Persistent Gastrointestinal Symptoms in the Ill-Returning Traveler

21  Persistent Gastrointestinal Symptoms in the Ill-Returning Traveler Mark S. Riddle, David R. Shlim, and Bradley A. Connor

KEY POINTS • Although most cases of travelers’ diarrhea are acute and self-limited, it is important for clinicians who treat returning travelers to be aware of a significant percentage of patients who develop persistent gastrointestinal symptoms. • The pathogenesis of persistent travelers’ diarrhea generally falls into one of three broad categories: persistent infections, postinfectious processes, or chronic gastrointestinal illnesses unmasked by an enteric infection. • Giardiasis is by far the most likely persistent infection in the returning traveler, making empiric therapy a reasonable option.

• The availability of multipathogen culture-independent diagnostics may aid clinical decision making in the traveler with persistent diarrhea. • Many patients with persistent diarrhea and abdominal complaints after return from travel, where no other cause is found, suffer from a postinfectious malabsorptive state or functional bowel disorder. • Patients with postinfectious gastrointestinal symptoms, particularly those with diarrhea-predominant irritable bowel syndrome, may benefit from antibiotics to eradicate small intestinal bacterial overgrowth.

INTRODUCTION

gastrointestinal complaints including cramping, pain, fullness, distention, bloating, and dyspeptic symptoms which can be found with or without diarrhea or constipation.2 In this chapter, we are taking an inclusive approach to the range and diversity of chronic gastrointestinal symptom-based illnesses that have been associated with an antecedent acute enteric infectious illness and refer to specific gastrointestinal diagnosis were appropriate and fall under the umbrella of persistent gastrointestinal symptoms (PGS). The terms “chronic” and “persistent travelers’ diarrhea” will be used interchangeably to describe a syndrome of at least 3 weeks’ duration, although the term “persistent” is preferred because it is appropriately less precise and implies a process that began acutely but lingered unexpectedly.

Acute and self-limited illnesses comprise the preponderance of cases of travelers’ diarrhea (TD). However, an important minority of patients will develop a more protracted course, lasting weeks, months, or even years. Persistent travelers’ diarrhea (PTD) is a syndrome frequently encountered by clinicians but poorly studied and characterized. As the duration of symptoms extends, the probability of an infectious etiology lessens and the more likely a patient will have a noninfectious postinfectious process causing symptoms that could be inflammatory, malabsorptive, or functional in etiology. A very small percentage may be suffering from a chronic noninfectious gastrointestinal disease, such as idiopathic inflammatory bowel disease (IBD), colorectal carcinoma, or celiac sprue, which has been unmasked and brought to medical attention by an antecedent enteric infection. When initial stool studies reveal the presence of a persistent pathogen, the management is generally quite straightforward. When this is not the case, effective management requires the understanding and application of sound principles of gastroenterologic and infectious disease.

DEFINITIONS AND EPIDEMIOLOGY TD may be defined as diarrhea that develops while abroad in, or shortly upon return from, a developing country. The dividing line between acute and chronic diarrhea has generally been accepted to occur at a symptom duration of 4 weeks.1 The term “persistent travelers’ diarrhea” is often used to describe a syndrome of intermediate duration, lasting >14 days. The term “persistent abdominal symptoms (PAS)” has also been used in recent literature to describe gastrointestinal symptoms following acute enteric infection that do not fit completely within the confines of a diarrheal illness and are characterized by an overlap of

Persistent Gastrointestinal Symptoms Incidence Current well-designed epidemiologic studies describing the populationbased incidence of PGS associated with travel are lacking, though historically studies have found that between 3% and 10% of travelers report diarrhea that lasts >2 weeks and an additional 1%–3% will report symptoms lasting ≥1 month.3–7 More recently a study from Mexico in which a cohort of 817 US students (excluding those with PAS at time of enrollment) who had a short stay (mean 23.3 days) in Mexico were followed up at 6 months for the development of PBS and irritable bowel syndrome (IBS).8 In this study, 27.9% had new-onset PAS at the 6-month followup, with 3.9% being diagnosed with incident IBS and increased risk associated with acute diarrhea and an inverse association between age and PAS risk. In addition, a recent systematic review identified persistent and chronic diarrhea accounting for approximately 6% of illnesses among travelers seeking care upon return from travel, supporting the relative importance of this problem.9 More studies are needed to define the incidence of the spectrum of PGS associated with travel.

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CHAPTER 21  Persistent Gastrointestinal Symptoms in the Ill-Returning Traveler Abstract

Keywords

Persistent gastrointestinal symptoms are a common and varied clinical entity encountered in the weeks to months following travelers’ return. There is a growing appreciation for a spectrum of illnesses that can include diarrhea and nondiarrheal gastrointestinal symptoms. Beyond the infectious etiologies that are known to cause persistent symptoms, our understanding of postinfectious processes including functional bowel disorder, malabsorptive states, and small intestinal bacterial overgrowth after acute infections associated with travel is growing. Advances in diagnostics are aiding the clinician in identifying specific etiologies in which targeted therapies can be applied. However more study is needed to fundamentally understand the pathoetiology of persistent gastrointestinal syndromes, as well as safe and effective therapies for a number of protozoal infections and syndromes where no etiology is identified.

Chronic diarrhea Functional bowel disorder Intestinal parasitosis Malabsorption Persistent diarrhea Soil-transmitted helminths

213.e1

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SECTION 5  Travelers’ Diarrhea

One can broadly subdivide the syndrome of PGS into several pathoetiologic subsets: persistent infection, postinfectious processes, and organic gastrointestinal disease unmasked by an infection.

gastrointestinal symptoms lasting <14 days and in 27% of patients with symptoms lasting >14 days.11,12 Parasites of the proximal small bowel are a particular concern when malabsorption is present in the presenting clinical syndrome. The parasites most likely to be encountered in PTD are discussed in brief in the following sections.

Persistent Infection or Coinfection

Giardia lamblia.  G. lamblia is by far the most commonly encountered

Infections acquired by travelers often reflect those acquired by the indigenous children of the developing world, the two groups having in common a naïveté to the pathogens of the environment.10 A more complete list of the relevant pathogens can be found in Table 21.1.

pathogen in patients with PTD (Fig. 21.1). Suspicion for giardiasis should be particularly high when upper gastrointestinal symptoms predominate (see Clinical Approach section).13 Untreated, symptoms may last for months, even in the immunocompetent host. The diagnosis can often be made through stool microscopy; however, shedding can be intermittent and the identification of cysts requires highly trained microscopists. It is unclear if specific Giardia antigen testing by enzymelinked immunosorbent assay (ELISA) significantly enhances sensitivity over multiple careful examinations of stool.14 Sampling of the duodenum for Giardia may be accomplished through several means. A string test, in which a long string is swallowed, carried by peristalsis into the duodenum and extracted per os, has fallen out of favor owing to its unreliability.15 Upper gastrointestinal endoscopy with aspiration of duodenal fluid and duodenal biopsy is probably the most sensitive means of making the diagnosis. Biopsy specimens generally show the typical trophozoites appearing as small wavy lines inhabiting the intestinal brush border, but not invading the epithelium. Molecularbased diagnostics are emerging as important diagnostic tools, as discussed in upcoming sections. Giardia is usually cured with therapy consisting of metronidazole 250 mg three times per day for 5–7 days or tinidazole as a single 2-g dose (or 1 g/day for 2 days). Occasionally, a repeat course may be required. Recently, resistance to both metronidazole and tinidazole has been reported. Nitazoxanide 500 mg every 12 hours for 3 days is an alternative. Albendazole 400 mg daily for 5 days, which has cured 100% of children tested, found mixed success in travelers.16,17 Other alternatives are listed in Table 21.2. Given the very high prevalence of Giardia in PTD, empiric therapy is reasonable in the appropriate clinical setting, after negative stool microscopy and in lieu of duodenal sampling.

PATHOETIOLOGIC MECHANISMS

Parasites As a group, parasites are the pathogens most likely to be isolated from patients with PTD, with their probability relative to bacterial infections increasing with longer duration of symptoms. In a study of travelers to Nepal, protozoans were detected in 10% of travelers with

TABLE 21.1  Differential Diagnosis of

Chronic Travelers’ Diarrhea

Persistent Infections or Infestations Protozoans Mastigophora: Giardia lamblia Coccidia: Cryptosporidium parvum, Cystospora belli Ciliophora: Balantidium coli Microspora: Enterocytozoon bieneusi, Septata intestinalis Eimeriidae: Cyclospora cayetanensis Rhizopoda: Entamoeba histolytica Histomonads and trichomonads: Dientamoeba fragilis Helminths Strongyloides stercoralis Schistosoma spp. Ascaris lumbricoides Capillaria philippinensis Bacteria Enterobacteriaceae: Escherichia coli (especially enteroadherent), Shigella spp., nontyphoidal Salmonella Campylobacter spp., Yersinia enterocolitica Vibrionaceae: Aeromonas spp., Plesiomonas spp. Clostridium difficile Viruses Unknown pathogen Brainerd diarrhea Tropical sprue

Entamoeba histolytica.  E. histolytica has the versatile capacity to produce acute or chronic symptoms, which may vary from mild diarrhea to severe, even fatal, colitis or dysentery. Its prevalence however has probably historically been overestimated as a cause of TD and PTD. Recently we have become aware of Entamoeba dispar, a morphologically

Postinfectious Processes Postinfectious malabsorptive states Disaccharide intolerance Bacterial overgrowth Postinfectious irritable bowel syndrome Chronic Gastrointestinal Diseases Unmasked by an Enteric Infection Idiopathic inflammatory bowel disease Ulcerative colitis Crohn disease Microscopic colitis Celiac sprue Colorectal adenocarcinoma Acquired immunodeficiency syndrome (AIDS enteropathy)

FIG. 21.1  Giardia lamblia trophozoites, classically described as reminiscent of a face, are seen in this wet prep of stool. (Courtesy of Murray Wittner, MD, Albert Einstein College of Medicine, Bronx, New York.)

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TABLE 21.2  Treatment Options for

Giardiasis Drug

Regimen

Metronidazole Nitazoxanide Paromomycin Albendazole Tinidazole

250 mg three times daily for 5–7 days 500 mg every 12 hours for 3 days 25–30 mg/kg/day in three doses for 7 days 400 mg once daily for 5 days 2 g for 1 day

indistinguishable and nonpathogenic protozoan, which seems to vastly outnumber the pathogenic E. histolytica in stool isolate prevalence by a factor of 10 : 1.18,19 E. dispar may be differentiated from E. histolytics by stool polymerase chain reaction (PCR). Diagnosis is typically made by finding cysts or trophozoites in stool microscopy specimens or by serology. Illness with amebiasis usually takes one of three forms. The first is asymptomatic cyst passage, detected in screening stool specimens. Nondysenteric amebiasis, the second form, often presents with cyclical alternations of diarrhea and constipation with fatigue. Amebic colitis, manifested by bloody diarrhea with cramping pain and tenesmus, is the third and most severe form of illness and is extremely uncommon in travelers. Stool specimens from patients falling into the first two categories should be carefully analyzed to ensure that the protozoan found is not E. dispar, an isolate which should simply be ignored. Patients in the first category with documented E. histolytica should be treated with a luminal cysticidal agent alone, such as paromomycin 500 mg three times daily for 10 days, iodoquinol 650 mg three times daily for 20 days, or diloxanide furoate.20–22 For patients in the second and third categories, therapy consists of metronidazole 750 mg three times daily for 10 days or tinidazole 2 g daily for 3 days, followed by a luminal cysticidal agent. Tinidazole is tolerated far better by patients than metronidazole in this dosage.

Dientamoeba fragilis.  A relatively rare cause of PTD, D. fragilis is generally diagnosed by stool microscopy and effectively treated by iodoquinol 650 mg three times daily for 20 days or tetracycline 500 mg three times daily for 10 days.23 It is associated with low-grade loose stools, gas, and fatigue over a long period of time.

Microsporidia.  Microsporidia including Enterocytozoon bieneusi and Encephalitozoon intestinalis have been identified in patients with PTD.24,25

Cyclospora cayetanensis.  C. cayetanensis is a coccidian parasite that appears to have marked geographic and seasonal risks. Untreated, the infection can persist for 2–12 weeks, with an average of 6 weeks. Persistence beyond 3 months is extremely rare in immunocompetent patients (Fig. 21.2).26–28 Symptoms are usually upper gastrointestinal and associated with profound fatigue, anorexia, weight loss, and malabsorption.29 Although it is twice as large as Cryptosporidium, detection of this protozoan (at 8–10 µm) often requires obtaining a modified acid-fast stain of the stool. Cyclospora infection can mimic bacterial diarrhea at onset, with 3 days of severe diarrhea associated in some cases with vomiting and fever. Patients may take an appropriate antibiotic for this initial illness, which appears to resolve, only to carry on with the lower grade symptoms for weeks. Cyclospora will not respond to either empiric quinolones or metronidazole. The effective therapy, trimethoprimsulfamethoxazole (given as 1 double-strength tablet twice daily for 7–10 days), is now relatively seldom used for treating diarrhea, thus such patients are likely to seek care after having failed multiple empiric therapy regimens.30

FIG. 21.2  Electron microscopy of an endoscopic duodenal biopsy specimen (×1.1K) revealing multiple Cyclospora cayetanensis organisms identified with dots around villus.

Cryptosporidium parvum.  Although originally described as an opportunistic pathogen causing diarrhea in AIDS patients, a 1993 waterborne outbreak of C. parvum affecting 400,000 Milwaukee residents demonstrated that the immunocompetent patients were also at significant risk.31 C. parvum has been reported as a cause of PTD in travelers from Egypt, Mauritius, and elsewhere.32 A large travel-related outbreak occurred when 7 of 34 Finnish students traveling to Leningrad became ill with profuse diarrhea.33 Like Cyclospora, C. parvum is more easily found upon acid-fast staining of stool specimens. In the immunocompetent patient, a self-limited illness usually lasting <1 month is observed. There is evidence of successful treatment of these infections with nitazoxanide, and to a lesser extent paromomycin, in AIDS patients and immunocompetent travelers.34

Cystospora Belli.  C. belli has been reported as a cause of diarrhea in travelers returning to the United States from the Caribbean, India, and West Africa.35 Successful therapy generally includes a 10-day course of trimethoprim-sulfamethoxazole double-strength four doses per day or pyrimethamine-sulfadiazine.

Bacteria

Enterobacteriaceae.  Enterobacteriaceae, such as Enterotoxigenic Escherichia coli (ETEC), Campylobacter, and Salmonella, which play the major role in acute TD,36 are probably a relatively uncommon cause of PTD. Whereas Salmonella and Shigella have both been reported to result in a carrier state, recrudescence of symptoms is unlikely. Enteroadherent E. coli (EAEC) have been implicated as an important cause of chronic diarrhea in children, AIDS patients, and travelers.37–39 Fluoroquinolones and rifaximin have been used safely and effectively to treat EAEC in affected travelers.40,41 Aeromonas, Plesiomonas, and Yersinia enterocolitica are other pathogens to consider for their ability to cause subacute symptoms, and have all been reported in patients with PTD.42,43

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SECTION 5  Travelers’ Diarrhea

Clostridium difficile.  C. difficile is an extremely relevant pathogen to consider in the patient with PTD. Its clinical presentation may vary from acute to chronic, and from mildly increased stool frequency to bloody diarrhea to toxic megacolon. Consequently, the initial workup of PTD should always include a C. difficile stool toxin assay. Many PTD patients have taken antibiotics for acute travelers’ diarrhea which may place them at risk for this opportunist.44 It is a special consideration in the patient with continuing PTD which seems refractory to multiple courses of empiric antibiotic therapy. Therapy with metronidazole, oral vancomycin, or fidaxomicin is generally successful, although resistance has been reported and recurrence may occur in upwards of 10% of patients. Since up to 10% of healthy travelers may be asymptomatic carriers of C. difficile, just finding the organism may not explain the traveler’s symptoms.

Unknown Pathogens There are many patients with a syndrome of PTD which bears the clinical and epidemiologic characteristics of a persistent infectious disease, yet in which extensive microbiologic analysis has failed to find a responsible pathogen. One has only to look back in recent history to predict that this is a category that will shrink in the future as diagnostic techniques, such as new stains, polymerase chain reaction, and ELISA techniques improve and our knowledge of emerging pathogens increases. Cases of TD due to Campylobacter jejuni, C. parvum, EAEC, and C. cayetanensis were deemed idiopathic infectious disease until the recent recognition of these organisms as common human pathogens in 1977, 1982, 1985, and 1991, respectively.45–48

Tropical Sprue.  Tropical sprue identifies a syndrome of persistent TD associated with malabsorption, steatorrhea, fatigue, and deficiencies of vitamins absorbed in both the proximal and distal small bowel (folate and B12, respectively).49 It most commonly affects longer term travelers and expatriates in certain areas of endemicity in the tropics, although short-term travelers are still at risk.50 It occurs more commonly in travelers with close contact with the indigenous population, often follows an acute infectious diarrhea, and is seen in household and seasonal epidemics. It has been included in this section of persistent infections causing PTD as it has long been known to reflect an infectious process. However, although modern microbiology and epidemiology provide evidence to support this statement, the past century has accomplished little in identifying a particular responsible pathogen. Competing theories implicate an overgrowth of mixed bacterial flora versus various protozoan species, including Cryptosporidium, Isospora, and Cyclospora.51 Endoscopic and histopathologic changes resemble those of celiac sprue, including fissuring and scalloping of mucosal folds and villous atrophy with crypt hyperplasia.49 The incidence of tropical sprue has declined dramatically over the years. In an active clinic in Nepal geared toward the care of travelers and expatriates, the diagnosis is made only five to six times among approximately 1500 patients presenting with diarrhea/year.52 The reason for this apparent decline in incidence is unknown. Treatment has generally consisted of tetracycline 250 mg four times daily for at least 6 weeks with folate supplements, though shorter courses with twice/day dosing and substitution with doxycycline have been tried successfully. Because the diagnosis is currently so rarely made, and the course of treatment is so prolonged, empiric therapy for this should be discouraged.

Brainerd Diarrhea.  Brainerd diarrhea was first described in 1983 when an epidemic of chronic diarrhea occurred in Brainerd, Minnesota, in which the unpasteurized milk of a local dairy was epidemiologically identified as the source.53 Although presumably infectious, extensive

microbiologic analysis has failed to identify a responsible pathogen and no antimicrobial agents have been found to be effective. At least seven subsequent Brainerd epidemics have been reported since its initial description, including six in the United States and one on a cruise ship in the Galapagos Islands of Ecuador.54,55 The watery diarrhea, associated with urgency, frequency (10–20 stools/day), cramping, weight loss, and a waxing and waning pattern, lasts from 2 to 42 months. At 1-year followup of the initial outbreak, 12% of patients were subjectively normal, 40% were improved, and 48% had unrelenting diarrhea. Biopsy specimens of the colon revealed a prominence of intraepithelial lymphocytes without markers consistent with microscopic or collagenous colitis. It is unknown whether this entity reflects a frequent cause of sporadic PTD.

Postinfectious Processes

Postinfectious Malabsorptive States. Malabsorption due to persistent infection or infestation of the proximal small bowel, such as giardiasis or tropical sprue, is readily recognized and understood by most clinicians. Less attention, however, has been paid to the issue of malabsorption that persists after an acute infection, such as a bacterial or viral gastroenteritis, has cleared. Disaccharidases, such as the enzymes used to digest lactose and sucrose, normally reside in the brush border overlying the intestinal epithelium. Any acute inflammatory process will readily disrupt the fragile brush border, leaving the patient with transient lactose and sucrose intolerance, which may take several weeks to resolve.56,57 In some patients with underlying subclinical disaccharidase deficiency a more permanent lactose intolerance may be seen following gastroenteritis. Exacerbation of symptoms with dairy products and concentrated sweets may not be elicited unless specifically queried, and may not even be apparent to the patient. Malabsorption of xylose, folate, and B12 has been well documented to occur in the setting of acute gastroenteritis.58 In most of the patients in this report malabsorption was quite transient; however, a handful showed continued malabsorption lasting weeks to months after the acute gastroenteritis had resolved. Occasionally the changes in bowel motility following acute TD can result in stasis and secondary bacterial overgrowth, ultimately leading to a combined osmotic and secretory diarrhea. This diagnosis should be entertained in the setting of positive fecal fat analysis and d-xylose testing in which both noninvasive and endoscopic duodenal sampling have failed to find a persistent pathogen. The diagnosis may be confirmed by lactulose hydrogen breath testing and usually responds to antibiotic therapy, including tetracyclines, amoxicillin-clavulanate, quinolones, and rifaximin.59,60 The prevalence of bacterial overgrowth in the PTD setting is unknown and many of these patients may be cured by tetracycline empirically administered for tropical sprue. Some authors have suggested that it has been widely underdiagnosed in the setting of PGS in general, and there is recent evidence to suggest that in many cases of postinfectious IBS (PI-IBS) (see next section) small intestinal bacterial overgrowth may be responsible for many of the hallmark symptoms, including bloating and gas.61,62

Postinfectious Functional Gastrointestinal Disorders Epidemiology and Pathogenesis.  Functional gastrointestinal disorders (FGD) are common disorders characterized by persistent and recurring gastrointestinal symptoms due to abnormal functioning of the enteric system and where no structural (e.g., tumors or masses) or organic (e.g., inflammation or ulcers) pathology is identified. Concurrent with the recognition of the importance of PGS as a presenting complaint following travel has been the observation that new-onset FGD and particularly IBS, are commonly found to be increased among individuals who have experienced an acute enteritis during travel (Table 21.3).63 PI-IBS has

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TABLE 21.3  Diagnosis of Select Postinfectious Functional Gastrointestinal Disorders Irritable Bowel Syndrome

Functional Dyspepsia

Functional Constipation

≥12 weeks (need not be consecutive) in the preceding 6 months of abdominal discomfort or pain with two or more of the following features: • Relieved by defecation • Onset associated with change in frequency of stool • Onset associated with change in form or appearance of stool

≥12 weeks (need not be consecutive) in the preceding 6 months where one or more of the following is identified: • Bothersome postprandial fullness • Early satiation • Epigastric pain • Epigastric burning

≥12 weeks (need not be consecutive) in the preceding 6 months where: 1. Two or more of the following symptoms are present: • Straining during at least 25% of defecations • Lumpy or hard stools in at least 25% of defecations • Sensation of incomplete evacuation for at least 25% of defecations • Sensation of anorectal obstruction/blockage for at least 25% of defecations • Manual maneuvers to facilitate at least 25% of defecations (e.g., digital evacuation, support of the pelvic floor) • Fewer than three defecations per week 2. Loose stools are rarely present without the use of laxatives 3. Insufficient criteria for irritable bowel syndrome

Following an episode of infectious gastroenteritis or travelers’ diarrhea Workup for microbial pathogens negative, and no evidence of structural disease that is likely to explain the symptoms

recently become a topic of considerable clinical and investigative interest, as evidence validating it as a diagnosis and elucidating its pathophysiology has accumulated. The initial enteric infection is usually characterized by diarrhea and often, but not always, a stool culture positive for bacteria or clinical response to an appropriate antibiotic.63,64 In a recent systematic review, the risk of PI-IBS was specifically evaluated following a bout of TD.65 Among six studies identified, there was an approximately threefold increase risk (absolute risk 4%) of IBS among those with TD compared to those who did not experience TD. Laboratory-confirmed TD risk was nearly fourfold, while self-reported TD was not as strongly associated. While not as well studied, postinfectious constipation has been described and a systematic review among nine studies (three among travelers) focusing on postinfectious functional dyspepsia (FD) found a twofold risk of FD following acute gastrointestinal infection.66 PI-IBS is the most studied FGD, and unique clinical features distinguish it from idiopathic IBS. Whereas IBS not known to arise from an acute infection is characterized by an insidious onset of symptoms, PI-IBS is characterized by the acute or new onset of symptoms in the presence of previously normal bowel function.63 In PI-IBS abnormal bowel habits typically persist continuously from the acute infectious episode, although they may wax and wane. Although symptoms diminish in severity from those of the acute infectious episode, preepisode bowel function is not regained. PI-IBS is more often characterized by diarrheal symptoms than by constipation; however, constipation-predominant and alternating subtypes also exist in both.67,68 While only a few studies have been described, the prognosis of PI-IBS suggests that symptoms may persist in up to 40%–60% of patients for as many as 8 years following initial onset.69 In support of the specific studies linking TD to PI-IBS, new-onset IBS following other gastrointestinal infections has been reported and ranges from 4% to 31%.64,68,71–80 It is important to recognize that there is significant heterogeneity of risk observed across the various studies which is likely due to variation in study design including retrospective case-control studies, heterogeneity in outcome and exposure definitions, and misclassification biases associated with exposure and outcomes used.81 However, the limitations of these studies notwithstanding, the preponderance of the data, which demonstrate consistency in effect and dose response,

provides evidence of causality; and the post-TD FGD risk is not an epiphenomenon. Additional supporting evidence for causality comes from specificity of association where it has been observed that the type of organism responsible for the acute bacterial infection may also influence the risk of developing PI-IBS. In studies of community-acquired gastroenteritis, PI-IBS was more common after infection with Campylobacter and Shigella than after infection with Salmonella.63 This difference may be attributed to the more severe mucosal injury and/or the longer duration of initial diarrheal illness caused by Campylobacter and Shigella compared to Salmonella. Consistent with this speculation, in one study bacterial toxicity in vitro was a strong determinant of the probability of developing PI-IBS by 3 months after C. jejuni enteritis infection.74 Research to date suggests that the duration of acute infectious illness may be the strongest risk factor for PI-IBS.68,78 In a community-based retrospective survey of individuals with culture-positive bacterial gastroenteritis in Nottingham, England, the number of days with acute infectious diarrhea was directly related to the risk of development of PI-IBS.68 Compared with individuals with acute infectious diarrhea lasting ≤7 days, those with acute infectious diarrhea lasting 8–14 days, 15–21 days, and ≥22 days were respectively 2.9, 6.5, and 11.4 times more likely to develop PI-IBS. The reason why longer duration of illness confers greater risk of developing PI-IBS than shorter duration of illness is not known. Insofar as longer duration of illness is a marker for more severe illness, greater illness severity rather than duration of illness per se may confer a risk of developing PI-IBS. This would explain the development of PI-IBS following acute TD, which is usually an illness of relatively short (<7 days) duration. This possibility is further supported by the finding that vomiting during acute gastroenteritis appears to protect against the subsequent development of PI-IBS, possibly by reducing the amount of inoculum and hence the severity of illness.68 Some consider this an argument for the early self-treatment or prophylaxis of TD. Beyond the epidemiologic data, experimental evidence suggests pathophysiologic mechanisms including inflammation, dysbiosis, and disorders of epithelial barrier integrity attributing acute bacterial infection to the development of PI-IBS.63 In some studies, those afflicted appear to be unable to downregulate intestinal inflammation following an

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acute infection,82 whereas others have found inflammation was accompanied by small-bowel permeability with post-Campylobacter infection increases in intraepithelial T lymphocytes and enterochromaffin cells up to 1 year after infection eradication.75,83 Enterochromaffin cell hyperplasia, which is thought to be a relatively nonspecific response to mucosal injury and inflammation, possibly contributes to the symptoms of PI-IBS through serotonin-mediated effects. Enterochromaffin cells are the source of nearly all intestinal mucosal serotonin, which stimulates enteric secretions, activates visceral sensory afferents, and mediates peristalsis. More recently, research has identified the possible role of the host response to the microbiome,84 microbial dysbiosis,85 and a potential link between autoimmune-related dysfunction associated with some enteric infections such as Campylobacter.86 While the pathoetiology of PI-FD is not as well studied, evidence includes delayed gastric accommodation and emptying, and mucosal hypersensitivity reported and accompanied by histopathologic findings of focal T-cell aggregates, decreased CD4+ cells, increased macrophage and eosinophil counts in duodenal biopsies, and associations between inflammation and epigastric burning in PI-FD patients compared to healthy controls.66

A

Chronic Gastrointestinal Diseases Unmasked by an Enteric Infection TD has an important potential to uncover latent noninfectious gastrointestinal disease. In the case of celiac sprue (gluten-sensitive enteropathy) and colonic adenocarcinoma, it seems clear that the acute infection acquired in travel is not causative, but has allowed the underlying pathology to become clinically apparent, bringing the patient to medical attention. In the case of IBD, it remains somewhat unclear whether the TD is only unmasking the chronic disease or actually initiating it.

Idiopathic Inflammatory Bowel Disease. Idiopathic IBD was diagnosed in 25% of patients in a retrospective British review of 129 cases of bloody diarrhea acquired during, or within 2 weeks of return from, a tropical sojourn.87 These patients denied gastrointestinal complaints predating travel, begging the question whether the infection acquired in travel was actually responsible for the initiation of the autoimmune cascade of IBD. As many of the prevailing hypotheses of the pathogenesis of IBD begin with an initiating antigenic pathogen in the setting of an alteration in intestinal permeability and a genetically determined imbalance of pro- and anti-inflammatory responses, such a scenario would seem plausible. The most common form of IBD uncovered in this setting is ulcerative colitis; however, Crohn disease88 and microscopic colitis, including collagenous and lymphocytic colitis, have also been seen. The latter group demonstrates a normal gross colonoscopic examination, but random biopsy specimens will demonstrate the underlying inflammatory process.

Celiac Sprue.  Celiac sprue is a disease of the small bowel in which genetically susceptible individuals sustain villous atrophy and crypt hyperplasia in response to exposure to antigens found in many grains, leading to malabsorption. From studies of healthy blood donors we know that clinically apparent disease with malabsorptive diarrhea accounts for only the tip of the celiac sprue iceberg, with the majority of cases being subclinical or presenting with associated symptoms such as osteoporosis or anemia.89 As 1 in 250 healthy Americans seems to harbor latent celiac disease, based on the screening of blood bank donations it is important to consider the unmasking of this entity by an enteric superinfection in patients with PTD. The disease is diagnosed by compatible gross and microscopic duodenal examination and by the presence of antiendomysial, antigliadin, antitissue transglutaminase

B

FIG. 21.3  (A) Endoscopic photograph of a patient with persistent travelers’ diarrhea due to unmasked celiac sprue, showing classic mucosal fissuring and scalloping of folds. (B) Low-power light photomicrograph of a duodenal biopsy specimen revealing marked villous blunting and crypt hyperplasia, consistent with sprue. Laboratory values in this patient were notable for iron and folate deficiency, with a normal B12 level consistent with a duodenal process and positive antigliadin and antitissue transglutaminase antibodies. A gluten-free diet was recommended.

antibodies,90 and is treated by a very effective, if difficult to maintain, gluten-free diet (Fig. 21.3).

Colorectal Cancer.  Colorectal cancer must be a consideration in patients with PTD, particularly those passing blood per rectum or found to have fecal occult blood or new iron-deficiency anemia.91 This is especially true if hematochezia persists after the diarrhea has resolved. In any such patient >50 years of age, a full colonoscopy should be performed even if the symptoms seem consistent with infectious colitis. Colorectal cancer is too prevalent, with the average lifetime risk of the individual in Western countries approaching 6%, and the consequences of missing an early diagnosis too great, not to request a complete colonic luminal evaluation in the older patient.

CHAPTER 21  Persistent Gastrointestinal Symptoms in the Ill-Returning Traveler

CLINICAL APPROACH History and Physical Examination It is important to elicit a complete and detailed history of the current illness (Table 21.4). What were the characteristics of the initial illness? Did symptoms begin with the abrupt onset of relatively uncomfortable diarrhea suggesting a bacterial pathogen, or were initial symptoms more insidious, suggesting protozoan infection? Have the symptoms been consistent throughout? Does the patient truly have persistent diarrhea, or do the persistent symptoms represent separate and distinct episodes of acute diarrhea, the most recent of which brings the patient to the physician? In eliciting the history of current illness it is critical to listen for gaps in wellness: a hiatus of 5–7 days without diarrhea suggests that an infection may have cleared and a new one begun.92 In addition, vomiting and fever usually occur at the onset of enteric infections, so that if a patient reports weeks of diarrhea followed by the initiation of vomiting and fever, the likelihood is that they are suffering from a new superimposed acute infection, rather than a chronic one. Travelers may develop multiple enteric infections, as suggested in a recent case-control study of travelers to Thailand, in which nearly 60% were diagnosed with more than one putative stool pathogen.93 The history should be used if possible to localize the pathology anatomically to either small or large bowel. Diarrhea that is large volume but relatively infrequent should suggest a small-bowel process, testament to the bulk of fluid absorption normally occurring in the small bowel, as well as the capacity of the noninflamed colon as a reservoir for stool. Other symptoms localizing to the upper gastrointestinal tract include nausea, vomiting, eructation, pyrosis, and reflux. Symptoms such as copious flatus or stools that are foul smelling, floating, or associated with oil droplets suggest a small-bowel process associated with malabsorption. The frequent, relatively small-volume diarrhea associated with

TABLE 21.4  Evaluation of the Patient With

Persistent Travelers’ Diarrhea

Persistent Infection or Coinfection Parasite or bacteria Culture-independent PCR testing or enzyme (to include immunologic assay for Giardia, Cryptosporidia, C. difficile) and Ameoba Tropical sprue C. difficile toxin assay CBC with differential D-xylose test Esophagogastroduodenoscopy (EGD) with duodenal aspirate and small-bowel biopsy Postinfectious Sequelae Lactose intolerance Lactose-restricted diet or lactose tolerance test PI-FGD D-Xylose test See Table 21.3 (diagnosis of PI-FGD) Underlying Gastrointestinal Disease Celiac serologies IBD serologies D-Xylose test Gastrointestinal endoscopy EGD with duodenal aspirate and small-bowel biopsy Colonoscopy/sigmoidoscopy with biopsy CBC, Complete blood count; IBD, inflammatory bowel disease; PI-FGD, postinfectious functional gastrointestinal disorder; PCR, polymerase chain reaction.

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infraumbilic cramping implies a colonic process (e.g., Brainerd diarrhea), in which additional symptoms of tenesmus, bloody mucus, or frank hematochezia would herald a colitis or dysentery. Fever, sweats, or chills would favor the presence of a continued invasive pathogen, but may also be seen in unmasked idiopathic IBD. Weight loss raises a concern for an ongoing infectious, malabsorptive, inflammatory, or malignant process and should be seen as inconsistent with merely functional syndromes such as PI-IBS. Another important aspect in the history of current illness is awareness of all preceding diagnostic and therapeutic management. In this regard, it is particularly important to elicit information on medications and/ or antibiotics taken, as well as reviewing all pretravel, intratravel, and posttravel care. Many patients will have taken antibacterial agents, malaria prophylaxis, and the like, predisposing them to antibiotic-associated diarrhea and C. difficile in addition to gastrointestinal side effects of the medications. The particular antibiotics given are important. Did they include broad coverage, as with a fluoroquinolone or macrolide? Did the patient take trimethoprim-sulfamethoxazole, which would have covered Cyclospora? In addition to the careful gastrointestinal history, a detailed travel history is important. In which season did the patient travel (Cyclospora being most prevalent in the spring and early summer months in South Asia)? Was the patient in rural or urban areas? Did the symptoms worsen on the flight home? (Air pressure changes in flight may cause inflamed bowel to distend, creating more discomfort.) Physical examination, though less helpful than history in these patients, remains important. Significant weight loss, abdominal tenderness, and the presence of positive fecal occult blood (in the absence of hematochezia) may be useful in directing further evaluation.

Noninvasive Laboratory Workup

Stool Studies.  Stool studies should be the first diagnostic step in the evaluation of PGS, after the history and physical examination. Traditionally culture-based enzyme immunoassays and microscopic diagnostics have been the reference standard tests to evaluate persistent gastrointestinal symptoms, but often suffer from sensitivity due to lack of utilization of specific culture methods and the requirement of three separate stool specimens for ova and parasite examination. The accuracy of these depends on the skill, experience, and integrity of the technician reading the slides and may often yield presence of nonpathogenic protozoa and unnecessary treatment. More recently a number of multipathogen culture-independent molecular-based platforms have been licensed in the United States and Europe, which appear to have advantages in sensitivity and timeliness of results (Table 21.5).94 However, these diagnostic platforms currently lack supporting evidence in clinical settings to support widespread use. While these are more sensitive in detection of putative pathogens, they also will often identify multiple potential pathogens resulting in unnecessary attention, patient angst, and perhaps inappropriate drug therapy. At present it is recommended that the utilization of these multipathogen diagnostic platforms should be considered in context of a pretest suspicion of an infectious etiology, as well as consideration of cost, relative challenge in obtaining multiple specimens, and expediency of results needed to properly manage a patient in a given clinical scenario.

Blood Testing.  As in the workup of any persistent gastrointestinal illness, reasonable laboratory evaluation should begin with a complete blood count with differential, particularly if infectious etiologies are ruled out. Eosinophilia, although suggestive of a parasitic infection, may be seen in cases of invasive helminthic infections but is usually not seen with intestinal protozoan infections. Leukocytosis with neutrophilia favors a bacterial process, and when marked (>20,000 cells/

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TABLE 21.5  Performance Characteristics of Commercially Available Multipathogen Molecular

Diagnostics Manufacturer

Luminex

Biofire Diagnostics Inc.

Diagenode Diagnostics

Test system Platform Relevant pathogen targets attributed PGS

GPP xTAG Cryptosporidium Entamoeba histolytica Giardia lamblia Clostridium difficile toxin A/B Campylobacter jejuni

G-DiaPara/Bact/Diff™ Various Cryptosporidium Entamoeba histolytica Giardia lamblia Clostridium difficile toxin A/B Campylobacter jejuni

Total no. of targets Detection time (h)

15 <5

Gastrointestinal Panel FilmArray Cryptosporidium Cyclospora cayetanensis Entamoeba histolytica Giardia lamblia Clostridium difficile toxin A/B Campylobacter jejuni 22 1–2

dL) suggests C. difficile infection. An elevated erythrocyte sedimentation rate or C-reactive protein, although neither sensitive nor specific, may be seen in either an infectious or inflammatory process and should steer the differential diagnosis away from PI-FGD. Abnormalities in albumin or prothrombin time may be seen in malabsorption or malnutrition. Abnormally low values for iron or folate suggest a process in the proximal small bowel, whereas deficiency in vitamin B12 generally stems from ileal disease relating to the area of normal absorption. The presence of both B12 and folate deficiency should raise suspicion for tropical sprue in its typical ability to involve wide-reaching segments of the alimentary canal. A recent blood test has been developed based on the notion that antibodies toward cytolethal distending toxin (Cdt) associated with an antecedent enteric infection and associated titers of homologous human cytoskeletal protein, vinculin, have been founding in a higher proportion of individuals with IBS compared to health controls and others with organic disease.95 This result has been validated in a small pilot study looking at post-Campylobacter incident IBS,86 and needs further validation in a traveler PI-FGD population. While a positive result does not direct a specific therapy, it may provide the individual psychologic benefit as well as improved shared decision making as to whether any additional invasive tests are warranted. d-Xylose testing is indicated as a noninvasive test for small-bowel malabsorption. After drinking a 25-g bolus of d-xylose, the patient may either submit a 5-hour urine collection or have a venous sample drawn. A normal result is excretion of >20% of the xylose load into the urine. Celiac serologies, including antigliadin and tissue transglutaminase antibodies, should be considered and HIV serologies obtained, as enteropathy may be the first clinical marker for HIV infection.

Endoscopic Evaluation.  Most patients with PGS after travel who have had nondiagnostic, noninvasive evaluations (as elaborated previously) should be considered for an endoscopic evaluation, although empiric therapy is an equally acceptable first line approach, such as for a parasitic illness like Giardia or bacterial illness. There are advantages and disadvantages to both strategies. There are no randomized data on the subject of empiric therapy versus endoscopic evaluation for PTD, and generally recommendations have come from infectious disease subspecialists rather than gastroenterologists, the former not having endoscopy as a tool immediately at hand. However, the argument for empiric therapy is the avoidance of procedures that carry some cost and some minimal risk. The use of antimicrobials or antiparasitic agents when no pathogen has been documented may confuse rather than clarify the issue. In addition to the risk of allergic reaction and other side effects particular to the individual drugs, these medications alter bowel flora and may confuse the picture by introducing antibiotic-associated

6 2

diarrhea. In addition, a lack of response to an empiric course of therapy may simply reflect antibiotic resistance rather than an incorrect diagnosis. Although empiric therapy remains an important tool in our armamentarium (see upcoming discussion), and an acceptable first line approach, there are selected groups of patients in whom an endoscopic evaluation should be performed, including (1) patients failing one or two unsuccessful empiric courses, (2) all patients aged >50 with occult or gross fecal blood or family history of colon cancer, (3) the setting of malabsorptive symptoms or signs, and/or (4) “red flags” consistent with an organic disease process including documented weight loss, anemia, fever, and symptoms worsening after antibiotic use. Endoscopy provides a sensitive means of identifying a lingering parasitic infestation or tropical sprue as well as identifying underlying structural gastrointestinal processes, including idiopathic IBD, celiac sprue, and colorectal carcinoma. It also provides an objective marker to follow in patients with persistent symptoms. From an evidence-based medicine standpoint, it demonstrates a useful diagnostic yield in the workup of chronic diarrhea in general96; however, the yield in PAS after TD remains less well studied. The choice of upper gastrointestinal endoscopy versus colonoscopy (or sigmoidoscopy) returns us to the importance of the medical history, using the clues described previously for localizing a process to the small or large bowel. Of key importance is that the endoscopist should take biopsies and aspirates of the duodenum at esophagogastroduodenoscopy (EGD) and the colon (and possibly terminal ileum) at lower endoscopy, regardless of the presence of gross mucosal disease, as the changes may be only visible at the microscopic level.

Therapy Empiric antiinfective therapy is both a useful diagnostic and therapeutic tool. A response to a quinolone or macrolide would simultaneously support the diagnosis of and treat bacterial disease. A response to a nitroimidazole might be similarly useful in clinically suspected giardiasis or amebiasis, as would trimethoprim-sulfamethoxazole for suspected cyclosporiasis. Many authors have recommended empiric courses of therapy for tropical sprue in the patient with PTD and malabsorption.92 Most recently an observational study was reported among Israeli travelers with PAS which initiated after travel and whom a workup for putative pathogens was negative.97 In this nonrandomized control study, 102 patients with a 16-month average duration of complaint before treatment received combination therapy of the broad-spectrum antiparasitic agents oral tinidazole and albendazole and were asked about symptoms at a 6-month followup. Pretreatment PAS of diarrhea, abdominal pain, flatulence, and bloating were common; additionally, two-thirds of patients complained of extreme fatigue. At a 6-month followup, 69% of the patients reported an improvement in gastrointestinal symptoms with

CHAPTER 21  Persistent Gastrointestinal Symptoms in the Ill-Returning Traveler over one-third reporting full recovery within a few weeks posttreatment, and treatment safety was not identified as an issue. Of note, those who demonstrated improvement were younger, predominantly female, had traveled to Central and South America, and had shorter pretreatment symptom durations. While the study lacked a control group and was subject to recall bias, the observed results provide important recognition that patients with persistent symptoms after travel may be suffering from a cryptic persistent infection treated by broad-spectrum antiparasitic therapies or alternatively that such drugs may be having an off-target effect on a dysbiotic process which is contributing to the symptomatology. As mentioned earlier, the use of empiric therapy for treatment of posttravel PGS without evidence of infection may yield diagnostic and therapeutic value. However, questions remain as to what agents to use, in what particular syndromic symptom-illness complex, for how long, and by what mechanism. Given the high incidence of posttravel PGS that have been identified, and global networks of travel clinics available, a randomized controlled trial (with a cross-over design) would advance the field in providing evidence-based recommendations. Symptomatic therapy is another important aspect of the clinical management of PGS after TD and begins with dietary modifications. Owing to the compromise of the brush border with a transient enteric infection, a trial should be undertaken of sequential avoidance of dairy products, sorbitol-containing products, fruit juices, concentrated sweets, and high-fat items, in that order. In patients with colitis, a low-residue, low-fiber diet should be advised. Treatment may be empiric, symptomatic, or directed (Table 21.6). Patients with PI-IBS may be helped by a host of empiric treatments such as elimination diets, increasing dietary fiber, digestive enzymes, probiotics including lactobacillus GG, VSL3, or Saccharomyces boulardii.98 In addition, symptomatic therapies such as antispasmodics (e.g., hyoscyamine) or the judicious use of an antidiarrheal such as loperamide may reduce symptoms. Low doses of tricyclic antidepressants may help reduce diarrhea by antagonizing the actions of serotonin and acetylcholine. Serotonin 3 (5HT3) antagonists, which increase colonic transit time and improve symptoms in patients with diarrhea-predominant IBS, may be helpful in PI-IBS.99,100 Also, 5HT4 agonists may be helpful in PI-IBS patients with predominance of constipation and bloating. Insofar as bacteria contribute to the pathophysiology of PI-IBS, antibiotics might be useful in its management. Antibiotics could be useful both in treating established PI-IBS and—when they are used either to treat or to prevent acute episodes of bacterial diarrhea—in preventing the development of PI-IBS.

TABLE 21.6  Treatment of PI-IBS Symptomatic Elimination diets Dietary fiber Digestive enzymes Probiotics Antispasmodics Antidiarrheals Tricyclic antidepressants Curative Treatment course of nonabsorbable antibiotic to eradicate associated small intestinal bacterial overgrowth (SIBO) (e.g., rifaximin 550 mg three times daily for 14 days) Followed by low-dose prokinetic (e.g., erythromycin 50 mg) at bedtime PI-IBS, Postinfectious irritable bowel syndrome.

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Antibiotics might prove effective in the treatment of established IBS by eradicating bacteria that cause or exacerbate symptoms. Research suggests that small intestinal bacterial overgrowth (SIBO), which is associated with a constellation of symptoms similar to those of IBS, may underlie some of the gastrointestinal symptoms in patients with IBS. In a recent meta-analysis undertaken to assess links between SIBO and IBS, an abnormal lactulose breath test (reflecting the presence of SIBO) was found in 84% of patients with IBS, and eradication of SIBO improved IBS symptoms by 75%, on average.101 Antibiotic therapy that reduces SIBO reduces or eliminates IBS symptoms in many patients.61,62 In a study of 111 patients with IBS meeting Rome I criteria, 84% of whom had an abnormal lactulose breath test at study entry, a course of treatment with the poorly absorbed antibiotic neomycin was associated with a 35% improvement in the Rome composite symptom score, compared to an 11% improvement with placebo. Improvement with neomycin versus placebo on this measure was more marked in the subgroup of patients with an abnormal lactulose breath test at study entry (35% with neomycin versus 4% with placebo). A similar pattern of results was reported for global improvement in IBS. The greatest improvements in IBS symptoms were observed among neomycin-treated patients with normal lactulose breath test results 7 days after completion of treatment. These data support the potential utility of antibiotics in the treatment of established IBS, particularly those associated with SIBO as reflected in a positive lactulose breath test. As these data were collected from patients with IBS not selected with respect to whether they had PI-IBS, the findings cannot necessarily be generalized to those with PI-IBS. Given the promising results with antibiotics in unselected patients, further study in patients with PI-IBS is warranted. Antibiotics with proven efficacy in SIBO are good candidates for additional research. Results of small studies with the poorly absorbed (<0.4%), gut-selective antibiotic rifaximin support its further testing in IBS. In a randomized, double-blind parallel-group study of 21 patients with SIBO, rifaximin given for 7 days at a dose of 1200 mg/day normalized lactulose breath tests in 70% of patients, compared to 27% of patients treated with chlortetracycline.60 Improvement in functional gastrointestinal symptoms was greater with rifaximin than with chlortetracycline. Likewise, in a randomized, double-blind parallel-group study of 34 patients with functional gastrointestinal symptoms (but not necessarily diagnosed with IBS), rifaximin, but not activated charcoal, improved lactulose breath test results and functional gastrointestinal symptoms.102,103 In two identically designed, phase 3 double-blind controlled studies in patients with IBS without constipation who were randomized to either rifaximin 550 mg three times daily or placebo for 2 weeks, significantly more patients in the rifaximin group had adequate relief of global IBS symptoms during the first 4 weeks after treatment (primary endpoint) and adequate relief of IBS-related bloating (key secondary end point) during the first 4 weeks after treatment.104 A certain proportion of subjects will get better after treatment but relapse weeks to months later. Most recently, extension of trial results were published which demonstrate that for IBS-D (the subtype most commonly associated with PI-IBS) repeated courses of rifaximin are effective for relapsing symptoms and do not appear to induce long-term effects on stool microbial susceptibility to rifaximin, rifampin, and non-rifamycin antibiotics.105,106 Some have suggested that the addition of a prokinetic agent such as erythromycin or 5HT4 agonist following an antibiotic treatment course will restore normal gastrointestinal motility, specifically phase III interdigestive waves, and prevent relapse of symptoms.104 The increasing recognition that acute bacterial gastroenteritis can frequently cause long-term sequelae, including PI-IBS, elevates the importance of effective treatment of the acute bacterial illness as a

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SECTION 5  Travelers’ Diarrhea

means of preventing the syndrome. Effective treatment of acute bacterial diarrheal illness with antibiotics might reduce the risk of PI-IBS by reducing the duration and severity of acute bacterial diarrheal illness and the associated chronic inflammation that may underlie functional bowel symptoms. If TD is a risk factor for the development of PI-IBS, then it stands to reason that early treatment, early self-treatment, or prophylaxis might provide a potential window of opportunity to prevent this complication. Although at present there are no data to support this hypothesis, the potential benefit in preventing this postinfective complication should be considered in addition to the other known benefits from antibiotic therapy of TD.

CONCLUSION This chapter has reviewed the various pathogenetic mechanisms underlying PGS following TD as well as outlining a logical clinical approach to the patient suffering from it. Particularly when initial stool studies fail to reveal a pathogen, considerable clinical acumen is required to appropriately direct diagnostic and therapeutic efforts to pursue diagnoses either not addressed or missed by the initial evaluation. Of course, every effort should be made to identify a persistent infection, and we should remain vigilant for emerging pathogens. It is equally essential, however, for the clinician to develop a level of comfort in the absence of a specific microbiologic or histopathologic diagnosis, as the majority of patients with PGS will not have one. In such cases, one must implement the tools of a thorough history and physical examination, blood and stool evaluations, empiric therapy, and, on occasion, endoscopy to localize the problem to the small or large bowel; to characterize the problem as a persistent infection, postinfectious syndrome, or the unmasking of a chronic gastrointestinal disease; and to treat the patient accordingly. Many patients with PGS where no other cause is found to suffer from a postinfectious functional bowel disorder, most commonly irritable bowel syndrome (PI-IBS), and may benefit from antibiotics to eradicate small intestinal bacterial overgrowth.

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61. Pimentel M, Chow EJ, Lin HC. Eradication of small intestinal bacterial overgrowth reduces symptoms of irritable bowel syndrome. Am J Gastroenterol 2000;95:3503–6. 62. Pimentel M, Chow EJ, Lin HC. Normalization of lactulose breath testing correlates with symptom improvement in irritable bowel syndrome. A double blind randomized, placebo-controlled study. Am J Gastroenterol 2003;98:412–19. 63. Deising A, Gutierrez RL, Porter CK, et al. Postinfectious functional gastrointestinal disorders: a focus on epidemiology and research agendas. Gastroenterol Hepatol (N Y) 2013;9(3):145–57. 64. Spiller RC. Post-infectious irritable bowel syndrome. Gastroenterology 2003;124:1662–71. 65. Schwille-Kiuntke J, Mazurak N, Enck P. Systematic review with meta-analysis: post-infectious irritable bowel syndrome after travellers’ diarrhoea. Aliment Pharmacol Ther 2015;41(11):1029–37. 66. Pike BL, Porter CK, Sorrell TJ, et al. Acute gastroenteritis and the risk of functional dyspepsia: a systematic review and meta-analysis. Am J Gastroenterol 2013;108(10):1558–63. 67. Dunlop SP, Jenkins D, Spiller RC. Distinctive clinical, psychological, and histological features of postinfective irritable bowel syndrome. Am J Gastroenterol 2003;98:1578–83. 68. Neal KR, Hebden J, Spiller R. Prevalence of gastrointestinal symptoms six months after bacterial gastroenteritis and risk factors for development of the irritable bowel syndrome: postal survey of patients. BMJ 1997;314:779–82. 69. Porter CK, Kowalcyk B, Riddle MS. Chronic health consequences of acute enteric infections in the developed world. Am J Gastroenterol 2016;3:S12. 70. Chaudhary NA, Truelove SC. The irritable colon syndrome. Quart J Med 1962;123:307–22. 71. McKendrick MW, Read NW. Irritable bowel syndrome—post salmonella infection. J Infect 1994;29:1–3. 72. Gwee KA, Graham JC, McKendrick MW, et al. Psychometric scores and persistence of irritable bowel after infectious diarrhoea. Lancet 1996;347:150–3. 73. Rodriguez LA, Ruigomez A. Increased risk of irritable bowel syndrome after bacterial gastroenteritis: cohort study. BMJ 1999;318:565–6. 74. Thornley JP, Jenkins D, Neal K, et al. Relationship of Campylobacter toxigenicity in vitro to the development of post-infectious irritable bowel syndrome. J Infect Dis 2001;184:606–9. 75. Dunlop SP, Jenkins D, Neal KR, et al. Relative importance of enterochromaffin cell hyperplasia, anxiety, and depression in post-infectious IBS. Gastroenterology 2003;125:1651–9. 76. Ilnyckyj A, Balachandra B, Elliott L, et al. Post-traveler’s diarrhea irritable bowel syndrome: a prospective study. Am J Gastroenterol 2003;98:596–9. 77. Parry SD, Stansfield R, Jelley D, et al. Does bacterial gastroenteritis predispose people to functional gastrointestinal disorders? A prospective, community-based, case-control study. Am J Gastroenterol 2003;98:1970–5. 78. Ji S, Park H, Lee D, et al. Post-infectious irritable bowel syndrome in patients with Shigella infection. J Gastroenterol Hepatol 2005;20(3):381–6. 79. Mearin F, Pérez-Oliveras M, Perelló A, et al. Dyspepsia and irritable bowel syndrome after a Salmonella gastroenteritis outbreak: one-year follow-up cohort study. Gastroenterology 2005;129(1):98–104. 80. Kowalcyk BK, Smeets HM, Succop PA, et al. Relative risk of irritable bowel syndrome following acute gastroenteritis and associated risk factors. Epidemiol Infect 2014;142(6):1259–68. 81. Connor BA, Riddle MS. Post-infectious sequelae of travelers’ diarrhea. J Travel Med 2013;20(5):303–12. 82. Gwee KA, Collins SM, Read NW, et al. Increased rectal mucosal expression of interleukin 1beta in recently acquired post-infectious irritable bowel syndrome. Gut 2003;52:523–6. 83. Spiller RC, Jenkins D, Thornley JP, et al. Increased rectal mucosal enteroendocrine cells, T lymphocytes, and increased gut permeability following acute Campylobacter enteritis and in post-dysenteric irritable bowel syndrome. Gut 2000;47:804–11.

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84. Pike BL, Paden KA, Alcala AN, et al. Immunological biomarkers in postinfectious irritable bowel syndrome. J Travel Med 2015;22(4):242–50. 85. Jalanka J, Salonen A, Fuentes S, et al. Microbial signatures in post-infectious irritable bowel syndrome–toward patient stratification for improved diagnostics and treatment. Gut Microbes 2015;6(6):364–9. 86. Pimentel M, Morales W, Pokkunuri V, et al. Autoimmunity links vinculin to the pathophysiology of chronic functional bowel changes following Campylobacter jejuni infection in a rat model. Dig Dis Sci 2015;60(5):1195–205. 87. Harries AD, Myers B, Cook GC. Inflammatory bowel disease: a common cause of bloody diarrhea in visitors to the tropics. BMJ 1985;291:1686–7. 88. Case records of the Massachusetts General Hospital. Case 29–1992. N Engl J Med 1992;91:182–91. 89. Trevisiol C, Not T, Berti I, et al. Screening for celiac disease in healthy blood donors at two immuno-transfusion centres in northeast Italy. Ital J Gastroenterol Hepatol 1999;31:584–6. 90. Ladinser B, Rossipal E, Pittschieler K. Endomysium antibodies in celiac disease: an improved method. Gut 1994;35:776–8. 91. Case records of the Massachusetts General Hospital. Case 33–1993. N Engl J Med 1993;329:561–8. 92. Taylor DN, Connor BA, Shlim DR. Chronic diarrhea in the returned traveler. Med Clin North Am 1999;83:1033–52. 93. Lertsethtakarn-Ketwalha P, Silapong S, Sakpaisal P, et al. Travelers’ diarrhea in Thailand: a quantitative analysis using TaqMan® Array Card. Clin Infect Dis 2018 Jan 17. 94. Binnicker MJ. Multiplex molecular panels for diagnosis of gastrointestinal infection: performance, result interpretation, and cost-effectiveness. J Clin Microbiol 2015;53(12):3723–8. 95. Pimentel M, Morales W, Rezaie A, et al. Development and validation of a biomarker for diarrhea-predominant irritable bowel syndrome in human subjects. PLoS ONE 2015;10(5):e0126438. 96. Shah RJ, Fenoglio-Preiser C, Bleau BL, et al. Usefulness of colonoscopy with biopsy in the evaluation of patients with chronic diarrhea. Am J Gastroenterol 2001;96:1091–5.

97. Nissan B, Lachish T, Schwartz E. The effectiveness of empirical anti-parasitic treatment in returning travellers with persistent abdominal symptoms. J Travel Med 2018;25(1). 98. Kirchhelle A, Fruhwein N, Toburen D. Treatment of persistent diarrhea with S. boulardii in returning travelers: results of a prospective study. Fortschr Med 1996;114:136. 99. Camilleri M, Mayer EA, Drossman DA, et al. Improvement in pain and bowel function in female irritable bowel patients with alosetron, a 5-HT3 receptor antagonist. Aliment Pharmacol Ther 1999;13: 1149–59. 100. Houghton LA, Foster JM, Whorwell PJ. Alosetron, a 5HT-3 receptor antagonist, delays colonic transit in patients with irritable bowel syndrome and health volunteers. Aliment Pharmacol Ther 2000;14:775–82. 101. Lin HC. Small intestinal bacterial overgrowth: a framework for understanding irritable bowel syndrome. JAMA 2004;292:852–8. 102. Di Stefano M, Strocchi A, Malservisi S, et al. Nonabsorbable antibiotics for managing intestinal gas production and gas-related symptoms. Aliment Pharmacol Ther 2000;15:1001–8. 103. Pimentel M, Park S, Kong Y, et al. Rifaximin, a non-absorbable antibiotic improves the symptoms of irritable bowel syndrome: a double-blind randomized controlled study. Am J Gastroenterol 2005;100:S321–45. 104. Pimentel M, Lembo A, Chey WD, et al. Rifaximin therapy for patients with irritable bowel syndrome without constipation. N Engl J Med 2011;364:22–32. 105. Lembo A, Pimentel M, Rao SS, et al. Repeat treatment with rifaximin is safe and effective in patients with diarrhea-predominant irritable bowel syndrome. Gastroenterology 2016;151(6):1113–21. 106. Pimentel M, Cash BD, Lembo A, et al. Repeat rifaximin for irritable bowel syndrome: no clinically significant changes in stool microbial antibiotic sensitivity. Dig Dis Sci 2017;62(9):2455–63.