1. Congenital Syphilis N.Frewan, PL2 Neonatology Division July 2008

3. Background Between 1905 -1910, 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

4. 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 “

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

8. Introduction Pathogenic treponemes are associated with 4 diseases : 1. Venereal syphilis -T pallidum pallidum 2. Yaws -T pallidum pertenue 3. Endemic syphilis (bejel) - T pallidum endemicum 4. 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.

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

10. 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

11. Congenital syphilis Severe, disabling, and often life- threatening infection seen in infants About half of all infected fetuses die shortly before or after birth

12. 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 1985-1990: overall incidence ↑ 75% ( Sex-Drug traffic)

13. 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

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

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

17. 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

18. Jul-2006

19. Pathophysiology CS Trans placental transmission Transmission rate:~ 60 - 100% 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

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

21. 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

22. 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

23. 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: 25-30 %, if untreated

24. 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

25. Early CS- Asymptomatic Occurs between 0 - 2 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)

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

27. 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

28. 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

29. 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

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

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

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

33. Intraoral mucous patches & facial skin lesions

34. Secondary lesions on feet Lesions first appeared during 4 th week

35. 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

36. 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 )

37. Hutchinson triad 1. Deafness (10 – 40 years) 2. Hutchinson’s teeth = centrally notched, widely-spaced peg-shaped upper central incisors 3. Interstitial Keratitis → blindness (5-20 years)

38. Notched incisors known as Hutchinson’s teeth

39. Moribund newborn with CS O ral / skin lesions and saddle nose

40. Metaphyseal osteomyelitis R adiolucent distal radius & ulna with cupping distal ulna

41. Osteochondritis of femur & tibia

42. 1-m-old. Classical Wimberger's sign of destructive metaphysitis involving medial aspects of distal femora and proximal tibae

43. “Saber shins” = Osteoperiostitis Tibia

44. Interstitial keratitis

45. Possible Complications Blindness Deafness Facial deformity Neurological problems

46. Labs Definitive diagnosis: 1. By direct visualization of spirochetes using darkfield microscopy 2. Or direct fluorescent antibody tests of lesion exudate or tissue (Placenta/UC) -Helpful early in the disease, prior to development of seroreactivity

47. 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

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

49. 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

50. 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

51. 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

52. 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 1 st 6 months of life, when maternal IgG is lost, would be required to make a diagnosis i.e. Loosing precious time in treatment initiation

53. Treponemal Specific Test T pallidum immobilization (TPI) Fluorescent treponemal antibody absorption (FTA-ABS) Microhemagglutination assay for antibodies to T pallidum (MHA-TP)

54. 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

55. 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

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

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

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

59. 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

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

61. 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

62. 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

63. CDC Newborn Evaluation Evaluation should include: 1. Maternal H/O syphilis including tx type & adequacy before and during the pregnancy 2. P/E of newborn 3. Quantitative NT & T tests 4. CBC, long bone x-rays, CSF (VDRL, cell count, protein), and CXR and/or LFT 5. Pathologic examination of placenta or umbilical cord using specific fluorescent antitreponemal antibody staining

64. CDC Newborn Evaluation A presumptive diagnosis, which results in tx, is made if baby has + serologic test and any of following: 1. Compatible findings on P/E 2. CSF abn. (+ VDRL, ↑ WBC, or ↑protein) 3. Osteitis on x-ray long bones 4. Placentitis 5. NT test 4x > than maternal 6. Positive FTA-ABS-19S IgM antibody

65. Treatment IV Penicillin G is the drug of choice for all stages of syphilis including CS Infants: - 100,000 - 150,000 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)

66. Treatment Indications: 1. If newborn meets any of criteria 2. If mother was treated < 4 weeks prior to delivery 3. If mother treated with other than penicillin 4. If maternal titers suggest inadequate response to treatment before or early in pregnancy

67. 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

68. 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

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

70. 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

71. 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

72. 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

73. Scenario 2 Normal P/E & serum quantitive NT titer ≤ 4 x maternal titer 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

74. Scenario 3 Normal P/E & serum quantitive NT titer ≤ 4 x maternal titer 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

75. Scenario 3 Normal P/E & serum quantitive NT titer ≤ 4 x maternal titer Recommended Evaluation ⇩ No evaluation required Recommended Regimen ⇩ Benzathine penicillin G 50,000 units/kg/dose IM in a single dose

76. Scenario 4 Normal P/E & serum quantitive NT titer ≤ 4 x maternal titer 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)

77. Scenario 4 Normal P/E & serum quantitive NT titer ≤ 4 x maternal titer Recommended Evaluation ⇩ No evaluation required Recommended Regimen ⇩ No treatment required

78. 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

79. References www.cdc.gov/STD/STATS/figs.gif Red Book (27 th 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.