Intravesical BCG is the most effective adjunctive agent and remains as the standard of care in the management of superficial bladder cancer. Although it is most effective in prevention of tumour recurrence and progression but it is also associated with significant adverse effects. The underlying pathogenic mechanisms of complications following BCG instillation remain not fully understood and on-going debate exists about whether it represents a form of hypersensitivity reaction or an active mycobacterial infection. This study aimed with bringing out the possible adverse effects associated with intravesical BCG and their management.
In a study of Brausi et al.  (1316 patients managed with intravesical BCG), the patients reported local and systemic side effects were 62.8% and 30.6%, respectively. Dysuria and mild fever are not very rare after BCG instillation. Fever after BCG therapy is not always a sign of systemic BCG infection since most fevers are limited to 24 h’s duration . However, patients with fever lasting beyond 24 h (especially if persists > 48 h) or has an intermittent evening pattern are more likely to have systemic BCG infection. These patients usually require hospitalization and administration of anti-tuberculosis agents and occasionally a short period of fluoroquinolone and systemic steroids. A progressively increasing symptomatology with each BCG cycle should prompt a delay, a lower dose or interruption of BCG instillations, which may preclude long-term complications related to the immunotherapy.
The largest series of BCG complications included over 2600 patients [16, 17]. The most common were LUTS (27–95%), fever (2.9%), hematuria (1.0%), granulomatous prostatitis (0.9%), granulomatous pneumonitis or hepatitis (0.7%), arthralgia (0.5%), epididymitis (0.4%), and severe disseminated BCG sepsis (0.4%), in addition very rare ureteral obstruction, rashes, renal abscesses and bladder contraction (all < 0.3%) [16, 17]. Here we report our experience of BCG complications.
Chemical cystitis is frequent after BCG administration which presents as irritative bladder symptoms . Urinalysis and urine cultures do not show any infection generally. Symptoms normally subside in 1–2 days; however, they recur with subsequent BCG instillations. Bacterial cystitis shows infection at urinalysis/urine cultures and requires therapy with antibiotics. BCG-related cystitis appears as circumferential bladder wall thickening with urothelial enhancement . In this study we found 23 cases (15.4%) of chemical cystitis and 16 cases (10.7%) of bacterial cystitis, which were lesser than other reported studies. Richard et al. in their study reported that abacterial cystitis and dysuria, occurring in 80% of patients, hematuria (40%) and low-grade fever (30%) . Jacoiste et al. study found dysuria and frequency (5–90% incidence), hematuria (1–34% incidence) and fever (3% incidence) .
Lamm et al.  had reported the bladder contraction rate of 0.2%. Nieder et al. in their review reported it only 0.09% [21, 22]. In this study 2 patients (1.3%) had bladder contractures that were managed conservatively without the need of augmentation procedure.
Granulomatous prostatitis (GP) following intravesical BCG is common due to reflux from the prostatic urethra to the prostatic ducts. Histologically there are necrotizing or non-necrotizing granulomas and acid-fast bacilli cannot be identified [23, 24]. The majority of patients are asymptomatic and it is mostly present in peripheral zone which confuses with prostate cancer. We had 5 (3.3%) such patients who were diagnosed with GP by the help of MRI. Stilmant described GP in case series of 6 patients receiving intravesical BCG . Another study by Oates et al. showed 41% histologically proven granulomatous prostatitis after BCG . In this study, 2 cases of Prostatic abscess were also seen with symptoms of fever, dysuria, and suprapubic pain. Abscess was drained by per rectal route and antibiotic coverage provided.
BCG-related epididymo-orchitis is rare (1%) event but can occur many years after intravesical BCG therapy [16, 26]. BCG generally affects the epididymis earlier than involving the testis. The causal mechanism is prostatic urethra-ejaculatory duct reflux. Patients present with fever, leucocytosis and scrotal swelling of acute or gradual onset. If the antibiotics fail; granulomatous epididymo-orchitis must be suspected and treated accordingly. Ultrasonography (US) shows bulky hyperaemic epididymis and/or testis, with a heterogeneous, hypoechoic, steady mass corresponding to granuloma formation . A testicular mass can mimic malignancy. Rischmann et al.  reported the epididymitis in only 0.2% of patients in their clinical trial. Another study showed 3.5% (10/282) patients developed epididymo orchitis with painless testicular enlargement, abscesses or cutaneous fistula . We had 4 cases of post BCG epididymo-orchitis and 1 case of testicular abscess which was not responsive to antibiotics, after initial incision and drainage; orchiectomy had to be done for that abscess. Hydrocele and scrotal thickening commonly exist after BCG and we had 7 such patients.
Ureteral stricture and papillary necrosis are common urinary tract complications after BCG Therapy. Renal granuloma formation or granulomatous nephritis is a rare. Although the suspected cause is reflux, instances without documented reflux have been seen [29, 30]. Furthermore, patients are usually asymptomatic or present with fever or mild abdominal ache. Renal granulomas are hypo vascular nodules and can be solitary, multifocal or bilateral [31, 32]. Prolonged antitubercular therapy should be initiated for granulomas, as we did in our 4 cases. Two patients developed abscess which was drained, no fistula formation was seen. Although spontaneous resolution of biopsy-proven renal granuloma has been reported , corticosteroids and antimycobacterial agents are the preferred remedies for these lesions. Nephrectomy or nephroureterectomy is the definitive remedy for patients who have non manageable fever or soreness despite the medicinal therapy . We did not require nephrectomy for any of our patient. Perez-Jacoiste et al.  reported the kidney parenchymal involvement in 3.5% patients, which were manifested as nephritis (granulomatous inflammation) or renal masses on abdominal imaging. Lamm et al.  had reported the incidence of such renal granulomas at a rate of 0.1% (2 cases out of 2602), whereas we found these at a higher proportion (2.6%) which may be attributed to Indian set up as well as to the fact that the previous study was almost 25 years back.
Balanitis is granulomatous infection of the penis, a rare complication following intravesical BCG therapy. Balanitis manifests as oedema, papules, ulceration, and abscess formation. Traumatic catheterization is a risk factor for this . An Indian study reported the penile lesions (granulomatous balanitis) in 5.9% cases after intravesical BCG . This occurred in 2 patients in our study. Abscess was drained and sent for mycobacterial culture, finding infective organism of balanitis became a bit challenging as culture from the abscess were negative for usual bacteria and culture for tuberculosis came positive later on.
BCG spondylodiscitis is similar to tuberculous spondylodiscitis or Pott disease and presenting as fever, weight loss, lower back pain, leg weakness, and paraesthesia’s [37, 38]. Endplate destruction of contiguous vertebral bodies with relative sparing of the disc in the early stage and a predilection for the lower thoracic spine is seen. MRI helps in identifying oedema, marrow infiltration, enhancement, spinal canal pathology and any epidural abscesses. Prevertebral and paraspinal abscesses might also choose to secondarily contain the psoas muscle mass or aorta. Some patients need abscess drainage, spinal stabilization or spinal cord decompression apart from the regular antimycobacterial therapy.
Osteomyelitis of the lengthy bones after BCG vaccination in youth has been stated, however not commonly. There are documented instances of septic arthritis of the left elbow, infections of hip and knee prostheses after intravesical BCG therapy [39, 40]. A psoas muscle abscess has been stated in the absence of vertebral involvement. In the literature up to 2018, only 23 cases of tuberculous spondylitis/vertebral osteomyelitis following intravesical BCG were reported . Aljada et al.  reported a case of Pott’s disease after BCG instillation. Van Thiel et al.  reported development of arthritis of the elbow eight month post-BCG therapy, a synovial aspirate grew Mycobacterium bovis and anti-tuberculous triple therapy (rifampicin, isoniazid and ethambutol) was instituted. We had 3 patients of arthritis/arthralgia. The symptoms subsided with conservative medication and discontinuation of BCG therapy. However, we did not have any patient with swelling at any joint.
Arterial pseudoaneurysm—saccular aneurysm can be seen on US or contrast-enhanced CT. Non-specific arteritis is also commonly seen. The abdominal aorta, thoracic aorta, femoral, popliteal and carotid arteries are affected in this order of decreasing frequency . Additional troubles involving aorto-enteric and aorto-bronchial fistulas have been reported . These patients have to be treated with open surgery and antimycobacterial therapy. Endovascular repair needs to be done but these patients who are poor candidates for surgery; associated hazard of future stent contamination should be considered . Patients with pre-existing stent grafts who are on intravesical BCG treatment additionally might be at chance for future stent illness . In the literature, about 30 BCG-related vascular complications have been reported . In a study by Perez-Jacoiste et al. of 282 patients, mycotic aneurysms and pseudoaneurysms were seen in 16 patients (5.7%) . We had 1 such patient who was managed with intravascular stenting.
Pneumonitis can result in 1% of patients . Symptoms can be fever, cough, dyspnoea and night time sweats, which are normally of gradual onset. The diagnosis can be mounted via the use of a mixture of transbronchial biopsy, bronchoalveolar lavage and imaging. Empirical therapy may also be initiated in the setting of a non-diagnostic workup. The pathogenesis of BCG-related pneumonitis is a hypersensitivity response to disseminated BCG; this idea is seconded by finding of lymphocyte predominant bronchoalveolar lavage studies, reviews of entire healing without treatment or with corticosteroids alone and normally negative stains/cultures [46, 47]. Most patients are treated with a combination of corticosteroids and antimycobacterial agents. Chest X-ray can also have regular findings or a diffuse reticulonodular pattern. CT images show diffuse micronodules mimicking tuberculosis, hematogenous metastases or fungal infection. Histologic findings of granulomatous contamination and diffuse alveolar damage can be seen.
As per the study by D. Lamm, the lungs complications following BCG instillation are uncommon, with an incidence of 0.3–0.7% of patients, presenting as interstitial pneumonitis or miliary dissemination [11, 20]. We had pneumonitis in 2 patients and granulomas in 3 patients on imaging. They presented as unrelenting fever of low grade after instillation along with cough. Chest X-ray was inconclusive. HRCT showed diffuse micronodules in one patient and multiple patchy areas in another patient, the physician asked to stop BCG administration. These lesions then resolved with ATT administration over next six months. In comparison to western literature we found unrelenting fever to be a peculiar finding in our patients and it should alert the physicians in this regard.
Granulomatous hepatitis is rare; it can be a hypersensitivity reaction or direct infection . Patients normally have fever and malaise; the liver can be enlarged and painful at physical examination. Laboratory assessment yields a peculiar hepatic panel and extended inflammatory markers. Imaging may additionally reveal hepatomegaly or ascites . The diagnosis needs to be suspected clinically and tested with biopsy. Lamm  reported that it is manifesting in less than 1% of patients. Another study by Pérez-Jacoiste et al.  reported hepatitis as a manifestation in 16 cases of 281 (5.7%). We had mild derangement of AST/ALT ratio in 14 patients and found granulomas in 2 of these patients. Granulomas when biopsied under USG guidance were positive for tuberculosis. The antitubercular agents are themselves a cause of LFT derangement and this must be kept in mind.
Granulomatous lymphadenitis following intravesical BCG has been mentioned . Enlarged lymph nodes on fluorine 18 fluorodeoxyglucose study can mimic metastatic disease. Three of our patients had enlarged tender neck lymphnodes and 1 patient also had axillary lymphnodes in addition to cervical ones giving rise to suspicion of metastases. However, histopathologic findings helped in separating granulomatous inflammation as an alternative than metastatic carcinoma. The pathogenesis may moreover be energetic contamination or a hypersensitivity reaction. Anti-tubercular treatment for six months resolved the lymphadenitis completely.
Sepsis, which is reported in 1/15,000 patients, is the most serious complication of BCG therapy and is possibly lethal . There are no attribute imaging findings. Treatment consists of antimycobacterial combined with corticosteroids. Disseminated BCG has been reported as a rare complication, Lamm reported incidence after intravesical treatment was 0.4% . We in our experience had only one unfortunate disseminated BCG infection when there was pleural effusion and bacteraemia and patient was admitted under ICU care and ventilatory support but survived with intensive therapy and later on antitubercular therapy. Mantoux test in this regard can be of great help wherein an indication can be sought of susceptibility to BCG dissemination, although it is not a very robust factor.
Other mentioned rare complications consist of peritonitis, choroiditis, parotitis and a contaminated cardiac conduction gadget .