|Year : 2021 | Volume
| Issue : 1 | Page : 54-62
Profile of hospitalization and death records associated to dengue and severe dengue in Minas Gerais between 2000 and 2015 from the Brazilian Public Health System perspective
Gabriel Henrique da Silva1, Clara Rodrigues de Andrade1, José Vítor Vieira Salgado1, Adriano Guimarães Parreira1, Isabella Piassi Dias Godói2
1 Universidade do Estado de Minas Gerais, Av. Paraná, 3001 - Jardim Belvedere, Divinópolis, MG, CEP 35501-170, Minas Gerais, Brazil
2 Researcher of the Group (CNPq) for Center for Research in Management, Society and Epidemiology in Nursing and in the Network of Health Care - Universidade do Estado de Minas Gerais; Av. Paraná, 3001 - Jardim Belvedere, Divinópolis - MG, CEP 35501-170, Minas Gerais; Researcher of the Group (CNPq) for Epidemiological, Economic & Pharmacological Studies of Arboviruses (EEPIFARBO); Institute of Health and Biological Studies - Universidade Federal do Sul e Sudeste do Pará, Avenida dos Ipês, s/n, Cidade Universitária, Cidade Jardim, Marabá, Pará, Brazil
|Date of Submission||09-Jan-2020|
|Date of Acceptance||07-Aug-2020|
|Date of Web Publication||18-Nov-2021|
Isabella Piassi Dias Godói
Institute of Health and Biological Studies - Universidade Federal do Sul e Sudeste do Pará; Marabá, Pará
Source of Support: None, Conflict of Interest: None
Background & objectives: Dengue is one of the most important arboviruses and public health problem associated with increasingly large outbreaks, especially in tropical countries such as Brazil. The state of Minas Gerais, in particular, has had high numbers of cases of this infection in recent years.
Methods: Our study evaluated the epidemiological impact of dengue fever in the state of Minas Gerais from the National Health System (Sistema Único de Saúde, SUS) perspective between 2000 to 2015 using the Brazilian Notifiable Diseases Information System (SINAN, notification cases) and Hospital Information System (SIH)/SUS (hospitalization registers) databases.
Results: The SUS database recorded 34,996 reports of dengue (International Classification of Diseases [ICD]: A90) as well as 1984 verified cases of severe dengue (ICD-A91). These hospitalizations for dengue and cases of severe dengue generally affected individuals aged 15–24 (17.74%) and 5–14 (20.86%) years, respectively. The epidemiological burden of dengue was substantial in Minas Gerais state, with the highest number of notifications nationally in 2013.
Interpretation & conclusion: From retrospective data associated with dengue records, our study sought to better highlight the locations with the largest number of dengue cases in the Minas Gerais state, and contribute to direct educational and surveillance actions of these regions applied to this infection.
Keywords: Dengue; Epidemiology; Arbovirus; Public Health; Minas Gerais; Brazil
|How to cite this article:|
da Silva GH, de Andrade CR, Salgado JV, Parreira AG, Godói IP. Profile of hospitalization and death records associated to dengue and severe dengue in Minas Gerais between 2000 and 2015 from the Brazilian Public Health System perspective. J Vector Borne Dis 2021;58:54-62
|How to cite this URL:|
da Silva GH, de Andrade CR, Salgado JV, Parreira AG, Godói IP. Profile of hospitalization and death records associated to dengue and severe dengue in Minas Gerais between 2000 and 2015 from the Brazilian Public Health System perspective. J Vector Borne Dis [serial online] 2021 [cited 2021 Nov 27];58:54-62. Available from: https://www.jvbd.org/text.asp?2021/58/1/54/321738
| Introduction|| |
Dengue, a mosquito-borne viral disease, is a serious global health problem and one of the most important arboviruses in the world, especially in tropical and subtropical countries,,. Dengue virus (DENV) belongs to the Flavivirus genus and Flaviviridae family and has four serotypes (DENV1-4) with distinct phylogenetic and antigenic characteristics. The transmission of the disease occurs from the bite of a female Aedes mosquito, especially A. aegypti and A. albopictus. The symptoms of the disease include acute fever, myalgia, asthenia and, in the most severe cases, haemorrhages, which can be fatal. Most DENV infections are asymptomatic, with clinical manifestations ranging from mild fever to severe life-threatening disease in the case of severe dengue,,. In addition, other characteristics have been reported, including the hyperendemicity of multiple DENV serotypes in several countries and the significant impact on human health and national economies, thus generating a global impact. There is currently no specific therapy against DENV; however, palliative treatments may be used to alleviate symptoms,,.
DENV is present in 128 countries in Africa, Southeast Asia, the Americas, and the Eastern Mediterranean and Western Pacific regions, with an estimated 390 million infections per year. The globalization of trade and rapid urbanization in Asia and Latin America and the abundance of vector breeding sites in overcrowded urban communities, high temperatures, and rainfall index, have contributed to the endemicity observed in these regions owing to the favorable conditions for the development of the vector,,,.
Dengue is a significant public health problem in Brazil and is endemic in all regions of the country, with mandatory notification to the Brazilian Notifiable Diseases Information System (SINAN). The SINAN was developed in 1990; the process involves individual notification forms and the follow-up of cases at three levels (municipality, state, and federal governments),,,. Approximately 9.5 million cases of dengue were reported between 2000 and 2015 in Brazil,,, with the highest numbers of hospitalizations (dengue: 708,800 and severe dengue: 29,759) in the Northeast and Southeast regions.
The Southeast region had a high number of registered cases during the 16 years between 2000 and 2015 (4,792,133). Within this region, the state of Minas Gerais had a considerable number of cases (1,232,577) and in 2013 had the highest number of cases associated with dengue nationwide. Strategies such as campaigns and social mobilization have been developed in all regions in this state to control the vector, however, the challenge continues. Only one study has reported the epidemiological impact of this arbovirus in Minas Gerais state over a short period and a limited number of publications have evaluated dengue in this state and its cities,,,.
In December 2015, the Anvisa approved the first dengue vaccine in Brazil, Dengvaxia®, which is indicated for the prevention of DENV infection in individuals aged 9–45 years,. Developed by the French laboratory Sanofi Pasteur, Dengvaxia® showed a global efficacy of 60% in volunteers less than 16 years of age; based on the immunogenicity results in adults, we could expect satisfactory efficacy in this population after commercialization. The vaccine is not indicated for Zika and chikungunya cases. Several endemic countries have granted regulatory approval for Dengvaxia®, including Mexico, the Philippines, Brazil, El Salvador, Costa Rica, Paraguay, Guatemala, Peru, Indonesia, Thailand, and Singapore,,,,,. Recently, the vaccine was approved for European endemic areas and the European Commission granted marketing authorization to Sanofi Pasteur for the vaccine. Our study evaluated the records associated with dengue and severe dengue in a time horizon (2000–2015) before the approval of the first dengue vaccine in Brazil.
In this context, the objective of this study was to demonstrate the profile of dengue and severe dengue records, especially associated with hospitalization and death, for sixteen years (2000–2015) in the state of Minas Gerais in Brazil. We believe this is the first study to fully evaluate the hospitalization and other National Health System (Sistema Único de Saúde, SUS) services in this state based on the reported frequency and all dengue case registrations over 16 years. This comprehensive approach can contribute to discussions of prevention strategies and control of this important arbovirus in Minas Gerais state. Retrospective data can contribute to better comprehension applied to a scenario, ordering to direct the planning of strategies and actions to the public health policy development to obtain the best results,,.
| Material & Methods|| |
Minas Gerais state is located in the Southeast region in Brazil. It is Brazil’s fourth largest state (586 528 km2) and has the second largest population (19,597,330 inhabitants). The state has 853 municipalities, nominal household income per capita of 1224 BRL, and is divided into 12 geographical regions (Northwest, North, Jequitinhonha, Vale Mucuri, Triângulo Mineiro, Central, Belo Horizonte Metropolitan, Vale do Rio Doce, West, South/Southwest, Campo das Vertentes and Zona da Mata),.
This study assessed the profile of the services and procedures performed for the treatment of dengue and severe dengue in Minas Gerais state between January 2000 and December 2015 based on information recorded in the SUS databases. All 823 municipalities and the 12 regions were included. The number of cases registered in the state per year associated with this infection was evaluated over 16 years from a SUS perspective. Dengue is a mandatory notification disease in Brazil however, only severe cases, in general, consume hospital services, with the majority of patients undergoing self-treatment at home, for which costs are not recorded. The data used were extracted through the deterministic-probabilistic link involving the SUS administrative databases, including the Hospital Information System (SIH) and Mortality Information System (SIM),,,,. In addition, the Mortality Information System (SIM/SUS) was also used to record deaths occurring between January 2000 and December 2015.
Until 2014, the common serious dengue manifestation, including bleeding and other severe symptoms, was denoted as dengue haemorrhagic fever; thereafter, this condition was changed to severe dengue. Both denominations have the same International Classification of Diseases (ICD) code (A91). Our study collected all registers with ICD-10 A90 and A91 in the SUS databases (SIH/SUS) and data involving dengue haemorrhagic fever (until 2014) and severe dengue (after 2014) to estimate the incidence of dengue notification. The SINAN (notification), SIH (hospitalization), and SIM (mortality) are independent SUS databases. The analyses were conducted using Microsoft Excel 2010.
The median incidence of dengue was estimated for each year based on all records of notification and hospitalization for dengue and severe dengue between 2000 and 2015. We included all individuals who had dengue (SUS codes 74500457, 74300440, and 0303010010) and severe dengue (SUS codes 74300628, 74500627, and 0303010029) registered by the SUS databases, similar to the process described in a previous study by our group. We considered the number of clinical procedures (treatment and diagnosis) undertaken each year for patients with dengue instead of the number of individuals infected to estimate the true incidence because individuals can be infected multiple times in a year. We assessed the distribution of dengue and severe dengue cases in Minas Gerais state considering the total number of patients on the hospitalization registers in terms of their sex, region, and age (in years) groups comprising children, adolescents and adults, similar to the process described in a previous publication by our group study in the context of the national scenario.
Mortality was assessed from the number of deaths associated with ICD-A90 (dengue) and A91 (severe dengue). In addition, the mortalities by age, year, and location were also evaluated. We also evaluated the number of dengue cases in each of the 12 regions of the state. We used information from the Brazilian Institute of Geography and Statistics (IBGE) regarding the municipalities associated with each region to determine the distribution of dengue cases in Minas Gerais.
This study was approved by the Ethics Committee of Federal University of Minas Gerais (COEP) (CAAE 57219816.0.0000.5149).
| Results|| |
A total of 36,330 individuals, including 34,384 with dengue (ICD-A90) and 1946 with severe dengue (ICD-A91) were notified by the SUS and registered in the SINAN databases, representing a total of 36,980 hospitalizations for this arbovirus between 2000 and 2015. The difference between the number of individuals and the number of hospitalizations is due to the fact that the same individual may have contracted the disease more than once. [Table 1] shows the characteristics of the population associated with dengue. The majority of cases were observed in women, who comprised 55.4% of dengue fever and 54.8% of severe dengue fever cases. Individuals aged 15–24 years represented 17.74% of the cases of dengue, which is the most prominent in the state, while those aged 5–14 years old represented 20.86% of the cases of severe dengue fever. [Figure 1]a shows the distribution of dengue and severe dengue by macro-regions established by the IBGE in Minas Gerais (Northwest, North, Jequitinhonha, Mucuri Valley, Central Triangle, Belo Horizonte Metropolitan, Rio Doce Valley, West, South/Southwest, Campo das Vertentes, and Zona da Mata). The Metropolitan Region of Belo Horizonte and the Vale do Rio Doce had the highest numbers of cases, representing together 39.7% of cases throughout the state. Campo das Vertentes had the lowest number of cases, representing 1% of cases in the state. The highest numbers of cases registered in the state occurred in 2002, 2010, 2013, and 2015. [Figure 2] shows the geographical distribution of cases of dengue and severe dengue per region in Minas Gerais.
|Figure 1: a Distribution of severe dengue and dengue cases by region in Minas Gerais (2000-2015); b: Hospitalization cases by year in Minas Gerais|
Click here to view
|Figure 2: Distribution of severe dengue and dengue cases by region in Minas Gerais|
Click here to view
|Table 1: Population characteristics: profile of dengue and severe dengue in Minas Gerais (2000-2015)|
Click here to view
[Figure 3] lists the epidemiological data on dengue and severe dengue with the age group. The highest percentage of dengue and severe dengue cases occurred in individuals aged 15–24 (17.74%) and 5–14 (20.86%) years, respectively. The number of dengue cases was higher among children, adolescents, and young adults and the number of deaths (total: 280) was higher among young adults, especially those 15–24 years of age.
|Figure 3: Distributions of dengue, severe dengue, and dengue deaths by age in Minas Gerais|
Click here to view
The number of cases recorded per year and the number of hospitalizations during the period 2000 to 2015 are presented in [Table 2]. The numbers of hospitalizations and deaths are shown in [Figure 4], with peaks in 2002, 2010, and 2013 associated with epidemics. [Table 2] verified an increase of dengue incidence in Minas Gerais state, especially, in the years 2010 and 2013, with, approximately, 1000 and 2000 notifications/100,000 inhabitants, respectively. In addition, the hospitalization cases incidence is less when compared to notification cases incidence, what is similar to found in another study developed in Brazil.
|Figure 4: Hospitalization cases and dengue deaths per year in Minas Gerais (2000-2015)|
Click here to view
|Table 2: Dengue and Severe Dengue records in Minas Gerais (2000-2015) from SUS perspective.|
Click here to view
| Discussion|| |
To our knowledge, this study is the first to comprehensively evaluate the health burden of dengue in an important state (Minas Gerais) in the Southeast region in Brazil. According to Godói and collaborators (2018), this region had the second highest number of hospitalizations in the country in 2000 and 2015 and Minas Gerais contributed to this situation. There was a total of 36,330 notification registers in the SINAN databases (dengue: 34,384; severe dengue: 1,946) and 36,980 hospitalizations associated with this infection in a 16-year period (2000–2015), reinforcing its relevance as a public health problem requiring control.
Only one previous study assessed the epidemiological impact of dengue in Minas Gerais state; however, it was limited by a short study period and absence of dengue case analysis. This historical cohort study used the SINAN database from the period between 2008 and 2010 to assess the epidemiological profiles of severe dengue and to identify factors associated with dengue death. The authors reported a total of 2,214 severe dengue cases and 156 deaths during this period, with dengue incidences of 211.4, 242.3, and 949.7/100,000 inhabitants, respectively, for 2008, 2009, and 2010. These results reflected the different epidemics associated with dengue in Minas Gerais state, as occurred in 2010, similar to the finding in our study using notification and hospitalization data. Our study demonstrated a global incidence for each scenario (Notifications: dengue, 186.21 and severe dengue, 0.96/100,000 inhabitants; Hospitalizations: dengue, 8.37 and severe dengue, 0.56/100,000 inhabitants) different from that reported by Campos and collaborators (2015. However, a similar tendency in the increased number of dengue notifications verified between 2008, 2009, and 2010 was also observed in our study.
Regarding the prevalence of dengue according to sex, in the present study, women were the most affected both by dengue (55.4%) and severe dengue (54.83%). These results were similar to those reported by Silva and collaborators (2016), who observed a female prevalence of 54–57% during 2007 and 2011 in Pará state (Belém-Metropolitan region) in the North of the country. In this context, Godói et al. (2018), who evaluated the economic and epidemiological impacts of dengue at a national level for a period of sixteen years from the SUS perspective, demonstrated higher proportions of dengue (53.69%) and severe dengue (52.15%) cases in women compared to those in men, corroborating with this frequency applied this infection in Minas Gerais as in the country.
Analysis of data from the SUS databases (SINAN/ SIH/SIM) revealed a higher incidence of cases in the 15–24 and 5–14-year age groups, respectively, for dengue and severe dengue. According to Escosteguy and collaborators (2013) during the epidemic in 2007, more than 50% of the hospitalization cases associated with severe dengue was observed in children and adolescents under 15 years of age. However, in a study conducted between 2007 and 2011 in Pará state, Silva and colleagues (2016) observed that adults 20–39 years of age were most affected by DENV, demonstrating the variability associated with this arbovirus according to locality, period, and social and economic factors.
To our knowledge, this study was the first to demonstrate the geographical distribution of dengue cases for each region of Minas Gerais. The most affected regions in the state were the Metropolitan Region of Belo Horizonte and Vale do Rio Doce, which together represented 39.7% of cases. The high population density, especially in Metropolitan region, and environmental conditions conducive to vector development may be associated with the considerable number of cases in these regions. According to the National Survey of Domicile conducted by the IBGE in 2010, Belo Horizonte had a population of 2.3 million people. In addition, dengue fever is associated with both macro-factors (environmental, political, social and socioeconomic) and micro-factors (characteristics related to the biological aspects of the virus, vector, and people affected). This type of analysis can contribute to discussions of prevention strategies such as campaigns and social mobilization to eliminate Aedes, the transmission vector of other arboviruses such as Yellow Fever, Zika, and chikungunya.
Dengue is one of the main arboviruses affecting humans. Disease transmission occurs from the bite of female Aedes mosquitoes, especially Ae. aegypti, which originated in Egypt and has spread worldwide, mainly in the tropical and subtropical regions due to suitable climatic conditions. According to the Ministry of Health, the first clinical and laboratory occurrence of the virus in the country occurred between 1981 and 1982 in Roraima state (capital: Boa Vista), which was associated with DENV-1 and DENV-4. As early as 1986, the first epidemic of the disease was registered in the state of Rio de Janeiro and in some capitals of the Northeast and has since continued in the country. In Minas Gerais state (Southeast region), many efforts have been made to control this vector. In May 2018, the Minas Gerais State Health Secretary (SES/ MG) reported a total of 706 social mobilization actions that were carried out by the Municipal Social Mobilization Centers.
According to Camara and collaborators (2007), in a retrospective study, demonstrated that the dengue in Brazil typically affects the hottest months of the year, with no qualitative differences for Brazilian regions, however, with important quantitative differences. They reinforce the relevance of aspects such as population size, as well as the success to the planning and execution of preventive strategies to combat the vector as important to the number of cases of this infection. Additionally, Claro and collaborators (2004) indicated that educational campaigns, although relatively efficient in transmitting information, carried out by health professionals in the municipalities, have not achieved their main objective, which is to change the behavior of populations for effective control of vector breeding sites in most the regions in Brazil.
Deininger and collaborators (2017) indicate in a study about the importance of using information to assess the health situation and make decisions with a view to directing intersectoral, educational and awareness actions. In this context, the understanding about the profile and distribution of records applied to health problems, such as the dengue, in a region occurred in the past, becomes essential to obtain better results applied to the control of this infection today and in the future.
The epidemiological impact of this arbovirus has led to studies on the development of dengue antiviral involving important DENV molecular targets such as the three structural proteins (capsid [C], precursor membrane protein [prM], and envelope [E]) and seven nonstructural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5),. In this context, medicinal chemistry projects have applied rational approaches to theoretical methodologies such as homology modeling,, virtual screening,, molecular docking,,,, molecular mechanics (MM), and quantum mechanics/molecular mechanics (QM/MM),,,,,,,. However, as yet, the only treatment against dengue is preventive and supportive care, reinforcing the necessity to develop a safe antiviral agent effective against the four DENV serotypes.
There are several challenges in the elimination of this infection, particularly with regard to vector control. In this context, the Institute of Biological Studies at the Federal University of Minas Gerais (Brazil) developed a vaccine to combat A. aegypti, a vector responsible for the spread of various infectious diseases. The advantage of this type of vaccine is that it acts directly on the disease vector. The vaccine contains relevant proteins for insect life and is able to generate antibodies against proteins relevant to DENV in vaccinated individuals. In other words, a mosquito that feeds on blood containing these antibodies may die or undergo physiological changes.
An important strategy for dengue prevention is utilization of the first dengue vaccine, Dengvaxia®, which was approved at the end of December 2015. The vaccine was developed by Sanofi Pasteur and has a reported global efficacy of 60%. Although the National Health Surveillance Agency (ANVISA) authorized the use of Dengvaxia® in Brazil, its incorporation into the National Vaccination Calendar in the National Vaccination Program was not recommended based on the clinical results, particularly regarding safety problems in sero-negative individuals vaccinated with this product, according to the World Health Organization’s Technical Advisory Group. In Brazil, Paraná state included Dengvaxia® in the state immunization program; however, from the target population of 400,000 inhabitants (80% coverage), only 190,000 received the first dose,.
This study has several limitations. First, we did not consider sub-notification cases, as our principal objective was to estimate the epidemiological impact involving the registers for dengue in the country according to the SUS databases (SINAN/SIH/SUS). In addition, it was not possible to characterize the population associated with the notified cases such as age at notification, as these data are not included in the SINAN published by Ministry of Health,,.
| Conclusion|| |
Our study demonstrated the epidemiological aspects of dengue in the state of Minas Gerais over a 16-year period from the perspective of the Unified Health System. The results founded demonstrated the increase of dengue notification and hospitalization incidences in different years in the state, especially in 2010 and 2013 and identified the most affected regions of this arbovirus, contributing to better target actions and efforts in the context of coping strategies.
From retrospective data associated with dengue records, our study sought to better highlight the locations with the largest number of dengue cases in the Minas Gerais state, and contribute to direct educational and surveillance actions of these regions applied to this infection. We emphasize the need for initiatives to combat the vector, which is associated with the transmission not only of DENV, but also of the other arboviruses such as yellow fever, chikungunya, and Zika. This study sought to contribute to the planning and discussion around dengue prevention in Minas Gerais state.
Conflict of interest
I.P.D Godói previously received financial support from CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior) (process number: 88881.134286/2016-01) by Doctoral Sandwich Program Abroad and C.R. Andrade received a scholarship (PAPq – UEMG). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
| Acknowledgments|| |
IPDG received financial support from CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior) (process number: 88881.134286/2016-01) through the Doctoral Sandwich Program Abroad and C.R. Andrade received a scholarship from UEMG (PAPq -UEMG).
| References|| |
Bhatt S, Gething PW, Brady OJ, Messina JP, Farlow AW, Moyes CL et al
. The global distribution and burden of dengue. Nature
2013; 496(7446): 504–507.
Godói IP, Silva LVD, Sarker AR, Megiddo I, Morton A, God-man B et al
. Economic and epidemiological impact of dengue illness over 16 years from a public health system perspective in Brazil to inform future health policies including the adoption of a dengue vaccine. Expert Rev Vaccines
2018; 17(12): 1123–1133
Brasil. Ministério da Saúde. Secretaria de Vigilância em Saúde. Departamento de Vigilância Epidemiológica. Fundação Nacional de Saúde (2002) Programa Nacional de Controle da Dengue. Brasília: Ministério da Saúde.
Brady OJ, Gething PW, Bhatt S, Messina JP, Brownstein JS, Hoen AG, et al
. Refining the global spatial limits of dengue virus transmission by evidence-based consensus. PLoS Neglected Tropical Diseases
2012; 6(8): e1760
Frecer V, Miertus S. Design, structure-based focusing and in silico screening of combinatorial library of peptidomimetic inhibitors of dengue virus NS2B-NS3 protease. Journal of Computer-Aided Molecular Design
2010; 24(3): 195–212
Forshey BM, Stoddard ST, Halsey ES. Direct feeding on dengue patients yields new insights into human to mosquito dengue virus transmission. Future Virology
2013; 8(12): 1145–1149.
Godói IP, Taranto MFR, Lima WG, Alves RJ, Comar M, Siqueira, et al
. NS2B-NS3pro as a Molecular Target Drugs Development against Dengue. Biochemistry and biotechnology reports
2014; 3(2): 16–30.
Godói IP, Lima WG, Junior MC, Alves RJ, Ferreira JMS, Kong DX, et al
. Docking and QM/MM Studies of NS2B-NS3pro Inhibitors: a Molecular Target against the Dengue Virus. Journal of the Brazilian Chemical Society
2016; 00(00): 1–12.
Tomlinson SM, Malmstrom RD, Watowich SJ. New approaches to structure-based discovery of dengue protease inhibitors. Infectious Disorders Drug Targets
2009; 9(3): 327–343.
Reiter P. Aedes albopictus and the world trade in used tires, 1988–1995: the shape of things to come? Journal of the American Mosquito Control Association
1998; 14(1): 83–94.
Thoisy B, Lacoste V, Germain A, Muñoz-Jordán J, Colón C, Mauffrey JF, et al
. Dengue infection in neotropical forest mammals. Vector and Borne Zoonotic Diseases
2009; 9(2): 157–169.
Simmons CP, Farrar JJ, Nguyen VV, Wills B. Current concepts dengue. The New England Journal of Medicine
2012; 366(15): 1423–32.
Lírio M, Dos Santos NP, Passos LAR, Kritski A, Galvão-Castro B, Grassi MFR. Completeness of tuberculosis reporting forms for disease control in individuals with HIV/AIDS in priority cities of Bahia state. Ciência & Saúde Coletiva
2015; 20(4): 1143–1148.
Galvão PRS, Ferreira AT, Maciel MDSG, De Almeida RP, Hinders DC, Schreuder PAM, et al
. An evaluation of the Sinan health information system as used by the Hansen’s disease control programme, Pernambuco state, Brazil. Leprosy
Brasil. Ministério da Saúde. Secretaria de Vigilância em Saúde. Brasília: Editora do Ministério da Saúde. Departamento de Vigilância Epidemiológica. Sistema de Informação de Agravos de Notificação–sinan: normas e rotinas/Ministério da Saúde, Secretaria de Vigilância em Saúde, Departamento de Vigilância Epidemiológica 2006. Availablefrom: http://bvsms.saude.gov. br/bvs/publicacoes/sistema_informacao_agravos_notificacao_ sinan.pdf
(Accessed on October 10, 2018)
Campos KB, Amâncio FF, De Araújo VE, Carneiro M. Factors associated with death from dengue in the state of Minas Gerais, Brazil: historical cohort study. Tropical Medicine & International Health (TM & IH)
2015; 20(2): 211–218.
Duarte HHP, França EB. Qualidade dos dados da vigilância epidemiológica da dengue em Belo Horizonte, MG. Revista Sa
Pública 2006; 40(1): 134–42.
Teixeira LAS, Lopes JSM, Martins AGC, Campos FAB, Miranzi SSC, Nascentes GAN. Persistência dos sintomas de dengue em uma população de Uberaba, Minas Gerais, Brasil. Cadernos de Sa
ública 2010; 26
Cunha MCM, Caiaffa WT, Oliveira CL, Kroon EG, Pessanha JEM, Lima JA,et al. Fatores associados à infecção pelo vírus do dengue no Município de Belo Horizonte, Estado de Minas Gerais, Brasil: características individuais e diferenças intra-urbanas. Epidemiologia Serviços de Saúde
2008; 17(3): 217–230.
Nascimento MC, Rodrigues-Júnior AL. Spatial analysis of dengue and Primary Health Care in Alfenas, Minas Gerais, Brazil. Atención Primaria
2014; 46(8): 449–451.
Godói IP, Lemos LLP, Araújo VE, Bonoto BC, Godman B, Guerra-Júnior AA. CYD-TDV dengue vaccine: systematic review and meta-analysis of efficacy, immunogenicity and safety. Journal of Comparative effectiveness research
2017; 6(2): 165–180.
Sanofi Pasteur. Dengvaxia®, world’s first dengue vaccine, approved in Mexico. 2015. Available from: www.sanofipasteur. com/en/articles/dengvaxia-world-s-first-dengue-vaccine-approved-in-mexico.aspx
(Accessed on October 20, 2018)
Sanofi Pasteur. Sanofi Pasteur’s dengue vaccine approved in the Philippines. 2015. Available from: www.sanofipasteur.com/en/ articles/sanofi-pasteur-dengue-vaccine-approved-in-the-philippines.aspx
(Accessed on October 20, 2018)
Sanofi Pasteur. Dengvaxia® first dengue vaccine approved in Brazil. 2015. Available from: www.sanofipasteur.com/en/articles/Dengvaxia-First-Dengue-Vaccine-Approved-in-Brazil. aspx
(Accessed on October 20, 2018)
Sanofi Pasteur. Sanofi Pasteur dengue vaccine approved in Costa Rica. 2016. Available from: www.sanofipasteur.ca/node/49001
(Accessed on October 20, 2018)
Sanofi Pasteur. First dengue vaccine approved in more than 10 countries. 2016. Available from: www.sanofipasteur.com/en/ Documents/PDF/PR/20161004_First_Dengue_Vaccine_Approved_in_More_than_10_Countries_EN.pdf
(Accessed on October 20, 2018)
Dengue Vaccine Initiative. Dengue vaccine initiative statement on SAGE dengue vaccine recommendations. 2016. Available from: www.denguevaccines.org/sites/default/files/DVI%20 Statement%20%20SAGE%20Recommendations%20Dengue%20Vaccines%20April%202016_0.pdf
(Accessed on October 20, 2018)
Câmara FP, Theophilo RLG, Santos GTD, Pereira SRFG, Câmara DCP, Matos RRCD. Estudo retrospectivo (histórico) da dengue no Brasil: características regionais e dinâmicas. Revista da Sociedade Brasileira de Medicina Tropical
Deininger LDSC, LUCENA KDTD, Figueiredo DCMMD, Silva CCD, Oliveira AECD, Anjos UUD. A sala de situação da dengue como ferramenta de gestão em saúde. Saúde em Debate
2014; 38(100): 50–56.
Hochman B, Nahas FX, Oliveira Filho RSD, Ferreira KM. Desenhos de pesquisa. Acta Cirúrgica Brasileira
2005; 20: 2–9.
Coeli CM, Camargo KJ. Avaliação de diferentes estratégias de blocagem no relacionamento probabilístico de registros. Revista Brasileira de Epidemiologia
2002; 5(2): 185.
Cherchiglia ML, Guerra Júnior AA, Andrade EIG, Machado CJ, Acúrcio FA, Júnior WM, et al
. A construção da base de dados nacional em terapia renal substitutiva (TRS) centrada no indivíduo: aplicação do método de linkage determinístico-probabilístico. Revista Brasileira de Estudos de População
2007; 24(1): 163.
Guerra Júnior AA, Acúrcio FA, Andrade EIG, Cherchiglia ML, Cesar CC, Queiroz OV, Silva GD. Cyclosporine versus tacrolimus in kidney transplants in Brazil: a cost comparison. Cadernos de Saúde P
ública 2010; 26
Acúrcio FA, Brandão CMR, Guerra Júnior AA, Cherchiglia ML, Andrade IG, Almeida AM, et al
. Perfil demográfico e epidemiológico dos usuários de medicamentos de alto custo no Sistema Único de Saúde. Revista Brasileira de Estudos de População
Silva FA, Rocha BMF, Gesta SSM, Fecury AA, Dias CAGM, Oliveira E. Perfil Soro Epidemiológico dos casos de dengue notificados no município de Belém/Pará. Revista Científica Multidisciplinar Núcleo do Conhecimento
2016; 1(4): 75–85.
Escosteguy CC, Pereira AGL, Medronho RA, Rodrigues CS, Chagas KKF. Diferenças, segundo faixa etária, do perfil clínico epidemiológico dos casos de dengue grave atendicdos no Hospital Federal dos Servidores do Estado, Rio de Janeiro- RJ, Brasil, durante a epidemia de 2008. Epidemiologia e Servi
Saúde 2013; 22(1): 67–76.
Claro LBL, Tomassini HCB, Rosa MLG. Prevenção e controle do dengue: uma revisão de estudos sobre conhecimentos, crenças e práticas da população. Cadernos de saúde pública
Bollati M, Alvarez K, Assenberg R, Baronti C, Cook S, Coutard B, et al
. Structure and functionality in flavivirus NS-proteins: perspectives for drug design. Antiviral Research
2010; 87(2): 125–48.
Bordoli L, Kiefer F, Arnold K, Benkert P, Battery J, Schwede T. Protein structure homology modeling using SWISS-MODEL workspace. Nature Protocols
Breda A, Basso LA, Santos DS, Azevedo Jr. WF. Virtual screening of drugs: Score functions, docking, and drug design. Current Computer-Aided Drug Designs
Kitchen DB, Decornez H, Furr JR, Bajorath J. Docking and scoring in virtual screening for drug discovery: methods and applications. Nature Reviews Drug Discovery
2004; 3(11): 935–49.
Trott O, Olson AJ. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. Journal of Computational Chemistry
2010; 31(2): 455–61.
Pujadas G, Vaqué M, Ardévol A, Bladé C, Salvado MJ, Blay M, et al
. Protein–ligand docking: a review of recent advances and future perspectives. Current Pharmaceutical Analysis
Zhao H, Guo Z. Medicinal chemistry strategies in follow-on drug discovery. Drug Discovery Today
Jaghoori MM, Bleijlevens B, Olabarriaga SD. 1001 Ways to run AutoDock Vina for virtual screening. Journal of Computer Aided Molecular Design
2016; 30(3): 237–49.
Lima WEA, Pereira A, Castro AA, Cunha EFF, Ramalho TC. Flexibility in the Molecular Design of Acetylcholinesterase Reactivators: Probing Representative Conformations by Chemometric Techniques and Docking/QM Calculations. Letters in Drug Design & Discovery
Yotmanee P, Rungrotmongkol T, Wichapong K, Choi SB, Wahab HA, Kungwan N, et al
. Binding specificity of polypeptide substrates in NS2B/NS3pro serine protease of dengue virus type 2: A molecular dynamics Study. Journal of Molecular Graphics & Modelling
2015; 60: 24–33.
Taranto AG, Carvalho P, Avery MA. QM/QM studies for Michael reaction in coronavirus main protease (3CL Pro). Journal of Molecular Graphics & Modelling
2008; 27(3): 275–85.
Andrade DVG, Góes-Neto A, Comar-Junior M, Taranto AG. Comparative modeling and QM/MM studies of cysteine protease mutant of Theobroma cacao. International Journal Quantum Chemistry
2012; 112(19): 3164–3168.
Lin H, Truhlar DG. QM/MM: what have we learned, where are we, and where do we go from here? Theoretical Chemistry Accounts
2007; 117(2): 185–199.
Field MJ, Bash PA, Karplus M. A combined quantum mechanical and molecular mechanical potential for molecular dynamics simulations. Journal of Computational Chemistry
1990; 11: 700.
Thompson JD, Higgins DG, Gibson TJ. CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Research
Breda A, Basso LA, Santos DS, De Azevedo Jr. WF. Virtual screening of drugs: score functions, docking, and drug design. Current Computer Aided Drug Design
Secretaria de Saúde do Paraná. Manual de Normas e Procedimentos para vacinação – Dengue. 2016. [cited 2018 Oct 20]. Available from: www.saude.pr.gov.br/arquivos/File/VacinaDENGUE_protocolo.pdf
(Accessed on October 20, 2018)
[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2]