Bernardino Alcázar Lanagrán

GRANADA-2009

ROBERT KOCH 1834-1910

Robert KochRobert Koch

24 MARZO 188224 MARZO 1882

Physiological Society of Berlin Physiological Society of Berlin lectura:lectura:

The etiology of tuberculosisThe etiology of tuberculosis

PREMIO NOBEL Octubre de 1905

Genetic epidemiology of TB

The analysis of the epidemic wave of tuberculosis observed in Europe in the XVIII and XIX centuries, have shown mortality frequencies that reach the 2% per year. In particular, in absence of chemotherapy, a spike can be observed in the first 50-100 years, followed by a slow decline in the next 200-250 years.

These data support the hypothesis, developped by E.R.N. Grigg, that in the first phase of the epidemic wave the most susceptible portion of population has been eliminated (rappresenting up to 20% of the whole population).

Grigg ERN. Am Rev Tuberc 1958; 78: 426-53

Manabe YC, Bishai WR.. Nat Med 2000; 6:

1327–1329.

Historia Natural de Infección por MTB

Innate ImmunityExpression of

IL-1, IL-6, TNF- αααα and ΝΟΝΟΝΟΝΟ

Hipersensibilidad Retardada

Mycobacterium tuberculosisAntigenic expression

(virulance and trascriptional factors,metabolic adaptation to the host etc.)

Specific T-cellresponse

Expression ofIL-2, IFN- γγγγ and TNF-αααα

X%Resuelve la Infección

5% en 2 años puede des,

Enfermedad5% puede des. Enf. A lo largo de su vida

La carga de TB en 2005

1.6 million deaths

in 2005

– 98% of these in

developing world

219,000 deaths

due to TB/HIV

MDR-TB present

in 102 of 109

countries and

settings surveyed,

XDR-TB emerging

8.9 million new

cases in 2005 –

80% in 22 high-

burden countries

TB GLOBAL ESTIMADA - 2006

Numero estimado de

casos

Muertes Estimadas

1.65 million1.65 million(25 per 100,000)(25 per 100,000)

9.15 million9.15 million(139 per 100,000)(139 per 100,000)

~130,000489,000

All forms of TB Greatest number of cases in Asia; greatest rates per capita in Africa

Multidrug-resistant TB (MDR-TB)

Extensively drug-resistant TB (XDR-TB)

~35,000 ~20,000

HIV-associated TB 709,000 (8%) 231,000

Tuberculosis estimada 2007Tuberculosis estimada 2007Tuberculosis estimada 2007Tuberculosis estimada 2007Tuberculosis estimada 2007Tuberculosis estimada 2007Tuberculosis estimada 2007Tuberculosis estimada 2007

Se estiman 9,27 millones de nuevos casos.

Se estima 1,32 millones de muerte no VIH.

En VIH + 456.000

Pero estas cifras si se comparan con el crecimiento de población.

Asi en 2004 era 142 por 100.000.

En el 2007 son de 139 por 100.00

OMS 24- Marzo-2009

TUBERCULOSIS EN ESPAÑA

• En 1996 Proyecto Multicéntrico de Investigación para TB se situó en 38,48 casos por 100,000,

• Según las declaraciones obligatorias EDO en el año 1997 era de 26,7/100,000. Situándose por debajo de 20 casos/100,000 en el año 2001.

Alveolar macrophage kill MTB: no infection

Infection: MTB released in extra-cellular space, recruitment of mononuclear cells

LATENT INFECTIONLATENT INFECTIONStrong effective cellular responseStrong effective cellular responseContainment of MTB proliferationContainment of MTB proliferation

ACTIVE DISEASEACTIVE DISEASEPoor ineffective immune responsePoor ineffective immune response

Progressive diseaseProgressive disease

REACTIVATIONREACTIVATIONHIVHIV

DrugsDrugsSenescenceSenescence

CoCo--morbiditiesmorbidities

Granuloma formationGranuloma formationSpread to lymph nodes, blood Spread to lymph nodes, blood

and other organsand other organs

Nat Med 2000; 6: 1327-9 modified

INFECCIO

N LATENTE

PUNTOS CLAVESPUNTOS CLAVES

1. Diagnostico de infección latente es de importancia para clinica y evaluación.

2. El método de diagnóstico más utilizado no es adecuado.

3. Son ahora posibles nuevos métodos diagnosticos.

HISTORY OF TUBERCULINHISTORY OF TUBERCULIN

1890189019071907190919091909190919101910192419241926192619341934

1950ies1950ies19581958--656519651965--9595

Koch old tuberculinKoch old tuberculinvon Pirquet scratch testvon Pirquet scratch testMoro patch testMoro patch testMendel intradermal testMendel intradermal testMantoux intradermal testMantoux intradermal testHastings noHastings no--lesion, reactor cattlelesion, reactor cattleCrawford heterologous antigensCrawford heterologous antigensSeibert PPDSeibert PPD--SSWHO surveysWHO surveysUS Navy recruit studyUS Navy recruit studyKorea surveysKorea surveys

www.tbrieder.org

r

C. Mantoux. Intradermo-réaction de la tuberculine. Comptes rendus de l’Académie des sciences.Paris, 1908; 147: 355-357

MANTOUX

Lectura a las 72 horas

POSITIVO > 5 mms

INFECCION TUBERCULOSA

En España se recomienda el derivado proteico purificado (PPD) de la tuberculina PPD- RT 23 con Tween 80, a dosis de 2 UT en 0,1 ml que es bioequivalente a la dosis de 5 UT de tuberculina de patrón internacional PPD S

Tuberculin skin test

• False Positives– People who have received the BCG vaccine

will show up positive– People exposed to mycobacteria in

environment will show up positive

• False Negatives– skin reaction is a very crude measure:

• Small responses not picked up (real problem in immunosuppressed patients)

• In active disease (only 75-90% sensitivity, worse in immunosuppressed)

Berlin, October 4th, 2008

Diagnostico de Infección latente

Tuberculosis Coalition for Technical Assistance. International Standards for Tuberculosis Care (ISTC). The Hague, TuberculosisCoalition for Technical assistance, 2006.

Pai M et al. Lancet Infect Dis 2004

Lalvani, A. Chest 2007;131:1898-1906

Diagrammatic representation of TST, ELISpot, and EL ISA for diagnosing M tuberculosis infection

infección tiempo

T cells

Inmunidad celular específica en infecciones persistentesPathogen load/immunity

equilibrio

immunosupresión

EnfermedadSintomas

ESTADO DE INMUNOSUPRESION

tiempo

Pathogen load/immunity

QuantiFERONQuantiFERON--TB Gold TB Gold In TubeIn Tube

TT--SPOT.SPOT.TBTB

ARE IGRA ARE IGRA DIFFERENT FROM DIFFERENT FROM

TST?TST?TT--SPOT.SPOT.TBTB QuantiFERONQuantiFERON--TBTB Tuberculin skin testTuberculin skin test

Antigens ESATESAT--6 + CFP106 + CFP10 ESATESAT--6 + CFP10 (TB7.7)6 + CFP10 (TB7.7) PPDPPD

Positive internal control YesYes YesYes NoNo

Uniformity of methods and reagents

YesYes YesYes NoNo

Potential for boosting effect in repeated tests

NoNo NoNo YesYes

Need for return visit NoNo NoNo YesYes

Time required for results 1616--20 hrs20 hrs 1616--24 hrs24 hrs 4848--72 hrs72 hrs

Test setting In vitroIn vitro In vitroIn vitro In vivoIn vivo

Test interpretationObjectiveObjective

(instrument(instrument--based)based)ObjectiveObjective

(instrument(instrument--based)based)SubjectiveSubjective

(operator(operator--based)based)

Richeldi L, AJRCCM 2006

5-10% every year

>30%lifetime

HIV+HIV+

5% first 2 years

<10%lifetime

RISK OF PROGRESSING TO ACTIVE TB ONCE LATENTLY RISK OF PROGRESSING TO ACTIVE TB ONCE LATENTLY INFECTED AND INFECTED AND NOTNOT TREATEDTREATED

Latent TB infection

Alveolar macrophage kill MTB: no infection

Infection: MTB released in extra-cellular space, recruitment of mononuclear cells

LATENT INFECTIONLATENT INFECTIONStrong effective cellular responseStrong effective cellular responseContainment of MTB proliferationContainment of MTB proliferation

ACTIVE DISEASEACTIVE DISEASEPoor ineffective immune responsePoor ineffective immune response

Progressive diseaseProgressive disease

REACTIVATIONREACTIVATIONHIVHIV

DrugsDrugsSenescenceSenescence

CoCo--morbiditiesmorbidities

Granuloma formationGranuloma formationSpread to lymph nodes, blood Spread to lymph nodes, blood

and other organsand other organs

Nat Med 2000; 6: 1327-9 modified

TUBERCULOSIS ENFERMEDAD

TUBERCULOSIS ENFERMEDAD

CURSO CLINICO.El COMIENZO

• acquired through inhalation

• engulfed by lung dendritic cells and

macrophages

• migration to lymph node and activation of T cells

• innate immune response / Th1 response result in

granuloma formation

• Th1 = delayed type hypersensitivity

• CD4 T cells act through secretion of IFN-gamma

that activates macrophages

• granuloma formation is important for infection

control and requires balances cytokine

expression

Salgame, Curr Op Immunol, 2005

immunosupresión

EnfermedadSintomas

ESTADO DE INMUNOSUPRESION

tiempo

Pathogen load/immunity

CURSO CLINICO

• development of progressive disease or latency

• MTB persists in macrophage phagosomes by

interfering with with membrane trafficing and

phagolysosome formation

• MTB kill macrophages

• Latency is supported also by specific latency

genes, under hypoxic conditions

• Reactivation• HIV / AIDS (CD4)• end stage renal disease• diabetes• lymphoma• Cortcosteroid• anti-TNF-therapy

LATENCIA

ENFERMEDAD

• « L’examen crucial est représenté par la recherche de bacilles dans l’expectoration. …on est frappé combien peu souvent on a recours à cet examen dans la pratique courante. Pourtant, il est simple... »

E. Arnold, Le diagnostic de la tuberculose, 1944

WHO targets

• ≥70% detection of infectious TB• >85% cured/completed

World Health Organization. Treatment of tuberculosis. Guidelines for National Programmes. WHO report 2003. Document WHO/CDS/TB 2003/313. Geneva, WHO, 2003

PAPEL IMPORTANTE DEL BACTERIOLOGPAPEL IMPORTANTE DEL BACTERIOLOGÍÍAA

Sputum-ZN stain

Esputo-auramina

Hoy aHoy aúún se utiliza:n se utiliza:

El numero de El numero de GaffkyGaffky --

Factores que tienen influencia al escoger el tratamiento

• Localización de la enfermedad.• Resultados Bacteriologicos • Riesgo de tratamiento anteriores para

resistencia.• Posibles efectos secundarios

interreacciones• Drogas disponibles.

La tinción de los bacilos va ligada a los ácidos micólicos de la pared micobacteriana, y éstosestán presentes en el resto de las micobacterias y no se pierden cuando el bacilo muere.

Mycobacterium tuberculosis (MTB)

24 h

DIASSemanas

Rifampicin

Ciprofloxacin

Liquefaction & decontamination in

transport medium at room temperature

MDR

SUSCEPTIBLE

Direct application of 2 drops to selective thin layer agar for incubation in room air for MDRTB testing & XDRTB screening

Color growth detection & microscopy

confirmation of morphology

MDR-XDRTB Color Test for Regional Labs*

Detection Isoniazid

Biosafety similar to sputum microscopy because sputum is smeareddirectly onto the plate which is then permanently double-sealed until autoclaving

1 2 3

*Carlton Evans, Welcome Trust, Peru

Robert KochRobert Koch

Koch RT. A further communication on a remedy for tuberculosis. BMJ

1890; 2: 1193-5

“I assume that the material will be valuable diagnostic

measure in the future. It will become possible to diagnose

questionable cases of phthisis even in those cases where

bacilli cannot be detected in the sputum.”

GenoType® MTBDR plustest procedure

1) DNAExtractionFrom NALC/NaOHProcessed sputum

2) Amplificationby PCR

3) HybridizationReverse hybridization ofamplified nucleic acidsto specific DNA probes

bound on strips

4) Evaluation

The fall of the wall, Berlin 1989The fall of the wall, Berlin 1989

1st-line agents

•INH

•RIF

•PZA

•EMB

Injectable agents

•SM

•KM

•AMK

•CM

Fluoroquinolones

•Cipro

•Oflox

•Levo

•Moxi

•Gati

2nd-line Oral agents

"3rd-line" agents•ETA/PTA

•PASA

•CYS

Not routinely recommended, efficacy unknown, e.g., amoxacillin/clavulanic acid, clarithromycin, clofazamine,

XDR= HR + 1 FQ + 1 Injectable (KM or AMK or CM)

MDR-TB among new cases 1994-2007

< 3%3-6 %> 6 %No data

The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. WHO 2006. All rights reserved

* Sub-national coverage in India, China, Russia, Indonesia.

En España se ha producido un aumento de población, pero hemos alcanzado el 12%de población nacida fuera de nuestro país,

Czech Rep.

The boundaries and names shown and the designations used on thismap do not im

ply the expression of any opinion

whatsoever on the part o

f the WHO concerning the legal status ofany country, te

rritory, city or area or of its

authoritie

s, or concerning the delimitation of its

frontiers or boundaries. D

otted lines on maps represent approximate

border lin

es for w

hich there may not yet be full agreement.

WHO 2005. All rig

hts reserved

Ecuador

Georgia

Argentina

Bangladesh

Germany

Rep of Korea

Armenia

Russian Fed.

South Africa

Portugal

Latvia

Mexico

Peru

USA

Brazil

UK

Sweden

Thailand

Chile

Based on information provided to WHO Stop TB Department - May 2008

Spain

China, Hong Kong SAR

France

Japan

Norway

Canada

Italy

Netherlands

Estonia

Lithuania

Ireland

RomaniaIsrael

Azerbaijan

Poland

Slovenia

India

Australia

Mozambique

Vietnam

Ukraine

Moldova

Philippines

Botswana

Nepal

Islamic Rep. of Iran

Lesotho

Swaziland

Namibia

Countries with confirmed XDR-TB cases as of June 2008

Countries with XDR-TB Confirmed cases as of September 2007

Czech R.

The boundaries and names shown and the designations used on thismap do not im

ply the expression of any opinion

whatsoever on the part o

f the WHO concerning the legal status ofany country, te

rritory, city or area or of its

authoritie

s, or concerning the delimitation of its

frontiers or boundaries. D

otted lines on maps represent approximate

border lin

es for w

hich there may not yet be full agreement.

WHO 2005. All rig

hts reserved

Ecuador

Georgia

Argentina

Bangladesh

Germany

Republic of Korea

Armenia

Russian Federation

South Africa

Portugal

Latvia

Mexico

Peru

USA

Brazil

UK

Sweden

Thailand

Chile

Based on information provided to WHO Stop TB Department September 2007

SpainIran

China, Hong Kong SAR

France

Japan

Norway

Canada

Italy

Netherlands

Estonia

Lithuania

Ireland

Romania

Israel

Azerbaijan

Poland

Slovenia India

Tuberculosis resistente a drogas

Migliori GB,. Eur Respir J 2007;29:423–427

TERAPIA EN EL TIEMPO viejas armas TERAPIA EN EL TIEMPO viejas armas

pueden ser pueden ser úútiles en XDRtiles en XDR

First sanatorium First sanatorium Germany, 1857Germany, 1857 First Dispensary, First Dispensary,

Scotland, 1897Scotland, 1897

Koch, Mtb,Koch, Mtb,18821882

Drugs, 1945Drugs, 1945--19621962

MMR,1950MMR,1950--19801980

Fox:Ambulatory treatment, 1968Fox:Ambulatory treatment, 1968

Styblo model, 1978Styblo model, 1978

DOTS, 1991DOTS, 1991

sanatoriasanatoria Outbreak Management,Outbreak Management,

Risk Group ManagementRisk Group Management

screeningscreening

BCG vaccinationBCG vaccination

drug therapydrug therapy

SocioSocio--economic improvementeconomic improvement

Pneumotorax, Italy, 1907Pneumotorax, Italy, 1907

EUROPEAN LUNG WHITE BOOK, 2003

WHO 2007

GlobalAllianceagainstchronicRespiratoryDiseases

I have called this principle, by whicheach slight variation, if useful, is preserved, by the term Natural Selection.

— Charles Darwin from "The Origin of Species"

Charles DarwinNaturalist1809 -1882

Europe

439 000 (5.0%)439 000 (5.0%)

Africa

2.4 m (26.9%)2.4 m (26.9%)

Eastern Mediterranean

634 000 (7.2%)634 000 (7.2%)South-East Asia

3.1 m (34.8%)3.1 m (34.8%)

The Americas

370 000 (4.2%)370 000 (4.2%)

The Western Pacific

1.9 m (21.9%)1.9 m (21.9%)

Estimated new TB (all) cases (2003)

Source: WHO. WHO report 2005: global tuberculosis control; surveillance, planning, financing. Geneva: WHO (WHO/HTM/TB/2005.349)

� 8.8 million new cases (80% in 22 countries, 30% in India and China)

� 1.7 million deaths (98% in developing world)

� 229 000 deaths due to TB/HIV

� > 0.4 million MDR-TB cases (in new or previously treated)

GRACIAS