Reacciones adversas de los diez fármacos más notificados. Matanzas 2014 al 2017 / Adverse reactions to the ten most reported drugs in Matanzas 2014-2017

RESUMEN Introducción: la toxicidad de los fármacos es compleja y difícilmente valorable, por la cantidad de factores que intervienen en su producción, como modo de aparición, duración y gravedad de las reacciones adversas. La importancia de estas reacciones está dada por la frecuencia y gravedad con que un fármaco o familia de fármacos las producen. Objetivo: caracterizar las principales reacciones adversas que provocan los medicamentos, los grupos de edades con más riesgos, los sistemas de órganos que se afectan, la frecuencia, imputabilidad y la intensidad de las mismas. Materiales y métodos: estudio observacional, descriptivo, de serie de casos en farmacovigilancia. El universo fue las reacciones adversas de los 10 fármacos más notificados por la Unidad Coordinadora Provincial de Farmacovigilancia en Matanzas, en el periodo 2014-2017. Se estudiaron las variables: medicamentos, grupo farmacológico, datos demográficos, nivel de atención, tipo de efecto adverso, intensidad, imputabilidad y frecuencia. Resultados: se notificaron 10 fármacos con 2 216 reacciones. La vacuna pentavalente fue la más notificada, con un 17,6 %, seguido por la amoxicilina y las penicilinas. Predominó el sexo femenino con 1 279 reportes, (59,1 %) y los adultos, con 1 010 notificaciones, (46,6 %). La atención primaria de salud fue la de mayor número de notificaciones, 2 082 reportes, (96,1 %). Las principales reacciones fueron: la erupción cutánea, la fiebre y la urticaria. Predominaron reacciones moderadas; 1 972 reportes, (91,1 %), aquellas clasificadas como probables, 1 887 reportes, (87,1 %) y las frecuentes con 1 284 reportes, (59,2 %). Conclusiones: el sistema de farmacovigilancia en la provincia proporcionó sistemáticamente información sobre la seguridad de los medicamentos, lo que permitió el conocimiento de la relación beneficio-riesgo de los medicamentos presentes en el mercado, así como los más usados.

ABSTRACT Introduction: drugs toxicity is complex and of difficult assessment, due to the quantity of factors intervening in its production, like emergency way, duration, and seriousness of the adverse reactions. The importance of these reactions is given by the frequency and seriousness a drug or a drug family produces them. Objective: to characterize the main adverse reactions caused by medicines, the age groups having higher risk, the most affec6ted systems of organs, frequency, imputability and intensity. Material and methods: descriptive, observational study of a series of cases in pharmacovigilance. The universe was the adverse reactions of the ten drugs most reported by the Provincial Coordinating Unit of Pharmacovigilance in the period 2014-2017. The studied variables were: drugs, pharmacological group, demographic data, health care level, kind of adverse effect, intensity, imputability and frequency. Results: ten drugs were reported with 2 216 reactions. The pentavalent vaccine was the most reported one, with 17.6 %, followed by amoxicillin and penicillin. There was a predominance of the female sex with 1 279 reports (59.1 %), and adult people with 1 010 reports (46.6 %). The highest number of reports was made by the primary health care, 2 082 (96.1 %). The main reactions were skin rash, fever and urticaria. There was a predominance of mild reactions: 1 972 reports (91.1 %); reactions classified as probable: 1 887 reports (87.1 %): ands frequent ones: 1 284 reports (59.2 %). Conclusions: the pharmacovigilance system in the province systematically provided information on drugs´ safeness that allowed knowing the benefit-risk relation of the medicines that are in the market, and also which are the most used ones.

Encefalopatía por virus herpes 6 como complicación de exantema súbito / Encephalopathy due to human herpesvirus 6 infection as exanthema subitum complication

La principal manifestación clínica del herpesvirus 6 es el exantema súbito (también conocido como roséola o sexta enfermedad) y el síndrome febril. Las manifestaciones en el sistema nervioso central no son infrecuentes en la infección por herpesvirus 6, y su fisiopatología no está esclarecida, pero precisan diagnóstico y tratamiento temprano para evitar secuelas potencialmente graves. Se presenta el caso de una niña inmunocompetente de 2 años con cuadro de encefalitis como complicación de infección por herpesvirus 6. Se destaca la importancia del diagnóstico oportuno a fin de instaurar un adecuado tratamiento y seguimiento para evitar complicaciones secundarias a la afectación del sistema nervioso central.

The main clinical manifestation of human herpesvirus 6 is exanthema subitum (also known as roseola infantum) and febrile syndrome. Central nervous system manifestations are not unusual in herpesvirus 6 infection, and even though the pathophysiology is not clear, they need to be early diagnosed and treated in order to avoid potentially serious damage. We present the case of an immunocompetent 2-year-old girl with encephalitis as a complication of herpesvirus 6 infection. We want to emphasize the significance of an early diagnosis and treatment in order to prevent further complications due to the central nervous system extension.

Diagnosis of human herpesvirus 6B primary infection by polymerase chain reaction in young children with exanthematic disease / Diagnóstico de infecção primária pelo herpesvírus humano tipo 6B através da técnica de reação em cadeia da polimerase em crianças com doença exantemática

INTRODUCTION: Exanthem subitum is a classical rash disease of early childhood caused by human herpesvirus 6B (HHV-6B). However, the rash is frequently misdiagnosed as that of either measles or rubella. METHODS: In this study, a nested multiplex polymerase chain reaction (PCR) was used to diagnose HHV-6B primary infection, differentiate it from infections caused by HHV-6A and compare it to antibody avidity tests. The samples were separated into case group and control group according to the results of the indirect immunofluorescence assay (IFA) technique. RESULTS: From the saliva samples analyzed, HHV-6A DNA was detected in 3.2 percent of the case group and in 2.6 percent of the control group. Regarding HHV-6B, PCR detected viral DNA in 4.8 percent of the case group and in 1.3 percent of the control group. Among the serum samples studied, a frequency of 1.7 percent was determined for HHV-6A in the case group and 1.2 percent in the control group. PCR did not detect HHV-6B DNA in serum samples. The sensitivity and specificity of the PCR technique ranged from 0 percent to 4.8 percent and 97.5 percent to 100 percent, respectively, compared to IFA. CONCLUSIONS: The PCR technique was not suitable for diagnosing primary infection by HHV-6B in children with exanthematic disease and should not substitute the IFA.

INTRODUÇÃO: O exantema súbito é uma doença comum durante a infância e pode ser causada pela infecção por herpesvirus humano tipo 6B (HHV-6B). No entanto, a erupção cutânea característica dessa doença, é frequentemente confundida com outras viroses como sarampo ou rubéola. MÉTODOS: Foi utilizada a técnica de reação em cadeia da polimerase (PCR) no formato nested multiplex para o diagnóstico de infecção primária por HHV-6B, diferenciação entre as infecções causadas pelo HHV-6A e comparação com testes de avidez de anticorpos. As amostras foram separadas em grupo caso e grupo controle, de acordo com os resultados do teste de imunofluorescência indireta (IFA). RESULTADOS: Nas amostras de saliva analisadas, o DNA do HHV-6A foi detectado em 3,2 por cento no grupo caso e em 2,6 por cento das amostras do grupo controle. Em relação ao HHV-6B, o DNA viral foi observado em 4,8 por cento no grupo caso e em 1,3 por cento no grupo controle. Após a realização da PCR nas amostras de soro, o DNA do HHV-6A foi detectado em 1,7 por cento no grupo caso e em 1,2 por cento no grupo controle, enquanto o DNA do HHV-6B não foi detectado. A sensibilidade e a especificidade da técnica de PCR variaram de 0 por cento a 4,8 por cento e de 97,5 por cento a 100 por cento, respectivamente, quando comparado com a IFA. CONCLUSÕES: A técnica de PCR não se mostrou adequada para o diagnóstico de infecção primária pelo HHV-6B em crianças com doença exantemática e não deve substituir a IFA.

Optimization of the Sybr Green real time PCR for the detection of Human Herpes Virus type 6 (HHV-6) / Otimização da PCR em tempo real - Sybr Green para detecção do Herpes Vírus Humano tipo 6 (HHV-6)

HHV-6 is the etiological agent of Exanthem subitum which is considered the sixth most frequent disease in infancy. In immuno-compromised hosts, reactivation of latent HHV-6 infection may cause severe acute disease. We developed a Sybr Green Real Time PCR for HHV-6 and compared the results with nested conventional PCR. A 214 pb PCR derived fragment was cloned using pGEM-T easy from Promega system. Subsequently, serial dilutions were made in a pool of negative leucocytes from 10-6 ng/µL (equivalent to 2465.8 molecules/µL) to 10-9 (equivalent to 2.46 molecules/µL). Dilutions of the plasmid were amplified by Sybr Green Real Time PCR, using primers HHV3 (5' TTG TGC GGG TCC GTT CCC ATC ATA 3)'and HHV4 (5' TCG GGA TAG AAA AAC CTA ATC CCT 3') and by conventional nested PCR using primers HHV1 (outer): 5'CAA TGC TTT TCT AGC CGC CTC TTC 3'; HHV2 (outer): 5' ACA TCT ATA ATT TTA GAC GAT CCC 3'; HHV3 (inner) and HHV4 (inner) 3'. The detection threshold was determined by plasmid serial dilutions. Threshold for Sybr Green real time PCR was 24.6 molecules/µL and for the nested PCR was 2.46 molecules/µL. We chose the Real Time PCR for diagnosing and quantifying HHV-6 DNA from samples using the new Sybr Green chemistry due to its sensitivity and lower risk of contamination.

HHV-6 é o agente etiológico do Exantema Súbito e considerado a sexta doença mais comum na infância. Em indivíduos imunocomprometidos, a reativação da infecção latente pode causar doença aguda ou morte. Padronizamos PCR em Tempo Real utilizando a química Sybr Green na detecção do HHV-6 e comparamos os resultados com a PCR convencional. Um fragmento de 214 pb foi clonado através do kit pGEM-T do sistema Promega. Com este clone, foram feitas diluições seriadas em um pool de leucócitos negativos a partir de 10-6 ng/µL (equivalente a 2465,8 moleculas/µL) até 10-9 (equivalente a 2,46 moleculas/µL). As diluições foram amplificadas por PCR em Tempo Real utilizando Sybr Green, com primers HHV3 5' TTG TGC GGG TCC GTT CCC ATC ATA 3' e HHV4 5' TCG GGA TAG AAA AAC CTA ATC CCT 3' e pelo método convencional, PCR nested usando primers HHV1 (externo): 5' CAA TGC TTT TCT AGC CGC CTC TTC 3'; HHV2 (externo): 5' ACA TCT ATA ATT TTA GAC GAT CCC 3', HHV3 (interno) e HHV4 (interno): 5' TCG GGA TAG AAA AAC CTA ATC CCT 3'. O limite de detecção foi determinado pelas diluições seriadas do plasmídio contendo um fragmento de HHV6: para o ensaio com Sybr Green, foi de 24,6 moleculas/µL e para a PCR nested, 2,46 moleculas/µL. Elegemos o PCR em Tempo Real - Sybr Green como método diagnóstico e quantitativo do HHV-6 devido a sua boa sensibilidade e menor risco de contaminação.

Outbreaks of human-herpes virus 6 (HHV-6) infection in day-care centers in Belém, Pará, Brazil

A total of 730 children aged less than 7 years, attending 8 day-care centers (DCCs) in Belém, Brazil were followed-up from January to December 1997 to investigate the occurrence of human-herpes virus 6 (HHV-6) infection in these institutional settings. Between October and December 1997 there have been outbreaks of a febrile- and -exanthematous disease, affecting at least 15-20 percent of children in each of the DCCs. Both serum- and- plasma samples were obtained from 401 (55 percent) of the 730 participating children for the detection of HHV-6 antibodies by enzyme-linked immunosorbent assay (ELISA), and viral DNA amplification through the nested-PCR. Recent HHV-6 infection was diagnosed in 63.8 percent (256/401) of them, as defined by the presence of both IgM and IgG-specific antibodies (IgM+/IgG+); of these, 114 (44.5 percent) were symptomatic and 142 (55.5 percent) had no symptoms (p = 0.03). A subgroup of 123 (30.7 percent) children were found to be IgM-/IgG+, whereas the remaining 22 (5.5 percent) children had neither IgM nor IgG HHV-6- antibodies (IgM-/IgG-). Of the 118 children reacting strongly IgM-positive ( > or = 30 PANBIO units), 26 (22.0 percent) were found to harbour the HHV-6 DNA, as demonstrated by nested-PCR. Taken the ELISA-IgM- and- nested PCR-positive results together, HHV-6 infection was shown to have occurred in 5 of the 8 DCCs under follow-up. Serological evidence of recent infections by Epstein-Barr virus (EBV) and parvovirus B19 were identified in 2.0 percent (8/401) and 1.5 percent (6/401) of the children, respectively. Our data provide strong evidence that HHV-6 is a common cause of outbreaks of febrile/exanthematous diseases among children attending DCCs in the Belém area

Apresentacao clinica de 52 criancas com exantema causado pelo Herpesvirus Humano tipo 6 / Clinical profile of 52 children with exhantem caused by human herpvirus type 6

Os autores descrevem e analisam manifestacoes clinicas observadas em criancas com exantema causado pelo Herpesvirus tipo 6. Foi realizado estudo prospectivo no Servico de Pronto-Atendimento Pediatrico do Hospital Universitario da USP, durante 15 meses, com as criancas que apresentavam exantema generalizado nao-bolhoso. Os pacientes deste grupo inicial foram examinados e receberam um diagnostico clinico previo. Destas criancas, foram incluidas na casuistica do presente estudo apenas as criancas menores de tres anos, que tivessem comprovacao laboratorial da presenca do Herpesvirus tipo 6 no sangue. O estudo laboratorial foi realizado atraves da reacao de polimerizacao em cadeia do acido nucleico do Herpesvirus humano tipo 6, em linfocitos de sangue periferico...