Challenges in quantifying the clear effect of malnutrition on diarrhoeal deaths
Authors: Elizabeth T Rogawski McQuade
Journal: The Lancet Global Health (2020)

The vicious cycle between diarrhoea and malnutrition was described decades ago1Scrimshaw NS Taylor CE Gordon JE Interactions of nutrition and infection.Monogr Ser World Health Organ. 1968; 57: 3-329PubMed Google Scholar and remains a refractory problem with continued high dual burden among children in low-resource settings.2Troeger C Blacker BF Khalil IA et al.Estimates of the global, regional, and national morbidity, mortality, and aetiologies of diarrhoea in 195 countries: a systematic analysis for the Global Burden of Disease Study 2016.Lancet Infect Dis. 2018; 18: 1211-1228Summary Full Text Full Text PDF PubMed Scopus (319) Google Scholar An acute manifestation of the interaction between diarrhoea and malnutrition is the effect of malnutrition on diarrhoeal mortality: the risk of death is far higher among acutely malnourished children with diarrhoea compared with better nourished children with diarrhoea.2Troeger C Blacker BF Khalil IA et al.Estimates of the global, regional, and national morbidity, mortality, and aetiologies of diarrhoea in 195 countries: a systematic analysis for the Global Burden of Disease Study 2016.Lancet Infect Dis. 2018; 18: 1211-1228Summary Full Text Full Text PDF PubMed Scopus (319) Google Scholar, 3Olofin I McDonald CM Ezzati M et al.Associations of suboptimal growth with all-cause and cause-specific mortality in children under five years: a pooled analysis of ten prospective studies.PLoS One. 2013; 8e64636Crossref PubMed Scopus (211) Google Scholar In The Lancet Global Health, Kirkby D Tickell and colleagues4Tickell KD Sharmin R Deichsel E et al.The effect of acute malnutrition on enteric pathogens, moderate-to-severe diarrhoea, and associated mortality in the Global Enteric Multicenter Study cohort: a post-hoc analysis.Lancet Glob Health. 2020; 8: e215-e224Summary Full Text Full Text PDF PubMed Scopus (13) Google Scholar add important nuance to our understanding of the interactions between malnutrition and diarrhoeal morbidity and mortality by assessing the relationships between specific pathogens and diarrhoeal outcomes in children with and without acute malnutrition. It is plausible that the effects of malnutrition-related susceptibilities could differ by pathogen, and this analysis indeed found that the associations between infections with enteric bacteria and moderate-to-severe diarrhoea and death were generally stronger among malnourished children, but the associations for infections with enteric viruses were generally weaker among malnourished children. The Article also highlights the importance of an often misunderstood and under-considered issue surrounding the difference between additive and multiplicative interaction, or equally, interaction on the absolute (risk difference) and relative (risk ratio or odds ratio) scales. Assessments of interaction at the population level rely on statistical models and are dependent on the scale of the model used. Non-intuitively, evidence for additive interaction can qualitatively differ from that for multiplicative interaction. Because additive interaction directly estimates excesses or reductions in the number of observed cases related to the interacting factor, this scale is more relevant for improving public health.5Rothman KJ Greenland S Lash TL Modern epidemiology.3rd edn. Lippincott William & Wilkins, Philadelphia, PA2008Google Scholar, 6VanderWeele TJ Explanation in causal inference: methods for mediation and interaction. Oxford University Press, New York, NY2015Google Scholar However, because multiplicative models (eg, logistic regression) are commonly used, the multiplicative scale is often the default choice when including interaction terms in models. There remains an unfortunate tendency to focus only on multiplicative interaction, despite the long-standing availability of methods to assess additive interaction with multiplicative models and in case-control studies.5Rothman KJ Greenland S Lash TL Modern epidemiology.3rd edn. Lippincott William & Wilkins, Philadelphia, PA2008Google Scholar, 7Hosmer DW Lemeshow S Confidence interval estimation of interaction.Epidemiology. 1992; 3: 452-456Crossref PubMed Scopus (767) Google Scholar, 8Richardson DB Kaufman JS Estimation of the relative excess risk due to interaction and associated confidence bounds.Am J Epidemiol. 2009; 169: 756-760Crossref PubMed Scopus (126) Google Scholar In the study by Tickell and colleagues,4Tickell KD Sharmin R Deichsel E et al.The effect of acute malnutrition on enteric pathogens, moderate-to-severe diarrhoea, and associated mortality in the Global Enteric Multicenter Study cohort: a post-hoc analysis.Lancet Glob Health. 2020; 8: e215-e224Summary Full Text Full Text PDF PubMed Scopus (13) Google Scholar the choice of additive versus multiplicative interaction has an important effect on the interpretation of results. Although estimates of the magnitude of interaction on moderate-to-severe diarrhoea were imprecise, the direction of apparent interaction differed between the two scales for more than half (nine of 17) of the pathogens assessed. For example, Shigella spp had a weaker association with moderate-to-severe diarrhoea among malnourished children on the multiplicative scale and a stronger association with moderate-to-severe diarrhoea among malnourished children on the additive scale. The most striking example of this incongruence was the interaction between Cryptosporidium spp and malnutrition with respect to its association with mortality, in which additive interaction suggested strong public health synergy but multiplicative interaction suggested antagonism. To show this conflict between scales more clearly, a crude analysis of multiplicative and additive interaction for Cryptosporidium spp and mortality is shown in the table. Although the estimated risk ratio linking this infection to death was smaller in the malnourished group than in the better nourished group, the estimated risk difference was larger in the malnourished group. Specifically, the increase in the risk of death associated with Cryptosporidium spp was an absolute 2·3% (95% CI −2·5 to 7·2) greater among malnourished children than among better nourished children. In this population, infection with Cryptosporidium spp would have to be prevented in only 31 (1/0·0322) malnourished children to reduce expected diarrhoeal mortality by one death. To obtain the same expected benefit in better nourished children, the infection would have to be prevented in an estimated 114 (1/0·0088) children.9Laupacis A Sackett DL Roberts RS An assessment of clinically useful measures of the consequences of treatment.N Engl J Med. 1988; 318: 1728-1733Crossref PubMed Scopus (1243) Google Scholar The multiplicative interaction analysis indicates different results from the additive analysis because the greater absolute effect estimated for the malnourished children is diluted by their substantially elevated baseline risk (8·0% in malnourished children vs 0·7% in better nourished children; table).TableCrude analysis of multiplicative and additive interaction between Cryptosporidium spp and malnutrition and its effect on 60-day diarrhoeal mortality, based on data by Tickell and colleagues4Tickell KD Sharmin R Deichsel E et al.The effect of acute malnutrition on enteric pathogens, moderate-to-severe diarrhoea, and associated mortality in the Global Enteric Multicenter Study cohort: a post-hoc analysis.Lancet Glob Health. 2020; 8: e215-e224Summary Full Text Full Text PDF PubMed Scopus (13) Google ScholarMalnourished childrenBetter nourished childrenDeathsTotalCrude risk (%)*Risk difference=3·2% (95% CI −1·5 to 8·0).Risk ratio (95% CI)DeathsTotalCrude risk (%)†Risk difference=0·9% (−0·1 to 1·8).Risk ratio (95% CI)Cryptosporidium spp2219611·2%1·40 (0·89 to 2·21)116861·6%2·23 (1·15 to 4·31)Other pathogens or no pathogen708758·0%1 (ref)4156970·7%1 (ref)* Risk difference=3·2% (95% CI −1·5 to 8·0).† Risk difference=0·9% (−0·1 to 1·8). Open table in a new tab We commend Tickell and colleagues4Tickell KD Sharmin R Deichsel E et al.The effect of acute malnutrition on enteric pathogens, moderate-to-severe diarrhoea, and associated mortality in the Global Enteric Multicenter Study cohort: a post-hoc analysis.Lancet Glob Health. 2020; 8: e215-e224Summary Full Text Full Text PDF PubMed Scopus (13) Google Scholar for estimating additive interaction in addition to multiplicative interaction. They provide an insightful explanation for why the interactions qualitatively differed on the two scales more often for the pathogens that are more frequently associated with severe diarrhoea and death (such as Shigella spp, rotaviruses, and Cryptosporidium spp). These virulent pathogens are strongly associated with poor outcomes in both malnourished and better nourished children. Because the overall risk is lower in better nourished children, the relative effect of these pathogens appears larger in better nourished children. Apart from the challenges of assessing interaction, the study highlights that 92 (64%) of 144 children with moderate-to-severe diarrhoea who died were acutely malnourished (56 [39%] had severe acute malnutrition), and crude mortality was an absolute 7·4% higher in malnourished children than in better nourished children. In a related study in The Lancet Global Health, Myron Levine and colleagues10Levine MM Nasrin D Acácio S et al.Diarrhoeal disease and subsequent risk of death in infants and children residing in low-income and middle-income countries: analysis of the GEMS case-control study and 12-month GEMS-1A follow-on study.Lancet Glob Health. 2020; 8: e204-e214Summary Full Text Full Text PDF PubMed Scopus (31) Google Scholar document that the overall 60-day risk of mortality was 2·0% among children with moderate-to-severe diarrhoea, which was much higher than the 0·3% risk in community-based controls. Children with moderate-to-severe diarrhoea in Pakistan had a particularly high risk of death and were more malnourished at baseline compared with children with moderate-to-severe diarrhoea at other sites.10Levine MM Nasrin D Acácio S et al.Diarrhoeal disease and subsequent risk of death in infants and children residing in low-income and middle-income countries: analysis of the GEMS case-control study and 12-month GEMS-1A follow-on study.Lancet Glob Health. 2020; 8: e204-e214Summary Full Text Full Text PDF PubMed Scopus (31) Google Scholar The evidence for the synergistic effects of malnutrition and diarrhoea on mortality suggests pathogen-agnostic strategies among the most vulnerable children will have the greatest effect on preventing child deaths. ETRM was supported by the National Institutes of Health (grant K01AI130326 ). I thank Charles Poole for his insightful feedback and suggestions. I declare no competing interests. Diarrhoeal disease and subsequent risk of death in infants and children residing in low-income and middle-income countries: analysis of the GEMS case-control study and 12-month GEMS-1A follow-on studyRisk of death is increased following MSD and, to a lesser extent, LSD. Considering there are approximately three times more cases of LSD than MSD in the population, more deaths are expected among children with LSD than in those with MSD. Because the major attributable LSD-associated and MSD-associated pathogens are the same, implementing vaccines and rapid diagnosis and treatment interventions against these major pathogens are rational investments. Full-Text PDF Open AccessThe effect of acute malnutrition on enteric pathogens, moderate-to-severe diarrhoea, and associated mortality in the Global Enteric Multicenter Study cohort: a post-hoc analysisAcute malnutrition might strengthen associations between specific pathogens and moderate-to-severe diarrhoea. However, the strong link between acute malnutrition and mortality during moderate-to-severe diarrhoea in children is not limited to specific infections, and affects a broad spectrum of enteric pathogens. Interventions addressing acute malnutrition could be an effective way to lower the mortality of both childhood malnutrition and diarrhoea. Full-Text PDF Open Access