Study Protocol for Preventing Early-Onset Pneumonia in Young Children Through Maternal Immunisation: A Multi-Centre Randomised Controlled Trial (PneuMatters).

Background: Preventing and/or reducing acute lower respiratory infections (ALRIs) in young children will lead to substantial short and long-term clinical benefits. While immunisation with pneumococcal conjugate vaccines (PCV) reduces paediatric ALRIs, its efficacy for reducing infant ALRIs following maternal immunisation has not been studied. Compared to other PCVs, the 10-valent pneumococcal-Haemophilus influenzae Protein D conjugate vaccine (PHiD-CV) is unique as it includes target antigens from two common lower airway pathogens, pneumococcal capsular polysaccharides and protein D, which is a conserved H. influenzae outer membrane lipoprotein. Aims: The primary aim of this randomised controlled trial (RCT) is to determine whether vaccinating pregnant women with PHiD-CV (compared to controls) reduces ALRIs in their infants' first year of life. Our secondary aims are to evaluate the impact of maternal PHiD-CV vaccination on different ALRI definitions and, in a subgroup, the infants' nasopharyngeal carriage of pneumococci and H. influenzae, and their immune responses to pneumococcal vaccine type serotypes and protein D. Methods: We are undertaking a parallel, multicentre, superiority RCT (1:1 allocation) at four sites across two countries (Australia, Malaysia). Healthy pregnant Australian First Nation or Malaysian women aged 17-40 years with singleton pregnancies between 27+6 and 34+6 weeks gestation are randomly assigned to receive either a single dose of PHiD-CV or usual care. Treatment allocation is concealed. Study outcome assessors are blinded to treatment arms. Our primary outcome is the rate of medically attended ALRIs by 12-months of age. Blood and nasopharyngeal swabs are collected from infants at birth, and at ages 6- and 12-months (in a subset). Our planned sample size (n = 292) provides 88% power (includes 10% anticipated loss to follow-up). Discussion: Results from this RCT potentially leads to prevention of early and recurrent ALRIs and thus preservation of lung health during the infant's vulnerable period when lung growth is maximum. The multicentre nature of our study increases the generalisability of its future findings and is complemented by assessing the microbiological and immunological outcomes in a subset of infants. Clinical Trial Registration: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=374381, identifier: ACTRN12618000150246.

Three-weekly doses of azithromycin for indigenous infants hospitalized with bronchiolitis: a multicentre, randomized, placebo-controlled trial.

BACKGROUND: Bronchiolitis is a major health burden in infants globally, particularly among Indigenous populations. It is unknown if 3 weeks of azithromycin improve clinical outcomes beyond the hospitalization period. In an international, double-blind randomized controlled trial, we determined if 3 weeks of azithromycin improved clinical outcomes in Indigenous infants hospitalized with bronchiolitis. METHODS: Infants aged ≤24 months were enrolled from three centers and randomized to receive three once-weekly doses of either azithromycin (30 mg/kg) or placebo. Nasopharyngeal swabs were collected at baseline and 48 h later. Primary endpoints were hospital length of stay (LOS) and duration of oxygen supplementation monitored every 12 h until judged ready for discharge. Secondary outcomes were: day-21 symptom/signs, respiratory rehospitalizations within 6 months post-discharge and impact upon nasopharyngeal bacteria and virus shedding at 48 h. RESULTS: Two hundred nineteen infants were randomized (n = 106 azithromycin, n = 113 placebo). No significant between-group differences were found for LOS (median 54 h for each group, difference = 0 h, 95% CI: -6, 8; p = 0.8), time receiving oxygen (azithromycin = 40 h, placebo = 35 h, group difference = 5 h, 95% CI: -8, 11; p = 0.7), day-21 symptom/signs, or rehospitalization within 6 months (azithromycin n = 31, placebo n = 25 infants, p = 0.2). Azithromycin reduced nasopharyngeal bacterial carriage (between-group difference 0.4 bacteria/child, 95% CI: 0.2, 0.6; p < 0.001), but had no significant effect upon virus detection rates. CONCLUSION: Despite reducing nasopharyngeal bacterial carriage, three large once-weekly doses of azithromycin did not confer any benefit over placebo during the bronchiolitis illness or 6 months post hospitalization. Azithromycin should not be used routinely to treat infants hospitalized with bronchiolitis. CLINICAL TRIAL REGISTRATION: The trial was registered with the Australian and New Zealand Clinical Trials Register: Clinical trials number: ACTRN1261000036099.

The prevalence of vitamin D deficiency in children in the Northern Territory.

AIMS: The primary aim of this study was to determine the frequency of vitD deficiency/insufficiency in an opportunistic sample of Northern Territory (NT) children. The secondary aim was to evaluate whether: (i) 25(OH)vitD (25(OH)D) levels differ between Indigenous/non-Indigenous children; and (ii) VitD insufficiency is associated with increased acute/infective hospitalisations. METHODS: Twenty-five (OH)D levels were measured in 98 children <16 years between August 2011 and January 2012 (children hospitalised acutely/non-acutely and well children from other studies based in Darwin). VitD deficiency was defined as 25(OH)D < 50 nmol/L, and insufficiency was postulated to be <75 nmol/L. Demographic data were collected, and computer records were reviewed. RESULTS: Median age was 59 months (range 2-161); 3.1% were vitD deficient, 19.4% insufficient. There was no significant difference in mean 25(OH)D level between Indigenous (93.2, standard deviation (SD) 21.9, n = 42) and non-Indigenous (97.3, SD 27.9, n = 56) children (P = 0.32). Median number of hospitalisations/year were similar (P = 0.319) between vitD sufficient (0.34, range 0-12, n = 76) and insufficient (0.22, 0-6, n = 22) children. There was no significant difference between number of infective admissions per year between vitD sufficient/insufficient groups (P = 0.119). CONCLUSIONS: Compared with US data (19% deficient, 65% insufficient) fewer NT children are vitD deficient/insufficient. In our limited sample, being vitD insufficient was not associated with increased acute/infective hospitalisations, but a larger unbiased sample of NT children is needed. More information is needed about the optimum level of vitD for non-bone-related health in children.

Retrospective review of 200 children hospitalised with acute asthma. Identification of intervention points: a single centre study.

AIM: Indigenous Australians with asthma have higher morbidity and mortality compared with non-Indigenous Australians. In children hospitalised with acute asthma, we aimed to (i) determine if acute severity, risk factors and management differed between Indigenous and non-Indigenous children; and (ii) identify intervention points to reduce morbidity and mortality of asthma. METHODS: Retrospective review of 200 children hospitalised to Royal Darwin Hospital with asthma. We compared admission characteristics, severity indices, treatment, discharge plans and readmissions in Indigenous and non-Indigenous children. RESULTS: Median age was 3.6 years (interquartile range 2.2, 6.8). A significantly higher proportion of Indigenous children (95.2%) were exposed to tobacco smoke compared with non-Indigenous children (45.7%). The difference in proportions was -0.41 (95% confidence interval (CI) -0.60, -0.22). Other risk factors, asthma severity (moderate 83.9% vs. 83.3%; severe 16% vs. 16.1%), length of stay (1.9 vs. 1.3 days) and readmission rate (27.4% vs. 27.5%) were similar between Indigenous and non-Indigenous children. Indigenous children were significantly more likely to be followed up in a community clinic (difference in proportions = 0.10, 95% CI 0.1, 0.17) and less likely by a paediatrician. Only 62.5% of all children had an asthma action plan on discharge. CONCLUSION: Unlike other common respiratory diseases requiring hospitalisation, biological factors are unlikely major contributors to the known gap in asthma outcomes between Indigenous and non-Indigenous children. Intervention points include better identification, documentation and management of tobacco smoke exposure, delivery of salbutamol and discharge planning (including education and utilisation of asthma action plans).

A single dose of azithromycin does not improve clinical outcomes of children hospitalised with bronchiolitis: a randomised, placebo-controlled trial.

OBJECTIVE: Bronchiolitis, one of the most common reasons for hospitalisation in young children, is particularly problematic in Indigenous children. Macrolides may be beneficial in settings where children have high rates of nasopharyngeal bacterial carriage and frequent prolonged illness. The aim of our double-blind placebo-controlled randomised trial was to determine if a large single dose of azithromycin (compared to placebo) reduced length of stay (LOS), duration of oxygen (O2) and respiratory readmissions within 6 months of children hospitalised with bronchiolitis. We also determined the effect of azithromycin on nasopharyngeal microbiology. METHODS: Children aged ≤18 months were randomised to receive a single large dose (30 mg/kg) of either azithromycin or placebo within 24 hrs of hospitalisation. Nasopharyngeal swabs were collected at baseline and 48 hrs later. Primary endpoints (LOS, O2) were monitored every 12 hrs. Hospitalised respiratory readmissions 6-months post discharge was collected. RESULTS: 97 children were randomised (n = 50 azithromycin, n = 47 placebo). Median LOS was similar in both groups; azithromycin = 54 hours, placebo = 58 hours (difference between groups of 4 hours 95%CI -8, 13, p = 0.6). O2 requirement was not significantly different between groups; Azithromycin = 35 hrs; placebo = 42 hrs (difference 7 hours, 95%CI -9, 13, p = 0.7). Number of children re-hospitalised was similar 10 per group (OR = 0.9, 95%CI 0.3, 2, p = 0.8). At least one virus was detected in 74% of children. The azithromycin group had reduced nasopharyngeal bacterial carriage (p = 0.01) but no difference in viral detection at 48 hours. CONCLUSION: Although a single dose of azithromycin reduces carriage of bacteria, it is unlikely to be beneficial in reducing LOS, duration of O2 requirement or readmissions in children hospitalised with bronchiolitis. It remains uncertain if an earlier and/or longer duration of azithromycin improves clinical and microbiological outcomes for children. The trial was registered with the Australian and New Zealand Clinical Trials Register. Clinical trials number: ACTRN12608000150347. http://www.anzctr.org.au/TrialSearch.aspx.

Randomized placebo-controlled trial on azithromycin to reduce the morbidity of bronchiolitis in Indigenous Australian infants: rationale and protocol.

BACKGROUND: Acute lower respiratory infections are the commonest cause of morbidity and potentially preventable mortality in Indigenous infants. Infancy is also a critical time for post-natal lung growth and development. Severe or repeated lower airway injury in very young children likely increases the likelihood of chronic pulmonary disorders later in life. Globally, bronchiolitis is the most common form of acute lower respiratory infections during infancy. Compared with non-Indigenous Australian infants, Indigenous infants have greater bacterial density in their upper airways and more severe bronchiolitis episodes. Our study tests the hypothesis that the anti-microbial and anti-inflammatory properties of azithromycin, improve the clinical outcomes of Indigenous Australian infants hospitalised with bronchiolitis. METHODS: We are conducting a dual centre, randomised, double-blind, placebo-controlled, parallel group trial in northern Australia. Indigenous infants (aged ≤ 24-months, expected number = 200) admitted to one of two regional hospitals (Darwin, Northern Territory and Townsville, Queensland) with a clinical diagnosis of bronchiolitis and fulfilling inclusion criteria are randomised (allocation concealed) to either azithromycin (30 mg/kg/dose) or placebo administered once weekly for three doses. Clinical data are recorded twice daily and nasopharyngeal swab are collected at enrollment and at the time of discharge from hospital. Primary outcomes are 'length of oxygen requirement' and 'duration of stay,' the latter based upon being judged as 'ready for respiratory discharge'. The main secondary outcome is readmission for a respiratory illness within 6-months of leaving hospital. Descriptive virological and bacteriological (including development of antibiotic resistance) data from nasopharyngeal samples will also be reported. DISCUSSION: Two published studies, both involving different patient populations and settings, as well as different macrolide antibiotics and treatment duration, have produced conflicting results. Our randomised, placebo-controlled trial of azithromycin in Indigenous infants hospitalised with bronchiolitis is designed to determine whether it can reduce short-term (and potentially long-term) morbidity from respiratory illness in Australian Indigenous infants who are at high risk of developing chronic respiratory illness. If azithromycin is efficacious in reducing the morbidly of Indigenous infants hospitalised with bronchiolitis, the intervention would lead to improved short term (and possibly long term) health benefits.

Risks of severity and readmission of Indigenous and non-Indigenous children hospitalised for bronchiolitis.

OBJECTIVE: To describe the characteristics of children admitted to Royal Darwin Hospital with bronchiolitis, and to compare the severity of illness and incidence of subsequent readmission in Indigenous and non-Indigenous children. DESIGN, SETTING AND PARTICIPANTS: Retrospective study of 101 children (aged

Validation of an Integrated Management of Childhood Illness algorithm for managing common skin conditions in Fiji.

OBJECTIVE: To assess the sensitivity of an Integrated Management of Childhood Illness (IMCI) algorithm to detect common skin conditions in children in Fiji. METHODS: We collected data from the assessments of children aged between 2 months and 5 years who presented to one of two health clinics. Every child was assessed by a nurse trained in the use of the IMCI algorithm and also an expert paediatrician. We used a kappa statistic to measure agreement between the nurse/algorithm assessment method and the paediatrician's diagnosis. FINDINGS: High sensitivity for identifying skin problems (sensitivity: 98.7%; 95% confidence interval, CI: 95.5-99.9) was found for the algorithm applied by IMCI-trained nurses, who were able to identify the one child with a severe skin infection and all three children with periorbital cellulitis. Sensitivity was high for the classification of abscess/cellulitis (sensitivity: 95%; 95% CI: 75.1-99.9) and infected scabies (sensitivity: 89.1%; 95% CI: 77.8-95.9), but lower for identification of impetigo, fungal infection and, in particular, non-infected scabies. CONCLUSION: The IMCI skin algorithm is a robust tool that should be incorporated into the IMCI after some modifications relating to scabies and impetigo. Its use by primary health-care workers will reduce the burden of skin diseases in children in Fiji through improved case identification and management. The algorithm should be considered in other countries where skin diseases in children are a priority, particularly in the Pacific region.

Airway inflammation in asymptomatic children with episodic wheeze.

Airway pathologies have been comprehensively researched in adult asthma, but in children, the extent of airway inflammation associated with episodic wheeze, often diagnosed as asthma, has not been fully characterized. It is not clear whether persistent airway inflammation is present in the absence of wheezing symptoms, and there is controversy regarding the role of age and atopy. This study assessed cellular and cytokine markers of airway inflammation in asymptomatic children with a history of episodic wheeze. Children with a history of episodic wheeze and cough (study group) and nonasthmatic patients requiring elective surgery (control group) were recruited. All subjects in the study group had a history of significant episodic wheezing (>2 episodes per year), and used only as-needed beta-agonist treatment. Bronchoalveolar lavage (BAL) was obtained using bronchoscopic lavage (study group) and nonbronchoscopic lavage (control group). Differential cell counts of BAL and flow cytometry were performed to identify T-lymphocyte phenotypes, and intracellular cytokine profiles were measured after phorbol-12-myristate 13-acetate (PMA) stimulation of BAL fluid T-cells. Twenty-one children with a history of 2-12 episodes of wheeze per year and 21 nonasthmatic subjects without respiratory symptoms were recruited. Study and control subjects were matched for age (median age, 5 years) and demographic characteristics. Study subjects had higher IgE levels, but their measurements were still within normal range. No significant differences in BAL differential cell counts were noted, and in both groups, the majority of T-cells were CD3+ CD8+, with a median CD4:CD8 ratio of 0.6. There was no significant difference in T-cell expression of the activation markers HLA-DR and CD25 (IL-2 receptor), or in PMA-induced production of the intracellular cytokines IFN-gamma, IL-2, IL-4, IL-5, and IL-10. The results of this study suggest that significant T-cell-driven airway inflammation is absent in mild or nonatopic, asymptomatic children of this age group who have episodic wheeze. Our findings support asthma management guidelines that do not recommend long-term treatment of this group of patients with anti-inflammatory medications.

Survey of childhood malnutrition at Dili National Hospital, East Timor.

OBJECTIVES: To describe the characteristics and short-term outcomes of children with malnutrition admitted to Dili National Hospital (DNH), East Timor. METHODS: A prospective observational survey using caretaker interviews and medical record review was conducted on the paediatric ward at DNH for 12 months from March 2002. Patients were children aged 2 months to 12 years, admitted with moderate to severe malnutrition as either a primary or secondary diagnosis. RESULTS: Malnutrition was present in 31.8% (280/880) of paediatric admissions during the study period. Sixty-one per cent of the malnutrition cases were severe malnutrition (weight-for-height below -3 Z-scores and/or oedema) and 53.7% were both wasted and stunted. The hospital case-fatality rate was 12.9% (36/280). Immunization coverage was low, with 39% of cases never immunized and 29% incompletely immunized according to the national immunization schedule. CONCLUSIONS: There is a high rate of malnutrition among paediatric inpatients at DNH, consistent with results of anthropometric surveys in the newly independent East Timor. Despite the introduction of a standardized protocol following WHO guidelines and associated training on the management of severe malnutrition, the hospital case-fatality rate for severe malnutrition was still high (12.9%).