Granulomatous Inflammation 4 (2)

8/6/2019 Granulomatous Inflammation 4 (2)

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Definition:Definition: Specific type of chronicSpecific type of chronicinflammation characterized byinflammation characterized by

formation of granulomaformation of granuloma

GranulomaGranuloma is a small, localized andis a small, localized andnodular mass, aboutnodular mass, about 0.50.5--2 mm2 mm inindiameter, and formed mainly bydiameter, and formed mainly byaggregates of aggregates of activated macrophagesactivated macrophages

(Epithelioid cell)(Epithelioid cell) surrounded by collar surrounded by collar of mononuclear leukocytes principallyof mononuclear leukocytes principallylymphocyteslymphocytes and occasionallyand occasionally plasmaplasmacellscells..

GranulomatousGranulomatous inflammationsinflammations



Epithelioid cellsEpithelioid cells [[ pathognomonicpathognomonic cells]cells]

-- Large, abundant pale eosinophilicLarge, abundant pale eosinophilic

cytoplasm, large vesicular nucleuscytoplasm, large vesicular nucleus

-- CytokinesCytokines fusion intofusion into

multinucleated giant cellsmultinucleated giant cells

LanghansLanghans giant cells:giant cells: Peripheral nuclei;Peripheral nuclei;

horsehorse -- shoe or bipolar patternsshoe or bipolar patterns

Foreign body giant cells:Foreign body giant cells:

Randomly scattered nuclei, mostlyRandomly scattered nuclei, mostly

towards the center of the celltowards the center of the cell

OldOld granulomasgranulomas develop an enclosing rim of develop an enclosing rim of

fibroblasts and collagen fibers.fibroblasts and collagen fibers.







Causes of Causes of granulomatousgranulomatous inflammation:inflammation:

11-- InfectiveInfective granulomasgranulomas::

-- Bacterial:Bacterial: T.B.T.B., leprosy,, leprosy, rhinoscleromarhinoscleroma-- Spirochetes: SyphilisSpirochetes: Syphilis

-- Parasites: SchistosomiasisParasites: Schistosomiasis

-- Deep fungal infection:Deep fungal infection: HistoplasmosisHistoplasmosis22-- Non infectiveNon infective granulomasgranulomas::

Silicosis,Silicosis, beryliosisberyliosis, dust, dust

33-- Unknown:Unknown: SarcoidosisSarcoidosis

Mechanisms of Mechanisms of granulomatousgranulomatous inflaminflam.:.:

11-- Indigestible particlesIndigestible particles

22-- CellCell -- mediated immunitymediated immunity



Types:Types:11-- Foreign body granuloma:Foreign body granuloma:

-- Inert indigestible F.B.: talk powder,Inert indigestible F.B.: talk powder,surgical suturessurgical sutures

-- No immune responseNo immune response

-- Epithelioid cells & F.B. giant cellsEpithelioid cells & F.B. giant cells

22-- Immune granuloma:Immune granuloma:Immunogenic indigestible particlesImmunogenic indigestible particles

CellCell--mediated immune responsemediated immune response

* Infectious agents:* Infectious agents:TuberculosisTuberculosis, leprosy,, leprosy, rhinoscleromarhinoscleroma

syphilis, bilharziasissyphilis, bilharziasis

* Non infectious agents:* Non infectious agents: Sarcoidosis,Sarcoidosis,

catcat--scratch dis., silicosis,scratch dis., silicosis, beryliosisberyliosis



T uberculosisT uberculosisChronicChronic granulomatousgranulomatous inflaminflam. disease. disease

Risk factors:Risk factors:

-- Poverty, malnutrition, overcrowding,Poverty, malnutrition, overcrowding,

lack of adequate medical carelack of adequate medical care

Decreased T cell mediated immunity:Decreased T cell mediated immunity:

*Diabetes mellitus,*Diabetes mellitus, chch. lung disease,. lung disease,

chch. Renal failure, Hodgkin·s lymphoma. Renal failure, Hodgkin·s lymphoma

*AIDS,*AIDS, immunosuppressionimmunosuppression

multimulti--drug resistant TB bacilli *drug resistant TB bacilli *

1.7 billion/ world *1.7 million death/ yr 1.7 billion/ world *1.7 million death/ yr



Causativ e organism:Causativ e organism:

M y cobact erium tuberculosis:M y cobact erium tuberculosis:

-- Slender, curved, rodSlender, curved, rod--shaped, nonshaped, nonmotile, acidmotile, acid-- fast (fast (ZeihlZeihl -- NeelsenNeelsen).).

-- Strictly aerobic, slowly growing,Strictly aerobic, slowly growing,

hard to kill, resist dryness, sensitivehard to kill, resist dryness, sensitiveto UV radiation and acidic PH ( <to UV radiation and acidic PH ( < 66..55))

-- Lipid fraction:Lipid fraction: MycolicMycolic acidacid Waxy sheathWaxy sheath

Protects against digestion and drugsProtects against digestion and drugs

-- Protein fraction:Protein fraction:

DDelayed hypersensitivityelayed hypersensitivity

-- Carbohydrate fraction:Carbohydrate fraction:

AAccumulation of PNLccumulation of PNL



M y cobact erium tuberculosisM y cobact erium tuberculosis







Mod e of transmission:Mod e of transmission:

InhalationInhalation lunglung && tracheobronchial LNtracheobronchial LN

IngestionIngestion M. BovisM. Bovis

TTonsilsonsils && cervical LNscervical LNsIntestineIntestine && mesenteric LNsmesenteric LNs

InoculationInoculation SSkinkin && draining LNsdraining LNs

TransTrans--placental: Maternal systemic T.B.placental: Maternal systemic T.B.



Pathog enesis ( on primar y exposure):Pathog enesis ( on primar y exposure):

11-- GlycolipidGlycolipid cover cover accumulation of accumulation of

PNLPNL llocalization (no lipase)ocalization (no lipase)

22-- Accumulation of Accumulation of macrophagesmacrophages

fail to kill the organismfail to kill the organism freefree

bacillary proliferationbacillary proliferation bacteremiabacteremia seedling of multiple sitesseedling of multiple sites

33-- Macrophages partially destroy TBMacrophages partially destroy TB

bacillibacilli

TuberculoproteinTuberculoprotein

Ag short peptide expressed byAg short peptide expressed by

macrophagesmacrophages on class II MHCon class II MHC

moleculesmolecules hilar hilar LNLN ILIL--1212



44-- TT--helper CD4+helper CD4+ cellscells recognize therecognize thepresented Agpresented Ag sensitizedsensitized TTHH1 cells1 cells

55-- Sensitized TSensitized THH

1 cells1 cells

CytokinesCytokines--ILIL--11 ClonalClonal expansionexpansion

memory cellsmemory cells tuberculin +tuberculin +veve

-- ILIL--22 AutoAuto--,, paracrineparacrine proliferationproliferation

of T cellof T cell

CytotoxicCytotoxic CD8+ TCD8+ T lymphocyteslymphocytes

kill infected macrophageskill infected macrophages

-- TNF,TNF, chemokineschemokines MonocytesMonocytes

recruitmentrecruitment

-- IFNIFN--KK Activates macrophagesActivates macrophages

immunity = resistanceimmunity = resistance



Activated macrophage =Activated macrophage = Epithelioid cellEpithelioid cell

-- Large cells, large vesicular nucleusLarge cells, large vesicular nucleus

abundant pale eosinophilic cytoplasmabundant pale eosinophilic cytoplasm-- Increased ability toIncreased ability to phagocytosephagocytose &&

killkill T.B. bacilliT.B. bacilli

-- Express moreExpress more class II MHC moleculesclass II MHC molecules facilitate Ag presentationfacilitate Ag presentation

-- TNF, ILTNF, IL--11,, chemokineschemokines promotepromote inflinfl

-- Secret TGFSecret TGF--B, PDGF, FGFB, PDGF, FGF

collagen synthesiscollagen synthesis fibrosisfibrosis

1.1. Serve to eliminate the offending antigenServe to eliminate the offending antigen

2.2. If sustainedIf sustained continued infl.continued infl. fibrosisfibrosis



55-- Collar of Collar of lymphocyteslymphocytes surrounds thesurrounds the

epithelioid cellsepithelioid cells small tubercle; 0.5small tubercle; 0.5--2 mm2 mm

fusionfusion largelarge avascular avascular massmass necrosisnecrosis

66 -- LanghansLanghans giant cells:giant cells:-- Fusion of Epithelioid cellsFusion of Epithelioid cells

-- Large, deep eosinophilic cytoplasmLarge, deep eosinophilic cytoplasm

-- Multinucleated with peripheral nucleiMultinucleated with peripheral nucleihorsehorse -- shoe or bipolar shoe or bipolar

-- Digest and remove necrotic tissueDigest and remove necrotic tissue

77-- Caseous necrosis (4Caseous necrosis (4--6 weeks):6 weeks):

-- Caused byCaused by avascularityavascularity, liberation of , liberation of cytotoxiccytotoxic factors,factors, cytotoxiccytotoxic CD8+ T cellsCD8+ T cells

NEA:NEA: Dry, cheeseDry, cheese--like, friable, creamy yellowlike, friable, creamy yellow

MPMP:: granular, eosinophilicgranular, eosinophilic

Acidic, anaerobic mediaAcidic, anaerobic media Kill bacilliKill bacilli



PathogenesisPathogenesis

Tuberculin +ve bactericidal activity

hypersensitivity ³immunity´





Fat e of T uberculous lesion:Fat e of T uberculous lesion:11-- HealingHealing

-- High immunityHigh immunity-- Epithelioid cellsEpithelioid cells FGF & PDGFFGF & PDGF

collagen synthesiscollagen synthesis fibrosisfibrosis

-- DystrophicDystrophic calcificationcalcification of caseatingof caseating

center center -- Sterile or contain dormant bacilliSterile or contain dormant bacilli

22-- Progressive Caseation and softeningProgressive Caseation and softening

-- Low immunityLow immunity-- Hallmark of activityHallmark of activity

-- CaseationCaseation softeningsoftening cold abscesscold abscess

drainingdraining sinusessinuses openopen tuberculosistuberculosis

OO22 bacillus proliferationbacillus proliferation



Primar y tuberculosisPrimar y tuberculosis

-- Infection of a nonInfection of a non -- sensitizedsensitized

immunoimmuno--competent person bycompetent person by

tubercle bacilli for the first timetubercle bacilli for the first time

-- Children >> adultsChildren >> adults



T he primar y com p lex : (Ghon²sT he primar y com p lex : (Ghon²scom p lex)com p lex)

11-- Primary focusPrimary focus22-- LymphangitisLymphangitis

33-- LymphadenitisLymphadenitis

Common sit es:

Common sit es:

11-- LungLung && tracheobronchial lymphtracheobronchial lymphnodesnodes

22-- TonsilsTonsils && deep cervical lymph nodesdeep cervical lymph nodes

33-- IntestineIntestine && mesenteric lymph nodesmesenteric lymph nodes

44-- SkinSkin && draining lymph nodesdraining lymph nodes

Draining lymph nodes show most of theDraining lymph nodes show most of the

reactionreaction



Primar y P ulmonar y T uberculosisPrimar y P ulmonar y T uberculosis

Transmission:Transmission: inhalationinhalationGhon·s complex:Ghon·s complex:

11-- Ghon·s focus:Ghon·s focus:

-- 11--11..55 cmcm -- Sub pleuralSub pleural

-- Upper part of lower lobe or lower Upper part of lower lobe or lower part of upper lobepart of upper lobe

-- Well circumscribed, grayish whiteWell circumscribed, grayish whitearea of consolidationarea of consolidation

-- Central caseationCentral caseation

22-- LymphangitisLymphangitis

33-- Lymphadenitis of Lymphadenitis of tracheotracheo-- bronchialbronchial

LNs:LNs: Enlarged, caseating, mattedEnlarged, caseating, matted









Fat e of the primar y com p lex :Fat e of the primar y com p lex :Healing or spread: Immunity, Virulence, dozeHealing or spread: Immunity, Virulence, doze

11-- Healing:Healing: Good immunity & low virulenceGood immunity & low virulence

(95%)(95%) -- AsymptomaticAsymptomatic Fibrosis, calcificationFibrosis, calcification

-- Tuberculin testTuberculin test positivepositive

-- Residual bacilliResidual bacilli reactivationreactivation 2ry2ry

22-- Progressive primary tuberculosisProgressive primary tuberculosis spreadspread

Lower immunity & highly virulent organismLower immunity & highly virulent organism

a) Directa) Direct Lung parenchyma & pleuraLung parenchyma & pleura

b) Lymphaticb) Lymphatic thoracic ductthoracic duct Rt. HeartRt. Heart lunglung

c) Bronchial treec) Bronchial tree caseous bronchopneumoniacaseous bronchopneumonia

d) Hematogenousd) Hematogenous** Pulmonary arteryPulmonary artery miliarymiliary TB of the lungTB of the lung

** Pulmonary veinPulmonary vein Miliary tuberculosis or Miliary tuberculosis or

Isolated organ tuberculosisIsolated organ tuberculosis

death due todeath due to tuberculoustuberculous meningitismeningitis









Secondar y P ulmonar y Secondar y P ulmonar y T uberculosisT uberculosis

-- PreviouslyPreviously sensitizedsensitized hosthost-- ExogenousExogenous rere--infection or reactivationinfection or reactivation

of latent primary T.B.of latent primary T.B.

-- AdultsAdults >> children>> children-- RapidRapid due to hypersensitivity (due to hypersensitivity (88--1212h)h)

wall off the focus of infectionwall off the focus of infection

lymph nodes are less involvedlymph nodes are less involved-- RightRight lung > leftlung > left

-- ApicalApical: high oxygen tension: high oxygen tension

no tissue fluidno tissue fluid





Course and Fat e Course and Fat e

of secondar y p ulmonar y tuberculosis:of secondar y p ulmonar y tuberculosis:

11-- Arrested tuberculosis:Arrested tuberculosis:

-- High resistance & low virulenceHigh resistance & low virulence

-- Small, apical,Small, apical, 11--22 cm.cm.-- Grayish white to yellow area of Grayish white to yellow area of

Consolidation with variable centralConsolidation with variable central

caseation and peripheral fibrosiscaseation and peripheral fibrosis-- MP: Coalescent tuberclesMP: Coalescent tubercles

-- Healing by fibrosis and calcificationHealing by fibrosis and calcification



22-- FibrocaseousFibrocaseous T. B.T. B. withwith cavitationcavitation

-- Elder or immunoElder or immuno--suppressed with Moderatesuppressed with Moderate

resistance & dose of organismresistance & dose of organism-- Extensive caseation of apical regionExtensive caseation of apical region

Erosion of a bronchusErosion of a bronchus coughedcoughed

OpenOpen pulmonary T.B.pulmonary T.B. ++veve sputumsputum

Cavity formation:Cavity formation:

Large, apical, poorly walled by fibrousLarge, apical, poorly walled by fibrous

tissue, lined by caseous necrotictissue, lined by caseous necrotic

tissue, traversed by arteriestissue, traversed by arteries

Erosion of Erosion of arteryartery haemoptysishaemoptysis

-- Fibrosis of the lung & pleura with adhesionsFibrosis of the lung & pleura with adhesions

-- Lymph nodes are slightly or not affectedLymph nodes are slightly or not affected









33-- Tuberculous pneumonia:Tuberculous pneumonia:

-- HHigh virulence,igh virulence, llow resistance,ow resistance,

advanced Immunosuppression.advanced Immunosuppression.

-- Rapid spread´ galloping consumptionµRapid spread´ galloping consumptionµ

-- WidespreadWidespread exudativeexudative CaseousCaseous

pneumonic consolidation,pneumonic consolidation,

-- NonNon--cavitarycavitary diseasedisease

-- Pleura & tracheobronchial lymphPleura & tracheobronchial lymph

nodes are affectednodes are affected

-- Large number of bacilliLarge number of bacilli



Complications of Complications of fibrocaseousfibrocaseous T.B.:T.B.:

II-- Spread of infection:Spread of infection:

11-- Direct spread to the pleuraDirect spread to the pleura-- Pleural effusionPleural effusion -- FibrousFibrous pleuritispleuritis

-- T.B. empyemaT.B. empyema -- PneumothxPneumothx..

Pyopneumothx.Pyopneumothx.22-- Natural passagesNatural passages

-- T.B.T.B. tracheotracheo--bronchitisbronchitis -- LaryngitisLaryngitis

-- GlossitisGlossitis -- EnteritisEnteritis

33-- lymphatic spreadlymphatic spread

aa-- Bronchial treeBronchial tree T.B.T.B. bronchopneumbronchopneum

bb-- LymphoLympho--hematogenoushematogenous miliarymiliary

T.B. of the lungT.B. of the lung

44 H t dH t d



44-- Hematogenous spreadHematogenous spread

*Acute*Acute miliarymiliary tuberculosis:tuberculosis:

-- Erosion of Erosion of pulmonary arterypulmonary artery miliarymiliary

tuberculosis of the lungtuberculosis of the lung

-- Erosion of Erosion of pulmonary veinpulmonary vein systemicsystemic miliarymiliary

TBTB liver, bone marrow, spleen, adrenals,liver, bone marrow, spleen, adrenals,

meningesmeninges, kidneys, fallopian tubes,, kidneys, fallopian tubes,epididymisepididymis..

*Isolated organ tuberculosis:*Isolated organ tuberculosis:

Miliary dissemination with destruction of Miliary dissemination with destruction of

the bacilli except at sites of isolatedthe bacilli except at sites of isolatedinfection:infection: meningesmeninges, kidneys adrenals, kidneys adrenals

(Addison d.), bones (Pott·s), spleen,(Addison d.), bones (Pott·s), spleen,

fallopian tubes,fallopian tubes, epididymisepididymis..

IIII-- Hemo t sisHemo t sis IIIIII-- 2r Am loidosis2r Am loidosis











Int estinal T uberculosisInt estinal T uberculosis

Primar y int estinal tuberculosis:Primar y int estinal tuberculosis:((TabesTabes mesent erica mesent erica ))

-- Ingestion of M. Bovis infected cowIngestion of M. Bovis infected cow

milkmilk

-- Ghon·s complex:Ghon·s complex:

Primary microscopic focusPrimary microscopic focus

LymphangitisLymphangitis

Lymphadenitis of mesenteric lymphLymphadenitis of mesenteric lymph

nodes:nodes: Enlarged, Caseating, mattedEnlarged, Caseating, matted



Secondary intestinal tuberculosis:Secondary intestinal tuberculosis:

Mode of transmission:Mode of transmission: Swallowing of Swallowing of

infected sputum in open pulmonary TBinfected sputum in open pulmonary TBNEA:NEA:

-- GranulomatousGranulomatous reaction in Payer'sreaction in Payer's

patchespatches

sloughing of the mucosa &sloughing of the mucosa &Formation of Formation of tuberculoustuberculous ulcers:ulcers:

multiple, oval, transverse, deep,multiple, oval, transverse, deep,

undermined edges, necrotic floor undermined edges, necrotic floor

-- Mesenteric LNs are slightly affectedMesenteric LNs are slightly affected

C li tiC li ti



--Complications:Complications:-- FibrosisFibrosis stenosis & intestinal obstructionstenosis & intestinal obstruction

-- PPerforationerforation hemorrhage, septic peritonitishemorrhage, septic peritonitis

-- Fistula with adjacent bowel loopsFistula with adjacent bowel loops



II) T uberculous Ost eom ye litisII) T uberculous Ost eom ye litis

Route of infection:Route of infection:11-- HematogenousHematogenous: active pulmonary T.B: active pulmonary T.B

22-- Direct extensionDirect extension

Site:Site:spongy bone more than compact bonespongy bone more than compact bone

-- Thoracic and lumbar vertebrae (Potts)Thoracic and lumbar vertebrae (Potts)

-- MetaphysealMetaphyseal ends of long bonesends of long bones

-- Small bones of hands and feetSmall bones of hands and feet ((dactylitisdactylitis



T uberculousS pond y litisT uberculousS pond y litis

P

ott²s Disease of T he S pine

P

ott²s Disease of T he S pine

Age: Age: ChildrenChildren -- young adultsyoung adults

Sex: Sex: Males > femalesMales > females

S ite:S ite: Thoracic> lumbar> cervicalThoracic> lumbar> cervicalPathogenesis:P athogenesis:

Caseating Caseating tuberculoustuberculous granuloma ingranuloma in

the marrow cavitythe marrow cavityendosteumendosteum

corticalcorticalnecrosis necrosis periosteumperiosteum intervertebralintervertebral

discdisc destruction of destruction of intervertebralintervertebral discdiscadjacent vertebraadjacent vertebra



NEA:NEA: Extensive bone Extensive bone

destructiondestruction

creamy yellow,creamy yellow,

cheesy necrotic debrischeesy necrotic debris

MP:MP:

-- Destructive CaseatingDestructive Caseatinggranulomagranuloma

-- Reparative processesReparative processes

�� Fibrosis Fibrosis

�� New bone formationNew bone formation



Com p lications:Com p lications:

11-- K yp hosis, scoK yp hosis, scoliosis:liosis:

-- Extensive destruction ofExtensive destruction of

vertebral bodies vertebral bodies

compression fracture compression fracture

deformity of the spinedeformity of the spine

--New bone formationNew bone formation

fixed malpositionfixed malposition

1- K yp hosis & scoliosis

22 C ld bC ld b

2 C ld b



22-- Cold abscesses:Cold abscesses:

-- lumbar vertebral bodies lumbar vertebral bodies parapara--

vertebral muscles vertebral muscles psoaspsoas abscessabscess-- cervical vertebrae cervical vertebrae retropharyngealretropharyngeal

abscessabscess

--thoracic vertebrae thoracic vertebrae

MediastinalMediastinal

33-- Potts paraplegia :Potts paraplegia : spinal cordspinal cordCompressionCompression -- extraduralextradural abscess abscess

--intraduralintradural abscess abscess

-- disc materialdisc material

-- sequestrated bonesequestrated bone

44-- Secondary amyloidosisSecondary amyloidosis

3-Pott²s para p legia

4- Secondar y am y loidosis

2-Cold abscess



TUBERCULOUSTUBERCULOUS D ACTYLITISD ACTYLITIS

Site:Site: Small bones of feet andSmall bones of feet andhandshands

Morphology:Morphology:

-- Destruction of phalanges andDestruction of phalanges andmetacarpal bonesmetacarpal bones

-- New bone formationNew bone formation fusiformfusiform

swellingswelling

T be l sis f the kid eT be l sis f the kid e



T uberculosis of the kidney T uberculosis of the kidney Miliar y Miliar y tuberculosis tuberculosis

Multiple small tubercles,Multiple small tubercles, 11--22 mm, centralmm, centralcaseationcaseation, more in cortex, more in cortex

Caseocav ernousCaseocav ernous tuberculosis tuberculosis

Starts at the base of pyramidsStarts at the base of pyramids enlarge &enlarge &caseatecaseate & spread to pelvis& spread to pelvis Large cavity Large cavity Com p lications:Com p lications:

11-- TB ureteritis:TB ureteritis: fibrosis and obstructionfibrosis and obstruction

22-- TBTB pyonephrosispyonephrosis::Ureteral obstructionUreteral obstruction bag of pus bag of pus

33-- TB cystitisTB cystitis



Miliary Miliary tuberculosistuberculosis CaseocavernousCaseocavernous

II) Ch i titiII) Ch i titi



II) C hronic c y stitisII) C hronic c y stitis11--C hronic nonC hronic non -- s pecific c y stitiss pecific c y stitisPersistent acute cystitisPersistent acute cystitis

-- NEA: NEA: Thickening of the bladder wallThickening of the bladder wall-- MP:MP: Lymphocytic infiltrationLymphocytic infiltration -- fibrosisfibrosis

22--C hronic s pecific c y stitisC hronic s pecific c y stitis

-- TuberculousTuberculous:: renalrenalHematuriaHematuria-- Bilharzial:Bilharzial:

The urinary bladder is the earliest, heaviest,The urinary bladder is the earliest, heaviest,

most commonmost commonSit e:Sit e: TrigoneTrigone, posterior bladder wall, ureteric, posterior bladder wall, ureteric

orificeorifice NEA: NEA: Contracted calcified bladderContracted calcified bladder





"It is nice to have money and the"It is nice to have money and the

things that money can buy, butthings that money can buy, but

it's important to make sure youit's important to make sure youhaven't lost the things moneyhaven't lost the things money

can't buy."can't buy."

George Lorimer

1867-1937, Editor of "Saturday Evening Post"

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Granulomatous Inflammation 4 (2)