Elsevier

The Lancet

Volume 389, Issue 10078, 15–21 April 2017, Pages 1550-1557
The Lancet

Seminar
Syphilis

https://doi.org/10.1016/S0140-6736(16)32411-4Get rights and content

Summary

Syphilis is a chronic bacterial infection caused by Treponema pallidum that is endemic in low-income countries and and occurs at lower rates in middle-income and high-income countries. The disease is of both individual and public health importance and, in addition to its direct morbidity, increases risk of HIV infection and can cause lifelong morbidity in children born to infected mothers. Without treatment the disease can progress over years through a series of clinical stages and lead to irreversible neurological or cardiovascular complications. Although syphilis is an ancient disease and the principles of recommended management have been established for decades, diagnosis and management are often challenging because of its varied manifestations and difficulty in interpretation of serological tests used to confirm diagnosis and evaluate response to therapy. In North America and western Europe, incidence of syphilis has increased dramatically in the past decade among men who have sex with men, particularly those with coexistent HIV infection. Only one drug, penicillin, is recommended for syphilis treatment and response to therapy is assessed based on changes over months in serological test titres. Treatment for patients who cannot receive penicillin and management of patients who do not serologically respond to treatment are common clinical problems.

Introduction

Syphilis is a chronic bacterial infection caused by Treponema pallidum, subspecies pallidum. The disease has been recognised by clinicians and the general public for hundreds of years. Over the same period, the disease has been highly stigmatised, which has hampered intervention strategies such as screening and partner notification.1 In low-income and middle-income countries (LMICs), syphilis infection is a relatively common problem that is a source of substantial morbidity, including adverse pregnancy outcomes and acceleration of HIV transmission.2 By contrast, in western Europe and the Americas, disease rates have tended to fluctuate periodically, challenging both clinicians and public health practitioners during highs then declining after strengthened control efforts, only to re-emerge after a period of lower disease incidence.3, 4, 5 Syphilis incidence has again begun to increase dramatically in western Europe and the Americas, and now disproportionately occurs among men who have sex with men (MSM).3, 4, 5

Clinical manifestations, transmissibility to others, and recommended treatment vary over the natural history of infection.6 Although readily recognisable in name to both clinicians and the general public, control efforts have sometimes been hampered by poor familiarity with syphilis clinical manifestations, diagnosis, and management. In this Seminar I will review the current epidemiology of syphilis and diagnosis and management strategies for general clinicians; a group who are now increasingly likely to see patients with current or past infection.

Section snippets

Epidemiology

Worldwide more than 5 million new cases of syphilis are diagnosed every year, with most infections occurring in LMICs where infections are endemic and congenital infections are not uncommon.2, 3 Led by WHO, antenatal screening programmes have reduced maternal and infant syphilis by more than one third, and congenital syphilis has been eliminated in at least one nation (Cuba).3 By contrast, in higher-income countries, infection is less common and occurs disproportionately in people living on the

Pathogenesis

Syphilis is caused by Treponema pallidum, subspecies pallidum, a long thin (from 0·15 μm by 6 μm to 15 μm), slowly growing bacterium that cannot be cultured for clinical purposes. T pallidum, subsp pallidum is closely related (>99% DNA homology) to other pathogenic spirochaetes including T pallidum subsp pertenue, the causative agent of yaws, and Treponema carateum, the organism that causes pinta.18 The high degree of DNA homology between subspecies has permitted use of syphilis serological

Clinical presentations and natural history

The natural history of syphilis is one of a chronic infection that can cause a series of highly variable clinical manifestations during the first 2–3 years of infection, followed by a typically prolonged latent stage that can evolve into clinically apparent tertiary infection stage years or even decades after initial infection.6, 20 Because syphilis lesions are often asymptomatic and can occur in regions of the body where they might go unnoticed, not all infected people have classic signs of

Neurological involvement in syphilis

Neurosyphilis is a feared but poorly understood complication of infection that can occur at any time during the course of infection.20, 24 T pallidum and cerebrospinal fluid (CSF) abnormalities can be detected in the CNS in a substantial proportion of patients with early syphilis, many of whom do not have obvious neurological signs or symptoms.25, 26 The importance of invasion and its impact on therapeutic decision making, particularly in the earlier stages of infection remains a subject of

Diagnosis

Sustained culture of T pallidum is difficult and usually used only in research. Animal models, most often using rabbit inoculation, have been valuable for isolation of T pallidum, as well as to study host response to infection.28 Direct detection of T pallidum from lesion exudate collected from patients with primary and secondary syphilis is preferable, but these tests are not readily accessible in many settings. Darkfield microscopy has traditionally been used for detecting T pallidum;

Diagnosis of neurosyphilis

Because neurosyphilis can be asymptomatic or present in many different ways, analysis of CSF is often helpful to confirm its presence. However, lumbar puncture and CSF analysis are presently only recommended for diagnosis of neurosyphilis in individuals with appropriate clinical syndromes, for evaluation of possible treatment failures, and for some patients with latent syphilis.23 In these situations, a reactive CSF VDRL test is diagnostic of neurosyphilis, while detection of an elevated CSF

Management

Penicillin has long been the drug of choice for treatment of syphilis. In recent years, manufacturing shortfalls have sometimes limited the availability of benzathine benzylpenicillin, the preferred formulation for most syphilis therapy.39 Long-acting formations of benzathine benzylpenicillin are the most commonly recommended drugs for syphilis treatment. Alternate therapy using multiple doses of procaine penicillin, doxycycline, or ceftriaxone can be used when intravenous therapy might be

Response to therapy

Response to therapy is indicated by a two (four-fold) or more dilution decline in non-treponemal serological test titres or, if initial titres are positive at a 1:1 or 1:2 dilution, by becoming non-reactive.23, 31, 32 However, serological response to therapy is not universal in successfully treated patients and 15–20% of patients with early syphilis might have so-called serofast titres, which do not change substantially (ie, remain positive at the initial titre or only decline a single

Control strategies

Beyond primary prevention using avoidance strategies and condoms, approaches for control of diagnosed syphilis are based on adaptation of recommendations made by US Surgeon General, Thomas Parran: widespread testing (screening), professional and public education and engagement, timely treatment, and continuing research to improve these efforts.19 In LMICs, syphilis management is most often started after presentation for evaluation of genital ulceration or as a result of prenatal care testing.38

Notification and partner management strategies

Other than for congenital syphilis, transmission of syphilis is thought to be transmitted almost entirely by individuals with early stage infection. For such patients, administration of preventive therapy (2·4 million units of benzathine benzylpenicillin administered parenterally) is recommended for all recent (30–90 days) sexual partners.23 Since lesions have not been present for some time in individuals with later latent syphilis (ie, latent syphilis of more than 1–2 year duration),23, 38

Conclusion and future research

Research is continuing into T pallidum biology and host response to infection as part of efforts to develop vaccines for syphilis prevention.46 At present, understanding for and the principles used to guide syphilis management are based on data collected in the pre-penicillin era when the disease was far more common than it is today. The clinical and prognostic significance of CNS invasion by T pallidum in patients with early syphilis and associated CSF abnormalities remains an area of great

Search strategy and selection criteria

I searched PubMed to identify peer-reviewed articles published in English between Jan 1, 2005, and June 30, 2016, using the terms “syphilis”, “syphilis epidemiology”, and “syphilis treatment”. I also referred to older literature on management and clinical presentations of the disease written in the pre-penicillin era.

This online publication has been corrected. The corrected version first appeared at thelancet.com on March 7, 2019

References (46)

  • SL Gottlieb et al.

    The global roadmap for advancing development of vaccines against sexually transmitted infections: update and next steps

    Vaccine

    (2016)
  • AM Brandt

    No Magic Bullet: A social history of venereal disease in the United States since 1880

    (1985)
  • Newman L, Rowley J, Hoorn SV, et al. Global estimates of the prevalence and incidence of four curable sexually...
  • Report on global sexually transmitted infection surveillance 2015

    (2016)
  • Sexually Transmitted Disease Surveillance 2014

    (2015)
  • Infection Report: Sexually Transmitted Infections

    (2015)
  • PF Sparling et al.

    Clinical Manifestations of syphilis

  • CM Hutchinson et al.

    Characteristics of patients with syphilis patients attending Baltimore STD clinics: multiple high risk subgroups and interactions with human immunodeficiency virus infection

    Arch Intern Med

    (1991)
  • W Phipps et al.

    Risk factors for repeat syphilis in men who have sex with men, San Francisco

    Sex Transm Dis

    (2009)
  • Notes from the field: Repeat syphilis infection and HIV coinfection among men who have sex with men—Baltimore, Maryland, 2010–2011

    MMWR Morb Mortal Wkly Rep

    (2013)
  • NC Grassly et al.

    Host immunity and synchronized epidemics of syphilis across the United States

    Nature

    (2005)
  • WW Darrow et al.

    Risk factors for human immunodeficiency virus (HIV) infection in homosexual men

    Am J Public Health

    (1987)
  • EW Hook

    Syphilis and HIV infection

    J Infect Dis

    (1989)
  • WE Stamm et al.

    The association between genital ulcer disease and the acquisition of HIV infection in homosexual men

    JAMA

    (1988)
  • TA Peterman et al.

    High risk for HIV following syphilis diagnosis among men in Florida, 2000-2011

    Public Health Rep

    (2014)
  • P Pathela et al.

    The high risk of HIV diagnosis following a diagnosis of syphilis: a population-level analysis of New York City men

    Clin Infect Dis

    (2015)
  • CM Hutchinson et al.

    Altered clinical presentations and manifestations of early syphilis in patients with human immunodeficiency virus infection

    Ann Intern Med

    (1994)
  • RT Rolfs et al.

    A randomized trial of enhanced therapy for early syphilis in patients with and without human immunodeficiency virus infection

    N Engl J Med

    (1997)
  • L Giacani et al.

    The endemic treponematoses

    Clin Microbiol Rev

    (2014)
  • T Parran

    Shadow on the Land. Syphilis

    (1937)
  • EW Hook et al.

    Acquired syphilis in adults

    N Engl J Med

    (1992)
  • KJ Mertz et al.

    Etiology of genital ulcers and prevalence of human immunodeficiency virus coinfection in 10 US cities

    J Infect Dis

    (1998)
  • T Gjestland

    The Oslo study of untreated syphilis: An epidemiologic investigation of the natural course of syphilitic infection based on a restudy of the Boeck-Bruusgaard material

    J Chronic Dis

    (1955)
  • Cited by (320)

    View all citing articles on Scopus
    View full text