Herpes Simplex Virus - HSV

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

Tabs Content

Clinical Overview

Key Points

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 – seronegative individuals are at risk of acquiring infection from seropositive partners
- HSV-1
  - Usually transmitted via nonsexual route
  - 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
- First-time (primary) infection of woman during pregnancy – increases the risk of transmitting virus to neonate during delivery
- Most neonatal infections are acquired intrapartum
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
Central nervous system (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 is unreliable and potentially clinically insignificant in many cases due to cross-reactivity between the 2 HSV types
Typing may be useful epidemiologically, for patient counseling regarding disease acquisition, and for some assistance with prognosis (CDC, 2014)
HSV subtype does not affect choice of treatment
Early false negative results may occur; type-specific antibody testing may not be positive until 2-3 months postinfection
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 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	Herpes Simplex Virus (HSV) Types I/II by Immunohistochemistry 3000101
Type-Specific Serology Tests^a
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 mos 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 FFPE Prepared Tissues/Cells
Not commonly ordered May be considered if tissue histology is suspicious for HSV	N/A
^aHSV-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. CIA, chemiluminescence immunoassay; CSF, cerebrospinal fluid; DFA, direct fluorescent antibody; HSV, herpes simplex virus; NAAT, nucleic acid amplification test; PCR, polymerase chain reaction; FFPE, formalin-fixed paraffin-embedded

Diagnosis

Indications for Testing

Genital or oral ulcerative or vesicular lesions
Central nervous system (CNS) infections
- Unidentified encephalitis
- Encephalitis with focal neurologic symptoms
- Herpes simplex virus (HSV)-related meningitis
Corneal ulcer
Transmission from mother to neonate – evaluate first-time (primary) infection of woman during pregnancy
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
Antiviral susceptibility for HSV (eg, acyclovir, foscarnet)

Criteria for Diagnosis

Genital herpes HSV case definition (CDC, 1996)

Laboratory Testing

Refer to Key Points for laboratory testing options
CNS disease – consider multiple panel testing on cerebrospinal fluid (CSF) and serum to rule out other viral illnesses (eg, varicella-zoster virus [VZV], mumps)

Histology

Refer to Key Points

Prognosis

Following active infection, HSV establishes latent infection that can be reactivated
Neonates
- Better prognosis with herpes simplex virus type 1 (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
Finger lesions – paronychia
Congenital disease
- VZV
- Rubella
- Toxoplasma gondii
- Treponema pallidum
- Parvovirus B19
- Cytomegalovirus

Screening

Serologic screening in asymptomatic persons not recommended (U.S. Preventive Services Task Force [USPSTF], 2016; Choosing Wisely, 2018)

Background

Epidemiology

Prevalence (CDC, 2014)
- Herpes simplex virus type 1 (HSV-1) – ~60% seropositivity in U.S. adults; >90% positivity in undeveloped countries
- Herpes simplex virus type 2 (HSV-2) – ~16% seropositivity in persons aged 14 to 49 years in the U.S.
Age
- 33% of cases <20 years
- 50% of cases >50 years
Sex – M<F (HSV-2)
Transmission
- HSV-1
  - Predominantly oral
  - Genital herpes cases increasing
  - Vertical transmission
- HSV-2
  - Predominantly sexually (can occur during asymptomatic periods)
  - Vertical transmission (perinatally)

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
Pregnancy
- Disease has higher rate of dissemination
- More commonly associated with visceral involvement
Clinical symptoms 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
- 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 partner infection
Pregnant women not infected with HSV-2 should be advised to avoid intercourse during the third trimester with infected partner

ARUP Lab Tests

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 herpes simplex virus (HSV) infection in cerebrospinal fluid (CSF), neonates, or when rapid diagnostic test for suspected HSV infection is necessary

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 HSV types 1 and 2

Reflex pattern – if HSV by polymerase chain reaction (PCR) result is detected, subtyping will be added

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 presence of PCR inhibitors in patient specimen or test-specific nucleic acid in concentrations below level of detection by this test

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; refer to HSV by PCR

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

Recommended Use

Detect HSV by viral culture and differentiate types 1 and 2; molecular testing generally preferred

Reflex pattern – if culture is positive for HSV, then HSV typing will be added

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 direct fluorescent antibody (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; refer to HSV by PCR

Reflex pattern – if DFA is negative or inadequate, then HSV culture will be added

Limitations

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

Herpes Simplex Virus (HSV) Types I/II by Immunohistochemistry 3000101
Method: Immunohistochemistry

Recommended Use

Aid in the histological diagnosis of HSV

Stained and returned to client pathologist; consultation available if needed

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 type 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

Detect HSV resistance to acyclovir

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

Recommended Use

Detect HSV resistance to foscarnet sodium

Medical Experts

Couturier, Marc Roger, PhD, D(ABMM), Medical Director, Microbial Immunology, Parasitology and Fecal Testing, and Infectious Disease Antigen Testing at ARUP Laboratories; Associate 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

References

Guidelines

2015 Sexually Transmitted Diseases Treatment Guidelines. Special Populations. Centers for Disease Control and Prevention. Atlanta, GA [Last updated: Jul 2015; Accessed: Oct 2017]
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: Oct 2017]
US Preventive Services Task Force, Bibbins-Domingo K, Grossman DC, Curry SJ, Davidson KW, Epling JW, Garcia FA, Kemper AR, Krist AH, Kurth AE, Landefeld S, Mangione CM, Phillips WR, Phipps MG, Pignone MP, Silverstein M, Tseng C. Serologic Screening for Genital Herpes Infection: US Preventive Services Task Force Recommendation Statement. JAMA. 2016; 316(23): 2525-2530. PubMed
American Academy of Family Physicians. Choosing Wisely - Twenty Things Physicians and Patients Should Question. American Board of Internal Medicine (ABIM) Foundation. Philadelphia, PA [Updated: Aug 2018; Accessed: Aug 2018]

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

Resources 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

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

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

Content Review:

November 2017

Last Update: December 2018

Herpes Simplex Virus - HSV

Key Points

Indications for HSV Testing

HSV Typing

Laboratory Testing for HSV

Diagnosis

Indications for Testing

Criteria for Diagnosis

Laboratory Testing

Histology

Prognosis

Differential Diagnosis

Screening

Background

Epidemiology

Organism

Clinical Presentation

Prevention

ARUP Lab Tests

Medical Experts

References

Guidelines

General References

Resources from the ARUP Institute for Clinical and Experimental Pathology®

ARUP Laboratories

ARUP Websites

ARUP Consult


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Herpes Simplex Virus - HSV

Key Points

Indications for HSV Testing

HSV Typing

Laboratory Testing for HSV

Diagnosis

Indications for Testing

Criteria for Diagnosis

Laboratory Testing

Histology

Prognosis

Differential Diagnosis

Screening

Background

Epidemiology

Organism

Clinical Presentation

Prevention

ARUP Lab Tests

Medical Experts

References

Guidelines

General References

Resources from the ARUP Institute for Clinical and Experimental Pathology®

ARUP Laboratories

ARUP Websites

ARUP Consult