Health Outcomes, Pathogenesis and Epidemiology of Severe Acute Malnutrition (HOPE-SAM): rationale and methods of a longitudinal observational study

Introduction Mortality among children hospitalised for complicated severe acute malnutrition (SAM) remains high despite the implementation of WHO guidelines, particularly in settings of high HIV prevalence. Children continue to be at high risk of morbidity, mortality and relapse after discharge from hospital although long-term outcomes are not well documented. Better understanding the pathogenesis of SAM and the factors associated with poor outcomes may inform new therapeutic interventions. Methods and analysis The Health Outcomes, Pathogenesis and Epidemiology of Severe Acute Malnutrition (HOPE-SAM) study is a longitudinal observational cohort that aims to evaluate the short-term and long-term clinical outcomes of HIV-positive and HIV-negative children with complicated SAM, and to identify the risk factors at admission and discharge from hospital that independently predict poor outcomes. Children aged 0–59 months hospitalised for SAM are being enrolled at three tertiary hospitals in Harare, Zimbabwe and Lusaka, Zambia. Longitudinal mortality, morbidity and nutritional data are being collected at admission, discharge and for 48 weeks post discharge. Nested laboratory substudies are exploring the role of enteropathy, gut microbiota, metabolomics and cellular immune function in the pathogenesis of SAM using stool, urine and blood collected from participants and from well-nourished controls. Ethics and dissemination The study is approved by the local and international institutional review boards in the participating countries (the Joint Research Ethics Committee of the University of Zimbabwe, Medical Research Council of Zimbabwe and University of Zambia Biomedical Research Ethics Committee) and the study sponsor (Queen Mary University of London). Caregivers provide written informed consent for each participant. Findings will be disseminated through peer-reviewed journals, conference presentations and to caregivers at face-to-face meetings.

[1]  B. Amadi,et al.  Characterizing the metabolic phenotype of intestinal villus blunting in Zambian children with severe acute malnutrition and persistent diarrhea , 2018, PloS one.

[2]  C. Melby,et al.  Impact of Childhood Malnutrition on Host Defense and Infection , 2017, Clinical Microbiology Reviews.

[3]  B. Amadi,et al.  Impaired Barrier Function and Autoantibody Generation in Malnutrition Enteropathy in Zambia , 2017, EBioMedicine.

[4]  J. Berkley,et al.  Diagnostic criteria for severe acute malnutrition among infants aged under 6 mo123 , 2017, The American journal of clinical nutrition.

[5]  D. Nokes,et al.  Mortality after Inpatient Treatment for Severe Pneumonia in Children: a Cohort Study , 2017, Paediatric and perinatal epidemiology.

[6]  K. Michaelsen,et al.  Biochemical and anthropometric correlates of bio-electrical impedance parameters in severely malnourished children: A cross-sectional study. , 2017, Clinical nutrition.

[7]  M. Manary,et al.  Metabolomic Changes in Serum of Children with Different Clinical Diagnoses of Malnutrition123 , 2016, The Journal of nutrition.

[8]  M. Netea,et al.  Mortality in children with complicated severe acute malnutrition is related to intestinal and systemic inflammation: an observational cohort study12 , 2016, The American journal of clinical nutrition.

[9]  W. Petri,et al.  Environmental Enteropathy: Elusive but Significant Subclinical Abnormalities in Developing Countries , 2016, EBioMedicine.

[10]  J. Wells,et al.  Chronic disease outcomes after severe acute malnutrition in Malawian children (ChroSAM): a cohort study , 2016, The Lancet. Global health.

[11]  S. Kariuki,et al.  Daily co-trimoxazole prophylaxis to prevent mortality in children with complicated severe acute malnutrition: a multicentre, double-blind, randomised placebo-controlled trial , 2016, The Lancet. Global health.

[12]  J. Berkley,et al.  Immune Dysfunction as a Cause and Consequence of Malnutrition , 2016, Trends in immunology.

[13]  C. Jones,et al.  HIV-exposed, uninfected infants: new global challenges in the era of paediatric HIV elimination. , 2016, The Lancet. Infectious diseases.

[14]  C. Mølgaard,et al.  Bioimpedance index for measurement of total body water in severely malnourished children: Assessing the effect of nutritional oedema. , 2016, Clinical nutrition.

[15]  N. Klein,et al.  Baseline Inflammatory Biomarkers Identify Subgroups of HIV-Infected African Children With Differing Responses to Antiretroviral Therapy , 2016, The Journal of infectious diseases.

[16]  B. Amadi,et al.  Endomicroscopic and Transcriptomic Analysis of Impaired Barrier Function and Malabsorption in Environmental Enteropathy , 2016, PLoS neglected tropical diseases.

[17]  Douglas S Kwon,et al.  Altered Virome and Bacterial Microbiome in Human Immunodeficiency Virus-Associated Acquired Immunodeficiency Syndrome. , 2016, Cell host & microbe.

[18]  Michael J. Barratt,et al.  Gut bacteria that prevent growth impairments transmitted by microbiota from malnourished children , 2016, Science.

[19]  S. Moore,et al.  Urinary N-methylnicotinamide and β-aminoisobutyric acid predict catch-up growth in undernourished Brazilian children , 2016, Scientific Reports.

[20]  L. Moulton,et al.  Assessment of Environmental Enteric Dysfunction in the SHINE Trial: Methods and Challenges , 2015, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[21]  T. Ahmed,et al.  Severe Sepsis in Severely Malnourished Young Bangladeshi Children with Pneumonia: A Retrospective Case Control Study , 2015, PloS one.

[22]  C. Michelo,et al.  Mortality and morbidity patterns in under-five children with severe acute malnutrition (SAM) in Zambia: a five-year retrospective review of hospital-based records (2009–2013) , 2015, Archives of Public Health.

[23]  Tanya Yatsunenko,et al.  Functional characterization of IgA-targeted bacterial taxa from undernourished Malawian children that produce diet-dependent enteropathy , 2015, Science Translational Medicine.

[24]  J. Berkley,et al.  Severe acute malnutrition and infection , 2014, Paediatrics and international child health.

[25]  A. Briend,et al.  The Immune System in Children with Malnutrition—A Systematic Review , 2014, PloS one.

[26]  J. Warner,et al.  Mesalazine in the initial management of severely acutely malnourished children with environmental enteric dysfunction: a pilot randomized controlled trial , 2014, BMC Medicine.

[27]  Qunyuan Zhang,et al.  Persistent Gut Microbiota Immaturity in Malnourished Bangladeshi Children , 2014, Nature.

[28]  G. Chagaluka,et al.  Follow-Up of Post-Discharge Growth and Mortality after Treatment for Severe Acute Malnutrition (FuSAM Study): A Prospective Cohort Study , 2014, PloS one.

[29]  M. Ngari,et al.  Childhood Malnutrition: Toward an Understanding of Infections, Inflammation, and Antimicrobials , 2014, Food and nutrition bulletin.

[30]  T. Mduluza,et al.  Cytokine Responses to the Anti-schistosome Vaccine Candidate Antigen Glutathione-S-transferase Vary with Host Age and Are Boosted by Praziquantel Treatment , 2014, PLoS neglected tropical diseases.

[31]  T. Scriba,et al.  Distinct T-cell responses when BCG vaccination is delayed from birth to 6 weeks of age in Ugandan infants. , 2014, The Journal of infectious diseases.

[32]  J. Bartlett,et al.  Severe acute malnutrition in childhood: hormonal and metabolic status at presentation, response to treatment, and predictors of mortality. , 2014, The Journal of clinical endocrinology and metabolism.

[33]  Z. Bhutta,et al.  Treatment of severe and moderate acute malnutrition in low- and middle-income settings: a systematic review, meta-analysis and Delphi process , 2013, BMC Public Health.

[34]  R. Martorell,et al.  Maternal and child undernutrition and overweight in low-income and middle-income countries , 2013, The Lancet.

[35]  C. Rieux,et al.  Infections in Children Admitted with Complicated Severe Acute Malnutrition in Niger , 2013, PloS one.

[36]  N. Kissoon,et al.  Pediatric Post-Discharge Mortality in Resource Poor Countries: A Systematic Review , 2013, PloS one.

[37]  L. Ursell,et al.  Gut Microbiomes of Malawian Twin Pairs Discordant for Kwashiorkor , 2013, Science.

[38]  K. Maleta,et al.  Children successfully treated for moderate acute malnutrition remain at risk for malnutrition and death in the subsequent year after recovery. , 2013, The Journal of nutrition.

[39]  M. Melbye,et al.  Trichuris suis ova therapy for allergic rhinitis does not affect allergen‐specific cytokine responses despite a parasite‐specific cytokine response , 2012, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[40]  S. Moore,et al.  Early childhood growth failure and the developmental origins of adult disease: do enteric infections and malnutrition increase risk for the metabolic syndrome? , 2012, Nutrition reviews.

[41]  T. Mduluza,et al.  Integrated Analysis of Innate, Th1, Th2, Th17, and Regulatory Cytokines Identifies Changes in Immune Polarisation Following Treatment of Human Schistosomiasis , 2012, The Journal of infectious diseases.

[42]  J. Angel,et al.  Human immunodeficiency virus and the gastrointestinal immune system: does highly active antiretroviral therapy restore gut immunity? , 2012, Mucosal Immunology.

[43]  P. Gluckman,et al.  Developmental origins of non-communicable disease: Implications for research and public health , 2012, Environmental Health.

[44]  C. Huttenhower,et al.  Metagenomic microbial community profiling using unique clade-specific marker genes , 2012, Nature Methods.

[45]  Bernard Henrissat,et al.  Metabolic Reconstruction for Metagenomic Data and Its Application to the Human Microbiome , 2012, PLoS Comput. Biol..

[46]  A. Prendergast,et al.  Enteropathies in the developing world: neglected effects on global health. , 2012, The American journal of tropical medicine and hygiene.

[47]  K. Maitland,et al.  Excess child mortality after discharge from hospital in Kilifi, Kenya: a retrospective cohort analysis. , 2011, Bulletin of the World Health Organization.

[48]  P. Kazembe,et al.  Pneumonia and malnutrition are highly predictive of mortality among African children hospitalized with human immunodeficiency virus infection or exposure in the era of antiretroviral therapy. , 2011, The Journal of pediatrics.

[49]  J. Gordon,et al.  Human nutrition, the gut microbiome and the immune system , 2011, Nature.

[50]  K. Maitland,et al.  The prognostic value of dipstick urinalysis in children admitted to hospital with severe malnutrition , 2010, Archives of Disease in Childhood.

[51]  B. Amadi,et al.  Dendritic Cell Anergy Results from Endotoxemia in Severe Malnutrition1 , 2009, The Journal of Immunology.

[52]  A. Tomkins,et al.  HIV prevalence and mortality among children undergoing treatment for severe acute malnutrition in sub-Saharan Africa: a systematic review and meta-analysis. , 2009, Transactions of the Royal Society of Tropical Medicine and Hygiene.

[53]  H. Freeze,et al.  Reduced production of sulfated glycosaminoglycans occurs in Zambian children with kwashiorkor but not marasmus. , 2009, The American journal of clinical nutrition.

[54]  A. Tomkins,et al.  Nutritional recovery in HIV-infected and HIV-uninfected children with severe acute malnutrition , 2008, Archives of Disease in Childhood.

[55]  A. Tomkins,et al.  The impact of HIV on mortality during in-patient rehabilitation of severely malnourished children in Malawi. , 2008, Transactions of the Royal Society of Tropical Medicine and Hygiene.

[56]  M. Chhagan,et al.  Case management of HIV-infected severely malnourished children: challenges in the area of highest prevalence , 2008, The Lancet.

[57]  George F Borm,et al.  A simple sample size formula for analysis of covariance in randomized clinical trials. , 2007, Journal of clinical epidemiology.

[58]  K. Maitland,et al.  Bacteremia among children admitted to a rural hospital in Kenya. , 2005, The New England journal of medicine.

[59]  G. Watt,et al.  Associations of height, leg length, and lung function with cardiovascular risk factors in the Midspan Family Study , 2003, Journal of epidemiology and community health.

[60]  P. Elwood,et al.  Leg length, insulin resistance, and coronary heart disease risk: The Caerphilly Study , 2001, Journal of epidemiology and community health.

[61]  C. Leeuwenburgh,et al.  Increased oxidative stress in kwashiorkor. , 2000, The Journal of pediatrics.

[62]  C. Schofield,et al.  Why have mortality rates for severe malnutrition remained so high? , 1997, Bulletin of the World Health Organization.

[63]  P. Lunn,et al.  Factors affecting the integrity of the intestinal mucosa of Gambian children. , 1987, The American journal of clinical nutrition.

[64]  D. Douek,et al.  HIV infection and the gastrointestinal immune system , 2008, Mucosal Immunology.

[65]  P. Bahwere,et al.  Community-acquired bacteremia among hospitalized children in rural central Africa. , 2001, International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases.

[66]  M. Golden.  Oedematous malnutrition. , 1998, British medical bulletin.