Herpes simplex virus

• Comprises herpes simplex virus 1 (HSV-1) and HSV-2, which are members of the Herpesviridae family
• Cause typical painful vesicular lesions on labia or external genitals
• Occasionally cause a viral encephalitis

Background

Microbiology

• Enveloped, double-stranded DNA virus
• HSV-1 and HSV-2 are morphologically and genetically distinct viruses
• Can be infected with both

Mechanisms of Resistance

• Resistance to acyclovir is usually conferred by a deficiency in thymidine kinase (which phosphorylates acyclovir)
  • Will also be resistant to valacyclovir and famciclovir

Epidemiology

• Worldwide distribution, and only found in humans
  • Most common cause of genital lesions
  • Most common cause of acute viral encephalitis in the US, with age peaks at 5 to 30 years and over 50 years
• Spread through person-to-person contact with skin or mucosa; not spread via fomits
• HSV-1 has seroprevalence of 50-90% among Canadian adults1
  • Often acquired in childhood in Asia and Africa
  • More common in lower SES populations
• HSV-2 has seroprevalence of 15-20% in Canada1
  • More common in women than men, in HIV-infected people, and in MSM
  • May be subclinical if already infected with HSV-1

Pathophysiology

• Fusion of envelope and cell membrane is mediated by viral glycoproteins B, C, and D and host cell proteins cellular heparin sulfate, TNF receptors, and immunoglobulins
• Internal capsid is released, which makes its way to the nucleus
• Viral DNA polymerase enzyme and viral DNA helicase are targets of antivirals
• Viral DNA may remain latent in about 10% of nearby neurons, characterized by latency-associated transcripts (LATs)
  • Despite being latent, virus can still be shed in mucosa anywhere from 1/10 to 3/4 of days
• HSV-1 prefers trigeminal ganglia as well as cervical ganglia, or sacral nerve root ganglia if genital

Clinical Manifestations

Primary Infection

• Incubation period usually within 5 days for primary infection
• Mucocutaneous lesiosn may become secondarily infected

Orofacial Infection

• Most common sites of primary infection are gingivostomatitis and pharyngitis
  • Includes lesions on hard and soft palate, gingiva, tongue, lips, and face
  • Pharyngeal lesions may be exudative or ulcerative
• May also have malaise, myalgias, anorexia or odynophagia, and cervical lymphadenopathy
• Self-resolving after 3 to 14 days
• Can cause a Bell palsy

Genital Infection

• Genital lesions typically last 10 to 12 days, especially with first episode
  • Often widely spaced bilateral lesions
  • First episode often also involves fever, headache, malaise, and myalgias
  • May have pain, itching, dysuria, genital discharge, and inguinal lymphadenopathy
• May develop extragenital sites of infection, including buttock, groin, and thigh with HSV-2 and perioral area with HSV-1
  • Rarely fingers and eyes
  • Develop around 14 days into the disease, likely from autoinoculation
• HSV-2 genital infections are less severe if the person has had HSV-1
• 12-month recurrence rate is up to 90% for HSV-2 and 55% for HSV-1

Neurological Complications

• These can include aseptic meningitis, transverse myelitis, and sacral radiculopathy
• Typically occur in conjunction with first episode of genital HSV-2 infection
• Aseptic meningitis
  • Mengitis is more common with HSV-2 than HSV-1
  • Often concurrent with primary genital infection, typically 3 to 12 days after start of symptoms
  • HSV-2 may also cause Mollaret's meningitis (benign recurrent lymphocytic meningitis)
• Autonomic dysfunction
  • May have hyperesthesia or anaesthesia of perineum, lumbar or sacrum, as well as urinary retention and constipation
  • Resolves over 4 to 8 weeks
• Transverse myelitis
  • Decreased strength and deep tendon reflexes in lower extremities in conjunction with autonomic dysfunction (as above)

Pelvic Inflammatory Disease

• Rare cause of PID, possibly representing dual infection with a typical bacterial copathogen

Disseminated Disease

• Rarely can disseminate
• Can be cutaneous, with concurrent meningitis, hepatitis, and pneumonitis
• Can also involve monocular arthritis, thrombocytopenia, adrenal necrosis, and myoglobinuria
• Patient factors include primary genital HSV in pregnancy, reactivation of genital HSV in a patient with cellular immunocompromise

Reactivation

• Typically localized to a single mucocutaneous area
• Symptoms are usually more minor than first-episode or primary infection, and include itching and pain
  • Lesions may be atypical, with fissures and unusual ulcers
  • May be subclinical, with intermittent viral shedding
  • May be preceded by a prodrome of tingling up to 2 days
• Average duration of an episode of reactivation orolabial herpes is 5 days
• HSV-1 reactivates more frequently around mouth, and HSV-2 in genitals
• Frequency
  • HSV-2 reactivates on average 4 to 5 times annually, with a gradual decrease over time

Herpetic Whitlow

• HSV infection of the finger, with acute onset swelling, pain, and tenderness with vesicles
• Also fever and regional lymphadenopathy
• Can be either acquired from parson-to-person exposure or through autoinoculation
• Higher rates in healtcare settins

Herpes Gladiatorum

• Herpes simplex infection essentially anywhere on the body (chest, ears, face, and hands) associated with wrestling

Ocular Herpes

• Keratitis, which presents with pain, blurred vision, chemosis, conjunctivitis, and corneal lesions
• May also cause blepharitis and conjunctivitis
• May cause chorioretinitis in infants and immunocompromised
• Acute necrotizing retinitis
  • Presents with painless vision loss in immunocompetent people as well as immunocompromised
  • 25% of cases are bilateral

Encephalitis

• Most commonly caused by HSV-1 (95% of cases)
• In children, it is often during primary infection
• Less clear in adults, where it may be primary, infection with a new strain, or reactivation of latent infection
• Characterized by acute onset fever and neurologic symptoms
  • Often affects temporal lobe, with behaviour changes
• CSF findings
  • CSF PCR may be negative initially, so may need to repeat LP
  • May not have a cerebrospinal pleiocytosis (normal CSF in 3%)

Visceral and Pulmonary Herpes

• Can disseminate hematogenously to organs
• Includes esophagus, lung, and liver most commonly
• Esophagitis is more common in patients with advanced HIV
  • Symptoms include odynophagia, dysphagia, chest pain, and weight loss
• Pneumonitis may occur in patients with immunosuppression
  • Focal necrotizing pneumonitis or bilateral interstitial pneumonitis, depending on pattern of spread
  • 80% mortality
  • However, must be distinguished from asymptomatic shedding during an intercurrent illness
• Hepatitis is rare but can be quite severe
  • May also have fever, leukopenia, and DIC

HIV Coinfection

• HSV, and specifically HSV-2, may be persistent in HIV coinfection
• HSV-2 also predisposes to HIV infection
• There is more frequent asymptomatic shedding of HSV, inversely proportional to CD4 count
• Frequency of lesions is lower on ART

Other Immunocompromised Patients

• Higher risk for severe HSV infections in organ transplantation, chemotherapy, malnutrition, or severe burns or eczema
• In these patients, it can disseminate to adrenals, liver, bone marrow, and GI tract
• Can also develop oropharyngeal and esophageal lesions
  • May be difficult to distinguish from chemotherapy mucositis
• Similar to other patients, asymptomatic shedding is also common, especially for 2 to 3 weeks after grafting

Pregnancy

• See HSV in pregnancy

Neonatal Herpes

• Can be acquired perinatally even without active lesions
  • Mostly HSV-2
  • Rarely can be congenital, with microcephaly, hydrocephalus, and chorioretinitis
• High risk for disseminated disease, including CNS in 70% of cases
• Requires prolonged treatment, with initial IV acyclovir for 21 days followed by 6 months of oral

Diagnosis

• Serology
  • Species-specific HSV-1 and HSV-2 antibody assays, most commonly to glycoproteins gG1 and gG2
  • Antibodies will be positive life-long, though you can use acute and convalescent titres for diagnosis of primary infection (not helpful for reactivation)
• Molecular tests
  • PCR is current standard, given its high sensitivity
• Viral culture
• Histology, with Wright, Giemsa, or Papanicolaou stains that show giant cells or intranuclear inclusions that are typical of HSV
  • Large granular plasma cells in CSF are the hallmark of Mollaret meningitis

Management

Genital and Rectal Herpes

• Mild-to-moderate infection
  • First episode
    • Acyclovir 400 mg po tid, acyclovir 200 mg po 5x/day, famciclovir 250 mg po tid, or valacyclovir 1 g po bid
    • Duration 5 to 10 days
  • Recurrence
    • Acyclovir 400 mg po tid, acyclovir 800 mg po bid, acyclovir 800 mg po tid, valacyclovir 500 mg po bid, famciclovir 125 mg po tid
    • Duration 5 days, except valacyclovir that is 3 days
  • Suppressive therapy
    • Acyclovir 400 mg po bid, famciclovir 250 mg po bid, valacyclovir 500 mg po daily, or valacyclovir 1 g po daily
• HIV patients
  • Recurrence
    • acyclovir 400 mg po tid, valacyclovir 1 g po bid, famciclovir 500 mg po tid
    • Duration 5 to 10 days
  • Suppressive therapy
  • Acyclovir 400 to 800 mg po bid to tid, famciclovir 500 mg po bid, or valacyclovir 500 mg po bid
• Severe infections, including CNS or ocular involvement, or disseminated disease
  • Acyclovir 5 to 10 mg/kg IV q8h for 5 to 7 days and until clinical resolution
  • For encephalitis, extend to 21 days
  • For neonates, extend IV to 21 days then step down to oral for 6 months
• Pregnant: use acyclovir

Stomatitis

• Acyclovir 400 mg po tid, acyclovir 200 mg po 5x/d, famciclovir 250 mg po tid, valacyclovir 1 g po bid
• Duration 7 to 10 days

Esophagitis

• Acyclovir 400 to 800 mg po 5x/day, famciclovir 500 mg po bid to tid, valacyclovir 1 g po bid, or acyclovir 5 mg/kg IV q8h
• Duration 7 to 10 days

Herpes Labialis Prophylaxis

• Acyclovir 400 mg po bid, famciclovir 250 mg po bid, valacyclovir 250 mg po bid or 500 mg po daily or 1 g po daily

Encephalitis and Meningitis

• Acyclovir 10 mg/kg IV q8h for 21 days
• Duration 21 days for encephalitis or 7 to 10 days for meningitis
• In neonates, this is followed by oral suppressive therapy

Ocular Infections

• Consult Ophthalmology

Immunosuppressed Patients

• HSV seropositive transplant patients: Acyclovir 5 mg/kg IV q8h for 7 days, followed by 200 to 400 mg po 3-5x/day for 1 to 3 months
• HIV patients: acyclovir 400 to 800 mg po bid to tid, valacyclovir 500 mg po daily, or famciclovir 500 mg po bid
• Burn patients: acyclovir 5 mg/kg IV q8h for 7 days, followed by 200 mg po 5x/day for 7 to 14 days

Acyclovir Resistance

• If unresponsive to acyclovir, consider foscarnet 40 to 80 mg/kg IV q8h until clinical resolution
• Can try cidofovir 5 mg/kg once weekly if severe infection