Marko Kerac

Probiotics and prebiotics for severe acute malnutrition (PRONUT study): a double-blind efficacy randomised controlled trial in Malawi

BACKGROUND Severe acute malnutrition affects 13 million children worldwide and causes 1-2 million deaths every year. Our aim was to assess the clinical and nutritional efficacy of a probiotic and prebiotic functional food for the treatment of severe acute malnutrition in a HIV-prevalent setting. METHODS We recruited 795 Malawian children (age range 5 to 168 months [median 22, IQR 15 to 32]) from July 12, 2006, to March 7, 2007, into a double-blind, randomised, placebo-controlled efficacy trial. For generalisability, all admissions for severe acute malnutrition treatment were eligible for recruitment. After stabilisation with milk feeds, children were randomly assigned to ready-to-use therapeutic food either with (n=399) or without (n=396) Synbiotic2000 Forte. Average prescribed Synbiotic dose was 10(10) colony-forming units or more of lactic acid bacteria per day for the duration of treatment (median 33 days). Primary outcome was nutritional cure (weight-for-height >80% of National Center for Health Statistics median on two consecutive outpatient visits). Secondary outcomes included death, weight gain, time to cure, and prevalence of clinical symptoms (diarrhoea, fever, and respiratory problems). Analysis was on an intention-to-treat basis. This trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN19364765. FINDINGS Nutritional cure was similar in both Synbiotic and control groups (53.9% [215 of 399] and 51.3% [203 of 396]; p=0.40). Secondary outcomes were also similar between groups. HIV seropositivity was associated with worse outcomes overall, but did not modify or confound the negative results. Subgroup analyses showed possible trends towards reduced outpatient mortality in the Synbiotic group (p=0.06). INTERPRETATION In Malawi, Synbiotic2000 Forte did not improve severe acute malnutrition outcomes. The observation of reduced outpatient mortality might be caused by bias, confounding, or chance, but is biologically plausible, has potential for public health impact, and should be explored in future studies. FUNDING Department for International Development (DfID).

Health Effects of Drought: a Systematic Review of the Evidence

Introduction. Climate change projections indicate that droughts will become more intense in the 21 century in some areas of the world. The El Niño Southern Oscillation is associated with drought in some countries, and forecasts can provide advance warning of the increased risk of adverse climate conditions. The most recent available data from EMDAT estimates that over 50 million people globally were affected by drought in 2011. Documentation of the health effects of drought is difficult, given the complexity in assigning a beginning/end and because effects tend to accumulate over time. Most health impacts are indirect because of its link to other mediating circumstances like loss of livelihoods. Methods. The following databases were searched: MEDLINE; CINAHL; Embase; PsychINFO, Cochrane Collection. Key references from extracted papers were hand-searched, and advice from experts was sought for further sources of literature. Inclusion criteria for papers summarised in tables include: explicit link made between drought as exposure and human health outcomes; all study designs/methods; all countries/contexts; any year of publication. Exclusion criteria include: drought meaning shortage unrelated to climate; papers not published in English; studies on dry/arid climates unless drought was noted as an abnormal climatological event. No formal quality evaluation was used on papers meeting inclusion criteria. Results. 87 papers meeting the inclusion criteria are summarised in tables. Additionally, 59 papers not strictly meeting the inclusion criteria are used as supporting text in relevant parts of the results section. Main categories of findings include: nutrition-related effects (including general malnutrition and mortality, micronutrient malnutrition, and anti-nutrient consumption); water-related disease (including E coli, cholera and algal bloom); airborne and dust-related disease (including silo gas exposure and coccidioidomycosis); vector borne disease (including malaria, dengue and West Nile Virus); mental health effects (including distress and other emotional consequences); and other health effects (including wildfire, effects of migration, and damage to infrastructure). Conclusions. The probability of drought-related health impacts varies widely and largely depends upon drought severity, baseline population vulnerability, existing health and sanitation infrastructure, and available resources with which to mitigate impacts as they occur. The socio-economic environment in which drought occurs influences the resilience of the affected population. Forecasting can be used to provide advance warning of the increased risk of adverse climate conditions and can support the disaster risk reduction process. Despite the complexities involved in documentation, research should continue and results should be shared widely in an effort to strengthen drought preparedness and response activities.

Operational implications of using 2006 World Health Organization growth standards in nutrition programmes: secondary data analysis

Objective To assess the implications of adopting the World Health Organization 2006 growth standards in combination with current diagnostic criteria in emergency and non-emergency child feeding programmes. Design Secondary analysis of data from three standardised nutrition surveys (n=2555) for prevalence of acute malnutrition, using weight for height z score (<−2 and <−3) and percentage of the median (<80% and <70%) cut-offs for moderate and severe acute malnutrition from the National Center for Health Statistics/WHO growth reference (NCHS reference) and the new WHO 2006 growth standards (WHO standards). Setting Refugee camps in Algeria, Kenya, and Bangladesh. Population Children aged 6-59 months. Results Important differences exist in the weight for height cut-offs used for defining acute malnutrition obtained from the WHO standards and NCHS reference data. These vary according to a childs height and according to whether z score or percentage of the median cut-offs are used. If applied and used according to current practice in nutrition programmes, the WHO standards will result in a higher measured prevalence of severe acute malnutrition during surveys but, paradoxically, a decrease in the admission of children to emergency feeding programmes and earlier discharge of recovering patients. The expected impact on case fatality rates of applying the new standards in conjunction with current diagnostic criteria is unknown. Conclusions A full assessment of the appropriate use of the new WHO standards in the diagnosis of acute malnutrition is urgently needed. This should be completed before the standards are adopted by organisations that run nutrition programmes targeting acute malnutrition.

Follow-up of post-discharge growth and mortality after treatment for severe acute malnutrition (FuSAM study): a prospective cohort study.

Background Management of Severe Acute Malnutrition (SAM) plays a vital role in achieving global child survival targets. Effective treatment programmes are available but little is known about longer term outcomes following programme discharge. Methods From July 2006 to March 2007, 1024 children (median age 21.5 months, IQR 15–32) contributed 1187 admission episodes to an inpatient-based SAM treatment centre in Blantyre, Malawi. Long term outcomes, were determined in a longitudinal cohort study, a year or more after initial programme discharge. We found information on 88%(899/1024). Results In total, 42%(427/1024) children died during or after treatment. 25%(105/427) of deaths occurred after normal programme discharge, >90 days after admission. Mortality was greatest among HIV seropositive children: 62%(274/445). Other risk factors included age <12 months; severity of malnutrition at admission; and disability. In survivors, weight-for-height and weight-for-age improved but height-for-age remained low, mean −2.97 z-scores (SD 1.3). Conclusions Although SAM mortality in this setting was unacceptably high, our findings offer important lessons for future programming, policy and research. First is the need for improved programme evaluation: most routine reporting systems would have missed late deaths and underestimated total mortality due to SAM. Second, a more holistic view of SAM is needed: while treatment will always focus on nutritional interventions, it is vital to also identify and manage underlying clinical conditions such as HIV and disability. Finally early identification and treatment of SAM should be emphasised: our results suggest that this could improve longer term as well as short term outcomes. As international policy and programming becomes increasingly focused on stunting and post-malnutrition chronic disease outcomes, SAM should not be forgotten. Proactive prevention and treatment services are essential, not only to reduce mortality in the short term but also because they have potential to impact on longer term morbidity, growth and development of survivors.

Prevalence of wasting among under 6-month-old infants in developing countries and implications of new case definitions using WHO growth standards: a secondary data analysis

Objectives To determine wasting prevalence among infants aged under 6 months and describe the effects of new case definitions based on WHO growth standards. Design Secondary data analysis of demographic and health survey datasets. Setting 21 developing countries. Population 15 534 infants under 6 months and 147 694 children aged 6 to under 60 months (median 5072 individuals/country, range 1710–45 398). Wasting was defined as weight-for-height z-score <−2, moderate wasting as −3 to <−2 z-scores, severe wasting as z-score <−3. Results Using National Center for Health Statistics (NCHS) growth references, the nationwide prevalence of wasting in infant under-6-month ranges from 1.1% to 15% (median 3.7%, IQR 1.8–6.5%; ∼3 million wasted infants <6 months worldwide). Prevalence is more than doubled using WHO standards: 2.0–34% (median 15%, IQR 6.2–17%; ∼8.5 million wasted infants <6 months worldwide). Prevalence differences using WHO standards are more marked for infants under 6 months than children, with the greatest increase being for severe wasting (indicated by a regression line slope of 3.5 for infants <6 months vs 1.7 for children). Moderate infant-6-month wasting is also greater using WHO, whereas moderate child wasting is 0.9 times the NCHS prevalence. Conclusions Whether defined by NCHS references or WHO standards, wasting among infants under 6 months is prevalent in many of the developing countries examined in this study. Use of WHO standards to define wasting results in a greater disease burden, particularly for severe wasting. Policy makers, programme managers and clinicians in child health and nutrition programmes should consider resource and risk/benefit implications of changing case definitions.

Influenza vaccination for immunocompromised patients: systematic review and meta-analysis from a public health policy perspective.

Background Immunocompromised patients are vulnerable to severe or complicated influenza infection. Vaccination is widely recommended for this group. This systematic review and meta-analysis assesses influenza vaccination for immunocompromised patients in terms of preventing influenza-like illness and laboratory confirmed influenza, serological response and adverse events. Methodology/Principal Findings Electronic databases and grey literature were searched and records were screened against eligibility criteria. Data extraction and risk of bias assessments were performed in duplicate. Results were synthesised narratively and meta-analyses were conducted where feasible. Heterogeneity was assessed using I2 and publication bias was assessed using Beggs funnel plot and Eggers regression test. Many of the 209 eligible studies included an unclear or high risk of bias. Meta-analyses showed a significant effect of preventing influenza-like illness (odds ratio [OR] = 0.23; 95% confidence interval [CI] = 0.16–0.34; p<0.001) and laboratory confirmed influenza infection (OR = 0.15; 95% CI = 0.03–0.63; p = 0.01) through vaccinating immunocompromised patie nts compared to placebo or unvaccinated controls. We found no difference in the odds of influenza-like illness compared to vaccinated immunocompetent controls. The pooled odds of seroconversion were lower in vaccinated patients compared to immunocompetent controls for seasonal influenza A(H1N1), A(H3N2) and B. A similar trend was identified for seroprotection. Meta-analyses of seroconversion showed higher odds in vaccinated patients compared to placebo or unvaccinated controls, although this reached significance for influenza B only. Publication bias was not detected and narrative synthesis supported our findings. No consistent evidence of safety concerns was identified. Conclusions/Significance Infection prevention and control strategies should recommend vaccinating immunocompromised patients. Potential for bias and confounding and the presence of heterogeneity mean the evidence reviewed is generally weak, although the directions of effects are consistent. Areas for further research are identified.

HIV prevalence in severely malnourished children admitted to nutrition rehabilitation units in Malawi: Geographical & seasonal variations a cross-sectional study

BackgroundSevere malnutrition in childhood associated with HIV infection presents a serious humanitarian and public health challenge in Southern Africa. The aim of this study was to collect country wide data on HIV infection patterns in severely malnourished children to guide the development of integrated care in a resource limited setting.MethodsA cross sectional survey was conducted in 12 representative rural and urban Nutrition Rehabilitation Units (NRUs), from each of Malawis 3 regions.All children and their caretakers admitted to each NRU over a two week period were offered HIV counselling and testing. Testing was carried out using two different rapid antibody tests, with PCR testing for discordant results. Children under 15 months were excluded, to avoid difficulties with interpretation of false positive rapid test results.The survey was conducted once in the dry/post-harvest season, and repeated in the rainy/hungry season.Results570 children were eligible for study inclusion. Acceptability and uptake of HIV testing was high: 523(91.7%) of carers consented for their children to take part; 368(70.6%) themselves accepted testing.Overall HIV prevalence amongst children tested was 21.6%(95% confidence intervals, 18.2–25.5%). There was wide variation between individual NRUs: 2.0–50.0%.Geographical prevalence variations were significant between the three regions (p < 0.01) with the highest prevalence being in the south: Northern Region 23.1%(95%CI 14.3–34.0%), Central Region 10.9%(95%CI 7.5–15.3%), and Southern Region 36.9%(95%CI 14.3–34.0%).HIV prevalence was significantly higher in urban areas, 32.9%(95%CI 26.8–39.4%) than in rural 13.2%(95%CI 9.5–17.6%)(p < 0.01).NRU HIV prevalence rates were lower in the rainy/hungry season 18.4%(95%CI 14.7–22.7%) than in the dry/post-harvest season 30.9%(95%CI 23.2–39.4%) (p < 0.001%).ConclusionThere is a high prevalence of HIV infection in severely malnourished Malawian children attending NRUs with children in urban areas most likely to be infected. Testing for HIV is accepted by their carers in both urban and rural areas. NRUs could act as entry points to HIV treatment and support programmes for affected children and families. Recognition of wide geographical variations in childhood HIV prevalence will ensure that limited resources are initially targeted to areas of highest need.These findings may have implications for the other countries with similar patterns of childhood illness and food insecurity.

Chronic disease outcomes after severe acute malnutrition in Malawian children (ChroSAM): a cohort study

Summary Background Tackling severe acute malnutrition (SAM) is a global health priority. Heightened risk of non-communicable diseases (NCD) in children exposed to SAM at around 2 years of age is plausible in view of previously described consequences of other early nutritional insults. By applying developmental origins of health and disease (DOHaD) theory to this group, we aimed to explore the long-term effects of SAM. Methods We followed up 352 Malawian children (median age 9·3 years) who were still alive following SAM inpatient treatment between July 12, 2006, and March 7, 2007, (median age 24 months) and compared them with 217 sibling controls and 184 age-and-sex matched community controls. Our outcomes of interest were anthropometry, body composition, lung function, physical capacity (hand grip, step test, and physical activity), and blood markers of NCD risk. For comparisons of all outcomes, we used multivariable linear regression, adjusted for age, sex, HIV status, and socioeconomic status. We also adjusted for puberty in the body composition regression model. Findings Compared with controls, children who had survived SAM had lower height-for-age Z scores (adjusted difference vs community controls 0·4, 95% CI 0·6 to 0·2, p=0·001; adjusted difference vs sibling controls 0·2, 0·0 to 0·4, p=0·04), although they showed evidence of catch-up growth. These children also had shorter leg length (adjusted difference vs community controls 2·0 cm, 1·0 to 3·0, p<0·0001; adjusted difference vs sibling controls 1·4 cm, 0·5 to 2·3, p=0·002), smaller mid-upper arm circumference (adjusted difference vs community controls 5·6 mm, 1·9 to 9·4, p=0·001; adjusted difference vs sibling controls 5·7 mm, 2·3 to 9·1, p=0·02), calf circumference (adjusted difference vs community controls 0·49 cm, 0·1 to 0·9, p=0·01; adjusted difference vs sibling controls 0·62 cm, 0·2 to 1·0, p=0·001), and hip circumference (adjusted difference vs community controls 1·56 cm, 0·5 to 2·7, p=0·01; adjusted difference vs sibling controls 1·83 cm, 0·8 to 2·8, p<0·0001), and less lean mass (adjusted difference vs community controls −24·5, −43 to −5·5, p=0·01; adjusted difference vs sibling controls −11·5, −29 to −6, p=0·19) than did either sibling or community controls. Survivors of SAM had functional deficits consisting of weaker hand grip (adjusted difference vs community controls −1·7 kg, 95% CI −2·4 to −0·9, p<0·0001; adjusted difference vs sibling controls 1·01 kg, 0·3 to 1·7, p=0·005,)) and fewer minutes completed of an exercise test (sibling odds ratio [OR] 1·59, 95% CI 1·0 to 2·5, p=0·04; community OR 1·59, 95% CI 1·0 to 2·5, p=0·05). We did not detect significant differences between cases and controls in terms of lung function, lipid profile, glucose tolerance, glycated haemoglobin A1c, salivary cortisol, sitting height, and head circumference. Interpretation Our results suggest that SAM has long-term adverse effects. Survivors show patterns of so-called thrifty growth, which is associated with future cardiovascular and metabolic disease. The evidence of catch-up growth and largely preserved cardiometabolic and pulmonary functions suggest the potential for near-full rehabilitation. Future follow-up should try to establish the effects of puberty and later dietary or social transitions on these parameters, as well as explore how best to optimise recovery and quality of life for survivors. Funding The Wellcome Trust.

The Interaction of Malnutrition and Neurologic Disability in Africa

Malnutrition and neurodisability are both major public health problems in Africa. This review highlights key areas where they interact. This happens throughout life and starts with maternal malnutrition affecting fetal neurodevelopment with both immediate (eg, folate deficiency causing neural tube defects) and lifelong implications (eg, impaired cognitive function). Maternal malnutrition can also increase the risk of perinatal problems, including birth asphyxia, a major cause of neurologic damage and cerebral palsy. Macronutrient malnutrition can both cause and be caused by neurodisability. Mechanisms include decreased food intake, increased nutrient losses, and increased nutrient requirement. Specific micronutrient deficiencies can also lead to neurodisability, for example, blindness (vitamin A), intractable epilepsy (vitamin B6), and cognitive impairment (iodine and iron). Toxin ingestion (eg, from poorly processed cassava) can cause neurodisability including a peripheral polyneuropathy and a spastic paraparesis. We conclude that there is an urgent need for nutrition and disability programs to work more closely together.

Improving the management of severe acute malnutrition in an area of high HIV prevalence.

AIM To assess the clinical outcomes of a combined approach to the treatment of severe acute malnutrition in an area of high HIV prevalence using: (i) an initial inpatient phase, based on WHO guidelines and (ii) an outpatient recovery phase using ready-to-use therapeutic food. METHODS An operational prospective cohort study implemented in a referral hospital in Southern Malawi between May 2003 and 2004. Patient outcomes were compared with international standards and with audits carried out during the year preceding the study. RESULTS Inpatient mortality was 18% compared to 29% the previous year. Programme recovery rate was 58.1% compared to 45% the previous year. The overall programme mortality rate was 25.7%. Of the total known HIV seropositive children, 49.5% died. CONCLUSIONS Inpatient mortality and cure rates improved compared to pre-study data but the overall mortality rate did not meet international standards. Additional interventions will be needed if these standards are to be achieved.