Varicella-Zoster Virus (Chickenpox)

Etiology

Chickenpox, or varicella, is caused by VZV, a herpes virus with worldwide distribution. The virus establishes latency after primary infection, a feature unique to most herpes viruses.[4] Chickenpox 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. The virus enters the circulation after 2 to 6 days, and another bout of viremia occurs in 10 to 12 days. At this time, the characteristic vesicles appear. Immunoglobulin (Ig)A, IgM, and IgG antibodies are produced, but the IgG antibodies confer lifelong immunity. After the primary infection, varicella localizes to sensory nerves and may reactivate later as shingles.

Risk factors for severe varicella in adolescents and adults are as follows:

• Steroid therapy: doses equivalent to 1 to 2 mg/kg/d of prednisolone administered for 2 weeks or longer are significant risk factors for severe illness. Even brief medication at these dosages shortly before or during the incubation period of varicella can result in severe or fatal varicella.[5]
• Immunocompromised conditions (eg, cancer, antineoplastic agents, human immunodeficiency virus, other congenital or acquired immunodeficiency disorders). Cellular immunodeficiency, as compared to humoral immunodeficiency, is thought to predispose individuals to severe varicella.
• Pregnant women are at an elevated risk of developing severe varicella, particularly pneumonia. Moreover, maternal varicella accompanied by viremia can be transmitted transplacentally to the fetus. This results in newborn varicella. Infants born between 5 days before and 2 days after the onset of the varicella rash in the mother are at the highest risk for serious illness.[6] The first month of a neonate's life is a vulnerable phase for severe varicella, particularly if the mother is seronegative. Delivery before 28 weeks of gestation predisposes a neonate to risk, as transplacental transfer of IgG antibodies occurs following this period.

Epidemiology

VZV has a global distribution, with 98% of the adult population being seropositive. Varicella occurs in all countries and is responsible for about 7000 deaths annually. Most cases occur in winter and spring. In the United States, VZV accounts for more than 9000 hospitalizations annually; its highest prevalence is in the 4- to 10-year-old age group. 

Following the implementation of the varicella vaccine in 1995, the overall incidence of varicella has diminished by approximately 85%, demonstrating evidence of herd immunity. The age of peak incidence transitioned from 5 to 9 years to 10 to 14 years, of age and an increased occurrence of breakthrough varicella among vaccinated children in the later age group prompted the inclusion of a second varicella vaccine dose in the standard childhood immunization schedule in 2006.[7]

Varicella is typically symptomatic, and before the introduction of the varicella vaccine, this condition affected 90% of children in the United States by the age of 10. Herpes zoster signifies the reactivation of latent VZV infection, occurring in around 20% of healthy adults and 50% of immunocompromised individuals, with considerable morbidity and mortality in the latter group. 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.  A case has been recently reported in a patient who is 81 years old.[8][9][10][11]

Pathophysiology

The causative agent, VZV, belongs to the human herpesvirus subfamily Alphaherpesvirinae and is a deoxyribonucleic acid virus similar to all herpesviruses. The virus invades via the respiratory system (conjunctival or upper respiratory mucosa) and establishes itself in the upper respiratory tract. Viral replication occurs in regional lymph nodes within 2 to 4 days; then, 4 to 6 days later, primary viremia disseminates the virus to reticuloendothelial cells in the spleen, liver, and other locations.

After a week, a secondary viremia propagates the virus to the internal organs and skin, resulting in the characteristic skin lesions. This viremia disseminates the virus to the respiratory regions and facilitates the transmission of varicella before the onset of the rash. During this period, infections of the central nervous system or liver may arise, including encephalitis, hepatitis, or pneumonia.[12] 

Varicella can contribute to humoral and cell-mediated immune responses. These responses elicit enduring immunity. Individuals may experience recurrent subclinical infections; however, secondary episodes of chickenpox are exceedingly uncommon in immunocompetent individuals. Reexposure and subclinical infections may enhance the immunity developed following a chickenpox episode. Exposure causes the production of host IgG, IgM, and IgA. 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, varicella is theorized to spread from 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. However, reactivation can still occur later in life, resulting in the clinically distinct syndrome of herpes zoster (shingles).[13][14]

Histopathology

Herpes simplex, varicella, and herpes zoster infections exhibit indistinguishable histological features. Intraepidermal vesicles often exhibit ballooning degeneration of keratinocytes together with the presence of multinucleated giant cells, which result from the fusion of infected keratinocytes. A hallmark is acantholysis, where individual keratinocytes separate and float freely within the blister space. These detached cells often display distinctive viral changes, including chromatin clumping at the nuclear edges, the presence of multiple nuclei, and inclusion bodies within the nuclei. Clinical correlation, immunohistochemistry, and viral culture or polymerase chain reaction are necessary to distinguish these viral infections.

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. An eruption of pruritic, erythematous macules and papules ensues on the head and face before disseminating to the trunk and limbs. Lesions swiftly develop within approximately 12 hours into 1 to 3 mm clear vesicles encircled by narrow red halos (“dew drops on a rose petal”).

The quantity of vesicles ranges from a few to several hundred, frequently including the oral mucosa. Sparing of the distal and lower extremities is common. Older vesicles develop into pustules and crusts, with each lesion healing within 7 to 10 days. The existence of lesions at all developmental stages is characteristic of varicella (see Image. Varicella Rash). 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 through small ulcers, which can be painful and itchy; this enanthem may precede the external exanthem by 1 to 3 days. These symptoms appear 10 to 21 days after exposure. Adults may have a widespread rash and more prolonged fever, and they are more likely to develop pneumonia, the most critical complication in adults. Because watery nasal discharge containing live virus precedes exanthems by 1 to 2 days, the infected person is contagious 1 to 2 days before recognizing the disease. In most cases, the infection resolves itself within 2 to 4 weeks.

Evaluation

The diagnosis of varicella infection is primarily based on the signs and symptoms. Confirmation is made 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 used for nonskin samples such as bronchoalveolar lavage 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 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 (deoxyribonucleic acid) test of the amniotic fluid can be performed. However, the risk of spontaneous abortion due to amniocentesis is higher than the risk of the baby developing fetal varicella.[15][16]

Treatment / Management

As a protective measure, those infected are usually required to stay home while infectious. Keeping nails short and wearing gloves may prevent scratching and reduce the risk of secondary infections.[17][18] Topical calamine lotion may relieve pruritus. Daily cleansing with warm water helps avoid secondary bacterial infection. Acetaminophen may reduce fever; however, aspirin should be avoided as it may cause Reye syndrome.[19]

• Children: Treatment is symptomatic relief. If taken within 24 hours of the start of the rash, acyclovir decreases symptoms by 1 day. Still, acyclovir does not affect complication rates and is not recommended for individuals with normal immune function.

• 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. Acyclovir, when initiated within 24 to 72 hours following the appearance of the cutaneous eruption, has demonstrated efficacy in reducing both the length and severity of varicella. 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 intravenous antivirals are indicated for immunocompromised patients, especially those undergoing chronic systemic corticosteroid therapy, due to their heightened risk of severe illness and sequelae. Supportive care, such as increasing water intake and using antipyretics and antihistamines, is essential to management. Administration of varicella zoster immune globulin (125 U/10 kg, maximum 625 U) intramuscularly within 96 hours after varicella exposure is advised to offer passive prophylaxis to nonimmune immunocompromised adults, pregnant women, and high-risk neonates. Protection endures for around 3 weeks. An alternative for postexposure varicella prophylaxis in these patient populations is the administration of intravenous immunoglobulin (intravenous immunoglobulin; ≥400 mg/kg), which possesses elevated concentrations of varicella-specific IgG. Prophylactic administration of oral acyclovir at standard varicella dosages for 1 week, commencing 7 to 10 days post-exposure, may also be contemplated. Finally, postexposure varicella immunization (given within 72 to 120 hours) may prevent or ameliorate the disease in nonimmune individuals 12 months and older who are immunocompetent and eligible for this live attenuated vaccine.[20]

Differential Diagnosis

The 3 dermatological conditions—monkeypox, smallpox, and chickenpox—are sometimes confused due to analogous presentations such as fever, rash, myalgia, chills, and headache; nevertheless, they can be differentiated by their unique symptoms. Despite the varying skin lesions associated with various rash-inducing illnesses, diagnostic testing can help distinguish them. The clinical diagnosis of monkeypox infection is often established based on its skin rash manifestation pattern. In varicella, it is feasible to concurrently observe lesions at several stages, including macular, papular, vesicular, pustular, and crusted forms; conversely, monkeypox lesions are uniformly at the same stage and progress at an identical rate.[21]

Monkeypox and chickenpox exhibit analogous appearances, occasionally resulting in a diagnostic dilemma.[22] Reports indicate the occurrence of coinfections, predominantly in the Central African region.[23] A widespread vesicular eruption is another symptom of smallpox; however, it is no longer a natural occurrence. Other differential diagnoses of varicella include vesicular viral exanthems (eg, caused by coxsackieviruses), disseminated herpes simplex virus infection, pityriasis lichenoides et varioliformis acuta, rickettsialpox, drug eruptions, bullous insect bite reactions, and scabies.

Prognosis

The prognosis is excellent in healthy children. However, the infection has high morbidity in immunocompromised individuals. While the majority of varicella infections provide lifelong protection, instances of clinical reinfection have been reported in healthy children.[24]

Complications

Chickenpox is often a mild illness in children; nearly all children recover without complications. Varicella in adolescents and adults is typically more severe than in children, characterized by more skin lesions. Significant complications may ensue in adults, immunocompromised individuals, and pregnant women as follows:

• A common complication is a secondary bacterial infection that can present as cellulitis, impetigo, or erysipelas, leading to scarring. Adults get deep and more prominent scars.
• Varicella pneumonia has a 10% to 30% mortality risk if left untreated.
• Individuals with a history of varicella have a 20% lifetime probability of acquiring zoster. An immunocompetent patient reportedly experienced the simultaneous occurrence of chicken pox and herpes zoster, along with facial nerve palsy. [25]
• Central nervous system consequences are infrequent (<1 per 1000 instances) and may encompass encephalitis, acute cerebellar ataxia, and Guillain-Barré syndrome. Varicella zoster can harm the arteries in the neck and head, resulting in a stroke.[13]
• Reye syndrome, characterized by encephalitis and fatty liver, has become rare due to the avoidance of aspirin in children with varicella. 
• Maternal varicella in the initial 20 weeks of gestation is linked to an approximately 2% incidence of congenital varicella syndrome (varicella embryopathy). Potential congenital anomalies encompass low birth weight, cutaneous scarring, ocular abnormalities, cortical atrophy, psychomotor delay, and hypoplastic limbs. Children whose mothers contracted varicella during gestation may get zoster early in life without ever experiencing extrauterine varicella. Severe neonatal varicella, characterized by the absence of maternal antibody protection, may arise when maternal varicella manifests between 5 days before and 2 days following delivery. Maternal herpes zoster, on the other hand, constitutes little risk of neonatal complications or congenital varicella syndrome, probably because of established circulating maternal antibodies.
• Varicella can result in serious complications and potentially fatal outcomes in immunocompromised individuals. These individuals commonly have a broader and unusual cutaneous eruption, sometimes accompanied by hemorrhagic or purpuric lesions. The lungs, liver, and central nervous system are primarily involved.
• Occasional complications include thrombocytopenia, hepatitis, glomerulonephritis, optic neuritis, keratitis, arthritis, myocarditis, pancreatitis, orchitis, and vasculitis.