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VARICELLA

Main statements

The causative agent is DNA-containing Varicella-Zoster virus (VZV), from Herpesviridae family.

The source of infection is a person with varicella or herpes zoster. Within 24-48 hours before rash onset there are catarrhal changes in

oropharynx and vesicles on the soft palate. Reinfections of the disease are seen in 2-4%. The rash elements are macula-papule-vesicle-crust; polymorphism is

typical, the rash is often accompanied by hyperthermia. If mother develops the disease 5 days before or 5 days after delivery,

infection in the newborn results in very severe forms of the disease, with 30% mortality rate.

Encephalitis develops most often on the 5-10th day of the disease. Etiotropic agent is acyclovir. Vaccination of healthy children in Ukraine is not obligatory, but

recommended; the vaccine is registered.

Varicella (chicken pox) is an acute infectious disease with airborne route of

transmission, which is caused by virus from the family Herpesviridae. It is characterized

by presence of macula – papule – vesicular rash.

Etiology. The causative agent of the infection is Varicella-Zoster virus (VZV),

which belongs to Herpesviridae family, subfamily α, 3rd type virus, genus Varicellavirus.

The size of the elementary virion particles is within 150 – 200 nm. The virus is DNA-

containing. The virus is susceptible to environmental factors and can only replicate in

human cells. Beyond human body, in saliva droplets and on clothes the virus can survive

during 10-15 minutes. Direct sunlight and heating kill the virus within several minutes.

The varicella virus has tropism to skin and mucus epithelium and, to a lesser degree, to

nervous system cells.

Epidemiology. The varicella virus under natural conditions does not cause any

similar to chicken pox disease in any other animals, except human.

The source of infection in varicella can only be the person suffering from varicella

or zoster. The entrance route of the causative agent is upper respiratory tract mucus. Viral

localization on the mucosa should be considered the main mechanism of viral spreading.

Transmission of the virus through third person is considered impossible. Intrauterine

acquisition of varicella is possible in case of chicken pox in a pregnant woman.

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Varicella is a typical airborne infection. All the particularities of airborne

transmission are typical for mechanism of varicella transmission. After removal of the

infection source from the room, without any specific measures, the air in the room quickly

clears from the causative agent, as the virus is unstable in the environment.

It is considered that life-long immunity develops after an episode of varicella.

However, according to modern epidemiological studies, repeated cases of varicella are

diagnosed in 2-4% of patients.

Susceptibility to varicella in children without history of this disease is very high.

Contagiousness index is 95-98%.

Similar to other infections with airborne way of transmission, the highest incidence

of varicella is observed in cold seasons of the year. Maximal amount of cases is seen in

February, with minimal in August.

Varicella can be diagnosed at any age, but nowadays most of the cases develop in

children 2 to 7 years of age.

Pathogenesis. The site of entry for varicella virus is upper respiratory tract mucosa.

At the beginning of incubational period the virus replicates in regional lymph nodes and is

spreading with blood flow to liver, spleen and other organs of reticulo-endothelial system.

At the end of incubational period secondary viremia develops. The virus spreads to

epithelial cells of the skin and mucosa and causes the development of vesicles with serous

contain, which are multicameral at first, but later become unicameral.

The development of varicella vesicle begins with protoplasmic edema of spiny layer

of skin epithelium. With fluid collection the cell protoplasm is only preserved as septa,

forming a distinctive radial reticulum (stage of reticular dystrophy). Further accumulation

of the fluid leads to membrane and nucleus edema, until complete dilution of the nucleus.

The cell body becomes round, loses its thorns and connection with other cells, transforms

into a vesicle – balloon (stage of balloon dystrophy). At the early stages of the process

round eosinophilic inclusions, described by Tizer, are formed in nuclei of damaged cells.

Clinical manifestations. Incubational period at varicella is 11-21 days, after

immunoglobulin injection it is prolonged till 28 days. Maximal frequency of disease onset

is on the 15th day after contact. Rash at varicella often appears at once, without prodromal

phase. In rare cases subfebrile fever, malaise, restlessness, appetite decrease, sometimes

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vomiting and diarrhea can be seen 1-5 days before rash appearance. Sometimes prodromal

symptoms also include seizures and scarlet fever-like exanthema, so called “rash-

exanthema”.

Appearance of rash at varicella coincides with fever or can be several hours later.

Rash initially presents with maculae, often quite small, like points. They rapidly increase

in size, the central part elevates over the skin, and papules appear. Later vesicles appear in

the center of the elements. The newly appeared vesicles look like dewdrops. They are

quite large, round, with transparent contain and thin glossy covers. Redness around it can

be absent. The vesicles are situated on the infiltrated basis. Later the vesicles become

irregular in shape, their borders become scalloped. It can be clearly seen when the vesicles

start to dry and become flatter. The content of the vesicles becomes cloddy. Vesicles are

fragile, soft to palpation, can be easily disrupted. At piercing the vesicles empty very

quickly due to their one-chamber structure. Vesicles dry out in 1-2 days. Drying begins

from the center, the central parts sink down, get darker, and gradually the vesicles are

transformed into thick, brown crusts.

First elements of rash can appear on any part of the body, but in most of the cases

they appear first on trunk and scalp. At the beginning only one element can appear. After

maturation of some elements of rash new ones appear. At typical cases, single scattered

rash elements are followed by abundant rash. The latter is usually accompanied by fever

and itching. Abundant rash is usually dense, evenly distributed, it covers scalp and trunk.

The rash is usually less prominent on the face and distal parts of extremities. The

appearance of rash is not simultaneous, but in crops every 1-2 days. The first elements, as

it was pointed out before, in most of the cases develop through the stages of macula-

papule, and are transformed into vesicles very quickly. The development of further

elements takes place slower, the size of the elements is smaller, and they do not always

develop into vesicles. The new rash at varicella usually appears during 2-4 days. In some

cases the new rash can appear till 7-9th day, and sometimes till the 14th day of the disease.

Such stepwise appearance causes polymorphic character of varicella rash. There can be

maculae, papules, vesicles and crusts on the same part of the body skin. Such

polymorphism is called “false”, as the apparently different rash elements are in reality just

different stages of the same process.

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Term of crusts rejection depends largely on the skin care. With meticulous care the

crusts are rejected much quicker. The most often the crusts are rejected between the 12 th

and 22nd days of the disease. The size of the crust is the same as the size of the preceding

vesicle. During drying out of the vesicle the surrounding redness disappears, and the crust

becomes surrounded by normal skin. Its rejection takes place from borders. After rejection

of the crusts there can remain small, round discolorated spots with pigmented borders.

Sometimes the crusts are rejected with scars formation; most commonly they are situated

on the face. Appearance of scars after acne rash can cause itching and joining of secondary

bacterial complications.

Besides skin, varicella typically is also characterized by the rash on oral mucosa,

nasal mucosa, more seldom on mucosa, conjunctive and genitals. Enanthema is usually

accompanied by fever and exanthema.

Rare localizations of varicella enanthema include rash on laryngeal mucosa. This

rash often precedes the appearance of elements on the skin and causes hoarse voice, rough

barking cough. Sometimes laryngeal stenosis can develop.

Inborn varicella

Varicella during pregnancy can cause congenital varicella syndrome of the fetus,

which can present with isolated or multiple defects: extremities hypoplasia, microcephaly,

eyes defects (microphthalmia, cataract, chorioretinitis), CNS defects with disorders of

motor and sensory functions, paralysis, dysphagia, intrauterine growth retardation, skin

scars. Risk of these defects is 0.5% if varicella develops at 2-12 weeks of pregnancy and

up till 1.4% with varicella at 2-12 weeks of pregnancy; embryopathies are caused by

cytopathic action of the virus and incomplete organogenesis. At antenatal ultrasound

investigation the signs of fetus infection can be venriculomegaly, microcephaly, anomalies

of extremities, intrauterine development delay, dysmorphism, calcifications in inner

organs, especially in liver.

Varicella at 24-28 weeks of pregnancy does not present any danger for both mother

and infant, because passive transport of maternal antibody through placenta is enough for

the fetus protection.

If mother develops varicella within 5 days before or 5 days after delivery, the

newborn develops severe form of varicella. Due to the lack of time for specific antibody

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production and their transport through placenta there is massive dissemination of the virus.

The symptoms appear 5-10 days after birth, newborns become severely ill and the

mortality is 30%. Newborns develop fever, respiratory distress, often there is pneumonia,

hepatitis. There is vesicular or hemorrhagic rash on the skin. Respiratory distress appears

on the 2-3rd day after first rash elements, and prognosis depends on the severity of

respiratory distress. The term between skin and respiratory symptoms is the same as the

term between rash and pneumonia in adults. Death is caused by severe lung damage and

disseminated intravascular coagulation syndrome (DIC).

If fetal infection occurs 5-21 days before delivery, the newborn will develop mild

form, with scarce vesicles. Similar clinical picture is seen if the newborn gets infected

within 7-29 days of age. Development and localization of rash is the same as in other age

groups. First elements can appear on trunk, then disseminating to other parts of the body.

Newborns present with more prominent polymorphism of the rash, with simultaneous

presence of maculae, vesicles, pustules and crusts on the skin.

Episode of varicella during pregnancy can cause development of shingles in the

child within first months of life. This reflects transplacental inoculation of the virus and its

penetration into nervous ganglia of the fetus with viral reactivation during first months of

life.

Shingles in a pregnant woman very seldom causes infection in the fetus.

Varicella in patients with oncohaematological diseases and immunodeficiency.

In 30-50% children with lymphoproliferative malignant diseases and solid tumors

without active antiviral therapy disseminated visceral form of varicella develops with

mortality more than 20%. The course of the disease is characterized by development of

pneumonia, hepatitis, encephalitis, severe coagulopathy, pancreatitis, esophagitis, necrotic

splenitis and enterocolitis. The disease is accompanied by severe abdominal and low back

pains.

The risk of visceral form of varicella is high when chemotherapy is performed in

incubational period and within first 5 days of the beginning of the disease. These children

are also highly susceptible to secondary bacterial infections complicating the course of

varicella. The children at high risk of generalized varicella are also organ transplantation

recipients, bone marrow recipients, children with T-cell immunodeficiency and with HIV

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infection. Main clinical presentations of varicella in these children are hepatitis and

thrombocytopenia.

There are cases of unusual clinical presentation of varicella in such children, which

are described in the literature and which present with hyperkeratosis and inner organ

involvement which lasts within several weeks and months after contact with varicella

patients.

Complications. Frequency of varicella complications is 5%, and up till 30-50% in

patients with compromised immunity. Varicella complications can develop due to damage

of vesicles entity, which will open the route for bacterial infections. Secondary infection

can result into abscesses, phlegmons, erysipelas, bullous streptococcal impetigo,

stomatitis, lymphadenitis. Most commonly they are caused by S. aureus and Str. pyogenes.

Purulent complications most commonly develop in weakened early age children, during

recovery from acute infectious diseases. Sometimes hematogenic dissemination of bacteria

leads to sepsis, pneumonia, arthritis, osteomyelitis, nephritis.

Nervous system complications at varicella most often develop on the 5-10 th days of

the disease. Sometimes it can happen on the 18-21st days. They are seen more often in

boys, at the age of 1-5 years. The frequency of these complications is 1 per 4000 cases of

varicella. 90% of all nervous system complications at varicella present with encephalitis.

This complication develops in 0.1-0.2% of all the patients with varicella. 13% of

encephalitis with determined etiology are due to varicella.

75% of encephalitis at varicella involve cerebellum and present with cerebellar

ataxia. Clinical signs and symptoms develop within 3-5 days and continue in general 2-4

weeks. 25% of varicella encephalitis also involve other brain structures into inflammatory

process (brain hemispheres, brain steam, basal ganglia, etc.). Symptoms of complication

usually develop on the 5-7th day after appearance of rash. Mortality from these

complications can reach 35%. Residuals such as paralysis, oligophrenia, repeated seizures

can take place in 12-15% of the patents.

Besides cerebellar ataxia and encephalitis, the following complications are also

possible at varicella: myelitis, encephalomyelitis, opticomyelitis, polyneuropathy, optic

nerve neuritis, serous meningitis.

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Special place among varicella complications belongs to demyelinization diseases of

nervous system, mediated by T-cell immune reaction to main protein, myelin. This

reaction is similar to allergic encephalomyelitis.

Varicella can be complicated by Reye’s syndrome, which has mortality 50-80% at

late diagnosis and treatment. Risk factor for Reye’s syndrome is usage of acetylsalicylic

acid and other drugs during varicella.

49% of patients with varicella show mild ALT elevation in blood serum due to virus

replication in liver.

Relatively common complication of varicella is acute thrombocytopenia with skin

petechiae, hemorrhages into vesicles, nasal hemorrhages, hematuria and gastrointestinal

hemorrhages. Clinical presentation of this complication is short-term, but level of blood

platelets can remain decreased within several weeks.

Kidney involvement at varicella develops seldom. Nephritis with hematuria, edema,

hypertension can develop during the first 3 weeks after rash. Interstitial pneumonia at

varicella is also possible, but it is more common in adults.

Ibuprofen can cause development of necrotic fasciitis at varicella; this anti-

inflammatory drug is not recommended at this infection.

Diagnosis. Diagnosis is based on typical clinical symptoms. In case of difficult

clinical diagnosis, the following laboratory methods are used: CBC shows leucopenia,

relative lymphocytosis and normal ERS since 48-72 hours from rash appearance.

Serological investigation shows 4-fold increase in antibody titers within 10-14 days. This

investigation is performed with the methods of reaction of complement fixation, reaction

of indirect hemagglutination, immunoenzyme analysis and radioimmune assay.

Specific IgG antibodies appear in blood serum since third day of the rash, and their

titer rapidly increases during recovery. Due to high frequency of false positive results, IgM

titers should not be measured in clinical practice.

Management. Etiotropic therapy of varicella is acyclovir. Indications for acyclovir

prescription at varicella are the following:

- patients with oncohaematological diseases;

- organ and marrow recipients;

- patients on corticosteroids;

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- children with inborn T-cell immunodeficiencies;

- children with HIV infection;

- inborn varicella;

- varicella with nervous system complications, hepatitis, thrombocytopenia,

pneumonia;

- severe forms of varicella.

Acyclovir is recommended to patients with varicella who have chronic diseases of

skin and lungs and those who receive salicylates, short-term corticosteroids, including

inhalatory forms.

Antiviral therapy is prescribed from the first day of the disease. Children with

immune deficiencies and with nervous system complications receive acyclovir

intravenously. Acyclovir dosage is 10 mg/kg or 500 mg/m2, three times a day. The course

of etiotropic therapy lasts 7 days or 48 hours after appearance of last rash elements.

Immunocompetent children with severe forms of varicella and immunocompromised

children with mild to moderate forms of the infection are given acyclovir orally. Acyclovir

dose for children under 2 years of age is 200 mg, from 2 to 6 years it is 400 mg and older

than 6 years it is 800 mg. This dosage is taken 4 times a day. Besides acyclovir, other

antiviral drugs as valaciclovir, famciclovir, ganciclovir are also effective at varicella.

For varicella treatment in newborns the dosage of acyclovir is 10-20 mg/day,

divided for three times per day; the course is 7 days. At severe forms of the disease high

doses are prescribed.

At severe, generalized forms of varicella, especially in newborns and children of the

first year of life, intravenous polyvalent immunoglobulin 0.4 g/kg/day, for 3-5 days, is

used, or specific varicella-zoster immunoglobulin in dose of 0.2 ml/kg.

At mild and moderate forms of varicella in immunocompetent patients the aim of

therapy is prophylaxis of secondary bacterial infections. It includes prevention of vesicles

rupture, clean linen and clothes of the patient, rash treatment with aniline dye solutions,

1% solution of potassium permanganate. In early age children aniline dyes should be used

carefully due to possible toxic effects.

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With the aim of prophylaxis of secondary bacterial infections in the mouth, after

meals it is recommended to rinse the mouth with 5% solution of boric acid, weak solutions

of potassium permanganate, furacilin or plain water.

Prophylaxis. Patient with varicella must be isolated for 5 days from appearance of

last rash elements. Isolation of contact children in groups is since the 11 th till the 21st day

from the contact. After immunoglobulin injection the term of isolation of contact children

increases till 28 days.

Passive immune prophylaxis of varicella is possible with high titer immunoglobulin

against varicella-zoster virus. Immunoglobulin is injected intramuscularly not later than

48-96 hours after contact, first of all to: children with immune deficiency, pregnant

women, children born to mothers who developed varicella within 5-10 days before

delivery and 2 day after, premature babies born before 28 weeks of pregnancy and with

body weight less than 1000g. Prophylaxis of varicella with regular immunoglobulin

without determination of specific antibody titer is considered to be ineffective.

Currently live vaccine against varicella is developed and used in 80 countries of the

world. Introduction of varicella vaccine in some countries considerable influenced the

varicella morbidity there.

European office of WHO recommends obligatory vaccination to selected patients

with leukemia in remission and those waiting for organ transplantation without previous

history of varicella.

National vaccination schedule of Ukraine includes varicella vaccination as

recommended to healthy children after 12 months of age, children before entering primary

school and health care workers with high risk of infection and without previous history of

varicella. This vaccine is obligatory for children with HIV infection.

Activities for varicella prophylaxis in pregnant women are very important,

considering high prevalence of the disease and periodic outbreaks in different regions.

Pregnant women without previous history of varicella or who lack this information should

be tested for VZV immunity: antibody level with immunoenzyme analysis. However, as a

rule, 85-90% of people who did not have any episode of varicella in the past still have

immunity to VZV. Pregnant women without immunity should be given VZV

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immunoglobulin in case of contact. Immunoglobulin prophylaxis is most effective if

administered within 96 hours after contact with the virus.

Newborns from mothers who developed varicella within 5 days before or 2 days

after delivery should immediately be injected with 125 IU of VZV immunoglobulin and

should be started with acyclovir in dosage 10 mg/kg/day. Immunoglobulin administration

does not decrease frequency of varicella in newborns but provides much milder form of

the disease in comparison to children without immunoglobulin prophylaxis.

If mother is diagnosed with varicella just before or during delivery, the newborn

should be isolated from other children till transformation of all the vesicles into crusts in

mother. The child should stay with the mother in maternity house. There is no single

opinion regarding breastfeeding if mother has varicella. It is considered that due to high

risk of viral transmission through milk, the first 5 days of rash breastfeeding should be

abstained from. Other clinicians have the opinion that breastfeeding should be interrupted

only in case of vesicles on the breasts, especially around nipples.

Questions for self-control

1. Etiology of varicella, characteristics of the causative agent.2. Epidemiological particularities of varicella, source of infection.3. Pathogenesis of varicella.4. Clinical presentation of typical form of varicella.5. Inborn varicella.6. Particularities of varicella in newborns and infants.7. Laboratory diagnosis of varicella.8. Nervous system involvement at varicella.9. Main approaches to varicella treatment (main antiherpetic drugs: drug characteristics, dosage).10. Prophylactic activities in varicella nidus.

Tests for self-control1. Causative agent of varicella is the following:A. Herpes simplex virus B. ParamyxovirusC. Varicella-Zoster virusD. Cytomegalovirus E. Epstein-Barr virus2. Minimal incubation period at varicella is:A. 3 days B. 5 daysC. 9 daysD. 11 daysE. 21 days 3. Particularities of rash at varicella:A. Appears on the 3-4th day of the diseases beginning

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B. “False” polymorphism is typicalC. Step-wise appearance D. It is not accompanied by itching E. It is seen in approximately 50% of patients4. What pattern of fever is typical for varicella?A. PermanentB. Remitting C. Wave-like D. Two-wavedE. New elements are accompanied by fever episodes. 5. Choose the most severe complication of varicella:A. Pneumonia B. CroupC. OtitisD. Encephalitis E. Phlegmona6. In newborns and infants with varicella the rash appears:A. On the first dayB. On the 2-5th dayC. On the 6-7th day D. On the 3-4th dayE. Rash can be absent7. Terms of isolation of patients with varicella?A. After 2 negative evaluations for Varicella-zoster virusB. Till clinical recoveryC. Since beginning of the disease till the 5th day after last vesicles appearance D. After 1 negative evaluation for Varicella-zoster virus E. Till 5 days after beginning of rash 8. Which part of brain is most often involved at varicella encephalitis:A. Brain hemispheres B. Brain stem C. CerebellumD. Meninges E. Basal ganglia9. Etiotropic antiviral therapy at varicella is not indicated at?A. Severe forms of varicella B. CNS complicationsC. Inborn varicellaD. Patients with HIV infection and AIDS E. Presence of bacterial complications 10. Which therapy is appropriate for treatment of typical mild varicella?A. Symptomatic therapy B. Interferon C. Normal human immunoglobulin D. Acyclovir E. Antibacterial drugs

Test answers

1-C, 2-D, 3-B, 4-E, 5-D, 6-B, 7-C, 8-C, 9-E, 10-A.