Stages of Syphilis in Men
Overview of Disease Progression
Syphilis progresses through four distinct stages: primary, secondary, latent (subdivided into early and late), and tertiary, with neurosyphilis potentially occurring at any stage. 1, 2
Primary Syphilis
Primary syphilis manifests as a painless ulcer (chancre) at the site of inoculation, typically in the anogenital region, accompanied by regional lymphadenopathy. 2, 3, 4
- The chancre appears approximately 3 weeks after initial infection and is the hallmark of primary disease 5, 4
- In HIV-infected men, multiple or atypical chancres may occur 6
- Nontreponemal tests (VDRL/RPR) are positive in only 71-73% of primary cases, meaning serologic testing can miss nearly one-third of primary infections 1
- The lesion heals spontaneously within 3-6 weeks even without treatment, but the infection persists 3, 4
Secondary Syphilis
Secondary syphilis develops 2-8 weeks after the primary chancre and is characterized by disseminated manifestations including a distinctive rash involving the palms and soles, mucocutaneous lesions (condyloma lata), generalized lymphadenopathy, and constitutional symptoms. 1, 7, 2
Cutaneous Manifestations
- The rash begins as macular lesions on the trunk, progressing to maculopapular or pustular lesions that spread peripherally 7
- Involvement of the palms and soles is pathognomonic for secondary syphilis 6, 7
- Condyloma lata (moist, flat papular lesions) appear in warm, intertriginous areas including the genital and perianal regions 1, 6, 7
Systemic Involvement
- Constitutional symptoms include fever, malaise, anorexia, arthralgias, and headache lasting days to weeks 1, 6
- Generalized lymphadenopathy accompanies the rash in most cases 7, 8
- Virtually all organ systems can be involved, including potential liver involvement (syphilitic hepatitis) 9
- Acute syphilitic meningitis can occur during this stage 6
Diagnostic Considerations
- Nontreponemal tests are positive in 97-100% of secondary syphilis cases, making this the most reliably seropositive stage 1
- HIV co-infection may cause more apparent clinical lesions and accelerated disease progression 6, 7
Latent Syphilis
Latent syphilis is defined as seroreactivity without clinical evidence of disease and is subdivided into early latent (acquired within the preceding year) and late latent (acquired more than one year ago or of unknown duration). 1, 2
Early Latent Syphilis
- Diagnosed when there is documented seroconversion, fourfold titer increase, unequivocal symptoms of primary/secondary syphilis within the past year, or a sex partner with documented early syphilis 1
- Nontreponemal tests are positive in approximately 85-100% of early latent cases 1
- Recurrence of secondary manifestations can occur, most commonly within 1-4 years after initial infection 6
Late Latent Syphilis
- Infection acquired more than one year previously 1, 3
- Nontreponemal test sensitivity drops to 61-76% in late latent disease 1
- Patients remain asymptomatic but seroreactive 1, 2
Tertiary (Late) Syphilis
Tertiary syphilis develops in approximately 25% of untreated patients after 3-12 years (typically 15-30 years) of latent infection and manifests as gummatous lesions, cardiovascular syphilis, or late neurologic complications. 1, 6, 3
Clinical Manifestations
- Gummas: Granulomatous inflammatory lesions affecting skin, bone, liver, and other internal organs 1, 9, 6
- Cardiovascular syphilis: Inflammatory lesions of the cardiovascular system, particularly aortitis 1, 6
- Late benign syphilis: Involvement of skeletal structures and other organs 1, 6
- Rarely affected structures include respiratory tract, eyes, abdominal organs, reproductive organs, lymph nodes, and skeletal muscle 1, 6
Diagnostic Challenges
- Nontreponemal test sensitivity is only 47-64% in tertiary syphilis, meaning serologic tests frequently miss late disease 1
- CSF examination is necessary when evaluating suspected tertiary syphilis 1
Neurosyphilis
Neurosyphilis can occur at any stage of infection and represents central nervous system invasion by T. pallidum, manifesting as either asymptomatic (CSF abnormalities only) or symptomatic disease (meningitis, meningovascular disease, or parenchymal disease). 1, 6, 2
Clinical Presentations
- Asymptomatic neurosyphilis: Elevated CSF protein, lymphocytic pleocytosis, or positive CSF serology without symptoms 6
- Symptomatic neurosyphilis: Meningitis, stroke, cranial nerve dysfunction, altered mental status, auditory disease, or loss of vibration sense 1, 6, 2
- Uveitis with concurrent meningitis may be more common in HIV-infected patients 6
Diagnostic Criteria
- Reactive serum syphilis serology plus reactive CSF VDRL confirms neurosyphilis 1
- CSF VDRL sensitivity is only 62.5-87.5% depending on whether neurosyphilis is symptomatic or asymptomatic, but specificity is 99% 1
Critical Clinical Pitfalls
- All men with syphilis at any stage must be tested for HIV infection, as co-infection alters disease presentation and progression 6, 7, 2
- Nontreponemal test sensitivity varies dramatically by stage (71% primary, 100% secondary, 85% early latent, 61% late latent, 47% tertiary), so negative serology does not exclude syphilis 1
- Darkfield microscopy or direct fluorescent antibody testing of lesion exudate remains the definitive diagnostic method for early syphilis when available 1
- Men who have sex with men comprised 32.7% of all males with primary and secondary syphilis in 2023 and require at least annual screening 2