Pulmonary FibrosisPulmonary FibrosisCase StudiesCase Studies

Harold R Collard, MDHarold R Collard, MDAssistant Professor of MedicineAssistant Professor of Medicine

Interstitial Lung Disease ProgramInterstitial Lung Disease ProgramUniversity of California San FranciscoUniversity of California San Francisco

Mr. H.Mr. H.

62 year old man62 year old manDry coughDry coughSlowly progressive Slowly progressive dyspneadyspnea on exertionon exertionExercise limitationExercise limitationDry Dry inspiratoryinspiratory cracklescracklesClubbingClubbing

QuestionsQuestions

What do I do with this patient?What do I do with this patient?DiagnosisDiagnosisPrognosisPrognosisManagementManagement

Pharmacologic therapyPharmacologic therapyNonNon--pharmacologic therapypharmacologic therapyTransplantationTransplantation

Normal LungNormal Lung

Pulmonary FibrosisPulmonary Fibrosis Mechanisms of fibrosisMechanisms of fibrosis

MMP/TIMP

TGFβInflammation

Clinical ClassificationClinical ClassificationPulmonary Fibrosis

Exposure-related:- Occupational- Environmental- Avocational- Medication

Idiopathic interstitial

pneumonia (IIP)

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

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

Idiopathic pulmonary

fibrosis (IPF)

Desquamative interstitial pneumonia (DIP)

Acute interstitial pneumonia (AIP)

Nonspecific interstitial pneumonia (NSIP)

Respiratory bronchiolitis interstitial lung dis. (RBILD)

Cryptogenic organizing pneumonia (COP)

Lymphocytic interstitial pneumonia (LIP)

DonDon’’t stop with t stop with ““pulmonary fibrosispulmonary fibrosis””

Reasons for a specific diagnosis:Reasons for a specific diagnosis:

Many forms are treatableMany forms are treatableTreatments depend on diagnosisTreatments depend on diagnosisPrognosis variesPrognosis variesClinical trial eligibility requirementsClinical trial eligibility requirements

Diagnostic AlgorithmDiagnostic AlgorithmSuspected PF

HRCTDetailed history + PFTs/Labs +

Smoking historyOcc/Env history

Autoimmune ROSFamily history

SpirometryLung volumes/DLCO

ANA, RF

HighHigh--resolution CT (HRCT)resolution CT (HRCT)

11--1.5 mm 1.5 mm collimationcollimation

Images taken every Images taken every 10 mm10 mm

Supine, prone and Supine, prone and expiratory imagesexpiratory images

Diagnostic AlgorithmDiagnostic AlgorithmSuspected PF

HRCTDetailed history +

Non-diagnosticDiagnostic

Lung biopsy

1. IPF2. Sarcoidosis3. CV-ILD4. Hypersensitivity

pneumonitis5. Rare disease

(LAM, PAP)

PFTs/Labs +

Smoking historyOcc/Env history

Autoimmune ROSFamily history

SpirometryLung volumes/DLCO

ANA, RF

Case 1Case 1

Case 1Case 160 year old man60 year old manShortness of breath for one yearShortness of breath for one yearOccasional nonproductive coughOccasional nonproductive cough

PMH: PMH: atrialatrial fibrillation, GERDfibrillation, GERDMeds: Meds: metoprololmetoprolol, , omeprazoleomeprazoleSH: h/o tobacco, quit 10 years agoSH: h/o tobacco, quit 10 years agoOH: retired school teacher, woodworkerOH: retired school teacher, woodworker

Case 1Case 1

Physical examinationPhysical examinationDesaturatesDesaturates to 86% with walkingto 86% with walkingBibasilar Bibasilar inspiratoryinspiratory cracklescracklesIrregularly irregular, no murmurIrregularly irregular, no murmurDigital clubbing, no edema, rashesDigital clubbing, no edema, rashes

Pulmonary function testsPulmonary function testsFVC 65% predicted, FEV1/FVC 0.85FVC 65% predicted, FEV1/FVC 0.85TLC 70% predictedTLC 70% predictedDLCO 32% predictedDLCO 32% predicted

Case 1: HRCTCase 1: HRCT Case 1: HRCTCase 1: HRCT

Case 1: HRCTCase 1: HRCT Diagnosis?Diagnosis?

A) A) SarcoidosisSarcoidosisB) Hypersensitivity B) Hypersensitivity pneumonitispneumonitisC) Idiopathic Pulmonary FibrosisC) Idiopathic Pulmonary FibrosisD) Cryptogenic Organizing PneumoniaD) Cryptogenic Organizing PneumoniaE) Connective Tissue Related ILDE) Connective Tissue Related ILDF) Requires more informationF) Requires more information

Diagnosis?Diagnosis?

A B C D E F

17% 17% 17%17%17%17%A) A) SarcoidosisSarcoidosisB) Hypersensitivity B) Hypersensitivity pneumonitispneumonitisC) Idiopathic Pulmonary C) Idiopathic Pulmonary FibrosisFibrosisD) Cryptogenic D) Cryptogenic Organizing PneumoniaOrganizing PneumoniaE) Connective Tissue E) Connective Tissue Related ILDRelated ILDF) Requires more F) Requires more informationinformation

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IPF: HRCT diagnosisIPF: HRCT diagnosis

Clinical ClassificationClinical ClassificationPulmonary Fibrosis

Exposure-related:- Occupational- Environmental- Avocational- Medication

Idiopathic interstitial

pneumonia (IIP)

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

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

Idiopathic pulmonary

fibrosis (IPF)

Desquamative interstitial pneumonia (DIP)

Acute interstitial pneumonia (AIP)

Nonspecific interstitial pneumonia (NSIP)

Respiratory bronchiolitis interstitial lung dis. (RBILD)

Cryptogenic organizing pneumonia (COP)

Lymphocytic interstitial pneumonia (LIP)

SurvivalSurvival

Median survival for IPF is 2Median survival for IPF is 2--3 years3 yearsOthers betterOthers better

BjorakerBjoraker. American Journal of Respiratory and Critical Care Medicine 199. American Journal of Respiratory and Critical Care Medicine 1998;v157:p199 8;v157:p199

IPF

IPF: Published DefinitionIPF: Published Definition

““A specific form of chronic A specific form of chronic fibrosingfibrosing interstitial interstitial pneumonia limited to the lung and associated pneumonia limited to the lung and associated with the with the histologichistologic appearance of usual appearance of usual interstitial pneumonia on surgical lung biopsy.interstitial pneumonia on surgical lung biopsy.””

AJRCCM 2000;161:646AJRCCM 2000;161:646

Usual Interstitial PneumoniaUsual Interstitial Pneumonia

Conventional therapyConventional therapy

Ineffective (and often harmful)Ineffective (and often harmful)

Collard Chest 2004;125:2169Collard Chest 2004;125:2169

p = 0.58

Corticosteroids

Adding Adding AcetylcysteineAcetylcysteine

Demedts NEJM 2005;353:2229

PREDNISONE AND AZATHIOPRINE PLUS

ACETYLCYSTEINE(80)

PREDNISONE AND AZATHIOPRINE

ALONE (75)

182 subjects

12 months

Change in FVC and DLCO

P/A/NP/A

P/A/NP/A

Novel therapiesNovel therapies

Interferon Interferon γγ 1b1bPirfenidonePirfenidoneBosentanBosentanEtanerceptEtanercept

TreatmentTreatment

Enroll in a clinical trialEnroll in a clinical trialConsider therapy:Consider therapy:

prednisone/prednisone/azathioprine/acetylcysteineazathioprine/acetylcysteinePulmonary rehabilitationPulmonary rehabilitationLung transplantation evaluationLung transplantation evaluation

Case 2Case 2

Case 2Case 250 year old woman 50 year old woman Progressive cough and dyspnea over 6 Progressive cough and dyspnea over 6 months months

PMH: PMH: ““arthritisarthritis””Meds: ibuprofen as neededMeds: ibuprofen as neededSH: former smoker, quit 1 year agoSH: former smoker, quit 1 year agoOH: Clerical work, OH: Clerical work, ““dusty officedusty office””

Case 2Case 2

Physical examinationPhysical examinationNo No desaturationdesaturation with walkingwith walkingScattered expiratory wheezesScattered expiratory wheezesRegular rate, rhythmRegular rate, rhythmNo clubbing, edemaNo clubbing, edema

Pulmonary function testsPulmonary function testsFVC 75% predicted, FEV1/FVC 68%FVC 75% predicted, FEV1/FVC 68%TLC 75% predictedTLC 75% predictedDLCO 65% predictedDLCO 65% predicted

Case 2: HRCTCase 2: HRCT

Case 2: HRCTCase 2: HRCT Case 2: HRCTCase 2: HRCT

Case 2: HRCTCase 2: HRCT Diagnosis?Diagnosis?

A) A) SarcoidosisSarcoidosisB) Hypersensitivity B) Hypersensitivity pneumonitispneumonitisC) Idiopathic Pulmonary FibrosisC) Idiopathic Pulmonary FibrosisD) Cryptogenic Organizing PneumoniaD) Cryptogenic Organizing PneumoniaE) Connective Tissue Related ILDE) Connective Tissue Related ILDF) Requires more informationF) Requires more information

Diagnosis?Diagnosis?

A B C D E F

17% 17% 17%17%17%17%A) A) SarcoidosisSarcoidosisB) Hypersensitivity B) Hypersensitivity pneumonitispneumonitisC) Idiopathic Pulmonary C) Idiopathic Pulmonary FibrosisFibrosisD) Cryptogenic D) Cryptogenic Organizing PneumoniaOrganizing PneumoniaE) Connective Tissue E) Connective Tissue Related ILDRelated ILDF) Requires more F) Requires more informationinformation

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Surgical Lung BiopsySurgical Lung BiopsyVATS is preferred VATS is preferred approachapproach

Requires single Requires single lung ventilationlung ventilation

Several disparate Several disparate biopsies takenbiopsies taken

Surgical PathologySurgical Pathology Surgical PathologySurgical Pathology

Diagnosis?Diagnosis?

A) A) SarcoidosisSarcoidosisB) Hypersensitivity B) Hypersensitivity pneumonitispneumonitisC) Idiopathic Pulmonary FibrosisC) Idiopathic Pulmonary FibrosisD) Cryptogenic Organizing PneumoniaD) Cryptogenic Organizing PneumoniaE) Connective Tissue Related ILDE) Connective Tissue Related ILDF) Requires more informationF) Requires more information

Diagnosis?Diagnosis?

A B C D E F

17% 17% 17%17%17%17%A) A) SarcoidosisSarcoidosisB) Hypersensitivity B) Hypersensitivity pneumonitispneumonitisC) Idiopathic Pulmonary C) Idiopathic Pulmonary FibrosisFibrosisD) Cryptogenic D) Cryptogenic Organizing PneumoniaOrganizing PneumoniaE) Connective Tissue E) Connective Tissue Related ILDRelated ILDF) Requires more F) Requires more informationinformation

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Clinical ClassificationClinical ClassificationPulmonary Fibrosis

Exposure-related:- Occupational- Environmental- Avocational- Medication

Idiopathic interstitial

pneumonia (IIP)

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

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

Idiopathic pulmonary

fibrosis (IPF)

Desquamative interstitial pneumonia (DIP)

Acute interstitial pneumonia (AIP)

Nonspecific interstitial pneumonia (NSIP)

Respiratory bronchiolitis interstitial lung dis. (RBILD)

Cryptogenic organizing pneumonia (COP)

Lymphocytic interstitial pneumonia (LIP)

ExposureExposure--related ILDrelated ILD

Inorganic agents (= pneumoconiosis)Inorganic agents (= pneumoconiosis)asbestosisasbestosissilicosissilicosis

Organic agents (= hypersensitivity Organic agents (= hypersensitivity pneumonitis)pneumonitis)

Fungal spores (water damage, moldy hay)Fungal spores (water damage, moldy hay)Animal proteins (birds!)Animal proteins (birds!)

MedicationsMedicationsAmiodaroneAmiodarone, , NitrofurantoinNitrofurantoin, , MethotrexateMethotrexate

Hypersensitivity Hypersensitivity PneumonitisPneumonitis Case 2: Expiratory imagesCase 2: Expiratory images

Case 2: Expiratory imagesCase 2: Expiratory images TreatmentTreatment

Removal from antigenRemoval from antigenImmunosuppressionImmunosuppression

CorticosteroidsCorticosteroidsAzathioprineAzathioprine

Pulmonary rehabilitationPulmonary rehabilitationLung transplantation evaluationLung transplantation evaluation

Case 3Case 3

Case 3Case 340 year old man 40 year old man PersistantPersistant cough and cough and dyspneadyspnea over 6 over 6 months months

PMH: asthmaPMH: asthmaMeds: Meds: albuterolalbuterol MDIMDISH: active smokerSH: active smokerOH: Machinist for aerospace companyOH: Machinist for aerospace company

Case 3Case 3

Physical examinationPhysical examinationNo No desaturationdesaturation with walkingwith walkingScattered cracklesScattered cracklesSkin nodules at site of Skin nodules at site of tatootatooNo clubbing, edemaNo clubbing, edema

Pulmonary function testsPulmonary function testsFVC 80% predicted, FEV1/FVC 75%FVC 80% predicted, FEV1/FVC 75%TLC 70% predictedTLC 70% predictedDLCO 55% predictedDLCO 55% predicted

Case 3: HRCTCase 3: HRCT

Diagnosis?Diagnosis?

A) A) SarcoidosisSarcoidosisB) Hypersensitivity B) Hypersensitivity pneumonitispneumonitisC) Idiopathic Pulmonary FibrosisC) Idiopathic Pulmonary FibrosisD) Cryptogenic Organizing PneumoniaD) Cryptogenic Organizing PneumoniaE) Connective Tissue Related ILDE) Connective Tissue Related ILDF) Requires more informationF) Requires more information

Diagnosis?Diagnosis?

A B C D E F

17% 17% 17%17%17%17%

A) A) SarcoidosisSarcoidosisB) Hypersensitivity B) Hypersensitivity pneumonitispneumonitisC) Idiopathic Pulmonary C) Idiopathic Pulmonary FibrosisFibrosisD) Cryptogenic D) Cryptogenic Organizing PneumoniaOrganizing PneumoniaE) Connective Tissue E) Connective Tissue Related ILDRelated ILDF) Requires more F) Requires more informationinformation

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SarcoidosisSarcoidosisIdiopathic disease affecting all organ systemsIdiopathic disease affecting all organ systems

Baughman. AJR

CC

M 2001;164:1885

Surgical PathologySurgical Pathology

Surgical PathologySurgical Pathology Radiographic StageRadiographic Stage

Stage 1 Stage 2

Stage 4Stage 3

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TreatmentTreatment

Stage 1 disease: often no therapyStage 1 disease: often no therapyStage 2Stage 2--3 disease:3 disease:

PrednisonePrednisoneMethotrexateMethotrexateHydroxychloroquineHydroxychloroquineAzathioprineAzathioprineInfliximabInfliximab

Stage 4 disease: transplantationStage 4 disease: transplantation