6/25/2010

Outline • Overview of diagnosis in ILD

A Review of Interstitial Lung Diseases Paul J. Wolters, MD Associate Professor Department of Medicine University of California San Francisco

– Why it is important – Definition/Classification – High-resolution CT scan – Multidisciplinary approach

• Cases – Interactive format (ARS) – Review of radiology and pathology – Treatments

• Questions

Why it is Important to be Aware of ILD’s

Don’t stop with “pulmonary fibrosis” • Reasons for a specific diagnosis: – Many forms are treatable – Treatment depends on the diagnosis – Prognosis varies – Eligibility for clinical trials

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Clinical Classification

Clinical History

Pulmonary Fibrosis Idiopathic Exposure-related: - Occupational - Environmental - Avocational - Medication

Idiopathic interstitial pneumonia (IIP) Idiopathic pulmonary fibrosis (IPF)

Connective tissue disease: - Scleroderma - Rheum. arthritis - Sjogrens - UCTD

Desquamative interstitial pneumonia (DIP)

Respiratory bronchiolitis interstitial lung dis. (RBILD)

Acute interstitial pneumonia (AIP)

Cryptogenic organizing pneumonia (COP)

Nonspecific interstitial pneumonia (NSIP)

Lymphocytic interstitial pneumonia (LIP)

Other: - Sarcoidosis - Vasculitis/Diffuse alveolar hemorrhage (DAH) - Langherhans cell histiocytosis (LCH) - Lymphagioleiomyomatosis (LAM) - Pulmonary alveolar proteinosis (PAP) - Eosinophilic pneumonias - Neurofibromatosis - Inherited disorders - Chronic aspiration - Inflammatory bowel disease

usual interstitial pneumonitis (UIP) = IPF nonspecific interstitial pneumonitis (NSIP) desquamative interstitial pneumonitis (DIP) respiratory bronchiolitis ILD (RBILD) acute interstitial pneumonitis (AIP)

Drugs

Collagen Vascular Joint c/o Sicca sx Skin rash Raynaud’s

Occupational/Environmental -Asbestos -Birds/Molds/Organic Material (HP)

CXR is Not Useful for Differentiating ILD’s

Exam: Clues to diagnosis • Lung: Crackles on exam. • Findings c/w sarcoid: Uveitis, skin rash, erythema nodosum, hepatomegaly. • Findings c/w CVD: Synovitis, rash, sclerodactaly. • Findings c/w IPF: Clubbing

Unclassified

HP IPF

CVD-ILD NSIP

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High-resolution CT (HRCT)
1-1.5 mm collimation

HRCT is the Key to Diagnosing ILD’s • Pattern of abnormality on HRCT scan may suggest a specific ILD.


Images taken every 10 mm

• HRCT findings guide subsequent diagnostic tests.


Supine, prone and expiratory images

• HRCT findings may be sufficient for diagnosis.

HRCT: Radiation Dose

Disease Patterns

Mayo et al, Radiology 2003

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Usual Interstitial Pneumonia (UIP) • Irregular lines in a patchy, basilar, subpleural distribution • Traction bronchiectasis • minimal Ground glass opacities. • Honeycomb lung

Desquamative Interstitial Pneumonia (DIP)

•Ground glass opacity with a basilar, subpleural, and lower lobe distribution •Lower lobe reticular opacities

Nonspecific Interstitial Pneumonitis (NSIP) • Ground glass opacities (100%) • Consolidation (98%) • Nodules (96%) • Traction bronchiectasis (95%) • Intralobular reticulation (87%) • Lower lobe predominance

Hypersensitivity Pneumonitis

•Subacute phase :
multifocal or diffuse GGO
poorly defined centrilobular nodules •Subacute and chronic phases :
mosaic perfusion
air trapping on expiratory images •CT may be normal in some cases

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Diagnostic Algorithm

Sarcoidosis

Suspected PF

• Perilymphatic nodules • Peribronchial nodules • GGO • Upper lobe predominant, +/- fibrosis

Detailed history, + PE

HRCT

Diagnostic 1. 2. 3. 4.

IPF Sarcoidosis CV-ILD Hypersensitivity pneumonitis 5. Rare disease (LAM, PAP)

Agreement (κ κ)

• Agreement increased with multidisciplinary approach

1

2

3 Step

4

5

PFTs/Labs

Non-diagnostic

Lung biopsy

Reevaluation of Pathology of IPF (1990’s)

Multidisciplinary approach 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0

+

Lumpers

Step

Assessment Method

Information Provided

1

Individual

HRCT

2

Individual

HRCT, clinical data

3

Discussion (clinician and radiologist)

HRCT, clinical data

4

Individual (clinician, radiologist and pathologist)

HRCT, clinical data, SLB

5

Discussion

HRCT, clinical data, SLB

Splitters

• IPF – Nonspecific interstitial pneumonitis (NSIP) – Lung fibrosis due to arthritis – Desquamative interstitial pneumonitis – Acute interstitial pneumonitis – IPF

Modified from: Flaherty KR, et al. Am J Respir Crit Care Med. 2004;170:904-910.

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Differentiating diseases predicts prognosis 1950-90’s: Lumpers

2000: Splitters

Case 1

DIP

/IPF

Bjoraker et al, Am J Resp Crit Care Med ‘98

Case 1 • 57 year old man • Abnormal CXR 3 months prior to presentation (notes “normal” CXR from 5 years ago) • Mild dyspnea on exertion, no cough • PMH: GERD for 30 years • Meds: omeprazole 40mg daily

Case 1 • Social: lifetime non-smoker, some mold in home, pharmacist • Family: no history of ILD • • • •

114/73 hr 70 rr 16 96% RA (93% walking) Dry inspiratory crackles at both bases Normal cardiac examination No clubbing, joint deformities, rashes

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Case 1

CXR

• PFTs – FVC 5.10 (83%) – FEV1 4.42 (90%) – FEV1/FVC 0.87 – TLC 7.40 (88%) – DLCO 23.41 (57%)

What additional testing would you perform next in this patient?

0% 0%

0%

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100%

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Bronchoalveolar lavage (BAL) BAL and transbronchial biopsy Serological evaluation High resolution CT scan Surgical lung biopsy No additional testing; 0% diagnosis is clear

B

1. 2. 3. 4. 5. 6.

HRCT

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HRCT

HRCT

HRCT

HRCT

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HRCT

Serological evaluation • ANA negative • RF = 4

What additional testing would you perform next in this patient? 1. Bronchoalveolar lavage (BAL) 2. BAL and transbronchial biopsy 3. Surgical lung biopsy 4. No additional testing; diagnosis is clear

VATS

50% 42%

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VATS

Diagnosis: IPF

• • • •

IPF: Traditional Therapy Problem

Corticosteroids + Immunomodulator (azathioprine or cyclophosamide @ 2 mg/kg/d)

General Management Pulmonary rehabilitation Weight loss (if overweight) Lung transplant referral Medical management

IPF: Traditional Therapy + NAC • IPF patients taking prednisone (0.5 mg/kg/d 10 mg/d) and azathioprine (2 mg/kg/d) were randomized to: – N-acetyl cysteine, 600 mg TID (n=80) – Placebo (n= 75)

Collard et al. Chest 2004

Demedts et al, NEJM ‘06

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IPF: Pirfenidone

IPF: Pirfenidone

Capacity Trial Capacity Studies

– PIPF006: 344 subjects randomized 1:1 (high dose, placebo) – PIPF004: 435 subjects randomized 2:1:2 (high dose, low dose, placebo)

Inclusion criteria

Change in FVC % Predicted

• Phase 3 double blind, randomized, placebo controlled trials.

– Age 40-80 – Diagnosis of IPF within 48 months – FVC > 50%, DLCO > 35%

Primary Endpoint: ∆ FVC at 72 weeks

5

-9.0

-9.6

-8.0 -9.9

-12.4

10

15

P = 0.50

= 006 = 004

P < 0.001

FDA Briefing Booklet (http://www.fda.gov/downloads/AdvisoryCommittees/ CommitteesMeetingMaterials /Drugs/Pulmonary -AllergyDrugsAdvisoryCommittee /UCM203081.pdf)

FDA Briefing Booklet (http://www.fda.gov/downloads/AdvisoryCommittees/ CommitteesMeetingMaterials/Drugs/Pulmonary-AllergyDrugsAdvisoryCommittee/UCM203081.pdf)

IPF: Pirfenidone

IPF: Pirfenidone

Secondary Endpoint

PIPF 006

Progression Free Survival

* 0.355

0.023

∆ 6 min walk distance

0.001

Time to worsening of IPF Survival

PIPF 004

Side Effect

PIPF 004

PIPF 006

Nausea

25.3 %

36.2 %

17.3%

0.171

Dyspepsia

13.8 %

19.1 %

7.5 %

0.248

0.515

Rash

17.2 %

32.2 %

11.5 %

0.872

0.191

Weight loss

9.2 %

8.1 %

3.5 %

* p= drug vs. placebo

Placebo

FDA Briefing Booklet (http://www.fda.gov/downloads/AdvisoryCommittees/ CommitteesMeetingMaterials/Drugs/Pulmonary-AllergyDrugsAdvisoryCommittee/UCM203081.pdf)

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IPF: Treatments • No therapy has been proven to be effective for improving survival. • Possibilities that hold promise.

Case 2

– Prednisone/Azathioprine/NAC – Pirfenidone

• Clinical Trials – – – –

Macitentan Ambrisentan Coumadin Prednisone/Azathioprine/NAC

Case 2 • 63-year-old woman • 5-month history of shortness of breath and nonproductive cough • PMH: hypertension, treated for TB exposure in 1980, arthritis • Medications: diltiazem

Case 2 • Social: former smoker (18 pk/yrs); office worker. • Family: No history of ILD • • • •

135/80 hr 90 rr 14 94% RA (90% walking) Dry inspiratory crackles at both bases Normal cardiac examination No clubbing, joint deformities, rashes

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CXR

HRCT

HRCT

HRCT

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HRCT

HRCT

HRCT

Serological evaluation • ANA 1:80, speckled • RF = 18, cyclic citrullinated antibody (CCP) negative

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What additional testing would you perform next in this patient? 1. Bronchoalveolar lavage (BAL) 2. BAL and transbronchial biopsy 3. Surgical lung biopsy 4. No additional testing; diagnosis is clear

VATS

81%

15%

VATS

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0%

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4%

Nonspecific Interstitial Pneumonitis (NSIP) • Uniform involvement of the lung with – Septal thickening – Interstitial inflammation (lymphocytes) – +/- Fibrosis

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What additional testing would you perform next in this patient?

RNP negative Scl70 negative SSA, SSB negative Jo-1 negative, CPK 104

4%

dd

A

an d A L B

37%

• • • •

tra

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48%

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Bronchoalveolar lavage (BAL) BAL and transbronchial biopsy Additional serologies No additional testing; 11% diagnosis is clear la rl av ...

1. 2. 3. 4.

Additional serologies

Diagnosis of NSIP Management • Treated with prednisone and mycophenolate (CellCept) • Pulmonary rehabilitation

NSIP • Distinguishing NSIP from UIP is a challenge! – Patients usually younger, more likely to be women – Honeycombing on HRCT is uncommon in NSIP – Surgical biopsy shows diffuse thickening of alveolar septae and few if any fibroblast foci

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IPF

NSIP

IPF

NSIP

IPF

NSIP

NSIP • The pathologic diagnosis of NSIP should prompt you to go back to look for an etiology – Occult connective tissue disease – Drug reaction – Exposure that could cause Hypersensitivity pneumonitis

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Case 3

Case 3

• 43 year old man • Subacute progressive dyspnea

• PMH: mild obstructive sleep apnea on CPAP 6 cm H20, seasonal allergies • Meds: cetirizine , multivitamin

Case 3 • Social: non-smoker, banker, no known exposures, no pets. • Family: no history of ILD • BP 116/56, hr 60, rr16, 98% RA (88% walking) • Moderately obese • Lungs clear to auscultation

Case 3 • PFTs: – FVC 3.17 (73%) – FEV1 2.43 (77%) – FEV1/FVC 0.77 – TLC 4.65 (82%) – DLCO 15.1 (58%)

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CXR

What additional testing would you perform next in this patient?

0% 0%

6%

0%

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0%

B

B

HRCT

94%

lv eo la rl av tra . .. ns br E o H nc ch ig hi oc h .. ar re di so og lu r t am io Su n rg C ic T N al sc o lu an ad ng di tio bi op na sy lt es tin g; ...

1. Bronchoalveolar lavage (BAL) 2. BAL and transbronchial biopsy 3. Echocardiogram 4. High resolution CT scan 5. Surgical lung biopsy 6. No additional testing; diagnosis is clear

HRCT

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HRCT

HRCT

HRCT

HRCT

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HRCT – expiratory views

HRCT – expiratory views

HRCT – expiratory views

Serological Evaluation • ANA negative • RF 12 • SS-A, SS-B negative

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What additional testing would you perform next in this patient? 1. Bronchoalveolar lavage (BAL) 2. BAL and transbronchial biopsy 3. Surgical lung biopsy 4. No additional testing; diagnosis is clear

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VATS Biopsy: Low Power

VATS Biopsy: High Power

VATS Biopsy: High Power

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1. Bronchoalveolar lavage (BAL) 2. Sputum culture 3. Serum precipitins 4. Additional history 5. No additional testing; diagnosis is clear

68%

16% 6% 6%

Additional history • Patient recently moved to a new home built on the site of a former pigeon farm. There is ongoing construction of new units around his home and lots of dust.

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• Airwaycentric inflammation • Poorly formed granuloma (giant cell) • Areas of organizing pneumonia

What additional testing would you perform next in this patient?

Sp

Hypersensitivity Pneumonitis

Hypersensitivity Pneumonitis Management • Remove antigen (Relocated from new home) • Treat with prednisone • Pulmonary rehabilitation

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UCSF Interstitial Lung Disease Clinic

Clinical Coordinator: (415) 353-8764 Clinic fax: (415) 353-2568 http://www.ucsfhealth.org/adult/medical_services/pulmonary/ild/index.html

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