Objective: Increased eosinophil level in bronchoalveolar lavage fluid (BALF) characterizes asthma in school-age children and adults and has been suggested as a marker for disease severity and response to treatment. We aimed to investigate the occurrence and yield of BALF eosinophil cell count in preschool children with recurrent wheezing and its possible relation to future diagnosis of asthma. Methods: BALF was retrospectively studied in young wheezy children and its relation to asthma at age 6 years was evaluated. BALF from children aged 1-48 months (mean = 20.4) was analyzed in preschool wheezy children. Children with anatomical airway obstruction and other lower airway/lung diseases who underwent BALF served as controls. Assessment of asthma was accomplished at 6 years. Results: Eighty-two children were included. The mean age during bronchoscopy and BAL was 20.4 +/- 14.4 months (range: 1-48 months). Twenty-six patients had recurrent preschool wheezing, 13 anatomical airway obstruction and 43 had other lower airways/lung diseases. Groups were comparable for age during bronchoscopy and gender. No difference was found between groups for any of the BALF cell types. Eosinophils were very low in all three groups [mean (interquartile range): 0 (0-0.4), 0 (0-0.8), and 0.4 (0-1), respectively, p = 0.25]. No difference in eosinophil levels during bronchoscopy was found between asthmatic children to non-asthmatic as defined at age 6 years. Conclusions: Wheezing in preschool children is not associated with increased BALF eosinophils; hence, at this age, the diagnostic yield of BALF for cell count analysis for diagnosing asthma is limited and is not routinely indicated.

Background: Primary Ciliary Dyskinesia (PCD) is rare and its features in Israel have not been described.Aims: to assess prevalence utilizing state-of-the-art diagnostic techniques, and describe clinical features, diagnostic and management practices in Israel.Methods: A national multicenter study from 2012 to 2013 recruited patients diagnosed or suspected of having PCD. Diagnosis was verified using: nasal Nitric Oxide (nNO); High-speed Video Microscope Analysis (HVMA); Transmission Electron Microscopy (TEM) of cilia; Immuno-fluorescence staining (IF) for ciliary proteins, and genetic analysis.Results: Of the 203 patients recruited from 14 pediatric centers, 150 had a PCD diagnosis verified. Median age was 15.05y, with range 0.15-60.5y. PCD prevalence was 1:54,000 for the general population and 1:25,000 in children (5-14 y). For the non-Jewish (mainly Druze and Arab Moslem) compared to Jewish populations, prevalence was 1:16,500 and 1:139,000 respectively (p < 0.0001) and parental consanguinity was 85.4% and 21.9% respectively (p < 0.0001).Clinical features included bronchiectasis (88%), rhinitis (81%), recurrent pneumonia (78%), recurrent otitis (62%), neonatal pneumonia (60%) and situs inversus (42%). Prior diagnostic practices varied widely between centers with TEM assessed in 55% and abnormal in 61% of these. Management included antibiotics and airway clearance.Diagnostic verification revealed for 150 PCD patients: 81% nNO<233 ppb, 62% abnormal HVMA, 51% diagnostic TEM, 58% diagnostic IF and, 57% genetic diagnosis.Conclusions: PCD in Israel is rare, with comprehensive diagnostic tests showing prevalence in children similar to Europe. Prevalence was higher in non-Jews, associated with parental consanguinity. Diagnostic and management practices vary. Referral centers providing comprehensive diagnostic and care capabilities should be established. (C) 2016 Elsevier Ltd. All rights reserved.

Objective To investigate fractional exhaled nitric-oxide (FeNO) levels in children with Crohn's disease (CD) and ulcerative colitis (UC) and their correlation to disease activity.Materials and methods Children with CD and UC (aged 8-18 years) and age-matched healthy controls without respiratory symptoms were recruited. Disease activity was assessed using validated scores. All children performed spirometry and FeNO tests and the association between intestinal disease parameters and pulmonary functions was studied.Results Thirty-five children with CD, nine with UC, and 24 healthy controls were enrolled. The mean FeNO level was higher in children with CD compared with the controls. Increased FeNO levels (>23 parts per billion) were more common among CD and UC compared with healthy children (46, 33, and 0%, respectively, P<0.05). Nevertheless, FeNO levels did not correlate with disease activity. There were no significant differences between CD, UC patients, and healthy controls in any of the spirometric variables.Conclusion FeNO level, a marker of airway inflammation, is elevated in children with inflammatory bowel diseases irrespective of their intestinal disease activity. Increased FeNO levels are not associated with respiratory symptoms, suggesting a latent pulmonary involvement in the systemic disease. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

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.

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.

Meeting abstractSince the 1980s, a few case reports described patients with oto-rhino-pulmonary symptoms and respiratory epithelia lacking cilia who were subsequently diagnosed to suffer from "ciliary aplasia" or "acilia syndrome". Via a whole exome sequencing approach, we analyzed "ciliary aplasia" candidates (including patients from previous reports) and identified recessive mutations in CCNO (encoding Cyclin O) and MCIDAS (encoding Multicilin) in 9 and 16 individuals, respectively [1, 2]. All individuals suffered from severe respiratory symptoms of the upper and lower airways and development of bronchiectasis at an early age. Thorough analysis of respiratory epithelial cells obtained by nasal brush biopsy by both transmission electron microscopy (TEM) and immunofluorescence analysis (IF) revealed that respiratory cilia were not completely absent; some cells still retained one or two cilia. These cells not only showed a reduction of cilia by TEM and IF, but also a reduction and mislocalization of basal bodies and rootlets throughout the cytoplasm. Detailed analyses by IF in both man and Xenopus revealed that this reduction of cilia number was due to a centriole amplification defect in the acentriolar pathway, which is specific for multiciliated cells [1, 2].IF showed that MCIDAS functions upstream of CCNO and FOXJ1, which is important for transcriptional control of axonemal motor proteins such as DNAH5 and CCDC39. Whereas cilia in CCNO-mutant cells still contain motility-related proteins such as DNAH5 and CCDC39 and can display normal beating patterns, MCIDAS-mutant cells are immotile and lack those axonemal motor proteins [1, 2] . MCIDAS and CCNO lie adjacently on chromosome 5q11 in a region related to multiciliogenesis, and act in the same pathway underlying multiciliogenesis. Based on these findings, we propose that this disease now should be referred to as "mucociliary clearance disorder with reduced generation of multiple motile cilia" (RGMC).

Lung inflammation from exposure to airborne particulate matter (PM) may be responsible for morbidity in asthma, but several studies using environmental monitoring data showed inconsistent results. Thus, the aim of this study was to evaluate the capability of induced sputum (IS) technology in order to biologically monitor PM in the lungs of urban asthmatic children.

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.

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.

Accumulating evidence suggests that the use of acetaminophen increases the risk of developing asthma and that its widespread use has contributed to the increasing prevalence of asthma. Study design. To investigate the immediate effect of a single dose of acetaminophen on airways reactivity and inflammation in asthmatic and controls. A double blind placebo-controlled study was conducted on 42 asthmatic children and 21 healthy age-matched controls. Each participant received one oral dose of acetaminophen (15 mg/kg [160 mg/mL]) and one dose of a volume-matched placebo. Physical examination, spirometry results, and fractional exhaled nitric oxide levels were assessed before and 60 minutes following acetaminophen or placebo ingestion. Results. None of the studied variables showed any significant change after acetaminophen or placebo ingestion in either the asthmatic or the control groups. Conclusions. One single dose of acetaminophen neither evokes a bronchoconstriction response nor an increase in airway inflammation in children with asthma.

OBJECTIVE To investigate fractional exhaled nitric oxide (FeNO) levels in infants during acute respiratory syncytial virus (RSV) bronchiolitis and during convalescence. DESIGN Prospective cohort study. Comparison of FeNO levels between infants with laboratory-confirmed acute RSV bronchiolitis and 2 control groups: healthy infants and infants with recurrent wheezing. SETTING The Department of Pediatric Emergency Medicine and the Pediatric Pulmonary Clinic of the Tel Aviv Medical Center from November 2008 to July 2009. The FeNO levels were measured at referral and at 2 visits over 4 months after convalescence. The FeNO level was measured using the multiple-breath exhalation technique. PARTICIPANTS Forty-four infants with acute RSV bronchiolitis (mean [SD] age, 6.8 [7.3] months), 21 infants with recurrent wheezing (mean [SD] age, 10.8 [7.59] months), and 32 age-matched healthy controls (mean [SD] age, 6.8 [9.1] months). Follow-up data were available for 22 children (55%) for the first follow-up visit and for 11 children (25%) for the second follow-up visit. EXPOSURE Acute RSV bronchiolitis. MAIN OUTCOME MEASURES The FeNO levels during acute RSV bronchiolitis vs controls and FeNO levels during follow-up vs acute-stage disease. RESULTS Mean FeNO levels for RSV-positive infants were significantly lower compared with healthy controls and infants with recurrent wheezing: mean (SD), 1.89 (1.76) parts per billion (ppb), 7.28 (4.96) ppb, and 4.86 (7.49) ppb, respectively (P<.001). The FeNO levels at the 2- and 4-month follow-up visits increased to 7.74 (5.13) ppb and 11.37 (6.29) ppb, respectively (P=.001). CONCLUSIONS The FeNO levels are temporarily reduced during acute RSV bronchiolitis and increase during convalescence to normal levels and higher. The mechanisms for this suppression and its relation to future wheezing and asthma need to be studied.

To the Editor: Sivan et al investigated the use of exhaled nitric oxide (FeNO) in the diagnosis of asthma in school-age children.1Sivan Y. Gadish T. Fireman E. Soferman R. The use of exhaled nitric oxide in the diagnosis of asthma in school children.J Pediatr. 2009; 155: 211-216Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar They found a remarkable high diagnostic yield of FeNO and concluded that the test should be considered in the evaluation of children suspected of having asthma. Earlier studies on the matter have led to inconclusive results.2Malmberg L.P. Pelkonen A.S. Haahtela T. Turpeinen M. Exhaled nitric oxide rather than lung function distinguishes preschool children with probable asthma.Thorax. 2003; 58: 494-499Crossref PubMed Scopus (190) Google Scholar, 3Prasad A. Langford B. Stradling J.R. Ho L.P. Exhaled nitric oxide as a screening tool for asthma in school children.Respir Med. 2006; 100: 167-173Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar, 4Thomas P.S. Gibson P.G. Wang H. Shah S. Henry R.L. The relationship of exhaled nitric oxide to airway inflammation and responsiveness in children.J Asthma. 2005; 42: 291-295Crossref PubMed Scopus (37) Google Scholar Unfortunately, neither Sivan et al nor other authors evaluated the additional value of FeNO compared with readily available information, such as a simple patient history.1Sivan Y. Gadish T. Fireman E. Soferman R. The use of exhaled nitric oxide in the diagnosis of asthma in school children.J Pediatr. 2009; 155: 211-216Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar, 2Malmberg L.P. Pelkonen A.S. Haahtela T. Turpeinen M. Exhaled nitric oxide rather than lung function distinguishes preschool children with probable asthma.Thorax. 2003; 58: 494-499Crossref PubMed Scopus (190) Google Scholar, 3Prasad A. Langford B. Stradling J.R. Ho L.P. Exhaled nitric oxide as a screening tool for asthma in school children.Respir Med. 2006; 100: 167-173Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar, 4Thomas P.S. Gibson P.G. Wang H. Shah S. Henry R.L. The relationship of exhaled nitric oxide to airway inflammation and responsiveness in children.J Asthma. 2005; 42: 291-295Crossref PubMed Scopus (37) Google Scholar The authors did compare the diagnostic yield of FeNO with that of sputum eosinophils.1Sivan Y. Gadish T. Fireman E. Soferman R. The use of exhaled nitric oxide in the diagnosis of asthma in school children.J Pediatr. 2009; 155: 211-216Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar It is not surprising that a combination of these 2 measurements did not improve the area under the receiver operating characteristic curve for the diagnosis of asthma, because both were highly correlated. The clinically relevant question remains: What is the added value of FeNO compared with available information in clinical practice? We would be interested to see this analysis performed on the study material of Sivan et al. Besides a clinical history, it would be useful to take specific immunoglobulin E into account. It has been suggested that a large part of the association between FeNO and asthma may be explained by the correlation between FeNO and atopy.5Franklin P.J. Stick S.M. The value of FeNO measurement in asthma management: the motion against FeNO to help manage childhood asthma—reality bites.Paediatr Respir Rev. 2008; 9: 122-126Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar Second, we want to express our concern about the exclusion criteria. Although not explicitly stated, it seems from the footnote of Table II that more than one-third of the children with asthma (n = 37; Table I) were excluded from analysis because of steroid use before the study inclusion.1Sivan Y. Gadish T. Fireman E. Soferman R. The use of exhaled nitric oxide in the diagnosis of asthma in school children.J Pediatr. 2009; 155: 211-216Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar Information on earlier steroid use in children without asthma is not provided. Exclusion of steroid users selectively from the asthma group and not from the non-asthma group leads to biased results, with overestimation of the diagnostic yield of FeNO. ReplyThe Journal of PediatricsVol. 156Issue 3PreviewTo the Editor: Full-Text PDF

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.

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. METHODS:HsCRP was measured in 63 asthmatic children aged 2-12 years. The measurements were performed in 37 children during an episode of acute exacerbation and in 42 children during remission. RESULTS:HsCRP level (14.28 +/- 8.45 mg/L) during exacerbation was significantly higher than the mean level (1.92 +/- 3.16 mg/L) during remission (P < 0.0001), with the decrease being more prominent in children with a low body mass index percentile (P < 0.05). A reciprocal relationship was found between forced expiratory volume in 1 s and high-sensitivity C-reactive protein values (P > 0.049). CONCLUSION:Elevated HsCRP levels were significantly associated with respiratory impairment in children.