Varicella (chickenpox, postvaricella encephalitis, varicella hemorrhagic pneumonitis, postvaricella myelitis, varicella with other specified complications, varicella with unspecified complication, varicella without mention of complication)

Are You Confident of the Diagnosis?

• What you should be alert for in the history

Varicella usually begins as a prodrome of mild fever, malaise and myalgia. Other prodromal symptoms may include pharyngitis, irritability and anorexia. This tends to be more pronounced in adolescents and adults than in children who may have no prodrome. The development of a generalized exanthem usually occurs within 24 hours of the prodrome. The fever may persist to accompany the rash, and tends to decline when the appearance of new lesions slows. Other symptoms that commonly occur include pruritus, which can be severe, and headache.

• Characteristic findings on physical examination

Following the prodromal symptoms, an eruption of pruritic, erythematous macules and papules occurs. Lesions tend to evolve, over 12-14 hours, into vesicles with clear serous fluid surrounded by a narrow red halo creating an appearance of ‘dew drops on a rose petal’. The number of vesicles can range from only a few to several hundred. Vesicles may develop into pustules before crusting. Vesicles tend to dry from the center outward resulting in an umbilicated appearance.

The hallmark of varicella is the presence of lesions of varying stages on physical examination. New lesions continue to develop for 3-5 days. Lesions usually crust within 6 days and heal in 1-2 weeks without leaving permanent scarring unless secondary infection occurs.

Skin lesions start on the scalp and face then spread to the trunk and extremities, with the greatest concentration on the trunk. On the extremities, lesions tend to be concentrated proximally rather than distally. Vesicles often develop on mucous membranes, such as the oropharynx, conjunctiva, trachea, vagina, and rectum but rapidly rupture to form shallow ulcers that heal without forming scabs. The rash is often more severe and lesions may be confluent in areas of the skin where there is local irritation such as skin folds (Figure 1).

Figure 1.

• Diagnostic modalities

The diagnosis of varicella is usually made based on history and physical examination alone. It may be critical to make such a diagnosis in a timely manner as it could affect the decision regarding antiviral therapy. If the diagnosis is challenging or the presentation is atypical, such as in immunocompromised patients, laboratory confirmation is recommended. Rapid testing with a Tzanck smear or demonstration of VZV DNA by direct fluorescent antibody (DFA) or polymerase chain reaction (PCR) may be performed using skin scrapings from the base of a vesicle and vesicular fluid.

The Tzanck smear shows multinucleated epithelial giant cells with characteristic intranuclear inclusions, visualized by light microscopy. This test is not specific because these cells are typical of both VZV and HSV infection. DFA or PCR, therefore is necessary for distinction as these tests are both sensitive and highly specific.

Additional testing includes viral culture and serology. Viral culture, although very specific, may take 1-2 weeks to obtain a result. Numerous serologic tests are available but are generally less specific and sensitive than PCR or DFA. As PCR is widely available, and confers highly specific and sensitive results from an array of clinical specimens, it is the most reliable method for confirming infection.

• Diagnosis confirmation

The differential diagnosis of varicella includes HSV, Coxsackie virus (hand, foot and mouth disease), contact dermatitis, pityriasis lichenoides et varioliformis acuta (PLEVA), drug eruption, rickettsialpox, insect bites and scabies.

Disseminated HSV may mimic varicella, but herpes simplex typically has a predominance of localized vesicle clusters at the primary site of infection. The viral exanthem of hand, foot and mouth disease favors the distal extremities and oral mucosa. Contact dermatitis is not associated with the prodrome of a varicella infection, and lesions are less likely on the trunk than on the extremities.

PLEVA is a chronic inflammatory disorder. In drug eruptions the appearance of multiple types of lesions is rare. Rickettsialpox is associated with an initial lesion at the site of a mite bite. Insect bites are associated with an underlying wheal and typically occur on the extremities. Scabies, which has a chronic development of lesions, tends to occur in body folds and is associated with linear burrows.

Who is at Risk for Developing this Disease?

Varicella is a common disease with a worldwide distribution. Most cases occur in childhood; 98% of the adult population is seropositive. Varicella affects 90% of unvaccinated children under the age of ten.

Since the widespread pediatric immunization in the United States in 1995, the incidence of varicella has declined dramatically. Prior to the vaccine, approximately 4 million cases occurred annually in the United States, resulting in approximately 11,000 hospitalizations and 100 deaths. Currently, less than 10 deaths occur per year, most of them in unimmunized people. Although vaccine coverage had exceeded 80% over the past few years, outbreaks of breakthrough varicella still occur in schools and daycare centers.

What is the Cause of the Disease?

• Etiology

• Pathophysiology

Varicella-zoster virus (VZV, human herpesvirus 3) is the causative agent of two distinct clinical entities, varicella (chickenpox) and zoster (shingles).

Varicella is a highly contagious disease, with secondary infection occurring in 61-100% of susceptible household contacts. Transmission of the virus occurs through contact with aerosolized droplets from nasopharyngeal secretions or vesicular fluid from skin lesions of an infected individual. The virus invades the mucosa of the upper respiratory tract and replicates in the local lymphoid tissue.

After 4-6 days, a small primary viremia results in spread to the reticuloendothelial cells in the liver, spleen and other organs where there is further replication until 10-12 days after exposure. A significant secondary viremia occurs at that time which results in the spread of the virus to the skin. The average incubation period for varicella infection is 14-16 days. The period of infectivity is considered to last from 48 hours prior to the onset of skin lesions until the lesions have fully crusted.

Systemic Implications and Complications

The most frequent complication of varicella in healthy children is secondary bacterial infection of skin lesions, usually due to Staphylococcus or Streptococcus. The superinfection may manifest as cellulitis, impetigo, erysipelas, furuncles, or bullous lesions. Primary infection complicated by group A streptococcal infection has been associated with myositis, necrotizing fasciitis, and toxic shock syndrome. Bacterial infection frequently leads to scarring, but rarely leads to septicemia.

Neurologic complications occur in less than 1 in 1000 cases, but include encephalitis, acute cerebellar ataxia, Reye’s syndrome, transverse myelitis, vasculitis, and Guillain-Barre syndrome. Reye’s syndrome is rare since aspirin is no longer recommended for children with varicella or other viral infections.

Primary varicella in adults tends to cause more severe clinical syndromes, more complications, and an increased number of skin lesions. Pneumonia may develop in affected adults, usually within 6 days after the onset of rash. The mortality rates in adults with varicella pneumonia are high, with death occurring in 10% of immunocompetent and 30% of immunocompromised individuals. Other rare complications that can occur include myocarditis, glomerulonephritis, pancreatitis, hepatitis, appendicitis, orchitis, arthritis, optic neuritis, and keratitis.

Patients with a history of underlying malignancy, steroid or immunosuppressive therapy, HIV infection or solid organ transplantation are susceptible for systemic involvement of varicella. Immunocompromised hosts who develop varicella experience more complications and higher mortality. This patient subset may have ongoing development of vesicles over weeks, which may become large and hemorrhagic. Immunocompromised individuals are more susceptible to developing pneumonia and widespread disease with disseminated intravascular coagulation.

Varicella infection in pregnant individuals can produce a wide array of fetal abnormalities, ranging from asymptomatic latency to severe congenital defects. The risk of congenital abnormalities is greatest when maternal infection occurs in the first trimester. Congenital defects include hypoplastic limbs, cortical atrophy, cicatricial skin lesions, ocular abnormalities, psychomotor retardation and low birth rate. The overall risk of embryopathy is estimated to be around 2% after primary maternal infection in the first 20 weeks of pregnancy.

Treatment Options

Adults with uncomplicated varicella

• Acyclovir 20 mg/kg (800 mg max) orally 4 times daily for 5-7 days (or)

• Famciclovir 500 mg orally 3 times daily for 7 days (or)

• Valacyclovir 1 gm orally 3 times daily for 7 days

Children with uncomplicated varicella

• Acyclovir 20 mg/kg (800 mg max) orally 4 times daily for 5 days

• Valacyclovir 20 mg/kg (1 g max) orally 3 times daily for 5 days

Immunocompromised adults

• Intravenous acyclovir 10 mg/kg every 8 hours for 7-10 days

Immunocompromised children ≥2 year of age and adolescents

• Acyclovir 1500 mg/m2 per day in three divided doses or 30 mg/kg/day in three divided doses

Adults who develop complicated disease

• Intravenous acyclovir 10 mg/kg every 8 hours for 7-10 days

Children ≥2 year of age and adolescents with complicated disease

• Acyclovir 1500 mg/m2 per day in three divided doses or 30 mg/kg/day in three divided doses

Note: For children or adults weighing less than 40 kg and not requiring inpatient treatment, acyclovir oral suspension (200 mg/5mL) may be preferred treatment option due to inability to easily dose 20 mg/kg with capsule formulations.

Optimal Therapeutic Approach for this Disease

Symptomatic treatment is key in treating varicella infections, especially in children. Pruritus can be controlled with antihistamines, calamine lotion, and tepid baths. Acetaminophen may be used as an antipyretic. Aspirin is to be avoided due to its potential to cause Reye’s syndrome. Fingernails should be closely trimmed to avoid significant excoriation and secondary bacterial infection.

Acyclovir has been shown to reduce the severity and duration of varicella infections if given within 24-72 hours of the development of skin lesions. It is FDA-approved for adults and children over two. Treatment is highly recommended for children who are at an increased risk of complicated disease such as those who are 12 years or older, those with chronic cutaneous or pulmonary disorders, or individuals on steroid or chronic salicylate therapy.

Acyclovir, as well as famciclovir and valacyclovir, is recommended for varicella in the adult population due to the increased risk of severe disease and complications.

Famciclovir and valacyclovir are not approved by the FDA for the treatment of primary varicella, but may be used at dosages indicated for zoster. Although there is not strong data to support these drugs, patients may prefer them due to the 3 times a day dosing.

Intravenous acyclovir should be given to immunosuppressed children and adults as well as individuals who have already developed systemic complications such as pneumonia or encephalitis.

Since the approval of the varicella vaccine in 1995, primary prevention of varicella has been the major focus for clinicians. In 2006, recommendations were made to go from one dose of the varicella vaccine to two. The Oka strain of the live attenuated VZV is recommended for children under 13, as well as healthy teenagers and adults without evidence of immunity. Two doses should be administered to children, at ages 12 months and 4-6 years, with a minimum interval between doses of 3 months. For healthy teenagers and adults without evidence of immunity, two doses should be administered at least 4 weeks apart. Two systematic reviews of ≥40 studies of varicella vaccine effectiveness, showed two-dose vaccination 92-93 percent effective in preventing varicella disease of any severity and ≥99 percent effective in preventing severe disease. vaccine or the measles-mumps-rubella and varicella vaccine (MMRV). MMRV vaccination is approved only in children 12 months through 12 years of age.

Vaccination with the live attenuated varicella vaccine appears safe and effective in children with atopic dermatitis. Vaccination is particularly important in this patient subset, as the frequency of secondary bacterial infection is higher in children with atopic dermatitis, likely due to the high rate of colonization of the skin with Staphylococcus aureus and other bacterial species.

The vaccine is not recommended in women who are pregnant or might become pregnant within four weeks of receiving the vaccine. Immunocompromised patients, such as those on immunosuppressive medications or those with hematologic malignancies should not be given the live attenuated vaccine. Patients with HIV may be offered the vaccine based on their current immune status.

The CDC guidelines recommend the vaccine to be given to HIV infected children with a CD4+T lymphocyte percentage of more than 15%. HIV infected adults with CD4 cell counts of ≥200 cells/microL can be given two doses of the vaccine 3 months apart. Additionally, only the single antigen vaccine should be given as the MMRV vaccine is not recommended in HIV infected patients.

The varicella zoster immune globulin (VariZIG), FDA-approved in 2013, can be given as post exposure prophylaxis in susceptible individuals. The injection contains high-levels of anti-varicella IgG antibodies. Recommended patient groups include immunocompromised, pregnant women and neonates of infected mothers and should be given this passive immunization within 96 hours after exposure.

Patient Management

Varicella is usually a self-limited disease in healthy individuals and does not require long-term follow-up. Patients should be instructed to remain isolated during infection in order to limit the spread of the highly contagious virus, avoiding pregnant women and those with compromised immune systems. Development of lesions for more than 7 days should alert physicians to consider an underlying immunodeficiency.

In children, symptomatic treatment may be sufficient, whereas teenagers and adults should be treated with antiviral therapy. Acyclovir is generally well tolerated, although gastrointestinal upset and headache may occur.

Since varicella pneumonia is the most common complication in the adult population, clinicians should be vigilant for signs of pneumonia including prolonged fever, cough and dyspnea. Chest radiography should be performed in suspected cases, which will show patchy or diffuse bilateral nodular infiltrate. Patients with varicella pneumonia should be hospitalized for intravenous treatment with acyclovir. Immunocompromised children and adults will also likely require hospitalization for administration of intravenous therapy and close monitoring.

The ten-year safety profile of more than 55 million doses of administered varicella vaccine has demonstrated that immunization is generally well tolerated. Injection site reactions, rash and febrile seizures have been reported. Incidence of febrile seizures was found to be slightly higher in children 12-23 months of age receiving the quadravalent MMRV vaccine; therefore, this vaccine is no longer the preferred vehicle of varicella immunization.

Unusual Clinical Scenarios to Consider in Patient Management

Although immunization has greatly reduced the incidence of varicella infection, it is important to still consider this diagnosis in individuals who have been previously vaccinated. Breakthrough varicella or mild varicella-like syndrome occurs in 1-3% of vaccinated children. Most of these cases are mild and the rash tends to be atypical, resulting in fewer lesions which tend to be maculopapular rather than vesicular (Figure 2).

Figure 2.

Immunocompromised patients who receive the varicella vaccine are at risk for developing severe and/or disseminated herpes zoster with either the vaccine strain of virus or wild-type VZV from an antecedent natural varicella infection. In such patients, the onset of symptoms can develop months after vaccination.

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