7%), there were no associations between the samples obtained from the nebulizers and those obtained from the patients in terms of the results of the cultures. Cleaning and disinfection of nebulizers were inappropriate in 22 cases (78.6%). Conclusions: In this sample of patients, despite the inappropriate disinfection techniques, nebulizers were not found to be a source of microbial contamination.

Keywords: Cystic fibrosis; Nebulizers and vaporizers; Disinfection.

Objective: To assess the quality of life (QoL) of patients with cystic fibrosis (CF) followed at a university referral center for CF. Methods: A cross-sectional study involving application of the Cystic Fibrosis Questionnaire (CFQ) and Shwachman score in CF patients between April of 2008 and June of 2009. Results: The sample consisted of 75 patients. The mean age was 12.5 ± 5.1 years (range, 6.1-26.4 years). The patients were divided into three groups by age in years: group I (< 12), II (12-14), and III (≥ 14). The highest and lowest CFQ scores were for the nutrition domain in group III (89.3 ± 16.2) and the social domain in group II (59.5 ± 22.3), respectively. Groups I and III differed significantly regarding the treatment domain (p = 0.001). Regarding Shwachman scores, there were significant differences between patients scoring ≤ 70 and those scoring > 70 in the social (group I; p = 0.045), respiratory (group II; p = 0.053), and digestive (p = 0.042) domains. In group III, severity did not correlate with QoL. In groups I and II, patients with an FEV1 < 80% of predicted did not differ from other patients for any CFQ domain. However, in group III, values for the following domains were significantly lower in patients with an FEV1 < 80%: physical (p = 0.012); body image (p = 0.031); respiratory (p = 0.023), emotional (p = 0.041); and social role (p = 0.024). Conclusions: It is important to assess QoL in CF patients, because it can improve treatment compliance.

Keywords: Cystic fibrosis; Quality of life; Questionnaires.

Objective: To identify associations between genetic polymorphisms (in the MBL2, TGF-β1 and CD14 genes) and the severity of the lung disease in patients with cystic fibrosis (CF), as well as between the presence of ΔF508 alleles and lung disease severity in such patients. Methods: This was a cross-sectional cohort study, based on clinical and laboratory data, involving 105 patients with CF treated at a university hospital in the 2005-2006 period. We included 202 healthy blood donors as controls for the determination of TGF-β1 and CD14 gene polymorphisms. Polymorphisms in the MBL2 and TGF-β1 genes at codon 10, position +869, were genotyped using the allele-specific PCR technique. The C-159T polymorphism in the CD14 gene was genotyped using PCR and enzymatic digestion. Results: Of the 105 CF patients evaluated, 67 presented with severe lung disease according to the Shwachman score. The MBL2 gene polymorphisms were not associated with disease severity in the CF patients. Analysis of the T869C polymorphism in the TGF-β1 gene showed an association only between TC heterozygotes and mild pulmonary disease. Although patients presenting the TT genotype of the C159T polymorphism in the CD14 gene predominated, there was no significant difference regarding lung disease severity. Conclusions: There was an association between the TC genotype of the T869C polymorphism (TGF-β1) and mild pulmonary disease in CF patients. In the CD14 gene, the TT genotype seems to be a risk factor for pulmonary disease but is not a modulator of severity. We found no association between being a ΔF508 homozygote and presenting severe lung disease.

Keywords: Cystic fibrosis; Polymorphism, genetic; Severity of illness index; Mannose-binding lectin; Transforming growth factor beta.

Objective: To describe the profile of patients with cystic fibrosis (CF). Methods: A prospective, cross-sectional study involving CF patients ≤ 18 years of age, evaluated between March and July of 2006 at a referral center in northeastern Brazil. Nutritional assessment was performed using Z scores for height/age (H/A), weight/age (W/A) and weight/height (W/H), as well as %weight/height (%W/H) and body composition measurements. Socioeconomic and clinical data were obtained. Results: Twenty-one patients were evaluated, 12 (57.1%) of whom were female. Mean age at diagnosis was 3.8 ± 3.9 years. The principal features at diagnosis were respiratory infection (85.7%), steatorrhea (66.7%) and nutritional deficit (47.6%). The mean Z scores for W/A, H/A and W/H were 0.73 ± 0.28, 0.34 ± 0.21 and 0.73 ± 0.35, respectively. Mean %W/H was 94.52 ± 1.58. The percentage of malnourished children assessed by Z score differed from that assessed by %W/H (nutritional deficit in 66.7% and 33.3%, respectively; p > 0.05). Socioeconomic status, clinical status and Shwachman score were better among well-nourished patients than among those classified as malnourished (p < 0.05 for Shwachman score). Conclusions: Normal nutritional status was identified based on nutritional indicators (W/A, H/A and W/H), whereas nutritional deficit was identified by assessing body composition. Socioeconomic factors proved favorable, especially maternal education and per capita income. Age at diagnosis was higher than that reported in the literature, although the Shwachman score and the incidence of respiratory infections demonstrated that the patients presented good clinical status.

Keywords: Cystic fibrosis; Nutritional assessment; Symptoms, clinical; Socioeconomic factors.

Objective: To determine the prevalence of allergic bronchopulmonary aspergillosis (ABPA) in patients with cystic fibrosis treated at a referral center in the state of Bahia, Brazil. Methods: A cross-sectional study, with prospective data collection, carried out at the Cystic Fibrosis Referral Center of Bahia of the Octávio Mangabeira Specialized Hospital. We evaluated 74 patients diagnosed with cystic fibrosis, older than six years of age, treated between December 9, 2003 and March 7, 2005. We analyzed the following variables: gender, age, forced vital capacity, forced expiratory volume in one second, pharmacodynamic response, chest X-ray findings, facial sinus X-ray findings, wheezing, cultures for Aspergillus spp., total immunoglobulin E (IgE), specific IgE for Aspergillus fumigatus and immediate skin test reactivity to A. fumigatus antigen. Results: Of the 74 patients, 2 were diagnosed with ABPA. We found total IgE levels > 1,000 IU/mL in 17 (23%), positive immediate skin reactivity to A. fumigatus antigen in 19 (25.7%) and wheezing in 60 (81.1%). Conclusions: The prevalence of ABPA was 2.7%. The high levels of total IgE, high incidence of wheezing and high rate of immediate skin test reactivity to A. fumigatus antigen suggest that these patients should be carefully monitored due to their propensity to develop ABPA.

Keywords: Cystic fibrosis; Aspergillosis, allergic bronchopulmonary; Immunoglobulin E/diagnostic use; Hypersensitivity, immediate/diagnosis; Gliotoxin.

Objectives: To characterize the main identified mutations on cystic fibrosis transmembrane conductance regulator (CFTR) in a group of children and adolescents at a cystic fibrosis center and its association with the clinical and laboratorial characteristics. Method: Descriptive cross-sectional study including patients with cystic fibrosis who had two alleles identified with CFTR mutation. Clinical, anthropometrical, laboratorial and pulmonary function (spirometry) data were collected from patients' records in charts and described with the results of the sample genotyping. Results: 42 patients with cystic fibrosis were included in the study. The most frequent mutation was F508del, covering 60 alleles (71.4%). The second most common mutation was G542X (six alleles, 7.1%), followed by N1303K and R1162X mutations (both with four alleles each). Three patients (7.14%) presented type III and IV mutations, and 22 patients (52.38%) presented homozygous mutation for F508del. Thirty three patients (78.6%) suffered of pancreatic insufficiency, 26.2% presented meconium ileus, and 16.7%, nutritional deficit. Of the patients in the study, 59.52% would be potential candidates for the use of CFTR-modulating drugs. Conclusions: The mutations of CFTR identified more frequently were F508del and G542X. These are type II and I mutations, respectively. Along with type III, they present a more severe cystic fibrosis phenotype. More than half of the sample (52.38%) presented homozygous mutation for F508del, that is, patients who could be treated with Lumacaftor/Ivacaftor. Approximately 7% of the patients (7.14%) presented type III and IV mutations, therefore becoming candidates for the treatment with Ivacaftor.

Keywords: Cystic fibrosis; Mutations; Genetics; Phenotype; Child

Objectives: To evaluate the self-reported degree of adherence to treatment in patients with cystic fibrosis (CF), investigating associations with characteristics of the disease and with the degree of adherence perceived by health professionals. Methods: This was a prospective, cross-sectional study involving patients with CF monitored at a Program for Adults with CF. The degree of adherence was evaluated using a questionnaire. Patients were divided into two groups: greater degree of adherence and moderate/poor degree of adherence. Clinical data, Shwachman-Kulczycki clinical score, Brasfield radiographic score and spirometry data were obtained for all patients. Results: Out of 38 patients studied, 31 (81.6%) were classified as presenting a greater degree of adherence and 7 (18.4%) as presenting a moderate/poor degree of adherence. The self-reported patient adherence score correlated with the clinical score (r = −0.36, p = 0.028). The self-reported patient adherence score (median = 0.79) was higher than that perceived by health professionals (median = 0.71, p = 0.003). A greater degree of adherence was self-reported for respiratory therapy (by 84.2%), exercise (by 21.1%), prescribed diet (by 65.8%), pancreatic enzymes (by 96.3%), vitamins (by 79.4%), inhaled antibiotic therapy (by 76.7%) and inhaled DNase (by 79.4%). Conclusions: Self-reported adherence of patients attending a Program for Adults with CF was good. The self-reported patient adherence score correlated inversely with the clinical score. Self-reported patient adherence was greater than the adherence perceived by health professionals.

Keywords: Cystic fibrosis; Patient compliance; Therapeutics.

Objective: To evaluate the perception of disease severity in patients with cystic fibrosis (CF), investigating its relationship with clinical score, radiographic score, respiratory function tests, adherence to treatment and perception of self-care practices. Methods: Prospective, cross-sectional study involving CF patients treated in a program for adults with CF. The perception of disease severity, adherence to treatment and reported self-care practices were evaluated by means of questionnaires. Clinical data, Shwachman-Kulczycki clinical score, Brasfield radiographic score and spirometry were obtained for all of the patients. Results: Of the 38 patients studied, 3 (7.9%) patients rated their perception of health status as well below average; 5 (13.2%), as below average; 15 (39.5%), as average; 10 (26.3%), as above average; and 5 (13.2%), as well above average. The perception of disease severity correlated significantly with clinical score (r = 0.43, p = 0.007), FVC (r = 0.34, p = 0.034), FEV1 (r = 0.38, p = 0.019) and self-care practices (r = 0.33, p = 0.044), but not with degree of adherence (r = -0.03, p = 0.842) and radiographic score (r = 0.33, p = 0.51). Conclusions: The perception of disease severity correlated with objective measurements of disease severity (clinical score and respiratory function tests) and with reported self-care practices, but not with adherence to treatment.

Keywords: Severity of illness index; Cystic fibrosis; Patient compliance; Respiratory function tests.

INTRODUCTION: Cystic Fibrosis is usually diagnosed in childhood. In Brazil, few studies have approached CF diagnosed in adulthood. OBJECTIVE:The aim of this study was to describe demographic and clinical characteristics and spirometric data of patients with CF diagnosed in adulthood (over 16 years of age) in Bahia, Brazil. METHODS: Twenty-eight patients with cystic fibrosis diagnosed in adulthood were evaluated at the Reference Center of Cystic Fibrosis of the state of Bahia. Variables of interest were age, gender, race, body mass index (BMI), sputum culture, presence of sinusitis and bronchiectasis, spirometric tests with the best values performed for forced expiratory volume in the first second (FEV1), forced vital capacity (FVC) and response to bronchodilators. RESULTS: Mean age of diagnosis was 31.1 ± 12.4 years. Of the patients, 53.4% were black and mulatto and the mean BMI was 18.7 ± 3.0 kg/m2. P aeruginosa was present in 12 (43%) of the total patients. The mean percentages ± SD of FVC and FEV1 were 58.9 ± 21.6% and 44.1 ± 23%, respectively. In the group of patients with presence of P. aeruginosa in sputum cultures, mean of the spirometry parameters were lower than those of the P. aeruginosa-free group. However, this difference achieved a statistically significant difference (p = 0.0007) only in FVC . CONCLUSIONS: In agreement with many authors, this study strengthen the point of view that CF must be investigated in patients with recurrent infections, sinusitis and bronchiectasis even in adulthood. Values of the percentages of FVC and FEV1 in relation to those foreseen were lower in patients bearers of P. aeruginosa thereby showing a higher deterioration of the pulmonary function.

Keywords: Cystic fibrosis/diagnosis. Adult. Spirometry/methods.

Once considered a childhood disease, cystic fibrosis is now also a disease of adults. Increased longevity has resulted in the aging of the cystic fibrosis population. The consequent age-related medical problems among adults with cystic fibrosis have increased medical care needs. These needs are being met by a growing number of non-pediatric pulmonologists and other non-pediatric specialists. The objective of this review was to summarize the current knowledge about diagnosis and treatment in adult cystic fibrosis. In most cases, the diagnosis is suggested by manifestations of chronic sinopulmonary disease and exocrine pancreatic insufficiency. The diagnosis is confirmed by a positive sweat test result. Adult patients may, however, present pancreatic sufficiency and atypical clinical features, sometimes in combination with normal or borderline sweat test results. In such cases, identifying cystic fibrosis mutations and measuring nasal potential difference can have diagnostic utility. The standard therapeutic approach to pulmonary disease includes the use of antibiotics, airway clearance, exercise, mucolytics, bronchodilators, oxygen therapy, anti-inflammatory agents and nutritional support. Appropriate application of these therapies results in most cystic fibrosis patients surviving into adulthood with an acceptable quality of life.

Keywords: Cystic fibrosis; Diagnosis; Therapeutics; Mucoviscidosis.