eMedicine Specialties > Pediatrics: General Medicine > Infectious Disease

Herpes Simplex Virus Infection: Differential Diagnoses & Workup

Author: Sherman Alter, MD, Associate Professor, Department of Pediatrics, Wright State University Boonshoft School of Medicine; Director, Division of Infectious Diseases, Director, Continuing Medical Education, Children's Medical Center of Dayton
Contributor Information and Disclosures

Updated: Aug 6, 2009

Differential Diagnoses

Aphthous Ulcers
Neonatal Sepsis
Cytomegalovirus Infection
Sepsis
Enteroviral Infections
Varicella
Erythema Toxicum
Zoster

Workup

Laboratory Studies

  • A definitive diagnosis of herpes simplex virus (HSV) infection is best confirmed by isolating the virus in tissue cultures.
    • Obtain scrapings of skin vesicles and mucosal lesions and expeditiously transfer them in appropriate viral-transport media to a diagnostic virology laboratory. A cytopathic effect usually develops within 24-48 hours after inoculation of any specimens containing infectious virus. Culture sensitivity may be improved with low-speed centrifugation or ultracentrifugation of the sample directly onto monolayers in centrifuge tubes (shell vials). Immunofluorescent staining of infected tissue culture cells helps in quickly identifying herpes simplex virus as being type 1 or 2.
    • A skin scraping of the lesion may reveal histologic appearances characteristic of herpesvirus infection, such as multinucleated giant cells and epithelial cells containing intranuclear inclusion bodies. Punch biopsy can provide optimal tissue for histologic diagnosis of a herpesvirus infection, particularly with atypical-appearing lesions.
    • A Tzanck preparation (see Procedures) may demonstrate the characteristic cytologic changes noted with herpesvirus infection. Cytologic examination has low sensitivity (approximately 60-70%).
  • Serologic diagnosis is of little clinical use. Therapeutic decisions cannot be delayed until serologic results become available.
    • Serologic testing is of value only to determine past exposure to herpes simplex virus. It may be helpful in demonstrating a primary seroconversion, particularly with herpes simplex virus type 1 (HSV-1) in childhood.
    • Because of antibody cross-reactivity, HSV-1 and herpes simplex virus type 2 (HSV-2) antibodies are not generally distinguishable unless a glycoprotein G antibody assay is used. Transplacental transfer of maternal herpes simplex virus antibody renders interpretation in neonates difficult.
  • Polymerase chain reaction (PCR) is the preferred diagnostic method for herpes simplex virus brain infection.
    • Evaluation of CSF specimens from patients with biopsy-proven herpes simplex virus encephalitis and in those with other proven diseases has a sensitivity of greater than 95% at the time of clinical presentation and a specificity that approaches 100%. Overall sensitivities of PCR in neonatal herpes simplex virus disease range from 75% to 100%, with overall specificities of 71-100%.
    • PCR results are positive early in the course of herpes simplex virus encephalitis and remains positive during the first week of therapy. PCR may be used to detect asymptomatic shedding or herpes simplex virus in skin lesions, but it is not a cost-efficient method.
    • Herpes simplex virus PCR results should be interpreted cautiously because neither the specificity nor the sensitivity of the analyses is 100%. In addition, performance of these tests may vary among laboratories. The results should be correlated with the clinical manifestations and the course of illness in determining their diagnostic significance.
  • Additional laboratory evaluations (eg, evaluation of CSF) are necessary in evaluating disseminated infection or infection involving single or multiple organ systems.
    • A slide prepared from scrapings of lesions may be examined for herpes simplex virus antigens by using immunofluorescent microscopy. Herpes simplex virus type-specific monoclonal antibodies, which are available in commercial antibody staining kits, permit the identification and typing of isolates in tissue samples. Slides containing cells from suspected herpes simplex virus lesions or specimens should be fixed with ethanol or methanol and immediately transported to the laboratory for analysis.
    • In patients with Mollaret meningitis, analysis of CSF reveals a mixed pleocytosis with neutrophils, lymphocytes, and endothelial cells (Mollaret cells). The CSF may have an increased gamma-globulin level. PCR of the CSF may demonstrate HSV-2.

Imaging Studies

  • In patients with herpes simplex virus encephalitis, CT scans and MRIs typically demonstrate focal abnormalities, frequently in the temporal lobe, that may be associated with edema and contrast enhancement.
  • Imaging may be useful in providing information suggesting etiologies other than herpes simplex virus. Some individuals have tumors or brain abscesses that may not be recognized immediately on CT scans. MRI may improve diagnostic capabilities (see Media file 6).

    MRI shows abnormal signal intensity in the left t...

    MRI shows abnormal signal intensity in the left temporal lobe of an 18-year-old man with herpes simplex virus (HSV) encephalitis.

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    MRI shows abnormal signal intensity in the left t...

    MRI shows abnormal signal intensity in the left temporal lobe of an 18-year-old man with herpes simplex virus (HSV) encephalitis.

Other Tests

  • Electroencephalograms (EEGs) are valuable for patients with herpes simplex virus encephalitis.
  • Periodic high-voltage spike-wave activity emanating from the temporal regions and slow wave complexes at 2-second to 3-second intervals is highly suggestive of herpes simplex virus brain infection.
  • Many physicians have started presumptive antiviral therapy on the basis of these EEG findings.

Procedures

  • The Tzanck preparation is useful for the cytologic identification of viruses in illnesses associated with vesicular exanthems caused by herpesviruses. The microscopist cannot differentiate infections caused by HSV-1, HSV-2, or varicella zoster virus.
    • An intact vesicle is aspirated with a sterile tuberculin syringe. This fluid may be submitted for viral isolation.
    • After the vesicle is aseptically unroofed, the base of the lesion is vigorously scraped with a scalpel or a wooden applicator.
    • The resultant material is placed on a slide, air dried, fixed, and stained, usually with Giemsa or Wright stain.
    • A positive result is the identification of typical giant cells or, uncommonly, Cowdry type A intranuclear inclusion bodies.
    • If the examiner is experienced, 40-80% of culture-positive specimens are recognized as positive by cytologic examination. Appropriate immunofluorescent antibody reagents facilitate the identification of different herpesviruses and some viruses other than herpesviruses.
  • Lumbar puncture (LP) with submission of CSF for the Gram staining, bacterial culture, and other analyses (eg, determination of cell counts, protein, and glucose levels) is essential when patients with encephalitis are evaluated.
    • Hemorrhagic CSF may be found in herpes simplex virus encephalitis. LP is contraindicated in patients with marked increased intracranial pressure.
    • All patients with neonatal CNS herpes simplex virus infection should undergo repeat LP at the end of intravenous (IV) acyclovir therapy to determine that the CSF specimen is negative for herpes simplex virus on PCR testing by a reliable laboratory and to document end-of-therapy CSF indices.
  • Brain biopsy results were frequently used to diagnose herpes simplex virus CNS disease and to exclude other potential pathologic processes. PCR is becoming the criterion standard for diagnosing herpes simplex virus infection of the brain. However, if PCR results are negative in a patient who has symptoms and signs of herpes simplex virus encephalitis, brain biopsy may be contemplated.

Histologic Findings

  • Herpes simplex virus tends to infect cells of ectodermal origin, entering through either the skin or mucous membranes.
  • Infected cells swell with intracellular edema and degenerate.
  • The nuclei of infected cells may undergo amitotic division, resulting in the formation of multinucleate giant cells. The nuclei of herpes simplex virus–infected cells then demonstrate eosinophilic intranuclear inclusions and marginated nuclear chromatin.
  • As cells manifest injury and as local inflammation progresses, intercellular edema develops and forms vesicles. Cutaneous vesicles may eventually be pustulated, dry, and crusted. Mucosal vesicles are transient and appear as shallow ulcers.

More on Herpes Simplex Virus Infection

Overview: Herpes Simplex Virus Infection
Differential Diagnoses & Workup: Herpes Simplex Virus Infection
Treatment & Medication: Herpes Simplex Virus Infection
Follow-up: Herpes Simplex Virus Infection
Multimedia: Herpes Simplex Virus Infection
References
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Further Reading

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Keywords

HSV, herpes, Herpesvirus hominis, human herpesvirus, herpesvirus type 1, herpesvirus type 2, HSV-1, HSV-2, herpes catarrhalis, herpes facialis, herpes febrilis, herpes labialis, orolabial herpetic infection, Simplex virus, Simplexvirus, neonatal HSV infection, SEM HSV disease, herpetic whitlow, herpes gladiatorum, meningitis, encephalitis, erythema multiform, EM, acuteherpetic pharyngotonsillitis, acute herpetic gingivostomatitis, genital herpes, Mollaret meningitis, keratoconjunctivitis, sexually transmitted disease, STD, genital HSV infections, neonatal HSV infection, orofacial infections, HSV encephalitis, disseminated HSV, odynophagia, orolabial vesicles, painful inguinal lymphadenopathy, aseptic meningitis syndrome, recurrent genital HSV, recurrent genital infections, transverse myelitis, HSV pneumonitis, HSV esophagitis, acute retinal necrosis, erythema multiforme, HSV keratoconjunctivitis, microphthalmos, retinal dysplasia, quadriplegia, microcephaly, recurrent HSV vesicular lesions, orolabial HSV infections, HSV pharyngotonsillitis, recurrent orolabial herpetic infection, HSV CNS disease, HSV-induced aseptic meningitis, HSV hepatitis, blepharitis, follicular conjunctivitis, uveitis, retinitis, punctate retinal lesions, congenital HSV infection

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Contributor Information and Disclosures

Author

Sherman Alter, MD, Associate Professor, Department of Pediatrics, Wright State University Boonshoft School of Medicine; Director, Division of Infectious Diseases, Director, Continuing Medical Education, Children's Medical Center of Dayton
Sherman Alter, MD is a member of the following medical societies: American Academy of Pediatrics, American Society for Microbiology, Infectious Diseases Society of America, Pediatric Infectious Diseases Society, and Society for Healthcare Epidemiology of America
Disclosure: Glaxosmithkline Grant/research funds Other; Merck Honoraria Speaking and teaching; Novartis Grant/research funds Speaking and teaching; SanofiPasteur Honoraria None

Medical Editor

Leonard R Krilov, MD, Chief of Pediatric Infectious Diseases, Vice Chair, Department of Pediatrics, Professor of Pediatrics, Winthrop University Hospital
Leonard R Krilov, MD is a member of the following medical societies: American Academy of Pediatrics, American Pediatric Society, Infectious Diseases Society of America, Pediatric Infectious Diseases Society, and Society for Pediatric Research
Disclosure: Medimmune Grant/research funds Cliinical trials; Medimmune Honoraria Speaking and teaching; Medimmune Consulting fee Consulting

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

Mark R Schleiss, MD, American Legion Chair of Pediatrics, Professor of Pediatrics, Division Director, Division of Infectious Diseases and Immunology, Department of Pediatrics, University of Minnesota Medical School
Mark R Schleiss, MD is a member of the following medical societies: American Pediatric Society, Infectious Diseases Society of America, Pediatric Infectious Diseases Society, and Society for Pediatric Research
Disclosure: Nothing to disclose.

CME Editor

Robert W Tolan Jr, MD, Chief, Division of Allergy, Immunology and Infectious Diseases, The Children's Hospital at Saint Peter's University Hospital; Clinical Associate Professor of Pediatrics, Drexel University College of Medicine
Robert W Tolan Jr, MD is a member of the following medical societies: American Academy of Pediatrics, American Medical Association, American Society for Microbiology, American Society of Tropical Medicine and Hygiene, Infectious Diseases Society of America, Pediatric Infectious Diseases Society, Phi Beta Kappa, and Physicians for Social Responsibility
Disclosure: GlaxoSmithKline Honoraria Speaking and teaching; MedImmune Honoraria Speaking and teaching; Merck Honoraria Speaking and teaching; sanofi pasteur Honoraria Speaking and teaching; Baxter Healthcare Honoraria Speaking and teaching

Chief Editor

Russell W Steele, MD, Head, Division of Pediatric Infectious Diseases, Ochsner Children's Health Center; Clinical Professor, Department of Pediatrics, Tulane University School of Medicine
Russell W Steele, MD is a member of the following medical societies: American Academy of Pediatrics, American Association of Immunologists, American Pediatric Society, American Society for Microbiology, Infectious Diseases Society of America, Louisiana State Medical Society, Pediatric Infectious Diseases Society, Society for Pediatric Research, and Southern Medical Association
Disclosure: None None None

 
 
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