Risk factors of real-world immune checkpoint inhibitor-related pneumonitis in patients with lung cancer: a meta-analysis_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

YE Lei ¹ , FANG Shencun ¹ , ZHANG Haitao ¹ , QI Wei ¹ ,  XIA Guanghui ² , XU Xiaoyu ³

1. Department of Respiratory Medicine, Brain Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu 210024, P. R. China;
2. Nursing Department, Brain Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu 210024, P. R. China;
3. Department of Intensive Care Medicine, Brain Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu 210024, P. R. China;

Corresponding author：

XIA Guanghui, Email: 755411389@qq.com

Keywords：

Lung cancer; immune checkpoint inhibitor-related pneumonitis; immune-related adverse events; real-world study; risk factors; meta-analysis

DOI：

10.7507/1671-6205.202304036

Video：

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Abstract Full text Figures/Tables Video References Cited by

Objective Risk factors for real-word immune checkpoint inhibitor-related pneumonitis in patients with lung cancer were analyzed by systematic analysis. Methods Computerized retrieval of PubMed, EMbase, Web of Science, the Cochrane Library , WanFang Data, CNKI and VIP databases was carried out. Studies were collected from the database establishment to March 2023. Three researchers independently screened the literature, extracted data, and evaluated the risk of bias in the included studies. Meta-analysis was performed using RevMan5.4.1software. Results A total of 18 studies were included with a total of 4 990 patients. The results of meta-analysis showed that, interstitial pneumonia [odds ratio (OR)=9.32, 95% confidence interval (CI) 4.66 - 18.67, P<0.01], smoking history (OR=2.39, 95%CI 1.29 - 4.45, P<0.01), chronic obstructive pulmonary disease (COPD) (OR=5.54, 95%CI 2.96 - 10.36, P<0.01), chest radiotherapy (OR=2.74, 95%CI 1.80 - 4.19, P<0.01), pulmonary fibrosis (OR=7.46, 95%CI 4.25 - 13.09, P<0.01), high programmed death ligand 1 (PD-L1) expression (OR=2.98, 95%CI 1.71 - 5.22, P<0.01), high absolute eosinophil count (AEC) (OR=3.92, 95%CI 2.17 - 7.08, P<0.01) and pembrolizumab (OR=2.90, 95%CI 1.56 - 5.37, P<0.01) were independent risk factors for immune checkpoint inhibitor-related pneumonitis in lung cancer patients. Conclusions Interstitial pneumonia, smoking history, COPD, Chest radiotherapy, pulmonary fibrosis, high PD-L1expression, high AEC and pembrolizumab are independent risk factors for immune checkpoint inhibitor-related pneumonitis in lung cancer patients. Due to insufficient evidence on the risk factors of low albumin, more studies are needed to further identify it.

Citation： YE Lei, FANG Shencun, ZHANG Haitao, QI Wei, XIA Guanghui, XU Xiaoyu. Risk factors of real-world immune checkpoint inhibitor-related pneumonitis in patients with lung cancer: a meta-analysis. Chinese Journal of Respiratory and Critical Care Medicine, 2023, 22(6): 408-417. doi: 10.7507/1671-6205.202304036 Copy

1.	Cao W, Chen HD, Yu YW, et al. Changing profiles of cancer burden worldwide and in China: a secondary analysis of the global cancer statistics 2020. Chin Med J (Engl), 2021, 134(7): 783-791.
2.	Hanna NH, Schneider BJ, Temin S, et al. Therapy for Stage IV Non-Small-Cell Lung Cancer Without Driver Alterations: ASCO and OH (CCO) Joint Guideline Update. J Clin Oncol, 2020, 38(14): 1608-1632.
3.	Antonia SJ, Villegas A, Daniel D, et al. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N Engl J Med, 2018, 379(24): 2342-2350.
4.	Postow MA, Sidlow R, Hellmann MD. Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med, 2018, 378(2): 158-168.
5.	Cho JY, Kim J, Lee JS, et al. Characteristics, incidence, and risk factors of immune checkpoint inhibitor-related pneumonitis in patients with non-small cell lung cancer. Lung Cancer, 2018, 125: 150-156.
6.	Nishino M, Giobbie-Hurder A, Hatabu H, et al. Incidence of programmed cell death 1 inhibitor-related pneumonitis in patients with advanced cancer: a systematic review and meta-analysis. JAMA Oncol, 2016, 2(12): 1607-1616.
7.	Shi YQ, Fang J, Zhou CZ, et al. Immune checkpoint inhibitor-related adverse events in lung cancer: real-world incidence and management practices of 1905 patients in China. Thorac Cancer, 2022, 13(3): 412-422.
8.	吴建辉, 储香玲, 王李强, 等. 中国肺癌患者真实世界免疫检查点抑制剂相关性肺炎的流行病学分析. 中国癌症杂志, 2022, 32(6): 469-477.
9.	De Velasco G, Je Y, Bossé D, et al. Comprehensive meta-analysis of key immune-related adverse events from CTLA-4 and PD-1/PD-L1 inhibitors in cancer patients. Cancer Immunol Res, 2017, 5(4): 312-318.
10.	中华医学会呼吸病学会分会肺癌学组. 免疫检查点抑制剂相关肺炎诊治专家共识. 中华结核和呼吸杂志, 2019, 42(11): 820-825.
11.	Ma K, Lu YL, Jiang SS, et al. The relative risk and incidence of immune checkpoint inhibitors related pneumonitis in patients with advanced cancer: a meta-analysis. Front Pharmacol, 2018, 9: 1430.
12.	陈康, 孙步彤. PD-1/PD-L1抑制剂在晚期肿瘤患者中的相关肺炎发生率和发生风险: 一项荟萃分析. 中国肺癌杂志, 2020, 23(11): 927-940.
13.	周巧, 余荷, 梁宗安. 免疫检查点抑制剂导致免疫相关性肺炎. 中国呼吸与危重监护杂志, 2021, 20(10): 753-756.
14.	Yamaguchi T, Shimizu J, Oya Y, et al. Risk factors for pneumonitis in patients with non-small cell lung cancer treated with immune checkpoint inhibitors plus chemotherapy: a retrospective analysis. Thorac Cancer, 2022, 13(5): 724-731.
15.	Chao YC, Zhou JB, Hsu SJ, et al. Risk factors for immune checkpoint inhibitor-related pneumonitis in non-small cell lung cancer. Transl Lung Cancer Res, 2022, 11(2): 295-306.
16.	Barrón F, Sánchez R, Arroyo-Hernández M, et al. Risk of developing checkpoint immune pneumonitis and its effect on overall survival in non-small cell lung cancer patients previously treated with radiotherapy. Front Oncol, 2020, 10: 570233.
17.	Chu XL, Zhao J, Zhou J, et al. Association of baseline peripheral-blood eosinophil count with immune checkpoint inhibitor-related pneumonitis and clinical outcomes in patients with non-small cell lung cancer receiving immune checkpoint inhibitors. Lung Cancer, 2020, 150: 76-82.
18.	Fukihara J, Sakamoto K, Koyama J, et al. Prognostic impact and risk factors of immune-related pneumonitis in patients with non-small-cell lung cancer who received programmed death 1 inhibitors. Clin Lung Cancer, 2019, 20(6): 442-450.e4.
19.	Osaki M, Arai T, Sumikawa H, et al. Immune checkpoint inhibitor-related pneumonitis in lung cancer patients with interstitial lung disease: significance of radiological pleuroparenchymal fibroelastosis. Oncology, 2023, 101(5): 303-312.
20.	Jia XH, Chu XL, Jiang LL, et al. Predicting checkpoint inhibitors pneumonitis in non-small cell lung cancer using a dynamic online hypertension nomogram. Lung Cancer, 2022, 170: 74-84.
21.	Sawa K, Sato I, Takeuchi M, et al. Risk of pneumonitis in non-small cell lung cancer patients with preexisting interstitial lung diseases treated with immune checkpoint inhibitors: a nationwide retrospective cohort study. Cancer Immunol Immunother, 2023, 72(3): 591-598.
22.	Suresh K, Voong KR, Shankar B, et al. Pneumonitis in non-small cell lung cancer patients receiving immune checkpoint immunotherapy: incidence and risk factors. J Thorac Oncol, 2018, 13(12): 1930-1939.
23.	Atchley WT, Alvarez C, Saxena-Beem S, et al. Immune checkpoint inhibitor-related pneumonitis in lung cancer: real-world incidence, risk factors, and management practices across six health care centers in North Carolina. Chest, 2021, 160(2): 731-742.
24.	Zhang C, Gao FY, Jin SD, et al. Checkpoint inhibitor pneumonitis in Chinese lung cancer patients: clinical characteristics and risk factors. Ann Palliat Med, 2020, 9(6): 3957-3965.
25.	Isono T, Kagiyama N, Takano K, et al. Outcome and risk factor of immune-related adverse events and pneumonitis in patients with advanced or postoperative recurrent non-small cell lung cancer treated with immune checkpoint inhibitors. Thorac Cancer, 2021, 12(2): 153-164.
26.	Cui PF, Liu ZF, Wang GQ, et al. Risk factors for pneumonitis in patients treated with anti-programmed death-1 therapy: a case-control study. Cancer Med, 2018, 7(8): 4115-4120.
27.	Lin XQ, Deng HY, Yang YL, et al. Peripheral blood biomarkers for early diagnosis, severity, and prognosis of checkpoint inhibitor-related pneumonitis in patients with lung cancer. Front Oncol, 2021, 11: 698832.
28.	郝娜. 晚期非小细胞肺癌免疫检查点抑制剂相关性肺炎的临床特征、危险因素及预后分析[D]. 河南: 郑州大学, 2022.
29.	汪婧媛, 孙虎, 冯慧晶, 等. 免疫检查点抑制剂治疗非小细胞肺癌产生免疫相关不良反应和肺炎的特点及其危险因素分析. 中国肿瘤生物治疗杂志, 2022, 29(11): 995-1001.
30.	卢梓荣. 非小细胞肺癌发生免疫相关性肺炎的危险因素研究和列线图模型构建[D]. 广州医科大学, 2022.
31.	Zhou PN, Zhao X, Wang GF. Risk factors for immune checkpoint inhibitor-related pneumonitis in cancer patients: a systemic review and meta-analysis. Respiration, 2022, 101(11): 1035-1050.
32.	Zhai XY, Zhang J, Tian YR, et al. The mechanism and risk factors for immune checkpoint inhibitor pneumonitis in non-small cell lung cancer patients. Cancer Biol Med, 2020, 17(3): 599-611.
33.	Suzuki Y, Karayama M, Uto T, et al. Assessment of immune-related interstitial lung disease in patients with NSCLC treated with immune checkpoint inhibitors: a multicenter prospective study. J Thorac Oncol, 2020, 15(8): 1317-1327.
34.	Mark NM, Kargl J, Busch SE, et al. Chronic obstructive pulmonary disease alters immune cell composition and immune checkpoint inhibitor efficacy in non-small cell lung cancer. Am J Respir Crit Care Med, 2018, 197(3): 325-336.
35.	Sun ZQ, Wang S, Du HD, et al. Immunotherapy-induced pneumonitis in non-small cell lung cancer patients: current concern in treatment with immune-check-point inhibitors. Invest New Drugs, 2021, 39(3): 891-898.
36.	代华平. 纤维化间质性肺疾病正确—早期识别与干预. 国际呼吸杂志, 2021, 41(21): 1601-1604.
37.	成超, 李杰. 放疗联合免疫检查点抑制剂治疗肺癌致放射–免疫相关性肺炎的研究进展. 中国癌症防治杂志, 2022, 14(6): 687-692.
38.	高鹏云, 武志峰. 免疫检查点抑制剂相关肺炎的临床与影像研究. 中华结核与呼吸杂志, 2022, 45(2): 238-242.
39.	Teng FF, Li M, Yu JM. Radiation recall pneumonitis induced by PD-1/PD-L1 blockades: mechanisms and therapeutic implications. BMC Med, 2020, 18(1): 275.
40.	Cousin F, Desir C, Ben Mustapha S, et al. Incidence, risk factors, and CT characteristics of radiation recall pneumonitis induced by immune checkpoint inhibitor in lung cancer. Radiother Oncol, 2021, 157: 47-55.
41.	王慧, 夏茸, 魏清雯, 等. 非小细胞肺癌免疫检查点抑制剂相关性肺炎的危险因素及预测生物标志物. 国际肿瘤学杂志, 2021, 48(5): 296-301.
42.	谢国钢. 非小细胞肺癌免疫检查点抑制剂治疗疗效预测标志物的研究现状. 中国医师进修杂志, 2022, 45(2): 97-100.
43.	Peng TR, Tsai FP, Wu TW. Indirect comparison between pembrolizumab and nivolumab for the treatment of non-small cell lung cancer: a meta-analysis of randomized clinical trials. Int Immunopharmacol, 2017, 49: 85-94.

1. Cao W, Chen HD, Yu YW, et al. Changing profiles of cancer burden worldwide and in China: a secondary analysis of the global cancer statistics 2020. Chin Med J (Engl), 2021, 134(7): 783-791.
2. Hanna NH, Schneider BJ, Temin S, et al. Therapy for Stage IV Non-Small-Cell Lung Cancer Without Driver Alterations: ASCO and OH (CCO) Joint Guideline Update. J Clin Oncol, 2020, 38(14): 1608-1632.
3. Antonia SJ, Villegas A, Daniel D, et al. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N Engl J Med, 2018, 379(24): 2342-2350.
4. Postow MA, Sidlow R, Hellmann MD. Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med, 2018, 378(2): 158-168.
5. Cho JY, Kim J, Lee JS, et al. Characteristics, incidence, and risk factors of immune checkpoint inhibitor-related pneumonitis in patients with non-small cell lung cancer. Lung Cancer, 2018, 125: 150-156.
6. Nishino M, Giobbie-Hurder A, Hatabu H, et al. Incidence of programmed cell death 1 inhibitor-related pneumonitis in patients with advanced cancer: a systematic review and meta-analysis. JAMA Oncol, 2016, 2(12): 1607-1616.
7. Shi YQ, Fang J, Zhou CZ, et al. Immune checkpoint inhibitor-related adverse events in lung cancer: real-world incidence and management practices of 1905 patients in China. Thorac Cancer, 2022, 13(3): 412-422.
8. 吴建辉, 储香玲, 王李强, 等. 中国肺癌患者真实世界免疫检查点抑制剂相关性肺炎的流行病学分析. 中国癌症杂志, 2022, 32(6): 469-477.
9. De Velasco G, Je Y, Bossé D, et al. Comprehensive meta-analysis of key immune-related adverse events from CTLA-4 and PD-1/PD-L1 inhibitors in cancer patients. Cancer Immunol Res, 2017, 5(4): 312-318.
10. 中华医学会呼吸病学会分会肺癌学组. 免疫检查点抑制剂相关肺炎诊治专家共识. 中华结核和呼吸杂志, 2019, 42(11): 820-825.
11. Ma K, Lu YL, Jiang SS, et al. The relative risk and incidence of immune checkpoint inhibitors related pneumonitis in patients with advanced cancer: a meta-analysis. Front Pharmacol, 2018, 9: 1430.
12. 陈康, 孙步彤. PD-1/PD-L1抑制剂在晚期肿瘤患者中的相关肺炎发生率和发生风险: 一项荟萃分析. 中国肺癌杂志, 2020, 23(11): 927-940.
13. 周巧, 余荷, 梁宗安. 免疫检查点抑制剂导致免疫相关性肺炎. 中国呼吸与危重监护杂志, 2021, 20(10): 753-756.
14. Yamaguchi T, Shimizu J, Oya Y, et al. Risk factors for pneumonitis in patients with non-small cell lung cancer treated with immune checkpoint inhibitors plus chemotherapy: a retrospective analysis. Thorac Cancer, 2022, 13(5): 724-731.
15. Chao YC, Zhou JB, Hsu SJ, et al. Risk factors for immune checkpoint inhibitor-related pneumonitis in non-small cell lung cancer. Transl Lung Cancer Res, 2022, 11(2): 295-306.
16. Barrón F, Sánchez R, Arroyo-Hernández M, et al. Risk of developing checkpoint immune pneumonitis and its effect on overall survival in non-small cell lung cancer patients previously treated with radiotherapy. Front Oncol, 2020, 10: 570233.
17. Chu XL, Zhao J, Zhou J, et al. Association of baseline peripheral-blood eosinophil count with immune checkpoint inhibitor-related pneumonitis and clinical outcomes in patients with non-small cell lung cancer receiving immune checkpoint inhibitors. Lung Cancer, 2020, 150: 76-82.
18. Fukihara J, Sakamoto K, Koyama J, et al. Prognostic impact and risk factors of immune-related pneumonitis in patients with non-small-cell lung cancer who received programmed death 1 inhibitors. Clin Lung Cancer, 2019, 20(6): 442-450.e4.
19. Osaki M, Arai T, Sumikawa H, et al. Immune checkpoint inhibitor-related pneumonitis in lung cancer patients with interstitial lung disease: significance of radiological pleuroparenchymal fibroelastosis. Oncology, 2023, 101(5): 303-312.
20. Jia XH, Chu XL, Jiang LL, et al. Predicting checkpoint inhibitors pneumonitis in non-small cell lung cancer using a dynamic online hypertension nomogram. Lung Cancer, 2022, 170: 74-84.
21. Sawa K, Sato I, Takeuchi M, et al. Risk of pneumonitis in non-small cell lung cancer patients with preexisting interstitial lung diseases treated with immune checkpoint inhibitors: a nationwide retrospective cohort study. Cancer Immunol Immunother, 2023, 72(3): 591-598.
22. Suresh K, Voong KR, Shankar B, et al. Pneumonitis in non-small cell lung cancer patients receiving immune checkpoint immunotherapy: incidence and risk factors. J Thorac Oncol, 2018, 13(12): 1930-1939.
23. Atchley WT, Alvarez C, Saxena-Beem S, et al. Immune checkpoint inhibitor-related pneumonitis in lung cancer: real-world incidence, risk factors, and management practices across six health care centers in North Carolina. Chest, 2021, 160(2): 731-742.
24. Zhang C, Gao FY, Jin SD, et al. Checkpoint inhibitor pneumonitis in Chinese lung cancer patients: clinical characteristics and risk factors. Ann Palliat Med, 2020, 9(6): 3957-3965.
25. Isono T, Kagiyama N, Takano K, et al. Outcome and risk factor of immune-related adverse events and pneumonitis in patients with advanced or postoperative recurrent non-small cell lung cancer treated with immune checkpoint inhibitors. Thorac Cancer, 2021, 12(2): 153-164.
26. Cui PF, Liu ZF, Wang GQ, et al. Risk factors for pneumonitis in patients treated with anti-programmed death-1 therapy: a case-control study. Cancer Med, 2018, 7(8): 4115-4120.
27. Lin XQ, Deng HY, Yang YL, et al. Peripheral blood biomarkers for early diagnosis, severity, and prognosis of checkpoint inhibitor-related pneumonitis in patients with lung cancer. Front Oncol, 2021, 11: 698832.
28. 郝娜. 晚期非小细胞肺癌免疫检查点抑制剂相关性肺炎的临床特征、危险因素及预后分析[D]. 河南: 郑州大学, 2022.
29. 汪婧媛, 孙虎, 冯慧晶, 等. 免疫检查点抑制剂治疗非小细胞肺癌产生免疫相关不良反应和肺炎的特点及其危险因素分析. 中国肿瘤生物治疗杂志, 2022, 29(11): 995-1001.
30. 卢梓荣. 非小细胞肺癌发生免疫相关性肺炎的危险因素研究和列线图模型构建[D]. 广州医科大学, 2022.
31. Zhou PN, Zhao X, Wang GF. Risk factors for immune checkpoint inhibitor-related pneumonitis in cancer patients: a systemic review and meta-analysis. Respiration, 2022, 101(11): 1035-1050.
32. Zhai XY, Zhang J, Tian YR, et al. The mechanism and risk factors for immune checkpoint inhibitor pneumonitis in non-small cell lung cancer patients. Cancer Biol Med, 2020, 17(3): 599-611.
33. Suzuki Y, Karayama M, Uto T, et al. Assessment of immune-related interstitial lung disease in patients with NSCLC treated with immune checkpoint inhibitors: a multicenter prospective study. J Thorac Oncol, 2020, 15(8): 1317-1327.
34. Mark NM, Kargl J, Busch SE, et al. Chronic obstructive pulmonary disease alters immune cell composition and immune checkpoint inhibitor efficacy in non-small cell lung cancer. Am J Respir Crit Care Med, 2018, 197(3): 325-336.
35. Sun ZQ, Wang S, Du HD, et al. Immunotherapy-induced pneumonitis in non-small cell lung cancer patients: current concern in treatment with immune-check-point inhibitors. Invest New Drugs, 2021, 39(3): 891-898.
36. 代华平. 纤维化间质性肺疾病正确—早期识别与干预. 国际呼吸杂志, 2021, 41(21): 1601-1604.
37. 成超, 李杰. 放疗联合免疫检查点抑制剂治疗肺癌致放射–免疫相关性肺炎的研究进展. 中国癌症防治杂志, 2022, 14(6): 687-692.
38. 高鹏云, 武志峰. 免疫检查点抑制剂相关肺炎的临床与影像研究. 中华结核与呼吸杂志, 2022, 45(2): 238-242.
39. Teng FF, Li M, Yu JM. Radiation recall pneumonitis induced by PD-1/PD-L1 blockades: mechanisms and therapeutic implications. BMC Med, 2020, 18(1): 275.
40. Cousin F, Desir C, Ben Mustapha S, et al. Incidence, risk factors, and CT characteristics of radiation recall pneumonitis induced by immune checkpoint inhibitor in lung cancer. Radiother Oncol, 2021, 157: 47-55.
41. 王慧, 夏茸, 魏清雯, 等. 非小细胞肺癌免疫检查点抑制剂相关性肺炎的危险因素及预测生物标志物. 国际肿瘤学杂志, 2021, 48(5): 296-301.
42. 谢国钢. 非小细胞肺癌免疫检查点抑制剂治疗疗效预测标志物的研究现状. 中国医师进修杂志, 2022, 45(2): 97-100.
43. Peng TR, Tsai FP, Wu TW. Indirect comparison between pembrolizumab and nivolumab for the treatment of non-small cell lung cancer: a meta-analysis of randomized clinical trials. Int Immunopharmacol, 2017, 49: 85-94.

Chinese Journal of Respiratory and Critical Care Medicine

Risk factors of real-world immune checkpoint inhibitor-related pneumonitis in patients with lung cancer: a meta-analysis

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