Herpes Simplex Virus Infections¶

Chapter 197 | Part 5: Infectious Diseases

KEY CLINICAL POINTS¶

HSV-1 and HSV-2 are double-stranded DNA viruses causing mucocutaneous, CNS, and visceral infections with distinct clinical presentations.
Antiviral therapy (acyclovir, valacyclovir, famciclovir) is central to managing HSV infections, with suppressive therapy reducing recurrence rates.
HSV encephalitis is a medical emergency requiring IV acyclovir, while neonatal HSV infections have high mortality without prompt treatment.
Immune responses, including CD8+ T cells and cytokines, play a critical role in controlling HSV reactivation and preventing dissemination.
Subclinical shedding and asymptomatic transmission contribute to the global spread of HSV, particularly HSV-2.

1. DEFINITION & OVERVIEW¶

Herpes simplex viruses (HSV-1, HSV-2) are neurotropic DNA viruses causing a spectrum of infections, including mucocutaneous, CNS, and visceral diseases. HSV-1 primarily affects the oral region, while HSV-2 is associated with genital infections. Latency in sensory ganglia is a defining feature, with reactivation driven by immunosuppression or triggers like UV light.

Table 197-1 Antiviral Chemotherapy for Herpes Simplex Virus (HSV) Infection¶

Patient Group	Acute Episode Treatment	Suppressive Therapy	Special Considerations
Immunocompetent (Genital)	Acyclovir 800 mg tid x 2-3 days	Valacyclovir 500 mg bid or Acyclovir 400-800 mg bid	Neurologic complications: IV acyclovir 5 mg/kg q8h x 5 days
Immunocompetent (Oral/Labial)	Acyclovir 200 mg qid x 5-10 days	Valacyclovir 500 mg daily	Topical penciclovir or amenamevir for localized use
Immunosuppressed	IV acyclovir 5 mg/kg q8h x 14-21 days	Valacyclovir 500 mg bid	Monitor renal function; avoid acyclovir in renal failure
Neonatal HSV	IV acyclovir 60 mg/kg/day x 21 days	Oral acyclovir suspension x 3-4 months	Cesarean delivery for HSV-2 seropositive mothers

1.1 Viral Structure and Replication¶

HSV has a 152-kb double-stranded DNA genome enclosed in an icosahedral capsid with a lipid envelope. Viral replication occurs in the nucleus, followed by cytoplasmic assembly. Latency is maintained in neuronal cells, with reactivation mediated by viral genes (e.g., ICP0, ICP47) and host immune status.

1.2 Immune Interactions¶

HSV evades immune detection via ICP47 (inhibiting MHC class I presentation) and latency-associated transcripts (LATs). CD8+ T cells and IFN- γ are critical for controlling reactivation. Immunosuppression increases susceptibility to severe disease and dissemination.

2. EPIDEMIOLOGY¶

HSV-1 and HSV-2 are globally prevalent, with HSV-1 affecting 66% of the population and HSV-2 infecting 13.2% of those aged 15-49. HSV-2 prevalence is higher in developing countries, with sub-Saharan Africa reporting up to 60% seroprevalence in pregnant women. Transmission occurs via mucocutaneous contact, with asymptomatic shedding contributing to spread.

2.1 Risk Factors¶

Sexual activity, immunosuppression (e.g., HIV, organ transplant recipients), and prior HSV infection increase risk. HSV-2 is more transmissible than HSV-1, with 30-50% reactivation rates in immunocompromised patients.

2.2 Demographics¶

HSV-2 is more common in women than men. Neonatal HSV occurs in 1/2000-3000 live births, with higher risk for mothers with recent HSV acquisition. HSV-1 is acquired earlier in life, with 70-90% of adults seropositive by age 50.

3. ETIOLOGY & PATHOPHYSIOLOGY¶

HSV-1 and HSV-2 share similar genomic structures but differ in host tropism. Viral entry occurs via mucosal surfaces or abrasions, followed by neuronal migration and latency. Reactivation is driven by immune suppression, stress, or hormonal changes. Viral latency in ganglia allows for recurrent infections and potential dissemination to visceral organs.

3.1 Viral Latency and Reactivation¶

Latency is maintained in sensory ganglia with minimal viral gene expression. Reactivation is triggered by immune suppression, UV light, or trauma, leading to viral replication and shedding. LATs and miRNAs modulate latency and reactivation.

3.2 Host-Virus Interactions¶

HSV evades immune detection via ICP47 (inhibiting MHC class I) and LATs. CD8+ T cells and IFN- γ are critical for controlling reactivation. Immunosuppression increases susceptibility to severe disease and dissemination.

4. CLINICAL FEATURES¶

HSV infections present with mucocutaneous lesions, CNS involvement (encephalitis), or visceral dissemination. Primary infections are systemic, while recurrent episodes are localized. Complications include encephalitis, disseminated infection, and neonatal mortality.

5. DIFFERENTIAL DIAGNOSIS¶

HSV infections must be differentiated from syphilis, gonorrhea, chancroid, and other viral infections (e.g., VZV, HIV). Erythema multiforme and bacterial infections (e.g., streptococcal pharyngitis) may mimic HSV lesions. PCR and viral culture are critical for confirmation.

6. INVESTIGATIONS & DIAGNOSIS¶

Diagnosis relies on PCR for HSV DNA, viral culture, and serology. CSF analysis (PCR, cell count, protein) is essential for CNS infections. Imaging (MRI) detects CNS involvement. Histopathology shows multinucleated giant cells and intranuclear inclusions.

6.1 Diagnostic Tests¶

PCR is the most sensitive method for detecting HSV DNA in lesions, CSF, or blood. Viral culture is less sensitive but useful for typing. Serology (IgG/IgM) aids in diagnosing recent infections but cannot distinguish subtypes.

6.2 Imaging and Biopsy¶

MRI detects CNS involvement in HSV encephalitis. Biopsy of skin or mucosal lesions confirms diagnosis, with histopathology showing characteristic intranuclear inclusions.

7. MANAGEMENT & TREATMENT¶

Antiviral therapy (acyclovir, valacyclovir, famciclovir) is the cornerstone of treatment. Suppressive therapy reduces recurrence rates. Foscarnet is used for acyclovir-resistant strains. Neonatal HSV requires aggressive IV acyclovir therapy.

7.1 Antiviral Therapy¶

Acyclovir (5 mg/kg q8h IV) is first-line for severe infections. Valacyclovir and famciclovir are preferred for outpatient use. Suppressive therapy (500 mg valacyclovir daily) reduces recurrence rates in immunocompetent patients.

7.2 Special Populations¶

Pregnant women with HSV-2 should receive suppressive therapy to prevent neonatal transmission. Neonatal HSV requires IV acyclovir (60 mg/kg/day x 21 days). Immunocompromised patients may need prolonged suppressive therapy.

8. PROGNOSIS & COMPLICATIONS¶

Most HSV infections are self-limiting, but encephalitis and disseminated infections have high mortality. Neonatal HSV has ~15% mortality with treatment. Complications include scarring, neurologic deficits, and recurrent infections in immunocompromised patients.

8.1 Long-Term Outcomes¶

Recurrence rates are 55-90% for HSV-2 and 40-50% for HSV-1. Chronic suppression reduces reactivation but does not eliminate latency. Immunosuppressed patients face higher risks of severe disease and dissemination.

8.2 Complications¶

HSV encephalitis can lead to seizures, cognitive deficits, or death. Disseminated HSV in immunocompromised patients may involve the liver, lungs, or CNS. Neonatal HSV can cause developmental delays or mortality.

9. SPECIAL CONSIDERATIONS¶

Pregnancy management includes suppressive therapy to prevent neonatal transmission. Neonatal HSV requires immediate IV acyclovir. In immunocompromised patients, prophylactic antiviral therapy is critical to prevent reactivation and dissemination.

9.1 Pregnancy¶

Suppressive acyclovir (400 mg tid) in late pregnancy reduces cesarean delivery but may not prevent neonatal transmission. Neonatal HSV requires IV acyclovir (60 mg/kg/day x 21 days).

9.2 Immunocompromised Patients¶

Immunosuppressed patients (e.g., HIV, transplant recipients) require suppressive therapy to prevent reactivation. Acyclovir-resistant strains may necessitate foscarnet or cidofovir.

10. KEY POINTS & CLINICAL PEARLS¶

HSV-1 and HSV-2 cause distinct but overlapping infections; acyclovir is the first-line treatment. 2. Neonatal HSV has high mortality without prompt IV acyclovir. 3. Suppressive therapy reduces recurrence rates in immunocompetent patients. 4. HSV encephalitis is a medical emergency requiring IV acyclovir. 5. Asymptomatic shedding contributes to transmission, especially in HSV-2.