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RUBELLA

Main statements

Before vaccine implementation most of the rubella cases were seen among 6-9 years old children, nowadays considerable number of rubella cases is diagnosed in adolescents and adults.

25-50% of patients with rubella have subclinical forms. The virus is excreted during 11-14 days (the rash is present during 1-3 days), children with inborn

rubella excrete the virus till 1-3 years Typical rash is roseolar and small macular papular. Rash elements do not merge, disappear

without pigmentation or desquamation. Enlarged lymph nodes can be seen 5-10 days before rash onset and within 1-2 weeks after it. Encephalitis is very rare but sever; mortality reaches 35% Frequency of fetal damage reaches 80-90% if infection develops in the first trimester of

pregnancy, 25-35% in the second trimester and 8-10% in the third trimester Fetal infection leads to damage of heart, eyes, brain, hearing organs, bones, other organs, as well

as pneumonia, anemia, hepatitis Specific rubella prophylaxis is done by live rubella vaccine at the age of 12 months with

consequent revaccination at 6 years There is no etiotropic treatment for rubella

Rubella is an acute viral infection characterized by short prodromal period,

exanthema during three days and lymphadenopathy. This disease can develop as acquired

or inborn with different mechanisms of transmission and different outcomes.

Etiology. Causative agent of rubella belongs to Togoviridae family and is the only

member of Rubivirus genus. This is RNA-containing virus which only has one antigenic

type. Virion particles have spherical form 65-70 nm in diameter. Nucleocapsid is

surrounded by lipid membrane which has tree structural glycoproteins Е1, Е2 and С on its

surface. Rubella virus is unstable in environment, at room temperature it is inactivated

within several hours, at 560С within one hour, at 1000С within several minutes. It is

rapidly inactivated by ultraviolet light, in acid or alkaline medium (pH<6.8 or > 8.1), but it

is well preserved at freezing. The virus is easily inactivated by action of ether, chloroform

or formalin.

Epidemiology. Rubella is exclusively anthroponotic infection. The sources of

infection are patients with acquired, inborn infections or viral carriers. The virus is

transmitted by airborne way. The viral shedding from oropharynx begins 7-10 days before

rash appearance (or 3-8th day from contact) and continues during the following 11-14 days.

The most extensive shedding of the virus from sick person takes place during the first 5

days after rash appearance. The most dangerous epidemically are people with subclinical

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rubella forms, who are seen several times more often than people with clinically apparent

forms.

Children with inborn rubella (IR) continue to excrete the virus from respiratory tract

and urine during the first year of life, and at dysgammaglobulinemias and other

immunodeficiencies till tree years of life. The long period of viral excretion makes rubella

very contagious disease. The child with inborn rubella is a dangerous source of infection.

There are cases of rubella described among medical staff providing care to children with

inborn rubella and rubella outbreaks in surgical and other departments where children with

inborn defects are treated. It is considered that contagiosity of children with inborn rubella

and intensity of viral excretion are more prominent than at acquired rubella. The danger is

even more prominent, as many cases of inborn rubella are not diagnosed, and these

children present hidden reservoir of infection.

Transmission route at acquired rubella is airborne. Rubella is easily transmitted at

close and prolonged contact. Virus presence in urine and stool of patients with rubella

does not exclude contact route of transmission. Presence of viremia justifies intrauterine

transmission from mother to fetus. Through third people rubella is not transmitted.

Immunity after episode of rubella is stable, long-term.

Pathogenesis. At acquired rubella the entrance route for virus is oropharyngeal

mucosa. Primary replication of the virus most probably occurs in epithelial cells of cheek

mucosa. Then infection of oropharynx and upper respiratory tract lymphoid tissue occurs;

later the virus spreads hematogenically and infects organs and systems. 7-9 days before

rash appearance the virus can be found in nasopharyngeal mucus and blood,

simultaneously with rash appearance in urine, cerebral spinal fluid and breast milk. In a

week after rash onset viremia is over; it coincides with appearance of neutralizing IgM and

IgG antibodies in blood. IgG antibodies are detected life-long in human body.

At inborn rubella the virus penetrates the fetus with maternal blood. Frequency of

pregnant woman infection after contact with rubella depends on presence of immunity to

this infection. Half of infected pregnant women have subclinical form of the disease. Most

of pathological changes which develop at inborn rubella are the results of virus-induced

necrotizing vasculitis. The virus infects epithelium of chorionic villi and endothelium of

placental blood vessels; from there the virus is transmitted into fetal blood flow in emboli.

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Development of pathological process resembles chronic infection. Frequency of

embryonic infection reaches 80-90% if pregnant woman develops disease in first trimester,

25-35% in second trimester and 8-10% in third trimester of pregnancy. If rubella infection

develops after 20 weeks of gestation, risk of birth defects is considerably lower; but

infection during this term can lead to development of chronic disease of nervous system

and sensory organs.

After birth the virus persists in the body. This creates conditions for development of

immunopathologic processes which are resulting into development of deafness,

retinopathy, diabetes and encephalitis in a child with inborn rubella.

Clinical manifestations. Acquired rubella. The main mechanism of infection

transmission at acquired rubella is airborne. Through third people rubella is not

transmitted.

Incubational period of acquired rubella is 11-21 days, more often 18 ± 3 days. In 2/3

of children rubella has subclinical course. Other children after completion of incubational

period develop short prodromal period, from several hours till 1-2 days. It includes

enlargement of occipital, post auricular and posterior cervical lymph nodes, which become

indurated and tender at palpation. Their enlargement can be so prominent that can be seen

visually. Besides lymphadenitis, at prodromal period there is also fever till 37.5-380С,

mild catarrhal changes of mucosa, roseolar enanthema on hard palate.

Prodromal period is more often seen in children of older age. Rubella has more

sever course in this age. Skin rash appears simultaneously all over the body, rash character

is roseolar and small macular papular in typical cases. Rash elements are confluent. The

rash is most concentrated on extensor surfaces of extremities, back, buttocks, outer surface

of thighs. On the second day or at the end of the first day the rash elements become much

less in number, they become small macular and look like rash at scarlet fever. The rash

disappears rapidly, during 1-3 days, without pigmentation or desquamation.

Polyadenitis is a permanent sign of rubella. It is characterized by moderate

enlargement of posterior cervical and occipital lymph nodes, more seldom of other groups

as well. Lymphatic nodes are elastic to palpation, not united to other tissues, mildly tender.

Enlarged lymph nodes can be found 5-10 days before rash appearance and within 1-2

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weeks afterwards. In some cases lymphadenitis can remain for many years after episode of

rubella.

Catarrhal changes of upper respiratory tract and conjunctiva mucosa are not seen

constantly, are mild and continue during 2-3 days.

Adolescents and adults develop more severe course of rubella, which is presented by

more prominent intoxication signs (headache, febrile fever, chills, myalgia) and catarrhal

signs (dry cough, throat tickling, prominent conjunctivitis with lacrimation, photophobia,

running nose). As a rule the rash is more abundant, macular-papular, with tendency for

confluence.

In this age, more often in girls, arthralgias and arthritis are seen which further are

transformed into chronic. Clinically they present with pain, redness, joint swelling.

Metacarpophalangeal joints of hands are more often affected, then knee joints and elbow

joints. Symptoms of joint damage appear, as a rule, a week after rash onset; they disappear

within one week afterwards. School age boys can develop testalgias. Thrombocytopenia

develops in rare cases, which can become chronic in 56% of cases.

The most serious complication of rubella is encephalitis which has autoimmune

character. More often encephalitis develops in school age children and adults. Rubella

encephalitis is seen in 1 per 5-10 thousand cases of rubella. It most often evolves at the

end of exanthema period but can develop several days before rash onset.

Prognosis of central nervous system damage in rubella is serious, in 20-35% of

cases lethal outcome occurs, and in 30% of children after the disease residual signs of

nervous system damage are seen.

Changes of complete blood count during rash period at rubella include leucopenia,

lymphocytosis and increased number of plasmatic cells (Turk cells) till 10-15%.

Inborn rubella. Early clinical presentations of the disease can be divided into

transitory and irreversible. Transitory, early clinical presentations of the disease are caused

by acute non-specific immune response to inborn viral infection. They include generalized

lymphadenopathy, hepatosplenomegaly, intrauterine fetal developmental delay, hepatitis,

jaundice, hemolytic anemia, pneumonia, meningoencephalitis, decreased bone density,

diarrhea. Thrombocytopenic purpura, petechial rash, crimson rash (”Blueberry muffin”),

which are areas of dermal erythropoesis, more often appear at rubella than at other inborn

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infections. However, these changes disappear during the first weeks of life, are quite well

treated and usually do not present negative long-term consequences.

In published book of N.Gregg in 1942 y. the typical inborn rubella birth defects are

described, such as cataract, microphthalmia, retinopathy, corneal caligo, heart defects and

low birth weight. Later deafness was also described. N.Gregg first described the classical

triad of inborn rubella: cataract, hart defects and deafness.

In the last 30 years classical triad of Gregg is seldom seen in children with inborn

rubella. Besides pointed out syndromes, newborns also have microcephalus, glaucoma,

cleft palate, interstitial pneumonia, hepatitis, myocarditis, meningoencephalitis, vestibular

apparatus defects, urinary tract defects, dermatitis, thrombocytopenia, hemolytic anemia,

hypogammaglobulinemia, dysembryogenic stigma (brachycephaly, auricle deformities,

hip dysplasia, syndactyly, clubfoot, etc.). Irreversible changes are caused due to heart,

eyes, brain and hearing organs damage.

Among heart defects the most commonly (78%) diagnosed is patent ductus

arteriosus. Aortic valve insufficiency, aortic stenosis, aortic coarctation, ventricular septal

defect and pulmonary stenosis are also diagnosed. At rubella atrial septal defect, aorta and

pulmonary transposition can also be seen. Heart defects of “blue” type almost never

develop at rubella.

Cataract is the result of direct cytopathic action of rubella virus, which can persist in

eye lens during several years. Cataract can be unilateral or bilateral and is often combined

(in 60%) with microphthalmia. This anomaly can be absent at birth and can develop later

in newborn period.

Glaucoma is diagnosed much more seldom than cataract, in ratio 1:10, and can

progress during newborn period. Glaucoma is almost never combined with cataract.

Among eye defects retinopathy is often revealed, which is characterized by retinal areas of

dark pigmentations and depigmentations. Eye changes can develop several years after

birth.

The most common birth defect at inborn rubella is deafness. It can be mild or

severe, unilateral or bilateral. Mild forms are often diagnosed several years after birth.

Deafness is often accompanied by vestibular dysfunction, the degree of which correlates

with degree of deafness.

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Nervous system damage at inborn rubella presents with decreased alertness,

sleepiness, irritability, seizures, decreased muscle tone, paralyses; in early postnatal period

acute or chronic encephalitis can occur. Later motor disorder of different severity,

hyperkinesias and seizures can be seen. Neurological symptoms also include intellectual

developmental delay.

Thrombocytopenic purpura develops right after birth and is most prominent on the

first week after birth. Hemorrhagic rash on the skin can be present during 2-3 months.

Typical presentations of inborn rubella also include damage of long bones

(osteoporosis). This pathology is typical for rubella and is diagnosed at X-ray examination.

It is characterized by alternations of areas of bone tissue rarefaction and consolidation.

Unlike similar changes at syphilis, bone changes at rubella disappear 1-2 months later.

Most of neonatal lesions also disappear within months.

Birth defects seen rarer at rubella include urinary tract defects (cryptorchism,

hypospadias, hydrocele, uterus bicornis, bilobal kidneys), gastrointestinal tract defects

(pylorostenosis, biliary duct atresia), different skin defects (dermatitis, pigment maculae),

brain calcifications.

Children with inborn rubella often have low body weight, lesser body length and

considerable delay in physical development. During first 4 years of life about 16% of these

children die. The death is most often due to heart defects, sepsis, defects of inner organs,

intercurrent viral and bacterial infections.

Prolonged period of follow up of children born to mothers with episodes of rubella

during pregnancy showed that, if these children did not have any presentations during

newborn period, they developed decreased intellectual abilities and changes of behavior on

the 3-7th year of life and they could not study at regular schools. These children also are at

risk of development of deafness, retinopathy, glaucoma, thyroiditis, diabetes mellitus

(which has 4 times higher frequency than in healthy children), arterial hypertension,

disease similar to schizophrenia. The fact of interest is that brain changes similar to those

at inborn rubella are seen in brains of patients with schizophrenia.

Diagnosis. Clinical criteria of acquired rubella:

- acute onset of the disease;

- fever till 37.5-380С;

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- transitory mild catarrhal changes of respiratory mucosa and conjunctive;

- sometimes roseolar rash on hard palate;

- enlargement and tenderness of posterior cervical and occipital lymph nodes;

- prodromal period can continue for several hours;

- rash appears on the first day of the disease;

- rash is roseolar or small macular-papular;

- rash elements do not merge;

- rash appears simultaneously all over the body;

- predominate localization of rash is on extensor surfaces of extremities, back,

buttocks, outer surface of thighs;

- rash disappears during 1-3 days, without pigmentations or desquamations;

- girls of pubertal age can develop arthritis and arthralgia;

- boys of school age can present with testalgias;

- rare presentation is thrombocytopenia.

Clinical criteria of inborn rubella:

Suspected case of inborn rubella in infant is probable history of maternal rubella

during pregnancy or the child with birth heart defects and/or cataract, decreased vision

fields, nystagmus, strabismus, microphthalmia, inborn glaucoma, suspected decreased

hearing.

Clinical case of inborn rubella is the case when the child has 2 pathologies from the

list (а) or one pathologies from the list (а) and on pathologies from the list (b):

а) cataract;

glaucoma;

inborn heart defects;

decreased hearing;

pigment retinopathy;

б) purpura;

splenomegaly;

microcephaly;

delay in psycho-motor development;

meningoencephalitis;

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osteoporosis (X-ray confirmed);

jaundice during the first 24 hours after birth.

Paraclinical investigations

Acquired rubella:

1. Complete blood count (leucopenia, neutrophilia, lymphocytosis, plasmatic cells,

normal ESR);

2. Serological methods (reaction of neutralization, reaction of inhibition of

hemagglutination, reaction of complement fixation, immunoenzyme analysis): antibody

titer increase 4 times and higher in dynamics;

3. Immunoenzyme analysis: determination of specific antibodies of IgM class in

acute period (1-2 weeks before rash appearance and till 3 weeks after its disappearance)

and IgG titer increase in dynamics.

4. Viral antigen visualization by immune fluorescent methods

5. Polymerase chain reaction (blood, if necessary cerebral spinal fluid): rubella RNA

identification.

Inborn rubella:

1. Immunoenzyme analysis: detection of specific antibodies of IgM class in blood.

The case of positive specific rubella IgM antibodies in a child without clinical presentation

is considered to be inborn rubella infection.

2. Presence of high titers of specific IgG in blood during long period without their

decrease.

3. Viral RNA identification (blood, urine, saliva, stool, cerebrospinal fluid) by PCR

method.

4. Children, born to mothers with episode of rubella or with contact with rubella

during pregnancy, should be followed till at least 7 years with obligatory regular

examination by pediatrician, ophthalmologist, ENT and neurologist.

Treatment. Currently there are no specific methods of treatment of both inborn and

acquired rubella.

Treatment of uncomplicated acquired rubella is done at home conditions:

1. Bed rest during acute period;

2. Hygienic measures;

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3. Frequent ventilation of the living rooms;

4. Symptomatic treatment: antipyretics at fever (paracetamol, ibuprofen), etc.

At development of complications the children are hospitalized into infectious

hospitals.

Management of children with inborn rubella depends on character of main clinical

syndromes. Children with suspicion for inborn rubella or with clinical case of inborn

rubella must be hospitalized into specially organized medical settings. These settings

(separated wards) must be first of all created on the basis of profile hospitals which

provide medical help to children with inborn defects (cardiovascular surgery,

ophthalmology, neurology, neonatal intensive care unit).

Prophylaxis. Specific rubella prophylaxis is performed by live rubella vaccine in

age 12 months with further revaccination at 6 years. The vaccination can be done by

monovaccine or combined vaccine which includes vaccines against rubella, measles,

mumps and varicella. Immunity is formed in 95% of vaccinated children.

According to WHO recommendations, children with suspected inborn rubella or

clinical case of inborn rubella must be hospitalized into specially organized in every

region medical settings where these children will be followed by qualified pediatricians

with experience of treatment of these children. These settings must be first of all created

on the basis of profile hospitals which provide medical help to children with inborn defects

(cardiovascular surgery, ophthalmology, neurology, neonatal intensive care unit, etc.).

Questions for self-control:

1. Which group of viruses does rubella virus belongs to.2. Epidemiological particularities of rubella virus.3. Particularities of rubella pathogenesis.4. Periods of rubella clinical course.5. Characteristics of clinical forms of rubella. Concept of inborn rubella. Gregg’s triad.6. Course and consequences of rubella.7. Laboratory diagnosis, current methods and interpretation of results.8. Prophylactic activities in rubella nidus.9. Main approaches to rubella treatment.10. Vaccination against rubella according to vaccination schedule.

Tests for self-control

1. Which family does the rubella virus belong to?A. Togavirus B. HerpesC. Enterovirus

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D. ParamyxovirusE. Hepadnavirus 2. Choose the entrance route for rubella virus:A. Upper respiratory tract mucosa B. Skin C. Gastrointestinal tract D. Eyes mucosa E. All the answers are correct 3. Choose the most typical way of rubella transmission:A. Fecal-oralB. Airborne C. Contact D. Parentheral E. Vertical 4. Name the defect which is not included into triad of inborn rubella:A. Heart defects B. Cataract C. DeafnessD. Anemia E. Thrombocytopenia5. The following mechanism does not play a role in inborn rubella pathogenesis:A. Presence of rubella virus in maternal respiratory tract B. Hematogenic and lymphogenic spread of the virus into fetal tissues C. Rubella virus tropism to embryonic tissues D. Dependence of fetal damage frequency from terms of pregnancy E. All the answers are correct6. Rash character at rubella:A. Small macular B. Abundant rash on back, buttocks, extensor surfaces of extremities C. Absence of rash on palms and solesD. Rash is not predisposed to mergingE. All the answers are correct 7. Which symptoms are not typical for rubella:A. FeverB. Small macular rash C. Enlargement of posterior cervical and occipital lymph nodes D. Rash is mostly large macular and papular E. Conjunctivitis 8. Name the methods which are not use for laboratory diagnosis of rubella:A. Virusological B. Bacteriological C. Serological D. PCRE. Antibody level by paired serum 9. Terms of isolation of patient with rubella:A. For 5 days from rash onset B. For 10 days from rash onsetC. For 2 weeks from disease onset D. For 3 days from rash onsetE. All the answers are correct10. Name the immunity which is formed after episode of rubella:A. Long-lived B. Short-lived C. Type specific

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D. Serospecific E. Antitoxic

Test answers

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