Pediatric Annals

Viral Diarrhea

J R Hamilton, MD, FRCP(C)

Abstract

What pediatricians had long suspected has now proven to be true - a virus is going around! Human rotavirus has emerged as the most common cause of acute diarrhea in babies throughout the world. During the past decade much has been learned about the causes of enteric infection and the way in which pathogens may interact with the gut to cause diarrhea. This research has had a highly beneficial impact on the management of acute diarrheal illness in developing countries, but in many developed regions of the world entrenched treatment practices have been relatively difficult to change. This article discusses the practical implications of recent advances in our understanding of viral diarrhea. The relevance of these pathophysiological insights to the management of acute diarrhea is clear. Nevertheless, the message needs emphasis, even in our most affluent communities where morbidity and even mortality rates from diarrhea are still a significant problem in young children. The possible relevance of acute viral injury to persisting intestinal dysfunction and chronic diarrhea is still rather speculative. However, as the viral lesion has become understood, a role for this normally transient infection in initiating prolonged symptoms has become a feasible hypothesis.

VIRAL ENTERIC PATHOGENS

Table 1 lists viruses capable of infecting the human intestine, and causing local damage and symptomatic enteritis. ' The list includes several candidate agents, for which absolute proof of pathogenicity is still lacking.2 By far the most important of the known pathogens is the human rotavirus (HRV) which causes 40% to 50% of all serious acute diarrhea in infants and young children. In general these enteric pathogens that cause diarrhea have not been amenable to culture systems; they are diagnosed by electron microscopy or by enzyme immunoassay. Most, like HRV, are hardy, retaining their infectivity under adverse conditions for prolonged periods so that their spread in institutions like children's hospitals can be rampant.3 No explanation is available for the prevalence of HRV infections during the winter months or in the tropics during rainy seasons.

MECHANISMS OF ACUTE VIRAL DIARRHEA

Our current understanding of the functional consequences of viral enteritis is based on a limited number of clinical studies,4'5 but largely on studies of acute corona virus enteritis occurring in piglets.6'9 This latter reproducible experimental disease, transmissible gastroenteritis (TGE), has striking similarities to rotavirus enteritis. In time, other human viral pathogens may, or may not, be shown to resemble TGE in their interaction with the intestine. Virus diffusely invades the epithelium of the proximal part of the small intestine; the lesion may extend to include part or all of the small bowel, the length of involvement no doubt, to some degree, determining symptom severity. Villus epithelial cells are the primary target of the virus; their infection triggers increased proliferation of the crypt epithelium, rapid shedding of infected enterocytes into the bowel lumen, and accelerated migration of dividing crypt cells up onto the villi. As a consequence, the villi may become short and the crypts elongate thus reducing surface area. Oi greater probable functional significance is the status of those cells that remain. Our data strongly suggest that these cells are relatively undifferentiated and in their transport and enzymic properties resemble epithelial cells normally confined to the intestinal crypts. Diarrhea actually begins when the virus has been shed from the bowel and the epithelium is composed of these relatively undifferentiated crypt-type epithelial cells.

During acute viral diarrhea, studies of solute transport have demonstrated a range of defects. The absorption of ionic solutes, Na and Cl, and nonionic solutes, glucose and amino acids is impaired. Several specific functional defects have been identified in viral diarrhea…

What pediatricians had long suspected has now proven to be true - a virus is going around! Human rotavirus has emerged as the most common cause of acute diarrhea in babies throughout the world. During the past decade much has been learned about the causes of enteric infection and the way in which pathogens may interact with the gut to cause diarrhea. This research has had a highly beneficial impact on the management of acute diarrheal illness in developing countries, but in many developed regions of the world entrenched treatment practices have been relatively difficult to change. This article discusses the practical implications of recent advances in our understanding of viral diarrhea. The relevance of these pathophysiological insights to the management of acute diarrhea is clear. Nevertheless, the message needs emphasis, even in our most affluent communities where morbidity and even mortality rates from diarrhea are still a significant problem in young children. The possible relevance of acute viral injury to persisting intestinal dysfunction and chronic diarrhea is still rather speculative. However, as the viral lesion has become understood, a role for this normally transient infection in initiating prolonged symptoms has become a feasible hypothesis.

VIRAL ENTERIC PATHOGENS

Table 1 lists viruses capable of infecting the human intestine, and causing local damage and symptomatic enteritis. ' The list includes several candidate agents, for which absolute proof of pathogenicity is still lacking.2 By far the most important of the known pathogens is the human rotavirus (HRV) which causes 40% to 50% of all serious acute diarrhea in infants and young children. In general these enteric pathogens that cause diarrhea have not been amenable to culture systems; they are diagnosed by electron microscopy or by enzyme immunoassay. Most, like HRV, are hardy, retaining their infectivity under adverse conditions for prolonged periods so that their spread in institutions like children's hospitals can be rampant.3 No explanation is available for the prevalence of HRV infections during the winter months or in the tropics during rainy seasons.

MECHANISMS OF ACUTE VIRAL DIARRHEA

Our current understanding of the functional consequences of viral enteritis is based on a limited number of clinical studies,4'5 but largely on studies of acute corona virus enteritis occurring in piglets.6'9 This latter reproducible experimental disease, transmissible gastroenteritis (TGE), has striking similarities to rotavirus enteritis. In time, other human viral pathogens may, or may not, be shown to resemble TGE in their interaction with the intestine. Virus diffusely invades the epithelium of the proximal part of the small intestine; the lesion may extend to include part or all of the small bowel, the length of involvement no doubt, to some degree, determining symptom severity. Villus epithelial cells are the primary target of the virus; their infection triggers increased proliferation of the crypt epithelium, rapid shedding of infected enterocytes into the bowel lumen, and accelerated migration of dividing crypt cells up onto the villi. As a consequence, the villi may become short and the crypts elongate thus reducing surface area. Oi greater probable functional significance is the status of those cells that remain. Our data strongly suggest that these cells are relatively undifferentiated and in their transport and enzymic properties resemble epithelial cells normally confined to the intestinal crypts. Diarrhea actually begins when the virus has been shed from the bowel and the epithelium is composed of these relatively undifferentiated crypt-type epithelial cells.

During acute viral diarrhea, studies of solute transport have demonstrated a range of defects. The absorption of ionic solutes, Na and Cl, and nonionic solutes, glucose and amino acids is impaired. Several specific functional defects have been identified in viral diarrhea (Table 2). Brush border membrane (disaccharidase activities, glucose transport, glucose and amino acid stimulated Na transport, neutral NaCl "transport") and basolateral membrane (Na/K/ ATPase activity) functions are reduced. These findings, combined with an intact or enhanced CAMP-mediated secretory mechanism, all fit with the concept of the predominance of a crypt-type epithelium during viral diarrhea. If the entire small bowel were involved (it rarely is), little absorptive function would remain. The determinants of the extent and severity of the lesion are not known but from animal studies it is likely that viral dose, and the patient's age and immune status are significant factors. Furthermore, this pathophysiological pattern for viral diarrhea differs distinctly from the ion secretion that characterizes toxigenic diarrheas like cholera; this difference is reflected in the different constituents of the diarrheal stools in the two types of disorders (Table 3).

Table

TABLE 1CAUSES OF HUMAN VIRAL ENTERITIS

TABLE 1

CAUSES OF HUMAN VIRAL ENTERITIS

Table

TABLE 2PATHOPHYSIOLOGICAL ABNORMALITIES IN THE INTESTINE DURING VIRAL DIARRHEA

TABLE 2

PATHOPHYSIOLOGICAL ABNORMALITIES IN THE INTESTINE DURING VIRAL DIARRHEA

Table

TABLE 3STOOL ELECTROLYTES- CHILDREN WITH ACUTE DIARRHEA*

TABLE 3

STOOL ELECTROLYTES- CHILDREN WITH ACUTE DIARRHEA*

POSSIBLE MECHANISMS FOR PERSISTING INTESTINAL DYSFUNCTION AFTER VIRAL INFECTION

Most pediatric practices are plagued by babies and toddlers with chronic diarrhea. Contrary to what most texts suggest, these cases are rarely associated with definable disease or even ill health. It is tempting to speculate that in many, the initial intestinal injury may be viral enteritis, given the recently revealed nature of this very common but normally transient (4 to 7 days) disease. Normal recovery from such a viral infection, as described above, depends on the mucosal epithelium regaining a population of mature differentiated enterocytes. In theory, several factors might interfere with that repair process, either by perpetuating damage to the mucosa or by interfering with the epithelial repair process. This concept of the pathogenesis of some cases of persisting diarrhea initiated by acute viral enteritis, while hypothetical at present, merits further comment because of its potential relevance to treatment practices. Of the factors known to delay epithelial repair shown in Table 4, those most relevant to infant diarrhea are nutrients and drugs. Clinical studies of chronically malnourished children suggest that in these patients the course of diarrheal illness may be prolonged.10 Our recent experiments using chronically malnourished piglets also found a persistence of intestinal transport dysfunction after TGE enteritis.11 Chronic malnutrition has relatively little impact on the healthy intestine but after injury such as that inflicted by viral infection, epithelial renewal appears to be vulnerable, particularly in the young.12 Roles for specific micronutrients like zinc, folic acid or vitamin B]2 in repair after mucosal injury have not yet been explored. Of the drugs, chemotherapeutic agents like methotrexate are known to interfere with cell division in the intestinal crypts,13 but many others, antibiotics for example, might impair the epithelial repair process when stressed by mucosal injury.

Normally virus is quickly shed from the intestinal mucosa. There is little potential for ongoing injury from the virus itself unless the host's immune function is compromised. Chronic malnutrition, and immune suppressive drugs in addition to intrinsic congenital or chronic disease-related immunological defects could interfere with viral shedding from the gut leading to prolonged dysfunction and diarrhea. It has also been suggested that the initial viral injury might predispose the child's intestine to secondary damage from other factors like enteric bacteria, dietary antigens or chemicals. These latter concepts are being pursued in clinical studies and in experimental models. In many parts of the world where severe malnutrition is common, hygienic conditions are appalling and in these populations bacterial contamination of the upper small bowel is common,14 but there is no convincing evidence that the small intestine during or after viral enteritis is unusually vulnerable to bacterial infection. However, antiperistaltic drugs and even oral antibiotics, if used in treatment, could interfere with bacterial clearing from the gut. With the initial viral infection, absorption of a variety of nutrients including sugars is impaired. In the lower bowel these substances are broken down by bacteria to form organic acids which may have the capacity to induce secondary damage to the mucosa,15 although normally their impact is likely to be felt in the lower small bowel and colon. Another group of potential chemical irritants are bile salts which might not be normally absorbed if ileal involvement with the virus is extensive.16 However, it is most unlikely that either organic acids or bile acids are important perpetrators of chronic mucosal injury and chronic diarrhea after transient viral injury.

Diet-induced intestinal mucosal damage is a controversial subject on which interesting new data are emerging. It has been shown that the normal small intestinal mucosa can transport antigenically significant quantities of protein macromolecules. 17 It follows that local immune-mediated reactions to dietary antigens might occur and it has been suggested that acute mucosal injury, might open the mucosa to increased quantities of dietary antigen resulting in ongoing local damage to the gut.18 In fact, clinical studies have suggested increased intolerance to cow's milk protein in infants with diarrhea convalescing from viral enteritis. 19 However our studies to date do not support this hypothesis. In the piglet TGE model, macromolecular transport is enhanced, but only in the few early hours of infection before the virus is shed from the mucosa and not during the diarrheal stage of the disease.20

TREATMENT

From the above discussion, some therapeutic messages are clear and convincing while others are tempting. First and foremost, prevention must be a top priority for a disorder that kills millions and sickens billions of the world's babies each year. Preliminary results from a clinical trial of the live attenuated rotavirus vaccine of bovine origin are extremely encouraging.21 In the meantime, even in "Middle America" breast milk has a proven protective value.22 Since our hospitals and institutions are rich sources of enteric viruses, admission of a young baby, particularly if bottle fed, and particularly during the winter, must be recognized as carrying a high risk for viral diarrhea.

For active treatment, effective anti- viral agents are not available and would not be expected to be effective by the time diarrhea begins, since at that stage the virus has already been shed from the intestine. Antibiotics similarly are not indicated and antidiarrheals, while recently shown to have some effect on secretagogue-induced ion secretion have no apparent place in treating viral diarrhea and carry the theoretical disadvantage of inhibiting gut motility, and potentially delaying the clearance of microorganisms.

The primary concern in active treatment should be for the child's fluid and electrolyte balance; actually it is a small percentage of the total cases that become significantly depleted. From the above pathophysiological discussions, it might appear that the modem pediatric practice of quickly instituting intravenous therapy for babies with viral diarrhea is best; indeed for the very seriously ill child with an extensive intestinal lesion some intravenous fluids, electrolyte and buffer may be necessary. However, recent field experience has clearly shown that judicious use of appropriate oral fluids can usually make sufficient use of existing intestinal function to tide the child over the acute phase of diarrhea and avoid intravenous therapy.23·24 Such fluids must not be hyperosmolar. The widely accepted remedies - flat soda drinks, fruit juices, or "jello" water are all highly hyperosmolar sugar solutions. If delivered to a bowel withcompromised sugar and glucosestimulated Na absorptive function they are liable to draw water from the body into the lumen, worsening diarrhea;25 Some debate continues as to the ideal formulation of oral fluid therapy but the glucose-electrolyte mixtures prepared and distributed by the World Health Organization (WHO) (Table 5) has proven to be effective for babies with viral diarrhea. Commercial firms are finally developing appropriate fluids for oral rehydration therapy but at present such treatment is more readily available to children in Bangladesh through WHO programs than to those in North America. For many patients, use of such mixtures may be impractical or unnecessary. However, if commercially available household beverages are to be given to babies with diarrhea it is logical to render them isotonic or hypotonic relative to plasma by diluting them at least in half with water.

Table

TABLE 4THEORETICAL CAUSES OF PROLONGED DIARRHEA AFTER ACUTE VIRAL INJURY

TABLE 4

THEORETICAL CAUSES OF PROLONGED DIARRHEA AFTER ACUTE VIRAL INJURY

If at all possible the breast fed child with diarrhea should continue on the breast, and receive extra fluid as required. For the weaned infant if the diarrhea is severe, it will be advisable to stop the usual diet or infant formula for 24 to 48 hours. The younger or more malnourished the infant, the greater the concern should be to provide calories as soon as possible. Contrary to the pediatrician's time-honored instincts to eliminate foods from the diet, it is logical to feed these children within 24 to 48 hours in order to promote healing of their mucosa. The diet should be balanced providing both fat and carbohydrate as sources of calories; a large sugar load may overload the damaged sugar hydrolytic and transport pathways thereby provoking more diarrhea. The child also will need dietary protein. Current data do not support the routine use of soy protein, hydrolysed protein, or elemental diets during convalescence from acute enteritis although the practice of limiting dietary cow milk after acute diarrhea has rather insidiously inserted itself into pediatric practice. Expensive and often unpalatable, these special milk substitutes may not be taken in sufficient quantity thereby contributing to a net nutritional deficit which, as suggested above, may perpetuate intestinal dysfunction. Their use should be reserved for those rare cases in which a specific need is identified.

Table

TABLE 5ORAL REHYDRATION SOLUTION (ORS) WORLD HEALTH ORGANIZATION

TABLE 5

ORAL REHYDRATION SOLUTION (ORS) WORLD HEALTH ORGANIZATION

When stools continue to be loose and no cause for persisting diarrhea is apparent, anxiety levels rise on all sides. From the above pathophysiological discussions, it is clear that the strong temptation to use drug treatment at this stage should be resisted. At least in the relatively sanitary North American environment, there is no basis to predict a beneficial effect of antibiotics and theoretically, these drugs could be detrimental to recovery. Since neither bile salt malabsorption nor intraluminal organic acid production have yet been shown to be important determinants of persisting diarrhea, the general use of binding resins like cholestyramine is not justified. Antidiarrheal agents, through their antisecretory activity, may improve stool consistency but they too should not be used routinely until their value has been objectively evaluated.

CONCLUSION

New information on the causes and mechanisms for viral diarrhea now provides a partial pathophysiological basis for the management of affected babies. Some time-honored practices, for example the administration of undiluted commercially available beverages, the prolonged withholding of food and the use of various drugs could be detrimental to the recovery of the seriously ill baby. Current data strongly support the use of isotonic oral fluids for rehydration of all but the most severely affected babies who may need intravenous fluids. Early use of a balanced nutrient intake and avoidance of excessive dietary sugars should hasten recovery. Viral diarrhea is usually a brief, mild illness, but improved treatment may reduce the incidence of persisting diarrhea in those children who are seriously ill. Treat the child and the parents, not just the stools.

REFERENCES

1. Blacklow NR, Cukor C: Viral gastroenteritis. N Engl J hied 1981; 304:397.

2- Bishop RF: Other small virus-like particles in humans, in Tyrell DAJ, Kapikian AZ (eds): Virus infections of the Gastrointestinal Tract. New York. Marcel Dekker, 1982, ? 295.

3. Middleton P], Siymanski MT, Perric M: Viruses associated with acute gastroenteritis in young children. Am ) Dis Chad 1977; 1 3 1 733.

4. Bishop RF, Davidson GP, Holmes IH, et al: Virus panicles in epithelial cells of duodenal mucosa from children with acute non-bacterial gastroenteritis. Lancet 1973: 2:1281.

5. Tallet S, MacKenzie C1 Middleton P, et al: Clinical, laboratory and epidemiologic features of a viral gastroenteritis in infants and children. Pediatrics 1977: 60:217.

6. Hamilton JR: Viral enteritis. A cause of disordered small intestinal epithelial renewal, in Lebenthal E (ed): Chronic DierrfieemCniktren. New York, Raven Press, 1984. ? 269.

7. Hamilton JR: Infectious diarrhea: Clinical implications of recent research. Con Med Assoc J 1980; 122:29.

8. Hamilton JR, Keljo D, ftrdue M: The small intestinal epithelium after viral invasion, in Robinson JWL, ftwling RH, Riacken EO (eds): Mechanisms of Intestina! Adaptation. Falk Symposium #30. Lancaster, PA, MTP Press, 1982, ? 607.

9. Hamilton JR1 Call DO: ftthophysiological and clinical features of viral enteritis, in Tyrell CAJ, Kapikian AZ (eds): Virus inactions of the Gastrointestmoi Tract, New York, Marcel Dekker, 1982, ? 227.

10. Black RE, Brown KH1 Becker S: Malnutrition is a determining factor in diarrheal duration but not incidence among young children in a longitudinal study in rural Bangladesh. Am J CIm Nutr 1984; 37:87

11. Butzner D, Butler D, Baird J, et al: Effect of malnutrition on small intestinal response to viral enteritis. Clin Im*sl Med 1983; 6(Suppl 2): 50.

12. Guiraldes E, Hamilton JR: Effect of chronic malnutrition on intestinal structure, epithelial renewal and eniymes in suckling rats, ftdiarr Ris 1981 ; 1 5:930.

13. Taminiau J, Gall DG, Hamilton JR: Response of the rat small intestine epithelium to methotrexate. Gut 1980; 21:486.

14. Gracey M, Suharjono MD, Sunato MD, et al: Microbial contamination of the gut. Another feature of malnutrition. Am 1 Clin Nutr 1973; 26: 1170.

15. Hamilton JR: Prolonged infusion of small intestine of the rat. Effect of dilute solutions of lactic acid on fat absorption and mucosal morphology. ftdiarr Res 1967; 1:341.

16. McCloy RM, Hoffmann AF: Tropical diarrhea in Viemam. A controlled study of cholestyramine rherapy. N Engl] Med 1971; 284:139.

17. Udall JN, Walker WA: The physiologic and pathologic basis for the transport of macromolecules across the intestinal tract. ) Pediatr Gastroenterol Nurr 1982; 1 :295.

18. Walker-Smith JA: Cow's milk intolerance as a cause of post enteritis diarrhoea. J Pediatr Gastroenterol Nutr 1982; 1:163.

19. lyngkaranN, Robinson NJ, SumithranE, et al: Cow s milk protein-sensitive enteropathy. An important factor in prolonging diarrhoea in acute infective enteritis in early Infancy. Arch Dis Child 1978; 53, 150.

20. Keljo DJ, Butter DG, Hamilton JR: Altered macromolecular transport across ftyer's patches during viral enteritis, abstracted. Gastroenterology 1984; 86(May):l 132.

21. Vesikari T1 lsolauri E, d'Hondt E, et al: Clinical protection studies of a live attenuated oral rotavirus vaccine of bovine origin (RlT 4237 strain), ftdiarr Res 1984; 18:10-48.

22. Larsen SA Jr. Hamer DR: Relation of breast milk versus bottle-feeding to hospitalization for gastroenteritis in a middle class vs population. J ftaalfr 1978; 92:417.

23. Editorial: Oral glucose electrolyte rherapy for acute diarrhea. Lancet 1975; 1:9.

24. Samosham M, Daum RS, Dellman L: Oral rehydration therapy of infantile diarrhea: A controlled study of well nourished children, hospitalized ih the United States and Rmama. N Engl; Med 1982; 306:1070.

25. Wendlarvd BE, Arbus GS: Oral fluid therapy: Sodium and potassium content and osmolality of some commercial "clear" soups, juices and beverages. Can Med Assoc 1 1979; 121:564.

TABLE 1

CAUSES OF HUMAN VIRAL ENTERITIS

TABLE 2

PATHOPHYSIOLOGICAL ABNORMALITIES IN THE INTESTINE DURING VIRAL DIARRHEA

TABLE 3

STOOL ELECTROLYTES- CHILDREN WITH ACUTE DIARRHEA*

TABLE 4

THEORETICAL CAUSES OF PROLONGED DIARRHEA AFTER ACUTE VIRAL INJURY

TABLE 5

ORAL REHYDRATION SOLUTION (ORS) WORLD HEALTH ORGANIZATION

10.3928/0090-4481-19850101-06

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