quinta-feira, 24 de setembro de 2015

Persistent Diarrhea: Still a Serious Public Health Problem in Developing Countries (Part 1)

Ulysses Fagundes-Neto

Division of Pediatric Gastroenterology, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil e-mail: ulyneto@osite.com.br


Diarrhea is still responsible for high rates of morbidity and mortality in children under 5 years of age. The prolongation of the acute episode may cause digestive and absorptive malfunction and, consequently, malnutrition, raising the risk of death.
The objective of this review is to supply the most recent knowledge in the field of persistent diarrhea and to contribute to the decrease of its incidence. Some possible etiologic agents may be involved, including viruses, bacteria, and parasites. 
Treatment must be addressed to avoid malabsorption of the nutrients of the diet, associated with replacement of the hydroelectrolytic losses, to prevent its prolongation. In the great majority of the episodes, antibiotics are not indicated. Breastfeeding, introduction of safe dietary strategies to prevent protein-energy malnutrition, and improvement of sanitary conditions and hygiene are measures to be promoted with the objective of decreasing the morbidity/ mortality of the diarrheic disease in children less than 5 years of age.


Collectively, the most important cause of death in children younger than 5 years has been infectious diseases, especially pneumonia, diarrhea, and malaria [1]. On the other hand, the most important single causes of death have been pneumonia, diarrhea, and preterm birth complications. Diarrhea is still responsible for high rates of death in children worldwide. Diarrhea is the third most common cause of death (16%) among children under 5 years of age, after neonatal causes (37%) and pneumonia (17%), despite the decline in the mortality rates that has been observed since the 1980s [2]. In 2008, diarrheal disease accounted for 1,336 million of the estimated 8,795 million deaths (15%) in children younger than 5 years of age around the world [3]. It is important to mention that 51% (0.678 million) of the deaths caused by diarrhea occurred in India, Nigeria, Afghanistan, Pakistan, and Ethiopia. Young children suffer from 3.2–12 diarrheal episodes per year [4]. The majority of the diarrheal illnesses are acute, lasting no more than 7 days; however, an estimated 3%–19% of the acute episodes lasting longer (14 days and more) are designated as persistent diarrhea (PD) [5]. PD cases are difficult to treat, their treatment cost is higher, and a case fatality rate as high as 60% has been reported [6]. It has been estimated that PD contributes to a loss of 3 million disability-adjusted life-years annually [7]. In our experience, studying 200 patients under 1 year of age suffering from acute diarrhea, we detected that when some strains of enteropathogenic Escherichia coli (EPEC) were isolated in the stools, the evolution to PD reached 28.4% of the cases, versus 6.9% when the process was due to another enteropathogenic agent [8]. In developing countries, over 50% of the deaths due to diarrhea are associated with the perpetuation of the diarrheic syndrome [9]. The majority of deaths occur in children of early age living in the rural regions of developing countries, where there is a lack of adequate sanitary conditions [10]. Repeated episodes of acute diarrhea in the first year of life usually lead to intestinal malabsorption of the nutrients of the diet and, consequently, malnutrition.

Considering that the perpetuation of the diarrheic episode in the majority of the cases occurs during a critical developmental period, both physical and intellectual, it could lead to severe damage to the rhythm of growth, cognitive and intellectual functions, and future performance at school, as well as an increasing morbidity/mortality due to other diseases [1113].

In the early 1980s in Brazil, several interventions of universal characteristics introduced by the Brazilian Public Health System, including important improvements in the sanitary conditions and in the quality of water, led to a dramatic decrease, of up to 90 %, in the mortality rates in childhood due to diarrhea [14]. Confirming these data, Maranhão et al. [15] conducted a case–control study in Natal, Rio Grande do Norte, in the northeast region of Brazil, including 206 infants under 2 years of age with acute diarrhea (103 patients), to evaluate the potential risk factors for persistence of diarrhea after 1 month of follow-up. The most frequent enteropathogens found in the stools in the infants with acute diarrhea were rotavirus (36%), EPEC (11.6%), and Shigella (11.6%). Only 5.2% of the patients showed persistence of the diarrhea. These results clearly demonstrated that implementation of vertical programs and long-term horizontal approaches can make the fourth Millennium Development Goal—to reduce by two thirds, between 1990 and 2015, the under-5-year mortality rate—achievable [16].


PD was defined by the World Health Organization (WHO) in 1987 as “a diarrheal episode of presumed infectious etiology that begins acutely, but has an unusually long duration, lasting more than 14 days,” leading to a deterioration of the nutritional status and a substantial risk of death. The term does not include chronic or recurrent diarrheal disorders, such as tropical sprue, celiac disease, cystic fibrosis, or other hereditary diarrheal disorders [17]. Although these other clinical entities were not included in the definition of PD by WHO experts, considering the present knowledge about the high prevalence of celiac disease around the world, it should be brought to attention as an important cause of protracted diarrhea that may lead to malnutrition, even in the developing countries [18].

Etiopathogenic Aspects

The enteric infections occur as a consequence of high levels of environmental contamination due to the lack of sanitary conditions and of access to potable water, associated with poor personal hygiene. Several different enteropathogenic agents can cause acute diarrhea in children. The agents that are isolated in the stools in children with PD are not always the same as those found in the acute phase of the episode. This finding suggests that a potential secondary infection may assume a relevant role in the persistence of the diarrheic process [19]. Moreover, isolation of multiple enteropathogenic agents in the stools of children with PD has also been reported [20]. The most frequent enteropathogenic microorganisms isolated from the stools of children with PD in several different centers around the world are listed in Table 1, modified from Bhutta [21].

PD represents the final consequence of a variety of injuries suffered by the child, who becomes prone to frequent and severe episodes of diarrhea due to a combination of several factors depending on the host and the undesirable effect of a prevalent environmental contamination. These episodes usually occur in children under 3 years of age [22]. Protein-energy malnutrition is seen as the major risk factor for the persistence of the diarrheic process [11]. Furthermore, other determinants must also be considered, such as a recent episode of acute diarrhea [23], zinc deficiency [24], lack of breastfeeding [2], male sex [25], infection due to EPEC and enteroaggregative Escherichia coli (EAEC) strains, Cryptosporidium [26], and past history of intrauterine growth retardation [25].

Table 1- Pathogens associated with persistent diarrhea

Enteroaggregative Escherichia coli
Entropathogenic Escherichia coli
Campylobacter Salmonella
Shigella spp
Clostridium difficile
Giardia lamblia
Blastocystis hominis1
Cryptosporidium spp.1
Entamoeba histolytica
Cyclospora cayetanensis1
Enterocytozoon bieneusi
(Microsporidium spp)
1 Especially associated with HIV infections

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