Bruce Whitehead

Critical link between TRAIL and CCL20 for the activation of TH2 cells and the expression of allergic airway disease

The role of tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) in immune responses mediated by T-helper 2 (TH2) lymphocytes is unknown. Here we characterize the development of allergic airway disease in TRAIL-deficient (Tnfsf10−/−) mice and in mice exposed to short interfering RNA targeting TRAIL. We show that TRAIL is abundantly expressed in the airway epithelium of allergic mice and that inhibition of signaling impairs production of the chemokine CCL20 and homing of myeloid dendritic cells and T cells expressing CCR6 and CD4 to the airways. Attenuated homing limits TH2 cytokine release, inflammation, airway hyperreactivity and expression of the transcriptional activator STAT6. Activation of STAT6 by interleukin-13 restores airway hyperreactivity in Tnfsf10−/− mice. Recombinant TRAIL induces pathognomic features of asthma and stimulates the production of CCL20 in primary human bronchial epithelium cells. TRAIL is also increased in sputum of asthmatics. The function of TRAIL in the airway epithelium identifies this molecule as a target for the treatment of asthma.

High-flow warm humidified oxygen versus standard low-flow nasal cannula oxygen for moderate bronchiolitis (HFWHO RCT): an open, phase 4, randomised controlled trial

BACKGROUND Bronchiolitis is the most common lung infection in infants and treatment focuses on management of respiratory distress and hypoxia. High-flow warm humidified oxygen (HFWHO) is increasingly used, but has not been rigorously studied in randomised trials. We aimed to examine whether HFWHO provided enhanced respiratory support, thereby shortening time to weaning off oxygen. METHODS In this open, phase 4, randomised controlled trial, we recruited children aged less than 24 months with moderate bronchiolitis attending the emergency department of the John Hunter Hospital or the medical unit of the John Hunter Childrens Hospital in New South Wales, Australia. Patients were randomly allocated (1:1) via opaque sealed envelopes to HFWHO (maximum flow of 1 L/kg per min to a limit of 20 L/min using 1:1 air-oxygen ratio, resulting in a maximum FiO2 of 0·6) or standard therapy (cold wall oxygen 100% via infant nasal cannulae at low flow to a maximum of 2 L/min) using a block size of four and stratifying for gestational age at birth. The primary outcome was time from randomisation to last use of oxygen therapy. All randomised children were included in the primary and secondary safety analyses. This trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12612000685819. FINDINGS From July 16, 2012, to May 1, 2015, we randomly assigned 202 children to either HFWHO (101 children) or standard therapy (101 children). Median time to weaning was 24 h (95% CI 18-28) for standard therapy and 20 h (95% CI 17-34) for HFWHO (hazard ratio [HR] for difference in survival distributions 0·9 [95% CI 0·7-1·2]; log rank p=0·61). Fewer children experienced treatment failure on HFWHO (14 [14%]) compared with standard therapy (33 [33%]; p=0·0016); of these children, those on HFWHO were supported for longer than were those on standard therapy before treatment failure (HR 0·3; 95% CI 0·2-0·6; p<0·0001). 20 (61%) of 33 children who experienced treatment failure on standard therapy were rescued with HFWHO. 12 (12%) of children on standard therapy required transfer to the intensive care unit compared with 14 (14%) of those on HFWHO (difference -1%; 95% CI -7 to 16; p=0·41). Four adverse events occurred (oxygen desaturation and condensation inhalation in the HFWHO group, and two incidences of oxygen tubing disconnection in the standard therapy group); none resulted in withdrawal from the trial. No oxygen-related serious adverse events occurred. Secondary effectiveness outcomes are reported in the Results section. INTERPRETATION HFWHO did not significantly reduce time on oxygen compared with standard therapy, suggesting that early use of HFWHO does not modify the underlying disease process in moderately severe bronchiolitis. HFWHO might have a role as a rescue therapy to reduce the proportion of children requiring high-cost intensive care. FUNDING Hunter Childrens Research Foundation, John Hunter Hospital Charitable Trust, and the University of Newcastle Priority Research Centre GrowUpWell.

Neurologic complications of influenza A(H1N1)pdm09 Surveillance in 6 pediatric hospitals

Objective: We sought to determine the range and extent of neurologic complications due to pandemic influenza A (H1N1) 2009 infection (pH1N1′09) in children hospitalized with influenza. Methods: Active hospital-based surveillance in 6 Australian tertiary pediatric referral centers between June 1 and September 30, 2009, for children aged <15 years with laboratory-confirmed pH1N1′09. Results: A total of 506 children with pH1N1′09 were hospitalized, of whom 49 (9.7%) had neurologic complications; median age 4.8 years (range 0.5–12.6 years) compared with 3.7 years (0.01–14.9 years) in those without complications. Approximately one-half (55.1%) of the children with neurologic complications had preexisting medical conditions, and 42.8% had preexisting neurologic conditions. On presentation, only 36.7% had the triad of cough, fever, and coryza/runny nose, whereas 38.7% had only 1 or no respiratory symptoms. Seizure was the most common neurologic complication (7.5%). Others included encephalitis/encephalopathy (1.4%), confusion/disorientation (1.0%), loss of consciousness (1.0%), and paralysis/Guillain-Barré syndrome (0.4%). A total of 30.6% needed intensive care unit (ICU) admission, 24.5% required mechanical ventilation, and 2 (4.1%) died. The mean length of stay in hospital was 6.5 days (median 3 days) and mean ICU stay was 4.4 days (median 1.5 days). Conclusions: Neurologic complications are relatively common among children admitted with influenza, and can be life-threatening. The lack of specific treatment for influenza-related neurologic complications underlines the importance of early diagnosis, use of antivirals, and universal influenza vaccination in children. Clinicians should consider influenza in children with neurologic symptoms even with a paucity of respiratory symptoms.

Eosinophilic airway inflammation and the prognosis of childhood asthma

Background Eosinophilic airway inflammation is a key pathophysiological feature of asthma that can predict treatment response. However, the prognostic value of sputum eosinophilia is not established.

Viral infections trigger exacerbations of cystic fibrosis in adults and children

To the Editors: Cystic fibrosis (CF) is the most common autosomal recessive condition causing disease in western societies, and despite important advances in understanding the disease, patients with CF develop progressive lung disease with recurrent endobronchial infection, eventually becoming chronically colonised with resistant organisms such as Pseudomonas aeruginosa . The clinical course is punctuated by periods of acute worsening of CF lung disease that increase with age and declining lung function, while the frequency of exacerbations is also an independent predictor for decline in lung function and mortality [1]. How and why exacerbations of CF occur is poorly understood. Recent data suggest that exacerbations are not associated with an acquisition of new strains of bacteria, but rather clonal expansion of existing strains [2]. The factors that lead to this imbalance between chronic bacterial infection and host immune response, which then results in CF exacerbations, are unclear. Viral infection may be an important factor that triggers these events. In children with CF, viral respiratory tract infections are associated with exacerbations [3, 4]. In CF a respiratory virus infection superimposed upon chronic bacterial infection potentially could enhance inflammation and shift the balance to favour infection with chronic bacterial pathogens. The aims of this study were to assess the prevalence and aetiology of viral respiratory tract infection in an adult population with CF, compare this to a group of children with CF and assess the impact of this on acute exacerbations of lung disease. We recruited 17 adults (age greater than 17 yrs) and nine children (6–17 yrs) from the CF clinic at John Hunter Hospital, New Lambton, Australia with CF diagnosed by a positive sweat test and CF genotyping. Participants were assessed at baseline and reviewed every 3 months for …

Paternal uniparental isodisomy for chromosome 14 with mosaicism for a supernumerary marker chromosome 14

Uniparental disomy (UPD) describes the inheritance of two homologous chromosomes from a single parent. Disease phenotypes associated with UPD and chromosomal imprinting, rather than with mutations, include Beckwith–Wiedemann syndrome (paternal UPD11p), Angelman syndrome (paternal UPD15), Prader–Willi syndrome (maternal UPD15), and transient neonatal diabetes (paternal UPD6). Here we report on the first case of paternal uniparental isodisomy of chromosome 14 with a mosaicism for a supernumerary marker chromosome 14. The patient demonstrated a small thorax with a ‘coat hanger’ shape of the ribs, kyphoscoliosis, hypoplasia of the maxilla and mandible, a broad nasal bridge with anteverted nares, contractures of the wrists with ulnar deviation bilaterally, diastasis recti, and marked muscle hypotonia. Vertical skin creases under the chin and stippled epiphyses of the humeri were features not previously described in patients with paternal UPD14. This case illustrates that as with the finding of an isochromosome, a supernumerary marker chromosome can be an important clue to the presence of UPD14.

Fat-soluble vitamin deficiency in children and adolescents with cystic fibrosis.

Aims Determine the prevalence of fat-soluble vitamin deficiency in children with cystic fibrosis (CF) aged ≤18 years in New South Wales (NSW), Australia, from 2007 to 2010. Methods A retrospective analysis of fat-soluble vitamin levels in children aged ≤18 years who lived in NSW and attended any of the three paediatric CF centres from 2007 to 2010. An audit of demographic and clinical data during the first vitamin level measurement of the study period was performed. Results Deficiency of one or more fat-soluble vitamins was present in 240/530 children (45%) on their first vitamin level test in the study period. The prevalence of vitamins D and E deficiency fell from 22.11% in 2007 to 15.54% in 2010, and 20.22% to 13.89%, respectively. The prevalence of vitamin A deficiency increased from 11.17% to 13.13%. Low vitamin K was present in 29% in 2007, and prevalence of prolonged prothrombin time increased from 19.21% to 22.62%. Fat-soluble vitamin deficiency is present in 10%–35% of children with pancreatic insufficiency, but only a very small proportion of children who are pancreatic-sufficient. Conclusions This is one of few studies of fat-soluble vitamin deficiency in children with CF in Australia. Fat-soluble vitamin testing is essential to identify deficiency in pancreatic-insufficient children who may be non-compliant to supplementation or require a higher supplement dose, and pancreatic-sufficient children who may be progressing to insufficiency. Testing of vitamin K-dependent factors needs consideration. Further studies are needed to monitor rates of vitamin deficiency in the CF community.

Persistence of rhinovirus RNA and IP-10 gene expression after acute asthma

Background and objective:  Viral nucleic acid may be detected for up to 6 months after an acute asthma deterioration, but the pattern and consequences of viral persistence after acute asthma are incompletely understood. This study investigates the frequency of viral persistence after acute asthma, assesses viral infectivity and determines the host inflammatory responses to viral persistence.

Novel inpatient surveillance in tertiary paediatric hospitals in New South Wales illustrates impact of first-wave pandemic influenza A H1N1 (2009) and informs future health service planning.

Aim:  To document the impact of pandemic influenza A H1N1 (2009) in New South Wales (NSW) childrens hospitals.

Polysomnography for the management of oxygen supplementation therapy in infants with chronic lung disease of prematurity

Abstract Aim: Some infants with bronchopulmonary dysplasia (BPD) may require oxygen supplementation at home but a role for overnight polysomnography (PSG) in the management of home oxygen therapy has been rarely described. Methods: Forty-one infants with BPD born at less than 30 weeks gestational age were discharged with continuous home oxygen supplementation therapy between 2010 and 2013. PSG data were recorded on oxygen supplementation versus room air at median corrected age of 2 months (range 1–5 months) (first PSG after discharge to home). Those infants who continued oxygen supplementation therapy at home had at least one more PSG before oxygen therapy was discontinued (last PSG). We also collected PSG data in 10 healthy term infants (median age 3.5 months; range 2–4 months). Results: In infants with BPD in room air, increased numbers of central apneas, hypopneas, and SaO2 desaturations were the predominant PSG features with a median apnea–hypopnea index (AHI) of 16.8 events per hour (range 0–155). On oxygen supplementation therapy, median AHI dramatically improved (2.2, range 0–22; p < .001) and was not different from control infants (2.0, range 0–3.9; p = .31). AHI on room air at the last PSG when home oxygen was ceased was 4.1 per hour (range 0–13.8) slightly higher than in healthy infants. Conclusion: Central sleep disordered breathing in infants with BPD dramatically normalizes with low flow nasal cannula home oxygen therapy and improves with age. Mild central sleep disordered breathing remains detectable, although much improved, when compared with healthy infants at the time when the decision to cease home oxygen therapy was made by the physician.