Camrelizumab-induced anaphylactic shock in an esophageal squamous cell carcinoma

lNTRODUCTlON

Since its approval in 2019 by the National Drug Administration, camrelizumab (SHR-1210), an immune checkpoint inhibitor (ICI), is in wide clinical use as a therapeutic option for various tumor types[1].However, reports of camrelizumab-associated adverse reactions are increasing gradually, with any organ or tissue being affected. Reactive cutaneous capillary endothelial proliferation is the most common adverse event that is associated with camrelizumab, with an incidence accounting for about two-thirds of all patients treated with camrelizumab[2]. It is followed by immune-related hepatitis,pneumonia, and myocarditis among other clinical complications[3,4]. Until now, allergic reactions induced by ICIs have been reported in various studies[5,6].

实践证明，火电厂通过采用新技术、新工艺，加大设备节能技术改造，提升设备能效，加强运行管理，优化机组运行方式，加强设备治理，科学合理开展小指标竞赛等措施可有效降低机组厂用电率，提高全厂的经济性。在当前发电行业不利的经营环境下，行之有效的节能措施既可以提升企业竞争力，又可为企业带来可观的经济效益，为企业今后的发展注入新的活力。

As a relatively new programmed cell death 1 (PD-1) inhibitor, camrelizumab-induced anaphylactic shock has not yet been reported. We report here, for the first time, a case of camrelizumab-induced anaphylactic shock in a patient being treated for esophageal squamous cell carcinoma.

认知因素主要包括儿童对社会性行为的认识和对情景信息的识别等。近年来，国外的一系列研究揭示了儿童的社会认知特别是对突然行为意图的认知对儿童攻击性行为的调节作用。当儿童把自己所面临的消极后果知觉为同伴有意造成的时候，一般倾向于对同伴做出报复性攻击；反之，如果认为同伴是由于意外或出于善意的动机而给他造成了消极后果时，一般倾向于消释其恶意认定。同时，攻击性与非攻击性儿童对他人行为意图认知存在着差异，攻击性儿童在他人行为意图不明时倾向于做出敌意性归因。

CASE PRESENTATlON

Chief complaints

An 84-year-old male patient (163 cm in height, 41 kg in weight) presenting with esophageal cancer was administered with radiotherapy and chemotherapy 11 years prior, after which he got better.

History of present illness

The patient had no significant personal or family history.

History of past illness

Camrelizumab is a humanized PD-1 inhibitor that was developed by Jiangsu Hengrui Medicine Co.Ltd.[10]. It blocks the binding between programmed death ligand 1 and programmed death ligand 2 by targeting PD-1, thereby inhibiting tumor cell evasion from the immune system and ultimately causing an anti-tumor effect[11]. Camrelizumab has been clinically approved for the treatment of various tumors, including relapsed or refractory classical Hodgkins lymphoma, esophageal squamous cell carcinoma, hepatocellular carcinoma, and non-small cell lung cancer, among others[1,12]. Camrelizumab has therapeutic effects and has been shown to clinically improve various tumors, while having a manageable safety profile[13-17]. Moreover, it has exhibited potential anti-tumor effects in patients who failed chemotherapy or in those who are resistant to chemotherapy, while having an acceptable toxicity profile[18,19]. Due to the widespread application of camrelizumab, it has the potential to become a routine option for tumor immunotherapy[10]. However, camrelizumab-associated adverse events,including common reactive cutaneous capillary endothelial proliferation[2], immune-related hepatitis and pneumonia[3], immune-associated myocarditis[4], abnormal hepatic functions, anemia, and diarrhea[20], among others, have been reported. Most camrelizumab-associated adverse events are mild and can be regulated by interrupting treatment[20]. Camrelizumab-associated anaphylactic shock is rare but potentially fatal. Only two studies have reported on hypersensitivities induced by anti-programmed death ligand 1 agents[5,6]. Camrelizumab-associated allergic reactions or anaphylactic shock have never been reported previously. Therefore, the understanding of allergic reactions or anaphylactic shock caused by immune preparations such as camrelizumab is limited, which may create the potential for delays in identification and management during the early stages of hypersensitivity. This can lead to a life-threatening outcome. Here, we provide the first report of camrelizumab-associated anaphylactic shock, which should arouse the interest of clinicians.

Personal and family history

In December 2020, the patient was diagnosed with advanced esophageal squamous cell carcinoma with liver metastasis, classified as stage TxN1M1. Based on the 2020 Chinese Society of Clinical Oncology guidelines, the patient was administered the first immunotherapeutic (camrelizumab 200 mg/each time+ 0.9% NS 100 mL, intravenous infusion, q3w) and did not exhibit any adverse reactions. On January 12,2021, the patient was admitted to the hospital for the second time to be administered the same therapy.On January 19, 2021, the patient was introduced to intravenous infusions of camrelizumab. However, 10 min after initiating intravenous camrelizumab, he suddenly developed a generalized rash in the chest and upper limbs. He also experienced chest tightness without chest pain, palpitations, and breathing difficulties with a sense of dying.

词，又称曲子词。初创阶段是配合着乐曲来演唱的，通常是乐曲先行，再根据曲的长短、节奏填上词句，乐曲有所属宫调，宫调不同，则声情不同。另外，词作的文本形式也根据不同的词牌有不同的格律形式。《词调史研究》中写道“词调声情，既指词调音乐形式所体现出的风格特征，也包含词调语文形式展示的音韵魅力”[4]61。所以本节从宫调与用韵着手，探析《卜算子》的声情特征。

建国以来，抗战胜利纪念日经历了从“八一五”到“九三”，从行政法规到国家立法的双重变化，为更好开展抗战胜利纪念日活动创造了前提。

Physical examination

Electrocardiograph (ECG) monitoring revealed a pulse rate of 70 beats/min, blood pressure of 69/24 mmHg, a respiratory rate of 28 breaths/min, and a pulse oximetry of 86% in room air (no other medication was administered concomitantly). The patient presented with drowsiness and weakened cardiac sounds as well as a weak major arterial pulse.

《水土保持定额》中，关于“炸药、雷管、导线”等工艺的计量名称定额子目，运用新型炮锺挖掘机设备替代增加定额子目，以满足施工阶段的投资控制。

Laboratory examinations

Blood analysis revealed white blood cell count of 7.04 × 10/L, neutrophil count of 2.81 × 10/L (normal range: 2.0-7.5 × 10/L), neutrophil percentage of 39.90%, red blood cell count of 2.35 × 10/L,hemoglobin level of 66.00 g/L (normal range: 110-160 g/L), platelet count of 219.00 × 10/L (normal range: 100-300 × 10/L), C-reactive protein level of 31.61 mg/L (normal range: ＜ 0.5 mg/L), potassium level of 2.12 mmol/L (normal range: 3.5-5.0 mmol/L), chloride level of 117.80 mmol/L (normal range:96-108 mmol/L), and calcium level of 1.41 mmol/L (normal range: 2.0-2.6 mmol/L). Markers of renal function and levels of cardiac enzyme and troponin were normal.

Imaging examinations

ECG (Figure 1) revealed a sinus rhythm. Enhanced computed tomography scan revealed chronic inflammation of the right lower lobe with left-side pleural slight effusion (Figure 2).

考虑到视频中相邻帧的重复率一般比较高，关键帧的提取可以减少帧数，进而提升图像特征点检测和匹配效率，同时也为图像拼接提供一个组织框架。针对这项关键技术，得到了研究者们的广泛关注，并取得了一定研究成果。文献[1]从相邻帧间的颜色或纹理信息变化程度出发，提出了基于视频内容的方法。文献[2]通过计算当前帧与类心之间特征值的距离，将视频中所有帧进行聚类分析，得到基于视频聚类的分析方法。文献[3]提出基于运动特征分析的算法，其基本原理是利用光流分析，将视频中运动量最小的一帧作为关键帧。

FlNAL DlAGNOSlS

Individual factors also lead to the occurrence of allergic diseases. Epidemiologically, most anaphylactic shock cases occur in the older population, with higher risks among those aged over 70 years[26]. The mortality rate for females is lower than that of males[9]. Our patient was an 84-year-old male with esophageal squamous cell carcinoma and liver metastases. Therefore, he was at a high risk of anaphylactic shock.

TREATMENT

The intravenous camrelizumab infusion was stopped immediately. In lieu, treatment was begun with corticoids, adrenaline, norepinephrine and intravenous fluid. Continuous supplementation of intravenous potassium and calcium were also provided.

OUTCOME AND FOLLOW-UP

The patient reported his chest tightness to be significantly relieved. He also experienced no shortness of breath, palpitations, or discomfort. The upper limbs and chest rash subsided rapidly, at approximately 2 h after treatment. ECG monitoring revealed a pulse rate of 78 beats/min, blood pressure of 112/68 mmHg, respiratory rate of 19 breaths/min, and pulse oximetry of 99% (oxygen absorption at 2 L/min).

On January 20, 2021, biochemical examination revealed that serum potassium and calcium levels were normal. The basic treatment was continued, without repeated anaphylactic shock. It is very unfortunate, however, that the patient refused to return to use of the camrelizumab, due to his excessive fear of anaphylactic shock, even after the physician provided a sufficient explanation. As such, we consulted the published literature and found switching to another type of anti-PD-1 antibody to be a feasible alternative. Indeed, such an approach has been successfully reported, with patients exhibiting relatively good clinical effects without allergic reactions[5,6].

Another type of anti-PD-1 antibody, nivolumab, is an ICI with a similar mechanism of action that is effective for treatment. The adverse eDect profile of nivolumab is similar to those of camrelizumab, so the drugs related to the prevention of allergic reactions should be administered as premedication 30 min prior to the nivolumab infusion. The drawback is that it is very expensive and, in China, it is not covered by insurance reimbursement plans. Therefore, the patient rejected the physician’s suggestion to replace the immunotherapy drugs. The patient was discharged on January 23, 2021.

DlSCUSSlON

Adverse reactions for this case were evaluated according to the national adverse drug reaction Evaluation Standard of China[21]. Our patient experienced sudden-onset of the anaphylactic shock,within 10 min after intravenous injection of the camrelizumab infusion, implying an obvious time correlation between camrelizumab administration and development of the adverse event. Although there is no description of anaphylactic shock adverse events in the instructions for camrelizumab, it has been reported that serious hypersensitivities can occur after administration of the same anti-PD-1 or anti-programmed death ligand 1 agents, such as nivolumab[5,6]. Anaphylactic shock is a special manifestation of anaphylactic reactions; therefore, based on the above evidence, it can be considered that camrelizumab may cause hypersensitivities, including anaphylactic shock. After withdrawal of camrelizumab and administration of related treatments (, oxygen inhalation, anti-allergies, stable blood pressure treatment, and fluid resuscitation) were initiated, out patient’s blood pressure returned to normal, chest tightness symptoms were significantly relieved, and all his other medications were continued while he gradually improved after 3 h. Since then, the patient has not had symptoms of anaphylactic shock. In addition, the patient had no history of drug anaphylaxis, and there were no changes in the use of other drugs before and after the occurrence of anaphylactic shock. The patient did not experience anaphylactic shock again after stopping the camrelizumab treatment; this allowed us to exclude the association of anaphylactic shock for the other drugs he was taking. Since his Naranjo Adverse Drug Reaction Probability Scale score was 5[22], we concluded that the anaphylactic shock was most likely caused by the camrelizumab administration.

The patient had a previous medical history free of allergy.

Anaphylactic shock is a serious life-threatening acute systemic hypersensitivity reaction that is characterized by rapid development of life-threatening bronchospasms, or respiratory failure, or cardiovascular abnormalities. Sometimes, it is accompanied by general urticaria, erythema, and skin itch[7,8]. The symptoms associated with anaphylactic shock usually occur within minutes or less than 1 h after administration of the precipitating drug and result from activation of tissue mast cells and blood basophils, which release histamine and other inflammatory mediators[8]. Drug-induced anaphylactic shock accounts for a significantly high mortality rate among in-patients. Therefore, if not handled in time, it is often life-threatening[9].

Infections can aggravate or induce the occurrence of severe allergic reactions. About 1.3% to 11.0% of adults with severe allergic reactions have infectious etiologies[23]. These allergic reactions may be attributed to the immunoglobulin G produced during infection[24,25]. The patient had no adverse reactions after the first camrelizumab therapy, and the second treatment plan was the same as the initial treatment. He had been admitted to the hospital due to esophageal tumor accompanied by lung infection. After anti-infection treatment, findings of routine blood tests, including white blood cell and neutrophil counts, were normal, while C-reactive protein levels decreased from 116.16 to 70.35 mg/L.Computed tomography of the patient’s lungs showed that his lesions were improved, while his lung infections had come under control. The patient suffered a sudden anaphylactic shock after second camrelizumab administration. Although the infection was controlled, the C-reactive protein levels remained elevated, implying that the inflammatory medium in the body had not been removed completely, which may have been one of the inducing factors of anaphylactic shock. Therefore, for patients with mixed infections, clinicians should be cautious in their application of camrelizumab.

AlGaN基日盲紫外探测器外延结构通常基于蓝宝石衬底异质外延生长得到。AlN的外延技术已经趋于成熟，晶体质量已经达到较高水平。高质量高Al组分AlGaN薄膜的外延生长仍旧存在诸多问题，研究学者们近年来发展了超晶格插入层、侧向外延生长等多种外延生长技术，能够有效提高AlGaN薄膜的晶体质量。国内众多研究机构在原来p型掺杂的技术上也发展出了一系列新的掺杂技术，为制备性能良好的AlGaN基日盲紫外探测器奠定了坚实的基础。

Solvent mediums and drug configurations play an important role in hypersensitivity or anaphylactic shock. Camrelizumab is a powder, requiring suspension for injection. The drug manual requires that every 200 mg of camrelizumab be dissolved in 5 mL of sterilized injection water. For this, the sterile injection water is slowly added along the wall of the bottle containing the camrelizumab powder and dissolved by slow vortexing, to avoid direct sprinkling of water droplets on the surface of the powder.Then, the compound solution is extracted to make a 100 mL 0.9% sodium chloride solution or 5%glucose injection in an infusion bag dilution for intravenous administration by drip over a 30-minutes period. For our patient, the drug was prepared in strict accordance with these instructions, and the patient had no allergic reaction during the first dose. Therefore, neither the drug configuration nor solvent factors explain the patient’s anaphylactic shock.

随着改革开放发展，我国经济水平得到迅速提高。2017年我国GDP总量达到827122亿元，对比前一年增长了6.9%，这之中第三产业增长427032亿，同比增长了8.0%，第三产业增长速度高于第一第二产业的同时还占了总GDP比重为51.6%。可见我国第三产业正高速发展，产业结构得到了进一步优化。

Based on the findings from the examination and investigations, we first considered the possibility of anaphylactic shock.

近年来，冬枣设施栽培在北方地区发展较快，面积逐年扩大，促进了冬枣提早成熟，延长了冬枣供应期，成为果农发家致富的一项新技术。但是冬枣采收期果实萎蔫现象发生日趋普遍，比率达到10%～20%，甚至更高，极大地影响了果农收益。为此，笔者进行了实地调查，分析了原因，提出了针对性预防措施。

Due to its increased clinical use, camrelizumab-associated hypersensitivity or anaphylactic shock should arouse the attention of clinicians. There are limited specific treatments for anaphylactic shock in clinical practice. Therefore, early identification is very important[27]. Generally, drugs that may cause anaphylactic shock should be immediately discontinued. Open venous channels, oxygen inhalation, and ECG monitoring should be performed[28]. Epinephrine is often administered for anaphylactic shock,which can excite α receptors and constrict peripheral blood vessels[29]. Rapid intravenous fluids can restore the effective blood volume, and generally about 250-500 mL of the fluids are recommended.Vasoactive drugs, including norepinephrine and dopamine, are recommended if blood pressure cannot be maintained after fluid resuscitation[30]. Secondly, glucocorticoids and histamine receptor antagonists should be administered as anti-allergic treatments. In cases of severe dyspnea and laryngeal edema,emergency organ intubation and tracheotomy are required[28]. It has not been conclusively determined whether immunotherapy should be restarted after the occurrence of anaphylactic shock. Studies reported continuous immunotherapeutic administration after successfully trying desensitization therapy. However, re-anaphylactic shock and failure of desensitization treatment can occur during desensitization[6,31], and the safety and efficacy of desensitization therapy for patients with anaphylactic shock both need to be verified further. Switching to another immunotherapeutic drug is,thus, recommended. This approach has been applied successfully in previous studies, with the reported patients exhibiting relatively good clinical effects without allergic reactions[5,6].

CONCLUSlON

Due to widespread use of camrelizumab, attention should be paid to anti-PD-1 blockade treatmentassociated hypersensitivity or anaphylactic shock. We have reported herein a case of camrelizumabinduced anaphylactic shock in a patient with esophageal squamous cell carcinoma. Strengthening the monitoring of adverse drug reactions and identification of allergic reactions caused by camrelizumab treatment in the early stages should be taken into consideration by clinicians.

FOOTNOTES

Xu BP and Liu K designed the study and drafted the manuscript; Wang T and Yang H collected and analyzed the data; Xu BP and Bao JF revised the manuscript critically for important intellectual content; all authors reviewed and approved the final manuscript.

the National Natural Science Foundation of China, No. 81873317; the Natural Science Foundation of Zhejiang, No. LSY19H030002; and the Science and Technology Projects of Hangzhou City, No. 20181228Y22.

Informed written consent was obtained from the patient for the publication of this report and any accompanying images.

The authors declare that they have no conflict of interest.

The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016).

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China

Kai Liu 0000-0001-8279-0760; Jian-Feng Bao 0000-0001-1130-8057; Tao Wang 0000-0003-1152-8399; Hao Yang 0000-0001-5334-3603; Bao-Ping Xu 0000-0001-6257-2766.

Guo XR

A

Guo XR