Peak Inspiratory Flow as a Predictive Therapeutic Biomarker in COPD
将吸气峰值流量作为慢性阻塞性肺病的预测性治疗生物标志物

Donald A. Mahler, MD, FCCP; and David M. G. Halpin, MD

Biomarkers in COPD may be clinical (prior exacerbation history), physiologic (

{FEV}_{1}

), or blood based (eosinophil count or fibrinogen level). Recent interest in using biomarkers to predict response to therapy in clinical practice has emerged. The benefits of inhaled therapy depend on the correct use of the inhaler, including an appropriate inspiratory flow. Of the available delivery systems, dry powder inhalers are unique because they have an internal resistance, are breath actuated, and are flow dependent. Ideally, the user inhales “forcefully” to generate turbulent energy (determined by an individual’s inspiratory flow and the resistance of the device) within the device that disaggregates the powder so that the individual inhales the medication particles into the lower respiratory tract. Because of specific features of dry powder inhalers and the required optimal inspiratory flow, an unmet need exists to identify individuals who are likely or unlikely to benefit from dry powder medications. Peak inspiratory flow, defined as the maximum airflow generated during inhalation against the simulated resistance of a dry powder inhaler, is a physiologic measure that has biological plausibility, has good test characteristics (repeatability and reliability), and is generalizable. Current evidence supports peak inspiratory flow as a predictive therapeutic biomarker to optimize therapy in both outpatients with COPD as well as those hospitalized for an exacerbation before discharge. This approach is consistent with the precepts of precision medicine, which considers differences in a person’s biological features, exposure, and lifestyle to prevent and treat disease.
慢性阻塞性肺病的生物标志物可以是临床的（既往病情加重史）、生理的（

{FEV}_{1}

）或血液的（嗜酸性粒细胞计数或纤维蛋白原水平）。最近，人们开始关注在临床实践中使用生物标志物来预测对治疗的反应。吸入疗法的益处取决于正确使用吸入器，包括适当的吸气流量。在现有的给药系统中，干粉吸入器是独一无二的，因为它具有内阻、呼吸驱动和流量依赖性。理想情况下，使用者 "用力 "吸气，在吸入器内产生湍流能量（由个人的吸气流量和吸入器的阻力决定），使粉末分解，从而将药物颗粒吸入下呼吸道。由于干粉吸入器的特殊性和所需的最佳吸气流量，目前还存在一种尚未满足的需求，即识别哪些人可能或不可能从干粉药物中获益。吸气流量峰值是指吸气时产生的最大气流与干粉吸入器的模拟阻力之间的比值，它是一种生理测量方法，具有生物学合理性、良好的测试特性（重复性和可靠性）以及可推广性。目前的证据支持将吸气峰值流量作为一种预测性治疗生物标志物，用于优化慢性阻塞性肺病门诊患者和出院前因病情加重住院患者的治疗。这种方法符合精准医疗的理念，即考虑个人的生物特征、暴露和生活方式的差异来预防和治疗疾病。

CHEST 2021; 160(2):491-498
胸部 2021；160（2）：491-498
KEY WORDS: biomarkers; bronchodilators; clinical decision-making; flow meters; pharmacotherapy
关键词：生物标志物；支气管扩张剂；临床决策；流量计；药物疗法

The National Institutes of Health defines biomarkers as characteristics that are objectively measured and evaluated as indicators of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention.

^{1}

Biomarkers may be clinical (eg, prior exacerbation history), physiological (eg,

{FEV}_{1}

), or blood based (eg, eosinophil count or fibrinogen level).

^{2}

Recently, considerable interest has emerged in using biomarkers as
美国国立卫生研究院将生物标志物定义为客观测量和评估的特征，作为正常生物过程、致病过程或对治疗干预的药理反应的指标。

^{1}

生物标志物可以是临床的（如既往病情加重史）、生理的（如

{FEV}_{1}

）或血液的（如嗜酸性粒细胞计数或纤维蛋白原水平）。

^{2}

近来，人们对使用生物标志物作为以下方面产生了浓厚的兴趣
predictors of response to therapy in clinical practice.

^{2, 3}

For example, the blood eosinophil count has emerged as a predictor of response to inhaled corticosteroids

^{4, 5}

and is included in treatment recommendations.

^{6}

在临床实践中，嗜酸性粒细胞计数是治疗反应的预测指标。

^{2, 3}

例如，血液嗜酸性粒细胞计数已成为吸入性皮质类固醇治疗反应的预测指标

^{4, 5}

，并被纳入治疗建议中。

^{6}

Pharmacologic management of COPD relies heavily on inhaled therapy.

^{7}

Adherence to therapy and ability to use inhalers correctly are crucial to achieving clinical benefit.

^{8, 9}

Delivery systems include
慢性阻塞性肺病的药物治疗主要依靠吸入疗法。

^{7}

坚持治疗和正确使用吸入器是获得临床疗效的关键。

^{8, 9}

给药系统包括

ABBREVIATIONS: DPI

=

dry powder inhaler; FIFmax

=

maximal forced inspiratory flow; IC = inspiratory capacity; PIF = peak inspiratory flow; PIFr = peak inspiratory flow against simulated resistance; pMDI

=

pressurized metered-dose inhaler; SMI = soft mist inhaler AfFiliations: From the Department of Medicine (D. A. Mahler, emeritus), Geisel School of Medicine at Dartmouth, Hanover, the Department of Respiratory Services (D. A. Mahler), Valley Regional Hospital, Claremont, NH; and the Department of Respiratory
缩略语：DPI

=

干粉吸入器；FIFmax

=

最大强制吸气流量；IC = 吸气容量；PIF = 吸气峰值流量；PIFr = 吸气峰值流量对模拟阻力；pMDI

=

加压计量吸入器；SMI = 软雾吸入器：来自汉诺威达特茅斯大学 Geisel 医学院医学系（名誉教授 D. A. Mahler）、新罕布什尔州克莱蒙特市 Valley 地区医院呼吸服务部（名誉教授 D. A. Mahler）和呼吸科。

Medicine (D. M. G. Halpin), University of Exeter Medical School, College of Medicine and Health, University of Exeter, Exeter, England. CORRESPONDENCE TO: Donald A. Mahler, MD, FCCP; email: mahlerdonald@gmail.com
英国埃克塞特，埃克塞特大学医学与健康学院，埃克塞特大学医学院（D. M. G. Halpin）。通信地址：英国埃克塞特，埃克塞特大学医学与健康学院，埃克塞特大学医学院：Donald A. Mahler, MD, FCCP; email：mahlerdonald@gmail.com
Copyright © 2021 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.
版权所有 © 2021 年美国胸科医师学会。由 Elsevier Inc.保留所有权利。
DOI: https://doi.org/10.1016/j.chest.2021.03.049
pressurized metered-dose inhalers (pMDIs), soft mist inhalers (SMIs), dry powder inhalers (DPIs), and nebulizers. Of these, DPIs are unique because they have an internal resistance, are breath actuated, and depend on inspiratory flow. Moreover, DPIs are prescribed widely in the treatment of patients with COPD. For example, in an observational study involving seven hospitals in the United States, Sharma and colleagues

^{10}

reported that

62 %

67 %

of patients were treated with a DPI before admission for an exacerbation of COPD.
加压计量吸入器（pMDIs）、软雾吸入器（SMIs）、干粉吸入器（DPIs）和雾化器。在这些吸入器中，干粉吸入器是独一无二的，因为它们具有内阻、呼吸驱动并依赖于吸气流量。此外，DPIs 被广泛用于慢性阻塞性肺病患者的治疗。例如，在一项涉及美国七家医院的观察性研究中，Sharma 及其同事

^{10}

报告称，

62 %

至

67 %

的患者在因慢性阻塞性肺病恶化入院前接受了 DPI 治疗。

Inhaler technique errors are common among patients with COPD with all three handheld devices.

^{11 - 13}

For example, Cho-Reyes and colleagues

^{12}

reported that

75 %

of adults in the United States with obstructive lung disease used pMDIs incorrectly. Errors with both pMDIs and DPIs have been associated with an increased risk of hospitalization, ED visits, and an increased requirement for courses of oral steroids and antibiotics.

^{13, 14}

Assessing a patient’s ability to use an inhaler correctly is key to obtaining the clinical benefit of therapy.

^{7}

慢性阻塞性肺病患者在使用所有三种手持设备时都会出现吸入器技术错误。

^{11 - 13}

例如，Cho-Reyes 及其同事

^{12}

报告称，

75 %

美国患有阻塞性肺病的成人使用 pMDIs 的方法不正确。使用 pMDIs 和 DPIs 的错误与住院风险增加、急诊室就诊以及口服类固醇和抗生素疗程需求增加有关。

^{13, 14}

评估患者正确使用吸入器的能力是获得临床治疗效果的关键。

^{7}

Specific unmet clinical need exists for a simple, reproducible, and reliable biomarker to identify individuals who are likely or unlikely to benefit from DPI-delivered therapy because of specific inhalation requirements. We believe that peak inspiratory flow (PIF), defined as the maximum airflow generated during inhalation in liters per minute against the simulated resistance of a DPI (PIFr), meets the criteria as a therapeutic biomarker. PIFr can be used to predict whether the individual patient is likely or, perhaps more importantly, is unlikely to achieve optimal drug delivery and clinical benefit when using a DPI.

^{15, 16}

If the PIFr value demonstrates that the patient has the inspiratory ability to use a DPI optimally, then the clinician needs to instruct and train the patient how to use the device correctly and undertake a holistic assessment of her or his capability to do so.

^{17}

临床上需要一种简单、可重复、可靠的生物标志物来确定哪些人可能或不可能从 DPI 给药疗法中获益，因为他们有特定的吸入要求，而这种生物标志物尚未得到满足。我们认为，吸气流量峰值（PIF）符合治疗生物标志物的标准，它的定义是吸气过程中产生的最大气流（单位：升/分钟）与 DPI 的模拟阻力（PIFr）的比值。PIFr 可用于预测患者在使用 DPI 时是否可能获得最佳的药物输送和临床疗效，或者更重要的是，是否不可能获得最佳的药物输送和临床疗效。

^{15, 16}

如果 PIFr 值表明患者具有以最佳方式使用 DPI 的吸气能力，那么临床医生就需要指导和培训患者如何正确使用设备，并对其能力进行全面评估。

^{17}

Several criteria have been proposed for consideration of a biomarker

^{18}

: (1) biological plausibility, that is, a strong, consistent, and independent relationship should exist between the biomarker and the clinical outcomes; (2) test performance, that is, the test should be reliable and repeatable, with high sensitivity and specificity for the outcome, and it should be generalizable to all patients; and (3) lack of confounder, that is, the biomarker association with treatment outcomes should be free of confounding influences unrelated to the disease itself. The following information examines whether PIF meets these criteria and should be
生物标志物

^{18}

的考虑标准有以下几条：(1) 生物合理性，即生物标志物与临床结果之间应存在牢固、一致和独立的关系；(2) 测试性能，即测试应可靠、可重复，对结果具有较高的灵敏度和特异性，并可推广到所有患者；(3) 缺乏混杂因素，即生物标志物与治疗结果的关联应不受与疾病本身无关的混杂因素影响。以下信息探讨了 PIF 是否符合这些标准，是否应
considered a predictive therapeutic biomarker in COPD. For clarity, the name of the DPI is specified if it were used for testing. Otherwise, we classify DPIs based on their internal resistances as low, medium low, medium, medium high, and high (Table 1).

^{19}

被认为是慢性阻塞性肺病的预测性治疗生物标记物。为清楚起见，如果用于测试，则注明 DPI 的名称。否则，我们将根据 DPI 的内阻将其分为低、中低、中、中高和高（表 1）。

^{19}

Biological Plausibility 生物合理性

PIF became relevant with the introduction of DPIs as a delivery system for inhaled medications used in the treatment of those with asthma and COPD. The first available DPI was the sodium cromoglycate Spinhaler in 1967, followed by salbutamol in the Rotahaler (Cipla Ltd) and Diskhaler (Glaxo Group Limited) 1 year later.

^{20}

To our knowledge, PIF was measured first in patients in 2001. Chodosh and colleagues

^{21}

used a pneumotach to measure PIF against the HandiHaler (Boehringer Ingelheim Pharma

GmbH & Co

) in 26 outpatients with COPD. Broeders and colleagues

^{22}

used a pressure transducer to measure PIF through the Diskus (Glaxo Group Limited) and the Turbuhaler (AstraZeneca AB) devices in 68 patients with airflow obstruction ( 10 had asthma and 58 had COPD). In each of these studies, the purpose of measuring PIF was to assess delivery of the dry powder medication into the lower respiratory tract.
随着用于治疗哮喘和慢性阻塞性肺病的吸入式药物给药系统 DPI 的问世，PIF 变得越来越重要。最早的 DPI 是 1967 年推出的色甘酸钠 Spinhaler，1 年后，沙丁胺醇被用于 Rotahaler（Cipla 有限公司）和 Diskhaler（葛兰素集团有限公司）。

^{20}

据我们所知，2001 年首次在患者中测量了 PIF。Chodosh及其同事

^{21}

在26名慢性阻塞性肺病门诊患者中使用气压计测量了HandiHaler（勃林格殷格翰制药公司

GmbH & Co

）的PIF。Broeders 及其同事

^{22}

使用压力传感器测量了 68 名气流阻塞患者（10 名哮喘患者和 58 名慢性阻塞性肺病患者）通过 Diskus（葛兰素集团有限公司）和 Turbuhaler（阿斯利康公司）设备的 PIF。在每项研究中，测量 PIF 的目的都是为了评估干粉药物进入下呼吸道的情况。

The powder medication within the DPI is formulated as an agglomerate or with the drug particles attached to a carrier, usually lactose. Each DPI, whether single-dose capsule or multidose, requires the user to create turbulent energy within the device to disaggregate the powder and break it into small particles.

^{23}

Turbulent energy is a function of the individual’s inspiratory flow and the resistance of the device, which varies according to the DPI.

^{24}

Each DPI has a minimum threshold energy below which disaggregation of the powder is insufficient and a reduced dose is emitted. As a result, the patient receives little or no clinical benefit. In vitro studies using lung models show that both drug delivery and fine particle dose, that is,

< 5 μ m

in diameter, are enhanced at increasing inspiratory flows.

^{25 - 29}

干粉吸入器中的粉末药物被配制成团块状或药物颗粒附着在载体（通常是乳糖）上。每种干粉吸入器，无论是单剂量胶囊还是多剂量，都需要使用者在设备内产生湍流能，以分解粉末并将其破碎成小颗粒。

^{23}

湍流能是个人吸气流量和设备阻力的函数，而设备阻力因 DPI 而异。

^{24}

每种干粉吸入器都有一个最低能量阈值，低于该阈值，粉末分解不充分，发射的剂量就会减少。因此，患者几乎得不到任何临床益处。使用肺部模型进行的体外研究表明，当吸气流量增加时，药物输送和细颗粒剂量（即直径

< 5 μ m

）都会增加。

^{25 - 29}

An optimal inspiratory flow can be determined when a plateau occurs in the emitted dose and fine particle dose, despite higher flows.

^{24}

An individual’s PIFr has been used to estimate whether an individual patient can achieve optimal drug delivery and clinical benefit.

^{15, 16}

Both minimal and optimal PIFr values have been proposed based on in vitro data. In general, for low- to medium-high-resistance DPIs, a minimal PIFr of

30 L / \min

and an optimal PIFr of

\geq 60 L / \min

have been proposed.

^{15, 24, 30}

For a high-resistance DPI, a minimal PIFr of

20 L / \min

and
最佳吸气流量可在发射剂量和微粒剂量出现高原时确定，尽管流量较高。

^{24}

个人的 PIFr 已被用于估计病人是否能获得最佳给药效果和临床益处。

^{15, 16}

根据体外数据提出了最小和最佳 PIFr 值。一般来说，对于低至中高抗药性的 DPI，已提出的最小 PIFr 值为

30 L / \min

，最佳 PIFr 值为

\geq 60 L / \min

。

^{15, 24, 30}

对于高抗药性 DPI，最小 PIFr 为

20 L / \min

，最佳 PIFr 为

\geq 60 L / \min

。

TABLE 1 ] Groupings of Dry Powder Inhalers Based on Internal Resistance

^{a}

表 1 ]基于内部电阻的干粉吸入器分组

^{a}

Resistance 阻力	Dry Powder Inhaler 干粉吸入器
Low 低	Breezhaler
Medium-low 中低	Accuhaler, Diskhaler, Diskus, and Ellipta Accuhaler、Diskhaler、Diskus 和 Ellipta
Medium 中型	Clickhaler, Genuair/Pressair, Spiromax/RespiClick/Digihaler, and Turbuhaler (Symbicort) Clickhaler、Genuair/Pressair、Spiromax/RespiClick/Digihaler 和 Turbuhaler (Symbicort)
Medium-high 中-高	Easyhaler (combination), NEXThaler, Turbuhaler (Pulmicort), and Twisthaler 简易吸入器（复方）、NEXThaler、Turbuhaler（Pulmicort）和 Twisthaler
High 高	Easyhaler (monotherapy) and HandiHaler 简易吸入器（单药治疗）和手持吸入器

^{a}

Dry powder inhalers are listed in alphabetical order within each of the five resistance groupings established by Clerke Clement International Limited.

^{19}

^{a}

干粉吸入器在克莱克克莱门特国际有限公司确定的五个阻力分组中按字母顺序排列。

^{19}

an optimal PIFr of

\geq 30 L / \min

have been proposed.

^{21, 30}

Although the optimal value of PIFr varies from device to device, the link between PIFr and optimal benefit remains, and the plausibility as a biomarker is maintained.

\geq 30 L / \min

的最佳 PIFr。

^{21, 30}

虽然 PIFr 的最佳值因设备而异，但 PIFr 与最佳效益之间的联系依然存在，而且作为生物标志物的合理性也得以保持。

Test Performance 测试性能

Assessment of PIF PIF 评估

PIF can be measured with spirometry or with an inspiratory flowmeter. Standard instructions are available for patients to perform this measurement.

^{19, 31}

Spirometry is measured with pulmonary function testing equipment that has minimal resistance to flow. Maximal forced inspiratory flow (FIFmax) is the term typically used to represent PIF on spirometry.
PIF 可通过肺活量计或吸气流量计进行测量。为患者提供了进行这种测量的标准说明。

^{19, 31}

肺活量测量是使用阻力最小的肺功能测试设备进行测量。最大用力吸气流量（FIFmax）通常用来表示肺活量。
Seven investigators examined whether FIFmax is an appropriate surrogate for PIFr (Table 2).

^{32 - 38}

Although
七位研究者研究了 FIFmax 是否是 PIFr 的合适替代指标（表 2）。

^{32 - 38}

虽然
correlations between FIFmax and PIFr generally are statistically significant, the range of

R^{2}

values (0.003-0.45) indicates that only a low to modest proportion of variance in PIFr can be explained by FIFmax (Table 2). For example, Malmberg and colleagues

^{34}

observed in a multivariate model that FIFmax, age, and sex accounted for only 18% of the variation in PIFr with the Easyhaler (Orion Corporation), a high-resistance DPI. These investigators concluded that the coefficient of determination “was too low to be useful for clinical purposes” and recommended that PIFr be measured directly. Similarly, both Price and colleagues

^{35}

and Ghosh and coworkers

^{36}

concluded that FIFmax was not adequate to serve as a surrogate for PIFr.
虽然 FIFmax 和 PIFr 之间的相关性通常具有统计学意义，但

R^{2}

值的范围（0.003-0.45）表明，FIFmax 只能解释 PIFr 变异的很小一部分（表 2）。例如，Malmberg 及其同事

^{34}

在一个多变量模型中观察到，FIFmax、年龄和性别仅占高阻力 DPI Easyhaler（Orion 公司）PIFr 变异的 18%。这些研究者得出结论认为，该测定系数 "太低，对临床用途没有帮助"，并建议直接测量 PIFr。同样，Price 及其同事

^{35}

和 Ghosh 及其同事

^{36}

也认为 FIFmax 不足以作为 PIFr 的替代物。

In a study of 303 outpatients with COPD, Duarte and colleagues

^{37}

used receiver operating characteristic curve analysis to demonstrate that a FIFmax threshold value of
在一项针对 303 名慢性阻塞性肺病门诊患者的研究中，Duarte 及其同事

^{37}

使用接收器操作特征曲线分析证明，FIFmax 临界值为

TABLE 2 ] Relationship Between FIFmax on Spirometry and PIFr on Flow Meter in Patients With COPD
表 2 ]慢性阻塞性肺病患者肺活量 FIFmax 与流量计 PIFr 之间的关系

Author, Year 作者，年份	No. of Patients 患者人数	$R^{2}$ Value for FIFmax and PIFr $R^{2}$ FIFmax 和 PIFr 的值	DPI Resistance $^{a}$ DPI 阻力 $^{a}$
Janssens and colleagues, 2008 $^{32}$ Janssens 及其同事，2008 年 $^{32}$ .	40	0.25	None 无
	. . .	0.45	Low 低
	. .	0.42	Medium-low 中低
	. . .	0.39	Medium-high 中-高
Malmberg and colleagues, 2010 $^{34}$ Malmberg 及其同事，2010年 $^{34}$	93	0.29	High 高
Seheult and colleagues, 2014 $^{33}$ Seheult 及其同事，2014 年 $^{33}$	27	${0.58}^{b}$	Medium-low 中低
Price and colleagues, $2018^{35}$ 普莱斯及其同事， $2018^{35}$	47	0.11	Low 低
	. . .	0.17	Medium-low 中低
	. . .	0.37	Medium-high 中-高
Duarte and colleagues, 2019 $^{37}$ 杜阿尔特及其同事，2019 $^{37}$	303	$\begin{aligned} 0.42 \\ {0.16}^{\circ} \end{aligned}$	Medium-low 中低
Ghosh and colleagues, $2019^{36}$ Ghosh 及其同事， $2019^{36}$ 。	66	0.003	Medium-low 中低
Ghosh and colleagues, $2019^{36}$ Ghosh 及其同事， $2019^{36}$ 。	. . .	0.01	High 高
Harb and colleagues, $2020^{38}$ Harb 及其同事， $2020^{38}$	180	0.04	Low to high 从低到高

The articles listed were identified by a comprehensive literature review performed by the authors. DPI = dry powder inhaler; FIFmax = maximal forced inspiratory flow; PIFr = peak inspiratory flow against simulated resistance.
所列文章由作者通过全面的文献综述确定。DPI = 干粉吸入器；FIFmax = 最大强制吸气流量；PIFr = 针对模拟阻力的吸气峰值流量。

^{a}

Inhaler resistance categories from Clement Clarke International Ltd.

^{19}

^{a}

克莱门特-克拉克国际有限公司的吸入器阻力分类。

^{19}

^{b} R^{2}

includes age in stepwise regression;

R^{2}

was not provided for FIFmax vs PIFr.

^{b} R^{2}

包括逐步回归中的年龄；

R^{2}

未提供 FIFmax 与 PIFr 的比较。

^{c}

Receiver operating characteristic curve for FIFmax threshold value of

215 L / \min

to identify patients with a PIFr of

> 60 L / \min

^{c}

用于识别 PIFr 为

> 60 L / \min

的患者的 FIFmax 阈值

215 L / \min

的接收者操作特征曲线。
tABLE 3 ] Test-Retest Reliability for PIFr Measured With the In-Check DIAL in Patients With COPD
表 3 ]慢性阻塞性肺病患者使用检查中 DIAL 测量 PIFr 的测试-重测信度

Author, Year 作者，年份	No. of Patients 患者人数	Resistance $^{a}$ 阻力 $^{a}$	PIFr, L/min PIFr, 升/分钟		$P$ Value $P$ 值
Author, Year 作者，年份	No. of Patients 患者人数	Resistance $^{a}$ 阻力 $^{a}$	Test 1 测试 1	Test 2 测试 2	$P$ Value $P$ 值
Celga, 2004 $^{40}$	60	Medium 中型	$78 \pm 19$	$79 \pm 20$	. 46
Celga, 2004 $^{40}$	. .	Medium-high 中-高	$55 \pm 17$	$56 \pm 19$	. 82
Mahler and colleagues, $2013^{41}$ 马勒及其同事， $2013^{41}$ 。	45	Medium-low 中低	$73 \pm 18$	$75 \pm 18$	. 59
Ghosh and colleagues, $2019^{36}$ Ghosh 及其同事， $2019^{36}$ 。	6	Medium-low 中低	65	64	. 69
Ghosh and colleagues, $2019^{36}$ Ghosh 及其同事， $2019^{36}$ 。	14	High 高	38	38	. 46

Data are presented as mean

\pm

SD or mean, unless otherwise indicated. The articles listed were identified by a comprehensive literature review performed by the authors. PIFr = peak inspiratory flow against simulated resistance.

^{a}

Inhaler resistance categories from Clement Clarke International Ltd.

^{19}

除非另有说明，否则数据均以

\pm

SD 或平均值表示。所列文章由作者通过全面的文献综述确定。PIFr = 峰值吸气流量与模拟阻力的关系。

^{a}

吸入器阻力类别来自克莱门特-克拉克国际有限公司。

^{19}

215 L / \min

identified patients with a PIF of

> 60 L / \min

against a medium-low resistance using the In-Check DIAL inhaler

(R^{2} = 0.16)

. These investigators suggested that "[c]linicians lacking easy access to an In-Check DIAL may use FIFmax measurement obtained from spirometry to determine a given patient’s ability to adequately use a DPI."37

215 L / \min

确定了使用 In-Check DIAL 吸入器

(R^{2} = 0.16)

的中低阻力患者的 PIF 为

> 60 L / \min

。这些研究人员建议："不方便使用 In-Check DIAL 的医生可以使用肺活量测量法获得的 FIFmax 测量值来确定特定患者是否有能力充分使用 DPI "37。

PIFr can be measured directly against fixed resistances using commercially available inspiratory flowmeters.
PIFr 可使用市售的吸气流量计直接对固定电阻进行测量。
The In-Check DIAL has been used most widely in part because it has an adjustable dial that enables the user to simulate the internal resistances of DPIs.

^{19}

It is portable, has a one-way disposable mouthpiece, and measures inspiratory flows from 15 to

120 L / \min

. The manufacturer states that its accuracy is

\pm 10 %

10 L /

min , whichever is greater.

^{19}

In-Check DIAL 使用最广泛的部分原因是它有一个可调节的刻度盘，使用户能够模拟 DPI 的内部电阻。

^{19}

它便于携带，配有单向一次性吹嘴，可测量 15 到

120 L / \min

的吸气流量。制造商称其精确度为

\pm 10 %

或

10 L /

分钟，以较高者为准。

^{19}

Repeatability of Measurement
测量的重复性

For spirometry, the American Thoracic Society/ European Respiratory Society recommend that patients obtain at least 3 measurements with acceptability and repeatability criteria based on

{FEV}_{1}

and

F V C^{31}

If these criteria are not met, then up to eight total measurements can be attempted. However, the document does not comment on repeatability of FIFmax.

^{31}

Of the seven studies that evaluated FIFmax (Table 2), in five, investigators had patients perform three maneuvers and then selected the highest FIFmax value; in one study, American Thoracic Society/European Respiratory Society guidelines were followed; and in one study, the number of FIFmax measurements was not provided.
对于肺活量测量，美国胸科学会/欧洲呼吸学会建议患者根据

{FEV}_{1}

和

F V C^{31}

的可接受性和可重复性标准至少进行 3 次测量。但是，文件没有对 FIFmax 的可重复性进行评论。

^{31}

在对 FIFmax 进行评估的七项研究中（表 2），有五项研究的研究者让患者进行了三次操作，然后选择最高的 FIFmax 值；有一项研究遵循了美国胸科学会/欧洲呼吸学会指南；还有一项研究未提供 FIFmax 测量次数。

With the In-Check DIAL, the typical approach has been to measure PIFr three times and select the highest value. Barnes and colleagues

^{39}

examined repeatability of PIFr against medium-low- and high-resistance DPIs in 206 patients with COPD. The repeatability limit was

10 L /

对于 In-Check DIAL，典型的方法是测量三次 PIFr，然后选择最高值。Barnes 及其同事

^{39}

研究了 206 名慢性阻塞性肺病患者在使用中低阻力和高阻力 DPI 时 PIFr 的可重复性。重复性极限为

10 L /

。
min for a medium-low-resistance DPI and

5 L / \min

for a high-resistance DPI.

^{39}

The authors concluded that using the two highest values for PIFr from the three inspiratory efforts met the repeatability limit.

^{39}

分钟，

5 L / \min

为高阻力 DPI。

^{39}

作者得出结论，使用三次吸气努力中 PIFr 的两个最高值符合可重复性限制。

^{39}

Reliability of Measurement
测量的可靠性

To our knowledge, no information is available about the reliability of FIFmax to assess use of a DPI in patients with COPD. For PIFr, three studies show good testretest reliability in patients with stable COPD (Table 3). For example, Cegla

^{40}

found no significant difference in PIFr values measured with a pressure transducer through placebo Novolizer and Turbuhaler devices before and 6 weeks after instruction on correct inhalation technique. Using the In-Check DIAL, both Ghosh and colleagues

^{36}

and Mahler and colleagues

^{41}

reported no significant differences in PIFr when measured at intervals of 14 to 28 days (range) and

317 \pm 225

days (mean

\pm SD

), respectively, in patients with COPD.
据我们所知，目前还没有关于 FIFmax 用于评估慢性阻塞性肺病患者使用干粉吸入器的可靠性的信息。就 PIFr 而言，有三项研究显示，在慢性阻塞性肺病稳定期患者中，测试可靠性良好（表 3）。例如，Cegla

^{40}

发现，在指导正确吸入技术之前和之后 6 周，通过安慰剂 Novolizer 和 Turbuhaler 设备使用压力传感器测量的 PIFr 值没有显著差异。Ghosh及其同事

^{36}

和Mahler及其同事

^{41}

使用In-Check DIAL分别报告了慢性阻塞性肺病患者在14至28天（范围）和

317 \pm 225

天（平均

\pm SD

）间隔内测量的PIFr无显著差异。

Lack of Confounding 缺乏混淆

Confounding for biomarkers describes the extent to which apparent relationships between the biomarker and the outcome of interest are the result of any additional factors that influence the biomarker and the outcome. For PIFr, no such confounders exist. PIFr is not confounded by

{FEV}_{1}

and generally does not correlate with

{FEV}_{1}

because PIFr and

{FEV}_{1}

are measured during different phases of respiration. Advanced age, female sex, and reduced inspiratory capacity (IC) are the most consistent patient characteristics associated with a lower

PIFr .^{42}

The effects of both older age and female sex are expected because these variables predict lower lung function. Height also affects predicted lung function, and short stature has been shown to correlate with a lower PIFr.

^{37, 41}

Reduced IC is a marker of lung hyperinflation that adversely affects respiratory muscle strength because of shortening
生物标志物的混杂因素是指生物标志物与相关结果之间的明显关系在多大程度上是由影响生物标志物和结果的其他因素造成的。对于 PIFr 而言，不存在此类混杂因素。由于 PIFr 和

{FEV}_{1}

是在呼吸的不同阶段测量的，因此 PIFr 不会受到

{FEV}_{1}

的干扰，一般也不会与

{FEV}_{1}

Clinical Validation 临床验证

Prevalence of Suboptimal PIFr
次优 PIFr 的流行率

Wide variance exists in the reported prevalence of suboptimal PIFr values in patients with COPD. For stable outpatients, the reported prevalence of suboptimal

PIFr (< 60 L / \min

) for low- to medium-high-resistance DPIs was

19 %

84 % .^{42}

The prevalence of suboptimal

PIFr (< 30 L / \min

) measured directly through the HandiHaler (Boehringer Ingelheim Pharma GmbH & Co) was

57 %

in 163 outpatients with COPD.

^{43}

据报道，慢性阻塞性肺病患者中 PIFr 值不达标的发生率存在很大差异。在 163 名慢性阻塞性肺病门诊患者中，直接通过 HandiHaler（Boehringer Ingelheim Pharma GmbH & Co）测量的

PIFr (< 60 L / \min

) 次优值的发生率为

19 %

至

84 % .^{42}

PIFr (< 30 L / \min

) 次优值的发生率为

57 %

。

^{43}

For patients hospitalized for an exacerbation and tested when clinically stable before discharge, the prevalence of suboptimal PIFr (

< 60 L / \min

) is

32 %^{10}

68 %^{38}

for a medium-low-resistance DPI and

40 %^{44}

100 %^{38}

for a medium-resistance DPI. For a high-resistance DPI, the reported prevalence of suboptimal PIFr is

21 %^{38}

The wide ranges in prevalence are likely the result of differences in baseline patient characteristics, methods of testing, and the specific internal resistance of the DPI.
对于因病情加重住院并在出院前临床稳定时接受检测的患者，中低耐药性 DPI 的 PIFr 不达标（

< 60 L / \min

）发生率为

32 %^{10}

至

68 %^{38}

，中耐药性 DPI 的 PIFr 不达标（

40 %^{44}

至

100 %^{38}

）发生率为

21 %^{38}

。对于高抗 DPI，所报告的次优 PIFr 患病率为

21 %^{38}

。患病率的巨大差异可能是由于患者的基线特征、检测方法和 DPI 的特定内部抗性不同造成的。

Broeders and colleagues

^{44}

reported PIF values in 15 hospitalized patients during the course of an exacerbation. As measured with a pressure transducer through the Turbuhaler (AstraZeneca AB ), the mean

\pm

SE PIFr was

59 \pm 5 L / \min

at day

1, 67 \pm 5 L / \min

at day 5 , and

72 \pm 5 L / \min

at 6 weeks after discharge. The gradual increases in PIFr are likely the result of improved inspiratory muscle function associated with deflation of the lung with treatment of the exacerbation.
Broeders 及其同事

^{44}

报告了 15 名住院患者在病情加重期间的 PIF 值。通过 Turbuhaler（阿斯利康公司）的压力传感器测量，平均

\pm

SE PIFr 在第

59 \pm 5 L / \min

天为

1, 67 \pm 5 L / \min

，第 5 天为

1, 67 \pm 5 L / \min

，出院后 6 周为

72 \pm 5 L / \min

。PIFr 的逐渐增加可能是由于治疗病情加重时肺部放气导致吸气肌肉功能改善的结果。

Relationship With Outcomes
与成果的关系

The most direct approach to assess PIFr as a biomarker predictive of outcomes is to compare the same molecule(s) in different delivery systems in patient with COPD based on PIF status. To our knowledge, no studies have been published using this design. At present, an open-label, crossover trial is being conducted that compares bronchodilation with formoterol and budesonide in a pMDI using a valved holding chamber vs the Turbuhaler (AstraZeneca AB) DPI in patients with severe to very severe COPD who have a PIF of

< 50 L / \min

using a simulated medium resistance (ClinicalTrials.gov Identifier: NCT04078126). Alternative approaches have examined the relationship between inspiratory flow and drug deposition, lung function, and hospital readmission rates.
评估 PIFr 作为预测预后的生物标志物的最直接方法是根据 PIF 状态对慢性阻塞性肺病患者不同给药系统中的相同分子进行比较。据我们所知，尚未有采用这种设计的研究发表。目前，一项开放标签、交叉试验正在进行中，该试验比较了福莫特罗和布地奈德在pMDI中的支气管扩张作用，pMDI使用了带阀的保持腔，而Turbuhaler（阿斯利康公司）DPI则使用了模拟中等阻力（ClinicalTrials.gov标识符：NCT04078126），适用于PIF为

< 50 L / \min

的重度至极重度慢性阻塞性肺病患者。其他方法研究了吸气流量与药物沉积、肺功能和再住院率之间的关系。

Drug Deposition at Different PIFrs: In 10 healthy participants, Borgstrom and colleagues

^{45}

showed that deposition of radiolabeled budesonide with the Turbuhaler (AstraZeneca AB) device was increased from

15 %

28 %

when inspiratory flow was increased from

36 L / \min

58 L / \min

.
不同 PIFrs 下的药物沉积：Borgstrom 及其同事

^{45}

对 10 名健康参与者的研究表明，当吸气流量从

36 L / \min

增加到

58 L / \min

时，使用 Turbuhaler（阿斯利康公司）装置的放射性标记布地奈德的沉积从

15 %

增加到

28 %

。

Effects of Nebulization vs DPI on Lung Function in Patients With Suboptimal PIFr: In a randomized, single-blind, crossover trial, the efficacy of two longacting

β

-agonists-arformoterol solution (

15 μ g / 2 mL

) via nebulization vs salmeterol dry powder

(50 μ g)

via the Diskus (Glaxo Group Limited) device-were compared.

^{46}

Twenty patients with COPD who showed suboptimal (

< 60 L / \min

) PIFr against a medium-lowresistance DPI on two separate occasions (to ensure consistency) were enrolled. The primary outcome was the change in lung function at peak bronchodilation

(2 h)

for each medication. At baseline,

{FEV}_{1}

after bronchodilator use was

0.83 \pm 0.31 L (38 \pm

12 %

predicted) and PIFr was

53 \pm 5 L / \min

. At peak effect, changes in FVC (

268 \pm 218 mL [+ 14 %]

vs 164

\pm 245 mL [+ 8 %]; P = .02)

and IC

[(195 \pm 154 mL

[+13%] vs

112 \pm 126 mL [+ 8 %]; P = .05)

were higher with nebulization than with dry powder delivery.

^{46}

Although the change in

{FEV}_{1}

2 h (84 \pm

72 mL [+ 11 %]

52 \pm 105 mL [+ 7 %]; P = .17

) was numerically higher with nebulization, the difference was not significant.

^{46}

The improvements in FVC and IC demonstrate greater volume responses with nebulization than with a DPI in this population.
雾化与干粉吸入对肺功能不达标患者的影响：在一项随机、单盲、交叉试验中，比较了两种长效

β

激动剂--通过雾化吸入的阿福莫特罗溶液（

15 μ g / 2 mL

）与通过 Diskus（葛兰素集团有限公司）设备吸入的沙美特罗干粉

(50 μ g)

的疗效。

^{46}

20名慢性阻塞性肺病患者分别在两个不同的场合（以确保一致性）对中低阻力DPI表现出次优(

< 60 L / \min

) PIFr。主要结果是每种药物在支气管扩张峰值

(2 h)

时的肺功能变化。基线时，使用支气管扩张剂后

{FEV}_{1}

为

0.83 \pm 0.31 L (38 \pm

12 %

预测值），PIFr为

53 \pm 5 L / \min

。在峰值效应时，雾化吸入比干粉给药的 FVC 变化（

268 \pm 218 mL [+ 14 %]

vs 164

\pm 245 mL [+ 8 %]; P = .02)

和 IC

[(195 \pm 154 mL

[+13%] vs

112 \pm 126 mL [+ 8 %]; P = .05)

更高。

^{46}

虽然

{FEV}_{1}

在

2 h (84 \pm

72 mL [+ 11 %]

52 \pm 105 mL [+ 7 %]; P = .17

时的变化在数值上高于雾化给药，但差异并不显著。

^{46}

FVC和IC的改善表明，在这一人群中，雾化治疗比DPI治疗的容量反应更大。

In a randomized, double-blind, double-dummy, 28days phase 3b study, 206 patients were recruited based on an inclusion criterion of a suboptimal PIFr (

< 60

L / \min

) against a medium-low-resistance DPI.

^{47}

Changes in lung function were compared between once daily long-acting muscarinic antagonists: revefenacin for nebulization vs dry powder tiotropium in the HandiHaler (Boehringer Ingelheim Pharma GmbH &

Co)

. At the initial visit,

{FEV}_{1}

was

37 \pm 16 %

predicted and PIFr was

45 \pm 12 L / \min

. In the intention-to-treat population, no significant difference was found in trough

{FEV}_{1}

, the primary outcome, between nebulized and dry powder long-acting muscarinic antagonists.

^{47}

In a prespecified analysis of patients with

{FEV}_{1} <

50 %

predicted (

n = 70

in each group), improvements were greater in trough

{FEV}_{1}

(mean difference,

+ 49.1 mL [95 % CI, 6.3 - 91.9 mL]

) and in trough FVC ( +103.5 mL [95% CI, 7.7-199.3 mL]) with a nebulized long-acting muscarinic antagonist compared with a DPI.

^{47}

在一项为期 28 天的随机、双盲、双哑药 3b 期研究中，根据针对中低阻力 DPI 的次优 PIFr（

< 60

L / \min

）纳入标准招募了 206 名患者。

^{47}

比较了每日一次的长效毒蕈碱类拮抗剂：雾化吸入用瑞芬那新与HandiHaler（勃林格殷格翰制药有限公司和

Co)

）干粉噻托溴铵的肺功能变化。初诊时，

{FEV}_{1}

为

37 \pm 16 %

预测值，PIFr为

45 \pm 12 L / \min

。在意向治疗人群中，雾化吸入和干粉长效毒蕈碱拮抗剂的谷值

{FEV}_{1}

（主要结果）无显著差异。

^{47}

在一项针对

{FEV}_{1} <

50 %

预测值（每组均为

n = 70

）患者的预设分析中，与干粉长效毒蕈碱拮抗剂相比，雾化长效毒蕈碱拮抗剂的谷值

{FEV}_{1}

（平均差，

+ 49.1 mL [95 % CI, 6.3 - 91.9 mL]

）和谷值FVC（+103.5 mL [95% CI, 7.7-199.3 mL]）改善幅度更大。

^{47}

Readmission Rates After Hospitalization for an
住院后的再入院率

Exacerbation and PIFr: Three studies examined the impact of suboptimal PIFr on readmissions in patients hospitalized for an exacerbation.

^{10, 48, 49}

In a retrospective analysis of 123 patients, Loh and colleagues

^{48}

found that those with a suboptimal PIF against no resistance showed a higher rate of 90-day COPD readmission (

28.1 %

13.6 %; P = .048

) and fewer number of days before all-cause readmission (65.5 days vs 101.0 days;

P = .009

) compared with those who showed an optimal PIF. Seventy-five percent of patients with suboptimal PIFr were receiving at least one maintenance therapy delivered via a DPI.

^{48}

In contrast, in a prospective study of 170 patients involving seven hospitals, Sharma and colleagues

^{10}

reported similar all-cause readmissions up to 180 days between cohorts with optimal and suboptimal PIFr measured against a medium-low resistance. In a prospective study of 75 patients admitted for an exacerbation of COPD, Samarghandi and colleagues

^{49}

observed no statistically significant differences in 30-day and 90-day all-cause readmission rates comparing those with optimal and suboptimal PIFr values against those with a medium-low resistance. Although the number of patients in each group was small, patients with a suboptimal PIFr

(n = 42

) showed a trend toward higher 30-day (

26.1 %

15.1 %

) and 90 -day (

40.4 %

33.3 %

) allcause readmission rates compared with those with optimal

PIFr (n = 33) .^{49}

病情加重与 PIFr：有三项研究探讨了PIFr不达标对因病情加重而住院的患者再入院的影响。

^{10, 48, 49}

Loh及其同事

^{48}

在对123名患者进行的回顾性分析中发现，与PIF达标的患者相比，PIF未达标而无抗药性的患者90天COPD再入院率更高（

28.1 %

13.6 %; P = .048

），全因再入院前的天数更少（65.5天 vs 101.0天；

P = .009

）。在 PIFr 不达标的患者中，75% 的患者至少接受了一种通过 DPI 提供的维持治疗。

^{48}

相比之下，Sharma及其同事

^{10}

在一项涉及七家医院的170例患者的前瞻性研究中报告称，在以中低耐药性为标准测量的最佳和次佳PIFr组群之间，180天内的全因再住院率相似。Samarghandi 及其同事

^{49}

对 75 名因慢性阻塞性肺病加重而入院的患者进行了一项前瞻性研究，结果发现，PIFr 值为最佳和次佳的患者与阻力为中低的患者相比，30 天和 90 天的全因再入院率没有显著的统计学差异。虽然每组患者人数较少，但与最佳 PIFr 值

(n = 42

的患者相比，次优 PIFr 值

26.1 %

的患者的 30 天（

26.1 %

15.1 %

）和 90 天（

40.4 %

33.3 %

）全因再入院率呈上升趋势。

Discussion 讨论

Despite recommendations about matching the most appropriate delivery system with the unique features of the individual patient (ie, precision medicine), little guidance exists on how this should be achieved. The Global Initiative for Obstructive Lung Disease strategy states, "The choice of an inhaler device has to be individually tailored and will depend on access, cost, prescriber, and most importantly, patient’s ability and preference."7 Although the Global Initiative for Obstructive Lung Disease document does not advise on how delivery systems should be chosen, Navaie and colleagues

^{50}

performed a systematic review and metaanalysis of inhaler device feature preferences among patients with obstructive lung diseases. The recent American Thoracic Society guideline for pharmacologic management of COPD provides specific recommendations based on the efficacy of different classes of medications.

^{51}

However, no information is
尽管有人建议根据患者的具体特点选择最合适的给药系统（即精准医疗），但关于如何实现这一目标的指导却少之又少。阻塞性肺病全球倡议》战略指出："吸入器装置的选择必须因人而异，并取决于可及性、成本、处方医生，最重要的是患者的能力和偏好。"7 尽管《阻塞性肺病全球倡议》文件并未就如何选择给药系统提出建议，但Navaie及其同事

^{50}

对阻塞性肺病患者对吸入器装置功能的偏好进行了系统回顾和荟萃分析。美国胸科学会最近发布的慢性阻塞性肺病药物治疗指南根据不同类别药物的疗效提出了具体建议。

^{51}

然而，没有资料显示
available about optimal delivery systems or the importance of ensuring patients can use inhaler devices correctly.

^{51}

有关最佳给药系统或确保患者能够正确使用吸入器装置的重要性的信息。

^{51}

In contrast to the recommended slow inhalation for using a pMDI and SMI or normal breathing with nebulized therapy,

^{16, 24}

inhalation from a DPI requires that patients generate sufficient turbulent energy within the device to disaggregate the powder and create fine particles. In the prescribing information, pharmaceutical companies provide similar, albeit different, instructions for how patients should inhale the dry powder medication from the specific DPI.

^{16}

The European Respiratory Society and the International Society for Aerosols in Medicine have a generic recommendation for using a DPI: “Patients should be instructed to inhale forcefully from the beginning of their inhalation.”

^{24}

与使用 pMDI 和 SMI 或正常呼吸进行雾化治疗时建议的缓慢吸入不同，

^{16, 24}

使用干粉吸入器吸入药物需要患者在设备内产生足够的湍流能量，以分解粉末并产生细小颗粒。在处方信息中，制药公司对患者如何从特定干粉吸入器吸入干粉药物提供了类似但不同的说明。

^{16}

欧洲呼吸学会和国际气溶胶医学学会对使用干粉吸入器提出了通用建议："应指导患者从吸入开始就用力吸入"。

^{24}

Because DPIs have unique features and inhalational requirements compared with the three other delivery systems, an unmet need exists to assess whether a patient can inhale “hard and fast” or “forcefully” enough to generate the required turbulent energy within the device to achieve clinical benefit.

^{24, 41}

By measuring PIFr, the health care professional can evaluate the ability of an individual to create turbulent energy and to achieve an optimal fine-particle dose. We recommend that PIFr be measured before prescribing inhaled therapy with a DPI and in patients currently using a DPI if the individual reports a poor or partial response to the dry powder medication.
与其他三种给药系统相比，干粉吸入器具有独特的功能和吸入要求，因此在评估患者是否能够 "快速用力 "或 "强力 "吸入，以便在设备内产生所需的湍流能量，从而获得临床疗效方面存在着尚未满足的需求。

^{24, 41}

通过测量 PIFr，医护人员可以评估个人产生湍流能量和达到最佳微粒剂量的能力。我们建议，在开具使用干粉吸入器进行吸入治疗的处方之前，以及在目前使用干粉吸入器的患者报告对干粉药物反应不佳或部分反应时，测量 PIFr。

As well as helping to identify patients who can and cannot use a DPI, inspiratory flow is emerging as a parameter that can be used to monitor effective use of inhalers. New digital technologies allow patients to receive feedback on inhaler use as well as providing clinicians with objective data on adherence and technique.

^{52}

It is now possible to measure a patient’s inspiratory flow during each use of an inhaler using sensors integrated into the device, allowing the identification and correction of problems with inhaler technique in real time.

^{53}

吸气流量不仅有助于确定哪些患者可以使用或不能使用 DPI，而且正在成为一种可用于监测吸入器有效使用情况的参数。新的数字技术可以让患者获得有关吸入器使用情况的反馈，并为临床医生提供有关坚持使用吸入器和吸入技术的客观数据。

^{52}

现在可以利用集成在设备中的传感器测量患者每次使用吸入器时的吸气流量，从而实时识别和纠正吸入器使用技巧方面的问题。

^{53}

Multiple dry powder medications in different devices (eg, the Diskus [Glaxo Group Limited], Ellipta [Glaxo Group Limited], HandiHaler [Boehringer Ingelheim Pharma GmbH & Co], InHub [Mylan Pharmaceuticals Inc], and Pressair [AstraZeneca AB]) are approved for the treatment of COPD and to reduce the risk during an exacerbation.

^{7}

However, if a patient is unable to inhale completely the medication from the DPI because of a suboptimal PIFr, then the therapy is unlikely to be
不同设备中的多种干粉药物（例如，Diskus [Glaxo Group Limited]、Ellipta [Glaxo Group Limited]、HandiHaler [Boehringer Ingelheim Pharma GmbH & Co]、InHub [Mylan Pharmaceuticals Inc]和 Pressair [AstraZeneca AB]）已被批准用于治疗慢性阻塞性肺病和降低病情加重时的风险。

^{7}

但是，如果患者由于 PIFr 不理想而无法完全吸入 DPI 中的药物，那么治疗就不可能达到预期效果。
effective. This is an important consideration because similar molecules exist in alternative delivery systems (pMDIs, SMIs, and nebulizers) that can be used to reduce the risk of an exacerbation if a suboptimal PIFr indicates that a DPI may be inappropriate.
有效。这是一个重要的考虑因素，因为在替代给药系统（pMDIs、SMIs 和雾化器）中也存在类似的分子，如果 PIFr 不理想表明 DPI 可能不合适，可以使用这些分子来降低病情恶化的风险。

Recovery from an exacerbation of COPD typically takes 4 to 6 weeks, although it may be even longer in some individuals. We recommend measuring PIFr at the time of discharge from the hospital to help guide selection of an inhaled delivery system. For example, if the patient has a suboptimal

PIFr (< 60 L / \min)

against a low- to medium-high-resistance DPI that the patient was using before hospitalization, then it is reasonable to prescribe an alternative delivery system (pMDI, SMI, or nebulizer) at discharge. Otherwise, the patient may not be able to inhale an optimal fine-particle dose of the medication into the lower respiratory tract. Whether this approach reduces hospital readmissions has not been studied prospectively. Certainly, PIFr should be reassessed when the patient has achieved clinical stability if consideration is made of restarting the DPI medication that the patient used previously.
慢性阻塞性肺疾病加重后的恢复期通常需要 4 到 6 周，但有些患者可能需要更长的时间。我们建议在出院时测量 PIFr，以帮助指导吸入给药系统的选择。否则，患者可能无法将最佳微粒剂量的药物吸入下呼吸道。这种方法是否能降低再入院率尚未进行前瞻性研究。当然，如果考虑重新开始使用患者之前使用的 DPI 药物，则应在患者达到临床稳定后重新评估 PIFr。

In summary, current evidence supports PIFr as a predictive therapeutic biomarker that can be helpful for optimizing therapy in a wide range of patients with COPD. PIFr has biological plausibility and good test characteristics and is generalizable. This approach is consistent with the precepts of precision medicine that consider a person’s biology, exposure, and lifestyle to prevent and treat disease.

^{54}

总之，目前的证据支持将 PIFr 作为一种预测性治疗生物标记物，有助于优化各种慢性阻塞性肺病患者的治疗。PIFr 具有生物学上的合理性和良好的测试特性，并且可以推广。这种方法符合精准医疗的理念，即考虑个人的生物学特性、暴露情况和生活方式来预防和治疗疾病。

^{54}

Acknowledgments 致谢

Financial/nonfinancial disclosures: The authors have reported to CHEST the following: D. A. M. serves on the advisory boards of AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Mylan, Teva, Theravance, and Verona; receives royalties from Salem Media Group (COPD: Answers to Your Questions (2015)) and pharmaceutical companies for the use of baseline dyspnea index/transition dyspnea index; and serves on the speaker’s bureau of AstraZeneca, Boehringer Ingelheim, and Teva. D. M. G. H. reports personal fees from AstraZeneca, personal fees and nonfinancial support from Boehringer Ingelheim, personal fees from Chiesi, personal fees from GlaxoSmithKline, personal fees and nonfinancial support from Novartis, personal fees from Pfizer, and personal fees from Sanofi.
财务/非财务披露：作者向《CHEST》报告了以下情况：D. A. M. 是阿斯利康、勃林格殷格翰、葛兰素史克、迈兰、梯瓦、Theravance 和 Verona 的顾问委员会成员；因使用基线呼吸困难指数/过渡呼吸困难指数而从 Salem Media Group（《慢性阻塞性肺病：问题解答》（2015 年））和制药公司获得版税；是阿斯利康、勃林格殷格翰和梯瓦的演讲人。D.M.G.H.报告了阿斯利康公司的个人酬金、勃林格殷格翰公司的个人酬金和非财务支持、Chiesi公司的个人酬金、葛兰素史克公司的个人酬金、诺华公司的个人酬金和非财务支持、辉瑞公司的个人酬金和赛诺菲公司的个人酬金。

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Peak Inspiratory Flow as a Predictive Therapeutic Biomarker in COPD 将吸气峰值流量作为慢性阻塞性肺病的预测性治疗生物标志物