48 Human immunodeficiency virus and inflammatory bowel disease
CHARLES MEL WILCOX
Introduction
We have now completed the second decade of the acquired immunodeficiency syndrome (AIDS) that first came to attention in 1981 [1]. The early years of the epidemic were devoted to describing the vast spectrum of, and defining optimum treatments for, the complications of AIDS. Over the past 10 years, there has been intense investigation into the virology of the human immunodeficiency virus (HIV) and, consequently, rapid progress in our understanding of the pathogenesis of this devastating worldwide infec- tious disease. These efforts have culminated in the development of highly active antiretroviral therapies, termed HAART, which have profoundly changed the paradigms for management of HI V-related com- plications including those involving the gastro- intestinal tract [2, 3]. Because of the widespread availability of these drugs and access to care [4] the fall in AIDS-related morbidity and mortality has been most pronounced in the developed world, whereas in contrast, and for the foreseeable future, complications related to HIV-associated immuno- deficiency will continue unabated in developing countries [1, 5].
Before the development of HAART, gastrointest- inal disorders occurred almost uniformly in patients with AIDS. Problems referable to the colon, usually diarrhea, were observed in 50% or more of patients at some point during the course of HIV and AIDS [5]. A l t h o u g h o p p o r t u n i s t i c i n f e c t i o n s a n d neoplasms comprise the majority of the colonic disorders in these patients, a number of cases of inflammatory bowel disease (IBD), both Crohn's disease (CD) and ulcerative colitis (UC), have been described [6-22]. In addition, an idiopathic inflam- matory disease of the colon, apparently distinct from IBD, has also been recognized [23, 24]. Given the potential for confusion clinically, endoscopically, and pathologically between opportunistic infections
of the colon and IBD, an appreciation of the clinical presentation, differential diagnosis, and manage- ment of IBD in HIV-infected patients is important.
In this chapter the relationship of HIV infection and IBD will be explored, focusing on the pathogenesis of IBD and what lessons we can learn from coexistent HIV infection; the chapter will review the clinical presentation and relationship to immunodeficiency of the reported patients with HIV infection; outline the differential diagnosis of IBD in the setting of HIV; and review management. Finally, criteria will be proposed for the diagnosis of idiopathic IBD in the setting of HIV infection.
Pathogenesis of IBD in relation to HIV Infection
Since the key element in the pathogenesis of IBD is the inflammatory cascade which includes T cells, and HIV disease is characterized by the destruction of CD4 T lymphocytes leading to immunodeficiency, it follows that the prevalence and natural history of IBD may be altered in patients with HIV infection.
Thus, the reported cases of coexistent HIV and IBD may provide insight into the pathogenesis of IBD.
It is well recognized that T cells play an important role in the expansion and perpetuation of the inflam- matory response in IBD [25]. When presented with specific antigens the T cell population expands, and these cells then interact with B cells, resulting in an expansion of antigen-specific B cells. Activated T cells recruit and activate macrophages and neutro- phils, which in turn produce cytokines amplifying and further perpetuating the inflammatory response.
CD4 T cells, the pivotal cell destroyed in HIV infection, play an important role in the pathogenesis of IBD. This has been directly demonstrated in multiple experimental models of IBD. Such studies have demonstrated that certain CD4 T cell subsets
Stephan R. Targan, Fergus Shanahan andLoren C. Karp (eds.), Inflammatory Bowel Disease: From Bench to Bedside, 2nd Edition, 863-873.
© 2003 Kluwer Academic Publishers. Printed in Great Britain
exist that can cause colitis, and other subsets exist that prevent it. Two of the major CD4 T cell subsets are T-helper 1 and T-helper 2. The Thl subset produces IL-2 and interferon gamma (IFN-y)and mediates cell-mediated immunity. The Th2 subset produces IL-4, IL-5, IL-6, and IL-10, and mediates antibody production. Based on the profile of measured cytokine production, CD appears to be most associated with Thl lymphocytes while UC may be more associated with Th2 lymphocytes, although this is much less clear.
Regulatory CD4 T cell subsets also exist. A CD4^
T cell subset denoted Th3 produces large amounts of active transforming growth factor (31 (TGF-Pi), a cytokine with broad inhibitory effects on lympho- cytes. The T-regulatory 1 (Trl) CD4"*"T cell produces large amounts of IL-10, another inhibitory cytokine, along with some TGF-Pi. It is likely that more regulatory CD4"^ T cell subsets will be identified in the future.
Several studies have examined T cell subsets in bowel tissue from HIV-infected patients. Generally, T lymphocyte subsets in the gut reflect the concentra- tion in the systemic circulation. HIV-infected patients with advanced immunodeficiency have markedly reduced numbers of CD4 cells both in the circulation and small bowel, with a corresponding increase in CDS cells [26, 27]. Likewise, quantitation of CD4 and CD8 cells in colonic biopsy samples from AIDS patients shows a similar pattern. Thus, the systemic CD4/CD4 T cell ratio and the absolute values of each subset reflect what can be found in the gut.
There is little information regarding cytokine production in bowel tissue from HIV-infected patients, especially those with more severe degrees of immunodeficiency. Snijders etal. [28] biopsied the jejunum of HIV-infected patients with diarrhea,
some of whom had small intestinal pathogens, HIV- infected patients without diarrhea, and HlV-sero- negative controls. No significant differences were detected in cytokine levels among the groups with low levels uniformly d e t e c t e d . In c o n t r a s t , McGowan et al. [29] found a significant increase in inflammatory cytokines, IL-ip and IFN-y in HIV- infected patients compared to controls, but lower levels of IL-10 in colonic biopsies. Proinflammatory cytokines have also been detected in rectal mucosa of AIDS patients with peak expression of TNF-oc and IL-ip in late-stage patients compared to patients with earlier-stage disease [30]. In contrast, one study [31] suggested defective function of colonic mono-
nuclear cells in AIDS patients as reflected by a reduction in TNF-oc secretion. The relationship of cytokine production to HIV-infected mucosal inflammatory cells is unclear. Overall, the number of HIV-infected cells identified in the lamina propria has been consistently low [32, 33].
If CD4 cells are important in the pathogenesis of IBD, then animal models of IBD with perturbations of CD4 T cell subsets would provide an ideal assess- ment of their role. Loss of CD4 T cells does improve disease activity in animal models. However, selective knockout of subpopulation has yet to be performed.
It follows from the above that the relationship between HIV infection and IBD is likely to be complex. Assuming that the CD4 T cell depletion occurs in all CD4 T cell subsets, including those that both mediate and prevent IBD, the net effect on the course of IBD will depend on which subset is more affected. For example, if the Thl subset were to be disproportionaltely depleted in a patient with CD, the activity of the IBD might improve. Conversely, if the regulatory CD4 T cell subset were to be dispro- portionately depleted, IBD activity might worsen.
Indeed, both improvement and worsening of IBD activity has been reported in patients with IBD who also develop HIV.
Review of reported cases of IBD and HIV Infection
Although there have been a number of reported cases
of coexistent HIV infection and IBD, given the
millions of patients with HIV infection worldwide,
coupled with the predominance of IBD in young
patients - those most afflicted by HIV - one might
anticipate many more reported cases. Two studies
have provided estimates of the prevalence of
coexistent HIV and IBD [10, 11]. In a retrospective
study [10], hospital discharge records for a 4-year
period were reviewed, and only three patients with
IBD of 1839 patients with a discharge diagnosis of
HIV/AIDS were identified. Four additional patients
were identified by phone survey of clinicians in
related outpatient clinics. Since both IBD and HIV
infections are primarily treated in the outpatient
setting, these results are likely to be an under-
estimate. In the study of Sharpstone et al. [11], HIV
clinic records were cross-referenced with pharmacy
records for 5-ASA compounds and rectal steroid
preparations. Eight patients were identified, yielding
a mean incidence of 41 /100 000 and a prevalence of
364/100 000. These numbers are high compared to recent US studies [34] and may reflect the small sample size.
A number of important considerations must be kept in mind when reviewing the case series of IBD in HIV-infected patients. First, the time-course of IBD and HIV infection should be well documented. The majority of the reported cases consist of patients with IBD who later became HIV-infected, or both disorders were diagnosed together. Importantly, the acquisition of HIV infection can rarely be precisely timed; thus, a long lag time between infection and the diagnosis of IBD is likely in most patients, which means there could be considerable overlap in the duration of the two diseases. Second, the stage of HIV-related immunodeficiency in relationship to the timing of the diagnosis of IBD must be character- ized. Most reported cases of de-novo IBD have been in HIV-infected patients with only modest immune dysfunction. The marker for staging immune dysfunction most frequently used, and for which there is compelling evidence, is the CD4 lymphocyte count [35, 36]. It is well established that significant immune dysfunction, as reflected clinically by the occurrence of opportunistic disorders, does not occur until the CD4 count falls below 200/jil, and most opportunistic infections involving the gastro- intestinal tract do not manifest until the CD4 count falls below 100/|il [3, 5, 35]. Thus, reports of HIV- infected patients with CD4 counts less than 100/)il with active IBD may provide better insight into any relationship between HIV-associated immuno- deficiency and IBD. Third, it is important to reflect on any differences as compared to non-HIV-infected patients in the manifestations and outcome of IBD, such as location and extent of disease, presence of extraintestinal complications, and response to
therapy, both medical and surgical. Fourth, it is critical that a thorough histopathologic examination of colonic and/or small bowel biopsies be performed to exclude opportunistic disorders which may masquerade as IBD. Since a number of opportunistic infections, most notably cytomegalovirus (CMV), may mimic IBD, the diagnosis of IBD may be difficult to establish conclusively. Also, the character- istic histologic findings of IBD should be specifically documented, including crypt distortion, chronic inffammation, etc. This potential confusion is further perpetuated by the absence of specific criteria for the diagnosis of IBD in the setting of AIDS.
Crohn's disease
To date there have been eight reports of CD [6-14]
totalling 12 HIV-infected patients (Table 1). Consis- tent with the epidemiology of AIDS, the majority of the patients were male homosexuals ranging in age from 14 to 48 years. Five of the 12 patients presented with CD after well-established HIV infection. Of the other seven patients with CD, the timing of HIV infection could be accurately determined in only two [13] (contaminated blood products) and, as noted above, it is likely that in many cases there was overlap of the two diseases. The descriptions of the radiographic and endoscopic findings were typical for CD. The diagnosis of CD was made by the findings on pathologic specimens, usually post-sur- gical, and non-caseating granulomas were reported as present in less than half the cases either on endoscopic biopsy or in the surgical specimen. His- tologic examination was generally extensive to exclude other diseases. However, long-term follow- up of the HIV-infected patients who subsequently
Table 1. Reported cases of Crohn's disease in HIV-infected patients
Reference Year No. of patients Sequence CD4 count Location
6 7 8 9 10 12 11 13
1984 1988 1994 1996 1996 1997 1996 1998
1 1 1 1 1 1 2 4
AIDS ^Crohn's Crohn's -^HIV HIV ^Crohn's Crohn's -^HIV HIV ^Crohn's HIV -^Crohn's Crohn's -^HIV Crohn's ^ H I V
230*
410 480 270*
210 100 336, 442 320, 5 0 M 6 2 , 34*
Colon, terminal ileum Colon
Colon, terminal ileum Colon, terminal ileum NA
Colon, terminal ileum Colon, small bowel/rectum Colon, terminal ileum
*CD4 count determined years after initial diagnosis of CD.
developed CD, which would add further security to the diagnosis, was rarely performed, including colo- noscopic re-examination.
The gastrointestinal tract involvement with CD appeared similar to what might be anticipated with most patients having both colon and terminal ileal disease and with no apparent site predilection.
Fistulous disease was reported in one patient [12]
and e x t r a i n t e s t i n a l m a n i f e s t a t i o n s were not described in any patient. To our knowledge there are no cases in which perianal disease was the sole manifestation.
One reported patient [14] had documented UC for 14 years and subsequently, at the time of recurrent symptoms, had colonoscopy as well as barium enema that was most suggestive of CD; granulomas were not seen on colon biopsy, and extensive histo- logic examination to exclude opportunistic disorders was not reported. Testing for HIV was not available at the time of publication (1986), but the helper- suppressor T cell ratio was very low, suggesting severe immunodeficiency. Whether this patient truly had UC or an overlap syndrome is unknown.
One of the most important features of these cases is the course of HIV-related immunodeficiency in relationship to the timing of IBD. Of the ^\VQ HIV- infected patients who later developed CD, the CD4 lymphocyte counts at the time CD was first docu- mented were 100/)il, 210/^1, 230/)il, 336/)il, and 480/|il. Only one of these patients had a history of opportunistic infections, and HIV testing was not
Table 2. Reported cases of UC in HIV-infected patients
Reference Year No. of patients Sequence
available at the time of publication [6]. One addi- tional reported patient with apparently advanced immunodeficiency, as reflected by the presence of opportunistic infections, had a low helper suppressor T cell ratio (0.25, normal 2.5) although the CD4 count was not reported [14]. As noted above, given these CD4 counts, only one of these three patients had substantial immunodeficiency, and this leaves open the possibility that severe immunodeficiency could be protective against the development of CD.
Since some reports [14] preceded the recognition of AIDS-related diseases which mimic CD, it is perhaps possible that some of these cases could represent a missed opportunistic infection. The relationship of the response to therapy, as well as natural history with regard to stage of HIV infection, will be discussed below.
Ulcerative colitis
To date there have been nine reports [10, 11, 14, 15, 17-22] of UC totaling 17 HIV-infected patients (Table 2). In four of these patients UC and HIV were diagnosed simultaneously. The CD4 count at diagnosis was 500/}il or greater in six patients tested, and greater than 200/nl in 13 (87%). Histologic criteria for diagnosis followed objective criteria in one [10], were not described in another [15] while the histology was reported as 'nonspecific' in one [18] or demonstrated acute inflammation and crypt abscess
CD4 count Extent
10
11
14 15 18 19 20 21 22
96
96
86 90 91 92 96 97 99
2 2 6
HIV^UC UC^HIV HIV - . U C HIV ^ U C U C - . H I V HIV -^UC HIV ^ U C HIV ->UC UC^AIDS UC/HIV UC/HIV HIV ^ U C HIV ^ U C HIV/ UC HIV/ UC
680, 700 530, 460 270 256 462 228 283 NA 500 546 170 NA 450 930
130
Proctitis, NA NA, right colon NA
NA
Transverse colon Pancolonic T colon Pancolonic Pancolonic Transverse colon NA = not available.
in the others. A missing element in most reports is a description of the characteristic histologic changes of chronicity which should be apparent at the time of diagnosis [37]. Of the patients undergoing colono- scopy the disease was limited to the rectum [10], reached the transverse colon [19] and right colon [10] in one patient each and was pancolonic in the other patient. Fulminant colitis requiring surgery was reported in four patients [11,17,22]. One patient developed significant articular symptoms (sacro- iliitis, arthritis) and later uveitus with flares of disease [21]. When described, the endoscopic appear- ance of the colon was typical for UC. As mentioned above for CD, the rigor with which other potential causes of colitis were excluded varied, extensive histologic examination was not always performed to exclude infection or evidence of chronicity documen- ted, and long-term follow-up to best assess diagnostic accuracy was not always reported.
Differential diagnosis
Given the apparent infrequency of IBD in AIDS, when confronted with an A I D S patient with suspected IBD the patient is more likely to have an AIDS-related disorder than idiopathic IBD. In con- trast, when immunodeficiency is not advanced (CD4 count >200/iil), gastrointestinal complaints are more likely non-HIV-related. Thus, recognition of the opportunistic disorders which may mimic IBD and their relationship to the stage of immuno- deficiency is critical. Furthermore, when correctly diagnosed, the majority of these AIDS-related disorders are amenable to therapy.
When evaluating any HIV-infected patient with gastrointestinal symptoms the level of immuno- deficiency must first be staged by the CD4 lympho- cyte count. Numerous studies have consistently shown that opportunistic disorders rarely manifest above a CD4 count of 200/|il with most occurring at levels less than 100/|il [35]. Recent evidence also suggests that HIV viral load provides additional prognostic information for disease progression, including the development of opportunistic disor- ders [38]. Two common gastrointestinal pathogens that occur in the setting of advanced immuno- deficiency are cytomegalovirus (CMV) and Myco-
bacterium avium complex (MAC) which commonlyinvolve the colon and small bowel, respectively, and which may mimic IBD [39-44]. In addition, some processes may cause pathologic changes of chroni-
city that may suggest underlying IBD (unpublished observations). The many reported cases of opportu- nistic infections which mimicked IBD clinically, radiologically, endoscopically, and/or histologically in this setting emphasize the importance of a high index of suspicion for these diseases, as well as appropriate endoscopic tissue sampling and histo- logic processing.
Another point to consider when discussing the differential diagnosis of IBD in the setting of HIV infection is that patients with IBD may develop opportunistic infections characteristic of AIDS caused by treatment-related immunodeficiency. The best example of this is CMV colitis complicating high-dose prednisone therapy. In this scenario one may be concerned that the patient has underlying HIV infection and CMV colitis rather than IBD complicated by CMV colitis. Likewise, apparent exacerbation of IBD in HIV-infected patients can reflect intercurrent CMV infection [11].
The most important disease in the differential diagnosis of IBD, especially UC, is CMV colitis.
Patients with CMV colitis almost uniformly present with a CD4 count less than 100/|il [39, 45]. In one study [39] the median CD4 count was 15/|il. CMV colitis can also be the index presentation of HIV infection. The most common manifestations of CMV colitis are crampy lower abdominal pain, chronic watery diarrhea which may be bloody, and proctitis symptoms, particularly when distal disease is prominent. Weight loss is also frequent and may be profound, while fever is uncommon. The similarity of these symptoms compared with IBD is readily apparent.
Endoscopically there are also many similarities of CMV colitis and IBD. In a study characterizing the endoscopic appearance of CMV colitis in 56 AIDS patients, Wilcox et al. [39] showed that the most common endoscopic manifestation was subepithelial hemorrhage, which was often confluent. Disease was located throughout the colon in 74%, but was limited proximal to the rectosigmoid colon in only 13%.
Well-circumscribed ulcerations typical for CD were observed in six patients, while a pancolitis character- istic of UC was noted in three patients. Pseudopolyps have not been reported as a manifestation of CMV colitis. These findings demonstrate that the endo- scopic appearance of CMV colitis may be suggestive o f e i t h e r U C o r C D .
To best diagnose CMV colitis, multiple biopsies
(at least six) of abnormal-appearing tissue should be
obtained with close inspection of the characterisitic
viral cytopathic effect of CMV. Immunohisto- chemical staining for CMV antigens may further assist in the diagnosis. Although not recommended routinely, viral culture of tissue biopsies may rarely be helpful. It should be noted that, in general, CMV colitis in AIDS is associated with numerous viral inclusions in the biopsies. Therefore, if the the viral cytopathic effect is rare (only one or two positively staining cells with numerous biopsies), one should consider another diagnosis; this should be consid- ered as CMV 'infection' rather than true 'disease' [46).
Other colonic infections in AIDS which have been reported to mimick IBD include Isospora [47], and histoplasmosis [48]. Although commonly reported as a cause of colonic disease, herpes simplex virus (HSV) is actually a very rare cause of colonic infec- tion in AIDS. Usually herpes simplex virus of the colon presents with limited anorectal disease. A number of other opportunistic diseases could theore- tically mimic IBD also, but no specific reports detailing these associations in HIV-infected patients have been published (Table 3).
Terminal ileal disease suggesting CD may result from either CMV or MAC infection. In a report of terminal ileitis and AIDS [44], small bowel follow- through showed nodularity and ulceration of the terminal ileum characteristic of CD. However, histo- pathologic examination of the resected ileum demonstrated numerous acid-fast bacilli diagnostic of MAC.
Several cases of colonic Kaposi's sarcoma (KS) mimicking UC have been reported [ 16, 17]. However, in these AIDS patients KS was not identified on the initial evaluation, but rather on follow-up colono- scopy. In one case [17], IBD was treated aggressively with corticosteroid therapy for 3 months prior to the identification of KS; thus, colonic KS found on subsequent colonoscopy could represent a recog- nized complication of steroid (immunosuppressive) therapy. The other patient [16] was treated with hydrocortisone enemas prior to the diagnosis of colonic KS. The lesions of KS are characterized endoscopically as circumscribed hemorrhagic lesions of variable size, and it is well recognized that deep biopsies are required to identify the character- istic histologic findings as the tumor generally resides in the submucosa.
As HIV-infected patients are growing older, age- related colonic diseases which may mimic IBD must also be considered. Focal inflammation in the setting of diverticulosis (diverticular colitis) is being increas-
Table 3. Differential diagnosis of IBD in HIV-infected patients Infection
Bacterial colitis Cytomegalovirus
Mycobactrium avium complex l\/lycobacterium tuberculosis Amebiasis
Isospora belli Histoplasmosis
Non-Infectious Ischemia
Drug-induced colitis Peridiverticulitis
Neoplasm
Kaposi's sarcoma
ingly recognized [49]. Ischemic colitis typically pre- sents with a segmental colitis which may mimic CD or CMV colitis; however, the histologic features of ischemia are usually apparent. Colonic neoplasms may occur in HIV-infected patients including adeno- carcinoma, and colonic lymphomas may appear indistinguishable endoscopically from adeno- carcinoma. Also, mass lesions have been reported with CMV colitis due to an exuberant inflammatory response, further highlighting the importance of adequate tissue sampling [5].
We and others have described HIV-infected patients with colorectal symptoms in whom focal areas of colitis and/or ulcers have been identified and which have remained idiopathic despite an extensive histologic examination for infections and neoplasms [23, 24]. These patients typically present with ulcers which can be large, and histologic exam- ination of multiple biopsies shows granulation tissue;
rarely crypt distortion was present which could mimic IBD. These ulcerative lesions are similar to the well-recognized idiopathic ulcer of the esophagus [50].
Hing et al. [24] reported on six HIV-infected
patients with a chronic colitis presenting as a chronic
diarrhea ranging from three to more than 10 stools
per day. The CD4 counts at diagnosis ranged from
256 to 449/|il. Stool studies were negative and
colonoscopy showed a diffuse colitis consisting of
ulceration, hemorrhage, and erosions, and in one
patient mild erythema. Histologically, crypt archi-
tecture was preserved with a mixed inflammatory cell
population of plasma cells, lymphocytes and neutro-
phils. Crypt abscess, crypt destruction, and granulo-
mas were absent and CMV and HSV were adequately excluded. Four patients entered remission 6-27 months following the diagnosis, although steroids and sulfasalazine were provided. Zidovudine (AZT) was given to five patients. This report suggests that a mild inflammatory disease of the colon distinct from UC can occur in these patients. The role of anti- inflamatory therapy or HIV-directed treatment (HAART) for this entity is unclear.
An increase in inflammatory cells of the distal colon [51] as well as small bowel [52, 53] has also been documented in HIV-infected patients. The mechanism(s) for this increase in inflammatory cells of these patients also remains unexplained.
Treatment
Because of the small number of reported cases of active IBD and HIV infection, the optimal treatment for both UC and CD in these patients is unknown. In addition, the recognized variability in response to medical therapy in IBD combined with the absence of controlled trials in this setting, makes it difficult to determine if the response to standard therapy for IBD in HIV-infected patients is altered either favorably or unfavorably.
Crohn's disease
For those patients with CD in whom therapy was described and follow-up reported, the clinical response does not appear different from non-HIV- infected patients. Three reports document the clinical response to standard therapy for CD.
Corticosteroids with or without aminosalicylates were usually given, and the initial dose of prednisone was ^ 40 mg per day. Of the three patients with active CD, all responded promptly to instituted therapy, achieving a clinical remission. One patient was treated with antibiotics and hydrocortisone supposi- tories. One of these patients had multiple relapses [9], all of which were treated successfully with pred- nisone and aminosalicylates. No long-term data are available describing the efficacy of maintenance therapy with aminosalicylates, and routine endo- scopic follow-up after therapy has not been reported.
Surgical therapy has also been undertaken for CD in these HIV-infected patients. Bernstein et al. [8]
reported one patient who required surgical resection for small bowel obstruction at the time of initial diagnosis. Postoperatively the patient did well, and
6-month follow-up found no recurrence. Other patients have required colectomy for toxic mega- colon, some of whom had colonic infections complicating IBD [11,17, 22].
Ulcerative colitis
Of the reported patients with active UC and HIV, treatment was effective in the majority, at least at the initial presentation, often resulting in clinical remis- sion. One patient [11] was treated with prednisone chronically, but after HIV seroconversion, his clinical course appeared to moderate. However, the medication regimens during this later time were not specifically defined (see below). One patient [18] had experienced several recurrences of disease, all of which responded to therapy; however, one episode later in the course of HIV infection was poorly responsive to high-dose corticosteroid therapy, ultimately requiring 1 month hospitalization. His CD4 count during this severe flare fluctuated between 2601 \A and 520/jil. Toxic megacolon refrac- tory to standard therapy required surgery in a patient with minimal immune dysfunction [17]. None of the a b o v e - r e p o r t e d p a t i e n t s received a d d i t i o n a l immunosuppressive therapies such as azathioprine.
Like the patients with CD, endoscopic follow-up with biopsies was not routinely performed to best document remission.
There appear to be few therapy-related side-effects
from the use of standard treatment for IBD in HIV-
infected patients. One of the main treatment
concerns is the use of an immunosuppressive drug,
such as prednisone, in patients who are already
immunosuppressed. Of the 10 reported IBD patients
who received prednisone in doses of 40 mg or greater,
usually in combination with aminosalicylates, side-
effects were reported in three. One patient with a
history of UC was found to be HIV-infected during
an exacerbation [14]. Following 40 mg of prednisone
and sulfasalazine only a slight improvement in symp-
toms was noted. A CD4 count was not reported,
although the T cell helper suppressor ratio was low
(0.19). After receiving prednisone and sulfasalazine
for approximately 2\ months, he developed diffuse
cutaneous KS. The prednisone therapy was discon-
tinued and his cutaneous lesions improved substan-
tially. One additional patient developed widespread
KS following 3 months of high-dose steroid therapy
[17]. Candida esophagitis was reported in one
additional patient [9]. It is tempting to speculate that
corticosteroid-induced immunosuppression may
have predisposed these HIV-infected patients to the development of cutaneous KS.
Prednisone has been used for a variety of indications in HIV-infected patients, even in those who are profoundly immunosuppressed, with little apparent toxicity [54]. Importantly, precipitation of other opportunistic infections or malignancies appears to be rare. The most common reported toxicity of prednisone in HIV-infected patients is oropharyngeal and esophageal candidiasis. Endo- crinologic complications such as diabetes may occur with prednisone as in any other patient. Because of the effect on cytokine production, prednisone has been shown to decrease HIV RNA in blood, suggest- ing a potential saluatory effect [55]. In the patient with severe immune dysfunction and prior CMV infection, caution must be exercised when tapering prednisone, given the possibility of unmasking adrenal insufficiency from CMVadrenalitis.
The use of aminosalicylates should be encouraged as primary therapy as there are no specific contra- indications to their use in HIV-infected patients.
Although there are numerous drug interactions with the protease inhibitors and other antiretroviral agents, there are no reported interactions with the aminosalicylates. There are also no reports on the use of azathioprine for the treatment of refractory IBD in HIV-infected patients. Likewise, there are no studies on the use of remicade (infliximab) in this setting. The use of infliximab may be contra- indicated, however, in patients with active infection, and HIV infection has been an exclusion criterion in trials of this agent.
Given the above we recommend that HIV-infected patients be treated similarly to any other IBD patient. The use of prednisone should not necessarily be discouraged; rather the patient should be mon-
itored closely for complications. For those patients with more severe immunodeficiency and history of thrush, prophylaxis with Nystatin or oral azoles should be considered. For the patient with distal colonic disease, local therapy with enemas should be considered as first-line therapy.
Natural history
There have been tantalizing suggestions that, as HIV-related immunodeficiency progresses, remis- sion of IBD may occur. Given that IBD is character- ized by periods of remission and exacerbation, it is important, however, to place these reports in the proper perspective. James [7] reported a patient with longstanding CD disease who subsequently devel- oped HIV infection. This patient had experienced typical Crohn's symptoms on an intermittent basis for the preceding 8 years. HIV testing was performed as a routine and was found to be positive; at that time the CD4 count was 410/)il. Following the diagnosis of HIV infection the patient experienced no further symptoms of disease for the ensuing 2 years of follow-up.
Pospai et al. [13] reported four patients with moderately active CD ranging in duration from 4 to 21 years who subsequently acquired HIV infection.
In only one of these four cases, however, could the exact date of HIV acquisition be documented. In this patient in whom the timing of HIV could be precisely determined (HIV infection was linked to contami- nated blood products), multiple exacerbations had occurred over the preceding 15 years, but the patient went into apparent remission after HIV infection.
Interestingly, within 1 year of acquiring HIV infection this patient had a CD4 count, when first
Table 4. Suggested criteria for the diagnosis of IBD in HIV-infected patients
1. Since there is no gold standard for the diagnosis of IBD, a combination of clinical presentation, endoscopic findings, response to therapy and follow-up must be employed
2. Exclusion of colonic and intestinal pathogens is mandatory A. Stool studies for bacterial pathogens
B. Stool studies for parasitic diseases C. Blood cultures for mycobacteria
3. Extensive histologic examination of multiple biopsy specimens is mandatory A. Cytomegalovirus immunohistochemical staining
B. Stains for fungi, mycobacteria
4. Documentation of the characteristic histologic changes of IBD including crypt distortion and type of inflammatory cell infiltrate 5. Appropriate follow-up to document response to therapy; both endoscopic and histologic follow-up after therapy should be performed
measured, of 320/|il. In the other three cases the patients had experienced exacerbations for many years, but lasting remission was noted following the estimated time of HIV infection. The long symptom- free intervals in these three patients in whom the time of acquisition of HIV infection could not be documented and the minimal immunodeficiency, particularly early on in HIV infection, makes the relationship between remission and HIV-associated immunodeficiency highly speculative. Also, patients did not routinely undergo follow-up colonoscopic evaluation or other imaging studies to evaluate for disease activity.
Yoshida et al [10] reported one patient with UC who subsequently developed HIV infection. Follow- ing the initial diagnosis (the CD4 count was 450/ml), the patient's symptoms appeared to decline over time coincident with the fall in the CD4 count. Six years after HIV seroconversion, at a time when the CD4 count was 20/|il, the patient underwent sigmoido- scopy and biopsy for an acute diarrhea, which demonstrated cryptosporidiosis but no active inflammatory bowel disease; the patient had not received any medical therapy for IBD during the preceding 14 months. Of six patients with IBD (four UC, two CD) followed by Sharpstone etal. [11], none developed a flare of disease when the CD4 count fell below 200/^d.
Conclusions
Given the long latency between HIV infection and development of symptoms referable to AIDS, coupled with the variability in the natural history of IBD, it may be impossible to conclude that the progressive immunodeficiency of AIDS results in remission of IBD. The complex nature of the inflam- matory response in IBD would suggest that loss of CD4 cells alone may not be 'therapy' for IBD. In addition, the multitude of opportunistic infections, some of which may mimic IBD, as well as the potential for some disorders (CMV) to result in histologic changes of chronicity further complicates any apparent relationship between HIV-related immunosuppression and the course of IBD. Guide- lines for the diagnosis of IBD in the setting of HIV are appropriate (Table 4).
More intriguing is the possibility that improve- ment in immune function may exacerbate IBD in HIV-infected patients. Some of the reported patients did receive AZT therapy without apparent effect on
the IBD; however, single-agent therapy with this drug generally has little long-lasting eff'ect on immune function. Now that effective combination antiretroviral therapy is available, we may see reports of exacerbations of IBD in HIV-infected patients who receive HAART. Nevertheless, similar caveats as pointed out for the reverse situation still hold; opportunistic infections must be carefully excluded and spontaneous remissions and exacerba- tions are always a consideration. Better objective markers for active IBD are required to truly determine whether IBD can be turned off* or on by HIV-related immunodeficiency.
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