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Summary Table

DOMAIN	DETAIL
Risk Factors	Childhood exposure via oral contact, immunocompromised state (HIV/AIDS, organ transplant recipients, chemotherapy), neonates born to mothers with active genital HSV, healthcare workers (herpetic whitlow), atopic dermatitis (eczema herpeticum)
Etiology	Herpes Simplex Virus Type 1, a double-stranded DNA virus of the Herpesviridae family; transmitted via direct contact with infected secretions or mucosal surfaces
Patient Presentation	Painful grouped vesicles on an erythematous base, most commonly on the lips or perioral region; may present with fever, malaise, and lymphadenopathy during primary infection; recurrent episodes are typically milder
Classic Physical Exam	Clustered vesicles on an erythematous base ("dewdrop on a rose petal" appearance), ulcerations after vesicle rupture, crusted lesions in healing phase; gingivostomatitis in children; temporal lobe predilection on imaging in encephalitis
Key Diagnostic Results	PCR of lesion swab or CSF (most accurate); Tzanck smear showing multinucleated giant cells (rapid but nonspecific); viral culture; MRI showing temporal lobe involvement in encephalitis; CSF with lymphocytic pleocytosis, elevated protein, RBCs, and normal glucose
Management	Oral acyclovir, valacyclovir, or famciclovir for mucocutaneous disease; IV acyclovir for encephalitis and severe/disseminated infection; topical antivirals are inferior and not first-line
Keywords	"Grouped vesicles on an erythematous base," "temporal lobe encephalitis," "gingivostomatitis in a child," "Tzanck smear with multinucleated giant cells," "dewdrop appearance," "latency in trigeminal ganglion"

1. Pathophysiology

HSV-1 is an enveloped, double-stranded DNA virus that belongs to the alpha-herpesvirus subfamily. Understanding its life cycle is central to understanding both its clinical behavior and why it recurs.

The virus enters the body through mucosal epithelium or breaks in the skin. It attaches to host cell surface receptors (primarily nectin-1 and herpesvirus entry mediator), fuses with the cell membrane, and releases its DNA into the host cell nucleus. There, it hijacks the host's transcriptional machinery to replicate. This lytic replication causes direct cytopathic damage to epithelial cells, producing the hallmark vesicular lesions. The destruction of epithelial cells, combined with the host inflammatory response, leads to the painful, fluid-filled vesicles that eventually ulcerate and crust over.

After the primary infection resolves, the virus does not get eliminated. Instead, viral particles travel in a retrograde fashion along sensory nerve axons to reach the trigeminal ganglion (for orofacial HSV-1). There, the viral genome persists in a latent state within neuronal cell bodies as a circular episome, expressing only latency-associated transcripts (LATs). This latency is the reason HSV-1 is a lifelong infection and why no antiviral can fully eradicate the virus. Antivirals like acyclovir only target actively replicating virus by inhibiting viral DNA polymerase; they have no activity against the dormant episomal form.

Reactivation occurs when the virus travels anterograde back down the sensory nerve to the skin or mucosa, typically triggered by UV exposure, stress, immunosuppression, fever, or local trauma. This produces the classic recurrent "cold sore" or "fever blister," characteristically at or near the vermilion border of the lip. Recurrent episodes are generally less severe because the host already has a partial adaptive immune response (preformed antibodies and memory T cells), which limits viral spread.

In the setting of severe immunosuppression, the virus can disseminate and cause life-threatening disease. HSV-1 encephalitis deserves special attention: the virus has a strong tropism for the temporal lobe, likely because the trigeminal ganglion's neuronal projections reach the temporal and frontal cortices via the meninges of the middle cranial fossa. This tropism produces a characteristic hemorrhagic, necrotizing encephalitis localized to the temporal lobes, which directly explains the clinical findings of personality changes, aphasia, olfactory hallucinations, and seizures.

In neonates, the immature immune system cannot contain the virus, leading to disseminated infection affecting the skin, eyes, mouth, CNS, and visceral organs such as the liver and lungs.

2. Classification and Clinical Manifestation

CLINICAL SYNDROME	TYPICAL POPULATION	KEY FEATURES
Primary Gingivostomatitis	Children aged 6 months to 5 years	Fever, irritability, refusal to eat; painful vesicles and ulcers on the gingiva, tongue, buccal mucosa, and palate; cervical lymphadenopathy; self-limited in 10 to 14 days
Herpes Labialis (Cold Sore)	Adolescents and adults (recurrent)	Prodrome of tingling/burning at the vermilion border of the lip, followed by grouped vesicles that crust and heal in 7 to 10 days; triggered by UV light, stress, fever
Herpetic Whitlow	Healthcare workers, children who suck thumbs	Painful vesicular lesion on the distal phalanx of a finger; may mimic bacterial paronychia; do NOT incise and drain
Herpes Keratitis	Any age; recurrent episodes common	Eye pain, tearing, photophobia; dendritic (branching) ulcer on slit-lamp with fluorescein staining; risk of corneal scarring and blindness if untreated
Eczema Herpeticum (Kaposi Varicelliform Eruption)	Patients with atopic dermatitis	Widespread, disseminated vesiculopustular eruption in areas of eczematous skin; can become life-threatening; requires systemic antiviral therapy
HSV Encephalitis	Any age (bimodal: neonates and adults over 50)	Fever, altered mental status, focal neurological deficits (especially temporal lobe signs: aphasia, personality change, olfactory hallucinations, seizures); hemorrhagic necrosis of temporal lobes on imaging
HSV Esophagitis	Immunocompromised (HIV/AIDS, transplant)	Odynophagia and dysphagia; well-circumscribed, shallow "punched-out" ulcers on endoscopy; biopsy shows multinucleated giant cells with Cowdry type A inclusions
Neonatal Herpes	Neonates (transmitted during vaginal delivery)	Three forms: (1) Skin-Eye-Mouth (SEM), (2) CNS disease, (3) Disseminated disease with multiorgan failure; high mortality without treatment

3. Diagnostic Workup

TEST	ROLE	KEY FINDINGS
PCR (Polymerase Chain Reaction)	Most accurate test for mucocutaneous disease and encephalitis	Detects HSV DNA; gold standard for CSF analysis in suspected encephalitis; highly sensitive and type-distinguishing (HSV-1 vs HSV-2)
Viral Culture	Traditional confirmatory test	Isolates live virus from vesicular fluid; sensitivity drops as lesions crust; takes 2 to 5 days; largely supplanted by PCR
Tzanck Smear	Rapid bedside screening	Scraping from the base of a vesicle shows multinucleated giant cells with ballooning degeneration; fast but does NOT distinguish HSV-1, HSV-2, or VZV
Direct Fluorescent Antibody (DFA)	Rapid test with typing ability	Detects viral antigens using fluorescent-labeled antibodies; faster than culture but less sensitive than PCR
Serology (Type-specific IgG)	Epidemiological or screening tool	Detects antibodies to glycoprotein G (gG-1 for HSV-1, gG-2 for HSV-2); useful for confirming prior exposure but NOT useful for diagnosing an acute episode
MRI Brain	Imaging of choice for encephalitis	Hyperintense signal in the medial temporal lobes (often unilateral early, then bilateral) on T2/FLAIR sequences
CSF Analysis	Encephalitis workup	Lymphocytic pleocytosis, elevated protein, normal glucose, and often red blood cells (reflecting hemorrhagic necrosis); HSV PCR of CSF is confirmatory
EEG	Supportive in encephalitis	Periodic lateralized epileptiform discharges (PLEDs) localized to the temporal lobe; supportive but not diagnostic

Best Initial Test: For mucocutaneous lesions, the clinical diagnosis is often sufficient when the classic appearance is present (grouped vesicles on an erythematous base). When laboratory confirmation is needed, PCR of the lesion swab is the best initial and most accurate test simultaneously. The Tzanck smear is rapid and inexpensive but cannot differentiate between HSV-1, HSV-2, and varicella-zoster virus, which limits its utility on exams when the question asks for the "most accurate" test.

Most Accurate (Confirmatory) Test: PCR is the gold standard across all clinical settings. For suspected HSV encephalitis, CSF PCR is the single most important diagnostic test and should be obtained urgently. However, treatment must not be delayed while awaiting results. If clinical suspicion for HSV encephalitis exists (fever, altered mental status, temporal lobe findings on MRI), IV acyclovir must be started immediately, even before PCR results return.

A key imaging pearl: on MRI, HSV encephalitis classically shows unilateral or bilateral temporal lobe hyperintensity on T2-weighted and FLAIR sequences. CT is often normal early in the disease course and is therefore inferior to MRI for this diagnosis.

Serology is a common distractor. Type-specific IgG antibodies are useful for determining prior exposure or seroprevalence but are NOT helpful in the acute setting because seroconversion takes weeks, and a positive IgG only confirms past infection, not that the current symptoms are caused by HSV.

4. Management and Treatment

CLINICAL SCENARIO	TREATMENT	DOSE AND DURATION
Primary Gingivostomatitis	Oral acyclovir	15 mg/kg (up to 200 mg) five times daily for 7 days in children; 400 mg three times daily for 7 to 10 days in adults
Recurrent Herpes Labialis (Episodic)	Oral valacyclovir	2 g every 12 hours for 1 day (two doses total); most effective when initiated during the prodrome
Recurrent Herpes Labialis (Suppressive)	Oral valacyclovir	500 mg to 1 g once daily for patients with 6 or more episodes per year
Herpes Keratitis	Topical trifluridine or oral acyclovir/valacyclovir	Topical trifluridine 1% drops every 2 hours (up to 9 times/day) for 14 days; systemic therapy added for stromal involvement; ophthalmology referral required
Eczema Herpeticum	IV acyclovir (severe) or oral acyclovir (mild)	IV: 5 to 10 mg/kg every 8 hours; transition to oral once improving
HSV Encephalitis	IV acyclovir	10 mg/kg IV every 8 hours for 14 to 21 days; do NOT delay for confirmatory testing
HSV Esophagitis	IV then oral acyclovir or valacyclovir	IV acyclovir 5 mg/kg every 8 hours, transitioning to oral once tolerating PO; duration 14 to 21 days
Neonatal Herpes	IV acyclovir	20 mg/kg IV every 8 hours; duration depends on type: 14 days for SEM disease, 21 days for CNS or disseminated disease
Herpetic Whitlow	Oral acyclovir or valacyclovir	Self-limited; antivirals may shorten course; absolute contraindication to incision and drainage

Acute Stabilization: The single most critical management concept for HSV-1 is the empiric initiation of IV acyclovir in any patient with suspected HSV encephalitis. The mortality of untreated HSV encephalitis exceeds 70%, and even with treatment, survivors frequently have residual neurological deficits. Delaying antiviral therapy to await PCR results is a well-known testing trap. On an exam, if a patient presents with fever, confusion, and temporal lobe changes on MRI, the "next best step" is always IV acyclovir, not lumbar puncture and not MRI.

Mechanism of Acyclovir: Acyclovir is a guanosine analog that requires three sequential phosphorylation steps to become active. The first phosphorylation is performed by viral thymidine kinase (TK), which is present only in HSV-infected cells. This is why acyclovir has selective toxicity for infected cells and low toxicity to uninfected host cells. The subsequent two phosphorylations are carried out by host cell kinases. The final triphosphate form inhibits viral DNA polymerase and causes chain termination upon incorporation into the growing viral DNA strand.

Valacyclovir is the L-valyl ester prodrug of acyclovir, with significantly higher oral bioavailability (approximately 55% versus 15 to 20% for oral acyclovir). This allows for less frequent dosing and better patient compliance, making it the preferred oral agent for outpatient management.

Famciclovir is another option (prodrug of penciclovir) with similar efficacy and convenient dosing.

Contraindications and Adverse Effects: Acyclovir is primarily renally cleared. The main adverse effect is crystalline nephropathy caused by precipitation of acyclovir crystals in renal tubules. This is preventable with adequate IV hydration and dose adjustment in renal insufficiency. Monitor renal function during IV therapy. Other adverse effects include neurotoxicity (tremor, confusion, seizures), particularly in patients with renal failure who accumulate the drug.

Acyclovir Resistance: Resistance occurs almost exclusively in immunocompromised patients and is caused by mutations in the viral thymidine kinase gene, rendering the virus unable to activate acyclovir. The treatment for acyclovir-resistant HSV is foscarnet, which directly inhibits viral DNA polymerase without requiring activation by thymidine kinase. Foscarnet's main toxicity is nephrotoxicity and electrolyte disturbances (hypocalcemia, hypomagnesemia, hypokalemia).

Long-Term Management: Suppressive therapy is indicated for patients with frequent recurrences (typically 6 or more episodes per year). Daily valacyclovir reduces recurrence frequency by approximately 70 to 80%. Suppressive therapy does not eliminate latent virus and recurrences may resume upon discontinuation.

5. Differential Diagnosis and Distractors

DIFFERENTIAL	WHY IT IS SIMILAR	KEY DISCRIMINATOR
Herpes Zoster (VZV Reactivation)	Grouped vesicles on an erythematous base; positive Tzanck smear	Zoster follows a dermatomal distribution and does NOT cross the midline; HSV-1 recurrence is clustered in one small area (vermilion border) and not dermatomal; zoster is more common in elderly or immunocompromised patients
Herpangina (Coxsackievirus A)	Vesicles and ulcers in the oral cavity of a child with fever	Herpangina lesions are on the posterior oropharynx (soft palate, tonsillar pillars); HSV gingivostomatitis affects the anterior mouth (gingiva, tongue, buccal mucosa, hard palate)
Hand-Foot-Mouth Disease (Coxsackievirus A16, EV-A71)	Oral vesicles in a child	HFMD has lesions on palms, soles, and buttocks in addition to the oral cavity; HSV gingivostomatitis is limited to the oral mucosa and perioral skin
Aphthous Ulcers (Canker Sores)	Painful oral ulcers	Aphthous ulcers occur on non-keratinized mucosa (buccal, labial, floor of mouth) and are NOT preceded by vesicles; HSV affects keratinized mucosa (gingiva, hard palate) and begins as vesicles before ulcerating; Tzanck smear is negative
Impetigo (S. aureus / S. pyogenes)	Crusted lesions on the face, particularly perioral	Impetigo produces honey-colored crusts without the preceding vesicular stage on an erythematous base; no prodrome of tingling; responds to topical or oral antibiotics
Erythema Multiforme	Can be triggered BY HSV; thus appears temporally related	EM presents with target lesions (three-zone pattern) on the extremities; recurrent EM is most commonly triggered by recurrent HSV; the question may test whether you recognize HSV as the underlying cause
CMV Esophagitis	Odynophagia in an immunocompromised patient	CMV esophagitis shows large, deep, linear ulcers (often a single large ulcer) vs. the multiple small "punched-out" shallow ulcers of HSV; biopsy of CMV shows intranuclear "owl-eye" inclusions in endothelial cells vs. multinucleated giant cells with Cowdry type A inclusions in HSV
Bacterial Meningitis	Fever, headache, altered mental status	Bacterial meningitis has low glucose and neutrophilic pleocytosis in CSF; HSV encephalitis has normal glucose, lymphocytic pleocytosis, and RBCs; imaging in HSV encephalitis targets the temporal lobe, not diffuse meningeal enhancement
Temporal Lobe Epilepsy	Seizures, behavioral changes	No fever, no CSF abnormalities, no temporal lobe edema or hemorrhage on MRI; EEG shows epileptiform activity without the infectious prodrome

6. Traps and High-Yield Pearls

The most common way students lose points on HSV-1 questions is by delaying IV acyclovir in suspected encephalitis to wait for diagnostic confirmation. The exam will present a patient with fever, confusion, focal neurological deficits (aphasia, personality changes), and possibly seizures. The MRI may show temporal lobe hyperintensity. The trap is choosing "lumbar puncture" or "obtain MRI" as the next best step when the clinical picture already strongly suggests HSV encephalitis. The correct answer is to start IV acyclovir immediately because every hour of delay worsens outcomes, and the test rewards the principle that empiric treatment should never be withheld for a potentially fatal, treatable infection.

A second common trap involves the Tzanck smear. Students often select it as the "confirmatory" or "most accurate" test. While the Tzanck smear is a useful rapid bedside test, it cannot distinguish between HSV-1, HSV-2, and VZV. When the question asks for the most accurate test, the answer is always PCR.

Third, watch for the herpetic whitlow vignette. A healthcare worker or child presents with a painful vesicular lesion on the fingertip. Students who do not recognize this entity may select "incision and drainage," assuming a bacterial felon or paronychia. Incision and drainage of herpetic whitlow is contraindicated because it risks bacterial superinfection, delays healing, and can facilitate viral spread.

Fourth, remember that recurrent erythema multiforme is most commonly caused by recurrent HSV infection. If a patient presents with repeated episodes of target lesions, particularly on the extremities and following a prodrome of oral tingling or lip vesicles, the underlying trigger is HSV, and the long-term management is suppressive antiviral therapy, not steroids.

Finally, for neonatal herpes, the tested concept is that all neonates with suspected HSV, regardless of clinical severity, must receive IV acyclovir at 20 mg/kg every 8 hours, and that the duration is 14 days for SEM disease but 21 days for CNS or disseminated disease. The question may present a neonate with isolated skin vesicles (seemingly benign SEM disease) and test whether you still initiate aggressive systemic antiviral therapy. The answer is always yes.

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