Claudio Mastroianni

Dipartimento di Sanità Pubblica e Malattie Infettive Direttore UOC Malattie Infettive, Latina

LA TBC NELL’ERA DEI BIOLOGICI

" Epidemiologia e screening“

“La vecchia nemica dell’umanità, conosciuta come tisi, la grande peste bianca, tubercolosi, o qualsivoglia altro nome, sta per essere ridotta ad un problema irrilevante per l’uomo.

Il futuro è invero brillante, e la completa eradicazione di questa malattia è ormai all’orizzonte.”

Estimated number of cases

Estimated number of deaths

1.5 million • 80,000 in children • 510,000 in women

9 million 126 per 100,000

• 550,000 in children • 3.3 m in women

480,000

All forms of TB

Multidrug-resistant TB

HIV-associated TB 1.1 million (13%) 360,000

Global Burden of TB in 2013

210,000

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480,000 MDR-TB, 9% with XDR

India, China, Russia, Pakistan and Ukraine have 60% of all MDR-TB cases

Highest % in the former USSR countries

Accelerated MDR detection, but widening treatment gap

136,000 detected (2013)

97,000 treated (2013)

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DIAGNOSTIC

GOOD NEWS

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Eskimos in Alaska, NW Canada and Greenland: 15% per year incidence decline

Highly focused & high intensity interventions

Screening and massive LTBI

TB care decentralised

BCG vaccination

Improved health access &

social protection

Economic development (?)

Recipe:

-17%/yea

r (1955-74)

-8.7%/yea

r (1972-74)

Grzybowski S, Styblo K, Dorken E. Tuberculosis in Eskimos. Tubercle 1976; (suppl.) 57: 1-58

I

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68.423 casi di tubercolosi (-6% rispetto al 2011); 13.5 casi/100.000 abitanti Sei Paesi hanno riportato tassi di notifica superiori a

20/100.000: Romania (85,2) Lituania (59,2), Latvia (48,6), Bulgaria (31,1), Portogallo (25,2) e Estonia (21,6)

13

In 2012, the overall proportion of TB cases of foreign origin in the EU/EEA was 26.8% (range 0.2–85.4%). Figure 4: Percentage of TB cases of foreign origin by country, EU/EEA, 2012

25 to 49.9%

≥ 75%

1 to 24.9%

50 to 74.9%

< 1%

Not included or not reporting

Multidrug-resistant TB

14

In 2012, the overall proportion of TB cases with multi-drug resistance in the EU/EEA was 4.6% (range 0–25.5%). Figure 7: Percentage of multidrug resistance among all confirmed TB cases by country, EU/EEA, 2012

2 to 4.9%

≥ 10%

1 to 1.9%

5 to 9.9%

< 1%

Not included or not reporting

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In 2012 (ECDC, 2014): •Notified cases: 3142 •Estimated prevalence: 5.2/100.000

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Incidenza di tubercolosi in Italia per classe d’età, sesso, e luogo di nascita

PAESE N° immigrati residenti in Italia

INCIDENZA stimata di casi

di TBC/100.000§

PREVALENZA di HIV (%) nei casi di

TBC§

Stima % di TB-MDR sul totale dei casi di TBC (LC

95%)^

Nuovi casi Ri-trattamenti

Albania 375.947 19 - 1,5 (0,3-10) 10

Cina 144.885 99 0.3 5,0 (4,6-5,5) 26

Ecuador 68.880 128 1.1 4,9 (3,5-6,6) 24

Egitto 65.667 24 0.1 2,2 (1,2-3,7) 38

Filippine 101.337 287 0.1 4,0 (2,9-5,5) 21

India 69.504 168 1.2 2,8 (2,3-3,4) 17

Marocco 343.228 93 0.4 0,5 (0,2-1,1) 12

Moldavia 55.803 141 0.4 19,4 (16,7-22,3) 51

Perù 66.506 162 2 5,3 (4,3-6,4) 24

Polonia 72.457 25 0.4 0,3 (0,1-0,6) 8.2

Romania 342.200 128 0.3 2,8 (1,8-4,2) 11

Senegal 59.857 270 2.7 2,1 (0,7-4,9) 17

Serbia e Montenegro 64.411 32 0.7 0,4 (0,1-0,9) 4.1

Sri Lanka 56.745 60 0.2 0,2 (0-1) 0.0

Tunisia 88.932 25 0.2 2,7 (0,4-15) 36

Ucraina 120.070 106 5.8 16,0 (13,7-18,4) 44

Incidenza di TB nei 16 Paesi con la frequenza più elevata di immigrati in Italia

• Aumentata incidenza di riattivazione di TB nei migranti • Possibile inefficacia della profilassi pre-terapia in pz con TB latente

da micobatteri INH/RIF resistenti • Importanza di eseguire IGRA per l’alta incidenza di soggetti vaccinati

Worldwide LTBI: size of the problem

LTBI 2 billion

Active TB

9 million

>200 fold difference

TB attiva bacillifera

TB LATENTE

Contagio respiratorio

RIDUZIONE Delle

DIFESE IMMUNITARIE

DIAGNOSI PRECOCE ISOLAMENTO TERAPIA

MIGLIORAMENTO SOCIO-ECONOMICO RIDUZIONE della immunodepressione (HIV) o depressione IATROGENA

TB attiva NON

bacillifera

IDENTIFICAZIONE DELLE TB LATENTI TERAPIA DI PROFILASSI FARMACOLOGICA

LTBI

x

From Goletti D

Persons at Risk for Developing TB Disease

• Those who have been recently infected • Those with clinical conditions that

increase their risk of progressing from LTBI to TB disease

Persons at high risk for developing TB disease fall into 2 categories

Risk groups considered for management of LTBI

• Persons with HIV infection • Adult contacts of persons with tuberculosis • Patients receiving tumor necrosis factor

blockers • Patients undergoing hemodialysis • Patients undergoing organ transplantation • Patients with silicosis • Prisoners • Health care workers • Immigrants from countries that have a high TB

burden • Homeless adults • Elderly persons

High risk of developing active TB, as reactivation of LTBI is closely related to the ability of host immunity to provide an adequate immune response

The risk of TB is increased from 5 to 100 times in patients treated with anti-TNF therapy

Anti-TNF and TB risk

Clin Microbiol Infect 2007

Screening for latent TB before starting TNF-α blocking treatment is mandatory for clinicians

Prevention efforts have partially decreased the risk of TB in this setting

However, optimal screening methods for latent TB represent an area of evolving controversy and active investigation

Risk of TB reactivation anti-TNF-α

Tuberculin skin test

Diagnosis of latent TB infection: TST

• Low specificity due to the cross-reactivity with the Bacillus Calmette-Guerin vaccine strains and MNT

• Reduced sensitivity in immunocompromised patients • Prone to “boosting” if repeated

Huebner R E, et al. The tuberculin skin test. Clin Infect Dis 1993.

Tissot F, et al. Infl uence of BCG vaccination on size of TST reaction: to what size? Clin Infect Dis 2005.

• Measure the cell- mediated immunity in the form of a DTH response to the PPD, which peaks after 48–72h

A TST should be considered positive if ≥5 mm of

induration.

• Recent TB infection (defined as 2 to 10 weeks after exposure)

• Anergy • Very young age (Newborns)

Factors that may cause false-negative TST reactions

IGRA The development of the Interferon-Gamma Release Assays has opened new perspectives for the detection of TB infection

The IGRA systems currently available are the QuantiFERON-TB Gold In-Tube and the T-SPOT.TB™

Diagnosis of latent TB infection: IGRAs

Effector T cells of individuals sensitized with TB antigens produce IFN-γ within a few hours of stimulation, when they reencounter mycobacterial antigens. A high level of IFN-γ production is indicative of M. tuberculosis infection

Patients with Active and Latent TB

Discordant results

True or false diagnosis of LTBI?

The clinical use of repeated blood tests and the correct interpretation of individual IFN-gamma changes could be

useful in identifying possible cases of LTBI reactivation or newly acquired tuberculosis

infection during longterm anti-TNF treatment

Multi-functional analysis of CD4+ T cells could be useful for ruling out TB infection in patients classified at screening as LTBI-negative but who show IGRA fluctuations under long term TNF antagonist treatment.

Analisi citofluorimetrica dei T poli-funzionali

Boolean Gate

IFN-γ + + + + - - -

TNF + - + - + - + IL- 2 + + - - + + -

Liinfociti T CD4+

TNF+ IL-2+ IFN-γ+

Sangue intero Stimolazione con: Ag TB-specifici, anti-CD28, anti-CD49d Colorazione di superficie anti-CD45-VioBlue, anti-CD4-PEVio770, Colorazione intracellulare anti-IFN-FITC, anti-TNF-APC, anti-IL-2PE. MACSQuant Analyzer Acquisizione 100.000 ev. FlowJo Software v 7.6.5 Analisi Boolean Gate

Analisi multi-citochinica dei linfociti T CD4+

Identificano lo stato di LTBI

?

Algoritmo per TB screening nei pazienti candidati al trattamento con anti-TNF-α

(‘triple-testing’ approach”) Storia clinica, identificazione fattori di rischio per TB

(provenienza zona ad alta endemia, contatto con TB attiva, precedente diagnosi di TB latente, tossicodipendente, homeless, reclusione, Rx indicativa di pregressa TB)

Test diagnostici per LTBI (TST + IGRAs)

Rx torace (se alterazioni compatibili con TB

escludere TB attiva, es. espettorato )

Giudizio clinico Se sospetto di LTBI sulla base dello screening,

iniziare terapia con INH o altro farmaco prima dell’inizio con anti-TNF-α

In discordant TST/IGRA, any positivity should be considered as indication of LTBI (unless related to a documented BCG vaccination)

Prefer IGRA over TST, or use both tests in a stepwise manner

In patients with strong epidemiologic TB risk factors it is reasonable to consider repeating IGRA, if TST and IGRA results are negative/or indeterminate at baseline

Immunocompromised subjects

LTBI: test screening

LTBI: serial testing

Full assessment of clinical and epidemiological TB risk factors improves LTBI detection

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