Disparity in Availability of Laboratory Testing for Syphilis Among Different Hospitals in Shandong Province, Eastern China

The aim of this study was to understand the availability of laboratory testing for syphilis among hospitals in Shandong province. Basic information on hospitals that provide clinical health service for sexually transmitted infections (STIs) and the type of laboratory tests for syphilis provided was collected and analyzed using the chi-square test. A total of 410 and 456 hospitals that provided clinical services for STI were surveyed in 2012 and 2018. Significant differences in the availability of nontreponemal tests were observed among different levels (χ2 = 6.624) and types (χ2 = 17.752) of hospitals in 2012, but not in 2018. A significant difference in the availability of treponemal tests was observed among different levels of hospitals in 2012 (χ2 = 9.937) but not in 2018. Significant differences in the availability of nontreponemal tests, titer of nontreponemal tests, and treponemal tests were observed among hospitals with different affiliations in 2018 (P = 0.000; χ2 = 15.274, P < .001; P = .021) but not in 2012. The availability of nontreponemal and treponemal tests for syphilis among hospitals in 2018 was higher than that in 2012 (90.13% vs. 57.56%, χ2 = 121.219). The availability of laboratory testing has been much improved. Further efforts are needed to reduce the disparity in the availability among different hospitals.


Introduction
Syphilis continues to be an important global public health issue. An estimated 17.721 million cases of syphilis occurred in people aged 15 to 49 years globally in 2012, including 5.6 million new cases. 1 Approximately 30% of undiagnosed and untreated patients with syphilis or those who received inadequate treatment progress to late stages of the disease, which can lead to cardiovascular syphilis, ocular syphilis, otic syphilis, and meningovascular disease. 2 Additionally, syphilis can enhance HIV acquisition and transmission. 2 If left untreated during pregnancy, then syphilis can cause early fetal loss, premature birth, stillbirth, low birth weight, and congenital infection. 3 The estimated global number of maternal syphilis is more than 98,900,000, generating approximately 661,000 total congenital syphilis cases, including 355,000 adverse birth outcomes. 4 The clinical manifestations of syphilis often mimic those of various skin diseases, or the disease may exist in a latent state. So, laboratory testing is a very important component of syphilis control and prevention. 5 Most adverse outcomes can be controlled with early detection and timely treatment. Early diagnosis and treatment is a cost-effective strategy for syphilis control. 6,7 A survey reported that the screening rate of prenatal HIV test was 95%, and that of syphilis test was only 47%. 8 The availability of laboratory testing is a prerequisite for early diagnosis of syphilis.
Many test methods with high sensitivity and specificity are available technically for syphilis. Direct detection tests, such as dark-field microscopy (DF), polymerase chain reaction (PCR) and serologic detection, including nontreponemal and treponemal tests are commonly used. 9 According to the case definition, the diagnosis of syphilis requires that at least one of the following tests is positive: DF, PCR, positive of nontreponemal, and treponemal tests. 10,11 However, the availability of laboratory testing for syphilis remains poor in some nations or regions. Some medical institutions still use either a nontreponemal or a treponemal test alone for the diagnosis of syphilis. 12 leading to the poor accuracy of diagnosis.
China is one of the countries with the high prevalence of syphilis worldwide. In 2017, 475,860 new cases of syphilis were reported in China. 13 Approximately 67.6% of maternal syphilis were latent syphilis, and 71.8% of maternal syphilis were reported in eastern areas, such as Shandong province. 14 A survey in Guangdong province showed that 81% of newly reported syphilis cases were diagnosed in hospitals, but only 22% were diagnosed early. 15 Another survey found that the coverage rate of syphilis screening in sexually transmitted infection (STI) clinics was only 40% in 2014. 16 The availability of laboratory testing plays a key role in national syphilis prevention and control programs. Several indicators related to syphilis testing contribute to the ultimate goal of the National Program for Prevention and Control of Syphilis in China (2010-2020). This goal includes the availability of laboratory tests for syphilis among 90% of institutions that provide STI clinical service, and the testing of 90% of pregnant women in urban and 70% in rural areas for syphilis by the end of 2020. Disparity in availability of laboratory testing for syphilis may exist among different hospitals and affect achieving the goal of the program. To understand the availability of laboratory testing for syphilis and evaluate the effectiveness of the program, we conducted two surveys among hospitals that reported syphilis cases in Shandong province, China.

Ethics Approval
We obtained ethics approval from the institutional review board at the Shandong Provincial Institute of Dermatology and Venereology (20190716-KYKT-002).

Study Objects
The study was conducted in Shandong province, eastern of China, which is subdivided into 17 prefecture-level cities and 137 county-level units. There were a total of 1,549 and 2,579 registered hospitals in the province in 2012 and 2018, respectively. 17

Study Hospitals
All hospitals with case reporting of STI in Shandong province in the past year were defined as hospitals provided clinical service for STI. All hospitals providing clinical services for STIs in Shandong province were included in the study.

Data Collection
A unified questionnaire designed by the National Center for STD Control, China CDC was used in each survey for data collection. The contents related to this study were covered, including basic information of the hospitals (level, type, and affiliation) and the types of laboratory tests for syphilis provided. In the survey, rapid plasma reagin test (RPR), toluidine red unheated serum test (TRUST), venereal disease research laboratory test (VDRL), and unheated serum regain test (USR) belong to nontreponemal tests. By contrast, Treponema pallidum particle agglutination assay (TPPA), T. pallidum hemagglutination assay (TPHA), T pallidum enzyme-linked immunosorbent assays (TP-ELISA), T. pallidum chemiluminescence immunoassay (TP-CLIA), and T. pallidum rapid test (TP-RT) belong to treponemal tests.
The first survey was conducted from September to November 2012 as part of the baseline assessment for the National Program for Prevention and Control of Syphilis in China (2010-2020). To assess the effectiveness of the program, we conducted a second survey from September to November 2018. Medical staff from the Center for Disease Control and Prevention at the county-level visited each hospital in their respective jurisdictions and filled in the questionnaires. All data were collected by EpiData database.

Data Analysis
Data collected were entered into Microsoft Excel for Windows (2012) and analyzed in SPSS (version 22.0). To reduce bias, we adopted the double-check method. The percentages of providing each laboratory tests for syphilis among hospitals according to levels, types, and affiliation were analyzed and compared. Descriptive analysis and chisquare test were used for statistical analysis. P values <.05 were considered statistically significant.

General Information
A total of 410 and 456 valid questionnaires were collected in 2012 and 2018 among hospitals that reported syphilis cases in 2012 and 2018 in Shandong province, respectively. The percentages of surveyed hospitals in each category by level, type, and affiliation in Shandong province are listed in Table 1.
Seventeen ( Availability of serologic test for syphilis among hospitals at different levels in 2012 and 2018. A significant difference in the availability of RPR or TRUST was observed among hospitals at different levels in 2012 (χ 2 = 6.624, P = .010) but not in 2018 (χ 2 = 2.773, P = .096). RPR or TRUST was more available in tertiary hospitals than sub-tertiary hospitals in 2012. Significant differences in the availability of titer of RPR or TRUST were observed among hospitals at different levels in 2012 (χ 2 = 12.909, P < .001) and 2018 (χ 2 = 5.872, P = .015). The titer of RPR or TRUST was more available in tertiary hospitals than sub-tertiary hospitals. A significant difference in the availability of TPPA or ELISA or TP-RT or CLIA was observed among hospitals at different levels in 2012 (χ 2 = 9.937, P = .002) but not in 2018. It was more available in tertiary hospitals than sub-tertiary hospitals in 2012.
A significant difference in the availability of RPR or TRUST was observed among different types of hospitals in 2012 (χ 2 = 17.752, P = .001) but not in 2018. This availability was significantly higher among specialized dermatological hospitals than in general western medicine hospitals (χ 2 = 10.855, P = .001), maternal and child health hospitals (χ 2 = 11.527, P = .001), Chinese medicine hospitals (χ 2 = 12.568, P < .001) and other specialized hospitals (P = .012, Fisher's exact test) in 2012. Significant differences in the availability of titer of RPR or TRUST were observed among different types of hospitals in 2012 (χ 2 = 24.607, P < .001) and 2018 (χ 2 = 11.132, P = .025). The availability of this test was significantly higher among specialized dermatological hospitals than in general western medicine hospitals (χ 2 = 13.811, P < .001) in 2012. However, the availability was significantly lower among Chinese medicine hospitals than general western medicine hospitals (χ 2 = 6.969, P = .008), specialized dermatological hospitals (χ 2 = 7.864, P = .005) and maternal and child health hospitals (χ 2 = 4.013, P = .045) in 2018. No significant differences in the availability of treponemal tests were observed among hospitals with different type in 2012 and 2018.

Discussion
In this study, we found that direct detection tests for syphilis, such as DF and PCR, were seldom used in Chinese hospitals, although they have advantages in the diagnosis of early syphilis as immediate and definitive methods. The high requirement for specific expertise in DF and the need of expensive equipment and reagents in PCR tests may prevent hospitals from adopting these methods. Although the sensitivity and specificity of treponemal and nontreponemal tests vary with the types of tests and the stages of syphilis infection, the mainstay of diagnosis for syphilis still depends on serologic testing in China.
RPR, TRUST, TPPA, ELISA, RT, and CLIA rather than VDRL, USR, FTA-ABS, and TPHA were commonly used in China, compared with other countries, such as the United States, Canada, and the United Kingdom. 18-20 VDRL, USR, FTA-ABS, and TPHA are unavailable in China mainly because of reagent shortage. CSF-VDRL and CSF-FTA-ABS tests are laborious and time-consuming, although they are valuable in detecting neurosyphilis. Studies found that CSF-FTA-ABS and CSF-VDRL tests can be replaced by CSF-TPPA (21) and CSF-TRUST test in the diagnosis of neurosyphilis in case that CSF-FTA-ABS and CSF-VDRL tests are lacking. 12,[21][22][23] However, CSF-RPR is not recommended for the diagnosis of neurosyphilis because its sensitivity is lower than that of VDRL. 24 Some improvements in the availability of laboratory testing for syphilis were observed in Shandong province in general. First, among hospitals providing STI clinical service, the availability of serologic tests was significantly improved at different levels of hospitals in the past 6 years. The improvement was greater among sub-tertiary hospitals than in tertiary hospitals. Second, the proportion of hospitals providing syphilis laboratory testing and STI clinical services among maternal and child health hospitals increased with increasing total number of hospitals, indicating that the coverage for maternal and congenital syphilis screening had been extended. This contrasted with the increased proportion among specialized dermatological hospitals due to the decreased number of hospitals. Third, the availability of both treponemal and nontreponemal tests was significantly improved in some hospitals providing STI clinical services, especially among sub-tertiary hospitals, general western medicine hospitals, maternal and child health hospitals, Chinese medicine hospitals and public hospitals, indicating the increased diagnosis capacity and accuracy rate of case reports among these hospitals.
In 2015, Zheng et al found that treponemal and non-treponemal tests were available in 907 (78.4%) hospitals,

<.001
Abbreviations: CLIA, chemiluminescence immunoassay; ELISA, enzyme-linked immunosorbent assays; RPR, rapid plasma regain; TRUST, toluidine red unheated serum test; TP-RT, T. pallidum rapid test; TPPA, Treponema pallidum particle agglutination assay. treponemal tests were available in 1003 (86.7%) hospitals, non-treponemal tests were available in 995 (86.0%) hospitals, and titres of non-treponemal test were available in 449 (38.8%) hospitals in China. 25 Meanwhile, Shen et al found that 22 (73.33%) hospitals provided treponemal and nontreponemal tests in 2016 in Guangdong province. 26 The availability of these tests was higher among some hospitals in China than that in 2012, but less than that in 2018 in Shandong.
What However, great disparities in the availability of syphilis laboratory tests exist among different hospitals, especially between public and private sectors. In the 2012 survey, about a quarter of hospitals in Shandong province reported syphilis cases, indicating that these hospitals could provide syphilis laboratory testing and STI clinical services. The proportion decreased to less than one fifth in the 2018 survey, mainly because the total number of hospitals largely increased but the number of hospitals that provided syphilis laboratory tests did not increase proportionately, especially in the private sector. In the past 6 years, the number of private hospitals disproportionately increased, but few could provide syphilis laboratory testing. Private hospitals are encouraged to provide additional medical services and cooperate with public sectors in recent years. 27 Although about half of public hospitals provided STI clinical service until 2018, the proportion was higher than that among private hospitals. Public hospitals still play a leading role in STI health care, and private sectors still need to meet the increasing demand for STI health service in China. In addition, one tenth of the hospitals providing STI clinical services in Shandong could not offer nontreponemal and treponemal tests until 2018, indicating that syphilis cases in these hospitals were not correctly diagnosed.
Titer of RPR or TRUST is a useful indicator for evaluating the treatment effects in syphilis patients. We found that titer of RPR or TRUST was less available in many hospitals where RPR or TRUST was provided. The major reason is that some hospitals only conducted screening rather than clinical service. Syphilis is a complicated disease that needs trained and skilled staff and continuous follow-up after treatment. Benzathine penicillin is preferred for the treatment of syphilis cases. However, it is also unavailable in many hospitals because of low profit and risk of allergy. Many hospitals are reluctant to provide clinical service for syphilis patients, and usually refer them to professional institutions for treatment, which may lead to low availability and low accessibility of STI clinical services in China.
Although the availability of laboratory testing for syphilis was improved, about 10% of hospitals could not carry out non-treponemal and treponemal tests, which indicated that syphilis cases in these hospitals were not correctly diagnosed and reported in 2018. As we all know, titres of RPR or TRUST correlate grossly with disease activity and are used to monitor disease activity and treatment efficacy. However, in 2018, 23% of hospitals could not provide titres of RPR or TRUST, which meant that we could not monitor disease activity and efficacy accurately.
Further efforts are needed to improve the availability of laboratory tests for syphilis in Shandong province, China. First, the application of point-of-care (POC) tests needs to be promoted. One of the main reasons for the poor availability of some syphilis tests is the requirement of trained professional technicians, essential equipment, and complicated and time-consuming procedures. POC tests have similar sensitivity and specificity to TRUST and TPPA, and can provide results in 15 to 20 minute without the need for a laboratory and equipment. 28,29 A diagnosis can be made at the first visit, so patients do not have to return for their results, and treatment can be immediately provided. Second, an effective referral system needs to be established. Referral service involves the outreach of medical personnel recommended to a suitable medical institution for service and help according to the needs of the target population. Any screened syphilis antibody-positive cases should be referred to proper medical institutions that can provide standardized clinical services if the screening institutions cannot provide them. One of the advantages of a referral system is increasing accessibility by integrating and making good use of various resources in resource-constrained countries or areas. However, the disadvantages include increasing burden of patients in costs, transportation and time. The referral rate for patients with suspected STIs can generally reach 95% to 100%, but the referral success rate is only 30% to 45%. Third, laboratory outsourcing service is allowed or encouraged by health administrative authorities in China, which may be beneficial for increasing the availability of syphilis laboratory testing. However, additional regulations are needed to monitor and manage these organizations providing laboratory outsourcing service.
This study has some limitations. First, the survey was conducted in Shandong province, representing the eastern coastal economically developed areas in China. Thus the results cannot be generalized to all regions of China. Second, the study focused on the availability of laboratory tests for syphilis. Issues related to the accessibility of syphilis testing and laboratory quality control, which are very important for screening and laboratory diagnosis of syphilis, were not considered.