Flexible bronchoscopy and bronchoalveolar lavage in pediatric patients with lung disease.

OBJECTIVE: The use of flexible bronchoscopy (FOB) and bronchoalveolar lavage (BAL) in investigating pediatric patient with airway abnormalities and pulmonary infiltrates are indispensable and are now a routine procedure in many centers. Immunocompromised and cancer patients, especially after bone marrow transplantation, and children who have undergone surgery for congenital heart disease (CHD) are at high risk for pulmonary disease. Our aim was to study the diagnostic rate, safety, and clinical yield of FOB in critically ill pediatric patients. DESIGN: : Retrospective chart review. SETTING: Pediatric intensive care unit in a tertiary university hospital. PATIENTS: Three hundred nineteen children who underwent 335 FOB procedures. The indications for bronchoscopy included infectious agent identification in immune-competent patients with new pulmonary infiltrates seen on chest radiograph (46%) and in patients with fever and neutropenia with respiratory symptoms (18%), airway anatomy evaluation in patients with upper airway obstruction (16%), CHD (15%), and airway trauma (5%). Data were obtained by reviewing the patients' charts, bronchoscopy reports, and laboratory results. MEASUREMENTS AND MAIN RESULTS: The diagnostic rate of FOB procedures was 79%. FOB and BAL resulted in alteration of management (positive clinical yield) in 70 patients (23.9%). A definite infectious organism was identified in 56 patients (17.6%). The clinical yield in patients with cancer or primary immune deficiency (38.7%) was significantly higher compared with patients with CHD (20.4%, p < 0.01) and pneumonia (17%, p < 0.01). Major complications were observed in two procedures (prolonged apnea), and minor complications (transient desaturation, stridor, and minor bleeding) were observed in 45 patients (14%). CONCLUSIONS: FOB and BAL have an important role in the evaluation of airway abnormality and pulmonary infiltrate in pediatric patients, in whom rapid and accurate diagnosis is crucial for survival. We suggest that FOB should be considered as an initial diagnostic tool in those critically ill patients.

Gentamicin-induced correction of CFTR function in patients with cystic fibrosis and CFTR stop mutations.

BACKGROUND: Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene containing a premature termination signal cause a deficiency or absence of functional chloride-channel activity. Aminoglycoside antibiotics can suppress premature termination codons, thus permitting translation to continue to the normal end of the transcript. We assessed whether topical administration of gentamicin to the nasal epithelium of patients with cystic fibrosis could result in the expression of functional CFTR channels. METHODS: In a double-blind, placebo-controlled, crossover trial, patients with stop mutations in CFTR or patients homozygous for the DeltaF508 mutation received two drops containing gentamicin (0.3 percent, or 3 mg per milliliter) or placebo in each nostril three times daily for two consecutive periods of 14 days. Nasal potential difference was measured at base line and after each treatment period. Nasal epithelial cells were obtained before and after gentamicin treatment from patients carrying stop mutations, and the C-terminal of surface CFTR was stained. RESULTS: Gentamicin treatment caused a significant reduction in basal potential difference in the 19 patients carrying stop mutations (from -45+/-8 to -34+/-11 mV, P=0.005) and a significant response to chloride-free isoproterenol solution (from 0+/-3.6 to -5+/-2.7 mV, P<0.001). This effect of gentamicin on nasal potential difference occurred both in patients who were homozygous for stop mutations and in those who were heterozygous, but not in patients who were homozygous for DeltaF508. After gentamicin treatment, a significant increase in peripheral and surface staining for CFTR was observed in the nasal epithelial cells of patients carrying stop mutations. CONCLUSIONS: In patients with cystic fibrosis who have premature stop codons, gentamicin can cause translational "read through," resulting in the expression of full-length CFTR protein at the apical cell membrane, and thus can correct the typical electrophysiological abnormalities caused by CFTR dysfunction.

Exercise challenge test in 3- to 6-year-old asthmatic children.

RATIONALE: The exercise challenge test (ECT) is a common tool to assess exercise-induced asthma (EIA) in school-aged children. EIA has not been explored in the early childhood setting. OBJECTIVE: To assess the existence of EIA in children in this age group. MEASUREMENTS AND MAIN RESULTS: A 6-min, controlled, free-run test was performed in 55 children (age range, 3 to 6 years old) who were classified into the following groups: 30 children in whom asthma had been previously diagnosed (group A); and 25 children with prolonged coughing (group B). Spirometry measurements were obtained before the run, and at 1, 2, 3, 5, 10, and 20 min after the run. A positive finding of EIA was defined as a 13% decrease from baseline FEV(1) or baseline forced expiratory volume in the first 0.5 s (FEV(0.5)). The actual duration of each run was age-related (mean [+/- SD] duration, 4.8 +/- 0.8 min). The nadir in indexes occurred after a mean time of 2.98 +/- 1.31 min. A positive EIA finding determined by FEV(1) was present in 15 children, and by FEV(0.5) in 34 children. Twenty-six children were from group A, but only 8 children were from group B. Wheezing and/or prolonged expiration were associated with a positive test result in 31 of 34 children. Coughing was frequent in children with both negative and positive ECT findings. CONCLUSION: The present study documents for the first time the presence of EIA in response to a free-run test in early childhood. Our findings suggest that a free-run test for the presence of EIA is suitable, but that the running duration is limited by age. The duration of airflow limitation after exercise is significantly earlier and shorter in young children with asthma compared with older children. FEV(0.5) is a better index than the traditional FEV(1) for describing positive ECT results in young children. The association of wheezing and/or prolonged expiration may help in defining EIA in early childhood in the absence of a spirometer.

Spirometry in early childhood in cystic fibrosis patients.

BACKGROUND: Spirometry data in cystic fibrosis (CF) patients in early childhood is scarce, and the ability of spirometry to detect airways obstruction is debatable. OBJECTIVE: To evaluate the ability of spirometry to detect airflow obstruction in CF patients in early childhood. METHODS: CF children (age range, 2.5 to 6.9 years) in stable clinical condition were recruited from five CF centers. The children performed guided spirometry (SpiroGame; patented by Dr. Vilzone, 2003). Spirometry indices were compared to values of a healthy early childhood population, and were analyzed with relation to age, gender, and clinical parameters (genotype, pancreatic status, and presence of Pseudomonas in sputum or oropharyngeal cultures). RESULTS: Seventy-six of 93 children tested performed acceptable spirometry. FVC, FEV1, forced expiratory flow in 0.5 s (FEV0.5), and forced expiratory flow at 50% of vital capacity (FEF50) were significantly lower than healthy (z scores, mean +/- SD: - 0.36 +/- 0.58, - 0.36 +/- 0.72, - 1.20 +/- 0.87; and - 1.80 +/- 1.47, respectively; p < 0.01); z scores for FEV1 and FVC were similar over the age ranges studied. However, z scores for FEV0.5 and forced expiratory flow at 25 to 75% of vital capacity were significantly lower in older children compared to younger children (p < 0.001), and a higher proportion of 6-year-old than 3-year-old children had z scores that were > 2 SDs below the mean (65% vs 5%, p < 0.03). Girls demonstrated lower FEF50 than boys (z scores: - 2.42 +/- 1.91 vs - 1.56 +/- 1.23; p < 0.001). Clinical parameters evaluated were not found to influence spirometric indices. CONCLUSIONS: Spirometry elicited by CF patients in early childhood can serve as an important noninvasive tool for monitoring pulmonary status. FEV0.5 and flow-related volumes might be more sensitive than the traditional FEV1 in detecting and portraying changes in lung function during early childhood.

N-terminal pro B-type natriuretic peptide (N-BNP) levels in cystic fibrosis patients.

BACKGROUND: The diagnosis of right heart failure and pulmonary hypertension in cystic fibrosis (CF) patients with advanced pulmonary disease is sometimes difficult on clinical grounds alone. B-type natriuretic peptide (BNP) & N-terminal pro-B-type natriuretic peptide (N-BNP) levels were found to be useful in differentiating heart failure from various pulmonary diseases. However, its level was never measured in CF patients. The aim of this study was to measure N-BNP level in CF patients without heart failure. METHODS: The study included 49 patients. Of these, 32 had CF and 17 were control subjects who were matched by age and sex variables to the study group. We looked for a correlation between N-BNP and lung function test, genetic profile, height percentiles, and weight percentiles. N-BNP level was measured using an immunoassay that contains polyclonal antibodies that recognize epitopes located in the N-terminal part of proBNP. RESULTS: N-BNP level among CF patients without heart failure, after age and sex adjustments, was similar to the control group (Median: 47 pg/ml vs. 38 pg/ml, P = 0.248, interquartile range: 33-99 pg/ml vs. 31-76 pg/ml). A correlation between N-BNP level to age was found in both groups (CF: R = -0.398; P = 0.024, CONTROL: R = -0.054; P = 0.024). There was no correlation between N-BNP level to FEV1, O2 saturation and nutritional status. Among CF patients, eight (25%) had a mildly elevated N-BNP level whereas none was found in the control group (P = 0.038). CONCLUSION: We conclude that N-BNP level among CF patients is similar to the normal population and that it has no correlation to lung function impairment. Therefore, measurement of elevated N-BNP level in CF patients might be a predictor to the development of pulmonary hypertension and heart failure.

Effect of low altitude at the Dead Sea on exercise capacity and cardiopulmonary response to exercise in cystic fibrosis patients with moderate to severe lung disease.

Oxygen supplementation may improve exercise tolerance and the physiological response to exercise in cystic fibrosis (CF) patients. Elevated barometric pressure at low altitude is a simple means of increasing the quantity of inspired oxygen. Our objectives were to examine the effect of natural oxygen enrichment (at the Dead Sea, 396 m below sea level) on exercise capacity, and the physiological responses to maximal and submaximal exercise in CF patients. Patients were tested twice: at sea level (barometric pressure, 754 +/- 6 mmHg, mean +/- SD), and at the Dead Sea (barometric pressure, 791 +/- 3 mmHg), in a randomized crossover design. We studied 14 CF patients (6 females, 8 males), aged 15-45 years, with moderate to severe lung disease (mean forced expired volume in 1 sec = 50.0 +/- 11.2% predicted). Tests at each site included resting spirometry, anthropometry, a graded submaximal exercise test, a maximal exercise test on a treadmill, and a 6-min walk test. Tests were performed in identical order at both sites. Tests at the Dead Sea were performed 72 hr after arrival. No differences between sites were observed in lung function at rest. Peak oxygen consumption was significantly improved at the Dead Sea compared with sea level (1.68 +/- 0.73 vs. 1.57 +/- 0.74 l/min, respectively, P = 0.05), along with an improvement in the ventilatory equivalent for oxygen (41.2 +/- 6.3 vs. 46.1 +/- 7.1, respectively, P < 0.05). During submaximal exercise, blood oxygen saturation improved at the Dead Sea compared with sea level at all exercise intensities (P < 0.05). In conclusion, these results suggest that even a brief stay at the Dead Sea area may have physiological benefits for CF patients with moderate to severe lung disease.

Lung transplantation in patients with cystic fibrosis: the Israeli experience.

BACKGROUND: Lung transplantation is a well-established therapeutic option for end-stage lung disease in cystic fibrosis. Although it confers a clear survival advantage, outcome differs among centers according to local experience, patient selection, transplantation procedure, and postoperative care. OBJECTIVES: To evaluate the national Israeli experience with lung transplantation in patients with CF. METHODS: We reviewed the medical charts of all CF patients who underwent lung transplantation between January 1996 and June 2005 at the two Israeli centers that perform this procedure. RESULTS: Eighteen transplantations were performed in 17 patients. Mean patient age at transplantation was 25.3 +/- 9.1 years, and mean duration of follow-up in survivors (n=14) was 37.2 months (range 1-113 months). The actuarial survival rate was 88% at 1 year and 74% at 5 years. Pulmonary function, expressed as percent of predicted normal forced expiratory volume in 1 sec, improved from 22.4 +/- 8.1% to 76 +/- 16.8% at one year after transplantation. Bronchiolitis obliterans syndrome was diagnosed in 5 patients (29%), of whom 2 died and 2 are currently candidates for retransplantation. Median time to onset of BOS was 34.2 months (range 17-64 months). CONCLUSION: In Israel, the early and intermediate-term results of lung transplantation for cystic fibrosis are encouraging. BOS remains a major complication that threatens long-term outcome.

Methacholine bronchial provocation measured by spirometry versus wheeze detection in preschool children.

BACKGROUND: Determination of PC20-FEV1 during Methacholine bronchial provocation test (MCT) is considered to be impossible in preschool children, as it requires repetitive spirometry sets. The aim of this study was to assess the feasibility of determining PC20-FEV1 in preschool age children and compares the results to the wheeze detection (PCW) method. METHODS: 55 preschool children (ages 2.8-6.4 years) with recurrent respiratory symptoms were recruited. Baseline spirometry and MCT were performed according to ATS/ERS guidelines and the following parameters were determined at baseline and after each inhalation: spirometry-indices, lung auscultation at tidal breathing, oxygen saturation, respiratory and heart rate. Comparison between PCW and PC20-FEV1 and clinical parameters at these end-points was done by paired Student's t-tests. RESULTS AND DISCUSSION: Thirty-six of 55 children (65.4%) successfully performed spirometry-sets up to the point of PCW. PC20-FEV1 occurred at a mean concentration of 1.70+/-2.01 mg/ml while PCW occurred at a mean concentration of 4.37+/-3.40 mg/ml (p < 0.05). At PCW, all spirometry-parameters were markedly reduced: FVC by 41.3+/-16.4% (mean +/-SD); FEV1 by 44.7+/-14.5%; PEFR by 40.5+/-14.5 and FEF25-75 by 54.7+/-14.4% (P < 0.01 for all parameters). This reduction was accompanied by de-saturation, hyperpnoea, tachycardia and a response to bronchodilators. CONCLUSION: Determination of PC20-FEV1 by spirometry is feasible in many preschool children. PC20-FEV1 often appears at lower provocation dose than PCW. The lower dose may shorten the test and encourage participation. Significant decrease in spirometry indices at PCW suggests that PC20-FEV1 determination may be safer.

Pregnancies and outcome in women with cystic fibrosis.

BACKGROUND: Along with the increased life expectancy in cystic fibrosis and the remarkable progress in its management and therapy, issues of female fertility and pregnancy are frequently raised. These include infertility, severity of lung disease, pancreatic insufficiency, poor nutritional status, glucose intolerance and diabetes, drug safety, and long-term maternal and neonatal outcome. OBJECTIVE: To describe the experience of our CF center in the management of CF pregnant woman from 1977 to 2004. METHODS: We analyzed 27 years of records (1977-2004) of the national CF registry of all CF women who wished to conceive and became pregnant. RESULTS: Eight CF women (mean age 24 +/- 4.5 years) who wished to conceive had 11 pregnancies and delivered 12 neonates. The pregestational results of forced expiratory volume per 1 second varied significantly among patients (59 +/- 23%), yet most (10/11) stayed stable throughout the pregnancy course. Maternal deterioration in CF condition occurred in only one mother, necessitating cesarean section. In 9 of the 11 pregnancies the women were pancreatic-insufficient. Of the 11 pregnancies, 2 CF women had diabetes mellitus and 3 developed gestational diabetes. One pregnancy occurred in a mother with a transplanted lung. Of the 12 neonates, 3 were preterm and one was born with esophageal atresia. No miscarriages, terminations or neonatal mortalities occurred. Although most of the CF mothers had FEV1 below 55% before pregnancy, the maternal and neonatal outcome was favorable and lung function tests generally remained stable. CONCLUSIONS: We conclude that pregnancy in CF is feasible with a positive maternal and neonatal outcome. Early participation of the CF physician in the wish of the CF woman to reproduce is required. The integration of an intensive multidisciplinary approach during pregnancy, which includes close follow-up of maternal and fetal condition by the various specialists, should ensure an optimal outcome.

Reversal of digital clubbing after lung transplantation in cystic fibrosis patients: a clue to the pathogenesis of clubbing.

Digital clubbing is a common sign in cystic fibrosis (CF) and in a variety of other diseases. However, its pathogenesis remains obscure. In diseases other than CF, regression of clubbing has been noted after cure of the underlying disease. The aim of this study was to assess whether clubbing is reversible in CF patients after lung transplantation. Digital clubbing was investigated in 3 CF patients, prior to and after lung transplantation. Distal phalangeal depth (DPD) and interphalangeal depth (IPD) of the index finger were measured using a skinfold caliper, and the DPD/IDP ratio was calculated. The mean DPD/IDP ratio was 1.08 +/- 0.05 prior to transplantation and 1.00 +/- 0.06, 0.96 +/- 0.06, 0.92 +/- 0.04, and 0.89 +/- 0.07 at 3, 6, 12, and 24 months after transplantation, respectively. In all 3 patients, the DPD/IDP ratio was greater than 1 before transplantation. In 2 patients, this ratio decreased to less than 1 within 3 months, and in the third patient within 9 months after surgery. We conclude that digital clubbing is reversible in CF patients who undergo lung transplantation. Regression was usually noted during the first 3 months posttransplantation. This could be explained either by adequate inactivation of a circulating clubbing-inducing molecule by the normal transplanted lungs, or by removal of the diseased lungs in which this presumably causative substance was produced.

Long-term non-invasive positive pressure ventilation among cystic fibrosis patients awaiting lung transplantation.

BACKGROUND: Pulmonary disease is the most frequent cause of morbidity and mortality in cystc fibrosis patients. New techniques such as non-invasive positive pressure ventilation have resulted in prolongation of life expectancy in CF patients with end-stage lung disease. OBJECTIVES: To determine the role of NIPPV in CF patients awaiting lung transplantation. METHODS: Between 1996 and 2001 nine CF patients (5 females) with end-stage lung disease were treated with bi-level positive airway pressure ventilation in the "spontaneous" mode. RESULTS: The patients' mean age at initiation of BiPAP was 15 years (range 13-40 years) and the mean duration of BiPAP usage was 8 months (range 3-16 months). Four patients underwent successful lung transplantation, three patients died while awaiting transplantation, and the remaining two are still on NIPPV while waiting for transplantation. Patients' body mass index increased significantly (P < 0.05) during BiPAP therapy (from 16.1 to 17.2 kg/m2). Blood pH, PaCO2, and bicarbonate improved significantly (from 7.31 to 7.38, 90.8 to 67.2 mmHg, and 48.9 to 40.3 mEq/L, respectively). Pulmonary function tests were not affected by BiPAP usage. The patients experienced a significant alleviation in morning headaches and improvement in quality of sleep (P < 0.003). There were no major complications during BiPAP usage. CONCLUSIONS: We demonstrated that long-term NIPPV can stabilize and improve physiologic parameters such as ventilation, arterial blood gases and body mass index, as well as subjective symptoms such as sleep pattern, daily activity level, and morning headaches in CF patients with end-stage lung disease. Further prospectively controlled studies are needed to evaluate the potential of BiPAP therapy and its influence on morbidity and mortality in the post-lung transplantation period.

The relation between age and time to maximal bronchoconstriction following exercise in children.

BACKGROUND: The exercise challenge test (ECT) is a common tool for assessment of asthma in children. Many studies suggest that the "time to maximal bronchoconstriction" (Nadir-t) after exercise challenge in asthmatic children may be age-dependent, although this has never been systematically studied. Such findings may influence epidemiological surveys where the schedule of post-exercise measurements is trimmed. This study systematically assesses the relation between age and time to maximal bronchoconstriction post-ECT. METHODS: Data were collected retrospectively from 131 subjects (87 male; 3-18 years) who were referred for ECT. The routine ECT was performed according to ATS recommendation of a 6-min run. Spirometry was measured at 1, 3, 5, 10, 15, and 20 min post-exercise. The post-exercise nadir of FEV1 (%baseline) (FEV1-nadir) and the time to maximal fall in Nadir-t (minutes) were sought and values were related to age. RESULTS: Baseline FEV1 values (mean+/-SD) were 90.5+/-13.8% predicted. FEV1-nadir was -23.6+/-11.7% from baseline values. The Nadir-t was reached at 5.1+/-2.6 min (range 2-12 min). A positive correlation between children's age and Nadir-t was observed (r2=0.542; SD of residuals=1.79; p<0.001), regardless of FEV1-nadir, whether the cutoff of point was -10% or -15% of baseline FEV1. Children <10 years of age showed Nadir-t at 3.4+/-1.7 min post-exercise and older children at 6.6+/-2.5 min post-exercise (p<0.0001). CONCLUSION: Our results indicate that the time to maximal bronchoconstriction is age-dependent in children and adolescents, and imply that the schedule of post-exercise FEV(1) measurements should be cautiously trimmed.

Long term nutritional rehabilitation by gastrostomy in Israeli patients with cystic fibrosis: clinical outcome in advanced pulmonary disease.

OBJECTIVES: Several studies have shown a linear correlation between nutritional status and pulmonary function in patients with cystic fibrosis. Our study aims were: 1) To evaluate the effect of nutritional supplementation via gastrostomy on nutritional, clinical, and pulmonary parameters, and 2) To identify predicting factors for success of long-term nutritional rehabilitation. METHODS: Twenty-one Israeli patients, aged 8 months to 20 years, underwent gastrostomy insertion from 1992 to 2001. All patients were pancreatic insufficient, and all carried severe mutations (W1282X in 62% of the patients). Anthropometric and clinical data were obtained for each patient: 0-12 months before and 6-12 months and 18-24 months after gastrostomy placement. Standard deviation scores (SDS) for height, weight, and body mass index as well as percent of height-appropriate body weight were calculated. RESULTS: The mean percent-of-predicted forced expiratory volume in 1 second (FEV1) decreased significantly during the first year of gastrostomy feeding (n = 16), from 44.2% +/- 13.9 to 41% +/- 13.3 (P = 0.05). However, during the second year of therapy (n = 10), a trend toward improvement was observed (from 39.4 +/- 12.1 to 41.4 +/- 16.1). Weight, and BMI z-scores as well as weight percent-of ideal body weight increased significantly. Height z-score for age decreased during the first year (from -1.9 +/- 1.3 to -2.1 +/- 1.4), However, a trend toward improvement was observed during the second year. A significant correlation was found between the change in weight z-score and height z-score during the first (r = 0.488, P = 0.016) and the second (r = 0.825, P < 0.001) years. There was no difference between compliers and noncompliers regarding height, weight, and BMI either before or after gastrostomy placement. A significant correlation between age at insertion of gastrostomy and improvement in height z-score (r = 0.52, P = 0.016) was observed. Cystic fibrosis related diabetes (n = 8) did not affect the response to supplemental feeding. CONCLUSIONS: We observed a trend toward improvement of pulmonary disease during the second year, and a significant improvement in weight, height, and BMI z-scores. Compliance, diabetes, and young age prior to tube insertion did not predict success of nutritional rehabilitation.