Herpes Simplex Virus - HSV

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

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 [VZV], 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

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

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 by PCR 0060041
Method: Qualitative Polymerase Chain Reaction

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

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

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

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

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

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

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"

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

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 Virus Type 2 (HSV-2) IgG Inhibition, by ELISA 2012135
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Guidelines

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

Last Update: August 2016