14.1 Herpesviridae Infections: HSV, VZV & HHV-8

14.1 Herpesviridae Infections: HSV, VZV & HHV-8

Overview and Biology of the Herpesviridae Family

The Herpesviridae are a family of large, enveloped, double-stranded linear DNA viruses characterized by an icosahedral capsid surrounded by an amorphous protein tegument and an outer lipid envelope embedded with viral glycoproteins (gB, gC, gD, gH, gL) that facilitate host cell attachment and entry. The hallmark biological feature of all herpesviruses is the capacity to establish lifelong, persistent latent infection within specific host cell reservoirs following primary infection, with periodic episodes of reactivation.

The family is classified into three distinct subfamilies based on genomic architecture, cellular tropism, and replication kinetics:

1. Alphaherpesvirinae (HSV-1, HSV-2, VZV / HHV-3): Characterized by variable host range, rapid lytic replication cycle in epithelial cells, efficient destruction of infected host cells, and establishment of latent infection exclusively within sensory nerve ganglia.
2. Betaherpesvirinae (CMV / HHV-5, HHV-6A, HHV-6B, HHV-7): Exhibit restricted host range, slow replication cycle, cytomegalic cellular enlargement, and latency within secretory glands, lymphoreticular cells, and hematopoietic progenitor cells.
3. Gammaherpesvirinae (EBV / HHV-4, HHV-8 / KSHV): Exhibit narrow host range, specific tropism for B lymphocytes or endothelial cells, and latent infection capable of driving oncogenic cellular transformation.

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Herpes Simplex Virus Types 1 & 2 (HSV-1 and HSV-2)

Pathogenesis, Latency Kinetics & Viral Shedding

• Transmission & Inoculation: Transmission occurs via direct contact with infectious secretions or cutaneous/mucosal lesions from a symptomatic or asymptomatic shedding individual. HSV enters keratinocytes through microabrasions via glycoprotein interactions (particularly glycoprotein D binding to nectin-1 and herpesvirus entry mediator [HVEM]).
• Retrograde Axonal Transport: Following lytic replication in the epidermis, intact virions or nucleocapsids penetrate local unmyelinated sensory nerve endings and travel by retrograde axonal transport mediated by dynein motors along microtubules to sensory ganglion cell bodies.
  • HSV-1: Primarily establishes latency in the trigeminal ganglion (cranial nerve V), innervating the perioral facial epithelium.
  • HSV-2: Primarily establishes latency in the sacral dorsal root ganglia (S2–S4), innervating the genital and perianal mucosa.
• Molecular Latency: Within the neuronal nucleus, the viral linear genome circularizes into a transcriptionally quiescent episome. Productive lytic genes are repressed, while latency-associated transcripts (LATs) are continuously expressed. LATs inhibit neuronal apoptosis and repress lytic promoter regions through heterochromatin assembly.
• Reactivation & Antegrade Transport: Environmental, immunological, or physical triggers perturb latent repression, initiating viral gene transcription. Progeny nucleocapsids are transported via antegrade axonal transport mediated by kinesin motors back to peripheral epidermal nerve endings, causing localized viral replication, epidermal vesicle formation, and viral shedding.
  • Trigger factors: Ultraviolet-B (UV-B) radiation ("solar herpes"), febrile illness, physical trauma (microdermabrasion, ablative laser resurfacing, chemical peels), psychological stress, menses, and systemic immunosuppression.
• Asymptomatic Viral Shedding: Both HSV-1 and HSV-2 periodically shed from intact mucosa in the complete absence of clinical lesions or prodromal symptoms. Asymptomatic shedding accounts for the majority of sexual transmissions. Continuous daily oral suppressive antiviral therapy reduces asymptomatic shedding episodes by 70% to 80%, substantially diminishing horizontal transmission risk.

Clinical Manifestations of HSV

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|                       CLINICAL SPECTRUM OF HSV                           |
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| Primary Oral (HSV-1)   | Acute gingivostomatitis, friable gums, high fever|
| Primary Genital (HSV-2)| Bilateral grouped ulcers, dysuria, radiculopathy |
| Recurrent Mucocutaneous| Unilateral clustered vesicles on red base, prodrome|
| Cutaneous Inoculation  | Herpetic whitlow (digits), Gladiatorum (torso)   |
| Reactive Dermatoses    | Erythema multiforme (HAEM; CD34+ cell transport) |
| Dermatologic Emergency | ECZEMA HERPETICUM (Kaposi varicelliform eruption)|
| Ophthalmic Emergency   | Herpes simplex keratitis (Dendritic ulcers)      |
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1. Primary Herpetic Gingivostomatitis

• Epidemiology: Most common primary presentation of HSV-1, predominantly affecting children aged 1 to 5 years.
• Clinical Signs: Abrupt onset of high fever (39–40°C), profound malaise, irritability, and painful vesicular eruptions across the hard and soft palate, tongue, buccal mucosa, and gingivae. Vesicles quickly rupture to form shallow, yellowish-grey erosions with erythematous halos.
• Pathognomonic Feature: Acute marginal gingivitis with fiery red, swollen, friable, bleeding gums. Marked submandibular and anterior cervical lymphadenopathy. Painful swallowing leads to dehydration requiring hospital admission.

2. Primary Genital Herpes

• Etiology: HSV-2 accounts for ~70% of recurrent genital herpes; however, primary genital herpes in young European cohorts is increasingly caused by HSV-1 via orogenital contact.
• Clinical Signs: Severe, bilateral, widely distributed grouped vesicles on an erythematous base across the labia majora/minora, vulva, vaginal introitus, cervix, penile glans, penile shaft, and perineum. Vesicles rapidly erode into exquisitely painful, punched-out ulcers.
• Systemic Symptoms: High fever, headache, myalgias, and tender bilateral inguinal lymphadenopathy. Complications include aseptic meningitis (10–30% of primary HSV-2 cases) and sacral autonomic radiculopathy (Elsberg syndrome), presenting with acute urinary retention, constipation, and perineal sensory loss.

3. Recurrent Mucocutaneous Herpes

• Course: Preceded by a sensory prodrome (burning, tingling, itching, or neuralgic pain) 6 to 24 hours prior to rash. Clustered, uniform vesicles on an erythematous base that rupture into superficial crusting erosions, resolving completely over 7 to 10 days without scarring.
• Herpes Labialis ("Cold Sores"): Typically localized to the vermilion border of the lip; HSV-1.
• Recurrent Genital Herpes: Typically unilateral, milder, smaller in surface area, and of shorter duration (4–6 days) than the primary episode.

4. Cutaneous Inoculation Variants

• Herpetic Whitlow: Inoculation of HSV-1 or HSV-2 into a digit via microtrauma. Common in dental personnel, nurses, respiratory therapists, and children who thumb-suck during primary gingivostomatitis. Characterized by deep-seated, painful, non-purulent vesicles on an erythematous swollen finger pulp. Critical Trap: Frequently misdiagnosed as a bacterial paronychia or felon; surgical incision and drainage is strictly contraindicated as it exacerbates tissue destruction, promotes secondary bacterial infection, and increases risk of systemic viremia.
• Herpes Gladiatorum ("Mat Herpes"): Cutaneous HSV-1 inoculation resulting from direct skin-to-skin friction during contact sports (wrestling, rugby). Presents with clustered painful vesicles on the face, neck, and shoulders.
• Herpes-Associated Erythema Multiforme (HAEM): Recurrent targetoid lesions appearing 7 to 14 days after an HSV outbreak. Driven by viral DNA fragments transported to the skin by CD34+ Langerhans cell precursors, eliciting a localized cell-mediated delayed-type hypersensitivity reaction. Suppressive continuous oral antiviral therapy is highly effective in terminating recurrent HAEM cycles.

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Dermatological Emergencies: Eczema Herpeticum & Ophthalmic HSV

1. Eczema Herpeticum (Kaposi Varicelliform Eruption)

• Pathophysiology: A life-threatening, disseminated cutaneous HSV infection (HSV-1 > HSV-2) developing in patients with pre-existing impaired skin barrier function. Most commonly occurs in atopic dermatitis, but can complicate Darier disease, Hailey-Hailey disease, severe burns, pemphigus foliaceus, Sézary syndrome, and mycosis fungoides. Pathogenesis involves reduced expression of epidermal antimicrobial peptides (cathelicidin LL-37 and human beta-defensins), defective claudin-1 tight junctional integrity, and Th2-skewed immune deviation blunting interferon-gamma release.
• Clinical Presentation: Explosive, sudden onset of high fever (39–40°C), rigors, severe malaise, and extensive, widespread monomorphic, punched-out, umbilicated vesicles and pustules that rapidly erode into "punched-out" circular erosions with hemorrhagic crusts. Lesions preferentially cluster on areas affected by atopic eczema (face, neck, antecubital and popliteal fossae), but rapidly extend across normal-appearing skin.
• Life-Threatening Risks: Secondary Staphylococcus aureus septicemia, disseminated systemic viremia involving the liver and lungs, and bilateral herpes simplex keratitis leading to permanent corneal perforation.
• Emergency Management Protocol:
  • Immediate hospital admission.
  • Intravenous Acyclovir (5–10 mg/kg IV q8h) in severe, toxic, or pediatric cases; or high-dose oral valacyclovir (1000 mg tid) in mild, early ambulatory adult presentations.
  • Urgent ophthalmological evaluation if periocular, eyelid, or facial lesions are present.
  • Concomitant empiric intravenous antistaphylococcal coverage (Flucloxacillin or Cefazolin) to treat or prevent bacterial superinfection.
  • Strict Contraindication: Topical calcineurin inhibitors (tacrolimus, pimecrolimus) and potent topical corticosteroids must be immediately discontinued during the acute eruptive phase, as they impair local innate immunity and accelerate viral dissemination.

2. Herpes Simplex Keratitis (Ophthalmic HSV)

• Clinical Features: Direct corneal epithelial invasion presenting with eye pain, foreign-body sensation, photophobia, tearing, and conjunctival injection.
• Diagnostic Sign: Slit-lamp examination with fluorescein staining under cobalt blue light reveals classic branching dendritic ulcers with terminal swollen bulbs.
• Management: Urgent ophthalmology referral. Topical ganciclovir 0.15% ophthalmic gel (5 times daily) or acyclovir 3% ointment, combined with systemic oral antivirals. Topical corticosteroids are absolutely contraindicated in epithelial dendritic keratitis because they paralyze local cell-mediated immunity, leading to rapid enlargement into "geographic ulcers" and corneal perforation.

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Varicella Zoster Virus (VZV / HHV-3)

Primary Varicella (Chickenpox)

• Transmission & Virology: Highly contagious transmission through inhalation of aerosolized respiratory droplets or direct contact with fluid from active cutaneous blisters. The primary incubation period spans 10 to 21 days.
• Clinical Morphology: Mild prodrome of fever, headache, and malaise, followed within 24 hours by a pruritic, centripetal eruption (scalp, face, and trunk > extremities). Lesions evolve rapidly through macules, papules, clear vesicles on an erythematous base resembling "dewdrops on a rose petal", turbid pustules, and crusts.
• Diagnostic Hallmark: Polymorphic appearance—lesions at all developmental stages (macules, papules, vesicles, crusts) are simultaneously present within the same anatomical area, in contrast to smallpox or mpox where lesions are monomorphic.
• Adult Complications: Primary varicella in adults carries a 15- to 20-fold higher rate of severe complications than in children. Varicella pneumonia is the most important adult complication; radiological changes are far commoner than clinically severe pneumonia. Severe pneumonia is most likely in cigarette smokers, pregnant women in the third trimester, and immunocompromised hosts, and presents with cough, dyspnea, tachypnea, and bilateral reticulonodular infiltrates on chest imaging. Historical mortality was 10% to 30%; it is lower with early aciclovir and intensive care.

Herpes Zoster (Shingles)

Herpes zoster represents the secondary reactivation of latent VZV residing within cranial nerve sensory ganglia or spinal dorsal root ganglia, descending along the sensory nerve to infect the corresponding dermatome.

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|                       HERPES ZOSTER: CLINICAL VARIANTS                   |
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| Classic Dermatomal    | Unilateral, respects midline, thoracic (T3-L2) >50%|
| Hutchinson Sign       | Nasociliary nerve (V1) -> High ocular risk (>75%) |
| Ramsay Hunt Syndrome  | Geniculate ganglion (CN VII) -> Palsy, otic rash  |
| Disseminated Zoster   | >20 vesicles outside dermatome -> Severe immuno-  |
|                       | compromise; requires IV acyclovir + workup        |
| Post-Herpetic Neuralgia| Pain persisting >90 days -> Age >50, early Rx key |
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Clinical Features & Dermatomal Distribution

• Prodrome (2 to 5 days): Unilateral dermatomal sensory disturbance: severe burning, shooting, throbbing, or lancinating radicular pain, hyperesthesia, and allodynia. Frequently misdiagnosed prior to rash onset as acute coronary syndrome, pleurisy, acute cholecystitis, nephrolithiasis, or sciatica.
• Eruptive Phase: Grouped, tense, clear vesicles on an erythematous, indurated base arranged in a unilateral dermatomal distribution strictly respecting the anatomical midline. Thoracic dermatomes (T3–L2) account for >50% of cases; ophthalmic division of the trigeminal nerve (V1) accounts for 10% to 15%.
• Evolution: Vesicles become umbilicated, pustular, and rupture into crusts over 7 to 10 days, with complete cutaneous healing taking 2 to 4 weeks. Scarring and hypopigmentation or hyperpigmentation may follow.

High-Yield Clinical Signs & Syndromes

1. Hutchinson's Sign & Herpes Zoster Ophthalmicus (HZO):
   • Reactivation involves the ophthalmic division of the trigeminal nerve (V1).
   • Hutchinson's Sign: Vesicles located on the tip, side, or ala of the nose. This indicates involvement of the external nasal branch of the nasociliary nerve.
   • Clinical Significance: Because the nasociliary nerve innervates both the nasal tip and the intraocular structures (cornea, iris, ciliary body), a positive Hutchinson's sign predicts a >75% incidence of ocular complications (anterior uveitis, dendritic/stromal keratitis, secondary glaucoma, optic neuritis, acute retinal necrosis). Immediate emergency ophthalmological consultation and systemic antiviral therapy are mandatory.
2. Ramsay Hunt Syndrome (Herpes Zoster Oticus):
   • Reactivation involves the geniculate ganglion of the facial nerve (cranial nerve VII), with inflammatory extension to the adjacent vestibulocochlear nerve (cranial nerve VIII).
   • Classic Triad:
     1. Acute peripheral facial nerve paralysis (inability to close eye, loss of nasolabial fold, mouth drooping).
     2. Severe otalgia accompanied by vesicular eruptions in the external auditory canal, concha, tympanic membrane, or pinna.
     3. Vestibulocochlear (CN VIII) dysfunction: sensorineural hearing loss, tinnitus, rotary vertigo, and nausea.
   • Loss of taste on the anterior two-thirds of the tongue reflects facial nerve (chorda tympani) involvement, not CN VIII.
   • Management: Combination of oral Valacyclovir (1000 mg tid) or Famciclovir (500 mg tid) PLUS systemic corticosteroids (oral Prednisolone 1 mg/kg/day for 7 days, tapered over 7 days) initiated within 72 hours significantly optimizes facial nerve recovery and hearing preservation.
3. Disseminated Herpes Zoster:
   • Defined as more than 20 aberrant vesicles outside the primary and immediately adjacent dermatomes, or multi-dermatomal crossing of non-contiguous dermatomes.
   • Strongly correlates with underlying severe cell-mediated immunodeficiency (advanced HIV, post-solid organ transplant, hematological malignancies, chemotherapy). Requires hospital admission, isolation in a negative-pressure room, and intravenous acyclovir.

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Post-Herpetic Neuralgia (PHN) & Prevention

Definition, Risk Factors & Pathophysiology

• Definition: Neuropathic pain persisting for more than 90 days (3 months) after the initial onset of the herpes zoster cutaneous eruption.
• Risk Factors: Advancing age is the single most powerful predictor (PHN risk rises steeply after 50 years and is highest in the elderly); severe acute pain during the prodrome or eruptive phase; severe extensive dermatomal blistering; and involvement of the ophthalmic (V1) dermatome.
• Pathogenesis: Intractable viral replication causes hemorrhagic necrosis, dense inflammatory destruction, and scarring within the dorsal root ganglion and peripheral nerve trunks. Loss of large inhibitory myelinated A-beta fibers leads to deafferentation, while unmyelinated nociceptive C-fibers exhibit aberrant regenerative sprouting, driving central sensitization of second-order dorsal horn neurons.

Prevention: Antivirals & Vaccination

• Early Antiviral Therapy: Initiation of oral acyclovir, valacyclovir, or famciclovir within 72 hours of rash onset significantly reduces the duration of acute viral shedding, accelerates cutaneous healing, reduces acute pain severity, and lowers the subsequent burden of PHN.
• Recombinant Zoster Vaccine (Shingrix):
  • Composed of recombinant glycoprotein E (gE) combined with the novel AS01B adjuvant system (containing MPL and QS-21 to stimulate potent CD4+ T-cell and antibody responses).
  • Administered as a 2-dose intramuscular series (0 and 2–6 months) to immunocompetent adults ≥50 years and immunocompromised adults ≥18 years.
  • Demonstrates >90% protective efficacy against herpes zoster and PHN across all age cohorts, maintaining durable protection for over a decade. Non-live, safe in immunosuppressed patients, and vastly superior to the older live-attenuated Oka-strain vaccine (Zostavax).

Pharmacological Management of Established PHN

• First-Line Topical Agents:
  • Lidocaine 5% medicated plaster: Applied to the painful, fully healed intact skin area for 12 hours on, 12 hours off. Blocks neuronal sodium channels with negligible systemic absorption; ideal in frail elderly patients.
  • Capsaicin 8% dermal patch: High-concentration patch applied under local topical anesthesia for 60 minutes in a specialized clinic. Agonizes and defunctionalizes the TRPV1 receptor, depleting substance P and providing analgesia for up to 12 weeks.
• First-Line Systemic Agents:
  • Gabapentinoids: Pregabalin (150–600 mg/day divided bid/tid) or Gabapentin (900–3600 mg/day divided tid). Bind the alpha-2-delta subunit of voltage-gated calcium channels, attenuating excitatory neurotransmitter release.
  • Tricyclic Antidepressants (TCAs): Amitriptyline or Nortriptyline (10–75 mg once daily at bedtime). Inhibit serotonin and noradrenaline reuptake; require baseline ECG in elderly due to QTc prolongation and anticholinergic side effects.
  • SNRIs: Duloxetine (60 mg daily) or Venlafaxine.

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Diagnostic Modalities: Diagnostic Gold Standards vs Bedside Tests

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European Antiviral Regimens & Renal Dosing Table

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|                 MECHANISM OF ACTION & RESISTANCE                         |
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| Acyclovir (Guanosine analog) -> Monophosphorylated by VIRAL THYMIDINE    |
| KINASE (TK) -> Triphosphorylated by CELLULAR KINASES -> Competitively    |
| inhibits VIRAL DNA POLYMERASE -> Obligate DNA chain termination.         |
|                                                                          |
| Resistance Mechanism: Mutations in viral TK gene (TK-negative strains).   |
| Occurs in immunosuppressed patients -> Managed with FOSCARNET / CIDOFOVIR|
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European Guideline-Based Antiviral Dosing Schedules

Renal Safety & Dose Adjustment Guidelines

Acyclovir, valacyclovir (rapidly hydrolyzed to acyclovir in the liver), and famciclovir (metabolized to penciclovir) are excreted predominantly via glomerular filtration and active tubular secretion.

• Acyclovir Crystal Nephropathy: Intravenous acyclovir has low aqueous solubility. Rapid infusion or inadequate patient hydration causes intratubular precipitation of needle-shaped acyclovir crystals, causing acute renal tubular obstruction and acute kidney injury (AKI). Vigorous intravenous hydration before and during infusion is mandatory.
• Neurotoxicity: Accumulation of acyclovir and its metabolite 9-carboxymethoxymethylguanine (CMMG) in renal impairment leads to severe neurotoxicity: confusion, visual hallucinations, myoclonus, cerebellar tremors, and coma.

Renal Titration Guidelines (Herpes Zoster Treatment as Model)

• Creatinine Clearance (CrCl) > 50 mL/min: Standard dosing: Valacyclovir 1000 mg PO q8h.
• CrCl 30–49 mL/min: Valacyclovir 1000 mg PO q12h.
• CrCl 15–29 mL/min: Valacyclovir 1000 mg PO q24h (or 500 mg PO q12h).
• CrCl < 15 mL/min (or Hemodialysis): Valacyclovir 500 mg PO q24h (administer post-dialysis on dialysis days, as hemodialysis removes ~60% of circulating acyclovir).

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Human Herpesvirus 8 (HHV-8 / KSHV) & Kaposi Sarcoma

Virology & Pathogenesis

Human Herpesvirus 8 (HHV-8), also termed Kaposi Sarcoma-Associated Herpesvirus (KSHV), is an oncogenic gamma-2 herpesvirus (genus Rhadinovirus). HHV-8 infects vascular and lymphatic endothelial cells and B cells.

• Viral Oncogenes: The virus encodes homologous human genes that drive oncogenesis: viral cyclin D (vCYC) which dysregulates CDK6; viral FLICE-inhibitory protein (vFLIP) which suppresses death-receptor-mediated apoptosis; viral G-protein-coupled receptor (vGPCR) which drives secretion of VEGF; and Latency-Associated Nuclear Antigen 1 (LANA-1).
• LANA-1 Function: LANA-1 tethers the viral episome to host chromosomes during mitosis, represses lytic replication, and directly inhibits the p53 and retinoblastoma (pRb) tumor suppressor pathways.

The Four Epidemiological Variants

Histopathology & Immunohistochemistry

Kaposi sarcoma progresses through three histological stages:

1. Patch Stage: Subtle, jagged, thin-walled, irregular vascular spaces in the upper reticular dermis dissecting through collagen bundles. Demonstrates the pathognomonic "promontory sign" (pre-existing dermal blood vessels and skin appendages protruding into the newly formed irregular neoplastic vascular lumens). Extravasated red blood cells, hemosiderin, and perivascular lymphocytes/plasma cells.
2. Plaque Stage: More extensive, interconnected vascular channels dissecting through the full-thickness dermis, surrounded by interlacing fascicles of spindle cells and abundant extravasated erythrocytes.
3. Nodular Stage: Well-circumscribed, dense cellular tumor composed of interlacing fascicles of atypical spindle-shaped endothelial cells forming narrow, slit-like vascular channels devoid of endothelial lining. Extravasated erythrocytes fill these slits. Diagnostic eosinophilic hyaline globules (representing phagocytosed degenerated red blood cells) are seen intra- and extracellularly.

• Definitive Immunohistochemical Gold Standard: Monoclonal antibody staining against LANA-1 (HHV-8) reveals a punctate, granular nuclear brown staining pattern in neoplastic spindle cells and endothelial cells. LANA-1 immunostaining exhibits 100% specificity, definitively distinguishing KS from histological mimics (bacillary angiomatosis, pyogenic granuloma, spindle cell hemangioma, angiosarcoma, and kaposiform hemangioendothelioma).

Therapeutic Principles

• AIDS-Associated KS: The fundamental cornerstone is the immediate initiation or optimization of Antiretroviral Therapy (ART) to restore CD4+ T-cell counts. ART alone achieves complete or partial regression in up to 70% of limited cases.
• Iatrogenic KS: Dose reduction of immunosuppression or switching calcineurin inhibitors to mTOR inhibitors (Sirolimus / Everolimus), which exert direct anti-angiogenic activity by down-regulating VEGF and blocking endothelial proliferation.
• Local Therapies (for localized, cosmetically distressing, or painful lesions): Cryotherapy with liquid nitrogen, intralesional vinblastine (0.1–0.2 mg/mL), localized superficial radiotherapy (KS is exquisitely radiosensitive), and topical alitretinoin 0.1% gel.
• Systemic Chemotherapy: Indicated for visceral involvement (pulmonary or gastrointestinal KS), rapidly progressive cutaneous disease, or extensive disabling lymphedema. Pegylated Liposomal Doxorubicin (PLD) (20 mg/m² IV every 2 to 3 weeks) is the first-line therapy of choice; Paclitaxel is the established second-line agent.