Bhutta, Zulfiqar Ahmed; Hendricks, Kristy M.*
Nearly a decade ago the World Health Organization (WHO) estimated that there were approximately 700 million episodes of diarrhea annually among children under 5 years old in developing countries, resulting in 4.6 million deaths (1). Despite vast improvement in the management of acute diarrheal disorders and oral rehydration therapy, it is estimated that diarrheal diseases still account for up to 30% of all hospital admissions in developing countries (2). A recent review of the global status of diarrhea indicates that although there has been a general reduction in mortality rates due to acute dehydration, there has been little decrease in the incidence of diarrheal disorders (3). Of the various aspects of childhood diarrheal disorders, in recent years persistent diarrhea (PD) has assumed special importance for health workers and program planners (4).
PD: DEFINITION AND GLOBAL SIGNIFICANCE
Although a variety of disorders can present with prolonged diarrhea in childhood—e.g., celiac disease, food allergies, hereditary bowel abnormalities, and toddler's diarrhea (5)—it is the diarrheal episode following infection, which starts acutely and becomes prolonged, that most concerns health-care providers in the developing world. A variety of different definitions for such prolonged episodes of diarrhea have been employed previously, including episodes of diarrhea requiring intravenous fluids for >72 h (6) and some which necessitate quantification of stool output (7). Some of the methodological issues in adequately defining PD to overcome the apparent heterogeneity of the disorder have been highlighted by Stanton and Clemens (8).
The WHO defines PD as “diarrheal episodes of presumed infectious etiology that begin acutely but last at least 14 days.” Such episodes have been recognized to account for between 3% and 20% of all diarrheal episodes in children under 5 years of age (4). In several large community-based studies of diarrhea (4,9,10) it has been shown that PD is directly responsible for between 36% and 54% of all diarrhea-related deaths. It has, however, been pointed out that such differences in mortality between different regions may be related to environmental characteristics as well as differences in utilization of health care and oral rehydration therapy (11). Although PD accounted for only 5% of all diarrheal episodes in a large prospective study of diarrhea in north India, the case fatality rate for PD was 14% in comparison with 0.7% for episodes of shorter duration (12). It has been recognized that diarrheal episodes in childhood form a continuum, with the majority being of short duration (i.e., less than 1 week) and a smaller proportion of episodes of longer duration (13). Although the aforementioned division of diarrheal episodes into acute and PD may be arbitrary, this operational definition does identify children with significantly increased diarrheal burdens. Lima et al. (14), in a prospective study in northeastern Brazil, demonstrated that all children with a heavy diarrheal burden (defined as >16% of total days spent with diarrhea) had at least one episode of PD during a 1-year study period. Similar observations by Moy et al. (15) from a rural cohort of 204 children in Zimbabwe indicated that although PD accounted for only 6% of all diarrheal episodes, these included 22% of the total days of diarrhea recorded in this study and that these children also had higher rates of diarrheal relapse at follow-up. Thus, children with PD may not represent a distinct subgroup but form part of a continuum in an individual's susceptibility to diarrhea.
Apart from the well-recognized association of PD with increased mortality, the nutritional impact of PD is most evident in the developing world. Prolonged and recurrent episodes of diarrhea frequently lead to stunting and growth failure in early childhood. The consequent malnutrition further predisposes to recurrent episodes of PD, and a vicious cycle of diarrhea-malnutrition-diarrhea follows. The negative nutritional effect of PD is compounded by anorexia, ineffective weaning practices, and food withdrawal by caretakers (16). PD has thus been aptly labeled as a nutritional disorder (17), and optimal nutritional therapy is generally considered a cornerstone of its management. Although a variety of issues are of interest in PD, this review will focus on different aspects of the management of PD in the developing world, where, in contrast to the various disorders causing prolonged diarrhea, the postinfectious nature of the disorder is more clearly defined and the therapeutic options relatively stark.
FACTORS PREDISPOSING TO PD: IMPLICATIONS FOR THERAPY
Given the aforementioned reasons, it is important to recognize the various factors associated with increased duration and severity of diarrhea, even though an episode may not strictly conform to the definition of PD. Recognition of factors predisposing to prolongation of diarrhea may allow interventions aimed at prevention of PD as well as institution of early and effective therapy.
Overall, the greatest risk of PD is in younger infants. In a large study from northern India the incidence of PD in infancy was five to sixfold higher than in the subsequent 2 years (12), and the risk was greatest in the 6-11-month age group. Similar data on age distribution have been reported from rural Bangladesh and Zaire (18,19). However, Lanata et al. (20), in a study of 677 children under 3 years of age in a periurban community near Lima, Peru, found that the proportion of PD episodes was highest in the 0-5-month age category compared to children aged 6-35 months (6.11% vs. 2.7%). Similarly, in South Africa, Househam et al. (21) observed that the likelihood of prolonged duration of diarrhea was highest in the very young infant (<3 months of age), especially in association with malnutrition. In the latter studies, however, PD episodes were related mostly to lactation failure and early initiation of artificial feeds. Where exclusive breast-feeding is the norm in the first half of infancy, diarrheal episodes and PD usually follow the introduction of weaning foods.
Although the close association between diarrhea and malnutrition has long been recognized, this view has been challenged by Briend (22). Several cohort studies, however, have demonstrated clear growth faltering with malnutrition after prolonged and recurrent diarrhea. Schorling et al. (9), in a study of malnourished children in Goncalves Dias, Brazil, observed an ablation of catch-up growth with progressively increasing diarrheal burdens. The same group also observed significantly increased frequency and duration of diarrhea in malnourished children, with an almost twofold increase in diarrheal burden in malnourished children (14,23). The association of malnutrition with PD has also been highlighted in a number of case-control studies from India (24,25) and Bangladesh (26). In a recent verbal autopsy review of 1,934 diarrhea-associated deaths from Bangladesh, Fauveau et al. (10) found that 49% of all deaths were in malnourished children with PD. Of 133 PD cases, 81% were associated with malnutrition, and the relative risk of dying with PD and severe malnutrition was 17-fold higher than in children with lesser degrees of malnutrition. The relationship between nutritional status and diarrhea has been recently reviewed by the Subcommittee on Nutrition and Diarrheal Diseases Control (Food and Nutrition Board, Institute of Medicine; 27). Malnutrition was indicated to be a significant risk factor for diarrheal disease, possibly by affecting one or more key factors (e.g., incidence, duration, or severity of illness). Impaired immune function, poverty, lack of breast-feeding, inadequate or inappropriate foods, and increased pathogen transmission may all play a role in this association. Although more longitudinal studies following growth, dietary intake and morbidity are needed, there does appear to be a predisposition to development of PD in malnourished children, and this risk should be recognized in every malnourished child with diarrhea.
Although the association between malnutrition and PD is multifactorial, altered immunity predisposing to increased risk of infection has been a major focus of attention. Black et al. (28) demonstrated an increase in the incidence of diarrhea with delayed cutaneous sensitivity but could not show an association with increased duration of diarrhea. Two subsequent studies from Bangladesh found a significant association between anergy and increased incidence and duration of diarrhea (29,30). Additional evidence linking nutritional status and immunity with increased risk of PD has emerged from studies of HIV-infected infants in both developed and developing countries. In a cohort of 429 Zairian infants (53 with HIV infection, 139 uninfected offspring of infected mothers, and 191 born to uninfected mothers) Thea et al. (19) identified significant growth-faltering 6-8 weeks prior to the onset of PD but not episodes of acute diarrhea in HIV-infected infants. These infants also had significantly increased mortality from PD but not acute diarrheal episodes. Increased diarrheal risk was also seen in uninfected infants whose mothers were ill or had died. The authors speculate that maternal inability to care for and feed infants was associated with this increased diarrheal morbidity and mortality. An increased risk of repeated episodes of diarrhea and development of PD in HIV infection, some effects of which may be attributable to malnutrition, has also been highlighted in a study from Baltimore (31).
The association of PD with alteration in nutritional status, immunity, and food and water contamination strongly suggests an infective basis. Recent light microscopic and ultrastructural studies of the bowel mucosa in children with PD are also indicative of a bacterial pathogenesis (32,33). In recent years there has also been considerable interest in the pathogenetic role played by enteroaggregative Escherichia coli, which have been found in children with PD from a number of different geographic locations, including India (12), Mexico (34), Brazil (35), and Peru (20). The protozoon Cryptosporidium has also been isolated more commonly from children with PD irrespective of their immune status (36,37) and has been shown to be independently associated with increased mortality in African children (38). However, several sequential studies looking at bacterial isolates in acute diarrheal disorders which went on to become persistent have failed to consistently identify any specific pathogens (13). It is conceivable that the syndrome of PD represents the end result of an infective process previously initiated some time ago, and bacteriological studies during individual episodes of PD may be inconclusive. Although several prospective studies exploring the possibility of small bowel bacterial overgrowth in PD have failed to find a consistent pattern (39,40), Hill et al. (41) reported a significantly improved stool output as well as protein and fat absorption in children with PD receiving a combination of oral gentamycin and cholestyramine. Two large randomized, controlled studies have subsequently failed to duplicate their observations and could not demonstrate any benefit of oral gentamycin in comparison to a placebo (42,43).
In summary, it appears that both acute and prolonged diarrhea can be initiated by a wide array of organisms, although certain organisms may be more likely to cause a prolonged intestinal inflammation leading to PD. Thus presently, unless a specific enteropathogen amenable to antibiotic therapy is identified in PD, such as Shigella, Giardia lamblia, Cryptosporidium, etc., blind antibiotic therapy is not indicated in a child with PD. However, it must be emphasized that many malnourished children with PD have significant coincidental infections requiring antibiotic therapy, and judicious and prompt use of antibiotics may be life-saving under these circumstances.
Given the observation that the duration of diarrheal episodes forms a continuum, most factors that increase the duration of acute diarrheal episodes would also be expected to predispose to the development of PD. Such additional factors include bloody or mucoid diarrhea, lack of breast-feeding, coexisting chest infection, and routine use of contaminated surface water (44). The association of increased duration of diarrhea with previous episodes of diarrhea has been highlighted in a number of studies (45,46). Although both bloody mucoid diarrhea (26,44) and increased severity of diarrhea in the first week (47) have been associated with an increased risk of developing PD, there are no laboratory features of acute diarrhea that are strongly predictive of the risk of developing PD (20). In summary, PD seems to represent the end result of a variety of insults in a child predisposed to frequent as well as more severe episodes of diarrhea by a combination of host factors and greater environmental contamination. Therefore, efforts should be made to promptly treat all episodes of diarrhea with appropriate follow-up.
PATHOPHYSIOLOGY OF PD AND IMPACT ON NUTRIENT ABSORPTION
A clear understanding of alterations in intestinal morphology and function is crucial in developing a strategy for nutritional intervention. Much of the difficulty in instituting satisfactory dietary therapy of PD stems from lack of a clear understanding of these alterations. While satisfactory absorption of macronutrients has been demonstrated in acute diarrhea (48,49) and during nutritional rehabilitation of protein energy malnutrition (PEM; 50), it is uncertain if the same holds true in PD.
In most cases the main nutritional impact of PD is on the bowel mucosa with altered bowel mucosal morphology and nutrient absorption. Lebenthal (51) has described the process as one of “prolonged intestinal mucosal injury with ineffective repair mechanisms.” In a recent study of Gambian children with PD, no consistent pattern of pathological changes was seen and a wide variety of mucosal abnormalities were highlighted (52). These ranged from a near normal appearance to mucosal flattening, crypt hypertrophy, and mucosal infiltration with lymphocytes. More elaborate light microscopic and electron microscopic studies on children with PD and malnutrition have revealed widespread patchy villous atrophy and a modest increase in intraepithelial lymphocytes but no evidence of plasma cell activation (32,33). Nichols et al. (53), employing monoclonal antibodies against brush border enzymes, have also indicated a mosaic pattern of brush border enzyme deficiency, suggesting acquired mucosal damage. Several other studies have highlighted the lack of correlation between mucosal lesions and disaccharidase activity (54-56), and although this has been labeled as an essential investigation for PD in developed countries (57), others have debated the issue (58). In the developing world, available evidence suggests that in the vast majority of children with PD an intestinal biopsy may not be necessary to plan or institute nutritional therapy. However, the procedure may be helpful in certain subgroups of children with alternative disorders, such as celiac disease, milk protein allergy, inflammatory bowel disease, etc., and should therefore be considered in children who fail to respond to standard treatment for PD.
In addition to the reduced absorptive surface area due to the enteropathy in PD, a number of other factors affect dietary absorption of macronutrients, including luminal, brush border, and intracellular enzymatic and digestive mechanisms. Luminal factors are of particular importance in fat absorption. Hydrophilic micelles are formed in the lumen in the presence of bile salts, which facilitate the passage of fatty acids and monoglycerides across the intestinal mucosa. Although alterations in pancreatic exocrine function have been observed in malnourished children (59,60), it is uncertain if these are of clinical significance. Schneider and Viteri (61,62), in a series of studies in malnourished children, some of whom had diarrhea, demonstrated reduced concentration of bile salts with altered micelle formation in the lumen and subsequently decreased fat absorption. However, values became normal with nutritional recovery. Studies in adults of production rates of pancreatic enzymes using 14C-labeled amino acids also indicate that the rate of enzyme production increases rapidly on reinstitution of amino acid supply (63). Several metabolic balance studies in malnourished children with PD have also demonstrated satisfactory tolerance and absorption of fat (64,65).
The major effect of diarrhea appears to be on the mucosal brush border enzyme systems, with the carbohydrate digestive mechanism being the most susceptible. These disaccharidases, located on the luminal enterocyte surface, are affected by most processes of mucosal injury. The lactase enzyme appears to be the most susceptible (66), but sucrase, glucoamylase, and isomaltase may also be affected to a lesser extent (67,68). The monosaccharide transport mechanisms are usually intact in children with PD, as judged by the tolerance of glucose-electrolyte solutions. However, in severe injury monosaccharide absorption may also be deficient. Such acquired monosaccharide intolerance, when present, probably represents a subset of severely affected children (69-71). An additional mechanism of fermentation of unabsorbed carbohydrate by colonic bacteria to short chain fatty acids also seems to be operational (72,73). Such “colonic salvage” of unabsorbed carbohydrate improves water and sodium absorption and reduces the osmotic penalty of carbohydrate malabsorption. There is clear evidence that short chain fatty acids released by colonic fermentation of dietary fiber stimulate intestinal epithelial proliferation (74,75). In view of the emerging evidence of the potential benefit of dietary fiber in feeding children with acute diarrhea (76), this may also have important implications for diet selection in children with PD.
The degree of effect on brush border peptidase activity is far less than that on disaccharidase activity (77), and satisfactory protein digestion can take place. However, the mucosal protein absorption and enteric losses of protein may be affected where PD follows an invasive diarrheal illness. Increased intestinal protein losses have been described after shigellosis (78,79), and it is conceivable that PD following dysenteric illnesses may be associated with greater endogenous protein loss, reduced protein absorption, and stunting (80). Such endogenous protein losses in PD may also account for comparatively greater reduction in coefficient of absorption (COA) of protein in various metabolic balance studies (Table 1; 64,65,81-85).
ROUTE OF FEEDING
Although the benefit of early reinstitution of enteral feeds in children with acute diarrhea has been well documented for some time (86), the optimal route of therapy in children with severe or PD continues to be a subject of much controversy. In a series of metabolic balance studies in children with prolonged diarrhea, Mann et al. (87) had suggested that enteral nutrition may not be possible with stool output exceeding 30 g/kg/day. In view of such concerns about the integrity and capacity of intestinal absorptive mechanisms and the potential of worsening gastrointestinal damage with continued feeding, earlier studies of nutritional rehabilitation of children with PD relied upon total or partial parenteral nutrition (88-90). Despite vast improvements in the techniques and substrates for total parenteral alimentation (91), this mode of therapy is very expensive and fraught with the risk of complications such as sepsis and metabolic derangement. In the context of the developing world, parenteral nutrition is clearly an impractical option. However, despite limitations, the option of intravenous feeding does save lives in circumstances where there is an unsatisfactory response to enteral therapy with continued clinical deterioration and should be available in specialized hospitals in the developing world (92).
Support for enteral nutritional rehabilitation also grew from experimental observations that lack of enteral stimulation delayed the intestinal mucosal recovery process and regeneration (93,94). In early studies by Greene et al. (54) comparing the response to various forms of nutritional therapy in malnourished infants with PD, those receiving total parenteral nutrition had a longer duration of hospitalization and a slower rate of recovery of intestinal brush border enzyme activity in comparison with those receiving additional enteral feeds (mean 46 vs. 34 days). Orenstein (95) randomly allocated 13 infants with intractable diarrhea to either total parenteral nutrition or continuous enteral infusion of an elemental formula. Although the rate of recovery of malnutrition was similar in both groups, the group receiving enteral infusion had a significantly faster resolution of diarrhea (2.8 vs. 9.8 weeks). In view of this evidence, most recent studies of nutritional intervention in PD have primarily focused on enteral feeding.
PRINCIPLES OF ENTERAL NUTRITIONAL THERAPY IN PD
Given the close association between PD and malnutrition, most of the principles governing nutritional therapy in PD are similar to those of nutritional rehabilitation of malnourished children. Given the practical limitations of hospitalizing a large number of children with PD for nutritional rehabilitation, it is imperative that optimal mechanisms be found for rapid nutritional rehabilitation in an ambulatory setting. While there is considerable evidence of a state of metabolic adaptation in children with prolonged malnutrition (96,97), in most cases PD and malnutrition represent a relatively acute situation, where nutritional rehabilitation should proceed with reasonable alacrity. As the duration of diarrheal episodes does represent a continuum, several of the principles of managing acute diarrhea are also pertinent to the management of PD. Close attention must be paid to correction of dehydration, acidosis, electrolyte abnormalities, and hypoglycemia, as well as treatment of concomitant infections. Once the initial resuscitative process in malnourished children has been completed, further rehabilitation can proceed fairly rapidly.
Studies in malnourished children indicate that many can gain substantial amounts of weight on ad libitum feeding, with rates of weight gain as high as 10-20 g/kg/day (98,99). In general, malnourished children (excluding kwashiorkor) with PD should be offered an initial caloric intake of at least 75 kcal/kg/day, increasing with increments of 25 kcal/kg/day to a target of 150 kcal/kg/day by day 4-5, and subsequently allowed to feed ad libitum until the child refuses further feeds or develops signs of intolerance (100). Although others (101) have noted a limitation in caloric intake despite ad libitum feeds in children with PD, our own studies of nutritional rehabilitation have indicated satisfactory tolerance of caloric intakes of 150-200 kcal/kg/day, with weight gain in excess of 10 g/kg/day (102). The fact that energy rather than protein may be the limiting factor in nutritional rehabilitation was pointed out several years ago by Waterlow (103) and Ashworth et al. (104). It was, therefore, recommended that high-energy feeds be given to such children to accelerate the recovery process by providing extra energy, usually in the form of fat as it is calorically most concentrated (98,105). The nature of weight gain achieved on these high-energy intakes has been questioned by others as being predominantly adipose tissue (105), and an optimal protein/energy ratio is recommended. Such an optimal composition of diets used for rehabilitation may be possible only by using an adequate mixture of milk (or formula) with additional concentrated calories. It has also been documented that selective micronutrient deficiencies may result during the course of therapy, which may in turn limit appetite and weight gain. Golden et al. (106,107) showed that in malnourished children fed a soy-based formula adequate in energy density and protein composition, although the rate of weight gain was adequate, body composition was altered with increased adipose tissue deposition. Subsequent studies of zinc supplementation in malnourished children indicated that the rates of both lean tissue deposition (108) and weight gain (109) improved. Studies of body composition in malnourished children provided 145 kcal/kg/day and a protein intake of 11% of daily energy intake have shown rapid weight gain (12-16 g/kg/day) and increased lean body mass (110,111). Kabir et al. (112) recently studied several malnourished children on a high-protein (15% of energy intake) diet during convalescence from shigellosis and demonstrated rapid catch-up growth and improvement in serum proteins. A crucial issue, therefore, is selection of a diet or dietary formulation which provides an optimal mix of micronutrients, a suitable protein/energy ratio, and adequate caloric density.
It has been shown elegantly by Brown (113) that non-breast milk foods consumed by children fail to provide an adequate nutrient density and the recommended daily dietary allowances, unless small amounts of milk are also added to the diet. Studies conducted by the Nutrition Collaborative Research Support Program (NCRSP) in Egypt, Kenya, and Mexico have shown that the amount and bioavailability of specific nutrients in the child's diet may be at least as important for growth as the total amount of food or energy available (114). Deficiencies of micronutrients have also been shown to decrease host resistance to infections; thus, a diet adequate in calories and protein but inadequate in micronutrients such as vitamin A, iron, and zinc may still leave the child vulnerable to diarrhea. In a recent review, Allen (115) concludes that the inconsistency in reported growth-promoting benefits of single-nutrient supplements may be partially explained by multiple growth-limiting nutrient deficiencies existing in the same child and that the focus should be on dietary patterns rather than single-nutrient intakes. Diarrhea is also likely to decrease the intake and increase the loss of multiple nutrients simultaneously. This emphasizes the importance of total dietary quality as a risk factor for malnutrition and diarrhea. Multi-mixes containing the staple cereal of a country and additional ingredients that complement cereal proteins, such as animal products, vegetables, nuts, and seeds, have been used throughout the developing world to improve the nutrient density of diets (116). This method of developing nutritious multi-mixes of two, three, or four ingredients, designed to complement and mutually reinforce one another, is becoming more desirable in managing malnourished children. The dietary pattern becomes increasingly nutritionally desirable the greater the number of ingredients, especially when small quantities of animal protein are available. Multi-mixes could theoretically supply most dietary constituents and micronutrients and may be suitable for children recovering from PD as well. As these mixtures vary based on cultural practices and food availability, they may be more acceptable for home use. The ultimate objective is to provide a nutritionally sound feeding using locally available foods that fit into local beliefs and practices. Few clinical investigations exist and more are needed on the effectiveness of balanced dietary feeding during diarrhea and convalescence, evaluating efficacy of feeding on both diarrheal recovery and nutritional status.
Thus, following stabilization, treatment of inter-current infections, and correction of acidosis, malnourished children with PD should receive an adequate dietary mix targeted to provide a daily caloric intake in excess of 150 cal/kg/day and an adequate protein intake (10-15% of energy intake or 1.5-2 g protein/kg/day). In addition, because volume of intake is frequently limited in PD, especially younger children, caloric density of a feeding is of particular importance. Thus, it has also been recommended that caloric density of the diet should range from 80 to 100 kcal/100 g (breast milk having a caloric density of 67 kcal/100 g) and that the osmolality of the dietary formulation should not exceed 350 mOsm/l to avoid the risk of osmotic diarrhea (100).
In addition to the crucial issue of diet composition and rate of refeeding, there are several other important factors which affect nutritional therapy of malnourished children with PD. Coexisting infections and metabolic complications of diarrhea, such as acidosis, could also affect appetite and hamper tolerance of dietary therapy. Concomitant enteral fluid losses and electrolyte imbalance would also need to be rectified. Additional requirements of large volumes of intravenous or oral rehydration fluids may also limit dietary intake during the early stages of rehabilitation (117). It is particularly in these circumstances, where an anorectic sick child requires frequent feeds, that food preparation time, caretaker fatigue, and inability to devote sufficient time to a single child become important. Such issues become particularly important in selecting diets for ambulatory therapy in malnourished children with PD.
WHAT TO FEED?
The various therapeutic options available for enteral nutrition in children with PD include the following broad categories: elemental diets; milk-based diets, including human, animal, or soy milk; chicken-based feeds; and traditional local diets. Given that the duration of diarrhea seems to form a continuum, many of the observations on feeding during acute diarrhea may be relevant for the dietary management of PD.
Elemental diets include a variety of liquid formulations containing crystalline amino acids or protein hydrolysates, mono- or disaccharides, and a combination of long and medium chain triglycerides. Some of these diets are also hyperosmolar, and glucose polymers may be added to counterbalance this effect. Elemental diets are frequently employed in developed countries in the therapy of PD and intestinal disease, especially when dietary protein sensitivity is suspected (5).
Earlier studies with a free amino acid and glucose diet in PD indicated abnormally low branched-chain amino acids and cystine absorption but satisfactory resolution of the diarrhea (118). Subsequent uncontrolled studies comparing elemental diets with total or partial parenteral nutrition indicated equally satisfactory resolution of diarrhea with both modalities of therapy (119,120). However, other studies comparing elemental diets with parenteral nutrition indicated significant advantage of enteral feeding with a more rapid resolution of diarrhea and reduced cost of therapy (54,95). In the developing world context, the efficacy of elemental diets in the therapy of PD in hospitalized children has been demonstrated by studies from Peru (121) and Thailand (64). Table 2 summarizes the pertinent findings and outcomes in various studies of feeding elemental diets to children with PD. In the developed world these elemental diets form the cornerstone of nutritional management of the child with prolonged diarrhea or food intolerance. Despite the evidence of their efficacy, elemental diets are usually unpalatable and frequently require nasogastric infusion to achieve satisfactory intakes. Moreover, the major limitations of elemental diets, in terms of therapy in the developing world, are their prohibitive cost and limited availability.
Given the propensity of PD in the younger age group, it is natural that milk forms a major part of the dietary intake in these children. The majority of studies have evaluated human milk, animal milk, and soy milk in PD.
Human Milk Feeds
Despite a significantly higher lactose content compared with formula feeds, it is unusual to see clinically significant lactose intolerance in breast-fed children. There is clear epidemiological evidence that breast-fed infants have infrequent and shorter episodes of diarrhea (122,123). The majority of cases of PD are also seen in the wake of failure of exclusive breast-feeding (44,124,125), and it is extremely unusual to see an exclusively breast-fed infant with PD. The reasons for this may be immunological as well as nutritional. However, it is not uncommon to see the disorder in partially breast-fed infants, especially after introduction of contaminated weaning foods and supplemental milk feeds (125-127).
There are ample clinical studies indicating the benefits of continued breast-feeding in acute diarrhea (128,129), and indeed feeding a modified human milk with high antirotavirus antibody titers to children with chronic rotavirus infection led to clinical improvement (130). MacFarlane and Miller (131) treated 11 infants with PD unresponsive to multiple formula changes with banked human milk and observed cessation of diarrhea and reversal of weight loss in all cases. In contrast, Shulman et al. (132), in a randomized clinical trial evaluating a continuous infusion of heat-processed human milk in comparison with sterile water feeds and parenteral nutrition in children with severe PD, observed a comparable time to clinical recovery (mean 47 vs. 46 days). However, the mean daily weight gain was higher with human milk feeds (13.8 vs. 9.7 g/kg/day), and it is possible that fresh human milk may have been more effective.
Although it is unlikely that adequate amounts of fresh human milk would be available for therapy of children with PD, in view of overwhelming evidence of nutritive and immunological benefits of human milk in infants with PD who are partially breast-fed, frequent breast-feeding should be encouraged.
Animal Milk-Based Feeds
The majority of children with PD are receiving artificial formula or intact animal milk (124,125); thus, it is prudent to explore the role of these nonhuman milks in PD.
Cow's milk-based formulas. The evidence to date exploring the role of cow's milk-based feeds in acute diarrhea indicates that the problem of potential lactose intolerance may have been overstated and that there is no advantage of a graded reintroduction of milk (133,134). In a general review of milk feeding in diarrhea, Brown and Lake (135) concluded that the median rates of complications were 15% higher with cow's milk-based feeds and that milk-containing regimens were associated with an 85% increase in stool output and a 42% increase in diarrheal duration. Milk feeding was also associated with a greater risk of therapeutic failure in younger children and those with severe diarrhea. Despite this evidence, as milk does form a substantial part of diet during infancy, several therapeutic options of feeding lactose-reduced or fermented milks and milk-cereal combinations have been studied. In two recent studies (136,137) the effect of feeding a combination of a mixed diet and milk were studied in children with acute diarrhea, and no evidence of lactose intolerance was found when the milk was offered in combination with a local staple.
Despite the evidence of milk tolerance in children with acute diarrhea, there is no clear consensus as to the efficacy of cow's milk-based feeds in PD. Solomons et al. (138) demonstrated poor tolerance of milk feeds in children with severe malnutrition, several of whom had diarrhea. Mann et al. (87), in a comparison of cow's milk, a soy formula, and a casein-based low lactose formula in children with prolonged dehydrating diarrhea of >7 days, also found a significantly better reduction in stool volume with the latter two formulations. It is, however, difficult to ascertain if the higher failure rate with the cow's milk formula is related to the lactose content alone, as other dietary constituents such as milk protein may also cause sensitization and enteropathy. To evaluate the specific effect of lactose feeding in PD, Penny et al. (83) randomized two groups of children with PD to receive a lactose-containing (6 g/kg/day) diet or a comparable amount of hydrolyzed lactose. The stool output and the duration of diarrhea were significantly higher in the lactose fed group. In addition, metabolic balance studies indicated that fecal losses of carbohydrate, protein, and energy were also significantly higher in the lactose fed group. These data from relatively well-nourished children with PD provided evidence that lactose content of diets fed to these children should not exceed 5 g/kg/day.
Unmodified animal milks. In the developing world unmodified animal, especially bovine, milk is commonly used by parents and physicians for several reasons, including cost, availability, and problems in artificial formula reconstitution and preparation. In many circumstances this may be the only therapeutic option available (139). Various studies of patterns of infant feeding have confirmed widespread use of animal milk in such circumstances (122,125). There is, however, recent epidemiological information to suggest that unmodified bovine milk feeds may be associated with an increased risk of development of PD in comparison with modified infant formula (124). This may be related to risks of dietary protein sensitization, a higher lactose load, or milk storage practices leading to an increased risk of bacterial contamination. In a randomized trial comparing a soy formula and a traditional diet-halfstrength buffalo milk combination in malnourished children with PD, Bhutta et al. (65) observed that a previously documented beneficial effect of feeding a rice-lentil (Khitchri) and yogurt combination was lost when dilute buffalo milk was also added to the diet. These data indicate that, unlike cow's milk-based formulas, unmodified bovine milk feeds or combinations in PD may not be appropriate. Further studies are also needed to assess the potential benefits of smaller amounts of milk feeds or combinations in PD. Table 3 presents the salient features and outcomes of several studies of cow's milk-based feeds in PD. Although recommendations for cow's milk feeds in diarrhea frequently fail to distinguish between intact animal milk and formula (140), further studies are needed to explore the issue of feeding unmodified animal milk in PD.
Another modified form of cow's milk is fermented milk or yogurt, in which by a process of fermentation and processing the protein digestibility is improved and the lactose content is reduced. In addition, live yogurt provides its own β-galactosidase for autodigestion, and a number of studies have indicated higher duodenal lactase activity with yogurt feeds (141-143). Petoello et al. (144) studied the effect of yogurt feeding in children with symptomatic lactose malabsorption and giardiasis and indicated improved lactose absorption with lower breath hydrogen excretion. Earlier studies evaluating yogurt feeding in acute diarrhea in comparison with half-strength skimmed milk and neomycin (145) also found a significant reduction in diarrheal duration. Similar studies by Singh (146) and Beau et al. (147) in the developing world indicated satisfactory tolerance of yogurt in acute diarrhea, with a significantly better outcome in comparison to milk feeds. There are, however, few controlled trials of live yogurt feeds in PD, either singly or in combination with other foods. Most studies conducted to date indicate a more complete digestion of dietary carbohydrate when given in the form of yogurt (102,148,149; Table 4). Given the evidence of satisfactory tolerance and absorption of yogurt feeds in PD, in circumstances where children with PD are receiving breast milk substitutes, it may be prudent to replace milk feeds with live yogurt or provide it in additional amounts.
Soy Milk Feeds
Although there have been concerns about the potential of soy milk protein sensitization (150), these formulas are somewhat cheaper than elemental formulas and widely used as cow's milk protein and lactose-free sources of feeding in children with PD. In a preliminary study of soy feeding in PD, Fagundes-Neto et al. (151) observed successful outcome in the majority (six of nine patients). In a subsequent randomized controlled trial comparing cow's milk formula, casien based lactose-reduced, soy formula, and a protein hydrolysate in children with prolonged dehydrating diarrhea, Rajah et al. (6) found significantly reduced stool output with the latter three diets in comparison with the cow's milk-based formula. Donovan and Pinedo (152), in a randomized comparison of different soy-carbohydrate combinations in children with PD, found that the maximal benefit in terms of stool reduction and clinical success was seen with the soy-lactose combination, indicating a possible absorptive mechanism related to soy protein-lactose coupling.
In addition to concerns about sensitization, the major limitation in the widespread use of these soy formulas has been their cost and limited availability in developing countries. It is, therefore, unlikely that soy formula would offer a viable therapeutic alternative in feeding children with PD.
Due to aforementioned problems with animal milk-based diets and soy and elemental formulas, many workers have attempted to evaluate milk-free diets based on chicken meat. Investigators have used both comminuted (blenderized) and minced chicken-based diets. There are advantages to using these diets, which are lactose-free, have a better digestibility, are hyposmolar, and are less expensive than other specialized formulas (153). Larcher et al. (154), in a preliminary report of a series of infants with protracted diarrhea, demonstrated satisfactory tolerance and weight gain with a comminuted chicken diet. In an uncontrolled evaluation of various diets in hospitalized children with PD, Roy et al. (155) placed 13 children who had not improved on either milk, rice, or soy-based diets, on a comminuted chicken preparation and achieved a clinical cure in 12 (92%). Maffei et al. (156), in an open study of a diet based on minced chicken, rice flour, maltodextrin, glucose, and corn oil, observed satisfactory tolerance of the diet, with a mean daily weight gain of 10g/day. However, five of 32 (16%) children receiving the diet died with continuing diarrhea. In a randomized controlled comparison of a comminuted chicken diet with an elemental formula based on hydrolyzed lactalbumin, Godard et al. (157) observed comparable recovery times in both groups, with a clinical success rate in excess of 90%. Table 5 summarizes the results of the main studies of chicken-based diets in PD. Despite the evidence of the usefulness of chicken-based formulations in PD, they require a longer period of cooking, are more difficult to prepare, and require refrigeration; also, chicken meat is frequently more expensive and less available in many impoverished countries and is therefore limited mostly to hospitalized children (153).
Given the limitations of nutritional rehabilitation in hospital and the magnitude of the problem of PD in the developing world, it is natural that considerable interest and effort has been expended in developing diets suitable for nutritional rehabilitation in the community (100). In many of the poorer communities of the world, PD and malnutrition occur in a backdrop of food insufficiency, along with high rates of environmental bacterial contamination and recurrent bouts of infection. Isolated programs of hospital-based nutritional rehabilitation have highlighted the high rates of relapse and mortality in these children (158,159). While some studies of short-term nutritional rehabilitation of malnourished children with acute diarrhea have been shown to have sustained long-term benefits (160), Paerregaard et al. (161), in an evaluation of 10 children with postenteritis enteropathy, found a prolonged phase of catch-up growth ranging from 4 to 36 months. It is therefore essential that suitable nutritional rehabilitation programs be based on sustainable models and culturally acceptable, home-available diets or dietary ingredients. Sullivan et al. (101), in a follow-up study of 22 malnourished Gambian children with PD who had received up to 4 weeks of hospital-based nutritional rehabilitation, highlighted the high risk of relapse (32%) and recurrence of malnutrition (16%) at 1 year. While this probably represented reinfection and recurrence of diarrhea in most, in several cases this may have reflected the failure to sustain an adequate level of nutritional intake in the home setting, especially after hospital-based nutritional rehabilitation, which may have been expensive and culturally “alien.” Past observations of high rates of mortality in children following diarrheal illnesses highlight the poor health system development in the developing world (162) as well as the vast differences in rural-urban health facilities (163). In the absence of adequate primary care facilities and referral systems in many developing countries, it is imperative that options for home-based therapy of PD be explored. Diets used for nutritional rehabilitation of children with PD should be based on home-available, inexpensive, and culturally acceptable ingredients (164,165). Where this has been possible, studies of growth patterns of children receiving nutritional supplements in the community indicate that the growth-faltering associated with recurrent bouts of diarrhea can be avoided (166,167).
A number of studies employing dietary combinations of home-available foods and multi-mixes have shown satisfactory tolerance and nutritional impact in malnourished children (168,169). A major question remains about their potential tolerance in diarrhea. Most of the data on the feasibility of feeding staple diets to children with PD stem from observations of feeding a variety of home-available foods to children with acute diarrhea. Several studies of staple diets, such as potatoes (170), wheat noodles (171), corn-cottonseed flour (172), and mixed diets (173,174), in malnourished children with acute diarrhea have indicated satisfactory tolerance. Other studies of combinations of milk and cereals in children with acute diarrhea (136,137) have also shown adequate nutritional outcomes and comparable recovery rates to hydrolyzed milk preparations. An additional advantage of staple diets is the apparent reduction in stool volume due to the high fiber content of the diets, thus offering advantages in parental acceptance of home therapy. Torun and Chew (175), in a review of the dietary management of acute diarrhea in developing countries, offer a number of useful practical suggestions highlighting the importance of considering issues of cost, availability, and cultural acceptance in dietary selection.
There are, however, very few studies employing staple diets in the therapy of PD in part because of lingering concerns over potential dietary intolerance and also because many such diets are relatively poorly defined in terms of their nutritional, fiber, and phytate contents (100). However, based on their efficacy in malnourished children with acute diarrhea and the likely parental acceptance and sustenance of this form of dietary therapy, balanced staple diets or combinations hold potential promise in the ambulatory dietary therapy of PD. Given the improved recovery rates from diarrhea with rice-based oral rehydration solutions (176,177), there has been recent interest in rice-based diets in children with PD. In a series of in vitro and in vivo studies in children with PD, Sloven et al. (178) demonstrated significantly improved hydrolysis and absorption of rice glucose polymers in comparison with corn glucose polymers. Roy et al. (84) evaluated a diet based on rice powder, egg white, soya oil, and glucose in the nutritional rehabilitation of children with PD. Although the rice-based diet was successful in 21/26 (81%) of the patients, it still did not offer a satisfactory solution for home therapy as the preparation and ingredients were both tedious and time-consuming. In a series of studies evaluating a traditional rice-lentil and yogurt combination (K-Y diet) in children with PD (102), we observed a better weight gain and diarrheal recovery rate on this diet in comparison to a soy formula. We randomized 102 consecutive male children with PD to receive either a soy formula or a traditional diet comprised of rice, lentils, and yogurt (K-Y). On a comparable caloric intake, children fed the traditional K-Y diet had significantly lower stool output during the first 7 days of therapy (38 ± 16 vs. 64 ± 75 g/kg/day, p < 0.05) as well as a higher weight gain (468 ± 373 vs. 68 ± 286 g/wk, p < 0.005). A comparable nutritional benefit, as assessed by weight gain, was observed when the traditional diet was added to soy formula in the second week of therapy (Fig. 1).
The potential benefits of staple, inexpensive local dietary formulations in PD are being currently evaluated in a large international multicenter trial, the results of which are eagerly awaited. It must, however, be emphasized that children with PD selected for ambulatory traditional food-based dietary therapy must be screened for complications and potential risk factors for failure of therapy. Risks of continuing to feed children a diet which they are unable to digest and absorb include continuation of diarrhea, nutrient losses, and prolonged recovery. Thus, although many children tolerate feeding through diarrhea, as the astute clinician knows, care must always be individualized. As discussed above, the greater the variety and complexity of foods in the diet, the more likely macro-and micro-nutrient needs will be met. As the diet is modified to meet individual tolerance (i.e., lactose- or fat-restricted), attention should be paid to the issues of total dietary quality discussed above, as well as total caloric and protein intake. This is especially true of excessive use of sugary foods and drinks, which make the diet particularly imbalanced. Not only primary care workers but parents must also be provided sufficient information to allow them to rapidly recognize such problems during ambulatory therapy.
Role of Micronutrients
A number of studies of acute diarrhea (179-181) have highlighted the high enteral losses of trace elements and the potential risk of trace element deficiency. It is, therefore, reasonable to assume that children with PD may be at a higher risk of concomitant micronutrient deficiencies. Several studies have also emphasized the importance of zinc deficiency in protein energy malnutrition (108,182,183), and a limited number of studies of zinc supplementation in PD have indicated improved nutritional and diarrheal outcome (184,185). Although and vitamin A deficiency has been convincingly shown to be associated with increased morbidity and mortality in childhood (186,187) and low vitamin A levels have been demonstrated in children with PD (188), studies of vitamin A supplementation in diarrheal disorders (189,190) have yielded mixed results. A recent study of vitamin A supplementation has instead revealed increased rates of diarrheal morbidity (191). Despite the lack of hard data on individual micronutrient requirements in PD and malnutrition, in view of studies mentioned earlier emphasizing total dietary quality, it seems prudent to ensure that dietary therapies or additional supplements to children with PD provide at least their daily recommended allowances (100).
OTHER FACTORS AFFECTING DIETARY THERAPY OF PD
Apart from the basic question of dietary composition and prompt oral rehydration therapy, a number of other factors affect nutritional rehabilitation. These include appropriate patient selection and prompt attention to rehydration therapy, associated metabolic complications, and coincidental infections.
It has been seen consistently in several studies of nutritional rehabilitation of children with PD that a few factors identify children at a high risk of treatment failure. These include high purging rates and vomiting, with a considerably increased risk of dehydration (153,164,192). Although studies by Molla et al. (193) failed to find any correlation between intestinal transit time in acute diarrhea and macronutrient absorption, recent studies by Roy et al. (194) in children with PD and malnutrition indicate that macronutrient absorption is significantly decreased when the median intestinal transit time is below 5 h. These results and evidence from the aforementioned studies of dietary therapy indicate that children with PD and high purging rates may represent a specific subgroup at a higher risk of therapeutic failure and dehydration. Brown and Perez (117), observing the factors determining dietary intake in Peruvian children with diarrhea, have also shown that acidosis and dehydration were major determinants of food intake. In a similar assessment of risk factors associated with failure of nutritional rehabilitation, Bhutta et al. (164) also identified younger age and vomiting as important prognostic factors in nutritional therapy. These observations are particularly important in planning ambulatory therapy. Thus, young children, especially with vomiting and high purging rates, are at an increased risk of treatment failure and should preferably receive their treatment in hospital or under close supervision.
These findings of higher rates of failure of therapy are also understandable in the context of poor intake and tolerance of dietary therapy in very young children. There are two major limitations in the dietary therapy of malnourished infants (100). Firstly, the gastric capacity to tolerate the diet may be a limiting factor. It has been estimated that functional gastric capacity is about 40-50 g/kg/feed in children weighing between 4 and 9 kg (100). Given the current energy density of most mixed diets in developing countries, which are starch-containing staples, this may be possible only with a very high volume intake, which is often impractical. Secondly, in much of the developing world weaning diets are introduced late and many young infants with PD have therefore had very meager weaning experiences. In a recent review of over 100 infants ranging from 6 to 18 months of age, we identified inadequate weaning experience in over 50% (Bhutta et al., unpublished observations). Such poorly weaned children, especially if only partially breast-fed, may find it extremely difficult to consume adequate quantities of starchy staples and viscous weaning diets during an episode of PD. In many situations it may not be possible to increase energy density of starch-containing diets without increasing their viscosity and bulk considerably with consequent inadequate dietary intake (195,196). However, recent studies on the addition of amylase to starch-based diets indicate that it is possible to decrease viscosity, increase energy density, retain palatability, and improve tolerance of such diets (197-199). Such developments in food germination technology and potential amylase enrichment of cereals may offer opportunities for more effective dietary therapy of young infants with PD, in comparison with other methods of viscosity reduction (200). It is, however, important to remember that such methods of improving quality of home-available foods may imply an increase in the time required to prepare and administer these foods, which is frequently difficult (201,202).
An additional important but poorly studies issue is that of appetite. Several factors are known to affect appetite in PD and malnutrition. A reference has previously been made to reduced food intake due to large volumes of oral rehydration fluids consumed during the early stages of dietary therapy. Similarly, concomitant infections, ranging from oral thrush to systemic infections, may reduce appetite. The high rates of bacterial infections in malnourished children are well known, and children with diarrhea are at considerable risk of infections with gram-negative organisms (203). Anorexia has been consistently associated with interleukin-1 elevation in animal models of infection (204) and may also be a manifestation of a specific micronutrient deficiency, such as zinc (205). Detailed observational studies of rural Guatemalan children with diarrhea have specifically identified the association of anorexia with PD and may account for malnutrition as a major risk factor for mortality with the disorder (206). The sedating qualities of some antimotility agents and antidiarrheals may also cause anorexia and impact nutritional recovery (207). Finally, the organoleptic characteristics of the diets—i.e., aroma, flavor, etc.—need to be considered as these would also influence the actual amounts consumed (113).
CONCLUSIONS AND RECOMMENDATIONS
Given the pathogenesis of PD and predisposing risk factors, it is imperative that management strategies also focus on preventive aspects. The single most effective diarrheal prevention strategy in young infants worldwide is exclusive breast-feeding (208). It is also important to treat all episodes of acute diarrhea promptly with adequate attention to early institution of feeding and oral rehydration therapy. While attempts have been made to formulate improved oral rehydration solutions and cereal-based oral rehydration fluids, recent evidence indicates that early feeds in combination with WHO standard oral rehydration fluids are equally efficacious (209,210). Despite the limited epidemiological information on the association of early unmodified animal milk feeds and PD, such feeds should be avoided in young children.
Once an episode of diarrhea becomes prolonged, these children should be identified for urgent nutritional therapy. Basic resuscitative measures, such as rehydration, correction of acidosis, and adequate treatment of concomitant infections, should receive priority. In partially breast-fed children frequent breast-feeds should be encouraged. Dietary therapy should be initiated with soft cereal- or vegetable-based weaning diets—e.g., rice-based diets. These can be prepared along with small amounts of vegetable oil to increase their energy content and improve palatability. It is usually necessary to provide small amounts of milk with these diets to insure an optimal protein/energy ratio. In partially breast-fed infants no further milk supplements may be necessary if maternal milk supply is adequate. While combinations of milk formula and home-available cereal-based diets are well tolerated, there are concerns about the continued use of unmodified animal milk in these children. We would presently recommend substitution of milk with live yogurt. In most malnourished children with PD, feeding can be initiated with 75 kcal/kg/day, with graded increments to provide a minimum of 140 kcal/kg/day in 4-5 days. Thereafter, feeding is allowed ad libitum. In the absence of clear recommendations of micronutrient supplementation, these should be given in a dose providing at least the daily recommended dietary allowances. It is also important to pay close attention to ongoing stool losses and varying daily needs for rehydration fluids. In most cases the response to dietary therapy is slow, clinical improvement being evident in 3-4 days. This point needs clear emphasis, especially in home-based management of PD, to avoid unnecessary dietary changes and medications. While the nutritional therapy of the vast majority of children with PD can take place in the home/community setting, certain high-risk groups need to be identified for hospitalization. These include very young infants (<6 months) and those with severe diarrhea, bloody dysentery, and severe malnutrition. Thus, programs geared toward providing home-based therapy for PD should incorporate aspects of parental and health-worker education for early recognition of children at a high risk of failure, with associated complications, and clinical indicators of those who do not satisfactorily respond to therapy.
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