John B. Eifler, MD
Michael S. Cookson, MD
BASICS
DESCRIPTION
• BCG sepsis: Potentially life-threatening event secondary to intravasation of intravesical BCG resulting in cardiovascular collapse and acute respiratory distress
– Possible etiologies include hypersensitivity reaction and bacterial sepsis
• “BCG-osis” is a term used to refer to disseminated disease in patients treated with BCG
– The lungs and liver are typically involved
– Patients are usually hemodynamically stable
EPIDEMIOLOGY
Incidence
• >95% of patients treated with BCG have no significant morbidity (1).
• 1 in 15,000 patients treated with intravesical BCG will develop BCG sepsis (2).
• 10 reported deaths due to BCG sepsis (3).
Prevalence
N/A
RISK FACTORS
• Inadequate delay after transurethral instrumentation (TURBT or bladder biopsy)
• Traumatic catheterization or gross hematuria at time of intravesical instillation
Genetics
N/A
PATHOPHYSIOLOGY
• BCG is live attenuated Mycobacterium bovis
• Intravasation of BCG through damaged urothelium with subsequent systemic response
• Symptoms may be related to mycobacterial infection and/or hypersensitivity reaction
ASSOCIATED CONDITIONS
• Recent transurethral instrumentation
• Traumatic catheterization
• Concomitant UTI
• Age >70
GENERAL PREVENTION
• The following will minimize the risk of BCG sepsis; however, no strategy has been shown to be effective at eliminating the risk (2,4)
– Defer installation of BCG at least 2 wk after instrumentation
– Abort instillation if hematuria or traumatic Foley catheter placement
– Do not treat with active UTI
– Avoid BCG in immunocompromised host
– BCG cystitis (see below): Delay future instillations until complete resolution of symptoms
– BCG sepsis: Avoid any future BCG instillation
DIAGNOSIS
HISTORY
• BCG cystitis: Dysuria, frequency 2–4 hr after installation +/– low-grade fever, malaise, hematuria
– Typically resolves within 48 hr
• Regional infection is common though often asymptomatic (eg, 75% develop granulomatous prostatitis) and distant infection (hepatitis, osteomyelitis, pneumonitis) may occur
• Symptoms often occur within 2 hr of instillation but may occur years after therapy
• Symptoms of systemic infection: Intermittent fever >39°C (102.2°F) with drenching night sweats lasting >48 hr
• BCG sepsis: Fever, rigors, progressing to vascular collapse and respiratory distress
– Often occurs within hours of instillation
PHYSICAL EXAM
• BCG sepsis
– High fevers (>38.5°C/101.3°F) within 2 hr of treatment, resembling gram-negative sepsis
– Hypotension/shock physiology
• BCG cystitis
– Suprapubic tenderness to palpation
– Hematuria
– Low-grade fevers
DIAGNOSTIC TESTS & INTERPRETATION
Lab
• Mild/moderate symptoms
– Urine culture
• Severe symptoms (Sepsis, severe cystitis symptoms >48 hr)
– Urine, blood cultures
– Liver function tests to assess for hepatitis
– CXR to assess for pneumonitis
– Acid-fast testing of urine
– Consider PCR testing for mycobacterial DNA if disseminated BCG suspected
• Coagulation studies: PT/PTT/fibrinogen if DIC suspected
Imaging
See “Lab”
Diagnostic Procedures/Surgery
See “Lab”
Pathologic Findings
• Noncaseating granulomas
– May be found in lung, liver, bone, prostate, kidney, epididymis
DIFFERENTIAL DIAGNOSIS
• Post-BCG bacterial cystitis
• BCG cystitis (cytokine release without intravasation of BCG)
• Gram-negative sepsis
TREATMENT
GENERAL MEASURES
• Consultation with infectious disease specialist is recommended for septic patients (2,4)
• If antitubercular therapy required, intravesical BCG should be discontinued (2)
MEDICATION
First Line
• Mild/moderate symptoms including low-grade fevers <48 hr (BCG cystitis) (2,4,5)
– Analgesics
– NSAIDs
– +/– Fluoroquinolone
Such as levofloxacin 500 mg/d
Helpful for bacterial cystitis and has mild antitubercular activity
• Antitubercular medications should be initiated for signs of sepsis or severe cystitis symptoms >48 hr (2 – 5)
– Typically isoniazid 300 mg/d and rifampin 600 mg/d for 3–6 mo
– For solid organ involvement, ethambutol 15 mg/kg/d added
– BCG resistant to cycloserine and pyrazinamide
– Prednisone 40 mg/d recommended for septic shock or if hypersensitivity reaction suspected
Second Line
N/A
SURGERY/OTHER PROCEDURES
Not indicated; supportive care only
ADDITIONAL TREATMENT
Radiation Therapy
N/A
Additional Therapies
N/A
Complementary & Alternative Therapies
N/A
ONGOING CARE
PROGNOSIS
Good if treatment initiated in timely manner
COMPLICATIONS
Solid organ involvement
FOLLOW-UP
Patient Monitoring
ICU admission with invasive monitoring for BCG sepsis
Patient Resources
N/A
REFERENCES
1. Lamm DL. Efficacy and safety of bacille calmette-guerin immunotherapy in superficial bladder cancer. Clin Infect Dis. 2000;31(suppl 3):S86.
2. Lamm DL, van der Meijden PM, Morales A, et al. Incidence and treatment of complications of bacillus Calmette-Guérin intravesical therapy in superficial bladder cancer. J Urol. 1992;147:596–600.
3. Rawls WH, Lamm DL, Lowe BA, et al. Fatal sepsis following intravesical bacillus Calmette-Guérin administration for bladder cancer. J Urol. 1990;144:1328–1330.
4. Jones JS, Larchian WA. Non-muscle-invasive bladder cancer (Ta, T1, and CIS). In: Wein AJ, Kavoussi LR, Novick AC, Partin AW, Peters CA, eds. Campbell-Walsh Urology. Vol. 3. Philadelphia, PA: Elsevier; 2011:2343–2346.
5. Durek C, Rüsch-Gerdes S, Jocham D, et al. Sensitivity of BCG to modern antibiotics. Eur Urol. 2000;37(suppl 1):21–25.
ADDITIONAL READING
• Gonzalez OY, Musher DM, Brar I, et al. Spectrum of bacille Calmette-Guérin (BCG) infection after intravesical BCG immunotherapy. Clin Infect Dis. 2003;36:140.
• Mehta AR, Mehta PR, Mehta RL. A cough conundrum in a patient with a previous history of BCG immunotherapy for bladder cancer. BMJ Case Rep. 2012;2012.
See Also (Topic, Algorithm, Media)
• Bladder Cancer, General
• Bladder Cancer, Nonmuscle-Invasive Bladder Cancer (Ta, T1).
• Bladder Cancer, Urothelial, Superficial Carcinoma In Situ (CIS) (NMIBC)
• Urosepsis
CODES
ICD9
• 038.8 Other specified septicemias
• 995.91 Sepsis
• 999.39 Infection following other infusion, injection, transfusion, or vaccination
ICD10
• A41.89 Other specified sepsis
• T80.29XA Infct fol oth infusion, transfuse and theraputc inject, init
CLINICAL/SURGICAL PEARLS
• Patients undergoing intravesical BCG therapy who have traumatic catheterization or gross hematuria should delay therapy until symptoms resolve.
• Patients with high fever (>38.5°C/101.3°F) or severe cystitis symptoms lasting >48 hr should be hospitalized and undergo additional testing.