How do the clinical presentation and diagnostic work‑up differ between herpes simplex virus (HSV) infection and varicella‑zoster virus (VZV) infection?

Clinical Presentation and Diagnostic Work-Up: HSV vs. Varicella-Zoster Virus

Clinical Presentation Differences

Herpes Simplex Virus (HSV)

HSV presents with distinct anatomical and age-related patterns that differ markedly from VZV. 1

• Neonatal HSV appears at 9-11 days of age with three patterns: disseminated disease (25%), CNS encephalitis (30-35%), or localized skin/eye/mouth disease (40%), with vesicular rash present in only 60% of disseminated/CNS cases but 80% of localized disease 1
• Primary HSV gingivostomatitis in children manifests with fever, irritability, tender submandibular lymphadenopathy, and superficial painful ulcers in the gingival/oral mucosa and perioral area 1
• Genital HSV produces infection of genital mucosa, genital skin, and perigenital region, with HSV-2 almost always associated with genital disease while HSV-1 causes both oro-pharyngeal and genital disease 1
• Immunocompromised patients may develop severe local lesions, disseminated HSV with visceral involvement (liver, adrenals, lung, kidney, spleen, brain), esophageal involvement, or CNS disease 1

Varicella-Zoster Virus (VZV)

VZV presents with prodromal pain followed by unilateral dermatomal vesicular eruption, a hallmark that distinguishes it from HSV's multifocal or localized patterns. 2

• Prodromal pain precedes skin findings by 24-72 hours, characterized by burning, itching, tingling, or paresthesia localized to a single dermatome 2
• Rash progression follows a predictable sequence: erythematous macules → papules → vesicles in a unilateral dermatomal distribution 2
• Lesion evolution continues for 4-6 days in immunocompetent hosts, with total disease duration approximately 2 weeks 2
• Immunocompromised patients develop new lesions for 7-14 days with slower healing, and may progress to chronic ulcerations with persistent viral replication 2, 3
• Atypical presentations include nonspecific lesions without vesicular appearance, faint or evanescent rash, or difficulty recognizing rash in darker skin pigmentation 2

Key Distinguishing Features

The unilateral dermatomal distribution with prodromal pain is pathognomonic for VZV, while HSV typically presents with grouped vesicles at mucocutaneous sites without dermatomal restriction. 1, 2

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Diagnostic Work-Up Differences

HSV Diagnostic Approach

Viral culture remains the gold standard for HSV, with specimens obtainable from multiple sites depending on clinical presentation. 1

Specimen Collection

• Neonatal HSV: Obtain cultures from blood, skin vesicles, mouth/nasopharynx, eyes, urine, and stool/rectum; positive cultures from non-blood sites >48 hours after birth indicate viral replication rather than intrapartum contamination 1
• Mucocutaneous lesions: Collect vesicle fluid or lesion scrapings for culture, which typically detects virus within 1-3 days 1

Diagnostic Modalities

• Viral culture: Gold standard, detects virus in tissue culture cells within 1-3 days 1, 4
• PCR of CSF: Replaced brain biopsy as the diagnostic test of choice for HSV encephalitis, detecting HSV DNA common to both HSV-1 and HSV-2 1
• Direct immunofluorescence: Detects HSV antigen on cells from skin, conjunctiva, or mucosal lesion scrapings 1
• Tzanck preparation: Shows multinucleated giant cells and eosinophilic intranuclear inclusions but cannot differentiate HSV type or HSV from VZV and is not routinely recommended 1
• Endoscopy with biopsy: Required for definitive diagnosis of HSV esophagitis, showing multinucleated giant cells with intranuclear viral inclusion 1

VZV Diagnostic Approach

PCR of vesicle fluid is the most sensitive and specific test for VZV, approaching 100% sensitivity and specificity, and can detect viral DNA even in crusted lesions. 2

When to Test

• Confirmatory testing is recommended for atypical presentations, immunocompromised patients, diagnostic uncertainty, or absence of characteristic pain 2
• Typical herpes zoster in immunocompetent patients does not require laboratory confirmation; clinical diagnosis based on typical vesicle appearance is sufficient 2
• Skin biopsy is not indicated for typical herpes zoster and is reserved for immunocompromised patients with atypical skin lesions 2

Diagnostic Modalities

• PCR of vesicle fluid: Most sensitive and specific (approaching 100%), detects viral DNA even in crusted lesions, and can distinguish wild-type from vaccine strain VZV 2, 5
• Direct fluorescent antibody (DFA): Provides rapid confirmation of VZV infection when PCR unavailable 2
• Tzanck smear: Demonstrates multinucleated giant cells confirming herpesvirus infection but cannot differentiate VZV from HSV; useful as bedside adjunct 2
• Viral culture: Can identify VZV but infrequently used due to longer turnaround time and lower practicality 2
• Serologic testing (VZV IgG/IgM): Does not aid in diagnosing active herpes zoster and should not be ordered 2

Additional Screening

• Diabetes screening should be considered when herpes zoster is identified, as infection may unmask underlying metabolic disease 2
• Evaluation for occult malignancy is advised when clinical features raise suspicion 2
• HIV screening, diabetes, malignancy, or immunosuppressive medication assessment increases risk and severity in immunocompromised patients 2

Comparative Diagnostic Performance

Nucleic acid amplification methods provide superior sensitivity and specificity for both HSV and VZV compared to culture or antigen detection, with the advantage of applicability to any lesion stage. 5, 6

• Real-time PCR vs. nested PCR: No significant difference in sensitivity for HSV or VZV detection from skin lesions 6
• PCR vs. viral culture: Nucleic acid amplification increased detection rate of HSV-2 (37% vs. 25%) and VZV (46% vs. 14%) compared to virus isolation 6
• Isothermal amplification (Solana): Concordance with RT-PCR was 98.3% for HSV-1,100% for HSV-2, and 99.3% for VZV, with advantage of rapid turnaround time 7
• PCR advantages: Applicable to blood, CSF, aqueous/vitreous humor, and mucosal surfaces; provides results within 24 hours; readily distinguishes HSV type and VZV source (wild-type vs. vaccine strain) 5

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Common Pitfalls to Avoid

• Do not rely on Tzanck smear alone for definitive diagnosis, as it cannot differentiate HSV from VZV or determine HSV type 1, 2
• Do not order VZV serology for acute herpes zoster diagnosis; it does not aid in confirming active infection 2
• Do not assume typical clinical presentation eliminates need for testing in immunocompromised patients, who frequently present atypically 2
• Do not delay antiviral therapy while awaiting diagnostic confirmation in immunocompromised patients with suspected HSV encephalitis or disseminated VZV 1, 2
• Do not use viral culture as first-line test when PCR is available, as culture has lower sensitivity especially for VZV and later-stage lesions 5, 6