clinical presentation of varicella zoster virus

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StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-.

StatPearls [Internet].

Varicella-zoster virus (chickenpox).

Folusakin Ayoade ; Sandeep Kumar .

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Last Update: October 15, 2022 .

Continuing Education Activity

Chickenpox or varicella is a contagious disease caused by the varicella-zoster virus (VZV). The virus is responsible for chickenpox (usually primary infection in non-immune hosts) and herpes zoster or shingles (following reactivation of latent infection). Chickenpox results in a skin rash that forms small itchy blisters which scab over. This activity describes the cause, presentation, and pathophysiology of chickenpox and highlights the role of the interprofessional team in the treatment and prevention of this infection.

Identify the etiology of chickenpox.
Review the presentation of chickenpox.
Outline the treatment and management options available for chickenpox.
Explain interprofessional team strategies for improving care coordination and outcomes in patients with chickenpox.
Introduction

Chickenpox or varicella is a contagious disease caused by the varicella-zoster virus (VZV). The virus is responsible for chickenpox (usually primary infection in non-immune hosts) and herpes zoster or shingles (following reactivation of latent infection). Chickenpox results in a skin rash that forms small, itchy blisters, which scabs over. It typically starts on the chest, back, and face then spreads. It is accompanied by fever, fatigue, pharyngitis, and headaches which usually last five to seven days. Complications include pneumonia, brain inflammation, and bacterial skin infections. The disease is more severe in adults than in children. Symptoms begin ten to 21 days after exposure, but the average incubation period is about two weeks.

Chickenpox is a worldwide, airborne disease that is spread by coughing and sneezing, and also by contact with skin lesions. It may start to spread one to two days before the rash appears until all lesions are crusted over. Patients with shingles may spread chickenpox to those who are not immune through blister contact. The disease is diagnosed based on the presenting symptoms and confirmed by polymerase chain reaction (PCR) testing of the blister fluid or scabs. Tests for antibodies may be performed to determine if immunity is present. Although reinfections by varicella may occur, these reinfections are usually asymptomatic and much milder than the primary infection.

The varicella vaccine was introduced in 1995 and has resulted in a significant decrease in the number of cases and complications. It prevents about 70% to 90% of infections and 95% of severe disease. Routine immunization of children is recommended. Immunization within three days of exposure may still improve outcomes in children. [1] [2] [3]

Chickenpox or varicella is caused by the varicella-zoster virus (VZV), a herpesvirus with worldwide distribution. It establishes latency after primary infection, a feature unique to most herpes viruses. [4]

It is acquired by inhalation of infected aerosolized droplets. This virus is highly contagious and can spread rapidly. The initial infection is in the mucosa of the upper airways. After 2-6 days, the virus enters the circulation and another bout of viremia occurs in 10-12 days. At this time the characteristic vesicle appears. IgA, IgM, and IgG antibodies are produced but it is the IgG antibodies that confer life long immunity. After the primary infection, varicella localized to sensory nerves and may reactivate later to produce shingles.

Epidemiology

Varicella occurs in all countries and is responsible annually for about 7000 deaths. In temperate countries, it is a common disease of children, with most cases occurring during the winter and spring. In the United States, it accounts for more than 9000 hospitalizations annually. Its highest prevalence is in the 4 to 10-year-old age group. Varicella has an infection rate of 90%. Secondary cases in household contacts tend to have more severe disease than primary cases. In the tropics, varicella tends to occur in older people and may cause more serious disease. Adults will get deep pock marks and more prominent scars. [5] [6] [7]

Pathophysiology

Exposure causes the production of host immunoglobulin G, M, and A. IgG antibodies persist for life and confer immunity. Cell-mediated immune responses are important in limiting the duration of primary varicella infection. After primary infection, it is theorized varicella spreads to mucosal and epidermal lesions to local sensory nerves. It then remains latent in the dorsal ganglion cells of the sensory nerves. The immune system keeps the virus in check but reactivation can still occur later in life and results in the clinically distinct syndrome of herpes zoster (shingles), postherpetic neuralgia, and sometimes Ramsay Hunt syndrome type II. Varicella zoster can harm the arteries in the neck and head, resulting in a stroke.

The United States Advisory Committee on Immunization Practices (ACIP) suggests that all adult older than the age of 60 years old get vaccinated to avoid herpes zoster. One in five adults who had chickenpox as children, especially those who are immune-suppressed, get singles. Shingles are most commonly found in adults older than the age of 60 who were diagnosed with chickenpox before the age of 1. [8] [9]

History and Physical

The prodromal symptoms in adolescents and adults are aching muscles, nausea, decreased appetite, and headache followed by a rash, oral sores, malaise, and a low-grade fever. Oral manifestations may precede the skin rash. In children, the illness may not be preceded by prodromal symptoms, and the initial sign could be a rash or oral cavity lesions. The rash begins as small red dots on the face, scalp, torso, upper arms and legs. Over the next ten to 12 hours it progresses to small bumps, blisters, and pustules; and eventually umbilication and scabs formation. Of note, the rash of chickenpox occur in crops and are typically at different stages of evolution.

At the blister stage, intense pruritus is present. Blisters may occur on the palms, soles, and genital area. Commonly, visible evidence develops in the oral cavity and tonsil areas in the form of small ulcers which can be painful and itchy; this enanthem may precede the external exanthem by one to three days. These symptoms appear ten to 21 days after exposure. Adults may have a more widespread rash and longer fever, and they are more likely to develop pneumonia, the most important complication in adults.

Because watery nasal discharge containing live virus precedes exanthems by one to two days, the infected person is contagious one to two days before recognition of the disease. In the majority of cases, the infection resolves itself within two to four weeks.

A common complication is a secondary bacterial infection that can present as cellulitis, impetigo or erysipelas.

Disseminated primary varicella is usually seen in immunocompromised individuals and carries a very high mortality. CNS complications are rare but may present as Guillain barre syndrome or encephalitis.

Primary varicella infection during pregnancy can also affect the fetus, who may present later with chickenpox. In addition, the virus also has the potential to cause the varicella congenital syndrome.

The diagnosis of varicella infection is primarily based on the signs and symptoms. Confirmation is by examination of the fluid within the vesicles, scraping of lesions that have not crusted or by blood for evidence of an acute immunologic response. Polymerase chain reaction (PCR) has the highest yield and can be utilized for non-skin samples such as bronchoalveolar lavage sample and cerebrospinal fluid. Direct fluorescent antibody testing has largely replaced the Tzanck test. The vesicular fluid can also be cultured, but the yield is low compared to PCR. Blood tests are used to identify a response to acute infection (IgM), previous infection, and subsequent immunity (IgG). Prenatal diagnosis of fetal varicella can be performed using ultrasound, though a delay of 5 weeks following primary maternal infection is advised. A PCR (DNA) test of the amniotic fluid can be performed, though the risk of spontaneous abortion due to amniocentesis is higher than the risk of the baby developing fetal varicella. [10] [11]

Treatment / Management

Treatment is symptomatic relief of symptoms. As a protective measure, those infected are usually required to stay at home while they are infectious. Keeping nails short and wearing gloves may prevent scratching and reduce the risk of secondary infections. [12] [13] [1]

Topical calamine lotion may relieve pruritus. Daily cleansing with warm water will help avoid secondary bacterial infection. Acetaminophen may be used to reduce fever. Avoid aspirin as it may cause Reye syndrome. People at risk of developing complications and who have had significant exposure may be given intramuscular varicella-zoster immune globulin, a preparation containing high titers of antibodies to varicella-zoster virus, to help prevent the disease. [14]

In children, acyclovir decreases symptoms by one day if taken within 24 hours of the start of the rash, but it has no effect on complication rates, and it is not recommended for individuals with normal immune function.
In adults, infection tends to be more severe, and treatment with antiviral drugs (acyclovir or valacyclovir) is advised if they can be started within 24 to 48 hours of rash onset. Supportive care such as increasing water intake and the use of antipyretics and antihistamines are an important part of the management. Antivirals are typically indicated in adults, including pregnant women because this group is more prone to complications. The preferred treatment is usually oral therapy, but for immunocompromised patients, intravenous antivirals are indicated.

The varicella-zoster immunoglobulin is used to manage patients who are immunocompromised. In addition, a live attenuated vaccine has been available since 1995. There is high seroconversion following the vaccine which is long lasting. Adverse effects of the vaccine are rare.

Differential Diagnosis
Insect bites
Drug eruptions
Dermatitis herpetiformis

In healthy children, the prognosis is excellent. However, in immunocompromised individuals, the infection has high morbidity.

Consultations
Pediatrician
Infectious disease consultant
Pearls and Other Issues

Chickenpox is rarely fatal. Non-immune pregnant women and those immunocompromised are at highest risk. Arterial ischemic stroke associated with childhood chickenpox is a significant risk. Varicella pneumonia is the most common cause of fatality in adults (10% to 30%), and in those requiring mechanical ventilation, this may reach 50%.

In pregnant women, antibodies produced as a result of immunization or previous infection are transferred via the placenta to the fetus. Varicella infection in pregnant women could spread via the placenta and infect the fetus. If infection occurs during the first 28 weeks of pregnancy, congenital varicella syndrome may develop. Effects on the fetus can include underdeveloped toes and fingers, structural eye damage, neurological disorder, and anal and bladder malformation.

If maternal infection occurs seven days before delivery and up to eight days following birth, the baby may develop neonatal varicella with presentation ranging from mild rash to disseminated infection. Newborns who develop symptoms are at a high risk of pneumonia and other serious complications.

Maternal herpes zoster, on the other hand, constitutes little risk of neonatal complications or congenital varicella syndrome probably because of established circulating maternal antibodies.

Enhancing Healthcare Team Outcomes

Chickenpox is usually acquired after inhalation of aerosolized droplets from an infected individual. The majority of cases occurring in children less than 10. The key to lowering the morbidity of chickenpox is via education. Besides the primary caregiver, the nurse practitioner and pharmacist play a vital role in patient education. The parents of infected children should be told to trim the child's fingernails to avoid or minimize skin damage and the associated bacterial infections. Further, parents should be told not to give aspirin to young children to control fever, because of the risk of developing Reye syndrome. Finally, the parents should be told to apply cold compresses and keep the skin moisturized to prevent the itching and dryness. [15] [16] [17] All clinicians should urge parents to get their children vaccinated because this can prevent the morbidity associated with the infection. The vaccine is safe and very effective. Children who are immunocompromised should be referred to an infectious disease specialist for further management. (Level V) Clinicians should also educate pregnant women who are seronegative for chickenpox to avoid contacts with patients with an active infection. All pregnant women who develop chickenpox must be managed by a team of specialists who can make a decision regarding treatment.

For most children who develop chickenpox, the outcome is excellent. However, in immunocompromised individuals, there is increased morbidity and mortality. [18] [19] [20] (Level V)

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Chickenpox (Varicella). Chickenpox in an unvaccinated child. Public Health Image Library, Public Domain, Centers for Disease Control and Prevention.

Disclosure: Folusakin Ayoade declares no relevant financial relationships with ineligible companies.

Disclosure: Sandeep Kumar declares no relevant financial relationships with ineligible companies.

This book is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ), which permits others to distribute the work, provided that the article is not altered or used commercially. You are not required to obtain permission to distribute this article, provided that you credit the author and journal.

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With chickenpox an itchy rash breaks out mostly on the face, scalp, chest, back with some spots on the arms and legs. The spots quickly fill with a clear fluid, break open and then turn crusty.

Chickenpox is an illness caused by the varicella-zoster virus. It brings on an itchy rash with small, fluid-filled blisters. Chickenpox spreads very easily to people who haven't had the disease or haven't gotten the chickenpox vaccine. Chickenpox used to be a widespread problem, but today the vaccine protects children from it.

The chickenpox vaccine is a safe way to prevent this illness and the other health problems that can happen during it.

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The rash caused by chickenpox appears 10 to 21 days after you're exposed to the varicella-zoster virus. The rash often lasts about 5 to 10 days. Other symptoms that may appear 1 to 2 days before the rash include:

Loss of appetite.
Tiredness and a general feeling of being unwell.

Once the chickenpox rash appears, it goes through three phases:

Raised bumps called papules, which break out over a few days.
Small fluid-filled blisters called vesicles, which form in about one day and then break and leak.
Crusts and scabs, which cover the broken blisters and take a few more days to heal.

New bumps keep showing up for several days. So you may have bumps, blisters and scabs at the same time. You can spread the virus to other people for up to 48 hours before the rash appears. And the virus stays contagious until all broken blisters have crusted over.

The disease is by and large mild in healthy children. But sometimes, the rash can cover the whole body. Blisters may form in the throat and eyes. They also may form in tissue that lines the inside of the urethra, anus and vagina.

When to see a doctor

If you think you or your child might have chickenpox, call your health care provider. Often, chickenpox can be diagnosed with an exam of the rash and other symptoms. You may need medicines that can help fight off the virus or treat other health problems that can happen because of chickenpox. To avoid infecting others in the waiting room, call ahead for an appointment. Mention that you think you or your child may have chickenpox.

Also, let your provider know if:

The rash spreads to one or both eyes.
The rash gets very warm or tender. This might be a sign that the skin is infected with bacteria.
You have more serious symptoms along with the rash. Watch for dizziness, new confusion, fast heartbeat, shortness of breath, shakiness, loss of the ability to use muscles together, a cough that becomes worse, vomiting, stiff neck or a fever higher than 102 F (38.9 C).
You live with people who've never had chickenpox and haven't gotten the chickenpox vaccine yet.
Someone in your household is pregnant.
You live with someone who has a disease or takes medicines that affect the immune system.

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A virus called varicella-zoster causes chickenpox. It can spread through direct contact with the rash. It also can spread when a person with chickenpox coughs or sneezes and you breathe in the air droplets.

Risk factors

Your risk of getting infected with the virus that causes chickenpox is higher if you haven't already had chickenpox or if you haven't had the chickenpox vaccine. It's extra important for people who work in child care or school settings to be vaccinated.

Most people who have had chickenpox or have gotten the vaccine are immune to chickenpox. If you've been vaccinated and still get chickenpox, symptoms are often milder. You may have fewer blisters and mild or no fever. A few people can get chickenpox more than once, but this is rare.

Complications

Chickenpox is often a mild disease. But it can be serious and can lead to other health problem including:

Infected skin, soft tissues, bones, joints or bloodstream caused by bacteria.
Dehydration, when the body runs too low on water and other fluids.
Pneumonia, an illness in one or both lungs.
Swelling of the brain called encephalitis.
Toxic shock syndrome, a dangerous complication of some illnesses caused by bacteria.
Reye's syndrome, a disease that causes swelling in the brain and liver. This can happen in children and teens who take aspirin during chickenpox.

In very rare cases, chickenpox could lead to death.

Who's at risk?

People who are at higher risk of chickenpox complications include:

Newborns and infants whose mothers never had chickenpox or the vaccine. This includes children under age 1, who have not yet had the vaccine.
Teens and adults.
Pregnant women who haven't had chickenpox.
People who smoke.
People with cancer or HIV who are taking medication that has an effect on the immune system.
People with a chronic condition, such as asthma, who take medicine that calms immune response. Or those who have had an organ transplant and take medicine to limit the immune system's action.

Chickenpox and pregnancy

Low birth weight and limb problems are more common in babies born to women who are infected with chickenpox early in their pregnancies. When a pregnant person catches chickenpox in the week before birth or within a couple of days after giving birth, the baby has a higher risk of getting a life-threatening infection.

If you're pregnant and not immune to chickenpox, talk to your health care provider about these risks.

Chickenpox and shingles

If you've had chickenpox, you're at risk of a complication called shingles. The varicella-zoster virus stays in your nerve cells after the chickenpox rash goes away. Many years later, the virus can turn back on and cause shingles, a painful cluster of blisters. The virus is more likely to come back in older adults and people who have weaker immune systems.

The pain of shingles can last long after the blisters go away, and it can be serious. This is called postherpetic neuralgia.

In the United States, the Centers for Disease Control and Prevention (CDC) suggests you get the shingles vaccine, Shingrix, if you're 50 or older. The agency also suggests Shingrix if you're 19 or older and you have a weaker immune system because of diseases or treatments. Shingrix is recommended even if you've already had shingles or you've gotten the older shingles vaccine, Zostavax.

Other shingles vaccines are offered outside of the United States. Talk to your provider for more information on how well they prevent shingles.

The chickenpox vaccine, also called the varicella vaccine, is the best way to prevent chickenpox. In the United States, experts from the CDC report that two doses of the vaccine prevent illness over 90% of the time. Even if you get chickenpox after receiving the vaccine, your symptoms may be much milder.

In the United States, two chickenpox vaccines are licensed for use: Varivax contains only the chickenpox vaccine. It can be used in the United States to vaccinate people age 1 or older. ProQuad combines the chickenpox vaccine with the measles, mumps and rubella vaccine. It can be used in the United States for children ages 1 to 12. This is also called the MMRV vaccine.

In the United States, children receive two doses of the varicella vaccine: the first between ages 12 and 15 months and the second between ages 4 and 6 years. This is part of the routine vaccination schedule for children.

For some children between the ages of 12 and 23 months, the MMRV combination vaccine may raise the risk of fever and seizure from the vaccine. Ask your child's health care provider about the pros and cons of using the combined vaccines.

Children 7 to 12 years old who haven't been vaccinated should receive two doses of the varicella vaccine. The doses should be given at least three months apart.

People age 13 or older who haven't been vaccinated should receive two catch-up doses of the vaccine at least four weeks apart. It's even more important to get the vaccine if you have a higher risk of getting exposed to chickenpox. This includes health care workers, teachers, child-care employees, international travelers, military personnel, adults who live with young children and all nonpregnant women of childbearing age.

If you don't remember whether you've had chickenpox or the vaccine, your provider can give you a blood test to find out.

Other chickenpox vaccines are offered outside the United States. Talk to your health care provider for more information on how well they prevent chickenpox.

Do not get the chickenpox vaccine if you're pregnant. If you decide to get vaccinated before pregnancy, don't try to get pregnant during the series of shots or for one month after the last dose of the vaccine.

Other people also shouldn't get the vaccine, or they should wait. Check with your health care provider about whether you should get the vaccine if you:

Have a weaker immune system. This includes people who have HIV or take medicines that have an effect on the immune system.
Are allergic to gelatin or the antibiotic neomycin.
Have any kind of cancer or are getting cancer treatment with radiation or medicines.
Recently received blood from a donor or other blood products.

Talk to your provider if you're not sure whether you need the vaccine. If you plan on getting pregnant, ask your provider if you're up to date on your vaccines.

Is it safe and effective?

Parents often wonder whether vaccines are safe. Since the chickenpox vaccine became available, studies have found that it's safe and it works well. Side effects are often mild. They include pain, redness, soreness and swelling at the site of the shot. Rarely, you might get a rash at the site or a fever.

Chickenpox (varicella). Centers for Disease Control and Prevention. https://www.cdc.gov/chickenpox/about/index.html. Accessed Jan. 14, 2019.
Centers for Disease Control and Prevention. Varicella (chickenpox). In: CDC Yellowbook 2018: Health Information for International Travel. New York, N.Y.: Oxford University Press; 2018. http://global.oup.com/. Accessed Jan. 14, 2019.
Papadakis MA, et al., eds. Viral and rickettsial infections. In: Current Medical Diagnosis & Treatment 2019. 58th ed. New York, N.Y.: McGraw-Hill Education; 2019. https://accessmedicine.mhmedical.com. Accessed Jan. 14, 2019.
Types of chickenpox vaccine. Centers for Disease Control and Prevention. https://www.cdc.gov/vaccines/vpd/varicella/public/index.html. Accessed Jan. 14, 2019.
Longo DL, et al., eds. Varicella-zoster virus infections. In: Harrison's Principles of Internal Medicine. 20th ed. New York, N.Y.: The McGraw-Hill Companies; 2018. https://accessmedicine.mhmedical.com. Accessed Jan. 14, 2019.
Chickenpox (varicella). Merck Manual Professional Version. https://www.merckmanuals.com/professional/infectious-diseases/herpesviruses/chickenpox. Accessed Jan. 14, 2019.
Stone K, et al. BET 2: NSAIs and chickenpox. Emergency Medicine Journal: EMJ. 2018;35:66.
AskMayoExpert. Chickenpox. Mayo Clinic; 2022.
Tosh PK (expert opinion). Mayo Clinic, Rochester, Minn. Feb. 1, 2019.
Chickenpox (varicella): Vaccination. Centers for Disease Control and Prevention. https://www.cdc.gov/chickenpox/vaccination.html. Accessed Dec. 30, 2022.
Guidelines for vaccinating pregnant women. Centers for Disease Control and Prevention. https://www.cdc.gov/vaccines/pregnancy/hcp-toolkit/guidelines.html. Accessed Dec. 30, 2022.
Chickenpox vaccination: What everyone should know. https://www.cdc.gov/vaccines/vpd/varicella/public/index.html. Accessed Dec. 30, 2022.
Shingles vaccination. Centers for Disease Control and Prevention. https://www.cdc.gov/vaccines/vpd/shingles/public/shingrix/index.html. Accessed Dec. 30, 2022.
Chickenpox (varicella): Prevention and treatment. Centers for Disease Control and Prevention. https://www.cdc.gov/chickenpox/about/prevention-treatment.html. Accessed Jan 10, 2023.
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Varicella zoster virus infection

Anne A. Gershon 1 ,
Judith Breuer 2 ,
Jeffrey I. Cohen 3 ,
Randall J. Cohrs 4 ,
Michael D. Gershon 5 ,
Don Gilden 4 ,
Charles Grose 6 ,
Sophie Hambleton 7 ,
Peter G. E. Kennedy 8 ,
Michael N. Oxman 9 ,
Jane F. Seward 10 &
Koichi Yamanishi 11

Nature Reviews Disease Primers volume 1 , Article number: 15016 ( 2015 ) Cite this article

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Herpes virus

Infection with varicella zoster virus (VZV) causes varicella (chickenpox), which can be severe in immunocompromised individuals, infants and adults. Primary infection is followed by latency in ganglionic neurons. During this period, no virus particles are produced and no obvious neuronal damage occurs. Reactivation of the virus leads to virus replication, which causes zoster (shingles) in tissues innervated by the involved neurons, inflammation and cell death — a process that can lead to persistent radicular pain (postherpetic neuralgia). The pathogenesis of postherpetic neuralgia is unknown and it is difficult to treat. Furthermore, other zoster complications can develop, including myelitis, cranial nerve palsies, meningitis, stroke (vasculopathy), retinitis, and gastroenterological infections such as ulcers, pancreatitis and hepatitis. VZV is the only human herpesvirus for which highly effective vaccines are available. After varicella or vaccination, both wild-type and vaccine-type VZV establish latency, and long-term immunity to varicella develops. However, immunity does not protect against reactivation. Thus, two vaccines are used: one to prevent varicella and one to prevent zoster. In this Primer we discuss the pathogenesis, diagnosis, treatment, and prevention of VZV infections, with an emphasis on the molecular events that regulate these diseases. For an illustrated summary of this Primer, visit: http://go.nature.com/14xVI1

Long COVID: major findings, mechanisms and recommendations

Hannah E. Davis, Lisa McCorkell, … Eric J. Topol

clinical presentation of varicella zoster virus

A guide to vaccinology: from basic principles to new developments

Andrew J. Pollard & Else M. Bijker

Mechanisms of SARS-CoV-2 entry into cells

Cody B. Jackson, Michael Farzan, … Hyeryun Choe

Varicella zoster virus (VZV, also known as human herpesvirus 3) is a ubiquitous alphaherpesvirus with a double-stranded DNA genome. VZV only naturally infects humans, with no animal reservoir; its main targets are T lymphocytes, epithelial cells and ganglia. Primary infection causes varicella (chickenpox), during which VZV becomes latent in ganglionic neurons. As cellular immunity to VZV wanes with advancing age or in immunocompromised individuals, VZV reactivates to cause zoster (shingles). Zoster can be complicated by chronic pain (postherpetic neuralgia (PHN)) and other serious neurological and ocular disorders (for example, meningoencephalitis, myelitis, cranial nerve palsies, vasculopathy, keratitis and retinopathy), as well as multiple visceral and gastrointestinal disorders, including ulcers, hepatitis and pancreatitis 1 , 2 ( Fig. 1 ). Antiviral drugs and vaccines against both varicella and zoster are available and are effective in treating and preventing VZV-induced disease 2 .

Primary infection with varicella zoster virus (VZV) in susceptible individuals causes varicella, which usually is harmless in healthy children whose immune system controls the infection. VZV establishes latency in ganglionic neurons, and reactivation of viral replication and spread of the virus to the skin innervated by these neurons causes zoster. Increasing age and compromised immune function are risk factors for complications of VZV infections. However, some of these complications, such as postherpetic neuralgia, can also occur without these predisposing factors.

PowerPoint slide

VZV is highly communicable and spreads by the airborne route, with an extraordinarily high transmission rate 3 in temperate countries. Traditionally, the virus was thought to spread to others from the respiratory tract, but such evidence is scant. Instead, most virus comes from skin where it is highly concentrated in vesicles; skin cells and cell-free VZV are frequently shed and are probably the major source of infectious cell-free airborne virus 4 , 5 . Infected children without skin lesions are not contagious to others 4 .

The highly efficient transmission of VZV assured that, before the introduction of the varicella vaccine, most children would contract varicella before 10 years of age. Varicella in children is usually self-limiting, although complications can be unpredictable, and long-lasting immunity follows once the patient recovers. Epidemics are also self-limiting because the high rate of transmission and disease-induced immunity deplete the pool of susceptible individuals 6 . Most older children and adults harbour latent wild-type VZV or vaccine-type VZV (vOka) 2 . Sporadic reactivation of VZV causes zoster and provides an evolutionary advantage for the pathogen by providing a source of infection in new, susceptible birth cohorts.

VZV occurs worldwide, but in some developed countries there is less concern for VZV than for other infectious agents, such as influenza virus, Ebola virus and multidrug-resistant staphylococci. However, even in countries where varicella vaccination is routine there has not been an eradication of VZV disease. Import of varicella from countries that do not vaccinate and zoster caused by reactivation of latent wild-type VZV or vOka can occur. Given the increasing number of immunocompromised individuals worldwide, it is important to maintain substantial levels of herd immunity against varicella in developed countries and to extend vaccination to developing countries. Recently, the WHO recommended “routine immunization of children against varicella in countries where varicella has an important public health impact” 7 . In addition, because of the current anti-vaccine movement in some countries, it is also wise to maintain interest in VZV research and to improve current methods to prevent and treat varicella and zoster. In this Primer article, we summarize the diseases and complications of VZV infection, how latency develops, how and when to vaccinate and treat patients, and we highlight open research questions ( Box 1 ).

Epidemiology

Varicella occurs worldwide and is endemic in populations of sufficient size to sustain year-round transmission, with epidemics occurring every 2–3 years 3 . Viral genomic studies have identified five viral clades and their geographical distribution: clades 1, 3 and 5 are of European origin; clade 2 includes Asian strains such as the parental Oka strain, from which varicella and zoster vaccines were derived; and clade 4 contains African strains 8 . Varicella epidemiology and disease burden have been studied primarily in developed countries. Although VZV seroprevalance data are becoming more widely available, additional data are needed on severe disease outcomes and deaths to better characterize the global health burden due to varicella, particularly in regions with high HIV prevalence, such as Africa and India 7 .

Varicella incidence ranges from 13 to 16 cases per 1,000 persons per year, with substantial yearly variation 3 . In temperate climates, age-specific varicella incidence is highest in preschool aged children (1–4 years of age) or children in early elementary school (5–9 years of age) with an annual incidence of greater than 100 per 1,000 children; as a result, >90% of people become infected before adolescence and only a small proportion (<5–10%) of adults remain susceptible 3 , 9 . In tropical climates, acquisition of varicella occurs at a higher overall mean age (for example, at 14.5 years in Sri Lanka), with a higher proportion of cases in adults 3 , 10 . Differences in varicella epidemiology between temperate and tropical climates might be related to the properties of VZV, for example, inactivation by heat and/or humidity, or factors affecting the risk of exposure 3 .

Varicella shows a strong seasonal pattern, with peak incidence during winter and spring or during the cool, dry season 3 , 11 . Outbreaks occur commonly in settings where children congregate, such as childcare centres and schools, but can also occur in other age groups and settings, including hospitals, facilities for institutionalized people, refugee camps and military and correctional facilities 12 – 14 .

Although varicella is usually a self-limiting disease, it can result in serious complications and death. In developed countries, ∼ 5 out of 1,000 people with varicella are hospitalized and 2–3 per 100,000 patients die 15 , 16 . Serious varicella complications include bacterial sepsis, pneumonia, encephalitis and haemorrhage 3 . Adults, infants and individuals who are severely immunocompromised are at higher risk of severe complications and death. Varicella acquired in the first two trimesters of pregnancy causes severe congenital defects in the newborn in ∼ 1% of affected pregnancies 17 .

In countries where varicella vaccination is routinely recommended in childhood, varicella epidemiology has changed dramatically ( Fig. 2 ). In the United States, where a one-dose vaccination programme was implemented in 1995 and a two-dose programme in 2007, varicella incidence, hospitalizations and deaths in children have declined by >95%. Furthermore, significantly less morbidity and mortality in vaccinated and in unvaccinated age groups indicate indirect vaccination effects such as herd immunity and interruption of annual epidemics 18 , 19 .

The introduction of the varicella vaccine in 1995 reduced the number of varicella cases substantially (data shown for Illinois, Michigan, Texas and West Virginia, USA). Reprinted with permission from Ref. 209 , Centers for Disease Control and Prevention (CDC).

Zoster epidemiology has been described almost exclusively from developed countries with long life expectancies. The incidence and severity of zoster increase with age due to declining cell-mediated immunity to VZV 3 , 20 . PHN is the most serious complication of zoster and occurs in ∼ 15% of cases. Age is the most important risk factor for PHN, with the risk increasing rapidly after 50 years of age 3 , 20 . The population incidence of zoster is ∼ 3–4 per 1,000 patient-years of observation, with the incidence varying from ∼ 1 per 1,000 patient-years of observation in children aged <10 years to >10 per 1,000 patient-years of observation in adults aged ≥60 years 20 – 22 . By the age of 85 years, >50% of the population reports at least one episode of zoster 20 . There are limited data on the age-specific incidence in low and middle income countries.

Before VZV vaccines were available, ∼ 30% of adults developed zoster 23 . Recently, however, a higher proportion of the population has exhibited impaired immunity to VZV and develops zoster, for example, due to the growing number of elderly people, immunosuppressed organ transplant recipients, patients receiving chemotherapy for cancer or autoimmune disease, HIV-infected individuals, and patients with chronic illnesses 24 . Race is a well-described protective, presumably genetic, factor: black adults in the United States and the United Kingdom have a 25–50% lower incidence of zoster compared with white adults 25 . Exposure to exogenous VZV protects against zoster and/or boosts cellular immunity 26 , 27 . Although mathematical modelling has predicted an increase in zoster where circulating VZV is reduced by childhood vaccination programmes 28 , the concept of exogenous VZV exposure as the only means for immune boosting remains an area of controversy (see below). Post-licensure surveillance data provide direct evidence of the impact of the varicella vaccine on zoster epidemiology 29 , 30 . Healthy varicella vaccine recipients have a lower risk of zoster than unvaccinated individuals, and this finding is consistent with pre-licensure studies demonstrating a similar effect in children with acute leukaemia 31 . The effect of varicella vaccination on overall zoster epidemiology continues to be evaluated. Most studies examining the overall population rates of zoster in developed countries (the United States, the United Kingdom, Canada, Spain, Japan and Australia) show increasing incidence trends in these countries, regardless of whether they have varicella vaccination programmes 3 , 7 . In the United States, where the varicella vaccine has been used for 20 years in children, increases in zoster incidence started years before the use of the varicella vaccine and the rate of increase is similar before and after implementation of the vaccination programme 3 , 29 , 30 .

Box 1: Questions to ponder while reading this Primer

Which molecular mechanisms of immunity control varicella zoster virus (VZV) in the human host?

How does VZV become latent, and why only in neurons?

What explains postherpetic neuralgia?

How does stress and immunosuppression lead to virus reactivation?

How do VZV vaccines confer host control of the virus?

Why is VZV readily controlled by vaccination whereas other human herpesviruses are not?

Will new vaccines and antivirals improve the control of VZV? If yes, by what means?

Mechanisms/pathophysiology

Vzv infection and replication.

Primary infection . Following transmission to susceptible hosts, VZV proliferates in the oral pharynx (tonsils), infects T cells that enter the circulation and disseminate virus to the skin and possibly other organs; infection is at first controlled by innate immunity 32 , 33 . VZV can remodel diverse T cell populations to facilitate skin trafficking 34 . VZV DNA can be detected in T cells (viraemia) as early as 10 days prior to the occurrence of a rash and can persist for a week afterwards 35 . Initially, innate immunity delays viral multiplication in the skin, which provides time for adaptive immunity to develop 32 . Eventually, cutaneous innate immune responses are overcome by the virus, and there is substantial viral replication in the skin (and sometimes the viscera), resulting in the characteristic rash of varicella 33 ( Fig. 3 ). High titres of cell-free VZV develop in skin vesicles and transmit VZV to others 5 . Important and unpredictable complications of varicella in previously healthy children include encephalitis, haemorrhagic manifestations, and bacterial superinfections involving skin, blood, bones and lungs.

Severe varicella in an 11-month-old infant who, during the incubation period, had received dexamethasone as part of therapy for pneumococcal meningitis. Pictured on day 5 of the rash, when he was still systemically unwell and acquiring new lesions. The infant made a full recovery with intravenous acyclovir therapy.

In this process of lytic infection ( Fig. 4a ), VZV expresses its 71 annotated genes and possibly additional genes that have not yet been identified. As described for other herpesviruses, gene expression is thought to proceed in an orderly cascade, beginning with immediate early genes, then early genes, followed by late genes. In latency, however, gene expression is restricted and possibly blocked ( Fig. 4b ). In reactivation, all VZV genes are expressed, again resulting in lytic infection 2 .

a | Lytic infection with varicella zoster virus (VZV) starts with attachment, fusion and uncoating of the virion. The virus capsid is then transported to the cell nucleus, where the viral DNA becomes circular. The full set of viral proteins, including immediate early (IE), early (E) and late (L) proteins, are expressed and enter the nucleus. New virions then bud in a two-step process. This full cycle of viral replication leads to substantial cell damage and eventually lysis; the acidic environmental in the endosome damages the virus particles and reduces their infectiousness. The micrograph shows VZV infection of guinea pig enteric neurons showing lytic infection 47 . Isolated neurons were cultured in vitro and infected with cell-free VZV to induce infection. The cultures were fixed and immunostained with antibodies against VZV ORF29p (red) and glycoprotein E (green). The neurons were analysed 48 h after infection with cell-associated virus; after lytic infection, neurons die with 48–72 h. The neuron is filled with cytoplasmic glycoprotein E immunoreactivity and the immunoreactivity of ORF29p has almost entirely translocated to the nucleus (arrow). b | The exact mechanisms of latent infection are unclear but viral replication is thought to stop at the circular DNA stage and no or only limited protein expression occurs. Furthermore, no viral proteins are found in the nucleus. Latent infection causes no easily observable changes of cell morphology (see micrograph). The micrograph shows VZV infection of guinea pig enteric neurons showing latent infection 47 . Isolated neurons were cultured in vitro and infected with cell-free VZV to induce infection. The cultures were fixed and immunostained with antibodies against VZV ORF29p (red) and glycoprotein E (green). The neurons were analysed 2 weeks after infection with cell-free VZV; after latent infection, neurons survive in vitro for as long as cultures can be maintained. Note that ORF29p immunoreactivity is confined to the cytoplasm; there is no nuclear immunoreactivity (arrow). TGN, trans-Golgi network. Adapted from Ref. 210 , Nature Publishing Group.

Latency . VZV is latent in neurons of cranial nerve ganglia, dorsal root ganglia, and enteric and autonomic ganglia 2 , 36 . Because sites of zoster often correspond to those most involved in varicella (face and trunk), VZV has long been thought to enter epidermal nerve endings during varicella and undergo retrograde axonal transport to reach neuronal cell bodies in the ganglia. Varicella-associated viraemia, however, is an even more likely means by which neurons may be latently infected, particularly enteric or other neurons that lack cutaneous projections. For example, latent VZV has been found in the dorsal root ganglia of children with no history of varicella and no epidermal involvement 37 . Moreover, when vOka is injected at a single location, it can establish latency not only in ganglia that innervate the injection site, but also bilaterally and at multiple levels of the nervous system 37 . Experimentally, viral DNA has been found in dorsal root ganglia days before a rash occurs in monkeys infected with simian varicella virus 38 , and VZV becomes latent in dorsal root ganglia and enteric neurons after intravenous injection of guinea pigs with VZV-infected lymphocytes 39 . However, it is unclear how VZV is transferred from infected lymphocytes to neurons, and the mechanism by which neurons become latently infected is also unclear.

Latent VZV was found in 34 (1.5%) out of 2,226 neurons and in none of the 20,700 satellite cells from the trigeminal ganglia of 18 deceased individuals with a history of varicella 40 . Latent VZV DNA is circular and non-replicating 36 ; moreover, histones containing post-translational modifications indicative of euchromatin are associated with immediate early genes, perhaps facilitating the expression of these genes, but not with late VZV genes 41 . Immediate early protein 63 (IE63) interacts with anti-silencing function protein 1 (ASF1) to increase its histone binding 42 . ASF1 mediates the deposition and eviction of histones from DNA during transcription, and IE63 through its interaction with ASF1 may regulate transcription of viral and/or cellular genes, a possibility that requires verification.

VZV gene expression during latency remains unresolved and highly controversial. Latency-associated VZV gene expression has been investigated in cadaver ganglia obtained at autopsy because human dorsal root ganglia and cranial nerve ganglia are rarely, if ever, resected during life. However, stress associated with terminal illness and the interval between death and autopsy might influence results by disrupting the regulation of VZV gene expression and permitting limited expression in cadaver ganglia; alternatively, death may transiently silence ongoing gene expression. Post-mortem reactivation and virus replication probably does not occur because infectious VZV cannot be recovered in cultures of explanted ganglia 43 , and VZV DNA also fails to increase as a function of time after death 44 . Multiple laboratories have reported the presence of transcripts encoding at least six immediate early and early VZV genes (open reading frame 4 ( ORF4 ), ORF21 , ORF29 , ORF62 , ORF63 and ORF66 ) in latently infected neurons of cadaver ganglia (reviewed in Ref. 2 ). More recently, however, only transcripts of ORF63 were found to be expressed in ganglia obtained <9 h post-mortem 44 . By contrast, transcripts encoding at least 12 VZV genes were detected when the ganglia were obtained later (>9 h post-mortem) 44 .

Enteric ganglia, however, can be examined immediately after surgical removal of bowel 37 , 45 . Transcripts encoding ORF4 , ORF21 , ORF29 , ORF62 , ORF63 and ORF66 were detected in surgical specimens of gut from 12 out of 13 healthy children with either a history of varicella or prior administration of the varicella vaccine, but not in 7 negative controls (infants <1 year old with no history of varicella or vaccination) 45 . Transcripts were also found in 26 out of 30 surgically removed specimens of adult intestine 46 . However, surgery and the disorder that necessitated it are undoubtedly stressful; thus, these transcripts could reflect stress-induced gene expression rather than latency-associated transcription. Interestingly, the same genes ( ORF4 , ORF21 , ORF29 , ORF62 , ORF63 and ORF66 ) are expressed during latency in guinea pig dorsal root ganglia and enteric neurons 39 , 45 – 47 that were obtained without stress to the animals or post-mortem delay.

When VZV reactivates, ganglia become necrotic and haemorrhagic 48 . VZV proteins are found in neurons and non-neuronal cells, and ganglionitis is marked by the upregulation of MHC class I and II proteins and the infiltration of CD4 + and CD8 + T cells 49 – 51 . Ganglionitis and CD8 + T cell infiltration can persist after zoster 51 . Expression of late viral proteins, such as envelope glycoprotein E, shows that lytic VZV infection has occurred 2 . However, the meaning of the immunocytochemical detection of immediate early and early proteins in neurons during latency is controversial 2 ; these proteins have been detected in latently infected neurons 52 – 54 . All latency-associated proteins are cytoplasmic, but become nuclear during productive infection 53 – 55 . Immediate early and early proteins are also cytoplasmic in latently infected guinea pig neurons and translocate to the nucleus when reactivation is induced 42 , 46 , 47 , 56 .

Concerns have been raised over the specificity of VZV immunostaining in adult human neurons because of pigments in neurons 57 and because immunocytochemical reagents may contain antibodies that cross react with blood group A antigens in neurons of patients with type A blood 58 . Neuronal pigments, however, are present in controls in which primary antibodies are omitted as well as in immunostained sections allowing pigment and reaction product to be distinguished 37 , 53 . Furthermore, cytoplasmic immunostaining of latency-associated proteins has been observed in neurons of patients who were determined to have blood type B 39 , 53 . Future studies are needed to resolve controversies of VZV transcription and translation during latency.

Neurological complications of zoster

Zoster paresis . Manifestations of zoster paresis include arm or diaphragmatic weakness after cervical zoster 59 , leg weakness after lumbar or sacral zoster and urinary retention after sacral zoster 60 . MRI reveals involvement of both dorsal and ventral roots of spinal nerves 61 . Rarely, cervical zoster paresis extends to the brachial plexus 62 . The prognosis varies, but ∼ 50% of patients recover completely 63 .

Neuralgia . PHN, the most common complication of zoster, is defined as pain that persists for at least 3 months after rash onset. Three non-mutually exclusive theories have been proposed to explain the cause and pathogenesis of PHN. One is that the excitability of ganglionic or spinal cord neurons is altered during recovery 64 . The second is that persistent productive VZV infection exists in ganglia, a notion that is supported by possible chronic ganglionic inflammation in PHN 65 . A third theory is that PHN might be due to gene expression and protein production without virus replication but with disturbance of neuronal physiology.

Recently, certain strains of VZV were postulated to produce PHN by altering voltage-gated sodium channels, leading to altered excitability 66 , 67 . Isolated and then cultured VZV strains from patients with PHN and those with zoster but without PHN were applied to neuroblastoma cells that express fast and slow sodium channels. Voltage-clamp recordings from infected neuroblastoma cells revealed that the amplitude of the sodium current was greater in cells infected with VZV isolated from those with PHN than in cells from those without PHN. Increased sodium current is associated with neuropathic pain; thus, VZV-induced increases in sodium currents could have a role in PHN. These experiments suggest that PHN might be partly attributable to the particular strain causing zoster. This intriguing possibility clearly needs confirmation and further research.

Virological analyses of ganglia from patients with PHN are lacking. One study reported the detection of VZV DNA in peripheral blood mononuclear cells (PBMCs) for up to 8 years after zoster in 11 out of 51 patients with PHN but not in controls 68 . A case report described a correlation between pain and VZV DNA detection in PBMCs in an immunocompetent elderly woman with PHN 69 . After treatment with famciclovir (a guanosine analogue antiviral drug), pain resolved and the PBMCs no longer contained VZV DNA.

If PHN is caused by persistent VZV replication in neurons, antiviral treatment might decrease its severity. Treatment with oral antiviral agents reduces pain associated with acute zoster; however, this acute treatment has not reduced the incidence, severity or duration of chronic pain of immunocompetent patients with PHN 70 – 73 . Acyclovir improved symptoms in 1 out of 10 patients with PHN 72 , whereas valaciclovir improved symptoms in 8 out of 15 patients 73 . Proof of a positive effect of antivirals on PHN would require a randomized controlled study of patients with PHN. Most studies, however, have not found antiviral therapy to be effective in the treatment of PHN 74 and regulatory authorities do not recommend antivirals to treat this condition 75 .

VZV meningoencephalitis . Acute VZV infection may present as meningitis or meningoencephalitis with or without rash. Detection of VZV DNA and antibodies in cerebrospinal fluid has confirmed VZV as a cause of aseptic meningitis 76 , meningoradiculitis 77 and cerebellitis 78 .

VZV vasculopathy . A serious complication of VZV reactivation is infection of the cerebral arteries (VZV vasculopathy), which causes ischaemic and haemorrhagic stroke. The incidence of VZV vasculopathy is unknown. In children, up to one-third of ischaemic arteriopathies are associated with varicella 79 . In adults, the risk of stroke is increased by 30% within 1 year of zoster 80 and by 4.5-fold after zoster in the ophthalmic branch of the trigeminal nerve 81 . One large population-based analysis showed that the risk was even higher: stroke was observed within a 1-year of follow-up in 8.1% of people with zoster ophthalmicus compared with only 1.7% in a matched control group 82 . However, no cases of vasculopathy or stroke were observed among 984 patients with documented zoster followed up for ≥6 months after rash onset, although 86% received antiviral therapy 22 . Indeed, stroke following zoster ophthalmicus is of high clinical importance 83 , 84 . VZV that reactivates in the trigeminal nerve can travel via the ophthalmic sensory nerves to the face and via afferent sensory fibres to the internal carotid artery and its intracranial branches 85 , 86 . Thereafter, the virus establishes infection in the arterial wall, which leads to inflammation, arterial weakening, aneurysm formation, occlusion and stroke 87 . Infected cerebral arteries contain multinucleated giant cells, Cowdry A inclusions (accumulations of viral DNA and protein in the cell nucleus) and herpesvirus particles, as well as VZV DNA and VZV antigens 81 , 85 .

VZV vasculopathy presents with headache, mental status changes and focal neurological deficits. Large and small vessels are involved 81 . Brain MRI frequently reveals lesions at grey–white matter junctions. In more than two-thirds of patients, angiography reveals focal arterial stenosis and occlusion, aneurysm or haemorrhage 81 .

VZV and giant cell arteritis . One of the most exciting recent developments is the detection of VZV antigen, VZV DNA and virus particles in the temporal arteries of patients with giant cell arteritis (inflammatory vasculopathy, most often involving the temporal arteries) 88 . Analysis of temporal artery biopsies from healthy individuals aged >50 years and from patients with arteritis revealed VZV antigen in the temporal arteries of 61 out of 82 (74%) of patients with arteritis compared with 1 out of 13 (8%) in normal temporal arteries 88 . This discovery, if confirmed, suggests that antiviral treatment might confer additional benefit to corticosteroids in patients with giant cell arteritis.

VZV-induced diseases of the eye . VZV can cause stromal keratitis with corneal anaesthesia, acute retinal necrosis and progressive outer retinal necrosis, particularly in immunocompromised individuals. Patients complain of eye pain and loss of vision. Retinal haemorrhages and whitening with bilateral macular involvement may occur. Zoster, aseptic meningitis, vasculitis or myelitis can precede retinal necrosis 89 . As with neurological disease, VZV-associated ocular disorders can also occur without rash.

Diagnosis, screening and prevention

Diagnosis of varicella and zoster is most often made clinically on the basis of the characteristic generalized or unilateral dermatomal vesicular rashes, respectively. Notable exceptions include the following characteristics: atypical rashes, such as disseminated zoster or a minimal or absent dermatomal rash; zosteriform herpes simplex; modified (breakthrough) varicella in vaccinated individuals; and rashes caused by enteroviruses, poxviruses, rickettsia, drug reactions or contact dermatitis; and VZV infection in the absence of a rash. The latter includes, for example, zoster without rash (known as zoster sine herpete, sometimes with or without facial palsy 90 ), meningitis 1 , 91 , 92 , stroke 81 , 93 – 97 , myelitis 98 and enteric (gastrointestinal) infections 45 , 99 – 102 . In these settings, rapid diagnosis is necessary to plan appropriate therapy and public health measures. Diagnosis by measurement of VZV-specific antibodies in serum samples is accurate but does not yield results rapidly enough to be clinically useful because of the time it takes for patients to develop antibodies. Serum antibodies are generally of no help unless anti-VZV IgM is detected and even its presence can be nonspecific.

For laboratory diagnosis of VZV infection, the following approaches are currently most useful: PCR on material from skin vesicles (submitted as swabs, fluid or scabs102–104), saliva 90 , 102 , 103 , 105 – 107 and cerebrospinal fluid if neurological symptoms or signs are present 91 , 92 , 108 , 109 . Detection of VZV antigens by direct immunofluorescence from vesicles is also rapid and specific, although less sensitive than PCR 110 . During varicella and zoster, viral DNA can be detected in saliva, and this method is diagnostically useful and specific in symptomatic patients with or without rash 102 , 104 , 106 . PCR along with restriction enzyme digest and sequencing of specific segments of the viral genome can be used to determine whether VZV is resistant to acyclovir 111 .

When symptoms develop in vaccinated individuals that suggest VZV infection, such as rash or meningitis (even without rash), it is important to identify VZV by PCR, and it can be useful to determine whether the virus is wild-type VZV or vOka 104 , 112 – 114 . In the United States, testing can be performed free of charge at either the National Virus Laboratory at the Centers for Disease Control and Prevention (CDC) or the Columbia University VZV Identification Program of the Worldwide Adverse Experience System of Merck & Co. The FDA is notified of these results if they are related to complications of vaccination, and clinical information on these vaccinated patients is often published 2 . Other countries have similar testing facilities (for example, the VZV Reference Laboratory in the United Kingdom) 115 .

Notably, VZV DNA can be detected transiently in the saliva of severely stressed adults 116 and children 117 in the absence of specific symptoms, indicating subclinical reactivation of the virus. Nevertheless, testing of saliva is remarkably specific because VZV DNA is rarely detected in asymptomatic human volunteers aged <60 years 40 , 102 , 118 . The presence of VZV DNA does not necessarily equate to the presence of infectious virus. During zoster, a single infected cell can contain thousands of copies of VZV DNA and that DNA can persist long after infectious VZV has been cleared. ‘Contained reversions’ (silent reactivation of latent VZV) ( Fig. 5 ) may also be a source of VZV DNA, which makes it problematic to demonstrate that vasculopathy without rash is a complication of zoster or that PHN is associated with continuing VZV replication. Furthermore, despite evidence of asymptomatic shedding of VZV DNA, there is little epidemiological evidence to indicate that asymptomatic individuals transmit VZV infection 3 , 4 . By contrast, most infections with herpes simplex virus result from asymptomatic shedding. Nevertheless, detection of VZV DNA in saliva or blood in immunocompetent individuals with minimal symptoms may permit diagnostic suspicion of early zoster before rash onset and the initiation of antiviral therapy sufficiently early to halt ganglionic infection before the damage responsible for PHN has occurred.

The classic model of zoster pathogenesis first described by Hope-Simpson 20 links viral replication and clinical disease with the levels of cell-mediated immunity (CMI). In primary infection, no immunity to varicella zoster virus (VZV) exists and infection becomes apparent as varicella. CMI then controls replication, and reactivation of the virus remains subclinical and asymptomatic (‘contained reversions’). Exogenous contact with VZV can boost CMI; nevertheless, CMI levels decrease over time and when they fall below a critical level, zoster can develop. Adapted with permission from Ref. 20 , The Royal Society of Medicine.

Routine screening of asymptomatic individuals for VZV infection is currently not recommended.

Varicella vaccine . A live attenuated varicella vaccine was developed in Japan by Takahashi and colleagues in 1974 (Ref. 119 ). VZV was isolated from a boy with varicella, and the virus was attenuated by cultivation for 33 serial passages in human and guinea pig fibroblasts, with some passages at low temperature (34 °C) 119 . Live, attenuated vOka consists of a mixture of distinct VZV genotypes, with 42 single nucleotide polymorphisms distinguishing vOka from the wild-type Oka parent strain 120 , 121 . The exact mechanisms for the attenuation of VZV in live vaccines remain unknown; mutations in ORF62 were identified in vOka 122 and mutations at positions 106262, 107252 and 108111 in ORF62 are important 112 , as is a stop codon mutation at position 560 in ORF0 (Ref. 123 ). These mutations, particularly the unique mutations at positions 106262 and 108111 in ORF62 , can be used to differentiate parental Oka and other wild-type strains of VZV from vOka 104 , 112 .

Initially, the vaccine was highly controversial because of the fear of latent vOka, the possibility that the virus might be oncogenic and the possibility that immunity from vaccination would not be long-lasting. The vaccine was tested in Japan for ∼ 5 years before reaching the rest of the world 124 , 125 . By 1979, there was much interest in the vaccine in the United States because many young children who had been cured of leukaemia died of varicella infection. In a large collaborative trial, >500 children with leukaemia in remission who were still receiving maintenance chemotherapy were vaccinated with vOka. The vaccine was considerably safer than infection with wild-type VZV and protected ∼ 85% of recipients from varicella 126 . Studies in healthy children also demonstrated a high degree of safety and protection against varicella 127 – 129 . In 1995, this live attenuated varicella vaccine was licensed in the United States and routine immunization recommended for healthy American children at 1 year of age 9 . In 2007, when a second dose was shown to offer even greater protection than one dose 130 , a two-dose schedule, with the second dose given at aged 4–6 years or at least 3 months after the first dose, was recommended by the CDC 9 . Two doses of the varicella vaccine are also recommended for older children, adolescents and adults without evidence of varicella immunity, including health-care workers. Currently, the varicella vaccine, using one or two doses, is also licensed in Australia, Brazil, Canada, China, Germany, Greece, Israel, Italy, Japan, Qatar, South Korea, Spain, Taiwan and Uruguay.

In countries without varicella vaccination, prevention by passive immunization (injection of VZV-specific antibodies) might be available, which provides temporary protection for several weeks 131 . Antiviral therapy has been used for the prevention of varicella 132 , 133 and zoster 134 , 135 in immunocompromised patients, but is not uniformly accepted as useful. Acyclovir-resistant VZV rarely develops in a small number of treated immunocompromised patients 136 – 138 .

Immunity after vaccination . The varicella vaccine is highly effective in preventing varicella, with little decline in immunity over time 139 , 140 . Between 1995 and 2003 the incidence of varicella decreased by 80% in some areas of the United States 141 , and the number of hospitalizations and deaths decreased 19 . In a study of >7,000 vaccine recipients, long-lasting (15 years) immunity was demonstrated, with 90% efficacy in preventing varicella despite 70% of children having received only one dose of the vaccine 139 . At present, there seems to be no need for booster doses of the varicella vaccine because significant waning immunity has not been observed 139 , 140 .

Silent reactivation (contained reversions) of latent VZV ( Fig. 5 ) can boost immunity endogenously 2 and is likely to contribute to long-lasting immunity to varicella and zoster 20 . Exogenous boosting due to exposure to individuals with VZV infections also occurs 27 , 142 ( Fig. 5 ). Not appreciating the potentially important role of asymptomatic reactivation in maintaining immunity to VZV, epidemiologists predicted that widespread vaccination and the resulting lack of exogenous immune stimulation would result in increased incidence of zoster 143 , 144 . This has been the justification for not using the varicella vaccine universally in children in several countries in Europe. The incidence of zoster has been increasing in the United States since the 1950s, long before the varicella vaccine was available, and increases are also reported in other countries without vaccination programmes 145 . Thus, it seems that the varicella vaccine is unlikely to contribute substantially to an increase in the incidence of zoster. The role of subclinical (or mild) endogenous reactivation of latent VZV in maintaining immunity is evidenced by a study performed in France: the rate of zoster (15–16%) in isolated populations over ∼ 30 years was no higher than it was in the general public 146 . Accordingly, latency (with the possibility of silent or minimal viral reactivation) might be an asset rather than a liability for the varicella vaccine 146 .

Vaccine safety . The varicella vaccine is safe and well tolerated. Serious adverse events after vaccination are unusual; ∼ 100 million children and adults have been vaccinated and vaccine-related serious adverse event reactions have been very rarely reported and have occurred almost exclusively in recipients who were immunocompromised but not recognized to be so 3 , 138 . The development of varicella in vaccine recipients (breakthrough varicella) is unusual, and when it occurs it is almost invariably mild 3 .

Vaccinated children who develop a rash in the first month after immunization rarely transmit vOka to close contacts; those who develop varicella due to wild-type VZV are more likely to transmit the virus to others 3 . Transmission is positively correlated with the number of skin lesions 4 , 147 . Rash caused by vOka is unusual following vaccination in children and even if it occurs, vaccinated children usually develop few skin lesions. When wild-type VZV infects vaccinated children, they rarely develop an extensive rash. Transmission of vaccine-type type VZV from vaccinated individuals is rare. The risk of developing zoster after vaccination is lower than after varicella caused by wild-type VZV; at present, 30–50% of cases of zoster in vaccinated children are attributable to wild-type VZV 148 , 149 .

Zoster vaccine . Development of the varicella vaccine paved the way for the development of a vaccine to prevent zoster and its complications 119 . Clinical observations by Hope-Simpson, reported in a landmark publication in 1965 (Ref. 20 ), provided the rationale for the development of a therapeutic zoster vaccine. Hope-Simpson postulated that primary VZV infection establishes life-long latency of VZV in sensory ganglia and induces immunity to VZV that prevents the reactivation, replication and spread of latent VZV and, therefore, zoster. He proposed that this immunity gradually decreases, eventually permitting latent VZV to reactivate, multiply and re-emerge as zoster. He further proposed that both exogenous and endogenous exposure to VZV stimulate the host's immunity ( Fig. 5 ). Noting that second episodes of zoster were uncommon, he proposed that an episode of zoster also stimulates immunity to VZV, essentially immunizing the host against another episode of zoster. Subsequent investigations have validated every component of Hope-Simpson's prescient hypothesis 3 , 150 .

In the Shingles Prevention Study (SPS), a double-blind, placebo-controlled trial, 38,546 healthy adults aged ≥60 years (median 69 years) were randomly assigned to receive a single dose of high-potency vOka (14 times greater potency than the varicella vaccine) or placebo 22 , 151 , 152 . Two co-primary end points were investigated: the burden of illness owing to zoster (a severity-by-duration measure representing the total pain and discomfort) and the incidence of clinically significant PHN. The incidence of zoster was also determined. The higher-potency vaccine was required to increase VZV-specific cell-mediated immunity in latently infected older adults 22 , 151 .

A total of 19,270 people who received the zoster vaccine and 19,276 who received placebo were followed up on average for 3.13 years 22 , 152 . There were 957 confirmed evaluable cases of zoster (315 in vaccine recipients and 642 in placebo recipients). In both groups, >93% of the subjects with zoster were positive for wild-type VZV DNA by PCR and none had vOka DNA 22 , 104 .

The vaccine reduced burden of disease by 61.1% (65.5% in people aged 60–69 years and 55.4% in people aged ≥70 years). The duration of pain and discomfort among subjects with zoster was shorter in vaccinated candidates compared with placebo recipients 22 , 152 . The vaccine reduced the incidence of zoster by 51.3% (63.9% in people aged 60–69 years but only 37.6% in people aged ≥70 years). The incidence of clinically significant PHN was reduced by more than 65% for both age groups. Furthermore, the zoster vaccine reduced the percentage of people with zoster who developed PHN by >31%, with most benefit in the group aged ≥70 years, which had the highest risk of developing this complication 22 , 152 . The SPS also demonstrated that the vaccine reduced the adverse impact of zoster on patients' capacity to perform activities of daily living and health-related quality of life 153 .

The zoster vaccine is safe. Rates of serious adverse events, systemic adverse events, hospitalizations and deaths in the SPS were low in vaccine recipients and comparable with those in placebo recipients 22 , 151 , 154 . During the first 42 days after vaccination, 24 cases of zoster in placebo recipients were reported and 7 cases in the vaccination group, none of which were caused by vOka 104 . In contrast to prophylactic vaccines, such as those against varicella and measles, the zoster vaccine is a therapeutic vaccine intended to prevent reactivation and replication of latent VZV with which the recipient is already infected before vaccination and to which the recipient already has substantial immunity.

The zoster vaccine was licensed by the FDA in 2006 and recommended by the CDC in 2008 for the routine immunization of healthy adults aged ≥60 years for prevention of zoster and its complications, primarily PHN 155 . Post-licensure studies have confirmed the vaccine's safety and efficacy 151 , 156 , 157 . Unfortunately, uptake of the zoster vaccine has been low, which is probably due to the high cost and general lack of appreciation of the importance of preventing infectious diseases in older adults 121 . The vaccine has now been shown to be safe and effective in healthy individuals aged 50–59 years 158 . At present, the zoster vaccine can be used in this age group but it is not yet officially recommended.

The SPS demonstrated persistent efficacy 4 years after vaccination. In additional substudies 159 , 160 , efficacy for burden of disease persisted for 10 years after vaccination but efficacy for the incidence of zoster persisted only for 8 years 160 . The CDC currently does not recommend booster doses of the zoster vaccine, but it might do in the future.

New subunit vaccine . The development by GlaxoSmithKline of a liposome-based subunit vaccine (HZ/su), which contains the VZV glycoprotein E and the adjuvant ASO1B, promises to change prospects for immunization against zoster and its complications. Phase I and II studies established that two doses of HZ/su containing 50 μg of recombinant VZV glycoprotein E administered 1 or 2 months apart were well tolerated and induced much more robust VZV-specific and VZV glycoprotein E-specific CD4 + T cell and antibody responses than vOka 161 , 162 . Two large Phase III placebo-controlled efficacy trials have been recently completed in individuals aged ≥50 years and in individuals aged ≥70 years 163 , 164 . The efficacy against zoster in the younger study group was ∼ 97%. HZ/su has not been tested for its efficacy in preventing varicella, partly because vOka is extremely effective for this purpose. The adjuvanted glycoprotein E vaccine is non-replicating, and can, therefore, be used in immunosuppressed patients who are currently precluded from receiving the live attenuated vOka zoster vaccine 155 .

Varicella and its complications

Most varicella in healthy children is mild, self-limiting and uncomplicated. Accordingly, and even though early antiviral therapy can reduce the duration of illness 165 , treatment of uncomplicated varicella in children is usually confined to symptomatic relief. Acetaminophen (paracetamol) is the preferred antipyretic agent because of the association between aspirin and Reye syndrome (life-threatening sudden onset encephalopathy and liver dysfunction) 166 and because of an epidemiological link between ibuprofen and an increased risk of invasive group A streptococcal disease in the context of varicella, although not necessarily a causal one 167 . Topical anti-pruritic agents are of anecdotal benefit. Antiviral therapy is reserved for those with severe varicella or who are considered at greater risk of developing complications owing to age, compromised immunity or chronic diseases of the skin or lungs 9 , 168 ( Fig. 6a ).

a | Antiviral treatment of varicella is indicated in immunocompromised individuals, neonates, patients with chronic skin or lung diseases and in individuals aged >13 years. Patients receive oral acyclovir (ACV), valaciclovir (VACV) or famciclovir (FCV; not approved by the FDA for use in children) unless they are clinically ill or at high risk (most immunocompromised patients are considered to be at high risk, except those who receive long-term, effective immunoglobulin replacement therapy or those who received only mildly immunosuppressive drugs a long time ago). Ill and high risk patients receive intravenous (IV) ACV or foscarnet if the infection is caused by ACV-resistant VZV. Intravenous treatment always needs careful consideration of kidney function. b | The treatment of zoster follows a similar algorithm; here compromised immunity, illness, severe rash, involvement of eyes or face, and other complications are indications for antiviral treatment. In addition to ACV, VACV and FCV, brivudin (BVDU; not approved by the FDA) might be used. Patients who develop varicella or zoster in hospital will generally receive antiviral therapy as part of an infection control strategy. PO, per os (oral administration).

Severe varicella is characterized by extensive and prolonged viral replication, often associated with fever, continued development of new skin vesicles for >5 days, and/or involvement of the lungs, liver and/or brain ( Fig. 3 illustrates a dense vesicular rash in a febrile infant on day 5). Severe varicella is a feared complication that was a major impetus towards vaccine development. Severe varicella has caused many deaths in individuals with congenital or acquired impairment of cellular immunity, even after the development of antiviral therapy 169 . Children with impaired innate immunity, for example, those with natural killer cell abnormalities, are also at risk for severe varicella, including that caused by vOka 170 . Thus, strenuous measures should be taken to prevent VZV infection in this group, including post-exposure prophylaxis 9 , 171 . Since the 1980s, the main treatment has been antiviral therapy with high-dose intravenous acyclovir 172 together with supportive intensive care. Acyclovir is a guanosine analogue that inhibits the synthesis of viral DNA ( Fig. 7 ) and treatment with acyclovir reduces visceral dissemination of the virus. It is typically given for 7–10 days and can be switched to oral therapy 48 h after the last lesions appear or continued until all lesions are crusted. Oral acyclovir has poor bioavailability; thus, the related drugs valaciclovir and famciclovir, which have excellent absorption from the intestinal tract, produce high blood antiviral activity and have a long half-life, should be used for oral therapy instead. Valaciclovir and famciclovir are prodrugs, which are converted to active guanosine analogues in vivo . As both prodrugs need less frequent administration than acyclovir, patient compliance is improved and they are frequently used in children aged >2 years and in adults. Immunocompromised patients with severe VZV infections still receive intravenous acyclovir, which results in higher blood levels than oral therapy. Alternatively, intravenous foscarnet and cidofovir can be used. However, because of toxicity, these drugs should be only used in immunocompromised individuals with acyclovir-resistant VZV. Notably, intravenous antivirals, including acyclovir, can be nephrotoxic; both acyclovir and foscarnet require dose adjustment in patients with renal impairment.

In cells infected with varicella zoster virus (VZV), acyclovir (ACV) is converted by the viral thymidine kinase (TK) to ACV-monophosphate (ACV-MP). The cellular enzymes guanylate (GMP) kinase and nucleoside-diphosphate (NDP) kinase further catalyse the production of ACV-diphosphate (ACV-DP) and ACV-triphosphate (ACV-TP). When the viral DNA polymerase uses ACV-TP, elongation of the DNA chain is terminated. Adapted from Ref. 211 , Nature Publishing Group.

VZV infection in individuals aged >13 years is associated with an increased risk of severe or fatal outcome, and oral antiviral therapy is recommended, even in otherwise healthy adolescents and adults 3 ( Fig. 6 ). In immunocompetent patients, oral acyclovir, or preferably famciclovir, or valaciclovir need to be started within 24 h of the first skin lesions to shorten the duration of fever and rash 173 ; 5 days and 7 days of treatment have comparable efficacy 174 .

Varicella in pregnant women is also problematic: pregnancy increases the risk of severe disease in the mother and VZV can harm the unborn child and lead to congenital abnormalities (congenital varicella syndrome) 17 , 175 . Thus, pregnant women with varicella are usually treated with intravenous acyclovir, even though this is a category B drug (that is, animal studies have failed to demonstrate a risk to the fetus but no well-controlled studies have been conducted in pregnant women) and not licensed in pregnancy. The effect of treatment on the development of congenital varicella syndrome is unknown. Maternal onset of varicella between 5 days before and 2 days after delivery is associated with a high risk of severe varicella in the newborn, who should receive prophylaxis with VZV-specific immunoglobulin 175 . Newborns with congenital varicella syndrome should receive high-dose intravenous acyclovir every 8 h owing to increased clearance of the drug in this age group. Oral acyclovir is poorly absorbed and should be used cautiously, if at all.

Bacterial superinfection is the most common severe complication of varicella; varicella is a major risk factor for invasive group A streptococcal disease 176 . Superinfection presents with recurrence of fever with or without localized signs of cellulitis (infection of the skin and subcutaneous fat tissue), bone and joint infection or pneumonia. Cellulitic features accompanied by disproportionate pain, fatigue and systemic signs and symptoms can indicate necrotizing fasciitis, even in the absence of fever, and should prompt immediate antibacterial therapy together with resuscitative measures, analgesia and urgent consideration of surgical debridement. Other possible complications of varicella are cerebellar ataxia, ischaemic stroke and acquired protein S deficiency with purpura fulminans and venous thrombosis 3 , 177 , 178 . The effect of antiviral therapy on individual complications is unclear but a pragmatic approach is to treat if there is evidence of ongoing viral replication (such as continuing new vesicle formation and/or persistent PCR positivity in blood or cerebrospinal fluid in a symptomatic patient).

Zoster and PHN

Antiviral therapy is recommended for patients with zoster, particularly those who are immunocompromised, aged ≥50 years, have lesions involving the face or eye, severe rash or other complications of zoster (reviewed in Refs 179 , 180 ) ( Fig. 6b ). Oral acyclovir, valaciclovir or famciclovir are used to treat immunocompetent patients in the United States. Oral brivudin is available in some European countries and VZV is more sensitive to brivudin than to other antivirals. As mentioned above, valaciclovir or famciclovir, rather than acyclovir, are preferred due to their higher bioavailability and easier dosing regimen; furthermore, they may be more effective than acyclovir for reducing acute zoster pain 181 , 182 . Treatment is usually given for 7–10 days and reduces the time to cessation of new lesion formation, to lesion crusting and to cessation of acute pain 183 . Immunocompromised patients, hospitalized patients or those with neurological complications are treated for 7–10 days with intravenous acyclovir, which has been shown to reduce the risk of visceral disease and skin dissemination 3 . Foscarnet is used for patients with acyclovir-resistant VZV. Antiviral therapy should be initiated within 3 days of the onset of rash if possible, but should still be initiated if patients are seen later with continuing new lesion formation. Although antiviral therapy reduces acute pain associated with zoster, it has not been shown to reliably reduce the risk of PHN, nor is it recommended to treat established PHN 74 . Prednisone reduces acute pain and improves the ability of patients with zoster to perform activities of daily living 184 ; however, prednisone does not reduce the risk of PHN 185 and many elderly patients have conditions such as hypertension, diabetes mellitus or osteoporosis, which may preclude the use of this drug. Antiviral therapy should be given whenever prednisone is used.

Mild pain associated with zoster can be treated with NSAIDs or acetaminophen. Lidocaine patches can reduce local pain, although they should only be used on intact skin and can cause local irritation. For more-severe pain, opioids or opioid agonists (oxycodone or tramadol), anticonvulsants (gabapentin or pregabalin) or tricyclic antidepressants (nortriptyline) have been used 180 , 186 . Oxycodone was more effective than gabapentin in a randomized controlled trial 186 . Systemic therapies need to be gradually increased as tolerated, and titrated specifically for each patient. Systemic therapies are often associated with drowsiness and/or dizziness; these adverse effects may be problematic, particularly in the elderly. Gabapentin and pregabalin can cause ataxia and peripheral oedema whereas nortriptyline has been associated with dry mouth, urinary retention and weight gain.

Immunocompetent patients with Ramsay Hunt syndrome (peripheral facial weakness, zoster rash and pain inside the ear, and loss of taste in the anterior part of the tongue) should be treated with oral antivirals and prednisone. Patients with zoster involving the eye should be evaluated by an ophthalmologist; additional therapy might be needed to reduce intraocular pressure, to reduce the risk of scar formation in the eye, or to treat keratitis, iritis or episcleritis. Early antiviral therapy has been correlated with a better outcome in patients with zoster ophthalmicus 187 . Patients with vasculopathy should be treated with intravenous acyclovir and prednisone 86 .

PHN is often very difficult to treat and fewer than half of patients have a substantial reduction in pain. Moreover, the currently available medications only treat symptoms and not the underlying cause of the pain. Treatments include topical lidocaine (often considered first-line therapy), topical capsaicin, gabapentin, pregabalin and tricyclic antidepressants 75 . Topical capsaicin is often difficult to tolerate owing to pain and erythema. Combined treatments, such as gabapentin and nortriptyline 188 , can be more effective, but adverse effects are often increased. As noted above, these systemic drugs all have adverse effects that can be challenging for elderly patients and the dosage must be titrated for each patient. Although opioids are sometimes used, they are considered third-line drugs because of the potential for abuse and uncertainty about their long-term benefits 189 . Referral to a pain specialist is often helpful. Other therapies, including acupuncture, intrathecal injection of corticosteroids, injection of local anaesthetics and nerve blocks have not shown consistent benefits.

Quality of life

In the early twentieth century, varicella and zoster seemed to be diseases of little consequence compared with other common infections such as influenza, measles and poliomyelitis, which frequently were fatal. There was little demand for treatment because both infections were usually mild and self-limiting. Life expectancy was shorter than it is today, which limited the number of zoster cases. Varicella illness lasted only a few days, and meant a few days off from school. School curricula permitted missing a few days without consequence and most families had one parent at home who could care for their sick children.

Then technological developments, new procedures, such as transplantation and drugs to treat cancer, improved medical care and increased life expectancy, but this also increased the number of people susceptible to severe VZV infection. For example, curing children with leukaemia became possible but, at the same time, damage to the immune system by chemotherapy and other curative drugs resulted in severe varicella 169 and subsequent bacterial infections 176 becoming threats. Now, healthy children and those with leukaemia can be protected from varicella by vaccination, the latter by herd immunity. The varicella vaccine also somewhat protects children from zoster 31 , 148 , 190 , 191 .

Today, the varicella and zoster vaccines have dramatically improved quality of life in the United States. Children rarely miss school due to varicella, and fewer working parents need to stay home to care for their sick children. As lifespans have increased, zoster vaccines have become increasingly important. Antiviral therapy and improved diagnostic methods have also decreased the damage VZV can inflict. Basic research has made a tremendous difference in controlling VZV infections and improving quality of life ( Box 2 ).

PHN is a feared consequence of zoster, particularly in the elderly and immunocompromised. Pain from PHN can be so severe it can lead to suicide, and often is a scourge of the retirement years. Zoster impairs activities of daily living and decreases the quality of life 192 . PHN is difficult to treat and thus prevention, for example, by preventing zoster by vaccination with vOka and, in the future, with the new subunit vaccine, remains crucial for the preservation of quality of life in the elderly.

Box 2: Vaccine and antiviral therapy benefits

Fewer cases of varicella and zoster in children and adults

Fewer complications of varicella such as pneumonia, encephalitis, congenital infections, zoster and deaths

Possibly fewer complications of zoster such as vasculopathy and stroke, postherpetic neuralgia, meningitis and paralysis

Convenience for families (fewer school absences, easier for single or working parents)

Decreased transmission of varicella in hospital settings

Given the considerable success of the VZV vaccines, it might be assumed that further research on this virus is unnecessary. This has been the attitude for other viruses such as measles and rubella for which vaccines are available. In fact, the opposite is true: much remains to be learnt about VZV, which, because of latency, is a complicated and persistent human pathogen.

Latency and reactivation

How VZV latency is achieved and maintained is a challenging question. It remains unclear whether VZV latency is a period of relative viral quiescence due to a transient block in complete gene expression or whether the virus is often or constantly in a state of abortive reactivation. Studies of surgical removal of enteric ganglia suggest a block in gene expression 43 , 44 , although recent autopsy studies support the hypothesis of abortive reactivation, but further research is needed 42 . Asymptomatic VZV reactivation is also of great interest. For example, whether some viral genes are translated with or without synthesis of virus particles, and whether these are delivered to skin by axonal transport with or without spread to satellite cells surrounding the neuron, remain unclear. Delivery of virions to skin may not necessarily cause lesions if replication is controlled rapidly by innate immunity and by adaptive immune responses. Further research in this area is important.

The recognition that VZV is a pathogen in the human gut was an unanticipated finding because VZV infections were long associated with cutaneous manifestations, which may not occur when VZV reactivates in enteric neurons. The nature of enteric zoster is, therefore, another issue that requires further study.

Autophagy and herpesviruses

Autophagy is one of the basic mechanisms required for cellular homeostasis and survival. An important role of autophagy is the removal of organelles through autophagosomes and lysosomes. Autophagy, however, is also linked to degenerative processes and cell death. Viruses can also be affected by autophagy. Many herpesviruses, such as herpes simplex virus, encode inhibitors of autophagy, including ICP34.5 and US11 (Refs 193 , 194 , 195 ). By contrast, VZV — the human herpesvirus with the smallest genome — encodes no such inhibitors 196 – 198 .

Perhaps the most intriguing question is why VZV lacks ICP34.5, a homologue of human PPP1R15A (protein phosphatase 1 regulatory subunit 15A; a protein that is involved in recovery from cell stress) 199 . Because ICP34.5 is present in herpes simplex virus 1 and 2, but lacking in VZV and betaherpesviruses, the gene may have been acquired by herpes simplex viruses more recently than 30 million years ago (before the common ancestor of all these viruses) 200 , 201 . Alternatively, VZV could have lost the gene at a later time. In either case, therefore, in an evolutionary sense, VZV is a minimalist herpesvirus that adopted an entirely different intracellular survival strategy than herpes simplex virus. Rather than inhibiting autophagy, VZV might actually depend on autophagy to prolong the life of the infected cell during both primary infection and reactivation 194 , 195 ( Fig. 8 ). However, this dependence on autophagy needs confirmation.

Autophagosomes are present in the skin vesicles during both varicella and zoster. Autophagy is required for the replication of varicella zoster virus (VZV), and replication is enhanced when autophagy is induced. Autophagy can be quantitated by enumeration of autophagosomes 194 . The figure illustrates a monolayer of VZV-infected cells labelled with antibodies against a VZV protein (IE62 protein; red) and autophagosomes (LC3II protein; green); nuclei were stained blue with Hoechst 33342. The monolayer was imaged by confocal microscopy, after which the confocal images were converted into a 3D animation by Imaris software. A single frame from the animation is shown in the figure 195 . Autophagosomes ( ∼ 100) appear as green dots against the background of blue nuclei ( ∼ 70). Many of the nuclei are clustered within a syncytium of VZV-infected cells (red cytoplasm). By contrast, only the nuclei of uninfected cells are visible in this image, as the cytoplasm of uninfected cells is not stained.

Asthma and zoster

Zoster occurs in children but much less often than in adults 20 . VZV reactivation is more common in highly immunosuppressed children who are receiving therapy for cancer or rheumatological diseases 202 . Asthma, a common illness in children, might also increase the rate of zoster 203 . Asthma is an inflammatory disorder of the airways with a skewed T cell response, increased IgE production and alterations in innate immunity, including cytokine dysregulation 203 . A population-based case–control study in Minnesota, USA, showed a higher incidence of zoster in children with asthma than in those without asthma; inhaled or systemic corticosteroids were excluded as a cause for this difference 204 . Subsequently, a similar analysis was carried out in a much larger adult study cohort in Spain, with similar results 205 . Asthma might, therefore, be a contributing cause to VZV reactivation in both children and adults, suggesting that intact innate immunity, a normal balance of T helper 1 and 2 responses or the absence of chronic inflammation from asthma may be involved in maintenance of latency. Further research on this subject is needed.

Research questions and needs

Although there is progress, eradication of VZV remains a challenge. Reactivation of VZV after natural infection or vaccination is a worldwide problem for elderly and immunosuppressed individuals. Zoster is considered to be a consequence of diminished adaptive cellular immunity 2 , 20 . A recent publication on VZV-specific antibody titres after zoster vaccination, however, raises a decades' old argument of whether higher adaptive humoral immunity can predict protection against zoster. Further exploration of this concept could be worthwhile because the development of an antibody test to predict the susceptibility to varicella and zoster would be extremely useful clinically.

A remaining question regarding VZV includes how similar VZV is to its close alphaherpesvirus relatives herpes simplex virus 1 and 2. For years it was claimed that all three viruses are highly similar, but with modern molecular research this concept has been challenged 206 . For example, reactivation of herpes simplex viruses has been claimed to be common, whereas reactivation of VZV is uncommon. More recently, it has been recognized that VZV frequently reactivates asymptomatically. One obvious and so far unexplained difference between VZV and herpes simplex viruses is why developing preventive and therapeutic VZV vaccines has been possible, whereas successful vaccines against herpes simplex viruses remain elusive. Further comparative research between these viruses is needed.

A challenge for VZV vaccination is how to broaden acceptance of the varicella vaccine worldwide and possibly to improve it by developing a more stable vaccine. The WHO now recommends the use of vOka in countries where varicella has a substantial impact on public health. Countries should consider vaccination of potentially susceptible health-care workers (that is, unvaccinated individuals with no history of varicella) with two doses of the varicella vaccine, even if it is not included in the routine immunization schedule, in settings where the risk of severe varicella in the population in direct contact with the health-care workers is high. In the future, the subunit zoster vaccine seems particularly useful for wide distribution because of its stability, probable relatively low cost, and the possibility of using it in immunocompromised individuals who cannot receive live, replicating vOka. However, whether the subunit vaccine can also be used to induce stable primary immunity to varicella is unclear. The broad immune responses stimulated by the live attenuated vaccine may be necessary to produce robust immunity to varicella. In fact, long-lasting immunity, which is essential, might depend on the ability of vOka to establish latency and reactivate subclinically. Thus, the inability of the subunit vaccine to establish latent infection might prove to be a disadvantage. Despite the current successes of VZV vaccines, further research in this area is likely to be productive.

In closing, the authors would like to acknowledge and memorialize the seminal contributions to our understanding of varicella and zoster by the following late pioneers in this field: Nobel Laureate Thomas Huckle Weller, MD 207 , 208 , Robert Edgar Hope-Simpson, MD 20 , and Michiaki Takahashi, MD 119 .

Gilden, D., Cohrs, R. J., Mahalingam, R. & Nagel, M. A. Neurological disease produced by varicella zoster virus reactivation without rash. Curr. Top. Microbiol. Immunol. 342 , 243–253 (2010).

CAS PubMed PubMed Central Google Scholar

Gershon, A. A. & Gershon, M. D. Pathogenesis and current approaches to control of varicella-zoster virus infections. Clin. Microbiol. Rev. 26 , 728–743 (2013).

Article CAS PubMed PubMed Central Google Scholar

Gershon, A. A., Takahashi, M. & Seward, J. F. in Vaccines (eds Plotkin, S., Orenstein, W. & Offit, P. ) 915–958 (Saunders Elsevier, 2011).

Google Scholar

Tsolia, M., Gershon, A. A., Steinberg, S. P. & Gelb, L. Live attenuated varicella vaccine: evidence that the virus is attenuated and the importance of skin lesions in transmission of varicella-zoster virus. National Institute of Allergy and Infectious Diseases Varicella Vaccine Collaborative Study Group. J. Pediatr. 116 , 184–189 (1990). A study demonstrating that VZV spreads from skin lesions.

Article CAS PubMed Google Scholar

Chen, J. J., Zhu, Z., Gershon, A. A. & Gershon, M. D. Mannose 6-phosphate receptor dependence of varicella zoster virus infection in vitro and in the epidermis during varicella and zoster. Cell 119 , 915–926 (2004). This study demonstrates the importance of the skin in VZV infection and identifies the cellular receptor that the virus uses for infection.

Weller, T. H. Varicella: historical perspective and clinical overview. J. Infect. Dis. 174 (Suppl.), S306–S309 (1996).

Article PubMed Google Scholar

World Health Organization. Varicella and herpes zoster vaccines: WHO position paper, June 2014. Wkly Epidemiol. Rec. 89 , 265–287 (2014).

Breuer, J., Grose, C., Norberg, P., Tipples, G. & Schmid, D. S. A proposal for a common nomenclature for viral clades that form the species varicella-zoster virus: summary of VZV Nomenclature Meeting 2008, Barts and the London School of Medicine and Dentistry, 24–25 July 2008. J. Gen. Virol. 91 , 821–828 (2010). This paper describes the five different clades of VZV.

Marin, M., Güris, D., Chaves, S. S., Schmid, S. & Seward, J. F. Prevention of varicella: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR. Recomm. Rep. 56 , 1–40 (2007).

PubMed Google Scholar

Liyanage, N. P. M. et al . Seroprevalence of varicella zoster virus infections in Colombo district Sri Lanka. Indian J. Med. Sci. 61 , 128–134 (2007).

Lolekha, S. et al . Effect of climatic factors and population density on varicella zoster virus epidemiology within a tropical country. Am. J. Trop. Med. Hyg. 64 , 131–136 (2001).

Izurieta, H. S., Strebel, P. M. & Blake, P. A. Postlicensure effectiveness of varicella vaccine during an outbreak in a child care center. JAMA 278 , 1495–1499 (1997).

Levy, M. H. et al . Pox in the docks: varicella outbreak in an Australian prison system. Publ. Health 117 , 446–451 (2003).

Article Google Scholar

Longfield, J. N., Winn, R. E., Gibson, R. L., Juchau, S. V. & Hoffman, P. V. Varicella outbreaks in army recruits from Puerto Rico. Varicella susceptibility in a population from the tropics. Arch. Intern. Med. 150 , 970–973 (1990).

Galil, K., Brown, C., Lin, F. & Seward, J. Hospitalizations for varicella in the United States, 1988 to 1999. Pediatr. Infect. Dis. J. 21 , 931–935 (2002). This paper describes the effects of the varicella vaccine (decreased morbidity and mortality in the United States).

Rawson, H., Crampin, A. & Noah, N. Deaths from chickenpox in England and Wales 1995-7: analysis of routine mortality data. BMJ 323 , 1091–1093 (2001).

Enders, G. Varicella-zoster virus infection in pregnancy. Prog. Med. Virol. 29 , 166–196 (1984).

CAS PubMed Google Scholar

Bialek, S. R. et al . Impact of a routine two-dose varicella vaccination program on varicella epidemiology. Pediatrics 132 , e1134–e1140 (2013).

Marin, M., Zhang, J. X. & Seward, J. F. Near elimination of varicella deaths in the US after implementation of the vaccination program. Pediatrics 128 , 214–220 (2011).

Hope-Simpson, R. E. The nature of herpes zoster: a long-term study and a new hypothesis. Proc. R. Soc. Med. 58 , 9–20 (1965). This paper demonstrates the age-dependent incidence and severity of zoster and presents a hypothesis regarding the complex immune response to the virus.

Weitzman, D. et al . A population based study of the epidemiology of herpes zoster and its complications. J. Infect. 67 , 463–469 (2013).

Oxman, M. N. et al . A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N. Engl. J. Med. 352 , 2271–2284 (2005). This article presents the first demonstration of a successful therapeutic vaccine against zoster.

Yawn, B. P. et al . A population-based study of the incidence and complication rates of herpes zoster before zoster vaccine introduction. Mayo Clin. Proc. 82 , 1341–1349 (2007).

Forbes, H. J. et al . Quantification of risk factors for herpes zoster: population based case–control study. BMJ 348 , g2911 (2014).

Schmader, K., George, L. K., Burchett, B. M., Pieper, C. F. & Hamilton, J. D. Racial differences in the occurrence of herpes zoster. J. Infect. Dis. 171 , 701–704 (1995).

Arvin, A. M., Koropchak, C. M. & Wittek, A. E. Immunologic evidence of reinfection with varicella-zoster virus. J. Infect. Dis. 148 , 200–205 (1983).

Thomas, S. L., Wheeler, J. G. & Hall, A. J. Contacts with varicella or with children and protection against herpes zoster in adults: a case–control study. Lancet 360 , 678–682 (2002).

Brisson, M. et al . Modeling the impact of one- and two-dose varicella vaccination on the epidemiology of varicella and zoster. Vaccine 28 , 3385–3397 (2010).

Hales, C. M., Harpaz, R., Joesoef, M. R. & Bialek, S. R. Examination of links between herpes zoster incidence and childhood varicella vaccination. Ann. Intern. Med. 159 , 739–745 (2013).

Article PubMed PubMed Central Google Scholar

Leung, J., Harpaz, R., Molinari, N.-A., Jumaan, A. & Zhou, F. Herpes zoster incidence among insured persons in the United States, 1993-2006: evaluation of impact of varicella vaccination. Clin. Infect. Dis. 52 , 332–340 (2011).

Hardy, I., Gershon, A. A., Steinberg, S. P. & LaRussa, P. The incidence of zoster after immunization with live attenuated varicella vaccine. A study in children with leukemia. Varicella Vaccine Collaborative Study Group. N. Engl. J. Med. 325 , 1545–1550 (1991). This article provides the first solid evidence that vaccination against varicella decreases the incidence of zoster.

Ku, C.-C., Padilla, J. A., Grose, C., Butcher, E. C. & Arvin, A. M. Tropism of varicella-zoster virus for human tonsillar CD4 + T lymphocytes that express activation, memory, and skin homing markers. J. Virol. 76 , 11425–11433 (2002).

Ku, C.-C. et al . Varicella-zoster virus transfer to skin by T cells and modulation of viral replication by epidermal cell interferon-α. J. Exp. Med. 200 , 917–925 (2004). This paper reveals how VZV infects human hosts in primary infection, how the virus spreads in the body and the early role of innate immunity in its control.

Sen, N. et al . Single-cell mass cytometry analysis of human tonsil T cell remodeling by varicella zoster virus. Cell Rep. 8 , 633–645 (2014). This article provides the first demonstration that VZV remodels host cells to increase its infectivity.

Levin, M. J. Varicella-zoster virus and virus DNA in the blood and oropharynx of people with latent or active varicella-zoster virus infections. J. Clin. Virol. 61 , 487–495 (2014).

Arvin, A. M. & Gilden, D. H. in Fields Virology (eds Knipe, D. & Howley, P. ) 2015–2057 (Lippincott, 2013).

Gershon, A. A. et al . Latency of varicella zoster virus in dorsal root, cranial, and enteric ganglia in vaccinated children. Trans. Am. Clin. Climatol. Assoc. 123 , 17–33; discussion 33–35 (2012).

PubMed PubMed Central Google Scholar

Mahalingam, R. et al . Simian varicella virus infects ganglia before rash in experimentally infected monkeys. Virology 279 , 339–342 (2001).

Gan, L., Wang, M., Chen, J. J., Gershon, M. D. & Gershon, A. A. Infected peripheral blood mononuclear cells transmit latent varicella zoster virus infection to the guinea pig enteric nervous system. J. Neurovirol. 20 , 442–456 (2014).

Levin, M. J., Cai, G.-Y., Manchak, M. D. & Pizer, L. I. Varicella-zoster virus DNA in cells isolated from human trigeminal ganglia. J. Virol. 77 , 6979–6987 (2003).

Gary, L., Gilden, D. H. & Cohrs, R. J. Epigenetic regulation of varicella-zoster virus open reading frames 62 and 63 in latently infected human trigeminal ganglia. J. Virol. 80 , 4921–4926 (2006).

Ambagala, A. P. et al . Varicella-zoster virus immediate-early 63 protein interacts with human antisilencing function 1 protein and alters its ability to bind histones h3.1 and h3.3. J. Virol. 83 , 200–209 (2009).

Plotkin, S. A., Stein, S., Snyder, M. & Immesoete, P. Attempts to recover varicella virus from ganglia. Ann. Neurol. 2 , 249 (1977).

Ouwendijk, W. J. D. et al . Restricted varicella-zoster virus transcription in human trigeminal ganglia obtained soon after death. J. Virol. 86 , 10203–10206 (2012).

Chen, J. J., Gershon, A. A., Li, Z., Cowles, R. A. & Gershon, M. D. Varicella zoster virus (VZV) infects and establishes latency in enteric neurons. J. Neurovirol. 17 , 578–589 (2011). This study demonstrates the latency of VZV in the enteric nervous system.

Gershon, A. A., Chen, J. & Gershon, M. D. A model of lytic, latent, and reactivating varicella-zoster virus infections in isolated enteric neurons. J. Infect. Dis. 197 (Suppl.), S61–S65 (2008).

Chen, J. J., Gershon, A. A., Li, Z. S., Lungu, O. & Gershon, M. D. Latent and lytic infection of isolated guinea pig enteric ganglia by varicella zoster virus. J. Med. Virol. 70 (Suppl. 1), S71–S78 (2003).

Head, H., Campbell, A. & Kennedy, P. The pathology of herpes zoster and its bearing on sensory localisation. Rev. Med. Virol. 7 , 131–143 (1997).

Schmidbauer, M., Budka, H., Pilz, P., Kurata, T. & Hondo, R. Presence, distribution and spread of productive varicella zoster virus infection in nervous tissues. Brain 115 , 383–398 (1992).

Steain, M. et al . Analysis of T cell responses during active varicella-zoster virus reactivation in human ganglia. J. Virol. 88 , 2704–2716 (2014).

Gowrishankar, K. et al . Characterization of the host immune response in human ganglia after herpes zoster. J. Virol. 84 , 8861–8870 (2010). This paper describes the immunological events in latently infected dorsal root ganglia.

Grinfeld, E. & Kennedy, P. G. E. Translation of varicella-zoster virus genes during human ganglionic latency. Virus Genes 29 , 317–319 (2004).

Lungu, O., Panagiotidis, C. A., Annunziato, P. W., Gershon, A. A. & Silverstein, S. J. Aberrant intracellular localization of varicella-zoster virus regulatory proteins during latency. Proc. Natl Acad. Sci. USA 95 , 7080–7085 (1998).

Cohrs, R. J., Gilden, D. H., Kinchington, P. R., Grinfeld, E. & Kennedy, P. G. E. Varicella-zoster virus gene 66 transcription and translation in latently infected human ganglia. J. Virol. 77 , 6660–6665 (2003). A study of the VZV gene expression in the latent infection of neurons.

Azarkh, Y., Gilden, D. & Cohrs, R. J. Molecular characterization of varicella zoster virus in latently infected human ganglia: physical state and abundance of VZV DNA, quantitation of viral transcripts and detection of VZV-specific proteins. Curr. Top. Microbiol. Immunol. 342 , 229–241 (2010).

Walters, M. S., Kyratsous, C. A., Wan, S. & Silverstein, S. Nuclear import of the varicella-zoster virus latency-associated protein ORF63 in primary neurons requires expression of the lytic protein ORF61 and occurs in a proteasome-dependent manner. J. Virol. 82 , 8673–8686 (2008).

Zerboni, L. et al . Expression of varicella-zoster virus immediate-early regulatory protein IE63 in neurons of latently infected human sensory ganglia. J. Virol. 84 , 3421–3430 (2010).

Zerboni, L. et al . Apparent expression of varicella-zoster virus proteins in latency resulting from reactivity of murine and rabbit antibodies with human blood group a determinants in sensory neurons. J. Virol. 86 , 578–583 (2012).

Stowasser, M., Cameron, J. & Oliver, W. A. Diaphragmatic paralysis following cervical herpes zoster. Med. J. Aust. 153 , 555–556 (1990).

Jellinek, E. H. & Tulloch, W. S. Herpes zoster with dysfunction of bladder and anus. Lancet 2 , 1219–1222 (1976).

Umehara, T., Sengoku, R., Mitsumura, H. & Mochio, S. Neurological picture. Findings of segmental zoster paresis on MRI. J. Neurol. Neurosurg. Psychiatry 82 , 694 (2011).

Choi, J.-Y., Kang, C. H., Kim, B.-J., Park, K.-W. & Yu, S.-W. Brachial plexopathy following herpes zoster infection: two cases with MRI findings. J. Neurol. Sci. 285 , 224–226 (2009).

Thomas, J. E. & Howard, F. M. Segmental zoster paresis — a disease profile. Neurology 22 , 459–466 (1972).

Smith, F. P. Pathological studies of spinal nerve ganglia in relation to intractable intercostal pain. Surg. Neurol. 10 , 50–53 (1978).

Watson, C. P., Watt, V. R., Chipman, M., Birkett, N. & Evans, R. J. The prognosis with postherpetic neuralgia. Pain 46 , 195–199 (1991).

Lai, J., Porreca, F., Hunter, J. C. & Gold, M. S. Voltage-gated sodium channels and hyperalgesia. Annu. Rev. Pharmacol. Toxicol. 44 , 371–397 (2004).

Kennedy, P. G. E. et al . Varicella-zoster viruses associated with post-herpetic neuralgia induce sodium current density increases in the ND7-23 Nav-1.8 neuroblastoma cell line. PLoS ONE 8 , e51570 (2013).

Mahalingam, R., Wellish, M., Brucklier, J. & Gilden, D. H. Persistence of varicella-zoster virus DNA in elderly patients with postherpetic neuralgia. J. Neurovirol. 1 , 130–133 (1995).

Gilden, D. H., Cohrs, R. J., Hayward, A. R., Wellish, M. & Mahalingam, R. Chronic varicella-zoster virus ganglionitis — a possible cause of postherpetic neuralgia. J. Neurovirol. 9 , 404–407 (2003).

Beutner, K. R., Friedman, D. J., Forszpaniak, C., Andersen, P. L. & Wood, M. J. Valaciclovir compared with acyclovir for improved therapy for herpes zoster in immunocompetent adults. Antimicrob. Agents Chemother. 39 , 1546–1553 (1995).

Degreef, H. Famciclovir, a new oral antiherpes drug: results of the first controlled clinical study demonstrating its efficacy and safety in the treatment of uncomplicated herpes zoster in immunocompetent patients. Int. J. Antimicrob. Agents 4 , 241–246 (1994).

Acosta, E. P. & Balfour, H. H. Acyclovir for treatment of postherpetic neuralgia: efficacy and pharmacokinetics. Antimicrob. Agents Chemother. 45 , 2771–2774 (2001).

Quan, D., Hammack, B. N., Kittelson, J. & Gilden, D. H. Improvement of postherpetic neuralgia after treatment with intravenous acyclovir followed by oral valacyclovir. Arch. Neurol. 63 , 940–942 (2006).

Chen, N. et al . Antiviral treatment for preventing postherpetic neuralgia. Cochrane Database Syst. Rev. 2 , CD006866 (2014).

Solomon, C. G., Johnson, R. W. & Rice, A. S. C. Postherpetic neuralgia. N. Engl. J. Med. 371 , 1526–1533 (2014).

Article CAS Google Scholar

Klein, N. C., McDermott, B. & Cunha, B. A. Varicella-zoster virus meningoencephalitis in an immunocompetent patient without a rash. Scand. J. Infect. Dis. 42 , 631–633 (2010).

Gunson, R. N., Aitken, C. & Gilden, D. A woman with acute headache and sacral dermatomal numbness. J. Clin. Virol. 50 , 191–193 (2011).

Ratzka, P., Schlachetzki, J. C. M., Bähr, M. & Nau, R. Varicella zoster virus cerebellitis in a 66-year-old patient without herpes zoster. Lancet 367 , 182 (2006).

Ciccone, S. et al . Stroke after varicella-zoster infection: report of a case and review of the literature. Pediatr. Infect. Dis. J. 29 , 864–867 (2010).

Kang, J.-H., Ho, J.-D., Chen, Y.-H. & Lin, H.-C. Increased risk of stroke after a herpes zoster attack: a population-based follow-up study. Stroke. 40 , 3443–3448 (2009).

Nagel, M. A. et al . The varicella zoster virus vasculopathies: clinical, CSF, imaging, and virologic features. Neurology 70 , 853–860 (2008). This paper demonstrates that VZV vasculopathies in cerebral arteries lead to strokes.

Lin, H.-C., Chien, C.-W. & Ho, J.-D. Herpes zoster ophthalmicus and the risk of stroke: a population-based follow-up study. Neurology 74 , 792–797 (2010).

Hilt, D. C., Buchholz, D., Krumholz, A., Weiss, H. & Wolinsky, J. S. Herpes zoster ophthalmicus and delayed contralateral hemiparesis caused by cerebral angiitis: diagnosis and management approaches. Ann. Neurol. 14 , 543–553 (1983).

Bourdette, D. N., Rosenberg, N. L. & Yatsu, F. M. Herpes zoster ophthalmicus and delayed ipsilateral cerebral infarction. Neurology 33 , 1428–1432 (1983). This paper shows the link between VZV infection and stroke.

Nagel, M. A. et al . Varicella zoster virus vasculopathy: analysis of virus-infected arteries. Neurology 77 , 364–370 (2011).

Gilden, D., Cohrs, R. J., Mahalingam, R. & Nagel, M. A. Varicella zoster virus vasculopathies: diverse clinical manifestations, laboratory features, pathogenesis, and treatment. Lancet Neurol. 8 , 731–740 (2009).

Grose, C. Stroke after varicella and zoster ophthalmicus: another indication for treatment and immunization. Pediatr. Infect. Dis. J. 29 , 868–869 (2010).

Gilden, D. et al . Prevalence and distribution of VZV in temporal arteries of patients with giant cell arteritis. Neurology 84 , 1948–1955 (2015).

Franco-Paredes, C. et al . Aseptic meningitis and optic neuritis preceding varicella-zoster progressive outer retinal necrosis in a patient with AIDS. AIDS 16 , 1045–1049 (2002).

Furuta, Y. et al . Varicella-zoster virus reactivation is an important cause of acute peripheral facial paralysis in children. Pediatr. Infect. Dis. J. 24 , 97–101 (2005).

Pahud, B. A., Glaser, C. A., Dekker, C. L., Arvin, A. M. & Schmid, D. S. Varicella zoster disease of the central nervous system: epidemiological, clinical, and laboratory features 10 years after the introduction of the varicella vaccine. J. Infect. Dis. 203 , 316–323 (2011). This paper describes meningitis and encephalitis caused by VZV, often without rash.

Gilden, D. H., Dueland, A. N., Devlin, M. E., Mahalingam, R. & Cohrs, R. Varicella-zoster virus reactivation without rash. J. Infect. Dis. 166 (Suppl.), S30–S34 (1992).

Gilden, D. H. et al . Varicella zoster virus, a cause of waxing and waning vasculitis: the New England Journal of Medicine case 5–1995 revisited. Neurology 47 , 1441–1446 (1996).

Kleinschmidt-DeMasters, B. K. & Gilden, D. H. Varicella-zoster virus infections of the nervous system: clinical and pathologic correlates. Arch. Pathol. Lab. Med. 125 , 770–780 (2001).

McKelvie, P. A. et al . Meningoencephalomyelitis with vasculitis due to varicella zoster virus: a case report and review of the literature. Pathology 34 , 88–93 (2002).

Langan, S. M., Minassian, C., Smeeth, L. & Thomas, S. L. Risk of stroke following herpes zoster: a self-controlled case-series study. Clin. Infect. Dis. 58 , 1497–1503 (2014).

Breuer, J., Pacou, M., Gauthier, A. & Brown, M. M. Herpes zoster as a risk factor for stroke and TIA: a retrospective cohort study in the UK. Neurology 82 , 206–212 (2014). This paper provides further recognition of the relationship between VZV and stroke.

Gilden, D. H. et al . Varicella-zoster virus myelitis: an expanding spectrum. Neurology 44 , 1818–1823 (1994).

Chen, J. J. et al . Latent, lytic and reactivating varicella zoster virus in the ENS of humans and guinea pigs: could intestinal shingles be a hidden cause of gastrointestinal disease? Neuroastroenterol. Motil. 15 , abstr. 196–237 (2003).

Edelman, D. A. et al . Ogilvie syndrome and herpes zoster: case report and review of the literature. J. Emerg. Med. 39 , 696–700 (2010).

Scholl, S., Hocke, M., Hoffken, K. & Sayer, H. G. Acute abdomen by varicella zoster virus induced gastritis after autologous peripheral blood stem cell transplantation in a patient with non-Hodgkin's lymphoma. Acta Haematol. 116 , 58–61 (2006).

Gershon, A. A., Chen, J. & Gershon, M. D. Use of saliva to identify varicella-zoster virus (VZV) infection of the gut. Clin. Infect. Dis. http://dx.doi.org/10.1093/cid/civ320 (2015). This paper identifies VZV infection of the gastrointestinal tract in the absence of rash.

Leung, J. et al . Evaluation of laboratory methods for diagnosis of varicella. Clin. Infect. Dis. 51 , 23–32 (2010).

Harbecke, R. et al . A real-time PCR assay to identify and discriminate among wild-type and vaccine strains of varicella-zoster virus and herpes simplex virus in clinical specimens, and comparison with the clinical diagnoses. J. Med. Virol. 81 , 1310–1322 (2009).

Mehta, S. K. et al . Rapid and sensitive detection of varicella zoster virus in saliva of patients with herpes zoster. J. Virol. Methods 193 , 128–130 (2013). This paper describes the diagnosis of VZV infection by analysing VZV DNA in saliva.

Mehta, S. K. et al . Varicella-zoster virus in the saliva of patients with herpes zoster. J. Infect. Dis. 197 , 654–657 (2008).

Furuta, Y., Ohtani, F., Sawa, H., Fukuda, S. & Inuyama, Y. Quantitation of varicella-zoster virus DNA in patients with Ramsay Hunt syndrome and zoster sine herpete. J. Clin. Microbiol. 39 , 2856–2859 (2001).

Puchhammer-Stöckl, E., Popow-Kraupp, T., Heinz, F. X., Mandl, C. W. & Kunz, C. Detection of varicella-zoster virus DNA by polymerase chain reaction in the cerebrospinal fluid of patients suffering from neurological complications associated with chicken pox or herpes zoster. J. Clin. Microbiol. 29 , 1513–1516 (1991).

Jääskeläinen, A. J., Piiparinen, H., Lappalainen, M. & Vaheri, A. Improved multiplex-PCR and microarray for herpesvirus detection from CSF. J. Clin. Virol. 42 , 172–175 (2008).

Vázquez, M. et al . The effectiveness of the varicella vaccine in clinical practice. N. Engl. J. Med. 344 , 955–960 (2001).

Sauerbrei, A., Taut, J., Zell, R. & Wutzler, P. Resistance testing of clinical varicella-zoster virus strains. Antiviral Res. 90 , 242–247 (2011).

Quinlivan, M. L., Jensen, N. J., Radford, K. W. & Schmid, D. S. Novel genetic variation identified at fixed loci in ORF62 of the Oka varicella vaccine and in a case of vaccine-associated herpes zoster. J. Clin. Microbiol. 50 , 1533–1538 (2012). This article describes the molecular differentiation between wild-type and vaccine-types of VZV using viral DNA from patients.

LaRussa, P. et al . Restriction fragment length polymorphism of polymerase chain reaction products from vaccine and wild-type varicella-zoster virus isolates. J. Virol. 66 , 1016–1020 (1992).

Ibraheem, M. et al . Fatal wild-type varicella-zoster virus encephalitis without a rash in a vaccinated child. Pediatr. Infect. Dis. J. 32 , 183–185 (2013).

National Health Service. Varicella Zoster Virus Reference Lab. Great Ormond Street Hospital for Children NHS Trust [online] (2011).

Mehta, S. K. et al . Stress-induced subclinical reactivation of varicella zoster virus in astronauts. J. Med. Virol. 72 , 174–179 (2004). This study describes asymptomatic reactivation of VZV as demonstrated by the transient presence of VZV DNA in saliva.

Papaevangelou, V. et al . Subclinical VZV reactivation in immunocompetent children hospitalized in the ICU associated with prolonged fever duration. Clin. Microbiol. Infect. 19 , E245–E251 (2013).

Birlea, M. et al . Search for varicella zoster virus DNA in saliva of healthy individuals aged 20–59 years. J. Med. Virol. 86 , 360–362 (2014).

Takahashi, M., Otsuka, T., Okuno, Y., Asano, Y. & Yazaki, T. Live vaccine used to prevent the spread of varicella in children in hospital. Lancet 2 , 1288–1290 (1974). This study describes the successful attenuation of VZV and the use of this live attenuated virus to prevent varicella, thereby demonstrating the first successful vaccine against varicella.

Gomi, Y. et al . Comparison of the complete DNA sequences of the Oka varicella vaccine and its parental virus. J. Virol. 76 , 11447–11459 (2002).

Oxman, M. N. Zoster vaccine: current status and future prospects. Clin. Infect. Dis. 51 , 197–213 (2010).

Yamanishi, K. Molecular analysis of the Oka vaccine strain of varicella-zoster virus. J. Infect. Dis. 197 (Suppl.), S45–S48 (2008). This study identifies the molecular features of the attenuated vaccine strain of VZV compared with the wild-type strain.

Peters, G. A. et al . The attenuated genotype of varicella-zoster virus includes an ORF0 transitional stop codon mutation. J. Virol. 86 , 10695–10703 (2012).

Asano, Y., Nakayama, H., Yazaki, T., Kato, R. & Hirose, S. Protection against varicella in family contacts by immediate inoculation with live varicella vaccine. Pediatrics 59 , 3–7 (1977). This is the first demonstration of the clinical effectiveness of the Oka strain in preventing varicella, together with immunological data.

Asano, Y. & Takahashi, M. Clinical and serologic testing of a live varicella vaccine and two-year follow-up for immunity of the vaccinated children. Pediatrics 60 , 810–814 (1977).

Gershon, A. A. et al . Live attenuated varicella vaccine. Efficacy for children with leukemia in remission. JAMA 252 , 355–362 (1984). This paper provides the first proof that the varicella vaccine is safe and effective in preventing varicella in children with underlying leukaemia.

White, C. J. Clinical trials of varicella vaccine in healthy children. Infect. Dis. Clin. North Am. 10 , 595–608 (1996).

White, C. J. et al . Varicella vaccine (VARIVAX) in healthy children and adolescents: results from clinical trials, 1987 to 1989. Pediatrics 87 , 604–610 (1991).

Weibel, R. E. et al . Live attenuated varicella virus vaccine. Efficacy trial in healthy children. N. Engl. J. Med. 310 , 1409–1415 (1984). This study demonstrates that varicella vaccination protects healthy children from chickenpox.

Shapiro, E. D. et al . Effectiveness of 2 doses of varicella vaccine in children. J. Infect. Dis. 203 , 312–315 (2011).

Centers for Disease Control and Prevention (CDC). FDA approval of an extended period for administering VariZIG for postexposure prophylaxis of varicella. MMWR Morb. Mortal. Wkly Rep. 61 , 212 (2012).

Lin, T. Y., Huang, Y. C., Ning, H. C. & Hsueh, C. Oral acyclovir prophylaxis of varicella after intimate contact. Pediatr. Infect. Dis. J. 16 , 1162–1165 (1997).

Huang, Y. C., Lin, T. Y. & Chiu, C. H. Acyclovir prophylaxis of varicella after household exposure. Pediatr. Infect. Dis. J. 14 , 152–154 (1995).

Klein, A., Miller, K. B., Sprague, K., DesJardin, J. A. & Snydman, D. R. A randomized, double-blind, placebo-controlled trial of valacyclovir prophylaxis to prevent zoster recurrence from months 4 to 24 after BMT. Bone Marrow Transplant. 46 , 294–299 (2011).

Ljungman, P. et al . Long-term acyclovir prophylaxis in bone marrow transplant recipients and lymphocyte proliferation responses to herpes virus antigens in vitro . Bone Marrow Transplant. 1 , 185–192 (1986).

Linnemann, C. C., Biron, K. K., Hoppenjans, W. G. & Solinger, A. M. Emergence of acyclovir-resistant varicella zoster virus in an AIDS patient on prolonged acyclovir therapy. AIDS 4 , 577–579 (1990).

Levin, M. J. et al . Development of resistance to acyclovir during chronic infection with the Oka vaccine strain of varicella-zoster virus, in an immunosuppressed child. J. Infect. Dis. 188 , 954–959 (2003). This paper demonstrates that VZV can reactivate in immunocompromised children and that the vaccine virus can become resistant to acyclovir.

Bhalla, P. et al . Disseminated, persistent, and fatal infection due to the vaccine strain of varicella-zoster virus in an adult following stem cell transplantation. Clin. Infect. Dis. 60 , 1068–1074 (2015).

Baxter, R. et al . Long-term effectiveness of varicella vaccine: a 14-year, prospective cohort study. Pediatrics 131 , e1389–e1396 (2013).

Vázquez, M. et al . Effectiveness over time of varicella vaccine. JAMA 291 , 851–855 (2004). This study shows that immunity to varicella after vaccination does not wane substantially with time.

Seward, J. F. et al . Varicella disease after introduction of varicella vaccine in the United States, 1995–2000. JAMA 287 , 606–611 (2002). This study demonstrates personal and herd immunity as a result of vaccination in healthy children.

Gershon, A. A. et al . The protective effect of immunologic boosting against zoster: an analysis in leukemic children who were vaccinated against chickenpox. J. Infect. Dis. 173 , 450–453 (1996).

Brisson, M., Edmunds, W. J. & Gay, N. J. Varicella vaccination: impact of vaccine efficacy on the epidemiology of VZV. J. Med. Virol. 70 (Suppl. 1), S31–S37 (2003).

Brisson, M., Gay, N. J., Edmunds, W. J. & Andrews, N. J. Exposure to varicella boosts immunity to herpes-zoster: implications for mass vaccination against chickenpox. Vaccine 20 , 2500–2507 (2002).

Reynolds, M. A., Chaves, S. S., Harpaz, R., Lopez, A. S. & Seward, J. F. The impact of the varicella vaccination program on herpes zoster epidemiology in the United States: a review. J. Infect. Dis. 197 (Suppl.), S224–S227 (2008).

Gaillat, J. et al . Does monastic life predispose to the risk of Saint Anthony's fire (herpes zoster)? Clin. Infect. Dis. 53 , 405–410 (2011). This paper shows that immunity to VZV does not require continued exogenous exposure to VZV and that asymptomatic episodes of reactivation of VZV are likely to have a role in maintaining long-term immunity to the virus.

Seward, J. F., Zhang, J. X., Maupin, T. J., Mascola, L. & Jumaan, A. O. Contagiousness of varicella in vaccinated cases: a household contact study. JAMA 292 , 704–708 (2004).

Weinmann, S. et al . Incidence and clinical characteristics of herpes zoster among children in the varicella vaccine era, 2005–2009. J. Infect. Dis. 208 , 1859–1868 (2013).

Galea, S. A. et al . The safety profile of varicella vaccine: a 10-year review. J. Infect. Dis. 197 (Suppl.), S165–S169 (2008).

Oxman, M. N. Immunization to reduce the frequency and severity of herpes zoster and its complications. Neurology 45 , S41–S46 (1995).

Levin, M. J. in Vaccines . (eds Plotkin, S., Orenstein, W. & Offit, P. ) 969–980 (Elsevier, 2013).

Book Google Scholar

Oxman, M. N. & Levin, M. J. Vaccination against herpes zoster and postherpetic neuralgia. J. Infect. Dis. 197 (Suppl.), S228–S236 (2008).

Schmader, K. E. et al . Effect of a zoster vaccine on herpes zoster-related interference with functional status and health-related quality-of-life measures in older adults. J. Am. Geriatr. Soc. 58 , 1634–1641 (2010).

Simberkoff, M. S. et al . Safety of herpes zoster vaccine in the shingles prevention study: a randomized trial. Ann. Intern. Med. 152 , 545–554 (2010).

Harpaz, R., Ortega-Sanchez, I. R. & Seward, J. F. Prevention of herpes zoster: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR. Recomm. Rep. 57 , 1–30; quiz CE2–CE4 (2008).

Tseng, H. F. et al . Herpes zoster vaccine in older adults and the risk of subsequent herpes zoster disease. JAMA 305 , 160–166 (2011).

Langan, S. M., Smeeth, L., Margolis, D. J. & Thomas, S. L. Herpes zoster vaccine effectiveness against incident herpes zoster and post-herpetic neuralgia in an older US population: a cohort study. PLoS Med. 10 , e1001420 (2013).

Schmader, K. E. et al . Efficacy, safety, and tolerability of herpes zoster vaccine in persons aged 50–59 years. Clin. Infect. Dis. 54 , 922–928 (2012).

Schmader, K. E. et al . Persistence of the efficacy of zoster vaccine in the shingles prevention study and the short-term persistence substudy. Clin. Infect. Dis. 55 , 1320–1328 (2012).

Morrison, V. A. et al . Long-term persistence of zoster vaccine efficacy. Clin. Infect. Dis. 60 , 900–909 (2014).

Berkowitz, E. M. et al . Safety and immunogenicity of an adjuvanted herpes zoster subunit candidate vaccine in HIV-infected adults: a phase 1/2a randomized, placebo-controlled study. J. Infect. Dis. 211 , 1279–1287 (2015).

Chlibek, R. et al . Safety and immunogenicity of an AS01-adjuvanted varicella-zoster virus subunit candidate vaccine against herpes zoster in adults ≥50 years of age. J. Infect. Dis. 208 , 1953–1961 (2013).

Lal, H. et al . Efficacy of an adjuvanted herpes zoster subunit vaccine in older adults. N. Engl. J. Med. 372 , 2087–2096 (2015). This is the first demonstration of an adjuvanted subunit vaccine that is not infectious can prevent zoster in the elderly.

Cohen, J. I. A. A new vaccine to prevent herpes zoster. N. Engl. J. Med. 372 , 2149–2150 (2015).

Klassen, T. P., Hartling, L., Wiebe, N. & Belseck, E. M. Acyclovir for treating varicella in otherwise healthy children and adolescents. Cochrane Database Syst. Rev. http://dx.doi.org/10.1002/14651858.CD002980.pub3 (2005).

Belay, E. D. et al . Reye's syndrome in the United States from 1981 through 1997. N. Engl. J. Med. 340 , 1377–1382 (1999).

Souyri, C., Olivier, P., Grolleau, S. & Lapeyre-Mestre, M. Severe necrotizing soft-tissue infections and nonsteroidal anti-inflammatory drugs. Clin. Exp. Dermatol. 33 , 249–255 (2008).

American Academy of Pediatrics Committee on Infectious Diseases. The use of oral acyclovir in otherwise healthy children with varicella. Pediatrics 91 , 674–676 (1993).

Feldman, S. & Lott, L. Varicella in children with cancer: impact of antiviral therapy and prophylaxis. Pediatrics 80 , 465–472 (1987).

Etzioni, A. et al . Fatal varicella associated with selective natural killer cell deficiency. J. Pediatr. 146 , 423–425 (2005). This study shows the importance of innate immunity in host defences against VZV.

Centers for Disease Control and Prevention (CDC). Updated recommendations for use of VariZIG — United States, 2013. MMWR . Morb. Mortal. Wkly Rep. 62 , 574–576 (2013).

Prober, C. G., Kirk, L. E. & Keeney, R. E. Acyclovir therapy of chickenpox in immunosuppressed children — a collaborative study. J. Pediatr. 101 , 622–625 (1982). This is the first demonstration of successful antiviral therapy to protect immunocompromised children from varicella.

Wallace, M. R., Bowler, W. A., Murray, N. B., Brodine, S. K. & Oldfield, E. C. Treatment of adult varicella with oral acyclovir. A randomized, placebo-controlled trial. Ann. Intern. Med. 117 , 358–363 (1992).

Balfour, H. H. et al . Controlled trial of acyclovir for chickenpox evaluating time of initiation and duration of therapy and viral resistance. Pediatr. Infect. Dis. J. 20 , 919–926 (2001).

Sauerbrei, A. & Wutzler, P. Herpes simplex and varicella-zoster virus infections during pregnancy: current concepts of prevention, diagnosis and therapy. Part 2: Varicella-zoster virus infections. Med. Microbiol. Immunol. 196 , 95–102 (2007).

Davies, H. D. et al . Invasive group A streptococcal infections in Ontario, Canada. Ontario Group A Streptococcal Study Group. N. Engl. J. Med. 335 , 547–554 (1996).

Phillips, W. G., Marsden, J. R. & Hill, F. G. Purpura fulminans due to protein S deficiency following chickenpox. Br. J. Dermatol. 127 , 30–32 (1992).

Science, M. et al . Central nervous system complications of varicella-zoster virus. J. Pediatr. 165 , 779–785 (2014).

Cohen, J. I. Clinical practice: herpes zoster. N. Engl. J. Med. 369 , 255–263 (2013).

Dworkin, R. H. et al . Recommendations for the management of herpes zoster. Clin. Infect. Dis. 44 (Suppl. 1), S1–S26 (2007).

McDonald, E. M., de Kock, J. & Ram, F. S. F. Antivirals for management of herpes zoster including ophthalmicus: a systematic review of high-quality randomized controlled trials. Antivir. Ther. 17 , 255–264 (2012).

Tyring, S. K., Beutner, K. R., Tucker, B. A., Anderson, W. C. & Crooks, R. J. Antiviral therapy for herpes zoster: randomized, controlled clinical trial of valacyclovir and famciclovir therapy in immunocompetent patients 50 years and older. Arch. Fam. Med. 9 , 863–869 (2000).

Lin, W. R. et al . Comparative study of the efficacy and safety of valaciclovir versus acyclovir in the treatment of herpes zoster. J. Microbiol. Immunol. Infect. 34 , 138–142 (2001).

Whitley, R. J. et al . Acyclovir with and without prednisone for the treatment of herpes zoster. A randomized, placebo-controlled trial. The National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group. Ann. Intern. Med. 125 , 376–383 (1996).

Han, Y. et al . Corticosteroids for preventing postherpetic neuralgia. Cochrane Database Syst. Rev. 3 , CD005582 (2013).

Dworkin, R. H. et al . A randomized, placebo-controlled trial of oxycodone and of gabapentin for acute pain in herpes zoster. Pain 142 , 209–217 (2009).

Severson, E. A., Baratz, K. H., Hodge, D. O. & Burke, J. P. Herpes zoster ophthalmicus in Olmsted County, Minnesota: have systemic antivirals made a difference? Arch. Ophthalmol. 121 , 386–390 (2003).

Gilron, I. et al . Nortriptyline and gabapentin, alone and in combination for neuropathic pain: a double-blind, randomised controlled crossover trial. Lancet 374 , 1252–1261 (2009).

McNicol, E. D., Midbari, A. & Eisenberg, E. Opioids for neuropathic pain. Cochrane Database Syst. Rev. 8 , CD006146 (2013).

Brunell, P. A., Taylor-Wiedeman, J., Geiser, C. F., Frierson, L. & Lydick, E. Risk of herpes zoster in children with leukemia: varicella vaccine compared with history of chickenpox. Pediatrics 77 , 53–56 (1986).

Civen, R. et al . The incidence and clinical characteristics of herpes zoster among children and adolescents after implementation of varicella vaccination. Pediatr. Infect. Dis. J. 28 , 954–959 (2009).

Coplan, P. M. et al . Development of a measure of the burden of pain due to herpes zoster and postherpetic neuralgia for prevention trials: adaptation of the brief pain inventory. J. Pain 5 , 344–356 (2004).

Orvedahl, A. & Levine, B. Viral evasion of autophagy. Autophagy 4 , 280–285 (2008).

Carpenter, J. E., Jackson, W., Benetti, L. & Grose, C. Autophagosome formation during varicella-zoster virus infection following endoplasmic reticulum stress and the unfolded protein response. J. Virol. 85 , 9414–9424 (2011).

Buckingham, E. M. et al . Autophagic flux without a block differentiates varicella-zoster virus infection from herpes simplex virus infection. Proc. Natl Acad. Sci. USA 112 , 256–261 (2015).

Davison, A. J. & Scott, J. E. The complete DNA sequence of varicella-zoster virus. J. Gen. Virol. 67 , 1759–1816 (1986). This paper provides the first complete DNA sequence of VZV.

McGeoch, D. J., Rixon, F. J. & Davison, A. J. Topics in herpesvirus genomics and evolution. Virus Res. 117 , 90–104 (2006).

Grose, C. Pangaea and the Out-of-Africa model of varicella-zoster virus evolution and phylogeography. J. Virol. 86 , 9558–9565 (2012).

Kojima, E. et al . The function of GADD34 is a recovery from a shutoff of protein synthesis induced by ER stress: elucidation by GADD34-deficient mice. FASEB J. 17 , 1573–1575 (2003).

Ravi, V., Kennedy, P. G. & MacLean, A. R. Functional analysis of the herpes simplex virus type 2 strain HG52 RL1 gene: the intron plays no role in virulence. J. Gen. Virol. 79 , 1613–1617 (1998).

Perelygina, L. et al . Complete sequence and comparative analysis of the genome of herpes B virus ( Cercopithecine herpesvirus 1 ) from a rhesus monkey. J. Virol. 77 , 6167–6177 (2003).

Grose, C. & Giller, R. H. Varicella-zoster virus infection and immunization in the healthy and the immunocompromised host. Crit. Rev. Oncol. Hematol. 8 , 27–64 (1988).

Holgate, S. T. Innate and adaptive immune responses in asthma. Nat. Med. 18 , 673–683 (2012).

Kim, B.-S. et al . Increased risk of herpes zoster in children with asthma: a population-based case–control study. J. Pediatr. 163 , 816–821 (2013).

Esteban-Vasallo, M. D., Domínguez-Berjón, M. F., Gil-Prieto, R., Astray-Mochales, J. & Gil de Miguel, A. Sociodemographic characteristics and chronic medical conditions as risk factors for herpes zoster: a population-based study from primary care in Madrid (Spain). Hum. Vaccin. Immunother. 10 , 1650–1660 (2014).

Straus, S. E. Clinical and biological differences between recurrent herpes simplex virus and varicella-zoster virus infections. JAMA 262 , 3455–3458 (1989).

Weller, T. H. & Stoddard, M. B. Intranuclear inclusion bodies in cultures of human tissue inoculated with varicella vesicle fluid. J. Immunol. 68 , 311–319 (1952). In this study, VZV was isolated in cell culture for the first time, which was critical for the eventual development of a vaccine.

Weller, T. H. Serial propagation in vitro of agents producing inclusion bodies derived from varicella and herpes zoster. Proc. Soc. Exp. Biol. Med. 83 , 340–346 (1953).

Centers for Disease Control and Prevention (CDC). Summary of notifiable diseases: United States, 2009. MMWR Morb. Mortal. Wkly Rep. 58 , 1–100 (2011).

Zerboni, L., Sen, N., Oliver, S. L. & Arvin, A. M. Molecular mechanisms of varicella zoster virus pathogenesis. Nat. Rev. Microbiol. 12 , 197–210 (2014).

De Clercq, E. Strategies in the design of antiviral drugs. Nat. Rev. Drug Discov. 1 , 13–25 (2002).

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Acknowledgements

J.B. receives funding from the National Institute for Health Research (NIHR) University College London (UCL)/University College London Hospitals NHS Foundation Trust (UCLH) Biomedical Research Centre, UK. J.I.C. is supported by the intramural research program of the National Institute of Allergy and Infectious Diseases, USA. R.J.C. is supported by grants NS082228 and AG032958 from the US National Institutes of Health (NIH). D.G. is supported by grants AG006127 and AG032958 from the NIH. C.G. is supported by grant AI89716 from the NIH. S.H. receives funding from the Sir Jules Thorn Charitable Trust. M.D.G. and A.A.G. receive funding from NIH R01 Grant DK 09394. M.N.O.'s work is partially supported by the James R. and Jesse V. Scott Fund for Shingles Research in the Veterans Medical Research Foundation. P.G.E.K. receives grant funding for research from the Wellcome Trust.

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Anne A. Gershon

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Introduction (A.A.G.); Epidemiology (J.F.S. and J.B.); Mechanisms/pathophysiology (D.G., R.J.C., P.G.E.K. and M.G.); Diagnosis, screening and prevention (A.A.G., M.N.O. and K.Y.), Management (J.I.C. and S.H.); Quality of life (A.A.G.); Outlook (C.G); and overview of Primer (A.A.G.).

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J.B., J.I.C., R.J.C., M.D.G., D.G., C.G., S.H., M.N.O. and J.F.S. declare no competing interests. A.A.G. declares service contracts from Merck to investigate the safety of VZV vaccines (identifying VZV in samples from patients with possible adverse reactions), chairs an independent data monitoring committee for GlaxoSmithKlines Phase III subunit glycoprotein E zoster vaccine trial, consults with Pfizer when invited, and has participated in an educational programme (supported by an unrestricted educational grant) on zoster for GlaxoSmithKline. P.G.E.K. has served on a scientific advisory board on zoster vaccination for Sanofi Pasteur MSD. Y.K. is Director General of the BIKEN foundation (The Research Foundation for Microbial Diseases of Osaka University), which produces varicella vaccines.

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Gershon, A., Breuer, J., Cohen, J. et al. Varicella zoster virus infection. Nat Rev Dis Primers 1 , 15016 (2015). https://doi.org/10.1038/nrdp.2015.16

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ORIGINAL RESEARCH article

Different clinical presentations and outcomes of disseminated varicella in children with primary and acquired immunodeficiencies.

1 Service de Pédiatrie, Hôpital Jean Verdier, Bondy, AP-HP (Assistance-Publique-Hôpitaux de Paris), France
2 Service d’Immunologie et Hématologie Pédiatrique, Hôpital Necker Enfants Malades, AP-HP, Paris, France
3 INSERM U976—Human Systems Immunology and Inflammatory Networks, Institut de Recherche de Saint Louis, Paris, France
4 Université de Paris, Paris, France
5 Département d’Hématologie Pédiatrique, Hôpital Robert-Debré, AP-HP, Paris, France
6 Service de Réanimation Pédiatrique, Hôpital du Kremlin-Bicêtre, Kremlin-Bicêtre, France
7 Université Paris XI, AP-HP, Paris
8 Université Paris Saclay, Saint-Aubin, France
9 Sorbonne Université, Service de d’Hématologie Oncologie Pédiatrique, Hôpital Armand Trousseau, AP-HP, Paris, France
10 Service de Radiologie Pédiatrique, Hôpital Necker Enfants Malades, AP-HP, Université de Paris, Paris, France
11 INSERM U1163, Institut IMAGINE, Paris, France
12 Sorbonne Paris Nord University, Bobigny, France
13 ACTIV Centre Hospitalier Intercommunal de Créteil, Créteil, France
14 Service de Néphrologie Pédiatrique, Hôpital Robert-Debré, AP-HP, Paris, France
15 Experimental Medicine, Collège de France, Paris, France

Primary infection with varicella-zoster virus (VZV) causes chickenpox, a benign and self-limited disease in healthy children. In patients with primary or acquired immunodeficiencies, primary infection can be life-threatening, due to rapid dissemination of the virus to various organs [lung, gastrointestinal tract, liver, eye, central nervous system (CNS)]. We retrospectively described and compared the clinical presentations and outcomes of disseminated varicella infection (DV) in patients with acquired (AID) ( n = 7) and primary (PID) ( n = 12) immunodeficiencies. Patients with AID were on immunosuppression (mostly steroids) for nephrotic syndrome, solid organ transplantation or the treatment of hemopathies, whereas those with PID had combined immunodeficiency (CID) or severe CID (SCID). The course of the disease was severe and fulminant in patients with AID, with multiple organ failure, no rash or a delayed rash, whereas patients with CID and SICD presented typical signs of chickenpox, including a rash, with dissemination to other organs, including the lungs and CNS. In the PID group, antiviral treatment was prolonged until immune reconstitution after bone marrow transplantation, which was performed in 10/12 patients. Four patients died, and three experienced neurological sequelae. SCID patients had the worst outcome. Our findings highlight substantial differences in the clinical presentation and course of DV between children with AID and PID, suggesting differences in pathophysiology. Prevention, early diagnosis and treatment are required to improve outcome.

Introduction

Primary infection with varicella-zoster virus (VZV), a ubiquitous, human-restricted double-strand DNA alpha-herpesvirus ( 1 , 2 ), causes chickenpox. In non-vaccinated populations, seroprevalence for VZV increases with age in children, reaching more than 90% by the age of 18 years in most ( 3 , 4 ), but not all countries ( 2 ). VZV reactivation after a quiescent phase in the sensory ganglia ( 3 , 4 ) causes shingles. The most common clinical presentation of chickenpox is a pruritic vesicular rash, beginning about 2 weeks after exposure and progressing in flares over several days, as patients typically have lesions at different stages of development ( 5 ). In previously healthy children, chickenpox is generally a mild and self-limited disease, but VZV infection in patients with primary or acquired immunodeficiencies can be life-threatening in rare cases, due to rapid dissemination of the virus, causing respiratory, gastrointestinal, hepatic, ocular (retinitis, keratitis), and central nervous system (encephalitis, meningitis, cerebellitis, central nerve palsy, vasculopathy) involvement. These disseminated varicella infections (DV) result in high morbidity and mortality ( 6 – 8 ). In patients with acquired immunodeficiencies (AID), diagnosis is often delayed due to unusual initial presentations ( 6 ), such as the absence of a rash, or the presence of isolated abdominal pain, with a severe fulminant course. Susceptibility to VZV infection is variable in patients with primary immune deficiencies (PID), dependent on the immune functions affected. No difference in the clinical course and outcome of disseminated VZV infection has yet been described between patients with PID and those with AID. In France, global vaccination for VZV is not currently recommended and limited to at-risk groups. We thus retrospectively analyzed 19 cases of DV in French children with acquired or primary immunodeficiencies, from 2003 to 2016. We show that these two groups have very different initial clinical presentations and outcomes, suggesting that the pathophysiology of the disease depends on the underlying cause of immunosuppression.

Materials and Methods

Study design and participants.

Patients with AID were recruited via a standardized survey sent to all specialists likely to have treated children hospitalized for DV in French university hospitals over a 13-year period (from 2003 to 2016). This call for collaboration was issued via the mailing lists of the Pediatric Infectious Disease Group, the French group of intensive care units and emergency departments, the French Society for Pediatric Hematology and Immunology (SHIP), the French Society for fight against Cancer and leukemias in Children and adolescents (SFCE) and the French Society for Pediatric Nephrology. Patients with primary immunodeficiencies (PIDs) were recruited from the immuno-hematology and rheumatology unit of Necker Hospital in Paris and were identified through the hospital data warehouse ( 9 , 10 ). The inclusion criteria for all patients were: i) Child or adolescent aged 0 to 18 years, ii) receiving immunosuppressive therapy or with a PID (using ESID criteria, whether or not diagnosed at the time of VZV infection) iii) hospitalized for a proven DV (at least one organ other than the skin involved; with at least one sample testing positive for VZV). Extensive varicella infections (severe mucocutaneous involvement) complicated with hemorrhagic disease only and cases of chickenpox with secondary bacterial infections only were not included. Patients undergoing hematopoietic stem cell transplantation (HSCT), patients infected with the human immunodeficiency virus and PID patients on immunosuppressive drugs were excluded. The study protocol was approved by an independent local ethics committee ( Comité Local d’Ethique pour la Recherche Clinique ; reference: CLEA-2016-029, October 12, 2016).

Data Collection

We retrospectively reviewed the files of all patients with disseminated varicella infection and retrieved data for the patient’s personal and familial medical history, clinical and radiological features, treatment and outcome.

Statistical Analysis

Statistics were performed using R (CRAN) version 3.6.0. We described patient characteristics as numbers and percentages for categorical variables, and median or means with interquartile ranges for quantitative ones. Wilcoxon test was used to compare quantitative variables and the Fisher's exact test for qualitative ones. Two-sided p-values < 0.05 were considered significant.

Between January 1, 2003 and January 1, 2016; 19 patients (seven with AID and 12 with PID) from six centers in France were included in the analysis. All patients had suffered from DV and satisfied the inclusion criteria. The characteristics of the patients are presented in Tables 1 – 3 .

Table 1 Demographic, clinical, biological, treatment and prognosis characteristics of the 7 patients with AID included in the French retrospective study of DV in children.

Table 2 Treatments of patients with AID.

Table 3 Demographic, clinical, biological, treatment and prognosis characteristics of the 13 patients with PID included in the French retrospective study of DV in children.

Disseminated Varicella Infection in Seven Patients With Acquired Immunodeficiencies

In patients with AID ( Table 1 ), the mean age at DV diagnosis was 10 years (range: 4–16 years). All but one of the patients were male. The underlying conditions were steroid-dependent nephrotic syndrome ( n =2), renal transplantation ( n =1) and malignant hemopathies ( n =4). Immunosuppressive treatments included corticosteroids, cyclophosphamide, tacrolimus and/or a combination of methotrexate and purinethol. The durations and doses of the immunosuppressive treatments are shown in Table 2 . Four of the seven patients were on corticosteroids at DV onset, and all patients had received corticosteroids as part of their treatment during the preceding 6 months. The median duration of immunosuppressive therapy before DV was 36 months (range: 0.5–168 months). All patients were living in France and none had been vaccinated against VZV. The index case of varicella infection was identified for only one of these patients, who then received prophylactic acyclovir.

Symptoms of Disseminated Varicella Infection in Patients With Acquired Immunodeficiency

The first symptom was abdominal pain in four of the seven patients, and all patients presented abdominal pain during the course of infection; five had bilateral hypoxic varicella pneumonia requiring oxygen therapy, and two presented seizures (one with confirmed VZV encephalitis). Five of the seven patients had a skin rash, but with an onset at least 48 h after the first symptom in all but one case, this last patient presenting a rash at onset. High liver enzyme levels were noted in all cases, and four patients developed fulminant hepatitis with acute liver failure. High pancreatic enzyme levels were also recorded in four cases, but there were no cases of severe pancreatitis. Two children had disseminated intravascular coagulopathy, including one with severe hemorrhagic syndrome. Two instances of concomitant infections were noted ( Candida albicans septicemia and Pseudomonas aeruginosa septicemia, in one patient each). All patients were admitted to an intensive care unit (ICU), for a median of 11 days (range: 2–27 days). The median time between disease onset and treatment initiation was 52 h (range: 35–96 h). All patients received intravenous acyclovir for 14 to 21 days (500 mg/m 2 /8 h in all cases). Six patients also received immunoglobulins: specific anti-VZV immunoglobulins ( n =1), polyvalent immunoglobulins ( n =3), or both ( n =2). Immunosuppressive drugs were suspended in all cases. Two patients died from multiple organ failure, nine and 30 days after disease onset. Outcome was favorable in four patients, who made a full recovery, and one patient survived but experienced neurological sequelae.

Disseminated Varicella Infection in 12 Patients With A Primary Immunodeficiency

In patients with a PID ( Table 3 ), median age at DV onset was 0.9 years (range: 0.2–12). Four of the patients were female and eight were male. In all patients, DV led to the diagnosis of the PID. Six patients suffered from severe combined immune deficiency (SCID) (γC deficiency n = 1, IL-7 receptor deficiency n = 1, JAK 3 deficiency n = 1, RAG-1 deficiency n = 2 and RAG-2 deficiency n = 1), and six had a combined immune deficiency (MHC class II deficiency n = 1, ZAP-70 deficiency n = 2, hypomorphic ARTEMIS deficiency n = 1, and combined immune deficiency with an unknown molecular diagnosis n = 2). None of the 12 patients or their relatives had been vaccinated against VZV.

Symptoms of Disseminated Varicella Infection in Patients With Primary Immunodeficiency

The first symptom was disseminated skin rash in all but one of the patients. Other manifestations included neurological symptoms ( n = 6) (meningo-encephalitis in five patients and radiculo-neuritis in one case), VZV-retinitis (aqueous humor positive for VZV) in one patient and pneumonitis in nine patients (with a positive PCR test for VZV on bronchoalveolar lavage for all five patients tested). One patient had a stroke following VZV vasculitis ( Figure 1 ). Two patients had high liver enzyme levels, but none presented acute liver failure. Three patients were admitted to the ICU at onset, due to respiratory distress. The symptoms of varicella infection were remarkably prolonged and required the administration of more than one intravenous antiviral drug, concomitantly and/or successively, in five cases. Treatment was prolonged in all patients and was maintained until immune recovery after hematopoietic stem-cell transplantation (HSCT) in 10 patients, or until complete clinical recovery and an undetectable viral load for VZV in the two CID patients who did not undergo HSCT. All patients received polyclonal immunoglobulins, but none received VZV-specific immunoglobulins. All four of the patients who died had SCID. Death occurred three to 4 months after HSCT, due to suspected immune reconstitution inflammatory disease (IRIS) ( n = 3) or disseminated VZV infection ( n = 1). Five of the eight patients who survived suffered from severe neurological sequelae ( n = 3) and/or skin sequelae (diffuse keloid scars n = 2). As expected, the course of the disease was more severe in patients with SCID, four of whom died, with two others surviving but experiencing neurological sequelae. All six patients with CID survived. One patient had neurological sequelae and two had keloid scars, whereas the other three of these patients had no sequelae. Of note, ten PID patients underwent HSCT, and IRIS was suspected in five of these patients after HCST.

Figure 1 MRI scan of patient N09, 1 year after stroke secondary to cerebral VZV vasculitis. Right hemisphere atrophy on axial FLAIR sequence (A–C) and coronal T2 sequence (D) and stenosis of internal carotid artery and posterior cerebral arteries in vascular sequences Time of flight (TOF) angiography (E, F) .

Differences in the Clinical Characteristics and Outcomes of Disseminated Varicella

Significant differences in the clinical characteristics and outcomes of DV were observed between patients with AID and PID, as highlighted in Table 4 . First, all the patients with AID were older than patients with PID (p=0.002, Wilcoxon test). Furthermore, patient with AID had a severe, fulminant clinical presentation, requiring hospitalization in the ICU for severe symptoms, such as multiple organ failure and coagulopathy. PID patients had an acute but not fulminant presentation, with persistent infection. At onset, the manifestations of the disease differed significantly between the two groups. Abdominal pain and hepatitis ( p <0.0001 and p <0.001, respectively) were more frequent, and skin rash was delayed or absent with AID relative to patients with PID. Mortality was high in both groups, but sequelae were more frequent in PID patients, due to the infection itself, or possibly due to IRIS occurring after HSCT.

Table 4 Comparison of clinical characteristics between patients with DV and AID or PID.

This study highlights substantial differences in the clinical presentations and outcomes of DV between patients with AID (due to corticosteroids and/or other immunosuppressive drugs) and patients with PID (i.e. T-cell deficiency in this series). Indeed, we observed a significantly older age in patients with AID. The disease also followed a more fulminant course in AID patients, with an early abdominal pain but a delayed rash as previously described ( 8 , 11 , 12 ), whereas patients with T-cell deficiency presented a more typical rash, with wide dissemination, persistent infection, a higher rate of sequelae and IRIS-related complications during immune reconstitution after HSCT. Mortality was high in both groups. It is not possible to draw definitive epidemiological conclusions from this study due to its retrospective nature and the potential underreporting or underdiagnosis of cases, particularly in AID patients.

These significant differences may be due to the underlying defect of immunity. Two distinct viremic phases occur after the natural acquisition of VZV. The initial phase is asymptomatic in immunocompetent hosts, occurs 5–7 days after inoculation, and engages innate immune responses, especially type I interferon production. The second phase of viremia begins after 11–21 days ( 5 ), when the skin rash occurs, and corresponds to the onset of specific adaptive immune responses. Early innate responses are important for triggering and amplifying the adaptive immune response leading to the acquisition of specific anti-VZV T cells, which are essential to prevent dissemination, ensure the resolution of acute infection and prevent reactivation. Among all PID described to date ( 13 ), susceptibility to VZV infection is heterogeneous ( 14 ). SCID and CID confer a high level of susceptibility to VZV as part of a broad predisposition to infection, further highlighting the major role of cellular immunity against VZV. CID constitute a large group of diseases, including some associated with a higher risk of extensive or disseminated varicella infection, such as autosomal recessive (AR) DOCK8 deficiency ( 15 ) and other PIDs related to actin-cytoskeleton abnormalities ( 16 ) (due to T-cell homing defect), in diseases with NK cell deficiencies among broader cellular deficiencies (AD GATA2 deficiency or AR MCM4 or GINS1 deficiencies) ( 17 – 19 ), AR DOCK2 deficiency, a PID that affect both innate and adaptive immunities, in which disseminated and fulminant varicella has been reported ( 20 – 22 ). A new PID conferring a narrow susceptibility to VZV has recently been described in patients with AR POLR3A and POLR3C deficiencies. The patients present a defective IFN type I and III production upon VZV infection ( 23 ) and displayed disseminated VZV with CNS or lung involvement.

Glucocorticoids have very broad immunosuppressive functions affecting both innate and adaptive immunity ( 24 ), which may account for the rapid dissemination of VZV and the severity of the infection in the AID group during the initial viremic phase, before the occurrence of a skin rash. The abdominal pain may be due to VZV replication in the digestive system (visceral varicella), as described in previous studies ( 25 , 26 ). In our series, no DV has been reported in patients on chemotherapy for solid cancers. We cannot exclude an underreporting of such cases. However, the immunosuppressive effect of chemotherapies used in these conditions is probably weaker than that of current chemotherapy treatments for lymphoma and leukemia, which include steroids at various stages ( 27 , 28 ). Indeed, the use of corticosteroids for immunosuppression was identified as a major risk factor for DV ( 22 , 29 ).

All the PID patients with DV in our series had defective or absent T-cell immunity (CID or SCID). Almost all presented with an extended skin rash as the first symptom, but dissemination and prolonged infection were the general rule in this group of patients. We can, thus, speculate that, despite the intact innate immune responses engaged during the first phase of viremia, defective adaptive immune responses account for the dissemination and the lack of resolution of the infection, which followed a prolonged course. DV is rare in SCID patients (six out of 101 SCID patients diagnosed during the study period in the immune-hematology unit of Necker), but is a severe event. Mortality and the risk of sequelae were high. Because we included only cases of disseminated varicella infection, it may have introduced a selection bias towards the patients with the most marked PID.

The prompt diagnosis of varicella infection is of the utmost importance in these populations of patients at high risk, but is particularly challenging in patients with AID, in whom the clinical presentation differs from that classically observed ( 29 , 30 ). The standard treatment for DV in immunocompromised patients includes prompt intravenous acyclovir treatment, initiated as soon as possible ( 31 ). Early treatment may improve prognosis ( 32 ). The addition of interferon-alpha, early in infection, may also improve outcome by helping to control of the initial viremia.

The prevention of VZV infection in the population at risk, with underlying PID or AID, is of considerable importance. Vaccination has been widely implemented in many countries and seems to have reduced the incidence of complications in otherwise healthy patients, and also in immunocompromised patients, through herd immunity ( 33 ). Unfortunately, the varicella vaccine currently available is a live vaccine that can cause infections in patients with profound T-cell immunodeficiency, as previously reported ( 34 – 36 ). The current recommendation in France is to propose anti-VZV vaccination to siblings and relatives of immunocompromised patients, with preventive treatment in cases of contact. Unfortunately, these recommendations are not fully applied, and are only partly efficient. In particular, for patients with PID, varicella infection may precede or lead to the diagnosis of PID. Neonatal screening for SCID should prevent primary infection in such patients before HSCT or gene therapy ( 37 ).

In conclusion, we highlight here major differences in the clinical presentations and outcomes of DV in patients with AID and PID, suggesting differences in the pathophysiology of the disease in these two groups. Abdominal pain is a major symptom in patients with AID, a prompt blood VZV PCR should be performed in the population at risk and acyclovir treatment initiated until the infection is ruled out, especially if liver enzymes are elevated. In the PID group, the prognosis of DV was worse for patients with SCID than for those with CID. The high mortality in this group of patients may reflect uncontrolled infection but IRIS, occurring at the time of immune recovery, should not be overlooked. The prevention of VZV infection in this high-risk population is of the utmost importance.

Data Availability Statement

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

Ethics Statement

The studies involving human participants were reviewed and approved by Comité Local d’Ethique pour la Recherche Clinique; reference: CLEA-2016-029, October 12, 2016. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.

Author Contributions

PB and AG collected the clinical data. LP and BN supervised the work. All authors contributed to the article and approved the submitted version.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

1. Straus SE, Ostrove JM, Inchauspé G, Felser JM, Freifeld A, Croen KD, et al. NIH conference. Varicella-zoster virus infections. Biology, natural history, treatment, and prevention. Ann Intern Med (1988) 108:221–37. doi: 10.7326/0003-4819-108-2-221

PubMed Abstract | CrossRef Full Text | Google Scholar

2. Rimseliene G, Vainio K, Gibory M, Salamanca BV, Flem E. Varicella-zoster virus susceptibility and primary healthcare consultations in Norway. BMC Infect Dis (2016) 16:254. doi: 10.1186/s12879-016-1581-4

3. Hyman RW, Ecker JR, Tenser RB. Varicella-zoster virus RNA in human trigeminal ganglia. Lancet Lond Engl (1983) 2:814–6. doi: 10.1016/S0140-6736(83)90736-5

CrossRef Full Text | Google Scholar

4. Sadzot-Delvaux C, Arvin AM, Rentier B. Varicella-zoster virus IE63, a virion component expressed during latency and acute infection, elicits humoral and cellular immunity. J Infect Dis (1998) 178(Suppl 1):S43–47. doi: 10.1086/514259

5. Heininger U, Seward JF. Varicella. Lancet Lond Engl (2006) 368:1365–76. doi: 10.1016/S0140-6736(06)69561-5

6. Morgan ER, Smalley LA. Varicella in immunocompromised children. Incidence of abdominal pain and organ involvement. Am J Dis Child 1960 (1983) 137:883–5. doi: 10.1001/archpedi.1983.02140350057014

7. Feldman S, Hughes WT, Daniel CB. Varicella in children with cancer: Seventy-seven cases. Pediatrics (1975) 56:388–97.

PubMed Abstract | Google Scholar

8. Wiegering V, Schick J, Beer M, Weissbrich B, Gattenlöhner S, Girschick HJ, et al. Varicella-zoster virus infections in immunocompromised patients - a single centre 6-years analysis. BMC Pediatr (2011) 11:31. doi: 10.1186/1471-2431-11-31

9. Garcelon N, Neuraz A, Salomon R, Faour H, Benoit V, Delapalme A, et al. A clinician friendly data warehouse oriented toward narrative reports: Dr. Warehouse. J Biomed Inform (2018) 80:52–63. doi: 10.1016/j.jbi.2018.02.019

10. Garcelon N, Neuraz A, Salomon R, Bahi-Buisson N, Amiel J, Picard C, et al. Next generation phenotyping using narrative reports in a rare disease clinical data warehouse. Orphanet J Rare Dis (2018) 13:85. doi: 10.1186/s13023-018-0830-6

11. Okuma HS, Kobayashi Y, Makita S, Kitahara H, Fukuhara S, Munakata W, et al. Disseminated herpes zoster infection initially presenting with abdominal pain in patients with lymphoma undergoing conventional chemotherapy: A report of three cases. Oncol Lett (2016) 12:809–14. doi: 10.3892/ol.2016.4683

12. Vinzio S, Lioure B, Goichot B. Varicella in immunocompromised patients. Lancet Lond Engl (2006) 368:2208. doi: 10.1016/S0140-6736(06)69888-7

13. Bousfiha A, Béziat V, Mogensen TH, Casanova J-L, Tangye SG, Zhang S-Y, et al. Human Inborn Errors of Immunity: 2019 Update of the IUIS Phenotypical Classification. J Clin Immunol (2020) 40:66–81. doi: 10.1007/s10875-020-00758-x

14. Jouanguy E, Béziat V, Mogensen TH, Casanova J-L, Tangye SG, Zhang S-Y. Human inborn errors of immunity to herpes viruses. Curr Opin Immunol (2020) 62:106–22. doi: 10.1016/j.coi.2020.01.004

15. Engelhardt KR, Gertz ME, Keles S, Schäffer AA, Sigmund EC, Glocker C, et al. The extended clinical phenotype of 64 patients with dedicator of cytokinesis 8 deficiency. J Allergy Clin Immunol (2015) 136:402–12. doi: 10.1016/j.jaci.2014.12.1945

16. Tangye SG, Bucciol G, Casas-Martin J, Pillay B, Ma CS, Moens L, et al. Human inborn errors of the actin cytoskeleton affecting immunity: way beyond WAS and WIP. Immunol Cell Biol (2019) 97:389–402. doi: 10.1111/imcb.12243

17. Gineau L, Cognet C, Kara N, Lach FP, Dunne J, Veturi U, et al. Partial MCM4 deficiency in patients with growth retardation, adrenal insufficiency, and natural killer cell deficiency. J Clin Invest (2012) 122:821–32. doi: 10.1172/JCI61014

18. Hughes CR, Guasti L, Meimaridou E, Chuang C-H, Schimenti JC, King PJ, et al. MCM4 mutation causes adrenal failure, short stature, and natural killer cell deficiency in humans. J Clin Invest (2012) 122:814–20. doi: 10.1172/JCI60224

19. Cottineau J, Kottemann MC, Lach FP, Kang Y-H, Vély F, Deenick EK, et al. Inherited GINS1 deficiency underlies growth retardation along with neutropenia and NK cell deficiency. J Clin Invest (2017) 127:1991–2006. doi: 10.1172/JCI90727

20. Dobbs K, Domínguez Conde C, Zhang S-Y, Parolini S, Audry M, Chou J, et al. Inherited DOCK2 Deficiency in Patients with Early-Onset Invasive Infections. N Engl J Med (2015) 372:2409–22. doi: 10.1056/NEJMoa1413462

21. Moens L, Gouwy M, Bosch B, Pastukhov O, Nieto-Patlàn A, Siler U, et al. Human DOCK2 Deficiency: Report of a Novel Mutation and Evidence for Neutrophil Dysfunction. J Clin Immunol (2019) 39:298–308. doi: 10.1007/s10875-019-00603-w

22. Alizadeh Z, Mazinani M, Shakerian L, Nabavi M, Fazlollahi MR. DOCK2 Deficiency in a Patient with Hyper IgM Phenotype. J Clin Immunol (2018) 38:10–2. doi: 10.1007/s10875-017-0468-5

23. Ogunjimi B, Zhang S-Y, Sørensen KB, Skipper KA, Carter-Timofte M, Kerner G, et al. Inborn errors in RNA polymerase III underlie severe varicella zoster virus infections. J Clin Invest (2017) 127:3543–56. doi: 10.1172/JCI92280

24. Cain DW, Cidlowski JA. Immune regulation by glucocorticoids. Nat Rev Immunol (2017) 17:233–47. doi: 10.1038/nri.2017.1

25. Han SB, Seo YE, Kim S-K, Lee JW, Lee D-G, Chung N-G, et al. Varicella with rapidly progressive hepatitis presenting with multiple hepatic nodules in a child with acute leukemia. J Infect Chemother Off J Jpn Soc Chemother (2016) 22:822–5. doi: 10.1016/j.jiac.2016.07.005

26. Smedegaard LM, Christiansen CB, Melchior LC, Poulsen A. Appendicitis Caused by Primary Varicella Zoster Virus Infection in a Child with DiGeorge Syndrome. Case Rep Pediatr (2017) 2017:6708046. doi: 10.1155/2017/6708046

27. Sutton SH. Infections associated with solid malignancies. Cancer Treat Res (2014) 161:371–411. doi: 10.1007/978-3-319-04220-6_13

28. Morrison VA. Infections in patients with leukemia and lymphoma. Cancer Treat Res (2014) 161:319–49. doi: 10.1007/978-3-319-04220-6_11

29. Hill G, Chauvenet AR, Lovato J, McLean TW. Recent steroid therapy increases severity of varicella infections in children with acute lymphoblastic leukemia. Pediatrics (2005) 116:e525–9. doi: 10.1542/peds.2005-0219

30. Dowell SF, Bresee JS. Severe varicella associated with steroid use. Pediatrics (1993) 92:223–8. doi: 10.1371/journal.pmed.1002024

31. Snoeck R, Andrei G, De Clercq E. Current pharmacological approaches to the therapy of varicella zoster virus infections: a guide to treatment. Drugs (1999) 57:187–206. doi: 10.1016/0091-6749(93)90165-C

32. Kim S-K, Kim MC, Han SB, Kim SK, Lee JW, Chung N-G, et al. Clinical characteristics and outcomes of varicella zoster virus infection in children with hematologic malignancies in the acyclovir era. Blood Res (2016) 51:249–55. doi: 10.2165/00003495-199957020-00005

33. Helmuth IG, Poulsen A, Suppli CH, Mølbak K. Varicella in Europe-A review of the epidemiology and experience with vaccination. Vaccine (2015) 33:2406–13. doi: 10.1016/j.vaccine.2015.03.055

34. Caniza MA, Hunger SP, Schrauder A, Valsecchi MG, Pui C-H, Masera G, et al. The controversy of varicella vaccination in children with acute lymphoblastic leukemia. Pediatr Blood Cancer (2012) 58:12–6. doi: 10.1016/j.vaccine.2015.03.055

35. Bayer DK, Martinez CA, Sorte HS, Forbes LR, Demmler-Harrison GJ, Bayer IC, et al. Vaccine-associated varicella and rubella infections in severe combined immunodeficiency with isolated CD4 lymphocytopenia and mutations in IL7R detected by tandem whole exome sequencing and chromosomal microarray. Clin Exp Immunol (2014) 178:459–69. doi: 10.1002/pbc.22759

36. Dutmer CM, Asturias EJ, Smith C, Dishop MK, Schmid DS, Bellini WJ, et al. Late Onset Hypomorphic RAG2 Deficiency Presentation with Fatal Vaccine-Strain VZV Infection. J Clin Immunol (2015) 35:754–60.

37. Puck JM. Newborn screening for severe combined immunodeficiency and T-cell lymphopenia. Immunol Rev (2019) 287:241–52. doi: 10.1007/s10875-015-0207-8

Keywords: varicella, primary immumunodeficiencies, steroids, innate immunity, disseminated varicella

Citation: Bastard P, Galerne A, Lefevre-Utile A, Briand C, Baruchel A, Durand P, Landman-Parker J, Gouache E, Boddaert N, Moshous D, Gaudelus J, Cohen R, Deschenes G, Fischer A, Blanche S, de Pontual L and Neven B (2020) Different Clinical Presentations and Outcomes of Disseminated Varicella in Children With Primary and Acquired Immunodeficiencies. Front. Immunol. 11:595478. doi: 10.3389/fimmu.2020.595478

Received: 16 August 2020; Accepted: 09 October 2020; Published: 05 November 2020.

Reviewed by:

Copyright © 2020 Bastard, Galerne, Lefevre-Utile, Briand, Baruchel, Durand, Landman-Parker, Gouache, Boddaert, Moshous, Gaudelus, Cohen, Deschenes, Fischer, Blanche, de Pontual and Neven. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Bénédicte Neven, [email protected]

† These authors have contributed equally to this work

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

Clinical Overview

Clinical features, complications, vaccination, transmission, epidemiology, herpes zoster in people who received varicella vaccine.

Herpes zoster, also known as shingles, is caused by reactivation of varicella-zoster virus (VZV), the same virus that causes varicella (chickenpox).

Primary infection with VZV causes varicella. After a person has varicella, the virus remains latent in the dorsal root ganglia. VZV can reactivate later in a person’s life and cause herpes zoster, a painful maculopapular and then vesicular rash.

People with herpes zoster most commonly have a rash in one or two adjacent dermatomes. The rash most commonly appears on the trunk along a thoracic dermatome or on the face and it usually does not cross the body’s midline.

The rash is usually painful, itchy, or tingly. A person can experience the following symptoms several days before the rash appears:

Photophobia (sensitivity to bright light)

The rash develops into clusters of vesicles. New vesicles continue to form over 3 to 5 days, and the rash progressively dries and scabs over. The rash usually heals in 2 to 4 weeks. Permanent skin discoloration and scarring can occur.

Postherpetic neuralgia (PHN)

PHN is the most common complication of herpes zoster. PHN is pain that persists in the area where the rash once was located and continues more than 90 days after rash onset. PHN can last for months or even years.

A person’s risk of having PHN after herpes zoster increases with age. Older adults are more likely to have longer lasting, more severe pain. Approximately 10% to 18% of people with herpes zoster will have PHN. PHN is rare in people younger than 40 years old. The likelihood of PHN is also higher in people who experience more pain with the rash or have a large rash.

Herpes zoster ophthalmicus

Herpes zoster that affects the ophthalmic division of the trigeminal nerve is called herpes zoster ophthalmicus. This can result in acute or chronic ocular sequelae, including vision loss.

Disseminated zoster

Disseminated zoster can include generalized skin eruptions where the lesions occur outside of the primary or adjacent dermatomes. It can be difficult to distinguish from varicella. Visceral involvement of the central nervous system (meningoencephalitis), lungs (pneumonitis), and liver (hepatitis) can also occur. Disseminated zoster generally occurs in people with compromised or suppressed immune systems.

Other complications of herpes zoster include:

Bacterial superinfection of the lesions, usually due to Staphylococcus aureus and, less commonly, due to group A beta hemolytic streptococcus
Cranial and peripheral nerve palsies

People with compromised or suppressed immune systems are more likely to have a severe, long-lasting rash and experience more severe complications from herpes zoster.

Recombinant zoster vaccine (RZV, Shingrix) is the recommended vaccine to prevent shingles and related complications. For information about vaccination recommendations see Shingles Vaccination .

People with active herpes zoster lesions can spread VZV , which causes varicella in people who never had varicella or never received varicella vaccine. Once varicella resolves, these people would be at risk for herpes zoster.

Active herpes zoster lesions are infectious through direct contact with vesicular fluid or through breathing in virus particles from the blisters until they dry and scab over. People with active herpes zoster lesions should cover their lesions and avoid contact with susceptible people in their household and in occupational settings until their lesions are dry and scabbed.

Also see Managing People at High Risk for Severe Varicella and Preventing VZV Transmission from Herpes Zoster in Healthcare Settings

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Risk Factors

Anyone who had varicella can develop herpes zoster. Approximately 99.5% of people born before 1980 in the United States were infected with wild-type VZV. Children who receive varicella vaccine have a lower risk of herpes zoster compared with children who were infected with wild-type VZV.

Approximately 1 in 3 people in the United States will develop herpes zoster during their lifetime. Most people have only one episode; however, herpes zoster can recur.

A person’s risk for herpes zoster and related complications sharply increases after 50 years of age. The reasons why VZV reactivates and causes herpes zoster are not well understood. However, a person’s risk for herpes zoster increases as their VZV-specific cell-mediated immunity declines. This decline in immunity can result from increasing age and medical conditions or medications that suppress a person’s immune system. People with the following conditions that compromise or suppress their immune system have an increased risk for herpes zoster:

Bone marrow or solid organ (renal, cardiac, liver, and lung) transplant recipients
Cancer, especially leukemia and lymphoma
Human immunodeficiency virus (HIV)
Taking immunosuppressive medications, including steroids, such as for treatment of autoimmune diseases and other immune system deficiencies

Other potential risk factors for herpes zoster have been identified, but the findings are either inconsistent or unexplained. For example:

More women than men develop herpes zoster.
Herpes zoster is less common in Blacks than in Whites.

Disease Rates

An estimated one million cases of herpes zoster occur annually in the United States.

The incidence of herpes zoster varies by age and is approximately 2–9 cases per 1,000 US population annually.

The precise incidence of recurrence is not known.

Approximately 10% to 18% of people with herpes zoster will have PHN.
Approximately 1% to 4% of people with herpes zoster are hospitalized for complications.
Older adults and people with compromised or suppressed immune systems are more likely to be hospitalized. About 30% of people hospitalized with herpes zoster have compromised or suppressed immune systems.

One study estimated 96 deaths occur each year where herpes zoster was the underlying cause (0.28 to 0.69 per 1 million population). Almost all the deaths occurred in older adults or those with compromised or suppressed immune systems.

Herpes zoster rates among adults in the United States gradually increased over a long period of time. We do not know the reason for this increase. However, the rates across age groups have recently plateaued or declined.

CDC studies have found that herpes zoster rates started increasing before varicella vaccine was introduced in the U.S. and did not accelerate after the routine varicella vaccination program started.

Varicella vaccines contain live attenuated VZV, which results in latent infection. Although herpes zoster has always been uncommon among children, the rate of herpes zoster in U.S. children has declined since the routine varicella vaccination program started in 1996.

Vaccinated children are less likely to become infected with wild-type VZV.
The risk of reactivation of vaccine-strain VZV in children is lower compared with reactivation of wild-type VZV.
Few older adults have received the varicella vaccine since it was licensed in 1995. There is very little information on the risk of herpes zoster in people who got varicella vaccine as adults.

CDC continues to monitor the impacts of the U.S. varicella and herpes zoster vaccination programs among adults and children.

CDC. Use of Recombinant Zoster Vaccine in Immunocompromised Adults Aged ≥19 Years: Recommendations of the Advisory Committee on Immunization Practices — United States, 2022 . MMWR Recomm Rep . 2022;71(3):80-84.
Leung et al. The Impact of Universal Varicella Vaccination on Herpes Zoster Incidence in the United States: Comparison of Birth Cohorts Preceding and Following Varicella Vaccination Program Launch . Journal of Infection Diseases . 2022.
Harpaz and Leung. The Epidemiology of Herpes Zoster in the United States During the Era of Varicella and Herpes Zoster Vaccines: Changing Patterns Among Older Adults . Clin Infect Dis .2019;69(2):341-344.
CDC. Prevention of herpes zoster: recommendations of the Advisory Committee on Immunization Practices (ACIP) Recommendations for use of Herpes Zoster Vaccines . MMWR Recomm Rep . 2018;67(03):103-108.
Thomas SL, Hall AJ. What does epidemiology tell us about risk factors for herpes zoster? Lancet Infect Dis . 2004;4(1):26-33.
Tseng HF, Smith N, Harpaz R, et al. Herpes zoster vaccine in older adults and the risk of subsequent herpes zoster disease . JAMA . 2011;305(2):160-6.
Mahamud A, Marin M, Nickell SP, et al. Herpes zoster-related deaths in the United States: validity of death certificates and mortality rates, 1979-2007 . Clin Infect Dis .2012;55(7):960-6.
Leung J, Harpaz R, Molinari NA, et al. Herpes zoster incidence among insured persons in the United States, 1993-2006: evaluation of impact of varicella vaccination . Clinical Infectious Diseases . 2011;52(3):332-340.
Yih W, Brooks D, Lett S, et al. The Incidence of varicella and herpes zoster in Massachusetts as measured by the Behavioral Risk Factor Surveillance System (BRFSS) during a period of increasing varicella vaccine coverage . BMC Public Health . 2005;5(68).
Jumaan AO, Yu O, Jackson LA, et al. Incidence of herpes zoster, before and after varicella vaccination-associated decreases in the incidence of varicella . Journal of Infectious Diseases . 2005;191:2002-7.
Hales CM, Harpaz R, Joesoef MR, Bialek SR. Examination of links between herpes zoster incidence and childhood varicella vaccination . Annals of Internal Medicine . 2013;159(11):739-45.
Russell ML, Dover DC, Simmonds KA, Svenson LW. Shingles in Alberta: before and after publicly funded varicella vaccination . Vaccine . 2014;32(47):6319-24.
Weinmann S, Chun C, Schmid DS, et al. Incidence and clinical characteristics of herpes zoster among children in the varicella vaccine era, 2005–2009 . Journal of Infection Diseases . 2013;208(11):1859-68.
Hardy I, Gershon AA, Steinberg SP, LaRussa P. The incidence of zoster after immunization with live attenuated varicella vaccine. A study in children with leukemia. Varicella Vaccine Collaborative Study Group . N Engl J Med . 1991;325(22):1545-50.
Information for Healthcare Professionals about Shingles (Herpes Zoster) Vaccines
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Varicella Zoster

Content information, disease information.

Varicella Fact Sheet
Varicella Fact Sheet, HP

Also known as: Chickenpox, VZV-varicella zoster virus

Responsibilities

Hospital: Report outbreaks
Infection Preventionist: Report outbreaks
Physician: Report outbreaks
Follow-up of investigation by Local Public Health Agency (LPHA): outbreaks only

Iowa Department of Public Health Disease Reporting Hotline: 1-800-362-2736

Varicella-Zoster is a member of the herpesvirus family.

B. Clinical Description

Symptoms: Primary infection results in varicella (chickenpox). A mild prodrome may precede the onset of a rash. Adults may have 1 to 2 days of mild fever and malaise. Prior to rash onset, but in children the rash is often the first sign of disease.

The rash is generalized, pruritic, and rapidly progresses from macules to papules to vesicular lesions before crusting. The rash typically consists of 250 to 500 lesions; appear first on the scalp, moves to the trunk, and then the extremities, with the highest concentration of lesions on the trunk (centripetal distribution). The vesicles are superficial and delicate; contain clear fluid on an erythematous base. Usually 2 to 4 successive crops of lesions, crops appear over several days, with lesions present in several stages of development. The rash is self-limited, generally lasting 4-5 days.

The clinical course in normal children is generally mild, with malaise, pruritus, and fever up to 102o F for 2-3 days. Adults may have more severe disease and have a higher incidence of complications. Respiratory and gastrointestinal symptoms are absent.

Complications: The risk of complications from varicella varies with age. Children with lesions due to varicella are at greater risk for secondary bacterial infections. Complications are infrequent among healthy children. They are much higher in persons > 15 years and infants < 1 year of age. Adults account for only 5% of reported cases of varicella, but account for approximately 35% of mortality.

Complications include bacterial superinfection of the skin lesions, pneumonia (viral or bacterial), thrombocytopenia, arthritis, hepatitis, cerebellar ataxia, encephalitis, meningitis, and glomerulonephritis. Reye Syndrome can follow some cases of chickenpox, although the incidence of Reye Syndrome has decreased dramatically with decreased use of salicylates during varicella or influenza-like illnesses. Severe and even fatal varicella has been reported in otherwise healthy children receiving intermittent courses of corticosteroids for treatment of asthma and other illnesses.

The hospitalization rate is 3 per 1000 cases. Death rate 1 per 60,000 cases.

Outcome: Recovery from primary varicella infection usually results in lifetime immunity. In otherwise healthy persons, a second occurrence of chickenpox is uncommon, but may occur, particularly in immunocompromised persons.

The virus establishes latency in the dorsal root ganglia during primary infection. Reactivation results in herpes zoster “shingles”. Grouped vesicular lesions appear in the distribution of 1 to 3 sensory dermatomes, sometimes accompanied by pain localized to the area. The immunologic mechanism that controls latency of VZV is not well understood. Approximately 15-30% of the population will experience zoster during their lifetimes. Factors associated with recurrent disease include aging, immunosuppression, intrauterine exposure to VZV, and varicella at a young age < 18 months. Post herpetic neuralgia is defined as pain that persists after resolution of the rash, may last as long as a year after the episode of zoster.

Herpes Zoster Vaccine

Zoster vaccine (licensed in 2006 Zostavax) is a live attenuated vaccine approved for persons 60 years of age and older. ACIP (Advisory Committee on Immunization Practices) recommends a single dose of zoster vaccine for adults 60 years of age or older whether or not they report a prior episode of herpes zoster. Persons with a chronic medical condition may be vaccinated unless a contraindication or precaution exists for the condition.

For more information on zoster vaccine, visit: www.cdc.gov/vaccines/vpd-vac/shingles/default.htm#clinical

The vaccine should be stored frozen at an average temperature of +5°F (-15°C) until it is reconstituted. Read and follow the package insert for storage and reconstitution instructions.

A person should not get shingles vaccine who:

has ever had a life-threatening allergic
reaction to gelatin,
the antibiotic neomycin,
or any other component of shingles vaccine.
has a weakened immune system because of
HIV/AIDS or another disease that affects the immune system,
treatment with drugs that affect the immune system, such as steroids,
cancer treatment such as radiation or chemotherapy,
a history of cancer affecting the bone marrow or lymphatic system, such as leukemia or lymphoma.
has active, untreated tuberculosis.

C. Reservoirs

Humans are the only source of infection for this highly contagious virus.

D. Modes of Transmission

Spread: The varicella zoster virus enters the body through the respiratory tract and conjunctiva. The virus is believed to replicate at the site of entry in the nasopharynx and regional lymph nodes. Primary viremia occurs 4-6 days after infection, which disseminates the virus to other organs, such as the liver, spleen and sensory ganglia. A secondary viremia occurs with viral infection of the skin.

Person-to-person transmission occurs by airborne spread from respiratory tract secretions and by direct contact with drainage from lesions in patients with varicella. Patients with zoster spread disease primarily by direct contact with drainage from zoster lesions. Transmission may also occur by respiratory contact with airborne droplets or by direct contact or inhalation of aerosols from vesicular fluid of skin lesions of acute varicella or zoster. Patients with disseminated zoster may also transmit disease via the airborne route. In utero infection also can occur as a result of transplacental passage of virus during maternal varicella infection.

E. Incubation period

The incubation period is from 14 to 16 days from exposure with a range of 10 to 21 days. Incubation may be prolonged in immunocompromised patients.

F. Period of Communicability or Infectious Period

Patients are most contagious from 1 to 2 days before to shortly after onset of the rash. Contagiousness persists until crusting of the lesions.

G. Epidemiology

Varicella is highly infectious, with secondary infection rates in susceptible household contacts approaching 90%. Secondary family cases may have more severe disease than that in the index case.

In temperate climates varicella is a childhood disease with a marked seasonal distribution with peak incidence during winter and early spring. In tropical climates, the epidemiology of varicella is different; acquisition of disease occurs at later ages, resulting in a higher proportion of adults being susceptible to varicella compared with adults in temperate climates.

In the prevaccine era (prior to 1995), most cases of varicella in the United States occurred in children younger than 10. With the implementation of universal immunization, a higher proportion of cases are expected to occur among adolescents and adults. As vaccine coverage increases and the incidence of wild-type varicella decreases, a higher proportion of varicella cases will occur in immunized people as break-through disease. In sites conducting active surveillance, cases of breakthrough disease have increased as a percentage of all cases from 4% in 1995 to 25% in 2000. This should not be confused as an increasing rate of breakthrough disease or as evidence of increasing vaccine failure.

H. Bioterrorist Potential

None - differentiate from smallpox.

I. Additional Information

The Council of State and Territorial Epidemiologists (CSTE) surveillance case definitions for Varicella can be found at: www.cdc.gov/osels/ph_surveillance/nndss/phs/infdis.htm#top

CSTE case definitions should not affect the investigation or reporting of a case that fulfills the criteria in this chapter. (CSTE case definitions are used by the state health department and the CDC to maintain uniform standards for national reporting.)

Comment: Two probable cases that are epidemiologically linked are considered cases, even in the absence of laboratory confirmation.

Advisory Committee on Immunization Practices Prevention of Varicella: Recommendations of the Advisory Committee on Immunization Practices (ACIP) MMWR1999; 48(NO.RR-6).

American Academy of Pediatrics. Red Book 2006: Report of the Committee on Infectious Diseases, 27th Edition. Illinois, American Academy of Pediatrics, 2006.

CDC. Manual for the Surveillance of Vaccine-Preventable Diseases, CDC, 2002.

CDC Web-site Herpes Zoster - Vaccine Q&As for Providers (Shingles) www.cdc.gov/vaccines/vpd-vac/shingles/hcp-vaccination.htm

Epidemiology and Prevention of Vaccine Preventable Diseases. Ninth Edition January 2006.

Heymann, D.L., ed. Control of Communicable Diseases Manual, 20th Edition. Washington, DC, American Public Health Association, 2015.

Reporting & Investigation

A. purpose of surveillance and reporting.

Varicella is not currently a nationally notifiable disease, and surveillance data are limited.

B. Laboratory Criteria for Diagnosis

Positive serologic test for varicella-zoster immunoglobulin M (IgM) antibody.
Isolation of varicella-zoster virus (VZV), demonstration of VZV antigen by direct fluorescent antibody (DFA), or by polymerase chain reaction (PCR) tests from a clinical specimen.
Significant rise in serum varicella immunoglobulin G (IgG) antibody level by any standard serological assay.

C. Local Public Health Agency Follow-up Responsibilities

Outbreak investigation .

A parent letter and varicella outbreak worksheet is available to help in an outbreak response.

Case investigation of all suspected cases of varicella is not feasible or necessary. Reporting of varicella outbreaks (child care centers, schools, institutions etc.) will facilitate public health action.

In addition, in certain high-risk settings (e.g., hospitals and other health-care settings) rapid case identification and public health action are important to prevent infection of susceptible persons at high risk for serious complications of varicella, such as immunocompromised persons and susceptible pregnant women.

Controlling Spread

A. isolation and quarantine requirements.

Isolation (exclusion) or cohorting of individuals with varicella until all of their lesions have crusted is routinely recommended for outbreak control. However, because substantial transmission of chickenpox occurs before rash onset, exclusion may have limited value as an outbreak control measure.

Quarantine measures: none.

Exclusion is also recommended for exposed susceptible individuals, who may be in contact with persons at high risk of serious complications (e.g., health-care workers, family members of immunocompromised persons). In these situations, exclusion is required for the duration of the period of communicability (i.e., from the 10th until the 21st day post-exposure).

B. Protection of Contacts of a Case

Epidemiologic and serologic studies confirm that greater than 90% of adults are immune to VZV. Rates of immunity may be lower for adults who were raised in certain tropical or subtropical areas.

Vaccination for Outbreak Control:

During a varicella outbreak, persons who have received one dose of varicella vaccine should, resources permitting, receive a second dose provided the appropriate vaccination interval has elapsed since the first vaccine. (Three month interval for persons 12 months through 12 years of age and at least a 28 day interval for persons 13 years of age and older.) Varicella vaccine, if administered within 72 hours and possibly up to 120 hours following varicella exposure, may prevent or significantly modify disease. If exposure to varicella does not cause infection, post-exposure vaccination with varicella vaccine should induce protection against subsequent infection. If the exposure results in infection, the vaccine may reduce the severity of the disease. There is no evidence that administration of varicella vaccine during the incubation period of illness increases the risk for vaccine-associated adverse events.

Antivirals may be considered for persons at increased risk of moderate to severe disease. The decision to use antiviral therapy and the route and duration of therapy should be determined by specific host factors, extent of infection, and initial response to therapy.

Antiviral drugs have a limited window of opportunity to affect the outcome of Varicella-zoster infection. In immunocompetent hosts, most virus replication has stopped by 72 hours after onset of rash; the duration is extended in immunocompromised hosts. Oral acyclovir is not recommended for routine use in otherwise healthy children with varicella. Administration within 24 hours of the onset of rash results in only a modest decrease in symptoms. A 7-day course of acyclovir may be given to susceptible adults beginning 7 to 9 days after varicella exposure if vaccine is contraindicated or more than 72 hours has elapsed from the time of exposure. (Most adults with no or uncertain history of chickenpox are nonetheless immune).

Oral acyclovir should be considered for people at increased risk of moderate to severe varicella, such as people older than 12 years of age, people with chronic cutaneous or pulmonary disorders, people receiving long-term salicylate therapy, and people receiving short, intermittent, or aerosolized courses of corticosteroids. Some experts also recommend use of oral acyclovir for secondary household cases in which the disease usually is more severe than in the primary case. Oral acyclovir is not recommended routinely for pregnant women with uncomplicated Varicella, because the risks and benefits to the fetus and mother are unknown. Intravenous acyclovir is recommended for the pregnant patient with serious complications of varicella.

Children with varicella should not receive salicylates or salicylate-containing products, because administration of salicylates to such children increases the risk of Reye syndrome. Acetaminophen may be used for control of fever.

Varicella zoster immune globulin (VariZIG):

This is recommended for post-exposure prophylaxis of susceptible persons who are at high risk for developing severe disease and when varicella vaccine is contraindicated. VariZIG is most effective in preventing varicella infection when given within 96 hours of varicella exposure; for maximum effectiveness it should be given as soon as possible after exposure. The decision to administer VariZIG to a person exposed to varicella should be based on 1) whether the person is susceptible, 2) whether the exposure is likely to result in infection, and 3) whether the patient is at greater risk for complications than the general public.

Such groups include:

Newborn infants whose mothers developed varicella around the time of delivery (< 5 days before to 2 days after delivery),
Immunocompromised children without history of varicella or varicella immunization.
Susceptible pregnant women,
Hospitalized premature infants > 28 weeks gestation whose mother had no history of varicella, and
Premature infants < 28 weeks gestation, regardless of the mother’s history of varicella.
VariZIG can be ordered from the distributor (FFF Enterprises, Inc., Temecula, CA) by calling 800-843-7477. VariZIG is given by intramuscular (IM) injection and contains between 10% and 18% Globulin and does not contain thimerosal. One vial (approximate volume, 1.25 ml) containing 125 U is given for each 10 kg of body weight and is the minimal dose. The suggested maximal dose of VariZIG is 625 U (i.e., 5 vials). For more information, visit: www.cdc.gov/mmwr/preview/mmwrhtml/mm6112a4.htm

C. Managing Special Situations

Prenatal & perinatal exposure:.

Women should be assessed prenatally for evidence of varicella immunity. Upon completion or termination of their pregnancies, women who do not have evidence of varicella immunity should receive the first dose of vaccine before discharge from the healthcare facility. The second dose should be administered 4 to 8 weeks later at the postpartum or other healthcare visit.

Prenatal infection is uncommon because most women of childbearing age are immune to VZV. Fetal infection after maternal varicella during the first or early second trimester of pregnancy occasionally results in varicella embryopathy, which is characterized by limb atrophy and scarring of the skin of the extremities (congenital varicella syndrome). Central nervous system and eye manifestations also can occur. The incidence of congenital varicella syndrome among infants born to mothers with varicella is approximately 2% when infection occurs before 20 weeks of gestation.

Children exposed to varicella-zoster virus in utero during the second 20 weeks of pregnancy can develop inapparent varicella and subsequent zoster early in life without having had extra uterine varicella.

Varicella infection can be fatal for an infant if the mother develops varicella from 5 days before to 2 days after delivery.

When varicella develops in a mother more than 5 days before delivery and gestational age is 28 weeks or more, the severity of disease in the newborn is modified by transplacental transfer of varicella-zoster virus (VZV) specific maternal IgG antibody of the parent.

Hospitalized Patient:

In addition to Standard Precautions, Airborne and Contact Precautions are recommended for patients with varicella for a minimum of 5 days after onset of the rash and as long as vesicular lesions are present, which in immunocompromised patients can be a week or longer. For exposed susceptible patients, Airborne and Contact Precautions from 10 until 21 days after exposure to the index patient also are indicated; these precautions should be maintained until 28 days or longer after exposure for those who received VariZIG.

Immunocompromised patients who have zoster (localized or disseminated) and immunocompetent patients with disseminated zoster require Airborne and Contact Precautions for the duration of illness. For immunocompetent patients with localized zoster, Contact Precautions are indicated until all lesions are crusted.

Healthcare worker:

The Advisory Committee on immunization Practices recommends that all healthcare workers be immune to varicella, either from a reliable history of disease or from vaccination. In a health-care institution serologic screening of personnel who have a negative or uncertain history of varicella is likely to be cost effective.

All susceptible exposed personnel should be furloughed or excused from patient contact from day 10 to day 21 after exposure to an infectious patient. The interval should be extended to 28 days or longer for people who have received VariZIG.

Varicella immunization is recommended for susceptible personnel if varicella does not develop from the exposure. Serologic testing for immunity is not necessary for personnel who have been immunized, because 99% of adults are seropositive after the second vaccine dose.

Outbreaks involving children covered by childcare or school requirements: Unvaccinated children with no history of varicella disease should be instructed to be vaccinated immediately or excluded from school for the duration of the period of communicability (i.e., from 10-21 days post exposure or for the duration of the outbreak.

Outbreaks in child care centers or schools:

The public health response includes informing parents and caregivers of the outbreak, providing them with information on varicella and its potential to cause complications, and providing information about the availability of vaccine. Children with uncomplicated chickenpox who have been excluded from school or child care may return when the rash has crusted, or in immunized people without crusts, when lesions have faded or new lesions have appeared in the last 24 hours.

Exclusion of children with zoster whose lesions cannot be covered is based on similar criteria. Children who are excluded may return when lesions are crusted. Lesions that are covered seem to pose little risk to susceptible people.

Institutional outbreaks or outbreaks involving adolescents or adults:

Vaccination of susceptible persons should be strongly considered because it is likely to limit or control the outbreak by interrupting transmission. Outbreak control should be considered at any stage of an outbreak if there are remaining susceptible persons.

D. Preventive Measures

Vaccination.

The Oka/Merck attenuated varicella vaccine was licensed in the United States in 1995. Because of the thermolability of the vaccine, the manufacturer’s requirements for maintaining the cold chain must be followed strictly. Vaccine that is not stored properly before administration could have reduced potency.

Recommendations for the use of varicella virus vaccine:

Routine administration of live attenuated varicella virus vaccine for all children 12-18 months of age. On June 2006 ACIP recommended a routine 2 dose varicella vaccine schedule for all children less than 13 years of age, with the first dose administered at 12-15 months of age and the second dose at 4-6 years of age (i.e., before a child enters kindergarten). The second dose can be administered at an earlier age provided the interval between the first and second dose is at least 3 months. However, if the second dose is administered at least 28 days following the first dose, the second dose does not need to be repeated
A second dose catch-up varicella vaccination is recommended for children, adolescents, and adults (without evidence of immunity) who previously had received only one dose, to improve individual protection against varicella and for more rapid impact on school outbreaks. The minimum interval between vaccine doses is 28 days. Catch-up vaccination can be implemented during routine health care provider visits.

Children with a reliable history of typical chickenpox can be assumed to be immune to varicella. Serologic testing of such children prior to vaccination is not warranted because the majority of children between 12 months and 12 years of age without a clinical history of chickenpox are not immune. Serologic testing of adolescents and adults with an uncertain or negative history is likely to be cost-effective because 70%-90% of these individuals are likely to be varicella-immune.

Serologic testing for varicella immunity following two doses of vaccine is not necessary because 99% of persons are seropositive after the second dose.

Transmission of varicella vaccine virus

Available data suggest that transmission of vaccine virus is a rare event. It appears that transmission occurs mainly and perhaps only, when the vaccinee develops a rash. If a vaccinated person develops a rash, it is recommended that close contact with persons who do not have evidence of varicella immunity and who are at high risk of complications of varicella, such as immunocompromised persons, be avoided until the rash has resolved.

Varicella Vaccine Contraindications and Precautions:

Severe allergic reaction to vaccine component or following a prior dose
Women known to be pregnant or attempting to become pregnant should not receive varicella vaccine. Pregnancy should be avoided for 1 month following receipt of varicella vaccine
Immunosuppression due to disease or medication
Moderate or severe acute illness
Recent blood product

See www.cdc.gov/mmwr/preview/mmwrhtml/00042990.htm for more information.

Varicella vaccination is contraindicated for all persons with moderate or severe cellular immunodeficiency due to human immunodeficiency virus (HIV) infection and is not recommended for adults who are HIV infected. However, vaccination should be considered for HIV-infected children if they have asymptomatic or mildly symptomatic HIV infection, in CDC class N, A, or B CD4+ T-lymphocyte percentage of > 15% and without evidence of varicella immunity should receive two doses of single antigen varicella vaccine at a minimum interval of three months. See www.cdc.gov/mmwr/PDF/rr/rr4806.pdf for more information.

Pre-licensure vaccine efficacy studies ranged from 70-90% for all disease and > 95% for severe disease while mild “breakthrough” varicella may be expected to occur in 10-20% of vaccinated children. The rate of varicella (mild or severe) among vaccinated children should be monitored; if the rate of breakthrough disease is higher than expected (e.g., > 30%) the cause of the problem should be investigated. “Breakthrough disease” is defined as a case of wild-type varicella infection occurring more than 42 days after vaccination. The disease is almost always mild with fewer than 50 skin lesions. Rash may be atypical maculopapular with few or no vesicles. Breakthrough disease is contagious.

Case Report
Open access
Published: 26 September 2016

Definition and management of varicella zoster virus-associated meningoradiculitis: a case report

Vincent Luisier 1 ,
Lalensia Weber 1 ,
Daniel Fishman 2 ,
Gérard Praz 3 ,
Joseph-André Ghika 4 ,
Didier Genoud 4 &
Joelle Nsimire Chabwine 4 nAff5

BMC Research Notes volume 9 , Article number: 451 ( 2016 ) Cite this article

2288 Accesses

3 Citations

Metrics details

The varicella zoster virus affects the central or peripheral nervous systems upon reactivation, especially when cell-mediated immunity is impaired. Among varicella zoster virus-related neurological syndromes, meningoradiculitis is an ill-defined condition for which clear management guidelines are still lacking. Zoster paresis is usually considered to be a varicella zoster virus-peripheral nervous system complication and treated with oral antiviral therapy. Yet in the literature, the few reported cases of herpes zoster with mild cerebral spinal fluid inflammation were all considered meningoradiculitis and treated using intravenous antiviral drugs, despite absence of systemic signs of meningitis. Nevertheless, these two clinical pictures are very similar.

Case presentation

We report the case of an alcohol-dependent elderly Caucasian man presenting with left lower limb zoster paresis and mild cerebral spinal fluid inflammation, with favorable outcome upon IV antiviral treatment. We discuss interpretation of liquor inflammation in the absence of clinical meningitis and implications for the antiviral treatment route.

From this case report we suggest that varicella zoster virus-associated meningoradiculitis should necessarily include meningitis symptoms with the peripheral neurological deficits and cerebral spinal fluid inflammation, requiring intravenous antiviral treatment. In the absence of (cell-mediated) immunosuppression, isolated zoster paresis does not necessitate spinal tap or intravenous antiviral therapy.

Varicella zoster virus (VZV) is an exclusively human virus primarily causing chickenpox [ 1 ]. After a latency period in ganglionic neurons, VZV can reactivate and cause herpes zoster (HZ). The latter is favored by advanced age or immunosuppression [ 1 – 3 ] but can also occur in immunocompetent individuals [ 4 – 8 ]. Reactivation of VZV may be accompanied by nervous system complications at both central (meningitis, encephalitis, vasculitis, cerebellitis, myelitis) and/or peripheral levels (cranial nerve palsies, radiculitis) [ 2 , 9 ]. The clinical symptoms, as well as complementary investigations (blood tests, imaging and electrophysiology), determine the neurological complications. Detecting VZV by real-time polymerase chain reaction (RT-PCR) in skin lesions confirms HZ diagnosis [ 10 ], while detection of VZV deoxyribonucleic acid (DNA) in cerebrospinal fluid (CSF) by RT-PCR or identification of intrathecal antiviral antibodies [ 2 ], indicates extension of the infection to the nervous system [ 11 , 12 ]. Antiviral therapy is effective against VZV complications, specifically oral treatment (acyclovir or its pro-drug valacyclovir with better oral absorption) in benign cases and intravenous (IV) acyclovir for severe conditions such as ocular and central nervous system (CNS) complications, especially in immunosuppressed individuals [ 2 , 3 ].

Here we report the case of an alcohol-dependent older man with zoster paresis in the context of a VZV-associated meningoradiculitis. This clinical entity is not precisely defined in the literature and clear management guidelines about oral versus IV antiviral therapy are scant [ 13 ]. Clearly, preventing severe HZ neurological complications should be balanced by careful analysis of the most effective, efficient and least harmful treatment course. We suggest a definition of meningoradiculitis that is usable in clinical practice, including the choice of antiviral therapy. Alcohol- and age-induced cell-mediated immunity (CMI) dysfunction is identified as a plausible precipitating factor of VZV reactivation in our patient.

A 74-year-old Caucasian man was admitted to the Emergency Room, addressed by his general practitioner for a 3-day history of progressive lower left limb weakness. He complained of a non-traumatic lumbar pain since 10 days. Shortly after, a skin rash appeared on his lower back and extended to the left lower limb. He did not have fever or other new neurological complaints (in particular there was no urine or bowel retention or incontinence). His medical history showed arterial hypertension (treated by an angiotensin converting enzyme and calcic inhibitor); alcohol dependence (with macrocytosis and lower limb polyneuropathy) and benign prostate hypertrophy managed using tamsulosin. Otherwise, he took Aspirin Cardio® and tramadol.

In addition to lower limb peripheral length-dependent abnormalities (ankle jerk areflexia, distal touch and vibration hypoesthesia), the initial neurological assessment revealed significant weakness in hip flexion (M3) and foot dorsiflexion (M2), absence of the left patellar reflex and disturbed position sense on the lower left limb. The Leri sign was positive on the left side. On general examination, clusters of small erythematous vesicular lesions were present on the anterior and internal sides of his left thigh and upper leg. A few similar lesions were also seen on the left part of the lower back. In summary, the clinical picture of the patient showed left L3–L4 sensory-motor deficit associated with radicular zoster. A lumbar computerized tomography (CT)-scan excluded local compression (there was only degenerative lumbar discopathy) and the skin smear was positive for VZV DNA but negative for Herpes simplex virus 1 and 2. The lumbar puncture (see Table 1 ), despite being traumatic, showed elevated white blood cells, almost exclusively lymphocytes, with high protein levels, blood brain barrier alteration, but no local production of immunoglobulin. Viral activity was detected in the CSF (positive VZV RT-PCR). Electrophysiological studies confirmed left L3–L4 motor and sensory radiculitis with axonotmesis and, as expected, a severe sensori-motor axonal lower limb polyneuropathy. Increased leucocytes and C-reactive protein evidenced mild systemic inflammation; the mean corpuscular volume and IgA levels were slightly increased whereas the thrombocyte rate was low (see Table 1 for more details and reference values). Liver function was normal, as well as thyroid stimulating hormone (TSH) and vitamin B12 and B9 levels. Viral (human immunodeficiency virus, HIV and hepatitis B virus, HBV), Borrelia burgdorferi and Treponema pallidum serology tests were all negative. At this point diagnosis of VZV meningoradiculitis was established.

It should be noted that the patient did not receive zoster vaccine. He was treated within the first 24 h with oral acyclovir followed by IV acyclovir (10 mg/kg every 8 h/ day for 10 days) and showed mainly motor improvement (mild psoas and tibialis anterior paresis finally scored to M4). A few days after admission he developed postherpetic neuralgia that improved with pregabaline and subsequent amitriptyline and a fentanyl patch. Unfortunately analgesic overtreatment led to acute encephalopathy (normal blood tests, brain magnetic resonance imaging and electroencephalogram) that was reversed with dose adjustment. The patient was then transferred to a stationary neurorehabilitation center before returning home.

Discussion and conclusion

The patient described here had zoster paresis associated with mild inflammation and VZV activity in the CSF; leading to treatment mainly by IV acyclovir. The very few reported cases of VZV meningoradiculitis in the literature can be divided into two groups. The first corresponds to radiculitis without meningitis symptoms (a total of 5 cases of which only 2 were referred to as meningoradiculitis) [ 14 – 16 ]. The second group consists of patients with clinically diagnosed meningitis (or encephalitis) associated with neurological peripheral deficits (only one of the two cases was explicitly mentioned as meningoradiculitis) [ 4 , 7 ]. Thus, the authors consider meningoradiculitis either to be a purely peripheral (parainfectious?) phenomenon [ 3 , 15 ] or a CNS complication of VZV infection [ 2 ]. Surprisingly, the CSF workup, when available, in these cases similarly displayed mild inflammation [ 4 , 7 , 14 , 16 ]. Furthermore, all patients with CSF results were treated by IV antiviral drug regardless of the presence of CNS symptoms or not, and without considering their immune status. In contrast, the 3 cases reported by Chan et al. (no CSF results available) only received supportive treatment (oral acyclovir was not yet available) [ 15 ] and yet the outcome did not differ significantly from the other reported cases. Thus, there are obviously contradictions in the definition and management of VZV meningoradiculitis. It appears from the literature that clinicians tend to prescribe IV antiviral treatment to patients with VZV radiculitis after performing CSF investigations, even if this choice does not clearly influence the prognosis.

If meningoradiculitis comprises clinical meningitis with peripheral nerve root involvement, then it should be treated, as with any other VZV-CNS complication, using IV antiviral drugs after spinal tap and other necessary investigations [ 2 , 6 , 12 ]. Alternatively, we suggest considering radiculitis without obvious meningitis symptoms to be a VZV peripheral nervous system complication [ 15 ]. Such patients should therefore be exempt from CSF workup and, as for most cases in everyday clinical practice (contrary to published cases), orally treated with acyclovir with generally good outcome [ 2 , 3 ]. The VZV peripheral nervous system complications are most probably underreported if we compare a rate of 3–5 % of herpes zoster [ 7 , 15 ] to the very low number of reported cases (which are therefore not representative of daily practice as mentioned above). What diagnostic value therefore should inflammatory CSF (with direct or indirect markers of VZV viral activity in the CSF) be given in VZV radiculitis, taking into account that inflammatory markers in the CSF are similar in patients with herpes-related clinical meningitis or encephalitis to those with meningoradiculitis (see above) [ 12 , 14 , 16 ]? Moreover, mild inflammation in the CSF is reported in up to half of all patients with HZ and the presence of viral activity in the CSF does not necessarily establish a causal relationship with neurological symptoms [ 3 ]. Along the same lines, in our patient, VZV RT-PCR was positive in the CSF without intrathecal production of immunoglobulin G (IgG) and local contamination from skin lesions in the lumbar region cannot be ruled out. Thus, CSF inflammation should not be used apart from the clinical context as a discriminating criterion between peripheral and central nervous system complications of VZV and should not solely determine the choice of the antiviral treatment route. In the cases published, clinicians perhaps over-treated patients by prescribing IV acyclovir without clinically evident VZV-related CNS symptoms associated with the radiculitis. This was most probably done to prevent severe neurological complications even if, as stated above, this reasoning cannot be fully justified.

None of the frequently reported immunosuppressive states (inflammatory rheumatic diseases, immunosuppressive treatments, HIV infection, etc.) triggering VZV reactivation [ 3 ] were found in our patient. However, he was in the most vulnerable age group (advanced age) for VZV reactivation and severity [ 3 ], due to age-dependent waning of VZV-related CMI [ 3 , 17 , 18 ]. CMI is important for the control of VZV infection. Similarly, he had signs of alcohol abuse (witnessed by macrocytosis, thrombopenia and increased serum IgA [ 19 – 21 ]), another condition that impairs CMI [ 21 ]. So in this case, in the absence of any other evident cause of immunosuppression, age and alcoholism were considered the factors lowering CMI and precipitating HZ. Nonetheless, clear guidelines do not exist for the choice of antiviral treatment in the context of such subtle immunosuppression.

In conclusion, the patient had VZV cutaneous infection with radiculitis coincident with mild CSF inflammation. Reactivation of VZV was most probably precipitated by age- and alcohol-induced cell-mediated immunosuppression. He was diagnosed with meningoradiculitis and treated with IV acyclovir, despite the absence of clinical meningitis. In available published cases, we did not find a consensual definition or management scheme for meningoradiculitis. The presence of CNS symptoms or abnormal CSF findings did not allow discrimination of severe from benign cases and these patients were generally IV treated. However, well-designed clinical trials are needed to review severity criteria for patients with VZV-associated (meningo)-radiculitis, to study the efficiency of oral versus IV antiviral treatment and establish clear guidelines for management. Mild elevation of inflammatory markers in the CSF is not specific or sensitive enough to establish a diagnosis of meningitis without evocative clinical symptoms. Therefore we suggest that until otherwise demonstrated, the term “meningoradiculitis” should be used for and IV antiviral drugs prescribed to patients with clinical meningitis associated with neurological peripheral deficit in the context of VZV infection. Patients with isolated VZV radiculitis should be exempt from CSF investigations and be given oral antiviral treatment, unless they are subject to any condition or pathology decreasing immunity, in particular CMI, in which case CSF workup and IV antiviral therapy may be necessary.

Abbreviations

cell-mediated immunity

central nervous system

cerebrospinal fluid

computerized tomography

deoxyribonucleic acid

hepatitis B virus

human immunodeficiency virus

herpes zoster

immunoglobulin G

intravenous

real-time polymerase chain reaction

thyroid-stimulating hormone

varicella zoster virus

Gilden D, Nagel MA, Cohrs RJ, Mahalingam R. The variegate neurological manifestations of varicella zoster virus infection. Curr Neurol Neurosci Rep. 2013;13:374.

Article PubMed PubMed Central Google Scholar

Nagel MA, Gilden D. Varicella zoster complications. Curr Treat Options in Neurol. 2013;15:439–53.

Article Google Scholar

Steiner I, Kennedy P, Pachner A. The neurotropic herpes viruses: herpes simplex and varicella-zoster. Lancet. 2007;6:1015–28.

Article CAS PubMed Google Scholar

Abe M, Araoka H, Kimura M, Yoneyama A. Varicella zoster virus meningoencephalitis presenting with Elsberg syndrome without a rash in an immunocompetent patient. Intern Med. 2015;54:2065–7.

Esposito S, Bosis S, Pinzani R, Morlacchi L, Senatore L, Principi N. A case of meningitis due to varicella zoster virus reactivation in an immunocompetent child. Ital J Pediatri. 2013;39:72.

Kangath R, Lindeman T, Brust K. Herpes zoster as a cause of viral meningitis in immunocompetent patients. BMJ Case Rep. 2012. doi: 10.1136/bcr-2012-007575 .

Google Scholar

Mantero V, De Toni Franceschini L, Lillia N, Guccione A, Santilli I, Agostoni E. Varicella-zoster meningoencephaloradiculoneuropathy in an immunocompetent young woman. J Clin Virol. 2013;57:361–2.

Article PubMed Google Scholar

Goyal H, Thakkar N, Bagheri F. Herpes zoster meningitis with multidermal rash in an immunocompetent patient. Am J Emerg Med. 2013;31:1622.e1–2.

Johnson R, Alvarez-Pasquin M-J, Bijl M, Franco E, Gaillat J, Clara J, et al. Herpes zoster epidemiology, management, and disease and economic burden in Europe: a multidisciplinary perspective. Ther Adv Vaccin. 2015;3:109–20.

Article CAS Google Scholar

Okuno Y, Takao Y, Miyazaki Y, Ohnishi F, Okeda M, Yano S, et al. Assessment of skin test with varicella-zoster virus antigen for predicting the risk of herpes zoster. Epidemiol Infect. 2013;141:706–13.

Denne C, Kleines M, Dieckhöfer A, Klaus R, Scheithauer S, Merz U, et al. Intrathecal synthesis of anti-viral antibodies in paediatric patients. Eur J Paediatr Neurol. 2007;11:29–34.

Kaewpoowat Q, Salazar L, Aguilera E, Wootton S, Hasbun R. Herpes simplex and varicella zoster CNS infections: clinical presentations, treatments and outcomes. Infection. 2015;44:337–45.

Kleines M, Scheithauer S, Schiefer J, Häusler M. Clinical application of viral cerebrospinal fluid PCR testing for diagnosis of central nervous system disorders: a retrospective 11-year experience. Diagn Microbiol Infect Dis. 2014;80:207–15.

Allorent J, Cozic C, Tanguy G, Cormier G. Sciatique déficitaire avec hémisyndrome de la ques de cheval secondaire à méningoradiculite au virus au zona-varicelle. Revue du Rhumatisme. 2013;80:416–25.

Chang CM, Woo E, Yu YL, Huang CY, Chin D. Herpes zoster and its neurological complications. Postgrad Med J. 1987;63:85–9.

Article CAS PubMed PubMed Central Google Scholar

Matsumoto H, Shimizu T, Tokushige S-I, Mizuno H, Igeta Y, Hashida H. Rectal ulcer in a patient with VZV sacral meningoradiculitis (Elsberg Syndrome). Intern Med. 2012;51:651–4.

Okamoto S, Hata A, Sadaoka K, Yamanishi K, Mori Y. Comparison of varicella-zoster virus-specific immunity of patients with diabetes mellitus and healthy individuals. J Infect Dis. 2009;200:1606–10.

Levin M, Smith J, Kaufhold R, Barber D, Hayward A, Chan C, et al. Decline in varicella-zoster virus (VZV)-specific cell-mediated immunity with increasing age and boosting with a high-dose VZV vaccine. J Infect Dis. 2003;188:1336–44.

Szabo G, Mandrekar P. A recent perspective on alcohol, immunity and host defense. Alcoholism. 2009;33:220–32.

Ballard H. The hematological complications of alcoholism. Alcohol Health Res World. 1997;21:42–52.

CAS PubMed Google Scholar

Cook R. Alcohol abuse, alcoholism, and damage to the immune system—a review. Alcohol Clin Exp Res. 1998;22:1927–42.

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Authors’ contributions

VL and LW collected data, drafted and reviewed the manuscript. DF contributed to data collection, discussed results, diagnoses and management, and reviewed the manuscript. GP contributed to the study design, discussed infectious diagnoses and results. J-AG contributed to discussion of neurological diagnoses and treatment, and reviewed the manuscript. DG participated in data collection, significantly participated in neurological diagnoses, discussion and reviewed the manuscript. JNC designed the study, discussed neurological diagnoses and treatment, wrote and reviewed the manuscript. All authors read and approved the final manuscript.

Acknowledgements

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The authors declare that they have no competing interests.

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The dataset supporting the conclusions of this article are included within the article.

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Written informed consent was obtained from the patient for publication of this Case Report and any accompanying images. A copy of the written consent is available for review by the Editor-In-Chief of this journal.

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This case report was performed in accordance with Swiss ethical law (“loi relative à la recherche sur l’être humain”, LRH) and international ethical rules.

The present study was not funded.

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Joelle Nsimire Chabwine

Present address: Neurology Unit, Department of Medicine, Faculty of Sciences, University of Fribourg, Chemin du Musée 5, 1700, Fribourg, Switzerland

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Internal Medicine Division, Valais Hospital, Avenue Grand Champsec, 80, 1951, Sion, Switzerland

Vincent Luisier & Lalensia Weber

Emergency Department, Valais Hospital, Avenue Grand Champsec, 80, 1951, Sion, Switzerland

Daniel Fishman

Infectious Disease Division (Central Institute), Valais Hospital, Avenue Grand Champsec, 80, 1951, Sion, Switzerland

Gérard Praz

Division of Neurology, Valais Hospital, Avenue Grand Champsec, 80, 1951, Sion, Switzerland

Joseph-André Ghika, Didier Genoud & Joelle Nsimire Chabwine

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Luisier, V., Weber, L., Fishman, D. et al. Definition and management of varicella zoster virus-associated meningoradiculitis: a case report. BMC Res Notes 9 , 451 (2016). https://doi.org/10.1186/s13104-016-2257-2

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Pediatric Peripheral Facial Palsy Following Varicella Zoster Infection

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Published: 12 April 2024

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Fatima Ezzahra Rizkou ORCID: orcid.org/0000-0001-6684-1089 1 ,
Laila Liqali 1 ,
Youssef Lakhdar 1 ,
Omar Oulghoul 1 ,
Mohammed Chahbouni 1 ,
Othmane Benhoummad 2 ,
Youssef Rochdi 1 &
Abdelaziz Raji 1

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Peripheral facial palsy, characterized by sudden weakness or paralysis of the facial muscles, can arise from various etiologies, including viral infections. While Ramsay Hunt syndrome is well-established in clinical practice, Varicella Zoster Virus (VZV) infection leading to facial nerve palsy in pediatric patients remains relatively uncommon.This comprehensive case report documents the clinical presentation, diagnostic evaluation, treatment, and outcomes of a 10-year-old boy who developed left peripheral facial palsy following a primary Varicella infection. The report underscores the importance of timely recognition and tailored management approaches in achieving a complete remission of symptoms in pediatric patients.

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Multiple cranial neuropathy due to varicella zoster virus reactivation without vesicular rash: a challenging diagnosis

Antonio Stornaiuolo, Rosa Iodice, … Fiore Manganelli

Bilateral facial paralysis as a rare neurological manifestation of primary Sjögren’s syndrome: case-based review

Zhang Wei, Shi Jiaying & Guo Junhong

Bilateral facial palsy after COVID-19 vaccination

Valentina Andreozzi, Beatrice D’arco, … Paolo Barone

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Poumerol G, Wilder-Smith A (2012) International travel and health. World Health Organisation Retrieved from https://www.who.int/ith

Yuen Teng L, Quen Lee W et al (2020) Varicella and isolated acute peripheral facial nerve palsy: a systematic review on natural history, prognosis and treatment. Neurol Asia 25(4):473–484

Google Scholar

Bozzola E, Tozzi AE et al (2012) Neurological complications of varicella in childhood: Case series and asystematic review of the literature. Vaccine 30:5785–5790

Article PubMed Google Scholar

LaRussa PS, Marin M (2011) Varicella-zoster virusinfections. In: Kliegman RM, Stanton BF, St. Geme JW, Schor NF, Behrman RE (eds) Nelson textbook of pediatrics, 19th edn. Elsevier Saunders, Philadelphia, PA, pp 1104–1110

Chapter Google Scholar

Oghan F, Topuz MF, Erdogan O (2017) Facial Paralysıs during Varicella Zoster Infectıon in a child. Heighpubs Otolaryngol Rhinol 1:016–019. https://doi.org/10.29328/journal.hor.1001004

Article Google Scholar

Girija AS, Rafeeque M, Abdurehman KP (2007) Neurological complications of chickenpox. Ann Indian Acad Neurol 10:240–246

Watanabe Y, Ikeda M, Kukimoto N, Kuga M, Tomita H (1994) A case report of facial nerve palsy associated with chickenpox. J Laryngol Otol 108(8):676–678

Article CAS PubMed Google Scholar

Hanalioğlu D, Özsürekci Y (2018) Acute peripheral facial paralysis following varicella infection: an uncommon complication. Turk J Pediatr 60:99–101. https://doi.org/10.24953/turkjped.2018.01.016

van der Flier M, van Koppenhagen C, Disch FJ, Mauser HW, Bistervels JH, van Diemen-Steenvoorde JA (1999) Bilateral sequential facial palsy during chickenpox. Eur J Pediatr 158(10):807–808

Ödemis E, Türkay S, Tunca A, Karadag A (2004) Acute peripheral facial palsy during chickenpox in a child. J Pediatr Neurol 2(4):245–246

Grose C, Bonthius D, Afifi AK (2002) Chickenpox and the geniculate ganglion: facial nerve palsy, Ramsay Hunt syndrome and acyclovir treatment. Pediatr Infect Dis J 21(7):615–617

Peitersen E (2002) Bell’s palsy: the spontaneous course of 2,500 peripheral facial nerve palsies of different etiologies. Acta Otolaryngol Suppl ;(549):4–30

Ferreira H, Dias Â, Lopes A Acute Peripheral Facial Palsy after Chickenpox: a Rare Association. Hindawi Publishing Corporation Case reports in Pediatrics 2014. Article ID 754390, 3 pages https://doi.org/10.1155/2014/754390

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Rizkou, F.E., Liqali, L., Lakhdar, Y. et al. Pediatric Peripheral Facial Palsy Following Varicella Zoster Infection. Indian J Otolaryngol Head Neck Surg (2024). https://doi.org/10.1007/s12070-024-04667-y

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Varicella / Chickenpox 2024 Case Definition

Cste position statement(s).

Varicella (chickenpox) is an acute infectious disease caused by primary infection with varicella-zoster virus (VZV). Varicella is generally a mild disease, but severe complications can occur in any age group. Fatalities are rare, but can occur, including in previously healthy persons. Following introduction of the 1-dose varicella vaccination program in 1995 and addition of a second dose in 2007 1 , varicella morbidity and mortality decreased dramatically in the U.S. 2,3 By 2019, overall incidence declined by >97% and hospitalizations and deaths declined by 94% and 97%, respectively, among persons aged 2,3 After 25 years of varicella vaccination in the U.S., classic varicella, with hundreds of vesicular skin lesions, scabs, and complications, has become an uncommon occurrence. 4 However, varicella can occur in vaccinated persons (termed breakthrough varicella). Breakthrough varicella is usually modified, with fewer skin lesions ( 4 Diagnosis of breakthrough varicella is important because these cases are infectious. Clinical diagnosis is especially challenging in cases with mild rashes, few lesions, or no vesicles. Consequently, laboratory confirmation of varicella is becoming increasingly necessary to understand the true burden of disease and is now routinely recommended.

As of 2022, case-based varicella surveillance is conducted by 40 states and the District of Columbia (D.C.), and outbreak surveillance is conducted by all jurisdictions. 3

Clinical Criteria

In the absence of a more likely alternative diagnosis:

An acute illness with a generalized rash with vesicles (maculopapulovesicular rash), OR
An acute illness with a generalized rash without vesicles (maculopapular rash).

Laboratory Criteria

Confirmatory Laboratory Evidence: a

Positive polymerase chain reaction (PCR) for varicella-zoster virus (VZV) DNA, b,c OR
Positive direct fluorescent antibody (DFA) for VZV DNA, OR
Isolation of VZV, OR
Significant rise (i.e., at least a 4-fold rise or seroconversion c,d ) in paired acute and convalescent serum VZV immunoglobulin G (IgG) antibody. c,e

Supportive Laboratory Evidence:

Positive test for serum VZV immunoglobulin M (IgM) antibody. c,f

Note: The categorical labels used here to stratify laboratory evidence are intended to support the standardization of case classifications for public health surveillance. The categorical labels should not be used to interpret the utility or validity of any laboratory test methodology. a A negative laboratory result in a person with a generalized rash with vesicles does not rule out varicella as a diagnosis. b PCR of scabs or vesicular fluid is the preferred method for laboratory confirmation of varicella. In the absence of vesicles or scabs, scrapings of maculopapular lesions can be collected for testing. c Not explained by varicella vaccination during the previous 6-45 days. d Seroconversion is defined as a negative serum VZV IgG followed by a positive serum VZV IgG. e In vaccinated persons, a 4-fold rise may not occur. f IgM serology has limited value as a diagnostic method for VZV infection and is not recommended for laboratory confirmation of varicella. However, an IgM positive result in the presence of varicella-like symptoms can indicate a likely acute VZV infection. A positive IgM result in the absence of clinical disease is not considered indicative of active varicella.

Epidemiologic Linkage

Confirmatory Epidemiologic Linkage Evidence:

Exposure to or contact with a laboratory-confirmed varicella case, OR
Can be linked to a varicella cluster or outbreak containing ≥1 laboratory-confirmed case, OR
Exposure to or contact with a person with herpes zoster (regardless of laboratory confirmation).

Presumptive Epidemiologic Linkage Evidence:

Exposure to or contact with a probable varicella case that had a generalized rash with vesicles.

Criteria to Distinguish a New Case from an Existing Case

The following should be enumerated as a new case:

Person with a new onset of symptoms that meets the criteria for a confirmed or probable case, OR
Person was previously enumerated as a case followed by a documented period of recovery AND newly meets the criteria for a confirmed or probable case*, OR
Person was previously reported but not enumerated as a confirmed or probable case, then subsequently available information meets the criteria for a confirmed or probable case.

* Varicella generally confers life-long protection. There have been reports of second episodes of varicella, but in most cases the first episode was not laboratory-confirmed.

Case Classification

Meets clinical evidence with a generalized rash with vesicles,
Confirmatory or presumptive epidemiologic linkage evidence, OR
Supportive laboratory evidence.
Confirmatory or supportive laboratory evidence.

* A person whose healthcare record contains a diagnosis of varicella or chickenpox.

Meets clinical evidence AND confirmatory laboratory evidence,
Meets clinical evidence with a generalized rash with vesicles AND confirmatory epidemiologic linkage evidence.
Marin M, Güris D, Chaves SS, Schmid S, Seward JF; Advisory Committee on Immunization Practices, Centers for Disease Control and Prevention (CDC). Prevention of varicella: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2007 Jun 22;56(RR-4):1-40. https://www.cdc.gov/mmwr/preview/mmwrhtml/rr5604a1.htm
Marin M, Leung J, Anderson TC, Lopez AS. Monitoring Varicella Vaccine Impact on Varicella Incidence in the United States: Surveillance Challenges and Changing Epidemiology, 1995-2019. J Infect Dis. 2022 Oct 21;226(Suppl 4):S392-S399. https://doi.org/10.1093/infdis/jiac221
Marin M, Lopez AS, Melgar M, Dooling K, Curns AT, Leung J. Decline in Severe Varicella Disease During the United States Varicella Vaccination Program: Hospitalizations and Deaths, 1990-2019.J Infect Dis. 2022 Oct 21;226(Suppl 4):S407-S415. https://doi.org/10.1093/infdis/jiac242
Dooling K, Marin M, Gershon AA. Clinical Manifestations of Varicella: Disease Is Largely Forgotten, but It's Not Gone. J Infect Dis. 2022 Oct 21;226(Suppl 4):S380-S384. https://doi.org/10.1093/infdis/jiac390

Related Case Definition(s)

Varicella / Chickenpox | 2010 Case Definition
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Varicella-Zoster Virus (Chickenpox)
Chickenpox or varicella is a contagious disease caused by the varicella-zoster virus (VZV). The virus is responsible for chickenpox (usually primary infection in non-immune hosts) and herpes zoster or shingles (following reactivation of latent infection). Chickenpox results in a skin rash that forms small, itchy blisters, which scabs over. It typically starts on the chest, back, and face then ...
Clinical features of varicella-zoster virus infection ...
INTRODUCTION. Varicella-zoster virus (VZV) is one of eight herpesviruses known to cause human infection and is distributed worldwide. VZV infection causes two clinically distinct forms of disease: varicella (chickenpox) and herpes zoster (shingles). Primary VZV infection results in the diffuse vesicular rash of varicella, or chickenpox.
Chickenpox (Varicella) for Healthcare Professionals
It is caused by varicella-zoster virus (VZV), which is a DNA virus that is a member of the herpesvirus group. After the primary infection, VZV stays in the body (in the sensory nerve ganglia) as a latent infection. Primary infection with VZV causes varicella. ... it can be difficult to make a diagnosis on clinical presentation alone. Laboratory ...
Varicella Zoster Virus (VZV): Infection & Diseases
Varicella-Zoster Virus (VZV) Varicella-zoster virus (VZV) is a type of herpes virus that causes chickenpox, shingles and other infections. The virus stays in your body and can reactivate years later. VZV infections can cause a painful or itchy rash, fever and other symptoms, depending on where you're infected.
Clinical features of varicella-zoster virus infection: Chickenpox
Varicella-zoster virus (VZV) is one of eight herpesviruses known to cause human infection and is distributed worldwide. VZV infection causes two clinically distinct forms of disease: varicella (chickenpox) and herpes zoster (shingles). Primary VZV infection results in the diffuse vesicular rash of varicella, or chickenpox.
Varicella-Zoster Virus (VZV) Clinical Presentation
Varicella-zoster virus (VZV) is the cause of chickenpox and herpes zoster (also called shingles). ... Goh CL, Khoo L. A retrospective study of the clinical presentation and outcome of herpes zoster in a tertiary dermatology outpatient referral clinic. Int J Dermatol. 1997 Sep. 36(9):667-72.
Chickenpox
Chickenpox is an illness caused by the varicella-zoster virus. It brings on an itchy rash with small, fluid-filled blisters. Chickenpox spreads very easily to people who haven't had the disease or haven't gotten the chickenpox vaccine. Chickenpox used to be a widespread problem, but today the vaccine protects children from it.
Epidemiology, clinical manifestations, and diagnosis of herpes zoster
Herpes zoster, also known as shingles, results from reactivation of latent VZV that gained access to sensory ganglia during varicella. Herpes zoster is characterized by a painful, unilateral vesicular eruption, which usually occurs in a single or two contiguous, dermatomes ( picture 1A-J ). This topic will address the epidemiology, clinical ...
Varicella zoster virus infection
Infection with varicella zoster virus (VZV) causes varicella (chickenpox), which can be severe in immunocompromised individuals, infants and adults. ... Figure 3: Clinical presentation of ...
PDF Varicella (Chickenpox) and Zoster (Shingles) Disease Varicella and
Varicella (Chickenpox) Clinical Features. Incubation period: 14 to 16 days (10-21 days) Mild prodrome for 1 to 2 days (adults) Rash generally appears first on the head; most concentrated on the trunk. Successive crops over several days with lesions present in several stages of development.
PDF Varicella (Chickenpox) and Herpes Zoster (Shingles)
Varicella-Zoster Virus (VZV) Human alpha-herpesvirus. Causes varicella (chickenpox) and herpes zoster (shingles) Primary VZV infection leads to varicella. VZV establishes latency in dorsal root ganglia after primary infection. VZV can reactivate at a later time, causing herpes zoster. There are 3 licensed vaccines to prevent varicella (Varivax ...
Frontiers
Introduction. Primary infection with varicella-zoster virus (VZV), a ubiquitous, human-restricted double-strand DNA alpha-herpesvirus (1, 2), causes chickenpox.In non-vaccinated populations, seroprevalence for VZV increases with age in children, reaching more than 90% by the age of 18 years in most (3, 4), but not all countries ().VZV reactivation after a quiescent phase in the sensory ganglia ...
Clinical Overview of Herpes Zoster (Shingles)
Herpes zoster, also known as shingles, is caused by reactivation of varicella-zoster virus (VZV), the same virus that causes varicella (chickenpox). Primary infection with VZV causes varicella. After a person has varicella, the virus remains latent in the dorsal root ganglia. VZV can reactivate later in a person's life and cause herpes zoster ...
Varicella Zoster
Varicella-Zoster is a member of the herpesvirus family. B. Clinical Description. Symptoms: Primary infection results in varicella (chickenpox). A mild prodrome may precede the onset of a rash. Adults may have 1 to 2 days of mild fever and malaise. Prior to rash onset, but in children the rash is often the first sign of disease.
Recent Advances in Varicella-Zoster Virus Infection
Since the previous NIH Combined Clinical Staff Conference on varicella-zoster virus infections 10 years ago , advances in molecular biology and immunology have provided insights into viral pathogenesis, and new antiviral agents and a live attenuated vaccine for varicella-zoster virus have been approved.This conference focuses on recent developments in the biology, clinical presentation ...
Definition and management of varicella zoster virus-associated
The varicella zoster virus affects the central or peripheral nervous systems upon reactivation, especially when cell-mediated immunity is impaired. Among varicella zoster virus-related neurological syndromes, meningoradiculitis is an ill-defined condition for which clear management guidelines are still lacking. Zoster paresis is usually considered to be a varicella zoster virus-peripheral ...
Immunogenicity and safety of an
Varicella, also known as chickenpox, is an infectious disease with a characteristic skin rash caused by the Varicella zoster virus. After the initial infection, varicella zoster virus can remain dormant and potentially reactivate in later life as herpes zoster, or shingles. 1 The currently licensed varicella vaccines are all live attenuated and ...
Pediatric Peripheral Facial Palsy Following Varicella Zoster ...
The Varicella-zoster Virus (VZV), a member of the Herpesviridae family, is a DNA virus known for its dual clinical presentations: varicella, commonly referred to as chickenpox, and herpes zoster, also known as shingles [1, 2].Varicella marks the inaugural encounter with VZV, establishing a persistent latent infection within sensory ganglia.
A Case of Varicella Zoster Virus Acute Retinal Necrosis, Vasculopathy
A Case of Varicella Zoster Virus Acute Retinal Necrosis, Vasculopathy, and Acute Ischemic Stroke in a Patient Newly Diagnosed with Systemic Sarcoidosis (P1-13.008) ... VZV is known to cause chickenpox. Upon reactivation later in life, it is also well-known for the clinical syndrome herpes zoster. Lesser-known complications exist including ...
Varicella / Chickenpox 2024 Case Definition
Varicella (chickenpox) is an acute infectious disease caused by primary infection with varicella-zoster virus (VZV). Varicella is generally a mild disease, but severe complications can occur in any age group. Fatalities are rare, but can occur, including in previously healthy persons. Following introduction of the 1-dose varicella vaccination ...
Mutagenesis and functional analysis of the varicella-zoster virus
In contrast to what is known about phage portal proteins, details concerning herpesvirus portal structure and function are not as well understood. A panel of 65 Varicella-Zoster virus (VZV) recombinant portal proteins with five amino acid in-frame insertions were generated by random transposon mutagenesis of the VZV portal gene, ORF54.

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