“Barriers" to Child Development and Human Potential: The Case for Including the “Neglected Enteric Protozoa" (NEP) and Other Enteropathy-Associated Pathogens in the NTDs

Abstract

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 socio-economically [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 [1]. Malnutrition and unfulfilled human potential are widely prevalent among the 1.4 billion people also afflicted by the principal NTDs. Over the last decade, we have become increasingly aware that alterations in intestinal function not only associate with malnutrition, but are likely one of its driving forces. It was recognized half a century ago that children in developing countries had intestinal mucosa that showed morphological flattening [4] and malabsorption [5] that were reversible upon exposure to a cleaner environment. Similarly, Lindenbaum also showed in the 1960s that Peace Corps volunteers with diarrhea and malnutrition had biochemical markers of malabsorption: 40% had decreased d-xylose levels, and 52% had low Schilling tests. Moreover, 88% of intestinal biopsies from these volunteers showed mild to moderate jejunitis with decreased villus∶crypt ratios [6]. Villus blunting along with chronic inflammation associates with impaired intestinal barrier function with resultant increased intestinal permeability [7]. This combination of altered villus architecture and barrier function, so uniquely dependent upon one's environment, has been termed “environmental (EE) [8]. These characteristic EE changes have been epidemiologically linked with growth faltering and are one hypothesis for why intensive nutritional supplementation interventions done under even ideal clinical trial conditions have significant but limited success in improving weight, linear growth, and cognitive function [9]–[11]. Syndemic with environmental enteropathy are high rates of childhood diarrhea. Although children may display “catch-up growth following isolated and short-lived (3 days) diarrheal episodes [12], prolonged and persistent diarrheal (>14 days) episodes strongly associate with stunting [13]–[16]. Testament to the effectiveness of WHO campaigns, the combination of oral rehydration solution (ORS) in the 1980s and its subsequent refinements, and the introduction of rotavirus vaccines in some populations [17], have led to significant reductions in diarrhea-related mortality from 4.5 million/year over a decade ago to 1.5 million/year in 2010 [18], [19]. Currently, however, there are still >700,000 deaths per year globally related to diarrheal diseases [20], and conversely, the frequency of diarrheal episodes has not declined but remains unacceptably high [21]. Among the myriad pathogens causing diarrhea in low/middle-income countries, the Giardia lamblia (synonymous with G. intestinalis/G. duodenalis) and Cryptosporidium spp. are among the most commonly isolated [22]. Although present in PLOS NTDs' expanded NTD list [23], and added to the WHO's NDI in 2004 [2], [24], these organisms are not mentioned in the 2010 WHO NTD report [1]. Despite the call for increased surveillance [2], the true global prevalence of these infections remains poorly defined [25]. In the past few years, we have learned important lessons that make imperative an emphasis on these “neglected enteric protozoa (NEP) and other enteropathy-associated pathogens within the NDI: The enteric should be classified with the soil-transmitted helminths (STHs) as pathogens associated with stunting. We need to restructure our theoretical framework to broaden our concept of “diarrheal disease to include “asymptomatic enteric infections. We must recognize that environmental enteropathy is likely both a common and complex disease, and that infections related to the development or exacerbation of environmental enteropathy deserve prioritization in disease control strategies. Therapeutic strategies against enteropathy-associated pathogens can and should be evaluated for efficacy within the existing NDI programs.