Severe diffuse proliferative bronchiolitis complicating culture-proven disseminated BCG infection after intravesical instillation for bladder cancer
- 1 General Medicine, Gloucester Royal Hospital, Gloucester, UK
- 2 General Medicine, Bristol Royal Infirmary, Bristol, UK
- Correspondence to Dr Faroakh Hosseini; faroakh.hosseini4@nhs.net
Abstract
A man in his 70s was admitted to hospital following several months of dyspnoea, night sweats, weight loss and, latterly, fevers. His symptoms correlated with a second maintenance cycle of intravesical BCG instillation for superficial bladder cancer. Blood tests showed raised C-reactive protein, alkaline phosphatase and gamma-GT, although extensive further investigations did not reveal any specific cause. Treatment for a presumed diagnosis of disseminated BCG infection was started, following which his fevers ceased. Later available results of liver biopsy taken prior to treatment supported this diagnosis, and mycobacterial blood and urine cultures grew Mycobacterium bovis. Recovery was complicated by a severe diffuse proliferative bronchiolitis which responded to corticosteroids. This case highlights an important dichotomy in the pathophysiology of disseminated BCG infection. It demonstrates how morbidity can be caused by both a direct dissemination of the organism and an immune hypersensitivity response in the same patient.
Background
Intravesical BCG instillation remains the standard treatment for high-risk non-muscle-invasive bladder cancer.1 Localised or disseminated BCG infection following this treatment in immunocompetent patients has been reported in the literature and may present in myriad ways.2 Since these cases are rare, current opinion is divided on the pathogenesis of disseminated BCG infection,3 in particular regarding how much of the damage is due to direct spread of the organism and how much is due to an immune hypersensitivity response.
Case presentation
A man in his 70s was admitted to hospital through his general practitioner following several months of general malaise, night sweats, weight loss and progressive dyspnoea. In the past week, he had also suffered daytime fevers, which prompted the acute admission.
His antecedents included a Grade 2 carcinoma-in-situ bladder cancer which had been treated by transurethral resection of the bladder tumour and intravesical mitomycin C instillation the year before. This had been followed by adjuvant induction intravesical BCG instillation and maintenance BCG instillations at 4 monthly intervals. He also had a history of peripheral vascular disease, ischaemic heart disease with prior stenting of his coronary arteries, a left renal artery stenosis and aneurysm which was under surveillance, diverticular disease and depression.
His symptoms seemed to correlate with the timing of his second cycle of maintenance intravesical BCG instillation.
He had fluctuating fevers throughout the early phase of his admission but his other vital parameters were stable and there were no focal findings on examination.
Investigations
On admission, he had a raised C-reactive protein of 82 mg/L (normal range <10 mg/L), alkaline phosphatase of 568 U/L (30–130 U/L) and a gamma-GT of 447 U/L (<61 U/L). Repeated standard blood cultures and a standard urine culture showed no growth. He underwent CT of the thorax, abdomen and pelvis which showed no evidence for either a malignant nor specific infective cause. Serum electrophoresis, urinary Bence-Jones proteins, serum immunoglobulins, an autoimmune profile and an anti-neutrophil cytoplasmic antibody screen were unremarkable. COVID-19 PCR testing was repeatedly negative during his admission and positive antibodies in the serum confirmed past immunisation. Tests for blood-borne viruses, B-glucan titre and an atypical infection serological screen were also negative. A T-Spot assay was negative. Transthoracic echocardiography showed normal heart function and no suspicion of vegetations.
The respiratory specialist consulted felt that bronchoscopy would be of doubtful benefit, given the absence of radiological abnormalities and the paucity of specific respiratory symptoms.
Differential diagnosis
At this stage, given his history and the above extensive negative investigations, the likely diagnosis was thought to be a disseminated BCG infection with involvement of the liver signalled by derangement in hepatic enzymes on admission. A liver biopsy was performed, then treatment for this probable diagnosis was initiated immediately because of high clinical likelihood and reluctance to delay definitive treatment while waiting for these results.
Treatment
He was started on an induction regimen for BCG infection consisting of rifampicin 600 mg, isoniazid 300 mg and ethambutol 1000 mg, all once daily.
Outcome and follow-up
Initiating treatment led to a cessation of his persistent intermittent fever. His liver biopsy showed several non-caseating granulomata within the portal tracts and liver lobules (figure 1). Significant inflammation of the periportal areas and an inflammatory infiltrate (consisting of scattered histiocytes, lymphocytes, plasma cells and the occasional eosinophil) within the portal tracts were also present. These findings were consistent with a diagnosis of granulomatous hepatitis secondary to disseminated BCG infection. Further Ziehl-Neelsen staining did not reveal acid-fast bacilli, as in most cases.3 4 Tissue culture for acid-fast bacilli has also typically a low yield,4 and unfortunately could not be attempted with our specimen which had been transported in formalin. The Xpert MTB/RF nucleic acid amplification test was available in our laboratory but applicable only to sputum specimens, and our patient had no cough.
Liver biopsy histology showing multiple non-caseating granulomata.
However, a few days into his treatment and following this initial improvement, symptoms of breathlessness abruptly worsened and he became hypoxic. A chest X-ray showed increased interstitial markings and pleural effusions. A high-resolution CT of the thorax demonstrated peribronchovascular ground-glass, nodularity and tree-in-bud opacities in keeping with a rapidly progressive proliferative bronchiolitis (figure 2). Since this deterioration followed his antimycobacterial treatment and there is a known association of disseminated BCG infection with an immune hypersensitivity response, high-dose prednisolone was started with a dramatic improvement in symptoms. Once weaned off supplementary oxygen, he was discharged home with a reducing course of prednisolone over 8 weeks plus rifampicin, isoniazid and ethambutol for 2 months followed by a further 7 months of rifampicin and isoniazid only.
High-resolution CT imaging of the thorax showing peribronchovascular ground-glass, nodularity and tree-in-bud opacities in keeping with a rapidly progressive proliferative bronchiolitis.
At 2-month follow-up, he had a complete resolution of symptoms, a normalisation of blood biochemistry and chest radiography, and had regained most of the weight lost during his initial illness. A follow-up flexible cystoscopy at this point was also reassuring, showing no evidence of recurrent bladder cancer.
Mycobacterial blood cultures and mycobacterial urine cultures following discharge grew Mycobacterium bovis and so confirmed the diagnosis.
Discussion
Conclusive investigations which can confirm a diagnosis of disseminated BCG infection are in practice often of limited use, due both to a delay in the results (histopathology can take days to weeks to process and mycobacterial cultures weeks to grow) and to the poor sensitivity of mycobacterial cultures.4 Interestingly, since T-Spot assay is negative with the attenuated BCG strain of M. bovis, as in our case, it has limited use as a diagnostic investigation.5 Furthermore, presentation with disseminated BCG infection may occur months or even years after the initial intravesical instillation.6 A high clinical index of suspicion, identification of a suitable site for biopsy and empirical treatment without waiting for culture results are therefore mandatory, particularly in aggressive infections.
This case is unique in clearly demonstrating a dual pathogenesis of disseminated BCG infection. The literature is ambivalent in this regard, with certain cases demonstrating direct spread and damage from the organism itself, and others a T-cell medicated immune hypersensitivity reaction occasionally successfully treated with corticosteroids alone.7 8 Our case shows evidence of a direct spread of M. bovis confirmed with positive blood and urine cultures, and the clinical cessation of fevers with antimycobacterial treatment. However, the patient also had an immune hypersensitivity reaction manifesting as rapid clinical deterioration from a severe diffuse proliferative bronchiolitis after antimycobacterial agents were initiated and requiring additional treatment with corticosteroids. This indeed gives evidence for both hypotheses within the same individual and provides additional insight into the pathogenesis of disseminated BCG infections.
Another phenomenon described in cases of Mycobacterium tuberculosis infections is that of a paradoxical drug reaction, where symptoms worsen following the initiation of mycobacterial treatment.9 10 Although commonly associated with HIV co-infection and co-treatment and representing inflammation secondary to reconstitution of a deficient immune system, it has also been described in immunocompetent individuals.10 Even more rarely, cases have been described in non-tuberculoid mycobacterial infections.11 The key difference between this phenomenon and the hypersensitivity reaction described in disseminated BCG lies in the longer period between treatment onset and deterioration (months rather than days).
Learning points
-
Disseminated BCG infection should be considered as a cause for a fever of unknown origin in an immunocompetent individual with a history of intravesical BCG instillation.
-
The diagnosis can be difficult to prove and conclusive investigations may take time to process; therefore, pre-emptive treatment based on a high clinical index of suspicion is necessary.
-
The pathogenesis of disseminated BCG infection in a single individual episode can be both from a direct spread of organisms and from immune hypersensitivity. In these cases, effective treatment demands both antimicrobial agents and corticosteroids.
Ethics statements
Patient consent for publication
Acknowledgments
We would like to thank Dr Chandima De Cates (Consultant Histopathologist) and Dr Amer Rehman (Consultant Radiologist) of Gloucestershire Hospitals NHS Foundation Trust for kindly providing the images seen.
Footnotes
-
Contributors AAAN reviewed the literature and led the writing up of the final manuscript. FH acquired the images seen, patient consent and contributed to revisions of the manuscript. NT conceived the paper, provided advice and guidance and contributed to revisions of the manuscript.
-
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
-
Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
-
Competing interests None declared.
-
Provenance and peer review Not commissioned; externally peer reviewed.
- © BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.
References
Use of this content is subject to our disclaimer