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ARCHIVED - Statement On Persistent Diarrhea In The Returned Traveller

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Canada Communicable Disease Report

Canada Communicable Disease Report
Volume 32 • ACS-1
15 February 2006

An Advisory Committee Statement (ACS)

Committee to Advise on Tropical Medicine and Travel (CATMAT)Footnote * Footnote + 

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16 Pages - 1.26 MB

 

 

Preamble

The Committee to Advise on Tropical Medicine and Travel (CATMAT) provides the Public Health Agency of Canada (PHAC) with ongoing and timely medical, scientific, and public health advice relating to tropical infectious disease and health risks associated with international travel. PHAC acknowledges that the advice and recommendations set out in this statement are based upon the best current available scientific knowledge and medical practices, and is disseminating this document for information purposes to both travellers and the medical community caring for travellers.

Persons administering or using drugs, vaccines, or other products should also be aware of the contents of the product monograph(s) or other similarly approved standards or instructions for use. Recommendations for use and other information set out herein may differ from that set out in the product monograph(s) or other similarly approved standards or instructions for use by the licensed manufacturer(s). Manufacturers have sought approval and provided evidence as to the safety and efficacy of their products only when used in accordance with the product monographs or other similarly approved standards or instructions for use.

Introduction

Diarrhea is the most common medical problem among travellers to low-income countries. A large number of enteric pathogens are much more prevalent in resource-poor countries, and the standards of water quality, sanitation, and food preparation result in an increased risk of transmission. Although travellers are advised to take food, water, and hygiene precautions to minimize their risk of enteric infectionFootnote 1, the effectiveness of these measures is limited in practice. Acute diarrhea may have many causes, but bacterial pathogens predominate. In general, no investigations are necessary, and self-treatment can be advocated for acute traveller's diarrhea (TD). However, even when empiric therapy is initiated, medical assistance should be sought for investigation and management as soon as possible when the patient is very ill (e.g., high fever, prostration, severe abdominal pain), has a significant underlying medical illness, is immunodeficient, or has bloody stools. In practice, the majority of diarrheal episodes resolve, even without treatment, after a period of between hours and weeks. However, noticeable changes in bowel habit often persist for considerably longer after documented bacterial gastroenteritisFootnote 2Footnote 3.

The present statement specifically addresses the returned traveller with persistent diarrhea, lasting ≥30 days, which began during travel or within 30 days after return from travel, usually to a low- or middle-income country. Relevant English, French, and Spanish language articles published between October 1990 and August 2005 were identified through MEDLINE using the terms "diarrhea" and "travel"; relevant articles cited in the bibliographies and personal files of the authors were searched manually.

The incidence of persistent diarrhea of ≥ 30 days in travellers has been estimated at 1% to 3% in several reportsFootnote 4Footnote 5. The condition has been described in children as well as adultsFootnote 6 and, indeed, such diarrhea may be more severe in childrenFootnote 7. Recent immigrants (adults and children) may also be at elevated risk of persistent diarrhea, although this group has not been well studied. Although the risk of persistent diarrhea is likely to be related to the style and duration of travel, there is no specific geographic association with persistent TD; the problem has been reported following travel to a wide range of low-income countries.

 

Etiology

In a high proportion of cases, no specific etiology has been identified in spite of extensive investigation. It has been postulated that there are intestinal pathogens that remain unidentified or unrecognized at the present timeFootnote 8Footnote 9; however, other mechanisms, including post-infectious functional disorders of intestinal secretion and motility, appear to be a more likely cause for persistent gastrointestinal (GI) symptoms. The management of some travellers with prolonged diarrhea may be complicated by their conviction, and that of their health care provider, that a parasite or other microbial agent persists, despite all evidence to the contrary.

Table 1. Etiology of persistent TD (no specific order)

Non-infectious

Lactose intolerance, irritable bowel syndrome, post-infectious disturbance of bowel function, bile-salt enteritis, “unmasked” inflammatory bowel disease or celiac disease

Other infections

Small-bowel overgrowth, tropical sprue, HIV

Parasites

Giardia lamblia, Cryptosporidium spp. Footnote 1.1 , Cyclospora cayetanensis†, Isospora belli, Entamoeba histolytica, Strongyloides spp., Dientamoeba fragilis, Blastocystis hominis Footnote 1.2

Bacteria

Various Escherichia coli, Shigella spp., Campylobacter spp., Aeromonas, Clostridium difficile toxin, Salmonella spp.

Minor or nomedicalimportance (probable commensals; at most, causing only minor symptoms that do not require specific therapy)

Endolimax nana, Entamoeba coli, Entamoeba dispar, Entamoeba hartmani, Entameoba polecki , Iodamoeba buetschlii, Chilomastix mesnili

Bacteria

Shigella, Salmonella, Campylobacter, various E. coli species, including enteroaggregative types, and other organisms more commonly associated with acute illness can, rarely, cause persistent diarrheaFootnote 10 and respond to appropriate antimicrobial therapyFootnote 11Footnote 12.

Clostridium difficile enters the differential diagnosis in a substantial proportion of travellers who have received antimicrobial treatment for any reason, including the use of doxycycline for malaria prophylaxis. It usually responds to standard therapy with metronidazole or vancomycin given orally, but relapse occurs relatively frequently.

Tropical sprue is an uncommon, acquired malabsorption syndrome believed to involve bacterial overgrowthFootnote 13Footnote 14. Prolonged antimicrobial therapy combined with supplementation of micronutrients, especially folate, is usually effective.

Protozoa

Giardia lamblia is a very widely distributed parasite, which can cause a subacute to chronic small bowel infection that may be asymptomatic or associated with diarrhea or even malabsorption. Metronidazole or any of several other agents is usually effective, but metronidazole resistance is increasingly recognized.

Entamoeba histolytica can cause subacute to chronic large-bowel infection. This organism is widely distributed, largely in the tropics and subtropics. It is often over-diagnosed in developing countries, where access to bacterial culture is not available. E. histolytica can also cause liver abscess. It is morphologically identical to non-pathogenic E. dispar, which complicates decisions about causation and therapy. Most cases of symptomatic E. histolytica are associated with positive serologic tests; molecular techniques to distinguish between E. histolytica and E. dispar are becoming available. Cryptosporidium parvum infection commonly results in a small-bowel infection, which is self-limiting after an average duration of approximately 2 weeks in the normal host but is often chronic in the immune suppressed. Its distribution is cosmopolitan and includes industrialized countries. Recent studies show benefit from treatment with nitazoxanideFootnote 15. Cyclospora cayetanensis is a cause of small-bowel diarrhea, often associated with fatigue and weight loss and lasting an average of 6 weeks without treatment. Treatment with cotrimoxazole is effective. Dientamoeba fragilis, which has been associated with enterobiasis (pinworm), is a non-invasive large-bowel organism occasionally associated with symptoms. A thorough search for the previously described, well-established enteric pathogenic organisms should be carried out before attributing symptoms to D. fragilis. Several agents have activity against this organism when treatment is felt to be indicated. Blastocystis hominis is a non-invasive organism of controversial pathogenicity, for which reliably effective therapy has not been establishedFootnote 16. Other: microsporidia have rarely been reported as causes of travel-related diarrheaFootnote 17.

 

Helminths

Helminths are uncommon causes of persistent diarrhea. The evidence for an association with diarrhea is strongest for Strongyloides stercoralis, Capillaria philippinensis, Trichuris trichiura, and Schistosoma sp.Footnote 18. Other intestinal flukes (e.g., Fasciolopsis buski) may also be associated with diarrhea.

Viruses

Persistent diarrhea is a relatively common manifestation of advanced immunosuppression with HIV, and cytomegalovirus may cause colitis in this setting. Viruses are otherwise not recognized as causes of chronic diarrhea.

Non-infectious post-infective functional bowel disorders

A change in bowel function following infectious enteritis may be much more common and last longer than generally recognized Footnote 2Footnote 3. "Post-travel irritable bowel syndrome" is for the most part a diagnosis of exclusion and likely reflects a spectrum of disturbance of bowel function following travel-related infection. Whether it is similar in its pathophysiology to irritable bowel syndrome not related to travel is not known.

Lactose intolerance precipitated by infectious injury to the brush border of the small bowel mucosa may contribute to persistent travel-related diarrhea.

Any cause of chronic diarrhea may be coincidentally related to travel.

“Unmasked” or coincidental inflammatory bowel disease, celiac disease, etc., and a number of small and large intestinal neoplasias and endocrine abnormalities may enter the differential diagnosis of persistent diarrhea.

Similarly, various drugs, including laxatives, Mg++-containing agents, thyroid replacements, herbal medications, and some antiretroviral agents, can cause or complicate persistent diarrhea.

 

Approach to the patient with persistent travel-related diarrhea

History

In the evaluation, the following specific elements of the history may be helpful:

  • Clarify whether there have been asymptomatic intervals. If so, this may suggest that repeated acute infections, not uncommon in the traveller, rather than one persistent illness explain the patient's course, which in turn would indicate a very different diagnostic and therapeutic approach.
  • Ascertain any relevant past medical history, specifically including baseline bowel habit and history of past GI symptoms, stress-induced symptoms, or irritable bowel syndrome-like symptoms antedating travel. If this history is present, if current symptoms are consistent with irritable bowel syndrome and if stool examination for common pathogens is negative, it may be appropriate to direct the focus to symptomatic management of the irritable bowel symptoms. A strong family history of inflammatory bowel disease could be a useful clue.
  • Determine comorbidity, such as with diabetes or HIV (or risk of HIV infection).
  • Enquire about medications taken, specifically including antimicrobials, either before or after diarrhea onset, and the effect of any therapy. A history of improvement following antimicrobial therapy is of limited diagnostic value. Recent antimicrobial use, usually within the previous 2 months, should prompt consideration of Clostridium difficile disease.
  • Ascertain travel history – destinations, duration, and conditions. Although many diarrheal pathogens are cosmopolitan, some, such as Schistosoma mansoni, have specific geographic distributions. A diagnosis of a similar illness in travelling companions may be useful.
  • Behavioural history, particularly food and water “precautions”, and the circumstances under which the diarrhea was likely to have been acquired may occasionally contribute to the assessment of diarrhea.

Characteristics of the diarrhea that could be of importance in the assessment of its significance and likely etiology

  • Onset (sudden or gradual, initial symptoms such as cramps or fever)
  • Duration
  • Frequency
  • Stool characteristics (particularly presence of blood or mucus)
  • Stool volumeTenesmus
  • Pattern – constant or intermittent/recurrent, nocturnal (a marker of a secretory diarrhea)
  • Associations (e.g., post-prandial, after ingestion of milk-containing or spicy foods, stress)
  • Abdominal symptoms such as pain or bloating and, if present, any temporal associations
  • Nausea or vomiting
  • Fecal incontinence
  • Fever
  • Weight loss: sustained or progressive weight loss or falling centile on the pediatric growth curve raises the level of concern, suggesting either malabsorption (and hence a small-bowel process) or more severe systemic effects associated with the GI disorder.

The following characteristics are associated with invasive, predominantly ileal, or large-bowel involvement: small-volume stools, lower abdominal cramps, blood and/or mucus or leukocytes in the stool, tenesmus and high/persistent fever.

Large-volume stools, without significant cramping or with mid-upper abdominal localization of pain and weight loss in the face of adequate caloric intake, are characteristic of small-bowel disorders. Most of the causes of persistent diarrhea involve either small or large bowel, so that localization can assist in predicting the likely etiology and can also guide investigations, both microbiological and endoscopic, when indicated. In many patients, the clinical picture does not fall clearly into either category or may even evolve.

 

Functional inquiry

Of particular practical importance in determining the extent and logical order of investigations are the following two issues: degree of interference with well-being and normal life activities, and trend in symptoms since onset, i.e. are they getting better or worse? Limited investigation may be appropriate in patients whose symptoms are mild or improving.

Recommendations

Acute diarrhea

In general, returned travellers with diarrhea of < 5 days' duration require no investigation and should be managed as per the CATMAT statement on TD1. Etiologic investigations may be appropriate for epidemiologic reasons in the case of an outbreak in a travelling group (e.g., cruise ship, organized tour).

B III

Associated fever and other symptoms

  • Any traveller with diarrhea who is febrile and who has visited a malaria-endemic area should have blood smears carried out to rule out malaria (A II), which may be associated with diarrhea either coincidentally or causally.
  
  • Blood culture examination should be undertaken if there is fever associated with the diarrhea.

A II
  • HIV serologic testing should be considered on the basis of the patient's history of risk or presence of suggestive features, such as oral candidiasis.

B III

Initial investigation of persistent diarrhea

The following elements should be included in the approach to the returned traveller with persistent diarrhea:

  • A complete history, including the points listed earlier. Evidence of disease antedating the trip should be sought, and a physical examination should be carried out.

B II
  • At least two stool samples collected on different days in preservative should be examined for ova and parasites at a competent laboratory. Such testing should not be limited to antigen testing and should include permanent stains and acid fast staining.

A II
  • A stool sample should be sent for bacterial culture.

A II
  • If there has been recent antimicrobial ingestion, evaluation for C. difficile cytotoxin should also be carried out.

A II
  • Stool examination for fecal leukocytes, lactoferrin, or even occult blood can also be helpful in identifying subjects with colitis of all etiologiesFootnote 19Footnote 20.

A II
  • A complete blood count may be helpful if it reveals anemia, leukocytosis, thrombocytosis, or eosinophilia.
  
  • While the results are awaited, advise the patient to avoid all dairy or lactose-containing products; a trial period of 3 to 5 days is often diagnostic (C III). Clinical improvement may avoid the need for further investigations. (A hydrogen breath test can confirm a suspicion of lactose tolerance if the diagnosis is suspected and the clinical response to milk avoidance is inconclusive.)
  

A II

Indications for GI endoscopy

Among patients with persistent and substantial symptoms, GI endoscopy may contribute to management in the following circumstances.

If sustained or progressive weight loss is a prominent feature, upper GI endoscopy with small-bowel biopsy should be performed. Alternatively, a 72-hour stool collection for fecal fat will confirm malabsorption, but not the cause. If the fecal fat excretion is elevated, upper GI endoscopy and biopsy would be clearly indicated.

B III

If features of large-bowel diarrhea or rectal bleeding are present, lower GI endoscopy with biopsies should be considered first.

B III

Endoscopic examination and biopsies may be considered for patients with persistence of significant diarrhea, even in the absence of the specific features mentioned, particularly if the empiric therapy and symptomatic measures outlined in the next paragraph have been unsuccessful.

 C III

Empiric therapy

Some authors have suggested a trial of an antibacterial agent such as a quinolone and/or an antiprotozoal agent such as metronidazole; indeed, some have advised this as an early step in the approach to the patientFootnote 21Footnote 22

C III

If major symptoms persist, or if symptoms such as weight loss progress, the full spectrum of non-travelrelated causes of diarrheaFootnote 23Footnote 24 may enter the differential diagnosis. Other investigations, such as measurement of serum anti-transglutaminase antibodies (for celiac disease), should be carried out, and consultation with a gastroenterologist should be considered.

C III

In the absence of a specific etiologic diagnosis, the following therapeutic modalities have been suggested:

Discontinue medications that cause diarrhea (e.g., laxatives, antacids containing magnesium, antibiotics, diuretics, theophylline, cholinergic drugs, promotility agents, prostaglandins).

B II
  • Antimotility agents (loperamide, diphenoxylate, and opiates) are likely to have some beneficial effect on diarrhea and crampsFootnote 25.

B II
  • Bismuth subsalicylate has been used to treat chronic idiopathic diarrhea and diarrhea caused by microscopic colitisFootnote 26.

B II
  • Probiotic agents, most commonly Lactobacillus or SaccharomycesFootnote 27, have been shown to be effective in reducing the duration and severity of acute diarrhea in adults and childrenFootnote 28, in preventing antibiotic-associated diarrheaFootnote 29, and possibly in reducing the frequency of relapse in C. difficile associated diarrheaFootnote 30. Some benefit has been shown in chronic diarrhea in childrenFootnote 31 and persistent post-travel diarrheaFootnote 32. Both Lactobacillus and Saccharomyces can rarely cause serious infection, usually in immunocompromised hosts, but have not been associated with serious adverse effects in otherwise healthy patients treated for diarrheal syndromes. These products have usually been approved through the Natural Health Products Regulations, a process different from the approval process for drugs in terms of requirements for safety and efficacy studies. The role of this approach, the preferred agent(s), and the doses have not been determined.
  
  • Dietary modifications are often recommended. It is essential that adequate nutrition – fluids, calories, protein, and micronutrients – not be compromised by any dietary strategy selected. Scant data exist in relation to dietary management of acute TDFootnote 33Footnote 34 and none in relation to chronic diarrhea. However avoidance of foods or beverages that the patient has found to cause bowel irritability should be considered, i.e. alcohol, spicy foods, and caffeine.

C III
  • Cholestyramine resin, in addition to its hydrophilic action, has the ability to bind bile acids. Thus, it has a specific usefulness in treating bile-acidinduced diarrhea due to malabsorption of bile acids in diseased ileum (e.g., Crohn's disease). Bile acid malabsorption confirmed by appropriate investigations has been reported to respond to cholestyramine following acute infectious diarrheaFootnote 35.

B II
  • Bulking agents, e.g., psyllium, a hydrophilic agent, increase fecal water-holding capacity, may increase stool consistency and reduce diarrheal symptoms, and have been proposed to have a toxin-binding effectFootnote 36. These agents, sometimes in conjunction with laxative agents such as lactulose, have often been found useful by clinicians with experience in the management of this condition.
  
  • New drugs available for irritable bowel syndrome have not been tested in chronic post-travel diarrheaFootnote 37.

C III

Prognosis in the absence of diagnosis

Patients who have no diagnosis after thorough investigation are thought to have “post-infectious” symptoms. Follow-up of these patients has demonstrated a tendency to improve over subsequent months to years. Unless new symptoms or findings appear, these patients can be reassured that life- or health-threatening disease is highly unlikelyFootnote 38. However, it is important to recognize that the patient's symptoms may have a substantial impact on his or her quality of life and to demonstrate an empathetic and supportive approach. Rigorous efforts should be made, with the patient, to explore measures that may provide symptom relief. An algorithm for the management of persistent travel-associated diarrhea is presented in Figure 1.

Figure 1. Approach to the management of persistent travel-associated diarrhea

Figure 1. Approach to themanagement of persistent travel-associated diarrhea

At any point in the algorithm, if the patient is other wise well and symptoms are improving or mild, consider postponing the next investigate step and trial of symptomatic treatment. C & S, culture and sensitivity; O& S and parasites.

 

Acknowledgements

Thanks go to Dr. Richard Fedorak, Division of Gastroenterology, University of Alberta, and to Dr. Jay Keystone, Toronto Hospital Tropical Disease Unit, for reviewing the manuscript and providing expert comments.

 

Relevant review articles

Taylor DN, Connor BA, Shlim DR. Chronic diarrhea in the returned traveller. Med Clin North Am 1999;83(4):1033-52.

Dupont HL, Capsuto EG. Persistent diarrhea in travelers. Clin Infect Dis 1996;22:124-28.

Giannella RA. Chronic diarrhea in travelers: diagnostic and therapeutic considerations. Rev Infect Dis 1986;8(suppl 2):S223-S226.

 

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