Update on heterogeneity of COPD, evaluation of COPD severity and exacerbation

Update on heterogeneity of COPD, evaluation of COPD severity and exacerbation Yung-Yang Liu, MD Taipei Veterans General Hospital Aug 29, 2015

G O lobal Initiative for Chronic bstructive L D ung isease

Description of Levels of Evidence Evidence Category A B C D Sources of Evidence Randomized controlled trials (RCTs). Rich body of data Randomized controlled trials (RCTs). Limited body of data Nonrandomized trials Observational studies. Panel consensus judgment

Definition of COPD COPD, a common preventable and treatable disease, is characterized by persistent airflow limitation that is usually progressive and associated with an enhanced chronic inflammatory response in the airways and the lung to noxious particles or gases. Exacerbations and comorbidities contribute to the overall severity in individual patients.

Mechanisms Underlying Airflow Limitation in COPD Small Airways Disease Airway inflammation Airway fibrosis, luminal plugs Increased airway resistance Parenchymal Destruction Loss of alveolar attachments Decrease of elastic recoil AIRFLOW LIMITATION

Heterogeneity of COPD - Genetic Phenotypes - Although smoking is the major risk factor for the development of COPD, the development of airflow obstruction in smokers is highly variable. Severe 1 antitrypsin deficiency is a proven genetic risk factor for COPD. - Familial aggregation of airflow obstruction within families of COPD patients has also been demonstrated. - A recent association study comprising 8300 patients and 7 separate cohorts found that a minor allele SNP of MMP12 (rs2276109) associated with decreased MMP-12 expression has a positive effect on lung function in children with asthma and in adult smokers. - Recent genome-wide association studies have identified several COPD loci, including a region near the hedgehog interacting protein (HHIP) gene on chromosome 4 and a cluster of genes on chromosome 15 that likely contain COPD susceptibility determinants. - Barreiro E. Update in Chronic Obstructive Pulmonary Disease 2013. Am J Respir Crit Care Med 2014;189:1337-44.

Heterogeneity of COPD - Allergy Phenotypes: - In the National Health and Nutrition Survey III (NHANES III), individuals with an allergic phenotype were more likely to wheeze and have chronic cough and phlegm and increased risk of exacerbations. - In the COPD and Domestic Endotoxin (CODE) cohort, sensitized subjects reported more wheeze, coughinduced nocturnal awakenings and exacerbations and acute health visits. - Active allergic symptoms may worsen the course of COPD. - Allergen avoidance or pharmacologic treatment of allergic disease is warranted in specific subjects with COPD. - Barreiro E. Update in Chronic Obstructive Pulmonary Disease 2013. Am J Respir Crit Care Med 2014;189:1337-44.

Heterogeneity of COPD

Heterogeneity of COPD - Clinical Phenotypes COPD: clinical phenotypes

Heterogeneity of COPD - Clinical Phenotypes - Soriano JB. Chest. 2003;124(2):474-481. Non-proportional Venn diagram of COPD showing subsets of patients with chronic bronchitis, emphysema, and asthma. The subsets comprising COPD are shaded. Patients with asthma whose airflow obstruction is completely reversible (9) are not considered to have COPD. Patients with unremitting asthma are classified as having COPD (6, 7, and 8). Chronic bronchitis and emphysema with airflow obstruction usually occur together (5), and some patients may have asthma associated with these two disorders (8).

Heterogeneity of COPD - Clinical Phenotypes - Soriano JB. Chest. 2003;124(2):474-481. Those with asthma, exposed to cigarette smoke, may develop chronic productive cough, which is a feature of chronic bronchitis (6). Such patients often are referred as having asthmatic bronchitis or the asthmatic form of COPD. Persons with chronic bronchitis and/or emphysema without airflow obstruction (1, 2, and 11) are not classified as having COPD. Patients with airway obstruction due to diseases with other specific pathology, e.g., cystic fibrosis or obliterative bronchiolitis (10), are not included in this definition.

Type 1 Type 2 Type 3 COPD-asthma: 12.1% CB: 44.7% E: 43.2%

Heterogeneity of COPD FEV1 (forced expiratory volume in 1 sec) is the hallmark of COPD because it is affected by inflammation and remodeling of the small airways as well as by emphysematous destruction of the terminal airspaces; however, defining a disease as COPD so heterogeneous exclusively based on the patient s FEV1 may not always be adequate.. - Coxson HO. Using Pulmonary Imaging to Move COPD Beyond FEV1. Am J Respir Crit Care Med 2014 May 29.

Heterogeneity of COPD COPD is a diverse disease with many clinical, radiological, and genomic features that may designate several different phenotypes that may have prognostic as well as therapeutic implications. Chest CT uses lung structure to characterize the COPD population into emphysema or airwaypredominant phenotypes that may provide keen insight into disease progression and response to therapy.. - Barreiro E. Update in Chronic Obstructive Pulmonary Disease 2013. Am J Respir Crit Care Med 2014;189:1337-44.

Heterogeneity of COPD Radiological phenotypes: Emphysema-predominant and airway-predominant E A M - Pistolesi M. Identification of a predominant COPD phenotype in clinical practice. Respir Med. 2008;102(3):367-76.

Heterogeneity of COPD

Heterogeneity of COPD - Stable moderate-to-severe COPD patients A : absence or with little emphysema but with or without bronchial wall thickening (BWT); E : emphysema without BWT; M : mixed type, emphysema with BWT - Kitaguchi Y. Characteristics of COPD phenotypes classified according to the findings of HRCT. Respir Med. 2006;100(10):1742-52.

Heterogeneity of COPD - Kitaguchi Y. Characteristics of COPD phenotypes classified according to the findings of HRCT. Respir Med. 2006;100(10):1742-52.

Heterogeneity of COPD

Heterogeneity of COPD

Heterogeneity of COPD The A type showed a higher prevalence of non-smoker and patients with wheezing both on exertion and at rest, higher values of DL CO, milder lung hyperinflation, and greater reversibility of airflow obstruction responsive to inhaled 2- agonist as compared with the E phenotype. The E type showed a significantly lower preference of BMI, declined DL CO, and poor response to inhaled 2-agnoist among three groups. The M type showed a higher prevalence of patients complaining of large amounts of sputum, productive cough and wheezing not only on exertion but also at rest, higher rate of acute exacerbation or hospitalization and greater reversibility of airflow obstruction responsive to inhaled 2-agnoist as compared with the E phenotype. - Kitaguchi Y. Characteristics of COPD phenotypes classified according to the findings of HRCT. Respir Med. 2006;100(10):1742-52.

Heterogeneity of COPD The degree of emphysema was significantly associated with Brinkman (smoking) index, lower BMI, a decrease in DL CO, lower FEV1/FVC values. The presence of bronchial wall thickening in A - and M - phenotype was significantly associated with reversibility responsive to treatment with inhaled corticosteroid and sputum eosinophilia. These findings indicated that the morphological phenotypes of COPD classified according to dominancy of emphysema and the presence of BWT showed several clinical characteristics and different bronchodilator responses. - Kitaguchi Y. Characteristics of COPD phenotypes classified according to the findings of HRCT. Respir Med. 2006;100(10):1742-52.

Heterogeneity of COPD COPD with E: - More severe PFT - More airway inflammation - Serious systemic dysfunction COPD with BE - Probable pathogenic bacterial culture - AE/year - Mortality COPD with BWT - Correlate with reversibility to BD - Bafadhel M. The role of CT scanning in multidimensional phenotyping of COPD. Chest. 2011;140(3):634-42.

Global Strategy for Diagnosis, Management and Prevention of COPD, 2014: Chapters Definition and Overview Diagnosis and Assessment Therapeutic Options Manage Stable COPD Manage Exacerbations Manage Comorbidities Updated 2014 Asthma COPD Overlap Syndrome (ACOS)

Diagnosis and Assessment: Key Points A clinical diagnosis of COPD should be considered in any patient who has dyspnea, chronic cough or sputum production, and a history of exposure to risk factors for the disease. Spirometry is required to make the diagnosis; the presence of a post-bronchodilator FEV 1 /FVC < 0.70 confirms the presence of persistent airflow limitation and thus of COPD.

Diagnosis and Assessment: Key Points The goals of COPD assessment are to determine the severity of the disease, including (1) the severity of airflow limitation, (2) the impact on the patient s health status, and (3) the risk of future exacerbations, in order to guide therapy. The risk of future exacerbations: estimated by the severity of airflow limitation and the history of previous exacerbations. Comorbidities occur frequently in COPD patients, and should be actively looked for and treated appropriately if present.

Diagnosis of COPD SYMPTOMS shortness of breath chronic cough sputum EXPOSURE TO RISK FACTORS tobacco occupation indoor/outdoor pollution SPIROMETRY: Required to establish diagnosis

Assessment of Airflow Limitation: Spirometry Spirometry should be performed after the administration of an adequate dose of a shortacting inhaled bronchodilator to minimize variability. A post-bronchodilator FEV 1 /FVC < 0.70 confirms the presence of airflow limitation. Where possible, values should be compared to age-related normal values to avoid overdiagnosis of COPD in the elderly.

Spirometry: Normal Trace Showing FEV 1 and FVC 5 FVC Volume, liters 4 3 2 1 FEV 1 = 4L FVC = 5L FEV 1 /FVC = 0.8 1 2 3 4 5 6 Time, sec

Spirometry: Obstructive Disease 5 Normal 4 Volume, liters 3 2 1 FEV 1 = 1.8L FVC = 3.2L FEV 1 /FVC = 0.56 Obstructive 1 2 3 4 5 6 Time, seconds

Assessment of COPD: Goals Determine the severity of the disease, its impact on the patient s health status and the risk of future events (for example exacerbations) to guide therapy. Consider the following aspects of the disease separately: current level of patient s symptoms severity of the spirometric abnormality frequency of exacerbations presence of comorbidities. S-S-E-C

Assessment of COPD Assess symptoms Assess degree of airflow limitation using spirometry Assess risk of exacerbations Assess comorbidities

Symptoms of COPD The characteristic symptoms of COPD are chronic and progressive dyspnea, cough, and sputum production that can be variable from day-to-day. Dyspnea: Progressive, persistent and characteristically worse with exercise. Chronic cough: May be intermittent and may be unproductive. Chronic sputum production: COPD patients commonly cough up sputum.

Assessment of COPD Assess symptoms: Assess degree of airflow limitation using spirometry COPD Assessment Test (CAT) Assess risk of exacerbations Assess comorbidities or Clinical COPD Questionnaire (CCQ) or mmrc Breathlessness scale

Assessment of Symptoms COPD Assessment Test (CAT): An 8-item measure of health status impairment in COPD (http://catestonline.org). Clinical COPD Questionnaire (CCQ): Selfadministered questionnaire developed to measure clinical control in patients with COPD (http://www.ccq.nl).

The equivalent cutpoint for the CAT is 10

CCQ questionnaire Calculation of scores: CCQ total score = (item 1 + 2 + 3 + 4 + 5 + 6 + 7 + 8 + 9 + 10)/10; Symptom = (item 1 + 2 + 5 + 6)/4; Functional state = (item 7 + 8 + 9 + 10)/4; Mental state = (item 3 + 4)/2. The equivalent cutpoint for the CCQ is 1.0 1.5

Assessment of Symptoms Breathlessness Measurement using the Modified British Medical Research Council (mmrc) Questionnaire: - relates well to other measures of health status and predicts future mortality risk.

Modified MRC (mmrc) Questionnaire Less breathlessness More breathlessness

Assessment of COPD Assess symptoms Assess degree of airflow limitation using spirometry Assess risk of exacerbations Use spirometry for grading severity Assess comorbidities according to spirometry, using four grades split at 80%, 50% and 30% of predicted value

Classification of Severity of Airflow Limitation in COPD* In patients with FEV 1 /FVC < 0.70: GOLD 1: Mild GOLD 2: Moderate GOLD 3: Severe FEV 1 > 80% predicted 50% < FEV 1 < 80% predicted 30% < FEV 1 < 50% predicted GOLD 4: Very Severe FEV 1 < 30% predicted *Based on Post-Bronchodilator FEV 1

- Jones PW. Health status and the spiral of decline. COPD 2009;6(1):59-63.

Assessment of COPD Assess symptoms Assess degree of airflow limitation using spirometry Assess risk of exacerbations Assess comorbidities An exacerbation of COPD is defined as an acute event characterized by a worsening of the patient s respiratory symptoms that is beyond normal day-to-day variations and leads to a change in medication.

Assess Risk of Exacerbations To assess risk of exacerbations use history of exacerbations and spirometry: Two or more exacerbations within the last year or an FEV 1 < 50 % of predicted value are indicators of high risk. One or more hospitalizations for COPD exacerbation should be considered high risk.

Exacerbations increase the decline in lung function, deterioration in health status and risk of death, the assessment of exacerbation risk can also be seen as an assessment of the risk of poor outcomes in general.

Combined Assessment of COPD Assess symptoms Assess degree of airflow limitation using spirometry Assess risk of exacerbations Combine these assessments for the purpose of improving management of COPD

Risk (GOLD Classification of Airflow Limitation)) Risk (Exacerbation history) Global Strategy for Diagnosis, Management and Prevention of COPD Combined Assessment of COPD 4 3 (C) (D) 2 or > 1 leading to hospital admission 2 1 (A) (B) CAT < 10 CAT > 10 Symptoms mmrc 0 1 mmrc > 2 Breathlessness 1 (not leading to hospital admission) 0

Combined Assessment of COPD Assess symptoms first (C) (A) (D) (B) If CAT < 10 or mmrc 0-1: Less Symptoms/breathlessness (A or C) If CAT > 10 or mmrc > 2: More Symptoms/breathlessness (B or D) CAT < 10 CAT > 10 Symptoms mmrc 0 1 mmrc > 2 Breathlessness

Risk (GOLD Classification of Airflow Limitation) Risk (Exacerbation history) Global Strategy for Diagnosis, Management and Prevention of COPD Combined Assessment of COPD Assess risk of exacerbations next 4 3 (C) (D) 2 or > 1 leading to hospital admission If GOLD 3 or 4 or 2 exacerbations per year or > 1 leading to hospital admission: High Risk (C or D) 2 1 (A) (B) CAT < 10 CAT > 10 1 (not leading to hospital admission) 0 If GOLD 1 or 2 and only 0 or 1 exacerbations per year (not leading to hospital admission): Low Risk (A or B) Symptoms mmrc 0 1 mmrc > 2 Breathlessness

Risk (GOLD Classification of Airflow Limitation)) Risk (Exacerbation history) Global Strategy for Diagnosis, Management and Prevention of COPD Combined Assessment of COPD 4 3 (C) (D) 2 or > 1 leading to hospital admission 2 1 (A) (B) CAT < 10 CAT > 10 Symptoms mmrc 0 1 mmrc > 2 Breathlessness 1 (not leading to hospital admission) 0 When assessing risk, choose the highest risk according to GOLD spirometric grade or exacerbation history. history.

Global Strategy for Diagnosis, Management and Prevention of COPD Combined Assessment of COPD When assessing risk, choose the highest risk according to GOLD grade or exacerbation history. (One or more hospitalizations for COPD exacerbations should be considered high risk) Patient Characteristic Spirometric Classification Exacerbations per year CAT mmrc A B C D Low Risk Less Symptoms Low Risk More Symptoms High Risk Less Symptoms High Risk More Symptoms GOLD 1-2 1 < 10 0-1 GOLD 1-2 1 > 10 > 2 GOLD 3-4 > 2 < 10 0-1 GOLD 3-4 > 2 > 10 > 2

Manage Stable COPD: Pharmacologic Therapy (Medications in each box are mentioned in alphabetical order, and therefore not necessarily in order of preference.) Patient Recommended First Choice Alternative Choice Other Possible Treatments A SAMA prn or SABA prn LAMA or LABA or SABA and SAMA Theophylline B LAMA or LABA LAMA and LABA SABA and/or SAMA Theophylline C ICS + LABA or LAMA LAMA and LABA or LAMA and PDE4-inh. or LABA and PDE4-inh. SABA and/or SAMA Theophylline D ICS + LABA and/or LAMA ICS + LABA and LAMA or ICS+LABA and PDE4-inh. or LAMA and LABA or LAMA and PDE4-inh. Carbocysteine SABA and/or SAMA Theophylline

Patients with symptoms disproportionate to the severity of obstruction (subgroup B) may be at higher risk of death!

Evidence to support this classification system Patients with a high risk of exacerbations tend to be in GOLD categories 3 and 4 (Severe or Very Severe airflow limitation) and can be identified quite reliably from the their own past history. Higher exacerbation rates are associated with faster loss of FEV1, and greater worsening of health status. Hospitalization for a COPD exacerbation is associated with poor prognosis. CAT score 10 are associated with significantly impaired health status.

Assess COPD Comorbidities COPD patients are at increased risk for: Cardiovascular diseases Osteoporosis, skeletal muscle dysfunction Respiratory infections Anxiety and Depression Diabetes, metabolic syndrome Lung cancer Bronchiectasis These comorbid conditions may influence mortality and hospitalizations and should be looked for routinely, and treated appropriately.

Differential Diagnosis: COPD and Asthma COPD Onset in mid-life Symptoms slowly progressive Long smoking history ASTHMA Onset early in life (often childhood) Symptoms vary from day to day Symptoms worse at night/early morning Allergy, rhinitis, and/or eczema also present Family history of asthma

Additional Investigations Imaging. Chest X-ray: Seldom diagnostic but valuable to exclude alternative diagnoses and establish presence of significant comorbidities. Computed tomography (CT) of the chest : Might help in D.D. when concomitant diseases exist. Lung Volumes and Diffusing Capacity: Help to characterize severity, but not essential to patient management. Oximetry and Arterial Blood Gases: Pulse oximetry can be used to evaluate a patient s oxygen saturation and need for supplemental oxygen therapy. Alpha-1 Antitrypsin Deficiency Screening: Perform when COPD develops in patients of Caucasian descent under 45 years or with a strong family history of COPD. 2013 Global Initiative for Chronic Obstructive Lung Disease

Additional Investigations Exercise Testing: Objectively measured exercise impairment, assessed by a reduction in self-paced walking distance (such as the 6 min walking test) or during incremental exercise testing in a laboratory, is a powerful indicator of health status impairment and predictor of prognosis. Composite Scores: Several variables (FEV 1, exercise tolerance assessed by walking distance or peak oxygen consumption, weight loss and reduction in the arterial oxygen tension) identify patients at increased risk for mortality. The BODE (BMI, Obstruction, Dyspnea, and Exercise) index is a better predictor of subsequent survival. 2013 Global Initiative for Chronic Obstructive Lung Disease

Consequences Of COPD Exacerbations Negative Impact on Quality of Life Impact on Symptoms and Lung Function Accelerated Lung Function Decline EXACERBATIONS Increased Mortality Increased Socioeconomic Costs

Manage Exacerbations: Assessments Arterial blood gas measurements (in hospital): PaO 2 < 60 mmhg with or without PaCO 2 > 50 mmhg when breathing room air indicates respiratory failure. Chest radiograph: useful to exclude alternative diagnoses. ECG: may aid in the diagnosis of coexisting cardiac problems. Whole blood count: identify polycythemia, anemia or bleeding. Purulent sputum: during an exacerbation: indication to begin empirical antibiotic treatment. Biochemical tests: detect electrolyte disturbances, diabetes, and poor nutrition. Spirometric tests: not recommended during an exacerbation.

Manage Exacerbations: Assessments The best predictor of exacerbations is a history of exacerbations!

Manage Exacerbations: Assessments

Manage Exacerbations: Treatment Options Oxygen: titrate to improve the patient s hypoxemia with a target saturation of 88-92%. Bronchodilators: Short-acting inhaled beta 2 -agonists with or without short-acting anticholinergics are preferred. Systemic Corticosteroids: Shorten recovery time, improve lung function (FEV 1 ) and arterial hypoxemia (PaO 2 ), and reduce the risk of early relapse, treatment failure, and length of hospital stay. A dose of 40 mg prednisone per day for 5 days is recommended.

Manage Exacerbations: Treatment Options Antibiotics should be given to patients with: Three cardinal symptoms: increased dyspnea, increased sputum volume, and increased sputum purulence. Who require mechanical ventilation.

Manage Exacerbations: Indications for Hospital Admission Marked increase in intensity of symptoms Severe underlying COPD Onset of new physical signs Failure of an exacerbation to respond to initial medical management Presence of serious comorbidities Frequent exacerbations Older age Insufficient home support

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