Varicella-Zoster Virus

Human alphaherpesvirus 3 (HHV-3), also known as varicella-zoster virus (VZV), is an enveloped, double-stranded DNA virus belonging to the family Herpesviridae that causes 2 distinct clinical conditions: varicella (chickenpox) and herpes zoster (shingles). A globally pervasive virus, VZV is 1 of 8 herpesviruses known to infect humans. It is an exclusively human pathogen without any known animal or insect vector or host.^1,2

History and Epidemiology of Varicella-Zoster Virus

Historically, VZV was thought to be harmless, and varicella was even considered a rite of passage for children, especially compared to other equally prevalent but more dangerous childhood diseases, such as smallpox and poliomyelitis. As the development of effective chemotherapy for childhood cancers, the rising number of bone marrow and organ transplants, and the increasing use of immunocompromising medications for autoimmune diseases has resulted in an increased population of immunocompromised children, the potential for serious and potentially fatal outcomes following varicella has become a significant concern.^1,3 

Prior to 1995, when the single-dose varicella vaccine was approved by the US Food and Drug Administration  (FDA), varicella was prevalent among children in the United States, with approximately 4 million cases reported annually.⁴ Between 11,000 and 13,500 hospitalizations and as many as 150 deaths were attributed to varicella annually.⁴ The introduction of a single, routine childhood dose of varicella vaccine in 1996 led to an approximate 90% decline in the incidence of varicella over the ensuing decade. In 2006, the vaccine schedule was adjusted to include a second childhood dose — with the first dose administered between the ages of 12 and 15 months, and the second dose administered between the ages of 4 and 6 years — in response to the persistence of varicella outbreaks.⁴  Since the implementation of the 2-dose varicella vaccine regimen in 2006 through 2014, the incidence of varicella declined 84.6%, most notably in children and adolescents aged 5 to 14 years.⁴

Table 1. FDA-Approved Vaccines for Varicella

			Dosage
Vaccine	Use	Administration	Adults	Children
Varivax® (Merck & Co., Inc.)	Varicella vaccine	0.5 mL via SC or IM injection	Adolescents and Adults ≥13 years: 1 dose at elected date and a second dose at least 4 weeks later.	<12 months: not established 12 months to 12 years: 1 dose. If a second dose is administered, separate by at least 3 months
ProQuad® (Merck & Co.,  Inc.)	Combined measles, mumps, rubella, and varicella vaccines	0.5 mL via SC or IM injection	Not recommended	<12 months or ≥13 year: not established ≥12 months through <13 years:  First dose at 12 to 15 months of age (or any time through 12 years of age); second dose at 4 to 6 years of age

The risk for herpes zoster is significant as approximately 99% of all adults in the United States born before 1980 are believed to have been infected with varicella-zoster virus.⁵  Approximately 1 million cases of herpes zoster are reported annually in the United States, and an estimated 33% of people will experience it in their lifetime.⁵ Herpes zoster is caused by reactivation of latent VZV. Factors contributing to the increased risk for VZV reactivation include waning cell-mediated immunity to VZV in individuals as they age, as well immunosuppression.⁶ The incidence of herpes zoster increases with age, with much of the increase beginning in adults aged 50 to 60 years. For those who live to be 85 years of age, approximately 50% will have experienced herpes zoster, with many experiencing postherpetic neuralgia, a chronic painful condition responsible for significant disability.^7-9 

Table 2. FDA-Approved Vaccine for Herpes Zoster (Shingles) in Adults

Vaccine	Use	Administration	Dosage
Shingrix® (GlaxoSmithKline)	Herpes Zoster	0.5 mL via IM injection in deltoid region of upper arm	≥50 years: 1 dose at month 0 followed by second dose given between 2 and 6 months later  Immunocompromised (≥18 years): 1 dose at month 0 followed by second dose given between 1 and 2 months later

Presentation and Diagnosis of Varicella and Herpes Zoster

Varicella is typically considered a childhood infection and presents as a mild disease in immunocompetent individuals. However, symptoms can be severe and even fatal in those who are immunocompromised. Transmission occurs via direct contact with vesicle fluid from skin lesions and close contact with aerosolized droplets.¹ The incubation period after exposure ranges from 10 to 21 days, with symptoms usually lasting between 4 and 7 days. Although individuals with varicella may experience fever and malaise 1 to 2 days prior to the onset of rash, a rash may also be the first sign of varicella, especially in younger children. The rash is generalized and often appears first on the face, chest, and back; it then spreads to the entire body. The lesions are classically present in all stages of development simultaneously. Individuals with varicella are contagious from 2 days before rash onset until all the lesions have crusted over without the appearance of any new lesions for 24 hours.²

After primary infection with VZV, the virus remains latent in the dorsal root ganglia and can reactivate later in an individual’s life to cause herpes zoster. Some individuals experience a prodromal phase that includes headache, photophobia, or malaise. The herpes zoster rash is typically painful, itchy, and tingly. It often begins with erythematous papules, progresses to vesicles, and then becomes pustular until the vesicles crust over (Figure 2). The rash classically forms along 1 or 2 adjacent dermatomes and does not cross the body’s midline. Individuals with herpes zoster can transmit the virus to individuals in close contact who have never had varicella.⁷

The diagnosis of varicella and herpes zoster is usually made clinically; however, additional diagnostic information can be useful in individuals who are immunocompromised and those who have either an atypical rash or disseminated disease without cutaneous lesions.⁷

Polymerase chain reaction (PCR) testing can confirm the presence of varicella-zoster virus. This test has the highest sensitivity, specificity, and turnaround time compared with other available testing, such as direct fluorescent antibody and viral culture.^7,9

The VZV enzyme immunoassay (EIA) screen detects both the immunoglobulin M (IgM) and VZV immunoglobulin G (IgG), which demonstrates either acute infection (IgM) or chronic infection (IgG). Serologic testing can show the presence of VZV antibodies, which corresponds to a history of varicella or vaccination and equates to protection from infection or reinfection with the virus. These VZV antibody immunity screens can help determine if an individual is at risk of contracting varicella and therefore may require VZV immunization. These screens also have been used in vaccine trials to assess response to immunization.^7,9

Differential Diagnosis of Varicella-Zoster Virus

The differential diagnosis for varicella-zoster virus infection can be extensive. The zoster-like lesions of varicella can appear similar to herpes simplex virus, which usually presents as lesions in the oral and genital mucosa. Other conditions that mimic varicella include enteroviral infections, impetigo, and rickettsialpox.¹⁰ Similarly, the characteristic rash of herpes zoster is similar to the vesicles present in patients with such dermatologic conditions as impetigo, candidiasis, contact dermatitis, and dermatitis herpetiformis.¹¹   The differential diagnosis for herpes zoster also includes herpes simplex virus, insect bites, and drug reactions.¹¹

Management of Varicella and Herpes Zoster

Individuals with varicella typically only require supportive care to manage their symptoms. The decision to initiate antiviral therapy depends on the patient’s age, clinical presentation, and the presence of comorbidities. As varicella is usually self-limited in healthy children younger than 13 years without comorbidities (other than neonates), antiviral therapy is likely not needed.¹² 

For patients who have risk factors for complications (eg, neonates, pregnant individuals, and individuals who are immunocompromised), antiviral therapy may be administered to reduce symptom severity and risk of complications. Antiviral therapy may also prevent the development of primary varicella pneumonia, which most often occurs in adults.¹ Supportive care, such as antihistamines, can help alleviate symptoms. Salicylates should be avoided, as aspirin has been associated with the onset of Reye syndrome in the setting of a viral infection in pediatric patients.²

The management of herpes zoster includes antiviral therapy for patients without additional risk factors and with uncomplicated herpes zoster if they present for treatment within 72 hours of clinical onset. There is minimal efficacy for treatment with antivirals beyond 72 hours except for individuals with herpes zoster ophthalmicus, those with neurologic complications, pregnant patients, and those who are immunocompromised.⁷ Antivirals increase healing of cutaneous lesions and reduce the severity of acute neuritis. Adjunctive therapy with gabapentin, tricyclic antidepressants, and glucocorticoids for patients with uncomplicated herpes zoster may be beneficial, except for those with severe neuritis.^7,9

Table 3. Antiviral Therapy for Varicella and Herpes Zoster

			Dosage*
Antiviral	Indications	Administration	Adults	Children
Acyclovir	Herpes Zoster	Tablets	800 mg every 4 hours (5 times daily) for 7 to 10 days
	Varicella		800 mg 4 times daily for 5 days (start at the earliest signs/symptoms)	Not recommended in children younger than 2 years ≥2 years: 20 mg/kg 4 times daily for 5 days to a maximum 80 mg/kg/d (start at the earliest signs/symptoms)>40 kg: dose as adult for varicella
Acyclovir	Varicella	Injection	Immunocompromised: 10 mg/kg IV every 8 hours for 7 days	Immunocompromised <12 years: 20 mg/kg IV every 8 hours for 7 days
Valaciclovir	Herpes Zoster	Tablets	1g every 8 hours; CrCl 30 to 49 mL/min: 1 g every 12 hours; CrCl 10 to 29 mL/min: 1g every 24 hours; CrCl <10 mL/min: 500 mg every 24 hours; all for 7 days (start within 48 hours of signs/symptoms)
	Varicella	Tablets		2 to <18 years: 20 mg/kg 3 times daily for 5 days; maximum 1g three times daily
Famciclovir	Herpes Zoster	Tablets	500 mg every 8 hours; CrCl 40 to 59 mL/min: 500 mg every 12 hours; CrCl 20 to 39 mL/min: 500 mg every 24 hours; CrCl <20 mL/min: 250 mg every 24 hour; all for 7 days (start within 72 hours of signs/symptoms)

Herpes zoster ophthalmicus is a condition in which VZV reactivates within the trigeminal nerve and can cause blindness. Early consultation with an ophthalmologist and treatment with antiviral therapy are critical for preventing vision loss.⁷  Adjunctive topical steroid drops may be used if there is significant inflammation or in the presence of complications such as stromal keratitis or uveitis; however, as topical steroid drops have been associated with worsening of epithelial disease, they should be used with caution.¹³

References

1. Gershon AA, Gershon MD. Pathogenesis and current approaches to control of varicella-zoster virus infections. Clin Microbiol Rev. 2013;26(4):728-743. doi:10.1128/CMR.00052-13
2. Arvin AM. Varicella-zoster virus. Clin Microbiol Rev. 1996;9(3):361-381. doi:10.1128/CMR.9.3.361
3. Cheatham WJ, Dolan TF Jr, Dower JC, Weller TH. Varicella: report of two fatal cases with necropsy, virus isolation, and serologic studies. Am J Pathol. 1956;32(5):1015-1035.
4. Lopez AS, Zhang J, Marin M. Epidemiology of varicella during the 2-dose varicella vaccination program – United States, 2005-2014. MMWR Morb Mortal Wkly Rep. 2016;65(34):902-905. doi:10.15585/mmwr.mm6534a4
5. Shingles (herpes zoster). Centers for Disease Control and Prevention.  Accessed April 19, 2023. https://www.cdc.gov/shingles/hcp/clinical-overview.html
6. Gershon AA, Breuer J, Cohen JI, et al. Varicella zoster virus infection. Nat Rev Dis Primers. 2015;1:15016.  doi:10.1038/nrdp.2015.16
7. Harpaz R, Ortega-Sanchez IR, Seward JF. Advisory Committee on Immunization Practices (ACIP) Centers for Disease Control and Prevention (CDC). Prevention of herpes zoster: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2008;57(RR-5):1-30; quiz CE2-4.
8. Yawn BP, Saddier P, Wollan PC, St Sauver JL, Kurland MJ, Sy LS. A population-based study of the incidence and complication rates of herpes zoster before zoster vaccine introduction [published correction appears in Mayo Clin Proc. 2008;83(2):255]. Mayo Clin Proc. 2007;82(11):1341-1349. doi:10.4065/82.11.1341
9. Schmader K. Herpes zoster in older adults. Clin Infect Dis. 2001;32(10):1481-1486. doi:10.1086/320169
10. Varicella. Centers for Disease Control and Prevention. Accessed April 19, 2023. https://wonder.cdc.gov/wonder/prevguid/p0000108/p0000108.asp#head001006000000000.
11. Sampathkumar P, Drage LA, Martin DP. Herpes zoster (shingles) and postherpetic neuralgia. Mayo Clin Proc. 2009;84(3):274-280. doi:10.1016/S0025-6196(11)61146-4
12. Swingler GH. Chickenpox. BMJ Clin Evid. 2007;2007:0912. 
13. Vrcek I, Choudhury E, Durairaj V. Herpes zoster ophthalmicus: a review for the internist. Am J Med. 2017;130:21-26. doi:10.1016/j.amjmed.2016.08.039

Author Bio

Mark Arredondo, MD, is an internal medicine physician who began his career as a scholar for the National Health Service Corps, serving the most medically underserved. He currently serves as medical director of the Portage County Combined General Health District in Ravenna, Ohio. Dr Arredondo is a member of the Master Teacher Guild and has taught medical students and nurse practitioner students for more than 25 years.