Congenital Syphilis

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Congenital Syphilis

• N.Frewan, PL2
• Neonatology Division
• July 2008

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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

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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

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Introduction

• Pathogenic members of this genus include
• - T pallidum
• - T pertenue
• - T carateum

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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.

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Treponema Pallidum

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

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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

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Congenital syphilis

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

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IncidenceUS

• 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)

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IncidenceUS

• 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

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Reported cases for infants rates of 1ry 2ry syphilis among women United
States, 19972006
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Rates for infants and the Healthy People 2010 target as per STD
surveillance
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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

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Jul-2006
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PathophysiologyCS

• 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

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Clinical Manifestations

• Intra-uterine -Placenta
• -Fetus
• Post-natal - Early
• - Late

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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

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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

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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

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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

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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)

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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

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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

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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

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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

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Symptomatic Early CS

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

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Congenital syphilis - early evidence of
infection - bullae and vesicular rash
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Multiple, punched out, pale, blistered lesions,
with associated desquamation of palms plantars
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Intraoral mucous patches facial skin lesions
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Secondary lesions on feet Lesions first appeared
during 4th week
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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

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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 )

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Hutchinson triad

• Deafness (10 40 years)
• Hutchinsons teeth centrally notched,
  widely-spaced peg-shaped upper central incisors
• Interstitial Keratitis ? blindness (5-20 years)

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Notched incisors known as Hutchinsons teeth
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Moribund newborn with CS Oral / skin lesions and
saddle nose
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Metaphyseal osteomyelitis Radiolucent
distal radius ulna with cupping distal ulna
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Osteochondritis of femur tibia
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1-m-old . Classical Wimberger's sign of
destructive metaphysitis involving medial aspects
of distal femora and proximal tibae
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Saber shins Osteoperiostitis Tibia
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Interstitial keratitis
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Possible Complications   

• Blindness
• Deafness
• Facial deformity
• Neurological problems

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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

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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

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Nontreponemal test

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

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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

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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

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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

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Nontreponemal testNewborn 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

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Treponemal Specific Test

• T pallidum immobilization (TPI)
• Fluorescent treponemal antibody absorption
  (FTA-ABS)
• Microhemagglutination assay for antibodies to T
  pallidum (MHA-TP)

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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

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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

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CBC

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

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LFT

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

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Imaging Studies

• CXR
• - Syphilitic pneumonia is common in CS
• - Fluffy diffuse infiltrate pneumonia alba

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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

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Imaging Studies

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

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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

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CDCNewborn 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

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CDCNewborn Evaluation

• 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

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CDCNewborn Evaluation

• 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

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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)

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Treatment 

• Indications
• If newborn meets any of criteria
• If mother was treated
• If mother treated with other than penicillin
• If maternal titers suggest inadequate response to
  treatment before or early in pregnancy

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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

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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

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Evaluation and Treatment of Infants During the
First Month of Life

• The following scenarios describe the evaluation
  and treatment of infants for congenital syphilis

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Scenario 1 Infants with proven or highly
probable disease and

• Abnormal P/E consistent with CS
• Serum quantitative NT titer 4x mothers titer
  or
• darkfield or fl. ab. test of body fluids

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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

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Scenario 2Normal 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 delivery

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Scenario 2Normal 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

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Scenario 3Normal 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

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Scenario 3Normal 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

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Scenario 4Normal P/E serum quantitive NT titer
4 x maternal titer

• Mothers treatment was adequate before
  pregnancy. and
• Mothers NT titer remained low and stable before,
  during pregnancy and at delivery (VDRL

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Scenario 4Normal P/E serum quantitive NT titer
4 x maternal titer

• Recommended Regimen
• ?
• No treatment required

• Recommended Evaluation
• ?
• No evaluation required

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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

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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.