“Pulmonology:What Every Practitioner Should

Know”

Pulmonary Medicine 2014 Year in Review MEAPA 25th Annual Winter CME

ConferenceFebruary 7, 2015

Joel A Wirth, MD, FCCP

Associate Clinical Professor of Medicine

Tufts University School of Medicine

Director, Division of Pulmonary and Critical Care Medicine

Maine Medical Center

Attending Physician, Chest Medicine Associates, South Portland, ME

Disclosures

Clinical Research Grant

Support: ActelionArenaGileadLung LLCReataUnited Therapeutics

Objectives

TO REVIEW & UPDATE

• Airways Disease : COPD

• Interstitial Lung Disease: IPF

• Pulmonary Vascular Disease: PAH

• Lung Cancer: Screening

Airways Disease

COPD Epidemiology

COPD Epidemiology Globally about 10-25% of people have COPD.

Up to 60-85% of people with COPD are undiagnosed (mostly milder cases).

90% related to tobacco smoking. Other causes include: woodstove use, secondhand smoke, air pollution and work exposures to fumes and dusts.

COPD = 4th leading cause of death worldwide. Will rise to 3rd leading cause of death within the next 15 yrs (COPD mortality rising while cardiovascular deaths are falling).

Annual estimated health care costs: $1-5 billion US

Pathophysiology of COPD COPD is characterized by:

Destruction of lung parenchyma with loss of elastic recoil (emphysema)

Inflammatory infiltration of the airway walls (chronic bronchiolitis / bronchitis)

These pathologies coexist/overlap in COPD

Alpha-1 Antitrypsin Deficiency (AAT Deficiency) : found in 1-2% of COPD cases and likely under

diagnosed/recognized

COPD and smoking cessation: Most experience FEV1 declines at the same rate as average

nonsmokers

Diagnosing COPD: GOLD 2014 Guidelines

CONSIDER COPD IN PATIENTS OVER 40 WITH:

Dyspnea: PersistentProgressiveExertional

Chronic Cough: Intermittent or persistentProductive or nonproductive

Chronic Sputum Any formProduction:

Risk Factors: Tobacco smokeSecond hand smokeOccupational dust and chemicals

Family History

Spirometry is essential to

diagnose COPD:

Diagnosing COPD: GOLD 2014 Guidelines

When Post bronchodilator FEV1/FVC < 70%

GOLD CLASS Severity FEV1

GOLD 1 Mild > 80%

GOLD 2 Moderate 50-80%

GOLD 3 Severe 30-50%

GOLD 4 Very Severe < 30%

Modified MRC Breathlessness Scale

Kim et al., BMC Pulmonary Medicine 2013, 13:35

Grade Description

0 I only get breathless with strenuous exercise.

1 I get short of breath when hurrying on level ground or walking up a slight hill.

2

On level ground, I walk slower than people of the same age because of breathlessness, or have to stop for breath when walking at my own pace.

3I stop for breath after walking about 100 yards or after a few minutes on level ground.

4 I am too breathless to leave the house or I am breathless when dressing.

COPD Risk: GOLD Guidelines 2014

Risk Class FEV1AECOPD

RatemMRC

A > 50% 0-1 0-1

B > 50% 0-1 2-4

C < 50% 2+ 0-1

D < 50% 2+ 2-4

• Long-acting bronchodilators (LABA: formoterol, salmeterol) and long-acting anticholinergics (tiotropium) have similar effects:– Increase post-bronchodilator FEV1 (~50-100 mL) – Improvement dyspnea (~3 points on the St. George’s

questionnaire) – Reduce daily short-acting beta-agonist use by ~1 inhalation– Reduce acute exacerbations of COPD (Tiotropium,

Salmeterol, ICS/LABA)– Reduce hospitalizations (Salmeterol, Tiotropium, ICS/LABA,

Combination)

• ICS/LABA combination drugs:– Reduce mortality slightly – NO increased risk of death from pneumonia– Cause osteoporosis in a small number of patients

• Bronchodilators and Cardiovascular Mortality:– LABA agents and Tiotropium are NOT associated with

increased cardiovascular events

Treatments for COPD: 2014 GOLD Guidelines

Treatments for COPD: 2014 GOLD Guidelines

Treatments for COPD: Additional TherapiesRoflumilast and Cilomilast

• Phosphodiesterase-4 Inhibitors

• Role unclear; shown to reduce AECOPD in severe COPD

patients

• “May be used for Chronic Bronchitis” with severely

reduced FEV1 if “not adequately controlled” with

bronchodilators

Azithromycin

• Reduced 27% AECOPD rate in one RCT

• Associated with hearing loss

• Associated with sudden cardiac death in pts with cardiac

disease

COPD Exacerbations• AECOPD: Increased dyspnea, cough, and sputum

production

– Moderate COPD patients average 1 AECOPD annually

– Severe COPD patients average 2 AECOPD annually

• Majority (~80%) of AECOPD caused by infections:

– COMMON (50-60% ): H. influenzae, S. pneumoniae, M.

catarrhalis, rhinovirus, coronavirus, and parainfluenza

– UNCOMMON: Pseudomonas aeruginosa, S. aureus, and

atypical bacteria (Mycoplasma, Chlamydia pneumonia)

• Minority (20%) AECOPD caused by other conditions:

– CHF, systemic infections, PE, CAP, air pollution, allergies,

smoking

Treatment of Acute COPD Exacerbations

1. Increase the dose of SA bronchodilators (albuterol and/or ipratropium)

2. Oral corticosteroids: Prednisone 40 mg po daily x 5 days

3. Antibiotic for one week

4. Oxygen if needed

5. Ventilatory support for respiratory failure if needed

Surgical Interventions for COPD:Lung Volume Reduction

Lung Volume Reduction Surgery (LVRS)

• Should be considered for patients with very severe upper

lobe emphysema and poor exercise capacity after

Pulmonary Rehabilitation

• Results in minor mortality reduction and improved quality

of life

Bronchoscopic Lung Volume Reduction

• Active research area for advanced COPD

• Endobronchial Valves limited by collateral ventilation

• Endobronchial Coils may be a more effective intervention

for some patients

Interstitial Lung Disease

INTERSTITIAL LUNG DISEASES (ILD)

DEFINITION

Interstitial lung diseases are a group of pulmonary disorders characterized clinically by:

1. Radiologic: Diffuse lung infiltrates2. Histologic: Distortion of the alveoli3. Physiologic: Restriction of lung volumes and

impaired oxygenation

DIAGNOSIS OF INTERSTITIAL LUNG DISEASE

The diagnosis of a specific ILD is based on:

1. Patient’s history and physical examination

2. Radiograph

3. Bronchoscopy for Transbronchial Bx & BAL

4. Open lung biopsy (VATS)

6. Biopsy of extrathoracic tissues

Classification of Interstitial Lung Disease (ILD)

R. M. du Bois Nature Reviews Drug Discovery 2010 9:129-140

Idiopathic Interstitial Pneumonias:Different pathologies, different

prognoses

Flaherty et al. Eur Respir J. 2002;19:275-283

IPF Clinical Presentation• Presents in 6th-7th decades of life

• VERY uncommon in pts < 50 yrs old

• Men > women

• Majority have history of cigarette smoking

• U.S. incidence between 6.8 and 16.3 per 100,000

• U.S. prevalence between 14.0 and 42.7 per 100,000

• Usual presentation: chronic exertional dyspnea, cough, bibasilar inspiratory crackles Raghu et al., Am J Respir Crit Care Med 2011; 183:788-24

Idiopathic Pulmonary Fibrosis

• Idiopathic pulmonary fibrosis (IPF) is the most common and lethal diffuse fibrosing lung disease

• IPF mortality rate exceeds that of many

cancers

• MANY clinical trials of novel drugs for IPF

• Results have been mostly disappointing

• The first two drugs with demonstrated efficacy for IPF treatment were approved by the FDA in 2014

R. M. du Bois Nature Reviews Drug Discovery 2010 9:129-140

Diagnosing IPF requires:

• Exclusion of other known causes of interstitial lung disease

• Presence of UIP pattern on HRCT (in patients without surgical biopsy)

• A HRCT pattern of definite/possible UIP with a Surgical lung biopsy showing Definite/Probable UIP

Raghu et al., Am J Respir Crit Care Med 2011; 183:788-24

IPF Diagnosis: HRCT Findings

YES• Subpleural

predominance

• Basilar predominance

• Reticular abnormality

• Honeycombing with/without traction bronchiectasis

NO• Upper lobe

predominance

• Peribronchovascular

• Extensive GGO

• Profuse micronodules

• Discrete cysts

• Diffuse mosaic pattern

• Consolidation

IPF Diagnosis:“Usual Interstitial Pneumonitis”

The Clinical Radiographic and Pathologic Diagnosis of IIP:

Clinical Gold Standard

Multidisciplinary communication

between the clinician, radiologist and

pathologist is essential to an

accurate diagnosis

Therapies Recommended by ATS

• Long-Term Oxygen Therapy

– No direct data in patients with IPF

• Pulmonary rehabilitation

• Treatment of asymptomatic GERD

• Corticosteroids for acute exacerbation

• Lung transplantation

IPF: New Medications (2014)

Pirfenidone Nintedanib

King TE Jr et al. NEJM 2014; 370: 2083-92 Richeldi L et al. NEJM 2014; 370: 2071-82

IPF: Therapies NOT recommended• Corticosteroid monotherapy

• Colchicine• Cyclosporine A• Combined corticosteroid and immune-

modulators• Combined NAC, azathioprine and

prednisone• NAC monotherapy• Anticoagulation• INF γ 1b• Bosentan• Etanercept

www.pulmonaryfibrosis.org

Pulmonary Hypertension

What is the Definition of PH/PAH?

PH

PAHMean PAP ≥25 mm Hg plusPAWP ≤15 mm Hg plusPVR >3 Wood Units

No Lung Disease or CTEPH

Mean PAP ≥25 mm Hg at rest during RHC

Hoeper MM et al. J Am Coll Cardiol. 2013;62:D42-D50.

Epidemiology of PH

All Participants(N=1413)

Overall Log Rank p<0.001

No Cardiopulmonary Disease (N=778)

Overall Log Rank p=0.002

Lam CSP et al. Circulation. 2009;119:2663-2670.

86420

Time (yr)

Cu

mu

lati

ve s

urv

ival

1.00

0.95

0.90

0.85

RVSP quintile1: 15-23 mm Hg2: 24-25 mm Hg3: 26-29 mm Hg4: 30-32 mm Hg*5: 34-66 mm Hg*

86420

Time (yr)

Cu

mu

lati

ve s

urv

ival

RVSP tertile1: 15-24 mm Hg2: 24-28 mm Hg3: 28-43 mm Hg*

1.000

0.975

0.950

0.925

0.900

Up to 20% of the US population has echo evidence of PH

5th World Symposium PH Classification (Nice, France)

1. Pulmonary arterial hypertension1.1 Idiopathic PAH1.2 Heritable PAH

1.2.1 BMPR21.2.2 ALK1, ENG, SMAD9, CAV1, KCNK31.2.3 Unknown

1.3 Drug- and toxin-induced1.4 Associated with

1.4.1 Connective tissue diseases1.4.2 HIV infection1.4.3 Portal hypertension1.4.4 Congenital heart disease (update)1.4.5 Schistosomiasis1.4.6 Chronic hemolytic anemia

1’. Pulmonary veno-occlusive disease and/orpulmonary capillary hemangiomatosis

1’’. PPHN

2. PH due to LHD2.1 LV systolic dysfunction2.2 LV diastolic dysfunction2.3 Valvular disease2.4 Congenital/acquired left heart inflow/outflow obstruction

3. PH due to lung diseases and/or hypoxia 3.1 COPD 3.2 Interstitial lung disease 3.3 Other pulmonary diseases with mixed

restrictiveand obstructive pattern

3.4 Sleep-disordered breathing 3.5 Alveolar hypoventilation disorders 3.6 Chronic exposure to high altitude 3.7 Developmental lung diseases (update)

4. CTEPH

5. PH with unclear multifactorial mechanisms 5.1 Hematological disorders: chronic hemolytic

anemia, myeloproliferative disorders, splenectomy

5.2 Systemic disorders: sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatosis, neurofibromatosis, vasculitis

5.3 Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders

5.4 Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure, segmental PH

Simonneau G et al. JACC 2013;62:D34-41.

Is There a Reason to Suspect PH?Clinical Presentation

History Exam (PH) Exam (RV Failure)• Dyspnea (86%)• Fatigue (27%)• Chest pain (22%)• Edema (22%)• Syncope (17%)• Dizziness (15%)• Cough (14%)• Palpitations

(13%)

• Loud P2 (listen at apex)• RV lift (left parasternal –

fingertips)• RV S3, S4• Systolic murmur (TR;

inspiratory augmentation)• Early systolic click• Midsystolic ejection

murmur• Diastolic murmur (PR)

• JVD; increased A wave, V wave; hepatojugular reflex

• Pulsatile liver• Hepatomegaly• Edema• Ascites• Low BP, low PP, cool

extremities

REVEAL. Brown LM et al. Chest. 2011;140:19-26. Adapted from McLaughlin VV et al. J Am Coll Cardiol. 2009;53:1573-1619.

Normal

Abnormal

RV enlargement into retrosternal clear space

Peripheral hypo-vascularity (pruning)

Prominent centralpulmonary artery

Adapted from McLaughlin VV et al. J Am Coll Cardiol. 2009;53:1573-1619.

Is There a Reason to Suspect PH? CXR

Is There a Reason to Suspect PH? Echo

• RV enlargement• Septal flattening• RA enlargement

• Loss of IVC collapse• Tricuspid regurgitation

• Pericardial effusion

• Reduced RV systolic function

– TAPSE reduced (tricuspid annular plane

systolic excursion)TAPSE 1.5 cmTAPSE 2.5 cm

Preserved RVSystolic function

RV SystolicDysfunction J Am Coll Cardiol. 2009;53:1573-1619

NORMALPULMONARY

HYPERTENSION

Diagnosis of Pulmonary Hypertension

• Identical algorithm for local practitioners and PH specialists

• Requires a thorough evaluation and interpretation of high quality studies

• Goals:–Establish a suspicion of PAH

–Confirm the diagnosis (right heart catheterization)

–Classify the type of PH (Group I-V)

–Determine the disease severity

–Select the appropriate treatment for patients with PAH

McLaughlin VV et al. J Am Coll Cardiol. 2009;53:1573-1619.

Echocardiogram

PFT’s

Polysomnography

VQ Scan

• Sleep Disorder

• Chronic PE

Functional Test(6MWT, CPET)

Overnight Oximetry

History

Exam

CXR

ECG

HIV

ANA

LFT’s

RH Cath

TEE

Exercise Echo

Pulmonary Angiography

Chest CT Angiogram

Coagulopathy Profile

Vasodilator Test

Exercise RH Cath

Volume Loading

ABG’s

• Index of Suspicion of PH

• RVE, RAE, RVSP, RV Function

• Left Heart Disease• VHD, CHD

• Ventilatory Function• Gas Exchange

Other CTD Serologies

• HIV Infection

• Scleroderma, SLE, RA

• Portopulmonary Htn

• Establish Baseline• Prognosis

• Confirmation of PH• Hemodynamic Profile• Vasodilator Response

Pivotal Tests Contingent Tests Contribute to Assessment of:

Left Heart CathMcLaughlin VV et al. J Am Coll Cardiol.2009;53:1573-1619.

AC

CF

/AH

A D

iagn

ostic

Alg

orith

m

PH Treatment Goals

• Improve survival• Improve quality of

life• Improve exercise

capacity – 6MWD– WHO functional

classification• Improve

hemodynamics

• Fewer/less severe symptoms

• Prevent clinical worsening– escalation of

therapy– hospitalization– lung

transplantation– death

• Supervised exercise training (I-A)

• Psycho-social support (I-C)• Avoid strenuous physical

activity (I-C)• Avoid pregnancy (I-C)• Influenza and pneumococcal

immunization (I-C)

• Oral anticoagulants: – IPAH, heritable PAH, and

PAHdue to anorexigens (IIa-C)

– APAH (Ilb-C)• Diuretics (I-C)• Oxygen (I-C)• Digoxin (IIb-C)

Continue CCB

WHO FC I-III CCB (I-C)

Sustained response (WHO FC I-II)

VASOREACTIVE NON-VASOREACTIVE

5th World Symposium on PH:2013 PAH Treatment Algorithm

Galiè N et al. J Am Coll Cardiol. 2013;62:D60-D72.

INITIAL THERAPY WITH PAH-APPROVED DRUGS

YES

NO

Acute vasoreactivity test (I-C for IPAH) (IIb-C for APAH)

Expert Referral (I-C)

General measures and supportive therapy

5th World Symposium on PH:2013 Treatment Algorithm

Galiè N et al. J Am Coll Cardiol. 2013;62:D60-D72.

Sequential CombinationTherapy (I-A)

Referral for Lung Transplantation (I-C)

Consider Eligibility for Lung

Transplantation

Inadequate Clinical Response

on Maximal Therapy

INITIAL THERAPY WITH PAH-APPROVED DRUGS

PDE-5 I or

SGCs

ERAs

Prostanoids

++

+

Balloon Atrial Septostomy (IIa-

C)

Inadequate Clinical Response

INITIAL THERAPY WITH PAH-APPROVED DRUGSLevel of evidence based on WHO-FC of majority of patients of studies

Evidence WHO FC II WHO FC III WHO FC IV

Recommendation

I A or B

•Ambrisentan, Bosentan

•Macitentan•Riociguat•Sildenafil •Tadalafil

•Ambrisentan, Bosentan, Epoprostenol IV

•Iloprost inh•Macitentan•Riociguat•Sildenafil •Tadalafil•Treprostinil SC, inh

•Epoprostenol IV

IIa C

•Iloprost IV*, Treprostinil IV

•Ambrisentan, Bosentan, Iloprost inh and IV*

•Macitentan•Riociguat•Sildenafil, Tadalafil•Treprostinil SC, IV, Inh*

IIb

B •Beraprost*

C•Initial Combination Therapy

•Initial Combination Therapy

5th World Symposium on PH:2013 PAH Treatment Algorithm

Galiè N et al. J Am Coll Cardiol. 2013;62:D60-D72. *Not approved in US.

Measuring PAH Determinants of Risk

McLaughlin VV et al. J Am Coll Cardiol. 2009;53:1573-1619.

LOWER RISK DETERMINANTS OF RISK HIGHER RISK

No Clinical evidence ofRV failure Yes

Gradual Progression of symptoms Rapid

II, III WHO class IV

Longer (>400 m) 6MWD Shorter (<300 m)

Peak VO2 >10.4 mL/kg/min CPET Peak VO2 <10.4 mL/kg/min

Minimal RV dysfunction Echocardiography

Pericardial effusion,significant RV

enlargement/dysfunction; RA enlargement

RAP <10 mm Hg;CI >2.5 L/min/m2 Hemodynamics RAP >20 mm Hg;

CI <2.0 L/min/m2

Minimally elevated BNP Significantly elevated

www.phassociation.org

Lung Cancer

LUNG CANCER AND SMOKING STATISTICS

• About 221,130 people (115,060 men and 106,070 women) were diagnosed with lung cancer in the U.S. in 2011 and 156,940 died.

• 94 million current and former smokers in the U.S.

• Overall smoking prevalence has declined from 20.9% in 2005 to 18.1% in 2012.

• Smoking is estimated to cause 85-90% of all lung cancer deaths.

• Lung cancer is the leading single cancer killer in the U.S.

• It has the highest incidence and mortality of all cancers in Maine.

National Lung Screening Trial

• Randomized controlled trial

• Inclusion criteria: age 55-74; current or

former smoker who quit <15 year with

≥30 pack years

• Low-dose CT screening vs. X-ray screening

among patients at high risk for lung cancer

• Followed for 3 yearsThe National Lung Screening Trial Research Team N Engl J Med 2011; 365:395-409

Efficacy of low-dose CT screening

• Lung cancer-specific mortality was reduced

by 20% (95% CI, 7% to 27%; P=0.004; NNT

= 320)

• All-cause mortality was reduced by 7%

(95% CI, 1% to 14%; P=0.02)

53,464 subjectsCT arm (n=26,722)

CXR arm (n=26,732)

52

NLST Outcomes Favorsscreening

Against screening

Events per 1,000

Death from lung cancer 3 fewer

Death from other causes 1 fewer

False positive screening test result 231 more

Invasive testing for benign disease 16 more

Major complication for benign disease 2 more

Challenges of lung cancer screening

Challenges of lung cancer screening

• Generalizability to community settings

(NLST was performed in center hospitals

and its participants were healthier)

• High false-positive rate

• Long-term effect from radiation

• Lack of insurance coverage

USPSTF Recommendation Statement

• Annual screening for lung cancer with LDCT

in adults aged 55 to 80 years who have a

30 pack year smoking history and currently

smoke or have quit within the past 15 years

is recommended.

• Pre-screening counseling

USPSTF December 2013

MMC Lung Cancer Screening Program• Thoracic Oncology Clinic(TOC)

• Low Dose Chest CT

• Experienced radiologists participating

• Research Support in Shared Decision

Making (CORE)

• No navigator

• Lack of outpatient smoking cessation clinic

NLST vs. Maine (MMC Program)

Demographics　

NLST(%)

MMC(%)

US census survey

(%)

Current smoker (%) 48 52 57

Former smoker (%) 52 48 43

Male(%) 59 56 59

Positive screen (%) 27 16 NA

Questions?jwirth@cmamaine.com