Multisystem Processes & Disorders

Varicella-zoster: primary, zoster, postherpetic neuralgia

Clinical Overview and When to Suspect Varicella-Zoster

— Primary varicella (chickenpox): generalized pruritic vesicular exanthem, typically in unvaccinated children or susceptible adults

— Herpes zoster (shingles): unilateral dermatomal reactivation, usually in adults >50 or immunocompromised hosts

— Susceptible patient (no vaccine, no prior infection) with fever, malaise, then crops of lesions in different stages (macule → papule → vesicle → crust) on face/trunk spreading centrifugally

— Outbreak exposure in daycare, college dorm, military, or unvaccinated immigrant

— Prodromal dermatomal pain, burning, or paresthesia for 2–3 days, followed by grouped vesicles on an erythematous base in a single dermatome that does not cross midline

— Most common dermatomes: T1–L2 thoracic (>50%) and V1 trigeminal

— Atypical hosts: HIV, hematologic malignancy, solid organ transplant, chronic steroids, biologics — may present with multidermatomal or disseminated disease

Varicella-zoster virus (VZV) is a human alpha-herpesvirus causing two distinct clinical syndromes separated by latency in dorsal root and cranial nerve ganglia:

Postherpetic neuralgia (PHN): neuropathic pain persisting ≥90 days after rash onset; the most common and most disabling sequela of zoster

Suspect primary varicella when:

Suspect zoster when:

Suspect PHN when: burning, lancinating, or allodynic pain persists in the affected dermatome >90 days post-rash; risk rises sharply with age >60, severe acute pain, ophthalmic involvement, and prodromal pain

Board pearl: "Lesions in different stages of evolution" = varicella; "lesions all the same stage in one dermatome" = zoster. This single phrase distinguishes the two on Step 3 vignettes.

Step 3 management: A primary care visit for a tingling unilateral rash in a 65-year-old should trigger same-day antiviral initiation if within 72 hours of vesicle onset — do not wait for confirmatory testing.

Presentation Patterns and Key History

— Incubation 10–21 days after exposure; contagious from 48 hours before rash until all lesions crust

— Prodrome (adults > children): fever 101–102°F, headache, malaise, anorexia 1–2 days before rash

— Rash starts on face/scalp/trunk, spreads centrifugally to extremities; intensely pruritic; 200–500 lesions typical

— Mucosal involvement (oropharynx, conjunctiva, genital) common

— Adults have more severe disease: higher fever, more lesions, 25× higher pneumonia risk

— Prodrome of dermatomal pain, itch, or paresthesia 48–72 hours before vesicles

— Unilateral, sharply demarcated band; vesicles evolve over 3–5 days, crust by 7–10 days

— Pain quality: burning, stabbing, electric; often misdiagnosed early as MI, cholecystitis, renal colic, or radiculopathy before the rash appears

— Zoster sine herpete: dermatomal pain without rash — rare, diagnosis often retrospective

— Immunization history (Varivax ×2 doses since 1995; Shingrix ×2 doses for age ≥50)

— Prior varicella or zoster episode (zoster can recur, ~5% lifetime)

— Immunosuppression: HIV status/CD4, chemotherapy, transplant, steroids ≥20 mg/day, TNF inhibitors, JAK inhibitors

— Pregnancy status and gestational age

— Household contacts: pregnant women, neonates, immunocompromised — exposure risk drives prophylaxis decisions

— Time since rash onset (drives antiviral eligibility)

Primary varicella:

Herpes zoster:

Key history to elicit:

Key distinction: Recurrent "zoster" in a young patient should prompt HIV testing and consideration of underlying immunodeficiency or lymphoma — zoster in someone <50 is an immunosuppression red flag until proven otherwise.

Board pearl: Ramsay Hunt syndrome = zoster of geniculate ganglion → ipsilateral facial palsy + ear vesicles + hearing loss/vertigo. Treat with antivirals plus corticosteroids and refer to ENT urgently.

Physical Exam Findings

— Polymorphic rash: simultaneous macules, papules, clear "dewdrop on rose petal" vesicles, pustules, and crusts in the same body region

— Centripetal distribution: denser on trunk/face than extremities

— Mucosal ulcers on palate, tonsils, conjunctiva

— Excoriations from scratching → bacterial superinfection risk (look for honey-crusts, expanding erythema, fluctuance)

— Check for cerebellar signs (ataxia), respiratory distress (varicella pneumonia), and purpura fulminans (DIC-associated)

— Unilateral grouped vesicles on erythematous base in one dermatome, sharply stopping at midline

— Lesions all in the same stage of evolution within a given crop

— Regional lymphadenopathy common

— Hutchinson sign: vesicles on tip/side of nose → nasociliary branch of V1 → predicts ocular involvement in herpes zoster ophthalmicus (HZO); urgent ophthalmology referral

— Cranial nerve exam in facial/head zoster: assess CN VII (Ramsay Hunt), CN V (corneal sensation), CN VIII (hearing)

— Healed/hypopigmented or scarred dermatomal skin

— Allodynia (light touch → pain), hyperalgesia, dysesthesia, sometimes sensory loss in the same dermatome

— Disseminated rash (>20 lesions outside primary dermatome) → consider IV acyclovir, isolation

— Tachypnea, hypoxia in adult varicella → varicella pneumonia

— Altered mentation, ataxia, focal deficits → VZV encephalitis or vasculopathy/stroke

— Eye pain, decreased vision, photophobia → keratitis, uveitis, acute retinal necrosis

Primary varicella exam:

Zoster exam:

PHN exam:

Red flag findings requiring escalation:

CCS pearl: On a CCS case of zoster, order an eye exam if V1 distribution, and document Hutchinson sign evaluation. Missing ophthalmology consult in HZO is a classic scoring trap.

Board pearl: Dermatomal vesicles that cross the midline or involve ≥3 non-contiguous dermatomes = disseminated zoster → treat as immunocompromised even if no known immune defect, and search for occult malignancy/HIV.

Diagnostic Workup — Initial Evaluation

— Atypical rash (no clear dermatome, no vesicles, prolonged course)

— Immunocompromised host with disseminated disease

— Suspected CNS involvement (encephalitis, meningitis, vasculopathy)

— Pregnant patient exposed to varicella with unknown immunity

— Healthcare worker, school, or outbreak setting requiring public health confirmation

— VZV PCR from vesicle fluid, crust, or swab of de-roofed lesion — most sensitive and specific; differentiates wild-type vs vaccine strain

— CSF VZV PCR for suspected meningoencephalitis or myelitis

— Plasma VZV PCR for disseminated disease monitoring in immunocompromised

— Direct fluorescent antibody (DFA): rapid, sensitive; distinguishes VZV from HSV, but less available

— Tzanck smear: multinucleated giant cells — cheap but cannot distinguish HSV from VZV; rarely used now

— Viral culture: slow (5–7 days), low sensitivity; mostly obsolete

— Serology (IgG): useful for immunity screening (pregnancy, healthcare workers, pre-vaccine) but not for acute diagnosis (IgM is unreliable)

— CBC, LFTs, BMP in severe/disseminated disease

— CXR if cough, dyspnea, hypoxia → diffuse nodular/reticular infiltrates suggest varicella pneumonia

— HIV test in any zoster patient <50 or with recurrent/disseminated disease

Diagnosis is overwhelmingly clinical for both varicella and zoster in typical presentations; testing is reserved for atypical, severe, immunocompromised, or public health–relevant cases.

When to test:

Preferred test: PCR

Other tests:

Adjunctive labs as indicated:

Key distinction: PCR > DFA > culture for sensitivity. If you can only order one test on a vignette, pick PCR of vesicle fluid.

Board pearl: A pregnant patient with uncertain varicella history and a known exposure → check VZV IgG immediately. If negative and within 10 days of exposure, give VariZIG (VZIG) for passive immunization — this is a Step 3 favorite preventive scenario.

Diagnostic Workup — Advanced and Confirmatory Studies

— Lumbar puncture: lymphocytic pleocytosis, elevated protein, normal glucose

— CSF VZV PCR (acute) and CSF VZV IgG with serum:CSF ratio (subacute/chronic vasculopathy — PCR may be negative by then)

— MRI brain with contrast: ischemic strokes at gray-white junction (VZV vasculopathy), or temporal/brainstem encephalitis pattern

— MRA or conventional angiography if vasculopathy suspected → beading/stenosis of large and small vessels

— Slit-lamp exam with fluorescein staining: pseudodendrites (mucous plaques, no terminal bulbs — vs true HSV dendrites)

— Intraocular pressure, dilated fundus exam for retinitis

— If decreased vision or floaters: evaluate for acute retinal necrosis (ARN) — peripheral white retinal lesions, vitritis, vasculitis

— Quantitative plasma VZV PCR to track viral load

— LFTs, lipase, CXR/CT chest, abdominal imaging if hepatitis, pancreatitis, or pneumonitis suspected

— Ophthalmology and neurology consults early

— Largely clinical; consider quantitative sensory testing or referral to pain specialty if refractory

— Rule out other causes of dermatomal pain: radiculopathy (MRI spine if motor deficit), shingles recurrence (re-examine skin), malignancy invading nerve root

— Healthcare workers, students, pregnant patients, pre-transplant: VZV IgG serology is the standard documentation of immunity (along with vaccination records or provider-diagnosed prior disease)

Suspected VZV CNS disease:

Herpes zoster ophthalmicus (HZO):

Disseminated/visceral zoster (immunocompromised):

Postherpetic neuralgia evaluation:

Immunity confirmation in special settings:

Step 3 management: A patient with unexplained ischemic stroke 1–3 months after zoster — order MRI/MRA + CSF VZV PCR and antibodies. VZV vasculopathy is treated with IV acyclovir + corticosteroids, a high-yield delayed complication.

Board pearl: Pseudodendrites (HZO) lack terminal bulbs; true HSV dendrites have them — a slit-lamp distinction tested on Step 3 ophtho vignettes.

Risk Stratification and First-Line Management Logic

— Healthy child <12 years: supportive care only (acetaminophen, antihistamines, calamine, oatmeal baths, nail trimming). Avoid aspirin (Reye syndrome) and avoid NSAIDs (associated with necrotizing soft tissue infections in varicella)

— Healthy adolescent ≥12, adult, or unvaccinated: oral acyclovir within 24 hours of rash onset shortens course

— Pregnant patient, immunocompromised, severe disease: IV acyclovir, hospitalize, isolate

— Chronic salicylate users, chronic lung/skin disease, second household case (often more severe): treat with oral antivirals

— All adults ≥50 with zoster, all immunocompromised, all ophthalmic/otic zoster, all with severe pain or disseminated disease → treat

— Antivirals most effective within 72 hours of rash onset; still consider beyond 72 hours if new vesicles are still forming, in immunocompromised, or with complications

— Young immunocompetent adult with mild truncal zoster and rash >72 hours, no new lesions: antivirals optional but commonly given

— Disseminated zoster, visceral involvement, ophthalmic with sight threat, CNS disease, severely immunocompromised

— High risk: age >60, severe acute pain (>5/10), prodromal pain, ophthalmic involvement, large rash area, immunocompromise

— Antivirals reduce duration of acute pain and may modestly reduce PHN; adequate acute pain control is a key prevention strategy

— Varicella: airborne + contact isolation until all lesions crusted

— Localized zoster in immunocompetent host: contact (standard) precautions, cover lesions

— Disseminated zoster or zoster in immunocompromised: airborne + contact

Primary varicella — management triage:

Zoster — who needs antivirals:

Indications for IV acyclovir (zoster):

PHN risk stratification at initial visit:

Isolation:

CCS pearl: On a CCS case of zoster in a 70-year-old, the highest-value early orders are valacyclovir, scheduled acetaminophen + gabapentin, ophthalmology consult if V1, and Shingrix counseling for after the episode resolves (vaccination 6–12 months after acute zoster).

Pharmacotherapy — First-Line Antiviral Regimens

— Valacyclovir 1 g PO TID × 7 days — preferred for adherence (better bioavailability)

— Famciclovir 500 mg PO TID × 7 days — alternative

— Acyclovir 800 mg PO 5×/day × 7 days — cheap but cumbersome dosing

— Acyclovir 20 mg/kg (max 800 mg) PO QID × 5 days for adolescents/adults

— Valacyclovir 20 mg/kg (max 1 g) PO TID × 5 days — option in children ≥2

— Acyclovir 10 mg/kg IV q8h (15 mg/kg q8h for VZV encephalitis) for disseminated disease, severe immunocompromise, ophthalmic with sight-threatening complications, visceral involvement, CNS disease

— Duration 7–14 days depending on syndrome; transition to oral once stable and improving

— Step 1: scheduled acetaminophen ± NSAIDs (NSAIDs OK in zoster, unlike varicella)

— Step 2: gabapentin titrated to 300–600 mg TID or pregabalin 75–150 mg BID — start early, reduces acute pain and may reduce PHN

— Step 3: short course opioids for severe breakthrough pain; tramadol in elderly with caution

— Topical: lidocaine 5% patch once lesions are crusted (not on open vesicles)

— Not routine for uncomplicated zoster — do not reduce PHN incidence

— Reasonable adjunct (with antivirals) for Ramsay Hunt and severe HZO to reduce acute inflammation/disability; avoid in diabetes, immunocompromise without infectious disease input

— Post-exposure prophylaxis for susceptible pregnant women, neonates (mother with varicella 5 days before to 2 days after delivery), immunocompromised, preterm infants

— Give within 10 days of exposure (ideally ≤96 hours)

Oral antivirals (zoster, immunocompetent adult ≥50, within 72 hours):

Oral antivirals (primary varicella):

IV antivirals:

Acute pain control (multimodal, start at first visit):

Corticosteroids:

VariZIG (varicella zoster immune globulin):

Board pearl: Steroids alone (without antivirals) in zoster = wrong answer. Steroids do not prevent PHN; treat PHN risk with early antivirals + aggressive acute pain control + gabapentinoids.

Expanded Pharmacology — PHN and Refractory Pain

— Gabapentin: start 100–300 mg qHS, titrate to 1800–3600 mg/day divided TID; sedation, dizziness, edema

— Pregabalin: start 75 mg BID, titrate to 300–600 mg/day; faster titration, similar efficacy, schedule V controlled substance

— TCAs (nortriptyline preferred over amitriptyline in elderly): start 10–25 mg qHS, titrate to 75–150 mg; monitor for anticholinergic effects, orthostasis, QT prolongation — get baseline ECG in age >65

— Topical lidocaine 5% patch: up to 3 patches for 12 hours/day; minimal systemic absorption — excellent first choice in frail elderly

— Topical capsaicin 8% patch (Qutenza): single 60-minute application in clinic; transient burning; requires specialist application

— Duloxetine 30–60 mg/day if comorbid depression or other neuropathic pain

— Tramadol for breakthrough — caution serotonergic interactions

— Opioids: generally avoided long-term; reserve for refractory cases with pain specialist

— Refer to pain medicine: consider intercostal nerve blocks, epidural steroid injections, spinal cord stimulation in select cases

— Evidence for sympathetic blocks and intrathecal therapies is limited but available at specialty centers

— Gabapentin/pregabalin + opioids → CNS depression, respiratory depression risk (FDA warning); counsel patients and avoid in OSA/COPD if possible

— TCAs + SSRIs → serotonin syndrome risk

— Valacyclovir + nephrotoxins (NSAIDs, aminoglycosides) → AKI; ensure hydration

Postherpetic neuralgia first-line agents (any of these can be started):

Second-line / adjunctive:

Refractory PHN:

Drug interactions and safety:

Vaccination as therapy? Shingrix is preventive, not therapeutic — do not give during acute zoster; wait until pain resolves and ≥6 months after acute episode (some experts say after rash resolves is sufficient, but practical timing is months later).

Step 3 management: For an 80-year-old with PHN and mild dementia, start lidocaine 5% patch first rather than gabapentin or TCA — lowest risk of falls, sedation, and delirium. This frailty-aware sequencing is classic Step 3 ambulatory geriatrics.

Special Populations — Elderly and Renal/Hepatic Impairment

— Higher incidence of zoster (immune senescence), higher severity, dramatically higher PHN risk (>30% in age >80)

— More likely to present with atypical pain syndromes mistaken for cardiac, abdominal, or musculoskeletal disease prior to rash

— Higher risk of bacterial superinfection, dissemination, and post-zoster vasculopathy/stroke

— Screen for fall risk before starting gabapentinoids or TCAs

— Beers Criteria: TCAs and benzodiazepines are potentially inappropriate; prefer nortriptyline over amitriptyline if TCA needed; consider topical lidocaine first

— Acyclovir, valacyclovir, famciclovir are all renally cleared

— Valacyclovir typical adjustments: CrCl 30–49 → 1 g q12h; CrCl 10–29 → 1 g q24h; CrCl <10 → 500 mg q24h

— Acyclovir IV: reduce dose and extend interval per CrCl; maintain hydration to prevent crystal nephropathy

— Monitor for neurotoxicity: confusion, myoclonus, hallucinations, tremor — classic in elderly with CKD on unadjusted valacyclovir

— Gabapentin and pregabalin also renally cleared — adjust per CrCl

— Acyclovir/valacyclovir/famciclovir not significantly hepatically metabolized — minimal adjustment

— Avoid acetaminophen >2 g/day in cirrhosis; avoid NSAIDs (renal, bleeding risk)

— TCAs hepatically metabolized — start low

— Reconcile meds; check for QT-prolonging combinations before TCA

— Consider deprescribing anticholinergics before adding gabapentinoid

Elderly (age ≥65):

Renal impairment — antiviral dose adjustment is critical:

Hepatic impairment:

Frailty and polypharmacy:

Board pearl: Confused 78-year-old on valacyclovir 1 g TID with CrCl 25 → acyclovir neurotoxicity until proven otherwise. Hold drug, hydrate, and consider hemodialysis in severe cases — acyclovir is dialyzable.

Step 3 management: Always calculate CrCl (not just creatinine) before prescribing valacyclovir in patients >70 — Step 3 vignettes love to bury a CrCl in the labs.

Special Populations — Pregnancy, Pediatrics, and Immunocompromised

— Maternal primary varicella in pregnancy → maternal pneumonia risk ~10–20%, mortality risk

— Congenital varicella syndrome (limb hypoplasia, cicatricial skin lesions, CNS/eye anomalies): risk highest in weeks 8–20 (~2%)

— Neonatal varicella: mother develops rash 5 days before to 2 days after delivery → severe disseminated neonatal disease, mortality up to 30% untreated

— Management:

— Susceptible pregnant patient exposed → VariZIG within 10 days (best ≤96 h); test IgG first if time allows

— Active maternal varicella → oral acyclovir if mild, IV acyclovir if severe/pneumonia

— Live varicella vaccine and Shingrix are contraindicated in pregnancy; vaccinate postpartum

— Universal varicella vaccine at 12–15 months and 4–6 years

— Otherwise healthy children with varicella: supportive care; antivirals reserved for older adolescents, second household case, chronic conditions, immunocompromise

— Avoid aspirin (Reye syndrome) and avoid ibuprofen if possible (necrotizing fasciitis association)

— Zoster in children is rare; if recurrent, evaluate for immunodeficiency

— Higher risk of dissemination, visceral involvement, CNS disease, prolonged shedding, antiviral resistance

— Treat early with IV acyclovir for moderate–severe disease; oral valacyclovir for mild cutaneous in selected stable patients

— Foscarnet for acyclovir-resistant VZV (TK-deficient strains, common in advanced HIV)

— Live varicella vaccine contraindicated; Shingrix (recombinant, non-live) is preferred and safe

— Susceptible workers exposed → furlough days 8–21 post-exposure (28 if VariZIG given)

Pregnancy:

Pediatrics:

Immunocompromised (HIV, transplant, chemo, biologics, high-dose steroids):

Healthcare workers and household contacts:

Board pearl: Neonate born to mother with rash onset day −4 to +2 around delivery → give VariZIG to the neonate immediately, regardless of maternal treatment. This is the highest-yield neonatal zoster question.

Complications and Adverse Outcomes

— Bacterial superinfection (Staph aureus, Group A Strep): impetigo, cellulitis, abscess, necrotizing fasciitis, toxic shock, sepsis — leading cause of varicella hospitalization in children

— Varicella pneumonia: primarily adults, smokers, pregnant; presents days 3–5 with cough, dyspnea, hypoxia; diffuse nodular infiltrates; mortality up to 10–30%

— Cerebellar ataxia: post-infectious, typically children, self-limited

— Encephalitis: rare, more severe; can occur in adults

— Hepatitis, thrombocytopenia, DIC, purpura fulminans

— Reye syndrome if aspirin used

— Postherpetic neuralgia (PHN) — most common; up to 30% in age >80

— Herpes zoster ophthalmicus (HZO): keratitis, uveitis, glaucoma, acute retinal necrosis, optic neuritis, permanent vision loss

— Ramsay Hunt syndrome: facial palsy + ear vesicles + vestibulocochlear dysfunction

— VZV vasculopathy: stroke risk increased ~30% for up to 1 year after zoster; risk ~4× in first weeks, especially HZO

— Myelitis, encephalitis, meningitis, cerebellitis

— Disseminated cutaneous + visceral zoster in immunocompromised: pneumonitis, hepatitis, pancreatitis

— Bacterial superinfection of vesicles

— Motor zoster: segmental weakness in the affected myotome (~3–5%)

— Bladder/bowel dysfunction with sacral zoster

— Sleep disruption, depression, anxiety, social isolation, decreased function

— Opioid exposure and dependence risk if not managed with neuropathic-pain-first algorithm

Primary varicella complications:

Herpes zoster complications:

PHN consequences:

Key distinction: Stroke shortly after zoster is not coincidence — Step 3 may show a 70-year-old with HZO 6 weeks ago and a new MCA stroke. Diagnosis: VZV vasculopathy → IV acyclovir + steroids, hold on stenting until vasculopathy treated.

Board pearl: Necrotizing fasciitis in a child with varicella → emergent surgical debridement + broad-spectrum antibiotics + IV acyclovir. NSAID use is a classic risk-amplifying detail in the stem.

When to Escalate Care — Inpatient, ICU, and Consults

— Varicella pneumonia (any adult with cough/dyspnea/hypoxia and primary varicella)

— Disseminated zoster (>20 lesions outside primary dermatome, or ≥3 dermatomes)

— Visceral involvement: hepatitis, pancreatitis, pneumonitis

— CNS disease: encephalitis, myelitis, meningitis, vasculopathy with stroke

— Severe immunocompromise with new zoster (transplant, induction chemo, advanced HIV)

— Neonatal varicella or maternal peripartum varicella

— Bacterial superinfection requiring IV antibiotics or surgical drainage

— Inability to tolerate PO, dehydration, AKI from valacyclovir

— Respiratory failure from varicella pneumonia

— Septic shock from bacterial superinfection

— Status epilepticus, depressed mental status from VZV encephalitis

— Hemodynamic instability, DIC, purpura fulminans

— Ophthalmology (same day): any V1 zoster, Hutchinson sign, eye pain, visual change

— ENT: Ramsay Hunt syndrome — facial nerve and hearing assessment

— Neurology: suspected vasculopathy, encephalitis, myelitis, persistent post-zoster motor weakness

— Infectious disease: disseminated disease, immunocompromised host, suspected antiviral resistance, pregnancy with complications

— Dermatology: atypical rash, diagnostic uncertainty

— Pain medicine: refractory PHN, opioid sparing strategy

— Maternal-fetal medicine: pregnant patient with active varicella or significant exposure

— Varicella, disseminated zoster, immunocompromised zoster → airborne + contact, negative-pressure room

— Localized zoster, immunocompetent → contact precautions, cover lesions

Admit for inpatient management:

ICU triggers:

Specialty consults:

Isolation orders on admission:

CCS pearl: On a CCS case of HZO admission, immediate orders should be IV/oral valacyclovir, ophthalmology consult, isolation precautions, IV fluids, scheduled analgesia, and gabapentin initiation — clustering these orders early scores points.

Step 3 management: The threshold to start IV acyclovir is low whenever there is uncertainty in an immunocompromised host — empiric treatment is preferred over delayed PCR results.

Key Differentials — Same-Category (Viral/Vesicular) Causes

— HSV-1: orolabial; HSV-2: genital; both can cause cutaneous and disseminated disease

— Vesicles grouped on erythematous base, non-dermatomal, recurrent at same site

— Eczema herpeticum: disseminated HSV in atopic dermatitis — punched-out monomorphic erosions

— Treat with acyclovir/valacyclovir/famciclovir (different doses than VZV)

— Distinguish via PCR or DFA when uncertain (Tzanck cannot)

— Children, oral ulcers + vesicles on palms, soles, buttocks; mild systemic illness; supportive care

— Lesions all in the same stage (unlike varicella), centrifugal (heavier on face/extremities than trunk), deep umbilicated; alert public health immediately

— Lesions often all in same stage, painful, sometimes anogenital; PCR confirms; treat with tecovirimat in severe cases

— Both can look polymorphic and widespread; key is dermatomal anchor lesions plus dissemination = zoster; no dermatomal pattern + truly polymorphic = primary varicella

— Especially sacral or lumbar; recurrent in same dermatome over months/years — PCR distinguishes

Herpes simplex virus (HSV):

Hand-foot-mouth disease (coxsackievirus A16, enterovirus 71):

Eczema vaccinatum (smallpox vaccine): rare today; consider in military/lab contexts

Disseminated CMV in immunocompromised: typically not vesicular but can mimic disseminated viral disease

Smallpox (variola) — historical but bioterrorism consideration:

Monkeypox (mpox):

Disseminated zoster vs varicella:

Recurrent dermatomal HSV (zosteriform HSV):

Key distinction: HSV recurs in the same spot repeatedly; zoster typically does not recur in the same dermatome more than once. Recurrent "shingles" in the same dermatome = check PCR — likely HSV.

Board pearl: Vesicles on the buttocks or sacrum in a young adult with frequent recurrences → sacral HSV-2, not zoster. Screen for and treat genital herpes; counsel on transmission.

Key Differentials — Other-Category Causes

— Acute coronary syndrome / MI: left T1–T5 dermatomal pain — get ECG and troponin if cardiac risk; do not anchor on "shingles" until vesicles appear

— Cholecystitis / biliary colic: right upper quadrant T7–T9 dermatomal pain

— Renal colic: T10–L1 flank pain

— Appendicitis: T10 periumbilical pain

— Pleurisy/PE: thoracic dermatomal pain

— Radiculopathy from disc disease: dermatomal but typically with mechanical features and no rash

— Trigeminal neuralgia: lancinating V2/V3 pain without rash

— Linear streaks of vesicles, intense pruritus, history of exposure, crosses midline and not dermatomal

— Honey-crusted or flaccid bullae; positive Nikolsky in SSSS

— Elderly, tense bullae on flexural surfaces, intensely pruritic, non-dermatomal

— Grouped pruritic vesicles on extensor surfaces (elbows, knees, buttocks); celiac disease association

— Cervical or thoracic radiculopathy (MRI if motor signs)

— Diabetic truncal radiculoneuropathy

— Intercostal neuralgia from rib fracture

— Tumor invasion of nerve root (lung apex Pancoast tumor mimicking T1–T2 zoster pain)

Pre-rash zoster pain mimics (the 48–72 hour diagnostic window):

Contact dermatitis (poison ivy, nickel):

Bullous impetigo / staphylococcal scalded skin syndrome:

Bullous pemphigoid:

Dermatitis herpetiformis:

Insect bites, scabies: clustered pruritic papules/vesicles in exposed areas; burrows in scabies

PHN differentials:

Board pearl: Persistent unilateral dermatomal pain without rash for >2 weeks → consider zoster sine herpete vs malignant nerve infiltration — image and obtain neurology input. Step 3 may test "shingles without rash" as a diagnostic challenge.

Step 3 management: A 60-year-old with left T4 burning pain and no rash for 72 hours, normal ECG/troponin → re-examine skin daily; vesicles often emerge within 3–4 days and confirm zoster.

Secondary Prevention and Long-Term Plan

— 2-dose series IM, 2–6 months apart

— Indications: all adults ≥50, and immunocompromised adults ≥19 (per ACIP)

— Efficacy: >90% reduction in zoster and PHN in immunocompetent ≥50; ~68–91% in immunocompromised

— Indicated even if:

— Prior zoster episode (wait until acute episode resolves; commonly 6–12 months after)

— Prior Zostavax (give Shingrix at least 2 months later)

— Unknown varicella history (most US adults are seropositive; do not need serology)

— Common reactogenicity: injection-site pain, myalgia, fatigue — counsel patients

— Safe in immunocompromised (non-live)

— Children: 12–15 months and 4–6 years

— Susceptible adolescents/adults: 2 doses 4–8 weeks apart

— Contraindicated: pregnancy, severe immunocompromise, anaphylaxis to neomycin/gelatin

— Post-exposure prophylaxis: give within 3–5 days of exposure to susceptible immunocompetent contacts

— Immunocompetent susceptible: Varivax within 5 days

— Immunocompromised, pregnant, neonate: VariZIG within 10 days (preferably ≤96 h); alternative IVIG if VariZIG unavailable

— Document the episode in the chart

— Counsel on Shingrix vaccination once recovered

— Reassess pain at every follow-up; titrate PHN therapy

— Address modifiable immune stressors: glycemic control, smoking cessation, alcohol, sleep

— In recurrent or atypical zoster: evaluate for HIV, hematologic malignancy, undisclosed immunosuppression

Shingrix (recombinant zoster vaccine, RZV):

Varivax (live varicella vaccine):

Post-exposure prophylaxis (PEP):

Long-term plan after acute zoster:

Board pearl: A 55-year-old who had zoster last year and asks about Shingrix → yes, give the 2-dose series now. Prior zoster is not a contraindication and recurrence prevention is the rationale.

Step 3 management: Pre-transplant or pre-biologic patients ≥19 → complete Shingrix before starting immunosuppression when feasible; document timing in the plan.

Follow-Up, Monitoring, and Counseling

— 48–72 hours after starting antivirals: phone or in-person check for new lesion formation, pain control, hydration, medication tolerance

— 1 week: assess rash crusting, pain trajectory, ophthalmic symptoms if V1, and need to adjust gabapentinoid dosing

— 2–4 weeks: evaluate for evolving PHN; reinforce neuropathic-pain regimen; address sleep and mood

— 3 months: if pain persists → formal PHN diagnosis; optimize therapy and consider pain specialist referral

— In patients on valacyclovir/acyclovir with CKD or dehydration: BMP within 3–7 days of starting therapy

— TCAs: baseline and follow-up ECG in older adults (QT)

— Gabapentin/pregabalin: monitor for sedation, edema, falls

— Contagion: zoster contains live virus in vesicles; can transmit varicella (not zoster) to susceptible contacts. Cover lesions, hand hygiene, avoid pregnant women, neonates, and immunocompromised until crusted

— Eye symptoms: call immediately if visual changes, eye pain, photophobia

— Red flags for escalation: spreading rash, fever, confusion, weakness, severe headache, persistent vomiting

— Vaccination: schedule Shingrix once recovered; plan 2-dose completion

— Sleep and mood: PHN drives depression and insomnia; screen with PHQ-2/PHQ-9

— Motor zoster with persistent weakness → PT/OT referral

— Ramsay Hunt with facial palsy → eye protection (artificial tears, taping at night), PT for facial reanimation, audiology follow-up

— Post-stroke from VZV vasculopathy → standard stroke rehab pathway

— Discharge summary should include antiviral course completion date, pain regimen, follow-up appointments, Shingrix plan, and isolation guidance

Acute zoster follow-up (ambulatory):

Monitoring labs:

Counseling at every visit:

Rehabilitation considerations:

Documentation and transitions:

CCS pearl: On a CCS zoster case, schedule follow-up at 1 week and 1 month, order PHQ-9 at month 1, and document Shingrix plan at the post-recovery visit — these "longitudinal" orders are Step 3 differentiators.

Ethical, Legal, and Patient Safety Considerations

— Use Vaccine Information Statements (VIS) for Shingrix and Varivax — required by federal law

— Discuss reactogenicity (significant arm pain, fatigue, myalgia 1–2 days), benefits, and the need for both doses; document refusal if applicable

— For adolescents and adults, obtain consent directly; for minors, parental consent with assent

— Varicella is a reportable disease in most US states; report confirmed and suspected cases to local public health, especially in outbreak settings (schools, daycares, healthcare facilities, long-term care)

— Healthcare facilities must verify VZV immunity in employees per OSHA/CDC guidance

— Children with varicella excluded from school until all lesions crusted

— Healthcare workers with localized zoster may work if lesions are covered, otherwise furlough; disseminated zoster → off duty until crusted

— Renal-dose valacyclovir is a high-risk discharge prescription in the elderly — confirm CrCl, reconcile dose, and arrange short-interval follow-up

— Gabapentin + opioids: counsel on respiratory depression, especially in OSA, COPD, and elderly; check state PDMP

— Avoid prescribing aspirin to children with varicella — counsel parents explicitly (Reye syndrome)

— Recurrent zoster prompting HIV testing should follow standard opt-out HIV testing consent; counsel privately, document, and follow state-specific HIV testing rules

— Live vaccine inadvertently given in pregnancy → not an indication for termination; report to manufacturer registry, counsel that no congenital varicella syndrome has been associated

— Shingrix uptake lower in patients without Medicare Part D and in minority populations; assist with pharmacy benefit navigation to reduce out-of-pocket costs

Informed consent for vaccination:

Mandatory reporting and public health:

Workplace and school exclusion:

Transitions of care safety:

Confidentiality and stigma:

Pregnancy decision-making:

Disparities and access:

Board pearl: Step 3 patient-safety vignette — elderly patient discharged on valacyclovir 1 g TID without CrCl check returns with confusion. The systems error to identify is failure of medication reconciliation and renal dose adjustment at discharge; the corrective action is pharmacist-driven discharge review.

High-Yield Associations and Rapid-Fire Clinical Facts

Varicella incubation: 10–21 days; contagious 48 h before rash until all lesions crust

Zoster antiviral window: ≤72 hours from rash onset (or while new lesions forming)

Best antiviral choice for adherence: valacyclovir 1 g TID × 7 days

Tzanck smear: shows multinucleated giant cells, cannot distinguish HSV from VZV — PCR is preferred

"Lesions in different stages" = varicella; "lesions in same stage, one dermatome" = zoster

Hutchinson sign (nose-tip vesicles) → high risk of ocular zoster → ophthalmology

Ramsay Hunt = CN VII palsy + ear vesicles + hearing/vestibular symptoms → antivirals + steroids

Pseudodendrites (HZO) lack terminal bulbs; true dendrites (HSV keratitis) have them

Aspirin + varicella → Reye syndrome (hepatic failure + encephalopathy in children)

NSAIDs in varicella → necrotizing fasciitis (Group A Strep)

VariZIG: pregnant susceptible, neonate (mother peripartum varicella), severely immunocompromised, preterm — within 10 days of exposure

Shingrix (recombinant, non-live) — adults ≥50, and immunocompromised ≥19, 2 doses 2–6 months apart, >90% efficacy

Prior zoster, prior Zostavax, unknown varicella history → still vaccinate with Shingrix

Live varicella vaccine contraindicated in pregnancy and severe immunocompromise

Recurrent zoster in same dermatome → suspect HSV (zosteriform)

Recurrent/disseminated zoster in age <50 → test for HIV and consider hematologic malignancy

PHN risk factors: age >60, severe acute pain, prodromal pain, ophthalmic involvement, immunocompromise

First-line PHN agents: gabapentin, pregabalin, TCAs (nortriptyline), lidocaine 5% patch

Steroids do not prevent PHN

Acyclovir neurotoxicity in CKD: confusion, myoclonus, hallucinations — dialyzable

VZV vasculopathy: stroke risk ~4× in first weeks, elevated up to 1 year post-zoster

Board pearl: Immunocompetent zoster patient with >20 lesions outside primary dermatome = disseminated → IV acyclovir, airborne + contact isolation, evaluate for occult immunosuppression.

Board Question Stem Patterns

Stem 1: 68-year-old with 2 days of right-sided burning chest pain, now with grouped vesicles in T5 dermatome. → Valacyclovir 1 g PO TID × 7 days, start scheduled acetaminophen + gabapentin; schedule Shingrix once recovered. Trap: choosing steroids alone or skipping antivirals because "rash already there 2 days."

Stem 2: 72-year-old with V1 zoster and a vesicle on the nose tip. → Hutchinson sign → ophthalmology referral + oral valacyclovir; admit if sight-threatening keratitis or retinitis. Trap: topical steroids without ophthalmology input.

Stem 3: 78-year-old with CrCl 22, started on valacyclovir 1 g TID, now confused with myoclonus. → Acyclovir neurotoxicity; hold drug, hydrate, consider hemodialysis. Lesson: dose-adjust antivirals in CKD.

Stem 4: 35-year-old pregnant patient (24 weeks) with chickenpox exposure, no prior history. → Check VZV IgG; if negative, VariZIG within 10 days. Trap: giving live vaccine.

Stem 5: Newborn whose mother developed varicella rash 3 days before delivery. → VariZIG to neonate immediately; consider IV acyclovir if disease develops. Trap: discharging without prophylaxis.

Stem 6: 40-year-old with recurrent multidermatomal zoster. → HIV testing; evaluate for immunodeficiency.

Stem 7: 70-year-old 3 months post-HZO presents with new MCA stroke. → VZV vasculopathy; MRI/MRA, CSF VZV PCR/antibodies; IV acyclovir + steroids.

Stem 8: 80-year-old with 4 months of burning T8 pain after healed zoster. → PHN; start lidocaine 5% patch or low-dose gabapentin. Avoid amitriptyline in frail elderly.

Stem 9: 6-year-old with varicella, given ibuprofen, now with rapidly expanding painful erythema and fever. → Necrotizing fasciitis; surgical emergency.

Stem 10: 55-year-old asks about Shingrix; had zoster 8 months ago. → Give Shingrix 2-dose series now.

Step 3 management: When the stem provides a CrCl, always use it to choose the correct valacyclovir dose — distractors will offer the standard dose.

One-Line Recap

Varicella-zoster virus causes primary varicella, latent reactivation as dermatomal zoster, and the disabling complication of postherpetic neuralgia — best managed by early antivirals within 72 hours, aggressive multimodal pain control, vigilance for ophthalmic, neurologic, and disseminated complications, and prevented by universal childhood Varivax and 2-dose Shingrix in adults ≥50 (and immunocompromised ≥19).

Acute zoster: Valacyclovir 1 g TID × 7 days within 72 hours; renally dose adjust; add scheduled acetaminophen and gabapentinoid early; ophthalmology for any V1 involvement; steroids only for Ramsay Hunt or severe HZO.

PHN: First-line gabapentin, pregabalin, nortriptyline, or topical lidocaine 5% patch (preferred in frail elderly); refer to pain medicine if refractory at 3 months.

Prevention: Shingrix 2 doses 2–6 months apart for all adults ≥50 and immunocompromised ≥19, regardless of prior zoster, prior Zostavax, or known varicella history; VariZIG within 10 days for susceptible pregnant, immunocompromised, and peripartum-exposed neonates.

Red-flag complications to never miss: Hutchinson sign with ocular zoster, Ramsay Hunt syndrome, disseminated zoster signaling occult immunosuppression, post-zoster VZV vasculopathy stroke, neonatal varicella from peripartum maternal infection, and necrotizing fasciitis in pediatric varicella with NSAID use.

Board pearl: If you see "lesions in different stages" think varicella; "same stage, one dermatome" think zoster; "burning pain >3 months after healed rash" think PHN; "stroke 1–3 months after zoster" think VZV vasculopathy — these four pattern recognitions answer the majority of Step 3 VZV vignettes.

Step 3 management: Every zoster visit should generate four orders — antiviral (dose-adjusted), multimodal analgesia, complication screen (eye/neuro/dissemination), and a Shingrix plan for after recovery — clustering these is the longitudinal ambulatory thinking Step 3 rewards.