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Disseminated mycobacteriosis secondary to intravenous Bacille Calmette-Guérin (BCG) vaccine
Correspondence to PRISCILLA RUPALI; priscillarupali@yahoo.com
[To cite: Acharya HH, Thampy A, Karthik R, Rupali P. Disseminated mycobacteriosis secondary to intravenous Bacille Calmette-Guérin (BCG) injection. Natl Med J India 2024;37:86–8. DOI: 10.25259/NMJI_316_2022]
Abstract
Bacille Calmette-Guérin (BCG) vaccine has been used increasingly in immunotherapy, including treatment of non-muscle-invasive bladder cancer, as an adjuvant therapy in metastatic prostate cancer and metastatic melanoma. However, systemic infection from inadvertent intravenous (instead of intravesical) injection is uncommon and can have systemic ramifications. We encountered 3 patients with disseminated Mycobacterium bovis infection that ensued after intravenous BCG injection.
INTRODUCTION
Intravesical Bacille Calmette-Guérin (BCG) is the standard of care in the treatment of non-muscle-invasive bladder cancer.1 However, unfamiliarity with this route of administration can often result in an incorrect route resulting in a life-threatening illness. A practitioner in a secondary set-up, tasked with the 2-week follow-up administration of intravesical BCG can often make a mistake regarding the mode of administration, thus causing disseminated mycobacteriosis due to M. bovis. Recognition of this rare entity is important as the patients may present within hours to days with a systemic inflammatory syndrome involving an extrapulmonary organ. Invasive techniques may be needed to make an early diagnosis and initiate treatment. Though M. bovis is part of the M. tuberculosis complex, it is intrinsically resistant to pyrazinamide,2 and the treating physician needs to be aware of the same. This assumes importance as patients receiving this therapy are often followed up and managed at a non-academic secondary or primary care centre.
THE CASES
Case 1
A 58-year-old man diagnosed with high-grade urothelial carcinoma was advised intravesical BCG injection following trans-urethral resection of bladder tumour (TURBT) at his hometown. He was inadvertently administered BCG intravenously and developed high-grade fever within 4 hours of administration. He presented to us 10 days later with persistent fever and night sweats. Baseline investigations revealed a mild bicytopenia and liver function studies were suggestive of cholestatic hepatitis (Table I). On further evaluation, bone marrow biopsy showed granulomatous inflammation, with negative acid-fast bacilli (AFB) smear and mycobacterial cultures. Histopathology from percutaneous liver biopsy was suggestive of non-caseating granulomatous hepatitis. Considering the temporal relationship of the illness to BCG instillation and evidence of granulomatous inflammation at multiple sites, Mycobacterium bovis (M. bovis) infection was strongly considered. He was started on non-hepatotoxic weight-based anti-mycobacterial therapy with ethambutol (E), amikacin, levofloxacin (L) and clarithromycin along with tapering doses of steroids. Follow-up of liver biopsy mycobacterial growth indicator tube (MGIT) showed Mycobacterium tuberculosis complex (which includes M. bovis) confirming the diagnosis (Table II). His fever subsided and liver function tests returned to normal after 2 weeks. The treatment was modified to weight-based regimen comprising isoniazid (H), rifampicin (R), E and L (Table III). The patient was treated for a duration of 12 months and followed up for 3 years, during which there was no relapse of the disease
| Investigation | Case 1 | Case 2 | Case 3 |
|---|---|---|---|
| Haemoglobin (g/dl) | 10.2 | 10.4 | 7.7 |
| Total leukocyte count (cmm) | 5200 | 4900 | 6300 |
| Platelet count (cmm) | 149 000 | 65 0 00 | 113 000 |
| Creatinine (mg/dl) | 0.82 | 0.72 | 0.72 |
| Total/direct bilirubin (mg/dl) | 4.6/4.2 | 4.4/4.1 | 13.2/11.6 |
| AST/ALT (U/L) | 216/669 | 394/176 | 132/81 |
| Alkaline phosphatase (U/L) | 644 | 171 | 706 |
| Total protein/albumin (g/dl) | 6.0/2.6 | 6.2/2.2 | 6.6/2.8 |
AST aspartate aminotransferase ALT alanine aminotransferase
| Tissue | Case 1 | Case 2 | Case 3 | |
|---|---|---|---|---|
| Histopathology | ||||
| Liver | Predominantly lobular non-caseating granulomatous inflammation | Lobular based non-necrotizing histiocytic aggregates including granulomas | – | |
| Bone marrow | Moderately hypercellular marrow with granulomatous inflammation | Normocellular marrow with trilineage haematopoiesis and focal granulomatous inflammation | Consistent with granulomatous inflammation | |
| Microbiology reports | ||||
| Liver | AFB smear | Negative | Negative | – |
| Xpert TB PCR | Negative | Negative | – | |
| Culture* | MGIT–Mycobacterium tuberculosis complex† | No growth | – | |
| Bone marrow | AFB smear | Negative | Negative | Negative |
| Xpert TB PCR | Negative | Negative | Negative | |
| Culture* | No growth | LJ-Mycobacterium tuberculosis complex† | No growth | |
| Treatment regimen | Case 1 | Case 2 | Case 3 |
|---|---|---|---|
| Intensive phase regimen (duration in months) | HRLE (3) | HRE* | HRLE (2) |
| Continuation phase (duration in months) | HRE (9) | HRE (9) | HRE (7) |
Case 2
A 27-year-old man diagnosed with high-grade urothelial carcinoma was advised intravesical BCG following TURBT. He was inadvertently administered intravenous BCG and presented to us 2 weeks later with high-grade intermittent fever starting few hours after the injection, and yellowish discolouration of sclera and pedal oedema for 1 week. Baseline investigations showed deranged liver function with bicytopenia (Table I). Multiple blood cultures obtained at the time of fever showed no growth. A bone marrow examination showed normocellular marrow with focal granulomatous inflammation. A transjugular liver biopsy showed non-necrotizing histiocytic aggregates including granulomas. AFB smears, tuberculosis polymerase chain reaction (TB PCR) and cultures for bacteria and fungi from bone marrow and liver were negative (Table II). In view of onset of illness within few hours of intravenous BCG injection, and evidence of disseminated granulomatous disease, a diagnosis of disseminated mycobacterial infection was considered and the patient was initiated on anti-mycobacterial therapy targeted to M. bovis (Table III). Levofloxacin was not given due to features of long QT syndrome in his ECG. His fever subsided within 1 week of initiation of therapy.
At follow-up, LJ culture reported growth of Mycobacterium tuberculosis complex (includes M. bovis) from the bone marrow providing microbiological confirmation of the diagnosis.
Case 3
A 57-year-old man diagnosed with non-muscle invasive urothelial cell carcinoma, post-TURBT was recommended intravesical BCG injection. He received inadvertent intravenous injection, and started having high-grade fever after a few hours. He presented to us 3 weeks later with high-grade intermittent fever, abdominal pain and loss of appetite and weight. Liver function was deranged at the baseline. He had bicytopenia and required one red cell transfusion for correction of anaemia (Table I). In view of the history and temporal profile, a strong clinical suspicion of dis-seminated mycobacterial infection was considered and the patient was evaluated. Bone marrow histopathology was consistent with granulomatous inflammation (Table II). He was initiated on anti-mycobacterial therapy targeted to M. bovis based on the clinical profile. The patient’s symptoms subsided after initiation of therapy, and there was no relapse of disease during a 1-year follow-up period.
All patients were treated with a weight-based regimen composed of HREL, without the addition of pyrazinamide2 (Table III).
DISCUSSION
The use of intravesical BCG is the standard of care in the treatment of non-muscle-invasive bladder cancer.1 Multiple doses and unfamiliarity with this route of administration can lead to mistakes regarding the mode of administration, resulting in a life-threatening illness. Factors including patient education and appropriate documentation of route of administration can help prevent the same. In all cases of accidental intravenous injection, patients present with a rapid onset febrile illness within a few hours of the injection. Commonly accompanying features include deranged liver function tests with granulomatous hepatitis on histo-pathology and granulomatous inflammation in the bone marrow.
Haematogenous spread of M. tuberculosis seems to show a predilection for the more vascular organs including the liver, spleen, bone marrow and brain. Organ involvement in miliary tuberculosis, caused by haematogenous spread, reports a high incidence of involvement of one or more cell lines (15%–87%), granulomatous hepatitis (79%) with elevated transaminases (42%) and alkaline phosphatase (83%).3–5 Fiberoptic bronchoscopy, bone marrow biopsy and liver biopsy are the most common investigations, which yield a tissue diagnosis in miliary disease.3 Seeding of the central nervous system and adrenal has also been noted; however, these rarely seem to cause symptomatic disease.6,7 M. bovis and M. tuberculosis, both part of the M. tuberculosis complex when grown in special culture media, are closely related and the disease they produce in humans is indistinguishable clinically, radiographically, pathologically or by direct smear microscopy. Though M. bovis is part of the M. tuberculosis complex, it is intrinsically resistant to pyrazinamide. Early initiation of therapy can help contain the spread and provide symptomatic relief to the patient.
Conclusion
Patients receiving BCG immunotherapy can be at risk of disseminated infection with M. bovis in case of incorrect route of administration, and the same needs to be explained to the patient. The presentation of a febrile illness with onset shortly after receiving BCG injection should prompt immediate referral to an infectious disease physician, to proceed with appropriate evaluation and early initiation of treatment.
Conflicts of interest
None declared
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