Publicações Científicas

NOVAS TERAPIAS

Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del CFTR.

Wainwright CE, Elborn JS, Ramsey BW, Marigowda G, Huang X, Cipolli M, Colombo C, Davies JC, De Boeck K, Flume PA, Konstan MW, McColley SA, McCoy K, McKone EF, Munck A, Ratjen F, Rowe SM, Waltz D, Boyle MP; TRAFFIC Study Group; TRANSPORT Study Group.

N Engl J Med. 2015

Abstract

BACKGROUND:

Cystic fibrosis is a life-limiting disease that is caused by defective or deficient cystic fibrosis transmembrane conductance regulator (CFTR) protein activity. Phe508del is the most common CFTR mutation.

METHODS:

We conducted two phase 3, randomized, double-blind, placebo-controlled studies that were designed to assess the effects of lumacaftor (VX-809), a CFTR corrector, in combination with ivacaftor (VX-770), a CFTR potentiator, in patients 12 years of age or older who had cystic fibrosis and were homozygous for the Phe508del CFTR mutation. In both studies, patients were randomly assigned to receive either lumacaftor (600 mg once daily or 400 mg every 12 hours) in combination with ivacaftor (250 mg every 12 hours) or matched placebo for 24 weeks. The primary end point was the absolute change from baseline in the percentage of predicted forced expiratory volume in 1 second (FEV1) at week 24.

RESULTS:

A total of 1108 patients underwent randomization and received study drug. The mean baseline FEV1 was 61% of the predicted value. In both studies, there were significant improvements in the primary end point in both lumacaftor-ivacaftor dose groups; the difference between active treatment and placebo with respect to the mean absolute improvement in the percentage of predicted FEV1 ranged from 2.6 to 4.0 percentage points (P<0.001), which corresponded to a mean relative treatment difference of 4.3 to 6.7% (P<0.001). Pooled analyses showed that the rate of pulmonary exacerbations was 30 to 39% lower in the lumacaftor-ivacaftor groups than in the placebo group; the rate of events leading to hospitalization or the use of intravenous antibiotics was lower in the lumacaftor-ivacaftor groups as well. The incidence of adverse events was generally similar in the lumacaftor-ivacaftor and placebo groups. The rate of discontinuation due to an adverse event was 4.2% among patients who received lumacaftor-ivacaftor versus 1.6% among those who received placebo.

CONCLUSIONS:

These data show that lumacaftor in combination with ivacaftor provided a benefit for patients with cystic fibrosis homozygous for the Phe508del CFTR mutation.


Potentiators (specific therapies for class III and IV mutations) for cystic fibrosis.

Patel S1, Sinha IP, Dwan K, Echevarria C, Schechter M, Southern KW.

Cochrane Database Syst Rev. 2015

Abstract

BACKGROUND:

Cystic fibrosis is the most common inherited life-shortening illness in Caucasians and caused by a mutation in the gene that codes for the cystic fibrosis transmembrane regulator protein (CFTR), which functions as a salt transporter. This mutation most notably affects the airways of people with cystic fibrosis. Excess salt absorption by defective CFTR dehydrates the airway lining and leads to defective mucociliary clearance. Consequent accumulation of thick, sticky mucus makes the airway prone to chronic infection and progressive inflammation; respiratory failure often ensues. Additionally, abnormalities with CFTR lead to systemic complications like malnutrition, diabetes and subfertility.Since the discovery of the causative gene, our understanding of the structure and function of CFTR and the impact of different mutations has increased and allowed pharmaceutical companies to design new mutation-specific therapies targeting the underlying molecular defect. Therapies targeting mutation classes III and IV (CFTR potentiators) aim to normalise airway surface liquid and help re-establish mucociliary clearance, which then has a beneficial impact on the chronic infection and inflammation that characterizes lung disease in people with cystic fibrosis. These therapies may also affect other mutations.

OBJECTIVES:

To evaluate the effects of CFTR potentiators on clinically important outcomes in children and adults with cystic fibrosis.

SEARCH METHODS:

We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched the reference lists of relevant articles and reviews. Last search: 05 March 2015.We searched the EU Clinical Trials Register, clinicaltrials.gov (US Clinical Trials Register) and the International Clinical Trials Registry Platform (ICTRP). Last search of clinical trial registries: 06 February 2014.

SELECTION CRITERIA:

Randomised controlled trials of parallel design comparing CFTR potentiators to placebo in people with cystic fibrosis. In a post hoc change we excluded trials combining CFTR potentiators with other mutation-specific therapies. These will be considered in a separate review.

DATA COLLECTION AND ANALYSIS:

The authors independently extracted data and assessed the risk of bias in included trials; they contacted trial authors for additional data. Meta-analyses were undertaken on outcomes at a number of time points.

MAIN RESULTS:

We included four randomised controlled trials (n = 378), lasting from 28 days to 48 weeks, comparing the potentiator ivacaftor to placebo. Trials differed in terms of design and participant eligibility criteria, which limited the meta-analyses. The phase 2 trial (n = 19) and two phase 3 trials (adult trial (n = 167), paediatric trial (n = 52)), recruited participants with the G551D mutation (class III). The fourth trial (n = 140) enrolled participants homozygous for the ΔF508 mutation (class II).Risks of bias in the trials were moderate. Random sequence generation, allocation concealment and blinding of trial personnel were well-documented. Participant blinding was less clear throughout all trials; in three trials, some participant data were excluded from the analysis. Selective outcome reporting was apparent in three trials. All trials were sponsored by industry and supported by other non-pharmaceutical funding bodies.No trial reported any deaths. Significantly higher quality of life scores in the respiratory domain were reported by the adult phase 3 G551D trial at 24 weeks, mean difference 8.10 (95% confidence interval (CI) 4.77 to 11.43) and 48 weeks, mean difference 8.60 (95% CI 5.27 to 11.93); but not by the paediatric phase 3 G551D trial. The adult phase 3 G551D trial reported improvements in relative change from baseline in forced expiratory volume at one second at 24 weeks, mean difference 16.90% (95% CI 13.60 to 20.20) and 48 weeks, mean difference 16.80% (95% CI 13.50 to 20.10); as did the paediatric G551D trial at 24 weeks, mean difference 17.4% (P < 0.0001)). No improvements in quality of life or lung function were reported in the ΔF508 participants.Combined data from both phase 3 G551D trials demonstrated increased reporting of cough, odds ratio 0.57 (95% CI 0.33 to 1.00) and increased episodes of decreased pulmonary function, odds ratio 0.29 (95% CI 0.10 to 0.82) in the placebo group. The adult phase 3 G551D trial demonstrated increased reporting of dizziness amongst the ivacaftor group, OR 10.55 (95% CI 1.32 to 84.47). No trial showed a difference between treatment arms in the number of participants interrupting or discontinuing the trial drug.In the phase 3 G551D trials, fewer participants assigned to ivacaftor developed serious pulmonary exacerbations. When considering all data for exacerbations, participants taking ivacaftor in the adult phase 3 G551D study developed fewer exacerbations, odds ratio 0.54 (95% CI 0.29 to 1.01). In the other G551D studies and in the ΔF508 study, there was no difference between groups in the number of participants who developed pulmonary exacerbations.Combined data from both phase 3 G551D trials demonstrated significant improvements in absolute change from baseline in forced expiratory volume at one second (% predicted) at 24 weeks, mean difference 10.80% (95% CI 8.91 to 12.69) and 48 weeks, mean difference 10.44% (95% CI 8.56 to 12.32); also in weight at 24 weeks, mean difference 2.37 kg (95% CI 1.68 to 3.06) and 48 weeks, mean difference 2.75 kg (95% CI 1.74 to 3.75). No improvements in these outcomes were reported in the ΔF508 participants.Significant reductions in sweat chloride concentration were reported in both G551D and ΔF508 participants: in combined data from both phase 3 G551D trials at 24 weeks, mean difference -48.98 mmol/L (95% CI -52.07 to -45.89) and 48 weeks, mean difference -49.03 mmol/L (95% CI -52.11 to -45.94); and from the ΔF508 trial at 16 weeks, mean difference -2.90 mmol/L (95% CI -5.60 to -0.20).

AUTHORS’ CONCLUSIONS:

Both G551D phase 3 trials (n = 219) demonstrated a clinically relevant impact of the potentiator ivacaftor on outcomes at 24 and 48 weeks, providing evidence for the use of this treatment in adults and children (over six years of age) with cystic fibrosis and the G551D mutation (class III). There is no evidence to support the use of ivacaftor in people with the ΔF508 mutation (class II) (n = 140). Trials on ivacaftor in people with different mutations are ongoing.


Safety, pharmacokinetics, and pharmacodynamics of ivacaftor in patients aged 2-5 years with cystic fibrosis and a CFTR gating mutation (KIWI): an open-label, single-arm study.

Davies JC1, Cunningham S2, Harris WT3, Lapey A4, Regelmann WE5, Sawicki GS6, Southern KW7, Robertson S8, Green Y9, Cooke J9, Rosenfeld M10; KIWI Study Group.

Lancet Respir Med. 2016

Abstract

BACKGROUND:

Ivacaftor has been shown to be a safe, effective treatment for cystic fibrosis in patients aged 6 years or older with a CFTR gating mutation. We aimed to assess the safety, pharmacokinetics, and pharmacodynamics of ivacaftor in children aged 2-5 years.

METHODS:

In the two-part KIWI study, we enrolled children aged 2-5 years weighing 8 kg or more with a confirmed diagnosis of cystic fibrosis and a CFTR gating mutation on at least one allele from 15 hospitals in the USA, UK, and Canada. Participants received oral ivacaftor 50 mg (if bodyweight <14 kg) or 75 mg (if bodyweight ≥14 kg) every 12 h for 4 days in part A (to establish the short-term safety of doses for subsequent assessment in part B), and then for 24 weeks in part B (to assess safety and longer-term pharmacodynamics). Children could participate in both or just one part of the study. Primary outcomes were pharmacokinetics and safety, analysed in all patients who received at least one dose of ivacaftor. Secondary outcomes were absolute change from baseline in sweat chloride concentrations and bodyweight, body-mass index (BMI), and height Z scores, and pharmacokinetic parameter estimation of ivacaftor. This study is registered with ClinicalTrials.gov, number NCT01705145.

 FINDINGS:

Between Jan 8, 2013, and March 1, 2013, nine patients were enrolled onto part A of the study, all of whom completed the 4 day treatment period, and eight of whom took part in part B. Between June 28, 2013, and Sept 26, 2013, 34 patients were enrolled in part B, 33 of whom completed the 24 week treatment period. All patients received at least one dose of ivacaftor. Results of ivacaftor pharmacokinetics suggested that exposure was similar to that reported in adults (median Cmin were 536 ng/mL for the 50 mg dose; 580 ng/mL for the 75 mg dose; median ivacaftor AUC values were 9840 ng × h/mL and 10 200 ng × h/mL, respectively). Common adverse events in part B included cough (in 19 [56%] of 34 patients) and vomiting (in ten [29%]). Five (15%) patients had liver function test (LFT) results that were more than eight times higher than the upper limit of normal, four of whom had study drug interrupted, and one of whom had study drug discontinued. Six (18%) of 34 patients had seven serious adverse events; a raised concentration of transaminases was the only serious adverse event regarded as related to ivacaftor and the only adverse event that resulted in study treatment discontinuation. At week 24, in patients for whom we had data, sweat chloride had changed from baseline by a mean of -46·9 mmol/L (SD 26·2, p<0·0001), weight Z score by 0·2 (0·3; p<0·0001), BMI Z score by 0·4 (0·4, p<0·0001), and height Z score by -0·01 (0·3; p=0·84).

 INTERPRETATION:

Ivacaftor at doses of 50 mg and 75 mg seems to be safe in children aged 2-5 years with cystic fibrosis with a gating mutation followed up for 24 weeks, although the frequency of elevated LFTs suggests that monitoring should be frequent in young children, particularly those with a history of elevated LFTs. Results of an ongoing extension study assessing durability of these effects and longer-term safety are warranted.


Ataluren for the treatment of nonsense-mutation cystic fibrosis: a randomised, double-blind, placebo-controlled phase 3 trial.

 Kerem E1, Konstan MW2, De Boeck K3, Accurso FJ4, Sermet-Gaudelus I5, Wilschanski M1, Elborn JS6, Melotti P7, Bronsveld I8, Fajac I9, Malfroot A10, Rosenbluth DB11, Walker PA12, McColley SA13, Knoop C14, Quattrucci S15, Rietschel E16, Zeitlin PL17, Barth J18, Elfring GL18, Welch EM18, Branstrom A18, Spiegel RJ18, Peltz SW18, Ajayi T18, Rowe SM19; Cystic Fibrosis Ataluren Study Group.

Lancet Respir Med. 2014

BACKGROUND:

Ataluren was developed to restore functional protein production in genetic disorders caused by nonsense mutations, which are the cause of cystic fibrosis in 10% of patients. This trial was designed to assess the efficacy and safety of ataluren in patients with nonsense-mutation cystic fibrosis.

 METHODS:

This randomised, double-blind, placebo-controlled, phase 3 study enrolled patients from 36 sites in 11 countries in North America and Europe. Eligible patients with nonsense-mutation cystic fibrosis (aged ≥ 6 years; abnormal nasal potential difference; sweat chloride >40 mmol/L; forced expiratory volume in 1 s [FEV1] ≥ 40% and ≤ 90%) were randomly assigned by interactive response technology to receive oral ataluren (10 mg/kg in morning, 10 mg/kg midday, and 20 mg/kg in evening) or matching placebo for 48 weeks. Randomisation used a block size of four, stratified by age, chronic inhaled antibiotic use, and percent-predicted FEV1. The primary endpoint was relative change in percent-predicted FEV1 from baseline to week 48, analysed in all patients with a post-baseline spirometry measurement. This study is registered with ClinicalTrials.gov, number NCT00803205.

 FINDINGS:

Between Sept 8, 2009, and Nov 30, 2010, 238 patients were randomly assigned, of whom 116 in each treatment group had a valid post-baseline spirometry measurement. Relative change from baseline in percent-predicted FEV1 did not differ significantly between ataluren and placebo at week 48 (-2.5% vs -5.5%; difference 3.0% [95% CI -0.8 to 6.3]; p=0.12). The number of pulmonary exacerbations did not differ significantly between treatment groups (rate ratio 0.77 [95% CI 0.57-1.05]; p=0.0992). However, post-hoc analysis of the subgroup of patients not using chronic inhaled tobramycin showed a 5.7% difference (95% CI 1.5-10.1) in relative change from baseline in percent-predicted FEV1 between the ataluren and placebo groups at week 48 (-0.7% [-4.0 to 2.1] vs -6.4% [-9.8 to -3.7]; nominal p=0.0082), and fewer pulmonary exacerbations in the ataluern group (1.42 events [0.9-1.9] vs 2.18 events [1.6-2.7]; rate ratio 0.60 [0.42-0.86]; nominal p=0.0061). Safety profiles were generally similar for ataluren and placebo, except for the occurrence of increased creatinine concentrations (ie, acute kidney injury), which occurred in 18 (15%) of 118 patients in the ataluren group compared with one (<1%) of 120 patients in the placebo group. No life-threatening adverse events or deaths were reported in either group.

 INTERPRETATION:

Although ataluren did not improve lung function in the overall population of nonsense-mutation cystic fibrosis patients who received this treatment, it might be beneficial for patients not taking chronic inhaled tobramycin.

FISIOTERAPIA

Physical exercise recommendations improve postural changes found in children and adolescents withcystic fibrosis: a randomized controlled trial.

Schindel CS1Hommerding PX2Melo DA3Baptista RR4Marostica PJ5Donadio MV6.

J Pediatr. 2015 Mar;166(3):710-6.e2. doi: 10.1016/j.jpeds.2014.12.001. Epub 2015 Jan 13.

Abstract

OBJECTIVE:

To evaluate postural changes and the distribution of plantar pressures in patients with cystic fibrosis (CF). We also sought to evaluate the effects of an educational guideline for physical activity on body posture in children and adolescents with CF.

STUDY DESIGN:

This was a 2-phase study of individuals between age 7 and 20 years. Phase I was a cross-sectional study in which healthy subjects were selected for postural evaluation and baropodometry, aiming to perform a later comparison with patients with CF. In phase II, we performed a randomized controlled clinical trial to assess the influence of the exercise guideline on the postural changes. Patients were assigned to 2 groups: control and intervention. The intervention consisted of a handbook with instructions for aerobic exercise and stretching. Main outcomes were postural abnormalities, plantar pressure distribution, and lung function.

RESULTS:

In phase I, 34 patients with CF and 34 healthy matched individuals were included. No significant baseline differences were identified. Children with CF presented more postural deviations compared with healthy subjects (P < .05), as to alignment of the head, shoulder girdle, and pelvis, increased cervical lordosis, and lateral chest distance. In phase II (n = 34), there were no baseline differences between groups. The intervention caused (P < .05) a decrease in cervical lordosis, thoracic kyphosis, lumbar lordosis, lateral chest distance, and abdominal protrusion, as well as in the baropodometric mean pressure and contact area.

CONCLUSIONS:

Children and adolescents with CF present postural changes when compared with healthy individuals. The educational guideline for exercise practice helped to improve posture, preventing the progression of some postural disorders.

Copyright © 2015 Elsevier Inc. All rights reserved.

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Long-term multicentre randomised controlled study of high frequency chest wall oscillation versus positive expiratory pressure mask in cystic fibrosis.

McIlwaine MP1, Alarie N, Davidson GFLands LC, Ratjen F, Milner ROwen BAgnew JL.

Thorax. 2013 Aug;68(8):746-51. doi: 10.1136/thoraxjnl-2012-202915. Epub 2013 Feb 13.

Abstract

BACKGROUND:

Positive expiratory pressure (PEP) is the most commonly used method of airway clearance (AC) in Canada for patients withcystic fibrosis (CF) whereas, in some countries, high frequency chest wall oscillation (HFCWO) is the preferred form of AC. There have been no long-term studies comparing the efficacy of HFCWO and PEP in the CF population.

OBJECTIVES:

To determine the long-term efficacy of HFCWO compared with PEP mask therapy in the treatment of CF as measured by the number of pulmonary exacerbations (PEs).

METHODS:

A randomised controlled study was performed in 12 CF centres in Canada. After a 2-month washout period, subjects were randomised to perform either HFCWO or PEP mask therapy for 1 year.

RESULTS:

107 subjects were enrolled in the study; 51 were randomised to PEP and 56 to HFCWO. There were 19 dropouts within the study period, of which 16 occurred prior to or at the time of randomisation. There were significant differences between the groups in the mean number of PEs (1.14 for PEP vs 2.0 for HFCWO) and time to first PE (220 days for PEP vs 115 days for HFCWO, p=0.02). There was no significant difference in lung function, health-related quality of life scores or patient satisfaction scores between the two groups. PEP masktherapy required a shorter treatment time.

CONCLUSIONS:

The results of this study favour PEP and do not support the use of HFCWO as the primary form of AC in patients with CF.

CLINICAL TRIAL REGISTRATION NUMBER:

NCT00817180.

KEYWORDS:

Cystic Fibrosis; Health Economist

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INFECÇÃO / ANTIBIÓTICOS

Adaptation of Pseudomonas aeruginosa to the cystic fibrosis airway: an evolutionary perspective.

Folkesson A1, Jelsbak L, Yang LJohansen HK, Ciofu O, Høiby N, Molin S.

Nat Rev Microbiol. 2012 Dec;10(12):841-51. doi: 10.1038/nrmicro2907. Epub 2012 Nov 13.

Abstract

The airways of patients with cystic fibrosis (CF) are nearly always infected with many different microorganisms. This environment offers warm, humid and nutrient-rich conditions, but is also stressful owing to frequent antibiotic therapy and the host immune response. Pseudomonasaeruginosa is commonly isolated from the airways of patients with CF, where it most often establishes chronic infections that usually persist for the rest of the lives of the patients. This bacterium is a major cause of mortality and morbidity and has therefore been studied intensely. Here, we discuss how P. aeruginosa evolves from a state of early, recurrent intermittent colonization of the airways of patients with CF to a chronic infection state, and how this process offers opportunities to study bacterial evolution in natural environments. We believe that such studies are valuable not only for our understanding of bacterial evolution but also for the future development of new therapeutic strategies to treat severe chronic infections.

J Bras Pneumol. 2013 Jun-Aug;39(4):495-512. doi: 10.1590/S1806-37132013000400015.

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Pseudomonas aeruginosa infection in patients with cystic fibrosis: scientific evidence regarding clinical impact, diagnosis, and treatment.

Silva Filho LV1Ferreira Fde AReis FJBritto MCLevy CEClark ORibeiro JD.

Abstract

Evidence-based techniques have been increasingly used in the creation of clinical guidelines and the development of recommendations for medical practice. The use of levels of evidence allows the reader to identify the quality of scientific information that supports the recommendations made by experts. The objective of this review was to address current concepts related to the clinical impact, diagnosis, and treatment of Pseudomonas aeruginosa infections in patients with cystic fibrosis. For the preparation of this review, the authors defined a group of questions that would be answered in accordance with the principles of PICO-an acronym based on questions regarding the Patients of interest, Intervention being studied, Comparison of the intervention, and Outcome of interest. For each question, a structured review of the literature was performed using the Medline database in order to identify the studies with the methodological design most appropriate to answering the question. The questions were designed so that each of the authors could write a response. A first draft was prepared and discussed by the group. Recommendations were then made on the basis of the level of scientific evidence, in accordance with the classification system devised by the Oxford Centre for Evidence-Based Medicine, as well as the level of agreement among the members of the group.

PMID: 24068273

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Serology as a diagnostic tool for predicting initialPseudomonas aeruginosa acquisition in children withcystic fibrosis.

Daines C1, VanDeVanter D2Khan U3Emerson J4, Heltshe S4McNamara S4, Anstead M5, Langkamp M6, Doring G7, Ratjen F8Ramsey B4Gibson RL4Morgan W9Rosenfeld M4EPIC Investigators.

J Cyst Fibros. 2014 Sep;13(5):542-9. doi: 10.1016/j.jcf.2014.06.005. Epub 2014 Jul 11.

Abstract

RATIONALE:

Pseudomonas aeruginosa (Pa) serology could potentially be a useful adjunct to respiratory culture methods for the detection of initial or early Pa infection in patients with cystic fibrosis (CF).

OBJECTIVE:

To evaluate the utility of Pa serology to predict Pa isolation from respiratory (generally oropharyngeal) cultures in the subsequent 6 or 12 months among young children with CF from whom Pa had never been previously cultured. Pa serology was also evaluated in a group of healthy controls.

METHODS:

Children ≤ 12 years of age without prior isolation of Pa from respiratory cultures participating in the Early Pseudomonal Infection Control EPIC Observational Study (EPIC OBS) had annual serum samples for measurement of antibodies against alkaline protease, elastase and exotoxin A using a commercial kit; controls had a single serum sample. Logistic regression with generalized estimating equations was used to characterize associations between log10 serum antibody titers and first isolation of Pa from a respiratory culture within the subsequent 6 or 12 months, with adjustment for sex and age. Receiver operating characteristic curves were used to optimize antibody titer cutpoints by age group. The diagnostic properties of each antibody were estimated using these optimized cutpoints.

RESULTS:

Pa serology was evaluated in 582 children with CF (2084 serum samples) and 94 healthy controls. There was substantial overlap between serum antibody titers among controls, CF patients who did not acquire Pa (N = 261) and CF patients who did acquire Pa (N = 321). The maximum positive predictive value for first Pa positive culture within the ensuing 6 months was 76.2% and maximum negative predictive value was 72.1% for any antigen or combination of antigens; values were similar for 12 months.

CONCLUSIONS:

Pa serology does not appear useful for predicting first Pa positive oropharyngeal culture among young CF patients.

Copyright © 2014 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

KEYWORDS:

Cystic fibrosis; Pseudomonas; ROC curves; Serology

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Assessment of IgG antibodies to Pseudomonas aeruginosa in patients with cystic fibrosis by an enzyme-linked immunosorbent assay (ELISA).

Mauch RMRossi CLRibeiro JDRibeiro AFNolasco da Silva MTLevy CE.

Diagn Pathol. 2014 Aug 22;9:158. doi: 10.1186/s13000-014-0158-z.

Abstract

BACKGROUND:

The usefulness of serological tests for detection of P. aeruginosa pulmonary infection in cystic fibrosis (CF) is controversial. Here, we assessed the value of detecting anti-P. aeruginosa IgG by a quantitative enzyme-linked immunosorbent assay (ELISA) for identification of P. aeruginosa infection in patients with cystic fibrosis.

METHODS:

Serum concentrations of anti-P. aeruginosa IgG were assessed in 117 CF patients classified according to their P. aeruginosa colonization/infection status (never colonized; free of infection; intermittently colonized and chronically infected) and in 53 healthy subjects by the ELISA test standardized with the St-Ag:1-17 antigen.

RESULTS:

The rate of IgG seropositivity and the median of IgG concentrations of this antibody in patients chronically infected were significantly higher than those found in the other CF groups and in the healthy control group.

CONCLUSION:

Detection of anti-P. aeruginosa IgG can be an useful tool for identification of P. aeruginosa chronic infection in patients with CF.

VIRTUAL SLIDES:

The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_158.

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Clinical impact of Achromobacter xylosoxidans colonization/infection in patients with cystic fibrosis.

Firmida MC1Pereira RH2Silva EA3Marques EA1Lopes AJ1.

Braz J Med Biol Res. 2016;49(4). pii: S0100-879X2016000400703. doi: 10.1590/1414-431X20155097. Epub 2016 Feb 23.

Abstract

The rate of diagnosis of colonization/infection of the airways with Achromobacter xylosoxidans has increased in cystic fibrosis patients, but its clinical significance is still controversial. This retrospective, case-control study aimed to evaluate the clinical impact of A. xylosoxidans colonization/infection in cystic fibrosis patients. Individuals who were chronically colonized/infected (n=10), intermittently colonized/infected (n=15), and never colonized/infected with A. xylosoxidans (n=18) were retrospectively evaluated during two periods that were 2 years apart. Demographic characteristics, clinical data, lung function, and chronic bacterial co-colonization data were evaluated. Of the total study population, 87% were pediatric patients and 65.1% were female. Individuals chronically colonized/infected with A. xylosoxidans had decreased forced expiratory volume in 1 s (51.7% in the chronic colonization/infection group vs 82.7% in the intermittent colonization/infection group vs 76% in the never colonized/infected group). Compared with the other two groups, the rate of co-colonization with methicillin-resistant Staphylococcus aureus was higher in individuals chronically colonized/infected with A. xylosoxidans (P=0.002). Changes in lung function over 2 years in the three groups were not significant, although a trend toward a greater decrease in lung function was observed in the chronically colonized/infected group. Compared with the other two groups, there was a greater number of annual hospitalizations in patients chronically colonized/infected with A. xylosoxidans (P=0.033). In cystic fibrosis patients, there was an increased frequency of A. xylosoxidans colonization/infection in children, and lung function was reduced in patients who were chronically colonized/infected with A. xylosoxidans. Additionally, there were no differences in clinical outcomes during the 2-year period, except for an increased number of hospitalizations in patients with A. xylosoxidans.

PMID: 26909788

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Antibiotic management of methicillin-resistant Staphylococcus aureus–associated acute pulmonary exacerbations in cystic fibrosis.

Fusco NM1Toussaint KA2Prescott WA Jr3.

Ann Pharmacother. 2015 Apr;49(4):458-68. doi: 10.1177/1060028014567526. Epub 2015 Jan 12.

Abstract

OBJECTIVE:

To review the treatment of methicillin-resistant Staphylococcus aureus (MRSA)-associated acute pulmonary exacerbations (APEs) in cystic fibrosis (CF).

DATA SOURCES:

A search of PubMed, MEDLINE, Cochrane Library and Clinicaltrials.gov databases through November 2014 was conducted using the search terms Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, pulmonary exacerbations, and cystic fibrosis.

STUDY SELECTION AND DATA EXTRACTION:

All English-language research articles, case reports, and case series were evaluated. A total of 185 articles were identified related to MRSA and CF; 30 articles that studied treatments of MRSA APE in CF were included.

DATA SYNTHESIS:

The persistent presence of MRSA in the respiratory tract of patients with CF has been associated with higher morbidity and an increased risk of death. Limited clinical data exist supporting the efficacy of any specific antimicrobial currently available for the treatment of APE secondary to MRSA.

CONCLUSIONS:

Data extrapolated from other populations suggest that vancomycin and linezolid are appropriate first-line treatment options for the treatment of APE secondary to MRSA. Second-line options include doxycycline or minocycline and trimethoprim/sulfamethoxazole, each of which may be useful in patients coinfected with other respiratory pathogens, for which they may provide overlapping coverage. Ceftaroline and ceftobiprole are newer antibiotics that appear to have a potential role in the treatment of APE in CF, but the latter is not currently available to the US market. Although potentially useful, clindamycin is limited by high rates of resistance, telavancin is limited by its toxicity profile, and tigecycline is limited by a lack of demonstrated efficacy for infections that are similar to that seen in the CF population. Studies investigating the clinical utility of the above-cited antibiotics for APE in CF secondary to MRSA are desperately needed to broaden the treatment armamentarium for this medical condition.

Send to:

Cochrane Database Syst Rev. 2015 Feb 24;2:CD009650. doi: 10.1002/14651858.CD009650.pub3.

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Interventions for the eradication of meticillin-resistant Staphylococcus aureus (MRSA) in people with cystic fibrosis.

Lo DK1Hurley MN, Muhlebach MS, Smyth AR.

Abstract

BACKGROUND:

Cystic fibrosis is an inherited recessive disorder of chloride transport that is characterised by recurrent and persistent pulmonary infections from resistant organisms that result in lung function deterioration and early mortality in sufferers.Meticillin-resistantStaphylococcus aureus (MRSA) has emerged as, not only an important infection in long-term hospitalised patients, but also as a potentially harmful pathogen in cystic fibrosis, and has been increasing steadily in prevalence internationally. Chronic pulmonary infection with MRSA is thought to confer cystic fibrosis patients with a worse overall clinical outcome and, in particular, result in an increased rate of decline in lung function. Clear guidance for the eradication of MRSA in cystic fibrosis, supported by robust evidence from good quality trials, is urgently needed.

OBJECTIVES:

To evaluate the effectiveness of treatment regimens designed to eradicate MRSA and to determine whether the eradication ofMRSA confers better clinical and microbiological outcomes for people with cystic fibrosis.

SEARCH METHODS:

Randomised and quasi-randomised controlled trials were identified by searching the Cochrane Cystic Fibrosis and Genetic Disorders Group’s Cystic Fibrosis Trials Register, PUBMED, MEDLINE, Embase, handsearching article reference lists and through contact with local and international experts in the field.Date of the last search of the Group’s Cystic Fibrosis Trials Register: 04 September 2014.

SELECTION CRITERIA:

Randomised or quasi-randomised controlled trials comparing any combinations of topical, inhaled, oral or intravenous antimicrobials with the primary aim of eradicating MRSA compared with placebo, standard treatment or no treatment.

DATA COLLECTION AND ANALYSIS:

The authors independently assessed all search results for eligibility. No eligible trials were identified for inclusion.

MAIN RESULTS:

No current published eligible trials were identified, although three ongoing clinical trials are likely to be eligible for inclusion in future updates of this review.

AUTHORS’ CONCLUSIONS:

We did not identify any randomised trials which would allow us to make any evidence-based recommendations. Although the results of several non-randomised studies would suggest that, once isolated, the eradication of MRSA is possible; whether this has a significant impact on clinical outcome is still unclear. Further research is required to guide clinical decision making in the management of MRSA infection in cystic fibrosis.

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Classification and identification of the Burkholderia cepacia complex: Past, present and future.

Vandamme P1, Dawyndt P.

Syst Appl Microbiol. 2011 Apr;34(2):87-95. doi: 10.1016/j.syapm.2010.10.002. Epub 2011 Jan 22.

Abstract

The Burkholderia cepacia complex is a group of closely related species with conflicting biological properties. Triggered by the devastating effect of pulmonary infections in cystic fibrosis patients, the scientific community generated an unusually large amount of taxonomic data for these bacteria during the past 15 years. This review presents the polyphasic, multilocus and genomic methodology used for the classification and identification of these bacteria. The current state-of-the-art demonstrates that present day taxonomists can replace traditional DNA-DNA hybridizations for species level demarcation and 16S rRNA sequence analysis for studying phylogeny by superior whole genome sequence-based parameters within the framework of polyphasic taxonomic studies.

Copyright © 2010 Elsevier GmbH. All rights reserved.

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Antibiotic treatment for Burkholderia cepacia complex in people with cystic fibrosis experiencing a pulmonary exacerbation.

Horsley A1Jones AMLord R.

Cochrane Database Syst Rev. 2016 Jan 20;1:CD009529. doi: 10.1002/14651858.CD009529.pub3.

Abstract

BACKGROUND:

Chronic pulmonary infection is a hallmark of lung disease in cystic fibrosis. Infections dominated by organisms of theBurkholderia cepacia complex, a group of at least 18 closely-related species of gram-negative bacteria, are particularly difficult to treat. These infections may be associated with a fulminant necrotising pneumonia. Burkholderia cepacia complex bacteria are resistant to many common antibiotics and able to acquire resistance against many more. Following patient segregation in cystic fibrosis medical care, the more virulent epidemic strains are not as frequent, and new infections are more likely to be with less virulent environmentally-acquired strains. Although evidence-based guidelines exist for treating respiratory exacerbations involving Pseudomonas aeruginosa, these cannot be extended toBurkholderia cepacia complex infections. This review, which is an update of a previous review, aims to assess the available trial evidence for the choice and application of treatments for these infections.

OBJECTIVES:

To assess the effectiveness and safety of different antibiotic regimens in people with cystic fibrosis experiencing an exacerbation and chronically infected with organisms of the Burkholderia cepacia complex.

SEARCH METHODS:

We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched the reference lists of relevant articles and reviews.Date of latest search: 28 August 2015.

SELECTION CRITERIA:

Randomised and quasi-randomised controlled trials of treatments for exacerbations of pulmonary symptoms in people with cystic fibrosis chronically infected with organisms of the Burkholderia cepacia complex.

DATA COLLECTION AND ANALYSIS:

No relevant trials were identified.

MAIN RESULTS:

No trials were included in this review.

AUTHORS’ CONCLUSIONS:

Burkholderia cepacia complex infections present a significant challenge for people with cystic fibrosis and their clinicians. The incidence is likely to increase as the cystic fibrosis population ages; and managing and treating these infections will become more important. There is a lack of trial evidence to guide decision making and no conclusions can be drawn from this review about the optimal antibiotic regimens for people with cystic fibrosis who have chronic Burkholderia cepacia complex infections. Clinicians must continue to assess each person individually, taking into account in vitro antibiotic susceptibility data, previous clinical responses and their own experience. Multicentre randomised clinical trials are needed to assess the effectiveness of different antibiotic regimens in people with cystic fibrosisinfected with organisms of the Burkholderia cepacia complex.

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GENÉTICA / FISIOPATOLOGIA

Origins of cystic fibrosis lung disease.

Stoltz DA, Meyerholz DK, Welsh MJ.

N Engl J Med. 2015 Jan 22;372(4):351-62. doi: 10.1056/NEJMra1300109.

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Cystic fibrosis genetics: from molecular understanding to clinical application.

Cutting GR1.

Nat Rev Genet. 2015 Jan;16(1):45-56. doi: 10.1038/nrg3849. Epub 2014 Nov 18.

Abstract

The availability of the human genome sequence and tools for interrogating individual genomes provide an unprecedented opportunity to applygenetics to medicine. Mendelian conditions, which are caused by dysfunction of a single gene, offer powerful examples that illustrate howgenetics can provide insights into disease. Cystic fibrosis, one of the more common lethal autosomal recessive Mendelian disorders, is presented here as an example. Recent progress in elucidating disease mechanism and causes of phenotypic variation, as well as in the development of treatments, demonstrates that genetics continues to play an important part in cystic fibrosis research 25 years after the discovery of the disease-causing gene.

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CFTR allelic heterogeneity in Brazil: historical and geographical perspectives and implications for screening and counseling for cystic fibrosis in this country.

Faucz FR1Souza DA, Olandoski M, Raskin S.

J Hum Genet. 2010 Feb;55(2):71-6. doi: 10.1038/jhg.2009.123. Epub 2009 Nov 27.

Abstract

The goal of the present study was to provide a complete and updated spectrum of cystic fibrosis (CF) transmembrane conductance regulator (CFTR) gene mutations in the Brazilian population combining all available in silico data for patients with CF in Brazil, including founder background and migration flow that consisted of the actual genetic pool of the Brazilian population. Information sources in international databases (PUBMED and SCIELO) were searched. The Brazilian population shows a wide variation in the frequency of CFTR mutations in states Rio Grande do Sul (RS), Santa Catarina (SC), Paraná (PR), São Paulo (SP), Rio de Janeiro (RJ), Minas Gerais (MG), Pará (PA) and Bahia (BA); this variation includes the most common mutation p.F508del. Apparently, this frequency variation is because of the different ethnic compositions. States such as SC and PR have a greater European admixture with almost 90% of CF alleles identified. In other states, such as BA, higher frequency of alleles that are common among African populations is seen. Overall, the CFTR mutational spectrum indicates the presence of European, African and Amerindian ethnic groups in the contemporary Brazilian CF patients. Here, we present an analysis of the CFTR allelic heterogeneity and discuss the origin of its genetic composition, in an attempt to provide improved perspective for the CF population screening in Brazil and genetic counseling.

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Cystic fibrosis transmembrane conductance regulator mutations at a referral center for cystic fibrosis.

Coutinho CA1Marson FARibeiro AFRibeiro JD, Bertuzzo CS.

J Bras Pneumol. 2013 Sep-Oct;39(5):555-61. doi: 10.1590/S1806-37132013000500005.

Abstract

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.

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DIAGNÓSTICO

Sweat conductivity: an accurate diagnostic test for cystic fibrosis?

Mattar AC1Leone C2Rodrigues JC3, Adde FV4.

J Cyst Fibros. 2014 Sep;13(5):528-33. doi: 10.1016/j.jcf.2014.01.002. Epub 2014 Jan 31.

Abstract

BACKGROUND:

Sweat chloride test is the gold standard test for cystic fibrosis (CF) diagnosis. Sweat conductivity is widely used although still considered a screening test.

METHODS:

This was a prospective, cross-sectional, diagnostic research conducted at the laboratory of the Instituto da Criança of the Hospital das Clínicas, São Paulo, Brazil. Sweat chloride (quantitative pilocarpine iontophoresis) and sweat conductivity tests were simultaneously performed in patients referred for a sweat test between March 2007 and October 2008. Conductivity and chloride cut-off values used to rule out or diagnose CF were <75 and ≥90 mmol/L and <60 and ≥60 mmol/L, respectively. The ROC curve method was used to calculate the sensitivity, specificity, positive (PPV) and negative predictive value (NPV), as well as the respective 95% confidence intervals and to calculate the area under the curve for both tests. The kappa coefficient was used to evaluate agreement between the tests.

RESULTS:

Both tests were performed in 738 children, and CF was ruled out in 714 subjects; the median sweat chloride and conductivity values were 11 and 25 mmol/L in these populations, respectively. Twenty-four patients who had received a diagnosis of CF presented mediansweat chloride and conductivity values of 87 and 103 mmol/L, respectively. Conductivity values above 90 mmol/L had 83.3% sensitivity, 99.7% specificity, 90.9% PPV and 99.4% NPV to diagnose CF. The best conductivity cut-off value to exclude CF was <75 mmol/L. Good agreement was observed between the tests (kappa: 0.934).

CONCLUSIONS:

The sweat conductivity test yielded a high degree of diagnostic accuracy and it showed good agreement with sweat chloride. We suggest that it should play a role as a diagnostic test for CF in the near future.

Copyright © 2014 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

KEYWORDS:

Conductivity; Cystic fibrosis; Pilocarpine; Sweat test

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Sweat conductivity and coulometric quantitative test in neonatal cystic fibrosis screening.

Domingos MT1Magdalena NI2, Cat MN2Watanabe AM3Rosário Filho NA2.

J Pediatr (Rio J). 2015 Nov-Dec;91(6):590-5. doi: 10.1016/j.jped.2015.03.003. Epub 2015 Jun 16.

Abstract

OBJECTIVE:

To compare the results obtained with the sweat test using the conductivity method and coulometric measurement of sweat chloride in newborns (NBs) with suspected cystic fibrosis (CF) in the neonatal screening program.

METHODS:

The sweat test was performed simultaneously by both methods in children with and without CF. The cutoff values to confirm CF were >50 mmol/L in the conductivity and >60 mmol/L in the coulometric test.

RESULTS:

There were 444 infants without CF (185 males, 234 females, and 24 unreported) submitted to the sweat test through conductivity and coulometric measurement simultaneously, obtaining median results of 32 mmol/L and 12 mmol/L, respectively. For 90 infants with CF, the median values of conductivity and coulometric measurement were 108 mmol/L and 97 mmol/L, respectively. The false positive rate for conductivity was 16.7%, and was higher than 50 mmol/L in all patients with CF, which gives this method a sensitivity of 100% (95% CI: 93.8-97.8), specificity of 96.2% (95% CI: 93.8-97.8), positive predictive value of 83.3% (95% CI: 74.4-91.1), negative predictive value of 100% (95% CI: 90.5-109.4), and 9.8% accuracy. The correlation between the methods was r=0.97 (p>0.001). The best suggested cutoff value was 69.0 mmol/L, with a kappa coefficient=0.89.

CONCLUSION:

The conductivity test showed excellent correlation with the quantitative coulometric test, high sensitivity and specificity, and can be used in the diagnosis of CF in children detected through newborn screening.

Copyright © 2015 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.

KEYWORDS:

Conductivity; Condutividade; Coulometric measurement; Cystic fibrosis; Dosagem coulométrica; Fibrose cística; Neonatal screening; Pilocarpina; Pilocarpine; Sweat test; Teste do suor; Triagem neonatal.

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Pulsed direct and constant direct currents in the pilocarpine iontophoresis sweat chloride test.

Gomez CC1, Servidoni Mde F, Marson FA, Canavezi PJ, Vinagre AMCosta ETRibeiro AFRibeiro MAToro AA, Pavan CR, Rondon MVLorena SL,Vieria FU JrRibeiro JD.

BMC Pulm Med. 2014 Dec 13;14:198. doi: 10.1186/1471-2466-14-198.

Abstract

BACKGROUND:

The classic sweat test (CST) is the golden standard for cystic fibrosis (CF) diagnosis. Then, our aim was compare the production and volume of sweat, and side effects caused by pulsed direct current (PDC) and constant direct current (CDC). To determine the optimal stimulation time (ST) for the sweat collection. To verify the PDC as CF diagnosis option.

METHODS:

Prospective study with cross-sectional experimental intervention. Experiment 1 (right arm): PDC and CDC. ST at 10 min and sweat collected at 30 min. Currents of 0.5; 0.75; 1.0 and 1.5 mA and frequencies of 0, 200, 1,000 and 5,000 Hz applied. Experiment 2 (left arm): current of 1.0 mA, ST at 5 and 10 min and sweat collected at 15 and 30 min with frequencies of 0; 200; 1,000 and 5,000 Hz applied Experiments 1 and 2 were performed with current density (CD) from 0.07 to 0.21 mA/cm2. Experiment 3: PDC was used in typical CF patients with two CFTR mutations screened and or with CF diagnosis by rectal biopsy and patients with atypical CF.

RESULTS:

48 subjects (79.16% female) with average of 29.54 ± 8.87 years old were enrolled. There was no statistical difference between the interaction of frequency and current in the sweat weight (p = 0.7488). Individually, positive association was achieved between weight sweat and stimulation frequency (p = 0.0088); and current (p = 0.0025). The sweat production was higher for 10 min of stimulation (p = 0.0023). The sweat collection was better for 30 min (p = 0.0019). The skin impedance was not influenced by ST and sweat collection (p > 0.05). The current frequency was inversely associated with the skin impedance (p < 0.0001). The skin temperature measured before stimulation was higher than after (p < 0.0001). In Experiment 3 (29 subjects) the PDC showed better kappa index compared to CDC (0.9218 versus 0.5205, respectively).

CONCLUSIONS:

The performance of the CST with CDC and PDC with CD of 0.14 to 0.21 mA/cm2 showed efficacy in steps of stimulation and collection of sweat, without side effects. The optimal stimulation time and sweat collection were, respectively, 10 and 30 min.

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Repeatability and Diagnostic Value of Nasal Potential Difference in a Genetically Admixed Population.

Sad IR1Higa LY1Leal T2Martins Rda S1de Almeida AC3Ramos EG4de Cabello GM5Peixoto MV3.

J Clin Med Res. 2016 Jan;8(1):15-24. doi: 10.14740/jocmr2312w. Epub 2015 Dec 3.

Abstract

BACKGROUND:

The genetic diversity of the Brazilian population results from three ethnic groups admixture: Europeans, Africans and Amerindians, thus increasing the difficulty of performing cystic fibrosis (CF) diagnosis. The nasal potential difference (NPD) evaluates thecystic fibrosis transmembrane conductance regulator (CFTR) and epithelial sodium channel (ENaC) activity. Despite being a useful CF diagnostic test and a biomarker of CFTR-modulator drugs, it is also highly operator dependent. Therefore, it may be difficult to get accurate results and to interpret them. Wilschanski and Sermet scores were proposed to address these issues. This study aimed to evaluate repeatability and diagnostic value of NPD parameters and Wilschanski and Sermet scores in a CF center in Rio de Janeiro.

METHODS:

NPD was performed in 78 subjects. Maximal PD, amiloride response, total chloride response, and Wilschanski and Sermet scores were explored as means (confidence interval, CI). One-way ANOVA was used to compare mean differences and Scheffe test was used to pair-wise comparisons. Repeatability was evaluated by scatter and Bland-Altman plots. The Ethics Committee of the CF Center has approved the study protocol. Parents and adult participants signed an informed consent form.

RESULTS:

Forty-eight healthy-volunteers, 19 non-CF and 11 CF patients were enrolled in this study. Significant differences were found when comparing CF patients’ NPD parameters to the other two groups (P = 0.000). Moreover, no significant differences were found when parameters from non-CF patients were compared with those from healthy volunteers (P > 0.05). The means of NPD parameters and diagnostic scores of each group were in concordance with disease/non-disease conditions. The repeatability data – Wilschanski and Sermet and NPD – allow NPD to be performed in this Brazilian CF Center.

CONCLUSIONS:

The present study gathered consistent data for Bland-Altman plots. The results of Wilschanski and Sermet diagnostic scores suggest that they were concordant with CF/non-CF conditions. More NPD tests should be performed in the Rio de Janeiro CF dynamic cohort to contribute to international NPD validation studies and to provide NPD as a biomarker in Brazil.

KEYWORDS:

Cystic fibrosis; Diagnostic test; Nasal potential difference; Repeatability; Sermet score; Wilschanski index

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Rectal forceps biopsy procedure in cystic fibrosis: technical aspects and patients perspective for clinical trials feasibility

Servidoni MFSousa MVinagre AMCardoso SRRibeiro MAMeirelles LRde Carvalho RB, Kunzelmann K, Ribeiro AFRibeiro JDAmaral MD.

BMC Gastroenterol. 2013 May 20;13:91. doi: 10.1186/1471-230X-13-91.

Abstract

BACKGROUND:

Measurements of CFTR function in rectal biopsies ex vivo have been used for diagnosis and prognosis of Cystic Fibrosis(CF) disease. Here, we aimed to evaluate this procedure regarding: i) viability of the rectal specimens obtained by biopsy forceps for ex vivo bioelectrical and biochemical laboratory analyses; and ii) overall assessment (comfort, invasiveness, pain, sedation requirement, etc.) of the rectal forceps biopsy procedure from the patients perspective to assess its feasibility as an outcome measure in clinical trials.

METHODS:

We compared three bowel preparation solutions (NaCl 0.9%, glycerol 12%, mannitol), and two biopsy forceps (standard and jumbo) in 580 rectal specimens from 132 individuals (CF and non-CF). Assessment of the overall rectal biopsy procedure (obtained by biopsy forceps) by patients was carried out by telephone surveys to 75 individuals who underwent the sigmoidoscopy procedure.

RESULTS:

Integrity and friability of the tissue specimens correlate with their transepithelial resistance (r = -0.438 and -0.305, respectively) and are influenced by the bowel preparation solution and biopsy forceps used, being NaCl and jumbo forceps the most compatible methods with the electrophysiological analysis. The great majority of the individuals (76%) did not report major discomfort due to the short procedure time (max 15 min) and considered it relatively painless (79%). Importantly, most (88%) accept repeating it at least for one more time and 53% for more than 4 times.

CONCLUSIONS:

Obtaining rectal biopsies with a flexible endoscope and jumbo forceps after bowel preparation with NaCl solution is a safe procedure that can be adopted for both adults and children of any age, yielding viable specimens for CFTR bioelectrical/biochemical analyses. The procedure is well tolerated by patients, demonstrating its feasibility as an outcome measure in clinical trials.

PMID: 23688510

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NUTRIÇÃO / GASTROENTEROLOGIA

Nutrition Status Parameters and Hydration Status by Bioelectrical Impedance Vector Analysis Were Associated With Lung Function Impairment in Children and Adolescents With Cystic Fibrosis.

Hauschild DB1Barbosa E2Moreira EA1Ludwig Neto N2Platt VB2Filho EP2, Wazlawik E1Moreno YM3.

Nutr Clin Pract. 2016 Feb 26. pii: 0884533615627157. [Epub ahead of print]

Abstract

BACKGROUND:

(1) To compare nutrition and hydration status between a group of children/adolescents with cystic fibrosis (CFG; n = 46; median age, 8.5 years) and a control group without cystic fibrosis (CG). (2) To examine the association of nutrition and hydration status with lung function in the CFG.

MATERIAL AND METHODS:

A cross-sectional study. Nutrition screening, anthropometric parameters, and bioelectrical impedance analysis (BIA) were assessed. The z scores for body mass index for age, height for age, mid upper arm circumference, triceps and subscapular skinfold thickness, mid upper arm muscle area, resistance/height, and reactance/height were calculated. Bioelectrical impedance vector analysis was conducted. Forced expiratory volume in 1 second <80% was considered lung function impairment. An adjusted logistic regression was applied (P < .05).

RESULTS:

In the CFG, lung function impairment was observed in 51.1%. All anthropometric parameters were lower, and the mean z-resistance/height and z-reactance/height were higher in the CFG (P < .05) compared with the CG. In the CFG, 43% were severely/mildly dehydrated, while none were in the CG (P = .007). In the CFG, there was an association between high nutrition risk-via nutrition screening (odds ratio [OR], 22.28; P < .05), lower values of anthropometric parameters, higher z-resistance/height (OR, 2.23; P < .05) and z-reactance/height (OR, 1.81; P < .05), and dehydration (OR, 4.94; P < .05)-and lung function impairment.

CONCLUSIONS:

The CFG exhibited a compromised nutrition status assessed by anthropometric and BIA parameters. Nutrition screening, anthropometric and BIA parameters, and hydration status were associated with lung function.

© 2016 American Society for Parenteral and Enteral Nutrition.

KEYWORDS:

cystic fibrosis; electrical impedance; forced expiratory volume; nutrition assessment; nutrition status; pediatrics

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Nutritional status of adolescents with cystic fibrosis treated at a reference center in the southeast region of Brazil

Del Ciampo IR1,2Del Ciampo LA3, Sawamura R3de Oliveira LR4Fernandes MI3.

Ital J Pediatr. 2015 Jul 30;41:51. doi: 10.1186/s13052-015-0159-x.

Abstract

BACKGROUND:

Several factors can interfere with the full physical and emotional growth of adolescents, among them chronic diseases. The aim was to determine the nutritional status of adolescents and to associate it with puberty, pancreatic sufficiency, lung function and age range of Cystic Fibrosis (CF) diagnosis.

METHODS:

An observational, cross-sectional, retrospective and analytical study was conducted using the data of medical records.

SETTING:

Reference center in the northeastern region of the state of São Paulo – Brazil.

PATIENTS:

All adolescents with CF attended in 2010 were included. Some variables included: pancreatic sufficiency (steatocrit >2 %), pancreatic enzymes replacement (yes/no), pubertal status-Tanner criteria (prepubertal: M1/G1, pubertal: M2/G2 to M4/G4, postpubertal: M5/G5), age at CF diagnosis (<2 and ≥2 years of age), Lung function, measured as a predicted forced expiratory volume in 1 s (FEV1). Main outcome measures Nutritional indicators: body mass index for age (BMI/A) and height for age (H/A) with z-score calculated with Anthro Plus software. Cut-off reference points: ≥ z-score -3 and < z-score -2 (thinness); z-score -2 and ≤ z-score-z +1 (normal weight); >z-score +1 (overweight or obesity), and z-score <-2 (low or very low H/A). The groups were compared by the Kruskal-Wallis test. Level of significance: p<0.05.

RESULTS:

Thirty adolescents. Median (min;max) age: 14.4 (10.1;19.8) years. BMI/A and H/A z-score, respectively: early diagnosis of CF (-0.8; -1.1) or late diagnosis of CF (-0.5;-0.8); with pancreatic insufficiency (-0.7; -0.8) or without pancreatic insufficiency (-0.8; -0.5) and prepubertal (-0.8; -0.7) pubertal (-0.2; -1.5) or postpubertal (-0.7; -0.5). No significant difference (p>0.05) was observed. Patients with and without pancreatic insufficiency, presented H/A borderline z-score (p=0.05). Association between H/A and FEV1 was borderline (p=0.05).

CONCLUSIONS:

Adolescents presented adequate nutritional status, although with slightly lower values than those of developed countries. FEV1 lower levels occurred more frequently in adolescents with low H/A.

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Relationship between body balance, lung function, nutritional status and functional capacity in adults withcystic fibrosis.

Penafortes JT1Guimarães FSMoço VJAlmeida VPMenezes SLLopes AJ.

Braz J Phys Ther. 2013 Sep-Oct;17(5):450-7. doi: 10.1590/S1413-35552012005000111. Epub 2013 Sep 10.

Abstract

BACKGROUND:

Cystic fibrosis (CF) is a hereditary condition in which lung disease affects all patients. In addition to pulmonary involvement, the multisystemic components of CF cause significant physical limitations. However, the impact of lung function on balance control in CF has not been studied.

OBJECTIVE:

To assess body balance in adults with CF and to test its possible associations with lung function, nutritional status, and functional capacity.

METHOD:

This was a cross-sectional study in which 14 adults with CF underwent pulmonary function testing (spirometry, body plethysmography, and carbon monoxide diffusing capacity (DLco), respiratory muscle strength, 6-min walking distance (6MWD), Berg balance scale (BBS), nutritional analysis (body mass index and bioelectrical impedance), and stabilometry. Body balance was quantified using stabilometry; all participants performed the following two trials: opened base, eyes open (OBEO); closed base, eyes closed (CBEC).

RESULTS:

In stabilometry, the median for the lateral range and anterior-posterior range in the CBEC trial was 0.10 (0.08-0.11) and 0.13 (0.11-0.22), respectively (p<0.05). The maximal inspiratory pressure (MIP) correlated inversely with the lateral standard deviation (ρ=-0.61; p<0.05) as the DLco correlated positively with the anterior-posterior range (ρ=0.54; p<0.05). There were significant relationships between body composition indexes and almost all stabilometric variables measured. There were no relationships of the BBS and 6MWD with the stabilometric variables.

CONCLUSIONS:

In adults with CF, imbalance occurs mainly in the anterior-posterior direction and is especially associated with body composition.

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Association of nutritional status, plasma, albumin levels and pulmonary function in cystic fibrosis.

Souza dos Santos Simon MI1, Drehmer M, de Abreu E Silva FAHoffmann A, Druck Ricachinewsky C, de Fonseca Andrade Procianoy E, Scattolin I,Saldanha Menna Barreto S.

Nutr Hosp. 2011 Nov-Dec;26(6):1322-7. doi: 10.1590/S0212-16112011000600019.

Abstract

BACKGROUND & AIMS:

Malnutrition is related with pulmonary disease. The aim was to analyze the association of lung function respectively to nutritional status, identified pulmonary pathogens and socioeconomic condition of patients attending a pediatric CF reference center.

METHODS:

Cross-sectional study performed with CF patients aged 6 to 18 years attending a CF-Center in southern Brazil. Nutritional status, plasma albumin level and pulmonary bacterial colonization were assessed. The outcome studied was forced expiratory volume in 1 second (FEV1).

RESULTS:

Eighty-five patients were included in this study. FEV1 was significantly associated with body mass index (BMI) percentiles, plasma albumin level and methicillin resistant Staphylococcus aureus (MRSA) pulmonary colonization. Regression analysis showed that BMI below the 10th percentile was associated with a 25.58% drop in FEV1, and plasma albumin levels equal to or lower than 4.1 mg/dL was associated with 18.6% FEV1 reduction. FEV1 was 14.4% lower in the MRSA infected patients. Plasma albumin of 4.25 mg/dL predicted FEV1 of 60% with 76.9% sensitivity and 72.2% specificity, and 85.7% accuracy. The socioeconomic status was not association with pulmonary function.

CONCLUSION:

BMI below the 10th percentile and albumin below 4.1 mg/dL were predictors of low FEV1. Chronic MRSA infection was associated with lower FEV1. Longitudinal studies may better complement these results.

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Management of endocrine disease: Cystic fibrosis-related diabetes: novel pathogenic insights opening new therapeutic avenues

Barrio R1.

Eur J Endocrinol. 2015 Apr;172(4):R131-41. doi: 10.1530/EJE-14-0644. Epub 2014 Oct 21.

Abstract

Cystic fibrosis (CF) is a recessive genetic disease caused by mutations in the CF transmembrane conductance regulator (CFTR). CFTR is primarily present in epithelial cells of the airways, intestine and in cells with exocrine and endocrine functions. Mutations in the gene encoding the channel protein complex (CFTR) cause alterations in the ionic composition of secretions from the lung, gastrointestinal tract, liver, and also the pancreas. CF-related diabetes (CFRD), the most common complication of CF, has a major detrimental impact on pulmonary function, nutrition and survival. Glucose derangements in CF seem to start from early infancy and, even when the pathophysiology is multifactorial, insulin insufficiency is clearly a major component. Consistently, recent evidence has confirmed that CFTR is an important regulator of insulin secretion by islet β-cells. In addition, several other mechanisms were also recognized from cellular and animals models also contributing to either β-cell mass reduction or β-cell malfunction. Understanding such mechanisms is crucial for the development of the so-called ‘transformational’ therapies in CF, including the preservation of insulin secretion. Innovative therapeutic approaches aim to modify specific CFTR mutant proteins or positively modulate their function. CFTR modulators have recently shown in vitro capacity to enhance insulin secretion and thereby potential clinical utility in CFDR, including synergistic effects between corrector and potentiator drugs. The introduction of incretins and the optimization of exocrine pancreatic replacement complete the number of therapeutic options of CFRD besides early diagnosis and implementation of insulin therapy. This review focuses on the recently identified pathogenic mechanisms leading to CFRD relevant for the development of novel pharmacological avenues in CFRD therapy.

© 2015 European Society of Endocrinology.

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