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