KEY TAKEAWAYS
- Neonatal HSV is a "can't-miss" emergency — untreated disseminated or CNS disease is frequently fatal, and outcomes hinge on early empiric acyclovir.
- Most infants have NO maternal history of HSV — asymptomatic maternal shedding is common, so a negative history does not exclude it.
- Three disease categories: SEM (skin, eye, mouth), CNS (encephalitis), and disseminated — they differ in prognosis and treatment duration.
- Frequently NO skin vesicles (about a third never have them) — consider HSV in any ill/septic-appearing neonate, especially with seizures, hepatitis, coagulopathy, or CSF pleocytosis with negative bacterial cultures.
- Treat with high-dose IV acyclovir: 60 mg/kg/day divided every 8 hours — 14 days for SEM, 21 days for CNS or disseminated disease.
- Repeat the LP at the end of CNS therapy to confirm CSF HSV PCR is negative, then give oral acyclovir suppression for 6 months.
1. Clinical Overview
Clinical Overview
Neonatal herpes simplex virus infection is uncommon but devastating, and it is one of the few neonatal diagnoses where empiric treatment while awaiting confirmation is not just acceptable but expected — because delay costs lives and brains. Most infections are acquired peripartum (passage through an infected birth canal), and the greatest risk is with maternal primary genital infection near delivery — yet the majority of mothers of affected infants have no known HSV history. The disease presents in three forms with sharply different prognoses, often without the skin vesicles that would make it obvious. The unifying clinical rule: think of HSV in the ill neonate, send the right tests, and start acyclovir immediately.
2. Definitions
| Term | Meaning |
|---|
| SEM disease | Localized to skin, eyes, and/or mouth — best prognosis, but can progress if untreated. |
| CNS disease | HSV encephalitis (± skin) — seizures, encephalopathy; high neurologic morbidity. |
| Disseminated disease | Multi-organ involvement (liver, lungs, adrenals, DIC) ± CNS — highest mortality. |
| High-dose acyclovir | 60 mg/kg/day IV divided every 8 hours — the standard neonatal treatment dose. |
| Suppression | Oral acyclovir for 6 months after acute therapy to improve outcomes/reduce recurrence. |
3. Pathophysiology & Transmission
Pathophysiology & Transmission
- Timing of acquisition: peripartum (~85%) — contact with infected maternal genital secretions during delivery; also postnatal (e.g., oral HSV-1 from a caregiver) and, rarely, intrauterine.
- Risk factors: maternal primary (first-episode) genital HSV near delivery (highest risk — low maternal antibody transfer), prolonged rupture of membranes, use of fetal scalp electrodes, and vaginal delivery with active lesions. Recurrent maternal infection carries lower (but non-zero) risk.
- Virus (HSV-1 or HSV-2) disseminates from the portal of entry; the immature neonatal immune system permits spread to skin, CNS, and viscera.
4. Clinical Presentation (by category)
Clinical Presentation (by category)
- SEM (skin, eye, mouth): vesicles (may cluster), keratoconjunctivitis/eye discharge, oral lesions. Usually presents in the first ~1–2 weeks. Best prognosis — but untreated SEM can progress to CNS/disseminated disease.
- CNS (encephalitis): seizures, lethargy, irritability, poor feeding, temperature instability, bulging fontanelle; often ~2–3 weeks of age; skin lesions may be absent.
- Disseminated: a sepsis-like picture with hepatitis (elevated ALT), coagulopathy/DIC, pneumonitis, shock, ± CNS, ± skin. Presents early and carries the highest mortality.
Crucial caveat: roughly one-third have no skin vesicles, so HSV must be considered in any ill neonate even without a rash.
5. Diagnostic Approach
Diagnostic Approach
Send a full HSV evaluation and start acyclovir empirically while results are pending:
- HSV PCR: CSF (CNS disease), blood (dissemination), and surface swabs (mouth/nasopharynx, conjunctivae, rectum), plus skin-vesicle swab/culture.
- Serum ALT (elevation suggests hepatic/disseminated involvement).
- Classify based on results: SEM = only surface/vesicle positive with negative CSF/blood and no visceral involvement; CNS = CSF PCR positive; disseminated = visceral involvement (e.g., hepatitis, pneumonitis).
- Additional: ophthalmologic exam, neuroimaging (MRI), and EEG for CNS disease.
- Consider HSV in sepsis evaluations — especially with maternal lesions, seizures, hepatitis, vesicles, or CSF pleocytosis with negative bacterial cultures — and treat empirically pending results.
(A positive blood PCR suggests dissemination but can occur across categories, so it shouldn't be used alone to classify.)
6. Management
Management
Acute antiviral therapy
- High-dose parenteral acyclovir: 60 mg/kg/day IV divided every 8 hours (i.e., 20 mg/kg/dose q8h; adjust interval in prematurity/renal impairment).
- Duration by category:
- SEM: 14 days.
- CNS or disseminated: 21 days.
- CNS disease: repeat lumbar puncture near the end of therapy to confirm CSF HSV PCR is negative — if still positive, continue acyclovir and re-test until negative.
- Start empirically and immediately in suspected cases — do not wait for confirmation.
Adjuncts & supportive care
- Ocular involvement: add a topical ophthalmic antiviral (with ophthalmology).
- Supportive care for disseminated disease: hemodynamic support, manage hepatitis/coagulopathy (DIC), respiratory support.
- Monitor acyclovir toxicity: neutropenia (check counts) and renal function (ensure hydration).
Suppression after acute therapy
- Oral acyclovir suppression for 6 months following completion of parenteral therapy — improves neurodevelopmental outcomes (CNS disease) and reduces skin recurrences. Monitor neutrophil counts during suppression. Baylor Ed. 33 gives the dose and schedule: acyclovir 300 mg/m²/dose three times daily for 6 months, for every infant surviving neonatal HSV of any classification, with the absolute neutrophil count at 2 and 4 weeks after starting, then monthly for the rest of the course. For CNS disease, repeat the CSF HSV PCR near the end of the 21-day course — if it is still positive, give 7 more days of IV acyclovir and repeat the PCR again. An infant born to a mother with primary HSV who has normal CSF indices, negative PCRs and a normal ALT is treated for 10 days. Ocular involvement adds topical 1% trifluridine or 0.15% ganciclovir alongside parenteral therapy. Every infant with neonatal HSV, whatever the classification, needs an ophthalmological examination and baseline neuroimaging — MRI is the most sensitive but may need sedation, so CT or cranial ultrasound are acceptable alternatives.
7. Monitoring
Monitoring
- CSF HSV PCR at end of CNS therapy (must clear before stopping).
- ANC/neutrophils during acyclovir treatment and suppression; renal function.
- Neurodevelopmental, ophthalmologic, and hearing follow-up.
- Watch for skin recurrences during/after suppression.
8. Complications
Complications
- Death — high with untreated disseminated (historically ~85%) and CNS (~50%) disease; reduced but persistent with high-dose acyclovir (disseminated highest).
- Neurodevelopmental impairment, seizures/epilepsy (CNS disease — a large fraction of survivors).
- Recurrent skin/eye disease, recurrent CNS disease.
- Ocular sequelae (keratitis, chorioretinitis).
- Acyclovir resistance — rare, described especially after prolonged therapy.
9. Safety Warnings
Safety Warnings
- ⚠️ Start acyclovir empirically in any suspected neonatal HSV — don't wait for confirmation.
- ⚠️ No maternal history does NOT exclude HSV — most mothers have none.
- ⚠️ HSV often has no skin lesions — consider it in the ill/septic neonate, especially with seizures or hepatitis.
- ⚠️ Use high-dose acyclovir (60 mg/kg/day divided q8h) — not lower adult-style dosing.
- ⚠️ Repeat the LP in CNS disease before stopping — don't stop with a still-positive CSF PCR.
- ⚠️ Give 6 months of oral suppression — and monitor neutrophils on acyclovir.
10. Common Mistakes
Common Mistakes
- Waiting for confirmation before starting acyclovir.
- Excluding HSV because there's no maternal history or no vesicles.
- Using too low an acyclovir dose (not 60 mg/kg/day).
- Using the wrong duration (SEM 14 vs CNS/disseminated 21 days).
- Not repeating the LP in CNS disease before stopping.
- Omitting 6-month oral suppression.
- Not monitoring neutropenia on acyclovir.
11. Clinical Pearls
Clinical Pearls
- 💡 Ill neonate + seizures/hepatitis + negative bacterial cultures → think HSV, start acyclovir.
- 💡 A third have no skin lesions — a normal skin exam doesn't reassure.
- 💡 60 mg/kg/day, divided q8h — memorize the high-dose regimen.
- 💡 14 for SEM, 21 for CNS/disseminated — durations differ, so classify carefully.
- 💡 CNS: clear the CSF before you stop.
- 💡 Six months of suppression improves the brain and cuts recurrences.
12. Summary Table
Summary Table
| Category | Features | Duration | Notes |
|---|
| SEM | Skin vesicles, keratoconjunctivitis, oral lesions | 14 days | Best prognosis; can progress if untreated |
| CNS | Seizures, encephalopathy (± skin) | 21 days | Repeat LP to confirm CSF PCR negative before stopping |
| Disseminated | Sepsis-like, hepatitis, DIC, pneumonitis (± CNS) | 21 days | Highest mortality; supportive care for organ involvement |
| Drug | IV acyclovir 60 mg/kg/day ÷ q8h | — | Monitor neutropenia/renal; start empirically |
| After acute Rx | Oral acyclovir suppression × 6 months | — | Improves CNS outcomes; reduces recurrence; monitor ANC |
13. Step-by-Step Bedside Algorithm
NEONATE: vesicles │ seizures/encephalopathy │ sepsis-like + hepatitis/DIC │ ill + negative
bacterial cultures / CSF pleocytosis (maternal history often ABSENT)
│
▼
SEND HSV WORKUP + START ACYCLOVIR EMPIRICALLY (don't wait)
• HSV PCR: CSF, blood, surface swabs (mouth/NP, conjunctivae, rectum), vesicle
• serum ALT; ophthalmology; MRI + EEG for CNS
│
▼
CLASSIFY
├─ Surface/vesicle only, CSF & blood negative, no visceral involvement → SEM → 14 days
├─ CSF PCR positive → CNS → 21 days
└─ Visceral involvement (hepatitis/pneumonitis) → DISSEMINATED → 21 days
│
▼
TREAT: IV ACYCLOVIR 60 mg/kg/day ÷ every 8 h
• monitor neutropenia + renal function; hydrate
• ocular disease → add topical ophthalmic antiviral
• disseminated → supportive care (hemodynamics, DIC, respiratory)
│
▼
CNS disease → REPEAT LP near end of therapy
├─ CSF PCR negative → complete course
└─ CSF PCR still positive → CONTINUE acyclovir, re-test until negative
│
▼
After acute therapy → ORAL ACYCLOVIR SUPPRESSION × 6 MONTHS (monitor ANC)
│
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Follow-up: neurodevelopment, ophthalmology, hearing; watch for recurrences
14. References to Verify
Confirm each against the primary source before clinical or published use.
- 1.High-dose acyclovir: Kimberlin DW, et al. Safety and Efficacy of High-Dose Intravenous Acyclovir in the Management of Neonatal HSV Infections. Pediatrics. 2001;108:230–238. (60 mg/kg/day; durations — verify.)
- 2.Oral suppression: Kimberlin DW, et al. Oral Acyclovir Suppression and Neurodevelopment after Neonatal Herpes. NEJM. 2011;365:1284–1292. (6-month suppression — verify.)
- 3.AAP guidance: AAP Committee on Infectious Diseases (Red Book) and clinical report on Guidance on Management of Asymptomatic Neonates Born to Women with Active Genital Herpes. (Verify.)
- 4.Diagnosis/classification: neonatal HSV diagnostic references (CSF/blood/surface PCR; classification). (Verify.)
- 5.CNS end-of-therapy LP: recommendation to confirm CSF PCR clearance before stopping. (Verify.)