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Colonic disease in patients with AIDS
Colonic D i s e a s e in Patients With AIDS Edmund J. Bini, MD, FACP, FACG, and David L. Diehl, MD, FACP
The colon is a common site of gastrointestinal disease in patients with AIDS, and the frequency and severity of disease increases as immunosuppression worsens. In these individuals, the most common manifestations of colonic disease include diarrhea, lower gastrointestinal bleeding, and abdominal pain. Gastroenterologists caring for HIV-infected patients with colonic disease must be aware of the causes of these diseases and the proper endoscopic techniques needed to make an accurate diagnosis. This article reviews the indications for lower endoscopy and the differential diagnosis of colonic disease in patients with AIDS. The authors also review the techniques of colonoscopy, sigmoidoscopy, ileal intubation, and biopsy. In addition, the authors discuss the endoscopic appearances of various colonic diseases in patients with AIDS to assist the endoscopist in correctly identifying these disorders. This is a US government work. There are no restrictions on its use.
astrointestinal disease is common in patients with human
G immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS). The clinical importance of colonic disease in this patient population is enormous. Chronic diarrhea, lower gastrointestinal bleeding, and abdominal pain are the most common manifestations of AIDS-associated coionic disease. Patients with AIDS and symptoms of colonic disease will frequently require an endoscopic evaluation. This article reviews the indications for lower endoscopy in patients with AIDS, discusses the techniques of colonoscopy, sigmoidoscopy, ileal intubation, and biopsy, and highlights the endoscopic appearance of various colonic diseases.
Indications for Colonoscopy and Sigmoidoscopy Chronic Diarrhea In the pre-highly active antiretroviral therapy (HAART) era, diarrhea has been reported in approximately 50% of AIDS patients in North America, and this estimate approached 100% in developing countries. 1-3 Diarrhea still occurs in the era of HAART and this symptom was the primary cause for hospitalization in 2.8% of the 15,000 patients with HIV that were hospitalized in New York State in 1998. 4 In these patients, chronic diarrhea results in a significant increase in morbidity From the Division of Gastroenterology, VA New York Harbor Healthcare System, Bellevue Hospital Center, and NYU School of Medicine, New York, NY. Address reprint requests to Edmund J. Bini, MD, FACP, FACG, VA New York Harbor Healthcare System, Division of Gastroenterology (111D), 423 East 23rd St, New York, NY 10010; e-mail: [email protected]. This is a US government work. There are no restrictions on its use. 1096-2883/02/0402-000550.00/0 doi:l 0.1053/tgie.2002.33010
and mortality. Compared to similar patients without diarrhea, HIV-infected patients with chronic diarrhea have a marked reduction in quality of life and incur higher health care costs. 5 The American Gastroenterological Association has published guidelines for the management of chronic HIV-related diarrhea. 6 In this medical position statement, a consensus panel recommended a stepwise approach tailored to the individual patient. The first step includes at least 3 sets of stool specimens for common enteric bacteria and parasites, including microsporidia and cryptosporidia. A stool sample for Clostridium difficile is recommended for patients at risk for antibiotic-associated diarrhea. In addition, febrile patients should have blood drawn for bacterial culture and, if the CD4 lymphocyte count is below 100 cells/mm 3, blood should be submitted for mycobacterial culture. If stool tests do not identify an enteric pathogen, flexible sigmoidoscopy with mucosal biopsy is recommended. The guidelines acknowledge that for certain patients, colonoscopy may be indicated instead of flexible sigmoidoscopy. When no pathogen is identified on lower endoscopy, upper endoscopy with biopsy of the duodenum for light-microscopic examination should be performed; optional biopsies for mycobacterial culture and electron microscopy may also be obtained at the time of endoscopy. Numerous studies have evaluated the diagnostic yield of sigmoidoscopy and colonoscopy in HIV-infected patients with chronic diarrhea, r 22 However, only a few of these studies have examined the diagnostic yield of lower endoscopy in patients with a negative stool evaluation. 8,9,13A6,2~ This discussion will focus on the role of lower endoscopy in patients with negative stool studies because in clinical practice, most gastroenterologists would not perform endoscopy prior to a comprehensive stool evaluation. The diagnostic yield of colonoscopy in HIV-infected patients with chronic diarrhea and negative stool studies ranged from 27% to 65%, with cytomegalovirus (CMV) being the most common cause identified (Table 1). In contrast, rectosigmoid biopsies obtained by flexible sigmoidoscopy had a somewhat lower diagnostic yield (22%). The higher yield of colonoscopy compared with flexible sigmoidoscopy was due to the detection of CMV limited to the proximal colon. 8,9,2~The study by Wilcox et a121 found isolated right-sided colonic disease in only 8% of patients. In contrast, the authors of this review8,9 and others ~<2~ have found that 23% to 46% of diagnoses in HIV-infected patients with chronic diarrhea were identified only on biopsies taken from the proximal colon. The decision to perform colonoscopy versus flexible sigmoidoscopy as the initial diagnostic endoscopic procedure is controversial. 23 In a study of 44 patients with CMV colitis, CMV was found only in the cecum in 39% of individuals. 24 Isolated right-sided CMV disease of the colon was found in 29% of 252 patients with CMV colitis. 25 Wilcox et a126 made a diagnosis of CMV disease limited to the proximal colon in 13% of 31 patients with CMV colitis undergoing colonoscopy. These find-
Techniques in Gastrointestinal Endoscopy, Vol 4, No 2 (April), 2002: pp 77-85
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TABLE 1. Diagnostic Yield of Lower Endoscopy in HIV-lnfected Patients With Chronic Diarrhea and Negative Stool Studies* Author
No. of patients
Endoscopic procedure
Cause of diarrhea identified %
Most common cause
Right-sided disease1- %
Wilcox et a121 Bini and Weinshel 9 Bini and Cohen 8
48 317 85 191 79 40
Colonoscopy Colonoscopy Sigmoidoscopy Colonoscopy Colonoscopy Colonoscopy
27 35 22 39 28 65
CMV CMV CMV CMV CMV CMV
8 30 N/A 28 23:1: 46
Kearney et a116 Wei et al2~
*Studies were included in this table only if patients had a negative stool evaluation prior to endoscopy and the diagnostic yield of flexible sigmoidoscopy or colonoscopy could be determined from the data provided. 1-The percentage of lesions that were identified only in the proximal colon (beyond the reach of the flexible sigmoidoscope). :l:Biopsies of the terminal ileum were obtained in 70% of patients.
ings support the policy of performing colonoscopy instead of flexible sigmoidoscopy in HIV-infected patients with chronic diarrhea. In addition, the use of colonoscopy resulted in a lower cost per pathogen identified ($2,787 v $3,353) compared to flexible sigmoidoscopy. 8 However, other investigators have found no beneft of performing colonoscopy over flexible sigmoidoscopy in this patient population. 15,2~,27 The reason for this discrepancy is not known but may be due to differences in the patient populations studied. The differential diagnosis of chronic diarrhea in patients with AIDS is extensive. The causes of chronic diarrhea in this patient population are shown in Table 2. In addition to the etiologies listed, consideration should also be given to protease-inhibitor induced diarrhea. This entity is seen most commonly with nelfinavir. 28
TABLE 2. Differential Diagnosis of Colonic Disease in AIDS Patients With Diarrhea Bacterial Salmonella Shigella flexneri Campylobacter jejuni Escherichia coli Clostridium difficile Yersinia enterocofitica Mycobacterium avium complex Mycobacterium tuberculosis Viral Cytomegalovirus Adenovirus Herpes simplex virus Calcivirus Astrovirus Protozoal Cryptosporidium parvum Isospora belli Entamoeba histolytica Giardia lamblia Balantidium coil Pneumocystis carinfi Toxoplasma gondii ? Blastocystis hominis Fungal Histoplasma capsulatum Candida albicans Coccidioides immitis Cryptococcus neoformans Strongyloides stercoralis Blastomyces dermatitidis Neoplastic Kaposi's sarcoma Lymphoma (Hodgkin's and non-Hodgkin's type)
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Lower Gastrointestinal Bleeding Lower gastrointestinal bleeding is another clinical presentation of colonic disease in patients with AIDS. Several studies have evaluated the causes of lower gastrointestinal bleeding in this patient population. 29 32 The differential diagnosis of lower gastrointestinal hemorrhage is shown in Table 3. In a large series of 312 HIV-infected patients with lower gastrointestinal hemorrhage, a source of bleeding was identified by colonoscopy or sigmoidoscopy in 94.6% of patients. 32 The diagnostic yield of colonoscopy was significantly higher than the yield of flexible sigmoidoscopy (96.6% v 88.6%, P = .02). In this study, the most common etiologies that were identified included CMV colitis (25.3%), lymphoma (12.2%), idiopathic colitis (12.2%), and Kaposi's sarcoma (10.3%). CMV colitis, lymphoma, and Kaposi's sarcoma were usually seen in patients with severe immunosuppression (CD4 count <200 cells/mm3). In those with CD4 counts greater than 200 cells/ mm 3, the causes of lower gastrointestinal bleeding were similar to HIV-negative patients, with colitis, diverticular hemorrhage, and hemorrhoids being the most common sources identified. 32 Endoscopic hemostasis may be required in certain cases, and treatment of acute lower bleeding in HIV-infected patients should be approached in a manner similar to the approach taken in HIV-negative individuals. In the series of 312 HIVinfected patients with acute lower gastrointestinal bleeding, major stigmata of hemorrhage were noted in 30.4% of patients, including active bleeding in 21.2%, adherent clots in 6.1%, and nonbleeding visible vessels in 3.2%.32 In this study, endoscopic hemostasis, consisting of epinephrine injection and/or bipolar electrocoagulation, was successful in achieving hemostasis in
TABLE 3. Causes of Acute Lower Gastrointestinal Bleeding in HIV-Infected Patients Cytomegalovirus colitis Lymphomas Idiopathic colitis Kaposi's sarcoma Diverticulosis Clostridium difficile colitis Hemorrhoids Rectal varices Anal fissures Mycobacterium tuberculosis Histoplasmosis Adenomas Carcinomas Vascular ectasias
BINI AND DIEHL
intestinal tract should be avoided in patients with suspected colon perforation. The individuals should be evaluated by computed tomography and a surgical consultation should be requested. Chronic abdominal pain in HIV-infected patients with coionic disease may be caused by involvement of the colonic wall by infectious or neoplastic diseases. Infectious causes include CMV disease, Mycobacterium avium complex, and other pathogens that cause colitis. Neoplastic diseases include lymphoma, Kaposi's sarcoma, and adenocarcinoma of the colon. Idiopathic ulcers of the colon may also cause chronic abdominal pain.
Other Indications
Fig 2. Proper biopsy technique for ulcers of the colon. The "X's" mark the locations from which biopsies should be obtained. It is important to sample from the edge of the ulcer as well as the base of the ulcer. The diagnosis of C M V may be missed if biopsies are not taken from the base of the ulcer.
93.9% of patients with active bleeding and 100% of those with nonbleeding visible vessels. The 30-day incidence of recurrent bleeding in this population was 17.6%, which is similar to what has been reported in HIV-negative patients with acute lower gastrointestinal hemorrhage. 33-35 However, the 30-day mortality rate in HIV-infected patients was 14.4% and this is higher than the 5% mortality rate in the general population. 34,35 In our experience, colonoscopy is superior to flexible sigmoidoscopy for the evaluation of lower gastrointestinal hemorrhage in this patient population. Prior to colonoscopy, gastrointestinal lavage should be done in the usual manner. The endoscopist should pay careful attention to detail and look closely for stigmata of recent hemorrhage. These stigmata may be located within ulcers, masses, colitis, or within a diverticulum. 32 Active bleeding and visible vessels should be treated the same way that they are treated in non-HIV-infected patients. The use of epinephrine injections and bipolar electrocoagulation are safe and effective.32,36 We prefer to use the Injection Gold Probe (Boston Scientiflc/Microvasive, Natick, MA), which allows injection of epinephrine followed by bipolar electrocoagulation (Fig 1). The advantages of Injection Gold Probes are the ability to irrigate, inject, and coagulate without probe removal. 37 For a detailed review on lower gastrointestinal bleeding in patients with AIDS, see Chalasani and W i l c o x , 38
Abdominal Pain Colonic disease may cause acute or chronic abdominal pain. The diagnosis of perforated CMV ulcers of the colon or CMVassociated appendicitis should be considered in HIV-infected patients with severe acute abdominal pain and peritoneal s i g n s . 39-41 Patients with Kaposi's sarcoma, lymphoma, or adenocarcinoma of the colon may also present with colon obstruction or perforation. Endoscopic evaluation of the lower gastroAIDS-ASSOCIATED COLONIC DISEASE
In addition to the manifestations of colonic disease described above, there are other indications for colonoscopy in patients with AIDS. These individuals are susceptible to many of the disease entities seen in immunocompetent individuals. With the widespread use of HAART, patients with AIDS are now living longer and many live well beyond the age of 50 years. These patients should be screened for colorectal cancer and colonoscopy may be performed for screening or to evaluate a positive fecal occult blood test. Adenomas and adenocarcinomas of the colon have been identified in patients with AIDS. 32,42 The role of HIV in increasing the incidence of colon adenocarcinoma is controversial. On occasion, an aggressive adenocarcinoma may be seen in a young AIDS patient, 42 and this has given rise to the thought that the occurrence of cancer in this setting is linked to immunosuppression. A single study suggested an increased risk in female patients with AIDS# 3 However, recent data do not suggest that adenocarcinoma of the colon is more common in patients with AIDS. 44
Intubation of the Terminal Ileum Intubation of the terminal ileum during colonoscopy is not routinely performed. However, intubation of the terminal ileum and ileal biopsy can increase the diagnostic yield of colonoscopy, especially in patients with AIDS. 45 In a prospective study of 138 patients undergoing colonoscopy, ileoscopy made a diagnosis in 2.7% of asymptomatic patients undergoing routine colonoscopy and 29% of patients with diarrhea. 45 The diagnostic yield of ileoscopy was even higher (67%) in HIVinfected patients with diarrhea. 45 In a prospective study of 79 HIV-infected patients with chronic diarrhea and negative stool studies, Kearney et a116 compared the diagnostic yield of a complete endoscopic workup (EGD and colonoscopy with biopsies of the terminal ileum) to a more limited approach (flexible sigmoidoscopy). They calculated the sensitivity of different sites using combined biopsies of the duodenum, left and right colon, and terminal ileum as the "gold standard." With this technique, the authors found that the sensitivity of combined biopsies from the left colon, right colon and terminal ileum was 100%, which was higher than the sensitivity of biopsies obtained from the left and right colon alone (82%). The addition of terminal ileal biopsies resulted in the diagnosis of 5 additional cases of microsporidia. 16 Other investigators have also made the diagnosis of microsporidiosis by ileal biopsy. 46 In HIV-infected patients with diarrhea, colonoscopy with ileal biopsy may obviate the need for upper endoscopy if the terminal ileum is entered successfully. 79
Fig 3. Fig 1.
80
Fig 4.
Fig 5.
Fig 6.
Fig 7.
Fig 8.
Fig 9. BINI AND DIEHL
Biopsy Techniques The endoscopic appearance of colonic disease is often variable in patients with AIDS and these findings are rarely pathognomonic. The wide spectrum of colonic diseases in this population makes diagnosis a challenge for the gastroenterologist. In addition, it is not uncommon to find multiple pathogens in a single patient. Therefore, mucosal biopsies are essential in making a diagnosis of colonic disease in patients with AIDS. During colonoscopy, all abnormalities should be biopsied multiple times. In addition, patients undergoing colonoscopy for diarrhea should have biopsies taken from the cecum/ascending colon as well as the rectosigmoid colon. Typically, rectosigmoid biopsies will yield a diagnosis. However, the disease may be limited to the right colon and biopsies from the cecum and ascending colon may be helpful, particularly in patients with CMV. 9 When ulcers are seen during endoscopy, multiple biopsy specimens should be obtained from the edges as well as the base of the ulcer because the diagnosis of CMV may be missed if biopsies are not taken from the base of the ulcer (Fig 2). The optimal number of biopsies to take during colonoscopy is not known. Cranston et a147 recommend that 3 biopsy specimens be taken from the rectosigmoid colon in patients with HIV-associated diarrhea. Although there are no studies evaluating the number of specimens necessary to make a diagnosis of colonic ulcer disease, Wilcox et a148prospectively evaluated the number of biopsies necessary for diagnosis of viral esophagitis in HIV-infected patients with esophageal ulcers and concluded that at least 10 biopsy specimens may be needed. We routinely take at least 6 to 10 specimens from all colonic abnormalities. In addition, we take a similar number of biopsy specimens from normal mucosa in the cecum/ascending colon and rectosigmoid colon in patients with diarrhea. We recommend using a Multibite biopsy forceps (Boston Scientific/Microvasive, Natick, MA) because this device enables the endoscopist to obtain multiple large mucosal samples in a single pass (Fig 3).
Endoscopic Appearance of Colonic Diseases A working knowledge of the endoscopic appearance of various HIV-associated diseases of the colon is critical for endoscopists who care for patients with AIDS. We will now discuss the endoscopic appearance of common AIDS-associated colonic diseases.
Salmonella, Shigella, and Campylobacter Salmonella typhimurium, Salmonella enteritidis, Shigella flexneri, and Campytobacterjejuni are the most common bacterial causes of colitis in patients with AIDS. Colonic infection with these bacteria can result in bloody diarrhea, tenesmus, and abdominal pain. The endoscopic appearance of these bacterial infections includes erythema, edema, and hemorrhagic and ulcerated mucosal lesions. 49 These findings may mimic ulcerative colitis.
Clostridium difficile Clostridium difficile colitis is common among patients with AIDS, resulting in bloody, mucoid diarrhea associated with fever and abdominal pain. One study has reported that C difficile colitis is more severe in patients with AIDS than in immunocompetent individuals9 However, other investigators did not find a difference in the severity of disease between immunodeficient and immunocompetent individuals. 51 Endoscopy usually reveals edema, erythema, and friability of the colonic mucosa that is covered by a yellow-white pseudomembrane (Fig 4). However, pseudomembranes may occasionally be absent in patients with AIDS. Disease is often localized to the rectosigmoid colon, but pancolonic or isolated right-sided colitis may be seen. Mycobacterium tuberculosis Although tuberculosis of the gastrointestinal tract is rare in the United States, cases still occur, especially in patients with AIDS. The diagnosis of gastrointestinal tract tuberculosis is challenging because this disease can mimic other disorders. 52 The ileocecal area and other regions of the colon are the most common sites of tuberculous involvement of the gastrointestinal tract. 52 The endoscopic appearance of colonic tuberculosis includes segmental ulcers and colitis, inflammatory strictures, mucosal nodules, and hypertrophic lesions resembling polyps and masses. 52-~4 An endoscopic photograph of Mycobacterium tuberculosis infection of the colon is shown in Figure 5. Tuberculous colitis can rarely present as diffuse colitis, which can appear similar to ulcerative colitis. 55 In a study of 50 patients with colonic tuberculosis, Shah et a153 noted that a nodular mucosa with areas of ulceration was the most common endoscopic finding. In this study, ileocecal disease was found in 16 patients, ileocecal and contiguous ascending colon disease in 14,
Fig 1. Injection Gold Probe can be used for the treatment of bleeding lesions in the colon. This device allows injection of epinephrine followed by bipolar electrocoagulation with a single combination probe. Fig 3. Multibite biopsy forceps or other large biopsy forceps should be used to obtain colonic biopsies because this device enables the endoscopist to obtain multiple large mucosal samples in a single pass. Fig 4. Clostridium difficile colitis in an AIDS patient with severe diarrhea, fever, and abdominal pain. There are extensive pseudomembranes overlying an erythematous, edematous, and friable mucosa. Fig 5. Mycobacterium tuberculosis disease of the colon. A deep ulcer of the colonic mucosa is seen in the absence of surrounding colitis. Fig 6. C M V colitis and ulcer of the colon. There is an ulcer seen at the bottom of the photograph and this ulcer is covered with a whitish exudate. There is also surrounding erythema and edema of the colonic mucosa. Fig 7. Histoplasma capsulatum infection of the colon. The endoscopic appearance of histoplasmosis resembles adenocarcinoma of the colon in this AIDS patient with abdominal pain, fever, and diarrhea. Fig 8. Kaposi's sarcoma of the colon in a homosexual male with AIDS. A reddish plaque-like lesion is noted in the sigmoid colon. Fig 9. Lymphoma of the colon. A large mass was located in the ascending colon in this patient with AIDS. Biopsies revealed a B-cell non-Hodgkin's lymphoma. AIDS-ASSOCIATED COLONIC DISEASE
81
segmental colonic tuberculosis in 13, ileocecal disease and nonconfluent involvement of another part of the colon in 5, and pancolitis in 2 patients. 53 These findings emphasize the importance of colonoscopy for diagnosing colonic tuberculosis.
Mycobacterium avium Complex Mycobacterium avium complex (MAC) is a group of nontuberculous mycobacteria and these organisms are a common cause of systemic infection in patients with AIDS. 56 MAC can cause colonic disease and diarrhea in immurlocompromised patients with CD4 lymphocyte counts below 100 cells/mm3. 57 Endoscopically, colonic MAC may present as granular white nodules 2 to 4 mm in diameter with a surrounding rim of erythema. 58 The mucosa may appear erythematous, edematous, friable, and ulcerated. 59 However, the colonic mucosa may appear completely normal in patients with MAC infection.
Cytomegalovirus
Although this organism primarily inhabits the microvillus border of intestinal epithelial cells, it may also infect the apical border of epithelial cells in the colon. Infection with C parvum can cause colonic cryptitis. 62 The endoscopic appearance may be normal or appear as colitis with erythema, edema, and friability. The colonic mucosa may be covered by a mucopurulent exudate in patients with severe disease.
Isospora belli Isospora belli is a coccidian protozoan that can cause diarrhea in patients with AIDS. Although it more commonly infects the small bowel, I belli can cause severe colitis. The endoscopic appearance of I belli infection of the colon is nonspecific and includes edema, erythema, and friability.
Entamoeba histolytica Entamoeba histolytica is a protozoan with worldwide distribu-
Cytomegalovirus is a ubiquitous virus that often affects the colon in patients with AIDS. The endoscopic appearance of CMV is variable, but most often appears as ulcers associated with colitis (erythema, edema, and friability). 25 The spectrum of CMV disease of the colon may also include colitis without ulcers, ulcers without colitis, or a normal appearing colon. 25,26 An endoscopic photograph of CMV disease of the colon is shown in Figure 6. Typically, CMV disease is seen in the distal colon or throughout the colon. 25,26However, isolated proximal colonic disease may occur. 8,9,24,25In addition, CMV-associated colonic disease can present with a mass lesion, also known as a "pseudotumor," which can be mistaken grossly for an adenocarcinoma. 6o
tion, but infection is most prevalent in developing countries. Invasive colonic disease may develop in patients with AIDS, especially in homosexual individuals who acquire the infection sexually. The spectrum of disease caused by E histolytica ranges from noninvasive colonization to a self-limited diarrhea to invasive colitis, including fulminant colitis and colonic perforation. 63 The endoscopic appearance includes a nonspecific colitis with edema, erythema, friability, and ulcerations. Large, geographic mucosal ulcers associated with yellow-green pseudomembranes may also be seen. 63 The mucosa adjacent to ulcerations may be hemorrhagic or inflamed, resembling ischemic colitis or idiopathic inflammatory bowel disease, respectively. 63 The disease may be focal and can appear anywhere throughout the colon.
Herpes Simplex Virus
Balantidium coli
Whereas most humans are infected at some time in their lives by herpes simplex virus type 1 or 2, diarrheogenic infections of the intestines by these double-stranded DNA viruses are rare in the population at large and virtually confined to individuals with impaired immunity. At endoscopy, infected mucosa may show erythematous areas with small vesicular lesions, or shallow ovoid ulcers with or without a vesicular rim. 3 These vesicles may rupture, forming small ulcers that may coalesce to form larger ulcers. Infection of the distal colon and rectum is often accompanied by involvement of the anal mucosa and perianal skin. 3
Balantidium coli is a large ciliate protozoan that has a worldwide
Adenovirus Adenoviruses are ubiquitous double-stranded DNA viruses that can cause diarrhea in patients with AIDS. Colonic infection with adenoviruses can result in enterocolitis with edema, erythema, and friability of the colonic mucosa. The endoscopic appearance of adenovirus colitis may be completely normal, making it difficult to diagnose this infection. In a study of 5 AIDS patients with adenovirus infection of the colon, colonoscopy revealed normal mucosa in 3 cases and mildly inflamed mucosa in 2. 61
Cryptosporidium parvum Cryptosporidiurn parvum is a coccidian protozoan that is one of the most common causes of diarrhea in patients with AIDS. 82
distribution. The organism can be found in the lumen of the terminal ileum, cecum, and colon. Infection may lead to an asymptomatic carrier state, to chronic intermittent diarrhea, or to severe dysenteric diarrhea. 64 Invasion of the mucosa results in ulceration, with endoscopic and microscopic features similar to those of invasive amebiasis. 64
Histoplasma capsulatum Histoplasma capsulatum is a dimorphic fungus that can cause severe colonic disease in patients with AIDS. This organism may infect any segment of the gastrointestinal tract. 65 The endoscopic spectrum includes colitis, ulcerations, or a mass lesion of the colon. 66-68 On endoscopic examination, histoplasmosis may appear as inflammation with elevated whitish plaques that can progress to ulcers. The most common endoscopic appearance of histoplasmosis is a mass lesion (Fig 7), and this can often be mistaken for colon carcinoma. 66,67 Histoplasmosis has also been reported to cause polypoid lesions of the colon. 66
Candida albicans The role of Candida species as a cause of colonic disease in patients with AIDS is controversial. Some investigators have implicated Candida species as a cause of diarrhea in patients with AIDS who did not have any other pathogens identified. 69 BINI AND DIEHL
In these patients, treatment of Candida resulted in resolution of diarrhea. Endoscopic evaluation of the colon in patients with Candida may reveal areas of patchy erythema or discrete ulcers that resemble those caused by CMV. One group of investigators has reported a case of necrotizing enterocolitis secondary to invasive candidiasis in a patient with AIDS. 7~
Kaposi's Sarcoma Kaposi's sarcoma is a malignant tumor of endothelial cell origin and is a common neoplasm in patients with AIDS. It is predominantly found in homosexual and bisexual men and gastrointestinal involvement is present in approximately 75% of those with oral mucosal lesions.r1 The diagnosis of Kaposi's sarcoma of the colon can be made by its characteristic appearance of a violaceous plaque-like lesion (Fig 8) during colonoscopy. 72 Colonic Kaposi's sarcoma lesions may be macular or nodular red, purplish, or violaceous lesions. These lesions may be sessile or polypoid and can have central umbilication or ulceration. 72,73Although they are usually several millimeters or centimeters in size, large masses have also been reported. Endoscopic biopsy may have a high false negative rate (77%) because Kaposi's sarcoma can be located deep in the submucosa. 7~
Lymphoma Lymphomas are common tumors found among patients with AIDS and the majority of these are the B-cell type. In patients with AIDS, the gastrointestinal tract is the most common extranodal site of involvement.75,76 These tumors are very aggressive and often present at an advanced stage. 76 Colonic lymphomas can cause diarrhea, hemorrhage, obstruction, and perforation. 75 The endoscopic appearance of lymphoma of the colon may include a bulky mass lesion that can resemble adenocarcinoma (Fig 9), ulcerations, colitis-like abnormalities of the colon, and necrotic abscesses. 76,77 In a series of 15 cases of primary colonic lymphoma, the cecum was the most common site of involvement (73% of patients), rs Other studies have also reported lymphoma of the colon limited to the ileum and cecum. r9 These findings emphasize the importance of colonoscopy instead of sigmoidoscopy for making the diagnosis of colonic lymphoma in patients with AIDS.
Changing Spectrum of Colonic Diseases The introduction of protease inhibitors and HAART has had a significant impact on the outcome of patients with HIV infection.80-85 Since the introduction of pro tease inhibitor-based regimens, there has been a decrease in the prevalence of certain opportunistic infections of the gastrointestinal tract. MOnkem{311er et a186 showed a significant decline in the prevalence of all opportunistic disorders from 69% to 13% among 166 HIVinfected patients presenting for endoscopic evaluation between 1995 and 1998. In addition, this study also reported a decline in the prevalence of CMV disease. This trend occurred as the proportion of individuals receiving HAART increased from 0% to 57%. Opportunistic disorders were present in 91% of patients on no antiretroviral therapy and in only 30% of those on HAART. s6
Conclusions The diagnosis of colonic disease in patients with AIDS is challenging. Although the prevalence of opportunistic diseases of AIDS-ASSOCIATED COLONIC DISEASE
the colon is decreasing, it is still important for endoscopists to be aware of the spectrum of disease so that they may readily diagnose and treat these disorders in patients with AIDS. Despite the excellent results achieved with HAART, gastrointestinal infections remain a significant problem in patients from developing countries, in those with undiagnosed or untreated HIV infection, and in those failing HAART.
References 1. Colebunders R, Francis H, Mann JM, et al: Persistent diarrhea, strongly associated with HIV infection in Kinshasa, Zaire. Am J Gastroenterol 82:859-864, 1987 2. Mayer HB, Wanke CA: Diagnostic strategies in HIV-infected patients with diarrhea. AIDS 8:1639-1648, 1994 3. Smith PD, Quinn TC, Strober W, et al: NIH conference. Gastrointestinal infections in AIDS. Ann Intern Med 116:63-77, 1992 4. Anastasi JK, Capili B: HIV and diarrhea in the era of HAART: 1998 New York State hospitalizations. Am J Infect Control 28:262-266, 2000 5. Lubeck DP, Bennett CL, Mazonson PD, et al: Quality of life and health service use among HIV-infected patients with chronic diarrhea. J Acquir Immune Defic Syndr 6:478-484, 1993 6. Wilcox CM, Rabeneck L, Friedman S: AGA technical review: Malnutrition and cachexia, chronic diarrhea, and hepatobiliary disease in patients with human immunodeficiency virus infection. Gastroenterology 111:1724-1752, 1996 7. Antony MA, Brandt LJ, Klein RS, et al: Infectious diarrhea in patients with AIDS. Dig Dis Sci 33:1141-1146, 1988 8. Bini EJ, Cohen J: Diagnostic yield and cost-effectiveness of endoscopy in chronic human immunodeficiency virus-related diarrhea. Gastrointest Endosc 48:354-361, 1998 9. Bini EJ, Weinshel EH: Endoscopic evaluation of chronic human immunodeficiency virus-related diarrhea: Is colonoscopy superior to flexible sigmoidoscopy? Am J Gastroenterol 93:56-60, 1998 10. Blanshard C, Francis N, Gazzard BG: Investigation of chronic diarrhoea in acquired immunodeficiency syndrome. A prospective study of 155 patients. Gut 39:824-832, 1996 11. Blanshard C, Gazzard BG: Natural history and prognosis of diarrhoea of unknown cause in patients with acquired immunodeficiency syndrome (AIDS). Gut 36:283-286, 1995 12. Bonacini M, Skodras G, Quiason S, et al: Prevalence of enteric pathogens in HIV-related diarrhea in the midwest. AIDS Patient Care STDS 13:179-184, 1999 13. Connolly GM, Forbes A, Gazzard BG: Investigation of seemingly pathogen-negative diarrhoea in patients infected with HIV1. Gut 31:886-889, 1990 14. Connolly GM, Ellis DS, Williams JE, et al: Use of electron microscopy in examination of faeces and rectal and jejunal biopsy specimens. J Clin Pathol 44:313-316, 1991 15. Connolly GM, Shanson D, Hawkins DA, et al: Non-cryptosporidial diarrhoea in human immunodeficiency virus (HIV) infected patients. Gut 30:195-200, 1989 16. Kearney DJ, Steuerwald M, Koch d, et ah A prospective study of endoscopy in HIV-associated diarrhea. Am J Gastroenterol 94:596602, 1999 17. Manatsathit S, Tansupasawasdikul S, Wanachiwanawin D, et al: Causes of chronic diarrhea in patients with AIDS in Thailand: a prospective clinical and microbiological study. J Gastroenterol 31: 533-537, 1996 18. Rene E, Marche C, Regnier B, et al: Intestinal infections in patients with acquired immunodeficiency syndrome. A prospective study in 132 patients. Dig Dis Sci 34:773-780, 1989 19. Smith PD, Lane HC, Gill VJ, et al: Intestinal infections in patients with the acquired immunodeficiency syndrome (AIDS). Etiology and response to therapy. Ann Intern Med 108:328-333, 1988 20. Wei SC, Hung CC, Chen MY, et al: Endoscopy in acquired immunodeficiency syndrome patients with diarrhea and negative stool studies. Gastrointest Endosc 51:427-432, 2000 21. Wilcox CM, Schwartz DA, Cotsonis G, et al: Chronic unexplained diarrhea in human immunodeficiency virus infection: determination of the best diagnostic approach. Gastroenterology 110:30-37, 1996 83
22. Rabeneck L, Gyorkey F, Genta BM, et ah The role of Microsporidia in the pathogenesis of HIV-related chronic diarrhea. Ann Intern Med 119:895-899, 1993 23. Bini EJ: Endoscopic approach to HIV-associated diarrhea: how far is far enough? Am J Gastroenterol 94:556-559, 1999 (editorial) 24. Dieterich DT, Rahmin M: Cytomegalovirus colitis in AIDS: Presentation in 44 patients and a review of the literature. J Acquit Immune Defic Syndr 4 Suppl 1:$29-$35, 1991 25. Bini EJ, Gorelick SM, Weinshel EH: Outcome of AIDS-associated cytomegalovirus colitis in the era of potent antiretroviral therapy. J Clin Gastroenterol 30:414-419, 2000 26. Wilcox CM, Chalasani N, Lazenby A, et ah Cytomegalovirus colitis in acquired immunodeficiency syndrome: a clinical and endoscopic study. Gastrointest Endosc 48:39-43, 1998 27. Connolly GM, Forbes A, Gleeson JA, et al: The value of barium enema and colonoscopy in patients infected with HIV. AIDS 4:687689, 1990 28. Deeks SG, Smith M, Holodniy M, et al: HIV-1 protease inhibitors. A review for clinicians. JAMA 277:145-153, 1997 29. Cappell MS, Geller AJ: The high mortality of gastrointestinal bleeding in HIV-seropositive patients: A multivariate analysis of risk factors and warning signs of mortality in 50 consecutive patients. Am J Gastroenterol 87:815-824, 1992 30. Cello JP, Wilcox CM: Evaluation and treatment of gastrointestinal tract hemorrhage in patients with AIDS. Gastroenterol Clin North Am 17:639-648, 1988 31. Chalasani N, Wilcox CM: Etiology and outcome of lower gastrointestinal bleeding in patients with AIDS. Am J Gastroenterol 93:175178, 1998 32. Bini EJ, Weinshel EH, Falkenstein DB: Risk factors for recurrent bleeding and mortality in human immunodeficiency virus infected patients with acute lower GI hemorrhage. Gastrointest Endosc 49: 748-753, 1999 33. DeMarkles MP, Murphy JR: Acute lower gastrointestinal bleeding. Med Clin North Am 77:1085-1100, 1993 34. Peura DA, Lanza FL, Gostout CJ, et al: The American College of Gastroenterology Bleeding Registry: Preliminary findings. Am J Gastroenterol 92:924-928, 1997 35. Longstreth GF: Epidemiology and outcome of patients hospitalized with acute lower gastrointestinal hemorrhage: A population-based study. Am J Gastroenterol 92:419-424, 1997 36. Lew EA, Dieterich DT: Severe hemorrhage caused by gastrointestinal Kaposi's syndrome in patients with the acquired immunodeficiency syndrome: treatment with endoscopic injection sclerotherapy. Am J Gastroenterol 87:1471-1474, 1992 37. Jutabha R, Jensen DM, Machicado G, et al: Randomized controlled studies of injection Gold Probes compared with monotherapies for hemostasis of bleeding canine gastric ulcers. Gastrointest Endosc 48:598-605, 1998 38. Chalasani N, Wilcox CM: Gastrointestinal hemorrhage in patients with AIDS. AIDS Patient Care STDS 13:343-346, 1999 39. Tatum ET, Sun PC, Cohn DL: Cytomegalovirus vasculitis and colon perforation in a patient with the acquired immunodeficiency syndrome. Pathology 21:235-238, 1989 40. Kram HB, Hino ST, Cohen RE, et al: Spontaneous colonic perforation secondary to cytomegalovirus in a patient with acquired immune deficiency syndrome. Crit Care Med 12:469-471, 1984 41. Dieterich DT, Kim MH, McMeeding A, et al: Cytomegalovirus appendicitis in a patient with acquired immune deficiency syndrome. Am J Gastroenterol 86:904-906, 1991 42. Cappell MS, Yao F, Cho KC: Colonic adenocarcinoma associated with the acquired immune deficiency syndrome. Cancer 62:616-619, 1988 43. Cooksley CD, Hwang LY, Waller DK, et al: HIV-related malignancies: Community-based study using linkage of cancer registry and HIV registry data. Int J STD AIDS 10:795-802, 1999 44. Goedert J J: The epidemiology of acquired immunodeficiency syndrome malignancies. Semin Oncol 27:390-401, 2000 45. Zwas FR, Bonheim NA, Berken CA, et al: Diagnostic yield of routine ileoscopy. Am J Gastroenterol 90:1441-1443, 1995 45. Weber R, Muller A, Spycher MA, et al: Intestinal Enterocytozoon bieneusi microsporidiosis in an HIV-infected patient: diagnosis by ileo-colonoscopic biopsies and long-term follow up. Clin Investig 70:1019-1023, 1992
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47. Cranston RD, Anton PA, McGowan IM: Gastrointestinal mucosal biopsy in HIV disease and AIDS. Gastrointest Endosc Clin N Am 10:637-667, 2000 48. Wilcox CM, Straub RF, Schwartz DA: Prospective evaluation of biopsy number for the diagnosis of viral esophagitis in patients with HIV infection and esophageal ulcer. Gastrointest Endosc 44:587593, 1996 49. Clerinx J, Bogaerts J, Taelman H, et al: Chronic diarrhea among adults in Kigali, Rwanda: association with bacterial enteropathogens, rectocolonic inflammation, and human immunodeficiency virus infection. Clin Infect Dis 21:1282-1284, 1995 50. Cappell MS, Philogene C: Clostridium difficile infection is a treatable cause of diarrhea in patients with advanced human immunodeficiency virus infection: A study of seven consecutive patients admitted from 1986 to 1992 to a university teaching hospital. Am J Gastroenterol 88:891-897, 1993 51. Lu SS, Schwartz JM, Simon DM, et al: Clostridium difficile-associated diarrhea in patients with HIV positivity and AIDS: A prospective controlled study. Am J Gastroenterol 89:1226-1229, 1994 52. Marshall JB: Tuberculosis of the gastrointestinal tract and peritoneum. Am J Gastroenterol 88:989-999, 1993 53. Shah S, Thomas V, Mathan M, et ah Colonoscopic study of 50 patients with colonic tuberculosis. Gut 33:347-351, 1992 54. Bhargava DK, Tandon HD, Chawla TC, et al: Diagnosis of ileocecal and colonic tuberculosis by colonosoopy. Gastrointest Endosc 31: 68-70, 1985 55. Ahuja SK, Gaiha M, Sachdev S, et ah Tubercular colitis simulating ulcerative colitis. J Assoc Physicians India 24:617-619, 1976 56. Horsburgh CR, Jr: Mycobacterium avium complex infection in the acquired immunodeficiency syndrome. N Engl J Med 324:13321338, 1991 57. Chin DP, Hopewell PC, Yajko DM, et ah Mycobacterium avium complex in the respiratory or gastrointestinal tract and the risk of M. avium complex bacteremia in patients with human immunodeficiency virus infection. J Infect Dis 169:289-295, 1994 58. Cappell MS, Philogene C: The endoscopic appearance of severe intestinal Mycobacterium avium complex infection as a coarsely granular mucosa due to massive infiltration and expansion of intestinal villi without mucosal exudation. J Clin Gastroenterol 21:323326, 1995 59. Nguyen HN, Frank D, Handt S, et al: Severe gastrointestinal hemorrhage due to Mycobacterium avium complex in a patient receiving immunosuppressive therapy. Am J Gastroenterol 94:232-235, 1999 60. Wisser J, Zingman B, Wasik M, et al: Cytomegalovirus pseudotumor presenting as bowel obstruction in a patient with acquired immunodeficiency syndrome. Am J Gastroenterol 87:771-774, 1992 61. Janoff EN, Orenstein JM, Manischewitz JF, et al: Adenovirus colitis in the acquired immunodeficiency syndrome. Gastroenterology 100: 976-979, 1991 62. Lumadue JA, Manabe YC, Moore RD, et al: A clinicopathologic analysis of AIDS-related cryptosporidiosis. AIDS 12:2459-2466, 1998 63. Chun D, Chandrasoma P, Kiyabu M: Fulminant amebic colitis. A morphologic study of four cases. Dis Colon Rectum 37:535-539, 1994 64. Clyti E, Aznar C, Couppie P, et al: A case of coinfection by Balantidium coil and HIV in French Guiana. Bull Soc Pathol Exot 91:309311, 1998 65. Lew EA, Poles MA, Dieterich DT: Diarrheal diseases associated with HIV infection. Gastroenterol Clin North Am 26:259-290, 1997 66. Halline AG, Maldonado-Lutomirsky M, Ryoo JW, et al: Colonic histoplasmosis in AIDS: unusual endoscopic findings in two cases. Gastrointest Endosc 45:199-204, 1997 67. Balthazar EJ, Megibow AJ, Barry M, et ah Histoplasmosis of the colon in patients with AIDS: imaging findings in four cases. A JR Am J Roentgenol 161:585-587, 1993 68. Hertan H, Nair S, Arguello P: Progressive gastrointestinal histoplasmosis leading to colonic obstruction two years after initial presentation. Am J Gastroenterol 96:221-222, 2001 69. Levine J, Dykoski RK, Janoff EN: Candida-associated diarrhea: A syndrome in search of credibility. Clin Infect Dis 21:881-886, 1995 70. Balthazar EJ, Stern J: Necrotizing Candida enterocolitis in AIDS: CT features. J Comput Assist Tomogr 18:298-300, 1994 71. Saltz RK, Kurtz RC, Lightdale CJ, et al: Kaposi's sarcoma. GastroBINI AND DIEHL
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intestinal involvement correlation with skin findings and immunologic function. Dig Dis Sci 29:817-823, 1984 Ell C, Matek W, Gramatzki M, et al: Endoscopic findings in a case of Kaposi's sarcoma with involvement of the large and small bowel. Endoscopy 17:161-164, 1985 Weprin L, Zollinger R, Clausen K, et al: Kaposi's sarcoma: Endoscopic observations of gastric and colon involvement. J CHn Gastroenterol 4:357-360, 1982 Friedman SL, Wright TL, Altman DF: Gastrointestinal Kaposi's sarcoma in patients with acquired immunodeficiency syndrome. Endoscopic and autopsy findings. Gastroenterology 89:102-108, 1985 Beck PL, Gill MJ, Sutherland LR: HIV-associated non-Hodgkin's lymphoma of the gastrointestinal tract. Am J Gastroentero191:23772381, 1996 Heise W, Arasteh K, Mostertz P, et al: Malignant gastrointestinal lymphomas in patients with AIDS. Digestion 58:218-224, 1997 Wang MH, Wong JM, Lien HC, et al: Colonoscopic manifestations of primary colorectal lymphoma. Endoscopy 33:605-609, 2001 Zighelboim J, Larson MV: Primary colonic lymphoma. Clinical presentation, histopathologic features, and outcome with combination chemotherapy. J Clin Gastroenterol 18:291-297, 1994 Auger M J, Allan NC: Primary ileocecal lymphoma. A study of 22 patients. Cancer 65:358-361, 1990
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80. Jacobson MA, French M: Altered natural history of AIDS-related opportunistic infections in the era of potent combination antiretroviral therapy. AIDS 12:$157-$163, 1998 (suppl) 81. Detels R, Munoz A, McFarlane G, et al: Effectiveness of potent antiretroviral therapy on time to AIDS and death in men with known HIV infection duration. Multicenter AIDS Cohort Study Investigators. JAMA 280:1497-1503, 1998 82. Hogg RS, Heath KV, Yip B, et al: Improved survival among HIVinfected individuals following initiation of antiretroviral therapy. JAMA 279:450-454, 1998 83. Vittinghoff E, Scheer S, O'Malley P, et al: Combination antiretroviral therapy and recent declines in AIDS incidence and mortality. J Infect Dis 179:717-720, 1999 84. Palella FJ, Jr, Delaney KM, Moorman AC, et al: Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med 338:853-860, 1998 85. Murphy EL, Collier AC, Kalish LA, et al: Highly active antiretroviral therapy decreases mortality and morbidity in patients with advanced HIV disease. Ann Intern Med 135:17-26, 2001 86. Monkemuller KE, Call SA, Lazenby A J, et al: Declining prevalence of opportunistic gastrointestinal disease in the era of combination antiretroviral therapy. Am J Gastroenterol 95:457-462, 2000
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The colon is a common site of gastrointestinal disease in patients with AIDS, and the frequency and severity of disease increases as immunosuppression worsens. In these individuals, the most common manifestations of colonic disease include diarrhea, lower gastrointestinal bleeding, and abdominal pain. Gastroenterologists caring for HIV-infected patients with colonic disease must be aware of the causes of these diseases and the proper endoscopic techniques needed to make an accurate diagnosis. This article reviews the indications for lower endoscopy and the differential diagnosis of colonic disease in patients with AIDS. The authors also review the techniques of colonoscopy, sigmoidoscopy, ileal intubation, and biopsy. In addition, the authors discuss the endoscopic appearances of various colonic diseases in patients with AIDS to assist the endoscopist in correctly identifying these disorders. This is a US government work. There are no restrictions on its use.
astrointestinal disease is common in patients with human
G immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS). The clinical importance of colonic disease in this patient population is enormous. Chronic diarrhea, lower gastrointestinal bleeding, and abdominal pain are the most common manifestations of AIDS-associated coionic disease. Patients with AIDS and symptoms of colonic disease will frequently require an endoscopic evaluation. This article reviews the indications for lower endoscopy in patients with AIDS, discusses the techniques of colonoscopy, sigmoidoscopy, ileal intubation, and biopsy, and highlights the endoscopic appearance of various colonic diseases.
Indications for Colonoscopy and Sigmoidoscopy Chronic Diarrhea In the pre-highly active antiretroviral therapy (HAART) era, diarrhea has been reported in approximately 50% of AIDS patients in North America, and this estimate approached 100% in developing countries. 1-3 Diarrhea still occurs in the era of HAART and this symptom was the primary cause for hospitalization in 2.8% of the 15,000 patients with HIV that were hospitalized in New York State in 1998. 4 In these patients, chronic diarrhea results in a significant increase in morbidity From the Division of Gastroenterology, VA New York Harbor Healthcare System, Bellevue Hospital Center, and NYU School of Medicine, New York, NY. Address reprint requests to Edmund J. Bini, MD, FACP, FACG, VA New York Harbor Healthcare System, Division of Gastroenterology (111D), 423 East 23rd St, New York, NY 10010; e-mail: [email protected]. This is a US government work. There are no restrictions on its use. 1096-2883/02/0402-000550.00/0 doi:l 0.1053/tgie.2002.33010
and mortality. Compared to similar patients without diarrhea, HIV-infected patients with chronic diarrhea have a marked reduction in quality of life and incur higher health care costs. 5 The American Gastroenterological Association has published guidelines for the management of chronic HIV-related diarrhea. 6 In this medical position statement, a consensus panel recommended a stepwise approach tailored to the individual patient. The first step includes at least 3 sets of stool specimens for common enteric bacteria and parasites, including microsporidia and cryptosporidia. A stool sample for Clostridium difficile is recommended for patients at risk for antibiotic-associated diarrhea. In addition, febrile patients should have blood drawn for bacterial culture and, if the CD4 lymphocyte count is below 100 cells/mm 3, blood should be submitted for mycobacterial culture. If stool tests do not identify an enteric pathogen, flexible sigmoidoscopy with mucosal biopsy is recommended. The guidelines acknowledge that for certain patients, colonoscopy may be indicated instead of flexible sigmoidoscopy. When no pathogen is identified on lower endoscopy, upper endoscopy with biopsy of the duodenum for light-microscopic examination should be performed; optional biopsies for mycobacterial culture and electron microscopy may also be obtained at the time of endoscopy. Numerous studies have evaluated the diagnostic yield of sigmoidoscopy and colonoscopy in HIV-infected patients with chronic diarrhea, r 22 However, only a few of these studies have examined the diagnostic yield of lower endoscopy in patients with a negative stool evaluation. 8,9,13A6,2~ This discussion will focus on the role of lower endoscopy in patients with negative stool studies because in clinical practice, most gastroenterologists would not perform endoscopy prior to a comprehensive stool evaluation. The diagnostic yield of colonoscopy in HIV-infected patients with chronic diarrhea and negative stool studies ranged from 27% to 65%, with cytomegalovirus (CMV) being the most common cause identified (Table 1). In contrast, rectosigmoid biopsies obtained by flexible sigmoidoscopy had a somewhat lower diagnostic yield (22%). The higher yield of colonoscopy compared with flexible sigmoidoscopy was due to the detection of CMV limited to the proximal colon. 8,9,2~The study by Wilcox et a121 found isolated right-sided colonic disease in only 8% of patients. In contrast, the authors of this review8,9 and others ~<2~ have found that 23% to 46% of diagnoses in HIV-infected patients with chronic diarrhea were identified only on biopsies taken from the proximal colon. The decision to perform colonoscopy versus flexible sigmoidoscopy as the initial diagnostic endoscopic procedure is controversial. 23 In a study of 44 patients with CMV colitis, CMV was found only in the cecum in 39% of individuals. 24 Isolated right-sided CMV disease of the colon was found in 29% of 252 patients with CMV colitis. 25 Wilcox et a126 made a diagnosis of CMV disease limited to the proximal colon in 13% of 31 patients with CMV colitis undergoing colonoscopy. These find-
Techniques in Gastrointestinal Endoscopy, Vol 4, No 2 (April), 2002: pp 77-85
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TABLE 1. Diagnostic Yield of Lower Endoscopy in HIV-lnfected Patients With Chronic Diarrhea and Negative Stool Studies* Author
No. of patients
Endoscopic procedure
Cause of diarrhea identified %
Most common cause
Right-sided disease1- %
Wilcox et a121 Bini and Weinshel 9 Bini and Cohen 8
48 317 85 191 79 40
Colonoscopy Colonoscopy Sigmoidoscopy Colonoscopy Colonoscopy Colonoscopy
27 35 22 39 28 65
CMV CMV CMV CMV CMV CMV
8 30 N/A 28 23:1: 46
Kearney et a116 Wei et al2~
*Studies were included in this table only if patients had a negative stool evaluation prior to endoscopy and the diagnostic yield of flexible sigmoidoscopy or colonoscopy could be determined from the data provided. 1-The percentage of lesions that were identified only in the proximal colon (beyond the reach of the flexible sigmoidoscope). :l:Biopsies of the terminal ileum were obtained in 70% of patients.
ings support the policy of performing colonoscopy instead of flexible sigmoidoscopy in HIV-infected patients with chronic diarrhea. In addition, the use of colonoscopy resulted in a lower cost per pathogen identified ($2,787 v $3,353) compared to flexible sigmoidoscopy. 8 However, other investigators have found no beneft of performing colonoscopy over flexible sigmoidoscopy in this patient population. 15,2~,27 The reason for this discrepancy is not known but may be due to differences in the patient populations studied. The differential diagnosis of chronic diarrhea in patients with AIDS is extensive. The causes of chronic diarrhea in this patient population are shown in Table 2. In addition to the etiologies listed, consideration should also be given to protease-inhibitor induced diarrhea. This entity is seen most commonly with nelfinavir. 28
TABLE 2. Differential Diagnosis of Colonic Disease in AIDS Patients With Diarrhea Bacterial Salmonella Shigella flexneri Campylobacter jejuni Escherichia coli Clostridium difficile Yersinia enterocofitica Mycobacterium avium complex Mycobacterium tuberculosis Viral Cytomegalovirus Adenovirus Herpes simplex virus Calcivirus Astrovirus Protozoal Cryptosporidium parvum Isospora belli Entamoeba histolytica Giardia lamblia Balantidium coil Pneumocystis carinfi Toxoplasma gondii ? Blastocystis hominis Fungal Histoplasma capsulatum Candida albicans Coccidioides immitis Cryptococcus neoformans Strongyloides stercoralis Blastomyces dermatitidis Neoplastic Kaposi's sarcoma Lymphoma (Hodgkin's and non-Hodgkin's type)
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Lower Gastrointestinal Bleeding Lower gastrointestinal bleeding is another clinical presentation of colonic disease in patients with AIDS. Several studies have evaluated the causes of lower gastrointestinal bleeding in this patient population. 29 32 The differential diagnosis of lower gastrointestinal hemorrhage is shown in Table 3. In a large series of 312 HIV-infected patients with lower gastrointestinal hemorrhage, a source of bleeding was identified by colonoscopy or sigmoidoscopy in 94.6% of patients. 32 The diagnostic yield of colonoscopy was significantly higher than the yield of flexible sigmoidoscopy (96.6% v 88.6%, P = .02). In this study, the most common etiologies that were identified included CMV colitis (25.3%), lymphoma (12.2%), idiopathic colitis (12.2%), and Kaposi's sarcoma (10.3%). CMV colitis, lymphoma, and Kaposi's sarcoma were usually seen in patients with severe immunosuppression (CD4 count <200 cells/mm3). In those with CD4 counts greater than 200 cells/ mm 3, the causes of lower gastrointestinal bleeding were similar to HIV-negative patients, with colitis, diverticular hemorrhage, and hemorrhoids being the most common sources identified. 32 Endoscopic hemostasis may be required in certain cases, and treatment of acute lower bleeding in HIV-infected patients should be approached in a manner similar to the approach taken in HIV-negative individuals. In the series of 312 HIVinfected patients with acute lower gastrointestinal bleeding, major stigmata of hemorrhage were noted in 30.4% of patients, including active bleeding in 21.2%, adherent clots in 6.1%, and nonbleeding visible vessels in 3.2%.32 In this study, endoscopic hemostasis, consisting of epinephrine injection and/or bipolar electrocoagulation, was successful in achieving hemostasis in
TABLE 3. Causes of Acute Lower Gastrointestinal Bleeding in HIV-Infected Patients Cytomegalovirus colitis Lymphomas Idiopathic colitis Kaposi's sarcoma Diverticulosis Clostridium difficile colitis Hemorrhoids Rectal varices Anal fissures Mycobacterium tuberculosis Histoplasmosis Adenomas Carcinomas Vascular ectasias
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intestinal tract should be avoided in patients with suspected colon perforation. The individuals should be evaluated by computed tomography and a surgical consultation should be requested. Chronic abdominal pain in HIV-infected patients with coionic disease may be caused by involvement of the colonic wall by infectious or neoplastic diseases. Infectious causes include CMV disease, Mycobacterium avium complex, and other pathogens that cause colitis. Neoplastic diseases include lymphoma, Kaposi's sarcoma, and adenocarcinoma of the colon. Idiopathic ulcers of the colon may also cause chronic abdominal pain.
Other Indications
Fig 2. Proper biopsy technique for ulcers of the colon. The "X's" mark the locations from which biopsies should be obtained. It is important to sample from the edge of the ulcer as well as the base of the ulcer. The diagnosis of C M V may be missed if biopsies are not taken from the base of the ulcer.
93.9% of patients with active bleeding and 100% of those with nonbleeding visible vessels. The 30-day incidence of recurrent bleeding in this population was 17.6%, which is similar to what has been reported in HIV-negative patients with acute lower gastrointestinal hemorrhage. 33-35 However, the 30-day mortality rate in HIV-infected patients was 14.4% and this is higher than the 5% mortality rate in the general population. 34,35 In our experience, colonoscopy is superior to flexible sigmoidoscopy for the evaluation of lower gastrointestinal hemorrhage in this patient population. Prior to colonoscopy, gastrointestinal lavage should be done in the usual manner. The endoscopist should pay careful attention to detail and look closely for stigmata of recent hemorrhage. These stigmata may be located within ulcers, masses, colitis, or within a diverticulum. 32 Active bleeding and visible vessels should be treated the same way that they are treated in non-HIV-infected patients. The use of epinephrine injections and bipolar electrocoagulation are safe and effective.32,36 We prefer to use the Injection Gold Probe (Boston Scientiflc/Microvasive, Natick, MA), which allows injection of epinephrine followed by bipolar electrocoagulation (Fig 1). The advantages of Injection Gold Probes are the ability to irrigate, inject, and coagulate without probe removal. 37 For a detailed review on lower gastrointestinal bleeding in patients with AIDS, see Chalasani and W i l c o x , 38
Abdominal Pain Colonic disease may cause acute or chronic abdominal pain. The diagnosis of perforated CMV ulcers of the colon or CMVassociated appendicitis should be considered in HIV-infected patients with severe acute abdominal pain and peritoneal s i g n s . 39-41 Patients with Kaposi's sarcoma, lymphoma, or adenocarcinoma of the colon may also present with colon obstruction or perforation. Endoscopic evaluation of the lower gastroAIDS-ASSOCIATED COLONIC DISEASE
In addition to the manifestations of colonic disease described above, there are other indications for colonoscopy in patients with AIDS. These individuals are susceptible to many of the disease entities seen in immunocompetent individuals. With the widespread use of HAART, patients with AIDS are now living longer and many live well beyond the age of 50 years. These patients should be screened for colorectal cancer and colonoscopy may be performed for screening or to evaluate a positive fecal occult blood test. Adenomas and adenocarcinomas of the colon have been identified in patients with AIDS. 32,42 The role of HIV in increasing the incidence of colon adenocarcinoma is controversial. On occasion, an aggressive adenocarcinoma may be seen in a young AIDS patient, 42 and this has given rise to the thought that the occurrence of cancer in this setting is linked to immunosuppression. A single study suggested an increased risk in female patients with AIDS# 3 However, recent data do not suggest that adenocarcinoma of the colon is more common in patients with AIDS. 44
Intubation of the Terminal Ileum Intubation of the terminal ileum during colonoscopy is not routinely performed. However, intubation of the terminal ileum and ileal biopsy can increase the diagnostic yield of colonoscopy, especially in patients with AIDS. 45 In a prospective study of 138 patients undergoing colonoscopy, ileoscopy made a diagnosis in 2.7% of asymptomatic patients undergoing routine colonoscopy and 29% of patients with diarrhea. 45 The diagnostic yield of ileoscopy was even higher (67%) in HIVinfected patients with diarrhea. 45 In a prospective study of 79 HIV-infected patients with chronic diarrhea and negative stool studies, Kearney et a116 compared the diagnostic yield of a complete endoscopic workup (EGD and colonoscopy with biopsies of the terminal ileum) to a more limited approach (flexible sigmoidoscopy). They calculated the sensitivity of different sites using combined biopsies of the duodenum, left and right colon, and terminal ileum as the "gold standard." With this technique, the authors found that the sensitivity of combined biopsies from the left colon, right colon and terminal ileum was 100%, which was higher than the sensitivity of biopsies obtained from the left and right colon alone (82%). The addition of terminal ileal biopsies resulted in the diagnosis of 5 additional cases of microsporidia. 16 Other investigators have also made the diagnosis of microsporidiosis by ileal biopsy. 46 In HIV-infected patients with diarrhea, colonoscopy with ileal biopsy may obviate the need for upper endoscopy if the terminal ileum is entered successfully. 79
Fig 3. Fig 1.
80
Fig 4.
Fig 5.
Fig 6.
Fig 7.
Fig 8.
Fig 9. BINI AND DIEHL
Biopsy Techniques The endoscopic appearance of colonic disease is often variable in patients with AIDS and these findings are rarely pathognomonic. The wide spectrum of colonic diseases in this population makes diagnosis a challenge for the gastroenterologist. In addition, it is not uncommon to find multiple pathogens in a single patient. Therefore, mucosal biopsies are essential in making a diagnosis of colonic disease in patients with AIDS. During colonoscopy, all abnormalities should be biopsied multiple times. In addition, patients undergoing colonoscopy for diarrhea should have biopsies taken from the cecum/ascending colon as well as the rectosigmoid colon. Typically, rectosigmoid biopsies will yield a diagnosis. However, the disease may be limited to the right colon and biopsies from the cecum and ascending colon may be helpful, particularly in patients with CMV. 9 When ulcers are seen during endoscopy, multiple biopsy specimens should be obtained from the edges as well as the base of the ulcer because the diagnosis of CMV may be missed if biopsies are not taken from the base of the ulcer (Fig 2). The optimal number of biopsies to take during colonoscopy is not known. Cranston et a147 recommend that 3 biopsy specimens be taken from the rectosigmoid colon in patients with HIV-associated diarrhea. Although there are no studies evaluating the number of specimens necessary to make a diagnosis of colonic ulcer disease, Wilcox et a148prospectively evaluated the number of biopsies necessary for diagnosis of viral esophagitis in HIV-infected patients with esophageal ulcers and concluded that at least 10 biopsy specimens may be needed. We routinely take at least 6 to 10 specimens from all colonic abnormalities. In addition, we take a similar number of biopsy specimens from normal mucosa in the cecum/ascending colon and rectosigmoid colon in patients with diarrhea. We recommend using a Multibite biopsy forceps (Boston Scientific/Microvasive, Natick, MA) because this device enables the endoscopist to obtain multiple large mucosal samples in a single pass (Fig 3).
Endoscopic Appearance of Colonic Diseases A working knowledge of the endoscopic appearance of various HIV-associated diseases of the colon is critical for endoscopists who care for patients with AIDS. We will now discuss the endoscopic appearance of common AIDS-associated colonic diseases.
Salmonella, Shigella, and Campylobacter Salmonella typhimurium, Salmonella enteritidis, Shigella flexneri, and Campytobacterjejuni are the most common bacterial causes of colitis in patients with AIDS. Colonic infection with these bacteria can result in bloody diarrhea, tenesmus, and abdominal pain. The endoscopic appearance of these bacterial infections includes erythema, edema, and hemorrhagic and ulcerated mucosal lesions. 49 These findings may mimic ulcerative colitis.
Clostridium difficile Clostridium difficile colitis is common among patients with AIDS, resulting in bloody, mucoid diarrhea associated with fever and abdominal pain. One study has reported that C difficile colitis is more severe in patients with AIDS than in immunocompetent individuals9 However, other investigators did not find a difference in the severity of disease between immunodeficient and immunocompetent individuals. 51 Endoscopy usually reveals edema, erythema, and friability of the colonic mucosa that is covered by a yellow-white pseudomembrane (Fig 4). However, pseudomembranes may occasionally be absent in patients with AIDS. Disease is often localized to the rectosigmoid colon, but pancolonic or isolated right-sided colitis may be seen. Mycobacterium tuberculosis Although tuberculosis of the gastrointestinal tract is rare in the United States, cases still occur, especially in patients with AIDS. The diagnosis of gastrointestinal tract tuberculosis is challenging because this disease can mimic other disorders. 52 The ileocecal area and other regions of the colon are the most common sites of tuberculous involvement of the gastrointestinal tract. 52 The endoscopic appearance of colonic tuberculosis includes segmental ulcers and colitis, inflammatory strictures, mucosal nodules, and hypertrophic lesions resembling polyps and masses. 52-~4 An endoscopic photograph of Mycobacterium tuberculosis infection of the colon is shown in Figure 5. Tuberculous colitis can rarely present as diffuse colitis, which can appear similar to ulcerative colitis. 55 In a study of 50 patients with colonic tuberculosis, Shah et a153 noted that a nodular mucosa with areas of ulceration was the most common endoscopic finding. In this study, ileocecal disease was found in 16 patients, ileocecal and contiguous ascending colon disease in 14,
Fig 1. Injection Gold Probe can be used for the treatment of bleeding lesions in the colon. This device allows injection of epinephrine followed by bipolar electrocoagulation with a single combination probe. Fig 3. Multibite biopsy forceps or other large biopsy forceps should be used to obtain colonic biopsies because this device enables the endoscopist to obtain multiple large mucosal samples in a single pass. Fig 4. Clostridium difficile colitis in an AIDS patient with severe diarrhea, fever, and abdominal pain. There are extensive pseudomembranes overlying an erythematous, edematous, and friable mucosa. Fig 5. Mycobacterium tuberculosis disease of the colon. A deep ulcer of the colonic mucosa is seen in the absence of surrounding colitis. Fig 6. C M V colitis and ulcer of the colon. There is an ulcer seen at the bottom of the photograph and this ulcer is covered with a whitish exudate. There is also surrounding erythema and edema of the colonic mucosa. Fig 7. Histoplasma capsulatum infection of the colon. The endoscopic appearance of histoplasmosis resembles adenocarcinoma of the colon in this AIDS patient with abdominal pain, fever, and diarrhea. Fig 8. Kaposi's sarcoma of the colon in a homosexual male with AIDS. A reddish plaque-like lesion is noted in the sigmoid colon. Fig 9. Lymphoma of the colon. A large mass was located in the ascending colon in this patient with AIDS. Biopsies revealed a B-cell non-Hodgkin's lymphoma. AIDS-ASSOCIATED COLONIC DISEASE
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segmental colonic tuberculosis in 13, ileocecal disease and nonconfluent involvement of another part of the colon in 5, and pancolitis in 2 patients. 53 These findings emphasize the importance of colonoscopy for diagnosing colonic tuberculosis.
Mycobacterium avium Complex Mycobacterium avium complex (MAC) is a group of nontuberculous mycobacteria and these organisms are a common cause of systemic infection in patients with AIDS. 56 MAC can cause colonic disease and diarrhea in immurlocompromised patients with CD4 lymphocyte counts below 100 cells/mm3. 57 Endoscopically, colonic MAC may present as granular white nodules 2 to 4 mm in diameter with a surrounding rim of erythema. 58 The mucosa may appear erythematous, edematous, friable, and ulcerated. 59 However, the colonic mucosa may appear completely normal in patients with MAC infection.
Cytomegalovirus
Although this organism primarily inhabits the microvillus border of intestinal epithelial cells, it may also infect the apical border of epithelial cells in the colon. Infection with C parvum can cause colonic cryptitis. 62 The endoscopic appearance may be normal or appear as colitis with erythema, edema, and friability. The colonic mucosa may be covered by a mucopurulent exudate in patients with severe disease.
Isospora belli Isospora belli is a coccidian protozoan that can cause diarrhea in patients with AIDS. Although it more commonly infects the small bowel, I belli can cause severe colitis. The endoscopic appearance of I belli infection of the colon is nonspecific and includes edema, erythema, and friability.
Entamoeba histolytica Entamoeba histolytica is a protozoan with worldwide distribu-
Cytomegalovirus is a ubiquitous virus that often affects the colon in patients with AIDS. The endoscopic appearance of CMV is variable, but most often appears as ulcers associated with colitis (erythema, edema, and friability). 25 The spectrum of CMV disease of the colon may also include colitis without ulcers, ulcers without colitis, or a normal appearing colon. 25,26 An endoscopic photograph of CMV disease of the colon is shown in Figure 6. Typically, CMV disease is seen in the distal colon or throughout the colon. 25,26However, isolated proximal colonic disease may occur. 8,9,24,25In addition, CMV-associated colonic disease can present with a mass lesion, also known as a "pseudotumor," which can be mistaken grossly for an adenocarcinoma. 6o
tion, but infection is most prevalent in developing countries. Invasive colonic disease may develop in patients with AIDS, especially in homosexual individuals who acquire the infection sexually. The spectrum of disease caused by E histolytica ranges from noninvasive colonization to a self-limited diarrhea to invasive colitis, including fulminant colitis and colonic perforation. 63 The endoscopic appearance includes a nonspecific colitis with edema, erythema, friability, and ulcerations. Large, geographic mucosal ulcers associated with yellow-green pseudomembranes may also be seen. 63 The mucosa adjacent to ulcerations may be hemorrhagic or inflamed, resembling ischemic colitis or idiopathic inflammatory bowel disease, respectively. 63 The disease may be focal and can appear anywhere throughout the colon.
Herpes Simplex Virus
Balantidium coli
Whereas most humans are infected at some time in their lives by herpes simplex virus type 1 or 2, diarrheogenic infections of the intestines by these double-stranded DNA viruses are rare in the population at large and virtually confined to individuals with impaired immunity. At endoscopy, infected mucosa may show erythematous areas with small vesicular lesions, or shallow ovoid ulcers with or without a vesicular rim. 3 These vesicles may rupture, forming small ulcers that may coalesce to form larger ulcers. Infection of the distal colon and rectum is often accompanied by involvement of the anal mucosa and perianal skin. 3
Balantidium coli is a large ciliate protozoan that has a worldwide
Adenovirus Adenoviruses are ubiquitous double-stranded DNA viruses that can cause diarrhea in patients with AIDS. Colonic infection with adenoviruses can result in enterocolitis with edema, erythema, and friability of the colonic mucosa. The endoscopic appearance of adenovirus colitis may be completely normal, making it difficult to diagnose this infection. In a study of 5 AIDS patients with adenovirus infection of the colon, colonoscopy revealed normal mucosa in 3 cases and mildly inflamed mucosa in 2. 61
Cryptosporidium parvum Cryptosporidiurn parvum is a coccidian protozoan that is one of the most common causes of diarrhea in patients with AIDS. 82
distribution. The organism can be found in the lumen of the terminal ileum, cecum, and colon. Infection may lead to an asymptomatic carrier state, to chronic intermittent diarrhea, or to severe dysenteric diarrhea. 64 Invasion of the mucosa results in ulceration, with endoscopic and microscopic features similar to those of invasive amebiasis. 64
Histoplasma capsulatum Histoplasma capsulatum is a dimorphic fungus that can cause severe colonic disease in patients with AIDS. This organism may infect any segment of the gastrointestinal tract. 65 The endoscopic spectrum includes colitis, ulcerations, or a mass lesion of the colon. 66-68 On endoscopic examination, histoplasmosis may appear as inflammation with elevated whitish plaques that can progress to ulcers. The most common endoscopic appearance of histoplasmosis is a mass lesion (Fig 7), and this can often be mistaken for colon carcinoma. 66,67 Histoplasmosis has also been reported to cause polypoid lesions of the colon. 66
Candida albicans The role of Candida species as a cause of colonic disease in patients with AIDS is controversial. Some investigators have implicated Candida species as a cause of diarrhea in patients with AIDS who did not have any other pathogens identified. 69 BINI AND DIEHL
In these patients, treatment of Candida resulted in resolution of diarrhea. Endoscopic evaluation of the colon in patients with Candida may reveal areas of patchy erythema or discrete ulcers that resemble those caused by CMV. One group of investigators has reported a case of necrotizing enterocolitis secondary to invasive candidiasis in a patient with AIDS. 7~
Kaposi's Sarcoma Kaposi's sarcoma is a malignant tumor of endothelial cell origin and is a common neoplasm in patients with AIDS. It is predominantly found in homosexual and bisexual men and gastrointestinal involvement is present in approximately 75% of those with oral mucosal lesions.r1 The diagnosis of Kaposi's sarcoma of the colon can be made by its characteristic appearance of a violaceous plaque-like lesion (Fig 8) during colonoscopy. 72 Colonic Kaposi's sarcoma lesions may be macular or nodular red, purplish, or violaceous lesions. These lesions may be sessile or polypoid and can have central umbilication or ulceration. 72,73Although they are usually several millimeters or centimeters in size, large masses have also been reported. Endoscopic biopsy may have a high false negative rate (77%) because Kaposi's sarcoma can be located deep in the submucosa. 7~
Lymphoma Lymphomas are common tumors found among patients with AIDS and the majority of these are the B-cell type. In patients with AIDS, the gastrointestinal tract is the most common extranodal site of involvement.75,76 These tumors are very aggressive and often present at an advanced stage. 76 Colonic lymphomas can cause diarrhea, hemorrhage, obstruction, and perforation. 75 The endoscopic appearance of lymphoma of the colon may include a bulky mass lesion that can resemble adenocarcinoma (Fig 9), ulcerations, colitis-like abnormalities of the colon, and necrotic abscesses. 76,77 In a series of 15 cases of primary colonic lymphoma, the cecum was the most common site of involvement (73% of patients), rs Other studies have also reported lymphoma of the colon limited to the ileum and cecum. r9 These findings emphasize the importance of colonoscopy instead of sigmoidoscopy for making the diagnosis of colonic lymphoma in patients with AIDS.
Changing Spectrum of Colonic Diseases The introduction of protease inhibitors and HAART has had a significant impact on the outcome of patients with HIV infection.80-85 Since the introduction of pro tease inhibitor-based regimens, there has been a decrease in the prevalence of certain opportunistic infections of the gastrointestinal tract. MOnkem{311er et a186 showed a significant decline in the prevalence of all opportunistic disorders from 69% to 13% among 166 HIVinfected patients presenting for endoscopic evaluation between 1995 and 1998. In addition, this study also reported a decline in the prevalence of CMV disease. This trend occurred as the proportion of individuals receiving HAART increased from 0% to 57%. Opportunistic disorders were present in 91% of patients on no antiretroviral therapy and in only 30% of those on HAART. s6
Conclusions The diagnosis of colonic disease in patients with AIDS is challenging. Although the prevalence of opportunistic diseases of AIDS-ASSOCIATED COLONIC DISEASE
the colon is decreasing, it is still important for endoscopists to be aware of the spectrum of disease so that they may readily diagnose and treat these disorders in patients with AIDS. Despite the excellent results achieved with HAART, gastrointestinal infections remain a significant problem in patients from developing countries, in those with undiagnosed or untreated HIV infection, and in those failing HAART.
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