Hui-Lin Zhang

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.

Factors Associated with Serological Cure and the Serofast State of HIV-Negative Patients with Primary, Secondary, Latent, and Tertiary Syphilis

Background Some syphilis patients remain in a serologically active state after the recommended therapy. We currently know too little about the characteristics of this serological response. Methods We conducted a cohort study using the clinical database from Zhongshan Hospital, Medical College of Xiamen. In total, 1,327 HIV-negative patients with primary, secondary, latent, and tertiary syphilis were enrolled. Bivariate and multivariate analyses were utilised to identify factors associated with a serological cure and serofast state in syphilis patients one year after therapy. Chi-square tests were used to determine the differences in the serological cure rate across different therapy time points. Results One year after the recommended therapy, 870 patients achieved a serological cure, and 457 patients (34.4%) remained in the serofast state. The serological cure rate increased only within the first 6 months. The bivariate analysis indicated that male or younger patients had a higher likelihood of a serological cure than female or older patients. Having a baseline titre ≤1∶2 or ≥1∶64 was associated with an increased likelihood of a serological cure. The serological cure rate decreased for the different disease stages in the order of primary, secondary, latent, and tertiary syphilis. A distinction should be drawn between early and late syphilis. The multivariate analysis indicated that a serological cure was significantly associated with the disease phase, gender, age, and baseline rapid plasma reagin (RPR) titre. Conclusions The serofast state is common in clinical work. After one year of the recommended therapy, quite a few syphilis patients remained RPR positive. The primary endpoint of the study indicated that disease phase, gender, age and baseline RPR titre were crucial factors associated with a serological cure.

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.

Clinical Spectrum of Neurosyphilis among HIV-Negative Patients in the Modern Era

Background: The clinical spectrum of neurosyphilis (NS) has changed over time. Objective: To describe the clinical spectrum and characteristics of NS in HIV-negative patients. Methods: A retrospective chart review was performed for 149 in patients with NS. Result: All patients were >25 years old, including 16.8% asymptomatic for NS, 15.4% with syphilitic meningitis, 24.2% with meningovascular NS, 38.9% with general paresis, 4.0% with tabes dorsalis and 0.7% with gummatous NS. The original misdiagnosis rate was 84.6%. All 149 patients had positive serum Treponema pallidum particle agglutination (TPPA) and rapid plasma reagin (RPR). The overall positive rates of cerebrospinal fluid RPR (CSF-RPR) and CSF-TPPA were 57.0 and 89.9%, respectively. CSF pleocytosis and elevated CSF protein were found in 40.3% of patients. Nonspecific abnormal brain magnetic resonance imaging and electroencephalography findings were present in 60.4 and 54.8% of NS patients, respectively. Conclusions: NS has various clinical manifestations, laboratory findings and magnetic resonance imaging and electroencephalography findings, but all studies lack specificity. Every patient with neurological or psychiatric symptoms that are without unambiguous causes should have blood tests for syphilis. When serology proves positive, patients should undergo CSF examination.

Spectrum and characterization of movement disorders secondary to neurosyphilis.

There have been frequent reports of Neurosyphilis with atypical features. Syphilitic infection of the central nervous system can result in various movement disorders (MD). The few reports of MD patients with neurosyphilis have been mainly of single patient. Between June 2005 and February 2012 we identified, 169 in-patients with neurosyphilis at Zhongshan Hospital. We performed a retrospective chart review to characterize MD findings, clinical signs and symptoms, misdiagnosis rate, laboratory findings, and brain magnetic resonance imaging results. We found that seven of the 169 neurosyphilis patients presenting with MD, had originally been misdiagnosed with Parkinsonism (4), laryngeal dystonia (1), corticobasal syndrome (1), and sensory ataxia (1). None of these patients were initially suspected of having neurosyphilis. The correct diagnosis was syphilitic meningitis (1), meningovascular neurosyphilis (2), general paresis (3), and tabes dorsalis (1). Among them, six patients had abnormal imaging studies, and sera rapid plasma reagin (RPR) and Treponema pallidum particle agglutination (TPPA) from all seven patients were positive. The cerebrospinal fluid (CSF) examinations showed that four patients were CSF-RPR positive (titers ≤1:16) by CSF syphilitic serologic testing, but all seven patients were CSF-TPPA reactive. Moreover, two patients had CSF pleocytosis and four patients had elevated CSF protein expression. Our findings reinforced the importance of routine serologic testing for syphilis should be a part of the evaluation of patients with atypical MD presentations or in whom alternative diagnoses are not forthcoming. When serology is positive, all patients should be examined more thoroughly for neurosyphilis by lumbar puncture.

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.

Laboratory findings in neurosyphilis patients with epileptic seizures alone as the initial presenting symptom

A retrospective chart review was performed to characterize the clinical presentation, the characteristic combination of serologic and cerebrospinal fluid (CSF) abnormalities, and the neuroimaging findings of neurosyphilis (NS) patients who had epileptic seizures alone as an initial presenting symptom. In a 6.75-year period, 169 inpatients with NS were identified at Zhongshan Hospital (from June 2005 to February 2012). We demonstrated that 13 (7.7%) of the 169 NS patients had epileptic seizures alone as an initial presenting feature. Epileptic seizures occurred in NS patients with syphilitic meningitis (2 cases), meningovascular NS (5 cases), and general paresis (6 cases). The types of epileptic seizures included simple partial, complex partial with secondary generalization (including status epilepticus), and generalized seizures (no focal onset reported). Nine of NS patients with only epileptic seizures as primary symptom were misdiagnosed, and the original misdiagnosis was 69.23% (9/13). Ten (10/13, 76.9%) patients had an abnormal magnetic resonance imaging, and 7 (7/13 53.8%) patients had abnormal electroencephalogram recordings. In addition, the sera rapid plasma reagin (RPR) and Treponema pallidum particle agglutination (TPPA) from all 13 patients were positive. The overall positive rates of the CSF-RPR and CSF-TPPA were 61.5% and 69.2%, respectively. Three patients demonstrated CSF pleocytosis, and 9 patients exhibited elevated CSF protein levels. Therefore, NS with only epileptic seizures at the initial presentation exhibits a lack of specificity. It is recommended that every patient with clinically evident symptoms of epileptic seizures should have a blood test performed for syphilis. When the serology results are positive, all of the patients should undergo a CSF examination to diagnose NS.

Whole genome sequence of the Treponema pallidum subsp. pallidum strain Amoy: An Asian isolate highly similar to SS14

Treponema pallidum ssp. pallidum (T. pallidum), the causative agent of the sexually transmitted disease syphilis, is an uncultivatable human pathogen. The geographical differences in T. pallidum genomes leading to differences in pathogenicity are not yet understood. Presently, twelve T. pallidum genomes are available to the public, all of which are American in origin and often co-infect patients with human immunodeficiency virus (HIV). In this study, we examined the T. pallidum subsp. pallidum strain Amoy, a syphilis pathogen found in Xiamen, China. We sequenced its genome using Illumina next-generation sequencing technology and obtained a nearly (98.83%) complete genome of approximately 1.12 Mbps. The new genome shows good synteny with its five T. pallidum sibling strains (Nichols, SS14, Mexico A, DAL-1, and Chicago), among which SS14 is the strain closest to the Amoy strain. Compared with strain SS14, the Amoy strain possesses four uncharacterized strain-specific genes and is likely missing six genes, including a gene encoding the TPR domain protein, which may partially account for the comparatively low virulence and toxicity of the Amoy strain in animal infection. Notably, we did not detect the 23S rRNA A2058G/A2059G mutation in the Amoy strain, which likely explains the sensitivity of Amoy strain to macrolides. The results of this study will lead to a better understanding of the pathogenesis of syphilis and the geographical distribution of T. pallidum genotypes.

Psychiatric Manifestations as Primary Symptom of Neurosyphilis Among HIV-Negative Patients

This study characterizes psychiatric manifestations as a primary symptom of neurosyphilis (NS). Fifty-two of the 169 NS patients presented with psychiatric manifestations, many patients had characteristics of more than one syndrome, including cognitive impairment, personality disorders, delirium, hostility, dysarthria, confusion, disruption of their sleep-wake cycle, fecal and urinary incontinence, dysphoria, paranoia, hallucinations, expansive mood, and mania. Fifty-two patients had positive sera RPR and T. pallidum particle agglutination (TPPA), 75% had positive CSF RPR, 96.2% had positive CSF TPPA, 44.2% had CSF pleocytosis and elevated CSF proteins, and 70.0% had nonspecific, abnormal brain MRIs. These results indicate that NS mimics almost all psychiatric disorders.

Neuropsychiatric disorders secondary to neurosyphilis in elderly people: one theme not to be ignored

BACKGROUND Neurosyphilis (NS) may present with neuropsychiatric disorders characterized by cognitive impairment, personality disorders, and confusion, among others. Very few studies have focused on neuropsychiatric disorders secondary to NS in elderly people. METHOD A retrospective chart review was performed to characterize the psychiatric findings, clinical signs and symptoms, laboratory findings, and brain magnetic resonance imaging results of ten elderly inpatients with NS. RESULTS In these ten patients, the most common presenting symptoms included a wide variety of psychiatric manifestations. The serum rapid plasma regain (RPR) and Treponema pallidum particle agglutination assay (TPPA) of the ten patients were positive, with positive CSF TPPA and RPR rates of 100% and 60%, respectively. In addition, 90% of the patients demonstrated abnormal imaging, including cerebral atrophy, infarct ischemic stroke, and hydrocephalus. CONCLUSIONS Our findings support the importance of serological tests for syphilis as a routine component of the evaluation of patients with clinically evident neurological or psychiatric symptoms. If the serology is positive, all of the patients should be examined with a lumbar puncture. Moreover, psychiatric illnesses secondary to NS in the elderly also deserve medical attention.