This comprehensive State of the Art review summarizes the current published knowledge base regarding the pathophysiology and microbiology of pulmonary disease in cystic fibrosis (CF). The molecular basis of CF lung disease including the impact of defective cystic fibrosis transmembrane regulator (CFTR) protein function on airway physiology, mucociliary clearance, and establishment of Pseudomonas aeruginosa infection is described. An extensive review of the microbiology of CF lung disease with particular reference to infection with P. aeruginosa is provided. Other pathogens commonly associated with CF lung disease including Staphylococcal aureus, Burkholderia cepacia, Stenotrophomonas maltophilia, Achromobacter xylosoxidans and atypical mycobacteria are also described. Clinical presentation and assessment of CF lung disease including diagnostic microbiology and other measures of pulmonary health are reviewed. Current recommendations for management of CF lung disease are provided. An extensive review of antipseudomonal therapies in the settings of treatment for early P. aeruginosa infection, maintenance for patients with chronic P. aeruginosa infection, and treatment of exacerbation in pulmonary symptoms, as well as antibiotic therapies for other CF respiratory pathogens, are included. In addition, the article discusses infection control policies, therapies to optimize airway clearance and reduce inflammation, and potential future therapies.

Pathophysiology and management of pulmonary infections in cystic fibrosis.

OBJECTIVE To compare once daily with thrice daily tobramycin for treatment of Pseudomonas aeruginosa infection in patients with cystic fibrosis . DESIGN 22 patients with cystic fibrosis, mean (SD) age 11 (3.4) years (range 5.6–19.3), with pulmonary pseudomonas exacerbations were randomly assigned to receive a 14 day course of tobramycin (15 mg/kg/day) either in three infusions (group A) (n = 10) or a single daily infusion (group B) (n = 12), combined with ceftazidime (200 mg/kg/day as three intravenous injections). Efficacy was assessed by comparison of pulmonary, nutritional, and inflammatory indices on days 1 and 14. Cochlear and renal tolerance were assessed on days 1 and 14. Tobramycin concentration was measured in serum and sputum 1, 2, 3, 4, 8, and 24 hours after the start of the infusion. Analysis was by non-parametric Wilcoxon test. RESULTS Variables improving (p  CONCLUSIONS Once daily tobramycin combined with three injections of ceftazidime is safe and effective for the treatment of pseudomonas exacerbations in cystic fibrosis patients.

https://adc.bmj.com/content/archdischild/78/6/536.full.pdf

Efficacy, tolerance, and pharmacokinetics of once daily tobramycin for pseudomonas exacerbations in cystic fibrosis

Chest radiography in patients with cystic fibrosis (CF) frequently shows more severe changes in the upper lobes. We performed bronchoalveolar lavage (BAL) on 12 clinically stable, young adult patients with CF to determine whether inflammation varies significantly among geographically distinct areas of the lung. We found that absolute numbers of neutrophils were generally greater in BAL fluid from the upper lobe (25.7 ± 7.9 × 105 neutrophils/ml [mean ± SEM]) of the right lung than that obtained from the right lower lobe (6.8 ± 2.8 × 105 neutrophils/ml; p < 0.01). The mean value of unopposed neutrophil elastase activity in upper-lobe BAL fluid (227 ± 91 nmol peptide hydrolyzed/ml/min) was also significantly greater than that in lower-lobe BAL fluid (84 ± 43 nmol/peptide hydrolyzed/ml/ min; p < 0.01), and similar differences were found for myeloperoxidase activity and DNA content. Neutrophil influx and unopposed neutrophil elastase for a given region correlated inversely with lung function or percentage of i...

Regional Variability of Lung Inflammation in Cystic Fibrosis

Gastroesophageal reflux (GER) is common in patients with cystic fibrosis (CF) and is often regarded as playing a role in the pathogenesis of CF lung disease. Individuals with CF have many predisposing factors to the development of GER, with a reported prevalence ranging from 35 to 81%. Several studies have suggested that patients with CF who have coexisting GER have more severe lung disease with lower pulmonary function and increased numbers of respiratory exacerbations. Furthermore, GER may alter the respiratory microbiology in CF. Both the acid and nonacid components of GER may have an effect on lung disease. More than 50% of U.S. patients with CF were being treated with proton pump inhibitors in 2012; however, data regarding safety and efficacy of these agents in CF are lacking. Pharmacologic and surgical treatment of GER may improve respiratory morbidity, although prospective controlled studies have not been performed. Given the lack of evidence-based guidelines for evaluation, diagnosis, and treatment of GER in CF, initiation of treatment for symptomatic GER should be based on standard guidelines for the general population. Because there is no clear evidence that GER leads to worse respiratory outcomes in CF or that treatment of GER improves pulmonary outcomes, invasive testing for GER in patients without reflux symptoms is not warranted. Further studies to determine the role of GER in CF lung disease and the risks and benefits of surgical and pharmacologic therapy for GER are warranted.

Prevalence of Gastroesophageal Reflux in Cystic Fibrosis and Implications for Lung Disease

The most common hepatic complications of cystic fibrosis (CF) are steatosis, fibrosis, biliary cirrhosis, atretic gallbladder, cholelithiasis, and sclerosing cholangitis. Cholestatic liver disease is a slow progressive disorder, but will stabilize for many patients. CF patients may suffer from the consequences of their liver disease and without liver transplantation, variceal hemorrhage, malnutrition, or end-stage liver disease can lead to death. Prospective data were collected and reviewed on 311 liver transplants performed in 283 patients at the Children's Medical Center of Dallas between October 1984 and November 2000. Ten children received an orthotopic liver transplant (OTLX) for end-stage liver disease associated with cystic fibrosis. Pulmonary function tests were obtained preoperatively in all cases. There were nine boys and one girl. Six are currently alive, and four are dead. Both patient and graft survival was 5.75 yr. Among those currently alive, mean patient and graft survival is 7.71 yr (range 0.10-12.62 yr). Mean patient and graft survival of those who died was 2.35 yr (range 0.78-5.33 yr). No survivor required re-transplantation and currently, all have normal serum aminotransferase values. Chronic sinusitis was not a significant pre- or post-transplant morbidity, although systematic radiographic evaluation of the sinuses did not occur. Pulmonary deaths occurred in three patients from pulmonary hemorrhage, pulmonary infection with Aspergillus and Candida glabrata, and acute bronchopneumonia associated with polymicrobial sepsis because of Pseudomonas, Klebsiella, and Candida albicans 1.44, 0.78, and 1.83 yr, respectively, after transplantation. The fourth death was associated with chronic rejection, and occurred 5.33 yr after transplantation. All non-survivors were below the 5th percentile for height and weight at the time of liver transplantation. Mean age at transplantation was 9.72 yr (range 1.23-19.09, median 9.61). Survivors were transplanted at a younger age than non-survivors (mean of 9.21 yr vs. 10.66 yr), and had shorter waiting times from diagnosis of end-stage liver disease to transplantation (6.87 months vs. 13.83 months). Eighty percentage (n = 8) of patients had pretransplant variceal bleeds (83% of survivors, 75% of non-survivors). While all non-survivors had a history of meconium ileus and preoperative need of pancreatic enzymes, only 67% of those alive experienced these complications. Preoperative forced vital capacity FVC was 103% for survivors and 95% for non-survivors. The corresponding numbers for forced expiratory flow (FEF) 25-75 were 74-84% respectively. Preoperative Aspergillus was identified in 30% of patients (n = 3). Two of these patients are alive. Cystic fibrosis constitutes an indication for 3.5% of pediatric liver transplants. Evaluation and transplantation for end-stage liver disease associated with cystic fibrosis should be undertaken at an early age. Most deaths were associated with pulmonary/septic events, and occurred less than 2 yr after OLTX. Those children who did not survive had poor growth and nutrition, prolonged waiting times prior to transplantation, were transplanted at an older age, and had a higher incidence of pancreatic insufficiency and meconium ileus. The presence of Aspergillus in the sputum does not constitute a contraindication for OLTX.

Liver transplantation for cholestasis associated with cystic fibrosis in the pediatric population.

Resume Un reflux gastroœsophagien (RGO) est frequemment observe au cours des affections respiratoires chroniques, et peut en aggraver l'evolution. Le but de ce travail etait de rechercher la frequence et les caracteristiques du RGO chez de jeunes enfants atteints de mucoviscidose (CF). Population et methodes. — Vingt-cinq enfants âges de 45 a 954 jours (moyenne: 219 jours), atteints de CF, ont eteetudies par pHmetrie de longue duree (19,45 ± 1,89 h) (moyenne ± DS), en l'absence de signes cliniques de surinfection bronchopulmonaire, et en l'absence de traitement bronchodilatateur. L'atteinte respiratoire a eteevaluee par le nombre de cures d'antibiotiques anterieurement recues et par l'analyse de la radiographic pulmonaire realisee au moment de la pHmetrie. La symptomatologie clinique evocatrice de RGO etait recherchee par l'interrogatoire des parents. Resultats. — Dix-neuf enfants etaient porteurs de RGO (76%); quatre des 19 enfants n'avaient pas de signes cliniques evocateurs de RGO. Tous les enfants avaient une atteinte respiratoire moderee. L'index de reflux (pourcentage du temps total d'enregistrement a pH Conclusions. — Le RGO est frequent au cours de la CF et atteint les jeunes enfants. Il semble primitif, non pas secondaire a l'atteinte respiratoire. Sa frequence et sa gravite potentielle incitent a pratiquer une pHmetrie systematique lors du bilan initial de tout enfant atteint de CF.

Fréquence du reflux gastroœsophagien chez le nourrisson et le jeune enfant atteints de mucoviscidose

Resume Des 1994, nous avons debute la rhDNase chez tous les patients atteints de mucoviscidose âges de plus de 5 ans et ayant une CVF ≥ 40 % de la valeur theorique. Population et methodes Nous avons analyse retrospectivement les effets de la rhDNase au cours de 2 ans de traitement chez 69 enfants et adolescents. Les patients ( 35 garcons, 34 filles) ont recu une dose unique journaliere de 2,5 mg de rhDNase. Ils etaient âges initialement de 8,5 ans (5 a 16,4 ans). Les valeurs spirometriques (pourcentage de la valeur theorique) et le statut nutritionnel de base etaient les suivants: CVF = 84,8 ± 21,7, VEMS = 80,8 ± 22,2, DEP = 89,7 ± 34,2, DEM 25-75 = 71, 8 ± 32,8, Z score poids/taille = -0,41 ± 1,14, Z-score poids/âge = −0,48 ± 1,25, index de Quetelet = 15,4 ± 1,8, ration calorique = 107 ± 25 % des apports journaliers recommandes. Les donnees spirometriques et nutritionnelles ont ete analysees apres 1, 3, 6, 12, 18 et 24 mois de traitement et comparees aux valeurs de base (resultats spirometriques exprimes en pourcentage des valeurs de base moyennes). Le score de Shwachman-Kulczycki etait de 87 ± 9 avant le traitement et a ete releve 24 mois plus tard. Resultats Une amelioration de la CVF (+ 10,7 %, p p p ≤ 0,01 ). Ceci a ete note en particulier chez les enfants âges de 5 a 10 ans, chez les garcons et chez les patients dont la CVF de base etait e ( p e mois ( p ≤ 0,02), essentiellement chez les filles. Les Z scores poids/âge et poids/taille se sont ameliores respectivement pendant les 3 premiers mois et apres 2 ans de traitement. Le score de Shwachman-Kulczycki est reste stable. Conclusion La rhDNase ameliore donc la fonction respiratoire et le statut nutritionnel des jeunes patients atteints de mucoviscidose et la reponse au traitement peut etre evaluee des les 3 premiers mois.

Effets de la rhdnase sur la fonction respiratoire et le statut nutritionnel de l'enfant et de l'adolescent atteints de mucoviscidose

Resume La transplantation hepatique est une solution therapeutique proposee chez les patients atteints de mucoviscidose presentant une insuffisance hepatique terminale. Lorsque ces patients sont porteurs chroniques de Pseudomonas aeruginosa , se pose la question du choix entre une transplantation hepatique isolee (TRH) et combinee foie-poumon. Observation. Une adolescente de 15 ans atteinte de mucoviscidose a beneficie d'une TRH en raison d'une cirrhose au stade terminal. Elle presentait depuis 3 ans un portage chronique de pyocyanique traite par cures antibiotiques intravcineuses systematiques. Il existait une insuffisance pancreatique exocrine. Il etait note une intolerance glucidique moderee lors des surinfections. Les suites operatoires immediates ont ete simples. Elle a presente par la suite un diabete necessitant une insulinotherapie pendant 9 mois. Il a ete constate des troubles majeurs de l'absorption de la ciclosporine orale ameliores secondairement par la prise d'une nouvelle forme hydrosoluble (Neoral ® ). Il n'y a pas eu de surinfection pulmonaire severe due au portage chronique du pyocyanique. Il a ete note un rattrapage du developpement pubertaire. Conclusion. Ce recul de 3 ans confirme que la TRH est une bonne alternative therapeutique pour les patients atteints de mucoviscidose presentant une insuffisance hepatique terminale et une atteinte pulmonaire moderee.

Transplantation hépatique chez une adolescente atteinte de mucoviscidose

Twenty cystic fibrosis patients aged 1.8–22 years (mean ±SD: 9.6 ± 4.8 years) withPseudomonas aeruginosa pulmonary exacerbations were treated with amikacin (AM) (35 mg/kg/day in one daily 30 min infusion) associated with either ceftazidime (200 mg/kg/day in 3 i.v. injections) (n = 19) or imipenem (n = 1) at the same dose. Glomerular and tubular functions (creatinine clearance, 24-h proteinuria, β2 microglobulinuria, lysozymuria) and audiometry remained within normal ranges from day 0 to day 14. A peak concentration of AM of 83 ± 19 mg/l and a trough concentration of 0.8 ±0.5 mg/l were observed in blood while AM levels in sputum were above the minimal inhibitory concentration 50 from 30 min to 16 h. No serum accumulation of AM was observed during the treatment. From day 0 to day 14, the following changes were observed: weight/height ratio: 96%–100% (P < 0.001); daily energy intake: 111%–128% of RDA (P < 0.001); prealbumin: 195–290 mg/l (P < 0.001); forced vital capacity (FVC): 66%–81% (P < 0.01); forced expiratory volume in 1 s: 60%–75% (P < 0.01); forced expiratory flow between 25% and 75% of FVC: 42%–56% (P < 0.01); nocturnal SaO2 also improved significantly; cardiac rate decreased from 89 ±18/min to 76 ± 16/min (P < 0.001); respiratory rate decreased from 31 ±15/min to 26 ± 10/min (P < 0.05); inflammatory parameters (white blood cells, polymorphonuclear cells, erythrocyte sedimentation rate) also improved.

Tolerance, pharmacokinetics and efficacy of once daily amikacin for treatment of Pseudomonas aeruginosa pulmonary exacerbations in cystic fibrosis patients

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Fréquence du reflux gastroœsophagien chez le nourrisson et le jeune enfant atteints de mucoviscidose

Effets de la rhdnase sur la fonction respiratoire et le statut nutritionnel de l'enfant et de l'adolescent atteints de mucoviscidose

Transplantation hépatique chez une adolescente atteinte de mucoviscidose

Tolerance, pharmacokinetics and efficacy of once daily amikacin for treatment of Pseudomonas aeruginosa pulmonary exacerbations in cystic fibrosis patients