NIH conference. Gastrointestinal infections in AIDS.

NIH

CONFERENCE

Gastrointestinal Infections in AIDS Moderator: Phillip D. Smith, MD; Discussants: Thomas C. Quinn, MD; Warren Strober, MD; Edward N. Janoff, MD; and Henry Masur, MD

• As the largest lymphoid organ in the body, the gastrointestinal tract is a potential reservoir for human immunodeficiency virus (HIV), the causative agent of the acquired immunodeficiency syndrome (AIDS), and it is an important site for HIV-induced immunodeficiency. The resulting defects in cellular and humoral defense mechanisms predispose the gastrointestinal tract to a spectrum of viral, fungal, bacterial, and protozoan pathogens that cause relentless morbidity and, in some cases, death. With a thorough diagnostic evaluation, physicians can identify one or more of these pathogens in a majority of patients with AIDS who have gastrointestinal symptoms. The identification of enteric pathogens in patients with AIDS is important because an increasing array of therapeutic regimens is becoming available to treat many of these infections.

cells and a higher incidence of extra-intestinal opportunistic infections than those without diarrhea, suggesting that patients with AIDS who develop diarrhea have a greater degree of immunosuppression than those who do not develop diarrhea (7). When diarrhea is chronic and accompanied by inanition, the sense of well-being and the ability to carry out the activities of daily living are profoundly impaired. This is particularly true for African patients with AIDS, who often have severe diarrhea and cachexia. Referred to as "slim disease" (11), this devastating symptom complex may reflect the presence of intestinal infection caused by opportunistic pathogens superimposed on underlying gastrointestinal infection caused by * 'traditional 1 ' tropical pathogens.

Diagnostic Evaluation Annals of Internal Medicine. 1992;116:63-77.

Dr Phillip D. Smith (Laboratory of Immunology, National Institute of Dental Research, National Institutes of Health [NIH]): Gastrointestinal symptoms, particularly diarrhea, occur in 30% to 50% of North American and European patients with the acquired immunodeficiency syndrome (AIDS) and in nearly 90% of patients in developing countries (1-4). Initially, diarrhea may be associated with nausea, anorexia, malaise, and other mononucleosis-like symptoms at the time of seroconversion (5). Later, diarrhea is often the presenting symptom of full-blown AIDS and is characterized by large volume, presence of blood, and abdominal pain, depending on which pathogen is present (6). Most patients with AIDS who develop diarrhea have some degree of malabsorption (7-10). That diarrhea contributes to the frequently accompanying cachexia is suggested by our observation that patients with AIDS who develop diarrhea have greater weight loss than such patients who do not develop diarrhea (7). Patients with AIDS and diarrhea also have lower numbers of CD4+ T An edited summary of a Clinical Staff Conference held 28 February 1990 in the Amphitheater, Building 10, National Institutes of Health, Bethesda, Maryland. The conference was sponsored by the National Institute of Dental Research, National Institute of Allergy and Infectious Diseases, and the Clinical Center, National Institutes of Health, U.S. Department of Health and Human Services. Authors who wish to cite a section of the conference and specifically indicate its author may use this example for the form of reference: Quinn TJ. Protozoan infections, pp. 66-68. In: Smith PD, moderator. Gastrointestinal infections in AIDS. Ann Intern Med. 1992;116:63-77.

We do a comprehensive diagnostic evaluation in patients with persistent or severe diarrhea, because a specific pathogen can be identified in a majority of patients (68% to 85%) and because specific therapy can often reduce the volume and frequency of the diarrhea (7, 12). Such pathogens include opportunistic agents that consistently cause severe, chronic, or frequent gastrointestinal disease and nonopportunistic agents that usually cause acute, treatable diarrheal illness (Table 1) (6). Our evaluation begins with a history and physical examination. Regarding the history, information on geographic location is particularly important because it may suggest which pathogens are more likely to be identified (1). For example, rotavirus has been detected in 18% of human immunodeficiency virus (HlV)-infected patients with diarrhea in Australia (13) but not in HIV-infected patients in the United States (7, 14). Other organisms, such as Cryptosporidium species and Isospora belli, are more common in patients in developing countries than in patients in the United States. After the history and physical examination, as many as three stool specimens are cultured for pathogenic bacteria, assayed for Clostridium difficile toxin, and examined for parasites (Table 2 [step 1]). The parasitologic examination includes saline, iodine, trichrome, and acid-fast preparations of direct or concentrated samples (or both) from each stool specimen. If these samples are negative or if therapy directed to the identified pathogen or pathogens is ineffective, we do esophagogastroduodenoscopy and colonoscopy to visually inspect the mucosa and to obtain biopsy specimens and luminal fluid (Table 2 [step 2]). Duodenal biopsy specimens are cultured for cytomegalovirus and mycobacteria, and colonic biopsy specimens are cultured for cytomegalovirus, adenovirus, mycobacteria, and herpes simplex virus. Duodenal and colonic tissue biopsy specimens are also examined for histologic changes and the presence of viral inclusion cells,

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Table 1. Gastrointestinal Pathogens in HIV-infected Patients* Organ

Pathogens

Esophagus Stomach Small intestine

Colon

Candida albicans; herpes simplex virus; cytomegalovirus Cytomegalovirus; Mycobacterium aviumintracellulare Cryptosporidium; Microsporidium; Isospora belli; Mycobacterium avium-intracellulare; Salmonella species; Campylobacter jejuni Cytomegalovirus; Cryptosporidium; Mycobacterium avium-intracellulare; Shigella flexneri; Clostridium difficile; Campylobacter jejuni; Histoplasma capsulatum; adenovirus; herpes simplex virus (rectum)

* HIV = human immunodeficiency virus.

mycobacteria, and invasive and noninvasive protozoa. For these examinations, formaldehyde-fixed biopsy specimens are stained with hematoxylin-eosin, Grocott methenamine-silver or Giemsa, and Fite. Duodenal fluid obtained at this time is examined for parasites. We no longer routinely culture stool specimens for Campylobacter-Uke organisms (Campylobacter fennelliae and Campylobacter cinaedi) that are associated with diarrhea in homosexual men (15) but not in patients with AIDS (7, 12). We also do not routinely culture duodenal fluid for quantitative bacterial counts. If the evaluation up to this point is still negative, we evaluate glutaraldehyde-fixed biopsy specimens of the duodenum for Microsporidia and of the colon for adenovirus by electron microscopy (Table 2 [step 3]). Using the above protocol, we have identified one or more pathogenic processes in up to 85% of patients with AIDS who have diarrhea (7). Culture and microbiologic examination of stool have been the most useful means for obtaining a diagnosis and have facilitated the identification of pathogenic bacteria and parasites in as many as 68% of cases in other studies (12, 16). Mucosal biopsy specimens were critical for the diagnosis of viral pathogens such as cytomegalovirus, which caused intestinal disease in 45% of our patients (7). Duodenal fluid was the least helpful specimen in yielding a diagnosis but may eventually prove to be useful in the identification of Microsporidia. A probability analysis of reported data has shown that an extensive diagnostic evaluation, including endoscopy, does not yield more remissions for a single, treatable pathogen than a "minimal" evaluation based solely on stool culture (17). A minimal evaluation, however, does not detect enteric parasites or invasive viruses. Viral Pathogens Cytomegalovirus Cytomegalovirus is one of the most common and potentially serious opportunistic pathogens of the gastrointestinal tract in patients with AIDS. Identified in the gastrointestinal tract in 7.7% of HIV-infected and 13.1% of patients with full-blown AIDS (18), cytomeg64

alovirus has been reported to cause severe or lifethreatening enteric disease in 2.2% of patients with AIDS (19). The most common manifestation of enteric cytomegalovirus disease is colitis. Cytomegalovirus-associated colitis is characterized by diarrhea, by fever, and frequently by hematochezia and abdominal pain (20, 21). The colon appears to be particularly susceptible to progression to ischemic necrosis and perforation (20). Virtually all other organs of the alimentary tract are susceptible to cytomegalovirus disease, which manifests clinically as esophagitis (22); gastritis (23); small intestinal enteritis (23); and, less frequently, acalculous cholecystitis (24), papillary stenosis (25, 26), sclerosing cholangitis (26), and pancreatitis (27). Although uncommon, cytomegalovirus-associated disease of the biliary tract (usually without icterus or pruritus) and of the pancreas should be included in the differential diagnosis of abdominal pain, nausea, and vomiting in patients with AIDS, regardless of whether or not they have diarrhea. Endoscopic findings in patients with cytomegalovirus-associated inflammation of the gastrointestinal mucosa range from localized hyperemia to hemorrhagic erythema to superficial or deep ulceration. We (7) and others (28) diagnose cytomegalovirus-associated gastrointestinal disease when the biopsy specimen shows cytomegalic inclusion cells with surrounding inflammation. Characteristic histopathologic findings include large (cytomegalic) mononuclear, epithelial, endothelial, or smooth muscle cells containing intranuclear or cytoplasmic inclusions; chronic inflammatory cells; and often (although not required for diagnosis) vasculitis. The intranuclear inclusion (replicating virions) may be surrounded by a space, giving the appearance of an "owl's eye" halo. Cytomegalovirus can also be detected by culture, immunochemical staining, and in-situ hybridization, but these techniques do not differentiate between the presence of cytomegalovirus alone and cytomegalovirus with inflammation.

Table 2. Diagnostic Evaluation of Patients with AIDS Who Have Diarrhea Step 1 Stool cultured for Salmonella species, Shigella flexneri, and Campylobacter jejuni at least three times and assayed for Clostridium difficile toxin Stool specimens (direct, concentrated, or both) examined for parasites using saline, iodine, trichrome, acid-fast preparations Step 2 Gastroduodenoscopy and colonoscopy to inspect tissue and to obtain biopsy specimens and luminal material Duodenal biopsy specimens cultured for cytomegalovirus and mycobacteria Colonic biopsy specimens cultured for cytomegalovirus, adenovirus, mycobacteria, and herpes simplex virus Biopsy specimens stained with hematoxylin-eosin for protozoa and viral inclusion cells, with methenamine silver or Giemsa for fungi, and with Fite for mycobacteria Duodenal fluid specimen examined as above for parasites Step 3 Biopsy specimens examined by electron microscopy for Microsporidia (duodenal tissue) and adenovirus (colonic tissue)

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Adenovirus Adenovirus is a recognized cause of diarrheal illness in children and immunosuppressed adults without HIV infection (29). Recently, we identified adenovirus by culture and transmission electron microscopy in inflamed colonic tissue of patients with AIDS who had chronic, watery, nonbloody, nonmucoid diarrhea (30). Patients with adenovirus-associated colitis usually showed weight loss and had no other identifiable enteric pathogen. The endoscopic evaluation of the colonic mucosa in these patients was either normal or showed areas of discrete, often raised, erythematous lesions that were several millimeters in diameter. Light microscopy revealed chronic inflammation surrounding adenovirus-infected mucosal cells that often contained intranuclear inclusions (Figure 1, top). In contrast to the classic haloed appearance of cytomegalic intranuclear inclusions, inclusions in adenovirus-infected cells filled the nucleus. Adenovirus appeared to infect only mucosal cells, especially goblet cells, sparing cells of the lamina propria, which are frequent targets of cytomegalovirus. At the ultrastructural level (Figure 1, bottom), adenovirus induced striking pathologic changes that were characterized by the degeneration, death, and focal necrosis of infected epithelial cells. These findings indicate that adenovirus can cause pathologic changes in the mucosa of patients with AIDS who have symptomatic colitis, although the virus may also be found in the stools of patients without diarrhea. A causal relation between these histopathologic changes and diarrheal symptoms, however, has not been clearly established. The full spectrum of adenovirus-induced colitis in patients with AIDS is under investigation.

Herpes Simplex Virus The three major manifestations of herpes simplex virus infection in patients with AIDS are perianal lesions, proctitis, and esophagitis. Perianal lesions are typically chronic, cutaneous ulcers (31). Proctitis often accompanies the perianal disease and may manifest as severe anorectal pain; tenesmus; constipation; inguinal lymphadenopathy; and, less often, difficulty in urinating and sacral paresthesias. These symptoms may also be associated with herpes simplex proctitis in seronegative homosexual men (32). Proctitis involving the rectum and distal sigmoid colon is occasionally associated with diarrhea (7). Esophagitis caused by herpes simplex virus is a common cause of odynophagia, with or without dysphagia, in patients with AIDS (33). Sigmoidoscopy and esophagoscopy are required to diagnose herpes proctitis and esophagitis, respectively. Lesions begin as small vesicles and progress to erosions that often coalesce into diffuse ulcers. Diagnosis is based on the cytologic identification of intranuclear (Cowdry type A) inclusions in multinucleated cells within the lesion and is confirmed by virus isolation. Serologic testing is usually not helpful because of the high prevalence of preexisting antibodies to herpes simplex virus.

Figure 1. Histopathology of adenovirus-associated colitis. Top panel. Light micrograph of a colon biopsy specimen from a patient with adenovirus-associated colitis showing a small focus of mucosal cell degeneration and necrosis with two epithelial cells that contain large, amphophilic, intranuclear inclusions (arrows). (Hematoxylin-eosin; original magnification, x 600.) Bottom panel. Transmission electron micrograph of another colon biopsy specimen from the same patient showing an enterocyte nucleus {large arrowhead) filled with adenovirus virions that has been extruded into the lumen from the necrotic cell located below; adjacent epithelial cells have foci of disrupted cytoplasm containing secondary lysosomes {small arrowhead). (Original magnification, x 34 000.) (Reproduced from Janoff and colleagues [32] with permission.) Fungal Infections Candida albicans In immunocompetent persons, Candida albicans is a common, nonpathogenic commensal of the gastrointestinal tract; however, in HIV-infected persons, this organism causes locally invasive mucosal disease in the oral cavity and esophagus. No evidence has been found that Candida species contribute to diarrheal disease in patients with AIDS. We recently observed a striking similarity among isolates of Candida albicans that cause oral and esophageal disease in patients with AIDS and isolates present in healthy persons (34), suggesting that AIDS-associated candidiasis is not caused by a unique or particularly virulent strain but likely results from a



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defect in host defense mechanisms. However, because neutrophil function remains relatively intact, disseminated disease is extremely rare. The presence of oral candidiasis in persons at risk for AIDS should alert the physician to possible HIV infection, because 60% of such persons develop an AIDS-related infection or Kaposi sarcoma within 2 years (35). Candida esophagitis often accompanies oral candidiasis (36), but infection of the two sites may occur independently. Consequently, esophagoscopy is required to confirm esophageal involvement. Lesions in either site characteristically show inflammatory erosions or superficial ulcers with an overlying white plaque or pseudomembrane containing Candida organisms and inflammatory cells. Diagnosis is confirmed histologically by the presence of hyphae, pseudohyphae, and yeast forms. Histoplasma capsulatum Disseminated H. capsulatum infection is emerging as an important opportunistic infection in patients with AIDS who reside in endemic areas (37, 38). Among patients with disseminated histoplasmosis, gastrointestinal involvement is detected by evaluation of biopsy specimens in approximately 70% of patients, but gastrointestinal symptoms are present in only approximately 10% of patients (39). Symptoms include diarrhea, weight loss, fever, and abdominal pain. Whether H. capsulatum infection itself induces these symptoms in patients with AIDS is unclear. Most patients with gastrointestinal manifestations have colonic involvement. Colonoscopy in such patients may show inflammation, ulcerations, or fungating lesions. The histologic examination of Giemsa-stained sections shows small intracellular yeast-like H. capsulatum within lamina propria macrophages. Diagnosis is established by culture.

on microscopic identification of organisms in stool specimens with a modified acid-fast stain. Many organisms are usually shed during symptomatic infection. Concentration techniques (zinc sulfate or Sheather sucrose flotation) may be required to optimize the detection of rare or very infrequent oocysts in patients with intermittent symptoms and shedding of organisms (44-47). Cryptosporidium organisms, which inhabit the brush border of intestinal epithelial cells throughout the gastrointestinal tract, may also be identified in biopsy specimens or duodenal fluid. Isospora belli Infection with /. belli may also cause severe and protracted diarrhea in patients with AIDS (48). The parasite is the cause of gastrointestinal infection in approximately 1% to 3% of patients with AIDS and diarrhea in the United States (48-50) but in 15% to 19% of patients in developing countries (51). Clinically, isosporiasis resembles cryptosporidiosis. Watery diarrhea without blood or inflammatory cells, cramping abdominal pain, weight loss, anorexia, malaise, and fever are usually present. Laboratory findings in isosporiasis may include steatorrhea and, in contrast to cryptosporidiosis, eosinophilia. Although heavily concentrated in the small intestine, /. belli can be identified throughout the entire gastrointestinal tract and in other organs (50). Diagnosis of isosporiasis is established by the detection of large (20 to 30 jum x 10 to 20 /xm), oval oocysts in stool with a modified Kenyoun acid-fast stain (52). Isospora belli oocysts contain two sporoblasts and differ from Cryptosporidium oocysts, which are small (4 to 6 /im), round, and contain four sporozoites. A biopsy specimen from the small intestine may show organisms within the lumen or within cytoplasmic vacuoles in enterocytes, localized mucosal inflammation, and atrophy.

Protozoan Infections Enterocytozoon bieneusi (Microsporidia) Cryptosporidium Species Dr. Thomas C. Quinn (Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, NIH): Ciyptosporidium infection is among the most common causes of enteric disease in patients with AIDS, occurring in 10% to 20% of patients with AIDS and diarrhea in the United States (7, 12, 40, 41) and in as many as 55% of patients with AIDS in developing countries (3, 4). After an incubation period of 2 to 14 days, the parasite causes debilitating diarrheal illness that is characterized by chronic, often voluminous, watery diarrhea; severe abdominal cramps; weight loss; anorexia; malaise; and low-grade fever. Although asymptomatic carriage has been reported (42), many patients require hospitalization because of dehydration, electrolyte imbalance, and severe wasting (43). Cryptosporidium species have also been implicated in the pathogenesis of biliary tract obstruction in some patients with AIDS (25, 26). Although cryptosporidiosis rarely causes death, it contributes substantially to the malabsorption and debilitation in many patients with AIDS. The diagnosis of Cryptosporidium infection is based 66

Enterocytozoon bieneusi is emerging as a potentially important enteric pathogen in patients with AIDS. Protozoan parasites that were first detected in patients with AIDS in 1985 (2, 53, 54), Microsporidia species have now been identified by Kotler and coworkers (55) in as many as 33% of patients with AIDS who have chronic, unexplained diarrhea. Enterocytozoon bieneusi appears to cause a chronic diarrheal illness similar to that associated with cryptosporidiosis and isosporiasis (55, 56). The watery diarrhea is usually nonbloody and nonmucoid and occurs sporadically throughout the day. Typically associated with gradual weight loss and no fever, the diarrhea may be severe enough to require fluid and electrolyte replacement. Surprisingly, many patients maintain a good appetite during infection. Mucosal findings in patients with microsporidiosis are nonspecific; mucosa may be normal or show diffuse erythema overlaid by a thin mucoid coating (55). Microscopy shows degeneration, necrosis, and sloughing of infected enterocytes, which appear to occur as the intensity of infection increases (57-59). Partial villous atrophy and a variable inflammatory response in the underlying lamina propria



may be present. The natural habitat of Enterocytozoon bieneusi, the only Microsporidia species yet identified in the intestine of patients with AIDS, appears to be confined to gut epithelial cells. Enterocytozoon cuniculi, a species widely distributed in mammals, reportedly caused hepatitis in one patient with AIDS (60). Microsporidia species are difficult to identify because of their small size, poor staining qualities, and the paucity of surrounding tissue reaction. Consequently, diagnosis is usually based on electron microscopic identification of round-to-oval meront (proliferative) and sporont (spore-forming) stages of Microsporidia species in the supranuclear cytoplasm of villous, but not crypt, epithelial cells in the duodenum or jejunum (Figure 2) (55, 56). An experienced pathologist can also detect organisms in semi-thin plastic sections stained with basic fuschin-methylene blue-eosin (56) or touch preparations stained with Giemsa (59). The recent identification of Enterocytozoon bieneusi spores in concentrated, Giemsa-stained stool specimens (61, 62) indicates that a noninvasive technique for identifying Microsporidia species may soon be available. Entamoeba histolytica, Giardia lamblia, and Blastocystis hominis We (63) and others (64, 65) have detected Entamoeba histolytica, Giardia lamblia, and Blastocystis hominis in the stools of 20% to 35% of homosexual men in selected populations. Although the rates of infection among homosexual men have declined recently, the rates of symptomatic infection with these parasites among patients with AIDS are still not significantly higher than those in HIV-seronegative persons (7, 12, 66). Consequently, the presence of these protozoa in persons at risk for AIDS is not predictive of HIV infection. Regarding clinical manifestations, Entamoeba histolytica is a nonpathogenic commensal in most infected homosexual men (66) and rarely causes invasive colitis in homosexual men or patients with AIDS (67). Acute giardiasis, as well as the response of G. lamblia to therapy, in HIV-infected persons is similar to that in immunocompetent persons (68). Despite anecdotal reports, there is no convincing epidemiologic or clinical evidence that B. hominis is pathogenic (69, 70). Bacterial Infections Mycobacterium avium-intracellulare Mycobacterium avium-intracellulare, the most common cause of systemic bacterial infection in HIV-infected persons, is identified primarily in patients with AIDS. Infection of the gastrointestinal tract with Mycobacterium avium-intracellulare, usually in the presence of disseminated disease, is associated with diarrhea, abdominal pain, malabsorption, weight loss, and fever with or without night sweats (71, 72). Although the role of Mycobacterium avium-intracellulare in causing diarrhea has not been established conclusively, some patients with diarrhea have such large numbers of mycobacteria in their intestinal mucosa and stool that a causative or contributory role for producing the diar-

Figure 2. Histopathology of Enterozoon bieneusi-associated enteritis. Top. Light micrograph of a small-bowel biopsy specimen from a patient with microsporidiosis that shows an enterocyte containing a cluster of Enterozoon bieneusi spores (arrow). (Original magnification, x 1400.) Middle. Light micrograph of another small-bowel biopsy specimen from the same patient showing the usual location of the microsporidial sporont between the nucleus and microvillous border of the enterocyte. (Original magnification, x 2000.) Bottom. Transmission electron micrograph of a small-bowel biopsy specimen from the same patient showing a plasmodial stage of Enterozoon bieneusi within an enterocyte. (Original magnification, x 15 000.)



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Table 3. Components of the Gut-associated Lymphoid Tissues Compartment Organized Diffuse

Tissue

Cells

Lymphoid aggregates M cells; antigen-respon(Peyer patches) sive B and T cells Epithelium Lymphokine-producing cells; cytotoxic T cells Lamina propria B cells; T cells; plasma cells; mast cells; macrophages

rhea seems likely. The small intestine appears to be involved more commonly than the colon (72). Mucosal changes seen on endoscopy include erythema, edema, friability, and, in some cases, small erosions and fine white nodules. Histologic examination shows organisms free and within foamy, periodic acid-Schiff-positive 1amina-propria macrophages, suggesting Whipple disease (73). However, ultrastructural morphology, positive acid-fast staining, and unresponsiveness to tetracycline therapy indicate that the organism is not the Whipple bacillus but a mycobacterium (74). Diagnosis of Mycobacterium avium-intracellulare infection is based on the visualization of typical acid-fast organisms in stool and tissue (touch preparation and fixed) specimens. Isolation and speciation is achieved by culture of organisms from stool and biopsy specimens (75, 76). Salmonella Species, Shigella flexneri, and Campylobacter jejuni The differential diagnosis of diarrhea and fever in HIV-infected patients, particularly those with AIDS, should also include infection with Salmonella species {Salmonella typhimurium and less frequently Salmonella enteritidis) (77-81), Shigella flexneri (82-85), and Campylobacter jejuni (86, 87). In patients with HIV infection, particularly those with AIDS, these bacteria have in common a substantially higher incidence of intestinal infection (100-fold higher for Salmonella typhimurium), associated bacteremia, and more prolonged or recurrent infections because of antibiotic resistance or compromised immune function, or both. Mechanisms of Mucosal Immunity in Relation to AIDS The Normal Mucosal Immune System Dr. Warren Strober (Mucosal Immunity Section, Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, NIH): The mucosal immune system comprises "organized" tissue, consisting of lymphoid aggregates (Peyer patches) in which cells are initially stimulated by mucosal antigens, and "diffuse" tissue, consisting of intraepithelial and lamina propria effector cells (Table 3) (88). A unique feature of the lymphoid aggregates is that they are associated with specialized epithelial cells known as "M" cells, which bind certain microorganisms and deliver them intact to the interior of the lymphoid aggregate by nondegradative transcytosis (88, 89). The M cells in the rectal 68

epithelium, therefore, are potential sites for entry of HIV. In addition, lymphoid aggregates contain germinal centers where cells develop that are capable of producing IgA, the immunoglobulin specifically adapted for the prevention of attachment and colonization by microorganisms (88, 90). The development of these IgA cells involves "directed" processes in which IgM B cells are induced by cell-cell interactions or cytokines, or both, to become IgA (as opposed to IgM or IgG) B cells, after which the IgA B cells are induced by cytokines to undergo terminal differentiation into IgA-producing plasma cells (91-93). Linked by a homing mechanism, cells in the organized tissues move via the lymphatics and systemic circulation to the diffuse tissues of the lamina propria. This mechanism ensures that cells with specificity for mucosal antigens will be focused at mucosal sites. The Mucosal Immune System in HIV Infection Human immunodeficiency virus has now been identified in mononuclear cells in the lamina propria of the intestine in 30% to 39% of patients (94-96) and in the lamina propria of the esophagus in 36% of patients (Smith PD. Unpublished data). In these studies, HIVinfected cells were detected infrequently and were associated with minimal inflammation. The presence of HIV-bearing cells did not correlate with the patient's clinical status but did correlate with increased renewal of epithelial cells (95). That HIV-infected cells are present in crypt epithelium (97, 98) remains controversial. These data are compatible with the view that HIV infection of lamina-propria cells in itself does not explain the enteric diseases associated with HIV infection and that secondary effects of HIV infection (for example, mucosal immune system impairment) explain such disease. The HIV infection of CD4+ T cells in the lymphoid aggregates and the destruction of CD4+ T cells in this all-important inductive area may be the key pathologic factors. Infection with HIV leads to a marked reduction in the number of CD4+ T cells in the mucosal T-cell population of the lamina propria (99-101). This reduction in CD4+ T cells is accompanied by an increase in the lamina-propria CD8 + T-cell population, sometimes to a greater extent than that seen in the peripheral blood (99, 100). This elevation is a manifestation of more advanced disease, occurring in patients with full-blown AIDS. Because the increase in CD8 + cells does not correct for the reduction in CD4+ cells, total T-cell numbers are decreased; nevertheless, total mononuclear cells in the lamina propria are increased, possibly because of an increase in the numbers of lamina propria macrophages. Similar alterations in CD4+ and CD8 + cells are seen in rectal lymphoid follicles, suggesting that inductive mucosal tissues (lymphoid aggregates) also contain reduced numbers of CD4+ T cells. This observation is important because, as noted above, CD4+ T cells in lymphoid aggregates are the source of such cells in diffuse tissues of the lamina propria. The T-cell abnormalities described above appear to be accompanied by a severe B-cell abnormality, which manifests in about 75% of patients with AIDS as a



decrease in the number of IgA plasma cells (102). This abnormality has been seen in patients with and without gastrointestinal disease, suggesting that it is a primary manifestation of HIV infection. The reduction in the number of IgA B cells is also partially corroborated by the recent observation that levels of serum and salivary IgA2, the form of IgA that predominates in the intestinal tract, are markedly decreased in patients with AIDS (103). However, the levels of IgAl, which is the major component of serum IgA, remain normal, thereby explaining the fact that the serum IgA levels are normal or even increased in patients with AIDS. The decrease in lamina propria IgA plasma cells in patients with AIDS could be due to the depletion of CD4+ T cells, which are necessary for switch and differentiation of IgA B cells. Alternatively, the decrease could be due to a B-cell homing defect secondary to impaired expression of mucosa-specific homing receptors on cells developing in Peyer patches; a lack of appropriate T-cell maturational factors; or, finally, suppression of IgA B-cell differentiation in the lamina propria secondary to high levels of CD8+ suppressor T cells.

AIDS-associated Enteropathy The gastrointestinal manifestations of HIV infection include, on the one hand, the presence of opportunistic pathogens and, on the other hand, villous atrophy and malabsorption in the absence of identifiable pathogens (2, 7-10). The most likely explanation for the latter is that in many, if not most, cases the microorganisms are either missed or have not yet been identified as pathogens. Nevertheless, Harriman and coworkers (10) found either reduced or normal levels of vitamin B 1 2 but found abnormal Shilling test results in a group of patients with AIDS who did not have gastrointestinal symptoms, weight loss, or detectable intestinal pathogens. The patients had mild chronic inflammation of the duodenal mucosa that, in some cases, was associated with partial villous atrophy (10), suggesting that patients with AIDS can occasionally manifest villous atrophy and malabsorption in the absence of identifiable pathogens (8-10). In studies to elucidate the pathogenesis of the impairment of small intestine structure and function in patients with AIDS, Ullrich and colleagues (95) found that patients with enteric infection had villous atrophy and crypt hyperplasia, whereas those without such infection had normal crypt depth, slightly reduced villous surface area, and reduced numbers of mitotic figures per crypt. These findings, together with the occurrence of lactase deficiency in the latter group of patients, provides additional evidence that patients with AIDS may develop an "enteropathy" in the absence of detectable enteric infection. Because the subtle morphologic changes were more evident in those patients whose lamina propria contained HIV p24 antigen, Ullrich and colleagues (95) have suggested that the enteropathy was caused by HIV itself. However, the low percentage of patients with intestinal HIV infection, the extremely small number of cells actually infected with the virus, and the absence of inflammation associated with the infected cells suggest the possibility of other explanations. An alternative ex-

planation is that low-grade bacterial overgrowth may contribute to the enteropathy. Support for the presence of increased numbers of bacteria in the small intestines of patients with AIDS comes from two studies. Budhraja and coworkers (101) detected 4.5 x 104 organisms/ml of small-bowel luminal fluid in patients with AIDS who had diarrhea, and Smith and coworkers (7) detected up to 105 organisms/mL of luminal fluid in their patients. Although aerobes predominated or were equivalent in number to anaerobes, these levels of luminal bacteria represent increases over the number of bacteria (103 organisms/ ml) generally accepted as the upper level of normal (104). Because excessive numbers of small-intestine bacteria, particularly anaerobes, are associated with malabsorption, low-grade bacterial overgrowth could contribute to the malabsorption that characterizes patients with AIDS, particularly those with enteropathy. The above description of mucosal immune abnormalities in HIV infection can explain both an early phase of covert or mildly overt malabsorption and a later phase of gastrointestinal superinfections characteristic of HIV disease. Accordingly, we postulate that the first effect of HIV infection on the mucosal immune system is to cause depletion of CD4+ T cells. This depletion, in turn, leads to altered IgA B-cell development and, ultimately, to reduced IgA production in the lamina propria. Altered IgA production, together with the impaired gastric-acid secretion reported to occur in HIV infection (105), leads to colonization of the small intestine with increased numbers of bacteria. These bacteria may contribute to mucosal inflammation through the release of products such as surface proteins that are absorbed into the mucosa and that are capable of recruiting (106) and activating monocytes-macrophages for release of inflammatory cytokines and products (107). The chronic mucosal inflammation promotes villous atrophy, which together with low-grade bacterial overgrowth, leads to malabsorption. These changes in the mucosal immune system in HIV infection are strikingly analogous to those present in common variable immunodeficiency, which also manifests as mild bacterial overgrowth, villous atrophy, and malabsorption. As HIV disease progresses, CD4+ T-cell depletion becomes more profound, leading to impaired effector T-cell responses such as those of cytotoxic T cells, which participate in host defense against such viruses as cytomegalovirus. In addition, HIV infection of mononuclear phagocytes leads to activation and functional impairment of monocyte-macrophages (108-110) and, by extension, monocytes passing through the mucosa and possibly resident mucosal macrophages. These cells undoubtedly play a critical role in defense against such intracellular pathogens as protozoa and mycobacteria. With the altered function of cytotoxic T cells and macrophages, the gastrointestinal tract becomes subject to infection with opportunistic pathogens. Role of Humoral Immunity in the Response to Intestinal Pathogens Dr. Edward N. Janoff (Laboratory of Immunology, National Institute of Dental Research, NIH, Bethesda,



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Table 4. Mechanisms of Immunity to Common Enteric Pathogens in HIV-infected Patients Organism Cytomegalovirus Herpes simplex Cryptosporidium Giardia lamblia Campylobacter jejuni Salmonella species Shigella flexneri Mycobacterium avium-intracellulare

Antibody Involved in Protective Immunity

Cells Involved in Protective Immunity*

Not

Natural killer; CTL Natural killer; CTL Possibly natural killer; possibly CTL Macrophages; PMN PMN Macrophages; natural killer PMN; natural killer Macrophages

Not Yest Yest Yes Yes Yes No

* CD4+ cells are also probably required to regulate the response involving other cells. CTL = cytotoxic T lymphocyte; PMN = polymorphonuclear leukocyte. t Antibodies to these organisms are usually detectable at presentation; antibodies to G. lamblia are present in chronic, but not acute, giardiasis (see Reference 73).

Maryland; and Division of Infectious Diseases, University of Minnesota School of Medicine and Veterans Affairs Medical Center, Minneapolis, Minnesota): Systemic and mucosal humoral immunity, together with cellular responses, are critical for defense against intestinal pathogens and profoundly influence the course of enteric infection in patients with AIDS (Table 4) (1). The ability to control these enteric infections depends on the patient's capacity to generate an immune response to new infections and on the patient's immunologic response to organisms to which he or she has had previous exposure.

This relative decrease in intestinal IgA supports the finding of Kotler and colleagues (102), who reported that the number of IgA-producing plasma cells was decreased in intestinal tissue from patients with AIDS. Preliminary data from our laboratory (120) and others (103) suggest that levels of IgA2, which are normally produced at mucosal surfaces in an amount approximately equal to that of IgAl, may be decreased in saliva and duodenal fluids from patients with AIDS. Immunoglobulin A2 is resistant to the activity of IgA proteases produced by invasive mucosal bacteria, and insufficient levels of IgA2 may place patients with AIDS at risk for infections with these pathogens (121).

Total Immunoglobulin Levels Total serum IgG levels are elevated early in the course of HIV infection, whereas serum IgA levels are elevated late in the course of infection, and total IgM levels are less frequently affected (111, 112). Specific systemic antibody responses to new infections and vaccines, however, are depressed at all stages of HIV infection (1, 111-116), thereby limiting the ability of HIV-infected persons to respond to acute infections and to the vaccines designed to prevent them. Despite this depressed production of antibody in response to new infections, patients with AIDS retain the ability to produce antibodies to various microbiologic and vaccine-related recall antigens encountered before HIV infection. These include antigens of Toxoplasma gondii (117), measles (118), cytomegalovirus and other herpes viruses (111, 119), and tetanus toxoid (118). These findings suggest that patients with AIDS may retain some elements of immunologic memory, thereby allowing humoral immunity to specific organisms acquired earlier in life to persist after HIV infection. Compared with the information on systemic antibody responses, data on local antibody responses of the mucosal immune system during HIV infection are limited. Recently, we measured the levels of total IgG, IgM, and IgA in duodenal fluids from both patients with AIDS and HIV-seronegative control subjects (120). No significant differences were noted in levels of total IgA or total IgM between the two groups. In contrast, levels of total IgG were almost nine times higher in the duodenal fluids from the patients with AIDS, suggesting that the amount of IgA relative to the amount of IgG in intestinal fluids from patients with AIDS is markedly lower. 70

Reduced Levels of Antibody to Newly Acquired Pathogens Human Immunodeficiency Virus Levels of local antibody to specific enteric pathogens have been examined for only one organism, HIV. Specific local responses to HIV have been detected in saliva (122, 123), semen (124), cervical fluid (125), and breast milk (126). In these body fluids, HIV-specific antibody is predominantly IgA. In contrast, we found that IgG was the principal antibody class recognizing HIV antigens in duodenal fluids (120). Removal of the IgG revealed reactivity of IgA with multiple HIV antigens. Human immunodeficiency virus transmission or infection in intestinal or cervical mucosa likely accounts for the presence of secretory IgA locally and at other mucosal sites. Campylobacter jejuni and Giardia lamblia Systemic antibody responses to enteric pathogens have been studied more widely than local responses. These studies suggest that the presence of pathogenspecific antibodies contributes to the immune mechanism or mechanisms responsible for controlling certain enteric pathogens, such as Campylobacter jejuni (87) and G. lamblia (127), and thereby influences the clinical outcome. For example, patients with AIDS who have severe, persistent Campylobacter jejuni infection often lack specific antibody to the organism (87). Similarly, among patients with AIDS who are infected with G. lamblia, we found that the absence of circulating G. lamblia-specific antibodies appeared to correlate with the presence of G/ard/a-associated gastrointestinal



symptoms (68). All patients with AIDS and G. lamblia infection who lacked detectable parasite-specific IgG had symptomatic giardiasis, whereas most patients with G. lamblia infection who had anti-G. lamblia antibodies did not have parasite-associated symptoms. The mechanisms by which specific antibody may influence infection with organisms such as G. lamblia include inhibition of adherence to and invasion of mucosal tissue by IgA, enhanced complement-mediated lysis by IgM, and opsonization for leukocyte phagocytosis (128, 129). Thus, the acute antibody responses to both Campylobacter jejuni and G. lamblia are depressed in patients with AIDS, but, in contrast to infection with C. jejuni, which may become chronic because of the development of resistance to antimicrobial therapy (87), infection with G. lamblia is usually cleared because the organism is highly sensitive to antimicrobial therapy (68). Salmonella Species Although the mechanisms conferring host protection against Salmonella species are not well established, natural killer activity (130), macrophage cytotoxicity (131), and antibody-dependent cellular cytotoxicity involving CD4+ T cells and IgA appear to be important (132, 133). As discussed above, these components of normal immune responses are impaired in patients with AIDS. In addition, natural antibacterial activity of serum against Salmonella species is depressed in patients with AIDS, reflecting both a decrease in anti-Salmonella IgA antibodies and an intrinsic defect in the function of anti-Salmonella CD4+ effector cells (134). These combined defects in cellular and humoral host defense mechanisms likely predispose patients with AIDS to Salmonella bacteremia and enteritis. Mycobacterium avium-intracellulare As with Salmonella infection, Mycobacterium aviumintracellulare infection is thought to result from primary environmental exposure rather than reactivation of endogenous organisms. The intestine is an important portal of entry for the organism (75), where exuberant bacterial replication may result in local clinical sequelae and bacteremia. The impaired antibody response to new antigens characteristic of patients with AIDS is paralleled by an impaired response to Mycobacterium avium-intracellulare (135). However, the primary mechanism of control of mycobacterial infections is cellular, not humoral, and involves intrinsic macrophage function that may be altered in patients with AIDS. Macrophages from patients with AIDS phagocytize Mycobacterium avium-intracellulare normally (136) but may be abnormally permissive to the intracellular growth of the organism (137). This could account for the large numbers of Mycobacterium avium-intracellulare within macrophages in intestinal mucosa and other organs of patients with AIDS (138). Inadequate macrophage stimulation by exogenous cytokines may also play a role. Although levels of gammainterferon, a known macrophage activation factor, are reduced in patients with AIDS (139), this cytokine does not appear to augment macrophage killing of Mycobacterium avium-intracellulare, at least by monocytes from normal persons (140). Also, isolates of Mycobacterium

avium-intracellulare cultured from patients with AIDS do not appear to be more virulent than those cultured from other hosts (141, 142); however, differences in plasmid profiles and an association between the presence of plasmids and virulence have been suggested (143).

Ineffective Antibody to Chronic or Reactivated Pathogens Cryptosporidium Species Although patients with AIDS may have reduced levels of antibody to the newly acquired pathogens described above, they may have specific antibodies to chronic or reactivated enteric pathogens; these antibodies, however, may be ineffective in controlling the infections. For example, parasite-specific antibodies have been identified in the serum of most patients with AIDS who are infected with Cryptosporidium species (144, 145). However, despite the presence of such antibodies, the diarrheal illness caused by this pathogen is usually severe and prolonged. Prolonged cryptosporidial disease occurs in patients with either humoral (41, 146) or cellmediated immune defects (147), suggesting that both components are necessary to eradicate the organism. Thus, despite the presence of parasite-specific antibodies in patients with AIDS, compromised cell-mediated immune responses, possibly involving CD4+ T cell function (148), predispose these patients to severe cryptosporidiosis. Cytomegalovirus Specific antibodies to cytomegalovirus, which are detected in virtually all HIV-infected patients (111), are also not protective in patients with AIDS. The reactivation of latent cytomegalovirus infection may be related to the compromised function of natural killer cells and cytotoxic lymphocytes (149), which normally express killing activity toward virus-infected host cells. Impaired function of these cells in patients with AIDS may, in turn, be due to insufficient stimulation by interleukin-2 (149). Shigella flexneri As in patients with Cryptosporidium or cytomegalovirus infections, the presence of antibodies to Shigella flexneri appears not to prevent prolonged symptomatic infection with the bacterium (83). Both humoral and cell-mediated immunity are required to control the infection (150-152).

Therapeutic Strategies for Enteric Infections in HIV-infected Patients Dr. Henry Masur (Critical Care Medicine Department, Clinical Center, NIH): During the initial decade of the AIDS epidemic, considerable progress was made in developing improved agents and strategies for managing gastrointestinal infections in patients infected with HIV. Many of these infections can now be effectively treated or at least suppressed with appropriate antimicrobial therapy (Table 5) (153).



71

Table 5. Current Therapy for Enteric Pathogens in Patients with AIDS Pathogen Bacteria Salmonella species

Shigella flexneri

Campylobacter jejuni Clostridium difficile Protozoa Giardia lamblia Entamoeba histolytica Isospora belli

Cryptosporidium species Microsporidium species Viruses Herpes simplex virus Cytomegalovirus Fungi Candida species

Amoxicillin (1 g orally three times a day for 3 to 14 days); or trimethoprim-sulfamethoxazole (1 doublestrength tablet orally twice daily for 14 days); or ciprofloxacin (500 mg orally twice daily for 7 days) Trimethoprim-sulfamethoxazole (1 double-strength tablet orally twice daily for 5 to 15 days); or ampicillin (500 mg orally four times a day for 5 days); or ciprofloxacin (500 mg orally twice daily for 7 days) Erythromycin (250 to 500 mg orally four times a day for 7 days); or ciprofloxacin (500 mg orally twice daily for 7 days) Metronidazole (500 mg orally three times a day for 7 to 10 days); or vancomycin (125 mg orally four times a day 7 to 10 days)

If recurrences are frequent

Metronidazole (250 mg three times a day for 5 days); or quinacrine (100 mg three times a day for 5 days) Metronidazole (750 mg three times a day for 10 days), then iodoquinol (650 mg three times a day for 20 days) Trimethoprim-sulfamethoxazole (160 mg of trimethoprim and 800 mg of sulfamethoxazole 3 times a day for 10 days, followed by twice weekly therapy for 3 weeks) Unknown Unknown

No


No No

No Trimethoprim-sulfamethoxazole or pyrimethamine-sulfadoxine Unknown Unknown

Acyclovir (200 mg five times a day) Ganciclovir (5 mg/kg body weight twice daily for 14 to 21 days)

If recurrences are frequent Yes

Nystatin (300 000 to 500 000 U six times a day); or ketoconazole (100 to 200 mg twice daily for 10 to 14 days); or fluconazole (50 to 200 mg daily for 10 to 14 days); or amphotericin (0.3 to 0.6 mg/kg body weight daily)


Therapy for Infectious Esophagitis The infectious causes of esophagitis in persons with AIDS include Candida albicans, herpes simplex virus, cytomegalovirus, and, occasionally, endemic mycoses (33). Human immunodeficiency virus itself has been associated with esophageal ulcers (154, 155), but the etiologic role of the virus in esophageal disorders remains to be determined. Candida esophagitis can be effectively treated with various topical, oral, and intravenous agents. These agents include nystatin, ketoconazole, fluconazole, and amphotericin B (156-158). Because Candida esophagitis in patients with AIDS is rarely associated with fungemia, perforation, or hemorrhage, thereby distinguishing them from neutropenic patients with cancer, topical and oral therapies are reasonable alternatives to amphotericin B therapy, which is the most effective but also the most toxic treatment currently available. Ketoconazole has been the agent of choice because of its easy administration. Many patients prefer oral tablets to the unpleasant taste of nystatin or to the inconvenience of lozenges. Several new imidazole and triazole agents, such as fluconazole and itraconazole, have in-vitro activity against Candida species and may be more effective than ketoconazole (156, 157). Fluconazole has a longer half-life (25 hours) than 72

Long-term Suppression

Acute Therapy

ketoconazole (6 to 9 hours) and, unlike ketoconazole, is not dependent on low gastric pH for absorption and does not suppress adrenal function. However, results from a small comparative trial have suggested that fluconazole and ketoconazole have similar efficacy and toxicity when used to treat AIDS-associated Candida esophagitis (158). Whether the potential advantages of fluconazole warrant its higher cost (one 100-mg tablet costs $6.88) compared with that of ketoconazole (one 100-mg tablet costs $1.00) is an arguable point. The advantages of itraconazole over these approved agents remain to be determined.

Therapy for Infectious Diarrhea Diarrhea in patients with AIDS is caused by such a wide array of pathogens that empiric antimicrobial therapy is usually not justified. While the diarrhea is being evaluated, however, many patients can benefit from supportive therapy with rehydration, electrolyte supplementation, and drugs that inhibit intestinal secretion or motility. Although the use of anti-motility agents is controversial in certain bacterial diarrheas, most patients can derive considerable symptomatic benefit from therapy with loperamide, diphenoxylate, Kaopectate (Up-



John, Kalamazoo, Michigan), or paregoric. Excluding patients with bloody diarrhea, fecal leukocytes, or substantial abdominal pain, there is little evidence that such therapy produces substantial clinical harm. Total parenteral nutrition may be a therapeutic consideration when the diarrhea is severe, prolonged, and unresponsive to specific therapy. However, total parenteral nutrition has considerable logistic, economic, and ethical implications that must be reviewed in terms of the patient's realistic progress. The agents that have been successful in treating or suppressing infectious causes of diarrhea in patients with AIDS are listed in Table 5. The choice of the specific agent does not differ in general from the choice of antimicrobial therapy in other patient populations. Except for Shigella flexneri and Campylobacter jejuni, which may develop resistance to multiple antibiotics, there is little evidence that pathogens isolated from patients with AIDS are more likely to be antibiotic resistant than pathogens isolated from other patient populations. One must remember, however, that some frequently used antibiotics, such as trimethoprim-sulfamethoxazole, may be poorly tolerated by HIV-infected patients. Adverse effects include rash, leukopenia, and transaminase elevation. In addition, consideration must be given to compatibility of these antibiotics with such agents as azidothymidine and dideoxyinosine. Ganciclovir and trimethoprim-sulfamethoxazole, for example, suppress bone marrow function and may be poorly tolerated by patients receiving azidothymidine. The ability to successfully treat cytomegalovirus-associated enteric disease represents a major advance (7, 22, 159). Ganciclovir and probably phosphonoformate can effectively reduce the signs and symptoms of enteric involvement by cytomegalovirus in patients who meet specific diagnostic criteria (159). The major disadvantages of ganciclovir, in addition to its enhanced toxicity when used in conjunction with azidothymidine, is that no tolerable regimen has been established that prevents disease from recurring. It appears that ganciclovir, in the regimens used to date, delays rather than prevents the recurrence of clinical disease. In addition, ganciclovir and phosphonoformate must be given intravenously, which is inconvenient and expensive. Trials are currently under way to determine whether ganciclovir has sufficient bioavailability when given orally. Oral drugs with activity against cytomegalovirus, including a pro-drug that is metabolized to ganciclovir and FIAU (l-2'deoxy-2'fluoro-l-B-D-arabinofuranosyl)-5 iodouracil, are also under development. Many of the diarrheal infections that occur in patients with AIDS eventually recur after the termination of therapy. Recurrences and the need for chronic suppressive regimens may predispose patients with AIDS to the development of disease caused by drug-resistant pathogens. Drug-resistant isolates of Shigella species (82), Campylobacter species (86), cytomegalovirus (160), and herpes simplex virus occur (161, 162) in patients with AIDS. Whether these drug-resistant isolates are as pathogenic as drug-sensitive isolates, whether they are as likely to recur, and whether they will become more prevalent remain to be determined. The emergence of herpes simplex virus and cytomegalovirus isolates that

are resistant to acyclovir and ganciclovir, respectively, may hasten the need to do routine viral susceptibility testing if effective alternative therapies become available. Infections with several clinically important pathogens, including Cryptosporidium, Microsporidia, and possibly Mycobacterium avium-intracellulare, cannot be successfully treated. In patients with these infections, other treatable processes should be excluded, supportive care should be implemented, and participation in a trial assessing a new therapy should be considered. Regarding therapy for Cryptosporidium infection, development of an effective antimicrobial regimen has been hampered by the absence of an in-vitro system for culturing Cryptosporidium organisms. Several reports have suggested potential therapeutic roles for spiramycin, diclazuril, leclazuril, bovine colostrum, transfer factor, and difluoromethyl-ornithine, but none of these agents has yet been effective in clinical trials (163-165). Somatostatin may inhibit the secretory-type diarrhea associated with crytosporidiosis in occasional patients (166); a controlled, multicenter trial using this agent is currently under way. Similarly, no effective therapy is available for patients with microsporidiosis. Many drugs, including ethambutol, rifampin, rifapentime, amikacin, ciprofloxacin, imipenem, and clofazamine have some activity in vitro against many Mycobacterium avium-intracellulare isolates (167). Although none of these agents is curative, a regimen consisting of amikacin, ethambutol, rifampin, and ciprofloxacin has shown promise in reducing both the mycobacterial load and systemic symptoms in patients with disseminated Mycobacterium aviumintracellulare infection (168). Several new macrolide drugs, especially clarithromycin and azithromycin, also appear to be promising. The management of patients with AIDS who have gastrointestinal disorders is associated with many unresolved problems because effective, tolerable, and convenient therapy is not available for certain causative agents. Nevertheless, the principles of therapeutic intervention summarized in Table 6 should be vigorously adhered to in treating enteric infections in HIV-infected persons. Because many episodes of gastrointestinal dysfunction are caused by treatable pathogens, an aggressive diagnostic evaluation is worthwhile. Even if an Table 6. Principles of Therapeutic Intervention for Enteric Infections in HIV-infected Patients Supportive therapy with fluids, electrolytes, and antimotility drugs is important Specific therapy is preferable to empiric therapy because differential diagnosis is extensive and drug intolerance and drug interactions are common Cause may be multifactorial; consequently, therapy may be partially but not completely beneficial Microorganisms may be resistant to currently used agents or may develop resistance in vivo Many infectious syndromes recur; consequently, long-term suppressive therapy is often necessary Role of total parenteral nutrition, anabolic steroids, and other appetite enhancers or metabolic modulators is uncertain Search for specific cause, institution of specific therapy, and supportive care can greatly enhance the quality and duration of patient survival



73

untreatable pathogen is identified, completion of the evaluation may determine whether other processes are present. In addition, supportive therapy can often provide considerable clinical benefit. Although new oral agents for the treatment of currently untreatable infections will probably be developed in the next decade, such development will likely be attended by an expanding spectrum of opportunistic pathogens and more complex patterns of drug resistance. Perhaps many of the lessons learned thus far about the evaluation, immunopathogenesis, and treatment of enteric infections in patients with AIDS will help us to meet this challenge.

21.

Requests for Reprints: Phillip D. Smith, MD, National Institutes of Health, Building 30, Room 322, Bethesda, MD 20892.

22.

Current Author Addresses: Dr. Smith: National Institutes of Health, Building 30, Room 322, Bethesda, MD 20892. Dr. Quinn: Division of Infectious Diseases, Johns Hopkins Hospital, Blalock 1111, 600 North Wolfe Street, Baltimore, MD 21205. Dr. Strober: Mucosal Immunology Section, LCI, NIAID, National Institutes of Health, Building 10, Room 11N250, Bethesda, MD 20892. Dr. Janoflf: Division of Infectious Diseases, Veterans Affairs Medical Center 111 F, 1 Veterans Drive, Minneapolis, MN 55417. Dr. Masur: Critical Care Medicine, National Institutes of Health, Building 10, Room 7D43, Bethesda, MD 20892.

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77

AIDS research. NIH digging in.

NIH wrestles with furor over conference.

Amsterdam AIDS Conference review.

Reprieve for AIDS conference.

NIH plans trials of controversial AIDS drug.

Genetics-and-crime conference cancelled in clash with NIH.

NIH conference. Insulin-like growth factors in health and disease.

NIH conference. Immunopathogenic mechanisms in human immunodeficiency virus (HIV) infection.

Conference ethics in the age of AIDS.

NIH Consensus conference. Diagnosis and treatment of early melanoma.

NIH conference. Diagnosis and management of asymptomatic primary hyperparathyroidism: consensus development conference statement.

Racial tensions entangle NIH in dispute over AIDS drug.

Crime conference. Back to the drawing board, says NIH.

AIDS and gastrointestinal endoscopy.

[Gastrointestinal infections].

AIDS conference: French not to attend.

Opportunistic intraocular infections in AIDS.

Letter from Barcelona: 14th International AIDS Conference.

Protests oust science at AIDS conference.

AIDS conference. European Parliament backs boycott.

Fungal infections in AIDS patients.

NIH report vindicates Gallo on conduct of AIDS research.

The gastrointestinal manifestations of AIDS.

Gastrointestinal infections after transplantation.