Tubercolosi: le nuove sfide di una vecchia...

Tubercolosi: le nuove sfide di una vecchia malattia

Andrea GoriDivision of Infectious Diseases,"San Gerardo" Hospital,University of Milano-BicoccaMonza (Milano)[email protected]

Lecco, 05 Novembre 2016

… una vecchia patologia emergente?

− 3 pandemie (HIV, Malaria e TB) 6 Milioni all’anno

− 1,6 Milioni per TB all’anno

− 5.000 morti per TB al giorno

− 5 epidemie di SARS al giorno

− 25 epidemie di avaria al giorno

− 50 epidemie di ebola al giorno

− 3 Titanic al giorno

− 15 Jambo Boing 747 al giorno

Casi di TBC nel quinquennio precedente (1988-1992)

0

5

10

15

20

25

30

35

40

1988 1989 1990 1991 1992

Casi TBC

1993 1994 1995 1996

Coinfezione HIV & TB

INFEZIONE DA HIV

TUBERCOLOSI

Casi di TB attesi e osservati, USA 1980-97

80 82 84 86 88 90 92 94 96

http://www.cdc.gov/nchstp/tb/pubs/slidesets/surv/surv1997/html/surv2.htm

http://www.cdc.gov/nchstp/tb/pubs/slidesets/surv/surv1997/html/surv2.htm

Impact of HIV on TB in Africa

Notified cases per 100,000 pop. 1980-2008

Percentage of global estimated HIV-positive TB cases

EMR

Cameroon

Thailand

Brazil

Democratic Republic of the Congo

China

Myanmar

EUR

Côte d'Ivoire

Malawi

United Republic of Tanzania

AMR

Zambia

WPR

Ethiopia

Mozambique

Kenya

Uganda

Zimbabwe

Nigeria

India

SEA

South Africa

AFR

1% 5% 10% 20% 50% 90% 0

100

200

300

400

500

600

700

1980 1984 1988 1992 1996 2000 2004 2008

Botswana

Côte d'Ivoire

DR Congo

Gabon

Guinea

Kenya

Malawi

Mozambique

South Africa

UR Tanzania

Zimbabwe

• 79% of all TB/HIV cases world-wide are in Africa• 50% of all TB/HIV cases world-wide in 9 African countries• 23% of the estimated 2 million HIV deaths due to TB

J Infect Dis 1997 Sep;176(3):637-42Nosocomial spread of human immunodeficiency virus-related multidrug-resistant tuberculosis in Buenos Aires, 1994-1995

Ann Ital Med Int 1998 Jul-Sep;13(3):139-45Mycobacterium tuberculosis drug resistance in patients with HIV and pulmonary tuberculosis infections in Rome: 1987-1996

MMWR 1990 Oct 12;39(40):718-22Nosocomial transmission of multidrug-resistant tuberculosis to health-care workers and HIV-infected patients in an urban hospital--Florida, 1988-1990

J Hosp Infect 2001 Feb;47(2):91-7Investigation and control of a large outbreak of multi-drug resistant tuberculosis at a central Lisbon hospital, 1995-1996

MMWR 1992 Jul 17;41(28):507-9Transmission of multidrug-resistant tuberculosis among immunocompromised persons in a correctional system--New York, 1991

Nosocomial MDR-TB outbreaks during the pre-HAART period

MMWR 1996 Apr 26;45(16):330-3Multidrug-resistant tuberculosis outbreak on an HIV ward--Madrid, Spain, 1991-1995

…how many drugs do we need?

TB Bacteria: Classification/Definitions

XDR-TB: definitions

XDR (3/06/06) -MDR TB + resistance to > 3/6 of major classes of 2nd-line drugs

-Need >four 2nd-line drugs for RX

XDR (since 10/06) –MDR TB + resistance to at least Fq & any injectable 2° -line (amikacin, kanamycin, capreomycin)

-Treatment outcomes (Latvia) ~ 60% vs <30%

CDC 2006

XDR

MDR1

MDR2

Mortality analysis: HIV+ vs HIV- patients

AIDS 1998,12:1095-1102 and CID 2002, 34

0%

20%

40%

60%

80%

100%

T0 10 weeks 20 weeks 30 weeks 40 weeks 50 weeks

HIV+ MDR-TB Milan1996

HIV+ Milan 2002

HIV- Atlanta 1994

HIV- Atlanta 1997

Emergence of MDR (XDR)-TB outbreaks(Lombardia, 1993-1998)

MDR M. tb Outbreak

Genotype: Type 20

Hospitals involved: 5

N° cases: 28

MDR M. tb Outbreak

Genotype: Type 65


N° cases: 29

'94

'94

'94

'95

'96

'95

'92

MDR M. tb Outbreak

Genotype: Type 1


N° cases: 157

MDR M. tb Outbreak

Genotype: Type 23


N° cases: 17

MDR M. tb Outbreak

Genotype: Type 580


N° cases: 28

Incidence of XDR tubercolosis in HIV+ patients (Milano, 1988-2006)

HAART

PRE-HAART

POST-HAART

HIV infection could be successfully treated

Incidence of XDR tubercolosis in HIV+ patients (Milano, 1988-2006)

HAART

0

10

20

30

40

50

60

70

80

tot

HIV

immigrati

MDR

pa

zie

nti

Impatto della trasmissione di TB tra pazienti

HIV+ e la popolazione generale

Impatto della trasmissione di TB tra pazienti

HIV+ e la popolazione generale

0

10

20

30

40

50

60

70

80

tot

HIV

immigrati

MDRpa

zie

nti

0

3

6

9

12

15

18

21

1994 1995 1996 1997 1998 1999 2000 2001

pa

zie

nti

0

5

10

15

20

25

30

35

40

1994 1995 1996 1997 1998 1999 2000 2001

pa

zie

nti

0

4

8

12

16

20

24

28

32

1994 1995 1996 1997 1998 1999 2000 2001

pa

zie

nti

TB in pazienti italiani e immigrati: (Milano, 1990-2001)

0%

20%

40%

60%

80%

100%

1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001

Pazienti italiani Pazienti immigrati

Rapporto Italiani/Immigrati (Milano 1989-2005)

0%

20%

40%

60%

80%

100%

1989 1991 1993 1995 1997 1999 2001 2003 2005

Italiani

Immigrati

Variabilità dei dati nelle diverse realtà geografiche

Non esiste una “omogeneicità dei flussi migratori nelle diverse realtà geografiche

Roma: prevalenza di Polacchi

Brescia: prevalenza di Senegalesi

Bologna: prevalenza di Pachistani

Veneto? Campania?

Modificazione della trasmissione di TB in relazione alle diverse etnie

0

50

100

150

200

250

300

altro

Est Europa

Brasile

Perù

Cina

SudEst Asia

India

Est Africa

West Africa

Nord-Africa

Un altro modo di vedere la terra…

XDR TB in KwaZulu-Natal South Africa

Spread of MDR e XDR-TB in HIV+

Franzetti et al. CID, 1999 e Gandhi et al, Lancet 2006

Milano 1992-1996(Franzetti et al.)

SudAfrica 2005(Gandhi et al.)

Pts with XDR-TB 90 53

Pts with a previous hospital admission

70% 67%

Prevalence of XDR-TB 43%

(among TB in HIV+ve pts)

39%(among overall TB pts)

Median CD4 cell count 12 43

Median survival time 94 days 16 days

Mortality (at 1 year) 93% 98%

Clustered strains by genotyping analysis

88% 85%

Factors contributing to the spread of XDR tuberculosis in the Milan

Overcrowded infectious disease wards inadequate compliance with infection control procedures

Poor adherence to treatment

Prolonged hospitalisation favouring exposure between patients

Delays in diagnosis

Obtainment of drug susceptibility test results

HAART unavailability

Adherence to basic administrative and source-control

measures

cough-inducing procedures in TB suspects

protocol for early diagnosis

placement of patients in single rooms

negative pressure rooms was made available for patient isolation

Control measurements implementation

… It is therefore arguable that final eradication of the outbreak was favoured by the use of HAART

s

i

v

e

R

e

s

i

s

t

a

n

c

e

t

o

S

e

c

o

n

d

-

L

i

n

s

i

v

e

R

e

s

i

s

t

a

n

c

e

t

o

S

e

c

o

n

d

-

L

i

n

XDR a worldwide issue

Patients XDR infected (Uzbekistan)

13 top settings with highest % of MDR-TB among new cases, 2001-2010

16.5

19.2

19.3

19.4

20.0

22.3

23.8

27.3

28.3

15.4

14.8

16.0

16.1

0 5 10 15 20 25 30

Tashkent, Uzbekistan (2005)

Estonia (2008)

Donetsk Oblast, Ukraine (2006)

Mary El Republic, Russian Federation (2008)

Dushanbe city and Rudaki district, Tajikistan (2009)

Belgorod Oblast, Russian Federation (2008)

Kaliningrad Oblast, Russian Federation (2008)

Republic of Moldova (2006)

Ivanovo Oblast, Russian Federation (2008)

Baku city, Azerbaijan (2007)

Arkhangelsk Oblast, Russian Federation (2008)

Pskov Oblast, Russian Federation (2008)

Murmansk Oblast, Russian Federation (2008)

35.3Minsk, Belarus (2010)Preliminary results

Efficacy of TB control measurements

“The Case of Peru”

Pu

lmo

nary T

B c

ases/

10

0,0

00

World Health Organization

50

100

150

200

250

1975 1980 1985 1990 1995 2000 2005

Case finding

Treatment success 86% globally

Global WHO Regions

8584

86 86

83

80

75

80

85

90

2003 2004 2005 2006 2007 2008

Tre

atm

en

t su

ccess r

ate

(%

)

Progress in most regions, but Europe lagging behind

65

70

75

80

85

90

95

2003 2004 2005 2006 2007 2008

W. Pacific

SE Asia

EMR

Africa

93

88

80

Americas

77

66

Europe

La strada per arrivare ai farmaci può essere un percorso ad ostacoli

Inaccessibilità dei servizi

Disinformazione

Stigma

Ineguaglianze

Costi economici della diagnosi

Liste di attesa

Impreparazione

Mancato coordinamento

Inefficace coinvolgimento del settore privato

Risorse insufficienti

Obiettivi dello studio

− Stimare il ritardo diagnostico e terapeutico nei pazienti con tubercolosi in Italia

− Descrivere le modalità di accesso alle cure e le eventuali occasioni mancate di diagnosi

− Identificare i fattori epidemiologici, sociali e clinici associati al ritardo

Materiali e metodi

• Studio multicentrico prospettico osservazionale sul territorio nazionale:

– Clinica di Malattie Infettive, H “San Gerardo” di Monza

– Clinica di Malattie Infettive, H “Luigi Sacco” di Milano

– Istituto “Villa Marelli” di Milano

– Clinica di Malattie Infettive, Spedali Civili di Brescia

– Clinica di Malattie Infettive, H “San Martino” di Genova

– Clinica di Malattie Infettive, Policlinico Gemelli di Roma

– UO Pneumotisiologia dell’ Ospedale Fallacara, Bari

Definizione di ritardato accesso alla terapia

RITARDO

DIAGNOSTICO

RITARDOTERAPIA

Tempo intercorso fra l’insorgenza dei sintomi e la diagnosi di micobatteriosi

polmonare

Tempo intercorso fra la diagnosi di micobatteriosi polmonare e

l’avvio del trattamento specifico

Definizione di ritardato accesso alla terapia

Tempo intercorso fra l’insorgenza dei sintomi e il I contatto con un sanitario

Tempo intercorso fra la diagnosi e l’avvio del trattamento

specifico

RITARDO

STRUTTURA

Tempo intercorso fra il I contatto e la diagnosi di micobatteriosi

polmonare

RITARDO

PAZIENTE

RITARDOTERAPIA

Ritardo diagnostico

Ritardo

(settimane) Totale Per sede Provenienza

Mediana(IQR)

PolmonareNon

polmonareItaliano Non italiano

Ritardo diagnostico

Ritardo paziente

Ritardo struttura

7.5 (3-18.5)

1 (0-5)

4 (0-13)

5 (2-10)*

0.5 (0-4.5)

1.5 (0-5.5)§

19 (7-33)*

1 (0-5)

17 (7-22)§

6 (3-22)

0 (0-3)

5 (1-12)

7.5 (3-18)

1 (0-7)

3 (0-13)

Ritardo terapia 0 (0-0) 0 (0-0) 0 (0-0) 0 (0-0) 0 (0-0)

* Wilcoxon P= <0,001; § Wilcoxon P= <0,001;

Percorso diagnostico

• 3/30 (10%) sospetto diagnostico

immediato

• Nei restanti casi, mediamente 4,4

valutazioni prima della diagnosi.


immediato




immediato



Fattori associati al ritardo diagnostico

− A differenza di altre casistiche, in Italia il ritardo diagnostico sembrerebbe essere principalmente sostenuto dal ritardo di struttura

− I pazienti che si rivolgono a strutture ospedaliere emedici specialistici hanno minor ritardo diagnostico

− differente gravità dei sintomi iniziali?

− precoce avvio verso esami specialistici?

TB care and

control

Development agenda

Research sensu lato

Health systems

and policies Free services, labs, quality

drugs, regulated private care,

better M&E

New tools

Operational research

Transfer of technology4444

Innovative Actions Needed in 4 Areas

Early & increased case detection: new

tools

Scale-up TB/HIV and MDR-TB

interventions

M&E and impact measurement

Engage all care providers

Active screening among at-risk

populations

Socio-economic factors:

living conditions, food

insecurity, awareness, risk

behaviour, access to care

MDR-TB, Multi drug resistant TB

M&E, Monitoring and evaluation

Innovative action needed in 4 spheres

Dal Mondo alla “Nostra” Africa

Acknowledgements

Clinical managementAntonio MuscatelloSilvia CostarelliLuca BisiAnna CappellettiSergio ForestiGiuseppe LapadulaSebastiano LeoneMarco MigliorinoAlessandro PerrettiFrancesca SabbatiniAlessandro SoriaAlberto DolaraMarianna RossiNicola SquillaceAlessandra Bandera

Data retrieval and analysisDavide MangioniSilvia Limonta

Statistical analysis (IRCCS Mario Negri)Liliane Chatenaud

Study coordinatorsValeria PastoreElena Cappelletti

Samples managementIlaria Beretta

Study nursesMarzia FiorinoPatrizia Acquaviva

Division of Onco-Haemathology, “San Gerardo” Hospital, University Milano-BicoccaMonza, ItalyLuisa VergaFausto RossiniPietro PioltelliEnrico Pogliani

Division of Division of Pathology, “San Gerardo” Hospital, University Milan-BicoccaMonza, ItalyAmbrogio BrennaSerena CuttinGiorgio Catoretti

Division of Microbiology and Virology Laboratories, “San Gerardo” Hospital, Monza, ItalySergio MalandrinAnnalisa Cavallero

Department of Surgery, “San Gerardo” Hospital, Monza, ItalyMarco PoleseVittorio Giardini

Haemathology and Transfusion Center, “San Gerardo” Hospital, Monza, ItalyPaolo PerseghinArianna Incontri

Institute of Clinical Infectious Diseases Catholic University of Sacred Heart, Rome, ItalySimona DigiambenedettoAndrea De LucaRoberto Cauda

Chair of Immunology,University of Milan, Milan, ItalyDaria TrabattoniMarina SaresellaMara BiasinMario (Mago) Clerici

Division of Infectious Diseases, “L. Sacco” Hospital, Milan, Italy,Stefania PiconiPaolo BonfantiGiuliano Rizzardini

Clinic of Infectious Diseases, “San Paolo” Hospital, University of MilanMilan, ItalyGiulia Marchetti Camilla TincatiAntonella d’Arminio Monforte

Back up Slides

Molecular epidemiology of tuberculosis spreading in European metropolitan

areas

Andrea GoriDivision of Infectious Diseases,"San Gerardo" Hospital,University of Milano-BicoccaMonza [email protected]

Individual patients/strains in the DB

5823 records

8 cities

2009-2012 (Jun)

TB PAN-NET: Work Package 1

- A.O. San Gerardo, Monza

- Fondazione Centro S. Raffaele,

Università Vita Salute, Milano

- Queen Mary and Westfield College,

University of London

- Forschungszentrum , Borstel,

Leibeniz-Zentrum fur Medizin

Biowissenschaften

- Swedish Institute for

Infectious Diseases Control

- Institut Pasteur, Lille

- Scientific Institute of Public

Health, Institute Pasteur

- Tartu University Hospital

- State Agency of Tuberculosis

and Lung Diseases

- Institute of Biotecnology

- National Tuberculosis and

Infectious Diseases HospitalGori A, et al. 2015

Individual patients/strains in the DB

Gori A, et al. 2015

6823 patients

Overall drug susceptibility

− 465 MDR (9%)− 183 mono INH-R− 96 mono RIF-R− 403 other R patterns

Gori A, et al. 2015

Risk factors distribution

Vilnius Tartu Brussels Milan

Alcohol abuse 41.2% 46.5% 3.7% 1.6%

Homeless 7.6% 7.3% 3.8% 4.1%

Drug abuse 1.3% 6.7% 1.1% 0.2%

Recent detention 2.3% 14.8% 1.9% 0.6%

HIV AbPositiveNegativeUnknown

1.3%61.4%37.3%

11.4%84.2%4.4%

6.6%61.3%32.1%

3%49.6%47.4%

Prevalence of different resistant patterns

Resistance pattern

Vilnius Tartu Hamburg Brussels Stockholm London

Susceptible 144 (48.6) 464 (56.0) 336 (89.8) 554 (80.1) 333 (84.1) 1242 (86.7)

INH resistance 47 (15.9) 54 (6.5) 17 (4.5) 35 (5.1) 49 (12.4) 62 (4.3)

RIF resistance 0 5 (0.6) 0 4 (0.6) 0 69 (4.8)

DIF resistance 21 (7.1) 41 (4.9) 18 (4.8) 71 (10.3) 1 (0.3) 24 (1.7)

MDR 84 (28.4) 265 (32.0) 3 (0.8) 28 (4.0) 13 (3.3) 36 (4.5)

Total 296 829 374 692 396 1433

− 6671 (97.4%) antibiograms

Gori A, et al. 2015

MDR-TB in the TB PAN-NET database

Epidemiological characteristics of MDR-TB

n % 95% CI

Foreignborn 61 16.2 12.8-20.2

Lived in healthcare facilities 12 3.2 1.8-5.5

Homeless 35 9.3 6.8-12.6

Have been in detention 49 13.0 10.0-16.8

Alcohol abuser 182 48.3 43.3-53.3

Drug abuser 21 5.6 3.7-8.4

HIV Positive 38 10.1 7.4-13.5

Tubercolosi: le nuove sfide di una vecchia...

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