Co-circulation of dengue, chikungunya, and Zika viruses in Colombia from 2008 to 2018

ABSTRACT Objective. This study aimed to identify the co-circulation patterns of three viruses (dengue, Zika, and chikungunya) in Colombia from 2008 to 2018 by using notification reports provided to the national surveillance system. Methods. This cross-sectional study was conducted through a review of data for 2008 through 2018 from Colombia’s Public Health Surveillance System (SIVIGILA). Results. In 2015, when chikungunya was first detected, it had a higher incidence (1 359.0 cases per 100 000 persons) than did the two other diseases. In 2016, when the circulation of Zika virus was first found, the incidence was 296.4 cases per 100 000 persons; that incidence declined dramatically in the next two years. Between 2015 and 2018, there was a substantial decrease in the frequency of dengue circulation, with it going from 334.1 cases per 100 000 persons in 2015 to 90.7 cases per 100 000 in 2017 and 173.1 cases per 100 000 in 2018. Conclusions. The decrease in the number of dengue cases after co-circulation of the three viruses could indicate possible cross-protection. This finding should be further analyzed.

In the Americas, CHIKV, which is an alphavirus, emerged for the first time at the end of 2013, and has infected over one million individuals since then (5). ZIKV is a flavivirus that emerged in the Americas in 2015 and 2016. An estimated 80% of acute ZIKV infections are asymptomatic, and the remaining 20% clinically resemble CHIKV and DENV infection, including with symptoms of fever, rash, headache, and arthralgia (5)(6)(7). Neurological complications, including Guillain-Barré syndrome, have also been reported after ZIKV infection (8,9). Importantly, ZIKV infection during pregnancy is associated with severe teratogenic effects, including microcephaly (8)(9)(10)(11).
This study aims to describe the co-circulation of DENV, CHIKV, and ZIKV in Colombia, in order to identify epidemiological patterns that may provide insight into the immunologic interactions of these co-circulating viral infections in that country.

MATERIALS AND METHODS
This cross-sectional study was performed in Colombia by reviewing data from the country's Public Health Surveillance System, which is under the leadership of the country's National Institute of Health.

Study area
Located in northwest South America, Colombia has a population of 47 million people. It is divided administratively and politically into 33 divisions: 32 departments (with their respective capital cities) and the capital district, Bogotá. The departments of Antioquia, Boyacá, Caldas, Cauca, Cundinamarca, Huila, Nariño, Norte de Santander, Quindío, Risaralda, Santander, Tolima, and Valle del Cauca compose the Colombian Andes, and most of their capital cities are at an altitude of more than 2 000 m above sea level. The departments of Boyacá, Cundinamarca, and Nariño have a cold climate, but the departments of Antioquia, Caldas, Cauca, Norte de Santander, Quindío, Santander, and Tolima are in a temperate or warm climate. The departments of Huila, Risaralda, and Valle del Cauca are in warm climates.

Colombian public health surveillance system
Colombia's Public Health Surveillance System (SIVIGILA) consists of an organized association of users, rules, procedures, and resources (financial, technical, and human) for the collection of data and for the analysis, interpretation, and dissemination of information regarding health events. Among the health concerns that SIVIGILA monitors are dengue, Zika, and chikungunya. Information on these diseases flows from clinics and hospitals to organizations responsible for health insurance and to territorial health entities, where data is consolidated and then sent to the National Institute of Health (INS), which is the governing body for health surveillance in Colombia.

Data collection and case definitions
The data reported in this article correspond to the cases reported to SIVIGILA. As described below, three SIVIGILA case definitions were used for data collection.
Dengue cases were defined as all people with acute febrile illness (< 7 days) with two or more of the following manifestations: headache, retro-orbital pain, myalgia, arthralgia, or rash. Dengue cases of concern included anyone who met the above definition and also displayed any of the following warning signs: intense pain, continuous abdominal pain, persistent vomiting, diarrhea, drowsiness and/or irritability, postural hypotension, painful hepatomegaly greater than 2 cm, decreased diuresis, hypothermia, mucous membrane hemorrhage, or abrupt drop in platelet levels (< 100 000) associated with hemoconcentration.
Zika cases were defined as all people with laboratoryconfirmed natural circulation of ZIKV two weeks before the onset of symptoms and who presented with rash and one or more of the following signs: fever < 38.5 °C, nonpurulent conjunctivitis or conjunctival hyperemia, arthralgia, myalgia, headache, or general discomfort. Laboratory confirmation included the detection of Zika-specific IgM antibodies in the serum.
Chikungunya cases were defined as all people who presented with fever > 38 °C, severe arthralgia or acute onset arthritis, erythema multiform, or symptoms that were not explained by other medical conditions. Furthermore, individuals must have resided or visited a municipality with evidence of CHIKV circulation or a municipality within 30 km of a municipality with viral circulation.

Data analysis and data summary
A descriptive data analysis involving the absolute and relative frequencies of variables and their proportions by department was performed. Additionally, the 95% confidence intervals (95% CIs) of the relative frequencies were determined. Quantitative variables, such as age, were described using median, standard deviation, minimum, and maximum values. Incidence was calculated per 100 000 inhabitants, and frequencies and percentages were used to describe the main characteristics of the cases for variables such as age, sex, and department. The rates were also stratified by department.

Study period
For dengue, data on cases reported since 2008 were used in this study. However, in addition, cases were reviewed since the 1970s to understand the historical behavior of DENV circulation in Colombia. For CHIKV and ZIKV, data obtained since these viruses first circulated in the country were used.

Data quality check
Because the information used in this study originated from secondary sources, misclassification bias was a potential limitation. We attempted to minimize this bias by using only laboratory-confirmed cases that were reported to the SIVIGILA.

Geographic distribution of cases
This analysis aimed to describe the geographic distribution of Zika, dengue, and chikungunya cases in Colombia based on the residence of people diagnosed with these viruses, and to identify areas with a high incidence of cases and co-circulation of the three viruses.
Colombia's 1991 constitution institutes the country as a unitary republic that is divided administratively and politically into 33 divisions: 32 departments and a capital district, Bogotá. The departments form geographic, cultural, and economic regions. In Colombia, resources pass from the nation to the departments and from departments to the municipalities, except for Bogotá, which receives resources directly from the nation because it is the capital district.
Besides the 32 departments and the capital district, Colombia also has special districts and metropolitan areas. The special districts are municipalities that stand out for aspects such as their economic, political, or population weight (1), and the metropolitan areas correspond to the subregional integration of departmental capitals. Colombia has 1 101 registered municipalities (including five special districts), plus 20 nonmunicipalized areas and the island of San Andrés.

Ethical aspects
Because data from anonymous secondary SIVIGILA sources was used, this study was classified as without risk, according to the current ethical norms in Colombia. This classification includes studies that employ techniques and methods of retrospective documentary research and those in which no intervention or intentional modification of biological, physiological, psychological, or social factors of the individuals participating in the study is performed, which includes medical record reviews, interviews, questionnaires, and other methods by which patients could be identified or sensitive aspects of their behavior could be revealed.
In 2016, the national incidence of CHIKV in urban populations was 72.4 cases per 100 000 inhabitants. In addition, 12 deaths associated with CHIKV infection were reported.

Co-circulation of DENV, CHIKV, and ZIKV in Colombia
Colombia is a hyperendemic country for DENV transmission (1). In 2014, the situation was further complicated with CHIKV circulation (2), followed by ZIKV circulation in 2015 (3). This combination of similar viruses circulating in the country     presents challenges regarding case confirmation, given the similar clinical presentations and cross-reactivity of DENV and ZIKV in serologic tests. As shown in Table 2, two or all three arboviral diseases have co-circulated in Colombia since 2015, with the highest incidence generally reported for dengue. In 2015, CHIKV had the highest incidence of the three viruses, whereas by 2016, the rate of ZIKV had increased and dengue circulation had decreased compared with historical averages.

DISCUSSION
DENV, CHIKV, and ZIKV are arboviruses of great concern because of their impact on public health, particularly in countries such as Colombia. Based on DENV endemicity patterns, transmission patterns of these newer arboviruses can be determined. DENV has been the most prevalent arbovirus in Colombia for the last several decades. DENV is a public health priority in Colombia for multiple reasons. Its reemergence and intense transmission, with an increasing tendency toward frequent and severe DENV outbreaks, are particularly concerning. The simultaneous circulation of different serotypes, reintroduction of serotype 3, and infestation by Aedes aegypti in more than 90% of the country's territory located at less than 2 200 m above sea level make DENV circulation challenging to control. Furthermore, the introduction of Aedes albopictus and the growing trend of urbanization of the Colombian population because of recent violent conflicts in multiple areas further complicate dengue control. Finally, DENV tends to erupt in epidemic cycles every two to three years, but these cycles can be challenging to predict. For example, the epidemics of 1977, 2002, 2007, and 2010 were notable for the high numbers of cases. The 2010 outbreak is considered the most massive registered DENV epidemic in Colombia, with more than 150 000 confirmed cases, 217 deaths, and simultaneous circulation of all four serotypes. Interestingly, the number of DENV cases reported in 2015 decreased during the large-scale CHIKV and ZIKV epidemics. Various possibilities might explain this phenomenon. For example, there may have been underreporting of cases during the Zika epidemic because the only institution in Colombia that could do laboratory confirmation was the INS. Another possibility is that mosquitoes are unable to transport and transmit DENV simultaneously with CHIKV and ZIKV.
DENV infection occurs more frequently in the youngest age groups in Colombia, with the highest incidence being reported in individuals 5 to 14 years of age (15). This epidemiological behavior can be explained by the high endemicity of the country, in which people acquire DENV infection at an early age, generating immunity after the first episode. Similar trends can be expected in the future for CHIKV and ZIKV in several Colombian municipalities because of the similar DENV, ZIKV, and CHIKV transmission cycles that create the endemic establishment of these arboviruses (4). Another characteristic is the higher frequency of cases in men, which may occur because of infection in workplaces where the vector is present.
Campos et al. (7) reported an association of ZIKV infection in 42% of selected patients in northeastern Brazil. The same study also revealed CHIKV co-circulation in 12.5% of investigated cases. Several studies have suggested that the related arboviruses show a level of cross-protection. That is, prior exposure to a virus generates an acquired response after exposure to the second virus, which may decrease the likelihood of sequential infections. The evident reduction in dengue incidence after the co-circulation of the three viruses supports this hypothesis if it occurs in areas endemic for arboviruses. That is because in susceptible persons, no preexisting immune response can be expected for any of the arboviruses, and thus a low cross-response would occur (8,14).
The data in this study are similar to data reported for the city of São José do Rio Preto, Brazil. In 2016, that city experienced a dengue outbreak characterized by the co-circulation of DENV-1 and DENV-2 and infections with concurrent ZIKV (16). This created epidemiological conditions for the coinfections. In this outbreak, 12 cases of coinfection by DENV and ZIKV were identified.
Related data also come from a cross-sectional study that was conducted in Thailand in 2016 during the rainy season, from May to October (10). The results identified 163 cases in 182 patients (89.56%) infected with DENV, with predominance of DENV-2. Among cases that were positive for DENV, coinfection with CHIKV was identified in 6 patients (3.68%) and coinfection with ZIKV was identified in one patient (0.61%).
In 2014, two patients from New Caledonia were coinfected with DENV and ZIKV (14). Evidence for chikungunyadengue co-infection has also been found in Angola, Gabon, India, Madagascar, Malaysia, Myanmar, Nigeria, Saint Martin, Singapore, Sri Lanka, Tanzania, Thailand, and Yemen (17). In addition, a case with dengue, chikungunya, and Zika was reported in Colombia (18). The synergistic effects of these viral infections were observed because the patients did not require hospitalization and recovered after mild clinical courses.
Endemic dengue transmission is maintained and persists because of the inadequate and prolonged storage of water for human consumption; misperceptions of individual, collective, and institutional responsibilities for the problem; and noticeable social inequalities (11,12). Additionally, the interconnection between countries and the higher frequency and intensification of commercial and air transport networks have favored the diffusion, introduction, and transmission of different serotypes because of the rapid transit of individuals with viremia throughout various countries (11,12).
The same conditions that favor DENV endemicity are likely to contribute to and facilitate the introduction and emergence of ZIKV and CHIKV. For example, there is increased displacement of the population as carriers of viruses move from countries with epidemic transmission to areas that are very receptive to infection because of the persistence of environmental risks and the vulnerability of the entire population to infection (4,11).

Limitations
This study has used a secondary source of information, from Colombia's Public Health Surveillance System. With this surveillance system, there may be underreporting of disease cases and thus underestimation of the disease burden. Additionally, improper classification of a condition may be related to difficulties in obtaining laboratory confirmation of cases. Further research is necessary to understand the current trends in the co-circulation of arboviruses in the countries of Latin America.

Conclusions and recommendations
In Colombia in 2015, there was a higher incidence of CHIKV than of ZKV and DENV. In 2016, the incidence of ZKV increased, with a subsequent decrease in the frequency of DENV and CHIKV. This situation may reflect a synergistic effect of these viral infections, given that most of the patients reported did not require hospitalization and recovered after a mild clinical course.
To better understand this phenomenon, additional studies should be performed to assess the immunological cross-protection that can develop among the three viruses and the possibility of synergy of the three infections when coinfection appears.
Author contributions. Alejandro Rico and Alexandra Porras designed the study, performed the data analysis, and formulated the discussion section of the manuscript. Aileen Chang, Liliana Encinales, and Rebecca Lynch supported the data analysis and the preparation of the discussion section of the manuscript. All the authors reviewed and approved the final version of the manuscript.