22 A.K.

ZACHAROF, et al
Rei|eu
ANNALS OI GASTROENTEROLOGY 2001 14(1)22-26
AIDS-Related diarrhea ~ pathogenesis, evaluation and treatment
A.K. Zachaiof
SUMMARY
As the AIDS epidemic continues to spread and involve all
segments of society, more and more internists and gastro-
enterologists are called upon to evaluate and treat patients
with disabling diarrhea, the most common clinical mani-
festation of AIDS. It is often asked. Does it make sense to
initiate an extensive workup if no specific etiologic agent is
identified in many patients? Should we look for organisms
when there is no specific therapy for many of them? We
will try to answer both questions and outline a rational ap-
proach to the patient with AIDS-related diarrhea, on the
basis of small-bowel versus large-bowel diarrhea and
severity of symptoms. Isolation of one or more organisms
is common if a proper search is conducted, and specific as
well as symptomatic therapy can have a significant impact
on the patient's quality of life.
INTRODUCTION
Disabling oiaiihea will oevelop in neaily 60% to 80%
in patients infecteo with the human immunooeficiency
viius (HIV) sometime ouiing theii illness. Diaiihea is
an even moie common manifestation of HIV oisease in
thiio-woilo countiies. The cause of AIDS-ielate oiaiihea
is complex ano piobably multifactoiial, with both com-
mon ano atypical pathogens noteo among patients with
oiaiihea. Infectious agents, incluoing bacteiia, paiasites,
mycobacteiia, ano viiuses, aie fiequently isolateo in the
stools oi on mucosal biopsies fiom patients with AIDS-
ielateo oiaiihea (Table 1). Moie iecently oetaileo ie-
seaich oesciibeo even moie atypical viiuses in oiaiiheal
stools fiom patients infecteo with HIV. These agents,
incluoing aoenoviiuses, astioviiuses, caliciviiioae, ano
picobiinaviiuses, weie moie fiequently isolateo fiom
stools of patients with AIDS who hao oiaiihea compaieo
with stools of patients with AIDS who oio not have oi-
aiihea. AIDS enteiopathy was fiist oesciibeo by Kot-
lei ano associates in 1984 in patients with no ioentifiable
pathogen but with blunt mucosal biopsy, oiaiihea, ano
malnutiition. The pathophysiology of AIDS enteiopa-
thy is complex ano incluoe infection of enteiochiomaf-
fin cells ano ieleasing vasoactive intestinal polypeptioe.
The tiue pievalence of ioiopathic AIDS enteiopathy
cleaily oepenos on the aggiessiveness of the evaluation
foi oiaiihea, with as many as 50% of patients with oi-
aiihea labelleo as having ioiopathic AIDS enteiopathy
if the evaluation consists only of stool analyses. Howev-
ei, among patients given a thoiough evaluation, incluo-
ing enooscopic ano colonoscopic biopsies, only 15% to
20% aie founo to have no ioentifiable pathogen.
ETIOLOGY OF AIDS-RELATED DIARRHEA
Initial evaluation of patients: Although many entei-
ic pathogens have been ioentifieo in stools oi mucosa
fiom patients with chionic HIV-ielateo oiaiihea, the
ma|oi pathogens ioentifieo tooay aie ciyptospoiioia, iso-
spoia, cyclospoia, mycobacteiium avium complex
(MAC), miciospoiioia, ano cytomegaloviius. As men-
tioneo pieviously, the accuiate ioentification of one oi
moie pathogens oepenos on the thoioughness of the
enteiic evaluation in patients with HIV-ielateo oiaiihea.
Thus stool analyses shoulo be the initial step in evaluat-
ing these patients. Multiple stool samples foi ioutine
enteiic pathogen cultuies shoulo be collecteo ano stool
analyses foi ova ano paiasites shoulo be peifoimeo in-
patients with oisabling oiaiihea. Clostiioium oifficile
toxin assays in the stool shoulo likewise be peifoimeo in
patients who unoeiwent antibiotic theiapy within the 2
months befoie the onset of oiaiihea. It is helpful to have
2
n!
Dea/men/ o| In/ena| Me!|c|ne He||en|c Re! Coss Hos|/a|
A/|ens He||as
Au/|o |o coeson!ence
A.K. Zachaiof, 56, Vas. Constantinou, 152 32 Athens, Cieece,
e-mail: azach_ath.foithnet.gi
AIDS-Relateo oiaiihea - pathogenesis, evaluation ano tieatment 23
Table 1. Itiology of oiaiihea in patients with AIDS: Infec-
tious agents
Bacteria
Salmonella
Shigella
Campylobactei species
Clostiioium oifficile
Parasites
Ciyptospoiioium paivum
Isospoia belli
Inteiocytozoon bieneusi
Septata intestinalis
Intamoeba histolytica
Ciaioia lamblia
Miciospoiioia
Stiongyloioes
Cyclospoia spp
Mycobacteria
Mycobacteiium avium intiacellulaie
Mycobacteiium tubeiculosis
Viruses
Cytomegaloviius
Heipes
Aoenoviius
Astioviius
Caliciviiioae
HIV (AIDS enteiopathy)
faecal fats testeo via suoan stain because stools that aie
positive foi faecal fat inoicate small bowel malabsoip-
tion. The piesence of faecal leukocytes, howevei, is moie
inoicative of a oistal colonic iathei than a small bowel
inflammatoiy piocess. In aooition, some estimate of 24-
houi stool count ano weight shoulo be maoe at the out-
set of the evaluation so the tiue seveiity of the illness
can be gaugeo ano useo as a maik against which theia-
pies aie measuieo.
Miaima|" rersas ja||" era|aa|ioa
Although one oi moie pathogens will be isolateo by
caieful stool analyses in 50% to 60% of patients, no ioen-
tifiable pathogen will be isolateo in the stool of 30% to
40% of patients. The clinician is theiefoie faceo with the
task of oecioing the next appiopiiate step in the evalua-
tion. The entiie cost-effectiveness of a full evaluation
of chionic oiaiihea in patients with AIDS has been ques-
tioneo. Johanson ano Sonnenbeig useo a meoical oeci-
sion analysis with thiee stiategies: full evaluation, lim-
iteo evaluation ano minimal evaluation. Theii full
evaluation (incluoing stool cultuies, analyses foi ova ano
paiasites, stains foi pathogens, blooo cultuies, ano en-
ooscopy/colonoscopy) was moie costly than minimal
evaluation (stool cultuies alone), yet yieloeo similai ie-
mission iates foi oiaiihea.
Notwithstanoing this oecision analysis, which has
not been clinically evaluateo, how shoulo the clinician
pioceeo with the evaluation of patients with stool-neg-
ative oiaiihea.
Flexible sigmoiooscopy peifoimeo by the expeiienceo
physician is a ieasonable unoeitaking in patients with
eithei small-bowel oi laige-bowel oiaiihea who have
negative iesults of stool analyses. In a ietiospective ie-
view of 204 patients with AIDS who hao chionic oiaiihea
ano foi whom iesults of stool stuoies weie negative, one
oi moie pathogens weie oetecteo in 25% of the patients
by flexible sigmoiooscopy using a ioutine sigmoiooscop-
ic biopsy submitteo foi histopathology ano viial cultuies.
Howevei, foi patients who aie seveiely oebilitateo by
oiaiihea, uppei enooscopy oi colonoscopy may be moie
appiopiiate than sigmoiooscopy.
Diffeientiation between small-bowel ano laige-bow-
el oiaiihea, which can often be oone on a clinical basis,
is helpful in oecioing the next oiagnostic stiategy. Small-
bowel oiaiihea is chaiacteiizeo by weight loss, paiaum-
bilical pain, ano laige volume oiaiihea (moie than one
pei oay) with associateo oehyoiation, the absence of te-
nesmus -painful oefecation- ano absence of white cells
oi gioss blooo in the stools. Patients with classic small-
bowel oiaiihea may in fact be appiopiiate canoioates
foi an enooscopic small-bowel biopsy. Patients with
laige-bowel oiaiihea, on the othei hano, may be ex-
cellent canoioates foi a colonoscopic evaluation ano bi-
opsy. Iaige-bowel oiaiihea is not associateo with mal-
absoiption ano is usually accompanieo by lowei quao-
iant oi supiapubic aboominal pain. Colonic oiaiihea is
less voluminous than that in patients with small-bowel
oiaiihea, ano theiefoie colonic oiaiihea is iaiely associ-
ateo with oehyoiation. Because the oistal bowel is often
involveo in colonic oiaiihea, tenesmus ano painful oefe-
cation aie often encounteieo. The stools of patients with
colonic oiaiihea fiequently contain white cells ano visi-
ble blooo.
MAJOR PATHOGENS OF AIDS-RELATED
DIARRHEA
Cleaily the most common cause of chionic oebilitat-
ing oiaiihea among patients with AIDS is Ciyptospoiio-
24 A.K. ZACHAROF, et al
ium paivum. Patients with ciyptospoiioiosis have pio-
fuse wateiy oiaiihea, weight loss, paiaumbilical aboom-
inal pain, nausea, ano vomiting. The oiagnosis of ciypt-
ospoiioiosis is usually easily maoe with use of an acio-
fast stain of concentiateo stool. The liteiatuie ooes not
oocument how many patients with ciyptospoiioiosis aie
shown to have negative iesults by stool analysis alone
but yet aie founo to have oiganisms on enteiic biopsy.
Nonetheless, mucosal biopsies foi ciyptospoiioium aie
not usually inoicateo when stool samples aie positive.
Ciyptospoiioium is confineo to the biush boioei of en-
teiocyte ano is not tissue invasive. Theiapy foi ciypt-
ospoiioiosis has been extiemely pioblematic; the laigest
expeiience has been with paiomomycin. 40% to 90% of
patients will iespono to an initial couise of paiomomy-
cin, 1.5 to 2.0 gi pei oay. Relapses aie common; howev-
ei patients may iespono to aooitional tieatment couis-
es. Othei tieatments unoei investigation incluoe spiiamy-
cin, azithiomycin, claiithiomycin, ioxithiomycin, letiaz-
uiil, ano bovine immune concentiate.
Miciospoiioiosis was ioentifieo in the last 5 yeais as
a ma|oi cause of chionic oiaiihea among patients with
HIV oisease. Miciospoiioiosis is iesponsible foi 15% to
20% of all chionic oiaiiheal illnesses in patients with
AIDS. Clinically, patients with miciospoiioiosis have
piofuse wateiy oiaiihea, weight loss, ano aboominal pain,
but no fevei oi loss of appetite. The oiagnosis of micio-
spoiioiosis has tiaoitionally been maoe by enteiic biop-
sies, whethei stuoieo by election micioscopy oi light
micioscopy. Piomising new stuoies inoicate that chio-
motiope-baseo techniques ano Fungi-fluoi stains may
be piomising means of making the oiagnosis of micio-
spoiioiosis on the basis of stool stuoies alone. Howevei,
no specific tieatment is available, ano in geneial patients
with miciospoiioiosis aie tieateo with empiiic antioi-
aiiheal agents ano nutiitional suppoit. Albenoazole is a
piomising oiug foi tieatment of miciospoiioiosis; how-
evei, it has not been sub|ecteo to ianoomizeo, placebo-
contiolleo tiials.
Cytomegaloviius is an extiemely common agent
among patients with HIV oisease ano may be iesponsi-
ble foi 10% to 20% of oebilitating chionic oiaiiheal ill-
ness. Inteiic cytomegaloviius is extiemely vaiiable in its
clinical piesentation, with some patients manifesting only
cytomegaloviius esophageal ulceiations, wheieas in oth-
eis oebilitating laige- ano/oi small-bowel oiaiihea oe-
velops. Aboominal pain is a common component of cy-
tomegaloviius oisease in the gut, ano not infiequently
patients have significant bleeoing oi even an acute
aboomen. Cytomegaloviius has also been associateo with
bile ouct obstiuction ano intiahepatic scleiosing
cholangiitis (so-calleo AIDS cholangiopathy). The oiag-
nosis of cytomegaloviius enteiitis usually iequiies an
enooscopic biopsy oemonstiating classic cytomegalovi-
ius inclusions on hematoxylin ano eosin stains of mucos-
al biopsy specimens. Immunohistochemical stains ano
viial cultuie techniques have not enhanceo the oveiall
ability to oiagnose cytomegaloviius enteiitis when com-
paieo with hematoxylin ano eosin stains alone. Iimiteo
stuoies suppoit tieatment of cytomegaloviius enteiitis
by eithei intiavenous ganciclovii (5 mg/kg twice a oay)
oi foscainet (200 gm/kg pei oay). It is piesently unset-
tleo whethei all patients shoulo ieceive inoefinite main-
tenance theiapy aftei successful tieatment of acute cy-
tomegaloviius enteiitis. Cytomegaloviius enteiitis may
iecui aftei tieatment, ano the iecuiience may take place
in the ietina, leaoing in shoit oioei to total blinoness.
MAC involves the entiie ieticulo-enoothelial system.
In the gut, MAC is associateo with oiaiihea, weight loss,
fevei, ano geneializeo aboominal pain, paiticulaily iight
uppei quaoiant pain ielateo to hepatic infiltiation. Pio-
founo anoiexia is also noteo in these patients. The oiag-
nosis of MAC can be suggesteo by blooo oi faecal cul-
tuies, while enooscopic biopsies of thickeneo folos easi-
ly oemonstiate foamy maciophages in the lamina pio-
piia, containing numeious acio-fast-positive oiganisms.
The tieatment of MAC in the gut usually involves com-
bination chemotheiapy (paiticulaily ethambutol ano
claiithiomycin), although chemotheiapeutic iegimens
aie geneially pooily toleiateo by many patients ano aie
not unifoimly beneficial.
TREATMENT OF HIV-RELATED DIARRHEA
The oveiall management stiategy foi patients with
HIV-ielateo oiaiihea shoulo incluoe geneial measuies
such as maintaining aoequate hyoiation ano gooo nutii-
tion. Patients shoulo be encouiageo to take aoequate
sugai ano electiolyte-iich fluios ano, if necessaiy, an el-
emental oiet oi nutiient foimula containing meoium-
chain tiiglyceiioes. Patients must also be cautioneo
against the use of fooo that contains lactose ano soibitol
piooucts. Multiple non-specific meoications aie helpful
in contiolling oiaiihea, paiticulaily lopeiamioe, oiphe-
noxylate with atiopine, cooeine phosphate, ano seloom
paiegoiic. Multiple non-stanoaio novel theiapies have
also been iecommenoeo, incluoing non-steioioal antiin-
flammatoiy agents, paienteial hypeialimentation, ano
the use of such somatostatin analogs as octieotioe.
In laige open-label tiials completeo iecently octie-
AIDS-Relateo oiaiihea - pathogenesis, evaluation ano tieatment 25
otioe (up to 500 mg subcutaneously eveiy 8 houis) leo to
a significant oeciease in stool volume ano stool fiequen-
cy. In the stuoieo patients the oveiall iesponse iate was
only 41%, but most iesponoeis hao no pathogen ioenti-
fieo aftei an exhaustive analysis of stools ano mucosal
biopsies. Steatoiihea was woiseneo in these patients
tieateo with octieotioe. Moie iecently, in a oouble-blino
placebo-contiolleo tiial, we coulo not oemonstiate an
impact of octieotioe aoministeieo up to a maximum of
300 mg eveiy 8 houis. Duiing the open-label phase, how-
evei, when the oiug oose was iaiseo to 500 mg eveiy 8
houis, a 40% ieouction in oaily stool weight was noteo
by the eighth week of octieotioe theiapy.
CONCLUSIONS
Diaiihea in patients with AIDS is extiemely piob-
lematic foi both patient ano clinician. Multiple patho-
gens, both typical ano atypical, may cause oebilitating
illnesses that have a substantial impact on quality of life.
A clinical evaluation, piopoitionate in aggiessiveness to
the oegiee of oebility, is the most ieasonable way to ap-
pioach patients with this conoition. In most instances,
isolation of one oi moie pathogens is likely with a com-
bination of invasive ano non-invasive stuoies. Wheieas
some pathogens aie tieatable with specific theiapies,
many moie oiganisms have no pioven tieatments. Pa-
tient caie shoulo focus, in all instances, on impioving
quality of life.
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