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Gastrointestinal imaging in HIV.

Introduction

Opportunistic infections and neoplasms can involve any segment of the gastrointestinal (GI) tract in patients with HIV infection, but most commonly the oesophagus and colon. When evaluating an HIV-infected patient with GI symptoms the most important aspects are (a) knowledge of the CD4 cell count and (b) whether the patient is taking highly active antiretroviral therapy (HAART) [1-3]. The CD4 cell count is the strongest predictor of opportunistic disorders. In general, cytomegalovirus (CMV) colitis or oesophagitis and idiopathic oesophageal ulceration rarely present until the CD4 lymphocyte count falls below 100 cells/[mm.sup.3] [2-4]. However, even in patients taking HAART, opportunistic disorders can occur [5]. Although Candida oesophagitis typically occurs in the setting of more advanced immunosuppression (CD4 count <200 cells/[mm.sup.3]), it may complicate acute HIV infection (HIV seroconversion syndrome) [6,7]. Mycobacterium avium complex (MAC) infection is associated with severe immunodeficiency (median CD4 lymphocyte count <50 cells/[mm.sup.3]) [6,7].

Endoscopy plays a major role in these patients, because it permits not only direct visualisation of the entire oesophagus, stomach, duodenum and colon, but also allows for tissue biopsy and endoscopic therapy (e.g. injection of bleeding vessels, steroid injections for idiopathic oesophageal ulcers). In addition, the frequent occurrence of multiple simultaneous disease processes (e.g. Candida and CMV oesophagitis) makes a definitive diagnosis essential [7,8].

[FIGURE 1 OMITTED]

Oesophagus

Oesophageal candidiasis appears endoscopically as multiple yellow-white plaques with the appearance of 'cottage cheese', which may be isolated or confluent or coat the entire oesophagus, causing luminal impingement [6,9,10,11] (Figure 1). Any portion of the oesophagus may be involved, but there appears to be a predilection for the proximal oesophagus with distal involvement in more severe disease. However, isolated involvement of the mid- or distal oesophagus may occur.

Although the endoscopic appearance of candidiasis is pathognomonic, a definitive diagnosis of Candida oesophagitis rests on the identification of typical yeast forms in endoscopic mucosal biopsies, oesophageal brushings or balloon cytology [10,11]. Candida rarely causes endoscopic or histopathological ulceration, thus, the presence of well-circumscribed ulceration(s) associated with Candida oesophagitis of any severity should be a clue to the presence of coexisting viral disease or some other process [10,12]. The possibility of missing a co-infection is greatest in the presence of moderate to severe Candida oesophagitis, because the extent of plaque material precludes an adequate inspection of the underlying oesophageal mucosa [10-12]. In a prospective study of Candida oesophagitis in HIV-infected patients, 24% of patients with grade 3 and 4 disease were found to have non-Candida oesophageal ulcers on repeat endoscopy, which were probably missed during initial examination [11].

[FIGURE 2 OMITTED]

The most common endoscopic manifestation of CMV is one or more large, well-circumscribed shallow or deep oesophageal ulcers (Figure 2) [6,9]. In the largest prospective study to date characterising 141 CMV ulcers in 33 patients with AIDS, disease wasmore common in the mid- (57%) and distal (32%) oesophagus [9,13]. Ulcers were multiple in 58%, with three patients (9%) having more than 10 ulcers. The depth of CMV ulcers was variable, with shallow ulcerations seen in 46% and deep lesions in 8% [9]. The diagnosis of CMV is established by the identification of viral cytopathic effect (intranuclear inclusions) in gastrointestinal mucosal biopsies by routine haematoxylin-eosin (H&E) stains [7]. CMV cytopathic effect is present in endothelial cells, ganglion cells and other mesenchymal cells located in the granulation tissue of the ulcer base. Since CMV does not infect squamous tissue, biopsy of the ulcer base is essential for diagnosis. Immunohistochemical stains of mucosal biopsies may be required to confirm the infection [7]; serological tests or cytology are not reliable to diagnose CMV gastrointestinal disease in patients with AIDS [8,9,12]. Viral culture of biopsy specimens is less sensitive and specific than mucosal biopsies because contamination of the specimen with blood can yield a false-positive result.

The endoscopic appearance of herpes simplex virus (HSV) oesophagitis is that of a diffuse erosive oesophagitis or multiple, small, well-circumscribed, superficial ulcerations (Figure 3) [14]. Occasionally, the erosions become confluent and form a larger ulcer. A whitish exudate overlying the shallow ulcers can mimic Candida oesophagitis. Although small vesicles may be observed in immunocompetent hosts, this finding is unusual in HIV-infected patients. HSV cytopathic effect (intranuclear Cowdry type A inclusions) is identified most reliably in viable squamous epithelium, thus, brushings or biopsy of the ulcer edge, rather than the ulcer base, will have the highest diagnostic yield (Figure 4) [12,14-16]. Immunohistochemical stains will also increase diagnostic accuracy. However, a large prospective study found that in the setting of a specialist gastrointestinal pathology laboratory special histological stains are rarely beneficial for the evaluation of HIV-related gastrointestinal infections [15].

[FIGURE 3 OMITTED]

[FIGURE 4 OMITTED]

The endoscopic appearance of idiopathic oesophageal ulcers is that of one or more well-circumscribed ulcers of variable depth [7,12,17-20]. The largest prospective endoscopic study published to date found that most idiopathic ulcers occur in the mid- and distal oesophagus, with only a minority (4%) occurring proximally [19,20]. In almost half of the patients, the ulcer was solitary, but in 43%, the number of ulcers ranged from two to four with some patients having up to seven. Most ulcers were less than 1.5 cm in diameter, but one-third of patients had ulcers >2 cm (giant ulcers). The depth of the ulcers was reported as shallow in 31%, intermediate in 22% and deep in 7%. Multiple biopsies of the ulcer base and margins are necessary to exclude CMV and HSV [7,12-16]. Because the diagnosis of idiopathic oesophageal ulcer is one of exclusion, the following criteria should be fulfilled: (i) the ulcer(s) should be identified endoscopically; (ii) histological examination should demonstrate necrosis and inflammation consistent with ulceration; (iii) evidence of viral disease or other aetiological agents should be absent with the use of routine (H&E) and special stains; (iv) in situ DNA hybridisation for HSV and CMV are negative; and (v) clinical and endoscopic evidence of gastro-oesophageal reflux disease and pill-induced oesophagitis should be absent [7,12,19,20].

[FIGURE 5 OMITTED]

[FIGURE 6 OMITTED]

Stomach

The stomach is infrequently involved in the majority of opportunistic processes that affect the gastrointestinal tract in HIV-infected patients [21]. The most common viral pathogen affecting the stomach is CMV. Endoscopically CMV results in oedema, erythema and thickened folds, most prominently in the body and antrum. Gastrointestinal Kaposi's sarcoma (KS), a tumour caused by human herpes virus 8, has been reported in up to 50% of HIV-infected patients with cutaneous disease, although it is generally asymptomatic. The endoscopic appearance of gastric KS is similar to cutaneous disease with multiple red-purple nodules that may become large and ulcerated (Figure 5). The tumour tends to be submucosal and thus may be missed by mucosal biopsies (Figure 6). Non-Hodgkin's lymphoma (NHL) affects various parts of the GI tract, the stomach being the second most common site. On endoscopy, NHL appears as giant gastric folds or one or multiple masses with an associated ulcerated centre [12,21]. The diagnosis is established by biopsy and histopathology. Flow cytometry is instrumental in determining the cell type, which helps define the most appropriate chemo- and radiation therapies.

Small intestine

The small intestine is a common site of involvement by various infectious processes in HIV-infected patients [22-25]. The endoscopic manifestations of most small intestinal infections are non-specific, thus requiring a high index of suspicion. The most commonly reported endoscopic abnormality is small intestinal cryptosporidiosis, a flattening and blunting of the intestinal villi, similar to that seen in coeliac sprue [23,24]. On endoscopy, intestinal MAC has been associated with characteristic yellow plaque-like lesions or fine white nodules. In a series of 35 HIV-infected patients with gastrointestinal MAC, Gray and Rabeneck [22] found that all the patients with fine white nodules of the duodenum were infected with MAC, but 77% of patients with a duodenum with a normal appearance were also found to harbour MAC on mucosal biopsy [22]. The sensitivity of these endoscopic abnormalities is unknown and may be limited to patients with more severe immunodeficiency and increased mycobacterial burden. In patients with MAC, bacteraemia is frequent and may be the initial clue to gastrointestinal involvement in the symptomatic patient [22].

[FIGURE 7 OMITTED]

[FIGURE 8 OMITTED]

[FIGURE 9 OMITTED]

[FIGURE 10 OMITTED]

The endoscopic features of CMV duodenitis in HIV-infected patients were described by Wilcox and Schwartz [25] as erythematous folds and diffuse subepithelial haemorrhages, as well as nodular erythema and multiple small stellate ulcerations. Jejunal and ileal CMV can produce oedema, subepithelial haemorrhages and ulcers of variable number and appearance (Figure 7). Perforation may complicate disease in this location [12,22-25]. In HIV-infected patients, the presence of peripheral eosinophilia should always raise the suspicion of the strongyloides hyperinfection syndrome. Endoscopically, the small bowel mucosa appears massively oedematous, occasionally ulcerated, but commonly covered by yellowish pseudomembranes ('catarrhal duodenitis') (Figure 8) [26].

Colon

In the HIV-infected patient with preserved immune function, bacteria are the most common cause of colitis (Clostridium difficile, Shigella flexneri, Salmonella enteritidis, Campylobacter jejuni) [27-29] but as the degree of immunodeficiency worsens, opportunistic pathogens (CMV, protozoa, mycobacteria, fungi) become more frequent. Among patients with AIDS and diarrhoea (colitis or enteritis), CMV has been identified in mucosal biopsies in as many as 45% of cases [30-33]. The frequent use of antibiotics, chemotherapeutic agents and frequent hospitalisations increase the risk of C. difficile colitis [34].

The endoscopic appearance of bacterial colitis in HIV-infected patients is similar to that in an uninfected patient regardless of the infecting pathogen [24,26-28]. With Salmonella, Shigella and Campylobacter colitis, the mucosa appears oedematous, friable, erythematous, haemorrhagic and/or ulcerated, but other causes of colitis including CMV and protozoa may also appear similarly [24,29-33]. The endoscopic appearance of C. difficile colitis is well recognised as multiple green-yellow plaques and 'pseudo-membranes' covering an oedematous colonic mucosa (Figure 9) [34-36].

The endoscopic features of CMV colonic disease are variable ranging from 'normal' with minimal erythema (very rare) and mucosal oedema to a haemorrhagic pancolitis (Figure 10) [30-32]. The colitis may be patchy in as many as 41% of cases and involve only the right colon or caecum in 18-44%. The principles of biopsy diagnosis of colonic CMV disease follow the same guidelines as for oesophageal disease: all suspicious lesions including any subtle abnormalities such as mucosal oedema require biopsy [12,24,31]. The endoscopic appearance of amoebic colitis is characterised by mucosal ulcers of various sizes covered by a thick green-yellow exudate, oedema and erythema. Endoscopically, colonic KS is characterised by discrete, sometimes friable submucosal nodules with an intense red to purple colour [34-36]. On colonoscopy, idiopathic ulcers appear singly or in groups without colitis. Like the idiopathic oesophageal ulcer, the diagnosis of idiopathic colonic ulcer is one of exclusion [31,37].

References

[1.] Gazzard BG. HIV and the gastroenterologist. Gut, 1988, 29, 1497-1505.

[2.] Kotler DP. Gastrointestinal manifestations of human immunodeficiency virus infection. Adv Intern Med, 1995, 40, 197-242.

[3.] Olmos MA, Fanin A, Araya V et al. Endoscopic approach in HIV infected-patients with upper gastrointestinal symptoms. Acta Gastroenterol Latinoam, 2004, 34, 120-126.

[4.] Monkemuller KE, Call SA, Lazenby AJ et al. Declining prevalence of opportunistic gastrointestinal disease in the era of combination antiretroviral therapy. Am J Gastroenterol, 2000, 95, 457-462.

[5.] Monkemuller KE, Lazenby AJ, Lee DH et al. Occurrence of gastrointestinal opportunistic disorders in AIDS despite the use of highly active antiretroviral therapy. Dig Dis Sci, 2005, 50, 230-234.

[6.] Wilcox CM. Esophageal disease in the acquired immunodeficiency syndrome: etiology, diagnosis, and management. Am J Med, 1992, 92, 412-421.

[7.] Monkemuller KE, Wilcox CM. Diagnosis of esophageal ulcers in acquired immunodeficiency syndrome. Semin Gastrointest Dis, 1999, 10, 85-92.

[8.] 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, 1996, 44, 587-593.

[9.] Wilcox CM, Straub RA, Schwartz DA. Prospective endoscopic characterization of cytomegalovirus esophagitis in patients with AIDS. Gastrointest Endosc, 1994, 40, 481-484.

[10.] Wilcox CM. Evaluation of a technique to evaluate the underlying mucosa in patients with AIDS and severe Candida esophagitis. Gastrointest Endosc, 1995, 42, 360-363.

[11.] Wilcox CM, Schwartz DA. Endoscopic-pathologic correlates of Candida esophagitis in acquired immunodeficiency syndrome. Dig Dis Sci, 1996, 41, 1337-1345.

[12.] Wilcox CM, Monkemuller KE. Endoscopic approach to gastrointestinal problems in HIV-infected patients. In: Advances in Gastrointestinal Endoscopy (Bhutani M, Tandon RK, eds), Jaypee Brothers Medical Publishers, New Delhi, 2000.

[13.] Francis ND, Boylston AW, Roberts AHG et al. Cytomegalovirus infection in gastrointestinal tract of patients infected with HIV-1 or AIDS. J Clin Pathol, 1989, 42, 1055-1064.

[14.] Genereau T, Lortholary O, Bouchaud O et al. Herpes simplex esophagitis in patients with AIDS: report of 34 cases. Clin Infect Dis, 1996, 22, 926-931.

[15.] Monkemuller KE, Bussian AH, Lazenby AJ, Wilcox CM. Special histologic stains are rarely beneficial for the evaluation of HIV-related gastrointestinal infections. Am J Clin Pathol, 2000, 114, 387-389.

[16.] Greenson JK, Beschorner WE, Boitnott JK et al. Prominent mononuclear cell infiltrate is characteristic of herpes esophagitis. Hum Pathol, 1991, 22, 541-549.

[17.] Wilcox CM, Zaki SR, Coffield LM et al. Evaluation of idiopathic esophageal ulcer in human immunodeficiency virus. Mod Pathol, 1995, 8, 568-572.

[18.] Strohlein S, Posner G, Colby S et al. Giant esophageal ulcers in patients with AIDS-related complex. Dysphagia, 1986, 1, 84-87.

[19.] Wilcox CM, Schwartz DA. Endoscopic characterization of idiopathic esophageal ulceration associated with human immunodeficiency virus infection. J Clin Gastroenterol, 1993, 16, 251-256.

[20.] Neumann H, Monkemuller K. Diagnosis and therapy of HIV-induced esophagitis (Diagnostik und Therapie der HIV assoziierten Osophagitis). Z Gastroenterol, 2007, 45, 1185-1190.

[21.] Monkemuller KE, Olmos M. Gastric disease in AIDS. Tech Gastrointest Endosc, 2002, 4, 58-60.

[22.] Gray JR, Rabeneck L. Atypical mycobacterial infection of the gastrointestinal tract in AIDS patients. Am J Gastroenterol, 1989, 84, 1521-1524.

[23.] Chalasani N, Lazenby AJ, Wilcox CM. Unusual endoscopic features of gastric and duodenal cryptosporidiosis in AIDS. Gastrointest Endosc, 1997, 45, 525-527.

[24.] Monkemuller KE, Wilcox CM. Management of infections of the esophagus, stomach and small intestine and colon in AIDS. In: AIDS Therapy (Dolin R, Masur H, Saag M, eds) Churchill Livingstone, New York, 2001, pp 885-901.

[25.] Wilcox CM, Schwartz DA. Symptomatic CMV duodenitis. An important clinical problem in AIDS. J Clin Gastroenterol, 1992, 14, 293-297.

[26.] Olmos JM, Gracia S, Villoria F et al. Disseminated strongyloidiasis in a patient with acquired immunodeficiency syndrome. Eur J Intern Med, 2004, 15, 529-530.

[27.] 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, 1988, 108, 328-333.

[28.] Smith PD, Macher AM, Bookman MA et al. Salmonella typhimurium enteritis and bacteremia in the acquired immunodeficiency syndrome. Ann Intern Med, 1985, 102, 207-209.

[29.] Monkemuller KE,Wilcox CM. Investigation of diarrhea in AIDS. Can J Gastroenterol, 2000, 14, 933-940.

[30.] Jacobson MA, O'Donnell JJ, Porteous D et al. Retinal and gastrointestinal disease due to cytomegalovirus in patients with the acquired immune deficiency syndrome: Prevalence, natural history, and response to ganciclovir therapy. Q J Med, 1988, 67, 473-486.

[31.] Monkemuller KE, Wilcox CM. Diagnosis and treatment of colonic disease in AIDS. Gastrointest Endosc Clin North Am, 1998, 8, 889-911.

[32.] Beaugerie L, Salauze B, Bure A et al. Results of colonoscopically obtained specimens for bacteria and fungi in HIV-infected patients with diarrhea. Gastrointest Endosc, 1996, 44, 663-666.

[33.] Rene E, Marche C, Regnier B et al. Intestinal infections in patients with acquired immuno-deficiency syndrome: a prospective study in 132 patients. Dig Dis Sci, 1989, 34, 773-780.

[34.] Wang CYE, Schroeter AL, Su WP. Acquired immunodeficiency syndrome-related Kaposi's sarcoma. Mayo Clin Proc, 1995, 70, 869-879.

[35.] Wang CYE, Snow JL, Su WPD. Lymphoma associated with human immunodeficiency virus infection. Mayo Clin Proc, 1995, 70, 665-672.

[36.] Smith PD, Monkemuller KE, Wilcox CM. Gastrointestinal complications of the Acquired Immunodeficiency Syndrome. In: Atlas of Gastroenterology (Yamada T, ed.), Lippincott Williams, Philadelphia, 2003, 76, pp 741-748.

[37.] Wilcox CM, Schwartz DA. Idiopathic anorectal ulceration in patients with human immunodeficiency virus infection. Am J Gastroenterol, 1993, 89, 599-604.

Correspondence to: Klaus Monkemuller, Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University, Leipziger Str. 44, 39120 Magdeburg, Germany Email: klaus.moenkemueller@med.ovgu.de
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Title Annotation:LEADING ARTICLE
Author:Neumann, H.; Fry, L.C.; Wilcox, C.M.; Monkemuller, K.
Publication:Journal of HIV Therapy
Article Type:Report
Geographic Code:4EUGE
Date:Sep 1, 2008
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