Micha Aviram

Deposition pattern of radiolabeled salbutamol inhaled from a metered-dose inhaler by means of a spacer with mask in young children with airway obstruction

BACKGROUND The exact amount of drug deposited in the respiratory and gastrointestinal tract in children with airway obstruction, when delivered from a metered-dose inhaler (MDI) via a spacer with mask, and its distribution in children with airway obstruction, are unknown. METHODS We studied 15 children, using salbutamol labeled with technetium 99m. Each patient was imaged with a gamma-camera immediately after one puff of labeled salbutamol was administered via a spacer with mask. Drug deposition was then analyzed to measure the distribution of the labeled spray in the oropharynx, the lungs, the stomach, and the spacer with mask (Aerochamber) itself. RESULTS Fifteen infants and children (mean age, 21 months (range, 3 months to 5 years); mean weight, 9.3 kg (range, 3.2 to 15 kg)) were studied. Mean aerosol deposition was 1.97% +/- 1.4% in the lungs, 1.28% +/- 0.77% in the oropharynx, and 1.11% +/- 2.4% in the stomach. The remainder was trapped in the spacer. Lung imaging after inhalation from an MDI via a spacer showed widespread deposition of the drug in central and peripheral intrapulmonary airways. In two adult volunteers the deposition after one puff of the same radiolabeled drug, inhaled from an MDI via a spacer with a mouthpiece, was 19% in the lungs and 2% in the stomach. CONCLUSIONS Infants and toddlers with obstructive lung disease can be reliably and safely treated with inhaled medication administered with an MDI via a spacer with mask. The doses of a drug given from an MDI to infants and toddlers when a spacer with mask is used are not yet well defined but should be higher than the currently recommended doses, perhaps as much as an adult dose.

Multicenter Cross-Sectional Study of Nontuberculous Mycobacterial Infections among Cystic Fibrosis Patients, Israel

A multicenter cross-sectional study showed prevalence appears to be increasing.

Evidence of Intestinal Inflammation in Patients With Cystic Fibrosis

Objectives: Treatment with pancreatic enzymes fails to completely correct malabsorption and gastrointestinal symptoms in patients with cystic fibrosis (CF). The aim of the present study was to examine the small intestine of patients with CF without overt evidence of gastrointestinal disease using capsule endoscopy (CE). Methods: Patients with CF received the agile patency capsule and, depending on the result of that procedure, then underwent standard CE using the PillCam SB capsule (Given Imaging, Yokneam, Israel). A stool specimen was taken on the same day as the CE for determination of the calprotectin level. Results: Forty-two patients with CF ages 10 to 36 years were included; 29 had pancreatic insufficiency. One patient failed to excrete the patency capsule after 36 hours and was withdrawn from the study. Pulmonary function was mild to moderate with FEV1 68.5% ± 16% predicted. Review of the CE videos showed that most of the patients had varying degrees of diffuse areas of inflammatory findings in the small bowel including edema, erythema, mucosal breaks, and frank ulcerations. There were no adverse events. Fecal calprotectin levels were markedly high in patients with pancreatic insufficiency, 258 μg/g (normal <50). Conclusions: Small bowel mucosal pathology may be detected using CE in most of the patients with CF. The high fecal calprotectin levels found are suggestive of mucosal inflammation, which may correlate with the CE findings. Additional study is required to examine the possible relation of these mucosal lesions, which may be part of a newly identified enteropathy associated with CF, with persistent intestinal malabsorption in many of these patients.

Clinical and Genetic Risk Factors for Cystic Fibrosis-related Liver Disease

Objective. The aim of this study was to define the role of possible risk factors for the development of cystic fibrosis (CF)-related liver disease and to analyze the association between liver disease and the different genotypes present in the Israeli CF patient population. Patients and Methods. All patients followed at the seven CF centers in Israel were included in this study. Liver disease was determined by persistently elevated serum liver enzymes and/or bilirubin, and/or significant ultrasonographic changes suggestive of chronic liver disease. The following clinical parameters were evaluated: ethnic origin, age at assessment of liver function, sex, history of meconium ileus, pancreatic function, history of distal intestinal obstruction syndrome, pulmonary function, and cystic fibrosis transmembrane conductance regulator mutation analysis. Results. Of the 288 patients screened, 80 (28%) had liver disease. Of the 256 patients with pancreatic insufficiency, 80 (31%) had liver disease compared with none of the 32 patients with pancreatic sufficiency. Genotype-phenotype correlation was performed on 207 patients carrying identified mutations that were previously classified according to phenotype severity. Liver disease was found in 56 (32%) of 173 patients carrying mutations associated with a severe phenotype and in 6 (38%) of 16 patients carrying at least one mutation associated with a variable genotype (G85E and/or 5T allele). None of the 18 patients carrying the 3849+10kb C->T mutation had liver disease. Prevalence of liver disease increased with age. No correlation was found between liver disease and severity of lung disease, nutritional status, history of meconium ileus, or distal intestinal obstruction syndrome. Conclusion. CF patients who have pancreatic insufficiency and carry mutations associated with a severe or a variable genotype are at increased risk to develop liver disease.

Restoration of the cystic fibrosis transmembrane conductance regulator function by splicing modulation

A significant fraction of disease‐causing mutations affects pre‐mRNA splicing. These mutations can generate both aberrant and correct transcripts, the level of which varies among different patients. An inverse correlation was found between this level and disease severity, suggesting a role for splicing regulation as a genetic modifier. Overexpression of splicing factors increased the level of correctly spliced RNA, transcribed from minigenes carrying disease‐causing splicing mutations. However, whether this increase could restore the protein function was unknown. Here, we demonstrate that overexpression of Htra2‐β1 and SC35 increases the level of normal cystic fibrosis transmembrane conductance regulator (CFTR) transcripts in cystic‐fibrosis‐derived epithelial cells carrying the 3849+10 kb C → T splicing mutation. This led to activation of the CFTR channel and restoration of its function. Restoration was also obtained by sodium butyrate, a histone deacetylase inhibitor, known to upregulate the expression of splicing factors. These results highlight the therapeutic potential of splicing modulation for genetic diseases caused by splicing mutations.

The changing face of the exocrine pancreas in cystic fibrosis: the correlation between pancreatic status, pancreatitis and cystic fibrosis genotype.

Objectives The aims of this study were to determine the current pancreatic status of the entire cystic fibrosis (CF) population of Israel, to analyze the clinical characteristics of the pancreatic sufficient (PS) patients, and to characterize the correlation between pancreatic status, pancreatitis, and CF genotype. Methods The Israeli CF database includes 505 patients. These patients were defined as being PS or insufficient according to their fecal pancreatic elastase level or by coefficient fat absorption findings. Mutations were categorized as severe (ΔF508, W1282X, G542X, S549R, N1303K, Q359K/T360K, 405+1G, and 1717) or mild/variable (3849+10 kb, D1152H, G85E, I1234V, R334W, and 5T) based on disease severity in patients carrying these mutations. Age at diagnosis, presenting symptoms, sweat–chloride concentrations, occurrence of pancreatitis, presence of diabetes, and liver disease were recorded. Results One hundred and thirty-nine (27.5%) of the CF patients were PS. None carried two mutations associated with severe disease. Over one third (34%) had normal or borderline sweat tests; 20 of these 139 patients had pancreatitis (14.3%) but none of the 366 pancreatic insufficient patients had it. Four initially PS patients became pancreatic insufficient: conversion followed several events of pancreatitis in three of them. Nasal potential differences were all pathological in 35 tested PS patients. None had either diabetes or liver disease. Conclusions A substantial number of CF patients are PS. All of them carry at least one mild mutation enabling production of a sufficient amount of normal mRNA to maintain exocrine pancreatic function. Pancreatitis occurs only in CF patients who are PS. These patients are at risk of progressing to pancreatic insufficiency.

Fatal Multiple Organ Failure Following Massive Hornet Stings

We describe a fatal outcome in a three-year-old child following massive stings by the oriental hornet (Vespa orientalis). The primary clinical features were coma, respiratory failure, coagulopathy, renal failure and liver dysfunction. On postmortem the main organs involved were brain, lungs, kidney and liver.

DNAH11 Localization in the Proximal Region of Respiratory Cilia Defines Distinct Outer Dynein Arm Complexes

Primary ciliary dyskinesia (PCD) is a recessively inherited disease that leads to chronic respiratory disorders owing to impaired mucociliary clearance. Conventional transmission electron microscopy (TEM) is a diagnostic standard to identify ultrastructural defects in respiratory cilia but is not useful in approximately 30% of PCD cases, which have normal ciliary ultrastructure. DNAH11 mutations are a common cause of PCD with normal ciliary ultrastructure and hyperkinetic ciliary beating, but its pathophysiology remains poorly understood. We therefore characterized DNAH11 in human respiratory cilia by immunofluorescence microscopy (IFM) in the context of PCD. We used whole-exome and targeted next-generation sequence analysis as well as Sanger sequencing to identify and confirm eight novel loss-of-function DNAH11 mutations. We designed and validated a monoclonal antibody specific to DNAH11 and performed high-resolution IFM of both control and PCD-affected human respiratory cells, as well as samples from green fluorescent protein (GFP)-left-right dynein mice, to determine the ciliary localization of DNAH11. IFM analysis demonstrated native DNAH11 localization in only the proximal region of wild-type human respiratory cilia and loss of DNAH11 in individuals with PCD with certain loss-of-function DNAH11 mutations. GFP-left-right dynein mice confirmed proximal DNAH11 localization in tracheal cilia. DNAH11 retained proximal localization in respiratory cilia of individuals with PCD with distinct ultrastructural defects, such as the absence of outer dynein arms (ODAs). TEM tomography detected a partial reduction of ODAs in DNAH11-deficient cilia. DNAH11 mutations result in a subtle ODA defect in only the proximal region of respiratory cilia, which is detectable by IFM and TEM tomography.

Cystic Fibrosis Transmembrane Conductance Regulator Ion Channel Function Testing in Recurrent Acute Pancreatitis

Goals To understand the relationship between acute recurrent pancreatitis and cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction. Background An emerging number of patients present with a nonclassic phenotype of cystic fibrosis (CF) with partial features or single-organ disease only. The association between the phenotype of recurrent pancreatitis CFTR dysfunction is unclear. Methods Patients with idiopathic recurrent pancreatitis were referred for electrophysiologic investigation. Results Thirty-three patients (18 males) aged 20±12 years with recurrent pancreatitis were studied. Three patients had mild asthma and 1 patient had mild ulcerative colitis. There was no family history of CF. All patients had normal imaging of the pancreatic duct by endoscopic retrograde cholangiopancreatography or magnetic resonance cholangiopancreatography. No patient was pancreatic insufficient. Mean sweat chloride values were 41±14 meq/L (range: 18 to 64). Nasal potential difference (NPD) measurement was pathologic in 7 patients. Mean basal potential difference in these 7 patients was −33±13 mV and there was an abnormal response to chloride-free and isoproterenol solutions. There was no difference in sweat chloride concentration between the 2 groups. Mutation analysis revealed W1282X/5T, D1152H/5T, and W1282X/− in 3 patients with abnormal NPD and 1 W1282X allele was found in 1 patient with normal NPD. Conclusions In this series, 21% of patients with recurrent pancreatitis have abnormalities of CFTR function. Patients presenting with recurrent, “idiopathic” pancreatitis require CFTR function testing.

Residual small airways lesions after kerosene pneumonitis in early childhood

AbstractTo assess residual lung damage after a single insult early in life, we studied 14 asymptomatic children, 10 years after an episode of kerosene pneumonitis. Immediately after kerosene ingestion all patients developed pulmonary symptoms. Eight had abnormal chest radiographs (group 1) whereas in six there were no radiographical changes (group 2). The average age at follow-up was 11.4 (range: 9.4–13.2). Lung volumes, expiratory flow-rates and their density dependence were measured and compared to an age, sex, and a height-matched control group. The volume of isoflow (Viso