Charles Hicks, MD, of Duke University Medical Center, presents "The Great Imitator in 2013 – Syphilis and HIV Infection"

1. The UC San Diego AntiViral Research Center sponsors weekly
presentations by infectious disease clinicians, physicians and
researchers. The goal of these presentations is to provide the most
current research, clinical practices and trends in HIV, HBV, HCV, TB
and other infectious diseases of global significance.
The slides from the AIDS Clinical Rounds presentation that you are
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audience. They may not be used for other purposes without the
presenter’s express permission.
AIDS CLINICAL ROUNDS

2. History
• 56 y.o Caucasian gay man with longstanding HIV
infection presents with fever and rash
• HIV diagnosed in 1986 – initially not in care
• Presented with PCP in 1994; Nadir CD4 count <10
cells/mm3
• Initiated antiretroviral therapy and did well with
CD4 count 382 cells/mm3 (18%) by Feb 2011
• HIV RNA (viral load) <48 copies/mL (undetectable)
• In autumn 2011 noted onset of fatigue, malaise
• Noted to have mildly elevated AST, ALT (new)

3. Biopsy results
• Liver biopsy 2/29/2012
– MILD TO MODERATELY ACTIVE INTERFACE AND LOBULAR
HEPATITIS WITH PLASMA CELLS AND MILD PERIPORTAL
CHOLESTASIS. PERIPORTAL AND PORTAL-PORTAL BRIDGING
FIBROSIS ARE SEEN IN ASSOCIATION WITH THE
INFLAMMATION
– SUSPICIOUS FOR AUTOIMMUNE HEPATITIS

4. Treatment
• Treatment for autoimmune hepatitis :
– Prednisone at 60mg started on 5 March 2012
– Azathioprine 150mg daily added on 13 March
• Approximately 48 hours after starting
azathioprine, rash developed
– Mainly on extremities
– Non-tender, non-pruritic
• Subsequently noted fever to 101.6 F
• Worsening malaise and fatigue

5. History
• Medications:
– Antiretroviral regimen:
• Raltegravir, Emtricitabine/Tenofovir
– Azathioprine 150mg daily
– Prednisone taper – now 15 mg daily
– Acyclovir 400mg BID (HSV prophylaxis)
– Testosterone replacement (gel)
– Atorvastatin 10mg once daily

6. Physical Examination
• T 38.9 C BP 112/52 HR 96 RR 16
• O2 sat 97% on 2L
• Alert and oriented, well-appearing
• Exam unremarkable except for rash
– Pale macular rash primarily involving palms, soles
– Extends to thighs and distal arms
– Spares trunk

9. Laboratory studies
• CBC:
– WBC 10.9 (72% N, 1% eos), Hgb 12.9, Plt 317
• Chemistries: Na 127, K 4.5, Cr 1.2
• ALT 55, AST 40, Alk phos 198, Alb 3.3
• U/A unremarkable
• CXR: no acute abnormalities
RPR reactive 1:256 – T. pallidum EIA positive

10. Update
• Liver biopsy 2/29
– MILD TO MODERATELY ACTIVE INTERFACE AND LOBULAR HEPATITIS WITH
PLASMA CELLS AND MILD PERIPORTAL CHOLESTASIS. PERIPORTAL AND
PORTAL-PORTAL BRIDGING FIBROSIS ARE SEEN IN ASSOCIATION WITH THE
INFLAMMATION SUSPICIOUS FOR AUTOIMMUNE HEPATITIS
• Addendum 4/10:
– Scattered spirochetes are present in the biopsy, seen only
using the immunohistochemical stain. Liver involvement in
secondary syphilis has been associated with bile ductular
proliferation and associated neutrophils, both of which were
identified in this case in addition to the more typical features of
autoimmune hepatitis (plasma cell-rich lobular and interface
hepatitis).

12. Some lessons from the case
• Syphilis can mimic many diseases
– the “Great Imitator”
– In this case - autoimmune hepatitis
• Current epidemic occurring disproportionately
in MSM, many with HIV infection
• STDs occur in persons over the age of 25 –
even over 55!

13. Return of the Great Imitator
Syphilis 2013
Charles Hicks, MD
Professor of Medicine
Duke University Medical Center

14. “Know syphilis in all its
manifestations and
relations, and all other
things clinical will be
added unto you.”
- Sir William Osler

15. History
 The first description of syphilis occurred during
and after the 1494 siege of Naples.
 Charles VIII invaded with 30,000 mercenary
soldiers who spread out over Europe after the
army was disbanded.
 They brought with them a mysterious new
illness known first as “the Neopolitan disease,”
later as the “French sickness” and “great pox.”
 During the 19th century the term syphilis became
universally accepted.

16. History
 Origins of syphilis in Europe uncertain
 Confused earlier with other diseases?
 Columbian theory
 Syphilis was endemic in New World
 Spread to Europe from returning sailors
 Whatever its origins, an aggressive form of
syphilis arose in the late 15th century -
“The Great Pox”

17. Girolamo Frascatoro 1483-1553

19. “In Englyshe Morbus Gallicus is named the
french pockes, whan than I was young they were
named the spanyshe pockes, the which be of
many kynds of the pockes…. The cause of these
impediments or infyrmytes doth come many
wayes…but specially it is taken when one pocky
person doth synne in lechary the one with
another. All the kinds of pockes be infectiouse.”
- Breviary of Healthe
Andrew Boord, 1547

20. Sick Report - Frigate “United States”
March 17, 1810

21. Dr. Julius Wagner-Jauregg
1927 Nobel Prize for Medicine for his discovery of “the therapeutic value
of malaria inoculation in the treatment of dementia paralytica”

23. Syphilis - Penicillin
• 1943 - John Mahoney reported first trial of
penicillin in syphilis
• Four patients with early syphilis given
25,000 units penicillin IM q4h for 8 days
• Darkfield became negative within 16 hours
• Total dose was 1.2 million units - this
remains a magical number in syphilis
therapy to this date.

25. Famous Persons with Syphilis
• Ivan the Terrible
• Peter the Great
• Catherine the Great
• Henry VIII of England
• Fredrich Nietzsche
• Albrecht Durer
• Benvenuto Cellini
• Guy de Maupassant
• Benito Mussolini
• Giovanni Cassanova
• Paul Gauguin
• Francisco Goya
• Vincent van Gogh
• John Keats
• Oscar Wilde
• Franz Schubert
• Moliere
• Heinrich Heine

27. 1972 - Peter Buxton, a
PHS official, complained
to a reporter about an
ongoing study of syphilis
being conducted in black
men living in Alabama.

28. The resulting stories in the NY
Times and Washington Star
created an uproar

29. Congressional hearings
convened and an outrageous
story was revealed

30. Tuskegee
• 1932: Study begins with about 600 black men
(more than 400 of whom had syphilis).
– Most are poor and uneducated
– Most from Tuskegee, Alabama, an area with the highest
syphilis rate in the U.S.
• Incentives for enrollment
– Free transportation to the hospital
– Free hot lunches
– Free medicine for any disease other than syphilis
– Free burial after autopsies were performed.
• By late 1940’s penicillin established as curative
for persons with syphilis, yet treatment not
provided to these men until decades later.

31. Tuskegee
• Understandably, the outrage was enormous,
especially in the African-American community
• Damage to the relationship with public health
community has been enduring and profound.
• This legacy of suspicion and distrust has made
public health and research efforts in HIV among
African-Americans extremely problematic.
– Belief among many African-Americans that HIV/AIDS is a
form of genocide that may have been created in a
laboratory does not seem so outlandish
• The Tuskegee study became for many blacks “a
symbol of their mistreatment by the medical
establishment, a metaphor for deceit, conspiracy,
malpractice, and neglect, if not outright racial
genocide.”

32. Remnants of the Tuskegee
Syphilis Study Effects on
University Freshmen: Yet a
Possible Barrier to Research
Participation?
Crystal B. Spivey, MPH, DrPH
March 9, 2004
Supported by: R24MD00151 NCMHD

33. Syphilis - Epidemiology
• Worldwide >12 million cases of syphilis annually
– 90% in the developing world
• U.S. cases peaked near the end of WWII, then fell
dramatically with the introduction of penicillin
• Mini-epidemic in late 1980s and early 1990s, then
declining to lowest level ever in 2000 (eradication?)
• Significant increase in cases thereafter which
continues….

35. Syphilis—Reported Cases by Stage of
Infection, United States, 1941–2011
2011-Fig 36. SR

36. Primary and Secondary Syphilis—Rates by Sex and
Male-to-Female Rate Ratios, United States, 1990–
2011
2011-Fig 38. SR

37. Primary and Secondary Syphilis—Rates by
Race/Ethnicity, United States, 2002–2011
2011-Fig 45. SR

38. Primary and Secondary Syphilis—Reported
Cases* by Sex, Sexual Behavior, and
Race/Ethnicity, United States, 2011
*Of the reported male cases of primary and secondary syphilis, 17.0% were missing sex of sex partner
information; 2.4% of sex partner data were missing race/ethnicity data.
†MSW=men who have sex with women only; MSM=men who have sex with men;
2011-Fig 47. SR

39. Primary and Secondary Syphilis—Rates by
Region, United States, 2002–2011
2011-Fig 39. SR

43. Trends in Internet Use for Sexual Encounters
by MSM with Syphilis: 2001 - 2003
17.4
20.8
26.7
0
5
10
15
20
25
30
PercentInternetusers
2001 2002 2003
Report Year
(N=899)
LAC - DHS

45. “The pleasure is
momentary, the position
ridiculous, and the expense
damnable”
-Attributed to Lord Chesterfield

46. Pathophysiology
 Syphilis is caused by the
spirochete Treponema
pallidum.
 It initiates infection after
gaining access to
subcutaneous tissues via
abrasions that occur
during sexual intercourse
 Can initiate infection on
intact skin

47. Pathophysiology
 After invading the
subcutaneous tissue the
organism establishes
the chancre.
 Some organisms also
establish infection in
regional lymph nodes
during early local
replication.

48. Pathophysiology
 Nearly all cases of syphilis are sexually acquired
(aside from congenital syphilis)
 Transmission rate during primary and secondary
syphilis is about 30% and requires exposure to
open lesions – either primary chancre or
mucocutaneous lesions.
 The incubation period varies but ranges from 10 –
90 days.

49. Clinical manifestations:
Primary syphilis
 The initial clinical manifestations is the primary
chancre.
 Usually painless, which distinguishes it from other
causes of genital ulcers: herpes simplex (genital
herpes) and Hemophilus ducreyi (chancroid).
 May be indurated (collar button)
 Most often heals without treatment over a period of
a few weeks.

50. Secondary syphilis
 If untreated,
approximately 25% of
patients will go on to
develop systemic
symptoms
 Rash
 Fever
 Headache
 Malaise
 Diffuse lymphadenopathy
 Alopecia

51. Secondary syphilis

52. Secondary Syphilis - Patchy Alopecia

53. Late vs. Latent syphilis
 Latent syphilis refers to patients without symptoms
who have positive serologic testing for syphilis.
 Early latent refers to duration less than one year
 Late latent refers to duration greater than one year or of
unknown duration
 Late or tertiary syphilis refers to the group of
clinical manifestations that may occur anywhere
between 1 and 30 years after infection when the
infection is not treated.

54. Tertiary syphilis
 Patients may not have
experienced symptomatic
primary or secondary
syphilis prior to developing
tertiary syphilis
 Most common
manifestations are central
nervous system, the
cardiovascular system, or
the skin and subcutaneous
tissues (gummas).

55. Neurosyphilis
 Neurosyphilis refers to invasion of the CSF by T.
pallidum and can occur at any stage of disease
 Early in the disease the most common manifestations
are asymptomatic meningitis, symptomatic meningitis,
and meningovascular disease.
 Late in disease, the most common forms involve the
brain and spinal cord parenchyma (general paresis
[progressive dementia] and tabes dorsalis).

56. Asymptomatic neurosyphilis
 By definition, no symptoms or signs of CNS
involvement
 Can occur within weeks of infection
 Characterized by lymphocytic pleocytosis typically <100 cells/µL, an
elevated protein concentration usually <100 mg/dL, a reactive VDRL, or
a combination of these.
 CSF WBC count >10 lymphocytes per microliter + a protein
concentration >45 mg/dL in patients without HIV infection is suggestive
 Reactive CSF-VDRL is diagnostic of neurosyphilis
 In HIV-infected patients with a negative CSF VDRL the diagnosis is
challenging since a mild CSF pleocytosis and elevated protein are
relatively common in HIV-infected patients

57. Syphilis and HIV
 HIV and syphilis are prevalent in the same risk groups,
particularly men who have sex with men (MSM)
 The two infections can enhance the acquisition and transmission
of one other
 Neurosyphilis may be more common in persons co-infected with
HIV; there have been many case reports of HIV+ patients
rapidly progressing from early syphilis to neurosyphilis
 Failure of benzathine penicillin to cross blood-brain barrier
may be more problematic in HIV-infected persons with syphilis

58. Syphilis and HIV Infection
• More florid presentations of early syphilis
• More rapid progression to symptomatic
neurosyphilis after early infection
• Risk of benzathine penicillin treatment failure -
CNS
• Delayed seroconversion (RPR, FTA-Abs) in early
syphilis
• Potential for sero-reversion of treponemal
serology
• Unusually high titer non-treponemal serologic
results
Nonetheless, most cases managed as if HIV-
negative

59. Syphilis and HIV
Aberrant Serologic Testing for Syphilis
• HIV-positive patients with syphilis often have higher
titers of reagin antibodies than HIV-uninfected
individuals.
• However, some patients with very late stage HIV
infection have delayed or absent serologic responses
(i.e., false negative tests), or are more likely to lose
their reactivity after appropriate therapy.
• This variability is thought to reflect abnormally active
B-cell function during early HIV infection and B-cell
failure during late stage infection.

60. Syphilis and HIV
Aberrant Serologic Testing for Syphilis
• The rate of decline of nontreponemal titers
following successful therapy may also be
influenced by HIV co-infection, falling more slowly
in those with HIV infection.
• In a large, randomized prospective study of persons
with early syphilis, the HIV-coinfected group had a
higher rate of serologically defined treatment
failure.
• However, in this and other studies, all patients
responded clinically to treatment, suggesting that
the significance of the diminished serologic
response may be minimal.

62. Diagnosis
 T. pallidum cannot be grown
in culture, so other methods
have been used to identify
organisms
 Dark field microscopy - direct
visualization of spirochetes taken
directly from lesions
 Direct fluorescent antibody
testing was previously used –
detected T. pallidum-specific
antigens
 Neither test currently available
 More often, serologic tests
are used, traditionally:
 Nontreponemal tests (VDRL and
RPR) measure reactivity of serum
from patients with syphilis to a
cardiolipin-cholesterol-lecithin
antigen. They measure IgG and
IgM antibodies and are reported
as titers.
 Treponemal tests (FTA-ABS, MHA-
TP and TPPA) are based upon the
detection of antibodies directed
against treponemal cellular
components.

71. If asymptomatic, who needs LP?
 Study of 239 patients with syphilis who
underwent LP analyzed to determine
predictors for neurosyphilis
 Neurosyphilis defined as +CSF VDRL and/or
CSF WBC > 20 cells/ml
 43 of 239 met diagnostic criteria. Predictors:
 Serum RPR > 1:32
 HIV infection with CD4 count < 350 cells /mm3
Marra et al. J Infect Dis 2004;189:369-76

73. Treatment of Syphilis

74. Treatment
 T. pallidum remains highly sensitive to penicillin and no resistance has been
reported to date despite several decades of use

75. Treatment
 Successful therapy requires maintenance of prolonged low concentrations of
drug in infected tissues
 Depot preparations such as benzathine penicillin accomplish this goal but
do not penetrate CNS
 Standard therapy for primary, secondary, or early latent syphilis is
benzathene penicillin G (one dose 2.4 million units IM)
 If the patient has had syphilis of greater than 1 year duration or if duration
is unknown, treatment should be benzathene penicillin G 2.4 million units IM
x 3 weekly doses
 Neurosyphilis and ocular syphilis: 18 to 24 million units per day,
administered as 3 to 4 million units IV every four hours or continuous
infusion, for 10 to 14 days

77. “Half of what we have taught
you is wrong. Unfortunately,
we do not know which half.”
– C. Sidney Burwell, M.D.
Address to the graduation class
Harvard Medical School