Interstitial Lung Disease

Diffuse Parenchymal lung disease

 Introduction
Interstitial lung disease, or diffuse
parenchymal lung disease, comprises a
heterogeneous group of disorders that share a
common response of the lung to injury:

• Alveolitis, or inflammation

• Fibrosis of the inter-alveolar septum

• The term "interstitial" is misleading since the
pathologic process usually begins with injury to the
alveolar epithelial or capillary endothelial cells

• Persistent alveolitis may lead to obliteration of

alveolar capillaries and reorganization of the lung
parenchyma, accompanied by irreversible fibrosis

• The process does not affect the airways proximal to

the respiratory bronchioles

• At least 180 disease entities may present as interstitial

lung diseases
Differential diagnosis of interstitial lung disease.
Drug-related   
• Antiarrhythmic agents (amiodarone)  
• Antibacterial agents (nitrofurantoin, sulfonamides)  
• Antineoplastic agents (bleomycin, cyclophosphamide,
methotrexate, nitrosoureas)  
• Antirheumatic agents (gold salts, penicillamine)  
• Phenytoin
Environmental and occupational (inhalation
exposures)   
• Dust, inorganic (asbestos, silica, hard metals, beryllium)  
• Dust, organic (thermophilic actinomycetes, avian antigens,
Aspergillus species)
• Gases, fumes, and vapors (chlorine, isocyanates, paraquat,
sulfur dioxide)  
• Ionizing radiation  
• Talc (injection drug users)
 Infections   
• Fungus, disseminated (Coccidioides immitis,
Blastomyces dermatitidis, Histoplasma capsulatum)   
• Mycobacteria, disseminated  Pneumocystis jiroveci   
• Viruses
Primary pulmonary disorders   
• Cryptogenic organizing pneumonitis (COP)  
• Idiopathic fibrosing interstitial pneumonia,Acute
interstitial pneumonitis, desquamative interstitial
pneumonitis, nonspecific interstitial pneumonitis,
usual interstitial pneumonitis, respiratory
bronchiolitis-associated interstitial lung disease  
• Pulmonary alveolar proteinosis
 Systemic disorders   
• Acute respiratory distress syndrome  
• Amyloidosis  Ankylosing spondylitis  `
• Autoimmune disease: Dermatomyositis, polymyositis,
rheumatoid arthritis, systemic sclerosis (scleroderma),
systemic lupus erythematosus  
• Chronic eosinophilic pneumonia  
• Goodpasture's syndrome 
•  Idiopathic pulmonary hemosiderosis  
• Inflammatory bowel disease  
• Langerhans cell histiocytosis (eosinophilic granuloma)  
• Lymphangitic spread of cancer (lymphangitic
carcinomatosis)  
• Lymphangioleiomyomatosis  
• Pulmonary edema  
• Pulmonary venous hypertension, chronic 
•  Sarcoidosis  
• Wegener's granulomatosis
 Etiology
• In most patients, no specific cause can be
identified

• In the remainder, drugs and a variety of

organic and inorganic dusts are the principal
causes
 Clinical Features
• The clinical consequence of widespread lung
fibrosis is diminished lung compliance, which
presents as restrictive lung disease

• Patients usually describe an insidious onset of

exertional dyspnea and cough

• Sputum production is minimal

• The history—particularly the occupational and
medication history—may provide evidence of
a specific cause

• Chest examination reveals fine, late inspiratory

crackles at the lung bases

• Digital clubbing
Digital clubbing
 Investigations
• Pulmonary function testing:
It shows a loss of lung volume with normal to
increased airflow rates
The diffusing capacity for carbon monoxide is
decreased

• Arterial Blood Gases:

Hypoxemia with exercise is common
In advanced cases, resting hypoxemia may be present
Chest radiograph:
• The chest radiograph is normal in some patients on presentation
• More typically, it shows patchy distribution of ground-glass,
reticular, or reticulonodular infiltratess
• In advanced disease there are multiple small, thick-walled cystic
spaces in the lung periphery ("honeycomb" lung)
• Honeycombing indicates the presence of locally advanced
fibrosis with destruction of normal lung architecture

CT:
Conventional CT and high-resolution CT imaging reveal in
greater detail the findings described on chest radiograph. In
some cases, high-resolution CT may be strongly suggestive of a
specific pathologic process.
End-stage pulmonary fibrosis of unknown origin, taken from an
autopsy
The findings of interstitial disease include not only that the process has the localized
increased density but also radiating linear findings consistent with air bronchograms
indicating filled the distal alveoli while retaining the capacity for aeration
Diffuse interstitial infiltrates bilaterally, somewhat more central
than peripheral. No pleural effusions. No cardiomegaly
Pronounced reticulonodular pattern in the lower lobes
Pronounced reticulonodular pattern in the lower lobes
CT scan of the chest demonstrates recurrent nodular
interstitial lung disease, with more extensive
involvement
Interlobular septal thickening is commonly seen in patients with
interstitial lung disease. On HRCT, numerous clearly visible
septal lines usually indicates the presence of some interstitial
abnormality
• Serologic tests for antinuclear antibodies and
rheumatoid factor are positive in 20–40% of
patients but are rarely diagnostic

• Antineutrophil cytoplasmic antibodies

(ANCAs) may be diagnostic in some clinical
settings
• Invasive diagnostic testing
• Three diagnostic techniques are in common use

• Bronchoalveolar lavage

• Transbronchial biopsy

• Surgical lung biopsy

• Bronchoalveolar lavage may provide a specific diagnosis in cases

of infection, particularly with P jiroveci or mycobacteria, or when
cytologic examination reveals the presence of malignant cells.
• Transbronchial biopsy through the flexible bronchoscope can
make a definitive diagnosis of sarcoidosis, lymphangitic spread
of carcinoma, pulmonary alveolar proteinosis, miliary
tuberculosis, and Langerhans cell histiocytosis.
• Surgical lung biopsy is the standard for diagnosis of interstitial
lung disease

• Two or three biopsies taken from multiple sites in the same

lung, including apparently normal tissue, may yield a specific
diagnosis as well as prognostic information regarding the
extent of fibrosis versus active inflammation

• Patients under age 60 without a specific diagnosis generally

should undergo surgical lung biopsy

• In older and sicker patients, the risks and benefits must be

weighed carefully
 Idiopathic Fibrosing Interstitial
Pneumonia (Formerly: Idiopathic Pulmonary
Fibrosis)

The most common diagnosis among

patients presenting with interstitial
lung disease is idiopathic pulmonary
fibrosis
 Patients with idiopathic fibrosing interstitial
pneumonia may present with any of the
histologic patterns

• Usual interstitial pneumonia (UIP) 

• Respiratory bronchiolitis- associated
interstitial lung disease (RB-ILD)
• Acute interstitial pneumonitis (AIP) 
• Nonspecific interstitial pneumonitis (NSIP) 
• Cryptogenic organizing pneumonitis
(formerly bronchiolitis obliterans
organizing pneumonia [BOOP]) 
 Evaluation
• The first step in evaluation is to identify patients
whose disease is truly idiopathic as most identifiable
causes of interstitial lung disease are infectious, drug-
related, or environmental or occupational agents

• Apart from acute interstitial pneumonia, the clinical

presentations of the idiopathic interstitial pneumonias
are sufficiently similar to preclude a specific
diagnosis
 Clinical Presentation
• Progressive exertional dyspnea

• Persistent dry cough

• Gross clubbing of fingers and toes

• Chest examination: Chest expansion is poor

• Numerous bilateral end-expiratory crackles

 Laboratory findings
• Pulmonary function tests show restrictive pattern

• Abnormal gas exchange is the hallmark of the disease

• Chest X-ray: Diffuse pulmonary opacities

• Advanced disease shows honeycomb lung: diffuse

pulmonary shadowing is interspersed with small
cystic translucencies

• High-resolution CT scans are occasionally diagnostic

even in early disease
• Patients with apparently idiopathic disease require
surgical lung biopsy to make a definitive diagnosis

• Accurate diagnosis allows the clinician to provide

accurate information about the cause and natural
history of the illness and also helps distinguish
patients most likely to benefit from therapy

• Surgical lung biopsy may spare these patients from

treatment with potentially morbid therapies
 Criteria for Diagnosis
Definitie Diagnosis

• Surgical Biopsy showing Usual interstitial pneumonia UIP

• Exclusion of other causes of interstitial lung disease e.g. drug

toxicities, environmental exposure and collagen vascular
diseases

• ↓ FEV1/FVC

• ↑ A-a DO2 and ↓ DL

• Chest X-ray and CT changes

 Clinical Diagnosis
• In the absence of surgical biopsy clinical diagnosis
includes all of the major criteria and at least 3 of the
4 minor criteria

• Major criteria:
1. Exclusion of other causes
2. Pulmonary function with restrictice pattern,
↓diffusing capacities, and ↑ A-a gradient
3. Bibasilar reticular abnormalities with ground glass
opacities on CT
4. Tranbronchial biopsies or Bronchialveolar lavage
 Minor Criteria

1. Patient older than 50 years

2. Insidious onset of otherwise unexplained
dyspnea upon exertion
3. Duration of illness more than 30 days
4. Bibasilarr inspiratory crackles
 Treatment
Therapeutic goal:

• To supress the alveolitis

• To prevent fibrosis

• Prevent continued destruction of lung

parenchyma
• Corticosteroids:
They are the drug of choice
Response is favorable if alveolitis is predominant and less
beneficial in advanced honeycombing

• Immunosuppressive agents:
They suppress B cells and T-cells function.
Used alone or in combination with steroids

• Antiviral Cytokines
Interferon gamma and interferon beta may be used to inhibit
proliferation of fibroblasts and suppress connective tissue
protein

• Antifibrotic agents
Pirfenidone inhibits Transforming growth factor beta stimulated
collagen synthesis, blocks fibroblast proliferation and decrease
extracellular matrix
 Sarcoidosis
It is a multisystem granulomatous disease
of unknown origin characterized by
activation of T lymphocytes and
mononuclear phagocytes at the site of
disease
 Etiology and Pathogenesis
• It can affect any organ but lungs and Intra-thoracic
lymph nodes are more commonly affected

• Cause is Unknown

• Current theory suggests that sarcoidosis develops in

genetically predisposed individuals who are exposed
to certain environmental agents that trigger an
exaggerated inflammatory immune response leading
to granuloma formation
 Pathology

Pathological hallmark is presence of discrete,

non-caseating, epithelioid cell granulomas
Histopathology of cutaneous sarcoidosis, demonstrating
the presence of ill-defined noncaseating granulomas
 Clinical features
• Patients may present with malaise, fever, and
dyspnea of insidious onset

• Symptoms referable to the skin, eyes,

peripheral nerves, liver, kidney, or heart may
also cause the patient to seek care

• Some individuals are asymptomatic and come

to medical attention after abnormal findings
(typically bilateral hilar and right paratracheal
lymphadenopathy) on chest radiographs
Erythema nodosum of the lower legs
Plaque of sarcoidosis on the face
Skin manifestations in patients with sarcoidosis
Multiple plaques of sarcoidosis on the trunk
Punched-out choroidoretinal lesions in a patient
with sarcoidosis
Conjunctival nodules in a patient with
sarcoidosis
• Physical findings are atypical of interstitial
lung disease: crackles are uncommon on chest
examination

• Other findings may include erythema

nodosum, parotid gland enlargement,
hepatosplenomegaly, and lymphadenopathy
 Laboratory Findings
• Laboratory tests may show leukopenia, an elevated
erythrocyte sedimentation rate, and hypercalcemia or
hypercalciuria.

(Sarcoidosis patients manufacture the 1,25-D hormone within the

inflammatory granuloma, under the influence of Angiotensin II and
Interferon-gamma, so most Sarcoidosis patients possess high levels of
1,25-D in their blood leading to hypercalcemia)

• Pulmonary function testing may reveal evidence of airflow

obstruction, but restrictive changes with decreased lung
volumes and diffusing capacity are more common

• Skin test anergy is present in 70%

• ECG may show conduction disturbances and dysrhythmias

 Imaging
• Radiographic findings include bilateral hilar
adenopathy, and parenchymal involvement

• Parenchymal involvement is usually manifested

radiographically by diffuse reticular infiltrates
but focal infiltrates, acinar shadows, nodules,
and, rarely, cavitation may be seen

• Pleural effusion is noted in fewer than 10% of

patients
Bilateral symmetrical hilar lymphadenopathy
and lung infiltration
Chest xray showing sarcoidosis
Sarcoidosis - hilar adenopathy
 Special Examinations
• The diagnosis of sarcoidosis generally requires histologic
demonstration of noncaseating granulomas in biopsies

• Biopsy of easily accessible sites (eg, palpable lymph nodes, skin

lesions, or salivary glands) is likely to be positive

• Transbronchial lung biopsy is positive, especially in patients with

radiographic evidence of parenchymal involvement

• Bronchoalveolar lavage fluid in sarcoidosis is usually characterized

by an increase in lymphocytes and a high CD4/CD8 cell ratio

• Bronchoalveolar lavage does not establish a diagnosis but may be

useful in following the activity of sarcoidosis in selected patients

• All patients require a complete ophthalmologic evaluation.

 Treatment
• Oral corticosteroids (prednisone, 0.5–1.0
mg/kg/d)

• Long-term therapy is usually required over

months to years.

• Immunosuppressive drugs and cyclosporine

have been tried, primarily when corticosteroid
therapy has been exhausted, but experience
with these drugs is limited