Identifying the molecular mechanisms leading to clinical phenotype, referred to as endotypes, can potentially assist in predicting which patient with chronic obstructive pulmonary disease (COPD) might benefit from specific treatments, according to a review published in Current Opinion in Pulmonary Medicine.1

COPD is a heterogeneous disease as reflected by its many phenotypes, defined as a combination of clinical disease characteristics that differentiates between patients. As phenotypes may not explain the underlying disease processes of COPD, they are not good predictors of response to treatment. Improved understanding of the pathophysiology of COPD may come from determining the endotypes, subtypes defined by distinct functional or pathophysiological mechanisms of the disease.2

Using information about the underlying biology to identify endotypes may assist in the efforts to develop new therapies for COPD and in treatment decisions related to new and existing therapies.

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The best known COPD endotype is alpha-1 antitrypsin deficiency secondary to a genetic abnormality in the alpha-1 antitrypsin, resulting in early onset emphysema. Another endotype of COPD that is related to genetic mechanism is a mutation of the telomerase gene TERT, resulting in early onset emphysema in smokers.3

The current review focused on emerging endotypes and those that may be used as therapeutic targets: eosinophilic inflammation, overproduction of interleukin-17, chronic bronchitis and altered nature of mucous, and chronic infection.

Eosinophilic Inflammation

While COPD is characterized by increased numbers of macrophages, neutrophils and lymphocytes in airways, lung parenchyma and pulmonary vessels, approximately a third of COPD patients have evidence of eosinophilic inflammation.4 There is a significant correlation between peripheral eosinophilia with airway eosinophilia.1

Several studies reported that blood eosinophil counts may predict response to treatment and prevention of exacerbations with inhaled corticosteroids, with better response to treatment at higher eosinophil counts and minimal effect in patients with eosinophil count < 100 cells/µL.5

The GALATHEA and TERRANOVA trials aimed at determining the efficacy and safety of benralizumab, an interleukin-5 receptor alpha–directed cytolytic monoclonal antibody, for patients with moderate to very severe COPD, eosinophilic inflammation (peripheral

eosinophil counts > 220/ml), and an increased risk of exacerbations.  The data suggest that adding benralizumab to maintenance treatment was not associated with reduced annual rates of COPD exacerbations, despite depletion of peripheral and sputum eosinophil counts.6

The results observed with benralizumab were similar to those of mepolizumab, an anti–interleukin-5 monoclonal antibody, in METREO (Mepolizumab vs. Placebo as Add-on Treatment for Frequently Exacerbating COPD Patients Characterized by Eosinophil Level) and METREX (Mepolizumab vs. Placebo as Add-on Treatment for Frequently Exacerbating COPD Patients) phase 3 trials, which evaluated the efficacy and safety of mepolizumab for patients with COPD and a history of exacerbations.7  The United States Federal Drug Administration did not approve mepolizumab for the treatment of COPD.1 

Overproduction of Interleukin-17

Interleukin (IL)-17 is a pro-inflammatory cytokine released by several immune cells, which is important in the defense against infections and may also play an important role in the pathogenesis of COPD.1,7 Recent studies have suggested that IL‐17 may play a role in viral and bacterial exacerbations, such as respiratory syncytial virus.7 The anti-IL-17A monoclonal antibody CNTO 6785 in patients with symptomatic moderate-to-severe COPD was not associated with improved lung function and resulted in an increased rate of COPD exacerbations, indicating that the role of this cytokine in COPD is quite complicated.8

Due to the important role of IL-17 in parenchymal lung destruction, anti-IL-17 agents may remain attractive. However, additional studies are needed, and these should also include an assessment of the risk for infections following IL-17 inhibition.

Chronic Infection

The microbiota plays a particularly important role in the development and functional integrity of the immune system and shifts or perturbations in the microbiota can lead to disease.  Many studies have investigated the relationships of dysbiosis of lung microbiome and COPD, indicating that the lung microbiome may impact COPD outcomes due to the potential effects of bacteria in the airways on inflammatory response and the direct airway damage through toxins.1 However, whether manipulating the bacterial community could treat or prevent COPD has not been well explored.9

Animal COPD models have shown an association between elevated cathelicidin LL-37 levels with better anti-inflammatory activity of budesonide, suggesting that high levels of cathelicidin are required for inhaled corticosteroids to be effective.9 Further studies are needed to better determine the association between cathelicidin levels, inhaled corticosteroids and outcomes in patients with COPD.

Chronic Bronchitis and Altered Nature of Mucous

Kesimar and colleagues reported that airway mucin concentrations have an important role in the chronic bronchitis pathophysiology, as higher mucin concentrations were associated with asthma and exposure to cigarette smoke.10 Interventions directed at changing the mucous ratio in patients with COPD to favor more mucin protein MUC5AC and less MUC5AB, may improve COPD outcomes.1

Previous studies have assessed the role of hypertonic saline, N-acetylcysteine, and inhaled liquid nitrogen, as potential interventions to improve mucous clearance in patients with COPD, but the data are limited and no clear evidence exist. Additional studies are required to identify interventions directed at mucous production, viscosity, and clearance.1


“Basic and clinical scientists continue to define endotypes that may be directly addressed with therapeutics. As of the time of this up-to-date review, there is yet to be an endotype-directed therapy to demonstrate great clinical effect,” wrote the researchers.


1. Burkes RM, Panos RJ, Borchers MT. How might endotyping guide chronic obstructive pulmonary disease treatment? Current understanding, knowledge gaps and future research needs. Curr Opin Pulm Med. 2021;27(2):120-124. doi:10.1097/MCP.0000000000000751

2. Garudadri S, Woodruff PG. Targeting chronic obstructive pulmonary disease phenotypes, endotypes, and biomarkers. Ann Am Thorac Soc. 2018;15(Suppl 4):S234-S238. doi:10.1513/AnnalsATS.201808-533MG

3. Stanley SE, Chen JJ, Podlevsky JD, et al. Telomerase mutations in smokers with severe emphysema. J Clin Invest. 2015;125(2):563-70. doi:10.1172/JCI78554

4. Tashkin DP, Wechsler ME. Role of eosinophils in airway inflammation of chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis. 2018;13:335-349. doi:10.2147/COPD.S152291

5. Bafadhel M, Peterson S, De Blas MA, et al. Predictors of exacerbation risk and response to budesonide in patients with chronic obstructive pulmonary disease: a post-hoc analysis of three randomised trials. Lancet Respir Med. 2018;6(2):117-126. doi:10.1016/S2213-2600(18)30006-7

6. Criner GJ, Celli BR, Brightling CE, et al. Benralizumab for the prevention of COPD exacerbations. N Engl J Med. 2019;381(11):1023-1034. doi:10.1056/NEJMoa1905248

7. Pavord ID, Chanez P, Criner GJ, et al. Mepolizumab for eosinophilic chronic obstructive pulmonary disease. N Engl J Med. 2017 Oct 26;377(17):1613-1629. doi: 10.1056/NEJMoa1708208.

8. Eich A, Urban V, Jutel M, et al. A Randomized, placebo-controlled phase 2 trial of CNTO 6785 in chronic obstructive pulmonary disease. COPD. 2017;14(5):476-483. doi:10.1080/15412555.2017.1335697

9. Wang L, Hao K, Yang T, Wang C. Role of the lung microbiome in the pathogenesis of chronic obstructive pulmonary disease. Chin Med J (Engl). 2017;130(17):2107-2111. doi:10.4103/0366-6999.211452

10. Kesimer M, Ford AA, Ceppe A, et al. Airway Mucin concentration as a marker of chronic bronchitis. N Engl J Med. 2017;377(10):911-922. doi:10.1056/NEJMoa1701632