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ANIS RASSI HOSPITAL
Sixth International Conference on Preventive Cardio logyFoz do Iguaçu - Brazil
May 21-25, 2005
Sixth International Conference on Preventive Cardio logyFoz do Iguaçu - Brazil
May 21-25, 2005
Anis Rassi Junior, MD, PhD, FACP, FACC, FAHAScientific Director, Anis Rassi Hospital
Goiânia (GO) - BRAZIL
Anis Rassi Junior, MD, PhD, FACP, FACC, FAHAScientific Director, Anis Rassi Hospital
Goiânia (GO) - BRAZIL
e-mail: [email protected] NO COMPETING INTERESTSNO COMPETING INTERESTS
Achievements in Preventing Chagas` Disease in Brazil
Achievements in Preventing Chagas` Disease in Brazil
ANIS RASSI HOSPITAL
Chagas: endemic countries
Chagas`DiseaseChagas`DiseaseAmerican Trypanosomiasis (zoonosis)•Impact: 10-12 million people infected (16 countries of Latin America)•Incidence: 200,000 new cases per year•Agent: Trypanosoma cruzi (I and II)•Hosts: all mammal species•Vector: Triatominae bugs (138 sp)•Morbidity of human Chagas`disease:20% to 43% develop cardiac and/or digestive disease•Control: Three multi-national control programs (Southern Cone, Andean Pact, and Central American)
American Trypanosomiasis (zoonosis)•Impact: 10-12 million people infected (16 countries of Latin America)•Incidence: 200,000 new cases per year•Agent: Trypanosoma cruzi (I and II)•Hosts: all mammal species•Vector: Triatominae bugs (138 sp)•Morbidity of human Chagas`disease:20% to 43% develop cardiac and/or digestive disease•Control: Three multi-national control programs (Southern Cone, Andean Pact, and Central American)
1909
ANIS RASSI HOSPITAL
Initial acute phase•asymptomatic•symptomatic
Chronic phase•indeterminate
form
Chronic phase•determinate forms
(cardiac and/or digestive)
Deathor major
permanentdamage
T. cruzi infection
Tertiaryprevention
Prevention ofmorbidity and
mortality
Prevention ofmorbidity and
mortality
Secondaryprevention
Secondaryprevention
Preventionor
inhibitionof diseasein cases
whereinfection
has occured
Preventionor
inhibitionof diseasein cases
whereinfection
has occured
Primaryprevention
Prevention oftransmissionPrevention oftransmissionLEVELS OF
PREVENTIONIN CHAGAS`
DISEASE
LEVELS OFPREVENTIONIN CHAGAS`
DISEASE
ANIS RASSI HOSPITAL
Chagas` DiseaseChagas` DiseasePrimary PreventionPrimary Prevention
Interventions designed to prevent the transmission of the disease
✓
ANIS RASSI HOSPITAL
Chagas` DiseaseTransmission
Chagas` DiseaseTransmission
> 80%
16%
2%
< 1%
�Vector-borne transmission
�Blood transfusion
�Congenital
�Other mechanisms: (i.e. oral, organ transplant, laboratory accident)
AB+blood
ANIS RASSI HOSPITAL
TRANSMISSION MECHANISMS OF HUMAN CHAGAS DISEASE and AVAILABLE PREVENTION TOOLS
TRANSMISSION MECHANISMS OF HUMAN CHAGAS DISEASE and AVAILABLE PREVENTION TOOLS
I : PRINCIPAL MECHANISMS
• Vector Transmission: insecticide, house improvement , education
• Blood Transfusion: donor selection, chemoprophilaxi s
• Congenital: early detection & treatment
II: OTHER MECHANISMS:
• Laboratory Accident: education, protection, chemopr ophilaxis
• Organ Transplantation: pre-selection, chemoprophila xis
• Oral Route: education, protection
No vaccine availableDIAS JCP
ANIS RASSI HOSPITAL
R. prolixus
T. dimidiata
T. infestans
T. sordida
T. brasiliensis
P. megistus
R. prolixusR. prolixus
T. dimidiataT. dimidiata
P. megistusP. megistus
Geographical distribution of the triatomine vector species of major epidemiological importance in Chagas´ diseaseGeographical distribution of the triatomine vector species of major epidemiological importance in Chagas´ disease
•Most important vector
•Strictly domiciliated
•Higher infection rate
with T. cruzi
T. infestansT. infestans
V
E
C
T
O
R
T
R
A
N
S
M
I
S
S
I
O
N
V
E
C
T
O
R
T
R
A
N
S
M
I
S
S
I
O
N
ANIS RASSI HOSPITAL
•Spraying with insecticides
•Housing improvements
•Health education
Elimination of T.infestans
ANIS RASSI HOSPITAL
INSECTICIDESYEARYEAR INSECTICIDESINSECTICIDES COMMENTSCOMMENTS
1975
1980
1950
MALATHION &FENTHION(Organophosphates)
DELTAMETHRIN(Pyrethroid)
HCH (BHC) &DIELDRIN(Organochlorines)
Strong and unpleasent smell;
not accepted by the
population
Residual effect of 12 months; applied just once; no smell; donot mark the house walls; lowanimal and human toxicity
Residual effect of short duration
(1 to 6 months); two sucessive
applications are needed
Ideal insecticide: low cost, easy manipulation, rapid onset of action, residual effect, no induction of resistance, and nontoxicIdeal insecticide: low cost, easy manipulation, rapid onset of action, residual effect, no induction of resistance, and nontoxic
ANIS RASSI HOSPITAL
Active Control Program to EliminateVector-Borne Transmission
Active Control Program to EliminateVector-Borne Transmission
a) Preparatory phase- mapping: number of species present, their dispersi on and infestation rates
- programming activities- estimation of resources
b) Attack phase- massive insecticide spraying of houses- second spraying 6 to 12 months later- selective re-spraying of re-infested homes
c) Surveillance phase- detection of residual foci of triatomines (involve ment of the community) – decentralized operations
MAP, SPRAY and PLACE UNDER COMMUNITY - BASED VIGILANCEMAP, SPRAY and PLACE UNDER COMMUNITY - BASED VIGILANCE
Moncayo A. Mem Inst Oswaldo Cruz 2003;98:577-591
ANIS RASSI HOSPITAL
Achievements in Eliminating T. infestans in Brazila) Regional Initiative: State of São Paulo (1965-198 9)
- executed by SUCEN- large scale spraying with BHC- complete eradication of the main vector, T. infest ans (first region in Latin America)
b) Brazilian National Campaign (1983-1986)- planned and executed by staff of SUCAM- spraying initially with BHC; progressively replace d with pyrethroids
- partially successfully: 75% of the geographic obje ctives had been attained (assigned to a secondary place in 1986 with the return of Aedes aegypti and risk of dengue)
c) The Southern Cone Initiative (1991-2000)- joint agreement between the governments of six countries (Argentina, Bolivia, Brazil, Chile, Paragu ay, and Uruguay) to eliminate T. infestans from its entire geographic distribution
ANIS RASSI HOSPITAL
No. of Municipalities Positive for Triatoma infestans in BrazilFollowing House Spraying Campaigns
No. of Municipalities Positive for Triatoma infestans in BrazilFollowing House Spraying Campaigns
XIIIa. Reunión Intergubernamental INCOSUR/Chagas, B s.As., Argentina, Marzo de 2004OPS/DPC/CD/308/04
ANIS RASSI HOSPITAL
Infestedareas byT. infestans ,Brazil, 1975/2000
Infestedareas byT. infestans ,Brazil, 1975/2000
363
53109
721
No. of positive municipalities
ANIS RASSI HOSPITAL
100
10
1
0.1
1985 1990 1995 20001980
Inci
denc
e ra
te (
%)
Year
UruguayBrazil ChileArgentinaParaguay
SOUTHERN CONE INITIATIVE(House Infestations by Triatomines)
SOUTHERN CONE INITIATIVE(House Infestations by Triatomines)
4.8%4.8%
26.0%26.0%
Source: National Chagas` disease control programmes
ANIS RASSI HOSPITAL
Serological Survey 100
10
1
0.1
0.011985 1990 1995 20001980
Inci
denc
e ra
te (
%)
Year
Uruguay (< 12 years)Brazil (7-14 years)Chile (< 10 years)Argentina (18 years)Paraguay (18 years)
SOUTHERN CONE INITIATIVE(Incidence of Infection)
SOUTHERN CONE INITIATIVE(Incidence of Infection)
0.2%0.2%
18.5%18.5%
Source: National Chagas` disease control programmes
ANIS RASSI HOSPITAL
Transfusion -transmitted Chagas`diseaseTransfusion -transmitted Chagas`disease•Second main route of T. cruzi infection•Potential problem in non-endemic countries
INFECTIVITY RISK (for a 500-ml transfusion unit): 1 2% to 49%INFECTIVITY RISK (for a 500-ml transfusion unit): 1 2% to 49%
Risk depends on:
1) Prevalence of the infection in blood donors
2) Type and number of T. cruzi infected blood products transfused
3) Parasite concentration in the infected unit trans fused
4) Virulence of the parasite strain
5) Immunological status of the transfused recipient
Risk depends on:
1) Prevalence of the infection in blood donors
2) Type and number of T. cruzi infected blood products transfused
3) Parasite concentration in the infected unit trans fused
4) Virulence of the parasite strain
5) Immunological status of the transfused recipientMoraes-Souza H, Bordin JO, Langhi Jr. D. Control of blood transfusion transmission of American Trypano somiases. In:Maudlin I, Holmes PH, Miles MA (eds). The Trypanosomiases. CABI Publishing - UK, 2004, pp 479-490
ANIS RASSI HOSPITAL
Reduction in the Prevalence of InfectedBlood Donors in Brazil (1949 -1999)1,2
7,33
2,182,8
0
1
2
3
4
5
6
7
8
1949-1979 1980-1989 1999
T. cruziinfection rate
amongblood recipients
(x 100)
2. Moncayo A. Mem Inst Oswaldo Cruz 2003; 98:577-591
1. Moraes-Souza H, Bordin JO, Langhi Jr. D. Control of blood transfusion transmission of American Tryp anosomiases. In:Maudlin I, Holmes PH, Miles MA (eds). The Trypanosomiases. CABI Publishing - UK, 2004, pp 479-490
ANIS RASSI HOSPITAL
Downward Trend in Chagas` Disease Seroprevalence
Reasons…
1) Progressive reduction in the number of infected p eople entering the age for blood donation (successful con trol of vector-borne transmission)
2) Mandatory screening of blood donors for Chagas´ di sease in Brazil and discard of blood units reactive to serolo gic assays
3) Increase in the proportion of altruistic donation s and decrease in the proportion of paid/replacement donors
4) Implementation and implantation of hemo-therapy s ervices
5) Use of autologous blood transfusion
ANIS RASSI HOSPITAL
Preventing T. cruzi TransmissionThrough Blood Tranfusion
1) Donor education
2) Identification of high-risk infectious blood dono rs by their history
3) Mandatory serology screening using at least two s erological tests
4) Elimination of all units of blood potentially inf ected, even those with nondiagnostic titers
5) Promotion of altruistic donations
6) Implementation of programs of quality control for serology
7) Treatment of the collected blood with gentian vio let in areas of high endemicity when serological tests cannot be pe rformed or when blood with positive serology cannot be disc arded
ANIS RASSI HOSPITAL
Oral Transmission of Chagas`DiseaseOral Transmission of Chagas`DiseaseIn the past: considered speculative
More recently: supported by 4 outbreaks of acute Ch agas` disease in Brazil, unequivocally related to the inge stion of contaminated food with T. cruzi . Associated with an unusual high number of fatal cases
RS (Teutônia)
PB (Catolé da Rocha)
AP (Igarapé da Fortaleza)
SC (roadside kiosk) Sugar cane juice
17
26
27
46
Regular meals and vegetables
Sugar cane juice and other foodstuff
Assai palm fruit juice
Local members of the community and tourists
Members of a farming community
Members of a wedding anniversary part
Local members of the community
6
2
???
6
1965
1986
2005
2005
Contaminatedfood
Year Locality No.deaths
Affected people No. acutecases
✓
✓
CONTAMINATION: 1) Feces of triatomines; 2) Marsupia l secretion;3) Crushed triatomine vector insects
ANIS RASSI HOSPITAL
Congenital Infection with T. cruziStrategies for Diagnosis and Control
Transmission rate: 1% to 12% (depends on the charac teristics from the infecting parasites, and the immunological , genetical and nutritional status of the mother)
Control: Etiological treatment of the newborn child (the sooner the best)
Diagnosis:
a) Mother: serological testing if positive history. Ideal: universal maternal serological testing
b) Children of mothers with positive Chagas serology :- At birth: parasitological tests (direct or indirec t)- After birth: conventional serological testing betw een 9 and 12 months of age
ANIS RASSI HOSPITAL
Southern Cone Initiative for Chagas Control (INCOSUR)
Southern Cone Initiative for Chagas Control (INCOSUR)
Created and approved in 1991,during the 3 rd Meeting ofMinistries of Health of theSouthern Cone, Brasilia,Resolution 04-3-CS.
Objectives1. Elimination of T.
infestans.2. Reduction of the
domestic infestation by other vectors.
3. Elimination of transmission by blood transfusion.
Interruption of T. cruzi transmissionin following countries:• 1997: Uruguay
Vectorial, transfusional• 1999: Chile
Vectorial• 2000: Brazil
Vectorial, 10 of 12 endemic states• 2001: Argentina
Vectorial, 12 of 19 provinces• 2002: Paraguay
Department of Amabay, working on rest of endemic area• 2002: Bolivia
Start of activities, IDB/PAHO/UNDP support
ANIS RASSI HOSPITAL
Chagas` DiseaseChagas` DiseaseSecondary PreventionSecondary Prevention
Interventions designed to reduce the chance of developing clinical illness (i.e. to prevent or inhibit disease in cases where infection has occurred)
✓
ANIS RASSI HOSPITAL
Chronic Chagas Heart DiseasePathologic Findings
Presence of T. cruzi antigens (arrows)Moderate myocarditis - no T. cruzi
Immunoperoxidase techniqueHematoxylin-eosin stain x 200
Bellotti et al . In vivo detection of Trypanosoma cruzi antigens in hearts of patients with chronic Chagas’ heart disease. Am Heart J 1996;131:301
ANIS RASSI HOSPITAL
BENZNIDAZOLE- More effective than Nifurtimox in Brazil. Similar efficacy in Argentina
- Dermopathy*- Peripheral sensitive polyneuropathy*- Dose of 10 mg/kg daily x 60 days: excellent tolerance and efficacy in children
NIFURTIMOX- commercialization discontinued- 2nd option (therapeutic failure or intolerance to Benznidazole)
✓
✓
*more frequent during treatment of patients in the c hronic phase
Etiological Treatment
ANIS RASSI HOSPITAL
Chagas` Disease
Indications for Etiological Treatment
ANTIPARASITIC DRUGS:- Nifurtimox- Benznidazole Acute Chagas Disease
Recently acquired infection (children)
Reactivation of the infection following treatment by immunosuppresive drugs
Organ transplantation procedures
Indeterminate form and mild chronic cardiac form (investigational)
✓
✓
✓
✓
✓
ANIS RASSI HOSPITAL
Trypanocidal Drugs for Chronic AsymptomaticT. Cruzi Infection
Meta-analysis of 5 randomized studies (n=756)
0,41 (0,09-1,85)
10,91 (6,07-19,58)*
5,37 (3,34-8,64)*
0,54 (0,31-0,84)*
OR (IC 95%)Outcome
ECG abnormalities
Negative seroconversion
Negative xenodiagnosis
Reduction of antibody titers
2/99
61/102
40/42
-
Placebo
5/99
6/98
21/43
-
Active
*p<0,01
Expressive results, particularly with the nitroimid azole derivatives (BZD & NFTMX)
Villar JC et al. The Cochrane Library, Issue 2, 200 3. OxfordVillar JC et al. The Cochrane Library, Issue 2, 200 3. Oxford
ANIS RASSI HOSPITAL
ETIOLOGICAL TREATMENT OF CHAGAS DISEASEWITH BENZNIDAZOLE IN THE CHRONIC PHASE
Adults (n=171)*
Adults (n=33)
Ad. & Ch (n=120)
Adults (n=201)
Adults (n=120)
Children (n=129)
8.8%
0.0%
63.6%
30.0%
14.3%
6.9%
Macedo et al, 1987
Ianni et al, 1993
Miranda et al, 1994
Viotti et al, 1994
Fragata F o et al, 1995
Andrade et al, 1996
7
8
10-16
8
7-8
3
6.7%
13.3%
10.5%
4.2%
7.0%
1.7%
Control/Placebo
Development of Cardiopathy (ECG)
Authors DrugFollow up
(years)Population
* Includes cases treated with Nifurtimox
Long term follow up and evolution to cardiopathy
Rassi A. Arq Bras Cardiol 1998;71:643-6.
ANIS RASSI HOSPITAL
ETIOLOGICAL TREATMENT OF CHAGAS DISEASE
0
10
20
30
40
50
60
70
80
Recent ChronicPhase
Acute Phase
60%70%
%CURE
CURE*
Negativation of xenodiagnosisNegativation of serological testsChange in the natural course of the disease
*
Rassi A. Unpublished data
ANIS RASSI HOSPITAL
Chagas` DiseaseChagas` DiseaseTertiary PreventionTertiary Prevention
Interventions designed to limit human incapacity and to prevent morbidity and mortality, once disease has occurred
✓
ANIS RASSI HOSPITAL
Chagas’ Heart DiseaseClinical Syndromes
• Arrhythmias- Tachyarrhythmias- Bradyarrhythmias
• Congestive Heart Failure- Biventricular (right > left)
• Thromboembolism- Systemic- Pulmonary
DEATHDEATH
ANIS RASSI HOSPITAL
ACE inhibitors
DiureticsDigitalis
K repletion/K sparing diureticsNitratesHigh doses of loop diuretics; combination of diuretics/IV; B-adrenergic agonistsBeta-blocking agents (low dose)
AmiodaroneOral anticoagulation
Aspirin
Heparin and/or thrombolitic agentsSpironolactone
Asymptomatic LV dysfunction; symptomatic heart failureVolume overloadCardiomegaly; S3 gallop; Low EF; AF with rapid ventricular responseDiuretic-induced hypokalemiaPersistent congestive symptomsResistant CHF
Refractory CHF with persistent sinus tachycardia
Complex ventricular arrhythmiasDocumented intracavitary thrombus; previous thromboembolic phenomena; chronic AFApical aneurysm; severe ventricular dysfunctionAcute thromboembolic phenomenaSymptomatic heart failure (NYHA class III/IV)
++
CHRONIC CHAGASIC CARDIOMYOPATHY - DRUG THERAPY
ANIS RASSI HOSPITAL
Cardiac transplantation
Intra-Aortic ballon pump
LV aneurysmectomy
Cardiac pacemaker
Catheter or surgical ablation
Automatic implantable defibrillator
Biventricular pacing
Catheter embolectomy
Refractory CHF, age < 55, NYHA class IV, PVR < 4 Wood units
To support patients until cardiac transplantation
Refractory CHF; multiple thromboembolic phenomena; refractory VT originating in regions adjacent to the aneurysm
Symptomatic SSS; 2nd degree AV block (MII); high grade AV block; 3rd degree AV block; AF with slow ventricular response
Drug refractory, hemodynamically stable and inducible VT
Refractory VF; drug refractory VT, not inducible or inducible but hemodynamically poor tolerated
CHF class II/III and ventricular desynchronism
Peripheral emboli
CHRONIC CHAGASIC CARDIOMYOPATHY - NONDRUG THERAPY
ANIS RASSI HOSPITAL
BENEFIT
BENEFIT
Antiparasitic clinical trialDrug: benznidazole
Population: Chagas’ heart disease
• International• Multicentre• Prospective• Randomized• Double -blind• Placebo -controlled
“ BENznidazole Evaluation For Interrupting Trypanosomiasis”
ANIS RASSI HOSPITAL
Coordination Steering Committee(Blinded)
Independent Data Safety Monitoring Board (DSMB)
50-70 clinical centers in 6 countries
BENEFIT: Study OrganizationBENEFIT: Study Organization
POPULATION HEALTHRESEARCH INSTITUTE
McMaster UniversityHamilton, Canada
National Coordinators(Blinded)
Co-Principal InvestigatorsJA Marin Neto (Brazil)
Carlos Morillo (Canada)
MembersÁlvaro Avezum Jr.
Stuart ConnolyRaul Espinosa
Fernando RosasSosa-Estani
Carlos MorilloAnis Rassi Jr.
Juan Carlos VillarAlberto Gianella
Alberto Laguna Torres
Anis Rassi Jr. (Brazil)
Sosa-Estani (Argentina)
Raul Espinosa (Venezuela)
Fernando Rosas (Colombia)
Alberto Gianella (Bolívia)
Victor Alberto LagunaTorres (Peru)
Co-ChairsSalim Yusuf
JA Marin Neto
PHRI
ANIS RASSI HOSPITAL
BENEFITTrial
1,500 patientsPLACEBO
3,000 patientschronic Chagas`heart disease
1,500 patientsBENZNIDAZOLE
RExclude severe disease
PRIMARY ENDPOINTcombination of death, cardiac arrest resuscitation, sustained ventricular tachyarrhythmias, need for
pacemaker or defibrillator implant, thromboembolic phenomena or hospitalization for CHF
mean follow up: 5 years
ANIS RASSI HOSPITAL
2 31
Inflammatorycells in
apoptosis
Cardiomyocyte Damagedcardiomyocyte
T. cruziamastigotes
Inflammatorycells
Bonemarrow
cells
Fibrosis
ANIS RASSI HOSPITAL
Heart of chronic chagasic mice transplanted with transgenic GFP - BMC (15 days)
Anti GFP + Anti Miosin
GFP- BMC Ribeiro-dos-Santos e cols (unpublished data).
ANIS RASSI HOSPITAL
Protocol• Prospective, single-center, open label, non-randomized, phase 1 clinical trial
• Feasibility, safety and potential efficacy
• 30 patients with advanced HF due to Chagas’ disease
• 180 days follow-up
Inclusion criteria:- Previous diagnosis of heart failure due to Chagas’ disease.- Stable (> 1 month) NYHA FC III and IV- Standard HF therapy- LVEF < 40% on echocardiogram (Simpson’s rule)- Both genders- Ages between 18 and 70 years.
Bone marrow cell transplantation in Chagas’ disease HF
Vilas Boas F
ANIS RASSI HOSPITAL
p = 0.057
Left ventricular ejection fraction on Echo (Simpson)
Left
vent
ricul
ar e
ject
ion
frac
tion
(%)
TimeN = 10Friedman testBars represent mean ± 1 SE
Bone marrow cell transplantation in Chagas’ disease HF
Time (months)4210 6
Vilas Boas F
ANIS RASSI HOSPITAL
Randomized Multicenter Study of Stem Cell Therapy i n Chagas` Heart Disease(EMRTCC)
•300 patients with CHF (age 18-75 years)•NYHA class III or IV; LVEF < 35%•No ICD; no Sust. VT; creatinine < 2,5 mg/dL•Optimized drug therapy
150 patientsSTEM CELL THERAPY
150 patientsPLACEBO (Saline)
Primary end point: - increase in LVEF (> 5% on avera ge)
Secondary end points: - total mortality- hospitalization- functional class- quality of life
randomization
Follow-up12 mo
sponsorsponsor
ANIS RASSI HOSPITAL
• To maintain political will and a governmental agenda in endemic countries;• To maintain the minimum technical personnel for control activities and
programme administration;
• To improve (or to start) control actions in some Countries and in new areas: agricultural frontiers, Amazon, urban spaces;
• To improve and to maintain a sustainable surveillance in yet controlled areas;
• To improve vector control techniques and tools for the peri-domestic cycle;• To develop new and more effective drugs for specific treatment;• To provide medical attention for infected individuals in all endemic area,
mainly in early stages of chronic disease; • To develop better drugs and procedures concerning heart failure and
fibrosis management
THE FUTURE: CHALLENGES AND PRIORITIES FORCHAGAS`DISEASE CONTROL AND RESEARCH
DIAS JCP
ANIS RASSI HOSPITAL
SCD
Thromboembolism
CHF
- ACEI, espironolactone- Amiodarone, PACE, ICD- Oral anticoagulant- Etiological treatment??- Bone marrow transplant??
AB+blood
CHAGASAcute
Chronicindeterminate
- Elimination of vectorial transmission- Prophylaxis of transfusionaltransmission
CHAGASChronic
Determinate
- Etiological treatment(BZD)