PO Box 2345, Beijing 100023, China Fax: +86-10-85381893 E-mail: wjg@wjgnet.com www.wjgnet.

com

World J Gastroentero, 2000; 6(2):177-186 World Journal of Gastroenterology Copyright2000 by the WJG Press ISSN 1007-9327

Etiology and evaluation of diarrhea in AIDS: a global perspective at the millennium

C. Mel Wilcox
Subject headings acquired immunodeficiency syndrome/etiology; acquired immunodeficiency syndrome/complications; diarrhea; HIV; immunocompetense; endoscopy
Wilcox CM. Etiology and evaluation of diarrhea in AIDS: a global perspective at the millennium. World J Gastroenterol, 2000;6(2):177-186

INTRODUCTION

It has now been almost 20 years since the initial descriptions of a heretofore unrecognized disorder afflicting homosexual men and manifesting as Pneumocystis carinii pneumonia and Kaposis sarcoma. With the identification of the human immunodeficiency virus (HIV) as the etiology of this syndrome, there has been exponential growth in our understanding of this devastating immune disorder. During the first decade of the acquired immunodeficiency syndrome (AIDS), there was an explosion of cases in the United States and Africa. Subsequently, there have be en successive waves of the epidemic throughout the world with cases now documented in essentially all countries. Elucidation of the infectious etiology and routes of transmission of HIV have provided opportunities for population-based preventative measures. Although these measures have been highly successful in many developed countries, the number of new cases worldwide still remains staggering. It is estimated that approximately 1 million people in the United States are HIV-infected. As of 1998 alone, more than 33 million people were infected with the AIDS virus worldwide with almost 6 million new cases occurring in 1998, representing approximately 16000 new cases each day, the majority of these occurring in developing countries[1]. By the year 2000, it is estimated that there will be almost 40 million HIV-infected people throughout the world. The epidemic currently inflicts a heavy human and economic toll on sub-Saharan Africa, and although the number of cases is currently small, the Russin and China could potentially be poised for the next
Department of Medicine, Division of Gastroenterology and Hepatology, Center for AIDS Research, University of Alabama at Birmingham, Birmingham, Alabama Presented in part at Digestive Disease Week Thailand, December 17, 1999, Chiang Mai, Thailand. Correspondence to: C. Mel Wilcox, M.D., University of Alabama at Birmingham, Division of Gastroenterology & Hepatology, Birmingham, AL 35294-0007, USA Tel. (205)-975-4958, Fax. (205)-934-1546 Email. mel_wilcox@gihep.uab.edu Received 2000-02-13 Accepted 2000-03-06

wave of the epidemic. Given their present rate of infection, the Indian subcontinent and southeast Asia will likely bare the greatest burden of the disease early in the 21st century. Since the initial descriptions, it was recognized that chronic diarrhea was one of the most common and debilitating complications of HIV infection, occurring in about 50% of patients in North America and in up to 100% of patients residing in developing countries [2-4] . Chronic diarrhea is important in these patients because it results in significant morbidity and mortality, reduced quality of life, and higher health care costs[5]. In the early stages of immunod eficiency, HIV-infected patients are susceptible to the same enteric pathogens that cause diarrhea in the immunocompetent host. However, as immunodeficiency progresses, these patients become susceptible to a wide variety of opportunistic infections (OI) many of which have a predilection for the gut [1-3,5]. In general, most opportunistic disorders are not observed until the CD4 count falls below 200106 cells/L, and usually <100106 cells/L[4,6]. Across all continents, the introduction and rapid implementation of potent comb ination antiretroviral therapy, termed highly active antiretroviral therapy (HAA RT), has profoundly affected the incidence and complications of AIDS including diarrhea. Cohort studies have clearly shown a fall in AIDS-related OI, hospital admissions as well as mortality rate of HIV-infected patients which began several years prior to 1996, the time when protease inhibitors were released[7-10]. These changes which occurred prior to protease inhibitors may be the result of combination therapy with reverse transcriptase inhibitors which have modest efficacy in reducing HIV RNA levels[10]. Since 1996, however, there has bee n even more substantial improvement in these outcomes. Although expensive, HAART appears to be cost-effective given the reduction in the number of hospital admissions and AIDS-related complications [11] . When effective, these drug regimens markedly and rapidly reduce HIV RNA while the CD4 lymphocyte count rises[12]. Studies which examine viral burden and architecture of lymph nodes have also demonstrated salutory effects of HAART [13]. Tangible evidence of immune reconstitution is that prophylaxis against Pneumocystis carinii pneumonia may be discontinued in patients who have an excellent

178

ISSN 1007-9327

CN 14-1018/R

World J Gastroentero April 2000 Volume 6 Number 2

virologic response to HAART an d a sustained rise in CD4 count to greater than 200106/L[14]. However, patients who have receive d multiple antiretroviral agents but who have persistently high level HIV viremi a will not have such profound immunologic and virological effects with these new regimens due to drug-resistance[15]. As the immune status of HIV-infected patients improves with HAART, they become less prone to opportunistic disorders and the infectious etiologies of diarrhea parallel that observed in immunocom petent patients. Nevertheless, several antiretroviral agents, particularly the protease inhibitors, can themselves cause diarrhea[16]. Thus because of HAART, the number of patients in whom OI are identified as causes of diarrhea has fallen while the frequency of unexplained and drug-induced diarrhea appears to be rising[17]. The identification of enteric pathogens in patients with diarrhea is important since a number of efficacious antimicrobial therapies are available[18]. Also, the use of HAART as primary therapy of OI represents a new paradigm for management; when effective in raising the CD4 count and lowering HIV RNA levels, OI may competely remit with HAART alone[19-20]. To best identify these OI, various approaches for the workup- of diarrhea in AIDS have been proposed[6,21-25]. However, the diagnostic methods often differ between studies making comparisons difficult. In addition, most of these diagnostic algorithms were derived in developed countries where endoscopy and mucosal biopsy is widely available, and are therefore not universally applicable. As we enter the new millennium, it seems appropriate to highlight changing concepts related to the etiology and evaluation of diarrhea in HIVinfected patients. Given that the spectrum of pathogens differs geographically and the resources for diagnostic evaluation vary widely, contrasts will be drawn based on these epidemiological and economic differences where applicable and where data is avail able to draw meaningful distinctions.
ETIOLOGY

developing countries[27,28]. Cryptosporidia is the most frequently identified parasitic cause of diarrhea throughout the world[23,26,29]. Cytomegalo virus (CMV), cryptosporidiosis, microsp-oridia and Mycobacterium avium complex (MAC) the classic gastrointestinal OI of AIDS become important pathogens when immunodefici-ency is advanced. AIDS-related neoplasms such as Kaposis sarcoma or lymphoma and fungi rarely cause diarrhea. As noted above, medications, usually protease inhibitors, have recently become important causes of diarrhea[16].
Table 1 Enteric pathogens in AIDS
Viruses Cytomegalovirus Astrovirus Picornavirus Coronavirus Rotavirus Herpesvirus Adenovirus Small round virus HIV Bacteria and mycobacteria Salmonella Shigella Campylobacter Clostridium difficile Treponema pallidum Spirochaetes Neisseria gonorrheae Vibrio cholerae Pseudomonas ? Staphylococcus aureus Mycobacterium avium-complex Mycobacterium tuberculosis Parasites Giardia lamblia Entamoeba histolytica Microsporidia - Enterocytozoon bieneusi - Encephalocytozoon intestinalis Cyclospora Cryptosporidium Isospora belli Blastocystis hominis? Fungi Histoplasma Candida albicans

Viral

The infectious causes of diarrhea in AIDS are extensive ( Table 1 ), and the most important etiologic agents will be briefly discussed individually focusing on geographic differences in prevalence. Worldwide, the most common causes of diarrhea in HIV-infected patients are enteric bacteria including Shigella flexneri, Salmonella enteritidis, and Campylobacter jejuni. In contrast to the normal host, these bacteria have been identified in stool from patients with chronic diarrhea [23,26,29] . Clostridium difficile is a prevalent pathogen typically reported in developed countries, whereas tuberculosis is a common complication of AIDS in

CMV is one of the most common OI in AIDS patients from developed countries presenting late in the course of HIV infection; the median CD4 count in most reports is <50106 cells/L and the CD4 count is <100106 cells/L in almost all patients. Amon g patients with AIDS and diarrhea from developed countries, CMV has been identified in gastrointestinal biopsies in as many as 45% of cases[22,30]. In contrast, one study of rectal biopsies from 29 African patients with chronic diarrhea and abnormal appearing rectal mucosa did not identify any patients histologically with CMV [31]. It is unclear whether CMV is less commonly reported

Wilcox CM. AIDS: global pespective

179

from developing countries due to the infrequent use of endoscopy or true differences in in fection. Another explanation for geographic disparities in the prevalence of CM V disease is the fact that AIDS patients from developing countries often die before immunodeficiency becomes so advanced that CMV manifests. Other viruses have been identified in stool from AIDS patients with chronic diarrhea including adenovirus, rotavirus, astrovirus, picobirna virus and coronavirus[32,33]; given the lack of specific therapy, the clinical relevance of these viruses is unclear (Table 2). There are also reports that HIV itself can be isolated from and identified in enterocytes and colonic cells, and that HIV may have a direct cytopathic effect on the intestinal mucosa causing an enteropathy.
Table 2 Laboratory tests used to investigate diarrhea in HIV infected patients
Stool studies Stool cultures ( Salmonella, Shigella, Campylobacter ) Toxin ( Clostridium difficile) Stool for ova and parasites ( Giardia lamblia, Entamoeba histolytica ) (using saline, iodine, trichrome and acid-fast stains) Stool stains: a. Modified Kinyoun acid-fast (Cryptosporidium and Isospora belli) b. Concentrated stool (Zinc sulfate, Shether sucrose flotation) Fecal fat Giardia antigen Blood studies CD4 cell count White blood cell and differential Creatinine, electrolytes Liver function tests Total albumin Blood cultures (Mycobacterium avium -complex) Tissue and fluids Duodenal aspirate ( Giardia lamblia, microsporidia) Biopsy: duodenum, jejunum, ileum, colon, rectum Biopsy stains: a. Hematoxylin-eosin b. Giemsa or methenamine silver (fungi) c. Methylene blue-azure II-basic fuchsin (microsporidia) d. Fite (mycobacteria) Immunohistochemical stains (Cytomegalovirus) In-situ hybridization (CMV) DNA amplification (CMV) Electron microscopy for cryptosopridia, adenovirus Touch preparation Culture of colonic mucosal biopsy a. Cytomegalovirus b. Herpes simplex virus c. Bacteria

HIV-infected patients from developed countries likely because of these patients frequent exposure to antimicrobials and requirement for hospitalization[36]. Small bowel bacterial overgrowth does not appear to be common in AIDS patients with chronic diarrhea[37]. Mycobacterium avium complex (MAC) is a common pathogen in AIDS patients with advanced immunosuppression; up to 39% of patients from the USA may develop this infection when the CD4 count remains <10106 cells/L[38]. MAC infection has been less frequently reported in AIDS patients with diarrhea from developing countries[27]. This apparent infrequency of MAC in third world countries is likely multifactorial and may relate to the fact that this infection is usually diagnosed by blood cultures or, like CMV, that patients from these countries die from other causes such as tuberculosis (TB) prior to developing such advanced immunosuppression required for MAC infection. The presentation of TB in AIDS is well recogniz ed to be different and often extrapulmonary. Autopsy studies suggest that the g astrointestinal tract is commonly involved in disseminated TB and such involvement can result in gastrointestinal symptoms including diarrhea[28]. In contrast to MAC, TB can manifest with less advanced immune deficiency, and CD4 cell counts may exceed 200106 cells/L.
Parasites

Bacterial and mycobacterial

The spectrum of bacterial pathogens causing diarrhea in HIV-infected patients is similar to the normal host. When comparing studies from throughout the world, no important differences, with the exception of -C. difficile, in the spectrum of bacterial infections are apparent. The most frequently identified pathogens are Campylobacter, Salmonella, Shigella[23,26,34]. Yersinia enterocolitica, Staphylococcus aureus, and Aeromonas hydrophila have also been associated with severe enterocolitis in HIV-infected patients[35]. C. difficile colitis is a frequent cause of diarrhea in

Among the protozoa, Cryptosporidium parvum is the most frequently identif ied parasite causing chronic diarrhea in AIDS even in developed countries[4,29,39]. Cryptosporidia is a very important cause of diarrhea in developing countries where prevalence rates of 20% are commonly reported[40]. This high prevalence perhaps is due to the fact that contaminated water is a common source for this pathogen[41]. Although a cause of acute diarrhea, cryptosporidiosis is typically identified in HIVinfected patients with chronic diarrhea. Microsporidia ( Enterocytozoon bieneusi and Encephalitozoon int estinalis) are now recognized as important causes of diarrhea in AIDS patients[39-42]. In some studies of HIV-infected patients with chronic diarrhea, microsporidia are the most commonly identified pathogens. In a study from New York[43], microsporidia were found in 39% of AIDS patients undergoing gastrointestinal evaluation for diarrhea; however, in other areas throughout the world and even the USA[44], this pathogen is rarely identified even in patients undergoing small bowel biopsy. These geographic differences, both globally and in the same country, in the prevalence of microsporidiosis are unexplained. Isospora belli is a rare gastrointestinal pathogen in HIV-infected in North America, whereas it is endemic in some developing countries such as Haiti[40]. The infrequency observed in

180

ISSN 1007-9327

CN 14-1018/R

World J Gastroentero April 2000 Volume 6 Number 2

developed countries has been attributed to widespread Pneumocystis carinii prophylaxis with trimethoprimsulfamethoxazole which is highly effective in the treatment of Isospora. Cyclos pora have also been identified in HIV-infected patients with chronic diarrhea most often from developing countries[45]. Despite a high frequency of stool carriage in asymptomatic homosexual men, amebic dysentery or invasive amebic disease (ameboma or liver abscess) have been rarely reported in HIV-infected patients, even from developing countries[46]. Stool carriage of ameba in HIV-infected patients is not only limited to non-pathogenic strains of ameba such as E. dispar, E. hartmanii and E. coli, but also to non-pathog enic E. histolytica[47]. Giardiasis is neither more common nor more severe among patients with AIDS than in the non-immunocompromised host and geographic differences in prevalence have not b een reported[4]. Helminths are rare causes of diarrheal disease but hav e been recognized most often in third world countries.
CLINICAL PRESENTATION An overview

When evaluating the HIV-infected patient with diarrhea, one should first attempt to determine the site of origin of the diarrhea, i.e., small bowel (ent eritis) or colon (colitis), and the clinical history alone may be helpful[48]. Not only will localizing the site of origin of diarrhea direct the diagnostic evaluation, but most pathogens have predilections for specific organs. For example, microsporidia and Giardia result in small bowel disease whereas bacteria cause colonic disease. Enteritis is classically manifested as large volume (often >2 L/d) watery stools, often associated with dehydration, electrolyte disturbances, malabsorption, and weight loss. Abdominal pain, when present, is usually crampy and periumbilical in location. Symptoms such as nausea, vomiting, bloating, distention, and borborygmi are also commonly associated with a small bowel diarrhea. In contrast, colitis is characterized by frequent, small volume stools, which m ay contain mucus, pus and/or blood, and is often accompanied by proctitis symptoms tenesmus, frequency, urgency, dyschezia and proctalgia. Abdominal pain is typical for colitis and tends to be localized to the lower abdomen. When colitis is severe, abdominal pain can be marked suggesting an acute abdomen. Fever is common with a systemic infection (e.g. MAC) or bacterial colitis. A fundoscopic examination may demonstrate retinitis consistent with CMV. The value of clinical parameters for tailoring the work-up of diarrhea remains controversial. Wilcox et al[48] demonstrated that the clinical presentation and severity of immunodeficiency were useful in predicting which patients with negative

stool tests may benefit from endoscopic examination. In this study[48], patients with no identifiable pathogen after endoscopic examination had less systemic symptoms (weight loss) and a higher CD4 count. Indeed, diarrhea remained un explained in patients who had not lost weight, and no OI was found in those patients with a CD4 > 50106 cells/L. Connolly et al[49]) also identified factors in a similar patient population which appeared to predict the presence of a gastrointestinal infection by endoscopic evaluation including weight loss[49]. In a later study from the same group, however, Blanshard et al[23] questioned the usefulness of clinical parameters. That study[23] concluded that the presenting clinical features and hematological and biochemical parameters could predict neither the presence nor site of pathogens. Although there were significant differ ences in CD4 counts, stool volumes, and weight loss between the patients with and without an identified pathogen, there was such a large overlap that these clinical features could not be reliably used to identify those patients most likely to have a pathogen[23]. The only presenting symptom and physical finding that was statistically significantly different between the two groups was the presence of abdominal pain, and this was most common in patients with CMV. Surprisingly, weight loss and malabsorption did not correlate with the presence of small bowel pathogens. In contrast to the clinical presentation alone, however, all studies support the value of the CD4 count in stratifying the risk for opportunistic disorders part icularly for patients with no prior AIDS-defining illness[6,23,26,50]. When blood testing is not widely available, surrogate markers of severe immuno compromise may be helpful to stratify risk including the presence of thrush, oral hairy leukoplakia, or the wasting syndrome. In summary, although all studies have not come to similar conclusions, history and physical examination remain an important part of the assessment of the patients general condition and hydration status and may help prioritize the evaluation.
CLINICAL MANIFESTATIONS BY ETIOLOGY Viral

CMV infection of the colon characteristically presents with chronic watery diarrhea, abdominal pain, wasting, anorexia, weight loss [51], and abdominal pain is an important clue to the diagnosis[23]. Fever is not universal. Small bowel infection with CMV is far less common than colonic disease. The diarrheal stools may be semiformed or formed and may be accompanied by gross bleeding and fecal leukocytes. Lower gastrointestinal hemorrhage without diarrhea may be the initial manifestation and results from either severe colitis or isolated well circumscr ibed ulcers[52]. When the

Wilcox CM. AIDS: global pespective

181

distal colorectum is involved, symptoms of proctitis are often reported. Toxic megacolon, intestinal perforation, mass lesions and colonic stricture have also been observed as complications of CMV enterocolitis[53]. Localized or diffuse pain may be elicited on abdominal examination. Other physical findings are non-specific, and will primarily reflect CMV-related complications such as dehydration, perforation (acute abdomen), gas trointestinal bleeding, or altered vision (retinitis). The most common colonic manifestation of HSV in HIV-infected patients is distal proctitis, which may be misinterpreted as diarrhea. If the disease extends to the proximal colon (very rare), proctocolitis with hematochezia and diarrhea may result[53]. Other viruses such as astrovirus, adenovirus, picobirnavirus have been associated with chronic watery diarrhea[32,33].
Bacteria

present as chronic diarrheal illness. Most commonly, gastrointestinal TB is identified incidentally at the time of autopsy in patients with disseminated disease[28].
Parasites

Cryptosporidia, microsporidia, cyclospora and Isospora belli are associate d with chronic, watery diarrhea, dehydration, malabsorption and weight loss- features typical for a severe small bowel diarrhea. Cryptosporidiosis is more severe in patients with marked immunosuppression, but is generally self200106 cells/L[6]. limited if the CD4 count is The disease may be par ticularly devastating in developing countries. Overall, diarrhea due to microsp oridiosis tends to be less severe than with cryptosporidia; weight loss is variable. Giardiasis characteristically presents with chronic diarrhea, abdominal bloating, borborygmi and intermittent abdominal pain.
TOOLS FOR INVESTIGATION

Although bacterial enterocolitis can occur at any stage of immunodeficiency, unusual presentations of these enteric bacteria became apparent early in the AIDS epidemic where Salmonellasp. [54] and Campylobacter sp. bacteremia[53] were reported as initial manifestations of AIDS. In general, however, the clinical presentation of these organisms in AIDS is similar to immunocompetent patients except that diarrhea may be chronic. Bacterial enterocolitis usually manifests a s an acute diarrheal illness (less than 2 weeks duration). Salmonella gastro enteritis more commonly presents with watery diarrhea, abdominal pain, fever, na usea and vomiting but can manifest as an enteric fever. Shigella and Camp ylobacter usually present as a dysentery with the classic colitis symptoms mucopurulent bloody diarrhea, tenesmus and fever. Lower abdominal pain and f ever may be prom inent, while nausea and vomiting are infrequent. Physical findings include fever, tachycardia and abdominal pain which may be severe. Digital rectal examination may demonstrate frank blood or pus. Initial experience suggested that the clinical presentation of C. difficile-colitis was different in the HIV-infected patient[55], but prospective studies have shown no differences as compared to nonimmunocompromised patients[56]. C. difficile can present fulminantly without diarrhea with clinical signs of peritonitis or even ascites[53]. The most common manifestations of MAC infection are fever, wasting, chronic diarrhea, abdominal pain, night sweats and intestinal malabsorption[4]. Frank colitis or hematochezia, which may be massive, are both rare presentations of gastrointestinal MAC infection[53]. Although gastrointestinal tube rculosis may be symptomatic, the clinical picture is often dominated by fever and wasting and/or pulmonary disease [27] . It is extraordinarily unusual for gastrointestinal TB to

Perhaps the most important assessment in the evaluation of diarrhea in HIV-infected patients is the CD4 count, because the absolute value reflects the patients stage of immunodeficiency thereby stratifying the risk for OI. As noted above, clinical surrogate markers, when present, can also be used to guage the degree of immunodeficiency. Since most opportunistic disorders are not observed until the CD4 count falls below 200106 cells/L, and usually <100106 cells/L, the method and extent of evaluation will depend on the absolute CD4 count. For example, if the CD4 count is higher than 100106 cells/L, evaluation for MAC is not necessary given that MAC infection occurs primarily when the CD4 count is <50106/L. Likewise, the yield of endoscopy for OI in a patient with a CD4 count > 200106/L will be very low[48,50]. Numerous stool culture media, histopathological stains of mucosal biopsies and molecular tools (e.g. polymerase chain reaction) have been employed to identify infectious agents as the cause of diarrhea in HIV-infected patients[57-60]. The list of diagnostic tests to evaluate diarrhea in HIV-infected patients is extensive (Table 3); however, rarely will it be necessary to use more than a few of these tests. Limited resources will also play an important role in defining the extent of the diagnostic evaluation. Local epidemiology o f infections should also dictate the approach.
Stool studies

Stool staining for fecal leukocytes with methylene blue is useful as their presence suggests an inflammatory origin of the diarrhea (colitis) and may help predi ct the presence of a colonic pathogen and yield of proctoscopy[48]. Sto ol cultures for Salmonella, Shigella and Campylobacter should be

182

ISSN 1007-9327

CN 14-1018/R

World J Gastroentero April 2000 Volume 6 Number 2

routinely submitted, even in patients with chronic diarrhea. A-C. difficile toxin screen is appropriate in developed countries and those at risk. Blanshard et al[23] has shown that the yield of stool cultures increases with multiple stool samples. They found that the yield of one stool culture was 18%, 3 stool cultures 38.7%, and 6 stool cultures 46.7%[23]. Culturing of colonic mucosal biopsies for enteric bacterial pathogens does not significantly increase the diagnostic yield[61]. Add itional stool tests should include ova and parasite examination, a modified acid fast stain to evaluate for cryptosporidia, Isospora and cyclospora and appropri ate staining for microsporidia. Giardiasis may be difficult to detect on routine stool ova and parasite examination; a stool antigen test for Giardia is now available[62]. As with any diagnostic strategy, the tests ordered should reflect the likely cause of infection, and in the HIVinfected patient, the history and immune status are most helpful.
Table 3 Drugs used in the therapy of diarrhea in AIDS
Condition Cytomegalovirus Herpes simplex Treatment Dosage Duration

antigenemia as a diagnostic test or predictor of subsequent disease of the gut has been best studied in the transplantation setting where high level CMV antigenemia seems to be p redictive of subsequent clinical disease[63]. In addition, when disease is active, CMV antigenemia is also usually present. Although CMV antigenemia is common in HIV-infected patients, particularly in those with advanced immunod eficiency, the diagnostic value for the symptomatic patient as well as the predictive value for subsequent gastrointestinal disease remains unknown. Positive cultures of blood or bone marrow biopsy establish the diagnosis of disseminated MAC, but do not prove active gastrointestinal involvement. Entamoeba antibody titer (ELISA ) is only useful for the evaluation of invasive amebiasis (e.g. liver abscess) and not for the diagnosis of amebic dysentery.
Radiographic studies

Cryptosporidia

Ganciclovir 5mg/kg,2/d 2-4wk Foscarnet 90mg/kg,2/d 2-4wk Acyclovir 400-800mg,14d (5/d) Foscarnet 60-90mg/kg,2/d 14d Valacyclovir 500mg,3/d 14d Famciclovir 500mg,2/d 7-10d No definite therapyknown Paromomycin 25-35mg/kg,3/d 14-28d Spiramycin 1g,3/d 14-28d Azithromycin 900mg,1/d 14-28d Letrazuril 50-100mg,1/d 14-28d Bovine colostrum 50g,1/d 14-28d Albendazole 400mg,2/d No definite therapy known Albendazole 400mg,2/d Metronidazole 500mg,3/d TMP-SMX DS 1 tab,4/d TMP-SMX DS 1 tab,4/d Metronidazole 500mg,3/d Metronidazole Iodoquinol 750mg,3/d 650mg,3/d 14-28d

Plain abdominal X-rays are not generally helpful for the evaluation of chronic diarrhea. With severe colitis, however, colonic dilation and thumbprinting of the mucosa may be observed, and computed tomography (CT) may reveal circumfe rential thickening of the wall of the colon with inflammatory infiltration of the mesentery. Barium studies including small bowel follow-through or barium enem a play no role in the evaluation of AIDSrelated diarrhea, but may be useful if Crohns disease is considered. If barium studies are clinically indicated, stool studies must be obtained first as barium interferes with the stool micro scopic examination.
Histology

Microsporidia Septata intestinalis Enterocystozoon

Isospora belli Cyclospora Giardia lamblia Entamoeba histolytica

14-28d 14-28d 10-14d 10-14d 10-14d 10-14d 10-14d 4wk

MAC

Clarithromycin 500mg,2/d EMB, Cipro, RFP Metronidazole Vancomycin Ciprofloxacin TMP-SMX DS Ciprofloxacin Ampicillin Ciprofloxacin Erythromycin 500mg,3/d 250mg,4/d 500mg,2/d 1 tab,4/d 500mg,2/d 500mg,4/d 500mg,2/d 500mg,4/d

Clostridium difficile Salmonella Shigella Campylobacter

10-14d 10-14d 10-14d 10-14d 10-14d 10-14d 10-14d 7-14d

RFP=Rifampicin, EMB=Etrhambutol, TMP-SMX=trimethoprim sulphamethoxazole, DS=double strength.

Blood tests and serology

Serologic studies for CMV antibodies are not diagnostically helpful in AIDS given the high positivity rate in these patients. The role of CMV

Histology plays a primary role in the diagnosis of most mycobacterial, viral and fungal etiologies of diarrhea. Parasitic infections may also be diagnosed histologically but are typically identified first on stool studies. Cytology, culture and in situ hybridization are also reliable diagnostic techniques. Immunohisto chemical stains of mucosal biopsies to confirm various viral infections may be required, but in most cases, their use does not offer an advantage over conventional light microscopy when reviewed by an experienced pathologist[58]. Viral culture of biopsy specimens are generally less sensitive and specific than multiple mucosal biopsies but when positive may help support the histologic findings[64]. Although electron microscopy of small bowel biopsies is considered the gold standard for the diagnosis of microsporidiosis, recent studies have shown hematoxylin and eosin, Gram stain, BrownBrenn, Giemsa, or modified trichrome staining of small bowel biopsies to have sensitivities of 77%83% with specificities approaching 100%[53,59,60]. In one study[60], electron microscopy only resulted in the detection of an additional 4% of cases. These

Wilcox CM. AIDS: global pespective

183

results suggest that the value of electron microscopy over conventional staining techniques for the detection of parasitic pathogens is negligible especially microsporidia.
Endoscopy

A number of studies have investigated the yield and impact of upper and lower en doscopy for the evaluation of diarrhea in AIDS (Tables 4-6). An obvious advantage of endoscopy is that it permits direct visualization of the gut and opportunity for mucosal biopsy. Conversely, the procedure is invasive, expensive and not readily available worldwide. The diagnostic yield of colonoscopy in HIV-infected patients with chronic diarrhea and negative stool studies ranges from 27% to 37%, with CMV being the most common etiology identified (Table 4). Since CMV usually involves the distal colon, sigmoidoscopy with biopsy may represent a sufficient work-up[23,25,48,52]. Nevertheless, in 13%-39% of patients, CMV infection can be limited to the right colon[24,51]. Therefore, if CMV is suspected as the cause of diarrhea and the distal colon is normal at sigmoidoscopy, a full colonoscopy is warranted. It is still not clear whether colonoscopy has a higher yield than flexible sigmoidoscopy for the detection of clinically relevant pathogens in a ddition to CMV[24]. This is an important issue worldwide as a limitede valuation, which includes a rectal biopsy obtained by proctoscopy or sigmoidoscopy, is easier to acquire and more readily available than colonoscopy. The value of upper endoscopy (EGD) for the evaluation of chronic diarrhea has also been demonstrated ( Table 5 ). As with colonoscopy, most studies focus on the diagnostic yield in patients with negative stool tests. The most common organisms detected by EGD and biopsy are cryptosporidia and microsporidia compromis ing > 90% of the identified pathogens. Wilcox et al[48] obtained small bowel biopsies in 48 HIV-infected patients with chronic diarrhea and nondiagnostic stool tests. In this study[48], a potential pathogen was detecte d in 21 patients (44%) with 7 patients (17%) having small bowel disease; microsporidia was most commonly found. In this study, ileal biopsies were not routinely obtained at colonoscopy. In another study patients with previous negative work-up by stool studies underwent duodenal, ileal, and colonic biopsies [50]; cryptosporidia were detected in 53% of biopsies. In contrast to these studies[48,50], Blansh ard et al[23]published their experience using endoscopy (EGD and flexible sigmoidoscopy) with biopsy in conjunction with stool testing as the initial evaluation in patients with chronic diarrhea. The usefulness of first-line endoscopy was demonstrated by the high yield (83%) of potential pathogens identified during the initial evaluation. Although this more aggressive

approach resulted in a high yield, it may not be applicable to most clinical practices. More recently, Kearney et al[25]studied 79 patients with chronic diarrhea and negative stool studies. The authors examined the yield of an endoscopic work-up (EGD and colonoscopy which included biopsies of the terminal ileum) including comparisons of proxi mal and distal colon biopsies. An infection was diagnosed in 22 of 79 patients (28%); biopsy of the left colon yielded an enteric pathogen in 17 of these 22 patients and in 100% of patients (15 of 15) with CMV colitis. Combined colonic and terminal ileal biopsies missed no pathogens. Duodenal biopsies yielded no addit ional pathogens beyond those identified by colonoscopy and terminal ileal biopsy. The authors concluded that for patients with CD4 counts less than 100106 cells/L and negative stool studies, flexible sigmoidoscopy with biopsy was a sufficient initial endos copic evaluation, and if colonoscopy was performed, biopsies of the terminalileum should be obtained.
Table 4 Yield of colonoscopy with biopsy in HIV infected patients with chronic diarrhea
Ref Proximal Connolly* Wilcox Kearney Bini No. pts. 81 48 79 317 Diagnosis Most common dx Distal (No.pts) 34 13 22 116 (42) (27) (100) (37) CMV CMV CMV CMV (12) (11) (15) (75) 32 12 17 60 (55) 33 + 1 1 (30)

Diagnosis expressed as number of patients (%). Numbers under distal and proximal represent number of patients. * patiens with Cryptosporidium on stool testing were excluded, some patients had more than one diagnosis; +CMV and KS in one patient each; biopsy of terminal ileum at time of colonoscopy; pts: patients; dx:disease. Three patients had diagnosis with biopsy at terminal ileum

Table 5 Yield of upper Endoscopy in HIV-infected patients with chronic diarrhea

References Connolly Wilcox Bown Kearney Bini No. pts. 33 48 56 79 442 Diagnosis n(%) Most common dxs 2 (36) 9 (19) 15 (26) 9 (11) 123 (28) Crypto 2 CMV 4 Micro 7, crypto 1 CMV 1 Crypto 6, micro 5 Micro 5 Micro 54 (12%)

Crypto: cryptosporidum; Micro: microsporidium; Dxs:diseases

Table 6 Yield of extensive work up of HIV-infected patients with negative stool studies
Ref Wilcox Kearney Connolly No. pts. 48 79 33 Diagnosis n(%) Most common diagnosis 21 (44) 22 (28) 12 (36) CMV 9 Micro 7 CMV 15 Micro 5 Crypto 5 CMV 4

Crypto: cryptosporidium; Micro: microsporidium.

184

ISSN 1007-9327

CN 14-1018/R

World J Gastroentero April 2000 Volume 6 Number 2

There remains some disagreement on the most cost-effective approach for the evaluation of diarrhea in AIDS, but the published data does provide the evidence to propose a reasonable diagnostic algorithm. Various authors[2,4], and more recently the American Gastroenterology Association[6], have proposed a stepwise approach for the evaluation of chronic diarrhea in AIDS. The first step includes at least three sets of stool samples to investigate for bacterial pathogens (Salmo nella, Campylobacter and Shigella) and parasites (cryptosporidia and microsporid ia). Testing for C. difficile was recommended for patients at risk for this infection (use of antibiotics, recent hospitalization). In HIV-infected patients with a CD4count < 100 106 cells/L and fever, blood cultures should be drawn to investigate for MAC. If these tests are negative, the second step is to perform flexible sigmoidoscopy. Colonoscopy was recommended only in select ed patients (i.e. patients with marked immunosuppression and clinical manife stations of dehydration, wasting, diffuse abdominal pain)[6]. If no etiology was found after steps one and two, EGD with biopsy of the duodenum was recommended to exclude microsporidia and cryptosporidia[6]. Although the available literature demonstrates that both upper and lower endoscopy play a crucial role in the work-up of HIV-patients with chronic diarrhea, the main question is at what point during the work-up should endoscopy be under taken and should both lower and upper endoscopy be performed in the same session. A stepwise approach seems reasonable when evaluating these patients, but it may not be ideal given the high diagnosticyield when performing stool studies combined with upper and lower endoscopy. Nevertheless, this aggressive approach[23] may not be widely applicable given the fact that in routine clinical practice stool studies are relatively inexpensive, noninvasive, and often positive. We still believe stool studies should generally be obtained before endoscopic evaluation. The predictive value of quantitating fecal fat and measuring dxylose absor ption for intestinal disease in HIVinfected patients with chronic diarrhea has not been established. When all tests are negative, symptomatic therapy with antidiarrheal agents is frequently successful in alleviating symptoms[66]. Occasionally, despite antimicrobial treatment of an identified pathogen, the diarrhea may continue. Under this circumstance, further investigations are warranted as the patient may be co-infected with other pathogens or have another cause for the diarrhea. Discontinuation of all antiretroviral agents may help determine if a drug-induce d diarrhea is causative.
CONCLUSIONS AND RECOMMENDATIONS

AIDS. In addition, routine blood tests are useful to evaluate objectively the severity of the diarrhea, such as hydration status and electrolyte disturbances. A markedly elevated white blood cell count may suggest bacterial colitis or a complication such as perforation or intra-abdominal abscess formation. A critical factor that will determine the diagnostic algorithm (s) is the immune status as ref lected by the absolute CD4 count and/or surrogate markers. We believe that a stepwise approach is reasonable and the first step should include stool studies. Although the positivity rate increases with the number of submitted samples, obtaining three or more stool samples is often difficult. We recommend at least one complete set and additional stool samples to further exclude parasitic diseases in the patient who has no localizing symptoms. From the published evidence, it is clear that endoscopy with biopsy should be performed sooner rather than later in patients in whom noninvasive tests are nondiagnostic especially those with CD4 counts <100106 cells/L. When either upper or lower gastrointestinal tract symptoms are present and stool studies are negative, endoscopy directed to the probable or gan of involvement is appropriate. If the patient is undergoing colonoscopy and there is additional suspicion for small intestinal pathogens, an attempt should be made to intubate and biopsy the terminal ileum during colonoscopy, as the yield of detecting microsporidia may be equivalent to EGD with small bowel biopsies[25]. If localizing symptoms are absent and stool studies are negative, the most appropriate test is sigmoidoscopy with biopsy. Emphasis should be placed on the changing epidemiology of diarrhea in AIDS in this era of HAART[67]. Combination antiretroviral therapy has been shown to lead to resolution of diarrhea caused by organisms such as microsporidia and cryptosp oridia[19] and thus represents a new paradigm for the management of OI. In addition, combination antiretroviral therapy improves the immune status of the HIV-infected patient making them less susceptible to opportunistic disorders. For patients receiving HAART, the infectious causes of diarrhea appears to be decreasing, while antiretroviral agents such as protease inhibitors (most commonly nelfinavir) are increasingly important as a cause of diarrhea[17]. The implications of these etiologic changes on the overall management of HIV-infected patients with diarrhea require further study.
THERAPY

A thorough history and physical examination are essential to evaluate the patients general condition and will help focus the work-up of diarrhea in

The objective of this article was to emphasize the investigation of diarrhea in AIDS, therefore the reader is referred to recent publications on the therapy of gastrointestinal infections in AIDS[18,66]. A table with the current drugs and dosages and duration of therapy for the most common gastrointestinal pat hogens is provided (Table 3).

Wilcox CM. AIDS: global pespective

185 1665 Wilcox CM, M-nkemller KE. Treatment of gastrointestinal infections in HIV-infected patients.Aliment Pharmacol Ther, 1997;11:425-443 19 Carr A, Marriott D, Field A, Vasak E, Cooper DA. Treatment of HIV-1 associated microsporidiosis and cryptosporidiosis with combination antiretroviral therapy.Lancet,1998;351:256261 20 OSullivan CE, Drew WL, McMullen DJ, Miner R, Lee JY, Lee Kaslow RA, Lazar JG, Saag MS. Decrease of cytomegalovirus replication in human immunodeficiency virus infected patients after treatment with highly active antiretroviral therapy. J Infect Dis,1999;180:847-849 21 Johanson JF, Sonnenberg A. Efficient management of diarrhea in the acquired immunodeficiency syndrome (AIDS). A medical decision analysis.Ann Intern Med,1990;1:942-948 22 Smith PD, Lane HC, Gill VJ, Manischewitz JF, Guinnan GV, Fauci AS, Masur H. Intestinal infections in patients with the acquired immunodeficiency syndrome (AIDS). Etiology and response to therapy. Ann Intern Med,1988;108: 328-333 23 Blanshard C, Francis N, Gazzard BG. Investigation of chronic diarrhoea in acquired immunodeficiency syndrome. A prospective study in 155 patients. Gut, 1996;39:824-832 24 Bini EJ, Weinshel EH. Endoscopic evaluation of chronic human immunodeficiency virus related diarrhea: is colonoscopy superior to flexible sigmoidoscopy. Am J Gastroenterol,1998;93: 56-60 25 Kearney DJ, Steuerwald M, Koch J, Cello JP. A prospective study of endoscopy in HIV associated diarrhea. Am J Gastroenterol,1999;94:596-602 26 Weber R, Ledergerber B, Zbinden R, Altwegg M, Pfyffer GE, Spycher MA, Briner J, Kaiser L, Opravil M, Meyenberger C, Flepp M. For the Swiss HIV cohort study. Enteric infections and diarrhea in human immunodeficiency virus-infected persons. Arch Intern Med,1999;159:1473-1480 27 Karp CL, Neva FA. Tropical infectious diseases in human immunodeficiency virus infected patients. Clin Infect Dis,1999; 28:947-965 28 Lanjewar DN, Anand BS, Genta R, Maheshwari MB, Ansari MA, Hira SK, DuPont HL. Major differences in the spectrum of gastrointestinal infections associated with AIDS in India versus the west: an autopsy study.Clin Infect Dis, 1996;23:482485 29 Cotte L, Rabodonirina M, Piens MA, Perreard M, Mojon M, Trep C. Prevelance of intestinal protozoans in French patients infected with HIV. J Acquir Immune Defic Synd,1993;6:10241029 30 Ren E, Marche C, Chevalier T, Rouziouz C, Regnier B, Saimot AG, Negesse Y, Matheron S, Leport C, Wolff B, Moriniere B, Katlama C, Godeberge B, Vittecoq B, Bricaire F, Brun-Vesinet C, Pangon B, Deluol AM, Coulaud JP, Modai M, Frottier J, Vilde JL, Vachon F, Mignon M, Bonfils S. Intestinal infections in patients with the acquired immunodeficiency syndrome: a prospective study in 132 patients.Dig Dis Sci,1989;34:773780 31 Clerinx J, Bogaerts J, Taelman H, Habyarimana JB, Nyirabareja A, Ngendahayo P, Van de Perre P. Chronic diarrhea among adults in Kigali, Rwanda: Association with bacterial enteropathogens, rectocolonic inflammation, and human immunodeficiency virus injection. Clin Infect Dis,1995;21:12821284 32 Grohmann GS, Glass RI, Pereira HG, Monroe SS, Hightower AW, Weber R, Bryan RT. Enteric viruses and diarrhea in HIV infected patients.N Engl Med,1993;329:14-20 33 Yan Z, Nguyen S, Poles M, Melamed J, Scholes JV. Adenovirus colitis in human immunodeficiency virus infection.Am J Surg Pathol,1998;22:1101-1106 34 Molina JM, Casin I, Hausfater P, Giretti P, Welker Y, Decazes 18

REFERENCES
1 2 3 Fauci AS. The AIDS epidemic. N Engl J Med,1999;341:10461050 Smith PD, Quinn TC, Strober W, Janoff EN, Masur H. Gastrointestinal infections in AIDS.Ann Intern Med,1992;116:6377 Colebunders R, Francis H, Mann JM, Bila KM, Izley L, Kimputu L, Behets F, Van der Groen G, Quinn TC, Curran JW. Persistent diarrhea, strongly associated with HIV infection in Kinshasa. Zaire.Am J Gastroenterol,1987;82:859-864 Mayer HB, Wanke CA. Diagnostic strategies in HIVinfected patients with diarrhea.AIDS,1994;8:1639-1648 Lubeck DP, Bennett CL, Mazonson PD, Fifer SK, Fries JF. Quality of life and health service use among HIV-infected patients with chronic diarrhea.J Acquir Immune Defic Syndr,1993; 6:478-484 Wilcox CM, Rabeneck L, Friedman S. Malnutrition and cachexia, chronic diarrhea, and hepatobiliary disease in patients with human immunodeficiency virus infection.Gastroenterology, 1996;111:1724 Chiesi A, Mocroft A, Dally LG, Miller V, Katlama C, Ledergerder B, Pederson C, Phillips AN, Arcieri R, Lundgren JD. Regional survival differences across Europe in HIV-positive people: the EuroSIDA study. AIDS, 1999;13:2281-2288 Pezzotti P, Napoli PA, Acciai S, Boros S, Urciuoli R, Lazzeri V, Rezza G. For the Tuscany AIDS study group. Increasing survival time after AIDS in Italy: the role of new combination antiretroviral therapies. AIDS, 1999;13:249-255 Beck EJ, Mandalia S, Williams I, Power A, Newson R, Molesworth A, Barlow D, Easterbrook P, Fisher M, Innes J, Kinghorn G, Mandel B, Pozniak A, Tang A, Tomlinson D. For the national prospective monitoring system steering group. Decreased morbidity and use of hospital services in English HIV-infected individuals with increased uptake of anti-retroviral therapy 1996-1997. AIDS,1999; 13:2157-2164 Forrest DM, Seminari E, Hogg RS, Yip B, Raboud J, Lawson L, Phillips P, Schecher MT, OShaughnessy V, Montaner JSG. The incidence and spectrum of AIDS defining illnesses in persons treated with antiretroviral drugs. Clin Infect Dis,1998;27: 1379-1385 Sendi PP, Bucher HC, Harr T, Craig BA, Schwietert M, Pfluger D, Gafni A, Battegay M. For the Swiss HIV Cohort Study. Cost effectiveness of highly active antiretroviral therapy in HIV infected patients. AIDS,1999:1115-1122 Schooley RT. Longer term immunologic effects and side effects of successful antiretroviral therapy. Clin Infect Dis,1999;29: 12-18 Landay AL, Bethel J, Schnittman S. Phenotypic variability of lymphocyte populations in peripheral blood and lymph nodes from HIV-infected individuals and the impact of antiretroviral therapy. DATRI 003 Study Group. Division of AIDS treatment research initiative. AIDS Res Hum Retroviruses,1998;14: 445-451 Furrer H, Egger M, Opravil M, Bernasconi E, Hirschel B, Battegay M, Telenti A, Vernazza PL, Rickenbach M, Flepp M, Malinverni R. Discontinuation of primary prophylaxis against Pneumocystis Carinii pneumonia in HIV-1 infected adults treated with combination antiretroviral therapy. N Engl J Med,1999; 340:1301-1306 Zolopa AR, Shafer RW, Warford A, Montoya JG, Hsu P, Katzenstein D, Merigan T, Efron B. HIV-1 genotypic resistance patterns predict response to saquinavir-ritonavir therapy in patients in whom previous protease inhibitor therapy had failed.Ann Intern Med,1999;131:813-821 Kartalija M, Sande MA. Diarrhea and AIDS in the era of highly antiretroviral therapy. Clin Infect Dis,1999;28:701-707 Call S, Mnkemller K, Saag M, Wilcox CM. The changing etiology of diarrhea in patients with the acquired immune deficiency syndrome (AIDS).Am J Gastroenterol,1998;63:

4 5

10

11

12

13

14

15

16 17

186

ISSN 1007-9327

CN 14-1018/R

World J Gastroentero April 2000 Volume 6 Number 2 Dieterich DT, Rahmin M. Cytomegalovirus colitis in AIDS: presentation in 44 patients and a review of the literature. J Acquir Immune Def Syndr,1991;1:S29-35 52 Wilcox CM, Chalasani N, Lazenby A, Schwartz D. Cytomegalovirus colitis in acquired immunodeficiency syndrome: A clinical and endoscopic study. Gastrointest Endosc,1998;48:39-43 53 Mnkemller KE, Wilcox CM. Diagnosis and treatment of colonic disease in AIDS.Gastrointest Endosc Clin North Am,1998; 8:889-911 54 Smith PD, Macher AM, Bookman MA, Boccia RV, Steis RG, Gill V, Manischewitz J, Gelmann EP. Salmonella typhimurium enteritis and bacteremia in the acquired immunodeficiency syndrome.Ann Intern Med,1985;102:207-209 55 Cozart JC, Kalangi SS, Clench MH, Taylor DR, Borucki MJ, Pollard RB, Soloway RD.Clostridium difficile diarrhea in patients with AIDS versus nonAIDS controls. J Clin Gastroenterol,1993;16:192-194 56 Lu SS, Schwartz JM, Simon DM, Brandt LJ. Clostridium difficile-associated diarrhea in patients with HIV positivity and AIDS: a prospective controlled study.Am J Gastroenterol,1994; 89:1226-1229 57 Culpepper-Morgan JP, Kotler DP, Scholes JV, Tierney AR. Evaluation of diagnostic criteria for mucosal cytomegalic inclusion disease in the acquired immune deficiency syndrome.Am J Gastroenterol,1987;82:1264-1270 58 M-nkemller KE, Bussian AH, Lazenby A, Wilcox CM. Role of special stains in the pathologic evaluation of human immunodeficiency virus (HIV)-related gastrointestinal infections. Gastroenterology,1998;114:A1042 59 Weber R, Bryan RT, Owen RL, Wilcox CM, Gorelkin L, Visvesvara GS. Improved light-microscopical detection of microsporidia spores in stool and duodenal aspirates.N Engl J Med,1992;326:161-166 60 Kotler DP, Giang TT, Garro ML, Orenstein JM. Light microscopic diagnosis of microsporidiosis in patients with AIDS. Am J Gastroenterol,1994;89:540-544 61 Beaugerie L, Salauze B, Bur A, Deluol AM, Hoyeau-Idrissi N, Carbonnel F, Ngo Y, Cosnes J, Rozenbaum W, Nicolas JC, Gendre JP. Utility of culturing colonic mucosa in HIV-infected patients with diarrhea.Gastrointest Endosc,1996;44:663-666 62 Addis DG, Mathews HM, Stewart JM, Wahlquist SP, Williams RM, Finton RJ, Spencer HC, Juranek DD. Evaluation of a commercially available enzyme-linked immunoabsorbent assay for Giardia lamblia antigen in stool. J Clin Microbiol,1991; 29:1137-1141 63 Bowen EF, Sabin CA, Wilson P, Griffiths PD, Davey CC, Johnson MA, Emery VC. Cytomegalovirus viraemia detected by polymerase chain reaction identifies a group of HIV-positive patients at high risk of CMV disease.AIDS,1997;11:889-893 64 Goodgame RW, Genta RM, Estrada R, Demmler G, Buffone G. Frequency of positive tests for cytomegalovirus in AIDS patients: endoscopic lesions compared with normal mucosa. Am J Gastroenterol,1993;88:338-343 65 Dobbins WO, 3rd, Weinstein WM. Electron microscopy of the intestine and rectum in acquired immunodeficiency syndrome. Gastroenterology,1985;88:738-743 66 Wilcox CM, Mnkemller KE. Management of gastrointestinal infections in AIDS. In: Dolin R, Masur H, Saag M, eds. AIDS therapy. New York: Churchill Livingstone Inc, 1999 67 M-nkemller KE, Call S, Lazenby AJ, Wilcox CM. Declining prevalence of opportunistic gastrointestinal disease in the era of highly active antiretroviral therapy. Am J Gastroenterol ,2000:in press Edited by Pan BR Proofread by Ma JY 51

35 36 37 38 39

40

41 42

43

44 45

46 47 48

49 50

J, Garrait V, Lagrange P, Modai J. Campylobacter infections in HIV-infected patients: clinical and bacteriological features.AIDS, 1995;9:881-885 Roberts IM, Parenti DM, Albert MB.Aeromonas hydrophila associated colitis in a male homosexual. Arch Intern Med,1987; 147:1502-1503 Hutin Y, Molina JM, Casin I. Risk factors for Clostridium difficile associated diarrhoea in HIV-infected patients. AIDS, 1993;7:1441-1447 Wilcox CM, Waites KB, Smith PD. No relationship between gastric pH, small bowel bacterial colonisation, and diarrhoea in HIV-1 infected patients. Gut,1999;44:101-105 Havlik JA, Horsburgh CR, Metchock B. Disseminated -Mycobacterium avium complex infection: clinical identification and epidemiologic trends.J Infect Dis,1992;165:577-580 Navin, RT, Weber R, Vugia DJ, Rimland D, Robert JM, Addiss DG, Visvesvara GS, Wahlquist SP, Hogan SE, Gallagher LE, Juranek DD, Schwartz DA, Wilcox CM, Stewart JM, Thompson SE, Bryant RT. Declining CD4+ T-lymphocyte counts are associated with increased risk of enteric parasitosis and chronic diarrhea: Results of a 3-Year longitudinal study. J Acquir Immune Defic Syndr,1999;20:154-159 Wuhib T, Silva TMJ, Newman RD, Garcia LS, Pereira ML, Chaves CS, Wahlquist SP, Bryan RT, Guerrant RL,Sousa A de Q.Cryptosporidial and microsporidial infections in human immunodeiciency virus-infected patients in northeastern Brazil. J Infect Dis,1994;170:494-497 Goodgame RW. Understanding intestinal spore forming protozoa: Cryptosporidia, microsporidia, isospora,and cyclospora. Ann Intern Med,1996;124:429-441 Molina JM, Sarfati C, Beauvais B, Lemann M, Lesourd A, Frechal F, Casin I, Lagrange P, Modigliani R, Derouin F. Intestinal microsporidiosis in human immunodeficiency virus-infected patients with chronic unexplained diarrhea: Prevalence and clinical and biologic features.J Infect Dis,1993;167:217-221 Kotler DP, Orenstein JM. Prevalence of intestinal microsporidiosis in HIV infected individuals referred for gastroenterological evaluation.Am J Gastroenterol,1994;89:540546 M nkemller KE, Bussian AH, Lazenby A, Wilcox CM. Diarrhea in human immunodeficiency virus infected patients: where did all the microsporidia go. Gastroenterology,1998;114:A1042 Cegielski JP, Ortega YR, McKee S, Madden JF, Gaido L, Schwartz DA, Manji K, Jorgensen AF, Miller SE, Pulipaka UP, Msengi AE, Mwakyusa DH, Sterling CR, Reller LB. gCryptosporidium, enterocytozoon, cyclosporag infections in pediatric and adult patients with diarrhea in Tanzania.Clin Infect Dis,1999;28:314-321 Allason Jones E, Mindel A, Sargeaunt P, Williams P. Entamoeba histolytica as a commensal intestinal parasite in homosexual men. N Engl J Med,1986;315:353-356 Petri WA, Singh U. Diagnosis and management of amebiasis. Clin Infect Dis,1999;29:1117-1125 Wilcox CM, Schwartz DA, Costonis G, Thompson SE. Chronic unexplained diarrhea in human immunodeficiency virus infection: determination of the best diagnostic approach. Gastroenterology,1996;110:30-37 Connolly GM, Forbes A, Gazzard BG. The investigation of apparently pathogen negative diarrhoea in patients infected with human immunodeficiency virus (HIV-1).Gut,1990;31:886-889 Bini EJ, Cohen J. Diagnostic yield and cost effectiveness of endoscopy in chronic human immunodeficiency virus-related diarrhea. Gastrointest Endosc, 1998;48:354-361