Showing papers in "Pediatric Pulmonology in 2013"

Lung ultrasound characteristics of community‐acquired pneumonia in hospitalized children

Abstract: Background The diagnosis of community-acquired pneumonia (CAP) is based mainly on the patient's medical history and physical examination. However, in severe cases a further evaluation including chest X-ray (CXR) may be necessary. At present, lung ultrasound (LUS) is not included in the diagnostic work-up of pneumonia. Aim To describe the ultrasonographic appearance of CAP at presentation and during the follow-up. Methods A total of 102 patients with clinical signs and symptoms suggesting pneumonia, who underwent a clinically driven CXR, were evaluated by LUS on the same day. LUS signs of pneumonia included subpleural lung consolidation, B-lines, pleural line abnormalities, and pleural effusion. The diagnostic gold standard was the ex-post diagnosis of pneumonia made by two independent experienced pediatricians on the basis of clinical presentation, CXR and clinical course following British Thoracic Guidelines recommendations. Results A final diagnosis of pneumonia was confirmed in 89/102 patients. LUS was positive for the diagnosis of pneumonia in 88/89 patients, whereas CXR was positive in 81/89. Only one patient with normal LUS examination had an abnormal CXR, whereas 8 patients with normal CXR had an abnormal LUS. LUS was able to detect pleural effusion resulting from complicated pneumonia in 16 cases, whereas CXR detected pleural effusion in 3 cases. Conclusions LUS is a simple and reliable imaging tool, not inferior to CXR in identifying pleuro-pulmonary alterations in children with suspected pneumonia. During the course of the disease, LUS allows a radiation-free follow-up of these abnormalities. Pediatr Pulmonol. 2013; 48:280–287. © 2012 Wiley Periodicals, Inc.

Practicability of nitrogen multiple‐breath washout measurements in a pediatric cystic fibrosis outpatient setting

Abstract: BACKGROUND: Although lung clearance index (LCI) is a sensitive indicator of mild cystic fibrosis (CF) lung disease, it is rarely measured due to lengthy protocols and the commercial unavailability of multiple-breath washout (MBW) setups and tracer gases. We used a newly validated, commercially available nitrogen (N(2) ) MBW setup to assess success rate, duration, and variability of LCI within a 20 min timeframe, during clinical routine. We also evaluated the relationship between LCI and other clinical markers of CF lung disease. METHODS: One hundred thirty six children (83 with CF) between 4 and 16 years were studied in a pediatric CF outpatient setting. One hundred eighteen out of 136 children were naive to MBW. Within 20 min, each child was trained, N(2) MBW was performed, and LCI was analyzed. We assessed intra- and between-test reproducibility in a subgroup of children. RESULTS: At least one LCI was feasible in 123 (90%) children, with a mean (range) of 3.3 (1.2-6.4) min per test. Two or more measurements were feasible in 56 (41%) children. Comparing LCI in CF versus controls, LCI mean (SD) was 12.0 (3.9) versus 6.1 (0.9), and the intra- and inter-test coefficient of repeatability was 1.00 versus 0.81 and 0.96 versus 0.62, respectively. LCI was correlated with spirometry, blood gases, and Pseudomonas aeruginosa infection. CONCLUSIONS: Using available N(2) MBW equipment, LCI measurements are practical and fast in children. LCI is correlated with markers of CF lung disease. Longer timeframes would be required for triplicate N(2) MBW tests in inexperienced children. Pediatr Pulmonol. © 2012 Wiley Periodicals, Inc.

Effect of HFNC flow rate, cannula size, and nares diameter on generated airway pressures: an in vitro study.

Abstract: Increased use of non-invasive forms of respiratory support such as CPAP and HFNC in premature infants has generated a need for further investigation of the pulmonary effects of such therapies. In a series of in vitro tests, we measured delivered proximal airway pressures from a HFNC system while varying both the cannula flow and the ratio of nasal prong to simulated nares diameters. Neonatal and infant sized nasal prongs (3.0 and 3.7 mm O.D.) were inserted into seven sizes of simulated nares (range: 3-7 mm I.D. from anatomical measurements in 1-3 kg infants) for nasal prong-to-nares ratios ranging from 0.43 to 1.06. The nares were connected to an active test lung set at: TV 10 ml, 60 breaths/min, Ti 0.35 sec, compliance 1.6 ml/cm H₂O and airway resistance 70 cm H₂O/(L/sec), simulating a 1-3 kg infant with moderately affected lungs. A Fisher & Paykel Healthcare HFNC system with integrated pressure relief valve was set to flow rates of 1-6 L/min while cannula and airway pressures and cannula and mouth leak flows were measured during simulated mouth open, partially closed and fully closed conditions. Airway pressure progressively increased with both increasing HFNC flow rate and nasal prong-to-nares ratio. At 6 L/min HFNC flow with mouth open, airway pressures remained 0.9 and 50% mouth leak, airway pressures rapidly increased to 18 cm H₂O at 2 L/min HFNC flow followed by a pressure relief valve limited increase to 24 cm H₂O at 6 L/min. Safe and effective use of HFNC requires careful selection of an appropriate nasal prong-to-nares ratio even with an integrated pressure relief valve.

Oral, inhaled, and intravenous antibiotic choice for treating pulmonary exacerbations in cystic fibrosis.

Abstract: Rationale Patients with cystic fibrosis experience frequent pulmonary exacerbations (PExs). Clinicians manage these episodes of worsening signs and symptoms in a variety of ways.

Lung function outcome at school age in very low birth weight children.

Abstract: Objective The aim of this study was to assess pulmonary function and its predictors in very low birth weight (birth weight ≤1,500 g) children (VLBWc) with or without bronchopulmonary dysplasia (BPD), born at gestational age ≤32 weeks at a single tertiary center during 1996–1999, after the introduction of surfactant therapy. Methods Of the 120 surviving VLBW children, 48 (40%) VLBWc (22 with prior-BPD) at age 8.5 ± 1.0 years and 46 age-matched controls (8.8 ± 1.4 years) born at term, underwent lung function study. Results Adjusted values (z-score) of forced vital capacity (z-FVC), forced expiratory volume in 1 sec (z-FEV1), forced expiratory flow 25–75% (z-FEF25–75), carbon monoxide lung diffusion capacity (z-DLCO), and DLCO/alveolar volume (z-DLCO/VA) were significantly lower than controls (mean difference, 95% CI: −1.35, −1.81 to −0.90, P < 0.001; −1.31, −1.73 to −0.90, P < 0.001; −0.87, −1.29 to −0.46, P < 0.001; −0.98, −1.72 to −0.23, P < 0.001; −0.70, −1.22 to −0.18, P < 0.05; respectively). Residual volume (z-RV) and RV/total lung capacity (RV/TLC) ratio (%) were significantly higher in VLBWc than controls (mean difference, 95% CI: 1.06, 0.44 to 1.68, P < 0.001; 9.54%, 5.73 to 13.3%, P < 0.001; respectively). No differences were found in lung function between VLBWc (no-BPD vs. BPD) with the exception of a significant higher RV/TLC ratio in the BPD-subgroup (mean difference, 95% CI: 7.0%, 0.4 to 13%, P = 0.03). Lung function abnormalities were found in 30 (63%) VLBWc with evidence of airway obstruction and diffusing capacity impairment. A weak relationship was observed between gestational age with z-FVC (r = 0.30, P = 0.04), birth weight with z-FEV1 (r = 0.30, P = 0.04) and RV/TLC ratio (r = −0.49, P = 0.001). The duration of oxygen treatment correlated negatively with the z-DLCO/Va (r = −0.5, P = 0.02). No differences were found in FeNO levels between VLBWc and controls. Conclusion VLBWc at school age showed lung function abnormalities characterized by airway obstruction, hyperinflation, and diffusion impairment. Neonatal lung damage together with preterm birth may play a role in worsening the functional respiratory outcome. Pediatr Pulmonol. 2013; 48:830–837. © 2012 Wiley Periodicals, Inc.

6 cmH2O continuous positive airway pressure versus conventional oxygen therapy in severe viral bronchiolitis: a randomized trial.

Abstract: Objective: To compare the effects of nasal continuous positive airway pressure (nCPAP) and conventional oxygen therapy on the clinical signs of respiratory distress and the respiratory muscle workload in acute viral bronchiolitis. Design: Prospective, randomized, monocentric study carried out in the pediatric intensive care unit (PICU) of a university hospital. Patients: Infants <6 months old, admitted to the PICU with severe respiratory syncytial virus bronchiolitis. Intervention: The patients were randomized into two groups for 6 hr. The nCPAP group (n = 10) received 6 cmH(2)O pressure support delivered by a jet flow generator and the control group (n = 9) received an air/oxygen mixture from a heated humidifier. Respiratory distress was assessed by the modified Wood's clinical asthma score (m-WCAS), and inspiratory muscle work was evaluated by calculating the pressure-time product per breath (PTP(insp) /breath) and per minute (PTP(insp) /min) from the esophageal pressure (Pes) recordings. Measurements and main results: Compared with control condition, nCPAP decreased m-WCAS [-2.4 (1.05) vs. -0.5 (1.3), P = 0.03], PTPes(insp)/breath [-9.7 (5.7) vs. -1.4 (8.2), P = 0.04], PTPes(insp) /min [-666 (402) vs. -116 (352), P = 0.015], and FiO(2) [-7 (10) vs. +5 (15), P = 0.05]. Significant worsening of m-WCAS was only observed in the control group (4/9 vs. 0/10, P = 0.03). Conclusions: nCPAP rapidly decreased inspiratory work in young infants with acute bronchiolitis. Improvement in the respiratory distress score at 6 hr was proportional to the initial clinical severity, suggesting the importance of rapid nCPAP initiation in the more severe forms of the disease.

Evaluation of a cystic fibrosis transition program from pediatric to adult care.

Abstract: Summary. Purpose: As the cystic fibrosis (CF) patient population median survival increase, the need for transitioning their care to adult care centers increase as well. We have a structured transition program since the early 1980s. The purpose of this study is to evaluate the experiences and opinions of patients in our adult CF center who went through a formal transition versus those who did not, in an attempt to evaluate the overall process and to identify means for improvement. Methods: A questionnaire was given to adult CF patients at the University of Michigan during a clinic visit or inpatient hospitalization, after consent was obtained. Inclusion criteria included diagnosis of CF in childhood, previous care in a pediatric center, and current participation in our adult CF clinic. Results: A total of 91 patients completed the questionnaire. 44 went through our structured transition program. On average, patients who participated in a formal transition process had higher satisfaction with both CF programs, perceived health status, and independence but no differences in their level of anxiety about transferring to the adult program. Patient opinions regarding when to transfer care were considered more often in patients who participated in a transition program (88% vs. 62% and P ¼ 0.02). Conclusion: Although structured transitions programs do not appear to decrease patient anxiety during this stressful period, it does appear to improve patient satisfaction, perceived health status, and independence. These findings suggest that establishing a transition program could be important in optimizing patient health, continuity of care and improving adherence. Pediatr

Inhaled foreign bodies in children: A global perspective on their epidemiological, clinical, and preventive aspects

Abstract: CONTEXT: While several articles describe clinical management of Foreign Bodies injuries in the upper air tract, little epidemiological evidence is available from injury databases. OBJECTIVE: This article aims to understand the burden of airway FB injuries in high-, low-, and middle-income countries as emerging from scientific literature. DATA SOURCES: One thousand six hundred ninety-nine published articles 1978-2008. STUDY SELECTION: A free text search on PubMed database ((foreign bodies) or (foreign body)) and ((aspiration) or (airways) or (tracheobronchial) or (nasal) or (inhalation) or (obstruction) or (choking) or (inhaled) or (aspirations) or (nose) or (throat) or (asphyxiation)) and ((children) or (child)). DATA EXTRACTION: Information on reported injuries according to country, time period, children sex and age, FB type, site of obstruction, symptoms, signs, diagnostic and therapeutic procedures, delay at the diagnosis, complications, number of deaths. RESULTS: Serious complications occur both in high-income and low-middle income countries in a considerable proportion of cases (10% and 20%, respectively). Similarly, death is not infrequent (5-7% of cases). CONCLUSIONS: Few countries have good systematic data collection and there's a lack of sensibility in parents and clinicians in terms of acknowledge of the choking risk. On the contrary, international surveillance systems able to collect information in a standardized way need to be implemented. Pediatr Pulmonol. © 2012 Wiley Periodicals, Inc. Language: en

Clinical Safety, Pharmacokinetics, and Efficacy of Ambrisentan Therapy in Children With Pulmonary Arterial Hypertension

Abstract: Recent trials in adult PAH revealed the efficacy of ambrisentan. However, in children with PAH, the clinical safety and pharmacokinetics of ambrisentan has not been well studied. Our aim was to investigate the clinical safety, pharmacokinetics, tolerability, and efficacy of endothelin receptor antagonist therapy with ambrisentan in children with pulmonary arterial hypertension (PAH). This retrospective cohort study provides clinical data from pediatric patients with PAH receiving ambrisentan as add-on therapy or transition from bosentan. Safety included evaluation of adverse events including aminotransferase abnormalities. The clinical impact was evaluated by improvement from baseline in clinical variables. A total of 38 pediatric patients with PAH received ambrisentan. Fifteen of 38 patients were switched from bosentan to ambrisentan. The remaining 23 children were treated with ambrisentan as an add-on therapy due to disease progression. In both transition and add-on cases, mean pulmonary artery pressure significantly improved (transition; 55 ± 18 vs. 45 ± 20 mmHg, n = 13, P = 0.04, add-on; 52 ± 17 vs. 45 ± 19 mmHg, n = 13, P = 0.03) during the follow-up. World Health Organization functional class improved in 31% of patients, but one patient required an atrial septostomy due to disease progression during the follow-up period (median, range; 20, 4–44 months). Five patients (13%) discontinued ambrisentan due to severe headache, lack of clinical efficacy, or near syncope. Ten patients (26%) had side effects associated with ambrisentan treatment, including nasal congestion, headache, and flushing. However, no patients had aminotransferase abnormalities and there were no deaths after initiation of ambrisentan during follow-up. Pharmacokinetics were evaluated in sixteen children treated with ambrisentan from 2.5 mg to 10.0 mg; the mean peak plasma concentration was 738 ± 452 ng/ml, mean time to peak plasma concentration was 3.2 ± 2.1 hours, and mean area under the curve plasma concentration was 6657 ± 4246 ng·hour/ml. In conclusion, initial experience with ambrisentan in children suggests that treatment is safe with similar pharmacokinetics to those in adults and may improve PAH in some children.

Respiratory impedance and bronchodilator responsiveness in healthy children aged 2–13 years

Abstract: Background The forced oscillation technique (FOT) can be used in children as young as 2 years of age and in those unable to perform routine spirometry. There is limited information on changes in FOT outcomes in healthy children beyond the preschool years and the level of bronchodilator responsiveness (BDR) in healthy children. We aimed to create reference ranges for respiratory impedance outcomes collated from multiple centers. Outcomes included respiratory system resistance (Rrs) and reactance (Xrs), resonant frequency (Fres), frequency dependence of Rrs (Fdep), and the area under the reactance curve (AX). We also aimed to define the physiological effects of bronchodilators in a large population of healthy children using the FOT. Methods Respiratory impedance was measured in 760 healthy children, aged 2-13 years, from Australia and Italy. Stepwise linear regression identified anthropometric predictors of transformed Rrs and Xrs at 6, 8, and 10Hz, Fres, Fdep, and AX. Bronchodilator response (BDR) was assessed in 508 children after 200 mu g of inhaled salbutamol. Results Regression analysis showed that Rrs, Xrs, and AX outcomes were dependent on height and sex. The BDR cut-offs by absolute change in Rrs8, Xrs8, and AX were -2.74hPasL-1, 1.93hPasL-1, and -33hPasL-1, respectively. These corresponded to relative and Z-score changes of -32%; -1.85 for Rrs8, 65%; 1.95 for Xrs8, and -82%; -2.04 for AX. Conclusions We have established generalizable reference ranges for respiratory impedance and defined cut-offs for a positive bronchodilator response using the FOT in healthy children. Pediatr Pulmonol. 2013; 48:707-715. (c) 2012 Wiley Periodicals, Inc.

RPGR mutations might cause reduced orientation of respiratory cilia.

Abstract: RPGR gene encodes retinitis pigmentosa guanosine triphosphatase regulator protein, mutations of which cause 70% of the X-linked retinitis pigmentosa (XLRP) cases. Rarely, RPGR mutations can also cause primary ciliary dyskinesia (PCD), a multisystem disorder characterized by recurrent respiratory tract infections, sinusitis, bronchiectasis, and male subfertility. Two patients with PCD_RP and their relatives were analyzed using DNA sequencing, transmission electron microscopy (TEM), immunofluorescence (IF), photometry, and high-speed videomicroscopy. The Polish patient carried a previously known c.154G>A substitution (p.Gly52Arg) in exon 2 (known to affect splicing); the mutation was co-segregating with the XLRP symptoms in his family. The c.824 G>T mutation (p. Gly275Val) in the Australian patient was a de novo mutation. In both patients, TEM and IF did not reveal any changes in the respiratory cilia structure. However, following ciliogenesis in vitro, in contrast to the ciliary beat frequency, the ciliary beat coordination in the spheroids from the Polish proband and his relatives carrying the c.154G>A mutation was reduced. Analysis of the ciliary alignment indicated severely disturbed orientation of cilia. Therefore, we confirm that defects in the RPGR protein may contribute to syndromic PCD. Lack of ultrastructural defects in respiratory cilia of the probands, the reduced ciliary orientation and the decreased coordination of the ciliary bundles observed in the Polish patient suggested that the RPGR protein may play a role in the establishment of the proper respiratory cilia orientation.

Severity scoring systems: Are they internally valid, reliable and predictive of oxygen use in children with acute bronchiolitis?

Abstract: Background: Severity scores are commonly used in research and clinically to assess the severity of bronchiolitis. However, there are limitations as few have been validated. The aim of our study was to: (i) determine the validity and reliability of a bronchiolitis scoring system, and (ii) examine if the score predicted the need for oxygen at 12 and 24 hrs. Children aged <24 months presenting to Royal Darwin Hospital with a clinical diagnosis of bronchiolitis were eligible to participate. Study Design: We reviewed published papers that used a bronchiolitis score and summarized the data in a table. We chose the Tal score that was easy to use and encompassed clinically important parameters. Three research nurses, trained to assess children, used two scoring systems (Tal and Modified-Tal; respiratory rate, accessory muscle use, wheezing, cyanosis, and oxygen saturation), blindly evaluated children within 15 min of each other. Results: The children's (n = 115) median age was 5.4 months (IQR 2.9, 10.4); 65% were male and 64% were Indigenous. Internal consistency was excellent (Tal: Cronbach alpha = 0.66; Modified-Tal: alpha = 0.70). There was substantial inter-rater agreement; weighted kappa of 0.72 (95% CI: 0.63, 0.83) for Tal and 0.70 (95% CI: 0.63, 0.76) for Modified-Tal. For predicting requirement for oxygen at 12 and 24 hrs; area under receiver operating curve (aROC) was 0.69 (95% CI: 0.13, 1.0) and 0.75 (95% CI: 0.34, 1.0), respectively. Conclusion: The Tal and Modified-Tal scoring systems for bronchiolitis is repeatable and can reliably be used in research and clinical practice. Its utility for prediction of O-2 requirement is limited.

Clinical risk factors are more relevant than respiratory viruses in predicting bronchiolitis severity.

Abstract: Summary. Background: The role of respiratory viruses in the pathogenesis of bronchiolitis was re-evaluated with the use of molecular methods such as PCR for virus detection. Whether specific viruses or the classical clinical risk factors are more important in determining severe bronchiolitis is not well established. Aim: To analyze the specific viruses and clinical variables that can predict severe bronchiolitis at admission. Methods: Nasopharyngeal aspirates were prospectively collected from 484 children <12 months admitted to the pediatrics ward or PICU

New reference equations to improve interpretation of infant lung function.

Abstract: Summary. Rationale: With increasing use of infant pulmonary function tests (IPFTs) in both clinical and research studies, appropriate interpretation of results is essential. Objectives: To investigate the potential bias associated with ‘‘normalising’’ IPF by expressing results as a ratio of body size and to develop reference ranges for tidal breathing parameters, passive respiratory mechanics (compliance [Crs] and resistance [Rrs]) and plethysmographic functional residual capacity (FRCp) for white infants during the first 2 years of life. Methods: IPFTs were measured using the Jaeger BabyBody system and standardized protocols. Reference equations, adjusted for body size, age, and sex where appropriate, were created using multilevel modeling. Results: The ratio of lung function to body length changes markedly with growth, thereby precluding its use for any outcome. While the ratio of tidal volume and Crs to body weight remained relatively constant with growth, this was not the case for FRCp .E ven in healthy infants, a strong inverse relationship was observed between lung function/body weight and weight z-score which could distort interpretation of results in growth-restricted infants with lung disease, such as cystic fibrosis. Reference equations were derived from 153 healthy white infants on 232 test occasions (median age 35.5 weeks [range: 2.6–104.7]). Crown-heel length was the strongest predictor of IPF. Conclusions: When reporting IPF, use of size-corrected ratios should be discouraged, with interpretation instead based on appropriate reference equations. The current equations are applicable to white infants and young children up to 2 years of age, studied using the same commercially available equipment. The extent to which these equations are applicable to infants and young children of other ethnic backgrounds or who are tested with different equipment needs to be established. Pediatr Pulmonol.

Variability and accuracy in interpretation of consolidation on chest radiography for diagnosing pneumonia in children under 5 years of age

Abstract: Background Consolidation on chest radiography is widely used as the reference standard for defining pneumonia and variability in interpretation is well known but not well explored or explained. Methods Three pediatric sub-specialists (infectious diseases, radiology and respiratory medicine) viewed 3,033 chest radiographs in children aged under 5 years of age who presented to one Emergency Department (ED) with a febrile illness. Radiographs were viewed blind to clinical information about the child and blind to findings of other readers. Each chest radiograph was identified as positive or negative for consolidation. Percentage agreement and kappa scores were calculated for pairs of readers. Prevalence of consolidation and reader sensitivity/specificity was estimated using latent class analysis. Results Using the majority rule, 456 (15%) chest radiographs were positive for consolidation while the latent class estimate was 17%. The radiologist was most likely (21.3%) and respiratory physician least likely (13.7%) to diagnose consolidation. Overall percentage agreement for pairs of readers was 85–90%. However, chance corrected agreement between the readers was moderate, with kappa scores 0.4–0.6 and did not vary with patient characteristics (age, gender, and presence of chronic illness). Estimated sensitivity ranged from 0.71 to 0.81 across readers, and specificity 0.91 to 0.98. Conclusions Overall agreement for identification of consolidation on chest radiographs was good, but agreement adjusted for chance was only moderate and did not vary with patient characteristics. Clinicians need to be aware that chest radiography is an imperfect test for diagnosing pneumonia and has considerable variability in its interpretation. Pediatr Pulmonol. 2013; 48:1195–1200. © 2013 Wiley Periodicals, Inc.

Respiratory function at age 8–9 after extremely low birthweight or preterm birth in Victoria in 1997†

Abstract: To determine if respiratory function at 8 years of age in extremely low birth weight (ELBW; birth weight 2,499 g) and term (37-42 weeks) controls, particularly in those ELBW/EPT children who had bronchopulmonary dysplasia (BPD). This was a cohort study of 201 consecutive ELBW/EPT survivors born in the state of Victoria during 1997, and 199 contemporaneous randomly selected NBW/term controls. Respiratory function was measured at 8 years of age according to standard guidelines, and compared with previous cohorts born in 1991-1992. Respiratory function data were available for almost 75% of both cohorts. ELBW/EPT subjects had substantial reductions in airflow compared with controls (e.g., mean difference in forced expiratory volume in 1 sec [FEV1 ] -0.91 SD, 95% confidence interval [CI] -1.19 to -0.63 SD, and in maximum expiratory flow between 25% and 75% of vital capacity [FEF25-75% ] -0.96 SD, 95% CI -1.22 to -0.71). These differences were similar to those observed between ELBW/EPT and controls subjects born in 1991-1992. Within the ELBW/EPT cohort, children who had BPD in the newborn period had significant reductions in both the FEV1 (-0.76 SD) and FEF25-75% (-0.58 SD) compared with those who did not have BPD, which were not statistically significant from those in the 1991-92 cohort. ELBW/EPT children born in 1997 still have significantly abnormal lung function compared with NBW/term controls, but results were similar to an earlier era when survival rates were lower. Pediatr Pulmonol. 2013; 48:449-455. © 2012 Wiley Periodicals, Inc.

Optimization of anti-pseudomonal antibiotics for cystic fibrosis pulmonary exacerbations: V. Aminoglycosides

Abstract: Summary Intravenous (IV) anti-pseudomonal aminoglycosides (i.e., amikacin and tobramycin) have been shown to be tolerable and effective in the treatment of acute pulmonary exacerbations (APEs) in both pediatric and adult patients with cystic fibrosis. The aim of this review is to provide an evidence-based summary of pharmacokinetic/pharmacodynamic, tolerability, and efficacy studies utilizing IV amikacin, gentamicin, and tobramycin in the treatment of APE and to highlight areas where further investigation is needed. The Cystic Fibrosis Foundation Pulmonary Guidelines recommend that once-daily administration of aminoglycosides is preferred over three times per day in the treatment of an APE. The literature supports dosing ranges for amikacin and tobramycin of 30–35 and 7–15 mg/kg/day, respectively, given once daily, with subsequent doses determined by therapeutic drug concentration monitoring. The literature does not support the routine use of gentamicin in the treatment of APE due to a lack of studies showing efficacy and evidence indicating an increased risk of nephrotoxicity. Further studies are needed to determine the optimal dosing strategy of amikacin in the treatment of an APE, and to further identify risk factors and determinants that influence the development of P. aeruginosa resistance with once-daily administration of tobramycin. Pediatr Pulmonol. 2013; 48:1047–1061. © 2013 Wiley Periodicals, Inc.

Exhaled breath condensate in pediatric asthma: promising new advance or pouring cold water on a lot of hot air? A systematic review

Abstract: Background Exhaled breath condensate (EBC) analysis is a simple non-invasive technique that allows repeated collection of breath samples with a minimum of inconvenience for the subject. These breath samples can potentially indicate lung disease activity and given the ease of collection, EBC is becoming a useful research tool in the study of respiratory diseases. It has the potential to be used in both population-based studies and in the context of pediatric asthma it may prove useful in diagnosis and monitoring. Methods A systematic review was conducted to identify studies of EBC markers in childhood asthma. Results Most of the studies were cross-sectional in design, and the results suggest that simple chemical entities such as hydrogen ions (as pH), hydrogen peroxide, and oxides of nitrogen are associated with pediatric allergic asthma and exacerbations. In addition, more complex molecules including leukotrienes, prostaglandins, and cytokines such as the interleukins IL-4 and IL-5 are also elevated in the breath of those with asthma. Conclusion EBC has the potential to aid diagnosis, and to evaluate the inflammatory status of asthmatic children. Future studies may be able to refine further how best to collect EBC samples, to interpret them, and the technique has the potential to allow repeated sampling which will allow studies of natural history, pathogenesis and response to treatment to be undertaken. Pediatr Pulmonol. 2013; 48:419–442. © 2013 Wiley Periodicals, Inc.

Role of spontaneous breathing trial in predicting successful extubation in premature infants

Abstract: Background The ability of clinicians to predict successful extubation in mechanically ventilated premature neonates is limited. Identifying objective criteria for predicting successful extubation may reduce the incidence of failed extubation and the duration of mechanical ventilation. Objective To evaluate the validity of objective measures of lung function and spontaneous breathing trial (SBT) in predicting successful extubation among premature neonates with attempted extubations within the first 3 weeks of life. Methods Respiratory compliance (Crs) along with SBT was performed prior to elective extubations within 3 weeks of age in premature infants ≤32 weeks. Extubation was considered successful if patients remained extubated for >72 hr. Ventilator settings including mean airway pressure (MAP), set rate, and fraction of inspired oxygen (FiO2) 24 hr after re-intubation were compared with pre-extubation settings, in patients requiring re-intubation. Results Thirty-nine of 49 infants (80%) were successfully extubated. Of 41 babies who passed SBT, only 5 infants failed extubation. SBT had 92% sensitivity, 50% specificity, 88% positive predictive, and 63% negative predictive value for successful extubation. Crs was comparable between infants who were successfully extubated and those who were not. Conclusions A SBT prior to extubation may be a practical objective adjunct in predicting successful extubation in ventilated premature infants. Pediatr Pulmonol. 2013; 48:443–448. © 2012 Wiley Periodicals, Inc.

Human amniotic fluid stem cells protect rat lungs exposed to moderate hyperoxia

Abstract: Background Treatment of bronchopulmonary dysplasia (BPD) remains as yet an unmet clinical need and recently stem cells have been proposed as a therapeutic tool in animal models We investigated the role of amniotic fluid stem cells (AFS) in an adult rat model of hyperoxia lung injury Methods Fifty Sprague-Dawley rats were, at birth, randomly exposed to moderate hyperoxia or room air for 14 days and a single dose of human amniotic fluid stem (hAFS) or human Fibroblasts (hF), cells was delivered intratracheally (P21) At P42 animals were euthanized and lung tissue examined using histology, immunohistochemistry, PCR, and ELISA hAFS cells characterization and homing were studied by immunofluorescence Results In rats treated with hAFS and hF cells 16S human rRNA fragment was detected Despite a low level of pulmonary hAFS cell retention (143 ± 02% anti-human-mitochondria-positive cells), the lungs of the treated animals revealed higher secondary crest numbers and lower mean linear intercept and alveolar size, than those exposed to hyperoxia, those left untreated or treated with hF cells Except for those treated with hAFS cells, moderate hyperoxia induced an increase in protein content of IL-6, IL-1β, as well as IF-γ and TGF-1β in lung tissues High VEGF expression and arrangement of capillary architecture in hAFS cell group were also detected Conclusions Treatment with hAFS cells has a reparative potential through active involvement of cells in alveolarization and angiogenesis A downstream paracrine action was also taken into account, in order to understand the immunodulatory response Pediatr Pulmonol 2013; 48:1070-1080 © 2013 Wiley Periodicals, Inc © 2013 Wiley Periodicals, Inc

Abnormal infant pulmonary function in young children with neuroendocrine cell hyperplasia of infancy.

Abstract: Rationale Lung function in children with neuroendocrine cell hyperplasia of infancy (NEHI) and correlations with future clinical outcomes are needed to guide clinical management. Objective To compare results of infant pulmonary function tests (IPFTs) in children with NEHI to disease control (DC) subjects and to correlate NEHI IPFTs with future outcomes. Methods We performed a retrospective, single center study of IPFT in subjects diagnosed by lung biopsy (NEHI) or clinically (NEHI syndrome) and in DC subjects evaluated for cancer or pre-hematopoietic stem cell transplantation (HSCT). Raised volume rapid thoracoabdominal compression (RVRTC) and plethysmography were performed on all infants and evaluated for quality. Standard spirometry measures, room air oxygen saturations (RA O2 sat), and weight percentiles were collected during follow up. Measurements and Main Results Fifty-seven IPFTs were performed in 15 NEHI, 22 NEHI syndrome, and 20 DC subjects. RVRTC and FRC measurements were obtained in 85% or more of subjects in all groups. Significant airflow limitation (FEV0.5 P-value ≤ 0.01) and air trapping (FRC P-value ≤ 0.01) were seen in NEHI and NEHI syndrome subjects compared to DCs. No significant correlations were found between IPFT, oxygen use, RA O2 sat, and weight at the time of the IPFTs. Initial FEV0.5 and FRC z-scores correlated with RA O2 sat (r = 0.60 and −0.49) at short-term follow up (6–12 months). Most measurements of RVRTC correlated with FEV1 (n = 5) measured 4–5 years later (r > 0.50). Conclusions IPFTs in NEHI subjects are feasible, demonstrate significant obstruction and air trapping, and correlate with future RA O2 sat and FEV1. IPFTs may provide valuable clinical information when caring for NEHI patients. Pediatr Pulmonol. 2013; 48:1008–1015. © 2012 Wiley Periodicals, Inc.

Tracheostomy placement in infants with bronchopulmonary dysplasia: Safety and outcomes

Abstract: Optimizing the timing and safety for the placement of a tracheostomy in infants with bronchopulmonary dysplasia (BPD) has not been determined. The purpose of the present study was to describe the data from a single institution about the efficacy and safety of tracheostomy placement in infants with BPD needing long-term respiratory support. We established a service line for the comprehensive care of infants with BPD and we collected retrospective clinical data from this service line. We identified patients that had a trachostomy placed using the local Vermont-Oxford database, and obtained clinical data from chart reviews. We identified infants who had a tracheostomy placed for the indication of severe BPD only. Safety and respiratory efficacy was assessed by overall survival to discharge and the change in respiratory supportive care from just before placement to 1-month post-placement. Twenty-two patients (750 ± 236 g, 25.4 ± 2.1 weeks gestation) had a tracheostomy placed on day of life 177 ± 74 which coincided with a post-conceptual age of 51 ± 10 weeks. At placement these infants were on high settings to support their lung disease. The mean airway pressure (MAP) was 14.3 ± 3.3 cmH2O, the peak inspiratory pressure was 43.7 ± 8.0 cmH2O, and the FiO2 was 0.51 ± 0.13. The mean respiratory severity score (MAP × FiO2) 1 month after tracheostomy was significantly (P = 0.03) lower than prior to tracheostomy. Survival to hospital discharge was 77%. All patients with tracheostomies that survived were discharged home on mist collar supplemental oxygen. In conclusion, the high survival rate in these patients with severe BPD and the decreased respiratory support after placement of a tracheostomy suggests that high ventilatory pressures should not be a deterrent for placement of a tracheostomy. Future research should be aimed at determining optimal patient selection and timing for tracheostomy placement in infants with severe BPD. Pediatr Pulmonol. 2013; 48:245–249. © 2012 Wiley Periodicals, Inc.

Effects of glucocorticoids and idebenone on respiratory function in patients with duchenne muscular dystrophy.

Abstract: In Duchenne muscular dystrophy (DMD) progressive weakness of respiratory muscles leads to a restrictive pulmonary syndrome that contributes to early morbidity and mortality. Currently no curative treatment exists for DMD. In a Phase II randomized placebo-controlled study (DELPHI) in 21 DMD boys at age 8–16 years, idebenone (450 mg/d) showed trends of efficacy for cardiac and respiratory endpoints. Since the DELPHI study population comprised both glucocorticoid-naive subjects and glucocorticoid-users, we now report a post-hoc analysis investigating the effects of glucocorticoids and idebenone on markers of respiratory weakness, particularly peak expiratory flow (PEF) percent predicted (PEF%p). Baseline values of PEF%p correlated well with the percent predicted values for maximal inspiratory mouth pressure (MIP%p), forced vital capacity (FVC%p), and forced expired volume in 1 sec (FEV1%p). Baseline PEF%p and FVC%p were significantly higher in patients on concomitant glucocorticoids compared to glucocorticoid-naive patients. In the latter subgroup, idebenone caused a 8.0 ± 12.1% improvement in PEF%p, whilst patients on placebo declined by −12.3 ± 17.9% (P < 0.05) in the course of the 12 month study. In patients receiving concomitant glucocorticoids, PEF%p remained stable (−0.4 ± 14.6%) in the idebenone group compared to a decline by −6.2 ± 12.4% (P = 0.24) in the placebo group. Idebenone showed a trend for efficacy on FVC%p only in glucocorticoid-naive patients. Because of the study limitations, these data are exploratory and preclude any firm conclusions. In conclusion, PEF appears to be a sensitive respiratory function parameter that could be a valid and clinically relevant endpoint in intervention studies in DMD. In DELPHI the effect size of idebenone on PEF%p was significantly larger in steroid-naive patients, possibly indicating a maximum treatment effect reached by steroids or steroid-mediated suppression of idebenone's effects. The impact of standard care glucocorticoids on respiratory function will have to be considered in the planning of future interventional trials in DMD. Pediatr Pulmonol. 2013; 48:912–920. © 2012 Wiley Periodicals, Inc.

Validation of novel wheeze phenotypes using longitudinal airway function and atopic sensitization data in the first 6 years of life: evidence from the Southampton women's survey

Abstract: BACKGROUND: In 1995 the Tucson Children's Respiratory Study (TCRS) identified clinically distinct phenotypes amongst early wheezers; the Avon Longitudinal Study of Parents And Children (ALSPAC) has recently re-examined these. OBJECTIVES: To validate statistically derived ALSPAC phenotypes in the Southampton Women's Survey (SWS) using infant and 6-year lung function, and allergic sensitization at 1, 3, and 6 years, comparing these with TCRS phenotypes. METHODS: Complete 6-year follow-up data were available for 926 children, selected from 1,973 infants born to 12,579 women characterized pre-conception. Ninety-five children had V'maxFRC and FEV0.4 measured age 5-14 weeks using rapid compression/raised volume techniques. At 6 years we performed spirometry (n = 791), fractional exhaled nitric oxide (FeNO, n = 589) and methacholine challenge (n = 234). Skin prick testing was performed at 12m, 3 and 6 years (n = 1,494, 1,255, 699, respectively). Using wheeze status questionnaire data at 6m, 12m, 2, 3 and 6 years we classified children into TCRS (never, transient early, persistent, late-onset) and ALSPAC based groups (never, early, transient, intermediate-onset, late-onset, persistent). RESULTS: Amongst ALSPAC groups, persistent and late-onset wheeze were associated with atopy at 3 and 6 years, whilst intermediate-onset wheeze showed earlier atopic association at 1 year; all three were associated with FeNO at 6 years. Persistent wheezers had lower infant (V'maxFRC P < 0.05) and 6-year lung function (FEV1, FEV1/FVC, and FEF(25-75), P < 0.05), whilst late and intermediate-onset wheezers showed no lung function deficits. Transient wheezers were non-atopic but showed persistent lung function deficits (V'maxFRC in infancy, FEV1 and FEF(25-75) at 6 years, all P < 0.05). Those who wheezed only in the first year (early phenotype) showed no lung function deficits. No associations were seen with 6 years bronchial hyper-responsiveness or infancy FEV0.4. CONCLUSION: SWS cohort data validates the statistically derived ALSPAC six-class model. In particular, lung function and atopy successfully differentiate persistent, late-onset and intermediate-onset wheeze, whilst the Tucson "transient early" wheeze phenotype can be sub-classified into groups that reflect early lung function. Since the 4-class model fails to adequately differentiate phenotypes based on lung function and atopy, we propose that strong consideration be given to using the 6-class paradigm for longitudinal outcome work in wheezing with onset in early life.

A 4 year prospective study to determine risk factors for severe community acquired pneumonia in children in southern China.

Abstract: Background Pneumonia is the major cause of death under 5 years. With high CAP numbers in China and growing access to PICUs, factors associated with severe CAP need to be determined to optimize care. Objective To prospectively determine PICU CAP admission features and outcomes. Methods A 4 year prospective study of CAP aged 1 month to <14 years admitted to PICU, Children's Hospital Affiliated to Soochow University, China. All were managed in a standard manner. Clinical, laboratory, and imaging findings were collected systematically. All received antibiotics. Results Eight hundred ten (7%) of 10,836 CAP hospital admissions needed PICU. Seven hundred seven (87%) were enrolled. PICU CAP children were young (76% ≤ 12 months) and 33% had co-morbid conditions; 21% congenital heart disease.21% required mechanical ventilation. The average length of PICU stay was 5 days (range, 3–27). The case fatality rate was 5.8%. Viruses were detected in 38%, RSV 24%; bacteria in 23%, Streptococcus pneumoniae 7%, Haemophilus influenza b 4%, Mycoplasma 11%. On single factor analysis, PICU admission respiratory rate >70/min, grunting/groaning, head nodding, cyanosis, and anemia were associated with respiratory failure and with fatality. On multivariate analysis only presence of congenital heart disease, Trisomy 21 and immunodeficiency correlated with fatality; not microbe nor PICU findings. Conclusions Young age and underlying congenital heart disease were associated factors for PICU support in CAP in China. Early referral if altered sensorium, high respiratory rate, head nodding, grunting and anemia, and universal access to conjugated vaccines may decrease morbidity and mortality. Pediatr Pulmonol. 2013; 48:390–397. © 2012 Wiley Periodicals, Inc.

Epidemiology and clinical manifestations of children with macrolide-resistant Mycoplasma pneumoniae pneumonia in Taiwan.

Abstract: Mycoplasma pneumoniae accounts for 10–30% of community-acquired pneumonia (CAP) in children. This study reveals the epidemiology and clinical manifestations of children with macrolide-resistant (MLr) M. pneumoniae pneumonia in Taiwan. Respiratory tract specimens were collected from children hospitalized with CAP for evaluation via PCR followed by DNA sequencing for several point mutations related to the MLr character. Of the 412 specimens collected during the study period, 60 (15%) were positive for M. pneumoniae, 14 (23%) of which presented point mutation (all A2063G) in 23S rRNA. Clinical symptoms and chest X-ray findings between the MLs and MLr groups were not significantly different. However, the MLr group had longer mean duration of fever after azithromycin treatment (3.2 days vs. 1.6 days, P = 0.02) and significantly higher percentage of changing antibiotics for suspected MLr strain (42% vs. 13%, P = 0.04). Although 58% of children in the MLr group did not receive effective antibiotics, all children were discharged without sequelae. In conclusion, 15% of CAP in children is caused by M. pneumoniae and the macrolide-resistance rate is 23% in Taiwan. Despite ineffective antibiotics, children with MLr M. pneumoniae pneumonia recover completely. Pediatr Pulmonol. 2013; 48:904–911. © 2012 Wiley Periodicals, Inc.

Optimization of anti-pseudomonal antibiotics for cystic fibrosis pulmonary exacerbations: II. cephalosporins and penicillins.

Abstract: Acute pulmonary exacerbations (APE) are well-described complications of cystic fibrosis (CF) and are associated with progressive morbidity and mortality. Despite aggressive management with two or more intravenous anti-pseudomonal agents, approximately 25% of exacerbations will result in a loss of lung function. The aim of this review is to provide an evidence-based summary of pharmacokinetic/pharmacodynamic (PK/PD), tolerability, and efficacy studies utilizing anti-pseudomonal cephalosporins (i.e., ceftazidime and cefepime) and penicillins (i.e., piperacillin–tazobactam and ticarcillin–clavulanate) in the treatment of APE and to identify areas where further study is warranted. The ceftazidime and cefepime dosing ranges from the literature are 200–400 mg/kg/day divided every 6–8 hr, maximum 8–12 g/day, and 150–200 mg/kg/day divided every 6–8 hr, up to 6–8 g/day, respectively. The literature supported dosing ranges for piperacillin and ticarcillin are 350–600 mg/kg/day divided every 4 hr, maximum 18–24 g/day of piperacillin component, and 400–750 mg/kg/day divided every 6 hr, up to 24–30 g/day of ticarcillin component, respectively. As a large portion of CF patients will not regain their lung function following an APE, we suggest the need to optimize antibiotic dosing and dosing regimens used to treat an APE in efforts to improve outcomes for CF patients infected with Pseudomonas aeruginosa. Future studies are needed to determine the clinical efficacy of higher than FDA-approved doses of ceftazidime, cefepime, and ticarcillin–clavulanate in APE. The usefulness of high dose piperacillin (>600 mg/kg/day) may be limited due to treatment-related adverse effects. Further understanding of these adverse effects in CF patients is needed. Pediatr Pulmonol. 2013; 48:107–122. © 2012 Wiley Periodicals, Inc.

Night-to-night consistency of at-home nocturnal pulse oximetry testing for obstructive sleep apnea in children.

Abstract: Rationale At-home nocturnal pulse oximetry has a high positive predictive value (PPV) for polysomnographically-diagnosed obstructive sleep apnea (OSA) but no studies have been published testing the night-to-night consistency of at-home nocturnal pulse oximetry for the evaluation of suspected OSA in children. We therefore determined the night-to-night consistency of nocturnal pulse oximetry as a diagnostic test for OSA in children. Methods We prospectively studied 148 children (96 male) aged 4.9 ± 2.4 (1.2–11.8) years, referred for suspected OSA. To evaluate night-to-night consistency, we compared an oximetry analysis method, the McGill Oximetry Score (MOS), from two consecutive at-home nocturnal pulse oximetry recordings. Results Pulse oximetry metrics were similar on the two nights. The MOS on the two nights showed excellent night-to-night consistency when analyzed as positive for OSA versus inconclusive, 143/148 (Spearman's correlation coefficient = 0.90). A more detailed analysis using four categories (MOS 1, 2, 3, and 4) of OSA severity showed very good night-to-night agreement, 133/148 (Spearman's correlation coefficient = 0.91). Variability was increased in children younger than 4 years of age compared to older children. Conclusions Night-to-night consistency of nocturnal pulse oximetry as a diagnostic test for OSA showed excellent agreement. Night-to-night consistency of pulse oximetry, as analyzed by the MOS, for diagnosis and severity evaluation further validates this abbreviated testing method for pediatric OSA. Polysomnography (PSG) is required to rule in or rule out OSA in children if a single night oximetry testing is inconclusive. Pediatr Pulmonol. 2013; 48:754–760. © 2012 Wiley Periodicals, Inc.

Adolescent asthma after rhinovirus and respiratory syncytial virus bronchiolitis.

Abstract: Background and Aims Asthma risk is increased after bronchiolitis in infancy. Recent studies have suggested that the risk may be dependent on the causative virus. The aim of the study was to evaluate the asthma risk in adolescence in subjects hospitalized for rhinovirus or respiratory syncytial virus (RSV) bronchiolitis in infancy. Subjects and Methods At the median age of 16.5 years, a questionnaire was sent to 96 study subjects hospitalized for bronchiolitis at <24 months of age and since then prospectively followed-up. Sixty-seven (70%) returned the fulfilled questionnaire. RSV and rhinovirus etiology of bronchiolitis had been studied in serum and respiratory samples obtained on admission in infancy. The occurrence of asthma was compared between former bronchiolitis patients and population controls recruited for this study in adolescence. Results Doctor-diagnosed asthma was present in 30% of former bronchiolitis patients and in 5% of controls (OR 7.9, 95% CI 3.3–19.3). The respective figures for self-reported asthma were 64% and 11% (OR 14.7, 95% CI 7.2–30.0). Self-reported asthma was more common in the former rhinovirus than RSV patients (83.3% vs. 47.6%, P = 0.023, mixed infections included; 81.3% vs. 50%, P = 0.067, mixed infections excluded). Conclusions Patients hospitalized for RSV and rhinovirus bronchiolitis at <24 months of age had an increased asthma risk at 15–18 years of age compared with population controls. Within the former bronchiolitis group, the risk of self-reported asthma was higher after non-RSV versus RSV and after rhinovirus versus non-rhinovirus bronchiolitis. Pediatr Pulmonol. 2013; 48:633–639. © 2012 Wiley Periodicals, Inc.

Pulmonary Exacerbations in Cystic Fibrosis: Young Children With Characteristic Signs and Symptoms

Abstract: Background A standard definition of pulmonary exacerbation based on signs and symptoms would be useful for categorizing cystic fibrosis (CF) patients and as an outcome measure of therapy. The frequently used definition of treatment with intravenous antibiotics varies with practice patterns. One approach to this problem is to use large data sets which include a patient’s signs and symptoms along with their clinician’s decision to treat with antibiotics for the diagnosis of pulmonary exacerbation. Previous analysis of such a data set, the Epidemiologic Study of Cystic Fibrosis (ESCF), found that new crackles, increased cough, increased sputum, and weight decline were the four clinical characteristics most strongly influencing providers to treat young CF patients for a pulmonary exacerbation. The objectives of this study were to confirm that these four characteristics influence the decision to treat with antibiotics for a pulmonary exacerbation in young CF patients; to evaluate their implications for future nutritional status and lung function; and to assess the effect of antibiotic treatment on these characteristic signs and symptoms.