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.[3–7]
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.
2 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.
2.1 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.
2.2 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.
2.3 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.
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.[9–18] 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.[8,19,20] 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.
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).[9–18] 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.[21,22]
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.
. Tavares A, Lima Neto JX, Fulco UL, et al. Inhibition of the checkpoint protein PD-1 by the therapeutic antibody pembrolizumab
outlined by quantum chemistry. Sci Rep 2018;8:1840.
. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012;366:2443–54.
. Bertrand A, Kostine M, Barnetche T, et al. Immune related adverse events associated with anti-CTLA-4 antibodies: systematic review and meta-analysis. BMC Med 2015;13:211.
. Chen TW, Razak AR, Bedard PL, et al. A systematic review of immune-related adverse event
reporting in clinical trials of immune checkpoint inhibitors. Ann Oncol 2015;26:1824–9.
. Gao J, He Q, Subudhi S, et al. Review of immune-related adverse events in prostate cancer patients treated with ipilimumab: MD Anderson experience. Oncogene 2015;34:5411–7.
. Horvat TZ, Adel NG, Dang TO, et al. Immune-related adverse events, need for systemic immunosuppression, and effects on survival and time to treatment failure in patients with melanoma treated with ipilimumab at memorial sloan kettering cancer center. J Clin Oncol 2015;33:3193–8.
. Johnson DB, Friedman DL, Berry E, et al. Survivorship in immune therapy: assessing chronic immune toxicities, health outcomes, and functional status among long-term ipilimumab survivors at a single referral center. Cancer Immunol Res 2015;3:464–9.
. Naidoo J, Wang X, Woo KM, et al. Pneumonitis
in patients treated with anti-programmed death-1/programmed death ligand 1 therapy. J Clin Oncol 2017;35:709–17.
. Lu CS, Liu JH. Pneumonitis
in cancer patients receiving anti-PD-1 and radiotherapies: three case reports. Medicine (Baltimore) 2017;96:e5747.
. Helber HA, Hada AL, Pio RB, et al. Immunotherapy-induced pneumonitis
: cases report. Einstein (Sao Paulo) 2018;16:eRC4030.
. Fiset PO, Shapera S, Butler MO, et al. Anti-PD-1-associated organizing pneumonia in a responding melanoma patient. Ann Oncol 2016;27:1649–50.
. Arays R, Wang P. A case of pembrolizumab
-induced localized organizing pneumonia. Scand J Immunol 2018;88:e12677.
. Rickard F, Hyams C, Low AT. Pneumonitis
: a serious adverse effect of PD-L1 inhibitors including pembrolizumab
. BMJ Case Rep 2018;2018:
. Leroy V, Templier C, Faivre JB, et al. Pembrolizumab
. ERJ Open Res 2017;3:
. Kuint R, Lotem M, Neuman T, et al. Organizing pneumonia following treatment with pembrolizumab
for metastatic malignant melanoma - a case report. Respir Med Case Rep 2017;20:95–7.
. Nishino M, Ramaiya NH, Hatabu H, et al. PD-1 inhibitor-related pneumonitis
in lymphoma patients treated with single-agent pembrolizumab
therapy. Br J Haematol 2018;180:752–5.
. Fragkou P, Souli M, Theochari M, et al. A case of organizing pneumonia (OP) associated with pembrolizumab
. Drug Target Insights 2016;10:9–12.
. Oltolini C, Ripa M, Andolina A, et al. Invasive pulmonary aspergillosis complicated by carbapenem-resistant pseudomonas aeruginosa infection during pembrolizumab
immunotherapy for metastatic lung adenocarcinoma: case report and review of the literature. Mycopathologia 2019;184:184–5.
. Cui P, Liu Z, Wang G, et al. Risk factors for pneumonitis
in patients treated with anti-programmed death-1 therapy: a case-control study. Cancer Med 2018;7:4115–20.
. Nishino M, Ramaiya NH, Awad MM, et al. PD-1 inhibitor-related pneumonitis
in advanced cancer patients: radiographic patterns and clinical course. Clin Cancer Res 2016;22:6051–60.
. Yoon YK, Kim MJ, Yang KS, et al. The role of serum procalcitonin
in the differential diagnosis of pneumonia from pulmonary edema among the patients with pulmonary infiltrates on chest radiography. Medicine (Baltimore) 2018;97:e13348.
. Sim JK, Oh JY, Lee EJ, et al. Serum procalcitonin
for differential diagnosis of acute exacerbation and bacterial pneumonia in patients with interstitial lung disease. Am J Med Sci 2016;351:499–505.