Infectious complications of intravesical BCG immunotherapy

INTRODUCTION — Intravesical administration of Bacillus Calmette-Guérin (BCG), a live attenuated strain of Mycobacterium bovis, is an adjunctive therapy for treatment of non-muscle invasive bladder cancer. The organism is referred to as M. bovis BCG. Issues related to treatment of patients with bladder cancer are discussed separately. (See "Treatment of primary non-muscle invasive urothelial bladder cancer".)

Intravesical BCG is usually well tolerated; uncommonly, severe local and systemic complications can occur [1-5]. Issues related to infectious complications of BCG immunotherapy will be reviewed here. Issues related to noninfectious complications of BCG are discussed separately. (See "Treatment of primary non-muscle invasive urothelial bladder cancer".)

PATHOGENESIS — BCG was initially developed as a vaccine against tuberculosis. (See "Prevention of tuberculosis: BCG immunization and nutritional supplementation", section on 'Bacille Calmette-Guérin vaccine'.)

The possibility of a role for BCG in cancer treatment was first raised in the 1920s, when an autopsy study noted a lower frequency of cancer in patients with tuberculosis and a higher frequency of tuberculosis among cancer survivors [6]. In the 1930s, a profound stimulatory effect of BCG on the reticuloendothelial system was described; in the 1980s, a lower incidence of leukemia was observed among children who had received neonatal BCG immunization [2,4].

The mechanism of BCG as an immunotherapeutic agent for treatment of bladder cancer is not fully understood; it is thought to induce local immune activation, leading to death of tumor cells. This is discussed further separately. (See "Treatment of primary non-muscle invasive urothelial bladder cancer".)

Complications associated with BCG immunotherapy may represent a hypersensitivity reaction, active infection, or both. In some case reports, granulomas have been observed on biopsy of respiratory, breast or other tissue, with negative staining and culture for acid-fast bacilli, negative molecular tests, and favorable clinical response to administration of systemic corticosteroids; these findings are suggestive of hypersensitivity reaction [3,7-10]. However, in other case reports, viable M. bovis BCG organisms, positive stains for acid fast bacilli and/or positive molecular tests have been observed in a variety of tissues or fluids outside the bladder, with evidence of inflammation, suggesting active infection [11-23]. Organisms likely gain access to the systemic circulation via uroepithelial disruption, leading to dissemination. (See "Tuberculosis: Microbiology, pathogenesis, and immunology".)

EPIDEMIOLOGY — Active M. bovis BCG infection at any site is relatively rare [5,24]. Between 2004 and 2015, 118 cases of BCG infection were reported to the US National Tuberculosis Surveillance System [24].

Intravesical BCG is associated with infectious complications in approximately 1 to 5 percent of cases [1,5,25]. In one retrospective cohort study including 6753 patients treated with intravesical BCG, BCG infection developed in 1 percent of cases [5]. In a review including more than 250 patients, infectious complications were observed in 4.3 percent of cases [1]. In a report of 332 patients with BCG infection, 5 patients (1.5 percent) had a severe systemic adverse events associated with BCG use, two of which resulted in death [26].

Risk markers for systemic infection associated with intravesical BCG include [27-29]:

●Traumatic catheterization (the most frequent cause)

●Active cystitis

●Persistent gross hematuria following transurethral surgery

●Immunosuppression

●Age ≥70 years

The likelihood of developing BCG-related complications appears to be more dependent on host characteristics (such as presence of bladder mucosal damage or presence of immunosuppression) than on other factors including the BCG dose, the number of BCG instillations, or the time interval since the transurethral surgery [1,30]. The type of BCG strain used has not been demonstrated to be a risk factor for infectious complications; a retrospective study has called for further study of this issue [31,32].

CLINICAL MANIFESTATIONS

Timing of onset — The clinical manifestations of early-onset infection (within ≤3 months of BCG instillation) differ from those of delayed-onset infection (>3 months after BCG instillation; may occur months to years later). Data are limited to retrospective reviews and case reports [1,27,30,32-43]:

●Early-onset active M. bovis BCG infection often presents with systemic manifestations that include constitutional symptoms (fever, sweats, weight loss). Organ system involvement such as pneumonitis and hepatitis may occur [36,37]. Symptoms may begin within hours, days or a few weeks after the last BCG dose [26].

●Delayed-onset BCG infection often presents with localized disease and positive urine mycobacterial cultures. Other organ systems may be involved [33,36-39]. A patient history of intravesical BCG therapy, even in the remote past, should be considered in clinical context.

Forms — In a review of 282 cases of BCG infection associated with intravesical BCG administration, the types of reported systemic and localized infections are summarized in the table (table 1) [1]. The median time from transurethral surgery to BCG instillation was 30 days, the median number of BCG instillations was six, and the median time from last instillation to onset of infection was 13.5 days (interquartile range 2 to 195 days) [1].

Localized disease — Localized disease involving the genitourinary tract typically presents with delayed-onset infection (>3 months after BCG instillation; may occur months to years later); manifestations may include [1,2,30,32,40-48]:

●Cystitis

●Bladder contracture

●Granulomatous prostatitis

●Prostate abscess

●Epididymo-orchitis

●Testicular abscess

●Pyelonephritis

●Renal abscess

●Ureteral stricture

●Penile granuloma

Common symptoms include bladder irritation, such as dysuria, frequency, and hematuria, within two to four hours of BCG instillation. These symptoms may be accompanied by low-grade fever and malaise, especially in patients who have received prior intravesicular instillations [7]. Such manifestations generally resolve within 48 hours. Persistence or escalation of genitourinary symptoms beyond 48 hours should prompt investigation of active infection, due to BCG or other non-mycobacterial pathogens.

Symptoms due to localized disease associated with intravesical BCG may be indistinguishable from those attributable to non-BCG-related urinary tract infection (UTI). For this reason, clinical suspicion for M. bovis BCG as a potential causative agent must be maintained in patients presenting with UTI symptoms within an appropriate clinical context.

Persistent cystitis (manifested as severe urgency, frequency, and dysuria) even after discontinuing BCG suggest development of BCG cystitis. This is an uncommon condition that presents with systemic symptoms and sterile pyuria (eg, leukocytes in the urine with negative cultures for bacteria other than mycobacteria). Symptoms may continue for weeks to months despite antimycobacterial therapy, suggesting a hypersensitivity component. Cystoscopically, the bladder appears red, beefy, and irritated, typically with acute and granulomatous inflammation [37,49]. Left untreated, this may lead to an end-stage microbladder due to granulomatous cystitis [50].

M. bovis BCG infection can spread locally from the bladder to involve other structures within the genitourinary tract. Such infections include granulomatous ulceration of the glans penis, prostatitis, epididymitis, ureteral obstruction, and renal abscess [44-46]. Postsurgical tissue injury may allow spread of the organism to the pelvis or peritoneum [51,52].

Prostatitis due to M. bovis BCG is relatively common but is often asymptomatic. In one series including 12 patients who underwent cystoprostatectomy for management of invasive bladder cancer following prior treatment with intravesical BCG, granulomatous prostatitis was observed in 9 cases; of these, 7 had positive acid fast bacilli (AFB) stain [53].

Intravesical BCG administration may be associated with transiently elevated prostate specific antigen in up to 40 percent of cases; this finding typically reverts to normal within three months [54].

M. bovis BCG may present causing active infection years after BCG intravesical therapy [47]. Therefore, clinical suspicion must be maintained in patients who have had BCG therapy. In one report of eight cases, the authors describe both early and late (>1 year) presentations of M. bovis BCG infection; the late disease involved local granulomatous infection in the genitourinary tract, usually with positive mycobacterial cultures [36]. Similarly, a late ulcerative inflammatory cystitis has been reported to be associated with persistent local M. bovis BCG infection [33].

Systemic complications — Systemic disease occurs when BCG disseminates outside the genitourinary tract via the bloodstream to other sites [2,13,30,32,36,40-43]. Systemic complications often present with early-onset infection (within ≤3 months of BCG instillation) but onset of infection may be delayed (>3 months after BCG instillation; may occur months to years later).

Disseminated BCG infection (in the form of miliary disease, sepsis, or fever associated with organ involvement) is the most commonly reported form of M. bovis BCG infection in the literature; in one review, it accounted for one-third of cases [1].

Sepsis syndrome — Onset of a sepsis syndrome soon after BCG instillation has been described; manifestations include a characteristic relapsing late diurnal fever with drenching night sweats and rigors that may progress rapidly to hypotension, disseminated intravascular coagulation, and respiratory failure [45]. The mechanism is likely attributable to cytokine release [55].

Cases of delayed-onset sepsis have been described years after an apparently uncomplicated BCG treatment. Compromise of the immune system (eg, due to administration of systemic glucocorticoids or immunosuppressants) may cause reactivation of a dormant focus [27,56].

Pulmonary — Dyspnea may be present, and progression to respiratory compromise can occur. In addition, relatively asymptomatic or subclinical cases have been described [39,57].

In some patients with disseminated BCG infection, chest radiography or computed tomography (CT) demonstrates a miliary nodular or interstitial pattern, sometimes associated with hilar adenopathy; these findings are observed most frequently in association with sepsis [8,58]. The sensitivity of chest radiography is limited; in one series including 216 patients with systemic BCG infection, chest radiography failed to reveal a miliary pattern in about 25 percent of patients with pneumonitis subsequently identified via CT scan [1].

Other pulmonary manifestations including pleural effusion and solitary pulmonary nodule have been described [59,60]. Pre-existing pulmonary disorders such as interstitial pneumonitis may be exacerbated after intravesical BCG [61].

Hepatic — Granulomatous hepatitis is a rare complication of intravesical BCG; it may arise as an early or delayed complication [7,62,63]. Clinical manifestations include fever, anorexia, and jaundice. This condition may occur in isolation or in association with disease at other sites (eg, genitourinary tract, respiratory tract, vascular sites) [64,65].

Musculoskeletal — Osteomyelitis is a rare complication of intravesical BCG. Most reported cases involve the spine, presumably due to spread from the urinary tract via the Batson plexus [66-69]. Bone involvement outside the spine has also been described.

Patients with spondylitis present with back pain and may have motor weakness. Vertebral infection may be accompanied by psoas abscess; in such cases, hip pain and inability to straighten the leg may be observed [68]. In addition, vertebral infection may also be accompanied by mycotic vascular infection [70]. (See "Bone and joint tuberculosis", section on 'Spondylitis (Pott disease)' and "Vertebral osteomyelitis and discitis in adults".)

Spinal metastases due to progressive bladder cancer or other malignancy must be distinguished from spinal osteomyelitis due to M. bovis BCG [71]. Care must be taken in interpretation of radiologic images. In one case report, vertebral osteitis likely due to M. bovis BCG was found on PET/CT scan to masquerade as metastatic prostate malignancy [72].

Osteoarticular complications of intravesical BCG are rare; they include reactive arthritis and osteoarticular infection [73]:

●Patients with reactive arthritis typically present within days or few weeks after BCG instillation with oligoarthritis or small-medium joint polyarthritis, predominantly of the lower extremities [74-77]. (See "Reactive arthritis".)

Associated genitourinary symptoms include frequency, cystitis, and hematuria. In addition, ocular manifestations may be observed; these include conjunctivitis and uveitis (Reiter syndrome) [78]. In one review including 43 cases of reactive arthritis, 53 percent of patients were positive for HLA-B27, and at least 19 percent had axial pain (compatible with spondyloarthritis) [74].

Reactive arthritis occurring post BCG intravesical installations is thought to be caused by a cross reactive immune response involving tissue self-antigens and mycobacterial antigens [79].

●Monoarthritis following intravesical BCG instillation should prompt suspicion for joint infection [73]. Septic arthritis may be due to M. bovis BCG or non-mycobacterial organisms.

Psoas abscess may occur as a complication of intravesical BCG installation, either alone or in combination with vertebral osteomyelitis and/or vascular infection [16].

Case reports of orthopedic hardware infection have been described [80-83].

Vascular — Vascular complications associated with intravesical BCG are rare. It has been postulated that these develop via hematogenous seeding of the vasa vasorum of the arterial wall, or as a result of contiguous extension from an adjacent site (such as a vertebral body, perivascular lymph nodes, or muscle abscess) [1,84]. Clinical manifestations include low-grade fever, malaise, and weight loss. Vascular involvement was associated with mortality rate of 16 percent in one series [1].

Case reports have described mycotic aneurysms, including one with subsequent involvement of an aortic graft, and another with involvement of multiple sites including a carotid aneurysm [17,23,65,85]. In a review of 14 cases, all occurred months (median 24 months; range 4 to 108 months) after BCG instillation [86]. Most (73 percent) involved the abdominal aorta and were identified on CT scan. Treatment usually involved surgical and medical therapy.

Other manifestations — Other manifestations of active infection that may be caused by BCG include:

●Fever of unknown origin accompanied by symptoms including night sweats, anorexia, fatigue, weight loss, and pancytopenia occurred in two patients who had granulomas in bone marrow; M. bovis was recovered in bone marrow cultures [19].

●Hematologic manifestations include cytopenia (including Evan's syndrome), granulomatous bone marrow involvement [38,43], immune thrombocytopenia with cryoglobulinemia [87], and autoimmune hemolytic anemia [88]. Hemophagocytic syndrome associated with bone marrow involvement, anemia, high plasma ferritin, and high triglycerides has been described [89].

●Central nervous system (CNS) involvement by BCG has been observed in a small number of cases [1,5,22,37,90,91]; both early-onset and delayed-onset presentations have been described. Manifestations include meningitis, brain tuberculomas, cerebellar abscess, small vessel vasculitis, and Guillain-Barre syndrome. Symptoms may be vague, including dizziness, ataxia, mental status changes, and headaches with or without associated fevers, night sweats, and weight loss; these may persist for weeks in a relapsing pattern. Focal neurologic signs may not be present until late in the course of the disease. Cerebrospinal fluid findings are as described in CNS disease due to Mycobacterium tuberculosis (lymphocytic pleocytosis, elevated protein levels, low glucose) [92]. (See "Central nervous system tuberculosis: An overview".)

●Ocular complications due to intravesical BCG therapy include conjunctivitis, uveitis, endophthalmitis, retinitis, choroidal tuberculoma, iritis, swelling of the optic nerve, and keratopathy [20,21,48,79]. Retinal detachment may be associated with choroidal tuberculoma [48].

●Cutaneous infection has been described as a complication of intravesical BCG therapy, and may manifest in the form of nodules, abscess, plaque or sporotrichoid patterned lesions [1,93]. An Id-like (autoeczematization) hypersensitivity skin rash associated with BCG administration has been described [9].

●Parotid infection due to M. bovis BCG has been reported after intravesical installation of BCG [94].

DIAGNOSIS

●Clinical suspicion

•Localized BCG infection should be suspected in patients treated with intravesical BCG who present with either early- or delayed-onset manifestations (>3 months after BCG instillation) involving the genitourinary tract (see 'Localized disease' above).

•Systemic BCG infection should be suspected in patients treated with intravesical BCG who present with systemic manifestations, particularly within ≤3 months of BCG instillation (see 'Systemic complications' above).

●Definitive versus presumptive diagnosis – A definitive diagnosis of M. bovis BCG infection may be established in a patient with evidence of active infection consistent with the diagnosis via positive culture of bodily fluids and/or tissue from involved sites, when obtainable.

However, the sensitivity of AFB stain and culture is subject to limitations. Therefore, in the appropriate clinical and epidemiologic setting and in the absence of evidence for an alternative etiology of these findings, a presumptive diagnosis may be made in the setting of other test results, which may include: positive acid-fast bacilli (AFB) smear (of bodily fluids or tissue from involved sites), positive polymerase chain reaction (PCR) or whole genome sequencing, and histopathology demonstrating (typically non-caseating) granulomas, and/or positive fluorescence in situ hybridization (FISH) [95,96]. (See 'Differential diagnosis' below.)

●Diagnostic evaluation – Diagnostic evaluation includes obtaining bodily fluids (urine, blood, and fluid from any involved sites) and/or tissue for AFB stain and mycobacterial culture. PCR and other mycobacterial diagnostic tests may be performed as well. Gram stain, bacterial culture, fungal stain, and fungal culture are helpful to exclude other possible diagnoses. Other studies should be guided by the sample type; for example, patients with joint involvement should have synovial fluid sent for cell count and crystal evaluation. Patients with systemic symptoms should have chest imaging to evaluate for pulmonary involvement; computed tomography (CT) or magnetic resonance imaging (MRI) are more sensitive than conventional radiography. (See 'Pulmonary' above.)

•Interpreting diagnostic results – The sensitivity of AFB smear, mycobacterial culture, and PCR is limited. Negative microbiologic tests do not rule out a diagnosis of M. bovis BCG infection [30]. In a review of 282 cases of BCG infection associated with intravesical BCG administration (including 216 patients with systemic disease), AFB staining was positive in 25 percent of cases, mycobacterial culture was positive in 41 percent of cases, and molecular testing was positive in 42 percent of cases [1]. Microbiologic diagnosis was established more frequently among patients with localized BCG infection (53 versus 38 percent). Among patients who underwent biopsy, histopathology demonstrated granulomatous inflammation in 86 percent of cases; the highest yield biopsy sites were lung, bone marrow, and liver. Caseous necrosis is typically absent [3].

Initial PCR testing of patient samples cannot differentiate between members of the Mycobacterium tuberculosis complex. Further targeted molecular testing can distinguish M. bovis from other members of M. tuberculosis complex.

Molecular typing may be used to compare the strain of M. bovis BCG isolated from a patient and the strain (if known) that was used in that individual's intravesical BCG treatment [56].

•Approach to biopsy – In the setting of noninvasive workup that yields no definitive diagnosis, the decision whether to pursue biopsy or initiate empiric anti-M. bovis BCG treatment involves careful consideration of risks and benefits. If biopsy is pursued, separate specimens should be sent for microbiology (including AFB stain, mycobacterial culture, mycobacterial molecular testing, Gram stain, bacterial culture, fungal stain, and fungal culture) and histopathology.

DIFFERENTIAL DIAGNOSIS

●Mild post-instillation symptoms – Minor symptoms following BCG administration are common (up to 85 percent of patients) [97]. These include fever, malaise, and bladder irritation (urination frequency, dysuria, or mild hematuria) within a few hours of BCG instillation [2]. Urinalysis shows nonspecific inflammation and cultures do not demonstrate evidence of infection. Such manifestations generally resolve within 48 hours and reflect a hypersensitivity reaction rather than an infectious complication of BCG. Management consists of analgesics and/or non-steroidal anti-inflammatory drugs [1]. Symptoms usually resolve within 48 hours, after which BCG may be resumed.

Occasionally, temperature >39.0°C (102.5°F) may develop acutely following BCG therapy, but does not necessarily signify active M. bovis BCG infection. In this setting, it may be impossible to distinguish an infectious versus a noninfectious event.

●Bacterial infection – Presence of genitourinary tract and/or systemic symptoms may reflect non-BCG bacterial infection. Up to 20 percent of patients receiving intravesical BCG develop a urinary tract infection due to bacteria other than M. bovis BCG at some point during treatment [98]. Bodily fluids and tissues should be sent for Gram stain and bacterial culture (in addition to workup for mycobacterial infection). (See "Acute complicated urinary tract infection (including pyelonephritis) in adults and adolescents" and "Gram-negative bacillary bacteremia in adults" and "Overview of infected (mycotic) arterial aneurysm".)

●Fungal infection – Presence of genitourinary tract and/or systemic symptoms may reflect fungal infection. Fungal infections such as histoplasmosis and blastomycosis are endemic in certain geographic regions and may cause genitourinary tract infection. If fungal urinary tract infection is suspected, urine may be sent for fungal stain and culture. (See "Pathogenesis and clinical manifestations of disseminated histoplasmosis" and "Diagnosis and treatment of disseminated histoplasmosis in patients without HIV" and "Clinical manifestations and diagnosis of blastomycosis".)

●Alternative mycobacterial infection – Other mycobacterial organisms include M. tuberculosis, M. bovis (non-BCG strain), and other mycobacterial strains. These may distinguished based on epidemiologic factors and results from mycobacterial culture and molecular tests. The tuberculin skin test (TST) and interferon-gamma release assay (IGRA) are tools designed for primarily for the diagnosis of Mycobacterium tuberculosis infection; in the setting of tuberculosis infection, one or both tests may be positive. In the setting of BCG infection, the TST may be positive but the IGRA is negative, since IGRA assay antigens are not shared with BCG [99]. However, neither TST nor IGRA definitively establishes or rules out either condition; therefore these tests are of little help in the diagnosis of active disease due to M. bovis BCG or M. tuberculosis. (See "Diagnosis of pulmonary tuberculosis in adults" and "Mycobacterium bovis" and "Overview of nontuberculous mycobacterial infections".)

●Alternative causes of granulomatous disease – Alternative causes of granulomatous lung disease include sarcoidosis and hypersensitivity pneumonitis. Alternative infectious causes of hepatic granulomas include fungal disease, Q fever, and brucellosis. Alternative noninfectious causes of hepatic granulomas include sarcoidosis, malignancy, and drug reaction. (See "Interpretation of lung biopsy results in interstitial lung disease", section on 'Granulomatous lung diseases' and "Evaluation of the adult patient with hepatic granuloma".)

●Malignancy – Radiographic findings of localized or systemic disease may be difficult to distinguish from malignancy localized to genitourinary tract (such as renal cell carcinoma) or metastatic disease (eg, to the spine). These conditions are distinguished via biopsy.

MANAGEMENT — The optimal approach to treatment of infectious complications associated with intravesical BCG is uncertain; there are no clinical trials. The approach is guided by case series, organizational recommendations and clinical experience with treatment of infection due to M. bovis BCG, which is usually susceptible to most of the commonly used antimycobacterial drugs except pyrazinamide and cycloserine [100,101]. (See "Mycobacterium bovis", section on 'Treatment'.)

The approach to treatment depends on the clinical presentation, as discussed in the following sections.

Localized disease

●Antimycobacterial therapy – For patients with symptoms localized to the genitourinary tract, management of infection consists of antimycobacterial therapy. The optimal antimycobacterial regimen and duration is uncertain; prospective trials are lacking [43]. Involvement of an expert in management of mycobacterial infections is recommended.

Patients with M. bovis BCG infection secondary to intravesical BCG therapy are treated with the same antituberculous medications used to treat M. bovis infection from other sources. Specifically, this involves an initial phase of isoniazid, rifampin, and ethambutol, followed by a continuation phase of isoniazid and rifampin, as discussed elsewhere [1,43]. (See "Mycobacterium bovis", section on 'Treatment'.) Studies report substitution of regimen components with other active anti-M. bovis BCG antimicrobials depending on sensitivity of the organism, site specific antimicrobial penetration, patient tolerance, and risk of adverse event [43,101-103].

In cases in which it is not clear whether the infection is due to M. bovis BCG or another mycobacterial species, the treatment regimen may need to be broadened to cover more than one potential microbiologic diagnosis [56].

The duration of therapy depends on disease severity and clinical response [1,40,42,43,101,102].

●Role of steroids – In cases of severe BCG cystitis, systemic steroids (in the form of a three to six-week [rapid to slow] prednisone taper) can provide rapid and durable relief from unremitting cystitis symptoms [37,49]. Given risk for potentiating BCG spread, the patient should be maintained on antimycobacterial therapy while on steroids.

●Role of surgery – In the setting of abscess or genitourinary tract obstruction, surgical evaluation is arranted [1].

For patients with persistent epididymo-orchitis despite antimycobacterial therapy, epididymectomy, and/or orchiectomy may be warranted.

Systemic disease — For patients with systemic symptoms, management consists of antimycobacterial therapy, with addition of glucocorticoids in some circumstances [1,43]. In addition, surgical evaluation is warranted in the setting of abscess, genitourinary tract obstruction, vascular infection, or infection involving a prosthetic device.

●Antimycobacterial therapy – The optimal antimycobacterial regimen and duration is uncertain; prospective trials are lacking [43]. Involvement of an expert in management of mycobacterial infections is recommended.

Patients with M. bovis BCG infection secondary to intravesical BCG therapy are treated with the same antimycobacterial medications used to treat M. bovis infection from other sources. Specifically, this involves an initial phase of isoniazid, rifampin, and ethambutol, followed by a continuation phase of isoniazid and rifampin, as discussed elsewhere [1] (see "Mycobacterium bovis", section on 'Treatment').

Studies report substitution of regimen components with other active anti-M. bovis antimicrobials based on sensitivity of the organism, site specific antimicrobial penetration, patient tolerance, and risk of adverse event [43,102,103].

The duration of therapy depends on disease severity and clinical response [1,40,42,43,101,102].

In cases in which it is not clear whether the infection is due to M. bovis BCG or another mycobacterial species, the treatment regimen may need to be broadened to cover more than one potential microbiologic diagnosis [56].

●Role of steroids – In the setting of extensive miliary involvement of the lungs and/or respiratory failure, case reports describe the use of glucocorticoids administered concomitantly with antimycobacterial agents, based on the potential role of hypersensitivity in the pathogenesis of the disease [1,25,43,49,97,104,105]. In cases in which hypersensitivity is thought to play a significant role in the patient’s illness, we suggest concomitant glucocorticoid therapy if potential benefit is felt to likely outweigh potential risk [1,97]. Use of glucocorticoids has been associated with clinical improvement in case reports [49,104-106].

There is no standard regimen for administration of adjunctive glucocorticoids; a regimen of prednisone 40 to 60 mg orally daily for three to five days, followed by a gradual taper over a few weeks, has been described.

Reactive arthritis or uveitis — For patients presenting with a hypersensitivity reaction manifesting as reactive arthritis or uveitis only, without signs of localized or systemic infection, antimycobacterial treatment is not indicated [1,76,79]. Involvement of a clinician with expertise in these conditions is recommended [74]. The approach to patients with reactive arthritis and uveitis, in general, is discussed elsewhere. (See "Reactive arthritis", section on 'Treatment of arthritis' and "Uveitis: Treatment".)

Following resolution of symptoms, BCG instillations may be resumed if benefit exceeds risk.

Further cancer treatment — Among individuals with infectious complications due to intravesicular BCG, the risk of repeat administration is uncertain; data are lacking. For patients who have experienced systemic BCG infection, we advise against repeat use of intravesical BCG, given potential risk of a recurrent episode [1]. (See "Treatment of recurrent or persistent non-muscle invasive urothelial carcinoma of the bladder".)

OUTCOME — In a review including 282 cases of BCG infection associated with intravesical BCG administration (including 216 patients with systemic disease), attributable mortality was 5.4 percent; long-term complications occurred in 7.4 percent of cases (most commonly permanent loss of visual acuity, chronic arthralgia, and end-stage kidney disease) [1].

PREVENTION — Patients with breaks in the urogenital epithelium (due to traumatic catheterization, active cystitis, or persistent gross hematuria following transurethral surgery) should have BCG instillation deferred for at least two to three weeks [1].

There are no proven interventions for preventing infectious complications associated with administration intravesical BCG. Screening urinalysis in asymptomatic patients prior to BCG administration has not been shown to reduce infectious complications [107], and patients with asymptomatic bacteriuria do not warrant antibiotic treatment [108].

There is no role for routine prophylactic administration of antimycobacterial therapy concurrently with intravesical BCG. Such an intervention could reduce the anti-tumor effect of BCG, given that live BCG requires replication to induce a host immune response. In one non-blinded randomized trial evaluating the efficacy prophylactic isoniazid, no reduction in infectious complications of BCG was observed, with low incidence in both groups [109]; in addition, disseminated infection has been observed despite use of prophylactic isoniazid [63,67].

Reducing the dose of BCG has been demonstrated to reduce the likelihood of noninfectious complications [1]. Issues related to BCG dosing are discussed separately (see "Treatment of primary non-muscle invasive urothelial bladder cancer")

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Bladder cancer".)

SUMMARY AND RECOMMENDATIONS

●Epidemiology – Intravesical administration of Bacillus Calmette-Guérin (BCG), a live attenuated strain of Mycobacterium bovis (M. bovis BCG), is an adjunctive therapy for treatment of non-muscle invasive bladder cancer. Intravesical BCG is usually well tolerated; uncommonly, severe local and systemic complications can occur. Risk factors include presence of bladder mucosal damage, presence of immunosuppression, and advanced age. (See 'Introduction' above and 'Epidemiology' above.)

●Clinical manifestations – Clinical manifestations include localized and systemic disease; the presentation depends in part on the timing of onset. In general, early-onset infection (≤3 months of BCG instillation) often presents with systemic manifestations including fever, night sweats, weight loss, pneumonitis, and hepatitis. Delayed-onset infection (>3 months after BCG instillation) often presents with localized disease and positive urine mycobacterial cultures. (See 'Clinical manifestations' above.)

●Diagnosis (See 'Diagnosis' above.)

•Definitive versus presumptive diagnosis – Definitive diagnosis of BCG infection may be established via positive M. bovis BCG culture of bodily fluids and/or tissue from involved sites; however, the sensitivity of culture is subject to limitations. In the appropriate clinical and epidemiologic setting and in the absence of evidence for an alternative etiology of these findings, a presumptive diagnosis may be made in the setting of one or more of the following: positive AFB smear (of bodily fluids or tissue from involved sites), histopathology from an involved site demonstrating granulomas and/or positive fluorescence in situ hybridization, positive PCR test on fluid or tissue.

•Diagnostic evaluation – Diagnostic evaluation includes obtaining bodily fluids (urine, blood, and fluid from any other involved sites) for AFB stain, mycobacterial culture, mycobacterial PCR test, Gram stain, bacterial culture, fungal stain, and fungal culture, as well as other studies guided by the specimen type, in order to investigate a range of diagnostic possibilities. Patients with systemic symptoms should have chest imaging to evaluate for pulmonary involvement.

●Treatment

•Antimycobacterial therapy – The optimal antimycobacterial regimen and duration for treatment of M. bovis BCG infection is uncertain; decisions should involve an expert in management of mycobacterial infections. (See 'Management' above.)

Patients with M. bovis BCG infection secondary to intravesical BCG therapy are treated with the same antimycobacterial medications used to treat M. bovis infection from other sources. Specifically, this includes an initial phase of combination therapy consisting of isoniazid, rifampin, and ethambutol, followed by a continuation phase of isoniazid and rifampin, as discussed elsewhere (see "Mycobacterium bovis", section on 'Treatment').

Regimen components may need to be substituted using other active anti-M. bovis BCG agents through clinical decision making that takes into consideration the sensitivity of the organism, penetration of the agents into the involved site, patient tolerance, and risk of adverse events. The duration of therapy depends on disease severity and clinical response.

•Role of steroids – In cases of extensive miliary involvement and/or respiratory failure in which hypersensitivity is thought to play a significant role in the patient's illness, we suggest concomitant glucocorticoid therapy if potential benefit is felt likely to outweigh potential risk (Grade 2C). (See 'Systemic disease' above.)

•Role of surgery – Surgical evaluation is warranted in the setting of abscess, genitourinary tract obstruction, vascular infection, or infection involving a prosthetic device. (See 'Management' above.)

●Further cancer treatment – Among individuals with infectious complications due to intravesicular BCG, the risk of repeat BCG administration is uncertain. For patients who have experienced systemic BCG infection, we advise against repeat use of intravesical BCG given potential risk of a recurrent episode. (See 'Further cancer treatment' above.)

●Prevention – There are no proven interventions for preventing infectious complications associated with administration intravesical BCG. Patients with breaks in the urogenital epithelium (due to traumatic catheterization, active cystitis, or persistent gross hematuria following transurethral surgery) should have BCG instillation deferred for at least two to three weeks. We suggest against routine prophylactic administration of antimycobacterial therapy (Grade 2C), when treating with intravesical BCG. Such an intervention has not been shown to be effective and could reduce the antitumor effect of BCG, given that live BCG requires replication to induce a host immune response. (See 'Prevention' above.)