Moving away from therapeutic nihilism in COPD
25 July, 2018
Living with advanced COPD in 2002
While in training to become a respiratory physician, a 57 year old formerly smoking man with severe chronic obstructive pulmonary disease (COPD) and chronic respiratory failure frequently visited my outpatient clinic in Maastricht University Medical Center (MUMC), the Netherlands. Despite regular treatment with a long-acting beta2-agonist and short-acting bronchodilators on an as-needed basis, he was persistently dyspnoeic and had a reduced exercise capacity. The very pronounced degree of lung hyperinflation probably contributed to his burden of disease. Since he had been treated with antibiotics and oral glucocorticosteroids for several exacerbations in the last year and the degree of chronic airflow limitation was severe, I initiated a trial of several months with inhaled glucocorticosteroids (ICS) to identify whether he might benefit from this approach. He was severely dyspnoeic during endurance training, resulting in poor programme compliance and thus pulmonary rehabilitation did not result in symptomatic improvement. In order to increase his life expectancy, long-term oxygen therapy was prescribed. In the years I treated him, until his death from an incident comorbid disease, I observed his progressive deterioration but had no additional treatment options.
Improved care for COPD
The Global Burden of Disease (GBD) 2015 study reported a modest increase in global death rates attributable to COPD from 2005-2015 (1). While population growth and ageing accounted for the increased overall mortality, I was intrigued by the finding that age-standardized and COPD-specific death rates fell by approximately 30% over this period (1). Thus, the GBD study showed that the life expectancy of patients with COPD of a certain age has substantially improved over the last decade. Several factors may explain this improved survival, including improvements in the socio-demographic development of multiple countries and regions of the world, improvements in public health programmes and access to medical care, and reductions of inequalities within societies. However, the results made me consider the actual improvements in medical care for COPD patients over the last decades and how these may, to a limited extent, contribute to the reduced mortality rates.
The first Workshop Summary of the Global Initiative for Chronic Obstructive Lung Disease (GOLD) was published in 2001 (2). By then, COPD was defined as a disease state characterized by airflow limitation that was not fully reversible and usually progressive. From the perspective of our current knowledge and management of the disease (3), diagnostics, classification and understanding of COPD pathophysiology have obviously progressed. As none of the existing medications had been shown to modify the long-term decline in lung function that was considered the hallmark of COPD, pharmacotherapy was prescribed to reduce symptoms and bronchodilator treatments consisting of beta2-agonists, anticholinergics, theophylline, and a combination of one or more of these drugs were considered central to the symptomatic management. The beneficial effects of inhaled bronchodilators on lung hyperinflation and exacerbation frequency had not been established and many new bronchodilator drugs and inhaler devices have become available over the last decades. GOLD 2001 recommended regular treatment with ICS for symptomatic patients with a documented spirometric response to ICS or for those with severe disease and repeated exacerbations (2). Evidence for increased treatment effects when combining difference classes of inhaled medications was limited. Also, use of antibiotics other than in treating infectious exacerbations was not recommended and no anti-inflammatory agents were available. Although pulmonary rehabilitation was considered beneficial for COPD, its role in the post-exacerbation period and its potential to reduce hospitalisation and mortality rates was unrecognized (4).
While long-term administration of oxygen to COPD patients with chronic respiratory failure had been shown to increase survival (5), long-term mechanical ventilatory support and lung volume reduction surgery for very severe disease were not recommended (2). The contribution of cardiovascular and other comorbidities (6) to COPD morbidity and mortality was unknown and no attention was directed to comorbidity management. Although still no effects of inhaled medications have been demonstrated on mortality or cardiovascular outcomes (7), significant effects on survival have been shown for several interventions in subgroups of patients with COPD, including weight gain in underweight patients (8), non-invasive positive pressure ventilation in chronic hypercapnic patients (9) and lung volume reduction surgery in patients with upper-lobe predominant emphysema and poor exercise capacity (10).
Living with advanced COPD in 2017
A 57 year old formerly smoking man with severe COPD and chronic respiratory failure was referred for inpatient pulmonary rehabilitation in my center CIRO, the Netherlands, after yet another exacerbation treated with antibiotics and oral glucocorticosteroids. Despite regular treatment with a long-acting dual bronchodilator and ICS, he experienced severe dyspnea, exercise limitation and a very pronounced degree of lung hyperinflation. Since he had been treated for several exacerbations in the last year, I initiated a one-year trial with a macrolide in order to reduce his future risk of these events. Although he already was on long-term oxygen therapy, chronic nocturnal non-invasive positive pressure ventilation was initiated alongside pulmonary rehabilitation and these successfully normalised his hypercapnia. As he was severely dyspnoeic during traditional exercise training, high-frequency neuromuscular electrical stimulation was initiated as the main training modality during his PR programme (11). He was able to adhere to the programme resulting in reduced dyspnea and care dependency. Although his exercise capacity improved after PR, he remained severely limited. Assessment for comorbid cardiovascular disease was negative. After careful screening for eligibility, he subsequently received uncomplicated endobronchial-valve treatment in MUMC, resulting in pronounced reduction in hyperinflation and further improvement in exercise tolerance and health status (12). Despite marked reduction in his present burden of disease, advance care planning was recently discussed during a palliative care consultation.
Future challenges for COPD
From the clinical case descriptions of very similar COPD patients in 2002 and 2017, it is clear that disease management has significantly improved over the last decades. While therapeutic options for patients with advanced disease were traditionally limited, new evidence-based interventions were introduced and may, to a certain extent, have contributed to the reduced age-standardized and COPD-specific death rates over this period (1). However, we must be aware that COPD remains a major cause of worldwide morbidity and mortality and that there are many barriers, including social, demographic and financial factors, preventing the worldwide implementation of these new interventions. Furthermore, the vast majority of patients will not develop advanced disease and thus will not be eligible for these treatments.
The disease cannot be cured and many patients are unresponsive to available pharmacologic and non-pharmacologic treatments, accompanied by significant costs and adverse effects. Although new pharmacologic approaches targeting COPD exacerbations became available over the last decade, these did not decrease mortality (13). Development of biomarkers to guide COPD pharmacotherapy is problematic (14) and regenerative therapies are still far from clinical reality (15). At the same time, studies with specific antibodies for subgroups of patients are ongoing and the potential of lifestyle interventions to slow down disease progression (16) is fascinating. There is an obvious need for innovative ideas, more precise targeting of available interventions and development of novel treatments in order to take our management of COPD patients (ranging from mild and/or early to very severe disease) to the next level. In the meantime, we must educate the respiratory community and patients about the evolving insights and treatment options in COPD in order to move away from the therapeutic nihilism of the past.
- Mortality GBD, Causes of Death C. Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980-2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet 2016; 388: 1459-1544.
- Pauwels RA, Buist AS, Calverley PM, Jenkins CR, Hurd SS. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) Workshop summary. Am J Respir Crit Care Med 2001; 163: 1256-1276.
- Vogelmeier CF, Criner GJ, Martinez FJ, Anzueto A, Barnes PJ, Bourbeau J, Celli BR, Chen R, Decramer M, Fabbri LM, Frith P, Halpin DM, Lopez Varela MV, Nishimura M, Roche N, Rodriguez-Roisin R, Sin DD, Singh D, Stockley R, Vestbo J, Wedzicha JA, Agusti A. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Lung Disease 2017 Report: GOLD Executive Summary. Eur Respir J 2017; 49.
- Puhan MA, Gimeno-Santos E, Cates CJ, Troosters T. Pulmonary rehabilitation following exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2016; 12: CD005305.
- Long term domiciliary oxygen therapy in chronic hypoxic cor pulmonale complicating chronic bronchitis and emphysema. Report of the Medical Research Council Working Party. Lancet 1981; 1: 681-686.
- Divo M, Cote C, de Torres JP, Casanova C, Marin JM, Pinto-Plata V, Zulueta J, Cabrera C, Zagaceta J, Hunninghake G, Celli B, Group BC. Comorbidities and risk of mortality in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2012; 186: 155-161.
- Vestbo J, Anderson JA, Brook RD, Calverley PM, Celli BR, Crim C, Martinez F, Yates J, Newby DE, Investigators S. Fluticasone furoate and vilanterol and survival in chronic obstructive pulmonary disease with heightened cardiovascular risk (SUMMIT): a double-blind randomised controlled trial. Lancet 2016; 387: 1817-1826.
- Schols AM, Slangen J, Volovics L, Wouters EF. Weight loss is a reversible factor in the prognosis of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998; 157: 1791-1797.
- Kohnlein T, Windisch W, Kohler D, Drabik A, Geiseler J, Hartl S, Karg O, Laier-Groeneveld G, Nava S, Schonhofer B, Schucher B, Wegscheider K, Criee CP, Welte T. Non-invasive positive pressure ventilation for the treatment of severe stable chronic obstructive pulmonary disease: a prospective, multicentre, randomised, controlled clinical trial. The Lancet Respiratory Medicine 2014; 2: 698-705.
- Fishman A, Martinez F, Naunheim K, Piantadosi S, Wise R, Ries A, Weinmann G, Wood DE, National Emphysema Treatment Trial Research G. A randomized trial comparing lung-volume-reduction surgery with medical therapy for severe emphysema. The New England journal of medicine 2003; 348: 2059-2073.
- Sillen MJ, Franssen FM, Delbressine JM, Vaes AW, Wouters EF, Spruit MA. Efficacy of lower-limb muscle training modalities in severely dyspnoeic individuals with COPD and quadriceps muscle weakness: results from the DICES trial. Thorax 2014; 69: 525-531.
- Klooster K, ten Hacken NH, Hartman JE, Kerstjens HA, van Rikxoort EM, Slebos DJ. Endobronchial Valves for Emphysema without Interlobar Collateral Ventilation. The New England journal of medicine 2015; 373: 2325-2335.
- Brusselle G. Why doesn't reducing exacerbations decrease COPD mortality? The Lancet Respiratory medicine 2014; 2: 681-683.
- Roche N, Chapman KR, Vogelmeier CF, Herth FJ, Thach C, Fogel R, Olsson P, Patalano F, Banerji D, Wedzicha JA. Blood Eosinophils and Response to Maintenance COPD Treatment: Data from the FLAME Trial. Am J Respir Crit Care Med 2017.
- Cheng SL, Lin CH, Yao CL. Mesenchymal Stem Cell Administration in Patients with Chronic Obstructive Pulmonary Disease: State of the Science. Stem Cells Int 2017; 2017: 8916570.
- Benck LR, Cuttica MJ, Colangelo LA, Sidney S, Dransfield MT, Mannino DM, Jacobs DR, Jr., Lewis CE, Zhu N, Washko GR, Liu K, Carnethon MR, Kalhan R. Association Between Cardiorespiratory Fitness and Lung Health from Young Adulthood to Middle Age. Am J Respir Crit Care Med 2017.