Pathogenesis of Granulomatous

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Pathogenesis of Granulomatous Interstitial
Airways Disease
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Granulomatous DiseaseNecrotizing vs
Non-necrotizing
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• Most necrotizing granulomatous disease is
  infectious (TB!)
• Responsible organism usually demonstrable in
  tissue
• All specimens should be cultured
• Non-infectious granulomatous inflammation
  sarcoidosis, Wegeners granulomatosis, Crohns,
  etc.

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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

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• Mycobacteria
• Aerobic organisms
• Difficult to stain
• 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

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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

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• 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

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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

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• 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

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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

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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 Langerhans type
  giant cells
• Mantle of B lymphocytes

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Primary TBResolution vs. Progression

• RESOLUTION
• Most common (if immunocompetent)
• Development of a fibrous capsule - eventually
  calcified scar
• Indefintely viable dormant bacteria

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• PROGRESSION
• 1. Tuberculous bronchopneumonia
• Erosion into bronchus - dissemination
• within bronchial tree (galloping
  consumption)
• Continuing casseation - cavitary fibrocasseous
  lesions
• 2. Pleural spread
• effusion, TB empyema
• 3. Miliary TB (haematogenous dissemination)
• Remainder of lung
• Cervical lymph nodes (scrofula)
• Meninges (tuberculous meningitis)
• Kidneys adrenals
• Bones (tuberculous osteomyelitis)
• veterbral TB Potts disease

Fibrocaseous
Miliary
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Secondary TB

• Reactivation of dormant lesion
• Re-infection
• Associations - alcoholism, diabetes, silicosis
  immunosuppression
• Pulmonary
• Resolution or progression
• N.B. Extensive firosis in healing process
• Pulmonary pleural fibrosis
• Bronchiectasis

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TB in the elderly immunocompromised

• TB in the elderly
• Disseminated miliary TB (non-reactive TB)
  little granulomatous response, necrosis, DAD
• TB in AIDS
• Conventional morphology
• Granulomas poorly formed
• Opportunistic MAC from environment

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Necrotizing Granulomas - Other Infectious Causes

• Bacteria
• Brucellosis
• Fungi
• Histoplasma, Coccidioides, Cryptococcus
  Blastomyces
• Parasitic roundworm
• Dirofilaria

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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

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Sarcoidosis

• Occurs worldwide but geographical variation
• more prevalent at higher latitudes Ireland,
  Scandinavia North America (African Americans)
• 10 per 105 in UK
• Females gt Males, peak incidence 30 - 40 yrs

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• 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

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• Clinical
• Variable depending on organ(s)
• Mild non-specific chest complaints, cough,
  dyspnoea
• 1/3 Erythema nodosum
• Radiology
• Bilateral hilar lymphadenopathy

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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

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Sarcoidosis - Prognosis

• Unpredictable clinical course
• Progessive chronicity or alternating activity
  remission
• 70 recover with steroid Rx
• 35 progress to interisital fibrosis cor
  pulmonale

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Interstitial Lung Disease

• Heterogeneous group of non-infectious,
  non-neoplastic disorders
• Predominanly diffuse and usually chronic
• Damage to the lung parenchyma (varying
  intersitial inflammation fibrosis)
• a.k.a alveolitis pulmonary fibrosis
• Restrictive lung disorders

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• Acute (e.g. DAD) vs. Chronic
• NB - Clinical, Radiology Pathology correlation!
• Aetiology / associations
• idiopathic, collagen vascular disease, drugs
  toxins, environmental

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Chronic ILD

• FIBROSING
• 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)

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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

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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

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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 workers pneumoconiosis
• Anthracosis
• Simple coal workers pneumoconiosis
• Progressive massive fibrosis
• Silicosis
• Silicotic nodules
• TB risk
• Asbestos
• Asbestosis (pulmonary fibrosis)
• Pleural disease (fibrous plaques, mesothelioma).

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Hypersensitivity Pneumonitis

• Immune-mediated granulomatous inflammation caused
  by inhaling organic dusts
• Mix type III (immune-complex deposition) type
  IV (cellular mediated) hypersensitivity

• Diffuse interstitial fibrosis (gt upper lobes)
• Progressive - honeycomb respiratory failure