Annual Percentage Change (APC) in syphilis cases
Between 2001 and 2017, 188,630 cases of CS and 235,895 cases of SiP were reported in Brazil. The mean overall rate of CS was 5.4 cases per 100,000 inhabitants during the period studied, ranging from 2.5 to 12.4, while the mean rate per 100,000 inhabitants of SiP was 6.3, ranging from 0.02 to 19.1. In regard to AS, 479,731 cases were estimated between 2010 and 2018, with a mean annual rate of 27.4 cases per 100,000 inhabitants (range: 8.6 to 45.3). From 2002 to 2016, joinpoint regression analysis revealed a generally increasing trend (Fig. 2), highlighting three distinct and statistically significant epidemiological periods. With respect to CS (Fig. 2A), an average annual notification rate of 2.9 cases per 100,000 inhabitants was seen in the first period (2002 to 2009; APC = 10.31 [95%CI: 0.5, 5.2], Z = 2.9, p < 0.05), which increased to 6.2 in the second period (2009 to 2014; APC = 25.47 [95%CI: 19.9; 31.3], Z = 11.8, p < 0.05). Finally, in the third period (2014 to 2016), the number of cases rose to 11.1 per 100,000 inhabitants (APC = 11.44 [95%CI: 1.3; 22.6], Z = 2.7, p < 0.05). Considering SiP (Fig. 2B), an average annual notification rate of 0.6 cases per 100,000 inhabitants was observed in the first period (2002 to 2006; APC = 203.26 [95%CI: 81.4; 406.9], Z = 5.1, p <0.05), which increased to 6.6 per 100,000 inhabitants (2006 to 2014; APC = 27.50 [95%CI: 23.8; 31.3], Z = 19.4, p < 0.05) in the second period. In the third period, the number of cases increased dramatically to 16.6 cases per 100,000 inhabitants (APC = 16.47 [95%CI: 3.6; 30.9], Z = 3.6, p < 0.05). Periods 1 and 2 of the three epidemiological periods identified by joinpoint regression in both CS and SiP were not similar in terms of length or specific years; however, Period 3 was coincident between these two infections. In spite of an increasing APC trend seen in AS during the period analyzed (2011-2017), no statistical significance was detected regarding this form of infection (data not shown).
Sociodemographic profile of syphilis in Brazil
Fig. 3 (see Additional file 2) illustrates changes in the profiles of the sociodemographic variables of CS cases during the three periods identified. Considering racial classification, the North, Northeast and Central-West macroregions reported more cases of CS among children who were identified as ‘mixed-race’ in the three periods: P1 (64.3%), P2 (78.6%), P3 (82.2%); P1 (51.2%), P2 (67.3%), P3 (70%) and P1 (29.6%), P2 (44.9%), P3 (51%), respectively. In the Southeast macroregion, more CS cases (25.9%) were identified among children identified as ‘white’ in P1, while in P2 (35.1%) and P3 (40.2%) more cases were identified as ‘mixed-race’. Conversely, in the South macroregion, CS was predominant among children identified as ‘white’ in P1 (59.7%), P2 (66.4%) and P3 (66.7%). With respect to age, more than 88% of the reported cases were diagnosed among children less than 7 days old in all periods and all macroregions. With respect to prenatal care among the CS cases, over 70% reported receiving prenatal care regardless of period and macroregion, suggesting a lack of protection against CS. Interestingly, CS was generally reported in all macroregions at similar frequencies among males and females (about 50%).
Fig. 4 (see Additional file 3) illustrates changes in the sociodemographic profile of SiP during the three distinct periods identified. With respect to self-reported skin color, the North and Northeast macroregions reported more cases of SiP in women who self-identified as ‘mixed-race’ throughout all periods: from 64.7% and 64.5% in P1, to 80.5% and 66.6% in P3, respectively. Among women who self-identified as ‘white’, most cases were concentrated in the South (49.7%) and Southeast (43.7%) macroregions in P1, while 67.1% of cases were reported in the South macroregion in P3. With respect to age, more than 66% of cases were reported in women aged 20 to 39 years in all macroregions and all three periods. Regarding education level, most reported cases were concentrated in pregnant women who had up to eight years of formal schooling in all three periods. With respect to clinical stage of syphilis, in P2 most pregnant women had primary syphilis (over 40% in all macroregions), while in P3 primary syphilis was predominant in the North (47.6%), Northeast (34.5%), South (35.2%) and Central-West (29%). Most cases of latent syphilis were concentrated in the Southeast (34.1%) in P3. No data was available in the SINAN database during period 1.
Space and time distribution analysis
Fig. 5 (see Additional file 4) illustrates the space and time distribution of reported AS cases over time, with significant changes seen in the notification rates of AS throughout Brazil in seven distinct time points by state. Initially, in 2011, relatively low numbers of AS cases (<16 cases per 100,000 inhabitants) were seen in almost all states, with the exception of Mato Grosso do Sul, São Paulo and Espírito Santo. By 2013, higher notification rates were concentrated in the states of Rio Grande do Sul, São Paulo and Espírito Santo (49-64 cases/100,000 inhabitants). By 2017, AS was much more widely distributed throughout the country, with notably significant increases seen in Rio Grande do Sul and Santa Catarina (>80 cases per 100,000 inhabitants), Mato Grosso do Sul (65-80 cases per 100,000 inhabitants), Paraná, São Paulo and Tocantins (49-64 cases per 100,000 inhabitants), as well as Minas Gerais, Rio de Janeiro, Sergipe, the Federal District and Roraima (33-48 cases per 100,000 inhabitants). Overall, the rate of AS rose around 400% from 2010 to 2018 in Brazil, with the most significant increases seen in Santa Catarina (+1010%), Rio Grande do Sul (+930%), Mato Grosso do Sul (+602%), as well as Tocantins, Paraná and Espírito Santo (+>500%) states.
Fig. 6 (see Additional file 5) depicts the space and time distribution of reported numbers of CS cases at 15 distinct time points. Overall, significant changes in the notification rates throughout Brazil are evidenced over time. Between 2002 and 2016, infection rates increased significantly from 2.5 to 12.4 per 100,000 inhabitants/year. The number of positive cases was found to increase in some microregions in Amapá, Espírito Santo, Tocantins, Pernambuco and Maranhão states, especially until 2007. The high numbers of cases were reported in the microregions of Macapá-AP (17.0 cases per 100,000 inhabitants), Linhares-ES (15.2 cases per 100,000 inhabitants) and Araguiana-TO (18.0 cases per 100,000 inhabitants). Interestingly, until 2012, increasing numbers of cases were notified in Continguiba-SE (29.3 cases per 100,000 inhabitants), Aracaju-SE (29.2 cases per 100,000 inhabitants) and Estância-SE (15.3 cases per 100,000 inhabitants). From 2012 to 2016, the cases of CS achieved a significant increase in almost all states, highlighting the South, Southeast, and Central-West macroregions.
The space and time distribution of reported rates of SiP is showed at 15 distinct time points in Fig. 7 (see Additional file 6). SiP rates were low in the country, in 2002 and 2003 years. Between 2002 and 2016, infection rates increased significantly from 0.04 to 19.1 per 100,000 inhabitants/year. In the North macroregion, Japurá-AM microregion shown high- notification rate from 2005 to 2016 reaching a peak of 5,122 cases per 1000,000 inhabitants in 2016. The Cassilândia-MS microregion also presented an increased in the numbers reaching 671 cases per 1000,000 inhabitants in 2016. On the other hand, from 2012 the number of positive cases was found to increase in some microregions of at least 13 states, as Santo Antônio de Pádua-RJ (1,994 cases per 1000,000 inhabitants in 2016), Itaguara-MG (1,278 cases per 1000,000 inhabitants in 2016), Jeremoabo-BA (791 cases per 1000,000 inhabitants in 2016) and Ibaiti-PR (683 cases per 1000,000 inhabitants in 2016). From 2001 to 2018 the relative risk of SiP increased about 4,000% in the country, highlighting only 556 microregions, except Oiapoque-AP and Brasília-DF which presented zero rates.
Spatial distribution of syphilis cases
Fig. 8 (see Additional file 7) illustrates the total number of cumulative cases of syphilis at the end of the evaluated periods, with states or microregions used as units of analysis. Between 2010 and 2018, most of the country experienced increased numbers of AS cases. By 2018, the highest rates of AS were found in the geographic south of the country (Rio Grande do Sul: 481, Espírito Santo: 459, and Mato Grosso do Sul: 424) versus 39 in Piauí and 37 in Alagoas states, both located in the geographic north. Of the 558 microregions evaluated between 2001 and 2017, 549 (98.4%) and 558 (100%) reported at least one case of CS and SiP, respectively. The spatial distribution of CS indicated that the Rio de Janeiro-RJ microregion had the highest cumulative notification rate (544/100,000). High numbers of cases were also reported in other microregions: Aracaju-SE (384/100,000), Cotinguiba-SE (366/100,000) and Araguaína-TO (359/100,000). With regard to SiP, higher notification rates were observed in the Japurá-AM (23,877/100,000), Santo Antônio de Pádua-RJ (14,603.7/100,000) and Itaguara-MG (6,441/100,000) microregions.