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 infectious 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 complications including those involving the gastrointestinal 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 immunodeficiency will continue unabated in developing
countries [1, 5].
Before the development of HAART, gastrointestinal 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 infections and
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 inflammatory 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 management 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 inflammatory 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 neutrophils, 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
864
Human immunodeficiency virus and inflammatory bowel disease
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 lymphocytes. 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 concentration 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, HIVinfected patients without diarrhea, and HlV-seronegative controls. No significant differences were
detected in cytokine levels among the groups with
low levels uniformly detected. 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 HIVinfected 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 assessment 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 disproportionately 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 underestimate. 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
C Mel Wilcox
865
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 characterized. 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 gastrointestinal tract do not manifest until the CD4 count
falls below 100/|il [3, 5, 35]. Thus, reports of HIVinfected patients with CD4 counts less than 100/)il
with active IBD may provide better insight into any
relationship between HIV-associated immunodeficiency 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 characteristic 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). Consistent 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-surgical, and non-caseating granulomas were reported
as present in less than half the cases either on
endoscopic biopsy or in the surgical specimen. Histologic examination was generally extensive to
exclude other diseases. However, long-term followup 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
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
*CD4 count determined years after initial diagnosis of CD.
CD4 count
230*
410
480
270*
210
100
336, 442
320, 5 0 M 6 2 , 34*
Location
Colon, terminal ileum
Colon
Colon, terminal ileum
Colon, terminal ileum
NA
Colon, terminal ileum
Colon, small bowel/rectum
Colon, terminal ileum
Human immunodeficiency virus and inflammatory bowel disease
866
developed CD, which would add further security to
the diagnosis, was rarely performed, including colonoscopic 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 extraintestinal manifestations 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 histologic examination to exclude opportunistic disorders
was not reported. Testing for HIV was not available
at the time of publication (1986), but the helpersuppressor 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 HIVinfected patients who later developed CD, the CD4
lymphocyte counts at the time CD was first documented 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
available at the time of publication [6]. One additional 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
Table 2. Reported cases of UC in HIV-infected patients
Reference
Year
No. of patients
10
96
11
96
2
2
6
14
15
18
19
20
21
22
86
90
91
92
96
97
99
NA = not available.
Sequence
CD4 count
HIV^UC
UC^HIV
HIV - . U C
HIV ^ U C
UC-.HIV
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, 130
460
270
256
462
228
283
NA
500
546
170
NA
450
930
Extent
Proctitis, NA
NA, right colon
NA
NA
Transverse colon
Pancolonic
T colon
Pancolonic
Pancolonic
Transverse colon
C Mel Wilcox
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 colonoscopy 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 (sacroiliitis, arthritis) and later uveitus with flares of
disease [21]. When described, the endoscopic appearance 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 documented, 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 AIDS patient with
suspected IBD the patient is more likely to have an
AIDS-related disorder than idiopathic IBD. In contrast, 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 immunodeficiency 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 immunodeficiency must first be staged by the CD4 lymphocyte 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 disorders [38]. Two common gastrointestinal pathogens
that occur in the setting of advanced immunodeficiency are cytomegalovirus (CMV) and Mycobacterium avium complex (MAC) which commonly
involve the colon and small bowel, respectively, and
which may mimic IBD [39-44]. In addition, some
processes may cause pathologic changes of chroni-
867
city that may suggest underlying IBD (unpublished
observations). The many reported cases of opportunistic 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 histologic 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 characteristic of UC was noted in three patients. Pseudopolyps
have not been reported as a manifestation of CMV
colitis. These findings demonstrate that the endoscopic appearance of CMV colitis may be suggestive
ofeitherUCorCD.
To best diagnose CMV colitis, multiple biopsies
(at least six) of abnormal-appearing tissue should be
obtained with close inspection of the characterisitic
868
Human immunodeficiency virus and inflammatory bowel disease
viral cytopathic effect of CMV. Immunohistochemical 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 considered 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 infection in AIDS. Usually herpes simplex virus of the
colon presents with limited anorectal disease. A
number of other opportunistic diseases could theoretically 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 followthrough showed nodularity and ulceration of the
terminal ileum characteristic of CD. However, histopathologic 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 colonoscopy. 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 recognized 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 characteristic histologic findings as the tumor generally resides
in the submucosa.
As HIV-infected patients are growing older, agerelated 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 presents 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 adenocarcinoma, and colonic lymphomas may appear
indistinguishable endoscopically from adenocarcinoma. 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 examination 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 architecture was preserved with a mixed inflammatory cell
population of plasma cells, lymphocytes and neutrophils. Crypt abscess, crypt destruction, and granulo-
C Mel Wilcox
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 antiinflamatory 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-HIVinfected 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 suppositories. One of these patients had multiple relapses [9],
all of which were treated successfully with prednisone and aminosalicylates. No long-term data are
available describing the efficacy of maintenance
therapy with aminosalicylates, and routine endoscopic 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
869
6-month follow-up found no recurrence. Other
patients have required colectomy for toxic megacolon, 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 remission. 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 refractory to standard therapy required surgery in a patient
with minimal immune dysfunction [17]. None of the
above-reported patients 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 HIVinfected 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, sideeffects 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 symptoms 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 discontinued and his cutaneous lesions improved substantially. 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
870
Human immunodeficiency virus and inflammatory bowel disease
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. Endocrinologic 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, suggesting 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 contraindications 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 contraindicated, 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, remission of IBD may occur. Given that IBD is characterized 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 developed 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 contaminated 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
C Mel Wilcox
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 symptomfree 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. Following 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 sigmoidoscopy 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.
871
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 exacerbations 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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2.
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4.
5.
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Conclusions
Given the long latency between HIV infection and
development of symptoms referable to AIDS,
coupled with the variability in the natural history of
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progressive immunodeficiency of AIDS results in
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CD4 cells alone may not be 'therapy' for IBD. In
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