Varicella

Varicella, commonly known as chickenpox, is an acute highly communicable viral exanthema. It primarily affects children, with a peak incidence between 5 and 9 years of age. The hallmark of varicella is the appearance of a papulovesicular rash along with mild constitutional symptoms, especially in immunocompetent individuals.

Disease severity can vary but tends to be more severe in immunocompromised individuals. Varicella is typically a self-limiting disease but can be associated with several complications, particularly in cases of congenital and perinatal infections. These complications may include impetiginization with Staphylococcal or Streptococcal superinfections, pneumonia, encephalitis, and bleeding diatheses.

Varicella represents the primary infection caused by the Varicella-Zoster Virus (VZV). After the acute phase, the virus establishes a lifelong, latent infection in sensory ganglion neurons. This latent infection can later reactivate, typically occurring in late adulthood or when an individual becomes immunocompromised, manifesting as herpes zoster, commonly known as shingles.

It's important to note that varicella and herpes zoster are distinct clinical syndromes, each with its own set of manifestations, caused by the same virus—the varicella-zoster virus (VZV).

• VZV (Varicella-Zoster Virus):

Varicella is caused by VZV, a double-stranded DNA virus. This virus is classified as a neurotropic human herpesvirus and belongs to the Herpesviridae family.

• Similarity to Herpes Simplex Virus (HSV):

VZV bears similarities to Herpes simplex virus (HSV), which is associated with conditions such as 'fever blisters' or 'cold sores.'

• Genomic Characteristics:

The VZV genome consists of DNA and encodes numerous proteins that serve as targets for both cellular and humoral immunity.

The pathogenesis of varicella involves a series of events that characterize the progression of the disease:

• Virus Transmission and Acquisition:

Varicella is transmitted through:

• Infected oropharyngeal secretions.
• Fluid from skin lesions of an infected individual, which can infect a new host through either aerosolization or direct contact.
• Primary Inoculation and Incubation:

The primary site of inoculation is the upper respiratory tract (URT) and related lymphoid structures. This marks the beginning of the incubation period.

• Viraemia and Spread:

Subsequently, subclinical primary viraemia occurs, leading to virus spread and multiplication in reticuloendothelial (RE) organs/system.

• Secondary 'Viraemic Shower':

A secondary 'viraemic shower' follows, lasting 3 to 7 days. During this period, peripheral blood monocytes play a role in propagating infected virus to the skin, resulting in new crops of vesicles. The virus is also transported back to the primary site of inoculation in the oropharynx and tonsils during the late incubation period, contributing to infectivity, which occurs 1 to 2 days before the rash appears.

• Host Immune Response and Recovery:

The host's immune response, including seroconversion, helps checkmate continuous virus replication, aiding in recovery.

• Immunocompromised Individuals:

In immunocompromised individuals, especially those with cellular immune deficiencies, continuous dissemination of the virus occurs, leading to severe complications involving multiple organs/systems, such as the lungs, brain, liver, and more.

• Latent Infection and Reactivation:

Varicella results in latent axonal/dorsal root ganglia infection, involving the entire spinal cord, due to retrograde spread through sensory neuronal axons.

Subsequent reactivation is associated with necrotic changes in the infected ganglia, resulting in skin lesions of similar morphology and histopathology. These lesions are limited to the corresponding dermatome of the involved dorsal root ganglia.

• Immune Response and Protection:

Varicella generates both humoral and cell-mediated immunity to VZV infection and suppresses symptomatic reinfection.

Re-exposure to VZV after latent infection provides better protection against reactivation as zoster infection.

The epidemiology of varicella, or chickenpox, is characterized by various key factors:

• Highly Contagious:

Varicella is highly contagious, primarily transmitted through close or direct contact with an index case of either varicella or zoster (shingles).

• Pre-Immunization Era:

In the pre-immunization era, varicella was predominantly a pediatric burden, with most children affected before the age of 15. In temperate climates, less than 5% of adults remained susceptible to varicella in adult life.

• Changing Age Incidence:

The peak age incidence used to be 5 to 9 years. However, of late, the late elementary school-age group has become the most vulnerable.

• Congenital, Perinatal, and Immunocompromised Cases:

Varicella can occur congenitally, perinatally, or in young infants and the immunocompromised. It tends to be more severe and serious in these populations. Epidemics of varicella are more common in winter and spring, similar to most airborne respiratory virus infections.

• Tropical Climes and Low Immunization Coverage:

In tropical regions with low immunization coverage, varicella appears to be more common in older children, adolescents, and adults, including the immunocompromised, who are at greater risk of severe complications.

• Transmission Rates:

Among susceptible household contacts, the transmission rate is about 65-86%, while it is lower among school or institutional contacts like nurseries.

• Contagious Period:

Varicella is most contagious 1-2 days before the typical rash (exanthema) appears and remains contagious until all skin lesions are crusted, often lasting 3-7 days post-onset of the rash.

• Impact of Vaccination:

After the introduction of one-dose varicella vaccination, there has been a substantial decline in morbidity and mortality in all age groups in the US. This includes those below the age of qualification for the vaccine, indicating secondary immunization/herd immunity via exposure to recipients of the live-attenuated virus vaccine. The median age-specific infection has also increased to late elementary school children.

• Herpes Zoster (Shingles):

Herpes zoster is a "virus-reactivation illness" and is not caused by re-exposure to VZV. It is very rare in children below 10 years, except in congenital VZV infections and those infected in the first year of life, where the risk is high.

• Re-Exposure and Zoster Risk:

Re-exposure can boost cell-mediated immunity in those with latent zoster infection. The lifetime risk of zoster in those with previous varicella infection is 10-20%, with over 75% of these reactivation infections occurring in individuals over the age of 45 years.

• Zoster Vaccine:

The zoster vaccine is recommended for susceptible cases aged 60 years and above.

The clinical manifestations of varicella, or chickenpox, include the following features:

• Subclinical Infection:

Subclinical infection is rare, with almost all exposed and susceptible individuals developing the characteristic exanthema (rash).

• Incubation Period:

The incubation period typically ranges from 10 to 21 days, with an average of 14 to 16 days.

• Pre-Exanthematous Stage:

Before the rash appears, a pre-exanthematous stage may involve:

• Common prodromal symptoms in older children and adolescents, which typically include non-specific symptoms like low-grade fever, malaise, headache, poor feeding or anorexia.

• 1-2 days before the rash, abdominal pain may occur.

• Most of these prodromal systemic symptoms are expected to resolve within 48-96 hours of the rash's onset.

• Exanthematous & Post-Exanthematous Stage:

The exanthematous (rash) stage and post-exanthematous stage are characterized by the following:

• The skin lesions are polymorphous, with different stages of the rash evident at a given time.

• Initially, the rash consists of intensely pruritic erythematous macular lesions, which quickly progress from maculopapular to vesicular lesions containing clear fluids (tear-drop vesicles).

• The vesicles subsequently become clouded and pustular, with a characteristic clouding and umbilication.

• Unlike smallpox, the distribution of the rash is mainly centripetal, starting on the scalp, face, and trunk. There are fewer lesions on the extremities.

• The number of skin lesions can vary, ranging from 200-400. However, previously healthy children may have as few as 10 or as many as 1500 lesions.

• Mucosal lesions are frequently ulcerative and can be found in the oropharynx, larynx, vagina, conjunctivae, or even the cornea, potentially threatening vision.

• Ulcerative laryngeal lesions may present with features of upper airway obstruction.

• Children with pre-existing skin disorders like eczema are likely to have more extensive lesions that persist for a longer duration.

• Hypo- or hyperpigmentation often follows, with persistence ranging from days to weeks, sometimes accompanied by secondary infection or impetiginization.

When evaluating a patient with suspected varicella (chickenpox), it's important to consider the following differential diagnoses:

• Alastrim (Smallpox):

In the smallpox era, differentiation from smallpox (alastrim) was crucial due to the potential severity and contagiousness of both diseases.

• Herpes Simplex Virus Infection:

Herpes simplex virus infection can present with similar skin lesions and should be considered, especially in cases of oral or genital involvement.

• Monkeypox:

Monkeypox shares some clinical features with varicella, and it is important to differentiate between the two.

• Enterovirus Infection (Especially Coxsackie Virus):

Enterovirus infection, including Coxsackie virus, can cause skin rashes that may resemble varicella.

• Disseminated Herpes Infection:

Disseminated herpes infection, caused by herpes simplex or herpes zoster, can present with widespread skin lesions.

• Rickettsial-Pox Infection:

Rickettsial-pox infection is another condition that may mimic varicella and should be considered in the differential diagnosis.

• Staphylococcal or Streptococcal Impetigo (In Complicated Cases):

In complicated cases, Staphylococcal or Streptococcal impetigo can result in skin lesions that need to be differentiated from varicella.

• Insect Bites:

Insect bites can sometimes be mistaken for varicella lesions, especially in areas with a high prevalence of insect vectors.

• Contact Dermatitis:

Contact dermatitis can cause skin irritation and rashes, which may resemble varicella if the rash is extensive.

• Scabies:

Scabies is a parasitic infestation that can lead to skin itching and rashes, which may need to be differentiated from varicella.

1. Breakthrough Varicella (Varicella Occurring in a Vaccinated Individual):

Breakthrough varicella refers to chickenpox occurring in someone who has received the usual 1-dose vaccine more than 42 days before the rash becomes noticeable (although it may occur between 14 and 42 days, which can be due to either the vaccine or the wild virus).

Characteristics of breakthrough varicella:

• Rash is atypical, predominantly maculopapular, with vesicles being an uncommon morphology.
• It is usually a mild disease with fewer than 50 skin lesions, shorter duration, fewer complications, and little or no fever.
• On average, breakthrough varicella is less infectious, but from a public health viewpoint, it should be considered potentially infectious like the wild type, and affected individuals should be excused from school.
• Up to 30% of breakthrough varicella cases, however, may be severe enough to be indistinguishable from the wild disease.
• 2-dose regime vaccines are probably less likely to result in breakthrough varicella compared to those who received the 1-dose regime.
2. Progressive Varicella

Progressive varicella is a severe complication of primary Varicella-Zoster Virus (VZV) infection characterized by continuing cutaneous vesicular lesions, multiple visceral organ involvement, coagulopathy, and severe hemorrhagic manifestations. Key manifestations include:

• Severe abdominal pain, resulting from mesenteric nodal and hepatic involvement.
• Haemorrhagic vesicular lesions.
• While it is more common in individuals with underlying immune-compromised status, these features may also be seen in otherwise healthy adolescents and adults.
• At-risk populations for progressive varicella include pregnant women, newborns, individuals with congenital immune deficiency states, and individuals with malignant conditions who began chemotherapy during the incubation period of primary VZV infection, resulting in absolute lymphopaenia of less than 55 cells/mm2. Additionally, untreated late-stage HIV infection may contribute to the risk.

Features and At-Risk Populations

Other at-risk populations for severe varicella complications, including progressive varicella, include:

• Children on long-term high-dose systemic corticosteroid treatment, including those using high-dose inhaled steroids.
• Solid organ transplant patients.
• Children who contract VZV while on antineoplastic chemotherapy and are not offered antiviral treatment face a high risk of mortality (approximately 7%), with death typically occurring due to varicella pneumonia within 3 days of diagnosis.
• Individuals with late-stage HIV infection and progressive varicella may additionally develop hyperkeratotic lesions resembling those seen in Congenital Varicella Syndrome.

Preventive measures, including VZV vaccination, are strongly recommended for at-risk populations, especially immunocompromised individuals, including those with HIV infection and a CD4+ T lymphocyte count of 15% or lower, individuals with leukemia, and children with solid organ tumors in remission or those for whom chemotherapy can be briefly interrupted for about 2 weeks to facilitate active vaccine administration.

3. Neonatal/Perinatal Varicella

Perinatal/neonatal Varicella-Zoster Virus (VZV) infection is frequently severe and carries a high mortality rate. Key points about this condition include:

• Transplacental acquisition from maternal viraemia is a more frequent source of infection than neonatal post-partum exposure to a VZV-infected mother.
• The highest risk of severe disease is observed in infants whose mothers develop the typical exanthema from 5 days before delivery to 2 days after. This is because of the paucity of maternally transferred IgG from the infected mother who has not yet seroconverted.
• Severity is often associated with complications such as pneumonia, hepatitis, or encephalitis.
• Such infants lack the mitigating effect of maternal anti-VZV IgG, hence disease severity is heightened.
• Significant and placental-transferable maternal anti-VZV antibodies are unlikely if delivery occurs before 30 weeks of gestation, as crossing the placental barrier occurs only afterward.

Management

The management of neonatal/perinatal varicella includes:

• Passive immunization with VariZIG or, less effectively, immune globulin IV (IGIV), which is indicated in the following cases:
• All premature infants < 28 weeks, even if maternal rash has appeared for more than 1 week.
• Neonates, regardless of gestational age, whose mothers show features of varicella 5 days before to 2 days after delivery.
• Prompt antiviral therapy with IV acyclovir at a dose of 10mg/Kg every 8 hours as soon as cutaneous lesions develop. This is necessary due to the usual severity of the condition, including the risk of multi-organ involvement and complications, and the associated high mortality.
4. Congenital Varicella Syndrome
• Follows in-utero VZV transmission but is uncommon because most adults in the developed world have high maternal IgG levels. Rare, even in the prevaccine era, e.g., ~44 cases per year.
• Associated with early infection in susceptible mothers and disease manifestations before 20 weeks of gestation (risk 0.4% before 13 weeks, i.e., 1st trimester, or 2% between 13 – 20 weeks).

Features of CVS Include:

• Characteristic cicatricial skin scarring, with zig-zag scarring in a dermatomal distribution.
• Limb hypoplasia or atrophy of the limb with the characteristic cicatricial lesion.
• Central nervous system manifestations comprising cortical atrophy associated with microcephaly and MR (mental retardation) and recurrent seizures.
• Ophthalmic manifestations comprising microphthalmia, cataract, and chorioretinitis.
• Autonomic manifestations comprising neurogenic bladder, dysphagia (swallowing difficulty), and consequently aspiration pneumonia.
• Features attributable to virus-induced injury to the nervous system, the brain, and certain body regions, with a preference for the cortex, autonomic nervous system, and certain body parts (e.g., the limbs).

Diagnosis of VZV Embropathy is Based on:

• Identification of the features in the newborn.
• History of gestational varicella.
• Detection of the virus in tissue using nuclear amplification technique (PCR).
• Post-partum detection of VZV-specific IgM antibodies in cord blood.
• Persistently positive VZV IgG antibody titre at 12 – 18 months is a reliable indicator.

Management

• Management is limited to the exposed susceptible mother in whom IV VZV immune globulin is indicated. In severe cases, acyclovir antiviral therapy may be administered, despite the need to administer this early (studies showed comparative prevalence of teratogenic stigmata in the infants of acyclovir and non-acyclovir mothers).
• Treatment of infants with acyclovir for CVS is unnecessary because fetopathy doesn’t progress post-partum.