Regional brain tissue changes in patients with cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF) patients present with a variety of symptoms, including mood and cognition deficits, in addition to classical respiratory, and autonomic issues. This suggests that brain injury, which can be examined with non-invasive magnetic resonance imaging (MRI), is a manifestation of this condition. However, brain tissue integrity in sites that regulate cognitive, autonomic, respiratory, and mood functions in CF patients is unclear. Our aim was to assess regional brain changes using high-resolution T1-weighted images based gray matter (GM) density and T2-relaxometry procedures in CF over control subjects. METHODS: We acquired high-resolution T1-weighted images and proton-density (PD) and T2-weighted images from 5 CF and 15 control subjects using a 3.0-Tesla MRI. High-resolution T1-weighted images were partitioned to GM-tissue type, normalized to a common space, and smoothed. Using PD- and T2-weighted images, whole-brain T2-relaxation maps were calculated, normalized, and smoothed. The smoothed GM-density and T2-relaxation maps were compared voxel-by-voxel between groups using analysis of covariance (covariates, age and sex; SPM12, p < 0.001). RESULTS: Significantly increased GM-density, indicating tissues injury, emerged in multiple brain regions, including the cerebellum, hippocampus, amygdala, basal forebrain, insula, and frontal and prefrontal cortices. Various brain areas showed significantly reduced T2-relaxation values in CF subjects, indicating predominant acute tissue changes, in the cerebellum, cerebellar tonsil, prefrontal and frontal cortices, insula, and corpus callosum. CONCLUSIONS: Cystic fibrosis subjects show predominant acute tissue changes in areas that control mood, cognition, respiratory, and autonomic functions and suggests that tissue changes may contribute to symptoms resulting from ongoing hypoxia accompanying the condition.

Liver involvement in the Hispanic population of North America with cystic fibrosis.

OBJECTIVES: The aim of the present article was to determine the prevalence of liver involvement in Hispanic patients with cystic fibrosis (CF) and identify associations with age and severity of liver involvement. METHODS: We used 1994-2005 Epidemiologic Study of CF data to compare abnormal liver findings between Hispanic and non-Hispanic white patients with CF. RESULTS: Of 30,727 patients with CF, 5015 had liver involvement. Of 1957 Hispanic patients, 20.8% had liver involvement compared with 16.0% of 28,770 non-Hispanic white patients (odds ratio [OR] 1.38, 95% confidence interval [CI] 1.23-1.54). This higher prevalence of liver involvement persisted after adjusting for demographics and meconium ileus and was especially high in the first year of life (adjusted OR 3.14, 95% CI 2.27-4.35). Ten percent of infants with only elevated liver enzymes progressed to more severe liver disease. CONCLUSIONS: The Hispanic population with CF has more liver involvement (both elevated liver enzymes and clinical liver disease) than the non-Hispanic white population with CF, especially during the first year of life.

Progressive gray matter changes in patients with congenital central hypoventilation syndrome.

INTRODUCTION: Patients with congenital central hypoventilation syndrome (CCHS) show brain injury in areas that control chemosensory, autonomic, motor, cognitive, and emotion functions, which are deficient in the condition. Many of these abnormal characteristics are present from the neonatal period; however, it is unclear whether tissue injury underlying the characteristics progressively worsens with time. We hypothesized that several brain areas in subjects with CCHS would show increased gray matter volume loss over time. METHODS: We collected high-resolution T1-weighted images twice (4 years apart) from seven subjects with CCHS (age at first study, 16.1 ± 2.7 years; four males) and three control subjects (15.9 ± 2.1 years; three males) using a 3.0-Tesla magnetic resonance imaging (MRI) scanner, and evaluated regional gray matter volume changes with voxel-based morphometry (VBM) procedures. RESULTS: Multiple brain sites in CCHS, including frontal, prefrontal, insular, and cingulate cortices; caudate nuclei and putamen; ventral temporal and parietal cortices; and cerebellar cortices showed significantly reduced gray matter volume over time. Only limited brain areas, including sensory, temporal, and medullary regions, emerged with increased gray matter at the later age. DISCUSSION: Patients with CCHS show reduced gray matter volume with age progression in autonomic, respiratory, and cognitive regulatory areas, an outcome that may contribute to deterioration of functions found in the syndrome with increasing age.

Carbon monoxide pollution and lung function in urban compared with rural Mongolian children.

BACKGROUND AND OBJECTIVE: Mongolia is experiencing rapid urbanization, and this presents a unique opportunity to assess the effects of this process on the lung health of children. METHODS: Two cross-sectional cohorts of school-age children (5-15years of age) from the capital (Ulaanbaatar) (n=116) and a rural district (Tuv Aimag) (n=108) were studied. Demographical information, exposure to tobacco smoke, and ambient and exhaled CO, as well as FEV(1) and FEF(25-75%) were recorded for each child. RESULTS: Ambient CO levels were threefold higher in the capital city than in the rural Aimag (0.63 vs 0.21 parts per million (ppm), P<0.00005), while exhaled CO was twofold higher (0.94 vs 0.47ppm, P<0.00001). Rural Mongolian children were 6cm shorter on average than urban children. However, when adjusted for age and height, FEV(1) was 140% of predicted in rural children compared with 106% of predicted in urban children (P<0.00001). There was no significant difference in small airway expiratory flow (FEF(25-75%) ; 104 in urban children, 100 in rural children, P=0.63). CONCLUSIONS: 'Normal' FEV(1) was actually 40% higher in rural Mongolian children than in urban children, suggesting that the FEV(1) of apparently healthy children living in urbanized societies may in fact not be normal, but may instead reflect the deleterious effects of air pollution in cities, as indicated by increased levels of both environmental and exhaled CO.

Overview of lung transplantation.

Although significant gains have been made in improving lung function and survival in cystic fibrosis (CF), ultimately respiratory failure is the leading cause of mortality in these patients. For CF patients with end stage lung disease, lung transplantation is an option for treatment. The field of lung transplantation has progressed markedly in the last 20 years. Nonetheless it remains a technically complex and challenging procedure, and patients are at risk for numerous short term and long term complications. Potential transplant recipients must be physically and psychologically prepared for the arduous process involved in lung transplantation. This article will review the history of lung transplantation, indications for transplantation, surgical techniques, and complications of transplantation.

Lung transplantation and survival in children with cystic fibrosis: solid statistics--flawed interpretation.

In their provocative paper, "Lung transplantation and survival in children with cystic fibrosis," Liou and colleagues state that "Prolongation of life by means of lung transplantation should not be expected in children with cystic fibrosis. A prospective, randomized trial is needed to clarify whether and when patients derive a survival and quality of life benefit from lung transplantation." Unfortunately, that conclusion is not supportable. Liou's dataset introduced bias against transplantation by using covariates obtained well before the time of transplant (when predicted survival was good) and having a cohort with lower than expected post-transplant survival than reported elsewhere. The calculated hazard ratios are based on factors that may have changed between listing and transplant, and do not reflect true benefit on a patient by patient basis. The findings of the study are contrary to other studies using similar methods. Finally, recent changes in US lung transplant allocation policy may have made the study findings moot. In contrast to Liou's suggestion to perform an ethically and logistically challenging randomized trial to verify the benefit of lung transplantation, a research agenda is recommended for pediatric lung transplantation for cystic fibrosis that focuses on developing strategies to continually reassess and maximize quality of life and survival benefit.

Analysis of a Pediatric Home Mechanical Ventilator Population.

BACKGROUND: The population of children requiring home mechanical ventilation has evolved over the years and has grown to include a variety of diagnoses and needs that have led to changes in the care of this unique population. The purpose of this study was to provide a descriptive analysis of pediatric patients requiring home mechanical ventilation after hospitalization and how the evolution of this technology has impacted their care. METHODS: A retrospective, observational, longitudinal analysis of 164 children enrolled in a university-affiliated home mechanical ventilation program over 26 years was performed. Data included each child's primary diagnosis, date of tracheostomy placement, duration of mechanical ventilation during hospitalization that consisted of home mechanical ventilator initiation, total length of pediatric ICU stay, ventilator settings at time of discharge from pediatric ICU, and disposition (home, facility, or died). Univariate, bivariate, and regression analysis was used as appropriate. RESULTS: The most common diagnosis requiring the use of home mechanical ventilation was neuromuscular disease (53%), followed by chronic pulmonary disease (29%). The median length of stay in the pediatric ICU decreased significantly after the implementation of a ventilator ward (70 d [30-142] vs 36 d [18-67], P = .02). The distribution of subjects upon discharge was home (71%), skilled nursing facility (24%), and died (4%), with an increase in the proportion of subjects discharged on PEEP and those going to nursing facilities over time (P = 0.02). CONCLUSIONS: The evolution of home mechanical ventilation has allowed earlier transition out of the pediatric ICU and with increasing disposition to skilled nursing facilities over time. There has also been a change in ventilator management, including increased use of PEEP upon discharge, possibly driven by changes in ventilators and in-patient practice patterns.

A decade of living lobar lung transplantation: recipient outcomes.

OBJECTIVE: Living lobar lung transplantation was developed as a procedure for patients considered too ill to await cadaveric transplantation. METHODS: One hundred twenty-eight living lobar lung transplantations were performed in 123 patients between 1993 and 2003. Eighty-four patients were adults (age, 27 +/- 7.7 years), and 39 were pediatric patients (age, 13.9 +/- 2.9 years). RESULTS: The primary indication for transplantation was cystic fibrosis (84%). At the time of transplantation, 67.5% of patients were hospitalized, and 17.9% were intubated. One-, 3-, and 5-year actuarial survival among living lobar recipients was 70%, 54%, and 45%, respectively. There was no difference in actuarial survival between adult and pediatric living lobar recipients (P =.65). There were 63 deaths among living lobar recipients, with infection being the predominant cause (53.4%), followed by obliterative bronchiolitis (12.7%) and primary graft dysfunction (7.9%). The overall incidence of acute rejection was 0.8 episodes per patient. Seventy-eight percent of rejection episodes were unilateral. Age, sex, indication, donor relationship, preoperative hospitalization status, use of preoperative steroids, and HLA-A, HLA-B, and HLA-DR typing did not influence survival. However, patients on ventilators preoperatively had significantly worse outcomes (odds ratio, 3.06, P =.03; Kaplan-Meier P =.002), and those undergoing retransplantation had an increased risk of death (odds ratio, 2.50). CONCLUSION: These results support the continued use of living lobar lung transplantation in patients deemed unable to await a cadaveric transplantation. We consider patients undergoing retransplantations and intubated patients to be at significantly high risk because of the poor outcomes in these populations.

Previous thoracic surgery does not increase peri-operative mortality in pediatric heart-lung transplant recipients.

BACKGROUND: Heart-lung transplant (HLT) is indicated in select children with end-stage cardiopulmonary disease. We sought to determine whether previous thoracic surgery increases peri-operative morbidity and mortality. METHODS: Retrospective data were analyzed using unpaired Student's t-test and Fisher's exact test. Results are reported as mean +/- SD. Peri-operative mortality was defined as death at

The necessity of complete CFTR mutational analysis of an infertile couple before in vitro fertilization.

OBJECTIVE: To determine the genotype of a triplet resulted from an IVF procedure, with discordant cystic fibrosis (CF) phenotype. DESIGN: Molecular diagnosis of CF. SETTING: Affected triplet followed at the CF Clinic Center of Children's Hospital Los Angeles was referred to Molecular Genetics Laboratory at Georgetown University Medical Center for comprehensive DNA analysis of the cystic fibrosis transmembrane regulator (CFTR) gene. PATIENT(S): Three affected children and the healthy parents with negative family history of CF. MAIN OUTCOME MEASURE(S): Temporal temperature gradient gel electrophoresis and direct DNA sequencing were used to detect and to identify the mutations. RESULT(S): The child with classic CF had DeltaF508 and R553X mutations. Two children with mild CF symptoms had DeltaF508 and R117C. The father carried two mutations, R553X and R117C. The mother is a carrier for DeltaF508. CONCLUSION(S): Mutational analysis of the CFTR gene should always be recommended to the infertile couples seeking for IVF. The CFTR mutation screening would be essential if the man has congenital bilateral absence of vas deferens (CBAVD) despite the negative family history of CF. Option of complete CFTR gene analysis at a cost of about 1,500-2,000 dollars should be made available if one mutation is found in the male partner with congenital bilateral absence of vas deferens.

Acute neurological deficits in a young adult with cystic fibrosis.

An abrupt onset of a neurological deficit is a rare occurrence in patients with cystic fibrosis (CF). As many CF patients have indwelling intravenous catheters, one of the complications may be deep venous thrombosis. Cerebral thromboembolism through an intracardiac shunt should be considered in CF patients who develop unexplained acute neurological deficits. We report on the case of a 19-year-old CF patient with insulin-dependent diabetes mellitus who was on oral contraceptives and had a Port-A-Cath(R) in place. The patient developed an acute neurological deficit after pulmonary function testing. Radiologic investigations of her head and neck were unremarkable, except for bilateral maxillary and ethmoid sinusitis. An electroencephalogram showed epileptiform discharges primarily from the right hemisphere. A transthoracic echocardiogram (TTE) revealed a small thrombus in the right atrium. A transesophageal echocardiogram (TEE) demonstrated a left-to-right shunt through a patent foramen ovale (PFO) that was not found by TTE. Extensive investigation to rule out congenital and acquired thrombophilia was negative. Treatment consisted of aspirin and discontinuation of oral contraceptives and vitamin K supplementation. Spontaneous complete recovery of the neurological deficits occurred within 24 hr after onset of symptoms.We conclude that paradoxical embolism should be in the differential diagnoses of CF patients who have indwelling intravenous catheters and who develop an unexplained stroke. An extensive investigation to rule out intracardiac abnormalities and thrombophilia should be considered. The risks and benefits of PFO closure vs. prophylactic anticoagulant and antiplatelet aggregation treatment in this group of patients should be carefully weighed.

Correlation between digital clubbing and pulmonary function in cystic fibrosis.

The correlation between digital clubbing and certain pulmonary function derangements (hypoxemia and FEV(1)) was previously described. However, the relationship between digital clubbing and other measures of pulmonary function or the presence of liver disease in patients with cystic fibrosis (CF) is poorly defined. Hence we compared the digital clubbing index (CI: ratio of distal phalangeal depth to interphalangeal depth) of 100 patients with CF (43 males, 57 females; mean age, 15.7 +/- 7.3 years) with that of 100 age- and gender-matched healthy controls. Digital clubbing was defined as a CI > or = 1.00 (mean + 2.6 SD; 99% of normal subjects). The CI and its relationship to pulmonary function and to liver disease was then evaluated in the CF patients. Digital clubbing was present in 75/100 (75%) of CF patients but was absent in all controls (P < 0.0001). In CF patients, CI was inversely correlated with PaO(2) (r = -0.555; P < 0.001), FEV(1) (r = -0.499; P < 0.001), and FEF(25-75%) (r = -0.404; P < 0.001), and was positively correlated with RV (r = 0.285; P < 0.05) and the slope of phase 3 of single-breath nitrogen washout (SP3N(2)) (r = 0.532; P < 0.01). There was no significant correlation between CI and age (r = 0.020; P = 0.84), TLC (r = -0.097; P = 0.34), PaCO(2) (r = 0.167; P = 0.10), or history of liver disease (P = 0.08). We conclude that in CF, the degree of digital clubbing is related to degree of hypoxemia, airways obstruction, hyperinflation, and nonuniformity of ventilation.

Pediatric recipients of living donor lobar lung transplants: postoperative care.

Bilateral living donor lobar lung transplantation is a treatment option for selected children and adults with end-stage lung disease. Careful donor evaluation, skilled intraoperative management and surgical technique, and diligent immediate postoperative care and follow-up all contribute to better outcomes. Although medical management of whole lung transplant recipients in the immediate postoperative period is similar to that of lobar lung transplant recipients, there are specific differences. Anatomical distinctions, such as the entire cardiac output flowing to 2 lobes instead of 5, and thoracic space issues with simultaneous mechanical ventilation and chest tube suction, contribute to these differences. Early postoperative care, including initial postoperative stabilization, ventilation, fluid management, rejection/infection surveillance and prophylaxis, and beginning rehabilitation, can be adapted to ensure successful outcomes in these patients.

Efficacy and safety of PANCREAZE® for treatment of exocrine pancreatic insufficiency due to cystic fibrosis.

BACKGROUND: Pancreatic enzyme replacement therapy (PERT) is critical for correction of exocrine pancreatic insufficiency (EPI) in patients with cystic fibrosis (CF). METHODS: This was a randomized, placebo-controlled PERT withdrawal study evaluating the efficacy and safety of PANCREAZE® (pancrelipase) in CF patients with EPI. Participants (n=49) entered an open-label, ≤ 14 day run-in phase, maintained a high-fat diet (100 ± 15 g/day), and received PANCREAZE® (10.5 or 21). Participants with a coefficient of fat absorption (CFA)≥ 80% (n=40) were then randomized (1:1) to receive either PANCREAZE® or placebo during a double-blind, ≤ 7 day withdrawal phase. RESULTS: PANCREAZE® improved fat absorption as shown by significantly lower mean ± SD change in CFA between open-label and double-blind phases for PANCREAZE® (-1.5 ± 5.88%; p<0.001) compared to placebo (-34.1 ± 23.03%). Protein absorption was similarly improved. No unexpected adverse events were reported. CONCLUSIONS: This study demonstrated PANCREAZE® was effective in treating EPI due to CF and was safe and well tolerated.

Does the 6-min walk test correlate with the exercise stress test in children?

Is there a correlation between the 6-min walk and aerobic fitness in children? We studied healthy and cystic fibrosis (CF) subjects age 8-20 years using the 6-min walk test, treadmill graded exercise stress test, and spirometry. Six-minute walk distance (6MWD) and the product of 6MWD and body weight (6MWORK) were related to aerobic capacity. Data were analyzed using Student's t-test and Pearson correlation. 13 healthy subjects [9 females, mean age 15.8 +/- 3.6 years, % predicted forced expiratory volume in one second (FEV(1)) 105 +/- 12%, 6MWD 557 +/- 73 m, peak oxygen uptake (V' O2 max) 41.4 +/- 7.2 ml/kg/min, and heart rate (HR) at V' O2 max 180 +/- 10] and 11 CF subjects (3 females, mean age 14.3 +/- 3.8 years, FEV(1) 67 +/- 25.9%, 6MWD 468 +/- 68 m, V' O2 max 27.0 +/- 8.1 ml/kg, and HR at V' O2 max 163 +/- 22] were studied. 6MWD correlates with V' O2 max in normal subjects (r = 0.59, P < 0.05) but not in CF subjects (r = 0.09, NS). 6MWORK correlates with V' O2 max in CF subjects (r = 0.65, P < 0.05) but not in normal subjects (r = 0.278, NS). We conclude that the 6MWD corresponds with aerobic fitness in normal pediatric subjects and 6MWORK corresponds with aerobic fitness in CF subjects. We speculate that 6MWORK is superior to 6MWD for assessment of aerobic fitness in children with CF.

EUR-1008 pancreatic enzyme replacement is safe and effective in patients with cystic fibrosis and pancreatic insufficiency.

BACKGROUND: EUR-1008 (Zenpep [pancrelipase]) is a new, enteric-coated, porcine-derived pancreatic enzyme product (PEP) developed for the treatment of cystic fibrosis (CF) patients with malabsorption associated with exocrine pancreatic insufficiency (EPI). Unlike currently marketed PEPs, EUR-1008 contains the label-claimed lipase content. Safety and efficacy were assessed in younger (<7 years) and older (> or =7 years) CF patients with EPI. METHODS: Two multicenter studies were conducted: a randomized, double-blind, placebo-controlled, crossover trial in patients > or =7 years of age (N=34) and a supplemental, open-label study in children <7 years of age (N=19). Use of any medications altering gastric pH/motility was prohibited during the studies. Outcome measures in the randomized trial included changes in the coefficient of fat absorption (CFA), coefficient of nitrogen absorption (CNA), and signs/symptoms of malabsorption for EUR-1008 vs. placebo. Outcome measures in the supplemental study included safety and response (defined as no steatorrhea and no overt signs/symptoms of malabsorption) to EUR-1008 vs. previous enzyme treatment. RESULTS: In the randomized trial, EUR-1008 treatment compared to placebo resulted in a significantly higher mean CFA (88.3% vs. 62.8%, respectively) and CNA (87.2% vs. 65.7%, respectively) (both p<0.001) and reduced the incidence of malabsorption signs and symptoms in 32 evaluable patients. In the supplemental study, 11 of 19 patients met the criteria for responder with EUR-1008 at the end of the study vs. 10 of 19 patients at screening (previous PEP), and improvements in clinical symptoms were reported with EUR-1008 treatment. EUR-1008 was safe and well tolerated, and no serious drug-related AEs were reported in either study. CONCLUSIONS: EUR-1008 was safe, well tolerated, and effective in CF patients of all ages with EPI-associated malabsorption in two clinical trials. Treatment led to clinically and statistically significant improvements in CFA and CNA in the randomized study, and control of malabsorption and clinical symptoms in both studies.

Lung transplantation for cystic fibrosis.

Lung transplantation is a complex, high-risk, potentially life-saving therapy for the end-stage lung disease of cystic fibrosis (CF). The decision to pursue transplantation involves comparing the likelihood of survival with and without transplantation as well as assessing the effect of wait-listing and transplantation on the patient's quality of life. Although recent population-based analyses of the US lung allocation system for the CF population have raised controversies about the survival benefits of transplantation, studies from the United Kingdom and Canada have suggested a definite survival advantage for those receiving transplants. In response to these and other controversies, leaders in transplantation and CF met together in Lansdowne, Virginia, to consider the state of the art in lung transplantation for CF in an international context, focusing on advances in surgical technique, measurement of outcomes, use of prognostic criteria, variations in local control over listing, and prioritization among the United States, Canada, the United Kingdom, and The Netherlands, patient adherence before and after transplantation and other issues in the broader context of lung transplantation. Finally, the conference members carefully considered how efforts to improve outcomes for lung transplantation for CF lung disease might best be studied. This Roundtable seeks to communicate the substance of our discussions.