Levalbuterol hydrochloride

健康元已从以“太太口服液”闻名的食品公司，转型为涵盖医药研发、生产与销售的综合性集团。历经30载风雨，健康元已从昔日以“太太口服液”闻名遐迩的食品企业，华丽转身成为一家集医药研发、生产与销售于一体的综合性集团公司。2022年财务报告揭晓，公司营收与归属于上市公司股东的净利润均取得了显著增长。特别值得一提的是，呼吸系统、精神等关键领域的重点制剂产品销售收入对整体营收的贡献日益凸显。 1.1 ▍ 三十年风雨历程 健康元自1992年成立以来，经历了多次战略转型和业务拓展。1993年，“太太口服液”的上市标志着女性保健品时代的开启；随后，公司在1994年更名为深圳太太保健食品有限公司，并在1995年进军药业领域，更名为深圳太太药业有限公司。经过一系列的收购和整合，公司在1997年成功转型为制药企业，并逐步拓展其业务范围。 1.2 ▍ 净利润增长 2022年，健康元表现出强劲的增长势头，实现营业收入高达171.43亿元，较上年同期增长了约7.79%。同时，归属于上市公司股东的净利润也达到15.03亿元，同比大幅增长了13.1%。对于这一系列的优异成绩，健康元在财报中进行了详细阐述。他们指出，公司积极执行销售策略，大幅提升了市场推广力度，并强化了销售的专业性。公司在过去四年中，净利润持续增长，2022年营收和净利润分别达到171.43亿元和15.03亿元，展现出公司在业界的影响力和盈利能力。 2.1 ▍ 产品增长与销售收入 2022年，健康元（不含丽珠集团、丽珠单抗）的营收情况如下：处方药板块贡献销售收入21.2亿元，较上年增长18.46%。呼吸系统用药销售收入增长迅猛，特别是呼吸领域在报告期内实现11.74亿元的新增销售收入，同比增长率高达103.37%。尽管抗感染领域销售收入为9.21亿元，同比下滑22.76%，但整体营收仍保持稳健。 2.2 ▍ 研发突破与市场扩展 健康元在呼吸系统用药领域的重点布局是其销售收入增长的另一大推动力。自2015年起，公司与钟南山院士所领导的广州呼研所携手合作，共同成立了广州健康元呼吸药物工程技术公司。通过与广州呼研所的合作，健康元在呼吸药研发创新方面取得了多项成功产品的上市，例如舒坦琳（复方异丙托溴铵吸入溶液）与丽舒同（盐酸左沙丁胺醇雾化吸入溶液）都成功纳入医保目录，进一步扩大了市场占有率。 3.1 ▍ 研发投入与费用调整 健康元持续的业绩提升，离不开其不断增强的研发实力。过去七年的研发投入增长显著，从2016年的6.09亿元跃升至2022年的17.42亿元，显示出公司在提升技术竞争力方面的战略投入。与此同时，健康元的销售费用、财务费用以及管理费用在一些年份也呈现出持续下降的趋势，有助于推动企业从营销驱动向科技创新驱动的转型。 3.2 ▍ 研发管线与技术探索 健康元的优质研发管线布局稳步推进，其在创新药及高壁垒复杂制剂领域积累了深厚的技术平台。健康元在创新药及复杂制剂领域有丰富研发管线，不但探索了AI药物设计等前沿技术，还在临床上验证了多种新药及复杂制剂的可开发性。通过临床价值为导向的短期确定性高的研发项目，以及长远布局具有潜力的前沿技术，健康元正在不断丰富其研发管线，促进企业的转型升级和高质量发展。

（本文译自世界过敏组织WAO发布资料） Allergic Asthma: Symptoms and Treatment Updated: October 2020；July 2015. Posted: May 2006 Updated by: Ashley A. Sullivan, MSN FNP, Student, Samuel Merritt University, Oakland, Ca RN, California Pacific Medical Center, Natalya M. Kushnir, MD, Director, Allergy and immunology Clinic of East Bay, Berkeley, CA Original authors: H. Henry Li, MD, PhD, FAAAAI, FACAAI, Institute for Asthma and Allergy Wheaton and Chevy Chase Maryland, Michael A. Kaliner, MD FAAAAI, Medical Director, Institute for Asthma and Allergy, Chevy Chase and Wheaton, Maryland, Professor of Medicine, George Washington University School of Medicine, Washington DC Definition and demographics定义和人口统计 Asthma is truly a syndrome encompassing several disease entities/endotypes. The word asthma derives from the Greek word for panting, or breathlessness, and thus describes the primary symptom of this disease. Asthma is recognized as a complex condition with differences in severity, natural history, comorbidities, and treatment response. It has been defined as "a chronic inflammatory disorder associated with variable airflow obstruction and bronchial hyperresponsiveness. It presents with recurrent episodes of wheeze, cough, shortness of breath, chest tightness."哮喘确实是一种包括多种疾病实体/内型的综合征。哮喘一词来源于希腊语中的喘息或呼吸困难，因此描述了这种疾病的主要症状。哮喘被认为是一种复杂的疾病，其严重程度、自然病史、合并症和治疗反应各不相同。它被定义为“一种与可变气流阻塞和支气管高反应性相关的慢性炎症性疾病。它表现为反复发作的喘息、咳嗽、呼吸急促、胸闷。” While the critical role of inflammation has been further substantiated, there is an evidence for considerable variability in the pattern of inflammation indicating phenotypic differences that may influence treatment responses. Gene-by-environmental interactions are important to the development and expression of asthma. Of the environmental factors, allergic reactions and pollution are of critical importance with expanding role for viral respiratory infections in these processes. The onset of asthma for most patients begins early in life with the pattern of disease persistence determined by early, recognizable risk factors including atopic disease, recurrent wheezing, and a parental history of asthma. Current asthma treatment with anti-inflammatory does not appear to prevent progression of the underlying disease severity.虽然炎症的关键作用得到了进一步证实，但有证据表明炎症模式存在相当大的差异，表明表型差异可能会影响治疗反应。基因与环境的相互作用对哮喘的发展和表达很重要。在环境因素中，过敏反应和污染至关重要，病毒性呼吸道感染在这些过程中的作用越来越大。大多数患者的哮喘发作始于生命早期，其疾病持续模式由早期可识别的风险因素决定，包括特应性疾病、复发性喘息和父母哮喘史。目前使用抗炎药治疗哮喘似乎并不能阻止潜在疾病严重程度的进展。 Asthma is the most common chronic respiratory disorders, affecting all age groups, worldwide. The most recent comprehensive analyses of the Global Burden of Disease Study (GBD) undertaken in 2008-2010 estimates the number of people with asthma in the world as high as 334 million. A lower figure of 235 million used in the Global Asthma Report 2011 came from the most up to date GBD information available at that time based on analyses from 2000-2002. Prevalence of childhood asthma varies widely between countries, and between centers within countries, and estimated at 14%. Prevalence of recent wheeze in adolescents varied widely. The highest prevalence (>20%) was generally observed in Latin America and in English-speaking countries of Australasia, Europe and North America as well as South Africa. The lowest prevalence (<5%) was observed in the Indian subcontinent, Asia-Pacific, Eastern Mediterranean, and Northern and Eastern Europe. In Africa, 10-20% prevalence was mostly observed. Overall, 4.3% of respondents to the World Health Survey aged 18-45 in 2002-2003 reported a doctor’s diagnosis of asthma, 4.5% had reported either a doctor’s diagnosis or that they were taking treatment for asthma, and 8.6% reported that they had experienced attacks of wheezing or whistling breath (symptoms of asthma) in the preceding 12 months.哮喘是最常见的慢性呼吸系统疾病，影响全球所有年龄段。2008-2010年对全球疾病负担研究（GBD）进行的最新综合分析估计，全球哮喘患者人数高达3.34亿。《2011年全球哮喘报告》中使用的2.35亿这一较低数字来自当时基于2000-2002年分析的最新GBD信息。儿童哮喘的患病率在国家之间以及国家内部各中心之间差异很大，估计为14%。青少年近期喘息的患病率差异很大。拉丁美洲、澳大拉西亚、欧洲和北美的英语国家以及南非的患病率最高（>20%）。印度次大陆、亚太地区、东地中海以及北欧和东欧的患病率最低（<5%）。在非洲，主要观察到10-20%的患病率。总体而言，2002-2003年世界卫生调查中，年龄在18-45岁之间的受访者中有4.3%报告医生诊断为哮喘，4.5%报告医生诊断或正在接受哮喘治疗，8.6%报告在过去12个月内经历过喘息或吹口哨（哮喘症状）发作。 Prevalence of asthma in middle-aged and older American adults is found to be higher in women ( 9.7%) and higher among adults who are poor (10.6%). There is greater difficulty of distinguishing asthma from other respiratory conditions, such as chronic obstructive pulmonary disease (COPD) in older age groups. Geriatric asthma can be complicated by comorbidities, potential loss of reversibility of airway obstruction, as well as impairment in the perception of breathlessness. Limited data remains in clinical trials on geriatric asthma as asthma medications are rarely tested on the elderly. Due to asthma being commonly thought of as a childhood disease, the elderly are often under-diagnosed and undertreated.研究发现，美国中老年人的哮喘患病率在女性中较高（9.7%），在贫困成年人中较高（10.6%）。将哮喘与其他呼吸系统疾病（如老年人的慢性阻塞性肺疾病（COPD））区分开来的难度更大。老年哮喘可能因合并症、气道阻塞可逆性的潜在丧失以及呼吸困难感知的损害而变得复杂。由于哮喘药物很少在老年人身上进行测试，老年哮喘的临床试验数据仍然有限。由于哮喘通常被认为是一种儿童疾病，老年人往往诊断不足，治疗不足。 Clinical Classification临床分类 It is increasingly clear that asthma syndrome is divided into distinct disease entities with specific mechanisms. The attempt for a new classification is made were "endotype" is proposed to be a subtype of a condition defined by a distinct pathophysiological mechanism. Criteria for defining asthma endotypes on the basis of their phenotypes and putative pathophysiology are suggested.越来越清楚的是，哮喘综合征被分为具有特定机制的不同疾病实体。尝试进行新的分类，提出“内型”是由不同病理生理机制定义的疾病的一种亚型。建议根据哮喘内型的表型和推定的病理生理学来定义哮喘内型。 Currently asthma is classified into atopic and non-atopic types based on the onset of symptoms. Atopic refers to early-onset whereas non-atopic refers to late-onset. Despite the differentiation, a significant degree of overlap exists between the two types. The severity of symptoms is further classified based on the GINA severity grades into mild intermittent, mild persistent, moderate persistent and severe persistent asthma. Furthermore, asthma severity classification is different for various ages.目前，哮喘根据症状的发作分为特应性和非特应性类型。特应性指早发性，非特应性指晚发性。尽管存在差异，但这两种类型之间仍存在很大程度的重叠。症状的严重程度根据GINA严重程度等级进一步分为轻度间歇性、轻度持续性、中度持续性和重度持续性哮喘。此外，哮喘严重程度分类因年龄而异。 Asthma Care Quick Reference哮喘护理快速参考 Signs and Symptoms of Asthma症状 To establish a diagnosis of asthma, the clinician should determine that:为了确定哮喘的诊断，临床医生应确定： Episodic symptoms of airflow obstruction or airway hyperresponsiveness are present.出现气流阻塞或气道高反应性的发作性症状。Airflow obstruction is at least partially reversible.气流阻塞至少部分是可逆的。Alternative diagnoses are excluded.排除其他诊断。 Recommended methods to establish the diagnosis are:推荐的诊断方法包括： Detailed medical history 详细的病史 Physical exam focusing on the upper respiratory tract, chest, and skin.体检重点是上呼吸道、胸部和皮肤。 Spirometry to demonstrate obstruction and assess reversibility, including in children 5 years of age or older. Reversibility is determined either by an increase in FEV1 of ≥12 percent from baseline or by an increase ≥10 percent of predicted FEV1 after inhalation of a short-acting bronchodilator.肺活量测定用于显示梗阻和评估可逆性，包括5岁或以上的儿童。可逆性由FEV1比基线增加≥12%或吸入短效支气管扩张剂后预测FEV1增加≥10%来确定。 Additional studies are not routinely necessary but may be useful when considering alternative diagnoses:额外的研究通常不是必需的，但在考虑替代诊断时可能有用： Additional pulmonary function studies (e.g., measurement of lung volumes and evaluation of inspiratory loops) may be indicated, especially if there are questions about possible coexisting COPD, a restrictive defect, VCD, or possible central airway obstruction. A diffusing capacity test is helpful in differentiating between asthma and emphysema in patients, such as smokers and older patients, who are at risk for both illnesses.可能需要进行额外的肺功能研究（例如，测量肺容量和评估吸气回路），特别是如果对可能共存的COPD、限制性缺陷、VCD或可能的中央气道阻塞有疑问。弥散能力测试有助于区分吸烟者和老年患者等患者的哮喘和肺气肿，他们都有患这两种疾病的风险。 Bronchoprovocation with methacholine, histamine, cold air, or exercise challenge may be useful when asthma is suspected, and spirometry is normal or near normal. For safety reasons, bronchoprovocation testing should be carried out by a trained individual in an Appropriate facility and is not generally recommended if the FEV1 is <65 percent predicted. A positive methacholine bronchoprovocation test is diagnostic for the presence of airway hyperresponsiveness, a characteristic feature of asthma that also can be present in other conditions (e.g., allergic rhinitis, cystic fibrosis, COPD, among others). Thus, although a positive test is consistent with asthma, a negative bronchoprovocation may be more helpful to rule out asthma.当怀疑哮喘，肺活量正常或接近正常时，使用乙酰甲胆碱、组胺、冷空气或运动挑战进行支气管扩张可能是有用的。出于安全原因，支气管激发试验应由受过训练的人员在适当的设施中进行，如果FEV1预测值<65%，通常不建议进行支气管激发试验。乙酰甲胆碱支气管激发试验阳性可诊断气道高反应性的存在，这是哮喘的一个特征，也可能存在于其他疾病中（如过敏性鼻炎、囊性纤维化、慢性阻塞性肺病等）。因此，尽管阳性检测与哮喘一致，但阴性支气管激发可能更有助于排除哮喘。 Chest x ray may be needed to exclude other diagnoses.可能需要胸部x光片来排除其他诊断。 Allergy testing过敏检测 Biomarkers of inflammation. The usefulness of measurements of biomarkers of inflammation (e.g., total and differential cell count and mediator assays) in sputum, blood, urine, and exhaled air as aids to the diagnosis and assessment of asthma. It is important to consider a diagnosis of asthma if certain elements of the clinical history are present – they are not diagnostic by themselves but increase the probability of a diagnosis of asthma:炎症的生物标志物。痰液、血液、尿液和呼出空气中炎症生物标志物的测量（如总细胞计数和差异细胞计数以及介质测定）作为哮喘诊断和评估的辅助工具的有用性。如果存在临床病史的某些因素，考虑诊断哮喘很重要——这些因素本身并不能诊断哮喘，但会增加诊断哮喘的可能性： Wheezing—high-pitched whistling sounds when breathing out—especially in children. (Lack of wheezing and a normal chest examination do not exclude asthma.)喘息——呼气时发出高音口哨声——尤其是儿童。（缺乏喘息和正常的胸部检查并不排除哮喘。） History of any of the following:以下任何一项的历史： Cough, worse particularly at night咳嗽，尤其是在晚上 Recurrent wheeze复发性喘鸣 Recurrent difficulty in breathing反复呼吸困难 Recurrent chest tightness反复胸闷 Symptoms occur or worsen in the presence of:症状在以下情况下出现或恶化： Exercise运动、Viral infection病毒感染、Animals with fur or hair有毛皮或毛发的动物 House-dust mites (in mattresses, pillows, upholstered furniture, carpets)屋尘螨（存在于床垫、枕头、软垫家具、地毯中）、Mold霉菌、Smoke (tobacco, wood)烟雾（烟草、木材） Pollen花粉、Changes in weather天气变化、Strong emotional expression (laughing or crying hard)强烈的情绪表达（大笑或大哭）、Airborne chemicals or dusts空气中的化学物质或粉尘、Menstrual cycles月经周期、Symptoms occur or worsen at night, awakening the patient.症状在夜间出现或恶化，唤醒患者。 Spirometry is needed to establish a diagnosis of asthma.需要肺活量测定来确定哮喘的诊断。 Physical examination should be focused on upper respiratory tract, chest, and skin. Certain findings present on physical exam increase the probability of asthma, while their absence does not rule it out, because the disease is by definition variable, and signs of airflow obstruction are often absent between attacks:体检应重点检查上呼吸道、胸部和皮肤。体检中的某些发现会增加哮喘的概率，但不排除哮喘的可能性，因为根据定义，这种疾病是可变的，发作之间通常没有气流阻塞的迹象： Hyper expansion of the thorax, especially in children; use of accessory muscles; appearance of hunched shoulders; and chest deformity.胸部过度扩张，尤其是儿童；辅助肌肉的使用；驼背的外观；胸部畸形。 Sounds of wheezing during normal breathing, or a prolonged phase of forced exhalation (typical of airflow obstruction). Wheezing may only be heard during forced exhalation, but it is not a reliable indicator of airflow limitation.正常呼吸时的喘息声，或长时间的强制呼气（典型的气流阻塞）。只有在强制呼气时才能听到喘息声，但这并不是气流限制的可靠指标。 Increased nasal secretion, mucosal swelling, and/or nasal polyps.鼻分泌物增加、粘膜肿胀和/或鼻息肉。 Atopic dermatitis/eczema or any other manifestation of an allergic skin condition.特应性皮炎/湿疹或任何其他过敏性皮肤病的表现。 The presence of concomitant diseases or conditions that may influence asthma, including:可能影响哮喘的伴随疾病或病症的存在，包括： Rhinosinusitis, Gastro-esophageal reflux or laryngopharyngeal reflux, and Bronchitis or smoking.鼻窦炎、胃食管反流或喉咽反流、支气管炎或吸烟。 Early in the disease, symptoms may include a vague, heavy feeling of tightness in the chest and in the allergic patient, there may be associated rhinitis and conjunctivitis symptoms. Typical symptoms which patients experience include coughing, wheezing, chest tightness and dyspnea. Cough in asthma is usually non-productive, but it may progress to expectoration of viscous, mucoid sputum which is difficult to clear. If the sputum turns purulent or discolored, an infection may be present, as the sputum in asthma is usually clear to light yellow in color.在疾病早期，症状可能包括胸部模糊、沉重的紧绷感，过敏患者可能会出现相关的鼻炎和结膜炎症状。患者的典型症状包括咳嗽、喘息、胸闷和呼吸困难。哮喘患者的咳嗽通常是非生产性的，但可能会发展为咳出难以清除的粘稠粘液痰。如果痰液变成脓性或变色，则可能存在感染，因为哮喘患者的痰液通常呈透明至淡黄色。 There is a subgroup of asthmatics whose asthma is characterized solely by cough, without overt wheezing, the "cough variant of asthma". Monitoring of PEF or methacholine inhalation challenge, to clarify whether there is bronchial hyperresponsiveness consistent with asthma, may be helpful in diagnosis. The diagnosis of cough variant asthma is confirmed by a positive response to asthma medication.有一个哮喘亚组，其哮喘的特征是仅咳嗽，没有明显的喘息，这是“哮喘的咳嗽变体”。监测PEF或乙酰甲胆碱吸入挑战，以澄清是否存在与哮喘一致的支气管高反应性，可能有助于诊断。咳嗽变异性哮喘的诊断通过对哮喘药物的积极反应得到证实。 In the completely asymptomatic patient, results of chest examination will be normal, although head, eye, ear, nose, and throat examination may disclose concomitant serous otitis media, allergic conjunctivitis, allergic rhinitis, nasal polyps, paranasal sinus tenderness, signs of postnasal drip, or pharyngeal mucosal lymphoid hyperplasia. Clubbing of the fingers is extremely rare in uncomplicated asthma, and this finding should direct the physician's attention toward diseases such as bronchiectasis, cystic fibrosis, pulmonary neoplasm, or cardiac disease. Many symptomatic asthmatics can be diagnosed by careful auscultation of the chest which reveals the presence of expiratory wheezing and a somewhat prolonged expiratory phase.对于完全无症状的患者，胸部检查的结果将是正常的，尽管头部、眼睛、耳朵、鼻子和喉咙检查可能会发现伴有浆液性中耳炎、过敏性结膜炎、过敏性鼻炎、鼻息肉、鼻旁窦压痛、鼻后滴漏征或咽粘膜淋巴增生。手指打结在无并发症的哮喘中极为罕见，这一发现应将医生的注意力引向支气管扩张症、囊性纤维化、肺肿瘤或心脏病等疾病。许多有症状的哮喘患者可以通过仔细听诊胸部来诊断，听诊结果显示存在呼气喘息和呼气期延长。 Exacerbations of asthma are acute or subacute episodes of progressively worsening shortness of breath, cough, wheezing, and chest tightness—or some combination of these symptoms. Exacerbations are characterized by decreases in expiratory airflow that can be documented and quantified by simple measurement of lung function (spirometry or PEF), can vary widely among individuals and within individuals from rare to frequent. It is important to understand that the severity of disease does not necessarily correlate with the intensity of exacerbations, which can vary from mild to very severe and life-threatening.哮喘的加重是呼吸急促、咳嗽、喘息和胸闷或这些症状的某种组合逐渐恶化的急性或亚急性发作。病情加重的特征是呼气气流减少，可以通过简单的肺功能测量（肺活量测定或PEF）来记录和量化，在个体之间和个体内部可能存在很大差异，从罕见到频繁。重要的是要明白，疾病的严重程度不一定与恶化的强度相关，恶化的强度可以从轻度到非常严重不等，甚至危及生命。 Patients at any level of severity, even intermittent asthma, can have severe exacerbations. For example, a person who has intermittent asthma can have a severe exacerbation during a viral illness or when exposed to allergens to which he or she is sensitized or to noxious fumes and irritants. In fact, the last classification “mild intermittent asthma” was changed to “intermittent asthma”, emphasizing that patients at any level of severity — including intermittent — can have severe exacerbations. The frequency of exacerbations requiring intervention with oral systemic corticosteroids now changed to classification of persistent, rather than intermittent asthma. However, severity can determine prolongation of the illness and is often characterized by unremitting symptoms with poor response to therapy. The duration of acute exacerbations may vary from a few hours to a few days. These unpredictable variations in exacerbations can present treatment dilemmas in clinical practice.任何严重程度的患者，即使是间歇性哮喘，都可能出现严重恶化。例如，患有间歇性哮喘的人在病毒性疾病期间或暴露于他或她敏感的过敏原或有毒烟雾和刺激物时可能会严重恶化。事实上，最后一个分类“轻度间歇性哮喘”改为“间歇性哮喘”，强调任何严重程度的患者，包括间歇性哮喘，都可能出现严重恶化。需要口服全身性皮质类固醇干预的急性发作频率现在改为持续性哮喘，而不是间歇性哮喘。然而，严重程度可以决定疾病的持续时间，通常以持续的症状为特征，对治疗反应不佳。急性加重的持续时间可能从几个小时到几天不等。这些不可预测的恶化变化可能会在临床实践中带来治疗困境。 Assessment of severity requires assessing the following components of current impairment:评估严重程度需要评估当前减值的以下组成部分： Symptoms症状、Nighttime awakenings夜间醒来、Need for SABA for quick relief of symptoms需要SABA快速缓解症状、Work/school days missed错过工作/上学日、Ability to engage in normal daily activities or in desired activities能够从事正常的日常活动或理想的活动、Quality-of-life assessments生活质量评估、Lung function, measured by spirometry: FEV1, FVC (or FEV6), FEV1/FVC (or FEV6 in adults). Spirometry is the preferred method for measuring lung function to classify severity. Peak flow has not been found to be a reliable variable for classifying severity.肺功能，通过肺活量测定法测量：FEV1、FVC（或FEV6）、FEV1/FVC（或成人FEV6）。肺活量测定是测量肺功能以分类严重程度的首选方法。峰值流量尚未被发现是严重程度分类的可靠变量。 Assessment of Risk风险评估 Assessment of the risk of future adverse events requires careful medical history, observation, and clinician judgment. Documentation of warning signs and adverse events will be necessary when a patient is felt to be at increased risk. Patients who are deemed at increased risk of adverse outcomes need close monitoring and frequent assessment by their clinicians.评估未来不良事件的风险需要仔细的病史、观察和临床医生的判断。当患者感觉风险增加时，有必要记录警告信号和不良事件。被认为不良后果风险增加的患者需要临床医生进行密切监测和频繁评估。 Predictors that have been reported to be associated with increased risk of exacerbations or death include:据报道，与加重或死亡风险增加相关的预测因素包括： Severe airflow obstruction, as detected by spirometry肺活量测定法检测到严重气流阻塞 Persistent severe airflow obstruction. Two or more ED visits or hospitalizations for asthma in the past year; any history of intubation or ICU admission, especially if in the past 5 years持续严重气流阻塞。在过去的一年中，因哮喘接受过两次或两次以上的急诊或住院治疗；是否有插管或ICU入院史，特别是过去5年 Patients report that they feel in danger or frightened by their asthma患者报告称，他们因哮喘而感到危险或害怕 Certain demographic or patient characteristics: female, nonwhite, nonuse of ICS therapy, and current smoking某些人口统计学或患者特征：女性、非白人、不使用ICS治疗和目前吸烟 Psychosocial factors: depression, increased stress, socioeconomic factors心理社会因素：抑郁、压力增加、社会经济因素 Attitudes and beliefs about taking medications对服药的态度和信念 Asthma in elderly老年哮喘 Asthma affecting individuals across the lifespan. Current evidence consistently suggests that asthma is common among elderly subjects. Because of increased longevity, the proportion of individuals aged 65 years and older is increasing worldwide. By 2030, elderly subjects will comprise ~20% and ~36% of the populations of the United States (U.S.) and China, respectively. Determining the exact prevalence of asthma in elderly is made difficult by under-diagnosis due to decreased perception or under-reporting of symptoms by patients, suboptimal utilization of spirometry, misclassification of asthma as chronic obstructive pulmonary disease (COPD), and failure to recognize asthma in subjects with co-morbidities such as congestive heart failure or COPD. In two nationwide surveys in the U.S. estimates of the prevalence of current asthma in the elderly were 5.9% for the period 1980–2004. In elderly subjects, asthma is more common in women than in men. Compared to children or younger adults, older adults and/or elderly subjects have greater morbidity and healthcare costs from asthma, thus it is important to recognize and treat asthma in older population.哮喘影响个体的整个生命周期。目前的证据一致表明，哮喘在老年人中很常见。由于寿命延长，全球65岁及以上人口的比例正在增加。到2030年，老年受试者将分别占美国和中国人口的20%和36%。由于患者对症状的感知或报告不足、肺活量测定的利用不够理想、将哮喘误分类为慢性阻塞性肺疾病（COPD）以及未能识别患有充血性心力衰竭或COPD等合并症的受试者的哮喘，因此难以确定老年哮喘的确切患病率。在美国的两项全国性调查中，1980年至2004年期间，老年人当前哮喘的患病率估计为5.9%。在老年受试者中，哮喘在女性中比男性更常见。与儿童或年轻人相比，老年人和/或老年受试者的哮喘发病率和医疗费用更高，因此识别和治疗老年人群的哮喘非常重要。 Causes of Asthma原因 The allergic asthma phenotype dominates in early life. Although asthma has a strong genetic component, environmental factors must occur for it to manifest. The paradigm for allergen induction of asthma is from allergen exposure → allergic sensitization → asthma development. While a variety of ambient and indoor allergic exposures have been implicated in the development and exacerbation of childhood asthma, the indoor environment has greatest influence on asthma development. Children sensitized to aeroallergens at a young age are likely to have persistent asthma symptoms into late childhood and adulthood and show poorer lung function than those not sensitized. House dust mite (HDM), furred pets, cockroach, rodent and mold, with regional variation, account for the large proportion of aeroallergens associated with sensitization and asthma. In many cases, exposure and sensitivity follow a. Evidence supporting dose-response relationship is particularly strong for dust mite and cat.过敏性哮喘表型在早期生活中占主导地位。尽管哮喘有很强的遗传成分，但必须发生环境因素才能表现出来。哮喘过敏原诱导的范式来自过敏原暴露→ 变应性致敏→ 哮喘发展。虽然各种环境和室内过敏暴露与儿童哮喘的发展和恶化有关，但室内环境对哮喘的发展影响最大。在年轻时对空气过敏原敏感的儿童可能会在儿童晚期和成年后出现持续的哮喘症状，并且其肺功能比未致敏的儿童差。屋尘螨（HDM）、长毛宠物、蟑螂、啮齿动物和霉菌在与致敏和哮喘相关的空气过敏原中占很大比例，具有区域差异。在许多情况下，暴露和敏感性遵循a。支持剂量反应关系的证据对尘螨和猫尤其强烈。 The steady increase in population trends towards urban centers also shares the trajectory of increasing air pollution. Indoor and ambient air pollution have been associated with a variety of adverse cardiopulmonary health effects including asthma symptoms, exacerbations and decline in lung function. The pollutants best studied are the gases nitrogen dioxide (NO2), ozone (O3), volatile organic compounds (VOCs), and particulate matter (PM) that comprises soot.人口向城市中心稳步增长的趋势也与空气污染加剧的轨迹相同。室内和环境空气污染与各种不良的心肺健康影响有关，包括哮喘症状、加重和肺功能下降。研究得最好的污染物是二氧化氮（NO2）、臭氧（O3）、挥发性有机化合物（VOC）和包含烟尘的颗粒物（PM）。 Recent evidence has demonstrated elevated pollution exposure in utero and in the first year of life may influence the development of asthma in young children. Exposure to indoor pollution of PM2.5 and VOCs is directly correlated with asthma inflammatory markers in schoolchildren with and without asthma, indicating potential induction of allergic airway inflammation with these exposures. 最近的证据表明，子宫内和生命第一年的污染暴露增加可能会影响幼儿哮喘的发展。暴露于PM2.5和挥发性有机化合物的室内污染与患有和不患有哮喘的学童的哮喘炎症标志物直接相关，表明这些暴露可能会引发过敏性气道炎症。Environmental tobacco smoke (ETS) is an independent determinant of the development of asthma. Tobacco smoke contains many VOCs and NO2, which are likely to serve as the conduits to poor respiratory outcomes. In vivo studies also suggest that exposure to ETS is associated with IL-13 and greater serum IgE in children with asthma compared to non-exposed asthmatic children and controls, suggesting an augmentation of the Th2 immunophenotype with exposure. 环境烟草烟雾（ETS）是哮喘发展的独立决定因素。烟草烟雾中含有许多挥发性有机化合物和二氧化氮，这可能会导致呼吸系统不良。体内研究还表明，与未暴露于ETS的哮喘儿童和对照组相比，暴露于ETS与哮喘儿童的IL-13和更高的血清IgE有关，这表明暴露于ETS会增强Th2免疫表型。Since the early 2000s the inverse relationship between farming, particularly traditional dairy farming lifestyle, and the development of asthma has been demonstrated early in life and appears to hold true well into adulthood. Children living on farms also had reduced rates of sensitization and other atopic conditions. Farm studies have implicated the rich diversity of microbial exposure both in the animal and home environments are strongly and inversely associated with asthma, implying that the early and persistent microbial environment influences the development of the immune system away from allergic and asthmatic predisposition.自21世纪初以来，农业，特别是传统的奶牛养殖生活方式，与哮喘的发展之间的负相关关系在生命的早期就得到了证实，并且似乎一直持续到成年。生活在农场的儿童也降低了致敏率和其他特应性疾病的发生率。农场研究表明，动物和家庭环境中微生物暴露的丰富多样性与哮喘密切相关，这意味着早期和持续的微生物环境会影响免疫系统的发展，使其远离过敏和哮喘易感性。The intestinal microbiome likely influences the immune system in a manner similar to that related to farm exposure.肠道微生物组可能以类似于农场暴露的方式影响免疫系统。 Because limiting exposure to allergens and allergy immunotherapy are both specifically helpful in treating allergic asthmatic subjects, a careful search for possible allergies is indicated in nearly all asthmatics, certainly all persistent asthmatics.由于限制接触过敏原和过敏免疫疗法都对治疗过敏性哮喘患者特别有帮助，因此几乎所有哮喘患者，当然是所有持续性哮喘患者，都需要仔细寻找可能的过敏反应。 In addition to allergen-induced asthma, many other factors and conditions such as exercise, infection, occupational chemical exposures, side effects to medications such as beta adrenergic blocking agents, bronchitis, and Churg-Strauss allergic granulomatosis can also cause asthma. Sinusitis, GERD, hyperthyroidism, pregnancy and viral illnesses may complicate asthma.除了过敏原诱导的哮喘外，许多其他因素和条件，如运动、感染、职业化学物质暴露、β肾上腺素能阻滞剂等药物的副作用、支气管炎和Churg-Strauss过敏性肉芽肿病，也可能导致哮喘。鼻窦炎、胃食管反流病、甲状腺功能亢进、妊娠和病毒性疾病可能会使哮喘复杂化。 Pathogenesis and genetics发病机制和遗传学 Over the last decade research has confirmed the important role of inflammation in asthma, unfortunately specific processes related to the transmission of airway inflammation to specific pathophysiologic consequences of airway dysfunction and the clinical manifestations of asthma have yet to be fully understood. Similarly, much has been learned about the host –environment factors that determine airways’ susceptibility to these processes, but the relative contributions of either and the precise interactions between them that leads to the initiation or persistence of disease is difficult to establish. The concepts underlying asthma pathogenesis have evolved dramatically in the past 25 years and are still undergoing evaluation as various phenotypes of this disease are defined and greater insight links clinical features of asthma with genetic patterns.在过去的十年中，研究证实了炎症在哮喘中的重要作用，不幸的是，与气道炎症传播到气道功能障碍的特定病理生理后果相关的具体过程以及哮喘的临床表现尚未得到充分了解。同样，关于决定气道对这些过程易感性的宿主-环境因素，我们已经了解了很多，但很难确定两者的相对贡献以及它们之间导致疾病发生或持续的精确相互作用。在过去的25年里，哮喘发病机制的基本概念发生了巨大的变化，目前仍在评估中，因为这种疾病的各种表型已被定义，更深入的了解将哮喘的临床特征与遗传模式联系起来。 Because asthma involves an integrated response in the conducting airways of the lung to known or unknown triggers, it is a multicellular disease, involving abnormal responses of many different cell types in the lung.因为哮喘涉及肺传导气道对已知或未知触发因素的综合反应，所以它是一种多细胞疾病，涉及肺中许多不同细胞类型的异常反应。 Environmental triggers concurrently act on airway afferent nerves (which both release their own peptide mediators and stimulate reflex release of the bronchoconstrictor acetylcholine) and airway epithelial cells to initiate responses in multiple cell types that contribute to the mucous metaplasia and airway smooth muscle bronchoconstriction that characterize asthma.环境触发因素同时作用于气道传入神经（既释放其自身的肽介质，又刺激支气管收缩剂乙酰胆碱的反射释放）和气道上皮细胞，以启动多种细胞类型的反应，这些细胞类型有助于哮喘特征的粘液化生和气道平滑肌支气管收缩。 Epithelial cells release TSLP and IL-33, which act on airway dendritic cells, and IL-25, which together with IL-33 acts on mast cells, basophils, and innate type 2 lymphocytes. These secreted products stimulate dendritic cell maturation that facilitates the generation of effector T cells and triggers the release of both direct bronchoconstrictors and Th2 cytokines from innate immune cells, which feedback on both the epithelium and airway smooth muscle and further facilitate amplification of airway inflammation through subsequent adaptive T cell responses.上皮细胞释放TSLP和IL-33，它们作用于气道树突状细胞，以及IL-25，IL-25与IL-33一起作用于肥大细胞、嗜碱性粒细胞和先天性2型淋巴细胞。这些分泌的产物刺激树突细胞成熟，促进效应T细胞的产生，并触发先天免疫细胞释放直接支气管收缩剂和Th2细胞因子，这些细胞因子对上皮和气道平滑肌进行反馈，并通过随后的适应性T细胞反应进一步促进气道炎症的放大。 Asthma is genetically heterogeneous. A few common alleles are associated with disease risk at all ages. Implicated genes suggest a role for communication of epithelial damage to the adaptive immune system and activation of airway inflammation. Asthma runs strongly in families, and its heritability has been estimated as 60%. Genetic studies offer a structured means of understanding the causes of asthma as well as identifying targets that can be used to treat the syndrome. Recent genome-wide association studies begun to shed light on both common and distinct pathways that contribute to asthma and allergic diseases. Associations with variation in genes encoding the epithelial cell-derived cytokines, interleukin-33 (IL-33) and thymic stromal lymphopoietin (TSLP), and the IL1RL1 gene encoding the IL-33 receptor, ST2, highlight the central roles for innate immune response pathways that promote the activation and differentiation of T-helper 2 (Th2) cells in the pathogenesis of both asthma and allergic diseases. The factor of atopy, or the genetic tendency for development of the condition, remains the strongest predisposing factor for the development of asthma. These and other genetic findings expanding our understanding of the common and unique biological pathways that are dysregulated in these related conditions and eventually will be helpful in design of new therapies and prevention modalities.哮喘在基因上是异质的。一些常见的等位基因与所有年龄段的疾病风险有关。相关基因表明，上皮损伤与适应性免疫系统的沟通以及气道炎症的激活起着重要作用。哮喘在家族中有很强的遗传性，其遗传率估计为60%。遗传研究提供了一种结构化的方法来了解哮喘的病因，并确定可用于治疗该综合征的靶点。最近的全基因组关联研究开始揭示导致哮喘和过敏性疾病的常见和不同途径。与编码上皮细胞衍生的细胞因子白细胞介素-33（IL-33）和胸腺基质淋巴生成素（TSLP）的基因变异以及编码IL-33受体ST2的IL1RL1基因的关联，突显了先天免疫反应途径在哮喘和过敏性疾病发病机制中促进T辅助2（Th2）细胞活化和分化的核心作用。特应性因素，或疾病发展的遗传倾向，仍然是哮喘发展的最强易感因素。这些和其他遗传发现扩展了我们对这些相关疾病中失调的常见和独特生物途径的理解，最终将有助于设计新的疗法和预防方式。 Prevention预防 Multifactorial disease requires multiple approaches in order to minimize development or progression of the clinical symptoms.多因素性疾病需要多种治疗方法，以尽量减少临床症状的发展或进展。 Environment control环境控制 Most convincing evidence for early life environmental exposures influencing the development of asthma would be from randomized controlled interventions to specifically addressing the offending agent and demonstrate lower incidence of asthma development. Allergen remediation strategies directed at cat, dog, mold, mouse and cockroach demonstrate substantially decrease exposure levels in homes. Interventions to reduce HDM alone have been effective and seem to improve early outcomes.早期生活环境暴露影响哮喘发展的最有说服力的证据将是从随机对照干预到专门针对致病因子，并证明哮喘发展的发生率较低。针对猫、狗、霉菌、老鼠和蟑螂的过敏原修复策略表明，家庭中的暴露水平大大降低。单独减少HDM的干预措施是有效的，似乎可以改善早期结果。 Recent meta-analyses have shown multifaceted allergen remediation programs to be protective against the development of asthma with 20-50% reduction in odds. The most protective effect was seen in children with greater than 5 years of follow-up, indicating a true decrease in risk to those prone to develop atopic asthma.最近的荟萃分析表明，多方面的过敏原修复计划可以预防哮喘的发展，几率降低20-50%。在随访时间超过5年的儿童中，保护作用最强，这表明易患特应性哮喘的儿童的风险确实降低了。 The best preventative effect of allergen avoidance was the Canadian Childhood Asthma Primary Prevention Study in a high-risk birth cohort. In this study, the intervention was avoidance of house dust mite, pets, and environmental tobacco smoke starting prenatally, and encouragement of breastfeeding with delayed introduction of solids. HDM interventions included encasing parents’ and infants’ mattresses and box springs, weekly hot water wash of all bedding and application of benzyl benzoate to carpets and upholstery before birth and at 4 and 8 months of age. Children receiving the intervention had significantly less physician diagnoses of asthma, wheeze in the past 12 months and wheeze apart from colds when evaluated at age 7 years. Another birth cohort study also observed significantly fewer asthma symptoms at age 8 years old in a high-risk birth cohort intervention focused on HDM and food allergen avoidance in early life, and a significant decrease in atopy at the 8-year time point.在高危出生队列中，避免过敏原的最佳预防效果是加拿大儿童哮喘一级预防研究。在这项研究中，干预措施是从产前开始避免尘螨、宠物和环境烟草烟雾，并鼓励母乳喂养，延迟摄入固体食物。HDM干预措施包括将父母和婴儿的床垫和弹簧盒包裹起来，每周用热水清洗所有床上用品，并在出生前以及4个月和8个月大时在地毯和室内装饰上涂抹苯甲酸苄酯。接受干预的儿童在7岁时接受评估时，医生对哮喘、过去12个月内的喘息和除感冒外的喘息的诊断明显较少。另一项出生队列研究还观察到，在一项高风险出生队列干预中，8岁时的哮喘症状明显减少，该干预侧重于早期避免HDM和食物过敏原，8年后特应性显著降低。 Large studies assessing increased exposure to indoor fungi before the development of asthma symptoms suggests that Penicillium, Aspergillus, and Cladosporium species pose a respiratory health risk in susceptible populations. Increased exacerbation of current asthma symptoms in children and adults were associated with increased levels of Penicillium, Aspergillus, Cladosporium, and Alternaria species, although further work should consider the role of fungal diversity and increased exposure to other fungal species.在哮喘症状出现之前评估室内真菌暴露增加的大型研究表明，青霉菌、曲霉和枝孢菌物种对易感人群的呼吸系统健康构成风险。儿童和成人当前哮喘症状的加重与青霉菌、曲霉、枝孢菌和链格孢菌物种水平的升高有关，尽管进一步的研究应考虑真菌多样性的作用和与其他真菌物种接触的增加。 Probiotics and vitamins益生菌和维生素 Early studies on the effect of probiotics to affect asthma development by influencing the perinatal microbiome have been mixed. A recent study found significant decrease in the risk of atopic sensitization associated with pre and post-natal administration of probiotics, however there was no effect on asthma or wheeze.关于益生菌通过影响围产期微生物组来影响哮喘发展的早期研究喜忧参半。最近的一项研究发现，与产前和产后服用益生菌相关的特应性致敏风险显著降低，但对哮喘或喘息没有影响。 Vitamins are essential constituents of our diet that have long been known to influence the immune system. Vitamins A and D have received particular attention in recent years as these vitamins have been shown to have an unexpected and crucial effect on the immune response.维生素是我们饮食中必不可少的成分，长期以来一直被认为会影响免疫系统。近年来，维生素A和D受到了特别关注，因为这些维生素已被证明对免疫反应具有意想不到的关键作用。 Experimental preventive therapies实验性预防疗法 In preterm infants without bronchopulmonary dysplasia, Palivizumab, a monoclonal antibody against RSV, reduces respiratory morbidity up to 78%. Recent findings in late preterm children without BPD suggests that prophylaxis through infancy may decrease recurrent wheeze in the first year of life by 10% and by up to 50% at three years of age. While encouraging, further longitudinal studies are necessary to evaluate the effect of palivizumab prophylaxis to decrease the incidence of asthma in childhood.在没有支气管肺发育不良的早产儿中，Palivizumab是一种抗呼吸道合胞病毒的单克隆抗体，可将呼吸道发病率降低高达78%。最近对没有BPD的晚期早产儿的研究结果表明，在婴儿期进行预防可能会使出生后第一年的复发性喘息减少10%，三岁时减少50%。虽然令人鼓舞，但有必要进行进一步的纵向研究，以评估帕利珠单抗预防对降低儿童哮喘发病率的影响。 Recent evidence suggests that anti-allergen immunotherapy to cross-link the FcέR1 receptor may diminish viral induced asthma symptoms. While alterations of the physical environment have been studied, little attention has been given to the approach of altering the immune constitution of high-risk individuals. In this respect, immunomodulators, such as Omalizumab may be of future interest.最近的证据表明，通过抗过敏原免疫疗法交联FcεR1受体可能会减轻病毒诱导的哮喘症状。虽然对物理环境的改变进行了研究，但很少有人关注改变高危人群免疫结构的方法。在这方面，Omalizumab等免疫调节剂可能会引起未来的兴趣。 Treatment治疗 Treatment with anti-inflammatory drugs can, to a large extent, reverse some of these processes; however, the successful response to therapy often requires weeks to achieve and, in some situations, may be incomplete.抗炎药物治疗在很大程度上可以逆转其中一些过程；然而，对治疗的成功反应通常需要数周时间才能实现，在某些情况下可能是不完整的。 The goals of asthma treatment include improving quality of life for people who have asthma in addition to controlling symptoms, reducing the risk of exacerbations, and preventing asthma-related death.哮喘治疗的目标包括改善哮喘患者的生活质量，以及控制症状、降低病情恶化的风险和预防哮喘相关死亡。 A recent large international trial demonstrated that significant reductions in the rate of severe exacerbations and improvements in quality of life were achieved by aiming at achieving guideline-defined asthma control and by adjusting therapy to achieve it. It is important, therefore, to examine how the disease expression and control are affecting the patient’s quality of life. Specific clinical assessment questionnaires were generated to assist practicing physicians in asthma patient evaluation:最近的一项大型国际试验表明，通过实现指南定义的哮喘控制并调整治疗来实现这一目标，可以显著降低严重恶化的发生率并提高生活质量。因此，研究疾病表达和控制如何影响患者的生活质量非常重要。生成了具体的临床评估问卷，以协助执业医师对哮喘患者进行评估： Asthma-Specific Quality of Life哮喘特异性生活质量 Mini Asthma Quality of Life Questionnaire小型哮喘生活质量问卷(Juniper et al. 1999a) Asthma Quality of Life Questionnaire哮喘生活质量问卷(Katz et al. 1999; Marks et al. 1993) ITG Asthma Short FormITG哮喘简表 (Bayliss et al. 2000) Asthma Quality of Life for Children儿童哮喘生活质量 (Juniper et al. 1996) Generic Quality of Life一般生活质量 SF-36 (Bousquet et al. 1994) SF-12 (Ware et al. 1996) The change in emphasis from previous practice guidelines is in periodic assessment of asthma control. For initiating treatment, asthma severity should be classified, and the initial treatment should correspond to the appropriate category of severity. Once treatment is established, the emphasis is on assessing asthma control to determine if the goals for therapy have been met and if adjustments in therapy (step up or step down) would be appropriate.与之前的实践指南相比，重点的变化是哮喘控制的定期评估。对于开始治疗，应对哮喘严重程度进行分类，初始治疗应与适当的严重程度类别相对应。一旦确定了治疗方法，重点是评估哮喘控制情况，以确定是否达到了治疗目标，以及是否需要调整治疗（加强或减少）。 Asthma Care Quick Reference哮喘护理快速参考 Components considered essential to effective asthma management:被认为对有效哮喘管理至关重要的组成部分： Measures of assessment and monitoring, obtained by objective tests, physical examination, patient history and patient report, to diagnose and assess the characteristics and severity of asthma and to monitor whether asthma control is achieved and maintained. 通过客观测试、体检、病史和患者报告获得的评估和监测措施，用于诊断和评估哮喘的特征和严重程度，并监测哮喘控制是否得到实现和维持。 Education for a partnership in asthma care哮喘护理伙伴关系教育 Control of environmental factors and comorbid conditions that affect asthma控制影响哮喘的环境因素和合并症 Pharmacologic therapy药理学治疗 The goals of therapy are to achieve asthma control by reducing impairment and risk:治疗的目标是通过减少损伤和风险来控制哮喘： Prevent chronic and troublesome symptoms (e.g., coughing or breathlessness in the daytime, in the night, or after exertion)预防慢性和麻烦的症状（例如，白天、晚上或劳累后咳嗽或呼吸困难） Require infrequent use (≤2 days a week) of inhaled SABA for quick relief of symptoms需要不经常使用（每周≤2天）吸入SABA以快速缓解症状 Maintain (near) “normal” pulmonary function维持（接近）“正常”的肺功能 Maintain normal activity levels (including exercise and other physical activity and attendance at work or school)保持正常的活动水平（包括锻炼和其他体育活动以及上班或上学） Meet patients’ and families’ expectations of and satisfaction with asthma care满足患者和家属对哮喘护理的期望和满意度 Prevent recurrent exacerbations of asthma and minimize the need for ED visits or hospitalizations预防哮喘复发，尽量减少急诊或住院的需要 Prevent progressive loss of lung function; for children, prevent reduced lung growth防止肺功能逐渐丧失；对于儿童，防止肺部生长减缓 Provide optimal pharmacotherapy with minimal or no adverse effects提供最佳的药物治疗，副作用最小或没有副作用 Patients’ detailed recall of symptoms decreases over time; therefore, the clinician may choose to assess over a 2-week, 3-week, or 4-week recall period. Symptom assessment for periods longer than 4 weeks should reflect more global symptom assessment, such as inquiring whether the patient’s asthma has been better or worse since the last visit and inquiring whether the patient has encountered any particular difficulties during specific seasons or events.患者对症状的详细回忆会随着时间的推移而减少；因此，临床医生可以选择在2周、3周或4周的回忆期内进行评估。超过4周的症状评估应反映更全面的症状评估，例如询问患者的哮喘自上次就诊以来是好转还是恶化，以及询问患者在特定季节或事件中是否遇到任何特殊困难。 Low FEV1 is associated with increased risk of severe asthma exacerbations. Regular monitoring of pulmonary function is particularly important for asthma patients who do not perceive their symptoms until airflow obstruction is severe. There is no readily available method of detecting the “poor perceivers.” The literature reports that patients who had a near-fatal asthma exacerbation, as well as older patients, are more likely to have poor perception of airflow obstruction.低FEV1与严重哮喘急性发作的风险增加有关。对于哮喘患者来说，定期监测肺功能尤为重要，因为他们直到气流阻塞严重时才意识到自己的症状。目前还没有现成的方法来检测“感知不良者”。文献报告称，患有近乎致命的哮喘急性发作的患者以及老年患者更有可能对气流阻塞感知不良。 Asthma Care Quick Reference哮喘护理快速参考 Long-term control medications长期控制药物 Corticosteroids: Block late-phase reaction to allergen, reduce airway hyperresponsiveness, and inhibit inflammatory cell migration and activation. They are the most potent and effective anti-inflammatory medication currently available. ICSs are used in the long-term control of asthma. Short courses of oral systemic corticosteroids are often used to gain prompt control of the disease when initiating long-term therapy; long-term oral systemic corticosteroid is used for severe persistent asthma.皮质类固醇：阻断对过敏原的晚期反应，降低气道高反应性，抑制炎性细胞迁移和活化。它们是目前可用的最有效和最有效的抗炎药物。ICSs用于哮喘的长期控制。在开始长期治疗时，通常使用短期口服全身性皮质类固醇来迅速控制疾病；长期口服全身性皮质类固醇用于治疗严重的持续性哮喘。 Cromolyn sodium and nedocromil: Stabilize mast cells and interfere with chloride channel function. They are used as alternative, but not preferred, medication for the treatment of mild persistent asthma. They can also be used as preventive treatment prior to exercise or unavoidable exposure to known allergens.色甘酸钠和奈多罗米：稳定肥大细胞并干扰氯离子通道功能。它们被用作治疗轻度持续性哮喘的替代药物，但不是首选药物。它们也可以在运动或不可避免地接触已知过敏原之前用作预防性治疗。 Immunomodulators: Omalizumab (anti-IgE) is a monoclonal antibody that prevents binding of IgE to the high-affinity receptors on basophils and mast cells. Omalizumab is used as adjunctive therapy for patients ≥12 years of age who have allergies and severe persistent asthma. Clinicians who administer omalizumab should be prepared and equipped to identify and treat anaphylaxis that may occur.免疫调节剂：奥马珠单抗（抗IgE）是一种单克隆抗体，可防止IgE与嗜碱性粒细胞和肥大细胞上的高亲和力受体结合。奥马珠单抗被用作≥12岁患有过敏和严重持续性哮喘的患者的辅助治疗。施用奥马珠单抗的临床医生应做好准备和装备，以识别和治疗可能发生的过敏反应。 Leukotriene modifiers: (Montelukast, pranlukast, zafirlukast, and zileuton). Target a single group of inflammatory mediators by either blocking the leukotriene receptor or reducing the activity of enzymes required for leukotriene synthesis. Two LTRAs are available—montelukast (for patients >1 year of age) and zafirlukast (for patients ≥7 years of age). The 5-lipoxygenase pathway inhibitor zileuton is available for patients ≥12 years of age; liver function monitoring is essential. LTRAs are alternative, but not preferred, therapy for the treatment of mild persistent asthma (Step 2 care). LTRAs can also be used as adjunctive therapy with ICSs, but for youths ≥12 years of age and adults. Zileuton can be used as alternative but not preferred adjunctive therapy in adults.白三烯调节剂：（孟鲁司特、普仑司特、扎鲁司特和齐留通）。通过阻断白三烯受体或降低白三烯合成所需酶的活性来靶向一组炎症介质。有两种LTRA可供选择——孟鲁司特（适用于1岁以上的患者）和扎鲁司特。5-脂氧合酶途径抑制剂齐留通适用于年龄≥12岁的患者；肝功能监测至关重要。白三烯受体拮抗剂是治疗轻度持续性哮喘的替代疗法，但不是首选疗法（第2步护理）。白三烯受体拮抗剂也可用作吸入性糖皮质激素的辅助治疗，但适用于≥12岁的青少年和成年人。Zileuton（齐留通）可作为成人的替代疗法，但不是首选的辅助疗法。 LABAs: Salmeterol and formoterol after a single dose administration have at least 12 hours duration of bronchodilation. Because of their slower onset of action, the uses of LABA for the treatment of acute symptoms or exacerbations is not currently recommended or is monotherapy for long-term control of asthma.长效β2受体激动药：单剂量给药后，沙美特罗和福莫特罗的支气管扩张持续时间至少为12小时。由于其起效较慢，目前不建议使用LABA治疗急性症状或加重，也不建议将其作为长期控制哮喘的单一疗法。 LABAs are used in combination with ICSs for long-term control and prevention of symptoms in moderate or severe persistent asthma (step 3 care or higher in children ≥5 years of age and adults)  LABA与ICSs（吸入性糖皮质激素）联合使用，用于长期控制和预防中度或重度持续性哮喘的症状（对≥5岁的儿童和成人进行3级或更高级别的护理） Of the adjunctive therapies available, LABA is the preferred therapy to combine with ICS in youths ≥12 years of age and adults在可用的辅助疗法中，LABA是≥12岁的青少年和成年人与ICS联合使用的首选疗法 The beneficial effects of LABA in combination therapy for the great majority of patients who require more therapy than low-dose ICS alone to control asthma (i.e., require step 3 care or higher) should be weighed against the increased risk of severe exacerbations, although uncommon, associated with the daily use of LABAs (see discussion in text).对于绝大多数需要比单独使用低剂量ICS更多治疗来控制哮喘的患者（即需要第3步或更高的护理），LABA在联合治疗中的有益作用应与每天使用LABA相关的严重恶化风险增加进行权衡，尽管这种情况并不常见（见正文中的讨论）。 For patients ≥5 years of age who have moderate persistent asthma or asthma inadequately controlled on low-dose ICS, the option to increase the ICS dose should be given equal weight to the option of adding LABA. For patients ≥5 years of age who have severe persistent asthma or asthma inadequately controlled on step 3 care, the combination of LABA and ICS is the preferred therapy.对于患有中度持续性哮喘或低剂量ICS控制不足的≥5岁患者，增加ICS剂量的选择应与添加LABA的选择同等重要。对于年龄≥5岁、患有严重持续性哮喘或在第3步护理中哮喘控制不足的患者，LABA和ICS的联合治疗是首选疗法。 LABA may be used before exercise, but duration of action does not exceed 5 hours with chronic regular use. Frequent and chronic use of LABA for EIB is discouraged, because this use may disguise poorly controlled persistent asthma.LABA可以在运动前使用，但长期定期使用的作用时间不超过5小时。不建议频繁和长期使用LABA治疗EIB，因为这种使用可能会掩盖控制不佳的持续性哮喘。 Methylxanthines: Sustained-release theophylline is a mild to moderate bronchodilator used as alternative, not preferred, adjunctive therapy with ICS (Evidence A). Theophylline may have mild anti-inflammatory effects. Monitoring of serum theophylline concentration is essential.甲基黄嘌呤：缓释茶碱是一种轻度至中度支气管扩张剂，用作ICS的替代疗法，而不是首选的辅助疗法（证据a）。茶碱可能具有轻微的抗炎作用。监测血清茶碱浓度至关重要。 Quick-relief medications快速缓解药物 Anticholinergics: Inhibit muscarinic cholinergic receptors and reduce intrinsic vagal tone of the airway. Ipratropium bromide provides additive benefit to SABA in moderate-to-severe asthma exacerbations. May be used as an alternative bronchodilator for patients who do not tolerate SABA (Evidence D).抗胆碱能药物：抑制毒蕈碱胆碱能受体，降低气道固有迷走神经张力。异丙托溴铵在中度至重度哮喘急性发作中为SABA提供了额外的益处。可作为不耐受SABA的患者的替代支气管扩张剂（证据D）。 SABAs: Albuterol, levalbuterol, and pirbuterol are bronchodilators that relax smooth muscle that have become constricted as a result of environmental stimuli. Therapy of choice for relief of acute symptoms and prevention of EIB. SABAs will provide rapid relief of symptoms, although do not target underlying inflammation associated with asthma. SABAs：沙丁胺醇、左旋沙丁胺醇和吡布特罗是支气管扩张剂，可以放松因环境刺激而收缩的平滑肌。缓解急性症状和预防EIB的首选疗法。SABA可以快速缓解症状，但不针对与哮喘相关的潜在炎症。 Systemic corticosteroids: Although not short acting, oral systemic corticosteroids are used for moderate and severe exacerbations as adjunct to SABAs to speed recovery and prevent recurrence of exacerbations.全身性皮质类固醇：虽然不是短效的，但口服全身性皮质类固醇用于中度和重度急性发作，作为SABA的辅助治疗，以加速恢复并防止急性发作的复发。 Asthma Care Quick Reference哮喘护理快速参考 Other treatments其它治疗 Allergen Immunotherapy过敏原免疫疗法 Allergen injection immunotherapy is effective in allergic asthma as well as in allergic rhinoconjunctivitis and has been shown to lead to highly significant improvements in symptoms, reduction in rescue medication, and improvements in both allergen specific and non-specific bronchial hyperresponsiveness. Immunotherapy is particularly effective in seasonal asthma, although less effective in perennial asthma. Bronchial asthma is a risk-factor for systemic reactions to immunotherapy and should not be considered in poorly controlled asthmatics. Allergy management is superimposed upon other treatment modalities for long-term control at all levels of asthma. Concurrent upper airway disease, eg, allergic rhinitis, sinusitis, should be treated, and the total dose of inhaled corticosteroids must be monitored.过敏原注射免疫疗法对过敏性哮喘和过敏性鼻结膜炎有效，已被证明可以显著改善症状，减少救援药物，改善过敏原特异性和非特异性支气管高反应性。免疫疗法对季节性哮喘特别有效，但对常年性哮喘效果较差。支气管哮喘是免疫治疗全身反应的危险因素，对于控制不佳的哮喘患者不应考虑。过敏管理与其他治疗方式叠加在一起，以长期控制各级哮喘。应治疗并发的上呼吸道疾病，如过敏性鼻炎、鼻窦炎，并必须监测吸入糖皮质激素的总剂量。 Biological treatment: Omalizumab (monoclonal anti-IgE antibody) may be considered as adjunctive therapy in step 5 or 6 care for patients who have allergies and severe persistent asthma that is inadequately controlled with the combination of high-dose ICS and LABA. Omalizumab is effective in reducing asthma exacerbations and hospitalizations in patients with increased levels of total IgE. It is recommended for use in moderate to severe asthma patients as an adjunctive therapy to inhaled steroids and during steroid tapering, in patients with steroid-resistant asthma, and in patients who need to reduce or withdraw their inhaled steroids.生物治疗：Omalizumab（单克隆抗IgE抗体）可被视为第5步或第6步护理中的辅助疗法，用于治疗高剂量ICS和LABA联合控制不足的过敏和严重持续性哮喘患者。奥马利珠单抗能有效减少总IgE水平升高的患者的哮喘加重和住院。建议将其用于中度至重度哮喘患者，作为吸入类固醇的辅助治疗，在类固醇减量期间，用于类固醇抵抗性哮喘患者，以及需要减少或撤回吸入类固醇的患者。 Bronchial thermoplasty (BT) is a novel therapy for patients with severe asthma. Using radio frequency thermal energy, it aims to reduce the airway smooth muscle mass. Several clinical trials have demonstrated improvements in asthma-related quality of life and a reduction in the number of exacerbations following treatment with BT. In addition, recent data has demonstrated the long-term safety of the procedure as well as sustained improvements in rates of asthma exacerbations, reduction in health care utilization, and improved quality of life.支气管热成形术（BT）是一种治疗重症哮喘的新方法。使用射频热能，其目的是减少气道平滑肌质量。几项临床试验表明，使用BT治疗后，哮喘相关的生活质量得到改善，病情恶化的次数减少。此外，最近的数据表明，该手术的长期安全性以及哮喘恶化率的持续改善、医疗保健利用率的降低和生活质量的提高。 In the past 10 years, there have been substantial advances in the understanding of asthma genetics, airway biology, and immune cell signaling. These advances have led to the development of small molecule therapeutics and biologic agents that may improve asthma care in the future. Several new classes of asthma drugs—including ultra-long acting β agonists and modulators of the interleukin 4 (IL-4), IL-5, IL-13, and IL-17 pathways—have been evaluated in randomized controlled trials. Other new drug classes—including dissociated corticosteroids, CXC chemokine receptor 2 antagonists, toll-like receptor 9 agonists, and tyrosine kinase inhibitors—remain in earlier phases of development.在过去的10年里，对哮喘遗传学、气道生物学和免疫细胞信号传导的理解取得了实质性进展。这些进展导致了小分子疗法和生物制剂的发展，这可能会改善未来的哮喘护理。在随机对照试验中，对几种新型哮喘药物进行了评估，包括超长效β激动剂和白细胞介素4（IL-4）、IL-5、IL-13和IL-17途径的调节剂。其他新药类别，包括游离皮质类固醇、CXC趋化因子受体2拮抗剂、toll样受体9激动剂和酪氨酸激酶抑制剂，仍处于早期开发阶段。 Other co-morbid conditions treatment其他合并症治疗 In all patients, symptomatic therapies are also given, to be used on an as needed basis. The goal in all of these patients is to tailor the medicines and their doses to control the level of the disease, always trying for optimal control with the lowest effective dose of medications. At least half of US adults with asthma have at least 1 other chronic condition. Having asthma and other chronic conditions are associated with poorer asthma outcomes. Several studies considered the relationship between asthma and other specific chronic conditions; results of these studies indicated that having depression or anxiety and/or panic disorder is associated with an increased risk of developing a new asthma diagnosis and with poorer asthma outcomes. In addition, results of these studies indicated that having asthma is associated with an increased risk of developing a new depression or anxiety and/or panic disorder diagnosis.对于所有患者，也会根据需要进行对症治疗。所有这些患者的目标都是定制药物及其剂量以控制疾病水平，始终试图用最低有效剂量的药物进行最佳控制。至少有一半患有哮喘的美国成年人至少还有一种其他慢性疾病。患有哮喘和其他慢性疾病与较差的哮喘预后有关。几项研究考虑了哮喘和其他特定慢性疾病之间的关系；这些研究的结果表明，患有抑郁症、焦虑症和/或恐慌症与新的哮喘诊断风险增加和哮喘预后较差有关。此外，这些研究的结果表明，患有哮喘与患新的抑郁症或焦虑症和/或惊恐障碍诊断的风险增加有关。 Current NIH guidelines recommend that all patient who have had an asthma-related hospitalization should be evaluated by asthma specialist. In doing so, patients may likely improve quality of life and decrease asthma-related morbidity and mortality.美国国立卫生研究院目前的指南建议，所有因哮喘住院的患者都应由哮喘专家进行评估。这样做，患者可能会提高生活质量，降低哮喘相关的发病率和死亡率。 Bibliography参考文献 National Heart, Lung, and Blood Institute National Asthma Education and Prevention Program Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma, Full report 2007 国家心肺血液研究所国家哮喘教育和预防计划专家小组报告3：哮喘诊断和管理指南，2007年完整报告 Asthma endotypes: a new approach to classification of disease entities within the asthma syndrome.哮喘内型：哮喘综合征疾病实体分类的新方法 Lötvall J1, Akdis CA, Bacharier LB, Bjermer L, Casale TB, Custovic A, Lemanske RF Jr, Wardlaw AJ, Wenzel SE, Greenberger PA. J Allergy Clin Immunol. 2011 Feb;127(2):355-60. doi: 10.1016/j.jaci.2010.11.037 Asthma in the elderly: what we know and what we have yet to know.老年哮喘：我们所知道的和我们还不知道的 Anahí Yáñez, Sang-Hoen Cho, Joan B Soriano, Lanny J Rosenwasser, Gustavo J Rodrigo, Klaus F Rabe, Stephen Peters, Akio Niimi, Dennis K Ledford, Rohit Katial, Leonardo M Fabbri, Juan C Celedón, Giorgio Walter Canonica, Paula Busse, Louis-Phillippe Boulet, Carlos E Baena-Cagnani, Qutayba Hamid, Claus Bachert, Ruby Pawankar, Stephen T Holgate. World Allergy Organ J. 2014; 7(1): 8. Published online 2014 May 30. doi: 10.1186/1939-4551-7-8 Perinatal and Early Childhood Environmental Factors Influencing Allergic Asthma Immunopathogenesis.影响过敏性哮喘免疫发病机制的围产期和幼儿期环境因素 Jonathan M. Gaffin, Watcharoot Kanchongkittiphon, Wanda Phipatanakul. Int Immunopharmacol. 2014 September; 22(1): 21–30. Published online 2014 June 19. doi: 10.1016/j.intimp.2014.06.005 PMCID: PMC4119505 Global strategy for asthma management and prevention: GINA executive summary.全球哮喘管理和预防战略：GINA执行摘要 Bateman ED, Hurd SS, Barnes PJ, Bousquet J, Drazen JM, FitzGerald M et al. Eur Respir J 31(1):143-78. 2008 DOI:10.1183/09031936.00138707 PMID: 18166595 The Genetics of Asthma and Allergic Disease: A 21st Century Perspective哮喘和过敏性疾病的遗传学：21世纪的视角 Carole Ober, Tsung-Chieh Yao. Immunol Rev. Author manuscript; available in PMC 2012 July 1. Published in final edited form as: Immunol Rev. 2011 July; 242(1): 1030.doi: 10.1111/j.1600-065X.2011.01029.x PMCID: PMC3151648 International Consensus On (ICON) Pediatric Asthma儿童哮喘国际共识 N. G. Papadopoulos, H. Arakawa, K.-H. Carlsen, A. Custovic, J. Gern, R. Lemanske, P. Le Souef, M. Makela, G. Roberts, G. Wong, H. Zar, C. A. Akdis, L. B. Bacharier, E. Baraldi, H. P. van Bever, J. de Blic, A. Boner, W. Burks, T. B. Casale, J. A. Castro-Rodriguez, Y. Z. Chen, Y. M. El-Gamal, M. L. Everard, T. Frischer, M. Geller, J. Gereda, D. Y. Goh, T. W. Guilbert, G. Hedlin, P. W. Heymann, S. J. Hong, E. M. Hossny, J. L. Huang, D. J. Jackson, J. C. de Jongste, O. Kalayci, N. Khaled, S. Kling, P. Kuna, S. Lau, D. K. Ledford, S. I. Lee, A. H. Liu, R. F. Lockey, K. Lodrup-Carlsen, J. Lotvall, A. Morikawa, A. Nieto, H. Paramesh, R. Pawankar, P. Pohunek, J. Pongracic, D. Price, C. Robertson, N. Rosario, L. J. Rossenwasser, P. D. Sly, R. Stein, S. Stick, S. Szefler, L. M. Taussig, E. Valovirta, P. Vichyanond, D. Wallace, E. Weinberg, G. Wennergren, J. Wildhaber, R. S. Zeiger. Allergy. Author manuscript; available in PMC 2015 May 26.Published in final edited form as: Allergy. 2012 August; 67(8): 976–997. Published online 2012 June 15. doi: 10.1111/j.1398-9995.2012.02865.x PMCID: PMC4442800 Additional references:其他参考文献： Buttaro, T.M., Polgar-Bailey, P., Sandberg-Cook, J. & Trybulski, J. (2017). Primary care: A collaborative practice (5th ed.) St. Louis, MO: Elsevier. https://www.nhlbi.nih.gov/files/docs/guidelines/asthma_qrg.pdf https://www.frontiersin.org/articles/10.3389/fimmu.2019.00821/full https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4818235/