Chapter 314. Varicella-Zoster Virus Infections

The human α-herpesvirus, varicella-zoster virus (VZV), is a highly successful pathogen that has coevolved with its human hosts over millennia. The majority of the world’s population has experienced primary VZV infection as varicella (“chickenpox”), with the acquisition of both lifelong immunity against reinfection and the risk of viral reactivation as zoster (“shingles”). In most children, chickenpox is a mild illness in which viral replication rapidly subsides. However, severe and complicated varicella does occur in previously healthy children and at much higher rates in certain risk groups (eg, immunocompromised persons, adults, newborns). The medical importance of VZV also extends to reactivation disease, which poses a major societal burden of morbidity in the form of postherpetic neuralgia, particularly in elderly individuals. A successful vaccination program against varicella is having profound effects on the epidemiology of VZV in the United States.

Epidemiology

Varicella is acquired through close contact with an infected individual. Natural varicella is the most communicable form of varicella-zoster virus (VZV) disease: household attack rates approach 90%, and outbreaks occur readily within groups of susceptible children.1 A milder form of varicella, occurring in vaccinated individuals with partial immunity, is only one third as transmissible,2 whereas zoster represents the least contagious form of disease.

In unvaccinated populations in temperate climates, seasonal peaks of varicella occur in the spring. These epidemics occur on a background of endemic disease, and 84% of children acquire infection by age 15 years.3,4 In contrast, the incidence of varicella in the tropics does not vary by season and tends to be delayed until adolescence or adult life.3 At this age, morbidity and mortality from varicella are significantly greater than in childhood, for reasons that are poorly understood.

Aside from adult age, the greatest risks for severe/fatal varicella are cellular immunocompromise (congenital or acquired), infancy (particularly, the neonatal period), and pregnancy (Table 314-1). In the prevaccine era, varicella was associated with approximately 11,000 hospitalizations and in excess of 100 deaths annually in the United States.5,6 Much of this burden was borne by previously healthy children. The epidemiology of VZV has been transformed since the introduction of universal varicella vaccination in the mid-1990s. The incidence of varicella has been strikingly reduced across all age groups, with concomitant reductions in office visits, hospitalizations, and deaths from varicella.7-10

Pathophysiology

Infectious virus is shed from the cutaneous lesions of varicella and zoster, and probably also from the respiratory tract 1 to 2 days prior to chickenpox. Thus, the infectious period extends from up to 48 hours before the appearance of rash until all skin lesions are crusted over, usually about 5 days in normal hosts. Following infectious contact, the incubation period for chickenpox is 10 to 21 days (median 14 days, up to 28 days following varicella-zoster immunoglobin [VZIG]). Events during this time are poorly understood, but are presumed to commence with infection of cells within the respiratory tract or conjunctivae by inhaled virions, followed by cell-associated spread to local lymph nodes. Later, Varicella-zoster virus (VZV) viremia is well documented in both immunocompetent and immunocompromised children and predates the chickenpox rash by approximately 5 days.11-13 Virus can be detected in circulating lymphocytes and monocytes. Evidence obtained in the humanized severe combined immunodeficiency (SCID) mouse model suggests that infected T lymphocytes have a predilection for homing to the skin, where they transmit virus to epidermal keratinocytes.14

Cell-to-cell spread of virus within the skin creates infected syncytia with a striking disruption of normal cellular architecture. Importantly, maturing epidermal keratinocytes support the release of infectious virions into vesicular fluid, owing to downregulation of the mannose-6-phosphate receptor.15 (In other tissues, this receptor routes nascent VZV virions via the acidic late endosome, where they undergo denaturation16; naked nucleocapsids may, however, pass from cell to cell by fusion.) VZV-infected keratinocytes appear to elicit a vigorous type I interferon response in neighboring, uninfected cells that restrains horizontal spread of virus and thus may contribute to the topology of the rash.14

In the immunocompetent host, VZV viremia and the appearance of new skin lesions are curtailed within a few days by a vigorous cellular immune response comprising both natural killer (NK) and antigen-specific (T-cell) components.17 Conversely, the failure to mount antigen-specific cellular responses is associated with progressive viral replication and dissemination, and a potentially fatal outcome. The importance of adaptive immunity is also implied by VZV’s utilization of immune evasion strategies including the downregulation of major histocompatibility complex (MHC) expression by infected cells.18-21

Individuals with disorders purely of humoral immunity do not suffer unusually severe or repeated episodes of varicella, indicating that cellular immunity affords sufficient protection against primary infection. However, a host humoral response is detectable within 4 days of the onset of the exanthem and can confer passive immunity; thus, pooled immunoglobulin derived from VZV-immune donors can be used to protect VZV-exposed subjects at high risk of severe chickenpox.1 The presence of VZV-specific antibodies is also the best available correlate of protection against primary infection, but is irrelevant to the risk of secondary (reactivation) disease.

Clinical Features

Prodromal symptoms of low-grade fever, headache, and malaise usually precede the characteristic vesicular exanthem by 24 to 48 hours. The rash typically begins as “dew drops on rose petals,” appearing on the face, trunk, or scalp and eventually spreading to involve the entire body (Fig. 314-1). The total number of lesions may vary from 50 to 500. The vesicles appear in crops for the first 3 to 5 days of the illness and may be exaggerated in areas of minor trauma or dermatitis, such as sunburn or eczema. The initial tiny vesicles evolve to larger vesicles, filled with clear fluid that becomes cloudy with cellular debris, and finally involute with crust formation. Lesions on the skin are usually intensely pruritic but not painful; however, lesions on mucous membranes become shallow ulcers, which may be painful. In the absence of secondary bacterial infection, healing occurs over 7 to 10 days without scar mformation, although discrete hypo- or hyperpigmented lesions may persist for several months.

Immunity following varicella is usually life long; however, primary infection in circumstances in which immune responses are incomplete may predispose to a second episode of varicella. “Breakthrough” varicella is the term applied to wild-type disease in an individual who has previously received the live-attenuated varicella vaccine. This is generally a highly modified illness in which skin lesions are few, systemic features such as fever are absent, and transmissibility is reduced by around two thirds compared with unmodified varicella.2,22 Not surprisingly, this may pose diagnostic difficulties.

In considering the differential diagnosis of a vesicular rash in children, rarer conditions such as disseminated herpes zoster or herpes simplex should be borne in mind, along with eczema herpeticum, insect bites, scabies, Stevens-Johnson syndrome, and bullous impetigo. In these uncertain days, we must again include smallpox on this differential, recalling its distinctive centrifugal distribution of pox (more numerous on the extremities than the trunk) and the fact that the skin lesions of smallpox mature simultaneously. Occasionally, drug eruptions may be mistaken for varicella. In the neonate, vesicular eruptions may accompany congenital syphilis, congenital candidiasis, neonatal herpes, pustular melanosis, and histiocytosis. Apparent second episodes of varicella may occur as a consequence of misdiagnosis of the first episode.

Varicella in the normal host is generally a benign self-limited disease. The occurrence of significant fever beyond the first 48 hours of exanthema, as well as the progression of erythema or tenderness around crusting lesions, should raise suspicion for secondary bacterial infection. Likewise, hemorrhagic lesions, significant abdominal pain or vomiting, or altered mental status should alert clinicians to possible complications that require prompt intervention.

Immune Deficiency

Individuals with congenital or acquired immune deficiencies that affect their ability to mount a cellular immune response to varicella-zoster virus (VZV) are at risk for progressive disseminated varicella, whereas individuals with isolated humoral immune deficiency are not (Table 314-1). Children being treated for lymphoid malignancy are at particular risk of fatal varicella.34 Progressive disseminated varicella involves multiple organ systems. Its onset may be heralded by severe abdominal pain or back pain before the appearance of a rash. Fever reaching to 40°C to 41°C (104°F–105.8°F) may persist for several days. Severe hepatitis, pneumonitis, thrombocytopenia, coagulopathy, encephalitis, and other organ dysfunction may ensue. Mortality is significant, even with treatment and supportive care. Because their ability to terminate viral replication is diminished, immunocompromised individuals with varicella are contagious for an extended period. Individuals with acquired immunodeficiency due to infection with HIV do not appear to be at the same degree of risk for progressive disseminated varicella.35,36 Rather, varicella may persist for several weeks to months. The incidence of zoster is extremely high, and recurrent disease is common.

Congenital and Neonatal Disease

When maternal varicella occurs in the first 20 weeks of gestation, approximately 0.4% of fetuses may manifest findings associated with varicella embryopathy.40,41 Among the constellation of features of congenital varicella-zoster virus (VZV) are cutaneous defects; classic cicatricial skin scarring and limb atrophy; microcephaly; cortical atrophy; seizures; chorioretinitis; microphthalmia; and significant neurologic deficits. Autonomic nervous system involvement may manifest as difficulty with sphincter control, intestinal obstruction, Horner syndrome, or other cranial nerve neuropathies (Moebius syndrome). Infants born to mothers who develop varicella less than 5 days before delivery or 2 days after delivery are at risk of severe or lethal neonatal varicella.42

Diagnosis

The diagnosis of varicella is usually clinically apparent, although the child with few lesions may go undiagnosed or be misdiagnosed as having “insect bites.” The lack of a definite history of exposure to varicella-zoster virus (VZV) certainly does not exclude the diagnosis of chickenpox; conversely, a prior history of varicella makes it very unlikely because most individuals obtain lifelong immunity after one episode.

In the face of diagnostic uncertainty and an ill patient. The preferred method is immunofluorescent antibody staining (DFA) of cells scraped from the base of a lesion using VZV-specific antibodies. This provides a rapid and specific way to diagnose VZV infection. Culture is slow and insensitive. Polymerase chain reaction (PCR) techniques for VZV are not yet in general use but provide helpful additional information in reference laboratory and research settings. In particular, PCR typing methods can distinguish vaccine and wild-type strains of virus. A variety of options are available for laboratory confirmation. The preferred method is immunofluorescent antibody staining (DFA) of cells scraped from the base of a lesion using VZV-specific antibodies. This provides a rapid and specific way to diagnose VZV infection, whereas viral isolation is slow and insensitive, even when early lesions are sampled. PCR techniques for VZV are not yet in general use but provide helpful additional information in reference laboratory and research settings. In particular, PCR typing methods can distinguish vaccine and wild-type strains of virus.

A variety of serologic tests for VZV have been used to determine preexisting infection, susceptibility to disease, and response to immunization; they are occasionally helpful in the context of varicella diagnosis.23 The fluorescent antibody–to–membrane antigen (FAMA) assay is the “gold standard” for determining biologically significant antibody; the technique, however, is cumbersome. Latex agglutination provides a convenient and rapid test, although negative sera should be retested at lower dilution to exclude a prozone effect. Commercially available VZV-IgG enzyme-linked immunosorbent assays (ELISAs) are often used to identify susceptible individuals who may be at risk for severe disease, such as those requiring transplantation. These tests do not reliably identify vaccine-derived immunity. Tests for VZV-IgM are not reliable, whereas measures of cellular immunity (eg, interferon-gamma ELISpot) are currently confined to the research setting.

Therapy

Children with risk factors for and/or symptoms of severe/complicated varicella must be identified promptly, and appropriate specialist care instituted. However, most children with varicella do not require specific therapy but rather general supportive measures, such as acetaminophen for fever, possibly a sedative antihistamine for pruritus at night, and advice on minimizing the risk of secondary infection and scarring (eg, keep nails short and skin clean, try to avoid scratching).

Oral acyclovir (ACV), begun within 24 hours of the appearance of rash, significantly decreases the number and duration of new lesions24; however, it is not routinely recommended in immunocompetent children because their disease is usually mild. ACV therapy should be considered in immunocompetent individuals at risk for more severe disease: for example, a second case in a household, adolescents, and adults.25,26 For maximum effectiveness, therapy should be initiated as soon as possible after the appearance of rash; after 24 hours, little benefit attaches to starting ACV in uncomplicated varicella. The suggested dose of oral ACV for the normal host is 20 mg/kg/dose (max 800 mg/dose) 4 times daily for 5 to 7 days.

Intravenous ACV is indicated for the treatment of the immunocompromised child with varicella or zoster because of the danger of dissemination. Suggested dosage of intravenous ACV for immunocompromised children ages 3 months to 12 years is 1500 mg/m2/day given in 3 divided doses. Outside this age range, dosing is calculated according to body weight (30–60 mg/kg/day up to 3 months and 30 mg/kg/day for immunocompromised children older than 12 years). The duration of therapy is usually 5 to 10 days or until lesions are crusted. The bioavailability of ACV following oral administration is limited and is unlikely to be adequate for these patients. The role of antiviral agents with better oral bioavailability, such as valaciclovir and famciclovir, has not been established for the treatment of varicella in children.

Intravenous ACV is also indicated for neonates who develop varicella from their mothers and should be considered for neonates who develop varicella following household exposure. The term infant should receive 10 to 20 mg/kg/dose given every 8 hours; in premature infants, the dosing interval should be decreased to every 12 hours. Oral ACV is generally not indicated for treatment of young infants because of limited bioavailability and erratic absorption in infants.

Complications

The rate of severe or complicated chickenpox is low among immunocompetent children, but such cases are numerically common in unvaccinated populations.27 The most frequent complication in the young is secondary bacterial infection of the skin. Many of the other complications of chickenpox reflect overwhelming viral infection and are more likely to occur in the context of defective cell-mediated immunity.

Secondary Bacterial Infection

Scratching of the intensely itchy skin lesions of chickenpox often leads to the introduction of bacteria, typically Staphylococcus aureus or Streptococcus pyogenes. Local skin infection in a well child can be treated with an oral antibiotic and kept under review. Progression of erythema around lesions, formation of bullae, or development of regional lymphadenitis should prompt consideration of intravenous antibiotic therapy. Recent varicella confers a significantly increased risk of invasive bacterial disease, particularly group A streptococcal (GAS) infections; these include necrotizing fasciitis, bacteremia, pneumonia, empyema, and toxic shock syndrome. It has been estimated that varicella directly precedes approximately 15% of invasive GAS infections.28 Pain in a muscle group, together with circumferential swelling of an extremity, may reflect necrotizing fasciitis despite the lack of significant overlying erythema. Urgent MRI or ultrasonography can be useful in defining soft tissue involvement. These severe infectious complications require that if a child with chickenpox appears excessively ill, especially with a recurrence of fever, urgent hospital evaluation is required. Pain in a muscle group, together with circumferential swelling of an extremity, may reflect necrotizing fasciitis despite the lack of significant overlying erythema. Urgent MRI or ultrasonography can be useful in defining soft tissue involvement, but active medical and surgical management is mandatory.

Varicella Pneumonia

Asymptomatic radiographic changes are common in immunocompetent adults with chickenpox, but varicella pneumonia affects only about 1:400.29 Although rates are lower among immunocompetent children, pneumonia commonly accompanies chickenpox in immunocompromised. Respiratory symptoms—dyspnea, tachypnea, chest tightness, cough—develop in the context of acute varicella (usually 1–6 days after the onset of the rash) and may progress rapidly to respiratory failure. The severity of clinical signs is a poor guide to prognosis; therefore, the patient with new respiratory symptoms in the context of varicella should be urgently evaluated. Intravenous antiviral therapy and improved intensive care have markedly improved survival of these patients over recent years, but deaths continue to occur.

Neurologic Complications

Chickenpox is classically associated with three neurologic pictures: (1) cerebellar ataxia, (2) encephalitis, and (3) Reye syndrome. Rarely, it has been associated with Guillain-Barré syndrome, stroke, transverse myelitis, and aseptic meningitis.30

Cerebellar ataxia complicates approximately 1 in 4000 cases of varicella31 and usually follows the onset of rash, making the diagnosis clear. Vomiting and headache often accompany the ataxia, whereas only one fourth of patients experience neck stiffness or nystagmus. It is not known whether this syndrome results from varicella-zoster virus (VZV) replication within the central nervous system (CNS) or instead reflects a parainfectious, autoimmune process. The cerebrospinal fluid (CSF) may be “active,” and polymerase chain reaction (PCR) can be positive for VZV DNA. The role of antiviral therapy is unclear because complete resolution of symptoms is the rule, but has been proposed for those patients with polymerase chain reaction evidence of VZV within the cerebrospinal fluid.30

More recent series of suspected viral encephalitis have suggested that VZV may be a major cause of this entity, along with herpes simplex and the enteroviruses, but many of these cases do not have the skin rash of chickenpox.30 Encephalitis has been reported to complicate 1 to 2 per 100,000 cases of varicella, and is marked by fever, altered level of consciousness, headache, photophobia, and seizures. Such patients require urgent diagnostic evaluation and therapy, including antiviral and supportive care. Varicella encephalitis is associated with a low but significant mortality rate; rarely, survivors suffer long-term sequelae.

Reye syndrome, once linked to chickenpox and influenza in children, has become exceedingly rare since the recognition of an epidemiologic link to the use of aspirin.32 The syndrome consists of a progressive encephalopathy accompanied by hepatotoxicity and a 30% risk of death (see Chapter 421).

Prevention

There are three ways in which varicella can be prevented: (1) avoidance of exposure, (2) postexposure prophylaxis, and (3) primary prophylaxis.

As part of their regular medical care, immunocompromised individuals at risk of severe chickenpox should be identified and counseled. If there is no clinical history of chickenpox (or zoster), their varicella-zoster virus (VZV) immune status should be clarified by serologic testing. Many such individuals turn out to be VZV seropositive and, thus, are at very low risk of varicella. VZV-seronegative individuals at risk of severe varicella should try to avoid contact with infectious persons. This can be facilitated by actively immunizing susceptible family members and health care workers, and by excluding infectious individuals from schools and open hospital areas. Should exposure occur, high-risk susceptible patients should be encouraged to present as soon as possible for evaluation and postexposure immunoprophylaxis with varicella-zoster immune globulin (VZIG; VariZIG in the United States). This intramuscular preparation confers significant (but not 100%) protection if given within 96 hours of exposure. However, it is an expensive blood product in relatively short supply; hence, clear and specific national guidance on its use should be followed. The criteria for use of VZIG include (1) high risk of severe varicella AND (2) significant exposure AND (3) current VZV seronegativity. High-risk groups include immunocompromised children and pregnant women without a prior history of varicella, newborn infants whose mothers developed varicella less than 5 days before or 2 days after delivery, premature infants more than 28 weeks’ gestation born to women with negative VZV histories, and premature infants less than 28 weeks’ gestation regardless of maternal history when a significant exposure has occurred. “Exposure” implies household contact, sharing a room for 15 minutes, or face-to-face contact with a case of varicella during the infectious period (from 2 days before the onset of rash until all lesions are crusted over). Zoster is only considered infectious if skin lesions are exposed (eg, face) or disseminated, or if the affected individual is immunosuppressed or in hospital. VZV seronegativity should be confirmed prior to VZIG administration, unless this would produce an unacceptable delay. Individuals receiving immunoglobulin replacement therapy generally achieve protective levels of VZV-specific immunity and do not require VZIG.

When VZIG is in short supply, oral acyclovir is recommended for postexposure prophylaxis, despite the lack of an evidence base for this practice in immunocompromised persons. This represents an “off-label” use of acyclovir, and therapy should be undertaken in discussion with a specialist. As with all postexposure prophylaxis, recipients should be counseled to seek medical advice in the event that symptoms of chickenpox do develop. Both VZIG and acyclovir (ACV) can be associated with lengthening of the incubation period.

A highly effective live-attenuated vaccine against varicella has been in widespread use in the United States since 1995, and more recently, has been introduced to several European countries. The vaccine offers protection directly to both immunized individuals and the community as a whole through herd immunity. With few exceptions, the vaccine is contraindicated in the immunocompromised, who therefore benefit from it only indirectly.38 Live vaccine is also effective as postexposure prophylaxis in the immunocompetent, making this a useful intervention in the outbreak setting. Two doses are given 4 to 8 weeks apart and are generally well tolerated, the main adverse reaction being a mild vaccine-associated rash.43

Varicella-zoster virus (VZV) is not eliminated from the host when varicella-associated viremia subsides. Rather, the virus establishes latent infection within sensory neurons of the dorsal root and trigeminal ganglia. Zoster (shingles) is the recurrent disease that results from viral reactivation. The incidence of zoster increases with increasing age, believed to be in response to declining immunity to VZV.44 Racial background plays a role; the lifetime incidence of zoster in African Americans is approximately half that reported for whites. Children with malignant disorders, particularly those with lymphomas, acute lymphocytic leukemia, or AIDS, are at increased risk of developing zoster.45 Normal children may also develop zoster. Zoster in the first 2 years of life is usually associated with maternal gestational varicella or varicella occurring during early infancy.

Hope-Simpson originally proposed that VZV reaches the sensory ganglia via the skin, traveling along sensory nerve axons, yet this process has still not been visualized directly.46 The establishment of latency may require that neurons are infected by infectious virions, which are produced within the VZV-infected epidermis in close proximity to sensory nerve endings.47 Latency is characterized by the presence of viral DNA, as well as a limited repertoire of RNA transcripts and viral proteins.48 Studies of postmortem material have confirmed that around 2% of neurons within dorsal root ganglia support latent infection by VZV. Reactivation of this virus within one or more adjacent ganglia produces zoster, with evidence of viral replication in both innervating neurons and satellite cells, as well as expression of the full complement of viral genes.49 Presumably, nascent viral particles reach the skin by retrograde axonal transport, as has been described for related neurotropic viruses such as herpes simplex virus. The switch from latent to lytic infection on reactivation is poorly understood in pathophysiologic terms, and indeed, the frequency of asymptomatic reactivation is unknown. Clearly, however, immunosuppression and natural senescence of T-lymphocyte surveillance mechanisms pose a risk for recurrent disease manifest as zoster.

Zoster classically appears as a unilateral process involving a single or possibly two adjacent dermatomes. Thoracic dermatomes are most often involved, followed by cranial nerve and lumbosacral regions. The lesions often appear first as patches of erythema, which then develop groups of vesicles. A few scattered lesions, remote from the dermatomes, may appear. The lesions progress over 3 to 5 days, and usually dry and crust within 2 weeks. Pain or paresthesia within the involved dermatome may precede the vesicular eruption; indeed, preeruptive thoracic pain has been mistaken for angina. Persistent pain, known as postherpetic neuralgia (PHN), is relatively uncommon in children, but occurs in 50% of individuals with zoster who are older than 60 years and may be severe and protracted.30 Zosteriform eruptions in the maxillary division of the fifth cranial nerve may occasionally be due to herpes simplex virus (HSV) rather than VZV, and hence, laboratory diagnostic evaluation is advised.

Generalized or disseminated zoster may occur in immunocompromised hosts. The greater the extent of immunosuppression is, the higher the risk of dissemination to noncontiguous dermatomes or to viscera. Multiorgan involvement may precede or follow rash in the untreated immunocompromised host, as has been described for varicella in this high-risk population. Immunosuppressed patients are also at relatively higher risk for PHN.50

Zoster should in general prompt specific treatment because antiviral agents given within 72 hours of onset reduce the severity and duration of symptoms and PHN.51 Oral therapy is usually suitable for immunocompetent persons, but intravenous acyclovir should be considered in those at risk of severe disease. Pain relief and other supportive measures may be required. In addition, individuals with ophthalmic involvement require specific evaluation and management. Disseminated zoster is a severe systemic illness that may require intensive care, as for severe varicella.