Granulomatous inflammations

Definition: Specific type of chronic

inflammation characterized by formation of granuloma Granuloma is a small, localized and nodular mass, about 0.5-2 mm in 0.5diameter, and formed mainly by aggregates of activated macrophages (Epithelioid cell) surrounded by collar of mononuclear leukocytes principally lymphocytes and occasionally plasma cells. cells.

Epithelioid cells [ pathognomonic cells] - Large, abundant pale eosinophilic cytoplasm, large vesicular nucleus - Cytokines fusion into multinucleated giant cells Langhans giant cells: Peripheral nuclei; horse - shoe or bipolar patterns Foreign body giant cells: Randomly scattered nuclei, mostly towards the center of the cell
Old granulomas develop an enclosing rim of fibroblasts and collagen fibers.

Causes of granulomatous inflammation: 1- Infective granulomas: granulomas: - Bacterial: T.B., leprosy, rhinoscleroma T.B., - Spirochetes: Syphilis - Parasites: Schistosomiasis - Deep fungal infection: Histoplasmosis 2- Non infective granulomas: granulomas: Silicosis, beryliosis, dust beryliosis, 3- Unknown: Sarcoidosis Mechanisms of granulomatous inflam.: inflam.: 1- Indigestible particles 2- Cell - mediated immunity

Types:
1- Foreign body granuloma: - Inert indigestible F.B.: talk powder, surgical sutures - No immune response - Epithelioid cells & F.B. giant cells 2- Immune granuloma: Immunogenic indigestible particles CellCell-mediated immune response * Infectious agents: Tuberculosis, Tuberculosis, leprosy, rhinoscleroma syphilis, bilharziasis * Non infectious agents: Sarcoidosis, catcat-scratch dis., silicosis, beryliosis

Tuberculosis
Chronic granulomatous inflam. disease inflam.

Risk factors:
- Poverty, malnutrition, overcrowding, lack of adequate medical care Decreased T cell mediated immunity: *Diabetes mellitus, ch. lung disease, ch. ch. ch. Renal failure, Hodgkins lymphoma *AIDS, immunosuppression multimulti-drug resistant TB bacilli * 1.7 billion/ world *1.7 million death/ yr

Causative organism: Mycobacterium tuberculosis:

- Slender, curved, rod-shaped, non rodmotile, acid- fast (Zeihl - Neelsen). acid(Zeihl Neelsen). - Strictly aerobic, slowly growing, hard to kill, resist dryness, sensitive to UV radiation and acidic PH ( < 6.5) - Lipid fraction: Mycolic acid Waxy sheath Protects against digestion and drugs - Protein fraction: Delayed hypersensitivity - Carbohydrate fraction: Accumulation of PNL

Mycobacterium tuberculosis

Mode of transmission:
lung & tracheobronchial LN M. Bovis Tonsils & cervical LNs Intestine & mesenteric LNs Inoculation Skin & draining LNs TransTrans-placental: Maternal systemic T.B. Inhalation Ingestion

Pathogenesis ( on primary exposure):

1- Glycolipid cover accumulation of PNL localization (no lipase) 2- Accumulation of macrophages fail to kill the organism free bacillary proliferation bacteremia seedling of multiple sites 3- Macrophages partially destroy TB bacilli Tuberculoprotein Ag short peptide expressed by macrophages on class II MHC molecules hilar LN IL-12 IL-

4- T-helper CD4+ cells recognize the presented Ag sensitized TH1 cells 5- Sensitized TH1 cells Cytokines -IL-1 Clonal expansion ILmemory cells tuberculin +ve +ve - IL-2 Auto-, paracrine proliferation ILAutoof T cell Cytotoxic CD8+ T lymphocytes kill infected macrophages - TNF, chemokines Monocytes recruitment - IFN-K Activates macrophages IFNimmunity = resistance

Activated macrophage = Epithelioid cell - Large cells, large vesicular nucleus abundant pale eosinophilic cytoplasm - Increased ability to phagocytose & kill T.B. bacilli - Express more class II MHC molecules facilitate Ag presentation - TNF, IL-1, chemokines promote infl IL- Secret TGF-B, PDGF, FGF TGFcollagen synthesis fibrosis
1. 2.

Serve to eliminate the offending antigen If sustained continued infl. fibrosis

5- Collar of lymphocytes surrounds the

epithelioid cells small tubercle; 0.5-2 mm 0.5fusion large avascular mass necrosis

6 - Langhans giant cells:

- Fusion of Epithelioid cells - Large, deep eosinophilic cytoplasm - Multinucleated with peripheral nuclei horse - shoe or bipolar - Digest and remove necrotic tissue

7- Caseous necrosis (4-6 weeks): (4- Caused by avascularity, liberation of avascularity, cytotoxic factors, cytotoxic CD8+ T cells NEA: Dry, cheese-like, friable, creamy yellow cheeseMP: MP: granular, eosinophilic Acidic, anaerobic media Kill bacilli

Pathogenesis

Tuberculin +ve hypersensitivity

bactericidal activity immunity

Fate of Tuberculous lesion:

1- Healing - High immunity
- Epithelioid cells FGF & PDGF collagen synthesis fibrosis - Dystrophic calcification of caseating center - Sterile or contain dormant bacilli

2- Progressive Caseation and softening

- Low immunity - Hallmark of activity - Caseation softening cold abscess draining sinuses open tuberculosis O2 bacillus proliferation

Primary tuberculosis
- Infection of a non - sensitized immunoimmuno-competent person by tubercle bacilli for the first time - Children >> adults

The primary complex: (Ghons complex)

1- Primary focus 2- Lymphangitis 3- Lymphadenitis

Common sites:
1- Lung & tracheobronchial lymph nodes 2- Tonsils & deep cervical lymph nodes 3- Intestine & mesenteric lymph nodes 4- Skin & draining lymph nodes
Draining lymph nodes show most of the reaction

Primary Pulmonary Tuberculosis

Transmission: inhalation Ghons complex: 1- Ghons focus: - 1-1.5 cm - Sub pleural - Upper part of lower lobe or lower part of upper lobe - Well circumscribed, grayish white area of consolidation - Central caseation 2- Lymphangitis 3- Lymphadenitis of tracheo- bronchial tracheoLNs: Enlarged, caseating, matted

Fate of the primary complex:

Healing or spread: Immunity, Virulence, doze 1- Healing: Good immunity & low virulence (95%) - Asymptomatic Fibrosis, calcification - Tuberculin test positive - Residual bacilli reactivation 2ry

2- Progressive primary tuberculosis

spread

Lower immunity & highly virulent organism a) Direct Lung parenchyma & pleura b) Lymphatic thoracic duct Rt. Heart lung c) Bronchial tree caseous bronchopneumonia d) Hematogenous * Pulmonary artery miliary TB of the lung * Pulmonary vein Miliary tuberculosis or Isolated organ tuberculosis death due to tuberculous meningitis

Secondary Pulmonary Tuberculosis

- Previously sensitized host

- Exogenous re-infection or reactivation reof latent primary T.B. - Adults >> children - Rapid due to hypersensitivity (8-12h) (8 12h) wall off the focus of infection lymph nodes are less involved - Right lung > left - Apical: high oxygen tension Apical: no tissue fluid

Course and Fate of secondary pulmonary tuberculosis: 1- Arrested tuberculosis:

- High resistance & low virulence - Small, apical, 1-2 cm. - Grayish white to yellow area of Consolidation with variable central caseation and peripheral fibrosis - MP: Coalescent tubercles - Healing by fibrosis and calcification

2- Fibrocaseous T. B.

with

cavitation

- Elder or immuno-suppressed with Moderate immunoresistance & dose of organism - Extensive caseation of apical region Erosion of a bronchus coughed Open pulmonary T.B. +ve sputum Cavity formation: Large, apical, poorly walled by fibrous tissue, lined by caseous necrotic tissue, traversed by arteries Erosion of artery haemoptysis - Fibrosis of the lung & pleura with adhesions - Lymph nodes are slightly or not affected

3- Tuberculous pneumonia:
- High virulence, low resistance, advanced Immunosuppression. - Rapid spread galloping consumption - Widespread exudative Caseous pneumonic consolidation, - Non-cavitary disease Non- Pleura & tracheobronchial lymph nodes are affected - Large number of bacilli

Complications of fibrocaseous T.B.:

I- Spread of infection: 1- Direct spread to the pleura - Pleural effusion - Fibrous pleuritis - T.B. empyema - Pneumothx. Pneumothx. Pyopneumothx. 2- Natural passages - T.B. tracheo-bronchitis - Laryngitis tracheo- Glossitis - Enteritis 3- lymphatic spread a- Bronchial tree T.B. bronchopneum b- Lympho-hematogenous miliary LymphoT.B. of the lung

4- Hematogenous spread *Acute miliary tuberculosis:

- Erosion of pulmonary artery

miliary

tuberculosis of the lung - Erosion of pulmonary vein systemic miliary TB liver, bone marrow, spleen, adrenals, meninges, meninges, kidneys, fallopian tubes, epididymis. epididymis.

*Isolated organ tuberculosis:

Miliary dissemination with destruction of the bacilli except at sites of isolated infection: meninges, kidneys adrenals meninges, (Addison d.), bones (Potts), spleen, fallopian tubes, epididymis. epididymis.

II- Hemoptysis II-

III- 2ry Amyloidosis III-

Intestinal Tuberculosis
Primary intestinal tuberculosis: (Tabes mesenterica) mesenterica)
- Ingestion of M. Bovis infected cow milk - Ghons complex: Primary microscopic focus Lymphangitis Lymphadenitis of mesenteric lymph nodes: Enlarged, Caseating, matted

Secondary intestinal tuberculosis: Mode of transmission: Swallowing of

infected sputum in open pulmonary TB

NEA: - Granulomatous reaction in Payer's

patches sloughing of the mucosa & Formation of tuberculous ulcers: multiple, oval, transverse, deep, undermined edges, necrotic floor - Mesenteric LNs are slightly affected

-Complications:
- Fibrosis stenosis & intestinal obstruction - Perforation hemorrhage, septic peritonitis - Fistula with adjacent bowel loops

II) Tuberculous Osteomyelitis

Route of infection: 1- Hematogenous: active pulmonary T.B Hematogenous: 2- Direct extension Site: spongy bone more than compact bone - Thoracic and lumbar vertebrae (Pott s) - Metaphyseal ends of long bones - Small bones of hands and feet (dactylitis

Tuberculous Spondylitis Potts Disease of The Spine

Age: Children - young adults Sex: Males > females Site: Thoracic> lumbar> cervical Pathogenesis: Caseating tuberculous granuloma in the marrow cavity endosteum cortical necrosis periosteum intervertebral disc destruction of intervertebral disc adjacent vertebra

NEA: Extensive bone destruction creamy yellow, cheesy necrotic debris MP: - Destructive Caseating granuloma - Reparative processes Fibrosis New bone formation

Complications:
1 Kyphosis, scoliosis: 1-- Kyphosis & scoliosis
- Extensive destruction of vertebral bodies compression fracture deformity of the spine -New bone formation fixed malposition

2- Cold abscesses: 2- Cold abscess - lumbar vertebral bodies paraparavertebral muscles psoas abscess - cervical vertebrae retropharyngeal abscess - thoracic vertebrae Mediastinal 3- Pott s paraplegia 3- Potts paraplegia : spinal cord Compression - extradural abscess - intradural abscess - disc material - sequestrated bone 4- Secondary amyloidosis 4- Secondary amyloidosis

TUBERCULOUS DACTYLITIS
 Site:

Small bones of feet and hands  Morphology: - Destruction of phalanges and metacarpal bones - New bone formation fusiform swelling

Tuberculosis of the kidney

 Miliary tuberculosis

Multiple small tubercles, 1-2 mm, central caseation, caseation, more in cortex  Caseocavernous tuberculosis Starts at the base of pyramids enlarge & caseate & spread to pelvis Large cavity Complications: 1- TB ureteritis: fibrosis and obstruction 2- TB pyonephrosis: pyonephrosis: Ureteral obstruction bag of pus 3- TB cystitis

Miliary tuberculosis

Caseocavernous

II) Chronic cystitis 1- Chronic non - specific cystitis Persistent acute cystitis - NEA: Thickening of the bladder wall - MP: Lymphocytic infiltration - fibrosis 2- Chronic specific cystitis - Tuberculous: renal Tuberculous: Hematuria - Bilharzial: The urinary bladder is the earliest, heaviest, most common Site: Trigone, posterior bladder wall, ureteric Trigone, orifice NEA: Contracted calcified bladder

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