Methods to Assess Adult and Adolescent Patients' Adherence to Antimalarial Treatment: A Systematic Review.

Malaria is a curable disease for which early diagnosis and treatment, together with the elimination of vectors, are the principal control tools. Non-adherence to antimalarial treatment may contribute to therapeutic failure, development of antimalarial resistance, introduction or resurgence of malaria in non-endemic areas, and increased healthcare costs. The literature describes several methods to directly or indirectly assess adherence to treatment, but no gold standard exists. The main purpose of this review is to systematize the methods used to assess patient adherence to antimalarial treatment. A systematic review was performed, in accordance with the PRISMA statement, of the following databases: LILACS, EMBASE, PUBMED, COCHRANE, GOOGLE SCHOLAR, WEB OF SCIENCE, SCOPUS, and OPENGREY, through 14 December 2021. A snowball search was also performed by screening the references of the included studies as well as those cited in relevant reviews. Inclusion criteria were reporting assessment of the patient's adherence to antimalarials in individuals with laboratory diagnosis of malaria, the description of antimalarials prescribed, and adherence estimates. Exclusion criteria were studies exclusively about directly observed therapy, studies of populations ≤12 yo and guidelines, commentaries, reviews, letters, or editorials. Study quality was assessed using MINORS and the Cochrane Risk of Bias Tool. Proportions were calculated to measure frequencies considering the number of articles as the denominator. Twenty-one studies were included in this review. Most of them (76.5%) assessed adherence to falciparum malaria treatment. Seventeen studies (80.9%) used a combination of methods. The methods described were pill counts, self-reports, biological assays, use of electronic pillboxes, and clinical cure. It was possible to identify different adherence classifications for all the methods used. Our review found that indirect methods like pill counts and self-reports are the most commonly used. Combining an method that gives solid proof of the ingestion of medication and a method that completes the research with information regarding factors, beliefs or barrier of adherence seems to be the best approach. Future studies of antimalarial treatment should standardize adherence classifications, and collect data on the types and causes of nonadherence, which can contribute to the development of tools to promote medication adherence. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020148054, identifier CRD42020148054.

Increased primaquine total dose prevents Plasmodium vivax relapses in patients with impaired CYP2D6 activity: report of three cases.

BACKGROUND: The relapsing nature of Plasmodium vivax infection is a major barrier to its control and elimination. Factors such as adequate dosing, adherence, drug quality, and pharmacogenetics can impact the effectiveness of radical cure of P. vivax and need to be adequately evaluated. CYP2D6 pathway mediates the activation of primaquine (primaquine) into an active metabolite(s) in hepatocytes, and impaired activity has been linked to a higher risk of relapse. CASES PRESENTATION: Three patients diagnosed with P. vivax malaria presented repeated relapses after being initially treated with chloroquine (25 mg/kg) and primaquine (3.5 mg/kg in 14 days) at a non-endemic travel clinic. Recurring episodes were subsequently treated with a higher dose of primaquine (7 mg/kg in 14 days), which prevented further relapses in two patients. However, one patient still presented two episodes after a higher primaquine dose and was prescribed 300 mg of chloroquine weekly to prevent further episodes. Impaired CYP2D6 function was observed in all of them. CONCLUSION: Lack of response to primaquine was associated with impaired CYP2D6 activity in three patients presenting multiple relapses followed in a non-endemic setting. Higher primaquine dosage was safe and effectively prevented relapses in two patients and should be further investigated as an option in Latin America. It is crucial to investigate the factors associated with unsuccessful radical cures and alternative therapeutic options.

A populational-based birth cohort study in a low-income urban area in Rio de Janeiro, Brazil: implementation and description of the characteristics of the study.

A comprehensive cohort study including an entomological surveillance component can contribute to our knowledge of clinical aspects and transmission patterns of arbovirosis. This article describes the implementation of a populational-based birth cohort study that included an entomological surveillance component, and its associated challenges in a low-income community of Rio de Janeiro, Brazil. The participants were recruited in two periods: from 2012 to 2014, and from 2015 to 2017. The children had scheduled pediatric consultations and in case of fever. Epidemiological, clinical data and biological samples were collected at pediatric visits. Active febrile surveillance was performed by telephone calls, social networking, message apps, and household visits. A total of 387 newborns and 332 new children were included during the first and second recruitment periods, respectively. By July 2017, there were 451 children on follow-up. During the study, 2,759 pediatric visits were performed: 1,783 asymptomatic and 976 febrile/rash consultations. The number of febrile or rash consultations increased 3.5-fold after the use of media tools for surveillance. No temporal pattern, seasonality or peak of febrile cases was observed during the study period. A total of 10,105 adult mosquitoes (including 3,523 Aedes spp. and 6,582 Culex quinquefasciatus) and 46,047 Aedes eggs were collected from households, schools, and key sites. Although challenging, this structured sentinel populational-based birth cohort is relevant to the knowledge of risks and awareness of emerging pathogens.

A populational-based birth cohort study in a low-income urban area in Rio de Janeiro, Brazil: implementation and description of the characteristics of the study / Um estudo de coorte de nascimento de base populacional em uma área urbana desfavorecida no Rio de Janeiro, Brasil: implementação e descrição das características do estudo / Estudio de una cohorte de nacimientos de base poblacional en un área urbana desfavorecida de Río de Janeiro, Brasil: implementación y descripción de las características del estudio

Abstract: A comprehensive cohort study including an entomological surveillance component can contribute to our knowledge of clinical aspects and transmission patterns of arbovirosis. This article describes the implementation of a populational-based birth cohort study that included an entomological surveillance component, and its associated challenges in a low-income community of Rio de Janeiro, Brazil. The participants were recruited in two periods: from 2012 to 2014, and from 2015 to 2017. The children had scheduled pediatric consultations and in case of fever. Epidemiological, clinical data and biological samples were collected at pediatric visits. Active febrile surveillance was performed by telephone calls, social networking, message apps, and household visits. A total of 387 newborns and 332 new children were included during the first and second recruitment periods, respectively. By July 2017, there were 451 children on follow-up. During the study, 2,759 pediatric visits were performed: 1,783 asymptomatic and 976 febrile/rash consultations. The number of febrile or rash consultations increased 3.5-fold after the use of media tools for surveillance. No temporal pattern, seasonality or peak of febrile cases was observed during the study period. A total of 10,105 adult mosquitoes (including 3,523 Aedes spp. and 6,582 Culex quinquefasciatus) and 46,047 Aedes eggs were collected from households, schools, and key sites. Although challenging, this structured sentinel populational-based birth cohort is relevant to the knowledge of risks and awareness of emerging pathogens.

Resumo: Estudos de coorte com um componente de vigilância epidemiológica podem contribuir para nosso conhecimento dos aspectos clínicos e dos padrões de transmissão de arboviroses. Este artigo descreve a implementação de um estudo de coorte de nascimento de base populacional que incluiu um componente de vigilância entomológica e desafios relacionados numa comunidade desfavorecida do Rio de Janeiro, Brasil. Os participantes foram recrutados em dois períodos: de 2012-2014 e de 2015-2017. As crianças tiveram consultas pediátricas agendadas e em caso de febre. Dados epidemiológicos, clínicos e amostras biológicas foram coletadas nas visitas pediátricas. A vigilância ativa febril foi realizada por meio de ligações telefônicas, redes sociais, aplicativos de mensagens e visitas domiciliares. Um total de 387 recém-nascidos e 332 novas crianças foram incluídas durante o primeiro e segundo períodos de recrutamento, respectivamente. Em Julho de 2017, havia 451 crianças em seguimento. Durante o estudo, foram realizadas 2.759 visitas pediátricas: 1.783 assintomáticas e 976 consultas por febre/exantema. O número de consultas por febre ou exantema aumentou 3,5 vezes após uso de ferramentas de mídia para vigilância. Nenhum padrão temporal, sazonalidade ou pico de casos de febre foi observado durante o período do estudo. Um total de 10.105 mosquitos adultos (incluindo 3.523 Aedes spp. e 6.582 Culex quinquefasciatus) e 46.047 ovos foram coletados de domicílios, escolas, e pontos estratégicos. Apesar dos desafios, esta coorte de nascimento sentinela de base populacional é relevante para o conhecimento dos riscos e de patógenos emergentes.

Resumen: Un estudio completro de cohorte que incluya una vigilancia entomológica puede contribuir a nuestro conocimiento de aspectos clínicos y patrones de transmisión de arbovirosis. Este artículo describe la implementación de un estudio poblacional de cohorte de nascimientos que incluyó el componente de vigilancia entomológica y los desafios asociados en una comunidad desfavorecida de Río de Janeiro, Brasil. Los participantes fueron captados en dos periodos: de 2012 a 2014 y de 2015 a 2017. Los niños tenían fijadas consultas pediátrica regulares y por fiebre. Durante las visitas pediátricas, se recogieron datos epidemiológicos y clínicos, así como muestras biológicas. Se realizó una vigilancia activa de la fiebre mediante llamadas telefónicas, redes sociales, aplicaciones de mensajes, y visitas a domicilio. Un total de 387 recién nacidos y 332 nuevos niños fueron incluidos durante el primer y segundo período de reclutamiento, respectivamente. En julio de 2017 se había realizado un seguimiento a 451 niños. Durante el estudio, se realizaron 2.759 visitas pediátricas: 1.783 asintomáticas y 976 por fiebre/urgencias. El número de consultas por fiebre o urgencias aumentó 3.5-veces tras el uso de herramientas de comunicación para la viglancia. No se observaron patrones temporales, estacionalidad o casos de picos de fiebre durante el periodo de estudio. Un total of 10.105 mosquitos adultos (incluyendo 3.523 Aedes spp. y 6.582 Culex quinquefasciatus) y 46.047 huevos fueron recogidos de viviendas, escuelas, y lugares estratégicos. A pesar de los retos, esta cohorte de nacimiento estructurada y supervisada, basada en población es relevante para el conocimiento de los riesgos y la concienciación sobre patógenos emergentes.

Early Evidence for Zika Virus Circulation among Aedes aegypti Mosquitoes, Rio de Janeiro, Brazil.

During 2014-2016, we conducted mosquito-based Zika virus surveillance in Rio de Janeiro, Brazil. Results suggest that Zika virus was probably introduced into the area during May-November 2013 via multiple in-country sources. Furthermore, our results strengthen the hypothesis that Zika virus in the Americas originated in Brazil during October 2012-May 2013.

Comparison of adverse events following immunization with pandemic influenza A (H1N1)pdm09 vaccine with or without adjuvant among health professionals in Rio de Janeiro, Brazil.

A vaccination campaign against pandemic influenza A (H1N1)pdm09 was held in Brazil in March 2010, using two types of monovalent split virus vaccines: an AS03-adjuvanted vaccine and a non-adjuvanted vaccine. We compared the reactogenicity of the vaccines in health professionals from a Clinical Research Institute in Rio de Janeiro, Brazil and there were no serious adverse events following immunization (AEFI) among the 494 subjects evaluated. The prevalence of any AEFI was higher in the AS03-adjuvanted vaccine at 2 h and 24 h post-vaccination [preva-lence ratio (PR): 2.05, confidence interval (CI) 95%: 1.55-2.71, PR: 3.42, CI 95%: 2.62-4.48, respectively]; however, there was no difference between the vaccines in the assessments conducted at seven and 21 days post-vaccination. The group receiving the AS03 post-adjuvanted vaccine had a higher frequency of local reactions at 2 h (PR: 3.01, CI 95%: 2.12-4.29), 24 h (PR: 4.57, CI 95%: 3.29-6.37) and seven days (PR: 6.05, CI 95%: 2.98-12.28) post-vaccination. We concluded that the two types of vaccines caused no serious AEFI in the studied population and the adjuvanted vaccine was more reactogenic, particularly in the 24 h following vaccination. This behaviour must be confirmed and better characterised by longitudinal studies in the general population.

Comparison of adverse events following immunization with pandemic influenza A (H1N1)pdm09 vaccine with or without adjuvant among health professionals in Rio de Janeiro, Brazil

A vaccination campaign against pandemic influenza A (H1N1)pdm09 was held in Brazil in March 2010, using two types of monovalent split virus vaccines: an AS03-adjuvanted vaccine and a non-adjuvanted vaccine. We compared the reactogenicity of the vaccines in health professionals from a Clinical Research Institute in Rio de Janeiro, Brazil and there were no serious adverse events following immunization (AEFI) among the 494 subjects evaluated. The prevalence of any AEFI was higher in the AS03-adjuvanted vaccine at 2 h and 24 h post-vaccination [preva-lence ratio (PR): 2.05, confidence interval (CI) 95%: 1.55-2.71, PR: 3.42, CI 95%: 2.62-4.48, respectively]; however, there was no difference between the vaccines in the assessments conducted at seven and 21 days post-vaccination. The group receiving the AS03 post-adjuvanted vaccine had a higher frequency of local reactions at 2 h (PR: 3.01, CI 95%: 2.12-4.29), 24 h (PR: 4.57, CI 95%: 3.29-6.37) and seven days (PR: 6.05, CI 95%: 2.98-12.28) post-vaccination. We concluded that the two types of vaccines caused no serious AEFI in the studied population and the adjuvanted vaccine was more reactogenic, particularly in the 24 h following vaccination. This behaviour must be confirmed and better characterised by longitudinal studies in the general population.

Unexpectedly long incubation period of Plasmodium vivax malaria, in the absence of chemoprophylaxis, in patients diagnosed outside the transmission area in Brazil.

BACKGROUND: In 2010, Brazil recorded 3343,599 cases of malaria, with 99.6% of them concentrated in the Amazon region. Plasmodium vivax accounts for 86% of the cases circulating in the country. The extra-Amazonian region, where transmission does not occur, recorded about 566 cases imported from the Amazonian area in Brazil and South America, from Central America, Asia and African countries. Prolonged incubation periods have been described for P. vivax malaria in temperate climates. The diversity in essential biological characteristics is traditionally considered as one possible explanation to the emergence of relapse in malaria and to the differences in the duration of the incubation period, which can also be explained by the use of chemoprophylaxis. Studying the reported cases of P. vivax malaria in Rio de Janeiro, where there is no vector transmission, has made it possible to evaluate the extension of the incubation period and to notice that it may be extended in some cases. METHODS: Descriptive study of every malaria patients who visited the clinic in the last five years. The mean, standard deviation, median, minimum and maximum of all incubation periods were analysed. RESULTS: From the total of 80 patients seen in the clinic during the study time, with confirmed diagnosis of malaria, 49 (63%) were infected with P. vivax. Between those, seven had an estimated incubation period varying from three to 12 months and were returned travellers from Brazilian Amazonian states (6) and Indonesia (1). None of them had taken malarial chemoprophylaxis. CONCLUSIONS: The authors emphasize that considering malaria as a possible cause of febrile syndrome should be a post-travel routine, independent of the time elapsed after exposure in the transmission area, even in the absence of malaria chemoprophylaxis. They speculate that, since there is no current and detailed information about the biological cycle of human malaria plasmodia's in Brazil, it is possible that new strains are circulating in endemic regions or a change in cycle of preexisting strains is occurring. Considering that a prolonged incubation period may confer advantages on the survival of the parasite, difficulties in malaria control might arise.

[Delayed diagnosis of malaria in a dengue endemic area in the Brazilian extra-Amazon: recent experience of a malaria surveillance unit in state of Rio de Janeiro]. / Diagnóstico tardio de malária em área endêmica de dengue na extra-Amazônia Brasileira: experiência recente de uma unidade sentinela no estado do Rio de Janeiro.

INTRODUCTION: The mortality of malaria in the extra-Amazon region is about 80 times higher than in the Amazon region, where malaria is concentrated (99.8% of cases). In areas of dengue transmission, delay in the diagnosis and treatment of malaria in patients with fever who reside in areas of malaria transmission can be due to the confusion between the clinical diagnoses of both diseases by nonspecialist doctors, among other factors. This work presents some of the consequences of delayed diagnosis in three patients with malaria by Plasmodium falciparum, P. malariae and P. vivax, who, after following the usual route for Dengue treatment, sought our institution, where they were correctly diagnosed and adequately treated. METHODS: Description of three cases of malaria with delayed diagnosed malaria referred to the Outpatient Clinic for Acute Febrile Diseases, IPEC/FIOCRUZ-RJ, between 2007 and 2008. RESULTS: A Brazilian from Mozambique, primo-infected with P. falciparum was diagnosed with malaria six days after the onset of fever and died of cerebral malaria and shock. Another patient with P.malariae malaria presented a severe and prolonged course, but was cured after specific treatment. A third patient, with delayed diagnosis of P. vivax malaria, acquired it in the Atlantic Forest region in the State of Rio. CONCLUSIONS: Health professionals from non-endemic areas for malaria should be trained to optimize the surveillance and early treatment of malaria and prevent morbid and fatal outcomes. An investigation of outbreaks of autochthonous malaria in the State of Rio de Janeiro is suggested.

Diagnóstico tardio de malária em área endêmica de dengue na extra-Amazônia Brasileira: experiência recente de uma unidade sentinela no estado do Rio de Janeiro / Delayed diagnosis of malaria in a dengue endemic area in the Brazilian extra-Amazon: recent experience of a malaria surveillance unit in state of Rio de Janeiro

INTRODUÇÃO: A letalidade da malária na região extra-amazônica é cerca de 80 vezes maior do que na Amazônia, que concentra 99,8 por cento dos casos do país. Em áreas de transmissão de dengue, como o Rio de Janeiro, o atraso no diagnóstico e tratamento da malária dos pacientes com febre, provenientes de áreas endêmicas de malária, pode ser, entre outros fatores, devido à confusão entre o diagnóstico das duas doenças pelos generalistas da rede de assistência médica. Neste trabalho, apresentamos as consequências do atraso diagnóstico em três pacientes com malária por Plasmodium falciparum; P. malariae e P. vivax, que, após o périplo habitual para tratamento de dengue, procuraram a nossa instituição onde foram corretamente diagnosticados e submetidos aos tratamentos adequados. MÉTODOS: Descrição de três casos de malária diagnosticada tardiamente e encaminhados ao IPEC/ FIOCRUZ, entre os anos de 2007 e 2008. RESULTADOS: uma brasileira proveniente de Moçambique, primo-infectada por P. falciparum, com malária diagnosticada após 6 dias do início da febre, morreu com malária cerebral e choque. Outro paciente com malária por P. malariae teve um curso grave e prolongado, mas ficou curado após o tratamento específico. A terceira paciente diagnosticada tardiamente apresentou malária por P. vivax adquirida na região de Mata Atlântica no Estado do Rio. CONCLUSÕES: Os profissionais de saúde do Rio devem ser treinados para aperfeiçoar a vigilância e o tratamento oportuno da malária e evitar desfechos mórbidos e fatais. Sugere-se que uma investigação de focos de malária autóctone em áreas de mata no estado seja realizada.

INTRODUCTION: The mortality of malaria in the extra-Amazon region is about 80 times higher than in the Amazon region, where malaria is concentrated (99.8 percent of cases). In areas of dengue transmission, delay in the diagnosis and treatment of malaria in patients with fever who reside in areas of malaria transmission can be due to the confusion between the clinical diagnoses of both diseases by nonspecialist doctors, among other factors. This work presents some of the consequences of delayed diagnosis in three patients with malaria by Plasmodium falciparum, P. malariae and P. vivax, who, after following the usual route for Dengue treatment, sought our institution, where they were correctly diagnosed and adequately treated. METHODS: Description of three cases of malaria with delayed diagnosed malaria referred to the Outpatient Clinic for Acute Febrile Diseases, IPEC/FIOCRUZ-RJ, between 2007 and 2008. RESULTS: A Brazilian from Mozambique, primo-infected with P. falciparum was diagnosed with malaria six days after the onset of fever and died of cerebral malaria and shock. Another patient with P.malariae malaria presented a severe and prolonged course, but was cured after specific treatment. A third patient, with delayed diagnosis of P. vivax malaria, acquired it in the Atlantic Forest region in the State of Rio. CONCLUSIONS: Health professionals from non-endemic areas for malaria should be trained to optimize the surveillance and early treatment of malaria and prevent morbid and fatal outcomes. An investigation of outbreaks of autochthonous malaria in the State of Rio de Janeiro is suggested.