Peak Inspiratory Flow Rate: An Emerging Biomarker in Chronic Obstructive Pulmonary Disease

To the Editor:

The research statement by Wu and colleagues (1) representing the American Thoracic Society and NHLBI identifies fibrinogen, a measure of inflammation, as the sole biomarker in chronic obstructive pulmonary disease (COPD). I propose that peak inspiratory flow rate (PIFR) measured against the simulated resistance (r) (PIFRr) of a specific dry-powder inhaler (DPI) be considered as an “emerging biomarker” in COPD. PIFR, the maximal airflow generated during inspiration, is a physiological measure that fits the definition of a biomarker (1). A suboptimal PIFRr value (<60 L/min) can identify individuals who are more likely to experience a less than favorable response to a dry-powder bronchodilator compared with those who exhibit an optimal PIFRr (≥60 L/min). The following information follows biomarker development steps (1).

Identify an Unmet Need

According to the 2019 Global Initiative for Chronic Obstructive Lung Disease (GOLD), pharmacotherapy for COPD should be individualized based on the severity of symptoms and risk of exacerbations (2). However, neither the GOLD strategy nor guidelines on COPD offer specific recommendations about which of the four delivery systems to use in which types of patients to achieve clinical efficacy. Patient factors for optimal drug delivery include the patient’s inspiratory flow rate, flow acceleration rate, time of inhalation, inhaled volume, and breath-hold time. For DPIs, higher inspiratory flows increase the fine particle fraction of the medication reaching the lungs. The unmet need is the ability to predict which patients are unlikely to respond optimally to a dry-powder medication (i.e., those with a suboptimal PIFRr).

DPIs are prescribed widely throughout the world to treat COPD. Each DPI has a unique internal resistance. The recommended use of dry-powder medications requires the patient to inhale “hard and fast” to create turbulent forces within the device to disaggregate the powder into fine particles (<5 μg in diameter) that are then inhaled into the lungs. PIFRr is determined by an individual’s effort and respiratory muscle strength.

Intended Use Population

PIFRr is intended as a biomarker in COPD. It may also be considered for use in other patients, such as those with asthma or cystic fibrosis, who use DPIs.

Biomarker Discovery

The importance of measuring PIFRr became clear with the introduction of the sodium cromoglycate Spinhaler in 1967 and the salmeterol Diskus inhaler in 1998. In 2001, Broeders and colleagues reported PIFRr values and inhalation profiles obtained with the Diskus and Turbuhaler (3).

Analytic Validation

The In-Check DIAL (Clement Clerke International Ltd.) has been used widely in studies to measure PIFRr (4–6, 8, 9). It is portable and provides an adjustable dial to simulate different DPI resistances. Although accuracy and reliability of PIFRr have been reported in patients with COPD (4), confirmation is required in larger patient populations.

Clinical Validation

The clinical phenotype of patients with a suboptimal PIFRr includes older age, female sex, and reduced inspiratory capacity, a marker of lung hyperinflation (4). A suboptimal PIFRr is common, being reported in 19–100% of stable outpatients (six studies) and 32–52% of inpatients (three studies) before discharge after admission to the hospital for an exacerbation (4–7). These wide ranges reflect measurements with different DPI resistances in different COPD populations. Two randomized controlled trials demonstrated that patients with severe to very severe COPD and a suboptimal PIFRr against the Diskus had greater improvements in lung function with a bronchodilator delivered by nebulization compared with a DPI (8, 9).

Additional Evidence Is Needed

To establish broad clinical application of the PIFRr, additional randomized controlled trials in both inpatients and outpatients are needed. For example, to reduce readmissions, many hospitals include measurement of the PIFRr before discharging a patient after a COPD exacerbation. A non-DPI delivery system is selected if the PIFRr is suboptimal. If the evidence shows greater bronchodilation and/or reduced readmissions with a non-DPI delivery system compared with a DPI in patients with a suboptimal PIFRr, then measurement of the PIFRr can be recommended in guidelines/strategies for COPD.