Table 1 Categorization and brief exposition of known etiologies for persistent/chronic diarrhea in returning travelers

1). Infectious

Bacterial: [5, 9, 10] Campylobacter spp., [5, 9, 10] Shigella spp., [5, 9] Aeromonas spp., [5, 9, 10]Clostridium difficile, [5, 9, 10] Salmonella spp.

Parasitic: [5, 7, 10] Cryptosporidium parvum, [5, 7, 9, 10] Entamoeba. histolytica, [5, 7, 9, 10] Giardia lamblia, [5, 9, 10] Isospora belli, [5, 7, 10] Cyclospora cayetanensis, [10] Microsporidia spp., [7, 9] Dientameba fragilis

Helminthic: [5, 9] Strongyloides stercoralis,, and [9]Schistosoma spp.

2). Presumed Infectious

[9] Brainerd’s Diarrhea, [7, 10] Tropical Sprue

3). Post infectious sequelae

[5, 9, 10] Lactose intolerance, [5, 7, 9, 10] Post infectious irritable bowel syndrome (PI-IBS), [7, 9, 10] Small intestinal bowel overgrowth (SIBO)

4). Unmasked

[5, 7, 10] Celiac disease, [5, 7, 9, 10] Inflammatory bowel disease (IBD), [10] Microscopic colitis

1). Infectious

Bacterial

1). Aeromonas is a gram negative bacilli, oxidase positive and associated with freshwater identified in chronic watery diarrhea cases and associated with asymptomatic carriage [11]. Diagnosis requires stool culture and treatment ensues with a fluoroquinolone or a third-generation cephalosporin.

2). Campylobacter spp. (primarily C. jejuni) is a major cause of acute diarrhea globally. It has been implicated in chronic diarrhea in travelers. Campylobacter spp. are foodborne illnesses, which may be transmitted person-to-person or via exposures to animal vectors (poultry). It may produce watery to bloody diarrhea (dysentery) and lead to post-infectious complications including reactive arthritis, PI-IBS, and Guillain-Barre syndrome. It is diagnosed by stool culture, and treated with macrolide or fluoroquinolone antibiotics (acknowledging increasing resistance to the latter in SE Asia) [10].

3). Clostridium difficile, a gram-positive anaerobic bacillus and the cause of pseudomembranous colitis, has emerged as a major infectious etiology of both acute and diarrhea (watery to bloody diarrhea), often associated with profound leukocytosis, and chronic diarrhea in travelers, regardless of antibiotic exposure [12].

4). Shigella spp. are aerobic gram-negative rods (non-motile, non-spore forming) in the family Enterobacteriaceae partitioned into four groups (group A: S. dysenteriae; Group B, S. flexneri; Group C, S. boydii; Group D, S sonnei). Shigella spp. is s a major cause of travelers associated acute diarrhea, endemic and travelers assoiated dysentery, and chronic diarrhea in travelers. It is transmitted by contaminated food and water or fecal orally. It may produce watery or frankly bloody diarrhea. Post infectious complications include reactive arthritis, and PI-IBS. It is diagnosed by stool culture and treated via macrolide or fluoroquinolone antibotics, although mirroring assertions for all bacterial enteropathogens, resistance is increasing [10].

5). Salmonella (non-Typhi) is a foodborne illness which may also be transmitted by aimals (reptiles, birds). It may produce watery diarrhea and occasionally may be culpable in producing frank dysentery and bacteremia. Post infectious complications include reactive arthritis and PI-IBS. It is diagnosed by stool culture. Treatment is withheld except for severe symptoms, or in elderly or very young patients [10].

Parasitic

1). Giardiasis is a ubiquitous parasitic infection exhibiting global transmission. This infection produces the classic steatorhea emanating from malabsorption associated with bloating, nausea, and emesis often mimicking IBS. The trophozoites localize in the small intestine. Giardia may be transmitted via contaminated food, water or direct person-person contact (fecal oral spread common in day care centers, residential institutions, and among MSM). The diagnosis is best rendered with a stool ELISA measuring the Giardia antigen often coupled with the Cryptosporidium parvum and Entameba histolytica. Treatment is effected with a 7–10 days course of metronidazole [10].

2). Cryptosporidium parvum is a coccidian protozoa with fastidious oocysts which typically causes chronic watery diarrhea (often associated in outbreaks) in immunesuppressed individuals, but has been identified as a cause of persistent/chronic diarrhea in travlers [6]. The oocytes resists chlorination, is transmitted fecal orally, linked to poor sanitation, diagnosed via stool microscopy (O&P and partial acid fast staining) or antigen testing (ELISA) [32].

3). Cyclospora cayetanensis is a coccidian protozoan (humans the only reservoir) producing a more severe clinical spectrum of diarheal disease than that of Cryptosporidium parvum. Diarrheal outbreaks have been reported in Peru, Nepal and Guatemala (imported Guatemalan raspberries) in the U.S. [6]. In contradistinction to Cryptosporidium spp., Cyclospora requires sporulation in the environment, thus human-human transmission is unlikely [6, 32]. The diagnosis requires partial acid-fast staining of a stool specimen (noting cysts are 10 μm in size (vice 5 μm for Cryptosporidium and 20–30 μm for Isospora belli-described below)) and responds to treatment with trimethoprim-sulfamethoxazole.

4). Isospora belli is a large protozoan responsible for diarrhea in immunocompromised patients and identified in persistent/chronic diarrhea in returning travelers. It is another ubiquitous low virulence organism markedly underdiagnosed. Diagnosis and treatment is similar to Cyclospora [6].

5). Microsporidia are intracellular spore forming protozoans referring to Enterocytozoon bieneusi and Encephalitozoon intestinalis genotypes associated with human intestinal infections [6]. This is another ubiquitous organism culpable for diarrhea in immune-compromised patients, and persistent/chronic diarrhea in returning travelers, and is likely underdiagnosed given difficulty in diagnosis (improved exloiting PCR methods) [33]. Unlike the Cryptosporidia, Cyclospora spp., and Isospora spp. diagnosed via partial acid fast staining, Microsporidia requires modified Trichrome staining [6]. Treatment options include albendazole.

6). Amebiasis, due to Entamoeba histolytica can present with a spectrum of disease manifestations including acute and persistent/chronic diarrhea in retruning travelers. This protozoan can be invasive (producing flask shaped abscesses) and may produce severe abdominal pain, fever, and bloody stools (dysentery). Complications include formation of liver abscesses. Transmission occurs via contaminated food and water, and fecal-oral contact. Diagnosis occurs via microscopy on stool specimens, stool antigen ELISA or PCR [5, 32]. Treatment entails metronidazole for invasive disease coupled to paromomycin or diloxanide as a luminal agent (to eradicate remaining cysts).

1). Strongyloides stercoralis is a nematode infection, primarily identified in tropical and sub-tropical areas globally, transmitted by exposure to contaminated soil. Filariform larvae penetrate the skin entering the lymphatics and migrating to the lung, thence the small intestines. The infection may remain dormant for decades, symptomatic after immune-suppression (steroids). It may also present with chronic diarrhea upon exposure during travel. The diagnosis ensues with culture, microscopy (identifying the larvae), and serology. Treatment is best effected with Ivermectin repeated at 2-weeks to treat the autoinfective cycle [34].

2). Schistosoma spp.: The etiology of schistosomiasis (bilharzia), these are blood flukes, (helminthic parasites, in the class Trematoda). They are prealent throughout the tropics (particularly in SSA and ME). Schistosomiasis involves a complex life cycle with water mollusks serving as intermediate hosts, infective cercariae entering the skin, honing to species specific trophic organism (bladder for S. hematobium, portal venous system for S mansoni), release of eggs and becoming miracidium once deposited in the environment to reinfect mollusks. Diagnosis requires stool, urine, or tissue evaluation for eggs, and serologic assays. Treatment with praziquantel quite effective requiring repeated dosing to prevent relapses [35].

2). Presumed Infectious

1). Brainerd’s diarrhea is an epidemic form of watery secretory diarrhea. It was first described after an outbreak which emerged in Brainerd Minnesota [36]. The symptoms exhibit a median duration of 15–16.5 months and may last for several years. Histopathologic analysis of colonic biopsies revieal patchy lymphocytic colonic inflammation. Although an infectious trigger is presumed, no microbiological entity has been identified to date. Risk factors have been identified via epidemiological investigations and include consumption of contaminated water and unpasteurized milk. Secondary transmission is rare [36].

2). Tropical sprue is a condition of unknown etiology characterized by chronic diarrhea, weight loss, fatigue, steatorrhea, and malabsorption, usually associated with evidence of micronutrient deficiency (anemia, folate, and vitamin D deficiency). It is endemic in tropical regions, and rare in North America and Europe [37]. It is thought to be precipitated by an unknown infectious trigger [38]. Tropical sprue represents one of the most common chronic enteropathies of the developing world mirroring the most common chronic enteropathy (celiac sprue) of the developed world, manifesting similar histologic features. This enteropathy is multifactorial characterized by bacterial overgrowth (SIBO), deranged gut motility, parasitic infections, and hormonal and histopathologic abnormalities [39]. Histopathologic analyses are similar to that noted in celiac disease exhibiting villous atrophy, crypt hyperplasia, and epithelial lymphocytosis [40]. Diagnosis requires excluding alternative etiologies (celiac disease, lactose intolerance, SIBO, IBS) and treatment is effective with empiric antiotics and folate supplementation [41].

3). Post infectious sequelae

1). Lactose Intolerance: Gastroenteritis may precipitate secondary enzymatic disaccharidase deficiency. These enzymes are located within the microvilli [brush border] of small intestinal enterocytes, which are responsible for carbohydrate (lactose, sucrose) hydrolysis contributing to malabsorption (maldigestion) and diarrhea. Perhaps the quintissential mucosal malabsorption syndrome, lactose intolerance involves a deficiency in the enzyme lactase which is responsible for lactose hydrolysis. The unabsorbed lactose leads to mild osmotic diarrhea associated with abdominal pain, cramping, bloating, and diarrhea. The enzymatic deficiency is typically transient, but in a minority (genetically predisposed) may be permanent [7]. Predisposed patients may harbor minimal digestive or absorptional reserve compensated until the superimposed enteritis depletes the remaining brush-border enzymatic function [38]. The contemporary diagnosis is primarily clinical [soliciting a history of diarrhea associated with lactose consumption]. Confirmatory testing includes identifying a low stool pH < 6 (a sensitive screening assay), accompanied by histopathologic evaluation with/without a mucosal lactase assay from a mucosal biopsy retrieved during endoscopy and/or hydrogen breath testing [7, 38].

2). PI-IBS: Mounting evidence supports an association between enteric infection, including TD, and IBS (hence referred to as post-infectious IBS (PI-IBS)) [30, 42]. PI-IBS has been associated with all families of enteropathogens [5]. Two meta-analyses have demonstrated a 6- to 7-fold increase in the risk of developing IBS following an antecedent episode of gastroenteritis [43, 44]. Recent data culled from the GeoSentinel network (1997–2011) quote a PI-IBS incidence of 2–5% [19, 29] and the prevailing consensus is that the incidence likely resides within a window of 5–10% [30, 31]. PI-IBS has been associated with increased duration and severity of the antecedent GI illness, comorbidities (anxiety, depression), concomitant psychological stressors, and enteropathogenic virulence and invasiveness (stronger associations with Yersinia spp, Campylobacter > Shigella > Salmonella) [5, 7, 43–46].

3). Small intestinal bowel overgrowth (SIBO): The small bowel is typically minimally colonized by bacteria (possessing < 10⁴ organisms/mL) (unlike the large bowel possessing upwards 10¹² cfu/ml) due to gastric acidity, intestinal peristalsis and a competent ileocecal valve. SIBO may be an isolated finding, or coexist with multiple GI derangements [dysfunctional intestinal motility, mucosal pathologies, reduced gastric acid barrier or dysfunctional anatomy stemming from surgery (blind loops emanating from gastric bypass)] or evolve from intestinal stasis induced by an episode of gastroenteritis and perpetuated by immune-deficiencies [7, 47]. The gold standard for diagnosing SIBO encompasses a quantitative culture of an aspirate of luminal fluid (via upper endoscopy) eclipsing 10⁵–10⁶ [normal < 10⁴] organisms/mL or by exploiting breath testing. Empiric antibiotic trials (including anaerobic coverage) may be both diagnostic and therapeutic (i.e., the non-absorbable antibiotic Rifaximin [47].

4). Unmasked

1). Celiac disease: celiac disease is an immune-based reaction to dietary gluten (storage protein for wheat, barley, and rye) that primarily affects the small intestine in those with a genetic predisposition and resolves with exclusion of gluten from the diet. Celiac disease is the most common small bowel inflammatory enteropathy in the Western world (afflicting 1% of Caucasians) and presents with diarrhea, steatorrhea, weight loss, bloating, flatulence, post-prandial abdominal pain, and a host of extraintestinal complications attributed to malabsorption including osteoporosis, neurologic and skin disorders (dermatitis herpetiformis) [47]. Its prevalence is increasing (attributed in part to detection bias) yet likely remains under-diagnosed [48]. The prevalence is higher in those manifesting autoimmune diseases [insulin dependent diabetes, thyroid disease, or primary biliary cirrhosis]. Celiac disease is classified as a malabsorptive disease associated with watery diarrhea mimicking IBS-D [48]. The differential diagnosis includes microscopic colitis, SIBO, tropical sprue, autoimmune enteropathy, hypogammaglobulinemic sprue, Whipples’ disease, Crohn’s disease, eosinophilic enteritis, intestinal lymphoma, TB, graft-host disease, and pancreatic exocrine insufficiency [48]. Laboratory abnormalities include [abnormal liver function tests, iron deficiency anemia, and micronutrient deficiencies (folic acid, vitamin B12, vitamin D, zinc, copper, fat soluble vitamins)]. The diagnosis is predicated upon serologic testing of celiac-specific antibodies with confirmation by duodenal mucosal biopsies revealing villous injury (effacement).

2). Inflammatory Bowel Disease: IBD encompasses ulcerative colitis (UC) and Crohn’s disease. IBD primarily affects patients in a bimodal age distribution with the majority of cases arising between the ages of 15 and 40 years. However, it may present in younger and older individuals. The disease involves exacerbations or flares manifesting with a spectrum of symptoms which may encompass abdominal pain, weight loss, diarrhea (with or without blood, and mucus), and frank hematochezia. Extraintestinal symptoms are prevalent including ocular (uveitis, episcleritis), musculoskeletal (arthritis, back pain), and/or dermatologic (pyoderma gangrenosum (UC); erythema nodosum). Triggers for IBD are unknown but the disease is multifaceted involving the interactions in host genes, immunity, and environment [7]. Interestingly, recent emerging research implicated an increased risk of IBD following acute infectious gastroenteritis (IGE) (OR 1.53, 95% CI 1.4–1.7) after controlling for important covariates including prior IBS diagnosis [49].

3). Microscopic colitis: microscopic colitis is an inflammatory bowel disease (Ohlsson, [50]) which mirroring bile acid malabsorption (BAM), is increasingly recognized as a common cause of chronic watery secretory diarrhea, (manifesting nocturnally as opposed to IBS) exhibiting increasing incidence [10–20% of chronic diarrhea cases; reaching 30% of attributable cases of chronic water diarrhea in the elderly (>65)] [48, 51]. The increased incidence may be attributed in part to detection bias (increased recognition and increased colonoscopic evaluation incorporating mucosal biopsies potentiating histopatholgic evaluation) [51]. It encompasses two primary diseases based upon histopathology, collagenous colitis (CC) and lymphocytic colitis (LC). This disease should always be considered in older patients with persistent nocturnal diarrhea unresponsive to fasting, and in the differential of diarrheal predominant IBS [50, 51].