Herpes Simplex Virus - HSV

Primary Author: Couturier, Marc Roger, PhD, D(ABMM).

  • Key Points
  • Diagnosis
  • Algorithms
  • Background
  • Lab Tests
  • References
  • Related Topics

Herpes simplex virus (HSV) infections are extremely common worldwide. The herpes simplex viruses comprise two distinct types of DNA viruses: herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2). While HSV subtyping is available, typing is not required for treatment. Treatment for HSV-1 and HSV-2 infections is the same.

Indications for HSV Testing

  • Sexually transmitted infection
    • Individuals who are seronegative for HSV-1 and/or HSV-2 are at risk of acquiring infection from seropositive partners
      • HSV-1
        • Usually transmitted via nonsexual route; however, an increasing proportion of genital herpes is due to HSV-1
      • HSV-2
        • Majority of persons positive for HSV-2 have not been diagnosed with genital herpes
        • Individuals with HSV-2 can have mild or unrecognized disease and may shed virus from genital area intermittently
        • HSV-2 infection increases the risk of acquiring HIV infection (refer to STDs and HIV – CDC Fact Sheet)
  • Transmission from mother to neonate
  • Reinfection with HSV
    • Rare, but dormant virus can be reactivated
  • Prognostic indicator and guide for treatment in transplant patients
    • Majority of HSV infections in transplant recipients result from reactivation of latent virus, especially during early posttransplant period and periods of severe immunosuppression
  • CNS infections
    • HSV-related meningitis – generally benign and controlled with antivirals
    • Untreated HSV-related encephalitis – >70% fatality rate
  • Antiviral susceptibility for HSV (eg, acyclovir)

HSV Typing

  • Typing may be useful epidemiologically, for patient counseling regarding disease acquisition, and for some assistance with prognosis (CDC, 2014); however, HSV subtype does not affect choice of treatment
  • Typing is unreliable and potentially clinically insignificant in many cases due to cross-reactivity between the two HSV types
  • Type-specific antibody testing may not be positive until 2-3 months postinfection
    • False negative results may occur, especially early after infection
  • If pursuing subtyping, HSV-1/-2 glycoprotein G (gG) antigen serology testing is recommended
    • “Type-specific” antibody testing
    • Does not detect cross-reacting antibodies
    • Provides more accurate serological assessment of HSV-1/HSV-2
  • IgM testing
    • Limited clinical utility; not reliable for diagnosis of genital lesions or neonatal herpes (CDC, 2014)

Laboratory Testing for HSV

  • HSV infection can be confirmed by direct detection of the virus, detection of antibodies to HSV, or immunohistochemical testing

Laboratory Testing for HSV
Virologic Testing (direct detection of HSV infection)
Test Description ARUP Tests
 Molecular testing (NAATs) for viral DNA detection (eg, PCR)
  • Preferred diagnostic method for
    • CSF testing
    • Neonates
    • Rapid diagnostic testing
  • May detect asymptomatic HSV shedding
  • Sensitivity/specificity – high 
  • Typing – some reflex tests include HSV typing
    

Typing NOT included

Herpes Simplex Virus by PCR 0060041

Typing included

Herpes Simplex Virus (HSV) by PCR with Reflex to HSV (HSV-1/HSV-2) Subtype by PCR 2011148

Herpes Simplex Virus (HSV-1/HSV-2) Subtype by PCR 2010095

Viral culture

  • Traditional gold standard test for identifying acute HSV infection in active lesions (eg, vesicles, ulcers, inflamed mucous membranes)
  • Molecular testing (eg, PCR)  generally preferred
  • Sensitivity/specificity – low sensitivity, especially for recurrent and healing lesions; highly specific
    • High rate of false negatives – sensitivity declines rapidly as lesions begin to heal
  • More often positive in primary infection (80-90%) than recurrences (30%) (CDC, 2014)
  • Typing – some reflex tests include HSV typing

Typing NOT included

Herpes Simplex Virus Culture 0065005

Typing included

Herpes Simplex Virus Culture with Reflex to HSV Typing 0065065

Antigen detection by direct immunofluorescence (DFA)

  • Rapid diagnostic test with culture backup for negative DFA results
  • Test may be helpful in identifying acute HSV infection in active lesions
  • Molecular testing generally preferred
  • Sensitivity – lower sensitivity compared to PCR
  • Typing – not included

Typing NOT included

Herpes Simplex Virus DFA with Reflex to Herpes Simplex Virus Culture 0060280

Cytology

  • Not recommended

n/a
Type-Specific Serology Tests*

Glycoprotein G-based type specific test is acceptable for HSV serologic diagnosis (CDC, 2015)

  • Based on HSV-specific glycoprotein G2 (HSV-2) and glycoprotein G1 (HSV-1)
    • May be useful for
      • Recurrent genital symptoms or atypical symptoms with negative HSV PCR or culture
      • Clinical diagnosis of genital herpes without laboratory confirmation
      • Patient whose partner has genital herpes
  • IgG testing
    • Sensitivity varies – false-negative results might be more frequent at early stages of infection
    • Type-specific HSV IgG antibodies may require 3-6 months to form
      • Follow-up testing required to confirm negative IgG glycoprotein result in context of positive HSV types 1 or 2 antibody results
  •  IgM testing – not recommended (CDC, 2015)
    • Lacks adequate predictive value for acute infection

Herpes Simplex Type 1 and Type 2 Glycoprotein G-Specific Antibodies, IgG by CIA 0051152

Herpes Simplex Virus Type 1 and/or 2 Antibodies, IgG with Reflex to Type 1 and 2 Glycoprotein G-Specific Ab, IgG 0051708
Antiviral Susceptibility Testing
Determine susceptibility to treatment in immunosuppressed patients (eg, patients with HIV or organ transplant)

Antiviral Susceptibility, Herpes Simplex Virus, Acyclovir 2010866

Antiviral Susceptibility, Herpes Simplex Virus, Foscarnet 2010785
Immunohistochemical Staining of PPFE Prepared Tissues/Cells
  • Not commonly ordered
  • May be considered if tissue histology is suspicious for HSV

 n/a
*HSV-1 and-2 are closely related antigenically and high cross-reactivity exists between the 2 common antigens, which may affect the accuracy of antigen-based typing tests. Serology tests that use HSV-1 or -2 glycoprotein G (gG) antigens are considered “type-specific” antibody tests and do not detect cross-reacting antibodies. Thus, they provide a more accurate serological assessment of whether the HSV is type 1 or 2. Because glycoprotein antibodies may require up to 3 months to form, follow-up testing is recommended to confirm a negative IgG glycoprotein in the context of positive HSV-1 or -2 antibody results.

Indications for Testing

Criteria for Diagnosis

Laboratory Testing

  • Refer to Key Points section for laboratory testing options
  • Central nervous system (CNS) disease

Histology

  • Refer to Key Points section

Prognosis

  • Following active infection, HSV establishes latent infection that can be reactivated 
  • Neonates
    • 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

Herpes simplex virus (HSV) occurs worldwide and produces a variety of clinical manifestations, ranging from mild stomatitis to fatal disease. HSV-2 causes recurrent genital herpes episodes more often than HSV-1, although HSV-1 is responsible for a growing number of genital herpes cases.

Epidemiology

  • Prevalence
    • Types 1 (HSV-1) and 2 (HSV-2)
      • HSV-1 – ~60% seropositivity in U.S. adults; >90% positivity in undeveloped countries (CDC, 2014)
      • HSV-2 – ~16% seropositivity in persons aged 14 to 49 years in the U.S. (CDC, 2014)
  • Age – 33% of cases <20 years; 50% of cases >50 years
  • Sex – M<F (HSV-2)
  • Transmission
    • HSV-1 – predominantly oral, but is responsible for a growing number of genital herpes cases
    • HSV-2 – predominantly sexually (can occur during asymptomatic periods) and perinatally
    • Vertical transmission

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

Clinical Presentation

  • Only 10-30% of new infections are symptomatic
  • Primary infections are usually longer in duration than reactive infections
  • HSV-2 causes recurrent genital herpes episodes more often than HSV-1
    • Genital herpes (primary and recurrent)
      • Increases risk for acquiring HIV
      • Usually presents as symptomatic and painful genital ulcer
  • Clinical syndromes are widespread and depend on clinical site, age, and immune status of host
    • 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
    • Herpes gladiatorum – vesicular skin eruptions usually in face, ears and neck areas
    • Eczema herpeticum – dissemination of oral herpes into a previously abnormal skin area (burns, atopic dermatitis)
    • Herpes sycosis – vesiculopapular lesions in beard area
    • 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
    • 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
    • Congenital – microcephaly, hydrocephalus, chorioretinitis, cutaneous vesicular lesions, myocarditis, skin lesions
    • Pregnancy
      • Disease has higher rate of dissemination
      • More commonly associated with visceral involvement
    • Proctitis – most common in homosexual men
    • Erythema multiforme – secondary HSV is one of the most common causes

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. Click on number for test-specific information in the ARUP Laboratory Test Directory.

Herpes Simplex Virus by PCR 0060041
Method: Qualitative Polymerase Chain Reaction

Recommended Use 

Preferred test for detecting HSV infection in CSF, neonates, or when rapid diagnostic test for suspected HSV infection is necessary

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

Herpes Simplex Virus (HSV) by PCR with Reflex to HSV (HSV-1/HSV-2) Subtype by PCR 2011148
Method: Qualitative Polymerase Chain Reaction

Recommended Use 

Detect and genotype herpes simplex virus (HSV) types 1 and 2

Reflex pattern – if HSV by PCR result is detected, subtyping will be added

Limitations 

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

Recommended Use 

Genotype HSV types 1 and 2

Limitations 

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

Recommended Use 

Traditional gold standard test for identifying acute HSV infection in active lesions (eg, vesicles, ulcers, inflamed mucous membranes)

Molecular testing is generally preferred

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

Recommended Use 

Detect HSV by viral culture and differentiates types 1 and 2

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

Recommended Use 

Rapid diagnostic test with culture backup for negative DFA results

Test may be helpful in identifying acute HSV infection in active lesions (eg, vesicles, ulcers, inflammation of mucous membranes)

Molecular testing is generally preferred

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"

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

Recommended Use 

In the absence of active lesions, this is the preferred serology test for diagnosing HSV infection  

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

Recommended Use 

Preferred testing for HSV when recent acquisition of HSV is suspected

Because glycoprotein antibodies may require 3-6 months to form, follow-up testing is recommended to confirm a negative IgG glycoprotein result in the context of positive HSV Types 1 or 2 antibody results

Refer to HSV IgG glycoprotein types 1 and 2 antibody test

Antiviral Susceptibility, Herpes Simplex Virus, Acyclovir 2010866
Method: Cell Culture, Susceptibility

Recommended Use 

Screen for HSV infection suspected to be acyclovir resistant

Antiviral Susceptibility, Herpes Simplex Virus, Foscarnet 2010785
Method: Cell Culture/Susceptibility

Recommended Use 

Screen for HSV infection suspected to be foscarnet resistant

Guidelines

2015 Sexually Transmitted Diseases Treatment Guidelines . Special Populations. Centers for Disease Control and Prevention . Atlanta, GA [Last updated Jul 2015; Accessed: Sep 2016]

CDC STD Prevention. STD Curriculum for Clinical Educators: Genital Herpes Simplex Virus (HSV) Module. Centers for Disease Control and Prevention. Atlanta, GA [Published Mar 2014; Accessed: Sep 2016]

General References

Anzivino E, Fioriti D, Mischitelli M, Bellizzi A, Barucca V, Chiarini F, Pietropaolo V. Herpes simplex virus infection in pregnancy and in neonate: status of art of epidemiology, diagnosis, therapy and prevention. Virol J. 2009; 6: 40. PubMed

Corey L, Wald A. Maternal and neonatal herpes simplex virus infections. N Engl J Med. 2009; 361(14): 1376-85. PubMed

Fatahzadeh M, Schwartz RA. Human herpes simplex virus infections: epidemiology, pathogenesis, symptomatology, diagnosis, and management. J Am Acad Dermatol. 2007; 57(5): 737-63; quiz 764-6. PubMed

Gupta R, Warren T, Wald A. Genital herpes. Lancet. 2007; 370(9605): 2127-37. PubMed

Kimberlin DW, Baley J, Committee on Infectious Diseases, Committee on Fetus and Newborn. Guidance on management of asymptomatic neonates born to women with active genital herpes lesions Pediatrics. 2013; 131(2): e635-46. PubMed

Kimberlin DW. Herpes simplex virus infections of the newborn. Semin Perinatol. 2007; 31(1): 19-25. PubMed

Neu N, Duchon J, Zachariah P. TORCH infections. Clin Perinatol. 2015 Mar;42(1):77-103, viii. PubMed

Sen P, Barton SE. Genital herpes and its management. BMJ. 2007; 334(7602): 1048-52. PubMed

Usatine RP, Tinitigan R. Nongenital herpes simplex virus. Am Fam Physician. 2010; 82(9): 1075-82. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology®

Crist GA, Langer JM, Woods GL, Procter M, Hillyard DR. Evaluation of the ELVIS plate method for the detection and typing of herpes simplex virus in clinical specimens. Diagn Microbiol Infect Dis. 2004; 49(3): 173-7. PubMed

Dames S, Bromley K, Herrmann M, Elgort M, Erali M, Smith R, Voelkerding KV. A single-tube nucleic acid extraction, amplification, and detection method using aluminum oxide. J Mol Diagn. 2006; 8(1): 16-21. PubMed

Dames S, Pattison DC, Bromley K, Wittwer CT, Voelkerding KV. Unlabeled probes for the detection and typing of herpes simplex virus. Clin Chem. 2007; 53(10): 1847-54. PubMed

Hanson KE, Alexander BD, Woods C, Petti C, Reller B. Validation of laboratory screening criteria for herpes simplex virus testing of cerebrospinal fluid. J Clin Microbiol. 2007; 45(3): 721-4. PubMed

Martins TB, Welch RJ, Hill HR, Litwin CM. Comparison of a multiplexed herpes simplex virus type-specific immunoglobulin G serology assay to immunoblot, Western blot, and enzyme-linked immunosorbent assays. Clin Vaccine Immunol. 2009; 16(1): 55-60. PubMed

Polage CR, Petti CA. Assessment of the utility of viral culture of cerebrospinal fluid. Clin Infect Dis. 2006; 43(12): 1578-9. PubMed

Stevenson J, Hymas W, Hillyard D. Effect of sequence polymorphisms on performance of two real-time PCR assays for detection of herpes simplex virus. J Clin Microbiol. 2005; 43(5): 2391-8. PubMed

Tan E, Erwin B, Dames S, Voelkerding K, Niemz A. Isothermal DNA amplification with gold nanosphere-based visual colorimetric readout for herpes simplex virus detection. Clin Chem. 2007; 53(11): 2017-20. PubMed

Medical Reviewers

Couturier, Marc Roger, PhD, D(ABMM), Medical Director, Microbial Immunology, Parasitology and Fecal Testing, and Infectious Disease Rapid Testing at ARUP Laboratories; Assistant Professor of Clinical Pathology, University of Utah

Hillyard, David R., MD, Medical Director, Molecular Infectious Diseases at ARUP Laboratories; Professor of Clinical Pathology, Adjunct Professor of Biology, University of Utah

Schlaberg, Robert, MD, MPH, Medical Director, Microbial Amplified Detection, Virology, and Fecal Chemistry; and Assistant Medical Director, Virology and Molecular Infectious Disease at ARUP Laboratories; Assistant Professor of Clinical Pathology, University of Utah

Couturier

Last Update: September 2016

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