重症哮喘患儿生物制剂的研究进展

我们有一个独特的机会，可以显着降低儿童哮喘的全球负担，从而影响成人的呼吸系统疾病。这将需要一种范式转变，旨在改变哮喘的自然史，减少哮喘急性发作，并预防儿童哮喘的长期不良后果。

在过去的50年中，我们已经看到哮喘管理模式大约每10年转变一次（图）。随着2007年哮喘指南的最新更新 ，这种模式转变侧重于实现两个领域内定义的哮喘控制：损伤和风险。减损包括昼夜症状，急救药物使用，肺功能和问卷调查，以便在短期内评估这些措施。风险将注意力集中在对恶化的可能性，药物的不良反应和疾病的进展的评估上。

图例：哮喘管理变化的总结，整合了疾病活动的重点和为解决这一治疗目标而开发的相应药物。

该图发表于Journal of Allergy and Clinical Immunology，Volume 142，Stanley J. Szefler，Asthma in the lifespan：Time for a paradigm shift，Pages 773-780，Copyright Elsevier（2018）。

哮喘治疗被组织成分步护理方式，以减少损伤，最小化风险，并提供实现控制的决策路径。作为该决策路径的一部分，重要的是随着时间的推移跟踪肺活量测定，以确定肺部生长的轨迹，测量哮喘负担，使用生物标记物来选择和监测治疗，仔细评估对当前管理计划的遵守情况，并解决社会决定因素健康决定加强治疗。此外，作为目前哮喘指南更新的一部分，正在解决六个关键问题，包括间歇使用吸入皮质类固醇（ICSs）和长效毒蕈碱拮抗剂，支气管热成形术的安全性和有效性，临床应用呼出一氧化氮的分数，室内过敏原减少的有效性，以及免疫疗法的作用。

药物当然在哮喘管理中发挥作用。近年来引入了几种，包括长效抗胆碱能药噻托溴铵; mepolizumab和reslizumab，抗白细胞介素（IL）5单克隆抗体; 贝那利珠单抗，一种针对嗜酸性粒细胞受体的抗体; 最近，dupilumab是一种针对IL4受体α亚基的人单克隆抗体。本综述简要总结了可用于批准的omalizumab，mepolizumab，reslizumab，benralizumab和dupilumab生物制剂的信息，以及一些正在评估的新药物。

当前和未来的生物制剂

对于患有严重哮喘的儿童，正在考虑生物疗法，特别是那些针对“过敏性”或T辅助2（Th2）途径的疗法。然而，这些生物疗法在儿童中的研究程度存在很大差异。

奥马珠单抗

Omalizumab是一种人源化抗免疫球蛋白（Ig）E单克隆抗体，可结合循环IgE，导致IgE水平降低; 抑制IgE与其受体的结合; 和下调肥大细胞，嗜碱性粒细胞和树突细胞上的IgE受体。 Omalizumab结合游离IgE，但不结合与肥大细胞结合的IgE，导致与过敏反应相关的炎症介质释放减少。

Omalizumab在成人和哮喘儿童中的使用减少了恶化和住院治疗，并增加了退出ICS治疗的可能性。

Omalizumab被美国食品和药物管理局批准用于6岁或以上环境过敏患者的中度至重度哮喘。正在对omalizumab进行研究，包括预防高风险儿童哮喘（PARK）研究，以确定2至3岁儿童中2年的omalizumab是否可以预防进展为持续性哮喘。

Mepolizumab，Reslizumab和Benralizumab

IL5是一种从骨髓中募集嗜酸性粒细胞并促进这些细胞活化和延长的细胞因子。已经批准了三种抗IL5生物疗法：mepolizumab，reslizumab和benralizumab。Mepolizumab和reslizumab是针对IL5的人源化单克隆抗体，而贝那利珠单抗是针对IL5受体的人源化单克隆抗体。

在12岁以下的儿童中，没有研究过这些疗法。Mepolizumab和benralizumab被批准用于12岁及以上患者的严重嗜酸性粒细胞性哮喘，而reslizumab仅被批准用于18岁及以上的患者。使用这些药物进行的研究主要限于嗜酸性粒细胞性哮喘，假设嗜酸性粒细胞增多可预测对这些药物的反应，尽管嗜酸性粒细胞增多的标准在研究中略有不同。虽然成人可以获得一些数据，但青少年可获得的信息较少。

Dupilumab
IL4细胞因子是Th2细胞极化的必需细胞因子，而IL13细胞因子与支气管上皮细胞中的periostin产生有关，最终导致平滑肌收缩，粘液产生，气道重塑和高反应性，以及杯状细胞增生。 IL13也与IL4一起导致IgE产生。 IL4受体（α亚基）对IL4和IL13信号转导都至关重要。

Dupilumab是IL4受体α亚基的人单克隆抗体，从而阻断IL4和IL13的活性，并且已经显示不仅可以减少哮喘急性发作，还可以改善肺功能。

Dupilumab最近被批准用于治疗12岁或以上患有嗜酸性粒细胞表型或口服皮质类固醇依赖性哮喘的中度至重度哮喘。一个研究正在进行中，在6岁至未满12年，失控的持续性哮喘患儿dupilumab。

Fevipiprant

目前在临床试验中，fevipiprant是Th2细胞（CRTh2）上表达的化学引诱物受体 - 同源分子的竞争性拮抗剂。 CRTh2是一种前列腺素D2受体，主要通过过敏细胞（如肥大细胞）的产生来介导炎症反应。使用fevipiprant的结果不一致，仅限于2期研究。

Tezepelumab

Tezepelumab是一种人类抗胸腺基质淋巴细胞生成素（TSLP）单克隆免疫球蛋白，可阻止TSLP与其受体结合，通过激活树突状细胞和肥大细胞来预防TSLP引发的炎症反应。

Tezepelumab仍在进行临床试验。虽然没有对儿科人群进行过研究，但是尽管中度至高度ICS和长效β受体激动剂治疗，对未成年人哮喘的成人中的tezepelumab进行的2期研究表明，恶化率显着降低。[ 6 ]最可能有反应的患者的生物标志物谱仍然未知。

未来还有什么

全球哮喘倡议最近发布了一份口袋指南，其中包括青少年和成人难以控制的哮喘的诊断和管理建议。该资源应该用于考虑患者的生物治疗; 然而，目前几乎没有信息可以区分各种生物制剂的比较功效。定义预测和监测生物标志物以评估患者对这些药物的反应的可能性将是重要的。在此之前，成本，便利性，可用的患者档案和家庭负担应该成为决策过程的一部分。还需要进行长期研究，以确定这些新疗法是否可以预防疾病进展，以及进一步预防甚至逆转已经发生的气道损伤。正在引入可能对疾病产生重大影响的新药物，但必须仔细评估风险与益处，尤其是儿童。

Review of Biologics in Children With Severe Asthma Shifts in Management

We have a unique opportunity to significantly reduce the worldwide burden of asthma in children and thus affect respiratory disease in adults. This will require a paradigm shift that is directed at altering the natural history of asthma, reducing asthma exacerbations, and preventing long-term adverse outcomes of childhood asthma.

For the past 50 years, we have seen paradigm shifts in asthma management about every 10 years (Figure). With the latest update of the asthma guidelines in 2007, this paradigm shift focused on achieving asthma control defined within two domains: impairment and risk. Impairment consists of day and night symptoms, rescue medication use, pulmonary function, and questionnaires to assess these measures over a short-term period. Risk directs attention to the assessment of the potential for exacerbations, adverse responses to medications, and progression of the disease.

Figure. A summary of the changes in asthma management that integrates the focus of disease activity and the corresponding medications developed to address this therapeutic target. This Figure was published in the Journal of Allergy and Clinical Immunology, Volume 142, Stanley J. Szefler, Asthma across the lifespan: Time for a paradigm shift, Pages 773-780, Copyright Elsevier (2018).

Asthma treatment is organized into a step-care fashion to decrease impairment, minimize risk, and provide a decision path to achieve control. As part of this decision path, it is important to follow spirometry over time to define trajectories of lung growth, measure asthma burden, use biomarkers to select and monitor therapy, carefully evaluate adherence to the current management plan, and address social determinants of health in making decisions to step up therapy. In addition, as part of the current update to the asthma guidelines, six key questions are being addressed, including the intermittent use of inhaled corticosteroids (ICSs) and long-acting muscarinic antagonists, the safety and effectiveness of bronchial thermoplasty, the clinical utility of fraction of exhaled nitric oxide, the effectiveness of indoor allergen reduction, and the role of immunotherapy.

Medications certainly play a role in asthma management. Several have been introduced in recent years, including tiotropium, a long-acting anticholinergic; mepolizumab and reslizumab, anti-interleukin (IL) 5 monoclonal antibodies; benralizumab, an antibody that is directed toward eosinophil receptors; and most recently dupilumab, a human monoclonal antibody to the alpha subunit of the IL4 receptor. This review briefly summarizes the information available for the approved biologics of omalizumab, mepolizumab, reslizumab, benralizumab, and dupilumab, in addition to a few new medications that are being evaluated.

Current and Future Biologics

Biologic therapies, in particular those targeting the "allergic" or T-helper 2 (Th2) pathway, are being considered for children with severe asthma. However, a great deal of variability exists in the extent to which these biologic therapies have been studied in children.

Omalizumab

Omalizumab is a humanized anti-immunoglobulin (Ig) E monoclonal antibody that binds circulating IgE, causing a decrease in IgE levels; inhibition of IgE binding with its receptors; and downregulation of IgE receptors on mast cells, basophils, and dendritic cells. Omalizumab binds to free IgE, but not to IgE bound to mast cells, resulting in a decreased release of inflammatory mediators related to the allergic response.

Omalizumab use in both adults and children with asthma reduced exacerbations and hospitalizations and increased the likelihood of withdrawing ICS therapy.

Omalizumab is approved by the US Food and Drug Administration for moderate to severe asthma in patients aged 6 years or older with environmental allergies. Studies are ongoing with omalizumab, including the Preventing Asthma in High Risk Kids (PARK) study, to determine whether 2 years of omalizumab in children aged 2-3 years will prevent progression to persistent asthma.

Mepolizumab, Reslizumab, and Benralizumab

IL5 is a cytokine that recruits eosinophils from the bone marrow and promotes both the activation and longevity of these cells. Three anti-IL5 biologic therapies have been approved: mepolizumab, reslizumab, and benralizumab. Mepolizumab and reslizumab are humanized monoclonal antibodies against IL5, whereas benralizumab is a humanized monoclonal antibody against the IL5 receptor.

None of these therapies have been studied in children younger than 12 years. Mepolizumab and benralizumab are approved for severe eosinophilic asthma for patients aged 12 years and older, while reslizumab is only approved for those aged 18 years and older. The studies performed with these medications have been largely limited to eosinophilic asthma under the assumption that eosinophilia is predictive of response to these medications, although the criteria for inclusion of eosinophilia has varied slightly among the studies. Whereas some data are available in adults, less information is available with adolescents.

Dupilumab

The IL4 cytokine is an essential cytokine to Th2 cell polarization, whereas the IL13 cytokine is associated with periostin production in the bronchial epithelial cells, ultimately resulting in smooth-muscle contraction, mucus production, airway remodeling and hyperresponsiveness, and goblet cell hyperplasia. IL13 also works with IL4 to result in IgE production. The IL4 receptor (alpha subunit) is critical for both IL4 and IL13 signal transduction.

Dupilumab is a human monoclonal antibody to the alpha subunit of the IL4 receptor, thereby blocking the activity of IL4 and IL13, and has been shown to not only reduce asthma exacerbations but also improve pulmonary function.

Dupilumab was recently approved for the treatment of moderate to severe asthma in patients aged 12 years or older with an eosinophilic phenotype or oral corticosteroid- dependent asthma. A study is ongoing with dupilumab in children aged 6 years to younger than 12 years with uncontrolled persistent asthma.

Fevipiprant

Currently in clinical trials, fevipiprant is a competitive antagonist to chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTh2). CRTh2 is a prostaglandin D2 receptor that mediates inflammatory effects largely through its production by allergic cells, such as mast cells. Results with fevipiprant have been inconsistent and limited to phase 2 studies.[4,5]

Tezepelumab

Tezepelumab is a human anti-thymic stromal lymphopoietin (TSLP) monoclonal immunoglobulin that prevents binding of TSLP with its receptor, preventing TSLP-initiated inflammatory responses through activation of dendritic cells and mast cells.

Tezepelumab is still undergoing clinical trials. Although no studies have been conducted in the pediatric population, a phase 2 study of tezepelumab in adults with uncontrolled asthma despite medium to high ICS and long-acting beta-agonist therapy noted significant reductions in exacerbation rates.[6] The biomarker profile of patients most likely to respond also remains unknown.

What Still Lies Ahead

The Global Initiative for Asthma recently published a pocket guide that includes recommendations for the diagnosis and management of difficult-to-control asthma in adolescents and adults.[7] This resource should be useful in the consideration of biologic treatments for patients; however, little information is currently available to differentiate the comparative efficacy of the various biologics. Defining predictive and monitoring biomarkers to assess the likelihood of patients responding to these medications will be important. Until then, cost, convenience, available patient profiles, and family burden should be part of the decision-making process. Long-term studies will also be needed to determine whether these new treatments can prevent disease progression as well as further prevent or even reverse airway damage that has already occurred. New medications are being introduced that may significantly affect the disease, but the risk versus benefit must be carefully assessed, especially in children, to determine which patients are most likely to show a favorable response.