Comparative Analysis of Clinical Characteristics of Patients with Malignant Solid Tumors Treated with and without Immunocheckpoint Inhibitors after COIVD-19 Infection
Background: With the continuous development of medical science, the application of immune checkpoint inhibitors (ICIs) in malignant solid tumors is becoming increasingly widespread. However, as a respiratory disease that may cause pneumonia, whether the clinical manifestations of novel coronavirus disease 2019 (COVID-19) in patients with malignant solid tumors treated with and without ICIs are different is one of the clinical concerns. Although COVID-19 does not have an outbreak, it is still commonly seen in clinical practice. Once a patient is co infected, whether it affects clinical treatment decisions remains a concern. Therefore, this study included post infection patients for relevant analysis in order to provide guidance for clinical selection. Objective: Therefore, the purpose of this study is to analyze the clinical manifestations of patients with malignant solid tumors infected with COIVD-19 in the ICIs treatment group and the non-ICIs treatment group, and explore the differences in clinical manifestations between the two groups and the possible reasons. Methods: Retrospectively collect the solid tumor patients who visited the First Department of Shaanxi Cancer Hospital from December 2022 to February 2023, and divide them into the ICIs treatment group and the non-ICIs treatment group according to whether they accept the inhibitors of the immune checkpoint, and use chi-square test to analyze whether there is a difference in the incidence of COVID-19 infection between the two groups. At the same time, among positive patients, we use chi-square test to analyze whether there are differences between the two groups in fever symptoms, cough and phlegm symptoms, and pneumonia incidence, and use the two-independent sample t test to analyze the positive duration. Results: Finally, 191 hospitalized solid tumor patients were included, including 68 in the ICIs treatment group and 123 in the non-ICIs treatment group. There were 57 and 98 positive infections in both groups, respectively. The incidence of COVID-19 infection in both groups was not statistically significant (p = 0.48). Among them, there were a total of 155 positive patients, including 57 in the ICIs treatment group and 98 in the non-ICIs treatment group. There was no statistically significant difference in the incidence of fever between the two groups (p = 0.67); There was no statistically significant difference in the duration of positivity between the two groups (p = 0.79); There was no statistically significant difference in cough and phlegm symptoms between the two groups (p = 0.99); A total of 142 chest CT cases were rechecked. Among the ICIs treatment group, the incidence of pneumonia was higher than that of the non-ICIs group, with a statistically significant difference (p = 0.03); There is no correlation between cough and sputum symptoms and pneumonia (p = 0.82). Conclusion: The incidence of pneumonia after COIVD-19 infection in solid tumor patients treated with ICIs is significantly increased, which may be due to the activation of the body’s immune system by ICIs, which leads to imbalance of immune homeostasis in the lungs and increases infiltration of lymph node cells in the lungs. However, COIVD-19 infection triggers the release of inflammatory factors in the body, which also leads to imbalance of immune function in the body. The interaction leads to a significant increase in the incidence of pneumonia.
Malignant Solid Tumor
恶性肿瘤患者因为癌症本身和抗癌治疗的影响常处于免疫抑制状态,所以COIVD-19流行期间,恶性肿瘤患者感染COVID-19后出现其他并发症的风险可能更高。免疫检查点抑制剂(immune checkpoint inhibiter, ICIs)是一种阻断程序性细胞死亡介导受体的单克隆抗体,可以导致T细胞活化增强抗肿瘤作用,已经成为恶性肿瘤治疗的常用手段之一。但是ICIs也可能引起免疫介导的毒副反应,包括T细胞介导的免疫反应、自身抗体释放以及炎症因子释放等等,而COIVD-19感染后也会导致体内免疫系统激活,以及炎症因子的释放,所以,使用ICIs治疗的恶性肿瘤患者感染COIVD-19后临床特征是否会发生改变呢?本文对2022-12至2023-02防疫政策调整群体免疫后入院的实体肿瘤患者的临床特征进行统计,以期为感染后患者的临床治疗选择提供参考。
回顾性收集2022-12至2023-02期间收治于陕西省肿瘤医院内一科的实体肿瘤患者的临床资料及临床症状。纳入标准:经病理确诊的实体肿瘤患者。新型冠状病毒肺炎诊断依据《新型冠状病毒肺炎诊疗方案(试行第九版)》,即需要满足以下两个条件之一:(1) 新型冠状病毒核酸检测阳性;(2) 未接种新型冠状病毒疫苗者新型冠状病毒特异性免疫球蛋白(IgM)抗体和IgG抗体均为阳性。排除临床资料缺失或无准确随访资料的患者。按照既往是否使用ICIs治疗(包括目前正在使用以及既往使用,停药时间3个月以内患者)分为ICIs治疗组和非ICIs治疗组。
收集患者的一般资料、临床症状以及影像学资料。一般资料包括年龄、性别、既往抗肿瘤治疗药物种类。临床特征包括最高体温、是否存在咳嗽咳痰症状以及COIVD-19感染后转阴天数。影像学资料为胸部CT,根据CT描述及影像学表现判定患者是否存在新发肺炎。
采用SPSS 26.0进行统计学分析,计数资料比较采取χ2检验或连续校正χ2检验;计量资料采用 表示,比较采用独立样本的t检验,以P < 0.05为差异具有统计学意义。
根据纳入及排除标准,2022-12至2023-02期间于陕西省肿瘤医院住院符合入组条件的患者共计191例,男性118例,女性73例,平均年龄为59.4岁。ICIs治疗组共68人,其中COIVD-19阳性57人,阴性11人;非ICIs治疗组共123人,COIVD-19阳性98人,阴性25人。两组患者中,COIVD-19感染率差异无统计学意义(P > 0.05) (见
组别 |
例数 |
是否有发热症状 |
|
是 |
否 |
||
ICIs治疗组 |
68 |
57 (83.82) |
11 (16.18) |
非ICIs治疗组 |
123 |
98 (79.67) |
25 (20.33) |
χ2值 |
0.493 |
||
P值 |
0.483 |
阳性患者共计155人,其中ICIs治疗组57人,有发热症状38人,无发热症状19人;非ICIs治疗组,98人,有发热症状62人,无发热症状36人。统计结果显示,发热症状在ICIs治疗组和非ICIs治疗中的发生率无统计学差异(P > 0.05) (见
组别 |
例数 |
是否有发热症状 |
|
是 |
否 |
||
ICIs治疗组 |
57 |
3 8(66.67) |
19 (33.33) |
非ICIs治疗组 |
98 |
62 (63.27) |
36 (36.73) |
χ2值 |
0.182 |
||
P值 |
0.670 |
所有阳性患者中,ICIs治疗组中出现咳嗽、咳痰症状者39人,非ICIs治疗组中出现咳嗽、咳痰症状者67人。统计结果显示,咳嗽咳痰症状在ICIs治疗组和非ICIs治疗中的发生率无明显统计学差异(P > 0.05) (见
组别 |
例数 |
是否有咳嗽或咳痰 |
|
是 |
否 |
||
ICIs治疗组 |
57 |
39 (68.42) |
18 (31.58) |
非ICIs治疗组 |
98 |
67 (68.37) |
31 (31.63) |
χ2值 |
0.000 |
||
P值 |
0.994 |
COIVD-19感染并完善胸部CT检查者共142例,ICIs治疗组52例,发生肺炎46例,未发生肺炎6例;非ICIs治疗组90例,发生肺炎66例,未发生肺炎24例。统计结果显示,肺炎的发生率在ICIs治疗组明显升高,与非ICIs治疗组相比差异具有统计学意义(P < 0.05) (见
组别 |
例数 |
影像学是否有炎症 |
|
是 |
否 |
||
ICIs治疗组 |
52 |
46 (88.46) |
6 (11.54) |
非ICIs治疗组 |
90 |
66 (73.33) |
24 (26.67) |
χ2值 |
4.527 |
||
P值 |
0.033 |
阳性患者并完善胸部CT检查者共 142例;有咳嗽、咳痰症状者97例,其中发生肺炎者77例,未发生肺炎者20例;无咳嗽、咳痰患者45例,其中发生肺炎者35例,未发生肺炎者10例。统计结果显示,咳嗽、咳痰与肺炎是否发生无相关性(P > 0.05) (见
组别 |
例数 |
影像学是否有炎症 |
|
是 |
否 |
||
有咳嗽或咳痰 |
97 |
77 (79.38) |
20 (20.62) |
无咳嗽或咳痰 |
45 |
35 (77.78) |
10 (22.22) |
χ2值 |
0.047 |
||
P值 |
0.828 |
阳性患者155人,ICIs治疗组57人,平均转阴天数为10.42 ± 8.45天;非ICIs治疗组98人,平均转阴天数为10.77 ± 7.18天。统计结果显示,两组转阴天数间差异不具有统计学意义(P > 0.05) (见
组别 |
例数 |
新冠感染持续时间( ,天) |
ICIs治疗组 |
97 |
10.42 ± 8.45 |
非ICIs治疗组 |
45 |
10.77 ± 7.18 |
t值 |
−0.270 |
|
P值 |
0.788 |
恶性实体肿瘤发病率一直居高不下,并呈逐年增加趋势
首先,既往有研究表明,当患者合并高血压、糖尿病、恶性肿瘤、自身免疫性疾病等基础疾病时,发生新型冠状病毒肺炎的风险及进展至重症的风险将显著高于无基础疾病患者
从临床症状角度来看,研究发现,患有Omicron的新冠肺炎患者最常见的症状是咳嗽、咳痰、发热、咽痛、咽部瘙痒、流鼻涕和鼻塞
姜天俊等
在肺炎的发生方面,本研究统计结果显示,ICIs治疗组肺炎的发生率明显高于非ICIs治疗组,两组差异具有统计学意义。从影像学表现来看,COIVD-19所致肺炎在初始常表现为GGO (磨玻璃密度ground glass opacity,GGO),当肺泡腔内渗出量明显增加时,肺泡腔内气体会被取代,从而融合形成实变。而铺路石征的出现主要因为小叶间质炎症渗出增厚,同时肺泡腔内大量巨噬细胞浸润
咳嗽咳痰的发生可能与病毒对支气管及肺泡的损伤相关,ICIs治疗组咳嗽咳痰症状发生率高,提示炎症因子等的释放,与病毒相互作用,可能导致咳嗽咳痰症状加重,这与影像学表现提示ICIs治疗组中肺炎发生率明显增加结果一致。但咳嗽咳痰症状最终统计结果无明显统计学差异,可能与数据量少以及入院患者均为轻症存在一定相关性。
总之,ICIs治疗后COIVD-19感染的患者临床症状相比非ICIs治疗组并未加重,未出现预期外的相关临床症状。但肺炎的发生率明显增加,所以,对于ICIs治疗后且COIVD-19感染的患者,免疫治疗可能通过双重免疫激活引发细胞因子风暴,加重病情。而接受过ICIs治疗后的患者,可能通过增强体内T细胞活性,在控制肿瘤的同时改善COIVD-19感染后的肺部炎症和器官功能障碍。COIVD-19感染对免疫治疗的影响因患者免疫状态、肿瘤类型及感染严重程度而异。现有证据支持在多数情况下,合理暂停治疗后重启是安全的,且免疫治疗本身未显著增加新冠死亡风险。未来需进一步扩大临床研究样本,优化治疗策略,以实现肿瘤控制与感染管理的平衡。从而积极干预,避免不可逆改变的发生或延误治疗危及生命。
本研究存在一定的局限性,例如患者的年龄、肿瘤类型、疾病分期、合并症等可能影响肺炎的发生率,可能对研究结论结果存在一定的影响。另外,ICIs相关肺炎的发生与患者免疫状态、药物相互作用及感染风险高度关联,需通过多维度评估。
本文受到西安市科技计划(医学研究一般项目No. 2024YXYJ0179)项目资助。
本文作者之间无利益冲突。
该病例报道已获得病人的知情同意。
*通讯作者。