Infect Dis Clin N Am 18 (2004) 101110

The impact of syphilis on humankind

Edmund C. Tramont, MD
Division of AIDS, National Institute of Allergy and Infectious Disease, National Institutes of
Health, 6700B Rockledge Drive, Bethesda MD 20892, USA

For a disease to have a lasting impact on human history, it must cause an

easily transmitted acute illness that results in a high incidence rate and a high
mortality rate; or it must be transmitted easily but cause a mild, nonfatal,
nondescript acute illness that progresses into a debilitating chronic illness.
Examples of the former are the impact of small pox on Amerindians and the
Bubonic plague in Europe during the middle ages, which reduced the
respective populations an estimated 90% and 40%, respectively [1]. Syphilis,
tuberculosis, and schistosomiasis are examples of the latter.

The disease
Syphilis is caused by the spirochete Treponema pallidum. It has a relatively
primitive genome that has remained stable and constant. It is likely for this
reason that it is virtually the only pathogenic organism that has remained as
sensitive to penicillin as it was when penicillin rst was introduced [2]. The
composition of its lipid outer surface, which is similar to that of human cells,
and the relative paucity of extruding proteins have important roles in
allowing this microorganism to often escape eective immune control and
establish a chronic infection [3].
Unless secondarily infected, a nonpainful asymptomatic ulcer known as
a chancre (primary syphilis) usually develops at the site of inoculation. If left
untreated, it customarily heals within a few weeks to months. This lack of
symptoms often leads patients to ignore the lesion, an event that often
occurred before the advent of the current medical mindset in which any
persistent ailment is likely to bring patients in contact with the medical
profession. Because little could be done to treat the lesions before the
antibiotic era, unpretentious skin lesions were ignored regularly.

E-mail address: etramont@niaid.nih.gov

0891-5520/04/$ - see front matter 2004 Elsevier Inc. All rights reserved.
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Soon after inoculation, the spirochete hematogenously spreads throughout the body, invading virtually every organ. The central nervous system is
invaded during this bacteremic phase in up to 40% of persons; this invasion
sets the stage for the development of neurosyphilis [2,4,5]. This bacteremia
stage, known as secondary syphilis, is the most clinically orid phase of the
Table 1
Clinical manifestations of secondary syphilis
Manifestation

Cases (%)

Skin
Rasha
Macular
Maculopapular
Papular
Pustular
Condyloma latum
Generalized lymphadenopathy
Mouth and throat
Mucous patches
Erosions
Ulcer (aphthous)
Genital lesion
Chancre
Chondyloma latum
Mucous patch
Constitutional symptoms
Fever of unknow origin
Malaise
Pharyngitis, laryngitis
Anorexia, weight loss
Arthralgias
Central nervous system
Asymptomatic
Symptomatic
Headache
Meningismus
Meningitis
Ocular
Diplopia
Impaired vision
Otitic
Tinnitus
Vertigo
Cranial nerve involvement (IIVIII)
Renal
Glomerulonephristis
Nephrotic syndrome
Gastrointestinal
Hepatitis
Intestinal wall invasion
Arthritis, osteitis, and periostitis

90

Commonly involves the palms and soles.

35

20

70

40
39
1

Unusual

Unusual
Unusual
Unusual
Unusual

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103

disease (Table 1), but it passes within a few weeks to months. As with primary
syphilis, this recovery for a long time was considered to be indicative of a cure.
This theory was in keeping with the common experience with other infectious
illnesses, before the introduction of the germ theory (in the mid-19th
century) or an understanding of the pathogenesis of syphilis (early 20th
century).
After this stage, the patients clinical recovery results in a cure, or the
patient may enter a clinically latent period (persistent slowly multiplying
spirochetes). Occasionally, the patient experiences a relapse of the secondary
phase that is usually less orid or symptomatic than the earlier episode. The
length of this latent, nonsymptomatic phase is variable, lasting from a few
years to as long as 25 years.
Once the spirochete and subsequent immune response has damaged
enough local tissue, signs and symptoms of late or tertiary syphilis ensue
(Table 2). Syphilis is unique in that it can progress into a chronic
neurodegenerative state. The multitude of signs and symptoms has been
captured in the pneumonic general paresis (Box 1). These neurocognitive
consequences resulted in the greatest impact on human history when
they aected societal leaders. It can also aect cognitive function as
a result of micro-cerebral-vascular infarctions or severe aortic insuciency
[2,47].
Appropriate antibiotic treatment abruptly and dramatically cures the
early stages of syphilis and halts the progressive detriments that are the
hallmark of late syphilis. Treatment does not reverse tissue damage or scarring, however.
Table 2
Clinical manifestations of late syphilis
Manifestation

Comment

Cardiovascular (cardiovascular syphilis)

Aneurysm ascending aorta with aortic
insuciency
Neurologic (neurosyphilis)
Meningovascular
Cerebrovascular
Diuse
Focal
Spinal
Parenchymatous
Paretic
Tabetic
Taboparetic
Ocular
Otic
Gummatous syphilis

Progressive debilitation

Involvement of cerebral
vasculature resulting in strokes

General paresis
Involvement of the spinal cord
Leads to gun-barrel sight or blindness
Tinnitus to deafness
Granulomatous-like lesion
occurring anywhere (eg,
nasal septum), resulting in a perforation

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Box 1. General paresis

General paresis is defined as changes in:
Personality
Affect
Reflexes (hyperactive)
Sensorium
Intellect
Insight
Judgment
The benign nature of primary syphilis, the routine recovery from
secondary syphilis to virtual normality, and the insidious development of
a chronic illness during a period of time in history when the infectious
nature of infectious diseases or the pathogenesis of diseases was not
appreciated resulted in syphilis becoming an important determinant of
human history, especially in the developed world.
Brief history
Few modern clinicians are aware of the prevalence of syphilis in the preantibiotic era, the persons of historical notoriety who may have been
infected, or the pervasiveness of this disease in medical practice [2,7,8].
Syphilis was the leading cause of neurologic and cardiovascular diseases
among middle-aged persons at the turn of the 20th century [4,8]. A new
discipline, syphilology, was born, and university chairs, specialized medical
journals, and societies were established [9,10].
The origins of syphilis still are being debated, such as whether the disease
was imported into the Old World from the New World by shipmates of
Christopher Columbus who contracted the disease from Native Americans
or was an established disease (eg, Yaws) that spread throughout Europe as
a consequence of urbanization and lifestyle changes. The two theories have
yet to be reconciled [1,11]. The proponents of the New World or Columbian
theory rest their case on the writings of Ruy Diaz de Isla, a physician who
claimed to have taken care of Columbuss infected shipmates (Tractado
Countra se Mal Serpintino, circa 1539); reports that the disease rst was
recognized in Spain, the country of disembarkment of Columbuss sailors;
and the absence of syphilitic bone lesions in old skeletons. The pathologic
distinction between old bone lesions of leprosy and endemic treponematosis
from lesions of syphilis is not precise. Examination of medieval skeletons
with modern molecular DNA ngerprinting suggest that treponemal disease
existed before 1492 [11,12], although the exact pathogenic treponeme have
not yet been determined because of the signicant genetic relatedness that
exists between species that cause human diseases.

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105

A pandemic known as the Great Pox (as distinguished from the small
pox) spread throughout Europe soon after Christopher Columbus had
returned from America. Mass movements of armies and populations also
were occurring at that time. Whether the pandemic was caused by
a particular virulent form of T pallidum is only speculation and cannot be
proved with certainty. Suggestive descriptions appeared soon after
Columbus returned to Spain [8,9], and the rst clear descriptions of this
illness, including the sexual mode of transmission, were recorded 50 years
later in Breviary of Helth, 1547 [13]:
[I]n englyshe Morbus Gallicus (syphilis) is named the french pockes, whan
that I was yonge they were named the spanyshe pockes the which be of
many kyndes of the pockes, some be moyst, some be waterashe, some be
drye, and some be skorvie, some be lyke skabbes, some be lyke ring
wormes, some be stuled, some be festered, some be cankarus, some be lyke
wennes, some be lyke biles, some be lyke knobbles or burres, and some
be ulcerous havyinge a lytle drye skabbe in the middle of the ulcerous
skabbe, some hath ache in the jioyntes and no singe of the pockes and yet it
may be the pockes . . . The cause of these impediments or infyrmytes doth
come many wayes, it maye come by lyenge in the shetes or bedde there
where a pocky person hath the night before lyenin, it maye come with
lyenge with a pocky person, it maye come by syttenge on a draught or sege
where as a pocky person did lately syt, it may come by drynkynge oft with
a pocky person, but specially it is taken when one pocky person doth synne
in lechery the one with another.

Studying historic records for evidence of when or where disease rst

invaded humans can be frustrating, especially because older terminology
cannot be tted easily to current classications of disease. Another diculty
in sorting through older writings is that distinctions among syphilis,
gonorrhea, and other venereal diseases did not emerge until the late 18th
century. John Hunters self-inoculation with urethral pus containing
Neisseria gonorrhoeae and T pallidum only served to prolong misconceptions, because the two diseases were considered the same for some time
thereafter.
Metchniko successfully transferred T pallidum from humans to
chimpanzees in 1903, and the organism was described in the primary lesion
and adjacent lymph nodes of syphilitic patients soon thereafter and given
the name Spirochaeta pallida. By 1906, Wassermann developed the
complement xation test for the serodiagnosis of syphilis, rst using an
extract from the liver of a syphilitic, stillborn baby. Later, extracts of
uninfected beef livers and hearts were shown to be equally as sensitive (the
forerunner of the present-day nontreponemal tests) because of the crossreactions between T pallidum and normal mammalian cell surface
composition [2].
Using this new tool, serologic testing determined the high prevalence of
the disease: Between 8% and 14% of adults living in such cities as Paris,

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Berlin, and New York had positive serologic test results [8]; however, the
serologic diagnosis of syphilis was not fully accepted early on. In 1914,
J. Homer Wright, Chief of the Department of Pathology at the
Massachusetts General Hospital, used a variation of the Wasserman test
and was quoted as saying, This precipitation test is too sensitive. If I tested
the blood of patients by this method, I would demonstrate that half of the
population of Boston was suering from syphilis and I would be the
laughing stock of the town.
During this same period, Ehrlich introduced an arsenic derivative,
arsphenamine or salvarsan, as therapy. Mercury and bismuth preparations
were added later. These nonstandardized heavy-metal therapies also caused
neurologic signs and symptoms that often were confused with those of
neurosyphilis. Induced-fever therapy (malaria, heat box, hot baths) was also
ecacious, and its benets had been known for more than 300 years. In
1927, Julius Wagner von Jauregg was awarded the Nobel Prize for
describing the use of malaria injections, with its subsequent fevers, to treat
paralytica dementia (neurosyphilis) [14]. These primarily palliative
therapies were quickly forgotten: No other disease was as dramatically
aected by the discovery of penicillin as syphilis.
Syphilis was pervasive in the pre-antibiotic era (pre-1950), and treatments
were more palliative than curative.
Societal leaders purported to have been infected with syphilis
As noted earlier, it cannot be proved with certainty prior to the advent of
serologic tests who was infected with T pallidum. Infection must be deduced
based on lifestyle, employment (eg, sailors, soldiers, mercenaries, philanders),
medical ailments, or ailments of the persons ospring. Because any organ
can be infected during the secondary bacteremic phase, signs and symptoms
of chronic syphilitic disease can and did ensue. In the pre-antibiotic era, it was
common practice for medical textbooks to classify diseases by congenital
abnormalities, cancer, trauma, infections, and two additional independent
descriptions: one for syphilis and one for tuberculosis (eg, congenital diseases
of the heart, infectious diseases of the heart, and so forth). The neurologic
manifestations of general paresis (changes in personality, aect, reexes,
sensorium, intellect, insight, judgment) are historically most conspicuous
with regard to societal leaders (see Box 1).
To illustrate the impact of syphilis on the fate of a country, much
literature has been written about King Henry VIII of England. His rst wife
Catherine of Aragon bore him four children, all of whom were stillborn or
died shortly after birth. His fth wife Mary, who later reigned as Bloody
Mary, had many signs and symptoms that could be attributable to
congenital syphilis (eg, thin, moth-eaten hair; protruding forehead; bad
eyesight). Henrys bitter disappointment in his rst wifes failure to produce
an heir led to his insistence of the legality of his succeeding four marriages,

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107

which in turn precipitated the break of England from Rome and Roman
Catholicism (Papists) and the establishment of the Church of England with
him as its head. His irritable inconsistencies and delusion of grandeur
(manifestations of general paresis) have been attributed to neurosyphilis.
Randolph Churchill, Sir Winston Churchills father, was an eective
statesman who was considered destined to become Englands prime minister.
He was given to dalliance and conviviality early life in his, and it has been
speculated that his erratic and unpredictable behavior in his later life was
secondary to the manifestations of late syphilis and cut short his promising
career. He died at the age of 46 [15]. It has been speculated that his sons drive
and ambition stemmed in part to redeem his fathers reputation.
Ivan the Terrible, Russias rst Czar, began his rein by crafty expansion of Russia into Siberia and along the Volga River but later reduced
nobles, ministers, merchants, and farmers to his servants through an administrative system called Oprichnina, which was subject to the Czar alone.
This megalomania has been attributed to late neurosyphilis. He died at
age 54.
Although the impact on human history would be most conspicuous with
statesman and politicians, other persons of notoriety have been suspected of
experiencing late manifestations of syphilis (Box 2). It has been surmised
that the severe hearing loss suered by Ludwig von Beethoven was caused
by late otic syphilis.
The pervasiveness of the disease and its tragic impact on people who
progressed to late syphilis or developed congenital syphilis was captured in
the literature of the time. There are many references to the ravages of
syphilis in the old classics, from Shakespeare to Joyce [1618].
Many persons of notoriety, from statesmen to artisans, seem to have been
infected with syphilis. It is tempting to speculate that any despot, such as
Hitler, was infected and that the disease impacted their decision making and
behavior; however, the evidence is speculative.
Impact on societal morays
The incidence of any sexually transmitted disease can be aected by
appropriate lifestyle changes. Studying the diseases of a society is revealing,
especially studying social diseases, such as alcoholism, drug abuse, and
sexually transmitted diseases. The disease that had the most inuence on the
morality (and literature) of western culture was syphilis [8,10]. One attempt
to change behavior, the adoption of societal standards aimed at deterring
sex and syphilis, was the new puritanical notion of decency spearheaded by
the Christian Church during the 16th and 17th centuries. This attempt was
manifested primarily by the wide adoption of modest dress that covered
most of the body [1].
The antivenereal disease (antisyphilis) campaign reached its pinnacle
after World War I, and posters, pamphlets, press articles, radio programs

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Box 2. Persons of notoriety strongly suspected of having

syphilis
Henry VIII of England
Ivan the Terrible
Francis I of France
Napoleon Bonaparte
Ludwig von Beethoven
Lord Randolph Churchill
Franz Schubert
John Keats
Al Capone
Florence Nightingale
became commonplace [10]. This campaign set the stage for pervasive
serologic testing [8]:
Young Housewives and future farm-wives, teach yourself to detect syphilis
in your cooks and servants. Choose your cowherds and cowgirls carefully.
Learn the signs. Be suspicious of headaches which do not respond to
treatment; hard frontal lumps (extosis); partial loss of hair; red eyes,
roseola, copper colored spots along the hair line; a dirty neck covered in
white blotches; white spots on the lips, hoarseness; nasal voice; a white line
in the middle or tail of the eyebrow; a thinning beard; a nose like the foot of
a cooking pot; badly formed teeth, half moon-shaped clefts in the two
upper incisors, jaundice.

Fear of syphilis (and other sexually transmitted diseases) impacted

societal norms.
Aect on public health practices
The high prevalence of syphilis recognized after the advent of serologic
testing naturally led to public health measures aimed at curbing the
epidemic. These measures included the establishment of venereal disease
clinics, establishment of public health departments, and policy of screening
of blood donated for blood transfusion [8].
In 1937, before the advent of penicillin, the Surgeon General of the
United States advocated widespread use of serologic testing [8]:
The danger to ones self and others of harboring syphilis without knowing it
could be averted if everyone were to submit voluntarily to a Wasserman
test, either in the course of a periodic health examinationwhich every
intelligent person should have a good doctor give him at least once
a yearor following suspected exposure
Some hospitals make the Wassermann test a regular procedure in the
admission of all patients for every cause. All hospitals should do it.

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109

Life-insurance companies might protably make a Wassermann test in

the medical examination of every applicant for a policy . . . [and] among law
breakers . . . for marriage licenses . . . for all applicants for positions in the
public service . . . [and] private business.

Impact on informed consent policies

Syphilis continues to have an impact on the practice of modern medicine.
From 1932 until 1962, 431 black men with untreated syphilis were followed
prospectively to better establish the natural history of the disease (the
infamous Tuskegee study). The study was undertaken when some clinicians
argued that the side eects of the treatments were more detrimental than the
disease itself and were not proved to cure the disease. The study was
continued despite the proven ecacy of penicillin by the late 1940s. The
abuse of trust in the medical profession exemplied by this US government
sponsored study was a major impetus for developing a legal basis for the
principles of informed consent by patients [1921]. The Tuskegee study is
a major impediment for recruiting blacks to participate in clinical trials [20].
It is ironic that the fear of the disease that fueled practices in the past,
which now would be considered as an invasion of privacy, helped establish
the principles and practice of informed consent.
Syphilis, HIV, and AIDS
The epidemiologies of syphilis, HIV, and AIDS are the same: The
microbe is passed through sexual contact and blood and can be passed on to
the fetus. In both instances, the host enters into a clinically latent asymptomatic phase; however, there are no other similarities. Untreated syphilis is
cured by the host at least 75% of the time; untreated HIV and AIDS kills its
host more than 99% of the time. Appropriate use of antibiotics eliminates T
pallidum from the body. Appropriate antiretroviral treatment ameliorates
but does not cure HIV and AIDS.
The societal impact of both diseases is the same. Medical quackery has
a fertile eld to plow. Victims often are isolated, discriminated against, and
stigmatized. Unless HIV and AIDS is brought under control, their impact
will be far greater than syphilis, because people with these diseases die in the
prime of their productive lives, leaving behind the very young and the old,
which in turn sets the stage for societal upheaval.
Summary
Syphilis impacted virtually every aspect of human life from the 16th to
mid-20th centuries. It impacted the fate of communities and countries when
it infected societal leaders. It impacted morays by fueling puritanical
practices that still remain in place and served as an important impetus for

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public health practices that still are used. It had a dramatic role in ushering
in the antibiotic era.

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