726

AIDS COMMENTARY

AIDS Enteropathy John G. Bartlett, Peter C. Belitsos, and Cynthia L. Sears

From the Department ofMedicine, Johns Hopkins University School ofMedicine, Baltimore, Maryland

-Merle A. Sande Diarrhea is a relatively common complication in patients with symptomatic infection due to the human immunode~­ ciency virus (HIV). The incidence has not been systematIcally studied, but most investigators report that this complication occurs in 30%-60% of patients with AIDS from industrialized countries [1-3] and in 60%-90% of patients with AIDS from Haiti [4-6] or Africa [7-9]. Appropriate diagnostic studies indicate that opportunistic infections account for most disease, although there is a substantial number of patients who have no likely microbial pa~ho~en; .a variety of hypothetical mechanisms have been applIed In thIS setting. The diagnostic evaluation of patients with advan~ed stages of HIV infection and chronic diarrhea is controversIal, but at least one report suggests that routine endoscopy cannot be justified as cost-effective [3]. Research in this area is moving rapidly along with the rest of HIV research; new microbial pathogens are now implicated, and new therapies for enteric disease are now widely advocated that may alter conclusions with regard to the use of endoscopy. The purpose of this report is to review the state of the art of our knowledge of diarrhea as a complication of late-stage HIV infection, with particular emphasis on AIDS enteropathy.

Received 15 July 1992. . . Grant support: This work was supported by the U.S. NatIOnal InstItute of Digestive Disease and Kidney Disease (5 RO 1 OK 4061802). . Reprints or correspondence: Dr. John G. B~r~lett, Ross Research Butlding, Johns Hopkins University School of Medlcme, 720 Rutland Avenue, Baltimore, Maryland 21205.

Clinical Infectious Diseases 1992;15:726-35 © 1992 by The University of Chicago. All rights reserved.

1058-4838/92/1504-0029$02.00

Classification Diarrhea. This is one of the few terms in medicine that is so easily communicated but so difficult to define by scientific criteria. Standard definitions include the total stool volume per day, the percentage of water content, or the number and character of motions. The usual definition of diarrhea for patients with AIDS is two to three or more loose or watery stools per day; for a diagnosis of chronic diarrhea, this symptom must be present for at least 30 days [3, 10-13]. Diarrhea/wasting syndrome. This syndrome is included as an AIDS-defining diagnosis by both the World Health Organization and the Centers for Disease Control (CDC; Atlanta) [10,14]. It is defined as diarrhea that persists for more than 1 month in association with otherwise unexplained weight loss of at least 10% of the premorbidity weight. Data from the CDC indicate that this syndrome is second only to Pneumocystis carinii pneumonia as the initial AIDS-defining diagnosis, and it now accounts for""" 17% of newly reported cases. This figure is obviously deceptive since many patients satisfy the diagnostic criteria late in the course of the disease or have symptoms of insufficient magnitude to meet the diagnostic criteria. Cachexia or malnutrition is a regular feature of late-stage disease, although nutritional changes have been difficult to disentangle because of the variable contributions ofopportunistic infections, malabsorption, and metabolic events. It is clear that most patients with severe wasting do not have overt diarrhea as defined above, but diarrhea may be a major contributing cause in some patients, and occult infection and/or malabsorption may playa role in the majority. AIDS enteropathy. Morphometric studies of the small in-

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Chronic diarrhea is one of the hallmarks of advanced human immunodeficiency virus (HIV) disease. The symptoms of this complication are troublesome, have a signific~?t i~pact. on the patient's quality of life, and in severe cases can lead to extrem.e abn~rmahtI~s 10 flUIds and electrolytes and can even cause death. The workup for AIDS-assocIated dIarrhea IS often frustrating and frequently unrewarding. However, during the last 10 years, much has been learned about the causes of diarrhea; while treatment is still often ineffective, some advances have been made. Dr. John G. Bartlett and his colleagues in the Department of Medicine at Johns Hopkins University School of Medicine have been responsible for many of these advances. In thi~ AIDS Co~­ mentary, these experts discuss recent advances that have enhance.d our understandmg o~ chromc diarrhea in HIV-infected persons and offer their recommendatIons for the most efficIent and effective approach to managing these patients.

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AIDS Enteropathy

ClD 1992; 15 (October)

Table 1. Infectious agents that cause AIDS enteropathy with chronic diarrhea. No. (%) of patients from whom indicated agent was isolated

Reference

[17]

Location

M.

hislO~l'lica

G. lambfia

Salmonella species

Others*

No pathogen f

0

5 (25)

3 (15)

5 (25)

3 (15)

3 (l5)t

5 (23)

0

0

1 (5)

0

0

11 (50)

No examination

1(4)

1(4)

0

0

0

1(4)

13 (57)t

14 (33)11

7 (16)

0

0

1(2)

1(2)

2 (5)

6 (14)

No. of patients

Criteria for inclusion

Cytomegalovirus

Cryptosporidia

Microsporidia

avium

/. belli

20

Diarrhea> I w, AIDS Diarrhea> I mo, negative stool examination, AIDS Diarrhea >2 w, AIDS Diarrhea> I mo, AIDS, ARC

9 (45)

3 (15)

No examination

I (5)

I (5)

1 (5)1

5 (23)

0

5 (22) 6 (14)11

[12]

Bethesda, Maryland Baltimore

22

[18]

Brazil

23

[12]

New York City

43

15 (35)

E.

ARC = AIDS-related complex. patient), C. jejuni (I), Strongyloides stercoralis (I). One patient had Kaposi's sarcoma. t Numbers do not all add up because two pathogens were occasionally isolated from patients. t The data from these reports may be less comparable because of the brevity of diarrhea and the inclusion of patients with pathogens that are usually detected on analysis of stool samples, which include Salmonella, Shigella, C. jejuni. and cryptosporidia. § According to a prior report by this group, 7 (16%) of 45 patients with AIDS and diarrhea were determined to have cryptosporidiosis on stool examination. II Microsporidia or cryptosporidia were detected in 19 (70%) of 27 patients with small-bowel injury and in 17 (77%) of 22 on electron microscopy.

testines of patients with AIDS who have chronic diarrhea show significant villus atrophy and crypt hypertrophy. The number of mitotic figures per crypt is found to be inappropriately low in relation to the extent of mucosal injury. Other hypoplastic enteropathies associated with similar morphologic changes are coeliac disease and malnutrition as well as those that result from chemotherapy and radiotherapy [13]. These findings in the presence of HIV infection have been referred to as AIDS enteropathy on the presumption that the changes (whether or not due to a microbial agent) account for chronic diarrhea. However, more recent work by our group has demonstrated comparable alterations in the villuscrypt ratio in AIDS patients who do not have diarrhea; the implication is that these morphologic changes are common features of late-stage HIV infection that are not necessarily expressed clinically by the presence of diarrhea [12]. Most patients with AIDS and chronic diarrhea have an opportunistic infection of the small intestine or colon (discussed below), but for some a diagnostic evaluation for pathogens will be negative. The term idiopathic AIDS enteropathy has been suggested as the appropriate appellation on the assumption that adequate diagnostic studies have been done, including endoscopy and appropriate diagnostic testing for microsporidia [15].

Etiology of Chronic Diarrhea Prospective studies of chronic diarrhea in patients with AIDS suggest that identifiable enteric pathogens account for 75%-85% of cases [11,12,16, 17] (table 1). The organisms most frequently identified are cryptosporidia, microsporidia, cytomegalovirus (CMV), and Mycobacterium avium. A multitude of other enteric pathogens have been found, but their

frequency among patients with chronic (vs. acute) diarrhea or status as established enteric pathogens is less impressive. The data provided in table 1 are summarized from four published reports on microbial agents that were detected using diagnostic studies including endoscopy. There are some major differences between the studies that presumably reflect variations in inclusion criteria for patients and in diagnostic techniques. The relatively low yield of cryptosporidia in our study [12], for example, reflects the fact that stool examinations that were negative for this organism were required as a criterion for inclusion. In the report by Smith et al. [16] the definition of diarrhea was loose stools for at least 1 week, and several organisms were included that are generally found on direct examination or culture of stool. That study [16] and the study in Brazil by Madi et al. [17] did not include use of adequate diagnostic techniques for detection of microsporidia. Nevertheless, despite these variations, the major findings are relatively consistent. eMv. According to the results ofautopsy studies, disseminated CMV infection is found in nearly 90% of patients with HIV infection. There may be involvement at any level ofthe gastrointestinal tract from the mouth to the anus, but CMV infection most characteristically occurs in the colon, with symptoms ranging from trivial complaints (or asymptomatic carriage) to severe, persistent diarrhea that is often accompanied by abdominal pain; occasional patients have a gangrenous bowel, intestinal perforation, toxic megacolon, a solitary ulcer, or hemorrhage [18-20]. Endoscopy may reveal a normal mucosa, patchy colitis or confluent colitis. When contrast studies or computed tomography are performed, typical findings include segmental colitis or pancolitis with mucosal granularity, thickened folds, spasticity, and/or superficial erosions [21, 22]. Histopathologic examination of biopsy speci-

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NOTE.

* Shigella (I

728

Bartlett, Belitsos, and Sears

matostatin analog, may be effective in controlling diarrhea [36-38]. Microsporidia. This term refers to a complex group of unicellular parasites that have only recently been recognized as human pathogens [39] and are now being detected with escalating frequency among patients with AIDS and chronic diarrhea. As implied by the name, these are small parasites that cannot easily be detected on routine microscopic studies of stool, and they are usually overlooked during histopathologic studies of small bowel biopsy specimens as well. The organisms have characteristic coiled, polar filaments inside the spore that houses the sporoplasm, which is the infectious component [40, 41]. The most common species implicated in diarrhea is Enterocytozoon bieneusi. Definitive diagnosis has usually required electron microscopy of small bowel biopsy specimens, although Giemsa-stained smears and standard hematoxylin-eosin-stained paraffin sections are appropriate screening procedures for experienced observers [4143]. More recently investigators from the CDC have reported on a special staining procedure for recognition ofmicrosporidial spores in stool that has good sensitivity and specificity [44]. With various diagnostic techniques, microsporidia have been detected in 14%-30% of patients with AIDS who have chronic diarrhea [11, 12, 43-49]. More recent work indicates that these may, in fact, be the most common identifiable enteric pathogens that cause chronic diarrhea during the advanced stages of HIV infection. As with cryptosporidia, asymptomatic carriage and involvement of the colon may occur but are both unusual [49]. There is no therapy with established merit. Eeftinck Schattenkerk et al. [47] reported favorable but short-term clinical responses to metronidazole for 10 of 13 patients, and the treatment failed to eradicate the pathogen in five who underwent repeated biopsy. An alternative explanation for this response is the possibility of bacterial overgrowth as a complicating factor. Preliminary studies have also shown an apparent clinical response in three of four patients treated with albendazole [50]. M. avium. It is estimated that --40% of patients with AIDS have disseminated infections due to M. avium. The water supply is thought to be the usual source of this agent, and the gut is believed to be the usual portal of entry [51]. For many patients with advanced HIV infection, this organism is isolated from stool as well as from various anatomical sites [51, 52]. Infection of the gastrointestinal tract is most often expressed clinically as chronic diarrhea, abdominal pain, malabsorption, and marked wasting [51, 52]. Biopsy specimens of the small intestine usually show changes similar to those seen in Whipple's disease, with wide villi, dilated lacteals, and infiltration of the lamina propria with macrophages that are positive for the PAS reaction [53]. As noted above, M. avium is commonly detected with use of acid-fast stains and in cultures of stool; this finding may simply support the diagnosis of disseminated disease without necessarily implying a diagnosis of enteritis due to M. avium com-

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mens may show typical CMV vasculitis with inflammation and hemorrhage in the lamina propria combined with typical intranuclear inclusions within endothelial cells; however, typical viral inclusions may also be seen in areas of entirely normal intestinal mucosa as well [20]. Thus, the diagnosis is best established when typical inclusions are found in association with inflammatory changes, especially vasculitis. Quantitative assessment may also be helpful since some investigators have found a correlation between diarrhea and concentrations of CMV inclusion bodies per millimeter of tissue [23]. The frequency with which CMV has been detected by observation of inclusion bodies and/or viral cultures among patients with AIDS who have chronic diarrhea ranges from 0-45% [11, 12, 16, 17, 19, 20]. This large difference between studies that presumably deal with similar patients and that are conducted by investigators using analogous techniques to detect an organism that is easily seen and grown remains largely unexplained. An additional dilemma that confounds interpretation of the clinical significance of CMV in the gastrointestinal tract concerns therapeutic options-the use of ganciclovir or foscarnet [24]. The published reports to date show inconsistent results in terms of therapeutic response among organ transplant recipients with CMV colitis [25,26], and the published experience on patients with AIDS is similarly inconclusive with respect to the response to therapy for diarrhea; however, studies tend to show a reduction in bowel symptoms and improvement in nutritional status [20,23,24,27]. The latter findings could reflect the benefit of treating CMV viremia; thus, the therapeutic role ofganciclovir or foscarnet in CMV infections per se, as with that of agents administered for CMV pulmonary infections in this population, remains enigmatic. Cryptosporidium. This protozoan parasite causes the initial AIDS-defining infection in -- 2% of patients with AIDS in the United States [28], and it has been detected in 16% of patients with AIDS and diarrhea in previous studies by our group [29] and in up to 57% of patients with AIDS and chronic diarrhea from Haiti [5]. Cardinal features include chronic, persistent, large-volume diarrhea that is often associated with localized abdominal pain and no fever [30-32]. Other features may include nausea, anorexia, associated hepatobiliary disease, and malabsorption of fat, D-xylose, and occasionally vitamin B 12 • Fluid loss may reach several liters per day, and although symptoms are usually intermittent, spontaneous cure during advanced stages of HIV infection is extremely rare. Experienced personnel may make the diagnosis easily by examining stool with use of a modified acidfast stain that appears to be relatively specific and detects -- 104 oocysts per gram of watery stool [30-34]. Asymptomatic carriage has been reported [35], but this seems to be extremely uncommon among patients with HIV infection [29]. To date, there is no antimicrobial therapy with established merit, although some studies indicate octreotide, a so-

CID 1992; 15 (October)

CID 1992; 15 (October)

AIDS Enteropathy

140 patients with advanced HIV infection, including 96 with diarrhea, were uniformly negative [62]. Clostridium difjicile. We reviewed our experience on the AIDS ward at Johns Hopkins Hospital for the 18-month period ending 5 July 1991. We found that diagnostic evaluations for diarrhea were performed for 200 of 749 patients admitted during that period and included assays for C. difjicile toxin; results in 25 (12.5%) cases were positive. Analysis of these 25 cases showed that 18 of the patients had recently received antibiotics that are frequently associated with this complication-ampicillin, clindamycin, or the cephalosporins. A particularly disturbing finding was that response of the patients to therapy with vancomycin or metronidazole seemed substantially less prompt compared with that of patients who were not infected with HIV; this complication was considered a major cause of death for four patients and a contributing factor in the deaths of three others. Miscellaneous organisms. Patients with HIV infection are subject to the same types of enteric pathogens that are encountered in healthy hosts; however, their infections may be unusually severe or prolonged, and some of the pathogens assume unusual virulence in the presence ofimmunosuppression. It is estimated that the frequency of salmonellosis among patients with HIV infection is increased approximately 20-fold over that observed for the general population. The most common isolate is Salmonella typhimurium [63]. Patients with HIV infection also have increased rates of infection with Shigella species, non-jejuni strains of Campylobacter, and possibly C. jejuni [64-66]. The frequency of infection with some bacterial pathogens may be reduced by the administration of zidovudine therapy since this drug shows good activity in vitro against Salmonella, Escherichia coli. and other Enterobacteraceae [67]. Fungal infections of the gastrointestinal tract are unusual, but disseminated histoplasmosis may cause such infection, most frequently in the small bowel or colon [68]. The major parasites are cryptosporidia and microsporidia, as described above. Giardia lamblia is occasionally encountered, but it never accounts for more than a small percentage of infections, and the course of clinical disease does not seem to be altered by concomitant HIV infection. Entamoeba histolytica is commonly found, especially in homosexual men, among whom prevalence rates approach 30%. However, infection with these organisms generally fails to produce symptoms; histological studies rarely demonstrate invasive infection, and serologic studies usually fail to provide evidence of a pathogenic role [69]. The presumed explanation for these observations is the fact that homosexual men who are infected with HIV and E. histolytica are almost invariably colonized by nonpathogenic zymodenes [70]. More controversial is the role of Blastocystis hominis, which has stimulated a lively debate with regard to this organism's pathogenicity in patients, both with and without HIV infection [71, 72]. Our previous studies of homosexual men

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plex, although our prior studies indicated a significant correlation between the detection of this organism in stool and the latter diagnosis for patients with AIDS who had chronic diarrhea when compared with those who did not have diarrhea. Despite this observation, the preferred method for diagnosis is small-bowel biopsy to demonstrate typical pathological changes and the presence of this organism. The frequency of enteritis due to M. avium among patients with AIDS and chronic diarrhea is variably reported at 5%-23% [3, 7, 10, 11]. Treatment has been problematic because of the relative resistance of this organism to most drugs; nevertheless, recent studies suggest the potential value of clarithromycin or azithromycin or one of these drugs in combination with ethambutol, clofazimine, or other antimycobacterial agents [54, 55]. Isospora belli. This organism is a protozoan parasite that invades the enterocytes of the small intestine and causes severe and protracted diarrhea in patients with AIDS. Histological studies of the small bowel and diagnostic testing with direct examination of stool are analogous to the procedures described for diagnosing Cf'jptosporidiosis [30]. The organism is acid-fast and can readily be distinguished from cryptosporidia on the basis of size; its oocysts measure 20-30 JLm, compared with those of cryptosporidia, which measure 4-6 JLm [56]. Data from the CDC suggest that isosporiosis is the initial AIDS-defining diagnosis for only --0.2% of patients with AIDS, making it about 10-fold less common than cryptosporidiosis [30]. Among patients from Zaire who have AIDS and chronic diarrhea, the frequency of isosporiosis is 19% [56], and for those from Haiti it is 15% [6]. Unlike infection due to cryptosporidia, that due to I. belli appears to respond well to antimicrobial agents, especially trimethoprim-sulfamethoxazole and pyrimethamine [57-59]. Adenovirus and rota virus. A recent report by Janoff et al. [60] showed evidence of adenovirus on electron microscopy and/or in culture for five (9.8%) of 51 patients with AIDS and chronic diarrhea; similar studies of 10 control patients who did not have diarrhea failed to yield adenovirus. Similarly, studies from Australia in which ELISA, electron microscopy, or cell culture were used showed evidence of adenovirus in 17 (34%) of 50 patients with advanced stages of HIV infection [61]. These investigators also found evidence of rotavirus in 26 (52%) of these 50 patients. Symptomatic disease with acute diarrhea or exacerbation of chronic diarrhea was significantly correlated with the presence or absence of either virus and with immunodeficiency (defined by CD4 cell count). By contrast, Smith et al. [16] did not detect rotavirus in any patients. In our collaborative studies with use of electron microscopy and ELISA on stools from patients with AIDS, we found that four (5%) of 77 patients with chronic diarrhea and two (8%) of 25 patients without diarrhea were infected with the conventional adenovirus [62]. Results of studies for group A and non-A rotavirus on specimens from

729

730

Bartlett, Belitsos, and Sears

Chronic Diarrhea Due to Alternative Mechanisms As noted in table 1, for 15%-25% of patients with chronic diarrhea during advanced stages ofHIV infection an identifiable infectious agent is not isolated despite extensive studies that include endoscopy, biopsy, and electron microscopy of stool and gut tissue. This represents a low rate of negative results when compared with that obtained in extensive diagcnostic evaluations performed for numerous other patient populations with suspected infectious diarrhea, including travelers, homosexual men, infants, and bone marrow-transplant recipients. The obvious concern is that there are multiple enteric pathogens yet to be described; in support of this thesis is the relatively long list of newly detected enteric pathogens that have appeared during the past 10 years: enterohemorrhagic E. coli, enteroaggregative E. coli, microsporidia, adenovirus types 40 and 41, the Cyanobacteriumlike organism, and multiple new species of Campylobacter. Nevertheless, the negative findings in evaluations for enteric pathogens in patients with AIDS have prompted speculation about the potential role of other mechanisms of diarrhea. These include HIV infection of the gut, autonomic denervation, lactase deficiency, dysregulation of the enteric immune system, local production of lymphokines, and overgrowth of bacteria in the small bowel. HIV infection of the gut. Several investigators have observed evidence of HIV infection ofgut tissue [74-80] (table 2). Techniques used for detection include in situ hybridization to detect posttranscriptional RNA [74, 77-79], immunohistochemical techniques [75, 76], and/or viral culture of

washed tissue [78]. The sources of biopsy specimens have usually been the duodenum and/or the rectum, and the diagnostic yield ranges from 30% to 56%. Biopsies of the small bowel generally reveal HIV antigen in the mononuclear cells ofthe lamina propria and occasionally in intraepitheliallymphocytes. There is a single report of a patient with evidence ofjejunal enterocyte infection by HIV [77]. In rectal biopsy specimens, the infected cells include enterochromaffin cells, lymphocytes, and macrophages [78, 79]. In general, biopsy specimens obtained at endoscopy from patients with symptomatic gastrointestinal disease are used for these studies, making correlation of findings with symptoms difficult because of the absence of appropriate controls. An additional problem that confounds conclusions is the fact that thorough evaluations for alternative pathogens, including studies for detection of microsporidia, are not included. With regard to the specific mechanisms ofdiarrhea in HIV infection of the gut, some investigators have suggested that direct involvement of HIV may playa role in the retardation of enterocyte maturation and function. Alternatively, infection of enterochromaffin cells suggests the possible role of HIV in the alteration of motility or neurohumoral regulation of intestinal secretion. Of possible relevance are the results of recent tests showing that HIV infects and replicates in primary cultures of normal human ileal and colonic epithelial cells [81] as well as in several human adenocarcinoma cell lines [82, 83]. Autonomic denervation. Several investigators have reported subclinical and overt autonomic neuropathy in patients with HIV infection [84-86]. Clinical expression, when present, includes disordered sweating, urinary retention, and abnormal cardiovascular hemodynamics. The possibility that autonomic denervation contributes to diarrhea in patients with AIDS has been suggested by Batman et al. [87]. These investigators examined jejunal biopsy specimens from 19 patients with various stages of HIV infection along with specimens from 10 controls with use of a neuron-specific polyclonal antibody, PGP 9.5. The results showed a significant reduction in axonal density in both villi and the pericryptal lamina propria of patients with HIV infection. This denervation was noted at all stages of HIV infection, and correlation of these findings with clinical findings showed a trend toward the development of unexplained diarrhea, although the difference was not statistically significant. Dysregulation of the enteric immune system. The severe dysfunction of T cells that accompanies the late stages of HIV infection suggests a contributing role for localized immune dysregulation in the pathophysiology ofAIDS enteropathy. Support for this hypothesis includes the observation of striking villus atrophy and crypt hyperplasia in fetal smallbowel explants when T cells are activated with pokeweed mitogens or anti-CD3 monoclonal antibodies [88-90]. Similar findings have been reported in allograft rejection of mouse intestine and in graft-versus-host disease of the intes-

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showed that the prevalence of this parasite in stool was 35% (82/243) among asymptomatic homosexual men compared with 34% (12/35) among homosexual men with diarrhea [29]. Among homosexual men with AIDS, there was no difference in the frequency of isolation of B. hominis among those with or without diarrhea, but there was a statistically significant reduction in rates of carriage of this parasite among homosexual men with AIDS compared with those who did not have HIV infection. In view of this experience, we agree with other investigators who consider B. hominis to be nonpathogenic to man. Similarly, we are not convinced that Endolimax nana, Entamoeba coli, Entamoeba hartmanni, and other nonpathogenic parasites are uniquely virulent in patients with HIV i~fection. More recent studies have implicated a Cyanobacterium-like organism that is acid-fast, spherical, and 9-1 0 ~m in diameter and appears to cause intermittent diarrhea [73]. This is another relatively new enteric pathogen that is classified as a blue-green alga and is recognized as a "large Cryptosporidium" on acid-fast staining ofstool. Clinical features are watery diarrhea in the absence of fecal leukocytes, low-grade fever or no fever, and symptoms that last for a median of 7 days but may be protracted.

CID 1992: 15 (October)

731

AIDS Enteropathy

CID 1992; 15 (October)

Table 2. Summary of data on detection of HIV in gut tissue.

Reference

Technique for detection

Biopsy site

No. of specimens positive/No. tested (%)

Cell type infected

Symptoms and conclusions

Macrophages and mature lymphocytes in lamina propria

HIV detected for 9 patients; 6 patients had HIV-related diarrhea, and 2 patients had diarrhea due to other causes Presence of HIV correlated with small-bowel atrophy and reduced mitotic figures No correlation between evidence of HIV and GI symptoms

In situ hybridization for detection of RNA

Colon, rectum

[75]

Immunostaining for p24 antigen

Duodenum

15/38 (39)

Mononuclear cells

[76]

Immunostaining for p24, p25, and p 18 antigens In situ hybridization for detection of RNA

Duodenum or rectum

38/127 (30)

Lymphocytes and macrophages in lamina propria (some activated CD 68+ cells) Enterocytes (1/9 patients), mononuclear cells in lamina propria Rectal crypt epithelium (enterochromaffin cells?) and lamina propria

[77]

9/25 (36)

Jejunum

5/9 (56)

[78]

In situ hybridization for detection of RNA. culture

Duodenum, rectum

5/10 (50)

[79]

In situ hybridization for detection of RNA PCR for detection of HIV RNA

Duodenum, rectum (Stool)

3/4 (75)

[80]

NOTE.

5/9 (56)

Rectal crypt epithelium and lamina propria Not known

Possible role in retarded enterocyte maturation and function Culture positive for HIV for 2/4 patients; HIV suggested as cause of diarrhea (possibly due to motility disorder) since no enteric pathogen found _ HIV suggested as cause of diarrhea since no enteric pathogen found Significant correlation with diarrhea and malabsorption

HIV = human immunodeficiency virus, GI = gastrointestinal; peR = polymerase chain reaction.

tine [90). Results of prior studies of patients with AIDS indicate that the mucosal T cells show changes similar to those noted in the peripheral circulation, with reversal of the CD4/ CD8 ratio and severe depletion of the CD4 cells [91, 92]. These findings suggest that loss and/or functional impairment of activated CD4 cells in the mucosa and increased suppressor activity may be responsible for altered regulation of small bowel epithelial proliferation and maturation, accounting for the previously noted morphological changes. The marked decrease in duodenal brush-border lactase activity noted in patients with HIV infection provides additional support for this hypothesis [75]. It should be noted that these morphological changes are observed in the absence of clinical expression (diarrhea) [12], so it is uncertain if the immune dysregulation noted is a contributing factor for diarrhea, even if it accounts for the abnormal epithelial proliferation. Lymphokines. Activation ofT cells in the lamina propria is known to induce release of lymphokines and increase the number of intraepithelial lymphocytes [93]. It is possible that the increase in intraepithelial lymphocytes in some patients with AIDS and chronic diarrhea reflects T cell activation with elevation of lymphokines, a process that is stimulated by infection with microsporidia or other pathogens [94]. In addition, recent studies indicate that levels of tumor necrosis factor-a (TNF-a) in stool correlate with disease activity in children who have idiopathic inflammatory bowel

disease [95]. Children with active Crohn's disease had mean stool levels ofTNF-a that were --20 times higher than those of control patients who had inflammatory bowel disease without diarrhea and than those ofcontrol patients with diarrhea due to other causes. In previous studies TNF-a-secreting cells were found in biopsy specimens from children with active Crohn's disease [96]. None of these studies showed increases in serum levels of TNF-a for this population; such a finding suggests that biopsy of gut tissue or examination of intraluminal contents is critical for assessment [94-96]. Similarly, interferon-')', another lymphokine secreted by activated T lymphocytes, has recently been shown to increase the permeability of monolayers of intestinal epithelial cells, a finding that suggests a role in the clinical expression of diarrhea [97]. Overgrowth ofbacteria in the small bowel. Several investigators have reported a relatively high frequency of gastric secretory failure in patients with AIDS. One of the most comprehensive studies was done by Lake-Bakaar et al. [98], who noted a mean pH of fasting gastric juice in 29 patients with AIDS to be 5.9 ± 3.2 (±l SO); this value was significantly different in controls, for whom the mean pH was 2.9 ± 0.1. The fasting gastric pH was regarded as abnormally high in 27 (93%) of29 patients with AIDS. The cause is not known, but two potential sequelae are the loss ofthe "gastric barrier" that may predispose to enteric infection and the predisposition to bacterial overgrowth, resulting in malabsorp-

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[74]

732

Bartlett, Belitsos, and Sears

tion, diarrhea, and wasting. We recently described a strong association between gastric hypoacidity and the presence of opportunistic enteric pathogens in patients with AIDS and chronic diarrhea [99].

Diagnostic Evaluation

difJicile toxin) cost approximately $95 at the Johns Hopkins Hospital Clinical Laboratory, although Johanson and Sonnenberg [3] have cited a cost of approximately $250. For patients who are febrile, blood cultures for bacteria, mycobacteria, and CMV should also be performed. Other noninvasive tests that should be considered are the hydrogen breath test for detection of small-bowel overgrowth and the recently described direct stool examination for microsporidia. However, we are aware of only a single report [44] that verifies the diagnostic accuracy of the latter, and we are not aware of any clinical laboratories that currently offer this assay. Endoscopy. Endoscopy is controversial because the cost is high, and impressions vary about what constitutes a treatable pathogen. Most authorities recommend a stepwise diagnostic evaluation, and the first step is always stool evaluation. On the basis ofmedical decision analysis, Johanson and Sonnenberg [3] recommended the following sequence: step 1, stool culture Xl; step 2, treatment of bacterial pathogens and empirical treatment with diphenoxylate hydrochloride of those whose cultures are negative for pathogens; and step 3, full diagnostic evaluation of nonresponders, including stool examination for parasites X 3, blood cultures X 2, and colonoscopy plus gastroduodenoscopy with biopsies. Important factors in the decision analysis were the assumptions that stool culture for bacterial pathogens would detect virtually all treatable agents, including those that would be adversely effected by treatment with antiperistaltic agents, that --65% of patients would have resolution of diarrhea after receiving diphenoxylate hydrochloride, and that agents detected only on examination of stool for ova and parasites and on endoscopy would not be eradicated by antimicrobial therapy. On the basis of the estimated cost of upper and lower endoscopy ($2,400), the cost per remission was $5,419 for the full evaluation compared with $1,700 for the limited evaluation that was advocated. An alternative three-step algorithm advocated by Smith et al. [100] is as follows: step 1, stool culture X 3, assay for C. difJicile toxin X I, and stool parasite examination Xl; step 2, colonoscopy and gastroduodenoscopy (with culture of a duodenal biopsy specimen for CMV and mycobacteria; culture ofa colonic biopsy specimen for CMV, adenovirus, mycobacteria, and herpes simplex virus; stains of biopsy specimens with hematoxylin-eosin for protozoa and viral inclusions, Grocott-Gomori methenamine-silver nitrate or Giemsa for fungi, and Fite for mycobacteria; and examination of duodenal fluid for parasites); and step 3, electron microscopy of a duodenal biopsy specimen for microsporidia and of a colonic biopsy specimen for adenovirus. Our recommendations represent a combination of these two algorithms: the initial evaluation addresses the role of medications, diet, and anxiety; screening studies include a stool culture for bacterial pathogens X 2, C. difJicile toxin assay Xl, and examination for stool parasites, including an

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The diagnostic evaluation usually consists of stool studies that are relatively inexpensive and noninvasive and endoscopy, which is invasive, expensive, and unpleasant for the patient. It is assumed that there has been adequate consideration of the role of diet, drugs, and other noninfectious causes of diarrhea before a more detailed evaluation is performed. Most of the diagnostic evaluation advocated for patients whose results of stool screening studies are negative is relevant for assessment of chronic diarrhea in patients with advanced stages of HIV infection. Stool studies. In 1987 we reported our observations concerning three patient cohorts of homosexual men; an encyclopedic menu of diagnostic studies was used for detection of -- 35 microbes with established or suspected roles as enteric pathogens [29]. One cohort included 49 patients with AIDS and diarrhea who were compared with 29 patients matched for stage ofdisease without diarrhea. The results ofthis study allowed three important conclusions to be drawn. (1) A likely enteric pathogen was detected in approximately onehalf of all patients; the most common was cryptosporidia. Other investigators have reported a comparable diagnostic yield with stool studies [3, 16], although there is some variation based on stage of disease and duration of diarrhea. (2) The organisms commonly encountered in homosexual men with proctitis or diarrhea (sometimes referred to as the "gay bowel syndrome") were rarely encountered in this series of patients with AIDS; the single exception was herpes simplex virus, which is a common cause of perirectal lesions in both groups but is not an agent ofdiarrheal disease. Other investigators have also reported a sparse yield of sexually transmitted pathogens in homosexual men with advanced stages of HIV infection complicated by chronic diarrhea [3, 11, 12, 16, 17]. (3) Although an extensive search was made for multiple microbes in stool specimens (including electron microscopy for viral agents), the organisms that were significantly associated with clinical disease were almost exclusively agents that could easily be detected with routine laboratory studies [29]. On the basis of these observations, our recommendations for the diagnostic evaluation include performance of routine cultures ofa fresh stool specimen to detect enteric pathogens (Salmonella, Shigella, and C. jejuni); assay for C. difJicile toxin; and direct examination for ova and parasites, including acid-fast staining. The latter procedure will permit detection of mycobacteria, cryptosporidia, I. belli, and blue-green algae (a Cyanobacterium-like organism). These studies (stool culture, examination for ova and parasites, and assay for C.

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