COPD Phenotypes - implications for care

Abstract

COPD phenotyping can help define clusters of patients with common characteristics that relate to clinically meaningful outcomes. In this review, we describe seven clinically meaningful COPD phenotypes that can be identified by the primary care provider as well as the specialist, and that carry specific management and prognostic implications. These are: the asthma-COPD overlap phenotype, the frequent exacerbator phenotype, the upper lobe-predominant emphysema phenotype, the rapid decliner phenotype, the co-morbid COPD phenotype, the physical frailty phenotype, and the emotional frailty phenotype.

How many COPD phenotypes are there, and why do we need to define them?

The Merriam-Webster dictionary defines phenotype as the observable properties of an organism that are produced by the interaction of the genotype and the environment. There are probably as many ‘phenotypes’ as there are COPD patients in the world. The 1995 ATS guidelines recognized airway disease phenotypes in the Venn diagram demonstrating the overlap between asthma, chronic bronchitis, and emphysema, however, the limited therapeutic toolkit available at the time rendered distinction along these pathways unproductive from the patient's or clinician's point of view¹).

In 2010, Han et al. proposed the following definition of COPD Phenotypes - a single or combination of disease attribute that describe differences between individuals with COPD as they relate to clinically meaningful outcomes (symptoms, exacerbations, response to therapy, the rate of disease progression, or death².

In 2011, the GOLD guidelines took a stride towards COPD phenotyping by incorporating the impact of COPD on activity and exacerbation, with the recently published 2017 guidelines further refining recommendations for pharmacotherapy based on symptoms and exacerbations independent of airflow limitation ³.

In this concise review, we chose to address 7 COPD phenotypes that can help individualize care, are defined by their implications regarding outcomes and day-to-day management, and not by delineation along anatomic, physiologic or pathologic schema (Fig. 1). An overlap between phenotypes, therefore, is expected, is likely the natural norm, and inclusion into one phenotype is not to the exclusion of the others.

Figure 1.

While the first asthma-COPD overlap phenotype, the frequent exacerbator phenotype, and the upper lobe-predominant emphysema phenotypes are well-established in COPD literature, the rapid decliner, and co-morbid phenotypes have been defined via cluster analysis⁴. Physical frailty and emotional frailty traits though not well defined in COPD patients have long been recognized as carrying direct and independent therapeutic implications for management, in addition to significantly impacting the quality of life, prognosis, and health-care utilization.

Asthma-COPD Overlap Phenotype

Asthma and COPD are regarded as separate conditions with differing underlying pathophysiology. Though their individual clinical presentations may be ‘typical’ and easily recognizable, in many patients, especially older people and smokers, determination of the etiology of chronic respiratory symptoms and airflow limitation as originating from asthma, smoking-related COPD or both can be challenging⁵. The hallmark being the coexistence of increased variability of airflow in a patient with incompletely reversible airway obstruction, based on the definition used and the population under study, the prevalence of the asthma-COPD overlap phenotype in patients with COPD has been reported to be from 12%–55%⁶.

The attempt to define this overlap of phenotypes was prompted by an association with a higher symptom burden, poorer outcomes (including more frequent and severe exacerbations), plus diagnostic and therapeutic uncertainties given that this set of patients was excluded from clinical trials that used strict definitions to identify patients with COPD or asthma^5,7–10. The entity in itself, and its defintion remain controversial due to a lack of broad consensus, however, until such time that obstructive airways diseases including COPD and asthma are categorized based on genotypes and endotypes, identifying patients with this overlap retains clinical utility in choosing pharmacologic therapy.

A consensus-based guideline proposed in 2012 that the diagnosis of the “Overlap Phenotype COPD–Asthma” be made when two major criteria, or, one major and two minor criteria are met. The major criteria are: a very positive bronchodilator test (increase in FEV₁≥15% predicted and ≥400ml), eosinophilia in sputum and personal history of asthma; and the minor criteria are high total IgE, personal history of atopy and positive bronchodilator test (increase in FEV₁≥12% predicted and ≥200ml) on two or more occasions¹¹.

In 2015, to aid further research efforts in patient with overlap, a joint GINA-GOLD ‘description’, instead of a ‘definition’ of the entity of Asthma-COPD Overlap Syndrome (ACOS) was put forth in the form of features that are likely to identify this¹².

The age at which features of the overlap phenotype manifest also appears to be important. Patients with onset of asthma-COPD overlap after the age of 40 (likely stemming predominantly from COPD with later onset of asthma-like features) seem to do worse compared to those with the onset of asthma-COPD overlap before the age of 40 (likely stemming from asthma) regarding lung function decline, health-care utilization, and mortality⁹.

In COPD patients where a diagnosis of asthma is being entertained but questioned, features such as high Exhaled Nitric Oxide (ENO), peripheral blood or sputum eosinophilia and other evidence of atopy may help identify patients who would benefit from the early institution and continuation of inhaled steroids¹⁰.

Practical implications

In patients with asthma-COPD overlap phenotype, therapy with inhaled steroids should be strongly considered in addition to long-acting bronchodilators.

The Frequent Exacerbator Phenotype

COPD exacerbations are defined by GOLD as acute events characterized by a worsening of the patient’s respiratory symptoms (baseline dyspnea, cough, and/or sputum production) that is beyond normal day-to-day variation and leads to a change in medication³. A widely accepted criterion for the ‘frequent exacerbator’ phenotype is the occurrence of 2 or more exacerbations per year¹³.

The proportion of patients defined and reported as frequent exacerbators has been between 13% to 47% based on the populations studied, and with the proportion increasing as the severity of airflow obstruction increases¹³.

The impact of frequent exacerbations is substantial – increased risk of depressive symptoms, the decline in lung function, poorer quality of life, decreased physical activity, increased healthcare utilization, and up to a three-fold increase in mortality¹⁴.

Of factors associated with frequent exacerbations, the most utilitarian in identifying this cohort appear to be a history of prior exacerbations and anxiety, the latter of which has been associated independently with very frequent exacerbations^15,16.

Long-acting inhaled anticholinergic and beta-agonists alone, and in combination with each other have been shown to reduce exacerbation frequency in COPD with moderate or worse airflow obstruction^17,18. The triple combinations of tiotropium/ fluticasone/ salmeterol and tiotropium/ budesonide/ formoterol also appear to be effective in reducing moderate-severe exacerbations, but the steroid-containing inhalers do confer an increased risk of pneumonia¹⁸.

Oral acetylcysteine added to an optimized inhaled medication regimen has been shown to reduce the frequency of COPD exacerbations^17,19.

Macrolides used to prevent exacerbations have the most data behind their use, though other antibiotics have also been studied; they provide benefits regarding reducing the frequency of exacerbations, hospitalizations and increased time to next exacerbation^17,20,21.

Roflumilast, an anti-inflammatory PDE-4 (phosphodiesterase-4) inhibitor has proven most beneficial in exacerbation prevention in a subset of patients older than 40 years with severe to very severe COPD, a history of chronic bronchitis and frequent exacerbations. Though drug tolerance has been an issue due to minor adverse effects, it has demonstrated efficacy in improving baseline lung function, reducing severe exacerbations and hospitalizations even in the setting of baseline use of long-acting bronchodilator(s) and inhaled corticosteroid ^17,22.

Practical implications

The addition of anti-inflammatory medication (antibiotics or PDE4 inhibitors) and/or acetylcysteine for exacerbation prevention may be a valuable and cost-effective add-on therapy in patients experiencing two or more moderate-severe exacerbations per year, and in whom basic components of COPD management have been reviewed, and are in place.

Upper lobe-predominant Emphysema Phenotype

Upper lobe-predominant emphysema is an anatomic phenotype with strong genetic underpinnings that lends itself to importance due to the potential for significant improvement by lung volume reduction surgery (LVRS).

LVRS is thought to improve ventilation-perfusion mismatch and cardiopulmonary hemodynamics by reducing dead space, improving ventilatory mechanics by decreasing hyperinflation, elastic recoil, airway tethering, and increasing respiratory muscle efficiency.

The landmark NETT (National Emphysema Treatment Trial) demonstrated in the early 2000s that in a carefully selected group of patients with upper lobe predominant emphysema, LVRS lead to durable improvement in exercise capacity, symptoms, and oxygen use²³. LVRS may be considered a palliative procedure that improves exercise capacity and symptoms with a potential survival advantage in a subset of patients.

Based on NETT, good candidates for LVRS consideration are patients with advanced upper lobe-predominant emphysema with air trapping, FEV1<45% predicted and DLCO of >20% predicted. Also, candidates need to have quit smoking, would be able to participate in pulmonary rehabilitation before and after surgery, and are acceptable from a surgical-risk standpoint²³.

Surgical LVRS has been shown to be a safe procedure with significant benefits when performed in carefully selected patients and experienced centers. Results of non-surgical lung volume reduction techniques attempted through bronchial valves, intrabronchial coils, and steam-induced thermal injury have been mixed and are not approved for clinical use in the United States as of yet.

Clinical implications

In patients with significant symptoms despite maximal therapy and upper lobe-predominant emphysema, consideration should be given to surgical LVRS.

The ‘Rapid Decliner’ phenotype

Cluster phenotyping of COPD patients has identified a cohort of relatively younger COPD patients without significant cardiovascular morbidities who appear to have a faster decline in lung function, poor nutritional and overall health status and high mortality⁴. Although the pathogenesis of this phenotype is unclear at this time, this is an important subset of the patient to be cognizant of so that they may be targeted for early referral to specialized centers. This would aid in aggressive disease management, and potentially lung transplantation gave that this was a population without a significant burden of cardiovascular comorbidities, and in some studies, younger overall in comparison to other phenotypes.

Practical implications

COPD patients who appear to have a rapid decline in lung function and poor nutritional status may constitute a subgroup of patients with high mortality, and should be referred for evaluation and aggressive disease management, including referral for lung transplantation.

The ‘Co-morbid’ Phenotype – the older patient with the moderate respiratory disease and a significant co-morbid burden

Cluster analyses have identified groups of subjects with “systemic COPD” characterized by a high body mass index, very high rates of diabetes, congestive heart failure and ischemic heart disease. Interestingly, they had higher levels of dyspnea, poorer quality of life, increased healthcare utilization and increased mortality risk than subjects with comparable airflow limitation but without a significant comorbid burden⁴.

Two independent reports suggest that the poor health outcomes and quality of life scores in this phenotype are likely predominantly determined by cardiovascular comorbidities^4,24. Although robust prospective studies are lacking, it appears that comorbidities appear to be the primary determinant of poor quality of life in patients’ symptoms are disproportionate to the degree of lung function abnormality, usually with mild-moderate. However, the level of airflow obstruction contributes more to impaired quality of life when lung function is severely compromised²⁴.

Practical implications

In persistently symptomatic COPD patients on optimal respiratory therapy and a significant comorbid burden of cardiovascular and metabolic comorbidities, targeting aggressive disease management of comorbidities may help improve symptoms and health outcomes.

The Physical Frailty Phenotype

Frailty is a multidimensional syndrome characterized by loss of physiologic and cognitive reserve that carries prognostic significance. It is a common geriatric syndrome but does not correlate with age only.

The most commonly utilized models of frailty are the Fried ‘frailty phenotype’ that is defined by meeting three or more of five criteria (weakness, slowness, low level of physical activity, self-reported exhaustion, and unintentional weight loss) and the Frailty Deficit Index (measured by cumulative deficits identified in a comprehensive geriatric assessment).

Frailty and respiratory impairment have a strong association that has been best explored in COPD. Frailty in COPD may be prevalent in as many as a half of diagnosed patients, especially in the elderly, is strongly associated with worse airflow limitation, symptoms, and exacerbation frequency, and can be mitigated through pulmonary rehabilitation^25–28.

Slowness determined by a four-meter gait speed (4MGS) <0.8 m/sec is a well-accepted, validated and sensitive cut-off for frailty screening in older community-dwelling adults, and has been shown to be associated with poor functional capacity and self-efficacy in patients with COPD²⁹. A 10-second cutoff on the Timed Up-and-Go test (TUGT) and a score of ≥3 on the PRISMA-7 tests are also sensitive instruments in screening for frailty²⁹.

Practical implications

Recognition of frailty should direct clinicians to place greater efforts in counseling and referring these patients to pulmonary rehabilitation, including non-hospital based programs to provide the greatest chance for participant retention and ongoing benefits after program completion. We recommend proactive screening for frailty in COPD patients, particularly in the elderly.

The Emotional Frailty Phenotype

Emotional frailty, an increasingly recognized phenotype in COPD merits recognition due to its significant and independent impact on outcomes, and implications for management. The characteristics of emotional frailty – anxiety, depression, and fear of breathlessness, are associated with a well-documented increase in morbidity, mortality, hospitalizations, length of stay and re-admissions, and can aid in its recognition^16,30,31.

Emotional frailty in COPD likely develops due to the complex interactions between the external and internal milieu of the patients and their disease - personality type, emotional intelligence, coping style, psychosocial support and stressors, biologic changes induced by disease, and the severity and manifestations of the COPD itself and other comorbidities (Fig. 2).

Figure 2.

Emotional intelligence and coping are intricately linked, and significantly impact depression, anxiety, and self-management in COPD ^32,33. On the other hand, a sense of coherence, resiliency , illness acceptance and presence of a social support system negatively correlate with anxiety and depression..

Fear of breathlessness identified by the question “How often during the LAST 2 WEEKS did you have a feeling of fear or panic when you had difficulty getting your breath?”, has been independently associated with hospitalizations³⁴. A score >3 in either PHQ-2 (Patient Health Questionnaire-2), a depression screen tool, or in GAD-2 (Generalized Anxiety Disorder-2) could also be used to screen COPD patients for emotional frailty.

While anxiety and depression must be sought and treated in COPD, the efficacy of pharmacologic treatment does not seem particularly encouraging or well defined at this time³⁵. The role of cognitive behavioral therapy (CBT) is plausible but robust data regarding efficacy and effect size is lacking ^35,36. Pulmonary rehabilitation by itself, and more so, in conjunction with more comprehensive programs that include education, psychosocial support and other behavioral and self-management techniques appear to equal or supersede the effects seen with pharmacologic therapy alone for anxiety and depression in COPD^37,38. Health coaching has recently been reported as effective to improve the emotional domain in COPD in a large randomized study of severe COPD patients discharged after an exacerbation.

Practical Implications

COPD patients with emotional frailty – those with anxiety, depressive symptoms or fear of breathlessness are at high risk for adverse health outcomes. They need to be proactively identified and enrolled in comprehensive pulmonary rehabilitation programs that include health coaching or CBT to address emotional frailty along with physical rehabilitation.

Limitations

We are aware that the list of proposed phenotypes is likely incomplete and possibly arbitrary. We also acknowledge that an overlap between the described phenotypes is likely common in clinical practice as these were distinguished by their common characteristics, prognostic significance, and outcomes, and not defined along rigid boundaries of anatomic, physiologic or pathologic criteria. Inclusion into one phenotype, therefore, is not to the exclusion of the other(s).

Conclusion

We have attempted to describe clinically meaningful COPD phenotypes that should be easily identifiable by the primary care provider, as well as the specialist. We recommend that patients in the primary care clinic who are challenging from a diagnostic or management perspective, or for whom further specialized evaluation such as for transplant are needed, be referred to the specialist. We hope that the recognition of these phenotypic characteristics will help guide personalized and effective care for COPD patients and positively impact their quality of life as well as health care utilization outcomes (see Table 1).

Table 1.

Phenotype-guided COPD Care

Phenotype	Clinical Significance	Identification	Phenotype-specific Management
Asthma-COPD Overlap Phenotype	Increased frequency and severity of exacerbation Faster FEV1 decline Increased health care utilization Increased co-morbid burden and mortality	Guidelines: 2 major criteria OR 1 major and 2 minor criteriaMajor Criteria: very positive bronchodilator test (increase in FEV1≥15% & ≥400ml) eosinophilia in sputum personal history of asthma) Minor criteria: high total IgE personal history of atopy positive bronchodilator test (increase in FEV1≥12% & ≥200ml) on ≥2 occasions)	Inhaled corticosteroids should be an essential part of the management in addition to long-acting bronchodilators Address atopy component as indicated
Frequent Exacerbator Phenotype	Faster decline in lung function Increased healthcare utilization Increased mortality up to 3-fold Increased risk of depressive symptoms	2 or more COPD exacerbation per year	Long-acting bronchodilators Inhaled Corticosteroids Anti-inflammatory treatment: macrolides, roflumilast, acetyl-cysteine.
Upper lobe-predominant Emphysema Phenotype	Potentially significant symptomatic benefit with LVRS	CT findings consistent of predominant upper lobe emphysema	Consider Surgical LVRS
‘Rapid Decliner’ Phenotype	High mortality	Rapid decline of lung function Relatively younger Poor nutritional status Spared of significant comorbidities	Early sub-specialty and lung transplant evaluation
Co-morbid Phenotype	increased healthcare utilization poorer quality of life increased mortality risk	Persistently symptomatic despite comprehensive therapy Symptoms are disproportionate with severity of airway obstruction High co-morbid burden, predominantly cardiovascular	Aggressive management of co-morbid disease
Physical Frailty Phenotype	Higher symptom burden Frequent exacerbations Poor functional capacity Poor disease management self-efficacy	Screening: 4MGSb (<0.8 m/sec), TUGTc >10 sec, PRISMA-7 score ≥3 Diagnosis: Fried Criteria, Frailty Deficit Index	Pulmonary Rehabilitation
Emotional Frailty Phenotype	Increased health-care utilization Poorer quality of life Poor disease management self-efficacy	Depression screen PHQ-2d >3points Anxiety screen GAD-2e>3points Fear of breathlessness: Screen with “How often during the LAST 2 WEEKS did you had a feeling of fear or panic when you had difficulty getting your breath?”	Comprehensive pulmonary rehab that includes behavioral interventions such as health coaching or cognitive therapy. Pharmacologic management

^a: ACOS - Asthma-COPD Overlap Phenotype;

^b: 4MG - 4-meter gait speed;

^c: TUGT - Time up-and-go test;

^d: PHQ-2 - Patient health questionnaire-2;

^e: GAD-2 - Generalized anxiety disorder-2

Abbreviations

COPD

Chronic obstructive pulmonary disease

FEV1

Forced expiratory volume in the 1^st second

GOLD

The Global Initiative for Chronic Obstructive Lung Disease

LVRS

Lung volume reduction surgery