3.1 General Considerations

The GI tract represents a common site of involvement of opportunistic infection and neoplasms in HIV infection. GI symptoms such as dysphagia, abdominal pain, diarrhea and weight loss are common and affect over 75% of patients with HIV infection at some time during the course of their disease. It is important to remember that HIV-infected patients may also have common gastrointestinal problems unrelated to the HIV infection. The approach to HIV-infected patients with gastrointestinal symptoms should be guided by the CD4 count. In patients with counts greater than 300 x 10⁶/mL an opportunistic infection or neoplasm is very unlikely, and the approach to investigation of these patients should be similar to that in immunocompetent individuals. Once the CD4 count falls below 300 x 10⁶/mL the risk for opportunistic problems increases, and they must be considered in the differential diagnosis.

Other issues that must be considered in the evaluation of HIV-positive patients with gastrointestinal symptoms are drug side effects and problems specific to risk factor groups. Many of the antiretroviral drugs and antimicrobials used in HIV infection have prominent GI side effects, which are often overlooked in the differential diagnosis of GI problems in these patients. Homosexual males are also at risk for a variety of gastrointestinal problems as a result of their sexual practices. This includes an increased risk of gastrointestinal parasitic infections and proctitis resulting from gonorrhea, syphilis or Chlamydia. Patients having receptive anal intercourse are at risk for rectal trauma manifesting as lacerations, fissures, perianal infections and rarely, bowel perforations. Intravenous drug users are also at risk for infection with hepatitis B and hepatitis C viruses.

Typical enteric bacterial pathogens such as nontyphoidal strains of Salmonella, Shigella species and Campylobacter jejuni occur with only a slightly increased frequency in HIV-infected patients. When they do occur in immunocompromised patients the presentation is often atypical with a high incidence of bacteremia in addition to the typical symptoms of enteritis or colitis. Immunocompromised HIV patients also appear to be unable to effectively eradicate these organisms so that recurrent infection is common, often necessitating the use of chronic antibiotic suppression. Diagnosis is made with stool cultures. Because of the high incidence of bacteremia, blood cultures should also be done in patients presenting with acute diarrhea and fever.

The principles of treatment for acute bacterial enteritis or colitis in HIV-infected patients are generally the same as for other patients, with supportive care and intravenous fluids as required. Immunocompetent patients will usually clear the infection, and indications for antibiotic therapy are the same as for other patients. Immunocompromised patients and those with bacteremia should be treated with appropriate antibiotics (Table 1). Chronic suppressive therapy is often required as a result of the high incidence of recurrent infection.   

3.3.1 MYCOBACTERIUM AVIUM-INTRACELLULARE

Mycobacterium avium-intracellulare (MAI) is an atypical mycobacterium of environmental origin that is a common opportunistic infection in immunocompromised HIV-infected patients (CD4 lymphocyte counts 100 x 10⁶/mL) and is an AIDS-defining illness. It usually presents as a chronic systemic illness including fever, night sweats, weight loss and lymphadenopathy in addition to diarrhea. The diarrhea is often mild to moderate in severity and may have features to suggest malabsorption. Hepatosplenomegaly is a common finding on examination, as the liver and spleen are also commonly involved in MAI infection. The organism commonly infects the small bowel mucosa where it causes thickening and blunting of the villi as a result of an increased number of macrophages in the lamina propria. The appearance on hematoxylin and eosin stains is strikingly similar to Whipple's disease. With mycobacterial stains the macrophages can be seen to be filled with acid-fast organisms. In addition to the liver and spleen, the intra-abdominal lymph nodes and bone marrow are also commonly involved with MAI. Diagnosis can usually be made with blood and stool cultures. Blood cultures will usually be positive within 3-4 weeks, as this is a rapidly growing mycobacterium. Barium radiographs of the small bowel will often show dilation of the small bowel and irregular thickening of the small bowel folds. Ultrasound or CT scan of the abdomen will document hepatosplenomegaly, and there will often be enlarged intra-abdominal lymph nodes. Small bowel biopsy showing typical histology can also be used to establish a diagnosis.

Therapy for MAI is difficult and requires combinations of 4-6 antituberculous drugs, and the results are generally poor (Table 1). The organism usually cannot be eradicated; the goal of therapy is chronic suppression. Drug side effects are common, and many patients are unable to tolerate full therapy. Despite treatment, many patients have progressive symptoms and wasting. Because of the difficulty in treating established MAI infection, prophylactic therapy is recommended, and recent studies have shown some benefit to using rifabutin 300 mg p.o. daily once the patient's CD4 cell count falls below 100 x 10⁶/mL. 

Pulmonary Mycobacterium tuberculosis (TB) is being seen with increased frequency in HIV-infected patients and is especially common in IV drug users. The incidence of multiple-drug-resistant tuberculosis is increasing at an alarming rate. In HIV infection the GI tract may be involved with extrapulmonary TB either as direct extension from pulmonary lesions, where the esophagus is usually involved, or from systemic spread, where any part of the GI tract including liver and pancreas may be involved. Isolated involvement of the GI tract is unusual. Diagnosis should be made with biopsy and culture of the most readily accessible lesions. It is important to culture and do sensitivities on isolates of TB because of the rising incidence of multiple drug resistance. Initial therapy should include three or four antituberculous drugs. Choice of drugs should be determined on the basis of local sensitivity patterns. 
   

3.4.1 CANDIDA ALBICANS

Candida albicans is one of the most common opportunistic infections in HIV-infected patients. Oropharyngeal candidiasis occurs frequently and is often one of the earliest clinical signs of immune impairment. When limited to the oropharynx it is often asymptomatic or associated with mild discomfort. Esophageal involvement is usually associated with dysphagia; however, many patients may have only vague epigastric discomfort during meals. Odynophagia can occur with esophageal candidiasis, but severe pain with swallowing is unusual and suggests other infections such as cytomegalovirus (CMV), herpes simplex virus (HSV) or nonspecific HIV-associated esophageal ulceration. Patients with esophageal involvement usually have evidence for oropharyngeal Candida, commonly seen as whitish plaques on the buccal mucosa and posterior oropharynx. Esophageal involvement may occasionally occur in the absence of oral Candida, but this is unusual.

Candidal esophagitis can be demonstrated with a barium swallow that shows abnormalities ranging from small filling defects on the mucosal surface representing mucosal plaques to thickening of the mucosal folds with a shaggy outline to the wall. Severe or deep ulcerations may be seen but are unusual. Diagnosis is best made with endoscopy, which shows typical white adherent pseudomembranous plaques. In severe cases the entire esophageal mucosa may be covered with a confluent white membrane. The diagnosis is confirmed by brush cytology or mucosal biopsy showing invasion of the candidal pseudohyphae into the squamous epithelium. Cultures are not routinely done, as these organisms are commonly present in normal individuals and tissue invasion should be demonstrated to confirm the diagnosis.

Oropharyngeal candidiasis can be treated with either local therapy using clotrimazole troches 100 mg p.o. 1-3 times/day or with systemic antifungals such as ketoconazole 200 mg p.o. daily, fluconazole 100 mg p.o. daily or itraconazole 200 mg p.o. daily. Esophageal involvement should be treated with one of the oral antifungal agents, as topical agents are generally not effective. Higher doses may be required for initial treatment in symptomatic patients (Table 1). Initial therapy should continue for approximately 14 days. Recurrence is common, and many patients require ongoing therapy with an oral antifungal agent. Resistance to oral antifungal agents is starting to emerge. Intravenous amphotericin B can be used in low doses for those who fail therapy with oral antifungal agents. Esophageal candidiasis is so common in HIV infection that many experts recommend empiric therapy in patients with esophageal symptoms, especially if oral Candida is present. Further investigation with endoscopy can be reserved for those who do not respond to empiric antifungal therapy or for those with atypical symptoms. Disseminated infection with Candida may occur in HIV infection but is unusual, as the infection usually remains mucocutaneous. Disseminated infection has a poor prognosis and is often fatal.

Other fungal infections seen in HIV infection include cryptococcosis, histoplasmosis and coccidioidosis. Disseminated infection of any of these fungi establishes a diagnosis of AIDS when present with a positive HIV antibody test. The incidence of these infections varies, and they are usually seen in patients who have lived in or have visited endemic areas. Clinically, patients usually present with prominent systemic symptoms such as fevers, night sweats and weight loss. Neurologic involvement is usually seen with cryptococcosis. With histoplasmosis, the liver is often involved as part of a disseminated infection producing abnormalities of liver chemistry. Diagnosis of these infections generally depends on the demonstration of fungi through examination or culture of clinical specimens. Serologic tests are not dependable in the immunocompromised patient. Therapy usually requires intravenous amphotericin B in high doses. The response to therapy is generally poor, with a high rate of relapse and a poor overall prognosis.

3.5.1 GIARDIASIS

Giardia lamblia is a common intestinal parasitic infection that is commonly seen in homosexual or bisexual males. Its increased frequency in HIV patients is likely due to the high frequency in homosexual men rather than as a direct result of the HIV infection, as it does not appear to have a significantly higher incidence in other risk groups. Transmission occurs via the fecal-oral route. It usually infects the small bowel mucosa where it may be asymptomatic but usually causes diarrhea with abdominal cramping, bloating and nausea. In severe cases it may produce malabsorption and steatorrhea. Dissemination is rare and does not appear to be a significant problem in HIV infection.

The diagnosis depends upon demonstrating Giardia in the stool with an examination for ova and parasites. It may also be diagnosed on a duodenal aspirate or duodenal biopsy taken at the time of endoscopy. Treatment with metronidazole 250 mg p.o. t.i.d. for 5 days is usually effective in eradicating the organism even in HIV-infected patients; alternatively, quinacrine 100 mg p.o. t.i.d. for 5 days can be used.

Entamoeba histolytica is an intestinal ameba that is also seen with increased frequency in HIV-infected patients as a result of its increased frequency in homosexual and bisexual males. It usually causes colitis with bloody diarrhea and abdominal cramps. Asymptomatic carriage is seen more commonly in HIV-infected patients than in patients with amebiasis who are not infected with the HIV. Dissemination is rare and is not seen more frequently in HIV-infected patients than in other Entamoeba histolytica patients. Diagnosis is made by demonstrating ameba on a stool examination for ova and parasites. Sigmoidoscopy may show evidence for colitis, and typically Entamoeba histolytica infection causes punched-out "flask-shaped" ulcers. Diagnosis can be confirmed by demonstrating organisms on biopsy or from a fresh stool aspirate.

Therapy for symptomatic Entamoeba histolytica infection is with metronidazole 750 mg p.o. t.i.d. for 10 days followed by iodoquinol 650 mg p.o. t.i.d. for 20 days. Asymptomatic carriers may just be treated with iodoquinol. Patients should have follow-up stool studies to confirm the eradication of the infection.

Cryptosporidium is a protozoal parasite that is now recognized as a cause of self-limited diarrhea in immunocompetent persons. Several epidemic outbreaks have been identified. In immunocompromised patients it causes chronic watery nonbloody diarrhea that can be severe, leading to significant dehydration with electrolyte disturbances and death. Patients may have associated abdominal cramps and bloating, but these are not usually severe. Cryptosporidiosis is an AIDS-defining illness in HIV-infected patients.

The diagnosis of Cryptosporidium infection is based upon the demonstration of cryptosporidial oocysts in stool or on mucosal biopsy from the small intestine or colon. Involvement of the bowel may be patchy and involve the ileum, so intestinal biopsy from the duodenum or distal colon is not reliable and examination of the stool is the best diagnostic test. Recently, special stains have been developed, which have increased the yield of diagnosis from stool tests. Therapy in immunocompromised patients usually is supportive with the use of intravenous fluids as necessary to correct volume depletion and antidiarrheal agents such as loperamide 2-24 mg per day to keep diarrhea under control. In severe cases where diarrhea cannot be controlled with antidiarrheal agents, the somatostatin analogue octreotide has been used successfully in doses ranging from 50 µg to 500 µg s.q. t.i.d. to control the diarrhea. To date, there is no proven therapy to specifically treat and eradicate Cryptosporidium. Trials using spiramycin and paromomycin have been reported, but the results have been disappointing.

Microsporidia are a group of intracellular protozoans that measure 1-2 µm in size and have been described in HIV-infected patients. The commonest organisms of this group identified are Enterocytozoon bieneusi and Septata intestinalis. They are believed to be pathogenic in most patients, but asymptomatic carriage in HIV patients has been documented. When symptomatic, infection with Microsporidium resembles that of Cryptosporidium, usually with watery nonbloody diarrhea of variable severity, mild abdominal cramps and bloating.

When these organisms were initially described, the diagnosis required electron microscopy of a small bowel biopsy to see the small intracellular parasites. More recently, special stains have been developed to detect Microsporidia in stool samples. Experienced pathologists can usually see the organisms with high-power microscopy of thin plastic sections of mucosal biopsies. Therapy of symptomatic microsporidial infection is similar to that of Cryptosporidium, with the use of supportive therapy and antidiarrheal agents. Octreotide has also been used successfully for severe watery diarrhea. Metronidazole and albendazole have been used to try to eradicate Microsporidium, but neither has been shown to be reliably effective.

Isospora belli is another intestinal protozoal parasite that has been identified as causing infection in the setting of HIV, and infection with Isospora belli is also an AIDS-defining illness. Uncommon in North America, it has been seen in up to 15% of Haitian patients with AIDS. Clinically it causes a nonspecific nonbloody watery diarrhea similar to that of Cryptosporidium. Diagnosis is usually easily made by examination of stool for ova and parasites. Unlike infection with Cryptosporidium and Microsporidium, isoporiasis can usually be treated successfully with trimethoprim-sulfamethoxazole 160 mg tmp/800 mg smx p.o. q.i.d. for 10 days, then b.i.d. for 3 weeks. Recurrence is common (approximately 50%), and some patients may need chronic therapy.

Strongyloides stercoralis is a nematode endemic in tropical areas. It usually infects a host by penetrating the skin as filariform larvae. The larvae then travel via the bloodstream to the lungs where they leave the alveolar capillaries, are coughed up and swallowed. Once they reach the small intestine they release eggs that develop into infective filariform larvae that burrow into the small bowel mucosa. Pruritus, papillary rashes and edema may occur at the site of skin entry. Intestinal involvement may result in fever, nausea, vomiting, diarrhea, abdominal pain and weight loss. Diagnosis can best be made by examination of duodenal aspirate but can also be done by examination of concentrated stool specimens. Treatment is usually successful with thiabendazole 50 mg/kg/day in 2 doses for 2 days. Disseminated strongyloidiasis may occur in immunocompromised individuals and is recognized as an AIDS-defining illness. Therapy in immunocompromised individuals may need to be continued for at least 7 days, and some may require chronic therapy.

Pneumocystis carinii is recognized as a common cause of pulmonary infection. Extrapulmonary infections of Pneumocystis have been recognized especially in patients who have received aerosolized pentamidine rather than systemic therapy for Pneumocystis carinii pneumonia (PCP) prophylaxis. Infection of the liver, spleen, intestine, bone marrow and peritoneal cavity (producing ascites) have all been reported. Diagnosis is made by demonstrating typical organisms on a methenamine-silver stain of clinical specimens. Therapy is similar to that of pneumocystis pneumonia.

3.6.1 CYTOMEGALOVIRUS

Cytomegalovirus is a common infection, with greater than 50% of Canadian adults showing serologic evidence of previous exposure to CMV. Homosexual men and intravenous drug users have a seroprevalence of CMV as high as 90%. In immunocompetent patients the infection is latent and rarely causes clinical illness. Reactivation of latent infection occurs as HIV-infected patients become immunocompromised and is usually seen when the CD4 lymphocyte count is below 50 x 10⁶/mL. CMV infection is increasing as an important clinical problem in HIV patients.

The two most common sites for CMV infection in HIV-infected patients are the retina and gastrointestinal tract. The infection can involve any part of the GI tract, where it produces ulcerating lesions. The esophagus and colon are the most common sites of GI involvement. Esophageal involvement usually presents with odynophagia and dysphagia. Endoscopy shows large shallow ulcerations that may be circumferential. Involvement of the colon produces an acute colitis presenting with diarrhea that may be bloody, often with severe abdominal pain. Sigmoidoscopy or colonoscopy shows a colitis with friable edematous mucosa and scattered ulcerations, a picture similar to Crohn's disease. Small intestinal, gastric and hepatic involvement are less common. Since CMV is commonly found in HIV patients, culture of virus from mucosal biopsies is not sufficient to make a diagnosis of CMV infection. The diagnosis is based upon demonstrating the presence of intranuclear inclusion bodies in biopsy specimens. The presence of an accompanying vasculitis with viral inclusions in endothelial cells further supports CMV as the cause of the lesion. Systemic infection can be confirmed by viral cultures of white blood cells from the buffy coat of a centrifuged specimen of blood.

Therapy of symptomatic CMV requires ganciclovir 5 mg/kg IV q12h initially for 14-21 days. Foscarnet 60 mg/kg IV q8h for 14-21 days can be used as an alternative. These treatments usually result in clinical improvement and healing of mucosal lesions. Recurrence is high, however, and many experts recommend chronic suppressive therapy with ganciclovir 6 mg/kg IV daily 5 times per week or foscarnet 90-120 mg IV daily after acute therapy. Chronic therapy appears to be required lifelong. Recently an oral formulation of ganciclovir has been developed and shown to be effective for chronic suppression of CMV retinitis. Its efficacy for suppression of gastrointestinal CMV infections has not yet been established.

Herpes simplex virus (HSV) most commonly infects the esophagus to produce multiple esophageal ulcerations. Clinically herpetic esophagitis presents with prominent odynophagia and dysphagia that are indistinguishable from symptoms of CMV esophagitis. Differentiation from other causes of esophagitis in these patients requires endoscopy. The ulcers produced by herpes simplex virus are usually multiple and small. Biopsies will show multinucleated giant cells and Cowdry type A intranuclear inclusion bodies. Viral culture of biopsy material should be positive for HSV.

HSV esophagitis can usually be treated effectively with oral acyclovir 200 mg p.o. 5 times per day. In patients unable to take oral medications because of odynophagia, acyclovir can be given intravenously in a dose of 5 mg/kg q8h. Initial therapy should continue for 10-14 days. Recurrence is common, and many patients require chronic therapy with oral acyclovir. Foscarnet has been used as alternative therapy in those unable to take acyclovir or who fail therapy with acyclovir.

It is not clear whether the HIV itself causes gastrointestinal pathology. Two situations where direct pathologic effect of the HIV in the GI tract is suspected are nonspecific esophageal ulcerations and HIV enteropathy. Esophageal ulcerations are most commonly due to CMV and herpes virus, as discussed above. Ulcerations thought possibly to be directly due to the HIV occur as one of the seroconversion syndromes and as the idiopathic nonspecific esophageal ulcers seen in later stages of HIV infection. Acute infection with the HIV is usually associated with a nonspecific viral illness. As part of this seroconversion syndrome some patients develop severe odynophagia and are found on endoscopy to have multiple superficial esophageal ulcers. Electron microscopy of these ulcers has shown viral particles consistent with retroviruses. The ulcerations and odynophagia typically spontaneously resolve.

Later in the course of HIV infection, esophageal ulcerations may occur which are negative for the usual pathogens. These ulcers are usually deep with undermined edges and may be multiple. Although usually found in the esophagus, they can also occur in the posterior pharynx. Symptomatically they present with severe odynophagia that often limits oral intake. Interestingly they usually respond dramatically to treatment with corticosteroids taken orally or injected intralesionally. The etiology of these lesions is not clear; the dramatic response to steroids and other immune modifiers such as thalidomide implies an immunologic basis to the ulcerations.

HIV enteropathy is a term that has been applied to describe chronic diarrhea, often accompanied by weight loss, where no identifiable pathogen can be found. It is unclear if this enteropathy is due to an unidentified pathogen or to a direct effect of the HIV on the gut. The HIV potentially could affect the gut directly by infecting enterocytes, or indirectly by inducing the local release of cytokines and other inflammatory mediators, which then may affect enterocyte function. Improvement in some patients has occurred with antiretroviral therapy. Otherwise, treatment is symptomatic only.

3.7.1 KAPOSI'S SARCOMA

Kaposi's sarcoma (KS) is the most common neoplasm seen in HIV-infected patients. It has been more common in homosexual or bisexual males than in other risk groups for HIV infection, and its incidence appears to be decreasing within this risk group over the last 10 years. An infective cofactor has been postulated to explain the epidemiology of HIV-related KS, although such a factor has not been definitely identified. KS predominantly involves the skin and oropharynx; gastrointestinal involvement is seen in up to 40% of patients with skin involvement. Rare cases of visceral KS in the absence of skin lesions have been reported.

In most cases, GI involvement with KS is asymptomatic. Mucosal lesions can occur throughout the GI tract and are usually incidentally found at endoscopy, where they appear as raised red to violaceous macules. Large lesions may be nodular and may ulcerate. Symptoms are usually the result of hemorrhage from ulceration or obstruction from bulky lesions. Diarrhea and protein-losing enteropathy have also been reported. The exact presentation will depend upon the location of the lesions in the GI tract. Visceral KS should be suspected in any HIV patient with skin KS who has GI symptoms.

The diagnosis is made by histologic examination of mucosal biopsies. A recently described infection, bacillary angiomatosis, has identical histology to KS; differentiation is made by demonstrating organisms on silver stains. Gastrointestinal involvement with bacillary angiomatosis has also recently been described. HIV-related KS can be treated by local or systemic therapy. Oral lesions are best treated with local radiation or laser excision. Symptomatic visceral involvement requires systemic therapy, usually with combination chemotherapy. Good responses to subcutaneous or intralesional interferon have also recently been reported.

B-cell lymphomas represent the second most common neoplasm occurring in HIV-infected patients. These are usually high-grade lymphomas of the large cell type; however, patients with Burkitt's lymphoma and Hodgkin's disease have also been reported. The gastrointestinal tract represents the second commonest site of involvement after the central nervous system. The lymphomas occurring in HIV infection are commonly extranodal.

Any part of the gastrointestinal tract can be involved, with the presentation and symptoms depending on the particular site. Systemic symptoms of fevers, night sweats and weight loss are commonly associated. The diagnosis is made by histologic examination of material obtained from endoscopy, or ultrasound- or CT-guided biopsy. Treatment requires combination chemotherapy similar to that for other high-grade lymphomas. Tolerance of therapy is generally poor, often as a result of the poor functional status of these patients when they develop lymphoma and the presence of other opportunistic infections. Full remissions can occur in patients who can tolerate combination chemotherapy, but the prognosis is generally poor.

Squamous cell carcinoma of the anal canal is seen with higher frequency in homosexual and bisexual men who practice anoreceptive intercourse. The increased risk is independent of HIV infection and, like cervical carcinoma in women, appears to be related to previous infection with human papilloma virus. Colorectal carcinoma is not seen with higher frequency in this risk group. Anal carcinoma may present with a mass and associated fissure or fistula. Local pain is usually present and there may be bleeding. The differential diagnosis includes infections such as syphilis, lymphogranuloma venereum and condyloma acuminatum, and benign perianal conditions of fissure in ano and anal trauma from intercourse or instrumentation. Definitive diagnosis is made through biopsy of suspicious lesions, especially those that fail to heal after treatment of any secondary infections. Treatment modalities include surgical excision, but many may be treated with combined radiation and chemotherapy, which has effected cures with good preservation of anorectal function.