Children's Infections: Chickenpox, Herpes Zoster & Cytomegalovirus

PART I — VARICELLA (CHICKENPOX) AND HERPES ZOSTER

Shared Etiology

I.A. VARICELLA (Chickenpox)

Epidemiology

• Highly contagious; distributed worldwide
• In temperate climates without vaccination, varicella is endemic with seasonal peaks in winter and spring, with periodic epidemics
• In Europe and North America, >90% of people acquire varicella before age 15 in the absence of vaccination
• Transmission occurs via:
  • Respiratory droplets/aerosols (most important — airborne transmission)
  • Direct contact with vesicular fluid
• Incubation period: 10–21 days (typically 14–16 days)
• Infectious from 1–2 days before the rash appears until all lesions have crusted over
• Secondary household attack rate among susceptible contacts: ~60–90%
• Outbreaks common in schools and daycare centers
• Live-attenuated Oka VZV vaccine has virtually eliminated varicella in countries where deployed

Pathogenesis & Morphogenesis

1. Primary inoculation: VZV enters via the upper respiratory tract mucosa
2. First viremia: Virus replicates in regional lymph nodes → seeds the reticuloendothelial system (liver, spleen)
3. Second viremia (~day 11–13): Major viremic phase disseminates virus hematogenously to skin and mucous membranes, producing the exanthem
4. The scattered distribution of lesions reflects viremic seeding (not neural spread)
5. At the skin: VZV infects epidermal cells → intranuclear inclusions (Cowdry type A), multinucleated giant cells, intraepidermal vesicle formation by ballooning degeneration of keratinocytes; vesicles contain serous fluid with inflammatory cells
6. Latency establishment: After resolution of primary infection, VZV travels retrogradely up sensory axons and establishes latent infection in dorsal root ganglia and cranial nerve ganglia (specifically within neurons, not satellite cells), where it persists for life

Clinical Features

• 2–3 days of mild fever, chills, malaise, headache, anorexia, backache, dry cough

• Begins on face/scalp → rapid centrifugal spread to trunk (denser on back between shoulder blades) → relative sparing of extremities
• Lesions evolve rapidly (within 12 hours): macule → papule → vesicle → pustule → crust
• Classic description: vesicle appears as a "dew drop on a rose petal" — thin-walled, 2–3 mm, elliptical, clear vesicle on an erythematous base
• Hallmark: Lesions in all stages simultaneously present in any given area (due to crops)
• Vesicles become umbilicated pustules then crust; crusts fall in 1–3 weeks
• Oral/mucosal lesions (enanthem) common — shallow painful ulcers on the palate, buccal mucosa

Complications

Outcomes

• In immunocompetent children: self-limited; full recovery in 1–2 weeks
• In adults, immunocompromised, neonates, pregnant women: higher morbidity and mortality
• Lifelong immunity follows natural infection (but latent VZV persists in ganglia)

I.B. HERPES ZOSTER (Shingles)

Etiology & Pathogenesis (Reactivation)

• Herpes zoster results from reactivation of latent VZV in sensory/autonomic ganglia following a prior episode of varicella (which may have been subclinical)
• Trigger: decline in VZV-specific cell-mediated immunity — occurring with aging, immunosuppression (HIV, malignancy, corticosteroids, organ transplant), psychological stress
• Reactivated VZV travels antegradely down sensory nerve axons to the skin of the corresponding dermatome → circumscribed dermatomal eruption
• Lesion distribution is neural (not hematogenous) → explains clustering in a single dermatome (vs. scattered lesions of varicella)
• Most common ganglia involved: thoracic (50–60%), trigeminal, cervical, lumbosacral

Epidemiology

• Most common in older adults (incidence rises sharply after age 50) and immunocompromised individuals
• Incidence of PHN: 13% in ages 60–64, rising to 21% in ages 80–84
• A meta-analysis of 18 cohort studies found PHN incidence increased by 1.22–3.11% per 10-year age increase
• Less contagious than varicella; ~1/3 the secondary attack rate; requires direct contact with open vesicles (or airborne in disseminated zoster)
• Susceptible contacts exposed to herpes zoster can develop primary varicella (not zoster)

Clinical Features

• Localized burning, aching, stabbing pain in the affected dermatome; may mimic pleurisy, cardiac disease, appendicitis before rash appears
• Hyperesthesia, allodynia, dysesthesia, pruritus

• Unilateral, dermatomal cluster of erythematous macules and papules → vesicles (closely grouped, on confluent erythematous base — contrast with varicella's scattered lesions)
• Vesicles: 3–5 days, then pustulate and crust over in 7–10 days; full resolution in 2–4 weeks
• Does not cross midline in immunocompetent patients

• Ophthalmic zoster (V1 branch of CN V): Risk of keratitis, uveitis, corneal scarring; Hutchinson sign (vesicles on tip/side of nose = nasociliary branch involvement) predicts eye involvement
• Ramsay Hunt syndrome: VZV reactivation in geniculate ganglion of CN VII → painful auricular vesicles + ipsilateral facial palsy + sensorineural hearing loss; ± vertigo
• Disseminated zoster: >20 vesicles outside primary/adjacent dermatomes; occurs in immunocompromised; risk of visceral involvement (pneumonia, hepatitis, encephalitis)

Complications

Morphology of VZV Lesions (Histology)

• Intraepidermal vesicles by ballooning degeneration and reticular degeneration of keratinocytes
• Cowdry type A intranuclear inclusions (eosinophilic inclusions surrounded by a halo) in epidermal cells and neurons
• Multinucleated giant cells (syncytia) — characteristic of herpesviruses
• In dorsal root ganglia: lymphocytic infiltration, neuronal necrosis, hemorrhage

PART II — CYTOMEGALOVIRUS (CMV) / CYTOMEGALY

Etiology

• Human CMV (Human Herpesvirus 5, HHV-5) — member of Herpesviridae, beta-herpesvirus subfamily (Betaherpesvirinae), genus Cytomegalovirus
• Largest human herpesvirus genome: double-stranded DNA, 196,000–240,000 bp, encoding ≥166 proteins
• Characterized by slow replication cycle ("cytomegalovirus" = cell-enlarging virus)
• Highly species-specific: only human CMV infects humans

Epidemiology

• Ubiquitous; widespread genetic diversity among strains
• No seasonal predilection
• Three peaks of acquisition:
  1. Early childhood (especially daycare/childcare settings)
  2. Adolescence
  3. Child-bearing years

• Horizontal: Direct person-to-person contact with virus-containing body fluids — saliva, urine, genital secretions, tears; sexual transmission (CMV is an STI)
• Vertical:
  • Transplacental (in utero) — most important for congenital disease
  • Intrapartum (passage through infected cervix)
  • Postnatal (via breast milk — usually benign in term infants, but can cause sepsis-like syndrome in preterm infants)
• Iatrogenic: Blood transfusions, organ/stem cell transplantation
• Childcare centers: Excretion rates from urine/saliva in children age 1–3 years = 30–70%; children shed large quantities for prolonged periods and frequently transmit to parents and caregivers

• ~5 per 1,000 live births infected in utero = most common congenital viral infection in the United States
• Higher in Black newborns (9.5/1,000) than non-Hispanic white (2.7/1,000) or Hispanic white infants (3.0/1,000)

• 75% of cases in U.S. born to women with nonprimary (reactivation/reinfection) infection

• First-trimester maternal primary infection → most severe fetal sequelae

Pathogenesis & Morphogenesis

1. Primary infection via mucosal surfaces → local replication → viremia (cell-associated, within monocytes/lymphocytes)
2. Viral dissemination to multiple organs: lungs, liver, CNS, retina, GI tract, kidneys
3. Establishment of latency in monocytes, CD34+ progenitor cells, lymphoid tissue
4. Lifelong persistence; reactivation triggered by immunosuppression or inflammation

• Infected cells are dramatically enlarged (cytomegaly) — up to 25–35 µm in diameter
• Intranuclear inclusion: Large, round, eosinophilic inclusion surrounded by a clear halo ("owl's eye" or "cytomegalic inclusion") with marginated chromatin
• Intracytoplasmic inclusions: Multiple basophilic/amphophilic granular inclusions (PAS- and GMS-positive, representing viral aggregates in cytoplasm)
• Cells affected: epithelial cells, endothelial cells, stromal cells, macrophages, neurons

Clinical Manifestations

1. Acquired CMV Infection (Postnatal, Immunocompetent)

• Majority: Asymptomatic — especially in children
• CMV mononucleosis (adolescents/adults): Infectious mononucleosis-like syndrome — prolonged fever, mild hepatitis, lymphocytosis; heterophile antibody (monospot) NEGATIVE — this distinguishes it from EBV mononucleosis
• Pharyngitis and lymphadenopathy are less prominent than EBV mononucleosis

2. Congenital CMV Infection

• ~90% asymptomatic at birth (but still at risk of late sequelae)
• ~10% symptomatic at birth (congenital CMV disease):
  • Jaundice (direct hyperbilirubinemia)
  • Petechiae (thrombocytopenia)
  • Hepatosplenomegaly
  • Microcephaly
  • Periventricular calcifications (intracerebral; pathognomonic pattern — distinguishes from toxoplasmosis which is diffuse)
  • Retinitis
  • Growth restriction, developmental delays
  • Mortality: 3–10% of symptomatic infants (0.3–1.0% of all congenital CMV)

• CMV is the leading non-genetic cause of SNHL in children
• Accounts for ~20% of hearing loss at birth and ~25% of all hearing loss at age 4
• Occurs in up to 50% of symptomatic congenital CMV and up to 15% of asymptomatic congenital CMV
• ~40% of CMV-associated SNHL is not detectable in the first month of life (late-onset)
• ~50% show progressive deterioration over time

3. Immunocompromised Hosts (HIV, Transplant, Malignancy)

• CMV retinitis: Most common serious manifestation in HIV/AIDS; "pizza pie" fundus appearance; can cause blindness
• CMV pneumonitis: Interstitial pattern; serious in hematopoietic stem cell transplant (HSCT) recipients
• CMV colitis: Bloody diarrhea, pain, ulceration
• CMV encephalitis/meningoencephalitis
• CMV syndrome: Fever, thrombocytopenia, leukopenia, mild hepatitis

4. Perinatal/Postnatal CMV in Preterm Infants

Complications & Outcomes

Morphological Summary of Organ Pathology

Comparative Summary Table

• Fitzpatrick's Dermatology, Chapters on Varicella and Herpes Zoster
• Red Book 2021: Report of the Committee on Infectious Diseases (AAP), CMV chapter
• Harrison's Principles of Internal Medicine, 22nd ed., CMV chapter