Download GRANULOMATOUS DISEASE & INTERSTITIAL LUNG DISEASE

Pathogenesis of
Granulomatous & Interstitial
Airways Disease
Granulomatous Disease
Necrotizing vs Non-necrotizing
• Most necrotizing granulomatous disease is infectious (TB!)
• Responsible organism usually demonstrable in tissue
• All specimens should be cultured
• Non-infectious granulomatous inflammation – sarcoidosis,
Wegener’s granulomatosis, Crohn’s, etc.
Tuberculosis
The mycobacteria that cause TB in man:
• Mycobacterium tuberculosis
– Lung is most common primary site
– Droplet infection = inhalation of infective droplets coughed or
sneezed by a patient with TB
• Mycobacterium bovis
– Drinking milk from infected cows – intestinal & tonsillar lesions
• M. avium & M. intracellulare (MAC complex)
– Opportunistic infection in IC
• Mycobacteria:
– Aerobic organisms
– Difficult to stain
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waxy cell wall
scanty in tissue
slow growth in culture
PCR
– Difficult to kill (dormancy)
• No toxins or histolytic enzymes
• Inhibition of phagosome-lysosome fusion & killing by
macrophages
• Induce delayed hypersensitivity (type IV - T cell mediated)
– Destructive effects
Epidemiology
• Developed countries:
– Considerable fall in incidence and mortality in 20th
century
• A disease of the elderly:
– Reactivation of quiescent infection acquired in youth
• Recent resurgence:
– AIDS, urban deprivation, immigrant & refugee
populations
• 1/3 world population infected (~1.7 billion)
• 8 million new cases every year
– 95% in developing countries
• 3 million deaths every year
– Largest cause of a death from a single pathogen
• TB kills twice as many adults as AIDS, malaria
and other parasitic diseases combined
TB & HIV
• Marked resurgence
– Poorer communities, drug abuse
• Multidrug resistant strains have emerged
• 6 million people world-wide have dual infection, majority
in sub-Saharan Africa
• HIV infection – particularly aggressive TB – widespread,
disseminated & poor host response
• HIV infection promotes infection with opportunistic
mycobacteria
• Primary TB:
– First time infection
– Formerly found mainly in children, now encountered in
adults
• Secondary/Postprimary TB:
– Adult type
– Reactivation of a dormant primary lesion
– Re-infection from re-inhalation
Primary Tuberculosis
• Transmitted through inhalation of
infected droplets
• Single tuberculous granuloma
(tubercle):
– within parenchyma (usually
subpleural/periphery) = Ghon focus
– also in hilar lymph nodes (common)
= Ghon complex
Ghon Complex - Sequence of Events
• Inhaled bacilli ingested by alveolar macrophages
• Macrophages with bacilli aggregate, forming microscopic
nodules that deform architecture
• Development of T-cell mediated immunity: CD4 (helper)
& CD8 (cytotoxic)
– CD4 – interferon – secretory changes in macrophages – epithelioid
(activated) histiocytes
– CD8 – kill macrophages – resulting in caseous necrosis
• Fusion of macrophages to form Langerhan’s type giant
cells
• Mantle of B lymphocytes
Primary TB
Resolution vs. Progression
• RESOLUTION:
– Most common (if immunocompetent)
– Development of a fibrous capsule - eventually calcified scar
– Indefintely viable dormant bacteria
• PROGRESSION:
1. Tuberculous bronchopneumonia
– Erosion into bronchus - dissemination
within bronchial tree (‘galloping consumption’)
– Continuing casseation - cavitary fibrocasseous lesions
Fibrocaseous
2. Pleural spread
– effusion, TB empyema
3. Miliary TB (haematogenous dissemination)
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Remainder of lung
Cervical lymph nodes (scrofula)
Meninges (tuberculous meningitis)
Kidneys & adrenals
Bones (tuberculous osteomyelitis)
• veterbral TB = Pott’s disease
– Fallopian tubes & epididymis
Miliary
Secondary TB
1. Reactivation of dormant lesion
2. Re-infection
Associations - alcoholism, diabetes, silicosis & immunosuppression
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Pulmonary
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Resolution or progression
N.B. Extensive firosis in healing process:
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Pulmonary & pleural fibrosis
Bronchiectasis
TB in the elderly &
immunocompromised
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TB in the elderly:
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Disseminated miliary TB – (non-reactive TB) little
granulomatous response, necrosis, DAD
TB in AIDS:
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Conventional morphology
Granulomas poorly formed
Opportunistic MAC from environment
Necrotizing Granulomas - Other
Infectious Causes
• Bacteria:
– Brucellosis
• Fungi:
– Histoplasma, Coccidioides, Cryptococcus &
Blastomyces
• Parasitic roundworm:
– Dirofilaria
Sarcoidosis
• Systemic disease of unkown aetiology
• Characterized by non-caseating granulomas in
many tissues & organs
– Lungs, lymph nodes, spleen, liver, bone marrow,
skin, eye, salivary glands and less frequently – heart,
kidneys, CNS, endocrine glands – pituitary
Sarcoidosis
• Occurs worldwide but geographical variation
– more prevalent at higher latitudes – Ireland,
Scandinavia & North America (African Americans)
– 10 per 105 in UK
• Females > Males, peak incidence 30 - 40 yrs
• Exact aetiology & pathogenesis unclear
• Several immunologic abnormlaities
– Enhanced cellular hypersensitivity at involved sites –
but depressed elsewhere
• Anergy to common skin test antigens
– Generally driven by CD4 T cells
– Increased CD4 lymphocytes in the lung
• Clinical:
– Variable depending on organ(s)
– Mild non-specific chest complaints, cough, dyspnoea
– 1/3 – Erythema nodosum
• Radiology:
– Bilateral hilar lymphadenopathy
Sarcodosis in the Lung
• Non-caseating granulomas (classic)
– Tight clusters of epithelioid histiocytes and occassional MNGCs
– Tight rim of concentric fibroblasts , few lymphocytes (‘naked
granulomas’)
– Schaumann bodies
• Laminated concretions (Ca2+ & protein)
– Asteroid bodies
• Stellate inclusions
• Histological diagnosis of exclusion
– DDx – infection, berylliosis, HP, IVDA, adjacent to tumour /
lymphoma
Sarcoidosis - Prognosis
• Unpredictable clinical course
– Progessive chronicity or alternating activity &
remission
• ~ 70% recover with steroid Rx
• ~ 35% progress to interisital fibrosis & cor
pulmonale
Interstitial Lung Disease
• Heterogeneous group of non-infectious, nonneoplastic disorders
– Predominanly diffuse and usually chronic
– Damage to the lung parenchyma (varying intersitial
inflammation & fibrosis)
• a.k.a alveolitis & pulmonary fibrosis
• Restrictive lung disorders
• Acute (e.g. DAD) vs. Chronic
• NB - Clinical, Radiology & Pathology correlation!
• Aetiology / associations:
– idiopathic, collagen vascular disease, drugs & toxins,
environmental
Chronic ILD
• FIBROSING:
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USUAL INTERSTITIAL PNEUMONIA (UIP/CFA/IPF)
Non-specific interstitial pneumonia (NSIP)
Cryptogenic organizing pneumonia (COP)
Connective tissue disease
Pneumoconiosis
Drug rections
Raditation pneumonitis
Lymphocytic interstitial pneumonitis (LIP)
• GRANULOMATOUS
– Sarcoidosis
– Hypersensitivity pneumonitis
• SMOKING-RELATED:
– Respiratory bronchiolitis (RB)
– Desquamative* interstitial pneumonitis (DIP)
Usual Interstitial Pneumonia
• Progressive fibrosing disorder of unknown cause
– ? Repeated acute lung injury (unknown agent)
• Patchy lung involvement – worst at bases, subpleural &
paraseptal distribution
– Dense fibrosis – remodelling of lung architecture
(‘honeycombing’)
– Fibroblastic foci
Usual Interstitial Pneumonia
• Adults 30 to 60 yrs
– Gradual onset of symptoms: dyspnea, non-prod cough
• Median survival ~ 3 years
– Respiratory and heart failure (cor pulmonale)
– Require transplantation
Pneumoconioses
• Disorders caused by inhalation
of inorganic elements, primarily
mineral dusts.
• Injury is determined by:
– Length of exposure
– Physicochemical characteristics
– Host factors
• Carbon dust - Coal worker’s
pneumoconiosis:
– Anthracosis
– Simple coal worker’s
pneumoconiosis
– Progressive massive fibrosis
• Silicosis
– Silicotic nodules
– TB risk
• Asbestos
– Asbestosis (pulmonary fibrosis)
– Pleural disease (fibrous plaques,
mesothelioma).
Hypersensitivity Pneumonitis
• Immune-mediated granulomatous inflammation caused by
inhaling organic dusts
– Mix type III (immune-complex deposition) & type IV (cellular mediated)
hypersensitivity
Farmer’s lung
Thermophilic actinomycetes in hay
Pigeon
breeder’s
Air-condition lung
• Diffuse interstitial fibrosis (> upper lobes)
– Progressive - honeycomb & respiratory failure
Thermophilic bacteria