Short summary

This project aims to describe the epidemiology of BCG infections after intravesical instillation in Denmark 2000-2017, including incidence, risk factors and course of BCG infection. Insufficient knowledge of BCG infections may contribute to inaccurate and delayed diagnostics and treatment. This study will provide important new overall knowledge of the epidemiology of BCG infections and suggest future strategies to decrease morbidity. 

Rationale

Bacillus Calmette-Guerin (BCG) is attenuated stain of the tuberculosis bacteria, Mycobacterium bovis, which in addition to its use as a vaccine, also is used as effective immunotherapy in bladder cancer.

Intravesical BCG instillation is the most effective immunotherapy for superficial bladder cancer. Though often well-tolerated, BCG can induce various side effects, as well as local and systemic BCG infections. BCG organisms might persist in the urinary tract for more than a year and provide a prolonged risk of subsequent local or disseminated infection. Current knowledge about infectious complications after BCG treatment comes primarily from individual reports.

We hypothesize that BCG infection is an overlooked disease, that most cases of BCG infections are local infections of the genitourinary tract and that the incidence of BCG infections is closely linked to the number of intravesical BCG instillations. Furthermore, we expect that the highest incidence will be observed among patients with co-morbidities, alcohol- and tobacco consumption and immunosuppression.

Study objectives:

• To study the disease incidence among adults stratified by age and sex
• To examine the duration of time from intravesical BCG treatment to disease and describe the manifestation of BCG infection
• To describe symptoms, time from symptoms to diagnosis, treatment, contacts to physician, hospital admission, blood tests results and pathology results
• To investigate whether age, sex, ethnicity, co-morbidities, tobacco and alcohol are risk factors for disease
• To investigate whether the risk of BCG infection is proportional with the number of intravesicular BCG treatments
• To explore the treatment and prognosis of BCG infection
• To investigate criteria for "BCG disease" vs. local reaction / colonisation 

Description of the cohort

The study will be carried out as a nationwide register-based cohort study from 2000-2017 in Denmark. The Danish National Hosptial Registry contains information on all patients discharged from Danish hospitals and outpatient clinics since 1977. From this registry, we will identify patients with BCG treatments by diagnoses codes according to the International Classification of Diseases (ICD)-10 system with the following ICD-10 diagnoses codes; "Intravesical BCG instillation" (ZZ9071), "Instillation of BCG into the bladder/urinary bladder"(BJHE11/BJHL11), and "Immunomodulatory BCG treatment" (BOHJ25). In order to acquire information on co-morbidities all discharge diagnoses will also be notified on patients with prior BCG treatments. We will identify those with subsequent BCG infection by cross-linkage to the International Reference Laboratory of Mycobacteriology, Statens Serum Institut.

Collaborating researchers and departments

Department of Infectious Diseases, Odense University Hospital

• Medical student, Emilie Stavnsbjerg Larsen, researcher
• Professor, Isik Somuncu Johansen, supervisor
• PhD-student, Inge Kristine Holden, co-supervisor
• MD, Anne Christine Nordholm, co-researcher 

International Reference Laboratory of Mycobacteriology, Statens Serum Institut, Copenhagen

• DMSc, Head of department, Troels Lillebæk, co-supervisor