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Background Pneumothorax can be classified as traumatic, iatrogenic or spontaneous (SP), which can be subdivided into primary spontaneous Pneumothorax (PSP) a condition without preexisting lung disease, or secondary spontaneous Pneumothorax (SSP) a complication of a preexisting lung disease. Recurrence rate of PSP is 30% whereas for SSP rate is unknown. This article explores the experience of a tertiary center over 20 years. Methods A retrospective case review of patients hospitalized with pneumothorax to investigate the natural history and treatment of SP in a young population in a single tertiary center was conducted. A search of the digital archive (going back to 01/01/1995) of Sheba Medical Center identified hospitalized patients below the age of 40. Results The database was composed of the records of 750 patients (612 males, 138 females) that were hospitalized. The recurrence risk for SP after non-operative treatment was significantly higher. Women were found to have an increased risk of SSP when having SP (OR 2.78). Asthma was the most prevalent disease causing SSP in young people. Conclusions In this large cohort we found that operative procedure has clear protective effect from recurrence in SP, so surgery should be positively considered when treating SP in hospitalized patients. Among young people and particularly in pediatric patients, when females have a SP, we strongly recommend looking for primary lung disease. More studies are needed to determine the risk factors and produce clear guidelines regarding surgery as first treatment.

Summary Background Tezacaftor–ivacaftor is an approved cystic fibrosis transmembrane conductance regulator (CFTR) modulator shown to be efficacious and generally safe and well tolerated over 8–24 weeks in phase 3 clinical studies in participants aged 12 years or older with cystic fibrosis homozygous for the Phe508del CFTR mutation (F/F; study 661-106 [EVOLVE]) or heterozygous for the Phe508del CFTR mutation and a residual function mutation (F/RF; study 661-108 [EXPAND]). Longer-term (>24 weeks) safety and efficacy of tezacaftor–ivacaftor has not been assessed in clinical studies. Here, we present results of study 661-110 (EXTEND), a 96-week open-label extension study that assessed long-term safety, tolerability, and efficacy of tezacaftor–ivacaftor in participants aged 12 years or older with cystic fibrosis who were homozygous or heterozygous for the Phe508del CFTR mutation. Methods Study 661-110 was a 96-week, phase 3, multicentre, open-label study at 170 clinical research sites in Australia, Europe, Israel, and North America. Participants were aged 12 years or older, had cystic fibrosis, were homozygous or heterozygous for Phe508del CFTR, and completed one of six parent studies of tezacaftor–ivacaftor: studies 661-103, 661-106, 661-107, 661-108, 661-109, and 661-111. Participants received oral tezacaftor 100 mg once daily and oral ivacaftor 150 mg once every 12 h for up to 96 weeks. The primary endpoint was safety and tolerability. Secondary endpoints were changes in lung function, nutritional parameters, and respiratory symptom scores; pulmonary exacerbations; and pharmacokinetic parameters. A post-hoc analysis assessed the rate of lung function decline in F/F participants who received up to 120 weeks of tezacaftor–ivacaftor in studies 661-106 (F/F) and/or 661-110 compared with a matched cohort of CFTR modulator-untreated historical F/F controls from the Cystic Fibrosis Foundation Patient Registry. Primary safety analyses were done in all participants from all six parent studies who received at least one dose of study drug during this study. This study was registered at ClinicalTrials.gov ( NCT02565914 ). Findings Between Aug 31, 2015, to May 31, 2019, 1044 participants were enrolled in study 661-110 from the six parent studies of whom 1042 participants received at least one dose of study drug and were included in the safety set. 995 (95%) participants had at least one TEAE; 22 (2%) had TEAEs leading to discontinuation; and 351 (34%) had serious TEAEs. No deaths occurred during the treatment-emergent period; after the treatment-emergent period, two deaths occurred, which were both deemed unrelated to study drug. F/F (106/110; n=459) and F/RF (108/110; n=226) participants beginning tezacaftor–ivacaftor in study 661-110 had improvements in efficacy endpoints consistent with parent studies; improvements in lung function and nutritional parameters and reductions in pulmonary exacerbations observed in the tezacaftor–ivacaftor groups in the parent studies were generally maintained in study 661-110 for an additional 96 weeks. Pharmacokinetic parameters were also similar to those in the parent studies. The annualised rate of lung function decline was 61·5% (95% CI 35·8 to 86·1) lower in tezacaftor–ivacaftor-treated F/F participants versus untreated matched historical controls. Interpretation Tezacaftor–ivacaftor was generally safe, well tolerated, and efficacious for up to 120 weeks, and the safety profile of tezacaftor–ivacaftor in study 661-110 was consistent with cystic fibrosis manifestations and with the safety profiles of the parent studies. The rate of lung function decline was significantly reduced in F/F participants, consistent with cystic fibrosis disease modification. Our results support the clinical benefit of long-term tezacaftor–ivacaftor treatment for people aged 12 years or older with cystic fibrosis with F/F or F/RF genotypes. Funding Vertex Pharmaceuticals Incorporated.

Currently, there are no approved treatments for infants with acute bronchiolitis, the leading cause for hospitalization of infants worldwide, and thus the recommended approach is supportive. Inhaled Nitric oxide (iNO), possesses anti-viral properties, improves oxygenation, and was shown to be safe in infants with respiratory conditions. Hospitalized infants with acute bronchiolitis were therefore recruited to a prospective double-blinded, multi-center, randomized controlled pilot study. They received intermittent high dose iNO (160 ppm) plus oxygen/air for 30 min or oxygen/air alone (control), five times/day, up to 5 days. Sixty-nine infants were enrolled. No difference was observed in frequencies of subjects with at least one Adverse Event (AE) in iNO (44.1%) vs. control (55.9%); neither was Methemoglobin7% safety threshold. No drug-related serious AEs (SAEs) were reported. Analysis of Per-Protocol population revealed that length of stay (LOS), time to SpO

MosheAshkenazi,1,2SaraySity,2 IfatSarouk,1,2Bat El Bar Aluma,1,2AdiDagan,1,2YaelBezalel,1,2LeaBentur3 KrisDe Boeck,4 OriEfrati1,2 1Pediatric Pulmonology and National CF Center, Edmond and Lilly Safra Children’s Hospital, Sheba Medical Center, Ramat Gan, Israel; 2Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; 3Pediatric Pulmonology Institute, Ruth Rappaport Children’s Hospital, Rambam Health Care Campus, Haifa, Israel; 4Pediatric Pulmonology, Department of Pediatrics, University of Leuven, Leuven, Belgium Background: Allergic bronchopulmonary aspergillosis (ABPA) is a condition characterized by a Th2 response, serum eosinophilia, and increased total serum IgE to Aspergillus fumigatus. ABPA occurs in cystic fibrosis (CF) and asthma. Omalizumab is a humanized recombinant monoclonal antibody against IgE. Previous studies reported borderline results when treating ABPA with omalizumab. Methods: A retrospective study to investigate the efficacy of omalizumab in the treatment of ABPA in CF patients was conducted at 3 CF centers in Israel and Belgium. Data were obtained from the digital archive. We measured 4 outcome parameters: forced expiratory volume in 1 second, body mass index, pulmonary exacerbations, and steroid sparing. Results: The database was composed on the records of 9 patients. None of the outcome parameters showed any improvement. A favorable outcome was observed in patients with higher levels of posttreatment total IgE than those with lower levels. CF-related diabetes and male gender showed trends for poorer outcomes. Conclusion: No benefits were detected on treating ABPA in CF with omlaizumb. Monitoring the total IgE was not helpful. A prospective randomized double-blind study is needed. Keywords: ABPA, Omalizumab, CF, IgE

Background Preconception carrier screening for cystic fibrosis (CF) is usually performed using ethnically targeted panels of selected mutations. This has been recently challenged by the use of expanded, ethnically indifferent, pan-population panels. Israel is characterized by genetically heterogeneous populations carrying a wide range of CFTR mutations. To assess the potential of expanding the current Israeli preconception screening program, we sought the subset of molecularly unresolved CF patients listed in the Israeli CF data registry comprising ~650 patients. Methods An Israeli nationwide genotyping of 152 CF cases, representing 176 patients lacking molecular diagnosis, was conducted. Molecular analysis included Sanger sequencing for all exons and splice sites, multiplex ligation probe amplification (MLPA), and next-generation sequencing of the poly-T/TG tracts. Results We identified 54 different mutations, of which only 16 overlapped the 22 mutations included in the Israeli preconception screening program. A total of 29/54 (53.7%) mutations were already listed as CF causing by the CFTR2 database, and only 4/54 (7.4%) were novel. Molecular diagnosis was reached in 78/152 (51.3%) cases. Prenatal diagnosis of 24/78 (30.8%) cases could have been achieved by including all CFTR2-causing mutations in the Israeli panel. Conclusions Our data reveal an overwhelming hidden abundance of CFTR gene mutations suggesting that expanded preconception carrier screening might achieve higher preconception detection rates.

Background We aim to assess the prevalence and describe characteristics of tracheal diverticula (TD) in patients with cystic fibrosis (CF). Methods This retrospective study included 92 patients with known CF treated in our medical center who had available chest CT, performed between 2001 and 2013. Presence, number, size, and location of TD were recorded on the most recent chest CT. The severity of CF-related pulmonary CT findings and pulmonary function tests were recorded and correlated with the presence of the diverticula. Results Twenty-six (28%) of the 92 patients (17 males, 9 females, age range 5–59years) had one or more TD. The size of TD ranged from 2mm to 32mm. TDs were on the right posterolateral aspect of the upper tracheain nearly all patients. Small TDs appeared as a focal paratracheal lucency and larger ones as a soft tissue mass with central air bubbles. There was no significant difference in the Bhalla score between patients with and without TD. There was no correlation between the Bhalla score and patients' age, size, or number of diverticula. Pulmonary function tests were worse and declined faster in patients with TD compared to those without. Conclusions TDs are quite common on chest CT of CF patients. Those with diverticula have significantly worse pulmonary function tests than those without.

The Mutation I1234V is a CF causing mutation; however the mechanisms leading to loss of function are not fully understood. In this study, we aimed to characterize phenotypically individuals with the I1234V variant, and to gain a structural point of view of the mutant CFTR using computational studies.We conducted a retrospective descriptive study, reviewing the clinical records of 9 Israeli patients. The study was designed to include patients either homozygous or compound heterozygous for the I1234V mutation. For a comparison we analyzed clinical data of 12 patients homozygous for the F508del mutation. Computer models were constructed for I1234V, 1234-1239del and wild type CFTR.Mean FEV1 was 73.8 ± 21% predicted with an average annual rate of decline of 1%. When compared to patients homozygous for F508del the mean annual values of FEV1% predicted during the 6 years of data collection ranged from 51 to 58 ± 22-30 in the F508del group versus 76-82 ± 14-19 in the I1234V group (p 0.05). Structural models did not demonstrate noticeable differences between the three simulated constructs. Although the mutation resides in the NBD2, no interference with ATP binding was detected.This study describes phenotypically patients carrying the I1234V mutation. Compared to patients homozygous for F508del, these patients present with more favorable outcome. Structural models show high similarity between the static and dynamics pictures obtained for both the mutated and the WT-CFTR; however this model does not explore the folding process and therefore may strengthen the notion of a misfolding mutation.

Background Airways of Cystic Fibrosis (CF) patients are Nitric Oxide (NO) deficient which may contribute to impaired lung function and infection clearance. Mycobacterium abscessus (M. abscessus) infection prevalence is increasing in CF patients and is associated with increased morbidity and mortality. Here, we assess the safety and efficacy of intermittent inhaled NO (iNO) as adjuvant therapy in CF patients with refractory M. abscessus lung infection. Methods A prospective, open-label pilot study of iNO (160 ppm) administered five times/day during hospitalization (14 days), and three times/day during ambulatory treatment (7 days) was conducted. The primary outcome was safety measured by NO-related adverse events (AEs). Secondary outcomes were six-minute walk distance (6MWD), forced expiratory volume in 1 s (FEV1), and M. abscessus burden in airways. Results Nine subjects were recruited. INO at 160 ppm was well-tolerated and no iNO-related SAEs were observed during the study. Mean FEV1 and 6WMD were increased relative to baseline during NO treatment. M. abscessus culture conversion was not achieved, but 3/9 patients experienced at least one negative culture during the study. Mean time to positivity in M. abscessus culture, and qPCR analysis showed reductions in sputum bacterial load. The study was not powered to achieve statistical significance in FEV1, 6WMD, and bacterial load. Conclusions Intermittent iNO at 160 ppm is well tolerated and safe and led to increases in mean 6MWD and FEV1. INO exhibited potential antibacterial activity against M. abscessus. Further evaluation of secondary endpoints in a larger cohort of CF patients is warranted to demonstrate statistical significance.

Familial dysautonomia (FD) is a rare hereditary sensory and autonomic neuropathy characterized by chronic lung disease and cyclic vomiting due to hyper-adrenergic crises. Most FD patients are in a depleted nutritional state; however, the phenotype of the disease is quite different between patients, as for the severity of lung disease and the intensity and frequency of these pathognomonic crises. In this study we wanted to investigate whether resting energy expenditure (REE) levels are increased in this population, and if correlations exist between REE levels and phenotype severity.Data was collected from 12 FD patients (6/6 m/f). REE measurements were conducted by indirect calorimeter. Measured REE % predicted were correlated with pulmonary function, severity of the scoliosis, serum C-reactive protein, yearly frequency of hyperadrenergic crisis, hospital admissions and the use of nocturnal noninvasive positive pressure ventilation.Mean REE was 112 ±13% predicted with 50% being in a hypermetabolic state (REE/HB 110%). Body mass index (BMI) was below normal range in 75% of patients, and reduced energy intake was also decreased in 75%. No significant correlations to disease severity factors were found. When dividing the subjects to REE levels above or below 125% predicted, Patients with REE above 125% predicted presented with significantly lower inspiratory capacity (42.7% predicted vs 62.8% predicted; P = 0.04).Hypermetabolic state was described in 50% of FD patients. The Low BMI is explained by combination of relative anorexia and increased REE. The REE levels are related to the underling respiratory disease.

Ashkenazi M, Sity S, Sarouk I, et al. J Asthma Allergy. 2018;11:101–107.On page 101, in the Conclusion section, the text “omlaizumb” should have been “omalizumab”.Read the original article.&nbsp

BACKGROUND: Inspiratory capacity (IC) is often overlooked as an important measured index of spirometry in patients with cystic fibrosis (CF). Abnormally low IC may indicate the onset of static/dynamic hyperinflation, which may be accompanied by dyspnea and an increase in the work of breathing. This cross-sectional study sought to determine whether measuring IC during spirometry, may add clinical value to FEV1 measurements in CF subjects. METHODS: Anthropometric, clinical, spirometry, and static lung volume data were gathered retrospectively from 98 of 165 subjects with CF (mean ± SD age 26.8 ± 11.0 y) registered in The Edmond and Lily Safra Children9s Hospital, Sheba Medical Centre, Israel. We compared the IC (% predicted) to FEV1, static lung volumes, and hospitalization days/year. RESULTS: IC decreased alongside FEV1 decline but at a slower pace (r2 = 0.32). Incremental trapped air, as measured by residual volume (RV), and a rapid elevation in the ratio of RV to total lung capacity occurred when IC deteriorated below 60% predicted values. The unique combination of IC 40% predicted induced an increase of up to 125 hospitalization days/year compared to subjects having IC > 50% predicted (up to 73 d/y, P CONCLUSIONS: Measuring IC in CF subjects may reveal silent worsening of lung function as indicated by a decline in IC 40% predicted. This condition may lead to inefficient breathing at high lung volumes, which may explain a subjective sensation of breathlessness and lead to an increase in hospitalization days/year.

Background Familial dysautonomia (Riley-Day syndrome, hereditary sensory autonomic neuropathy type-III) is a rare genetic disease caused by impaired development of sensory and afferent autonomic nerves. As a consequence, patients develop neurogenic dysphagia with frequent aspiration, chronic lung disease, and chemoreflex failure leading to severe sleep disordered breathing. The purpose of these guidelines is to provide recommendations for the diagnosis and treatment of respiratory disorders in familial dysautonomia. Methods We performed a systematic review to summarize the evidence related to our questions. When evidence was not sufficient, we used data from the New York University Familial Dysautonomia Patient Registry, a database containing ongoing prospective comprehensive clinical data from 670 cases. The evidence was summarized and discussed by a multidisciplinary panel of experts. Evidence-based and expert recommendations were then formulated, written, and graded using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system. Results Recommendations were formulated for or against specific diagnostic tests and clinical interventions. Diagnostic tests reviewed included radiological evaluation, dysphagia evaluation, gastroesophageal evaluation, bronchoscopy and bronchoalveolar lavage, pulmonary function tests, laryngoscopy and polysomnography. Clinical interventions and therapies reviewed included prevention and management of aspiration, airway mucus clearance and chest physical therapy, viral respiratory infections, precautions during high altitude or air-flight travel, non-invasive ventilation during sleep, antibiotic therapy, steroid therapy, oxygen therapy, gastrostomy tube placement, Nissen fundoplication surgery, scoliosis surgery, tracheostomy and lung lobectomy. Conclusions Expert recommendations for the diagnosis and management of respiratory disease in patients with familial dysautonomia are provided. Frequent reassessment and updating will be needed.

Background Ivacaftor is a drug that increases the probability of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel remaining open. Information about the efficacy of ivacaftor in patients carrying the rare p.Ser549Arg (S549R) CFTR mutation is sparse. Aim Efficacy of ivacaftor treatment in patients carrying the p.Ser549Arg (S549R) CFTR mutation. Methods Data obtained from CF patients receiving ivacaftor for one year. Results Eight CF patients, mean age 21 ± 10 years, received ivacaftor. After one year, significant improvement was found in FEV 1 , increasing from 74% to 88% (p 25-75 , 59%–76% (p = 0.019). Sweat chloride concentration decreased from 116 ± 8 mmol/L to 51 ± 17 mmol/L (p Conclusions Ivacaftor therapy resulted in significant clinical improvement in patients carrying the p.Ser549Arg (S549R) CFTR mutation.

Rationale: Airways obstruction and lung volume restriction, major features of lung disease in cystic fibrosis (CF), may regress independently, causing dysanapsis between these parameters.Objectives: To explore the significance of dysanapsis (FEF25–75/FVC) ratio in CF.Methods: Yearly best spirometry data, collected during 8.6 ± 1 year per patient, was determined from 93 patients with CF. Three groups were formed according to initial FEV1. Group-N (n = 35; control, FEV1 above 80%predicted); Group-B (n = 38; FEV1 below 80%predicted); and Group-LT (n = 20; data collected before lung transplantation). The yearly decline in spirometry indices was defined in relation to the preceding year. Decline exceeding −2 z scores from Group-N in each index was considered “rapid decline.”Measurements and Main Results: Group-N's yearly decline of FEV1, FEF25–75, and FEF25–75/FVC were similar and reached −1.88 ± 2.93%, −1.41 ± 3.37%, and −1.81 ± 4.48%, respectively. Rapid decline was equal to −6.5%, −10.8%, and −8.1%, respect...

BACKGROUND Treatment of respiratory exacerbations in Cystic Fibrosis (CF) is important in slowing disease progression. The treatment may be given either at home or at the hospital. The aim of our study was to compare both treatment settings. MATERIAL/METHODS We retrospectively analyzed data of 139 treatments in 54 CF patients (age range 12-47 y) treated for respiratory exacerbations at the hospital (n = 84) and/or at home (n = 55). Primary outcomes were improvement in pulmonary function tests (PFTs), weight gain and duration of treatment in relation to treatment setting. Secondary outcomes were these same parameters, but in relation to different clinical preconditions and CF-related complications. RESULTS Mean improvement in FEV1 (% predicted) was similar between the hospital and home treatments (14.3 ± 34.4% vs. 14.3 ± 20.2%, respectively; NS), yet treatment duration was significantly shorter at the hospital (9.7 ± 6.7 vs. 16.3 ± 9.1 days, respectively; P < 0.02), especially for patients colonized with Pseudomonas aeruginosa (11.1 ± 5.5 vs. 18.0 ± 11.0 days, respectively; p

SummaryBackgroundThe 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.MethodsData 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 20min 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.ResultsBaseline 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±2.6min (range 2–12min). A positive correlation between children's age and Nadir-t was observed (r2=0.542; SD of residuals=1.79; p

Background Cystic fibrosis (CF) patients are predisposed to infection and colonization with different microbes. Some cause deterioration of lung functions, while others are colonizers without clear pathogenic effects. Our aim was to understand the effects of Nocardia species in sputum cultures on the course of lung disease in CF patients. Material and methods A retrospective study analyzing the impact of positive Nocardia spp. in sputum of 19 CF patients over a period of 10 years, comparing them with similar status patients without Nocardia growth. Pulmonary function tests (PFTs) are used as indicators of lung disease severity and decline rate in functions per year is calculated. Results No significant difference in PFTs of CF patients with positive Nocardia in sputum was found in different sub-groups according to number of episodes of growth, background variables, or treatment plans. The yearly decline in PFTs was similar to that recognized in CF patients. The control group patients showed similar background data. However, a small difference was found in the rate of decline of their PFTs, which implies a possibly slower rate of progression of lung disease. Conclusions The prognosis of lung disease in CF patients colonized with Nocardia does not seem to differ based on the persistence of growth on cultures, different treatment plans or risk factors. Apparently, Nocardia does not cause a deterioration of lung functions with time. However, it may show a trend to faster decline in PFTs compared to similar status CF patients without isolation of this microorganism in their sputum.

Background Population carrier screening (PCS) has been available in Israel since 1999 and universally subsidized since 2008. We sought to evaluate its impact. Methods A retrospective review of governmental databanks, the national CF registry and CF centers. Results CF rate per 100,000 live births has decreased from 14.5 in 1990 to 6 in 2011. From 2004–2011 there were 95 CF births: 22 utilized PCS; 68 (72%) had 2 known CFTR mutations; 37% were pancreatic sufficient. At diagnosis, age was 6 (0–98) months; 53/95 had respiratory symptoms, 41/95 failure to thrive and 19/95 pseudomonas. Thirty-four (36%) were Arabs and 19 (20%) orthodox Jews, compared to 20% and 8% respectively, in the general population. Conclusions PCS markedly reduced CF birth rates with a shift towards milder mutations, but was often avoided for cultural reasons. As children regularly have significant disease at diagnosis, we suggest a balanced approach, utilizing both PCS and newborn screening.

Leptin, adiponectin, and ghrelin have diverse roles in the control of inflammation and metabolism in a normal state as well as in a chronic disease state. The aim of this study was to evaluate their role in the extreme metabolic and proinflammatory state after burn injury and during the initial weeks of recovery.A prospective descriptive study in a tertiary care center was undertaken. Patients were comprised of 5 children aged 20-108 months with severe burn injury; burn size ranged from 15%-36% of total body surface area. Early enteral feeding, according to estimated energy expenditure, was initiated as 150% of the recommended dietary allowance and in accordance with the patients' nitrogen balance. Seven blood samples were collected sequentially, approximately 5 days apart, during the first 65 days after the burn injury. Samples were tested for leptin, ghrelin, and adiponectin.Leptin, ghrelin, and adiponectin had a similar trajectory of concentration over time: low levels at the beginning, increasing until 2-3 weeks post-burn, where they reached a plateau at 5 weeks post-injury. The typical inverse correlations of ghrelin and adiponectin with leptin were absent. Interleukin-6 was negatively associated with ghrelin and adiponectin and was not associated with leptin. Insulin-like growth factor-1 (IGF-1) had a positive association with the 3 hormones; however, their profiles differ in their relationship to the expected concentration based on a literature review. Ghrelin and adiponectin were higher, leptin and IGF-1 were lower than expected.In the early weeks after burn injury, the hypermetabolic state and inflammation have a major effect on leptin, ghrelin, and adiponectin. The concurrent and similar change of the 3 hormones serves the parallel anabolic and catabolic processes during the recovery from burn injury. .

Intractable hypotension due to septic shock is associated with high mortality rates in critically ill children worldwide. The use of terlipressin (triglycyl-lysine-vasopressin), an analog of vasopressin with a longer duration of action, recently emerged as a treatment of hypotension not responsive to vasopressors and inotropes. This was a retrospective study set in an 18-bed pediatric critical care department in a tertiary care children's hospital. We reviewed the files of all children with septic shock who were treated with terlipressin between January 2003 and February 2004. Fourteen children (mean age, 5.6 years; range, 4 days to 17.7 years) were treated with terlipressin in 16 septic shock episodes. Significant improvements in respiratory and hemodynamic indices were noted shortly after treatment. Mean arterial blood pressure increased significantly from 54 +/- 3 to 72 +/- 5 mmHg 10 min after terlipressin administration (P = 0.001). Heart rate decreased from 153.0 +/- 6.5 beats/min to 138.0 +/- 7.5 beats/min 12 h after treatment onset (P = 0.003). Epinephrine infusion was decreased or stopped in eight patients after terlipressin administration. Urine output increased from 1.6 +/- 0.5 mL/kg/h to 4.3 +/- 1.2 mL/kg/h 1 h after treatment onset (P = 0.011). PaO2 increased from 95.1 +/- 12.3 mmHg to 110.1 +/- 20.5 mmHg, and the oxygenation index decreased from 10.2 +/- 2.2 to 9.2 +/- 1.7. Terlipressin treatment of hypotension due to septic shock was successful in eight out of 16 episodes. Six of the 14 patients with poor prognosis for survival recovered. We conclude that terlipressin improves hemodynamic indices and renal function in critically ill children. Terlipressin should be considered as a rescue therapy in intractable shock not responsive to catecholamines in children.

Morbidity and mortality in cystic fibrosis patients is mainly attributed to pulmonary infection and inflammation. Chemokines play a pivotal role in the inflammatory process. Although genotype-phenotype correlation in cystic fibrosis patients has been defined, a clear relationship between the defect in the cystic fibrosis transmembrane regulator (CFTR) gene and pulmonary inflammation has not been established. The aim of this study was to assess whether serum chemokines levels in cystic fibrosis patients correlate with genotype and pulmonary function tests, as well as with other clinical characteristics. Serum levels of interleukin-8, RANTES, and monocyte chemoattractant protein-1 were measured in 36 cystic fibrosis patients grouped according to their genotype. Group A included 25 patients who carried two mutations associated with a pathological sweat test and pancreatic insufficiency (deltaF508, W1282X, G542X, N1303K, S549R). Group B included 11 compound heterozygote patients who carried one mutation known to cause mild disease with borderline or normal sweat test and pancreatic sufficiency (3849+10kb C to T, 5T). Associations between chemokine levels, genotype, pulmonary function, Pseudomonas aeruginosa colonization, age, sweat chloride level, and pancreatic and nutritional status were examined. Mean interleukin-8 and monocyte chemoattractant protein-1 levels were significantly higher in group A than group B (11.4 +/- 2.1 pg/ml vs. 5 +/- 0.9 pg/ml and 157 +/- 16 pg/ml vs. 88.8 +/- 16.4 pg/ml, respectively) (P0.01). No difference in RANTES levels were found between groups. interleukin-8 levels were inversely related to forced expiratory volume in 1 s (r = -0.37, P0.02), while there was no association between the latter and RANTES and monocyte chemoattractant protein-1 levels. The Pseudomonas colonization rate was higher among group A patients than group B (88% vs. 40%, P0.01). No relationship was found between measured chemokines and age, sweat chloride levels, and pancreatic and nutritional status. Our study demonstrates an association between interleukin-8, forced expiratory volume, and cystic fibrosis genotype. Hence, elevated interleukin-8 serum levels could serve as an indicator of an early inflammatory process and encourage the initiation of anti-inflammatory treatment.

Arginine-vasopressin (AVP) may be more effective than epinephrine in shock states and as an end-of-life salvage maneuver. However, there is only limited experience using AVP in children. Our study aim was to evaluate the effect of AVP administration on hemodynamic and ventilatory parameters in critically ill children. Eight critically ill children (1 month to 12 years old) were treated with AVP during the years 2000-2001. Two patients had had head trauma, and six had surgical correction of congenital heart disease. All patients suffered severe septic or cardiogenic shock with a low cardiac output state and were considered to be near death. AVP was administered continuously at a dose of 0.0003-0.002 U/kg/min. Hemodynamic and ventilatory parameters and vasopressor doses were compared before and after AVP initiation. One patient survived with a good neurologic outcome. Seven patients succumbed while receiving AVP. Systolic and diastolic blood pressure increased significantly (P < 0.03) following AVP initiation. The epinephrine requirement decreased from 2.3 to 1.7 μg/kg/min. Blood gases improved with a significant (P < 0.05) increase of PaO 2 . Oxygenation index and PaO 2 /FiO 2 ratio improved significantly, and ventilatory support requirements and positive inspiratory pressure (PIP) decreased significantly. Despite a significant improvement in hemodynamic and ventilatory support parameters, survival to hospital discharge was not achieved when AVP was used in critically ill pediatric patients. We hypothesize that earlier administration of AVP may be more beneficial.

Summary Rationale Forced vital capacity (FVC) values decrease with progress of the disease in Ataxia telangiectasia (AT). Objective To study the effect of this process on airway obstruction determination and life span in AT. Methods Clinical data and yearly best spirometry maneuvers were collected retrospectively from 37 AT patients (196 spirometry tests) during 5.4 ± 1.8yrs (initial age 4–21 y). Twelve patients were walking (7 of them had recurrent respiratory system infections); 25 subjects were confined to wheelchair, of them 8 patients were towards end-stage lung disease. Spirometry indices included Forced Vital Capacity (FVC), mid-expiratory-flow (FEF25-75), and tidal volume (VT). We calculated FEF25-75/FVC and VT/FVC ratios. Results FVC declined from 67 ± 8 while walking to 19 ± 6 %predicted values. FEF25-75 values that were elevated (116 ± 23 %predicted) while walking, decreased to 69 ± 27 %predicted at end-stage where 7 patients responded to bronchodilators. VT/FVC ratio was 0.25 ± 0.06 while walking, increased to 0.35 once on wheelchairs, and further increased to 0.57 ± 0.19 at end-stage disease. FEF25–75/FVC ratio was 2.54 ± 0.70 above normal (∼1.0) increasing to 4.16 ± 0.75 at end stage. A sharp elevation was seen in FEF25–75/FVC ratio when FEV1 was still ∼45 %predicted and 2-years prior to death. Conclusions Having a low baseline-FVC (60% predicted) artificially raises FEF25-75 values, so FEF25-75 of “mild obstruction” values may indicate severe airway obstruction in AT subjects. VT/FVC and FEF25-75/FVC ratios may therefore assist in revealing higher than normal breathing effort. The results further suggest adding VT/FVC and FEF25-75/FVC ratios to pulmonary function assessments in patients with AT.

BACKGROUND: Cough is part of life in patients with cystic fibrosis (CF). Weak coughing may add to increased respiratory disease that affects the mechanical properties of cough in these patients. In this study, we investigated cough characteristics in relation to forced expiratory flow/volume indices in CF. METHODS: This prospective study included 54 subjects (26 10 y old) with CF. Similar indices of the maneuvers were compared. Additionally, other cough characteristics revealed by the maneuvers were investigated. Cough was considered efficient with 6 or more secondary spikes at a flow of > 2.67 L/s. RESULTS: Cough peak flows similar to peak expiratory flows (regardless of FEV1 severity level) were found in 98% of subjects. The secondary spike flows deteriorated alongside the percent-of-predicted FEV1 (r 2 0.17, P .002), yet inefficient secondary spike flows could also be found when FEV1 was within normal range. Mean efficient spike number was low (2.5 1.2 spikes/maneuver). Most cough spike flows were very small (< 0.9 L/s), resembling vibration that may contribute to the propulsion of mucus toward the central airways. Cough maneuver duration ended faster than forced expiration duration (3.7 1.7 s vs 6.8 2.5 s, P < .001), resulting in a smaller cough vital capacity compared with expiratory vital capacity (2.1 0.9 l vs 3.1 0.7 l, P < .001). Inspiratory volume below 2.23 0.07 L reduced efficient secondary spike number. CONCLUSIONS: The cough flow/volume maneuver reveals abnormalities in cough velocities and volume. A low secondary spike correlates with FEV1 severity level. The method may lead to earlier

Summary Background Treatment of respiratory exacerbations in Cystic Fibrosis (CF) is important in slowing disease progression. The treatment may be given either at home or at the hospital. The aim of our study was to compare both treatment settings. Material/Methods We retrospectively analyzed data of 139 treatments in 54 CF patients (age range12–47 y) treated for respiratory exacerbations at the hospital (n=84) and/or at home (n=55). Primary outcomes were improvement in pulmonary function tests (PFTs), weight gain and duration of treatment in relation to treatment setting. Secondary outcomes were these same parameters, but in relation to different clinical preconditions and CF-related complications. Results Mean improvement in FEV1 (% predicted) was similar between the hospital and home treatments (14.3±34.4% vs. 14.3±20.2%, respectively; NS), yet treatment duration was significantly shorter at the hospital (9.7±6.7 vs. 16.3±9.1 days, respectively; P

Treatment of hemato-oncologic patients is often associated with severe pulmonary complications. Pulmonary function is routinely evaluated in older children, whereas in young patients, forced spirometry measurements are infrequently performed.To assess severity of airway disease using forced spirometry measured prior to and after treatment (over 3 years) in hemato-oncologic children aged 3-7 years in comparison to a healthy population.42-children (18-males; age 3-7 years old) with hemato-oncologic illnesses participated in the study. Spirometry was performed before the definitive treatment and up-to 3-years thereafter. Values were compared to those of healthy children of corresponding age.Most children (n=38) showed only minor long term airflow impairment (z-scores of FEV1 at last measurement was -0.00 to -0.45 SD). Prior to definitive treatment eight children presented severe airflow limitation (z-score =-1.35 + or - 0.72; -1.61 + or - 0.66 and -2.49 + or - 0.34 for FEV1, FEV0.5; and FEF25-75 respectively). Four of eight children resumed normal pulmonary function; the spirometry values of the other four children further deteriorated, in association with GVHD and development of bronchiolitis obliterans.Our study suggests that it is important to follow spirometry in young children with hemato-oncologic diseases in order to detect these patients, whose condition may have prognostic implications for their treatment.

T-cell immunodeficiency may pose a diagnostic challenge to clinicians, especially when the basic T-cell immune workup is not sufficiently informative. An intensive assessment of thymus capabilities that involves either measuring the recent thymic emigrant cells or analyzing the T-cell receptor (TCR) repertoire is often required to estimate the severity and nature of the immune disorder. A comprehensive T-cell immune workup, including TCR excision circles (TRECs) and TCR repertoire analyses, was performed in three patients with various degrees of severity of T-cell immunodeficiency. All three patients had normal peripheral CD3+ T lymphocytes. TCR repertoire analysis revealed oligoclonal (patient 1), restricted (patient 2), and near-normal (patient 3) patterns. TREC quantification was significantly reduced in patients 1 and 2 but normal in patient 3. Based on clinical features at presentation and at follow-up, and supported by the results of immunologic studies, patients 1 and 2 were diagnosed as having significant T-cell immunodeficiency and patient 3 as having T-cell immunocompetence. Assessment of thymus capabilities by TRECs and TCR repertoire analyses is helpful in diagnosing patients with T-cell immunodeficiency and should be part of the evaluation of every patient suspected of having that condition.

Objective To identify the characteristics of CF patients with hemoptysis in Israel and to compare clinical features and risk factors to a control group of CF patients without hemoptysis. Design Retrospective chart review. Patients All CF patients in Israel who experienced hemoptysis between 2001 and 2005 and a control group of sex- and age-matched patients with no history of hemoptysis. Results 40/440 CF patients (9.1%) experienced hemoptysis during the study period, 50% were male. Ten patients (25%) were under 13 years old at the first hemoptysis episode. Pulmonary exacerbation was the precipitating factor in 90%. Twenty three patients showed moderate or major hemoptysis. 35/40 patients responded well to conservative therapy. Bronchial artery embolization (BAE) was performed in 5 patients with no recurrence of bleed within 24 h. However all of these patients experienced recurrent hemoptysis. One patient died during the follow-up period because of end stage lung disease. Pulmonary function tests, body-mass index, coagulation tests, pancreatic status, presence of bronchiectasis, sputum cultures and genetic mutations were similar in the two groups. A high incidence (57.5%) of associated diseases including cystic fibrosis related diabetes, cirrhosis and portal hypertension, and distal intestinal obstruction syndrome was found among hemoptysis patients, compared to only 5.2% in the control group ( p Conclusions Hemoptysis, even major, did not seem to be a risk factor for mortality in our patients. A higher incidence of hemoptysis was found in our pediatric patients compared to other series. BAE shows a high immediate rate of success in controlling hemoptysis, but does not prevent future disease.

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.To evaluate the national Israeli experience with lung transplantation in patients with CF.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.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).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.

Vasopressin is an alternative drug to adrenaline in intractable ventricular fibrillation. However, vasopressin can cause significant bradycardia, resulting in reduced cardiac output. We investigated whether pre-treatment with atropine abrogates vasopressin-induced bradycardia in a beating-heart canine model.Five adult mongrel dogs received endotracheal vasopressin (1.0 U/kg) with or without endotracheal atropine (0.02 mg/kg) or a placebo (10 ml saline) after being anesthetized and ventilated. Hemodynamic variables and arterial blood gases were determined. Each dog (studied 3 times, one week apart) served as its own control.Endotracheal vasopressin produced early and significant (p0.05) bradycardia (from 55+/-7 mmHg to 35+/-5 beats/min) compared with controls, starting one minute post-injection and lasting one hour. In contrast, in atropine-pretreated animals the heart rate increased significantly (p0.05) for as long as one hour post-atropine and vasopressin administration. In addition, animals treated with vasopressin with or without atropine exhibited a significant rise in diastolic blood pressure (from 83+/-5 to 160+/-15 and from 83+/-3 to 108+/-10 mmHg, respectively). Systolic and mean blood pressures also increased significantly compared with controls. Blood gases remained unchanged in all groups.Endotracheal administration of vasopressin can cause protracted bradycardia. Pretreatment with atropine can abrogate this effect. We suggest that atropine administration be considered when vasopressin is administered during cardio-pulmonary resuscitation. Further studies are warranted to evaluate the effect of vasopressin and atropine in a closed-chest model of cardio-pulmonary resuscitation.

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.To determine the role of NIPPV in CF patients awaiting lung transplantation.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.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 (P0.05) 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 (P0.003). There were no major complications during BiPAP usage.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.

Vasopressin is a potent endogenous vasoconstrictor that increases blood pressure and systemic vascular resistance. The administration of exogenous vasopressin during closed and open cardiopulmonary resuscitation in humans was shown to be more effective than optimal doses of epinephrine in several clinical studies. We summarize here the recent experimental and clinical data on the use of vasopressin in cardiopulmonary resuscitation and septic shock. As the use of vasopressin in human resuscitation is now in its early stages, it is expected that accumulated future experience will shed more light regarding the risk-benefit aspects of its use.

AIM: To investigate the long-term follow-up of distal intestinal obstruction syndrome (DIOS) in Israeli cystic fibrosis (CF) patients. METHODS: This is a multi-center, comparative, retrospective study in which we reviewed the medical records of all CF patients from three major CF centers in Israel who were treated in the period from 1980 to 2012. Patients diagnosed with DIOS were defined as the study group. The patients were diagnosed with DIOS based on their clinical presentation and typical findings on either abdominal X-ray or computerized tomography scan. For the control group, CF patients with no DIOS were matched to the patients in the study group for age, sex, and cystic fibrosis transmembrane conductance regulator (CFTR) mutations. For both groups, the collected data included age, sex, CFTR genotype, weight, height, and body mass index. Clinical data included respiratory function tests in the last five years prior to the study, respiratory function test immediately before and after the DIOS event, number of hospitalizations, sputum culture results, and CF-related conditions diagnosed according to the CF clinical practice guidelines. In the study group, data on the DIOS treatment and tendency for DIOS recurrence were also analyzed. RESULTS: The medical charts for a total of 350 CF patients were reviewed. Of the 350 CF patients, 26 (7.4%) were diagnosed with DIOS. The control group included 31 CF patients with no DIOS diagnosis. The mean follow-up period was 21.6 ± 8.2 years. The total of DIOS episodes in the follow-up period was 60. The distribution of DIOS episodes was as follows: 6/26 (23.1%) study patients had one episode of DIOS in their lifetime, 7/26 (26.9%) had two episodes, 7/26 (26.9%) had three episodes, and 6/26 (23.1%) had four or more episodes. Compared to the control group, DIOS patients had a significantly higher incidence of meconium ileus in the past (65.4% vs 0%, respectively, P < 0.02), more Aspergillus spp. colonization (34.6% vs 3.2%, respectively, P < 0.02), and a higher number of hospitalizations due to respiratory exacerbations (8.6 vs 6.2 mean total hospitalizations per follow-up period, respectively, P < 0.02). No other significant differences were found between the control and study groups. The conservative treatment of DIOS, which mainly includes hydration and stool softeners, was successful in 82% of the episodes. The survival rate was similar for both groups. CONCLUSION: CF patients with DIOS suffer from recurrent hospitalizations and airway pathogen acquisition. Although recurrence of DIOS is common, conservative treatment is successful in most patients.

The aim of the study was to evaluate long-term pulmonary function tests in pediatric survivors of acute respiratory distress syndrome (ARDS).Observational study based on a telephone poll of retrospectively identified post ARDS children who were hospitalized in a pediatric intensive care unit (PICU) in a general 1200-bed teaching, tertiary, regional referral center for children.Follow-up pulmonary function tests were achieved in only 7 children, with a mean age of 7.3+/-4.3 years (range 3-12) and following 5.6+/-4.3 years after PICU discharge. The etiology for ARDS included: lymphoma (n=2), pneumonia (n=2), aspiration (n=1), petrol ingestion (n=1) and snake envenomation (n=1). The children had been ventilated for 9.4+/-7.3 days and their worst PaO2/FiO2 ratio was 65.1+/-17.0 mm Hg. The follow-up pulmonary functions in all the children was within normal limits except for one child who had mildly reduced DLCO and one who had mild exercise-induced hypoxemia (oxyhemoglobin saturation of 94%). Neither of the two nor the others showed subjective symptoms or clinical physical limitations.Children who survive ARDS apparently enjoy long-term normal pulmonary function. Some, however, may present subclinical dysfunction that persists for many years after the acute episode and evoked only by sophisticated lung tests.

IV adrenaline increases coronary and cerebral perfusion pressures during cardiopulmonary resuscitation. We recently showed that endotracheal adrenaline can decrease blood pressure (BP), a detrimental effect presumably mediated by the beta 2-adrenergic receptor unopposed by alpha-adrenergic vasoconstriction. This prospective, randomized, laboratory comparison of endotracheal adrenaline (0.05 mg/kg diluted with normal saline to 10 mL total volume) with or without nonselective beta-blocker (propranolol) pretreatment was conducted in an attempt to clarify the mechanism of this BP decrease. Five mongrel dogs were given 0.05 mg/kg endotracheal adrenaline (diluted) or 0.05 mg/kg endotracheal adrenaline followed by an IV propranolol (0.1 mg/kg) pretreatment. Each dog served as its own control (10 mL of normal saline administered endotracheally) and received each regimen at least one week apart. Endotracheal adrenaline given after the propranolol pretreatment produced an increase in systolic, diastolic, and mean arterial BPs, from 165/110 mm Hg (mean 128 mm Hg) to 177.5/125 mm Hg (mean 142.5 mm Hg), respectively, as opposed to the hypotensive effect of isolated endotracheal adrenaline (P0.03). Thus, endotracheal adrenaline was associated with predominantly beta-adrenergic-mediated effects, causing hypotension via peripheral vasodilatation unopposed by alpha-adrenergic vasoconstriction. The search for the optimal dose of endotracheal adrenaline should be aimed at achieving the higher alpha-adrenergic vasoconstrictive threshold.