Enfermedad de Chagas - Human Health Campus · 2016-08-09 · Enfermedad de Chagas Epidemiología,...

Enfermedad de Chagas

Epidemiología, enfoque clínico y diagnóstico

(no incluye medicina nuclear)

Juan Carlos Villar, MD, MSc, PhD

Curso regional diagnóstico cardiopatía dilatada

Bogotá, Noviembre 5 de 2012

Chagas’ natural history and treatment options

T. cruzi Infection

(18 million)

Acute phase (AP) (99% undiagnosed)

Indeterminate phase (IP): Clin[-] T+ ECG[-] Chest Rx (–)

Chronic phase (CP) (10-30%) Heart failure Sudden death thrombo-embolisms, etc

Treatment ?? Vector control

Trypanocidal drugs

% Subclinical Vs no disease? Rate of events?

Markers of risk?

Symptomatic treatment

Preventive interventions:

CHICAMOCHA

Puntos a cubrir en la presentación

1-Diagnostico de la infección por T. cruzi

2- Clasificación clínica de los individuos con infección

2- Estado del conocimiento en tratamiento

3- Calidad del cuidado por ofrecer al infectado

1-Diagnostico de la infección por T. cruzi

2- Clasificación clínica de los individuos con infección

2- Estado del conocimiento en tratamiento

3- Calidad del cuidado por ofrecer al infectado

Puntos a cubrir en la presentación

Villar JC, Lazzari J, Rassi A Jr, Maguire J

Management of clinical disease

WHO Scientific Working Group

http://www.fac.org.ar/ccvc/llave/c051/villar.php

Métodos indirectos

• Serología convencional

• Serología especial

Métodos directos

• Xenodiagnóstico

• Hemocultivo

• PCR

Diagnóstico infección crónica por T. cruzi

Diagnóstico infección crónica por T. cruzi

Métodos indirectos

• Serología convencional

• Serología especial

Métodos directos

• Xenodiagnóstico

• Hemocultivo

• PCR

Sensibilidad

Especificidad

Concordancia pruebas serológicas (1/2)

Serological techniques being compared

ELISA vs IHA ELISA vs IIF IHA vs IIF

| Status with 2nd technique Status with 2nd technique Status with 2nd

technique

Status with 1st technique Neg Pos Neg Pos Neg Pos

Neg (%) 1809 6 440 0 438 25

Pos (%) 50 707 40 542 22 487

Kappa (95% CI) 0.95 (0.91-0.99) 0.92 (0.86-0.98) 0.90 (0.84-0.97)

ELISA: Enzyme-linked immunoassay; IHA: Indirect haemagglutination; IIF: Indirect immunofluorescence

Concordancia pruebas serológicas (2/2)

Villar JC, Herrera VM, Smieja MJ, et al (submitted)

C H I C A M O C H A

Coding of T. cruzi serology status C H I C A M O C H A

Origin of participants (n, %)

Consistency of status, 1st and 2nd visit, whole cohort

Blood donors with negative screening

(n=1322)

Blood donors with positive screening

(n=469)

Sero[-] Sero[+] Sero[-] Sero[+]

Baseline status (%) 1315 (99.5) 7 (0.5) 152 (32.4) 317 (67.6)

With 2nd measurement available (% of the original group)

988 (75.1) 7 (100) 115 (75.7) 259 (81.7)

Status at 2nd assessment

Sero[-] 987 1 104 12

Sero[+] 1 6 11 247

Kappa (95% CI) 0.86 (0.79-0.92) 0.86 (0.75-0.96)

Consistency of status, 2nd and 3rd visit, Subgroup having cardiac function

Blood donors with negative screening

Blood donors with positive screening

assessment (n=157) (n=362) Sero[-] Sero[+] Sero[-] Sero[+]

Status in 2nd visit (%) 151 (96.2) 6 (3.8) 112 (30.9) 250 (69.1) With 3rd measurement available (% of the original group)

125 (82.8) 4 (66.7) 98 (87.5) 160 (64.0)

Status at 3rd assessment

Sero[-] 125 0 84 10

Sero[+] 0 4 14 150

Kappa (95% CI) 1 (0.83-1) 0.80 (0.68-0.92)

Villar JC, Herrera VM, Smieja MJ, et al (submitted)

Tasa de positividad PCR

J Clin Microbiol. 2003 Nov;41(11):5066-70

Two scenarios of clinical care (after diagnosis of T. cruzi chronic infection)

Symptoms / complaints / concerns??

Diagnosis of the extent of cardiac abnormalities

Prognosis / Therapy

Prevention scenario Exclusion of sub-clinical abnormalities

Follow up versus prevention treatment

Treatment scenario Extent of lesions

Trypanocidal and/or non-specific treatment

Villar JC, Lazzari J, Rassi A Jr, Maguire J http://www.fac.org.ar/ccvc/llave/c051/villar.php



Prognosis / Therapy


Follow up versus prevention treatment








Prognosis / Therapy


Follow up with/without trypanocidal treatment (??)




Clinical staging of chronic infection

Classical forms Kuschnir

(Cardiac forms)

ECG Radiographs Symptoms

Indeterminate 0 - - -

Determinate

- Cardiac

- Digestive

1 + - -

2 + + -

3 + + +

Kuschnir E, et al

Arq Bras Cardiol. 1985 ; 45: 249-56.

Hallazgos electrocardiográficos

Hallazgos electrocardiográficos

C H I C A M O C H A

Asociación electrocardiograma - ELISA

C H I C A M O C H A

Baseline classification End-of-study classification

T. cruzi Serology

ECG Rhythm/conductio

n abnormalities Study group T. cruzi

serology ECG Rhythm/conduction

abnormalities Study group

n (%)

ECG[-] 200 87.0% Sero[-]

ECG[+] 25 10.9%

ECG[-] 2 0.9% ECG[-] 230 (85.8%)

Sero[+] ECG[+] 3 1.2%

ECG[-] 22 57.9% Sero[-]

ECG[+] 15 39.5%

ECG[-] 0 0%

Sero[-] (n=268)

ECG[+] 38 (14.2%)

Sero[+] ECG[+] 1 2.6%

ECG[-] 1 2.8% Sero[-]

ECG[+] 0 0%

ECG[-] 98 80.3% ECG[-] 122 (78.2%)

Sero[+] ECG[+] 23 18.9%

ECG[-] 0 0% Sero[-]

ECG[+] 1 2.9%

ECG[-] 18 52.9%

Sero[+] (n=156)

ECG[+] 34 (21.8%)

Sero[+] ECG[+] 15 44.2%

Overall group agreement = 77.4% (chance expected agreement: 38.2%) Kappa statistic= 0.63, 95% CI: 0.57-0.70

Consistency of serology/ECG - 6.5 years (n=424) C H I C A M O C H A

Villar JC, Smieja MS, Herrera VM, Chaves AM, Thabane L Guyatt GH (unpublished)

Classical staging: Pros & cons

Prevention scenario ECG: Key, reliable and valid tool

Main virtue: Specificity

Sensitivity => Ruling out disease

Does ECG miss important subclinical disease??

Treatment scenario Basic diagnostic tools are OK for diagnosis

Low precision (reliability)

Doing more is justified if it guides treatment decisions


Figure 4.1. Proportions of diagnostic abnormalities found among participants by T. cruzi serology

status. Top figure shows the proportions with values over the 95th tile of seronegative individuals

for each of the five selected responses. Echocardiography indices are height-adjusted. Cardiac

Autonomic function indices are adjusted for baseline heart rate. The bottom figure shows the

proportions with at least two of the five responses over the 95th tile and 90th tile of seronegative

(left and right groups of bars, respectively)

0.0%

2.5%

5.0%

7.5%

10.0%

12.5%

15.0%

17.5%

LV diast. vol LV short. Fr. LV syst. Diam. Deep br. test Max. HR (tilted)

p=0.012 p=0.725 p<0.001 p=0.001 p=0.019

Indeterminate SeropositiveSeronegative

0%

5%

10%

15%

20%

25%

2+ abnormalities ≥95th tile seroneg 2+ abnormalities ≥90th tile seroneg

p<0.001 p<0.001

C H I C A M O C H A

Subclinical abnormalities

Prevalence (1/2)

Villar JC, Smieja MS, Chaves AM, Peña JL, Guyatt GH (unpublished)

Figure 4.1. Proportions of diagnostic abnormalities found among participants by T. cruzi serology

status. Top figure shows the proportions with values over the 95th tile of seronegative individuals

for each of the five selected responses. Echocardiography indices are height-adjusted. Cardiac

Autonomic function indices are adjusted for baseline heart rate. The bottom figure shows the

proportions with at least two of the five responses over the 95th tile and 90th tile of seronegative

(left and right groups of bars, respectively)

0.0%

2.5%

5.0%

7.5%

10.0%

12.5%

15.0%

17.5%

LV diast. vol LV short. Fr. LV syst. Diam. Deep br. test Max. HR (tilted)

p=0.012 p=0.725 p<0.001 p=0.001 p=0.019

Indeterminate SeropositiveSeronegative

0%

5%

10%

15%

20%

25%

2+ abnormalities ≥95th tile seroneg 2+ abnormalities ≥90th tile seroneg

p<0.001 p<0.001

C H I C A M O C H A


Subclinical abnormalities

Prevalence (2/2)

-10

-5

0

5

10

15

20

25

30

Mean

4-year

change

(%, 95%CI)

LV Systolic diameter LV diastolic diameter LV mass

p=0.021 p=0.870 p=0.003

Serology code

◊ Sero negative (n=158) * Indeterminate (n=128) ● Positive (n=176)

Four-year change by serology group


Survival in patients with Chagas’ heart isease (n=424)

Rassi A Jr, et al NEJM 2006; 355: 799-808

Multivariate Cox Proportional Analysis and Point Scoring System*

* Due to missing data on some variables the final sample used in our multivariate analysis consisted of 331 patients with 98 deaths. CI denotes confidence interval, NYHA New York Heart Association, WMA wall motion abnormality, and VT ventricular tachycardia. † Assignment of points to risk factors was based on a linear transformation of the corresponding b regression coefficient. The coefficient of each variable was divided by 0.54 (lowest b = male sex), multiplicated by a constant (2), and rounded to the nearest integer.


Kaplan-Meier Survival Curves According to Our

Three Group Prognostic Classification


C H I C A M O C H A

Chagas

Leishmaniasis

Sleeping sickness

HIV - AIDS

Malaria

TB

The big picture:

Chagas’ among the world’s most neglected diseases

Adapted from:

Yamey G, Torreele E BMJ 2002;325:176-177

http://bmj.bmjjournals.com/content/vol325/issue7357/images/large/yamg3282.f1.jpeg

http://bmj.bmjjournals.com/content/vol325/issue7357/images/large/yamg3282.f1.jpeg

Clinical efficacy of Trypanocidal therapy (prevention and treatment scenario)

Clinical

progress

Definitive

end points Obs adults

UNMET

GOAL

Surrogate


Infection

Parasite

material

RCT

Children

Surrogate

markers

RCTs

Children

Uncertain, not

replicated

Uncertain

replicated

Certain, not

replicated

Certain,

Replicated

Causal

inference

Levels of the evidence reported

Clinical efficacy of Trypanocidal therapy (prevention and treatment scenario)

Clinical

progress

Definitive


UNMET

GOAL

Surrogate


Infection

Parasite

material

RCT

Children

Surrogate

markers

RCTs

Children

Uncertain, not

replicated

Uncertain

replicated

Certain, not

replicated

Certain,

Replicated

Causal

inference

Levels of the evidence reported


Panorama

Efecto de

tratamiento

Tripanocida

Sobre

parásito

Villar JC, Pérez JG, Cortes OL

Cochrane database syst reviews

(submitted)

Panorama

Efecto de

tratamiento

Tripanocida

Sobre

huesped

Villar JC, Pérez JG, Cortes OL

Cochrane database syst reviews

(submitted)

Efectos colaterales en ECA con BZD (1/2)

Características del estudio Efectos adversos

1er Autor Población Tipo de efecto adverso BZD n/N (%)

Control n/N (%)

Riesgo relativo (95% IC)

Andrade Niños escolares

Exantema / prurito 8/64 (12.5) 2/65 (3.1) 4.0 (0.88, 18.11)

Abandono del tratamiento 1/64 (1.6) 0/65 (0) Indeterminado Adherencia (final) 58/64 (90.6) 54/65 (83.1) 1.09 (0.95, 1.25) Sosa-Estani Niños

escolares Tasa global <20% NA NA

Efectos adversos moderados

GINT 6/55 (10.9) 0/51 Indeterminado

Andrade AL, Lancet. 1996;348:1407-13.

Sosa-Estani S, Am J Trop Med Hyg. 1998;59:526-9.

Características del estudio Efectos adversos

1er Autor Población Tipo de efecto adverso BZD n/N (%)

Control n/N (%)

Riesgo relativo (95% IC)

Riarte et al Adultos Prurito 84/352(23.9) 27/357(7.6) 3.16(2.10,4.74) Rash 128/352(36.4) 25/357(7.0) 5.19(3.47,7.77) Exantema 75/352(21.3) 12/357(3.4) 6.34(3.51,11.45) Cefalea 83/352(23.6) 72/357(20.2) 1.17(0.88,1.55) Irritabilidad/insomnio 16/352(4.5) 8/357(2.2) 2.03(0.88,4.68) Fiebre 16/352(4.5) 1/357(0.3) 16.23(2.16,121.71) Adenopatías 9/352(2.5) 0/357(0) - Artralgias/artritis 10/352(2.8) 1/357(0.3) 10.14(1.31,78.81) Edemas 19/352(5.4) 5/357(1.4) 3.85(1.46,10.21) Hepatitis tóxica 4/352(1.1) 0/357(0) - Neuropatía periférica 10/352(2.8) 1/357(0.3) 10.14(1.31,78.81)

Efectos colaterales en ECA con BZD (2/2)

Riarte A, et al. Rev Méd Rosario 2008 (Supl) 16 S

Clinical efficacy of non-specific therapy (treatment scenario)

Chagas Definitive

end points ??? ??? Obs ???

Surrogate

Markers Obs

Definitive

endpoints RCTs RCTs RCTs RCTs RCTs

No

Chagas

Surrogate

markers RCTs RCTs RCTs RCTs RCTs

ACE

Inhibitors

ACE

inhibitors

Beta

Blockers Digitalis

Amio

darone Others

Causal

inference

Proven therapies


Clinical efficacy of non-specific therapy (treatment scenario)

Chagas Definitive

end points ??? ??? ??? Obs ???

Surrogate

Markers Obs

Definitive

endpoints RCTs RCTs RCTs RCTs RCTs

No

Chagas

Surrogate

markers RCTs RCTs RCTs RCTs RCTs

ACE

Inhibitors

ACE

inhibitors

Beta

Blockers Digitalis

Amio

darone Others

Causal

inference

Proven therapies


Treatment for tomorrow

What should be the ideal product for tomorrow?

-Antiparasitic??

-Disease modifier??

- Both??


Gaps on therapy

Efficacy of trypanocidal therapy on:

a) Prevention of disease

b) Prevention of disease progression

Improving effectiveness of trypanocidal therapy

Efficacy of conventional interventions for heart disease

Adequacy of care

Diagnostic gap (infection >> disease)

(urban vs rural)

Diagnosis of cases without prior diagnosis of infection

Unacceptable!

Infection / clinical diagnosis from index cases

Coverage / Comprehensiveness / Continuity of care Unknown!!

Different emphasis for prevention and treatment scenarios


10 cosas para hacer

A manera de conclusión (1 de 2)

1. Pensar en la enfermedad de Chagas

2. Los niños se pueden curar!!

3. Tamizar embarazadas en regiones endémicas

4. Tamizar familiares de “casos índice”

5. Confirmar diagnóstico (repetir serología)

10 cosas para hacer

A manera de conclusión (2 de 2)

6. Tratar seropositivos menores de 20 años

7. Tamizar con electrocardiograma (eco si es posible)

8. Dar continuidad al cuidado!!

9. Hacer tratamiento coadyuvante de falla cardíaca

10. Hablar del problema con pacientes y autoridades

100 años sin solución!!

Enfermedad de Chagas - Human Health Campus · 2016-08-09 · Enfermedad de Chagas Epidemiología,...

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Transcript of Enfermedad de Chagas - Human Health Campus · 2016-08-09 · Enfermedad de Chagas Epidemiología,...