Sifilis

01Pathophysiology

Syphilis is caused by Treponema pallidum subspecies pallidum, a thin, motile spirochete that cannot be cultured on artificial media. The organism enters the body through microscopic breaks in mucous membranes or skin during sexual contact (genital, oral, or anal), through contaminated needles, through contaminated blood products, or transplacentally from mother to fetus.

Once T. pallidum penetrates the epithelium, it multiplies locally at the site of inoculation and simultaneously disseminates hematogenously within hours. This is a critical concept: syphilis is a systemic disease from the very beginning, even though the initial lesion appears localized. The immune response at the inoculation site produces the classic chancre of primary syphilis, an ulcer formed by the inflammatory infiltrate attempting to contain the organism. This chancre is painless because T. pallidum does not produce toxins that trigger significant nociceptor activation, and the immune response is predominantly a granulomatous-type reaction rather than a neutrophilic one.

The bacterium's outer membrane lacks lipopolysaccharide (LPS), which is why the early immune response is relatively muted and why the organism can evade detection for prolonged periods. T. pallidum also has very few surface-exposed proteins, making it a so-called "stealth pathogen" that avoids antibody-mediated clearance.

If untreated, the primary chancre resolves spontaneously in 3 to 6 weeks (even without treatment), which is a classic exam trap: resolution does not mean cure. The spirochetes continue to circulate, and the disease transitions to secondary syphilis as the immune system mounts a broader, systemic response to the now-widespread organism. The diffuse rash of secondary syphilis reflects the hematogenous dissemination that occurred weeks earlier. The involvement of palms and soles is a high-yield finding because these are areas with thick keratinized skin that most rashes spare; the ability of T. pallidum to infiltrate dermal vasculature even in these areas is distinctive.

Condylomata lata arise in warm, moist intertriginous areas (perianal, vulvar folds) because T. pallidum thrives in these environments. These flat, moist, highly infectious lesions are rich in spirochetes. They should not be confused with condylomata acuminata (genital warts caused by HPV), which are pointed and verrucous rather than flat.

After secondary syphilis, the disease enters a latent phase where the patient is asymptomatic but serologically reactive. This phase is subdivided by duration: early latent (less than 1 year since transmission) and late latent (more than 1 year). The distinction matters because infectivity and treatment regimen differ.

In approximately one-third of untreated patients, tertiary syphilis develops years to decades later. This stage involves three main patterns: gummatous disease (granulomatous destruction of skin, bone, or viscera), cardiovascular syphilis (obliterative endarteritis of the vasa vasorum of the aorta, leading to aortitis, aortic aneurysm, and aortic regurgitation), and neurosyphilis (which can actually occur at any stage). The cardiovascular manifestation typically appears 10 to 30 years after the initial infection, while gummas can appear from 1 to 46 years later.

Neurosyphilis deserves special attention because it does not fit neatly into the staged progression. Treponemal invasion of the CNS can occur early (meningitis, cranial nerve palsies) or late (general paresis, tabes dorsalis). The Argyll Robertson pupil, which accommodates but does not react to light, is a classic late neurosyphilis finding tested frequently.

In congenital syphilis, T. pallidum crosses the placenta, with the risk of fetal infection increasing with maternal spirochetemia. Early congenital syphilis (manifesting before age 2) can present with rhinitis ("snuffles"), maculopapular rash, hepatosplenomegaly, and bony changes. Late congenital syphilis (manifesting after age 2) produces the classic Hutchinson's triad: interstitial keratitis, Hutchinson's teeth (peg-shaped notched incisors), and eighth cranial nerve deafness. Other findings include saddle nose, frontal bossing, saber shins, and mulberry molars.

02Classification and Clinical Manifestation

Classification Overview

Clinical Manifestation by Stage

Complications

03Diagnostic Workup

Diagnostic Approach in Detail

The diagnostic workup for syphilis relies on two separate categories of serologic testing, and understanding the logic behind each is what exam questions test.

Non-treponemal tests (RPR and VDRL) detect antibodies directed against cardiolipin-lecithin-cholesterol antigens released during cell damage. They are not directed against the spirochete itself. These tests become positive approximately 4 weeks after initial infection, meaning they can be negative during early primary syphilis when the chancre is already present. This is the classic "window period" trap on exams: a patient with a painless genital ulcer and a negative VDRL may still have syphilis.

Non-treponemal titers are quantitative and correlate with disease activity. They are therefore used to monitor treatment response. A successful treatment is defined as a four-fold or greater decline in titer (e.g., from 1:32 to 1:8). After successful treatment, titers should decline and may become non-reactive. However, some patients become serofast, meaning their titer plateaus at a low level (typically 1:8 or below) and never fully converts to non-reactive. Serofast status within 1-2 years after treating early syphilis is not considered treatment failure.

False-positive non-treponemal results are a heavily tested concept:

The titer for false positives is generally low, typically 1:4 or below.

Another important pitfall is the prozone phenomenon: in secondary syphilis, antibody levels can be so high that they overwhelm the test, producing a false-negative result. If secondary syphilis is strongly suspected clinically despite a non-reactive VDRL/RPR, request dilution of the sample and retest.

Treponemal tests (TPHA, TP-Rapid, TP-PA, FTA-ABS) detect antibodies directed against T. pallidum itself. They become positive earlier, approximately 14 days after infection, and generally remain positive for life even after successful treatment. This means they cannot be used to monitor treatment response or distinguish active from prior treated infection.

Treponemal tests can also produce false positives in infections with other treponemes, including T. pallidum subspecies pertenue (the causative agent of yaws/frambusia), which is relevant in tropical endemic areas.

Interpretation of Combined Serologic Results

Direct Detection Methods

When a patient presents with a primary chancre and serology is still negative (within the first 4 weeks), direct visualization with dark-field microscopy of the lesion exudate can identify motile spirochetes. This is not widely available in clinical practice but remains a valid initial diagnostic method for active ulcerative lesions.

PCR is the molecular alternative, detecting T. pallidum DNA from ulcer or erosion specimens. It has high sensitivity and is particularly useful when dark-field microscopy is unavailable.

For suspected neurosyphilis, CSF analysis via lumbar puncture is required. CSF findings include elevated protein, lymphocytic pleocytosis, and a reactive CSF-VDRL (highly characteristic but not perfectly sensitive).

04Management and Treatment

Early Acquired Syphilis (Primary, Secondary, Early Latent)

The cornerstone of treatment is Benzathine penicillin G (BPG) 2.4 million units, given as a single intramuscular injection. The dose is split between two injection sites (1.2 million units per buttock). Before administering BPG, penicillin allergy testing should be performed to rule out hypersensitivity. The patient should be observed for 30 minutes post-injection to monitor for anaphylaxis.

For patients with confirmed penicillin allergy who are not pregnant, the first alternative is doxycycline 100 mg orally twice daily for 14 days. The second alternative is ceftriaxone 1 gram intravenously once daily for 10 days. Note that doxycycline is contraindicated in pregnancy; for pregnant patients with penicillin allergy, penicillin desensitization followed by standard penicillin therapy is the recommended approach.

Late Acquired Syphilis (Late Latent, Gummatous, Cardiovascular)

The regimen is Benzathine penicillin G 2.4 million units IM once weekly for three consecutive weeks. A critical rule: the interval between each dose must not exceed 14 days. If a dose is delayed beyond this window, the full three-dose course must be restarted. This is a commonly tested point.

For non-pregnant, penicillin-allergic patients, the alternative is doxycycline 100 mg orally twice daily for 21 to 28 days. For pregnant, penicillin-allergic patients where desensitization is not feasible, erythromycin 500 mg four times daily for 30 days can be used, but this is suboptimal: since erythromycin and azithromycin do not cross the placenta reliably, the neonate must be treated for congenital syphilis at birth regardless of maternal treatment.

Pregnancy-Related Considerations

Treatment during pregnancy must be initiated within 4 weeks before delivery to be considered adequate. Each week of treatment delay increases the transmission risk by up to 125%, and for gestational ages of 28 weeks or more, the risk of transmission doubles. HIV co-infected patients receive the same syphilis treatment regimen as HIV-negative patients.

Jarisch-Herxheimer Reaction

After initiating treatment (especially in early syphilis), patients may develop the Jarisch-Herxheimer reaction within 4 to 6 hours. This is characterized by fever, chills, myalgia, arthralgia, and headache. It is caused by the sudden release of treponemal antigens from dying organisms and resolves spontaneously within 24 hours. It is not an allergic reaction to penicillin and should not prompt discontinuation of therapy. Management is supportive with aspirin or ibuprofen. This reaction is not dependent on the type or dose of antibiotic used.

If clinical signs, symptoms, or laboratory findings suggest neurosyphilis (symptomatic or asymptomatic), ocular syphilis, or otosyphilis, the patient should be referred to a venereology subspecialist for further evaluation and specialized management.

Sexual Partner Management

Follow-Up and Treatment Response

Prognosis

Treponema pallidum remains sensitive to penicillin. Although treatment failure can occur and may be more common in HIV-co-infected patients, penicillin therapy is generally effective across all stages. Recurrence is more commonly due to reinfection than true relapse, and reinfection is most likely during the first year after treatment.

05Differential Diagnosis and Distractors

Primary Syphilis

Secondary Syphilis

Condylomata Lata vs. Condylomata Acuminata

06Traps and High-Yield Pearls

The most common way students get syphilis questions wrong is by confusing the roles of treponemal and non-treponemal tests. Non-treponemal tests (RPR/VDRL) are used for screening and monitoring, not confirmation. Treponemal tests (TPHA, FTA-ABS) are used for confirmation, not monitoring. Using the wrong test for the wrong purpose is the core mistake. If a question asks "how do you confirm treatment success," the answer is a declining RPR/VDRL titer, never a treponemal test.

The second major trap involves the window period in primary syphilis. A patient with a painless genital ulcer and a negative VDRL may still have syphilis. The non-treponemal test does not become positive until approximately 4 weeks after infection, while the chancre can appear as early as 3 weeks. During this gap, the correct diagnostic step is dark-field microscopy or PCR of the lesion, or repeat serology in 2 to 4 weeks.

Third, students often fail to recognize that the resolution of the chancre does not mean the disease is cured. The chancre heals spontaneously in 3 to 6 weeks regardless of treatment. If a vignette describes a patient whose genital ulcer "resolved on its own" and now presents weeks later with a diffuse rash, you are looking at the progression from primary to secondary syphilis.

Fourth, understand the Jarisch-Herxheimer reaction. A patient who develops fever, chills, and worsening rash within hours of receiving penicillin for syphilis is having this reaction, not a penicillin allergy. This distinction is critical: allergic reactions involve urticaria, angioedema, or anaphylaxis; the Jarisch-Herxheimer reaction involves flu-like symptoms that resolve within 24 hours.

Fifth, the prozone phenomenon is a classic board-style question. A patient with all the classic features of secondary syphilis who has a negative RPR/VDRL should prompt you to request sample dilution and retesting. The antibody excess in florid secondary syphilis can paradoxically produce a false-negative result.

Sixth, remember that in pregnancy, doxycycline is contraindicated and macrolides (erythromycin, azithromycin) do not adequately cross the placenta. The only acceptable approach for pregnant patients with penicillin allergy is desensitization followed by penicillin therapy. Even if the mother receives erythromycin, the neonate must still be treated for congenital syphilis.

Finally, the core competency being tested in syphilis questions is pattern recognition across stages and correct sequencing of diagnostic tests. A painless chancre is primary. A rash on palms and soles with condylomata lata is secondary. An asymptomatic patient with positive serology needs staging by duration to determine the treatment regimen (single dose vs. three weekly doses). A four-fold decline in RPR/VDRL titer confirms treatment success. These are the patterns that repeat across exam questions.