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Malnutrition and cryptosporidiosis form a vicious cycle and lead to acute and long-term growth impairment in children from developing countries. Insights into mechanisms underlying the vicious cycle will help to design rational therapies to mitigate this infection. We tested the effect of short-term protein malnutrition on Cryptosporidium parvum infection in a murine model by examining stool shedding, tissue burden, and histologic change and explored the mechanism underlying the interaction between malnutrition and cryptosporidiosis through immunostaining and immunoblotting. Protein malnutrition increased stool shedding and the number of intestine-associated C. parvum organisms, accompanied by significant suppression of C. parvum-induced caspase 3 activity and expression of PCNA and Ki67, but activation of the Akt survival pathway in intestinal epithelial cells. We find that even very brief periods of protein malnutrition may enhance (or intensify) cryptosporidiosis by suppressing C. parvum-induced cell turnover and caspase-dependent apoptosis of intestinal epithelial cells. This implicates a potential strategy to attenuate C. parvum's effects by modulating apoptosis and promoting regeneration in the intestinal epithelium.

Background The protozoan Cryptosporidium is a leading cause of diarrhoea morbidity and mortality in children younger than 5 years. However, the true global burden of Cryptosporidium infection in children younger than 5 years might have been underestimated in previous quantifications because it only took account of the acute effects of diarrhoea. We aimed to demonstrate whether there is a causal relation between Cryptosporidium and childhood growth and, if so, to quantify the associated additional burden. Methods The Global Burden of Diseases, Injuries, and Risk Factors study (GBD) 2016 was a systematic and scientific effort to quantify the morbidity and mortality associated with more than 300 causes of death and disability, including diarrhoea caused by Cryptosporidium infection. We supplemented estimates on the burden of Cryptosporidium in GBD 2016 with findings from a systematic review of published and unpublished cohort studies and a meta-analysis of the effect of childhood diarrhoea caused by Cryptosporidium infection on physical growth. Findings In 2016, Cryptosporidium infection was the fifth leading diarrhoeal aetiology in children younger than 5 years, and acute infection caused more than 48 000 deaths (95% uncertainty interval [UI] 24 600–81 900) and more than 4·2 million disability-adjusted life-years lost (95% UI 2·2 million–7·2 million). We identified seven data sources from the scientific literature and six individual-level data sources describing the relation between Cryptosporidium and childhood growth. Each episode of diarrhoea caused by Cryptosporidium infection was associated with a decrease in height-for-age Z score (0·049, 95% CI 0·014–0·080), weight-for-age Z score (0·095, 0·055–0·134), and weight-for-height Z score (0·126, 0·057–0·194). We estimated that diarrhoea from Cryptosporidium infection caused an additional 7·85 million disability-adjusted life-years (95% UI 5·42 million–10·11 million) after we accounted for its effect on growth faltering—153% more than that estimated from acute effects alone. Interpretation Our findings show that the substantial short-term burden of diarrhoea from Cryptosporidium infection on childhood growth and wellbeing is an underestimate of the true burden. Interventions designed to prevent and effectively treat infection in children younger than 5 years will have enormous public health and social development impacts.

The World Health Organization (WHO) has set forth ambitious efforts to control, and where possible, eliminate the neglected tropical diseases (NTDs) that contribute to poverty and ‘‘impair the ability of those infected to achieve their full potential, both developmentally and socioeconomically’’ [1,2]. This neglected disease initiative’s (NDI) purpose has been to close the existing poverty gap between individuals living in low/middle-income and high-income countries, and thus facilitate the achievement of the 2000 Millennium Developmental Goals [3]. The gap is still large. Yet, some marked achievements of the NDI, including coordinated administration of preventive chemotherapy to nearly 670 million children globally and the imminent elimination of dracunculiasis, give hope that the WHO’s NTD paradigm, a ‘‘five-pronged’’ approach of 1) preventive chemotherapy, 2) intensified case-management, 3) vector control, 4) provision of safe water, sanitation, and hygiene, and 5) veterinary public health, are proving beneficial

The paper by Ajjampur et al. in this issue confirms and extends several previous studies from developing countries which show alarming and robust associations between enteric infections, child growth and neuro-development.1 Their findings that symptomatic giardiasis and diarrhoea predicted wasting and poor performance on a test of cognition (and perhaps lower ‘social quotient’) are profoundly important and add to the increasing evidence that early childhood enteric infections have long-term growth and developmental consequences which must be addressed if children are to achieve their full potential.2–10 Indeed, evidence is mounting that intestinal infections might have harmful effects not only on childhood stunting — itself an important predictor of IQ — but also on cognitive development which might be independent of the effect of diarrhoea on malnutrition. In an analysis of IQ data from 184 countries, Eppig et al. have recently shown that infectious diseases were the most powerful predictor of mean national IQ, even when temperature, GDP per capita and educational indicators were taken into account.11 Furthermore, although ‘nutritional stress’ correlated with national IQ, even this correlation was lost when the effects of infectious diseases were removed. Although this analysis did not assess enteric infections or diarrhoea per se, their specific suggestion that diarrhoeal diseases may lead infectious diseases in causing lifelong detrimental effects on brain development is strongly supported by original reports from our group over the last decade.2–7 As with Ajjampur and colleagues’ data on the correlation between wasting and ‘social quotients’, our data suggest that stunting (height-for-age Z-score ≤2 SD below the median) at age 2 years may be a surrogate marker of heavy early childhood diarrhoea burdens and a key predictor of later cognitive development. Further follow-up studies of national HAZ-2, wasting and IQ are needed. Similar to earlier findings in children with intestinal helminthiases by Stephenson et al. and Nokes et al., 12–14 we and others have reported that early childhood diarrhoea and Cryptosporidium infections have lasting effects on child growth and cognitive development.2–5,8,9 Furthermore, similar to the results of Eppig et al., we find that diarrhoea, independent of its significant effects on growth, impairs cognitive development (Pinkerton et al, submitted). Clearly, more studies of the long-term impact of major enteric infections, with or without overt diarrhoea, are urgently needed to assess adequately the magnitude and mechanisms by which these devastating developmental impairments occur. We and others have identified stunting as one of the best surrogate markers of the deleterious effects of early childhood diarrhoeal illness; the decline in cognitive function is apparent 4–8 years later.2,3,5,15 In Ajjampur et al.’s study, the lack of significant correlation between cognitive function and stunting when cumulative diarrhoeal episodes (and cryptosporidiosis) were taken into account might be explained by younger age at assessment (3 years). Assessing cognition at such a young age can be difficult and it would be interesting to see the results if the children were followed to an older age. In addition, more comprehensive cognitive testing might provide a clearer picture. Complex regional and pathogen-specific brain injury might lead to reductions of certain cognitive domain functions which are difficult to assess without a full cognitive battery of tests at an age older than 3 years. Some cognitive domains may require further maturation of neural circuitry which is better assessed in mid-childhood. The finding by Ajjampur’s group that Giardia spp. infections are associated with cognitive impairment in children in early life is of special interest. Our group also found a significant association between Giardia infections and cognitive impairment, especially in apolipoprotein E4 (APOE4)-negative children but not in APOE4 carriers,16–18 showing that it is likely that a genetic component is also involved in this effect of Giardia infections on brain development. Finally, the finding by Ajjampur’s group that breastfeeding might spare cognitive impairment is also of interest as secretory IgA (SIgA) found in breast-milk might also help reduce Giardia infections in the offspring.19 Limitations of current studies include data from single sites (e.g. India, Peru and Brazil) and a relatively moderate number of children for multivariate analyses. Multi-country studies with long-term intense follow-up of birth cohorts, with complete data on factors hypothesised to be associated with IQ, a battery of tests for different aspects of cognitive function, and community-level data on specific symptomatic and asymptomatic infections will help untangle these complex relationships. The answers to these critical questions cannot come soon enough. Diarrhoea mortality has not fallen in the last 5 years20 and diarrhoea morbidity might be increasing in fast-growing populations. Improved diarrhoea prevention and control are urgently needed to improve this mortality; however, to break this vicious cycle, new research is required as well as strategies to address growth and IQ deficits in surviving children.