Epstein-Barr virus( Epstein-Barr virus infection or EBV infection)

Epstein-Barr virus infection( EBV) is one of the most common human diseases. According to WHO, the Epstein-Barr virus infected about 55-60% of young children( up to 3 years), the vast majority of the adult population of the planet( 90-98%) have antibodies to EBV.The incidence in different countries varies from 3-5 to 45 cases per 100 thousand population and is a rather high indicator. EBVI belongs to the group of uncontrolled infections, in which there is no specific prevention( vaccination), which certainly affects the incidence rate.

Epstein-Barr virus infection is an acute or chronic human infectious disease caused by the Epstein-Barr virus from the family of herpes viruses( Herpesviridae), which has a favorite feature of the defeat of the lymphoreticular and immune systems of the body.

The causative agent of

The Epstein-Barr virus( VEB) is a DNA-containing virus from the Herpesviridae family( gamma-herpesvirus), is herpesvirus type 4.First detected from the cells of Burkett's lymphoma about 35-40 years ago.

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The virus has a spherical shape with a diameter of up to 180 nm. The structure consists of 4 components: core, capsid, inner and outer shell. The core includes a DNA consisting of 2 strands comprising up to 80 genes. The viral particle on the surface also contains dozens of glycoproteins necessary for the formation of virus neutralizing antibodies. The viral particle contains specific antigens( proteins required for diagnosis):
- capsid antigen( VCA);
- early antigen( EA);
- nuclear or nuclear antigen( NA or EBNA);
- membrane antigen( MA).
The significance, the timing of their appearance with different forms of EBVI is not the same and has its own specific meaning.

Virus Epstein-Barr

The Epstein-Barr virus is relatively stable in the external environment, quickly dies when dried, exposed to high temperatures, and also by the action of common disinfected products. In biological tissues and liquids, the Epstein-Barr virus can feel itself favorably when it enters the blood of a patient with EBVI, brain cells of a perfectly healthy person, cells in cancer processes( lymphoma, leukemia and others).

The virus has a certain tropism( predilection to infect the favorite cells):
1) tropism to the cells of the lymphoreticular system ( lesions of lymph nodes of any groups, enlargement of the liver and spleen);
2) tropism to the cells of the immune system ( the virus multiplies in B-lymphocytes, where it can persist for life, which violates their functional state and causes immunodeficiency);In addition to B-lymphocytes, the cell link of immunity( macrophages, NK - natural killers, neutrophils and others) is also disturbed in EBVI, which leads to a decrease in the general resistance of the organism to various viral and bacterial infections;
3) tropism to the epithelial cells of the upper respiratory tract and digestive tract , so that children may experience respiratory syndrome( cough, dyspnea, "false cereal"), diarrhea syndrome( loosening of the stool).

The virus Epstein-Barr has allergic properties of , which is manifested by certain symptoms in patients: 20-25% of patients have an allergic rash, Quincke's edema may develop in some patients.

Special attention is drawn to the property of the Epstein-Barr virus, as " lifelong persistence in the body ".Thanks to the infection of B-lymphocytes, these cells of the immune system acquire the capacity for unlimited life( the so-called "cellular immortality"), as well as the continuous synthesis of heterophilic antibodies( or autoantibodies, for example, antinuclear antibodies, rheumatoid factor, cold agglutinins).In these cells, VEB lives constantly.

There are currently known 1 and 2 strains of the Epstein-Barr virus, which do not differ serologically.

Causes of Epstein-Barr virus infection

The source of infection with is a patient with a clinically severe form and a virus carrier. The patient becomes infectious in the last days of the incubation period, the initial period of the disease, the height of the disease, and the entire period of convalescence( up to 6 months after recovery), and up to 20% of those who have recovered retain the ability to periodically isolate the virus( that is, they remain carriers).

Mechanisms of EBVI infection:
is an aerogenic( airborne transmission pathway) in which saliva and mucus from the oropharynx are contagious, which is released by sneezing, coughing, talking, kissing;
- contact mechanism( contact-household transmission), in which there is a mushrooming of household items( dishes, toys, towels, etc.), but due to the instability of the virus in the external environment has an unlikely value;
- the transfusion mechanism of infection is allowed( with transfusion of infected blood and its preparations);
- alimentary mechanism( water-food transmission pathway);
- the transplacental mechanism of fetal infection has now been proven with the possibility of developing congenital EBVI.

Susceptibility to EBVI: infants( up to 1 year old) have Epstein-Barr virus infection rarely due to the presence of passive maternal immunity( maternal antibodies), most susceptible to infection and the development of a clinically pronounced form of EBVI are children from 2 to 10 years.

Despite the variety of ways of infection, among the population there is a good immune layer( up to 50% of children and 85% of adults): many get infected from carriers without developing symptoms of the disease, but with the development of immunity. That is why it is believed that for the environment of a patient with EBVI, the disease is not contagious, since many already have antibodies to the Epstein-Barr virus.

Rarely in closed institutions( military units, dormitories), nevertheless, there may be outbreaks of EBVI that are of little intensity and also stretched in time.

For EBVI, and in particular its most frequent manifestation - mononucleosis - the spring-autumn seasonality is characteristic.
Immunity after the transferred infection is formed strong, lifelong. It is impossible to get sick again with an acute form of EBVI.Repeated cases of the disease are associated with the development of a relapse or chronic form of the disease and its aggravation.

The pathway of the Epstein-Barr virus in the human body

The entrance gate of the infection is the mucosa of the mouth and nasopharynx where the virus multiplies and organizes non-specific( primary) defense. The outcomes of primary infection affect: general immunity, concomitant diseases, the state of the entrance gate infection( there are or are no chronic diseases of the mouth and nasopharynx), as well as the infectious dose and virulence of the pathogen.

The outcomes of primary infection can be: 1) sanation( destruction of the virus in the entrance gate);2) subclinical( asymptomatic form);3) clinically defined( manifest) form;4) a primarily latent form( in which reproduction of the virus and its isolation are possible, and there are no clinical symptoms).

Further from the entrance gate of the infection, the virus enters the blood( viremia) - the patient may have a temperature and intoxication. At the entrance gate is formed a "primary focus" - catarrhal angina, obstruction of nasal breathing. Further, the virus enters the various tissues and organs with the predominant lesion of the liver, spleen, lymph nodes and others. It is during this period that "atypical tissue mononuclears" appear in the blood on the background of a moderate increase in lymphocytes. The outcomes of the disease can be: recovery, chronic VEB infection, asymptomatic carriage, autoimmune diseases( systemic lupus erythematosus, rheumatoid arthritis, Sjogren's syndrome and others), oncological diseases, with oncological diseases and congenital VEB infection - is possibledeath.

Symptoms of EBV infection

Depending on the climate, certain clinical forms of EBVI predominate. In countries with a temperate climate, including the Russian Federation, infectious mononucleosis is more common, and if there is no deficit of immunity, a subclinical( asymptomatic) form of the disease may develop. Also, the Epstein-Barr virus can cause a "chronic fatigue syndrome", autoimmune diseases( rheumatic diseases, vasculitis, ulcerative colitis).In countries with a tropical and subtropical climate, malignant neoplasms( Burkitt's lymphosarcoma, nasopharyngeal carcinoma and others) are possible, often with metastases to various organs. In HIV-infected patients, EBVI is associated with the occurrence of hairy leukoplakia of the tongue, lymphoma of the brain and other manifestations.

The fact of direct connection of the Epstein-Barr virus with the development of acute mononucleosis, chronic EBVI( or EBV infection), congenital EBV infection, "chronic fatigue syndrome", lymphoid interstitial pneumonia, hepatitis, oncological lymphoproliferative diseases( Burkitt's lymphoma, T-cell lymphoma, nasopharyngeal carcinoma or NFC, leiomyosarcoma, non-Hodgkin's lymphomas), HIV-associated diseases( "hairy leukoplakia", brain lymphoma, common neoplasmlymph nodes).

More on some manifestations of EBV infection:

1. Infectious mononucleosis , which manifests itself as an acute form of the disease with cyclicity and specific symptoms( fever, catarrhal angina, difficulty in nasal breathing, enlargement of groups of lymph nodes, liver, spleen, allergic rash,specific changes in the blood).For more details see the article "Infectious mononucleosis".
Symptoms unfavorable in the development of chronic VEB infection:
- prolonged nature of the infection( prolonged subfebrile condition - 37-37.5 ° - up to 3-6 months, preservation of enlarged lymph nodes more than 1.5-3 months);
- the occurrence of recurrences of the disease with the resumption of symptoms of the disease within 1.5-3-4x months after the onset of the primary attack of the disease;
- preservation of IgM antibodies( to EA, VCA VEB antigens) for more than 3 months from the onset of the disease;absence of seroconversion( seroconversion - disappearance of IgM antibodies and the formation of IgG antibodies in different antigens of the Epstein-Barr virus);
- untimely started or completely absent specific treatment.

2. Chronic EBV infection of is formed not earlier than 6 months after the acute infection, and in the absence of acute mononucleosis in the anamnesis - 6 months or more after infection. Often, the latent form of infection with a decrease in immunity passes into a chronic infection. Chronic VEB infection can occur in the form of: chronic active EBV infection, hemophagocytic syndrome associated with EBV, atypical forms of EBV( recurrent bacterial, fungal and other infections of the digestive system, respiratory tract, skin and mucous membranes).

Chronic active EBV infection is characterized by a prolonged course and frequent relapses. Patients are concerned about weakness, fatigue, excessive sweating, prolonged low temperature up to 37.2-37.5 °, skin rashes, sometimes joint pain, muscle pain in the trunk and extremities, heaviness in the right hypochondrium, a feeling of discomfort in the throat, a small coughand stuffiness in the nose, in some patients neurological disorders - uncaused headaches, memory impairments, sleep disorders, frequent mood changes, a tendency to depression, patients are inattentive, a decrease in intelligence. Often, patients complain of an increase in one or a group of lymph nodes, possibly an increase in internal organs( spleen and liver).
Along with such complaints, when inquiring of a patient, it becomes clear that there have been frequent cold infections, fungal diseases, joining other herpetic diseases( for example, herpes simplex on the lips or genital herpes, etc.).
In confirmation of clinical data there will be laboratory signs( blood changes, immune status, specific antibody tests).
With a pronounced decrease in immunity in chronic active EBV infection, generalization of the process occurs and possible damage to the internal organs with the development of meningitis, encephalitis, polyradiculoneuritis, myocarditis, glomerulonephritis, pneumonia and others.

Hemophagocyte syndrome associated with VEB manifests itself in the form of anemia or pancytopenia( a reduction in the composition of virtually all blood elements associated with oppression of germs of hematopoiesis).Patients may experience fever( wave-like or intermittent, in which both rapid and gradual increases in temperature are possible with recovery to normal values), enlargement of lymph nodes, liver and spleen, abnormal liver function, laboratory changes in blood in the form of a decrease in both erythrocytes andand leukocytes and other elements of blood.

Erased( atypical) forms of EBVI : most often it is a fever of an unclear genesis lasting for months, years, accompanied by an increase in lymph nodes, sometimes joint manifestations, muscle pains;another option is secondary immunodeficiency with frequent viral, bacterial, fungal infections.

3. Congenital EBV infection of occurs when there is an acute form of EBVI or chronic active EBV infection that occurred during the mother's pregnancy. It is characterized by possible damage to the internal organs of the child in the form of interstitial pneumonia, encephalitis, myocarditis and others. There may be prematurity, premature birth. In the blood of a born baby, both the maternal antibodies to the Epstein-Barr virus( IgG to EBNA, VCA, EA antigens) and the clear confirmation of intrauterine infection can circulate-the child's own antibodies( IgM to EA, IgM to VCA antigens of the virus).

4. " Syndrome of chronic fatigue " is characterized by constant fatigue, which does not pass after a long and full rest. For patients with chronic fatigue syndrome, muscle weakness, periods of apathy, depressive states, mood lability, irritability, sometimes outbursts of anger, aggression are characteristic. Patients are listless, complain of memory impairment, decrease of intelligence. Patients do not sleep well, and it is disturbed as a phase of falling asleep, and intermittent sleep is observed, insomnia and drowsiness during the day are possible. At the same time, vegetative disturbances are typical: trembling or tremor of fingers, sweating, occasionally low temperature, poor appetite, pain in the joints.
Workaholics are at risk, people with increased physical and mental work, people who are in acute stress situations, and in chronic stress.

5. HIV-associated diseases
"Hairy leukoplakia" of the tongue and oral mucosa appears with expressed
immunodeficiency, associated more often with HIV infection. On the lateral surfaces of the tongue, as well as on the mucous membrane of the cheeks and gums, whitish folds appear, which gradually merge, forming white patches with a non-uniform surface, as if covered with furrows, cracks and erosive surfaces are formed. As a rule, there is no pain in this disease.

Hairy leukoplakia of the

language Lymphoid interstitial pneumonia is a poly-tyological disease( there is a connection with pneumocysts as well as with the EBV) and is characterized by shortness of breath, low-producing cough
against the background of the temperature and symptoms of intoxication, and the progressive weight loss of patients. The patient has an increase in the liver and spleen, lymph nodes, an increase in the salivary glands. In the radiographic study, bilateral lower-longitudinal interstitial foci of inflammation of the lung tissue, the roots are broadened, unstructured.

6. Oncological lymphoproliferative diseases ( Burkitt's lymphoma, nasopharyngeal carcinoma-NFC, T-cell lymphoma, non-Hodgkin's lymphoma and others)

Diagnosis of Epstein-Barr virus infection

1. Preliminary diagnosis of is always made on the basis of clinical and epidemiological data. The suspicion on EBVI is confirmed by clinical laboratory tests, in particular, a general blood test, which can reveal indirect signs of viral activity: lymphomonocytosis( increased lymphocytes, monocytes), less monocytosis in lymphopenia( increase in monocytes with decreasing lymphocytes), thrombocytosis( increase in platelets), anemia(reduction of erythrocytes and hemoglobin), the appearance of atypical mononuclear cells in the blood.

Atypical mononuclear cells( or virotsity) are mutated lymphocytes, which by morphological features have some similarity with monocytes. These are single-nucleated cells, are young cells, appear in the blood to fight viruses. It is the latter property that explains their appearance in EBVI( especially in its acute form).The diagnosis of infectious mononucleosis is considered to be confirmed with the presence of atypical mononuclear cells in the blood of more than 10%, however their number can vary from 10 to 50 and more%.

For the qualitative and quantitative determination of atypical mononuclear cells, the leukocyte concentration method is used, which is a highly sensitive method.

Date of appearance: Atypical mononuclear cells appear in the first days of the disease, at the height of the disease, their quantity is the maximum( 40-50% or more), in some patients their appearance is fixed one week after the onset of the disease.

Duration of their detection: in most patients, atypical mononuclears continue to be detected within 2-3x weeks from the onset of the disease, in some patients - disappear by the beginning of the 2nd week of the disease.40% of patients in the blood continue to detect atypical mononuclear cells for up to a month or more( in this case it makes sense to actively prevent the process from becoming chronic).

Also at the stage of preliminary diagnosis, a blood biochemical test is performed in which there are signs of liver damage( a slight increase in bilirubin, an increase in the activity of enzymes - ALT, AST, GGTP, timol probes).

2. The final diagnosis of is exhibited after specific laboratory tests.

1) Heterophilic test - detection of heterophilic antibodies in serum, is detected in the vast majority of patients with EBVI.Is an additional method of diagnosis. Heterophilic antibodies are produced in response to infection with EBV - this is an autoantibody that is synthesized by infected B lymphocytes. These include antinuclear antibodies, rheumatoid, cold agglutinins. They refer to antibodies of IgM class. Appear in the first 1-2 weeks from the time of infection, characterized by a gradual increase in the first 3-4 weeks, then gradually decline in the next 2 months and the preservation of the whole period of convalescence in the blood( 3-6 months).If in the presence of symptoms of EBVI this test is negative, then it is recommended to repeat it in 2 weeks.
False positive result on heterophilic antibodies can give such conditions as hepatitis, leukemia, lymphoma, drug use. Also positive antibodies of this group can be for: systemic lupus erythematosus, cryoglobulinemia, syphilis.

2) Serological tests for antibodies to the Epstein-Barr virus using the ELISA method ( enzyme immunoassay).
• IgM to VCA ( to the capsid antigen) - are detected in the blood in the first days and weeks of the disease, they are maximal by the 3rd to 4th week of the disease, can circulate up to 3 months, and then their quantity decreases to an undetectable value and disappears altogether. Preserving them for more than 3 months indicates a prolonged course of the disease. Discovered in 90-100% of patients with acute EBV.
• IgG to VCA ( to the capsid antigen) - appear in the blood 1-2 months after the onset of the disease, then gradually decreases and remains at the threshold( low level) for life. An increase in their titer is characteristic for exacerbation of chronic EBVI.
• IgM to EA ( to the early antigen) - appears in the blood in the first week of the disease, persists for 2-3x months and disappears. It is found in 75-90% of patients. The preservation in high titles for a long time( more than 3-4 months) is alarming in terms of the formation of a chronic form of EBVI.The appearance of them in chronic infection serves as an indicator of reactivation. Often can be detected during primary infection in carriers of EBV.
• IgG to EA ( to the early antigen) - appear on the 3-4th week of the disease, become maximal for 4-6 weeks of illness, disappear after 3-6 months. The appearance of high titers repeatedly indicates the activation of a chronic infection.
• IgG to NA-1 or EBNA ( to nuclear or nuclear antigen) - are late because they appear in the blood 1-3 months after the onset of the disease. Long time( up to 12 months) from the titer is high enough, and then the titer decreases and remains at the threshold( low) level for life. In young children( up to 3-4 years), these antibodies appear late - 4-6 months after infection. If a person has severe immunodeficiency( stage AIDS in HIV infection, cancer processes, etc.), then there may not be any such antibodies. Reactivation of a chronic infection or relapse of acute EBV is observed at high titers of IgG to NA antigen.

Schemes of interpretation of results

*Serological data*	*Status*
IgM VCA, IgM EA, IgG EA	Acute EHVI( infectious mononucleosis)
IgG VCA, IgG NA in low titres	Reconvalence of EBVI
IgM EA, IgM VCA for more than 3 months	Prolonged flow of EBVI
IgG NA,IgG VCA in high titers, sometimes IgG EA IgM VCA, sometimes IgM EA	Chronic EBV infection activation of
Persistent persistence of high titers At of IgM class to VCA, At class IgG to EA	Chronic EBV infection, VEB - inducedtumors, autoimmune diseases
Absence of antibodies	Expressed immunodeficiency states

Rules for the qualitative diagnosis of EBV infection:
is a dynamic laboratory study: in most cases, a single antibody test is not sufficient to diagnose. Repeated studies are necessary after 2 weeks, 4 weeks, 1.5 months, 3 and 6 months. The algorithm of dynamic research and its necessity is determined only by the attending physician!
- to compare the results made in one laboratory.
- there are no general standards for antibody titers;the evaluation of the result is carried out by the doctor in comparison with the reference values of the specific laboratory, after which it is concluded how many times the sought-for antibody titer is increased compared to the reference value. The threshold level, as a rule, does not exceed 5-10 times the increase. High titers are diagnosed at a 15-30-fold increase and higher.

3) PCR diagnosis of EBV infection - qualitative detection of the DNA of the Epstein-Barr virus by PCR.
The material for the study is saliva or roto- and nasogloss mucus, scraping of epithelial cells of the urogenital tract, blood, cerebrospinal fluid, secretion of the prostate, urine.
Both EBVI patients and carriers can have positive PCR.Therefore, PCR analysis with a given sensitivity is carried out for their differentiation: for carriers up to 10 copies in the sample, and for active infection - 100 copies in the sample. In young children( up to 1-3 years) due to insufficiently formed immunity, the diagnosis of antibodies is difficult, therefore in this group of patients, PCR-analyzes come in handy.
The specificity of this method is 100%, which practically excludes false positive results. However, due to the fact that PCR analysis is informative only when the virus replicates, there is a certain percentage of false-negative results( up to 30%), related specifically to the lack of replication at the time of the study.

PCR analysis

4) Immunogram or immunological examination of blood.
There are two types of immune status changes in EBVI:
• Increase in its activity( increase in serum interferon level, IgA, IgM, IgG, increase in CIC, increase in CD16 + natural killers, increase in CD4 + T-helper or CD8 + T suppressor)
• Immune dysfunction or insufficiency( decreased IgG, increased IgM, reduced avidity of antibodies, decreased CD25 + lymphocytes, decreased CD16 +, CD4 +, CD8, decreased activity of phagocytes).

Treatment of EBV infection

1) Organizational-regime measures of include hospitalization in an infectious clinic of patients with acute form of EBVI, depending on the severity. Patients with reactivation of chronic infection are more often treated as outpatients. Dietotherapy is reduced to a full diet with mechanical, chemical shining digestive tract.

2) Drug-specific therapy of EBVI.
• Antiviral drugs( isoprinosin from the first days of life, arbidol from 2 years, valtrex from 2 years, famvir from 12 years, acyclovir from the first days of life in the absence of other drugs, but much less effective).
• Interferon preparations( viferon from the first days of life, kipferon from the first days of life, reaferon EU-lipid over 2 years, interferons for parenteral administration over 2 years).
• Interferon inductors( tsikloferon over 4 years old, neovir from the first days of life, amixin from 7 years, anaferon from 3 years).

Rules for specific therapy for EBVI:
1) All drugs, dose, courses are prescribed exclusively by the treating doctor.
2) After the main course of treatment, a sustained support course is needed.
3) Combinations of immunomodulators are prescribed with caution and only by a doctor.
3) Preparations to enhance the intensity of treatment.
- Immunocorrection( after immunogram examination) - immunomodulators( thymogen, polyoxidonium, derinat, lycopide, ribomunil, immunorix, roncoleukin and others);
- Hepatoprotectors( carpel, hepaben, hepatofalk, Essentiale, heptral, ursosan, ovesol and others);
- Enterosorbents( white coal, filter, lactofiltrum, enterosgel, smect);
- Probiotics( bifidum-forte, probiophore, biovestin, bifiform and others);
- Antihistamines( zirtek, klaritin, zodak, erius and others);
- Other medications as indicated.

Clinical examination of patients with acute and chronic form of ECG

All dispensary observation is carried out by an infectious disease specialist, in pediatric practice in the absence of such an immunologist or pediatrician. After the transferred infectious mononucleosis, observation is established within 6 months after the disease. Examinations are carried out monthly, if necessary, by consulting a narrow specialist: a hematologist, an immunologist, an oncologist, an ENT doctor and other
. Laboratory tests are carried out on a quarterly basis( once every 3 months), and if necessary, a general blood test is performed on a monthly basis for the first 3 months. Laboratory tests include: a general blood test, antibody tests, a PCR test of blood and oropharyngeal mucus, a biochemical blood test, an immunogram, an ultrasound scan, and others according to indications.

Prevention of Epstein-Barr virus infection

No specific prevention( vaccination).Preventative measures are reduced to strengthening immunity, tempering children, precautions when the patient appears in the environment, compliance with personal hygiene rules.

Doctor infectious diseases Bykova N.I.