Herpes Simpleks Tipe I

01Pathophysiology

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.

02Classification and Clinical Manifestation

03Diagnostic Workup

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.

04Management and Treatment

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.

05Differential Diagnosis and Distractors

06Traps 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.