Syphilis: A Giant Pox on Humanity

(Written for my clinical microbiology class, April 2008.)

Syphilis, the human disease caused by the bacterial pathogen Treponema pallidum pallidum, is one of the best known and, at one time, one of the most prevalent sexually-transmitted diseases (STD) to afflict the human race.

A short history of T. pallidum pallidum as a human pathogen

Syphilis came to Europe from the Americas with sailors under the Genoese explorer Christoffo Corombo (Christopher Columbus) in the late 15^th century. The disease first exploded into the conscious of the European populace with the epidemic of syphilis which struck the army of Charles VIII of France as it invaded Italy in 1495 and ultimately caused its collapse.

At its initial appearance, syphilis had much greater mortality and morbidity than the version we are familiar with today, with the course of the disease from inoculation to death being a few weeks or months rather than years, and it was likely spread by other than just sexual contact. The papules (boils) were much larger and when they became pustules (open, oozing sores) exuded a stinking puss whose smell was nearly intolerable.

The disease was so dreaded, in fact, that the name “smallpox” was given to the viral disease (caused by Variola spp.) to distinguish it from the “great pox”. Within five to seven years, however, the virulence of the disease had greatly modified to approximately what we see today, perhaps as a function of evolutionary survival. The reduction of its morbidity to the individual, however, had little to do with the speed of its spread, and by 1512, it was reported in Japan.

At the turn of the 20^th century, syphilis was by far the most reported of all sexually-transmitted diseases. However, with the advent of the use of penicillin to treat syphilis (and gonorrhea), beginning with American servicemen during the Second World War, the rate of syphilis infection across the population began to decline drastically.

With nominal periods in the rise and fall of the rates of T. pallidum pallidum infection, the number of cases of primary and secondary stage (P&S) syphilis reported to the Centers for Disease Control and Prevention (CDC) fell to just 37,000 in 2000, the all-time low. By contrast, the number of cases for some other STD’s were as follows: trichomoniasis, 7.4 million; human pampilloma virus (HPV), 6.2 million; chlamydia, 2.8 million; herpes simplex virus 2 (HPV2), 1.6 million; and gonorrhea (GC), 718,000.

After noticing that how low the rate was becoming in the late 1990’s, the CDC began to see the possibility of eradicating the disease from the United States entirely and established the Syphilis Elimination Effort (SEE) in 1999, revising its plan in 2006. The CDC’s Healthy People objection for 2010 with regards to syphilis is 0.2 cases per 100,000 people.

The number of P&S syphilis cases in Georgia for 2008 was 914, or 9.6 out of 100,000 persons. The number of P&S syphilis cases in Tennessee for 2008 was 413, or 6.7 out of 100,000 persons. With the national average at 4.5 cases per 100,000 persons, that meant the two states ranked 4^th and 6^th respectively.

The two population groups most effected by syphilis infection today are those of the South, and of men who have sex with men (MSM), particularly high risk (no prophylaxis) sex.

The pathogenic agent

As mentioned above, the pathogen which causes syphilis in humans is the bacterium Treponema pallidum pallidum.

T. pallidum pallidum is a spirochete, or spiral-shaped bacillus, that is highly fastidious, very motile with endoflagella, and microaerophilic, and which cannot be cultured in vitro in the lab. It has the ability to coat itself with the hosts proteins to protect itself against the immune system and can attach to endothelial cells such as those that line the walls of blood vessels.

T. pallidum pallidum is one of three subspecies of the genus Treponema which cause human diseases, the other two being T. pallidum pertenue, which causes yaws, and T. pallidum endemicum, which causes bejel. A fourth microbe of this genus, Treponema carateum, is a separate species which causes the disease pinta.

The course of the disease

Untreated syphilis progresses through three stages in the human host, with one and sometimes two (or more) periods of latency. In addition, neurosyphilis, the invasion of the central nervous system (CNS) by the pathogen, can take place at any stage of the disease, including the primary stage.

Infection takes place by one of two routes: the organism enters the host either through visible or microscopic abrasions in the skin or mucous membrane during sexual intercourse, or transplacentally from mother to fetus. In just a few hours after the inoculation, the organism spreads to the lymph nodes by way of the lymphatic system, then from there throughout the entire body via the blood system.

In the primary stage, the main symptom is a chancre that appears at the site of the inoculation, beginning as a large, raised papule and progressing to an ulcerated pustule, which is usually painless. In about a quarter of the cases, multiple chancres appear. The chancre(s) can mimic the appearance of genital herpes or of chancroid. Primary stage syphilis lasts one to six weeks and is highly contagious throughout.

In the secondary stage, lesions spread over the body in several forms of rash, in particular on the soles of the feet and the palms of the hands, in nearly all hosts. From half to three-quarters experience lymphadenopathy. Malaise is common at this stage. Up to a third of hosts get mucous patches. Candylomata lata (moist, wart-like papules) are another possible symptom at this stage, concentrating in the host’s gluteal folds, perineum, and perianal area, and these are highly infectious. Hair loss, or alopecia, can happen at this stage also, as well as liver and kidney involvement and splenomegaly.

Latency, or the period in which no symptoms show and the disease is uninfectitious, is categorized as either early or late depending on how much time has passed since the inoculation occurred. If less than a year, it is dubbed early latency, if equal to or greater than a year, it is dubbed late latency.

In the tertiary stage, occurring from one to twenty years after first inoculation without treatment, gummatous lesions, or granuloma, appear on the skeleton, spine, mucosal areas, eyes, lungs, stomach, heart, liver, genitals, breasts, and/or brain. These granuloma can mimic carcinoma.  Cardiovascular symptoms can appear after ten to fifteen years. Lesions on the aortic vasovasorum are possible after twenty to thirty years. Without treatment, physical disfigurement, blindness, and death can occur.

As mentioned above, neurosyphilis can occur at any stage of the disease. Early neurosyphilis can manifest as acute syphilitic meningitis, basilar meningitis, or meningovascular meningitis. Late neurosyphilis is rare, and is characterized by paralysis and severe balance and motor control problems resulting from the destruction of the dorsal columns of the spinal cord.

Early congenital syphilis manifests with lesions on the skin or mucous membrane which are usually inflamed. The patient can suffer a variety of symptoms such as alopecia, lymphadenopathy, meningitis, oteitis, osteochondritis, and hepatosplenomagaly.

Hematological symptoms include thrombocytopenia and anemia. Late congenital syphilis includes immunological and more destructive symptoms, with interstitial keratitis common and bond and teeth involvement possible but not common.

In the clinical medical laboratory (CML)

In primary stage syphilis, diagnosis is made through a combination of identification of the physicals symptoms (i.e., the chancre) and of the T. pallidum spirochete on dark field microscopy. Since syphilis chancres can mimic theirs, the patient should also be screened for Haemophilus ducreyi and Herpes simplex virus (HSV) 2.

In the secondary and tertiary stages, the most common initial screening tests are the Rapid Plasma Reagent (RPR) and the Venereal Disease Research Laboratory (VDRL) tests. Since these two tests are nonspecific, however, they should be followed up with more specific tests such as the Treponema pallidum hemagglutination assay (TPHA) and the fluorescent treponemal antibody absorption (FTA-ABS) test. Even these can give a false positive for other Treponema species, but the physician would diagnose based on both the tests and the patient’s symptoms. The enzyme-linked immunosorbent assay (EIA) is another more specific test that can be used to test for T. pallidum.

The only sure method for distinguishing T. pallidum pallidum from its sister subspecies is through restriction fragment length polymorphism (RFLP) analysis of polymerase chain reaction (PCR) amplified specimens; there is a single difference in the genetic code.

Cerebral-spinal fluid (CSF) should be tested if neurological or opthamalic symptoms are present, there is evidence of active tertiary symptoms, treatment is failing, of HIV infection.

Treatment

Unlike gonorrhea (GC), syphilis remains highly susceptible to penicillin, the usual form used being benzathins penicillin G. The preferred alternatives for those allegic to penicillin are doxycycline and tetracycline; previously erythromycin was used as an alternative but no longer.

BIBLIOGRAPHY

http://www2a.cdc.gov/STDTraining/Self-Study/syphilis.asp. Self-Study STD Module – Syphilis. Centers for Disease Control and Prevention, Atlanta, Georgia.

Engelkirk, Paul G., and Janet Duben-Englekirk. Laboratory Diagnosis of Infectious Diseases, pp. 374-376. (Baltimore: Lippincott Williams & Wilkins, 2008).

Gladwin, Mark, and Bill Trattler. Clinical Microbiology made ridiculously simple, Edition 4. (Miami: MedMaster, Inc., 2008).

Quetel, Claude, transl. by Judith Braddock and Brian Pike. History of Syphilis. (Baltimore: John Hopkins University Press, 1990).

Zuk, Marlene. “A Great Pox’s Greatest Feat: Staying Alive”. New York Times.