重症新冠病毒肺炎患者的抢救性治疗之四--PD1抗体引发免疫性肺炎治疗方案的启示

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新冠病毒引发的免疫性肺炎和PD1抗体引发的免疫性肺炎是有相通之处的。


先看看PD1抗体引发的免疫性肺炎的治疗方案。
这是2018年的ASCO/NCCN指南， 所以安全性有保证。
注意这里有几种不同的选择， 最轻的用药是prednisolone静脉注射， 如果48小时无效，会添加Infliximab, 或者是mycophenolate mofetil, IVIG, cyclophosphamide中的一个。


考虑到重症病人的肺部已经出现显著损伤，我会建议跳过prednisolone静脉注射这一步。直接进行prednisolone联合Infliximab， 或者是prednisolone联合mycophenolate mofetil， 或者是prednisolone联合cyclophosphamide。


这个表格里面没有妥珠单抗，实际上IL-6受体抗体妥珠单抗和TNF-alpha抗体头对头的在治疗类风湿性关节炎的4期临床实验比较过。
4期临床的结果是IL-6受体抗体妥珠单抗的治疗效果优于TNF-alpha抗体。


而妥珠单抗也已经在最近一些临床实验中用于治疗PD1抗体引发的免疫毒性。
J Oncol Pharm Pract. 2019 Apr;25(3):551-557. doi: 10.1177/1078155217745144. Epub 2017 Dec 5.
Tocilizumab for the management of immune mediated adverse events secondary to PD-1 blockade.

Stroud CR1, Hegde A1, Cherry C1, Naqash AR1, Sharma N1, Addepalli S1, Cherukuri S1, Parent T1, Hardin J1, Walker P1.
Author information

Abstract
BACKGROUND:
Immune checkpoint inhibitors are poised to revolutionize the management of a growing number of malignancies. Unfortunately, the management of steroid-refractory immune mediated adverse events is based on a paucity of randomized data and limited to single center experiences. Our initial experience with the IL-6 receptor antagonist tocilizumab showed clinical improvement in a wide variety of irAEs. As a result, we adopted the use of tocilizumab for the management of steroid refractory irAEs.
METHODS:
The character and clinical course of irAEs were abstracted from the medical record and analyzed. The dose of tocilizumab was 4mg/kg given IV over one hour. C-reactive protein was drawn at first nivolumab infusion and at q two weeks (and with irAEs) thereafter. Clinical improvement was defined as either: documentation of resolution of symptoms or hospital discharge within seven days.
RESULTS:
Of the initial 87 patients that were treated with nivolumab, 34 required tocilizumab (39.1%). All patients were on corticosteroids. The majority (88.2%) were lung cancer patients. The index grade 3/4 irAE was pneumonitis in 35.3%, serum sickness/SIRS in 35.3%, cerebritis in 14.7% and one case each of hypophysitis, colitis, pancreatitis, hepatitis and immune mediated coagulopathy. Median time between first nivolumab and initiation of tocilizumab was 76 days (range 1-429). There was a statistically significant increase in C-reactive protein from a median of 23mg/L (range 0.1-238.5) at baseline to 109.3mg/L (21.5-350.4) at the time of index irAE, followed by a decrease to 19.2mg/L (0.25-149) after tocilizumab ( p<0.00001). Clinical improvement was noted in 27/34 patients (79.4%). Some patients (52.9%) required a single dose, while 38.2% required two, 8.8% required three and 1 patient required four doses. Twenty-seven doses were given in the inpatient setting (49.1%). Median time to discharge was four days (range 1-27). Seventy-four percent of patients were discharged home. For the 53 doses of tocilizumab that were delivered when infliximab was an option, there was a cost savings of $141,048.72 (WAC) during the 18 month study period.
CONCLUSIONS:
Tocilizumab may be a therapeutic option for the management of steroid refractory irAEs secondary to immune checkpoint blockade. However, randomized trials are needed to better elucidate the relative efficacy and safety of these agents.
妥珠单抗治疗PD1抗体免疫毒性的临床有效率79.4%， 并且52.9%的病人只需要一次注射就可以了。


所以对于重症的新冠病毒肺炎病人， 标准的方案应该考虑新冠病毒抑制剂（克力芝或者remdesivir）联合免疫抑制剂（妥珠单抗/阿达木单抗/mycophenolate mofetil/cyclophosphamide）。


吗替麦考酚酯（霉酚酸酯）mycophenolate mofetil由于可以抑制冠状病毒，可能会有加成的治疗效果。


我写的这一系列文章，你们可以看到我推荐的治疗方案是不断进化的， 从一开始的HIV病毒蛋白酶抑制剂克力芝，到后面的冠状病毒广谱抑制剂remdesivir， 再到免疫抑制剂妥珠单抗，阿达木单抗和吗替麦考酚酯（霉酚酸酯）的介绍，最后到remdesivir和免疫抑制剂的联用， 一步步的推进，每一种药物的选择都需要考虑是否适合新冠病毒的生物学特性还有病人的临床进展程度。


作为一个医生， 需要解决临床上的复杂问题，面对全新的冠状病毒肺炎，考验的就是基础知识的积累，文献的查阅分析，理性的思考和大胆的决策。


这次的浩劫过去之后，我请你们如果有可能，关心一下蒋医生。他若能安度晚年， 日后还会有像他这样的人在出现人间浩劫的时候挺身而出， 他若晚景凄惨，便是寒了众人的心。