Travellers' diarrhea in children

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Travellers' diarrhea in children. Pierre J Plourde MD FRCPC. The following mini-review is one of a series of articles prepared by members of the Committee to ...
CATMAT ARTICLE

Travellers’ diarrhea in children Pierre J Plourde MD FRCPC PJ Plourde. Travellers’ diarrhea in children. Paediatr Child Health 2003;8(2):99-103. Diarrhea is the most common medical problem affecting all travellers to developing countries. Younger children are at especially high risk of acquiring travellers’ diarrhea and of suffering more severe consequences. Up to 50% of travellers from developed to developing countries can expect to have at least one episode of acute diarrhea during a two-week stay. Episodes of travellers’ diarrhea usually begin abruptly, either during travel or soon after returning home, and are generally self-limited.

La diarrhée du voyageur chez l’enfant La diarrhée est le problème médical le plus courant chez tous les voyageurs qui se rendent dans des pays en voie de développement. Les jeunes enfants sont particulièrement vulnérables à la diarrhée du voyageur et aux conséquences plus graves de cette maladie. Jusqu’à 50 % des voyageurs des pays industrialisés qui se rendent dans un pays en voie de développement peuvent s’attendre à présenter au moins un épisode diarrhéique aigu pendant un séjour de deux semaines. D’ordinaire, les épisodes diarrhéiques du voyageur commencent de manière abrupte, pendant le voyage ou peu après le retour à la maison, et se règlent spontanément.

Key Words: Children; Travellers’ diarrhea

EPIDEMIOLOGY Although travellers’ diarrhea can be caused by both foodand waterborne pathogens, most cases are due to food contaminated with enterotoxigenic bacteria. Factors that may be associated with a higher probability of acquiring travellers’ diarrhea include risky eating habits, poor hygiene, gastric hypochlorhydria (1,2), immunodeficiency diseases and a relative lack of gut immunity characteristic of children (3,4). The most common cause of travellers’ diarrhea, enterotoxigenic Escherichia coli (ETEC), is most often associated with foodborne transmission. However, recent outbreaks of ETEC on cruise ships highlight the possibility of waterborne transmission as well (5). There are numerous opportunities in developing countries for food to become contaminated, including the fertilization of crops with human fecal material, inadequate storage and transport of food, unreliable refrigeration, lack of pasteurization and unhygienic food handling practices. The potential sources of foodborne illnesses are numerous, including poorly cooked meat, contaminated raw vegetables and unpasteurized dairy products. Even adequately cooked foods allowed to stand for several hours at ambient temperatures can present substantial risk because many foods provide an excel-

lent bacterial culture medium. High risk food items include custards (6,7), mousses (8), potato salads (9,10), hollandaise sauce (11), mayonnaise (12) and seafood (13). Although eating food purchased from street vendors can enhance cross-cultural experiences, the inadequate sanitary facilities and poor refrigeration typical of such food stalls carries an increased risk of travellers’ diarrhea (14). Even meticulous peeling and washing of fruits may not be a guarantee of safety because fruits and vegetables are sometimes injected with contaminated water to increase their weight and hence their value. Waterborne diarrheal illness usually results from the ingestion of viruses and parasites in water contaminated by human or agricultural fecal waste. The lesser importance of water as a cause of travellers’ diarrhea is likely due to the relatively lower concentration of contaminating organisms in liquid versus solid foods. Although commercially bottled water is generally safe, the unscrupulous practice of selling tap water as “safe, purified, bottled water” can increase the likelihood of ingesting contaminated water. Carbonated beverages are too acidic to sustain enteric pathogens and are, therefore, safe to drink (15). However, the ice cubes that are frequently added to carbonated beverages are often made from contaminated tap water (16).

The following mini-review is one of a series of articles prepared by members of the Committee to Advise on Tropical Medicine and Travel (CATMAT) and others interested in the health and safety of travelling children. CATMAT produces a wide range of recommendations and guidelines for travel safety and health. Interested readers can access further information through Health Canada’s information for travellers Web site (www.travel health.gc.ca) or through its fax retrieval system, FAXlink, at 613-941-3900. Winnipeg Regional Health Authority, Winnipeg, Manitoba Correspondence: Dr Pierre J Plourde, 1800-155 Carlton Street, Winnipeg, Manitoba R3C 4Y1. Telephone 204-926-7096, fax 204-926-8008, e-mail [email protected] Paediatr Child Health Vol 8 No 2 February 2003

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Bacterial pathogens, with incubation periods measured in days, cause over 80% of cases of travellers’ diarrhea (17). The most commonly isolated organisms include E coli, primarily enterotoxigenic strains (ETEC), Campylobacter jejuni, Salmonella species, and Shigella species. Clostridium difficile is an infrequent cause of travellers’ diarrhea that must always be considered in those using antibiotics, including older children taking doxycycline for malaria prophylaxis (18). Although uncommonly identified, parasitic pathogens that can cause travellers’ diarrhea with incubation periods of one to two weeks, include Giardia lamblia, Cryptosporidium parvum, Cyclospora cayetanensis and Entamoeba histolytica (19,20). Viral agents, most notably Norwalk virus and rotavirus, can also cause travellers’ diarrhea within hours of exposure (19). Resistance to antimicrobial agents is an increasingly common problem in enteric bacterial isolates from developing countries. Resistance to tetracyclines, sulfonamides (including trimethoprim/sulfamethoxazole [TMP/SMX]) and ampicillin is almost universal (21). Resistance to fluoroquinolones is rapidly increasing, especially among Campylobacter species isolated from Southeast Asia (22-24). PREVENTION Prevention strategies for travellers’ diarrhea include: education about the ingestion of safe food and beverages; water purification; chemoprophylaxis with nonantibiotic drugs or antibiotics; and vaccines. Often ignored is the importance of frequent handwashing while travelling in developing countries. Although soap and water are not always available, commercially available waterless hand sanitizing agents are suitable, convenient alternatives to use with children. The judicious choice of food and water with the adage ‘boil it, cook it, peel it, or forget it’ seems reasonable, but is often not practical. Few travellers are able to comply with strict dietary recommendations and some data suggest that the presumed association between dietary mistakes and the incidence of travellers’ diarrhea is tenuous (25). On the other hand, common sense would dictate that avoidance of potentially contaminated food and water should reduce exposure to large inocula of organisms. Because foodborne illness is more prevalent than waterborne disease, particular attention should be given to the choice of foods. Foods that have been well cooked, recently cooked and served piping hot are best. Salad bars, raw vegetables, fruits that cannot be easily cleaned (eg, grapes, strawberries and raspberries), custards, mousses, mayonnaise, hollandaise sauce and raw seafood are best avoided. Fruits and vegetables should be either freshly peeled or freshly cooked. Raw lettuce, the main ingredient of most salads, is nearly impossible to clean properly and should not be eaten. Raw and incompletely cooked fish and meat should be avoided. Children should not eat large reef fish such as snapper, barracuda, grouper, jack and moray eel, which carry the risk of ciguatera poisoning, particularly in travellers to the Caribbean and the South Pacific (26,27). Ciguatera toxin is heat stable and, 100

therefore, not neutralized by cooking. The effects of ciguatera toxin may be disproportionately increased in children due to reduced body mass. Safe beverages that are readily available in developing countries include carbonated soft drinks without ice, carbonated bottled water and bottled fruit juices. Noncarbonated commercially bottled water should be safe as long as the cap seal is intact. Ice cubes should be regarded as potentially contaminated and best avoided. Properly collected and stored rain water is usually safe to drink. Only pasteurized and properly refrigerated dairy products should be eaten. For infants, premixed formula should be considered for a shorter duration trip. On longer trips powdered formula should be prepared with boiled water. Meticulous cleanliness of bottles used for formula feeding should be ensured. Breasfeeding is a preferred option to formula because it is more hygienic and may also provide immunoglobulin A antibody protection against gut pathogens. Water purification may be achieved either by heat, filtration or chemical disinfection. Boiling is the most effective way of producing water that is safe to drink. Simply bringing water to a bubbling boil, irrespective of altitude, is sufficient to kill virtually all organisms that commonly cause travellers’ diarrhea (28,29). Small portable heater coils may be a practical way for travellers to boil small quantities of water. Alternatively, carrying a water bottle along with a portable 0.5 to 1 L kettle with electrical outlet and current flexibility, is another inexpensive way to ensure a reliable supply of purified water. If no other choices are available, tap water that is too hot to touch should also be reasonably safe to drink once it has cooled. Filters that exclude particles above a specified size (eg, 0.2 microns) are effective against bacteria and parasites, but do not protect against viral pathogens. Therefore, water filtration should be complemented by chemical decontamination with a halogen. Some water purification products combine a 0.2 micron filter with iodine-impregnated resins, although there is limited evidence to confirm their efficacy and they are relatively expensive. Another purification method is the addition of a halogen such as iodine, chlorine or chlorine dioxide directly to water. Adding an appropriate concentration of iodine as a liquid or crystal to water can eliminate all bacterial, protozoal and viral pathogens. Iodine-treated water is often unpalatable and the addition of orange juice crystals may improve the taste. However, dehalogenation with vitamin C should be performed only after 15 to 30 min contact time has elapsed. Chlorine, available as tablets or simply in commercial household bleach, is relatively ineffective against the cysts of G lamblia and C parvum (30-32). Chlorine dioxide (currently marketed as Pristine [Advance Chemicals Ltd, Langley]) is an attractive and relatively palatable alternative form of halogenation that may be effective against G lamblia and C parvum. Chemoprophylaxis using bismuth subsalicylate (PeptoBismol [Procter & Gamble, Toronto]) or antimicrobial Paediatr Child Health Vol 8 No 2 February 2003

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agents has been shown to be effective in preventing travellers’ diarrhea in adults (33,34). However, important issues deserving consideration include cost, drug interactions, drug side effects including severe allergic reactions such as Stevens-Johnson syndrome or anaphylaxis, antibiotic resistance and alteration of normal bowel flora causing C difficile-associated diarrhea. Prophylactic bismuth subsalicylate has an efficacy of about 60% in adults and must be administered four times daily (35). Bismuth subsalicylate should be avoided by children with acetylsalicylic acid allergy, renal insufficiency, and those taking anticoagulants, probenecid or methotrexate. Caution should be exercised when using bismuth subsalicylate in children because of a potential risk of Reye’s syndrome. Bismuth subsalicylate has not been approved for children younger than two years of age. Antibiotic prophylaxis is typically administered once daily, and although it is 70% to 95% efficacious in adults (37-39), it should only be considered in selected high risk short term child travellers such as: • those for whom a brief illness cannot be tolerated, such as elite athletes; • those with increased susceptibility to travellers’ diarrhea due to achlorhydria, gastrectomy or history of repeated severe travellers’ diarrhea; • those who are immunosuppressed due to HIV infection with depressed CD4 count or other immunodeficiency states; and • those with chronic illnesses in whom there is a high risk of severe consequences from travellers’ diarrhea such as chronic renal failure, congestive heart failure, insulin-dependent diabetes mellitus and inflammatory bowel disease. There are no established guidelines for appropriate doses of once daily antimicrobial travellers’ diarrhea prophylaxis in children. Consultation with an infectious diseases specialist is recommended. Prophylactic antibiotics or bismuth subsalicylate should be considered only for short term travel to a maximum of three weeks, with the possible exception of immunosuppressed HIV-positive children who may require long term prophylaxis for prolonged travel. Although there are currently no effective vaccines available for the prevention of travellers’ diarrhea, immunoprevention for the most frequent cause, namely ETEC, could significantly reduce the incidence of disease. A killed, whole-cell ETEC vaccine appears to be safe and efficacious (39,40), but is not yet available. As well, a vaccine against Campylobacter jejuni is being developed and may prove to be useful (41). Typhoid vaccine has a protective efficacy of 50% to 75% and is recommended for travellers who will have significant exposure to contaminated food and water, in smaller cities and villages or rural areas off the usual tourist itineraries. Two typhoid vaccines are currently available; a parenteral, inactivated Vi capsular polysaccharide vaccine for children two years of age and older, and an oral (liquid or enteric-coated capsules) attenuated live vaccine Paediatr Child Health Vol 8 No 2 February 2003

Ty21a for children three years of age and older (42). The risk of cholera for the majority of travellers is so low that cholera vaccination is not generally recommended (43). THERAPY Fluid replacement is of primary importance in managing all cases. Diarrhea-induced dehydration is a significant risk in children but can usually be managed with oral rehydration solutions (44), widely available in developing countries. Children less than two years of age are at particularly high risk of acquiring travellers’ diarrhea and of suffering subsequent dehydration (4). Instructions for commercially available oral rehydration salts, prepared using boiled or treated water, should be carefully followed. Oral rehydration solutions should be consumed or discarded within 12 h if held at room temperature or 24 h if kept refrigerated. The dehydrated child should continue to breastfeed on demand or, if bottle-fed, should be given full-strength lactose-free or lactose-reduced formulas. Recommended foods for older children with dehydration include starches (such as rice, noodles, potatoes), cereals, lactose-free yogurt, fruits and vegetables. Immediate medical attention is required for the infant with diarrhea who develops signs of moderate to severe dehydration such as sunken eyes, absence of tears, reduced amount of or concentrated urine or more than 5% loss in body weight. As well, infants and children with bloody diarrhea, fever higher than 38.9°C (102°F), or persistent vomiting should receive immediate medical attention. For most older children with otherwise uncomplicated travellers’ diarrhea, hydration can be maintained with canned juices, carbonated soft drinks, purified water or clear salty soups. Beverages containing caffeine are discouraged because they may increase gastrointestinal motility and fluid secretion. Dairy products, prune juice, orange juice and apple juice may also aggravate diarrhea. Fluids should be consumed at a rate to allay thirst and maintain pale-coloured urine. Adjunctive therapy may be aimed at reducing bowel motility or may be directed against bacterial toxins and/or against bacterial pathogens (Table 1). Antimotility agents are both safe and efficacious if judiciously used. Loperamide (Imodium [McNeil Consumer & Specialty Pharmaceuticals, Guelph]) is probably the most effective antimotility agent available to reduce the duration and severity of diarrhea in mild to moderate cases of travellers’ diarrhea (ie, minimal cramps, no fever and no blood in the stools) in children over two years of age (45). However, caution should be exercised when using antimotility agents in younger children because there is an increased risk of severe complications including toxic megacolon (46) and hemolytic uremic syndrome in children infected with E coli O157:H748. Diphenoxylate (Lomotil [Pharmacia, USA]) is not recommended because it has been associated with toxic megacolon in patients with bacterial dysentery (48). Bismuth subsalicylate has antisecretory, antibacterial and anti-inflammatory properties, and may reduce the 101

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TABLE 1 Treatment of travellers’ diarrhea Agent Antimotility agents Loperamide

Dose

Comments

1-2 mg initially + 1-2 mg after each loose stool (maximum 3 mg daily in 2-5 year olds, 4 mg daily in 5-8 year olds and 6 mg daily in 8-12 year olds)

Contraindicated in infants younger than 2 years old

Two, 262 mg tablets orally for children older than 14 years; 15 mL (17.6 mg/mL) suspension 10-14 years; 7.5 mL for 5-9 years; 5 mL for 2-4 years; all every 30 min – 8 doses maximum per 24 h

Contraindicated in acetylsalicylic acid allergy; risk of Reye’s syndrome; not recommended in children younger than 2 years old

Antibiotic agents Azithromycin

5-10 mg/kg (max 500 mg) once daily for 3 days

Cefixime

8 mg/kg (max 400 mg) once daily for 3 days

Ciprofloxacin

15-20 mg/kg (max 500 mg) q12h for 3 days

Trimethoprim/Sulfamethoxazole

One double strength tablet (160/800 mg) for children older than 12 years of age; 4-5 mg/kg TMP or 20-25 mg/kg SMX paediatric suspension for children younger than 12 years of age; all twice daily for 3 days

Agent of choice for quinoloneresistant bacteria Alternative if macrolides and quinolones contraindicated Not indicated in children younger than 16 years of age* Widespread antibiotic resistance; effective against cyclosporiasis

Antisecretory/anti-inflammatory agents Bismuth subsalicylate

*In children with severe travellers’ diarrhea, the benefits of a three-day course of a quinolone antibiotic far outweigh the risks (56)

severity and duration of travellers’ diarrhea when used as treatment in adults (49). The principle disadvantages of bismuth subsalicylate as therapy include the delayed onset of action, frequent dosing and interference with the absorption of doxycycline, sometimes taken by older children as an antimalarial agent. Parent-administered antibiotic therapy with an extended-spectrum macrolide (such as azithromycin) or a fluoroquinolone may be indicated for those with moderate to severe travellers’ diarrhea (Table 1). Therefore, with few exceptions, most parents should be advised to carry a threeday course of antibiotic (paediatric formulation), as well as loperamide and a thermometer. Fluoroquinolones are currently the drugs of choice for the empiric treatment of travellers’ diarrhea in adults (50) (Table 1). Ciprofloxacin has been shown to reduce the duration of diarrhea, relieve associated symptoms such as cramps and reduce the number of liquid stools passed (51). Although single-dose regimens of fluoroquinolones usually provide equivalent effects compared with the standard three-day regimens, significant failure rates have been documented with Shigella dysenteriae-induced disease (52). In countries such as Thailand where fluoroquinolone resistance among Campylobacter species is almost universal, azithromycin is a more effective antibiotic (23). For children younger than 16 years of age, in whom fluoroquinolones are generally not recommended, azithromycin and cefixime (53,54) may be more appropriate agents. However, in children with severe travellers’ diarrhea, the benefits of a three-day course of a quinolone antibiotic far outweigh the risks (55). In unique circumstances where Cyclospora species are prevalent, such as Nepal during the summer months, and symptoms are sug102

gestive of this infection, a more rational choice for empiric antimicrobial therapy for travellers’ diarrhea may be TMP/SMX (56) (although TMP/SMX is ineffective against most other common causes of travellers’ diarrhea). Finally, any febrile child with diarrhea who has visited a malaria endemic area must have blood films performed immediately to rule out malaria. Children with severe travellers’ diarrhea not responding to empiric therapy and those with severe underlying medical conditions, immunosuppression or grossly bloody stools should be referred to an infectious diseases specialist immediately for further evaluation. Children with persistent diarrhea lasting longer than 14 days despite therapy should be managed according to the CATMAT statement of persistent diarrhea in the returned traveller (57). REFERENCES 1. Holt P. Severe salmonella infection in patients with reduced gastric acidity. Practitioner 1985;229:1027. 2. Neal KR, Scott HM, Slack RC, et al. Omeprazole as a risk factor for campylobacter gastroenteritis: Case-control study. BMJ 1996;312:414-5. 3. Steffen R. Epidemiologic studies of travellers’ diarrhea, severe gastrointestinal infections, and cholera. Rev Infect Dis 1986;8(Suppl 2):S122-30. 4. Pitzinger B, Steffen R, Tschopp A. Incidence and clinical features of traveler’s diarrhea in infants and children. Pediatr Infect Dis J 1991;10:719-23. 5. Daniels NA, Neimann J, Karpati A, et al. Traveler’s diarrhea at sea: Three outbreaks of waterborne enterotoxigenic Escherichia coli on cruise ships. J Infect Dis 2000;181:1491-5. 6. Brugha R, Vipond IB, Evans MR, et al. A community outbreak of food-borne small round-structured virus gastroenteritis caused by a contaminated water supply. Epidemiol Infect 1999;122:145-54. 7. Evans MR, Tromans JP, Dexter EL, Ribeiro CD, Gardner D. Consecutive salmonella outbreaks traced to the same bakery. Epidemiol Infect 1996;116:161-7.

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