Gastrointestinal Complications of HIV Disease
Diseases of the gastrointestinal tract are common among those who are HIV-infected. Sometimes the first clue that a previously undiagnosed inmate/patient is HIV-infected is the presence of an HIV-associated gastrointestinal condition. These conditions can lead to significant morbidity including pain, difficulty swallowing, diarrhea, and weight loss. Early diagnosis and treatment can substantially improve the lives of those who are afflicted by these conditions. Although identifying the specific etiology of a patient's symptoms can be challenging, a methodical approach can usually identify a treatable condition. This article focuses on some of the most common abnormalities of the gastrointestinal system that correctional health care providers are likely to encounter among their HIV-infected patients.
The most common HIV-associated oral condition is candidiasis, or thrush. Thrush is usually found in those with advanced immunodeficiency, generally in patients with a CD4+ T-cell count less than 300 cells/mm3. Oral candidiasis is associated with progression to AIDS, and the presence of thrush in someone who is not known to be HIV infected should prompt a recommendation for HIV testing. Thrush most commonly appears as a white cheesy exudate that can be easily wiped off. Alternatively, thrush can present as erythema without exudates. The lesions are most commonly seen on the soft palate and tongue. Mild thrush can be treated with topical nystatin or clotrimazole troches. In more severe cases, oral fluconazole is highly effective. In cases of thrush caused by azole-resistant Candida, a higher dose of the azole can sometimes overcome resistance. If treatment with an azole drug is unsuccessful, a short course of either amphotericin swish and swallow or intravenous amphotericin is sometimes required. Candida can also cause angular cheilitis, or fissures located at the angle of the mouth. These lesions also occur in the setting of anemia or vitamin deficiency, but are more commonly due to Candida and typically respond promptly to oral azole therapy or even topical nizoral cream.
Oral hairy leukoplakia (OHL) generally presents as filamentous or hairy projections on the lateral borders of the tongue. The lesions are usually poorly demarcated and can have a flattened appearance. In contrast to thrush, the lesion of OHL cannot be brushed off. Thought to be due to Epstein-Barr virus, the lesions are asymptomatic and are generally of only cosmetic importance. OHL sometimes responds to acyclovir or valacyclovir, although probably the best treatment is HAART-induced immune reconstitution. As with thrush, OHL is highly predictive of HIV infection.
Aphthous ulcers are common and often severe in those who are HIV infected. Ulcers are traditionally classified as minor (<10mm) or major (>10mm) in size, and can be single or multiple. The lesions are typically painful, well-demarcated ulcerations that can be either shallow or deep. Ulcers can be found on the buccal or labial mucosa, tongue, soft palate, or pharynx. Not uncommonly, the patient will have a tender adjacent submandibular node. Aphthous ulcers are of unknown etiology. Some clinicians recommend treatment with topical suspensions of tetracycline with or without nystatin or hydrocortisone, while others recommend topical Kenalog® in Orabase, which is a paste that will stick to the wet surfaces of the mouth and form a protective film over the mouth ulcer. Minor aphthae usually heal without scarring in <10 days regardless of therapy. Perhaps the best approach is analgesics such as ibuprofen and, prior to meals, topical viscous lidocaine. Avoidance of acidic foods such as tomatoes and citrus is also useful while lesions are present. Major aphthae can be more painful and take longer to heal. Aphthae can also present in a herpetiform pattern, with multiple small ulcerative lesions. Oral lesions that do not heal within two weeks or those that are accompanied by systemic signs such as fever should be biopsied to rule out other etiologies such as deep fungal infection or malignancy. Single shallow painless ulcerations can be due to syphilis (condyloma lata), and should be screened for with a rapid plasma reagin (RPR) test.
Warts can be found on the lips or in the oral cavity and are typically painless. Caused by human papillomavirus, lesions can be either flat or cauliflower shaped and are often multiple in number. Lesions can be removed with a scalpel, by electrosurgery, laser ablation, or liquid nitrogen. If the lesion is flat and located on the tongue, consider other potential causes, such as syphilis.
Kaposi's sarcoma (KS) can be found anywhere in the GI tract. When found in the oral cavity, KS is most commonly red, blue, or purple in color and can be either macular or nodular. Lesions are most commonly found on the hard palate, but can also be seen on the gingiva or oropharynyx. The diagnosis is made by histologic examination of tissue obtained by biopsy. The most effective treatment is immune reconstitution by HAART, but in those for whom this is not possible intralesional chemotherapeutic agents such as vinblastine have been used.
Disease involving the esophagus is common in advanced HIV infection, and is most commonly due to Candida. Patients with candidal esophagitis usually have orpharyngeal involvement as well and present with dysphagia and odynophagia. In patients with a typical presentation, most clinicians empirically treat to cover Candida and reserve further evaluation for those who fail to respond. Oral fluconazole (200 mg on day one followed by 100 mg daily for two weeks) is usually highly effective, although azole resistance can be present at baseline or develop while on treatment. Intravenous fluconazole or low-dose amphotericin B (0.3 mg/kg/day) can be used in patients who cannot swallow. Voriconazole may be effective in some cases of fluconazole resistant Candida. Caspofungin, an antifungal in the echinocandin class, has also shown clinical activity in some cases of azole-resistant candidal infections.
In cases of esophagitis that fail to respond to antifungal therapy, endoscopy with biopsy is required to rule out other etiologies such as herpes simplex virus, (HSV) cytomegalovirus, (CMV), malignancy, or aphthous ulcerations. Patients with CMV esophagitis commonly have systemic symptoms such as fever, nausea, emesis, diarrhea, abdominal pain, and weight loss. Biopsy reveals CMV infected cells with intranuclear inclusion bodies. CMV esophagitis can be treated intravenously with ganciclovir (5 mg/kg q 12 hours for 14 days) or foscarnet (60 mg/kg q 8 hours for 14 days). Ganciclovir can lead to myelo-suppression, while foscarnet can cause renal insufficiency, electrolyte disturbances, and penile ulcerations.
Esophageal HSV can present with odynophgia, dysphagia, retrosternal pain, nausea, and emesis. Untreated patients can develop tracheoesophageal fistulas, necrosis, stricture, or hemorrhage. Biopsy demonstrates cytoplasmic inclusion bodies, ground glass appearance of nuclei, and multinucleated giant cells. HSV responds to intravenous acyclovir.
Major aphthae involving the esophagus can persist and be significantly debilitating. In some cases, systemic steroids or oral thalidomide is useful in hastening healing.
Worldwide, diarrhea is the most common cause of morbidity and mortality among those who are HIV-infected. Diarrhea can be caused by bacterial, viral, or parasitic infections, or by a medication. In many cases, a careful search can identify a treatable etiology of the patient's diarrhea. There is little data specifically addressing the etiologies of diarrhea among the incarcerated. One would expect that the frequency of some pathogens would differ among those recently incarcerated as compared to those who have been institutionalized for an extended period of time. Likewise, the causes of diarrhea among foreign-born inmates and those who have traveled outside of the United States may differ from those who have never left the country.
The evaluation of a patient with diarrhea begins with a thorough history and physical examination. Patients may use the word diarrhea to describe anything from a rectal discharge, to occasional loose stools, to frequent large volume bowel movements. Additionally, acute self-limited diarrhea occurs frequently in otherwise healthy adults. Diarrhea that has been present for years with little if any weight loss is more likely to be due to irritable bowel, inflammatory bowel, or lactose intolerance than to an infectious etiology. In patients with advanced immunodeficiency, fever, and anemia, opportunistic infections such as those caused by Mycobacterium avium complex (MAC) and CMV must be considered. Medications or dietary changes are often an overlooked cause of changes in bowel frequency or consistency. In jails and prisons, regulated access to toilets and toilet paper can cause those who experience medication-induced diarrhea to adhere poorly to prescribed treatments. Drugs that commonly cause a change in bowel motility include laxatives, antacids, cardiac medications, some psychiatric medications, and antiretroviral agents such as ddI, ritonavir and nelfinavir. Antibiotics can alter intestinal flora and lead to loose stools.
In those who present with symptoms of greater than one-week duration associated with weight loss, fever, dehydration, or bloody stools, diagnostic studies are indicated. The intensity of the work-up is subject to debate, but most would agree that a stepwise approach is usually appropriate in those who are not critically ill. Generally, in HIV infected patients it is most appropriate to begin with evaluation of stool specimens for presence of ova, parasites, Clostridium difficile toxin, Salmonella, Shigella, Campylobacter, E. coli 0157 H7, Cryptosporidium, and Microsporidia. To increase the yield, it is recommended to send three separately collected specimens for ova and parasite analysis. If the patient is febrile, blood cultures for bacteria should be collected. In those with advanced immunodeficiency (CD4 <75/mm3) blood cultures for mycobacteria are also indicated. If stool studies and blood cultures fail to identify an etiology, flexible sigmoidoscopy or colonoscopy with biopsy should be performed. Biopsy specimens should be cultured for Salmonella, Shigella, Campylobacter, mycobacteria, CMV, and HSV. Histologic evaluation should include staining for mycobacteria, fungi, protozoans, and viral inclusions.
Bacterial Causes of Diarrhea
In non-incarcerated HIV-infected persons in the U.S., the most common bacterial causes of diarrhea are Salmonella, C. difficile, MAC, Shigella, and Campylobacter. The overall incidence of bacterial colitis has been reduced in this country by the widespread use of trimethoprim/sulfamethoxazole (TMP/FMX) for Pneumocystis prophylaxis.
Fever is more commonly seen in Salmonella infection than in other bacterial cause of diarrhea. Blood in the stool suggest Shigella or Campylobacter rather than Salmonella. Among those infected with HIV, Salmonella is more likely to lead to bacteremic disease and to relapse after treatment. Predictors of relapse include septicemia and low CD4 lymphocyte counts. Salmonella can be treated with TMP/FMX, a quinolone, or azithromycin. Among those with CD4 counts less than 50 cells/mm3 who have experienced relapsed infection with Salmonella, ongoing maintenance therapy with ciprofloxacin should be considered. If bacterial colitis is suspected, medications that decrease bowel motility such as diphenoxylate, loperamide, paregoric, and tincture of opiates should be avoided because they have been associated with the development of toxic megacolon or prolongation of infection. Clustering of cases of bacterial diarrhea caused by Salmonella, Shigella, or E. coli 0157H7 may indicate a food borne outbreak or person-to-person transmission and should lead to an investigation.
Infection with C. difficile can lead to diarrhea in patients with AIDS. Both receiving antibiotics and being hospitalized are associated with an increased risk for C. difficile infection. Diagnosis can be made by the detection of C. difficile toxin in stool. The first line treatment is oral metronidazole at a dose of 500 mg by mouth 3X/day for 10-14 days. Because of the concern for encouraging the development of resistant organisms, oral vancomycin should be reserved for only those patients who fail to respond to metronidazole.
Disease due to MAC is uncommon among those who have a CD4 lymphocyte count of >100/mm3 and those who are taking macrolide prophylaxis. Among those with severe immunosuppression, disseminated MAC can cause diarrhea with fever, sweats, anemia, neutropenia, weight loss, and hepatosplenomegaly. Stool or blood cultures for acid-fast bacilli (AFB) can confirm the diagnosis. While culture of the organism from a tissue specimen is the gold standard for diagnosis, endoscopic biopsy showing foamy macrophages and acid-fast organisms can be used as evidence of infection as well. Cultures are necessary to differentiate MAC from tuberculosis. Treatment with combinations of medications including rifampin or rifabutin, ethambutol, ciprofloxacin, amikacin, and clarithromycin or azithromycin have been used with some success. Ultimately, the only long-term effective strategy for controlling MAC disease relies on immune restoration with HAART.
Parasitic Causes of Diarrhea
Common parasitic causes of diarrhea include Cryptosporidium, Microsporidium and Entamoeba histolytica. Cryptosporidium parvum is found worldwide in drinking water that has been contaminated by fecal cysts from grazing animals. Water that is drawn from wells is less likely to be affected. Heat and chlorine are not effective against Cryptosporidia. Illness due to Cryptosporidium can last for months in those who are HIV-infected, leading to dehydration, electrolyte abnormalities and wasting. Treatment of Cryptosporidium is only of marginal benefit. The non-absorbable aminoglycoside paromomycin is most commonly used for treatment in this country.
Microsporidia species are spore-forming parasites that can cause a wide variety of clinical syndromes among those who are HIV-infected. The microsporidial organisms Enterocytozoon bieneusi and Encephalitozoon intestinalis can cause diarrhea and wasting, and albendazole can be effective for treatment.
In most cases, E. histolytica is a colonizer and does not cause symptoms; however, some strains of E. histolytica can lead to cramping, abdominal pain, painful bowel movements, and bloody stools. E. histolytica is diagnosed by stool examination or blood serology. Treatment for symptomatic disease (i.e., invasive disease) is metronidazole 750 mg 3X/day for 10 days. There is disagreement as to the benefit of treating those who are asymptomatic but have been demonstrated to pass cysts. If the goal is to eradicate cysts from the intestinal lumen, the recommended treatment is iodoquinol 650 mg 3X/day for three weeks.
Giardia lamblia is an enteric protozoan with a worldwide distribution that causes acute and chronic diarrhea throughout the world. Giardiasis can be transmitted through water and person-to-person by the fecal-oral route. Most of those who ingest Giardia cysts will not become infected. Of those who are infected, some will become asymptomatic cyst passers while others will develop diarrhea. Symptoms can include cramps, diarrhea, bloating, flatulence, and weight loss. Giardia is diagnosed by the detection of cysts or trophozoites in the stool by direct examination or antigen assay. Treatment is generally metronidazole at a dose of 250 mg 3X/day for five days.
Viral Causes of Diarrhea
Diarrhea due to rotavirus or other viral agents is relatively common but is usually self-limited. In most cases these illnesses are of short duration and require no specific diagnostic or therapeutic intervention other than oral fluids and over-the-counter antimotility agents.
In those with advanced immunosuppression (typically CD4 counts of <50/mm3) CMV can lead to colitis, but since the introduction of HAART, the incidence of active CMV disease has fallen dramatically in the U.S. Diagnosis is usually made by flexible sigmoidoscopy or colonoscopy. CMV can lead to areas of erythema, ulceration, and hemorrhage. Histologic examination of biopsy specimens reveals intranuclear inclusion bodies in infected epithelial, endothelial, or smooth muscle cells.
Acute treatment of CMV colitis is ganciclovir IV 10-15 mg/kg/day in two to three divided doses. Foscarnet is also effective at a dose of 180 mg/kg/day IV in two or three divided doses. In the absence of immune restoration, active disease commonly recurs. In the event of relapse, retreatment followed by daily maintenance therapy is indicated. The only long term effective treatment for CMV is HAART-induced immune restoration.
Fungal Causes of Diarrhea
Disseminated fungal diseases are uncommon causes of diarrhea in those who are HIV-infected. Histoplasmosis can involve the gastrointestinal tract, leading to diarrhea, fever, pain, and weight loss. Diagnosis can be made by the detection of intracellular budding yeast in colonic biopsy specimens. The histoplasmosis urinary antigen is very useful for diagnosing this infection and for monitoring therapy. Initial therapy of disseminated histoplasmosis is generally amphotericin B, followed by maintenance with either amphotericin B or itraconazole. Maintenance must be continued lifelong, unless HAART leads to significant sustained immune reconstitution.
Anorectal disease is very common among those who are HIV-infected. Oftentimes patients will not divulge that they have anorectal symptoms or lesions. Clinicians should routinely ask patients about anorectal symptoms, and periodically perform a visual inspection of the external anal area.
Herpes Simplex Virus
Both HSV1 and 2 commonly cause anorectal disease. HSV infection can also lead to urinary symptoms, impotence, and sacral paresthesias. In HIV-infected patients who present with perianal ulcerative lesions or fissures, the most common cause is HSV. Patients should be treated with oral acyclovir or valacyclovir for ten to fourteen days. Lesions that fail to respond should be cultured for HSV, and if positive, sent for susceptibility testing. Lesions that are acyclovir resistant can be effectively treated with intravenous foscarnet. Relapses are quite common but can be decreased in frequency by the use of suppressive therapy with acyclovir at a dose of 200-400 mg 2X/day.
Gonorrhea, Syphilis and Chlamydia
Patients who are infected with Neisseria gonorrhoeae and/or Chlamydia trachomatis can present with symptoms that include anal discharge, pain, tenesmus, and bleeding. Cultures of rectal swabs and urine ligase chain reaction (LCR) for Gonorrhea or Chlamydia infection can be useful in making the diagnosis. Ceftriaxone 250 mg IM for one dose, followed by either doxycycline 100 mg 2X/day for seven days or azithromycin 1,200 mg for one dose is recommended for both anorectal gonorrhea and chlamydia. Syphilis can also cause painful or painless ulcers of the anal mucosa or rectum. The diagnosis is usually made clinically in conjunction with a serum RPR test.
Warts, caused by human papillomaviruses, (HPV) are commonly found in the perianal area. Lesions can be either flat or cauliflower-shaped, are usually multiple and asymptomatic but can cause itching or bleeding. Small warts can spontaneously resolve, and removing visible warts does not reliably eradicate the causative virus. HPV can frequently be isolated from individuals who have no visible lesions. Regardless of the type of treatment, warts commonly recur. Some strains of HPV are associated with anal cancer, and biopsy should be performed in those with extensive lesions and patients who do not respond to therapy. Data have been presented this past year concerning the development of therapeutic and preventive vaccines for HPV. These vaccines hold great promise for reducing the risk for anal and genital lesions and most importantly for decreasing the likelihood of cervical and anal carcinoma. Although beyond the scope of this article, there is a growing body of literature that discusses the potential role of anal pap smears in the early diagnosis of malignancy. Some of the most commonly used treatments for warts are outlined in Table 1.
Joseph Bick, M.D., is Chief Medical Officer at the California Medical Facility, California Department of Corrections. Disclosures: Nothing to disclose.