Driss Raissi, MD Department of Internal Medicine

A 61- year old female smoked cigarettes for 10 years

but stopped smoking 5 years ago. She has experienced increasing dyspnea for months along with a nonproductive cough. A chest radiograph shows prominent hilar lymphadenopathy. A transbronchial biopsy is performed, and the microscopic findings include interstitial fibrosis and small noncaseating granulomas. One of the granulomas contains an asteroid body in a giant cell. The disease is believed to be caused by
A.) Delayed hypersensitivity response to an unknown antigen B.) Immune complexes formed in response to inhaled antigens C.) Diffuse alveolar damage (DAD) D.) Smoke inhalation for many years E.) Infection with atypical mycobacteria

 Which of the following clinical or

morphological features is common to all forms of pneumoconiosis?

A.) Marked thickening of the pleura

B.) Increased risk of bronchogenic carcinoma C.) Formation of noncaseating granulomas D.) Interstitial pulmonary fibrosis E.) Increased risk of tuberculosis

Definition
A heterogenous group of diseases characterized

predominantly by diffuse and chronic involvement of the pulmonary connective tissue, principally the most peripheral and delicate interstitium in the alveolar walls
Interstium consists of: The basement membrane of the endothelial and epithelial cells Collagen fibers Elastic tissue Proteoglycans Fibroblasts Mast cells Occasionally lymphocytes and monocytes

History
Inherited forms of ILD- commonly

between the ages of 20-40 years Idiopathic Pulmonary Fibrosiscommonly over the age of 50 Most ILDs have a male predominance
lymphangioleiomyomatosis and tuberous

sclerosis have a predominance of premenopausal women

Familial History
Autosomal dominant- Idiopathic

pulmonary fibrosis, Sarcoidosis, Tuberous sclerosis, Neurofibromatosis

Autosomal Recessive- Niemann Pick

disease, Gauchers disease, HermanskyPudlak syndrome

Symptoms and Signs

Shortness of Breath on

exertion (dyspnea)major symptom Persistent dry Cough (as in flu or postviral infection) Hemoptysis Arthralgia

Physical Exam Crackles/ Velcro rales Inspiratory squeaks/ high-pitched rhonchi Cor pulmonale mid to late pulmonary fibrosis Pulmonary Hypertension Cyanosis- late manifestation Clubbing- IPF, asbestosis late manifestation

Laboratory Studies
Chest X-ray- initial test Normal in up to 10% of patients Reticular, nodular, and mixed patterns Hematological tests to check for anemia,

polycythemia, or leukocytosis High Resolution CT Serum markers

Surfactant protein A and B (SP A/B) Monocyte chemoattractant protein-1 (MCP-1) KL-6- circulating high molecular weight

glycoprotein

expressed by type II pneumocytes

Microscopic findings

Alveoli filled with inflammatory exudate

Pulmonary Function Testing

Complete lung function testing
Spirometry, lung volumes, diffusing

capacity Obstructive vs. Restrictive

Most have a restrictive pattern: decreased total

lung disease, functional residual capacity, and residual volume Decreased flow rates (FEV1 and FVC) proportionally, therefore the FEV1/ FVC ratio is normal (or increased)

Pulmonary Function Test

Resting room air arterial blood gases
May be normal Hypoxemia due to mismatched

ventilation/perfusion Respiratory alkalosis Carbon dioxide retention (rare)- evidence of end stage disease

Pulmonary Function Test

Measuring the diffusing capacity Commonly decreased due to:
Effacement of alveolar capillary units Mismatched ventilation and perfusion of alveoli

Moderate to sever reduction with normal

lung volumes suggest possibilities of:

Combined emphysema and ILD

Pulmonary vascular disease

Pulmonary Langerhans cell histocytosis Lymphangioleiomyomatosis

Assessment
Bronchoalveolar Lavage (BAL) Lung Biopsy Fiber optic bronchoscopy with transbronchial lung biopsy initial choice
Sarcoidosis, lymphangitic carcinamatosis,

Surgical lung biopsy

eosinophilic pneumonia, Goodpastures syndrome, pulmonary Langerhans cell histocytosis, or infection

Larger and multiple lung tissue samples Samples obtained by either open thoracotomy or by

video-assisted thorascopic lung surgery

Open thoracotomy required because of severe pleural

disease or more definitive control of bleeding

Lung Biopsy
Indications Provide a specific diagnosis
Especially useful in patients with atypical features,

progressive course, rapidly changing chest X-ray, unexplained extrapulmonary manifestations, or unexplained pulmonary vascular disease

Access disease activity Exclude neoplastic and infectious processes Identify a more treatable process Make a definitive diagnosis and predictive

prognosis for effective therapy

Bronchoalveolar Lavage
BAL fluid of a healthy, non-smoking

adult without lung disease includes a small amount of lymphocytes, neutrophils, and eosinophils with a predominant population of alveolar macrophages Most diagnostic for malignancies or opportunistic infections

BAL
Pulmonary Hemorrhage

-frankly bloody or blood-tinged BAL fluid -hemophagocytosis by alveolar macrophages -presence of hemosiderin-laden macrophages Sarcoidosis -predominance of T-lymphocytes with an elevated CD4/CD8 -late/advanced stage- increase in CD8 lymphocytes and neutrophils Hypersensitivity pneumonitis -Lymphocytosis and a decreased CD4+/CD8+ ratio -May also have a substantial number of mast cells indicating ongoing exposure -Advanced stages demonstrate eosinophilia -Active Alveolitis is indicated by plasma cells and higher immunoglobulin and IgG to albumin ratios

Idiopathic Pulmonary Fibrosis

Inflammatory response to an unknown

agent

Characterized histologically by diffuse

interstitial inflammation and fibrosis

Disease of the lower respiratory tract

that damages the alveoli leading to decreased oxygen transfer to blood Common among 50-70 years old

IPF

Normal Lung- cut surface and pleura smooth and homogenous IPF- cut surface demonstrates patchy involvement of lung with fibrous scarring around dilated airspaces forming a honey comb pattern

IPF- Diagnosis
Chest X-ray
Routine blood test CT scan of Chest

Pulmonary Function Test

Bronchoscopy with transbronchial lung

biopsy Surgical lung biopsy Arterial blood gas analysis

Pathogenesis
Stereotyped inflammatory response of

alveolar walls

Some form of injury to alveolar wall resulting in

interstitial edema and accumulation of inflammatory cells (alveolitis) Type I pneumocytes especially susceptible to injury Hyperplasia in Type II pneumocytes in attempts to regenerate alveolar epithelial lining Fibroblasts proliferate and progressive fibrosis of both intra-alveolar exudate and interalveolar septa results in obliteration of normal pulmonary

IPF- Microscopic findings

Normal lung- alveolar wall consists mainly of a single capillary loop with minimal connective tissue IPF- interstitial fibrosis and replacement of alveolar epithelium by bronchiolar epithelium

Clinical Course
Patients exhibit varying degrees of

respiratory difficulty Advanced cases lead to hypoxemia and cyanosis Can develop severe secondary pulmonary hypertension, cor pulmonale, and cardiac failure Median survival is less than 5 years

Hypersensitivity Pneumonitis (Extrinsic Allergic Alveolitis)

Describes a spectrum of

immunologically mediated, predominantly interstitial lung disorders caused by intense, prolonged exposure to inhaled organic dusts and related occupational antigens Categorized as acute, subacute, or chronic
Depends on the frequency, length,

intensity of exposure, and duration of subsequent illness

Acute Hypersensitivity Pneumonitis

Most classic form
May follow heavy exposure to an inciting agent Symptoms confused with a viral or bacterial infection Fever, chills, malaise, nausea, cough, chest tightness, and dyspnea without wheezing Physical exam Tachypnea and diffuse fine rales Initially treated with antibiotics

Removal of exposing agent results in subsiding of

symptoms within 12 hours to several days and complete resolution May recur with reexposure

Acute HP
Laboratory findings (limited use) Increased ESR Increased quantitative immunoglobulins Increased serum LDH decline with improvement Positive precipitating IgG serum antibodies to common antigens May also find positive Rheumatoid factor
Elevated C-reactive protein Circulating immune complexes

BAL may show lymphocytosis

Arterial blood gases show mild hypoxemia Pulmonary function test- restrictive ventilatory defect during

symptomatic episodes

Acute HP
Histopathology
Poorly formed, noncaseating

interstitial granulomas Mononuclear cell infiltration in a peribronchial distribution with prominent giant cells
Radiographic findings
Fleeting, micronodular,

interstitial pattern in lower and middle lung zones CXR usually normal, HRCT used for confirmation

Subacute Hypersensitivity Pneumonitis

Gradual development
Symptoms Productive cough, dyspnea, fatigue, anorexia, and weight loss Physical Exam Tachypnea and diffuse rales

Removal from exposure results in

complete resolution (weeks to months) Corticosteroid therapy may be required

Subacute HP
Laboratory findings BAL shows lymphocytosis Mild hypoxemia Pulmonary function test

Radiographic findings Micronodular or reticular opacities Most prominent in middle and upper lung zones HRCT

Restrictive or mixed ventilatory pattern Reduced DLCO

Histopathology Well formed noncaseating granulomas in interstitium Bronchiolitis with or without organizing pneumonia Interstitial fibrosis

Diffuse micronodules Ground-glass attenuation Focal air trapping or emphysema Mild fibrotic changes

Chronic Hypersensitivity Pneumonitis

Lack history of acute episodes
Insidious onset of cough, dyspnea,

fatigue, and weight loss Advanced disease- clubbing of digits, disabling/irreversible respiratory findings from pulmonary fibrosis Removal of exposing agent results in only partial improvement with requirement of prednisone therapy

 Lab findings (minimal use) BAL- lymphocytosis, neutrophilia,

Chronic HP

eosinophilia Restrictive, mixed, or severe obstructive pattern Reduced diffusing capacity Resting or exertional hypoxemia Radiographic findings Progressive fibrotic changes with loss of lung volume mostly effecting the upper lobes Honeycombing and/or emphysema Diagnostic evaluation Requires open or video assisted thorascopic lung biopsy Biopsy shows diffuse interstitial pneumonitis, bronchiolitis obliterans, distal destruction of alveoli (honeycombing), and densely fibrotic zones

Pulmonary Eosinophilia
Disorders that share the feature of

abnormally increased numbers of eosinophils within the pulmonary parenchyma Defining characteristics needed for diagnosis:
Peripheral blood eosinophilia with identified

pulmonary abnormalities Lung tissue eosinophilia in transbronchial or open lung biopsies Increased eosinophils in BAL

Helminthic infections Lofflers syndrome

From Ascaris lumbricoides,

hookworm, and Strongyloides stercoralis Life cycles in which infecting larvae reach the lungs via the bloodstream, penetrate the alveoli and ascend the airways before descending down to small bowel Symptomatic patients- irritating, nonproductive cough and burning substernal discomfort aggravated by coughing or deep breathing. Also present with dyspnea, wheezing, fever, and blood tinged sputum contain eosinophil derived Charcot Leyden crystals Chest radiograph may show round or oval infiltrates

 Pulmonary parenchymal invasion Directly invades pulmonary parenchyma and produces long lasting manifestations Paragnonimus lung flukes invade lungs and produce pleural effusions or eosinophil enriched inflammatory infiltrates Symptoms- recurrent hemoptysis, chocolate colored sputum composed of a mixture of blood, inflammatory cells, and paragonimus eggs Blood eosinophila prominent in early stages Heavy hematogenous seeding Pulmonary responses provoked by heavy deposition of helminthic larvae or eggs carried via the bloodstream to the lungs Symptoms- cough, wheezing, dyspnea, and blood eosinophilia Tropical pulmonary eosinophilia From a distinct immune response to the bloodborne microfilarial stages of the lymphatic filarie (Wuchereria bancrofti and Brugia malayi)

Helminthscontinued..

Medications and Toxins

Toxin exposures Aluminum silicate and particulate metals Scorpion stings Inhalation of heroin or crack cocaine Inhalation of dust or smoke Inhalation of organic chemicals during rubber manufacture Most common medications- NSAIDs and

antimicrobials

Less common- phenytoin, L-tryptophan, rantidine,

trazodone, GM-CSF

Acute vs Chronic Eosinophilic pneumonia Acute (AEP)

Idiopathic, possibly cause of acute respiratory

Chronic (CEP) Idiopathic Predominantly women and nonsmokers affected Abnormal accumulation of eosinophils in lungs Subacute illness with cough, fever, progressive breathlessness, weight loss, wheezing and night sweats Asthma may accompany or precede 50% of cases Chest radiograph- pathognomonic finding is peripheral or pleural based infiltrates described as photographic negative of pulmonary edema

failure Acute febrile illness less than 7 days with nonproductive cough, and dyspnea Histopathology shows diffuse alveolar damage, hyaline membranes, and marked numbers of interstitial and alveolar eosinophils

Churg-Strauss Syndrome
Vasculitic disorder

characterized by sinusitis, asthma, and prominent peripheral blood eosinophilia Chest X-ray consist of transient and patchy opacities without lobar or segmental distribution Lung biopsy reveals eosinophilic infiltrates, an eosinophilic vasculitis, interstitial, and perivascular necrotizing granulomas

 History

Diagnostic approach to pulmonary eosinophilia

Blood eosinophilia Imaging

Medication and chemical exposures Travel and immigration histories Respiratory history and findings Presence of symptoms or signs of extrapulmonary organ involvement

Most useful in diagnosis of AEP, CEP, and allergic bronchopulmonary

aspergillosis (ABPA)

AEP- triad of interlobular septal thickening, bronchovascular bundle thickening,

Invasive diagnostics

and pleural effusions CEP- airspace consolidation and areas of ground glass attenuation predominantly in the peripheral regions of the middle or upper lung zones

BAL- fluid evaluated for the total and differential leukocyte counts If BAL is unrevealing- transbronchial, open lung biopsy, or video-assisted

thorascopic surgery may be performed

Other ILDs.
Desquamative interstitial Pnemonitis
Bronchiolitis Obliterans-Organizing

Pneumonia (BOOP) Diffuse Pulmonary Hemorrhage Syndromes

Goodpasture syndrome

Idiopathic Pulmonary Hemosiderosis

Pulmonary Alveolar Proteinosis

Pneumoconiosis
Describes the non-neoplastic lung

reaction to inhalation of mineral dusts commonly encountered in the workplace

Coal dust anthracosis Asbestosis Silicosis Berylliosis Less common dusts- iron dust, tin dust,

and barium dust

Coal workers pneumoconiosis Anthracosis

Asymptomatic anthracosis Pigment accumulates without a perceptible cellular reaction
Simple coal workers pneumoconiosis Accumulations of macrophages occur with little or no pulmonary dysfunction Complicated coal workers pneumoconiosis Fibrosis is extensive and lung function is compromised

Morphology
Inhaled carbon pigment is engulfed by

alveolar or interstitial macrophages Accumulate in the connective tissue along the lymphatics (including pleural lymphatics), in lymphoid tissue along the bronchi, or in the lung hilus

Simple CWP vs Complicated CWP

Simple Characterized by coal macules and larger coal nodules Coal macules consist of carbon laden macrophages Involves mainly the upper lobes and upper zones of the lower lobes Primarily located adjacent to respiratory bronchioles May lead to centrilobular emphysema in which there is dilation of adjacent alveoli Complicated Requires many years to develop Characterized by intensely blackened scars larger than 2 cm (up to 10 cm) Lesions consist of dense collagen and pigment, with central necrosis

Caplan Syndrome
Coexistence of Rheumatoid arthritis

with a pneumoconiosis Development of distinctive nodular pulmonary lesions Nodules have central necrosis surrounded by fibroblasts, macrophages, and collagen. May also be present in asbestosis and silicosis

 What is it?

Pneumoconiosis caused by

Asbestosis

inhalation of asbestos fibers Characterized by slowly progressive, diffuse pulmonary fibrosis

Asbestos bodies (Ferruginous

bodies)

Composed of transparent

asbestos fibers surrounded by a coating of iron and protein

Exposure to asbestos results

from:

Mining and milling of the

fibers Industrial applications (work with textiles, cement, insulation, shipbuilding) Nonoccupational exposure to airborne asbestos (renovation/

Asbestosis
Most likely caused by direct toxic effects of the fibers on

pulmonary parenchymal cells

In addition there is release of various mediators (reactive oxygen

Fibers deposit at respiratory bronchiole and alveolar duct

species, proteases, cytokines, and growth factors) by inflammatory cells

bifurcations leading to an accumulation of alveolar macrophages

Causes an inflammatory reaction which extends into the terminal

Most fibers are removed from the lungs by mucociliary

respiratory bronchioles and adjacent alveolar interstitium

mechanisms, however some are uptaken by alveolar macrophages and alveolar type I cells

Smoking increases progression rate of asbestosis possibly by

Late stage characterized by loss of alveolar type I and II cells

interfering with the mucociliary clearance of inhaled fibers

and an increase in the number of alveolar and interstitial macrophages, neutrophils, lymphocytes, and eosinophils
Eventually leads to fibroblast proliferation and collagen

accumulation

 Most patients asymptomatic for

Asbestosis- Clinical Findings

20-30 years after initial exposure Latency period between exposure and symptoms is inversely proportional to intensity of asbestos exposure Earliest symptom- insidious onset of breathlessness with exertion (dyspnea) With progression may develop:
Bibasilar, fine end-inspiratory

crackles Clubbing Cor pulmonale with peripheral edema, JVD, hepatojugular reflux, and/or right ventricular heave or gallop

Asbestosis- Pulmonary Function Tests

Earliest Abnormalities

- Decreased single breath DLCO - Decreased pulmonary compliance - Presence of exertional hypoxemia Reduced lung volumes- especially vital capacity and total lung capacity Absent airflow obstruction (normal FEV1/FVC ratio)
Airway obstruction may be present with an

additional exposure to cigarette smoking

AsbestosisRadiographic/Imaging studies
Small bilateral parenchymal opacities with a multinodular or reticular

pattern Begins in lower lung zones Associated with bilateral mid-lung zone plaques on the parietal pleura Hallmark of asbestos exposure is pleural involvement
About 50% of persons exposed to asbestos develop pleural plaques Involve mostly the parietal pleura adjacent to the ribs (6th- 9th) and along

Pleural adhesions may cause atelectasis of part of the peripheral lung

the diaphragm

which appears as a rounded appearance on a chest x-ray Early stages- hazy ground glass appearance that may blur the diaphragm and heart border leading to the shaggy heart sign Within 15 years of first exposure, production of benign exudative pleural effusions which resolve spontaneously
Advanced stage- honeycombing and upper lobe involvement

However they leave visible blunting of the costophrenic angle or thickening

of the visceral pleura

Asbestosis- imaging studies

Asbestosis- HRCT
High Resolution CT more sensitive than plain films
30% of exposed produce an abnormal HRCT despite

a normal chest x-ray Findings of asbestosis include:

Subpleural linear densities of varying length parallel to the

pleura Basilar and dorsal lung parenchymal fibrosis with peribronchiolar, intralobular, and interlobular septal fibrosis Coarse parenchymal bands Coarse honeycombing Pleural plaques

Diagnosing Asbestosis
Reliable history Proper latency period from onset of exposure to time of symptom presentation
Evidence of interstitial fibrosis- manifested

by:

Reduced lung volumes and/or DLCO end-inspiratory crackles Typical chest x-ray or HRCT findings Evidence of asbestos fibers/bodies in BAL fluid or

biopsy tissue

Management of Asbestosis
No specific treatment, mostly preventitive

measures

Smoking cessation Early detection- physiological or radiographical Prevention of further airborne asbestos exposure Supplemental oxygen for hypoxemia Prompt treatment of respiratory infections Pneumoccocal and influenza vaccination

Complications in Asbestosis
Respiratory Failure Risk factors

Malignancy Most common risk factor for malignant mesothelioma Greatly increased by coexisting exposure to cigarette smoking

Cumulative asbestos exposure Duration of exposure Fiber type (chrysotile vs amphibole) Symptoms of dyspnea Cigarette smoking Diffuse pleural thickening Honeycombing on HRCT High concentration of inflammatory cells and fibronectin in BAL fluid

Risk of dying of lung cancer with asbestosis increased 16x with history of

Other associated malignancies include cancers of larynx, oropharynx,

smoking 20+ cigarettes a day and a 9x increase with less than 20 cigarettes a day

kidney, esophagus, and biliary system

Berylliosis
Patient considered to have Berylliosis if they

have the following:

History of exposure Positive blood or BAL beryllium lymphocyte

proliferation test Noncaseating pulmonary granulomas on lung biopsy

85% of patients with Berylliosis have an HLA-

DPB1 variant containing a glutamine for lysine substitution

Marker for susceptibility to beryllium sensitivity

Pathogenesis of Berylliosis
Elicits immunologic reactions including a typical

delayed-type hypersensitivity reaction Induces a proliferative response in peripheral blood lymphocytes Lung mononuclear cell inflammation and granuloma formation is maintained by the accumulation of numerous CD4+ memory T cells in the lung Predominately Th1 response involving interferon gamma and IL-2 BAL- rich in CD4+ T cells and cells express increased levels of tumor necrosis factor-alpha and IL-6

 Common symptoms Dry cough, SOB, night sweats, fatigue, and weight loss Bronchial involvement includes symptoms similar to asthma Cutaneous nodules form on exposed surfaces Physical Exam Bibasilar rales Advanced disease- cor pulmonale and clubbing

Clinical and Lab Signs of Berylliosis

Continued.
Hypercalciuria and Hypercalcemia CXR- may be normal or show hilar adenopathy with reticulonodular

opacification Thin section CT more sensitive

Presence of parenchymal nodules, septal lines, ground glass opacities and

Pulmonary function test Early stage- increased VD/VT and abnormal gas exchange Diminished DLCO Airflow limitation , restriction, or a mixed pattern Blood Beryllium lymphocyte proliferation test (BePLT) Uses peripheral blood or BAL mononuclear cells Cell proliferation measured by the incorporation of triated thymidine into DNA of dividing cells Transbronchial biopsies Demonstrate noncaseating granulomas and/or mononuclear cell interstitial cell infiltrates (noncaseating granulomas also seen in skin nodules)

hilar or mediastinal adenopathy Pleural thickening adjacent to areas of dense subpleural parenchymal nodules

Treatment of Beryilliosis
Oral prednisone (20-40 mg) daily or every

other day for 3-6 months

Used when about 10% of lung volumes decreased

or a decrease in gas exchange compared to baseline

Immunosuppressive agents such as

Methotrexate (10-25mg/wk in divided doses) may be used if there is no response to steroids TNF-alpha agonists may also be an alternative

Silicosis
Inhalation of free crystalline silica
Include quartz, cristobalite, and tridymate

Three main radiographic presentations

Simple Silicosis Progressive massive fibrosis Silicoproteinosis

Radiographic Presentations of Silicosis

Simple Silicosis Profusion of small (less than 10mm diameter) nodule
Progressive Massive Fibrosis Gradual enlargement and coalesces of these nodules Form larger nodules in upper or midzone opacities Enlargement of opacities retract hila upwards with upper lobe fibrosis and hyperinflation of lower zones Presence of hilar adenopathy with prominent calcification In advanced stages cavitations may be present Silicoproteinosis Follows overwhelming exposure to silica in a short time period Hallmark of acute silicosis Characteristic basilar alveolar filling pattern without rounded opacities or lymph node calcifications in lower zone Progress to form large masses of coalesced parenchymal tissue in mid to lower zones that are typically bilateral but not symmetrical
Nodules are rounded and predominantly found in upper lung zones

Clinical and lab studies of Silicosis

Clinical symptoms- differentiated on interval between exposure

and development of symptoms

Chronic silicosis- develops slowly usually 10-30 years after first

exposure Acute silicosis develops after exposure to high concentrations and develops within a few weeks to a few years
Rapid onset of symptoms- cough, weight loss, fatigue, pleuritic pain,

Progressive massive fibrosis- develops within 10 years of initial

crackles, cyanosis, cor pulmonale, and respiratory failure Poor prognosis- survival less than 4 years
May be asymptomatic with only a abnormal CXR Symptomatic- chronic cough and dyspnea

exposure

coarse adventitious sounds or wheezing, decreased breath sounds, signs of chronic respiratory failure, and cor pulmonale Radiographic evidence- progressive coalescence of silicotic nodules leading to respiratory impairment (air trapping/ emphysema)

Associated Conditions with Silicosis

Increased susceptibility to Mycobacterial

infection Airflow obstruction Chronic bronchitis Possible lung cancer Tuberculosis Connective tissue disorders- strong association with scleroderma Also associated rarely with SLE, mixed connective tissue disease, systemic vasculitis, end-stage renal disease

Diagnosis of Silicosis
Three key elements History of silica exposure Chest imaging that shows opacities consistent with silicosis Absence of another disease
Pulmonary function test Excessive decline in spirometric performance
Mixed obstructive and restrictive ventilatory impairment with

decreased FEV1 and FEV1/FVC Decreased compliance and decreased DLCO also seen in PMF

Lung Biopsy Open lung biopsy preferred with an increased risk of pneumothorax

Pathology of Silicosis
Earliest changes seen in workers with chronic low

level exposure

Dust-laden macrophages and loose reticulin fibers in

peribronchial, perivascular, and paraseptal or subpleural areas Hallmark- silicotic nodules

Central zone of nodule is hyalinized and composed of

concentrically arranged collagen fibers Peripheral zone is whorled and less organized at the edges Nodules coalesce and forms progressive massive fibrosis Further enlarge and aggregate undergoing ischemic necrosis and cavitation Rarely seen in acute silicosis
Acute silicosis demonstrates alveolar filling with phospholipids or

surfactant

Cavitation commonly found in Progressive Massive Fibrosis

Treatment of Silicosis
No specific therapy
Symptomatic therapy Treatment of airflow obstruction with bronchodilators Treatment of respiratory tract infection with antibiotics and supplemental oxygen to prevent chronic hypoxemia Corticosteriod therapy used to interrupt inflammation Lung transplantation highly recommended for end-stage silicosis

Other Interstitial Lung Diseases..

Sarcoidosis
A systemic disease of unknown cause

characterized by noncaseating granulomas in many tissues 90% cases demonstrate visible bilateral hilar lymphadenopathy or lung involvement on CXR Eye and skin lesions are the next frequently involved Higher prevalance in women than men 10x higher in American blacks than whites Disease is almost unknown among Chinese and Southeast Asians

Pathogenesis
Increases in CD4+ lymphocytes within the

lung and an elevated level of soluble IL-2 receptors in serum and lung lavage fluid Macrophages show an increased class II HLA expression and increased antigen presenting capacity Activated T cells in lungs indicate a delayed hypersensitivity response to an inhaled antigen T cell proliferation in the sarcoid lung is oligoclonal rather than a generalized, nonspecific response

Clinical Course
May be discovered unexpectedly on routine chest films

Insidious onset of respiratory abnormalities

Bilateral hilar adenopathy May have peripheral lymphadenopathy Cutaneous lesions Eye involvement Splenomegaly Hepatomegaly SOB Cough Chest pain hemoptysis

Constitutional signs and symptoms

Fever/ night sweats Fatigue Weight loss/ anorexia

Clinical Coursecontinued
65-70% of affected patients recover with minimal or no residual

manifestations 20% have permanent loss of some lung function or some permanent visual impairment Remaining 10%- death by cardiac or CNS damage, progressive pulmonary fibrosis, and cor pulmonale Stage 1- Patients with hilar lymphadenopathy alone
Stage 2- Patients with adenopathy and pulmonary infiltrates Stage 3- Patients with pulmonary disease and no adenopathy
Few spontaneous remissions Most likely to develop chronic pulmonary fibrosis Best prognosis

 Classical noncaseating granulomas Composed of an aggregate of tightly clustered epitheloid cells Often have Langhans or foreign body type giant cells No central necrosis Chronic disease Granulomas may be enclosed within fibrous rims or may be replaced by hyaline fibrosis scars Laminated concretions composed of calcium and proteins (Schaumann bodies) Stellate inclusions (asteroid bodies) enclosed within giant cells Lymph node involvement Almost present in all cases- especially hilar and mediastinal nodes Nodes characteristically enlarged, discrete, and sometimes calcified Tonsils involved in 1/4 to 1/3 of cases Other lesions Skin
Eye

Morphology

Discrete subcutaneous nodules, focal slightly elevated erythematous plaques Lesions may be seen on mucous membranes of the oral cavity, larynx and upper respiratory tract

Iritis (bilateral or unilateral) Corneal opacities Glaucoma/ total vision loss Suppression of lacrimation due to inflammations in lacrimal glands

Sarcoidosis

Picture A- Granulomas in lymphangitic distribution around vessels

and bronchioles, with associated fibrosis Picture B- well defined granulomas of tight clusters of macrophages and giant cells with a rim of lymphocytes with no evidence of necrosis

Drug-Induced Lung Disease

Amiodarone Pulmonary Toxicity

Used for suppressing ventricular and

supraventricular tachyarrythmias Toxicity closely correlates with total dosage rather than serum drug levels Clinical presentations maybe in several forms
Chronic interstitial pneumonitis Organizing pneumonia Acute respiratory distress syndrome Solitary pulmonary mass

Clinical Presentations
Chronic Interstitial pneumonitis Most common presentation- seen after 2-3 months of therapy Insidious onset of nonproductive cough, dyspnea, and weight loss CXR- focal or diffuse interstitial opacities Organizing pneumonia Seen in 25% of cases More acute presentation Nonproductive cough, pleuritic chest pain, fever, dyspnea, crackles, and pleural rub CXR- patchy alveolar opacities

Pathology
Chronic interstitial pneumonitis- characterized

by nonspecific interstitial pneumonitis predominantly composed of mononuclear cells, foamy alveolar macrophages, type II hyperplasia, and fibrosis All other exposed patients present with numerous foamy macrophages in the air spaces
Cells filled with amiodarone-phospholipid

complexes Accumulation of phospholipids within lysosomes in

Mechanism of Amiodarone induced toxicity

Direct toxic injury vs. Indirect immunologic reaction
Direct toxic injury Long half life of med and high affinity for lung tissue Accumulation of cellular drug-phospholipid complexes leading to direct cell injury and death Alters phospholipid bilayer disrupting cellular and organelle membrane function Toxic oxygen species injuring tissue Chronic inflammation leading to cellular injury

Indirect immunologic reaction Lymphocytic infiltration with intraalveolar buds CD8 T-cell lymphocytosis Positive IgG

Risk factors
Drug dosage >400 mg/day
Duration of therapy exceeding 2

months Increasing age Preexisting lung disease Thoracic/non-thoracic surgery Pulmonary angiography

Diagnosis
One of exclusion Differentials

Necessities for clinical diagnosis (3 or more required)

Heart failure Infectious pneumonia Pulmonary embolism malignancy

New or worsening symptoms New abnormalities on CXR Decline in total lung capacity or DLCO Presence of phospholipids in lung cells Marked CD8+ lymphocytosis in lavage fluid Lung biopsy revealing diffuse alveolar damage, organizing pneumonia, interstitial pneumonitis, or fibrosis Improvement in lung manifestations following withdrawal of drug

Diagnosiscontinued
Symptoms
Nonproductive cough and dyspnea in 50-75% of patients Pleuritic pain, weight loss, fever and malaise in 33-50% of patients Bilateral inspiratory crackles Peripheral blood findings are nonspecific but include increased

Lab/ Imaging studies

WBCs, LDH and ESR Measurement of KL-6 (mucin-like HMW glycoprotein secreted by proliferating type II pneumocytes) is a promising marker CXR- diffuse or localized interstitial, alveolar, or mixed opacities CT- increased attenuation in lungs, liver, and spleen due to accumulation of iodinated drug in tissue macrophages Increased gallium uptake in the lung is a sensitive marker

Diagnosis.continued
BAL

Lung biopsy Reveals parenchymal lung changes consistent with nonspecific interstitial pneumonitis, organizing pneumonia, or diffuse alveolar damage Pulmonary function test Not diagnostic

Lymphocytosis Neutrophilia Eosinophilia Normal BAL cellular counts Detection of foam cells CD8 predominant lymphocytic or neutrophilic alveolitis Increased phospholipid content

Treatment
Primarily stopping amiodarone
Corticosteroid therapy for severe cases

or ones in which patients do not recover from withdrawal alone

prednisone 40-60 mg/day with tapering

over 2-6 months

Bleomycin Pulmonary Toxicity

Chemotherapeutic antibiotic Contains an enzyme bleomycin hydrolase which is active

in all tissues except the skin or lungs, which may lead to toxicity Acute pulmonary toxicity may be a result of DNA strand scission with resulting chromosomal injury Chronic fibrotic response associated an acquired loss of bleomycin hydrolase activity mediated by an immunologic mechanism Migration of activated effector cells in the lung and release of proinflammatory mediators that result in pulmonary fibrosis Fatality occurred about 4x as frequently in patients who received >500mg in comparison to patients receiving <450 mg

Bleomycin toxicity- risk factors

Risk of toxicity increased by high

concentrations of inspired oxygen, whereas low oxygen concentrations greatly reduce the risk Thoracic irradiation Renal insufficiency

Clinical presentation
Subacutely- between 1-6 months after

treatment

Symptoms- nonspecific, nonproductive

cough, dyspnea, pleuritic or substernal chest pain, fever, tachypnea, rales, lung restriction, and hypoxemia CXR- bibasilar subpleural opacification with volume loss and blunting of the costophrenic angles sometimes with fine nodular densities Progresses to form honeycombing

Pathological findings
Subpleural distribution of lung injury and

fibrosis Patchy distribution of diffuse alveolar damage Inflammatory component consisting predominantly of lymphocytes and plasma cells Endothelial and type I epithelial cell necrosis with type II epithelial cell hyperplasia and hyaline membranes Fibroproliferative lesions and excess collagen

Diagnosis and Treatment

Differentials include Lung infection Radiation-induced pulmonary fibrosis Metastatic disease Adverse reaction to other meds
Sputum analysis to exclude infection is

mandatory Treatment is discontinuation of medication

Possible use of corticosteroids but symptoms may

relapse after therapy is tapered

Cyclophosphamide Pulmonary Toxicity

An immunosuppressive alkylating agent
Pulmonary toxicity increased by

concomitant use of radiation, oxygen therapy, or use of other pulmonary toxic drugs Early- onset vs late-onset pneumonitis

Early vs Late Onset Pneumonitis

Early- onset
Present with cough and dyspnea within 1-6 months

Late- onset

after therapy May also present with fever and fatigue CXR- interstitial inflammation and/or ground glass appearance Discontinuation of drug and use of corticosteroids result in complete resolution

After treatment of several months to years with low

doses Onset of symptoms is insidious with slowly progressive dyspnea and a nonproductive cough Lacks clubbing and inspiratory crackles Almost always leads to terminal respiratory failure

Pathological findings
Diffuse alveolar damage
Bronchiolitis obliterans organizing

pneumonia Alveolar hemorrhage

Diagnosis
No significant lab tests CXR- bilateral reticular or nodular diffuse opacities

are hallmark in both early and late onset Early- onset

Ground glass opacities predominantly in periphery of upper

Late- onset More fibrotic appearance Bilateral pleural thickening of mid and upper lung zones Irreversible damage with a chronically progressive course Pulmonary function test- reduced diffusing capacity

lungs Reversible damage with good prognosis after discontinuation of medication

Pulmonary Involvement in Collagen Vascular Disorders

Scleroderma
Lupus erythematous Rheumatoid Arthritis 5 forms
Chronic pleuritis with or without effusion Diffuse interstitial pneumonitis and fibrosis Intrapulmonary rheumatoid nodules Rheumatoid nodules with pneumoconiosis

(Caplan syndrome) Pulmonary hypertension

 A 61- year old female smoked cigarettes for 10 years

but stopped smoking 5 years ago. She has experienced increasing dyspnea for months along with a nonproductive cough. A chest radiograph shows prominent hilar lymphadenopathy. A transbronchial biopsy is performed, and the microscopic findings include interstitial fibrosis and small noncaseating granulomas. One of the granulomas contains an asteroid body in a giant cell. The disease is believed to be caused by
A.) Delayed hypersensitivity response to an unknown antigen B.) Immune complexes formed in response to inhaled antigens C.) Diffuse alveolar damage (DAD) D.) Smoke inhalation for many years E.) Infection with atypical mycobacteria

A.) Delayed hypersensitivity response to an unknown antigen

 Which of the following clinical or

morphological features is common to all forms of pneumoconiosis?

A.) Marked thickening of the pleura

B.) Increased risk of bronchogenic carcinoma C.) Formation of noncaseating granulomas D.) Interstitial pulmonary fibrosis E.) Increased risk of tuberculosis

D.) Interstitial Pulmonary Fibrosis