The Road to Precision Medicine in COPD Is Paved With Phenotypes

  • Each phenotype of emphysema has been linked to distinct features, such as greater smoking history in the centrilobular phenotype and less physiologic impairment in the paraseptal phenotype.
  • Studies have demonstrated the importance of phenotyping by anatomic distribution, including a randomized trial showing that lung volume-reduction surgery conferred a survival advantage in patients with upper-lobe emphysema, but not in those with non-upper-lobe emphysema.5

Chronic Bronchitis

  • Chronic cough and sputum production are the defining features of this phenotype.1
  • Airway inflammation is characterized by increased neutrophil, macrophage, and cytotoxic CD8 lymphocyte counts.1
  • As progressive incoordination of breathing with swallowing may occur, it “is not surprising that newer culture-independent techniques used to characterize the lower airway microbiota demonstrate the presence of upper airway commensals such as Streptococcus, Prevotella, and Veillonella species,” the review authors stated.1
  • This phenotype has been associated with more severe dyspnea and airway obstruction, increased airway wall thickening, and more frequent exacerbations, as well as comorbid cardiovascular disease and sleep apnea.1
  • The effectiveness of the phosphodiesterase 4 inhibitor roflumilast appears be greater in patients with this phenotype.6,7

Asthma-COPD Overlap

  • This phenotype has been defined as persistent airflow limitation with several features of both asthma and COPD, although this definition is controversial.1
  • There is “increasing awareness of the involvement of the small airways and non-[T-helper cell type 2] type of inflammation in asthma, as well as involvement of the large airways and eosinophils in patients with COPD,” wrote Segal et al, although these patterns have typically been associated with COPD and asthma, respectively.1
  • Asthma-COPD overlap is associated with co-occurring gene expression alterations and greater disease burden compared with other patients with COPD.
  • The therapeutic implications of this phenotype will “likely involve better understanding of the endotype, and this is an area of active investigation for the use of biologics (eg, anti-[immunoglobulin E] and anti-[interleukin 5]).”1,8
  • According to current guidelines, treatment should be based on the most dominant phenotype.1

Although these emerging results offer valuable clues, the pathophysiological distinctions between different phenotypes of COPD are still poorly understood. “Distinction of different treatable traits should lead to a more personalized approach and, hopefully, a much better treatment response,” said Dr Segal.

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There is a need for pathophysiological and translational studies focusing on the early disease stages of COPD. Dr Segal added, “This is important because once the disease is more advanced, it is difficult to dissect pathophysiological mechanisms in the presence of multiple confounders that these patients have, such as recurrent exacerbations, use of steroids, and comorbidities.”


1. Segal LN, Martinez FJ. Chronic obstructive pulmonary disease subpopulations and phenotyping. J Allergy Clin Immunol. 2018;141(6):1961-1971.

2. McDonough JE, Yuan R, Suzuki M, et al. Small-airway obstruction and emphysema in chronic obstructive pulmonary disease. N Engl J Med. 2011;365(17):1567-1575.

3. ATS/ERS. American Thoracic Society/European Respiratory Society statement: standards for the diagnosis and management of individuals with alpha-1 antitrypsin deficiency. Am J Respir Crit Care Med. 2003;168(7):818-900.

4. Chapman KR, Burdon JG, Piitulainen E, et al. Intravenous augmentation treatment and lung density in severe alpha1 antitrypsin deficiency (RAPID): a randomised, double-blind, placebo-controlled trial. Lancet. 2015;386(9991):360-368.

5. Fishman A, Martinez F, Naunheim K, et al; National Emphysema Treatment Trial Research Group. A randomized trial comparing lung-volume-reduction surgery with medical therapy for severe emphysema. N Engl J Med. 2003;348(21):2059-2073.

6. Rennard SI, Calverley PM, Goehring UM, Bredenbroker D, Martinez FJ. Reduction of exacerbations by the PDE4 inhibitor roflumilast—the importance of defining different subsets of patients with COPD. Respir Res. 2011;12(1):18.

7. Calverley PM, Rabe KF, Goehring UM, et al. Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials. Lancet. 2009;374(9691):685-694.

8. Christenson SA, Steiling K, van den Berge M, et al. Asthma-COPD overlap. Clinical relevance of genomic signatures of type 2 inflammation in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2015;191:758-766.