Syphilis continues to be a major cause of morbidity throughout the world despite its sensitivity to penicillin and its success of the 1950’s and 1960’s in reducing the incidence. Even in developed countries with good medical care the incidence of syphilis is rising dramatically and it is even more worrying that many cases are associated with HIV infection also. Many diagnoses are made late as many health care workers are unfamiliar with the early features of infectious syphilis.
Definition of stages
If syphilis is considered to be present for less than two years it is termed early syphilis, anything over two years is called late syphilis. In primary syphilis incubation period is considered to be 9 to 90 days with an average of 3 weeks. The rash of secondary syphilis usually develops 1 to 2 months after the primary lesion and in many cases the primary lesion can still be present. This can be confusing as mucous membrane ulceration is also a feature of the signs of secondary syphilis.
Latent syphilis is when there are no overt signs of syphilis but the serological tests are positive. Confusingly latent syphilis is also divided into early and late with 2 years being used as the cut off. So an individual can have latent syphilis even in the stages of early, i.e. less than 2 years since infection, syphilis.
It is relatively easy if someone presents with an ulcer in the genital area that is painless, indurated and they have a good history of contact. If dark ground microscopy is also available then the diagnosis can be further supported, if typical spirochetes are seen in exudate from the lesions. Events, however are rarely as clear cut and straightforward as that. Lesions are often in extra genital sites and health care workers may not consider an oral or nasal lesion as syphilis if they have never seen it before. A rash of secondary syphilis is often quite dramatic and involves the palm and the soles. Yet, however, less florid cases are often misdiagnosed and the rash can often look like measles!
Most cases are diagnosed by serology as often the initial ulcer is not considered as syphilis or dark ground microscopy is negative when it is done. Luckily, newer serological tests are positive in most cases of early, even in primary, syphilis.
Syphilis serology can be divided into specific and non specific tests. Non specific tests have been available for years and generally include the RPR (rapid plasma reagin) and the VDRL (venereal disease research laboratory test). These tests depend on a coincidental antibody and hence are not specific . However they are best used as an indicator of activity and can be useful in following up patients after treatment.
Enzyme linked immunosorbant assay (EIA) are now commonly used as the initial screening test and they are very specific and sensitive. However even these tests may not be positive in primary syphilis. Studies show about 80% positivity in primary syphilis. Fluorescent Treponema Antibody Tests (FTA) are generally positive within 3-5 weeks post exposure. EIA- IgM tests are also available and can help in the differentiation of early from late or reactivation disease. The Treponema Pallidum Haemagglutination Antibody (TPHA) was widely used in the UK but has been replaced by a more sensitive particle agglutination test, the Treponema Pallidum particle agglutination (TPPA) test. This test is positive in most cases of even primary syphilis.
In summary EIA tests are automated and easy to perform on large numbers of samples, hence are usually used in screening tests. When there is clinical suspicion of early syphilis this should be indicated on the request and further analysis requested i.e. TPPA and EIA-IgM.
ATLAS OF AN STD : SYPHILIS
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A 52 year old man attended his GP with two large ulcers on the foreskin. Fig 1. He had been on a Caribbean cruise and had been at risk. He was married, but had not had sex with his wife since the contact. The lesions were painless and indurated and dark ground microscopy was positive. Syphilis serology was also positive. He was treated with intramuscular Procaine Penicillin and the lesions resolved.
A 26 year old Japanese student arrived in the UK after having had unprotected sex in Japan a few weeks earlier. He had a single large lesion on the prepuce which looked very red and beefy. Figs 2a,2b. Dark ground microscopy was positive. Syphilis serology was also positive, and he was commenced on IM Procaine Penicillin. Within three days the lesions were healing rapidly. Note the granulation tissue and the healed margins. Figs 2c,2d.
A 55 year old heterosexual man had attended clinic with a rash on the penis which had been present for almost two months. There were some whitish areas and the lesion was fairly dry, Fig 3a, so an initial tentative diagnosis of lichen sclerosus was made, and he was given 1% hydrocortisone cream and asked to re-attend in a week. When he re-attended he wondered if the cream had given him an allergic reaction, as he now had a rash all over his body (Figs 3b,3c). This was typical of secondary syphilis and, of course, by now his blood test results from his first attendance were back showing positive syphilis serology. The lesion resolved on treatment with IM Procaine Penicillin.
A 28 year old gay man attended with an anal fissure which had been present for several weeks. He had been putting haemorrhoid cream on this and it seemed to be helping. On examination: there was a well defined fissure that appeared to be healing Figs 4a,4b. He had previously attended three months earlier and HIV and syphilis serology was negative then, but on this occasion syphilis serology was positive. This was then diagnosed as primary syphilis and responded completely to IM Procaine Penicillin treatment.
A 26 year old man attended clinic with a urethral discharge. He was gay. He was diagnosed as having gonorrhoea and was given Ceftriaxone IM and 1 gram of Zithromax. Bloods at that time were negative for syphilis, hepatitis B, and HIV. He was advised to have repeat bloods again in 2.5 months time to cover the window period. Six weeks later he re-attended with two small herpetic type ulcers on the penis. He was given Acyclovir and he re-attended in two weeks, the ulcers had not healed and bloods again were negative for syphilis and HIV. He was given a second course of Acyclovir and when he re-attended two weeks later there was still a herpetic like ulcer at the base of the penis Fig5a, with unusual erythema around the glans penis Figs 5b,5c. There was also left inguinal adenopathy. Again, herpes viral culture was taken and also chlamydia swabs from these areas, as there was now suspicion of LGV. He was commenced on Doxycycline 100 mg BD for four weeks and asked to re-attend within one week. When he re-attended in a week his RPR was 16 and TPHA was 1:1280, so in hindsight the diagnosis was syphilis. The glans penis now had ulcers that looked like “snail track” Fig 5d. Dark ground was negative – probably from the doxycycline. He was commenced on Benzathine Penicillin. He re-attended two weeks later and the lesions had completely healed, Figs 5e,5f. However, he was still complaining of malaise and fevers. At this stage, his HIV test also became positive. In view of the systemic symptoms and the background HIV he was given a total of 17 days of Procaine Penicillin 2.4 Mega Units IM. Both the treponema gel agglutination test and the RPR were negative within two months.
A 31 year old gay man returned from a holiday in the Far East feeling unwell with fever, malaise, generalised lymphadenopathy and a dramatic rash all over his body involving face, scalp, trunk, limbs, including palms and soles Figs 6a,6b,6c,6d. There was no history of any primary chancre, but the rash was suspicious of secondary syphilis; the RPR was positive at 1:64 and the TPHA was greater than 1:5120. He was treated with intramuscular Procaine Penicillin and made a rapid recovery. He was HIV Negative and still negative three months later.
A 68 year old housewife attended the usual Rheumatology clinic as she had sero-positive rheumatoid arthritis. She was on a wide range of drugs, including Methotrexate, Lansoprazole, Ibuprofen, Bendrofluazide, Amlodipine and folic acid. She had developed a widespread papular rash over the previous three to four weeks which had failed to respond to Betnovate and antihistamines. An urgent dermatology consultation was also arranged and Prednisolone 40 mg daily for three days was prescribed. She was then seen two weeks later at a Dermatology follow-up appointment and there were still quite a few inflamed papules and plaques on trunk and limbs, Figs 7a,7b, and a skin biopsy was done. The differential considered was Sweet’s, connective tissue disorders, drug eruption, mycosis fungoides and papular squamous disorders. The biopsy reported cuffing of superficial and deep vessels by dense lymphohistioplasmacytic infiltrate Figs 7c,7d,7e. No specific diagnosis was suggested. On review at Dermatology clinic three weeks later, it was also noted that there were some enlarged lymph nodes in axilla and groin. However, the rash had started to settle. A wide differential diagnosis was considered, including syphilis, but no blood tests were sent. At this time, she also developed a right anterior uveiitis and was referred to Ophthalmology where an SHO included syphilis serology in the investigations. This was positive with RPR of 64 units and a treponema gel agglutination test >5120. She was shocked at the diagnosis but seen immediately in the GU Medicine clinic. She still had the rash at this point. She had no recollection of any primary lesion.
However, her 57 year old husband had had a extra-marital contact three months prior to all this. He had developed an ulcer on the scrotum. This had healed very slowly over six weeks and although he had a biopsy done, it was almost healed by the time biopsy was taken, Fig.7f. He had not developed a rash of secondary syphilis. His syphilis serology was also strongly positive with RPR of 32 units, with positive IgM and a treponema gel agglutination test of >1:5120.
In hindsight both biopsies are consistent with syphilitic infection, but there was obviously a wide differential diagnosis. They were both treated with Doxycycline 200 mg BD for one month. Injections were refused. They tolerated the oral medication and all symptoms resolved.
A 28 year old gay man attended his general practitioner with an ulcer on his lip that was taking a long to heal Fig 8a. As he was gay, the GP thought a referral to GU Medicine for a full screen would be appropriate initially. Syphilis serology was positive and a previous negative result from a GUM attendance was noted six months earlier, so it’s assumed this was a healing primary chancre. IM Benzathine Penicillin 2.4 Mega Units once a week over two weeks produced rapid healing and the lesion was almost clear within a week, Fig 8b.
A 41 year old man was referred to the eye clinic with rapidly progressing loss of vision in his right eye. He also coincidentally attended the GU Medicine clinic, as he had perianal warts and a lot of erythema and excoriation. In view of the perianal lesions, he was given Fluconazole 50 mg daily for seven days and Doxycycline 100 mg BD for two weeks, and also had a full screen, including bloods for syphilis, hepatitis B and HIV. His bloods were positive for both syphilis and HIV. He was recalled and the Doxycycline was increased to 200 mg BD. He was known to be allergic to Penicillin. He had a marked uveitis with disk swelling, macular deposits and evidence of vasculitis Fig 9a. He also had an episcleritis Fig9b. The visual symptoms were only responding slowly and he was switched to intramuscular Ceftriaxone 1 gram once daily, as it is thought it has better CNS penetration than Doxycycline. Review of previous attendances at GUM when he had refused HIV testing showed him also to be HIV Positive six months prior to this event, but the syphilis serology was negative then. Six months later the treponema gel agglutination and the RPR were negative.
This 50 year old man was seen at a review clinic as he had previously been diagnosed as having congenital syphilis. His mother had been diagnosed with syphilis in the 1940’s but had apparently defaulted from treatment. He became blind by the age of 12. It was only later that a retrospective diagnosis of congenital syphilis was made and obviously at this stage treatment with Penicillin had no impact on the damaged eyes. The figure shows marked keratitis Fig 10.
A 30 year old man attended Dermatology clinic in late January 1994 with a five week history of painful ulcers on his scalp, left hand and interscapular area Figs 11a,11b. He had several gay partners. He had also had a negative full STD screen, including HIV, syphilis, and hepatitis B in April 1993 at another local GUM clinic. He had fever, marked cervical lymphadenopathy and was admitted to general medicine. Biopsy of the cervical node showed granulomas but no acid and alcohol fast bacilli Fig 11c. The final conclusion was chronic semi granulomatous lymphadenitis of unknown aetiology, but probably infectious. Although stains for TB were negative it was assumed this was some form of tuberculous disease and he was commenced Rifampicin, Ethambutol and Clarithromycin. The skin lesions healed rapidly developing a parchment like texture to the scar tissue (Fig.11d, 11e, & 11f). He then developed painful nodules overlying mid shaft of right tibia and dorsum of the right foot, Fig 11g. Plain x-ray suggested an infectious process Fig.11h, and a isotope bone scan demonstrated focal areas of increased uptake in both tibia, ribs and throughout the skull vault, Fig11i. These were suggestive of multi focal osteomyelitis. CT scan of his right tibia showed a defect and a sequestrum Fig 11j. A CT guided biopsy of this was attempted but no diagnostic tissue or cultures were found Fig 11k. He was finally referred to the GU Clinic for a full STD screen, including syphilis serology, T4 count, etc. The T4 count was 766 cells per ml. The VDRL was positive at 1:4 and the TPHA positive at >1:512. The FTA was strongly positive, as was the IgM. In view of this positive syphilis serology the histopathology was reviewed and features were, of course, now considered compatible with syphilis. The histology was not considered hypocellular enough to be diagnostic of gumma, but all the findings were certainly consistent with syphilitic infection. He was treated with 0.9 Mega Units Procaine Penicillin IM for 21 days. The bony lesions resolved and the RPR and VDRL were negative within three months.