Syphilis


Introduction

Syphilis is a sexually and vertically transmitted infection (STI) caused by the spirochaete Treponema pallidum subspecies pallidum (order Spirochaetales).

  • Great Imitator/Mimicker d/t varied and often subtle manifestations that can mimic other infections
  • M/C cause of STI-related mortality outside of HIV: Congenital syphilis
  • 2nd M/C cause of preventable stillbirths worldwide (#1 malaria)
  • No known animal reservoir

Epidemiology

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WHO estimates of incident cases of syphilis by region in 2012 | Newman, L., Rowley, J., Vander Hoorn, S., Wijesooriya, N. S., Unemo, M., Low, N., … Temmerman, M. (2015). Global Estimates of the Prevalence and Incidence of Four Curable Sexually Transmitted Infections in 2012 Based on Systematic Review and Global Reporting. PloS One, 10(12), e0143304–e0143304. https://doi.org/10.1371/journal.pone.0143304

Aetiology

Treponema pallidum:

  • Gram-negative spirochete
  • Contain endoflagellumspiral shape
  • Characteristic motility: Rapid rotation about its longitudinal axis and bending, flexing, and snapping about its full length
  • Obligate human pathogen
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Treponema pallidum: A) Like all spirochetes, T. pallidum consists of a protoplasmic cylinder and cytoplasmic membrane bounded by a thin peptidoglycan sacculus and outer membrane. Usually described as spiral-shaped, T. pallidum is actually a thin planar wave similar to Borrelia burgdorferi, the agent of Lyme borreliosis. The bacterium replicates slowly and poorly tolerates desiccation, elevated temperatures and high oxygen tensions. B) Periplasmic flagellar filaments, a defining morphological feature of spirochetes, originate from nanomotors situated at each pole and wind around the cylinder atop the peptidoglycan, overlapping at mid-cell. Force exerted by the rigid filaments against the elastic peptidoglycan deforms the sacculus to create the flat wave morphology of the spirochete. C) Ultra-thin section of T. pallidum showing the outer and cytoplasmic membranes and flagellar filaments (endoflagella) within the periplasmic space. D) Surface rendering of a flagellar motor based on cryoelectron tomograms. E) Darkfield micrograph showing the flat-wave morphology of T. pallidum. The arrow and arrowhead indicate segments that are oriented 90° from each other. The different appearances of the helical wave at 90° to the viewer can be explained only by a flat wave morphology; a corkscrew would appear the same from any angle. | Peeling, R. W., Mabey, D., Kamb, M. L., Chen, X.-S., Radolf, J. D., & Benzaken, A. S. (2017). Syphilis. Nature Reviews. Disease Primers, 3, 17073. https://doi.org/10.1038/nrdp.2017.73

Pathophysiology

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The Calgary Guide | http://calgaryguide.ucalgary.ca/

Clinical features

Clinical manifestations result from the local inflammatory response elicited by spirochetes replicating within tissues.

Clinical types:

  • Early syphilis
    • Infections that can be transmitted sexually (including primary, secondary and early latent infections) and is synonymous with active (infectious) syphilis
    • WHO definition: <2 years duration
  • Late syphilis

Disease course:

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The clinical stages of syphilis: The clinical stages of syphilis from contact with T pallidum through to development of tertiary disease. During the first year of latent infection, 25% of patients will relapse to the secondary stage. | GJESTLAND, T. (1955). The Oslo study of untreated syphilis; an epidemiologic investigation of the natural course of the syphilitic infection based upon a re-study of the Boeck-Bruusgaard material. Acta Dermato-Venereologica. Supplementum, 35(Suppl 34), 3–368; Annex I-LVI.

Primary ‘localised’ syphilis:

1-3 weeks after infection

Chancre
Painless ulceration (rolled edges with hard base), rich in spirochetes at site of entry of sexual/physical contact (vulva, vagina, cervix, anorectal region, pharynx, tongue, lips or fingers)

Chancres heal in a few months 
or
Lymphadenopathy
(SECONDARY STAGE)

640px-chancres_on_the_penile_shaft_due_to_a_primary_syphilitic_infection_caused_by_treponema_pallidum_6803_lores
This image shows chancres on the penile shaft due to a primary syphilitic infection caused by Treponema pallidum bacteria. The primary stage of syphilis is usually marked by the appearance of a single sore called a chancre. The chancre is usually firm, round, small, and painless. It appears at the spot where T. pallidum bacteria entered the body, and lasts 3-6 weeks, healing on its own. | Content Providers(s): CDC/M. Rein, VD Creation Date: 1978

Secondary ‘disseminated’ stage:

6-12 weeks post-infection
  • M/infectious stage
  • Resolve within weeks/months

Generalised lymphadenopathy

Spirochetemia
(dissemination in blood)

Spirochetes attach to small superficial vessels

Non-pruritic maculopapular rash
(flat/raised small bumps)
Spread: trunk → genitalia, arms, legs → palms, soles
Types: Pustular/papulosquamous, condylomata lata, snail track ulcers

  • Condylomata lata (smooth, white, painless wart-like lesions in moist areas: genitalia, anal region, armpits)
  • Snail track ulcers (serpiginous lesions affecting oral mucosa)

Latent ‘dormant/asymptomatic’ stage

Period of absent clinical manifestations but positive serology (spirochetes in capillaries of organs & tissues)
  • Phases:
    • Early latent phase (within 1 year): Infective stage where spirochetes can re-enter blood to cause secondary syphilis
    • Late latent phase (after 1 year): Reduced amount of spirochetes but cause type IV hypersensitivity reaction resulting in tertiary syphilis

Tertiary ‘systemic’ syphilis (30%)

  • Type IV hypersensitivity reaction
  • Gumma: Classic granulomatous lesion with accumulation of immune cells surrounded by fibroblast and a resultant central focus of coagulative necrosis
  • Types:
    • Cardiovascular syphilis
    • Neurosyphilis
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Clinical presentation of primary, secondary and congenital syphilis: A) Primary chancre. B) Primary chancre with rash of secondary syphilis. C) Secondary syphilis in a pregnant woman, who has palmar rash. D) Secondary syphilis as palmar rash. E) 3-month old baby with congenital syphilis, showing hepatosplenomegaly and desquamating rash. The child also presented with nasal discharge. F) Typical palmar desquamating rash in baby with congenital syphilis. | Peeling, R. W., Mabey, D., Kamb, M. L., Chen, X.-S., Radolf, J. D., & Benzaken, A. S. (2017). Syphilis. Nature Reviews. Disease Primers, 3, 17073. https://doi.org/10.1038/nrdp.2017.73

Complications

Cardiovascular syphilis:

  • Endarteritis of vaso vasorum → aortitisaortic aneurysm 
  • Valvular disease

Neurosyphilis:

  • Posterior spinal capillariesTabes dorsalis (slow demyelination of dorsal columns and roots of spinal cord resulting in loss of proprioception, vibration, and discriminative touch)
  • Anterior spinal capillariesGeneral paresis (loss of sensation/paralysis of mostly lower limbs)
  • Cerebral blood vessels: Paresis & mental degeneration (Slurred speech, altered behaviour, memory loss, loss of coordination, paralysis)
  • Eye: Argyl Robertson pupil (ARP) (loss of light reflex with retained accommodation reflex)
  • Gummas: Classical, specific, necrotic & ulcerative nodular lesions


Diagnosis

Diagnostic algorithm:

Layout 1
Syphilis diagnostic scheme | Pastuszczak, M., & Wojas-Pelc, A. (2013). Current standards for diagnosis and treatment of syphilis: selection of some practical issues, based on the European (IUSTI) and U.S. (CDC) guidelines. Postepy Dermatologii i Alergologii, 30(4), 203–210. https://doi.org/10.5114/pdia.2013.37029

Serology:

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Serological response to primary and secondary syphilis: Diagnosis of syphilis can be made by measuring a patient’s serological response to infection. IgM antibodies against Treponema pallidum proteins are the first to appear, followed a few weeks later by IgG antibodies. Both IgM and IgG antibodies can be measured using treponemal tests such as the T. pallidum Haemagglutination Assay (TPHA), T. pallidum Particle Assay (TPPA), Fluorescent Treponemal Antibody Absorption assay (FTA-ABS), enzyme immunoassays (EIA) and Chemiluminescent immunoassays (CIA). IgM and IgG antibodies against proteins that are not specific to T. pallidum (non-treponemal antibodies) can be detected using the Rapid Plasma Reagin (RPR), Venereal Disease Research Laboratory (VDRL) or toluidine red unheated serum (TRUST) tests and usually appear 2–3 week after treponemal antibodies. With effective treatment (which is arbitrarily shown here at 6 months), the non-treponemal antibody levels decline whereas the treponemal antibodies remain high for many years. In ~20% of patients, non-trepnemal antibodies persist 6 months after treatment; these individuals are labelled as having a serofast status. Despite repeated treatment, ~11% of patients remain serofast. Here, we show early syphilis (including primary, secondary and early latent infections; infectious syphilis) and late syphilis (including late latent and tertiary infections) as being ≤2 year in duration and >2 year in duration, respectively, in line with WHO guidelines. Beyond primary and secondary syphilis, the pattern of serological response over time is less well defined and is accordingly not shown. | Reproduced with permission (Diagnostic tools for preventing and managing maternal and congenital syphilis: an overview. Bull World Health Organ 2004;82:439–446). FTA-Abs = fluorescent treponemal antibody absorbed; IgM = immunoglobulin M; RPR = rapid plasma reagin; TPHA = T pallidum hemagglutination assay; VDRL = Venereal Disease Research Laboratory.
CPJ2013003616 114..122
Interpretation of serologic tests in syphilis | Henao-Martínez, A. F., & Johnson, S. C. (2014). Diagnostic tests for syphilis: New tests and new algorithms. Neurology. Clinical Practice, 4(2), 114–122. https://doi.org/10.1212/01.CPJ.0000435752.17621.48

CSF studies:

CPJ2013003616 114..122
CSF profiles in different neurosyphilis stages | Henao-Martínez, A. F., & Johnson, S. C. (2014). Diagnostic tests for syphilis: New tests and new algorithms. Neurology. Clinical Practice, 4(2), 114–122. https://doi.org/10.1212/01.CPJ.0000435752.17621.48
  • Primary syphilis:
    • Dark ground illumination microscopy of chancre scrapings: Spirochaetes
    • Negative serology
  • Secondary syphilis:
    • Dark ground illumination microscopy of condylomata latum scrapings: positive
    • Postive serology
  • Tertiary syphilis:
    • Positive serology
    • Neurosyphilis: CSF positive

Non-specific tests/screening tests:

  • Venereal disease research laboratory (VDRL)
  • Rapid plasma reagin (RPR)

Management

Medical management:

  • Penicillins are the first line of therapy for all stages.
CPJ2013003616 114..122
List of syphilis treatment options per disease stage | Henao-Martínez, A. F., & Johnson, S. C. (2014). Diagnostic tests for syphilis: New tests and new algorithms. Neurology. Clinical Practice, 4(2), 114–122. https://doi.org/10.1212/01.CPJ.0000435752.17621.48

Treatment of partner:

Layout 1
Sex partner care scheme | Pastuszczak, M., & Wojas-Pelc, A. (2013). Current standards for diagnosis and treatment of syphilis: selection of some practical issues, based on the European (IUSTI) and U.S. (CDC) guidelines. Postepy Dermatologii i Alergologii, 30(4), 203–210. https://doi.org/10.5114/pdia.2013.37029

Summary

Peeling, R. W., Mabey, D., Kamb, M. L., Chen, X.-S., Radolf, J. D., & Benzaken, A. S. (2017). Syphilis. Nature Reviews. Disease Primers, 3, 17073. https://doi.org/10.1038/nrdp.2017.73
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