A 71-year-old man of British origin, who has a lifelong smoking history, got admitted with dysuria, haematuria, lethargy, rigors, and temperature of 39 °C. Further review of systems was negative for any other foci of infection. He had urinary catherization for maintenance BCG immunotherapy earlier that day in the morning with an interval of about 10 h between catheterization and fever onset). It is noteworthy that it was a difficult catheterization and his catheter tip had a tiny speck of blood on the first go. In view of potential infectious complications, the possibility of postponing treatment was contemplated, but the patient was keen on proceeding with BCG instillation.
His past medical history is significant for bladder carcinoma in situ (G2pTa TCC + CIS), which was diagnosed 1-year ago. He had previously received six installations of BCG vaccine, which is a live attenuated Mycobacterium Bovis (OncoTICE BCG 12.5 mg per vial containing 2–8 × 108 CFU Tice BCG), without any immediate side effects. Following this, he had rigid cystoscopy with biopsy and was found to have no evidence of recurrence of his malignancy, and was, therefore, started on maintenance BCG immunotherapy.
Two years ago, he had laparoscopic anterior resection for low rectal cancer with defunctioning loop ileostomy which was closed after one year, along with parastomal hernia repair. Surveillance CT scans and carcinoembryonic antigen (CEA) level did not show any evidence of recurrence of bowel cancer to date. His other medical problems include asymptomatic renal calculus in the right kidney, atrial fibrillation, hypertension, and hypercholesterolemia. He has had no prior history of Tuberculosis (TB) and denied any close TB contacts. Likewise, there was no evidence to suggest immunocompromised status.
Examination revealed a temperature of 39 °C, Blood Pressure 112/77 mmHg, heart rate 77 bpm, respiratory rate 20/min, and oxygen saturation 96% in room air. He had normal respiratory and heart sounds.
Likewise, no signs of infective endocarditis, meningitis, or skin or joint infection were noted. Abdomen was soft and non-tender.
His urine dip was positive (Nitrate+, Leukocytes+ ++ , Erythrocytes+++, Protein+++ and bilirubin+). Blood tests showed White blood Cells (WBC) of 8.5 /mm3, C Reactive Protein (CRP) 47 mg/L. Chest x-ray was normal. ECG showed rate-controlled atrial fibrillation. Urine culture was sent and the patient was given gentamycin for likely Urinary tract infection (UTI) based on his symptoms, urine dip and history of recent catherization. His early urine and blood culture did not show any growth.
Despite one week of empirical gentamycin for presumed UTI, he continued to spike temperature. Keeping his previous history of kidney stones in mind, a fresh CT-KUB was requested, which did not show any hydronephrosis or change in size or position of the stone along with left adrenal adenoma. He subsequently had transthoracic echocardiography which did not reveal any evidence of infective endocarditis which was suspected because Streptococcus Bovis endocarditis has a well-known association with colorectal cancer [5], CT thorax was, therefore, requested, which revealed a 12-mm subcarinal lymph node along with sub-centimetre lymph nodes at the paratracheal region.
At this point (day 10 of his admission), the respiratory consultant suspected BCG-Osis clinically, and so, 3 successive early morning urine samples were sent for acid-fast bacilli (AFB) and cultures. Although the patient was initially reluctant to take anti-tuberculosis medication (due to diagnostic uncertainty and lack of evidence in favour of tuberculosis), he agreed later on when he was counselled regarding the expected time frame required for TB tests outcome, and thus a potential significant delay in treatment initiation. He was commenced on anti-tuberculous treatment (ATT) comprising Isoniazid 300 mg OD, Rifampicin 600 mg OD, and Ethambutol 1400 mg (15 mg/kg) along with weekly 50 mg pyridoxine. M. Bovis has an innate resistance to Pyrazinamide, therefore, it was excluded from the treatment regimen [6]. This regimen is extrapolated from TB treatment evidence and previous reports on the treatment of BCG infection. However, he continued to spike a temperature and had variable leukopenia (range 2.4–8.5mm3), lymphopenia (range 0.1–1 mm3), and neutropenia (range 1.5 to 6.9mm3), with normal white blood cell morphology. This lack of improvement made the patient more frustrated.
Due to these blood changes, a haematologist opinion was sought (on day 31 of admission), who performed bone-marrow aspiration and trephine biopsy. The slides were stained with Haematoxylin and Eosin (H&E), Ziehl–Neelsen (ZN), periodic acid schiff (PAS), and Grocott’s technique. Immunohistochemistry for lymphoid markers (CD3 and CD20) was also performed.
Then, a repeat CT Chest-Abdomen-Pelvis was done because of persistent pyrexia while being on the antimycobacterial regimen for more than 2-weeks. It reported focal patchy opacification in both lung bases, bilateral subpleural nodularity, with no evidence of internal abscesses. A few enlarged lymph nodes were noted in the mediastinum with the largest subcarinal node measuring 13 mm in the short axis. There was a sub-centimetre right hilar lymph node (see Fig. 1). It was not amenable to biopsy after MDT discussion with interventional radiology consultant.
Meanwhile, 33 days after admission, the trephine biopsy was reported, showing hypercellular bone marrow with numerous non-caseating epithelial granulomata. ZN, PAS and Grocott stains were negative. His immunoglobulin levels were normal. Possible differentials were inflammatory or infectious changes with no evidence of malignancy (see Fig. 2). However, special stains for acid-fast bacilli and fungi were negative.
Finally, after a long wait of almost 82 days after admission, Mycobacterium Bovis was isolated from one of his three early morning urine specimens using BacT/ALERT ® culture media (bioMérieux United Kingdom and Ireland). It was sensitive to Rifampicin, isoniazid, Ethambutol, quinolone group, but resistant to Pyrazinamide. He became afebrile approximately 3 weeks after the start of ATT. Ethambutol was stopped after 2 months, and Rifampicin and Isoniazid were continued for another 4 months. He remained under respiratory, urology and lower GI follow-ups till completion of the treatment course which was well tolerated with no significant side effects. He is now well and apyrexial. His latest follow-up CT chest showed resolution of subpleural nodules (see Fig. 1) and he has been discharged from respiratory follow-up.
Urologically, his bladder was clear on recent check flexible cystoscopy. A shared decision, involving the patient and the multidisciplinary team (MDT), was made not to offer any further intravesical BCG and just continue endoscopic surveillance with the further plan of management if recurrence or progression occurs in the future.