Interstitial Lung Diseases

Kamon Kawkitinarong, M.D.

Department of Medicine Chulalongkorn University

1. How can we know .

this is the CASE?

How to make a diagnosis ?

Symptomatology
L A B

Anatomical Dx

L A B

Nature of disease

Cough Dyspnea Pleurisy Airway disease Parenchymal disease Interstitial disease Vascular disease Pleural disease Neuromuscular disease

Other system diseases

RESPIRATORY DISEASES

ANATOMY OF DISEASE

NATURE OF DISEASE

Airway disease Parenchymal disease Interstitial disease Vascular disease Pleural disease CXR, PFT, ABG

Congenital Trauma Infection, inflammation Tumor, neoplasm Fibrosis Degenerative disease

Dyspnea: a non specific symptom Dyspnea: uncomfortable sensation of breathing

Dyspnea. Mechanisms, assessment, and management: A consensus statement. American Thoracic Society. Am J Respir Crit Care. 1999; 159: 321-340. Manning, H. L. et al. N Engl J Med 1995;333:1547-1553

Character of dyspnea
Dyspnea at rest Pneumonia, heart failure,
pulmonary embolism, asthma/COPD exacerbations

Dyspnea on exertion increased work of breathing

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

Inverse correlation with exertion

Dyspnea: evaluation
Historical clues time course and baseline functional status Exam findings wheezes, crackles, S3, P2 Radiographic abnormalities air space filling, interstitial, chest wall Pulmonary function tests obstructive, restrictive, mixed

Dyspnea: know the time-course

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

Chronic
Asthma COPD Interstitial lung disease Cardiac dysfunction Pulmonary hypertension

 Differences of time course of dyspnea in various pulmonary diseases?

Effects of Smoking to Lung Function

Nonsmoker
Quit at age 45

COPD

Non-susceptible smoker
Quit at age 55

Threshold of limitation during daily activity

YEARS !

Dyspnea

COPD

ILD, PPH
Exacerbations, pneumonia, HF

Days Months-year Years

2. Other abnormalities ?
Chest radiograms ? Pulmonary function tests ?
Obstructive Restrictive Normal ??? Arterial blood gases FEV1 FEV1/FVC, TLC, FVC% pre, DLCO Correlation of all things

Dyspnea Obstruction
Chronic bronchitis Emphysema Asthma Obliterative bronchiolitis LAM, EG
Silicosis, Asbestosis, Hypersensitivity pneumonitis

Without obstruction Restriction

CXR Diffuse infiltration

Crackles Restrictive pattern Occupational History Hilar adenopathy

Normal
Signs PHT RVH-ECG, Echo, Rt. Heart cath
Sarcoidosis, etc.

Interstitial fibrosis

PHT

 NOW

Lets go through the topics .

Interstitial Lung diseases (ILDs)

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

Interstitial Lung diseases (ILDs)

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

Interstitial Space

Potential Causes of ILDs

Inhaled agent l Inorganic: Silica, Asbestos, Beryllium l Organic: Animal/bird antigens l Drug-Induced l Antibiotics l Antiarrhythmics l Anti-inflammatory l Chemotherapeutic agents l Antidepressants l Radiation, oxygen therapy l Infectious l Atypical pneumonia l PCP, TB
l

Connective tissue disease l Scleroderma l Polymyositis/ dermatomyositis l SLE, RA l Mixed connective tissue disease l Ankylosing spondylitis l Primary Sjogren syndrome l Idiopathic l Sarcoidosis l Eosinophilic granuloma l BOOP, LAM l UIP, NSIP, DIP, LIP, RBILD, AIP l Malignant l Lymphangitic carc., BAC
l

Classification of ILDs

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

Classification of ILDs
Diffuse 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 Drug Connective tissue disease Occupation Idiopathic

By patterns of disease

3.

What now!

The clue to reach the diagnosis .

General Diagnostic Approach

l

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

Clinical Evaluation of Patient with ILD l Thorough clinical history

l

Careful physical examination

Chief complaint/ onset of symptoms l Comprehensive review of multiple systems l Identification of all medications and drugs l Review of past medical history, social, family and occupational history

These approaches will help to narrow the broad differential diagnosis to few possible disorders

Smoking related: IPF, EG, RBILD, HP (negative) l Age/sex:

l

Clinical Evaluation of Patient with ILD

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

l

younger: sarcoidosis, EG, familial IPF l LAM: middle age female l EG: young male, smoking l IPF>50 yrs l RBILD: both men and women
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 pneumonitis l Diffuse alveolar hemorrhage syndrome/vasculitis : Goodpastures, SLE, Behcet, Wageners granulomatosis, CSS l ARDS , HF Uncommon in IPF, EG, CTD (except SLE,polymyositis)
l

ILD acute onset (days to weeks)

Clinical Evaluation of Patient with DPLD

Clinical Evaluation of Patient with ILD

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 dyspnea

l

Cough, hemoptysis, pleuritic chest pain, wheezing

Respiratory signs:
Extrapulmonary symptoms
l l l l l

Dyspepsia, GERD (scleroderma) Inflammatory arthritis, skin lesions, sinusitis Neurological symptoms: CN involvement, Bells palsy Lower gastrointestinal symptoms Polyuria and polydipsia (DI)

Clinical Evaluation of Patient with ILD

l

Extrathoracic signs:
l

skin lesions, hepatosplenomegaly, lymphadenopathy l skin changes in CTD, tuberous sclerosis, NF l muscles weakness, tenderness, arthritis l sclerodactyly, Raynauds, telangiectasia l neurological findings, uveitis, conjunctivitis

It is .
The time of investigation
Chest X-ray is always needed in all patients complaint with dyspnea !
HRCT

The next proper one is ?

Bronchoscopy Open lung biopsy

Investigation for interstitial lung disease

CXR
Acute alveolar filling Chronic interstitial infiltrates Pulmonary function tests HRCT Tissue diagnosis

R/O infection
Alveolar hemorrhage BOOP Acute interstitial pneumonia Acute eosinophilic pneumonia Acute hypersens pneumonitis ARDS

Bronchoscopy Open lung biopsy

CXR : SOME USEFUL PATTERNS

l

Decreased lung volume Increased or preserved lung volume Upper zone predominate Lower zone predominate Peripheral zone Normal (rare) Mediastinal/ hilar node enlargement Kerley B line

CXR : SOME USEFUL PATTERNS

l

Micronodules Septal thickening Honeycombing Migratory or remitting infiltrates Pleural involvement Pneumothorax

l
l

Rare patient with ILD will have normal CXR

CXR : SOME USEFUL PATTERNS

l l

Increased or preserved lung volume: LAM, EG, coexist COPD, HP, tuberous sclerosis, PAP, sarcoidosis Hilar node egg shell calcification: silicosis, sarcoidosis Diffuse alveolar infiltration: PAP, pulmonary alveolar hemorrhage syndrome, lupus pneumonitis 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 Middle and lower lung zone: IPF, eosinophilic pneumonia, asbestosis, CTD associated PF, acute HP Hilar adenopathy: sarcoidosis, lymphoma, metastatic cancer, berylliosis, amyloidosis, pulmonary lymphangitic carcinomatosis

Kerley B line: venous congestion, MS, lymphagitic carcinomatosis, pulmonary venoocclusive disease, LAM Reverse pulmonary edema: chronic eosinophilic pneumonia Pleural thickening/calcification predominately in lower lung: asbestosis Pleural effusion: CTD (RA,SLE), drug induced, LAM, lymphagitic carcinomatosis, asbestos Pneumothorax: LAM, EG, tuberous sclerosis, NF

CXR : SOME USEFUL PATTERNS

CXR : SOME USEFUL PATTERNS

l l

Central bronchiectasis: ABPA Migratory infiltrates: chronic eosinophilic pneumonia, ABPA, Loefflers syndrome

High Resolution Computerized Tomography (HRCT)

l

More sensitive than plain CXR A standard procedure during the initial evaluation of

almost all patients who have ILD suggestive of a particular set of diagnostic possibilities

Normal Lung Anatomy

Central, 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.

Normal anatomy of the lung

Interstitium
Interstitium 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

Anatomic patterns of HRCT

Secondary Pulmonary Lobule

Common findings in HRCT

Lines Nodules Consolidation Ground-glass appearance Cysts

HRCT : Linear abnormalities

thickened interlobular septa

bronchovascular interstitial thickening

HRCT : Linear abnormalities

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

Interlobular septal thickenings

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

Intralobular 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

Peribronchovascular Interstitial Thickenings

Increase in bronchial wall thickness Increase in of pulmonary artery branches Equivalent to peribronchial cuffing on CXR

Traction Bronchiectasis
Bronchiectasis resulting from fibrosis Absent mucous plugging Associated with other findings of fibrosis e.g. honeycombing UIP = common cause

Honeycombing
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

HRCT as a tool for diagnosis

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..

Guide but not definite !

HRCT 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

UIP NSIP AIP LAM EG

Nodules
Sarcoidosis HP Silicosis Lymphagitis carcino Infection Malignancy ..

Linears
Kerley B ?

Nodes

Subpleural nodules Present

Nodules: patchy subpleural peribronchovascular septal Nodules: uniform diffuse

Absent
Centrilobular distribution
Tree-in-bud present Bronchial disease Tree-in-bud absent
Bronchial or vascular disease

Perilymphatic distribution
*Sarcoidosis *Lymphangitic carcinoma *Silicosis

At random distribution

*Hematogenous metastases *Infectious or inflammatory *Infectious or inflammatory bronchiolitis bronchiolitis *Miliary tuberculosis *Endobronchial *Follicular bronchiolitis *CMV spread of neoplasm *Cystic fibrosis *Herpes infection *Pulmonary edema *Endobronchial *Bleeding spread of neoplasm *Vasculitis *Hypersensitivity pneumonitis

IPF: diagnosis without surgical lung biopsy

Major criteria

Minor criteria

Diagnostic Process in DPLD

History, physical examination, chest radiograph, lung function tests

Not IIP Clinical IPF Bronchoscopy R/O infection Surgical lung biopsy

Possible IIP

HRCT

Bronchoscopy and tissue diagnosis

l

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

Transbronchial biopsy Sarcoidosis, EG l Pulmonary alveolar proteinosis l Lymphangitis carcinomatosis, BAC, HP l Infection
l

Surgical lung biopsy : IPF

Diagnostic Approach for ILD

Patient suspected of ILD Hx and PE, routine laboratory, PFT, CXR, (HRCT) Pertinent exposure ( occupational, environmental) Further test if appropriate Remove exposure Complete recovery? Specific diagnosis Yes Typical clinical and HRCT for IPF No Surgical Lung Biopsy IIP other than IPF No Histological pattern of UIP? Yes IPF BAL/TLB No Specific systemic disorder? Yes No further work up Yes IPF (clinical Dx) Yes

Diagnostic Approach for ILD

Patient suspected of having ILD Hx and PE, routine laboratory, PFT, CXR Yes Is bronch diagnositc? Yes Diagnosis likely by bronch? No No Further test if appropriate

Diagnosis

HRCT
Suspected other ILD Atypical for IPF Clinical and HRCT Dx of other ILD Typical clinical and HRCT for IPF

Diagnosis

Diagnosis likely by bronch? Yes Is bronch diagnositc? Yes No No

Diagnosis
VATS or Lung Bx

Diagnosis

Diagnosis

Diagnosis

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 right-sided rightpneumothorax in the past 1 year.

Diffuse cystic lesions

LAM

CASE 2
A man, 60 years old, dyspnea on exertion for 6 months He cant 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

Subpleural and Basal Predominance

UIP: Traction Bronchiectasis

What should you do next ?

Is it IPF ?
A clinical diagnosis of UIP was applied without open lung biopsy Bronchoscopy is needed to rule out infection Ummm, it looks like but we need to look for other possible causes

ANA = 1: 40 homogenous type, RF = +ve, no S&S of CNT diseases, occupation , no drug use before, antiHIV = negative, malignancy ?
He was treated by oral prednisolone 0.5 mg/kg/day and imuran 1 mg/kg/d

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. 2. 3. 4. 5. HRCT Open lung biopsy Bronchoscopy with biopsy Mediastinoscopy with lymph node biopsy 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, uniform noncaseating granuloma HP : CD4 / CD8 ratio < 1 : lymphocytes : Bx = loose noncaseating granuloma

Anterior uveitis is the most common ocular manifestations

Crazy-paving appearance

CHF, MS Kerley B lines Lymph.carcinomatosis Pulm. venoocclusive dis Interlobular lymphatics

Chronic eosinophilic pneumonia Loefflers pneumonia CBC Bronchoscopy Photonegative or reverse type pulmonay edema Stool parasites

Silicosis : Progressive massive fibrosis

Central bronchiectasis

Drug-induced pulmonary diseases

Therapy drugs only

Drug-induced ILDs

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 (Amiodarone), minocycline, nitrofurantoin Most drugs incl amiodarone weeks P edema ILD ILD

months-years

Amiodarone, nitrosoureas, RT

ILD delayed fibrosis

Occupational lung disease

Occu. asthma

Hypersensitivity pneumonitis

Pneumoconiosis Silicosis

Byssinosis
Asthma presentation

Reaction to germs

Asbestos-related lung disease

Asbestosis

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
Drug / occupation Depend on etiology Avoidance Idiopathic : steroids + immunosuppressive drugs

The good idea is REFER !!! You do need specialists