Airway disorders network: Asthma and COPD section
Betting on asthma: The over and under of diagnosis
Asthma is one of the major chronic respiratory diseases worldwide (WHO 2020), yet it is a clinical syndrome that lacks a consensus on its definition, is comprised of nonspecific respiratory symptoms, and is without a gold standard diagnostic test or a set guideline on confirmation of bronchial hyperresponsiveness (Sá-Sousa A et al. Clin Transl Allergy. 2014 Aug 4;4:24). In addition, once adequately treated, there is an absence of an algorithm to diagnose disease remission (Aaron SD et al. Am J Respir Crit Care Med. 2018 Oct 15;198[8]:1012-20). It is estimated that 20%-70% of people with asthma worldwide across the spectrum of all ages remain undiagnosed.
Dr. Richa Nahar
Spirometry and bronchoprovocation challenges with fixed cut-off values demonstrate reduced sensitivity with day-to-day, diurnal, and long-term variation in airflow obstruction, inflammation, and bronchial hyperresponsiveness (Wang R et al. Thorax. 2021 Jun;76[6]:624-31). Inflammatory biomarkers like fractional exhaled nitric oxide (FeNO) have higher specificity but are subject to diurnal variation and confounding diagnoses.
Dr. Allen J. Blaivas
Overdiagnosis of asthma can result in lost opportunity to diagnose significant cardiopulmonary diseases, unnecessary escalation of the asthma treatment regimen for poorly controlled respiratory symptoms, potential for medication adverse effects, and, increased cost burden to the patient and to the health care system (Aaron SD et al. JAMA. 2017;317:269-79; Shaw D et al. Prim Care Respir J. 2012;21:283-7). Among the newly physician-diagnosed asthmatics, <50% have spirometry performed within 1 year of diagnosis (Sokol KC et al. Am J Med. 2015 May;128[5]:502-8). Spirometry was further underutilized with limit on aerosol-generating procedures during COVID-19 pandemic (Kankaanranta H et al. J Allergy Clin Immunol Pract. 2021 Dec;9[12]:4252-3); 30%-35% obese and nonobese patients with physician-diagnosed asthma did not have current asthma when objectively assessed for airflow limitation (Aaron SD et al. JAMA. 2017;317:269-79; van Huisstede A, et al. Respir Med. 2013;107:1356-64).
Clinical remission is greater in early-onset asthma as compared with late-onset asthma (De Marco R et al. J Allergy Clin Immunol. 2002;110:228-35). If asthma is well controlled, a stepping down treatment regimen is suggested (Global Initiative for Asthma 2021;Usmani et al. J Allergy Clin Immunol Pract. 2017 Sep-Oct;5[5]:1378-87.e5; Hagan JB et al. Allergy. 2014 Apr;69[4]:510-6), and although a randomized trial is lacking, it may be feasible to “undiagnose” patients who don’t experience clinical worsening, airflow obstruction, or bronchial hyperresponsiveness after being tapered off all asthma medications with a low relapse rate (Aaron SD et al. JAMA. 2017;317:269-79; J Fam Pract. 2018;67(11):704-7).
Asthma over- and underdiagnosis is prevalent and has clinical and global health consequences. New standardized algorithms with improved biomarkers may help alter this oversight.
Richa Nahar, MD
Network Member-at-Large
Allen J. Blaivas, DO, FCCP
Network Steering Committee Chair
Diffuse lung disease and lung transplant network: Interstitial lung disease section
Future therapies for IPF
Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease characterized by progressive fibrosis, respiratory failure, and a mortality rate of 80% at 5 years. Only two drugs are currently FDA-approved for IPF treatment.
Dr. Adrian Shifren
The antifibrotics pirfenidone and nintedanib reduce the rate of forced vital capacity (FVC) decline and improve progression free survival (King TE et al. N Engl J Med. 2014;370:2083-92; King TE et al. N Engl J Med. 2014;370:2071-82). While considered revolutionary when introduced, these medications neither reverse disease progression nor improve symptoms. More recently, the Galapagos ISABELA Phase III clinical trial of ziritaxestat in IPF was discontinued due to an unfavorable risk-benefit profile. Despite this, several prospects for IPF therapy exist.
Post hoc analysis of the INCREASE Trial demonstrated a positive effect of inhaled treprostinil on FVC in patients with IPF and group 3 pulmonary hypertension (Waxman A et al. N Engl J Med. 2021;384:325-34). Consequently, a phase 3 randomized trial investigating its safety and efficacy in patients with IPF alone is ongoing. Additional targeted therapies for IPF are also emerging. Recombinant human pentraxin-2, an inhibitor of monocyte differentiation into proinflammatory macrophages, and pamrevlumab, a recombinant human monoclonal antibody against connective tissue growth factor, both demonstrated attenuation of FVC decline compared with placebo in phase 2 trials. Both are currently in phase 3 studies (Raghu G et al. JAMA. 2018 Jun 12;319[22]:2299-307; Sgalla G et al. Expert Opin Investig Drugs. 2020 Aug;29[8]:771-7) Lastly, in February the Food and Drug Administration granted breakthrough therapy designation to BI 1015550 for treatment of IPF based on a 12-week phase 2 randomized, double-blind, placebo-controlled trial. (Data will be presented at ATS). BI 1015550 is an oral, phosphodiesterase 4B (PDE4B) inhibitor with both antifibrotic and anti-inflammatory properties. These advances in drug development provide hope for a future where IPF is transformed from a fatal disease to one manageable over many years.
Adrian Shifren, MD
Network Member-at-Large
Gabriel Schroeder, MD
Network Member-at-Large