Syphilis -- a Dreadful Disease on the Move

Until 1997, it seemed that syphilis rates were declining in Canada. However, since then, outbreaks of syphilis have been reported in every major Canadian urban centre. These outbreaks are not occurring in isolation -- parallel outbreaks of syphilis, particularly among men who have sex with men (MSM), are also occurring in major urban centres in North America, Western Europe and Australia. Before we delve into a recent Canadian report about syphilis, here is some background information.

Transmission

Syphilis is the name given to a chronic infection caused by the germ T. pallidum. This disease can be spread in the following ways:

• kissing

• anal, oral or vaginal sexual contact

• sharing needles and other equipment for substance use

• from an infected mother to child during pregnancy or birth

The germs that cause syphilis (called treponemes) can cause sores on the genitals, rectum and mouth. These sores can be an entry point for HIV and other sexually transmitted infections (STIs) to get inside the body. Once inside the body, treponemes, like HIV, can enter the lymphatic system or the blood stream. From there, in a matter of hours or a few days, treponemes can quickly spread throughout the body and reach the brain.

Primary Syphilis

In early stages of syphilis a sore can appear on the penis or in the rectum or, in women, on the cervix. In people co-infected with HIV, multiple sores can appear. Because the sores appear in hidden locations, early-stage syphilis might go unnoticed in both men and women.

Lymph nodes in the groin may become swollen, usually within a week of the appearance of the syphilitic sore. Although the sore, sometimes called a chancre, can heal within four to six weeks, lymph nodes may remain swollen for several months.

Still, early-stage syphilis can have minimal symptoms and may go unnoticed by affected people. Troublingly, treponemes have been found in the spinal fluid of people with primary syphilis, regardless of HIV infection.

Secondary Syphilis

In this stage, generally two to 12 weeks after the appearance of the chancre, symptoms of a widespread T. pallidum infection occur. Symptoms can vary considerably but the following can be common:

• skin rash

• low-grade fever

• lack of energy

• sore throat

• lack of appetite

The skin rash can begin on the trunk but may also appear anywhere else, including on the palms of the hands and soles of the feet. If the rash affects a hairy area, temporary patchy hair loss can occur. For instance, thinning of the eyebrows, beard or parts of the head can be a feature of syphilitic rash.

Painless lesions called mucous patches can appear on the wet tissues of the genitals, mouth, throat and tonsils. These lesions are teeming with treponemes and are highly infectious.

In up to 40% of people with secondary syphilis, the brain and spinal cord (CNS -- central nervous system) can become infected, with or without symptoms. In some cases, symptoms such as the following may appear:

• ringing in the ears

• decrease in the ability to hear clearly

• difficulty seeing clearly

• headache

If left untreated, neurosyphilis can develop, leading to severe complications.

The germs that cause syphilis can also infect the liver, causing liver damage or hepatitis, detected by increasing levels of liver enzymes in the blood.

Secondary syphilis can also turn into latent syphilis. In this case, no symptoms are present and the infection is only detectable with blood tests. However, despite the lack of symptoms, the disease is still eating away at the body.

Late Syphilis (Tertiary Syphilis)

In this stage of illness, any organ of the body may become slowly inflamed and affected by T. pallidum. Generally, late syphilis can affect the nervous system (neurosyphilis), the heart and blood vessels (cardiovascular syphilis) and just about any organ/system where a syphilitic lesion can appear. Such solitary lesions are called gummas.

If left untreated, late-stage syphilis can eventually lead to unpleasant and dreadful complications, including the following:

• difficulty falling asleep

• peripheral neuropathy

• problems getting and maintaining an erection

• changes in personality

• poor memory

• decreased capacity for insight and good judgment

• meningitis

• poor control of muscles

• damaged joints

• seizures

• stroke

Given all of these, regular blood tests for syphilis (and other STIs) are important for sexually active people who wish to remain healthy.

Testing

Different tests are available for assessing syphilis. For further information about which tests are available in your region, contact your local laboratory.

Blood tests commonly used to help diagnose syphilis include the following:

• VDRL (venereal disease research laboratory)

• RPR (rapid plasma regain)

These two tests are indirect tests in that they detect antibodies produced against proteins unrelated to T. pallidum but that still occur in cases of syphilis. In people with primary syphilis or latent syphilis, these indirect tests may not always work. In such cases, where syphilis is suspected, the Public Health Agency of Canada (PHAC) recommends that doctors repeat the indirect test several weeks later and also consider the use of tests that specifically assess the presence of antibodies to T. pallidum. These tests include the treponemal enzyme immunoassay (EIA). Other tests that may be useful include FTA-ABS, MHA-TP.

PCR tests are not routinely used to detect T. pallidum and they cannot distinguish between live and dead treponemes. Moreover, PCR tests are only available at specialized laboratories, including Canada's National Microbiology Laboratory.

Recently, researchers in the Netherlands have suggested that routine assessment of blood for syphilis may be useful in HIV positive MSM because this disease can, at least initially, be symptom-free. This Dutch study will be the focus of an upcoming CATIE News story.

Treatment

Unlike the case with many other diseases, one syphilis expert writing in an infectious disease textbook noted that "there have not been many well-controlled, carefully planned, prospective studies to determine [the best dose or length] of therapy." Current recommendations for treatment of syphilis are based on extrapolations of older data. Despite these drawbacks, an antibiotic called benzathine penicillin G is considered the gold standard of anti-syphilis therapy.

Drug Levels

Ideally, maintaining high levels of penicillin in the blood should keep T. pallidum from reproducing and still higher levels can help kill these germs. So, for treating early syphilis, high levels of penicillin G are needed for at least seven days. The most convenient way to achieve this while avoiding the issue of patient adherence is an injection of benzathine G penicillin into muscle. However, it is important to note that this dose is inadequate for neurosyphilis; indeed, levels of penicillin that can kill treponemes in the CNS are not reliably achieved with a single injection of benzathine penicillin G 2.4 million units. Yet, in cases of early diagnosis, where, in theory, there are fewer treponemes, the evidence shows that treatment with a single injection of penicillin is sufficient therapy for the average person with primary syphilis.

Other Antibiotics

Antibiotics such as doxycycline impair the growth of treponemes and are sometimes used in patients who are allergic to penicillin. Bear in mind that unlike penicillin, doxycycline does not kill treponemes and may be less effective in people with severely weakened immune systems. In cases of penicillin allergy, some experts prefer to desensitize their patients to penicillin -- a course of action suggested by PHAC. Penicillin desensitization is also recommended for cases of syphilis in pregnant women.

Another potential treatment is the antibiotic azithromycin (Zithromax). However, reports have emerged of cases of syphilis resistant to azithromycin in the United States, Ireland and recently in the province of British Columbia. All of the B.C. cases of azithromycin-resistant syphilis were in MSM. PHAC does not recommend the use of this antibiotic for the routine treatment of syphilis.

Also, the antibiotic ceftriaxone is not recommended for routine treatment of syphilis in Canada.

What About HIV Infection?

The treatment of syphilis in people co-infected with HIV is controversial. Some physicians are in favour of the same therapy that would be used in HIV negative people -- a single intramuscular injection of benzathine penicillin G 2.4 million units. However, because of a number of factors, some doctors may opt for more rigourous therapy in HIV positive people. These factors can include the following:

• There is a high risk of treponemes invading the brain, even in primary syphilis, and so a single injection of penicillin may be inadequate therapy in such cases.

• Syphilis can damage the brain.

• HIV positive people are at high risk for neurological problems and neurosyphilis may add to this burden.

• HIV infection weakens the immune system and possibly its ability to control syphilis.

• Syphilis is a relatively common STI among sexually active MSM.

Such considerations have prompted some physicians to use benzathine penicillin G 2.4 million units, injected intramuscularly, once weekly for three consecutive weeks as treatment in HIV positive people for primary or secondary syphilis.

Alternatively, other physicians may opt for the antibiotic doxycycline 100 mg taken orally twice daily for two to four consecutive weeks. Although effective in early-stage syphilis, doxycyline has not been tested for late-stage syphilis, so syphilis experts recommend desensitization to penicillin in patients with penicillin allergy, followed by penicillin therapy. Moreover, unlike penicillin, doxycycline does not kill treponemes.

For neurosyphilis, regardless of HIV infection status, PHAC recommends therapy with penicillin G 3 to 4 million units given intravenously every four hours each day (for a total of between 16 and 24 million units daily) for 10 to 14 days.

PHAC has excellent guidelines (updated in 2008) for the management of patients with syphilis, including a penicillin desensitization plan, available at:

www.phac-aspc.gc.ca/std-mts/sti\_2006/pdf/510\_Syphilis.pdf

For further information about syphilis and HIV, see "The Story of Syphilis" in The Positive Side magazine (spring/summer 2004), available at:

www.positiveside.ca/e/V6I4/Syphilis_e.htm

Recently, doctors in the Ottawa region have been studying an outbreak of syphilis to try to better understand it. Our report on this appears in the next CATIE News bulletin.

References

1. Lukehart SA, Hook EW 3rd, Baker-Zander SA, et al. Invasion of the central nervous system by Treponema pallidum: implications for diagnosis and treatment. Annals of Internal Medicine. 1988 Dec 1;109(11):855-62.

2. Expert working group. Canadian guidelines on sexually transmitted infections. January 2008. Available at: ww.phac-aspc.gc.ca/std-mts/sti_2006/sti_intro2006-eng.php. [Accessed 19 November 2008]

3. Tramont EC. Treponema pallidum (syphilis). In: Mandell GL, Bennett JE and Dolin R, editors. Principles and Practice of Infectious Diseases. Sixth ed. Philadelphia: Elsevier; 2005. P. 2362-2379.

4. Lukehart SA. Syphilis. In: Fauci AS, Braunwald E, Kasper DL, editors. Harrison's Principles of Internal Medicine. 17th ed. McGraw-Hill Companies, Inc.; 2008. P. 956-962.

5. Dowell ME, Ross PG, Musher DM, et al. Response of latent syphilis or neurosyphilis to ceftriaxone therapy in persons infected with human immunodeficiency virus. American Journal of Medicine. 1992 Nov;93(5):481-8.

6. Gordon SM, Eaton ME, George R, et al. The response of symptomatic neurosyphilis to high-dose intravenous penicillin G in patients with human immunodeficiency virus infection. New England Journal of Medicine. 1994 Dec 1;331(22):1469-73.

7. Marra CM, Maxwell CL, Smith SL, et al. Cerebrospinal fluid abnormalities in patients with syphilis: association with clinical and laboratory features. Journal of Infectious Diseases. 2004 Feb 1;189(3):369-76.

8. Thorne C, Malyuta R, Semenenko I, et al. Mother-to-child transmission risk is increased among HIV-infected pregnant women in Ukraine with serological test results positive for syphilis. Clinical Infectious Diseases. 2008 Oct 15;47(8):1114-5.

9. Leslie DE, Higgins N, Fairley CK. Dangerous liaisons -- syphilis and HIV in Victoria. Medical Journal of Australia. 2008 Jun 2;188(11):676-7.

10. Buchacz K, Klausner JD, Kerndt PR, et al. HIV incidence among men diagnosed with early syphilis in Atlanta, San Francisco, and Los Angeles, 2004 to 2005. Journal of Acquired Immune Deficiency Syndromes. 2008 Feb 1;47(2):234-40.

11. Peeling RW, Hook EW 3rd. The pathogenesis of syphilis: the Great Mimicker, revisited. Journal of Pathology. 2006 Jan;208(2):224-32.

12. Lukehart SA, Godornes C, Molini BJ, et al. Macrolide resistance in Treponema pallidum in the United States and Ireland. New England Journal of Medicine. 2004 Jul 8;351(2):154-8.

13. Marra CM, Colina AP, Godornes C, et al. Antibiotic selection may contribute to increases in macrolide-resistant Treponema pallidum. Journal of Infectious Diseases. 2006 Dec 15;194(12):1771-3.

14. Morshed MG, Jones HD. Treponema pallidum macrolide resistance in BC. Canadian Medical Association Journal. 2006 Jan 31;174(3):349.