Copd phenotypes

INTRODUCTION
• Chronic Obstructive Pulmonary Disease (COPD) is
currently the fourth leading cause of death in the
world but is projected to be the 3rd leading cause
of death by 2020.
• The Global Burden of Disease Study reports a
prevalence of 251 million cases of COPD globally in
2016.
• COPD represents an important public health
challenge that is both preventable and treatable.

• COPD is a major cause of chronic morbidity and
mortality throughout the world; many people
suffer from this disease for years, and die
prematurely from it or its complications.
• Globally, the COPD burden is projected to increase
in coming decades because of continued exposure
to COPD risk factors and aging of the population.

DEFINITION
• GOLD defines , Chronic Obstructive Pulmonary
Disease (COPD) is a common, preventable and
treatable disease that is characterized by persistent
respiratory symptoms and airflow limitation that is
due to airway and/or alveolar abnormalities usually
caused by significant exposure to noxious particles
or gases.
• The most common respiratory symptoms include
dyspnea, cough and/or sputum production

Phenotype definition
• In 2010, Han et al proposed the following definition
of COPD phenotypes:
• “A COPD phenotype is a single or combination of
disease attributes that describe differences
between individuals with COPD as they relate to
clinically meaningful outcomes (symptoms,
exacerbations, response to therapy, rate of disease
progression, or death).”
• In COPD, whereby the underlying genes are mainly
unknown or poorly characterized, phenotype has
become almost synonymous with clinical subgroup.
Clin Chest Med 35 (2014) 1–6

• COPD phenotypes that can help individualize care.
• Chosen based on implications regarding outcomes
and day-to-day management, and not defined by
delineation along anatomic, physiologic, or
pathologic schema
• An overlap between phenotypes is expected and is
likely the natural norm, and inclusion into one
phenotype is not to the exclusion of the others

• Non-proportional Venn diagram of chronic
obstructive pulmonary disease (COPD) produced by
the American Thoracic Society.
• The subsets comprising COPD are shaded.
• Patients with asthma whose airflow obstruction is
completely reversible (subset 9) are not considered
to have COPD, because in many cases it is virtually
impossible to differentiate patients with asthma
whose airflow obstruction does not remit
completely from persons with chronic bronchitis
and emphysema who have partially reversible
airflow obstruction with airway hyperreactivity,
patients with unremitting asthma are classified as
having COPD (subsets 6, 7 and 8).

• Chronic bronchitis and emphysema with airflow
obstruction usually occur together (subset 5), and
some patients may have asthma associated with
these two disorders (subset 8)
• Individuals with asthma who have been exposed to
chronic irritation, as from cigarette smoke, may
develop chronic productive cough, which is a
feature of chronic bronchitis (subset 6).
• Persons with chronic bronchitis and/or emphysema
without airflow obstruction (subsets 1, 2 and 11)
are not classified as having COPD.
• Patients with airway obstruction due to diseases
with known aetiology or specific pathology such as
cystic fibrosis or obliterative bronchiolitis (subset
10) are not included in this definition.

1.ASTHMA-COPD OVERLAP
PHENOTYPE
• Definition : airflow obstruction that is not
completely reversible, accompanied by symptoms
or signs of increased obstruction reversibility.
• Hallmark : coexistence of increased variability of
airflow in a patient with incompletely reversible
airway obstruction.
Mayo Clin Proc. n July 2017;92(7):1104-1112

• Although 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
challenging.

• Diagnosis of the “overlap phenotype COPD-
asthma” be made when 2 major criteria or 1 major
and 2 minor criteria are met.
• Population under study : 12% to 55%.
• The major criteria are
1. Persistent airflow limitation
2. Tobacco smoking
3. Previous asthma or reversibility > 400ml in FEV1

• The minor criteria are
1. High total IgE level and high blood eosinophil
count
2. Personal history of atopy
3. Positive bronchodilator test result (increase in
FEV1 of ≥12% of predicted and ≥ 200 mL) on 2 or
more occasions

• Patients with onset of asthma-COPD overlap after
age 40 years (likely stemming predominantly from
COPD with later onset of asthma like features)
seem to do worse compared with those who have
the onset of asthma-COPD overlap before age 40
(likely stemming from asthma) regarding lung
function decline, health care utilization, and
mortality.

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

2.FREQUENT EXACERBATOR
PHENOTYPE
• Criterion for the frequent exacerbator phenotype is
the occurrence of 2 or more exacerbations per year.
• Population under study : 13% to 47%
• Impact : increased risk of depressive symptoms,
decline in lung function, poorer quality of life,
decreased physical activity, increased health care
utilization, and up to a 3-fold increase in mortality

M. Miravitlles et al. / Arch Bronconeumol.
2012;48(3):86–98

• Recently, Suggested that gastroesophageal reflux
disease (GERD) predispose patients to frequent
exacerbations.
• Mechanisms : alterations in the swallowing reflux
and microaspiration
2012;48(3):86–98

TREATMENT :
• Long-acting inhaled anticholinergics and b-agonists
alone and in combination reduces exacerbation
frequency in COPD with moderate or worse airflow
obstruction.
• Triple combinations of tiotropium-fluticasone-
salmeterol and tiotropium-budesonide-formoterol
effective
• Oral acetylcysteine : reduce the frequency of COPD
exacerbations.
• Macrolides : prevention of exacerbations,
hospitalizations and increase the time between
exacerbations.

• Roflumilast : anti-inflammatory phosphodiesterase
type 4 inhibitor , prevention in a subset of patients
older than 40 years with severe to very severe
COPD, a history of chronic bronchitis, and frequent
exacerbations.

PRACTICAL IMPLICATIONS
• The addition of anti-inflammatory medication
(antibiotics or phosphodiesterase type 4 inhibitors)
and/or acetylcysteine for exacerbation prevention -
a valuable and cost-effective add-on therapy in
patients experiencing 2 or more moderate to
severe exacerbations per year in whom basic
components of COPD management have been
reviewed and are in place.

3.UPPER LOBE- PREDOMINANT
EMPHYSEMA PHENOTYPE
• Anatomic phenotype with strong genetic
underpinnings - potential for notable improvement
with surgical lung volume reduction (LVR)
• Pulmonary emphysema is defined, in
anatomopathologic terms, as the permanent
destruction of the air spaces beyond the terminal
bronchioles.
• Present dyspnea and intolerance to exercise and
accompanied by signs of hyperinflation.
• Have lower BMI.

• The use of double bronchodilator therapy
(formoterol and tiotropium) versus bronchodilator
monotherapy or versus the fluticasone-salmeterol
combination offers an added functional benefit
with reduction of the need for rescue medication,
improvement in the symptoms and quality-of-life
questionnaires.
• LVRS improves ventilation- perfusion mismatch and
cardiopulmonary hemodynamics by reducing dead
space, improving ventilatory mechanics by
decreasing hyperinflation, elastic recoil, and airway
tethering, and increasing respiratory muscle
efficiency.

Clinical Implications
• Surgical LVR considered in patients with severe
symptoms despite maximal therapy and upper lobe
predominant emphysema.
• Good candidates : patients who have advanced
upper lobe predominant emphysema with air
trapping, an FEV1 of less than 45% of predicted,
and a diffusing capacity of the lung for carbon
monoxide of more than 20% of predicted

4. INFREQUENT EXACERBATOR
• Patient experiencing less than two exacerbations
per year.
• Currently no anti-inflammatory treatment indicated
or licensed for infrequent exacerbators, irrespective
of having predominant emphysema or chronic
bronchitis
• Treatment : long-acting bronchodilators, alone or in
combination, and the possible addition of
theophyllines in the more severe cases

5. ALPHA 1 ANTITRYPSIN
DEFECIENCY
• Alpha-1 antitrypsin deficiency (AATD) is a genetic
cause of emphysema, whereas smoking is the most
important risk factor of non-AATD emphysema.
• Emphysema usually starts causing symptoms when
about 20% of the lungs are affected
• Airflow limitation is one of the pathophysiological
reasons for reduced exercise capacity in patients
with emphysema.
Janssen, R., Piscaer, I., Franssen, F. M., &
Wouters, E. F. (2019). Emphysema: looking
beyond alpha-1 antitrypsin deficiency. Expert
Review of Respiratory Medicine.

• The clinically most relevant variants are panlobular
(PLE) and centrilobular emphysema (CLE), also
referred to as panacinar and centriacinar
emphysema
• Cigarette smoking is the single most important risk
factor for CLE, whereas AATD is the most common
cause of PLE.
• Paraseptal emphysema (PSE) is another frequent
variant that associates with lung function
impairment (i.e. reduced FEV1/forced vital capacity
(FVC) ratio and DLCO) and predisposes to
pneumothorax

RISK FACTORS
• The presence of emphysema on CT is strongly
correlated with the incidence of lung cancer.
Emphysema patients have about 3-times higher risk
of pulmonary malignancies than subjects without
emphysema
DIAGNOSIS
• The Fleischner Society proposed to classify disease
severity of CLE on CT as either trace (i.e. < 5%), mild
(0.5-5%), moderate (>5%), or severe

MANAGEMENT
1. Smoking cessation
2. Pharmacotherapy
• GOLD strategy does not make a distinction in the
recommended pharmacological management for
COPD patients with or without emphysema
• The effect of inhalation therapy with budesonide
and formoterol on lung function was assessed in
COPD patients with distinct phenotypes
• FEV1 declined in those with predominant
emphysema, whereas FEV1 improved in non-
emphysematous participants after one year use of
the inhalation corticosteroid/long-acting beta2-
agonist (ICS/LABA) combination. Janssen, R., Piscaer, I., Franssen, F. M., &

• Beneficial effect of triple versus dual inhaled
therapy was neither seen in the emphysema nor
mixed emphysema/bronchitis subgroups.
• Combination therapy of tiotropium/olodaterol
(LAMA/LABA) resulted in more reduction of
hyperinflation than monotherapy with either drug.
• The LAMA/LABA combination
indacaterol/glycopyrronium also had favorable
effects on cardiac function in subjects with COPD
and hyperinflation
• High-dose orally administered roflumilast
ameliorated inflammation and fully prevented
emphysema formation

3. Stem cell therapy
• Future therapy to rebuild destructed lung
parenchyma.
4. Lung volume reduction surgery
• For the removal of emphysematous destroyed
areas in order to reduce over-inflation, and
allowing the remaining less affected lung tissues to
expand and improve function
5. Endobronchial lung volume reduction
• Less invasive methods than LVRS to achieve similar
lung volume reduction with less adverse events.
• Best-studied and most promising techniques are
endobronchial placement of valves and coils

6. AUGMENTATION THERAPY
• Weekly infusions of AAT would raise to normal
plasma and lung epithelial fluid levels of AAT in
AAT-deficient individuals
• Trypsone , Prolastin, Aralast NP, Zemaira and
Glassia - available brands
• Intravenous 60 mg/kg weekly- FDA approved

6. COMBINED PULMONARY FIBROSIS
AND EMPHYSEMA
• Although emphysema and pulmonary fibrosis seem
to be opposite entities, areas of both coexist within
lungs of patients with combined pulmonary fibrosis
and emphysema (CPFE)
• In CPFE, emphysema is located in the upper lobes
and usually precedes the onset of basal fibrosis
• First described as a syndrome by Cottin in 2005
• Characterized by exertional dyspnea, upper-lobe
emphysema and lower-lobe fibrosis, preserved lung
volume and severely diminished capacity of gas
exchange Janssen, R., Piscaer, I., Franssen, F. M., &

• Usually older, male and with a heavy smoking
history.
• Thick-walled cystic lesions (TWCLs) : unique
radiological and pathological feature
• Frequently complicated by pulmonary
hypertension, acute lung injury and lung cancer
and prognosis is poor with a 5-year survival of 35-
80%

TREATMENT:
• Smoking cessation, halts the progression of disease
• Long-term oxygen therapy and take vaccination
against influenza viruses and streptococcus
pneumonia
• Systemic corticosteroids and immunosuppressant
therapy
• Those who have a radiological/pathological feature
of UIP, Cottin et al. recommended the use of N-
acetylcysteine (1.8 g/day) in CPFE
• Perfenidone and Nintedanib – not very effective
• Lung transplantation- final answer

7. COPD- BRONCHIECTASIS
• Share common symptoms of cough with sputum
production and susceptibility to recurrent
exacerbations driven by new or persistent infection;
presenting de novo may therefore result in a
diagnostic challenge.
• Physiological criteria for the diagnosis of COPD and
structural criteria for the diagnosis of
bronchiectasis create the possibility for individual
patients to fulfil both, resulting conceptually in
either co-diagnosis or an overlap syndrome
between the two conditions.
Eur Respir J 2015; 45: 310–313

• The prevalence of this overlap will vary depending
on the respective prevalence of COPD and
bronchiectasis in the population under
consideration.

RECOMMENDATIONS
bronchiectasis and COPD may co-exist as an
overlap syndrome (BCOS)
1. Important to assess whether COPD or
bronchiectasis is the primary diagnosis in
order to guide investigative strategy and
treatment .
In those patients where this is not possible,
investigating both conditions may be
necessary
Eur Respir J 2015; 45: 310–313

2. In patients with primary bronchiectasis, fixed
airflow obstruction is best considered one marker
of disease severity, identifying patients with a
poorer prognosis.
3. The anatomical airway abnormalities of
bronchiectasis in patients with primary COPD are
best considered a phenotype of the COPD disease
spectrum
4. For patients with both diagnoses, who therefore
have a true overlap syndrome, there is the need
to understand more about the condition with
specific regard to epidemiology, natural history
and treatment.
Eur Respir J 2015; 45: 310–313

7. EOSINOPHILIC COPD
• Recent evidence suggests it may be identified by
sputum cytokine profile
• Use of sputum eosinophilia as a guide to the use of
steroids was effective , and systemic eosinophil
counts may also be a useful guide to treating
exacerbations with oral corticosteroid
• Blood eosinophil counts >2% predicted a response
to ICS in several major COPD trials
• Trials suggest that steroids are more beneficial in
this group than in other COPD patients
• Benralizumab, an anti-IL-5 receptor antibody, in
eosinophilic COPD defined as sputum eosinophil
counts > 3%.

8. BIOMASS FUEL COPD
• Common in females, in the developing world
• Airway predominant phenotypes with bronchial
hyperresponsiveness (BHR) being a particular
feature in wood smoke exposure
• Increased prevalence of an overlap between
asthma and COPD
• Systemic and pulmonary inflammation is similar to
cigarette smoke-induced disease with less
emphysema and less rapid FEV1 decline
• Patients decline more slowly if the biomass
exposure is reduced

• It is not clear whether inhaled therapies used for
“usual COPD” are of similar efficacy.
• The presence of BHR ( bronchial hyper
responsiveness) and overlap with asthma suggests
that ICS might be an effective strategy, though no
clinical trials have been reported yet

Assessing severity in COPD
• Studies suggest that, although COPD patients with
more severe airflow limitation suffer more
respiratory symptoms, worse quality of life and
greater comorbidities than those with milder
impairment, lung function alone does not
adequately assess the impact of the disease.
• FEV1 has to be measured since spirometry is
essential for the diagnosis of COPD, to evaluate the
degree of airflow limitation, to monitor disease
progression, and to guide therapy.
2012;48(3):86–98

RISK FACTORS
1. Cardiovascular disease
2. Lung cancer
3. Nutritional anomalies, anxiety/depression and
metabolic pathologies
4. Osteoporosis
5. Metabolic and psychological comorbidities
6. Depression and/or anxiety
7. Lower BMI
8. Metabolic syndrome and/or type 2 diabetes

COPD AND ASTHMA | A.M. TURNER ET AL, Eur
Respir Rev 2015; 24: 283–298

Phenotype-based therapeutic
approach
• The Spanish guideline proposes treatment of COPD
based on four clinical phenotypes and disease
severity.
• Both physiologic measures and patient- reported
outcome questionnaires will help identify these
patient phenotypes and allow for optimal
pharmacological treatment to be implemented

• Any given patient can belong to more than one
clinical phenotype
• Chronic respiratory failure, whose prognosis is
improved by long-term home oxygen therapy in
COPD should not be considered a COPD phenotype
because it is a final functional state common to
many other diseases. It is, however, a marker of
“severity” of the disease
• All phenotypes will benefit from non-
pharmacological measures such as smoking
cessation, influenza and pneumococcal vaccination,
minimum of 150 min/week of moderate to intense
physical activity, and pulmonary rehabilitation
programs.

COPD AND ASTHMA | A.M. TURNER ET AL.,
Eur Respir Rev 2015; 24: 283–298

Conclusion
• The clinical presentation of some clinical
phenotypes may change (for better or worse) over
time due to either the effect of therapy and/or the
natural course of the disease
• Two prevalent diseases can coexist (for instance,
COPD and asthma or COPD and obstructive sleep
apnea
• COPD often results from a combination of genetic
susceptibility, poor lung growth, and an excess loss
of lung function in adulthood.

• No single mechanism can account for the complex
pathology in COPD.
• The clinical presentation is highly heterogeneous,
and therefore the clinical characterization should
be multidimensional and should consider factors
related to disease severity, activity, and impact.
• Several disease phenotypes of COPD that benefit
from specific treatment have been identified.

Copd phenotypes

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