Syphilis in the AIDS Era: Diagnostic Dilemma and Therapeutic Challenge (co-authored with John...

SYPHILIS IN THE AIDS ERA:

DIAGNOSTIC DILEMMA AND THERAPEUTIC

CHALLENGE

JOHN B. SCYTHES* and COLMAN M. JONES

Community Initiative for AIDS Research, Toronto, Canada

(Received: 8 April 2013; accepted: 20 April 2013)

This review argues that syphilis has been underdiagnosed and undertreated, a

problem that goes back to the beginning of the Wassermann era, and indeed long be-

fore. Non-treponemal tests do not detect the larger pool of persons with latent syphilis,

the immunological consequences of which have not been systematically investigated

in the context of HIV infection and progression to AIDS. Recent efforts to confirm the

prevalence of syphilis in high-risk patients by reverse sequence screening, i.e. using a

treponemal test first, as the screening test, have revealed untreated syphilis at higher

rates than expected. Further testing using PCR discovered even more previously unde-

tected cases. We suggest that latent syphilis is a chronic active immunological condi-

tion that drives the AIDS process and cannot be managed with the older Wasser-

mann-based algorithm, and that non-treponemal tests have failed to associate syphilis

with immune suppression since this screening concept was developed in 1906. In light

of the overwhelming association between a past history of syphilis and HIV sero-

conversion, more sensitive tools, including recombinant antigen-based immunologi-

cal tests and direct detection (PCR) technology, are needed to adequately assess the

role of latent syphilis in persons with HIV/AIDS. Repeating older syphilis reino-

culation studies may help establish a successful animal model for AIDS, and resolve

many paradoxes in HIV science.

Keywords: syphilis, diagnosis, treatment, etiology, Treponema pallidum, hu-

man immunodeficiency virus, acquired immune deficiency syndrome

1217-8950/$20.00 © 2013 Akadémiai Kiadó, Budapest

Acta Microbiologica et Immunologica Hungarica, 60 (2), pp. 93–116 (2013)DOI: 10.1556/AMicr.60.2013.2.2

* Corresponding author; E-mail: [email protected]

Introduction

“Know syphilis in all its manifestations and relations, and all other things

clinical will be added unto you.” Back at the turn of the 20th century, when Sir

William Osler taught this to his students at Johns Hopkins University, he would

have never guessed that a century later, the age-old disease known as the Great Im-

itator would be displaced by a new mysterious virus. HIV, wrote two modern-day

neurologists in 1992, “has replaced syphilis as the ‘great masquerader’” [1]. In-

deed, HIV research has usurped the lion’s share of research funding in the STD

field, syphilis being relegated to the sidelines. However this might turn out to be a

serious mistake, given the many unanswered questions about syphilis manage-

ment and AIDS etiology.

The sexual revolution: Syphilis out of control

In the two decades leading up to the modern AIDS epidemic, authors in the

United Kingdom reported that most syphilis in homosexual men was not being de-

tected, other than the classical early presentations [2–5]. Most exposed patients

were not traced as a result of a failure of public health measures, despite the best

efforts of patient activists and public health workers. Authors in the U.S. made

similar observations: while over 80% of syphilis cases were treated by private

physicians, these physicians only reported 12% of these cases for proper control

measures [6].

It is often assumed that happenstance therapy took care of these cases.

While antibiotics were dispensed (for other indications) to latent syphilitics, incu-

bating syphilitics, and persons with syphilis of unknown duration, there is no em-

pirical evidence that this was a useful therapeutic measure for syphilis control [7].

In fact, by 1980 most experienced authorities in syphilis control were of the opin-

ion that under-treatment was far worse than no treatment at all, and induced la-

tency. Hungarian investigators use the phrase ‘decapitated syphilis’ to describe

this unfortunate outcome.

“Far from eradicating syphilis,” wrote one California urologist in 1970,

“antibiotics are driving the disease underground and increasing the difficulty of

detection. Although the incidence of disease has more than tripled since 1955, the

chancre and secondary rash no longer are commonly seen. Undoubtedly, some of

these lesions are being suppressed and the disease masked by the indiscriminate

use of antibiotics. The ominous prospect of a widespread resurgence of the dis-

Acta Microbiologica et Immunologica Hungarica 60, 2013

94 SCYTHES and JONES

ease in its tertiary forms looms ahead” [8]. Yet, despite reliable estimates of some

325,000 cases of untreated syphilis in the U.S. in 1981 [9], this “widespread resur-

gence of the disease in its tertiary forms” never appeared to materialize.

Is HIV just an opportunistic infection arising from latent syphilis?

There is a strong epidemiological association between a past history of

syphilis and HIV/AIDS, with odds ratios between 20 and over 100 when control-

ling for HIV [10–19]. Some studies have found that syphilis is more highly corre-

lated with HIV seroconversion than the absolute number of sexual partners or type

of sexual activity [20–22]. This association was documented yet again in a recent

study that found that men who have sex with men have a 140-fold higher risk for

newly diagnosed HIV and syphilis compared with heterosexual men in New York

City [23]. Despite these alarming rates of syphilis among HIV-infected popula-

tions [24, 25], no AIDS patient has ever been documented as having died from

complications of syphilis.

It is striking that, despite sincere efforts, very capable modern investigators

have been unable to find any significant influence of HIV infection, even

full-blown AIDS, on the clinical presentation of syphilis [26–30] or the response

to therapy [31–37].

One would have quite rightly expected a large effect, and these repeated ob-

servations remain unexplained [38]. Indeed, one of these authors has questioned

whether HIV impacts syphilis at all [39].

Investigators at St. Paul’s Hospital in Vancouver have suggested [40] that

HIV expression may be epiphenomenal (“opportunistic” to use their word choice)

as a result of underlying immunological injury from other unidentified causes in

their high risk gay male cohort. Other investigators have argued along the same

lines [41–50]. Syphilis leads to nodal B-cell follicle hyperplasia that is indistin-

guishable from the nodes seen in advancing HIV disease, except as regards the se-

verity in the progressing HIV cases [51, 52], and results in immuno-regulation

against CMI and over-expression of the Th2 phenotype. IL-2 and IL-12 are sup-

pressed, and IL-6 and IL-10 increase – a hallmark of AIDS immunology – as syph-

ilis remains untreated over time in both experimental and human subjects [53–65].

The great masquerader may indeed continue to elude us.

The paradox that HIV has no seeming impact on the course of syphilis, or

the response to therapy, suggests that syphilis has often re-infected people silently,

due to the failure of immunological memory, and that advanced HIV cases are al-


SYPHILIS IN THE AIDS ERA 95

ready latent syphilitics. The occasional presentations of multiple primaries, over-

lapping stages, high antibody titers and precocious tertiarism among today’s HIV

cases are all old (i.e. pre-AIDS) phenomena, and are collectively best explained by

immunological priming and a different treponemal strain. This is likely what hap-

pened when Columbus returned to a ‘syphilized’ Europe.

The precedent of syphilization

The historical concept of syphilization, a term coined in mid-19th century

by the French researchers Philip Ricord and Joseph-Alexandre Auzias-Touraine

and expanded on by many others [66], provides a possible explanation for why we

do not see syphilis behaving opportunistically in AIDS today. Syphilization was

based on the idea that there would be symptomatic relief by inoculating syphilis

patients with exudates from other syphilitics, exudates presumed to contain the re-

sponsible substance. Caesar Boeck, an Oslo-based dermatologist, expanded on

this work between 1890 and 1910, by leaving syphilis untreated among his pa-

tients. He believed the treatments of the time were of little value, and that it was

better for patients to become syphilized, as opposed to interrupting the develop-

ment of immunity with inadequate treatment. This work became the basis for the

Oslo study of untreated syphilis [67–70].

Syphilization appeared to work, as the patients rarely developed further late

manifestations [71, 72]. However, according to the Oslo study [73], and various

reviews from that era [74–78], including actuarial reports [79–81], conditions

such as reactivation TB, cancer, and pneumonia dispatched many of these pa-

tients, and most of the latent syphilis cases were missed anyway.

Prostitutes were rarely maimed by syphilis, oddly enough, despite living in

an era when syphilis was everywhere in Western society – otherwise the brothels

would have simply shut down for lack of business. The best explanation, looking

back in retrospect, is that these commercial sex workers were syphilized [82]

(much like may be the case with multi-partner gay men today).

Pre-1960 authors were studying repeated exposures to Treponema palli-

dum without understanding the outcome for either experimental animal or human

subjects. Albert Neisser was undoubtedly correct when he stated that the essential

relationship between T. pallidum and humankind is an “infection immunity” pro-

cess, and that chancre immunity is false immunity.

The famous American syphilologist Evan W. Thomas wrote in 1949,

“Within 2 years after infection, untreated syphilis produces immune changes in



the host which, with rare exceptions, are permanent and make it impossible for tis-

sues to react to subsequent infection with development of early syphilitic lesions”

[83].

Once a person is syphilized, i.e. not responding clinically to further syphi-

lis, neither the various preparations based on Paul Erlich’s original 606, nor peni-

cillin (a presumably superior treatment) could reverse this immunological pattern

of unresponsiveness, even if treatment appeared to have killed most of the

treponemes [84–87].

It is entirely possible that an acquired immune deficiency syndrome –

AIDS – was in fact the outcome of these repeated exposures to T. pallidum, and the

available experimental evidence [88–92] suggests that a successful animal model

for AIDS can finally be created – without HIV – in the syphilitic rabbit, guinea

pig, mouse or primate, given the correct timing and frequency of exposures.

AIDS: A hidden history ignored by modern popular science

In the first half of the 20th century, long before the discovery of HIV, most

of the opportunistic infections associated with AIDS today were well-documented

in inner-city American hospitals [93–95]. Reactivation TB, reactivation pneumo-

cystis, and unmanageable fungal, herpetic and papilloma infections together

killed or disabled tens of thousands of people in mid-life before 1950. Acquired

immune deficiency, not primary immunodeficiencies, is the only possible expla-

nation.

Today’s advocates of AIDS as a novel syndrome commonly cite as proof

the paucity of fatal pneumocystis or fatal Kaposi’s sarcoma in adults before 1960.

But this is easily explained by the TB wasting/consumption among what were

largely midlife male and previously healthy persons, long before they became sick

enough to succumb to the infections now understood as AIDS-defining today.

Also, curious was the significant male-to-female ratio among cachectic and

terminal reactivation TB patients at that time [96, 97]. Even more mysterious was

how susceptibility to reactivation TB could be sexually transmitted, a phenome-

non that was investigated at the Mayo Clinic before 1960 [98], and strangely mir-

roring the sexual transmission of AIDS today. Arnold R Rich and Ira Leo

Schamberg were likely mistaken when they dismissed syphilis as a contributing

factor to this susceptibility to reactivation TB [99, 100].

Bernhard Dattner, working in his syphilis clinic at the Vienna General Hos-

pital just before World War II, demonstrated profound immune suppression with



negative TB skin tests in over 80% of his syphilitic patients, while over 80% of

general hospital admissions were TB skin test positive [101]. Croton oil testing

was also negative in these patients, as is also found in AIDS patients using modern

T-cell mitogens. The cutaneous anergy observed in these syphilitic patients meant

they had no Gell and Coombs type IV recall (i.e. no delayed-type hypersensitivity

– DTH), therefore no T-help – in other words, AIDS.

According to William Kirby, author of the TB chapter in the second edition

of Principles of Internal Medicine, by 1950 about 0.3% of TB-infected persons

had active disease – about 400,000 cases at that time among about 120 million in-

fected Americans. He concluded that TB mortality had dropped about tenfold

since 1900. This had little to do with the just-introduced triple drug therapies for

TB, but was instead likely due to the aggressive control of syphilis in the first half

of the 20th century.

While infant AIDS is also assumed to be a new phenomenon, tens of thou-

sands of infant deaths from pneumocystis and cytomegalic inclusion body pneu-

monitis (called CMV in the lungs today) were reported in papers published in the

1950s [102, 103], with hundreds of references. Syphilis was likely working be-

hind the scenes here as well, damaging the immune systems of tens of thousands

of women of child-bearing age before 1960, with all these resulting AIDS babies.

Given that AIDS is not a new phenomenon, the conspicuous absence of op-

portunistic and/or fatal complications of classical late syphilis in AIDS raises

questions over whether our current understanding of these diseases is correct.

Clinical latency vs. immunity

Standard teaching suggests that latent syphilis is inactive syphilis, and

therefore poses little danger, other than the 2 to 5 percent who may develop ful-

minant destructive stages. However, the exact translation of the Latin verb latere is

“to lie hidden” and this was what pre-penicillin authors meant – there was never an

implication that latent syphilis was somehow under control. If that were indeed the

case, one would expect to see a tuberculin-like DTH reaction to syphilis antigens

among most patients with latent disease, as found with tuberculin for TB, and with

antigens of endemic fungi, etc. This is the reaction that the older authors before

World War Two were researching with their syphilis skin test studies.

However, unlike many other diseases where skin testing has helped estab-

lish prevalence and therefore our understanding of the natural immunity to the in-

fection, skin tests developed for syphilis consistently lacked sensitivity, and were



therefore abandoned [104, 105]. Today, researchers look for this DTH reaction in

syphilis vaccine studies, and find it inconsistently [106]. Experimental studies

have only raised further questions about the reliability of immunological memory

in syphilis [107–112].

The origin of the word immunity is immunitas in Latin, which translates

best as “exemption from”, and was never intended to represent only clinical im-

munity, i.e. Wassermann immunity, but instead true biological immunity or resis-

tance (DTH). Indeed, experts from the New York State Laboratories clearly state,

“There is no natural immunity to syphilis, and past infection offers no protection”

[113].

Re-interpreting the history of syphilis

The recent discovery of a larger than expected pool of latent syphilis in

high-risk cohorts, as outlined in this review, has considerable implications for in-

terpreting the classic historical studies of the natural history of syphilis such as

Oslo and Tuskegee [114]. J. Arthur Myers from the Mayo Clinic, made these very

relevant comments in 1965, 15 years after the widespread use of penicillin began,

and 10 years after the final Oslo report:

“Unless the natural history of a lifetime disease is known, it is impossible to determine

with accuracy the effectiveness or ineffectiveness of any therapeutic or preventive mea-

sure. Therefore, in a program designed to eradicate a disease it is essential to know the

course it takes among people in the absence of specific treatment.

Tuberculosis and syphilis run somewhat parallel courses in that each one begins with pri-

mary lesions which usually subside without causing serious illness or much destruction of

tissues. Dependable immunity does not develop. In both tuberculosis and syphilis,

chronic forms of the disease usually do not appear until years and even decades after the

initial infection.

When seemingly effective drugs became available for treatment of syphilis, attention was

called to the absence of a well-documented study on the natural history of untreated syph-

ilis. Therefore, the immediate and remote prognosis in untreated cases was not known”

[115].

Syphilis is like an iceberg: Most of an iceberg lies under the surface – it just might

be this serious with respect to syphilis detection and non-treponemal tests. Con-

sidering there was no affordable and generally applicable treponemal test during

the years that the Olso and Tuskegee studies were conducted, our understanding of

syphilis from these studies is fundamentally flawed.



Judging from more recent serological and molecular findings detailed be-

low, the prevalence of latent syphilis (and its consequences) appears to have gone

largely undocumented. J. Earle Moore may have been correct when he postulated:

“In spite of 400 years of study, we still do not know the actual importance of syphilis as a

cause of death. To what extent does death directly from syphilis masquerade under other

diagnoses: or to what extent is syphilis an indirect cause of death from other conditions?

Is it justifiable to assume, as did Osler, that syphilis actually ranks first, instead of its ap-

parent tenth, among killing infections?” [116]

Support for Moore’s suspicions were clear from his colleague, Frank W. Reynolds

at the “Medicine One” syphilis clinic at the Johns Hopkins Hospital in Baltimore.

Reynolds pointed out that “all anatomic evidence of infection may disappear, so

that, at necropsy, when the patient finally dies from some other cause, all evidence

of syphilis is conspicuous by its absence” [117].

In Moore’s and Reynold’s day, only the Wassermann-positive patients, re-

sponding immunologically in the non-treponemal tests, were followed for the pur-

poses of analyzing morbidity and mortality. The latent cases were left to die either

in the TB sanitoria or more commonly at home.

Wassermann’s discovery – and its pitfalls

Wassermann’s initial screening test from 1906 used a non-syphilitic anti-

gen (connective tissue-based) in various ways, and formed the basis of non-trepo-

nemal testing, with subsequent refinements, the better known including those by

John A. Kolmer in 1922, Reuben Kahn in 1923, William Augustus Hinton in

1934, and Harry Eagle in 1937. If one of these older Wassermann-type tests was

positive, in the absence of signs or symptoms, or a positive darkfield, this finding

defined a case of latent syphilis, and treatment was aggressively offered.

However, a large body of experimental evidence suggests this first genera-

tion of syphilis immunological tests missed most latent cases. In 1936, an astute

American observer in Boston noted that non-treponemal tests did not react when

T. pallidum was applied to mucosal surfaces of experimental animals [118], prov-

ing the existence of latent syphilis in the absence of a screening test response. The

implications of these findings for congenital syphilis and for AIDS remain un-

known.

It was also well recognized as far back as the 1930s that the syphilitic

mouse is 100% screen test negative, but infectious when mouse brain emulsions

were inoculated into New Zealand white rabbits [119, 120], raising questions over



the altered propagative or survival forms of T. pallidum [121, 122]. A half century

later, at the National Dermatology Institute in Budapest (OBNI), the syphilis labo-

ratory director proved that all his mice were FTA-Abs positive, but negative in the

modern non-treponemal tests (RPR/VDRL) [123]. So here is an animal model that

is 100% screen test negative, and therefore a latent model from the start.

Another famous investigator immunized rabbits over a 37-week period,

and the animals were resistant to substantial inoculums [124]. But 8 out of 11 of

these rabbits had no antibody in any immunological test, treponemal or non-trepo-

nemal. This raises serious questions about the role of antibodies in protection

against syphilis.

Given all these animal findings, it remains unclear why serologic tests –

based only on part of an immune response – continue to be trusted in humans

[125]. And indeed, one CDC expert has commented that the non-treponemal tests,

if introduced today, would never be licensed for screening [126]. RPR/VDRL

tests are only 100% reactive in the first instance of secondary syphilis. They do not

react anamnestically (i.e. there is no booster effect) in re-exposed patients with la-

tent disease, nor do the tests react in over a third of early (infectious) relapsing pa-

tients [127].

Therefore, all through the 1960s and 1970s, when physicians relied on

non-treponemal tests, they significantly underestimated the true prevalence of the

disease in all its stages. Up to half of latent syphilitics eventually become negative

in non-treponemal tests without treatment, as is taught in regular STD training

[128]. Accordingly, the lack of sensitivity of the non-treponemal tests strongly ar-

gues against estimating syphilis morbidity and mortality on the basis of a non-tre-

ponemal management algorithm.

An added layer of sensitivity: Treponemal tests in the AIDS era

Treponemal tests use T. pallidum proteins, either whole or ground-up tre-

ponemes derived from rabbit syphilomas (e.g. TPI, FTA-Abs, MHA-Tp/TPPA).

With the advent of these earlier treponemal tests – initially used only for confirm-

ing Wassermann positive results – the definition of latency began to expand and

include persons with positive treponemal tests only; the T. pallidum immobiliza-

tion test (TPI) in 1949 solved many clinical dilemmas.

A generation later, as an apparently new syndrome grabbed the STD lime-

light, some experts were not so sure all was well with the old disease. Following

up on studies in the mid-1980s from Europe [129] and the U.S. [130, 131], a group



of suspicious laboratory workers and curious physicians in Toronto began pro-

spective studies using non-treponemal and treponemal serological tests simulta-

neously in high-risk persons, including in HIV clinics [132–134]. This repre-

sented the first university-based use of reverse sequence screening on high-risk

patients in North America, using the FTA-Abs and MHA-Tp (quantified) as

screening tests, instead of VDRL/RPR.

The public health laboratory for Ontario (OPHL) documented a presence of

treponemal antibody up to 5 times the number of cases picked up by RPR or

VDRL screening [135]. In Vienna, similar observations have been made [136,

137], although the prevalence of treponemal reactions was only about twice the

RPR rate, because the study included hundreds of thousand of samples from all of

Austria, not just the capital region.

After these sequential screening results began to accumulate over a few

years, the Toronto HIV clinicians involved in the syphilis detection project [138]

and others [139–142] noted dropping titers and/or reversion to negative in

treponemal tests among those with HIV. This loss of antibody, observed over a

relatively brief window, was not as a result of specific syphilis treatment, and the

OPHL found it to be independent of antibody responses to other infections. This

selective antibody loss during polyclonal B-cell activation has not only been doc-

umented among AIDS patients, but also in HIV cases who are relatively

immunocompetent [143], and has only further limited the assessment of syphilis

in HIV(+) persons [144], and its possible contribution to the AIDS process [145,

146]. The best explanation for this observation is an upregulation of the trepo-

nemal infection, i.e. a re-infection or a relapse.

After following the patients over time, the Toronto group began to note that

this loss of treponemal antibody was correlated with more advanced immune sup-

pression, with average cell counts of 78 CD4/mm3 among sero-reverters, com-

pared to an average CD4 count of 400/mm3 among all HIV clinic patients [147]. In

fact, what the group uncovered was an inverse relationship between AIDS and

positive treponemal tests. In an effort to help these patients, many were aggres-

sively treated as for late latency, and surprisingly, some even began to make

treponemal antibody again, at the test cutoffs back then [148]. While this treat-

ment regime did not resolve AIDS for these men, it certainly encouraged investi-

gators to continue to improve the sensitivity of the immunological tests, without

sacrificing specificity.



Modern advances in diagnostic technology

As T. pallidum cannot reliably be grown on any laboratory culture medium,

recombinant technology to produce purified treponemal antigens has been applied

to syphilis serodiagnosis since the early 1990s [149]. These newer, treponemal

tests have much better specificity than the older treponemal tests discussed above

[150], and therefore offer increased sensitivity. One of these tests, the TrepChek,

developed by Robert H Notenboom at Phoenix BioTech Corp, was used in a

downtown Toronto STD clinic, and confirmed his earlier observation that approx-

imately 5 times as many patients had been exposed to syphilis as had ever been

treated [151]. OPHL finally began screening with the recombinant-antigen based

Abbott Architect treponemal test in 2008. Other reference labs and managed care

consortiums in the U.S. (Kaiser Permanente) have evaluated and adopted the

TrepSure test, another recombinant antigen-based assay developed by Phoenix

BioTech, for screening. The CDC’s experts have acknowledged the TrepSure is

the best treponemal test developed to date [152], yet this test is not generally de-

ployed in the high-risk patients where it is needed most.

Molecular testing using PCR (CDC’s Multiplex) has only further con-

firmed the problems with non-treponemal tests when used in patients with ulcer-

ative STDs [153]. In the Republic of South Africa, the use of the Multiplex system

confirmed infectious early syphilis with sensitivity of the RPR at only 36% in pa-

tients with genital ulcers [154]. In this study, other co-infections seemed to com-

plicate antigen processing, and many of the lesions did not look like infectious

early syphilis.

PCR screening for T. pallidum DNA in Budapest has revealed latent syphi-

lis in the absence of any reaction in either non-treponemal or treponemal tests at

the standard cut-offs [155–157]. Thirteen out of 183 high-risk STD clinic patients

were syphilis PCR (+), even though 9 out of these 13 had no history of syphilis,

nor had antibody in any standard syphilis test, treponemal or non-treponemal. The

remaining four PCR (+) cases were treated patients who also had positive trepo-

nemal tests, and are likely still latent syphilitics – yet another problem [158].

Yet, when reverse sequence screening or PCR suggests untreated syphilis

in the absence of a reactive non-treponemal test, the results are often disputed by

HIV physicians who do not consider these positive test results to be indicative of

latent syphilis. This means most syphilis patients are not managed appropriately

– i.e. with better antibody tests, or real-time PCR, and possibly more therapy – and

thus remain infected (and potentially infectious).



Doubts over adequate treatment

While the concept of happenstance therapy has been advanced to suggest

that these cases newly discovered by reverse sequence screening were somehow

adequately treated in the past, the available evidence suggests that happenstance

therapy is nothing more than undertreatment, which induces latency as explained.

Few of these patients were ever cured.

Questions remain over whether even the standard penicillin G syphilis

treatment was adequate for latent disease during the 1960s and 1970s, as the syn-

drome now called AIDS was incubating in these STD core groups. In 1963, the

chief of the Venereal Disease Division of the Communicable Disease Center, Wil-

liam J. Brown, standardized the 2.4 mega IM penG therapy for all early syphilis,

including early latent syphilis, over considerable objections [159, 160]. Standard-

izing this regimen, although justified from an economic and logistical perspective

at the time, nonetheless left a substantial subset of patients inadequately treated,

by the arbitrary standard of a 4-fold drop in the RPR/VDRL titre [161–171].

Today, the CDC admits that “definitive criteria for cure or failure have not

been established” [172] and a recent literature review supports this conclusion

[173].

Conclusion

We can only conclude [174, 175], as have others [176–181], that there is a

high level of VDRL/RPR-negative syphilis complicating AIDS cases today. In

1990, leading American investigator and clinician Daniel Musher found that“19

of 36 randomly selected HIV-infected homosexual men (53%) had IgM reactive

with at least six outer membrane proteins of T. pallidum” [182]. IgM detection is

usually a reliable marker for untreated syphilis in HIV-infected patients [183,

184], yet none of these 19 cases were reactive in the RPR/VDRL screen tests. This

led Musher to state that “a substantial proportion of HIV-infected men may have

unrecognized, latent, inadequately treated syphilis. These findings support more

aggressive treatment of T. pallidum infection in this patient population”.

Furthermore, latent syphilis may have been responsible for a far wider

spectrum of clinical conditions than attributed to it. In 1991, Sandra A Larsen,

the former director of the treponemal laboratory at the CDC for many years, ob-

served:



“The clinical manifestations of syphilis, which have taken various forms over the centu-

ries, have now been transformed to mimic the appearance of the opportunistic infections

and cancers that may accompany HIV infection, as well as the clinical symptoms of AIDS

itself” [185].

As a group of clinicians in the UK noted in 2001, “In our enthusiasm to diagnose

primary HIV infection, the clinical similarity to secondary syphilis must be re-

membered and caution taken in interpreting preliminary test results” [186].

Accordingly, it is incumbent on today’s STD and HIV experts to investi-

gate whether clinical conditions currently attributed to HIV infection are in fact

the result of latent syphilis. The study populations are the same today as they were

in the era before penicillin, when syphilis was also concentrated in inner city indi-

viduals at high risk for STDs, and homosexual behavior was for the most part ob-

scured by marriage and fear of reprisal [187].

The syphilis research community and the public health infrastructure per-

sist in believing that Wassermann got it right in 1906. Although one modern au-

thor, Justin Radolf, has referred to T. pallidum as the “stealth pathogen” [188], this

concept is only discussed these days in the context of the organism evading im-

mune recognition, but unfortunately without questioning Wassermann’s non-tre-

ponemal test algorithm.

Radolf, along with Sheila Lukehart, co-edited and contributed to the mod-

ern textbook, Pathogenic Treponema Molecular and Cellular Biology [189].

These experts may have adjusted the history of syphilis so as to exclude a possible

outcome of AIDS in homosexual men repeatedly exposed to syphilis, and instead

blame what appears by all indications to be a neutralized and ancient retrovirus

[190–193].

The immune response to HIV, both cellular and humoural [194–196], ap-

pears to be far more robust than that against syphilis. Although HIV is quantified

using messenger RNA amplification, the viral proteins are conspicously absent in

a standard density gradient. This is in contrast to other acute retroviral infections,

including the SIV animal model in the Old World Rhesus macaque, a model which

bears little in common with HIV in humans [197]. HIV isolation techniques have

been seriously questioned [198], and Luc Montagnier has made it quite clear that

classical viral isolation has not correlated with the mRNA test result. In addition,

the failure of every single vaccine effort continues to confuse most observers, in-

cluding many working in the HIV field itself [199–201]. As Margulis et al. note,

“Robert Gallo characterized the failure of the latest STEP vaccine trial, as a ‘catastro-

phe’. Ronald C. Desrosiers, a molecular geneticist at Harvard University stated that



‘none of the products currently in the pipeline has any reasonable chance of being effec-

tive in field trials’” [181].

Renewed research efforts in syphilis basic science and diagnostic tech-

niques, supported by adequate ongoing funding, are urgently required to shed

light on the unresolved questions about the natural history of syphilis and its man-

agement. In addition to trying to develop an AIDS animal model with T. pallidum

reinoculation studies, the experimental work using PCR [202–206] needs to be

made commercially available for latent syphilis detection and treatment fol-

low-up. This is proving so far to be a significant challenge [207].

Early and aggressive syphilis control will spare many persons from AIDS,

with a fortune in healthcare dollars saved along the way. Syphilis remains the most

dangerous infection in humankind, and will continue to exact a high toll in human

misery and suffering until these fundamental questions are resolved.

Dedication

This paper is dedicated to the memory of Professor Lynn Margulis of the

University of Massachusetts at Amherst, whose work on the interaction of spiro-

chetes and their hosts, and her support and encouragement over the years, proved

invaluable.

Acknowledgement

We gratefully acknowledge the assistance of Robert H Notenboom, direc-

tor for many years of the immunological section of the Ontario Public Health Lab-

oratory, in providing critique and commentary.

References

1. Simpson DM, Olney RK. Peripheral neuropathies associated with human immunodefi-

ciency virus infection. Neurol. Clin. 10, 685–711 (1992).

2. British Co-operative Clinical Group. Homosexuality and venereal disease in the United

Kingdom. A second study. Br. J. Vener. Dis. 56, 6–11 (1980).

3. Morton RS, Harris JRW (eds). Recent Advances in Sexually Transmitted Diseases. London:

Churchill Livingstone, 1975, Part 2, pp. 94–95.



4 Ostrow DG, Sandholzer TA, Felman YM (eds). Sexually Transmitted Diseases in Homo-

sexual Men. New York: Plenum Medical Book, 1983, pp. 39–41, 51–52.

5. Fichtner RR, Aral SO, Blount JH, Zaidi AA, Reynolds GH, Darrow WW. Syphilis in the

United States: 1967–1979. Sex. Transm. Dis. 10, 77–80 (1983).

6. KK Holmes, in Harrison’s Principles of Internal Medicine, 7th edition. New York City:

McGraw-Hill, 1974, pp. 876–887.

7. Steen R, Chersich M, Gerbase A, Neilsen G, Wendland A, Ndowa F, Akl EA, Lo YR, de

Vlas SJ. Periodic presumptive treatment of curable sexually transmitted infections among

sex workers: A systematic review. AIDS 26, 437–445 (2012).

8. Pereyra AJ, Voller RL. A graphic guide for clinical management of latent syphilis. Calif

Med 112, 13–18 (1970).

9. Centers for Disease Control. Sexually Transmitted Diseases Fact Sheet (35th ed.). Publica-

tion No. 81-8195, U.S. Dept. of Health and Human Services, Center for Prevention Ser-

vices, Atlanta, GA, 1981. Cited by Wicher K, Wicher, V. In: Tsieh S (ed.) Sexually Related

Infectious Diseases. New York: Field, Rich & Associates, 1986, p. 15.

10. Messiah A, Rozenbaum W, Vittecoq D, Brunet JB. Possible correlation between exposure

to AIDS risk factors, clinical presentation in AIDS, and subsequent prognosis. Eur. J.

Epidemiol. 5, 336–342 (1989).

11. Berger JR, McCarthy M, Resnick L, Fletcher MA, Klimas N, La Voie L. History of syphilis

as a cofactor for the expression of HIV infection. Int. Conf. AIDS 5, 93 [abstr. M.A.P. 90]

(1989).

12. Rose TP, Ford W, Kerndt P, Mohilef E, Onorato I, Los Angeles County Dept of Health Ser-

vices, CDC. An Association of Syphilis Episodes with HIV in STD Patients in Los Angeles

County. Int. Conf. AIDS 5, 360 [abstr. W.B.P. 53] (1989).

13. Miotti PG, Dallabetta G, Ndovi E, Liomba G, Saah AJ, Chiphangwi J. HIV-1 and pregnant

women: Associated factors, prevalence, estimate of incidence and role in fetal wastage in

Central Africa. AIDS 8, 733–736 (1990).

14. Renzullo PO, McNeil JG, Gardner LI, Brundage JF. Inpatient morbidity among HIV-in-

fected male soldiers prior to their diagnosis of HIV infection. Am. J. Public Health 10,

1280–1284 (1991).

15. Para M, Fass R, Pearl D, Whitacre C. Clinical and laboratory progression of HIV infection is

correlated with history of STD. Int. Conf. AIDS 8, C299 [abstr. PoC 4325] (1992).

16. Horváth I, Banhegyi D, Balazs E, Varkonyi V, Horváth A. Prevalence of syphilis

anamnestic data and seroreactivity in HIV infected homosexual population in Hungary.

Sex. Transm. Dis 21, Suppl. 2, p. S199 [abstr. 321] (1994).

17. Johnson EH, Gilbert D, Lollis C. Characteristics of African-American college students with

HIV/AIDS. J. Natl. Med. Assoc. 86, 931–40 (1994).

18. Persaud NE, Klaskala W, Tewari T, Shultz J, Baum M. Drug use and syphilis. Co-factors for

HIV transmission among commercial sex workers in Guyana. West Indian Med. J. 48,

52–56 (1999).

19. Blocker ME, Levine WC. HIV prevalence in patients with syphilis, United States. Sex.

Transm. Dis. 27, 53–59 (2000).

20. Weber JN, McCreaner A, Berrie E, Wadsworth J, Jeffries DJ, Pinching AJ, Harris JR. Fac-

tors affecting seropositivity to human T cell lymphotropic virus type III (HTLV-III) or

lymphadenopathy associated virus (LAV) and progression of disease in sexual partners of

patients with AIDS. Genitourin. Med. 62, 177–180 (1986).



21. Veuqelers PJ, van Zessen G, Sandfort TG, Coutinho RA, van Griensven GJ. HIV prevalence

and magnitude of the male homosexual population in Amsterdam. Int Conf AIDS. 8, C326

[abstr. PoC 4486] (1992).

22. Page-Shafer K, Veugelers PJ, Moss AR, Strathdee S, Kaldor JM, van Griensven GJ. Sexual

risk behavior and risk factors for HIV-1 seroconversion in homosexual men participating in

the Tricontinental Seroconverter Study, 1982–1994. Am. J. Epidemiol. 146, 531–542

(1997).

23. Pathela P, Braunstein SL, Schillinger JA, Shepard C, Sweeney M, Blank S. Men who have

sex with men have a 140-fold higher risk for newly diagnosed HIV and syphilis compared

with heterosexual men in New York City. J. Acquir. Immune Defic. Syndr. 58, 408–416

(2011).

24. Department of Health and Human Services CfDCaP, National Center for HIV, STD and TB

Prevention, Division of STD Prevention. Sexually transmitted diseases surveillance 2004

supplement: Syphilis surveillance report. Atlanta: Department of Health and Human Ser-

vices CfDCaP, National Center for HIV, STD and TB Prevention, Division of STD Preven-

tion, 2005.

25. Centers for Disease Control and Prevention. Primary and secondary syphilis – United

States, 2003–2004. Morb. Mortal. Wkly. Rep. 55, 269–273 (2006).

26. Rompalo AM, Joesoef MR, O’Donnell JA et al. Clinical manifestations of early syphilis by

HIV status and gender. Results of the syphilis and HIV study. Sex. Transm. Dis. 28,

158–165 (1997).

27. Lukehart SA, Hook EW 3rd, Baker-Zander SA, Collier AC, Critchlow CW, Handsfield HH.

Invasion of the central nervous system by Treponema pallidum: Implications for diagnosis

and treatment. Ann. Intern. Med. 109, 855–862 (1988).

28. Gregory N, Sanchez M, Buchness MR. The spectrum of syphilis in patients with human im-

munodeficiency virus infection. J. Am. Acad. Dermatol. 22, 1061–1067 (1990).

29. Hutchinson CM, Hook EW 3rd, Shepherd M, Verley J, Rompalo AM. Altered clinical pre-

sentation of early syphilis in patients with human immunodeficiency virus infection. Ann.

Intern. Med. 121, 94–100 (1994).

30. McBroom RL, Styles AR, Chiu MJ, Clegg C, Cockerell CJ, Radolf JD. Secondary syphilis

in persons infected with and not infected with HIV-1: A comparative immunohistologic

study. Am. J. Dermatopathol. 21, 432–441 (1999).

31. Rolfs RT, Hindershot E, Hackett K, Augenbraun M, Bolan G, Johnson SR, Wagner K,

Brady WE, Joesoef M, Larsen S, and the Syphilis and HIV Study Group. Treatment of Early

Syphilis in HIV-Infected and HIV-Uninfected Patients – Preliminary Results of the Syphilis

HIV Study. Sex. Trans. Dis. 21, Suppl. 2, S134 [abstr. 109] (1994).

32. Rolfs RT, Joesoef MR, Hendershot EF, Rompalo AM, Augenbraun MH, Chiu M, Bolan G,

Johnson SC, French P, Steen E, Radolf JD, Larsen S. A randomized trial of enhanced ther-

apy for early syphilis in patients with and without human immunodeficiency virus infection.

The Syphilis and HIV Study Group. N. Engl. J. Med. 337, 307–314 (1997).

33. Rompalo AM, Lawlor J, Seaman P, Quinn TC, Zenilman JM, Hook EW. Modification of

syphilitic genital ulcer manifestations by coexistent HIV infection. Sex. Transm. Dis. 28,

448–454 (2001).

34. Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guide-

lines 2006. Mol. Morb. Wkly. Rep. 55 (No. RR-11) (2006).

35. Ghanem KG, Erbelding EJ, Cheng WW, Rompalo AM. Doxycycline compared with

benzathine penicillin for the treatment of early syphilis. Clin. Infect. Dis. 42, e45–49 (2006).



36. Long CM, Klausner JD, Leon S, Jones FR, Giron M, Cuadros J, Pajuelo J, Caceres C, Coates

TJ and NIMH Collaborative HIV/STD Prevention Trial Group. Syphilis treatment and HIV

infection in a population-based study of persons at high risk for sexually transmitted dis-

ease/HIV infection in Lima, Peru. Sex. Transm. Dis. 33, 151–155 (2006).

37. Farhi D, Dupin N. Management of syphilis in the HIV-infected patient: Facts and controver-

sies. Clin. Dermatol. 28, 539–545 (2010).

38. Radolf JD, Lukehart SA (eds). Pathogenic Treponema Molecular and Cellular Biology.

Norfolk, United Kingdom: Caister Academic Press, 2006, pp. 212–213.

39. Marra CM, Maxwell CL, Tantalo L, Eaton M, Rompalo AM, Raines C, Stoner BP, Corbett

JJ, Augenbraun M, Zajackowski M, Kee R, Lukehart SA. Normalization of cerebrospinal

fluid abnormalities after neurosyphilis therapy: Does HIV status matter? Clin. Infect. Dis.

38, 1001–1006 (2004).

40. Marion SA, Schechter MT, Weaver MS, McLeod WA, Boyko WJ, Willoughby B, Douglas

B, Craib KJ, O’Shaughnessy M. Evidence that prior immune dysfunction predisposes to hu-

man immunodeficiency virus infection in homosexual men. J. Acquir. Immune Defic.

Syndr. 2, 178–186 (1989).

41. Osborn JE. Co-factors and HIV: What determines the pathogenesis of AIDS? Bioessays 5,

287–289 (1986).

42. Veronesi R, Focaccia R, Mazza CC. [Pathogenesis of AIDS: possible role of co-factors in

HIV reactivation]. Rev. Hosp. Clin. Fac. Med. Sao Paulo. 44, 115–120 (1989).

43. Sher A, Gazzinelli RT, Oswald IP, Clerici M, Kullberg M, Pearce EJ, Berzofsky JA,

Mosmann TR, James SL, Morse HC 3rd. Role of T-cell derived cytokines in the down-

regulation of immune responses in parasitic and retroviral infection. Immunol. Rev. 127,

183–204 (1992).

44. Clerici M, Shearer GM. A TH1 ® TH2 switch is a critical step in the etiology of HIV infec-

tion. Immunol. Today 14, 107–111 (1993).

45. Rook GA, Onyebujoh P, Stanford JL. TH1/TH2 switching and loss of CD4+ T cells in

chronic infections: An immunoendocrinological hypothesis not exclusive to HIV. Immunol.

Today 14, 568–569 (1993).

46. Clerici M, Shearer GM. The Th1-Th2 hypothesis of HIV infection: New insights. Immunol.

Today 15, 575–581 (1994).

47. Kalinkovich A, Maayan S, Weisman Z, Harpaz N, Bentwich Z. Immune activation, a

co-factor for HIV transmission in Thailand? Lancet 343, 1506–1507 (1994).

48. Larralde C, Huerta L. Network between main protagonists and events leading to AIDS.

Arch. Med. Res. 27, 107–113 (1996).

49. Bentwich Z, Maartens G, Torten D, Lal AA, Lal RB. Concurrent infections and HIV

pathogenesis. AIDS 14, 2071–2081 (2000).

50. Clerici M, Declich S, Rizzardini G. African enigma: Key player in human immunodefi-

ciency virus pathogenesis in developing countries? Clin. Diagn. Lab. Immunol. 8, 864–866

(2001).

51. Ost A, Baroni CD, Biberfeld P, Diebold J, Moragas A, Noël H, Pallesen G, Rácz P, Schipper

M, Tenner-Rácz K, Van Den Tweel JG. Lymphadenopathy in HIV infection: Histological

classification and staging. APMIS Suppl. 8, 7–15 (1989).

52. Farhi DC, Wells SJ, Siegel RJ. Syphilitic lymphadenopathy: Histology and human immuno-

deficiency virus status. Am. J. Clin. Pathol. 112, 330–334 (1999).

53. Hrncír Z, Kraus Z, Tichý M. Non-specific humoural immunity response in latent and ter-

tiary syphilis. Br. J. Vener. Dis. 48, 108–112 (1972).



54. Wright DJ, Grimble AS. Why is the infectious stage of syphilis prolonged? Br. J. Vener.

Dis. 50, 45–49 (1974).

55. Shannon R, Booth SD. The pattern of immunological responses at various stages of syphilis.

Br. J. Vener. Dis. 53, 281–286 (1977).

56. Gschnait F, Schoenwald E, Schmidt BL, Luger A. Laboratory evidence for impaired cellu-

lar immunity in different stages of syphilis. J. Invest. Dermatol. 79, 40–41 (1982).

57. Wicher K, Wicher V. Immunopathology of syphilis. In: Schell RF, Musher DM (eds).

Pathogenesis and Immunology of Treponemal Infection. New York: Marcel Dekker, 1983,

p. 139.

58. Baughn, RE. Immunoregulatory Effects in Experimental Syphilis. In: Schell RF, Musher

DM (eds) Pathogenesis and Immunology of Treponemal Infection. New York: Marcel

Dekker, 1983, p. 271.

59. Fitzgerald TJ. The Th1/Th2-like switch in syphilitic infection: Is it detrimental? Infect.

Immun. 60, 3475–3479 (1992).

60. Podwimska J, Zaba R, Chomik M, Bowszyc J. The ability of peripheral blood mononuclear

cells of rabbits infected with Treponema pallidum to produce IL-2. FEMS Immunol. Med.

Microbiol. 7, 257–264 (1993).

61. Sell S, Hsu PL. Delayed hypersensitivity, immune deviation, antigen processing and T-cell

subset selection in syphilis pathogenesis and vaccine design. Immunol. Today 14, 576–582

(1993).

62. Podwimska J, Lusiak M, Zaba R, Bowszyc J. The pattern and level of cytokines secreted by

Th1 and Th2 lymphocytes of syphilitic patients correlate to the progression of the disease.

FEMS Immunol. Med. Microbiol. 28, 1–14 (2000).

63. Podwimska J, Lusiak M. Interleukin 10 and Its Role in the Regulation of the Cell-Mediated

Immune Response in Syphilis. Archivum Immunologiae et Therapiae Experimentalis 49,

417–421 (2001).

64. Podwimska J, Lusiak M, Yaba, R. IL-12 and its role in protection against Treponema

pallidum. Przegl. Dermatol. 88, 233–242 (2001).

65. Fan YM, Zeng WJ, Wu ZH, Li SF. Immunophenotypes, apoptosis, and expression of fas and

Bcl-2 from peripheral blood lymphocytes in patients with secondary early syphilis. Sex.

Trans. Dis. 31, 221–224 (2004).

66. Gamgee JS. Clinical remarks on syphilisation. Assoc. Med. J. 2, 694–696 (1854).

67. Bruusgaard E. Uber das Schicksal der nicht spezifisch behandelten Luetiker (The fate of

syphilitics denied specific treatment). Arch. Dermatol. Syph. 157, 309–332 (1929).

68. Sowder WT. An interpretation of Bruusgaard’s paper on the fate of untreated syphilitics.

Am. J. Syph. 24, 684–691 (1940).

69. Gjestland T. The Oslo study of untreated syphilis. Acta Dermat-Venereol. (Stockholm)

Suppl. 34, 35 (1955).

70. Harrison LW. The Oslo study of untreated syphilis, review and commentary. Br. J. Vener.

Dis. 32, 70–78 (1956).

71. Quetel C. History of Syphilis. Baltimore: The Johns Hopkins University Press, 1990, pp.

112–114.

72. Sherwood J. Syphilization: Human experimentation in the search for a syphilis vaccine in

the nineteenth century. J. Hist. Med. Allied Sci. 54, 364–386 (1999).

73. Gjestland T, ibid. pp. 343–366.

74. Neisser A, Landsteiner K, In: Chesney, A. Immunity in Syphilis. Baltimore: Williams and

Wilkins Co., 1927, p. 26.



75. Strickler A. Diseases of the Skin and Syphilis. Philadelphia: F.A. Davis Co., 1927, p. 369.

76. Hall AF. Under-treatment versus over-treatment of syphilis. J. Indiana Med. Ass. 28, 587

(1935).

77. Morgan HJ. The Prognosis of Syphilis. JAMA 112, 311–317 (1939).

78. Moore JE. The Modern Treatment of Syphilis. 2nd edition. Springfield, IL: Charles C.

Thomas, 1941, p. 36.

79. Wendstrand, DEW. Syphilis from a life insurance standpoint. Urol. and Cutan. Review, 22

(1918).

80. Hobbs AB. Syphilis; A study. Ass. Life. Ins. Dir. Am. 13, 14–31 (1925).

81. Blakely DN. Syphilis from the life insurance standpoint. Med. Ins. & Health Conserv. 42,

446 (1927).

82. Quetel C, ibid, pp. 119, 219, 242.

83. Thomas EW. Syphilis: Its Course and Management. New York: The Macmillan Com-

pany, 1949, p. 10.

84. Landsteiner K, In: Chesney, A. Immunity in Syphilis. ibid.

85. Arnold RC, Mahoney JF, Cutler JC. Reinfection in experimental syphilis in rabbits fol-

lowing penicillin therapy (Part I). Am. J. Syph., Gonor., and Ven. Dis. 31, 264–267

(1947).

86. Arnold RC, Mahoney JF, Cutler JC. Reinfection in experimental syphilis in rabbits fol-

lowing penicillin therapy: Reinfection in early latent syphilis (Part II). Am. J. Syph.,

Gonor., and Ven. Dis. 31, 489 (1947).

87. Magnuson HJ, Thomas EW, Olansky S, Kaplan B, DeMello L, Cutler JC. Inoculation

syphilis in human volunteers. Medicine 35, 33–82 (1956).

88. Rosahn PD. The adverse influence of syphilitic infection on the longevity of mice and

men. Am. Med. Ass. Arch. Derm. Syph. 66, 547–568 (1952).

89. Smith JL. Spirochetes in Late Seronegative Syphilis. Springfield, IL: Charles C. Thomas,

1969, pp. 181–221.

90. Chandler FW, McClure HM, Campbell WG, Watts JC. Pulmonary pneumocystosis in

nonhuman primates. Arch. Pathol. Lab. Med. 100, 163–167 (1976).

91. Horváth I, personal communication re: rabbits and “bag of bones”, 1991.

92. Tseng CK, Hughes MA, Hsu PL, Mahoney S, Duvic M, Sell S. Syphilis superinfection ac-

tivates expression of human immunodeficiency virus i in latently infected rabbits. Am. J.

Pathol. 138, 1149–1164 (1991).

93. Martin DS. Fungous diseases. In: Harrison TR (ed.). Principles of Internal Medicine, 2nd

Edition. New York: McGraw Hill, Inc., 1954, pp. 986–995.

94. Duesberg PD. Human immunodeficiency virus and acquired immunodeficiency syn-

drome: Correlation but not causation. Proc. Natl Acad. Sci. (USA) 86: 755–764 (1989).

95. Root-Bernstein RS. Rethinking AIDS: The Tragic Cost of Premature Consensus. New

York: The Free Press, 1993.

96. Pinner M. Pulmonary Tuberculosis in the Adult. Springfield, IL: Charles Thomas, 1944,

pp. 496–498, 508–512.

97. Myers JA. Invited and Conquered. St Paul, MN: Webb Publishing, 1949, pp. 83, 423,

618–620.

98. Myers JA, ibid. pp. 38–42.

99. Schamberg IL. The prognosis of syphilis. Am. J. Syph. 29, 529–550 (1945).

100. Rich AR. The Pathogenesis of Tuberculosis, 2nd edition. Springfield, IL: Charles Thomas,

1951, p. 637.



101. Dattner B. The Management of Neurosyphilis. New York: Grune & Stratton, 1944, p. 333.

102. Gruenwald P, Mendel J. Mononuclear pneumonia in sudden death or rapidly fatal illness

in infants. J. Pediatr. 39, 650–652 (1951).

103. Gajdusek DC. Pneumocystis carinii; etiologic agent of interstitial plasma cell pneumonia

of premature and young infants. Pediatrics 19, 543–565 (1957).

104. Harrison LW. Modern Diagnosis and Treatment of Syphilis Chancroid and Gonorrhea.

Toronto: McClelland & Stewart, 1925, pp. 27–28.

105. Stokes JH, Beerman H, Ingrahm NR. Modern Clinical Syphiliology, 3rd edition. Philadel-

phia: WB Saunders Co., 1944, p. 124.

106. Morgan CA, Lukehart SA, Van Voorhis WC. Immunization with the N-terminal portion

of Treponema pallidum repeat protein K attenuates syphilitic lesion development in the

rabbit model. Infect. Immun. 70, 6811–6816 (2002).

107. Arnold, RC. Part I, Part II, ibid.

108. Beerman H. The problem of reinoculation of human beings with Spirochaeta Pallida. Am.

J. Syph. Gonor. & Ven. Dis. 30, 173–192 (1946).

109. Magnuson HJ, Rosenau BJ, Clark JW. The duration of acquired immunity in experimental

syphilis. Am. J. Syph. Gonor. & Ven. Dis. 33, 297–302 (1949).

110. Smith, JL, ibid. pp. 181–221.

111. Wicher K, Wicher V. Experimental syphilis in guinea pig. Crit. Rev. Microbiol. 16,

181–234 (1989).

112. Tseng CK et al. ibid.

113. New York State Department of Health Fact Sheet. http://www.health.ny.gov/dis-

eases/communicable/syphilis/docs/fact_sheet.pdf Accessed 17 August 2012.

114. Kampmeier RH. Final Report on the “Tuskegee Syphilis Study”. South. Med. J. 67,

1349–1353 (1974).

115. Myers JA. The natural history of tuberculosis in the human body; forty-five years of obser-

vation. JAMA 194, 1086–1092 (1965).

116. Moore JE. Unsolved clinical problems of syphilology. Am. J. Syph. Gonor. & Ven. Dis.

23, 710 (1939).

117. Reynolds F. Syphilis. In: Christian HA (ed.). Oxf Med 5, 665–668 (1948).

118. Hinton WA. Syphilis and its Treatment. New York: The Macmillan Company, 1936, p.

81.

119. Levaditi C. Nouvelles Recherches Experimentales sur la Syphilis. Paris: Libraires de

l’Academie de Medicine, 1933.

120. Stokes JH. Modern Clinical Syphilology, 2nd edition, Philadelphia: W. B. Saunders, 1936,

pp. 20–21.

121. Beerman H. Future Research Needs. Proceedings of World Forum on Syphilis and Other

Treponematoses. 202 (1962).

122. Willcox RR, Guthe T. Treponema pallidum. A bibliographical review of the morphology,

culture and survival of T. pallidum and associated organisms. Bull. World Health Organ.

35, 1–169 (1966).

123. Horváth I. Experimental Mouse Syphilis for the Syphilis Eradication Program. WHO Bi-

ology and Pathogenicity of Treponemes conference, University of Birmingham (1989).

124. Miller JN. Immunity in experimental syphilis. VI. Successful vaccination of rabbits with

Treponema pallidum, Nichols strain, attenuated by gamma-irradiation. J. Immunol. 110,

1206–1215 (1973).



125. Farhi D, Dupin N. Origins of syphilis and management in the immunocompetent patient:

Facts and controversies. Clin. Dermatol. 28, 533–538 (2010).

126. Larsen SA, CDC, personal communication.

127. Moore JE. The Modern Treatment of Syphilis, p. 26.

128. Luger A. Serological diagnosis of syphilis. In: Young H, McMillan A (eds) The Immuno-

logical Diagnosis of Sexually Transmitted Diseases. New York: Marcel Dekker, 1988, pp.

251, 265.

129. Luger A. ibid., pp. 249–274.

130. McKenna JJ, Miles R, Lemen D, Dunford SA, Renirie R. Unmasking AIDS: Chemical

immunosuppression and seronegative syphilis. Med Hypotheses 21, 421–430 (1986).

131. Caiazza S. Chronic spirochetal infection and the pathogenesis of AIDS. Quantum Medi-

cine 1, 117–127 (1988).

132. MacFadden DK, Notenboom RH, Scythes JB. Syphilis – A role in sexually acquired

AIDS? WHO Biology and Pathogenicity of Treponemes Conference, University of Bir-

mingham (1989).

133. Notenboom RH, MacFadden DK. Reliability of syphilis tests in HIV-positive individuals.

Int. Conf. AIDS 8, p. B94 [abstr. POB 3044] (1992).

134. Fralick RA, Scythes JB, Notenboom RH, MacFadden DK. Syphilis and HIV:

Seroprevalence and clinical observations in HIV clinic, Toronto. Sex. Trans. Dis. 21,

Suppl 2, S183 [abstr. 271] (1994).

135. Notenboom RH, personal communication.

136. Schmidt B, Gschnait F. Parallel testing with VDRL laboratory test and MHA-Tp in syphi-

lis serology. Int J STD AIDS 13 (Suppl 1), O31 (2002).

137. Geusau A, Kittler H, Hein U, Dangl-Erlach E, Stingl G, Tschachler E. Biological

false-positive tests comprise a high proportion of Venereal Disease Research Laboratory

reactions in an analysis of 300,000 sera. Int. J. STD AIDS 16, 722–726 (2005).

138. Notenboom RH et al., ibid.

139. Evans BA, McLean KA, Dawson SG, Teece SA, Bond RA, MacRae KD, Thorp RW.

Trends in sexual behaviour and risk factors for HIV infection among homosexual men,

1984–7. BMJ 298, 215–218 (1989).

140. Haas JS, Bolan G, Larsen SA, Clement MJ, Bacchetti P, Moss AR. Sensitivity of

Treponemal tests for detecting prior treated syphilis during human immunodeficiency vi-

rus infection. J Infect Dis. 162, 862–866 (1990).

141. Sjövall P, Flamholc L, Kroon BM, Bredberg A. HIV infection and loss of treponemal test

reactivity. Acta Derm. Venereol. 71, 458 (1991).

142. Johnson PD, Graves SR, Stewart L, Warren R, Dwyer B, Lucas CR. Specific syphilis

serological tests may become negative in HIV infection. AIDS 5, 419–423 (1991).

143. Janier M, Chastang C, Spindler E, Strazzi S, Rabian C, Marcelli A, Morel P. A prospective

study of the influence of HIV status on the seroreversion of serological tests for syphilis.

Dermatology 198, 362–369 (1999).

144. Erbelding EJ, Vlahov D, Nelson KE, Rompalo AM, Cohn S, Sanchez P, Quinn TC,

Brathwaite W, Thomas DL. Syphilis serology in human immunodeficiency virus infec-

tion: evidence for false-negative fluorescent treponemal testing. J. Infect. Dis. 176,

1397–1400 (1997).

145. Horváth I, Nagy K, Scythes J, Horváth A, Notenboom R. Syphilis serology in HIV pa-

tients. Abstr. Int. Congr. Sex. Transm. Dis. p. 199 [abstr. P828] (1997).



146. Horváth I, Nagy K, Várkonyi V, Scythes J, Notenboom W, Horváth A. Syphilis Serology

in HIV infection: Evidence for false-positive fluourescent Treponemal testing. IUSTI Eur.

Congr. STDs & Genit. Derm., Göteborg, Sweden [abstr. P46] (1998).

147. Fralick, RA, ibid.

148. Fralick, RA. Interview, Lest We Forget: Syphilis in the AIDS Era. Television documen-

tary (1993) youtube.com/watch?v=sHp6UB08pXQ @51:51. Accessed 17 August 2012.

149. Schmidt BL, Edjlalipour M, Luger A. Comparative evaluation of nine different en-

zyme-linked immunosorbent assays for determination of antibodies against Treponema

pallidum in patients with primary syphilis. J. Clin. Microbiol. 38, 1279–1282 (2000).

150. Radolf, JD, personal communication.

151. denHollander N, Berry R, Fearon M. Treponemal Based Screening for Syphilis – Detect-

ing Latent Cases. 100th General Meeting of the American Society for Microbiology, May

21–25, 2000, Los Angeles, California. Session 260/C, Paper C-367.

152. Cox D, personal communication to Notenboom, RH.

153. Woznicová V, Heroldová M. Detection of treponema pallidum DNA in the serum of an

adequately treated patient with latent syphilis. Acta Derm. Venereol. 87, 379–380 (2007).

154. Ballard RC, Ye H, Fehler G, Chen CY, Morse S. Interpretation of serologic tests for pri-

mary syphilis in the era of HIV infection and multiplex PCR for genital ulcer disease. Int.

J. STD & AIDS 12 Suppl 2, 43 (2001).

155. Talha E, Kemeny B, Horváth I, Scythes J, Nagy K, Notenboom R, Horváth A. Syphilis

PCR: molecular detection of T. pallidum in seronegative cases. Bõrgyógyászati és

Venerológiai Szemle (Review of Dermato-Venerology) 79, 65–68 (2003). (in Hungarian)

156. Nagy K, Scythes JH, Horvath I, Kemeny B, Talha E, Notenboom R, Horváth A. Experi-

ence of molecular screening of syphilis by PCR [abstract 0312]. In: Program and abstracts

of the 15th Biennial Congress of the International Society of Sexually Transmitted Disease

Research (ISSTDR) (Ottawa). ISSTDR, 111 (2003).

157. Talha E, Juhász E, Kanizsai S, Nagy K. Molecular detection of T. pallidum by PCR in

seronegative cases. Acta Microbiol. Immunol. Hung. 56, 181–189 (2009).

158. Wicher K, Abbruscato F, Wicher V, Collins DN, Auger I, Horowitz HW. Identification of

persistent infection in experimental syphilis by PCR. Inf. Immun. 66, 2509–2513 (1998).

159. Musher DM. How much penicillin cures early syphilis? Ann. Intern. Med. 109, 849–851

(1988).

160. Nicholas L. Proceedings of World Forum on Syphilis and Other Treponematoses. Penicil-

lin review (1962).

161. Smith JL, Israel CW. Spirochetes in the aqueous humor in seronegative ocular syphilis.

Persistence after penicillin therapy. Arch. Ophthalmol. 77, 474–477 (1967).

162. Yobs AR, Clark JW Jr., Mothershed SE, Bullard JC, Artley CW. Further observations on

the persistence of Treponema pallidum after treatment in rabbit and humans. Br. J. Vener.

Dis. 44, 116–130 (1968).

163. Yogeswari L, Chacko CW. Persistence of T. pallidum and its significance in penicil-

lin-treated seropositive late syphilis. Br. J. Vener. Dis. 47, 339–347 (1971).

164. Sparling PF. Diagnosis and Treatment of Syphilis. N. Engl. J. Med. 284, 642–653 (1971).

165. Collart P, Pechere JC, Franceschini P, Dunoyer P. Persisting virulence of T. pallidum after

incubation with penicillin in Nelson-Mayer medium. Br. J. Vener. Dis. 48, 29–31 (1972).

166. Tramont EC. Persistence of Treponema pallidum following penicillin G therapy. Report

of two cases. JAMA 236, 2206–2207 (1976).



167. Dunlop EM. Survival of treponemes after treatment: Comments, clinical conclusions, and

recommendations. Genitourin. Med. 61, 293–301 (1985).

168. Dowell ME, Ross PG, Musher DM, Cate TR, Baughn RE. Response of latent syphilis or

neurosyphilis to ceftriaxone therapy in persons infected with human immunodeficiency

virus. Am. J. Med. 93, 481–488 (1992).

169. Colby WD. Treating syphilis. Can. Fam. Physician 38, 2671–2674, 2677–2678 (1992).

170. Stoner BP. Current controversies in the management of adult syphilis. Clin. Infect Dis. 44,

Suppl 3, S130–146 (2007).

171. Blank LJ, Rompalo AM, Erbelding EJ, Zenilman JM, Ghanem KG. Treatment of syphilis

in HIV-infected subjects: A systematic review of the literature. Sex. Transm. Infect. 87,

9–16 (2011).

172. Centers for Disease Control and Prevention. Sexually transmitted diseases treatment

guidelines, 2010. Mol. Morb. Wkly. Rep. 59 (No. RR–12), 29 (2010).

173. Blank LJ, Rompalo AM, Erbelding EJ, Zenilman JM, Ghanem KG. Treatment of syphilis

in HIV-infected subjects: A systematic review of the literature. Sex. Transm. Infect. 87,

9–16 (2011).

174. Scythes JB, Jones CM, Notenboom RH. A new gold standard for syphilis? J. Eur. Acad.

Dermat. & Vener. 18, Suppl 1, PS 230 (2004).

175. Scythes JB, Jones CM. Can we reliably diagnose syphilis? Int. J. STD & AIDS, 17, Suppl

1, O0001 (2006).

176. McKenna JJ et al. ibid.

177. Coulter HL. AIDS and Syphilis: The Hidden Link. Berkeley, CA: North Atlantic Books,

1987.

178. Caiazza S, ibid.

179. Leishman K. AIDS and syphilis. Atlantic Monthly 263, 17–26 (1988).

180. Mitchell RB. Syphilis as AIDS. Austin, TX: Banned Books, 1988.

181. Margulis L, Maniotis A, MacAllister J, Scythes J, Brorson O, Hall J, Krumbein WE, Chap-

man MJ. Spirochete round bodies, syphilis, Lyme disease & AIDS: Resurgence of “the

Great Imitator”? Symbiosis 47, 51–58 (2009).

182. Musher DM, Hamill RJ, Baughn RE. Effect of human immunodeficiency virus (HIV) in-

fection on the course of syphilis and on the response to treatment. Ann. Intern. Med. 113,

872–881 (1990).

183. Luger A, ibid.

184. Sato SN. Serologic Response to Treatment in Syphilis. In: Sato SN (ed.), Syphilis – Rec-

ognition, Description and Diagnosis. Vienna: InTech, 2011, p. 112.

185. Larsen SA. Syphilis Diagnosis Dynamics. 9th International Meeting of the ISSTDR, Banff,

Alberta [abstr. C-12] 273 (1991).

186. Poulton M, Curtis S, McElborough D, Williams DI, Fisher M. Syphilis: Mimicking yet an-

other disease! Sex Transm Infect. 77, 325 (2001).

187. Maynard S. Busted for sex – in 1917. Xtra 723 (2012).

188. Salazara JC, Hazletta KRO, Radolf JD. The immune response to infection with

Treponema pallidum, the stealth pathogen. Microbes Infect. 4, 1133–1140 (2002).

189. Radolf JD, Lukehart SA (eds) Pathogenic Treponema Molecular and Cellular Biology.

Norfolk, UK: Caister Academic Press, 2006.

190. Grmek M. History of AIDS: Emergence and Origin of a Modern Pandemic. Princeton, NJ:

Princeton University Press, 1990.



191. Mindell DP, Shultz JW, Ewald PW. The AIDS pandemic is new, but is HIV New? Syst.

Biol. 44, 17–48 (1995).

192. Gao F, Bailes E, Robertson DL, Chen Y, Rodenburg CM, Michael SF, Cummins LB, Ar-

thur LO, Peeters M, Shaw GM, Sharp PM, Hahn BH. Origin of HIV-1 in the chimpanzee

Pan troglodytes troglodytes. Nature 397, 436–441 (1999).

193. Gifford RJ. Viral evolution in deep time: Lentiviruses and mammals. Trends Genet. 28,

89–100 (2012).

194. Stiegler G, Armbruster C, Vcelar B, Stoiber H, Kunert R, Michael NL, Jagodzinski LL,

Ammann C, Jäger W, Jacobson J, Vetter N, Katinger H. Antiviral activity of the neutraliz-

ing antibodies 2F5 and 2G12 in asymptomatic HIV-1-infected humans: A phase I evalua-

tion. AIDS 16, 2019–2025 (2002).

195. Richman DD, Wrin T, Little SJ, Petropoulos CJ. Rapid evolution of the neutralizing anti-

body response to HIV type 1 infection. Proc. Natl Acad. Sci. 100, 4144–4149 (2003).

196. Frost SD, Trkola A, Günthard HF, Richman DD. Antibody responses in primary HIV-1 in-

fection. Curr Opin HIV AIDS 3, 45–51 (2008).

197. Max Essex, personal communication, Barcelona AIDS conference, 2002.

198. Papadopulos-Eleopulos E, Turner VF, Papadimitriou JM, Causer D, Page BA. HIV anti-

body tests and viral load – more unanswered questions and a further plea for clarification.

Curr Med Res Opin. 14, 185–186 (1998).

199. Cohen J. AIDS research: Promising AIDS vaccine’s failure leaves field reeling. Science

318, 28–29 (2007).

200. Brown D. Vaccine failure is setback in AIDS fight: Test subjects may have been put at ex-

tra risk of contracting HIV. Washington Post March 21, 2008, pg. A01.

201. O’Neill B. The exploitation of Aids: The Aids scare was one of the most distorted, duplici-

tous and cynical public health panics of the last 30 years. The Guardian (UK) published

online June 12, 2008. http://www.guardian.co.uk/commentisfree/2008/jun/12/aids.health

Accessed 17 August 2012.

202. Burstain JM, Grimprel E, Lukehart SA, Norgard MV, Radolf JD. Sensitive detection of

Treponema pallidum by using the polymerase chain reaction. J. Clin. Microbiol. 29, 62–69

(1991).

203. Schmidt BL, Luger A. 11th ISSTDR 1995 [abstr. 133] (Int. J. STD & AIDS suppl, April

1996).

204. Zoechling N, Schluepen EM, Soyer HP, Kerl H, Volkenandt M. Molecular detection of

Treponema pallidum in secondary and tertiary syphilis. Br. J. Dermatol. 5, 683–686

(1997).

205. Centurion-Lara A, Castro C, Shaffer JM, Van Voorhis WC, Marra CM, Lukehart SA. De-

tection of Treponema pallidum by a sensitive reverse transcriptase PCR. J. Clin.

Microbiol. 35, 1348–1352 (1997).

206. Liu H, Rodes B, Chen CY, Steiner B. New tests for syphilis: Rational design of a PCR

method for detection of Treponema pallidum in clinical specimens using unique regions of

the DNA polymerase I gene. J. Clin. Microbiol. 39, 1941–1946 (2001).

207. Wang LN, Li J, Huang W, Zheng HY, Zuo YG, Liu YX, Wang XF, Liu XR. Detection of

the Treponema pallidum gene and variation of treponemal DNA load before and after ther-

apy. Int. J. STD & AIDS 23, e6–8 (2012).



Syphilis in the AIDS Era: Diagnostic Dilemma and Therapeutic Challenge (co-authored with John...

Documents

Transcript of Syphilis in the AIDS Era: Diagnostic Dilemma and Therapeutic Challenge (co-authored with John...