Ruth Soferman

MCIDAS mutations result in a mucociliary clearance disorder with reduced generation of multiple motile cilia

Reduced generation of multiple motile cilia (RGMC) is a rare mucociliary clearance disorder. Affected persons suffer from recurrent infections of upper and lower airways because of highly reduced numbers of multiple motile respiratory cilia. Here we report recessive loss-of-function and missense mutations in MCIDAS-encoding Multicilin, which was shown to promote the early steps of multiciliated cell differentiation in Xenopus. MCIDAS mutant respiratory epithelial cells carry only one or two cilia per cell, which lack ciliary motility-related proteins (DNAH5; CCDC39) as seen in primary ciliary dyskinesia. Consistent with this finding, FOXJ1-regulating axonemal motor protein expression is absent in respiratory cells of MCIDAS mutant individuals. CCNO, when mutated known to cause RGMC, is also absent in MCIDAS mutant respiratory cells, consistent with its downstream activity. Thus, our findings identify Multicilin as a key regulator of CCNO/FOXJ1 for human multiciliated cell differentiation, and highlight the 5q11 region containing CCNO and MCIDAS as a locus underlying RGMC.

The Use of Exhaled Nitric Oxide in the Diagnosis of Asthma in School Children

OBJECTIVES To evaluate the yield of the fractional exhaled nitric oxide (FeNO) in the diagnosis of asthma compared with spirometry and induced sputum cytologic study in school-age children. STUDY DESIGN Consecutive children referred for evaluation of possible asthma were included. At referral, all children completed FeNO measurement, sputum induction for eosinophil count (eos%) and spirometry. The diagnosis of asthma was performed after 18 months with conventional criteria. Receiver operating curves were used to determine cutoff points for disease status, and accuracy was calculated. RESULTS A total of 150 children were included: 69 with steroid-naïve asthma, 44 without asthma, and 37 with asthma treated with controllers. FeNO and eos% levels were significantly higher in those with steroid-naïve asthma (P < .0001). The area under the receiver operating curve for FeNO and eos% were very high compared with forced expiratory volume in 1 second (0.906, 0.921, 0.606, respectively). The sensitivity, specificity, and positive and negative predictive values for best cutoff points of FeNO (19 parts per billion) were 80%, 92%, 89%, and 86%, respectively, and were similar to eos% (best cutoff = 2.7%): 81%, 92%, 89%, 85%, respectively. CONCLUSIONS FeNO measurement is useful in early diagnosis of pediatric asthma. We suggest considering FeNO measurement in the evaluation of children suspected of having asthma, especially in cases where the diagnosis is not clear.

HsCRP levels: Measurement of airway inflammation in asthmatic children

Background: The inflammatory marker, high‐sensitivity C‐reactive protein (HsCRP), is known to be related to non‐allergic asthma, obesity, cardiovascular disease and smoking in adults. The aim of the present study was to determine whether HsCRP is related to respiratory symptoms and pulmonary function test findings in asthmatic children.

Ultrafine particle content in exhaled breath condensate in airways of asthmatic children

Air pollution triggers and exacerbates airway inflammation. Particulate material (PM) in ambient is characterized as being coarse (PM 10, aerodynamic diameter range 2.5-10 µm), fine (PM 2.5, 2.5-0.1 µm) and ultrafine (UFP, nano-sized, <0.1 µm). It is known that smaller inhaled PM produced more inflammation than larger ones. Most data on human exposure to PM are based on environmental monitoring. We evaluated the effect of individual exposure to UFP on functional respiratory parameters and airway inflammation in 52 children aged 6-18 years referred to the Pulmonary and Allergic Diseases Laboratory due to respiratory symptoms. Spirometry, bronchial provocation challenge, induced sputum (IS), exhaled breath condensate (EBC) and franctional exhaled nitric oxide evaluations were performed by conventional methods. UFP content in EBC was analyzed by using a NanoSight Light Microscope LM20. The total EBC UFP content correlated with wheezing (r = 0.28, p = 0.04), breath symptom score (r = 0.3, p = 0.03), and sputum eosinophilia (R = 0.64, p = 0.005). The percent of EBC particles in the nano-sized range also correlated with wheezing (r = 0.36, p = 0.007), breath symptom score (r = 0.33, p ≤ 0.02), and sputum eosinophilia (r = 0.72, p = 0.001). Respiratory symptoms and airway inflammation positively correlated to UFP content in EBC of symptomatic children.

Changes in sensitivity to methacholine after inhalation with distilled water: the role of the bronchoconstrictive response

The inhalation of distilled water can induce bronchoconstriction and a transient increase in sensitivity to methacholine in asthmatics. The purpose of this study was to determine the role of the induced bronchoconstriction in the increased sensitivity to methacholine which follows the challenge with distilled water. Eighteen asthmatic children (age 9-17 yrs) were challenged by inhalation of distilled water. Bronchial responsiveness, the provocative concentration of methacholine producing a 20% decrease in forced expiratory volume in one second (PC20), was determined before inhalation of distilled water, and 1.5 and 24 h thereafter. Following inhalation of distilled water, eight patients (Group I) had a greater than 15% decrease in FEV1 (mean 23%); whereas, in the remaining 10 (Group II) the decrease was less than 7% (mean 1%). PC20 to methacholine, geometric mean and 95% confidence interval (CI), decreased transiently only at 1.5 h following inhalation of distilled water. The decrease was from 0.78 mg.ml-1 (95% CI 0.11-5.54 mg.ml-1) at baseline to 0.25 mg.ml-1 (95% CI 0.03-2.14 mg.ml-1) after challenge in Group I; and from 2.67 mg.ml-1 (95% CI 0.35-20.34 mg.ml-1) at baseline to 0.72 mg.ml-1 (95% CI 0.18-14.87 mg.ml-1) after challenge in Group II. The transient increase in sensitivity to methacholine observed following inhalation of distilled water occurred independently of the bronchoconstrictive response. This finding may have important clinical implications when hypo-osmolar solutions are used for delivery of drugs.

Cystic fibrosis and neonatal calcified scrotal masses

We report a case of an infant who presented with failure to thrive and in whom the identification of calcified scrotal masses led us to the diagnosis of cystic fibrosis.

Pediatric pulmonologists approach to the pre-operative management of the asthmatic child

Abstract Objective: No consensus guidelines exist for the respiratory treatment of asthmatic children referred for elective surgery. The aim of this study was to evaluate the attitude of pediatric pulmonologists regarding the pre-operative management of these children. Methods: A survey of pre-operative management of asthmatic children was conducted. All 48 certified pediatric pulmonologists in Israel completed a questionnaire that comprised 20 questions regarding their approach to pre-operative management including six case scenarios with a variety of clinical situations and treatments of children with asthma. Results: Response rate was 100%. All believed that pre-operative treatment should be considered in all asthmatic children. Almost 50% suggested that a pediatric pulmonologist should be consulted in all pre-operative assessments. 50% recommended consultation only in individual cases. Overall, results showed a very wide variability between responders especially in pre-school and poorly controlled school children. The variability referred to the use of bronchodilators, inhaled corticosteroids and their combination during the pre-operative days, the addition of systemic CS and the length of pre-operative treatment. Almost all participants suggested either the initiation or augmentation of pre-operative treatment in high risk situations. Conclusions: This data demonstrate an important variability among pediatric pulmonologists in Israel regarding the practice of pre-operative treatment of infants and children with asthma especially for the less controlled and high risk children. This is most probably explained by the paucity of evidence-based data and the lack of established guidelines. Consensus guidelines for the pre-operative management of asthmatic children are needed.

Interleukin-12 Peripheral Blood Levels in Asthmatic Children

Interleukin-12 (IL-12) was measured in 45 asthmatic children aged 3 to 16 years. The assessments were performed on 20 children during an episode of acute exacerbation and on 25 children during remission. There was no significant difference between the mean IL-12 level during exacerbation (1.63 ± 2.08 pg/mL) and during remission (0.88 ± 0.56 pg/mL) (p = .83). A positive, but insignificant, correlation was found between forced expiratory volume in 1 second and IL-12 (p = .634). IL-12 levels were significantly lower in children with a positive family history of asthma (1.13 ± 1.78 pg/mL) compared with those without (1.31 ± 1.06 pg/mL) (p < .012), supporting the theory that the gene-environment interactions affect the immune responses. IL-12 peripheral blood levels had no detectable impact on the course of established asthma in the study population.