on 29-Feb-2024 (Thu)

Confusion and controversies also arise from the disease’s protracted natural history, which is classically divided into the following stages: (1) an incubation period lasting up to 90 days (average of 3 weeks); (2) a primary stage characterized by an ulcer, the chancre, at the site of inoculation, often associated with regional lymphadenopathy; (3) a florid, disseminated stage (secondary syphilis), typically characterized by generalized skin rash, mucocutaneous lesions, and lymphadenopathy, but capable of involving any organ system, including the central nervous system (CNS); (4) an asymptomatic latent period lasting years, detectable only through reactive serologic tests; and, (5) in approximately one-third of untreated persons, a recrudescent, tertiary stage involving the ascending aorta (cardiovascular syphilis) or the CNS (neurosyphilis) or causing necrotizing granulomatous lesions (gumma) in almost any organ

The debate currently centers around whether venereal syphilis was imported into Europe by shipmates of Christopher Columbus in 1493 or was an established entity that erupted in epidemic form throughout Europe as a consequence of urbanization and social upheaval.15–19 The controversy over these two mutually exclusive theories is fueled by the imprecision and uncertainties inherent in the historical record, radiocarbon dating, and paleopathologic findings believed to represent the signature of treponemal disease in skeletal remains

The discovery of yaws-like treponemes that infect nonhuman primates (NHPs) in Africa29–31 strongly supports another key tenet of the “pre-Colombian” hypothesis as first proposed by Hackett14—that the human treponematoses originated as a zoonosis that spilled over from an NHP reservoir. T. pallidum subsp. pallidum presumably evolved during the subsequent human diaspora from Africa.

Universally agreed on is that an epidemic known as the Great Pox (as distinguished from smallpox) ravaged Europe shortly after the return of Columbus from his first voyage of discovery.4,32

Although it cannot be proved with certainty that T. pallidum was the cause of this scourge, the first clear descriptions of the serious ailment dubbed “the French Disease” by contemporary physicians and chroniclers noted its sexual mode of transmission and traced its origins to the West Indies and members of Colombus’s expedition.4,32 From these primary historical accounts the Colombian hypothesis took root.

During the pandemic of the early 16th century, syphilis in adults manifested as a fulminant, often fatal, illness that progressed rapidly from genital ulceration to gummas. Whether the comparatively mild nature of the present-day ailment reflects a change in the virulence of T. pallidum, an adaptation of the human host, or the disappearance of a concomitantly occurring but unknown illness is an enduring mystery. A remarkable phylogenetic comparison of genomic sequences of geographically widespread T. pallidum strains, many obtained directly from clinical samples, has added to this conundrum.33 This study revealed that all modern-day syphilis spirochetes diverged from a common ancestor less than 500 years ago, a time frame roughly congruent with the explosive emergence of syphilis on the European scene. Variation in outer membrane proteins (OMPs),34 which was not examined by these investigators,33 driven by herd immunity as the spirochete gained traction within European populations35,36 might explain changes in its virulence properties over the ensuing centuries.

One of the difficulties in sorting through medical writings from the 17th and 18th centuries is that unequivocal clinical distinctions between syphilis, gonorrhea, and other venereal diseases did not emerge until the late 18th century. John Hunter’s misguided self- inoculation experiment with urethral pus containing both Neisseria gonorrhoeae and T. p alli dum served only to prolong the misconception that syphilis and gonorrhea are the same disease.4 By the mid-19th century, however, syphilis had been distinguished from gonorrhea and its principal clinical features defined, although not without some erroneous teachings. One prominent example is the dogma of Ricord, the greatest syphilologist of the 19th century, that material from secondary syphilis lesions is noncontagious.4

By 1906, Wa s se r ma n n ha d de v el o p e d h i s c om p le m e nt fixation test using an extract from the liver of a syphilitic stillborn baby. Subsequently, it was shown that extracts from uninfected beef livers and hearts were equally sensitive and that a phospholipid extracted from beef heart (cardiolipin) repro- duced the Wassermann reaction when mixed with lecithin and cholesterol.

In 1910, Ehrlich introduced his 606th arsenic preparation, arsphenamine or salvarsan, for syphilotherapy, hailed at the time as “the magic bullet.”

In 1912, Nichols and Hough37 used rabbit inoculation to isolate the organism from the cerebrospinal fluid (CSF) of a patient who developed neurosyphilis after salvarsan therapy for secondary syphilis. In addition to being the first demonstration of early CNS invasion by T. pallidum, their findings suggested that the CNS may serve as a sanctuary for the spirochete during inadequate therapy of early syphilis, a concern to this day.38 Also noteworthy is that the “Nichols” isolate became the reference laboratory strain of T. pallidum and was the source of DNA for the T. pallidum genome sequencing project.39 Of note, another interesting observation from genomic sequencing is that the phylogenetic cluster (clade) containing the Nichols strain greatly diminished in prevalence during the latter part of the 20th century and is being replaced by a second clade represented by the high-level erythromycin-resistant street-strain 14 (SS14).12,33,40

In 1943, John Mahoney of the US Public Health Service treated the first syphilis patients with penicillin,42 the true magic bullet, work that won him the Lasker Award in 1947. Not surprisingly, syphilis rates plummeted over the next decade

Despite alarming comebacks, most notably the “drugs for sex” cocaine-fueled epidemic of the late 1980s to early 1990s43 and the substantial upswing in cases among men who have sex with men (MSM) beginning in the late 1990s,44 syphilis rates have never approached pre–World War II levels

In an effort to better understand the natural history of syphilis, from 1932 to 1972 the US Public Health Service conducted the “Tuskegee Study of Untreated Syphilis in the Negro Male” in which 412 indigent African-American men with latent syphilis in rural Macon County, Alabama were followed without treatment along with 192 black males without serologic evidence of syphilis.45,46 The revelation 4 decades after the study’s inception that treatment had been withheld for years despite the proven efficacy of penicillin sparked outrage and charges of abuse of authority and racial exploitation on the part of the US government and the medical profession.47

Susan Reverby, a Wellesley College historian investigating Dr. John Cutler, one of the physicians involved in the implementation of the Tuskegee Study, inadvertently discovered that from 1946 to 1948 the US Public Health Service conducted studies in Guatemala in which male prisoners were unknowingly inoculated with T. pa llidum and allowed to transmit syphilis to their sexual partners as part of a plan to evaluate prophylactic treatment regimens. Among the many disturbing revelations was that Parran had approved funding for the studies and appears to have followed their progress.

The causal agent of venereal syphilis is T. pallidum subsp. pallidum, which belongs to the order Spirochaetales, the family Spirochaetaceae, and the genus Treponema.

Other members of the genus Treponema that can infect humans are T. pallidum subsp. pertenue (yaws), T. pallidum subsp. endemicum (bejel or endemic syphilis), and Treponema carateum (pinta)

In addition to the pathogenic spirochetes, commensal treponemes have been isolated from humans, particularly from the oral cavity and the prepuce of uncircumcised men, and they have been identified by amplification of 16S ribosomal RNA genes from the gut microbiomes of hunter-gatherer and traditional agrarian populations.51,52

ll four pathogenic treponemes are morphologically indistinguishable and induce antibodies detected with the routine serologic tests used to diagnose venereal syphilis.7,58 In clinical situations, distinction among the corresponding infections rests on geography, clinical manifestations, patient age, and other demographic features.7,58 Of the four pathogens, only T. pallidum subsp. pallidum is transmitted routinely by sexual contact.59 Because the other three are transmitted nonsexually, the diseases they cause are collectively referred to as the endemic or nonvenereal treponematoses.58

A relatively small number of nucleotide differences in the T. palli dum subsp. pallidum and pertenue genomes, which are 99.8% identical, appear to be responsible for profound differences in tissue tropisms and clinical manifestations.61,62

T. pallidum is approximately 0.2 μm in diameter, has tapering ends, and ranges in length from 6 to 20 μm (Fig. 237.1)

T. pall id um is often described as gram negative. In addition to this description being erroneous from a phylogenetic standpoint,72 the syphilis spirochete lacks the genes for synthesis of lipopolysaccharide (LPS),39 the hallmark glycolipid of gram-negative organisms, and does not take up Gram stain

For many years, it was believed that T. pallidum possesses a coat of serum proteins and mucopolysaccharides that shields it from the host’s immune system.78 It is now widely accepted that the paucity of proteins and pathogen-associated molecular patterns (PAMPs) on the spirochetal surface is the basis for the bacterium’s impressive capacity for immune evasion, which has earned for it the name “stealth pathogen.”34,73,79

The genomes of pathogenic treponemes consist of single circular chromosomes of approximately 1.1 MB,39 near the low end of the spectrum for eubacteria and only half the size of the genomes of oral treponemes.80,81 The absence of plasmids, pathogenicity islands, transpos- able elements, and restriction-modification systems indicates that the organism has limited capacity for uptake of exogenous DNA, perhaps explaining why it has remained exquisitely sensitive to penicillin for more than 7 decades.

T. pallidum subsp. pallidum replicates slowly (doubling time of approximately 30 hours in rabbits)82 and poorly tolerates desiccation, elevated temperatures, and high oxygen tensions.83

A meta-analysis of global typing studies reported the existence of at least 57 subtypes, with wide variation in geographic distribution, although a small number of subtypes predominate overall.86