Varicella
Salient
features
·
Varicella
(chickenpox) and herpes zoster (shingles) are distinct clinical entities caused
by a single member of the herpes virus family, varicella-zoster virus (VZV).
·
Varicella,
a highly contagious exanthem that occurs most often in childhood, is the result
of primary VZV infection of a susceptible individual.
·
The
rash of varicella usually begins on the face and scalp and spreads rapidly to
the trunk, with relative sparing of the extremities. Lesions are scattered,
rather than clustered, reflecting viremic spread to the skin, and they progress
sequentially from rose-colored macules to papules, vesicles, pustules, and
crusts. Lesions in all stages are usually present at the same time.
·
In
immunocompetent children, systemic symptoms are usually mild and serious
complications are rare. In adults and immunocompromised persons of any age,
varicella is more likely to be severe and can be associated with
life-threatening complications.
·
Varicella
results in lifelong latent VZV infection of sensory and autonomic neurons, and
host immunity to VZV.
·
Live
attenuated Oka VZV varicella vaccines have virtually eliminated varicella in many countries where they have been deployed.
Definition
Varicella, an acute, highly contagious vesicular exanthem
that occurs most often in childhood, is the result of exogenous primary VZV
infection of a susceptible individual. In contrast, herpes zoster results from
reactivation of endogenous virus that persists in latent form within ganglionic
neurons following an earlier attack of varicella.
Epidemiology
Age of Primary Infection
Without
immunizaton, 90% of cases occur in children <10 years, and only <5% in persons
older than 15 years. With active immunization, the incidence is markedly
reduced.
Varicella is extremely contagious, and 90% of susceptible
household contacts develop a clinically evident infection. A typical patient is
infectious for 2 days (rarely, 3–4 days) before the exanthem appears, and for 4
or 5 days thereafter, that is, until the last crop of vesicles has crusted. Crusts are not infectious. The immunocompromised
patient, who may experience many successive crops of lesions for a week or
more, is infectious for a longer period of time. The mean incubation period of
varicella is 14. It is often prolonged in patients who develop varicella after
passive immunization with varicella-zoster immune globulin (VZIG) or zoster immune
plasma (ZIP), or after post exposure immunization with live attenuated Oka
strain varicella vaccine.
Transmission
Both portal of entry and portal of VZV are through
the mucosa of the upper respiratory tract. Chickenpox can easily spread from
person to person by breathing in airborne respiratory droplets from an infected
person's coughing or sneezing. VZV can be aerosolized from vesicle fluid in either varicella
or herpes zoster disease containing a large amount of virus and may be a route
of droplet infection and can transmit VZV to seronegative individuals, leading
to varicella.
Pathogenesis
VZV enters through mucosa of upper respiratory tract of naive
persons by inhalation. In the upper respiratory tract it is assumed that the
virus infects dendritic cells (DCs) of the respiratory mucosa which transport
the virus to local lymph nodes (tonsils) by lymphatics where VZV infects
preferentially tonsillar CD4+ T cells, which disseminate
virus via lymphatics and the blood producing a brief primary viremia. Infected
T cells carry virus to the reticuloendothelial system such as liver, spleen and
other organs, the major site of virus replication during the remainder of the
incubation period and is
then followed by a much larger (secondary) viremia, and widespread dissemination of
the virus to the epidermis
of the skin (the virus travels to the epidermis by invading capillary
endothelial cells) coinciding with the onset of the rash about 2 weeks post-exposure. During
the last 2 days of incubation period VZV transported back to the mucosa of the
upper respiratory tract and release the virus into the respiratory secretions, permitting
spread to the susceptible contact. Skin lesions appear in
successive crops, reflecting a cyclic viremia, which in the normal host is
terminated after about 3 days by VZV-specific humoral and cellular immune
responses. During
the course of varicella, VZV passes from the mucocutaneous lesions to the sensory ganglia along the spine and cranial
nerves where it can remain dormant (latent) for several decades before
being reactivated in later life to cause HZ (shingles). The VZV genome persists, both in the neurons and in the
glial cells.
Natural varicella (i.e., varicella caused by wild-type
VZV) generally confers life-long immunity to the disease. In varicella, IgG, IgM and IgA anti-VZV
antibodies appear 2–5 days after the
onset of the rash, and their levels peak during the second and third weeks. Thereafter,
the titers gradually fall although IgG persists at low levels. Antibodies
seem to have incomplete protective effect; maternal or administered antibody
reduces the severity of infection, but does not prevent it and recurrent
varicella has been reported.
Cell-mediated immunity to VZV also develops during the
course of varicella, persists for many years, and is more important in both
protection against and control of infections. If the primary infection occurs when cell‐mediated immunity is impaired as in immunocompromised
patients, varicella may be severe and occasionally fatal.
When
VZV-specific cellular immunity falls below some critical level, virus
multiplies and spreads within the ganglion, causing neuronal necrosis and
intense inflammation, produces a painful ganglionitis. VZV then travels down the
sensory nerve, resulting in neuritis with severe
neuralgia along the
affected dermatome(s) innervated by a corresponding sensory ganglion, followed
by skin lesions of herpes zoster. Since the neuritis precedes the skin
involvement, pain or itching appears before the skin lesions are visible.
The pathogenesis of chickenpox
Primary infection with
varicella-zoster virus occurs when virus-laden water droplets contact the
respiratory mucosa or conjunctivae of a susceptible host. The pathogenesis most
likely includes a biphasic course with primary and secondary viremia followed by
the typical vesicular exanthema with enanthema of chickenpox. Based on this schema, varicella-zoster immune
globulin must be given before primary viremia to prevent chickenpox in the
exposed host.
Host
Immune Response
When initially infected
by naturally acquired primary varicella-zoster virus, the first response of the
host is mediated by the innate immune system through antiviral cytokines and
activation of the NK cells. These responses are necessary for the initial control
of the virus at mucosal sites of inoculation and to trigger the adaptive immune
system for varicella-zoster virus immunity. Activation of the NK cells is a
major source of interferon-γ production which causes enhancement of the clonal
expansion of antigen-specific T cells. The NK cells lyse the infected cells to
combat the spread of the virus.
Varicella-zoster virus-specific T cells are necessary to prevent
disseminated infection as children with T cell immunodeficiencies are at risk for
life-threatening varicella. B cells are also activated during the adaptive
immune response and make varicella-zoster virus IgG and IgM antibodies.
However, there is no correlation between B cell immunodeficiencies and severe
varicella which indicates that the B cells are not as important in the adaptive
immune response to the virus as T cells.
The memory immune
response that follows the initial infection of the naturally acquired
varicella-zoster virus infection includes varicella-zoster virus IgG antibodies,
IgA antibodies in most cases, and virus specific CD4 and CD8 T cells.
Varicella-zoster virus-specific IgG antibodies bind to the viral proteins and
mediate neutralization and antibody-dependent toxicity. Neutralization of the
virus occurs at sites of inoculation when re-exposed to the virus through
contact with individuals who have varicella. If the virus is able to evade this
line of defense as well as the innate immune response, the varicella-zoster
virus-specific T cells are important for preventing symptomatic disease after
re-exposure. Also, because the varicella-zoster virus establishes latency in
the sensory ganglia, the memory T cells are needed to prevent symptomatic
reactivation of the endogenous virus. The age-related decrease in varicella-zoster
virus-specific T cells and a decrease from immunosuppressive diseases are
associated with an increased risk of shingles due to reactivation of the virus.
The live attenuated
vaccine elicits varicella-zoster virus-specific IgG and T cell immunity in naive
host cells.
Prodrome of Varicella
In children, prodromal symptoms are uncommon. In adolescence
and adults, the rash is often preceded by 2–3 days of fever, chills, malaise,
headache, anorexia, severe backache, and, in some patients, sore throat and dry
cough.
Rash of Varicella
In unvaccinated persons, the rash begins on the face and
scalp and then spreading rapidly and inferiorly to the trunk and limbs. New
lesions appear in successive crops, but their distribution remains centripetal.
The
lesions are most profuse in areas least exposed to pressure, i.e., on the back
between the shoulder blades, flanks, axillae, popliteal and antecubital fossae.
Density is highest on the trunk, then on the face and scalp and less on the
limbs. On the limbs the
eruption is more profuse on thighs and upper arms than on lower legs and
forearms. It is not uncommon to have a few lesions on the palms and soles, and
vesicles often appear in larger numbers in areas of inflammation, such as
diaper rash or sunburn. Children have so few lesions that the disease goes
unnoticed. Adolescence and adults have a more extensive eruption involving all
areas, sometimes with lesions too numerous to count.
A striking feature of varicella lesions is their rapid
progression. Over as little as 12 hours, the lesions progress sequentially from
rose-colored macules to papules, vesicles, pustules, and crusts. Lesions are
scattered rather than clustered, reflecting viremic spread to the skin. The
typical vesicle of varicella is 2–3 mm in diameter and elliptical, with its
long axis parallel to the folds of the skin. The early vesicle is clear, superficial
and thin-walled, and it is surrounded by an irregular area of erythema, which
gives the lesions the appearance of a “dewdrop on a rose petal.” The vesicular
fluid soon becomes cloudy with the influx of inflammatory cells, which convert
the vesicle to a pustule with a scalloped border. The lesion then dries,
beginning in the center, and depressed, first producing an umbilicated pustule
and then a crust, which eventually replaces the remaining portion of the
pustule at the periphery. After
about 4 days, no new crops of lesions appear and existing vesicles dry and
crust. Crusts
fall off spontaneously in 1–3 weeks, leaving shallow pink depressions that
gradually disappear. Scarring is rare unless the lesions are traumatized by the
patient or superinfected with bacteria. Healing lesions may leave hyper‐ or hypo pigmented spots
that persist for weeks to months; if scars occur they are depressed, pox-like.
Vesicles also develop in the mucous membranes
of the mouth (most
common on hard palate),
nose, pharynx, larynx, trachea, gastrointestinal tract, urinary tract, and vagina.
These mucosal vesicles rupture so rapidly that the vesicular stage may be
missed. Instead, one sees small scattered erosions
2–3 mm in diameter, which are
covered by yellowish exudates, and bordered by a narrow red hem.
A distinctive feature of varicella is the simultaneous
presence of lesions in all stages of development in each affected sites
with papules, vesicles, pustules, crusts, i.e., polymorphic. Studies
have shown that the average number of lesions in healthy children ranges from
250 to 500; secondary cases resulting from household exposure are more severe
than primary cases resulting from exposure at school, presumably because more
intense and prolonged exposure at home results in a higher virus inoculum.
Fever usually persists as long as new lesions continue to
appear, and its height is generally proportional to the severity of the rash.
It may be absent in mild cases or rise to (105°F) in severe cases with
extensive rash. Prolonged fever or recurrence of fever after defervescence may
signify a secondary bacterial infection or another complication. The most
distressing symptom is pruritus, which is usually present throughout the
vesicular stage.
Clinical
variants
Hemorrhagic
chickenpox, also called malignant chickenpox, is a serious complication mostly seen in immunocompromised patients in whom there is very extensive eruption of vesicles and bullae with hemorrhage at the base. Patients are usually toxic, have high fever
and delirium, and may develop convulsions and coma. They frequently bleed from
the gastrointestinal tract and mucous membranes.
Pregnant
women and neonates
Chicken pox during pregnancy can have gestational age-specific
adverse outcomes both in the mother and in the fetus. Varicella vaccine is
contraindicated in pregnancy. Non-immune exposed expectant mothers can be
offered VZIG as prophylaxis before infection occurs. Once infection occurs,
oral or intravenous acyclovir can be advised depending on the severity of
infection. Neonatal varicella infection should be treated promptly with
intravenous acyclovir.
Consequences of varicella infection during pregnancy according
to gestational age
Maternal Varicella in
the First and Second Trimesters
"Fetal
varicella syndrome" develops in babies born to mothers infected with
varicella between 7 and 20 weeks of pregnancy, through transplacental
infection. The
risk is greatest (about 2%) when infection occurs between 13 to 20 weeks of
pregnancy with a high mortality rate of 30% in
the first month of life. Clinically,
the newborn presents cutaneous scars in a dermatomal distribution, ocular
abnormalities like cataract, microphthalmia and chorioretinitis, bone and
muscle hypoplasia of limbs, neurological abnormalities like mental retardation,
seizures, hydrocephalus, cortical atrophy and microcephaly. Ultrasound is the method of choice for
objectifying clinical signs. If fetal abnormalities are discovered, parents
should be made aware of the possibility of associated brain damage, and the
termination of pregnancy should be discussed.
Third trimester
Maternal varicella in the third
trimester, particularly between 25–36 weeks of gestation may result in
undetected fetal chickenpox that may result in zoster occurring postnatally
without ever having extrauterine varicella, often in the first 2 years of life.
Pregnant women who
contract varicella in the last trimester are at a higher risk of severe pneumonia
and death. Pneumonia can occur in up to 10-20% of pregnant women with chicken
pox, with a mortality rate of 14%, whereas in the general population, varicella
pneumonia has a mortality rate of 10%. Risk factors for the development of varicella pneumonitis
in pregnancy include third trimester infection, cigarette smoking, chronic
obstructive lung disease, history of taking systemic steroid in the preceding 3
months or immunosuppression or more than 100 skin lesions or hemorrhagic
lesions.
Near birth
If the mother has varicella last 3 weeks to >5 days before delivery, the fetus may be infected in utero
and be born with or develop lesions 1 to 4 days after birth. Transplacental
maternal antibody protects the infant and the course is usually benign.
If the onset of
varicella in the mother is 5 days before delivery to 2 days after delivery, an
estimated 20-50% of the newborns contract "neonatal varicella," and
30% of them develop "severe or fulminant neonatal varicella" with
disseminated cutaneous lesions and visceral involvement and the death rate may be
as high as 20%. This period
correlates with the development of maternal IgG; hence, the neonate does not
get enough time to acquire passively transferred maternal antibody and there is
also a relative immaturity of the neonatal immune system. These neonates
develop varicella at 5–10 days of age. In that case, the neonate should be given
prophylactic VZIG immediately after birth and acyclovir at a dosage of 10 mg/kg
every 8 h intravenously for 5-7 days should be administered promptly within 24
hours of the onset of rash as it reduces the duration and severity of chicken
pox.
Modified varicella-like syndrome
Children and adults immunized with
live attenuated varicella vaccine may develop varicella of reduced severity on
exposure to natural varicella caused by wild-type VZV at a rate of 1%–3% per
year compared to an attack rate of 8%–13% per year in unvaccinated children. This has been called modified varicella-like syndrome
(MVLS) or “breakthrough” varicella. The illness occurs an average of 15 days
after exposure to people with active varicella and consists primarily of
macules and papules with fewer lesions (i.e., less than 60) and fewer vesicles
than the rash of natural varicella. The average number of lesions is about
35–50, compared with natural varicella, which usually has about 300 lesions.
The majority of patients are afebrile and the illness is mild, lasting fewer
than 5 days on average.
Complications
and co‐morbidities
In the normal child, varicella is rarely complicated. The
disease course is usually self-limited and benign. The most common complication in children <5
years is secondary bacterial infection of skin lesions, usually by
Staphylococci or Streptococci, which may produce impetigo, furuncles,
cellulitis, erysipelas, and, rarely, gangrene (‘varicella gangrenosa’). These local infections
often lead to scarring and, rarely, to septicemia with metastatic infection of
other organs. Invasive group A streptococcal infections are particularly
virulent. In the absence of varicella vaccination, up to one-third of varicella
is associated with invasive group A streptococcal infections; they usually
occur within 2 weeks of the onset of the varicella rash. Widespread varicella
vaccination appears to have markedly reduced the percentage of invasive group A
streptococcal hospitalizations associated with varicella.
In adults, fever and constitutional symptoms are more
prominent and prolonged, the rash of varicella is more profuse with an
increased number of skin lesions and complications are more frequent.
Pneumonia
Primary varicella pneumonia occurs in 1 of every 400
cases and is the most common serious complication of adult varicella. In most
cases it is asymptomatic and can be detected only with a chest x-ray
examination but some patients develop severe respiratory symptoms, with cough,
dyspnea, tachypnea, high fever, pleuritic chest pain, cyanosis, and hemoptysis
1–6 days after onset of the rash. The death rate for adult varicella pneumonia
is 10% of immunocompetent patients and 30% of immunocompromised patients.
Neurologic complications
CNS complications of varicella are uncommon (less than 1
in 1,000 cases) and may include acute cerebellar ataxia and encephalitis. Acute cerebellar ataxia is more common than
the other neurologic complications of varicella, occurring in 1 in 4,000 cases,
and is more benign, self-limited and complete recovery occurs. Encephalitis is
much less common, occurring in 1 in 33,000 cases, but it frequently causes
death or permanent neurologic sequelae. The pathogenesis of cerebellar ataxia
and encephalitis remains obscure, but in many cases it is possible to detect
VZV antigens, VZV antibodies, and VZV DNA in the cerebrospinal fluid of patients,
suggesting direct infection of the CNS.
Immunocompromised
patients
Immunocompromised patients including those with leukemia,
lymphoma, or human immunodeficiency virus (HIV) infection, and those with a
history of organ or bone marrow transplantation, may develop severe, progressive and fatal
varicella. Any patient receiving or having received systemic steroids in the
prior 3 months, regardless of dose, is considered at increased risk for severe
varicella. In these patients, continued virus replication and dissemination
result in a prolonged high-level viremia, a more extensive rash, a longer
period of new vesicle formation, and clinically significant visceral
dissemination. Features
associated with a progressive varicella include pneumonitis, hepatitis,
encephalitis and hemorrhagic complications of varicella, which range
in severity from mild febrile purpura to severe and often fatal purpura fulminans
and “malignant” varicella.
Thrombocytopenic
purpura, beginning on the 5th to 10th day and usually recovering spontaneously
after 3 or 4 months, occasionally follows otherwise benign varicella.
Clinical Diagnosis of
Varicella
In most cases, the diagnosis of
varicella is clinical. The distinctive features of varicella are the
centripetal distribution, the polymorphism in each affected site and the rapid
progression of the individual lesion from papules to crust and particularly when
there is a history of exposure within the preceding 2–3 weeks.
Disseminated herpes zoster may be mistaken for varicella
when there is widespread dissemination of VZV from a small, painless area of
herpes zoster or from the affected sensory ganglion in the absence of an
obvious dermatomal eruption. This is frequently seen in profoundly
immunosuppressed, seropositive persons.
Disseminated HSV infections may resemble varicella;
however, there is often an obvious concentration of lesions at and surrounding
the site of the primary or recurrent infection (e.g., the mouth or external
genitalia) and there may be marked toxicity and encephalitis.
Laboratory Diagnosis
The diagnosis of VZV infection is usually made on
clinical grounds based on the presence of the characteristic skin lesions of
chickenpox or HZ. However, additional diagnostic techniques may be needed to
confirm the diagnosis and these include: (1) virus isolation by culture which
carries a low yield rate, (2) serology using enzyme-linked immunosorbent assay
(ELISA), (3) direct fluorescent antibodies on scrapings obtained from active
skin lesions, and (4) real-time polymerase chain reaction (RT-PCR) which has
higher sensitivity than serological assays.
A Tzanck smear, PCR or DFA can assist in quickly
confirming the diagnosis. The latter two (but not the Tzanck smear) can
differentiate between HSV and VZV.
Varicella and herpes zoster has the same histologic
findings as HSV infections, but immunohistochemical (immunoperoxidase) staining
on the biopsy specimen can distinguish between the two viruses.
Additional laboratory tests include viral culture and
serology.
Viral culture is a very specific test; however, it is not
very sensitive and results may not be available for >1 week as VZV grows poorly
and slowly in the laboratory. Serologic assays are diagnostic of VZV if the
convalescent serum has at least a fourfold increase in the VZV titer relative
to the acute serum. As a result, serology is only useful in retrospect.
The quickest
and most reliable way to confirm diagnosis is by PCR that detects
VZV DNA in vesicle fluid
or a scraping taken from the base of a vesicle. It has revolutionized
the diagnosis of VZV infections, and can distinguish among wild type and Oka
vaccine strains of VZV and HSV.
Detection of VZV antigen by direct
fluorescent antibody (DFA test) staining of a smear from the base of a vesicle
offers an alternative
test.
Prevention
This
can be by pre‐exposure vaccination, post‐exposure
immunoglobulin and antiviral prophylaxis.
Pre‐exposure prophylaxis
A live attenuated varicella vaccine (Oka strain) was approved by the FDA in
1995.
In 2005, the FDA approved a combined measles, mumps,
rubella, and varicella vaccine (MMRV)
for routine immunization of children 12 months to 12 years of age.
Because of the frequency of breakthrough varicella caused
by wild-type VZV, the Advisory Committee on Immunization Practices (ACIP) now
recommends two 0.5-mL doses of varicella vaccine for healthy children aged ≥12
months, adolescents, and adults without evidence of immunity. Two doses of the vaccine,
routinely given, one between age 12–15 months and the second booster dose between
4–6 years, are now recommended in order to improve protection and counteract
waning vaccine-induced immunity. This resulting in approximately 90% seroconversion
with 75% of responding recipients maintaining detectable antibody for up to 10
years. Studies indicate that one dose of the vaccine is 70–90% effective
in preventing infection and 95–100% effective in preventing severe disease, and
recipients of two doses are more than threefold less likely to develop
breakthrough varicella than those who received one dose. The incidence and
severity of both varicella (usually due to wild-type VZV) and zoster (most
often due to the attenuated Oka strain) are decreased in vaccine recipients
compared to unimmunized children. However,
vaccine can be given at any time and for children aged 12
months—to 12 years, the recommended minimum interval between the two doses is 3
months, although the second dose may be administered as soon as 28 days after
the first and for persons aged >13
years, the recommended minimum interval between the two doses is 4 weeks.
Second dose catch-up varicella vaccination is recommended for children,
adolescents, and adults who previously received only one dose.
The varicella vaccine is available as a monovalent
vaccine (Varivax) and as part of a quadrivalent measles-mumps-rubella-varicella
vaccine (MMRV). There is a slightly increased risk of febrile seizures among
children aged 12 to 23 months who received MMRV for their initial dose. A
personal or family history of seizures is considered a precaution for use of MMRV;
so at this age it is recommended that the first dose be administered as
separate measles-mumps-rubella (MMR) and varicella vaccines. For the second
dose at any age or the first dose at ages 48 months and older, the combination
MMRV vaccine is recommended.
The immunity to varicella induced by
varicella vaccine is not as solid as that induced by wild-type VZV infection,
and the duration of vaccine-induced immunity is not yet known. Of note, because this is a live viral vaccine,
administration is contraindicated during pregnancy and in individuals with immunosuppression
due to diseases or drugs and HIV infection. If immunosuppressive therapy can be
stopped, vaccination can be given at least 3 and preferably 6 months after
discontinuation. Pregnant
women should wait until after they have given birth to be vaccinated against
chickenpox. Women should not become pregnant for 1 month after receiving the
chickenpox vaccine.
Herpes zoster has been reported in vaccines, but it
occurs at a significantly lower frequency than herpes zoster in persons of
similar age following varicella caused by wild-type VZV. Herpes zoster in vaccines
included some cases caused by reactivation of the vaccine virus and others
caused by reactivation of wild-type virus acquired prior to vaccination as a
consequence of unrecognized varicella.
Post‐exposure prophylaxis
Patients with varicella and herpes zoster may transmit
VZV to susceptible individuals. Preventive measures include the varicella
vaccine, varicella
zoster immune globulin (ZIG), and post-exposure chemoprophylaxis
with acyclovir.
Active
immunization with the live attenuated varicella vaccine may prevent or modify varicella severity in seronegative, immunocompetent individuals who are ≥12
months of age if
used within 3 days after exposure. Whereas protection afforded by zoster immune
globulin is transient, varicella vaccine induces long-lasting (active) immunity
to VZV and protection against subsequent exposures. Therefore, the ACIP
recommends varicella vaccine for post exposure prophylaxis in unvaccinated
persons without evidence of immunity.
VariZIG is the only varicella-zoster
immune globulin preparation available for post-exposure prophylaxis of
varicella in persons at high risk for severe disease who lack evidence of
immunity to varicella and are ineligible for varicella vaccine. VZIG treatment
does not reduce the frequency of infection, but it does reduce the severity of
infection and complications. VariZIG is a purified immune globulin preparation
made from human plasma containing high levels of antibody to VZV
(immunoglobulin class G [IgG]). Administration of varicella zoster immune
globulin (125 U/10 kg, 625 U maximum) intramuscularly within 10 days of
varicella exposure is recommended to provide passive prophylaxis to non immune immunocompromised
individuals and pregnant women as well as high-risk neonates.
VariZIG is
not known to be useful in treating clinical varicella. The duration of
protection is estimated to be 3 weeks. Patients exposed again more than 3 weeks
after a dose of VariZIG should receive another full dose. VZIG is given
intramuscularly.
CDC guidelines for varicella vaccine and varicella zoster
immunoglobulin
Antiviral
prophylaxis
In susceptible immunocompetent person following household exposure to varicella, prophylactic oral
acyclovir administration with usual varicella dosing for 1 week, about 9 days
after exposure, appears to be effective in reducing the severity of chickenpox
and allows immunity to develop. In the immunocompromised, such prophylaxis only
delays the onset of the disease.
Treatment
Topical Therapy
Varicella
in normal immunocompetent children is generally benign and self-limited and can be treated symptomatically. Cool compresses or
calamine lotion locally, tepid baths with baking soda or colloidal oatmeal
(three cups per tub of water) and oral antihistamines may relieve itching. Diluted solutions
containing menthol are appropriate for itching. Creams and lotions containing
glucocorticoids and occlusive ointments should not be used. Dressing the
patient in light, cool clothing, and keeping the environment cool may all
relieve some of the symptomatology. Antipyretics
(e.g. acetaminophen)
may be needed, but aspirin and other salicylates as antipyretics must be
avoided because of their association with Reye syndrome. Minor bacterial
infections are treated with warm soaks, but for bacterial cellulitis systemic
antimicrobial therapy effective against Staphylococcus aureus and group A β-hemolytic
streptococcus is required.
Antiviral Therapy
Normal Children
A large randomized, controlled trial of acyclovir
treatment of healthy children 2–12 years of age found that early treatment
(within 24 hours of the appearance of rash) with oral acyclovir (20 mg/kg,
maximum 800mg per dose, four times a day for 5 days) modestly reduced the
maximum number of lesions, the time to cessation of new lesion formation, and
the duration of the rash, fever, and constitutional symptoms. The American
Academy of Pediatrics Committee on Infectious Diseases published
recommendations for the use of oral acyclovir in otherwise healthy children
with varicella. Recommendations are that: (1) oral acyclovir therapy is not
routinely recommended for the treatment of uncomplicated varicella in otherwise
healthy children because varicella is a relatively benign infection in
children, the clinical benefits of treatment are modest, and the complications
of varicella are infrequent in children and that (2) for certain groups at
increased risk of severe varicella or its complications, oral acyclovir therapy
for varicella should be considered if it can be initiated within the first 24
hours after the onset of rash. Treatment initiated more than 24 hours after
rash onset is not effective. These groups include otherwise healthy, non pregnant
individuals 13 years of age or older; children older than 12 months with a
chronic cutaneous disorders such as atopic dermatitis, darier’s disease,
congenital ichthyosiform erythroderma, cystic fibrosis; chronic pulmonary
disorders; receiving chronic salicylate or steroid therapy, or receiving short,
intermittent, or aerosolized courses of corticosteroids. Because secondary
cases among susceptible children in the household are generally more severe
than the index cases, and because early initiation of treatment is more readily
accomplished in secondary cases, treatment with acyclovir seems reasonable for
such secondary cases.
Normal Adolescents and
Adults
Oral
acyclovir is recommended for varicella in all healthy adolescents and adults (13 and older).Treatment should be started as early as possible, preferably
within the first 1 or 2 days. The virus is less sensitive to acyclovir in
vitro than HSV and higher doses are usually recommended, typically 800 mg five times a
day orally. A randomized, placebo-controlled trial of oral acyclovir in healthy
young adults with varicella showed that early treatment (within 24 hours of
rash onset) with oral acyclovir (800 mg five times a day for 7 days)
significantly reduced the time to crusting of lesions, the extent of disease,
and duration of symptoms and fever. Thus, routine treatment of varicella in
adults seems reasonable. Although not tested, it is likely that famciclovir 500 mg PO q8h or valacyclovir 1,000 mg PO q8h
would be convenient and appropriate substitutes for acyclovir in normal
adolescents and adults.
Antiviral Treatment of Varicella in the Normal and
Immunocompromised Host
|
Patient Group |
Regimen |
|
Normala |
|
|
Neonate |
Acyclovir
10 mg/kg IV every 8 h for 10 days |
|
Child (2 to 12 years of age) |
Symptomatic treatment alone, or |
|
Secondary household cases |
Acyclovir
20 mg/kg po four times a day × 5 days (not to exceed 3200 mg/day) |
|
Adolescent (≥40 kg) or adult |
Acyclovir
800 mg po five times for 7days or Valacyclovir 1
g po three times for 7 days or |
|
Famciclovir
500 mg po three times for 7 days |
|
|
Pneumonia |
Acyclovir
800 mg po five times a day for 7 days |
|
Acyclovir
10 mg/kg IV every 8 h × 7–10 days |
|
|
Pregnancy |
Routine use of acyclovir
is not recommended. |
|
If there are complication (e.g., pneumonia) treat
pneumonia as per recommendation above. |
|
|
Immunocompromised |
|
|
Mild varicella or mild compromise |
Valacyclovir 1
g po every 8 h for 7–10 days or |
|
Famciclovir
500 mg po every 8 h for 7–10 days or |
|
|
Acyclovir
800 mg po five times a day for 7–10 days |
|
|
Severe varicella or severe compromise |
Acyclovir
10 mg/kg IV every 8 h for 7–10 days |
|
Acyclovir resistant (advanced AIDS) |
Foscarnet
40 mg/kg IV every 8 h until healed |
a Oral acyclovir or
preferably, famciclovir or valacyclovir,
should be considered for otherwise healthy persons at increased risk for moderate-to-severe
varicella (e.g., persons aged >12 years, persons with chronic cutaneous or
pulmonary disorders, persons receiving long-term salicylate therapy, and
persons receiving short, intermittent, or aerosolized courses of
corticosteroids).
Treatment of complications of Varicella in
(a) Normal Persons
In immunocompetent adults with varicella pneumonia suggests
that early treatment (within 36 hours of hospitalization) with IV acyclovir (10
mg/kg q8h) may reduce fever and tachypnea and improve oxygenation. Other
serious complications of varicella in the immunocompetent host, such as
encephalitis, meningoencephalitis, myelitis, and ocular complications, should
be treated with IV acyclovir.
(b) Immunocompromised Patients
Intravenous
acyclovir is indicated for varicella at any age in immunocompromised patients
and neonates, due to their increased risk of more severe disease and
complications. In
immunocompromised patients with varicella demonstrated that treatment with IV acyclovir 10 mg/kg 8‐hourly, adjusted for
creatinine clearance, decreases the incidence of life-threatening visceral
complications when treatment is initiated within 72 hours of rash onset. Courses of 5, 7 and
10 days have been used and some advocate a change from intravenous to oral drug
once
lesions stop appearing (usually after 48 hours).
Immune compromise, however, is a
continuum ranging from minimal to severe. Intravenous acyclovir has been the
standard of care for varicella in patients with substantial immunodeficiency. If
the patient is hospitalized for therapy, strict isolation is required. Patients
with varicella should not be admitted to wards with immunocompromised hosts or
on to pediatric wards, but rather are best placed on wards with healthy
patients recovering from acute trauma. Oral therapy with acyclovir, famciclovir or valacyclovir might suffice for patients with mild degrees
of immune impairment.
Management
of maternal and neonatal varicella
If the pregnant mother is exposed to varicella and is
uncertain about her immunity to varicella, then a varicella-zoster IgG assay
should be done. If the IgG assay is positive, she can be reassured that she is
immune. If the IgG is negative, she should be offered prophylaxis with either
VZIG or acyclovir. If she develops infection despite prophylaxis, she should be
treated with therapeutic doses of acyclovir for seven days. Should she develop
one of the serious sequelae of varicella, she should be hospitalized and
treated with intravenous acyclovir. Following treatment, serial ultrasound
examinations should be performed to assess for findings suggestive of
congenital varicella.
How to Manage Maternal Varicella Infection
Many physicians do not prescribe oral acyclovir in
uncomplicated varicella during pregnancy because the risk to the fetus of
treatment is unknown. Other physicians recommend oral antiviral therapy for
infections in the third trimester when organogenesis is complete, when there
may be a heightened risk of varicella pneumonia, and when infection can be
spread to the newborn. Intravenous acyclovir is often considered for pregnant
women with varicella who have extensive cutaneous and/or systemic disease.
All varicella in pregnancy should be
treated with oral acyclovir, 800 mg five times a day for 7 days starting within 24-72 hours of onset of rash (except
perhaps during the first month, when a specialist should be consulted). Fetal ultrasound scan 5 weeks after the primary
infection and appropriate follow-up is recommended to all pregnant women who
develop varicella during the first or second trimester to screen for fetal
abnormalities. They should be advised to avoid contact with other pregnant
women and neonates during the period of communicability, which starts 1-2 days
prior to the eruption, until the lesions have all crusted, which usually starts
5 days after the onset of rash. Symptomatic treatment and hygiene is advised to
prevent secondary bacterial infection of the lesions.
In case of
progression to varicella pneumonitis, if the severity of infection warrants,
intravenous acyclovir (10-15 mg/kg, every 8 hours for 5-10 days) can be
considered and renal
function should be carefully monitored, and the patient should be switched to
oral therapy once lesions stop appearing (usually in 48–72 hours).
How to Prevent
Maternal Varicella
Pregnant women who
have never had varicella infection in the past and/or have not received
varicella vaccine, or in whom varicella antibody serology (IgG) is negative,
are considered non-immune.
Varicella zoster
immunoglobulin (VZIG), which is a disease-specific immunoglobulin prepared by
pooling plasma of donors with high levels of varicella zoster antibody, is
recommended as post-exposure prophylaxis for non-immune pregnant women. It has
been shown to lower varicella infection rates if administered within 72-96 h
after exposure. Protection
is estimated to extend through 3 weeks, which corresponds with the half-life of
the immunoglobulin. VZIG has no therapeutic benefit once chicken pox has
already developed. Acyclovir, as preventive therapy, has been suggested by some
authors and is best given on the seventh day post-exposure, but the
prophylactic role of this drug in chicken pox is yet to be established.
Varicella vaccine (Varivax) contains live
attenuated virus derived from the Oka strain. It is not recommended for
pregnant women or for those expected to be pregnant in the next 1 month.
However, termination of pregnancy should not be recommended in case of
inadvertent vaccination during pregnancy. Varicella vaccination pre-pregnancy (at least 1 month prior conception)
or post-partum can be considered for women who are found to be seronegative for
VZV IgG before pregnancy or in the post-partum period.
