Context Might Differ but Optimal Treatment Can Be Consistent Across Contexts

For children with sickle cell disease a stroke is probably the most devastating complication. Until recently the standard treatment was multiple blood transfusions. The logic behind this treatment is that these transfusions suppress the bone marrow of the recipient. As a result, the concentration of normal haemoglobin rises as the concentration of abnormal haemoglobin drops. In other words, the proportion of haemoglobin that is abnormal is reduced. As this happens, the risk of stroke declines. The risk of stroke can be predicted by means of Doppler ultrasound in the cranial vessels – flow rates return to normal as the proportion of normal haemoglobin in the blood increases.

However, people in low-income countries are often unwilling to undergo multiple transfusions. They cannot afford the time; transfusions are expensive; and there is a shortage of blood for people with acute emergencies, such as postpartum haemorrhage. However, there is another treatment for sickle cell disease called hydroxyurea. I was privileged to attend an inaugural lecture at the University of Ibadan given by the new professor of pediatrics, one Prof IkeOluwa Lagunju. She showed that this alternative treatment was just as good as multiple transfusions in improving blood flows in the cranial circulation. In an uncontrolled follow-up study she showed that the incidence of stroke in treated children was much lower than that predicted from the epidemiology.[1] That this purely medical treatment can improve blood flow to the same extent as multiple transfusions has subsequently been confirmed in a large, multi-centre randomised trial in high-income countries.

As you well know, I have an interest in the relevance of research in high-income countries for low-income countries and vice-versa.[2] I think this is a nice example of the growth in knowledge testing similar treatments across different contexts.

— Richard Lilford, CLAHRC WM Director

References:

1. Lagunju I, Brown BJ, Oyinlade AO, et al. Annual stroke incidence in Nigerian children with sickle cell disease and elevated TCD velocities treated with hydroxyurea. Pediatr Blood Cancer. 2018; 66(3): e27252.
2. Lilford RJ. How Can Research in Low- and Middle-Income Countries (LMICs) Help People in High-Income Countries? NIHR CLAHRC West Midlands News Blog. 31 July 2015.

Another Very Interesting Paper on Molecular Analysis of Stool in Childhood Diarrhoea

We have previously summarised the results of a study using molecular analysis to examine samples from children with and without diarrhoea. Among many interesting findings, this showed that Shigella is one of the most common bacterial causes of childhood diarrhoea.[1][2] A further study by the same investigator team tested stool samples from 1,715 children from eight countries for presence of 29 entertopathogens.[3] This was a reanalysis of a previously published dataset (MAL-ED) using quantitative PCR methods in order to refine the aetiology estimates by increasing the pathogens tested for.

While the original study found that 32.8% of diarrhoea samples were attributable to an infectious aetiology, this new analysis found 64.9% attributable. Thus, the more rigorous method doubled the proportion of diarrhoea cases that could be attributed to a specific pathogen. Diarrhoea attributable to pathogens during the first year of life was lower (50.5%) than during the second year (82.8%). The study also found that viral diarrhoea was most common (36.4%), then bacterial (25.0%) and parasitic (3.5%). Ten pathogens accounted for 95.7% of attributable diarrhoea. Again, Shigella was shown to be the most common (26.1%), followed by sapovirus (22.8%) and rotavirus (20.7%).

The CLAHRC WM Director has questions:

1. What causes the unattributable cases, especially in the first year of life?
2. Did all cases really have diarrhoea? It is a diagnosis that is partly ‘in the eye of the beholder’.[4]
3. Contrary wise, how can we be sure that the agent detected was causal of the condition?

— Richard Lilford, CLAHRC WM Director
— Peter Chilton, Research Fellow

References:

1. Liu J, Platts-Mills JA, Juma J, et al. Use of quantitative molecular diagnostic methods to identify causes of diarrhoea in children: a reanalysis of the GEMS case-control study. Lancet. 2016; 388: 1291-301.
2. Lilford RJ. Did You Ever Want to Know What Bugs Were Actually in Diarrhoea? NIHR CLAHRC West Midlands News Blog. 11 November 2016.
3. Platts-Mills JA, Liu J, Rogawski ET, et al. Use of quantitative molecular diagnostic methods to assess the aetiology, burden, and clinical characteristics of diarrhoea in children in low-resource settings: a reanalysis of the MAL-ED cohort study. Lancet Glob Health. 2018; 6(12): e1309-18.
4. Lilford RJ. Childhood Diarrhoeal Diseases – Update of the Famous Wolf Review. NIHR CLAHRC West Midlands News Blog. 19 October 2018.

Probiotic Treatment Reduces the Incidence of Severe Sepsis in Neonates in India

Every now and then the CLAHRC WM Director spots an article that was published a few years ago, that he would have summarised had he seen it, and that is still topical. Such an article was an RCT of a probiotic administered in combination with a nutritional supplement. The idea behind the nutritional agent is that it will enable the probiotic bacteria to flourish in the host intestine [1] – the combination of probiotic and nutritional agents is called a ‘synbiotic’. Over four-and-a-half-thousand infants (2 to 4 days old), across 149 villages, were randomised to intervention or control. The trial, reported in Nature, had to be stopped early, so great was the reduction in neonatal sepsis in the intervention group.

Interestingly, the death rates in the Nature study were not different between study arms, but then only ten children died overall. Very interestingly, the incidence of pneumonia was reduced, alongside sepsis, in the intervention group. This study was completed in 2012, but was not published until 2017.

An updated systematic review from 37 RCTs found that probiotics significantly decreased the risk of late-onset sepsis (p=0.0007).[2] This study of nearly 10,000 babies is the largest of any meta-analysis in Neonatology. The results are significant even if studies at high risk of bias are excluded. There was no evidence of small study / publication bias in the funnel plot. Overall, the result remained significant irrespective of which bacterial strains were retained in the meta-analysis.

So, the meta-analysis, now reinforced by the Nature study, really does suggest that probiotics are effective. Lactobacillus and Bifidus are the two most widely used bacterial species, but the Nature study used only Lactobacilli.

— Richard Lilford, CLAHRC WM Director

References:

1. Panigrahi P, Parida S, Nanda NC, et al. A randomized symbiotic trial to prevent sepsis among infants in rural India. Nature. 2017; 548: 407-12.
2. Rao SC, Athalye-Jape GK, Deshpande GC, Simmer KN, Patole SK. Probiotic Supplementation and Late-Onset Sepsis in Preterm Infants: A Meta-Analysis. Pediatrics. 2016; 137(3): e20153684.

The Role of Fathers in Child Rearing

A recent article published in the Pediatrics journal summarises evidence on the role of fathers in development of children.[1] The studies are mainly of an observational nature, as one might expect, but the article pays scant attention to the limitations of this sort of evidence. However, despite the methodological naivety of the article, many of the findings are of interest. Furthermore, they are consistent across a large number of studies.

There are strong and consistent correlations between the presence of a father and psychological and functional outcomes for children. Similar findings apply in the adolescent years. Fathers tend to play more with their children than do mothers. Roughhouse play is particularly associated with healthy adaptation in the children. The mental health of fathers is strongly associated with child development. Interestingly, male testosterone levels increase during conception and decrease during child rearing. There are consistent differences between mothers and fathers in the neurological pathways that are activated during child rearing.

The CLAHRC WM Director found these results emotionally appealing, and wonders about the effect of grandparents on child development.

— Richard Lilford, CLAHRC WM Director

Reference:

1. Yogman M, Garfield CF, Committee on Psychosocial Aspects of Child and Family Health. Fathers’ Roles in the Care and Development of Their Children: The Role of Pediatricians. Pediatrics. 2016; 138(1): e20161128.

Interventions Targeted Across a Community vs. Interventions Targeted at Specific Individuals

Behaviour change has often been viewed as an individual issue. Since individuals are the target of a behaviour change intervention, it seems natural to focus the intervention on the individuals whose behaviour one wishes to change. So, if one wishes to improve breastfeeding or encourage hygienic preparation of infant foods, then the target group would naturally be young mothers.

However, these targeted interventions have often produced disappointing results when evaluated rigorously. There are a number of reasons to think that a more general, or community-wide, intervention would be more effective (or augment the effect of the personal approach). Firstly, in terms of evolutionary theory, humans have evolved to work collaboratively in hierarchical groups. Humans could not get very far in the savannah as individuals; so like many animals their success depended on group action. Secondly, the emerging acceptance of the trans-theoretical framework has emphasised multiple barriers, including social barriers. Bandura showed how exquisitely sensitive individuals are to social signals and to the influence of leaders.[1]

As a result of this thinking, interventions are increasingly targeted, not only at the front line, but also the local social structures and hierarchies. For example recent work on infant hygiene and breastfeeding has been focused at the community level, rather than on individual mothers.[2][3] Similarly, interventions to improve services recognise the importance off including, not only front line staff, but other levels in the hierarchy.[4][5]

— Richard Lilford, CLAHRC WM Director

References:

1. 1. Bandura A. Social Learning Theory. Englewood Cliffs, NJ: Prentice Hall, 1977.
   2. Lilford RJ. Cluster Trial of Home Visits for Newborn Children in Sub-Saharan Africa. NIHR CLAHRC West Midlands News Blog. 6 May 2016.
   3. Kirkwood BR, Manu A, ten Asbroek AHA, et al. Effect of the Newhints home-visits intervention on neonatal mortality rate and care practices in Ghana: a cluster randomised controlled trial. Lancet. 2013; 381(9884): 2184-92.
   4. Lilford RJ. Reports of a Hospital-Wide Improvement Programme. NIHR CLAHRC West Midlands News Blog. 21 June 2019.
   5. Chatfield SC, Volpicelli FM, Adler NM, et al. Bending the cost curve: quasi-experimental analysis of a value transformation program at an academic medical center. BMJ Qual Saf. 2019; 28: 449–58.

 

Rotavirus Vaccine

Gastroenteritis as a result of rotavirus infection is a major cause of morbidity and mortality among children under 5 years old, with around 215,000 deaths in 2013.[1] Thankfully there is now a vaccine available, and hospital admissions and deaths have been shown to have declined significantly since its introduction. However, not all countries have incorporated the rotavirus vaccine into their national immunisation programmes. A recent paper in Lancet Global Health used data from the WHO-coordinated Global Rotavirus Surveillance Network to look at the impact the vaccine has had worldwide, as it had not previously been analysed using primary data.[2]

More than 400,000 children from 82 countries were admitted to hospital with acute gastroenteritis over the study period, with around one-third being tested positive for rotavirus. The impact analysis of the study looked at a subset of ~300,000 children and found that there was a decline of 39.6% (95% CI 35.4-43.8) in admissions in countries that had introduced the vaccine into their immunisation programme, compared to the years before, resulting in rotavirus being detected in around 23% of admissions. Meanwhile, in countries that did not include the vaccine there was no significant change in rotavirus detected over time, remaining stable at around 38% of admissions. Further, in countries that had introduced the vaccine, the age distribution of children that tested positive for rotavirus gastroenteritis was skewed towards older children, perhaps as a result of the improved protection.

References:

1. Tate JE, Burton AH, Boschi-Pinto C, Parashar UD; World Health Organization-Coordinated Global Rotavirus Surveillance Network. Global, regional, and national estimates of rotavirus mortality in children <5 years of age, 2000–2013. Clin Infect Dis. 2016; 62: S96-S105.
2. Aliabadi N, Antoni S, Mwenda JM, et al. Global impact of rotavirus vaccine introduction on rotavirus hospitalisations among children under 5 years of age, 2008–16: findings from the Global Rotavirus Surveillance Network. Lancet Glob Health. 2019; 7(7): e893-903.

Nutritional Interventions for Childhood Stunting in Slums

For many people living in slums, getting sufficient food is a challenge, especially when children are involved. A lack of proper nutrition is one of many risk factors for stunting in children, which can lead to increased risk of infection, cognitive and behavioural problems, and lower work performance and earnings as an adult. Various interventions have been shown to successfully reduce the incidence of childhood stunting, including interventions focussed on nutrition. However, these have not been extensively assessed in urban slums.

A team of researchers from Loughborough University recently conducted a Cochrane systematic review looking at this, finding 15 studies that were conducted in slums or poor urban areas, primarily in Bangladesh, India and Peru.[1] Fourteen of the studies were RCTs, and all looked at nutrient supplementation or educational interventions. In total the studies included 9,261 infants and 3.664 pregnant women.

The studies did not take into account the unique challenges found in slums (such as high mobility, lack of social services, and high loss of participants to follow-up) in their design stages, which meant they had low to moderate reliability. Even so, the authors were able to conclude that nutritional interventions in slums had not been successful in decreasing childhood stunting as expected (based on evidence from non-slums). Future research will not only need to take into account the slum environment, but also combine multi-sectoral components, innovative targeting and have long-term follow-up.

— Peter Chilton, Research Fellow

Reference:

1. Goudet SM, Bogin BA, Madise NJ, Griffiths PL. Nutritional interventions for preventing stunting in children (birth to 59 months) living in urban slums in low‐ and middle‐income countries (LMIC). Cochrane Database Syst Rev. 2019: CD011695.

Using Machine Learning to Diagnose Childhood Depression

Although we may think of childhood as a care-free time, it is estimated that as many as one in five children develop depression or anxiety, with it even being seen in children as young as four years old. Unfortunately, due to the abstract nature of the emotions involved, children are often unable to clearly communicate their problems. Further, signs are not easily recognised by parents. This can lead to a lack of support, and eventually cause the child to internalise their disorders, something that is associated with long-term negative outcomes. Current diagnosis requires long interviews with trained clinicians, which can further hinder assessment. However, researchers at the universities of Vermont and Michigan have developed a new approach for identifying such children using machine learning.[1] This involves tasking the children with preparing and then presenting a three-minute speech that is then interrupted after 90 and 150 seconds by a buzzer. Caregivers were then interviewed for 1-2 hours using the gold standard technique (K-SADS-PL), and completed questionnaires in order for a standard diagnosis to be provided for the child. Subsequent machine analysis of the audio data was able to identify signs of depression and anxiety in the children’s speech patterns with 80% accuracy (54% sensitivity, 93% specificity). In comparison, identifying children with depression and anxiety using the Child Behaviour Checklist (a 15-minute, parent-reported questionnaire) was found to have a lower accuracy (67-77%), though with similar sensitivity and specificity.

This process is significantly quicker and easier than the current methods used, and can hopefully led to earlier diagnosis and ensure children get the help they need while they are still developing.

— Peter Chilton, Research Fellow

Reference:

1. McGinnis EW, Anderau SP, Hruschak J, et al. Giving Voice to Vulnerable Children: Machine Learning Analysis of Speech Detects Anxiety and Depression in Early Childhood. IEEE J Biomed Health Inform. 2019; 1.

Over 40 Years of Test Tube Babies

Yes, it is more than 40 years since the birth of Louise Brown back in 1978. Test tube babies are a little smaller, even allowing for prematurity, than age-matched controls. However, a recent large database study from Finland shows that this difference disappears if the controls are siblings from the same family.[1] The cause of this family effect, is completely unknown.

The results of the Finnish study are broadly reassuring for people having in vitro fertilisation (IVF). However, some of the new methods might have unexpected risks. For example, cryopreservation and thawing of embryos apparently increases the risk of heavier babies, while keeping the embryo out of the body until the blastocyst stage may cause epigenetic changes, with unknown implications for succeeding generations. The corollary is the need for careful prospective studies of these new techniques.

— Richard Lilford, CLAHRC WM Director

Reference:

1. Goisis A, Remes H, Martikainen P, Klemetti R, Myrskylä M. Medically assisted reproduction and birth outcomes: a within-family analysis using Finnish population registers. Lancet. 2019; 393: 1225-32.

Vertical Health Care Programmes or Health System Strengthening: A False Dichotomy

Health care development is sometimes classified as vertical or horizontal. Vertical programmes target specific diseases or disease clusters. For example tuberculosis, HIV and malaria, are targeted by the Global Fund. Horizontal programmes, by contrast, seek to strengthen the system within which health care is embedded. Such programmes are concerned with human resources, financing, education, and supply chains, among many other functions.

There has been a strong push to move from vertical to horizontal programmes from many corners, including from this News Blog. Supporters of such a change in emphasis cannot but acknowledge the massive successes that vertical programmes have notched up, especially in the fields of infant health, maternal health, and infectious diseases.

However, the limitations of a purely diseased-based approach have become increasingly evident. Logically, it is not even possible to instigate a vertical approach in a complete system vacuum. For example, it would be difficult, if not impossible, to instigate a programme to improve HIV care, if the supply chain could not make drugs available and if the health system could not support basic diagnostic services. That said, vertical surfaces should not be able to siphon off more than their fair share of the health services infrastructure.

A recent Lancet paper on health services in Ethiopia made a further important point,[1] that vertical systems can make a very good platform to extend and deepen generic health systems. In fact, that is precisely what has happened in that country, with full support from the Global Fund and GAVI, the Vaccine Alliance. They refer to this combination of vertical and generic development as a “diagonal” investment approach. We would prefer to describe the relationship as one of symbiosis in which vertical and horizontal programmes are designed to reinforce each other.

The Ethiopian initiative involved strengthening the system at multiple levels, from health service financing, human resources policies, education, investment in primary care, and community outreach activities, along with support for community action and self-help (including the “IKEA model” previously described in this news blog).[2] Certainly, Ethiopia, along with other countries such as Bangladesh, Thailand and Rwanda, stand out for having achieved remarkable improvements over many dimensions of health. In Ethiopia the reduction in mortality for children under the age of five years was 67% from the 1990 baseline, while there was a 71% decline in the maternal mortality ratio and deaths from malaria, tuberculosis and HIV were halved. This took place against a financial backdrop of declining international aid but increasing domestic expenditure. The combination of vertical programmes and health system strengthening seems to have ensured that the money was not wasted.

— Richard Lilford, CLAHRC WM Director

References:

1. Assefa Y, Tesfaye D, Van Damme W, Hill PS. Effectiveness and sustainability of a diagonal investment approach to strengthen the primary health-care system in Ethiopia. Lancet. 2018; 392: 1473-81.
2. Lilford RJ. Pre-payment Systems for Access to Healthcare. NIHR CLAHRC West Midlands News Blog. 18 May 2018.