N.Frewan, PL2 Neonatology Division July 2008

N.Frewan, PL2 Neonatology Division July 2008
Congenital Syphilis

Background Between , Schaudinn & Hoffman identified T pallidum as the cause of syphilis The name "syphilis" was coined by Italian physician and poet Girolamo Fracastoro in his Latin written poem “Syphilis sive morbus gallicus” ("Syphilis or The French Disease") in 1530 The protagonist of the poem is a shepherd named Syphilus (perhaps a variant spelling of Sipylus, a character in Ovid's Metamorphoses). Syphilus is presented as the first man to contract the disease, sent by the god Apollo as punishment for the defiance that Syphilus and his followers had shown him. It had been called "French disease" in Italy & Germany, and the "Italian disease" in France, the Dutch called it "Spanish disease", the Russians called it "Polish disease and the Tahitians called it "British disease“ These 'national' names are due to the disease often being present among invading armies or sea crews, due to the high instance of unprotected sexual contact with prostitutes It was also called "Great pox" in the 16th century to distinguish it from smallpox

Introduction Curable STD caused by the Treponema pallidum organism
1998: Complete genetic sequence of T. pallidum was published which helped understanding the pathogenesis of syphilis Belongs to “Spirochaetaceae family” The genus name, Treponema, is derived from the Greek term for "turning thread“

Introduction Pathogenic members of this genus include: - T pallidum
- T pertenue - T carateum

Introduction Pathogenic treponemes are associated with 4 diseases :
Venereal syphilis -T pallidum pallidum Yaws -T pallidum pertenue Endemic syphilis (bejel) - T pallidum endemicum Pinta - T carateum The treponemes responsible for these diseases cannot be distinguished serologically, morphologically, or by genome analysis, and they have not been successfully cultivated on artificial media.

Treponema Pallidum Thin Motile Extremely fastidious
Survive only briefly outside host Not cultivated successfully on artificial media

Transmission Direct sexual contact with ulcerative lesions of skin or mucous membranes Trans placental: Typically during second half of pregnancy As early as 6 weeks of gestation Pregnant with primary or secondary syphilis are more likely to transmit the disease than those with latent (not clinically apparent) disease Cannot be spread through contact with toilet seats, doorknobs, swimming pools, hot tubs, bathtubs, shared clothing, or eating utensils

Congenital syphilis Severe, disabling, and often life-threatening infection seen in infants About half of all infected fetuses die shortly before or after birth Despite the fact that this disease can be cured with antibiotics if caught early, rising rates of syphilis among pregnant women in the United States have recently increased the number of infants born with congenital syphilis.

Incidence US Despite the fact of being curable if caught early, rising rates among pregnant ♀ in the US have recently ↑ the number of infants born with congenital syphilis : overall incidence ↑ 75% ( Sex-Drug traffic) This resurgence was primarily due to ↑ illegal drug use (particularly crack cocaine) that was associated with an exchange of sex for drugs

Incidence US 1998: 81.3% of reported cases of CS occurred because the mother received no/inadequate penicillin tx before or during pregnancy According to the CDC: 40% of births are stillborn 40-70% of the survivors will be infected & 12% of these will subsequently die In the United States, health officials reported over 36,000 cases of syphilis in 2006, including 9,756 cases of primary and secondary (P&S) syphilis. In 2006, half of all P&S syphilis cases were reported from 20 counties and 2 cities; and most P&S syphilis cases occurred in persons 20 to 39 years of age. The incidence of P&S syphilis was highest in women 20 to 24 years of age and in men 35 to 39 years of age. Reported cases of congenital syphilis in newborns increased from 2005 to 2006, with 339 new cases reported in 2005 compared to 349 cases in 2006. Between 2005 and 2006, the number of reported P&S syphilis cases increased 11.8 percent. P&S rates have increased in males each year between 2000 and 2006 from 2.6 to 5.7 and among females between 2004 and 2006. In 2006, 64% of the reported P&S syphilis cases were among men who have sex with men (MSM).

Reported cases for infants < 1 year of age and rates of 1ry & 2ry syphilis among women: United States, 1997–2006

Rates for infants < 1 year of age: US, 1997–2006 and the Healthy People 2010 target as per STD surveillance

Incidence International
Worldwide, predominantly in large cities Certain European countries have seen ↑in congenital syphilis cases Major public health problem in sub-Saharan Africa and developing world Main focus in control: Antenatal screening & treatment of infected mothers

Jul-2006

Pathophysiology CS Trans placental transmission
Transmission rate:~ % With early onset disease, manifestations result from trans placental spirochetemia and are analogous to secondary stage of acquired syphilis CS does not have a primary stage

Clinical Manifestations
Intra-uterine: -Placenta -Fetus Post-natal: - Early - Late

Intra-uterine: Placenta
The placenta is typically large and edematous Characteristic placental findings include: - Hydrops placentalis Chronic villitis Perivillous fibrous proliferation Normoblastemia Necrotizing funisitis Acute chorioamnionitis Plasma cell deciduitis

Intra-uterine: Fetus Depends on stage of development at time of infection & duration of untreated infection Initially characterized by placental involvement and hepatic dysfunction (e.g., abnormal LFT), followed by amniotic fluid infection, hematologic abnormalities, ascites, and hydrops Stillbirth / Neonatal death

Intra-uterine: Fetus >24 weeks gestation: 66 % of fetuses have either congenital syphilis or T.Pallidum detected in amniotic fluid Intrauterine death: 25 % of affected Perinatal mortality: %, if untreated

Post-Natal Among survivors, manifestations been divided into:
Early stage = First 2 years Late stage = After 2 years Inflammatory changes do not occur in the fetus until after first trimester → organogenesis is unaffected Nevertheless, all organ systems may be involved

Early CS- Asymptomatic
Occurs between years If asymptomatic : - Identified on routine prenatal screening - If not identified and treated, these newborns develop poor feeding and rhinorrhea ➨ Earliest signs of CS may be poor feeding and snuffles (i.e., syphilitic rhinitis)

Symptomatic Early CS If Symptomatic: Variable
Appear within 1st 5 weeks of life Stillborn/ Premature Failure to gain weight or FTT Fever / Irritability Severe congenital pneumonia

Symptomatic Early CS Most striking lesions affect the mucocutaneous tissues and bones: - Mucous patches - Rhinitis =snuffle - Condylomatous lesions ➨ ➨ highly characteristic features of mucous membrane involvement in CS

Symptomatic Early CS Snuffles → Followed quickly by diffuse maculopapular desquamative rash that involves extensive sloughing of the epithelium, on the palms & soles and around the mouth & anus When chronic → “Saddle Nose” Lesions & nasal fluid: highly infectious

Symptomatic Early CS Bullous skin disease known as “pemphigus syphiliticus” ➲ Early rash -- small blisters on the palms and soles → Ulcerated ➲ Later rash -- copper-colored, flat or bumpy rash on the face, palms, and soles

Symptomatic Early CS Other early manifestations include hepatosplenomegaly (100%), jaundice, anemia Metaphyseal dystrophy and periostitis often are noted on radiographs at birth +/_ Pseudoparalysis

Congenital syphilis - early evidence of infection - bullae and vesicular rash

Multiple, punched out, pale, blistered lesions, with associated desquamation of palms & plantars

Intraoral mucous patches & facial skin lesions

Secondary lesions on feet Lesions first appeared during 4th week

Late-onset CS Develop from scarring related to early infection
Can be prevented by treatment within first 3 months Can appear as late as 40 years after

Late-onset CS Manifestations include neurosyphilis and involvement of teeth, bones, eyes, and 8th cranial nerve E.g.: Frontal bossing, short maxilla, high palatal arch, Hutchinson triad, saddle nose, and perioral fissure (Rhagades = bacterial infection of skin lesions )

Hutchinson triad Deafness (10 – 40 years)
Hutchinson’s teeth = centrally notched, widely-spaced peg-shaped upper central incisors Interstitial Keratitis → blindness (5-20 years)

Notched incisors known as Hutchinson’s teeth

Moribund newborn with CS Oral / skin lesions and saddle nose

Metaphyseal osteomyelitis Radiolucent distal radius & ulna with cupping distal ulna

Osteochondritis of femur & tibia

1-m-old . Classical Wimberger's sign of destructive metaphysitis involving medial aspects of distal femora and proximal tibae

“Saber shins” = Osteoperiostitis Tibia

Interstitial keratitis

Possible Complications
Blindness Deafness Facial deformity Neurological problems

Labs Definitive diagnosis:
By direct visualization of spirochetes using darkfield microscopy Or direct fluorescent antibody tests of lesion exudate or tissue (Placenta/UC) -Helpful early in the disease, prior to development of seroreactivity

Serologic tests - Presumptive diagnosis can be made using
Nontreponemal ( False + in medical conditions) Treponemal (False+ in other spirochetal Diseases) → So use of only one type is insufficient - If nontreponemal test is +→ confirmatory testing is performed with a specific treponemal test

Nontreponemal test VDRL (Venereal Disease Research Laboratory)
RPR (Rapid plasma reagin) ART (Automated reagin test)

Nontreponemal test - Used for screening (sensitive but not specific)
- Inexpensive, performed rapidly, and provide quantitative results → helpful indicators of disease activity & monitor treatment response Measures Ab directed against lipoidal Ag from T. Pallidum, Ab interaction with host tissues or both - Nonspecific Ab develop 4-8 weeks following infection

Nontreponemal test False negative Early primary S Latent acquired S
Late CS Prozone phenomenon False Positive Viral infection ( EBV, Hepatitis, Varicela, Measles) Lymphoma TB Malaria Endocarditis CT diseases Pregnancy IV drugs Wharton Jelly contamination in cord samples Prozone phenomenon: Sometimes a weak reaction occur and diluting serum results in positive test A prozone phenomenon occurs in approximately 2% of patients, especially in those with secondary syphilis and those who are pregnant. High levels of antibody in undiluted serum cause an obscured positive test result. When clinical findings strongly suggest syphilis (eg, an infant with the appearance of congenital syphilis, despite negative maternal serology), perform appropriate dilutions to exclude this phenomenon

Nontreponemal test Any reactive NT test must be confirmed by Treponemal test to exclude false positive Treatment should not be delayed if symptomatic or at high risk of infection Monitor: Sustained 4 fold ↓NT test titer after treatment → Adequate treatment - Sustained ↑: Re-infection or relapse

Nontreponemal test Newborn Dilemma
Testing of newborn often is problematic because IgG antibody may be a reflection of maternal rather than infant infection Unless NT titer is much higher in baby than in mother → f/u serology over 1st 6 months of life, when maternal IgG is lost, would be required to make a diagnosis i.e. Loosing precious time in treatment initiation

Treponemal Specific Test
T pallidum immobilization (TPI) Fluorescent treponemal antibody absorption (FTA-ABS) Microhemagglutination assay for antibodies to T pallidum (MHA-TP) The immunoglobulin M (IgM) FTA-ABS measures antibody specific to the infant born to an infected mother. However, this test is less specific than once thought and is available only at the Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia so its general usefulness is questionable.

Treponemal Specific Test
Confirm + nontreponemal reaginic test Remain positive for life i.e. Result do not correlate with disease activity and tests are not quantified False + reactions: → Other spirochetal diseases (e.g., yaws, pinta, leptospirosis, rat-bite fever, relapsing fever, Lyme disease

Cerebrospinal Fluid Analysis
CSF VDRL Could be negative and still develop signs of neurosyphilis →Therefore, all those with presumptive CS should be treated A nonquantitative VDRL test is the only serologic test that should be performed on CSF Other test like FTA-ABS are less specific on CSF samples

CBC CS characterized by anemia, thrombocytopenia, and either leukopenia or leukocytosis Evidence of Coombs-negative hemolytic anemia or a leukemoid reaction may be present

LFT Syphilitic hepatitis is characterized by a disproportionately ↑ alk.ph and N or +/-↑s.bilirubin but no cholestasis Enzymes usually ↑ Prothrombin time may be ↑

Imaging Studies CXR: - Syphilitic pneumonia is common in CS
- Fluffy diffuse infiltrate “pneumonia alba”

Imaging Studies Long bone radiography
95% of symptomatic infants and 20% of asymptomatic Multiple sites of osteochondritis at wrists, elbows, ankles and knees and periostitis of long bones The lower extremities almost always affected

Imaging Studies Neuroradiography: Findings nonspecific
May mimic herpes simplex virus MRI may reveal cerebral hypertrophy and hyperintensity in the temporal lobes

Other Tests LIAISON Treponema Assay
One-step sandwich chemiluminescent immunoassay (CLIA), was compared with conventional tests. The test demonstrated higher sensitivity and specificity as a screening and confirmatory tool compared with conventional methods Real-time polymerase chain reaction (PCR) is an effective and sensitive assay used to detect T pallidum in the vitreous in patients with syphilitic chorioretinitis

CDC Newborn Evaluation
The diagnosis of CS is complicated by the trans placental transfer of maternal nontreponemal and treponemal IgG Abs to fetus ➨ Making interpretation of reactive serologic tests for CS difficult

Evaluation should include: Maternal H/O syphilis including tx type & adequacy before and during the pregnancy P/E of newborn Quantitative NT & T tests CBC, long bone x-rays, CSF (VDRL, cell count, protein), and CXR and/or LFT Pathologic examination of placenta or umbilical cord using specific fluorescent antitreponemal antibody staining

A presumptive diagnosis, which results in tx, is made if baby has + serologic test and any of following: Compatible findings on P/E CSF abn. (+ VDRL, ↑ WBC, or ↑protein) Osteitis on x-ray long bones Placentitis NT test 4x > than maternal Positive FTA-ABS-19S IgM antibody Although CSF findings are a component of the case definition, at least one retrospective study has called into question their value . Among a group of 329 asymptomatic infants whose mothers had untreated or inadequately treated syphilis, only two (0.6 percent) had positive CSF VDRL, and neither the WBC nor protein differed from a control group of newborns undergoing a sepsis evaluation with negative results. Among the other criteria, the nontreponemal test only occasionally is fourfold higher than the maternal one, and the 19S IgM test is not readily available. The infant also is presumed to have syphilis if the mother has a history of contact with an individual with primary or secondary syphilis within 90 days of delivery and did not receive treatment

Treatment IV Penicillin G is the drug of choice for all stages of syphilis including CS Infants: - 100, ,000 U/kg/d IV Q12 x 7 d. then Q 8 to complete 10 days - Or Procaine Penicillin G 50,000 U/kg/d IM once for 10 days (adequate CSF conc. may not be achieved)

Treatment Indications: If newborn meets any of criteria
If mother was treated < 4 weeks prior to delivery If mother treated with other than penicillin If maternal titers suggest inadequate response to treatment before or early in pregnancy Treatment of the mother during pregnancy is effective; in one prospective study of 340 pregnant women, the overall success rate for therapy was 98 percent, with the lowest rate of 95 percent in those with secondary syphilis

Syphilis In Pregnancy In communities in which risk for CS is high → serologic testing and a sexual history also should be obtained at 28 weeks gestation and at delivery Treat all pregnant patients with penicillin, regardless of the stage of pregnancy If a pregnant mother is identified as being infected with syphilis, treatment can effectively prevent congenital syphilis from developing in the unborn child, especially if she is treated before the sixteenth week of pregnancy. a woman in the secondary stage of syphilis decreases her child's risk of developing congenital syphilis by 98% if she receives treatment before the last month of pregnancy[4

Syphilis In Pregnancy 3 doses of benzathine penicillin
(2.4 million U IM at 1-week intervals) No proven alternative treatment for patient allergic to penicillin i.e. Erythromycin for patient allergic to penicillin is not reliable treatment for fetus

Evaluation and Treatment of Infants During the First Month of Life
The following scenarios describe the evaluation and treatment of infants for congenital syphilis

Scenario 1 Infants with proven or highly probable disease and
Abnormal P/E consistent with CS Serum quantitative NT titer 4x > mother’s titer or + darkfield or fl. ab. test of body fluids

Scenario 1 Infants with proven or highly probable disease and
Recommended Evaluation CSF analysis for VDRL, cell count & protein CBC w. diff.& PL count Other tests as clinically indicated ( long-bone x-rays, CXR, LFT, HUS, ophthalmologic exam, and BAER) Recommended Regimens Aqueous crystalline penicillin G 50,000 U/kg/dose IV Q 12 hrs. first 7 DOL and Q 8 hrs thereafter for a total of 10 days OR Procaine penicillin G 50,000 units/kg/dose IM in a single daily dose for 10 days The absence of a fourfold or greater titer for an infant does not exclude congenital syphilis CSF test results obtained during the neonatal period can be difficult to interpret; normal values differ by gestational age and are higher in preterm infants. Values as high as 25 white blood cells (WBCs)/mm3 and/or protein of 150 mg/dL might occur among normal neonates; some specialists, however, recommend that lower values (i.e., 5 WBCs/mm3 and protein of 40 mg/dL) be considered the upper limits of normal. Other causes of elevated values should be considered when an infant is being evaluated for congenital syphilis. If >1 day of therapy is missed, the entire course should be restarted. Data are insufficient regarding the use of other antimicrobial agents (e.g., ampicillin). When possible, a full 10-day course of penicillin is preferred, even if ampicillin was initially provided for possible sepsis. The use of agents other than penicillin requires close serologic follow-up to assess adequacy of therapy. In all other situations, the maternal history of infection with T. pallidum and treatment for syphilis must be considered when evaluating and treating the infant.

Scenario 2 Normal P/E & serum quantitive NT titer ≤ 4 x maternal titer
Mother not / inadequately treated, or no documentation Mother was treated with erythromycin or other nonpenicillin regimen or Mother received treatment < 4 weeks before delivery

Recommended Evaluation CSF analysis for VDRL, cell count, and protein CBC w. diff. and PLT count Long-bone X-rays Recommended Regimens Aqueous cryst. penicillin G 50,000 u./kg/dose IV Q 12 hrs during the 1st 7 DOL and Q 8 hrs thereafter for a total of 10 days OR Procaine penicillin G 50,000 units/kg/dose IM in a single daily dose for 10 days OR Benzathine penicillin G 50,000 units/kg/dose IM in a single dose A complete evaluation is not necessary if 10 days of parenteral therapy is administered. However, such evaluations might be useful; a lumbar puncture might document CSF abnormalities that would prompt close follow-up. Other tests (e.g., CBC, platelet count, and bone radiographs) may be performed to further support a diagnosis of congenital syphilis. If a single dose of benzathine penicillin G is used, then the infant must be fully evaluated (i.e., through CSF examination, long-bone radiographs, and CBC with platelets), the full evaluation must be normal, and follow-up must be certain. If any part of the infant’s evaluation is abnormal or not performed or if the CSF analysis is rendered uninterpretable because of contamination with blood, then a 10-day course of penicillin is required.†† Some specialists prefer the 10 days of parenteral therapy if the mother has untreated early syphilis at delivery. A woman treated with a regimen other than those recommended in these guidelines for treatment should be considered untreated. If the infant’s nontreponemal test is nonreactive and the likelihood of the infant being infected is low, certain specialists recommend no evaluation but treatment of the infant with a single IM dose of benzathine penicillin G 50,000 units/kg for possible incubating syphilis, after which the infant should receive close serologic follow-up.

Mother was treated during pregnancy, tx. was appropriate for the stage of infection, and treatment was administered > 4 weeks before delivery….. and Mother has no evidence of reinfection or relapse

Recommended Evaluation ⇩ No evaluation required Recommended Regimen ⇩ Benzathine penicillin G 50,000 units/kg/dose IM in a single dose Some specialists would not treat the infant but would provide close serologic follow-up in those whose mother’s nontreponemal titers decreased fourfold after appropriate therapy for early syphilis or remained stable or low for late syphilis.

Mother’s treatment was adequate before pregnancy…. and Mother’s NT titer remained low and stable before, during pregnancy and at delivery (VDRL <1:2; RPR <1:4)

Recommended Evaluation ⇩ No evaluation required Recommended Regimen ⇩ No treatment required however, some specialists would treat with benzathine penicillin G 50,000 units/kg as a single IM injection, particularly if follow-up is uncertain.

Outlook (Prognosis) Infected early in pregnancy ➨ stillborn
Treatment of expectant mother ↓ risk of CS Babies who become infected when passing through birth canal have better outlook Death from CS is usually through pulmonary hemorrhage

References www.cdc.gov/STD/STATS/figs.gif
Red Book (27th edition)- 2006 Overview of TORCH infections: Karen E Johnson, MD. Uptodate 2006 Early congenital syphilis: Ameeta Singh, BMBS MSc,* Karen Sutherland, RN BScN,† Bonita Lee, MD MSc- pubmed Congenital syphilis re-emerging. Simms I, Broutet N.

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N.Frewan, PL2 Neonatology Division July 2008

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