Journal of Pharmacy and Pharmacology 6 (2018) 130-135

doi: 10.17265/2328-2150/2018.02.003
D DAVID PUBLISHING

Colonic Bleeding Due to Histoplasma and

Mycobacterium Coinfection in Renal Transplant Patient

Arthur Ivan Nobre Oliveira, Luiz Ricardo Pinheiro de Santana, Cicelys Andreina Malave, Flair Jose Carrilho and
Andre Zonetti de Arruda Leite
Department of Gastroenterology, Division of Clinical Gastroenterology and Hepatology, Hospital das Clínicas - University of Sao
Paulo School of Medicine, Sao Paulo 05403-010, Brazil

Abstract: Introduction: Histoplasmosis is a rare infectious condition caused by the fungus Histoplasma capsulatum that can be
presented from asymptomatic to severe forms. Tuberculosis, still an endemic infection in some developing countries, can also have
variable clinical presentations. Both diseases involve the lungs mostly, but in immunocompromised patients, especially those with
advanced HIV infection and transplant patients, disseminated forms are more frequently found. Gastrointestinal involvement is
unusual, and digestive bleeding is an even rarer complication. Case presentation: We report the case of a 39-year-old female who was
diagnosed with a Mycobacterium tuberculosis and Histoplasma capsulatum coinfection occurring 11 years after a
living-donor-related renal transplant. The patient presented a severe gastrointestinal bleeding caused by an ulcer in the ascending
colon. She improved after a combined treatment with tuberculostatic and fungicidal drugs. Conclusions: Simultaneous
gastrointestinal involvement by histoplasmosis and tuberculosis, presenting as severe digestive bleeding, with minimal respiratory
symptoms associated, make this an extremely rare case and a diagnostic challenge. Therefore, it is important to keep a high clinical
suspicion of opportunistic infection, especially in immunocompromised patient who presents with LGB.

Key words: Disseminated histoplasmosis, intestinal tuberculosis, colonic ulcer, lower gastrointestinal bleeding, renal transplant.

1. Introduction asymptomatic to disseminated disease, and only a few

cases reported as LGB [3]. On the other hand,
LGB (lower gastrointestinal bleeding), currently
tuberculosis is still an endemic disease in developing
defined as bleeding originating distal to the ileocecal
countries, which involve primarily the lung, but also
valve, is a frequently self-limited condition, but it can
can affect different organs, especially in
be severe and require specific therapeutic intervention
immunocompromised patients, when it may be
in up to 15-20% of times [1]. Diverticulosis is the
associated with a more severe disease. Even so, the
leading cause of LGB, mainly among the elderly,
bowels are rarely affected (less than 2%), mostly
followed by vasculopathies and then by inflammatory
causes [2]. Infections are rarely related to clinically associated with the pulmonary form Ref. [4].
significant bleeding (less than 5%), being more Intestinal coinfection by histoplasmosis and
relevant among immunocompromised patients [1]. tuberculosis has been rarely reported, and it carries a
Histoplasmosis is a rare infectious condition that significant prognostic and therapeutic burden.
usually affects immunocompromised patients, mostly Intestinal bleeding caused by opportunistic infectious
with advanced HIV infection, and secondly disease is even more unusual. The aim of this report is
transplants patients. It presents in variable forms, from to reinforce the importance of systematic search for
opportunistic infections in immunocompromised

Corresponding author: Arthur Ivan Nobre Oliveira, M.D.,
patients who present with an undetermined LGB
research fields: gastroenterology, hepatology and endoscopy. associated with unusual acute lesion in the intestine.
 Colo
onic Bleeding
g Due to Histo
oplasma and Mycobacterium Coinfection in Renal T
Transplant Pa
atient 131

2. Case Prresentation wass 57.2 mg/L. Serum album min was 2.4 g/dL (3.5 too
5.5 g/dL), creatinine miildly increassed, but a
The patieent is a 39-year-old fem
male, from São
dispproportionatee raise in bloood urea. Liv ver enzymess
Paulo—Brazzil, who hadd long been diagnosed with
w
werre normal. Im mmunodeficieency virus (H HIV) test wass
SLE (systemic lupus erythematosuus) and arterial
neggative. Othher viral serologic tests forr
hypertensionn. She had a renal trannsplant 11 years
y
cytoomegaloviruss (IgG and IIgM), hepatitis B and C
before from a living donoor, but had developed chrronic
viru
us were all neegative.
antibody m
mediated reejection and returned to
Volemic
V resuscitation wass promptly peerformed andd
hemodialysiis eight yeaars later. She
S was takking
fourr packed redd cells were transfused. Spontaneouss
prednisone and
a everolimuus as immunoosuppressantss.
cesssation of thhe intestinal bleeding haappened stilll
She first presented
p witth intermittennt abdominal pain during her initiall assessment.
moderately severe fouur weeks before hosppital Right
R after cllinical improvvement, uppeer endoscopyy
admission, and a weighht loss of abbout 10% off her wass performed, with no significant abnormalities
a s
usual body weight
w in thee meantime. She
S was admiitted foun nd. Colonosccopy revealedd a large single ulceratedd
after a suddden and massive lower inttestinal bleedding, lesiion proximallly in the ascending colon, whichh
with hemoddynamic insstability. At admission, she invo olved the illeocecal valvve and overr 1/3 of thee
looked seveerely ill, thhe heart ratee was 110/m
min, muccosa round surface (Figg. 1). The ulcer had a
respiration rate 24/min,, temperaturre 37.1 °C, and hard dened consisstency and iits bed was covered byy
blood presssure 80/54 mmHg.
m Thee patient loooked fibrrin and hematin. Numeroous biopsies were takenn
emaciated; lung ausculttation revealed bilateral fine fromm the edges and
a bed of thee lesion.
crackles, annd the abdom
men was diffuusely tender, but A abdominaal computed tomography
An y (CT scan))
without anyy masses; no
n other abnnormalities were
w reveealed pariettal thickeninng of the cecum andd
found. asceending colon, which were narrowed, an nd associatedd
Laboratorry investigatiions upon admission reveealed regiional lymphaadenomegalyy up to 20 mm, a mildd
mia (hemoglobbin 5.0 g/dL,, hematocrit 0.16
severe anem spleenomegaly, a normal asppect graft kiidney in thee
L/L), platelet count 1444,000/mm3 and
a WBC (w white righ
ht pelvis, andd minimal asscites (Fig. 2A). 2 A chestt
blood cell) count was 8,100/μL with w a neutroophil CT scan r
revealed nnumerous centrilobularr
count of 82%
%. ESR (erythhrocyte sedim
mentation ratee) of miccronodules inn the lower lobes, with a branchingg
80 mm at thhe end of 1 h and CRP (C--reactive prottein) disttribution and sequelae
s calciifications amidst (Fig. 2B).

Fig. 1 Colon
noscopy revealling an ulcerated lesion in thee ascending co
olon, which invvolved the ileoccecal valve.
132 Colo
onic Bleeding
g Due to Histo
oplasma and Mycobacterium Coinfection in Renal T
Transplant Pa
atient

Fig. 2 (A) Coronal

C CT abbdomen image demonstrates a sub-stenosin ng parietal thiickening of thee cecum. (B) Axial
A CT chestt
image revealiing reticulonod
dular infiltratees with tree-in--bud (branchin
ng).

Fig. 3 (A) Biopsy

B wing active granulomatous coolitis, with fungal structures characteristicc
of the coolonic ulcerateed lesion show
of Histoplasm
ma capsulatum and also positive for acid-allcohol fast bacilli. (B) Immunnohistochemistry for cytomeegalovirus wass
negative and positive for an
nti-BCG in macrophages.

Acid-alcoohol fast baacilli in thee sputum were w Thus,

T it was established a diagnosis of coinfectionn
negative. Cuultures takenn from periphheral blood were
w by H. capsullatum and M. tubercu ulosis, withh
also negativve. However,, the analysiss of the bioppsies dissseminated dissease (lung aand GI tract) complicatedd
taken from m the colonnic lesion revealed acctive by a colonic ulceer and severee intestinal bleeeding.
granulomatoous colitis, with funngal structtures The
T initial treatment
t w
was the quaadruple drugg
characteristiic of Histoplaasma capsulaatum, and it was regiimen with riifampin, isonniazid, pyrazzinamide andd
also positive for acid-allcohol fast bacilli
b (Fig. 3A).
3 ethaambutol for tuberculosiss, lasting 8 weeks, andd
Immunohisttochemistry for cytom megalovirus was intrravenous liposomal amphotericin n B forr
negative; itt turned outt positive when
w tested for histtoplasmosis during
d 14 daays. All drug gs were welll
anti-BCG (M M. bovis) inn macrophages (Fig. 3B)). A toleerated by thee patient. Orral itraconazo ole was thenn
tissue PCR (polymerase chain reaction) was posiitive starrted after thhe first 2 wweeks in sub bstitution forr
for Mycobaccterium tuberrculosis. amp photericin, anda rifampin with isoniazid weree
 Colonic Bleeding Due to Histoplasma and Mycobacterium Coinfection in Renal Transplant Patient 133

maintained after 8 weeks. A close outpatient Histoplasmosis is a systemic mycosis caused by the
follow-up was done due the well-known interaction of agent Histoplasma capsulatum, a dimorphic fungus
rifampin with itraconazole. Triple immunosuppression that dwells as a mold in soils contaminated by feces of
was withdrawn, and monotherapy with prednisone birds and bats. Its pathogenic mechanism involves the
20 mg daily was kept. Tuberculostatic drugs were inhalation of propagules and initial lung infection,
maintained for a total of 4 months after induction forming local granulomata, and also at distant sites
phase and itraconazole for a total of 12 months. after hematogenous dissemination [6, 7].
The patient greatly improved during the following Immunocompetent hosts usually have asymptomatic
weeks; the abdominal pain vanished and she gained or subclinical infection, recovering without medical
weight; intestinal bleeding did not recur. Minor intervention. Histoplasmosis as a syndrome is
asymptomatic liver enzymes elevation occurred classically seen in immunocompromised patients and
during treatment (AST and ALT up to twice the is likely to present as an acute or chronic pulmonary
normal reference value), but resumed to their normal condition, in the form of pneumonia, pulmonary
value afterwards. Repeated CT scans upon completion nodules or cavitary lung disease. Some patients,
of treatment revealed significant reduction of the however, might develop extrapulmonary or
colonic thickening and of the lymphadenomegaly, as disseminated disease, with a diversity of clinical
well as of the lung findings. She was enrolled again forms involving mostly the liver, spleen, bone marrow,
for a new renal transplant. skin, adrenal glands, central nervous system, and the
digestive tract [7].
3. Discussion
Gastrointestinal clinically manifest disease is
Lower gastrointestinal bleeding is rarely associated unusual and occurs in 3 to 12% of cases, usually in the
to infectious causes, representing only a small fraction disseminated form, even though necropsy series report
of cases in the general population [2]. Data about LGB it in up to 70%, which evidences subclinical
in immunocompromised patients are not well reported, involvement most at the times [8]. Chronic diarrhea
but opportunistic infections in the gastrointestinal tract associated to systemic symptoms, such as fever and
certainly turn out to be more prevalent in this group. weight loss, is the most common clinical
Opportunistic infections are considerably common manifestations, but severe complications might also
complications in immunosuppressed patients, such as occur, like obstruction, perforation and bleeding.
those with advanced HIV infection and solid organ Endoscopic findings vary from non-specific
transplants. The patient in the current case was a renal inflammatory signs to extensive ulcerated and
transplant who had been taking several stenosing lesions. The association of histoplasmosis
immunosuppressant drugs for over 10 years when the and renal transplant is well reported and the peak
colonic bleeding occurred. Investigation revealed an incidence occurs in the first two years. Mortality rates
ulcer as the source of bleeding, and its cause was a reach up to 10% of cases [9]. Colonic involvement is
rare and unexpected coinfection by histoplasmosis and rare and even more unusual presenting as a severe
tuberculosis, making this a diagnostic and treatment digestive bleeding [10].
challenge. The only well documented case that has Diagnosis can be established by means of specific
been published up to now with a similar presentation serological tests, the finding of the fungus at
was in an HIV patient with advanced disease [5]; to our histopathological examination or, in disseminated
knowledge, there are no reported cases in transplant disease, on bone marrow examination or tissue culture,
patients. which could take, however, up to 4 to 6 weeks for the
134 Colonic Bleeding Due to Histoplasma and Mycobacterium Coinfection in Renal Transplant Patient

final result [3]. On histological examination, the individualized, though Refs. [9, 11]. Colonic
typical finding is a sarcoid-like epithelioid granuloma; tuberculosis is treated the same way as its pulmonary
yeasts can be observed inside phagocytic cells with form, with 6 to 9 months (which can be extended)
special stains like Grocott (methenamine silver) and duration course of the quadruple drug regimen:
PAS (periodic acid Schiff) [11, 12]. Serologic tests for rifampin and isoniazid throughout the entire treatment,
the histoplasmin antigen might yield false-negative and pyrazinamide and ethambutol in the first two
results in disseminated disease in months. It’s advised that treatment in renal transplant
immunocompromised patients. The patients be done likewise. Alternative regimens can be
radioimmunoassay antigen detection is another widely undertaken according to adverse effects of the drugs
used method, with a reported sensitivity of up to 85% [13].
in blood and 95% in urine [10]. It is important to keep in mind that rifampin, in
TB (tuberculosis) has a pathogenic mechanism spite of being the preferred drug to treat tuberculosis,
similar to histoplasmosis, affecting preferably is a strong cytochrome P450 inducer, decreasing
immunocompromised patients. It is considered a serum levels of itraconazole and interfering with its
major opportunistic infection in transplant patients, efficacy, as well as with some immunosuppressants
presenting in a diversity of forms. Most cases are like calcineurin inhibitors and sirolimus [15, 16]. An
originated from the reactivation of a latent infection alternative regimen including quinolones, like
by the agent Mycobacterium tuberculosis, but up to levofloxacin, can be done with adequate efficacy, and
5% of patients acquire it from an infected donor. there are some reports with favorable outcomes in
Among solid-organ transplant patients, disseminated renal transplants [17]. In our case, the patient had a
or extrapulmonary disease occurs in approximately satisfactory evolution with the four-drug anti-TB
one third to half of all cases [13]. Intestinal medication (rifampin, isoniazid, pyrazinamide and
tuberculosis, a very rare form (less than 2% of cases), ethambutol), associated with amphotericin B followed
can be asymptomatic or presented as severe ulcerative by itraconazole, not developing any relevant side
colitis, complicating with intestinal obstruction or effects that caused further harm.
bleeding. In a Brazilian series with more than 7,000
4. Conclusions
renal transplant patients, eight developed intestinal
tuberculosis, and three of them presented lower Colonic bleeding in immunosuppressed patients
gastrointestinal bleeding, which demonstrates that this may be caused by much more diverse pathological
is an exceptional form of the disease [14]. conditions than in the rest of the population, and could
Histoplasmosis treatment is done with antifungal be the first clue to search for an underlying
agents like amphotericin B, preferably lipidic opportunistic infection. Even though emergency
formulations because of their lower potential for therapy for the source of bleeding might not differ from
causing renal damage, or azoles, itraconazole being the remaining situations, the delay to correctly
more effective than fluconazole. In disseminated or diagnose and treating the causative agent can result in
severe forms of the disease, an initial course of serious consequences and negative impacts on the
amphotericin, lasting from 14 days to two months, is prognosis of the patient. In the light of this, a high
preferred, depending on the severity of the condition clinical suspicion and a systematic search for
and tolerability of the patient. An oral course of opportunistic infections in immunocompromised
itraconazole is carried out in the sequence, lasting at patients who present with an undetermined LGB are
least 12 months; its total duration is to be advised, even in cases of unusual presentations.
 Colonic Bleeding Due to Histoplasma and Mycobacterium Coinfection in Renal Transplant Patient 135

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