Safety of hymenoptera venom immunotherapy: a systematic review

INTRODUCTION: The efficacy of venom immunotherapy (VIT) in patients with insect sting allergy is not questioned. However, its safety, especially when honeybee is used, is a matter of concern. AREAS COVERED: A systematic review of the literature on VIT was done, with both aqueous and depot extracts, to compare the frequency of systemic reactions to honeybee and vespid venoms. A Medline search was performed using the keywords 'venom immunotherapy', 'safety' and 'tolerability'. The articles obtained were analyzed regarding the total number of patients treated with either honeybee or vespid VIT, the number and severity of systemic reactions during therapy, the type of extract used (aqueous or depot) and the administration regimen. EXPERT OPINION: The incidence of systemic reactions to VIT was 25.1% for honeybee venom and 5.8% for vespid venom (p < 0.0001), while it was similar with aqueous and depot extracts in the whole population of patients. This confirms that during VIT systemic reactions are significantly more frequent with honeybee venom compared with vespid venom, while there are no significant overall differences in systemic reactions between aqueous and depot extracts.     

舌下特异性免疫疗法治疗变应性鼻炎和/或过敏性哮喘的安全性研究

目的探讨舌下特异性免疫疗法治疗变应性鼻炎和过敏性哮喘的安全性。方法对182名过敏性鼻炎和/或过敏性哮喘患者,采用舌下特异性免疫疗法和对症用药相结合的方式进行免疫治疗;跟踪并统计在免疫治疗过程中患者产生的不良反应及其严重程度。结果没有患者出现全身性的不良反应,轻中度不良反应的总发生率为8.24%;14岁以下的患者出现不良反应的比例高于14岁以上的患者。结论舌下特异性免疫治疗引起的不良反应都只是轻中度的,它是一种高安全性的免疫治疗方法。     

Management of Double Sensitization to Vespids in Europe

Wasp allergy with a diagnostic profile of double sensitizations to vespid venom is a frequent clinical problem in areas where different genera of wasps are present. Identification of the insect responsible for serious reactions poses a diagnostic challenge as the only effective treatment to date is immunotherapy based on the specific venom. In southern Europe, the double sensitization to Vespula and Polistes venoms is highly frequent. It has been shown that the major allergenic proteins (Phospholipase A1 and Antigen 5) share sequences across the different genera and species, which would be the cause of cross-reactivity. Additionally, the minor allergens (Dipeptidyl-peptidases, Vitellogenins) have been found to share partial sequence identity. Furthermore, venom contains other homologous proteins whose allergenic nature still remains to be clarified. The traditional diagnostic tools available are insufficient to discriminate between allergy to Vespula and Polistes in a high number of cases. IgE inhibition is the technique that best identifies the cross-reactivity. When a double sensitization has indeed been shown to exist or great uncertainty surrounds the primary sensitization, therapy with two venoms is advisable to guarantee the safety of the patient. In this case, a strategy involving alternate administration that combines effectiveness with efficiency is possible.     

Value of component based diagnostics in IgE-mediated hymenoptera sting reactions

Background: Stings by insects can precipitate many signs and symptoms of dermatological and ocular diseases. Of particular importance is the anaphylaxis after Hymenoptera stings. Selection of the appropriate venom for immunotherapy requires a precise diagnosis, which is frequently difficult to confirm since the history presented by the patient is many times not conclusive and diagnostic tests are often positive for bee venom (BV) and vespula venom (VV). This double positivity is either caused by true double sensitization or by antibodies cross-reactive to homologous peptide sequences or to cross-reactive carbohydrate determinants (CCDs). In this study, we analyzed in 39 patients, tested positive for specific immunoglobulin E (sIgE) against BV and VV and CCDs whether the routine detection of sIgE against the recombinant species-specific major allergens (SSMAs) rApi m1 and rVes v5 enables the discrimination between genuine double sensitization and cross reactivity and therefore may be superior to other in vitro assays such as IgE-inhibition test or the basophil activation test.

Materials and methods: Thirty-nine patients each with allergic reactions to vespula and/or honey bee stings and tested positive for sIgE antibodies against CCDs were analyzed for sIgE against BV, VV, CCDs (MUFX3) and SSMAs by UNICAP (CAP) and to BV, VV, bromelain, horseradish peroxidase and ascorbat oxidase by Immulite 2000 (IMMU). In 12 cases results from a basophil activation test, in nine cases results from IgE-inhibition assays and in 10 cases an unambiguous history of the patient were taken into consideration.

Results: A definite diagnosis could be assigned to each patient: sensitization to BV n = 7, sensitization to VV n = 29 and true double sensitization to both venoms n = 3. Detection of sIgE against BV and VV by CAP leads in three cases to the diagnosis BV allergy, in 35 cases to the diagnosis double sensitization and in one case to the diagnosis VV allergy. Detection of sIgE against BV and VV by IMMU leads in five cases to the diagnosis BV allergy, in 27 cases to the diagnosis double sensitization and in seven cases to the diagnosis VV allergy. Detection of sIgE against rApi m1 and rVes v5 by CAP leads in six cases to the diagnosis BV allergy, in eight cases to the diagnosis double sensitization, in 21 cases to the diagnosis VV allergy and in four cases to a false double-nagative result implicating no allergy.

Discussion and conclusion: Detection of sIgE to rApi m 1 and rVes v 5 by CAP is the most reliable diagnostic procedure to discriminate between true double sensitization and cross reactivity in patients with double-positive IgE results to venom extracts in the presence of sIgE against CCDs. In this study, however, we demonstrate that in nine of 39 patients tested positive for sIgE against CCDs, even the allergen component based diagnostic produces false double-positive and also false double-negative test results. Thus, we conclude that especially in hard to diagnose CCD positive patients beside the detection of sIgE, in vitro assays such as the IgE-inhibition test or the basophil activation test are still of importance. Detection of sIgE against only two SSMAs is not sufficient for a precise diagnosis. We propose inclusion of further SSMAs in diagnostic procedures.     

链球菌免疫针剂不良反应或不良事件的系统评价研究

目的:本研究根据现有证据评价链球菌免疫针剂在中国地区应用的安全性。方法:电子检索Cochrane图书馆、MEDLINE,EMBASE,CNKI,CBM以及国家不良反应监测中心报告,收集链球菌免疫针剂的临床试验、病例报告等涉及链球菌免疫针剂的不良反应报道。两名研究者独立选择、提取数据,并交叉核对。结果:本研究纳入278篇,1 231例链球菌免疫针剂不良反应/不良事件(ADR/AE)。经系统评价研究得出:①患有呼吸系统疾病史患者较易发生ADR/AE。②静脉滴注,配液含有葡萄糖的较容易发生ADR/AE。③据估计,ADR/AE发生率低于0.000 5%,发作时间主要在30 min内,轻型占87.9%,重型占12.1%,2005年后ADR/AE发生率显著下降可能与新质量标准执行有关。结论:当前强度不高的证据表明,链球菌免疫针剂的ADR/AE风险很低,但不恰当使用可能导致严重的ADR/AE的发生。应鼓励临床工作者在医学期刊参照中药ADR报告建议规范发表ADR/AE报告。     

Safety of fluconazole in paediatrics: a systematic review

Purpose

To determine the safety of fluconazole in neonates and other paediatric age groups by identifying adverse events (AEs) and drug interactions associated with treatment.

Methods

A search of EMBASE (1950–January 2012), MEDLINE (1946–January 2012), the Cochrane database for systematic reviews and the Cumulative Index to Nursing and Allied Health Literature (1982–2012) for any clinical study about fluconazole use that involved at least one paediatric patient (≤17 years) was performed. Only articles with sufficient quality of safety reporting after patients’ exposure to fluconazole were included.

Results

We identified 90 articles, reporting on 4,209 patients, which met our inclusion criteria. In total, 794 AEs from 35 studies were recorded, with hepatotoxicity accounting for 378 (47.6 %) of all AEs. When fluconazole was compared with placebo and other antifungals, the relative risk (RR) of hepatotoxicity was not statistically different [RR 1.36, 95 % confidence interval (CI) 0.87–2.14, P?=?0.175 and RR 1.43, 95 % CI 0.67–3.03, P?=?0.352, respectively]. Complete resolution of hepatoxicity was achieved by 84 % of patients with follow-up available. There was no statistical difference in the risk of gastrointestinal events of fluconazole compared with placebo and other antifungals (RR 0.81, 95 % CI 0.12–5.60, P =?0.831 and RR 1.23, 95 %CI 0.87–1.71, P?=?0.235, respectively). There were 41 drug withdrawals, 17 (42 %) of which were due to elevated liver enzymes. Five reports of drug interactions occurred in children.

Conclusion

Fluconazole is relatively safe for paediatric patients. Hepatotoxicity and gastrointestinal toxicity are the most common adverse events. It is important to be aware that drug interactions with fluconazole can result in significant toxicity.     

Safety and tolerability of 5-grass pollen tablet sublingual immunotherapy: pooled analysis and clinical review

Introduction: The 5-grass pollen tablet (Oralair®, Stallergenes, Antony, France) is a once-daily preseasonal and coseasonal sublingual immunotherapy (SLIT) that is effective in controlling the symptoms of allergic rhinoconjunctivitis and in reducing the need for symptomatic medication.

Areas covered: The body of safety data gathered from the 5-grass pollen tablet clinical development program, post-approval studies, and more than 6 years of real-life experience demonstrates the safety and tolerability profile of the 5-grass pollen tablet across all age groups. Adverse events (AEs) are generally mild or moderate in severity, and rarely lead to treatment discontinuation. AEs also tend to decline in frequency and severity over time and with repeated treatment. The most frequent treatment-emergent AEs are local-site oropharyngeal reactions (e.g., oral pruritus, throat irritation, tongue pruritus, mouth edema, ear pruritus), which are consistent with the sublingual route of administration.

Expert opinion: The first dose of the 5-grass pollen tablet should be administered under the supervision of an experienced physician, to allow for optimal monitoring and timely management of AEs, should they occur. The 5-grass pollen tablet can be administered at home after the first dose, and patients and carers should be educated on how to manage adverse reactions, unplanned treatment interruptions and situations in which SLIT should be withheld.     

Safety of sublingual immunotherapy started during the pollen season

ABSTRACT

Background: Sublingual immunotherapy (SLIT) is safer than subcutaneous immunotherapy (SCIT) and this has lead to the reconsideration of the use of ultra-rush schedules for SLIT. The aim of this study was to assess the safety of ultra-rush SLIT in pollen-allergic children according to different timing of administration in relation to the pollen season.

Methods: In total, 34 children with pollen-induced rhinitis and 36 with pollen-induced asthma and rhinitis, were enrolled and assigned to three study groups: group?1 (n?=?17 patients): conventional pre-seasonal-SLIT treatment; group?2 (n?=?23 patients), seasonal SLIT ended before the pollen seasonal peak; group?3 (n?=?30 patients), SLIT began after the pollen seasonal peak and ended after the pollen season. SLIT was performed using extracts from Stallergenes (Antony, France) and following an ultra-rush schedule, consisting in four doses at a 30-min intervals, and maintenance treatment by administering the top dose three times a week.

Results: In all, 54 adverse events (AEs) were reported: 12 in nine patients in group?1 (9/17, 52.9%), 22 in 14 patients in group?2 (14/23, 60.9%), and 20 in 13 patients in group?3 (13/30, 43.3%). No statistically significant differences were found between the three groups. Local AEs (oral itching and burning) were short lasting and self-resolving. Systemic AEs were also mild, except for a case of asthma, which lasted 5?days, in a patient from group?1. There were no severe reactions, and none of the patients dropped out.

Conclusions: This study suggests that SLIT with pollen extracts may be safely started at the beginning and also during the pollen season, with a tolerability profile comparable to the conventional pre-seasonal SLIT.     

Safety of epidural drugs: a narrative review

Introduction: Epidural analgesia is a popular approach to postoperative and labor pain. Neurotoxicity and drug-specific systemic side effects can occur after epidural administration. As an increasing number of epidural drugs are studied and clinically applied, drug efficacy and safety evaluation are crucial.

Areas covered: In this narrative review, the authors provide a thorough overview on the safety of the most widely used epidural drugs, focusing on potential neurotoxicity, side effects, and complications in the adult, non-pregnant population. A combined text and MeSH heading search strategy was used to identify relevant publications.

Expert opinion: The search for the ideal epidural medication has resulted in a surplus of drug combinations with extensive heterogeneity amongst studies, while the value of investigating these is not always evident. Epidural drugs pose a potential threat of neurotoxicity and other side effects. Consequently, we should pursue safe epidural drug administration to patients and refrain from drugs with minimal proven benefit. Also, studies should compare epidural with systemic application. Because why use a drug epidurally, which can be safely used systemically? Future research should focus on providing solid evidence regarding efficacy of epidural analgesia compared to new and already existing modalities and optimizing presently used medicinal regimens.     

The Safety of available immunotherapy for the treatment of glioblastoma

Introduction: Glioblastoma (GBM) is the most common malignant primary brain tumor in adults. Current standard of care involves maximal surgical resection combined with adjuvant chemoradiation. Growing support exists for a role of immunotherapy in treating these tumors with the goal of targeted cytotoxicity. Here we review data on the safety for current immunotherapies being tested in GBM.

Areas covered: Safety data from published clinical trials, including ongoing clinical trials were reviewed. Immunotherapeutic classes currently under investigation in GBM include various vaccination strategies, adoptive T cell immunotherapy, immune checkpoint blockade, monoclonal antibodies, and cytokine therapies. Trials include children, adolescents, and adults with either primary or recurrent GBM.

Expert opinion: Based on the reviewed clinical trials, the current immunotherapies targeting GBM are safe and well-tolerated with minimal toxicities which should be noted. However, the gains in patient survival have been modest. A safe and well-tolerated combinatory immunotherapeutic approach may be essential for optimal efficacy towards GBM.     

变应原特异性免疫治疗致全身不良反应的观察及防控管理

目的：通过观察变应原特异性皮下免疫治疗（subcutaneous immunotherapy,SCIT）注射后出现的全身不良反应,分析危险因素及处理措施,以便更安全地实施SCIT。方法：对2017年1月至2020年12月在淄博市中心医院过敏门诊行SCIT后发生全身不良反应的病例资料进行回顾性分析。结果：在739例患者的16 337次注射中,共16例患者发生了18次全身不良反应,全身不良反应的发生率为2.2%,以皮肤、结膜和呼吸道症状为主,其中Ⅰ级6次,Ⅱ级8次,Ⅲ级4次。速发型反应16次,迟发型反应2次。发生在初始治疗剂量快速上升阶段和维持治疗阶段共17次。10岁以下儿童易发生全身不良反应,sIgE 4级以上的患者易发生重度全身不良反应。结论：全身不良反应多发生在初始治疗剂量快速上升阶段和维持治疗阶段,多为速发型反应,低龄、伴多种过敏性疾病、感染、接触变应原、剧烈运动、情绪应激等都是诱发全身不良反应的危险因素。医护人员应在每次注射前询问患者的病史以及与危险因素相关的生活史。根据患者的健康状况、前次注射时的反应等及时调整变应原剂量,提高临床对药物不良反应的预防、鉴别和处理能力。     

沙格列汀治疗糖尿病安全性的系统评价

目的:系统评价沙格列汀治疗2型糖尿病的安全性。方法:电子检索PubMed,EMBase,Cochrane,CNKI,VIP,CBM数据库,对纳入的随机对照试验(RCT)进行方法学质量评价和Meta分析。结果:共纳入6个RCT。治疗过程中,实验组和对照组严重不良反应及低血糖的发生率低,且组间差异无显著性。常见不良反应包括鼻咽炎,头疼,低血糖,腹泻,上呼吸道感染,尿路感染,关节痛,高血压,背疼,咳嗽和下肢疼痛等。除头疼,关节痛和高血压的发生率实验组高于安慰剂组外,其他不良反应的发生率,实验组与安慰剂组相似或低于安慰剂组。结论:沙格列汀的安全性好,但纳入研究随访时间较短,其长期安全性还需进一步验证。     

艾塞那肽治疗2型糖尿病安全性的系统评价

目的:系统评价艾塞那肽治疗2型糖尿病所致不良反应的发生情况。方法:计算机检索PubMed,EMBase,Cochrane,CNKI,VIP,CBM数据库,对纳入的随机对照试验(RCT)进行方法学质量评价,并用RevMan5.0软件进行Meta分析。结果:共纳入10个RCT,研究结果显示:艾塞那肽最主要的不良反应是胃肠道反应,恶心发生的概率最大,均高于安慰剂组和胰岛素组,但反应均较轻微,绝大多数患者可以耐受。结论:艾塞那肽不良反应较轻微,因此可以用来治疗口服降糖药不能有效控制血糖的2型糖尿病患者,但因纳入研究随访时间较短,其长期安全性还需进一步验证。     

The possible of immunotherapy for COVID-19: A systematic review

The novel coronavirus (2019-nCoV) is an emerging pathogen that was first described in late December 2019 and causes a severe respiratory infection in humans. Since the outbreak of COVID-19, international attention has raised to develop treatment and control options such as types of immunotherapies.The immunotherapy is an effective method for fighting against similar viral infections such as SARS-CoV, and MERS-CoV. These methods include several types of vaccines, monoclonal antibody candidates, and etc.This systematic review article was designed to evaluate the existing evidence and experience related to immunotherapy for 2019-nCoV. Web of Science (ISI), PubMed, and Scopus databases were used to search for suitable keywords such as 2019-nCoV, novel coronavirus, Immunotherapy, interleukin, vaccine and the related words for relevant publications up to 24.3.2020. The present systematic review was performed based on PRISMA protocol. Data extraction and quality valuation of articles were performed by two reviewers. 51 articles were the results of the search and based on the inclusions and exclusions criteria, 7 articles were included in the final review.As a conclusion of these studies demonstrated that although no serious research has been done on this subject at the time of writing this article, similar studies on the related viruses showed notable results. So immunotherapy for this virus can also be a suitable option.     

过敏性哮喘脱敏治疗效果的系统评价

目的探讨评价变应原脱敏治疗（SIT）对过敏性哮喘的疗效。方法利用计算机查找及筛选出pubmed（1966-2007）、eoehrane图书馆（Issue2，2007、8）、BMBASE（-2007）、VIP（1989-2007）、中国生物医学文献数据库（CBMDISC）（1978-2007）、中国学术期刊全文数据库（CJFD）（1979—2007）等数据库中所需的文献。并手工检索相关资料，检索本领域专家近年来使用脱敏疗法治疗哮喘病的研究成果。并对纳入的研究的方法学质量按Cochrane协作网推荐的方法进行了评价。结果共纳入10篇随机对照试验（298例患者），描述性分析表明：与安慰剂组比较，脱敏疗法显著改善了哮喘患者的临床症状和减少了对药物的需求量，在提高FEV1值方面效果显著。脱敏治疗对哮喘患者生活质量的提高，也有统计学意义。结论脱敏技术在哮喘研究中已趋于完善，脱敏治疗能够改善患者的临床症状和肺部功能，并且能减少对药物的需求量。同时脱敏治疗的不良反应（比如过敏反应）发生率低，推荐用于临床。     

Subcutaneous specific immunotherapy for seasonal allergic rhinitis: a review of treatment practices in the US and Europe

Abstract

Background:

Subcutaneous specific immunotherapy (SCIT) is claimed to be successful both in the US and Europe, yet treatment methodology differs.     

Safety of botulinum toxin type A: a systematic review and meta-analysis

SUMMARY

Objective: To define quantitatively the safety and tolerability profile of botulinum toxin type A (BTX-A) across all common therapeutic indications. The review was limited to the evaluation of the safety profile of one preparation of BTX-A (Botox*) because distinct formulations of BTX-A are associated with different clinical profiles, requiring separate consideration for an analysis of safety.

Research design and methods: We identified randomized controlled trials of BTX-A through searches of the MEDLINE, EMBASE, and Cochrane Controlled Trial databases for the years 1966–2003. Studies were double-blind, randomized, crossover, or of parallel group design. The search strategy included the terms ‘botulinum toxin’, ‘therapeutic use’, ‘randomized controlled trial’, ‘controlled clinical trial’, ‘randomized clinical trial’, and ‘placebo controlled trial’. Only randomized controlled trials of at least 7?days duration that reported adverse events were included in the analysis.

Main outcome measure: Safety was assessed by means of a meta-analysis of the number and frequency of adverse events.

Results: Thirty-six studies involving 2309 subjects met the inclusion criteria. These reported on 1425 subjects receiving BTX-A treatment. No study reported any severe adverse events. The meta-analysis of any mild to moderate adverse events showed a rate of roughly 25% in the BTX-A-treated group (353/1425 patients) compared with 15% in the control group (133/884 patients, p < 0.001). Focal weakness was the only adverse event that occurred significantly more often with BTX-A treatment than control.

Conclusion: The results of this meta-analysis and experience from long-term, open-label investigations demonstrate that the formulation of BTX-A evaluated here has a favorable safety and tolerability profile across a broad spectrum of therapeutic uses.