Treponema Pallidum Infections: A Contemporary Review for the Internist

Dr Neeraj Manikath , claude.ai

Abstract

Syphilis, caused by Treponema pallidum subspecies pallidum, remains a significant global health challenge despite the availability of effective treatment. After decades of declining incidence in developed nations, syphilis rates have resurged dramatically since 2000, with particular increases in men who have sex with men (MSM), persons living with HIV, and pregnant women. This review synthesizes current understanding of treponemal infections, emphasizing diagnostic challenges, evolving epidemiology, and management pearls essential for internal medicine practitioners.

Introduction

The spirochete Treponema pallidum represents one of medicine's great paradoxes: a fragile, fastidious organism that cannot be cultured on artificial media, yet capable of causing devastating multisystem disease across decades. While penicillin remains universally effective after nearly 80 years of use, the organism's remarkable ability to evade immune surveillance and persist in immunologically privileged sites continues to challenge clinicians.

The genus Treponema comprises four subspecies pathogenic to humans: T. pallidum subspecies pallidum (venereal syphilis), T. pallidum subspecies endemicum (endemic syphilis or bejel), T. pallidum subspecies pertenue (yaws), and T. carateum (pinta). This review focuses primarily on venereal syphilis, the form most relevant to internists in developed nations.

Epidemiology and Current Trends

The 21st century has witnessed a concerning resurgence of syphilis globally. In the United States, primary and secondary syphilis rates increased by over 70% between 2014 and 2018, with continued rises through 2023. Similar trends have been documented across Europe, Australia, and Asia. This resurgence disproportionately affects MSM, who account for approximately 85% of primary and secondary syphilis cases in the United States, with particularly high rates among those coinfected with HIV.

Pearl: The syphilis epidemic is increasingly affecting heterosexual populations, with alarming increases in congenital syphilis. Cases of congenital syphilis in the United States have increased more than 10-fold since 2012, reaching levels not seen since the 1990s. This represents a sentinel public health failure, as congenital syphilis is entirely preventable with adequate prenatal screening and treatment.

Pathophysiology and Immune Evasion

T. pallidum is a helical bacterium measuring 6-15 μm in length with remarkable structural adaptations. Its outer membrane contains unusually few surface-exposed proteins, rendering it relatively "invisible" to the immune system. This paucity of surface antigens, combined with active mechanisms including coating with host fibronectin and downregulation of immune responses, facilitates systemic dissemination within hours of inoculation.

The organism divides slowly (every 30-33 hours), contributing to the prolonged incubation period and chronic nature of infection. Despite rapid spirochetemia, T. pallidum can establish persistent infection in immunologically privileged sites including the central nervous system, eyes, and inner ear, often within the first weeks of infection.

Hack: Understanding that neurosyphilis can occur at any stage of infection—even during primary syphilis—fundamentally changes our approach to neurologic symptoms in any patient with active syphilis. The traditional teaching of "late" neurosyphilis is outdated; early neurologic involvement is far more common than previously recognized.

Clinical Manifestations

Primary Syphilis

The classic chancre appears at the inoculation site after an average incubation period of 21 days (range: 10-90 days). Typically described as a painless, indurated ulcer with clean base and raised borders, chancres are frequently atypical. Multiple chancres occur in up to 40% of cases. Importantly, chancres can occur at any site of sexual contact, including oral, anal, and genital locations, and may be painful when secondarily infected or located in certain anatomic sites.

Oyster: The absence of a visible chancre does not exclude primary syphilis. Chancres may be internal (cervical, rectal, oral), may have healed by the time the patient presents, or may be misdiagnosed as trauma or herpes simplex virus infection. Regional lymphadenopathy—typically bilateral, firm, and non-tender—provides an important diagnostic clue.

Secondary Syphilis

Secondary syphilis represents systemic spirochetemia occurring weeks to months after the primary chancre. The protean manifestations reflect widespread dissemination and can affect virtually any organ system. The classic maculopapular rash affecting palms and soles occurs in approximately 50-70% of patients, but presentations vary widely.

Constitutional symptoms including fever, malaise, weight loss, and diffuse lymphadenopathy are common. Less recognized manifestations include:

Hepatitis: Elevated alkaline phosphatase disproportionate to transaminases is characteristic
Nephritis: Immune complex glomerulonephritis or minimal change disease
Ocular involvement: Uveitis, retinitis, optic neuritis (occurs in 5-10% of secondary syphilis)
Gastric involvement: Causing hypertrophic gastritis
Alopecia: Patchy "moth-eaten" appearance

Pearl: The rash of secondary syphilis can mimic virtually any dermatosis. When evaluating any unexplained rash, especially if accompanied by systemic symptoms or lymphadenopathy, consider syphilis. The "great imitator" remains a relevant clinical descriptor.

Latent Syphilis

Latent syphilis is defined serologically: positive treponemal tests with or without positive non-treponemal tests in the absence of clinical manifestations. Early latent syphilis (within one year of infection) carries higher transmission risk and potential for relapse. Late latent syphilis (greater than one year) has lower transmission risk but carries the same risk of progression to tertiary disease without treatment.

Tertiary Syphilis

Occurring in approximately 25-40% of untreated patients, tertiary manifestations develop years to decades after initial infection. Classical tertiary disease includes:

Cardiovascular syphilis: Ascending aortitis leading to aortic regurgitation, coronary ostial stenosis, or aortic aneurysm. While rare in the antibiotic era, clinicians should maintain suspicion in patients with aortic root disease and positive syphilis serology.

Gummatous syphilis: Granulomatous lesions affecting skin, bones, or viscera, now exceedingly rare.

Neurosyphilis: Discussed separately below due to its importance.

Neurosyphilis: A Critical Focus

Neurosyphilis represents invasion of the central nervous system by T. pallidum and can occur at any stage of infection. Contemporary understanding recognizes that CSF abnormalities occur in 40% of patients with early syphilis, challenging historical staging systems.

Clinical Forms

Asymptomatic neurosyphilis: CSF abnormalities without neurologic symptoms. This diagnosis requires lumbar puncture in at-risk populations.

Meningeal neurosyphilis: Acute or subacute meningitis, typically during early infection. Presenting symptoms include headache, meningismus, and cranial nerve palsies (especially CN VII and VIII).

Meningovascular neurosyphilis: Arteritis affecting medium and small vessels, causing stroke-like presentations. Typically occurs 5-10 years after initial infection but can present much earlier.

Parenchymatous neurosyphilis: Includes general paresis (progressive dementia, personality changes, psychosis) and tabes dorsalis (posterior column degeneration causing ataxia, lancinating pains, loss of deep tendon reflexes, Argyll Robertson pupils). While rare, these remain relevant in underserved populations with untreated infection.

Ocular syphilis: Now classified under neurosyphilis, presenting as uveitis, panuveitis, optic neuritis, or retinitis. Cases have increased substantially in recent years, often requiring aggressive treatment.

Otic syphilis: Hearing loss, tinnitus, or vertigo from eighth nerve or inner ear involvement.

Hack: When evaluating any patient with unexplained stroke (especially in young patients), aseptic meningitis, cranial neuropathy, uveitis, or sudden hearing loss, always check syphilis serology. The threshold for lumbar puncture in seropositive patients should be low.

Diagnostic Approach

Syphilis diagnosis relies primarily on serologic testing due to the inability to culture T. pallidum. Understanding the complementary roles of non-treponemal and treponemal tests is essential.

Non-Treponemal Tests

Rapid plasma reagin (RPR) and venereal disease research laboratory (VDRL) tests detect antibodies against cardiolipin-cholesterol-lecithin antigen. These tests are:

Quantitative (titers correlate with disease activity)
Used for screening and monitoring treatment response
Typically positive within 1-4 weeks of chancre appearance
Subject to prozone phenomenon (false negatives in secondary syphilis due to antibody excess)
May be false positive (1-2% of population) due to pregnancy, autoimmune disease, infections, or malignancy

Pearl: A fourfold (two dilution) change in titer is considered significant for diagnosis of reinfection or treatment failure. A fourfold decrease post-treatment indicates successful therapy.

Treponemal Tests

Fluorescent treponemal antibody absorption (FTA-ABS), T. pallidum particle agglutination (TP-PA), and enzyme immunoassays (EIA) detect antibodies specific to T. pallidum. These tests:

Remain positive for life in most patients (useful for confirming diagnosis, not monitoring treatment)
Are more specific than non-treponemal tests
Become positive earlier in infection (sometimes before non-treponemal tests)

Many laboratories now use "reverse sequence" screening, performing treponemal EIA first. While efficient, this approach can identify previously treated patients or those with very early infection (treponemal-positive/non-treponemal-negative), requiring careful interpretation.

Direct Detection Methods

Dark-field microscopy: Examination of material from chancres or moist lesions remains the definitive diagnostic method but requires expertise and immediate processing. Rarely available outside reference laboratories.

Nucleic acid amplification tests (NAAT): Increasingly available and highly sensitive for detecting T. pallidum DNA in lesions, blood, or CSF. Not yet FDA-approved but used in many reference laboratories.

Neurosyphilis Diagnosis

CSF evaluation should be performed when neurosyphilis is suspected or in certain high-risk situations:

Neurologic, ocular, or otic signs or symptoms
Treatment failure
HIV coinfection with CD4 <350 cells/μL or RPR ≥1:32
Tertiary syphilis
Planned non-penicillin treatment

CSF findings in neurosyphilis include:

VDRL: Specific but insensitive (50-70% sensitivity)
Pleocytosis: >5-20 WBC/μL (lower threshold in HIV-negative patients)
Elevated protein: >45-50 mg/dL
Positive CSF treponemal testing: Sensitive but not specific

Oyster: CSF-VDRL is specific but insensitive. A negative CSF-VDRL does not exclude neurosyphilis. Diagnosis often relies on clinical findings combined with CSF pleocytosis and elevated protein in a patient with positive serum serology.

Treatment

Penicillin G remains the treatment of choice for all stages of syphilis. No resistance has been documented despite 75+ years of use, though treatment failures occasionally occur.

Treatment Regimens

Primary, secondary, and early latent syphilis:

Benzathine penicillin G 2.4 million units intramuscularly, single dose

Late latent syphilis, latent syphilis of unknown duration, tertiary syphilis (non-neuro):

Benzathine penicillin G 2.4 million units intramuscularly weekly for three doses

Neurosyphilis:

Aqueous crystalline penicillin G 18-24 million units daily (administered as 3-4 million units IV every 4 hours or continuous infusion) for 10-14 days
Alternative: Procaine penicillin G 2.4 million units IM daily plus probenecid 500 mg orally four times daily, both for 10-14 days

Congenital syphilis:

Aqueous crystalline penicillin G 50,000 units/kg IV every 12 hours (first 7 days of life) then every 8 hours for 10 days total

Penicillin Allergy

For non-pregnant penicillin-allergic patients, doxycycline 100 mg orally twice daily for 14 days (early syphilis) or 28 days (late latent syphilis) is an alternative. However, for neurosyphilis, ocular syphilis, congenital syphilis, or syphilis in pregnancy, penicillin desensitization is strongly recommended as no alternative regimen has comparable efficacy.

Hack: When documenting penicillin allergy history, distinguish between true IgE-mediated reactions (anaphylaxis, urticaria) and other reactions (GI upset, non-specific rash). Many patients labeled "penicillin allergic" can safely receive penicillin after careful evaluation or formal allergy testing. Given the superior efficacy of penicillin, pursuing penicillin desensitization is worthwhile for patients requiring treatment.

Jarisch-Herxheimer Reaction

This acute febrile reaction occurs within 24 hours of treatment in up to 90% of patients with early syphilis, caused by release of treponemal lipoproteins triggering cytokine release. Patients experience fever, myalgias, headache, and temporary worsening of skin lesions. Management is supportive with antipyretics. Patients should be warned preemptively, as the reaction can be concerning.

Pearl: Jarisch-Herxheimer reaction is neither an allergic reaction nor a contraindication to completing therapy. Its occurrence actually confirms the diagnosis and viability of organisms.

Special Populations

HIV Coinfection

HIV-syphilis coinfection is common, with each infection facilitating transmission of the other. Important considerations include:

More frequent atypical presentations
Higher rates of neurosyphilis
Possible serologic blunting (lower titers) or exaggerated responses
Accelerated progression through stages
Higher treatment failure rates

All HIV-positive patients should be screened for syphilis at baseline, annually if sexually active, and with any genital ulcer or rash. Consider CSF evaluation more liberally.

Pregnancy

Syphilis in pregnancy poses severe risks to the fetus including stillbirth, neonatal death, prematurity, and congenital syphilis. All pregnant women should be screened at the first prenatal visit, with repeat testing at 28 weeks and delivery in high-risk populations.

Treatment during pregnancy must include penicillin; no alternative is considered adequate for preventing congenital syphilis. Pregnant patients with penicillin allergy require desensitization.

Monitoring Treatment Response

Follow-up non-treponemal testing should be performed at 6 and 12 months for primary and secondary syphilis, with additional testing at 24 months for latent syphilis. Treatment success is defined by:

Fourfold decrease in titer within 6-12 months
Resolution of clinical symptoms

Treatment failure or reinfection should be suspected with:

Fourfold increase in titer
Failure to achieve fourfold decrease by 12-24 months
Persistent or recurrent symptoms

Oyster: Some patients, particularly those treated for latent syphilis, may remain "serofast" with persistently low but stable non-treponemal titers despite adequate treatment. This does not necessarily indicate treatment failure if titers decreased appropriately and remain stable. Close monitoring is warranted, but retreatment may not be required.

Prevention Strategies

Primary prevention focuses on behavioral interventions, barrier methods, and partner notification. Recent developments include:

Doxycycline post-exposure prophylaxis (doxy-PEP): Studies have shown that doxycycline 200 mg taken within 72 hours of condomless sex reduces syphilis incidence by approximately 75% in MSM. This strategy is increasingly recommended for high-risk populations, though concerns about antimicrobial resistance require ongoing monitoring.

Regular screening: Frequent screening (every 3-6 months) of high-risk populations enables early detection and treatment, interrupting transmission chains.

Emerging Challenges

Antimicrobial Resistance

While penicillin resistance remains absent, macrolide resistance is widespread due to 23S rRNA mutations, rendering azithromycin ineffective in many regions.

Diagnostic Innovations

Point-of-care treponemal tests are increasingly available, enabling same-day diagnosis and treatment in resource-limited settings. Multiplex molecular panels are improving early detection.

Vaccine Development

Despite decades of research, no effective syphilis vaccine exists. The organism's immune evasion mechanisms and lack of strong natural immunity following infection pose substantial challenges.

Conclusion

Syphilis remains highly relevant to contemporary internal medicine practice. The current epidemic demands renewed vigilance, with internists playing crucial roles in screening, diagnosis, treatment, and prevention. Key takeaways include: maintaining high clinical suspicion for atypical presentations, understanding that neurosyphilis can occur at any disease stage, recognizing the limitations and appropriate use of serologic testing, ensuring appropriate penicillin-based treatment, and implementing comprehensive partner notification and prevention strategies.

The convergence of syphilis and HIV epidemics, rising congenital syphilis rates, and emerging prevention strategies including doxy-PEP require internists to remain current with evolving guidelines. As Osler noted, syphilis is the great teacher of medicine; in the 21st century, it continues to challenge our diagnostic acumen and demands our sustained attention.

References

Peeling RW, Mabey D, Chen XS, Garcia PJ. Syphilis. Lancet. 2023;402(10398):336-346.
Stamm LV. Syphilis: antibiotic treatment and resistance. Epidemiol Infect. 2015;143(8):1567-1574.
Hook EW 3rd. Syphilis. Lancet. 2017;389(10078):1550-1557.
Workowski KA, Bachmann LH, Chan PA, et al. Sexually Transmitted Infections Treatment Guidelines, 2021. MMWR Recomm Rep. 2021;70(4):1-187.
Ghanem KG, Ram S, Rice PA. The modern epidemic of syphilis. N Engl J Med. 2020;382(9):845-854.
Marra CM. Update on neurosyphilis. Curr Infect Dis Rep. 2009;11(2):127-134.
Luetkemeyer AF, Havlir DV, Currier JS. Complications of HIV disease and antiretroviral therapy. Top Antivir Med. 2012;20(2):48-60.
Tudor ME, Al Aboud AM, Milner DA, Leslie KS. Dermatologic manifestations of syphilis. Dermatol Online J. 2021;27(5):13030.
Centers for Disease Control and Prevention. Sexually Transmitted Disease Surveillance 2020. Atlanta: U.S. Department of Health and Human Services; 2021.
Luetkemeyer AF, Donnell D, Dombrowski JC, et al. Postexposure doxycycline to prevent bacterial sexually transmitted infections. N Engl J Med. 2023;388(14):1296-1306.