Septic Shock after Intravesical BCG Instillation—A Case Report

doi:10.4236/aid.2013.34036

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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.

Email: #[email protected]

Received September 18th, 2013; revised October 15th, 2013; accepted October 20th, 2013

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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