Advances in Infectious Diseases, 2013, 3, 243-247
Published Online December 2013 (http://www.scirp.org/journal/aid)
http://dx.doi.org/10.4236/aid.2013.34036
Open Access AID
243
Septic Shock after Intravesical BCG Instillation—A Case
Report*
Cristóvão Figueiredo1#, Diana Póvoas1, Carlos Alves1, Alcina Ferreira1, Paulo Figueiredo1,
Teresa Carvalho2, Angélica Ramos2, Lurdes Santos1, António Sarmento1
1Infectious Diseases Intensive Care Unit, Research and Development Unit (FCT-725), Faculty of Medicine, University of Porto,
Centro Hospitar São João EPE, Porto, Portugal; 2Microbiology Laboratory of Clinical Pathology Department, Centro Hospitar São
João EPE, Porto, Portugal.
Received September 18th, 2013; revised October 15th, 2013; accepted October 20th, 2013
Copyright © 2013 Cristóvão Figueiredo et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
ABSTRACT
Bacillus Calmette-Guérin (BCG) is a live attenuated form of Mycobacterium bovis, initially used in medicine as a vac-
cination agent only. The discovery of its antineoplastic effects in bladder cancer has led to the widespread recognition
of BCG intravesical instillation as a therap eutic option. Although sepsis following BCG intravesical instillation is rare,
it is nonetheless a dreadful and potentially fatal complication. Therapy usually relies on antituberculous therapy and ste-
roids, alongside with intensive care unit admission. The authors report a case of a 67-year-old male patient who devel-
oped septic shock with multiple organ dysfunction after intravesical BCG instillation and review the currently avail-
able knowledge concerning the risk factors, diagnosis, management and prevention of BCG sepsis.
Keywords: Bacillus Calmette-Guérin; BCG; Sepsis; Shock
1. Introduction
Bacillus Calmette-Guérin (BCG) is a low-virulence my-
cobacteria originated from successive cultures of Myco-
bacterium bovis [1], and intravesical instillation of BCG
is a therapeutic option in bladder cancer [2]. Sepsis is a
rare complication of this procedure, and certain aspects
concerning its diagn ostic and treatment are still debatab le.
We report the case of a patient who developed septic
shock with multiple organ dysfunction after intravesical
BCG instillation and review the currently available know-
ledge concerning the risk factors, diagnosis, management
and prevention of BCG sepsis.
2. Case Report
We report the case of a 67-year-old male patient, with
known Alzheimer’s and cerebrovascular disease, who
had been diagnosed with a vesical urothelial carcinoma
(pT1) on February 2012 and underwent transurethral re-
section (TUR) in the following month. He began monthly
intravesical Bacillus Calmette-Guérin (BCG) instillation
on May 2012. After each session he complained of low-
grade fever, which spontaneously waned on the follow-
ing 24 - 48 h.
On May 10th of 2013 (Day 1 - D1), he presented to the
outpatient clinic complaining of persistent fever and in-
creased sudoresis for 2 weeks, after the 12th BCG instil-
lation; he denied any other symptoms. The physical ex-
amination was unremarkable, apart from being slightly
more disoriented than usual. The analytic panel revealed
an elevated C reactive protein, elevated liver enzymes
with normal bilirubin; elevated creatinine (see Table 1)
and mild leucocyturia (89 cells/µL) without any other
urinary changes. On abdominal ultrasonography, an en-
larged liver with heterogenic parenchyma was noted, sug-
gesting acute hepatitis.
He was admitted to our hospital, a urine culture for
mycobacteria was collected, and he began oral levoflox-
acin (500 mg id). His clinical condition deterio rated, and
on D6 he was admitted to the Infectious Diseases Inten-
sive Care Unit (ID-ICU) due to dyspnoea and oxygen
desaturation (86% on pulse oximetry) which did not re-
solve with oxygen supplementation. He presented ta-
chypnea (36 cpm), tachycardia (106 bpm), poor distal
*Conflict of interest: The authors have no co nf l i ct o f i n terest to declare.
#Corresponding author.

Septic Shock after Intravesical BCG Instillation—A Case Report
244
Table 1. Patients evolution before and dur ing ID-ICU admission.
Paramater ( units) Day 1 Day 6 Day 10 Day 15Day 20 Day 25
Haemoglobin (g/dL) 11.8 9.9 9.6 8.8 7.0 9.0
Leukocytes (×106/L) 6.180 17.540 7.030 4.900 4.300 5.960
Neutrophils (%) 60.8 83.7 74.8 57.6 60.2 64.4
Platelets (×109/L) 112 133 13 47 114 223
C Reactive Protein (mg/L) 135.4 139.9 188.7 40.5 56.7 52
Creatinine (mg/dL) 1.63 1.20 1.60 1.63 1.01 0.82
ALT (IU/L) 198 334 80 23 26 28
Total/Conjugated Bilirrubin
(mg/dL) 0.71/0.34 1.61/1.00 7.80/5.05 4.11/2.292.21/1.04 2.17/0.92
aPTT/PT (sec) -/- 50.2/17.3 54/15.3 32.9/13.833.3/12 -
pO2/FiO2 ratio - 53 131 223 224 200
Lactate (mmol/L) - 6.59 2.56 2.43 1.67 1.92
Comments Levo ID-ICU admission
Added RIF, INH, ETBAdded steroids Stop RIF - PRBC transfusion Stop amminergic support Discharged from ID-ICU
ALT—alanine aminotransferase; aPTT—activated partial thromboplastin time; ETB—ethambutol; ID-ICU—Infectious Diseases Intensive Care Unit; INH—
isoniazid; PRBC—1 unit of packed red blood cells; PT—prothrombin time; RIF—rifampicin.
perfusion signs and bilateral crackles on lung ausculta-
tion. The chest roentgenography revealed bilateral and
diffuse patchy infiltration, suggestive of ARDS. The ar-
terial blood gases analysis showed a pO2/FiO2 ratio of
122, along with respiratory alkalosis and hyperlactatemia
(3.74 mmol/L). Orotracheal intubation was needed and
mechanical ventilation started. Despite fluid therapy, va-
sopressor suppo rt was requir ed. Apart for norepinephr ine,
dobutamine was added due to severely depressed left
ventricular function noted on transthoracic echocardi-
ography. Besides the septic shock, he had cardiovascular,
respiratory, renal, liver, and haematological dysfunction.
Blood, urine and endotracheal aspirate were collected for
both bacteria and mycobacteria cultures and he was start-
ed on intravenous therap y with isoniazid (300 mg id), ri-
fampicin (600 mg id), levofloxacin (750 mg id) and oral
ethambutol (1200 mg id) for systemic BCG infection; in-
travenous ceftriaxone (2 g id) was added to widen anti-
bacterial coverage, since levofloxacin was apparently in-
sufficient to restrain an eventual bacterial infection.
Over the next days, deterioration of cardiovascular, he-
patic, renal and hematologic dysfunctions was observed.
On D10, rifampicin was suspended due to hepatotox icity
and steroids (2 mg/kg daily prednisolone equivalent) were
started; ceftriaxone was suspended after all bacteriologic
cultures were known to be negative. Subsequently, the
patient progressiv ely improved, with vasopresso r support
being withheld on D19; successful extubation was ac-
complished on D20. He was transferred from the ID-ICU
on D25, and was finally discharged home on D36, main-
taining oral therapy with isoniazid, ethambutol and levo-
floxacin (same dosages). Corticosteroids were stopped
after tapering.
Acid-fast auramine stain exams of urine, blood and
respiratory samples were negative. Mycobacterium tuber-
culosis complex DNA detection exam was also negative.
The broth cultures of blood, endotracheal aspirate and
urine (with Middlebrook medium and monitored by BD
Bactec™ 9000 MB and BD Bactec™ MGIT™ 960 sys-
tems) were negative.
3. Discussion
Mycobacterium bovis was isolated in 1902 by the French
veterinarian and microbiologist Edmond Nocard [1]. Ba-
cillus Calmette-Guérin (BCG) is a low-virulence myco-
bacteria originated from successive cultures of M. bovis,
resulting from the combined efforts done of Albert Cal-
mette and his assistant Camille Guérin [1]. This strain
was initially used to vaccinate cattle to prevent tubercu-
losis and later was successfully used in humans. Nowa-
days, it is implemented in many countries with a high in-
cidence of tuberculosis, mainly in the setting of routine
newborn immunization.
Apart from vaccination, BCG is also widely used in
the treatment of bladder cancer. The intravesical instilla-
tion of BCG appears to stimulate significantly the im-
mune response, inducing the production of large amounts
of cytokines that draw cytotox ic activity by natural killer
cells and cytotoxic cells against transitional cancer cells,
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Septic Shock after Intravesical BCG Instillation—A Case Report 245
diminishing the prob ability of recidivant or invasive neo-
plasia [2].
Intravesical administration of BCG can be associated
with several complications. These may be local or sys-
temic and occur early or late on the course of BCG treat-
ment. The majority of patients experience local symp-
toms (such as dysuria and frequency) within two hours of
BCG instillation, which may be accompanied by low-
grade fever and malaise. Like in the case reported, these
symptoms usually resolve within 48 hours and may be
more frequent in patients who have previously received
intravesical instillations [3]. Some authors suggest that
the occurrence of low fever and cystitis after intrav esical
instillation may be signs of a good therapeutic response
[4]. However, local complications can occur, and there
are reports of granulomatous ulceration of the glans penis,
prostatitis, epididymitis, ureteral obstruction, bladder con-
tracture and renal abscess [5].
In the majority of the intravesical BCG sepsis cases,
symptoms developed only after several instillation s. How-
ever, in a case described by Frey et al. [6], septic shock
developed rapidly after the first BCG intravesical instil-
lation in a 31-year old patient not previously immunized
with BCG. In the present case, the patient was on BCG
treatment for a year. After the last instillation (without
any known local trauma associated) he presented with
persisting fever for 2 weeks, which alerted the clinicians
for a possible complication.
BCG-related sepsis diagnosis is freq uently challenging
since symptoms are indistinct from other sepsis causes:
patients often develop high fever, chills, hypotension, dis-
orientation, disseminated intravascular coagulation, res-
piratory insufficiency, jaundice and leucopenia. Lamm et
al. [4] have suggested that fever or shivering during or
shortly after BCG intravesical instillation may b e predic-
tive for the risk of developing a severe infection.
This patient had no lower urinary tract symptoms, but
there was mild leucocyturia; persistent fever was the only
sign of possible disseminated infection, but the seem-
ingly benign clinical appearance led to assumption of
local complication, and so he began the treatment with
levofloxacin. This proved to be rather insufficient, since
he subsequently developed septic shock with multiple
organ dysf unction.
Although BCG instillations contain live attenuated
mycobacteria, the likelihood that BCG can be isolated
through culture is affected by many factors, including the
number of organisms present (which, in turn, reflects the
ability of the immune system to control infection), the
handling of the samples, and culture technique [7]. As
happened in the case described, there is no direct proof of
infection by M. bov is in almost a third of cases of serious
complications [8]. In BCG disseminated infection or sep-
sis, both the tuberculin skin test and the interferon gam-
ma release assay (IGRA) can be positive, although IGRA
performance for detection of active disease has not been
fully evaluated and should not be part of the routine di-
agnostic approach for M. bovis infection suspicion [9].
Staining of specimens for acid-fast bacilli, cultures and
PCR testing for mycobacterial DNA should be performed
in any patient with suspected disseminated BCG infec-
tion, even though all of these procedures can b e negative
in some cases. However, it is important to note that nu-
cleic acid hybridization probe assays cannot be used to
distinguish among members of the M. tuberculosis com-
plex directly from samples, since they lack sensitivity. So
the identification of mycobacteria through these techni-
ques relies on the cultural isolation of M. bovis [9].
There are no controlled studies that determined the op-
timal therapy of intravesical BCG-related sepsis. In a cli-
nically suspected case of BCG related co mplication, some
studies recommend immediate start of fluoroquinolone
therapy, since this treatment is effective against both
BCG and Gram-negative urinary pathogens [10]. Like M.
bovis, BCG is susceptible to most of the antituberculous
drugs, apart from pyrazinamide and cycloserine [11]. Iso-
niazid (300 mg id) and rifampicin (600 mg id) are usual-
ly recomm ended fo r 6 - 9 months [12,1 3].
Additionally to antituberculous therapy, some human
and animal studies have suggested potentially beneficial
effect of corticosteroid use in the treatment of severe
cases of disseminated BCG infection [12-17]. The me-
chanism related to this beneficial effect may be related to
the possible hypersensitivity reaction developed during
BCG treatment [2,12]. In the case reported, standard
treatment for septic shock was started, and the antituber-
culous scheme was broadened; nevertheless, the patient’s
status deteriorated during the next 4 days. Steroid use in
septic shock (of any aetiology) as long been controversial,
but in this case it was only after steroid therapy introdu c-
tion that the patient slowly (yet steadily) improved. We
started with 2 mg/kg/daily prednisolone equivalent, tape-
ring the dose to half every 3 - 4 days until suspension
after 23 days. It’s rather tempting to attribute the initial
improvement of this patient to the anti-inflammatory ef-
fect of steroids. Yet, mixed outcomes and recognized
side-effects associated with steroids lead to uncertainties
concerning its recommendation. Besides, there have been
descriptions of clinical aggravation after steroid suspen-
sion [13]. Although potentially helpful in some cases of
septic shock, steroid therap y in the setting of BCG sepsis
remains debatable. With the increasing development of
anti-inflammatory therapies (especially monoclonal an-
tibodies), perhaps new and tailored-made therapies could
have beneficial impact on this rare yet potentially fatal
complication.
Since optimal therapy is still uncertain, measures to
prevent infection by BCG are of paramount importance.
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Septic Shock after Intravesical BCG Instillation—A Case Report
246
These include deferral of BCG instillation in patients
with difficult bladder catheterizations, cystitis, or persis-
tent haematuria following transurethral resection of the
bladder tumour [13]. Furthermore, BCG intravesical in-
stillations should be permanently suspended in patients
who develop infectious complications requiring antitu-
berculous therapy. Drug prophylaxis has also been tested.
Isoniazid (either 300 mg id, or concurrent administration
with intravesical instillation of BCG) showed no efficacy
in preventing BCG related complications and suggested
contributing to lesser efficacy of BCG instillation treat-
ment, since live organisms seem to be required for the in-
stillation’s immunological effect [18,19]. Ofloxacin ad-
ministered after each BCG instillation reduced the in-
cidence of severe local reactions and the need for antitu-
berculous therapy; a recent study using prulifloxacin re-
ported similar findings [20]. Somehow, this strategy
doesn’t seem to affect the efficacy of BCG anti-neoplasic
treatment. Yet, present data is not sufficient for a clear
recommendation about drug prophylaxis.
4. Conclusion
BCG-induced sepsis after intravesical instillation for
bladder cancer is a rare complication. Pathophysiology
remains largely unknown, but BCG’s low virulence sug-
gests that an immunological hipersensitivity reaction pro-
bably plays a role. In severe cases, high-dose steroids
could be added to antituberculous therapy and the corner-
stone of BCG-induced sepsis. Measures to prevent BCG
infection should be strictly observed.
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