Disease in Childhood

Theophylline and aminophylline for prevention of acute kidney injury in neonates and children: a systematic review Objective To compare the efficacy and safety of theophylline or aminophylline for prevention of acute kidney injury (AKI) in neonates and children. Design Systematic review and meta-analysis with application of Grading of Recommendations, Assessment, Development and Evaluation system. Data sources PubMed/MEDLINE, Embase, Google Scholar and Cochrane renal group were searched from 1970 to May 2018. Eligibility criteria Randomised clinical trials and quasi-randomised trials comparing the efficacy and safety of prophylactic theophylline or aminophylline for prevention of AKI in neonates and children were included. The primary outcomes were: incidence of AKI, serum creatinine levels and all-cause mortality. Results A total of nine trials were included in the qualitative synthesis. Six trials including 436 term neonates with birth asphyxia who received a single dose of theophylline were finally included in the meta-analysis. The pooled estimate showed 60% reduction in the incidence of AKI in neonates with severe birth asphyxia (RR: 0.40; 95% CI 0.3 to 0.54; heterogeneity: I2=0%) (moderate quality evidence), decrease in serum creatinine over days 2–5 (very low to low quality evidence) without significant difference in all-cause mortality (RR: 0.88; 95% CI 0.52 to 1.50; heterogeneity: I2=0%) (very low-quality evidence). A significant difference in the negative fluid balance, increase in GFR and decrease in urinary β2 microglobulin was seen in favour of theophylline. Conclusion and relevance A single dose of prophylactic theophylline helps in prevention of AKI/severe renal dysfunction in term neonates with severe birth asphyxia (moderate quality evidence) without increasing the risk of complications and without affecting all-cause mortality (very low-quality evidence). Trial registration number CRD 42017073600.

Pathways to inequalities in child health From birth, children living in disadvantaged socioeconomic circumstances (SECs) suffer from worse health than their more advantaged peers. The pathways through which SECs influence children's health are complex and inter-related, but in general are driven by differences in the distribution of power and resources that determine the economic, material and psychosocial conditions in which children grow up. A better understanding of why children from more disadvantaged backgrounds have worse health and how interventions work, for whom and in what contexts, will help to reduce these unfair differences. Macro-level change is also required, including the reduction of child poverty through improved social security systems and employment opportunities, and continued investment in high-quality and accessible services (eg, childcare, key workers, children's centres and healthy school environments). Child health professionals can play a crucial role by being mindful of the social determinants of health in their daily practice, and through advocating for more equitable and child-focussed resource allocation.

Reclaiming the systems approach to paediatric safety Introduction Prior to the emergence of the patient safety movement as a distinct science, it was assumed that the safety of patients was an outcome of good professional acumen, and that if healthcare providers could individually perform well then their patients would remain safe at all times. It is now 20 years since the publication of To Err is Human,1 the first major review of healthcare safety in the USA. In the UK, the publication Organisation with a Memory2 in 2000 supported the view that patient safety required a wider system approach. Both documents reframed safety and error in healthcare as an organisational or system issue rather than one of individual error, whether of omission or of commission. Over the past 20 years, there has been major progress in the understanding of patient safety and the complexity of the systems involved in providing healthcare. In a recent...

No association between abdominal pain and Dientamoeba in Dutch and Belgian children Objective To study the association between Dientamoebafragilis colonisation and faecal calprotectin to see whether the parasite is a harmless commensal or a gut pathogen. Design Cross-sectional study of previously collected stool samples. Setting and patients Two hundred stool samples originated from children aged 5–19 years with chronic abdominal pain and diarrhoea, who were seen in paediatric clinics in the Netherlands and Belgium and in whom somatic gastrointestinal disorders were excluded. Another 122 samples came from a healthy community-based reference population of the same age. All stool samples were analysed with real-time PCR for the detection of D. fragilis and with an ELISA for calprotectin—a biomarker of gastrointestinal inflammation. Main outcome measures Prevalence of D. fragilis colonisation and results of stool calprotectin testing. Results D. fragilis was detected in 45% (95% CI 38% to 51%) of patients and in 71% (95% CI 63% to 79%) of healthy children. Median (IQR) concentrations of calprotectin in patients and healthy children with a positive PCR result were not different from those with a negative PCR result (40 (40–55) μg/g vs 40 (40–75) μg/g, respectively). Conclusion Since D. fragilis colonisation is most prevalent in healthy children and is not associated with an increase in faecal calprotectin concentration, our data do not support the inference that D. fragilis is a pathogenic parasite. Routinely testing for D. fragilis in children with chronic abdominal pain should therefore be discouraged.

Epidemiology of paediatric chronic fatigue syndrome in Australia Objective To estimate the paediatrician-diagnosed incidence of chronic fatigue syndrome (CFS) in Australia, and describe demographic and clinical features, as well as approaches to diagnosis and management. Methods The Australian Paediatric Surveillance Unit facilitates monthly national surveillance of uncommon conditions seen by paediatricians. Data from young people aged <18 years diagnosed with CFS were collected. Incidence was estimated based on new cases reported from April 2015 to April 2016. Results A total of 164 cases of newly diagnosed CFS in young people aged 4–17 years were identified for inclusion. The estimated national incidence for children aged 4–9 years was 0.25 per 100 000 per annum. In children aged 10–17 years, the estimated incidence of paediatrician-diagnosed cases for Victoria (17.48 per 100 000) was substantially greater than other Australian states (range 1.31–5.51 per 100 000). Most cases were female and Caucasian, most commonly presenting after an infectious illness with symptoms gradual in onset. The majority were diagnosed at least 13 months after symptom onset. Symptoms, associations, investigations and management strategies were highly variable. Conclusions Current findings suggest that, consistent with other countries, the Australian incidence of CFS in children aged <10 years is very low. In contrast, the national incidence of CFS in older children and adolescents (aged 10–17 years) is more unclear, with marked variability between geographical regions apparent. This may be due to variation in service accessibility and clinician understanding of CFS. Accordingly, national initiatives to improve equity of care for children with CFS may be required.

Persistence of pneumococcal antibodies after primary immunisation with a polysaccharide-protein conjugate vaccine Introduction Despite immunisation, antibiotics and intensive care management, infection with Streptococcus pneumoniae remains a major cause of morbidity and mortality in children. The WHO currently recommends vaccinating infants with either a 3+0 schedule (6 weeks, 3–4 and 4–6 months of age) or 2+1 schedule (2 doses before 6 months of age, plus a booster dose at 9–15 months of age). This study investigated pneumococcal antibody responses, including persistence of antibodies, after immunisation of healthy infants with a 3+0 schedule. Methods We measured pneumococcal antibody concentrations to all 13 antigens included in the 13-valent pneumococcal conjugate vaccine (PCV13) after immunisation with a 3+0 schedule in 91 infants at 7 months and in 311 infants at 13 months of age. The geometric mean concentrations (GMCs) and the proportion of infants with an antibody concentration above the standard threshold correlate of protection (seroprotection rate) were calculated at both time points. Results At 7 months of age, GMCs varied between 0.52 µg/mLand 11.52 µg/mL, and seroprotection rates varied between 69% and 100%. At 13 months of age, GMCs had decreased to between 0.22 µg/mLand 3.09 µg/mL, with the lowest responses against serotype 4, followed by 19A, 3, 6B and 23F. Seroprotection rates at 13 months of age were below 90% for most serotypes, with the lowest rates for serotype 4 (23%) followed by 19A (50%), 23F (61%) and 6B (64%). Conclusion Our study shows that at 13 months of age, many infants vaccinated with a 3+0 schedule have pneumococcal antibody concentrations below the standard threshold correlate of protection. To optimise protection against pneumococcal disease through early childhood and to improve antibody persistence and indirect protective effects, immunisation schedules with booster doses might be necessary.

Highlights from the literature Separating craniopagus twins Lucina doesn't normally feature surgical case reports, but this one reported in the NEJM is remarkable (Heuer G et al doi:10.1056/NEJMoa1805132). A highly-skilled team from the Children's Hospital of Philadelphia successfully separated conjoined twin girls, who shared skull bones and a common sagittal sinus, but not brain tissue. They were delivered at 30 weeks, and pre-operatively required tissue expansion techniques over several months to make separation easier. Meticulous planning, which involved computerised modelling and 3-D printing, led to an 11 hours separation procedure at age 10 months. Remodelling the venous sinuses was a particular challenge. The girls have done well, with intact skulls and only mild neurocognitive deficits. Conjoined twins are rare and craniopagus even rarer, so each case has to be looked at afresh as new technologies emerge. EMLA in infants 'Magic cream', or topical local anaesthetic EMLA (eutectic mixture of lidocaine/lignocaine and prilocaine), is frequently used for...

Air pollution and autism It's clear that genetics plays a major role in the aetiology of autistic spectrum disorder (ASD), but the genuine increase in prevalence over recent decades suggests that environmental factors are also responsible. If ASD is considered to be a neurodevelopmental disorder, rather than a social construct, then antenatal influences during early brain development may be important. Potential prenatal causes suggested thus far are many and varied, including paracetamol (Archivist Oct 2016 doi.org/10.1136/archdischild-2016–3 11 708), antidepressant drugs (Archivist March 2016 doi.org/10.1136/archdischild-2016–3 10 462), ultrasound (Archivist Sept 2018 doi.org/10.1136/archdischild-2018–3 15 816), season of conception (Lucina Dec 2016 doi.org/10.1136/archdischild-2016–3 12 102), and obesity, among many others. Several studies have hinted at a link with maternal air pollution exposure, but these have been inconsistent or inconclusive. ASD definitions have been imprecise, exposure indicators not sufficiently localised, and types of pollution lumped together. Importantly, confounding factors need to be accounted for, as families with the highest psychosocial risks for autism may tend to live...

Screentime and child health The media are obsessed with the issue of 21st century children spending too much time staring at screens: some reports have amounted to a moral panic (www.telegraph.co.uk/news/2018/09/26/two-hours-screentime-day-could-damage-childrens-brain-development). The release of a statement from the UK's Royal College of Paediatrics and Child Health (RCPCH) was therefore welcome (rcpch.ac.uk/resources/health-impacts-screen-time-guide-clinicians-parents). It was based on a systematic 'review of reviews' which synthesised the large amount of evidence available (Stiglic N, Viner R. doi: 10. 1136/bmjopen- 2018–0 23 191). Rather than go back to the primary data, they identified 13 reviews of varying quality that had already done this. They assessed each review's conclusions qualitatively, rather than doing further meta-analyses. Screentime use included television (TV), computers, tablets and smartphones. TV-watching predominated in most reviews. Different outcome domains were considered. With regards to obesity or adiposity, they concluded that there was a positive association with TV screentime, but they could not define a 'safe threshold' of time....

At what weight should preterm infants be transferred from incubator to open cot? Scenario A preterm infant born at 28 weeks' gestation is 5 weeks old, weighs 1600 g and nursed in an incubator. During the round, the medical team instructs the nurse to transfer the infant to open cot. The nurse in charge is concerned that weaning the infant from incubator to cot at this weight might affect the temperature stability, weight gain and may delay the discharge of the infant. The third-year paediatric resident offers to review the literature and report the findings to the multidisciplinary team. Structured clinical question In a medically stable preterm infant with a birth weight of less than 1600 g, not on any respiratory support, nursed in incubator (patient), whether transferring the infant from incubator to unheated open cot at a lower weight (<1700 g) (intervention) compared with a higher weight (>1700 g) (comparison) will affect the temperature stability, weight gain and length of hospital stay of the...

Highlights from this issue Global child healthVitamin A The history of the vitamin A supplementation studies from the initial excitement of the reduction in measles related mortality trials in West Africa 25 years ago has been a chequered one. The routine population supplementation from 6 months to 5 years of age is now established, but the issue over neonatal supplementation and its effect on infant mortality and morbidity has remained unresolved, trials showing different directions of effect, or no effect. The paper from the WHO Vitamin A supplementation group addresses this in a meta-analysis of the 11 published studies. Pooled analysis showed no effect of early (first 2 to 3 days) vitamin A supplementation on mortality at either 6 months (RR 0.97, 95% CI 0.89 to 1.06) or 1 year. There were subtle differences in the sub-analyses stratified by region: in South Asia (but not Africa) where Vitamin A deficiency (defined by established...

Fetal hydrops: diagnosis and prognosis The causes and outcomes of fetal hydrops have been well described in the literature over many years. Anti-D immunoglobulin has dramatically reduced the rate (and mortality) of immune hydrops such that non-immune hydrops (NIHF) now accounts for 90% of cases.1 Hydrops is a challenging condition to counsel for due to the relative rarity (1 in 1700–3000 pregnancies) and the fact it is the preterminal manifestation of many different pathophysiological processes.2–4 The paper published in our sister journal Fetal & Neonatal by Gilby et al5 addresses two key questions that all expectant parents faced with this problem would ask: what is the cause of the hydrops and will my baby survive? Diagnosis in NIHF is of paramount importance to accurate counselling. The more refined the phenotype the more accurate information a clinician is able to provide on mortality, morbidity and treatment options.

'Death is not the answer: the challenge of measuring the impact of early warning systems We can all remember individual children in whom a deterioration went unrecognised. Sometimes fatally. Our defences were little more than the pearls offered by senior colleagues of grave warning signs: 'beware grunting in an infant' or 'watch out for a tachycardia after the temperature has fallen'. But this advice was unstructured, and children are so different, and their comorbidities so broad, we failed some of them. Paediatric Early Warning Systems (PEWS) are serious attempts to reduce the unacceptable and dangerous variability in this recognition and response process. Scoring systems should provide age-appropriate thresholds for concern for single parameters or aggregated abnormal physiology and prompt standardised responses. The idea has such natural appeal that PEWS use was soon advocated by a number of national bodies1 2 without evidence. This may have been a mistake. Many of the scores in widespread use were not calibrated or validated....

Biological therapeutic drug monitoring: a step towards precision medicine? Biological medications including monoclonal antibodies against tumour necrosis factor-α (TNF-α), such as infliximab and adalimumab, have revolutionised the treatment of children and young people with autoimmune conditions such as inflammatory bowel disease, juvenile idiopathic arthritis (JIA) and childhood chronic inflammatory uveitis. Emerging evidence is increasingly supporting the use of therapeutic drug monitoring (TDM) to help optimise biological efficacy, safety and cost-effectiveness. The pharmacokinetics of biologics is complex and in contrast to traditional medications; predominantly due to their large molecular size and structural complexity, they do not undergo hepatic metabolisation and are instead broken down by intracellular lysosomal proteolytic degradation. Also, unlike traditional medications, they have immunogenic potential and the formation of antidrug antibodies (ADA) can significantly affect their pharmacokinetic profile. ADA directed against the corresponding biologic can trigger proteolytic elimination in the reticuloendothelial system (RES) leading to increased clearance of these molecules. Conversely, an immune complex that does not...

Improving the quality of care delivered to adolescents in Europe: a time to invest Introduction While many governments, non governmental organisations (NGOs) and United Nations (UN) agencies have focused in the past on the health of mothers, infants and young children, there is now growing evidence that the healthcare system should also address the well-being and problems of adolescents, defined by WHO as individuals aged 10–19 years. They represent 1.2 billion individuals in the global population and between 10% and 25% of the population in European countries.1 In September 2015, the UN Secretary-General announced that the 'Every Woman, Every Child' agenda would move forward to 2030 as a Global Strategy for Women's, Children's and Adolescents' Health. In 2017, WHO responded to the large number of health problems affecting adolescents by launching a state-of-the-art review of programmes and interventions targeting the health burden of adolescents around the world, the AA-HA initiative ('Accelerated Action for the Health of Adolescents'). Adolescents' morbidities such as sexually transmitted...

Early neonatal vitamin A supplementation and infant mortality: an individual participant data meta-analysis of randomised controlled trials Background Biannual vitamin A supplementation is a well-established survival tool for preschool children 6 months and older in vitamin A deficient populations but this schedule misses the opportunity to intervene on most young infant deaths. Randomised trials of neonatal vitamin A supplementation (NVAS) in the first few days of life to assess its impact on under 6-month mortality in low/middle-income countries have had varying results. Methods Investigators of 11 published randomised placebo-controlled NVAS trials (n=163 567 children) reanalysed their data according to an agreed plan and pooled the primary outcomes of mortality from supplementation through 6 and 12 months of age using random effects models and meta-regression. One investigator withdrew but allowed use of the data. Findings Overall there was no effect of NVAS on infant survival through 6 (risk ratio (RR) 0.97; 95% CI 0.89 to 1.06) or 12 months of age (RR 1.00; 95% CI 0.93 to 1.08) but results varied by study population characteristics. NVAS significantly reduced 6-month mortality among the trials conducted in Southern Asia (RR 0.87; 95% CI 0.77 to 0.98), in contexts with moderate or severe vitamin A deficiency (defined as 10% or higher proportion of women with serum retinol <0.7 µmol/L or 5% or more women with night blindness) (RR 0.87; 95% CI 0.80 to 0.94), early infant mortality was 30 or more per 1000 live births (RR 0.91; 95% CI 0.85 to 0.98), 75% or more of infant mortality occurred in the first 6 months of life (RR 0.92; 95% CI 0.84 to 1.01), or where >32% mothers had no schooling (RR 0.88; 95% CI 0.80 to 0.96). NVAS did not reduce mortality in the first 6 months of life in trials conducted in Africa, in contexts characterised by a low prevalence of vitamin A deficiency, lower rates of infant mortality and where maternal education was more prevalent. There was a suggestion of increased infant mortality in trials conducted in Africa (RR 1.07; 95% CI 1.00 to 1.15). Individual-level characteristics such as sex, birth weight, gestational age and size, age at dosing, parity, time of breast feeding initiation, maternal education and maternal vitamin A supplementation did not modify the impact of NVAS. Conclusion NVAS reduced infant mortality in South Asia, in contexts where the prevalence of maternal vitamin A deficiency is moderate to severe and early infant mortality is high; but it had no beneficial effect on infant survival in Africa, in contexts where the prevalence of maternal vitamin A deficiency is lower, early infant mortality is low.

Mass antibiotic distribution to reduce mortality among preschool children? Worldwide, under-fives mortality has halved since 1990 from 93 to 41 deaths per 1000 live births in 2016. However, progress has been very uneven. Child mortality is still highest in Africa (76 per 1000 live births) (figure 1) and neonatal mortality has declined at a slower rate so is now approaching 50% of all under-fives mortality.1 Research and programmatic efforts are focussed on reducing child mortality in the highest burden areas. An intriguing and controversial idea to reduce mortality has arisen from mass antimicrobial distribution programmes for the prevention of blindness caused by trachoma. Trachoma has a predilection for the poorest, most remote communities with low levels of hygiene. Chlamydia trachomatis is spread by direct contact with fluid from an infected person's eyes or nose, or indirect contact with these fluids via clothing or flies. It is endemic across Africa from South Sudan and Ethiopia...

Linear growth following complicated severe malnutrition: 1-year follow-up cohort of Kenyan children Background Stunting is the most common manifestation of childhood undernutrition worldwide. Children presenting with severe acute malnutrition (SAM) are often also severely stunted. We evaluated linear growth and its determinants after medically complicated SAM. Methods We performed secondary analysis of clinical trial data (NCT00934492) from HIV-uninfected Kenyan children aged 2–59 months hospitalised with SAM. Outcome was change in height/length-for-age z-score (HAZ) between enrolment and 12 months later. Exposures were demographic, clinical, anthropometric characteristics and illness episodes during follow-up. Results Among 1169 children with HAZ values at month 12 (66% of those in original trial), median (IQR) age 11 (7–17) months and mean (SD) HAZ –2.87 (1.6) at enrolment, there was no change in mean HAZ between enrolment and month 12: –0.006Z (95% CI –0.07 to 0.05Z). While 262 (23%) children experienced minimal HAZ change (within ±0.25 HAZ), 472 (40%) lost >0.25 and 435 (37%) gained >0.25 HAZ. After adjusting for regression to the mean, inpatient or outpatient episodes of diarrhoea and inpatient severe pneumonia during follow-up were associated with HAZ loss. Premature birth and not being cared by the biological parent were associated with HAZ gain. Increases in mid-upper arm circumference and weight-for-age were associated with HAZ gain and protected against HAZ loss. Increase in weight-for-height was not associated with HAZ gain but protected against HAZ loss. No threshold of weight gain preceding linear catch-up growth was observed. Conclusions Interventions to improve dietary quality and prevent illness over a longer period may provide opportunities to improve linear growth.

Child mortality: how does the USA compare? In March 2015, an Archives editorial featured a Lancet paper describing neonatal, infant and child mortality trends, comparing UK data to other European countries and Canada, but not the USA (doi: 10.1136/archdischild-2014–3 07 678). The UK was improving more slowly than the comparator countries. Now American authors have done something similar (Khan S et al doi:10.1001/jamapediatrics.2018.3317). Using the US National Centre for Health Statistics database, and comparing to equivalent data from England/Wales (E&W) and Canada, they found that the US is actually doing much worse than the UK. They looked at annual mortality rates for all individuals up to age 24, from 1999 to 2015, throughout the US. As seen in other countries, there was a striking decline in overall mortality rates for most age groups over the 16 year period, except for young adults aged 20–24 where there was a decline until 2012 and then a slight increase. In all age...

Research priorities for childhood chronic conditions: a workshop report Background Chronic conditions are the leading cause of mortality, morbidity and disability in children. However, children and caregivers are rarely involved in identifying research priorities, which may limit the value of research in supporting patient-centred practice and policy. Objective To identify priorities of patients, caregivers and health professionals for research in childhood chronic conditions and describe the reason for their choices. Setting An Australian paediatric hospital and health consumer organisations. Methods Recruited participants (n=73) included patients aged 8 to 14 years with a chronic condition (n=3), parents/caregivers of children aged 0 to 18 years with a chronic condition (n=19), representatives from consumer organisations (n=13) and health professionals including clinicians, researches (n=38) identified and discussed research priorities. Transcripts were thematically analysed. Results Seventy-eight research questions were identified. Five themes underpinned participants' priorities: maintaining a sense of normality (enabling participation in school, supporting social functioning, promoting understanding and acceptance), empowering self-management and partnership in care (overcoming communication barriers, gaining knowledge and skills, motivation for treatment adherence, making informed decisions, access and understanding of complementary and alternative therapies),strengthening ability to cope (learning to have a positive outlook, preparing for home care management, transitioning to adult services), broadening focus to family (supporting sibling well-being, parental resilience and financial loss, alleviating caregiver burden), and improving quality and scope of health and social care (readdressing variability and inequities, preventing disease complications and treatment side effects, identifying risk factors, improving long-term outcomes, harnessing technology, integrating multidisciplinary services). Conclusion Research priorities identified by children, caregivers and health professionals emphasise a focus on life participation, psychosocial well-being, impact on family and quality of care. These priorities may be used by funding and policy organisations in establishing a paediatric research agenda.