Drug‐induced interstitial pneumonia after intravesical Bacillus Calmette‐Guerin administration for bladder cancer with scleroderma

Abstract

Introduction

Intravesical Bacillus Calmette‐Guerin administration is the standard therapy for high‐risk nonmuscle invasive bladder cancer and is usually well tolerated. However, some patients experience severe, potentially fatal, complications including interstitial pneumonitis.

Case presentation

A 72‐year‐old female with scleroderma was diagnosed with bladder carcinoma in situ. She developed severe interstitial pneumonitis with the first administration of intravesical Bacillus Calmette‐Guerin after the cessation of immunosuppressive agents. Six days after the first administration, she experienced dyspnea at rest, and computed tomography revealed scattered frosted shadows in the upper lung. The following day, she required intubation. We suspected drug‐induced interstitial pneumonia and started steroid pulse therapy for 3 days, resulting in a complete response. No exacerbation of scleroderma symptoms or recurrence of cancer was observed 9 months after Bacillus Calmette‐Guerin therapy.

Conclusion

For patients receiving intravesical Bacillus Calmette‐Guerin therapy, close observation of the respiratory condition is necessary for early therapeutic intervention.

Abbreviations

ABG

arterial blood gas

ABPC

ampicillins

AZM

azithromycin

BCG

Bacillus Calmette‐Guerin

CIS

carcinoma in situ

CMV

cytomegalovirus

CT

computed tomography

DLST

drug‐induced lymphocyte stimulation test

GCV

ganciclovir

MEPM

meropenem

mPSL

methylprednisolone

NMIBC

nonmuscle invasive bladder cancer

PSL

prednisolone

SBT

sulbactam

ST

sulfamethoxazole and trimethoprim

TURBT

transurethral resection of the bladder tumor

Keynote message.

Intravesical administration of Bacillus Calmette‐Guerin (BCG) is the standard therapy for high‐risk nonmuscle invasive bladder cancer and sometimes evokes fatal conditions. We report a case in which steroid pulse therapy was very effective for managing severe interstitial pneumonitis with an early diagnosis, in patients on the first induction of intravesical BCG.

Introduction

Intravesical administration of BCG is widely used as an adjuvant immunotherapeutic modality for CIS and for the prevention of recurrence of NMIBC. ¹ , ² Intravesical BCG therapy is usually well‐tolerated, however, severe local and systemic complications may occur. ³ , ⁴ In particular, interstitial pneumonitis is a rare complication in 0.7% of patients following intravesical BCG therapy that may lead to potentially lethal outcomes. ⁵

Here, we describe the case of a 72‐year‐old woman who received intravesical BCG therapy for CIS of the bladder after the withdrawal of immunosuppressive agents for scleroderma. The patient developed severe interstitial pneumonitis and was treated with steroids, with a complete response.

Case presentation

A 72‐year‐old woman with scleroderma presented with frequent urination. Urine cytology was positive, and subsequent cystoscopy revealed irregular bladder mucosa on the posterior wall. Based on these findings, we suspected bladder cancer and performed TURBT. At 2 months, after she was diagnosed with Grade 3 pT1 plus pTis urothelial carcinoma in TURBT, she underwent a second TURBT, resulting in no malignant findings in the resected specimens. We decided to perform intravesical BCG administration (80 mg Tokyo 172 strain), and she ceased azathioprine and steroids 2 months and 2 days before the administration of BCG because her scleroderma was stable (KL‐6 of 651 U/mL).

The day after the first administration of intravesical BCG, the patient presented with frequent urination, hematuria, low‐grade fever, and oxygen desaturation. Five days later, she experienced dyspnea at rest, and CT revealed scattered frosted shadows centered on the pulmonary hilum in the upper lung fields in addition to coexisting interstitial pneumonitis in the lower lung fields with primary scleroderma (Fig. 1). The clinical course of this patient is shown in Figure 2. We initially suspected drug‐induced interstitial pneumonia due to BCG allergy and performed a DLST. Pneumocystis carinii and CMV pneumonia were dismissed due to negative results for β‐D glucan and CMV antigenemia. PCR tests for tuberculosis bacillus and COVID‐19 also ruled out lung tuberculosis and COVID‐19 pneumonia.

Fig. 1.

Chest CT before and after the initiation of intravesical BCG. Six days after initiating the first intravesical BCG therapy, CT examination revealed scattered frosted shadows centered on the pulmonary hilum in the upper lung fields (red arrows), in addition to coexisting interstitial pneumonitis in the lower lung fields with primary scleroderma (blue arrows).

Fig. 2.

Clinical course of the case in the present study. After steroid pulse therapy for 3 days (red arrows), pulmonary infiltration gradually resolved, and the patient was extubated. During the clinical course of treatment, antibiotics were administered to prevent secondary bacterial infection.

On the 7th day after intravesical BCG, her respiratory condition deteriorated rapidly, her SpO₂ fell below 90% under 15 L/min of oxygen, and an ABG test revealed a PaO₂ of 55.6 mmHg and PaCO₂ of 34.0 mmHg. There was no change in KL‐6 level (621 U/mL). She was intubated with a diagnosis of drug‐induced interstitial pneumonia (Fig. 3a), then we started 1000 mg mPSL of steroid pulse therapy for 3 days. After switching to oral PSL, pneumonia gradually improved within the next 4 days, and the patient was extubated on the 11th day with the result of an ABG test (PaO₂ of 95.0 mmHg and PaCO₂ of 32.0 mmHg) (Fig. 3b). With a gradual decrease in PSL, the patient's general condition stabilized. Antibiotics were administered throughout the treatment period to prevent secondary bacterial pneumonia. On the 18th day after intravesical BCG administration, the DLST result was positive, and we finally diagnosed the patient with BCG drug‐induced pneumonia. During the therapeutic course of interstitial pneumonia, there was no exacerbation of scleroderma symptoms. Finally, the patient maintained no recurrence of cancer for 9 months after BCG therapy.

Fig. 3.

Chest X rays at the time of intubation and extubation. (a) Chest X ray at the time of intubation. PaO₂/FiO₂ ratio was 170. (b) Chest X ray at the time of extubation. PaO₂/FiO₂ ratio was 300.

Discussion

Interstitial pneumonitis is a rare complication of intravesical BCG therapy with signs and symptoms including fever, chills, productive cough, and dyspnea. ⁵ , ⁶ Diagnosis is usually made by the presence of a diffuse infiltrative pattern on chest X‐ray or CT scan and a positive biopsy for noncaseating epithelioid granuloma. ⁶ To date, in Japan, 21 cases of interstitial pneumonia after intravesical BCG therapy have been reported, including the case presented here (Table 1). The median patient age was 73 years (range 49–84 years). All cases were male, except for our case. Sixteen patients (76.2%) developed interstitial pneumonia during the first three cycles of intravesical BCG. The mortality rate was 23.8%, despite intensive steroid treatment. There was no patient with autoimmune disease except for our case.

Table 1.

Summary of the previous reports of interstitial pneumonitis after the initiation of intravesical BCG

Case	Age	Sex	The number of intravesical BCG	Steroid	DLST	Outcome
1	58	Male	2	PSL 40 mg/day	Unknown	Alive
2	76	Male	6	PSL 40 mg/day	Unknown	Alive
3	61	Male	3	Pulse	Positive	Alive
4	84	Male	4	Pulse	Unknown	Alive
5	61	Male	3	Pulse	Unknown	Alive
6	80	Male	6	Unknown	Unknown	Alive
7	72	Male	8	Pulse	Unknown	Death
8	75	Male	2	Pulse	Unknown	Alive
9	53	Male	6	Unknown	Unknown	Alive
10	65	Male	6	Pulse	Unknown	Alive
11	76	Male	4	Pulse	Unknown	Death
12	67	Male	8	PSL 30 mg/day	Unknown	Alive
13	70	Male	5	Pulse	Unknown	Death
14	75	Male	4	Pulse	Unknown	Death
15	78	Male	8	Unknown	Unknown	Alive
16	81	Male	5	Pulse	Positive	Death
17	80	Male	5	Pulse	Unknown	Alive
18	49	Male	5	Pulse	Positive	Alive
19	60	Male	Unknown	Pulse	Unknown	Alive
20	75	Male	7	Pulse	Positive	Alive
21	72	Female	1	Pulse	Positive	Alive

Steroid pulse therapy was performed with 1000 mg/day of mPSL for 3 days.

In this case, the patient had scleroderma treated with immunosuppressive drugs before starting intravesical BCG. Intravesical BCG therapy is usually contraindicated in patients receiving immunosuppressive drugs owing to the risk of disseminated infection and the limited efficacy, although a retrospective small cohort study reported the safety of BCG therapy in selected patients who are immunosuppressed (Level C evidence). ⁷ , ⁸ In consideration of the patients' safety, we first confirmed that there was no sign of worsening scleroderma after the withdrawal of azathioprine and steroids in stages.

As drug‐induced interstitial pneumonia is highly lethal, early detection is crucial for a prompt differential diagnosis. We successfully excluded the possibility of various infectious diseases, including Pneumocystis carinni, CMV, tuberculosis, and COVID‐19 pneumonia, and suspected drug‐induced interstitial pneumonitis that was later diagnosed using the DLST test. As shown in Table 1, only five cases were diagnosed as DLST‐positive since the DLST test may not be conducted in the other cases, which evokes the importance of performing this test.

Although it has been the major treatment for high‐risk NMIBC for almost 40 years, ⁹ the mechanism of intravesical BCG in controlling urothelial carcinoma continues to evolve. ¹⁰ Recently, Antonelli et al. reported that intravesical BCG leads to proliferation, activation, and differentiation of CD4⁺ T cells as well as previously reported CD8⁺ T cell‐driven immunoreactivity. ¹¹ , ¹² Given that the adverse reaction of intravesical BCG may be associated with a hypersensitivity immune reaction, corticosteroid use should be initiated immediately for lifesaving while ruling out the possibility of viral infectious disease. ¹³

In conclusion, intravesical BCG therapy has proven effective against NMIBC; however, interstitial pneumonia can be fatal. For patients receiving intravesical BCG therapy, close observation of their respiratory condition is necessary for early therapeutic intervention to achieve better clinical outcomes.

Author contributions

Fumie Yoshioka: Conceptualization; data curation; writing – original draft. Taigo Kato: Conceptualization, data curation, formal analysis, writing – original draft, writing – review and editing. Yoshihito Shima: Conceptualization; writing – review and editing. Koji Hatano: Formal analysis; writing – review and editing. Atsunari Kawashima: Formal analysis; writing – review and editing. Shinichiro Fukuhara: Formal analysis; writing – review and editing. Ryoichi Imamura: Formal analysis; writing – review and editing. Norio Nonomura: Supervision; writing – review and editing.

Conflict of interest

The authors declare that they have no conflict of interest.

Approval of the research protocol by an Institutional Reviewer Board

Not applicable.

Informed consent

Written informed consent was obtained.

Registry and the Registration No. of the study/trial

Not applicable.