Pathology of inflammation

LECTURE OUTLINE

summary of the
most important points

Warning!

The sole purpose of this outline is to stop the urge of students to

write down every text seen on the slides. The outline does not
substitute reading the textbook nor attending the lectures.

2018
Exam questions

Preparations Slides
1. Fibrinous pericarditis – cor villosum 1. Fibrinous
2. Pseudomembranous colitis pericarditis – cor villosum
3. Lobar pneumonia 2. Pseudomembranous colitis
4. Bronchopneumonia 3. Lobar pneumonia
5. Purulent meningitis 4. Bronchopneumonia
6. Pulmonary abscess 5. Purulent meningitis
7. Chronic cholecystitis 6. Acute appendicitis
8. Sarcoidosis – BHL 7. Chronic cholecystitis
9. Miliary tuberculosis of the lungs 8. Sarcoidosis in lymph node
10. Phthisis cavernosa 9. Foreign body granuloma
10. Miliary tuberculosis of the lung
11. Myocardial infarct with organisation
Topics
28. Vascular and cellular mechanisms and mediators of acute inflammation
29. Clinicopathological classification of acute inflammation. Organ examples.
30. Definition, causes, cellular and humoral mechanisms of chronic inflammation.
31. Pathogenesis and clinicopathology of tuberculosis.
32. Granuloma, granulomatous inflammation.
Topic layout

Major subtopics
acute inflammation vascular changes
acute inflammation cellular changes
acute inflammation humoral mechanisms
acute inflammation types based on exudate
repair – outcome of acute inflammation
chronic inflammation
granuloma Cases shown
tuberculosis familial mediterranean fever
meningococcal sepsis
Mucormycosis
silicotuberculosis
Inflammation

defensive response of vascularized living tissue

goals:
removal of the offending agent
removal of damaged cells/tissues
regeneration
Causes of inflammation (examples)

Infection
common cold, pneumonia
Allergy
hay fever, asthma
Autoimmunity
thyroiditis, vasculitis, glomerulonephritis

Chemical damage
alcoholic gastritis, hepatitis

Physical damage
burn, radiation

Inflammation playing a role in disease

atherosclerosis
Alzheimer’s disease
prostate hyperplasia
infiltration of malignant neoplasms
Types of inflammation

Acute inflammation
minutes - hours
neutrophil granulocytes
vascular changes

Chronic inflammation
days - weeks
lymphocytes
connective tissue proliferation - reparation

Subacute inflammation
„between acute and chronic,
closer to acute”
mild, prolonged acute inflammation
Acute inflammation

Vascular changes Cellular events Mediators

recognition
vasodilation cell-derived
recruitment
permeability increase plasma-derived
removal
Vascular changes

Vasoconstriction
transient
axon reflex, sympathic effect

Vasodilatation
histamine, NO, PGI2 (see: later)
arteriolar vasodilatation – active hyperemia

capillary stasis (capillary congestion)

Hyperemia and congestion

Hyperemia = more blood

Hyperemia
(active hyperemia) – increased arterial perfusion

Congestion
(passive hyperemia) – decreased venous drainage
Vascular changes – permeability increase
Immediate, transient response
within seconds – 15-30 minutes
endothelial contraction of postcapillary venules
histamine, bradykinin, leukotrienes

Immediate, sustained response

within seconds – 4-6 hours
endothelial necrosis of arterioles, capillaries, venules
direct injury

Delayed, prolonged response

after 2-12 hours – for hours or days
venules and capillaries
cytoskeleton reorganisation? endothelial apoptosis?

Other mechanisms
leukocyte-mediated endothelial damage
increasing transcytosis
Inflammatory edema

Transudate Exudate
protein-poor edema protein-rich edema

similar to normal fibrinogen – fibrin

interstitial fluid plasma proteins
inflammatory cells

Sp.gravity: 1,012
Protein: 20 g/l

Rivalta’s test
Cellular events - cells
Inflammatory cells- leukocytes
Neutrophil granulocyte
most frequent leukocyte – 2,5-7,5 × 109/l in blood
first to accumulate – major cell of acute inflammation
phagocytes, produce cytokins, antimicrobial agents

Eosinophil granulocyte
IgE-mediated reaction - allergic reaction, parasite-infection
leukotrienes, PAF, antimicrobial agents
has a part in chronic inflammation as well

Basophil granulocyte
IgE receptors
produce histamine, chemotactic factors, leukotrienes
relatives of mast cells
Cellular events - cells
Inflammatory cells- leukocytes
Monocyte/macrophage
histiocyte, Kupfer-cell, microglia, alveolar macrophage
phagocytes, produce cytokines
major cells of reparation/chronic inflammation

Lymphocyte
major cell of adaptive immunity
chronic inflammation

Other important cells

Endothelial cell
Platelet
Fibroblast
Cellular events - recognition

Pathogen-asszociated molecular pattern

(PAMP)
signal: eg.: lipopolysaccharide (Gram-), endotoxin,
flagellin, lipoteichoic acid (Gram+), dsRNA, etc.
TLR polymorphism
receptor: Toll-like receptors
sepsis and asthma
effect: NFκB signaling
susceptibility

Danger-associated molecular pattern

(DAMP)
signal : ATP, uric acid, chromatin associated
proteins, extracellular matrix fragments, etc .
receptor: NOD-like receptors
effect: inflammasome activation – IL1
familiar mediterranean fever
pyrin mutation – too much IL1
chr. inflammation - amyloidosis
Cellular events - recruitment

MARGINATION
due to capillary stasis

ROLLING
due to transient adhesions (selectins)
P-selectin/PSGL1; E-selectin/PSGL1

Leukocyte adehesion
ADHESION
defect 1
due to strong adhesions (integrins)
CD18 defect (LFA1)
LFA1/ICAM1; VLA4/VCAM1

TRANSMIGRATION
PECAM1(CD31) activation

CHEMOTAXIS
due to chemotactic mediators
movement along a chemical gradient
Cellular events - removal
OPSONISATION
eg. complement, Ig
receptor: complement receptor, Fc-receptor

ENGULFMENT

PHAGOLYSOSOME FORMATION Chediak-Higashi

disease
killing in a contained abnormal
environment phagolysosome
formation

CHEMICAL KILLING Chronic

oxygen derived free radicals (NADPH-oxidase, MPO) granulomatous
- oxydative burst disease
nitrogen derived free radicals (inducible NO synthase) NADPH-oxidase
other enzymes (eg. lysozyme, elastase, MBP, etc.) defect
Cellular events - removal

EXTRACELLULAR KILLING

leakage at phagosome-lysosome fusion

frustrated phagocytosis (eg. immunocomplexes embedded in GBM
phagolysosome ijury (eg. silicosis)
extracellular traps (neutrophil/eosinophil granulocyte)
Mediators of inflammation

Cell derived mediators Plasma derived mediators

vasoactive amines
complement system
arachidonate metabolites (eiconasoids)
coagulation proteins
cytokines
other (PAF, NO)
Mediators of inflammation – vasoactive amines
Histamine
source:
mast cell, basophil, thrombocyte
inducing factor:
trauma, heat; IgE; C3a, C5a, neuropeptides, cytokines
effect:
arteriolar vasodilatation, venular permeability increase

Serotonin
source:
neurons, neuroendocrine cells;
endothel and thrombocytes take up and store
inducing factor:
thrombocyte aggregation, endothelial activation
effect:
permeability increase, vasodilatation/constriction
bronchial constriction
Meidators of inflammation – arachidonate metabolites
steroid

phospholipase
phospholipids arachidonate LTB4
chemotaxis
aspirin
anti-
NSAID
asthmatics
5-HPETE

PGH2 many sources

LTA4

endothel thrombocyte PGD2 /PGE2 thrombocyte

vasodilatation
fever
bronchospasm LXA/B4
PGI2 TXA2 LTC/D/E4
vasodilatation vasoconstriction chemotaxis,
transmigration bronchospasm
plt inactivation plt activation
LTC/D/E4 inhibition permeability
Mediators of inflammation – cytokines

Interleukin
cytokine responsible for communicating between leukocytes

Lymphokine
cytokine produced by lymphocytes

Monokine
cytokine produced by monocytes

Interferon
cytokine with antiviral function originally

Chemokine
cytokine mediating chemotaxis
Mediators of inflammation – cytokines
Tumor necrosis factor (TNFα)
every cell, especially endothel, epithel, macrophage, dendritic cell
vasodilation, permeability increase, endothelial activation
heart contractility↓, cachexia, acute phase reaction
fibroblast proliferation, collagen synthesiss

IL-1
every cell, especially endothel, epithel, macrophage, dendritic cell
IL-1 family – 11 members
fever, pain, vasodilation

IL-6
T-cell, macrophage, muscle cell, fat cell
pyrogen, acute phase reaction
myokine
Mediators of inflammation – cytokines

Interferon gamma (IFNγ)

NK-cell, NKT-cell, TH1 -cell, CD8+ cytotoxic T-cell
macrophage activation, TH1 differentiation

IL-12
macrophages, dendritic cells
IFN-γ production

IL-17
TH17 –cells
increases chemokine expression – recruitment of neutrophils
Mediators of inflammation – others

Platelet activating factor – PAF

source: plt, leukocytes, endothelial cell
effect: plt-aggregation, vasodilatation, leukocyte adhesion, oxidative burst
chemotaxis, permeability increase

Nitrogen-monoxide – NO

source: endothel (EDRF), macrophages, neurons

effect: vasodilatation
plt-aggregation inhibition
leukocyte adhesion inhibition
Mediators of inflammation – complements
chemotaxis
mast cell degranulation
arachidonate metabolism
classic
C3a C5a
pathway

Ig/C1q/4b/2b Ig/C1q/4b/2b/3b
MBL/C4b/2b MBL/C4b/2b/3b
MAC
lectin C3 konvertase C5 konvertase
cell lysis
pathway
C3b/Bb C3b/Bb/3b
C3b

paroxysmal
alternative nocturnal opsonisation
pathway haemoglobinuria
CD55/CD59
defect
Mediators of inflammation – clotting factors

THROMBIN

leukocyte adhesion
PAF production
arachidonate metabolism activated
Mediators of inflammation – kinins

FXII Plasminogen

Prekallikrein

Plasmin

Kallikrein fibrin degradation

C3a conversion
TGFβ activation

HMW kinin Bradykinin

vasodilatation
permeability increase
pain
C5a conversion
Signs of acute inflammation

Local signs

Systemic signs
Local signs of acute inflammation

CALOR
RUBOR
TUMOR
DOLOR
FUNCTIO LAESA
Systemic signs of acute inflammation

Acute phase reaction

Fever TNF, IL1 prostaglandins

Acute phase proteins IL6

CRP – C-reactive protein; opsonisation of apoptotic cells
SAA – serum amyloid A; HDL-asszociated apolipoprotein, cholesterol-transport
fibrinogen – increased sedimentation (ESR)

Leukocytosis TNF, IL1, CSF

leukemoid reaction, hypereosinophily, lymphocytosis

Other TNF
elevated pulse, chills, insulin resistance, loss of appetite
Sepsis

Terms:
Sepsis: Gr. = decay
most common
Septicemia: bacterial toxins/bacteria in the blood cause
of death in ICU
(not recommended)
Bacteremia: bacteria in the blood 40% mortality

Septic shock: schock due to sepsis

Definitions:
Sepsis: “life-threatening organ dysfunction caused by a deregulated host
response to infection”

Septic shock: “subset of sepsis in which underlying circulatory, cellular

and metabolic abnormalities are profound enough to
substantially increase mortality”

Singer M et al. The Third International Consensus Definitions

for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):801.
Sepsis

organ
infection host reponse
dysfunction

cardiovascular
neuronal
autonomic
pro-inflammation
hormonal
anti-inflammation
metabolic
energetic
coagulation related changes

most
20-40% common
mortality cause of
death at ICU
Sepsis

Pathomechanism

endotoxins
other proteins
FXII

complement NO, PAF,

Free radicals
TNF, IL1, IL6 IL10, TGFβ

Platelet
activation
Endothel

vasodilatation sytemic immuno-

DIC
permeability↑ effects suppression

Septic shock
Puerperal fever
Ingácz Semmelweis Saviour of mothers
(1818-1865)

1847: Jacob Kolletschka dies of sepsis

after a legal autopsy

Semmelweis recognized that the incidence of puerperal fever

at the clinic in Wien
is linked to autopsy teaching

In 1847 he introduced desinfective hand washing:

incidence dropped from 10% to 1-2%
Morphological classification of acute inflammation

Serous

Fibrinous

EXUDATE
Purulent
COMPOSITION
Hemorrhagic

Gangrenous
Serous inflammation

Characteristics
protein-poor exudate (almost like transudate)
mild, superficial inflammation
catarrhal inflammation: mucous-serous, mucosal

Causes
viral and autoimmune inflammation
mild trauma/burns (skin)

Examples
common cold
hay fever
viral meningitis
bullous pemphigoid
Fibrinous inflammation
Characteristics
fibrin-rich exudate
Causes
bacterial infection, early stage
autoimmune inflammation
chemical inflammation
Examples
fibrinous pericarditis
fibrinous pleuritis
Fibrinous pericarditis
uremia
viral infection
rheumatic fever
SLE
myocardial infarct
Complication
constrictive pericarditis:
pericardial layers grow together with scar tissue
concretio pericardii:
pericardial layers adhere to each other
accretio pericardii:
parietal pericardium adheres to pleura
Fibrinous inflammation

Rheumatic fever fever, ESR↑, CRP↑,

Leukocyte↑
Streptococcus infection antibody autoimmune
pharyngitis cross-reaction inflammation
M factor
MacCallum polyarthritis
plaques
aortic endocarditis
stenosis erythema
vegetations marginatum
mitral
stenosis
myocarditis Sydenham-
Chronic phase myocardial
chorea
Aschoff nodules
fibrosis
fibrinous
pericarditis
induratio
brunea congestive
pulmonum heart failure Acute phase
Pseudomembranous inflammation

Clostridium colitis
Clostridium difficile
toxin A, B: disrupt cytoskeletal regulation
disrupt tight junctions
intrinsic apoptosis pathway
anoikis

Diphtheria
Diphtheria
Corynebacterium diphtheriae
respiratory diphtheria
cutaneous diphtheria
Purulent inflammation

Characteristics
neutrophil-rich exudate
three classical forms

Causes
bacterial (pyogenic) infection

Examples
purulent meningitis Pus = neutrophils, tissue debris
typical pneumonia
abscesses
Pyogenic = pus-forming
erysipelas (S. pyogenes)
purulent pyelonephritis
Purulent inflammation

Characteristics
neutrophil-rich exudate
three classical forms

Abscess demarcated pus in tissue

Phlegmone pus spreading in connective tissue

Empyema pus in body cavity

Purulent inflammation
Purulent meningitis
Epidemiology
2,5 / 100.000 population
mean age in 1986: 1 years; now: 25 years
H. influenzae – now rare due to vaccination

Infective agents
Infants: E. coli (and other Gram-negatives),
S. agalactiae
Old age: S. pneumoniae, Listeria monocytogenes
Others: Neisseria meningitidis, S. pneumoniae

Clinical picture
headache, fever, stiff neck, photophobia, reduced consciousness
Meningococcal sepsis: purpuras in skin and tissues
Purulent inflammation - abscess
Cerebral abscess
hematogenous: inf. endocarditis, lung
local extension: oral, nasal, paranasal infection
anaerobes: Bacteroides
aerobes: Staphylococcus

Lung abscess
aspiration
obstruction
bronchopneumonia
inf. endocarditis (right ventricle)
anaerobes: Bacteroides
aerobes: Staphylococcus, Klebsiella

Dermal abscess
furuncle (boil): deep folliculitis (S. aureus)
carbuncle: confluating boils
Example of the changing nature of the exudate

Community acquired, typical pneumonia

bronchopneumonia
lobar pneumonia

congestion (capillary stasis) – serous exudate

hepatisatio rubra – blood-rich exudate
hepatisatio grisea – fibrin-rich exudate
hepatisatio flava – purulent exudate
carnification – reparation with granulatin tissue
Hemorrhagic inflammation
Characteristics
large amount of blood in exudate

Causes
bacterial, viral, parasitic infection
chemical inflammation

Examples
haemorrhagic cystitis: BK cystitis, cyclophosphamide
viral hemorrhagic fever: eg. ebola
herpes encephalitis: severe inflammation caused by HSV
plague: Yersinia pestis (G-negative), rats disseminate
bubonic plague: lymph node enlargement, lung plague: hemorrhagic pneumonia

anthrax: Bacillus anthracis (G-positive), bioterrorism!

skin anthrax – ulcer sepsis; lung anthrax – hemorrhagic pneumonia

uremic pericarditis
Gangrenous inflammation

Characteristics
purulent inflammation + ischemic necrosis

Causes
bakterium (többnyire anaerob)
diabetes is a risk factor

Examples
appendicitis acuta gangaenosa
lung gangrene
Fournier-gangrene
noma
Gangrenous inflammation
Acute appendicitis
Causes Morphologic classification
obstruction (theory) (without much practical significance)
fecolith catarrhal
lymphatic hyperplasia ulcerous
food ulcerophlegmonose
ischemia? gangrenous
hypersensitivity reaction? perforative
infection?

Epidemiology
periappendicular abscessus
most frequent between 5-40 years
Outcome of acute inflammation

Full recovery sanatio per primam intentionem

minimal tissue necrosis/exudate
tissue capable of regeneration
minimal organisation and scar

Scarring sanatio per secundam intentionem

significant necrosis or exudate
limited regeneration capability
fibrosis/sclerosis – connective tissue accumulation

Persistent inflammation chronic inflammation

mononuclear inflammatory cells
granulation tissue and fibrosis
active chronic inflammation – neutrophils and chronic inflammation
Reparation

•tissue necrosis (eg. infarct)

•neutrophil granulocytes (acute inflammation, 18-20 hours)
•macrophages (24-48 hours) (matrix metalloproteases, others)
•fibroblast-activation (TGFβ, PDGF)
•angiogenesis (2-6 days) (VEGF, FGF2)
•fibrosis –scar (weeks)

granulation tissue: fibroblasts, macrophages, angiogenesis

Scarring

Callus pleurae
fibrous pleuritis
pleural fibrosis

Cirrhosis
pseudolobular scarring
Ito-cell activation

Acquired valve disease (vitium)

„chronic endocarditis”
scarring after previous inflammation

Old infarct
Chronic inflammation

General characteristics Examples Granuloma

causes
definitions
cells of chronic chronic gastritis
mechanism
inflammation rheumatoid arthritis
types
mediators of chronic
inflammation
Chronic inflammation

Characteristics
prolonged (weeks/months) inflammation
mononuclear inflammatory cells
reparation
non-specific / specific

Causes
prolonged acute inflammation
autoimmune inflammation
viral infection
difficult to degrade foreign materials
loss of balance of pro- and anti-inflammation
Cells of chronic inflammation

Monocyte/macrophage
histiocyte, Kupfer-cell, microglial cell, alveolar macrophage
phagocytes, production of cytokines
major cells of reparation and chronic inflammation

Lymphocyte
major cell of adaptive immunity
plays a part in chronic inflammation

Fibroblast
production and remodeling of collagen and EC matrix
activating angiogenesis
myofibroblastic differentiation
mesenchymal progenitor cells
Cells of chronic inflammation
CD8+ CD4+ T-cell
T-cell TH1 IL12 IL4 TH2
IL5
IFNγ
IgG
TGFβ IL1
IFNγ IL13 IgE
IL6 IL4
TH17

Klasszikus aktiváció
Alternative activation
IL17
IL22

IL12
IL1 TGFβ IL10
TNFα
TGFβ

Pro-inflammatory Anti-inflammatory
Phagocytosis Fibrosis
cytokines cytokines
Mediators of chronic inflammation
Transforming growth factor (TGFβ)
produced by many cells – in „latent” form
activated macrophages activate a lot of TGFβ
plasmin activates TGFβ
antiproliferative and fibrosis enhancing effect

Platelet derived growth factor (PDGF)

platelets, activated macrophages, endothelial cells, smooth muscle cells
effect: fibroblast and smooth muscle cells stimulation

Fibroblast growth factor

mostly fibroblasts, but other cells as well
endothelial cell proliferation, macrophage and fibroblast activation

Vascular endothelial growth factor (VEGF)

produced by many cells due to hypoxia, PDGF, TGFβ
major angiogenesis factor
Chronic inflammation

Chronic gastritis

H. pylori gastritis
Gram-negative rods
Causes >50% globally
Helicobacter pylori
antrum gastritis
autoimmune gastritis
hyperacidity
bile reflux
Risk:
caffeine/alcohol/smoking
peptic ulcer
others
gastric lymphoma
gastric adenocarcinoma
Chronic inflammation
Rheumatoid arthritis
Epidemiology
1% incidence; 75% female, 20-40 years

Pathomechanism
type IV hypersensitivity
Th1 and/or Th17 reaction
RhF detectable in 80% Morphology
pannus
Clinical picture „rice bodies”
symmetrical polyarthritis rheumatoid nodule
80% RhF (anti-IgG IgM antibodies)
anti-CCP antibody (98% specificity)
vasculitis, rheumatoid nodules
rarely: amyloidosis, lung fibrosis
Consequence
long term NSAID/steroid treatment
Granuloma

DANGER! WARNING!

granulocyte leukocyte (neutrophil, eosinophil or basophil

granulation tissue fibroblasts + angiogenesis + connective tissue
granuloma circumscibed, specific chronic inflammation

fibrin formed from fibrinogen (thrombus or exudate)

fibroblast mesenchymal cells with multiple function
fibrosis connective tissue accumulation (mostly type I collagen)
Granuloma
Definition
circumscribed chronic inflammation with many, activated macrohages

Causes
material degradable only with special activation
macrophage activation
epithelioid change – wide, eosinophilic cytoplasm
giant cells
TH1 immune response (type IV hypersensitivity) – caseous necrosis

foreign body Langhans Touton

type giant cell type giant cell type giant cell
Granuloma types, examples

Non-immune granuloma (no type IV HS)

Lipogranuloma
Foreign-body granuloma
Xanthogranulomatous inflammation

Immune granuloma (type IV HS)

Tuberculosis
Leprosy
Syphilis
Cat scratch disease
Fungal infection (Histoplasma, Cryptococcus, etc.)

Unknown pathomechanism
Sarcoidosis
Non-immune granuloma

Lipogranuloma
after traumatic fat necrosis
chronic inflammation

Foreign-body granuloma
non-degradable material
keratin, cholesterol, sperm

Xanthogranulomatous inflammation
chronic inflammation in lipid rich areas
eg.: gallbladder, sebaceus glands
xanthoma: subcutaneous macrophages
xanthelesma: small xanthoma on eyelid
Immune granuloma

Leprosy
Mycobacterium leprae
first human pathogen! described by Armauer Hansen (and Albert Neisser)
2012: 180,000 cases globally
inflammation of skin, peripheral nerves, upper airways
not very infective

tuberculoid / lepromatous lepra

Immune granuloma

Syphilis
Treponema pallidum (spirochete)

Primary syphilis
2-5 weeks: chancre (painless ulcer)

Secondary syphilis
6-8 weeks skin lesions, lymph node enlargement, condyloma latum

Tertiary syphilis – the big immitator

gumma – skin, bone, mucosa
aortitis
neurosyphilis

Paul Ehrlich and Sahachiro Hata:

1909 – Salvarsan (compound 606), first chemotherapy

Paul Ehrlich: Nobel prize in 1908 together with Mechnikov (descriptor of phagocytosis)
Immune granuloma

Cat scratch disease

Bartonella henselae (G-negative)
suppurating reticulohistiocytic
lymphadenitis
suppurating granulomas
Granuloma of unknown etiology
Sarcoidosis
Characteristics Morphology
unknown etiology, granulomatous disease non-caseating granulomas
most common between 20-40 years asteroid bodies
non-caseating granulomas Schaumann bodies
mostly is resolved in 1-2 years

Pathomechanism
genetic predisposition
?infection
?foreign body (nanoparticulum?)
?abnormal Th1 stimulation + anergy
Theory: not one disease, rather a manifestation
may be an abnormally enhanced CMI – without necrosis
Granuloma of unknown etiology
Sarcoidosis
systemic signs
lung
90% interstitial lesion
rarely lung fibrosis
lymphnodes
BHL – bilateral hilar
lymphadenopathy
skin
erythema nodosum

glands
Heerfordt syndrome
Mikulicz syndrome

haematology
anemia, leukopenia

others
Tuberculosis

Epidemiology

Microbiology

Pathomechanism

Primary tuberculosis

Postprimary tuberculosis

Non-tuberculotic
mycobacterial infection
Tuberculosis - epidemiology

Every third human is infected with TB

•2016: 10,4 million new cases

•2016: 1,5 million deaths
•2010: 10 million orphans due to TB
•approx. 80% in 22 countries

•TB is the major cause of death with HIV

•approx. 10% of TB patients are HIV+
•Lesotho: 665/100.000 incidence (2017)
•Hungary: 7/100.000 incidence (2017)
Tuberculosis - microbiology

Mycobacterium tuberculosis complex

description: Robert Koch (1943-1910) – Nobel prize in 1905
obligate aerob bacillus
facultative intracellular pathogen
slow proliferation
agent of the White Plague

Mycobacterium bovis
bovine pathogen
may cause extrapulmonary TB in humans – now rare

Mycobacterium avium/intracellulare
opportunist pathogen
Tuberculosis - microbiology

cord factor
forms cords in vitro
IFNγ inhibition, TNFα increase
Ziehl-Neelsen stain
mycolic acid „acid fast bacterium”
cell wall component
defends against complement, free radicals
defends against phagocytosis

lipoarabinomannan
cell wall gycolipid – decrease inflammation

Multidrug resistant TB (MDR-TB) (20%)

rifampicin and isoniazid resistance

Extensively drug resistant TB (XDR-TB) (2%)

MDR+ fluoroquinolon + 2nd-line resistance
Tuberculosis - pathomechanism

TB bacillus quantity
Primary tuberculosis

TB bacillus virulence

innate immunity Postprimary tuberculosis

Endogenous reactivation
adaptive immunity Exogenous reinfection
Primary tuberculosis

Non-progressive, primary TB (95%)

exudation: neutrophils first, than mononulcear cells

prolilferation: 2-4 weeks later, due to type IV HS
- epithelioid-cell granulomas and necrosis

Ghon-focus: primary lung involvement

unilateral, subpleural, in middle lung zones
Ghon-complex: Ghon-focus + lymphangitis + lymphadenitis
Ranke-complex: fibrotized, calcified primary focus + enlarged lymph node

healing - fibrosis
Primary tuberculosis

Progressive primary TB (5%)

Bronchogenous Lymphogenous Hematogenous
dissemination dissemination dissemination

pleuritis/effusion caseous pneumonia

scrophulosis miliary TB
basilaris meningitis

primary cavity Landouzy sepsis

epituberculosis
acute phthisis
Postprimary tuberculosis
Endogenous reactivation (late generalisation) (70%)
Exogenous reinfection (30%)
fibro-caseous form fibrotic form
Assman’s Simon foci
infiltrate (tuberculosis
fibrosa densa)

bronchogenous spread – acinodular TB hematogenous spread – chronic miliary TB

tuberculoma: tumorlike focus cavity could appear
cavity: open TB pleuritis, pleural callus
Rasmussen aneurysm
phthisis, pleural callus, pleuritis
caseous pneumonia - phthisis
miliary TB
extrapulmonary manifestations
Extrapulmonary tuberculosis
Central nervous system
meningitis basilaris tuberculosa
especially children: miliary TB 25% meningitis as well
following hematogenous spread even after latency
meningitis develops from cortical lesions

CNS tuberculoma
tumorlike lesions
usually <30 years

Bone tuberculosis
spondylitis tuberculosa – Pott’s disease
compression vertebral fracture
severe kyphosis
often associates with:
abscessus frigidus (cold abscess)
Extrapulmonary tuberculosis
Kidney
miliary kidney TB
miliary lesion in cortex

phthisis renalis
confluating foci to form cavities
putty kidney: tuberculotic pyelonephritis + uretral obstruction

Gastrointestinal tract
M. bovis infection – drinking contaminated milk: ileal mucosa + Peyer plaque + lymphnodes
due to M. tuberculosis infection even (generalisation)
consequence: ulcer, bleeding, malabsorption, tabes mesaraica

Skin
primary TB – direct inoculation
secondary TB – due to generalisation (miliary TB; lupus vulgaris)
could be due to direct extension (eg. lymph nodes)

Other organs
adrenals, epididymis, testis, uterus, ovaries, fallopian tubes
Tuberculosis; a few clinical points

Mantoux test
tuberculin test
PPD – purified protein derivate
subcutaneous infection – measure induration 48 hours later

BCG vaccine
Bacillus Calmette-Guérin: attenuated M. bovis
variable efficacy, variable length of effect
does not protect against secondary TB
major effect: miliary TB/meningitis tuberculosa risk is decreased

Lung screening
prevention of adults (Mantoux test is not helpful with mandatory vaccination)
postprimary TB early recognition – not yet open TB
Mycobacterium avium complex

Mycobacterium avium/intracellulare
rarely causes infection with normal immune system
patients often have severe immunsuppression, especially with AIDS
weekly Gram positive
often extrapulmonary and dissemination