Pediatrician (St. Petersburg)Pediatrician (St. Petersburg)2079-78502587-6252Eco-Vector1122810.17816/PED9677-82Research ArticleVEB-mononucleosis in children at the hospital stage in modern conditionsTimchenkoVladimir N.<p>MD, PhD, Dr Med Sci, Professor, Head, Department of Infectious Diseases in Children named after Prof. M.G. Danilevich</p>detinfection@mail.ruBannovaSvetlana L.<p>MD, PhD Associate Professor, Department of Infectious Diseases in Children named after Prof. M.G. Danilevich</p>detinfection@mail.ruPavlovaNatalia V.<p>MD, PhD Assistant Professor, Department of Infectious Diseases in Children named after Prof. M.G. Danilevich</p>detinfection@mail.ruPavlovaElena B.<p>MD, PhD Associate Professor, Department of Pharmacology</p>detinfection@mail.ruKaplinaTatyana A.<p>MD, PhD Associate Professor, Department of Infectious Diseases in Children named after Prof. M.G. Danilevich</p>detinfection@mail.ruFedorovaAnna V.<p>Assistant Professor, Department of Infectious Diseases in Children named after Prof. M.G. Danilevich</p>detinfection@mail.ruBulinaOksana V.<p>MD, PhD Associate Professor, Department of Rehabilitation AF and DPO</p>detinfection@mail.ruBalashovAlexey L.<p>Associate Professor, Department of Propedeutics of Children's Diseases with a Course of General Care</p>balashovAL7@yandex.ruHakizimanaJean-Claude<p>Postgraduate Student, Department of Infectious Diseases in Children named after Prof. M.G. Danilevich</p>detinfection@mail.ruSt. Petersburg State Pediatric Medical University1512201896778226022019Copyright © 2018, Timchenko V.N., Bannova S.L., Pavlova N.V., Pavlova E.B., Kaplina T.A., Fedorova A.V., Bulina O.V., Balashov A.L., Hakizimana J.2018<p>VEB-mononucleosis is an actual infection of childhood. We analyzed 764 medical records of inpatients with VEB mononucleosis. Two groups of patients were formed: group I (young age) was 411 people (from 1 to 7 years), group II (schoolage) 353 people (from 7 to 17 years). In the I group, boys predominated, the peak of the disease occurred in the spring period, in group II girls, the incidence of the incidence was noted in the winter. In both groups, moderate forms of the disease predominated, 684 people (89.5%). Severe forms of the disease prevailed in the children of group II. In group I the disease began acutely, and in the second group subacute. In both groups, the whole syndrome of VEB mononucleosis was observed: fever, intoxication, acute tonsillitis, lymphadenopathy. The defeat of the nasopharynx and hepatosplenomegaly was more common in the I group. In this case, the increase in the size of the liver and spleen was up to 2 cm from the age norm. In the biochemical analysis of blood, an increase in ALT activity was detected with the same frequency in both age groups. Moreover, in the I group there was a moderate activity of ALT, in the II group more significant. In clinical blood analysis, most patients in both age groups had leukocytosis. Lymphocytosis was more common in children of group I. Monocytosis was more common in children of group II. Increased ESR was observed in both groups with the same frequency. Atypical mononucleary in children of the I group appeared on the first, and in the older group on the second week ofthe disease. A set of laboratory methods was used to diagnose VEB mononucleosis. In 100% of the observed children receiving viferon, there was a significant decrease in the duration of fever, intoxication, acute tonsillitis, lymphadenopathy, adenoiditis, hepatomegaly, splenomegaly and reduction in hospital stay.</p>Epstein-Barr virusVEB mononucleosisyounger childrenschool childrenrecombinant interferonviferonвирус Эпштейна - БаррВЭБ-мононуклеозмладшие детишкольникирекомбинантный интерферонвиферон<p>EBV-mononucleosis is predominantly an infection of childhood [2, 5, 6, 10]. The highinterest to this infection results from its involvement in pathologicalprocesses in different organs and systems, its association with anumber of malignancies, lymphoproliferative and autoimmune diseases. Moreover, EpsteinBarr viruscontributes to the progression of HIV infection, is a markerfor opportunistic infection in AIDS and acts as a triggerfactor for the virus-associated hemophagocytic syndrome [2, 812]. There areserious diagnostic difficulties in the pre-hospital and hospital stages [13,6, 7]. A differential diagnosis is carried out between EBV-mononucleosisand tonsillitis, sinusitis, pseudotuberculosis, hepatitis, HIV infection, and leukemia [2,5, 6, 11]. One of the most frequent causes foradmission of patients to the hospital is nasopharyngitis, which issimilar to the symptoms of ear,nose, and throat inflammationof different etiology[13]. Hepatosplenomegaly with hepatic hyperenzymemia is detectedin 10%90% of EBV-mononucleosis cases[1,4, 8, 11];therefore,adifferential diagnosis must be initiated between EBV-mononucleosis and hepatitis. Hemogram changes likelymphocytosis and atypicalmononuclear cells, which are characteristic to EBV-mononucleosis,are found in 50%90% of the cases; however such changesare also observed in other respiratory infections [1, 4,6, 7]. Considering that in the majority of healthy population,the virus can be excreted with saliva and mononucleosis canbe asymptomatic, a complex of laboratory diagnostic methods is usedto verify the etiology of infectious mononucleosis and determine thestage of the disease [1, 2, 6, 7, 10].</p>
<p>Theaim of this study is to evaluate the clinical efficacyof Viferon drug in a complex therapy in childrenwith EBV-mononucleosis.</p>
<h2>MATERIALS AND METHODS</h2>
<p>764 medical records of hospitalized children withEBV-mononucleosis at the Department of infectious diseases No. 1 ofthe Saint Petersburg State Pediatric Medical University clinic in20162017 period. The majority of the hospitalized children were inthe 37years age interval (n = 240, 31.4%). Thehospitalized patients with EBV-mononucleosis were divided into two groups: groupIwith 411 patients (53.8%) aged 17 years (mean age= 3.8 0.1 years), and group II with 353school-age children (46.2%) aged717 years (mean age = 11.9 0.2 years) (Fig.1).</p>
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<div class="preview fancybox" style="text-align: center;"><a title="Fig. 1. Age composition of children(%)with VEB mononucleosis" href="/files/journals/4/articles/11228/supp/11228-47691-1-SP.png" rel="simplebox"><img style="max-height: 300px; max-width: 300px;" src="/files/journals/4/articles/11228/supp/11228-47691-1-SP.png" /></a></div>
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<p><strong>Fig. 1. Age composition of children(%)with VEB mononucleosis</strong></p>
<p><strong>Рис. 1. Возрастной состав детей (%), больных ВЭБ-мононуклеозом</strong></p>
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<h2>RESULTS AND DISCUSSION</h2>
<p>In the groupI, boys were affected more frequently (<em>n</em>= 259, 63.0%)than girls (<em>n</em>= 152, 37.0%), whereas in the groupII, girls were affected more frequently(<em>n</em>= 202, 57.3%)than boys (<em>n</em>= 151, 42.7%).Patients in group Iweremore frequently hospitalized in spring. In group I, 219 patients(53.3%) were admitted to the hospital in spring, 94patients (22.9%) in winter, 69patients (16.8%) in autumn, and29 patients in summer (7.0%). Patients in group II weremore frequently admitted to the hospital in winter. In thegroupII, 140 patients (39.6%) were hospitalizedinwinter, 109patients in spring (30.9%), 81 patients in autumn (23.0%), and23 patients in summer (6.5%).</p>
<p>Patients admitted to thehospital with the diagnosis infectious mononucleosis were 188 patients(45.7%) in group I, whereas they were only95 patients (26.9%) in group II. In contrast, morepatients in the group Iwere admitted to hospital withthe diagnosis of lacunar tonsillitis (132 patients, 37.4%) than ingroupII (78 patients, 19.0%). The remaining patients werereferred to the hospital with other diagnoses, such as pseudotuberculosis(<em>n</em>= 88, 11.5%), ARVI (<em>n</em>= 77, 10.1%), andARVI with exanthema (<em>n</em>= 106, 13.9%).</p>
<p>320 patients (77.8%) ingroup Iand 154 patients (43.6%) in group II wereadmitted to the hospital at week 1 of onset ofthe disease (average on day6). At week 23 ofonset of the disease (average on day 11), thenumber of patients in group II (<em>n</em>= 199, 56.4%)admitted to the hospital were higher than in group I(<em>n</em>= 91, 22.2%). The moderate form of disease waspredominant in both groups: 392 cases in group I(95.4%)and 292 cases in group II (82.7%). The severeform of disease was more often noted in patients ofthe older group, with 61cases (17.3%) against 19 cases ingroup I(4.6%).</p>
<p>While analyzing the clinical presentation of the disease,the acute onset of the disease was detected in 63%of children (<em>n</em>= 483), with a reparition of 328patients (79.8%) in group I, and 155 patients (43.9%) ingroup II. In 281 patients (36.8%), a subacute onset ofthe disease was observed with gradually increasing fever and intoxication,83 patients (20.2%) and 198patients (56.1%)in group IandII accordingly. Allpatients had typical EBV-mononucleosis syndromes. From day1 of the disease, sickness syndrome was observed in allpatients in both groups, which was characterized by lossof appetite, weakness, and apathy.</p>
<p>Fever was recorded in 726patients (95.0%), whereas in 38 patients (5.0%) the body temperatureremained normal. In both groups, fever characterized by febrile numbers(38.039.0C) was registered in 261 patients (63.5%) and 204patients (57.8%) in groups Iand II respectively. The fever average duration was 7.1 0.6 and11.7 0.7 days in group Iand group II,respectively.</p>
<p>Acute tonsillitis was also registered in all patients. Therewere 263 patients in group I(64.0%) and 271patientsin group II (76.8%) who complained of the sore throatwhen swallowing and with exudative plaques primarily on the palatinetonsils. Inflammatory changes in the oropharynx were limited to catarrhalsigns in 87 patients (21.2%) in group Iand 36patients (10.2%) in group II. HyperplasiaIII of the tonsilswas registered in 248 cases in group I(60.3%)and in 181 cases (51.3%) in group II. Olderpatients are more likely to develop hyperplasia IIIII ofthe tonsils, 135 patients (38.2%) and 92 patients (22.4%), ingroup Iand II respectively. Acute tonsillitis persisted longer inthe group II and lasted for 9.5 0.7 daysas opposed to 5.9 0.5 days in group I.A microbial exam of the flora oropharyngeal mucous revealedavarious bacterial flora in 47.4% of patients with EBV-mononucleosis.<em>Staphylococcus aureus</em>prevailed inboth groups, namely 67 patients (32.0%)in the group Iand 52 (34.0%) in the groupII. Pathogenic streptococci were more often found in the patientsof the groupI(<em>n</em>= 69, 33.0%), and<em>P.aeruginosa</em>in 12patients (7.8%) and<em>H. influenzae</em>in 9patients(5.9%) in the groupII. Combined flora was more common in group II (27patients, 17.6%) than that in the group I(14 patients,6.7%).</p>
<p>Inflammation of the pharyngeal tonsil was observed in 531 patientswith EBV-mononucleosis (69.5%) and was accompanied by nasal congestion, impairednasal airflow with scarce discharge, rasping, and stertorous breathing throughthe mouth, snoring during sleep, face puffiness, and theeyelids swelling. All manifestations of adenoiditis were more common inthe group I(<em>n</em>= 358, 87.1%) than in thegroup II (<em>n</em>= 173, 49.0%). The duration of adenoiditiswas shorter in the group I; for instance, it lastedfor 6.2 0.4 days in group Icomparedto its duration of 7.6 0.5 days in thegroup II.</p>
<p>Lymphadenopathy occurred in all patients. From day 1 ofthe disease, the lymph nodes mostly of the cervical group:anteroposterior and posterior were affected; 277 patients (67.4%) and 310patients(75.4%) in group I, 223 patients (63.2%) and168patients(47.6%) in group II, respectively. In addition,other lymph nodes were also involved in the pathological processof EBV-mononucleosis. Supramandibular lymph nodes were affected in 56 patientsin group I(13.6%) and 41 patients in goup II(11.6%);inguinal lymph nodes were affected in 43 cases in groupI(10.5%) and 39 cases in group II(11.0%). Axillary lymph nodes were significantly affected in patients in groupII, i.e., 61 cases in group II (17.3%) against21cases in group I(5.1%). Lymph nodes were painless,dense, with a round-shape or chain-like configuration. Upon visualization, thelymph nodes were from 2 to 6 cm in diameterand the skin color over them did not change. Theduration of lymphadenopathy syndrome in the groups Iand IIpediatric patients were 9.4 0.6 and 15.0 0.7days, respectively.</p>
<p>Simultaneous involvement of the liver and spleen in thepathological process was present in every second or third patient(<em>n</em>= 455 patients, 59.6%). Hepatomegaly syndrome was registered ina total of 511 patients (66.9%), 314 in group I(76.4%) and 197 in group II (55.8%). In mostcases, its edge protruded 12 cm from under the costalarch in 187 (59.6%) and 101 (51.3%) patients in groupsIand II respectively. Patients complained of abdominal pain, aswell as mild tenderness of the liver during palpation. Hepatomegalysyndrome was more prolonged in the group II and lastedfor 16.8 0.9 days, compared with 9.9 0.7days in the group I. Upon admission to thehospital,a total of 621 patients (81.3%) with EBV-mononucleosis manifested anincrease in ALTactivity: 344 cases in group I(83.7%), and 277 cases in group II (78.5%). ModerateALT activity (from 40.0 to 100.0 U/l) was noted in208 patients in group I(50.6%) and 111 patients ingroup II (31.4%). In the school-age group (group II), therewas a significant hyperenzymemia (200 U/l and higher) in 92patients (26.1%) against 29patients (7.1%) in the group I.The average indicators in the group Iamounted to 74.6 5.9 U/l, whereas they were 169.3 14.2 U/lin the group II.</p>
<p>Splenomegaly syndrome was present in a totalof 372 patients (48.7%), primarily in group I(63.5%) bythe end of week 1 of the disease. Patients fromboth groups manifested an increase in the spleen sizethat did not exceed 2 cm, 152 patients (58.2%) ingroup Iand 71 (64.0%) in group II. However,the duration of splenomegaly syndrome was longer in group IIthan that in group I(9.2 0.6 days versus6.4 0.5days in group II and I, respectively).</p>
<p>Ablood test in patients with EBV-mononucleosis showed that in 650patients (85.1%), there was an increase in the leukocyte count, in 348 patients (84.7%) and patients (85.6%) in groupIand group II respectively. It was noted that atotal of 114 patients (14.9%) had normocytosis, 63 patients (15.3%)in group Iand 51 patients (14.4%) in group II.Lymphocytosis in EBV-mononucleosis was registered in 345patients (45.2%), ingroup I- 203 patients (49.4%) and in group II-142 patients(40.2%). Monocytosis was more common in school-aged patients (197 patientsor 55.8%) than in patients in the younger age group(124 patients, 30.2%). Atypical mononuclear cells (AMCs) were recorded in515 patients (67.4%), and their number varied within a widerange from 1% to 51%, namely in group I-314 patients(76.4%) (average 18.4 0.9%); and in groupII-201 patients (56.9%) (average 24.9 1.1%). AMCs were detectedat different terms after the onset of the disease. Atweek1 of the disease, AMCs were noted in 281patients (54.6%), with a proportion of 228patients (72.6%) ingroupIand 53 patients (26.4%) in group II. Atweek 2, AMCs were found in 147patients (28.5%) (49patients in group Iand 98 in group II)and. At week 3, AMCs were found in 87 patients(16.9%); in group I-37 patients (11.8%) and in group II-50patients (24.8%). Thus, in the group I, AMCs appeared atearly stages of the disease, and at later stages inthe group II patients. The erythrocyte sedimentation rate (ESR) was250 mm/h. Increased ESR was observed in 186 patients ingroup I(45.3%) and in 182 patients ingroup II (51.6%) (anaverage of 30.4 3.5 and 39.8 2.4 mm/h, respectively).</p>
<p>Specific antibodies EBVIgM were found in almostall patients: 371 patients in group I(90.3%) and339 patients in group II (96.0%).</p>
<p>PCR was usedto determine the EBV DNA in patients blood salivasamples. In almost half of the patients (<em>n</em>= 364, 47.4%), EBVDNA was detected in the saliva and blood of patients;group I-195 patients (47.4%) and 169 patients in group II(47.9%). TheEBV DNA was only detected in the salivaof 183patients (24.0%); in group I-83 patients (20.2%) andin group II-100 patients (28.3%), and only in theblood of 133 patients in group I(32.4%) and84patients in group II (23.8%).</p>
<p>In therapy,patients were randomized into two groups. The study group comprisedpatients who received aetiotropic treatment with Viferon and background therapy, group I: younger- age group of 156patients(38.0%) and group II: school-age group of 101 patients (28.6%). The comparison group includeda similar number of patients of both ages who receivedonly background therapy. Viferon, which is human recombinant interferon -2b with antioxidants (vitamin C and vitamin E), was prescribedbased on the following scheme: 150,000 IU administered twice aday in the group aged 17 years (group I), and500,000 IU twice a day in the group aged 717 years (group II); the course therapy lasted 5 days.</p>
<p>The analysis of theclinical efficacy of Viferon showed clear positive dynamics of clinicalsymptoms in all patients with EBV-mononucleosis (Fig.2, 3). Comparedwith patients who received only background therapy. All patients who received Viferon showed asignificant decrease in the duration of fever, intoxication, acute tonsillitis,lymphadenopathy, adenoiditis, hepatomegaly, and splenomegaly. In patients treated with Viferon, the average stay in the hospital was 6.1days in group I(8.2 days in thecomparison group), and 6.2 days in group II (8.3 daysin the comparison group).</p>
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<div class="preview fancybox" style="text-align: center;"><a title="Fig. 2. Clinical efficacy of viferon in young children with VEB mononucleosis (days)" href="/files/journals/4/articles/11228/supp/11228-47692-1-SP.png" rel="simplebox"><img style="max-height: 300px; max-width: 300px;" src="/files/journals/4/articles/11228/supp/11228-47692-1-SP.png" /></a></div>
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<p><strong>Fig. 2. Clinical efficacy of viferon in young children with VEB mononucleosis (days)</strong></p>
<p><strong>Рис. 2. Клиническая эффективность виферона у детей младшего возраста, больных ВЭБ-мононуклеозом (сутки)</strong></p>
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<div class="preview fancybox" style="text-align: center;"><a title="Fig. 3. Clinical efficacy of viferon in school-age children with VEB mononucleosis (days)" href="/files/journals/4/articles/11228/supp/11228-47693-1-SP.png" rel="simplebox"><img style="max-height: 300px; max-width: 300px;" src="/files/journals/4/articles/11228/supp/11228-47693-1-SP.png" /></a></div>
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<p><strong>Fig. 3. Clinical efficacy of viferon in school-age children with VEB mononucleosis (days)</strong></p>
<p><strong>Рис. 3. Клиническая эффективность виферона у детей школьного возраста, больных ВЭБ-мононуклеозом (сутки)</strong></p>
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<p>Following hospital discharge, the 3-month follow-up showeda smooth course of late recovery period in both groupswho received Viferon. On the contrary, an unsmooth course ofthe disease was observed in 26,3% cases among patients ofthe comparison group (subfebrile condition in 6.3% of cases, lymphadenopathyin 2.9% of cases, and deposit ARVI in 17.1% ofcases).</p>
<h2>CONCLUSION</h2>
<p>EBV-mononucleosis in children of different ages (from 1 yearto 17 years) occurs in moderate form (89.5%) with acharacteristic syndrome complex: fever, intoxication, acute tonsillitis, adenoiditis, lymphadenopathy, hepatosplenomegaly.Most of the patients were hospitalized within winter and springperiods; EBV-mononucleosis incidence was high in boys from the younger-age group, and girls from the school-age group. Patients of group Iwere admitted to the hospital more often at week 1 of the onset of thedisease, and those of group II were admitted at weeks2 and 3.</p>
<p>When Viferon was included in the therapy for EBV-mononucleosis, the duration of all clinicalsyndromes was significantly reduced compared with patients who received onlybackground therapy. In young children, the duration of fever periodwas reduced by 2 times. Manifestations of sickness syndrome significantly decreasedby the day 34 of the disease. Theduration ofthe lymphoproliferative syndrome (lymphadenopathy, acute tonsillitis, adenoiditis, and hepatosplenomegaly) wasalso significantly reduced by 1.52 times. School-age patients who receivedViferon had even earlier remarkable positive changes of the main clinicalsyndromes.</p>
<p>In our study, Viferon therapy helped to reduce theduration of all-age patients stay in the hospital andreduce the economic burden of treatment.</p>
<p>During therapy with Viferon,a smooth course of EBV-mononucleosis was noted in the periodof clinical manifestations (absence of complications) and in the long-termperiod (absence of ARV superinfection during 3-month follow-up). No adversereactions and events were registered in the usage of Viferon.</p>[Баннова С.Л. Сравнительная характеристика инфекционного мононуклеоза Эпштейна - Барр вирусной природы у детей дошкольного и школьного возраста // Ученые записки СПбГМУ им. акад. И.П. Павлова. - 2010. - Т. 17. - № 2. - С. 43-45. [Bannova SL. Comparative data on Epstein-Barr virus infectious mononucleosis in preschool and school age children. Scientific notes of the I.P. Pavlov St. Petersburg State Medical University. 2010;17(2):43-45. (In Russ.)]][Исаков В.А. Герпесвирусные инфекции человека: руководство для врачей. - СПб.: СпецЛит, 2013. [Isakov VA. Gerpesvirusnye infektsii cheloveka: rukovodstvo dlya vrachey. Saint Petersburg: SpetsLit; 2013. (In Russ.)]][Тимченко В.Н., Быстрякова Л.В., Павлова Е.Б., и др. Воздушно-капельные инфекции в практике педиатра и семейного врача: руководство для врачей всех специальностей. - СПб.: ЭЛБИ-СПб, 2007. [Timchenko VN, Bystryakova LV, Pavlova EB, et al. Vozdushno-kapel’nye infektsii v praktike pediatra i semeynogo vracha: rukovodstvo dlya vrachey vsekh spetsial’nostey. Saint Petersburg: ELBI-SPb; 2007. (In Russ.)]][Тимченко В.Н., Баннова С.Л., Калинина Н.М., и др. Клиническая и иммунологическая эффективность рекомбинантного интерферона-альфа-2b при остром Эпштейна - Барр вирусном мононуклеозе у детей дошкольного возраста // Детские инфекции. - 2016. - Т. 15. - № 3. - С. 30-37. [Timchenko VN, Bannova SL, Kalinina NM, et al. Clinical and Immunological Efficacy of the Recombinant Interferon alfa-2b of Acute Epstein-Barr Viral Mononucleosis in Preschool Children. Detskie infektsii. 2016;15(3):30-37. (In Russ.)]][Тимченко В.Н., Баннова С.Л., Федорова А.В., Назарова А.Н. Клинико-лабораторные критерии тяжести и принципы терапии острого инфекционного мононуклеоза Эпштейна - Барр вирусной этиологии у детей // Педиатр. - 2015. - Т. 6. - № 4. - С. 147-153. [Timchenko VN, Bannova SL, Fedorova AV, Nazarova AN. Clinical and laboratory criteria of gravity and the principles of treatment of acute infectious mononucleosis, Epstein-Barr virus etiology of the children. Pediatrician (St. Petersburg). 2015;6(4):147-153. (In Russ.)]. doi: 10.17816/PED64147-153.][Тимченко В.Н., Хмилевская С.А. Болезни цивилизации (корь, ВЭБ-мононуклеоз) в практике педиатра: руководство для врачей. - СПб.: СпецЛит, 2017. [Timchenko VN, Khmilevskaya SA. Bolezni tsivilizatsii (kor’, VEB-mononukleoz) v praktike pediatra: rukovodstvo dlya vrachey. Saint Petersburg: SpetsLit; 2017. (In Russ.)]][Хмилевская С.А., Зайцева И.А. Клинико-эпидемиологические аспекты инфекционного мононуклеоза у детей // Эпидемиология и вакцинация. - 2010. - № 5. - С. 45-50. [Khmilevskaya SA, Zaytseva IA. Clinical and Epidemiologic Aspects of Infectious Mononucleosis in Children. Epidemiol Vakcinoprofil. 2010;(5):45-50. (In Russ.)]][Цинзерлинг А.В., Цинзерлинг В.А. Современные инфекции. Патологическая анатомия и вопросы патогенеза. Руководство. - СПб.: Sotis, 2002. [Tsinzerling AV, Tsinzerling VA. Sovremennye infektsii. Patologicheskaya anatomiya i voprosy patogeneza. Rukovodstvo. Saint Petersburg: Sotis; 2002. (In Russ.)]][Ader F, Chatellier D, Le Berre R, et al. Fulminant Epstein-Barr virus (EBV) hepatitis in a young immunocompetent subject. Med Mal Infect. 2006;36(7):396-398. doi: 10.1016/j.medmal.2006.03.002.][Okano M. Epstein-Barr virus infection and its role in the expanding spectrum of human diseases. Acta Paediatr. 2007;87(1):11-18. doi: 10.1111/j.1651-2227.1998.tb01377.x.][Oertel SH, Riess H. Antiviral Treatment of Epstein-Barr Virus-Associated Lymphoproliferations. Recent Results in Cancer Research. 2002;159:89-95. doi: 10.1007/978-3-642-56352-2_11.][Yuge A, Kinoshita E, Moriuchi M, et al. Persistent hepatitis associated with chronic active Epstein-Barr virus infection. Pediatr Infect Dis J. 2004;23(1):74-76. doi: 10.1097/01.inf.0000105182.51471.4b.]