Copd phenotypes

Copd phenotypes

1. COPD PHENOTYPES DR ANUSHA CM

2. 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.

3. 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.

4. 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

5. 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

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

7. 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 ).

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.

9. 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

10. 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.

11. 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 Persistent airflow limitation Tobacco smoking Previous asthma or reversibility > 400ml in FEV1

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

13. 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.

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

15. 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

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

17. Recently, Suggested that gastroesophageal reflux disease (GERD) predispose patients to frequent exacerbations. Mechanisms : alterations in the swallowing reflux and microaspiration M. Miravitlles et al. / Arch Bronconeumol. 2012;48(3):86–98

18. 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.

19. 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.

20. 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.

21. 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.

22. 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.

23. 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

24. 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

25. 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.

26. 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 Janssen, R., Piscaer, I., Franssen, F. M., & Wouters, E. F. (2019). Emphysema: looking beyond alpha-1 antitrypsin deficiency. Expert Review of Respiratory Medicine.

27. 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 Janssen, R., Piscaer, I., Franssen, F. M., & Wouters, E. F. (2019). Emphysema: looking beyond alpha-1 antitrypsin deficiency. Expert Review of Respiratory Medicine.

28. MANAGEMENT Smoking cessation 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., & Wouters , E. F. (2019). Emphysema: looking beyond alpha-1 antitrypsin deficiency. Expert Review of Respiratory Medicine.

29. 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

30. 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

31. 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

32. 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., & Wouters, E. F. (2019). Emphysema: looking beyond alpha-1 antitrypsin deficiency. Expert Review of Respiratory Medicine.

33. 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%

34. 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

35. 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

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

37. RECOMMENDATIONS bronchiectasis and COPD may co-exist as an overlap syndrome (BCOS) 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

38. In patients with primary bronchiectasis, fixed airflow obstruction is best considered one marker of disease severity, identifying patients with a poorer prognosis. The anatomical airway abnormalities of bronchiectasis in patients with primary COPD are best considered a phenotype of the COPD disease spectrum 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

39. 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%.

40. 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

41. 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

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

43. RISK FACTORS Cardiovascular disease Lung cancer Nutritional anomalies, anxiety/depression and metabolic pathologies Osteoporosis Metabolic and psychological comorbidities Depression and/or anxiety Lower BMI Metabolic syndrome and/or type 2 diabetes

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

45. 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

46. 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.

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

48. 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.

49. 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.