Yu-Yan Chen

Analysis of 3 Algorithms for Syphilis Serodiagnosis and Implications for Clinical Management

BACKGROUND Algorithms for the diagnosis of syphilis continue to be a source of great controversy, and numerous test interpretations have perplexed many clinicians. METHODS We conducted a cross-sectional study of 24 124 subjects to analyze 3 syphilis testing algorithms: traditional algorithm, reverse algorithm, and the European Centre for Disease Prevention and Control (ECDC) algorithm. Every serum sample was simultaneously evaluated using the rapid plasma reagin, Treponema pallidum particle agglutination, and chemiluminescence immunoassay tests. With the results of clinical diagnoses of syphilis as a gold standard, we evaluated the diagnostic accuracy of the 3 syphilis testing algorithms. The κ coefficient was used to compare the concordance between the reverse algorithm and the ECDC algorithm. RESULTS Overall, 2749 patients in our cohort were diagnosed with syphilis. The traditional algorithm had the highest negative likelihood ratio (0.24), a missed diagnosis rate of 24.2%, and only 75.81% sensitivity. However, both the reverse and ECDC algorithms had higher diagnostic efficacy than the traditional algorithm. Their sensitivity, specificity, and accuracy were 99.38%-99.85%, 99.98%-100.00%, and 99.93%-99.96%, respectively. Moreover, the overall percentage of agreement and κ value between the reverse and the ECDC algorithms were 99.9% and 0.996, respectively. CONCLUSIONS Our research supported use of the ECDC algorithm, in which syphilis screening begins with a treponemal immunoassay that is followed by a second, different treponemal assay as a confirmatory test in high-prevalence populations. In addition, our results indicated that nontreponemal assay is unnecessary for syphilis diagnosis but can be recommended for determining serological activity and the effect of syphilis treatment.

Incidence and Risk Factors for the Prozone Phenomenon in Serologic Testing for Syphilis in a Large Cohort

BACKGROUND The prozone phenomenon is known to be associated with high antibody titers; other associations, such as host factors, have not been elucidated. METHODS A retrospective analysis was conducted to evaluate the incidence of the prozone phenomenon of the syphilis rapid plasma reagin (RPR) test among 46 856 clinical samples, between June 2010 and June 2013. Logistic regression was used to analyze the risk factors of the prozone phenomenon. RESULTS Our results showed that the incidence of the prozone phenomenon was low (0.83%) and could occur during any clinical phase, particularly during primary and secondary syphilis. Pregnancy and neurosyphilis were associated with the prozone phenomenon; sex, age, and whether the patient had been treated were not. The results also revealed that the prozone phenomenon not only occurred in patients with a high titer but also could occur in patients with a moderate/low titer. In fact, almost 31% of the patients with the prozone phenomenon had titers ≤1:16. CONCLUSIONS The prozone phenomenon in the RPR test was associated with the phase of syphilis, pregnancy, and neurosyphilis as well as a range of RPR titers between 1:8 and 1:512. This latter finding is in contrast to previous reports that the prozone phenomenon is associated with very high RPR titers.

Characterization of the classical biological false-positive reaction in the serological test for syphilis in the modern era

To characterize the CBFP reaction in the modern era, we analyzed the results of parallel rapid plasma reagin (RPR) and Treponema pallidum particle agglutination (TPPA) tests from a total of 63,765 blood samples obtained at Zhongshan Hospital in the Medical College of Xiamen University from May 2008 to February 2013. Among the 63,765 tested blood samples, 206 (0.32%) had the CBFP reaction. In multivariate analysis, an increased likelihood of the CBFP reaction was associated with female subjects, subjects ≥80years old, and subjects between 16 and 35years old (P<0.05). The CBFP reaction occurred in association with 17 categories of disease, including 60 types of diseases, in the 206 subjects. To our knowledge, a number of these diseases had not been previously reported to be associated with the CBFP in the RPR test, including false labor, megaloblastic anemias, aplastic anemias, redundant prepuce, congenital malformation of heart, and salpingitis. Among the 206 patients with the CBFP reaction, 35 patients were subjected to follow-up for five years. 26 out of 35 these patients were at a 1:1 initial RPR titer, 8 out of 35 patients were at a 1:2 initial RPR titer, and 1 out of 35 patients were at a 1:4 initial RPR titer. 30 subjects had their RPR seroreverted. In our opinion, additional CBFP research using a large sample population will contribute to the identification of additional underlying serious disorders that are not related to syphilis. Such results could be useful for the prediction and diagnosis of these diseases.

Association between neurosyphilis and diabetes mellitus: Resurgence of an old problem 神经梅毒与糖尿病的关系：“旧事”再现

Syphilis, a sexually transmitted disease, is commonly referred to as the “great imitator” because of its wide‐ranging clinical presentations. Recently, we noticed that patients with neurosyphilis (NS) seemed to be more susceptible to complications of diabetes mellitus (DM). This is an interesting phenomenon, but it also puzzles clinicians because of scant knowledge about this situation.

Clinical and laboratory characteristics in patients suffering from general paresis in the modern era

BACKGROUND No gold standard currently exists for the diagnosis of general paresis (GP), thus often resulting in unnecessarily delayed therapeutic decision. METHODS A retrospective chart review was performed for 85 inpatients with GP in Zhongshan Hospital, Medical College of Xiamen University, and the characteristics of their clinical profiles, serum and cerebrospinal fluid (CSF) examinations, neuroimaging examination, and electroencephalogram (EEG) data were analyzed. RESULTS Among the 85 GP patients, the clinical symptoms that were frequently observed upon admission included a variety of psychiatric-behavioral symptoms and varying degrees of cognitive impairment. All of the patients had positive serum Treponema pallidum particle agglutination (TPPA) assays, 96.47% of the patients had positive CSF TPPA assays, and 41.18% of the patients had both CSF pleocytosis and elevated CSF protein levels. Focal atrophy in one cerebral region or in multiple regions was evident in neuroimages. The EEG data primarily showed slightly abnormal EEG activity. CONCLUSION These results demonstrate the complexity of the clinical characteristics of GP and highlight the importance of early diagnosis.

Evaluation of the Boson Chemiluminescence Immunoassay as a First-Line Screening Test in the ECDC Algorithm for Syphilis Serodiagnosis in a Population with a High Prevalence of Syphilis

ABSTRACT We developed a new Boson chemiluminescence immunoassay (CIA) and evaluated its application with cross-sectional analyses. Our results indicated that the Boson CIA demonstrated strong discriminatory power in diagnosing syphilis and that it can be used as a first-line screening test for syphilis serodiagnosis using the European Centre for Disease Prevention and Control algorithm or as a confirmatory test when combined with a patients clinical history.

A better definition of active syphilis infection

Syphilis, caused by the spirochete Treponema pallidum subsp. pallidum, is a chronic infectionwithmany diverse clinical manifestations that occur in distinct stages [1]. Because T. pallidum cannot be cultured [2], the diagnosis of syphilis is based on clinical findings, examination of lesion exudates and serologic tests. Serology is the primary method for the laboratory diagnosis of syphilis and can be divided into two groups: treponemal tests, including the T. pallidum hemagglutination test (TPHA), the T. pallidum particle agglutination assay (TPPA), the fluorescent treponemal antibody absorption test (FTA-ABS), Western blotting, and several ELISAs; and nontreponemal tests, including the Venereal Diseases Research Laboratory (VDRL) test, the rapid plasma reagin (RPR) circle card test, and the toluidine red unheated serum test (TRUST) [3]. Treponemal-specific IgM and IgG antibodies are usually generated two and fourweeks after infection, respectively [4], appearing earlier than nontreponemal antibodies. The IgM antibody may persist and does not disappear, even if the patient receives adequate treatment [5,6]. Moreover, reaginic antibodies may be negative in cases of late, latent, or post-treatment syphilis (due to seroreversion) [7]. The accuracy of diagnostic tests is critical for the successful control of epidemic syphilis outbreaks, which requires both identifying cases and promptly delivering therapy to infected individuals [8,9]. Moreover, definitive diagnosis of the infection status of syphilis is very important in clinical practice. If an active syphilis infection is not diagnosed and effectively treated, syphilis can develop into more serious diseases, such as gummatous disease and cardiovascular disease, or progress to involvement of the central nervous system [10]. Active syphilis infection is particularly dangerous in pregnant women, as syphilis has long been recognized as amajor cause of death and disability in infants born to infectedwomen. In the presence of active syphilis infection, it is estimated that adverse outcomes occur in 50–80% of pregnancies that continue past 12 weeks of gestation, primarily in the form of spontaneous abortions in the second and early third trimesters, stillbirths, and congenital syphilis [11]. Thus, establishing an accurate definition of active syphilis infection is necessary. However, no definitive reference standard has been defined for active syphilis infection. Donkers et al. [12] describe a new assay for the diagnosis of syphilis. The authors compared the SiemensADVIA Centaur® Syphilis assaywith 2 other commercial assays and evaluated its performance and usability. In this work, the authors used the VDRL test and Western blotting for IgG and IgM to define the different clinical statuses of syphilis infection, including active infection and old infection. Interestingly, the authors considered a VDRL titer of ≥1:8 to be a prognostic indicator of active syphilis infection. However, this definition of active syphilis infection should be reconsidered. Many studies have shown [11,13–17] that active syphilis infection should be defined by positive treponemal tests and any positive RPR/VDRL titer, rather than only by a VDRL

Comparison of Clinical and Laboratory Characteristics of General Paresis and Non-Neurosyphilis Dementia

Background: The differential diagnosis of general paresis (GP) and non-neurosyphilis (NS) dementia is not clearly defined. The present study examined the differences in clinical and laboratory features of GP and non-NS dementia. Materials and Methods: We retrospectively examined clinical and laboratory features of 85 GP patients and 196 non-NS dementia patients. Data were collected from Zhongshan Hospital between June 2005 and June 2014. Results: The GP group had a higher percentage of males (83.53%, 71/85) and younger median age ([52 [interquartile range 47.0–61.0] vs. 76 [68.3–82.0] years) than the non-NS dementia group. GP have higher Mini-Mental State Examination (MMSE; Z = –5.809; p = 0.000) than non-NS dementia. Distribution of CDR scores were significantly higher in the non-NS group than GP group (χ2 = 29.153; p = 0.000). The laboratory findings showed significantly different total cholesterol (CH), low-density lipoprotein CH and homocysteine levels between the 2 groups. Serologic testing for syphilis revealed that the GP group had higher seropositive rapid plasma reagin (RPR) and Treponema pallidum particle agglutination (TPPA) rates than the non-NS dementia group (96.47% [82/85] vs. 0.51% [1/196], Z = –2.663, p = 0.008; 100% [85/85] vs. 1.02% [2/196], Z = –2.663, p = 0.008). Interestingly, cerebrospinal fluid (CSF) biochemical indices, including pleocytosis rates, increased protein levels, and positive RPR and TPPA rates in the GP group were higher than that in the non-NS dementia group. Conclusions: Based on these preliminary data, patients with clinically evident symptoms of dementia, especially middle-aged males, should undergo blood tests for syphilis. All patients with positive serology results should undergo CSF examinations to diagnose GP dementia before further pharmaceutical and behavioral interventions.

Treponema pallidum promotes macrophage polarization and activates the NLRP3 inflammasome pathway to induce interleukin-1β production

BackgroundThe involvement of inflammasome activation and macrophage polarization during the process of syphilis infection remains unknown. In this study, A series of experiments were performed using human macrophages to research the role of NLRP3 inflammasome regulation in interleukin (IL)-1β production and its influence on macrophage polarization triggered by T. pallidum.ResultsThe results showed that in M0 macrophages treated with T. pallidum, the M1-associated markers inducible nitric oxide synthase (iNOS), IL-1β and TNF-α were upregulated, and the M2-associated markers CD206 and IL-10 were downregulated. In addition, we observed NLRP3 inflammasome activation and IL-1β secretion in T. pallidum-treated macrophages, and the observed production of IL-1β occurred in a dose- and time-dependent manner. Moreover, the secretion of IL-1β by macrophages after T. pallidum treatment was notably reduced by anti-NLRP3 siRNA and caspase-1 inhibitor treatment. NAC, KCl, and CA074-ME treatment also suppressed IL-1β release from T. pallidum-treated macrophages.ConclusionsThese findings showed that T. pallidum induces M0 macrophages to undergo M1 macrophage polarization and elevate IL-1β secretion through NLRP3. Moreover, the process of NLRP3 inflammasome activation and IL-1β production in macrophages in response to T. pallidum infection involves K+ efflux, mitochondrial ROS production and cathepsin release. This study provides a new insight into the innate immune response to T. pallidum infection.

Association between neurosyphilis and diabetes mellitus: Resurgence of an old problem 神经梅毒与糖尿病的关系：“旧事”再现: Neurosyphilis and diabetes mellitus

Syphilis, a sexually transmitted disease, is commonly referred to as the “great imitator” because of its wide‐ranging clinical presentations. Recently, we noticed that patients with neurosyphilis (NS) seemed to be more susceptible to complications of diabetes mellitus (DM). This is an interesting phenomenon, but it also puzzles clinicians because of scant knowledge about this situation.