Pneumonitis and concomitant bacterial pneumonia in patients receiving pembrolizumab treatment: Three case reports and literature review.

RATIONALE: Pembrolizumab, a monoclonal antibody against the programmed cell death 1 (PD-1) protein, can induce a stable regression of some malignancies refractory to conventional chemotherapy. Despite such therapeutic benefits, pembrolizumab can induce immune-related adverse events, with pneumonitis being the most critical problem. PATIENT CONCERNS: All 3 patients complained of fever, cough, and dyspnea after a variable time interval (1-21 days) from pembrolizumab treatment. DIAGNOSES: Chest computed tomography invariably showed ground glass opacity. All tests for possible infectious agents were negative. Based on high procalcitonin level, one of 3 patients was diagnosed to have accompanying bacterial pneumonia.
INTERVENTIONS: All patients received antibiotics and steroid treatments (methylprednisolone, 1 mg/kg). OUTCOMES: The 3 patients showed different clinical courses ranging from mild pneumonitis to rapidly progressing respiratory failure. Among the 3 patients, 2 fully recovered with steroid treatment; 1 died from superimposed bacterial pneumonia. LESSONS: The prognosis of pembrolizumab-induced pneumonitis with a superimposed bacterial pneumonia would be poor. It is important to distinguish pure pneumonitis from that with a superimposed bacterial pneumonia.

Introduction

The monoclonal antibodies (mAbs) against programmed cell death 1 (PD-1) and programmed death ligand 1 (PD-L1) are immune checkpoint inhibitors blocking inhibitory T-cell activities.[ Anti-PD-1/PD-L1 mAbs have emerged as a therapeutic option for melanoma and other tumor types including non-small-cell lung cancer and renal cell carcinoma refractory to conventional chemotherapy.[ Despite the therapeutic benefits of these immune checkpoint inhibitors, their use can induce immune-related adverse events (irAEs) including hypophysitis, colitis, hepatitis, pneumonitis, and rash.[

Currently, mAbs targeting PD-1, including nivolumab and pembrolizumab, are approved in many countries around the world.[ Among them, pembrolizumab is a humanized mAb (IgG4 subclass) with potential immune checkpoint inhibitory and antineoplastic activities.[ Despite its favorable antineoplastic activities, pneumonitis, the most serious irAE, is known to develop in 5% of cases after anti-PD-1/PD-L1 mAb treatment.[ Herein, we present 3 cases of pembrolizumab-induced pneumonitis with different clinical courses ranging from mild pneumonitis to rapidly progressing respiratory failure. In the cases reported here, pembrolizumab-induced pneumonitis was diagnosed excluding other possible causative agents.

Case report

The case reports were approved by the Institutional Review Board (IRB) of GSAM Medical Center (No. G2019007). The IRB exempted patient's consents for publication of the following case reports and accompanying images.

Case 1

A 52-year-old woman with metastatic colon cancer presented with high fever (38.8°C) and dyspnea (Table 1). She had been treated 1 day prior to presentation with 100 mg pembrolizumab. She complained of cough productive of thick, purulent sputum. Coarse breathing sounds with crackles and wheezing were noted on auscultation of the bilateral lung fields. Oxygen saturation was 90% on room air. On the 2nd day, C-reactive protein (CRP) and procalcitonin (PCT) increased from 70 mg/dL and 0.11 ng/mL to 83 mg/dL and 0.38 ng/mL, respectively. Chest X-ray imaging and computed tomography (CT) showed ground-glass opacities (GGOs) and focal nodular consolidations on right middle lobe (Fig. 1). Based on the high PCT level, although bacterial pathogen was not identified, this case was clinically diagnosed to have accompanying bacterial pneumonia. Despite steroid (methylprednisolone, 1.0 mg/kg per day) and antibiotic (piperacillin/tazobactam, 4.5 g every 8 hours) treatments, the patient died from rapidly progressing respiratory failure on the 4th day.

Table 1

Clinical manifestations, laboratory data, and treatment outcome of patients with pembrolizumab-induced pneumonitis.

Figure 1

Chest X-ray and computed tomography (CT) findings: ground glass opacities (GGOs) were observed on both lower lung fields and focal nodular consolidations were found on right middle lung fields (case 1); bilateral multifocal GGOs were observed (case 2); bilateral multifocal GGOs were noted with left-sided pleural effusion (case 3).

Case 2

A 55-year-old man with metastatic nasopharyngeal cancer who was treated with 100 mg pembrolizumab presented a week later complaining of fever (peak body temperature 37.8°C), dry cough, and dyspnea (Table 1). On auscultation, decreased breath sounds were noted in the left lung field without crackles. Despite a 5-day antibiotic therapy (piperacillin/tazobactam, 4.5 g every 8 hours), his fever did not subside. CRP increased from 56 to 94 mg/dL and initial PCT level was 0.10 ng/mL. Chest X-ray imaging and CT showed GGOs on both lung fields (Fig. 1). Intravenous methylprednisolone at a dose of 1 mg/kg per day was started. After methylprednisolone treatment, his fever subsided, and his symptoms immediately improved. The patient was treated with methylprednisolone for a total of 7 days.

Case 3

A 55-year-old woman with breast cancer and malignant pleural effusion who was treated with pembrolizumab (100 mg) 21 days prior presented with a dry cough, dyspnea, and fever (peak body temperature 37.9°C) (Table 1). On auscultation, breath sounds were decreased without crackles. She was treated with piperacillin/tazobactam (4.5 g every 8 hours) for suspected nosocomial bacterial pneumonia. Despite 10 days of antibiotic treatment, her symptoms persisted and chest CT showed GGOs on both lung fields (Fig. 1). Transbronchial lung biopsy was performed, and methylprednisolone was administered at a dose of 1.0 mg/kg per day. Lung biopsy showed focal septal lymphocytic infiltration (Fig. 2). After a 10-day methylprednisolone treatment, her dyspnea resolved, her chest X-ray findings improved, and her CRP levels decreased from 52 to 4 mg/dL. The patient subsequently recovered without any complications.

Figure 2

Histopathologic findings of lung biopsy specimen (case 3). There is focal lymphocytic infiltration at the interlobular septum.

Discussion

Pneumonitis is one of the major irAEs of anti-PD-1/PD-L1 mAbs.[ Although anti-PD-1/PD-L1 mAbs are generally recognized as safe, 27 of 578 cases (5.0%) treated with these mAbs were complicated by pneumonitis in one multicenter study.[ The same study reported that 12% (5 cases) of these pneumonitis cases died despite steroid therapy. The mortality rate was dependent on the grade of pneumonitis: grade 1 (0%, 0 of 17), grade 2 (0%, 0 of 14), and grades 3 to 5 (42%, 5 of 12).[ Among the 5 fatal cases, 3 died from accompanying infections. Histologic findings were diverse: interstitial pneumonitis (4 of 11), organizing pneumonia (3 of 11), diffuse alveolar damage (1 of 11), and no identified abnormalities (3 of 11).[

Table 2 summarizes previously published case reports on pembrolizumab-induced pneumonitis. As shown in Table 2, pembrolizumab-induced pneumonitis developed with variable intervals after treatment, ranging from 1 week to 2 years.[ Pneumonitis occurred after diverse dose (median, 4 doses) of PD1 inhibitor treatment, ranging from 1 to 38 doses.[ Regarding the risk factors for pembrolizumab-induced pneumonitis, little is known, but smoking, prior treatment, lung cancer, prior thoracic radiotherapy, and prior lung disease were suggested to promote pneumonitis development.[ In this study, case 1 developed pneumonitis just 1 day after exposure to pembrolizumab. The preexisting risk factors (diffuse lymphangitic lung metastasis) might contribute to the rapid development of pembrolizumab-induced pneumonitis.

Table 2

Baseline characteristics and treatment outcome of patients with pembrolizumab-induced pneumonitis.

As for the radiographic findings of PD1 inhibitor-induced pneumonitis, GGOs (100%), reticular opacities (90%), and consolidation (60%) were commonly observed in the previous reports.[ Consistently, GGOs were noted in all 3 cases, while focal consolidation was also observed in case 1.

The overall mortality rate (20.8%) in reports in Table 2 is higher than that (12%) reported in the multicenter study by Naidoo et al.[ This difference might be due to the prompt recognition and early treatment by more experienced clinicians in the multicenter study. In the previous case reports, almost all cases were treated with steroid and more than 60% received antibiotics (Table 2).[ However, descriptions of the accompanying infections were lacking (Table 2). According to the multicenter study, 60% (3 of 5) of the fatal cases had accompanying infections.[ Similarly, in this study, the 1st case that was fatal had a superimposed bacterial pneumonia which, in combination with the pneumonitis, most likely led to the demise of the patient. Thus, it is likely that her prognosis was poor because of her superimposed infection. However, it may be difficult to distinguish pure pneumonitis from that with superimposed bacterial pneumonia. In this regard, markers like PCT could be useful to differentiate pure pneumonitis from that complicated with bacterial pneumonia. Similarly, PCT has been shown to be useful in distinguishing lung infection from interstitial lung disease and pulmonary edema.[

Author contributions

Conceptualization: Jiho Jun, Joon Young Song.

Data curation: Jiho Jun, Sang-Ryung Lee, Ji Yean Lee, Hong Gi Lee.

Methodology: Jiho Jun, Min Joo Choi, Ji Yun Noh, Hee Jin Cheong, Woo Joo Kim, Joon Young Song.

Writing – original draft: Jiho Jun, Joon Young Song.

Writing – review & editing: Jiho Jun, Sang-Ryung Lee, Ji Yean Lee, Min Joo Choi, Ji Yun Noh, Hee Jin Cheong, Woo Joo Kim, Joon Young Song.