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Epidemiolog a de las Infecciones asociadas a Shigatoxinas

E.coli Enterohemorrgica (EHEC) Caracterizacin. Se les ha dado el nombre de EHEC por su capacidad de producir brotes de colitis hemorrgicaComo producen una potente citotoxina, Shigatoxina, tambin se las ha llamado STECEstas bacterias se diseminan por va fecal-oralEs muy bajo el nmero de o

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Epidemiolog a de las Infecciones asociadas a Shigatoxinas

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    1. Epidemiologa de las Infecciones asociadas a Shigatoxinas Dr. Eduardo L. Lpez Hospital de Nios Dr. Ricardo Gutirrez Universidad Del Salvador

    2. E.coli Enterohemorrgica (EHEC) Caracterizacin Se les ha dado el nombre de EHEC por su capacidad de producir brotes de colitis hemorrgica Como producen una potente citotoxina, Shigatoxina, tambin se las ha llamado STEC Estas bacterias se diseminan por va fecal-oral Es muy bajo el nmero de organismos necesarios para producir infeccin (102 - 202)

    3. EHEC Patogenia y Factores de Virulencia Shigatoxinas (Stxs) Factor de adherencia intestinal: intimina, protena de membrana externa Enterohemolysina Plsmido de O157? Otros factores de virulencia potenciales: LPS, transporte de Fe++

    4. Shiga Toxins (Stxs): Major Characteristics Stxs: Are the major virulence factor and a defining property of EHEC. They are a family of shigatoxins, being the most common members Stx1 and Stx2

    5. Comparison of Stx1 and Stx2

    6. Infecciones por STEC en humanos Espectro Clnico Portadores asintomticos Diarrea acuosa Diarrea con sangre colitis hemorrgica Clicos abdominales (50-70%); prolapso rectal (10%); vmitos (30-50%) Complicaciones Invaginacin intestinal Apendicitis Formas Incompletas SUH SUH

    7. Clinical Illness in STEC Infection Incubation period: 2-4 days (inoculum: 102-202 organisms) First manifestations are usually non-bloody diarrhea, abdominal cramps. At the 2nd/3rd day of illness bloody diarrhea develops with low fever. Cramps are an important findings in infants and children If no complication develops, the disease usually resolves within a week

    8. Epidemiologic Patterns in HUS Three epidemiologic patterns have been described: Outbreaks and clusters cases: mainly associated with water and food-borne infection with diarrhea, ie: USA, U. Kingdom, Japan,etc Endemic cases: with an increase of number of cases during spring and summer seasons, ie: Buenos Aires (Argentina), Alberta (Canada), Baviera (Germany) Sporadic cases: are observed throughout the world

    9. Incidence of Hemolytic Uremic Syndrome in Different Areas of the World

    10. Etiological agents in patients with Diarrhea in Buenos Aires

    11. Caractersticas y Objetivos del Estudio Estudio Prospectivo Estacional de Nios con Diarrea, seguidos los das 0,2,3, 5 y 10 das. Objetivo Para establecer incidencia de diarrea por E.coli productores de Shigatoxinas y factores de riesgo de desarrollar SUH.

    12. STEC Infections in Argentina Site: Hospital de Nios Ricardo Gutirrez Buenos Aires Screened Patients: N= 1692 Screening Methods: Premier O157/Immunocard STAT Premier EHEC PCR (stx1 and stx2)

    13. Riesgo de SUH en pacientes con Diarrea Poblacin en Estudio* Perodo de Estudio: 1/98 - 12/00 Pacientes estudiados N=1338 Diarrea con sangre N= 819 (61.2%) Diarrea acuosa N= 519 (38.8%)

    14. Synsorb Study - Site Buenos Aires Patients Enrollment

    15. Riesgo de SUH en pacientes con Diarrea Poblacin en Estudio

    16. Diarrea asociada a STEC Poblacin en Estudio

    17. STEC Associated Diarrhea O157 vs. NON-O157 Infections

    18. STEC Infections Rate of O157 strains Site: Hospital de Nios R. Gutirrez

    19. STEC Infections in Argentina Age Distribution

    20. Diarrea Sanguinolenta y Riesgo de SUH Diarrea con sangre: N=819 STEC-Diarrea con sangre: N= 199 SUH si no si 19 180 D.S. no 1 619 p<0.0000001 X2= 51.84

    21. Risk of HUS in STEC-Diarrhea N of patients: 668*

    22. Risk of HUS in Bloody Diarrhea N of patients: 1318+

    23. Tipo de Shigatoxinas aisladas en Pacientes con SUH (I) Stx(+): 149 (62.1%) N= 240 Stx (-): 91 (37.9%)

    24. Tipo de Shigatoxinas aisladas en pacientes con SUH (II)*

    25. Type of Toxin in Patients with HUS Center: Hospital de Nios R. Gutirrez

    26. Riesgo de SUH en pacientes con Diarrea con Sangre segn Tipo de Toxina

    28. Value of Rapid Methods to Detect Shigatoxin-producing E.coli (STEC) Infections in Children with Diarrhea and HUS in Buenos Aires From Jan, 1998 to Dec, 2000, 1338 stool samples from patients less than 5 days of diarrhea, were studied for diagnosis of STEC infections. During the same period 105 HUS patients also were studied. All samples were tested by: SMAC Culture Premier E.coli O157 or Immunocard STAT O157 Premier EHEC PCR for stx genes (swab from MacConkey sorbitol plates culture or E.coli isolates)

    29. Sensitivity and specificity of SMAC Culture vs. Premier O157/Immunocard STAT O157 in Patients with Diarrhea and HUS No. of cases: 1443 SMAC Culture (+) (-) (+) 63 14 Premier O157 ImmunocardSTAT (-) 2 1364 OR: 30.69 Chi square:1130.3 p< 0.0001 Sensitivity: 96.9% Specificity: 98.9% Predictive Positive Value: 81.8% Predictive Negative Value: 99.8%

    30. Sensitivity and specificity of Premier O157/ Immunocard STAT O157 vs. PCR in HUS patients No. of cases: 105 Premier O157/Immunocard STAT O157 (+) (-) (+) 13 21 PCR (-) 1 62 OR: 38.38 Chi square: 24.02 p< 0.0001 Sensitivity: 92.8% Specificity: 74.6% Predictive Positive Value: 38.2% Predictive Negative Value: 98.4%

    31. Sensitivity and specificity of Premier EHEC vs. PCR in E.coli O157 Diarrhea Children No. of cases: 69/1338 Premier EHEC (+) (-) (+) 56 3 PCR (-) 2 8 OR:74.67 Chi square: 35.81 p<0.0001 Sensitivity: 97% Specificity: 73% Predictive Positive Value: 95% Predictive Negative Value: 80%

    32. Sensitivity and specificity of Premier EHEC vs. PCR in E.coli NON-O157 Diarrhea Children No. of cases: 1269 Premier EHEC (+) (-) (+) 95 24 PCR (-) 46 1104 OR: 95 Chi square: 627.89 p<0.0001 Sensitivity: 73% Specificity: 98% Predictive Positive Value: 80% Predictive Negative Value: 96%

    33. Factores de Riesgo Hematolgicos en Anlisis de Rutina

    34. White Blood Cell Count as Risk to Develop HUS/Incomplete HUS in BD-Stx(+)

    35. Valores de Plaquetas en pacientes con Formas Incompletas de SUH*

    36. Risk Factors to develop HUS Age: < 5 years Bloody Diarrhea Bloody Diarrhea Stx(+) Shigatoxin Type II (Stx-II) White Blood Cells Count >15.000/mm3

    38. Anlisis Preliminar del Estudio Fase III de SYNSORB PK TIPO DE ESTUDIO: ESTUDIO FASE III, MULTICENTRICO, RANDOMIZADO DOBLE CIEGO VERSUS PLACEBO OBJETIVO DEL ESTUDIO: DETERMINAR LA EFICACIA DE SYNSORB EN LA PREVENCION DE SUH PUNTO PRIMARIO DE EVALUACION: DESARROLLO DE SUH

    39. POBLACION ESTUDIADA: 526 nios PACIENTES ESTUDIADOS EN ARGENTINA: 306 nios (58.2%)

    40. RESULTADOS PRELIMINARES DEL ESTUDIO SYNSORB PK VS. PLACEBO RESULTADOS EN EL TOTAL DE PACIENTES ENROLADOS: En los 526 nios con diarrea STEC (+) tratados dentro de los cinco das de comienzo de la diarrea, no hubo diferencias significativas entre el grupo que recibi SYNSORB PK vs. PLACEBO. Solo se observ una tendencia limitada de mayor eficacia en el grupo SYNSORB PK.

    41. RESULTADOS PRELIMINARES DEL ESTUDIO SYNSORB PK VS. PLACEBO PACIENTES INCORPORADOS DENTRO DE LAS 48 HORAS DE APARICION DE LA DIARREA

    42. Resultados Preliminares del Estudio Fase III de SYNSORB PK VS. PLACEBO

    43. Diarrea asociada a STEC Opciones Teraputicas Anlogos del Receptor para Shigatoxinas (Gb3)? (Synsorb-Pk), Starfish. Solamente? Asociado con antibiticos? Antibiticos solamente? Anticuerpos Monoclonales Humanizados? Vacunas?

    50. Caracterizacin Genes de Shigatoxina circulante en Buenos Aires Estudio realizado en cepas de STEC aisladas de pacientes con Diarrea con Sangre y en pacientes con SUH Caracterstica de las cepas: PCR-Stx (+) Mtodo de Estudio: PCR y anlisis RFLP (enzimas de restriccin)

    51. Tipos de Toxina Muestras de Materia Fecal PCR (+)

    52. Caracterizacin de genes para Shigatoxina*

    53. Variantes de Genes de Stx-2 segn cuadro clnico

    54. Variantes de genes para Stx-2 en cepas de E.coli O157 vs. No- O157 Pacientes con Diarrea con Sangre

    55. Conclusiones El genotipo Stx-2 + STx-2a fue prevalente en pacientes con Diarrea con Sangre (63.1% y en pacientes con SUH (69.3%) El genotipo Stx-2 + Stx-2b y Stx-2b no se encontraron en pacientes con SUH El genotipo STx-2 + Stx-2a fue ms frecuentemente encontrado en cepas de E.coli O157 que en cepas No-O157 (p<0.0000001)

    56. Estos datos preliminares sugieren que el uso de Anticuerpos Monoclonales como teraputica potencial, deberan neutralizar los genotipos stx-2 y/o stx2 + stx-2a en Argentina

    58. Infecciones por STEC Estudio prospectivo en nios de 6 meses a 14 aos Perodo de estudio: Enero 1998 - Abril 2000 (septiembre-abril) Pacientes en Screening: n=1654 Tipo de diarrea: Con sangre 61.8% Acuosa 38.2%

    59. Risk of HUS/Incomplete HUS in STEC-Diarrhea HUS/Incomplete HUS Yes No BD-Stx(+) 25 306 WD-Stx(+) 1 131

    60. Risk of HUS/Incomplete HUS in Bloody Diarrhea HUS/Incomplete HUS Yes No Stx(+) 25 306 Bloody Diarrhea Stx(-) 9 624

    61. Mtodos de Estudio Mtodos de Screening SMAC agar Premier O157 (Meridian Diagnostic, Co.) Immunocard Stat O157 Plus (Meridian Diagnostic, Co) Premier EHEC (Meridian Diagnostic, Co) Latex Test Agglutination E.coli O157 (Oxoid) Tests Confirmatorios PCR (para genes stxs-I y II, eaeA y hlyA )

    62. Study Population Patients were studied during spring and summer season

    63. STEC Infections: Outbreaks and Endemic Disease

    64. Type of Toxin in Patients with BD (Synsorb Study) Center: Hospital de Nios R. Gutirrez

    65. Riesgo de SUH Segn Tipo de Toxina

    66. Premier E.coli O157/Immunocard STAT O157: directly from raw stool. The test is a rapid invitro microwell procedure for the qualitative determiantions of Escherichia coli O157 antigen in feces. It was used as a screening tool to allow rapid presumptive determination follows SMAC culture plates. SMAC Culture: for identification of non-sorbitol fermenter colonies, and E.coli strains isolation (sorbitol fermenters and non-fermenters). Premier EHEC: it was used as a rapid in vitro microwell EIA for detection of stx-1 and stx-2 in stool specimens and MacConkey broth culture. PCR assay: it was performed on DNA obtained from swab of SMAC culture plates and/or 10-20 E.coli isolated strains. Multiplex PCR using Strockbines primers were used to detect stx-1 and stx-2 genes. After amplification, a 894 bp and 478 bp fragment for Stx-1 and 2 were observed, respectively.

    67. Conclusions STEC infections are more frequent in Bloddy Diarrhea than Watery Diarrhea (p<0.0001) Non-O157 STEC infections are more common than O157 infections in Argentina (p=0.003) Premier EHEC sensitivity and specificity was 97% and 73% in O157 infections in children with diarrhea and 92.3% and 98.8% in HUS with O157 infections Premier EHEC sensitivity and specificity was 73% and 98% in Non-O157 infections in diarrhea patients and 65% and 84.5% in HUS patients with Non-O157 intfections, respectively There is a high correlation between SMAC Culture (confirmed by Oxoid Latex Agglutination test for E.coli O157) vs. Premier O157 / Immunocard STAT O157, in children with Diarrhea and HUS patients

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