Precision respiratory medicine in clinical practice: at the balance between facts and trivia
5 January, 2017
Approximately half of the smoking population is considered susceptible to, and will develop, chronic obstructive pulmonary disease (COPD)(1).
However, the risk of developing COPD is about 23% lower in active smokers with moderate to high levels of physical activity, compared to inactive smokers (2). Once chronic airflow limitation has developed, lung cancer is up to five times more likely to occur than in smokers with normal lung function (3) and one in every five COPD patients will have undiagnosed chronic heart failure (4). In fact, approximately 28% of patients with a moderate degree of airflow limitation will die due to a cardiac cause (5). Before that unhappy moment, patients with COPD using dual long-acting bronchodilation therapy are nearly 25% more likely to have a positive response on health status compared to monotherapy with a long-acting bronchodilator (6). Exacerbations however, have a negative impact on this health status, occur very frequently in about one third of patients (7) and may result in hospitalisation, after which the cumulative chance of being considered eligible, being referred and completing a course of pulmonary rehabilitation(PR) is less than 10% (8). If completed however, almost half of patients will benefit from a clinically-meaningful improvement in functional capacity (9).
I was consulted by a 58-year old male smoker with twenty packyears because of symptoms of dyspnea, cough and fatigue. He had been a construction worker for the last 25 years and was a fanatic cyclist in his leisure time. He was diagnosed with COPD, but the degree of airflow limitation was very moderate (forced expiratory volume in the first second; FEV1 74%) and was not quite matching his level of shortness of breath, evaluated by me as modified Medical Research Council (mMRC) grade 2. Chest radiology did not show major pathologies. Since bronchodilator therapy did not result in symptomatic relief, I referred him to the cardiologist, who did not find any abnormalities. Last winter, he suffered an exacerbation and he succesfully gave up smoking. I referred him to our PR programme. Although his cycling time increased significantly after the programme, his COPD Assessment Test (CAT) for health status remained invariably high.
The rather random facts about COPD pathophysiology and management that I described above are derived from a lecture that I gave earlier this year for medical students at Maastricht University. While I was presenting, I noticed the students were intensively taking notes of this information as if these facts were going to enable them to manage COPD patients in real-life. At the same time however, it crossed my mind that these scientific data are actually trivia in a real-life clinical COPD setting and I thought about my patient. Despite his active lifestyle, he developed COPD as a result of smoking; his symptoms did not respond to bronchodilation therapy and he did not have chronic heart failure as an explanation for his high dyspnea sensation. While he was among the minority of patients worldwide completing a course of PR, the outcome of this non-pharmacologic intervention was variable. My patient reminded me that scientific data about populations of patients still are relatively useless in clinical practice.
In the last decades, our understanding of the pathophysiology of COPD has increased tremendously, as have the pharmacologic and non-pharmacologic opportunities to manage our patients. Also, the possibilities for outcome assessment have expanded enormously. Exercise training, bronchodilator and anti-inflammatory therapies, long-term oxygen therapy, smoking cessation counseling and endobronchial lung volume reduction are examples of evidence-based therapeutic options for patients with this disease. However, while these interventions on average provide clinical benefits for COPD patients, non-response occurs in a large proportion of patients. Moreover, adverse events may occur in addition to a lack of clinical treatment effects and both are hard to predict in individual patients. This also applies to the natural history of disease, that is characterised by heterogeneity and lack of predictability for each individual patient. Finally, the non-occurrence of deleterious events (exacerbations, lung function decline) as a result of successful pharmacotherapy cannot be distiguished from natural variability in event rates over time in individual patients.
In order to address this complexity across multiple dimensions, a lot of scientic effort is put into endotyping and clinical phenotyping the disease. Ultimately, this should enable us to provide prognostic information on COPD development and progression and determine the appropriate treatment for every individual patient. Recently, identification and targeting of treatable traits was proposed as the way towards precision medicine of COPD (10).
While I fully endorse approaches towards individualised COPD management, we must be aware that current clinical practice is far from there. New challenges will arise in disease management of individual patients if these are considered as a sum of treatable traits. For example, a pharmacologic or non-pharmacologic intervention may target multiple treatable traits (for example, dyspnea, lung function and health status) in COPD and show clinical benefit across all of these in a study population, but not all individuals will profit. Most importantly however, individuals that benefit on a certain outcome (for example, FEV1) are not necessarily the same people that benefit on another outcome (for example, health status).
Moreover, the method of outcome assessment will effect the observed benefit. We recently demonstrated the clinical relevance of this problem by profiling the response to PR in COPD (9). Individual patients reporting a clinically-relevant decrease in dyspnea following PR only partially overlapped with patients showing a clinically relevant increase in exercise capacity, although significant benefits were achieved at population level. Moreover, individual patients showing an increase in walking distance were not the same patients as those with a significant improvement in cycling capacity, highlighting the impact of the choice of outcome measure within the domain of a single treatable trait. Our study indicated that COPD patients respond differentially on outcome measures that are regularly used in clinical trials and in daily practice. Instead of choosing a limited number of outcomes and interpreting these in isolation, the clinical complexity of COPD probably requires multidimensional outcome profiling in order to advance towards individualised management. In addition to identifying good responders to intervention, this approach will reveal the true poor responders to available interventions, enable us to rethink current disease management and stimulate a personalised approach.
Until precision medicine is truly applicable in COPD, I will give countless lectures full of disease trivia unveiling this intriguing chronic respiratory condition and will continue to treat my patients at the balance between scientific evidence and real-world complexity.
- Lundback B, Lindberg A, Lindstrom M, Ronmark E, Jonsson AC, Jonsson E, Larsson LG, Andersson S, Sandstrom T, Larsson K, Obstructive Lung Disease in Northern Sweden S. Not 15 but 50% of smokers develop COPD?--Report from the Obstructive Lung Disease in Northern Sweden Studies. Respir Med 2003; 97: 115-122.
- Garcia-Aymerich J, Lange P, Benet M, Schnohr P, Anto JM. Regular physical activity modifies smoking-related lung function decline and reduces risk of chronic obstructive pulmonary disease: a population-based cohort study. Am J Respir Crit Care Med 2007; 175: 458-463.
- Young RP, Hopkins RJ. Link between COPD and lung cancer. Respir Med 2010; 104: 758-759.
- Rutten FH, Cramer MJ, Grobbee DE, Sachs AP, Kirkels JH, Lammers JW, Hoes AW. Unrecognized heart failure in elderly patients with stable chronic obstructive pulmonary disease. European heart journal 2005; 26: 1887-1894.
- Mannino DM, Doherty DE, Sonia Buist A. Global Initiative on Obstructive Lung Disease (GOLD) classification of lung disease and mortality: findings from the Atherosclerosis Risk in Communities (ARIC) study. Respir Med 2006; 100: 115-122.
- Oba Y, Lone NA. Comparative efficacy of long-acting muscarinic antagonists in preventing COPD exacerbations: a network meta-analysis and meta-regression. Ther Adv Respir Dis 2015; 9: 3-15.
- Hurst JR, Vestbo J, Anzueto A, Locantore N, Mullerova H, Tal-Singer R, Miller B, Lomas DA, Agusti A, Macnee W, Calverley P, Rennard S, Wouters EF, Wedzicha JA, Evaluation of CLtIPSEI. Susceptibility to exacerbation in chronic obstructive pulmonary disease. The New England journal of medicine 2010; 363: 1128-1138.
- Jones SE, Green SA, Clark AL, Dickson MJ, Nolan AM, Moloney C, Kon SS, Kamal F, Godden J, Howe C, Bell D, Fleming S, Haselden BM, Man WD. Pulmonary rehabilitation following hospitalisation for acute exacerbation of COPD: referrals, uptake and adherence. Thorax 2014; 69: 181-182.
- Spruit MA, Augustin IM, Vanfleteren L, Janssen DJ, Gaffron S, Pennings HJ, Smeenk F, Pieters W, van den Bergh JJ, Michels AJ, Groenen MT, Rutten EP, Wouters EF, Franssen FM, Network CR. Differential response to pulmonary rehabilitation in COPD: multidimensional profiling. Eur Respir J 2015.
- Agusti A, Bel E, Thomas M, Vogelmeier C, Brusselle G, Holgate S, Humbert M, Jones P, Gibson PG, Vestbo J, Beasley R, Pavord ID. Treatable traits: toward precision medicine of chronic airway diseases. Eur Respir J 2016; 47: 410-419.