By 2030 COPD projected third leading cause of death worldwide – how better biomarkers could alleviate this

The World Health Organization (WHO) predicts that by 2030 Chronic obstructive pulmonary disease (COPD) will become the third leading cause of death worldwide. The disease is already the fourth leading cause of death in the US today.

COPD is mainly caused by tobacco smoke and passive exposure. Epidemiological studies of nonsmokers suggest that other causes (especially for women and those in developing countries) also include indoor air pollution as a result of burning biomass fuels for cooking and heating purposes. Nevertheless, not everyone exposed to these situations develop the disease hinting at an important genetic component.

COPD Pathogenesis:

Recent studies have illustrated that there are three different mechanisms of airflow obstruction in COPD pathogenesis: (1)

  • loss of support of the small airways in emphysema, leading to their collapse and irreversible damage to the parenchyma
  • chronic inflammation or the bronchiolitis (chronic bronchitis), taking place in the small airway caused by overproduction of mucus by goblet cells
  • presence of mucus in the small airways, which further contributes to the airflow obstruction led by chronic bronchitis and causing small airway disease.

copd pathogenesisCOPD is characterized by chronic, low-grade systemic inflammation and is recognized as an inflammatory disease state which research has shown involves multiple inflammatory cells and mediators. In its physiopathology are implicated macrophages and neutrophils.They release proteolytic enzymes and oxidants, which cause tissue damage and also the appearance of cytokines, which can trigger an immune response and increase inflammation. (2)

COPD in Women:

Despite the high incidence and seriousness of COPD, studies strongly suggest that it is underdiagnosed, especially in women, because they have started to smoke later and their statistical data are poorer. Also, some findings may suggest a gender difference in susceptibility to the lung-damaging effects of cigarette smoking, but alternative explanations should be considered. (5)

COPD and gender

COPD and Asthma:

Unlike Asthma, COPD is not only an inflammatory disease.(3) although there are patients with an overlapping syndrome (~15–25%); these are usually asthmatics who are smokers which can make it difficult to differentiate between the diseases and leads to treatments being prescribed for both (4). Although COPD is often confused with Asthma (6)(b), the underlying pathology is different hence pointing towards a need for better differential diagnosis. For these reasons, therapeutic agents that are effective in asthma patients may not be optimal in COPD patients.

We can find some similarities and differences between COPD and Asthma:

Table 1: COPD and Asthma, some similarities and differences 0

Table 1: COPD and Asthma, some similarities and differences 1

Promising COPD biomarkers (systematic review)

■ Although based on a single study, FeNO on admission may predict a significant post-treatment increase in FEV1. An optimum cut-off point of 26.8 ppb had a sensitivity of 74% and a specificity of 75% [12].■ Among sputum biomarkers, the following ones appear more promising:

  • Spontaneous sputum NE, IL-8 and TNF-a may reflect clinical severity and symptomatic recovery [38,39,41].
  • Spontaneous sputum antimicrobial peptides (lysozyme, LL37 and SLPI) were associated to the acquisition of H. influenza and M. catarrhalis, and distinct trends of change were observed at ECOPD as compared to colonization [40].
  • Spontaneous sputum TNF-α, IL-8, NE and IL-1β as well as induced sputum IL-6, IL-8, TNFα, LTB4 and MPO directed towards an etiological diagnosis [38,48,57,59,64]. Among induced sputum biomarkers TNFα was the best predictor of a bacterial ECOPD [57], whereas sputum IL-1b performed better than CRP in determining bacteria-associated ECOPD [59].
  • The decrease of spontaneous sputum IL-8, MPO, LTB4 and albumin leakage was more substantial when bacterial eradication was achieved [49].

■ IL-6 was associated with a rhinovirus infection both in induced sputum [54,56] and in BAL [67].

■ Combinations of different pulmonary and/or systemic biomarkers may perform better than single biomarkers in identifying the causal etiology of ECOPD [39,59].

■ Current evidence on the clinical usefulness of exhaled breath condensate and BAL biomarkers in ECOPD is limited.

■ Several biomarkers sampled during stable COPD have the potential to identify patients at risk for frequent ECOPD, whereas patients with more severe COPD may exhibit greater rises in inflammation at ECOPD [63].

Angela Koutsokera. Pulmonary biomarkers in COPD exacerbations: a systematic review. Respiratory Research 2013, 14:111  doi:10.1186/1465-9921-14-111

Opportunities for new biomarker discovery, diagnostic & treatment innovations:

Despite the advance of knowledge about the pathogenesis and pathophysiology of COPD over the last 30 years only a few biomarkers for have been validated, one new class of medication been introduced and even the rate of new treatments being developed is slowing.(8)

As a consequence, around 2011 the COPD Biomarker Qualification Consortium (CBQC) was created to help fast track research for better treatment to help improve the lives of those suffering from COPD. This is a collaborative public-private partnership, aiming to undertake regulatory qualification of emerging biomarkers and clinical assessments to facilitate the development and approval of novel treatments. (9)

Arguably, new opportunities around COPD and biomarker discovery/ validation should be focused on non invasive methods such a induced sputum and exhaled breath. Not only would tests developed based off these sample types be more convenient to patients but intuitively because they are linked to the lungs &/or respiratory pathways may be a rich source for new biomarker discoveries.

Role of biomarkers in COPD

Broadly, biomarker projects should be focused on helping:

  1. Define populations that will derive most benefit from a drug (pharmacogenetics)
  2. Improve drug development (pharmacokinetics)
  3. Predict disease course (to justify more intense or prolonged treatments) (diagnostics and prognostics)
  4. Monitor the effects of therapy (pharmacodynamics)
  5. Predict clinical outcomes (surrogate endpoints)
  6. Monitor adverse events (safety biomarkers)
  7. Identify new biological pathways involved in the pathology of COPD and identify new treatment opportunities

Moreover, biomarkers that could elucidate gaps in our knowledge of COPD etiology could be very useful such as:

  • The gender differences.
  • The mechanism by which inflammation causes fibrosis in the airways and loss of tissue next to it.(10) (11)
  • The leading cause of death from COPD is respiratory failure. COPD exacerbations are intensified inflammatory events compared with stable COPD and the way to manage and avoid these situations. (12)
  • Why patients with mild-to-moderate COPD tend to succumb to cardiovascular disease or lung cancer, two of the comorbidities of COPD (13) (14) (15). This likely occurs from chronic low-grade inflammation, which is involved in all two COPD diseases (respiratory failure, cardiovascular disease, lung cancer,)  (16) (17)
  • Find specific biomarkers for clearly differentiate asthma from COPD.
  • The triggers of this inflammation, the relevant pathways and identifying the SNPs which affect the risk of inflammation to improve the knowledge of COPD leading to prevention, early detection and development  of better treatments.

 

COPD biomarkers in blood

Blood has often been an important source for the discovery of new biomarkers and this has also been the case for COPD. Some promising blood based biomarkers include:

  • CRP, fibrinogen and leukocyte count: In some studies where there are more elevated levels of CRP, fibrinogen and leukocyte count more than in individuals with COPD than in healthy individuals and they can be a significant long-term predictor of future COPD outcomes in individuals with airway obstruction. There is an evolving evidence that fibrinogen is a useful biomarker in COPD, particularly in defining lung function decline in COPD patients and in acting as a surrogate marker of treatment success.(18) Like one of the conclusions of the ECLIPSE project (19) (20)
  • And surfactant protein D (SP-D) Some researches point that pulmonary surfactant protein D (SP-D) can be considered a candidate biomarker for lung integrity and for disease progression. The correlation of serum SP-D levels with the BODE (body mass index, airflow obstruction, dyspnea, exercise capacity) index suggests that circulating SP-Ds can reflect the overall severity of stable COPD (SCOPD) (21)(22).

 

COPD Biomarkers in exhaled breath condensate (EBC)

Out of the non invasive sample types, exhaled breath condensate provides an exciting opportunity for the development of diagnostic tests. Most notably, breath based diagnostics have successfully been commercialized for Asthma and tests for COPD may also be soon available.

The current technologies for the analysis and measurement of different biomarkers in exhaled breath are:

  • the immunoassays mass spectrometry
  • high-performance liquid chromatography
  • nuclear magnetic resonance spectra
  • luminometry
  • spectophotometry
  • and pH-meter

The key obstacle with these technologies is that the biomarkers still need to be validated by reference analytical techniques. Some of the concentrations are often close to the detection limit of the assays making analytical data less reliable and the dilution the of airway lining fluid may influence the results of biomarkers analysis in EBC.(6)

Nevertheless these obstacles could be avoided by a) testing for several biomarkers and calculating ratios among them and b) Identification of a substance that serves as an on-off indicator of an abnormality. To achieve successful standardisation and validation it’s important to pay special attention to technical issues of flow and time dependence, influence of respiratory patterns, origin markers in exhaled breath condensate (EBC), and possible contamination by nasal, saliva and or sputum.(6)

Another area some of the technologies useful for EBC could be applied include substances contained within tobacco smoke. It is recommended that doctors enquire as part of treatment planning which tobacco brand and type patients smoke(d). It is possible that based off the differences between tobacco types exist tobacco based biomarkers that could provide an explanation of different treatment response and help better optimize treatment plans. Moreover, these biomarkers may also further elucidate aspects around the severity of symptoms and exacerbations of COPD and other respiratory diseases such as lung cancer.(23)(24)(c)

What are your suggestions for the discovery of new COPD biomarkers? What are some interesting studies that you think should be conducted?

Please share comments below.

See References
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  3. Kim SR, Rhee YK. Overlap between asthma and COPD: where the two diseases converge. Allergy Asthma Immunol. Res.2(4), 209–214(2010).
  4. Louie S, Zeki AA, Schivo M et al. The asthma–chronic obstructive pulmonary disease overlap syndrome: pharmacotherapeutic considerations. Expert Rev. Clin. Pharmacol.6(2), 197–219(2013).
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  6. Barbara P. Yawn. Differential Assessment and Management of Asthma vs Chronic Obstructive Pulmonary Disease.Medscape J Med. 2009; 11(1): 20. Published online Jan 21, 2009
  7. O. Toungoussova. Sputum and exhaled breath analysis. ERS handbook for SEPAR
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  9. Debora Merrill, M.B.A. COPD Foundation. New Biomarkers: Why Are They Critical to the Future of COPD Research? How the COPD Biomarker Qualification Consortium (CBQC) Work Will Deliver Results LUNG HEALTH PROFESSIONAL MAGAZINE• VOLUME 4 NUMBER 3 – 2013.
  10. Barnes PJ. Immunology of asthma and chronic obstructive pulmonary disease. Nat. Rev. Immunol.8(3), 183–192(2008).
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  13. Decramer M. Chronic obstructive pulmonary disease and comorbidities. Lancet Respir Med. 2013 Mar;1(1):73-83. doi: 10.1016/S2213-2600(12)70060-7. Epub 2013 Jan
  14. Masaki Miyazaki. Analysis of comorbid factors that increase the COPD assessment test scores.Respiratory Research 2014, 15:13 doi:10.1186/1465-9921-15-13
  15. Baty F. Comorbidities and Burden of COPD: A Population Based Case-Control Study. PLoS ONE 8(5): e63285. doi:10.1371/journal.pone.0063285 (2013)
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  18. Mona Fattouh. Inflammatory biomarkers in chronic obstructive pulmonary disease. Open Access funded by The Egyptian Society of Chest Diseases and Tuberculosis.
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  20. Mette Thomsen, MD. Inflammatory Biomarkers and Exacerbations in Chronic Obstructive Pulmonary Disease. JAMA. 2013;309(22):2353-2361. doi:10.1001/jama. 2013.5732
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  25. Kim DK. Genome-wide association analysis of blood biomarkers in chronic obstructive pulmonary disease.Am J Respir Crit Care Med. 2012 Dec 15;186(12):1238-47. doi: 10.1164/rccm.201206-1013OC. Epub 2012 Nov 9. PMID: 23144326. Article first published online: 19 MAR 2012 DOI: 10.1002/em.21689

Elena Sánchez-Vizcaíno

Co-founder at Medbiomarkers
Elena Sánchez-Vizcaíno is a co-founder of Medbiomarkers, a company accelerating the translation of biomarker research via providing data and software solutions and building biomarker related consortia. Medbiomarkers helps diagnostics and drug discovery companies to effectively incorporate biomarker research into their product pipelines as well as tech transfer offices and biomarker discovery organizations to accelerate the licensing of their inventions.