Herpes simplex virus

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  • 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



  • 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


  • 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 adultshoward2003re
    • Often acquired in childhood in Asia and Africa
    • More common in lower SES populations
  • HSV-2 has seroprevalence of 15-20% in Canadahoward2003re
    • More common in women than men, in HIV-infected people, and in MSM
    • May be subclinical if already infected with HSV-1


  • 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


  • 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


  • 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


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


  • 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


Genital and Rectal Herpes



Herpes Labialis Prophylaxis

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