Herpes Simplex Virus - HSV

Diagnosis

Indications for Testing

Criteria for Diagnosis

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 the following 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 and HSV-2 subtype 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

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

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
Test Name and Number Recommended Use Limitations Follow Up
Herpes Simplex Virus by PCR 0060041
Method: Qualitative Polymerase Chain Reaction

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%

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

 
Herpes Simplex Virus (HSV-1/HSV-2) Subtype by PCR 2010095
Method: Qualitative Polymerase Chain Reaction

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

Includes subtyping

Sensitivity – 97-98%

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

 
Herpes Simplex Virus Culture 0065005
Method: Cell Culture/Immunoassay

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%
   
Herpes Simplex Virus Culture with Reflex to HSV Typing 0065065
Method: Cell Culture/Immunoassay

HSV typing is done by DFA on positive specimens

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

   
Antiviral Susceptibility, Herpes Simplex Virus, Acyclovir (Temporary Referral as of 9/18/14) 2010866
Method: Cell Culture, Susceptibility

Screen for HSV infection suspected to be acyclovir resistant

   
Antiviral Susceptibility, Herpes Simplex Virus, Foscarnet (Temporary Referral as of 9/18/14) 2010785
Method: Cell Culture/Susceptibility

Screen for HSV infection suspected to be foscarnet resistant

   
Herpes Simplex Virus DFA with Reflex to Herpes Simplex Virus Culture 0060280
Method: Direct Fluorescent Antibody Stain/Cell Culture

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)

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

 
Varicella-Zoster Virus and Herpes Simplex Virus DFA with Reflex to Varicella-Zoster Virus Culture and Herpes Simplex Virus Culture 0060283
Method: Direct Fluorescent Antibody Stain/Cell Culture

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

Sensitivity of DFA methodology dependent upon adequacy of specimen; if there are fewer than 20 cells, DFA result will be reported as "sample inadequate"  
Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
Herpes Simplex Virus Types 1 and 2 Glycoprotein G-Specific Antibodies, IgG by Immunoblot 0050459
Method: Qualitative Immunoblot

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

Herpes Simplex Type 1 and Type 2 Glycoprotein G-Specific Antibodies, IgG by CIA 0051152
Method: Semi-Quantitative Chemiluminescent Immunoassay

Detect antibodies to HSV-1 and HSV-2

Herpes Simplex Virus Type 1 and/or 2 Antibodies, IgG, CSF 0050394
Method: Semi-Quantitative Chemiluminescent Immunoassay

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

Herpes Simplex Virus Type 1 (HSV 1) by Immunohistochemistry 2003944
Method: Immunohistochemistry

Aid in histologic diagnosis of HSV

Stained and returned to client pathologist; consultation available if needed

Herpes Simplex Virus Type 2 (HSV 2) by Immunohistochemistry 2003954
Method: Immunohistochemistry

Aid in histologic diagnosis of HSV

Stained and returned to client pathologist; consultation available if needed

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

Detect antibodies to HSV

Differentiate between types 1 and 2 for epidemiological purposes

Herpes Simplex Virus Type 1 and/or 2 Antibodies, IgG and IgM with Reflex to Type 1 and 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 with Reflex to Herpes Simplex Virus Types 1 and 2 Glycoprotein G-Specific Antibodies, IgG, CSF 2008917
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-1, and HSV-2

Meningoencephalitis Panel with Reflex to Herpes Simplex Virus Types 1 and 2 Glycoprotein G-Specific Antibodies, IgG, Serum 2008918
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-1, and HSV-2

Herpes Simplex Virus Type 1 and/or 2 Antibodies, IgG and IgM 0050291
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative 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 CIA 0050294
Method: Semi-Quantitative Chemiluminescent Immunoassay

Differentiate between HSV-1 and HSV-2

Herpes Simplex Virus Type 1 Glycoprotein G-Specific Antibody, IgG by CIA 0050292
Method: Semi-Quantitative Chemiluminescent Immunoassay

Differentiate between HSV-1 and HSV-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: Semi-Quantitative 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: Semi-Quantitative Chemiluminescent Immunoassay/Quantitative 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 with Reflex to Herpes Simplex Virus Types 1 and 2 Glycoprotein G-Specific Antibodies, IgG, CSF 2008916
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Chemiluminescent Immunoassay
Encephalitis Panel with Reflex to Herpes Simplex Virus Types 1 and 2 Glycoprotein G-Specific Antibodies, IgG, Serum 2008915
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay/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