# July 2022
The protocol review process resulted in numerous updates throughout the document, including:
- Revised guidance in the previous letters to healthcare providers has been incorporated into the relevant sections of the protocol. - Section 3.1: Clarification of staging of congenital syphilis in the case of non-reactive serology at 18-24 months of age. - Section 6.4: Advice on staging (further clarification on early latent and late latent) and treatment of asymptomatic individuals (also included in Sections 3.4). - Section 8.3.5: How to administer penicillin G benzathine.
- Section 9: Key Investigations for Public Health Response, including new documentation guidance for public health.

# Summary of Addenda added to Previous Version of the Protocol (July 2014)
- Updates to Syphilis Protocol Congenital Syphilis and Syphilitic Stillbirth Case Definitions and Reporting (October 12, 2021)
- Clarification of the treatment of syphilis in pregnancy greater than 20 weeks gestation (October 20, 2020)
Syphilis is primarily a bacterial sexually transmitted infection (STI). Syphilis can also be acquired through congenital transmission to the newborn, and rarely through blood-borne transmission. It is a systemic disease caused by the spirochete Treponema pallidum subspecies pallidum (1). Syphilis occurs exclusively in humans; there is no animal reservoir (2).
Non-venereal treponemal infections cause pinta, yaws, and bejel. These diseases are endemic to some regions of the world and may be seen in Manitoba primarily as a result of immigration. Serologic testing cannot distinguish syphilis from these endemic treponematoses (3).

# Case Definitions

# Congenital Syphilis

# Early Congenital Syphilis (within two years of birth) Lab Confirmed Case -Early Congenital Syphilis (within two years of birth)
Identification of T. pallidum by dark-field microscopy a direct fluorescence antibody b or detection of T. pallidum deoxyribonucleic acid (DNA) by nucleic acid amplification test (NAAT) such as polymerase chain reaction (PCR) in an appropriate clinical specimen, or equivalent examination of material from nasal discharges, skin lesions, placenta or umbilical cord, or autopsy material of a neonate (up to four weeks of age).
Note: A nasopharyngeal (NP) swab should also be collected for syphilis PCR as many cases are positive by this relatively non-invasive but less sensitive method. The specimen collection procedure is the same as the Cadham Provincial Laboratory (CPL) NP swab collection for respiratory virus detection described here:  OR Reactive serology (treponemal and nontreponemal) from venous blood (not cord blood) in an infant/child with or without clinical, other laboratory, or radiographic evidence consistent with congenital syphilis c but who has one or both of the following:
1) Rising syphilis serologic titres (at least four-fold higher) upon follow-up where there is evidence that the mother or birthing parent had a syphilis infection during pregnancy.
2) Titres greater than or equal to fourfold higher than those of the mother or birthing parent when collected at the same time or within a week, in the immediate post-natal period.
Reactive serology (treponemal and nontreponemal) from venous blood (not cord blood) in an infant/child with clinical, other laboratory, or radiographic evidence consistent with congenital syphilis c whose mother or birthing parent was seropositive or PCR positive for syphilis during pregnancy, at delivery, or in the immediate post-partum period.
A child who does not meet the above criteria but has persistently reactive treponemal serology between 18 and 24 months of age (regardless of treatment status and infectious status of the mother or birthing parent).

# Probable Case -Early Congenital Syphilis (within two years of birth) d
Reactive serology (treponemal and nontreponemal) from venous blood (not cord blood) in an infant/child without clinical, laboratory, or radiographic manifestations of congenital syphilis whose mother or birthing parent had
- untreated or inadequately treated syphilis e prior to delivery OR - evidence of reinfection or relapse in the pregnancy following appropriate treatment (e.g., rising nontreponemal titres at least four-fold higher)
Note: A child that meets a probable case definition should remain staged as a probable case if testing at 18-24 months is negative. If they still have a reactive treponemal test at  18 months old, then their classification should be changed to "lab confirmed".

# Lab Confirmed Case -Syphilitic Stillbirth
A fetal death that occurs after 20 weeks gestation with laboratory confirmation of infection (i.e., detection of T. pallidum DNA in an appropriate clinical specimen, direct fluorescent antibody b or equivalent examination of material from placenta, umbilical cord or autopsy material).
Note: In order to improve capture of congenital syphilis stillbirths, it is critical that stillbirth investigation protocols include a swab (e.g., nasopharyngeal, placenta, oral, umbilical cord) for syphilis PCR testing. Ensure that local stillbirth protocols include syphilis PCR testing of all stillbirths.

# Probable Case -Syphilitic Stillbirth
A fetal death that occurs after 20 weeks gestation where the mother or birthing parent had untreated or inadequately treated syphilis prior to delivery OR whose mother or birthing parent had evidence of reinfection or relapse in pregnancy following appropriate treatment (such as rising nontreponemal titres at least four-fold higher), with no other cause of stillbirth established.

# Late Congenital Syphilis (greater than two years after birth)
Lab Confirmed Case -Late Congenital Syphilis (greater than two years after birth)
Reactive treponemal serology (regardless of nontreponemal test reactivity) along with characteristic late manifestations of congenital syphilis f in a child whose mother or birthing parent was known or considered to be seropositive for syphilis during pregnancy, without documented evidence of adequate treatment,
No other known source of exposure (i.e., infection must have occurred in utero).

# Primary Syphilis Lab Confirmed Case -Primary Syphilis
Identification of T. pallidum by dark-field microscopy a fluorescent antibody b or detection of T. pallidum DNA by NAAT (e.g., PCR), or equivalent examination of material from a chancre, consistent mucocutaneous lesion, or regional lymph node; OR Presence of one or more typical lesions (e.g., chancres), and reactive treponemal serology, regardless of nontreponemal test reactivity, in individuals with no previous history of syphilis; OR Presence of one or more typical lesions (e.g., chancres) and at least a fourfold (e.g., 1:8 to 1:32) increase in titre over the last known nontreponemal test, in individuals with a past history of (adequate) syphilis treatment (4).

# Secondary Syphilis
Lab Confirmed Case -Secondary Syphilis Identification of T. pallidum by dark-field microscopy a fluorescent antibody b or detection of T. pallidum DNA by NAAT, or equivalent examination of mucocutaneous lesions and condyloma lata and reactive serology (nontreponemal and treponemal); OR Presence of typical signs or symptoms of secondary syphilis (e.g., rash, mucocutaneous lesions, alopecia, loss of eyelashes and lateral third of eyebrows, iritis, generalized lymphadenopathy, fever, malaise, or splenomegaly); AND either a reactive serology (nontreponemal and treponemal) OR at least a fourfold (e.g., 1:8 to 1:32) increase in titre over the last known nontreponemal test (4).

# Early Latent Syphilis (less than one year after infection)
Note: May include or be referred to as incubating syphilis. For provincial surveillance purposes, any cases reported as "incubating" will be categorized as early latent syphilis.

# Lab Confirmed Case -Early Latent Syphilis
An asymptomatic person with reactive serology (treponemal and/or nontreponemal) 1 who within the previous 12 months had ONE of the following:
1) Nonreactive serology; or 2) Symptoms suggestive of primary or secondary syphilis; or 3) Sexual exposure involving a partner(s) with primary, secondary or early latent syphilis (4).
Note: When staging is uncertain in an asymptomatic person who within the past year had an exposure to a sexual partner(s) with unknown syphilis status, stage as early latent for reporting and contact tracing purposes (refer to Section 8.2 Management of Contacts), but treat as late latent (i.e. three weekly doses of penicillin G benzathine; see Table 2: Treatment of Syphilis).

# Late Latent Syphilis (greater than one year after infection) Lab Confirmed Case -Late Latent Syphilis
An asymptomatic person with persistently reactive treponemal serology (regardless of nontreponemal serology reactivity) who does not meet the criteria for early latent disease and who has not been previously treated for syphilis (4).

# Tertiary Syphilis

# Lab Confirmed Case -Tertiary Syphilis
Reactive treponemal serology (regardless of nontreponemal test reactivity) together with characteristic late abnormalities which may involve the cardiovascular system, central nervous system, bone, skin or other structures, in the absence of other known causes of these abnormalities (T. pallidum is rarely seen in these lesions, although when present, is diagnostic) (4).
For more details on symptoms of tertiary syphilis, see Section 5 Clinical Presentation and Natural History.
Neurosyphilis refers to a site of infection and is not a stage of infection. Neurosyphilis can occur at any time after initial infection and may be seen during any stage of syphilis -congenital, primary, secondary, early latent, late latent, or tertiary.

# Early Neurosyphilis (less than one year after infection)
Fits the criteria for primary, secondary, or early latent syphilis (above) and ONE of the following:
1) Reactive Venereal Disease Research Laboratory (VDRL) test in non-bloody cerebrospinal fluid (CSF) followed by reactive treponemal specific antibodies in CSF; or 2) Clinical evidence of disease consistent with early neurosyphilis (see Section 6.6 Neurosyphilis) AND either elevated CSF leukocytes OR elevated CSF protein, in absence of other known causes (4).

# Late Neurosyphilis (greater than one year after infection)
Fits the criteria for tertiary, or late latent syphilis (above) and ONE of the following: e. Inadequate treatment consists of any non-penicillin therapy or penicillin administered during pregnancy but less than 30 days before delivery, or despite treatment there has been an inadequate drop in nontreponemal titres. Note: The type of penicillin administered is important and is usually penicillin G benzathine in pregnancy, with the exception of treatment for neurosyphilis.
f. An older child may have stigmata (e.g., interstitial keratitis, sensorineural hearing loss, anterior bowing of shins, frontal bossing, mulberry molars, Hutchinson teeth, saddle nose, rhagades, or Clutton joints) (5).

# Reporting and Other Requirements
All positive laboratory results for T. pallidum are reportable to the Manitoba Health Surveillance Unit (MHSU) by secure fax (204-948-3044).

# Health Care Professional
Approximately 90% of all syphilis is sexually transmitted. Exposure mainly occurs during anal, oral, or vaginal intercourse. Transmission occurs through direct contact with infectious exudates from moist skin lesions or mucus membranes of infected persons during sexual contact (1,6). Primary, secondary, and early latent stages are considered infectious, with an estimated risk of transmission per partner of 60% (7). There is a 25% chance of relapse from early latent syphilis to secondary stage (7).
Transmission following blood transfusion, sharing of needles and drug equipment, or accidental direct inoculation (e.g., needle stick injury) is rare (7). Syphilis can be transmitted via transfusion of contaminated blood and solid organ transplantation, but is rare due to donor screening and blood processing. Ulcerative STIs like syphilis promote HIV transmission and/or acquisition by augmenting HIV infectiousness and susceptibility.
Pregnant people can transmit the infection transplacentally to the fetus at all stages of pregnancy during the course of untreated disease or during passage through the birth canal (8).
Infectious syphilis is on the rise in Canada, with declared syphilis outbreaks in many provinces. The number of cases of congenital syphilis has also significantly increased since 2015, in parallel to the increase observed in rates of infectious syphilis. National epidemiological reports are available at  6. Clinical Presentation and Natural History

# Incubating Syphilis
Persons with incubating syphilis are asymptomatic. They are identified through self-reporting or case investigation and include those exposed to a confirmed syphilis case within the last 90 days. An early spirochetemia develops during this phase, which results in widespread secondary invasion throughout the body (3).
Note: For provincial surveillance purposes, any cases reported as "incubating" should be categorized as early latent syphilis.

# Primary Syphilis
Primary syphilis most often presents as a single lesion (i.e., chancre) that develops at the site of inoculation. For a primary chancre, the incubation period is three days to three months, usually about three weeks (3). Chancres are typically painless, but some may be painful (12). The chancre is most commonly found in the anogenital area, but may occur at any site, including the mouth and fingers. The individual may be asymptomatic, and chancres that are internal (inside the vagina or anus) may go unnoticed. The chancre usually resolves spontaneously in one to four months. Painless, firm regional lymphadenopathy, often associated with genital chancres, is common and occurs in up to 80% of patients.
Variations in clinical presentation have been more commonly reported in individuals living with HIV, including multiple single chancres and chancres that may be slower to resolve (9).

# Secondary Syphilis
The secondary stage occurs 2 weeks to 6 months following exposure, and is a disseminated form of the infection which can produce a range of symptoms.
The most common feature is a skin rash, which is present in about 90% of cases. This rash may be macular, papular, papulosquamous, pustular, or non-specific, and typically involves the palms of the hands and soles of the feet. The rash usually resolves without scarring over several weeks.
Other symptoms include:
- Condylomata lata -painless, large fleshy lesions that are highly infectious and develop in warm moist areas such as the perineum and perianal skin, axillae, and beneath the breasts - Constitutional symptoms such as fevers, muscle aches, headache, and weight loss - Mucosal lesions - Temporary alopecia or patchy hair loss The original anal, genital, or oral chancre is still present in up to 30% of patients with secondary syphilis.
There may be evidence of central nervous system involvement such as signs and symptoms of meningitis (e.g. headaches), uveitis/retinitis (e.g. blurred vision, eye redness, flashes or floaters), or otic symptoms (e.g. hearing loss, tinnitus).

# Latent Syphilis
Left untreated, secondary syphilis may progress to a period of subclinical infection where individuals are asymptomatic.
Latent syphilis is divided into early latent and late latent syphilis.
A patient with early latent syphilis is considered infectious, and has a 25% risk of relapse to secondary syphilis. Individuals are classified as having early latent disease if they are asymptomatic and have acquired the infection within the past year, including those who:
- have seroconverted within the past year, or,
- have had unequivocal symptoms of primary or secondary syphilis within the past year,
- have had a sexual encounter with a partner(s) with primary, secondary or early latent syphilis within the past year, - have had a sexual encounter within the past year with a partner(s) with unknown syphilis status.
Note: When staging is uncertain in an asymptomatic person who within the past year had an exposure to a sexual partner(s) with unknown syphilis status, stage as early latent for reporting and contact tracing purposes (refer to Section 8.2 Management of Contacts), but treat as late latent (i.e. three weekly doses of penicillin G benzathine; see Table 2: Treatment of Syphilis).
Individuals are classified as having late latent disease if they are asymptomatic and have acquired the infection more than one year ago. Late latent syphilis is not considered infectious. However, a pregnant person with late latent syphilis can infect their fetus in utero.

# Tertiary Syphilis
Tertiary syphilis is a slowly progressive, inflammatory disease that can affect any organ in the body and produces clinical illness 10-30 years after the initial infection. Tertiary syphilis refers to gummatous or cardiovascular syphilis, or late neurosyphilis.

# Gummatous syphilis (late benign syphilis)
Gumma or granulomatous-like lesions are indolent and most commonly found in the skeletal system, skin, and mucous membranes, but can develop in any organ. Lesions rarely cause incapacity or death, but when lesions occur in organs like the brain or heart, serious complications occur.

# Cardiovascular syphilis
Cardiovascular syphilis results from destruction of the elastic tissue of the aorta which leads to ascending aortitis and the formation of aneurysms that, rarely, rupture.
Central Nervous System (CNS) disease can occur during any stage of syphilis. Consultation with an infectious disease specialist is recommended for all cases of neurosyphilis.
A patient who has clinical evidence of neurologic involvement with syphilis (e.g., cognitive dysfunction, motor or sensory deficits, ophthalmic or auditory symptoms, cranial nerve palsies, and symptoms or signs of meningitis) should have a CSF examination (10). Co-infection with HIV increases the risk of neurosyphilis. Neurosyphilis is divided into early (acute) neurosyphilis and late (chronic) neurosyphilis (3). Both early and late neurosyphilis can be asymptomatic (no signs or symptoms of CNS disease).
Early neurosyphilis occurs within the first year of infection. Symptoms of early neurosyphilis include meningitis, involvement of the eye (most commonly uveitis), hearing loss, or ischemic stroke.
Late neurosyphilis occurs more than one year after infection. Typical findings of late neurosyphilis are general paresis and tabes dorsalis. General paresis is a severe progressive deterioration of mental function, which may also include motor changes. Tabes dorsalis is a disease of the posterior columns of the spinal cord and of the dorsal roots. It most commonly presents as sensory ataxia and lancinating pains. (11)

# Syphilis in Pregnancy and Congenital Syphilis
Syphilis can be transmitted transplacentally to the fetus at all stages of syphilis (9). Syphilis can also be transmitted during passage through the birth canal when the newborn infant contacts a genital lesion (8). Breastfeeding does not result in transmission of syphilis unless an infectious lesion is present on the breast. Pregnancy has no known effect on the clinical course of syphilis in the birthing parent. The rate of perinatal transmission in an untreated person is 70-100% in primary or secondary syphilis, 40% for early latent syphilis, and less than 10% for late latent disease in pregnancy. Spontaneous abortion, fetal demise, and late-term stillbirth occur in approximately one third of untreated early pregnancy infections.
Clinical manifestations of congenital syphilis are divided into early (appear within the first two years of life) and late (after first two years of life) stages.
Most clinical signs of early congenital syphilis develop within the first three months of life, usually by five weeks of age. The majority of infants with congenital syphilis are asymptomatic at birth. The most common findings in symptomatic infants include:
- snuffles or persistent rhinitis (the nasal discharge may be profuse, purulent, or blood-tinged and is highly infectious) - hepatomegaly with or without splenomegaly - skeletal abnormalities - rash (often maculopapular that results in desquamation, but other presentations include bullous or ulcerative lesions, fissures, mucous patches, and condylomata lata) - jaundice - generalized lymphadenopathy In addition, there may be CNS involvement, either asymptomatic or symptomatic. However, symptomatic presentation is rare, unless the infant did not receive treatment in the neonatal period. Other manifestations of early congenital syphilis have been described, but are rarely seen.
Late congenital syphilis usually manifests after two years of age with some of the clinical findings not appearing until later in childhood and rarely in adulthood. Late manifestations include Hutchinson's triad of interstitial keratitis, peg-shaped upper incisors, and eighth cranial nerve deafness. Hearing loss can be sudden and usually occurs at eight to 10 years of age.

# HIV and Syphilis
HIV and syphilis coinfection is common. As with other ulcer-causing infections, syphilis can enhance the acquisition of HIV. Syphilis in individuals living with HIV can be highly aggressive, and can progress from primary to tertiary syphilis over several years.
Syphilis infection in people with HIV co-infection may present differently such as more constitutional symptoms, greater organ involvement, atypical and florid skin rashes, multiple genital ulcers, concomitant chancre during the second stage, and a significant predisposition to develop symptomatic neurosyphilis, especially uveitis, may be seen with HIV co-infection. However, these manifestations can also be seen in individuals without HIV co-infection (3).
Co-infected individuals should be managed in consultation with an infectious disease specialist or physician knowledgeable in HIV.

# Diagnosis of Syphilis
The diagnosis of syphilis is based on history, physical examination, and laboratory investigation.

# Who to test for syphilis?
- All people who present with symptoms of syphilis such as anal, genital, or oral ulcers, generalized maculopapular rash (especially if including palms and soles) and/or lymphadenopathy - All sexual contacts to syphilis cases - All pregnant people (see below for details) - All people with new, multiple, or anonymous sexual partners should be routinely tested every three to six months - All people requesting STI testing - All people with any confirmed or suspected STI such as gonorrhea, chlamydia or HIV - Consider offering STI testing to all clients/patients as part of routine care.
Serologic tests for syphilis are essential for diagnosis of individuals, for following treatment response, and for screening purposes. They detect antibodies formed during the course of a syphilitic infection. Two tests are performed: treponemal test and non-treponemal test. Treponemal tests are necessary to establish a diagnosis of syphilis. Nontreponemal tests, such as Rapid Plasma Reagin (RPR) or VDRL, are useful for monitoring treatment response and can be useful for staging particularly in determining recent infection or reinfection. Serologic test results for syphilis, on rare occasions, may be negative in active cases, especially in older patients, or very early in primary infections. See Table 1: Interpretation of Serologic Tests for Syphilis.
There are two types of serologic screening algorithms used: traditional and reverse algorithms. The traditional algorithm uses the nontreponemal test to screen. If positive, it is followed by one or two treponemal test. The reverse algorithm, which is used in Manitoba at CPL, starts with a treponemal test to screen. If positive, it is followed by a nontreponemal test and sometimes a second confirmatory treponemal test. CPL performs a second confirmatory treponemal test for all individuals who test positive, in Manitoba, for the first time.
All clinical serology testing and screening for syphilis are performed at CPL. Samples are routinely tested Monday-Friday within 24 hours of being received. Contact the Serology section at CPL at 204-945-6123 for questions about testing and 204-945-6805 to order CPL requisition forms. After hours testing is conducted for transplant and other emergent purposes. An appropriate sample is 5-10 ml of blood collected in a red-stoppered tube which should be sent to CPL with a request for "Syphilis Screen" or broader STBBI screening. The CPL lab requisition should also provide information on the reason for testing (sex partner of case, genital ulcer, clinical findings, etc.). It is extremely important to include the relevant history on the lab requisition. For prenatal screening, practitioners should check the prenatal panel box on the CPL requisition.
Routine screening of umbilical cord blood is NOT recommended for serological testing where a diagnosis of congenital syphilis is considered. Cord blood that is contaminated with blood from the mother or birthing parent may lead to a false positive test result. Such specimens will be stored but not tested. To assess for congenital syphilis, specimens collected from both the mother or birthing parent and infant by venipuncture are recommended to provide reliable results.
In situations where maternal or birthing parent syphilis infection status is unknown (e.g., no testing done during the pregnancy), testing of maternal or birthing parent serum is preferred to testing infant serum alone because infant serum can be nonreactive if maternal or birthing parent serology is low titre or if the infection was late in pregnancy. Contact CPL if further diagnostic strategies are sought.

# Nontreponemal Tests (VDRL and RPR)
Syphilis infection leads to the production of nonspecific antibodies (IgM and IgG) directed against a lipoidal antigen resulting from the interaction of host tissues with T. pallidum or from T. pallidum itself. This antibody-antigen reaction is the basis of nontreponemal tests such as the VDRL and the RPR. The RPR test is more sensitive than the VDRL. CPL uses both RPR (for serum specimens) and VDRL (for CSF) tests. In the situation where RPR and VDRL in serum is obtained in the same individual over time, it is important to note that the titre values obtained from these tests do not directly correlate, therefore only one of these tests should be used to monitor treatment response.
After adequate treatment of syphilis, nontreponemal tests (NTT) usually become nonreactive. However, even with sufficient treatment, patients sometimes have a persistent low-level positive NTT referred to as serofast. NTT titres of people who have been treated for latent or late stages of syphilis or who have become reinfected do not decrease as rapidly as do those of people in the early stages of their first infection. In fact, they may remain serofast for life (13).
VDRL and RPR become positive one to four weeks after the appearance of the primary chancre or six weeks after exposure. Biologic false positive reactions occur at a rate of 1-2% in the general population.
Serial NTT are useful to determine the stage of the disease; a fourfold rise in titre may indicate recent infection, immune suppression, or reinfection in an adequately treated person, or relapse in an inadequately treated person. Adequate treatment of infectious syphilis is indicated by a fourfold or greater decline in titre within one year. Titres should generally become nonreactive or weakly reactive within one year following treatment of primary syphilis and within two years after treatment for secondary syphilis. Treatment of late latent syphilis usually has little or no effect on the titre and should not be used to gauge the adequacy of the treatment. Titres tend to become lower with time after treatment of late latent syphilis, but serum frequently remains reactive, usually at a low titre. As with all quantitative serologic tests, only a fourfold or greater change in titre is meaningful. Please see Table 4: Adequate Serologic Response to gauge treatment response.

# Specific Treponemal Tests
These tests measure antibodies against specific T. pallidum antigens and help confirm the diagnosis of syphilis. The specific treponemal antibody tests performed in most laboratories are treponemal-specific chemiluminescent microparticle immunoassay (CMIA), T. pallidum particle agglutination tests (TP-PA) and fluorescent treponemal antibody-absorption test (FTA-ABS).
Most patients who have reactive treponemal tests will have reactive tests for the remainder of their lives, regardless of treatment or disease activity. Up to 15% lose their treponemal-specific antibodies over time, particularly if they were treated early during the primary stage. Treponemal test antibody titres correlate poorly with disease activity and should not be used to assess treatment response.
False positive results can occur, especially with the FTA-ABS test, in patients with Lyme disease, HIV, pregnancy, substance use, toxoplasmosis, Helicobacter pylori, autoimmune disorders like lupus and rheumatoid arthritis, and in those with FTA-ABS results of < 3+ in intensity. Other spirochetal illnesses, such as relapsing fever (Borrelia spp.), the nonvenereal treponematoses (yaws, bejel, pinta), leptospirosis, or rat-bite fever (Spirillum minus), also yield positive nontreponemal and treponemal test results (3); however, the clinical and epidemiologic characteristics differentiate these infections from syphilis.