30 years of fatal dengue cases in Brazil: a review

The first reports of a disease with signs and symptoms compatible with dengue fever in Brazil, date back to 1846 [10]. Late 1981 and early 1982, a first dengue outbreak, caused by DENV-1 and DENV-4 was characterized in Brazil, which was restricted to the city of Boa Vista, Roraima (RR) in the north region [11]. In1986, after 4 years without dengue cases confirmation, an epidemic occurred due to the DENV-1 introduction in the state of Rio de Janeiro (RJ), which spread to other states [12]. Five fatal cases were confirmed in 1986. DENV-2 was detected, for the first time in RJ, in 1990 [13], when the first DHF/SCD cases occurred (n = 8). In the following years, DENV-1 and DENV-2 co-circulated and caused epidemics throughout the country [14] . Through 1999, a total of 75 fatal cases were reported (1991–1999), Fig. 1.

In December 2000, a newly introduced serotype, DENV-3, was initially detected in RJ [15] and quickly spread to other states of the country. The 2002 epidemic, caused mainly by DENV-3, was the largest and most severe epidemic experienced in the country so far, with increased hospitalizations and 150 deaths confirmed. It was suggested that, the introduction of a new serotype of Asian origin (Genotype III), would have been an explanation for the severity of the epidemic [16]. Despite the prevalence of Genotype III in Brazil, the co-circulation of Genotypes III and V was detected in Rondônia [17]. In 2002, the number of DHF deaths exceeded malaria deaths for the first time in the country [14].

Seventeen years after its introduction, DENV-2 reemerged in 2007 causing a major epidemic in 2008, with a higher proportion of DHF, more than double the number of cases reported in previous years [18]. A total of 561 deaths, mainly caused by this serotype, were reported only in that year (Fig. 1A). Oliveira et al. [19] observed that the DENV-2 emerged in the 2008 epidemic was genetically different from the strain introduced in 1990, and despite belonging to the same genotype, those viruses were considered a new lineage (Lineage II). Studies by Faria et al. [20] concluded that there were no nucleotide changes between the two strains that led to an increase in the severity of Lineage II viruses. On the other hand, Nunes et al. [21] demonstrated that the viremia of the DENV- 2 Lineage I cases was lower than that observed by Lineage II cases. Furthermore, severe cases caused by Lineage II, had 1000 times more circulating virus than those from Lineage I. The factors that led to the severity of this particular epidemic are still unclear. However, one cannot exclude the difficulties experienced in public health systems in controlling the epidemic, and the situation caused panic and insecurity throughout the Brazilian society [22, 23].

In 2009, DENV-1 reemerged with the possibility of a new epidemic, considering the low circulation of this serotype since the beginning of the decade. The 2010 epidemic presented a pattern quite different from the 2002 and 2008 epidemics, with the highest number of deaths (n = 656), reported. The DENV-1 isolated in Brazil between 2009 and 2010, belonged to Genotype V (American /African) and grouped in a clade (Lineage II) distinct from that of the previous isolates (Lineage I). Moreover, strains isolated in 2011 grouped in another distinct clade (Lineage III) [24]. The introduction of new strains resulted in the substitution of the circulating lineage and the increase in the genetic diversity of DENV-1, probably as a result of local evolution, or introduction of exogenous viruses during the same period or at different times [25].

In 2010, the risk of DENV-4 reintroduction into the country was imminent, as this serotype circulated in neighboring countries such as Venezuela and Colombia [26]. However, only in July of 2010, the first DENV-4 cases were identified in RR and Amazonas (AM), about 30 years after its first detection in the country. Less than 20 cases of DENV-4 were confirmed during the second half of 2010, and the first cases resulting from the spread of the virus, were detected only in January 2011, isolated in Amazonas and Pará. In March of 2011, the first DENV-4 cases were reported in RJ, introduced by the municipality of Niteroi [27, 28].

An increase in deaths was evidenced, especially in 2015, with an explosive epidemic of 1,649,008 dengue cases reported and 986 fatal cases confirmed. In 30 years a total of 11,084,755 suspected dengue cases were reported, with the confirmation of 5399 deaths nationwide (Fig. 1). The years that had the greatest chances of death were 2007–2009 (CI 95% 2.23–19.8), mainly due to the DENV-2 epidemic. The years of 2014–2015 had OR of 3.08–17.97 and, despite the co-circulation of the four serotypes, DENV-4 was predominant. In 2010–2011 OR were (CI 95% 2.492–14.48), when DENV-1 reemerged and DENV-4 was introduced (Table 1).

In 30 years, the Southeast region reported 43% (n = 2225) of all dengue deaths in the country. São Paulo (SP) confirmed 945 fatal cases, RJ, 738, Minas Gerais (MS) and Espírito Santo (ES) registered 430 and 196 deaths, respectively. In the Northeast, the states with the highest number of fatal cases were Ceará (CE) with 506, Pernambuco (PE) with 277, Bahia (BA) with 228 and Maranhão (MA) with 166. The Midwest region was responsible for 18% of the fatal cases, where the state of Goiás (GO) reported 600 deaths, Mato Grosso (MT), 187, Mato Grosso do Sul (MS), 128 and Distrito Federal (DF), 66. In the North region, only 7% of the deaths were confirmed. Pará (PA) was the state that reported the highest number of dengue deaths (n = 141) in the period. The South region, historically less affected by dengue cases, reported consequently the lowest number of dengue fatal cases (2%). Only Paraná (PR) (n = 108) and Rio Grande do Sul (RS) (n = 4) reported dengue deaths.

During 30 years of epidemics, we have observed that RJ historically contributed to the introduction and dissemination of DENV-1, 2 and 3, and since then, has constantly reported dengue fatal cases (Fig. 2). After 2000, deaths occurred in almost all states, with the exception of Santa Catarina (SC) and RS. From 2006 to 2010, possibly due to the introduction of DENV-3 and DENV-4, and re-emergence of DENV-1 and DENV-2, the number of deaths increased, with higher mortality rates in the states of RJ, Sergipe (SE), MS, Rondônia (RO) and RR. Rates were even higher in GO, but the state of MT had the highest mortality rate in this period. From 2011 to 2015, GO became the state with the highest mortality rate in the country, and RS reported the first dengue fatal outcomes.

The analysis of the mortality rates by municipality showed an increase of dengue fatal cases and distribution by the Brazilian territory over the years. In 2008, the North, Northeast and Southeast regions had higher mortality rates. In 2009, dengue deaths were distributed in the North and Midwest regions. From 2010 to 2012, dengue deaths occurred throughout the Brazilian regions (Fig. 2).

According to the WHO [9] dengue case criteria, infections were classified as dengue fever (DF), DHF and DSS. However, in 2000, the Brazilian MoH proposed the DCC classification, to define severe dengue cases that did not meet the WHO criteria for DHF/DSS. From January 2014 and on, Brazil adopted the new WHO 2009 classification. Therefore, in this analysis, DHF/DSS, DCC, DwWS and SD denominations were used, considering the epidemic year analyzed. The timeline and the characteristics of each classification are available in Table 2.

DHF cases fatality rates were high in 1994, 1997, 1998, 2006, 2012, and 2013. By DCC, deaths were more frequently reported in 2003, 2006, 2007, with increasing numbers from 2008 to 2013 and the latter, being the highest peak of DCC mortality. Considering the new classification, 3% of DwWS patients died in 2014. In 2014 and 2015, 8 and 7% of SD cases died, respectively (Fig. 3A).

The five-year case fatality rate of each state is shown in Fig. 4. From 1986 to 1990 the DHF fatality rate was up to 10% in RJ and Alagoas (AL). From 1991 to 1995, only RJ reported a DHF fatality rate up to 10%. That rate was five times higher (up to 50%) in CE, from 1996 to 2001. On the following years (2001 to 2005), fatality rates were up to 50% in MS, followed by GO (up to 40%), PB (up to 20%), and RJ, ES and PE with up to 10% of DHF cases evolving to death. From 2006 to 2010, this scenario changed and case fatality rate increased in almost all states, being higher in DF (up to 50%), PR (up to 40%), PA and RR (up to 30%) and TO (up to 20%). From 2011 to 2013, the states of PR, SP, MG, TO, PI, AP had up to 20% DHF fatality rate, however those were higher in CE with 21–30% and DF with 31–40% (Fig. 4A). In the years of 1999–2003, 11 to 20% of the cases with DCC died in RR, and in MT, MS, PR, SP, RJ, BA, SE, AL, CE, MA and AP, up to 10% (Fig. 4B).

From 2004 to 2008, increased numbers of fatal cases by DCC were also reported in other Brazilian states, and AC, MS, PR reported up to 20%, RJ up to 30% and DF up to 40% of fatality rates, Fig. 3B. In 2009 and 2013 the number of deaths was lower, and the states of MA, CE, MS, MG, RJ, ES and PR had up to 20% of case fatality rate. Only the state of SC did not report fatal cases by DCC (Fig. 4B).

Considering the new WHO [1] criteria, case fatality rate by DwWS in PA, AC, RO, MT, MS, PR, SP, MG, RJ, ES, BA, CE RN and PE was around 5%, however in PB and AM, it reached 15% in 2014–2015 (Fig. 4C). In the same period, deaths from SD occurred in all states, except in SC, with high case fatality rates in the states of AC and RS (100%), AM, PB and DF with 81 to 99%, MG, SP, MS, MT, MA, PE, PB, CE, PA, RO with 51 to 80%, RJ, ES, BA, GO, TO, RR, SE, AL with 21 to 51% and in PR, PE and AP, with up to 20%, Fig. 4D.

In the 30 years period (1986–2015), a total of 2682 dengue deaths occurred on males and 2455 on females and, during the years, an equal distribution between the sexes, was observed.

From 1986 to 2006, dengue deaths occurred more often in individuals over 15 years old, Fig. 4B. This changed in 2007–2008, with the DENV-2 re-emergence, as more than 53% of the dengue deaths cases occurred in children 15 years old and under. In 2008 alone, 190 fatal cases on children from that age group were reported (Fig. 3C). After 2009, there was a decrease in fatal cases in children 15 years old and under, while fatal cases on individuals above 15 years old became more frequent, with peaks in the years 2010, 2013 and 2015.