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      Plasmodium vivax malaria relapses at a travel medicine centre in Rio de Janeiro, a non-endemic area in Brazil

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          Abstract

          Background

          Malaria is a potentially severe disease widely distributed in tropical and subtropical regions worldwide. Clinically, the progression of the disease can be life-threatening if it is not promptly diagnosed and properly treated. Through treatment, the radical cure of Plasmodium vivax infection can be achieved, thus preventing potential relapses and the emergence of new cases outside the Amazon region in Brazil. Surveillance for therapeutic failure in non-endemic areas is advantageous, as it is unlikely that recurrence of the disease can be attributed to a new malaria infection in these regions.

          Methods

          An observational study of 53 cases of P. vivax and mixed ( P. vivax and Plasmodium falciparum) malaria was conducted at a travel medicine centre between 2005 and 2011 in Rio de Janeiro and a descriptive analysis of the potential factors related to recurrence of P. vivax malaria was performed. Groups with different therapeutic responses were compared using survival analysis based on the length of time to recurrence and a set of independent variables thought to be associated with recurrence.

          Results

          Twenty-one relapses (39.6%) of P. vivax malaria were observed. The overall median time to relapse, obtained by the Kaplan-Meier method, was 108 days, and the survival analysis demonstrated an association between non-weight-adjusted primaquine dosing and the occurrence of relapse (p < 0.03). Primaquine total dose at 3.6 mg/kg gave improved results in preventing relapses.

          Conclusions

          A known challenge to individual cure and environmental control of malaria is the possibility of an inappropriate, non-weight-based primaquine dosing, which should be considered a potential cause of P. vivax malaria relapse. Indeed, the total dose of primaquine associated with non-occurrence of relapses was higher than recommended by Brazilian guidelines.

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          Most cited references29

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          Concurrent and predictive validity of a self-reported measure of medication adherence.

          Adherence to the medical regimen continues to rank as a major clinical problem in the management of patients with essential hypertension, as in other conditions treated with drugs and life-style modification. This article reviews the psychometric properties and tests the concurrent and predictive validity of a structured four-item self-reported adherence measure (alpha reliability = 0.61), which can be easily integrated into the medical visit. Items in the scale address barriers to medication-taking and permit the health care provider to reinforce positive adherence behaviors. Data on patient adherence to the medical regimen were collected at the end of a formalized 18-month educational program. Blood pressure measurements were recorded throughout a 3-year follow-up period. Results showed the scale to demonstrate both concurrent and predictive validity with regard to blood pressure control at 2 years and 5 years, respectively. Seventy-five percent of the patients who scored high on the four-item scale at year 2 had their blood pressure under adequate control at year 5, compared with 47% under control at year 5 for those patients scoring low (P less than 0.01).
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            Determinants of relapse periodicity in Plasmodium vivax malaria

            Plasmodium vivax is a major cause of febrile illness in endemic areas of Asia, Central and South America, and the horn of Africa. Plasmodium vivax infections are characterized by relapses of malaria arising from persistent liver stages of the parasite (hypnozoites) which can be prevented only by 8-aminoquinoline anti-malarials. Tropical P. vivax relapses at three week intervals if rapidly eliminated anti-malarials are given for treatment, whereas in temperate regions and parts of the sub-tropics P. vivax infections are characterized either by a long incubation or a long-latency period between illness and relapse - in both cases approximating 8-10 months. The epidemiology of the different relapse phenotypes has not been defined adequately despite obvious relevance to malaria control and elimination. The number of sporozoites inoculated by the anopheline mosquito is an important determinant of both the timing and the number of relapses. The intervals between relapses display a remarkable periodicity which has not been explained. Evidence is presented that the proportion of patients who have successive relapses is relatively constant and that the factor which activates hypnozoites and leads to regular interval relapse in vivax malaria is the systemic febrile illness itself. It is proposed that in endemic areas a large proportion of the population harbours latent hypnozoites which can be activated by a systemic illness such as vivax or falciparum malaria. This explains the high rates of vivax following falciparum malaria, the high proportion of heterologous genotypes in relapses, the higher rates of relapse in people living in endemic areas compared with artificial infection studies, and, by facilitating recombination between different genotypes, contributes to P. vivax genetic diversity particularly in low transmission settings. Long-latency P. vivax phenotypes may be more widespread and more prevalent than currently thought. These observations have important implications for the assessment of radical treatment efficacy and for malaria control and elimination.
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              Malaria in Brazil: an overview

              Malaria is still a major public health problem in Brazil, with approximately 306 000 registered cases in 2009, but it is estimated that in the early 1940s, around six million cases of malaria occurred each year. As a result of the fight against the disease, the number of malaria cases decreased over the years and the smallest numbers of cases to-date were recorded in the 1960s. From the mid-1960s onwards, Brazil underwent a rapid and disorganized settlement process in the Amazon and this migratory movement led to a progressive increase in the number of reported cases. Although the main mosquito vector (Anopheles darlingi) is present in about 80% of the country, currently the incidence of malaria in Brazil is almost exclusively (99,8% of the cases) restricted to the region of the Amazon Basin, where a number of combined factors favors disease transmission and impair the use of standard control procedures. Plasmodium vivax accounts for 83,7% of registered cases, while Plasmodium falciparum is responsible for 16,3% and Plasmodium malariae is seldom observed. Although vivax malaria is thought to cause little mortality, compared to falciparum malaria, it accounts for much of the morbidity and for huge burdens on the prosperity of endemic communities. However, in the last few years a pattern of unusual clinical complications with fatal cases associated with P. vivax have been reported in Brazil and this is a matter of concern for Brazilian malariologists. In addition, the emergence of P. vivax strains resistant to chloroquine in some reports needs to be further investigated. In contrast, asymptomatic infection by P. falciparum and P. vivax has been detected in epidemiological studies in the states of Rondonia and Amazonas, indicating probably a pattern of clinical immunity in both autochthonous and migrant populations. Seropidemiological studies investigating the type of immune responses elicited in naturally-exposed populations to several malaria vaccine candidates in Brazilian populations have also been providing important information on whether immune responses specific to these antigens are generated in natural infections and their immunogenic potential as vaccine candidates. The present difficulties in reducing economic and social risk factors that determine the incidence of malaria in the Amazon Region render impracticable its elimination in the region. As a result, a malaria-integrated control effort - as a joint action on the part of the government and the population - directed towards the elimination or reduction of the risks of death or illness, is the direction adopted by the Brazilian government in the fight against the disease.
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                Author and article information

                Journal
                Malar J
                Malar. J
                Malaria Journal
                BioMed Central
                1475-2875
                2012
                28 July 2012
                : 11
                : 245
                Affiliations
                [1 ]Instituto de Pesquisa Clínica Evandro Chagas (IPEC), Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro. Av. Brasil 4365. Manguinhos, Rio de Janeiro, RJ - CEP 21.045-900, RJ –, Brazil
                [2 ]Centro de Pesquisa, Diagnóstico e Treinamento em Malária (CPD-Mal), Fiocruz and Secretaria de Vigilância em Saúde (SVS), Ministério da Saúde (MS), Brazil
                [3 ]Laboratório de Pesquisas em Malária. Instituto Oswaldo Cruz, Fiocruz. Pavilhão Leônidas Deane, 5° andar. Av. Brasil 4365. Manguinhos, Rio de Janeiro, RJ, CEP 21.045-900, RJ, Brazil
                Article
                1475-2875-11-245
                10.1186/1475-2875-11-245
                3416703
                22839416
                4f3c1294-aaf9-4d4d-9d38-fa2ab1cf3be1
                Copyright ©2012 Pedro et al.; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 5 December 2011
                : 16 July 2012
                Categories
                Research

                Infectious disease & Microbiology
                weight-based dosing,therapeutic failure,relapse,plasmodium vivax malaria

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