Best Practice & Research Clinical Gastroenterology 26 (2012) 563–571

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Best Practice & Research ClinicalGastroenterology

2

Infectious causes of chronic diarrhoea

Lisa Kaiser, MD, Senior Fellow,Christina M. Surawicz, M.D., Professor of Medicine *

Department of Medicine, Division of Gastroenterology, University of Washington School of Medicine,Seattle, WA 98104, USA

Keywords:Chronic diarrhoeaCryptosporidiaAeromonasPlesiomonasYersiniaEntamoeba histolytica

* Corresponding author. Harborview Medical Ce7070; fax þ1 206 744 8698.

E-mail address: surawicz@uw.edu (C.M. Surawi

1521-6918/$ – see front matter � 2012 Elsevier Lthttp://dx.doi.org/10.1016/j.bpg.2012.11.001

a b s t r a c t

Infections are an uncommon cause of chronic diarrhoea. Parasitesare most likely, including protozoa like giardia, cryptosporidia andcyclospora. Bacteria are unlikely to cause chronic diarrhoea inimmunocompetent individuals with the possible exception ofYersinia, Plesiomonas and Aeromonas. Infectious diarrhoea cantrigger other causes of chronic diarrhoea, including inflammatorybowel disease, irritable bowel syndrome and “Brainerd-type”diarrhoea. A thorough evaluation should detect most infectionscausing chronic diarrhoea.

� 2012 Elsevier Ltd. All rights reserved.

Introduction

While most infectious diarrhoeas are acute (defined as less than two weeks) or persistent (definedas lasting between two and four weeks), some can cause chronic diarrhoea, defined as a diarrhoealasting longer than four weeks. Parasitic infections are the most common cause, although manyparasitic infections can be asymptomatic. Chronic bacterial infections are less common. Chronic fungaland viral infections are very uncommon in immunocompetent individuals. In this paper, we reviewparasites that cause chronic diarrhoea, both protozoa and helminths, we also review chronic diarrhoeaof presumed infectious causes, including tropical sprue and “Brainerd” diarrhoea as well as post-infectious irritable bowel syndrome.

nter, 325 9th Ave, Box 359773, Seattle, WA 98104 , USA. Tel.: þ1 206 744

cz).

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Parasites

Protozoa

AmoebaeThere are many amoebae that may infect humans; while some are pathogenic, others are not.

Entamoeba histolytica is the best known invasive pathogen which is usually acquired through thefecal-oral route, such as drinking contaminated water, but can also be transmitted per rectum.Typical symptoms are abdominal pain and diarrhoea [1]. The organism predominantly affects the rightcolon, with both a luminal phase and a tissue phase.

Among the other amoebae, Dientamoeba fragilis is likely to be pathogenic also. Thenonpathogenic amoebae include: Entamoeba dispar, Entamoeba coli, Entamoeba hartmanii,Endolimax nana and Iodamoeba buetschlii. Although E. dispar may appear indistinguishable fromE. histolytica on microscopic stool exam, these two can be differentiated based on the presence ofphagocytozed red blood cells in the cytoplasm, which indicate the pathogenic nature of theamoebae. Moreover, the serologic response is only present with E. histolytica secondary to itsinvasive nature, and not with E. dispar. The diagnosis of pathogenic amoebae is usually made bystool examination, but serology can also be helpful. Colonoscopy with biopsy of the ulcers mayshow the organisms as well. PCR is an emerging tool [3]. Treatment of both luminal and tissuephases is necessary [2].

Giardia lambliaGiardia is a world-wide, water-borne protozoa. Well publicized epidemics have been reported in

a Colorado ski resort and St. Petersburg, Russia, due to the contaminated drinking water. Symptoms canbe nonspecific and include vague abdominal pain, bloating, and chronic diarrhoea which may result inmalabsorption. The best diagnostic test is stool giardia antigen, as stool examination for ova andparasites has a lower yield. Rarely duodenal aspirate or duodenal biopsy will be needed for diagnosis.Patients with IgA deficiency are more likely to develop chronic infection. This can easily be tested for bymeasuring serum IgA levels.

CyclosporaAlthough it was first reported in stool samples of individuals in Papua, New Guinea, Cyclospora

cayatenensis (also called “blue-green algae”) is present worldwide. It also has been reported as a causeof traveller’s diarrhoea in Nepal [4]. In the United States, Cyclospora epidemics have been associatedwith imported raspberries (Guatemala) and basil (Thailand). Transmission is via the fecal-oral route.Typical symptoms are watery diarrhoea, abdominal cramps, fever, malaise, weight loss, as well asheartburn. Diagnosis is made by stool exam.

Cryptosporidia cayatenensisCryptosporidia, a water-borne parasite, which was first described as an infectious agent, affecting

humans in 1976, gained a wide-spread recognition in 1980 during an epidemic in those who wereexposed to infected cattle, and then as a virulent untreatable cause of profuse watery diarrhoea inpatients with Acquired Immune Deficiency Syndrome, (now known as Human ImmunodeficiencyVirus (HIV) infection [5]. There was no effective treatment for this infection until the recent approval ofnitazoxanide therapy in the paediatric population.

CystoisosporiaCystoisosporiasis belli, (formerly known as Isospora belli), has been recognized as a cause of chronic,

but self-limited tropical watery diarrhoea in individuals in tropical countries. The chronic diarrhoea ismore common in patients with immunosuppression. Although it is more common in tropical andsubtropical areas, it has been reported worldwide. Transmission is via the fecal-oral route, but oral–anal transmission can occur. The oocysts passed in the stool are immature, and will become infectiveafter being outside the host for several days [6,7]. It is often associated with eosinophilia. Oocysts canbe detected in acid-fast stained stools.

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MicrosporidiaMicrosporidia can cause a chronic diarrhoea in both immune competent and immune suppressed

individuals, but the disease is more severe in patients with immunosuppression. It is more common intropical areas [6]. Diagnosis is made by microscopic stool examination, or molecular tests such as PCR.

Blastocystis hominisThis parasite has been reclassified as a yeast. Its pathogenicity is debated as some studies show

resolution of diarrhoea after treatment of this organism, while others showed the presence of thisorganism in stools of asymptomatic individuals. One reasonable approach is to treat if there are a largenumber of this organisms in the stool of a symptomatic patient [8].

Helminths

StrongyloidesStrongyloides stercoralis infection in humans can beginwhen the larvae present in the contaminated

soil come in contact with the skin of an individual. This organism is common in Asia and SoutheastAsia, and the rural part of the southern United States. The larvae can penetrate the skin, migrate to thelungs, ascend the bronchial tree and then be swallowed. The larvae burrow into the small bowelmucosa and may live there for many years. The female produces non-infectious eggs (rhabditiformlarvae) which are passed in the stool.

Auto-infection can occur as the organism can replicate in the host. The rhabditiform larvae canmature into the filariform larvae, which penetrate the colonic mucosa to auto-infect the host. Symp-toms of primary infection include skin rash (larva currens), pulmonary symptoms (dry cough, andwheezing) and GI manifestations which may be nonspecific including nausea, vomiting, anorexia, anddiarrhoea. Chronic asymptomatic infection is common. Eosinophilia is common in asymptomatic andsymptomatic cases [9].

Hyperinfection syndrome occurs in immunocompromised patients. Common symptoms are fever,nausea, vomiting, anorexia, diarrhoea, abdominal pain, dyspepsia, wheezing, cough and haemoptysis.Gram negative bacteraemia, and meningitis can occur. Eosinophilia may be absent in these cases. It isimportant to test anyone with above symptoms, as well as immunosuppressed patients with unex-plained eosinophilia, and pre-transplant patients with possible exposure to this microorganism asmortality is high. Diagnosis is based on serology and examination of at least 2 stool samples while 6samples would be optimal. Treatment is with ivermectin or albendazole. Disseminated infection mayrequire extended dosing of these agents, as well as the addition of antibiotics for treatment of theassociated bacterial sepsis [10].

Ascaris lumbricoidesAscariasis is very common worldwide, especially in tropical and subtropical areas. It is acquired by

swallowing foodwhich is contaminatedwith ascaris eggs. The larvaewill hatch in the intestine and canthen invade the mucosa and travel to the lungs via the bloodstream. Small intestinal infection leads tochronic diarrhoea with malabsorption. Diagnosis is made by finding eggs in the stool samples.Treatment is with antiparasitic drugs such as albendazole or mebendazole [11].

Hookworm (Ancylostoma duodenale and Necator americanus)There are two types of hookworms which can infect humans: A. duodenale and N. americanus. They

infect the small intestine. Typical symptoms are occult gastrointestinal tract blood loss and irondeficiency anaemia as the worms ingest blood. Diarrhoea may be present, and can be intermittent, ormay alternate with periods of constipation. Diagnosis rests in detecting eggs in the stool samples.Eosinophilia is a typical finding. Treatment is with albenadazole or mebendazole [11].

TrichiuraTrichuris trichiura, also called whipworm, is a roundworm that infects the colon. It is acquired by

ingesting the eggs from fecal or soil contaminated food. Eggs hatch in the small intestine; the infectivelarvae invade the cecum and mature into adult worms. Symptoms are diarrhoea which can be bloody,

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iron deficiency anaemia and rectal prolapse. Diagnosis is made by stool examination, although theorganisms can sometimes be seen during colonoscopy. Treatment is with metronidazole or albenda-zole. This infection is often asymptomatic, but can occasionally cause dysentery, especially in children[12].

TapewormsAlthough many infected patients are asymptomatic, Cestodes (tapeworms) can infect the intestines

and cause diarrhoea. There are several tapeworms that can infect humans. Symptoms are nausea,fatigue, weight loss and malnutrition [13]. Hymenolopsis nana (dwarf tapeworm) is the most commonroute. Person to person transmission is the most common with eggs ingested through fecal-oral routebut H nana can also be transmitted by infected fleas or beetles.

Taenia saginata is found in beef, Taenia solium in pork, and Diphyllobothrum latum in freshwater fish.

Bacteria

Although the list of bacteria known to cause acute diarrhoeal infection is long and continues toexpand, the number of bacteria known to cause chronic diarrhoea in immunocompetent hosts is farmore limited.

Yersinia enterocolitica

Y. enterocolitica is a gram negative cocco-bacillus which can cause acute and chronic infection. Y.enterocolitica comprises a heterogeneous group of strains with variable virulence patterns [14], withthe majority of strains being pathogenic to humans. These pathogens affect the terminal ileum andproximal colon [15]. Transmission of Y. enterocolitica to humans is usually through undercooked porkor contaminated water. Pig intestines (chitterlings) are a common source, especially in the southernUnited States [16]. Acute infection causes fever, diarrhoea, occasionally bloody diarrhoea, with rightlower quadrant pain due to terminal ileitis and mesenteric adenitis. This presentation can mimicCrohn’s disease or appendicitis. Terminal ileal findings during endoscopy are oedema, ulcers, andround or oval elevations of the mucosa. In the colon, apthous ulcers can be found, which are generallylocated in the right side [17]. Symptoms can last for several weeks, and the organism can be shed in thestool for up to 3 months. Patients with iron overload syndromes (i.e. haemochromatosis) and thosebeing treated with desferoxamine are more susceptible to systemic infection and sepsis [18–20].Additionally, a post-infectious arthropathy has also been described (in association with HLA-B27positivity) [15]. Y. enterocolitica is a siderophilic bacteria (iron-loving) and must be cultured withcold enrichment media techniques. Most cases of acute enterocolitis due to Y. enterocolitica do notrequire treatment with antimicrobials. Clinical data for treatment of Y. enterocolitica is fairly limited,but in disseminated disease or chronic infection, treatment with a fluoroquinolone, doxycycline, ortrimethoprim–sulfamethoxazole is effective.

Aeromonas hydrophila

Aeromonas spp. is a heterotrophic gram negative rod which is mostly associated with acute diar-rhoea, although can cause chronic diarrhoea on rare occasions. The diarrhoea is generally watery, butcan sometimes be bloody. In developing countries, Aeromonas is commonly found in drinking waterand a variety of foods, particularly seafood. Three species of Aeromonas are associated with acutediarrhoea: A. caviae, A. hydrophila, and A. veronii biovar sobria. In the developing world, isolation ofAeromonas spp. ranges between 1 and 88% in patients with diarrhoea, and 0–45% in asymptomaticpatients [21]. The virulence factors of various strains appear to play an important role in the clinicalmanifestations of the disease, although the exact mechanisms are not completely understood.Different strains appear to produce different toxins including haemolytic, cytotoxic, and enterotoxic[21,22]. Only the small bowel is affected in approximately two thirds of cases, but the right colon canalso be involved [23]. In rare cases, the diarrhoea can become chronic, with symptoms lasting longerthan four weeks. Case reports have implicated Aeromonas as a cause of chronic colitis that mimicked

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ulcerative colitis clinically and endoscopically [24,25]. Other case reports suggest that Aeromonasinfection has triggered the development of ulcerative colitis, even after the infection had been cleared[26,27]. Aeromonas is also associated with a number of other infections, including cellulitis and aspi-ration pneumonia.

Plesiomonas shigelloides

This organism is a gram-negative rod, found in fresh water and in several animal hosts. It is asso-ciated with an acute diarrhoeal syndrome, which can sometimes be bloody, as well as abdominal painand vomiting. On occasions, this can persist as a chronic diarrhoea lasting more than four weeks. Arecent retrospective study in Hong Kong found 197 isolates of Plesiomonas on stool cultures between1995 and 1998. Most patients had self-limited acute gastroenteritis, but 9 (5.4%) had diarrhoea whichlasted for over 2 weeks [28]. The enteropathogenicity of P. shigelloides appears to be related to cytotoxinproduction consisting of a complex protein and lipopolysaccharide [29].

Recurrent Clostridium difficile Infection

C. difficile is an anaerobic, spore-forming gram positive rod which is the most common nosocomialinfection of the gastrointestinal tract. C. difficile infection (CDI) is commonly the result of antibiotictreatment with subsequent alteration of the normal gut flora, allowing overgrowth of C. difficile andproduction of toxins A and B. The toxins cause diarrhea and bacterial pseudomembranes can form insevere cases, which can be seen at colonoscopy. Since 2000, there has been a dramatic increase in casesof CDI in the US and Canada. More recently, a strain known as BI/NAP1/027 has been identified which ismore virulent and is resistant to fluoroquinolones [30].

Frequent outbreaks occur in hospitals and long term care facilities. Mortality due to C. difficileinfection ranges from 1.2% to 6.9% but can be much higher during severe outbreaks [31]. Costs asso-ciated with CDI represent an increasing burden on our health care system, and can range from $2800 to$4800 for primary CDI and up to $18,000 for recurrent infection [32].

Testing for C. difficile has historically relied upon ELISA testing for toxin A and B, with a reportedsensitivity of 60–80% and specificity of 91–99% [33]. More recently, many institutions have turned toPCR-based testing to increase the sensitivity. Treatment of C. difficile associated diarrhoea mostcommonly utilizes either metronidazole or vancomycin for 10 days. Both are effective in the treatmentof mild to moderate disease; however, vancomycin is recommended as the first line therapy for severedisease or if metronidazole is contraindicated as in early pregnancy. Most patients get better within 5days and are asymptomatic at the end of therapy. However, 10–20% will have recurrent diarrhoea dueto C. difficile. The likelihood of further recurrences can be as high as 40–60% after one recurrence [34].The recurrent C. difficile infection (RCDI) is more difficult to treat. A repeat course of antibioticisnecessary, either metronidazole or vancomycin. A pulse regimen of vancomycin, such as every otherday for 1–2 weeks may decrease recurrences. Other treatments including rifaximin, fidaxomicin,probiotics, and immune globulin have all been tried, with limited success. Stool transplant known asfecal microbiota transplant which restore the normal fecal flora has been successful in some cases ofrefractory or recurrent disease, with a success rate of 92% [35]. Although there are no controlled trialsavailable, there is a study that has been funded by the NIH recently.

Mycobacterium tuberculosis

Tuberculosis enterocolitis generally presents with nonspecific symptoms, including weight loss,fever, diarrhoea, blood in the stool, and abdominal pain [36]. Any part of the gastrointestinal tract canbe involved, but the cecum and ileocaecal valve are most commonly affected. The pathogenesis of TBenterocolitis has been attributed to four different mechanisms: ingestion of contaminated food, hae-matogenous spread in the setting of active pulmonary TB, swallowing of infected sputum, andcontiguous spread from adjacent organs. Notably, only about 50% of patients with tuberculosisenterocolitis have concomitant pulmonary involvement [37–39]. Endoscopically and histologically,tuberculosis can mimic Crohn’s disease, so a high index of suspicion is necessary. PCR testing of colonic

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tissue can confirm the diagnosis before the culture result is available. In comparison to Crohn’s ulcerswhich are linear with normal adjacent tissue, tuberculosis generally presents with transverselyoriented ulcerations with sharp margins and inflamed adjacent tissue. A patulous or destroyed ileo-caecal valve is highly suggestive of tuberculosis [40,41].

Tropheryma whipplei

T. whipplei is a gram positive, period acid-Schiff-positive actinobacteria that has been identified asthe causative organism of Whipple’s disease. Although it is notoriously difficult to culture; theseorganisms are easily detected with PAS staining of biopsy specimens and PCR.

The clinical manifestations of T. whipplei infection are broad and can range from multi-systemicWhipple’s disease with arthralgias, cognitive dysfunction, abdominal pain, and chronic diarrhoea toasymptomatic colonization. Classic Whipple’s disease is quite rare with an estimated annual incidencebelow 1/1,000,000 [42]. The disease appears to have a predilection for white males, and several studieshave shown that subtle defects of the cell-mediated immunity predispose to the disease [42–44].Whipple’s disease is thought to be due to colonization of the T. whipplei throughout the gastrointestinaltract, lymphoreticular system and CNS. Symptoms include migratory arthralgias of large joints, chronicdiarrhoea, weight loss, massive adenopathy, ascites due to chronic serositis, and cognitive dysfunction.Pathognomonic CNS findings include oculomasticatory myorhythmia (continuous rhythmic move-ments of eye convergence with concurrent contractions of the masticatory muscles) and oculo-facial-skeletal myorhythmia [45]. Endoscopically, Whipple’s disease has a wide range of features, includingoedema, brown discolouration of the mucosa, erythematous spots, and flattened villi. Histologicalevaluation shows coarse, granular cytoplasm and foamy macrophages that stain strongly with PAS-reagent [46]. Diagnosis can be confirmed with PCR testing or immunohistochemistry [42]. Treat-ment for Whipple’s disease relies on prolonged course of antibiotic therapy. The only randomizedprospective treatment trial suggests a 14 day intravenous induction therapy with meropenem orceftriaxone in combination with an oral continuation therapy with TMP-SMX for 12 months asa treatment modality for this disease [47]. Relapsing disease is often treated with alternativeantibiotics.

Viruses

Enteroaggregative E. coli

Enteroaggregative E. coli has recently been recognized as a common cause of travelers’ diarrhoea,but also a cause of chronic diarrhoea in malnourished hosts in developing countries [48].

Viral infections of the GI tract are usually self-limited. Cytomegalovirus can cause chronic colitis orenteritis in immune suppressed individuals.

Fungi

Fungal infections are uncommon in immunocompetent individuals. However, there are case reportsof candida overgrowth causing chronic diarrhoea that responded to anti-fungal therapy [49].

Presumed infectious diarrhoea

Brainerd diarrhoea

Several outbreaks of acute diarrhoea, felt to be infectious, have been reported in the literature[50–52]. Some of those affected, went on to develop a chronic diarrhoea. The most well-knownoutbreak occurred in Brainerd, Minnesota between December 1983 and July 1984. One hundredtwenty two people were affected, many of whom had consumed raw milk from a single dairy. Thediarrhoea was characterized as acute in onset without major systemic symptoms, as well as a failure torespond to antimicrobial medications. Laboratory testing revealed a secretory mechanism; however,

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extensive testing did not reveal an etiologic agent [50]. Another outbreak in Henderson County, Illinoiswas likely due to contaminated water as those affected had drunk untreated well water. While mostwith acute diarrhoea had rapid resolutions of symptoms, a small number developed chronic waterydiarrhoea. Most of these individuals did have resolution of diarrhoea within 3 years. One follow upstudy indicated resolution of diarrhoea over a two year period [53].

Post-infectious irritable bowel syndrome

The observation that acute gastroenteritis could be followed by typical symptoms of irritable bowelsyndrome (IBS) dates to the 1950’s. This entity has not only been linked to bacterial dysentery but alsoto viral gastroenteritis. The incidence can vary from 2 to 10%. Risk factors include female gender, andmore severe acute illness. Over a two year period, half of the affected individuals will have resolution oftheir symptoms. Post-infectious IBS can occur after bacterial, parasitic or viral gastroenteritis. Diar-rhoea is more common than constipation or alternating diarrhoea and constipation [54–56].

Summary

Infections are an uncommon cause of chronic diarrhoea. They should be suspected in high riskindividuals (patients who are immune-compromised or individuals with history of travel to theendemic areas). Clinical evaluation, including appropriate stool and blood tests should be able to findthe aetiology in most cases so that appropriate therapy can be given [57].

Practice points

Infections are an uncommon cause of chronic diarrhoea.Bacterial stool culture for persistent diarrhoea (2–4 wks duration) is indicated to exclude path-ogens such as Yersinia, Aeromonas and Plesiomonas.Parasites should be excluded as a cause of chronic diarrhoea; this should include 3 stool exams forova and parasites, as well as stool giardia and cryptosporidia antigen testing.GI infections (both bacterial and viral) can result in post-infectious IBS (PI-IBS).Infections are likely implicated in the pathophysiology of Brainerd diarrhoea, tropical sprue, andpossibly other chronic diarrhoeas.

Research agenda

Newmolecular tests may detect pathogens in chronic diarrhoea syndromes and should be used inepidemiologic studies of acute and chronic diarrhoea.The effect of early treatment of bacterial GI infections to reduce or prevent PI-IBS needs to beevaluated in future studies.Studies of the fecal microbiomemay help in better preventive and treatment plans for agents thatcause GI tract infections.

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