Summary
Syphilis is a predominantly sexually transmitted bacterial infection with the spirochete Treponema pallidum. The disease presents with four distinct, successive clinical stages if left untreated. Primary syphilis manifests with a painless chancre (primary lesion), typically on the genitals. Secondary syphilis is characterized by a polymorphic, maculopapular rash that also appears on the palms and soles. The first two stages are followed by an asymptomatic phase (latent syphilis), in which the disease may resolve entirely or progress to tertiary syphilis. During the tertiary stage, characteristic granulomas (gumma) may appear, which can cause irreversible organ damage, particularly in the cardiovascular system (syphilitic aortic aneurysm) and the CNS (neurosyphilis). Diagnosis requires serologic analyses, including nontreponemal tests for screening purposes and treponemal tests for confirmation. Further tests may directly detect T. pallidum (darkfield microscopy, PCR) if a specimen of infected tissue or blood can be obtained. The first-line treatment for syphilis is penicillin, which should be administered after an infection has been confirmed. Congenital syphilis, a complication seen in children of women who have syphilis during pregnancy, is discussed in another article.
Epidemiology
References:[1]
Epidemiological data refers to the US, unless otherwise specified.
Etiology
- Pathogen: Treponema pallidum: gram-negative, spiral-shaped bacteria belonging to the spirochete family
-
Transmission [2][3]
- Sexual contact (via small mucocutaneous lesions)
- Vertical
- Blood transfusion or organ donations (rare)
Treponema bacteria (particularly during stages I and II) are highly contagious.
Pathophysiology
- Spirochetes invade the body → disseminate systemically within hours → bind to endothelial cells → inflammatory reaction → endarteritis and perivascular inflammatory infiltrates [2]
Clinical features
Incubation period [4]
- 10–90 days
- On average 21 days
Primary syphilis
-
Localized disease
- 90–95%: genital primary syphilis
- 5–10%: extragenital primary syphils (most commonly, the oral cavity, finger, and anus or perianal region)
- Primary lesion (chancre)
- Nontender regional lymphadenopathy (e.g., involvement of the inguinal lymph nodes in genital primary syphilis)
Secondary syphilis
- Disseminated disease due to the systemic spread of the spirochetes, inducing an immunologic reaction
- Begins approx. 8–12 weeks after primary infection and typically lasts 2–6 weeks [5]
-
Constitutional symptoms
- Generalized nontender lymphadenopathy
- Fever, fatigue, myalgia, headache
- Polymorphic rash
-
Condylomata lata
- Broad-based, wart-like, smooth, white papular erosions
- Painless
- Located in the anogenital region, intertriginous folds, and on oral mucosa
- Additional lesions
- Patchy alopecia (moth-eaten alopecia)
- Sore throat (acute syphilitic tonsillitis)
-
Special variant of secondary syphilis: malignant syphilis
- Severe clinical course in the setting of underlying immunosuppression (e.g., concurrent HIV infection)
- Multiple necrotic ulcerations
Remember that Secondary Syphilis causes Systemic Symptoms.
Latent syphilis
- No clinical symptoms, despite seropositivity
- May last months, years, or even for the entire life of the patient
- Disease may resolve, reactivate, or progress to tertiary syphilis
Tertiary syphilis
- Gumma
-
Cardiovascular syphilis: aortitis, ascending aortic aneurysm (thoracic aortic aneurysm), syphilitic mesaortitis, aortic root dilation and insufficiency
- Due to Treponema-induced vasculitis of the vasa vasorum of the large vessels (especially the aorta), resulting in vessel wall atrophy, and thereby, aneurysm formation
-
Neurosyphilis: invasion of the CNS, causing an inflammatory reaction of the meninges and the surrounding vessels, as well as the cerebral parenchyma
- Acute meningeal syphilis: symptoms of acute meningitis (e.g., neck stiffness, nausea)
- Meningovascular syphilis : subacute stroke, cranial neuropathies
- Late (parenchymal) neurosyphilis
-
Paretic neurosyphilis: chronic, progressive meningoencephalitis, resulting in widespread cerebral atrophy and major neurocognitive disorder
- Early manifestations include personality changes and deficits of memory and judgment.
- Can cause neurologic symptoms, including dysarthria, hypotonia, and tremors
- Argyll Robertson pupil
-
Tabes dorsalis (syphilitic myelopathy): demyelination of the dorsal columns and the dorsal root ganglia
- Impaired proprioception → progressive sensory broad-based ataxia (Romberg test is positive)
- Absent deep tendon reflexes
-
Dysesthesias
- Loss of sensation, predominantly in the lower extremities
- Sharp, shooting pain in the legs and the abdomen
- Charcot joint
-
Paretic neurosyphilis: chronic, progressive meningoencephalitis, resulting in widespread cerebral atrophy and major neurocognitive disorder
Syphilis (also known as “the great imitator”) may have a very broad clinical presentation that mimics many other diseases!
Syphilis during pregnancy
- See “Congenital syphilis.”
Diagnostics
Approach [6]
- Use nontreponemal serological tests to screen for syphilis and treponemal tests and PCR to confirm the diagnosis.
- If skin or mucous membranes eruptions (chancre or condylomata) are present, the pathogen can be directly detected in the material with darkfield microscopy or PCR.
-
If neurosyphilis is suspected: After serum screening and confirmation tests, perform CSF tests.
- Routine CSF analysis: pleocytosis (> 5 WBCs/mm3) or elevated protein
- CSF-VDRL
- In the case of pleocytosis and/or protein elevation with nonreactive CSF-VDRL, perform CSF-FTA.
Serological testing [7][8]
Two separate serological tests are required to establish a diagnosis of syphilis: Nontreponemal tests are used for screening purposes, while treponemal tests confirm the diagnosis. In early primary syphilis, both types of tests may be nonreactive. Therefore, direct detection of the treponemes is usually preferred during this stage.
Nontreponemal tests
- Indications: screening, evaluation of disease activity , monitoring response to treatment
- Method: detection of anti-cardiolipin antibodies (high sensitivity but low specificity)
-
Commonly used tests: quantitative tests that are cost-efficient and widely available
- Rapid Plasma Reagin (RPR): generally the test of choice
-
Venereal Disease Research Laboratory (VDRL)
- Especially useful in the evaluation of neurologic involvement using cerebrospinal fluid
- Positive in ∼ 80% of patients with primary syphilis [9]
-
False-positive results, caused by cross-reacting antibodies, can occur due to:
- Pregnancy
- Viral infections (e.g., EBV, viral hepatitis)
- Rheumatic fever
- Systemic lupus erythematosus (SLE)
- Leprosy
- Drugs (e.g., chlorpromazine, procainamide)
False-Positive results on VDRL with Pregnancy, Viral infection (eg, EBV, hepatitis), Drugs (eg, chlorpromazine, procainamide), Rheumatic fever (rare), Lupus, and leprosy.
Treponemal tests
- Indication: confirmatory test after a positive or equivocal nontreponemal test (high positive predictive value)
- Method: detection of specific antibodies to treponemal antigens
- Interpretation: Positive results indicate active syphilis or persistent antibodies from a prior infection.
-
Commonly used tests
- Treponema pallidum particle agglutination (TPPA)
- Fluorescent treponemal antibody absorption test (FTA-ABS): becomes positive 2–3 weeks after infection and has a high positive predictive value (PPV). [9][10]
Direct detection of the pathogen [7][8]
- Indication: definite tests to detect primary and secondary syphilis when a specimen can be obtained (e.g., exudative chancre, condyloma)
- Interpretation: confirmation of diagnosis, but negative results do not rule out syphilis
-
Available tests
- Darkfield microscopy, may be combined with immunofluorescence (light microscopy is unable to visualize treponemes because of their small size)
- PCR
Imaging
- Angiography: aneurysms of the ascending aorta or aortic arch
-
Chest CT
- Heavily calcified aortic root, ascending aorta, aortic arch, or even thoracic aorta
- Tree bark appearance of the aorta due to intimal calcifications
Treponema pallidum cannot be cultivated in vitro.
Patients diagnosed with syphilis should also be screened for other sexually transmitted diseases (HIV, gonorrhea, chlamydia).
Treatment
-
First-line therapy: benzathine penicillin G
- Primary, secondary, or early latent: IM, a single dose is sufficient
- Late latent, tertiary, or date of transmission unknown: weekly IM injections over a 3-week course
- Sexual contacts should also be treated
- Neurosyphilis: IV penicillin G for 10–14 days
-
Alternatively: in the case of allergy to penicillin (confirmed with skin testing)
- Treat with doxycycline or ceftriaxone
- In neurosyphilis and during pregnancy: desensitization and treatment with penicillin
Penicillin is the drug of choice for treatment of syphilis.
References:[7]
Complications
-
Jarisch-Herxheimer reaction: acute, transient, systemic reaction to bacterial endotoxins and pyrogens that are released after initiation of antibiotic therapy [7][11][12]
-
Epidemiology
- Commonly seen during treatment of infections with spirochetes (Borrelia, Leptospira)
- In syphilis, the Jarisch-Herxheimer reaction is most often seen if treatment begins in the early phases of the secondary stage.
- Clinical features
- Flu-like symptoms: fever, chills, headache, myalgia
- Accompanied by tachypnea, hypotension, and tachycardia
- Syphilitic exanthema may flare up
- Usually self-limiting within 12–24 hours
- Treatment
- NSAIDs for symptomatic treatment
- May consider meptazinol
-
Epidemiology
- Chorioretinitis [13]
We list the most important complications. The selection is not exhaustive.
Prevention
- Condoms prevent transmission of syphilis and other STDs.
- Syphilis is a nationally notifiable disease. [14]