Global Nutrition Review. Systematic Review of Management of Childhood Severe Malnutrition

Transcription

1 Global Nutrition Review Systematic Review of Management of Childhood Severe Malnutrition Tahmeed Ahmed, A.M. Shamsir Ahmed, Mustafa Mahfuz, Kawsari Abdullah, Alejandro Cravioto, David Sack ICDDR,B Global Nutrition Review Team Mainstreaming Nutrition Initiative June 2007

2 Introduction About 10 million under-five children are suffering from severe acute malnutrition (SAM) which is defined as severe wasting (weight-for-height less than -3 standard deviations) and/or the presence of bipedal edema (1). In Bangladesh, for example, a quarter of a million children are currently severely wasted (2). These children are very susceptible to infections and death. Although data on mortality rates among severely malnourished children living in the community are sparse, case-fatality rates of children hospitalized for severe malnutrition (and acute illnesses) range typically from 10-40% (3). Childhood mortality reduction, as envisaged in the Millennium Development Goal 4, will not be possible unless sustained efforts are taken to properly manage children with severe malnutrition and to contain case-fatality rates. A recent study in hospitals in rural South Africa has shown a high case-fatality rate (CFR) of 32% (4). An overall CFR of 26% has been reported from North-eastern Zambia, with 13% for children with kwashiorkor, 19% for marasmus, and 28% for marasmic kwashiorkor (5). This extremely high CFR has been attributed to faulty case management, lack of staff motivation and commitment, and overall neglect shown to the field of malnutrition treatment in the past (3, 5, 6). The introduction of a standardized protocol for the management of SAM and appropriate training of staff results in a reduction in CFR by as much as 50% (4, 7). The key elements of the protocol are early initiation of appropriate feeding, broad-spectrum antimicrobial therapy, micronutrient supplementation, slow rehydration with emphasis on oral rehydration, and expedient management of complications (8). As these elements are based on the WHO treatment guidelines for severe malnutrition (9), which have been found to result in reduced CFR in many centers. A generic training course has been developed by the WHO; centers whose staff received the training have been able to substantially reduce case fatality among children with severe malnutrition (10). Because the number of facilities is always sub-optimal in developing countries, facilitybased treatment cannot cater to the huge numbers of severely malnourished children living in the community. Moreover, feeding therapeutic diets including F-75 and F-100 at home is not recommended because of the propensity of these liquid diets to become contaminated in the home environment. Therapeutic feeding centres (TFCs) for taking care of severely malnourished children in emergency settings have huge requirements for resources, skilled staff and, often, imported therapeutic food (11). This makes the approach expensive and the coverage low in emergency settings (12). To overcome this problem, ready-to-use-therapeutic food (RUTF) has been developed and used in field situations (13). Collins and Sadler have reported its use in emergency relief programs (14). If prepared as per prescription, RUTF has the nutrient composition of F-100 but is more energy dense and does not contain any water. Bacterial contamination, therefore, does not occur and the food is safe for use also in home conditions. The prototype RUTF (Plumpynut, Nutriset, France) is made of peanut paste, milk powder, vegetable oil, mineral and vitamin mix as per WHO recommendations. It is available as a paste in a sachet, does not require any cooking and children can eat directly from the sachet. Local production of RUTF has commenced recently and several studies have concluded that local RUTF is as good as the prototype RUTF (15).

3 The purpose of this review is to find out the evidence for efficacy/effectiveness of WHO guidelines for management of severe malnutrition and the role of RUTF in communitybased management of severe malnutrition. Search Strategy Pre-set search methods were used to search and retrieve reports of controlled trails using the electronic data base PubMed. Manual searching was used as well as a search of the Cochrane Library. An initial search combining all search key words retrieved 119 articles where as a second search using a combination shown below yielded 276 articles. Only 25 and 44 articles related to management of severe malnutrition were initially selected from the two searches. A total of 21 original articles (as opposed to review papers or reports) were finally selected for the analyses because they were based on clinical trials. Additionally, reports of consultation meetings were also used. Electronic search of databases was done as well as hand search of other documents including agency reports etc. The concept of RUTF and community-based management of SAM being relatively new, not many papers were found. Of them, papers based on controlled trails are few. A brief description of service statistics and controlled trials of RUTF in the management of severe malnutrition follows. In order to evaluate the effects of RUTF on management of childhood severe acute malnutrition, literature search was undertaken on PubMed database. The date of last search was 11 June 2007 and it yielded only 19 articles related to RUTF. By hand search we selected 4 articles. Finally 5 articles were selected for the impact estimation; these articles are related to controlled trials on RUTF. Meta-analyses were done to estimate effects on weight gain of children during rehabilitation phase with RUTF and also among the moderately malnourished children. The RevMan software (version 4.2.8, RevMan 2003) was used for the meta-analysis. Search key words 1. severe malnutrition*[text Word] OR severe malnutrition[title/abstract] 2. therapy*[text Word] OR therapy[title/abstract] 3. management*[text Word] OR management[title/abstract] 4. treatment*[text Word] OR treatment[title/abstract] 5. (Child*[Text Word] OR Child[MeSH Terms] OR Child[Title/Abstract] OR infant*[text Word] OR infant[mesh Terms] OR Infant[Title/Abstract] OR baby*[text Word] OR babies*[text Word] OR pre-school*[text Word] OR preschool*[text Word]) 6. randomized controlled trial[publication Type] OR controlled clinical trial[publication Type] OR randomized controlled trials [MeSH Terms] OR random allocation [MeSH Terms] OR double-blind method [MeSH Terms] OR

4 single-blind method [MeSH Terms] OR clinical trial [Publication Type] OR clinical trials [MeSH Terms] OR ( clinical trial [Text Word]) OR ((singl*[text Word] OR doubl*[text Word] OR trebl*[text Word] OR tripl*[text Word]) AND (mask*[text Word] OR blind*[text Word])) OR ( latin square [Text Word]) OR placebos [MeSH Terms] OR placebo*[text Word] OR random*[text Word] OR research design [mh:noexp] OR comparative study [MeSH Terms] OR evaluation studies[mesh Terms] OR follow-up studies[mesh Terms] OR prospective studies [MeSH Terms] OR cross-over studies [MeSH Terms] OR control*[text Word] OR prospectiv*[text Word] OR volunteer*[text Word] Limit Human And also used following key in the second search #6 AND #5 AND Malnutrition Management Limit Human Level of Evidence from Literature Level of Type of evidence evidence 1++ High quality meta-analyses, systematic reviews of RCTs (including cluster RCTs), or RCTs with a very low risk of bias 1+ Well conducted meta-analyses, systematic reviews of RCTs, or RCTs with a low risk of bias 1 * Meta-analyses, systematic reviews of RCTs, or RCTs with a high risk of bias 2++ High quality systematic reviews of, or individual high quality nonrandomised intervention studies (controlled non-randomised trial, controlled before-and-after, interrupted time series), comparative cohort and correlation studies with a very low risk of confounding, bias or chance 2+ Well conducted, non-randomised intervention studies (controlled nonrandomised trial, controlled before-and-after, interrupted time series), comparative cohort and correlation studies with a low risk of confounding, bias or chance 2 * Non-randomised intervention studies (controlled non-randomised trial, controlled before-and-after, interrupted time series), comparative cohort and correlation studies with a high risk of confounding, bias or chance 3 Non-analytical studies (eg case reports, case series) 4 Expert opinion, formal consensus * Studies with a level of evidence ( ) should not be used as a basis for making recommendations Source: adapted from SIGN (2001)

5 Results This review looked at the evidence of efficacy (implementation under ideal conditions) of different types of interventions focusing on management of childhood severe malnutrition. The interventions included facility-based as well as community-based management. Facility-based management refers to the treatment in a health care facility of the acutely ill, severely malnourished child. -based management means treatment provided at home with some external input that may include help from a health worker, treatment from a primary health care clinic, or in a day-care center to achieve catch-up growth. The level of evidence was considered highest when a paper published in a peer-reviewed journal was based on high quality meta-analyses, or systematic review of randomized controlled trials (RCTs), or RCTs with a very low risk of bias. Papers based on retrospective studies, expert opinion, or formal consensus carried least evidence on a scale of 1 to 5 with lower the scale, robust the level of evidence. Out of the 21 studies reported as original articles, 12 studies had a level of evidence of 2+ or more. A meta-analysis was performed using results pooled from 9 studies evaluating the efficacy of the WHO guidelines in reducing the case fatality rate of children with SAM (Figure 1). Only two studies did not show any impact. However, the overall relative risk was 0.52 (95% CI 0.43, 0.64), suggesting that the risk of death is reduced by 48% if the WHO guidelines are followed instead of conventional treatment (no routine antibiotics, no standardized feeding with therapeutic diets F-75 and F-100, less caution in the use of intravenous and oral rehydration fluids during rehydration, suboptimal management of micronutrient and electrolyte deficiencies, etc). The WHO guidelines for the management of severe malnutrition represent a major advancement in the area. The need now is for further refinement of the guidelines to improve efficacy and effectiveness and for the development of complementary guidelines that address malnutrition in community settings. The WHO guidelines do not address the management of infants less 6 months of age. Effective management of severe malnutrition in emergencies and disaster situations also needs more emphasis in the WHO guidelines. -based management (CBM) involves identification of children with severe acute malnutrition (SAM), treating SAM children with complications in a facility following WHO guidelines, and managing SAM children without complications at home providing rations of RUTF. In emergency situations, provision of supplementary feeding is a pre-requisite for a better program outcome. A mid-upper arm circumference of less than 110 mm is a suitable criterion to identify SAM children in the community aged 6-59 months since it is a good predictor of death among these children and is easier to measure than weight and height. RUTF can be used successfully to treat SAM children more than 6 months old in the community. Service data from field programs show that management of severe malnutrition at home can be effective and achieve high coverage. Case-fatality rates among 23,511 unselected severely malnourished children treated in 21 programs of community-based therapeutic care in Malawi, Ethiopia, and Sudan, between 2001 and 2005, was 4 1%, with recovery and default rates 79 4% and 11 0% respectively (16). However, there is a need to exercise caution when extrapolating these results to settings with different resources, staff skills and levels of malnutrition (17). The provision of RUTF in countries like India, Pakistan or Bangladesh where the burden of SAM is very

6 high, will be challenging. When families have access to nutrient-dense foods, SAM without complications can be managed at home without RUTF, by means of diets made from low-cost family food and providing micronutrients, as has been shown in Bangladesh (18). There is a need for further documenting the efficacy, cost-effectiveness and sustainability of CBM using RUTF in Asian countries plagued with highest burdens of SAM. Research on identification of SAM infants less than 6 months of age as well diets appropriate for them are now considered as priority. The authors acknowledge the paucity of published data based on controlled trials of RUTF. Some of the published articles do not show a level playing field for comparison. However, meta-analysis (Figure 2) reveals an advantage of weight gain of 3.0 g/kg/day (WMD= 3.0; 95% CI= -1.70, 7.70) in favor of RUTF against F-100, although the results were not significant when the random effects model was used. RUTF has also been compared with maize/soy flour in managing severely malnourished children during the nutritional rehabilitation phase. It was found to significantly increase weight gain by 2.10 g/kg/day (WMD= 2.10; 95% CI= 1.97, 2.23) (Figure 3). We also investigated the use of RUTF in promoting growth of moderately malnourished children. RUTF in such children was associated with significant increment in weight gain by 1.36 g/kg/day (WMD= 1.36; 95% CI= 0.33, 2.40) (Figure 4).

7 Figure 1. Meta-analysis of the efficacy of WHO guidelines in management of severe acute malnutrition Review: Facility-based treatment of SAM Comparison: 01 Mortality Outcome: 01 Mortality Study Treatment control RR (random) RR (random) or sub-category n/n n/n 95% CI 95% CI Ahmed T /334 49/ [0.35, 0.82] Ashworth /48 12/ [0.23, 0.90] Ashworth 2004a 18/98 18/ [0.41, 1.29] Deen /125 10/ [0.29, 0.99] Deen 2003a 7/39 16/ [0.41, 2.03] Falbo A. 19/117 47/ [0.30, 0.77] Nu Shwe T /186 25/ [0.30, 0.97] Nu Shwe T 2003a 3/66 10/ [0.07, 0.86] Wilkinson D 8/138 32/ [0.14, 0.62] Total (95% CI) [0.43, 0.64] Total events: 134 (Treatment), 219 (control) Test for heterogeneity: Chi² = 7.12, df = 8 (P = 0.52), I² = 0% Test for overall effect: Z = 6.33 (P < ) Favours Treatment Treatment: WHO guidelines; Control: non-who guidelines Favours Control

8 Figure 2. Meta-analysis of the efficacy of home-based RUTF treatment and standard facility-based treatment with F-100 during rehabilitation of children with severe acute malnutrition Review: Comparison: Outcome: Efficacy of RUTF in managment of severe acute malnutrition 03 RUTF supplement at home and standard therary 01 RUTF supplement or standard therapy and weight gain (g/kg/day) Study RUTF F-100 WMD (random) WMD (random) or sub-category N Mean (SD) N Mean (SD) 95% CI 95% CI Cilberto MA (4.30) (8.80) 0.70 [-0.96, 2.36] Diop el HI (6.15) (3.36) 5.50 [2.99, 8.01] Total (95% CI) [-1.70, 7.70] Test for heterogeneity: Chi² = 9.77, df = 1 (P = 0.002), I² = 89.8% Test for overall effect: Z = 1.25 (P = 0.21) Favours control Favours intervention Figure 3. Meta-analysis of the efficacy of home-based RUTF treatment and maize/soy flour supplementation during rehabilitation of children with severe acute malnutrition Review: Comparison: Outcome: Efficacy of RUTF in managment of severe acute malnutrition 02 RUTF and maize/soy flour supplement at home 01 RUTF or maize/soy flour supplementation at home and weight gain (g/kg/day) Study RUTF Maize flour WMD (random) WMD (random) or sub-category N Mean (SD) N Mean (SD) 95% CI 95% CI Manary MJ (0.50) (0.30) 2.10 [1.97, 2.23] Total (95% CI) [1.97, 2.23] Test for heterogeneity: not applicable Test for overall effect: Z = (P < ) Favours control Favours treatment

9 Figure 4. Meta-analysis of the efficacy of home-based RUTF treatment and cereal supplementation in children with moderate acute malnutrition Review: Comparison: Outcome: Efficacy of RUTF in managment of severe acute malnutrition 04 Efficacy of RUTF in promoting growth of moderately malnourished children 01 Weight gain (g/kg/day) Study RUTF Corn flour WMD (random) WMD (random) or sub-category N Mean (SD) N Mean (SD) 95% CI 95% CI Maleta (3.46) (3.26) 0.54 [-1.15, 2.23] Patel (2.70) (2.50) 1.70 [0.88, 2.52] Total (95% CI) [0.33, 2.40] Test for heterogeneity: Chi² = 1.47, df = 1 (P = 0.23), I² = 31.9% Test for overall effect: Z = 2.59 (P = 0.009) Summary of review Favours control Favours treatment 1. The WHO guidelines are effective in reducing case fatality rate of children with severe acute malnutrition (SAM). 2. Because of the relatively new concept, electronic as well as hand search revealed not many papers on RUTF and its role in the management of severe malnutrition. 3. RUTF seems to play an important role in the management of severe malnutrition in disaster and emergency settings. A supplementary feeding program providing food rations to families of the affected child should be in place. So should be a stabilization centre for taking care of acutely ill severely malnourished children who need facility-based care based on WHO guidelines. 4. For countries in Asia including India, Bangladesh and Pakistan which have the highest burden of child malnutrition, there is a need for research on cost-effectiveness and sustainability of management of severe malnutrition using ready-to-use-therapeutic food (RUTF).

10 Table 1: Characteristics of articles on RUTF included in the review Author/year Country Design Sample size Setting Intervention Diop 2003 (19) Senegal Open labeled, randomized trial RUTF n=35, F-100 n=35 Seventy 6-36 months old children, severely malnourished on admission, or WHZ score <-2 after edema resolved. Manary 2004 (20) Malawi Controlled trial, with systemic allocation Maleta 2004 (21) Malawi Controlled trial, randomization and allocation not mentioned HIV-negative, severely malnourished children aged months. These children were enrolled during rehabilitation phase for comparing three different diets : RUTF (n=69); RUTF supplement (n=96); maize/soy flour (n=117) as home-based therapy. Underweight and stunted, months old children recruited from the community, RUTF n=30, maize/soy n=31. Facility The children received either 3 meals of F-100 or RUTF daily ad libitum. Weight gain measured when children reached WFH z score On average, weight gain during the rehabilitation phase was 10.1 g/kg body weight/day (95% CI: 8.7, 11.4) in the F-100 group and 15.6 g/kg body weight/day (95% CI: 13.4, 17.8) in the RUTF group (P < 0.001). The average duration of rehabilitation was 17.3 days (95% CI: 15.6, 19.0) in the F-100 group and 13.4 days (95% CI: 12.1, 14.7) in the RUTF group (P < 0.001). The first dietary group received RUTF in a quantity sufficient to meet their nutrient requirements for full catch-up growth (175 kcal/kg/day). The second group received a multivitamin/mineral fortified RUTF supplement providing about 33% (25 50%) of the daily energy requirement. The third group was given enough maize/soy flour to feed the entire nuclear family, including the affected child, who received a quantity sufficient for full catch-up growth, and a separate multivitamin/mineral supplement. Participants had a WHZ range from -1.8 to -2.0, and 81% to 84% had edema. The primary outcome for the study was reaching graduation weight; secondary outcomes were rate of weight gain, rate of stature growth, rate of growth in MUAC, prevalence of infectious symptoms, and anthropometric indices six months after graduation. Over a period of 12 weeks, children were provided with one of two supplements: RUTF (92 g/day) or maize and soy flour (140g/day).

11 Author/year Ciliberto 2005 (22) Country Design Sample size Setting Intervention Malawi CT, instead of randomization, Facility and prospective systematic allocation with stepped wedge design was used. Patel 2005 (23) Malawi Controlled trial. A steppedwedge design with systematic allocation was used for assigning children Children aged mo in the NRU as well as children brought by caretakers from the surrounding community were screened for eligibility for the second phase of treatment for childhood malnutrition. Standard therapy with F- 100, n=186; home-based therapy with RUTF, n=992 Children, aged months at risk of malnutrition, weight-forheight 80-85% without edema. RUTF (n=331) or micronutrient-fortified corn/soy-blend (n=41). Home-based RUTF and standard therapy in children with moderate and severe wasting. Malawian criteria for nutritional status used rather than the WHO criteria. Comparison between standard therapy and home-based therapy done in a subgroup (WHZ < -3z). Two supplementary foods (RUTF and Corn soy blend) given for 8 weeks in children at risk for development of malnutrition. The primary outcomes were recovery, defined as weight-for-height >90%, and the rate of weight gain. Table 2: Characteristics of articles on RUTF excluded from the review Author/year Country Design Sample size Setting Intervention Briend 1999 (13) Chad Observational study 20 severely malnourished children Facility Safety trial for RUTF Collins 2002 (14) Ethiopia Retrospective study, no control Assessed clinical records of 170 children aged months, either marasmus, kwashiorkor or marasmic kwashiorkor. RUTF rations after getting treatment (?acute phase) from outpatient therapeutic feeding program site. Outcomes were mortality, default from program, discharge from the program, rate of weight gain and length of stay in program.

12 Author/year Country Design Sample size Setting Intervention Sandige 2004 (15) Malawi Controlled trial with systematic allocation Ndekha 2005 (24) Malawi Controlled trial, with systemic allocation Colorado 2005 (25) Sierra Leone Clinical trial, treatment group alternately received BP-100 and F-100 Children aged 1 to 5 years discharged from the NRU upon resolution of complications and return of appetite were eligible for home-based therapy: local RUTF (n= 135), imported RUTF (n= 125) HIV-infected, severely malnourished children aged months. These children were enrolled during rehabilitation phase for comparing three different diets: RUTF (n=20), RUTF supplement (n=28) Maize/soy flour (n=45) Non breastfed, age between months and approaching the end of transition phase of standard therapy. Control group (F-100) n=26 Mixed group (F-100 and BP-100) n=25 Facility Children received home therapy with either imported, commercially produced RUTF or locally produced RUTF. The first dietary group received RUTF in a quantity sufficient to meet their nutrient requirements for full catch-up growth (175 kcal/kg/day). The second group received a multivitamin/mineral fortified RUTF supplement providing about 33% (25 50%) of the daily energy requirement. The third group was given enough maize/soy flour to feed the entire nuclear family, including the affected child, who received a quantity sufficient for full catch-up growth, and a separate multivitamin/mineral supplement. During the first 3 days of the rehabilitation phase, patients in the study group received F-100, with one of the meals replaced by equivalent quantity (in kcals) of BP-100. From day 4 the mixed group received 6 alternate meals of F-100 and BP-100. Chaiken 2006 (26) Ethiopia Observational study Not mentioned Measured coverage of CTC and compared with Sphere indicators

13 Author/year Ciliberto 2006 (27) Country Design Sample size Setting Intervention Malawi Observational study Children aged mo presenting the NRU Each participant was given enough RUTF and the recommended daily intake of micronutrients. No antibiotics or additional vitamin A were given to the participants. Participation lasted 8 wk. Children were discharged from follow-up before 8 wk if they reached a weight-for-height z score /0 based on their admission height, clinically relapsed (recurrence of oedema or evidence of systemic infection) or died. Children who did not return for two consecutive follow-up visits were visited at home to determine whether they had died or relapsed. The three primary outcomes were recovery, resolution of edema within 4 wk and attainment of WHZ>-/2; failure to gain weight, or relapse and death. Collins 2006 (28) Review Case-fatality rates among 23,511 unselected severely malnourished children treated in 21 programs of community-based therapeutic care in Malawi, Ethiopia, and Sudan, between 2001 and 2005, was 4 1%, with recovery and default rates 79 4% and 11 0% respectively. 74% of these severely malnourished children were treated solely as outpatients. Average coverage was 72 5% substantially higher than coverage rates seen in comparable centre-based programs which are often less than 10%. Tectonidis 2006 (29) Linneman 2007 (30) Niger Observational study Children Author describes the experiences of management acute malnutrition in a crisis situation with few data. Malawi Observational study Children aged 6-60 months either moderate or severely malnourished, severe malnutrition n=2131, moderate malnutrition n=806. Locally produced RUTF for 8 weeks, discharge if they reached WHZ >0 before 8 weeks. Collins 2007 (31) Review Almost similar to Collins 2006 review Food Nutr Bull Sep;27(3 Suppl), SCN Nutrition Policy paper no.21 also reviewed. No article selected for meta-analyses from the supplement, as all the studies already reviewed separately and included in the table 1 and 2.

14 References 1. WHO/SCN report, Ahmed T, Roy SK, Alam N, et al. Baseline survey National Nutrition Programme. ISBN: ; Special publication No. 124, ICDDR,B, December Schofield C, Ashworth A. Why have mortality rates for severe malnutrition remained so high? Bulletin of the World Health Organization 1996;74: Puoane T, Sanders D, Chopra M, Ashworth A, Strasser S, McCoy D, Zulu B, Matinise N, Mdingazwe N. Evaluating the clinical management of severely malnourished children--a study of two rural district hospitals. South African Medical Journal 2001;91: Gernaat HB, Dechering WH, Voorhoeve HW. Mortality in severe protein-energy malnutrition at Nchelenge, Zambia. Journal of Tropical Pediatrics 1998;44: Waterlow J. Treatment of children with malnutrition and diarrhoea. Lancet 1999;354: Ahmed T, Ali M, Ullah M, Choudhury IA, Haque ME, Salam MA, Rabbani GH, Suskind RM, Fuchs GJ. Mortality in severely malnourished children with diarrhoea and use of a standardised management protocol. Lancet 1999;353: Ahmed T, Begum B, Badiuzzaman, Ali M, Fuchs G. Management of severe malnutrition and diarrhea. Indian Journal of Pediatrics 2001; 68: Management of severe malnutrition: a manual for physicians and other senior health workers. Geneva: World Health Organization; WHO. Training modules on management of severe malnutrition. Geneva: World Health Organization, Boelaert M, Davis A, Le Lin B, et al. Nutrition guidelines (1st edition). Paris: Medicins Sans Frontieres, Collins S. Changing the way we address severe malnutrition during famine. Lancet 2001;358: Briend A, Lacsala R, Prudhon C, Ready-to-use therapeutic food for treatment of marasmus. Lancet 1999;353(9166): Collins S, Sadler K. Outpatient care for severely malnourished children in emergency relief programmes: a retrospective study. Lancet 2002;360: Sandige H et al. Home-based treatment of malnourished Malawian children with locally produced or imported ready-to-use food. JPGN 2004;39: Collins S, Sadler K, Dent N. Key issues in the success of community-based management of severe malnutrition. Food Nutr Bull 2006 Sep;27(3 Suppl) S49- S Kolsteren P, Roberfroid D, Huybregts L, Lachat C. Management of severe acute malnutrition in children. Lancet 2007;369(9563): Ahmed T, Islam M, Adhikari S, et al. Management of severe malnutrition: mortality among children treated by the adapted WHO protocol and catch-up growth on indigenous diets. Ann Nutr Metab 2001;45: Diop EHI, Dossou NI, Ndour MM, et al. Comparison of the efficacy of a solid ready to use food and a liquid milk-based diet for the rehabilitation of severely malnourished children: a randomized trial. Am J Clin Nutr 2003;78:302 7.

15 20. Manary MJ, Ndkeha MJ, Ashorn P, Home based therapy for severe malnutrition with ready-to-use food. Arch Dis Child Jun;89(6): Maleta K, Kuittinen J, Duggan MB, Supplementary feeding of underweight, stunted Malawian children with a ready-to-use food. J Pediatr Gastroenterol Nutr Feb;38(2): Ciliberto MA, Sandige H, Ndekha MJ, Comparison of home-based therapy with ready-to-use therapeutic food with standard therapy in the treatment of malnourished Malawian children: a controlled, clinical effectiveness trial. Am J Clin Nutr Apr;81(4): Patel MP, Sandige HL, Ndekha MJ, Supplemental feeding with ready-to-use therapeutic food in Malawian children at risk of malnutrition. J Health Popul Nutr Dec; 23(4): Ndekha MJ, Manary MJ, Ashorn P, Home-based therapy with ready-to-use therapeutic food is of benefit to malnourished, HIV-infected Malawian children. Acta Paediatr Feb;94(2): Navarro-Colorado, Clinical trial of BP 100 vs F100 milk for rehabilitation of severe malnutrition. Field Exchange 2005; 24: Chaiken MS, Deconinck H, Degefie T, The promise of a community-based approach to managing severe malnutrition: A case study from Ethiopia. Food Nutr Bull Jun;27(2): Ciliberto MA, Manary MJ, Ndekha MJ, Home-based therapy for oedematous malnutrition with ready-to-use therapeutic food. Acta Paediatr Aug;95(8): Collins S, Dent N, Binns P, Management of severe acute malnutrition in children. Lancet Dec 2;368(9551): Tectonidis M. Crisis in Niger - outpatient care for severe acute malnutrition. N Eng J Med 2006;354(3): Linneman Z, Matilsky D, Ndekha M, A large-scale operational study of homebased therapy with ready-to-use therapeutic food in childhood malnutrition in Malawi. Matern Child Nutr Jul;3(3): Collins S. Treating severe acute malnutrition seriously. Arch Dis Child 2007;92: