Herpes Simplex Virus - HSV

Diagnosis

Indications for Testing

• Ulcerative lesions, unidentified encephalitis, encephalitis with focal neurologic symptoms, corneal ulcer

Criteria for Diagnosis

• HSV case definition (CDC, 1996)

Laboratory Testing

• Diagnosis typically made by lesion appearance and clinical history
• Nucleic acid amplification methods – most sensitive, specific and timely methods for diagnosis of acute lesions (eg, vesicles, ulcers, inflammation of mucous membranes, cerebrospinal fluid [CSF])
• PCR – rapid diagnostic testing that is recommended in certain conditions
  • Specimen is likely to have low viral load (CSF in herpes encephalitis)
  • Cultures are negative
  • Patient has AIDS
  • Patient has recurrent meningitis
  • Infant has suspected neonatal herpes
  • Lesions are several days old (culture will likely be negative)
• Viral culture – less sensitive (~50%) compared to PCR
  • Fluid should be obtained from unroofed vesicles
• Antigen detection tests for HSV – rapid, relatively inexpensive
  • 80% sensitive for acute vesicular lesions
  • 60-75% sensitive for resolving lesions or asymptomatic shedding
• Tzanck smear – rapid; does not differentiate between simplex and zoster
  • Performed on swabs from lesions
• HSV antibody titers are not useful for rapid diagnosis of acute infections
  • May be useful in patients with negative cultures
  • Primary HSV infections do not present significant IgG or IgM titer elevation for10-14 days in mucocutaneous disease and 3-4 weeks in herpes encephalitis
  • Reactivated/recurrent infections have high serum antibody titers at onset; levels do not change during convalescence
  • IgM tests cannot accurately distinguish between HSV-1 and HSV-2 antibodies
  • Type-specific testing for HSV-1 or HSV-2 can be done with IgG serology
    • Test does not perform as well in low-prevalence populations
• Central nervous system (CNS) disease – consider multiple panel testing on CSF and serum to rule out other viral illnesses (eg, varicella-zoster virus, mumps)
• HSV-1/HSV-2 testing
  • May differentiate disease severity
  • Used to identify a subclinical HSV-2 infection that may be transmitted to partner
  • Distinguishing between HSV-1 and HSV-2 in early stage disease with IgG may not be possible
    • All testing to distinguish HSV-1 from HSV-2 needs to be correlated with clinical history, epidemiological data and other data
    • Test does not distinguish between recently and remotely acquired diseases
  • ELISA method preferred for rapidity; however, immunoblot may detect rare nontypeable HSV with reactivity to the common antigen when type specific HSV-1 and HSV-2 are negative

Histology

• Immunohistochemistry – HSV-1, HSV-2

Prognosis

• Neonates – HSV-1 versus HSV-2 typing
  • Better prognosis with HSV-1 ocular, oral, cutaneous disease
  • Less neurologic morbidity with HSV-1 encephalitis
  • More sequelae from HSV-1 disseminated disease

Differential Diagnosis

• Oral disease
  • Acute necrotizing ulcerative gingivitis
  • Aphthous ulcers
  • Behçet syndrome
  • Erythema multiforme
  • Enterovirus
  • Herpangina (coxsackievirus)
  • Impetigo
  •  Pemphigus
  • Stevens-Johnson syndrome
• Genital disease
  • Atopic dermatitis
  • Behçet syndrome
  • Erosive lichen planus
  • Haemophilus ducreyi
  • Treponema pallidum
  • Urethritis
• Skin lesions
  • Herpes gestationis
  • Pemphigus vulgaris
  • Varicella-zoster virus
• Finger lesions
  • Paronychia

Clinical Background

Herpes simplex virus (HSV) occurs worldwide and produces a variety of clinical manifestations, ranging from mild stomatitis to fatal disease.

Epidemiology

• Prevalence
  • Types 1 (HSV-1) and 2 (HSV-2)
    • HSV-1 – 70-80% seropositivity in U.S. adults; 100% positivity in undeveloped countries
    • HSV-2 – 10-40% seropositivity in U.S. adults
• Age – 33% of cases <20 years; 50% of cases >50 years
• Sex – M<F (HSV-2)
• Transmission
  • HSV-1 – predominantly oral
  • HSV-2 – predominantly sexual (can occur during asymptomatic periods)
  • Vertical transmission
• Ethnicity – more often found in African Americans

Organism

• Double-stranded DNA virus of the Herpesviridae family
  • HSV-1 – majority of nongenital HSV infections
  • HSV-2 – cause of genital infections in >80% of patients
• Biological features unique to herpes virus
  • Latency
  • Reactivation

Risk Factors

• HSV-1 – lower socioeconomic status
• HSV-2
  • High number of sexual partners
  • Previous history of sexually transmitted infections
  • First sexual experience at an early age
  • Lower socioeconomic status
  • Older age
  • Female
  • Black race

Clinical Presentation

• Manifestations and clinical course of HSV depend on clinical site, age and immune status of host
• Only 10-30% of new infections are symptomatic
• HSV-2 causes recurrent genital herpes episodes more often than HSV-1
• Primary infections are usually longer in duration than reactive infections
• Common clinical syndromes
  • Gingivostomatitis – widespread oral ulcers with lymphadenopathy (submandibular, cervical)
  • Recurrent herpes labialis – erythematous papules and vesicles on lips
  • Keratitis – eye pain, light sensitivity, corneal dendritic ulcers (can lead to blindness)
  • Conjunctivitis – increases risk of keratitis
  • Vesicular skin eruptions usually in face, ears and neck areas (herpes gladiatorum); dissemination of oral herpes into a previously abnormal skin area (burns, atopic dermatitis; referred to as eczema herpeticum); vesiculopapular lesions in beard area (herpes sycosis)
  • Herpetic whitlow – vesicular eruption located on pulp of distal phalanges of hands
  • Aseptic meningitis and recurrent meningitis (Mollaret meningitis)
    • Occurs as a complication of HSV-1 or HSV-2 primary infection
    • Seizures may be first presentation
  • Primary and recurrent genital herpes
    • Increases risk for acquiring HIV
    • Usually presents as symptomatic and painful genital ulcer
  • Visceral herpes (esophagitis, pneumonitis, hepatitis) – more common in immunocompromised patients
  • Meningitis/encephalitis – associated with focal neurologic findings
  • Neonatal herpes – infection may be acquired in utero, intrapartum, or postnatally
    • Encephalitis
    • Disseminated infection
    • Localized disease
    • Congenital – microcephaly, hydrocephalus, retinitis, cutaneous vesicular lesions
    • Pregnancy
      • Disease has higher rate of dissemination
      • More commonly associated with visceral involvement
  • Proctitis – most common in homosexual men
  • Secondary HSV is one of the most common causes of erythema multiforme

Treatment

• Early diagnosis is important; treatment with antivirals may substantially alter course of HSV infections
  • Untreated herpes encephalitis and neonatal herpes are fatal in 70% of patients; neurologic sequelae in most survivors
  • Disseminated disease, usually in immunocompromised patients, requires aggressive therapy
  • Intravenous acyclovir therapy indicated in patients with severe HSV disease and with complications such as disseminated infection, pneumonitis, hepatitis, and encephalitis
  • Intravenous foscarnet or topical cidofovir gel may be used in acyclovir-resistant refractory mucocutaneous HSV infections
• Suppressive therapy may be useful in treating repeated reactivation infections
• Antiviral therapy (acyclovir, valacyclovir, or famciclovir) indicated for both primary and recurrent genital HSV infection

Prevention

• Barrier contraception and daily suppressive therapy recommended to prevent infecting partner with genital herpes
• Pregnant women not infected with HSV-2 should be advised to avoid intercourse during the third trimester with men who have genital herpes

Indications for Laboratory Testing

• Tests generally appear in the order most useful for common clinical situations
• Click on number for test-specific information in the ARUP Laboratory Test Directory

Click the plus sign to expand the table of additional tests.

Test Name and Number	Comments
Herpes Simplex Virus Type 1 and/or 2 Antibodies, IgG with Reflex to Type 1 and 2 Glycoprotein G-Specific Ab, IgG 0051708 Method: Semi-Quantitative Chemiluminescent Immunoassay/Semi-Quantitative Enzyme-Linked Immunosorbent Assay	Detect antibodies to HSV Differentiate between types 1 and 2 for epidemiological purposes
Herpes Simplex Virus Type 1 and/or 2 Antibodies, IgG & IgM with Reflex to Type 1 & 2 Glycoprotein G-Specific Ab, IgG 0050916 Method: Semi-Quantitative Chemiluminescent Immunoassay/Semi-Quantitative Enzyme-Linked Immunosorbent Assay	Identify type of HSV in a patient who is exhibiting symptoms or in a patient who has recent exposure but has yet to show symptoms Low levels of IgM antibody may persist months after initial infection
Meningoencephalitis Panel, CSF with Reflex to HSV Type 1 and Type 2 Glycoprotein G-Specific Ab, IgG 2001765 Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Indirect Fluorescent Antibody/Semi-Quantitative Chemiluminescent Immunoassay	Panel components include California encephalitis, Eastern equine encephalitis, St. Louis equine encephalitis, Western equine encephalitis, West Nile virus, measles, mumps, varicella-zoster virus, HSV types 1 and 2, and lymphocytic choriomeningitis antibodies
Meningoencephalitis Panel, Serum with Reflex to HSV Type 1 and Type 2 Glycoprotein G-Specific Ab, IgG 2001764 Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Indirect Fluorescent Antibody/Semi-Quantitative Chemiluminescent Immunoassay	Panel components include California encephalitis, Eastern equine encephalitis, St. Louis equine encephalitis, Western equine encephalitis, West Nile virus, measles, mumps, varicella-zoster virus, HSV types 1 and 2, and lymphocytic choriomeningitis antibodies
Herpes Simplex Virus Type 1 and/or 2 Antibodies, IgG & IgM 0050291 Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Chemiluminescent Immunoassay	Diagnose acute infection Note: Acute and convalescent samples required for proper interpretation, even with tests for IgM antibody because low levels of IgM antibody may persist months after initial infection
Herpes Simplex Virus Type 2 Glycoprotein G-Specific Antibody, IgG by ELISA (HerpeSelect®) 0050294 Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay	Differentiate between HSV-1 and -2
Herpes Simplex Virus Type 1 Glycoprotein G-Specific Antibody, IgG by ELISA (HerpeSelect®) 0050292 Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay	Differentiate between HSV-1 and -2 A few patients will not form glycoproteins, so testing will be negative
Herpes Simplex Virus Type 2 Glycoprotein G-Specific Antibody, IgG by ELISA, CSF 0050359 Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay	Identify the type of HSV in a patient with meningitis Patients may not exhibit antibody in early disease PCR is primary means of establishing diagnosis of herpes encephalitis
Herpes Simplex Virus Type 1 and/or 2 Antibodies, IgG & IgM (CSF) with Reflex to Type 1 & 2 Glycoprotein G-Specific Ab, IgG 0050364 Method: Semi-Quantitative Chemiluminescent Immunoassay/Semi-Quantitative Enzyme-Linked Immunosorbent Assay	Identify type of HSV in a patient with meningitis Detect antibodies to HSV in CSF
Herpes Simplex Virus Type 1 Glycoprotein G-Specific Antibody, IgG by ELISA, CSF 0050379 Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay	Patients may not exhibit antibody in early disease
Herpes Simplex Virus Type 1 and/or 2 Antibodies, IgM by ELISA, CSF 0050408 Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay	CNS testing has no utility in the diagnosis of acute CNS HSV and should not be ordered.  For acute CNS HSV diagnosis, use HSV by PCR.
Herpes Simplex Virus Type 1 and/or 2 Antibodies, IgG 0050293 Method: Chemiluminescent Immunoassay	Patients may not exhibit antibody in early disease
Herpes Simplex Virus Type 1 and/or 2 Antibodies, IgM by ELISA 0050641 Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay	Test has no utility and should not be ordered. If necessary to test for type specific antibodies, then IgG testing may be considered after 3-6 months.
TORCH Antibodies, IgG 0050772 Method: Chemiluminescent Immunoassay
TORCH Antibodies, IgM 0050665 Method: Semi-Quantitative Chemiluminescent Immunoassay/Semi-Quantitative Enzyme-Linked Immunosorbent Assay
Herpes Simplex Virus Typing 0060847 Method: Cell Culture/Immunofluorescence	Used for epidemiological purposes
Encephalitis Panel, CSF with Reflex to HSV Type 1 and 2 Glycoprotein G-Specific Ab, IgG 2001741 Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Indirect Fluorescent Antibody Semi-Quantitative Chemiluminescent Immunoassay
Encephalitis Panel, Serum with Reflex to HSV Type 1 and Type 2 Glycoprotein G-Specific Ab, IgG 2001742 Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Indirect Fluorescent Antibody/Semi-Quantitative Chemiluminescent Immunoassay
Viral Culture, Non-Respiratory, and Cytomegalovirus Rapid Culture 2006496 Method: Cell Culture/Immunofluorescence
Viral Culture, Non-Respiratory 2006498 Method: Cell Culture
Viral Culture, Respiratory, and Cytomegalovirus Rapid Culture 2006497 Method: Cell Culture/Immunofluorescence

Diagnostic Algorithm

  HSV Infection During Pregnancy Testing Algorithm