ILD Flashcards
Describe Interstitial Lung Diseases (ILD)
• Disorders of the interstitial space of the lung
o Primarily affects lung parenchyma (alveolar/capillary units)
• Diverse group of disorders
• Range from acute to chronic pulmonary disorders
Common features: o Clinical presentation o Interstitial changes on chest x-rays o Injury and/or inflammation in parenchyma of lung with variable interstitial fibrosis o Architectural distortion o Restrictive pattern of ventilation
Types of ILD
Idiopathic forms of ILD
• Idiopathic pulmonary fibrosis IPF)
Dysregulated inflammatory response • Granulomatous Disorders (Ex: sarcoidosis) • CT disorders • Eosinophilic pneumonias • Alveolar hemorrhage syndromes
Exogenous injurious exposures
• Occupational/environmental/inhalational (ex. Asbestosis)
• Iatrogenic pneumonitis/fibrosis
• Drugs: amiodarone (atrial fibrillation), nitrofurantoin (UTI antibiotic) and methotrexate & bleomycin (anti-neoplastic agent)
Inherited disorders
Miscellaneous ILDs
common pathophysiology of ILD
o Inflammation and/or scarring of alveolar interstitial spaces
Results:
• Accumulation of inflammatory cells and T cells within alveolar interstitium → remodeling of lung parenchyma
• Parenchymal cells (epithelial, endothelial, or mesenchymal) release cytokines and mediators = contribute to inflammation
• Matrix components (collagen) = enhance inflammatory process
• Fibrosis
• Increased elasticity of lung (less able to inflate due to decreased lung compliance) → restrictive lung physiology
• Low TLC, FRC, RV
• Increases work of breathing
• Destruction of alveolar/capillary gas exchanging surfaces → low DLCO, high A-a gradient
• Thickening of alveolar/capillary interface → diffusion limitation with exercise
• Exercise-induced hypoxemia
Progression of ILDs
- Increased PaCO2
- Decreased PaO2
- Severe pulmonary hypertension → cor pulmonale over time
- Most commonly occurs in patients with IPF or scleroderma
Pulmonary fibrosis
o Decreased lung compliance → Restrictive ventilatory defect (decreased FVC, RV, TLC)
o Decreased compliance and increased dead space → increased respiratory rate
o Decreased alveolar-capillary membrane surface area; diffusion impairment → decreased DLCO
o Low V/Q → increased A-a O2 gradient
o Decreased V/Q, loss of pulmonary vascular bed, diffusion limitation, low mixed venous O2 tension, +/- shunt → exertional oxyhemoglobin desaturation
Pulmonary function testing in IPF
FEV1: decreased FVC: decreased FEV1/FVC: normal or increased TLC: decreased RV: decreased DLCO: very decreased
Change in FVC% = best validated marker of disease progression; correlates with survival
ILD: common symptoms
o Dyspnea on exertion (from increased work of breathing)
o Non-productive (paroxysmal) cough
o Abnormal breath sounds to auscultation
• Crackles or rales
• Most prominent over lower lobes
o Fatigue or malaise
ILD: helpful physical exam findings
Crackles/rales –> Idiopathic pulmonary fibrosis; Asbestosis»_space; other ILD
Mid-inspiratory squeaks –> Hypersensitivity pneumonitis; Bronchiolitis
Digital clubbing –> Idiopathic pulmonary fibrosis; Asbestosis; Chronic hypersensitivity pneumonitis; Desquamative interstitial pneumonia
Anterior uveitis –> Sarcoidosis; Wegener
Skin lesions/rashes –> Sarcoid; Collagen vascular disease; TS/NF
Joint disease –> Collagen vascular disease
Muscle weakness –> Polymyositis
Laboratory evaluation of ILD patient
o Serologic testing to evaluate for CTD
o Chest x-ray or CT (interstitial opacities)
• Use previous x-rays = time of onset/chronicity, rate of progression
• Patterns: interstitial, nodular, etc.
• Adenopathy
• Pleural disease (plaques, effusions)
• Regional prominence (upper vs. lower)
ILD: diagnostic tests
• Exercise with O2 saturation or PaO2 (6-MWT)
Bronchoscopy (in selected patients)
• Ex. Sarcoidosis, hypersensitivity pneumonia
1) Bronchoalveolar Lavage (BAL)
• Usually not diagnose, but can support a diagnose
2) Transbronchial biopsy (TBLB)
• Less invasive
• Less risky
• Limited use because ILD can be patchy so may not get representative tissue sample
Surgical lung biopsy in selected patients
• Gold standard
• When unable to establish a diagnosis from above studies
• Greater risk to patient
Sarcoidosis: definition
o Diffuse inflammatory disorder
o Characterized by granulomatous inflammation
o Most often affects lungs and lymphatics, but variable multi-organ effects
Sarcoidosis: epidemiology
o Worldwide prevalence o Can occur at any age • Young adults more frequently affected • Peaks in 20’s; smaller peak in 50’s o Higher prevalence in females and certain ethnic groups (African-American, northern European)
Sarcoidosis: clinical features
o Usually subacute symptom onset (but can be acute)
o Often asymptomatic (30-60%)
• Instead = incidental finding on routine chest x-ray
• See bilateral hilar hymphadenopathy
o Most common affected organs = lungs > nodes > skin > eyes
o Can affect any organ
Symptoms
• Fatigue, lethargy, malaise
• Cough
• Fever, arthralgias, weight loss
Physical exam: Lungs usually clear to auscultation May have skin involvement o Erythema nodosum (vasculitis with red, raised lesions affecting lower extremities) o Sarcoid plaques May have eye involvement o Uveitis o Retinitis Extrapulmonary diseases may be present o Cardiac rhythm disturbance o Transaminitis (eleveated ALT, AST) o Hypercalcemia o Nephrolithiasis o Neurologic complications Course: can be relapsing, remitting, or chronic
Sarcoidosis: pathogenesis
o T-cell driven immune response
o Inciting event = antigen processing and presentation by macrophage (APC)
o Classic TH1 response with granuloma formation
o Release of IL-2, IL-12, IFN-gamma, TNF-alpha
o Consequences of granulomas and tissue inflammation in lung:
• Volume of inflammatory cells → distorts lung architecture → alters gas exchange
• Granulomatous inflammation → tissue damage and fibrosis → pulmonary dysfunction
• Can develop pulmonary HT (even without extensive fibrosis)
Sarcoidosis: pathology
o Tightly formed, non-caseating granulomas
o Often in clusters in intersitium and bronchovascular bundle
Sarcoidosis: Radiography
o Classify into stages (showing pulmonary involvement)
o see nodules on CT
Stages of Sarcoidosis
1) Bi-hilar LAD (likelihood of spontaneous remission >80%)
2) Bi-hilar LAD + pulmonary infiltrates (65%)
3) Pulmonary infiltrates, no LAD (30%)
4) Fibrosis (usually on upper lobes); no LAD (0%)
Sarcoidosis: therapy
Therapy of Sarcoidosis o No treatment if minimal disease or no evidence of progression Immunosuppressive therapies • Corticosteroids • Cytotoxic agents (ex: methotrexate) • Hydroxychloroquine Immunomodulatory agents • Anti-TNF antibodies • Thalidomide Lung transplantation
Lofgren’s Syndrome
• Acute onset of o Hilar lymphadenopathy o Erythema nodosum (usually on shins) o Fever o Arthritis • Usually spontaneous remission within 2 years
Idiopathic Pulmonary Fibrosis (IPF): defintions
o Most common form of idiopathic interstitial pneumonia
o Lung injury/fibrosis cannot be linked to CT disease, drug exposure, or inhaled pro-fibrotic dust (asbestos)
Idiopathic Pulmonary Fibrosis (IPF): epidemiology
o Increasing incidence and prevalence
o Usually occurs after 5th decade (highest in elderly)
o Affects males slightly more than females
o Poor prognosis: median survival is 2-3 years post-diagnosis
Idiopathic Pulmonary Fibrosis (IPF): associated risk factors
Environmental • Smoking • Dusts (metal, wood) • Farming • Hair dressing • Stone cutting or polishing
Genes
• Telomerase
• MUC5B
Chronic viral infection
• EBV
Associations with other conditions
• Gastroesophageal reflux +/- HH → microaspiration
• Diabetes mellitus
• advanced age
Idiopathic Pulmonary Fibrosis (IPF): pathology
o Architectural distortion of lung
o Areas of intense fibrosis
o Intervening areas of normal lung (heterogeneity)
o Fibroblastic foci
• At junction of normal lung and fibrotic change
• With fibroblasts and collagen
o Peripheral zones of chronic scar and honeycombing (small peripheral cysts)
o Interstitial inflammatory change = usually only mild and focal
Idiopathic Pulmonary Fibrosis (IPF): pathogenesis
o Recurrent alveolar epithelial cell injury
• Exposure + susceptibility
o Loss of homeostatic function
o Release of profibrotic mediators
Result: formation of serum rich “wound clot”
• Activation of coagulation cascade
• Influx of resident mesenchymal cells and circulating fibrocytes
• Local epithelial-mesenchymal transition
o Myofibroblast differentiation and reorganization of wound clot → fibroblastic focus
o Cycle repeats = can’t resolve wound-healing response; progressive tissue remodeling and architectural distortion
Idiopathic Pulmonary Fibrosis (IPF): diagnosis
o Gradual onset
o High resolution CT compatible with usual interstitial pneumonia (UIP)
o If typical changes are present → HRCT is diagnostic:
• Irregular reticular lines (diffuse)
• Subpleural, posterior, and lower lobe predominance
• Subpleural honeycombing
• Strong predictor of IPF diagnosis
• Have worse prognosis with honeycombing
• Minimal ground glass opacities
• Traction bronchiectasis (later in disease course)
o Surgical lung biopsy shows UIP o Exclude other causes: • CT disease • Drug toxicity • Asbestosis
Idiopathic Pulmonary Fibrosis (IPF): clinical course
o Poor prognosis
o Progressive deterioration of pulmonary function
• Even with immunosuppressive and/or antifibrotic therapies
o Lung transplantation improves QoL and survival
• But 5 year survival is only 50%
• Most patients not candidates for transplant
Idiopathic Pulmonary Fibrosis (IPF): treatment
o No current FDA approved medications
o Anti-reflux therapies (because GERD associated)
o Chronic/rotating anti-infective therapy (bronchiectasis)
o Pulmonary rehabilitation and regular exercise program
o Supplemental O2
o Screen/treat co-morbidities
o Treat ILD-associated pulmonary HT
o Support groups
o Assisted ventilation
o Relief of dyspnea/palliative care/hospice
o Lung transplant for eligible patients
Acute exacerbation of IPF
o Acute SOB
o New radiographic infiltrate
o Worsening gas exchange
o No evidence of other cause (infection, HF, thromboembolism, pneumothorax)
Identify occupational and environmental exposures that can cause lung disease directly or cause other disorders via inhalation and access to the pulmonary and systemic circulation.
• Silica
• Asbestos (increased risk with tobacco smoking)
• Combustion products of fossil fuel hydrocarbons
o Diesel engine exhaust
o Soot
o Coke oven emissions
o Coal gas and coal tar volatiles
• Radon progeny
• Metals (arsenic, aluminum, beryllium, chromium, cadmium, nickel, iron, lead, mercury)
Asbestos: exposures
strong linear response curve o Plumbing, insulators, sheet metal o Shipbuilding o Brake workers o Dockworkers o Remodeling, demolition o Milling, mining o Soils, Turkey, Albania
List the related Asbestos diseases
Asbestosis
Pleural Disease
Malignant mesothelioma
Bronchogenic carcinoma
Asbestosis
= ILD from asbestos exposure
• Asbestos fibers can’t be cleared by lungs and are biologically active
• Lead to generation of oxygen free radicals → injure local tissue
• Long latency (>20 years)
• Concomitant tobacco use is common
• Earliest symptoms = dyspnea with exertion
Exam:
• Bibasilar fine crackles
• Clubbing
PFT
• Decreased DLCO (usually earliest PFT abnormality)
• Diminished lung compliance
• Reduced lung volume
Chest CT
• Peripheral and basilar interstitial fibrosis and honeycombing
• UIP pattern of fibrosis
Pathology:
• Ferrunginous bodies
• Iron-coated asbestosis fibers (sometimes with associated macrophage trying to engulf it)
• Number correlates with total exposure and degree of fibrosis
• Total number of uncoated fibers is 5000-10,000x higher than number of visible fibers
Pleural Disease
• Often first manifestation of asbestos-related lung disease
- Benign asbestos pleural effusion (BAPE)
- Benign because occurs without mesothelioma
- Usually unilateral
- Often bloody and eosinophilic
- Thought to be a reaction to asbestos fibers in pleural space
- Hyaline pleural plaques (in 50% patients with significant exposure)
- Diffuse pleural thickening
- Rounded atelectasis secondary to pleural adhesions
Malignant mesothelioma
• Tumor from pleural or parietal mesothelium • Forms a pleural mass or “rind” • Often with associated effusion • Predominantly related to occupational exposure to asbestos • NOT related to tobacco use Poor prognosis: • Median survival < 1 year • 5 year survival < 5%
Bronchogenic carcinoma
- Greatly increased risk with tobacco use
- Thus = especially important for asbestos-exposed patients not to smoke
- No preferential pathologic subtype
Silica Exposure
o Mining
o Foundry work
o Sand blasting
o Ceramics
Silica Pathogenesis
o Chronic dust exposure > 5 years o Long latency period (>15 years) o Leads to clinically evident disease If asymptomatic → progression • Slow = chronic silicosis • Rapid = accelerated silicosis o Complications = TB, COPD, cor pulmonale
Silica clinical symptoms
o Acute: dyspnea, cough, fatigue, occasional pleuritic pain
o Chronic: frequently asymptomatic
Silicosis: PFTs
o Restrictive pattern (low TLC, FEV1, FVC, DLCO) if significant fibrosis
Silicosis: associated illnesses
o Mycobacterial infections o Malignancy (silica = a carcinogen; increased risk with smoking)
Silicosis: pathology
o Lymph node “egg shell” calcification
o Upper lobe pulmonary nodules (well-formed, peribronchial)
• Pigment laden macrophages
• Cholesterol clefts
o Nodules may extend/coalesce to large masses
o Progressive massive fibrosis (upper lobe prevalent)
o Associated with COPD (tobacco cessation important)
Silicosis: therapy
o None established
o Avoidance/prevention
o Surveillance guidelines for high risk occupations
Hypersensitivity Pneumonitis (HP): Definition
o Lung disease from recurrent exposure to organic particles
• Usually < 5 micrometers (so able to reach alveoli)
o Results in inflammatory lung disease
o Immunologically driven (but not IgE mediated)
Hypersensitivity Pneumonitis (HP): clinical symptoms
• Can present in acute, sub-acute, and chronic forms:
Acute
• Associated with one-time, large exposure to antigen
• Fevers, chills, muscle aches, cough, dyspnea
• Occasionally fine crackles
Sub-acute/chronic: • Chronic, repetitive small exposures • Indolent presentation • Dyspnea on exertion • Cough, crackles, inspiratory squeaks
Hypersensitivity Pneumonitis (HP): pathogenesis
o Susceptible subjects sensitized to inciting antigen
o Develop bronchiolocentric granulomatous lymphocytic infiltrates
o Immune complex and cell-mediated immunity
o Early influx of neutrophils (<48 hrs)
o Later lymphocytes predominate (2-5 days)
Hypersensitivity Pneumonitis (HP): pathology
o Imaging: • Diffuse bilateral reticulo-nodular pattern • Diffuse fibrosis • Honeycomb • Traction bronchioectasis • Micronodules • Ground-glass opacities • Loose granuloma • Interstitial mononuclear inflammation
Hypersensitivity Pneumonitis (HP): treatment
o Avoidance of exposure
o Corticosteroids for subacute or severe acute
o Lung transplants for eligible patients
Silo filler’s disease
- Acute toxic lung injury
- Caused by inhalation of nitrogen dioxide (formed from nitric oxide and stored silage)
- Result: bronchitis, bronchiolitis, ARDS
Organic dust toxic syndrome (ODTS)
• Inflammatory pneumonitis after massive exposure to organic dust
o Dust may contain bacterial endotoxins, mycotoxins, or spores
• Symptoms:
o Flu-like; fevers and chills
o Usually self-limited (last <234 hours)
• Does not require prior sensitization
• Dose-related reaction
