In one line
Genital ulcer disease in South Africa is, until proven otherwise, herpes — but every ulcer is treated empirically for herpes and syphilis at first contact, every patient is offered an HIV test, and every pregnant woman with syphilis is treated with penicillin or her baby is at risk, because the ulcer in front of you is both a diagnosis and a marker of bidirectional HIV synergy.
The pathogen-level groundwork — how each organism causes disease and what its ulcer looks like — is assumed here. Revise it at STI pathology and the diagnostic approach to discharge and ulcers. The work at this level is the syndromic decision under uncertainty, the staging and treatment of syphilis (including in pregnancy), and the appraisal of why treating ulcers has not turned out to be the HIV-prevention lever it once promised to be.
Mechanism & pathophysiology
Five pathogens account for almost all genital ulcer disease, and in the South African epidemic their order is not the textbook order — it is set by HIV.
Herpes simplex virus (predominantly HSV-2, with HSV-1 an increasing share of first episodes) is the commonest cause of genital ulceration in South Africa: it accounted for 49% of genital ulcers in national aetiological surveillance, against 26% for syphilis. HSV establishes lifelong latency in sacral dorsal-root ganglia after primary mucosal infection; recurrences are reactivations that travel back down the sensory axon to the dermatome. The ulcers are multiple, shallow, painful and grouped, preceded by vesicles, and the first episode is the most florid (systemic symptoms, bilateral lesions, tender inguinal nodes). The consultant point is why HSV dominates: it is not curable, so prevalence accumulates in a population, and HIV both increases reactivation frequency and prolongs viral shedding, so a high-HIV-prevalence population is a high-HSV-shedding population.
Treponema pallidum (syphilis) produces the chancre — classically single, indurated and painless, with painless rubbery lymphadenopathy — at the site of inoculation 3 weeks after exposure. Untreated, the spirochaete disseminates haematogenously, and the disease becomes a staged systemic illness: a primary chancre that heals spontaneously, a secondary bacteraemic phase weeks to months later (the maculopapular rash including palms and soles, condylomata lata, mucous patches, generalised lymphadenopathy), a latent phase defined only serologically (early latent <1 year, late latent ≥1 year or unknown duration), and in a minority a tertiary phase years later (gummata, cardiovascular aortitis, neurosyphilis). Neurosyphilis is not confined to tertiary disease — the CNS can be seeded early, and it is over-represented in HIV co-infection.
Haemophilus ducreyi (chancroid) causes painful, ragged, deeply undermined ("worm-eaten") ulcers with painful suppurative inguinal buboes that can rupture; it was historically a major SA cause but has become uncommon as effective syndromic treatment and the scale-up of HIV care reshaped the ulcer ecology — a useful illustration that the aetiological mix is dynamic, not fixed. Chlamydia trachomatis serovars L1–L3 (lymphogranuloma venereum) is a more invasive biovar than the discharge-causing serovars: it produces a transient, easily-missed painless primary ulcer, then the clinically dominant inguinal syndrome — painful matted buboes that classically straddle the inguinal ligament as the "groove sign" and may suppurate — or, increasingly recognised, an anorectal syndrome (proctocolitis with discharge, pain and tenesmus) in receptive anal intercourse, where it is a re-emerging problem. Untreated, the lymphatic destruction leads to chronic fibrosis, strictures and genital elephantiasis. Klebsiella granulomatis (donovanosis/granuloma inguinale) is the chronic, painless, beefy-red, highly vascular ulcer that bleeds readily on contact and spreads by autoinoculation to adjacent skin; it is rare and endemically clustered, indolent, and — because it can mimic carcinoma — a lesion that warrants biopsy if there is any diagnostic doubt.
The mechanistic centre of gravity in this setting is the bidirectional synergy between genital ulceration and HIV, and it operates at the level of the mucosa. An ulcer breaches the epithelial barrier and draws activated CD4 T cells, dendritic cells and macrophages — precisely the target cells HIV needs — to the mucosal surface; HSV-2 specifically upregulates CCR5 on those cells and recruits CD4 lymphocytes that persist in the genital mucosa even between clinical recurrences and even after antiviral suppression, which is why subclinical HSV-2 matters as much as visible ulcers. An ulcer is therefore simultaneously a portal of entry (acquisition) and, in an HIV-positive person, a site of enriched local HIV replication and shedding (transmission). The epidemiology bears this out: HSV-2 infection raises the risk of acquiring HIV roughly three- to fivefold (adjusted RR 2.7 for prevalent and 4.7 for incident HSV-2 in general populations), and an HIV-positive person with a genital ulcer sheds more HIV from that lesion. Each direction amplifies the other, which is why the SA STI guidelines read as HIV-prevention documents as much as ulcer-treatment documents — and why the persistence of a mucosal target-cell infiltrate despite aciclovir, rather than ongoing ulceration, became the leading explanation for the failure of HSV suppression to prevent HIV.
Two further mechanisms drive the obstetric stakes. Congenital syphilis follows transplacental spirochaetaemia: T. pallidum crosses the placenta at any gestation (the old teaching that it cannot before 16–18 weeks is wrong), and untreated maternal infection — highest-risk in the early, bacteraemic primary and secondary stages — causes mid-trimester miscarriage, stillbirth, hydrops, preterm birth and the multisystem disease of the liveborn infant (hepatosplenomegaly, rash, rhinitis, bone lesions, later stigmata). Neonatal herpes is acquired overwhelmingly at delivery from contact with virus shed in the maternal genital tract; the risk is highest when the mother acquires a first genital HSV infection near term (she has no protective transplacental antibody and sheds high viral loads), and far lower with recurrent disease — a distinction that drives the delivery decision.
Assessment
The diagnostic reality is that South Africa manages genital ulcers syndromically — empirically, at first contact, without waiting for a microbiological diagnosis — because the clinical appearance of ulcers overlaps too much to be trusted, mixed infection is common, and HIV blunts the classical signs. The assessment therefore runs in parallel with treatment, not before it.
- History and examination. Onset and recurrence pattern (recurrent grouped painful vesicular lesions point to HSV), pain (painful → HSV/chancroid; painless → syphilis/donovanosis/LGV primary lesion), discharge, systemic symptoms, sexual history, and pregnancy status. Examine the ulcer (number, base, edge, induration), the inguinal nodes (tender and fluctuant in chancroid/LGV; rubbery and painless in syphilis), and the whole skin and mucosae for the rash of secondary syphilis. Do not over-read morphology — in practice it discriminates poorly, which is the justification for syndromic treatment.
- Syphilis serology is the workhorse, and its logic must be understood, not memorised. Non-treponemal tests (RPR, VDRL) are quantitative, become positive a week or two after the chancre appears, and fall with treatment — so they track disease activity and response (a fourfold, i.e. two-dilution, fall confirms an adequate response; failure to fall suggests treatment failure, re-infection or neurosyphilis). Treponemal tests (TPHA/TPPA, FTA-ABS, or a treponemal immunoassay) confirm exposure and stay positive for life regardless of treatment. The two are used together: a reactive treponemal test with a reactive RPR titre indicates active or recent infection needing treatment, while a reactive treponemal test with a non-reactive RPR usually means previously treated or late latent disease. The reverse-sequence algorithm now common in laboratories screens with an automated treponemal immunoassay first, then reflexes to RPR for activity and a second treponemal test to resolve discordance. Two failure modes recur: a false-negative RPR from the prozone phenomenon (antibody titres so high — typically in secondary syphilis or HIV co-infection — that the antigen–antibody lattice fails to form, so a frankly infected patient screens "negative"; the laboratory must dilute the serum to unmask it, and you must ask for that if the clinical picture fits), and the fact that a positive treponemal test alone cannot distinguish active from previously treated infection, so it is never used alone to decide treatment.
- Staging syphilis is a clinical-plus-serological exercise, because the stage sets both the regimen and the duration. Primary = chancre. Secondary = the systemic bacteraemic phase (rash including palms/soles, condylomata lata, mucous patches, lymphadenopathy, sometimes hepatitis or nephrotic syndrome). Latent = positive serology with no clinical signs, subdivided into early latent (acquired within the past 12 months — documented seroconversion, a fourfold RPR rise, or recent symptoms/contact) and late latent or latent of unknown duration (everything else). The early/late line matters because late and unknown-duration disease needs the longer three-dose course. Neurosyphilis is suspected on neurological, ophthalmic or otological symptoms (and over-represented in HIV); it is confirmed by CSF examination (reactive CSF-VDRL, pleocytosis, raised protein) and treated as a separate, more intensive category irrespective of the systemic stage.
- Aetiological tests where available. HSV is confirmed by PCR of a swab from the ulcer base (more sensitive than viral culture and the test of choice). Syphilis can be confirmed directly by dark-field microscopy or PCR of chancre exudate where the facility exists, though serology carries most of the diagnostic load. Chancroid, LGV and donovanosis are clinical or specialised-laboratory diagnoses (LGV needs C. trachomatis NAAT with genotyping; donovanosis shows Donovan bodies on a crush smear).
- An HIV test is strongly recommended and actively offered to every patient presenting with a genital ulcer, as provider-initiated testing with informed consent, confidentiality and the right to decline without loss of other care, because the ulcer is both a risk marker and a treatment-modifying comorbidity, and the consultation is the strongest single opportunity to diagnose HIV and link the patient to care. Offer it actively, document the result, link a new diagnosis to ART or PrEP, and repeat after the window period if the first test is negative in a recent exposure.
- In pregnancy, syphilis is screened, not waited for. Every pregnant woman is screened serologically at booking (and re-screened later in pregnancy and at delivery in high-prevalence settings) because untreated maternal syphilis causes stillbirth, prematurity and congenital syphilis, and the entire point of antenatal screening is to treat early enough to protect the fetus.