Clinical features of varicella-zoster virus infection: Chickenpox

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. Endogenous reactivation of latent VZV typically results in a localized skin infection known as herpes zoster, or shingles.

Primary varicella infection in children is generally a mild disease compared to more severe presentations in adults or immunocompromised patients of any age. The rates of infection, hospitalizations, and mortality have all declined in the US since the introduction of the varicella vaccine in 1995; immunization is recommended in all children before the age of five years and in nonimmune adults. (See "Vaccination for the prevention of shingles (herpes zoster)" and "Epidemiology of varicella-zoster virus infection: Chickenpox".)

The major clinical manifestations and complications of chickenpox will be reviewed here. Infection in the neonate and the treatment and prevention of this infection, including the varicella vaccine, and herpes zoster are discussed separately. (See "Varicella-zoster infection in the newborn" and "Treatment of varicella (chickenpox) infection" and "Vaccination for the prevention of chickenpox (primary varicella infection)" and "Measles, mumps, and rubella immunization in adults" and "Epidemiology, clinical manifestations, and diagnosis of herpes zoster" and "Vaccination for the prevention of shingles (herpes zoster)".)

TRANSMISSION AND VIROLOGY — Chickenpox is highly contagious, with secondary household attack rates of >90 percent in susceptible individuals [1,2].

Infection control issues within hospitals are discussed elsewhere. (See "Prevention and control of varicella-zoster virus in hospitals".)

Transmission routes — Transmission occurs in susceptible hosts via contact with aerosolized droplets from nasopharyngeal secretions of an infected individual or by direct cutaneous contact with vesicle fluid from skin lesions [1]. Airborne transmission of VZV to susceptible nursing staff has also been reported in a hospital unit [3].

Viremia — VZV is a double-stranded, linear DNA virus encoding approximately 75 proteins [1,4,5] and possessing a lipid-containing envelope with glycoprotein spikes. After gaining entry, the virus undergoes localized replication at an undefined site with concurrent replication in regional lymph nodes by days four to six [6]. This is followed by a primary viremic phase with seeding of the reticuloendothelial system. A secondary phase of viremia occurs after approximately nine days [7] and persists through the development of skin lesions [8,9].

Incubation period — The average incubation period for varicella infection is 14 to 16 days, although this interval can range from 10 to 21 days [10]. The period of infectivity is generally considered to last from 48 hours prior to the onset of rash until skin lesions have fully crusted.

Administration of varicella-zoster immune globulin (VZIG) following exposure can prolong the incubation period from 21 days to 28 days. (See "Prevention and control of varicella-zoster virus in hospitals".)

Reinfection — It has been generally thought that second episodes of varicella infection in immunocompetent individuals rarely occur [11,12], although subclinical reinfection with VZV is common [13]. However, post-vaccine surveillance programs have suggested that a second episode of primary varicella in immunocompetent individuals might be more common than previously thought [14]. More than 95 percent of first infections were physician diagnosed, epidemiologically linked to another case, or had a rash consistent with varicella; the same was true for reported second infections. The study demonstrated the following results:

●While the overall incidence of primary varicella declined substantially after the introduction of vaccine (2934 versus 587 cases in 1995 and 1999, respectively), the proportion of cases of varicella in individuals with a previous history of the disease increased from 4.5 to 13.3 percent. None of the patients with a second episode of varicella had been vaccinated.

●People who reported reinfections were generally healthy. There was a family history of repeat infections in 45 percent of people who reported reinfections.

Of note, diagnoses made within this study were clinically-based and not laboratory-confirmed.

CLINICAL MANIFESTATIONS — Primary infection with VZV routinely occurs during childhood and is usually a benign self-limited illness in immunocompetent children. However, varicella can be a severe disease in adolescents, adults, and immunosuppressed or immunocompromised individuals of any age. Secondary cases in household contacts appear to be more severe than primary cases [10].

Uncomplicated varicella — The clinical manifestations of varicella in healthy children generally develop within fifteen days after the exposure and typically include a prodrome of fever, malaise, or pharyngitis, loss of appetite [1], followed by the development of a generalized vesicular rash, usually within 24 hours.

The vesicular rash of varicella, which is usually pruritic, appears in successive crops over several days. The lesions begin as macules that rapidly become papules followed by characteristic vesicles; these lesions can then develop a pustular component followed by the formation of crusted papules [10] (picture 1). The patient with varicella typically has lesions in different stages of development on the face, trunk and extremities. New vesicle formation generally stops within four days, and most lesions have fully crusted by day six in normal hosts [1]. Crusts tend to fall off within about one to two weeks and leave a temporary area of hypopigmentation in the skin [10].

Impact of vaccine on clinical manifestations — Approximately 20 percent of children who receive one dose of varicella vaccine may develop varicella infection, known as "breakthrough disease", if exposed to VZV [15,16]. A report on the clinical and epidemiological characteristics of varicella in populations with increasing vaccine coverage between 1997 and 2005 identified the following trends [15]:

●In vaccinated children 1 to 14 years of age, varicella was more often mild and modified than in unvaccinated children (eg, less fever and a lower number of lesions).

●The accompanying rash was significantly more likely to be atypical in nature among vaccinated children (eg, maculopapular).

●Complications were less likely to be reported among vaccinated children than unvaccinated children.

●Neurologic complications (eg, encephalitis) continue to be rare [17].

COMPLICATIONS OF VARICELLA — Prior to the introduction of varicella vaccine in 1995, healthy children and adolescents accounted for 80 percent of the estimated 9300 annual varicella-related hospitalizations in the United States [2,18].

A survey was conducted from 1990 to 1992 of over 250,000 members of a health maintenance organization to assess the epidemiology of varicella and its complications [19]. Following a medical record review process, a total of 107 confirmed complications were identified, including bacterial skin infections and pneumonia. Skin infections were associated with the most hospitalizations in the youngest age group (<15 years of age); pneumonia was associated with hospitalization in persons >19 years of age. (See "Epidemiology of varicella-zoster virus infection: Chickenpox".)

After the introduction of vaccine, the number of complications in children dramatically declined, although the most common complication has remained bacterial superinfections; in the Varicella Active Surveillance Project (VASP), complications included skin and soft tissue infections (42 percent), dehydration (11 percent), and neurologic complications (9 percent) [17].

Although vaccine attenuates disease manifestations substantially, complications can still occur and are discussed below [15].

Skin/soft tissue infections — Primary varicella infection in children has been associated with an increased incidence of invasive group A streptococcal soft tissue infection [20-23]. Infectious complications have included cellulitis, myositis, necrotizing fasciitis, and toxic shock syndrome [20-25].

Neurologic complications — Encephalitis and, mostly in the past, Reye syndrome, are the most serious complications of VZV infection, although they are uncommonly seen [17]. Other less common neurologic complications include transient focal deficits, aseptic meningitis, transverse myelitis, vasculitis, and hemiplegia [1].

Encephalitis — In one series of serious varicella-related complications, encephalitis accounted for 20 percent of varicella-related hospitalizations [26]. Two distinct forms of encephalitis have been described [1,17,26]:

●Acute cerebellar ataxia

●Diffuse encephalitis

These disorders typically develop toward the end of the first week of the exanthem, but there are cases in which central nervous system involvement has preceded the rash [27,28].

Acute cerebellar ataxia most often develops in children, occurring in about 1 in 4000 varicella infections in children younger than 15 years of age [29]. It has a limited time course and is generally followed by complete recovery. These issues are discussed in detail separately. (See "Acute cerebellar ataxia in children".)

Diffuse encephalitis most often occurs in adults, but young children are also at increased risk [30,31]. The clinical manifestations include delirium, seizures, and focal neurologic signs. Pathologic examination has revealed three main patterns; although one usually predominates, mixed features are seen in many cases [32]:

●A medium to large vessel vasculopathy with bland or hemorrhagic infarctions

●A small vessel vasculopathy with mixed ischemic and demyelinating lesions

●A ventriculitis or periventriculitis

Reported mortality rates approach 10 percent and long-term neurologic sequelae reported in up to 15 percent of survivors [30,31,33]. Not surprisingly, varicella encephalitis is more severe in immunosuppressed hosts, such as patients with AIDS and transplant recipients. Such patients typically have a fulminant course with seizures, mental status changes, and focal deficits including stroke syndromes.

There is no proven effective therapy once encephalitis occurs. Acyclovir has been used with anecdotal success [34,35].

Reye syndrome — Reye syndrome, an illness developing during the course of varicella infection in children, typically presents with a distinct constellation of symptoms including nausea, vomiting, headache, excitability, delirium, and combativeness with frequent progression to coma [36]. Since salicylate use was identified as a major precipitating factor for the development of Reye syndrome [37], this complication has virtually disappeared, concomitant with advisories against using salicylates in febrile children. In a surveillance study from 1980 through 1997, 1207 cases were reported; the number of cases peaked in 1980 at 555 and dramatically declined, with warnings issued against the use of aspirin in patients with varicella or influenza [38]. From 1987 to 1993 fewer than 36 cases per year were reported; fewer than two cases per year were noted from 1994 to 1997. (See "Acute toxic-metabolic encephalopathy in children", section on 'Reye syndrome'.)

Pneumonia — In immunocompetent children with varicella, pneumonia remains an uncommon complication; in contrast, pneumonia accounts for the majority of morbidity and mortality seen in adults with varicella, although it is infrequently seen since the introduction of vaccine (eg, 60 per 10,000 cases) [17].

In immunocompetent adults, varicella pneumonia has a reported incidence of about one in 400 cases [29,39,40] and carries an overall mortality of between 10 and 30 percent [41,42]. However, in patients with respiratory failure who require mechanical ventilation, mortality rates approach 50 percent despite institution of aggressive therapy and appropriate supportive measures [43-45].

Risk factors linked to the development of varicella pneumonia include cigarette smoking [33,41,46], pregnancy [47], immunosuppression [31], and male sex [39]. Pregnancy may be an additional risk factor for severe varicella pneumonia although the incidence of pneumonia does not appear to be higher in pregnant patients with varicella [48]. (See "Varicella-zoster virus infection in pregnancy".)

Varicella pneumonia typically develops insidiously within one to six days after the rash has appeared with symptoms of progressive tachypnea, dyspnea, and dry cough; hemoptysis has occasionally been reported [42]. Patients demonstrate impaired gas exchange with progressive hypoxemia. Chest radiographs typically reveal diffuse bilateral infiltrates; in the early stages a nodular component may be present, which can subsequently become calcified [42,49,50]. Prompt administration of intravenous acyclovir has been associated with clinical improvement and resolution of pneumonia in selected series [42,44,51]. (See "Acyclovir: An overview".)

The use of steroids as adjunctive therapy for the treatment of life-threatening varicella pneumonia is controversial and has not been well studied. An uncontrolled study evaluated 15 adult patients with varicella pneumonia; 11 of these 15 patients (73 percent) were smokers and eight (53 percent) required mechanical ventilation [45]. All were treated with intravenous acyclovir and supportive measures; six also received steroids. The patients who received steroids had a shorter hospitalization (median difference of 10 days) and a shorter ICU stay (median difference eight days). The authors of this report suggested a randomized trial, which to date has not been performed.

Hepatitis — Biopsy proven visceral hepatic involvement with varicella is uncommon, but when it occurs, generally affects immunosuppressed hosts including transplant recipients and AIDS patients; the outcome is frequently fatal [52-55]. Clinical varicella hepatitis in healthy individuals is rare despite the fact that asymptomatic or subclinical transaminase elevation, coincident with the onset of varicella, has been documented in 77 percent of children in one series [56].

In immunosuppressed hosts with varicella hepatitis, the most common presenting features have typically included cutaneous vesicular lesions, fever, and acute abdominal or back pain [55,57]. However, the rash may precede [54], appear coincident with [52], or follow [53] the onset of hepatitis, which can delay the diagnosis of this complication. The development of varicella hepatitis with widespread visceral dissemination has been reported in a bone marrow transplant patient in the absence of a rash [58]. Fulminant liver failure with disseminated intravascular coagulation (DIC) and gastrointestinal hemorrhage with dissemination have also been reported [59,60].

Other — Other clinical manifestations among children and adults have included diarrhea, pharyngitis, and otitis media [17].

IMMUNOSUPPRESSED HOSTS — Patients with a history of underlying malignancy, steroid use or immunosuppressive therapy, HIV infection, or solid organ transplantation are susceptible for disseminated varicella due to impaired cellular immunity. Immunosuppressed hosts who develop varicella experience more frequent severe morbidity and higher mortality rates compared to normal hosts. While only 0.1 percent of varicella infections develop in this population, this group accounted for as many as 25 percent of varicella-related deaths in the prevaccine era [1].

Patients with rheumatologic diseases treated with tumor necrosis factor (TNF) antagonists remain at selectively increased risk for more severe primary varicella infections compared with the general population [61]. A retrospective review utilizing a hospital database and national patient registry of rheumatologic diseases, conducted in Spain, evaluated hospitalizations due to chickenpox in patients with rheumatic diseases. In rheumatologic patients exposed to TNF antagonists, the estimated incidence rate of hospitalization due to chickenpox was 26 cases per 100,000 (95% CI 10-69) compared with the expected rate of 1.9 (95% CI 1.8-2.0) in the general population.

Clinical manifestations in the immunosuppressed host can include ongoing development of crops of vesicles over weeks, large and hemorrhagic skin lesions, pneumonia, or widespread disease with disseminated intravascular coagulation [10].

Varicella vaccine programs appear to have had a positive impact on severe varicella infection in this patient subset. Surveillance mortality data compiled from the National Center for Health Statistics during the period from 1990-2001 [62] reviewed mortality rates in high-risk individuals for which varicella was identified as the underlying cause of death. High-risk individuals were defined as those with conditions for which vaccination is contraindicated: cancer, HIV infection or AIDS, and other immunodeficiencies:

●Between 1990 and 2001, cancer accounted for the greatest proportion of high-risk conditions among those younger than 20 years (71 percent) and those of 50 years of age or older (90 percent). Among high-risk persons 20 to 49 years of age, HIV infection or AIDS were the most common conditions (58 percent).

●Overall, however, patients with high-risk conditions accounted for few of the varicella deaths in this study (approximately 20 percent).

The authors surmised that patients who were identified to be at high risk for severe varicella may have received early aggressive therapy with intravenous acyclovir that favorably impacted survival. A higher rate of varicella vaccination among close contacts of persons ineligible for vaccination may also have occurred; thus herd immunity may have prevented some cases of primary infection [62]. (See "Acyclovir: An overview".)

There are few data on varicella in HIV-infected children. One natural history in 57 HIV-infected children included patients with primary varicella or HIV-infected controls without a history of varicella (matched by age and CD4 count) [63]. Thirty children developed varicella, but only one case was judged to be severe; 22 of 30 had received acyclovir therapy.

While the outcome of primary infection was favorable in this population of HIV-infected children, the incidence of later herpes zoster infection was high. Of the children with a history of varicella, eight (27 percent) developed herpes zoster an average of 1.9 years after the episode of primary varicella [63].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Varicella-zoster virus".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Chickenpox (The Basics)")

●Beyond the Basics topics (see "Patient education: Chickenpox prevention and treatment (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Virology – 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). (See 'Introduction' above.)

●Transmission – Chickenpox is highly contagious, with secondary household attack rates of >90 percent in susceptible individuals. Transmission occurs in susceptible hosts via contact with aerosolized droplets from nasopharyngeal secretions of an infected individual or by direct cutaneous contact with vesicle fluid from skin lesions. (See 'Transmission and virology' above.)

●Clinical manifestations – Primary varicella infection in children is generally a mild disease compared to more severe presentations in adults or immunocompromised patients of any age.

•Uncomplicated varicella – The clinical manifestations of varicella generally develop within fifteen days after the exposure and typically include a prodrome of fever, malaise, or pharyngitis, followed by the development of a generalized vesicular rash. (See 'Clinical manifestations' above.)

•Complications – Complications of varicella in children can include bacterial superinfection while pneumonia is more common in adults. (See 'Complications of varicella' above.)

•Disseminated varicella – Patients with a history of underlying malignancy, steroid use or immunosuppressive therapy, HIV infection, or solid organ transplantation are susceptible for disseminated varicella due to impaired cellular immunity. (See 'Immunosuppressed hosts' above.)

●Impact of vaccination – The incidences of infection, hospitalizations, and mortality have all declined since the introduction of the varicella vaccine in 1995. Varicella vaccination is discussed separately. (See "Vaccination for the prevention of chickenpox (primary varicella infection)".)