Avigdor Hevroni

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.

Natural history of five children with surfactant protein C mutations and interstitial lung disease

Interstitial lung diseases in infants and children are uncommon and may be caused by specific inborn errors of surfactant metabolism. Five children with open lung biopsy diagnosed interstitial lung disease were followed (mean of 27.2 years) and evaluated for surfactant protein gene mutations. Four of the children were originally diagnosed as desquamative interstitial pneumonitis and one as chronic interstitial pneumonitis. All had good response to chloroquine or hydroxychloroquine treatment for periods of 7–38 months. Lung function tests, incremental exercise tests, and rentgenological studies were performed in the children. Surfactant protein gene mutations were searched in all the patients and in part of their families.

Collecting clinical data in primary ciliary dyskinesia- challenges and opportunities

Rationale: Primary ciliary dyskinesia (PCD) is under diagnosed and underestimated. Most clinical research has used some form of questionnaires to capture data but none has been critically evaluated particularly with respect to its end-user feasibility and utility. Objective: To critically appraise a clinical data collection questionnaire for PCD used in a large national PCD consortium in order to apply conclusions in future PCD research. Methods: We describe the development, validation and revision process of a clinical questionnaire for PCD and its evaluation during a national clinical PCD study with respect to data collection and analysis, initial completion rates and user feedback. Results: 14 centers participating in the consortium successfully completed the revised version of the questionnaire for 173 patients with various completion rates for various items. While content and internal consistency analysis demonstrated validity, there were methodological deficiencies impacting completion rates and end-user utility. These deficiencies were addressed resulting in a more valid questionnaire. Conclusions: Our experience may be useful for future clinical research in PCD. Based on the feedback collected on the questionnaire through analysis of completion rates, judgmental analysis of the content, and feedback from experts and end users, we suggest a practicable framework for development of similar tools for various future PCD research.

Infant pulmonary function testing in chronic pneumonitis of infancy due to surfactant protein C mutation

Pulmonary function testing is a vital tool in evaluation and management of adult ILD patients and is rarely overlooked during workup. However, there is paucity of data regarding its usefulness in management of infants with suspected interstitial lung disease. In this paper, we present the contribution of infant pulmonary function testing (iPFT) to the management of two infants with biopsy confirmed chronic pneumonitis of infancy due to surfactant protein C mutation. We have productively and safely used serial iPFT for decision making both during diagnosis and follow‐up of these infants. Pediatr Pulmonol. 2015; 50:E17–E23.

Relation between partial and raised volume forced expiratory flows in sick infants

The maximal expiratory flow–volume (MEFV) and the partial expiratory flow–volume (PEFV) maneuvers are interchangeably performed when testing infant lung function. In recent years, the MEFV has gained popularity over the PEFV as it offers the investigator various forced expiratory flow and volume variables in addition to the sole, maximal flow at functional residual capacity (

Use of tidal breathing curves for evaluating expiratory airway obstruction in infants

{\dot {\rm {V}}}{\max} {\rm FRC}

Recurrent Pneumonia due to Fibrosing Mediastinitis in a Teenage Girl: A Case Report with Long-Term Follow-Up

) available from the PEFV maneuver. Both types of measure are considered to provide information on airway function.

Bronchodilator responsiveness in wheezy infants predicts continued early childhood respiratory morbidity

ABSTRACT Objective: To evaluate tidal breathing (TB) flow-volume and flow-time curves for identification of expiratory airway obstruction in infants. Methods: Pulmonary function tests were analyzed retrospectively in 156 infants aged 3–24 months with persistent or recurrent respiratory complaints. Parameters derived from TB curves were compared to maximal expiratory flow at functional residual capacity (maxFRC) measured by rapid thoracoabdominal compression technique. Analyzed parameters were: inspiratory time (tI), expiratory time (tE), tidal volume, peak tidal expiratory flow (PTEF), time to peak tidal expiratory flow (tPTEF), expiratory flow when 50% and 25% of tidal volume remains in the lungs (FEF50, FEF25, respectively), and the ratios tPTEF/tE, tI/tE, FEF50/PTEF, and FEF25/PTEF. Statistical comparisons between flow indices and TB parameters were performed using mean squared error and Pearsons sample correlation coefficient. The study population was also divided into two groups based on severity of expiratory obstruction (above or below z-score for maxFRC of −2) to generate receiver operating characteristic (ROC) curves and calculate discriminatory values between the groups. Results: TB parameters that were best correlated to maxFRC were: tPTEF/tE, FEF50/PTEF, and FEF25/PTEF, with r = 0.61, 0.67, 0.65, respectively (p < 0.0001 for all). ROC curves for FEF50/PTEF, FEF25/PTEF and tPTEF/tE showed areas under the curve of 0.813, 0.797, and 0.796, respectively. Cutoff value z-scores of −0.35, −0.34, and −0.43 for these three parameters, respectively, showed an 86% negative predictive value for severe airway obstructions. Conclusion: TB curves can assist in ruling out severe expiratory airway obstruction in infants.

Predictive Value of Adenosine 5′-Monophosphate Challenge in Preschool Children for the Diagnosis of Asthma 5 Years Later

A teenage girl was evaluated for recurrent right pneumonia. The evaluation revealed a calcified mediastinal mass that compressed the right intermediate and middle lobar bronchi, as well as the right pulmonary artery and veins. The clinical picture together with imaging studies and borderline positive serology testing suggested a diagnosis of fibrosing mediastinitis associated with histoplasmosis. This rare condition is characterized by the local proliferation of invasive fibrous tissue within the mediastinum due to a hyperimmune reaction to Histoplasma capsulatum. Antifungal and anti-inflammatory therapies are usually ineffective, and surgical intervention contains a high morbidity risk. Palliative surgery and stenting of the compressed airway have been suggested. In the past, the prognosis was thought to be poor, but recent studies demonstrate a more positive outcome. Our patient had been radiologically and functionally stable under follow-up for over thirteen years and has married and delivered two healthy children, both following an uneventful pregnancy.

Primary ciliary dyskinesia in Israel: Prevalence, clinical features, current diagnosis and management practices

Abstract Objective: Spirometry including bronchodilator responsiveness is considered routine in the workup of asthma in older children. However, in wheezy infants the existence of bronchodilator responsiveness and its prognostic significance remain unclear. Methods: Infants (< 2 years) with chronic or recurrent wheezing or coughing were evaluated by infant pulmonary function testing (PFT). Maximal expiratory flow at the point of functional residual capacity (V̇maxFRC) was measured before and 20 minutes after salbutamol administration. Only infants with an obstructive profile (V̇maxFRC < 80% predicted) were included. The infants were divided into two groups with regard to whether or not a response to salbutamol was observed on PFT. A response was defined as a mean V̇maxFRC after salbutamol administration exceeding the upper confidence interval limit of individual pre-bronchodilator V̇maxFRC measurements. Follow-up data was gathered after a mean of 2 years. Measurements and Main Results: Sixty infants were included in the study of which 32 (53%) demonstrated responsiveness to bronchodilators. The infants in the responsive group had a significantly higher frequency of physician visits for wheezing than the non-responders (3.0 mean visits/yr vs. 1.5 respectively, P = 0.03), and had a higher likelihood of having received asthma medication in the last year of the follow-up period (84% vs. 50% respectively, RR: 1.68[1.10–2.56]). At the end of the follow-up period, more parents in the responsive group reported continued respiratory disease (71% vs. 22%, RR:3.21[1.30–7.95]). Conclusions: Bronchodilator responsiveness can be demonstrated by infant PFT in infants with recurrent wheezing and can predict increased respiratory morbidity until 3 years of age.