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doi:10.1111/jpc.12711
REVIEW ARTICLE
Diagnosis and treatment of severely malnourished children with diarrhoea Lora L Iannotti,1 Indi Trehan,1,2,3 Kathryn L Clitheroe1 and Mark J Manary1,2,4,5 1
Institute for Public Health, George Warren Brown School of Social Work, 2Department of Pediatrics, Washington University in St. Louis, St. Louis, Missouri, Children’s Nutrition Research Center, Baylor College of Medicine, Houston, Texas, United States and Departments of 3Paediatrics and Child Health and 4 Community Health, University of Malawi, Zomba, Malawi 5
Abstract: Children with severe acute malnutrition complicated by diarrhoea require special care due to their unique physiological vulnerability and increased mortality risks. A systematic literature review (1950–2013) was conducted to identify the most effective diagnostic and therapeutic measures for the community-based management of severely malnourished children with diarrhoea. No studies directly addressed this question, so the search was broadened to include inpatient care. Of the 129 studies identified, 32 were selected for full review and found to contain varying degrees of indirectness, inconsistency and bias. Evidence from diagnostic studies point to the use of both prolonged and persistent diarrhoea as morbidity markers, rapid hypoglycaemia diagnosis and the frequent aetiological role of Cryptosporidium. Therapeutic studies suggest benefits from routine antiparasitic medication and feeding regimens with ready-to-use-therapeutic foods, lactose-free diets and zinc supplementation. Existing rehydration treatment guidelines were affirmed, but the utility of glutamine and low osmolarity feeds were inconclusive. Key words:
Cryptosporidium; diarrhoea; GRADE review; ready-to-use therapeutic food; severely malnourished children; zinc.
Studies have shown that as many as one-half to two-thirds of children with severe acute malnutrition (SAM) present with diarrhoea.1,2 Undernutrition precipitates deaths due to Key Points 1 Diagnosis and treatment of severely malnourished children with diarrhoea in community outpatient care should be a research and policy imperative to reduce relapse and case fatality rates. 2 This Grading of Recommendations Assessment, Development and Evaluation review of the literature identified eight diagnostic studies and 24 therapeutic trials related to severe malnutrition with diarrhoea but had varying levels of indirectness in study population, inconsistencies in definitions of diarrhoea and malnutrition, and study biases. 3 Protocols for management of diarrhoea with severe malnutrition should routinely apply rapid diagnostics including those for hypoglycaemia and prolonged and persistent diarrhoea morbidities; address parasitic infections such as Cryptosporidium; adhere to existing rehydration guidelines; integrate preventative measures; and incorporate ready-to-use therapeutic foods and zinc supplementation. Correspondence: Dr Lora L Iannotti, Institute for Public Health, George Warren Brown School of Social Work, Washington University in St. Louis, Campus Box 1196, St. Louis, MO 63130-4899, USA. Fax: +1 314 935 4396; email: [email protected] Conflict of interest: L Iannotti, I Trehan, K Clitheroe, and M Manary have no conflicts of interest. Accepted for publication 11 July 2014.
diarrhoea, and similarly, diarrhoea often leads to SAM in young children.3–5 Diarrhoea perturbs solute and water homeostasis, leading to dehydration and electrolyte imbalances.6,7 Given the overall fragility of children with SAM, there is a need to be particularly careful in the management of their diarrhoea and dehydration.8 World Health Organization (WHO) guidelines specify inpatient treatment of children with SAM for ‘continuing diarrhoea’.9 No specific recommendations exist for outpatient, community-based programmes, which is where the preponderance of cases is actually encountered and managed. Optimal management in the outpatient setting thus has great potential for reducing relapse and mortality rates and promoting catch-up growth. This issue was recently identified by a WHO advisory groups as needing review. Here, we present the findings from a Grading of Recommendations Assessment, Development and Evaluation (GRADE) review of the literature addressing this question.
Methods Two questions were examined in this review. For children receiving community-based management for SAM who also have diarrhoea without moderate or severe dehydration, what are the most effective (i) diagnostic and (ii) therapeutic strategies to evaluate and manage their diarrhoea. The following interventions were considered: antibiotics, antiparasitics, oral rehydration solutions (ORSs), modified feeding strategies, glutamine supplementation, probiotics and prebiotics, and zinc supplementation.
Journal of Paediatrics and Child Health (2014) © 2014 The Authors Journal of Paediatrics and Child Health © 2014 Paediatrics and Child Health Division (Royal Australasian College of Physicians).
1
Severe malnutrition and diarrhoea review
LL Iannotti et al.
A literature review was undertaken to search for all observational and randomised controlled trials (RCT) from 1950 to 2013. Databases searched included MEDLINE, EMBASE, Google Scholar and clinical trial registries at clinicaltrials.gov, www.pactr.org and apps.who.int/trialsearch. Key words for the searches included ‘malnutrition’, ‘severe malnutrition’, ‘kwashiorkor’, ‘marasmus’, ‘therapeutic food’, ‘CMAM’, ‘outpatient’, ‘OTP’, ‘community-based care’, ‘diarrhoea’, ‘zinc’, ‘glutamine’, ‘oral rehydration solution’, ‘ORS’, ‘prebiotics’, ‘probiotics’, ‘antibiotics’, ‘antiparasitics’, ‘mebendazole’, ‘albendazole’ and ‘metronidazole’. A number of outcome measures were sought, including mortality, weight gain, nutritional recovery, resolution of diarrhoea and duration of therapy. Further terms were added iteratively to the search based on results obtained from the initial searches. Studies were included for full review based on population of interest, related study interventions, study design, outcome measures and an assessment of the study’s methodological rigor and quality. These studies were then assessed by GRADE criteria.10 Indirectness was based on study relevance to the review question in terms of population, intervention and outcome measures.11 Inconsistency was assessed by examining heterogeneity of methods, definitions and statistical analyses;12 and imprecision on sample sizes; and the 95% confidence intervals surrounding the observed effects.13 Study limitations included risk of bias (selection, recall, information/observation and misclassification), blinding, losses in follow-up, inappropriate controls and failure to adjust for confounding factors.14 Each study was assigned a quality ranking ranging from low to high. Only those studies with some degree of medium or high (i.e. low–medium, medium, medium–high or high) quality ranking were included in this review.
Results No studies were identified that directly addressed the question of managing diarrhoea in children with SAM as outpatients in community-based programmes, so the search was broadened to include patients treated as inpatients. In total, 1694 abstracts were identified as having keywords diarrhoea and malnutrition, and 129 were considered relevant and selected for full review. Thirty-two articles were of low–medium to high quality based on GRADE criteria (Fig. 1).
For children with SAM and diarrhoea, what are the most effective diagnostic approaches? Eight studies of diagnostic approaches for children with varying degrees of malnutrition and diarrhoea receiving inpatient care or at-home monitoring met GRADE criteria at least the low– medium level (Table 1). Among the studies that did quantify the degree of malnutrition, varying definitions of SAM were used, adding inconsistency to these results.
Prognostic categorisation Promptly and accurately diagnosing severely malnourished children with varying degrees of diarrhoea and associated conditions may help identify those at greatest risk for significant dehydration, other superimposed infections and mortality.23 One case-control study among children with SAM and diarrhoea that found hypoglycaemia diagnosed with a simple finger glucose test was associated with mortality.15 Diarrhoeal episodes of longer duration are associated with poor shortterm and long-term nutritional outcomes in children with SAM. Among the studies considered in this review, the
1694 records screened after duplicates removed 1565 records excluded Full text reviewed for eligibility (n = 129) 97 studies of low quality excluded Studies included (n = 32)
Diagnostic studies (n = 8): - Morbidity indicators (n = 2) - Pathology indicators (n = 5) - Rapid diagnostic tests (n = 1)
2
Therapeutic randomized controlled studies (n = 24): - Antiparasitics (n = 2) - Oral rehydration solutions (n = 2) - Modified feeding strategies (n = 10) - Glutamine (n = 1) - Probiotics and prebiotics (n = 3) - Zinc supplementation (n = 6)
Fig. 1 Flow diagram for studies included in Grading of Recommendations Assessment, Development and Evaluation (GRADE) review.
Journal of Paediatrics and Child Health (2014) © 2014 The Authors Journal of Paediatrics and Child Health © 2014 Paediatrics and Child Health Division (Royal Australasian College of Physicians)
Observational, cohort (10 years) Aim: To study diarrhoea, enteric pathogens, and anthropometry in Brazilian children (from birth to 10 years)
Observational, cohort Aim: To determine whether malnutrition is associated in increased risk of diarrhoea in Mexican children (
doi:10.1111/jpc.12711
REVIEW ARTICLE
Diagnosis and treatment of severely malnourished children with diarrhoea Lora L Iannotti,1 Indi Trehan,1,2,3 Kathryn L Clitheroe1 and Mark J Manary1,2,4,5 1
Institute for Public Health, George Warren Brown School of Social Work, 2Department of Pediatrics, Washington University in St. Louis, St. Louis, Missouri, Children’s Nutrition Research Center, Baylor College of Medicine, Houston, Texas, United States and Departments of 3Paediatrics and Child Health and 4 Community Health, University of Malawi, Zomba, Malawi 5
Abstract: Children with severe acute malnutrition complicated by diarrhoea require special care due to their unique physiological vulnerability and increased mortality risks. A systematic literature review (1950–2013) was conducted to identify the most effective diagnostic and therapeutic measures for the community-based management of severely malnourished children with diarrhoea. No studies directly addressed this question, so the search was broadened to include inpatient care. Of the 129 studies identified, 32 were selected for full review and found to contain varying degrees of indirectness, inconsistency and bias. Evidence from diagnostic studies point to the use of both prolonged and persistent diarrhoea as morbidity markers, rapid hypoglycaemia diagnosis and the frequent aetiological role of Cryptosporidium. Therapeutic studies suggest benefits from routine antiparasitic medication and feeding regimens with ready-to-use-therapeutic foods, lactose-free diets and zinc supplementation. Existing rehydration treatment guidelines were affirmed, but the utility of glutamine and low osmolarity feeds were inconclusive. Key words:
Cryptosporidium; diarrhoea; GRADE review; ready-to-use therapeutic food; severely malnourished children; zinc.
Studies have shown that as many as one-half to two-thirds of children with severe acute malnutrition (SAM) present with diarrhoea.1,2 Undernutrition precipitates deaths due to Key Points 1 Diagnosis and treatment of severely malnourished children with diarrhoea in community outpatient care should be a research and policy imperative to reduce relapse and case fatality rates. 2 This Grading of Recommendations Assessment, Development and Evaluation review of the literature identified eight diagnostic studies and 24 therapeutic trials related to severe malnutrition with diarrhoea but had varying levels of indirectness in study population, inconsistencies in definitions of diarrhoea and malnutrition, and study biases. 3 Protocols for management of diarrhoea with severe malnutrition should routinely apply rapid diagnostics including those for hypoglycaemia and prolonged and persistent diarrhoea morbidities; address parasitic infections such as Cryptosporidium; adhere to existing rehydration guidelines; integrate preventative measures; and incorporate ready-to-use therapeutic foods and zinc supplementation. Correspondence: Dr Lora L Iannotti, Institute for Public Health, George Warren Brown School of Social Work, Washington University in St. Louis, Campus Box 1196, St. Louis, MO 63130-4899, USA. Fax: +1 314 935 4396; email: [email protected] Conflict of interest: L Iannotti, I Trehan, K Clitheroe, and M Manary have no conflicts of interest. Accepted for publication 11 July 2014.
diarrhoea, and similarly, diarrhoea often leads to SAM in young children.3–5 Diarrhoea perturbs solute and water homeostasis, leading to dehydration and electrolyte imbalances.6,7 Given the overall fragility of children with SAM, there is a need to be particularly careful in the management of their diarrhoea and dehydration.8 World Health Organization (WHO) guidelines specify inpatient treatment of children with SAM for ‘continuing diarrhoea’.9 No specific recommendations exist for outpatient, community-based programmes, which is where the preponderance of cases is actually encountered and managed. Optimal management in the outpatient setting thus has great potential for reducing relapse and mortality rates and promoting catch-up growth. This issue was recently identified by a WHO advisory groups as needing review. Here, we present the findings from a Grading of Recommendations Assessment, Development and Evaluation (GRADE) review of the literature addressing this question.
Methods Two questions were examined in this review. For children receiving community-based management for SAM who also have diarrhoea without moderate or severe dehydration, what are the most effective (i) diagnostic and (ii) therapeutic strategies to evaluate and manage their diarrhoea. The following interventions were considered: antibiotics, antiparasitics, oral rehydration solutions (ORSs), modified feeding strategies, glutamine supplementation, probiotics and prebiotics, and zinc supplementation.
Journal of Paediatrics and Child Health (2014) © 2014 The Authors Journal of Paediatrics and Child Health © 2014 Paediatrics and Child Health Division (Royal Australasian College of Physicians).
1
Severe malnutrition and diarrhoea review
LL Iannotti et al.
A literature review was undertaken to search for all observational and randomised controlled trials (RCT) from 1950 to 2013. Databases searched included MEDLINE, EMBASE, Google Scholar and clinical trial registries at clinicaltrials.gov, www.pactr.org and apps.who.int/trialsearch. Key words for the searches included ‘malnutrition’, ‘severe malnutrition’, ‘kwashiorkor’, ‘marasmus’, ‘therapeutic food’, ‘CMAM’, ‘outpatient’, ‘OTP’, ‘community-based care’, ‘diarrhoea’, ‘zinc’, ‘glutamine’, ‘oral rehydration solution’, ‘ORS’, ‘prebiotics’, ‘probiotics’, ‘antibiotics’, ‘antiparasitics’, ‘mebendazole’, ‘albendazole’ and ‘metronidazole’. A number of outcome measures were sought, including mortality, weight gain, nutritional recovery, resolution of diarrhoea and duration of therapy. Further terms were added iteratively to the search based on results obtained from the initial searches. Studies were included for full review based on population of interest, related study interventions, study design, outcome measures and an assessment of the study’s methodological rigor and quality. These studies were then assessed by GRADE criteria.10 Indirectness was based on study relevance to the review question in terms of population, intervention and outcome measures.11 Inconsistency was assessed by examining heterogeneity of methods, definitions and statistical analyses;12 and imprecision on sample sizes; and the 95% confidence intervals surrounding the observed effects.13 Study limitations included risk of bias (selection, recall, information/observation and misclassification), blinding, losses in follow-up, inappropriate controls and failure to adjust for confounding factors.14 Each study was assigned a quality ranking ranging from low to high. Only those studies with some degree of medium or high (i.e. low–medium, medium, medium–high or high) quality ranking were included in this review.
Results No studies were identified that directly addressed the question of managing diarrhoea in children with SAM as outpatients in community-based programmes, so the search was broadened to include patients treated as inpatients. In total, 1694 abstracts were identified as having keywords diarrhoea and malnutrition, and 129 were considered relevant and selected for full review. Thirty-two articles were of low–medium to high quality based on GRADE criteria (Fig. 1).
For children with SAM and diarrhoea, what are the most effective diagnostic approaches? Eight studies of diagnostic approaches for children with varying degrees of malnutrition and diarrhoea receiving inpatient care or at-home monitoring met GRADE criteria at least the low– medium level (Table 1). Among the studies that did quantify the degree of malnutrition, varying definitions of SAM were used, adding inconsistency to these results.
Prognostic categorisation Promptly and accurately diagnosing severely malnourished children with varying degrees of diarrhoea and associated conditions may help identify those at greatest risk for significant dehydration, other superimposed infections and mortality.23 One case-control study among children with SAM and diarrhoea that found hypoglycaemia diagnosed with a simple finger glucose test was associated with mortality.15 Diarrhoeal episodes of longer duration are associated with poor shortterm and long-term nutritional outcomes in children with SAM. Among the studies considered in this review, the
1694 records screened after duplicates removed 1565 records excluded Full text reviewed for eligibility (n = 129) 97 studies of low quality excluded Studies included (n = 32)
Diagnostic studies (n = 8): - Morbidity indicators (n = 2) - Pathology indicators (n = 5) - Rapid diagnostic tests (n = 1)
2
Therapeutic randomized controlled studies (n = 24): - Antiparasitics (n = 2) - Oral rehydration solutions (n = 2) - Modified feeding strategies (n = 10) - Glutamine (n = 1) - Probiotics and prebiotics (n = 3) - Zinc supplementation (n = 6)
Fig. 1 Flow diagram for studies included in Grading of Recommendations Assessment, Development and Evaluation (GRADE) review.
Journal of Paediatrics and Child Health (2014) © 2014 The Authors Journal of Paediatrics and Child Health © 2014 Paediatrics and Child Health Division (Royal Australasian College of Physicians)
Observational, cohort (10 years) Aim: To study diarrhoea, enteric pathogens, and anthropometry in Brazilian children (from birth to 10 years)
Observational, cohort Aim: To determine whether malnutrition is associated in increased risk of diarrhoea in Mexican children (
