Shingles in Children

INTRODUCTION Varicella-zoster virus (VZV) causes chickenpox and shingles. Chickenpox, the primary infection, is highly contagious, and in populations without high varicella vaccination coverage, around 80% of children are infected by the age of 10 years. Some countries, such as the United States, Latvia, Italy, and Hungary, have introduced routine national varicella vaccination programs. After the introduction of varicella immunization in the United States, a reduction in chickenpox incidence by 76–87% has been observed.1 Herpes zoster (HZ), also known as shingles, is a reactivation of a latent VZV infection. In countries with low varicella vaccination coverage, chickenpox in early childhood and immunosuppression are the main risk factors for HZ in children. However, widespread immunization may change dynamics in the prevalence of HZ. Vaccine-strain virus, introduced during immunization, is also capable of latent infection.2 Moreover, it has been debated, whether, without the booster effect of widely prevalent varicella, HZ may become more prevalent and appear in younger age groups. This review aims to describe the current epidemiology and risk factors for shingles in children. In addition, the clinical course and the management of HZ are discussed. EPIDEMIOLOGY AND RISK FACTORS HZ is a reactivation of a latent virus that resides in the nerve cells after inoculation during primary infection (chickenpox). Due to the different pathogenesis, the seasonality and epidemics that are characteristic of chickenpox, are not observed in HZ.1 The general incidence of HZ worldwide has been estimated at 3–5 cases per 1000 person-years.3 However, most of these cases occur in elderly patients. The incidence of HZ in the pediatric population is 4–7 times lower, with around 0.74 cases per 1000 person-years.4 Between the ages of 1 and 9 years, the incidence rate is around 0.4 cases per 1000 person-years and it increases to 1.06 in the group of children >10 years.4 In an American study, the incidence rate in unvaccinated children was estimated at 1.7 per 1000 person-years. Studies from Iceland and France showed incidence rates of 1.6 and 2.2, respectively.5,6 In addition, a short rise and then a fall in HZ incidence in children were observed after the introduction of routine varicella vaccination.4 The observed decline may be attributed to the immunity induced in vaccinated individuals and reduced viral circulation due to herd immunity. According to Weinmann et al4 children vaccinated against varicella had a 78–79% lower risk of HZ compared with unvaccinated counterparts during an 11-year observation period, and the incidence was even lower after 2 doses of the vaccine. However, in several of the immunized children, latent infection in the dorsal ganglia may develop. Among vaccinated children who developed HZ, the vaccine strain is responsible for around half of the cases, whereas the wild VZV strain is a causative agent in the other half.2 The vaccine strain is distinctly less neurovirulent compared with the wild type and neurologic sequels of HZ, such as meningitis and encephalitis, are uncommon.7 Rash after varicella vaccination is a risk factor for zoster in the future.8 Although the overall risk of HZ is reduced after vaccination, for vaccinated children aged 1–2 years it is slightly higher than in unvaccinated children.2,4 Correspondingly, children who develop chickenpox <1 year of age are also at higher risk of HZ.2 This phenomenon may be explained by an immature T-cell response and difficulty in containing infection in the latent phase. The male-to-female ratio among children suffering from HZ differs between studies. In the United States, a slight predomination of females has been reported, in Europe (Poland), the ratio was equal, whereas in Asia (Korea), the male-to-female ratio was 1.6:1.4,9,10 Asian and Caucasian descent is associated with a higher risk for HZ in both adults and children.11 Immunosuppressed children have a 5–6 times higher risk of HZ with a ratio of 4 cases per 1000 person-years.4 Children living with HIV have an even higher risk of HZ with an incidence rate of 10 cases per 1000 person-years.12 Some chronic diseases have been associated with a higher risk of HZ, for example, adjusted OR for asthma is 1.5–2.5.13 This may be explained, for example, by the long-term use of inhaled corticosteroids. A link between acute infections, especially those associated with lymphopenia, such as COVID-19, and HZ is suspected.14 The role of sex hormones and puberty in the reactivation of VZV has been proposed as an explanation for the increased incidence in teenagers.15 CLINICAL COURSE HZ manifests with vesicles on an erythematous basis, and it is usually limited to one, two or rarely more contiguous unilateral dermatomes. Regional lymphadenopathy, pruritus, pain, malaise and fever can occur before or simultaneously with the appearance of the rash. New lesions stop forming within 3–7 days. Although common in adults with HZ, pain occurs in less than half of the pediatric patients: it is reported by 28% of children aged less than 5 years and up to 60% of children aged 15–19.16 This symptom is uncommon in children vaccinated against varicella; in 1 study none of the vaccinated patients with HZ developed a painful rash.17 In immunocompromised children, fever is more often observed than in immunocompetent kids.10 The most common localization of lesions was thoracic dermatome (59% of immunocompetent and 32% of immunocompromised cases).10 Similar domination was shown in other studies.14 However, in children with vaccine-strain HZ, lumbar and cervical dermatomes are more commonly involved.2 The distribution of dermatome involvement by Bieńkowski et al10 is shown in Figure 1.FIGURE 1.: Dermatome involvement in immunocompetent children (outer circle) and in immunocompromised children (inner circle). The diagram was created based on the data by Bieńkowski et al.10COMPLICATIONS The hospitalization rate is established at 13%–37% of cases and immunocompetent children constitute many hospitalized patients.10,18 Hospitalization lasts longer in immunocompromised children.19 The suggested prevalence of complications is between 11 and 13%. Surprisingly, in one of the studies, immunocompetent children were more likely to develop complications, which might have been due to the preemptive antiviral therapy and early hospitalization in immunocompromised children compared with immunocompetent children.10,18,20 The most common complication, both in immunocompetent and immunocompromised children, is bacterial superinfection of the skin lesions, which constitutes around 5.2%–9.3% of all complications in immunocompetent patients and 3.8%–14.7 % in immunocompromised cases. Other complications, such as meningitis, sepsis, facial palsy, uveitis and keratitis, and postherpetic neuralgia are rare.10,18 Postherpetic neuralgia occurs more often in immunocompromised children. Disseminated HZ may be found in up to 40% of immunocompromised patients.19 Some of the more unique complications include: 1. HZ ophthalmicus (HZO)–involvement of the V1 branch of the trigeminal nerve; the incidence in adults has been estimated at around 8%; it is more common in immunocompetent children than in immunocompromised children.21 In around 50% of HZO cases, there is eye involvement with a risk of vision loss.22 HZO has also been reported in immunocompetent, vaccinated children. 2. Ramsey Hunt syndrome (RHS)–involvement of the facial nerve presenting with unilateral facial palsy, otalgia and zoster of the auricle or external auditory canal, sometimes presenting simultaneously with symptoms from the vestibulocochlear and trigeminal nerves.22 Due to the possibility of zoster sine herpete, VZV should always be considered as a cause of acute facial paralysis. 3. Laryngeal HZ–symptoms include severe throat pain and dysphagia, sometimes accompanied by fever and cervical lymphadenopathy; it is diagnosed based on the laryngoscopic examination that shows mucosal lesions with a concomitant increase in VZV serum antibody titers or positive polymerase chain reaction (PCR) of the mucosal lesion23,24; possible complications include chronic persisting cough.25 Laryngeal HZ should be considered in a patient with characteristic symptoms and poor response to antibiotics.24 DIAGNOSIS Diagnosis of HZ usually relies on clinical presentation and does not involve additional testing. Anti-VZV antibody testing is recommended only if the patient's history of varicella/varicella vaccination is unknown. DNA analysis using the PCR of fluid from vesicles may help to determine the etiology in atypical cases in VZV seropositive patients. PCR may also be used to distinguish between vaccine and wild-type strains, although it is not routinely available. TREATMENT Acyclovir, famciclovir, valaciclovir and brivudine limit the appearance of new lesions and accelerate healing. Acyclovir and valacyclovir reduced the time to cessation of new vesicle formation by about 1.5 days and the time to 50% lesion healing by about 2.5 days.26 Due to the worse bioavailability, acyclovir requires more frequent dosing compared with valacyclovir. The choice of the drug depends on the healthcare professional's experience, local drug availability, and other factors, such as chronic diseases (e.g., nephrotoxic drugs should be avoided in children suffering from renal problems) or medications. Antiviral treatment should be considered in all children presenting within 72 hours of onset of the disease. Patients presenting after 72 hours may still benefit from the antiviral treatment and it may be implemented in the following cases: 1. involvement of the face or neck, 2. complications, 3. severe rash, 4. severe atopic dermatitis or eczema. The recommended dose of acyclovir is 60–80 mg/kg per day in 4 doses (max. 800 mg per dose) orally. Immunosuppressed children or those with serious complications, such as involvement of the eye, require hospitalization and intravenous administration of the drug.27 Intravenous acyclovir every 8 hours is recommended with 500 mg/m2 or 10 mg/kg per dose. The therapy should last 7 days or should be stopped 2 days after no new lesions have formed. The most common side effects include headache and nausea/vomiting. The dose should be adjusted in the case of renal impairment, and administration with other potentially nephrotoxic drugs should be carefully considered.12 In case of significant improvement after intravenous therapy, a switch to oral therapy may be considered. Long-term valacyclovir suppressive treatment as secondary prophylaxis might be beneficial in HZO, but no consensus on the duration of this prophylaxis exists.28 Hopefully, the ongoing Zoster Eye Disease study in adults will shed some light on this topic. No consensus exists on the chronic use of valacyclovir for the prevention of the recurrent HZ. WORK-UP: WHEN TO SEARCH FOR IMMUNODEFICIENCIES AND NEOPLASMS? A comprehensive history of a child with HZ seems to be sufficient for selecting patients at risk of malignancy or immune deficiencies and broad investigations are not indicated.5 Worth mentioning is also the fact that infantile HZ may develop in otherwise healthy infants who were exposed to varicella antenatally or in the first months of life.29 However, in an Indian study of 26 children with HZ with no previous medical history no symptoms or signs of immunodeficiency, HIV infection was diagnosed in 4 patients.30 In world regions with a higher incidence of HIV infection in the general population, with poor general medical access or lack of regular medical appointments, testing for HIV infection in children with HZ should be considered. As a first-line testing for immunodeficiencies, we recommend: 1. complete blood count, 2. peripheral blood smear, 3. quantitative serum IgG, IgM and IgA levels, 4. HIV antigen and antibodies combined testing, 5. assessment of populations of lymphocytes. Although older studies debated the correlation between HZ and the risk of developing neoplasm in adults, newer papers show only an elevated risk of hematologic cancer with a hazard ratio between 1.15 (for lymphoma) and 1.63 (for multiple myeloma).31 The number of such studies in children is limited. In the study by Petursson et al5 children were followed for a maximum of 6 years after the HZ diagnosis, and no correlation between HZ and the risk of neoplasm was found.5 The choice of laboratory and imaging tests aimed at searching for neoplasms will depend on the symptoms found in the medical history and physical examination and may include, for example, chest radiograph, abdominal ultrasonography, complete blood count, erythrocyte sedimentation rate, C-reactive protein, liver and kidney function test, uric acid, lactate dehydrogenase and ions (sodium, potassium, calcium, magnesium, and phosphorus) levels. CONCLUSION Countries where the varicella vaccine was introduced have witnessed a fall in the incidence of pediatric HZ. HZ in children differs compared with adults, with usually milder clinical presentation and relatively rare complications. Early diagnosis and prompt treatment are recommended to alleviate symptoms and prevent potential complications.