The clinically significant actions of oral azithromycin in modifying progressive cystic fibrosis (CF) lung disease have been well documented. In vitro and clinical data suggests that clarithromycin has immunomodulatory properties similar to other 14-member macrolides, however two previously reported short term, open label trials of clairthromycin in small numbers of patients with CF failed to show significant benefits in modifying lung function or inflammation. We performed an international double blind, cross-over trial in which 63 subjects with CF were studied while receiving either placeo or 500 mg oral clarithromycin twice daily for 5 months, with a 1-month wash-out. The primary efficacy end point was the change in lung function (FEV1 and FVC) during the clarithromycin treatment period compared to placebo treatment. Secondary efficacy end points included; quality of life, number of pulmonary exacerbations, height and weight, sputum inflammatory mediator content, sputum transportability and surface properties, bacterial flora, nasal potential difference, and breath condensate. No significant difference in either the primary efficacy end point or any secondary end point was seen during the period of clarithromycin treatment compared to those seen during placebo administration. We conclude that clarithromycin is not effective in treating CF lung disease. Pediatr Pulmonol. © 2012 Wiley Periodicals, Inc.

In mechanically ventilated neonates it is not uncommon to observe obstructive atelectasis from various causes. However it is extremely rare to see mucous plugging and massive pulmonary atelectasis in the absence of infection, aspiration, and respiratory distress syndrome in the first couple of days of life. In this report we describe a neonate born with cystic fibrosis (CF) who presented to us with hypoxic respiratory failure, pulmonary hypertension, and hypercarbia without lactic acedemia from sticky mucous plugging and massive lung collapse. Neonatal respiratory distress and wide spread pulmonary atelectasis has not been reported in infants born with CF. Pediatr Pulmonol. © 2012 Wiley Periodicals, Inc.

We report three children with an unusual radiological sign: “trachea with an air fluid level.” We suggest this is related to paucity of cough leading to recurrent chest infections. Voluntary cough suppression as a cause of chronic lower respiratory tract infection is recorded in adults (The Lady Windermere Syndrome) but has not previously been reported in children. We propose that in these children impaired airway mucus clearance may be also be caused by voluntary cough suppression. However, the complex physiology of coughing means it is difficult to distinguish between true voluntary cough suppression and paucity of cough due to a subtle neurological deficit. In two patients, the cycle has led to permanent lung damage with bronchiectasis and reduced lung function. In the third, early diagnosis and multidisciplinary intervention has so far delayed progression to bronchiectasis. With greater awareness of this phenomenon in children, there is potential for effective early intervention with medical, physical, and psychological therapies. Pediatr Pulmonol. © 2011 Wiley Periodicals, Inc.

Azithromycin maintenance therapy results in improvement of respiratory function in patients with cystic fibrosis (CF). In azithromycin maintenance therapy, several dosing schemes are applied. In this review, we combine current knowledge about azithromycin pharmacokinetics with the dosing schedules used in clinical trials in order to come to a dosing advise which could be generally applicable. We used data from a recently updated Cochrane meta analysis (2011), the reports of clinical trials and pharmacokinetic studies. Based on these data, it was concluded that a dose level of 22–30 mg/kg/week is the lowest dose level with proven efficacy. Due to the extended half-life in patients with CF, the weekly dose of azithromycin can be divided in one to seven dosing moments, depending on patient preference and gastro-intestinal tolerance. No important side effects or interactions with other CF-related drugs have been documented so far. Pediatr Pulmonol. © 2011 Wiley Periodicals, Inc.

Herein we describe three infants with the rare presentation of pneumonia with septic shock as their initial medical encounter leading to the diagnosis of cystic fibrosis (CF). At the time of their presentation all three children had significant nutritional deficiency. We initiated an aggressive treatment regimen including nutritional supplementation which resulted in improvement in their pulmonary status and no further recurrences.This series highlights the possible presentation of CF in infancy as a life-threatening invasive infection of Staphylococcus aureus or Pseudomonas aeruginosa. It also supports neonatal screening and emphasizes the role of early attention to nutritional status and vitamin supplementation. Pediatr Pulmonol. © 2011 Wiley Periodicals, Inc.

BackgroundWe previously performed a randomized placebo-controlled trial to examine the effects of azithromycin in children and adolescents 6–18 years of age with cystic fibrosis uninfected with Pseudomononas aeruginosa and demonstrated that while azithromycin did not acutely improve pulmonary function, azithromycin-reduced pulmonary exacerbations, decreased the initiation of new oral antibiotics, and improved weight gain. We now report the results of the open-label, follow-on study to assess durability of response to azithromycin and continued safety and tolerability.MethodsEligible participants were enrolled in a 24-week open-label study of azithromycin to compare efficacy and safety endpoints during the placebo-controlled trial versus open-label study in two groups: participants initially on azithromycin continued azithromycin (azithromycin–azithromycin) and participants initially on placebo who then received azithromycin (placebo–azithromycin). As in the placebo-controlled trial, the azithromycin dose in the open-label study was 250 mg Monday–Wednesday–Friday for participants weighing 18–35.9 kg and 500 mg Monday–Wednesday–Friday for participants weighing 36 kg or greater.ResultsOf 174 eligible participants, 146 (83.9%) enrolled in the open-label study. No significant improvements in lung function were observed within either group. There were no differences in outcomes in the placebo–azithromycin group during the placebo-controlled versus open-label phase. The azithromycin–azithromycin group had comparable odds of experiencing an exacerbation during the two phases (OR 1.6, CI95 0.8, 3.0) and stable weight gain, but new oral antibiotics were initiated more frequently during the open-label study (OR 1.9, CI95 1.0, 3.5). In both groups, adverse event rates were comparable during the placebo-controlled and open-label study and treatment-emergent pathogens were rare.ConclusionsDuring the open-label study, we observed continued durability of treatment response to azithromycin, as measured by pulmonary exacerbations and continued weight gain, although use of oral antibiotics increased. There were no new safety concerns. Currently available data suggest that azithromycin reduces exacerbations and improves weight gain for 6–12 months among children and adolescents with CF uninfected with P. aeruginosa. Pediatr Pulmonol. © 2011 Wiley Periodicals, Inc.

ObjectivesRapid and reliable confirmatory sweat testing following a positive newborn screen (NBS) for cystic fibrosis (CF) is preferred to allow for early diagnosis and to decrease parental anxiety. The Cystic Fibrosis Foundation (CFF) recently recommended a quantity not sufficient (QNS) rate of ≤10% in infants <3 months of age referred for quantitative sweat chloride analysis. Two CFF-approved methods are available by which to quantitatively measure chloride concentration in sweat. Our objective was to compare the performance of the Macroduct® sweat collection system (MSCS) with the Gibson and Cooke technique (GCT) in the acquisition of samples for the determination of sweat chloride concentration in infants with a positive Minnesota State NBS for CF.MethodsA retrospective database review of infants referred to the core Minnesota CF Center or its affiliate site for confirmatory sweat testing was performed to compare the QNS rates for the two techniques. Associations between birthweight, age at test, race, and QNS rates were examined.ResultsFive hundred sixty-eight infants were referred for 616 sweat tests from March 2006 to January 2010. The mean age was 32.8 days at the initial sweat test. The GCT had a significantly higher QNS rate compared to the MSCS (15.4% vs. 2.1%, P < 0.0001). There was no association between age and the probability of QNS. The probability of QNS decreased as birthweight increased (P = 0.02). After adjusting for age, the odds of QNS using the GCT remained 8.34 (95% CI: 3.72–18.71) times that of the MSCS. Non-White infants had a significantly higher likelihood of QNS compared to non-Hispanic White infants (P = 0.0025).ConclusionsGiven the performance of the MSCS, the Minnesota CF Center has implemented the MSCS as its method of choice for diagnostic sweat testing in infants following a positive state NBS. Pediatr Pulmonol. © 2011 Wiley Periodicals, Inc.

ObjectiveTo examine cystic fibrosis (CF) physician adherence to the 2007 CF Foundation (CFF) Pulmonary Guidelines for Chronic Medications. Specifically adherence and barriers to prescribing level A medication recommendations (i.e., inhaled tobramycin and dornase alfa) and level B medication recommendations (i.e., macrolide antibiotics and hypertonic saline) were studied.MethodsDuring Spring 2010, the CFF emailed survey invitations to directors of 136 accredited CF care centers treating 50+ CF patients. Directors were asked to forward the invitations to their physician colleagues. One hundred thirty-three surveys were included in the analyses, representing 92 centers. Barriers were conceptualized based on Cabana et al.'s framework for adherence to guidelines. Adherence was assessed via a case vignette.ResultsLogistic regression analysis revealed that higher outcome expectancy (OR = 1.099, CI 1.010–1.196) and fewer environmental/system barriers (OR = 1.484, CI 1.158–1.902) were significantly associated with Vignette Adherence. A trend for an association between Familiarity and Vignette Adherence (OR = 1.642, CI 0.953–2.828) was evident, while no demographic variables were significantly associated with Vignette Adherence.ConclusionTargeting outcome expectancy and external barriers with multifaceted, ongoing interventions may improve guideline adherence. Pulmonologists are clearly looking for empirical evidence that these medications benefit their patients over the long-term and offset patient treatment burden with improved health. Pediatr Pulmonol. © 2011 Wiley Periodicals, Inc.

RationaleChest CT scans detect structural abnormalities in children with cystic fibrosis (CF), even when pulmonary function tests (PFTs) are normal. The use of chest CT is limited in clinical practice, because of concerns over expense, increased resource utilization, and radiation exposure. Quantitative chest radiography scores are useful in detecting mild lung disease, but whether they are sensitive to the presence of CT scan abnormalities has not been evaluated.ObjectiveTo determine in a cross-sectional study if quantitative chest radiography is a more sensitive marker of chest CT abnormalities than other lung disease surrogates.MethodsBrody chest CT scores were calculated for 81 children enrolled in the Wisconsin CF Neonatal Screening Project. We determined the sensitivity for Wisconsin (WCXR) and Brasfield (BCXR) chest radiography scores, PFTs, positive cultures for P. aeruginosa (PA), and parental report of symptoms to detect a Brody score worse than the median score for study participants.Measurements and Main ResultsThe mean FEV1 for the study population was 91% predicted. Abnormal WCXR and BCXR scores had the highest sensitivity to detect a chest CT score worse than the median; abnormal PFTs, parental report of symptoms, and the presence of PA had much lower sensitivity (P < 0.001).ConclusionsIn this cross sectional study, quantitative chest radiography has excellent sensitivity to detect an abnormal chest CT and may have a role in monitoring lung disease progression in children with CF. Pediatr Pulmonol. © 2011 Wiley Periodicals, Inc.

ObjectiveTo describe a series of ex-preterm infants admitted to pediatric intensive care unit due to impending hypoxaemic respiratory failure complicated by pulmonary hypertension (PH) who were treated electively combining noninvasive ventilation (NIV) and nebulized iloprost (nebILO).DesignOpen uncontrolled observational study.SettingPediatric Intensive Care Unit, University Hospital.PatientsTen formerly preterm infants with impending hypoxaemic respiratory failure and PH, of whom eight had moderate to severe bronchopulmonary dysplasia.Measurements and Main ResultsMedian age and body weight were 6.0 (2.75–9.50) months and 4.85 (3.32–7.07) kg, respectively. We observed a significant early oxygenation improvement in terms of PaO2/FiO2 increase (P = 0.001) and respiratory rate reduction (P = 0.01). Hemodynamic also improved, as shown by heart rate (P = 0.002) and pulmonary arterial pressure systolic/systolic systemic pressure (PAPs/SSP) ratio reduction (P = 0.0137). NebILO was successfully weaned in positive response cases: 4 infants were discharged on oral sildenafil. Three patients failed noninvasive modality and needed invasive mechanical ventilation; hypoxic–hypercarbic patients were most likely to fail noninvasive approach. Only one patient requiring invasive ventilation died and surviving babies had a satisfactory 1-month post-discharge follow-up.Conclusions.The noninvasive approach combining NIV and nebILO for ex-preterm babies with impending respiratory failure and PH resulted to be feasible and quickly achieved significant oxygenation and hemodynamic improvements. Pediatr Pulmonol. © 2011 Wiley Periodicals, Inc.

The ethics of invasive mechanical ventilation for children with the neurodegenerative disease Spinal Muscular Atrophy Type I (SMA I) is highly debated, and wide variability in clinical outcomes exists internationally. We conducted this international survey to identify physician characteristics associated with recommendation for tracheostomy and ventilation for SMA I. A cross-sectional online survey was distributed to 1,772 pediatric pulmonologists and pediatric intensivists from online membership directories of American Thoracic Society, American College of Chest Physicians, and European Respiratory Society. Questions explored physician demographics, attitudes and experience with SMA and end-of-life care, knowledge of consensus guidelines, and recommendations for respiratory care of SMA I. A logistic regression model assessed the independent effects of physician variables on the recommendation for invasive ventilation for SMA I. A total of 367 (21%) physicians completed the survey; 82% were pediatric pulmonologists; and 16% pediatric intensivists. Seventy percent of respondents were from the U.S. Fifty percent of physicians were aware of SMA consensus guidelines. Physicians from Commonwealth countries (U.K., Canada, Australia, etc.) were less likely to recommend tracheostomy/ventilation than U.S. physicians (7% vs. 25%, P = 0.005). Logistic regression modeling identified years of experience, pediatric pulmonology specialty, agreement with a pro-life statement, and recommendation for non-invasive ventilation as predictive of recommendation for long-term invasive ventilation for SMA I. In the largest international survey on this topic, we identified regional differences in physician recommendation for invasive ventilation for children with SMA I. Our data demonstrate a need for increased awareness of consensus guidelines and further dialog about the physician role in variability of care for children with SMA I. Pediatr Pulmonol. © 2011 Wiley Periodicals, Inc.

Ultrasound imaging allows in vivo assessment of tracheal kinetics and cartilage structure. To date, the impact of mechanical ventilation (MV) on extracellular matrix (ECM) in airway cartilage is unclear, but an indication of its functional and structural change may support the development of protective therapies. The objective of this study was to characterize changes in mechanical properties of the neonatal airway during MV with alterations in cartilage ECM. Trachea segments were isolated in a neonatal lamb model; ultrasound dimensions and pressure–volume relationships were measured on sham (no MV; n = 6) and MV (n = 7) airways for 4 hr. Tracheal cross-sections were harvested at 4 hr, tissues were fixed and stained, and Fourier transform infrared imaging spectroscopy (FT-IRIS) was performed. Over 4 hr of MV, bulk modulus (28%) and elastic modulus (282%) increased. The MV tracheae showed higher collagen, proteoglycan content, and collagen integrity (new tissue formation); whereas no changes were seen in the controls. These data are clinically relevant in that airway properties can be correlated with MV and changes in cartilage ECM. MV increases the in vivo dimensions of the trachea and is associated with evidence of airway tissue remodeling. Injury to the neonatal airway from MV may have relevance for the development of tracheomalacia. We demonstrated active airway tissue remodeling during MV using an FT-IRIS technique which identifies changes in ECM. Pediatr Pulmonol. © 2011 Wiley Periodicals, Inc.

Hydatid disease is still an important public health problem throughout the world. Diagnosis of the disease is generally based on clinical and radiological findings. Evaluation of pulmonary disorders by flexible bronchoscopy (FOB) is a rapidly developing facility, but diagnostic and therapeutic FOB for pulmonary hydatid cysts is still controversial. This study examines the findings of endobronchial hydatid cyst disease in five pediatric patients from Turkey, and clinical experience about this subject is reviewed. All our patients presented with unusual symptoms of the disease, and for all of them, diagnosis had been delayed using current diagnostic methods. As a result of our experience, it can be reported that the endobronchial appearance of the hydatid cyst membrane is whitish-yellow, and it is difficult to differentiate it radiologically from some other common causes of endobronchial lesions in childhood, such as endobronchial tuberculosis, foreign body aspirations, mucous plaques, and granulation scars. The findings of these cases show that, hydatid cyst should also be kept in mind in differential diagnosis of endobronchial lesions. In the diagnosis of pulmonary hydatid cyst in children without typical clinical and radiological findings of the disease, FOB examination is a valuable diagnostic procedure. Pediatr Pulmonol. © 2011 Wiley Periodicals, Inc.

The course of cystic fibrosis (CF) progression in children is affected by parent adherence to treatment plans. The Theory of Reasoned Action (TRA) posits that intentions are the best behavioral predictors and that intentions reasonably follow from beliefs (“determinants”). Determinants are affected by multiple “background factors,” including spirituality. This study's purpose was to understand whether two parental adherence determinants (attitude towards treatment and self-efficacy) were associated with spirituality (religious coping and sanctification of the body). We hypothesized that parents' attitudes toward treatment adherence are associated with these spiritual constructs. A convenience sample of parents of children with CF aged 3–12 years (n = 28) participated by completing surveys of adherence and spirituality during a regular outpatient clinic visit. Type and degree of religious coping was examined using principal component analysis. Adherence measures were compared based on religious coping styles and sanctification of the body using unpaired t-tests. Collaborative religious coping was associated with higher self-efficacy for completing airway clearance (M = 1070.8; SD = 35.8; P = 0.012), for completing aerosolized medication administration (M = 1077.1; SD = 37.4; P = 0.018), and for attitude towards treatment utility (M = 38.8; SD = 2.36; P = 0.038). Parents who attributed sacred qualities to their child's body (e.g., “blessed” or “miraculous”) had higher mean scores for self-efficacy (airway clearance, M = 1058.6; SD = 37.7; P = 0.023; aerosols M = 1070.8; SD = 41.6; P = 0.020). Parents for whom God was manifested in their child's body (e.g., “My child's body is created in God's image”) had higher mean scores for self-efficacy for airway clearance (M = 1056.4; SD = 59.0; P = 0.039), aerosolized medications (M = 1068.8; SD = 42.6; P = 0.033) and treatment utility (M = 38.8; SD = 2.4; P = 0.025). Spiritual constructs show promising significance and are currently undervalued in chronic disease management. Pediatr Pulmonol. © 2011 Wiley Periodicals, Inc.

BackgroundPrimary tracheobronchomalacia (TBM) is a disease of the large airways. Long-term follow-up studies of TBM patients have not been reported. This study was undertaken to further elicit the natural history of this condition and the presence of concomitant reactive airways disease through clinical profiling and pulmonary function testing.MethodsTwenty-one children diagnosed with TBM by bronchoscopy between 1998 and 2001 in Queensland were recruited in 2008. Parents completed a questionnaire detailing their child's respiratory symptoms over the previous 12 months. Children then undertook pulmonary function and flow–volume loop classification. Mannitol bronchial provocation testing or post-bronchodilator spirometry was performed to assess for the confounding presence of reactive airways disease.ResultsData from 19 children (12 males) were able to be analyzed. The median age was 9.4 (range 7.6–14.3) years. 15 parents indicated their child's symptoms were unresolved. The mean FEV1 was 81% predicted with 7 <80% predicted. This was significantly lower than the percent predicted population mean (P = 0.0005). Mean FEV1/FVC, FEF25–75, and PEF were also significantly reduced (P = < 0.0001). Four participants had a classical TBM flow–volume loop on analysis. One of 15 (6.7%) participants recorded a positive test for reactive airways disease.ConclusionsClinical symptom profiles and pulmonary function indicate persistent functional mechanical abnormalities of the large and small airways in TBM patients, and the absence of reactive airways disease. Pediatr Pulmonol. © 2011 Wiley Periodicals, Inc.

The Lung Clearance Index (LCI) is superior to spirometry in detecting early lung disease in cystic fibrosis (CF) and correlates with structural lung changes seen on CT scans. The LCI has the potential to become a novel outcome parameter for clinical and research purposes. However longitudinal studies are required to further prove its prognostic value. Multi-center design is likely to facilitate realization of such studies.Therefore the aim of the present study was to assess multi-center feasibility and inter-center variability of LCI measurements in healthy children and adolescents. Comparative measurements were performed in unselected patients with CF to confirm previous single-center results.LCI measurements were performed in eight centers using the EasyOne Pro, MBW Module (ndd Medical Technologies, Zurich, Switzerland).The overall success rate for LCI measurements was 75.5%, leaving 102/151 measurements in healthy volunteers and 139/183 measurements in patients with CF for final analysis. Age ranged between 4 and 24 years. Mean LCI (range of means among centers) was 6.3 (6.0–6.5) in healthy volunteers and thus normal. Inter-center variability of center means was 2.9%, ANOVA including Schffé procedure demonstrated no significant inter-center differences (P > 0.05). Mean LCI (range of means among centers) was 8.2 (7.4–8.9) in CF and thus abnormal.Our study demonstrates good multi-center feasibility and low inter-center variability of the LCI in healthy volunteers when measured with the EasyOne Pro MBW module. Our data confirm published LCI data in CF. However, central coordination, quality control, regular training, and supervision during the entire study appear essential for successfully performing multi-center trials. Pediatr Pulmonol. © 2011 Wiley Periodicals, Inc.

ObjectiveBoth healthy preterm infants and those with bronchopulmonary dysplasia (BPD) have poor lung function during childhood and adolescence, although there is no evidence whether prematurity alone explains the reduction in lung function found in BPD infants. Our study seeks to know if lung function, measured in infancy by means of rapid thoracic compression with raised volume technique, is different between preterm infants with and without BPD.MethodsLung function was measured in 43 preterm infants with BPD and in 32 preterm infants without BPD at a chronological age range of 2–28 months. Forced vital capacity (FVC), forced expiratory volume at 0.5 sec, and forced expiratory flows at 50, 75, 85%, and 25–75% of FVC were obtained from maximal expiratory volume curves by means of rapid thoracic compression with raised volume technique. Maximal flow at functional residual capacity was measured using rapid thoracic compression at tidal volume. Multiple regression analysis and generalized least squares (GLS) random-effects regression model were used to control for variables such as gender, weeks of gestation, age, birth weight, and tobacco smoke exposure. A sub-analysis was performed in infants born at 28+ weeks of gestation.ResultsBPD was associated to significantly lower flows (regression coefficients: −0.51, −0.54, −57, −0.53, and −0.82, respectively for FEF50, FEF75, FEF85, FEF25–75). This association was driven by males and maintained in the subgroup of infants born at 28+ weeks of gestation.ConclusionBPD is associated with an additional decrease of lung function during the first 2 years of life in infants born preterm. Pediatr Pulmonol. © 2011 Wiley Periodicals, Inc.

While it is recognized that beta-blockers can exacerbate asthma symptoms in older children and adults, there are few descriptions of a similar effect in infants. We describe three infants who developed wheeze during treatment with a beta-blocker for infantile hemangiomas and conclude that physicians should inquire about respiratory symptoms in this group of children. Pediatr Pulmonol. © 2011 Wiley Periodicals, Inc.

BackgroundSmoking is the single most important risk factor for the development of chronic obstructive pulmonary disease, and more than 80% of adult smokers started smoking before the age of 20. The aim of our study was to evaluate the early impact of smoking on lung function, health, and well-being in adolescents.MethodsTwenty-four non-smokers (10 male, 14 female, mean age 17.6 years) and 24 smokers (mean of 3.5 pack-years; 15 male, 9 female, mean age 17.8 years) were compared in terms of lung function, bronchial hyperreactivity (BHR), levels of exhaled carbon monoxide (eCO), exhaled nitric oxide (eNO), and blood counts. A questionnaire containing items from the ISAAC study was used to detect differences in health and well-being.ResultsThere were no significant differences in lung function values between non-smokers and smokers (VC 95% vs. 103%, FEV1 106% vs. 116%, FEV1%/VC MAX 94.6% vs. 95.2%), whereas BHR significantly differed (P < 0.05). Furthermore, significant differences were found for eCO, eNO, Hb, leukocytes, and neutrophils. Health and well-being in terms of sleep and physical activity were significantly worse in smokers.ConclusionOur results suggest an early impact of smoking on health after as few as 3.5 pack-years. Early signs of smoking are an increase in BHR, changes in blood count and a decrease of eNO even before changes in lung function become apparent. Pediatr Pulmonol. © 2011 Wiley Periodicals, Inc.

Familial dysautonomia (FD) is a profound sensory and autonomic nervous system disorder associated with an increased risk for sudden death. While bradycardia resulting from loss of sympathetic tone has been hypothesized to play a role in this mortality, extended in-home monitoring has failed to find evidence of low heart rates in children with FD. In order to better characterize the specific cardio-respiratory pathophysiology and autonomic dysregulation in patients with FD, 25 affected children and matched controls were studied with in-home technology, during day and night. Respiratory and heart rate timing and variability metrics were derived from inductance plethysmography and electrocardiogram signals. Selective shortening of inspiratory time produced an overall increase in respiratory frequency in children with FD, with higher daytime respiratory variability (vs. controls), suggesting alterations in central rhythm generating circuits that may contribute to the heightened risk for sudden death. Overall heart rate was increased and variability reduced in FD cases, with elevated heart rates during 20% of study time. Time and frequency domain measures of autonomic tone indicated lower parasympathetic drive in FD patients (vs. controls). These results suggest withdrawal of vagal, rather than sympathetic tone, as a cause for the sustained increase and dramatic lability in respiration and heart rates that characterize this disorder. Pediatr Pulmonol. © 2011 Wiley Periodicals, Inc.

Progression of lung disease is a major event in children with cystic fibrosis (CF), but regional differences in its evolution are unclear. We hypothesized that regional differences occur beginning in early childhood. We examined this issue by evaluating 132 patients followed in the Wisconsin Neonatal Screening Project between 1985 and 2010. We scored chest X-rays obtained every 1–2 years with the Wisconsin chest X-ray system, in which we divided the lungs into quadrants, and gave special attention to ratings for bronchiectasis (BX) and nodular/branching opacities. We compared the upper and lower quadrant scores, and upper right and left quadrant scores, as patients aged using a multivariable generalized estimation equation (GEE) model. We did a confirmatory analysis for a subset of 81 patients with chest computerized tomography (CT) images obtained in 2000 and scored using the Brody scoring system. The chest X-ray analysis shows that the upper quadrants have higher BX (P < 0.001) and nodular/branching opacities (P < 0.001) scores than the lower quadrants. CT analysis likewise reveals that the upper quadrants have more BX (P = 0.02). Patients positive for mucoid PA showed significantly higher BX scores than patients with non-mucoid PA (P = 0.001). Chest X-ray scoring also revealed that the upper right quadrant has more BX (P < 0.001) than the upper left quadrant, and CT analysis was again confirmatory (P < 0.001). We conclude that pediatric patients with CF develop more severe lung disease in the upper lobes than the lower lobes in association with mucoid PA infections and also have more severe lung disease on the right side than on the left side in the upper quadrants. A variety of potential explanations such as aspiration episodes may be clinically relevant and provide insights regarding therapies. Pediatr Pulmonol. © 2011 Wiley Periodicals, Inc.

We report undescribed pulmonary findings in a child with mucolipidosis II (ML-II). Children with ML-II bear significant pulmonary morbidity that may include extensive pulmonary fibrosis, persistent hemosiderosis as well as pulmonary airway excrescences as they reach preschool age. Pediatr Pulmonol. © 2011 Wiley Periodicals, Inc.

ObjectivesNonacid gastroesophageal reflux (GER), particularly in patients taking acid suppression, has been implicated as a cause of respiratory infections. We hypothesize that children with cystic fibrosis (CF) and a higher nonacid reflux burden have greater rates of Pseudomonas aeruginosa (Pa) infection than patients with a lower reflux burden.Study DesignWe reviewed the multichannel intraluminal impedance (pH-MII) tracings of 35 patients with CF between 2003 and 2010. We compared the reflux profiles between those patients who were Pa positive and Pa negative.ResultsThe mean age was 13.5 ± 5.8 years. Twenty-seven patients (76%) were Pa positive. Ninety seven percent of patients were taking proton pump inhibitors during pH-MII testing. The mean percentage of time pH was <4 was 8.5 ± 12%. Pa patients had a significantly higher total, acid and proximal nonacid reflux burden (P < 0.009). There was a negative correlation between nonacid reflux burden and FEV1 (r = −0.397, P = 0.03) and between total number of reflux events and FEV1 (r = −0.474, P = 0.009). After adjusting for age and FEV1, total reflux burden remains significantly associated with Pa positivity (P = 0.055).ConclusionsIncreased reflux burden may predispose patients to Pa infection and worse lung function. Pediatr Pulmonol. © 2011 Wiley Periodicals, Inc.

Hydatid disease of the lungs is caused by larval cysts of the Echinococcus tapeworm. Pulmonary cysts may occasionally invade bronchi or pleura as a result of coughing, trauma, or elevated intra-abdominal pressure. We present the case of a patient evaluated for non-resolving pneumonia whose radiographic and bronchoscopic findings were strikingly similar to those seen in pulmonary tuberculosis with endobronchial invasion; he was ultimately diagnosed with pulmonary echinococcosis. This case underscores the importance of considering unusual diagnoses even when typical features of more common conditions are present. Pediatr Pulmonol. © 2011 Wiley Periodicals, Inc.

ObjectiveTo define reference ranges for oxygen saturation (SpO2) values in healthy full-term infants in the first days of life and in preterm infants off supplemental oxygen as they approach neonatal intensive care unit (NICU) discharge.MethodsFrom April 2009 to March 2010, we enrolled convenience samples of full-term infants from the newborn nursery and former preterm infants who did not require supplemental oxygen at the time of discharge from the NICU. Overnight SpO2 and signal quality recordings were obtained and analyzed for duration of artifact-free recording time (AFRT), time (s) with SpO2 less than several different target saturations (90–95%), and number of falls in SpO2 by ≥4% and ≥10%.ResultsWe studied 102 full-term infants and 52 preterm infants. Preterm and full-term infants spent similar amounts of time less than 90%, 91%, 92%, 93%, 94%, and 95% although preterm infants had more falls in SpO2 by ≥4% per hour of AFRT. Over 67% of term and preterm infants spent less than 6% of their time below 93%.ConclusionThese data represent reference SpO2 ranges for both preterm infants not requiring supplemental oxygen at NICU discharge and full-term infants in the first days of life. As we currently lack guidelines dictating the optimal target oxygen saturations for infants and the acceptable maximal time that they can safely spend below set target saturations, our data may serve as a guide to interpreting SpO2 recordings of premature outpatient infants who are weaning from supplemental oxygen. Pediatr Pulmonol. © 2011 Wiley Periodicals, Inc.

ObjectiveWe aimed to determine the correlation and the agreement between end-tidal carbon dioxide (ETCO2) and partial pressure of arterial carbon dioxide (PaCO2) in very low birth weight infants (VLBWI); furthermore, we assessed factors that could affect the ETCO2–PaCO2 relationship.MethodsSimultaneous end-tidal and arterial CO2 pairs were obtained from ventilated VLBWI who were monitored by mainstream capnography and had umbilical arterial catheter. Correlation and agreement between ETCO2 and PaCO2 were evaluated by using Spearman test and Bland-Altman method, respectively.ResultsA total of 143 simultaneous ETCO2–PaCO2 pairs were analyzed from 45 ventilated VLBWI. There was a significant correlation (r = 0.69; P < 0.0001) between ETCO2 and PaCO2 values. The ETCO2 value was lower than the corresponding PaCO2 value in 94% pairs, with a mean bias of 13.5 ± 8.4 mmHg (95% agreement levels, −3.0 to 29.9 mmHg). Mean PaCO2–ETCO2 bias was similar between ELBWI (13.1 ± 7.7 mmHg; 95% agreement levels, −1.9 and 28.2 mmHg) and infants with birth weight 1,001–1,500 g (14.8 ± 9.7 mmHg; 95% agreement levels −4.3 and 33.8 mmHg). The bias between ETCO2 and PaCO2 was significantly increased with increasing FiO2, mean airway pressure and oxygenation index. Within each patient, there was a positive correlation (r = 0.78, P < 0.0001) between the changes in PaCO2 and the simultaneous changes in ETCO2.ConclusionsIn ventilated VLBWI, the correlation between mainstream ETCO2 and PaCO2 is good, but the agreement is poor and negatively influenced by the severity of pulmonary disease. Capnography is feasible in ELBWI. ETCO2 should not replace PaCO2 measurements in ventilated VLBWI, but may have a role to detect trends of PaCO2. Pediatr Pulmonol. © 2011 Wiley Periodicals, Inc.

ObjectiveTo analyze cross-sectional and longitudinal associations between lung function measures and clinical features in a cohort of preschool children with cystic fibrosis (CF).MethodsLongitudinal eight-center observational study of children with CF aged 36–60 months at enrollment, who underwent semiannual pulmonary function tests (PFTs) for up to 2 years consisting of spirometry (all 8 sites), forced oscillometry (FO, 5 sites), and measures of thoracoabdominal asynchrony using respiratory inductive plethysmography (IP, 5 sites).ResultsNinety-three subjects were enrolled; 181 acceptable spirometry measurements from 71 subjects, 128 FO from 47 subjects, and 142 IP from 50 subjects were available for analysis. Cross sectional analyses did not detect an association between any PFT parameter at enrollment and Pseudomonas aeruginosa (Pa) status, CF gene mutation class, Wisconsin cough score, Shwachman score, environmental tobacco smoke exposure, family history of asthma, or nutritional indices. In longitudinal analyses, Pa infection within 6 months preceding enrollment was associated with a significantly greater rate of decline in z-scores for forced expiratory flow between 25 and 75% of forced vital capacity (FEF25–75) (−1.3 vs. −0.4 Z scores/year, P = 0.024) and greater thoracoabdominal asynchrony measured by IP (mean phase angle difference 4.6°, P = 0.004). No other significant longitudinal associations were observed.ConclusionsPrior Pa infection is associated with a greater rate of decline in FEF25–75 z-score and mild thoracoabdominal asynchrony in preschool children with CF. In this multicenter US study, significant associations between other lung function measures and clinical features were not detected. Pediatr Pulmonol. © 2011 Wiley Periodicals, Inc.

RationaleConducting clinical trials in cystic fibrosis (CF) preschoolers has been limited by lack of sensitive lung function measures performed across sites.Objectives(1) Assess feasibility and short-term reproducibility of spirometry, forced oscillometry (FO), and inductance plethysmography (IP) in a multi-center preschool population; (2) compare ability of each technique to differentiate lung function of CF preschoolers and controls; (3) evaluate longitudinal changes in lung function; (4) estimate sample sizes for future trials.MethodsA longitudinal, multi-center study of CF preschoolers was conducted utilizing standardized equipment, rigorous site training, and centralized lung function data review. CF subjects participated in up to four study visits 6 months apart, plus a 2-week reproducibility visit. Controls had one study visit.ResultsNinety-three CF subjects and 87 controls participated. Acceptability rates were lowest for spirometry (55%) and highest for IP (77%). Spirometry success increased with age and having a prior acceptable measurement. FEV1, FEV0.5, and FEF25–75 were lower for CF subjects than for controls; spirometric z-scores declined with age. IP measures of thoracoabdominal asynchrony were greater for CF subjects than for controls. FO indices did not distinguish CF from controls. FEV1 and FEV0.5 are able to detect the smallest treatment effect for a given sample size.ConclusionsSpirometry appears more sensitive than IP or FO for detecting lung disease in CF preschoolers; spirometric indices decline with age. Future trials using spirometry should include a run-in period for training and require acceptable data prior to enrollment. However, near-normal spirometric measurements in CF preschoolers may lead to difficulty detecting a treatment effect. Pediatr Pulmonol. © 2011 Wiley Periodicals, Inc.

Previous studies of pulmonary diffusing capacity in children differed greatly in methodologies; numbers of subjects evaluated, and were performed prior to the latest ATS/ERS guidelines. The purpose of our study was to establish reference ranges for the diffusing capacity to carbon monoxide (DLCO) and alveolar volume (VA) in healthy Caucasian children using current international guidelines and contemporary equipment.Healthy children from the United States (N = 303) and from Australia (N = 176) performed acceptable measurements of single breath pulmonary diffusing capacity and alveolar volume according to current ATS/ERS guidelines. The natural log of DLCO and VA were associated with height, age and an age–sex interaction term, while DLCO/VA was related to height and the age–sex interaction term only. Adjustment of DLCO for hemoglobin (n = 303; USA data only) resulted is a small but significant decrease in DLCO of ∼1% but did not significantly alter the regression equations. In this dataset there was no influence of center for DLCO or DLCO/VA, while Australian children had a statistically smaller VA (mean difference 0.14 L after accounting for height, age and age–sex; P = 0.012).We report that diffusing capacity outcomes can be collated from multiple centers using similar equipment and collection protocols. Using collated data we have derived regression equations for pulmonary diffusing capacity outcomes in healthy Caucasian children aged 5–19 years. Pediatr Pulmonol. © 2011 Wiley Periodicals, Inc.

BackgroundTopiramate, which is used as an anticonvulsant and for migraine prophylaxis in children, causes oligohydrosis as a side-effect, but its effect on sweat chloride concentrations has not been studied systematically.MethodsTwenty-one children receiving topiramate and 20 healthy controls with no signs or symptoms of pulmonary or gastrointestinal disease and a negative family history for cystic fibrosis (CF) underwent bilateral pilocarpine iontophoresis and sweat collection via Macroduct® system.ResultsAdequate samples (>15 µl volume) were obtained from 17/19 topiramate subjects (89%), and 19/20 (95%) controls. The mean sweat chloride concentration was 37.7 ± 18.8 mmol/L for patients receiving topiramate, and 15.9 ± 6.9 mmol/L for controls (p = 0.0001). The mean sweat volume was 29.1 ± 17.4 µl for patients receiving topiramate, and 41.2 ± 17.5 µl for controls (p = 0.037). Overall 8/17 (47%) of patients on topiramate with a measurable sweat chloride had either an intermediate (>40 mmol/L but <60 mmol/L) or elevated (>60 mmol/L) sweat chloride test result, while 0/19 control subjects had elevated sweat chloride (p = 0.0008). Further analysis of the in vitro activity of topiramate on cultured human bronchial epithelial cells in modified Ussing chambers showed no differences in chloride conductance measured in cells exposed to 10 or 50 µg/ml of topiramate when compared to non-exposed cells.ConclusionsThis is the first report of a medication affecting sweat chloride values and shows that topiramate therapy can cause elevated sweat chloride concentrations in the absence of clinical manifestations of CF. Pediatr Pulmonol. © 2011 Wiley Periodicals, Inc.

Current evidence supports a major role for inherited factors in determining bronchopulmonary dysplasia (BPD) susceptibility. The Toll-like receptor (TLR) family of proteins maintain pulmonary homeostasis in the developing lung by aiding pathogen recognition and clearance, regulating inflammation, and facilitating reparative tissue growth. We hypothesized that sequence variation in the TLR pathway genes would alter the susceptibility/severity of BPD in preterm infants. Very low birth-weight infants were recruited prospectively in a multi-center study involving collection of blood samples and clinical information. Nine TLR pathway single-nucleotide polymorphisms were genotyped using a multiplexed single-base extension assay. BPD outcomes were compared among infants with and without the variant allele using Chi-square or Fisher's exact tests. In our cohort (n = 289), 66 (23.6%) infants developed BPD, out of which 32 (11.2%) developed severe BPD. The TLR5 (g.1174C > T) variant was associated with BPD (P = 0.03) and severe BPD (P = 0.004). The TIRAP (g.2054C > T) variant was associated with BPD (P = 0.04). Infants heterozygous for the X-linked IRAK1 (g.6435T > C) variant had a lower incidence of BPD compared to infants homozygous for either the reference or variant allele (P = 0.03). In regression models that controlled for potential epidemiological confounders, the TIRAP variant was associated with BPD, and the TLR5 variant was associated with severe BPD. Our data support the hypothesis that aberrant pathogen recognition in premature infants arising from TLR pathway genetic variation can contribute to BPD pathogenesis. Pediatr Pulmonol. © 2011 Wiley Periodicals, Inc.

ObjectiveAsthma control represents a major challenge in the management of asthmatic children; however, correct perception of control is poor. The aim of the study was to evaluate the association between subjective answers given to the Childhood Asthma Control Test (C-ACT) and objective evaluation of exercise-induced bronchonstriction (EIB) by standardized treadmill exercise challenge.MethodsEIB was evaluated by standardized treadmill exercise challenge and related to C-ACT scores in 92 asthmatic children.ResultsOf the 92 studied children only six children had a concordance between a positive challenge test (ΔFEV1 ≥ 13%) and a positive response to the exercise-related issue of the C-ACT questionnaire (C-ACT total score ≤ 19). There was no significant association between the degree of EIB and the scores relative to the single question on exercise-related problems while a significant association was found when considering the whole questionnaire with C-ACT total score > 19 (r = −0.40, P < 0.001). The two single questions showing a significant association were those focusing on nocturnal asthma. The areas under the ROC curve (AUC) for the sum of the scores of these questions in relationship to a positive response to the exercise test was 0.74. The AUC of the C-ACT total score was 0.76 and 0.55 for the specific question on EIB related problems.ConclusionThe discrimination power of the C-ACT total score in relationship to EIB was moderately good, and C-ACT questionnaire was capable of correctly predicting the absence of EIB in children reporting a global score > 19. However, direct questions on EIB are associated with a high number of false positive and negative responses; better associations are found questioning on the presence on nocturnal symptoms. Pediatr Pulmonol. © 2011 Wiley Periodicals, Inc.

BackgroundMulti-center research studies that include pulmonary function as an objective outcome are increasingly important in pediatric respiratory medicine. The need for local controls rather than depending on published normative data for lung function remains debatable.AimTo compare pulmonary function in childhood controls with no respiratory symptoms from three centers in the United Kingdom and ascertain the extent to which current reference equations are appropriate for this population.MethodsSpirometry, plethysmographic lung volumes, and specific airways resistance (sRaw) were measured within specialized pediatric laboratories in children from three geographical locations throughout the UK (London, Leicester, and Glasgow), using identical equipment, software and standard operating procedures. Results were compared between centers and in relation to recent or commonly used UK pediatric reference values.ResultsPulmonary function was assessed in 94 healthy children (mean (SD) age: 7.7 (0.6) years; 88% white Caucasians; ∼30 from each center). There were no significant differences in background demographics or spirometric outcomes when compared between centers. By contrast, statistically significant differences in plethysmographic lung volumes and sRaw were observed between-centers. Significant differences in relation to published reference data for white subjects were noted for FEV1 in all three centers and occasionally for other lung function measures but the differences from predicted values were small (within ± 0.5 z-score) and not clinically significant.ConclusionAfter appropriate inter-laboratory standardization, spirometric measurements in children can be measured in different centers without evidence of systematic differences. However, even after extensive standardization procedures, plethysmographic measures appear more prone to inter-center differences and cannot, at present, be reliably compared across centers without incorporating controls at each location. Pediatr Pulmonol. © 2011 Wiley Periodicals, Inc.

BackgroundThe use of portable fractional exhaled nitric oxide (FENO) devices is increasingly common in the diagnosis and management of allergic airways inflammation.MethodsWe tested two handheld FENO devices, to determine (a) if there was adequate intradevice repeatability to allow the use of single breath testing, and (b) if the devices could be used interchangeably. In a mixed pediatric population, including normal, asthmatic, and children with peanut allergies, 858 paired values were collected from the NIOX-MINO® and/or the NObreath® devices.ResultsThe NIOX-MINO® showed excellent repeatability (mean difference of 0.1 with 95% limits of agreement between −7.93 to 7.72 ppb), while the NObreath® showed good repeatability (mean difference of −1.61 with 95% limits of agreement between −14.1 and 10.8 ppb). Intradevice repeatability was good but not adequate and the NIOX-MINO® systematically produced higher results than the NObreath® [mean difference of 7.8 ppb with 95% limits of agreement from −11.55 to 27.52 ppb (−33% to 290%)].ConclusionsOur results support the manufacturer's advice that single breath testing is appropriate for the NIOX-MINO®. NObreath® results indicate that the mean of more than one breath should be utilized. The devices cannot be used interchangeably. Pediatr Pulmonol. © 2011 Wiley Periodicals, Inc.

In children, post-obstructive pulmonary edema is a rare condition, caused by a sudden change in upper airway patency. It causes dyspnea, tachypnea, hypoxemia, and at times hemoptysis and respiratory insufficiency. It occurs as a complication in the immediate post-operative period. Pediatricians should be aware of this clinical entity. Pediatr Pulmonol. © 2011 Wiley Periodicals, Inc.

A 4-year-old girl with cystic fibrosis (CF) presented with unrelenting pyrexia commencing shortly after flushing of the central venous catheter (CVC). Mycobacterium gordonae was subsequently isolated from bronchoalveolar lavage, gastric washings, and lung biopsy. While this case most likely represents central line infection by a non-tuberculous mycobacterial (NTM) species, it is difficult to state this definitively in the absence of positive cultures from the CVC. We suggest that infection with NTM should always be considered in CF patients with indwelling devices and unexplained fever. Pediatr Pulmonol. © 2011 Wiley Periodicals, Inc.

ObjectiveTo establish children and adolescents' perspectives regarding their asthma and its impact upon their daily lives.DesignA 14-item questionnaire.SettingCanada, Greece, Hungary, The Netherlands, the United Kingdom, and South Africa.ParticipantsChildren/adolescents (aged 8–15 years) with physician-diagnosed asthma.InterventionInterviews were conducted by telephone (Canada, Greece, Hungary, The Netherlands, and the United Kingdom) or face-to-face (South Africa).Outcome MeasuresAsthma symptoms, impact on activities, and quality of life.ResultsOf the 943 children/adolescents interviewed, 60% were male. Most (81%) described their asthma as “not too bad” or “I only get it every now and then,” with only 4% reporting their asthma as being “very bad”; however, 92% experienced asthma-related coughing and 59% reported nocturnal awakening. Over half (57%) of children/adolescents believed they could predict when their asthma would make them ill; the most common initial symptoms being breathlessness (41%) and bad cough (33%). They considered the worst things about having asthma to be the symptoms of an asthma attack (32%) and not being able to play sport (25%). Almost half (47%) of children/adolescents felt that their asthma affected their ability to play sport or engage in physical activity. One in ten reported they had suffered asthma-related bullying.ConclusionsChildren/adolescents underestimate the severity of their asthma, and overestimate its control, indicating that they expect their illness to be symptomatic. Asthma has a substantial impact on their daily lives, particularly on physical activity and social functioning. Efforts are required to improve asthma control and expectations of health in children/adolescents. Pediatr Pulmonol. © 2011 Wiley Periodicals, Inc.

BackgroundParapneumonic effusion has been reported to develop either in typical bacterial infection or in viral pneumonia with bacterial co-infection and to cause death. Swine-origin influenza A (H1N1) virus infection can be accompanied with pleural effusion; however, there are no reports about the significance of pleural effusion in H1N1 pneumonia. We retrospectively analyzed both the clinical characteristics and the significance of pleural effusion associated with H1N1 pneumonia in children and adolescent.MethodEighty-nine patients who were admitted with H1N1 pneumonia were divided into two groups: 17 patients with pleural effusion (i.e., the effusion group), and 72 patients without pleural effusion (the non-effusion group).ResultsLymphopenia (P = 0.030), elevation of the C-reactive protein (P = 0.026), and positive rate of anti-sptreptolysin O titer (P = 0.040) were significantly increased in the effusion group than in the non-effusion group. In addition, the need for treatment with both oxygen (P < 0.001) and oseltamivir (P = 0.013) was significantly increased in the effusion group. However, there was no significant difference between the two investigated groups in the duration of the treatment with intravenous antibiotics, the time of fever remission calculated from admission, and the days of hospital stay. Also, there was no documented bacterial co-infection in any of the studied groups.ConclusionThis result suggested that pleural effusion in H1N1 pneumonia could develop without bacterial co-infection and had mild clinical course. Pediatr Pulmonol. © 2011 Wiley Periodicals, Inc.

IntroductionBronchiectasis is a well-known sequela of chronic pulmonary aspiration (CPA) that can result in significant respiratory morbidity and death. However, its true prevalence is unknown because diagnosis requires high resolution computed tomography which is not routinely utilized in this population. This study describes the prevalence, time course for development, and risk factors for bronchiectasis in children with CPA.Materials and MethodsUsing a cross-sectional design, medical records were reviewed for all patients with swallow study or airway endoscopy-confirmed aspiration in our airway center over a 21 month period. All patients underwent rigid and flexible bronchoscopy, and high resolution chest computed tomography. Prevalence, distribution, and risk factors for bronchiectasis were identified.ResultsOne hundred subjects age 6 months to 19 years were identified. Overall, 66% had bronchiectasis, including 51% of those less than 2 years old. The youngest was 8 months old. Severe neurological impairment (OR 9.45, P < 0.004) and history of gastroesophageal reflux (OR 3.36, P = 0.036) were identified as risk factors. Clinical history, exam, and other co-morbidities did not predict bronchiectasis. Sixteen subjects with bronchiectasis had repeat chest computed tomography with 44% demonstrating improvement or resolution.DiscussionBronchiectasis is highly prevalent in children with CPA and its presence in young children demonstrates that it can develop rapidly. Early identification of bronchiectasis, along with interventions aimed at preventing further airway damage, may minimize morbidity and mortality in patients with CPA. Pediatr Pulmonol. © 2011 Wiley Periodicals, Inc.

Prenatal cigarette smoke (CS) exposure, in combination with hypoxia and/or hyperthermia can lead to gasping and attenuated recovery from hypoxia in 7 days old rat pups. We studied 95 unanesthetized spontaneously breathing 14 days old rat pups to investigate if the destabilizing effects of increased ambient temperature and prenatal CS exposure on respiratory control observed in 7 days old rats were still evident at day 14. This postnatal age was selected as it is beyond the analogous risk period for SIDS in human. Furthermore, we investigated if the breathing responses to hypercapnia are affected by prenatal CS exposure. Since high ambient (HA) temperature can lead to gasping and aberrant respiratory control, we recorded respiratory patterns at low (24–25°C) and high (29–30°C) ambient temperatures, and under hypoxic or hypercapnic states. No gasping was observed in 14 days old rat pups. During hypoxia, breathing frequency increased in the CS-exposed group under low and HA temperatures. Rectal temperature decreased only in the sham group in response to low ambient temperature hypoxia. At HA temperature, breathing frequency increased in both sham and CS-exposed groups during hypercapnia, however, it remained elevated during washout period only in the sham group. We demonstrate that prenatal CS exposure continues to have profound effects on respiratory and thermoregulatory responses to hypoxia and hypercapnia at day 14. The attenuated respiratory and thermoregulatory responses to acute hypoxia and hypercapnia on day 14 demonstrate a strong interaction between CS exposure, respiratory control, and thermoregulation during postnatal maturation. Pediatr Pulmonol. © 2011 Wiley Periodicals, Inc.

Pneumocystis jirovecii is a leading cause of opportunistic infections among the immune compromised. During the 1980s, attention focused on patients with HIV, however, with the advent of anti-retroviral therapy, we wished to revisit the question of underlying diseases associated with Pneumocystis pneumonia in children. We identified 80 cases from 1986 to 2006 and performed a retrospective chart review to identify clinical characteristics for each of the cases. HIV was the single most common associated underlying condition seen in this cohort, accounting for 39% of the cases overall, however, it was seen in just 15% of the cases since 1998. Transplant recipients and oncology patients together comprised another 39% of the cases, with 9% of cases attributed to primary immune deficiency and another 9% of cases associated with less well-recognized causes of susceptibility. This study documents the ongoing need for vigilance to diagnose Pneumocystis pneumonia in less well-recognized clinical scenarios. Pediatr Pulmonol. © 2011 Wiley Periodicals, Inc.

Aspiration is a significant cause of respiratory morbidity and sometimes mortality in children. It occurs when airway protective reflexes fail, especially, when dysphagia is also present. Clinical symptoms and physical findings of aspiration can be nonspecific. Advances in technology can lead to early diagnosis of dysphagia and aspiration, and, new therapeutic advances can significantly improve outcome and prognosis. This report first reviews the anatomy and physiology involved in the normal process of swallowing. Next, the protective reflexes that help to prevent aspiration are discussed followed by the pathophysiologic events that occur after an aspiration event. Various disease processes that can result in dysphagia and aspiration in children are discussed. Finally, the various methods for diagnosis and treatment of dysphagia in children are reviewed. Pediatr Pulmonol. © 2011 Wiley Periodicals, Inc.

BackgroundRecent studies have shown the presence of lung disease in even asymptomatic infants with cystic fibrosis (CF). While pulmonary function testing (PFT) is often used to follow progression of lung disease and guide treatment in older children with CF, little data is available on change in infant PFTs in young children with CF.ObjectiveTo determine change in infant PFTs before and after antibiotic therapy for pulmonary exacerbation in infants with CF.MethodsRetrospective cohort study of infants with CF who underwent clinically indicated infant PFTs before and after antibiotic therapy for CF pulmonary exacerbation at the University of North Carolina at Chapel Hill.ResultsPre- and post-antibiotics PFT data was available on 11 infants with CF, with a mean age of 102 weeks at time of first PFT. The majority of infants were symptomatic prior to antibiotics, and showed statistically significant improvement in clinical parameters following treatment. Prior to antibiotics, PFTs showed evidence of substantial obstructive disease (mean z-scores for FVC, FEV0.5, and FEF25-75 of −1.81, −3.06, and −4.5, respectively) and air-trapping/hyperinflation (mean z-scores for FRCpleth, RV, and RV/TLC of 8.86, 7.1, and 3.31, respectively). Following antibiotics, all of the above parameters showed statistically significant improvement.DiscussionWe have shown a statistically significant improvement in infant PFT measures following antibiotic therapy in a cohort of 11 infants with CF, which paralleled improvement in clinical parameters. Though infant PFTs showed improvement, they remained abnormal in the majority of subjects, with persistent air-trapping and hyperinflation after antibiotic therapy. Our findings suggest that infant PFTs are sensitive to acute clinical changes in children with CF, and may be a useful tool in managing infants with CF. Pediatr Pulmonol. © 2011 Wiley Periodicals, Inc.

The assessment of apnea and asynchronous breathing requires the application of a facemask connected to a pneumotachograph and inductive transducer bands placed around the chest wall. These contact devices may alter the breathing pattern and are difficult to implement, especially in infants and children. This study validates a contactless image-processing system that simultaneously retrieves breath-related thermal variations from nasal, ribcage, and abdomen regions of interest (ROI) from infrared thermographic video recordings of children. Thermographic videos were obtained in 17 supine, spontaneously breathing unsedated children (0.33–13.75 years), including 8 patients with respiratory pathology. Representative thermographic signals were obtained from each ROI on a frame-by-frame basis. Cronbach's Alpha reliability coefficient assessed the correlation between control nasal pressure period, the visually scored respiratory rate and the fundamental period in the frequency domain of thermographic signals. A cross-correlation function calculated the time delay and the phase angle between ribcage and abdomen variability. A Cronbach's Alpha value of 0.976 (0.992–0.944 95% CI) suggests a small-scale measurement error between thermographic and control periods. The ribcage-abdomen time delay in children with respiratory disease (−0.42 ± 0.707 sec) significantly differed from healthy children (0.22 ± 0.426 sec, P = 0.0125). This novel system reliably acquired time-aligned nasal airflow and thoracoabdominal motion estimates without relying on attached sensor performance and detected asynchronous breathing in pediatric patients. Pediatr Pulmonol. © 2011 Wiley Periodicals, Inc.

Despite its extensive use, there is no evidence that spirometry is useful in the assessment of progression of lung disease in primary ciliary dyskinesia (PCD). We hypothesize that high-resolution computed tomography (HRCT) is a better indicator of PCD lung disease progression than spirometry. We retrospectively evaluated two paired spirometry and HRCT examinations from 20 PCD patients (age, 11.6 years; range, 6.5–27.5 years). The evaluations were performed in stable state and during unstable lung disease. HRCT scans were scored blind by two raters. Compared to the first assessment, at the second evaluation spirometry did not change while HRCT scores significantly worsened (P < 0.01). Age was significantly related to HRCT total (r = 0.5; P = 0.02) and bronchiectasis scores (r = 0.5; P = 0.02). At both evaluations, HRCT total score correlated with FEV1 (r = −0.5, P = 0.01; r = −0.7, P = 0.001, respectively) and FVC Z scores (r = −0.6, P = 0.006; r = −0.7, P = 0.001, respectively), and bronchiectasis score was related to FEV1 (r = −0.5, P = 0.03; r = −0.6; P = 0.002, respectively) and FVC Z scores (r = −0.6, P = 0.008; r = −0.7, P = 0.001, respectively). No relationship was found between the change in HRCT scores and the change in spirometry. In PCD, structural lung disease may worsen despite spirometry being stable. Pediatr Pulmonol. © 2011 Wiley Periodicals, Inc.

BackgroundThere are limited data assessing bronchodilator responsiveness (BDR) in infants and toddlers with recurrent wheezing, and factors associated with a positive response.ObjectivesIn a multicenter study of children ≤ 36 months old, we assessed the prevalence of and factors associated with BDR among infants/toddlers with recurrent episodes of wheezing.MethodsForced expiratory flows and volumes using the raised-volume rapid thoracic compression method were measured in 76 infants/toddlers [mean (SD) age 16.8 (7.6) months] with recurrent wheezing before and after administration of albuterol. Prior history of hospitalization or emergency department treatment for wheezing, use of inhaled or systemic corticosteroids, physician treatment of eczema, environmental tobacco smoke exposure, and family history of asthma or allergic rhinitis were ascertained.ResultsUsing the published upper limit of normal for post bronchodilator change (FEV0.5 ≥ 13% and/or FEF25–75 ≥ 24%) in healthy infants, 24% (n = 18) of children in our study exhibited BDR. The BDR response was not associated with any clinical factor other than body size. Dichotomizing subjects into responders (defined by published limits of normal) or by quartile to identify children with the greatest change from baseline (4th quartile vs. other) did not identify any other factor associated with BDR.ConclusionsApproximately one quarter of infants/toddlers with recurrent wheezing exhibited BDR at their clinical baseline. However, BDR in wheezy infants/toddlers was not associated with established clinical asthma risk factors. Pediatr Pulmonol. © 2011 Wiley Periodicals, Inc.

ObjectivePersistent lung atelectasis is difficult to treat and perfluorochemical (PFC) liquid may be an option for bronchioalveolar lavage (BAL).Case reportA 4-year-old girl with spinal muscle atrophy was admitted in respiratory failure. On admission, the X-ray confirmed the persistence of total right-sided lung atelectasis, which had been present for 14 months. She was endotracheally intubated and ventilated from the day of admission. BAL with normal saline was performed twice without improvement. Following failed extubation and being dependent on continuous respiratory support, a trial of BAL using PFC liquid (Perfluorodecalin HP) was carried out. The PFC was delivered through the endotracheal tube on three consecutive days. A loading dose of 3 ml/kg was administered, followed by a varying dose in order to more effectively lavage the lungs. She tolerated the procedure well the first 2 days, although there were no clinical signs of improvement in the atelectasis. Intentionally, higher inflation pressures were applied after PFC instillation on day 3. Chest X-ray then showed hazy infiltrates on her left lung and she required more ventilatory support. However, lung infiltrates cleared over the next 3 days. A tracheotomy was done 6 days after the last PFC instillation. She had a slow recovery and was successfully decanulated. Clinical improvement of lung function was seen including less need of BiPAP and oxygen. A chest CT scan showed then functional lung tissue appearing in the previous total atelectatic right lung.ConclusionLavage with PFC can safely be performed with a therapeutic effect in a child with unilateral total lung atelectasis. Pediatr Pulmonol. © 2011 Wiley Periodicals, Inc.

IntroductionAfter intensive tobacco control efforts in recent decades, the prevalence of active smoking has decreased. However, the hazardous effect of indirect exposure to cigarette smoke is often underestimated, especially in children. We aimed to investigate the effect of parental smoking on the respiratory morbidity of the children of parents who smoke by evaluating the relationship between parental smoking behavior and children's respiratory symptoms.MethodsWe conducted a cross-sectional follow-up study of 31,584 children aged 6–11 in an urban community in Anyang City, Korea. The children's parents were asked about their smoking status and completed questionnaires regarding their children's symptoms related to asthma and other upper or lower respiratory illnesses. Our analysis focused on a comparison of the frequency of respiratory and ocular symptoms according to parental smoking status, whether it was non-smoking (Non-S), indirect passive smoking (third-hand smoking, THS) or direct passive smoking (second-hand smoking, SHS).ResultsThe children with Non-S patients were 40.9%, THS group 40.6%, and SHS group 18.5%. THS group showed lower ORs for most respiratory symptoms when compared with those of SHS group, however, THS group revealed increased ORs compared with Non-S in cough-related symptoms. There was a linear trend in frequencies of cough and sputum-related symptoms according to the degree of exposure to cigarette smoke (P < 0.05).ConclusionThe prevalence of respiratory symptoms increased in children exposed to parental smoking including SHS and THS. To avoid the risk of respiratory and allergic disease by environmental tobacco smoke, absolute smoking cessation by parents is strongly recommended. Pediatr Pulmonol. © 2011 Wiley Periodicals, Inc.

BackgroundAsthma is the most common chronic inflammatory disease in childhood and some reports have demonstrated systemic inflammation. The relevance of high-sensitivity assays for C-reactive protein (hs-CRP), which are known to be a sensitive marker of low-grade systemic inflammation, has not been fully studied in childhood asthma.Aim of studyThis cross sectional case–control study aimed at evaluating serum hs-CRP in asthmatic children with different grades of severity and control.MethodsSerum hs-CRP, sputum cytology study, and forced expiratory volume in 1 sec (FEV1) % of predicted for age and sex were estimated in 60 asthmatic children (30 uncontrolled steroid-naïve, and 30 controlled on inhaled steroid). They were recruited from Pediatric Chest Clinic, Children's Hospital, Ain Shams University. Sixty healthy children-age and sex-matched were included as a control group.ResultsSerum hs-CRP concentrations were significantly higher in asthmatics than in controls with a median of 1.93 mg/L and 0.24 mg/L, respectively. Serum hs-CRP levels were significantly higher in uncontrolled steroid-naïve asthmatics than those controlled on inhaled steroid with a median of 3.15 mg/L and 1.55 mg/L, respectively. Serum hs-CRP showed a sensitivity of 72% and a specificity of 93%.ConclusionsDespite that pulmonary function tests and clinical classification are the gold standard for grading of asthma, hs-CRP can be considered as a new marker for assessment of different grades of asthma severity and control. It can be used for indirect detection and monitoring of airway inflammation, disease severity, and response to steroid treatment in asthmatic children. Pediatr Pulmonol. © 2011 Wiley Periodicals, Inc.

BackgroundA reliable standardized diagnosis of pneumonia in children has long been difficult to achieve. Clinical and radiological criteria have been developed by the World Health Organization (WHO), however, their generalizability to different populations is uncertain. We evaluated WHO defined chest radiograph (CXRs) confirmed alveolar pneumonia in the clinical context in Central Australian Aboriginal children, a high risk population, hospitalized with acute lower respiratory illness (ALRI).MethodsCXRs in children (aged 1–60 months) hospitalized and treated with intravenous antibiotics for ALRI and enrolled in a randomized controlled trial (RCT) of Vitamin A/Zinc supplementation were matched with data collected during a population-based study of WHO-defined primary endpoint pneumonia (WHO-EPC). These CXRs were reread by a pediatric pulmonologist (PP) and classified as pneumonia-PP when alveolar changes were present. Sensitivities, specificities, positive and negative predictive values (PPV, NPV) for clinical presentations were compared between WHO-EPC and pneumonia-PP.ResultsOf the 147 episodes of hospitalized ALRI, WHO-EPC was significantly less commonly diagnosed in 40 (27.2%) compared to pneumonia-PP (difference 20.4%, 95% CI 9.6–31.2, P < 0.001). Clinical signs on admission were poor predictors for both pneumonia-PP and WHO-EPC; the sensitivities of clinical signs ranged from a high of 45% for tachypnea to 5% for fever + tachypnea + chest-indrawing. The PPV range was 40–20%, respectively. Higher PPVs were observed against the pediatric pulmonologist's diagnosis compared to WHO-EPC.ConclusionsWHO-EPC underestimates alveolar consolidation in a clinical context. Its use in clinical practice or in research designed to inform clinical management in this population should be avoided. Pediatr Pulmonol. © 2011 Wiley Periodicals, Inc.

BackgroundChronic lung disease of prematurity (CLDP) is a frequent complication of premature birth. Infants and children with CLDP are often prescribed complex medication regimens, which can be difficult for families to manage.ObjectiveWe sought to determine whether non-adherence was associated with increased CLDP-related morbidities and to identify predictors of adherence.MethodsRecruited caregivers of 194 children with CLDP completed questionnaires regarding self-reported adherence, respiratory outcomes, and quality of life (January 2008–June 2010). Adherence data were available for 176 subjects, of whom 143 had self-reported data only, and 33 had prescription claims data, which were used to calculate a medication possession ratio (MPR). Participants in the Prescription Claims Sample (n = 33) were more likely to have public insurance (P < 0.001).ResultsSelf-reported adherence substantially overestimated medication possession; the mean MPR was 38.8% (n = 33) and was not associated with self-reported adherence (P = 0.71; n = 26). In a small sample, higher MPR was associated with decreased odds ratios of visiting the emergency department (ED) (OR = 0.75 for a 10% increase in MPR [95%CI: 0.58, 0.97]; P = 0.03; n = 74 questionnaires from 28 participants), activity limitations (OR = 0.71 [95%CI: 0.53, 0.95]; P = 0.02; n = 70 questionnaires from 28 participants), and rescue medication use (OR = 0.84 [95%CI: 0.73-0.98]; P = 0.03; n = 70 questionnaires from 28 participants). Increasing caregiver worries regarding medication efficacy and side effects were associated with lower MPR (P = 0.04 and 0.02, respectively; n = 62 questionnaires from 27 participants). Socio-demographic and clinical risk factors were not predictors of MPR (n = 33).ConclusionsWe found that non-adherence with respiratory medications was common in premature infants and children with CLDP. Using multiple timepoints in a small sample, non-adherence was associated with a higher likelihood of respiratory morbidities. Although self-reported adherence and demographic characteristics did not predict MPR, concerns about medications did. We suggest that addressing caregiver concerns about medications may improve adherence and ultimately decrease CLDP-related morbidities. Larger, prospective studies are needed to confirm these findings and determine which factors predict non-adherence. Pediatr Pulmonol. © 2011 Wiley-Liss, Inc.

ObjectivesWe evaluated safety and efficacy of recombinant human growth hormone (rhGH) for improving growth, lean body mass (LBM), pulmonary function, and exercise tolerance in children with cystic fibrosis (CF) and growth restriction.Study designMulticenter, open-label, controlled clinical trial comparing outcomes in prepubertal children <14 years with CF, randomized in a 1:1 ratio to receive daily rhGH (Nutropin AQ) or no treatment (control) for 12 months, followed by a 6-month observation (month 18). Safety was monitored at each visit, including assessments of glucose tolerance.ResultsSixty-eight subjects were randomized (control n = 32; rhGH n = 36). Mean height standard deviation score (SDS) in the rhGH group increased by 0.5 ± 0.4 at 12 months (mean ± SD, P < 0.001); the control group height SDS remained unchanged. Weight increased by 3.8 ± 1.8 versus 2.8 ± 1.5 kg, (mean ± SD, P = 0.0356) and LBM increased by 3.8 ± 1.8 versus 2.1 ± 1.4 kg (P = 0.0002) in the rhGH group versus controls, respectively. Forced vital capacity increased by 325 ± 319 in the rhGH group compared with 178 ± 152 ml in controls (mean ± SD, P = 0.032). Forced expiratory volume in 1 sec improved in both groups with a significant difference between groups after adjustment for baseline severity (LS mean ± SE: rhGH, 224 ± 37, vs. controls, 108 ± 40 ml; P = 0.04). There was no difference between groups in exercise tolerance (6-min walk distance) at 1 year. Changes in glucose tolerance for the two groups were similar over the 12-month study period, with three subjects developing IGT and one CFRD in each group. One rhGH-treated patient developed increased intracranial pressure.ConclusionsTreatment with rhGH in prepubertal children with CF was effective in promoting growth, weight, LBM, lung volume, and lung flows, and had an acceptable safety profile. Pediatr Pulmonol. © 2011 Wiley-Liss, Inc.

It has been hypothesized that exhaled breath temperature (EBT) is related to the degree of airway inflammation/remodeling in asthma. The purpose of this study was to evaluate the relationship between the level of airway response to exercise and EBT in a group of controlled or partly controlled asthmatic children. Fifty asthmatic children underwent measurements of EBT before and after a standardized exercise test. EBT was 32.92 ± 1.13 and 33.35 ± 0.95°C before and after exercise, respectively (P < 0.001). The % decrease in FEV1 was significantly correlated with the increase in EBT (r = 0.44, P = 0.0013), being r = 0.49 (P < 0.005) in the children who were not receiving regular inhaled corticosteroids (ICS) and 0.37 (n.s.) in those who were. This study further supports the hypothesis that EBT can be considered a potential composite tool for monitoring asthma. Pediatr Pulmonol. © 2011 Wiley-Liss, Inc.

BackgroundDuring severe exacerbations, asthmatic children vary significantly in their response to high-dose continuous β2-adrenergic receptor (ADRβ2) agonist therapy. Genetic polymorphisms have been identified within the ADRβ2 that may be functionally relevant, but few studies have been performed in this population. Our hypothesis was that genotypic differences are associated with magnitude of response to ADRβ2 agonist treatment during severe asthma exacerbations in children.MethodsChildren aged 2–18 years admitted to the ICU (intensive care unit) with a severe asthma exacerbation between 2006 and 2008 were eligible. Genotyping of the ADRβ2 was performed.ResultsEighty-nine children consented and were enrolled. Despite similar clinical asthma scores on admission, children with the Gly16Gly genotype at amino acid position 16 had significantly shorter ICU length of stay (LOS) and hospital LOS, compared to children with Arg16Arg and Arg16Gly genotypes. Children with either the Gln27Glu or Glu27Glu genotype at amino acid position 27 also had significantly shorter ICU LOS and hospital LOS compared to children with the Gln27Gln genotype. The Arg16Gly-Gln27Gln haplotype was associated with the longest ICU LOS, but this was not statistically different from other haplotypes.ConclusionsIn this cohort of children with severe asthma exacerbations, ADRβ2 polymorphisms were associated with responses to therapy. Knowledge of the genetic profile of children with asthma may allow for targeted therapy during acute exacerbations. Pediatr Pulmonol. © 2011 Wiley-Liss, Inc.

Maternal diabetes is associated with increased risk for abnormal fetal organogenesis, but its effects on the developing lungs are still insufficiently known. To determine the effect of maternal hyperglycemia on postnatal lung development, we studied lung structural and cellular changes in newborn rats exposed to intrauterine hyperglycemia. We induced hyperglycemia in Sprague–Dawley rats with i.p. streptozotocin before pregnancy and allowed the hyperglycemic and control dams deliver at term. Lungs were obtained on postnatal day (d) 0, d7, and d14 and analyzed for lung weight and morphology, as well as cellular apoptosis (TUNEL staining) and proliferation (PCNA staining). Quantitative micro-CT analysis of the lung vasculature was additionally performed at d14. At birth, maternal hyperglycemia resulted in decreased relative lung weight, thinner alveolar septa and increased cellular apoptosis and proliferation, when compared to controls. At 1 and 2 weeks of age pulmonary cell apoptosis and alveolar chord length remained unchanged, but cell proliferation and number of secondary crests were increased in the hyperglycemia-exposed neonatal lungs in comparison with the controls. Density of small arterioles on histological examination and the structure of pulmonary arterial vasculature in micro-CT analysis of the neonatal lungs were not influenced by maternal hyperglycemia. Our results suggest, that maternal hyperglycemia is related to developmental structural alterations in postnatal rat lungs. These early changes may reflect aberrant maturational adaptation in response to the hyperglycemic fetal environment. Pediatr Pulmonol. © 2011 Wiley-Liss, Inc.

Bronchopulmonary dysplasia (BPD) poses a significant global health problem. It mainly occurs in preterm infants. It is histopathologically characterized by fewer and larger alveoli and less secondary septa, suggesting an arrested or disordered lung development. To date, the mechanisms that lead to the pathophysiological changes in BPD have still not been totally understood. In embryonic development, histone deacetylase (HDAC) plays an important role by regulating gene transcription. Here, we hypothesize that a decreased HDAC expression and activity, caused by preterm birth or environmental stresses, contribute to a disorder in alveolar development in BPD. To this end, newborn Sprague–Dawley rats subjected to hyperoxia (85% O2) were used to investigate the gene expression and protein activity of HDAC and alveolar development in lungs. Our results showed that hyperoxia exposure led to a suppression of the HDAC1/HDAC2 expression and activity, and the overall HDAC activity, as well as arrest of alveolarization, and an elevated expression of the cytokine-induced neutrophil chemoattractant-1 (CINC-1) in the lungs of newborn rats. However, preservation of HDAC activity by theophylline significantly improved alveolar development and attenuated CINC-1 release, all of which were blocked by a specific HDAC inhibitor, trichostatin A (TSA). TSA alone can disturb the alveolar development in neonatal rats. Our findings indicate that a persistent exposure to hyperoxia leads to a suppressed HDAC activity, which causes disorders in pulmonary development. This effect may be mediated by CINC-1. Attenuation of CINC-1-mediated inflammation by activating HDAC may have a protective effect in BPD. Pediatr Pulmonol. © 2011 Wiley-Liss, Inc.

We describe the case of a 14-year-old male who presented with a right upper lobe aspergilloma forming in a previously occult congenital pulmonary airway malformation. This is the first case describing an aspergilloma forming within a CPAM. Pediatr Pulmonol. © 2011 Wiley-Liss, Inc.

Given the difficulties in diagnosing, or even defining, asthma in children, claims of a pediatric asthma epidemic in Canada and other developed countries are accepted with surprisingly little critical examination. We reviewed a broad range of data sources to understand how the epidemic evolved during the last 50 years and also to assess the reliability of the conclusions drawn from that data. We obtained Canadian National and Provincial data from Statistics Canada National Population Health Survey, and the British Columbia Ministry of Health respiratory database. International data were obtained by extensive review of pediatric asthma epidemiological surveys published during the last 50 years. In many developed countries, there have been three separate epidemics involving different aspects of pediatric asthma during the last 50 years: a double peaked mortality epidemic (1960s and 1980s), a hospital admission epidemic (peaked around 1990) and a steadily growing epidemic of children who report asthmatic symptoms on questionnaires. Canadian pediatric rates for asthma mortality (1–2/million/year) and hospital admission (1–2/thousand/year) are low and have fallen for the last 20 years. Rates based on questionnaire studies are high (10–15/hundred) and rose steadily over the same period. Objective reductions in asthma deaths and hospital admission likely reflect improved education and treatment programmes. Current claims of an epidemic based largely on subjective self-reported symptoms require more careful analysis. The possibility that symptom misperception, disease fashions, and poor recall, may be part of the explanation for the current high levels of self-reported symptoms deserves more attention. Pediatr Pulmonol. © 2011 Wiley-Liss, Inc.

BackgroundVentilator-dependent children have complex chronic conditions that put them at risk for acute illness and repeated hospitalizations.ObjectivesTo determine the 12-month incidence of and risk factors for non-elective readmission in children with chronic respiratory failure (CRF) after initiation on home mechanical ventilation (HMV) via tracheostomy.MethodsA retrospective cohort study of 109 HMV patients initiated and followed at an university-affiliated children's hospital between 2003 and 2009. Patient characteristics are presented using descriptive statistics; generalized estimated equations are used to estimate adjusted odds ratios of select predictor variables for readmission.ResultsThe 12-month incidence of non-elective readmission was 40%. Close to half of these readmissions occurred within the first 3 months post-index discharge. Pneumonia and tracheitis were the most common reasons for readmission; 64% were pulmonary- or tracheostomy-related. Most demographic and clinical patient characteristics were not statistically associated with non-elective readmissions. Although, a change in the child's management within 7 days before discharge was associated readmissions shortly after index discharge.ConclusionNon-elective readmissions of newly initiated pediatric HMV patients were common and likely multifactorial. Many of these readmissions were airway-related, and some may have been potentially preventable. Pediatr Pulmonol. © 2011 Wiley-Liss, Inc.

BackgroundAdult cystic fibrosis (CF) patients are an expanding cohort that is taken care of in a variety of hospital settings including adult centers located within pediatric institutions. This study compared costs and discharge rates among adult CF patient hospitalizations in terms of location of hospitalization.MethodsThe 2007 Nationwide Inpatient Sample was utilized to identify adult CF patient admission data on patients aged 18–44. Data were separated into pediatric and adult facilities based on percentage discharge rate for patients >18. Primary outcomes measures were length of stay (LOS) and total hospital charges. Secondary predictors were geographic, primary payer, and co-morbidity effects on LOS and total hospital charges.ResultsLOS was higher for adult CF patient admissions in pediatric facilities compared to adult facilities by a mean of 2.5 days. Mean total hospital charges were not significantly different. Adult hospitals in the Western U.S. had a mean total charge more than $50,000 greater than any region in the U.S. Self-pay patients had significantly fewer hospital days and charges across all hospital types. Adult facilities had 7% more CF patients discharged home with home healthcare use. Depressed CF patients had longer LOS by 1.5 days regardless of facility type.ConclusionsLOS for adult CF inpatient admissions was significantly lower in adult facilities compared to pediatric facilities without a significant difference in hospital charges and is influenced by geographic hospital location. Depressed patients had longer lengths of stay regardless of facility type. Self-insured adult CF patients have a significant reduction in LOS and hospital charges when compared to all other payers regardless of hospital type. Pediatr Pulmonol. © 2011 Wiley-Liss, Inc.

BackgroundInterferon-γ (IFN-γ) release assay (IGRA) is used for diagnosis of latent tuberculosis infection (LTBI), and for serial testing of active tuberculosis (TB). The aim of this study was to evaluate the results of IGRA for diagnosis and treatment monitoring of children with LTBI and children with TB. IGRA was performed in BCG vaccinated children before and six months after the beginning of treatment.MethodsA total of 59 BCG vaccinated children aged 4–18 years were investigated due to exposure to active TB. The participants were divided into two groups: Group 1, children with LTBI (N = 41), and Group 2, children with TB (N = 18). IGRA (QuantiFERON-TB Gold In-Tube) was performed twice, i.e., before treatment and at the end of prophylaxis and therapy.ResultsThere was no significant difference in IFN-γ concentrations between Group 1 and Group 2 subjects either before or after the treatment. Difference between pre-treatment and post-treatment IFN-γ concentrations compared in either Group 1 or Group 2 was not statistically significant. During follow-up, children with LTBI did not develop active TB. In addition, in children with TB, signs and symptoms of TB improved with anti-TB therapy.ConclusionThis study showed that the concentrations of IFN-γ did not differ in children with LTBI and TB either before or at the end of treatment. IGRA may remain positive over a long period of time. It seems that IGRA is not useful for monitoring treatment of children with LTBI and children with TB. Pediatr Pulmonol. © 2011 Wiley-Liss, Inc.

The use of wood as heating and cooking fuel can result in elevated levels of indoor air pollution, but to what extent this is related to respiratory diseases and allergies is still inconclusive. Here, we report a cross-sectional study among 744 school adolescents (median age 15 years) using as main outcomes respiratory symptoms and diseases, exhaled nitric oxide, total and aeroallergen-specific IgE in serum, and two epithelial biomarkers in nasal lavage fluid (NALF) or serum, that is, Clara cell protein (CC16) and surfactant-associated protein D (SPD). Information about the wood fuel use and potential confounders was collected via a personal interview of the adolescent and a questionnaire filled out by the parents. Two approaches were used to limit the possible influence of confounders, that is, multivariate analysis using the complete study population or pairwise analysis of matched sub-populations obtained using an automated procedure. Wood fuel use was associated with a decrease of CC16 and an increase of SPD in serum, which resulted in a decreased serum CC16/SPD ratio (median −9%, P = 0.001). No consistent differences were observed for the biomarkers measured in exhaled breath or NALF. Wood fuel use was also associated with increased odds for asthma [odds ratio (OR) 2.2, 95% CI: 1.1–4.4, P = 0.02], hay fever (OR = 2.4, 95% CI: 1.4–4.3, P = 0.002), and sensitization against pollen allergens (OR = 2.1, 95% CI: 1.3–3.4, P = 0.002). The risks of respiratory tract infections, self-reported symptoms, and sensitization against house-dust mite were not increased by wood fuel use. The increased risks of asthma, hay fever and aeroallergen sensitization, and the changes of lung-specific biomarkers consistently pointed towards respiratory effects associated with the use of wood fuel. Pediatr Pulmonol. © 2011 Wiley-Liss, Inc.

BackgroundThe clinical relevance of parallel detection of multiple viruses by real-time polymerase chain reaction (RT-PCR) remains unclear. This study evaluated the association between the detection of multiple viruses by RT-PCR and disease severity in children with bronchiolitis.MethodsChildren less than 2 years of age with clinical symptoms of bronchiolitis were prospectively included during three winter seasons. Patients were categorized in three groups based on disease severity; mild (no supportive treatment), moderate (supplemental oxygen and/or nasogastric feeding), and severe (mechanical ventilation). Multiplex RT-PCR of 15 respiratory viruses was performed on nasopharyngeal aspirates.ResultsIn total, 142 samples were obtained. Respiratory Syncytial virus (RSV) was the most commonly detected virus (73%) followed by rhinovirus (RV) (30%). In 58 samples (41%) more than one virus was detected, of which 41% was a dual infection with RSV and RV. In RSV infected children younger than 3 months, disease severity was not associated with the number of detected viruses. Remarkably, in children older than 3 months we found an association between more severe disease and RSV mono-infections.ConclusionDisease severity in children with bronchiolitis is not associated with infection by multiple viruses. We conclude that other factors, such as age, contribute to disease severity to a larger extent. Pediatr Pulmonol. © 2011 Wiley-Liss, Inc.

BackgroundInfection and inflammation are important in the pathogenesis of bronchiectasis. However, there are few published data describing the lower airway microbiology and cellularity in children.MethodsChildren with non-cystic fibrosis (CF) bronchiectasis who underwent bronchoalveolar lavage (BAL) within 4 weeks of diagnosis were identified by a retrospective patient-record review. The effects of infection (≥105 colony-forming units of respiratory bacteria/ml; or detectable Pseudomonas aeruginosa; mycobacteria, fungi, mycoplasma, or respiratory viruses) on airway cellularity and the impact of age, gender, indigenous status, immune function, radiographic involvement and antibiotic usage on infection risk were evaluated.ResultsOf 113 children [median age 63 months (IQR 32–95)] with newly diagnosed bronchiectasis, 77 (68%) had positive BAL cultures for respiratory bacterial pathogens. Haemophilus influenzae was most commonly detected, being present in 53 (47%) BAL specimens. P. aeruginosa was found in just 7 (6%) children, five of whom had an underlying disorder, while mycobacterial and fungal species were not detected. Respiratory viruses were identified in 14 (12%) children and Mycoplasma pneumoniae in two others. Overall, 56 (49.5%) children fulfilled our definition of a lower airway infection and of these, 35 (63%) had more than one pathogen present. Compared to children without infection, children with infection had higher total cell counts (610 vs. 280 × 106/L), neutrophil counts (351 vs. 70 × 106/L), and neutrophil percentages (69% vs. 34%). Age at diagnosis was most strongly associated with infection.ConclusionsBAL microbiology of children with newly diagnosed bronchiectasis is dominated by H. influenzae. In the absence of CF, isolation of P. aeruginosa may suggest a serious co-morbidity in this group. Airway neutrophilia is common, especially with higher bacterial loads. Pediatr Pulmonol. © 2011 Wiley-Liss, Inc.

IntroductionThere is growing use of nasal continuous positive airway pressure ventilation (nCPAP) for infants with bronchiolitis, based on clinical assessment of severity. Despite this there have been no studies which identify clinical predictors for the requirement of nCPAP.ObjectiveTo identify clinical factors in infants with acute bronchiolitis in the emergency department (ED), which might predict a requirement for nCPAP following admission.Materials and MethodsRetrospective review of pediatric ED case notes was conducted on bronchiolitis admissions to one dedicated Paediatric ED over a 12-month period. Potential predictors were identified through literature review. Data extraction of predictors was carried out and recorded for each case. Logistic regression was conducted for each variable to identify statistically significant predictors of nCPAP requirement.ResultsTwenty-eight (17%) of the 163 admitted infants received nCPAP. The strongest predictors of nCPAP requirement in were as follows: oxygen requirement within the ED (P < 0.001), lower oxygen saturation (P < 0.001), younger age at presentation (P = 0.002), higher respiratory rate (P = 0.002), higher heart rate (P = 0.003), lower Glasgow Coma Scale score (0.006), and younger gestational age (P = 0.024).ConclusionWe have identified clinical variables that were predictive of nCPAP requirement in infants admitted to our unit with bronchiolitis, oxygen requirement in the ED being the strongest single predictor. This is the first such study in the UK, and we hope it may be a starting point for further work that may provide an evidence base to aid clinicians in predicting the use of nCPAP in infants with bronchiolitis. Pediatr Pulmonol. © 2011 Wiley-Liss, Inc.

RationaleThe pathobiology of ventilator-associated pneumonia (VAP) in children is poorly understood; investigation has been limited by lack of universally applied diagnostic criteria and reliable biomarkers for this condition.ObjectivesWe evaluated the clinical pulmonary infection score (CPIS) in diagnosing VAP and prospectively characterized the relationship between surfactant protein-D (SP-D) metabolism and VAP.MethodsChildren admitted to an Egyptian PICU requiring intubation were screened for the absence of primary pulmonary pathology. Thirty-nine children underwent two evaluations: during the first 36 hr following intubation and after 4 days of mechanical ventilation. During both, bronchoalveolar lavage fluid (BALF) was obtained for culture and SP-D assay. CPIS was computed during the second evaluation.ResultsOptimum performance of the CPIS against BALF culture occurred at a cutoff value of 6, (ROC AUC of 0.89 ± 0.05). Children who developed VAP had significantly higher SP-D levels, both preceding (129.9 ± 33.5 ng/ml at the 1st BAL)—and following positive BALF culture (249.5 ± 51.2 ng/ml at the 2nd BAL), compared to children whose BALF remained sterile (62.6 ± 18.1 ng/ml and 64.9 ± 9.4 ng/ml; P < 0.001). This increase in SP-D levels was most evident in children infected with Pseudomonas aeruginosa compared to children with Klebsiella pneumonia or S. aureus.ConclusionsThe CPIS performed well against BALF culture. We observed a bacterial species-specific difference in SP-D levels in children who developed VAP; this change preceded detection of infection by CPIS or BALF culture. Pediatr Pulmonol. © 2011 Wiley-Liss, Inc.

Some studies have suggested that lung clearance index (LCI) is age-independent among healthy subjects early in life, which implies that ventilation distribution does not vary with growth. However, other studies of older children and adolescents suggest that ventilation becomes more homogenous with somatic growth. We describe a new technique to obtain multiple breath washout (MBWO) in sedated infants and toddlers using slow augmented inflation breaths that yields an assessment of LCI and the slope of phase III, which is another index of ventilation inhomogeneity. We evaluated whether ventilation becomes more homogenous with increasing age early in life, and whether infants with chronic lung disease of infancy (CLDI) have increased ventilation inhomogeneity relative to full-term controls (FT). FT (N = 28) and CLDI (N = 22) subjects between 3 and 28 months corrected-age were evaluated. LCI decreased with increasing age; however, there was no significant difference between the two groups (9.3 vs. 9.5; P = 0.56). Phase III slopes adjusted for expired volume (SND) increased with increasing breath number during the washout and decreased with increasing age. There was no significant difference in SND between full-term and CLDI subjects (211 vs. 218; P = 0.77). Our findings indicate that ventilation becomes more homogenous with lung growth and maturation early in life; however, there is no evidence that ventilation inhomogeneity is a significant component of the pulmonary pathophysiology of CLDI. Pediatr Pulmonol. © 2011 Wiley-Liss, Inc.

The incidence of venous thromboembolism (VTE) is increasing in the pediatric population. Individuals with cystic fibrosis (CF) have an increased risk of thrombosis due to central venous catheters (CVCs), as well as acquired thrombophilia secondary to inflammation, or deficiencies of anticoagulant proteins due to vitamin K deficiency and/or liver dysfunction. CVC-associated thrombosis commonly results in line occlusion, but may develop into serious life-threatening conditions such as deep venous thrombosis (DVT), superior vena cava syndrome or pulmonary embolism (PE). Post-thrombotic syndrome (PTS) may be a long complication. Local occlusion of the catheter tip may be managed with instillation of thrombolytics (such as tPA) within the lumen of the catheter; however, CVC-associated thrombosis involving the proximal veins is most often is treated with systemic anticoagulation. Initial treatment with heparin is a standard approach, but thrombolytic therapy, which may carry higher bleeding risks, should be considered for life and limb threatening episodes of VTE. Recommended duration of anticoagulation with low molecular weight heparin (LMWH) or warfarin ranges from 3 to 6 months for major removable thrombotic risks; longer anticoagulation is considered for recurrent thrombosis, major persistent thrombophilia, or the continued presence of a major risk factor such as a CVC. While CVCs are the most common risk for development of VTE in children, studies have not demonstrated a clear benefit with routine use of systemic thromboprophylaxis. The incidence and risk factors of VTE in CF patients will be reviewed and principles of diagnosis and management will be summarized. Pediatr Pulmonol. 2012; 47:105–112. © 2011 Wiley Periodicals, Inc.

BackgroundThe childhood asthma control test (C-ACT) is a validated symptom score for assessing asthma control in children. We used a slightly modified version (C-ACTM) of the German C-ACT and compared our results with the literature, correlated the children's part of C-ACT (C-ACTchildren) with a visual analogue scale (VASchildren), explored the agreement between C-ACTM and GINA levels of asthma control, as well as the relationship between C-ACTM and lung function and exhaled nitric oxide (FeNO).MethodsWe investigated 107 children with a diagnosis of asthma. The study protocol consisted of a clinical examination, assessment of asthma control according to GINA guidelines, administration of C-ACTM, VASchildren, lung function, and FeNO.ResultsOf our patients 66% had, according to GINA, partly controlled-/uncontrolled asthma, 18% were uncontrolled according to C-ACTM. Children with partly controlled-/uncontrolled asthma according to GINA had lower C-ACTM scores than did children with controlled asthma (16.1 ± 3.6 SD vs. 25.4 ± 1.8 SD; P < 0.000), and children with a C-ACTM score ≤ 19 had poorer lung function (mean FEV1% predicted 81.5 ± 13.5 SD vs. 94.2 ± 12.1 SD; P = 0.002). Spearman's rank correlation coefficients revealed significant correlations between all symptom scores. Multiple linear regression adjusted for age, gender, FEV1 and FeNO demonstrated a significant relationship between C-ACTM, VASchildren, and FEV1 (P = 0.003, resp. <0.000), but no significant correlation between C-ACTM, VASchildren, and FeNO.ConclusionsThe German version of C-ACTM is valid and useful for monitoring children with asthma along with tests aimed to follow up lung function and airway inflammation. Concordance between C-ACTM and GINA is moderate, because asthma control assessed by C-ACTM allows more symptoms and lung function is not included in the scoring. Pediatr Pulmonol. 2012; 47:113–118. © 2011 Wiley Periodicals, Inc.

BackgroundGastro-esophageal reflux (GOR) may contribute to lung disease in children with cystic fibrosis (CF). There is conflicting evidence regarding the effect of chest physiotherapy (CPT) in the head-down position on GOR. Furthermore, there is currently no evidence on the impact of physiotherapy on GOR as assessed by pH-multichannel intraluminal impedance (pH-MII).Aims(1) To characterize GOR in young children with CF. (2) To determine whether the head-down position during physiotherapy exacerbates GOR.MethodsChildren were studied using pH-MII monitoring over 24-hr, during which they received two 20-min sessions of CPT. One session was performed in “modified” drainage positions with no head-down tilt and the alternate session in “gravity-assisted” drainage positions, which included 20° head-down tilt.ResultsTwenty children with CF (8 males), median age 12 months (range 8–34) were recruited. A total of 1,374 reflux episodes were detected in all children, of which 869 (63%) were acid and 505 (37%) were non-acid. Seventy-two percent of the episodes migrated proximally. During CPT, there was no significant difference between total number of reflux episodes in the modified or gravity-assisted positions, median [inter-quartile range (IQR)] 1 (0–2.5) compared to 1 (0.75–3) episode, respectively, P = 0.63. There was also no significant difference between the number of reflux episodes which migrated proximally, median (IQR) 1 (0–2) compared to 0 (0–2) episodes, respectively, P = 0.75.ConclusionIn young children with CF, GOR is primarily acidic and proximal migration is common. Physiotherapy in the head-down position does not appear to exacerbate GOR. The impact of GOR on lung disease remains to be elucidated. Pediatr Pulmonol. 2012; 47:119–124. © 2011 Wiley Periodicals, Inc.

RationaleThe risk of pulmonary exacerbation following Pseudomonas aeruginosa (Pa) acquisition in children with cystic fibrosis (CF) is unknown.ObjectivesTo determine if failure of antibiotic therapy to eradicate Pa and frequency of Pa recurrence are associated with increased exacerbation risk.MethodsThe cohort included 282 children with CF who participated in the EPIC trial ages 1–12 with newly acquired Pa, defined as either a first lifetime Pa positive respiratory culture or positive after two years of negative cultures (past isolation of Pa but >2 years prior to the trial). All received antibiotics to promote initial eradication followed by 15 months of intermittent maintenance antibiotics. Quarterly cultures were used to define initial eradication success and subsequent number of Pa recurrences. A standardized symptom-based definition of exacerbation was utilized. Cox proportional hazards models were used to estimate exacerbation risk.ResultsFailure to initially eradicate Pa was associated with exacerbation risk (hazard ratio [HR]: 2.49, 95% confidence interval [CI] 1.26, 4.93). In 245/282 with successful initial eradication during the trial, past isolation of Pa >2 years before the trial was the most significant predictor of exacerbation (HR 1.62, 95% CI 1.12, 2.35). In 37/282 who failed initial eradication, persistent Pa during the maintenance phase (1 or more Pa recurrences after failure to initially eradicate) added even greater exacerbation risk (HR 4.13, 95% CI 1.28, 13.32).ConclusionsChildren with CF who fail to eradicate after initial antibiotic treatment are at higher risk of subsequent exacerbation, suggesting clinical benefit to successful early eradication of Pa infection. Pediatr Pulmonol. 2012; 47:125–134. © 2011 Wiley Periodicals, Inc.

BackgroundDespite improving survival in cystic fibrosis (CF) patients, there is a mortality peak in early adulthood. Defining risk factors that predict significant worsening of lung disease in young adulthood may identify opportunities to improve outcomes in adults.MethodsWe identified 4,680 patients in the Epidemiologic Study of Cystic Fibrosis 1994–2005 with data in both adolescence (age 14.0–17.4 years) and young adulthood (age 18.5–22.0 years) and analyzed 2,267 who had ≥5 encounters and ≥5 measurements of forced expiratory volume in 1 second (FEV1) spanning ≥1 year during both adolescence and young adulthood, and ≥1 encounter with weight and height and ≥1 FEV1 measurement age 17.5–18.5 years. We compared the annualized rates of decline in FEV1 during adolescence and young adulthood stratified by best FEV1 around age 18. Logistic regression was used to identify risk factors associated with substantial decline (>20 points) in FEV1% predicted in young adulthood.ResultsAnnual rate of decline was greater in young adulthood than in adolescence. Risk factors for substantial decline included slower rate of FEV1 decline, greater FEV1 variability, faster body mass index (BMI) decline, male sex, chronic inhaled antibiotics, Haemophilus influenzae detection, and absence of multidrug-resistant Pseudomonas aeruginosa in adolescence, and lower than expected FEV1 and BMI around age 18.ConclusionsDecline in lung function accelerates in young adults with CF, especially in those with early stage lung disease. Adolescents at risk for substantial decline in lung function in young adulthood have higher FEV1 and worse nutritional status, among other identifiable risk factors. Pediatr Pulmonol. 2012; 47:135–143. © 2011 Wiley Periodicals, Inc.

BackgroundIn 2003, the Cystic Fibrosis (CF) Foundation in the United States published evidence-based infection control guidelines and distributed these to CF care centers. However, it is unclear how well the guidelines have been disseminated to patients and families, how well patients and families understand the principles of infection control, and what barriers they experience implementing the guidelines.MethodsWe assessed infection control knowledge, attitudes, and practices among CF patients and their families at 17 randomly selected CF centers. Anonymous surveys were completed by CF patients (≥16 years old) or their family members (patients <16 years old). To adjust for similarities of patients within each center, generalized estimating equations regression was used.ResultsFrom January 2007 to May 2009, 1,399 respondents completed surveys of whom 38% were patients and 62% were family members (overall mean age of patients = 14 years). Overall, 65% of respondents were aware of the CF infection control guidelines, but only 30% had discussed them more than once with their CF care team. More than one discussion was associated with increased knowledge of infection control, including routes of pathogen transmission; the importance of avoiding close contact with other CF patients; increased confidence in practicing infection control; and increased belief in the health benefits of infection control.ConclusionsThis study revealed that many CF patients and families are aware of the infection control guidelines, but that few had discussed them more than once with their CF teams. These findings underscore the importance of engaging patients and their families in regular discussions about infection control that address questions and concerns including the potential impact of infection control on health and well-being. Further strategies are needed to overcome barriers to implementing these guidelines. Pediatr Pulmonol. 2012; 47:144–152. © 2011 Wiley Periodicals, Inc.

BackgroundClinical testing for PHOX2B mutations is widely used for patients with any symptoms suggestive of hypoventilation (with/without anatomic/physiologic autonomic dysregulation), though not necessarily with the congenital central hypoventilation syndrome (CCHS) phenotype. Consequently, a multitude of referrals for clinical PHOX2B testing (fragment analysis of the 20 polyalanine repeat region and/or sequencing of entire coding region) have no identifiable mutation. Whole gene deletions/duplications have recently been identified as a common disease-causing mechanism, but have not been reported in a clinical population referred for PHOX2B testing. The objective of this study was to determine if PHOX2B exon or whole gene deletion/duplication would be identified in a subset of patients referred for PHOX2B testing.HypothesisWe hypothesized that PHOX2B exon or whole gene deletion or duplication would be identified in a subset of cases who were referred for genetic testing but not found to have a PHOX2B mutation with currently available clinical PHOX2B testing.MethodsGenomic DNA samples from patients that tested negative for PHOX2B mutations using fragment analysis and/or sequencing, and control samples, were screened for PHOX2B exon deletions/duplications by multiplex ligation-dependent probe amplification with confirmation by array comparative genomic hybridization.ResultsDeletions of/in PHOX2B were identified in 4/250 patients and 0/261 controls. The deletions ranged from 6,216 base pairs (involving only PHOX2B exon 3) to 2.6 megabases (involving all of PHOX2B and 12 other genes). The case with PHOX2B partial exon 3 deletion had a CCHS-compatible phenotype (hypoventilation, Hirschsprung disease). Phenotypes for the other three cases, all PHOX2B whole-gene deletions, were varied including: (1) apparent life threatening event, (2) full CCHS necessitating artificial ventilation with ganglioneuroblastoma, and (3) hypoventilation during sleep. Family studies of two of the four probands showed these deletions to be maternally inherited; the mothers also had phenotypic findings of autonomic dysfunction.ConclusionsPHOX2B exon or whole gene deletion should be considered as another mechanism of disease which may include CCHS, Hirschsprung disease, and/or tumors of neural crest origin, although the genotype–phenotype relationship requires further clarification. Pediatr Pulmonol. 2012; 47:153–161. © 2011 Wiley Periodicals, Inc.

Intrauterine growth restriction (IUGR) increases the risk of respiratory compromise throughout postnatal life. However, the molecular mechanism(s) underlying the respiratory compromise in offspring following IUGR is not known. We hypothesized that IUGR following maternal food restriction (MFR) would affect extracellular matrix deposition in the lung, explaining the long-term impairment in pulmonary function in the IUGR offspring. Using a well-established rat model of MFR during gestation to produce IUGR pups, we found that at postnatal day 21, and at 9 months (9M) of age the expression and abundance of elastin and alpha smooth muscle actin (αSMA), two key extracellular matrix proteins, were increased in IUGR lungs when compared to controls (P < 0.05, n = 6), as determined by both Western and immunohistochemistry analyses. Compared to controls, the MFR group showed no significant change in pulmonary resistance at baseline, but did have significantly decreased pulmonary compliance at 9M (P < 0.05 vs. control, n = 5). In addition, MFR lungs exhibited increased responsiveness to methacholine challenge. Furthermore, exposing cultured fetal rat lung fibroblasts to serum deprivation increased the expression of elastin and elastin-related genes, which was blocked by serum albumin supplementation, suggesting protein deficiency as the predominant mechanism for increased pulmonary elastin deposition in IUGR lungs. We conclude that accompanying the changes in lung function, consistent with bronchial hyperresponsiveness, expression of the key alveolar extracellular matrix proteins elastin and αSMA increased in the IUGR lung, thus providing a potential explanation for the compromised lung function in IUGR offspring. Pediatr Pulmonol. 2012; 47:162–171. © 2011 Wiley Periodicals, Inc.

ObjectiveTo determine the utility of overnight polysomnography (PSG) in assessing pulmonary reserve in stable preterm children with chronic lung disease (CLD).Study designA retrospective review and descriptive study of overnight PSGs and clinic visits of preterm infants/children less than 3 years of age who were diagnosed with bronchopulmonary dysplasia at discharge from the hospital and enrolled in the Johns Hopkins CLD patient registry between 2008 and 2010.ResultsSixty-two clinically stable patients underwent at least one overnight polysomnogram for clinical indications. The majority of patients were referred for oxygen titration (71%). PSGs from first studies revealed a mean respiratory disturbance index (RDI) of 8.2 ± 10.1 events/hr and a mean O2 saturation (SaO2) nadir of 86.2 ± 5.7%. In patients who underwent more than one PSG (n = 23), a significant decrease in RDI (P < 0.001) was found between the first study (mean age: 8.0 ± 3.3 months) and second study (mean age: 13.4 ± 5.2 months). Outpatient clinical measures of mean room air SaO2 and respiratory rate were not predictive of PSG measures of RDI and SaO2 nadir.ConclusionMean RDI was higher in stable preterm infants/children with CLD compared to previously published controls. RDI decreased with age in stable preterm infants/children with CLD suggesting improved pulmonary reserve with age. Outpatient clinical measures (respiratory rate and room air SaO2) did not correlate with RDI and SaO2 nadir indicating that overnight PSG is more sensitive in assessing pulmonary reserve than outpatient clinical measures. Pediatr Pulmonol. 2012; 47:172–179. © 2011 Wiley Periodicals, Inc.

ObjectiveWe aimed to examine the hypothesis that behavioral and neurocognitive functions of preschool children with Obstructive Sleep Apnea Syndrome (OSAS) are impaired compared to healthy children, and improve after adenotonsillectomy (TA).MethodsA comprehensive assessment battery was used to assess cognitive and behavioral functions, and quality of life in children with OSAS compared to matched controls.Results45 children (mean age 45.5 ± 9 months, 73% boys, BMI 15.7 ± 2) with OSAS were compared to 26 healthy children (mean age 48.6 ± 8 months, 46% boys, BMI 16.4 ± 2). Mean AHI in the OSAS group was 13.2 ± 10.7 (ranging from 1.2 to 57). Significantly impaired planning and fluency (executive function) were found in children with OSAS, as well as impaired attention and receptive vocabulary. Parents and teachers described the OSAS group as having significantly more behavior problems. Quality of life questionnaire in children with OSAS (mean 2.3, range 0.7–4.3) was significantly worse compared to controls (mean 0, range: 0–4), P < 0.004. One year following TA, 23 children with OSAS and 18 controls were re-evaluated. Significant improvement was documented in verbal and motor fluency, sustained attention, and vocabulary. After TA, fewer behavioral problems were seen.ConclusionsPreschool children with OSAS present significantly impaired executive functions, impaired attention and receptive vocabulary, and more behavior problems. One year after TA, the prominent improvements were in behavior and quality of life. These findings suggest that the impact of OSAS on behavioral and cognitive functions begins in early childhood. Pediatr Pulmonol. 2012; 47:180–188. © 2011 Wiley Periodicals, Inc.

Perfluorochemical (PFC) is theoretically a good vehicle for delivering biological agents to the lungs. This study was designed to investigate the efficacy of intratracheal (IT) instillation of meropenem using PFC liquid as a vehicle in a piglet model of acute lung injury (ALI). Eighteen piglets were injured with lung lavages to induce ALI, and randomly assigned to intravenous (IV) infusion or IT instillation groups, the latter using either PFC or normal saline (NS) as a delivery vehicle for meropenem. Blood samples were obtained at 0, 15, 30, and 60 min, and then hourly for 6 hr. Sera and extracts of lung tissues were assayed for meropenem content using high-performance liquid chromatography. We found that the IV group had significantly higher serum concentrations of meropenem during the first hour after dosing (P < 0.05). There was no significant difference between IT-PFC and IT-NS groups regarding changes in serum meropenem concentrations during the experimental period. Meropenem content in lung tissue was highest in the IT-PFC group, lower in the IT-NS group, and undetectable in the IV group (P < 0.05). The IT-NS group had the highest peak inspiratory pressure (P < 0.05), but there were no significant differences in other cardiopulmonary parameters among the three groups studied. In conclusion, meropenem can be safely administered to injured lungs by IT instillation in a meropenem/PFC suspension. Using PFC liquid as an IT vehicle to carry meropenem provides better pulmonary drug depositions than IV injection or IT instillation with NS in ALI. Pediatr Pulmonol. 2012; 47:189–198. © 2011 Wiley Periodicals, Inc.

Somatoform respiratory disorders represent conditions with dysfunctional breathing unexplained by structural abnormalities. This heterogeneous group includes disorders with neural dysregulation of respiration (vocal cord dysfunction) or with dysregulation of the respiratory pattern (hyperventilation, sighing dyspnea), psychogenic disorders such as unjustified anxiety of suffocation, and stereotype conditions such as throat clearing or habit cough. Many symptoms are nonspecific and largely overlap with respiratory disease symptoms of somatic etiology. Most patients will present in a nonspecialized clinical setting. This article provides symptom-based criteria for the definition of somatoform respiratory disorders and their differentiation from somatic disease. Emphasis is put on clinical criteria which can be easily integrated in a routine setting. Owing to the multifaceted etiology of somatoform respiratory disorders therapeutic approaches integrating somatic medicine, respiratory therapy and psychology are crucial. The introduction of defined clinical criteria may facilitate the discrimination of somatoform respiratory disorders from somatic disorders in routine patient encounters and avoid therapeutic detours. Pediatr Pulmonol. 2012; 47:199–205. © 2011 Wiley Periodicals, Inc.

Publication year: 2012
Source: Paediatric Respiratory Reviews, Available online 17 January 2012
Sam Mehr, Nicholas Wood
Invasive pneumococcal infection remains a leading global cause of morbidity and mortality in young children. In developed nations, a substantial decrease in the incidence of IPD has been achieved with inclusion of the 7 valent protein conjugated pneumococcal vaccines (7vPCV) into paediatric vaccine schedules. In contrast, the incidence of IPD has changed little in developing nations. This is likely due to poor access to medical care and pneumococcal vaccination, the accompanying HIV and malnutrition burden, and the fact that 7vPCV does not contain the most common serotypes (1,5, 6A) responsible for IPD in many developing nations. The battle against IPD in developed nations is not over, with the rise of non-7vPCV serotypes since routine 7vPCV vaccination. This has necessitated the development and distribution of pneumococcal vaccines containing 3 or 6 additional serotypes. This article provides an overview on pneumococcal carriage and risk factors for IPD, the rise of non-7vCPV serotypes in the era of 7vPCV vaccination, and the current and newly available broader valent pneumococcal vaccines.

Publication year: 2011
Source: Paediatric Respiratory Reviews, Available online 24 December 2011
Tuomas Jartti, Maria Wendelin-Saarenhovi, Inka Heinonen, Jaakko Hartiala, Timo Vanto
The fraction of exhaled nitric oxide (FeNO) has gained interest as a non-invasive tool to measure airway inflammation in asthma since it reflects allergic inflammation. Recent controlled clinical studies have, however, questioned its role in the management of asthma in children. To assess the clinical value of FeNO in paediatric asthma management, a meta-analysis was performed on the controlled studies of childhood asthma management guided by repeated FeNO measurements, and relevant publications on the confounders of FeNO were reviewed. The data suggests that utilising FeNO to tailor the dose of inhaled corticosteroids in children cannot be recommended for routine clinical practice since there is a danger of excessive inhaled corticosteroid doses in children without meaningful changes in clinical outcomes. Many disease and non-disease related factors (most importantly atopy, height/age and infection) affect FeNO levels which can easily confound the interpretation.

Publication year: 2011
Source: Paediatric Respiratory Reviews, Available online 8 December 2011
Maria Francesca Patria, Susanna Esposito
Many children are affected by recurrent lower respiratory tract infections (LRTIs), but the majority of them do not suffer from serious lung or extrapulmonary disease. The challenge for clinicians is to distinguish the recurrent RTIs with self-limiting or minor problems from those with underlying disease. The aim of this review is to describe a practical approach to children with recurrent LRTIs that limits unnecessary, expensive and time-consuming investigations. The children can be divided into three groups on the basis of their personal and family history and clinical findings: 1) otherwise healthy children who do not need further investigations; 2) those with risk factors for respiratory infections for whom a wait-and-see approach can be recommended; and 3) those in whom further investigations are mandatory. However, regardless of the origin of the recurrent LRTIs, it is important to remember that prevention by means of vaccines against respiratory pathogens (i.e. type bHaemophilus influenzae, pertussis, pneumococcal and influenza vaccines) can play a key role.

Publication year: 2011
Source: Paediatric Respiratory Reviews, Available online 30 November 2011
Heinz Burtscher, Karen Schüepp
Interest in ultrafine particles (UFP) has been increasing due to their specific physico-chemical characteristics. Ultrafine particles are those with an aerodynamic diameter of < 0.1 μm and are also commonly know as nanoparticles (0.1 μm = 100 nm). Due to their small size UFP contribute mostly to particle number concentrations and are therefore underestimated in actual pollution measurements, which commonly measure mass concentration. Children represent the most vulnerable group in regard to particulate exposure due to their developing status and different exposures compared to adults. This review discusses the sources of ultrafine particles as well as the specific exposures of children highlighting the importance and uniqueness of this age group.

Publication year: 2011
Source: Paediatric Respiratory Reviews, Available online 30 November 2011
G. Biskos, A. Schmidt-Ott
Engineered nanoparticles (ENPs) are the building blocks of novel materials and consumer products that hold great promise for our societies. When ENPs are released to the environment, however, they can induce irreversible processes that can affect human health. To ensure safety for all nanoparticle-based products throughout their life cycle we urgently need to develop techniques for determining their toxic effects and the exposure levels of humans to ENPs. In an attempt to estimate whether nanotechnology can threaten more sensitive parts of the population such as children, we provide a brief overview of the potential pathways of introducing ENPs into the environment and the state-of-the-art techniques for assessing human exposure, as well as our current knowledge on their toxic effects.

Publication year: 2011
Source: Paediatric Respiratory Reviews, Available online 30 November 2011
Peter D. Sly, Karen Schüepp

Publication year: 2011
Source: Paediatric Respiratory Reviews, Available online 21 November 2011
F. Nicole Dijk, Julie Curtin, David Lord, Dominic A. Fitzgerald
Unlike in adults, pulmonary embolism (PE) is an infrequent event in children. It has a marked bimodal distribution during the paediatric years, occurring predominantly in neonates and adolescents. The most important predisposing factors to PE in children are the presence of a central venous line (CVL), infection, and congenital heart disease. Clinical signs of PE are non-specific in children or can be masked by underlying conditions. Diagnostic testing is necessary in children, especially with the lack of clinical prediction rules. Recommendations for tests are derived from adult studies with ventilation/perfusion (V/Q) scintigraphy being well established. There exists an increasing role for computerised tomography pulmonary angiography (CTPA) and magnetic resonance pulmonary angiography (MRPA). Thrombotic events in children are initially treated with unfractionated heparin (UFH) or low molecular weight heparin (LMWH). For the extended anticoagulant therapy LMWH or vitamin K antagonists can be used with duration of treatment recommendations extrapolated from adult data. Mortality rates for PE in children are reported to be around 10%, with death usually related to the underlying disease processes. Exact data about recurrence risk in children is unknown. Because of the difference in aetiology, presentation, diagnostic methods and treatment between adults and children further research is necessary to assess the validity of recommendations for children.

Publication year: 2011
Source: Paediatric Respiratory Reviews, Available online 28 September 2011
Bruce K. Rubin
A highlight of many journals is a review of pertinent literature in a specific field that has been published in the preceding year. Although such “Year in Review” presentations are important, at PRR we are pleased to present the news that has not yet happened. In this manuscript, which is a combination of science and fiction, I will present the very best research that has not yet been conducted but will be published sometime in 2012 or 2013. This will cover all aspects of pediatric pulmonary disease. Any resemblance to real research that is actually published during this time period is strictly coincidental and the product of a fertile imagination. However, if these ideas inspire you to do these studies and publish the results it would make this science fiction even more interesting. To quote the famous baseball player, Yogi Berra, “It's difficult to make predictions, especially about the future.”

Publication year: 2011
Source: Paediatric Respiratory Reviews, Available online 28 September 2011
Andreas Jung, Irmela Heinrichs, Christian Geidel, Roger Lauener
Inpatient pulmonary rehabilitation programs have evolved from tuberculosis sanatoriums to modern medical centres providing standardized comprehensive care in a multidiciplinatory environment. Goals of rehabilitation programs for children and adolescents include restoration of professional activity, improvement of health condition, compliance and disease management as well as restoration of quality of life. Eligibility for an intervention is assessed by defined social and medical criteria. Comprehensive pulmonary rehabilitation programs provide a wide range of health care recourses, including diagnostic procedures, specific medical care, educational interventions and a multiprofessional team. Paediatric rehabilitation programs for chronic respiratory diseases, such as asthma or cystic fibrosis, have been shown to reduce symptoms, increase aerobic fitness and physical strength, improve pulmonary function and inflammation and enhance compliance, self-management, quality of life and psychological symptoms. Regional climatic effects have demonstrated an additional positive effect on the rehabilitation outcome. In addition, first evidence suggests an overall reduction of health care costs.

Publication year: 2011
Source: Paediatric Respiratory Reviews, Available online 25 September 2011
Karen Schüepp, Peter D. Sly
Nanoparticles have unique physico-chemical properties compared to larger particles that have the potential to provide promising new possibilities for biomedical applications. Considerable research is currently exploring these potentials of nanotechnology. In contrast, airborne particles as components of indoor air, ambient air pollution associated with traffic-related pollution, industry, power plants, and other combustion sources have the potential to harm children's health. However, a similar research effort into the potential health effects of exposure to nanoparticles is lacking. Children differ markedly from adults in their developmental biology rendering young children the most vulnerable group with regard to potentially harmful effects induced by particulate exposure. This review discusses the differences between children and adults in regard to nanoparticle exposure highlighting the uniqueness and vulnerability of children.

Publication year: 2011
Source: Paediatric Respiratory Reviews, Available online 25 September 2011
Karen Schüepp, Peter D. Sly
Nanoparticles have unique physico-chemical properties compared to larger particles that have the potential to provide promising new possibilities for biomedical applications. Considerable research is currently exploring these potentials of nanotechnology. In contrast, airborne particles as components of indoor air, ambient air pollution associated with traffic-related pollution, industry, power plants, and other combustion sources have the potential to harm children's health. However, a similar research effort into the potential health effects of exposure to nanoparticles is lacking. Children differ markedly from adults in their developmental biology rendering young children the most vulnerable group with regard to potentially harmful effects induced by particulate exposure. This review discusses the differences between children and adults in regard to nanoparticle exposure highlighting the uniqueness and vulnerability of children.

Publication year: 2011
Source: Paediatric Respiratory Reviews, Available online 23 September 2011
Susanne I. Fuchs, Monika Gappa
Multiple breath washout (MBW) has been demonstrated to be sensitive for assessing ventilation inhomogeneity (VI). VI is supposed to reflect changes in peripheral airways which are not apparent using spirometry. The lung clearance index (LCI) is the most robust parameter to quantify VI, and is largely independent of age; therefore, it potentially qualifies as a surrogate outcome parameter for clinical and research purposes, particularly during childhood.This review summarizes the current evidence regarding the clinical value of measuring LCI in children. Feasibility, reproducibility and diagnostic accuracy have been demonstrated; available data confirm that LCI is superior to spirometry in detecting small air way disease. However, there is little information regarding the value in the individual patient, and sparse longitudinal data looking at its prognostic value. Currently, only in patients with Cystic Fibrosis, it appears likely that knowledge of LCI will be useful for routine clinical management.

Publication year: 2011
Source: Paediatric Respiratory Reviews, Available online 17 September 2011
Paul L.P. Brand
Although montelukast is claimed to be preferable to inhaled corticosteroids in children with asthma and allergic rhinitis, virus-induced exacerbations, exercise induced asthma, and in those experiencing difficulties with inhalation therapy, there is no scientific evidence to support any of these claims. In comparative trials and systematic reviews, inhaled corticosteroids are clearly more effective than montelukast in reducing asthma exacerbations, improving lung function, symptom scores, and rescue medication use. The effects on exercise induced bronchoconstriction appear to be similar. Because of their superior efficacy and excellent long-term efficacy and safety profile, inhaled corticosteroids are the treatment of first choice for the maintenance therapy of childhood asthma, irrespective of age or clinical phenotype.

Publication year: 2011
Source: Paediatric Respiratory Reviews, Available online 17 September 2011
Larry C. Lands

Publication year: 2011
Source: Paediatric Respiratory Reviews, Available online 17 September 2011
Peter Paul van Asperen
Asthma is a heterogeneous disease and it is therefore unrealistic to expect that inhaled corticosteroids (ICS) would be appropriate first line preventer therapy for all children with asthma. There is good theoretical and clinical trial evidence demonstrating that leukotriene receptor antagonists (LTRAs) are more effective than ICS for viral induced wheezing and equivalent to ICS for mild persistent asthma in children. LTRAS do not have the systemic adverse effects of ICS, are generally well tolerated and their once daily oral administration enhances adherence. LTRAs should therefore be first line preventer therapy for children with frequent intermittent or mild persistent asthma while ICS should be reserved as first line treatment for children with moderate to severe persistent asthma. Given the skew in paediatric asthma severity towards the milder end, this effectively means that LTRAs should be tried first in 2 of every 3 children with asthma requiring preventer treatment.