Prof.(Dr.) Pranab Baruwa

1
ICS-Dr. S.N. Tripathy Oration.
"PHENOTYPES IN COPD. WHAT IS NEW?"

• Prof.(Dr.) Pranab Baruwa
• MBBS,DTCD,MD(TBChest Dis.),
• MNAMS(Resp.Med.) Fellow ICS
• Trained in USA as WHO Fellow.
• Formerly
• Prof. Head, Dept. of TB Chest Dis. Gauhati
  Medical College,. Guwahati.
• Principal cum Chief Superintendent, Tezpur
  Medical College, Tezpur.
• Principal cum Chief Superintendent, Assam Medical
  College, Dibrugarh.
• Dean, Faculty of Medicine, Dibrugarh University,
  Dibrugarh.
• President,Indian Chest Society 2010-2011

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PHENOTYPES IN COPD
ICS-Dr. S.N. Tripathy Oration.

• COPD is a preventable and treatable disease
  state characterized by airflow limitation that is
  not fully reversible. It is usually progressive
  and is associated with an abnormal inflammatory
  response of the lung to noxious particles or
  gases.
• Exacerbations and co morbidities contribute to
  the overall severity in individual patients.
• COPD is a leading cause of morbidity and
  mortality globally. It is on the rise.
• On average, 10 of adult worldwide have COPD.

Pawels RA, Buist AS et al Am J Respir Crit Care
Med. 2001. 163 1256-1276 Celli BR, Mac Nee W.
Eur Resp J. 2004.23932-946 Buist AS, Meburnie
MA. et.al. Lancet 2007.370741-750
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PHENOTYPES IN COPD
ICS-Dr. S.N. Tripathy Oration.

• The Predominant risk factor for COPD is cigarette
  smoking.
• The relationship between smoking and COPD is not
  absolute.
• COPD can occur in lifelong non-smokers.
• More than 15 of subjects worldwide who die from
  COPD are non-smokers.
• Less than 30 of subjects with significant
  smoking history develop COPD.
• Several factors influence in the development of
  COPD- inhaled gases particles, Genetics, health
  in early life, Nutrition, Gender, Socio-economic
  status, BMI etc.

Lawlor DA., Ebrahim S.et.al. Thorax
2005,60851-858. Silverman EK. Med. Clin North
Am. 1996,80501-522. A Lakke PL., Scharling H.
et.al. Thorax.200661935-939
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Decline in Lung Function
PHENOTYPES IN COPD
ICS-Dr. S.N. Tripathy Oration.

• In non smokers FEV1 declines at the rate of 20-30
  ml/yr in adult.
• In most smokers FEV1 declines at the rate of
  30-45 ml/yr
• In Susceptible/ COPD persons FEV1 declines at the
  rate of 80-100 ml/yr.

David AL Silverman EK. Respir Res 2001,220-26
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PHENOTYPES IN COPD
ICS-Dr. S.N. Tripathy Oration.

• Response to treatment in different COPD Patient
  is not same.
• Clinical presentation, pathological/ radiological
  findings and even prognosis are different.
• Likely to be a group of heterogeneous disorders

J A Wedzicha Thorax 200055631-632
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PHENOTYPES IN COPD
ICS-Dr. S.N. Tripathy Oration.
How to define prognosis?

• COPD severity measured by forced expiratory
  volume in 1 second (FEV1) alone does not
  recognise pathophysiological abnormalities in
  this heterogeneous condition.
• Several indexes has been developed over the time
  to explain the prognosis of COPD with limited
  benefit
• BODE index(BMI, FEV1, dyspnoea and exercise
  capacity)
• ADO index (age, dyspnoea, FEV1)
• DOSE index (dyspnoea, FEV1, smoking, and
  exacerbation frequency)

Celli BR., Cote CG et.al. N. Engl. J. Med
20043501005-1012 Puhan MA., GarciaAymerich J.
et.al. Lancet 2009374704-711 Jones RC.,
Donalson G.C. et.al. Am J Respir Crit Care
Med.20091801189-1195
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PHENOTYPES IN COPD
ICS-Dr. S.N. Tripathy Oration.

• All patients do not respond equally to all drugs.
  
• The need to identify responders to a particular
  therapeutic intervention is crucial.
• Thus the concept of a clinical phenotype in COPD
  has emerged.
• Phenotyping in COPD is a relatively young
  endeavor as compared to many other fields.
• A MEDLINE search revealed just over 400
  Phenotyping papers published in COPD, compared to
  more than 5000 in breast cancer.

Respiratory Research 200910-41. MeiLan K. Han,
Agusti A. et.al. Am J Respir Crit Care Med.
Med.2010182598-604.
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PHENOTYPES IN COPD
ICS-Dr. S.N. Tripathy Oration.
Evolving concept of phenotype

• Historically, Dornhorst in 1955 for the first
  time described two clinical phenotypes of COPD-
  the classic Blue Bloaters Pink Puffers.

• The classic 'Blue Bloater' was described as a
  younger patient with chronic bronchitis, who
  often presented with congestive right heart
  failure.
• The classic 'Pink Puffer' was an older and
  skeletal muscle-wasting patient who had
  unrelenting, disabling dyspnea and clear evidence
  of emphysema.
• Dornhorst AC Lancet 195511185-1187

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PHENOTYPES IN COPD
ICS-Dr. S.N. Tripathy Oration.
Evolving concept of phenotype

• There are several other diseases where management
  revolves around phenotypes e.g.-
• In Breast cancer, presence of Estrogen
  Progesterone receptors within the tumour
  determines response to therapy.
• In Asthma- cellular phenotypes of asthma
  (Eosinophilic,Neutrophilic pauci granulocytic)
  were use to direct successful application of
  Mepolizumab (anti IL-5) therapy
• In COPD, Roflumilast was initially tried in a
  general COPD patients without much benefit.
  However, a sub population of COPD patients with
  FEV1 lt50 predicted, chronic cough and sputum
  production demonstrated greatest clinical
  response.

Rakha EA,Ellis IO Pathology2009414047 Wenzel
SE.N. Engl.J.Med.200936010261028 Meilan K
Han.Augusti A. et. al. Amer.J. Resp. and
Crit.Care Med.2010182598604.
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PHENOTYPES IN COPD
ICS-Dr. S.N. Tripathy Oration.

• The classic definition of Phenotype is the
  observable structural and functional
  characteristics of an organism determined by its
  genotype and modulated by its environment.
• An international group of experts has defined
  COPD phenotype as 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 treatment, speed of
  progression of the disease or death)

Rice JP., Saccone NL. et.al. Adv. Genet
20014269-76. Han M.K., Augusti A. et. al.
Amer.J. Resp Crit care Med 2010 182 598-604.
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PHENOTYPES IN COPD
ICS-Dr. S.N. Tripathy Oration.

• Han MK et.al. have suggested that clinical
  phenotypes in COPD should-
• Have predictive value
• Be prospectively validated for each of the out
  comes to which they may relate
• Be able to classify patients into distinct
  subgroups that provide prognostic information
  thereby help us to determine the most
  appropriate therapy.

Han M.K., Augusti A. et. al. Amer.J. Resp Crit
care Med 2010 182 598-604.
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PHENOTYPES IN COPD
ICS-Dr. S.N. Tripathy Oration.

• Proportional Venn diagram of OLD in the United
  States (NHANES III surveys from 1988 to 1994) and
  United Kingdom (GPRD 1998) for all ages.

Soriano JB, Davis KJ. et.al. CHEST 2003
124474481
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PHENOTYPES IN COPD
ICS-Dr. S.N. Tripathy Oration.

• Proportional Venn diagram of OLD in the United
  States (NHANES III surveys from 1988 to 1994) and
  United Kingdom (GPRD 1998) for all ages.

Soriano JB, Davis KJ et al.CHEST 2003 124474481
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ICS-Dr. S.N. Tripathy Oration.
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PHENOTYPES IN COPD
ICS-Dr. S.N. Tripathy Oration.
Various studies have identified several clinical
phenotypes in COPD
Casanova C ., Cole C. et al Am. J Resp crit care
med.2005171591-597 Kitagushi Y., Fujimoto k. et
al. Resp. Med. 2006 100 1742-1752 Makita H.
Nasuhara Y. et al. Thorax 200762932-937 Marsh
SE, Travers J. et al Thorax 200863761-767
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PHENOTYPES IN COPD
ICS-Dr. S.N. Tripathy Oration.
Burgel PR. Paillsseur J.I et al. Eur.Resp.Jour.
2010 36531-539. Hurst J.R, Vestbo J. et al.
N.Engl. J. Med. 2010 363 1128-1138. Jo KW, Ra
SW et al. Int. J. Tuber.Lung.Dis.
2010.141481-1488. Garcia Aymerich J., Gomez FP.
et al. Thorax 201166430-437.
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PHENOTYPES IN COPD
ICS-Dr. S.N. Tripathy Oration.
Based on a series of factors, majority of the
studies have identified distinguished 3-5
Phenotypes in COPD.
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ICS-Dr. S.N. Tripathy Oration.
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ICS-Dr. S.N. Tripathy Oration.
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ICS-Dr. S.N. Tripathy Oration.
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ICS-Dr. S.N. Tripathy Oration.

• MeiLan K Han et al stated that phenotype
  classically refers to any observable
  characteristic of an organism, and up until now,
  multiple disease characteristics have been termed
  COPD phenotypes.
• Proposed the following variation on COPD
  definition 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).
• This more focused definition allows for
  classification of patients into distinct
  prognostic and therapeutic subgroups for both
  clinical and research purposes.

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Characteristics of COPD phenotypes
ICS-Dr. S.N. Tripathy Oration.
Classified according to HRCT findings

• A total of 172 patients with stable COPD
  (FEV1lt80) were examined by chest HRCT.
• Emphysematous changes and bronchial wall
  thickening (BWT) were evaluated visually.
• COPD patients were classified into three
  phenotypes absence of emphysema, with little
  emphysema with or without bronchial wall
  thickening (A phenotype), emphysema without
  bronchial wall thickening (E phenotype), and
  emphysema with bronchial wall thickening
  phenotype (M phenotype).
• Morphological phenotypes of COPD show several
  clinical characteristics.
• Different responsiveness to treatment with
  bronchodilators and ICS to different Phenotypes.
  

Fusimoto K., Kitaguchi Y. et.al Respirology
200611731-740
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PHENOTYPES IN COPD
ICS-Dr. S.N. Tripathy Oration.
Garcia Aymerich et.al in the Phenotypic
Characterization and Course of COPD (PAC-COPD)
study recruited 342 patients with COPD at their
1st hospitalization and followed them for 4
years. 3 different COPD Phenotypes were
indentified and prospectively validated Severe
respiratory COPD, Moderate respiratory COPD and
Systemic COPD.
Garcia. Aymerich J., Federico P. et.al Arch.
Bronconeumol 200945(1)4-11. Garcia Aymerich J.,
Gomez F.D. et.al Thorax 2010 doi101136/thx.2010
1544-84.
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PHENOTYPES IN COPD
ICS-Dr. S.N. Tripathy Oration.
Study of COPD Phenotypes by using Principal
Component and cluster analysis.
Burgel et.al defined 4 different clinical
phenotypes, different from GOLD classification.
Patients with comparable airflow limitation
(FEV1) belonged to different phenotypes, had
marked differences in symptoms, co-morbidities
and predicted mortality.
Burgel P.R., Pailaseur J.L. et.al Eur. Respir J.,
201036531-539.
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PHENOTYPES IN COPD
ICS-Dr. S.N. Tripathy Oration.
Proportional classification of COPD Phenotypes

• Marsh et.al defined 3 phenotypic subgroups in a
  study on 96 COPD patients
• 18/96 subjects (19) had classical phenotypes of
  chronic bronchitis and/or emphysema but no
  asthma.
• 53/96 (55) COPD patients asthma was the
  predominant COPD phenotype.
• 25/96 (26) COPD patients had no classical
  asthma, chronic bronchitis or emphysema.

Marsh SE., Travers J. et.al Thorax
200863761-767.
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PHENOTYPES IN COPD
ICS-Dr. S.N. Tripathy Oration.

• According to Marc Miravitlles et.al. among all
  phenotypes described, there are 3 principal
  phenotypes that are associated with distinct
  clinical, prognostic and different therapeutic
  response to currently available therapies.
• Overlap or mixed COPD-asthma phenotype
• (2) Exacerbator phenotype and
• (3) Emphysema hyperinflation phenotype

Miravitlles M. Myriam Calle et.al. Arch
Bronconeumol. 20124886-98.
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PHENOTYPES IN COPD
PHENOTYPES IN COPD
PHENOTYPES IN COPD
ICS-Dr. S.N. Tripathy Oration.
Other Phenotypes
Other Phenotypes

• Other phenotypes have been defined, but these
  have very little clinical significance.
• Fast decliner- a patient who suffers a loss of
  lung function, expressed by FEV1, faster than
  average. To identify this phenotype a strict
  follow-up of the lung function for at least 2
  years is required, no specific treatment has been
  identified for this type of patients.
• Rapid decline in FEV1 is predictive of morbidity,
  mortality and hospitalization rates.

Celli BR., Thomas NE. et.al. Amer J. Respir Crit
Care Med. 2008178331-338. Wise RA. Am J. Med.
20061194-11.
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PHENOTYPES IN COPD
ICS-Dr. S.N. Tripathy Oration.
Other Phenotypes

• Chronic bronchitis phenotypes, defined as cough
  and expectoration for at least 3 months of the
  year for 2 consecutive years. This phenotype is
  usually associated with airway disease, which can
  be visualized with high-resolution computed
  tomography (HRCT).
• Chronic bronchitis can accompany any of the three
  phenotypes.
• COPD patients with chronic bronchitis are
  younger, more commonly men, more likely to be
  current smoker, more symptomatic and have more
  frequent comorbidities.

Am. Thora. Society. Amer J. Respir Crit Care Med.
199515277-121 Victor Kim, Mailan K. Hans et.al.
Chest 2011140626-633.
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PHENOTYPES IN COPD
ICS-Dr. S.N. Tripathy Oration.
Other Phenotypes

• Bronchiectasis phenotypes.
• Martinez-Garcia and Collegues in a series on 91
  Spanish patients with well characterized,
  clinically stable-moderate to severe COPD
  patients have shown 57.6 to have Bronchiectasis
  on HRCT. They were associated with severe airflow
  obstruction, isolation of potentially pathogenic
  micro organism (PPM) from sputum and at least one
  hospitalization for COPD exacerbations in the
  previous year.
• In the East London COPD study 50 of patients
  with COPD had Bronchiectasis.
• 29 of patients with COPD in primary care in U.K.
  were reported to have Bronchiectasis.

Martínez-García MA , Soler-Cataluña JJ, et al
Chest . 2011 140 ( 5 ) 1130 - 1137
. Garcia-aymerich J., Gomez FP. et.al. Thorax
201166432-437 OBrien C, Guest PJ. et.al.
Thorax 200055635-642. Bafadhal M.Umar I. et.al.
chest 2011140634-642
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PHENOTYPES IN COPD
ICS-Dr. S.N. Tripathy Oration.
Other Phenotypes

• A systemic phenotype has also been defined in
  patients who present obesity, cardiovascular
  disease, diabetes or systemic inflammation.
• One special phenotype is emphysema due to alpha-
  1-antitrypsin deficiency, appears early in life,
  particularly in smokers and has a genetic base.

Garcia-aymerich J., Gomez FP. et.al. Thorax
201166432-437 Videl R., Blanco I. et.al. Arch.
Bronconeumol 200642645-659
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PHENOTYPES IN COPD
ICS-Dr. S.N. Tripathy Oration.
MeiLan K. Han., Agusti A. et.al. Am J. Respir
Crit Care Med 2010182598-604
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ICS-Dr. S.N. Tripathy Oration.
PHENOTYPES IN COPD
Mixed COPD-Asthma Phenotype

• Patients present with characteristics of more
  than one obstructive airway disease.
• About 13-20 COPD patients reported to have
  overlap phenotypes.
• Increasing trend in elderly population up to 50
  in those aged over 70 years.
• Marsh et.al have reported 55 COPD patients to
  be mixed COPD- Asthma Phenotype.

Hardin M., Silverman E K et.al. Respri, Res.
2011.12127. Soriano J B., Davis K J. et.al.
Chest. 2003124474481. Marsh S.E., Travers J.
et.al Thorax 200863761-767.
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PHENOTYPES IN COPD
PHENOTYPES IN COPD
PHENOTYPES IN COPD
ICS-Dr. S.N. Tripathy Oration.
Definition of the Mixed (COPD-Asthma) Phenotype

• Recently consensus diagnostic criteria for
  Overlap (mixed) phenotype has been defined by a
  group of experts.
• To be diagnosed with an Overlap phenotype a
  patient must fulfil 2 Major criteria or 1 Major
  and 2 Minor criteria among the following.
• A Major criteria very positive bronchodilator
  response (gt 400ml and gt15 FEV1), sputum
  eosinophilia or previous diagnosis of asthma.
• B Minor criteria increased total serum IgE,
  previous history of atopy or positive
  bronchodilator test (gt200ml and gt12 in FEV1) on
  atleast 2 occasions.

Soler-Cataluna J.J., Coslo B. et.al. Consensus
document on overlap asthma-COPD. Phenotype. Arch
Bronconeumol.2012.
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ICS-Dr. S.N. Tripathy Oration.
PHENOTYPES IN COPD
Definition of the Mixed (COPD-Asthma) Phenotype

• The diagnosis of the mixed phenotype will be
  established by the presence of a combination of
  the following factors
• History of asthma and/or atopy,
• Reversibility in the bronchodilator test,
• Notable eosinophilia in respiratory and/or
  peripheral secretions,
• High IgE,
• Positive prick test to pneumoallergens and
• High concentrations of exhaled NO

Papi A, Romagnoli M. et.al. Am J. Respir Crit
Care Med. 20001621773-1777.
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ICS-Dr. S.N. Tripathy Oration.
PHENOTYPES IN COPD
Mixed (COPD-Asthma) Phenotype
Mixed (COPD-Asthma) Phenotype
Differential Treatment
Differential Treatment

• The clinical justification for the mixed
  phenotype lies in its demonstrated sensitivity to
  the anti-inflammatory action of Inhaled
  Corticosteroids.(ICS)
• Treatment with steroid reduces number of sputum
  eosinophils.
• Serum Surfactant Protein D (SP-D) levels
  indicate rensponse to ICS.
• Greater airflow reversibility, a high
  concentration of eosinophils in spontaneous or
  induced sputum or a greater concentration of
  exhaled NO as markers of the response to ICS in
  COPD, even in mild to moderate stages.

Brightling CE., Monteiro W et.al. Lancet
20003561480-1485, Brightling CE., Mckenna S.
et.al. Thorax 200560193-198, Lee J.H., Lee Y.K.
et.al. Resp. Med. 2010104542-549, Fujinoto K.,
Kubo K. Chest 1999115697-702, Sin D.D., Man SFP
et.al. Am J. Respir Crit Care Med.
20081771207-1214.
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PHENOTYPES IN COPD
ICS-Dr. S.N. Tripathy Oration.
Mixed (COPD-Asthma) Phenotype
Differential Treatment

• Based on the clinical, functional and
  inflammatory characteristics of COPD patients.
  i.e. in Mixed phenotypes, (instead of severity of
  airflow obstruction measured FEV1 alone), a high
  dose ICS treatment has been recommended.
• The Canadian Guideline specify that if the
  asthma component in COPD is prominent, earlier
  introduction of ICS may be justified
• The Japanese Guideline dedicates a chapter to
  treatment of COPD complicated by Asthma.
• The Spanish Guideline of COPD direct treatment
  according to phenotypes.

Anderson D., MacNee W. Int. J. COPD.20094321-335
Miravitlles M. Arch. Bronconeumol.
2009.4527-34. ODonnel DE., Aaron S. et.al.
Can. Respir. J. 200714(suppl B) 5-32. Nagi A.,
Aizawa H. et.al. 2009http/www/s.orjp.
Miravitlles M., Calle M., et.al. Arch.
Bronconeumol. 20124886-98.
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ICS-Dr. S.N. Tripathy Oration.
PHENOTYPES IN COPD
Exacerbator Phenotype

• Exacerbators are defined as those COPD patients
  who present with 2 or more exacerbations per
  year.
• These exacerbations should be separated by at
  least 4 weeks after the end of treatment of the
  previous exacerbation or 6 weeks after the onset
  of the exacerbation in cases that have received
  no treatment.
• Exacerbator phenotype of COPD is independent of
  disease severity.
• Estimation of Serum Amyloid-A (SAA) is a better
  marker for diagonosis of exacerbations.

Soler-cataluna J.J., Rodriguez R.R. COPD
20107276-284. Bozinovski S., Hutchinson A.
et.al. Am J. Respir Cirt Care Med.
2008177269-278. Shahab L., Jarvis M.J. et.al.
Thorax 2006611043-1047. Seemungal T., Harper
O.R. et.al. Am J. Respir Cirt Care
Med.20011641618-1623. Hurst J.R., Vestbo J.
et.al. N. Engl J. Med.20103631128-1138.
38
ICS-Dr. S.N. Tripathy Oration.

• Hurst et al analyzed the frequency and
  associations of exacerbation in 2138 patients
  enrolled in the Evaluation of COPD Longitudinally
  to Identify Predictive Surrogate Endpoints
  (ECLIPSE) study.
• Results
• Exacerbations became more frequent (and more
  severe) as the severity of COPD increased.
• 22 of patients with stage 2 disease, 33 with
  stage 3, and 47 with stage 4 had frequent
  exacerbations.
• The single best predictor of exacerbations,
  across all GOLD stages, was a history of
  exacerbations.
• phenotype was also associated with a history of
  gastroesophageal reflux or heartburn, poorer
  quality of life, and elevated white-cell count.

N Engl J Med 20103631128-1138.
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PHENOTYPES IN COPD
ICS-Dr. S.N. Tripathy Oration.
Exacerbator Phenotype

• RISK FACTORS ASSOCIATED WITH REPEATED
  EXACERBATIONS.
• Older age
• COPD severity
• History of previous exacerbations
• Inflammation
• Bacterial load (stable phase)
• Chronic bronchial hypersecretion
• Comorbidity/extrapulmonary manifestations

Greater baseline dyspnea Low FEV1
Low Pao2
Greater airway inflammation Greater
systemic inflammation
Cardiovascular Anxiety-depression
Myopathy Reflux disease
M. Miravitlles., Moiriam C. et.al. Arch.
Bronconeumo. 20124886-98
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PHENOTYPES IN COPD
ICS-Dr. S.N. Tripathy Oration.
Exacerbator Phenotype
Differential Treatment

• Long-acting bronchodilators (LABA), have been
  shown to reduce the frequency of exacerbations
• ICS in patients who present frequent
  exacerbations, especially when associated with
  bronchodilators, produces a significant reduction
  in the number of exacerbations and an improvement
  in HRQL.
• Tiotropium has been shown to reduce exacerbation
  rates, improve quality of life and increases
  FEV1.

Vogelmeier C., Hederer B. et.al. N. Engl. J. Med
20113641093-1103. Kardos P., Wencker M et.al.
Am J. Respir Crit Care Med 2007175144-149.
Wedzicha JA., Calverley PMA el.al. Am J. Respir
Crit Care Med 200817719-26.
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PHENOTYPES IN COPD
PHENOTYPES IN COPD
PHENOTYPES IN COPD
PHENOTYPES IN COPD
PHENOTYPES IN COPD
ICS-Dr. S.N. Tripathy Oration.
Exacerbator Phenotype
Differential Treatment

• Roflumilast is a new oral anti-inflammatory drug
  that acts by selectively inhibiting
  phosphodiesterase IV has been approved for
  preventing exacerbations in patients with severe
  COPD with FEV1lt50 with cough and chronic
  expectoration and frequent exacerbations.
• Roflumilast is indicated for the exacerbator
  phenotype with chronic bronchitis.
• Macrolides may be administered for a prolonged
  time, as they have anti-inflammatory and
  immunomodulatory actions in addition to their
  possible antibacterial action.

Calverley PMA., Sanchez-Toril F. et.al. Am J.
Respir Crit Care Med 2007176154-161. Fabbri LM,
Calverley PMA. et.al. Lancet 2009374695-703.
Sevilla-Sanchez D, Soy-Muner D. et.al. Arch.
Bronconeumol.201046244-254.
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PHENOTYPES IN COPD
PHENOTYPES IN COPD
PHENOTYPES IN COPD
PHENOTYPES IN COPD
PHENOTYPES IN COPD
ICS-Dr. S.N. Tripathy Oration.
Exacerbator Phenotype
Differential Treatment

• PULSE (Pulsed moxifloxacin Usage and its
  Long-term impact on the reduction of Subsequent
  Exacerbation) study, studied the efficacy of 5
  days cycles of 400mg of Moxifloxacin every 8
  weeks in patients with stable COPD.
• This treatment reduced the risk for exacerbation
  by 20 in the intention-to-treat (ITT) analysis,
  25 in the per-protocol (PP) analysis and 45 in
  patients who presented purulent or mucopurulent
  sputum, without a significant increase in
  bacterial resistances.
• Administration of Nebulized Tobramycin in Severe
  COPD colonized by Pseudomonas aerugenosa reduced
  No. of severe exacerbation by 42.

Sethr S., Jones PW., et.al. Respir Res
20101110. Dal Negro R., Micheletto C. et.al.
Adv. Ther. 2008251019-1030.
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PHENOTYPES IN COPD
ICS-Dr. S.N. Tripathy Oration.
Definition of Emphysema-Hyperinflation Phenotype
COPD patients who present dypnoea and intolerance
to exercise as the predominating symptoms. They
are characterized by presence of functional data
of hyperinflation, Emphysema on HRCT study,
variability of the Carbon Monoxide (CO) diffusing
capacity(DLCO), tendency towards a lower BMI.
Miravitlles M. et.al. Arch Bronconeumol
20124886-98.
Grydeland TB., Thorsen et.al. Respir Med.
2011105343-351.
Mair G. Maclay J. et.al. Respir Med
20101041683-1690.
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PHENOTYPES IN COPD
ICS-Dr. S.N. Tripathy Oration.
Diagnosis of Emphysema-Hyperinflation Phenotype

• HRCT.
• FEV1 is strongly related to COPD severity.
• FEV1 Predicted is weakly related to the extent
  of emphysema.
• Reduction in DLCO is more strongly correlated
  with the severity of emphysema as assessed by
  HRCT.

Hoidal JR., Eur Respir J. 2001 18741-743, Baldi
S. Miniati M. et.al. Am. J. Respir Crit Care Med
2001164585-589.
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PHENOTYPES IN COPD
PHENOTYPES IN COPD
ICS-Dr. S.N. Tripathy Oration.
Differential Treatment of Emphysema-Hyperinflation
Phenotype

• Several studies have demonstrated improvements in
  forced vital capacity (FVC) after administration
  of long acting bronchodilator (LABA), with
  improvement in Inspiratory Capacity and reduction
  in air trapping with no significant improvements
  in FEV1.
• This improvement in the volume (FVC) without
  changes in airflow(FEV1) is more frequent as the
  bronchial obstruction becomes more severe.

Newton MF., ODonnell DE et.al. Chest
20021211042-1050, Tashkin DP, Celli B et.al. Am
J. Respir Crit Care Med 2008177164-169.
46
PHENOTYPES IN COPD
ICS-Dr. S.N. Tripathy Oration.
Differential Treatment of Emphysema-Hyperinflation
Phenotype

• NETT study also did not demonstrate the
  superiority of surgical intervention versus
  conservative treatment, however, in patients with
  emphysema in the upper lobes and low exercise
  capacity, a significant reduction in mortality
  was achieved after lung volume reduction surgery
  (LVRS).
• In addition, the improvement in lung function
  after surgery was accompanied by a significant
  reduction in the number of exacerbations and
  prolonged period of exacerbation-free life.

Martinez FJ., Foster G. et.al. Am J. Respir Crit
Care Med 20061731326-1334. Washko GR., Fan VS
et.al. Am J. Respir Crit Care Med
2008177164-169.
47
PHENOTYPES IN COPD
ICS-Dr. S.N. Tripathy Oration.
Differential Treatment of Emphysema-Hyperinflation
Phenotype

• Long-acting bronchodilators (LABA) are the
  Principal drug for treatment.
• They improve symptoms and exercise capacity and,
  consequently, improve the state of health
• Benefits reached at the clinical level do not
  translate into an improvement of the degree of
  obstruction (changes in FEV1) with improvements
  in degree of dyspnea and exercise tolerance.
• Tiotropium has been shown to improve quality of
  life and degree of dyspnoea.

Tashkin DP., Cooper CB. Chest 2004125249-259. O
Donnell FT., Gerken F. et.al. Eur Respir J.
200423832-840
48
PHENOTYPES IN COPD
ICS-Dr. S.N. Tripathy Oration.
Differential Treatment of Emphysema-Hyperinflation
Phenotype

• Anti-inflammatory treatment with inhaled
  corticosteroids(ICS), has not been shown to be as
  effective as in other phenotypes.
• Oral anti-inflammatory Roflumilast did not offer
  good results for reduction of exacerbations.

Lee JH., Lee YK et.al. Respir Med
2010104542-549. Rennard SI., Calverley PMA.
et.al. Respir Res 201112-18.
49
PHENOTYPES IN COPD
ICS-Dr. S.N. Tripathy Oration.
Differential Treatment of Emphysema-Hyperinflation
Phenotype

• Patients with an emphysema-hyperinflation
  phenotype could benefit more from a double
  bronchodilator therapy -- Formoterol and
  Tiotropium, Fluticasone-Salmeterol combination.
• They are benefitted more from respiratory
  rehabilitation due to its beneficial effects on
  dyspnea and exercise tolerance.

Rabe KF., Timmer W. et.al. Chest
2008134255-262, Casaburi R, Zuwallack R.N. Eng.
J. Med 20093601329-1335.
50
PHENOTYPES IN COPD
ICS-Dr. S.N. Tripathy Oration.
SUMMARY

• COPD is a leading cause of morbidity and
  mortality Globally.
• It is on the rise.
• FEV1 can not be used in isolation for optimal
  diagnosis, assessment of severity, follow-up and
  response to therapy.
• Significant heterogeneity of clinical
  presentation, disease progression and response to
  different medications exists.
• Phenotypes should be able to classify COPD
  patients into subgroups for determining the
  specific therapy to achieve better clinical
  results.
• Phenotyping in COPD is a relatively young
  endeavor.
• Efforts should be made to bring out International
  consensus statement on phenotypes based
  management of CPOD.

51
ICS-Dr. S.N. Tripathy Oration.
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