Keywords

AIDS, cytomegalovirus (CMV), endoscopy, esophagitis, Kaposi's sarcoma (KS), oropharyngeal disease.

Abstract

Endoscopy plays a key role in the management of acquired immune deficiency syndrome (AIDS) patients with gastrointestinal complaints, because opportunistic disorders of the gastrointestinal tract are best diagnosed by endoscopy with biopsy. Importantly, in patients with AIDS, gastrointestinal symptoms are most frequently due to opportunistic infections and/or neoplasms, and multiple simultaneous processes are typical. Many of these disorders have a characteristic appearance at endoscopy, which helps guide the approach to biopsy and histopathological examination and, in some settings, empiric therapy pending biopsy results.

Introduction

Since the first descriptions in 1981 of acquired immunodeficiency syndrome (AIDS), remarkable accomplishments have been made in our understanding of the pathogenesis of this disease. While the incidence of human immunodeficiency virus (HIV) infection in developed countries has stabilized, the epidemic continues unabated in much of Africa, and dramatic growth within the next decade is predicted in Eastern Europe, the Soviet Union, as well as India. A dramatic fall in AIDS-related gastrointestinal complications has occurred since the introduction of highly active antiretroviral therapy (HAART), and these changes have been most notable in developed countries (1). Despite these welcomed changes in the frequency of opportunistic infections (OIs), AIDS-related complications remain important because of their prevalence worldwide, morbidity, and impact on health-care resources. Given the importance of endoscopy for diagnosis of these gastrointestinal disorders, this pictorial review will highlight the endoscopic manifestations of the most frequent causes of gastrointestinal disease based on organ system and review endoscopic diagnostic methods.

Principles of Endoscopic Practice in AIDS

Several important principles, many of which are unique to patients with AIDS, guide the endoscopic approach to the HIV-infected patient with gastrointestinal complaints:

1. The rule of parsimony does not apply to patients with AIDS as multiple co-existent diseases are commonplace.
2. Opportunistic disorders occur when immunodeficiency is severe. Therefore, the CD4 lymphocyte count will stratify the risk for an opportunistic process (2).
3. Demonstration of a pathogen in tissue is the most specific means of establishing an etiologic diagnosis.
4. The endoscopic appearance of many opportunistic disorders is characteristic.
5. Biopsy technique and tissue sampling should be guided by the risk for opportunistic disease(s) and the endoscopic characteristics of the lesion(s).

Oropharyngeal Diseases

Diseases of the oropharynx are prevalent in HIV infection, and oropharyngeal candidiasis (thrush) is a common index manifestation of HIV infection and AIDS. Oropharyngeal or hypopharyngeal pain generally reflects an ulcerative process, and aphthous ulcers are the most common cause of single or multiple well-circumscribed ulcers (Figure 1). Other causes of oropharyngeal ulcers in these patients include herpes simplex virus (HSV) (Figure 2), cytomegalovirus, (CMV), and rarely other infections. Kaposi’s sarcoma (KS) appears as characteristic purple plaques or nodules (Figure 3); cutaneous disease is usually present. Biopsy of oropharyngeal lesions is not mandatory but appropriate when the appearance of the lesion is nondiagnostic, neoplasia is suspected, or empiric therapy is ineffective. With the exception of thrush where topical agents are effective, treatment for oropharyngeal diseases parallels that for the esophagus.

Figure 1	Figure 2	Figure 3

Esophageal Diseases

Figure 4

Figure 5

Figure 6

Figure 7

Disorders of the esophagus are frequent in patients with AIDS, observed in up to 40% of patients who do not receive HAART (3). Candida esophagitis is etiologic in 40-70% of patients followed by viral diseases, most commonly CMV (4-6). Another important cause of esophageal disease is the HIV-associated apthous or idiopathic esophageal ulcer (IEU), the pathogenesis of which remains enigmatic. Multiple coexistent esophageal disorders may be identified in up to 24% of patients which complicates endoscopic management (7).  

Odynophagia is an important and reliable clue to the presence of an esophageal infection or ulcer. When symptoms are localized to the neck or throat, hypopharyngeal rather than esophageal disease should be suspected and evaluated accordingly. Dysphagia may reflect an underlying stricture (8) but may also be the result of Candida esophagitis. Examination of the oropharynx may provide clues to the cause of esophageal complaints. For example, the majority of patients (66%) with Candida esophagitis have concomitant thrush. Oropharyngeal ulcerations are frequently associated with HSV esophagitis but rarely are present with CMV esophagitis and IEU. In a prospective study of esophageal ulcers in AIDS, only 11% had concomitant oral ulcerative lesions (9).

Most esophageal diseases in AIDS have a characteristic appearance. Candida has a pathognomonic endoscopic appearance in both AIDS and non-AIDS related immunodeficiencies (Figure 4). Viral esophagitis manifests as one or more ulcerations. Herpes simplex virus esophagitis typically presents with multiple shallow ulcers typically small in size, some of which may have a volcano appearance (Figure 5). A large solitary ulcer would be very uncommon for HSV. CMV esophagitis can present with one or more ulcers which are typically deep and large in contrast to HSV (10). The appearance of CMV ulcers parallels that of IEU and is indistinguishable (Figure 6, Figure 7) (11). Given the similar appearance of CMV and IEU, multiple biopsies of the ulcer base to obtain granulation tissue are essential for diagnosis of CMV given the very different therapies.  

Esophageal neoplasms are uncommon in AIDS. Kaposi's sarcoma (KS) is the most common neoplasm involving the esophagus, and is usually asymptomatic. These lesions typically present as a submucosal nodular lesion with a purplish hue similar to their appearance in the oropharynx and on the skin. Rarely, these lesions may be large and bulky. Adenocarcinoma and squamous cell carcinoma have been described in these patients, but are not increased in incidence in AIDS. Lymphomas manifest as a bulky lesion or raised ulceration.  

Endoscopy with biopsy is the definitive diagnostic test for esophageal disease in AIDS. At the time of endoscopic evaluation, the appearance of some disorders is diagnostic, and all lesions may be biopsied. When an ulcer is identified, multiple biopsies (at least 10) should be obtained to maximize sensitivity (12). Vigorous biopsy of the ulcer base is essential for detecting CMV, while HSV is identified in squamous epithelium from the ulcer edge (13). Thus, based on the appearance of the lesion, biopsies can be taken from sites with the highest diagnostic yields. Cytological brushings and viral culture of ulcer tissue generally adds very little over multiple biopsies alone (14). Immunohistochemical stains for viral pathogens improve the diagnostic yield and specificity over routine hematoxylin and eosin staining. Additional histological staining for other infections should be applied selectively based upon the clinical, endoscopic, and histological findings (15). When Candida is severe, the endoscope can be used to remove the candidal debris and expose the underlying mucosa for lesions (Figures 8A and 8B). An ulcer can be considered idiopathic (IEU) when infections are excluded by appropriate histological studies and if pill-induced esophagitis and reflux disease are not suggested by the clinical presentation and endoscopic findings. It is important to communicate with the pathologist when a suspected diagnosis is not confirmed pathologically to ensure that adequate tissue was acquired (13).  

Figure 8A	Figure 8B

Gastric Diseases

Clinically apparent gastric disorders are relatively infrequent in patients with AIDS. While a number of infections have been reported, CMV is the most prevalent opportunistic infection involving the stomach in AIDS (16). Gastric KS, the most common gastric tumor, is generally asymptomatic, unless the lesions are large and bulky which may then lead to abdominal pain, pyloric obstruction, or bleeding. As with all gut symptoms, nonopportunistic causes deserve consideration regardless of the CD4 count.

Epigastric pain, nausea, and vomiting are the most common symptoms of gastric diseases, but are nonspecific. Overt gastrointestinal hemorrhage suggests ulceration. Nausea and vomiting are particularly common complaints in HIV-infected patients, and may reflect a variety of different etiologies including medications. In light of the broad differential diagnosis of upper gastrointestinal complaints in patients with AIDS, endoscopy and mucosal biopsy are generally required for definitive diagnosis. Computerized tomography (CT) may suggest the presence of gastric disease, and may also identify extraintestinal disease implicating a widely-disseminated process.

Ulceration, as in the esophagus, is the most frequent endoscopic manifestation of opportunistic disease. CMV manifests as one or multiple ulcerations which may be large and generally associated with subepithelial hemorrhage (gastritis) (Figure 9). Mass lesions have also been reported from CMV (17). Mass lesions due to adenocarcinoma have also been described. Infrequent diseases primarily infectious such as Cryptosporidia, and Mycobacterium avium complex involve the stomach in the process of dissemination (16,18). Kaposi’s sarcoma commonly involves the stomach in patients with cutaneous disease but is generally asymptomatic and found incidentally at the time of endoscopy for some other reason. As throughout the gastrointestinal tract, violacious purple lesions are seen which have a nodular appearance (Figures 10A and 10B). Lymphoma appears as one or more nodular lesions, which may ulcerate (Figure 11).

Figure 9	Figure 10A	Figure 10B	Figure 11

Small Bowel Diseases

Intestinal disorders are highly prevalent complications in HIV-infected patients, and this frequency may be related to altered gut immune function.

Infections are the most common diseases of the small bowel in AIDS; however, in contrast to the esophagus and stomach, these generally result in no endoscopic lesions. Ulcerations suggest CMV disease whereas mass lesions would be typical for lymphoma. Diffuse inflammation has been observed with a variety of infections (Figure 12) (19). Multiple yellow plaques are characteristic of Mycobacterium avium complex, and acid-fast staining of mucosal biopsies often show multiple organisms (Figures 13A and 13B) (20). Other fungal diseases reported to involve the intestine include Cryptococcus. Tuberculosis would most typically involve the ileum and be suspected at the time of colonoscopy.

Figure 12	Figure 13A	Figure 13B

Atrophy resembling sprue has been reported with several of these infections primarily parasitic (Cryptosporidia) (21).

Colonic Diseases

In contrast to the frequency of protozoan infections of the small intestine, bacteria and CMV are the most important colonic pathogens in patients with AIDS. The spectrum of bacterial pathogens parallels the normal host. Clostridium difficile colitis continues to be a common pathogen in patients with AIDS, and the clinical presentation, response to therapy, and relapse rate is no different in HIV-infected patients than in other patients (22). As in the normal host, bacterial colitis presents acutely with fever, abdominal pain, and watery or bloody diarrhea. Diffuse subepithelial hemorrhage may suggest acute bacterial colitis. Biopsy is mandatory in all symptomatic patients.

CMV colitis is one of the more common causes of chronic diarrhea in late-stage HIV disease, most patients having a CD4 count < 70/mm3 (23). In addition, untreated (no HAART) patients with a low CD4 count have an incidence of disease of ≈ 10% (24). Although the presentation of CMV colitis is variable, the clinical hallmarks of disease are abdominal pain and watery diarrhea (25). Fever is inconsistent, whereas weight loss is almost universal. Gastrointestinal bleeding and perforation are uncommon (26). CMV colitis should be suspected in any AIDS patient with abdominal pain, chronic diarrhea, weight loss, and repeatedly negative stool culture and ova and parasite examinations (23,27). Biopsy of normal appearing colon is generally not helpful to exclude CMV but may exclude other causes of diarrhea.

CMV colitis has a characteristic colonoscopic appearance (25). Subepithelial hemorrhage is prominent, and there may be one or multiple ulcerations usually shallow (Figure 14, Figure 15). An appearance resembling idiopathic inflammatory bowel disease, either ulcerative colitis or Crohn’s, may also be appreciated. Rarely, the disease may be limited to the right colon, and colonoscopy is necessary for diagnosis (28). Bacterial infection resembles that in the normal host as does C. difficile colitis. Multiple biopsies of any abnormality are essential, and multiple diagnoses are frequent. CT may suggest the diagnosis when the colon is markedly thickened, although this finding is non specific. The diagnosis of CMV colitis is best established by identification of the pathognomonic viral cytopathic effect in colonic biopsy specimens. Treatment is similar for disease elsewhere in the gut.

Figure 14	Figure 15

Kaposi’s sarcoma less commonly involves the colon but resembles disease elsewhere.

In most patients with advanced immunodeficiency and colorectal symptoms, stool testing and endoscopic evaluation of the colon are most appropriate (20,29). While a number of other infections and neoplasms may involve the colon, differentiation between them clinically and endoscopically may be difficult, again emphasizing the importance of endoscopic examination with biopsy.

Anorectal Diseases

As with all anorectal diseases, the usual manifestations are anorectal pain, dyschezia, bleeding, urgency, tenesmus, and frequent low volume stools (30). Dyschezia (painful evacuation) is usually a manifestation of ulceration of the anal canal (fissure, infection). Careful inspection of the anorectum should be performed with attention to the presence of ulceration, fissure, fistula, hemorrhoids, or mass lesions. Culture of perianal ulcers is the best method for the diagnosis of HSV, while confirmation of suspected CMV infection may require ulcer biopsy. Visualization of the anorectum is best performed with anoscopy and proctoscopy, or sigmoidoscopy. When dyschezia is severe, evaluation under conscious sedation or general anesthesia may be required.

A variety of ulcerative lesions may be seen of the anorectum in AIDS. Idiopathic ulcers have been described (31). Disorders due to trauma should be excluded by history. Squamous cell carcinoma is greatly increased in frequency in patients with AIDS, presumably due to the sexual acquisition of human papilloma virus combined with the known effects of immunodeficiency on tumorigenesis of some viral-associated neoplasms (32,33).

Summary

While the prevalence of GI complications has fallen due to HAART, gastrointestinal complaints remain a frequent source of morbidity. Given the wide spectrum of potential causes, the evaluation must be tailored to the history, physical examination, and routine laboratory tests including the CD4 lymphocyte count. Endoscopists must recognize the appearance of common AIDS-related gastrointestinal disorders using a pattern approach and by doing so provide optimal care.

References

1. Monkemuller KE, Call SA, Lazenby AJ, Wilcox, CM. Declining prevalence of opportunistic gastrointestinal disease in the era of combination antiretroviral therapy. Am J Gastroenterol 2000; 95:457-62. <Related link>

2. Bacellar H, Munoz A, Hoover DR, et al. for the Multicenter AIDS cohort study. Incidence of clinical AIDS conditions in a cohort of homosexual men with CD4+ cell counts < 100/mm3. J Infect Dis 1994;170:1284-7. <Related link>

3. Connolly GM, Hawkins D, Harcourt-Webser JN, Parsons PA, Husain OAN, Gazzard BG. Oesophageal symptoms, their causes, treatment, and prognosis in patients with the acquired immunodeficiency syndrome. Gut 1989;30:1033-9. <Related link>

4. Bonacini M, Young T, Laine L. The causes of esophageal symptoms in human immunodeficiency virus infection: A prospective study of 110 patients. Arch Intern Med 1991;151:1567-72. <Related link>

5. Wilcox CM, Alexander LN, Clark WS, Thompson SE. Fluconazole compared with endoscopy for human immunodeficiency virus-infected patients with esophageal symptoms. Gastroenterology 1996;110:1803-9. <Related link>

6. Wilcox CM, Schwartz DA, Clark WS. Causes, response to therapy, and long-term outcome of esophageal ulcer in patients with human immunodeficiency virus infection. Ann Intern Med 1995; 122: 143-9. <Related link>

7. Wilcox CM. A technique to examine the underlying mucosa in patients with AIDS and severe Candida esophagitis. Gastrointest Endosc 1995;42:360-3. <Related link>

8. Wilcox CM. Esophageal strictures complicating ulcerative esophagitis in patients with AIDS. Am J Gastroenterol 1999;94:339-43. <Related link>

9. Wilcox CM, Straub RF, Clark WS. Prospective evaluation of oropharyngeal findings in human immunodeficiency virus-infected patients with esophageal ulcers. Am J Gastroenterol 1995;90:1914-5. <Related link>

10. Wilcox CM, Straub RF, Schwartz DA. Prospective endoscopic characterization of cytomegalovirus esophagitis in AIDS. Gastrointest Endosc 1994;40:481-4. <Related link>

11. Wilcox CM, Schwartz DA. Endoscopic characterization of idiopathic esophageal ulceration associated with human immunodeficiency virus infection. J Clin Gastroenterol 1993;16:251-6. <Related link>

12. 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;44:587-93. <Related link>

13. Lazenby AJ. Gastroenterologist/Pathologist Partnership. Techniques Gastro Endosc 2002;4:95-100.

14. Wilcox CM, Rodgers W, Lazenby A. Prospective comparison of brush cytology, viral culture, and histology for the diagnosis of ulcerative esophagitis in AIDS. Clin Gastroenterol Hepatol 2004; 2:564-7. <Related link>

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;114:387-94. <Related link>

16. Pensa E, Borum ML. Opportunistic infections. Gastric infections in HIV/AIDS. AIDS Read 2000;10:347-9, 354, 356-8. <Related link>

17. Chen J, Savides TJ. CMV pseudotumor of the colon in an AIDS patient. In VHJOE (Volume 3, Issue 3) [electronic journal]. Aurora, CO 2003. Available at www.vhjoe.org/Volume3Issue3/3-3-5.htm; INTERNET.

18. Cersosimo E, Wilkowske CJ, Rosenblatt JE, Ludwig J. Isolated antral narrowing associated with gastrointestinal cryptosporidiosis in acquired immunodeficiency syndrome. Mayo Clin Proc 1992;67:553-6. <Related link>

19. Meine GC, Dietz J, Rocha M, Mattos T, deSouza AR, Conteletti FR. Atypical gastric presentation of strongyloidiasis in HIV-infected patient – case report. Digestive and Liver Disease 2004;36:760-2. <Related link>

20. Wilcox CM. Etiology and evaluation of diarrhea in AIDS: a global perspective at the millennium. World J Gastroenterol 2000;6:177-86. <Related link>

21. Shah VH, Rotterdam H, Kotler DP, Fasano A, Green PH. All that scallops is not celiac disease. Gastrointest Endosc 2000;51:717-20. <Related link>

22. Pulvirenti JJ, Mehra T, Hafiz I, DeMarais P, Marsh D, Kocka F, Meyer PM, Fischer SA, Goodman L, Gerding DN, Weinstein RA. Epidemiology and outcome of Clostridium difficile infection and diarrhea in HIV infected inpatients. Diagn Microbiol Infect Dis 2002;44:325-30. <Related link>

23. Wilcox CM, Schwartz DA, Cotsonis GA, Thompson WE III. Evaluation of chronic unexplained diarrhea in human immunodeficiency virus infection: determination of the best diagnostic approach. Gastroenterology 1996;110:30-7. <Related link>

24. Jacobson MA, Mills J. Serious cytomegalovirus disease in the acquired immunodeficiency syndrome (AIDS). Clinical findings, diagnosis, and treatment. Ann Intern Med 1988;108:585-94. <Related link>

25. Wilcox CM, Chalasani N, Lazenby A, Schwartz DA. Cytomegalovirus colitis in acquired immunodeficiency syndrome: a clinical and endoscopic study. Gastrointest Endosc 1998;48:39-43. <Related link>

26. Chalasani N, Wilcox CM. Etiology and outcome of lower gastrointestinal bleeding in patients with AIDS. Am J Gastroenterol 1998;93:175-8. <Related link>

27. Blanshard C, Francis N, Gazzard BG. Investigation of chronic diarrhea in acquired immunodeficiency syndrome. A prospective study of 155 people. Gut 1996; 39:824-32. <Related link>

28. Bini EJ, Weinshel EH. Endoscopic evaluation of chronic human immunodeficiency virus-related diarrhea: is colonoscopy superior to flexible sigmoidoscopy? Am J Gastroenterol 1998;93:56-60. <Related link>

29. Kearney DJ, Steuerwald M, Koch J, Cello JP. A prospective study of endoscopy in HIV-associated diarrhea. Am J Gastroenterol 1999; 94:556-9. <Related link>

30. Brar HS, Gottesman L, Surawicz C. Anorectal pathology in AIDS. Gastrointest Endosc Clin N Am 1998;8:913-31. <Related link>

31. Wilcox CM, Schwartz DA. Idiopathic anorectal ulceration in patients with human immunodeficiency virus infection. Am J Gastroenterol 1994;89:599-604. <Related link>

32. Stadler RF, Gregorcyk SG, Euhus DM, Place RJ, Huber PJ, Simmang CL. Outcome of HIV-infected patients with invasive squamous-cell carcinoma of the anal canal in the era of highly active antiretroviral therapy. Dis Colon Rectum 2004;47:1305-9. <Related link>

33. Welton ML, Sharkey FE, Kahlenberg MS. The etiology and epidemiology of anal cancer. Surg Oncol Clin N Am 2004;13:263-75. <Related link>