Precision medicine remains the holy grail in pulmonology. Nowhere is that more evident than in chronic obstructive pulmonary disease (COPD), in which clinicians are still determining the appropriate treatment options, disease severity, and therapeutic response.1
The Case for Biomarkers in COPD
The rationale for using biomarkers in COPD is that these objective measures could guide clinicians in making more appropriate decisions in therapy.1 The reality, however, is that many of the measures in COPD such as bronchoalveolar lavage, sputum samples, and exhaled breath condensate are not reliably reproducible.1 Blood draws, however, provide that feature and much more.1 Biomarkers may be time sensitive: early-phase COPD biomarkers may be completely different from those seen at later stages of the disease.1 Additionally, researchers may be heavily reliant on a single biomarker to identify multiple factors that influence disease severity and activity.1
The difficulty in using biomarkers to guide treatment decisions is that many biomarker trials have used healthy control groups to test their hypotheses, rendering the biomarkers irrelevant.1 A more meaningful use of biomarkers may be in first gathering information about the patient’s phenotype (such as emphysema and frequent exacerbations) and endotype (disease mechanisms) to interpret the data.1 For now, biomarkers represent investigational data that one day may lead to breakthroughs in treatment and prognostication.1
Pulmonologist Robert A. Stockley, MD, from the Lung Investigation Unit, Medicine-University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital Birmingham, in the United Kingdom, said of the paper’s findings, “I hope this provides some home truths on data interpretation.” He described the current state of clinical trials in attempting to identify appropriate biomarkers for COPD: “This is a feature of data fishing and having assays not designed to answer a question but in the hope that something turns up as it invariably will if you study it enough.”
Promising, Yet Still Investigational
Determining endotypes with biomarkers and giving greater credence to phenotypes will propel more individualized COPD treatment.2 Singh and colleagues cited several examples of patients who would likely benefit from more targeted therapeutic approaches.2 For example, clinicians know that patients who have COPD exacerbations that are bacterial infections vs eosinophilic inflammations will benefit from preventive measures such as treatment with macrolides in combination with bronchodilators.2
Likewise, biomarkers could guide treatment from the time of COPD diagnosis.2 There is no evidence for initiating therapy with a combination long-acting beta2-agonist and long-acting muscarinic antagonist and there are insufficient data for augmenting a regimen with triple therapy when exacerbations occur.2
Singh and colleagues noted the attributes of investigational biomarkers, all of which have yet to be validated at the individual level for clinical use2:
- Fibrinogen, used as a marker of cardiovascular risk, has also been studied as a predictor of exacerbations and mortality.2
- Club cell protein 16 (CC16), an immunosuppressant, can signal lung function decline.
- Soluble receptor for advanced glycation end products (sRAGE) may be linked with emphysema severity and disease progression.
- Blood eosinophils in some studies have predicted higher exacerbation rates and response to inhaled corticosteroids.
- Blood leukocytes and serum interleukin-6, as well as C-reactive protein (CRP), have predicted all-cause mortality and exacerbations in studies.
“A more individualized approach to each patient is needed, based on clinical features and hopefully (in the future) greater use of biomarkers. Current treatment is often prescribed toward symptoms,” said pulmonologist Dave Singh, MD, from the Centre for Respiratory Medicine and Allergy, at the University of Manchester and University Hospital of South Manchester, in Manchester, United Kingdom. “More consideration of the best way to prevent exacerbations is needed. The use of inhaled corticosteroids needs to be more personalized and rational.”
Although the current state of biomarkers is investigational, blood eosinophils hold some promise for predicting response to treatment. “This biomarker helps predict which patients will have the greatest likelihood of experiencing a treatment benefit with inhaled corticosteroids,” Dr Singh said.
Biomarkers: Better Together Than Individually
Because COPD is such a heterogeneous disease, biomarkers could further define endotypes and aid in prognosis. This, in turn, would help researchers develop more targeted therapy for this complex disease. Zemans and colleagues hypothesized that combinations of biomarkers, rather than individual ones, could be more precise in predicting outcomes.3
Their study combined 2 large cohorts of patients with COPD, COPDGene (n=1465) and ECLIPSE (n=2746).3 The biomarkers included fibrinogen, CRP, surfactant protein D (SP-D), sRAGE, and CC16.3 When researchers used combinations of biomarkers, the correlations with COPD outcomes were 2 to 10 times more powerful than were correlations with individual biomarkers.3
For predicting decline in forced expiratory volume in 1 second, the biomarkers CC16, fibrinogen, and sRAGE in combination were most useful in the COPDGene cohort, whereas the addition of CRP and SP-D in the ECLIPSE cohort improved the prognostication.3 To gauge the severity of emphysema, CRP, SP-D, fibrinogen, and sRAGE in combination had the greatest correlation in both cohorts; CC16 added to the model in the ECLIPSE cohort.3 The combination of CRP, fibrinogen, and SP-D best predicted mortality in the ECLIPSE cohort, but all 5 biomarkers were necessary to predict mortality in the COPDGene cohort.3
Summary and Clinical Applicability
The objectivity of biomarkers in COPD to predict medication response, disease severity, and prognosis shows promise. Future trials, however, need to examine biomarkers’ response in patients with COPD subtypes to make them relevant.
Limitations and Disclosures
1. Stockley RA, Halpin DMG, Celli BR, Singh D. COPD biomarkers and their interpretation [published online December 28, 2018]. Am J Respir Crit Care Med. doi: 10.1164/rccm.201810-1860SO
2. Singh D, Roche N, Halpin D, Agusti A, Wedzicha JA, Martinez FJ. Current controversies in the pharmacological treatment of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2016;194(5):541-549.
3. Zemans RL, Jacobson S, Keene J, et al. Multiple biomarkers predict disease severity, progression and mortality in COPD. Respir Res. 2017;18(1):117.