Syphilis has been known to western medicine for over five centuries, but it remains with us despite the availability of a cheap single-dose cure for 65 years. The clinical manifestations of the capricious causative micro-organism, Treponema pallidum subspecies pallidum, continue to confound and elude physicians.
In Australia, the incidence of syphilis was at a historical low from the 1980s to the early 2000s, resulting in little clinical exposure to this previously common disease for most physicians in training. However, syphilis has resurged in our cities requiring that physicians include the possibility of syphilis in their differential diagnosis once again.
Therefore, the purpose of this review is to highlight the common and not-so-common clinical appearances of syphilis in adults, to review the role of diagnostic tools, to describe treatment options and to discuss modern controversies, such as the effects of human immunodeficiency virus (HIV) co-infection and the indications for lumbar puncture.
Epidemiology of syphilis in Australia
Prior to modern antibiotics, syphilis was widespread in the Australian community, with incidence rates of almost 200 per 100 000 reported in most states.1 The incidence dramatically dropped after the introduction of penicillin and was further reduced in the wake of the HIV epidemic, with only 4.2 notified cases of infectious syphilis per 100 000/year in 2004.2 However, since 2001, the number of reported cases in Australian cities has increased more than tenfold. In Sydney, six cases of infectious syphilis were reported in 1999, rising to 162 in 2003. This rise has been mirrored in other cities and is concentrated in men who have sex with men, a half of whom are also HIV positive.3 While the notifications have reached a plateau, 1098 cases of infectious syphilis were diagnosed nationally during 2010, 416 of which were in New South Wales.2
In New Zealand, a similar pattern has emerged. Cases of syphilis increased by 150% between 2008 and 2009, predominantly in Auckland; however, surveillance is hampered as syphilis is not a notifiable disease in New Zealand.4
The situation for Aboriginal and Torres Strait Islander Australians, particularly those living in remote settings, has historically been very different. In 2006, incidence rates were over 100 times that of the general Australian population and equivalent to the rates seen in the pre-antibiotic era.2 However, since 2006, the reported incidence was falling leading some to speculate that elimination of this infection from remote Aboriginal communities may be achievable.5 However, the challenges to achieve this goal are demonstrated by a substantial local outbreak of heterosexually acquired syphilis beginning in 2011 in the remote Gulf Country of Queensland.6
Serological tests for syphilis
Screening for syphilis in Australia utilises sensitive and specific treponemal tests, such as enzyme immune assay (EIA) that may contain both immunoglobulin G and immunoglobulin M components. These are then confirmed by supplementary specific tests, such as Treponema pallidum particle agglutination assay (TPPA) or the fluorescent treponemal antibody absorption test (FTA-abs). These tests do not, however, give any indication of disease activity and will normally remain positive for life regardless of treatment. Therefore, a non-specific test (sometimes called non-treponemal test), such as the rapid plasma reagin (RPR), or Venereal Disease Research Laboratory (VDRL) test, is used to provide a titre (e.g. 1:8, 1:16, and 1:32) that can be used to stage the infection, assess treatment response and detect reinfection. The RPR and VDRL are less sensitive for screening, are sometimes slower to rise in primary disease and may miss latent infection. All tests may produce false-positive results, so at least two types of test need to be positive in an asymptomatic person.
The classic solitary chancre (ulcer) of primary syphilis is described as typically appearing between 9 and 90 days after exposure to the disease, with a median of between 21 and 30 days.7 It occurs at the point of inoculation, and thus may develop on the penis, vulva, cervix, anus or oral cavity depending on the type of sexual exposure. Because chancres are usually painless, many may not be noticed by the patient. Chancres are often associated with painless local lymphadenopathy. Multiple chancres may occur, and up to one quarter may be painful,8 especially if superinfected with skin flora, or with herpes simplex virus. Non-genital lesions may be mistaken for oral apthous ulceration or perianal fissures, thus a sexual history and a high index of suspicion are required.
Within a few days of initial infection, T. pallidum begins to spread systemically and is detectable by polymerase chain reaction (PCR) in the blood in over 20% of those with primary disease.9 The chancre usually heals without scarring in 2–6 weeks, but it can recur (‘chancre redux’).
Immediate diagnosis may be made by dark-ground microscopy (not recommended for oral lesions due to commensal spirochaetes), but this is a dying art. A chancre swab collected for T. pallidum PCR testing is highly sensitive and specific, available in several reference laboratories and approved by the National Association of Testing Authorities, Australia. Direct immunofluorescence is an alternative. Syphilis serology should be performed but may be falsely negative in up to 10% of cases of primary syphilis, so it should be repeated if suspicion remains high.10
Secondary manifestations of syphilis may begin 3–5 months after infection, and in a third of patients with secondary disease, a residual chancre will be present. Untreated secondary syphilis may recur up to 2 years after infection, with 90% of recurrences in the first year.11 The list of possible features of secondary syphilis is vast.7 However, the majority of patients will have some evidence of systemic involvement, such as headache, malaise, mild fever, lymphadenopathy or sore throat. The typical maculopapular and subsequently scaly rash affecting the palms and soles occurs in over 75% of cases. In the pre-antibiotic era a variety of pustular and psoriatic forms of this rash were described and may still be seen today.
Other features of secondary disease include condylomata lata (pale elevated papules that develop at moist body orifices), patchy alopecia, oral mucosal erosions, mild hepatosplenomegaly and raised liver function tests, in particular alkaline phosphatase. Cardiovascular, bone and renal complications are all occasionally seen.
Neurological and ophthalmological complications can occur in secondary syphilis. Acute syphilitic meningitis is a cause of a lymphocytic meningitis and may result in transient cranial nerve deficit, the eighth cranial nerve being the most frequently affected. Uveitis, iritis, retinitis and optic neuritis are also described, and thus syphilis serology is a routine investigation for these disorders. At least 25% of patients with secondary disease will have cerebrospinal fluid (CSF) abnormalities if lumbar puncture is performed.12 However, in the absence of neurological or ophthalmological symptoms or signs, lumbar puncture is not necessary because standard treatment is curative.
Both specific treponemal serology and RPR/VDRL are universally positive in cases of secondary syphilis, and negative tests essentially rule out the diagnosis. Dark ground microscopy or T. pallidum PCR may be used to detect directly the organism from abraded secondary skin lesions or condylomata lata, but both tests are less sensitive for dry lesions.
Latent syphilis is arbitrarily divided into early or late latent infection. For a case to be considered early latent, the patient must have no signs of primary or secondary disease and have positive syphilis serology, preceded by negative serology within the last 2 years (1 year in the USA)13 or recent contact with an infectious case. Early latent syphilis is considered infectious to sexual partners, whereas late infection is probably not. Asymptomatic patients with no evidence of recent negative serology or previous treatment are classified as having late latent infection, or syphilis of unknown duration. Because syphilis serology may remain positive for life even after successful treatment, reasonable effort should be applied to excluding prior infection.
In the pre-antibiotic era, one third of patients with syphilis progressed to symptomatic late disease (tertiary syphilis).11 This may manifest as neurosyphilis, cardiovascular syphilis or late benign syphilis (gummatous disease).
This is perhaps the most feared complication of syphilis, and in the pre-antibiotic era, it affected 10% of men and 5% of women.11 CSF abnormalities may be present in the absence of symptoms or signs of neurological disease, and this is termed asymptomatic neurosyphilis. However, because lumbar puncture is not routinely recommended in early or latent disease in the absence of such symptoms or signs, this diagnosis is of limited clinical relevance. A detailed classification of neurosyphilis was proposed by Merritt in 1946.14
Meningovascular neurosyphilis, typically occurring 5–12 years after initial infection (but occasionally as early as the first year), may cause a stroke-like syndrome. The territory of the middle cerebral artery is commonly affected, but meningovascular syphilis can cause infarction secondary to endarteritis in any vessel, including those of the spinal cord. Focal or generalised seizures have also been documented. Syphilis serology should therefore be included in the work-up of young patients, or those from high-risk groups or high-risk countries.
Parenchymatous neurosyphilis is the cause of general paresis of the insane. During the interwar years, this disease was present in 10% of psychiatric admissions in Australia and led to over 200 deaths annually.15 Early symptoms include irritability, memory loss, personality change and insomnia. These may progress over many years to result in depression, confusion and disorientation, delusions of grandeur, paranoia and seizures. The symptoms may be combined with physical signs of facial tremors, papillary abnormalities, expressionless facies and hyperreflexia. Dementia progresses to death within months to years.
Tabes dorsalis is the other major consequence of untreated parenchymatous neurosyphilis. It peaks around 20 years after initial infection, but along with the other manifestations of neurosyphilis, it is now very rare in the western world. It is characterised by lightning pains, reduced deep tendon reflexes, paraesthesias, sensory abnormalities of vibration and joint position sense, Charcot's joints, and Argyll-Robertson pupils. Bladder and bowel disturbances are common. The classic visceral crises of tabes may result in severe gastrointestinal pains or laryngeal pain and hoarseness.
Laboratory diagnosis of neurosyphilis
Specific syphilis serology, such as EIA or TPPA, will be detectable in serum, and the serum RPR/VDRL will normally be positive. However, CSF analysis is required to confirm a case of neurosyphilis. The CSF white cell count (usually lymphocytes) is typically raised at >5 cells/mm3, protein levels are increased, and glucose normal or reduced. CSF VDRL confirms the diagnosis if positive, but it does not exclude active disease if negative. Some experts believe that a negative FTA-abs test on the CSF excludes the possibility of neurosyphilis.16 The interpretation of these results in patients with a bloody CSF tap requires caution, and the presence of coexisting HIV infection may itself impact on the CSF white cell count and protein. When considering lumbar puncture, it is worth reflecting that the likelihood of discovering CSF abnormalities if the serum RPR/VDRL is negative is reportedly very low.17 As early neuroinvasion by T. pallidum is common in the absence of abnormal CSF, the role of CSF PCR is yet to be determined.
Cardiovascular syphilis classically results in proximal aortic aneurysm and aortic regurgitation after 15–30 years of clinical latency. It previously accounted for 25% of those patients with symptomatic late infection,11 but it is rarely seen in high-income countries since the advent of effective antibiotics. Men are disproportionally affected at a ratio of 3:1. Because the aneurysms are associated with vascular wall thickening, they do not commonly dissect.
A routine chest X-ray in patients with syphilis serology over 55 years of age was once recommended, but studies have not found this to be of great utility in asymptomatic patients, so reserve it for those with signs of aneurysm or regurgitation.18 Other imaging modalities, such as echocardiogram or computed tomography, may be more sensitive if aneurysm is suspected.
Late benign syphilis (gumma)
Gummas are proliferative granulomatous lesions thought to represent an inflammatory response to small numbers of treponemes. They may occur cutaneously, when ulceration is common, or within any viscera or bone. They have become unusual in the antibiotic era, but it should be included in the differential diagnosis in patients with recalcitrant cutaneous ulcers or space occupying lesions and positive syphilis serology. Gummas may occur as early as the first year, but usually the incubation period is over 5 years.
Treatment of syphilis
Penicillin has remained the first line treatment for all stages of syphilis for over 65 years (Table 1).19 Oral doxycycline is an alternative in those who are penicillin allergic, intolerant of injections or non-pregnant. Azithromycin has shown to be at least as effective in producing serological cure as penicillin,20 but initial enthusiasm has waned with the demonstration of high levels of azithromycin resistance in regions where macrolide use is high. In Sydney, the prevalence of the azithromycin resistance gene A2058G on the 23 s ribosome of T. pallidum was present in over 85% of samples.21 Ceftriaxone has also shown to be successful at generating serological cure, but the data are more limited.
Table 1. Recommendation for antibiotic treatment of syphilis (abbreviated from the British Association for Sexual Health and HIV (BASHH) 2008 guidelines)19
|Primary/secondary or early latent||1.8 g (2.4 MU) IM benzathine penicillin G single dose||Doxycycline 100 mg twice daily orally for 14 days|
|Ceftriaxone 500 mg IM daily for 10 days|
|Late latent, cardiovascular or gummatous disease||1.8 g (2.4 MU) IM benzathine penicillin G 3x doses at weekly intervals||Doxycycline 100 mg twice daily orally for 28 days|
|Neurosyphilis†||2.4 g (2.4 MU) IM procaine penicillin G daily plus probenecid 500 mg 4 times a day orally for 14–17 days‡||Doxycycline 200 mg twice daily orally for 28 days|
|3–4 MU benzyl penicillin IV every 4 hours for 14–17 days||Ceftriaxone 2 g IM or IV daily for 10–14 days|
Pregnant women should receive the usual adult dose of penicillin and may require desensitisation to facilitate this. Patients with proven or probable symptomatic neurosyphilis, including those with ophthalmic signs, should receive a regimen that achieves high treponemocidal drug levels in the CSF.
Treatment response is monitored using the RPR or VDRL titres, and a fourfold (two-titre) reduction within 6–12 months is considered a cure. Non-response or rising titres after treatment are most commonly due to reinfection. While most patients treated for infectious syphilis will have negative RPR/VDRL results at 12–24 months post treatment,22 a significant minority may have persistent low-level ‘serofast’ titres. Patients treated for late disease may exhibit static RPR/VDRL titres post treatment, particularly if the titre was very low (1:1, 1:2) prior to treatment.
The Jarisch–Herxheimer reaction is a post-treatment febrile cytokine-mediated reaction caused by endotoxin release from spirochaete lysis.23 It occurs 3–12 hours after treatment and is more common in secondary (60%) and primary (30%) infections than the other stages. Rigors and headache may also develop, and secondary lesions may transiently worsen. The reaction is managed by advising the patient in advance, non-steroidal anti-inflammatories as needed, and usually passes within 24 hours. In pregnant women, it may induce uterine contractions leading some authorities to recommend brief hospital admission during this period. The reaction has not, however, been associated with adverse pregnancy outcomes. Because the transient worsening of lesions might have serious consequences in important small vessels, such as those around the coronary ostium or optic nerve, British guidelines19 advise consideration of oral prednisolone therapy beginning 24 hours prior to antibiotic treatment in those with optic nerve or cardiovascular involvement in an attempt to dampen the inflammatory response. However, this has never been proven to be effective in reducing such a response, and the USA guidelines do not therefore make this recommendation.13
HIV and syphilis co-infection
Syphilis is certainly more common in HIV-positive than in HIV-negative people in Australia,24 with theoretical concerns about immunodeficiency and reduced spirochaete clearance from the CSF. Some studies suggest that HIV-positive individuals with syphilis are more likely to exhibit atypical manifestations, such as multiple chancres25 or CSF abnormalities.26 However, these phenomena were well documented by syphilologists in the pre-HIV era. RPR/VDRL seroreversion after treatment may also be slower, leading to confusion about whether cure has been achieved. Intercurrent syphilis may temporarily increase HIV viral load and reduce CD4 count,27,28 although this will resolve after treatment. Raised viral load, along with the presence of mucosal lesions, may help explain the impact of syphilis on onward HIV transmission.
The main area of debate concerns whether neurosyphilis is more common in HIV-positive patients, and thus whether different treatment and investigation algorithms are required. One of the difficulties in interpreting the data, which is usually case series-level evidence, is that HIV itself can cause a host of neurological phenomena, and may cause a raised CSF white cell count and protein count. The diagnostic white cell count criteria for neurosyphilis in the context of HIV should accordingly be raised from >5 cells/mm3 to >20 cells/mm3.26 Furthermore, studies reporting neurological relapse of syphilis in HIV-positive patients after standard treatment rarely take into account the high rate of reinfection in this population. As in the HIV-negative host, HIV-positive patients with early syphilis frequently show CSF abnormalities. CSF abnormalities are more common with a CD4 <350 or an RPR >1:32 and less common on antiretroviral therapy. However, there are no longitudinal studies to determine the significance of these findings.
Given these findings, and the necessity of achieving high drug concentrations in the CSF to treat neurosyphilis, enhanced treatment protocols have been studied in HIV-positive patients. One study used standard therapy augmented with high-dose amoxycillin and probenecid, yet failed to show improved treatment responses.12 Current treatment guidelines recommend the same antibiotic regimens in both HIV-positive and HIV-negative patients.
Over the last 30 years, many thousands of HIV-positive patients (aware of their HIV status or not) have been treated with benzathine penicillin. If this regimen was ineffective, confirmed neurosyphilis would not be the rarity it is today. If HIV-positive patients display unusual neurological signs despite treatment for syphilis and exclusion of other pathology, they might be better served by commencing antiretroviral therapy; such therapy has shown to reduce significantly the risk of being diagnosed with neurosyphilis.29
We believe therefore that lumbar puncture is indicated in HIV-positive patients with syphilis only in the presence of neurological or ophthalmological signs or lack of treatment response when reinfection has been excluded. This scenario is very uncommon in our service.
Given the high syphilis incidence in HIV-positive men who have sex with men, syphilis serology should be part of routine HIV monitoring bloods.30
Contact tracing and follow up
Contact tracing is the responsibility of the diagnosing clinician, although it is usually done by the patient. The diagnosing clinician needs to support patients to inform sexual partners of their exposure and to provide the tools to achieve this. Online notification services can provide anonymity for those unwilling to make personal contact, for example, http://www.thedramadownunder.info, and sexual health services can assist with provider referral in difficult or complex cases. Contacts presenting within 3 months of exposure to infectious syphilis should be empirically treated as a case of incubating syphilis with the same regimen as for primary syphilis because serology may be falsely negative during this period. Contacts from greater than 3 months ago can defer treatment until serology results are known. How far back to contact trace depends on the disease stage and is summarised in Table 2.31
Table 2. Contact tracing for syphilis31
|Primary||All sexual partners from 3 months before the onset of symptoms|
|Secondary||All sexual partners from 6 months before the onset of secondary symptoms|
|Early latent syphilis||All sexual partners within the last 12 months|
|Late syphilis (symptomatic or asymptomatic)||No specific recommendation; current sexual partner should be screened|
Patients treated for syphilis should have repeat RPR/VDRL samples taken at 3, 6 and 12 months post treatment to ensure serological cure and to identify reinfection. If at ongoing risk, then at least an annual RPR testing is advised. All patients with syphilis should have a sexual health screen performed, including an HIV test.
The increase in cases of syphilis over the last decade necessitates renewed awareness of this infection and its varied manifestations. This is particularly so for patients from higher risk populations. Diagnostic and treatment algorithms are fortunately well established and offer high sensitivity, specificity and cure. Despite an interesting debate around the interaction of HIV and syphilis, there is little evidence to suggest HIV-positive patients who acquire syphilis should receive non-standard antibiotic regimens or be encouraged to undergo lumbar puncture in the absence of conventional indications. Regular screening, contact tracing and treatment remain important tools in identifying asymptomatic carriers, reducing the infectious period and preventing reinfection.32