Syphilis

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Authors

Neetu Bhari (Department of Dermatology and Venereology, All India Institute of Medical Sciences, New Delhi, India)

Somesh Gupta (Department of Dermatology and Venereology, All India Institute of Medical Sciences, New Delhi, India)

Executive summary

The present guidelines aim to provide comprehensive information on syphilis, including the epidemiology, clinical features, diagnosis and management. The guidelines provide evidence-based recommendations on the diagnosis, prevention and treatment of syphilis in adults in Asia, including patients with HIV co-infection.

Methodology

A PubMed search was performed, using the keywords “syphilis”. A total of 3044 results were found in the last five years’ publications. A careful review of the titles and abstracts was done to find all the studies pertaining to epidemiology, clinical features, diagnosis, treatment and prevention of syphilis. After review, 262 studies were selected for analysis of full text.

Diagnosis

Dark field microscopy (LE: 2a)

Serology

  1. Non-treponemal test (e.g. Rapid plasma reagin and Venereal Disease Research Laboratory) confirmed by TPHA (a treponemal test) (LE: 2a)
  2. Reverse algorithm of syphilis serologic screening (LE: 2a)
  3. IgM/IgG sensitive enzyme immune-assay (LE: 2a)
  4. Plasmonic enzyme-linked immunosorbent assay (LE: 2b)
  5. Western blotting (LE: 2b)

Point of care tests (LE: 1a)

Polymerase chain reaction (LE: 1a)

CSF analysis in suspected neurosyphilis (LE: 2a)

Treatment

Penicillin

Benzathine penicillin 2.4 million units single dose is used for early syphilis and three weekly doses are recommended in late syphilis. (LE: 1a) Similar schedule for HIV-positive population, although, for the treatment of early infectious syphilis, enhanced therapy with three dosages of benzathine penicillin G has been under consideration. (LE: 3)

Azithromycin

Azithromycin 2.0 gm administered orally as a single dose in early syphilis. (LE: 1a)

Tetracycline group

Oral doxycycline (100 mg twice daily) or oral tetracycline (500 mg 4 times a day) for 14 days for early syphilis. (LE: 3)

Cephalosporins

Ceftriaxone 1-2gm per day, given intravenously for 10-21 days in early syphilis. (LE: 2a)

Drug resistance

Azithromycin

Due to A2058G and the A2059G mutation in 23s ribosomal RNA. (LE: 2b)

Prevention

Interleukin-2 expression plasmid (pIL-2) enhanced a TpGpd DNA vaccine. (LE: 2b)

Introduction

Syphilis is a complex, systemic disease caused by the spirochete Treponema palladium. Syphilis is most commonly transmitted sexually or congenitally and can involve nearly every organ system. Its clinical course involves several well-characterized stages: an incubation period, a primary stage, a secondary stage, a latent stage and a late or tertiary stage.[1]

Epidemiology

According to the World Health Organization estimation, at least 12 million people worldwide are currently infected with syphilis.[2]

In 2014, baseline HIV and syphilis prevalence in China were 0.49% and 17.29% respectively. Syphilis incidence rate was 7.22 per 100 person-years.[3] Syphilis prevalence increased steadily from 5.1% in 2008 to 8.4% in 2012.[4] Unprotected receptive anal intercourse and multiple sexual partners in the last six months were the most important risk factor noted incrosssectionalanalysis of 570 patients.[5]LE(3)In the Chinese population, the HLA-DRB1*14 allele was more prevalent in syphilis patients than in the healthy controls.[6] (LE: 2a)

In India, Treponema pallidum was confirmed as the etiologic organism in 23% of genital ulcer, in a study of 194 patients.[7] In the Nagaland state of India, 426 female sex workers (FSWs) were recruited in 2006 and the prevalence of syphilis was found to be 21.1% and HIV prevalence was 11.7%. Being married, widowed/divorced/separated, illiterate or having a history of drug use increases the likelihood of syphilis infection.[8] (LE: 3) In India, targeted FSW interventions and STI treatment, resulted in reductions in syphilis risk.[9] (LE: 3)

In Bangkok, Thailand, during 2005-2011, a prevalence of HIV infection among 4,762 men having sex with men (MSM) was 28.3% and of syphilis was 9.8%.[10] In Hyderabad, Pakistan, fifty female sex workers were studied. Syphilis was identified in 22 (44%) females.[11]

The risk of syphilis is increased in HIV-positive population. In a study of the 402 consecutive HIV-positive patientsfrom China, the prevalence of syphilis was 12.4% and latent syphilis was the most common form. Men who have sex with men (MSM) were the largest group. (LE: 3) [12]Prevalence of syphilis infection was 16.5% in a cross-sectionalsurvey of 200 HIV-positive patients in China. Factors associated with syphilis seropositivity included receptive anal sex with a male partner in the last six months, illicit drug use in the last six months and use of antiretroviral medications .[13] (LE: 3)

An outbreak of syphilis was noted in Darkhan-Uul Province of Mongolia in 2012, the total notification rate was 62.3 per 100,000. Only 10% of cases reported using condoms during their last sexual encounter, with 65.5% reported having casual sex or multiple sex partners.[14]

Clinical

Primary syphilis

The classic solitary chancre (ulcer) of primary syphilis is seen approximately 9 to 90 days after exposure to the disease. Commonly affected sites include penis, vulva, cervix, anus, nipple, fingers, hand, eyelid, arm or oral cavity depending on the type of sexual exposure.[15][16][17][18][19][20] Because chancres are painless, presentation is usually delayed. Indurated chancre results in difficulty in retraction of the prepuce which flips over on retraction (dory-flap sign).[21] Chancre at the urethral meatus and development of stricture are rare complications of syphilis.[22] Chancres are often associated with painless local lymphadenopathy. Multiple chancres may occur and up to one-fourth may be painful, especially if superinfected with skin flora or with herpes simplex virus.[23]

Syphilitic balanitis of Follmann is a rare condition which is considered as a manifestation of primary syphilis. It presents with diffuse indurated dark red erythema of the glans penis accompanied by bilateral inguinal lymphadenopathy.[24]

Secondary syphilis

Secondary manifestations of syphilis usually begin after 3–5 months of initial infection and in a third of patients with a secondary disease, a residual chancre will be present. It presents with the classical triad of skin rash, mucosal ulceration and lymphadenopathy. It may be associated with a headache, malaise, mild fever, lymphadenopathy or sore throat. The typical maculopapular and subsequently scaly rash affecting the palms and soles occurs in over 75% cases. Other common forms of the cutaneous rash are pustular and psoriasiform lesions. Papulonodular lesions are also seen.[25][26][27] Nodular secondary syphilis simulating lepromatous leprosy have been reported.[28] It can also mimic cutaneous lymphoma[29][30] or Kaposi sarcoma.[31][32] Vesicular lesions are seen rarely.[33] Syphilitic alopecia occurs in only 4% of patients with syphilis.[34][35] Presentation as depigmented macules is known as “leucoderma syphiliticum”.[36] Erythema multiforme and pityriasis lichenoides like lesions can also be seen.[37][38]

Other features of the secondary disease include condylomata lata (pale elevated papules over moist body orifices), oral mucosal erosions, mild hepatosplenomegaly and raised liver function tests, in particular, alkaline phosphatase. Cardiovascular, bone and renal complications are seen occasionally. Diffuse polyostotic osteitis with skull involvement was seen in a case of secondary syphilis in an HIV-infected patient.[39] Neurological and ophthalmological complications can occur rarely and it can also cause adrenal insufficiency and Addison’s disease.[23][40][41]

Oropharyngeal involvement is common in syphilis. In one study of HIV-infected MSM, nine out of forty-four patients of syphilis had oropharyngeal manifestations. Lesions involving the anterior tonsillar pillar were the most common.[42] In a retrospective review of 23 reports describing 34 patients, the oral lesions described were non-specific ulcers, mucosal patches, keratosis, pseudomembranes and gumma. In a case series of 12 patients with oral syphilis, polymorphic types of oral lesions were found such as white patches, blistering mucositis, chronic non-specific ulcers, gumma, and necrosis of the dorsum of the tongue.[43]

Secondary syphilis can be a presenting feature secondary to an immune reconstitution syndrome in an HIV-positive patient.[44] It can also be acquired through blood transfusion, presenting without preceding primary stage, known as Syphilis d' emblee.[45]

Latent syphilis

Latent syphilis is arbitrarily divided into early or late latent infection. In early latent syphilis, the patient do not have any signs of primary or secondary disease and have positive syphilis serology, preceded by negative serology within the last two years or recent contact with an infectious case. Early latent syphilis is considered infectious to sexual partners, whereas late infection is probably not.[23] (LE: 3) 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, a reasonable effort should be made to exclude prior infection.

About one-third of patients with latent syphilis progresses to symptomatic late disease (tertiary syphilis), which may manifest as neurosyphilis, cardiovascular syphilis or late benign syphilis (gummatous disease).[23] In a hospital-based five-year survey in STD clinic in India, describing 570 cases, 7.36% cases were diagnosed with syphilis. Primary syphilis was diagnosed in 21 (50%), secondary in 10 (24%), and latent in 11 (26%) cases. Concomitant primary chancre and lesions of secondary syphilis were seen in 2 (20%) patients.[46]

Neurosyphilis

This is a rare complication of syphilis, which affected 10% of men and 5% of women in the preantibiotic era. A detailed classification of neurosyphilis was proposed by Merritt in 1946. In asymptomatic neurosyphilis, CSF abnormalities may be present in the absence of symptoms or signs of neurological disease.

Meningovascular neurosyphilis typically occurs 5–12 years after initial infection. It usually affects the territory of the middle cerebral artery and may cause a stroke-like syndrome. Focal or generalised seizures can also occur sometimes.

Parenchymatous neurosyphilis is the cause of general paresis of the insane. Early symptoms include irritability, memory loss, personality change and insomnia. These may progress over many years to result in depression, confusion, disorientation, delusions of grandeur, paranoia and seizures. Dementia progresses to death within months to years.

Tabes dorsalis is seen as a consequence of untreated parenchymatous neurosyphilis. It is characterised by lightning pains, reduced deep tendon reflexes, paraesthesias, sensory abnormalities, 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.[23]

Clinical profiles of 16 patients with neurosyphilis in north-east India was studied, between August 2008 and December 2010. The clinical spectrum included: neuropsychiatric syndromes (10), myelopathy (5), and posterior circulation stroke (1). Neuropsychiatric symptoms were dementia, behavioural abnormalities, chronic psychosis, and myelopathy syndromes including acute transverse myelitis (ATM), chronic myelopathy and syphilitic amyotrophy.[47]

A retrospective review was performed for 149 patients with neurosyphilis in China, 16.8% patients were found asymptomatic for neurosyphilis, 15.4% with syphilitic meningitis, 24.2% with meningovascular neurosyphilis, 38.9% with general paresis, 4.0% with tabes dorsalis and 0.7% with gummatous neurosyphilis.[48]

Cardiovascular syphilis

Cardiovascular syphilis is seen after 15–30 years of initial infection and results in the proximal aortic aneurysm and aortic regurgitation. It was seen in 25% of patients with symptomatic late infection in pre-antibiotic era, but is uncommon in current practice.[23]

Late benign syphilis (gumma)

Gummas are proliferative granulomatous lesions which represent an inflammatory response to small numbers of treponemes. They may occur in the skin or within any viscera or bone. Gummas may occur as early as in the first year but usually the incubation period is over five years.[23] Nodular tertiary syphilis has been reported as the presenting manifestation of HIV.[49]

In HIV era, syphilis may promote HIV acquisition and transmission and HIV infection may alter the course and response of syphilis to treatment.[50] Malignant syphilis or lues maligna is a severe form of secondary syphilis, which is seen in HIV-infected individuals.[51] In this case of secondary syphilis, pustular lesions progress rapidly to painful ulcerative lesions associated with severe constitutional symptoms.[52][53][54]

Diagnosis

Dark field microscopy is considered as a point of care test for syphilis. (LE: 2a)[55] It becomes positive before the serological response, therefore, has diagnostic utility in very early chancre.

Serology

Nontreponemal serological tests are traditionally used for the screening followed by a treponemal specific confirmatory test. A non-treponemal test such as RPR and VDRL reactivity are known to decrease in response to therapy, in contrast to the lifelong persistence of treponemal test positivity. (LE: 2a)[56] To improve the accuracy of detection and confirmation of syphilis, it is recommended that all sera reactive in VDRL positive results regardless of their titre, should be confirmed by TPHA, a treponemal test, and low titre positivity should not be ignored. (LE: 2a)[57]

The reverse algorithm of syphilis screening using initially a treponemal assay instead of the non-treponemal assay and those who are tested positive are confirmed using non-treponemal assay. It detects a higher number of patients with positive results compared to traditional screening by rapid plasma reagin (RPR). This screening algorithm facilitates the detection of latent and early syphilis, but it also results in overtreatment and higher cost. (LE: 3)[58] On comparison of traditional and the reverse screening algorithm, reverse algorithm has higher diagnostic efficacy than the traditional algorithm with high sensitivity and specificity. (LE: 2a)[59], (LE: 2b)[60] The 2-step algorithms of nontreponemal followed by treponemal (Nontrep-First) and treponemal followed by nontreponemal (Trep-First) were compared with the 1-step algorithms (treponemal only [Trep-Only] and nontreponemal only [Nontrep-Only]) test, in a cohort of 10,000 individuals. Overtreatment rates were seen substantially higher (more than three times) for the 1-step algorithms. Among the 2-step algorithms, Nontrep-First was found to be more cost-effective. (LE: 2a)[61]

Biological false positive (CBFP) results can be seen in serological testing. Among the 63,765 tested blood samples, 206 (0.32%) had the CBFP reaction. Female sex and old age were associated with an increased likelihood of the CBFP reaction. (LE: 2b)[62] An IgM/IgG sensitive enzyme immuno-assay (EIA) can be an effective alternative to VDRL for syphilis screening. Six hundred seventy four specimens were tested by VDRL and EIA and TREP-SURE EIA was found to be marginally less sensitive than the VDRL test for screening, but it was significantly more specific. (LE: 2a)[63]

In a case series of 52 patients of primary syphilis, twenty-eight (53.8%) had a positive TS-EIA. Forty patients (76.9%) had a positive RPR including 15 patients (37.5%) with negative TS-EIA results. Thus, RPR was found to be significantly more sensitive than the EIA. (LE: 2a)[64] Plasmonic enzyme-linked immuno-assay is an enzyme-linked immuno-assay involves antibody induced enzyme-mediated surface plasmon resonance (SPR) of gold nanoparticles (AuNPs).This allows the quantitative assay of T. pallidum antibodies due to the remarkable colour and absorption spectral response changes of the reaction system. Sensitivity of this test is 1000-fold higher than a conventional ELISA.: (LE: 2b)[65] Western blotting is done with the serum of affected patients and is analysed for the expression of IgM and IgG against the four protein antigens Tp15, Tp17, Tp45, and Tp47. (LE: 2b)[66]

The incidence of the prozone phenomenon is low (0.83%) and it is seen particularly during primary and secondary syphilis. Pregnancy and neurosyphilis were also associated with the prozone phenomenon. It usually occurs due to high titres of antibodies, but it has also been seen in patients with a moderate/low titre. (LE: 3)[67]

Point of care tests

In resource-limited settings with poor access to laboratories for syphilis screening, rapid point-of-care (POC) tests can help in increasing the coverage of syphilis screening tests. Four POC tests most commonly used are: (i) Determine Syphilis TPH (Inverness Medical Japan Co, Ltd, Chiba, Japan); (ii) Onsite Syphilis Ab Combo Rapid TestH (CTK Biotech, San Diego, CA, USA); (iii) SD Bioline Syphilis 3.0H (Standard Diagnostics Inc, Kyonggi-do, Korea); and (iv) DPP Syphilis Screen and Confirm AssayH (Chembio Diagnostic Systems Inc, Bedford, NY, USA). All four tests use an immunochromatographic strip design where a visible coloured line appear if treponemal antibodies are detected in the specimen. The DPP Syphilis test, in addition, simultaneously detects non-treponemal antibodies by a separate coloured line on the same test strip. All four tests are almost equally sensitive and specific though sensitivity for the primary syphilis is highest with the Determine test. (LE: 2b)[68]

A systematic review and meta-analysis were conducted to evaluate the sensitivity and specificity of rapid and POC tests in blood and serum samples and rapid and POC treponemal tests showed comparable sensitivity and specificity to laboratory-based treponemal tests. (LE: 1a)[69] In India, between December 2007 and February 2008, rapid point of contact diagnostic tests (Syphicheck-WB, Qualpro Diagnostics, India) using finger-prick samples were introduced for syphilis screening. The introduction of rapid tests significantly increased the uptake of syphilis screening in this high-risk population in India. (LE: 2a)[70]

In a comparison of treponemal and nontreponemal serological tests, treponemal tests are found to be more sensitive and are recommended for clinical routine screening of syphilis. However, nontreponemal tests perform better in therapy response assessment. (LE: 2a)[71] Polymerase chain reaction

The real-time polymerase chain reaction (PCR) is sensitive and specific in the detection of T. pallidum and herpes simplex virus and it appears superior to serology in early T. pallidum infections. (LE: 2a)[72] A nested PCR (nPCR) assay specifically amplifying the tp47 gene of T. pallidum from swab and blood specimens was evaluated in a cohort of 294 patients and was found to be highly sensitive and specific for all stages of syphilis. (LE: 2a)[73]

In a systematic review of polymerase chain reaction (PCR) technique in syphilis, sensitivity was highest in the swabs from the primary genital or anal chancres and in blood from neonates with congenital syphilis. Thus PCR is a useful diagnostic tool in ulcerative lesions of syphilis, especially when serology is still negative. (LE: 1a)[74]

Diagnosis of neurosyphilis

In CSF analysis, the CSF white blood cell levels, the CSF-LDH levels, the albumin quotient and the IgA index are associated with high risk of NS. Optimal cut-off values are 10 × 106 cells/L for the CSF-WBC concentration, 19.3 U/L for the CSF lactate dehydrogenase concentration, 7.08 for the albumin quotient and 0.14 for the IgA index. LE(2a)[75] A correlation was found between CSF CXCL2 concentrations with neurosyphilis and it was shown that the CSF level of CXCL2 can be used to distinguish those with and without neurosyphilis in HIV-infected patients. (LE: 2b)[76]. Patients with asymptomatic neurosyphilis had significantly higher levels of IL-17A (8-fold) and IFN-γ (7.8-fold) in the CSF compared with patients in the no-neurosyphilis group in a case series of 33 patients with secondary and early latent syphilis. (LE: 2a)[77]

Treatment

Penicillin

Benzathine penicillin 2.4 million units (MU) single dose is used for the treatment of all persons with early syphilis. (LE: 1a) 2,78 Three weekly doses are recommended in late syphilis. (LE: 1a)[2][78]

Enhanced therapy with three dosages of benzathine penicillin G for the treatment of early infectious syphilis has been under consideration, particularly in the human immunodeficiency virus type 1 infected population. In a study of HIV-1 infected individuals, cure rates were 97% after three dosages of benzathine penicillin G compared to 88% after a single dose. (LE: 3)[79] In an another study, HIV-positive patients with early syphilis were treated with three doses of benzathine penicillin (2.4 MU I.M.) and 92.2% cases showed a successful response. (LE: 3)[80] However, there is limited data to recommend the use of enhanced therapy.

Jarisch- Herxheimer (JH) occurs occasionally after treatment with the penicillin group. Risk factors for JH reaction include high rapid plasma reagin titers, early syphilis and prior penicillin treatment. Penicillin treatment was given to 240 patients of syphilis in a case series and the overall rate of JH reaction was 31.5% (34.6% in HIV-infected patients and 25.2% in HIV-uninfected patients). (LE: 2b)[81]

Tetracycline group

A 14-day course of oral doxycycline (100 mg twice daily) or oral tetracycline (500 mg four times a day) is recommended in early syphilis. In a study of 641 patients, a similar serological treatment success rate was observed in penicillin-treated patients and in patients treated with doxycycline/tetracycline. (LE: 3)[82]

Azithromycin

In a multicentre randomized clinical trial of early syphilis patients, similar efficacy was observed with azithromycin 2.0 g administered orally as a single dose and benzathine penicillin G at a dosage of 2.4 million units administered intramuscularly. (LE: 1a)[2][83] Similarly, in a meta-analysis, the efficacy of azithromycin and benzathine penicillin was found to be similar in the treatment of syphilis.[2]

Drug resistant T. pallidum strains, caused by the mutations in the 23S ribosomal RNA (23S rRNA) gene are widespread and increasingly prevalent. It is most common in men who have sex with men. A2058G and A2059G mutations are the commonly found mutations. (LE: 2b)[84]

Azithromycin resistance due to the A2058G mutation was also noticed in T. pallidum in Australia. (LE: 2a)[85] Treatment failure with azithromycin has been noted in China, in both primary and secondary syphilis. Clinical as well as serological failure occurred with doses of azithromycin used for treatment in a range from four to thirty gram. This suggests that azithromycin has limited therapeutic value in this setting. (LE: 2b)[86]

Cephalosporins

Ceftriaxone 1-2 gram per day, given intravenously for 10-21 days have shown a comparable efficacy with penicillin in active syphilis in HIV-infected patients. (LE: 2a)[87] Similarly, equal efficacy with doxycycline has been seen in the treatment of early syphilis. (LE: 2b)[88] Five hundred and sixty HIV-positive syphilis patients were treated with cephalosporins and treatment failure was noticed in 51 (9.0%) patients. Multivariate logistic regression modelling demonstrated that the predictive factors associated with treatment failure were baseline RPR titer ≤ 1:16, a previous history of syphilis and a CD4 T-cell count below 350 cells/ml. (LE: 2b)[89]

Vaccine

Interleukin-2 expression plasmid (pIL-2) enhanced TpGpd DNA vaccine (pTpGpd) has been used in a rabbit Tp skin challenge model. It has shown to increase anti-TpGpd antibodies and T-cell proliferation. Clinically, it resulted in the decrease in a number of ulcer lesions and the fastest recovery. Thus, these vaccines efficiently improve the protective effect against T. pallidum spirochete infection and attenuate syphilitic lesion development. LE(2b)[90]

Abbreviations

CBFP: Chronic biological false positive results, CSF: Cerebrospinal fluid, DNA: Deoxyribonucleic acid, EIA: Enzyme immunoassay, ELISA: Enzyme-linked immunosorbent assay, FSW: Female sex worker, HIV: Human immunodeficiency virus, JH: Jarisch- Herxheimer reaction, MSM: Men who have sex with men, NS: Neurosyphilis, PCR: Polymerase chain reaction, POC: Point of care test, RNA: Ribonucleic acid, rRNA: Ribosomal ribonucleic acid, RPR: Rapid plasma reagin, STI: Sexually transmitted infection, TPHA: Treponemal haem agglutination test, VDRL: Venereal Disease Research Laboratory

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