Journal of Infection and Chemotherapy xxx (xxxx) xxx
Contents lists available at ScienceDirect
Journal of Infection and Chemotherapy
journal homepage: www.elsevier.com/locate/jic
Guideline
Asian guidelines for syphilis
Nikhil Mehta, Neetu Bhari, Somesh Gupta
Department of Dermatology and Venereology, All India Institute of Medical Sciences, New Delhi, India
ARTICLE INFO
Keywords:
Asian guidelines
Syphilis
Neurosyphilis
There is no consensus about the need for treatment of asymptomatic
neurosyphilis.
1. Executive summary
1.2. Treatment
1.1. Diagnosis
1.2.1. Early syphilis
1.1.1. Darkfield microscopy, then chng other section numberings
Darkfield microscopy is considered a point of care test for early
1.2.1.1. Penicillin. Benzathine penicillin 2.4 million units single dose is
syphilis, especially primary syphilis [1].(LE: 1a)
used for early syphilis.(LE: 1a). Same regimen for HIV-positive patients
with syphilis.
1.1.2. Serology
Two-step algorithm preferred over 1-step algorithm.(LE: 1a) The
reverse screening algorithm is more sensitive and ensures better detec-
1.2.1.2. Azithromycin. Azithromycin 2.0 gm administered orally as a
tion of late syphilis, but has more false positivity compared to the single dose in early syphilis,(LE: 1a) good evidence from earlier studies
traditional screening algorithm.(LE: 1b)
although not currently recommended due to documented increase in
resistance and treatment failure in many places, including some regions
1.1.3. Point-of-care tests
of Asia.
The point-of-care tests have shown similar or slightly less sensitiv-
ities and specificities compared to the well-established treponemal tests,
1.2.1.3. Tetracycline group. Oral doxycycline (100 mg twice daily) or
(LE: 1a) although they have not been in widespread use as conventional
oral tetracycline (500 mg 4 times a day) for 14 days for early syphilis.
treponemal tests and lack field data.
(LE: 3a)
1.1.4. Molecular methods
1.2.1.4. Cephalosporins. Ceftriaxone 1 gm per day, given intravenously
Polymerase Chain Reaction (PCR) and multiplex PCR have good
or intramuscularly for 10 days, has recently shown a good serological
sensitivity in the early primary chancre stage when the serological tests
response equivalent to benzathine penicillin in a recent RCT.(LE: 1b)
are often negative.(LE: 2a)
1.2.1.5. Amoxicillin. Oral amoxicillin 1.5–3 gm/day divided into three
1.1.5. Diagnosis of neurosyphilis
doses with or without 0.75–1.5 gm/day probenecid for 2–4 weeks is also
Contrary to serum tests, a CSF VDRL is specific and a CSF treponemal
an effective alternative for early syphilis.(LE: 4)
test is sensitive for neurosyphilis.(LE: 1a)
There is no consensus about the need for lumbar puncture in patients
with syphilis without any neurological, ocular or otological symptoms,
except for those with tertiary syphilis.
Corresponding author.
E-mail address: someshgupta@aiims.edu (S. Gupta).
https://doi.org/10.1016/j.jiac.2022.04.023
Received 18 January 2022; Received in revised form 1 April 2022; Accepted 22 April 2022
1341-321X/? 2022 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All ri ghts reserved.
Please cite this article as: Nikhil Mehta, Journal of Infection and Chemotherapy , https://doi.org/10.1016/j.jiac.2022.04.023N. Mehta et al. Journal of Infection and Chemotherapy xxx (xxxx) xxx
treat or investigate for neurosyphilis.(LE: 5)
Abbreviations There is no consensus about the need for repeat lumbar punctures to
monitor response to therapy in neurosyphilis, although there is some
CDC Centers for disease control and prevention evidence that serum non-treponemal test titers can be used instead.(LE:
4)
CSF Cerebrospinal fluid
FSW Female sex worker
HIV Human immunodeficiency virus 2. Introduction
LE Level of evidence
MSM Men who have sex with men Syphilis is a complex, cutaneous and multi-system disease caused by
PCR Polymerase chain reaction the spirochete Treponema palladium. Syphilis is transmitted sexually,
congenitally, and through blood products. It can involve nearly every
POC Point-of-care
RCT Randomized controlled trial organ system. Its clinical course involves several well-characterized
RPR Rapid plasma regain stages: an incubation period, a primary stage, a secondary stage, a
STD Sexually transmitted disease latent stage, and a late or tertiary stage [2].
STI Sexually transmitted infection The present guidelines aim to provide comprehensive information on
SDG Sustainable development goal syphilis, including epidemiology, clinical features, diagnosis, and man-
TPHA Treponemal haemagglutination test agement. The guidelines provide evidence-based recommendations on
VDRL Venereal Disease Research Laboratory the prevention and treatment of syphilis in adults in Asia, including
special populations like pregnant females and patients with HIV coin-
fection. In these guidelines, March 2009 Oxford Centre for Evidence-
Based Medicine’s Levels of Evidence have been used to classify the
1.2.2. Late syphilis
level of evidence of various assertions and recommendations.
1.2.2.1. Penicillin. Treated with injection benzathine penicillin 2.4
3. Methodology
million units intramuscularly once weekly for three weeks.(LE: 5)
A PubMed search was last performed on August 11, 2021, using the
1.2.2.2. Tetracycline group. An alternative in penicillin-allergic patients
keywords “syphilis”. A total of 4299 results were found in the last five
is a 28-day course of oral doxycycline (100 mg twice daily) or oral
years’ publications. A careful review of the titles and abstracts was done
tetracycline (500 mg four times a day).(LE: 5)
to find all the studies on epidemiology, clinical features, diagnosis,
treatment, and prevention of syphilis. The 2021 US Centers for Disease
1.2.2.3. Amoxicillin. Another effective alternative in such patients is Control and Prevention (CDC) Sexually Transmitted Infections Treat-
ment Guideline, the 2020 edition of the European guideline on the
oral amoxicillin 1.5–3 gm/day divided into three doses with or without
0.75–1.5 gm/day probenecid for 4–8 weeks.(LE: 4) However, amoxi- management of syphilis, the 2020 German guidelines on the diagnosis
and treatment of neurosyphilis by the German Society for Neurology, the
cillin is not effective for preventing congenital syphilis when given to
pregnant females with late syphilis. 2015 United Kingdom national guidelines on the management of
syphilis, and 2019 Chinese expert consensus statement on diagnosis and
1.2.3. Neurosyphilis treatment of syphilis were also reviewed. After review, 397 studies were
Aqueous crystalline penicillin G 18–24 million units per day, either selected for analysis of the full text.
divided as 3–4 million units administered intravenously every 4 h or as a
continuous infusion for 10–14 days, is the treatment of choice for neu- 4. Epidemiology
rosyphilis.(LE: 5)
Another alternate regimen is an injection of ceftriaxone 2 g once The decline in the incidence of syphilis at the beginning of this
daily administered intravenously or intramuscularly, for 10–14 days. millennium has now plateaued, and in some areas, has reversed. This
(LE: 5) worldwide trend is also seen in Asia.
World Health Organization estimation for the year 2016 reported
1.2.4. Pregnant patients that the estimated prevalence of syphilis was 0.5% in the reproductive
age group, corresponding to 19.9 million cases of syphilis, and incidence
The treatment for proven penicillin-allergic pregnant females with
syphilis is the same penicillin regimen as in non-pregnant patients, with was 6.3 million cases per year. This estimate is similar to the revised
penicillin desensitization.(LE: 5) estimate of 2012 values. The prevalence was reported to be higher in the
African and American regions compared to South-East and East Asia
1.2.5. Screening, counselling and partner treatment (0.26%). Using the Sustainable Development Goal (SDG) regions,
Screening, with or without presumptive treatment before the result grouping Asian countries together as South-East and East Asia, and
as per the setting and regional guidelines, should be provided for sexual having a separate group of Oceania (Western Pacific Islandsexcluding
partners within the preceding 3 months plus the duration of symptoms Australia and New Zealand), Oceania is the SDG region with the highest
for patients of primary syphilis, within 6 months plus the duration of estimated incidence and prevalence of syphilis, even more than the
symptoms for those with secondary syphilis, and within 1–2 years for African and American regions [3].
patients with early latent syphilis.(LE: 5) In the United States, CDC data indicates that primary and secondary
syphilis has been rising, not just in MSMs but also in females. The rates of
1.2.6. Follow-up and monitoring congenital syphilis have also shown a rising trend [4].
To detect serological failure, monitoring with non-treponemal Incidence of syphilis has risen in Japan, with the estimated number of
testing may be performed every 3–6 monthly for 1–2 years, depending new syphilis cases from the period 2008–2016 being 1070 males and 302
upon the stage of syphilis.(LE: 5) Titers fall slower in late syphilis, hence females, compared to 269 males and 71 females in the preceding period
less frequent but longer monitoring can be opted. (1999–2007) with the same interval [5]. Japan’s increased incidence of
Serofast patients can be followed-up for 12 months in early syphilis, syphilis is considered more due to heterosexual exposure compared to
and 24 months after treatment, in late syphilis, before deciding to re- homosexual exposure in western countries. The incidence of syphilis in
reproductive-age women and congenital syphilis has also risen [6].
2N. Mehta et al. Journal of Infection and Chemotherapy xxx (xxxx) xxx
In China, the incidence of syphilis rose rapidly from 2005 to 2013, seen occasionally in the modern age. Diffuse polyostotic osteitis with
then relatively plateaued till 2016. It is expected to rise further. The skull involvement was seen in a case of secondary syphilis in an HIV-
number of reported syphilis cases in 2017 was 4,75,860 and the inci- infected patient [36]. Neurological and ophthalmological complica-
dence was 34.5 per lakh, the highest of all STDs in China [7]. tions can occur rarely and they can also cause adrenal insufficiency and
In Sri Lanka and Thailand, countries with a consistent reporting Addison’s disease [20,37,38].
system, in the last half-century, after a rapid decline followed by pla- Oropharyngeal involvement is common in syphilis. In one study of
teauing, the incidence of syphilis has started increasing again indicating HIV-infected MSM, nine out of forty-four patients with syphilis had
rebound transmission. Incidence rates of syphilis in Sri Lanka and oropharyngeal manifestations. Lesions involving the anterior tonsillar
Thailand in 2017 were 3.6 and 8.2 cases per 1,00,000 population, pillar were most common [39]. In a retrospective review of 23 reports
respectively, compared to 7.1 cases per 1,00,000 population in Europe. describing 34 patients, the oral lesions described were non-specific ul-
Both countries had recently eliminated congenital syphilis. In Thailand cers, mucosal patches, keratosis, pseudomembranes, and gumma. In a
and Sri Lanka, syphilis cases increased to 2.4 and 5.1 times, respectively, case series of 12 patients with oral syphilis, polymorphic types of oral
from 2000 to 2009 to 2010–2019, while gonorrhoea cases increased to lesions were found such as white patches, blistering mucositis, chronic
1.7 times in Thailand over the same periods [8]. non-specific ulcers, gumma, and necrosis of the dorsum of the tongue
In India, Treponema pallidum was confirmed as the etiologic or- [40].
ganism in 23% of cases of genital ulcers, second to genital herpes (48%), Secondary syphilis can be a presenting feature secondary to an im-
in a study of 194 patients [9]. In the Nagaland state of India in 2006, the mune reconstitution syndrome in an HIV-positive patient [41]. It can
prevalence of syphilis was found to be 21.1% in female sex workers also be acquired through blood transfusion, presenting without pre-
(FSW) and HIV prevalence was 11.7%. Being married, widow- ceding primary stage, known as Syphilis d’ emblee [42].
ed/divorced/separated, illiterate, or having a history of drug use were
shown to increase the likelihood of syphilis infection [10]. LE(4) In 5.3. Latent syphilis
India, targeted FSW interventions and STI treatment were shown to be
associated with a reduction in the risk of acquiring syphilis [11].LE(4) Latent syphilis is arbitrarily divided into early or late latent in-
fections. In early latent syphilis, patients do not have any signs of pri-
5. Clinical features mary or secondary disease and have positive syphilis serology, preceded
by negative serology within the last two years or recent contact with an
5.1. Primary syphilis infectious cause. Early latent syphilis is considered infectious to sexual
partners, whereas late infection is probably not [20]. LE(3) Asymp-
The classic solitary chancre (ulcer) of primary syphilis is seen tomatic patients with no evidence of recent negative serology or previ-
approximately 9–90 days after exposure to the disease. Commonly ous treatment are classified as having late latent infection or syphilis of
affected sites include penis, vulva, cervix, anus, nipple, fingers, hand, unknown duration. Because syphilis serology may remain positive for
eyelid, arm, or oral cavity depending on the type of sexual exposure life even after successful treatment, a reasonable effort should be made
[12–17]. Because chancres are painless, presentation is usually delayed. to exclude prior infection.
Indurated chancre results in difficulty in retraction of the prepuce which About one-third of untreated patients with latent syphilis progresses
flips over on retraction (dory-flap sign) [18]. Chancre at the urethral
to symptomatic late disease (tertiary syphilis), which may manifest as
meatus and development of stricture are rare complications of syphilis neurosyphilis, cardiovascular syphilis, or late benign syphilis (gumma-
[19]. Chancres are often associated with painless local lymphadenopa-
tous disease) [20]. In a hospital-based five-year survey in an STD clinic
thy. Multiple chancres may occur and in up to one-fourth of cases may be in India, describing 570 cases, 7.36% cases were diagnosed with syph-
painful, especially if superinfected with skin flora or with herpes simplex ilis. Primary syphilis was diagnosed in 21 (50%), secondary in 10 (24%),
virus [20]. and latent in 11 (26%) cases. Concomitant primary chancre and lesions
Syphilitic balanitis of Follmann is a rare condition that is considered of secondary syphilis were seen in 2 (20%) patients.
a manifestation of primary syphilis. Instead of an ulcer, there’s diffuse
involvement of the glans penis in form of diffuse indurated dark red
5.4. Neurosyphilis
erythema accompanied by bilateral inguinal lymphadenopathy [21].
Neurosyphilis, which affected 10% of men and 5% of women in the
5.2. Secondary syphilis pre-antibiotic era, is now rare. A detailed classification of neurosyphilis
was proposed by Merritt in 1946. In asymptomatic neurosyphilis,
Secondary manifestations of syphilis usually begin after 3–5 months CSFabnormalities may be present in the absence of symptoms or signs of
of initial infection. In about a third of patients with secondary syphilis, a neurological disease.
residual chancre is seen at presentation. It presents with the classical Meningovascular neurosyphilis typically occurs 5–12 years after
triad of skin rash, mucosal lesions/ulceration, and lymphadenopathy. It initial infection, although it can also occur any time from the first month
may be associated with a headache, malaise, mild fever, lymphade- onwards, including early syphilis [43]. About 0.8%–1.7% of early
nopathy,and sore throat. The typical maculopapular and subsequently syphilis cases have probable or confirmed neurosyphilis [44,45]. It
scaly rash affecting the palms and soles occurs in up to 75% of cases. usually affects the territory of the middle cerebral artery and may cause
Other common forms of cutaneous rash are pustular and psoriasiform a stroke-like syndrome. Focal or generalized seizures can also occur
lesions. Papulonodular lesions are also seen [22-24]. Nodular secondary sometimes.
syphilis simulating lepromatous leprosy has been reported [25]. It can Parenchymatous neurosyphilis is the cause of general paresis of the
also mimic cutaneous lymphoma [26,27] or Kaposi sarcoma [28,29]. insane. Early symptoms include irritability, memory loss, personality
Vesicular lesions are rarely seen [30]. Syphilitic alopecia occurs in only change, and insomnia. These may progress over many years to result in
about 4% of patients with syphilis [31,32]. Presentation as depigmented depression, confusion, disorientation, delusions of grandeur, paranoia,
macules is known as “leucoderma syphiliticum” [33]. Erythema multi- and seizures. Dementia progresses to death within months to years.
forme and pityriasis lichenoides like lesions can also be seen [34,35]. Tabes dorsalis is seen as a consequence of untreated parenchymatous
Other features of the secondary disease include condylomata lata neurosyphilis. It is characterized by lightning pains, reduced deep
(pale elevated papules over moist body orifices), oral mucosal erosions, tendon reflexes, paraesthesias, sensory abnormalities, Charcot’s joints,
mild hepatosplenomegaly, and raised liver function tests, in particular, and Argyll-Robertson pupils. Bladder and bowel disturbances are com-
alkaline phosphatase. Cardiovascular, bone and renal complications are mon. The classic visceral crises of tabes may result in severe
3N. Mehta et al. Journal of Infection and Chemotherapy xxx (xxxx) xxx
gastrointestinal pains or laryngeal pain and hoarseness [20]. overtreatment hence is not preferred [54].(LE: 1a) There are two types
Clinical profiles of 16 patients with neurosyphilis in northeast India of 2-step algorithms. The traditional algorithm entails that non-
were studied, between August 2008 and December 2010. The clinical treponemal serological tests like VDRL and RPR tests are used for the
spectrum included: neuropsychiatric syndromes (10), myelopathy (5), screening followed by a treponemal-specific confirmatory test. When
and posterior circulation stroke (1). Neuropsychiatric symptoms were using the traditional 2-step regimen, all positive VDRL results should be
dementia, behavioural abnormalities, chronic psychosis, and myelop- confirmed by a treponemal test like TPHA, regardless of their titer. This
athy syndromes including acute transverse myelitis, chronic myelop- improves the accuracy of detection and confirmation of syphilis. Low
athy, and syphilitic amyotrophy [46]. titer positivity should not be ignored [55].(LE: 1b) In the case of a
A retrospective review was performed for 149 patients with neuro- positive non-treponemal test followed by a negative treponemal test, the
syphilis in China, 16.8% of patients were found asymptomatic for neu- low titer treponemal test can be considered as biologically false positive.
rosyphilis, 15.4% with syphilitic meningitis, 24.2% with meningovascular (LE: 1b)
neurosyphilis,38.9% with general paresis, 4.0% with tabes dorsalis, and If the non-treponemal test is negative but there’s a strong clinical
0.7% with gummatous neurosyphilis [47]. suspicion of primary or secondary syphilis, the laboratory at the centre
can be instructed to perform the non-treponemal test in further dilution
5.5. Cardiovascular syphilis or to go ahead with the treponemal test despite the negative non-
treponemal test, to rule out prozone phenomenon.(LE: 5) The inci-
Cardiovascular syphilis is seen after 15–30 years of initial infection dence of the prozone phenomenon is low (0.83%) and it is seen partic-
ularly during primary and secondary syphilis. Pregnancy and
and results in the proximal aortic aneurysm and aortic regurgitation. It
was seen in 25% of patients with symptomatic late infection in the pre- neurosyphilis are also associated with the prozone phenomenon. It
usually occurs due to high titers of antibodies, but it has also been seen
antibiotic era but is uncommon in current practice [20].
in patients with a moderate/low titer [56].(LE: 4)
The reverse algorithm of syphilis screening entails using a trepo-
5.6. Late benign syphilis (gumma)
nemal assay initially instead of the non-treponemal assay, and those who
test positive are confirmed using the non-treponemal assay. It detects a
Gummas are proliferative granulomatous lesions that represent an
inflammatory response to small numbers of treponemes. They may occur higher number of patients with positive results compared to the tradi-
tional algorithm. This screening algorithm facilitates the detection of
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 late syphilis, including late latent syphilis, yielding better sensitivity and
[20]. Nodular tertiary syphilis has been reported as the presenting more case detection compared to the traditional algorithm, but it also
manifestation of HIV [48]. results in more false positivity [57,58],(LE: 1b) overtreatment, and
In the HIV era, syphilis may promote HIV acquisition and trans- higher cost [54].(LE: 2b) A positive treponemal test followed by a
negative non-treponemal test can indicate either earlier adequately
mission and HIV infection may alter the course and response of syphilis
to treatment [49]. Malignant syphilis or lues maligna is a severe form of treated syphilis (which may be documented or not, can be incidental or
wilful treatment) or late syphilis (in which non-treponemal tests have
secondary syphilis, which is seen in HIV-infected individuals [50]. In
this case of secondary syphilis, pustular lesions progress rapidly to lower positivity rates compared to treponemal tests). Such cases should
be confirmed by a second treponemal test. If the second treponemal test
painful ulcerative lesions associated with severe constitutional symp-
toms [51–53]. is found to be positive, then a patient with high-risk behaviour and
without any past documented treatment should be treated as late
6. Diagnosis syphilis.(LE: 5) High titers of the first treponemal test may obviate the
need for the second, but these cut-off values have not been standardized,
6.1. Darkfield microscopy and are not in common use. If the second treponemal test is negative and
the patient has a low clinical and epidemiological probability of having
Darkfield microscopy is considered a useful point-of-care test for syphilis, the first treponemal test can be labelled as false positive,
early syphilis, especially primary syphilis [1].(LE: 1a) It becomes posi- without requiring treatment.(LE: 5)
The traditional algorithm is better for smaller centers with low
tive before the serological response, therefore, has diagnostic utility in
early chancre. The utility of darkfield microscopy for oral lesions is testing volume and concerns of cost-effectiveness, as manual non-
treponemal tests are usually less expensive. The reverse algorithm is
limited due to commensals that resemble Treponema pallidum. As it re-
quires trained manpower, its availability is generally limited, although it better suited for areas with centers with higher testing volumes and
large laboratories as automated platforms provide a better turnaround
is recommended to be done wherever available.
time [59]. Whatever the policy of a centre, the results (and the subse-
quent decision to treat) should always be correlated clinically.
6.2. Serology
Various automated non-treponemal tests utilising different reagents
are commercially available. The results of various non-treponemal
Treponemal tests have higher specificity, and higher sensitivity,
especially in late syphilis, and can be automated, while non-treponemal manual methods like VDRL and RPR tests are reported as non-
consecutive titer values as they are read from serial dilutions. But the
tests are cheaper, decline with treatment (hence can be used for moni-
toring response to treatment), and are read manually. Treponemal tests results of some automated tests are reported in consecutive values as
‘RPR units’ as they are measured by measuring the absorbance of sam-
will stay positive in adequately treated patients while non-treponemal
ples in machines [60]. The RPR units of these automated methods are
tests are more commonly biologically false positive. Treponemal tests
reagent and manufacturer-specific. Their corresponding or correlating
become positive earlier than non-treponemal tests in early syphilis. Both
manual RPR values are not well defined. There are no rigorous recom-
treponemal and non-treponemal serological tests should be done in a
suspected case of syphilis. Although requisition for both types of tests mendations in guidelines on how to use values of the automated
methods during follow-up serological monitoring to look for a successful
can be sent together for diagnosis to save patient visits, laboratories and
institutions have protocols to do one of them first in a sample for serological outcome, but the use of a four-times decline in these values
similar to those of manual methods has been shown to correlate with
screening followed by the second on the same or different sample
depending on the result of the first test, in form of a 2-step algorithm. results of manual methods in a study [61].(LE: 2b)
Using only one test, either treponemal or non-treponemal alone to
decide the treatment is termed a 1-step regimen and leads to significant
4≤μ≥≤≤
N. Mehta et al. Journal of Infection and Chemotherapy xxx (xxxx) xxx
6.3. Point-of-care tests biochemical indicators of syphilis or neurosyphilis which indicate
adequate treatment.
In resource-limited settings with poor access to laboratories for 2. In patients of syphilis with HIV, who have either out of - serum RPR
syphilis screening, rapid point-of-care (POC) serological tests can help in 1:32, CD4 count 350 L, detectable viral load, or history of
increasing the syphilis screening and its treatment [62]. These are treatment with non-penicillin alternative treatment as these findings
mostly treponemal tests, although few dual treponemal and raise the odds of asymptomatic neurosyphilis [68,69].(LE: 4)
non-treponemal tests also exist. The latter are yet to be validated in large
field trials. Most of them are based on immunochromatography. The No consensus exists on the above two scenarios, as these patients
POC tests have similar or slightly less sensitivities and specificities have no neurological, ocular, or otologic symptoms, and even if they are
compared to the well-established treponemal tests [63],(LE: 1a) found to have CSF pleocytosis and VDRL positivity, they would be said
although they have not been in widespread use as conventional trepo- to have asymptomatic neurosyphilis. There’s no consensus or evidence if
nemal tests and are relatively more recent. They should be used when treatment of asymptomatic neurosyphilis leads to better outcomes [67].
access to conventional treponemal and non-treponemal tests is limited Ideally, three different tests- a non-treponemal test like VDRL
and there’s a significant loss to follow up.(LE: 4) They are commonly (preferred over RPR), a treponemal test like TPHA or FTA-ABS or TPPA,
being used in blood banks too for screening in many countries. In the and CSF cell and protein analysis can all be sent together. Contrary to
case of a positive POC test, the reverse algorithm approach should be serum tests, a CSF VDRL is specific and a CSF treponemal test is sensitive
followed by referring the patient to a higher centre for a non-treponemal for neurosyphilis.(LE: 1a) CSF VDRL is more sensitive and has lesser
test. If this is not feasible, then a patient with strong clinical suspicion of false negatives (hence preferred) than CSF RPR [70]. A negative CSF
syphilis and with no history of treatment for it should be treated without treponemal test like CSF TPHA can be considered to rule out neuro-
additional testing [62].(LE: 4) In many countries including India, a syphilis in absence of ocular or otologic symptoms or signs, although this
syndromic approach in resource-limited settings involves treating sus- is questioned in recent reviews [71]. CSF pleocytosis and low protein
pected primary syphilis patients empirically without any investigations, levels can guide empirical treatment when CSF VDRL is negative and a
which seems to have worked well [64]. POC tests can also be added to treponemal test is not available, in highly suspicious or symptomatic
enhance this approach for better sensitivity and specificity.(LE: 5) cases, in both HIV negative and HIV positive cases, although it has poor
specificity [66].(LE: 5) As HIV itself causes mild pleocytosis, the cut-off
values of CSF pleocytosis may be considered higher (20 leucocy-
6.4. Molecular methods
3 3)
tes/mm ) than that in non-HIV patients (5 leucocytes/mm , as pleo-
cytosis above this value is unlikely to be due to HIV alone [69].(LE: 4)
Polymerase Chain Reaction (PCR) and multiplex PCR have good
If a sequential testing algorithm is to be followed with the CSF
sensitivity for the screening of syphilis from moist ulcers, especially from
sample of a symptomatic patient, CSF VDRL can be done first, and if
the early primary chancre stage, when the serological tests are often
found to be negative, then CSF treponemal test or cell counts to look for
negative [65].(LE: 2a) Due to its non-availability and cost, its use is
pleocytosis can be done. Symptomatic patients with either of these tests
limited to research settings. Other potential areas include diagnosis of
being positive can be treated.(LE: 5)
neurosyphilis from CSF samples and diagnosis of congenital syphilis. Its
The sensitivity of PCR tests to diagnose neurosyphilis is currently
potential use in secondary and early latent syphilis is limited due to the
lesser than serological tests [72].
good sensitivity of the alternative, that is, serology, in these stages.
7. Treatment
6.5. Diagnosis of neurosyphilis
7.1. Early syphilis
There is no uniformly accepted algorithm or combination of tests to
diagnose neurosyphilis. A combination of clinical features and CSF in- Benzathine penicillin 2.4 million units (MU) single dose is used for
vestigations are required to diagnose neurosyphilis [66]. Neurological the treatment of all persons with early syphilis.(LE: 1a) [73,74]
symptoms should be enquired in all cases of syphilis at baseline irre- In the absence of benzathine penicillin, or in non-pregnant patients
spective of the stage. In patients with syphilis of any stage, neurosyphilis with penicillin allergy, a 14-day course of oral doxycycline (100 mg
should be suspected, and CSF sampling should be performed in- twice daily) or oral tetracycline (500 mg four times a day) is recom-
mended in early syphilis. It has shown an equivalent serological
1. Patients who have neurological symptoms [67].(LE: 4) response rate as benzathine penicillin in multiple retrospective
2. Patients who have ocular and otologic symptoms and signs for which comparative studies [75–79].(LE: 3a) Doxycycline is preferred over
there is no clear alternative diagnosis, or for which neurosyphilis tetracycline because of less frequent dosing and gastric side effects.(LE:
cannot be ruled out by ophthalmologists or otolaryngologists.(LE: 4) 5) Another alternative in such patients is ceftriaxone, 1 g once daily for
74
In patients with isolated ocular or otologic symptoms without any 10 days, through the intravenous or intramuscular route. The level of
symptoms of cranial nerve involvement, CSF samples and in- evidence of ceftriaxone for treatment in early syphilis has raised recently
vestigations can frequently be normal. There is no consensus about because of a recent randomized control trial demonstrating its serolog-
the requirement of CSF sampling in these cases to obtain baseline ical response rate equivalent to benzathine penicillin [80], in addition to
CSF VDRL titer values to enable follow-up monitoring. multiple retrospective comparisons [74,81,82].(LE: 1b) Another alter-
3. Patients with a form of tertiary syphilis, but without neurological, native in such patients, shown to be effective in many recent case-series,
ocular, or otological symptoms.(LE: 5) especially from Japan, is oral amoxicillin 1.5–3 gm/day divided into
three doses with or without 0.75–1.5 gm/day probenecid for 2–4 weeks
Other indications when a CSF examination may be performed in [83–86].(LE: 4)
patients lacking neurological, ocular, and otological symptoms include- Although a single dose of 1–2 g azithromycin administered orally has
been demonstrated to have equivalent response rates to benzathine
1. Patients with treatment failure in form of lack of an appropriate fall penicillin in multiple RCTs in the past [87](LE: 1a), because of the
in serum titers of non-treponemal tests [68].(LE: 5) However, there emergence of azithromycin resistant Treponema pallidum, use of azi-
may be serofast states, defined as lack of four-fold fall of titer of thromycin for other STIs, lack of consistent reporting of azithromycin
non-treponemal tests in patients with a baseline low VDRL titer resistant patterns, and availability of better alternatives, azithromycin is
( 1:4 or 1:8), despite resolution of all other clinical and not recommended for treatment of primary syphilis. Clinical treatment
5≤≤
N. Mehta et al. Journal of Infection and Chemotherapy xxx (xxxx) xxx
failure has been demonstrated in many patients in China [88], although 7.5. Screening, counselling, and partner treatment
in areas of documented low macrolide resistance, azithromycin is still as
good as benzathine penicillin in terms of serological response [89]. Screening for other STDs should be done as per regional guidelines.
When there’s a shortage or lack of consistent availability of benza- Abstinence till the completion of the course of treatment, and complete
thine penicillin, the institutional policy should be directed towards healing of skin lesions should be advised to patients. Patients and
ensuring consistent and easy availability of benzathine penicillin rather partners should undergo appropriate counselling to prevent re-infection,
than replacing it with alternatives, as clinicians have the maximum other STDs, and alteration of high-risk behaviours.
experience with it and expect maximum compliance and ease of treat- Screening, with or without presumptive treatment before the result
ment with its single-dose institutional observed injection.(LE: 5) as per the setting and regional guidelines, should be provided for sexual
Enhanced therapy with three dosages of benzathine penicillin G for partners within the preceding 3 months plus the duration of symptoms
the treatment of early infectious syphilis, which was earlier considered for patients of primary syphilis, within 6 months plus the duration of
based on observational studies, especially in HIV co-infected in- symptoms for those with secondary syphilis, and within 1–2 years for
dividuals, has demonstrated equivalent response rates in an RCT and is patients with early latent syphilis.(LE: 5) These periods are based on the
not recommended [90,91].(LE: 2b) calculated incubation period and the natural course of the disease.
7.6. Follow-up and monitoring
7.2. Late syphilis
A four-fold decline in non-treponemal test titers correlates well with
Late syphilis, including late latent syphilis and tertiary syphilis and
clinical response in early syphilis and is the established serological
excluding neurosyphilis, is treated with injection benzathine penicillin
73,92 standard for the cure [93]. This response should ideally occur by 6
2.4 million units intramuscularly once weekly for three weeks. This
months in early syphilis, and by 12 months in late syphilis.(LE: 4)
treatment regimen precludes the prevalent use of randomized controlled
Failure of this decline to occur in the stipulated time frame has been
trials. As it has shown good results in a long clinical experience of the
variably termed serofast state, serological non-response, inadequate
world, wasn’t confirmed through clinical trials and is recommended
serological response, or serological failure [94]. A serofast state is
strongly despite having a low level of evidence.(LE: 5) The reason for
inconsistently defined but generally entails a lack of a four-fold decline
repeated doses is hypothesized to be the slow replication of treponemes
and/or persistence of baseline low titer ( 1:4 or 1:8 in different
in later stages of infection.(LE: 5) A delay leading to an interval of 10–14
studies), 6–12 months after adequate treatment [94–96]. These patients
days between the doses is acceptable, but further delay warrants re-
usually do not have any clinical evidence of treatment failure.
initiation of the course and all three doses [92].(LE: 5) An alternative
Patients who become seronegative should not be re-treated, and
regimen in the absence of benzathine penicillin, or in non-pregnant
patients who have a four-fold rise compared to pre-treatment titer or
patients with penicillin allergy, involves a 28-day course of oral doxy-
recurrence of signs and symptoms should be re-treated, considering
cycline (100 mg twice daily) or oral tetracycline (500 mg four times a
treatment failure or re-infection depending upon the context. But there’s
day).(LE: 5) Another effective alternative in such patients is oral
no consensus about the need for re-treatment for patients with serofast
amoxicillin 1.5–3 gm/day divided into three doses with or without
state. In a study, re-treatment of such patients after failure of four-fold
0.75–1.5 gm/day probenecid for 4–8 weeks [83–85].(LE: 4) However,
fall in 1 year did not lead to an increase in serological cure rates more
amoxicillin is not effective for preventing congenital syphilis when given
than the patients who were not re-treated [96]. Hence the utility of
to pregnant females with late syphilis, and 33% pregnant females with
re-treatment of such patients at this duration is doubtful. The proportion
late syphilis treated with amoxicillin had children with congenital
of serofast state decreases with an increase in the follow-up period and is
syphilis as the birth outcome in a recent retrospective review of records
more in late syphilis compared to early syphilis, and more in those with
from Japan [86]. Ceftriaxone use for late syphilis other than neuro-
low baseline titers [95,97].(LE: 4) Serofast patients can be followed-up
syphilis isn’t recommended by experts.
for 12 months after treatment, that is, 6 more months, in early syphilis,
and 24 months after treatment, that is, 12 more months, in late syphilis,
7.3. Neurosyphilis
before deciding to re-treat or to investigate for neurosyphilis.(LE: 5)
Serofast patients may instead be closely monitored and investigated.
Benzathine penicillin does not concentrate well in CSF. Aqueous
This decision may also depend on the baseline titers, although there is no
crystalline penicillin G 18–24 million units per day, either divided as 3–4
evidence that a lack of a four-fold fall is indicative of treatment failure in
million units administered intravenously every 4 h or as a continuous
patients with a high baseline titer any more than in those with a low
infusion for 10–14 days, is the treatment of choice for neurosyphilis.(LE:
baseline titer. At any stage in follow-up, recurrence of clinical signs
5)
suggestive of syphilis or neurosyphilis warrant treatment as per their
An alternative regimen when aqueous penicillin is unavailable or
regimens. In case re-treatment is opted for a case of early syphilis which
when there’s a lack of in-patient care facility is procaine penicillin G 2.4
was treated with a single dose of benzathine penicillin 1–2 years ago but
million units administered intramuscularly once daily, along with tablet
has an inadequate serological response, three weekly doses should be
probenecid 500 mg orally four times a day, both for 10–14 days.(LE: 5)
given (similar to the regimen for late syphilis) after ruling out neuro-
Another alternate regimen is injection of ceftriaxone 2 g once daily
syphilis.(LE: 5)
administered intravenously or intramuscularly, for 10–14 days.(LE: 5)
To detect serological failure, monitoring with non-treponemal
Ocular and otologic syphilis, in the absence of concomitant neuro-
testing may be performed every 3–6 monthly for 1–2 years, depending
syphilis, are managed similarly to neurosyphilis.(LE: 5)
upon the stage of syphilis.(LE: 5) Titers fall slower in late syphilis, hence
less frequent but longer monitoring can be opted.
7.4. Pregnant patients Retro-negative serofast patients of early syphilis do not have a sig-
nificant improvement in serological cure rate with treatment [98].(LE:
The first line preferred regimen in pregnant females is the same as 4)
non-pregnant patients for both early and late syphilis. As doxycycline For neurosyphilis, the response can be monitored by clinical pa-
cannot be given to pregnant females, and ceftriaxone has not been rameters and serum non-treponemal test titers, and repeat lumbar
studied in this age group, the treatment for proven penicillin-allergic punctures to see CSF VDRL titers and pleocytosis are not required,
pregnant females with syphilis is the same penicillin regimen with although they are still preferred over serum titers by many experts and
penicillin desensitization. (LE: 5) are recommended in some guidelines [99].(LE: 4) However, in case
6′′¨?′ˇ?′′
N. Mehta et al. Journal of Infection and Chemotherapy xxx (xxxx) xxx
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