Herpes simplex infection

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

HSV enters through mucosa or damaged skin, replicates locally and travels retrogradely to sensory ganglia, where latency persists for life. Reactivation returns virus to skin or mucosa with symptoms or asymptomatic shedding. HSV-1 and HSV-2 have tendencies rather than absolute anatomical boundaries.

Most disease is local and self-limited, but consequences are site and host dependent. Corneal infection scars the visual axis, eczema herpeticum spreads across a defective barrier, encephalitis causes haemorrhagic temporal necrosis, and neonatal or profoundly immunocompromised infection can disseminate through multiple organs.

The infectious-disease decisions are whether HSV is invasive, whether aciclovir must start before confirmation, which sample will answer the question and how renal function changes dosing. Cutaneous morphology overlaps with dermatology, while detailed genital suppression and obstetric transmission planning are addressed in the linked genital-herpes material.

Aciclovir resistance is uncommon in immunocompetent people but becomes important with prolonged antiviral exposure during substantial immunosuppression. Failure to improve should trigger repeat sampling, adherence and absorption review, resistance testing and specialist therapy rather than repeated unmodified courses.

Key points

HSV-1 commonly causes orolabial, ocular and encephalitic disease; HSV-2 commonly causes genital, neonatal and meningitic disease, but either type can occur at either site.
Painful grouped vesicles become shallow erosions, while prodromal tingling and recurrent lesions in the same region reflect ganglionic latency and reactivation.
Confirm atypical mucocutaneous disease with PCR from a freshly unroofed lesion base; serology cannot prove that a current lesion is herpetic.
For suspected encephalitis, send CSF HSV PCR and obtain MRI, but start intravenous aciclovir within six hours when results are unavailable or the patient is very unwell.
Give intravenous aciclovir 10 mg/kg every eight hours for adult HSV encephalitis, with renal adjustment, one-hour infusion and careful hydration.
Neonatal disseminated or CNS HSV requires aciclovir 20 mg/kg intravenously every eight hours for 21 days; skin-eye-mouth disease requires 14 days under neonatal care.
HSV keratitis needs same-day ophthalmology; topical antiviral and any corticosteroid phase must be directed by the corneal findings.
Genital recurrence, suppression and pregnancy prevention are covered in the dedicated genital-herpes pathway; invasive and non-genital disease are emphasised here.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Direct mucosal inoculation

Virus in saliva, genital secretion or lesion fluid enters oral, ocular, genital or damaged cutaneous epithelium during close contact.

Asymptomatic shedding

Reactivated virus reaches mucosa without visible lesions, allowing transmission from a person who feels entirely well.

Perinatal exposure

A neonate encounters HSV in the genital tract around delivery, with greatest risk after recent maternal primary acquisition.

Autoinoculation

Fresh virus can move from an active lesion to a finger, eye or eczematous skin through direct touch.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Epithelial cytolysis
Local replication destroys epithelial cells, creating painful grouped vesicles that rupture into shallow erosions and release infectious virus.
2
Neuronal latency
Viral DNA travels retrogradely to sensory ganglia and persists episomally, largely hidden from immune clearance between episodes.
3
Axonal reactivation
Stress, fever, ultraviolet exposure or immune change permits anterograde transport back to skin or mucosa and recurrent shedding.
4
Necrotising encephalitis
HSV invasion and inflammation preferentially injure temporal and frontal tissue, causing oedema, haemorrhage, seizures and neuronal death.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Orolabial herpes

Tingling or burning precedes grouped painful lip or perioral vesicles that erode, crust and recur in a similar area.

Herpetic gingivostomatitis

Diffuse painful oral vesicles, ulcers, gingivitis, fever and poor intake can cause dehydration during a primary episode.

Herpetic whitlow

A painful swollen distal finger with grouped vesicles follows inoculation and can be mistaken for a bacterial felon.

Eczema herpeticumRed flag

Monomorphic punched-out erosions spread rapidly across eczematous skin with pain, fever and possible ocular or systemic involvement.

HSV keratitisRed flag

Unilateral red painful photophobic eye with reduced vision and a fluorescein-staining dendritic epithelial ulcer is sight threatening.

HSV encephalitisRed flag

Fever, behavioural change, confusion, dysphasia, focal seizure and impaired consciousness reflect frontotemporal inflammation and necrosis.

Red flags requiring action

Fever with new confusion, personality change, focal seizure, dysphasia or reduced consciousness requires immediate encephalitis assessment and empirical intravenous aciclovir.
Eye pain, photophobia, red eye, reduced vision or a dendritic corneal lesion requires same-day ophthalmology and no unsupervised topical steroid.
Rapidly spreading painful monomorphic erosions with fever in eczema suggests eczema herpeticum and needs same-day systemic antiviral treatment.
A neonate with vesicles, lethargy, poor feeding, seizures, hepatitis or sepsis-like illness needs immediate intravenous aciclovir after urgent cultures and PCR samples.
Widespread mucocutaneous lesions, hepatitis, pneumonitis, coagulopathy or shock during pregnancy or immunosuppression suggests disseminated HSV.
Urinary retention, saddle sensory change or leg weakness can indicate HSV sacral radiculitis rather than uncomplicated genital or cutaneous disease.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
Lesion-base HSV PCRFirst step
Why
Confirm HSV and type an active mucocutaneous lesion.
Interpretation and limitations
Sample a fresh vesicle or firmly swab the ulcer base; a negative late, crusted or superficial sample has reduced sensitivity.
02
CSF HSV PCR
Why
Diagnose HSV encephalitis or meningitis after safe lumbar puncture.
Interpretation and limitations
A positive result confirms CNS infection; very early sampling can be negative, so repeat CSF and continue treatment when clinical and MRI suspicion remains high.
03
MRI brain
Why
Identify encephalitic inflammation and competing structural diagnoses.
Interpretation and limitations
Temporal, insular or orbitofrontal signal change supports HSV, but normal early imaging does not safely exclude disease.
04
EEG
Why
Detect non-convulsive seizures and support localisation in encephalopathy.
Interpretation and limitations
Temporal periodic discharges can support HSV encephalitis but are not pathogen specific and do not replace CSF PCR.
05
Corneal assessment
Why
Define epithelial, stromal, uveal or retinal HSV disease.
Interpretation and limitations
Visual acuity, fluorescein and slit-lamp examination guide treatment; topical anaesthetic is diagnostic only and must not be supplied for home use.
06
Dissemination screen
Why
Identify viraemia and organ involvement in neonates or immunosuppressed patients.
Interpretation and limitations
Use blood HSV PCR, FBC, coagulation, liver and renal tests plus site-specific imaging or CSF; negative skin findings do not exclude disseminated neonatal infection.
07
Immune and resistance assessment
Why
Explain severe, chronic or treatment-refractory disease.
Interpretation and limitations
Review HIV status, transplant or immunosuppressive therapy, adherence, absorption and antiviral exposure; persistent PCR-positive lesions permit susceptibility testing through virology.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Varicella-zoster virus

Dermatomal vesicles and neuropathic pain favour VZV, although lesion or CSF PCR is needed in atypical neurological disease.

Aphthous ulceration

Discrete non-vesicular oral or genital ulcers recur with inflammatory triggers and remain negative on correctly sampled HSV PCR.

Bacterial whitlow

A felon or paronychia produces focal pus, throbbing pressure and bacterial culture findings rather than grouped clear vesicles.

Autoimmune encephalitis

Psychiatric change, seizure and dyskinesia can mimic HSV, requiring parallel immune investigation after infection is treated or excluded.

Acanthamoeba keratitis

Contact-lens exposure, disproportionate corneal pain and ring infiltrate suggest amoebic keratitis requiring urgent specialist microscopy and culture.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01ENCEPHALITISTreat before confirmationFirst stepFever and encephalopathy, focal seizure, dysphasia or compatible temporal features raise suspicion of viral encephalitis.

1Stabilise airway, breathing and circulation, treat seizures and hypoglycaemia, obtain blood cultures and cover bacterial meningitis when clinically indicated.
2Perform lumbar puncture promptly unless a specific contraindication requires imaging first; send cell count, protein, glucose and HSV or VZV PCR.
3Start intravenous aciclovir 10 mg/kg every eight hours within six hours if CSF or imaging will be delayed, the patient deteriorates or suspicion remains high.
4Use MRI and EEG, repeat CSF PCR when early results conflict with the syndrome and define a 14- to 21-day course with infection or neurology specialists.

02EYEProtect the corneaPain, photophobia, red eye or visual change accompanies facial herpes or a suspected dendritic lesion.

1Record visual acuity, avoid contact-lens use and arrange same-day slit-lamp assessment rather than treating empirically as simple conjunctivitis.
2Start topical or systemic antiviral treatment according to the ophthalmologist's epithelial, stromal, uveal or retinal diagnosis.
3Never use topical corticosteroid alone in active epithelial HSV; steroid timing requires antiviral cover and specialist supervision.
4Review until epithelial healing and inflammation control are documented because recurrent stromal disease produces cumulative scarring.

03SKINSeparate local from extensive diseasePainful grouped vesicles, punched-out erosions or a herpetic whitlow is identified.

1Assess distribution, eye proximity, pain, fever, hydration, pregnancy, atopic skin disease and immune status before choosing topical, oral or intravenous therapy.
2Use lesion PCR for atypical or severe disease and start systemic aciclovir promptly for eczema herpeticum or extensive immunocompromised infection.
3Do not incise a herpetic whitlow as though it were a bacterial abscess; cover the lesion and prevent direct contact transmission.
4EscalationEscalate fever, rapid spread, ocular involvement, hepatitis or systemic instability for admission and intravenous treatment.

04NEONATETreat neonatal HSV urgentlyA baby has vesicles, sepsis-like illness, hepatitis, poor feeding, lethargy or seizures, especially after maternal HSV risk.

1Obtain surface, lesion, blood and CSF HSV PCR plus bacterial cultures, FBC, coagulation and liver tests without delaying treatment.
2Start intravenous aciclovir 20 mg/kg every eight hours immediately and involve neonatal infection specialists.
3Treat skin-eye-mouth disease for 14 days and CNS or disseminated disease for 21 days, repeating CSF PCR near the end of CNS therapy.
4Arrange suppressive oral aciclovir and neurodevelopmental, hearing and ophthalmic follow-up according to the neonatal protocol.

05FAILUREInvestigate refractory HSVLesions progress or remain PCR positive despite an adequate, absorbed and correctly dosed aciclovir course.

1Confirm adherence, enteral absorption, renal dosing, immune status and whether the lesion represents HSV rather than CMV, malignancy or inflammatory disease.
2Send a fresh lesion sample for PCR and resistance testing through virology while continuing clinically necessary treatment.
3Suspect thymidine-kinase-deficient aciclovir resistance particularly after prolonged exposure in transplantation or advanced immune suppression.
4Use foscarnet or another non-thymidine-kinase-dependent strategy only with infection-specialist oversight and intensive renal and electrolyte monitoring.

Key medicines and prescribing safety5 treatments · regimens, roles and cautions

First-line time-critical empirical and definitive antiviral therapy for suspected or confirmed HSV encephalitis in adults.

Intravenous aciclovir for HSV encephalitis

Give 10 mg/kg intravenously every eight hours by one-hour infusion, usually for 14 to 21 days under the encephalitis protocol, with renal and obesity-adjusted dosing.

Check creatinine, hydrate and renally adjust; crystal nephropathy and accumulation-related confusion or tremor can mimic worsening encephalitis.

Systemic treatment for significant primary or recurrent mucocutaneous HSV when oral absorption is reliable.

Oral aciclovir for mucocutaneous HSV

Give 200 mg orally five times daily at roughly four-hour intervals while awake for five days; extend or use 400 mg per dose in defined severe immune impairment under specialist advice.

Start early, adjust for renal impairment, maintain hydration and use intravenous therapy for encephalitis, dissemination, severe eczema herpeticum or inability to absorb.

Treats epithelial HSV keratitis when selected after slit-lamp assessment of corneal disease.

Topical aciclovir eye ointment

Apply a 1 cm ribbon of 3% ophthalmic ointment into the lower conjunctival sac five times daily and continue for at least three days after epithelial healing, under ophthalmology direction.

Do not use cutaneous cream in the eye, avoid contact lenses and never add topical corticosteroid without specialist antiviral cover and supervision.

Immediate treatment for suspected or confirmed neonatal HSV before irreversible neurological or multiorgan injury occurs.

Intravenous aciclovir for neonatal HSV

Neonatal regimen: give 20 mg/kg intravenously every eight hours for 14 days in skin-eye-mouth disease or 21 days in CNS or disseminated infection.

Use neonatal renal and gestational-age dosing guidance, secure venous access, monitor neutrophils and renal function, and repeat CSF PCR in CNS disease before stopping.

Bypasses viral thymidine kinase and treats confirmed or strongly suspected aciclovir-resistant HSV in profoundly immunosuppressed patients.

Foscarnet for aciclovir-resistant HSV

Use only a virology and infection-specialist intravenous weight- and renal-adjusted protocol with susceptibility support; induction dosing and duration depend on site and response.

Major nephrotoxicity, calcium, magnesium, phosphate and potassium disturbance, seizures and genital ulceration require hydration and intensive biochemical monitoring.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Permanent neurological injury

HSV encephalitis can leave epilepsy, memory loss, language impairment, behavioural change, motor disability or death despite viral control.

Corneal scarring

Recurrent epithelial or stromal inflammation damages corneal transparency and sensation, reducing vision and promoting further epithelial injury.

Disseminated herpes

HSV viraemia during pregnancy or profound immune suppression causes hepatitis, pneumonitis, encephalitis, coagulopathy, shock and progressive multiorgan failure.

Neonatal disability

CNS and disseminated neonatal infection cause death, seizures, cerebral palsy, developmental impairment, hearing loss and visual injury.

Antiviral resistance

Thymidine-kinase or polymerase mutations emerge under prolonged drug pressure, producing chronic progressive lesions in immunosuppressed hosts.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

In encephalitis, monitor consciousness, seizures, sodium, renal function and aciclovir dosing daily, with repeat imaging or EEG when the trajectory changes.
Repeat CSF HSV PCR when a very early negative result conflicts with compatible disease and near treatment completion in neonatal CNS infection.
During intravenous aciclovir, track creatinine and urine output, maintain hydration and distinguish drug neurotoxicity from advancing infection.
Follow HSV keratitis until corneal epithelial closure, visual recovery and inflammatory control are documented by ophthalmology.
After neonatal disease, continue the prescribed suppressive course and structured hearing, vision and neurodevelopmental surveillance.
For recurrent mucocutaneous disease, review trigger burden, diagnostic confirmation, adherence, immune status and whether suppressive therapy offers meaningful benefit.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

PCR timing matters

CSF HSV PCR may be negative very early, so a strongly compatible syndrome warrants continued therapy and repeat sampling.

Aciclovir can confuse

Renal accumulation causes tremor, hallucination and confusion, making dose review essential when neurology worsens during treatment.

Whitlow is not an abscess

Surgical incision adds bacterial infection and tissue injury without treating viral vesicles in a herpetic finger.

Steroid needs antiviral cover

Ophthalmic corticosteroid can be useful in selected stromal inflammation but is hazardous in untreated epithelial viral replication.

Neonates may lack vesicles

Disseminated or CNS neonatal HSV can present as sepsis or hepatitis without skin lesions, so absence of rash is not reassuring.

Scope boundary

Invasive, ocular and non-genital HSV are emphasised here; genital recurrence and pregnancy prevention have a dedicated pathway.

11Common pitfallsFrequent interpretation and management errors.

01
Do not delay intravenous aciclovir for MRI or lumbar puncture when encephalitis investigations cannot be completed within six hours.
02
Do not stop aciclovir after one very early negative CSF PCR when temporal features and MRI remain strongly compatible.
03
Do not diagnose an active lesion from HSV IgG; use lesion PCR because seropositivity is common and anatomically non-specific.
04
Do not prescribe topical ocular steroid for a dendritic ulcer without same-day ophthalmology and concurrent antiviral strategy.
05
Do not incise herpetic whitlow or treat eczema herpeticum with topical steroid alone while systemic virus is spreading.
06
Do not dismiss neonatal HSV because the mother reported no genital lesions or the baby has no vesicles.