Authors: Karakosta P. MD, Aslanidis Th. MD, PhD, Thoma G. MD, Agaliadou-Dioritou U. MD, PhD
Intensive Care Unit,St. Paul General Hospital, Thessaloniki,Greece
Intravesical bacillus Calmette-Guerin (BCG) therapy, recommended for superficial bladder tumors, triggers side effects in fewer than 5% of patients. Yet, when encountered, high level of suspition and early detection is essential for their succesfull management. In the present article, we present a case of severe sepsis and Steven Johnson syndrome in a male patient after intravesical BCG instillation.
Intravesical instillation of Bacillus Calmette-Guérin (BCG) is frequently used as the treatment of choice for carcinoma in situ and non-invasive high-grade superficial tumor of the urinary bladder1. BCG is a live attenuated strain of Mycobacterium bovis and is the most widely used intravesical agent2. Adverse events occur in fewer than 5 % of cases, ranging from mild local symptoms to severe sepsis and death1-3. In the present article, we report a case of successful management of septic shock with concomitant Steven Johnson syndrome after intravesical BCG instillation and perform a short review of the relevant literature.
An 83-yearold man with a history of bladder cancer (ICD10-C67), treated initially with transurethral resection and subsequent intravesical BCG instillations, presented to our hospital for fever (38ºC),general fatigue and hematuria, soon after the second BCG instillation.No prophylactic isoniazid had been given during their BCG instillation treatment.His medical history also included arterial hypertension. (ICD10-I10) and chronic kidney disease stage IIIa (ICD10 –N18.2) with bad compliance to therapy.
Upon hospital admission, he further developed dyspnea with tachypnea (respiratory rate of 25 /min) with measured oxygen saturation SpO2 82%. Arterial blood gases exam revealed severe acidosis (pH 7.185, PaCO2 41mmHg and PaO2 52.6mmHg), with worsening hemodynamics (blood pressure of 60/35 mmHg and heart rate of 105 bpm)and gradually worsening of his mental status (Glasgow Coma Scale E3/V1/M4).Epidermolysis with blisters inhis body and ulcers in his mouth were also noted.
An emergency dermatology consultation set the diagnosis of Steven Johnson syndrome. Management with oxygen therapy, fluids infusion and intravenous vancomycin and clindamycin was not effective; thus the patient was intubated and transported to ICU for further management 6 hours later.
On ICU admission the patient had a severity APACHE IV score of 160/286; high fever (39.30 C).Modification of therapy upon admission included vasopressors (noradrenaline) infusion, broad spectrum intravenous antibiotics (levofloxacin, meropenem and teicoplanin), pulse steroid therapy, intravenous fungustatin and cream mometazone with septomide spray for the ulcers in his body.
Microbiological cultures from blood, bronchial secretions and urine turn out negative. Interferon-gamma (IFN-γ) release assay (QuantiFERON TB Gold test) for Mycobacterium tuberculosis was also negative. Yet, Tuberculosis- Polymerase Chain Reaction (PCR) test of urine was positive and mycobacterial therapy with rifampicin-isoniazid was also added. The course of its Laboratory exams values are in Table 1.
Table 1.Laboratory values course.
Hct – haematocrit (%), WBC – white cells (k/μl, PLT–platelets (k/μl), CRP – c reactive protein (mg/dl), PCT – procalcitonin (ng/ml), Bil – bilirubin (tot-total, dir-direct) (mg/dl), LDH – lactate dehydrogenase (iu/ml), γ – GT – gamma glutaryl transpherase(iu/ml), SGOT – Serum glutamicoxaloacetic transaminase (iu/ml), SGPT- Serum glutamicpyruvic transaminase(ui/ml), ALP – alcaline phosphatase (ui/ml), Cr – creatinine (mg/dl), Ur – urea (mg/dl), CPK – creatine phosphatase (mg/dl).
The patient’s general condition improved very slowly, and he was finally discharged from ICU after 27 days.
BCG has been used for more than 40 year, with positive results in the majority of cases2. Several BCG strains have been developed since the original strain of 1921; yet there is no consensus about the appropriate use of each strain2,4. The mechanism of action of BCG therapy is complex and incompletely understood. The general concept, as reported by Fuge et al, can be divided in 3 stages:
1) infection of urothelial and/or bladder cancer cells, mediated by fibronectin and integrins
2) induction of immune response, mediated by various cell types (granulocytes, T helper (Th) cells, natural killers (NK) and macrophages), various immune molecules (major histocompatibility complex MHC class I, CD4+) and various cytokines (interleukin IL-1, IL-2, IL-6, IL-8, IL-10, IL-12, IL-17, tumour necrosis factorTNF-α, interferon IFN- γ) ; and
3) induction of antitumor effects via acquired (Th1, CD4 and CD8 T cells) and innate (via Th2, NK, macrophages and neutrophil recruitment) immunity2,5.
BCG administration may be associated with a broad spectrum of local and systemic side effects. Most cases include lower urinary tract irritation symptom (25-75%) while less frequent are fever over 39.5oC (2.9%) and haematuria (1%), granulomatous prostatitis, pneumonitis and/or hepatitis, arthralgia, epididymitis, renal abscess, contracted bladder or ureteral obstruction6. Severe BCG sepsis and rash are rare complication (0.4% and 0.3% of the cases respectively)6. Since BCG antitumor mechanism is unclear, the mechanism behind its infectious complications is also a matter of debate. One hypothesis considers these complications as hypersensitivity reaction (also called cytokine storm) based upon the presence of granulomas and the absence of recoverable organisms and a positive response to glucocorticoids. By contrast, other reports demonstrated viable organism in various tissues, supporting the idea of ongoing infection6-7. Despite the one that prevails, it seems that both mechanisms play a key role in the pathogenesis of BCG therapy complications. The latter is what we suggest that happened in our case, where Steven Johnson syndrome empowers cytokine storm hypothesis while PCR test confirms M.bovis presence. Literature displays large diversity in the management of such cases: antituberculosis therapy alone, antituberculosis therapy and surgery, nonsteroidal anti-inflammatory drugs alone, corticosteroid therapy alone, surgical therapy alone andother regimens9. However, the combination of antituberculosis therapy and systemic corticosteroids seems to prevail.The most common combination include isoniazid, rifampicin and ethambutol with or without pyrazinamide, followed by the combination of rifampicin – isoniazid8-9.
Disseminated infection is a very rare complication of intravesical BCG therapy. Nevertheless, clinician should always have it in mind, as early diagnosis is essential for successful management.
- Babjuk M, Burger M, Compérat EM, et al . European Association of Urology Guidelines on Non-muscle-invasive Bladder Cancer (TaT1 and Carcinoma In Situ) – 2019 Update Eur Urol. 2019 Nov;76(5):639-657.
- Alhunaidi O, Zlotta AR. The use of intravesical BCG in urothelial carcinoma of the bladder. Ecancermedicalscience. 2019; 13:905.
- Privé BM, Bruins HM, Mulder B, et al. Complications after intravesical BCG instillationNed Tijdschr Geneeskd. 2019;163. pii: D3277.
- D’Andrea D, Gontero P, Shariat SF, et al. Intravesical bacillus Calmette-Guérin for bladder cancer: are all the strains equal? Transl Androl Urol. 2019 ;8(1):85-93.
- Fuge O, Vasdev N, Allchorne P, et al. Immunotherapy for bladder cancer. Res Rep Urol. 2015 May 4;7:65-79. doi: 10.2147/RRU.S63447.
- MacLeod LC, Ngo TC, Gonzalgo ML. Complications of Intravesical Bacillus Calmette-Guérin Can Urol Assoc J 2014;8(7-8): e540-4.
- Gerogianni I, Gravas S, Gourgoulianis K, et al. Disseminated Bacillus Calmette-Guerin infections after intravesical therapy. Indian J Med Microbiol. 2014;32(4):438-9.
- O’Donell MA, Infectious complications of intravesical BCG immunotherapy. Uptodate 2018. Available from :https://www.uptodate.com/contents/infectious-complications-of-intravesical-bcg-immunotherapy (accessed 10/01/2020)
- Pérez-Jacoiste Asín MA, Fernández-Ruiz M, López-Medrano F, et al. Bacillus Calmette-Guérin (BCG) infection following intravesical BCG administration as adjunctive therapy for bladder cancer: incidence, risk factors, and outcome in a single-institution series and review of the literature. Medicine. 2014;93(17):236-54.
Authors have Karakosta P., Aslanidis Th., Thoma G., Agaliadou-Dioritou U. have no conflicts of interest or financial ties to disclose.
Paschalia Karakosta MD,
3 Viopoulou str , PC 55132,Thessaloniki,Greece.