Interstitial Lung DiseasesInterstitial Lung Diseases

Kamon Kawkitinarong, M.D.Kamon Kawkitinarong, M.D.

Department of MedicineDepartment of MedicineChulalongkorn UniversityChulalongkorn University

How can we know ….

this is the CASE?1.

How to make a diagnosis ?

Nature of disease

Symptomatology

Anatomical DxLLAABB

LLAABB

CoughCoughDyspneaDyspnea

PleurisyPleurisy

Airway diseaseAirway disease

Parenchymal diseaseParenchymal disease

Interstitial diseaseInterstitial disease

Vascular diseaseVascular disease

Pleural diseasePleural disease

Neuromuscular diseaseNeuromuscular disease

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↑ ↑ ↑↑

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Other system diseasesOther system diseases

Airway disease

Parenchymal disease

Interstitial disease

Vascular disease

Pleural disease

NATURE OF DISEASEANATOMY OF DISEASE

RESPIRATORY DISEASESRESPIRATORY DISEASES

Congenital

Trauma

Infection, inflammation

Tumor, neoplasm

Fibrosis

Degenerative diseaseCXR, PFT, ABG

Manning, H. L. et al. N Engl J Med 1995;333:1547-1553

Dyspnea: a non specific symptomDyspnea: uncomfortable sensation of breathing

Dyspnea. Mechanisms, assessment, and management: A consensus statement. American Thoracic Society. Am J Respir Crit Care. 1999; 159: 321-340.

• Dyspnea – at rest

• Dyspnea – on exertion– increased work of breathing

• Inverse correlation with exertion

Pneumonia, heart failure, pulmonary embolism, asthma/COPD exacerbations

COPD, ILD, anemia, decreased CO—pulmonary HT, IHD

Character of dyspnea

Dyspnea: evaluationHistorical clues

time course and baseline functional status

Exam findingswheezes, crackles, S3, P2

Radiographic abnormalitiesair space filling, interstitial, chest wall

Pulmonary function testsobstructive, restrictive, mixed

Dyspnea: know the time-courseAcuteAcute ChronicChronic

Acute myocardial ischemia Congestive heart failure Cardiac tamponade Bronchospasm Pulmonary embolism PneumothoraxBronchitis, pneumonia Aspiration

AsthmaCOPDInterstitial lung diseaseCardiac dysfunctionPulmonary hypertension

• Differences of time course of dyspnea in various pulmonary diseases?

Effects of Smoking to Lung FunctionEffects of Smoking to Lung Function

Non-susceptible smoker

Threshold of limitation during daily activity

COPD

Nonsmoker

Quit at age 45

Quit at age 55

YEARS !

Dyspnea

Days

Months-year

Years

COPD

ILD, PPH

Exacerbations, pneumonia, HF

Other abnormalities ? •• Chest radiograms ?Chest radiograms ?•• Pulmonary function tests ? Pulmonary function tests ?

–– ObstructiveObstructive–– RestrictiveRestrictive–– Normal ???Normal ???

2.

FEVFEV11/FVC,/FVC,TLC, FVC% pre,TLC, FVC% pre,DLCODLCO

Arterial blood gases Correlation of all things

DyspneaDyspnea

Obstruction Restriction Without obstructionChronic bronchitis

Emphysema

Asthma

Obliterative bronchiolitisLAM, EG

CXR

NormalDiffuse infiltration Signs PHT

RVH-ECG, Echo, Rt. Heart cath

PHT

Hilar adenopathy

CracklesRestrictive pattern

Interstitial fibrosis

Occupational History

Silicosis, Asbestosis,

Hypersensitivity pneumonitis

Sarcoidosis, etc.

• NOW

“Let’s go through the topics ….”

Interstitial Lung diseases (ILDs)

l Interstitial lung diseases (ILDs) are diverse group of disorders involving the distal lung parenchymal Interstitium: microscopic anatomic space between basement membrane of epithelial and endothelial cells (containing fibroblast-like cells and extracellular matrix)

l ILD usually involve more than interstitial space (entire pulmonary parenchyma is usually involved) so the name interstitial lung disease is misnomerl Diffuse infiltrative pulmonary disease or diffuse parenchymal lung disease may be more appropriate

Interstitial Lung diseases (ILDs)

Interstitial Space

Potential Causes of ILDsl Inhaled agent

l Inorganic: Silica, Asbestos, Berylliuml Organic: Animal/bird antigens

l Drug-Inducedl Antibioticsl Antiarrhythmicsl Anti-inflammatoryl Chemotherapeutic agentsl Antidepressantsl Radiation, oxygen therapy

l Infectiousl Atypical pneumonial PCP, TB

l Connective tissue diseasel Sclerodermal Polymyositis/ dermatomyositisl SLE, RAl Mixed connective tissue diseasel Ankylosing spondylitisl Primary Sjogren syndrome

l Idiopathicl Sarcoidosisl Eosinophilic granulomal BOOP, LAMl UIP, NSIP, DIP, LIP, RBILD, AIP

l Malignantl Lymphangitic carc., BAC

Classification of ILDs

l Occupational and environmental factors (inhalation)l Collagen vascular diseasesl Granulomatous lung disease of know and unknown causes (hypersensitive pneumonitis, sarcoidosis)l Inherited causesl Iatrogenic/ drug inducedl Certain specific entities (LAM, pulmonary langerhans cell granulomatosis)l Idiopathic interstitial pneumonia (IIP)

Classification of ILDsDiffuse Parenchymal Lung disease

DPLD of known causes e.g durgs

or related with CTD

Idiopathic interstitial

Pneumonia

Granulomatous DPLD e.g. sarcoidosis

Rare form of DPLD e.g. LAM,

eosinophilics granuloma

Idiopathic Pulmonary fibrosis Usual Interstitial Pneumonia

IIP other than IPF

Desquamative Interstitial Pneumonia (DIP)

Acute interstitial pneumonia (AIP)

Nonspecific interstitial pneumonia (NSIP)

Respiratory bronchiolitis associated interstitial lung disease (BBILD)

Cryptogenic organizing pneumonia

Lymphocytic interstitial pneumonia (LIP)

Classification of ILDs

Diffuse Parenchymal Lung disease

By cause By patterns of disease

• Drug

• Connective tissue disease

• Occupation

• Idiopathic

What now!

The clue to reach the diagnosis ….

3.

General Diagnostic Approach

l Integrated clinical, radiographic and pathologicalis essential for accurate diagnosis of ILDl Complete clinical evaluation is considered a key diagnostic step in patient with ILD

Clinical Evaluation of Patient with ILDl Thorough clinical historyl Chief complaint/ onset of symptomsl Comprehensive review of multiple systemsl Identification of all medications and drugsl Review of past medical history, social, family and occupational history

l Careful physical examinationThese approaches will help to narrow the broad differential diagnosis to few possible disorders

l Smoking related: IPF, EG, RBILD, HP (negative)l Age/sex: l younger: sarcoidosis, EG, familial IPFl LAM: middle age femalel EG: young male, smoking l IPF>50 yrsl RBILD: both men and women

l Occupational/exposure: HP, pneumoconiosisl Risk factors for HIV infection

Clinical Evaluation of Patient with ILD

l ILD acute onset (days to weeks)l Infection (TB, atypical pathogen, fungi, PCP, toxocara)l Cryptogenic organizing pneumonia (COP = BOOP)l Acute interstitial pneumonia (AIP)l Acute eosinophilic pneumonia (AEP)l Drug-induced pulmonary injuries (cytotoxics, amiodarone)l Acute hypersensitivity pneumonitisl Diffuse alveolar hemorrhage syndrome/vasculitis : Goodpasture’s, SLE, Behcet, Wagener’s granulomatosis, CSS l ARDS , HF

Uncommon in IPF, EG, CTD (except SLE,polymyositis)

Clinical Evaluation of Patient with DPLD

• SUBACUTE: less than 4 weeks: BOOP, drug induced, hypersensitivity pneumonitis, eosinophilic pneumonia

• Chronic with acute recurrent:– Hypersensitivity pneumonitis– Chrug-Struss syndrome– BOOP– Eosinophilic pneumonia– ABPA

Clinical Evaluation of Patient with ILD

• Chronic progressive– IPF (UIP), NSIP– PAP– Chronic HP– CVD-associated ILD– Asbestosis, Silicosis

Clinical Evaluation of Patient with ILD

l Respiratory symptoms other than dyspneal Cough, hemoptysis, pleuritic chest pain, wheezing

l Respiratory signs: มักไมชวยในการแยกโรคl Extrapulmonary symptoms

l Dyspepsia, GERD (scleroderma)l Inflammatory arthritis, skin lesions, sinusitisl Neurological symptoms: CN involvement, Bell’s palsyl Lower gastrointestinal symptomsl Polyuria and polydipsia (DI)

Clinical Evaluation of Patient with ILD

l Extrathoracic signs: มักมีความสําคัญกวาl skin lesions, hepatosplenomegaly, lymphadenopathyl skin changes in CTD, tuberous sclerosis, NFl muscles weakness, tenderness, arthritisl sclerodactyly, Raynaud’s, telangiectasial neurological findings, uveitis, conjunctivitis

Clinical Evaluation of Patient with ILD

It is ….It is ….The time of investigationThe time of investigation

• Chest X-ray is always needed in all patients complaint with dyspnea !

• The next proper one is ?HRCT

Bronchoscopy

Open lung biopsy

CXR

Investigation for interstitial lung disease

Acute alveolar filling

Chronic interstitial infiltrates

Pulmonary function tests

HRCT

Tissue diagnosis

R/O infectionAlveolar hemorrhage

BOOP

Acute interstitial pneumonia

Acute eosinophilic pneumonia

Acute hypersens pneumonitis

ARDS

Bronchoscopy Open lung biopsy

l Decreased lung volume

l Increased or preserved lung volume

l Upper zone predominate

l Lower zone predominate

l Peripheral zone

l Normal (rare)

l Mediastinal/ hilar node enlargement

l Kerley B line

CXR : SOME USEFUL PATTERNS

l Micronodules

l Septal thickening

l Honeycombing

l Migratory or remitting infiltrates

l Pleural involvement

l Pneumothorax

CXR : SOME USEFUL PATTERNS

l Rare patient with ILD will have normal CXRl Increased or preserved lung volume: LAM, EG, coexist

COPD, HP, tuberous sclerosis, PAP, sarcoidosisl Hilar node egg shell calcification: silicosis, sarcoidosisl Diffuse alveolar infiltration: PAP, pulmonary alveolar

hemorrhage syndrome, lupus pneumonitisl Diffuse micronodular: sarcoidosis, silicosis, HP, EG,

infection (TB, histoplasmosis), metastatic tumor (breast cancer, melanoma, renal cell CA)

CXR : SOME USEFUL PATTERNS

l Upper zone predominant: Sarcoidosis, EG, berylliosis, silicosis, AS, cystic fibrosis, chronic HP, drug-induced (amiodarone, gold), rheumatoid nodules

l Middle and lower lung zone: IPF, eosinophilic pneumonia, asbestosis, CTD associated PF, acute HP

l Hilar adenopathy: sarcoidosis, lymphoma, metastatic cancer, berylliosis, amyloidosis, pulmonary lymphangitic carcinomatosis

CXR : SOME USEFUL PATTERNS

l Kerley B line: venous congestion, MS, lymphagitic carcinomatosis, pulmonary venoocclusive disease, LAM

l Reverse pulmonary edema: chronic eosinophilic pneumonia

l Pleural thickening/calcification predominately in lower lung: asbestosis

l Pleural effusion: CTD (RA,SLE), drug induced, LAM, lymphagitic carcinomatosis, asbestos

l Pneumothorax: LAM, EG, tuberous sclerosis, NF

CXR : SOME USEFUL PATTERNS

CXR : SOME USEFUL PATTERNSl Central bronchiectasis: ABPAl Migratory infiltrates: chronic eosinophilic pneumonia,

ABPA, Loeffler’s syndrome

l More sensitive than plain CXR

l A standard procedure during the initial evaluation of almost all patients who have ILD suggestive of a particular set of diagnostic possibilities

High Resolution Computerized Tomography (HRCT)

Normal Lung AnatomyCentral, branching pulmonary arteries and bronchi. The bronchovascular bundles are made up of these paired structures and their surrounding interstitium (connective tissue). In cross section, the bronchus is a thin-walled, white circle with central air (black), and the adjacent artery appears as a solid, white circle.

More peripherally, numerous small "dots" and a few branching lines represent small pulmonary arteries and veins. Throughout, arteries branch at acute angles, and veins branch at 90°angles.

InterstitiumInterstitiumInterstitium in the normal lung is mostly invisible on HRCT.Interstitial Compartments of the Lung • Bronchovascular interstitium (surrounds the bronchovascular bundle) • Centrilobular interstitium (surrounds the distal bronchiolovascular bundle) • Interlobular septal interstitium (often seen as lines perpendicular to the pleura) • Pleural interstitium

Normal anatomy of the lung

Anatomic patterns of HRCT

Secondary Pulmonary Lobule

Common findings in HRCT • Lines• Nodules• Consolidation• Ground-glass appearance• Cysts

thickened interlobular septa

bronchovascular interstitial thickening

HRCT : Linear abnormalities

“Reticular” refers to an intricate network of criss-cross lines.

HRCT : Linear abnormalities

• Interlobular septa ≅ 0.1 mm thick

• Pulmonary vein & lymphatics line within the septa

• Numerous visible interlobular septa almost always indicate the presence of an interstitial abnormality

Interlobular septal thickenings

• Thickening of the intralobular interstitium

• Fine lace- or netlike appearance

• Isolated findings, M.C seen in pulmonary fibrosis

• Differential diagnosis similar to interlobular septal thickening

Intralobular septal thickenings

Intralobular septal thickenings

• Increase in bronchial wall thickness • Increase in ∅ of pulmonary artery branches• Equivalent to “peribronchial cuffing” on CXR

Peribronchovascular Interstitial Thickenings

• Bronchiectasis resulting from fibrosis

• Absent mucous plugging

• Associated with other findings of fibrosis e.g. honeycombing

• UIP = common cause

Traction Bronchiectasis

• Extensive interstitial & alveolar fibrosis resulting in disruption and bronchiolectasis

• Often associated with other findings of fibrosis such as– Architectural distortion– Traction bronchiectasis– Intralobular septal thickening

• Indicates the presence of end-stage lung• Air-filled cystic spaces, 3-10 mm in ∅, Share walls,

Peripheral & subpleural lung, Several layers

Honeycombing

HRCT as a tool for diagnosis

Guide but not definite !

In patients with DLD, HRCT was reported to be most helpful in determining the extent and distribution of disease and in detecting pulmonary abnormalities in patients with normal or nonspecific chest radiographs..

HRCT features of some DLPDsHRCT features of some DLPDs• IPF (UIP): subpleural reticulation predominate periphery and

lower lungs, traction bronchiectasis, honeycomb appearance.• Asbestosis: same as IPF, common associated with pleural

plaques, thickened interlobular septa, reticulonodular opacities• Sarcoidosis: micronodules with bronchovascular and

subpleural distribution, lymph node enlargement, +/-conglomerate mass

• Hypersensitivity pneumonitis: poorly defined centrilobular micronodules, air trapping on expiration phases; late stage == look like IPF

• Lymphangioleiomyomatosis: thin-walled cysts surrounded by normal lungs

• Eosinophilic granuloma: cysts of bizarre shape, nodules, upper lungs, SMOKING!

HRCT

IPF ? Cyst Nodules Linears Nodes

UIP

NSIP

AIP

LAM

EG

Sarcoidosis

HP

Silicosis

Lymphagitis carcino

Infection

Malignancy

…..

Kerley B ?

Nodules:patchy

subpleuralperibronchovascular

septal

Nodules:

uniformdiffuse

*Sarcoidosis*Lymphangitic

carcinoma*Silicosis

*Hematogenous metastases*Miliary tuberculosis

*CMV*Herpes infection

*Infectious or inflammatorybronchiolitis

*Follicular bronchiolitis*Cystic fibrosis*Endobronchial

spread of neoplasm

*Infectious or inflammatory bronchiolitis

*Endobronchial spread of neoplasm*Pulmonary edema

*Bleeding*Vasculitis

*Hypersensitivity pneumonitis

Subpleural nodules

Present Absent

Perilymphatic distribution

At randomdistribution

Centrilobulardistribution

Tree-in-budpresent

Tree-in-budabsent

Bronchial or vasculardisease

Bronchial disease

IPF: IPF: diagnosis without surgical lung biopsydiagnosis without surgical lung biopsy

Major criteria

Minor criteria

Diagnostic Process in DPLD

History, physical examination, History, physical examination, chest radiograph, lung function testschest radiograph, lung function tests

Not IIP Possible IIP

HRCT

Surgical lung biopsy

Bronchoscopy

R/O infection

Clinical IPF

l BAL : diagnostic

l Inorganic dusts, malignancy, PAP, sarcoidosis, HP, hematologic disease, drug induced

l Transbronchial biopsyl Sarcoidosis, EGl Pulmonary alveolar proteinosisl Lymphangitis carcinomatosis, BAC, HPl Infection

l Surgical lung biopsy : IPF

Bronchoscopy and tissue diagnosis

Diagnostic Approach for ILDPatient suspected of ILD

Hx and PE, routine laboratory, PFT, CXR, (HRCT)

Pertinent exposure ( occupational, environmental)

Remove exposure

Complete recovery?

Yes

Further test if appropriate

Specific systemic disorder?

Yes

BAL/TLB No

No further work up

Specific diagnosisYes

Typical clinical and HRCT for IPF Yes IPF (clinical Dx)

Surgical Lung Biopsy

Histological pattern of UIP? Yes IPFIIP other than IPF No

No

Diagnostic Approach for ILDPatient suspected of having ILD

Hx and PE, routine laboratory, PFT, CXR

Diagnosis likely by bronch?

Is bronch diagnositc?

Diagnosis

Yes

HRCT

Typical clinical and

HRCT for IPF

Yes

NoNo

Clinical and HRCT Dx of

other ILD

Further test if appropriate

Suspected other ILD

Diagnosis likely by bronch?

Is bronch diagnositc?

YesNo

No

VATS or Lung Bx

YesDiagnosisDiagnosis

Diagnosis Diagnosis

Diagnosis

Atypical for IPF

CASE 1

• A woman, 35 years old, with progressive dyspnea on exertion for 1 year

What more history should we take ?

• Cough• Dyspnea : baseline and now• Exacerbation ? • Wheezing• Others : rash, weight loss, arthritis• Occupation • Drug use• HIV risk

Airway

• main airway

Interstitial

Vascular

Diaphragm

Outside the lung

PE : no stridor, decreased breath sound generalizedly, no wheezing

no RV heaves, P2 normal, no murmur

PFT: FVC = 60%p, FEV1/FVC = 70%, RV =50%p

PH: she has two episodes of rightPH: she has two episodes of right--sided sided pneumothorax in the past pneumothorax in the past 1 1 year.year.

Diffuse cystic lesions

LAM

CASE 2

• A man, 60 years old, dyspnea on exertion for 6 months

• He can’t work as usual now, FC = 2-3, weight loss 4 kg in 2 months

• He went to hospital and has been treated as heart failure and bronchodilators but not improved

“VELCRO” SIGN

Dry inspiratory crackles (crepitation), no wheezing

Clubbing +

No signs of heart failure, no edema

UIP: Traction Bronchiectasis

Subpleural and Basal Predominance

What should you do next ?

Is it IPF ?

Ummm, it looks like

but we need to look for other possible causes

A clinical diagnosis of UIP was applied without open lung biopsy

Bronchoscopy is needed to rule out infection

He was treated by oral prednisolone 0.5 mg/kg/day and imuran 1 mg/kg/d

ANA = 1: 40 homogenous type, RF = +ve, no S&S of CNT diseases, occupation เผาถาน, no drug use before, antiHIV = negative, malignancy ?

CASE 3

• A Thai woman, 30 years old, present with abnormal CXR, asymptomatic

• PE was unremarkable

Sarcoidosis

Lymphoma

Metastatic cancer

TB ? ? ?

Hilar adenopathy

• What should you do next ?1. HRCT2. Open lung biopsy3. Bronchoscopy with biopsy4. Mediastinoscopy with lymph node biopsy5. Follow up

NODULES type ?

Subpleural ?

YES !

Non-caseating granuloma was found, consistent with sarcoidosis

TT = negative, anergy

All mycobacterial C/S = neg

Even asymptomatic, her PFT showed mild restrictive defect (FVC = 70%p),

treatment in this patient should be ……

Oral prednisoplone 1 mg/kg/d taper down in 6 months

Sarcoidosis : ↑ CD4 / CD8: Bx = tight, uniformnoncaseating granuloma

HP : ↓ CD4 / CD8 → ratio < 1 : ↑ lymphocytes: Bx = loose noncaseating granuloma

Anterior uveitis is the most common ocular manifestations

Crazy-paving appearance

Kerley B lines

Interlobular lymphatics

CHF, MS

Lymph.carcinomatosis

Pulm. venoocclusive dis

Photonegative or reverse type pulmonay edema

Chronic eosinophilic pneumonia

Loeffler’s pneumonia

CBC

Bronchoscopy

Stool parasites

Silicosis : Progressive massive fibrosis

Central bronchiectasis

Drug-induced pulmonary diseases

Drug-induced ILDs

Therapy drugs only

www.pneumotox.com

Diagnostic criteria• Hx of exposure to the agent (current/recent)• Exposure to other pneumotoxic drugs (evaluate

w. Pneumotox ®)• Hx of recent removal of corticosteroids• Hx of exposure to other drugs or radiation• Hx of adverse lung reaction to other drugs• Normalcy of chest radiograph and pulmonary f°

prior to Rx with the suspect agent• Strength of signal in literature (conclusive

evidence)• Consitent time to onset (temporal eligibility)

Temporal eligibility

min-hrs

months-years

delayed

Most drugs incl

amiodarone

Amiodarone, nitrosoureas, RT

weeks(Amiodarone), minocycline, nitrofurantoin ILD

ILDfibrosis

P edema

ILD

Occupational lung diseaseOccupational lung disease

Occu. asthma

Hypersensitivity pneumonitis Pneumoconiosis

Silicosis

Asbestos-related lung disease

ByssinosisReaction to germs

Asthma presentationAsbestosis

Activity of disease

• How to evaluate activity of disease ?– Bronchoscopy + BAL– HRCT : ground glass appearance– Inflammatory mediators

• Clinical progression of disease– Functional class– Exercise tolerance : 6MWT

Treatment of ILDs

• Depend on etiology• Avoidance • Idiopathic : steroids + immunosuppressive

drugs

The good idea is “REFER !!!”

You do need specialists

Drug / occupation