重癥哮喘患兒生物制劑的研究進展

我們有一個獨特的機會，可以顯著降低兒童哮喘的全球負擔，從而影響成人的呼吸系統疾病。這將需要一種范式轉變，旨在改變哮喘的自然史，減少哮喘急性發作，并預防兒童哮喘的長期不良后果。

在過去的50年中，我們已經看到哮喘管理模式大約每10年轉變一次（圖）。隨著2007年哮喘指南的最新更新 ，這種模式轉變側重于實現兩個領域內定義的哮喘控制：損傷和風險。減損包括晝夜癥狀，急救藥物使用，肺功能和問卷調查，以便在短期內評估這些措施。風險將注意力集中在對惡化的可能性，藥物的不良反應和疾病的進展的評估上。

圖例：哮喘管理變化的總結，整合了疾病活動的重點和為解決這一治療目標而開發的相應藥物。

該圖發表于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）。

哮喘治療被組織成分步護理方式，以減少損傷，最小化風險，并提供實現控制的決策路徑。作為該決策路徑的一部分，重要的是隨著時間的推移跟蹤肺活量測定，以確定肺部生長的軌跡，測量哮喘負擔，使用生物標記物來選擇和監測治療，仔細評估對當前管理計劃的遵守情況，并解決社會決定因素健康決定加強治療。此外，作為目前哮喘指南更新的一部分，正在解決六個關鍵問題，包括間歇使用吸入皮質類固醇（ICSs）和長效毒蕈堿拮抗劑，支氣管熱成形術的安全性和有效性，臨床應用呼出一氧化氮的分數，室內過敏原減少的有效性，以及免疫療法的作用。

藥物當然在哮喘管理中發揮作用。近年來引入了幾種，包括長效抗膽堿能藥噻托溴銨; mepolizumab和reslizumab，抗白細胞介素（IL）5單克隆抗體; 貝那利珠單抗，一種針對嗜酸性粒細胞受體的抗體; 最近，dupilumab是一種針對IL4受體α亞基的人單克隆抗體。本綜述簡要總結了可用于批準的omalizumab，mepolizumab，reslizumab，benralizumab和dupilumab生物制劑的信息，以及一些正在評估的新藥物。

當前和未來的生物制劑

對于患有嚴重哮喘的兒童，正在考慮生物療法，特別是那些針對“過敏性”或T輔助2（Th2）途徑的療法。然而，這些生物療法在兒童中的研究程度存在很大差異。

奧馬珠單抗

Omalizumab是一種人源化抗免疫球蛋白（Ig）E單克隆抗體，可結合循環IgE，導致IgE水平降低; 抑制IgE與其受體的結合; 和下調肥大細胞，嗜堿性粒細胞和樹突細胞上的IgE受體。 Omalizumab結合游離IgE，但不結合與肥大細胞結合的IgE，導致與過敏反應相關的炎癥介質釋放減少。

Omalizumab在成人和哮喘兒童中的使用減少了惡化和住院治療，并增加了退出ICS治療的可能性。

Omalizumab被美國食品和藥物管理局批準用于6歲或以上環境過敏患者的中度至重度哮喘。正在對omalizumab進行研究，包括預防高風險兒童哮喘（PARK）研究，以確定2至3歲兒童中2年的omalizumab是否可以預防進展為持續性哮喘。

Mepolizumab，Reslizumab和Benralizumab

IL5是一種從骨髓中募集嗜酸性粒細胞并促進這些細胞活化和延長的細胞因子。已經批準了三種抗IL5生物療法：mepolizumab，reslizumab和benralizumab。Mepolizumab和reslizumab是針對IL5的人源化單克隆抗體，而貝那利珠單抗是針對IL5受體的人源化單克隆抗體。

在12歲以下的兒童中，沒有研究過這些療法。Mepolizumab和benralizumab被批準用于12歲及以上患者的嚴重嗜酸性粒細胞性哮喘，而reslizumab僅被批準用于18歲及以上的患者。使用這些藥物進行的研究主要限于嗜酸性粒細胞性哮喘，假設嗜酸性粒細胞增多可預測對這些藥物的反應，盡管嗜酸性粒細胞增多的標準在研究中略有不同。雖然成人可以獲得一些數據，但青少年可獲得的信息較少。

Dupilumab
IL4細胞因子是Th2細胞極化的必需細胞因子，而IL13細胞因子與支氣管上皮細胞中的periostin產生有關，最終導致平滑肌收縮，粘液產生，氣道重塑和高反應性，以及杯狀細胞增生。 IL13也與IL4一起導致IgE產生。 IL4受體（α亞基）對IL4和IL13信號轉導都至關重要。

Dupilumab是IL4受體α亞基的人單克隆抗體，從而阻斷IL4和IL13的活性，并且已經顯示不僅可以減少哮喘急性發作，還可以改善肺功能。

Dupilumab最近被批準用于治療12歲或以上患有嗜酸性粒細胞表型或口服皮質類固醇依賴性哮喘的中度至重度哮喘。一個研究正在進行中，在6歲至未滿12年，失控的持續性哮喘患兒dupilumab。

Fevipiprant

目前在臨床試驗中，fevipiprant是Th2細胞（CRTh2）上表達的化學引誘物受體 - 同源分子的競爭性拮抗劑。 CRTh2是一種前列腺素D2受體，主要通過過敏細胞（如肥大細胞）的產生來介導炎癥反應。使用fevipiprant的結果不一致，僅限于2期研究。

Tezepelumab

Tezepelumab是一種人類抗胸腺基質淋巴細胞生成素（TSLP）單克隆免疫球蛋白，可阻止TSLP與其受體結合，通過激活樹突狀細胞和肥大細胞來預防TSLP引發的炎癥反應。

Tezepelumab仍在進行臨床試驗。雖然沒有對兒科人群進行過研究，但是盡管中度至高度ICS和長效β受體激動劑治療，對未成年人哮喘的成人中的tezepelumab進行的2期研究表明，惡化率顯著降低。[ 6 ]最可能有反應的患者的生物標志物譜仍然未知。

未來還有什么

全球哮喘倡議最近發布了一份口袋指南，其中包括青少年和成人難以控制的哮喘的診斷和管理建議。該資源應該用于考慮患者的生物治療; 然而，目前幾乎沒有信息可以區分各種生物制劑的比較功效。定義預測和監測生物標志物以評估患者對這些藥物的反應的可能性將是重要的。在此之前，成本，便利性，可用的患者檔案和家庭負擔應該成為決策過程的一部分。還需要進行長期研究，以確定這些新療法是否可以預防疾病進展，以及進一步預防甚至逆轉已經發生的氣道損傷。正在引入可能對疾病產生重大影響的新藥物，但必須仔細評估風險與益處，尤其是兒童。

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.