GRANULOMATOUS LUNG DISEASE
&
INTERSTITIAL LUNG DISEASE
GRANULOMATOUS DISEASENecrotizing vs non-necrotizing
• Most necrotizing granulomatous disease is infectious
• Responsible organism usually demonstrable in tissue
• All specimens should be cultured
• Non-infectious granulomatous inflammation – sarcoidosis, Wegener’s granulomatosis & other angiitides
TUBERCULOSIS (Robert Koch – 1882)
The mycobacteria that cause TB in man:
• Mycobacterium Tuberculosis – droplet infection = inhalation of infective droplets coughed or sneezed by a patient with TB
• Mycobacterium Bovis – drinking milk from infected cows – intestinal and tonsillar lesions
• M. Avium & M. Intracellulare (MAC complex) cause opportunistic infection in IC
• Mycobacteria are Aerobic organisms
Difficult to stain - waxy cell wall - scanty in tissue - slow growth in culture - PCR
Difficult to kill They have no toxins or histolytic enzymes they inhibit phagosome-lysosome fusion and killing
by macrophages they induce delayed hypersensitivity
TUBERCULOSIS
• Developed countries – considerable fall in incidence and mortality in 20th century
• A disease of the elderly – recrudescence of quiescent infection acquired in youth
• Recent resurgence – AIDS, urban deprivation, immigrant & refugee populations
TUBERCULOSIS - Epidemiology
• 1/3 world population infected (1700 million)• 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• > 80% of TB toll in developing countries is in
the economically most productive age-group (15-60 years)
TUBERCULOSIS - Epidemiology
• Alarming 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 dissem. & poor host response
• HIV infection promotes infection with opportunistic mycobacteria
TUBERCULOSIS – The impact of HIV infection
Primary TB• First time infection • Formerly found mainly in children, now
encountered in adultsPostprimary TB • Adult type • Previously sensitized fresh infection or
reactivation of a dormant primary lesion
TUBERCULOSIS
PRIMARY TB - Ghon Focus• Inhaled tubercle 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 histiocytes
• CD8 – kill macrophages – resulting in caseous necrosis
• Fusion of macrophages to form Langerhan’s type giant cells
• Mantle of B lymphocytes
GHON COMPLEX
(1) Parenchymal subpleural lesion at the subpleural fissure between upper
and lower lobes
&
(2) the enlarged hilar / mediastinal caseous lymph nodes draining the
parenchymal focus
PRIMARY TB – Possible outcomes• Resolution – development of a fibrous capsule - eventually
calcified scar
• Progression- erosion into bronchus – cavitation – dissemination within bronchial tree (galloping consumption!)
• Pleural spread – effusion, TB empyema
• Compression by caseous nodes of bronchus or trachea – collapse, compression, stridor
• Haematogenous dissemination = Miliary TB
cervical lymph nodes (scrofula), meninges (tuberculous meningitis), kidneys, adrenals, bones (tuberculous osteomyelitis) [veterbral TB = Pott’s disease], fallopian tubes, epididymis
POSTPRIMARY TBEndogenous vs Exogenous
Associations - alcoholism, diabetes, silicosis, immunosuppression
Pulmonary Apical diseaseCaseous pneumonia in lower lobesCavities – ca, colonization, bronchiectasisPleural & pulmonary fibrosisObliterative endarteritis of pulmonary & bronchial aa –
but “Rasmussen’s aneurysm”Extrapulmonary complications – amyloid
Tuberculosis in the elderly & immunocompromisedTB in the elderly Disseminated miliary TB – (non-reactive TB) little granulomatous response, necrosis, DAD
TB in AIDS 1. conventional morphology2. granulomas poorly formed3. opportunistic MAC from environment, spindle cell pseudotumours
TB – Skin tests & vaccinations
• Old tuberculin – now purified protein derivative (ppd)
• Intradermal injection – Mantoux• Multi-pronged devices – Heaf test
• Positive reaction indicates that a person has been infected by tubercle bacillus
• Prophyllactic immunization with strain of low virulence – Bacillus Calmette Guerin (BCG)
Necrotizing Granulomas other infectious causes
• Brucellosis
• Fungi – Histoplasma, Coccidioides
Cryptococcus, Blastomyces
• Dirofilaria
SARCOIDOSIS
• A disease of unknown cause 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
• Occurs worldwide, more prevalent at higher latitudes – Scandinavia, northern Europe and North America
• B>W, F>M, but rare in American Indians, Eskimos
• Communicable agent suspected but as yet undiscovered
• Enhanced cellular hypersensitivity at involved sites – but depressed elsewhere
• Increased CD4 lymphocytes in the lung
• Clinical: mild non-specific chest complaints, cough, dyspnoea
1/3 – Erythema nodosum Increased serum Ca, ACE, gammaglobulins
• Radiographic Staging: I Hilar adenopathy alone (best) II Hilar adenopathy & parenchymal infiltrates III Parenchymal infiltrates alone (worst)
SARCOIDOSIS
Non-caseating granulomas
• Tight clusters of epithelioid histiocytes and occassional MNGCs
• Tight rim of concentric fibroblasts , scattered lymphocytes (naked granulomas)
• Laminated concretions – Schaumann Bodies• Stellate inclusions – Asteroid Bodies
Distribution – along lymphatics (TBBx)
• Granulomatous vasculitis
DDx – infection, berylliosis, HP, IVDA, adjacent to tumour / lymphoma
SARCOIDOSIS in the lung
INTERSTITIAL LUNG DISEASE• A heterogeneous group of non-neoplastic disorders
resulting from damage to the lung parenchyma by varying patterns of inflammation and fibrosis
• Interstitium (space between the epithelial and endothelial BM) - primary site of injury
• These disorders frequently also affect the airspaces, airways and vessels
• Clinical – Radiology – Pathology correlation NB
• Aetiology / associations: idiopathic, collagen vascular disease, drugs & toxins, environmental
• Usual interstitial pneumonia (UIP) aka Cryptogenic fibrosing alveolitis (CFA) aka Idiopathic pulmonary fibrosis (IPF)
Vs.The others:Non-specific interstitial pneumonia (NSIP)Organizing pneumonia (OP)Respiratory bronchiolitis (RB)Desquamative interstitial pneumonitis (DIP)Lymphocytic interstitial pneumonitis (LIP)
INTERSTITIAL LUNG DISEASE
• Patchy lung involvement – worst at bases, subpleural & paraseptal distribution
• Dense fibrosis – remodelling of lung architecture – “honeycombing”
• Fibroblast foci
• Gradual onset of symptoms: dyspnea, non-prod cough
• Median survival 2.5 – 3.5 years
Usual Interstitial Pneumonia