The Great Imitator in 2013 – Syphilis and HIV Infection
The UC San Diego AntiViral Research Center sponsors weeklypresentations by infectious disease clinicians, physicians andresearchers. The goal of these presentations is to provide the mostcurrent research, clinical practices and trends in HIV, HBV, HCV, TBand other infectious diseases of global significance.The slides from the AIDS Clinical Rounds presentation that you areabout to view are intended for the educational purposes of ouraudience. They may not be used for other purposes without thepresenter’s express permission.AIDS CLINICAL ROUNDS
History• 56 y.o Caucasian gay man with longstanding HIVinfection presents with fever and rash• HIV diagnosed in 1986 – initially not in care• Presented with PCP in 1994; Nadir CD4 count <10cells/mm3• Initiated antiretroviral therapy and did well withCD4 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)
Biopsy results• Liver biopsy 2/29/2012– MILD TO MODERATELY ACTIVE INTERFACE AND LOBULARHEPATITIS WITH PLASMA CELLS AND MILD PERIPORTALCHOLESTASIS. PERIPORTAL AND PORTAL-PORTAL BRIDGINGFIBROSIS ARE SEEN IN ASSOCIATION WITH THEINFLAMMATION– SUSPICIOUS FOR AUTOIMMUNE HEPATITIS
Treatment• Treatment for autoimmune hepatitis :– Prednisone at 60mg started on 5 March 2012– Azathioprine 150mg daily added on 13 March• Approximately 48 hours after startingazathioprine, rash developed– Mainly on extremities– Non-tender, non-pruritic• Subsequently noted fever to 101.6 F• Worsening malaise and fatigue
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
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 abnormalitiesRPR reactive 1:256 – T. pallidum EIA positive
Update• Liver biopsy 2/29– MILD TO MODERATELY ACTIVE INTERFACE AND LOBULAR HEPATITIS WITHPLASMA CELLS AND MILD PERIPORTAL CHOLESTASIS. PERIPORTAL ANDPORTAL-PORTAL BRIDGING FIBROSIS ARE SEEN IN ASSOCIATION WITH THEINFLAMMATION SUSPICIOUS FOR AUTOIMMUNE HEPATITIS• Addendum 4/10:– Scattered spirochetes are present in the biopsy, seen onlyusing the immunohistochemical stain. Liver involvement insecondary syphilis has been associated with bile ductularproliferation and associated neutrophils, both of which wereidentified in this case in addition to the more typical features ofautoimmune hepatitis (plasma cell-rich lobular and interfacehepatitis).
Some lessons from the case• Syphilis can mimic many diseases– the “Great Imitator”– In this case - autoimmune hepatitis• Current epidemic occurring disproportionatelyin MSM, many with HIV infection• STDs occur in persons over the age of 25 –even over 55!
Return of the Great ImitatorSyphilis 2013Charles Hicks, MDProfessor of MedicineDuke University Medical Center
“Know syphilis in all itsmanifestations andrelations, and all otherthings clinical will beadded unto you.”- Sir William Osler
History The first description of syphilis occurred duringand after the 1494 siege of Naples. Charles VIII invaded with 30,000 mercenarysoldiers who spread out over Europe after thearmy was disbanded. They brought with them a mysterious newillness known first as “the Neopolitan disease,”later as the “French sickness” and “great pox.” During the 19th century the term syphilis becameuniversally accepted.
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 ofsyphilis arose in the late 15th century -“The Great Pox”
“In Englyshe Morbus Gallicus is named thefrench pockes, whan than I was young they werenamed the spanyshe pockes, the which be ofmany kynds of the pockes…. The cause of theseimpediments or infyrmytes doth come manywayes…but specially it is taken when one pockyperson doth synne in lechary the one withanother. All the kinds of pockes be infectiouse.”- Breviary of HealtheAndrew Boord, 1547
Dr. Julius Wagner-Jauregg1927 Nobel Prize for Medicine for his discovery of “the therapeutic valueof malaria inoculation in the treatment of dementia paralytica”
Syphilis - Penicillin• 1943 - John Mahoney reported first trial ofpenicillin in syphilis• Four patients with early syphilis given25,000 units penicillin IM q4h for 8 days• Darkfield became negative within 16 hours• Total dose was 1.2 million units - thisremains a magical number in syphilistherapy to this date.
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
1972 - Peter Buxton, aPHS official, complainedto a reporter about anongoing study of syphilisbeing conducted in blackmen living in Alabama.
The resulting stories in the NYTimes and Washington Starcreated an uproar
Congressional hearingsconvened and an outrageousstory was revealed
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 highestsyphilis 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 curativefor persons with syphilis, yet treatment notprovided to these men until decades later.
Tuskegee• Understandably, the outrage was enormous,especially in the African-American community• Damage to the relationship with public healthcommunity has been enduring and profound.• This legacy of suspicion and distrust has madepublic health and research efforts in HIV amongAfrican-Americans extremely problematic.– Belief among many African-Americans that HIV/AIDS is aform of genocide that may have been created in alaboratory does not seem so outlandish• The Tuskegee study became for many blacks “asymbol of their mistreatment by the medicalestablishment, a metaphor for deceit, conspiracy,malpractice, and neglect, if not outright racialgenocide.”
Remnants of the TuskegeeSyphilis Study Effects onUniversity Freshmen: Yet aPossible Barrier to ResearchParticipation?Crystal B. Spivey, MPH, DrPHMarch 9, 2004Supported by: R24MD00151 NCMHD
Syphilis - Epidemiology• Worldwide >12 million cases of syphilis annually– 90% in the developing world• U.S. cases peaked near the end of WWII, then felldramatically with the introduction of penicillin• Mini-epidemic in late 1980s and early 1990s, thendeclining to lowest level ever in 2000 (eradication?)• Significant increase in cases thereafter whichcontinues….
Syphilis—Reported Cases by Stage ofInfection, United States, 1941–20112011-Fig 36. SR
Primary and Secondary Syphilis—Rates by Sex andMale-to-Female Rate Ratios, United States, 1990–20112011-Fig 38. SR
Primary and Secondary Syphilis—Rates byRace/Ethnicity, United States, 2002–20112011-Fig 45. SR
Primary and Secondary Syphilis—ReportedCases* by Sex, Sexual Behavior, andRace/Ethnicity, United States, 2011*Of the reported male cases of primary and secondary syphilis, 17.0% were missing sex of sex partnerinformation; 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
Primary and Secondary Syphilis—Rates byRegion, United States, 2002–20112011-Fig 39. SR
Trends in Internet Use for Sexual Encountersby MSM with Syphilis: 2001 - 200317.420.826.7051015202530PercentInternetusers2001 2002 2003Report Year(N=899)LAC - DHS
“The pleasure ismomentary, the positionridiculous, and the expensedamnable”-Attributed to Lord Chesterfield
Pathophysiology Syphilis is caused by thespirochete Treponemapallidum. It initiates infection aftergaining access tosubcutaneous tissues viaabrasions that occurduring sexual intercourse Can initiate infection onintact skin
Pathophysiology After invading thesubcutaneous tissue theorganism establishesthe chancre. Some organisms alsoestablish infection inregional lymph nodesduring early localreplication.
Pathophysiology Nearly all cases of syphilis are sexually acquired(aside from congenital syphilis) Transmission rate during primary and secondarysyphilis is about 30% and requires exposure toopen lesions – either primary chancre ormucocutaneous lesions. The incubation period varies but ranges from 10 –90 days.
Clinical manifestations:Primary syphilis The initial clinical manifestations is the primarychancre. Usually painless, which distinguishes it from othercauses of genital ulcers: herpes simplex (genitalherpes) and Hemophilus ducreyi (chancroid). May be indurated (collar button) Most often heals without treatment over a period ofa few weeks.
Secondary syphilis If untreated,approximately 25% ofpatients will go on todevelop systemicsymptoms Rash Fever Headache Malaise Diffuse lymphadenopathy Alopecia
Late vs. Latent syphilis Latent syphilis refers to patients without symptomswho 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 ofunknown duration Late or tertiary syphilis refers to the group ofclinical manifestations that may occur anywherebetween 1 and 30 years after infection when theinfection is not treated.
Tertiary syphilis Patients may not haveexperienced symptomaticprimary or secondarysyphilis prior to developingtertiary syphilis Most commonmanifestations are centralnervous system, thecardiovascular system, orthe skin and subcutaneoustissues (gummas).
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 manifestationsare asymptomatic meningitis, symptomatic meningitis,and meningovascular disease. Late in disease, the most common forms involve thebrain and spinal cord parenchyma (general paresis[progressive dementia] and tabes dorsalis).
Asymptomatic neurosyphilis By definition, no symptoms or signs of CNSinvolvement Can occur within weeks of infection Characterized by lymphocytic pleocytosis typically <100 cells/µL, anelevated protein concentration usually <100 mg/dL, a reactive VDRL, ora combination of these. CSF WBC count >10 lymphocytes per microliter + a proteinconcentration >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 ischallenging since a mild CSF pleocytosis and elevated protein arerelatively common in HIV-infected patients
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 transmissionof one other Neurosyphilis may be more common in persons co-infected withHIV; there have been many case reports of HIV+ patientsrapidly progressing from early syphilis to neurosyphilis Failure of benzathine penicillin to cross blood-brain barriermay be more problematic in HIV-infected persons with syphilis
Syphilis and HIV Infection• More florid presentations of early syphilis• More rapid progression to symptomaticneurosyphilis after early infection• Risk of benzathine penicillin treatment failure -CNS• Delayed seroconversion (RPR, FTA-Abs) in earlysyphilis• Potential for sero-reversion of treponemalserology• Unusually high titer non-treponemal serologicresultsNonetheless, most cases managed as if HIV-negative
Syphilis and HIVAberrant Serologic Testing for Syphilis• HIV-positive patients with syphilis often have highertiters of reagin antibodies than HIV-uninfectedindividuals.• However, some patients with very late stage HIVinfection have delayed or absent serologic responses(i.e., false negative tests), or are more likely to losetheir reactivity after appropriate therapy.• This variability is thought to reflect abnormally activeB-cell function during early HIV infection and B-cellfailure during late stage infection.
Syphilis and HIVAberrant Serologic Testing for Syphilis• The rate of decline of nontreponemal titersfollowing successful therapy may also beinfluenced by HIV co-infection, falling more slowlyin those with HIV infection.• In a large, randomized prospective study of personswith early syphilis, the HIV-coinfected group had ahigher rate of serologically defined treatmentfailure.• However, in this and other studies, all patientsresponded clinically to treatment, suggesting thatthe significance of the diminished serologicresponse may be minimal.
Diagnosis T. pallidum cannot be grownin culture, so other methodshave been used to identifyorganisms Dark field microscopy - directvisualization of spirochetes takendirectly from lesions Direct fluorescent antibodytesting was previously used –detected T. pallidum-specificantigens Neither test currently available More often, serologic testsare used, traditionally: Nontreponemal tests (VDRL andRPR) measure reactivity of serumfrom patients with syphilis to acardiolipin-cholesterol-lecithinantigen. They measure IgG andIgM antibodies and are reportedas titers. Treponemal tests (FTA-ABS, MHA-TP and TPPA) are based upon thedetection of antibodies directedagainst treponemal cellularcomponents.
If asymptomatic, who needs LP? Study of 239 patients with syphilis whounderwent LP analyzed to determinepredictors for neurosyphilis Neurosyphilis defined as +CSF VDRL and/orCSF WBC > 20 cells/ml 43 of 239 met diagnostic criteria. Predictors: Serum RPR > 1:32 HIV infection with CD4 count < 350 cells /mm3Marra et al. J Infect Dis 2004;189:369-76
Treatment T. pallidum remains highly sensitive to penicillin and no resistance has beenreported to date despite several decades of use
Treatment Successful therapy requires maintenance of prolonged low concentrations ofdrug in infected tissues Depot preparations such as benzathine penicillin accomplish this goal butdo not penetrate CNS Standard therapy for primary, secondary, or early latent syphilis isbenzathene penicillin G (one dose 2.4 million units IM) If the patient has had syphilis of greater than 1 year duration or if durationis unknown, treatment should be benzathene penicillin G 2.4 million units IMx 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 continuousinfusion, for 10 to 14 days
“Half of what we have taughtyou is wrong. Unfortunately,we do not know which half.”– C. Sidney Burwell, M.D.Address to the graduation classHarvard Medical School