Interstitial lung disease

Deepak Aggarwal
Dept of Pulmonary Medicine
Government Medical College and Hospital,
Chandigarh
 What is Interstitium
• The interstitial space is defined as
continuum of loose connective tissue
throughout the lung
• It is the tissue between the air sacs of the
lungs
 Subdivisions of lung interstitium

Axial interstitium
(peribronchovascular) peripheral interstitium Centrilobular interstitium
Surrounding the bronchi, contains the pulmonary situated between the alveolar
arteries, and veins from the venules, lymphatics and and capillary basement
lung root to the level of the interlobular septae membranes
respiratory bronchiole;
• Centrilobular bronchus (single wide white arrow) and artery (double white arrow, 1-mm
size)
• Interlobular septa (single arrowhead,0.1-mm thickness)
• Pulmonary vein (double arrowheads,0.5-mm size)
• Visceral pleura (single black arrow, 0.1-mm thickness)
• pulmonary acinus (single thin white arrow,5– 10 mm size
 Introduction
• There are >200 disorders
• Can classified into
– known vs unknown with subcategory
of granulomatous and
nongranulomatous. OR
– occupational vs nonoccupational
– Acute vs Chronic
 ILD Classification
Approach to
ILD

Idiopathic Granulomatous
ILD of known
Interstitial Lung Diseases Others
Cause
Pneumonias (Sarcoidosis)

LAM
Drugs Exposure CVD IPF IIP other than IPF Histiocytosis X
Malignancy

Respiratory
Desquamative
Hypersensitivity Bronchiolitis-
Pneumoconiosis Interstitial
Pneumonitis Interstitial Lung
Pneumonia
disease

Cryptogenic
Acute Interstitial Organizing
Toxic Inhalation Radiation
Pneumonia Pneumonia

Lymphocytic Non Specific

Interstitial Interstitial
Pneumonia Pneumonia
Classification of idiopathic
interstitial pneumonia
 Classification
Interstitial Lung Diseases
Sarcoidosis UIP/IPF
Hypersensitivity Pneumonitis Fibrosis

AIP

“IIP”
1970s LIP 2007
COP
Asbestosis Cellular
LAM NSIP
etc Fibrotic
IPs=Interstitial pneumonias
LAM=lymphangioleiomyomatosis RB-
Adapted from Ryu JH, et al. Mayo Clin Proc. 1998;73:1085-1101. DIP
Adapted from ATS/ERS. Am J Respir Crit Care Med. 2002;165:277-304.
ILD Inflammation
 Distribution
Occupation
11% DILD
Sarcoidosis
5% DAH
8%
4%

CTD
9%

Other
11%

Pulmonary Fibrosis
52%
 Common features in ILD

– Dyspnea
– Diffuse disease on X ray
• Often the first suggestion of disease but correlates poorly
with severity of disease
– Restrictive PFTs
• Restrictive intrathoracic pattern: Normal airway flow rates but
low FVC
– Elevated A-a gradients
 History
• 1935, Hamman and Rich described “diffuse
interstitial fibrosis of the lungs”. It was rapidly
progressive and all patients died within a few
weeks or months
• Cases with chronic diffuse pulmonary fibrosis
with a much slower progression- “Idiopathic
Pulmonary Fibrosis”.
• Based on pathological concept -in 1960s and
70s, the concept of diffuse interstitial
pneumonitis was developed or IIP
• Liebow’s Classification (1975) - based on cases
which had been classified as IPF and 5
pathological subgroups
Idiopathic Pulmonary Fibrosis
 PATHOGENESIS AND
COURSE OF UIP / IPF
UIP / IPF
Multiple microscopic foci of injury leading to inflamation
( stage of alveolitis)

Focal fibroblast proliferation (fibroblastic foci)

Collagen deposition ( Stage of fibrosis)

Recurrent microscopic injury

Progressive clinical course

Death
Katzenstein ALA et al. Am J Respir Crit Care Med. 1998;157:1301.
 Clinical context
• Idiopathic Pulmonary Fibrosis (IPF) affects
predominantly middle-aged and older subjects

• Subacute to chronic dry cough, progressive

breathlessness

• The “Velcro” crackles is nearly universal with IPF

• digital clubbing - in up to two thirds of patients

with IPF but is rare in patients with sarcoidosis
 Approach to Diagnosing diffuse lung disease
Clinical Evaluation: History, PE, CXR, PFTs, 6MWT

Not IIP Potential IIP

HRCT

Diagnostic of diffuse lung Diagnosis uncertain

disease
Transbronchial Bx or BAL

Diagnostic Nondiagnostic

Surgical lung biopsy

Not IPF IPF

Adapted from ATS/ERS Consensus Statement. Am J Respir Crit Care Med.

2002;165:277-304.
 Approach to the diagnosis
• Thorough medical history is a must

o age
o duration
o symptoms
o smoking history
o occupational and environmental exposures
o medications and drugs
o family medical history
o signs and symptoms of connective tissue disease
should be carefully elicited
Patterns of ILD on X-ray
 Typical Features of IPF on
Chest X-Ray

Normal CXR Abnormal CXR

 Chest Radiograph

• Abnormal >90%
• peripheral reticular opacities
• more profuse at lung bases
• bilateral
• asymmetrical
• commonly associated with
decreased lung volumes
• confluent alveolar opacities,
lymphadenopathy and pleural
involvement uncommon
 HRCT Chest

• More sensitive and specific

• Better diagnostic accuracy
• Assessment of disease activity
• May obviate need of biopsy
• Site for biopsy
• Follow up
• Prognosis

INITIAL DIAGNOSTIC MODALITY OF CHOICE

 High resolution CT

Pattern
• Patchy, peripheral, subpleural, bibasal
reticular opacities
• limited areas of ground glass opacities
• traction bronchiectasis and/or subpleural
honeycombing suggests severe involvement
Early HRCT Findings in IPF
Subpleural and Basal Predominance

Slide courtesy of W. Richard Webb, MD.

Honeycombing
“Traction” Bronchiectasis
 High resolution CT

• Differential diagnosis of HRCT pattern

Connective tissue diseases
Asbestosis
Hypersensitivity pneumonitis
Sarcoidosis

• Extensive GROUND GLASS OPACITIES on CT of lung

should prompt alternative diagnosis such as DIP, RBILD,
NSIP, idiopathic BOOP, hypersensitivity pneumonitis
etc.
Spirometry
 Approach to the diagnosis of IPF
Pulmonary function testing

• LUNG VOLUMES
TLC , FRC, RV are decreased

• AIRWAY MECHANICS
FVC, FEV1, PEFR are often decreased
FEV1/FVC is maintained or increased
 Pattern of PFT abnormalities in ILD
Diseases FVC FEV1/FVC DLco TLC
IPF ↓↔ ↓↔ ↓ ↓↔
Connective tissue diseases ↓↔↑ ↓↔↑ ↓ ↓↔
Sarcoidosis ↓↔ ↓↔↑ ↓↔ ↓↔
Hypersensitivity pneumonia ↓↔ ↓↔↑ ↓↔ ↓↔↑
Pulmonary alveolar proteionosis ↓↔ ↓↔ ↓↔ ↓↔
Langerhans’s cell histiocytosis ↓↔ ↓↔↑ ↓ ↔↑
Lymphangioleiomyomatosis ↓↔ ↓↔ ↓ ↔↑
Cryptogenic organic pneumonia ↓ ↓↔↑ ↓ ↓
Obliterative bronchiolitis ↓ ↓ ↓ ↑

Alhamad et al. Clinics of Chest Medicine 2001;22:715-742

 Role of BAL vs Biopsy in IPF

Procedure Role
• May rule out alternate diagnoses but
Brochoalveolar Lavage (BAL) not diagnostic of IPF

• May rule out alternate diagnoses but

Transbronchial Biopsy (TBLB) not diagnostic of IPF
• Often abnormal in IPF but does not
confirm diagnosis

• Preferred technique
Video-assisted Thoracoscopic Biopsy (VATS) • Provides best tissue samples
• Excludes other processes that mimic IPF
• Biopsies should be obtained from more
than one lobe of the lung

ATS/ERS Consensus Statement. Am J Respir Crit Care Med. 2000;161:646-664;

2002;165:277-304.
 CONTRASTING PATHOLOGIC FEATURES OF IIP
Feature UIP DIP/RBILD AIP NSIP

Temporal appearance Variegated Uniform Uniform Uniform

Interstitial inflammation Scant Scant Scant Usually

prominent
Collagen fibrosis Patchy Variable, diffuse No Variable,
diffuse
in DIP; focal, mild
in RBILD
Fibroblast proliferation Fibroblastic foci No Diffuse Occasional,
diffuse, or rare
fibroblastic foci
Organizing pneumonia No No No Occasional,
focal
Honeycomb changes Yes No No Rare
Intraalveolar macrophage Occasional, focal Diffuse in DIP; No Occasional,
patchy
accumulation peribronchiolar in
RBILD
Hyaline membranes No No Occasional, No
focal
Katzenstein ALA et al. Am J Respir Crit Care Med. 1998;157:1301.
ATS/ERS diagnostic criteria for IPF
ATS/ERS diagnostic criteria for IPF
TREATMENT OF IPF
RATIONALE FOR TREATEMENT
 Treatment is based on concept that
inflammation leads to injury and fibrosis

 Most treatment strategies have been based

on eliminating the inflammatory component

 Little information has appeared to support the

theory that fibrosis can be reversed
 TREATMENT OF IPF
CONVENTIONAL TREATMENT OPTIONS
 CORTICOSTEROIDS
 IMMUNOSUPPRESSIVE / CYTOTOXIC AGENTS
AZATHIOPRIM
CYCLOPHOSPHAMIDE
 ANTIFIBROTIC AGENT
COLCHICINE
PIRFENIDONE
D-PENICILLAMINE
 RECOMMENDATIONS FOR TREATMENT
Initiation of therapy
 CORTICOSTEROIDS (PREDNISONE)

0.5 mg/kg/day orally for 4 weeks then

0.25 mg/kg/day for 8 weeks then
0.125 mg/kg/day or
0.25 mg/kg every alternate day
 TREATMENT OF IPF
CONVENTIONAL TREATMENT OPTIONS
 CORTICOSTEROIDS
- Maintenance steroid therapy to be reserved for
patients exhibiting stabilization or objective
improvement

- Relapses or deterioration warrant escalation of dose or

addition of an immunosuppressive agent
 TREATMENT OF IPF
CONVENTIONAL TREATMENT OPTIONS
 CYTOTOXIC AGENTS ( Steroid sparing)
Indications
- steroid non-responders
- patients experiencing serious adverse affects from
steroids
- patients at high risk of steroid complications (age
> 70 years, poorly controlled diabetes mellitus
or hypertension, severe osteoporosis , or peptic
ulcer disease)

Am Rev Respir Dis.1991;144:291-296

 TREATMENT OF IPF
CONVENTIONAL TREATMENT OPTIONS

AZATHIOPRIM
 combination with steroids was associated with modest
improvement and enhanced survival in some patients

 2-3 mg/kg (LBW)/day (max. 150 mg/day)

 begin at 25-50 mg/day increase by 25 mg every 7-14

days
 TREATMENT OF IPF
POTENTIAL ALTERNATIVE TREATMENTS
Possible future therapeutic strategies include

- agents that inhibit cytokines, proteases, `

oxidants, or fibroblast growth factors
- antifibrotic agents
- dietary modifications
- diphosphonates
- antioxidants
- gene therapy
 TREATMENT OF IPF
POTENTIAL ALTERNATIVE TREATMENTS
 OTHER ANTIFIBROTIC AGENTS

Interferon Y
Interferon B
Pirfenidone
Halfuginone
Suramin
Prostaglandin E2
TREATMENT OF IPF
POTENTIAL ALTERNATIVE TREATMENTS

 OTHER NOVEL AGENTS

- Antioxidant
- Glutathione
- Niacin
- N-acetylcysteine
 STAGING AND PROGNOSIS

 INDICATORS OF GOOD PROGNOSIS

 Younger age < 50 years
 Female
 Shorter symptomatic period (<1year) with less
dyspnea, relatively preserved lung function
 Presence of ground glass and reticular opacities on
HRCT
 RECOMMENDATIONS FOR TREATMENT
Length of therapy

 Objective response to therapy may not be evident

until the patient has received  3 months of therapy
 In absence of complications or adverse effects the
therapy should be continued for at least 6 months
 RECOMMENDATIONS FOR TREATMENT
Pulmonary Rehabilitation Program

 For motivated patients a combination of exercise

training, education, and psychological support
may help, not by improvement in lung function, but by
improvement in exercise tolerance, decreased symptoms
of breathlessness, improved quality of life, and less need
for health care services.

Chest.1998;113:263S-268S
 RECOMMENDATIONS FOR TREATMENT
Lung Transplantation
 INDICATIONS
Severe functional impairment
oxygen dependency
deteriorating course
 CONTRAINDICATIONS
Unstable psychosocial profile
significant extrapulmonary disorders
age > 60 years

Am J Respir Crit Care Med. 1998; 158:335-339

RISK FACTORS FOR
PROGRESSIVE DISEASE
 Age: >50 yr
 Gender: male
 Dyspnea: moderate to severe with exertion
 History of cigarette smoking
 Lung function: moderate to severe loss (especially
gas exchange with exercise)
 BAL fluid: neutrophilia or eosinophilia at presentation
 HRCT scan: reticular opacities or honeycomb changes
 Response to corticosteroids: poor
 Pathology: more fibrosis, fibroblastic foci
 CONCLUSSION
(Treatment of IPF)

 Till date insufficient clinical evidence to

conclude that any treatment improves
survival or quality of life for patients with
IPF
ILD secondary to Connective
tissue diseases
 Rheumatoid arthritis
 Systemic sclerosis
 Sjogren syndrome
 Systemic lupus erythematosus
 Idiopathic inflammatory myopathies
General approach
 ILD is often asymptomatic at presentation
 Rarely , it may be the first sign of
presentation of disease
 Systemic disease so disease usually has
features in joints, skin, etc
 Difficulty in swallowing, raynaud’s
phenomena, proximal muscle weakness.
 Restrictive pattern on PFT
Serological tests
Treatment principles
 Treatment of underlying disease
 Steroids and immunosuppressive agents
 Multi-disciplinary approach
 Long duration of treatment
 Supportive treatment and pulmonary
rehabilitation
 Treat co-morbidities and limit treatment
related side effects
 Lung transplantation
Thank You