COPD and Phenotyping: A New Approach

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Table of Contents

Introduction
Background
Literature review
Discussion
Conclusion
References

Introduction

Chronic obstructive pulmonary disease (COPD) is a disorder that belongs to the category of respiratory, airway obstructions being its primary characteristic. COPD progresses slowly and manifests itself in a variety of ways including dyspnea and panting, inability to exercise, coughing and/or producing sputum, etc. (Qaseem et al., 2011). The prevalence of the disease is increasing despite the drop in smoking and other risk factor exposure in recent years on the global scale.

As yet, clinicians rely on preventative measures, management, and rehabilitation practices to improve the COPD clients’ well-being. Most commonly, COPD is treated with pharmacological means such as bronchodilators and steroids. In recent years, however, deeper research has been made into the genomic issues related to COPD. While current guidelines suggest spirometry assessment and unified pharmacological interventions in treatment, the body of evidence justifying phenotype-driven therapy is expanding.

The purpose of the present paper, therefore, is to review the existing literature (including the recent clinical guidelines) and estimate whether there is a tendency to deploy personalized approaches based on phenotyping in COPD management. The paper provides a background of what is known about the disease, the review of peer-reviewed studies and a guideline, and a discussion part. The articles were retrieved from medical journal databases; the search was conducted using keywords such as “COPD management / guideline / phenotyping / genomics” and no publications before 2010 were taken into account.

Background

Manifestation

Most cases of COPD are characterized by chronic cough with or without sputum – the substance coughed up from trachea and bronchi. Another common symptom of COPD is shortness of breath or uneven breath (e.g., an exhale is longer than an inhale). COPD patients can experience exacerbation – acute worsening of the condition where the breathing is harder and more sputum is produced. The color of sputum may alternate from translucent to yellowish or green (Qaseem et al., 2011).

Risk factors

The risk groups are typically constituted by persons who smoke and/or are exposed to air pollution in their place of residence or at work (e.g., dust and chemicals). Genetics have their part in the development of the disease, as described below. Those aged over 35-40 are at higher risk of developing the disease if they have been exposed to the said factors over some period in life.

Genetics

The term “phenotype” has been more actively used in relation to COPD clients in recent years. This can be explained by the number of studies suggesting that the ways the disease manifests itself can be caused by genetic factors. Some phenotypes singled out are:

the exacerbator;
ACOS (asthma-COPD overlap syndrome);
the emphysema-hyperinflation (Miravitlles, Calleb, & Soler-Cataluña, 2012).

The phenotypes are known to have diverse characteristics and be able to determine the ways of treatment. The genome-wide studies of COPD have made such classification possible, and the genomic studies of COPD pathogenesis are currently being integrated into network approaches to establish molecular interaction patterns (Hobbs & Hersh, 2014).

Approaches to treatment

The traditional approach to COPD management (the one that relies on the unified spirometry) suggests the cessation of smoking and pollution exposures and pulmonary rehabilitation. A new treatment method emerging from genomic research on COPD is phenotype-driven therapy which firstly assesses the phenotype and tailors the treatment accordingly. Within the literature review, a more detailed account of genetic issues concerning the subject is going to be retrieved, as well as some evidence of the new treatment method application acceptance.

Literature review

The official 2011 update to the guideline on COPD by American College of Physicians has a number of recommendations regarding the COPD treatment. Namely, the guide suggests conducting spirometry test to determine whether the airflow obstruction is present. As to the treatment, the guideline suggests inhaled bronchodilators, oxygen therapy, or pulmonary rehabilitation for patients with diverse forced expiratory volumes (FEV₁). Clinicians are also advised to choose either inhaled anticholinergics or beta-agonists for monotherapy depending on the patients’ budget and preferences, as well as their clinical history (Qaseem et al., 2011).

Indeed, most studies published 4-6 years ago agree on bronchodilators as the most optimal solution for pharmacological management of COPD (Alifano et al., 2010). These are said to reduce exacerbations and improve the overall well-being. Apart from that, studies provide information on other medications to curb the disorder, namely: corticosteroids, theophylline, and phosphodiesterase-4 inhibitors (Alifano et al., 2010). The positive effects of corticoids are debatable as they are likely to cause lung dysfunction; still, the combined effects of bronchodilators, LAMA, and corticosteroids are known to increase the ability to exercise. Weak bronchodilators such as theophylline have been shown to reduce exacerbations, as well as the inhibitors. Research such as this, however, admits COPD to be a complex disorder which cannot be administered by using medications alone. At that, pulmonary rehabilitation is also deemed effective in terms of disease-related QOL improvement.

Albeit the efficacy of rehabilitation (which consists of education on pharmacotherapy compliance and regular exercise), the disease continues to be one of the leading causes of death on the global scale (Berndt, Leme, & Shapiro, 2012). Although the relationship between FEV₁, dosage, and dose response has been established, the responses demonstrate considerable variance. It is known that alpha-1 antitrypsin (AAT) deficiency leads to COPD on genetic level but the prevalence of such cases is quite low. Berndt et al. (2012), therefore, speak for the role of the interaction of genome variations and environmental conditions associated with COPD in the pathogenesis of the disorder. Early research determined that COPD was hereditary. Today, the loci of COPD susceptibility have been established by genome-wide research, and the association studies (GWAS) may assist in explaining the build-up of COPD in phenotypes (Hobbs & Hersh, 2014).

As said, increased attention is currently being given to phenotypes, which, in relation to COPD, denote variance of disorder attributes between patients (Miravitlles et al., 2012). The abovementioned three phenotypes can be correlated with disorder forecast and the response to the therapeutic interventions currently available. There is, in fact, a greater number of phenotypes that have been singled out by various studies and vary for clients of different age groups, gender, ethnicity, genetic and external risk factors, etc. (Pinto et al., 2015). No unified account on the phenotypes exists in literature as yet; the given three are the most common. Patients of exacerbator phenotype are the ones to have experienced no less than two acute worsenings during one year. A prognosis can be made that such clients will require anti-inflammatory medications as well as bronchodilators. The ACOS phenotype is characterized by varying airflow obstruction rates. This phenotype is known to respond to corticoids paired with bronchodilators. The emphysema phenotype, contrastingly, does not respond to anti-inflammatories or corticosteroids. With this phenotype, bronchodilators and pulmonary rehabilitation are deemed the most effective combination (Miravitlles et al., 2012).

It is true that there is a number of unresolved genomic issues concerning COPD. However, the method of phenotyping is crucial in clinical practice because it is currently reframing the ways the disorder is managed. Patients of different phenotypes respond to different medications and treatment modes; predictions on the progression of the disease can also be made based on phenotypes (Montuschi, Malerba, Santini & Miravitlles, 2014). There is evidence that phenotyping helps increase the response rates as opposed to unified pharmacotherapeutic approach presupposing bronchodilators for most patients. The more so, stratification of patients based on phenotype-driven variables (e.g., airflow obstructions, age, BMI, emphysemas, and comorbidities) is known to decrease mortality rates (Zbozinkova et al., 2016). It is possible to say, therefore, that personalized approach driven by phenotype is currently in favor.

Discussion

The existing body of research demonstrates a tendency to a personalized approach using phenotypes in treatment of COPD. The involvement of genetics in COPD studies seems to be justified by the complexity of the disorder. Indeed, studies of a disease that progresses on the background of external factors and each individual client’s predispositions can only benefit from the discovery of the molecular pathways of its pathogenesis. A heterogeneous disorder such as this can and should be treated with all the particularities taken into account, which is what justifies phenotyping.

The recent updates to clinical guidelines do not take phenotyping into account, instead continuing to rely solely on FEV₁to assess the obstruction. Considering the importance of phenotyping as a clinical practice (as well as the fact that it is already successfully used by clinicians all over Europe and has proved to be efficient), the inclusion of phenotyping as a clinical guideline recommendation is desirable.

It would be true to say that phenotyping, as a developing practice, may present several limitations to implementation. Specifically, various literatures are not entirely consistent with the characteristics of particular phenotypes. Besides, there is evidence of researcher bias in some such studies, wherein the investigators allowed for gender discrimination in their sample selection (Pinto et al., 2015). However, a tendency to agree upon three fundamental phenotypes is observable among the studies. The difficulties presented by these three phenotypes (exacerbator, ACOS, and emphysema-hyperinflation) can include inability of the clinicians to infallibly attribute every individual case to this or that one, primarily because there are many more of them. However, the clients’ histories, for example, the number of exacerbations during the year, can provide a clinical picture to facilitate phenotype recognition. Recommendations to assess the clients’ histories will be beneficial if included in the guidelines.

Conclusion

To reiterate, a new approach to management and treatment of COPD is currently emerging, as evidenced by current literature. Phenotyping is undoubtedly beneficial for treating COPD as opposed to traditional unified pharmacotherapy because it is capable of assessing the particular cases and provide treatment that different phenotypes are known to better respond to. Phenotyping is coming into actual practice, although it is not reflected in clinical guidelines or theoretical literature. Inclusion of phenotyping in the guidelines is desirable, as well as further research to establish a more comprehensible set of characteristics for each individual phenotype.

References

Alifano, M., Cuvelier, A., Delage, A., Roche, N., Lamia, B., Molano, L. C.,…Devillier, P. (2010). Treatment of COPD: from pharmacological to instrumental therapies. European Respiratory Review, 19(115), 7-23.

Berndt, A., Leme, A. S., & Shapiro, S. D. (2012). Emerging genetics of COPD. EMBO Molecular Medicine, 4(11), 1144-1155.

Hobbs, B. D., & Hersh, C. P. (2014). Integrative Genomics of Chronic Obstructive Pulmonary Disease. Biochemical and Biophysical Research Communications, 452(2), 276-286.

Miravitlles, M., Calleb, M., & Soler-Cataluña, J. J. (2012). Clinical Phenotypes of COPD: Identification, Definition and Implications for Guidelines. Archivos de Bronconeumología, 48(3), 86-98.

Montuschi, P., Malerba, M., Santini, G., & Miravitlles, M. (2014). Pharmacological treatment of chronic obstructive pulmonary disease: from evidence-based medicine to phenotyping. Drug Discovery Today, 19(12), 1928-1935.

Pinto, L. M., Alghamdi, M., Benedetti, A., Zaihra, T., Landry, T., & Bourbeau, J. (2015). Derivation and validation of clinical phenotypes for COPD: a systematic review. Respiratory Research, 16(50), 1-13.

Qaseem, A., Wilt, T. J., Weinberger, S. E., Hanania, N. A., Criner, G., van der Molen, T.,…the European Respiratory Society. (2011). Diagnosis and Management of Stable Chronic Obstructive Pulmonary Disease: A Clinical Practice Guideline Update from the American College of Physicians, American College of Chest Physicians, American Thoracic Society, and European Respiratory Society. Annals of Internal Medicine, 155, 179-191.

Zbozinkova, Z., Barczyk, A., Tkacova, R., Valipour, A., Tudoric, N., Zykov, K.,…Koblizek, V. (2016). POPE study: rationale and methodology of a study to phenotype patients with COPD in Central and Eastern Europe. International Journal of Chronic Obstructive Pulmonary Disease, 11(1), 611-622.

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