New screening approach to detecting congenital syphilis in China: a retrospective cohort study.

BACKGROUND: Diagnosis of congenital syphilis (CS) is not straightforward and can be challenging. This study aimed to evaluate the validity of an algorithm using timing of maternal antisyphilis treatment and titres of non-treponemal antibody as predictors of CS. METHODS: Confirmed CS cases and those where CS was excluded were obtained from the Guangzhou Prevention of Mother-to-Child Transmission of syphilis programme between 2011 and 2019. We calculated sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) using receiver operating characteristics (ROC) in two situations: (1) receiving antisyphilis treatment or no-treatment during pregnancy and (2) initiating treatment before 28 gestational weeks (GWs), initiating after 28 GWs or receiving no treatment for syphilis seropositive women. RESULTS: Among 1558 syphilis-exposed children, 39 had confirmed CS. Area under the curve, sensitivity and specificity of maternal non-treponemal titres before treatment and treatment during pregnancy were 0.80, 76.9%, 78.7% and 0.79, 69.2%, 88.7%, respectively, for children with CS. For the algorithm, ROC results showed that PPV and NPV for predicting CS were 37.3% and 96.4% (non-treponemal titres cut-off value 1:8 and no antisyphilis treatment), 9.4% and 100% (non-treponemal titres cut-off value 1:16 and treatment after 28 GWs), 4.2% and 99.5% (non-treponemal titres cut-off value 1:32 and treatment before 28 GWs), respectively. CONCLUSIONS: An algorithm using maternal non-treponemal titres and timing of treatment during pregnancy could be an effective strategy to diagnose or rule out CS, especially when the rate of loss to follow-up is high or there are no straightforward diagnostic tools.

Syphilis in Children.

Syphilis, caused by Treponema pallidum, is transmitted both sexually and transplacentally. Untreated syphilis is a progressive disease that may result in death or disability in children and adults. Syphilis diagnosis requires 2-stage serologic testing for nontreponemal and treponemal antibodies. Congenital syphilis diagnosis requires careful review of maternal testing and treatment, comparison of maternal and neonatal nontreponemal antibody titers, and clinical evaluation of the neonate. In this review, we present the current epidemiology of syphilis, and the clinical manifestations, diagnosis, and management of syphilis as they relate to pediatric practice, specifically, congenital syphilis and acquired syphilis in adolescents and pregnant women.

Early Congenital Syphilis: Recognising Symptoms of an Increasingly Prevalent Disease.

BACKGROUND: Congenital syphilis (CS) is an infectious disease resulting from transplacental transmission of Treponema pallidum spirochetes from an infected mother to fetus during pregnancy. While uncommon, CS has shown an increased incidence in Canada and the United States since 2001 and 2012, respectively. CASE REPORT: We present the case of a 5-week-old female infant with blistering rash on the palms and soles. The infant displayed decreased movement of the left upper extremity, clinically consistent with Parrot pseudoparalysis. Cutaneous involvement was limited to few tan crusted papules on the palms and soles. Mother reported a "false-positive" result of rapid plasma reagin (RPR) testing at 31 weeks. Cerebrospinal fluid studies of the infant resulted with positive Venereal Disease Research Laboratory (VRDL) test and positive microhemagglutination assay (MHA-TP). Histopathology of a crusted papule revealed a lichenoid infiltrate composed of lymphocytes, histiocytes, and plasma cells. Immunohistochemical staining for T pallidum was negative. The patient completed treatment with a 10-day course of intravenous penicillin. DISCUSSION: While CS is largely considered a historic entity, it has been increasing in incidence in the United States since 2012 and in Canada since the early 2000s. Diagnosis of CS can be difficult as infants may be asymptomatic or present with nonspecific signs. This case highlights the presentation of minimal cutaneous involvement as well as skeletal involvement after birth. RPR testing may result in false negatives or indeterminate results, further complicating diagnosis. Given these difficulties in screening and the increasing incidence of CS, clinicians may need to refamiliarise themselves with its clinical findings.

Contribution of a Comparative Western Blot Method to Early Postnatal Diagnosis of Congenital Syphilis.

Serology has a pivotal role in the diagnosis of congenital syphilis (CS), but problems arise because of the passive transfer of IgG antibodies across the placenta. The aim of this study was to assess the diagnostic value of a comparative Western blot (WB) method finalized to match the IgG immunological profiles of mothers and their own babies at birth in order to differentiate between passively transmitted maternal antibodies and antibodies synthesized by the infants against Treponema pallidum Thirty infants born to mothers with unknown or inadequate treatment for syphilis were entered in a retrospective study, conducted at St. Orsola-Malpighi Hospital, Bologna, Italy. All of the infants underwent clinical, instrumental, and laboratory examinations, including IgM WB testing. For the retrospective study, an IgG WB assay was performed by blotting T. pallidum antigens onto nitrocellulose sheets and incubating the strips with serum specimens from mother-child pairs. CS was diagnosed in 11 out of the 30 enrolled infants; 9/11 cases received the definitive diagnosis within the first week of life, whereas the remaining two were diagnosed later because of increasing serological test titers. The use of the comparative IgG WB testing performed with serum samples from mother-child pairs allowed a correct CS diagnosis in 10/11 cases. The CS diagnosis was improved by a strategy combining comparative IgG WB results with IgM WB results, leading to a sensitivity of 100%. The comparative IgG WB test is thus a welcome addition to the conventional laboratory methods used for CS diagnosis, allowing identification and adequate treatment of infected infants and avoiding unnecessary therapy of uninfected newborns.

Maternal/child seroprevalence of antibodies against Treponema pallidum at four general hospitals in the state of Morelos, Mexico.

BACKGROUND AND AIMS: Treponema pallidum can cause syphilis in pregnant women and congenital syphilis in the newborn. In Latin America, 330,000 pregnant women are diagnosed with syphilis every year. Adequate prenatal care to detect syphilis reduces maternal morbidity and fetal and neonatal mortality and morbidity. We undertook this study to determine T. pallidum seroprevalence among pregnant and puerperal women from Morelos, Mexico, as well as to evaluate the sexual behavior, demographic and clinical variables associated with the infection. METHODS: A cross-sectional study was carried out among pregnant and puerperal women from four general hospitals from Morelos, Mexico during 2005-2009. Women answered a questionnaire and provided a blood sample to detect antibodies against T. pallidum. RESULTS: A total of 2331 women were analyzed with 0.26% of T. pallidum seroprevalence. There were four cases with active syphilis and two cases with latent syphilis, as well as two cases of congenital syphilis. Illiterate women had 6.7 times higher risk of being infected. Women who did not undergo a urine test had a 5.3 times higher risk for infection and women who do not have piped water inside their household had a 5.0-fold higher risk of having anti-T. pallidum antibodies. All seropositive cases were from the same hospital (Cuautla General Hospital) with demographic, sexual behavior and medical care characteristics different from the other three hospitals. CONCLUSIONS: Syphilis during pregnancy and congenital syphilis are still present in Mexico. It may be that the more urban a population the higher the chance of the prevalence of maternal syphilis. It would be beneficial to reinforce the observance of the Official Mexican Norm and to implement rapid diagnostics tests to contend with this public health problem.

Rastreamento das infecções perinatais na gravidez: realizar ou não? / Perinatal infections screening during pregnancy: perform it or not?

Devido à conhecida importância das infecções adquiridas intraútero, vários serviços médicos em todo o mundo preconizam o rastreio das doenças passíveis de transmissão vertical. Entretanto, há muitos questionamentos na literatura a respeito da real relevância, custo-benefício e aplicabilidade do rastreamento. Corrobora essa assertiva a terapêutica ineficiente, a baixa prevalência para algumas dessas afecções e a reduzida confiabilidade e elevado custo de certos testes laboratoriais usados para o rastreamento. Por outro lado, o rastreio e posterior tratamento de algumas infecções resultam na diminuição da morbimortalidade, o que é de extrema relevância, uma vez que reduz sequelas fetais e auxilia na manutenção da saúde das gestantes. Mais estudos são necessários para o estabelecimento de um panorama completo a respeito do rastreamento das infecções perinatais, pois, além dos impasses expostos, é importante considerar as características epidemiológicas de cada população, o que requer pesquisas mais aprofundadas. Esta revisão da literatura teve como objetivo reunir evidências quanto à recomendação ou não do rastreamento destas doenças durante o pré-natal nas diversas entidades de relevância nacional e internacional.

Due to the importance of intrauterine acquired infections, severalguidelines suggest the screening of diseases that can be vertically transmitted. However, there are questionsabout the real relevance, cost-benefit and applicability of this practice. The absence of an efficient treatmentand the small prevalence of some of these disorders combined with the reduced reliability and high costsof some laboratorial tests used for screening, confirm this statement. On the other hand, the possibility oftreatment associated with the screening and the subsequent reduction of morbimortality are a very relevantpoint, once it attenuates fetal sequelae and helps keeping pregnant women health. More studies are needed toestablish a complete picture of the screening of perinatal infections because beyond the impasses presentedabove, it is important to consider the epidemiological characteristics of each population, which requires moreextensive research. This literature review attempted to gather information about the importance of the prenatalscreening of perinatal infections in different and relevant national and international entities.

[Western blot as a confirming test in the laboratory diagnosis of syphilis].

Two hundred and ninety-five patients who had been found to have Treponema pallidum antibodies detected by enzyme immunoassay were additionally studied by a Western blot test to confirm their presence. Every four cases were ascertained to be false-positive, false seropositivity being more frequent in the presence of IgM antibody against T. palladium. Spinal fluid analysis provided evidence for the course of neurosyphilis in 5 cases. The diagnosis of congenital syphilis was verified in 2 children who had p15, p17, p45, and 47. The findings demonstrate it necessary to extensively use a Western blot in the health care system.

Influence of mother VDRL titers on the outcome of newborns with congenital syphilis.

Congenital syphilis still represents a significant public health problem worldwide, and particularly in developing countries. Despite years of research on different clinical and immunological features, many physiopathological aspects still lacks of knowledge, one of them the role of immune response against Treponema pallidum by infected mothers on the birth outcomes, e.g. birthweight. In this study we analyzed if the mother VDRL titers were significantly associated with the birthweight of newborns with congenital syphilis. We observed a highly significant association between both variables, finding at the linear regression that with higher mother VDRL titers, the newborn birthweight was lower (p=0.0345). We identified that higher VDRL titers are associated with lower birth weights, although the physiopathological reasons to explain this still remains unclear.

Comparison of a Treponema pallidum IgM immunoblot with a 19S fluorescent treponemal antibody absorption test for the diagnosis of congenital syphilis.

We compared an in-house Treponema pallidum IgM immunoblot (IB) with a 19S fluorescent treponemal antibody absorption (IgM) test during routine use for the diagnosis of congenital syphilis (CS) in a national reference laboratory in a nonendemic setting. The overall agreement between the assays was high (97%), and 19S positive samples had at least 2 reactive bands in the IB. The high agreement is mainly caused by the large number of negative results (95%). If the 19S is taken as the gold standard, the estimate sensitivity of the IB was at least 88% with a specificity of 97.2%. Analysis of the discrepancies revealed that the IB was positive with 1 or 2 specific bands in 2.8% of the cases, whereas 19S was negative, possibly indicating higher sensitivity of the IB. We conclude that the IB is a sensitive method to detect contact with T. pallidum in neonates and can replace the 19S in routine laboratory screening for CS cases.

[Changes and clinical significance of Toll-like receptor 2 and 4 expression in neonatal infections].

OBJECTIVES: Neonates are vulnerable to various infections because of their immature immune responses. Toll-like receptors could induce immune responses, both the innate and the acquired immune responses. The aim of the present study was to investigate the changes of TLR2 and TLR4 in neonatal infections, and to determine their roles in anti-infection immune reaction. METHODS: A total of 200 infants were divided into six groups: sepsis group (n = 21), bacterial pneumonia group (n = 70), bacterial meningitis group (n = 17), urinary tract infection group (n = 38), congenital syphilis group (n = 11) and non-infection group (n = 48). The TLR mRNA was determined by RT-PCR. The protein expression of TLR and the percentage of TLR positive cells were evaluated through flow cytometric analysis. RESULTS: 1. The TLR2 mRNA expression increased significantly in the sepsis group (6.14 +/- 0.80), most significantly in the Gram positive sepsis group (6.43 +/- 0.74). TLR2 mRNA expression was also significantly higher in the bacterial pneumonia group (5.49 +/- 0.62), the bacterial meningitis group (5.61 +/- 0.60) and the congenital syphilis group (5.89 +/- 0.38). TLR2 protein expression was the highest in the sepsis group and significantly increased in the bacterial pneumonia group, bacterial meningitis group and the congenital syphilis groups as well, all were higher than the TLR2 protein expression of the non-infectious group (1.27 +/- 0.75). The TLR2 protein expression in the Gram positive bacterial sepsis group was 2.54 +/- 0.68, that of Gram negative bacterial sepsis group was 1.25 +/- 0.51 (P < 0.05). The percentage of TLR2 positive cells in the neonatal infection group was (70.95 +/- 20.15)%, which did not differ significantly from that of non-infection group. 2. The mRNA expression of TLR4 was the highest in the sepsis group (6.20 +/- 1.59), while that in the Gram negative bacterial sepsis group was 6.78 +/- 1.79, higher than that of the Gram positive bacterial sepsis group, 5.39 +/- 0.78, (t = 2.29, P = 0.037). TLR4 mRNA expression increased significantly in the bacterial pneumonia group (5.33 +/- 1.07), the bacterial meningitis group (5.87 +/- 0.70) and the urinary tract infection group (5.38 +/- 0.91). There were no significant differences in TLR4 protein expression among these groups. The percentage of TLR4 positive cells in the neonatal infection groups was (0.71 +/- 0.31)%, higher than that of non- infection group (0.29 +/- 0.36)%. 3. In the Gram positive bacterial sepsis group, the mRNA expression of TLR2 (6.43 +/- 0.74) was higher than the mRNA expression of TLR4 (5.39 +/- 0.78), (t = 1.56, P = 0.024). In the Gram negative bacterial sepsis group, the mRNA expression of TLR4 (6.78 +/- 0.79) was significantly higher than the mRNA expression of TLR2 (5.64 +/- 0.68) (t = 2.63, P = 0.011). In the sepsis group, the TLR2 protein expression was significantly higher than the expression of TLR4 (t = 1.06, P = 0.044). The percentage of TLR4 positive cells was lower than the percentage of TLR2 positive cells among all these groups, P < 0.01. 4. Correlation analysis on gestational age and the mRNA expression, the protein expression and the percentage of TLR2 and TLR4 positive cells among all these groups did not show any statistical significance. CONCLUSIONS: The mRNA and the protein expression of TLR2 and the mRNA expression of TLR2 increased significantly in the studied neonatal infection groups, especially in the severe sepsis groups. The mRNA expression of TLR2 increased mainly in the Gram positive bacterial infection groups, and the mRNA expression of TLR4 increased in the Gram negative bacterial infection groups, suggesting that both the TLR2 and TLR4 signal pathway took part in the immune mechanism of neonatal infection, providing new idea and experimental basis for further understanding of immune mechanism of neonatal infection.

Congenital syphilis in an immunocompromised neonate: case report.

Syphilis is a notifiable and preventable disease, congenital syphilis more so. Consequently, attention has been recently focused on prenatal diagnosis of foetal syphilis by the use of ultrasonography apart from the conventional serologic screening. Congenital syphilis has not been reported from the Kingdom of Lesotho. We report the case of a 3.0 kg male neonate with florid joint and bone lesions of congenital syphilis associated with HIV infection seen at the Queen Elizabeth II Hospital, Maseru, Kingdom of Lesotho. Co-existing HIV infection influences the clinical manifestation of syphilis, the progression of neurosyphilis and the response to standard therapy. The baby had the recommended standard treatment with good response and he was followed-up for a period of twelve months with serologic screening and radiographic evaluation.

Treatment of syphilis in pregnancy and prevention of congenital syphilis.

Studies about the management of syphilis during pregnancy were reviewed. They lacked uniformity in diagnostic criteria and study design. Currently recommended doses of benzathine penicillin G are effective in preventing congenital syphilis in most settings, although studies are needed regarding increased dosing regimens. Azithromycin and ceftriaxone offer potential alternatives for penicillin-allergic women, but insufficient data on efficacy limit their use in pregnancy. Ultrasonography provides a noninvasive means to examine pregnant women for signs of fetal syphilis, and abnormal findings indicate a risk for obstetric complications and fetal treatment failure. Ultrasonography should precede antepartum treatment during the latter half of pregnancy to gauge severity of fetal infection. However, optimal management of the affected fetus has not been established; collaborative management with a specialist is recommended. Antepartum screening remains a critical component of congenital syphilis prevention, even in the era of syphilis elimination.

Congenital syphilis and fluorescent treponemal antibody test reactivity after the age of 1 year.

BACKGROUND: Many believe that a persistently reactive fluorescent treponemal antibody absorption (FTA-ABS) is manifested with congenital syphilis after the age of 1 year, that it is useful in the retrospective diagnosis of children with congenital syphilis, and that it can be used to confirm other treponemal tests. GOAL: To determine whether a reactive FTA-ABS after the age of 12 months is indicative of congenital syphilis. STUDY DESIGN: Prospective outpatient follow-up evaluation until at least the age of 12 months was conducted for 194 babies born to mothers with reactive syphilis serology at delivery, and for two additional children with congenital syphilis diagnosed when they were younger than 1 year (total, 196 children). RESULTS: In the study group, 54 children had reactive FTA-ABS (reactors) until the age of at least 12 months or more, and 142 children had nonreactive FTA-ABS (nonreactors) at the age of 12 months or more. Of the 54 reactors, 17 (31%) had evidence of congenital syphilis at birth, whereas evidence of congenital syphilis was seen in 14 of the 142 (10%) nonreactors (P = 0.0002). At 15 months, nonreactive FTA-ABS developed in six reactors, and eventually in 15 of 44 reactors (34%) tested. CONCLUSIONS: A reactive FTA-ABS may be seen at 12 months in children with and without evidence of congenital syphilis at birth. Not all children with congenital syphilis will manifest reactive FTA-ABS at 12 months, and FTA-ABS reactivity wanes with time.

Treponema pallidum subsp. pertenue displays pathogenic properties different from those of T. pallidum subsp. pallidum.

The present study described the susceptibility of C4D guinea pigs to cutaneous infection with Treponema pallidum subsp. pertenue Haiti B strain. The general manifestations of the disease in adults and neonates differ, to a certain degree, from those induced by T. pallidum subsp. pallidum Nichols strain. Noticeable differences between the infections were reflected in the character of the skin lesions, their onset and persistence, and the kinetics of the humoral response. The incidence and dissemination of cutaneous yaws lesions in very young guinea pigs were remarkably different from the low frequency observed in a similar age group of syphilis infection, 100 versus 17%, respectively. Moreover, as opposed to T. pallidum subsp. pallidum, T. pallidum subsp. pertenue does not cross the placenta. Offspring born to yaws-infected mothers did not produce immunoglobulin M antibodies and their organs, examined by PCR and rabbit infectivity test (RIT), were all negative. Examination of a large number of tissues and organs in adult, neonate, and maternal yaws by PCR and RIT clearly demonstrated that, unlike syphilis, there was a low incidence and short persistence of the yaws pathogen in internal organs. These findings stress the dermotropic rather than the organotropic character of yaws and provide further evidence of distinctive biological and pathological differences between yaws and venereal syphilis.

Vertical transmission of Treponema pallidum to various litters and generations of guinea pigs.

The transmission of congenital syphilis was studied in a 4-generation guinea pig family with 10 litters and 38 offspring. By use of one or all of the following tests (ELISA-IgM, polymerase chain reaction, and rabbit infectivity), transplacental infection was demonstrated through 5 litters and up to 4 generations. Twenty-eight (93%) of 30 animals were positive by >/=1 test, and 2 (7%) were negative by 1 or 3 tests. While transmission of the pathogen appeared to be unaffected by the maternal acquisition of immunity, signs of smoldering infection in the young was suggested by the decline in humoral responses in successive progeny and by unusual rabbit infectivity test results. With each pregnancy there was a remarkable booster in the maternal humoral response, which dropped significantly prior to term. These findings shed new light on the understanding and interpretation of serologic testing during pregnancy and the perinatal period.

Congenital syphilis in a newborn: an immunopathologic study.

A 3-week-old girl presented to the emergency room with respiratory distress and generalized maculopapular rash. The newborn was hospitalized with a presumptive diagnosis of congenital syphilis, but she died after 2 days of therapy. Tissue from the gastrointestinal tract, brain, liver, spleen, and lung was studied by using direct fluorescent antibody and immunohistochemical analysis (IHC) for Treponema pallidum. The inflammatory infiltrate was characterized by using IHC against CD3, CD20, CD68, and smooth muscle actin. The diagnosis of congenital syphilis was confirmed by demonstrating spirochetes in tissues with IHC and direct fluorescent antibody examination. IHC showed abundant treponemes in the small intestine and liver and occasional spirochetes in the meninges. Bacteria were seen as intact spirochetes, granular staining, or large extracellular collections of antigen. A constant pathologic feature throughout the tissues was concentric macrophage (CD68-positive) infiltrate around vessels, giving an onion-skin appearance. IHC identified the macrophages as the prime immune response in congenital syphilis.

[Serologic studies of non-venereal treponematoses in infants in Niamey, Niger]. / Etude sérologique des tréponematoses non vénériennes chez l'enfant à Niamey, Niger.

Though no longer reported by health centers, non-venereal treponematoses is still endemic in both arid (Bejel) and Sahelo-soudanian (Pian) areas of Niger. This study describes randomized TPHA testing carried out among children under 5 years of age living in three different sections of Niamey. Clinical examination was not performed before testing. In the overall sample of 183 children, the percent of positive tests was 12.0% with no difference according to place of residence or age. Only 3 of 37 children under the age of 12 months were seropositive Relative levels were too high to be dismissed as serological artifacts. The most likely explanation for the high antitreponemic antibodies is endemic syphilis, or Bejel, which is increasing in this region. Results in children under the age of 12 months suggest that congenital syphilis is uncommon.

Nonimmune hydrops fetalis due to congenital syphilis associated with negative intrapartum maternal serology screening.

We present an unusual case, in which a woman presenting with markedly decreased fetal movements at 29 weeks gestation following a recent increase in fundal height was noted sonographically to have fetal hydrops consisting of scalp edema, marked hepatomegaly, ascites, and polyhydramnios. No lethal structural congenital anomaly was noted. Admission laboratory examinations revealed a negative antibody screen and a negative RPR. Emergent cesarean section was performed due to prolonged fetal bradycardia during biophysical profile testing. The acidotic hydropic neonate weighing 1825 g was resuscitated yet succumbed at 3 hr of life following intravenous administration of antibiotics. Neonatal blood was RPR positive at 1:16. Postmortem pathology examination demonstrated severe multiorgan system failure secondary to overwhelming congenital syphilis. Extensive extramedullary hematopoiesis was noted and histopathology with Dieterle stains revealed numerous hepatic spirochetes. Postpartum reexamination of the maternal blood with serial dilutions revealed a positive RPR at 1:1024. This case emphasizes that initial negative screening for syphilis may be seen despite overwhelming infection, a condition that has been termed the "prozone effect."