Gastrointestinal Manifestations of Acquired Immunodeficiency Syndrome

Radiologic-Pathologic Correlation

Abstract Introduction

Opportunistic Infections AIDS-Associated Neoplasms Conclusion

Source Information References

Opportunistic Infections

Viral Pathogens

Cytomegalovirus Infection.--Cytomegalovirus (CMV), a double-stranded DNA virus in the herpesvirus family, is the most common cause of life-threatening opportunistic viral infection in AIDS patients (4). Infection with CMV is ubiquitous among humans and occurs at an early age in populations with poor sanitation and crowded living conditions. Disease due to CMV in persons with HIV infection is almost always the result of reactivation of the latent virus in a previously infected host. These patients usually do not present with CMV disease until their CD4 cell count is less than 100 cells per microliter (5). CMV is one of the most common causes of enteric disease and accounts for 13% of gastrointestinal diseases in AIDS patients (6). The colon is the most frequent site, followed by the small bowel, esophagus, and stomach (7). CMV most commonly infects mesenchymal cells and endothelial cells; glandular and surface epithelial cells are infrequently affected (8). The diagnosis of CMV disease is made based on histologic findings of large mononuclear, epithelial, or endothelial cells that contain intranuclear or cytoplasmic inclusions with surrounding inflammation (9).

The radiologic appearance of CMV disease of the gastrointestinal tract varies widely and depends on the presence and severity of inflammatory, vasculitic, and fibrotic processes. Single or multiple large superficial ulcers, which are most commonly found in the esophagus (10,11), reflect mucosal destruction due to an acute inflammatory process. Narrowing of the intestinal lumen secondary to marked bowel wall thickening and thickened irregular folds are common radiologic findings in patients with CMV disease of the intestine (12,13) (Figure 1). Pathologically, the endothelium of submucosal capillaries and venules is involved by CMV; this involvement causes diffuse vasculitis and leads to thrombosis and ischemia of the bowel wall. Penetrating ulcers may develop, and perforation occasionally occurs. An inflammatory mass, the "CMV pseudotumor," is the least common radiologic manifestation and may range in size from a small nodule to a large mass. Pathologically, the mass is composed of granulation and fibrotic tissue in addition to ongoing acute and chronic inflammatory tissue. Although CMV pseudotumor is considered uncommon, it has been reported increasingly in the past 5 years (14,15,16). This trend probably can be explained by the longer survival of patients with AIDS as they receive improved prophylaxis and treatment of opportunistic infections. Radiologically, CMV pseudotumor may mimic Kaposi sarcoma and lymphoma, which are opportunistic neoplasms. However, the CT finding of infiltrative changes in the mesenteric fat adjacent to the mass is more suggestive of CMV pseudotumor than neoplasm because it represents contiguous inflammation (15).

Intussusception, as a manifestation of CMV infection, is very unusual (17). The Armed Forces Institute of Pathology collection includes one such case (Figure 2). Submucosal edema was believed to initiate the intussusception process in this case.

Hepatobiliary disease caused by CMV is not commonly seen in the clinical setting, although it is frequently seen at autopsy (4). It is postulated that CMV vasculitis leads to periductal fibrosis (18). However, cells with CMV inclusion bodies and surrounding inflammation are not consistently found in AIDS-related cholangiopathy. Cryptosporidium organisms have been detected as often as CMV in these lesions (19,20). Thus, the cause of AIDS-related cholangiopathy remains uncertain. Common radiologic findings include gradual and regular stenosis of the distal common bile duct, so-called papillary stenosis, and dilatation of extra- and intrahepatic bile ducts (18,21) (Figure 3). Strictures and irregularity of bile ducts may be seen and may resemble primary sclerosing cholangitis (18,21). Intraluminal polypoid filling defects, which represent granulation tissue, have also been reported but are rare (22).

Herpes Simplex Virus Infection.--Herpes simplex virus types 1 and 2 are DNA viruses of the herpes family that are neurotropic, characterized by latency, and endemic in the United States, with reported prevalences of 70% and 16%, respectively (23). In HIV-infected homosexual men, however, the prevalence of the type 2 antibody is much higher than it is in the general population. Herpes simplex virus infection results from direct inoculation of the virus through mucous membrane contact. Traveling via afferent nerves, the virus reaches the nerve root ganglia, where it persists in a latent state. When reactivated at some later time, the virus replicates and is transported back via the efferent nerves to the mucocutaneous surface, where clinically apparent lesions may result. Diagnosis of herpes simplex virus infection is made based on the cytologic or histologic identification of intranuclear inclusions in multinucleated cells and is confirmed by means of virus isolation, immunohistochemistry analysis, or DNA hybridization (9).

Because infection and latency occur in peripheral nerves accessible to direct inoculation, the major sites of gastrointestinal tract involvement are the oral cavity, esophagus, rectum, and anus. A common radiologic manifestation at all sites is the appearance of multiple, small, discrete ulcers in an otherwise normal background mucosa (24). Esophageal ulcers in the AIDS patient tend to be slightly larger than those that occur in the immunocompetent host, whose intact immune system prevents enlargement of ulcers (25).

HIV Infection.--HIV has been implicated as a cause of ulcers of the gastrointestinal tract, most commonly in the esophagus. HIV-related ulcer is not an AIDS-defining illness, but it is included here because of its clinical importance and because of the increasing recognition of this entity. HIV-related ulcer occurs either during acute HIV infection with transient immunosuppression or after AIDS has developed. It is postulated that HIV-infected cells cause alterations in cytokines (secreted polypeptides important for immune interaction between cells); these alterations then lead to infiltration of inflammatory cells within the submucosa. The inflammatory cells destroy mucosal tissue and ulcers form (26). HIV-related ulcer is a diagnosis of exclusion in AIDS patients. Biopsy samples, brushings, and cultures must be obtained and must be found negative for other viral, fungal, and bacterial infections. HIV is often isolated from the ulcers (27,28). Diagnosis of HIV-related ulcers is important because the ulcers respond to treatment with corticosteroids (29,30). Correct diagnosis thus helps avoid the complications that result from the potentially toxic antiviral agents.

HIV-related ulcers are relatively large (>2 cm) and are solitary, although small, multiple ulcers have also been uncommonly described (28). In the esophagus, both esophagography and endoscopy show a large, well-defined ulcer with a relatively flat, shallow crater localized to the mid- or distal esophagus. The surrounding mucosa appears normal. This large, shallow ulcer is very similar to that caused by CMV infection (31). Deep ulcer and fistula formation have been reported but appear to be uncommon (30) (Figure 4). In the colon, similar superficial ulcers have been visualized at colonoscopy (32). Thus far, radiologic findings have not been reported.

Fungal Pathogens

Candidiasis.--C albicans is a commensal organism in the gastrointestinal tract. Mucosal candidiasis is extremely common in individuals with advanced HIV disease. In the gastrointestinal tract, the esophagus is the most common site of infection. The reported frequency of esophageal candidiasis in AIDS patients is 10% 20% in the United States and is as high as 80% in developing countries (33). Candidal esophagitis accompanied by thrush is common. However, the absence of thrush does not exclude the diagnosis of candidal esophagitis, which is made based on the endoscopic appearance of patchy, creamy white plaques that cover a friable erythematous mucosa. Direct smears from these plaques often demonstrate the pseudohyphae and yeast forms of the fungus.

The common radiologic findings of candidal esophagitis include discrete linear or irregular filling defects that tend to be longitudinally oriented (Figure 5). These filling defects represent the heaped-up areas of mucosal plaques that consist of necrotic debris and colonies of C albicans. With more extensive inflammation, multiple plaques and ulcers develop, and esophagography shows marked irregularity and a shaggy appearance of the mucosa (34). An ulcerative mass that mimics carcinoma, which is an unusual radiologic finding, has also been reported (34). In cases of long-standing esophageal candidiasis, gastric bezoars due to large Candida fungus balls may develop (35).

Although cellular immunity is important in the prevention of mucosal candidiasis, neutrophil function is important in the prevention of hematogenous dissemination. Thus, despite a low CD4 cell count and heavy mucosal colonization by Candida organisms in AIDS patients, systemic candidiasis is rare because of the preserved neutrophil function in most of these patients. If disseminated candidiasis has been diagnosed in an AIDS patient, the possibility of granulocytopenia due to chemotherapy or of direct inoculation of the fungus made possible by an indwelling catheter should be considered.

Radiologic findings associated with disseminated gastrointestinal candidiasis have been reported in only two cases. One case involved the ileum, and mild dilatation and thickened folds were seen at barium study (36). The other case had a more fulminant course, and necrosis of the ileum and ascending colon was seen. CT in this case showed bowel dilatation as well as air within the bowel wall and within the intrahepatic branches of the portal vein (37).

Histoplasmosis.--H capsulatum, a dimorphic fungus, is a common opportunistic pathogen in AIDS patients who live in areas where the fungus is endemic. Disseminated histoplasmosis is observed more often when the CD4 cell count is less than 200 cells per microliter (38). This condition generally results from reactivation of a latent infection (39). Although the lung is the usual portal of entry, chest radiographs are normal in 30% 40% of the cases of disseminated histoplasmosis (40). Gastrointestinal involvement occurs in about 10% of AIDS patients with disseminated histoplasmosis (41). The colon is the most common site of involvement of Histoplasma organisms in the gastrointestinal tract in AIDS patients (41,42,43). The diagnosis is made based on the histologic finding of intracellular yeast within macrophages of the lamina propria with Grocott-Gomori methenamine silver nitrate or other fungal stains and is confirmed by means of culture.

Radiologic findings of colonic histoplasmosis include segmental colonic inflammation, apple-core lesions that mimic carcinoma, and stricture (41,42,43). Although the small bowel, especially the terminal ileum, is the most common gastrointestinal site of disseminated histoplasmosis in the non-AIDS immunocompromised patient, this site has been reported less frequently in AIDS patients (44) (Figure 6).

Hepatosplenomegaly is a common finding in patients with disseminated histoplasmosis. Diffuse hypoattenuation of the spleen has been shown at CT (45). Perisplenic abscess due to histoplasmosis is very unusual but does occur (Figure 7). Superimposed bacterial infection is likely to play a role in abscess formation in this setting. Mesenteric lymphadenopathy also occurs commonly. These enlarged lymph nodes have either soft-tissue attenuation or low attenuation on CT scans (45). Low-attenuation lymphadenopathy in histoplasmosis may be difficult to distinguish from that in M tuberculosis infection.

Histoplasmosis that involved the omentum and mesentery in an AIDS patient has been described in a single case report. CT in this case showed diffuse thickening of the omentum and mesentery with fine nodularity and hazy linear strands (46). These findings are similar to those observed in cases of tuberculous peritonitis.

Protozoan Pathogens

Cryptosporidiosis.--Cryptosporidium organisms are intracellular parasites that can infect epithelial cells of the digestive or respiratory tract of most vertebrates. Infection with these organisms is one of the most common causes of enteric disease in patients with AIDS; it occurs in AIDS patients who present with diarrhea at a rate of about 16% in the United States and about 48% in developing countries (47). Although any part of the gastrointestinal tract may be infected, the small bowel, especially the jejunum, is the most common site, followed by the stomach and colon. Hypersecretion of fluids and electrolytes is characteristic of cryptosporidiosis, although its pathogenesis is still obscure. The diagnosis of cryptosporidiosis is made based on microscopic identification of the organism in stool specimens. Organisms localized within the brush border of intestinal epithelial cells also may be identified in biopsy specimens.

The common radiologic findings of small bowel cryptosporidiosis include thickening of the folds secondary to inflammatory cell infiltration; effacement of the folds due to atrophy, blunting, fusion, or loss of villi; and dilution of barium due to hypersecretion of the intestinal fluids (48). Stomach involvement is less common than small bowel involvement and may be manifested radiologically by marked antral narrowing, secondary to extensive inflammatory changes (49,50). A rectovesical fistula caused by Cryptosporidium organisms and shown at CT has also been reported (51).

Cryptosporidium organisms have been implicated as a cause of AIDS-related cholangiopathy (52). The bile duct strictures shown radiologically are similar to those caused by CMV. Pathologically, the organisms are associated with an exuberant periductal inflammation and granulation tissue.

Pneumocystosis.--P carinii is a eukaryotic microbe that is believed to be either a protozoon or a fungus (53). Because of its failure to grow on fungal culture media and its good response to antiprotozoan drugs, it is discussed among the protozoan pathogens. The lung is the portal of entry, and pneumonia, which is the most common manifestation of P carinii infection, occurs in about 75% of AIDS patients in the United States (54). Hematogenous dissemination to other organs occurs infrequently and accounts for less than 1% of cases with P carinii infection; it is especially likely to occur with aerosolized pentamidine administration (55). Aerosolized delivery produces a high local drug level but limited systemic absorption, which results in a very low plasma pentamidine level (56). Therefore, P carinii organisms that spread from the lungs to distant sites could grow undisturbed and eventually produce disease. The liver, spleen, and lymph nodes are the most common sites of extrapulmonary pneumocystosis (57). The diagnosis is made based on the histologic finding of pneumocystic cysts within the tissue specimens.

Imaging findings of extrapulmonary pneumocystosis commonly include visceral and nodal calcification, and the liver and spleen are the most common sites (57). US findings of multiple, tiny echogenic foci within the liver parenchyma have been reported to be a sign of an early stage of infection (58). Evolution of splenic involvement has been observed on CT scans, with multiple lesions of varying size and low attenuation being described as the starting point (Figure 8). These low-attenuation lesions are secondary to foamy eosinophilic material shown histologically to be filled with numerous P carinii cysts and trophozoites. These lesions become smaller or disappear and may appear progressively calcified, in either a rimlike or punctate fashion, on follow-up CT scans (59).

Pancreatic pneumocystosis that accompanies splenic involvement has been reported to appear on CT scans as a low-attenuation lesion with coarse calcification (60). Gut involvement has been described in biopsy and autopsy series (61,62). Thus far, however, the associated radiologic findings have not been reported, to our knowledge.

Bacterial Pathogens

Tuberculosis.--M tuberculosis is the most common cause of serious HIV-related infection worldwide, although it is less common in the United States than in other countries. About 43% of HIV-infected persons develop tuberculosis in developing countries (63), whereas only 4% develop tuberculosis in the United States (64). Tuberculosis in HIV-infected patients tends to occur earlier than other AIDS-defining opportunistic infections, usually when the patient's CD4 cell count is in the range of 150 350 cells per microliter (65,66). Extrapulmonary manifestations are common and occur at a rate of 40% 80% in AIDS patients with tuberculosis. The lymph nodes, peritoneum, and gastrointestinal tract are the most common sites of such involvement (67). In the gastrointestinal tract, common locations include the ileum, colon, and ileocecal valve, although any part of the gut may be involved. Routes of gastrointestinal tract infection include (a) swallowing of infected sputum during active pulmonary tuberculosis; (b) hematogenous spread from active pulmonary tuberculosis; and (c) direct extension from adjacent tissues, especially lymph nodes. The diagnosis is made based on histologic detection of acid-fast bacilli, with cultures used for confirmation.

In the esophagus, common radiologic findings include deep esophageal ulceration, intramural dissection, and fistula formation (68). Imaging findings of tuberculosis in the stomach in AIDS patients have been reported only in a case report (69). The abnormalities included an ulcer located on the lesser curvature of the proximal stomach with an associated retrogastric mass and lymphadenopathy. Intestinal perforation secondary to tuberculosis in HIV-infected patients has been described (70); in these patients, abdominal radiography showed free air under the diaphragm with air-fluid levels within the small bowel.

The ileocecal region is the most common site of tuberculosis in the gastrointestinal tract. The common imaging findings include thickening of the ileocecal valve and adjacent ileum and colon. At CT, mesenteric lymphadenopathy with low attenuation suggestive of necrosis is typically found, although soft-tissue attenuation nodes occasionally occur (71). Colonic tuberculosis can take several forms, including segmental ulceration (Figure 9), inflammatory strictures, and hypertrophic lesions that resemble polyps and masses (67).

Disseminated tuberculosis that involves the peritoneum, liver, spleen, and pancreas occurs in AIDS patients. Common imaging findings of tuberculous peritonitis include high-attenuation ascites, peritoneal and omental nodules, and low-attenuation lymphadenopathy (72). Lesions within the liver and spleen may be detected with US and CT (73). These findings mimic those of M avium and P carinii infections.

M Avium Complex Infection.--The most common nontuberculous mycobacterial infection in AIDS patients is caused by M avium. Because this species is biochemically and morphologically indistinguishable from Mycobacterium intracellulare, these conditions were referred to as M avium-intracellulare infections in early reports. Genetic analyses of M avium-intracellulare isolated from AIDS patients rather than non-AIDS patients have demonstrated that nearly 100% of these isolates are M avium (74,75). Therefore, the organisms that cause these infections will be referred to as M avium complex rather than M avium-intracellulare to emphasize the importance of M avium.

M avium complex is a facultative, intracellular, acid-fast bacillus. It is the most common opportunistic infection of bacterial origin in AIDS patients in developed countries (76). Both the respiratory tract and the gastrointestinal tract appear to be portals of entry and sources of dissemination. In the gastrointestinal tract, M avium complex invades Peyer patches and adjacent mesenteric lymph nodes, similar to M tuberculosis. True granulomas with Langhans giant cells and caseous necrosis rarely occur, however, because the infection usually develops in patients with advanced disease (those with CD4 cell counts below 100 cells per microliter) whose cell-mediated immune responses are very ineffective (77). In the final stage of this infection, the tissues are laden with aggregates of foamy histiocytes that contain many bacilli. Histiocytes infected with M avium complex stain positively with periodic acid Schiff stain, results similar to those obtained in cases of Whipple disease. However, a positive acid-fast stain and unresponsiveness to tetracycline indicate that the organism is not the Whipple bacillus but rather a mycobacterium. A diagnosis of M avium complex infection is made based on the visualization of large numbers of intracellular acid-fast bacilli in tissue specimens and is confirmed by means of culture.

In the gastrointestinal tract, the most common site of involvement is the jejunum, although any part of the gut may be involved. Diffuse thickening of jejunal folds without ulceration is a common radiologic finding that is due to infiltration by many mycobacteria associated with minimal or no tissue destruction.

Dissemination of the M avium complex occurs very often via hematogenous or lymphatic routes. Lymphadenopathy and hepatosplenomegaly are common manifestations of disseminated M avium complex infection. Lymphadenopathy usually involves retroperitoneal and mesenteric lymph nodes, which have a characteristic homogeneous soft-tissue attenuation (Figure 10). Low-attenuation lymphadenopathy is not a characteristic of M avium complex infection but does occasionally occur (78). Small lesions that involve the liver and spleen may manifest as multiple, tiny, echogenic foci at US (79). Large lesions may be hypoechoic at US or show low attenuation at CT. These findings are similar to those associated with tuberculosis and pneumocystosis. Histologic examination with special stains helps differentiate the causes.

Other Infections

Bacillary angiomatosis is a recently described infectious disease in AIDS patients that is caused by Rickettsiales Bartonella henselae. The name, bacillary angiomatosis, describes the characteristic pattern of vascular proliferation observed histopathologically along with the bacilli. Cutaneous lesions, which mimic those of Kaposi sarcoma, are the most common manifestation (80). The liver and spleen may be involved, and peliosis (blood-filled cystic spaces) of the hepatic and splenic parenchyma has been described (81). Abdominal lymphadenopathy, which resembles that of Kaposi sarcoma and enhances on CT scans after intravenous administration of contrast material, has been reported (82).

Isospora belli and Microsporidia organisms are protozoan pathogens that may cause severe, watery diarrhea, and infections with these organisms may resemble cryptosporidiosis. The small intestine is a common site of these infections. Barium examination usually shows the nonspecific finding of thickened folds of the small bowel. Histologic findings include oval oocysts within the lumen and epithelial cells, localized inflammation, and atrophy.

Entamoeba histolytica and Giardia lamblia are protozoan pathogens that have been detected in the stools of homosexual men (83,84). Apparently, they are without increased pathogenicity in patients with AIDS. The rates of symptomatic infection and clinical severity in HIV-infected persons are not significantly higher than in those without HIV infection (47).

Salmonella species, Shigella flexneri, and Campylobacter jejuni are not opportunistic pathogens. However, infections due to these organisms occur more frequently and are more clinically severe in HIV-infected patients than in other patients because of impaired immune function and antibiotic resistance secondary to prolonged or recurrent infection.

Adenovirus has been reported as a cause of colitis in AIDS patients (85). Histologically, adenovirus appears to infect only mucosal cells and to spare cells of the lamina propria, which are common targets of CMV. The relationship between adenovirus-associated colitis and AIDS is still under investigation.

Abstract Introduction

Opportunistic Infections AIDS-Associated Neoplasms Conclusion

Source Information References