Wilcox CM. Etiology and evaluation of diarrhea in AIDS: A global perspective at the millennium. World J Gastroenterol 2000; 6(2): 177-186 [PMID: 11819553 DOI: 10.3748/wjg.v6.i2.177]
Corresponding Author of This Article
C. Mel Wilcox, M.D., University of Alabama at Birmingham, Division of Gastroenterology & Hepatology, Birmingham, AL 35294-0007, USA. mel_wilcox@gihep.uab.edu
Article-Type of This Article
Review
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This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
C. Mel Wilcox, 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.
ORCID number: $[AuthorORCIDs]
Author contributions: All authors contributed equally to the work.
Correspondence to: C. Mel Wilcox, M.D., University of Alabama at Birmingham, Division of Gastroenterology & Hepatology, Birmingham, AL 35294-0007, USA. mel_wilcox@gihep.uab.edu
Telephone: (205)-975-4958, \ Fax. (205)-934-1546
Received: February 13, 2000 Revised: March 1, 2000 Accepted: March 6, 2000 Published online: April 15, 2000
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 Kaposi’s 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 been 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 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 immune competent 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 200 × 106 cells/L, and usually ＜ 100 × 106 cells/L[4,6].
Across all continents, the introduction and rapid implementation of potent combination 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 been 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 countrises[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 virologic response to HAART and a sustained rise in CD4 count to greater than 200 × 106/L[14]. However, patients who have received 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 immune competent 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 work-up- 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 HIV-infected 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 available to draw meaningful distinctions.
ETIOLOGY
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 developing countries[27,28]. Cryptosporidia is the most frequently identified parasitic cause of diarrhea throughout the world[23,26,29]. Cytomegalo virus (CMV), cryptosporidiosis, microsporidia and Mycobacterium avium complex (MAC) the classic gastrointestinal OI of AIDS become important pathogens when immunodeficiency is advanced. AIDS-related neoplasms such as Kaposi’s sarcoma or lymphoma and fungi rarely cause diarrhea. As noted above, medications, usually protease inhibitors, have recently become important causes of diarrhea[16].
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 ＜ 50 × 106 cells/L and the CD4 count is ＜ 100 × 106 cells/L in almost all patients. Among 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 from developing countries due to the infrequent use of endoscopy or true differences in infection. Another explanation for geographic disparities in the prevalence of CMV 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.
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
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 HIV-infected patients from developed countries likely because of these patient’s 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 ＜ 10 × 106 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) priorto developing such advanced immunosuppression required for MAC infection. The presentation of TB in AIDS is well recognized to be different and often extrapulmonary. Autopsy studies suggest that the gastrointestinal 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 200 × 106 cells/L.
Parasites
Among the protozoa, Cryptosporidium parvum is the most frequently identified 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 HIV-infected patients with chronic diarrhea. Microsporidia (Enterocytozoon bieneusi and Encephalitozoon intestinalis) 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 gastrointestin al pathogen in HIV-infected in North America, whereas it is endemic in some developing countries such as Haiti[40]. The infrequency observed in developed countries has been attributed to widespread Pneumocystis carinii prophylaxis with trimethopr imsulfamethoxazole which is highly effective in the treatment of Isospora. Cyclospora 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-pathogenic 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 been reported[4]. Helminths are rare causes of diarrheal disease but have 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 (“enteritis”) 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 ＞ 2L/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 may 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 pre sentation 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 ＞ 50 × 106 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 differences 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 particularly 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 patient's 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 circumscribed ulcers[52]. When the 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), gastrointestinal 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
Although bacterial enterocolitis can occur at any stage of immunodeficienc y, unusual presentations of these enteric bacteria became apparent early in the AIDS epidemic where Salmonella sp.[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 as an acute diarrheal illness (less than 2 wk duration). Salmonella gastro enteritis more commonly presents with watery diarrhea, abdominal pain, fever, nausea 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 fever may be prominent, 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 non-immunocompromised 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 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 associated 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 self-limited if the CD4 count is ≥ 200 × 106 cells/L[6]. The disease may be particularly devastating in developing countries. Overall, diarrhea due to microsporidiosis 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
Perhaps the most important assessment in the evaluation of diarrhea in HIV-infected patients is the CD4 count, because the absolute value reflects the patient’s 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 200 × 106 cells/L, and usually ＜ 100 × 106 cells/L, the method and extent of evaluation will depend on the absolute CD4 count. For example, if the CD4 count is higher than 100 × 106 cells/L, evaluation for MAC is not necessary given that MAC infection occurs primarily when the CD4 count is ＜ 50 × 106/L. Likewise, the yield of endoscopy for OI in a patient with a CD4 count ＞ 200 × 106/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 of infections should also dictate the approach.
Table 3 Drugs used in the therapy of diarrhea in AIDS.
Condition
Treatment
Dosage
Duration
Cytomegalovirus
Ganciclovir
5 mg/kg, 2/d
2-4 wk
Foscarnet
90 mg/kg, 2/d
2-4 wk
Herpes simplex
Acyclovir
400-800 mg, 14 d (5/d)
Foscarnet
60-90 mg/kg, 2/d
14 d
Valacyclovir
500 mg, 3/d
14 d
Famciclovir
500 mg, 2/d
7-10 d
Cryptosporidia
No definite therapy
known
Paromomycin
25-35 mg/kg, 3/d
14-28 d
Spiramycin
1g, 3/d
14-28 d
Azithromycin
900 mg, 1/d
14-28 d
Letrazuril
50-100 mg, 1/d
14-28 d
Bovine colostrum
50 g, 1/d
14-28 d
Microsporidia
Septata intestinalis
Albendazole
400 mg, 2/d
14-28 d
Enterocystozoon
No definite therapy
known
Albendazole
400 mg, 2/d
14-28 d
Metronidazole
500 mg, 3/d
14-28 d
Isospora belli
TMP-SMX DS
1 tab, 4/d
10-14 d
Cyclospora
TMP-SMX DS
1 tab, 4/d
10-14 d
Giardia lamblia
Metronidazole
500 mg, 3/d
10-14 d
Entamoeba histolytica
Metronidazole
750 mg, 3/d
10-14 d
Iodoquinol
650 mg, 3/d
10-14 d
MAC
Clarithromycin
500 mg, 2/d
4 wk
EMB, Cipro, RFP
Clostridium difficile
Metronidazole
500 mg, 3/d
10-14 d
Vancomycin
250 mg, 4/d
10-14 d
Salmonella
Ciprofloxacin
500 mg, 2/d
10-14 d
TMP-SMX DS
1 tab, 4/d
10-14 d
Shigella
Ciprofloxacin
500 mg, 2/d
10-14 d
Ampicillin
500 mg, 4/d
10-14 d
Campylobacter
Ciprofloxacin
500 mg, 2/d
10-14 d
Erythromycin
500 mg, 4/d
7-14 d
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 predict the presence of a colonic pathogen and yield of proctoscopy[48]. Stool cultures for Salmonella, Shigella and Campylobacter should be 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]. Additional 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 HIV-infected patient, the history and immune status are most helpful.
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 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 predictive 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
Plain abdominal X-rays are not generally helpful for the evaluation of chronic diarrhea. With severe colitis, however, colonic dilation and “thum bprinting” 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 AIDS-related diarrhea, but may be useful if Crohn’s 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
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, Brown-Brenn, 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 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 endoscopy for the evaluation of diarrhea in AIDS (Table 4, Table 5, Table 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 addition to CMV[24]. This is an important issue worldwide as a limited evaluation, which includes a rectal biopsy obtained by proctoscopy or sigmoidoscopy, is easier to acquire and more readily available than colonoscopy.
Table 4 Yield of colonoscopy with biopsy in HIV infected patients with chronic diarrhea.
Ref Proximal
No. pts.
Diagnosis
Most common dx (No.pts)
Distal
Connolly*
81
34 (42)
CMV (12)
32
+
Wilcox
48
13 (27)
CMV (11)
12
1
Kearney
79
22 (100)°
CMV (15)
17
1
Bini
317
116 (37)
CMV (75)
60 (55)
33 (30)
Table 5 Yield of upper Endoscopy in HIV-infected patients with chronic diarrhea.
References
No. pts.
Diagnosis n (%)
Most common dxs
Connolly
33
2 (36)
Crypto 2
CMV 4
Wilcox
48
9 (19)
Micro 7, crypto 1
CMV 1
Bown
56
15 (26)
Crypto 6, micro 5
Kearney
79
9 (11)
Micro 5
Bini
442
123 (28)
Micro 54 (12%)
Table 6 Yield of extensive work up of HIV-infected patients with negative stool studies.
Ref
No. pts.
Diagnosis n (%)
Most common diagnosis
Wilcox
48
21 (44)
CMV 9
Micro 7
Kearney
79
22 (28)
CMV 15
Micro 5
Connolly
33
12 (36)
Crypto 5
CMV 4
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 org anisms detected by EGD and biopsy are cryptosporidia and microsporidia compromising ＞ 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 detected 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], Blanshard 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 proximal 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 additional pathogens beyond those identified by colonoscopy and terminal ileal biopsy. The authors concluded that for patients with CD4 counts less than 100 × 106 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 terminal ileum should be obtained.
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 step-wise 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 (Salmonella, Campylobacter and Shigella) and parasites (cryptosporidia and microsporidia). Testing for C. difficile was recommended for patients at risk for this infection (use of antibiotics, recent hospitalization). In HIV-infected patients with a CD4-count ＜ 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 selected 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 rec ommended 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 diagnostic yield 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 d-xylose absorption for intestinal disease in HIV-infected 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. Di scontinuation of all antiretroviral agents may help determine if a drug-induced diarrhea is causative.
CONCLUSIONS AND RECOMMENDATIONS
A thorough history and physical examination are essential to evaluate the patients’ general condition and will help focus the work-up of diarrhea in AIDS. In addition, routine blood tests are useful to evaluate objectively the severity of the diarrhea, such as hydration statusand 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 reflected 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 comp leteset 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 ＜ 100 × 106 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 cryptosporidia[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
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 pathogens is provided (Table 3).
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