Herpes Simplex Virus

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

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

Tests generally appear in the order most useful for common clinical situations

Test name: Herpes Simplex Virus DFA with Reflex to Herpes Simplex Virus Culture

ARUP #: 0060280

Methodology: Direct Fluorescent Antibody Stain

Use:

Rapid diagnostic test with culture backup

Culture is gold standard test for identifying acute HSV infection in acute lesions (eg, vesicles, ulcers, inflammation of mucous membranes)

Limitations:

Sensitivity of DFA methodology dependent upon adequacy of specimen; if there are fewer than 20 cells, DFA result will be reported as "sample inadequate"

Test name: Herpes Simplex Virus by PCR

ARUP #: 0060041

Methodology: Qualitative Polymerase Chain Reaction

Use:

Rapid diagnostic for

CSF in herpes encephalitis - standard of care
CSF in unusual CNS syndromes and in AIDS patients
Patients with recurrent meningitis
Infants with suspected neonatal herpes where cultures have been negative (eg, CSF nasopharyngeal aspirate)
Resolving etiology of lesions several days old in situations where cultures are more likely to be negative

Sensitivity 97-98%

Limitations:

Negative result does not rule out PCR inhibitors in patient specimen or herpes simplex virus DNA concentrations below level assay can detect

Test name: Herpes Simplex Virus Culture

ARUP #: 0065005

Methodology: Cell Culture/Immunoassay

Use:

Traditionally, gold standard test for identifying acute HSV infection in acute lesions (eg, vesicles, ulcers, inflammation of mucous membranes)

Skin lesion stages

Vesicle - sensitivity >90%
Ulcer - sensitivity 95%
Scab - sensitivity 70%
Mucosa - sensitivity 30%

Test name: Varicella-Zoster Virus & Herpes Simplex Virus DFA with Reflex to Varicella-Zoster Virus Culture & Herpes Simplex Virus Culture

ARUP #: 0060283

Methodology: Direct Fluorescent Antibody Stain

Use:

Rapid diagnostic test with culture backup that may be helpful when uncertain whether a lesion is due to VZV or HSV

Limitations: Sensitivity of DFA methodology dependent upon adequacy of specimen; if there are fewer than 20 cells, DFA result will be reported as "sample inadequate"

Test name: Herpes Simplex Virus Type 1 & Type 2 Glycoprotein G-Specific Antibodies, IgG by Immunoblot (HerpeSelect®)

ARUP #: 0050459

Methodology: Qualitative Immunoblot

Use:

Differentiate between HSV-1 and HSV-2 for epidemiological purposes

Limitations:

Individuals infected with HSV may not exhibit detectable IgG antibody to glycoprotein G in the early stages of infection; 5-10% of infections may occur with glycoprotein G-deficient virus

Test name: Herpes Simplex Type 1 & Type 2 Glycoprotein G-Specific Antibodies, IgG by ELISA (HerpeSelect®)

ARUP #: 0051152

Methodology: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Use:

Detect antibodies to HSV-1 and HSV-2

Limitations:

Patients may not exhibit antibody in early disease

Test name: Herpes Simplex Virus Culture with Reflex to HSV Typing

ARUP #: 0065065

Methodology: Cell Culture/Immunoassay

Use:

HSV typing can be done by DFA on positive specimens

PCR is standard of care for diagnosing HSV meningitis/meningoencephalitis in CSF specimens

Test name: Herpes Simplex Virus Type 1 and/or 2 Antibodies, IgG, CSF

ARUP #: 0050394

Methodology: Quantitative Chemiluminescent Immunoassay

Use:

Identify from CSF specimens seropositive organ transplant recipients who often have prophylactic antiviral therapy initiated prior to the transplantation procedure

Test name: Herpes Simplex Virus Type 1 (HSV 1) by Immunohistochemistry

ARUP #: 2003944

Methodology: Immunohistochemistry

Use:

Aid in histologic diagnosis of HSV

Stained and returned to client pathologist; consultation available if needed

Test name: Herpes Simplex Virus Type 2 (HSV 2) by Immunohistochemistry

ARUP #: 2003954

Methodology: Immunohistochemistry

Use:

Aid in histologic diagnosis of HSV

Stained and returned to client pathologist; consultation available if needed

Additional Tests Available

Test name: Herpes Simplex Virus Type 1 and/or 2 Antibodies, IgG with Reflex to Type 1 and 2 Glycoprotein G-Specific Ab, IgG

ARUP #: 0051708

Methodology: Refer to individual components.

Comments:

Detect antibodies to HSV

Differentiate between types 1 and 2 for epidemiological purposes

Test name: Herpes Simplex Virus Type 1 and/or 2 Antibodies, IgG & IgM with Reflex to Type 1 & 2 Glycoprotein G-Specific Ab, IgG

ARUP #: 0050916

Methodology: Refer to individual components

Comments:

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

Test name: Meningoencephalitis Panel, CSF with Reflex to HSV Type 1 & Type 2 Glycoprotein G-Specific Ab, IgG

ARUP #: 2001765

Methodology: Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Indirect Fluorescent Antibody

Comments:

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

Test name: Meningoencephalitis Panel, Serum with Reflex to HSV Type 1 & Type 2 Glycoprotein G-Specific Ab, IgG

ARUP #: 2001764

Methodology: Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Indirect Fluorescent Antibody/Chemiluminescent Immunoassay

Comments:

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

Test name: Herpes Simplex Virus Type 1 and/or 2 Antibodies, IgG & IgM

ARUP #: 0050291

Methodology: Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Chemiluminescent Immunoassay

Comments:

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

Test name: Herpes Simplex Virus Type 2 Glycoprotein G-Specific Antibody, IgG by ELISA (HerpeSelect®)

ARUP #: 0050294

Methodology: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Comments:

Differentiate between HSV-1 and -2

Test name: Herpes Simplex Virus Type 1 Glycoprotein G-Specific Antibody, IgG by ELISA (HerpeSelect®)

ARUP #: 0050292

Methodology: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Comments:

Differentiate between HSV-1 and -2

A few patients will not form glycoproteins, so testing will be negative

Test name: Herpes Simplex Virus Type 2 Glycoprotein G-Specific Antibody, IgG by ELISA (HerpeSelect®), CSF

ARUP #: 0050359

Methodology: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Comments:

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

Test name: Herpes Simplex Virus Type 1 and/or 2 Antibodies, IgG & IgM (CSF) with Reflex to Type 1 & 2 Glycoprotein G-Specific Ab, IgG

ARUP #: 0050364

Methodology: Refer to individual components

Comments:

Identify type of HSV in a patient with meningitis

Detect antibodies to HSV in CSF

Test name: Herpes Simplex Virus Type 1 Glycoprotein G-Specific Antibody, IgG by ELISA (HerpeSelect®), CSF

ARUP #: 0050379

Methodology: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Comments:

Patients may not exhibit antibody in early disease

Test name: Herpes Simplex Virus Type 1 and/or 2 Antibodies, IgM by ELISA, CSF

ARUP #: 0050408

Methodology: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Comments:

Test name: Herpes Simplex Virus Type 1 and/or 2 Antibodies, IgG

ARUP #: 0050293

Methodology: Chemiluminescent Immunoassay

Comments:

Patients may not exhibit antibody in early disease

Test name: Herpes Simplex Virus Type 1 and/or 2 Antibodies, IgM by ELISA

ARUP #: 0050641

Methodology: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Comments:

Test name: TORCH Antibodies, IgG

ARUP #: 0050772

Methodology: Chemiluminescent Immunoassay

Comments:

Test name: TORCH Antibodies, IgM

ARUP #: 0050665

Methodology: Refer to individual components

Comments:

Test name: Herpes Simplex Virus Typing

ARUP #: 0060847

Methodology: Cell Culture/Immunofluorescence

Comments:

Used for epidemiological purposes

Test name: Encephalitis Panel, CSF with Reflex to HSV Type 1 & 2 Glycoprotein G-Specific Ab, IgG

ARUP #: 2001741

Methodology: Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Indirect Fluorescent Antibody

Comments:

Test name: Encephalitis Panel, Serum with Reflex to HSV Type 1 and Type 2 Glycoprotein G-Specific Ab, IgG

ARUP #: 2001742

Methodology: Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Indirect Fluorescent Antibody

Comments:

Guidelines

General

ARUP Institute for Clinical and Experimental Pathology®

Comprehensive Review: November 2011
Last Update: November 2011

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