Chloride Conductance, Nasal Potential Difference and Cystic Fibrosis Pathophysiology.

PURPOSE: Cystic fibrosis (CF) is a multisystem genetic disease caused by dysfunction of the epithelial anionic channel Cystic Fibrosis Transmembrane conductance Regulator (CFTR). Decreased mucociliary clearance because of thickened mucus is part of the pulmonary disease pathophysiology. It is controversial if the thickened airway surface liquid (ASL) is caused by the deficient chloride secretion and excessive sodium (through ENaC) and water hyperabsorption from the periciliar fluid or by the lack of bicarbonate secretion with relative acidification of the ASL. Correlations between the magnitude of in vivo chloride conductance with phenotypic characteristics and CF genotype can help to elucidate these mechanisms and direct to new treatments. METHODS: Nasal potential difference was measured in 28 CF patients (age from 0.3 to 28 year) and correlated with pulmonary function, pancreatic phenotype, pulmonary colonization and genotype severity. RESULTS: The CFTR-chloride conductance was better in older patients (r = 0.40; P = 0.03), in patients with better pulmonary function (r = 0.48; P = 0.01), and was associated with genotype severity. Higher chloride diffusion in the presence of a favorable chemical gradient was associated with Pseudomonas aeruginosa negativity (P < 0.05). More negative NPDmax was associated with pancreatic insufficiency (P < 0.01) as well with genotype severity, but not with the pulmonary function. CONCLUSIONS: The anion permeability through CFTR, mainly chloride, but bicarbonate as well, is the most critical factor in CF airway pathophysiology. Treatments primarily directed to correct CFTR function and/or airway acidity are clearly a priority.

Glucose intolerance in patients with cystic fibrosis: sex-based differences in clinical score, pulmonary function, radiograph score, and 6-minute walk test.

OBJECTIVE: To determine the sex-specific relationships between glucose intolerance and Shwachman-Kulczycki clinical score, lung function, Brasfield chest-radiograph score, and exercise capacity in patients with cystic fibrosis (CF). METHODS: We used a cross-sectional study design and included CF patients ≥ 10 years old. All patients had clinical and nutritional evaluation, oral glucose tolerance test, spirometry, chest radiograph, and 6-min walk test (6MWT). Patients were classified as having normal glucose tolerance, impaired glucose tolerance, or CF-related diabetes mellitus. RESULTS: We included 88 patients: 59 with normal glucose tolerance, 15 with impaired glucose tolerance, and 14 with CF-related diabetes. Shwachman-Kulczycki clinical score (P = .04), at-rest S(pO(2)) (P = .001), S(pO(2)) difference before versus after 6MWT (P = .001), and Brasfield chest-radiograph score (P = .01) were significantly lower in the impaired-glucose-tolerance group than in the normal-glucose-tolerance group, but did not differ from the CF-related-diabetes group. In female patients only, percent-of-predicted FEV(1) was significantly lower in the impaired-glucose-tolerance group than in the normal-glucose-tolerance group (P = .02), but did not differ from the CF-related-diabetes group (P = .10). There was a significant relationship between glucose intolerance and sex when clinical score, 6-min walk distance, FEV(1), and radiograph score were combined in a multivariate analysis. CONCLUSIONS: In patients with CF, glucose intolerance was associated with poor clinical score, lower at-rest S(pO(2)), greater S(pO(2)) difference before versus after 6MWT, poor lung function, and lower radiograph score. Overall, multivariate analysis indicated poorer performance in the latter variables in female patients with glucose intolerance than in male patients with glucose intolerance.

Sleep-disordered breathing in patients with cystic fibrosis.

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-1ß 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 (ß = -0.386; p = 0.014); SpO2 (ß = -0.453; p = 0.005), and the Epworth Sleepiness Scale score (ß = 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.

Low-level resistance and clonal diversity of Pseudomonas aeruginosa among chronically colonized cystic fibrosis patients.

A prospective study was conducted in Brazil to evaluate antimicrobial resistance patterns and molecular epidemiology of Pseudomonas aeruginosa isolates from cystic fibrosis (CF) patients with chronic lung infection. All isolates were obtained between May 2009 and June 2010 from 75 patients seen in four reference centers in Brazil: HCPA (20 patients) and HEOM (15 patients), located in southern and northeastern Brazil, respectively; IFF (20 patients) and HUPE (20 patients), both in southwestern Brazil. Antimicrobial susceptibility testing, PCR for detection of carpapenemases, and pulsed-field gel electrophoresis (PFGE) were performed in 274 isolates. A total of 224 PFGE types were identified and no clones were found circulating among the centers or within the same center. Despite the chronic infection, most patients were colonized by intermittent clones. Only three patients (4%) maintained the same clone during the study. The resistance rates were lower than 30% for the majority of antimicrobials tested in all centers and only 17% of isolates were multiresistant. Isolates (n = 54) with reduced susceptibility to imipenem and/or meropenem presented negative results for blaSPM-1, blaIMP-1, blaVIM , and blaKPC genes. Our results indicate an unexpected low level of antimicrobial resistance and a high genotypic diversity among P. aeruginosa from Brazilian chronic CF patients.

Cystic fibrosis in adults: diagnostic and therapeutic aspects.

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.

Comparison among pulmonary function test results, the Shwachman-Kulczycki score and the Brasfield score in patients with cystic fibrosis.

OBJECTIVE: To study correlations among pulmonary function, chest radiology and clinical status in cystic fibrosis. METHODS: A retrospective cross-sectional study was performed to evaluate chest X-rays and clinical charts of patients treated at the Hospital de Clínicas de Porto Alegre. Spirometry findings, Shwachman-Kulczycki (S-K) scores and Brasfield scores were analyzed. RESULTS: The final sample consisted of 40 patients (mean age 9.72 +/- 3.27). The following mean S-K scores were obtained: total, 80.87 +/- 10.24; general activity, 24.75 +/- 1.1; physical examination, 18.87 +/- 4.59; nutrition, 21.87 +/- 4.18; radiology, 15.37 +/- 5.23. The mean Brasfield score was 18.2 +/- 4. The pulmonary function test results, in percentage of predicted, were as follows: forced vital capacity (FVC), 82.99 +/- 14.36%; forced expiratory volume in one second (FEV1), 83.62 +/- 18.26%; and forced expiratory flow between 25 and 75% of FVC (FEF25-75), 74.63 +/- 2.53%. The S-K score correlated moderately with FVC, whereas it correlated strongly with FEV1 and FEF25-75. The Brasfield score correlated strongly with the S-K total and radiology score, whereas it correlated moderately with pulmonary function. Physical examination correlated moderately with FVC, FEV1 and FEF25-75; as did nutrition with FEF25-75; and radiology with FEV1 and FEF25-75. General activity was the domain that had the greatest influence on the total S-K score. CONCLUSIONS: These two scoring systems are complementary, correlating with each other, as well as with pulmonary function tests. The radiology domain of the S-K scoring system is a good alternative to the Brasfield score.

Cystic fibrosis patient with Burkholderia pseudomallei infection acquired in Brazil.

Burkholderia pseudomallei is rarely isolated from cystic fibrosis patients outside known areas of endemicity. We report the recovery of B. pseudomallei from the sputum of a cystic fibrosis patient who lives in Brazil. We highlight the importance of careful attention to unusual nonfermentative gram-negative rods in cystic fibrosis patients.

Comparação entre provas de função pulmonar, escore de Shwachman-Kulczycki e escore de Brasfield em pacientes com fibrose cística / Comparison among pulmonary function test results, the Shwachman-Kulczycki score and the Brasfield score in patients with cystic fibrosis

OBJETIVO: Estudar as relações entre função pulmonar, radiologia de tórax e estado clínico em fibrose cística. MÉTODOS: Em estudo transversal e retrospectivo, analisaram-se prontuários e radiografias de pacientes do Hospital de Clínicas de Porto Alegre. Foram estudados as espirometrias e os escores de Shwachman-Kulczycki (S-K) e de Brasfield. RESULTADOS: A amostra final constituiu-se de 40 pacientes com média de idade de 9,72 ± 3,27. Foram obtidas as seguintes médias dos escores de S-K: total, 80,87 ± 10,24; atividade geral, 24,75 ± 1,1; exame físico, 18,87 ± 4,59; nutrição, 21,87 ± 4,18; e radiologia, 15,37 ± 5,23. A média do escore de Brasfield foi de 18,2 ± 4. As médias das variáveis espirométricas foram, em porcentagem do previsto: capacidade vital forçada (CVF), 82,99 ± 14,36 por cento; volume expiratório forçado no primeiro segundo (VEF1), 83,62 ± 18,26 por cento; e fluxo expiratório forçado entre 25 e 75 por cento da CVF (FEF25-75), 74,63 ± 2,53 por cento. O escore de S-K correlacionou-se moderadamente com a CVF e fortemente com VEF1 e FEF25-75. O escore de Brasfield correlacionou-se fortemente com o escore de S-K total e da radiologia, e moderadamente com a função pulmonar. O escore do exame físico correlacionou-se moderadamente com CVF, VEF1 e FEF25-75, bem como o da nutrição com FEF25-75 e o da radiologia com VEF1 e FEF25-75. A atividade geral foi a categoria que mais contribuiu para a pontuação total do S-K. CONCLUSÕES: Esses escores utilizados para a monitorização da fibrose cística são complementares, correlacionando-se entre si e com as provas funcionais. A categoria radiologia do escore de S-K é um bom substituto para o escore de Brasfield.

OBJECTIVE: To study correlations among pulmonary function, chest radiology and clinical status in cystic fibrosis. METHODS: A retrospective cross-sectional study was performed to evaluate chest X-rays and clinical charts of patients treated at the Hospital de Clínicas de Porto Alegre. Spirometry findings, Shwachman-Kulczycki (S-K) scores and Brasfield scores were analyzed. RESULTS: The final sample consisted of 40 patients (mean age 9.72 ± 3.27). The following mean S-K scores were obtained: total, 80.87 ± 10.24; general activity, 24.75 ± 1.1; physical examination, 18.87 ± 4.59; nutrition, 21.87 ± 4.18; radiology, 15.37 ± 5.23. The mean Brasfield score was 18.2 ± 4. The pulmonary function test results, in percentage of predicted, were as follows: forced vital capacity (FVC), 82.99 ± 14.36 percent; forced expiratory volume in one second (FEV1), 83.62 ± 18.26 percent; and forced expiratory flow between 25 and 75 percent of FVC (FEF25-75), 74.63 ± 2.53 percent. The S-K score correlated moderately with FVC, whereas it correlated strongly with FEV1 and FEF25-75. The Brasfield score correlated strongly with the S-K total and radiology score, whereas it correlated moderately with pulmonary function. Physical examination correlated moderately with FVC, FEV1 and FEF25-75; as did nutrition with FEF25-75; and radiology with FEV1 and FEF25-75. General activity was the domain that had the greatest influence on the total S-K score. CONCLUSIONS: These two scoring systems are complementary, correlating with each other, as well as with pulmonary function tests. The radiology domain of the S-K scoring system is a good alternative to the Brasfield score.

Cystic fibrosis in adults: diagnostic and therapeutic aspects / Fibrose cística no adulto: aspectos diagnósticos e terapêuticos

A fibrose cística, que já foi considerada uma doença da infância, é agora também uma doença do adulto. O aumento da longevidade resultou em mais problemas médicos relacionados com a idade e com a própria doença. O crescente número de adultos com fibrose cística resultou em aumento da necessidade de cuidados médicos. Essa necessidade tem sido suprida por um crescente número de pneumologistas de adultos e outros especialistas. O objetivo dessa revisão é sumarizar o conhecimento corrente sobre o diagnóstico e tratamento no adulto com fibrose cística. Na maioria dos casos, o diagnóstico é sugerido por manifestações de doença sinopulmonar crônica e insuficiência pancreática exócrina, e, então, confirmado por um teste do suor positivo. Pacientes adultos podem, entretanto, apresentar suficiência pancreática e características clínicas atípicas, às vezes, associadas com teste do suor normal ou limítrofe. Em tais casos, a possibilidade de realizar pesquisa de mutações para fibrose cística e de medir a diferença de potencial nasal pode ser de utilidade diagnóstica. A abordagem terapêutica padrão para a doença pulmonar inclui: antibióticos, higiene das vias aéreas, exercício, mucolíticos, broncodilatadores, oxigênio, agentes anti-inflamatórios e suporte nutricional. A utilização adequada dessas terapias resulta em mais pacientes com fibrose cística sobrevivendo na vida adulta com uma aceitável qualidade de vida.

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.

Avaliaçäo evolutiva da espirometria na fibrose cística / Spirometry evolution assessment of cystic fibrosis

OBJETIVO DO ESTUDO: Avaliar o padräo da evoluçäo dos fluxos e volumes pulmonares dinâmicos dos pacientes com fibrose cístuca ( FC ), assim como analisar a relaçäo entre a gravidade do comprometimento ventilatório com a idade, sexo, genótipo e colonizaçäo pulmonar. MATERIAL E MÉTODO: Na Unidade de Pneumologia Infantil e Serviço de Pneumologia do Hospital de Clínicas de Porto Alegre, foram analiadas de 1987 a 1999. Do prontuário médico foram extraída informaçöes sobre idade ao diagnóstico, pequisa genética, colonizaçäo brônquica e os valores absolutos e pacientes variou absolutos e percentuais para fluxos e volumes da melhor espirometria de cada ano. RESULTADOS: A idade dos pacientes variu de quatro a 26 anos ( média = 13,04 ñ 4,8 2). Dos 52 pacientes, 49 ( 94 por cento ) tiveram pelo menos uma cultura de escarro com p.aeruginosa, 45 ( 86 por cento ) com S.aureus e 13 ( 25 por cento ) com B. foram de 114,24 por cento e 112,25 por cento, respectivamente. A média da CVF mateve-se acima do normal até os 18 anos, quando apresentou queda súbita para 67,2 por cento ( p = 0,00002 ). A média do VEF1 atingiu valores abaixo de 80 por cento aos dez anos, estando em 50 por cento aos 18 anos ( p < 0,00001 ). A relaçäo VEF1/CVF por cento , índice mais sensível de obstruçäo, mostrou-se diminuída já na primeira avaliaçäo, sendo 85 por cento entre os quatro e seis anos, com declínio lento progressivo, chagando a 63 por cento aos 18 anos. Os valores médios do FEF50, FEF75 e FMEF inicialmente foram normais ( 94 por cento, 80 por cento e 90 por cento, respectivamente ), mostraram queda maior e mais precoce, estatisticamente significativa, atingindo valores médios aos 18 anos de 37 por cento, 12,5 por cento e 19 por cento, respectivamente. Embora houvesse tendência para fluxos terminais mais baixos para as meninas, as diferenças näo tiveram valor estatístico. Também näo foram detectadas ou o genótipo. CONCLUSÄO: O padräo evolutivo das alteraçöes funcionais pulmonares encontrado nos pacientes está de acordo com o descrito na literatura, onde predomina o distúrbio ventilatório obstrutivo com reduçäo precoce dos fluxos terminais e acometimento tardio da CVF