Disseminated Bacillus Calmette–Guérin (BCG) infection and acute exacerbation of interstitial pneumonitis: an autopsy case report and literature review

Intravesical administration of Bacillus Calmette–Guérin (BCG) has proven useful for treatment and prevention of recurrence of superficial bladder cancer and in situ carcinoma [1]. Although most patients have improved clinical outcomes without fatal complications, both local and systemic complications may occur following instillation [2]. The underlying mechanisms of such complications are not fully understood. However, hypersensitivity reactions and mycobacterial infection are at least two possibilities [3, 4]. Interstitial pneumonitis (IP) is reported to occur in 0.7% of patients treated with intravesical administration of BCG [5]. However, to our knowledge, there have been no reports of patients with acute exacerbation of existing IP. We report the case of a patient with fatal IP after intravesical BCG treatment and the pathological findings of the autopsy.

A 77-year-old man with fever and malaise was referred to our hospital. He had undergone transurethral resection of a bladder tumour on the right wall 1 month before admission. Because the pathological diagnosis was malignant cancer, he had received an 40 mg of intravesical injection of BCG 1 day before the admission for the first time. His medical history included hypertension, diabetes, dyslipidaemia and subclinical IP, which had been diagnosed 5 months ago at a medical check-up. He had smoked around 20 cigarettes a day until 14 years ago.

On the first admission, his vital signs were as follows: body temperature 38.6 °C, heart rate 102 beats/min, and blood pressure 138/87 mmHg. His oxygen saturation was 94% on room air. Physical examination revealed fine crackles in the bilateral chest. Laboratory examinations revealed slightly high serum levels of hepatobiliary enzymes (AST 84 IU/L, ALT 39 IU/L, γ-GTP 116 IU/L, LD 268 IU/L, T-Bil 2.00 mg/dL) and C − reactive protein (CRP; 6.7 mg/dL). The white blood cell (WBC) counts were within the normal ranges. Sputum culture, urinary culture and two sets of blood cultures were negative for bacterial, mycobacterial, and fungal cultures. Mycobacterial cultures were performed by using BD BACTEC MGIT960® (Becton, Dickinson and company, New Jersey). A chest computed tomography (CT) scan revealed bilateral ground-glass shadow, unchanged compared to 5 months prior (Fig. 1a).

Because his fever occurred soon after the intravesical BCG injection, infection with BCG was suspected. The patient received antituberculosis drugs including rifampicin (RFP), isoniazid (INH) and ethambutol (EB). His fever, serum levels of hepatobiliary enzymes, and CRP immediately decreased to normal ranges within 4 days. He was discharged home on the sixth day with continuing antituberculosis drugs.

However, he was referred to our hospital again because of a high fever 5 days after discharge. On readmission, his vital signs were as follows: body temperature 39.9 °C, heart rate 115 beats/min, and blood pressure 166/74 mmHg. His oxygen saturation was 93% on room air. Fine crackles on the bilateral chest remained. He also showed rice grain–sized red papules on broad areas of his face, and red bean–sized erythema with pruritus and infiltration over his trunk and limbs (Fig. 2a). No other abnormal findings were noted on physical examination.

Laboratory examinations revealed high serum levels of hepatobiliary enzymes (AST 57 IU/L, ALT 41 IU/L, γ-GTP 552 IU/L, LD 390 IU/L, ALP 653 IU/L, T-Bil 1.89 mg/dL) and CRP (5.2 mg/dL). Other blood examinations, including WBC, were within the normal ranges. T-SPOT.TB (a type of interferon-gamma release assay) was negative. We took sputum culture, urinary culture and two sets of blood cultures again. However, they were negative for bacterial, mycobacterial, and fungal cultures.

A chest CT scan revealed bilateral ground-glass shadow, unchanged since the last hospitalisation. We could not detect the inflammatory focus by CT scan, so we presumed three possibilities for his fever: 1. initial aggravation of the BCG treatment: an allergic reaction against antigens of dead mycobacterium, 2. exacerbation of infection: inadequate treatment, 3. antituberculosis drug–induced fever. To make the correct diagnosis, we stopped the antituberculosis drugs. Skin biopsy of the exanthema revealed a drug eruption (Fig. 2b). The exanthema had regressed on the 20th day of hospitalisation after discontinuing antituberculosis drugs.

On day 20 from the first admission, a contrast-enhanced CT scan revealed hepatosplenomegaly (Fig. 1d). Liver biopsy revealed multiple epithelioid cell granulomas with Langhans giant cells (Fig. 2f). Caseous necrosis was not observed. Furthermore, Mycobacterium was not detected on Ziehl–Neelsen stain (Fig. 2g) or the rabbit polyclonal anti-BCG antibody (Dako)–based immunohistochemistry (IHC; Fig. 2h).

Leukopenia gradually proceeded after hospitalisation (day 12: 3900/μL, day 13: 5410/μL, day 18: 2110/μL). The blood level of haemoglobin decreased following the leukopenia. Bone marrow biopsy revealed multiple epithelioid granulomas (Fig. 2c). In the epithelioid cell granulomas, neither caseous necrosis nor Mycobacterium was detected with Ziehl–Neelsen stain and anti-BCG IHC (Fig. 2d). Berlin blue stain was negative (Fig. 2e). The bone marrow infection of BCG was suspected to be responsible for the leukoerythropenia. However, bone marrow, sputum and blood PCR for Mycobacterium (COBAS® TaqMan® MTB, Roche Diagnostics, Tokyo) were negative.

On day 20, the follow-up CT scan demonstrated a new ground-glass shadow on the bilateral upper lobe (Fig. 1c). The patient’s oxygen demand gradually worsened at this point (oxygen saturation was 94% on 2 L/min of oxygen). On day 27, his oxygen demand worsened drastically, and the ground-glass shadow had expanded on the CT scan. Moreover, the serum levels of KL-6 (1020 U/mL) and SP-D (330 ng/mL) were high, suggesting acute exacerbation of IP. The serum level of adenosine deaminase (ADA) was also high (183.2 U/L). From the high levels of ADA, KL-6, SP-D and the pathological findings of the biopsies, we diagnosed an acute exacerbation of IP associated with Mycobacterium bovis infection or hypersensitivity. We restarted antituberculosis drugs immediately. Because the antituberculosis drugs were suspected of causing drug eruption, we changed RFP to rifabutin (RFB). Furthermore, we used INH at a desensitisation amount and gradually increased. For IP, high-dose methylprednisolone (500 mg/day × 3 days intravenously) was also commenced. Prednisolone (50 mg/day [1 mg/kg] orally) was administered after the high-dose methylprednisolone.

Although no allergic symptoms occurred, including exanthema, the patient’s respiratory condition gradually worsened, and he died on day 35. The results of a drug-induced lymphocyte stimulation test on day 20 were negative for RFP, INH and EB.

We report a patient with mortal acute exacerbation of IP after intravesical BCG treatment. Pneumonitis is a rare complication of intravesical BCG treatment that occurs in less than 0.7% of patients following the repeated administration of BCG [5]. Some reports IP following BCG use. However, no reports have involved patients with chronic IP. Moreover, to our knowledge, this is the first case with anatomical pathology performed after BCG instillation.

Pathological findings revealed granuloma with Langhans giant cells in the liver, bone marrow, spleen and heart (Fig. 3a–e). From the episode of intravesical BCG treatment and the distribution of epithelioid cell granulomas, it is reasonable that the granuloma formation was a result of BCG dissemination, with or without hypersensitivity to its adjuvant, at least originally. If only the hypersensitivity to BCG had induced his clinical symptoms, the granulomas would have been found in the other organs. So, we suspect that, at least once, the BCG dissemination had occurred. In this case, we initially diagnosed BCG infection because the patient’s fever reduced only with administration of antituberculosis drugs. However, the examinations for Mycobacterium infection, including stain for acid-fast bacilli, culture, and PCR-based assay were all negative. Pérez et al. reported that microbiological-based diagnosis for BCG infection was positive in only 118 of 246 patients [4]. This suggests that all microbiological examinations being negative does not exclude the possibility of BCG infection.

Besides the acute exacerbation of IP, myelosuppression and hepatosplenomegaly were observed in this patient. Myelosuppression is reported in 0.1% of patients after BCG treatment [5]. It appears in tuberculosis when the bone marrow is involved in the infection. Cho et al. reported a patient who showed myelosuppression after intravesical BCG treatment. In that report, granulomas were found in the bone marrow biopsy [6]. Some reports have described miliary tuberculosis inducing myelosuppression. In those reports, antituberculosis drugs or other haematological disease complicated with tuberculosis have been suspected as one cause of myelosuppression [7]. In the present case, anti-BCG antibody–based IHC detected no Mycobacterium in the bone marrow biopsy, so whether the myelosuppression was induced by the infection or hypersensitivity is uncertain.

Hepatitis has been reported in 0.7% of patients after intravesical BCG treatment [5]. The mechanism of granulomatous hepatitis (as well as IP) after intravesical BCG treatment is not clear, but hypersensitivity and BCG infection have been proposed.

Since the mechanisms are still unclear, the treatment of IP following intravesical BCG treatment has not been established. Some reports have recommended using steroids because of the possibility of hypersensitivity [8, 9]. In particular, Israel-Biet et al. described three cases of IP related to intravesical BCG treatment [9]. They reported that the pulmonary complications induced by intravesical BCG therapy are rarely related to infection, because of negative bronchoalveolar lavage (BAL) cultures for mycobacterium and the increased population of activated lymphocytes highly sensitised to purified protein derivative on BAL. Moreover, one of the three patients fully recovered with corticosteroids alone, without antituberculosis drugs [9]. However, other reports have recommended combination therapy with antituberculosis drugs and steroids because of the possibility of infection [5]. Table 1 shows the previously reported cases of IP secondary to intravesical BCG treatment. Except for one case, all patients were treated with combination therapy using antituberculosis drugs and steroids (Table 1). The remaining case (case 13 in Table 1) received tacrolimus (TAC) and everolimus (EVL) for kidney transplantation; therefore, all patients received immunosuppression therapies. Nine out of sixteen cases underwent steroid pulse therapy and six recovered. All of the seven cases without steroid pulse therapy recovered. Although not enough cases exist for definitive conclusions, the use of steroid pulse therapy might have no effect on prognosis. In this case, we tried steroid pulse therapy with antituberculosis drugs; however, the patient’s IP did not improve. Kitani et al. reported high mortality in IP secondary to intravesical BCG treatment, at 26.9% [22]. Besides the high mortality, acute exacerbation of past IP might be a reason for the treatment resistance in this case.

Intravesical BCG treatment has proven effectiveness against urothelial cancer, but its rare side effects can be fatal. For patients receiving intravesical BCG treatment, close observation for respiratory condition, myelosuppression and hepatitis is necessary for early therapeutic intervention. Early diagnosis and treatment can improve the clinical outcomes of the patients with IP secondary to intravesical BCG treatment.