carlos chagas sergio sosa-estani, md, phd. cendie, iecs, conicet, buenos aires, argentina...
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Carlos Chagas
Sergio Sosa-Estani, MD, PhD. CeNDIE, IECS, CONICET, Buenos Aires, Argentina
International Symposium on the Centenary of Chagas disease Discovery
Therapy, diagnosis and prognosis of chronic Chagas disease: insight gained in Argentina
9,000 y BC
1909 discover
1920-2009 Dx
1960-1970 Tr
Salvador Mazza
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Diagnosis of infectionSerological tests
• Complement fixation (Muniz & Freitas 1944)
• Indirect immunofluorescence assay (Alvarez et al. 1968)
• Indirect hemagglutination assay (Cerisola et al. 1962)
• Enzyme immune assay (Voller 1975)
QUALITY CONTROL PROGRAM
Transfusion 2009
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Appropriate Technology for taking blood samples for screening T. cruzi infection.
• Filter paper 1966-1983
• Capillary blood w/glycerin (Serokit®) 1985
• Immunocromatography (x ej. Stat-Pak®) 2003
Foto: MSF Honduras
Foto: MS Honduras
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Markers associated with Progression
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Prescription of Specific Treatment against T. cruzi Infection
• All patients undergoing the acute phase
• Children and young patients undergoing the chronic phase
• Laboratory or surgical accident
• Organ transplant recipients or donors
• Chronic phase, indetermined or incipient cardiac form in adults may be
considered, although with limited evidence
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Clinical Studies (Observational) to assess treatment of T. cruzi Infection
T. cruzi-specific T lymphocytes secreting IFN-g in response
to T. cruzi lysate in patients with chronic Chagas disease treated and not treated
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Clinical Studies (RCT) to assess treatment of T. cruzi Infection
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I – Incidence of ECG abnormalities / BZD- children Source BZD n/N Plac n/N Weight % OR (95% CI)
Andrade 1/59 4/58 71 0.28 (0..05, 1.69)
Sosa-Estani 1/40 1/41 29 1.03 (0.06, 16.99)
Pooled 2/99 5/99 100 0.41 (0.09, 1.85)
Heterogeneity test X2 =0.58 p=0.45 / Overall effect test Z=-1.16 p=0.2 II- Negative seroconversion (AT ELISA – children – BZD) Source BZD N/N Plac n/N Weight % OR (95% CI)
Andrade 37/58 3/54 57.8 12.35 (5.72, 26.68)
Sosa-Estani 24/44 3/44 42.2 9.19 (3.73, 22.64)
Pooled 61/102 6/98 100 10.91 (6.07, 19.58)
Heterogeneity test X2 =0.24 p=0.63 / Overall effect test Z=8.0 p=0<0.001
III- Negative xenodiagnosis Source All TT n/N Plac n/N Weight % OR (95% CI)
Apt 314/336 146/165 48.9 1.93 (0.98, 3.81)
Coura 43/53 1/24 24.1 22.24 (8.45, 58.56)
Gianella 1/13 0/17 1.4 10.05 (0.19, 524.8)
Sosa-Estani 40/42 21/43 25.6 9.61 (3.76, 24.58)
Pooled 398/404 168/249 100 5.37 (3.34, 8.64)
Heterogeneity test X2 =18.54, p<0.001 / Overall effect test Z= 6.94 p<0 .001 0.01 0.1 1 10 100
Benznidazole Meta-analysisVillar JC, et al Cochrane Database Syst Rev. 2002;(1)
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Slow seronegativization without evidence of parasitimia after treatment:
a) related attribute of the host (humoral immune response against Tc I and Tc II)?;
b) related mixed mechanism to cure (1st drugs against Tc I and T cII ?; 2nd immune response as a complement to complete clearance)?
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Antibodies kinetic with long term of follow-up of children undergoing chronic T. cruzi infection, and treated with
benznidazole. Salta, Argentina, 1991-2005
Sosa-Estani S et al. 1998, AJTMH, and unpublished data
Not Cured
Cured
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Antibodies kinetic with long term of follow-up of children undergoing chronic T. cruzi infection treated with benznidazole,
and cured. Salta, Argentina, 1991-2005
Sosa-Estani S unpublished data
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Yun O et al. PLoS Negl Trop Dis. 2009 Jul 7;3(7):e488.
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How to assess a treatment during chronic phase?(Successful=do not find Ab; Failure= find parasite)
• Immunological tests– Serological tests - Commercially Available
• Need long follow up to demonstrate efficacy (Seronegativization)– Serological tests - Not commercially available, tested as useful
• Need shorter time of follow up, but > 3 years• Need validation
– Specific cellular immune response (?) (under research)
• Parasitological tests– Direct tests (low sensitivity, not practical)– Xenodiagnosis (Center of reference, only for research-isolates , low sensitivity)– Hemoculture (available but only in few centers, not practical, low sensitivity)– PCR (higher sensitivity, currently under standardization, new techniques for
quantitative PCR with rapid developments)
RT-PCR
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Some strategies to getting new treatments• New schemes / New prescriptions (i.e. BENEFIT Project. Efficacy of Bz
in Patients with cardiac disease)
• Pediatric formulation (i.e. dispersable tables and suspention-LAFEPE-DNDi, Solution-UNR)
• Registered drugs with anti-T. cruzi activity (i.e Posaconazole, Itraconazole (antimicotic), Bisphosphonates (osteoporosis) , Miltefosine (antineoplastic, antiprotozoal), Clomipramine (tricyclic antidepressant), Liposomal amphotericin (antifungical, antiprotozoal)
• Evaluation of Combination (i.e. Combination of registered compounds (Benznidazole/Nifurtimox) with drugs with demonstrated activity in Chagas’ disease)
• Evaluation of library of existing compounds (i.e. Furazolidone, Clemastine)
• Develop an specific new drug (i.e. inhibitors of trans-sialidase, cysteine proteinase, trypanothione reductase, others)
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Evaluation of Care Quality for Diagnosis and Treatment,Argentina, 2007
Variable Obs % Valuation
Appropriate confirmation of infection 178 98% Good
Treatments completed 130 97% Good
Records with completed data (essentials) 195 5% Bad
Records with data about dates of Treatment 195 36% Bad
Opportunity of tratment (<30 days) 43 52.3 Regular
Tolerance 123Good tolerance 99%
Regular tolerance 1%
Records with data about monitory 195 56% Regular
Rodriguez V, Rubinstein F, Sosa-Estani S, unpublished data
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Control of Congenital Transmission of Trypanosoma cruzi
Screening of Pregnant WomenScreening of Pregnant Women
Mother REACTIVEMother REACTIVE Mother Non-ReactiveDischarge
Mother Non-ReactiveDischarge
Parasitological Test in Newborn Negative
Parasitological Test in Newborn Negative
Parasitological Test in NewbornPOSITIVE
Treatment and Monitoring
Parasitological Test in NewbornPOSITIVE
Treatment and Monitoring
Serological Test >= 10 m oldNon-Reactive
Discharge
Serological Test >= 10 m oldNon-Reactive
Discharge
Serological Test >= 10 m oldREACTIVE
Treatment and Monitoring
Serological Test >= 10 m oldREACTIVE
Treatment and Monitoring
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Screening of Pregnant Women
Screening of Pregnant Women
Mother REACTIVEMother REACTIVE Mother Non-ReactiveDischarge
Mother Non-ReactiveDischarge
Parasitological Test in Newborn Negative
Parasitological Test in Newborn Negative
Parasitological Test in Newborn
POSITIVETreatment and Monitoring
Parasitological Test in Newborn
POSITIVETreatment and Monitoring
Serological Test >= 10 m old
Non-ReactiveDischarge
Serological Test >= 10 m old
Non-ReactiveDischarge
Serological Test >= 10 m oldREACTIVE
Treatment and Monitoring
Serological Test >= 10 m oldREACTIVE
Treatment and Monitoring
In the health system:-Low rate of detection by parasitological test.-Health workers do not know the procedures.- Health workers do not have adequate training.-Health workers do not have good working conditions.
Hypotheses of Lost Opportunities for the Adequate Diagnosis of Congenital Trypanosoma cruzi Infection
In the community:-Mothers do not know the procedure.- Mothers do not understand the instructions.-Mothers do not have financial resources to get to the health center.
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Early diagnosis of congenital Trypanosoma cruzi infection using PCR, hemoculture, and capillary concentration, as
compared with delayed serology. Mora MC, et al. J Parasitol. 2005;91(6):1468-73.
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Diagnosis of Congenital Trypanosoma cruzi Infection by ELISA SAPA (matched samples from mothers infected and their newborns [n=31]).
Index (Subtraction OD ELISA-SAPA Newborn; OD ELISA-SAPA Mother), Ushuaia, Tierra del Fuego,
Argentina.
Mallimaci C, Sosa-Estani S, Russomando G, et al, Submitted, 2009
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Detection of Specific T. cruzi Antibodies by Commercial ELISA and Shed Acute Phase Antigen
(SAPA) on Non- Infected Infants (n=36 ) under Follow-up.
Ushuaia, Tierra del Fuego, Argentina.
Mallimaci C, Sosa-Estani S, Russomando G, et al, Submitted, 2009
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Evaluation of technology – Implementation research• New tools must to be addressed to the PHC System• Main user National Programs, Public Health S• Wide range of beneficiaries
Photo: H Freilij. BsAs, ARG Photo: S Sosa-Estani, Las Lomitas, Formosa, ARG
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They are waiting for:•the researcher to research,
•the politician to decide, •and the health worker to act