Diarrhea in the HIV-infected patient

Gastrointestinal manifeslations may be encountered throughout, the course of HIV disease. The problems range from asymptomatic hairy leukoplakia lo overwhelming diarrhea due to opportunistic infections such as cryptosporidiosis. Diarrheal disease is an important contributing factor to wasting in advanced HIV disease. Considerable progress has been made in recents years regarding our understanding or HIV-related diarrhea, including etiological agents, diagnostic methods and treatment.

Three lypes of entcric infeclions include lhe following (2): • Nonin Oammatory processes involving primarily lhe proximal porlion of the sma ll bowel as a resull of an enleroloxin (eg.enleroloxigenic Escherichia coli) or infeclion lhat inlerferes with small bowel absorplion (eg.cryplospo ridium.giarclia.rotavirus.Norwalk-like viruses, CMV.M avium and possib ly 11rv).• lnOammatory dysentery, which involves lhe colon as a resull of invasive infeclion.possibly including a cyloloxin (eg.Shigella .Salmonella and Campyl.obaclerspecies.C difficile or amcbiasis).Included in this category of d isease are lhe various causes of sexu al ly transmilled proclitis (eg.herpes s implex virus, gonococcus .ch lamydia and Treponema pallidu m).• An enteric fever syndrome, which may occur with bacleremic illness, oflen associaled wilh constipation early in the course of lhe disease (eg.Salmonella species, and occasionally campylobacter or yersinia).Patients presenling with lhe noninOammalory diarrhea involving predom inanlly small bowel lend lo have sofl lo watery bowel movemenls.which may be associated wilh midabdominal discomforl. in lhe absence of blood or mucus per rectum.In contrast, inflammato1y dysentery involving the colon or rectum usually results in frequent.smaller volume diarrhea, with or without lower abdominal pain.tenesmus, rectal urgency and blood or mucus per rectum.Fecal leukocytes are usua lly absent in noninflammatory diarrhea, but are often present in inflammatory diarrhea involving the colon or rectum: however.the sensitivity of fecal leukocyte smears for the diagnosis of inllammatory diarrhea is unclear.and has not been evaluated in HIV-infected patients.
The commonly identified causes of chronic diarrhea in AIDS patients include cryplosporidiosis.microsporidiosis, isosporiasis.or intestinal involvement with M avium or cytomegalovirus.No specific etiology is found in 30 to 50% of cases of 1 -nv-related chronic diarrhea.By exclusion.these cases have been diagnosed as idiopathic JJJV enteropalhy (3).although the diagnostic criteria for this entity have been debated (4).and the etiological significance of other enleric viruses such as aslrovirus and picobimavirus has not been detem1ined in HIV-infected patients (5).

CRYPTOSPORIDIOSIS
Cryptosporidiosis is a zoonosis.Both animal to person and person lo person transmission have been documented.Risk factors for c1yplosporidiosis include deficient cellular or humoral immunity, infancy, close contact with infected individuals, travel to developing countries.poor sanila1y facilities and occupational exposure (animal workers and day care centre employees) (6).The infection has also been documented to be waterborne.The two recognized species are Cryplosporidium parvum and Cryptosporidium muris.
Infection of the gastrointestinal tract with cryplosporidium is one of the most common causes of chronic diarrhea in AIDS patients (7) and accounts for considerable morbidity.
A significantly higher mortality rate has been associated with AIDS patients who have cryptosporidiosis compared with those who do not.suggesting that the infection often results in general deterioration (8).The prevalence of cryptosporidiosis is 3 to 4% for AIDS patients in the United Stat.es compared with prevalence as high as 50% in Haiti and Af1ica (7).The disease may affect both the normal and immunocompromised host and usually results in self-limited and chronic disease.respectively.
Clinical presentation includes diarrhea that. is often severe and ranges up to 25 bowel movements per day.The stools are watery, voluminous (up to 20 L/day) and not associated with blood or inflammatory cellular exudate.Frequently there is marked weight loss.and both lactose intolerance and fat.malabsorption have been documented in association with c1yplosporidiosis.In the normal host the infection is usually self-limited with symptoms resolving within two weeks.but.stools remain positive for the organism for an additional two HIV-related diarrhea lo three weeks (9).Chronic c1yplosporidiosis lasting longer than one month in patients without other causes of immunodeficiency is an AIDS-defining illness.Among 111v-infecled individuals with cryptosporidiosis.selflimited disease has been associated with higher CD•t cell counts (mean 312 cells/mm 3 ) compared with those cases of persistent.infection (mean CD4 counts 57 cells/ mm 3 ) (10).Flanigan et.al (10) observed spontaneous resolution of cryplosporidiosis in all patients (n=8) with CD4 counts greater than 180 cells/mm 3 : however.34 of 39 (87%) cases with CD4 counts less than 180 cells/ 111111 3 had persistent.disease.Symptoms of cryplosporicliosis lend to wax and wane even without treatment (11).
Cryplosporidiosis has been shown pathologically lo involve all portions of the gastrointestinal tract from lhe pharynx lo the rectum including the biliary tree.Most often the disease is largely confined lo the small and large intestine.Exlrainleslinal sites of infection have included the biliary tract.pancreatic duel.liver and lung (6).The pathology of cryplosporidiosis is similar lo that seen in giardiasis.including small intestinal changes with epil11elial loss.villou atrophy.crypl elongation and oft.en minimal inflammatory infiltrate in the adjacent lamina propria (6.12).Diagnosis is most readily made by stool smears which may be stained using a number of techniques including modified acid-fast stain.fluorescent auraminerhodaminc slain, pe1iodic acid-Schiff and carbolfuchsin stains (7).The modified acid-fast slain is generally the preferred method for diagnosis.Methods for concen lraling stool samples are usually not required for diagnosis in acute cases.A sodium ch loride layering technique followed by ethyl acetate sedimentation has been shown lo be supe1ior to other concentration methods (13).Radiographs of the bowel in patient with cryptosporidiosis usually show non pecific findings including prominent.mucosa!folds, thickened intestinal wall and disordered motility.lnlestinal biopsy is generally considered lo be less sensitive than stool examinations because of the patchy nature of the discas and the absence of gross signs of inflammation lo help direct the endoscopist.. Intestinal biopsy may reveal the presence of 4 lo 5 µm diameter organisms.which are adherent lo the epithelial surface on the microvilli and which are contained in a vacuole that is considered intracellular.but extracytoplasmic to the enterocyte (7).Management of cryptosporidiosis in AIDS has been mainly supportive (6.7,9).There are now some potentially beneficial anliparasitic agents, but none prov n effective in randomized, placebo controlled, comparative trials.Oral and sometimes intravenous fluid replacement may be required.Antimotilily agents are not always helpful and in some patients may be associat d with increased abdominal cramping (7).Intravenous hyperalimentation is helpful for stabilizing occasional patients but may be inappropriate for terminally ill patients.and is further limited by cost considerations .r,,..r,,.m ()

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• g USE and potential complications.It is believed that the biliary tree may serve as a reservoir for cryptosporidiosis and thereby contributes to recurrent infections because of difficu lty in eradicating the organism from this s ite.A wide range of spec ific treatments has been employed for cryplosporidiosis (6. 7,9.14) wilh some reported clinical and microbiological responses .Favourable responses have been observed in association with paromomycin (15).bovine hyperimmune colostrum (16), and lelrazuril (17).
An important aspect of management is reducing transmission by good hygiene including hand washing and awareness of lhe risks of direct fecal-oral exposure (9).Nosocomial spread of this infection has been documented.

ISOSPORIASIS
lsosporiasis is an uncommon cause of chronic diarrhea in 111v-infected individuals in North America (less than 0.2%) but has been observed in up to 15% of AIDS patients in I laili.ll i clinically indistinguishable from cryptosporidiosis.typically presenting with chronic.watery diarrhea without b lood or mucus.and associated with crampy abdominal pain.nausea and weight loss (18).Stool smears are usually negative for fecal leukocytes, and the diagnosis is established by stool smears (mod ified acid-fast slain or iodine preparation) demonstrating the 25 lo 30 pm diameter oocyst .which are larger than the 5 pm c1yplosporidial cysts.Other means of establishing !.he diagnosis include duodenal aspirate or biopsy in which organisms are demonstrated within the cytoplasm of villous epithelium.ln contras!. lo cryptosporidiosis.most patients respond promptly lo treatment (Table 1).but relapse occurs in approximately 50% without secondary prophylaxis (18).

MICROSPORIDIOSIS
Microsporidiosis is an inleslinal protozoa!infection caused by Enlerocytozoon bieneusi.It has been found to be an import.antcause of chronic diarrhea in 111vinfected patients when routine stool microbiology has been negative (12).Microsporidia are spore-forming.obligate.intracellular protozoan parasites.and the organism resides in lhe cytoplasm of the intestinal epithelial lining cells.The clinical presentation is indistinguishable from that of cryplosporidiosis.with watery.nonbloody diarrhea associated wilh progressive weight loss and usually no fever.Previously lhe diagnosis was usually only established by duodenal or jejuna!biopsy wiU1 the parasite identified on hemalo:>-.'}'linand eosin or Giemsa slain.Electron microscopy has been used lo confirm lhe diagnosis.although in a recent study.light microscopy appeared lo be of similar sensitivity (19) .Recenlly.a practical method using a modified lrichrome slain was reported for the identification of the spores of E bieneusi in fecal samples (20).Optimal lrealmenl for intestinal microsporidiosis has not been

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HIV-related diarrhea established .but responses have been reported wilh melronidazole as well a albendazolc (Table I) (21 .22).I lowever.patients with microsporiclia infection may not have diarrhea.This observation prompted Rabeneck el al (23) to question lhe role of microsporiclia in the pathogenesis of 111v-related chronic diarrhea.

CYTO MEGALOVIRUS COLITIS
CMV disease may occur al any site of the gastrointestinal tract in 111v-infecled patients, but mos t often affects the colon.esophagus.stomach or hcpalobiliary ystem.CMV colitis occurs in approximately 5 to I 0% of AIDS patients.and is usually associated with chronic diarrhea.abdominal pain.anorexia.weight loss and fever (24).Diarrhea is usually nonbloody.although complications may include gastrointestinal hemorrhage or perforation.Diagnosis is most reliably established by the presence of C MV inclusions on intes tinal biopsy specimens.and is supported by lhe presence of CMV antigen or positive biopsy viral cull ure for C MV.The absence of other inleslinal pathogens is also helpful in cslablishing the relationship of gaslroint slinal complaint lo positive findings for C MV .The efficacy of antiviral therapy for CMV disease has not.been documented as clearly for colitis as il has for retinitis.A recent placebo controlled trial showed that ganciclovir lreated patients had improvement in mucosa!abnormalities seen on colonoscopy and some protection acrainst development of new cxtra intestinal C MV disease, compared with placebo.l lowever.clinical e ndpoints (cg.diarrhea.body weight.etc) did not differ between lhe groups (25).Diarrhea response may have been confounded by the use of anlicliarrhea agents in bolh am1s of the study.The need for long lcrm maintenance therapy with ganciclovir or foscarnct has nol been established.but should al least be offered lo those individuals experiencing frequent relapse .which appear lo respond to treatment.

M YCOBACTERIUM AV/UM
M auium infection occurs in 30 to 50% of AIDS patients.usually beginning wilh a lo alizcd ga lrointestinal infection (duodenum.small or large bowel) and frequently followed by dissemination.Macrophages are infected and pathological involvement mainly involves the reticuloendothelial system, including lymph nodes.liver.spleen.bone marrow and gaslroinleslinal tract (26).The clinical presentation of dis eminaled M auium infection often includes fevers, night weals.weight loss and progressive anemia.The presence of abdominal pain and diarrhea without evidence for other enleric pathogens suggests specific gastrointestinal tact involvement, which is often associated with me enteric lymphadenopathy.Intestinal involvement may result in a malabsorption syndrome, similar clinically and pathologically to Whipple's disease except for the presence of macrophages laden wilh acid -fast bacilli including acid-fast stain (5) and modified trichrome stain • ± blood cultures if fever (7) • ± Clostridium difficile culture and toxin assay (6) • ± blood cultures if fever (7)  HIV-related diarrhea (27).Endoscopic biopsy and mycobaclerial cullure are most reliable for establishing lhe diagnosis.The role of slool smears for acid-fasl bacilU in lhe diagnosis of either intestinal or disseminated infection is unclear because of variable sensitivily, and the possibility of mycobacterial colonization and symptoms related lo other etiologies.

BACTERIAL ENTERIC PATHOGENS
Bacterial enleric pathogens should be considered in patients with infiammalory diarrhea: however.approximately half of salmonellosis cases presenl wilh fever in the absence of colitis.Salmonellosis (28) and possibly shigellosis (29) are more likely to be associated with bacteremia in the HIV-infected patient than lhe general population.Unlike the immunocompetenl host, all 111v patients with uncomplicated salmonella gastroenteritis require antimicrobial therapy.Recurrent bacterial enteric infections require long lerm suppressive therapy (Table 1 receiving antimicrobial agents for prophylaxis or treatment.of various opportunistic infections. AIDS ENTEROPATHY Idiopathic Ams-associated enleropalhy has been defined as chronic diarrhea (longer lhan one monlh) associated wilh negative investigations for enleric pathogens.with or wilhou l lhe demonstration of villous atrophy.The negative studies should include stool microbiology, endoscopy and biopsies, as outlined in Figure 1.Possible etio logies for Ams-associated enteropathy include: previously unrecognized or seldom isolated enleric pathogens (5): low grade bacterial overgrowth possibly due lo impaired development of gul B lymphocytes (related lo CD4 lymphocle depletion) and immunoglobulin A production (l); or 111v (30).

MANAGEMENT
Management of rnv-relaled diaiThea is summarized in the algorithm (Figure 1).Treatment of specific.selected enleric pathogens is summarized in Table 1 (31).
Modified trichrome stain Is the optimal method for light microscopy identification of microsporidia in stool and duodenal aspirate sample (N Engl J Med 1992:326:161).Entamoeba histolytica is a nonpathogenic commensal in most infected homosexual men (N Engl J Med 1986;3 l 5: 353), and rarely causes invasive colitis in AIDS patients.

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If recent antibiotic use, then also include C difficile culture and toxin assay.

Figure 1 )
Figure 1) *P/1:'ase see Foolnolcs lo Figure 1 011Jollowi11g page ). C difficile colitis.which appears to be more common in HIV patients, should be considered in those Stool acid-fast staining is needed for identification of cryptosporidium and lsospora be/Ii.However, stool smear for acid-fast bacilli not routinely recommended because of variable results of sensitivity and specificity for true mycobacterial infection versus colonization.Positive stool smear may be more likely than mycobacterial stool culture to reflect invasive infection rather than colonization.CAN J INFECT DIS VOL 5 SUPPL E SEPTEMBER 1994

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Routine blood cultures should be obtained In patients with fever and diarrhea to exclude bacteremia due to salmonella, shigella and campylobacter.Salmonellosls is 20 times more common in AIDS patients and five times more likely to be associated with bacteremia than in the general population (J Infect Dis 1987;156:998).Mycobacterial blood cultures are indicated if persistent or recurrent fever develops in association with CD4 lymphopenia.8.Antidiarrheal agent of c hoice is loperamlde (lmodium), which is not associated with narcotic dependency, but this may occur with diphenoxylate (Lomotil) (Gastroenterology 1980;79:1272).Diarrhea and abdominal cramps respond earlier with loperamide than bismuth subsalicylate (JAMA 1986:255:757).Antimotility agents should usually be avoided in patients with fever or bloody stools, because they may worsen dysentery due to shigella (JAMA 1973;226: 1525) or C difficile (JAMA 1976;235: 1454).Loperamlde dosing: 4 mg Initially, then 2 mg after eac h unformed stool (maximum 16 mg/day).When daily dose established, it may be given as one to four divided doses/day.9. Sigmoidoscopy specimens should include wet mount (E histolytica).Biopsies are obtained for pathology, viral (CMV, adenovirus, herpes simplex virus) and mycobacterial culture.Barium enema and colonoscopy are seldom useful for the investigation of chronic diarrhea In HIV-infected patients (AIDS 1990:4:687)., acid-fast and modified trichrome stains), and biopsies for hematoxylin and eosin, acid-fast.±Giemsa stains looking primarily for protozoa (microsporidia, isospora.giardia), mycobacteria and CMV.Electron microscopy may be helpful for d iagnosis of microsporidiosis but is expensive and usually not necessary (Ninth International Conference on AIDS, 1993, Abst WS-B20-2).A specimen may be prepared for electron microscopy but not examined unless other specimens are nondiagnostic.11.Octreotide (Sandostatin) is a synthetic analogue of somatostatin, and in doses of 50 to 500 ~1g subcutaneously l 0. Upper gastrointestinal endoscopy for duodenal fluid specimens should be sent promptly for parasitology (wet ONLY• IO NOT COPY mount