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Episode #21 – Sailor’s Salutation

21 Cover Art OPT

Summary

Fine tune your syphilology prowess with Drs. Zach Lorenz and Khalil Ghanem!

Credits

Host(s): Zach Lorenz, Sara Dong

Guest: Khalil Ghanem

Writing: Zach Lorenz, Sara Dong

Producing/Editing/Cover Art/Infographics: Sara Dong

Our Guests

Khalil Ghanem, MD, PhD

Dr. Khalil Ghanem is a Professor of Medicine in the Division of Infectious Diseases at Johns Hopkins University School of Medicine and in the Division of Population, Family, and Reproductive Health at the Johns Hopkins Bloomberg School of Public Health. He has been the Principal Investigator of the CDC-funded Johns Hopkins STD/HIV Prevention Training Center since 2014. His research focuses on reproductive tract infections- in particular syphilis and the vaginal microbiome. He is the current president of the American Sexually Transmitted Diseases Association.

Zach Lorenz, MD

Dr. Lorenz is an internal medicine resident at Hopkins Bayview IM Residency

Twitter

Culture

Khalil is an avid collector of art and bringing home pieces that make your heart pitter patter!

“Find artistic things you love, collect them, keep them close at hand and look at them every day”

Consult Notes

Consult Q

44 yo male with newly diagnosed HIV who presented with rash and fever

One-liner

44 yo male with newly diagnosed HIV who presented with ocular and neurosyphilis

Key Points

Jump to:

Syphilis Resources
Syphilis Diagnostics
Clinical manifestations
Management
Who needs an LP?

This episode is all about SYPHILIS / Treponema pallidum.  A summary of points from the episode are noted below but before that, here are some reading resources:

Khalil gave an overview on interpretation of syphilis serologic testing!

There are two types of serologic tests for syphilis: nontreponemal and treponemal

    • Nontreponemal tests = RPR (serum) or VDRL (serum or CSF)
        • False positives can occur with: endemic treponematoses, old age, pregnancy, autoimmune diseases, viral infections (including HIV)
        • Reactive nontreponemal test results must be confirmed with a treponemal test
        • False negative can occur with prozone effect
        • Four-fold change in titer (i.e. 2-dilution) decline after treatment = CURE (irrespective of end titer)
        • Titers will decline over time and might become nonreactive with or without treatment
    • Treponemal tests = MHA-TP, TPPA, FTA-Abs, EIAs, CIA
        • Once reactive, always reactive (even after appropriate therapy)
        • False positives can occur with: endemic treponemal infections (eg, yaws, pinta, bejel), Lyme disease, old age, severe gingivitis, or rarely in autoimmune conditions
        • Treponemal titers do not predict treatment response and shouldn’t be used for this purpose
  • Use of only one type of serologic test (nontreponemal or treponemal) is insufficient for diagnosis → so there are two types of algorithms for syphilis testing
      • Traditional or standard algorithm starts with nontreponemal test.  If positive, then use treponemal test to confirm diagnosis
      • Reverse sequence algorithm starts with treponemal test.  If positive, then use nontreponemal test to stage the patient
  • Khalil’s 4 rules for mastering syphilis serologies
      • #1 Both treponemal and nontreponemal serologies may be nonreactive in early primary syphilis
          • Up to 30% of persons with primary syphilis may be nonreactive, so testing should be repeated in 2 wks if initial test is nonreactive
      • #2  Both treponemal and nontreponemal antibodies can be reactive due to other non-syphilis reasons
          • See above for false positives in nontrep and trep tests
      • #3  Treponemal antibodies: once positive, always positive, irrespective of treatment history (why they are not useful in managing patients)
          • Up to 24% of patients treated in the early stage of syphilis have seroreversion years after therapy
      • #4  Nontreponemal Ab may become nonreactive in persons who are treated for syphilis, but also decline over time in absence of treatment

No single test can be used to diagnose neurosyphilis

      • Diagnosis of neurosyphilis depends on a combination of CSF tests (CSF cell count, protein, or reactive CSF-VDRL) in presence of reactive serologic test (nontreponemal and treponemal) results and neurologic s/s
      • 50% of neurosyphilis cases may have negative CSF VDRL; it is highly specific but insensitive
      • CSF treponemal tests are very sensitive but not specific (i.e. high false positives) → may be used to rule out neurosyphilis
      • ~30% of persons with late neurosyphilis may have nonreactive serum nontreponemal test
      • If you get a normal LP, you have effectively ruled out neurosyphilis!  CSF pleiocytosis is the most sensitive test for neurosyphilis, although not specific.  

Khalil discussed the question that often arises: a patient without pleiocytosis, negative CSF VDRL, but a slightly increased CSF protein.  This likely is not neurosyphilis given lack of pleiocytosis.  One strategy that can be used is ordering a CSF treponemal test, which is not specific but is sensitive.  If positive, it does not rule in neurosyphilis — but if negative, further evidence that this is not neurosyphilis.  

In secondary syphilis, usually everyone has reactive serologies. If they don’t, think about prozone phenomenon (Need to dilute sample, usually an imbalance between Ag-Ab). Short of prozone though, if you have negative serologies in suspected secondary syphilis, reconsider what might be going on.

Some notes on the clinical manifestations of syphilis

Khalil gave a great summary of the classic differences in syphilis between PLWH and immunocompetent persons

  • Clinical manifestations are similar but timeline may be compressed in PLWH → more rapid progression through the stages of syphilis in persons with HIV
      • You might even see the primary and secondary stages coexist in these patients!
  • Persons with HIV are more susceptible to early neurosyphilis 
  • Testing and therapy similar to HIV-uninfected, but:
      • Serological failure is more likely among people with HIV
      • Serological response may be slower among people with HIV
      • Follow-up more frequent (every 3 months)

Early syphilis

      • Incubation ~3 weeks
      • Primary early syphilis classically presents as solitary painless chancre or ulcer at site of infection that resolves in 3-6 wks. May have localized lymphadenopathy or multiple painful anogenital ulcers in some cases
      • Secondary early syphilis (disseminated) is characterized by systemic symptoms and usually occurs ~1-2 mo after primary syphilis (usually ~3 mo after initial infection)
          • Low grade fever, malaise, sore throat, lymphadenopathy, myalgias
          • Rash may be initially be mild, nonpruritic, macular dry rash followed by red (or “copper”) papular eruption (involving palms and soles); mucosal lesions (gray plaques or ulcers) may be present; condyloma lata
          • Other possible manifestations: 
            • Uveitis
            • Alopecia
            • Hepatitis (**mild elevation of aminotransferases with disproportionately high alkaline phosphatase)
            • Gastritis
            • Periostitis
            • Glomerulonephritis

Neurological manifestations of syphilis

      • Can occur during any stage of infection and may be asymptomatic or symptomatic
      • Asymptomatic early neurosyphilis
          • Treponemal CNS invasion with abnormal CSF findings impacts up to half of persons after early infection → CSF changes resolve typically after recommended therapy for early syphilis
                • CDC does not recommend routine CSF exam for persons with early syphilis, irrespective of HIV status, unless neurologic signs are present
      • Symptomatic early neurosyphilis
          • Typically in first year after infection
          • Mainly among HIV+ persons
          • Presents as meningitis (headaches, photophobia, CN abnormalities, ocular symptoms), often basilar form
      • Symptomatic late neurosyphilis (tertiary syphilis)
          • Usually occurs ~10 years after primary infection
          • Can be divided into 2 categories: meningovascular and parenchymatous
                • Meningovascular (tend to be 5-12 yrs after initial infection): endarteritis of small blood vessels in meninges, brain, spinal cord
                  • Typical manifestations = strokes (MCA distribution is classic) and seizures
                • Parenchymatous (tend to occur later >15 years after infection): due to actual destruction of nerve cells
                  • Tabes dorsalis: shooting pains, ataxia, CN abnormalities, optic atrophy
                  • General paresis: dementia, psychosis, slurring speech, Argyll Robertson pupil

Ocular syphilis and otic syphilis are distinct clinical entities from neurosyphilis, but may occur concomitantly. Ocular and otic syphilis also may occur during any stage of infection

    • Ocular syphilis:
        • May involve any portion of the eye, but posterior uveitis is most common clinical presentation
        • Uveitis and neuroretinitis: mainly secondary stage
        • Interstitial keratitis: occurs in both congenital (typically at age 5-20; 80% bilateral) and acquired (both early and late infections)
        • CSF examination normal in ~30% of cases of ocular syphilis
    • Otic syphilis
        • Sensorineural hearing loss with vestibular complaints (sudden or fluctuating hearing loss, tinnitus, or vertigo)
          • Congenital (early and late)
          • Acquired (secondary and late stages)
        • CSF examination is normal in >90% of cases of otic syphilis
    • **No need for CSF examination in patients who only have isolated ocular and otic symptoms or signs**

Tertiary syphilis: about ⅓ of untreated syphilis will develop manifestations of tertiary syphilis

    • Cardiovascular involvement: 15-30 years after latency, more in men
        • Aortic aneurysm, aortic insufficiency, coronary artery stenosis, myocarditis
    • Late benign syphilis
        • ‘Gummas’: Granulomatous process involving skin, cartilage, bone (less commonly in viscera, mucosa, eyes, brain)
    • Late neurosyphilis (also noted above)
        • General paresis
        • Tabes dorsalis

Latent infections: asymptomatic infection

    • Early latent syphilis: infection <12 months
        • Can occur between the primary and secondary stages and after resolution of secondary stage lesions
    • Late latent syphilis: infection  >=12 months ago (or time unknown)
    • CDC uses 1-year cutoff point for duration of early latent vs late latent syphilis because most relapses occur within 1 year

Management of syphilis

  • Penicillin G is the preferred drug for treating patients in all stages of syphilis → the preparation used (i.e. benzathine, aqueous procaine, or aqueous crystalline), dosage, and length of treatment depend on stage and clinical manifestations
    • Selection of the appropriate PCN preparation is important because T.pallidum can reside in sequestered sites (such as CNS and aqueous humor) that might be poorly accessed by certain forms

 

  • Early stages (primary, secondary, early latent)
      • 2.4 million units benzathine PCN G IM in a single dose
      • Alternative: doxycycline 100mg PO BID x 14 days
  • Late latent syphilis (>1 years’ duration or unknown duration)
      • 2.4 million units benzathine PCN G IM x 3 doses (over 2 weeks, 7.2 million units total) 
      • Alternative: doxycycline 100mg PO BID x 4 wks
  • Neurosyphilis, Ocular syphilis, Otic syphilis – while these are distinct clinical entities, all are treated the same
      • Aqueous crystalline PCN G 18 to 24 million units IV per day x 10-14 days
      • Alternative: [Procaine PCN G 2.4 million units IM QD + probenecid 500mg PO QID] x 10-14 days
      • Alternative: Ceftriaxone 1-2g IV/IM x 10-14d (2nd line regimen)
      • Goal of treatment is to stop progression (symptoms are not necessarily reversible, particularly if further out in time — don’t be surprised if s/s don’t resolve completely)
  • Other notes on treatment:
      • Resistance to penicillin has not been observed
      • Persons with documented penicillin allergies should have desensitization to PCN
      • The data on the alternative agents mentioned above are limited
  • A quick reminder about the Jarisch-Herxheimer reaction
      • Acute febrile reaction frequently accompanied by headache, myalgia, fever
      • Within 6 hrs (up to 24 hrs) after therapy of (usually) early syphilis
      • Can use antipyretics for symptom management if needed
      • **It is reaction to treatment and not an allergic reaction**
      • May induce early labor or cause fetal distress in pregnant women
  • Khalil discussed the controversy about use of steroids with ocular / neuro / otic syphilis.  There are no convincing data, although what is available is limited.  His opinion: if patient doesn’t have contraindication to steroids, it is not unreasonable if there is evidence of inflammation — but he generally would not recommend.  Does require relatively high doses of steroids though, often 14-21d.  
  • Khalil also discussed the question of whether we need to do a follow-up LP after 6 months.

A key part of the evaluation of a patient with syphilis is asking about neuro, ocular, and otic symptoms!!  

Which patients need an LP / CSF examination?  (in patients with evidence of serological infection with syphilis or clinical evidence if early primary syphilis with negative serologies)

  • Evidence of neurological symptoms (e.g., cranial nerve dysfunction, meningitis, stroke, acute or chronic altered mental status, loss of vibration sense)
      • If only ocular or otic symptoms, do NOT need an LP (up to 30% with ocular syphilis and >90% with otic syphilis will have normal CSF exam → and ultimately would still treat with 14d of IV PCN)
  • Tertiary syphilis (cardiovascular or gummatous) → 30-40% of these patients have concomitant asymptomatic neurosyphilis and this would change their treatment (tertiary = 3 doses of benzathine PCN G, but neurosyphilis = PCN IV x 14d)
  • Failure or inadequate response to treatment
      • If you treat appropriately, would expect titers to go down 4-fold.  If titers go up 4-fold and there is no possibility of re-infection, this should make you consider LP to make sure not missing asymptomatic neurosyphilis as cause of rising titers
  • The other question that sometimes arises is whether all persons with HIV + syphilis should have an LP.  As Khalil discussed, there is no data to suggest better outcomes (although data is limited).  If the patient has no symptoms, it is not clear there is any reason to add an LP.  
      • There is technically the possibility of missing asymptomatic neurosyphilis in a small number of patients.  Some might consider the LP in an asymptomatic pt with HIV if CD4 <350 or RPR >1:32 (given these are risk factors for neurosyphilis) — although that’s not unreasonable, many experts like Khalil would not pursue.  This guidance is also noted in the new 2021 STI guidelines

Khalil ended the episode by discussing a frequent call/page that can frustrate ID fellows: what to do when RPR titers don’t do what they are supposed to!!  Here is the summary of points related to serologic nonresponse:

Other miscellaneous mentions and notes:

Episode Art & Infographics

Goal

Listeners will be able to describe the clinical manifestations, diagnosis and management of syphilis

Learning Objectives

After listening to this episode, listeners will be able to:

  • Identify the stages of T.pallidum infection and their clinical manifestations
  • Compare and interpret diagnostic serologies for T.pallidum infection
  • Discuss the indications for CSF evaluation in patients with syphilis
  • Apply CDC recommended treatment regimens for early, late, and neurosyphilis

Disclosures

Our guest (Khalil Ghanem) as well as Febrile podcast and hosts report no relevant financial disclosures

Citation

Ghanem, K., Lorenz, Z., Dong, S. “#21: Sailor’s Salutation”. Febrile: A Cultured Podcast. https://player.captivate.fm/episode/3c2d83ac-d156-4634-95fe-76c89b0076fa

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