Research advances in traveler's diarrhea syndrome

Recently, Professor Robert from the University of Zurich in Switzerland published a review in the January 2015 issue of JAMA magazine detailing recent advances in the risk factors, causes, and prevention and treatment of traveler's diarrhea.

Concepts and Epidemiology

Traveler's diarrhea, which often occurs in people traveling to low- and middle-income countries in high-income countries, is defined as the appearance of 3 or more unformed stools every 24 hours after the traveler arrives at their destination with at least one other symptom (e.g., abdominal cramps, tenesmus, nausea, vomiting, fever, or urgency to bowels).

Figure 1 The incidence of traveler's diarrhea in different countries around the world (1996-2008), the darker the color, the higher the incidence.

Incidence is inversely proportional to the income level of the destination country. Over the past 20 years, the incidence of traveler's diarrhea has decreased from 65% to 10% to 40%. The regional distribution is shown in Figure 1.

Risk factors

1. Environmental factors

The risk of food contamination at street stalls is high, and food exposure to warm environments in high-end social settings can also easily induce traveler's diarrhea.

The incidence of gastrointestinal discomfort is lower during beach vacations and nautical tourism than in land tourism, but passengers and crew are more susceptible to uncontrollable outbreaks of Noroc virus in nautical tourism. The incidence of traveler's diarrhea is seasonal and its winter incidence is low.

2. Host factors

Younger travellers are more susceptible to traveller diarrhoea, with no gender differences, with infants and young children being more severely ill and requiring hospitalization. Living in areas with a high incidence of traveler's diarrhea and exposure to ETEC may allow travelers to develop partial immunity. However, taking immunosuppressive drugs does not change the incidence of the disease.

Clinical presentation and course of the disease

When a pathogen invades the intestinal mucosa, patients develop systemic symptoms such as bloody stools or fever, at which point traveler's diarrhea progresses to dysentery. The average duration of untreated traveler's diarrhea is 4 to 5 days, but only 3% of these cases have more than 10 unformed stools in a single day. Short-term loss of function occurs in 12% to 46% of patients with traveler's diarrhea, but the average duration is less than 1 day.

Long-term complications of traveler's diarrhea are mainly chronic gastrointestinal symptoms (persistent or chronic diarrhea) with irritable bowel syndrome (PI-IBS) as distinct from irritable bowel syndrome (IBS). Factors associated with the occurrence of PI-IBS include: the severity of diarrhea, the number of episodes, whether diarrhea occurred before travel, whether adverse life events occurred before travel, and whether the causative agent was E. coli (ETEC), which is intolerant to thermotoxin-producing. Reactive arthritis and Guillain-Barré syndrome may be associated with traveler's diarrhea.

Etiology / Microbiology

Traveler's diarrhea is caused by ingestion of contaminated food or beverages, and the causative agent is identified on examination in 50% to 90% of patients. Gut bacteria cause most travelers' diarrhea, but they cause less than 15% of adult endemic diarrhea. Invasive bacterial pathogens (Shigella, Salmonella, Campylobacter, etc.) and parasites often cause prolonged diarrhea.

In developing countries or regions, the causative agents of traveler's diarrhea are, in descending order of importance: ETEC, Intestinal Invasive E. coli, Diffuse adhesion E. coli, Norwalk virus, Rotavirus, Salmonella, Campylobacter jejuni, Shigella spp., Aeromonas spp., Oryctomycetes shigae, Enterotoxin bacillus, and Vibrio cholerae.

Parasites (Duodenal Giardia, Cryptosporidium, Amoeba dysentery, microsporidium, etc.) can also be pathogenic for diarrhea in tourists, but there are regional differences. Toxoplasma gondii plays an increasingly important role in the onset of traveler's diarrhea and is often accompanied by co-infection.

ETEC is the most common causative agent of traveler's diarrhea in many regions, but this is not the case in Southeast Asia (campylobacter and aeromonas are common in the region). Cases of unexplained diarrhea may be caused by bacteria, viruses, or parasites.

Prevention of traveler's diarrhea

1. Diet prevention

Recommendations for avoiding contaminated foods and beverages often include: "boil, cook, peel or leave it alone," which, while plausible, does not in fact reduce the incidence of traveler's diarrhea. An environment of 100 °C can kill intestinal pathogens, and many foods are safe enough to be cooked to 60 °C, but food often does not reach a sufficient temperature to kill pathogens.

Food is often in a warm external environment, which may not always be able to isolate the invasion of external pathogens. During the trip, most tourists will eat a self-service salad contaminated with bacteria or drink a mushroom drink with ice cubes.

2. Drug prevention

Certain antibiotics and non-antibiotic drugs can be used to prevent traveler's diarrhea. Bismuth salicylate provides modest protection for patients with traveler's diarrhea, and taking it four times a day while traveling can reduce the incidence of traveler's diarrhea by 65%, with the main adverse effects being the darkening of the tongue and stool after taking it.

Bismuth salicylate contains salicylate and should be avoided in patients taking anticoagulation or using salicylic acid drugs for a long time, its toxicity is rare, but when used in long-term use or in aids patients, a metabolically produced refractory mixture of bismuth can lead to encephalopathy.

Rifaximin is an intestinal selective antibiotic that is not easily absorbed. Studies have shown that rifaximin significantly reduces the incidence of non-invasive traveler's diarrhea, and rifaximin is effective for nearly half of travelers to South and Southeast Asia.

Systemic prophylactic use of antibiotics can reduce the incidence of illness in travellers by more than 90%, and the most commonly used drug is fluoroquinolone. But the prophylactic use of antibiotics remains controversial, with opponents mainly concerned about their adverse effects and the emergence of drug resistance. Therefore, chemoprophylaxis with systemic antibiotics is recommended for only a small proportion of travelers for no more than 2 to 3 weeks.

Chemotherapy of antibiotics is indicated for travelers prone to diarrhoeal complications, including those who are intolerant to dehydration (patients with a history of stroke or transient ischemic attacks, insulin-dependent diabetes mellitus, or chronic kidney failure), travelers prone to complex diarrhea (patients with inflammatory bowel disease and AIDS), and patients undergoing ileostomy and colostomy. Short-haul travelers with work assignments may also consider the use of chemopreventive measures.

To date, there is no vaccine that provides satisfactory protection for patients with traveler's diarrhoea, and cholera vaccines, as the only option, have only limited cross-protection against thermotoxin-producing ETEC. Travellers planning to travel to cholera-affected areas may consider using it.

Treatment of traveler's diarrhea

Treatment of traveler's diarrhea attacks follows standard guidelines: avoid dehydration, alleviate diarrhea, alleviate symptoms such as abdominal cramps and nausea. Typical symptoms of traveler's diarrhea should be made widely available among travellers, and travellers should be reminded of the amount of water intake and informed of how to manage the diarrhoea.

Infants, young children, the elderly, and chronically ill patients can use oral rehydration solutions to prevent dehydration, and healthy older children and adults can maintain their hydration with sugar-sweetened teas, soups, and a gradual increase in regular foods in their diet.

There is evidence that self-treatment is effective in the treatment of traveler's diarrhea. The use of non-antibiotic drugs (e.g., bismuth salicylate or the antidynamic agent loperamide) is often effective when symptoms are mild (1 to 3 loose stools in 24 hours with or without mild bowel symptoms and unaffected activity).

When travelers cannot adapt to frequent intestinal movements, loperamide can rapidly reduce the amount of loose stools. Bismuth salicylate is effective in controlling nausea symptoms, but it takes longer to reduce symptoms of diarrhea than loperamide. Loperamide cannot be used in patients younger than 2 years of age, and loperamide alone without antibiotics should not be used alone when patients with traveler's diarrhea have a temperature above 38.5°C or a bloody stool.

For severe nausea and vomiting, the serotonin antagonist ondansetron can be used in pediatric patients and the antihistamine drug iprazide can be used in youth and adults. Ondansetron and promethazine are suitable for long-haul travelers or seafarers who do not have easy access to treatment, loperamide is often used in travelers with nausea symptoms, and probiotics may have a therapeutic effect on acute childhood diarrhea.

Antibiotics can shorten the course of illness in moderate to severe patients by about a day and a half, and the choice of antibiotics depends on the geographical location of the traveler. Fluoroquinolones (ciprofloxacin or levofloxacin) are often used in most tourist destinations, but azithromycin is often used in areas where the causative agent is Campylobacter spp., such as South and Southeast Asia, and care needs to be taken to assess the sensitivity of Campylobacter to lipids in the macrocyclic ring to ensure ongoing drug sensitivity.

In general, monotherapy with antibiotics or treatment for 3 days cures the disease. Although azithromycin is well tolerated in most patients and can be used in pregnant women and children, it can occur in adults with short-term nausea. At the same time, azithromycin may induce sudden cardiovascular events and should be used with caution in travelers with coronary heart disease.

Rifaximin is not inferior to fluoroquinolones in the treatment of non-invasive intestinal bacterial infections, but treatment with rifaximin cannot be used because of the possible resistance of these bacteria to rifaximin when treating invasive bacterial infections with fever and suspected Shigella, Campylobacter, or invasive Salmonella infections.

When rapid relief of symptoms is required, a combination of loperamide and antibiotics may be used. Antiparasitic drugs are often not included in travelers' travel kits and are only considered when traveling long distances for long periods of time.

Evaluation of patients with traveler's diarrhea after return

1. Simple diarrhea

Many patients return home with relief of symptoms of diarrhea and often do not seek or need treatment. Among most travelers seeking treatment for a serious illness after the return journey, the bacterial pathogen is the most common causative agent, often with antimicrobial treatment without a stool test. Adult traveler's diarrhea without fever or without dysentery can be treated with rifaximine (200 mg tid; 3 days); ciprofloxacin (750 mg, Qd; 1 to 3 days); azithromycin (500 mg, Qd; 3 days), or azithromycin (1000 mg at a time).

2. Traveler's diarrhea complicated by fever or bloody stools

Indications for laboratory testing in returning patients are temperature >101.3°F, dysentery, cholera-like diarrhea with any degree of dehydration, or persistent diarrhea (≥ 14 days). Fever may be caused by Shigella, Salmonella, Campylobacter, Yersinia, or Norwalk virus infection. Blood cultures are required in patients with traveler's diarrhea with fever or bloody stools.

Travelers with symptoms of systemic toxicity and fever should consider typhoid fever due to bacteremia, as well as blood cultures and stool cultures. Laboratory tests for routine pathogens and Vibrio cholerae V require suspicion of infection with Vibrio cholerae and invasive bacterial pathogens in the O1 group and stool culture. When patients do not respond to self-administration of fluoroquinolones and develop persistent diarrhea, Clostridium difficile-related diarrhea and STEC-related intestinal disorders need to be considered.

3. Complex traveler's diarrhea characterized by persistent or refractory diarrhea

Persistent diarrhea is defined as diarrhea lasting more than 14 days and occurs in nearly 2% of travelers' diarrhea. Refractory diarrhea is defined as traveler's diarrhea that does not respond to antimicrobials or recurs after a significant clinical response, often due to infection with antibiotic-resistant bacteria and parasites (Giardia or Cryptosporidium).

After refractory diarrhea, stool samples should be collected and checked for salmonella, Shigella, or Campylobacter, and the parasite should be detected using microscopy or enzyme immunoassay. Treatment of persistent diarrhea depends on the determination of the causative agent of the intestine and the antimicrobial susceptibility test. In some cases, a more extensive gastrointestinal evaluation is required to rule out colon cancer or Crohn's disease.