Herpes Simplex Virus (HSV)

• The topic is Herpes simplex virus

Herpesviridae Family Virus

• Includes Herpes Simplex 1 (α), Herpes Simplex 2 (α), Varicella Zoster Virus (α), Cytomegalovirus (CMV) (β), Epstein Barr virus (EBV) (γ), Human herpes virus 6 (β), Human Herpes viru 7 (β), Human herpes virus 8 (γ), and Human B virus (α).
• The family has latency.
• Transmission occurs through direct contact, blood products (e.g., EBV, CMV, HHV8), perinatally (HSV1-2, VZV, EBV), or via aerosol (VZV).
• Several viruses have similar clinical manifestations.
• Some family strains cause oncogenesis such as EBV, and HHV-8.
• Intranucelar inclusions occur in tissues.

HSV Microbiology

• Alpha-herpesviruses that are 150 to 200 nm
• Structurally comprised of four major components
• dsDNA
• nucleocapsid (viral core)
• tegument (matrix=protein rich layer)
• lipid envelope (contains 12 glycoproteins)

Epidemiology

• Most prevalent STD in the USA.
• HSV 1 and 2 can cause genital infection.
• Most genital herpes are caused by HSV-2, but Genital HSV-1 is increasing
• HSV-2 is not a notifiable condition, therefore prevalence and incidence data are not accurate.
• HSV -2 seroprevalence decreased from 18% to 12% from 2000-2016
• Seroprevalence is higher in females (15.9%) than males (8.2%).
• Seroprevalence increases with age.
• HSV-1 prevalence sits at 54% vs 48.1%
• HSV-2 prevalence sits at 18% vs 12.1%
• Age-Adjusted HSV -2 Seroprevalence according to Lifetime Number of Sex Partners in NHANES in 1999-2004

HSV Pathogenesis

• Primary infection: herpesvirus enters the body through skin or mucous membranes and spreads into dorsal root ganglia.
• Virus migrates within the neuron to the epidermal area and reactivates, resulting in skin lesions or subclinical shedding.

Genital Herpes

• Women: Vulva and perianal area
• Men: penile skin and perianal area
• Higher rates occur in people with frequent outbreaks, first year after acquisition, primary infection (12 days), and recurrent infection (2-3 days).
• Oral antiviral suppressive Tx shortens the duration but does not eliminate viral shedding.
• Viral shedding is highest in the first year after infection and decreases with time.
• Transmission is most efficient from infected male to susceptible female partner.

Population at Risk

• HSV-1 affects everyone.
• Athletes in contact sports (rugby and wrestling), especially herpes gladiatorum
• Healthcare workers are at risk for herpetic whitlow.
• Herpetic whitlow has one digit involvement, pain, and itching
• HSV-1 affects paramedics, dentists, respiratory therapists, and the general population.
• HSV-2 affects the general population.
• HSV-2 affects sexually-active people, people with multiple sex partners, people with a known infected sexual partner, and newborns from infected mothers.

Clinical Manifestations

• Includes encephalitis, keratitis, mucocutaneous disease in immunocompromised hosts, primary/recurrent genital herpes (HIV-2 or HSV-1), Primary HSV-1 Oropharyngeal Herpes and recurrent labialis, and neonatal herpes

Primary Infection HSV 1

• Asymptomatic
• Pharyngitis, gingivostomatitis, follicular conjunctivitis, dendritic keratitis, blepharitis Most common in children < 5 years in day care centers/schools
• Incubation period is 2 to 12 days
• Resolved by 10-14 days
• Fever or inability to swallow and LAD
• Lip lesions are mostly recurrent and can last a lifetime
• No sequelae

Primary Genital Infection

• Severe multiple genital ulcers, pain, itching, dysuria, vaginal or urethral discharge, tender inguinal LAD.
• Lesions last 2-3 weeks.
• Viral shedding lasts 10 to 12 days.
• Constitutional symptoms: fever, myalgias, HA, aseptic meningitis, urinary retention.
• Cervicitis, proctitis
• Primary HSV-2 infection has no antibodies detected (because they take a while to develop).
• Non-Primary HSV infection presence of pre-existing Abs

Recurrent Disease

• Lesions heal more rapidly.
• Frequency of symptom recurrences decreases from 4 to 5 recurrences during the first year to 3 to 4 in subsequent years.
• HSV-2 Oro-labial recurrent infections is less common than with HSV-1
• More recurrent episodes occur in women
• More recurrent episodes occur in persons with prolonged symptoms with primary infection.

Recurrent Infections

• Herpes labialis consists on prodromal symptoms, often on the vermilion border of the lip. The area progresses from vesicle to ulcer to crusted lesion
• Genital lesions present on the labia majora, mons pubis, and buttocks

Precipitating factors for recurrent episodes

• UV light
• Fever
• Local trauma
• Trigeminal nerve manipulation
• Menstruation
• Emotional stress
• Immunosuppression
• Sexual intercourse

Diagnosis

• Send scraping of lesions for viral culture or PCR-NAAT which is the preferred test
• Perform PCR of CSF for encephalitis
• Type-specific serology using ELISA or a Western Blot for accurate identification
• Cytologic exam with a Tzanck smear is low sensitivity and does not differentiate HSV1 from HSV 2

Complications

• Aseptic Meningitis: HSV-2
• Encephalitis: HSV-1
• Neonatal infection
• Immunocompromised Host (HIV & transplant)

Herpes Simplex Encephalitis (HSE)

• Life-threatening complication of HSV-1
• Untreated cases have a mortality rate > 80%
• Occurs with either primary or recurrent infection
• Occurs in all ages, both sexes, and all seasons
• Leads to temporal lobe, necrotizing hemorrhagic encephalitis
• Patients will experience focal seizures, olfactory hallucinations, and exhibit bizarre behavior

Herpes Simplex Encephalitis Diagnostic Tests

• Electroencephalography:
  • Sensitivity of ~84%
  • Periodic lateralizing epileptiform discharges (PLEDs)
• Neuroimaging:
  • Computed tomography (lesions in 50-75% of patients)
  • Magnetic resonance imaging (>90% of cases)
• Brain biopsy:
  • Inflammation with widespread hemorrhagic necrosis
  • Intranuclear inclusions (50% of patients)
  • Reserve for patients not responding to acyclovir therapy

Neonatal Herpes

• Risk of intrauterine infection is 5% and is transplacental or ascending.
• Intrapartum infection risk is 85%.
• Postnatal infection risk is 10%.
• Infants can have viremia/disseminated disease (25%), superficial skin, eye, and/or mouth involvement (45%), or neuronal spread leading to localized encephalitis (30%).
• The highest risk of neonatal infection is with primary infection late in pregnancy, occurring in 30-50% of cases.
• The highest risk is with shedding of HSV-1
• If genital lesions are detected, deliver the infant by cesarean section.
• Very high mortality rate
• It is worse if the mother has a primary HSV infection during her last trimester of pregnancy or close to giving birth

HSV in the Immunocompromised Host

• Recurrences are more severe and prolonged
• Infection in unusual sites
• Post-transplantation causes tracheobronchitis, pneumonitis, esophagitis, and hepatitis.
• In AIDS patients, it causes perianal ulcers, colitis, esophagitis, and acute retinal necrosis.

Erythema Multiforme

• 75% of cases are preceded by an attack of HSV-1 or HSV-2.
• Immune-mediated and may recur.

Treatment

• Acyclovir (ACV) mechanism of action.
• It is a nucleoside analogue that requires tri-PO4 by virally-encoded cellular kinase to inhibit HSV.
• It inhibits HSV DNA polymerase.
• In immunocompromised hosts, ACV is used for treatment and suppression.
• ACV-resistant strains exist in HIV-infected individuals (Foscarnet) needs to be used
• Mutants arise due to lack of TK or altered substrate

Recommended Treatment for HSV

• First Episode: ACV 400 mg po tid X 7-10 days, 250 mg tid X 7-10 days, 1 g po bid X 7-10 days
• Recurrent Symptomatic Episode: ACV 800 mg po bid X 5 days, FCV 1 G po BID X 1 day, VCV 1 g po qd X 5days
• Daily Suppressive therapy: ACV 400 mg po bid, FCV 250mg po BID , VCV 500 mg po qd or 1 g po qd
• Treatment of episodic HSV /HIV: ACV 400 mg po tid X 5-10 days OR 200 mg po 5X/d X 5-10 days, FCV 500 mg po bid X 5-10 days, VCV 1 g po bid X 5-10 days
• Daily Suppressive in HSV / HIV: ACV 400-800 mg po bid to tid, FCV 500 mg po bid, VCV 500 mg po bid
• MMWR Recomm Rep. 2021;70(No. RR-4):1-187.
• 2021 STI Treatment Guidelines

Treatment by Condition

• Encephalitis: ACV 10 mg/kg IV q 8 hr X 21 days
• Meningitis and Bell’s palsy: there are no controlled trials and Oral ACV 200 mg 5X/d should be administered
• Neonatal herpes: IV ACV decreases mortality

Prevention

• Use of latex condoms
• Contact Isolation
• Use of gloves
• Use of sunscreen
• Cesarean section if active genital disease before rupture of membranes