Gastrointestinal Consequences of Infection with Human Immunodeficiency Virus

Odynophagia and Dysphagia

Before HAART was available, these esophageal complaints (dysphagia and odynophagia) occurred in at least one third of patients during the course of HIV disease. Because of HAART, the incidence of esophageal disease has markedly fallen, and the number of patients with diseases not unique to AIDS (e.g., GERD) has risen.

Candida albicans , the most frequent esophageal infection in AIDS, often coexists with other disorders in this setting. Although most cases occur in the setting of AIDS, Candida esophagitis may occur during primary HIV infection as a result of transient immunosuppression. Oral thrush often predicts concurrent esophagitis in patients with esophageal complaints (see Fig. 24.2 ). However, the absence of thrush does not exclude the possibility of esophageal candidiasis.

Patients with esophageal candidiasis generally complain of substernal dysphagia. Odynophagia, when present, is usually not severe. Definitive diagnosis is established by upper endoscopy, which reveals either focal or diffuse plaques in association with mucosal hyperemia and friability. A well-circumscribed ulcer or ulcers suggest(s) an additional process. Biopsies show desquamated epithelial cells with typical-appearing yeast forms; fungal invasion is usually present only in the superficial epithelium.

Although CMV is the most commonly identified pathogen in AIDS, its association with esophageal disease is less frequent than Candida . CMV characteristically causes mucosal ulceration. Thus, patients with CMV esophagitis complain of odynophagia or substernal chest pain, characteristically severe. Dysphagia is much less common than in patients with Candida esophagitis and is rarely the primary complaint. Fever is rare. Generally, upper endoscopy reveals extensive ulcerations that are large and deep, although the endoscopic pattern is variable (see Fig. 35.2 ). Candidal coinfection is common. Mucosal biopsies should demonstrate viral cytopathic effect in mesenchymal and/or endothelial cells in the granulation tissue. Characteristic inclusions may be absent, necessitating confirmation by immunohistochemical stains. Biopsy of granulation tissue in the ulcer base provides the highest yield for viral cytopathic effect, whereas viral culture is less sensitive, and cytologic brushings are unhelpful.

A syndrome of nonspecific (idiopathic, aphthous) esophageal ulceration is common ( Fig. 35.3 ). The clinical presentation and endoscopic appearance are indistinguishable from esophageal CMV infection. Criteria for diagnosis of idiopathic ulcers include: (1) endoscopic ulcer confirmed by histopathology, (2) no evidence of viral cytopathic effect (CMV, HSV) by both routine histology and immunohistochemical studies, and (3) no clinical or endoscopic evidence of GERD or pill-induced esophagitis. As with CMV ulcers, nonspecific ulcers occur in late-stage disease, with most patients having a CD4 count less than 50/mm ³ . However, they have also been described in acute HIV infection. The pathogenesis of these ulcers remains unknown.

In contrast with other immunocompromised hosts, HSV esophagitis is infrequent in AIDS. In immunocompetent patients, herpetic esophagitis is usually due to HSV type 1. However, AIDS patients may have esophagitis due to either type 1 or type 2 HSV. The disease is similar to herpetic infections of other mucous membranes in that the pathogenetic features follow a predictable sequence. Discrete vesicles form, then shallow ulcers occur, and finally coalesce into regions of diffuse shallow ulceration. In contrast with CMV esophagitis and nonspecific ulcer, the ulcers tend to be shallow; large, deep ulcers are rare ( Fig. 35.4 ). Biopsies and cytologic brushings taken from the margin of the ulcers (the sites of active viral replication) are most likely to show epithelial cell invasion and nuclear changes typical of herpes infections. Viral cultures of biopsy specimens are usually positive.

Isolated cases of esophagitis/ulcerations have been reported from a variety of other infections as well as pills (zidovudine [AZT], didanosine [ddI]).

AIDS patients may also be at increased risk for esophageal neoplasms. Reported neoplasms include Hodgkin and various non-Hodgkin lymphoma, Kaposi sarcoma, squamous cell carcinoma, and adenocarcinoma.

A specific cause of esophageal complaints in the AIDS patient cannot be made based on symptoms or physical examination alone ( Box 35.1 ). Nevertheless, a few generalizations may be made. The presence of oral thrush associated with mild to moderate dysphagia without odynophagia is likely caused by Candida esophagitis. In contrast, the patient with severe odynophagia without dysphagia or thrush is more likely to have ulcerative esophagitis (viral, idiopathic). The patient complaining of substernal burning and regurgitation is most likely to have GERD, especially if on HAART.

Endoscopy with biopsy is the only means of establishing a specific etiology for the cause of dysphagia and odynophagia. Multiple mucosal biopsies are preferred over brush cytology for ulcerated lesions. Barium swallow radiography may play a diagnostic role in the HIV-infected patient with preserved immune function when a motility disorder is suspected.

Given the preponderance of Candida infection, an empirical approach to the management of esophageal symptoms is reasonable in most patients with AIDS. Patients with dysphagia and/or odynophagia who also have oral thrush should be treated empirically with fluconazole 100 mg/day after a 200-mg loading dose. Itraconazole or fluconazole suspensions are effective alternatives. If symptoms persist despite a 1-week empirical trial, endoscopy with biopsy should be performed rather than initiation of other empirical trials or escalation of the dose of fluconazole. Relapse of Candida esophagitis is invariable unless immune function is improved with HAART. Furthermore, despite chronic prophylaxis, relapse of esophagitis due to antifungal resistance frequently occurs.

CMV and HSV infection should be treated similarly to other gut involvement with these viruses (see following). Idiopathic ulcers respond in more than 90% of patients to oral glucocorticoids (e.g., 40 mg prednisone per day initially, tapered over 4 weeks). The basis for glucocorticoid efficacy is unknown; infectious causes should be assiduously excluded before administering glucocorticoids in this setting. Thalidomide is also highly effective and may be curative when prednisone fails. The devastating teratogenic effects mandate its use be limited to men. HAART itself has been shown to result in ulcer healing.

Diarrhea

Before HAART, diarrhea occurred in up to 90% of patients during the course of HIV disease, especially those from resource-poor countries. In the era of HAART, diarrhea is a less frequent complaint and etiologically is now most often medication-induced (HAART) or caused by disorders unrelated to HIV infection.

HIV infection results in a rapid CD4 T cell depletion throughout the GI tract, as well as an enteropathy characterized by increased inflammation of the lamina propria and damage to the GI epithelial cell layer, which is associated with microbial translocation and immune activation. Alterations in the mucosal immune system in AIDS predispose to intestinal infections, may lead to untreatable chronic infection by organisms that typically cause self-limited infection in immunocompetent hosts (e.g., Cryptosporidium parvum ), and may contribute to a more virulent clinical course of common enteric infections (e.g., Salmonella , Shigella , Campylobacter species). Clinical and socioenvironmental factors are associated with intestinal OIs, including low CD4 lymphocyte count and nonuse of HAART, low socioeconomic status, lack of availability of safe drinking water, and exposure to farm animals. Despite the vast spectrum of protozoal, viral, bacterial, and fungal organisms that can cause diarrhea in the patient with AIDS, a differential diagnosis can be developed on the basis of the clinical presentation and degree of immunodeficiency ( Box 35.2 ).

Protozoa are the most prevalent diarrheal pathogens in most series, largely because many of these infections can lead to chronic diarrhea and are refractory to treatment. Cryptosporidia species such as C. parvum , a cause of self-limited diarrhea in healthy hosts, remain the most frequent protozoa identified in HIV-infected patients worldwide. Clinical presentation and outcome are related to the degree of immunocompromise and the subtype of organism. The small bowel is the most common site of infection, although the organisms can be recovered in all regions of the gut as well as in biliary and respiratory epithelium. Diarrhea is typically severe, with stool volumes of several liters per day not uncommon. Borborygmi, nausea, and weight loss are frequently associated symptoms; right upper quadrant pain suggests biliary tract involvement (see later). The pathogenesis of this infection is uncertain. The diagnosis of intestinal cryptosporidiosis is most often made by acid-fast stain of the stool, where the organisms appear as bright-red spherules similar in size to red blood cells. The sensitivity of stool testing varies and depends on the burden of organisms, character of the stool (formed vs. liquid), and primary site of infection. Stool antigen detection and PCR markedly increase sensitivity of stool testing. Cryptosporidia may be identified in small bowel or rectal biopsies even when the stool examination is negative.

Specific antimicrobial treatment of cryptosporidial infection remains disappointing. Numerous antimicrobial agents have been tested, most without significant effect ( Table 35.1 ). Currently, the most effective therapy for cryptosporidia is HAART, in which improvement of immune function results in a clinical remission of diarrhea and clearance of cryptosporidia from the stool and on small bowel biopsy. For patients failing HAART and/or in whom antimicrobial therapy is ineffective, symptomatic treatment should include fluid support and antidiarrheal agents, occasionally including opiates to control the diarrhea.

Cystoisospora belli is a sporozoan and, like Cryptosporidium parvum , is a cause of both acute and chronic diarrhea in patients with AIDS. The disease is rare in the US, but it is more frequent and endemic in resource-poor countries. The organism may be identified by acid-fast stain of the stool or duodenal secretions or on mucosal biopsy. Unlike cryptosporidiosis, infection with Cystoisospora belli can be effectively treated with antibiotics, specifically trimethoprim/sulfamethoxazole or ciprofloxacin.

Cyclospora species are coccidian parasites andinfrequently causes acute or chronic diarrhea in both immunocompetent and immunodeficient individuals. Its prevalence in AIDS is low. The organism is detectable by stool studies and is treatable with trimethoprim/sulfamethoxazole or ciprofloxacin.

Microsporidia emerged as common intestinal infections in AIDS, but their prevalence has markedly fallen in the HAART era. Intestinal and hepatobiliary disease may be caused by 2 species of microsporidia: Enterocytozoon bieneusi (most common species) and Encephalitozoon intestinalis . The reported prevalence of microsporidia without HAART varies from 15% to 39%. Typical symptoms include watery, nonbloody diarrhea of mild to moderate severity, usually without associated crampy abdominal pain. Infection is associated with severe immunodeficiency, with median CD4 counts of infected individuals of less than 100/mm ³ . As with infection from cryptosporidia, the pathogenesis of disease remains poorly defined. Microsporidia can be discerned by light microscopy when tissue is embedded in plastic or paraffin ( Fig. 35.5 ). Staining of embedded mucosal biopsies with Brown-Brenn, Gram stain, or modified Masson trichrome stain is superior to routine H&E staining. Encephalitozoon intestinalis can usually be differentiated from Enterocytozoon bieneusi by its larger size and infection of lamina propria macrophages; electron microscopy is definitive. Stool staining techniques are only moderately sensitive, whereas small bowel biopsies are generally positive. Although albendazole has shown effective for Encephalitozoon Intestinalis , no widely available therapy is effective for E. bieneusi . As with cryptosporidiosis, HAART is the best therapy, resulting in resolution of diarrhea with clearance of this pathogen.

For unclear reasons, infections by the protozoa Giardia lamblia and Entamoeba histolytica are not consistently seen with increased frequency or virulence in AIDS. However, in East Asia, where Entamoeba histolytica is endemic, amebic colitis was identified as a common cause of diarrhea. The nonpathogenic Entamoeba dispar is morphologically similar to E. histolytica and can only be distinguished by more specific stool or enzyme-linked immunosorbent assay tests. Blastocystis hominis , Endolimax nana , and Entamoeba coli are nonpathogenic protozoa that are seen more commonly in men who have sex with men (MSM) and are often found in association with other protozoal parasites. Rare cases of enteric leishmaniasis (endemic), Pneumocystis jiroveci infection, and toxoplasmosis have been reported.

Helminths, particularly Strongyloides stercoralis and Ascaris lumbricoides , are uncommon pathogens in AIDS patients. Infected patients may present with abdominal pain, diarrhea, and eosinophilia. The clinical syndrome and recurrence rate associated with these parasites do not appear to be altered in the setting of HIV infection.

Viral infection of the large bowel, and rarely the small bowel, is an important cause of diarrhea in HIV infection. CMV is the most common viral cause of diarrhea and the most frequent cause of chronic diarrhea in patients with AIDS and multiple negative stool tests. This infection characteristically occurs late in the course of HIV infection when the CD4 lymphocyte count is below 100/L (see Fig. 35.1 ). Infection is most common in the colon, but concomitant disease in the esophagus, stomach, or small bowel may be observed (see Fig. 35.2 ). Isolated gastric or small bowel disease typically results in abdominal pain rather than a diarrheal illness.

The clinical manifestations of enteric CMV infection vary greatly and include asymptomatic carriage, nonspecific symptoms of weight loss and fevers, and focal enteritis/colitis including appendicitis or diffuse ulcerating hemorrhagic involvement with bleeding or perforation. As a result, patients can present with any of several constellations of symptoms, including abdominal pain, peritonitis, watery nonbloody diarrhea, or hematochezia. The most common presentation, however, is abdominal pain associated with chronic diarrhea. Although the endoscopic spectrum is variable, the hallmark of CMV enteritis/colitis is subepithelial hemorrhage and mucosal ulceration ( Fig. 35.6 ).

As noted previously, the diagnosis of GI CMV infection is best established by demonstrating viral cytopathic effect including confirmation by immunostaining in tissue specimens. If inclusions are few and demonstrable in tissue that appears macroscopically normal, the patient should be considered to have CMV colonization rather than true CMV infection.

Several effective therapies are available for the treatment of CMV (see Table 35.1 ). Ganciclovir, an acyclovir derivative typically given intravenously, is effective in approximately 75% of cases. Valganciclovir, an oral prodrug of ganciclovir, has excellent GI absorption and efficacy for CMV retinitis, but has not been well studied for induction therapy in GI disease. Immune reconstitution with HAART will negate the need for long-term suppressive therapy. At the time of diagnosis of GI CMV infection, all patients should have an ophthalmologic examination to exclude CMV retinitis, because this site of infection requires close follow-up to ensure remission, thereby preventing blindness. Although widely used in the transplant setting, the role of CMV antigenemia or DNA concentrations by PCR to predict subsequent disease and guide the use of preemptive therapy remains less well defined.

A number of other viruses (e.g., Norwalk, adenovirus, rotavirus), as well as novel noroviruses, have been identified in symptomatic and asymptomatic patients, but their overall contribution to diarrheal disease in AIDS is small.

The evidence for a role of HIV itself as a diarrheal pathogen is limited. An idiopathic AIDS enteropathy has been proposed to account for the diarrhea in AIDS patients who lack an identifiable pathogen and may reflect indirect effects of HIV on enteric homeostasis. With improvements in diagnostic techniques, greater awareness of the spectrum of diarrheal pathogens in AIDS, recognition of the importance of adverse drug effects as additional causes of diarrhea, and use of panendoscopy with biopsy for patients with negative stool tests, a diminishing fraction of AIDS patients have truly “idiopathic diarrhea.” Institution of HAART has been shown to improve chronic unexplained diarrhea.

Infections by enteric bacteria are more frequent and more virulent in HIV-infected individuals compared with healthy hosts. Salmonella , Shigella , and Campylobacter have higher rates of bacteremia and antibiotic resistance. Diagnosis is straightforward because the organisms usually can be grown from stool samples (see Chapter 110 ). These enteric infections typically present with high fever, abdominal pain, and diarrhea that may be bloody. Abdominal pain can be severe, mimicking an acute abdomen. As noted, bacteremia is common, and parenteral antibiotics should be administered empirically in severely ill patients when these infections are suspected until results of stool and blood cultures and sensitivities are available, after which antibiotics can be tailored to the pathogen isolated.

Diarrhea due to Clostridium difficile has emerged as a common bacterial pathogen, not because it is an OI, but rather because antibiotic use is far greater and hospitalization more frequent in this population than in healthy hosts. The clinical presentation, response to therapy, and relapse rate are no different than in immunocompetent patients. Diagnosis rests on standard assays of stool for C. difficile enterotoxin (see Chapter 112 ).

Small bowel bacterial overgrowth (see Chapter 105 ) is uncommon in AIDS patients, and its role in causing diarrhea appears limited.

Mycobacterial involvement of the bowel with Mycobacterium avium intracellulare (MAC) or TB may lead to diarrhea, abdominal pain, and rarely, obstruction or bleeding in patients with late-stage AIDS. A large number of patients with MAC have an asymptomatic GI infection whereas Mycobacterial tuberculosis appears to be symptomatic in all cases. Duodenal involvement by MAC is most common and may be suspected at endoscopy by the presence of yellow mucosal nodules, often in association with malabsorption, bacteremia, and systemic infection. Diagnosis of GI MAC infection is best made by endoscopic biopsy; fecal acid-fast smear is much less sensitive than culture. The organism is readily seen on biopsy specimens with acid-fast staining, and the number of organisms is often striking ( Fig. 35.7 ). Blood culture positivity may suggest the diagnosis. Affected patients have severe malabsorption and weight loss in association with blunting of villi and suffusion of macrophages with mycobacteria. A pseudo–Whipple syndrome with periodic acid–Schiff (PAS)-positive macrophages has been noted, although in contrast to MAC, acid-fast bacilli (AFB) positivity rather than PAS-positive macrophages are identified; electron microscopy will distinguish Whipple versus this pseudo–Whipple disease. As is typical of MAC infection, in AIDS there is a poorly formed inflammatory response, and granulomas are rarely present. Response to multidrug antibiotic therapy is variable and depends in part on the extent of immunocompromise. However, eradication is rarely achieved. As with other OIs, institution of HAART in these patients may improve immune function, hasten clinical resolution of the infection, prevent relapse such that long-term antimicrobial therapy will become unnecessary, and enhance survival.

Although extrapulmonary TB is characteristic of AIDS, luminal GI tract involvement remains infrequent but, when present, usually involves the ileocecal region or colon. Fistula formation, intussusception, and perforation, as well as peritoneal and rectal involvement, also have been reported. Tuberculous involvement of the gut in HIV infection is most commonly found in resource-poor countries. In contrast with MAC, TB infections in AIDS generally respond to multidrug antituberculous therapy (e.g., RIPE [see Table 35.1 ]).

Infections caused by mycobacteria (e.g., MAC lymphadenitis) and viruses (e.g., CMV uveitis) have been described following institution of HAART. This immune reconstitution inflammatory syndrome (IRIS) results in an exuberant inflammatory response directed toward previously quiescent or incubating pathogens. In addition, following the diagnosis of the OI and institution of HAART, paradoxical exacerbations of these infections may lead to a worse outcome.

Among fungal infections of the gut in AIDS, histoplasmosis has been most commonly described and occurs in the setting of disseminated infection, often in association with pulmonary and hepatic histoplasmosis. Histoplasmosis may manifest as a diffuse colitis with large ulcerations and diarrhea, as a mass, or as serosal disease in association with peritonitis. The diagnosis of disseminated histoplasmosis may be suspected in a patient with high fever and markedly elevated serum LDH levels. The diagnosis is established by fungal smear and culture of urine, infected tissue, or blood; urinary histoplasmosis antigen assay may provide supportive evidence. Rare cases of systemic cryptococcosis, coccidioidomycosis, and Talaromyces marneffei infection (principally in Southeast Asia) with gut involvement also have been described.

With the advent of HAART, drug-induced diarrhea became increasingly important. Although almost any therapeutic regimen is associated with diarrhea, the most common agents associated with diarrhea are the protease inhibitors, with nelfinavir having the highest rate. Generally, the diarrhea is mild to moderate in severity and is not associated with weight loss. The mechanism(s) for diarrhea due to these agents is poorly understood. Symptomatic therapies are generally effective. A botanical agent, crofelemer, may be useful for diarrhea in this setting. A suggested approach to the evaluation of diarrhea is outlined in Box 35.3 .