Interstitial Lung Disease & Pulmonary Rehabilitation Jim Allen, M.D.

January 28, 2016

Outline of today’s talk: 1. Overview of interstitial lung disease 2. Idiopathic pulmonary fibrosis 3. Pulmonary rehabilitation in interstitial lung disease 4. Some other interstitial lung diseases you should know about

Interstitial Lung Disease What is it? • Normal alveoli replaced by: - Scar (fibrosis) - Inflammation - Both

• Symptoms: - Cough - Dyspnea

Interstitial Lung Disease What causes it? • About 150 etiologies • Diagnosis requires combination of:

–Clinical presentation –Radiology (high resolution chest CT) –Pathology (sometimes)

• Prognosis and treatment dependent on diagnosis

Interstitial Lung Diseases • • • • • • • • • • • • • • • • • • • 5

Desquamative Interstitial Pneumonitis Lymphocytic Interstitial Pneumonitis Eosinophilic pneumonia Alveolar Proteinosis Amyloidosis Lymphangitic Carcinomatosis Radiation Pneumonitis Langerhan’s Cell Granulomatosis Lymphangioleiomyomatosis Tuberous Sclerosis Neurofibromatosis Hypersensitivity Pneumonitis Sarcoidosis Berylliosis Ankylosing Spondylitis Rheumatoid Arthritis Silicosis Asbestosis Lymphoma

• • • • • • • • • • • • • • • • • • • •

Hemosiderosis



IgG4 disease

Wegener’s Granulomatosis



Hard metal disease

Drug-Induced Fibrosis



Crohn’s disease

Systemic Sclerosis



Ulcerative collitis

Systemic Lupus Erythematosus



Idiopathic inflammatory myopathy

Sjogren’s Syndrome



Familial IPF

Mycobacterial Infection



Hermansky-Pudlak syndrome

Histoplasmosis



Gaucher’s disease

Aspiration



Goodpasture’s syndrome

Lipoid Pneumonia



Nitrofurantoin

Polymyositis



Methotrexate

Mixed Connective Tissue Disease



Amiodarone

Microlithiasis



Talc granulomatosis

Churg-Strauss Syndrome



Siderosis

Pneumocystis carinii



Tannosis

Oxygen Toxicity



Coal worker’s pneumoconiosis

Cryptogenic Organizing Pneumonia



Sulfasalazine

Non-Specific Interstitial Pneumonitis



Minocycline

Usual Interstitial Pneumonitis Bleomycin

Common Identifiable Causes Of Interstitial Lung Disease

• Drugs • Collagen vascular disease • Radiation • Occupations • Hypersensitivity pneumonitis • Smoking (desquamative interstitial pneumonitis) • Talc granulomatosis

Interstitial Lung Diseases Of Unknown Cause:

• Idiopathic pulmonary fibrosis • Sarcoidosis • Cryptogenic organizing pneumonia

Interstitial Lung Disease Clinical Presentation:

• History: - Cough - Dyspnea

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• Physical Exam: - Crackles - Clubbing

Evaluation of interstitial lung disease:

• Chest x-ray • Laboratory tests • High resolution chest CT • Pulmonary function tests • Sometimes bronchoscopy with bronchoalveolar lavage (BAL) • Sometimes lung biopsy

High Resolution Chest CT

• Honeycomb infiltrates never improve with treatment • Ground glass infiltrates may improve with treatment • Ground glass infiltrates may predict response to treatment better than biopsy

Pulmonary Function Tests In Interstitial Lung Disease:

• PFTs:

- Restriction - Low diffusing capacity

• Exercise tests

- Hypoxemia - Reduced maximum -

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oxygen uptake Reduced ventilatory reserve

Case: • 57 y.o. man with dyspnea and cough for 1 year; now activity limiting

• PMHx: hypertension • Meds: HCTZ (diuretic) • SHx: 30 pack year smoking history, quit 10 years ago

12

Case: • Exam: • Lungs with bibasilar dry crackles • Ext with clubbing • PFTs: • FVC 69% predicted • FEV1 72% predicted • TLC 62% predicted • DLCO 53% predicted • 6 Minute walk: Walks 1100 feet with an initial sat of 96% dropping to 79% on room air

Normal chest CT

Case CT scan: subpleural reticular infiltrates

Case CT scan: traction bronchiectasis

16

Case CT scan: basilar honeycomb infiltrates

17

Normal lung alveoli: medium power

Case Lung Biopsy: Collagen deposition Temporal heterogeneity Fibroblastic foci

Idiopathic Pulmonary Fibrosis • Most common ILD of unknown etiology • Mainly affects people > 50 yrs, most are over the age of 60 yrs

• Incidence is estimated at 7.4-10.7 cases per 100,000 per year

• Prevalence of IPF is estimated at 13-20/100,000 • Possible risk factors for developing IPF include cigarette smoking, occupational/environmental exposures

Idiopathic Pulmonary Fibrosis • History/Exam • Gradual onset and progressive dyspnea and/or a nonproductive cough • Bibasilar inspiratory crackles (Velcro crackles) • Clubbing also common • Later in the clinical course, signs of right heart failure and peripheral edema

• PFTs show restriction, low diffusing capacity and desaturation with exertion

What causes IPF?

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#1 Genetic Predisposition • Surfactant proteins C

#2 Epithelial Injury • Dusty environment

• Surfactant protein A2 • TERT • TERC • MUC5B

• Tobacco smoke • Viruses • Acid reflux/aspiration

IPF Treatment: What Works?

• Oxygen • Pulmonary rehabilitation • Anti-fibrotic drugs: - Pirfenidone - Nintedanib

• Lung transplant

Home Oxygen Options

Pulmonary Rehabilitation In Interstitial Lung Disease: 2014 Meta Analysis

• 9 studies met meta analysis criteria

- 3 studies were IPF only - 1 study was sarcoidosis only - 5 studies were a variety of interstitial lung diseases

• Compared pulmonary rehab versus no rehab • Outcomes: - Exercise capacity - Quality of life - Dyspnea

Cochrane Database Syst Rev. 2014 Oct 6

Effect on 6 MWT

• Average increase in distance for all interstitial lung diseases = 44 meters

All patients

IPF only

• Average increase in distance for IPF = 35 meters

Severe lung disease

• Benefit is similar to COPD (48 meters)

Patients who desaturate

Effect on mVO2

• Average increase in mVO2 for all interstitial lung diseases = 1.24 mL/kg/min

All patients

IPF only

• Average increase in mVO2 for IPF = 1.46 mL/kg/min

Severe lung disease

Patients who desaturate

Effect on dyspnea

• Average drop in

All patients

dyspnea for all patients = -0.66

• Average drop in

IPF only

dyspnea for IPF patients = -0.68 Severe lung disease

Patients who desaturate

Effect on quality of life

• Average increase in

All patients

QOL for all patients = 0.59

• Average increase in

IPF only

QOL for IPF patients = 0.59

Severe lung disease

Patients who desaturate

Effect on 6-month survival

• Only 1 study

All patients

addressed this

• Pulmonary rehab had no effect on survival

IPF only

Severe lung disease

Patients who desaturate

Inpatient pulmonary rehab can be effective

It is never too late for pulmonary rehab

Effect of pulmonary rehab and nighttime non-invasive ventilation in patients with hypercapnic interstitial lung disease

The benefit of pulmonary rehab is reduced over time

Holland, et al. Respir Med 2012; 106:429-35

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Nuances of pulmonary rehabilitation in interstitial lung disease

• ILD-specific education often lacking • Purse lipped breathing probably won’t help • Bronchodilators usually won’t help • Must use plenty of oxygen • Exacerbations of ILD may offer opportunity

for inpatient engagement by pulmonary rehab staff • End-of-life and hospice discussions may be important in patients with IPF

Survival after lung transplant for IPF 90% 80% 70% 60% 50%

Single Lung Double Lung

40% 30% 20% 10% 0% 1 Year

5 Year

Nathan et al. J Heart Lung Transplant. 2010;29:1165-71.

Lung transplant contraindications

• Age > 65 (sort of…) • BMI > 30 • Smoking in the past 6 months • Uncured malignancy • HIV, Hepatitis C/B • Active infection • Chest wall deformity • Non-compliance • Inadequate psychosocial support

What doesn’t work for IPF?

• Corticosteroids • Azathioprine • Cyclophosphamide • Everolimus • Anticoagulation • N-acetylcysteine

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• Bosentan • Ambrisentan • Interferon-gamma • Etanercept • Imatinib • Ribavarin

What does work for IPF? Pirfenidone • Anti-fibrotic TGFβ inhibitor

Nintedanib • Tyrosine kinase inhibitor

• Slows rate of progression

• Slows rate of progression

• 3 capsules three times

• 150 mg twice daily • Side effects:

by about half daily

• Side effects: -

Sun sensitivity Nausea, weight loss Increased liver enzymes

• $90-100,000 per year 39

by about half

-

Diarrhea Nausea, weight loss Increased liver enzymes

• $90-100,000 per year

Change in FVC (ml)

Pirfenidone versus Placebo 0 -50 -100 -150 -200 Pirfenidone Placebo

-250 -300 -350 -400 -450 -500

0

12

24

Weeks N Engl J Med 2014; 370:2083-2092

36

52

Change in FVC (ml)

Nintedanib versus Placebo 0 -50 -100 Nintedanib Placebo

-150 -200 -250 -300

0

12

24

Weeks N Engl J Med 2014; 370:2071-2082

36

52

Sildenafil Prevents Loss Of 6 MWT Distance In IPF Patients with right ventricular enlargement Right Ventricular Hypertrophy

Placebo 40 20 0 -20 -40 -60 -80 -100

Sildenafil

P = ns

Chest 2013; 143:1699-1708 42

Change in 6 MWT distance (meters)

Change in 6 MWT distance (meters)

Normal Right Ventricle

Placebo 40 20 0 -20 -40 -60 -80 -100

Sildenafil

P = 0.01

Esophageal reflux and IPF mortality GERD Medication

1.0

Mortality

Mortality

1.0

Nissen Fundoplication

0

0 0

Days

3,000

0

Days

3,000

- Treatment - No treatment Lee, et al. Am J Respir Crit Care Med 2011; 184:1390-4 43

Typical Clinical Course

Disability

Death 1

2

3

4

Time (years) 44

5

When patients with IPF are worse:

• Progression of IPF • Anemia • Heart failure • Pulmonary embolism • Lung cancer • Infection • Pneumothorax

“Stair-Step” Clinical Course (exacerbations of IPF)

Disability

Death 1

2

3

4

Time (years) 46

5

Cough and IPF Are there other causes: • ACE inhibitors?

• Chronic rhinitis? • Asthma/COPD? • Reflux?

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Palliating the IPF cough: • Non-opioid anti-tussives (eg, benzonatate)

• Opioids • Nebulized lidocaine? • Thalidomide? • Low dose corticosteroids?

Fatigue and IPF

• Anemia? • Thyroid disease? • Sleep apnea? • Heart failure? • Exertional hypoxemia?

Sleep apnea is common in IPF:

• Incidence* = 88%!!!

- 20% mild - 68% moderate-severe

• Undiagnosed sleep apnea contributes to fatigue • Quality of life can improve with CPAP

*Chest 2009; 136:772-778

IPF: taking care of the whole person

• Oxygen • Smoking cessation • Maintain normal BMI • Depression • Improve mobility & environment • Vaccinations • End-of life discussions

Image: JohannesJ

Image: Stannah Stairlift

Image: Ohio DMV 51

Vaccinations for patients with IPF:

• Influenza • Pertussis (Tdap) • 23-valent pneumococcal vaccine • 13-valent pneumococcal vaccine (Prevnar)

Start end-of-life discussions early

• Resuscitation and intubation • Hospice • How patients die

Galata Morente, Capitoline Museum, Rome Photo: Anthony Majanlathi

Outcome of patients admitted to the ICU with respiratory failure

Die in ICU Die in hospital Discharged home

Crit Care Resusc 2009; 11:102-109

Hospice

• Anticipated life

expectancy < 6 months (sort of) • Levels of care:

- Routine home care - Continuous home care - Inpatient care - Respite care

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• Physician services • Nursing services • Social services • Supplies • Medications • Bereavement counseling • Hospice aide • PT/OT/ST

How do patients with IPF die?

Subacute Respiratory Failure Acute Respiratory Failure Non-Respiratory Disease

And some other interstitial lung diseases…

Non-Specific Interstitial Pneumonitis • Second most common idiopathic interstitial pneumonia • Affects men and women equally with an average age about • • •

10 years younger than IPF Almost always seen in the setting of rheumatologic disease Shortness of breath and dry cough Physical findings include inspiratory crackles, clubbing

Non-Specific Interstitial Pneumonitis

• Important to differentiate from IPF • NSIP 5 year mortality 6-10 years

• Treatment

• Prednisone • Mycophenolate • Azathioprine • Cyclophosphamide

Hypersensitivity Pneumonitis • Etiology often hard to

identify – Birds, feathers, down – Hot tubs – Occupation – Drugs

• Pathology: – T-suppressor cell alveolitis – Poorly formed granulomas

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• Treatment: – Remove offending antigen – Prednisone

• Outcome: – Complete resolution – Chronic fibrosis

Photo: Kathrin Gaisser

Photo: David Shankbone

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Desquamative Interstitial Pneumonitis

• > 90% are smokers

–Rarely associated with collagen vascular disease

• Typical age = 30-50 • Chest CT:

–Ground glass infiltrates –CXR may be normal

• Pathology:

–Abundant smoker’s macrophages –Little alveolar wall inflammation –Little fibrosis

Desquamative Interstitial Pneumonitis Treatment

• Smoking cessation • Corticosteroids • Azathioprine • Cyclophosphamide • Mycophenolate?

Prognosis is generally good!

Sarcoidosis • Multisystem disease • Characterized by granulomatous inflammation • Dyspnea, cough, chest pain are common presenting •

• •

symptoms Radiographically: • Hilar, mediastinal lymphadenopathy • Interstitial fibrosis or ground glass infiltrates • Peri-bronchial infiltrates/thickening • Pulmonary nodules PFTs can show restriction or obstruction Responds well to corticosteroids (prednisone) and/or methotrexate

Common Occupational Lung Diseases

• Silicosis: miners, quarry workers, sandblasters,

foundry workers, many others • Asbestosis: boilermakers, plumbers, pipefitters • Mixed dust pneumoconiosis: demolition workers

Cryptogenic Organizing Pneumonia • Initially present with a subacute flu-like syndrome that lasts for a few weeks

• Cause unknown • Physical examination, laboratory testing is nonspecific • Lung biopsy is diagnostic • Usually responds to corticosteroids • Good prognosis is caught early

Hiatal hernias and interstitial lung disease

• Chronic aspiration and/or GERD can cause

interstitial lung disease • Chronic aspiration and/or GERD can worsen preexisting interstitial lung disease • Consider when patients have aspiration symptoms or hiatal hernia • Treatment:

- Stomach acid suppression - Surgical repair of hiatal hernias - Speech therapy for dysphagia

Large Hiatal Hernia

Drug-induced lung disease

• Difficult to predict • No reliable clinical, imaging, bronchoalveolar

lavage (BAL), or histopathologic feature that is specific of, or diagnostic for drug-induced ILD • Establish a definite temporal relationship between exposure to the agent and the onset of the lung disease • Stop the drug, consider corticosteroids

Drug-induced lung disease

• Dozens of drugs implicated • Common drugs: • Minocycline • Nitrofurantoin (macrodantin) • Amiodarone • Methotrexate

Talc Granulomatosis

• History = remote IV

drug use (especially Ritalin) • Exam = soft basilar crackles • PFTs = resemble emphysema • HRCT = often normal • Biopsy = polarizable foreign body material • Treatment = none 71

In Summary: Pulmonary Rehabilitation… It’s Not Just For COPD