Rapid increase of syphilis in Tokyo: an analysis of infectious disease surveillance data from 2007 to 2016

The objective of this study was to examine the trends of primary and secondary syphilis in Tokyo between 2007 and 2016 using national infectious disease surveillance data. We analysed all 3269 cases reported during these 10 years. A statistically significant increase in cases was observed after 2010 with a more rapid rate of increase after 2014 mainly in urban areas in Tokyo. The notification rates per 100 000 population in 2010, 2014 and 2016 were 0.9 (n = 113), 2.2 (n = 295) and 8.7 (n = 1190), respectively. Domestic syphilis transmission was suspected in 92.6–99.3% of cases during the period 2007–2016. Until 2013, the increase was mainly observed among men who have sex with men (MSM); however, heterosexual transmission became more dominant and eventually surpassed transmission among MSM in 2015. In 2016, the notified cases of infections through heterosexual contact were 22.3 and 40.4 times higher in men and women, respectively, compared to those in 2010. The median ages of affected heterosexual men and women were 37 (interquartile range: 28–46) and 26 (interquartile range: 22–32) years, respectively. Reports of oropharyngeal lesions have been increasing among both men and women with syphilis. The number of congenital syphilis cases reported in Tokyo was 0 to 3 cases per year during the study period. More information and further analysis are needed to explain the reason for this increase.

The objective of this study was to examine the trends of primary and secondary syphilis in Tokyo between 2007 and 2016 using national infectious disease surveillance data. We analysed all 3269 cases reported during these 10 years. A statistically significant increase in cases was observed after 2010 with a more rapid rate of increase after 2014 mainly in urban areas in Tokyo. The notification rates per 100 000 population in 2010, 2014 and 2016 were 0.9 (n = 113), 2.2 (n = 295) and 8.7 (n = 1190), respectively. Domestic syphilis transmission was suspected in 92.6-99.3% of cases during the period 2007-2016.
Until 2013, the increase was mainly observed among men who have sex with men (MSM); however, heterosexual transmission became more dominant and eventually surpassed transmission among MSM in 2015. In 2016, the notified cases of infections through heterosexual contact were 22.3 and 40.4 times higher in men and women, respectively, compared to those in 2010. The median ages of affected heterosexual men and women were 37 (interquartile range: 28-46) and 26 (interquartile range: 22-32) years, respectively. Reports of oropharyngeal lesions have been increasing among both men and women with syphilis. The number of congenital syphilis cases reported in Tokyo was 0 to 3 cases per year during the study period.
More information and further analysis are needed to explain the reason for this increase.
The objective of this study was to examine the trends of primary and secondary syphilis in Tokyo between 2007 and 2016 using national infectious disease surveillance data. We analysed all 3269 cases reported during these 10 years. A statistically significant increase in cases was observed after 2010 with a more rapid rate of increase after 2014 mainly in urban areas in Tokyo. The notification rates per 100 000 population in 2010, 2014 and 2016 were 0.9 (n = 113), 2.2 (n = 295) and 8.7 (n = 1190), respectively. Domestic syphilis transmission was suspected in 92.6-99.3% of cases during the period 2007-2016.
Until 2013, the increase was mainly observed among men who have sex with men (MSM); however, heterosexual transmission became more dominant and eventually surpassed transmission among MSM in 2015. In 2016, the notified cases of infections through heterosexual contact were 22.3 and 40.4 times higher in men and women, respectively, compared to those in 2010. The median ages of affected heterosexual men and women were 37 (interquartile range: 28-46) and 26 (interquartile range: 22-32) years, respectively. Reports of oropharyngeal lesions have been increasing among both men and women with syphilis. The number of congenital syphilis cases reported in Tokyo was 0 to 3 cases per year during the study period.
More information and further analysis are needed to explain the reason for this increase. S yphilis is a common sexually transmitted infection. In 2012, an estimated 5.6 million new syphilis infections among people aged 15 to 49 years were reported globally. 1 In Japan, a venereal disease prevention law passed in 1948 mandated a syphilis patient notification system. The Ministry of Health, Labour and Welfare consolidates data using the National Epidemiological Surveillance of Infectious Disease (NESID) system. 2,3 Although syphilis cases nationwide decreased from 216 617 in 1948 to 621 in 2010, they rebounded afterwards, reaching 4546 in 2016. 2,3

Surveillance
Medical institutions report cases to NESID through public health centres. In 2015, 31 public health centres and approximately 13 600 medical institutions served the 13.5 million residents of Tokyo. 4,5 Syphilis diagnosis and treatment are widely available throughout the metropolitan area, including at community medical facilities. Free and anonymous syphilis and HIV testing is also offered by most municipal public health centres and the Tokyo Metropolitan Testing and Counselling Offices.
Physicians are required to report cases of early symptomatic (primary and secondary [P&S]) syphilis, late symptomatic syphilis, asymptomatic syphilis and congenital syphilis (CS) via facsimile to public health centres using a designated paper notification form. Public health centre staff then register cases online to NESID. Demographic and clinical information, date of diagnosis and epidemiological information (e.g. location of disease transmission, sexual history) are consolidated in NESID. All registered syphilis cases are verified by surveillance officers in the Tokyo Metropolitan Infectious Disease Surveillance Center (TMIDSC), which publishes weekly surveillance reports. 6

Data collection
We extracted cases of P&S syphilis and CS in Tokyo from 1 January 2007 to 31 December 2016 from NESID. Tokyo consists of 23 special wards (central), the Tama area (suburban) and the islands (suburban) (Fig. 1). We used Descriptive analysis of CS was performed considering date of diagnosis.

Regression analysis
We focused on P&S syphilis to analyse trends in cases using a generalized linear model. We offset a Poisson regression model by the estimated annual population and compared every pair of adjacent years by two-sample tests for equality of proportion. For comparison, we employed the notified cases of P&S syphilis and the estimated annual population of Tokyo.
All statistical analyses were done with R software version R-3.4.1 (R Foundation for Statistical Computing, Vienna, Austria). A p value of <0.05 was considered statistically significant. We performed Bonferroni corrections for multiple comparisons. The number of tests that compared adjacent years was nine, so the significance level for each test was set to 0.0056. NESID surveillance definitions to define early symptomatic syphilis and CS. Early symptomatic syphilis was defined as an individual who tested positive in both nontreponemal and specific treponemal tests with at least one clinical sign or symptom (primary: painless chancre; secondary: painless inguinal lymphadenopathy, syphilitic roseola, papular syphilide or condyloma lata). 2,3 CS was defined as a live infant with signs or symptoms of CS or a positive serological examination. 2,3

Descriptive analysis
We performed descriptive analysis of early symptomatic syphilis cases considering sex, age, diagnosis date, syphilis stage, symptoms, sex of partner, suspected location of disease transmission (Tokyo, other prefectures in Japan, outside of Japan or unknown) and location of the reporting medical facility (central or suburban Tokyo). Sex partner preferences were categorized as men who have sex with men (MSM), men who have sex with women only (MSW), men who have sex with men and women (MSMW), women who have sex with men only (WSM), women who have sex with women (WSW), women who have sex with women and men (WSWM) or sexual contact type unknown. The notification rate was calculated

Ethics statement
This study was exempt from ethical review committee review since the data were surveillance data conducted under the provisions of Japanese law. The data collected in this study do not contain personal information.

Notifications and rates
Overall and by sex The notification rate of P&S syphilis was 8.7 per 100 000 population (n = 1190) in 2016, 9.7 times higher compared to 0.9 (n = 113) in 2010 and a fourfold increase compared to 2.2 (n = 295) in 2014 (Fig. 2). The annual notification rate for men exceeded that for women throughout the period of 2007 to 2016. Both men and women had the highest notification rate in 2016, which was 13.0 (n = 875) for men and 4.6 (n = 315) for women.

Sources of notification reports
Annual notification rates from central Tokyo exceeded those from the suburbs (Fig. 2). In central Tokyo, the notification rate was 1.

Trend analysis
The model shows that cases trended upward throughout the study period (P < 0.001) (Fig. 3). There was a statistically significant increase in the number of cases from 2012-2013, 2014-2015 and 2015-2016 (P < 0.0056).

Suspected location of disease transmission
The proportions of cases with suspected transmission within Japan ranged from 92.6% to 99.3% during the study period. The proportions of domestically acquired infections stemming from Tokyo ranged from 87.6% to 96.3%.  (Fig. 6B). Affected MSW with oropharyngeal lesions sharply increased in 2015 and 2016 (Fig. 7); the proportion was 3.5% in 2015 and 3.4% in 2016.

Men who have sex with men and women
The notified cases in MSMW were 0 to 3 cases per year in 2007 to 2015. In 2016, six cases were reported.

Disease stage
A total of 1198 primary cases and 2071 secondary cases were reported from 2007 to 2016 (Fig. 4). The number of primary syphilis cases had been declining; they started increasing again after 2010. The number of secondary syphilis cases has consistently increased since 2007. In 2016, the number of primary cases was 533, a 31-fold increase since 2010. The number of secondary cases was 657, a sevenfold increase during the same period.

Men who have sex with men
Infections among MSM steadily increased from 2007 to 2016 (Fig. 5). The number of cases among MSM was 4.  (Fig. 6C). Oropharyn-

Women who have sex with men only
The notified cases in WSM were stable between 2007 and 2012; however, they increased in 2013 to 2014 and markedly increased in 2015 and 2016, mirroring the trend seen in the MSW population (Fig. 5). There and WSM increased rapidly after 2014, resulting in a larger number of cases transmitted through heterosexual contact than among MSM in 2015. We conclude that heterosexual transmission is a significant driver of the increase in syphilis cases in Tokyo with a contributing increase of cases among MSM.
The disproportionate increase in primary-stage syphilis may be due to increased ascertainment from prompt health-care seeking and improved recognition among clinicians. However, secondary syphilis also increased sevenfold, suggesting that the increase in primary syphilis cases may be due to increased incidence. Reports of oropharyngeal lesions increased among both men and women with syphilis. The proportion of those with oropharyngeal lesions did not vary considerably among MSM, MSW and WSM. The oral cavity can be a point of entry for syphilis, and an oropharyngeal lesion can be a source of syphilis infection. 7 Providers and the public should be aware that syphilis can be transmitted through oral sex.
We are concerned about the increase of syphilis in young women. An increase of syphilis among women occurred in the 2010s in the United States of America that resulted in increased CS incidence. 8 CS is preventable; pregnant women and their partners should be encouraged to seek appropriate prenatal care, including routine prenatal screening and treatment of syphilis. geal lesions increased among WSM in 2015 and 2016 (Fig. 7); the proportion was 4.1% in 2015 and 4.2% in 2016.

Women who have sex with women
Only one case of syphilis, reported in 2015, involved WSW.

Women who have sex with women and men
Two cases, reported in 2015, were in WSWM.

Sex of partner
In response to the increase in syphilis cases, TMG provided clinician training sessions on testing and treatment, expanding syphilis testing opportunities, adding home address and nationality to surveillance information and updating public educational materials (including an e-learning curriculum).
Targeted interventions are needed to curb the rising number of syphilis cases. Continued surveillance and additional analysis are needed to identify and mitigate factors causing the increase. Public health strategies to prevent and treat infections in young women are imperative to preventing CS. Curbing syphilis cases in Tokyo depends on increased awareness and the collaborative efforts of health-care providers, educators, media, academia and the public.
The notification rate in central Tokyo exceeded that in the suburbs. One potential explanation is that there are more medical facilities with infectious disease departments in central Tokyo. Though the notification rate in suburban areas is low, it has increased, highlighting that syphilis is not a public health problem limited to urban areas.
During the study period, trends in syphilis cases at the national level were like those in Tokyo. National syphilis cases started increasing in 2011. Most cases were from large metropolitan areas such as Tokyo and Osaka. Cases among MSM and heterosexual men and women increased during the years 2011-2016. 2,3 Syphilis has been increasing globally since the 2000s, 9 including in countries neighbouring Japan. 10, 11 Global travel contributes to the spread of sexually transmitted infections; one study found that 20.4% of travellers have casual sexual contact during foreign trips. 12 As the Tokyo Metropolitan Government (TMG) is hosting the Olympic and Paralympic Games in 2020, it is expected that more people will visit Tokyo. Foreign visitors may introduce or acquire syphilis in Japan, potentially spreading syphilis both in Japan and their home countries.

Limitations
We used census and surveillance data collected by government departments. Identifying the reasons behind the increased number of syphilis cases in Tokyo is beyond the scope of this study since NESID data do not contain risk factor information. Other studies outside of Japan have cited increased health-care access and utilization, improved diagnostic testing or increased high-risk sexual behaviour as reasons for increasing syphilis incidence. 13, 14 Physicians may have increased reporting in response to heightened awareness that syphilis is a notifiable disease and the availability of the syphilis case reporting form on the TMIDSC website. 6 Not all cases of syphilis are diagnosed; patients often do not seek medical care for an initial lesion, which is painless and disappears spontaneously. Since the clinical presentation is non-specific, syphilis testing may not be performed for those who do seek care. Some diagnosed cases are likely never reported. Also, the Prevention of Infectious Diseases and Medical Care for Infectious Patients Act has no express provision for contact tracing, 15 which is necessary to detect and treat sexual contacts. The number of CS cases may also be underestimated since only live births are classified as CS.