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Summary Table

Domain	Details
Risk Factors	Sexually active adults (especially for HSV-2), multiple sexual partners, immunocompromised individuals (HIV/AIDS), neonates born to mothers with active genital lesions, history of other STIs
Etiology	Herpes Simplex Virus type 1 (HSV-1) and type 2 (HSV-2). HSV-2 predominantly causes genital herpes, but HSV-1 can also cause genital infection through oral-genital contact.
Patient Presentation	Painful vesicles, erosions, or shallow ulcers on an erythematous base in the genital area, often preceded by prodromal symptoms (tingling, burning, itching). Systemic symptoms (fever, malaise, myalgia) common in primary episodes.
Classic Physical Exam	Grouped vesicles/erosions/ulcers on an erythematous base, multiple, sometimes with a dirty ulcer base or crust. Inguinal lymphadenopathy. Pain at the lesion site.
Key Diagnostic Results	Diagnosis is primarily clinical. Confirmatory: NAAT (sensitivity 90.9 to 100%). Viral culture (67 to 70% from vesicles). Type-specific IgG serology for HSV-1/HSV-2. Tzank test is rapid but low sensitivity (<40%).
Management	Primary episode: Acyclovir 5x200 mg/day or 3x400 mg/day PO for 7 to 10 days (1A). Valacyclovir 2x500 mg/day PO for 7 to 10 days (1A). Recurrent (severe): Acyclovir 5x200 mg/day PO for 5 days. Suppressive (>=6 recurrences/year): Acyclovir 2x400 mg/day PO for 6 to 12 months (1A).
Keywords	"Grouped vesicles on an erythematous base," "painful genital ulcer," "prodromal tingling/burning," "recurrent genital lesions," "latency in dorsal root ganglia," "dew drops on a rose petal"

1. Pathophysiology

Genital herpes is caused by Herpes Simplex Virus (HSV), a double-stranded DNA virus belonging to the Herpesviridae family. There are two serotypes: HSV-1 and HSV-2. HSV-2 is classically associated with genital infection, while HSV-1 can also cause genital herpes through oral-genital contact. Both viruses can infect the genital area.

The virus enters the body through mucosal surfaces or breaks in the skin. After initial replication in epithelial cells (which produces the visible lesions), HSV travels retrograde along sensory nerve fibers to establish lifelong latency in the sacral dorsal root ganglia. This latency is the reason the infection is chronic and incurable. The virus remains dormant within neurons, evading the immune system because neuronal cells have limited MHC class I expression.

Reactivation occurs when the virus travels anterograde back down the nerve axon to the genital skin or mucosa, producing a new round of lesions. Triggers for reactivation include physical or psychological stress, other illnesses, menstruation, excessive sexual activity, alcohol use, trauma, fatigue, and immunosuppression. Importantly, reactivation can also occur without visible lesions (asymptomatic viral shedding), which is a major mechanism of transmission.

The reason primary episodes are more severe than recurrences is immunological. During a first encounter with the virus, the host has no pre-existing antibodies, so viral replication proceeds relatively unchecked. This leads to more extensive lesions, prolonged duration (12 to 21 days untreated), and systemic symptoms such as fever, malaise, and lymphadenopathy. In contrast, a non-primary first episode (first clinical genital herpes in someone who already has antibodies against the other HSV type, e.g., prior HSV-1 oral infection now presenting with HSV-2 genitally) is milder because of partial cross-reactive immunity. Recurrent episodes are the mildest, as the host already has type-matched antibodies and T-cell memory.

The connection between HSV-2 and HIV is clinically important. Genital HSV-2 infection increases the risk of acquiring HIV by two to threefold, because mucosal disruption provides a portal of entry for HIV, and local inflammation recruits CD4+ T cells (HIV target cells) to the genital tract. This is why HIV testing is recommended in all patients diagnosed with genital herpes.

2. Classification and Clinical Manifestation

Classification	Description
Primary First Episode	First-ever HSV infection (no prior antibodies to HSV-1 or HSV-2). Most severe presentation.
Non-Primary First Episode	First clinical genital episode of one HSV type in a patient who already has antibodies against the other type. Milder than true primary.
Recurrent	Reactivation of latent virus from sacral ganglia. Milder, shorter, and localized.
Asymptomatic	No clinical lesions. Diagnosis made only by reactive serology (herpes antibodies).
Atypical	Non-classic lesion morphology: erythematous macules, fissures, excoriations, or hypertrophic ulcers with recurrent history.

By Episode Type

Episode	Genital Herpes Presentation
Primary First Episode	Prodrome: fever, malaise, headache, myalgia. Classic sequence: prodrome, then papule, vesicle, ulcer, thick crust, and healing over 5 to 15 days. Multiple grouped vesicles/erosions/ulcers on erythematous base, painful. Inguinal lymphadenopathy. Dysuria may occur. Vaginal or urethral discharge possible. Neuropathy (urinary retention, constipation, paresthesia) can develop. New lesions may continue forming for up to 10 days. Total duration 12 to 21 days untreated.
Non-Primary First Episode	Fewer and less extensive lesions compared to primary infection. Same morphology but milder. Duration 10 to 14 days untreated. Rarely accompanied by discharge, dysuria, systemic symptoms, or neuropathy.
Recurrent	Fewer, smaller lesions. Localized, unilateral. Shorter duration, resolving within approximately 5 days. Preceded by prodromal paresthesia 1 to 2 days before onset. Usually affects the same dermatome (penis, vulva, anus, buttocks). History of prior episodes. Triggers: physical/psychological stress, excessive sexual activity, alcohol, menstruation. Triggers are sometimes unidentifiable.
Asymptomatic	No clinical symptoms whatsoever. Only reactive herpes serology (antibodies detected).
Atypical	Lesions do not follow classic morphology. Can present as erythematous macule, fissure, excoriation, or hypertrophic ulcer with recurrent history. Extra-genital forms include herpetic whitlow and eczema herpeticum. Subclinical herpes may appear as mild erythema or erosion with occasional vesicles and radiculopathy pain. In immunocompromised patients, lesions can be atypical ulcers (large and deep), more prolonged, more severe, and more frequently recurrent.

3. Diagnostic Workup

Test	Sensitivity	Role
Viral Culture	67 to 70% (vesicle), 32% (pustule), 17% (crust)	Traditional standard. Best yield from early vesicular lesions.
NAAT (Nucleic Acid Amplification Test)	90.9 to 100%, high specificity	Most sensitive test. Preferred confirmatory test.
PCR (Polymerase Chain Reaction)	High	For suspected CNS infection (meningitis, encephalitis) and systemic/neonatal herpes.
Enzyme Immunoassay (EIA)	57.4% sensitivity, 39.8% specificity	Low accuracy. Can also use fluorescent antibody.
Type-Specific Serology (IgG anti HSV-1 and HSV-2)	Variable	Identifies HSV type and prior infection. IgM is NOT recommended.
Tzank Test	<40%	Rapid bedside test (multinucleated giant cells). Low sensitivity, useful for quick assessment only.
HIV Testing	N/A	Recommended for all genital herpes patients. HSV-2 increases HIV acquisition risk 2 to 3 fold.

The diagnosis of genital herpes is primarily clinical. When the presentation is classic (grouped vesicles on an erythematous base in the genital region, painful, with regional lymphadenopathy), laboratory confirmation is not strictly necessary. However, when the clinical picture is atypical or ambiguous, ancillary testing is warranted.

Best initial test: Clinical examination. The classic evolution of lesions (papule to vesicle to erosion/ulcer to crust) on an erythematous base, grouped in clusters, with associated pain and inguinal lymphadenopathy, is highly suggestive.

If laboratory confirmation is needed, the preferred test is NAAT, which offers sensitivity of 90.9 to 100% with high specificity. This has largely replaced viral culture as the gold standard in many settings. NAAT can detect viral DNA even in crusted or healing lesions where culture yield drops considerably.

Viral culture remains useful and was historically the gold standard. Its main limitation is that sensitivity depends heavily on the stage of the lesion: 67 to 70% from an intact vesicle, 32% from a pustule, and only 17% from a crusted lesion. If you are going to culture, sample early and from a fresh vesicle.

Tzank test (scraping the base of a vesicle and looking for multinucleated giant cells under light microscopy) is a rapid bedside test but has a sensitivity below 40%. It cannot distinguish HSV from Varicella-Zoster Virus. It is useful as a quick triage tool when nothing else is available.

Type-specific IgG serology is useful for identifying prior infection and determining the HSV type (HSV-1 vs. HSV-2), which has implications for counseling because HSV-2 recurs genitally more frequently than HSV-1. IgM serology is not recommended because it does not reliably distinguish between primary and recurrent infection and has high false-positive rates.

PCR of cerebrospinal fluid is the test of choice for suspected HSV encephalitis or meningitis.

HIV testing should be performed in all patients with genital herpes, because HSV-2 infection increases HIV acquisition risk two to threefold due to mucosal disruption and local immune cell recruitment.

4. Management and Treatment

Scenario	Drug	Dose and Duration
Primary First Episode	Acyclovir (PO)	5x200 mg/day for 7 to 10 days, OR 3x400 mg/day for 7 to 10 days
	Valacyclovir (PO)	2x500 mg/day for 7 to 10 days, OR 2x1000 mg/day
	Famciclovir (PO)	3x250 mg/day for 7 to 10 days
	Acyclovir (IV), severe cases	5 to 10 mg/kg q8h for 7 to 10 days
Recurrent, severe	Acyclovir (PO)	5x200 mg/day for 5 days, OR 5x400 mg for 5 days, OR 3x400 mg/day for 5 days, OR 2x800 mg/day for 2 days, OR 3x800 mg/day for 2 days
	Valacyclovir (PO)	2x500 mg/day for 3 to 5 days, OR 1x1000 mg/day for 5 days
	Famciclovir (PO)	2x500 mg/day, OR various short-course regimens
Suppressive (>=6/year)	Acyclovir (PO)	2x400 mg/day OR 1x800 mg/day for 6 to 12 months, then re-evaluate
	Valacyclovir (PO)	1x500 to 1000 mg/day OR 2x500 mg/day OR 2x250 mg/day
	Famciclovir (PO)	2x250 mg/day OR 3x125 mg/day OR 3x250 mg/day
Immunocompromised (episodic)	Acyclovir (PO)	3x400 mg/day OR 5x400 mg/day for 5 to 10 days
	Valacyclovir (PO)	2x500 to 1000 mg/day for 5 to 10 days
	Famciclovir (PO)	2x250 to 500 mg/day for 5 to 10 days
Immunocompromised (suppressive)	Acyclovir (PO)	2 to 3x400 to 800 mg/day
	Valacyclovir (PO)	2x500 mg/day OR 1x1000 mg/day
	Famciclovir (PO)	2x500 mg/day
Pregnancy (primary)	Acyclovir (PO)	5x200 mg for 10 days
Pregnancy (primary)	Valacyclovir (PO)	2x500 mg for 10 days
Pregnancy (suppressive, from 36 wk)	Acyclovir (PO)	3x400 mg/day
Pregnancy (suppressive, from 36 wk)	Valacyclovir (PO)	2x500 mg/day
Neonatal Herpes	Acyclovir (IV)	20 mg/kg q8h; 14 days (skin/mucosal) or 21 days (disseminated/CNS)
Acyclovir-resistant	Foscarnet (IV)	80 to 120 mg/kg/day divided in 2 to 3 doses; monitor renal function
Acyclovir + Foscarnet resistant	Cidofovir (IV)	5 mg/kg weekly x2 weeks, then every 2 weeks; or 1 mg/kg IV q2d or 3x/week

Symptomatic care applies to all forms and includes analgesics, antipyretics, and antipruritics as needed. Antiseptic compresses or a sit bath with povidone iodine can help dry lesions, prevent secondary bacterial infection, and accelerate healing.

Primary first episode is the most severe presentation and always warrants antiviral therapy. The first-line agent is acyclovir, given orally at 5x200 mg/day or 3x400 mg/day for 7 to 10 days. Valacyclovir (the L-valyl ester prodrug of acyclovir with superior bioavailability and less frequent dosing) at 2x500 mg/day for 7 to 10 days is equally effective. Famciclovir at 3x250 mg/day for 7 to 10 days is the third option. For severe cases requiring hospitalization (extensive lesions, urinary retention, meningitis, inability to take oral medication), intravenous acyclovir at 5 to 10 mg/kg every 8 hours for 7 to 10 days is indicated.

Recurrent episodes are stratified by severity. Mild recurrences are managed with symptomatic treatment alone. Severe recurrences are treated with shorter antiviral courses, reflecting the fact that the immune system is now more capable of controlling viral replication. Options include acyclovir 5x200 mg/day for 5 days, or the highly practical "weekend regimen" of 2x800 mg/day for 2 days. Early initiation of therapy (ideally during the prodrome) is critical for efficacy.

Suppressive therapy is indicated when a patient experiences six or more recurrences per year. The goal is to reduce the frequency of outbreaks, decrease viral shedding, and improve quality of life. Treatment is continued for 6 to 12 months and then re-evaluated. First-line suppressive regimens include acyclovir 2x400 mg/day or valacyclovir 1x500 to 1000 mg/day. Suppressive therapy also reduces (but does not eliminate) the risk of transmission to sexual partners.

Immunocompromised patients (including those with HIV/AIDS) require longer treatment courses, and therapy should continue until clinical symptoms fully resolve. If the patient is at high risk for dissemination or cannot tolerate oral medication, IV acyclovir at 5 mg/kgBB every 8 hours for 7 to 14 days (or longer, up to 14 to 21 days) is indicated. If confirmed systemic infection occurs (hepatitis, pneumonia, encephalitis), escalate to acyclovir IV 3x10 to 15 mg/kgBB/day for at least 10 days.

Acyclovir resistance occurs primarily in immunocompromised patients. The alternative is foscarnet at 80 to 120 mg/kg/day IV divided in 2 to 3 doses. Renal function must be monitored closely because foscarnet is nephrotoxic. Topical alternatives include imiquimod 5%, cidofovir 1% gel, trifluridine, or foscarnet 1% topical. If resistance to both acyclovir and foscarnet develops, cidofovir IV is the third-line agent.

Pregnancy is a high-stakes scenario. Primary genital herpes in pregnancy is treated with acyclovir 5x200 mg for 10 days or valacyclovir 2x500 mg for 10 days. Recurrent episodes are treated for 5 days. IV acyclovir is given when manifestations are severe. If a pregnant woman has active genital herpes within 6 weeks of delivery, cesarean section is recommended before or within 4 hours of membrane rupture. Suppressive therapy with acyclovir 3x400 mg/day or valacyclovir 2x500 mg/day starting at 36 weeks of gestation can prevent lesions at delivery. Routine cesarean section is NOT indicated for recurrent genital herpes unless there is evidence of active viral shedding or visible genital lesions at the time of delivery.

Neonatal herpes is treated with acyclovir 20 mg/kg IV every 8 hours. Duration depends on extent: 14 days for disease limited to skin, eyes, and mouth, and 21 days for disseminated infection or CNS involvement.

Non-pharmacological measures apply across all forms:

Patient education about transmission, including asymptomatic viral shedding.
Abstinence from sexual contact with uninfected partners during prodromal symptoms or active lesions.
Screening for other sexually transmitted infections and HIV.
Partner notification.
Consistent use of condoms and spermicidal agents (reduces but does not eliminate transmission).
Circumcision reduces HSV-2 acquisition and transmission.
Avoidance of known triggers where possible.
Psychiatric referral when recurrent infections impair quality of life.

No approved vaccine for genital herpes currently exists.

Prognosis: Quo ad vitam: bonam. Quo ad functionam: bonam. Quo ad sanationam: dubia ad bonam (reflecting the chronic, recurrent nature of the disease).

5. Differential Diagnosis and Distractors

Differential	Why It Is Similar	Key Discriminator
Chancroid (Haemophilus ducreyi)	Painful genital ulcer with inguinal lymphadenopathy.	Chancroid produces a single, deep, ragged, "punched-out" ulcer with purulent base and undermined edges. Herpes produces multiple, shallow, grouped vesicles/erosions. Chancroid lymph nodes may suppurate (bubo).
Primary Syphilis (Treponema pallidum)	Genital ulcer with lymphadenopathy.	The syphilitic chancre is painless, solitary, with a clean base and indurated edges. Herpes ulcers are painful and multiple. Darkfield microscopy or treponemal serology confirms syphilis.
Lymphogranuloma Venereum (LGV) (Chlamydia trachomatis L1-L3)	Genital ulcer followed by inguinal lymphadenopathy.	LGV starts with a painless, transient papule/ulcer that often goes unnoticed. The hallmark is painful, unilateral inguinal lymphadenopathy (bubo) that may develop a "groove sign." Herpes has prominent vesicles.
Granuloma Inguinale (Donovanosis) (Klebsiella granulomatis)	Genital ulcerative lesion.	Donovanosis produces beefy-red, painless, progressive granulomatous ulcers WITHOUT lymphadenopathy. Biopsy shows Donovan bodies (intracytoplasmic inclusions in macrophages). Herpes is painful with lymphadenopathy.

6. Traps and High-Yield Pearls

The most common way students get herpes questions wrong is by confusing the ulcer characteristics with other genital ulcer diseases. The exam loves to present a patient with a "painful genital ulcer" and ask for the most likely diagnosis. The critical discriminator is that herpes produces multiple, shallow, grouped vesicles or erosions on an erythematous base, while chancroid produces a single deep purulent ulcer, and syphilis produces a single painless ulcer with clean edges. If the vignette says "painful" and "multiple" and "vesicles," it is herpes until proven otherwise.

A second common trap is the primary vs. non-primary vs. recurrent distinction. Students often underestimate the severity of the primary episode. A vignette describing a sexually active young patient with their first-ever genital vesicular eruption accompanied by fever, myalgia, and bilateral inguinal lymphadenopathy is describing a primary first episode, not a recurrence. This matters because the treatment duration differs: 7 to 10 days for a primary episode versus 5 days or less for recurrent episodes.

A third testing point involves pregnancy management. The "next best step" question for a pregnant woman at 36 weeks with a history of recurrent genital herpes is to start suppressive acyclovir (3x400 mg/day). The cesarean section question hinges on whether there are active lesions or viral shedding at the time of delivery. Recurrent herpes alone is NOT an automatic indication for cesarean section.

Students also stumble on the IgM trap. IgM serology for HSV is not recommended because it does not reliably differentiate primary from recurrent infection and can be falsely positive. The correct serologic test is type-specific IgG for HSV-1 and HSV-2.

The acyclovir resistance pathway is tested in the context of immunocompromised patients (especially HIV/AIDS) who fail to respond to standard antiviral therapy. The next step is foscarnet (with renal monitoring), not simply increasing the acyclovir dose.

Finally, remember the HIV connection. Any time a question mentions a new diagnosis of genital herpes, the next best step in screening includes HIV testing, because HSV-2 increases HIV acquisition risk two to threefold.

The core competency being tested is the ability to: (1) recognize classic and atypical presentations of genital herpes, (2) correctly sequence the diagnostic workup (clinical first, then NAAT or culture if needed, with type-specific IgG serology for typing), (3) select the appropriate antiviral regimen and duration based on episode type and patient population, and (4) manage high-risk scenarios including pregnancy, neonatal exposure, immunocompromised hosts, and antiviral resistance.

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