Eosinophil cell count in bronchoalveolar lavage fluid in early childhood wheezing: is it predictive of future asthma?

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.

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.

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

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.

Pulmonary functions in children with inflammatory bowel disease.

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.

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.

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

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.

Biological monitoring of particulate matter accumulated in the lungs of urban asthmatic children in the Tel-Aviv area.

PURPOSE: 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. METHODS: We collected clinical, demographic, biological and environmental monitoring data on 136 children referred for asthma evaluations. The study participants were divided into two groups according to IS eosinophil counts of <3% (non-eosinophilic inflammation, n = 52) and ≥3% (eosinophilic inflammation, n = 84). RESULTS: The eosinophilic group displays significantly higher levels of fractional exhaled nitric oxide than the non-eosinophilic one (58.8 ± 47.5 vs 28.9 ± 34.2 ppm, p = 0.007). Particles (0-2.5 and 0-5 µm) comprised a strong risk factor for eosinophilic inflammation in IS (≥3%). Children with >80% of particles (0-2.5 µm) out of the total PM accumulated in the airways displayed the highest OR 10.7 (CI 2.052-56.4 p = 0.005) for an existing eosinophilic inflammation. Heme oxygenase-1 (HO-1) enzyme levels in IS positively correlated with % eosinophils and with particles in IS ranging between 2 and 3 µm. The level of HO-1 enzyme activity and FEV1/FVC in children with <3% eosinophils, but not ≥3%, was positively and significantly correlated, showing a protective effect of HO-1. CONCLUSION: Accumulation of PM involves oxidative stress pathways and is a risk factor for developing eosinophilic inflammation in asthmatic children. IS can biologically monitor this process.

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 effect of a single dose of acetaminophen on airways response in children with asthma.

UNLABELLED: 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.

Exhaled nitric oxide in acute respiratory syncytial virus bronchiolitis.

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.

Use and yield of chest computed tomography in the diagnostic evaluation of pediatric lung disease.

OBJECTIVE: Computed tomography is commonly used in the diagnosis of pediatric lung disease. Although the radiation is not negligible, the yield has never been studied. METHODS: Clinical and imaging data were collected for all children who underwent chest computed tomography, as part of the diagnostic process. Cases were grouped according to type of lung disease, based on clinical data and the question addressed to the radiologist. A positive yield was defined as computed tomography providing >or=1 of the following: (1) a diagnosis, (2) a clinically important new finding that had not been recognized previously, (3) alteration of the plan for further evaluation or treatment, or (4) exclusion of lung disease. No yield was defined when computed tomography did not add new information and did not affect evaluation or treatment. RESULTS: Ages ranged from 2 weeks to 16 years, and 59% were male. The overall positive yield was 61% (64 of 105 cases). Yields were relatively low, that is, 23% (8 of 35 cases) for the evaluation of diffuse lung disease, 46% (6 of 13 cases) for localized disease, 50% (6 of 12 cases) for pleural disease, and 98% (41 of 42 cases) for congenital malformations. CONCLUSIONS: The yield of chest computed tomography depends on the type of disease. Computed tomography has a significant yield for congenital anomalies. The yield is particularly low in the evaluation of acquired diffuse pulmonary disease and is relatively low in acquired focal lung disease. We suggest that chest computed tomography be used more judiciously.

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. 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.

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.

Diagnosis of laryngomalacia by fiberoptic endoscopy: awake compared with anesthesia-aided technique.

RATIONALE: Fiberoptic flexible laryngoscopy (FFL) is the diagnostic procedure of choice in patients with laryngomalacia. Two techniques can be applied, either when the infant is awake or using anesthesia/sedation. The choice of technique may effect the diagnosis. STUDY OBJECTIVES: To compare the two techniques for diagnosing laryngomalacia. PATIENTS AND INTERVENTIONS: A total of 42 infants who underwent awake fiberoptic laryngoscopy for congenital stridor, in whom either laryngomalacia was diagnosed or no cause for stridor was found, underwent a repeat laryngoscopy using anesthesia/sedation. The 84 video recordings of the supraglottic portions were copied onto a videotape along with 25 recordings of normal upper airways without stridor and 31 duplicate cases with stridor. A total of 140 recordings was mixed at random on a videotape. Sound was not included. MEASUREMENTS: Three investigators (Y.S., J.B.A., and A.D.) independently scored each recording using a laryngomalacia scoring system (scoring range, 0 to 8). RESULTS: A threshold score of 2 was the optimal cutoff point for discriminating laryngomalacia from normal condition. The awake technique (WT) missed three cases of laryngomalacia and overdiagnosed one healthy control subject. The anesthesia technique was superior with a sensitivity of 100%, a specificity of 100%, a positive predictive value of 100%, and a negative predictive value of 100% compared with 93%, 92%, 97%, and 79%, respectively, for the WT. CONCLUSIONS: The diagnosis of laryngomalacia with FFL is more accurate using anesthesia/sedation. The WT may be appropriate for screening or for patients with mild cases having a characteristic presentation.

Immunopathophysiologic mechanisms of cystic fibrosis lung disease.

Cystic fibrosis is a life-threatening autosomal recessive disorder with a highly variable clinical presentation. The pathophysiology is related to the mutant transmembrane conductance regulator (CFTR), a chloride channel that is encoded by the CF single gene located on chromosome 7. The variability of the clinical presentations, even among patients carrying the same mutation, is extensive enough to justify the hypothesis that other pathophysiologic mechanisms participate in the evolution of the disease phenotype. Presented here are recent lines of research on the contributing factors to respiratory tract morbidity, as well as the innate defense mechanisms in the CF lungs, the cytokines and chemokines that influence the inflammatory processes, the antioxidative system, and the composition of the airways surface fluid. These studies concluded that the clinical presentation is determined by pathology of the CFTR as well as by other mechanisms, some of which are related to the CFTR functions and others to the products of modifier genes as well as the influence of the environment.

Soluble CD14 as a predictor of subsequent development of recurrent wheezing in hospitalized young children with respiratory syncytial virus-induced bronchiolitis.

BACKGROUND: Respiratory syncytial virus (RSV) infection in infancy that causes severe bronchiolitis had been implicated as potentially responsible for the subsequent development of asthma. The CD14 receptor responds to the microbial burden in the environment and modulates the development of the allergic phenotype. OBJECTIVE: To investigate the relationship between the serum level of soluble CD14 (sCD14) in children hospitalized because of RSV-induced bronchiolitis and the subsequent development of recurrent wheezing. METHODS: Serum levels of sCD14 were measured in 21 children younger than 14 months who were hospitalized because of RSV-induced bronchiolitis. The diagnosis of significant wheezing was evaluated by recurrent episodes of coughing, wheezing, and respiratory distress, which were relieved by inhalation of beta-agonists and corticosteroids. RESULTS: Of the 21 children, 19 were followed up for 12 months. The mean sCD14 serum level of 14,521 +/- 1,773 pg/mL in the group of 6 children who did not exhibit recurrent wheezing was significantly higher than the level of 11,243 +/- 3,264 pg/mL in the group of 13 children who exhibited significant recurrent wheezing (P < .05). The subsequent development of recurrent wheezing was not influenced by positive family history of asthma, number of siblings, sex, or breast-feeding. CONCLUSION: A follow-up period of 12 months in this small pilot group showed that high serum levels of sCD14 modulate the influence of RSV on subsequent recurrent episodes of wheezing.

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.