| Abstract|| |
Persistent diarrhea (i.e. acute episodes lasting more than 14 days) has been recognized by the WHO as a major public health problem in developing countries and a research topic of high priority. Persistent diarrhea is often associated with malnutrition, growth faltering, and a substantial risk of mortality in children below 5 years of age. Reported incidence and case-fatality rates from persistent diarrhea vary substantially. Substantial disagreement exists regarding definition, incidence and various putative risk factors. Resolution of such measurement related problems will allow for an accurate estimate of the force of morbidity and mortality from presistent diarrhea, while the elucidation of its risk factors will simplify policy making and the tailoring of intervention programs.
|How to cite this article:|
Galal OM. Persistent diarrhea as an emerging child health problem. Saudi J Gastroenterol 1997;3:34-40
Diarrheal diseases have been recognized as an important public health problem of children in developing countries  . The management of acute diarrhea with Oral Rehydration Therapy (ORT) has led to a significant decline in acute diarrhea-related mortality in the developing world  . However, improvement in the rates of use of ORT is unlikely to reduce mortality due to persistent diarrhea  . Persistent Diarrhea (PD) has been recognized in recent years as a major source of morbidity and mortality in the developing world  . A recent multicenter analysis of data from four countries showed that between 25% and 65% of diarrheal deaths could be attributed to persistent diarrhea  . However, the reported incidence of persistent diarrhea varies substantially in the literature, with no agreement on the exact magnitude of the problem. This disagreement arises partly out of measurement related isssues , .
This situation further confounded by the disagreement regarding risk factors for persistent diarrhea  . Research efforts need to concentrate on the elucidation of putative risk factors with a special focus on its association with malnutrition and growth faltering. Such a focus will enable policy makers to design appropriate intervention programs. Moreover, resolution of the measurement related problems will allow policy makers to properly assess the effectiveness of their interventions. This paper describes the putative risk factors of persistent diarrhea with emphasis on their relationship with malnutrition. It also discusses, briefly, some methodological issues pertinent to the measurement of persistent diarrhea.
| Definition of Persistent Diarrhea|| |
The World Health Organization in December 1987 recommended that persistent diarrhea be operationally defined as " a diarrheal episode that begins acutely and lasts for at least 14 days or more "  . Studies reported so far often used this cutoff point for describing the epidemiology of persistent diarrhea. However, studies in Brazil have shown that the duration of acute diarrhea episodes forms a continuum, most episodes terminating within seven days, and progressively smaller proportions persisting for 14,21 or 28 days  . Viewed from this perspective, "persistent diarrhea" as defined above does not represent a discrete subgroup of acute episodes, and its definition is arbitary. It is noteworthy to mention that the term "persistent diarrhea" is not intended to encompass chronic diarrheal disorders, such as hereditary syndromes, gluten-sensitive enteropathy or blind loop syndrome  .
| Incidence of Persistent Diarrhea|| |
Studies from around the world show that the incidence of persistent diarrhea (among children under the age of five) per 100 child-years varies substantially with a range of 7 to 150 episodes per 100 child-years. The ratio of acute diarrheal episodes to persistent diarrheal episodes also shows a high degree of variation, ranging from a low of 3.3 to a high of 30 acute episodes per persistent episode. The incidence of acute diarrhea also shows a similar pattern of variation. Probably most of the vatiations seen [Table - 1] are due to the different definitions of diarrhea employed by different studies , . However, there may also be inherent differences among separate geographical settings.
The incidence of persistent diarrhea varies with age and is highest in the first or second year of life after which it declines progressively [Table - 2]. This pattern is similar to the incidence of acute diarrhea and thereby provides additional evidence for the link between the two types. Most community-based studies report that the incidence of acute diarrhea and of persistent diarrhea does not differ by gender ,,,,,,,.
| Pathogens of Persistent Diarrhea|| |
A broad variety of enteric pathogens is associated with diarrheal incidence in the developing world. To ascertain this association, it is important to examine the enteric pathogens found during the first week of persistent diarrheal episodes as compared to those pathogens found during acute episodes. [Table - 3] shows the microbiological results from three prospective community-based studies ,, .
The data in [Table - 3] show that both (acute and persistent) types of episodes can be initiated by any of the wide array of enteric pathogens; although, it seems that Entero Adherent E. Coli does have an association with persistent diarrhea in some settings. Cultures of diarrheal episodes that have continued for more than two weeks yield a spectrum of enteric pathogens of frequency similar to that shown in [Table - 3]. In addition, examination of sequential cultures in the same episode in Bangladesh and Peru suggests that some of the persistent episodes might be due to sequential infections with different pathogens , . However, besides micro pathogens, it is probable that there are other host or environmental factors that influence the duration of diarrheal episodes.
| Malnutrition as a risk factor of persistent diarrhea|| |
Identification of risk factors for the persistence of an acute episode of diarrhea may be most useful in designing interventions and identifying children at risk. Risk factors, such as malnutrition, that can be modified by specific community-based interventions are of particular interest.
Association of malnutrition and persistent diarrhea
A strong association has been reported between persistent diarrhea and malnutrition ,,, . A prospective case-control study of 756 children followed for 18 months showed that among underweight children there is an increased risk of persistent diarrhea  . Another study reported that malnutrition was found to be the most frequent complication of persistent diarrhea, and that more than one-third of the children with malnutrition and persistent diarrhea died even after correcting dehydration  . These examples indicate that there is a mutually causative interaction between persistent diarrhea and malnutrition. That is, persistent diarrhea precipitates and exacerbates malnutrition while malnutrition predisposes to persistent diarrhea.
Malnutrition and feeding practices
Feeding practices are of particular importance in considering risk factors for malnutrition and persistent diarrhea. The concept of "weanling diarrhea"was first reported by Gordon et al. in 1963 describing the diarrhea that occurs with the transition of breastfed infants to a mixed diet  . Although the cause of weanling diarrhea is not well understood, the role played by malnutrition and infection appears to be crucial  . The risk of diarrhea is believed to be associated with weanling because (i) addition of food other than breastmilk exposes the child to environmental contamination, specially in communities with poverty and poor sanitation, and (ii) weanling is often a period of nutritional deficiency making the child more susceptible to infection  . In addition, food in developing countries are frequently contaminated with fecal organisms, and it has been shown that this contamination is a result of practices such as storing food at ambient temperatures for prolonged periods ,, . A case -control study by Galal et al compared children with persistent diarrhea to children with no instance of persistent diarrhea (matched for birthdates )  . Nature of the introductory solid food was the most strongly associated (p<0.1) factor with cases less likely than controls to have had yogurt as the first food. This finding should be investigated by further research, because if yogurt has a beneficial effect on the duration of diarrheal episodes then yogurt (an inexpensive and easily available food item) can be promoted as a "weanling food"in the developing countries. Available evidence suggests that lack of breast-feeding is associated with a higher risk of persistent diarrhea, a fact which has obvious policy implications. Recent studies also show the protective value of breast-feedig in preventing, in particular, deaths from persistent diarrhea , .
Malnutrition and micronutrients
Decreased cell-mediated immunity is known to be associated with malnutrition, but the specific mechanisms of this association are vague , . However, it is possible that this immunosuppression is associated with specific micronutrient deficiencies. Vitamin A, zinc, iron, and other micronutrients are known to affect the functioning of the immune system  . Micronutrient deficiencies may also reduce cell renewal and this might explain the relation between such micronutrients as zinc and diarrhea morbidity  . Vitamin A deficiency may either predispose to prolonged diarrhea or may be a consequence of it. In a prospective community-based study, Sommer et al showed that children with mild xerophthalmia were three times more likely to suffer from diarrhea than those without  . Community-based intervention studies have also shown that vitamin A supplementation in children with subclinical vitamin A deficiency significantly reduced mortality , . These studies however did not identify the process through which mortality is reduced. It is plausible that the mortality reducing effect of vitamin A is mediated partially via its beneficial effect on persistent diarrhea.
Malnutrition and mucosal injury
In malnourished children, many of whom also have diarrhea, a number of histologic abnormalities are seen in the small intestine. These abnormalities include thin mucosa, blunt microvilli, and a decreased mitotic index , . The latter finding suggest that intestinal repair may be delayed. Protein-energy malnutrition is known to affect the ability of the intestinal mucosa to regenerate providing an attractive explanation for this association  . Additional information is required to ascertain the role of malnutrition in the structural and functional abnormalities of the intestinal epithelium and the importance of these changes in the pathophysiology of persistent diarrhea and growth faltering.
Malnutrition and oxidative stress
Oxidative stress as induced by oxygen free radicals has been implicated in the pathogenesis of many human diseases in recent years  . Considerable literature dealing with the role of oxidative stress in human disease has been published ,, . Surprisingly, although malnutrition is an underlying cause of many infectious diseases, very little effort has been made to evaluate the role of oxidative stress in the infectious diseases of malnourished children, particularly the diarrheal diseases. Recently an attempt was made to put together some evidence to implicate the role of oxidative stress in the pathogenesis of diarrheal diseases of malnourished children  . Further research is required to elucidate the machanism through which oxidative stress acts in the pathogenesis of diarrheal diseases, including persitent diarrhea.
Causal hypothesis of persistent diarrhea
Different causal hypotheses have been advanced in order to explain why some episodes of diarrhea last for more than 14 days  . One of these suggests that the delayed recovery is a function of some weakness of the host rather than the infecting agent. The most compelling argument for this hypothesis is the close association between preexisting malnutrition and duration of diarrhea. The importance of considering this hypothesis is that if focuses our attention on a series of possible treatment strategies that merit further investigation. It is important to point out that the presence of many causal hypothesis do not change the adverse consequences of persistent diarrhea or the need for interventions to reduce the mortality and morbidity associated with this sequelea of acute diarrhea. The fact remains, diarrhea is bad for children's health and when children have more diarrhea as in a persistent episode then the consequences are more serious. Thus, differences in the underlying cause of persistent diarrhea should not lead us to ignore the adverse nutritional aspects of persistent diarrhea; instead we should focus our attention on providing adequate nutrition during all diarrheal episodes, especially when they are prolonged.
Measurement of persistent diarrhea
In community studies, diarrheal morbidity experienced by a child is usually measured either as the total number of days with diarrhea during a specified period, or the total number of episodes during a specified period. These alternatives are related respectively to the prevalence and incidence of diarrhea in the study population. Using the total number of episodes as a measure of diarrheal morbidity raises several problems. The main problem is the definition of an "episode". In most studies, a record is available for each day stating whether the child had diarrhea on a particular day or not. Such data usually reveal a pattern composed of a sequence of diarrheal days followed by a few "diarrhea-free" days, followed again by another sequence of diarrheal days. Interpretation of such a pattern poses the question: are there two episodes or is it a single interrupted episode ?
Episode definition is the most serious and ambiguous issue in the measurement of persistent diarrhea , . The usual approach to the definition of diarrheal episodes is to state that a sequence of days with diarrhea will be regarded as a new episode provided it is separated from previous episodes by a gap of "n" diarrhea-free days. The value assigned to "n"has varied from 2 to 14 days, with 3 days being the most common  . However, the basis for this choice remains unclear. Pickering and associates studied 244 children in a Gambian community for 15 weeks and observed that the number of persistent episodes doubled when seven rather than three "diarrhea-free" days were requird to define a new episode and tripled when seven (rather than one) "diarrhea-free" days were required  . They concluded that the length of an episode was most sensitive to the choice of definition. Baqui and colleagues in a study of 512 Bangladeshi children observed a 14 percent increase in the incidence of PD when a three"diarrhea-free" days definition of episode was replaced by a seven "diarrhea-free" days definition  . In general, increasing the number of "diarrhea-free" days will increase the number of persistent diarheal episodes. This picture is further complicated by the fact that there is no standard criterion for classifying a day as a "day with diarrhea". For classifying a day as a "day with diarrhea" different studies have used different definitions. Among the most common are: at least three or more loose stools in 24 hours; at least four or more loose stools in 24 hours; at least one stool containing blood in 24 hours. Any day with less than three loose stools or stool with no blood is classified as a "diarrhea-free day". However, the term "loose stools" is very problematic as stool consistency is not solely determined by the water content  . Similarly, it is not uncommon to see a healthy child or infant pass four or more stools per day  . Thus, neither stool frequency nor stool consistency is always reliable in determining pathologic diarrhea. These differences in definitions and classifications tend to overestimate cases of persistent diarrhea and underestimate total rates of diarrhea or vice versa thus making the presence of trends, if any, and obscuring the true magnitude of the problem. There is an urgent need for developing universally acceptable definitions for a "diarrheal episode" and for the number of stools required to classify a day as a "day with diarrhea". Overcoming these measurement problems will allow for an accurate estimate of the force of morbidity and mortality from presistent diarrhea. Availability of accurate estimates will enable policy makers to measure the "true" impact of intervention strategies.
| Conclusion|| |
In the view of the author, one way to partially overcome this "measurement problem" is to describe the diarrheal morbidity experience of study subjects in terms of the proportion of time spent in diarrheal episodes during a given period, i.e. episodic prevalence , . The use of episodic prevalence as opposed to incidence will be free from the "errors" introduced by the curent lack of a universally acceptable number of "diarrhea-free" days for separating two diarrheal episodes; it will also mitigate the uncertainties arising from simple point prevalence measurements. Furhtermore, if the objective is to assess the impact of diarrheal morbidity on the well-being of the child, for example, its effects on growth, proportion of time spent with diarrhea (episodic prevalence) might be the preferred measure. Adoption of episodic prevalence will also make it possible to elucidate further the differences between populations (by examining their respective frequency distributions) , . Therefore, it is suggested that from now on all geographic studies of diarrhea should attempt to give the proportion of time spent in episodes by the study subjects. This suggestion should not be understood as an endorsement of episodic prevalence over incidence (or other prevalence) measures, instead it is a pragmatic approach for describing the diarrhea-related morbidity experience of a community and for comparing the experience of one community to another. The importance of using validated and standardized definitions in epidemiological studies cannot be over emphasized. Lack of standardized definitions are likely to lead to disease misclassifications and to imprecise estimates of the disease-burden in communities, thereby reducing the comparability of findings from different studies. For diarrhea control programs to receive their due portions of the scarce health resources, the impact of diarrhea on the community must be well described.
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Osman M Galal
Intemationl Health Program, University of California, Los Angeles School of Public Health, 10833, Le Conte Avenue, Los Angeles, CA 90024-1772
Source of Support: None, Conflict of Interest: None
[Table - 1], [Table - 2], [Table - 3]