Tuberculosis. Sepsis.

Which receptors does MT use when entering by phagocytosis?

- C (opsonisation by C3b) - Mannose - Ig R (Gfc gamma) - Scavenger receptor A

Primary tbc occurs ___

- Directly after infection

What is IFN-gamma responsible for?

- Enhance formation of phagolysosome in the macrophage - Enhance iNOS expression NO production in the macrophage - Enhance oxidative destruction of MT cell wall and DNA - Mobilize antimicrobial peptides: defensins - Enhance efficient autophagy of MT-damaged organoids

What is the natural course of tuberculosis?

- First-year death rate: 30% - Five-year death rate 50% o (65% MT+) o Among 5-year-survivors: --> 60% spontaneously recovered; --> 40% chronically ill

What is the importance of the Tuberculosis?

- Frequent; - Death rate within 5 years: 50 - 65% - Effective treatment is available in most cases

Explain the progression of ganuloma

- Granuloma increase in size - Adjacent foci (other granulomas) are formed - Confluence of foci into the infiltrate - Destruction of bronchial wall - Expectoration of caseous necrotic mases o Cavity - carvern o Bronchogeneous dissemination o MT+ - Development of fibrosis

What are the main processes of Secondary / postprimary /reactivation of tbc?

- Infiltration - Cavitation - Fibrosis - Systemic manifestations

What happens during the first three weeks of MT infection?

- MT proliferation in macrophages - Bacteremia - Patients have no complaints or respiratory virus infection like - mild illness

Dissemination og Progressive primary pulmonary tbc may lead to ___

- Meningitis - Miliary tbc

What is the predilection area of Secondary / postprimary /reactivation of tbc?

- Pulmonary apex - The posterior segments of upper lobes - The upper segments of lower lobes

What are the characteristics of a tuberculoma?

- Remission - Pulmonary or extrapulmonary - Single or multiple

What are the characteristics of Progressive primary pulmonary tuberculosis?

- Resemble acute bacterial pneumonia - In middle and lower lobes - Hilar lymphadenopathy - Pleurisy - Occasionally - caverns (less frequent than in secondary tbc) - Dissemination: o Meningitis o Miliary tbc

What are the risk factors of progression of primary tbc?

- Small children - HIV - Malnutrtion

What does IFN gamma activation of M/ph induce?

- TNF synthesis - recruitment of new m/ph

Explain the ways of progression of primary tbc.

- Tuberculosis pleuritis - Progressive primary lung tuberculosis

What are the characteristics of Ghon complex?

1. Arise in the place of MT entrance: mostly in lung + LN 2. Subpleural 3. 1 - 1.5 cm: Ghon focus - Necrotising granulomatous inflammation with caseous necrosis 4. LM involvement - Developing immunity - Necrotising granulomatous inflammation with caseous necrosis 5. Ghon focus + LM: Ghon complex

How does the mechanism of blocking the phagosome confluence with lysosome occur?

1. Blocked increase of intracellular Ca2+ concentration 2. ↓ Ca / Calmodulin way of inducing phagosome - lysosome fusion 3. ↓ expression of maturation markers in the phagosome membrane 4. autophagy of phagosome resulting in double membrane layer 5. ↓ acidity

Progression of primary tbc; Hilar and paratracheal lymphadenopathy may lead to ___

1. Bronchial compression - Total: atelectasis - Partial: o Stenosis o Ball-valve mechanism / hyperinflation 2. LM erosion towards bronchus 3. Bronchiectasis

Name the risks of infection by Mycobacterium tuberculosis (exogenous)

1. Contact with patient / MT+ - Pulmonary, bronchial or laryngeal tbc with tissue destruction 2. Length of contact 3. Intimacy of contact 4. The amount of MT discharge - MT- in smear / MT+ in culture: less infectious (20%) - NOT infectious: MT"-" (culture); extrapulmonary tbc - Less infectious: HIV+ tbc

What are the outcomes of primary complex / Ghon complex?

1. Dissemination 2. DTH - delayed type hypersensitivity 3. In 95%: fibrosis, calcinosis / Ranke complex 4. Infrequently - progression to clinically manifest disease: primary tuberculosis

Name the risks of tbc disease (endogenous)

1. Immune system status: risk ↑ - Diabetes mellitus - Status post transplantation 2. Cellular immunity status: risk ↑ - HIV - Inborn immunodefficiencies affecting the cellular immunity 3. General status - Malnutrition - Malabsorbtion etc

What happens after the MT multiplication in the macrophages?

1. MT multiplication in the macrophages 2. Lysis of macrophages 3. Infection of surrounding macrophages 4. Recruitment of new macrophages - MT induce MMP9 expression in adjacent epithelial cells - MT cAMP enters the cytoplasm of Mf and induces TNF alfa production 5. M/ph lysis: release of MT antigens 6. Dendritic cells / lymph nodes / T : - MT Ag / MHC II - IL-12 7. In 3 (2 - 4) weeks : Th1 activate M/ph

What is the result of T activation in 2-4w?

1. Mf activation 2. Tissue destruction by formation of caseous necrosis - Survival of MT in the necrotic masses is more difficult due to low [O] content, but it is possible 3. The clinical picture is influenced by the balance of these 2 reactions 4. Granuloma formation involve both results

What are the characteristics of Secondary pulmonary tbc?

1. Sensibilised host 2. Source of infection: exogenous or endogenous 3. Apical: [O] 4. DTH (delayed type hypersensitivity) is present: - Lymphadenopathy is not marked - Tissue destruction is characteristic (due to DTH): cavernous tbc

Renal TBC

10% of extrapulmonary TBC Local - can be absent - frequent urination, dysuria, nicturia, hematuria hydronephrosis due to ureteral stricture 75%: Lung TBC

Bone TBC

10% of extrapulmonary TBC Spread: hematogenous Predilection: Weight-bearing bones: 40% spine - Upper Th in children - Lower Th/L in adults 13% hip 10% knee

Pleural pathology in TBC

20% of extrapulmonary TBC Exudative pleuritis - Hypersensitivity - Direct spread from subpleural focus Tuberculous empyema - Rupture of a cavern towards pleural space - Less frequent

LN tuberculosis

35-40% of extrapulmonary TBC Historically - scrofulosis Pulmonary TBC: 50%

Death rate of TBC pericarditis

40%

CNS tuberculosis

5% of extrapulmonary TBC 2 Types: - Tuberculous meningitis - Tuberculoma

What kind of infection is Tuberculosis?

Aerogeneous, occasionally alimentary - 10% MT reach alveoli

What is the definition of Tuberculosis?

An infectious disease caused by Mycobacterium tuberculosis (MT) complex

Tuberculosis of other organs

Any organ can be affected - e.g. thyroid gland etc. Suprarenal TBC with suprarenal insufficiency = Addison's disease

SIRS

At least 2 criteria is needed

How does the MT reach alveolar macrophages?

By phagocytosis using the following receptors: - C (opsonisation by C3b); - Mannose - Ig R (Gfc gamma) - Scavenger receptor A

What are the types of tuberculosis?

By time: 1. Primary 2. Secondary By localisation: 1. Pulmonary 2. Extrapulmonary

TBC diagnostics

Clinical picture Epidemiology Radiology Identification of MT - In smear - By culture Histology

Relative risk of secondary TBC

Continued here: - Gastrectomy = 2-5 - Status after transplantation = 20-70 - Smoking = 2-3 - Malnutrition = 2

Pathogenesis of local symptoms

Cough Hemophthysis - 20-30-50% - Can be small - Can be massive If massive: - destruction of large BVs - Rasmusen Aneurysm - Aspergilloma

Special forms of miliary TBC

Cryptic - Aged patients - prolonged course - Meningitis Non-reactive - Associated with massive hematogenous dissemination - Pancytopenia - Predominant necrosis - Rapidly fatal

Severe sepsis

Dysfunction of distant organs

What is another word for "primary complex" of tbc disease?

Ghon complex

Typical patient groups with LN tuberculosis

HIV Children

Spread of TBC pericarditis

Hematogenous Direct from mediastinal or hilar LN

Spread of TB peritonitis

Hematogenous Direct: - GI, fallopian tubes - LN

Tuberculous empyema

Hydropneumothorax thick content Ly Drug treatment/surgery Can result in severe fibrosis/ restrictive pulmonary lesion. Surgical decortication can be necessary

Exudative tuberculous pleuritis

Hyrothorax Clear yellow or reddish exudate Cells: Ly/Neu Reacts on drug treatment

What does Th1 produce?

IFN-gamma

Genital TBC

In females - Salpingitis, endometritis - Pain, infertility, bleeding In males - Epididymis - Fistula - Possible orchitis and prostatitis

TBC of upper airways

Larynx, pharynx, epiglottis Spread from lungs due to expectoration of infected necrotic masses

Symptoms of GI TBC

Local - Obstruction, ulcers, fistulae - Rectal fistulae - Resemble Crohns disease Systemic manifestations

Extrapulmonary TBC

Locations in order of decreasing frequency - Lymph nodes (LN) - Pleura - Urogenital system - Bones - CNS - GI - Peritoneum - Pericardium

How does MT spread throughout the body?

Lymphogenous and / or hematogenous spread - Bacteremia - Early involvement of LN - Retrograde dissemination - Haematogeneous dissemination within lungs - Systemic dissemination

Where does MT undergo replication, and what happens during this process?

MT undergoes replication in macrophage blocking the confluence of phagosome with lysosome (Ca2+ / protein turnover and expression)

Miliary lung TBC

Milia => multiple small foci of necrotizing granulomatous inflammation, affecting all lobes of both lungs Lymphogenous retrograde spread Blood-borne spread via pulmonary circulation Local symptoms and radiological findings are scant

Miliary TBC

Milia: Ø1-2mm Spread: Hematogenous - Associated with primary TBC - Associated with secondary TBC in adults Symptoms - Local - NOT marked - Systemic - Difficult to establish the diagnosis

Peculiarities of TBC in HIV

More frequent More rapid course Depend on stage: - Secondary type if immune function is preserved - Primary-like - 40-60% extrapulmonary

Differential diagnosis of LN TBC

Mts Lymphoma Other causes of necrotizing lymphadenitis

Which mechanism acts against MT in large dust particles?

Mucociliary clearance

Predilection sites of LN tuberculosis

Neck LN Supraventricular LN

Course of LN tuberculosis

Necrotizing granulomatous inflammation LN increase in size but are not painful Soft Fistula formation

Symptoms of TB peritonitis

Pain: Inflammation, adhesions Exudation Fever and other systemic manifestations

Glucocorticoids in TBC pericarditis

Pathogenically OK to prevent constrictive pericarditis Effect shown in HIV

Bacteremia

Presence of bacteria in blood by culture

What are the differences between primary and secondary tuberculosis?

Primary: - Naive host: no previous immunity - Exogenous source - 5% of infected persons develop clinical illness Secondary: - in sensitised

Gastrointestinal TBC

Rare in developed countries: 3,5% USA Geographic variations in frequency Routes: - Hematogenous - Peroral by infected sputum - Peroral by infected milk Predilection: Terminal ileum + caecum

Explain the morphology of secondary TBC

Reactivation focus: 1-2cm consolidation located 1-2 cm from apical pleura Necrotizing granulomatous inflammation This results in: Progression by increase of focus, conluence of foci, destruction of bronchial wall, bronchogeneous dissemination Fibrosis and calcinosis

Sepsis

SIRS + proved or possible infection

Septic shock

Sepsis + arterial hypertension + no reaction to fluid infusion

Tuberculous meningitis

Spread: hematogenous Course: - Slow progress (1-2w) - Basal predominance: Cranial nerves - Vascular damage leading to ischemia - Coma, hydrocephalus, intracranial hypertension

Course of TBC pericarditis

Subacute or acute Heart temponade Constrictive pericarditis

SIRS

Systemic inflammatory reaction/response syndrome

Systemic manifestations of Tuberculosis

Systemic manifestations of inflammation Mf: TNF, IL-1 Fever, mainly low grade Night sweats Weakness Anorexia Weight loss

Septic shock criteria

TA < 90mmHg or TA decreases with 40mmHg TA is decreased at least for 1h, despite adequate fluid resuscitation OR vasopressors in order to preserve TA above 90mmHg Refractory septic shock => lasts more than 1h and show no reaction with fluid treatment

TNF blockers in the treatment of ______ ______ are associated with greater risk of tbc.

TNF blockers in the treatment of rheumatoid arthritis are associated with greater risk of tbc.

There is a high/low rate of multi-drug resistant tuberculosis.

There is a high rate of multi-drug resistant tuberculosis.

Endobronchial TBC

Usually associated with bronchogeneous dissemination

TBC myocarditis

VERY rare Spread: - Direct from TBC pericarditis - Retrograde lymphogenous spread from mediastinal LN Deadly in most cases

Primary tbc mainly occur in ___

children

The risk of tbc disease is ___

endogenous

The risk of tbc infection is ___

exogenous

Secondary pulmonary tbc - Source of infection?

exogenous or endogenous

What doe Th1 enhance activation of?

granuloma

Primary tbc affcets mainly ___

middle and lower lobe of lung

What is a tuberculoma?

necrotic mases delimited by fibrous tissue

What is the mechanism of Secondary / postprimary /reactivation of tbc?

reactivation or reinfection (30%)

Tuberculoma

very rare Manifest by neurologic and radiologic symptomatics