Dengue: 30 years of cases in an endemic area

The present study aimed to review literature on studies of dengue cases conducted over 30 years in the state of Ceará. Between November 2015 and January 2016, articles published in Portuguese and English in 7 databases were searched using keywords and a Boolean operator. A total of 191 articles were identified in the databases; 133 were excluded according to the exclusion criteria, and 58 were included in the study. Of the 58 articles analyzed, 6 reported data from Brazil; including the Northeast region and the state of Ceará; 41 reported data for only the city of Fortaleza; 7 reported data for the state of Ceará; 4 reported data for cities in the interior of the state; and 3 included only children. The studies adopted different approaches and focused on different aspects of the disease. Study outcomes included the identification of serological, epidemiological, clinical, and laboratory characteristics; potential larvicides and biological predators of mosquitoes; potential antiviral agents; vector density characteristics; and educational dengue prevention and control strategies. Additionally, one vaccine trial was included. Although studies on dengue in the state of Ceará are scarce, they are encompassing, including several lines of research, and the number of studies and reports on dengue in the state of Ceará continues to increase.


' INTRODUCTION
The first dengue epidemic in Brazil is believed to have occurred between 1846 and 1853 in the cities of São Paulo and Rio de Janeiro (RJ) (1,2). At that time, the disease was known by other names, such as polka (a fashionable dance at the time), polka fever, and break-bone fever (3). However, dengue cases were first reported in medical literature in 1916 in the city of São Paulo and in 1923 in Niterói (1,2) . The first epidemic documented from a clinical and laboratory viewpoint occurred in late 1981 and early 1982 in Boa Vista, Roraima; this epidemic was caused by the dengue-1 (DENV-1) and dengue-4 (DENV-4) serotypes (4). In 1955, Brazil succeeded in eradicating Aedes aegypti (A. aegypti), eliminating the last mosquito source on the 2nd of April in a rural area in the municipality of Santa Terezinha, Bahia (5).
The first cases of A. aegypti reinfestation following eradication occurred in 1967 in Belém (Pará) and in 1968 in São Luiz (Maranhão); the source populations were finally eliminated in 1973. A. aegypti was again detected in 1976 in Salvador (Bahia) and in 1977 in RJ and then spread to other states (6,7). In 1986, a dengue epidemic (DENV-1 serotype) circulated in the state of RJ and quickly reached Northeast Brazil (7,8). From 1986 to 1990, dengue epidemics were limited to some Brazilian states in the Southeast (RJ, São Paulo and Minas Gerais) and Northeast regions (Alagoas, Bahia, Ceará and Pernambuco) (9).
A. aegypti was reintroduced in the Ceará cities of Aquiraz, Beberibe and Fortaleza in the mid-1980s (10). The first dengue cases occurred in August 1986, originating from tourists from RJ, where a dengue epidemic (DENV-1) was occurring, who were visiting the cities of Fortaleza and Canoa Quebrada (11).
For the dengue cases reported in the state of Ceará over 30 years, seven epidemics were recorded (1987, 1994, 2001, 2008, 2011, 2012 and 2015) (12,13). Ceará has 184 municipalities, 167 of which reported DENV transmission in 2015. From 1986 until 2016, 302,015 dengue cases were reported in the state (14). Dengue has therefore been endemic to Ceará for 30 years, resulting in high incidence rates caused by four circulating serotypes. The present study aimed to review literature on studies involving dengue cases in the state of Ceará conducted during these 30 years.

' METHODOLOGY
Between November 2015 and January 2016, articles in the Portal of CAPES Journals, Biblioteca virtual em saúde (BVS), Ebsco Host, Scientific Electronic Library Online (SciELO), PubMed, Science Direct and Google Scholar databases were searched. Scientific reports about dengue in Ceará from 1986 until 2016 were identified. The search was performed in both Portuguese and English using the Boolean operator ''and'' and the following keywords: ''Dengue and Ceará'', ''Dengue and Fortaleza'', ''Dengue virus and Ceará'', ''Dengue virus and Fortaleza'', ''Dengue virus Ceará'' and ''Dengue virus Fortaleza''. To organize the information contained in the scientific articles identified with the descriptors, the articles were fully read, and the objectives, study type, location, period, methods, importance and results were identified. Published scientific reports such as letters, original articles and brief communications to national and international journals were included in the search according to the descriptors and peer reviewed. After preanalysis, scientific literature identified in more than one database that was accounted for as a single work, congress abstracts, theses, dissertations and articles that included no data for the state of Ceará were excluded. A total of 191 articles were identified in the databases; 133 articles were excluded according to the exclusion criteria, and 58 articles were included in the study (Figure 1).  To correlate laboratory tests during the progression of dengue fever with symptoms to predict the severity of the disease. In patients with CD, thrombocytopenia and elevated transaminase levels were observed; in those with DHF, the thrombocytopenia and elevated transaminase levels were similar to those in patients with SD, while the hemoconcentration was not. The results can be used as markers for more severe forms of the disease. To report a fatal case of coinfection with severe dengue and melioidosis. Melioidosis should be considered among differential diagnoses in endemic disease areas.

2013
Retrospective To report myocarditis due to dengue, which is rarely diagnosed. Myocarditis caused by DENV occurred in four confirmed cases. Therefore, there is a need to assess cardiac function in all patients with acute dengue who may benefit from therapy to prevent death from heart disease. To investigate the hypothesis that some specific comorbidities increase the likelihood of DF progressing to DHF in adults. The progression to DHF was associated with hypertension and skin allergy.
Therefore, these patients should remain in healthcare facilities to monitor progression.

2015
Descriptive To describe clinical manifestations and renal involvement in cases of dengue in renal transplant patients. Of the renal transplant recipients, 10 were diagnosed with dengue, 5 were hospitalized, 4 developed DHF, and none died.

35
' RESULTS AND DISCUSSION Of the 7 databases analyzed, only Google Scholar did not contain articles related to the descriptors of the present work.
Of the 58 reports analyzed, 6 (10.3%) reported data from Brazil, including the Northeast region and the state of Ceará; 41 (70.6%) reported data for only the city of Fortaleza; seven (12%) reported data for the state of Ceará; and four (6.8%) reported data for cities in the interior of the state (one in Icaraí (Caucaia); one in Juazeiro do Norte, Crato and Barbalha; one in Tauá and one in Pacoti) (Tables 1 and 2). Of the reports analyzed, 39 (67.2%) included only adults, 16 (27.5%) included children and adults, and 3 (5.2%) included only children (15)(16)(17).

Epidemiological aspects
A literature study about dengue and the control of A. aegypti in Ceará, based on epidemiological bulletins, found that five dengue epidemics, with high incidence rates, occurred in Ceará between 1986 and 2011, and children were most affected from 2008 to 2010. Annually, during the studied period, an average of 120 municipalities reported infestation with A. aegypti, and 84 reported dengue transmission (18).
In 2014, the city of Fortaleza was a World Cup host city, and a study was performed to investigate the potential for a dengue epidemic in the 12 World Cup host cities (19). Realtime seasonal climate forecasts were performed based on several international sources, and epidemiological predictions for dengue in Brazil were analyzed. The results showed reduced risks of dengue in the cities of Brasília, Cuiabá, Porto Alegre and São Paulo. Some cities were considered to have moderate risk (Belo Horizonte, Salvador and Manaus), and some cities, such as Recife, Natal and Fortaleza, located in Northeast Brazil, were considered to have high risk (19).

Clinical and laboratory aspects
For the period analyzed (1986-2016), we selected manuscripts that described the clinical and laboratory aspects of the disease in Ceará (Table 1).

Larvicides and biological predators/antiviral drugs/ vectors
Larvicides and biological predators are used as methods to fight the spread of mosquitoes. In the present review, following stratification of the 58 selected reports, 13 (22.4%) were found to address the use of larvicides and biological predators against A. aegypti (40-52) ( Table 2). Other studies examined the vectors A. aegypti and Aedes albopictus (A. albopictus) (53-58) or investigated antiviral drugs against dengue (59,60). The main findings of these studies are listed below (Table 2).

Educational actions
After stratification, two reports about educational actions were found. The first was performed in Icaraí (Caucaia) and concerned dengue prevention and control actions, evaluating the limitations and difficulties found. The seventeen individuals who participated in the study were distributed into three groups: eight were users of a Basic Health Unit, four were endemic disease control agents, and five were health care professionals. Data were collected by participant observation and professional/user interactions that occurred throughout the study. The study concluded that actions that To analyze cases of severe dengue in the early postoperative period of renal transplantation. After performing renal transplantation, two severe cases of dengue were reported.
The authors report the importance of screening for dengue before transplantation in endemic disease areas. To report the detection of undeclared dengue deaths. Ninety dengue deaths were detected that were not suspected during disease progression. The authors suggest the need to improve primary health care to identify cases of fatal dengue and thus prevent death.  values of 67 ppm and 60 ppm, respectively, and the authors suggest a beneficial use of these essential oils for controlling A. aegypti.

Capraria biflora
To evaluate the larvicidal activity of C. biflora against A. aegypti.
C. biflora oil contains 14 essential oil constituents and shows good larvicidal activity against A. aegypti.

49
Leaves of Hyptis martiusii Benth To evaluate the insecticidal activity of the chemical components of the volatile oils of H. martiusii Benth.
Twenty-six compounds, representing 93.2% of the leaf essential oils, were characterized, and the leaf essential oil and 1,8-cineole showed an insecticidal effect against A. aegypti larvae.

Seed extract of Myracrodruon urundeuva
To isolate m-pentadecadienyl-phenol from M. urundeuva seeds and test its activity in three life stages of A. aegypti to elucidate its mode of insecticidal action.
m-Pentadecadienyl-phenol was shown to be a potent larvicide, with inhibitory activity on pupae and in the egg incubation phase.

Temephos
To evaluate the susceptibility of A. aegypti eggs and larvae to the organophosphate temephos.
Resistance to temephos was observed, demonstrating that populations of A. aegypti are under strong temephos selection pressure, compromising efficacy. Temephos and the pyrethroid cypermethrin To describe resistance to temephos and the pyrethroid cypermethrin in three populations and to use biochemical and molecular assays to characterize resistance mechanisms.
Two populations of A. aegypti were under strong temephos selection pressure, compromising the efficacy of this organophosphate, and resistance to cypermethrin was observed in two of the three populations studied.

A. albopictus
To publish the first record of A. albopictus in an urban area in the city of Fortaleza, state of Ceará .
Thirteen specimens of A. albopictus were identified (all female), and their introduction into Fortaleza was favored by the migration of people from other regions.

54
A. aegypti and A. albopictus To identify the areas of occurrence, breeding sites, and associations with A. aegypti and other Culicidae.
The absence of one of the species at the breeding sites increased infestation by the other species, and breeding sites not infested by A. albopictus had twice the prevalence of A. aegypti.

55
A. aegypti To evaluate the daily survival probability of A. aegypti.
Survival analyses indicated that the mortality of A. aegypti varied with the age of the mosquitoes and with the local environment.

A. aegypti
To estimate the variability of the survival rate of A. aegypti and determine how the climate is related to this variation. strengthened the power and responsibility of individuals over their own history and their local citizenship were needed (61). The second report was a case study involving six blocks, with each block corresponding to 40 houses in Fortaleza. The aim of the study was to evaluate the implementation of an intervention strategy to decrease the amount of A. aegypti. Fortaleza is divided into six administrative regions (SERs), and in this study, one block in each of the six SERs was selected to understand the ecological, biological, and social complexity and diversity in Fortaleza.
The results showed a complex interaction between socioenvironmental inequalities and dengue control. The ethnographic data and interviews of those in the studied SERs reflected the environmental and socioeconomic complexity of a large city in a developing country such as Brazil, which has struggled with the serious public health problem of dengue (62). Two reports concerning risk factors associated with dengue were included. One case-control study analyzed low-income housing development on the coast of Fortaleza with the aim of increasing the efficacy of control measures against dengue during a dengue outbreak. A total of 211 households were investigated using a questionnaire to collect socioeconomic, behavioral, and environmental risk data for cases and controls. Cases were defined according to the national guidelines for the control of dengue based on the detection of dengue IgM antibodies; 34 cases and 34 controls were investigated. An analysis of the epidemic in a lowincome housing development showed the presence of several known risk factors because human behavioral components are difficult to manipulate. However, other factors, such as the frequency of visits by vector control agents, could be solved by making simple changes within municipal services (63).
Another study evaluated the implementation of an intervention strategy to decrease the amount of A. aegypti in 2012 and 2013. Participants were divided into 10 intervention groups and 10 control groups, and activities such as workshops, cleaning campaigns, and student and older inhabitant mobilization were conducted. Differences in social participation, commitment and leadership were observed between the groups, and a higher efficacy was observed in the intervention group than in the control group. Social participation and environmental management are viable and promising alternatives to vector measures for dengue vector control (64).

' CONCLUSION
Dengue remains a serious public health problem and constitutes a threat to the Brazilian population. The tropical climate of Brazil favors the proliferation of dengue and the four serotypes (DENV-1 to DENV-4) that circulate in Brazil. Vector control is still the most effective means of protection against the spread of the disease but remains ineffective against the numerous epidemics occurring every year in Brazilian cities. Serological diagnostic tests also need to be improved because cross-reactions with other arboviruses often occur.
From the present review, we conclude that although studies on dengue in the state of Ceará are scarce, they are encompassing, including several lines of research, and the number of studies and reports on dengue in the state of Ceará continues to increase.

' ACKNOWLEDGMENTS
The authors would like to thank the Medical Sciences Graduate Program of the University of Fortaleza, the Edson Queiroz Foundation, the Cearense Foundation for Scientific and Technological Development Support (FUN-CAP), and the National Council for Scientific and Technological Development (CNPq). Grant holders: Danielle Malta Lima (PQ-2 CNPQ), Jane Cavalcante Amaral (PIBIC/CNPq) and Daniela Cristina Sensato Monteiro (FUNCAP).

' AUTHOR CONTRIBUTIONS
Monteiro DCS contributed to the study design, data collection, analyzed and interpreted data. Cavalcanti LPG and Colares JKB assisted with the design of the study survey, data interpretation and manuscript reviews. Araújo FMC assisted with data interpretation, and manuscript writing and review. Martins VEP and Ramalho ILC reviewed the manuscript. Souza NV, Amaral JC and Lima KB participated in the conceptualization of the study, data collection and manuscript reviews. Lima DM conceived the study, participated in the study design, coordination, and reviewed the manuscript. All authors read and approved the final version of the manuscript.