LAUSR

Although the protozoan parasite Cryptosporidium spp. was recognized as a human pathogen in 1976 [1], it was only after a major outbreak in 1993 that sickened more than 400,000 and killed 69 in Milwaukee, Wisconsin, United States of America [2], that its impact as a diarrheal disease-causing pathogen began to be widely appreciated. Cryptosporidium has since been recognized as the most frequently identified pathogen in US waterborne outbreaks [3]. However, because otherwise healthy people recover spontaneously, it continues to be viewed in the US primarily as an opportunistic pathogen causing chronic diarrhea in AIDS patients and other immunocompromised people. In 2013, publication of the first results from the Global Enteric Multicenter Study (GEMS) highlighted the impact of this parasite among children in lowresource settings (LRS), including seven African and Asian countries. Cryptosporidium was found to be one of the three most important diarrhea-causing pathogens in children under 12 months old and the most common cause of mortality due to moderate-to-severe diarrhea among 12to 23-month olds [4,5]. Subsequent epidemiological studies reinforced these findings, including MAL-ED (Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development) and more recent surveys by the Global Burden of Disease (GBD) and the GEMS-1A follow-on study to GEMS. At eight Asian and African sites, the MAL-ED study found Cryptosporidium was among the five most important pathogens causing diarrhea in community clinics [6]. The GBD study estimated that globally Cryptosporidium is responsible for more than 44.8 million episodes of diarrhea and 48,000 deaths annually [7]. GEMS-1A confirmed and extended the findings from GEMS by showing that Cryptosporidium was associated with a greater than 2-fold increased risk of death among 12to 23-month olds with moderate-to-severe diarrhea [8]. Despite this substantial and well-documented burden, the impact of cryptosporidiosis is still under-recognized by the wider global health community: Cryptosporidiosis is not designated as a neglected tropical disease (NTD) by the World Health Organization nor is it included on the list of tropical diseases eligible for a priority review voucher (PRV) from the US Food and Drug Administration (FDA). We highlight below the reasons why cryptosporidiosis strongly deserves inclusion on the FDA list of tropical diseases and how this could help stimulate development of improved therapies. The current toolbox of interventions against cryptosporidiosis is severely limited. There are no approved vaccines, and there is only a single anticryptosporidial drug, nitazoxanide. Although nitazoxanide reduces the duration of illness in immunocompetent adults, it is inadequate for the populations with the greatest need. Nitazoxanide is no better than placebo in severely immunocompromised subjects, such as HIV patients [9], and only modestly effective PLOS NEGLECTED TROPICAL DISEASES