Introduction to Sexually Transmitted Diseases and Syphilis (Treponema pallidum)
Reading Assignments: (1) Text Chapter 24, 40, 66 (2) Handout: Plates 95, 96, and 98, In Kapit, W. and L.M. Elson. 1977. The Anatomy Coloring Book, Harper and Row Publishers, New York; (3) Salyers, A.A. and D.D. Whitt. 1994. “Host Defenses Against Bacterial Pathogens- Defenses of Body Surfaces”, In Bacterial Pathogenesis – A Molecular Approach, ASM Press, Washington, D.C. (handed out in Lecture 3); (4) “Genital Warts and Blisters: Friends for Life”, pp. 179-182 and “Management of Syphilis”, pp. 171-173, In Gates, R. H. 1998. Infectious Disease Secrets, Hanley and Belfus, Inc., Philadelphia; (5) Gilligan, P.H., M. L. Smiley, and D.S. Shapiro. 1997. Cases in Medical Microbiology and Infectious Diseases (2nd. ed.), ASM Press, Washington, D.C., (6) Cunha, B.A., 1999. (Patients 7 and 34) Infectious Disease Pearls, Hanley and Belfus, Inc., Philadelphia.
A. How Important Are Sexually Transmitted Diseases?
The Nationally Notifiable Diseases Surveillance system is a national passive surveillance system comprising 52 infectious diseases designated as reportable to CDC. Based on the reported nationally notifiable diseases for 1995, sexually transmitted diseases (STD's) predominated and were reported among all age groups.
The 10 most frequently reported nationally notifiable infectious diseases in the United States for 1995 were, in descending order, chlamydia, gonorrhea, acquired immunodeficiency syndrome (AIDS), salmonellosis, hepatitis A, shigellosis, tuberculosis, primary and secondary syphilis, Lyme disease, and hepatitis B. The STDs of chlamydia, gonorrhea, AIDS, primary and secondary syphilis, and hepatitis B accounted for 87% of cases reported for these 10 diseases.
From: MMWR 45:883-884, 1996. CDC.
B. Why Is The Incidence of STDs Increasing Worldwide? The reasons may
include:
1. Sexually transmitted infections usually cause disease. (The exception to the
iceberg concept of infectious diseases.)
2. The emergence of new organisms (HIV) and the reemergence of old STDs
(Syphilis).
3. The increasing density and mobility of human populations.
4. The difficulty of changing human sexual behavior.
5. The absence of vaccines for almost all STDs.
6. Increased antimicrobial resistance.
The emergence of HIV infection has overshadowed other STDs, but the incidence of
AIDS is still less common than other STDs. Important relationship between
AIDS and the other STDs (See pp. 618-619 in the Text, and be able to discuss this
bidirectional relationship.)
C. What Do STDs Have in Common?
1. Epidemiology
a. Groups at Risk (See Text pp. 614-615)
1. The long term consequences of STDs disproportionately affect women
and infants. (See Text Table 66.4)
2. In the United States, STDs occur most often among young people
(less than 25 yrs old). Why? (See Text p. 615)
3. Minority groups in the United States are disproportionately affected by
STDs. (see Text p. 615)
b. Reservoirs – the asymptomatic human carrier (no animal reservoirs)
c. Transmission –via the mucous membranes of the genitourinary tract (vagina,
cervix, urethra), rectum, or oropharynx. (Most are sensitive to chemical and
physical agents and are not able to survive free in the environment.)
2. Prevention and Control of STDs (See Text pp. 619-620) – a multifaceted problem
with few ideal solutions!
a. How can STDs be prevented and controlled?
1. By preventing infection?
2. By stopping transmission?
3. By preventing disease and/or disease progression?
b. The “Ideal Tools” necessary to achieve these goals include :
1. Efficacious vaccines
2. Safe and effective (female-controlled) chemical barriers (topical
microbicides) for STD prophylaxis
3. Inexpensive, simple, rapid, and fail-safe screening and diagnostic
tests
4. Safe and effective single dose curative therapies
5. A health care system oriented towards disease prevention through
education (including behavioral choices).
D. What Are The Most Common Manifestations of STDs?
1. Acute STDs– most cause primary lesions at or near the site of entry:
a. Mucopurulant urethritis and cervicitis -gonorrhea and chlamydiae
b. Vaginitis (Candida albicans and Trichomonas vaginalis)
c. Genital ulcer disease – syphilis and genital herpes
d. Genital warts and dysplasia – human papilloma viruses.
2. Progression to Chronic Disease (the most serious consequence
of acute STDs)
a. Pelvic Inflammatory Disease (PID)– an ascending infection of the uterus and
fallopian tubes (gonococci and chlamydiae) (See Text pp. 616-618)
b. Anogenital Cancer, including cancer of the cervix and penis
c. Secondary and Tertiary Syphilis
d. Recurrent herpes infections
3. Long Term Sequelae from Chronic STDs
a. PID – - - can lead to fallopian tube scarring and adhesions of surrounding
tissues causing ectopic pregnancies, infertility, and chronic pelvic pain.
b. Congenital Diseases (syphilis, herpes, papilloma virus disease, and
chlamydial infection)
c. Increased risk of acquiring HIV – due to genital ulcers (syphilis and herpes) or
altered genital mucosa (gonorrhea and chlamydial infections)
d. Adverse Outcomes of Pregnancy – including premature termination of
pregnancy and low birth weight babies.
E. What Are the Top Ten Sexually Transmitted Diseases in the World?
F. What Are the Nonspecific and Specific Defenses of the Genitourinary Tract? (See
Reading Assignment (3).
2. Genital Warts caused by Human Papillomaviruses (See Text Chapter 40 and Reading Assignment
(4) “Genital Warts and Blisters: Friends for Life”,
3. A Look at the Pathogenic Spirochetes (Order Spirochetales)
A. The Spirochetes are grouped together on the basis of their common morphological
characteristics
1. Treponema pallidum – Syphilis (other nonvenereal treponemes)
2. Borrelia burgdorferi – Lyme Disease (tick borne)
3. Borrelia recurrentis – Relapsing fever (louse borne)
4. Leptospira interrogans – Leptospirosis
B. Common Characteristics of the Spirochetes
1. Thin-walled, flexible, spiral rods
2. Resemble Gram-negative bacteria – have an outer membrane which is lipid rich, but it
has no LPS and very few proteins
3. Motile through undulation of endoflagella that are contained within the periplasm.
4. Treponemes and Leptospira are so thin they can only be seen with darkfield
microscopy, silver impregnation, or immunofluorescence.
Borrelia are larger and can be stained with Giemsa or other blood stains, and can be
seen with the standard light microscope.
4. Treponema pallidum – Syphilis
“He who knows syphilis, knows medicine” Sir William Osler
A. A Disease With A History (see Text pp. 244-245)
1. Where did it come from?
a. The New World – Columbian Theory – endemic in Haiti and acquired and
carried to Europe by Columbus
b. Old World – Pre-Columbian Theory – syphilis originated in Central Africa and
was introduced into Europe before the voyage of Columbus
Regardless of the origin – it is clear that by 1495 a widespread epidemic had
spread throughout Europe and from there the disease spread to India (1498)
and China (1505).
2. Names
a. Great Pox
b. Lues venereum (Lover's plague)
c. Morbus gallicus (French Disease)
d. Italian, Spanish, German, or Polish Disease
e. Syphilis – from a mythical shepherd – Syphilus – described in a poem by
Fracastorius in 1530 – “Syphilis or the French Disease”
3. Early investigators believed syphilis and gonorrhea were the same disease. However
in 1838, Ricord demonstrated that they were separate diseases by inoculating 2,500
human volunteers. Ricord also proposed the classification scheme of Primary,
Secondary and Tertiary stages – used today.
4. 1905, Schaudinn and Hoffman – demonstrated spirochetes for the 1st time in Giemsa-
stained smears from secondary syphilitic lesions.
5. Serologic tests were devised by Wassermann in 1906.
6. Early treatments – “One Night with Venus, The Rest of Life With
Mercury”
a. Mercury, arsenic compounds (Ehrlich's “606”- the first synthetic
chemotherapeutic agent) and bismuth until the advent of penicillin.
b. In 1943, four cases were successfully with penicillin and this is still the drug
of choice.
1. Humans are the sole reservoir.
2. Transmission
a. Sexual contact – primary mode
b. Transfer across the placenta
3. Occurrence – World wide and increasing.
In the United States, syphilis is one of the leading notifiable diseases in the U.S.
Many cases go unreported. 1/3 of all new cases in the U.S. occur in homosexual
men.
4. Race and Sex
a. Higher incidence among African Americans, Hispanics, and Native
Americans. (In 1990, African Americans accounted for 80% of cases).
Identified risk factors include younger age, geographic instability, and poverty.
b. In the past (1980) male-to female ratio of primary and secondary syphilis 3.5
to 1. Since then male-to- female ratio has fallen to 1:1.
Increase in women attributed to prostitution related to crack cocaine.
Men have a higher rate of primary syphilis and women a higher rate of
secondary syphilis. (Women are less likely to see the primary lesion
than men because they are internal; men have lower rates of secondary
syphilis due to higher rates of diagnosis and treatment of primary
disease.)
5. Regional Differences – highest rates in the South followed by Northeast, West, and
Midwest. Highest rates in urban areas.
6. Congenital Syphilis – increasing with maternal crack cocaine use and
underutilization of prenatal care. 1n 1993, African Americans accounted for 72% of
cases.
7. In the Developing Countries – 12,000,000 new cases in 1995. Greatest numbers in
South and Southeast Asia and in sub-Saharan Africa.
C. Pathogenesis and Clinical Findings
1. Why don't we know more about the pathogenesis of syphilis?
Understanding has been hampered because:
a. T. pallidum has never been grown on bacteriologic media or cell culture.
b. There is not a suitable animal model to study the infections. Most of the
information has been garnered from experimental inoculation of rabbits.
2. Overview of pathogenesis: Following its deposition on the genital mucosa, T.
pallidum initiates an inflammatory response at the site of infection and then invades
to produces systemic disease. It produces no toxins but virulence is associated with
hyaluronidase and the ability of the organism to avoid host immune surveillance using
molecular mimicry. This pathogen can persist in host tissues for extended periods
without causing clinical symptoms but retains the ability to rapidly kill the host with
advanced disease.
3. Entry into the host:
a. By small breaks in the mucous membranes during sexual intercourse.
b. Infectious dose:
In rabbits – 2 organisms produced disease 47% of the time; 20 produced
disease 71% of the time and 200,000 organisms produced disease 100% of the time. When a large intracutaneous inoculum is used,(107) the chancre appeared in 5-7 days. Similar findings in humans.
c. With animal inoculations, organisms appear within minutes in the bloodstream
and disseminate widely within hours. (This process takes weeks in humans.)
4. Known Virulence Factors
a. Hyaluronidase – allows for breakdown of hyaluronic acid in host tissue,
enhancing the ability of the pathogen to invade many organs and tissues.
b. Molecular mimicry - The outer sheath that encases T. pallidum contains
glycosylaminoglycans (gags) modified with sialic acid residues. These
antigens resemble common molecules found on the surface of human cells
and help T. pallidum evade the host's immune response by molecular
mimicry.
(While the outer membrane contains poorly immunogenic proteins, there
are highly immunogenic lipoproteins anchored to the cytoplasmic membrane.)
5. The Three Stages of Syphilis
a. Primary Syphilis
After entering the host through the mucous membranes, the organisms
first multiply locally in the subepithelial tissue. They spread to local
lymph nodes and then over a period of three weeks to the bloodstream with dissemination throughout the body. After an incubation period of 2 – 10 weeks, a single, painless, indurated lesion with a clear base (the chancre) appears at the site of inoculation due to inflammation.
(Men – site of the lesion the coronal sulcus and glans penis;
Homosexual men – anorectal lesion; women – labia majora or labia
minora.
b. Secondary Syphilis – The ulcer heals spontaneously, but the organisms
continue to disseminate in the tissues, localizing in blood vessels and
spreading to skin, liver, joints, muscle and brain. After 1-3 months, about 25-
50% of patients then develop the observable signs of secondary syphilis.
The rest remain asymptomatic.
1. Maculopapular rash notable on the palms and soles, or as moist
papules on skin and mucous membranes. Classic lesions have been
described as “raw ham” or copper-colored. Moist lesions in the
genital area are called condylomata lata.
2. There may be multi-organ involvement including meningitis, hepatitis,
nephritis, etc.
3. The skin rash, which is rich in spirochetes and highly infectious,
disappears spontaneously (without treatment) over a 2-6 week
course.
c. After secondary syphilis:
1. About 1/3 of cases progress to cure without treatment.
2. About 1/3 of cases remain latent (3 – 30 years) – no clinical signs
of disease – T. pallidum reside in local lymph nodes and the
spleen.lesions; positive serology indicates continuing infection.
a. Early Latent Stage (< 2 years after infection)– symptoms of
secondary syphilis can reappear and patients can infect
others.
b. Late Latent Stage- no symptoms occur (for years) and
patients are not infectious.
3. 1/3 of cases progress to tertiary syphilis – 3 manifestations (may
have one or a combination of the following):
a. Development of gummas – granulomatous lesions in skin,
bones, liver and testes. On the skin – appear as nodules of
irregular shape and outline. Gumma formation appears to be
a chronic inflammatory (cell mediated hypersensitivity
response) to treponemal antigens. The lesions contain few
spriochetes compared to primary and secondary lesions.
b. Cardiovascular lesions and heart failure – including aortic
aneurysm
c. Neurosyphilis – degenerative CNS disease – with a variety
of symptoms including headache, confustion, focal seizures,
paralysis, tabes dorsalis and dementia.
Tabes dorsalis - degeneration of the dorsal columns of the
spinal cord and of the sensory nerve trunks with wasting
(tabes) due to infection of the CNS with T. pallidum. Marked
by paroxysms of intense (lightning) pains affecting the lower
limbs, loss of coordination, loss of reflexes, and loss of bowel
and bladder control.
Even with antibiotic treatment tertiary syphilis has a high
mortality because of the complications associated with CNS
invasion.
d. Congenital Syphilis – an infected woman can transfer T. pallidum to the
fetus after the 3rd month of pregnancy. Transmission in utero may result in
the birth of an asymptomatic infant or in miscarriage, stillborn birth, or death of
the fetus. Babies born with asymptomatic disease may go on to display
multiorgan dysfunction with CNS complications.
6. Unanswered questions:
a. Why does the primary chancre heal?
b. Why don't the body's defense mechanisms prevent secondary syphilis?
c. How do the organisms survive in the body for such long periods of time?
d. Are the organisms extracellular or intracellular?
e. Does the specific immune response contribute to disease?
Is the damage done in teritary syphilis due to an overactive delayed type
hypersensitivity response or do antibodies play a role?
The host makes antibody against T. pallidum. Is the damage done in
teritiary syphilis due to circulating tremponemal proteins, fibronectin, and
host antibodies? (Fibronectin is believed to be the receptor for
attachment to host cells.) Perhaps a tightly bound treponemal antigen-
fibronectin complex causes the immune system to recognize fibronectin
as a foreign antigen, and the immune system attacks host tissues.
D. Treatment – Penicillin G effective at all stages of disease. A single injection can eradicate T.
pallidum and cure early syphilis. No resistance to penicillin.
In more than 50% of patients with secondary syphilis – influenza-like symptoms
(including fever, myalgia, and rarely shock) can be experienced a few hours after
receiving the antibiotic. This reaction (the Jarisch-Herxheimer reaction) is believed to be
due to the lysis of the treponemes and the release of endotoxin-like substances.
What molecules are released to cause this reaction? Not known.
a. Darkfield microscopy
b. Direct Fluorescent antibody staining
2. Culture – not available
3. Serological Tests for Syphilis (see the handout)- looking for patient antibody!
a. Nonspecific Tests for Syphilis (nontreponemal tests-the antigen is not T.
pallidum)
Early in this century it was discovered by Wasserman and colleagues
that the sera from patients with syphilis had antibodies that would
react with an extract of normal human tissue. These antibodies, a
mixture of IgG and IgM, are called “reagin antibodies”. The VDRL
(Venereal Disease Research Laboratory) and RPR (Rapid Plasma
Reagin) tests are two nontreponemal tests that use a cardiolipin-
lecithin-cholesterol mixture (extracted from beef heart) as the antigen.
Flocculation (clumping) of the cardiolipin occurs in the presence of
antibody to T. pallidum.
These two tests are not specific for syphilis, but they are rapid and
inexpensive and are used as screening tests. Most cases of primary
syphilis give a positive reaction and almost all cases of secondary syphilis are
positive. After effective treatment, the titer declines, and the tests become
negative. False positive reactions occur with other diseases including many
autoimmune diseases. Positive tests must be confirmed with a specific test
(see below).
b. Specific Serological Tests (Treponemal tests – the antigen is T. pallidum)
1. FTA-ABS (Fluorescent Treponemal Antibody-Absorbed Test)- an
indirect FA test
a. Patient's serum is absorbed with non-pathogenic treponemes
to remove cross reacting antibodies.
b. T. pallidum antigen on a slide is reacted with patient serum
(containing antibodies?)
c. Slide is rinsed and reacted with fluorescein- labeled antibody
against human IgG . A + test = green- glowing treponemes
after illumination with UV light.
2. MHA-TP (Microhemagglutination-Treponema pallidum test)
The patient's serum is reacted with sheep erythrocytes coated with
antigens of T. pallidum. If antibodies are present, hemagglutination
occurs.
Specific tests are positive in most cases of primary syphilis
(antibody appears in 2-3 weeks after infection.) Patients remain
positive for life.
F. Prevention
Depends on early diagnosis and adequate treatment, serologic follow-up of infected
patients and their contacts, the administration of antibiotics after suspected exposure,
and the use of condoms.