Varicella-zoster virus (VZV) causes primary varicella (chickenpox) and herpes zoster (HZ, shingles). Primary varicella replicates within T-lymphocytes and epithelial cells, causing a widespread highly contagious vesicular eruption in children, typically lasting 5–7 days.1 The virus then enters epidermal nerve endings and travels in a retrograde fashion via sensory nerves to the dorsal root ganglion, establishing latency for years. VZV can also establish latency in neuronal cell bodies via transient viremia.1
HZ is a reactivation of latent VZV, usually occurring as cellular immunity wanes with advancing age or immunocompromised status. Herpes zoster ophthalmicus (HZO) involving the ophthalmic division of the fifth cranial nerve requires urgent evaluation by ophthalmology to assess for internal and external ocular pathology. HZO can cause corneal scaring, glaucoma, diminished vision and rarely blindness. Hutchinson’s sign—the presence of vesicles on the tip or side of the nose—is a predictor of ocular involvement.2
The live-attenuated monovalent varicella vaccine has been routinely administered to children at 12 months of age in the United States since 1995, leading to a significant decline in the incidence of both primary VZV and HZ involving the wild-type virus.3 There is also a quadrivalent measles-mumps-rubella-varicella vaccine approved in 2005 for children 12 months through 12 years of age.4 The monovalent or measles-mumps-rubella-varicella vaccine is usually administered at 12–15 months of age and again at 4–6 years of age. Vaccine-strain (Oka) VZV establishes latency in the dorsal root ganglion in the same manner as wild-type VZV, and reactivation can cause vaccine-strain HZ in both immunocompromised and immunocompetent individuals.1 Rarely, the vaccine-strain also can travel by viremia, which can explain cases of HZ distant from the vaccine site.1
In countries where VZV immunization is widespread, primary varicella and HZ are rare in children. Patients who are immunocompromised, have a history of primary VZV (especially before age 1) and/or VZV exposure in utero are more likely to develop pediatric HZ.2 Pediatric HZ is rarely associated with post-herpetic neuralgia compared with adult cases.2
We present a novel case of HZO in an otherwise healthy 14-month-old male associated with vaccine-strain VZV, treated successfully with acyclovir without cutaneous or ocular sequelae. Reactivation only 11 weeks after monovalent varicella vaccine administration and ocular involvement makes this case unique. HZO, especially in the setting of familial immunoglobulin A (IgA) deficiency, prompted further immunologic workup.
History and Clinical Examination
A previously healthy 14-month-old male presented to his pediatrician with a 3-day history of a painful unilateral rash involving the right ophthalmic (V1) dermatome, consisting of eroded papules with yellow adherent crust on the upper eyelid, forehead and frontal scalp (Fig. 1). There were no intact vesicles or pustules, and Hutchinson’s sign was negative. All vital signs were normal. Associated symptoms included irritability, difficulty sleeping and decreased oral intake. He had no associated fever, chills, neurologic deficits, upper respiratory symptoms, nausea, vomiting or diarrhea.
Ophthalmology examination confirmed external HZ ocular involvement with surface disease including punctate erosions of the conjunctiva and cornea. Immediately after evaluation by ophthalmology, dermatology obtained surface swabs for herpes simplex virus (HSV) and VZV. Although HSV infection was in the differential, the clear dermatomal demarcation made VZV the most likely etiology. He was directly admitted to the hospital for intravenous antiviral treatment.
He had no history of significant rashes or serious infections. Newborn screening was negative for severe combined immunodeficiency or T cell lymphopenia. He had no close contacts with shingles or chicken pox, and no known exposure to varicella in utero or after birth. The patient was up to date on age-appropriate vaccinations and the varicella vaccine was administered to the right thigh 11 weeks before presentation. His mother had chicken pox as a child. His father, paternal uncles and paternal grandmother have selective IgA deficiency.
HSV PCR was negative. VZV PCR was positive, and the Wisconsin State Laboratory of Hygiene confirmed a positive test for the vaccine-strain.
Extensive immune testing was performed during acute illness and after recovery (14–24 months of age). CBC with differential was normal, and HIV testing was negative. Flow cytometry showed normal numbers of T cells, B cells and natural killer cells. T cell proliferation response was normal with mitogen, T cell receptor crosslinking and VZV stimulation. Natural killer cell cytotoxic activity was normal. Initially, total serum IgG was low at 302 mg/dL (ref: 475–1210 mg/dL) with both IgA (ref: 21–291 mg/dL) and IgM (ref: 41–183 mg/dL) in the normal range. Repeat testing at 18 months demonstrated a persistently low IgG level at 321 mg/dL, a slightly decreased IgM level of 40 mg/dL and a normal IgA level. At 24 months, IgG remained below the lower limit of normal with an upward trend at 421 mg/dL, and IgA and IgM decreased to 14 and 29 mg/dL, respectively. Pneumococcal, tetanus and varicella vaccine titers showed protective levels.
Treatment and Course
There was rapid improvement after 1 day of intravenous acyclovir, 30 mg/kg/day in 3 divided doses. Vital signs remained normal, and he was transitioned to oral acyclovir 250 mg 3 times daily for a total course of 7 days. He was treated with topical erythromycin for comfort and prophylaxis during healing of his ocular and corneal erosions, which resolved after 1 week. There was no cutaneous scarring or post-herpetic neuralgia.
Data from post-licensure surveillance of previously immunized patients have identified cases of both wild-type and vaccine-strain HZ in immunocompetent and immunocompromised children.5 Given the potentially serious consequences of HZ and the possible association between HZ and immunodeficiency, pediatricians must be equipped to recognize and manage this disease. Herein, we provide an overview of pediatric HZ and review the underlying immunology.
There are few reports of HZ caused by reactivation of the VZV vaccine-strain in children, typically treated with acyclovir. Whereas pediatric wild-type HZ typically involves thoracic dermatomes, vaccine-strain HZ favors the lumbar and cervical dermatomes.3 One case series describes 7 immunized immunocompetent children who presented with HZ at the varicella vaccination site on average 2 years after immunization, highlighting how the vaccine-strain infects sensory nerves around the injection site and travels to the dorsal root ganglion in a retrograde fashion.6
In a series of 22 cases of HZ in immunocompetent patients <18 years of age attributed to varicella vaccination, 6 patients developed HZ in the V1 distribution, and 5 patients had HZO.7 The mean age of developing HZ was 5.3 years, with onset 3.3 years after vaccination on average. In contrast, the patient described in this case was 14 months of age, with only an 11-week interval between immunization and development of HZO. Of the 16 cases that underwent genotype testing, the vaccine-strain virus was identified in 50% while wild-type virus was identified in the remainder. There was no history of primary VZV or exposure in utero, but a subclinical exposure to VZV cannot be ruled out. Vaccine-strain VZV transmission to contacts is extremely rare with only a few reported cases.8,9
Whereas antiviral treatment is not recommended for healthy younger children with primary VZV, the decision to use antiviral therapy should be determined by host factors and the extent of infection in children with HZ.4 Treatment is most effective the sooner it is started, ideally within 72 hours; however, mild cases may self-resolve. For this patient, we elected for intravenous treatment given the severity of his infection and ocular involvement.
Intact cellular immunity is critical for terminating VZV viremia and cutaneous replication as well as suppressing reactivation. While primary VZV infection elicits production of anti-varicella antibodies (IgG, IgM and IgA), primary varicella infections in children with untreated agammaglobulinemia, which involves the humoral branch of the immune system, are usually uncomplicated.10 Conversely, children with primary cell-mediated immunodeficiency who are infected with varicella experience a high mortality rate.10 The short interval between primary VZV infection and HZ in young children and infants with intrauterine or early postnatal varicella exposure likely results from poor induction of cell-mediated immunity.10
Genetic variants of the vaccine-strain virus may be implicated in some cases of HZ. Moodley et al11 describe a case of vaccine-strain HZ on the left lower back of an immunocompetent 3-year old who received the varicella vaccine in his right upper arm 19 months prior. The HZ location may reflect a period of viremia in which latency was established in neurons distant from the site of vaccination. Genetic sequencing of the vaccine-strain virus showed a wild-type allele rather than a vaccine-type allele within ORF0, an open reading frame with a potential role in vaccine attenuation.11
A high index of suspicion is necessary for timely diagnosis and treatment of vaccine-strain HZ. PCR testing that distinguishes between vaccine-strain and wild-type VZV is available.4 Given the overwhelming evidence-based benefits of varicella vaccination,4 the rare possibility of vaccine-strain HZ should not defer children from routine varicella immunization. An immunologic workup in children with HZ should be performed on a case-by-case basis. For our patient, the severity of his presentation, his young age and his family history prompted further workup. Although he does not have an identifiable immunodeficiency and immune testing results have been reassuring, continued monitoring is ongoing by the immunology service.
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