Travelers' diarrhea

TRAVELERS' DIARRHEA iii

SHERWOOD L. GORBACH, M.D. DONALD W. HOSKINS, M.D.

0011-5029/80/10 0001-44-$05.00 O 1980, Year Book Medical Publishers, Inc.

TABLE OF CONTENTS DEFINITION

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EPIDEMIOLOGIC CONSIDERATIONS .

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MICROBIAL PATHOGENS CAUSING TRAVELERS' DIARRHEA TOXIGENIC DIARRHEAS

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CLINICAL DIAGNOSIS OF DIARRHEAL DISEASE PREVENTION OF TRAVELERS' DIARRHEA TREATMENT OF TRAVELERS' DIARRHEA .

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CHRONIC OR LATE-APPEARING TRAVELERS' DIARRHEA

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is a graduate of Tufts University School of Medicine. Dr. Gorbach completed his medical training at Bellevue Hospital in New York City and his infectious disease training at Tufts-New England Medical Center. He received a degree in parasitology and entomology at the London School of Hygiene and Tropical Medicine, and worked in gastroenterology research at the H a m m e r s m i t h Hospital. His studies of diarrheal diseases were conducted in Calcutta and Mexico, where he sampled a broad range of intestinal ailments. Dr. Gorbach's research interests have focused on the intestinal tract, including metabolic activities of the microflora and anaerobic infections, in addition to diarrheal disorders.

i s Clinical Associate Professor of Medicine, Cornell University Medical College, and a member of the Divisions of International Medicine and Gastroenterology. He also serves as Consultant (Tropical Medicine), Memorial Hospital, and Chairman, Department of Medicine, Doctors Hospital, New York City. Following graduation from Cornell Medical College, he trained in internal medicine and gastroenterology at the New York Hospital. A practicing internist with a tropical medicine subspecialty, Dr. Hoskins is particularly interested in protozoal and helminthic infections of the intestinal tract.

D I A R R H E A L I L L N E S S h a s p l a g u e d t r a v e l e r s for c e n t u r i e s . I t h a s i n f i l t r a t e d all r a n k s , g i v e n rise to n u m e r o u s t h e o r i e s of c a u s a t i o n a n d a c h i e v e d w o r l d - w i d e f a m e b y its v a r i o u s e u p h e m i s m s , s o m e of w h i c h a r e lilting, o t h e r s b r a c k i s h . W i t h i n t h e g l o s s a r y of d e s c r i p t i v e e p i t a p h s t h a t h a v e b e e n

applied to the intestinal agonies of travelers are GI trots, gypsy tummy, Casablanca crud, Aden gut, Barsa belly, Turkey trot, Hong Kong dog, Delhi belly, Aztec two-step, Montezuma's revenge and turista. Most recently, a disease acquired by travelers to the Soviet Union associated with Giardia infection has been called "the Trotskys." At times, battles have been decided less by strength of force or ingenuity of plan than by the extent of enteric losses. Interruption of international business or long-planned vacations by intestinal illness has led to financial loss as well as discomfort and disappointment. Annually, more than one-quarter billion people travel from one country to another and tourism has become economically significant, especially to developing countries. 1 United States travelers to Mexico alone number three million annually. With an attack rate of 2 5 - 50%, diarrheal illness may affect upward of one million visitors yearly, close to 30% of whom are ill enough to require confinement to bed and another 40% to alter their scheduled a c t i v i t i e s / F e a r and concern over potential illness has led the traveler to a variety of nostrums for the prevention and t r e a t m e n t of diarrheal illness, some comforting, others ineffective and still others potentially harmful as well as ineffective. This review will attempt to summarize our current knowledge of causative agents, diagnosis, t r e a t m e n t and prevention of travelers' diarrhea.

DEFINITION Most authorities consider diarrhea to be present when the patient has 2 - 3 , or more, times the usual n u m b e r of stools per 24 hours and they are liquid in consistency. (A working description used in field studies labels a diarrheal stool as one that assumes the shape of the container.) The loose bowel movements are associated with one or more of the following: fever, chills, abdominal cramping, nausea or vomiting. Some observers record the extent of diarrheal illness (mild, moderate, severe) based primarily on the numbers and severity of associated symptoms and the length of confinement.

Typically, the traveler is welI for the first 2 - 3 days, with the onset of illness beginning 4 - 6 days after arrival. The disease begins abruptly with abdominal cramps followed by watery diarrhea, numbering most often between 3 and 8 stools per day, rarely more t h a n 15 per day. By the second or third day, diarrhea usually has lessened and normal activity gradually resumes. Duration of illness is variable, averaging 2 days in some studies~ (1- 3 days in 90% of patients) whereas others report a median duration of 5 d a y s / C e r t a i n beleaguered travelers experience 2 - 3 such episodes of diarrhea, even during a relatively short stay. In some instances, diarrhea persists and m a y last for weeks. Besides loose bowel movements, a series of associated symptoms is involved with travelers' diarrhea. The following figures are derived from an unpublished study (by Gorbach and Kean) of North American students who were afflicted with travelers' diarrhea while studying at a Mexican university. SYMPTOM

PERCENTAGE

Gas Fatigue Cramps Nausea Fever Abdominal pain Anorexia

79 74 68 61 56 55 53

SYMPTOM

Headache Chills Backache Dizziness Vomiting Malaise Arthralgia

PERCENTAGE

39 38 35 34 29 24 23

EPIDEMIOLOGIC CONSIDERATIONS The most important d e t e r m i n a n t in travelers' d i a r r h e a is the destination of the voyage. Studies by Kean and Smillie 4 in the 1950s showed t h a t travelers in northern European countries had a much lower incidence of diarrhea t h a n those in Mediterranean countries. Since then, most studies have concentrated on "tropical" or developing countries. For example, the incidence of diarrhea among North American travelers in Mexico has varied in recent surveys between 25% and 50%. 2 Such high incidences have been reported for other Latin American countries (Salvador, Peru), Africa (Morocco, Kenya), Mediterranean countries (Spain, Greece), Middle East (Iran, Egypt) and Far Eastern countries

(Pakistan, India, Bangladesh, Thailand). This list does not exhaust the areas of high risk, but indicates those in which surveys have been carried out. In contrast, low-risk areas are the British Isles, Scandinavia, northern and western Europe, the United States and Canada. In one investigation, simultaneous interviews were carried out at the San Francisco airport of North American travelers returning from Hawaii or Mexico; the Hawaiian travelers had an attack rate of diarrhea of 7%, whereas Mexican travelers reported an incidence of 33%. 5 A warm climate per se is not the important factor; besides the low incidence in Hawaii, another study from Miami showed an incidence of 2% of travelers' diarrhea at an international conference in t h a t city2 The origin of the traveler is another important factor in liability to develop diarrhea. In international meetings held in Teheran 7 and Mexico City, 2, s an incidence of 40 - 50% of diarrhea was reported by North Americans, South Africans and western Europeans, compared with 1 - 8% among visitors from Asia, South America and southern Europe. The purpose of travel and style of eating play significant roles. The highest incidence of diarrhea occurs in people traveling for study purposes or tourism whereas the lowest incidence is seen in those visiting relatives. Intermediate risk is associated with business travel. More diarrhea occurs in people eating in restaurants and school cafeterias, with a particularly high risk, as might be imagined, in those who succumb to the wares of street vendors. The safest place to eat is in a private home2 There is a r a t h e r poor correlation between diarrhea and any particular type of food or drink. In several studies, people who took great care by avoiding tap water, unpeeled fruits and fresh vegetables were no better protected t h a n those who were relatively indiscriminate. One study did show, however, t h a t travelers who consumed fresh salads were somewhat at greater risk for diarrheaY Within recent years , diarrheal epidemics in certain developing countries have been traced to commercially bottled beverages, so t h a t even these items cannot be considered safe havens for the thirsty traveler. (Although the incidence of travelers'

diarrhea may not be significantly reduced by avoiding tap water, raw fruits and fresh vegetables, m a n y other pathogens are carried by these vehicles, not necessarily those registered in the column of "travelers' diarrhea." Therefore, these items still should be avoided by the judicious traveler.) Advancing age is associated with a lower incidence of travelers' diarrhea. It is not known whether this protection is due to i m m u n i t y gained after frequent attacks or differences in eating habits.

MICROBIAL PATHOGENS CAUSING TRAVELERS' DIARRHEA Elucidation of the microorganisms responsible for travelers' diarrhea has come only recently, as laboratory technology has advanced in this field. Studies from several parts of the world-Mexico, Morocco, Salvador, Kenya, Banglad e s h - have shown the same litany of pathogens associated with this condition: MICROORGANISMS

INCIDENCE IN TRAVELERS ~ DIARRHEA

Toxigenic E. coli Invasive E. coli Salmonella Shigella

40-70% 0-4% 0-15% 0- 20%

V. parahaemolyticus Giardia lamblia E. histolytica

0- 2% 0- 2% 0- 2% 0 - 4% 0 0 10- 35%

Reovirus Parvovirus Enterovirus Undiagnosed

As noted, m a n y cases still lack an etiologic diagnosis. In other individuals, more t h a n one potential pathogen is isolated from the diarrheal stool, and it is difficult to assign a causal role to a specific organism. There also is a high incidence of asymptomatic infections; for example, approximately 15% of h e a l t h y travelers acquire toxigenic E. coli, and a similar number may acquire Shigella. TM Despite these

reservations, the studies of prophylaxis with the antibiotic doxycycline (discussed below) demonstrates protection in 90% of the treated travelers, suggesting that approximately 90% of such infections are caused by bacteria sensitive to this drug. Even though our laboratory technology still is imperfect, it can be assumed that most cases of travelers' diarrhea are caused by an infectious microorganism, probably a coliform bacterium. Special epidemiologic circumstances m a y produce a different range of pathogens. On cruise ships there have been epidemics of Shigella, Salmonella and V. p a r a h a e m o l y t i c u s that have caused large numbers of cases." American and Scandinavian travelers to the Soviet Union have experienced a high infection rate with Giardia, representing in some series 2 0 - 4 0 % of all visitors to that country.12

TOXIGENIC DIARRHEAS Several studies have shown that the major cause of travelers' diarrhea is enterotoxin-producing strains ofE. coli. '~ ,3-,5 The enterotoxin elaborated by this organism has a direct effect on the small intestine, resulting in secretion of fluid and electrolytes. The prototype of this disease is cholera, but this organism is extremely rare in travelers. Besides E. coli, other bacteria have been associated with enterotoxin production and acute diarrheal illness, including Klebsiella, Citrobacter, Enterobacter, Pseudomonas, Proteus, Serratia, Aeromonas and Yersinia. In addition, enterotoxins are made by organisms that cause food poisoning, such as Clost r i d i u m perfringens, Staphylococcus aureus and Bacillus cereus. As can be seen, the list of potential pathogens grows each year; unfortunately, clinical laboratories do not yet have the facilities to diagnose these enterotoxigenic strains. Toxigenic diarrheas are characterized by watery, often dehydrating diarrhea that has its origin in the upper small bowel. As a rule, the pathogen does not invade the mucosal surface, so bacteremia is extremely rare. Rather, the organism colonizes the small bowel, sticking to the epithelial cells and elaborating its enterotoxin.

ESCHERICHIA COLI

Certain strains ofE. coli cause diarrheal disease by elaborating enterotoxins. Two types of toxins are produced by these organisms. The first, known as LT (heat-labile toxin), is a protein t h a t acts physiologically like choleratoxin by activating adenyl cyclase. The second toxin, known as ST (heat-stable toxin), has a low molecular weight, fails to activate adenyl cyclase and has no biochemical relationship to choleratoxin. E. coli strains can elaborate either LT or ST, or both. Both toxins have been shown to cause disease in travelers. Most of the other gram-negative organisms t h a t have been associated with acute diarrhea (see above) elaborate toxins physiologically similar to those found in E. coli. 16, 17 Toxigenic E. coli are isolated in 4 0 - 70% of travelers with diarrhea and in 10 - 20% of asymptomatic travelers. A large number of bacteria are needed to initiate infection; for this reason, contaminated food is thought to be the major vehicle of spread. Certain E. coli strains, not necessarily those producing enterotoxins, have been associated with severe epidemics of diarrhea in neonatal nurseries. These organisms, known as "enteropathogenic E. coli" (EPEC), are designated by their somatic serotype. Approximately 15 such pathogenic serotypes have been identified, including the well-known ones, 055 and 0111. EPEC rarely are associated with travelers' diarrhea. In addition to toxigenic E. coli there is an entirely different group of pathogenic E. coli t h a t causes a diarrheal disease similar to bacillary dysentery. These E. coli do not elaborate an enterotoxin but cause diarrhea by direct invasion of the colonic mucosa. Such "penetrating" strains have been isolated in Southeast Asia and occasionally in the United States and are considered an uncommon cause of diarrhea in travelers. TREATMENT.--E. coli diarrhea usually is a self-limited event t h a t does not require specific treatment. Some studies have shown a marginal benefit with tetracycline therapy in severely ill, hospitalized patients. However, the slight im-

provement observed with tetracycline in what usually is a benign condition does not justify antibiotic t r e a t m e n t in all suspected cases. The mainstay of therapy is symptomatic, with replenishment of fluid and electrolytes, usually via the oral route. The various narcotic analogues (paregoric, diphenoxylate, loperamide) probably are helpful in relieving abdominal cramping and associated symptoms, although there is no evidence that intestinal fluid excretion actually is diminished. Pepto-Bismol, taken orally in doses of 3 0 - 6 0 ml every half hour for 8 doses, has reduced the number and improved the consistency of stools as well as reduced abdominal cramping in toxigenic E. coli infections in Mexico.18 SALMONELLOSIS

More than 1700 serotypes of Salmonella exist in nature, many of which are pathogenic for man. It is estimated that approximately 1% of the United States population is infected annually with one of these serotypes. In travelers, the incidence has ranged from 0 to 14%, although most studies show that less than 5 % are infected by these organisms. The most common clinical syndrome associated with Salmonella is diarrhea. The usual incubation period is 6 - 4 8 hours, although latency can last as long as 7 - 12 days. Initial symptoms are nausea and vomiting, followed by abdominal cramps and diarrhea. The diarrhea lasts 3 - 4 days and is accompanied by fever in 50% of individuals. In general, the pain of Salmonella gastroenteritis is localized in the periumbilical area or the right lower quadrant. The diarrhea can vary from a few loose stools to dysentery with grossly bloody feces or a cholera-like syndrome. Persistent fever or severe toxicity suggests bacteremia or focal infection. The main site of attack is the terminal ileum. The inflammatory response often is mild, much less ulcerative than seen in bacillary dysentery. Hence, inflammatory cells usually are absent from the feces, although this is a variable finding. TM Typhoid fever is a relatively uncommon disease of travel10

ers. Most cases are caused by S. typhi, but other Salmonella serotypes occasionally can cause this syndrome as well. Although the portal of entry is the gastrointestinal tract, typhoid fever should not be considered a diarrheal disease. Indeed, many patients present with constipation or have no intestinal symptoms. Compared with other forms of Salmonella infection, typhoid fever has a longer incubation period ( 7 - 1 2 days), usually involves the reticuloendothelial system (liver, spleen, lymph nodes) and has a much more hectic course/o TREATMENT. -- Antimicrobial agents have no impact on the clinical course of Salmonella gastroenteritis. Indeed, these drugs actually are contraindicated in the usual case, since such treatment prolongs the intestinal carrier rate. 21 Certain people with underlying conditions are at special risk for Salmonella infection, and antibiotics are indicated in these settings: lymphoproliferative disorders; cardiovascular disease with prosthetic heart valves, vascular grafts, aneurysms and valvular heart disease; hemolytic anemias; and patients at the extreme ages of life (< 6 months and > 75 years). In these selected categories, ampicillin or trimethoprim-sulfamethoxazole ( T M P - S M X ) is recommended for initial therapy. Typhoid fever is improved by antimicrobial drugs, as indicated by defervescence in 4 - 5 days, lowered mortality rate and reduced gastrointestinal hemorrhage. In our view, chloramphenicol is the drug of choice for typhoid fever. Equal claims have been made, but not as strongly substantiated, for amoxicillin and T M P - SMX.

SHIGELLOSIS

Bacillary dysentery is an acute, often febrile, diarrheal illness caused in the main by Shigella or, on rare occasions, by invasive strains of E. coli. Shigellae are distributed throughout the world, occurring in some tropical countries as a major form of diarrheal illness. Person-to-person transmission is the general rule, since the organisms are highly infectious. However, transmission by contaminated food or 11

drink has been well documented, and these vehicles are the threat to travelers. The most common Shigella species in tropical countries is S. flexneri, followed by S. sonnei. 17 (This order of frequency is reversed in the United States and Europe. 22) A more severe form of dysentery is caused by S. dysenteriae I CShiga"), an organism associated with a severe epidemic of dysentery in Mexico and Central America during 1969- 1971. The unique feature of dysentery, distinct from most other forms of diarrhea, is the exudative nature of the fecal effluent. In approximately 3 0 - 5 0 % of cases, a grossly bloody, purulent stool is passed. Microscopic examination of the stool in virtually all cases, however, reveals a sea of polymorphonuclear leukocytes and red blood cells. Sigmoidoscopy reveals a friable, ulcerative, diffusely inflamed mucosa; these findings are indistinguishable from acute idiopathic ulcerative colitis. Lower abdominal pain is the rule, and some patients complain bitterly of incapacitating rectal pain Ctenesmus"). Shigellosis often is heralded by watery diarrhea, occasionally leading to dehydration, b u t the character of the feces usually changes after 24 hours to a mucoid stool of small volume. 16, 17 Shigellae cause disease by penetrating through the large bowel mucosa, producing a severe ulcerative colitis. Many Shigella strains elaborate an enterotoxin that is thought to be responsible for the watery diarrhea often noted at the onset of illness. TREATMENT.--The major determinant in the decision to use antimicrobial agents is the severity of the disease. Many cases of bacillary dysentery are mild, often not requiring a physician's attention, and they pass as self-limited events. In moderate to severe dysentery, the weight of evidence favors the use of antimicrobial agents; these patients have frequent uncomfortable evacuations associated with abdominal pain and mild fever. A presumptive diagnosis of bacillary dysentery can be established by examining the fecal effluent for PMNs. On the basis of an exudative stool, it is recommended that treatment with ampicillin be initiated. For adults who are able to take oral medication, a dose of 2 gm daily, divided into 4 equal doses, is suggested. 12

(Amoxicillin, a close relative of ampicillin, should not be used in this disease.) Many strains of Shigellae are resistant to ampicillin 23 and frequently to tetracycline, sulfonamides and chloramphenicol as well. ~4 A useful alternative drug is trimethoprim-sulfamethoxazole administered for 5 days at a dose of 160 mg TMP and 800 mg SMX twice daily (pediatric dose is 10 mg TMP kg/day, 50 mg SMX/kg/day in 2 divided doses)YS, 26 Narcotic-containing drugs are interdicted, since they prolong the diarrhea and can even provoke toxic megacolon, a dire complication of dysentery. 27

Vibrio Parahaemolyticus Vibrio parahaemolyticus is a marine organism, preferring a high salt milieu. It colonizes in fish and shellfish and causes clinical illness when these foods are eaten raw or partially cooked, a common practice in J a p a n and other Far Eastern countries. The infection is largely confined to the summer months and can occur in epidemic proportions. This organism can cause disease in travelers. It has even been responsible for epidemics on cruise ships, airplanes and at specific eating places. 11, 28 Clinically, diarrhea and abdominal cramps usually begin within 1 2 - 2 4 hours of ingesting the contaminated seafood, with an illness lasting for 2 4 - 72 hours. Some patients note blood and mucus in the stool, and there are reports of an extensive colitis during the course of the illness. Bacteremia is quite rare with this organism, although it has been known to occur with other marine Vibrio organisms, particularly in patients with underlying liver disease. There is considerable debate concerning the virulence mechanism in V. parahaemolyticus. Various toxins have been demonstrated and an invasive process also has been shown. '7 In the laboratory, pathogenic Vibrios can be differentiated from the nonpathogenic s t r a i n s b y the " K a n a g a w a reaction," a zone of hemolysis t h a t surrounds the pathogens when cultured on a blood agar plate. 29 V. parahaemolyticus causes an acute, often uncomfortable diarrheal disease, which invariably is self-limited and subsides without treatment. 13

CAMPYLOBACTER Recognized since 1909 by veterinarians as a cause of disease in cattle, sheep and birds, Campylobacter (formerly Vibrio fetus) infection in m a n was first described in 1947. Derived from the Greek, the name Campylobacter means a curved rod; microscopically, it is a motile, S-shaped gramnegative bacillus. The subspecies C. fetus jejuni, the major isolate, and C. fetus intestinalis are pathogenic for man. 3~ 31 It was only in 1972 t h a t Campylobacter was first cultured from the stool, a delay in recognition t h a t was largely attributable to the requirement of fecal isolates for selective media and microaerophilic conditions whereas blood isolates grow in standard laboratory media. 32 An increasing number of reports indicate t h a t Campylobacter is responsible for 1.3- 11% of diarrheal illnesses, though, to date, for less t h a n 2% of travelers' diarrhea. 3~ Sources of contamination include unpasteurized milk, 33,34 poultry products (both dressed and partially cooked) and dogs. 35 It is interesting t h a t 20% of patients with Campylobacter enteritis in England reported foreign travel in the recent past. With proper culture methods, it is anticipated t h a t this organism would be responsible for some of the cases t h a t have been labeled "culture-negative" travelers' diarrhea. Diarrhea is a constant feature of Campylobacter enteritis. In about one-half of patients, the diarrhea is preceded by prodromal systemic complaints, including fever, malaise, headache, myalgias and anorexia. Abdominal pain occurs in most affected individuals. Within 24 hours there is the onset of loose stools, frequently bile-stained, which often become watery or mucoid and m a y progress to melena or gross blood. The acute diarrheal episode generally lasts for 2 - 3 days, but the patient typically feels unwell for a total of 1 - 2 weeks. Stools contain an inflammatory cellular exudate in 80% of patients, similar to t h a t seen with bacillary dysentery. Fresh blood is present in two-thirds of cases. 3G TREATMENT.-- Patients with Campylobacter enteritis do well without therapy and most individuals are on the road to recovery when the bacteriologic diagnosis is made. Anti14

biotic therapy, however, appears to be indicated in protracted or severe cases. Presently, erythromycin is the drug of choice for the diarrheal illness. Recommended doses range from 500 mg twice a day to 50 mg/kg/day for adults. The larger doses are associated with nausea. Although experience is limited, it appears t h a t t r e a t m e n t with erythromycin reduces the length of illness in some individuals. ~~ VIRAL ENTERITIS

There has been a tendency, unfounded in scientific terms, to label all undiagnosed diarrheal illnesses as "intestinal flu." Notwithstanding such sloppy terminology, viral agents have been associated with acute diarrhea, although their role in travelers' diarrhea is considered minimal. Among the earliest studies in travelers' diarrhea, a search for Enteroviruses (polio, Echo, Coxsackie) was undertaken, and it proved to be fruitless. 37 Certainly these viral agents are common in the tropics, probably more so t h a n in temperate climates, but they were found not to be associated with diarrhea among travelers to these areas. A recently described agent known as Reovirus currently is held responsible for most cases of infantile diarrhea. 38 Known also by the terms duovirus, orbivirus and rotavirus, this agent measures approximately 70 nm in diameter and has a single capsid. The clinical disease occurs mostly in children under the age of 2 years. Epidemiologic studies have suggested t h a t between 30% and 60% of children with acute diarrhea, in both the United States and the tropics, are infected by this agent. Although the organism can be shed by adults, it is relatively less common for them to develop the clinical disease. The virus is visualized by electron microscopy in fecal effluents of infected individuals. A serologic test also is available. Based on our current knowledge, it appears t h a t two or three serotypes of this agent are capabte of infecting humans.39, 40 Among adult travelers in Mexico, Reovirus has been implicated in a small number of cases. The organism often was found in these studies to be associated with asymptomatic 15

carriers or with other pathogens in a sick individual. 41Thus, it is difficult to estimate the role of this virus, but it probably causes less t h a n 5% of travelers' diarrhea. Another group of viruses, known as Parvovirus, can cause diarrheal disease in all age groups. This virus has been recognized as the cause of major epidemics as in Norwalk, Ohio, which provided the initial appellation for this organism, "the Norwalk agent." At least three serotypes are known to exist. Infection with Parvovirus involves the proximal small bowel, producing damage to the mucosal architecture, shortening the villi and causing hyperplasia of the crypts. Vomiting is a frequent symptom in the initial stages of the disease, and may even be more impressive t h a n the diarrhea t h a t usually follows. Studies of Parvovirus infection in travelers generally have been negative, with either no evidence of infection by serologic or direct stool examination or the same incidence of acquisition in sick and asymptomatic individuals. Laboratory diagnosis of Reovirus and Parvovirus is extremely tedious because of the inability to grow the agents in tissue culture. There m a y be other viruses t h a t have not been even recognized as a cause of diarrhea. On the basis of current evidence, it must be stated t h a t viruses are not important in the etiology of travelers' diarrhea; however, strong disclaimers of infallibility must be added at this stage of our knowledge. GIARDIASIS

Giardia lamblia, a flagellated protozoan, colonizes the upper small bowel, causing watery diarrhea and abdominal cramps. It is not limited to the world traveler or to exotic areas. Epidemics of giardiasis have occurred in Camas, Washington42; Berlin; New Hampshire; Rome; New York43; and Aspen and Boulder, Colorado. 44 Recent reports indicate t h a t male homosexuals in major U.S. cities are experiencing giardiasis, amebiasis and shigellosis in epidemic proportions; venereal transmission appears to be the likely route. 45 Travelers returning from Leningrad and other cities in the U.S.S.R. are especially suspect, with an attack rate of 23% 16

reported in American visitors. 12 The disease is also highly prevalent in Asia, west and central Africa, South America and Mexico. SOURCE. The infection is largely waterborne. It has been related to contamination of rivers by untreated sewage effluent, failure of water purification systems and sewer-line obstruction. Recently, Giardia-infected beavers have been found near contaminated rivers and have been incriminated in spreading the disease to humans. 46 -

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CLINICAL PRESENTATION.--Most often, the initial symptoms do not occur until 1 - 3 weeks postexposure, often beginning just after the traveler returns home. When added to the usual delay in consulting a physician, the clinical picture usually is fully evident at the initial visit. The patient complains of abdominal cramps, distention, flatulence, nausea, anorexia and foul-smelling, often yellowish stools. Weight loss can occur, but it seldom is more than 5 - 1 0 pounds unless the course is prolonged or is associated with malabsorption. DIAGNOSIS.-- Examination of a fresh stool directly and by concentration with formalin-ether is positive in 5 0 - 7 5 % of cases by single-specimen and possibly up to 90% by twospecimen analysis. 46a It is the remaining 1 0 - 2 0 % of cases that vex the physician. When the diagnosis is strongly suspected clinically and not corroborated by multiple stool examinations, duodenal-jejunal intubation and aspiration may reveal the trophozoite. Entero-Test (manufactured by Hedeco Co., Mountain View, California), a gelatin capsule containing a string, m a y be an alternative to oral/nasogastric tube duodenal aspiration. For those trained in peroral small bowel biopsy and with facilities available, this procedure should be the next step. Biopsy sections stained with Giemsa or direct examination of the mucus obtained with the biopsy specimen m a y reveal the parasite. 47 It is important to recognize that a number of commonly prescribed drugs and over-the-counter products can mask the diagnosis by interfering with proper stool examination or shedding of the parasite: antacids, antimicrobials, antidiarrheals, oily sub17

stances, certain cathartics and barium are among the chief offenders. Repeat stool examinations after the patient has been offthese agents a week or more may enable the diagnosis to be made without more complicated techniques. Even with optimal stool examinations and small bowel aspiration, some cases of presumed giardiasis escape detection. These are patients who respond to "empirical" therapy, not a particularly satisfactory maneuver to conclude a diagnostic work-up but one that may be forced by the clinical situation. Giardia trophozoites have been observed "lining' the luminal face of the intestinal mucosa. The villous architecture is normal in nearly all cases, but partial villous atrophy has been noted in instances of severe infection. 4s The parasite has been observed within the epithelial cell and in the lamina propria in a small group of patients with steatorrhea, all of whom were heavily infected. TR~ATMENT.--Quinacrine hydrochloride (Atabrine), 100 mg 3 times a day for 1 week, is 8 0 - 9 5 % effective in the t r e a t m e n t of Giardia infection; rarely a second course is necessary 1 - 2 weeks later. Metronidazole (Flagyl), although not approved for this use by the Food and Drug Administration, is slightly less effective than quinacrine, though perhaps better tolerated. Taken orally, 250 mg 3 times a day for 1 week, it does not usually produce the adverse effects encountered with the tripling of dose required by amebiasis. Furazolidone, available as a suspension, is used for young children, with cure rates close to 80% reported. No drug is without its adverse reactions. Quinacrine rarely yellows the skin in the doses recommended. Toxic psychosis, fever, rash and gastric intolerance have been noted, fortunately as infrequent occurrences. Metronidazole has been associated with mutagenesis and carcinogenicity in mice, a subject that is discussed further under Amebiasis. Which of these two drugs, quinacrine or metronidazole, to use in treating a case of giardiasis is problematic. Quinacrine has many side effects and metronidazole has the aura of mutagenesis; opinions concerning the relative safety and efficacy are divergent. However, patients suffering from 18

giardiasis usually will accept the minimal hazards of therapy with one or the other drug in order to obtain relief from the disabling symptoms. 49 AMEBIASIS Infection with Entamoeba histolytica, always a consideration, nevertheless is an uncommon cause of travelers' diarrhea. There has been a tradition, spawned by medical folklore, to indict this organism as the cause of diarrhea in travelers or expatriates residing in tropical countries. This has given rise to the famous remark by Elsdon-Dew t h a t "amebiasis is the refuge of the diagnostically destitute." Amebiasis is a cosmopolitan disease, respecting neither age nor socioeconomic class. The most frequent form of infection is asymptomatic cyst passage. In the United States, approximately 4% of the population have cysts in their stools without experiencing symptoms. Careful studies, however, have revealed mucosal invasion in some individuals, so this condition m a y not be totally benign. The symptomatic forms of amebiasis are diarrheal-dysenteric (mild to severe), chronic dysenteric colitis, ameboma and amebic appendicitis. Most episodes of amebiasis tend to be subacute in nature, with alternating periods of diarrhea and relative well-being. The symptoms m a y last for weeks, months or even years if untreated. Although such recurrent cases do exist, it is also important to recognize t h a t m a n y patients, even with dysentery, experience spontaneous cure. The severe complications of amebiasis are hemorrhage, intussusception, perforation and peritonitis, postdysenteric colitis and stricture. The most common site of intestinal invasion is the cecum, followed by the sigmoid, rectum and splenic flexure. The ulcerations tend to be spotty, with normal intervening mucosa. The classic pathologic description is an initial erosion t h a t causes necrosis of the lamina propria to produce a "flask-shaped" ulcer with a small opening on the surface and a large necrotic zone beneath. Typically, there is a paucity of inflammatory cells in the necrotic debris and only a narrow rim of plasma cells, lymphocytes and eosinophils surround19

ing the ulceration. The stool effluent shows red blood cells but relatively few inflammatory cells, thereby distinguishing it from the exudative discharge of shigellosis. Diagnosis of amebiasis requires demonstration of the protozoa, either in the stool, in aspirated mucus or pus at the time of sigmoidoscopy or in a section of rectal biopsy. In most cases of intestinal disease, the organism can be identified by collecting three stool specimens, preferably on different days. If the stool is loose, semiformed or frankly bloody, it is best to examine it fresh. In the event of delay, it should be placed in a fixative such as polyvinyl alcohol (PVA), and the fixed preparation should be examined by the trichrome stain. All fresh specimens should be examined directly for motile trophozoites as well as stained for studying fine detail. Three careful stool examinations can identify up to 90% of intestinal infections. 5~ Serologic tests can be utilized for diagnosing intestinal or extraintestinal amebiasis. 51 A multiplicity of such tests currently is available, but the most reliable, proved in several laboratories, is the indirect hemagglutination test (IHA). A diagnostic IHA titer is 1 : 128 or greater. Metastatic amebiasis is uncommon but, when seen, usually takes the form of liver abscess. The right lobe of the liver is favored, with a predilection for males over females, 7 : 1. Rarely, pleural, pulmonary or pericardial involvement is present, usually representing extension from below the diaphragm. Various scanning techniques, combined with serologic studies, are useful in the diagnosis of extraintestinal amebiasis. Skin infections also can occur, although rarely. TREATMENT. Several drugs are available for the therapy of amebic infections (Table 1). However, as Kean 52 has pointed out, the choice of an appropriate agent is complicated increasingly by reports of new forms of toxicity, withdrawal of effective drugs from the m a r k e t and economic pressures on drug companies that impede the testing and clearance of new drugs by the Food and Drug Administration. The choice of therapy depends on the clinical classification and the severity of the disease. There is no firm agreement -

20

-

TABLE

1.--RECOMMENDED TREATMENT REGIMENS FOR AMEBIASIS

Asymptomatic cyst carrier Intestinal amebiasis

Diloxanide furoate (Furamide) 500 mg TID x 10 days or

Diiodohydroxyquin 650 mg TID x 20 days Metronidazole 750 mg TID x 10 days or Paromomycin 250-500 mg TID x 5-10 days plus Diloxanide furoate (Furamide) or

Extraintestinal amebiasis (liver abscess)

Diiodohydroxyquin Metronidazole 750 mg TID x 10 days or Dehydrometine (or emetine) 1.0 mg/kg/day (maximal dose 60 mg) IM x 10 days (when parenteral therapy is required) plus Diloxanide furoate (Furamide) or Diiodohydroxyquin

a b o u t t h e m a n a g e m e n t of a s y m p t o m a t i c i n d i v i d u a l s w i t h cysts in t h e i r stools. S o m e a u t h o r i t i e s p r a c t i c e e n l i g h t e n e d n e g l e c t a n d p r e f e r not to t r e a t . O t h e r s r e c o m m e n d specific c h e m o t h e r a p y in all cases. D i i o d o h y d r o x y q u i n is a d m i n i s t e r e d in a dose of 650 m g 3 t i m e s a d a y for 20 d a y s . T h e r e a r e occasional r e a c t i o n s to t h e iodine c o n t a i n e d in t h i s compound. O f m o r e serious i m p o r t a r e t h e r a r e i n s t a n c e s of optic a t r o p h y a n d p e r i p h e r a l n e u r o p a t h y t h a t h a v e b e e n reported, e s p e c i a l l y w i t h p r o l o n g e d use. D i l o x a n i d e f u r o a t e ( F u r a m i d e ) is h i g h l y effective for cyst c a r r i e r s , w i t h v e r y few r e p o r t e d side effects. B e c a u s e of licensing, t h i s d r u g is not r e a d i l y a v a i l a b l e in t h e U n i t e d S t a t e s , a l t h o u g h it c a n be o b t a i n e d f r o m t h e P a r a s i t i c D r u g Service, C e n t e r for Dise a s e Control, A t l a n t a , Georgia. M e t r o n i d a z o l e (Flagyl) r e m a i n s t h e d r u g of choice for t r e a t i n g m o s t clinical f o r m s of a m e b i a s i s . T h e dose is 750 m g o r a l l y 3 t i m e s a d a y for 10 days. M a n y i n d i v i d u a l s a r e u n a b l e to t o l e r a t e t h i s dose b e c a u s e of v o m i t i n g or n a u s e a , a n d 500 m g 3 t i m e s a d a y c a n be u s e d in t h e s e c i r c u m stances. Since t h i s t h e r a p y m a y fail to e l i m i n a t e cysts, t h e r e h a s b e e n a h i g h incidence of r e l a p s e w i t h m e t r o n i d a z o l e . A 21

second drug, such as diiodohydroxyquin or diloxanide furoate, should be used in combination. Paromomycin (Humatin) is an alternative agent for treating symptomatic intestinal amebiasis. Emetine and its synthetic isomer, dehydroemetine, should be used only in extreme cases of dysentery or in extraintestinal amebiasis (liver abscess).49, 53 In treating parasitic infections there often is a therapeutic imperative to use drugs with potential toxicity for lack of alternative agents. Metronidazole fits in this category, since it is the preferred treatment for amebiasis and, in the view of some authorities, for giardiasis as well. The potential side effects of metronidazole are minor, consisting of a metallic taste in the mouth, mild GI symptoms and an Antabuse-like effect. Mild leukopenia is seen occasionally during drug therapy and a distal sensory neuropathy also has been described. A major issue, however, concerns potential carcinogenesis. It has been shown that metronidazole causes mutagenesis in the Ames Salmonella typhimurium bacterial mutagenesis system and in tissue culture models, and m a y even increase tumor formation in susceptible experimental animals, although the latter point has been strongly debated. 54 A recent article surveyed retrospectively women treated for vaginal trichomoniasis with metronidazole between 1960 and 1970; no statistically significant increase in the incidence of malignancy was noted in these women. 55 Although this information provides some comfort, there remains a lingering doubt, especially since this drug exerts its antimicrobial effects on the DNA within the cell. Yet, metronidazole is an excellent therapeutic agent that should be used for treating parasitic disease where alternative therapy is not available.

CLINICAL DIAGNOSIS OF DIARRHEAL DISEASE A pathophysiologic approach can be used for making a presumptive etiologic diagnosis in patients with infectious diarrhea. It is most convenient to separate pathogens that involve the small intestine from those attacking the large bowel. Toxigenic bacteria (E. coli, cholera), viruses and the 22

parasite Giardia are examples of small bowel pathogens. These organisms produce w at er y diarrhea, which m a y lead to dehydration. Vomiting commonly is present. Abdominal pain, although often diffuse and poorly defined, generally is periumbilical in location. Microscopic e x a m i n a t i o n of t he stool fails to reveal formed cellular elements such as erythrocytes and leukocytes. A large bowel pathogen, the major one being Shigella, is an invasive organism t h a t causes the clinical syndrome of dysentery. Characteristic rectal pain, known as tenesmus, or among the aficionados as "dry heaves at the rectum," strongly implicates colonic involvement. Although the initial fecal effluent m a y be watery, by the second or third day of illness it becomes a stool of relatively small volume t h a t often is bloody and mucoid. Microscopic ex amin ation of the stool invariably reveals a b u n d a n t e r y th r o cy tes and leukocytes. Proctoscopy shows a diffusely ulcerated, hemorrhagic and friable colonic mucosa. These features are summarized in Table 2. Salmonella does not fit into this simple schema, since this organism has features of both groups. It is invasive, but TABLE

2 . - - C L I N I C A L FEATURES OF DIARRHEAL DISEASE SMALL BOWEL DIARRHEA

Pathogens

Location of pain Volume of stool

Blood in stool Leukocytes in stool

E. coli (LT/ST*) V. cholerae

Reovirus Parvovirus Giardia Midabdomen Often large and watery, causing dehydration Cit pours") Very rare Very rare

LARGE BOWEL DIARRHEA

(invasive) Shigella Amebiasis

E. coli

Lower abdomen and rectum Usually small, may be mucoidCdysenteric")

Very common Very common (except amebiasis) Proctoscopy Normal Mucosal ulcers, hemorrhagic, friable *LT= heat-labile toxin; ST= heat-stable toxin. 23

generally in the ileum, and it causes fluid secretion, often in voluminous quantities. In addition, septicemia and metastatic spread of the pathogen to other organs occurs in some cases. Incomplete information is available for infections caused by Campylobacter and V. parahaemolyticus to distinguish them on the basis of their pathogenic mechanisms. However, epidemiologic aspects and clinical features can suggest the diagnosis in some patients.

PREVENTION OF TRAVELERS" DIARRHEA BRIEFING THE PATIENT ABOUT TRAVEL ABROAD All persons traveling to developing countries, especially those areas known to be at high risk for travelers' diarrhea, should be given guidance in the principles of preventing intestinal infection. Most of these measures are well known and have been covered previously. They include avoidance of tap water, ice cubes, salads, unpeeled fruits and vegetables, custards and cream deserts, unpasteurized milk and dairy products, items offered by street vendors and "buffet foods" t h a t are left out at room temperature or undergo reheating. In one study, food items, particularly salads, r a t h e r t h a n tap water, were noted to be the primary source of infection. This finding can be attributed to the poor sanitary practices of food handlers and to the high inoculum required to initiate disease by m a n y of the bacterial pathogens. (Bacteria flourish better in contaminated food t h a n in clear liquids.) Bottled water, canned and bottled carbonated beverages, wines, beer, tea and coffee should be the source of fluid for travelers to such areas. Experienced travelers often rely on hot tea or coffee, since the heating process destroys most pathogens. PROPHYLACTIC DRUGS

Pepto-Bismol, an over-the-counter preparation with bism u t h subsalicylate as the active agent, has been shown to be effective in both prophylaxis and t r e a t m e n t of travelers' 24

diarrhea. Insoluble bismuth salts have been recommended for treating gastrointestinal disorders for more t h a n a century, without any proof of efficacy. Recently, the bismuth subsalicylate preparation has demonstrated activity in laboratory models of diarrheal disease induced by toxigenic E. coli or Vibrio cholerae. The experimental studies suggest t h a t it is the subsalicylate moiety and not the bismuth t h a t is the active component, since bismuth subcarbonate was ineffective. The subsalicylate component may exert this effect by its antiprostaglandin activity, a mechanism t h a t has been proved to be important in other forms of experimental diarrhea. ~6 In a study of U.S. students newly arrived in Mexico, bismuth subsalicylate was used as a prophylactic agent in a dose of 2 oz (60 ml) 4 times a day. Untreated students had a 61% incidence of diarrhea, compared to 23% in the treated individuals, a difference t h a t is statistically significantY The limitation on such prophylactic use is the requirement to pack 1 bottle per day or 14 bottles (8 oz) for a 2-week voyage. An extra suitcase perhaps would suffice, and this would permit additional room on the return trip for souvenirs. Even if these bottles could be accommodated in a 44-pound weight allotment, m a n y tourists would be reluct a n t to face this drug 4 times a day during what should be a vacation. However, these investigators stated t h a t the minimal dose has not been determined and it may be possible to use less of this drug. When considering a lower dose, it should not be overlooked t h a t 23% of students developed diarrhea, even on the higher dose schedule. ANTIMICROBIAL AGENTS.- In a study performed nearly 20 years ago, North American college students traveling to Mexico were given either neomycin 1 gm/day or phthalylsulfathiazole (a nonabsorbable sulfonamide) 2 gm/day in an effort to prevent diarrhea. Both drugs reduced the incidence of moderate to severe travelers' diarrhea. The protection was 70% with the sulfonamide; in the case of neomycin, it shifted the disease to a milder form of involvement without an overall decrease in the incidence of diarrhea. 5s Because of the potential side effects and the marginal benefit of these drugs, they are not currently recommended for prophylaxis. A legendary mystique, passed on by word of mouth to suc-

25

cessive generations of international travelers, has surrounded the drug iodochlorhydroxyquin (Enterovioform). In a well-designed study of prophylactic use among North American students in Mexico, no benefits from iodochlorhydroxyquin could be demonstrated over a placebo. Other studies, poorly designed under the drug company's auspices, did show a protective effect among British rugby players engaged in matches on 5 continents. Besides the considerable controversy over efficacy, a more important issue of toxicity has been raised, since iodochlorhydroxyquin has been implicated in subacute myelo-optic neuropathy (SMON), a condition associated with neurologic dysfunction and blindness. ~9 Currently, iodochlorhydroxyquin is not recommended for therapeutic or prophylactic use, and it is not presently licensed in the United States. Two studies of Peace Corps volunteers in Kenya 6~ and Morocco6' have demonstrated the effectiveness of a single daily dose of doxycycline (100 mg) in the prevention of travelers' diarrhea. This drug is a tetracycline compound; it has advantages over other tetracyclines, namely, broader spectrum of activity, longer half-life and higher concentrations in the gut. However, doxycycline is more expensive than other tetracyclines and it shares the range of toxicity found in other members of this class. In the volunteers in Kenya, only 1 of 18 in the treated group developed diarrhea, compared with 13 of 27 in the placebo group. Parenthetically, the treated individual who developed diarrhea in fact had dysentery with a Shigella resistant to tetracycline and ampicillin. These studies subsequently have been repeated in Morocco, with the same results. It appears that protection lasts during the period of t r e a t m e n t and for at least 1 week thereafter. No side effects of the drug were reported in these studies. Culture of the stools, however, revealed an increased incidence of antibiotic-resistant bacteria in the treated subjects. The application of doxycycline prophylaxis to other geographic locales is not clear. A recent study with this drug, at a dose of 100 mg twice weekly for 3 weeks, in Peace Corps volunteers newly arrived in Honduras showed no benefit in preventing diarrhea. G2The incidence of fecal E. coli resistant 26

to doxycycline was 66% in the placebo group, suggesting a high level of endemic resistance of E. coli in Honduras to this class of antibiotics. It is not clear whether the semiweekly dose of drug or the high level of antibiotic-resistant E. coli was responsible for the equivocal benefit of the drug. Doxycycline has been successful in preventing travelers' diarrhea, with the provisos t h a t it be t a k e n once a day and t h a t the infecting pathogens are sensitive. However, there has been a general reluctance to recommend this drug to the millions of travelers to high-risk countries who could be considered candidates for receiving it. There are m a n y problems, both real and potential, t h a t can be associated with its use. 1. The pressure of drug usage would induce antibiotic resistance in bacteria found within the normal flora of the host. Such resistance often extends to 4 or more other antibiotics. The genes for such resistance can be t r a n s m i t t e d to other E. coli and to Salmonella and Shigella. 2. The normal intestinal flora provides protection for the host against invasion by Salmonella and Shigella. Suppression of the flora by antimicrobial agents m a y be associated with a higher incidence of such infections. In a study among Swedish travelers receiving oxyquinoline prophylaxis, a higher incidence of Salmonella infections was noted in the treated individuals. As mentioned above, the one person in the doxycycline trial who developed bacillary dysentery was an individual receiving the prophylactic antibiotic. 3. Certain areas of the world already have a high incidence of resistance among toxigenic E. coli. In a recent study, 60% of the toxigenic E. coli isolates from patients in the Philippines, Korea and Indonesia were resistant to tetracyclines23 Similar findings have been noted in Mexico. These studies suggest t h a t doxycycline m a y not be a useful antibiotic because of bacterial resistance in certain countries in which travelers' diarrhea is prevalent. 4. Tetracyclines m a y cause side effects t h a t can be particularly troublesome to a traveler. The most common untoward reaction's with these drugs relate to the GI t r a c t - i . e . , nausea, abdominal pain and diarrhea. The drug should not be given to persons with known sensitivities or allergies to 27

tetracycline, nor should it be prescribed for pregnant women or children less than 8 years of age, because of the risk of staining the teeth in the fetus or the developing child. Another hazard is skin photosensitivity, a reaction that m a y be distressing to those planning vacations in sunny, tropical countries. Tetracyclines, as a class, tend to induce Candida vaginitis. We recommend extreme selectivity in the use of doxycycline for prophylaxis of travelers' diarrhea. It m a y be considered in the following circumstances: for travelers to highrisk developing countries; for short-term visits (3 weeks or less); in experienced travelers with a proved track record of severe diarrhea; and for business travelers who have planned brief stays during which they require uninterrupted use of their time.

TREATMENT OF TRAVELERS' DIARRHEA The major pillar of t r e a t m e n t in diarrheal diseases, including those in travelers, is rehydration with appropriate fluids and electrolytes. Although travelers m a y experience voluminous purging, the period of severe fluid loss usually is brief. In addition, travelers tend to be rather healthy and they are able to sustain these fluid losses, as long as there is some replenishment. The electrolyte content of fecal effluent in patients with infectious diarrhea tends to be rather stereotyped. The diarrheal stool is isotonic with plasma, but the specific electrolyte composition reflects the unique transport system in the TABLE 3. --STOOL ELECTROLYTESIN INFECTIOUS DIARRHEA ELECTROLYTES Sodium

Potassium Bicarbonate Chloride 28

MEQ./L 125

20 45 90

bowel. T h e r e t e n d s to be excessive loss of b i c a r b o n a t e a n d p o t a s s i u m (Table 3), a n d t h e s e p a t i e n t s develop a h y p o k a lemic acidosis. Most p a t i e n t s c a n be r e h y d r a t e d by t h e oral route. A balanced electrolyte-glucose solution h a s b e e n devised (Table 4) by t h e World H e a l t h O r g a n i z a t i o n for oral t r e a t m e n t . G4,G0 An i m p o r t a n t e l e m e n t in this solution is glucose, w h i c h is absorbed across t h e i n t e s t i n a l m u c o s a despite t h e active sec r e t o r y process induced by the d i a r r h e a l disease. T h e absorption of glucose is linked to sodium, a n d w a t e r follows in a passive m a n n e r . P a t i e n t s c a n be a d e q u a t e l y r e h y d r a t e d by this scheme, w i t h t h e i m p o r t a n t c a v e a t t h a t t h e y are not s e v e r e l y d e h y d r a t e d at t h e onset, to t h e point of i m p e n d i n g v a s c u l a r collapse. T r a v e l e r s do not g e n e r a l l y h a v e access to this b a l a n c e d e l e c t r o l y t e solution. As a m a k e s h i f t compromise, a n approxi m a t i o n of the ideal solution can be m a d e by a d d i n g t h e following i n g r e d i e n t s to 1 liter of p u r e w a t e r . Potassium chloride Sodium bicarbonate Sodium chloride Glucose or Sucrose

~/4teaspoon ~/2teaspoon Y2 teaspoon 2 tablespoons 4 tablespoons

An a l t e r n a t i v e method, s o m e w h a t less a c c u r a t e b u t serviceable, is t h e following: Glass Number I

Glass Number 2

Orange juice or other fruit 8 oz Pure water 8 oz juice (for potassium content) Table salt 1 pinch Honey or corn syrup 1/2 tsp Baking soda 1/4 tsp (for glucose) (sodium bicarbonate) or Table sugar 1 tsp (sucrose) Instructions: Drink alternately from each glass. Additional fluids may be taken ad lib. It is i m p o r t a n t to c a u t i o n p a t i e n t s w i t h s e v e r e d i a r r h e a a g a i n s t d r i n k i n g only w a t e r or bottled sodas to r e h y d r a t e 29

TABLE 4.--WORLD HEALTH ORGANIZATION ORAL REHYDRATION FLUID GM/L H20

Sodium chloride Sodium bicarbonate Potassium chloride Glucose

3.5 2.5 1.5 20.0

CONCENTRATION

Sodium Bicarbonate Potassium Glucose

90 mEq. 30 20 120 mmole

themselves, since these solutions lack the vital electrolytes t h a t are being lost in the stool. Although most cases of travelers' diarrhea can be managed with oral rehydration, it is apparent t h a t some individuals require more intensive therapy by the parenteral route. Young children are less able to withstand dehydration, so special concern is required in this setting. Older people with cardiovascular disease also are at a high risk for sustaining d a m a g i n g effects from dehydrating diarrhea. DIET Dietary m a n a g e m e n t of gastrointestinal disorders has been influenced more by fads and fancies t h a n by clinical science. The traditional approach to any diarrheal illness is dietary abstinence, which restricts the intake of calories, fluids and electrolytes t h a t are needed by the patient. During an acute attack, the patient often finds it more comfortable to avoid high-fiber foods, fats and spices, all of which can increase stool volume and/or intestinal motility. "Giving the bowel a rest" provides symptomatic relief, as long as there is maintenance of oral fluids containing calories and some electrolytes. It is wise to avoid milk and dairy products during the acute episode, especially in children, since lactase deficiency m a y intervene; ingestion of milk in this setting could potentiate fluid secretion and stool volume. Beverages t h a t contain caffeine or theophylline products should be avoided, since these agents increase intestinal motility. Thus, coffee, strong tea, cocoa and soft drinks such as colas all contain chemicals t h a t can potentiate abdominal cramps 30

and diarrhea. Alcohol has similar effects on the gut and abstinence in this regard is recommended. Besides the oral rehydration fluids listed above, acceptable fluids include fruit juices and various bottled soft drinks. (It is advisable to "defizz" a carbonated drink by letting it stand in a glass before consuming it.) "Soft," easily digestible foods are most acceptable to the patient with acute diarrhea. NONSPECIFIC REMEDIES.-- Literally hundreds of antidiarrheal nostrums can be found in pharmacies, apothecary shops, herbal stands, homeopathy stores, soothsayer's booths, witchcraft dispensaries and assorted medical establishments throughout the world. Each country has its own brand names and labeling requirements. Travelers should be advised to exercise extreme care in purchasing such items for symptomatic relief from intestinal ailments; these products often contain a combination of drugs, most of them therapeutically worthless, others potentially dangerous. For example, many such products contain chloramphenicol, a drug whose indiscriminate use in outpatients can have disastrous effects on the bone marrow. Others contain iodochlorhydroxyquin, which may cause neurologic damage and optic atrophy. Certain analgesics and anti-inflammatory drugs, which have been restricted severely or eliminated from the marketplace in North America and Europe, still are incorporated into the antidiarrheal preparations sold over the counter in many countries. Various starches, talcs, chalks and absorbent compounds have been prescribed for diarrheal illness for as long as there is recorded history. Kaopectate is one such popular remedy, consisting of kaolin, hydrated aluminum silicate and pectin. Theoretically, it absorbs water, converting a loose bowel movement into a mushy, lumpy movement. Although this m a y have some aesthetic appeal, and perhaps reduces the number of evacuations, there is no evidence that Kaopectate offers benefit in diminishing intestinal fluid losses. Thus, it is considered by most authorities to have a limited value in treating acute diarrheal disease. NARCOTIC ANALOGUES(ANTIMOTILITYAGENTS).- There is a family of drugs, all related to opiates, that is useful in pro-

31

viding symptomatic relief for acute diarrhea. The major products are as follows. 1. Paregoric A hydroalcoholic opium preparation with benzoic acid, camphor and anise oil. Being a black, rather sticky liquid, it tends to stain the clothing, a misadventure that could occur when a bottle breaks in the luggage. In addition, there is an unpleasant taste. Dosage: 1 - 2 tsp ( 5 - 1 0 ml) after each loose stool, or 4 times a day. 2. Tincture of opium A hydroalcoholic solution containing 10% opium. Dosage: 0 . 5 - 1 . 5 ml 4 times a day. 3. Diphenoxylate (Lomotil). A congener of meperidine, usually prepared with a small amount of atropine (to prevent abuse). Dosage: 2 . 5 - 5.0 mg (1 - 2 tablets) every 6 hours until diarrhea is controlled. 4. Loperamide (Imodium). A recently introduced agent that is similar in structure to diphenoxylate. Dosage: 4 mg initially (2 tablets), followed by 2 mg after each unformed stool, up to 16 mg (8 tablets) per day. It is believed that the narcotic analogues act by reducing propulsive motility Cantiperistaltic"). Recently, opiates have been shown to inhibit fluid secretion in experimental diarrhea, and this m a y provide another explanation for the beneficial effects of these agents. The synthetic agents, diphenoxylate and loperamide, have relatively low analgesic activity and dependence potential when used at the recommended dose. The entire class of drugs should not be used in young children, because of suppression of respirations that has been observed in this age group. In addition, pregnant women should avoid these agents whenever possible. It is known that excessive use in idiopathic ulcerative colitis and amebiasis of the drugs in this family can have disastrous effects by provoking toxic dilatation of the colon. In patients with bacillary dysentery, the narcotic analogues have been observed to enhance symptoms and to prolong fecal excretion of the pathogenY 7 (This observation was made during the course of a vaccine trial in shigellosis with a small group of volunteers.) Although these proscriptions should be scrupulously followed in proved cases of dysentery, such caution does not 32

apply generally to uncomplicated diarrhea in travelers. To be sure, there are no controlled studies to verify the efficacy of the antimotility drugs in travelers' diarrhea, although benefit has been established in several forms of chronic diarrhea. However, it is widely believed by experienced travelers that these drags do relieve cramps and possibly shorten the duration of symptoms. In addition, there is no recorded experience of prolonging disease or worsening symptoms in travelers when the drugs are used with reasonable caution. We recommend these agents in the following circumstances. 1. To be used for acute travelers' diarrhea, but limited to 3 - 4 doses over a 24-hour period. If relief has not been experienced by 24 hours, the drug should not be used further. A dose should be taken only when there has been a loose bowel movement since the previous dose. Often, 1 tablet of diphenoxylate or loperamide is sufficient to abate the symptoms. A small dose of 1 - 2 tablets may be taken on successive days if there is demonstrated relief and the patient is otherwise free from systemic symptoms (fever, rigors, severe toxicity). 2. The traveler should be advised against using these drugs when there is gross blood or purulence in the stool. Such findings suggest dysentery or amebiasis, conditions for which these drugs are contraindicated. In addition, the coexistence of high fever, shaking chills or severe toxicity interdicts their use, and the traveler should seek medical attention as soon as possible. 3. These agents should not be taken by pregnant women and young children. Following these simple instructions should avoid serious complications with the "antimotility" drugs. Bacillary dysentery and amebiasis have been relatively uncommon causes of travelers' diarrhea. There is a widely shared belief, not rigorously proved by therapeutic trials, t h a t the narcotic analogues do offer short-term relief to the beleaguered traveler. BISMUTH SUBSALICYLATE.- This preparation, an over-thecounter product with the trade name Pepto-Bismol, has been used to treat travelers' diarrhea in Mexico with some success. Taken orally in 3 0 - 6 0 - m l doses (2 oz) every half

33

hour for 8 doses, it reduced the number of evacuations by 50%. TM There were virtually no side effects from this treatment. As noted above, the large dose is somewhat inconvenient, but it m a y be worth the trouble to attain the 50% relief. ANTIBIOTICS.- Investigators working in Bangladesh with patients hospitalized for severe diarrhea due to toxigenic E. coli found that tetracycline, 500 mg orally every 6 hours for 3 days, significantly shortened the duration of illness and excretion of the pathogen. A beneficial effect was established for infections caused by E. coli producing the heatlabile toxin (LT) but not for infections with only ST. (STonly strains represent about one-third ofE. coli infections in travelers.) It should be noted that the benefits, although statistically significant, did not have a great impact on the disease, which was rather brief in duration even in the untreated patients2 ~ Furthermore, the study population in Bangladesh did not represent the usual group of tourists, and the severe dehydration seen in Bengalis must be considered an extreme variant of travelers' diarrhea. Thus, this report should not be taken as an endorsement of antibiotic therapy. It is recommended that antibiotics not be used for the typical case of travelers' diarrhea. The disease caused by toxigenic E. coli usually is short-lived and resolves spontaneously without specific treatment. Similarly, diarrhea caused by Salmonella (with few exceptions), V. parahaemolyticus bacterial food poisoning organisms and viruses should not be treated with antibiotics. Patients with bloody diarrhea or with systemic toxicity should seek medical attention for a more definitive diagnosis. As indicated above, infections due to Shigella, Campylobacter, Amebae and Giardia require specific therapy.

CHRONIC OR LATE-APPEARING TRAVELERS' DIARRHEA Although most episodes of travelers' diarrhea are brief, lasting 1 - 3 days, this is not always the case. A study of North American s~udents in Mexico revealed that 20% of 34

those with diarrhea were ill for 5 or more days. A prolonged latent period m a y coincide with the journey home, especially in the era of jet airplanes, so the traveler m a y develop diarrhea after returning to his home. In a study of American physicians traveling to Mexico for a conference, 10% developed diarrhea during the initial 7 days after coming homey The following conditions should be considered when a traveler seeks medical attention for diarrhea after returning from an overseas journey. UNRECOGNIZED PATHOGENS.-- The cause for chronic or late-appearing travelers' diarrhea m a y be an unwelcome microbial souvenir t h a t was acquired during the trip. Salmonella gastroenteritis can last as long as 3 weeks and m a y have an extended incubation period. When this organism involves the large bowel, as it does on rare occasions, there may be a prolonged colitis, lasting several weeks. An untreated Shigella infection can produce chronic bacillary dysentery t h a t persists for weeks to months. In some individuals, the acute symptoms resolve without treatment, but there continues to be a carrier state, which then can erupt weeks later in a recrudescence of dysentery. Appropriate antimicrobal therapy should abort this sequence. Two other bacterial pathogens, Campylobacter and Yersinia, are notorious for producing chronic diarrhea. Special culture conditions are required to isolate the pathogen in the stool. Giardiasis has a prolonged incubation period, usually 1 week or more, and also has an extended course when untreated. The same situation applies to amebiasis, although this organism admittedly is uncommon in travelers. SLOW RESOLUTION.- Perhaps the most common cause for persistent diarrhea after an overseas trip is slow resolution, for reasons unknown, which occurs with spontaneous cure or even after appropriate therapy for a recognized organism. Microbial pathogens, especially invasive ones, cause widespread damage to the intestinal mucosa, which may require days to weeks for repair. The patient with bacillary dysentery who is treated appropriately with antimicrobial agents experiences an improvement in symptoms and rids the stool of the pathogen, but m a y not r e t u r n to normal bowel habits

35

for 1 - 4 weeks after the treatment. Occasionally, a patient with giardiasis treated successfully undergoes this slow resolution. Undiagnosed travelers' diarrhea also can have this phase of delayed resolution. In these circumstances, appropriate stool cultures and parasitologic examinations are obtained; if negative, and the patient is improving spontaneously, strong reassurance about eventual cure can be given. There is a condition known as ~'postamebic colitis," in which the patient with amebic dysentery apparently is cured of the protozoan infection but continues to have persistent symptoms and pathologic changes in the colonic mucosa. It is not clear whether E. histolytica can initiate what becomes chronic ulcerative colitis, but such is the sequence of events that has been reported. DISACCHARIDASE DEFICIENCY.-- An attack of acute infectious diarrhea can precipitate intestinal disaccharidase deficiency, the most common being hypolactasia. The enzyme deficiency m a y be temporary, resolving after several weeks, or may become permanent. In the latter situation, it is possible that the patient had a genetic predisposition that was provoked by the infectious agent. Lactase deficiency is quite common after acute diarrheal episodes, particularly in young children. This has led to the advice that milk be withheld from the diet during acute diarrhea and given only sparingly after the acute episode has passed. The ingestion of milk or dairy products causes intestinal cramps, distention and watery diarrhea. Occasionally, sucrase deficiency is induced by acute diarrhea, producing symptoms when sucrose-containing foods such as fruits or preserves are consumed. U N M A S K I N G A P R E - E X I S T I N G C O N D I T I O N . - - A foreign trip may be blamed for a condition that, in fact, antedated the journey. Such patients present with a history of diarrhea that has persisted since their travel several weeks or months earlier. On careful questioning, it becomes apparent that such symptoms existed prior to the trip, although they were not considered significant by the patient. A subsequent investigation may reveal inflammatory bowel disease (ulcerative colitis or Crohn's disease). Occasionally, a patient with irri-

36

table colon blames overseas travel for his chronic problem. It is also true that patients m a y develop inflammatory bowel disease for what apparently is the first time after a trip abroad. It could be argued that foreign travel is rather frequent and that this disease is also relatively common, so the chance occurrence of both m a y be coincidence rather than a causal relationship. On the other hand, it is possible that some infectious agent acquired while traveling m a y have precipitated inflammatory bowel disease. Whatever the explanation, this condition should be considered in the extraveler with persistent diarrhea. TROPICAL JEJUNITIS. -- Foreign travelers or expatriates develop a diarrheal disease known variously as tropical or nonspecific jejunitis, tropical malabsorption syndrome or tropical sprue. The condition is most likely to occur in visitors to the Indian subcontinent (India, Pakistan, Bangladesh and Sri Lanka), Indonesia and the Caribbean (Puerto Rico and Haiti). It has also been reported from West Africa and Colombia, South America, and the geographic area m a y be broader than previously realized. The level of sanitation and hygiene as well as the length of stay are correlated with the likelihood of developing the disease. Many patients date the onset of their illness to an acute diarrheal episode, which merges into chronic diarrhea with weight loss, abdominal cramps and distention. The syndrome of tropical jejunitis represents a spectrum, ranging from asymptomatic individuals (most common) to chronic diarrhea and weight loss. The symptomatic patients have some or all of the following abnormalities: steatorrhea; carbohydrate malabsorption (i.e., D-xylose); vitamin B12 malabsorption; abnormal intestinal transport of water and electrolytes (producing net fluid secretion and diarrhea); abnormal small bowel microflora with overgrowth of coliforms in the upper intestine; and pathologic changes in the intestinal mucosa, featured by blunting of villi and an inflammatory infiltrate in the lamina propria. The patient with florid illness tends to have resided in a high-risk area for a considerable period, and m a y display all of these abnormalities. The duration of symptoms is extremely variable.

37

In general, the disease improves and resolves spontaneously within weeks to months after return to the home country. In rare cases, however, symptoms have persisted for as long as 20 years after return from overseas before the diagnosis was established and treatment was instituted. Many of the physiologic abnormalities are related to abnormal bacterial colonization of the small intestine. For this reason, antibiotic therapy has been highly effective in treating the diarrhea and malabsorption syndrome. Several antibiotic regimens have been recommended, b u t tetracycline (250 mg 3 times a day) appears to control most cases. The duration of treatment, particularly in the mild case, is also variable. For the returning traveler or expatriate, a course of 2 - 4 weeks usually is sufficient to give relief. Since there is a tendency for relapse after therapy is discontinued, such patients should be followed carefully and treatment reinstituted when appropriate. Folic acid certainly should be prescribed when a deficiency exists; routine use in this disease is of questionable value. D I A G N O S T I C I N V E S T I G A T I O N S FOR CHRONIC OR LATE-APP E A R I N G TRAVELERS' DIARRHEA ( F i g 1). -- F o r t u n a t e l y , most

returning travelers who seek medical attention for diarrhea get well within I - 3 weeks after their initial visit to the physician, regardless of the therapy. The following investigations, in this sequence, are recommended. I. After initial history and physical examination, assuming that the patient is afebrile and lacking specific physical findings, 3 stool specimens should be obtained for bacteriologic culture and parasitologic examination. By the time these stools are collected, processed in the laboratory and the results transmitted to the patient, there usually is resolution of the problem, for which the physician can take credit by having practiced watchful waiting. The identification of a specific pathogen in the stool obviously requires appropriate therapeutic intervention. 2. A careful history regarding tolerance to milk products should be taken. If there is any suggestion of lactose-related symptoms, the patient should undergo a lactose tolerance test and be advised concerning dietary management. 38

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3. If symptoms persist beyond this initial period of observation, generally 1 - 3 weeks, and the stool examinations are negative, it may be necessary to intensify the search for Giardia (tube aspiration of jejunal fluid, "string test" or jejunal biopsy) or for amebiasis (sigmoidoscopy and rectal biopsy). It is at this stage t h a t an "empirical" t r e a t m e n t course for presumed giardiasis should be considered, depending on the character of the symptoms. 4. Should these measures prove unhelpful, it would be appropriate then to perform sigmoidoscopy and to initiate radiographic studies such as barium enema and upper GI series with small bowel follow-through. A careful history should be t a k e n regarding inflammatory bowel disease (including family history) and irritable colon. Previous episodes of diarrhea and food intolerance should be inquired about. 5. If the x-ray studies are unrewarding, and inflammatory bowel disease or irritable colon seems untenable, the diagnosis of tropical jejunitis should be considered. (The small bowel series may display a nonspecific malabsorption pattern, which is a clue to the diagnosis.) Depending on their availability, it would be useful to obtain a D-xylose test, studies for B12 and fat malabsorption (Schilling test and stool fats) and a small bowel biopsy. If the clinical suspicion is sufficiently strong, a brief trial of tetracycline m a y be justified at this point. Patients with tropical jejunitis should respond to t r e a t m e n t rather promptly, with some improvement of symptoms and physiologic abnormalities within 1 week. It must be emphasized again t h a t tropical jejunitis with florid symptoms would be r a t h e r uncommon in the vacation traveler who has spent a few weeks overseas. REFERENCES 1. International Conference on the Diarrhea of Travelers: New directions in research. Summary of the proceedings. Washington, D.C., 1976. 2. Merson,M. H., Morris, G. K., Sack, D. A., Wells, J. G., Feeley, J. C., Sack, R. B., Creech, W. B., Kapikian, A. Z., and Gangarosa, E. J.: Travelers' diarrhea in Mexico:A prospective study of physicians and family members attending a congress, N. Engl. J. Med. 294:1299, 1976. 40

3. Kean, B. H.: The diarrhea of travelers to Mexico: Summary of fiveyear study, Ann. Intern. Med. 59:605, 1963. 4. Kean, B. H., and Smillie, W. G.: Intestinal protozoa of American travelers returning from Europe, N. Engl. J. Med. 251:471, 1954. 5. Kean, B. H., and Waters, S. R.: The diarrhea of travelers: I. Incidence in travelers returning to the United States from Mexico, A.M.A. Arch. Indust. Health 18:148, 1958. 6. Ryder, R. W., Wells, J. G., and Gangarosa, E. J.: A study of travelers' diarrhea in foreign visitors to the United States, J. Infect. Dis. 136: 605, 1977. 7. Kean, B. H.: Turista in Teheran, Lancet 2:583, 1969. 8. Loewenstein, M. S., Balows, A., and Gangarosa, E. J.: Turista at an international congress in Mexico, Lancet 1:529, 1973. 9. Tjoa, W. S., DuPont, H. L., Sullivan, P., Pickering, L. K., Holquin, A. H., Olarte, S., Evans, D. G., and Evans, D. V., Jr.: Location of food consumption and travelers' diarrhea, Am. J. Epidemiol. 106:61, 1977. 10. Gorbach, S. L., Kean, B. H., Evans, D. G., Evans, D. V., Jr., and Bessudo, D.: Travelers' diarrhea and toxigenic Escherichia coli, N. Engl. J. Med. 292:933, 1975. 11. Lawrence, D. N., Blake, P. S., Yashuk, J. C., Wells, J. G., Creech, W. B., and Hughs, J. H.: Vibrio parahaemolyticus gastroenteritis et~breaks aboard two cruise ships, Am. J. Epidemiol. 109:71, 1979. 12. Brodsky, R. E., Spencer, H. C., and Schultz, M. G.: Giardiasis in American travelers to the Soviet Union, J. Infect. Dis. 130:319, 1974. 13. Sack, D. A., Kaminsky, D. C., Sack, R. B., Wamola, I. A., Orskov, F., Orskov, I., Slack, R. C. B., Arthur, R. R., and Kapikian, A. Z.: Enterotoxigenic Escherichia coli diarrhea of travelers: A prospective study of American Peace Corps volunteers, Johns Hopkins Med. J. 141:63, 1977. 14. Sack, R. B., Gorbach, S. L., Banwell, J. G., Jacobs, B., Chatterjee, B. D., and Mitra, R. C.: Enterotoxigenic Escherichia coli isolated from patients with severe cholera-like disease, J. Infect. Dis. 123:378, 1971. 15. Shore, E. G., Dean, A. G., Holik, K. J., and Davis, B. R.: Enterotoxin producing Escherichia coli and diarrheal disease in adult travelers: A prospective study, J. Infect. Dis. 129:577, 1974. 16. DuPont, H. L.: Enteropathogenic organisms: New etiologic agents and concepts of disease, Med. Clin. North Am. 62:945, 1978. 17. Hornick, R. B.: Bacterial Infections of the Intestine, in Weinstein, L., and Fields, B. A. (eds.), Seminars in Infectious Disease (New York: Stratton Intercontinental Medical Book Corp., 1978), Vol. 1, Chap. 3, p. 68. 18. DuPont, H. L., Sullivan, P., Pickering, L. K., Haynes, C., and Ackerman, P. B.: Symptomatic treatment of diarrhea with bismuth subsalicylate among students attending a Mexican university, Gastroenterology 73:715, 1977. 19. Harris, J. C., DuPont, H. L., and Hornick, R. B.: Fecal leucocytes in diarrheal illness, Ann. Intern. Med. 76:697, 1972. 20. Sprinz, H.: Pathogenesis of intestinal infections, Arch. Pathol. 87:556, 1969. 41

21. DuPont, H. L., and Hornick, R. B.: Clinical approach to infectious diarrheas, Medicine 52:265, 1973. 22. Center for Disease Control, U.S. Public Health Service: Surveillance Summary, Shigellosis-United States, 1978, Morbidity and Mortality Weekly Report, Vol. 28, No. 41, Atlanta, Georgia, October 19, 1979, p. 486. 23. Haltalin, K. C.: Ampicillin and shigellosis, Am. J. Dis. Child. 125:458, 1973. 24. Ross, S., Controni, G., and Khan, W.: Resistance of shigellae to ampicillin and other antibiotics. Its clinical and epidemiological implications, JAMA 221:45, 1972. 25. Nelson, J. D., Kusmiesz, H., Jackson, L. H., and Woodman, E.: Trimethoprim-sulfamethoxazole therapy for shigellosis, JAMA 235: 1239, 1976. 26. Chang, M. J., Dunkle, L. M., Van Rekan, D., Anderson, D., Wong, M. L., and Feigen, R. D.: Trimethoprim-sulfamethoxazole compared to ampicillin in the treatment of shigellosis, Pediatrics 59:726, 1977. 27. DuPont, H. L., and Hornick, R. B.: Adverse effects of Lomotil therapy in shigellosis, JAMA 226:1525, 1973. 28. Dadisman, T. A., Nelson, R., Molenda, J. R., and Garber, H. J.: Vibrio parahaemolyticus gastroenteritis in Maryland. I. Clinical and epidemiologic aspects, Am. J. Epidemiol. 96:414, 1972. 29. Miyamoto, Y., Kato, T., Obara, S. A., Takizawa, K., and Yumai, S.: In vitro hemolytic characteristic of Vibrio parahaemolyticus: Its close correlation with human pathogenicity, J. Bacteriol. 100:1147, 1969. 30. Skirrow, M. B.: Campylobacter enteritis; a "new disease," Br. Med. J. 2:9, 1977. 31. Guerrant, R. L., Lahita, R. G., Winn, W. C., and Roberts, R. B.: Campylobacteriosis in man: Pathogenic mechanisms and review of 91 bloodstream infections, Am. J. Med. 65:584, 1978. 32. DeKeyser, P., Gosscun-Detigin, M., Butzler, J. P., and Sternon, J.: Acute enteritis due to related vibrio: First positive stool culture, J. Infect. Dis. 125:390, 1972. 33. Robinson, D. A., Edgar, W. J., Gibson, G. L., Marchett, A. A., and Robertson, L.: Campylobacter enteritis associated with consumption of unpasteurised milk, Br. Med. J. 1:1171, 1979. 34. Taylor, P. R., Weinstein, W. M., and Bryner, J. H.: Campylobacter fetus infection in human subjects: Association with raw milk, Am. J. Med. 66:779, 1979. 35. Center for Disease Control, U.S. Public Health Service: Campylobacter enteritis-Iowa, Morbidity and Mortality Weekly Report, Vol. 28, No. 47, Atlanta, Georgia, November 30, 1979, p. 565. 36. Lambert, M. E., Schofield, P. F., Ironside, A.G., and Mandal, B. K.: Campylobacter colitis, Br. Med. J. 1:857, 1979. 37. Rosenbluth, M. A., Schaffner, W., and Kean, B. H.: Diarrhea of travelers. IV. Viral studies of visiting students in Mexico with further bacteriologic and parasitologic observations, Am. J. Trop. Med. Hyg. 12: 239, 1963. 38. Kapikian, A. Z., Kim, H. W., Wyatt, R. G., Cline, W. L., Arrobio, J. O., 42

39.

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47. 48. 49. 50. 51. 52. 53. 54.

Brandt, C. D., Rodriquez, W. J., Sack, D. A., Chanock, R. M., and Parrott, R. H.: Human reovirus-like agent as the major pathogen associated with "winter" gastro~nteritis in hospitalized infants and young children, N. Engl. J. Med. 294:965, 1976. Blacklow, N. R., Schreiber, D. ~:,,and Trier, J. S.: Viral Enteritis, in Weinstein, L., and Fields, B. N. (eds.),.Seminars in Infectious Disease (New York: Stratton Intercontinental l~edical Book Corp., 1978), Vol. 1, pp. 256-277. """ Schreiber, D. S., Trier, J. S., and Blacklow, N. R~: Recent advances in viral gastroenteritis, Gastroenterology 73:174, 1977. Bolivar, R., Conklin, R. H., Vollet, J. J., Pickering, L. K., DuPont, H. L., Walters, D. L., and Kohl, S.: Rotavirus in travelers' diarrhea: Study of adult student population in Mexico, J. Infect. Dis. 137:324, 1978. Center for Disease Control, U.S. Public Health Service: Morbidity and Mortality Weekly Report, Vol. 26, No. 21, May 27, 1977. p. 169. Shaw, P. K., Brodsky, R. E., Lyman, D. O., Wood, B. T., Hibler, C. P., Healy, G. R., MacLeod, K. I. E., Stahl, W., and Schultz, M. G.: A community wide outbreak of giardiasis with evidence of transmission by a municipal water supply, Ann. Intern. Med. 87:426, 1977. Moore, G. T., Cross, W. M., McGure, D., Mollohan, C. S., Gleason, N. N., Healy, G. R., and Newton, L. H.: Epidemic giardiasis at a ski resort, N. Engl. J. Med. 281:402, 1969. Schmerin, M. J., Jones, T. C., and Klein, H.: Giardiasis: Association with homosexuality, Ann. Intern. Med. 88:801, 1978. Wolfe, M. S.: Current concepts in parasitology: Giardiasis, N. Engl. J. Med. 298:319, 1978. Abadie, S. (revised by): Some Laboratory Diagnostic Methods, in Hunter, G., III, Swartzwelder, J. C., and Clyde, D. (eds.), Tropical Medicine (5th ed.; Philadelphia: W. B. Saunders Company, 1976), Section XII, Chap. 73, p. 803. Hartong, W. A., Courley, W. K., and Arvanitakis, C.: Giardiasis: Clinical spectrum and functional-structural abnormalities of the small intestinal mucosa, Gastroenterology 77:61, 1979. Saha, T. K., and Ghosh, T. K.: Invasion of small intestinal mucosa by Giardia lamblia in man, Gastroenterology 72:402, 1977. Kean, B. H., and Hoskins, D. W.: Drugs for Intestinal Parasitism, in Modell, W. (ed.), Drugs of Choice 1980-1981 (St. Louis: The C. V. Mosby Company), p. 357. Krogstad, D. J., Spencer, H. C., Jr., and Healy, G. R.: Current concepts in parasitology: Amebiasis, N. Engl. J. Med. 298:262, 1978. Lobel, H. O., and Kagan, I. G.: Seroepidemiology of parasitic disease, Annu. Rev. Microbiol. 32:329, 1978. Kean, B. H.: The treatment of amebiasis-a recurrent agony, JAMA 235:501, 1976. Drugs for Parasitic Infections, Med. Lett. Drugs Ther., Vol. 21, No. 26, December 28, 1979, p. 105. Is Flagyl dangerous?, Med. Lett. Drugs Ther., Vol. 17, No. 13, June, 1975, p. 53. 43

55. Beard, C. M., Noller, K. L., O'Fallon, W. M., Kurland, L. T., and Dockerty, M. B.: Lack of evidence for cancer due to use of metronidazole, N. Engl. J. Med. 301:519, 1979. 56. Ericsson, C. D., Evans, D. G., DuPont, H. L., Evans, D. G., Jr., and Pickering, L. K.: Bismuth subsalicylate inhibits activity of crude toxins of Escherichia coli and Vibrio cholerae, J. Infect. Dis. 136:693, 1977. 57. DuPont, H. L., Sullivan, P., Evans, D. G., Pickering, L. K., Evans, D. J., Jr., Vollet, J. J., Ericsson, C. D., Ackerman, P. B., and Tjoa, W. S.: Prevention of travelers' diarrhea (emporiatric enteritis), JAMA 243:237, 1980. 58. Kean, B. H., Schaffner, W., Brennan, R. W., and Waters, S. R.: The diarrhea of travelers. V. Prophylaxis with phthalylsulfathiazole and neomycin sulfate, JAMA 180:367, 1962. 59. Tsubaki, T., Honma, Y., and Hoshi, M.: Neurological syndrome associated with clioquinol, Lancet 1:696,1971. 60. Sack, D. A., Kaminsky, D. C., Sack, R. B., Itotia, S. N., Arthur, R. R., Kapikian, A. Z., ~rskov, F., and ~rskov, I.: Prophylactic doxycycline for travelers' diarrhea. Results of a prospective double-blind study of Peace Corps volunteers in Kenya, N. Engl. J. Med. 298:758, 1978. 61. Sack, R. B., Froehlich, J. L., Zulich, A. W., Hidi, D. S., Kapikian, A. Z., ~rskov, F., ~rskov, I., and Greenberg, H. B.: Prophylactic doxycycline for travelers' diarrhea. Results of a double-blind study of Peace Corps volunteers in Morocco, Gastroenterology 76:1368, 1979. 62. Santosham, M., Sack, R. B., Froelich, J., Javier, C., Medina, C., and Greenberg, H.: Bi-weekly prophylactic doxycycline for travelers' diarrhea, 19th Interscience Conference on Antimicrobial Agents and Chemotherapy, Boston, Mass., October, 1979, Abst. 571. 63. Echeverria, P., Ulyamgco, C. V., Ho, M. T., Verhaert, C., Komolarini, S., and Orskov, F.: Antimicrohial resistance and enterotoxin production among isolates of Escherichia coli in the Far East, Lancet 2: 589, 1978. 64. World Health Organization: Treatment and prevention of dehydration in diarrheal diseases, Geneva, Switzerland, 1976. 65. Pierce, N. F., and Hirschhorn, N.: Oral f l u i d - a simple weapon against dehydration in diarrhoea, WHO Chron. 31:87, 1977. 66. Merson, M. H., Sack, R. B., Islan, S., Saklayen, G., Houda, N., and Rahaman, M.: Tetracycline therapy of enterotoxigenic Escherichia coli diarrhea, 17th Interscience Conference on Antimicrobial Agents and Chemotherapy, New York, N.Y., 1977, Abst. 401.

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