RU2815303C1 - Method of treating covid-19 in children at risk of severe clinical course of disease - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to infectious diseases and paediatrics. Performing antiviral, symptomatic, antibacterial therapy with underlying therapy for the underlying disease, wherein the child is additionally administered a preparation Human immunoglobulin against COVID-19 in dose of 0.3–1.1 mg/kg of body in amount of 1–3 infusions. Infusions are carried out every 24–72 hours if there is a positive control result of IgG to SARS-CoV-2. Control of IgG to SARS-CoV-2 is carried out by means of PCR test or rapid test for SARS-CoV-2. Treatment according to the declared method is carried out with virus release of SARS-CoV-2, lasting more than 10 days, regardless of the form of severity of the disease and manifestation of syndromes.

EFFECT: method provides a wider range of methods for treating coronavirus infection COVID-19 in children, promotes a more favourable clinical course of the disease and is an effective and safe method of treatment, enables to prevent disease progression in children at risk of severe course of COVID-19 and to eliminate SARS-CoV-2 virus from the body in immunocompromised children.

3 cl, 11 tbl, 3 ex

Description

The invention relates to medicine, namely to infectious diseases and pediatrics, and can be used to treat the new coronavirus infection COVID-19 in children at risk of severe disease, including children with immunodeficiency conditions.

At the end of 2019, an outbreak of a new coronavirus infection occurred in the People's Republic of China (PRC), with the epicenter in the city of Wuhan (Hubei Province). Coronavirus infection (COVID-19) is an acute viral disease affecting all vital organs, caused by an RNA genomic virus of the Betacoronavirus genus of the Coronaviridae family, which was named Severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) due to its high homology ( ~80%) with SARS-CoV. This virus caused acute respiratory distress syndrome (ARDS) and high mortality in 2002-2003.

The nucleocapsid protein of the virus was found in the cytoplasm of epithelial cells of the salivary glands, stomach, duodenum and rectum, urinary tract, tear fluid, sperm, and vaginal secretions. However, the main and quickly accessible target of SARS-CoV-2 is alveolar type II (AT2) cells of the lungs, which determines the development of diffuse alveolar damage. It is believed that gastroenterocolitis can develop with COVID-19, since the virus affects epithelial cells of the stomach, small and large intestine that have ACE2 receptors. With the development of an infectious process, blood vessels (endothelium), as well as the myocardium, kidneys and other organs can be affected. Changes in immunocompetent organs have not been studied enough. The possibility of specific damage to lymphocytes with their apoptosis and pyroptosis (underlies the characteristic and prognostically unfavorable lymphopenia), macrophage hyperactivity syndrome and hemophagocytic syndrome, NETosis of neutrophil leukocytes (as one of the causes of disseminated intravascular coagulation (DIC)) is discussed.

In most countries, when assessing the severity of the disease, they are guided by the presence or absence of signs of respiratory failure, the development of pneumonia and ARDS, distinguishing asymptomatic, mild, moderate, severe (severe pneumonia) and critical forms (ARDS, septic shock, sepsis, MWS).

Currently available data indicate that children make up up to 10% of those infected with SARS-CoV-2 and up to 2% of patients with diagnosed clinical cases of COVID-19. The disease is also recorded in newborns.

At least a quarter of children experience the infection asymptomatically. Up to 10% of children require hospitalization. A severe course is observed on average in 1% of cases of COVID-19 infection in children; most often, complicated forms of the disease develop in children with severe concomitant diseases.

Risk factors for severe disease in children are:

- unfavorable premorbid background;

- co-infection with respiratory syncytial virus (RSV), influenza virus and other pathogens.

- immunodeficiency states of various origins.

The presence of severe underlying diseases in the fields of cardiology, rheumatology, nephrology, hematology, immunology, pulmonology, endocrinology, and oncology are indications for hospitalization of a child in a hospital, regardless of the severity of COVID-19.

Congenital defects in humoral immunity or acquired immunodeficiencies associated with immunosuppressive therapy for hematological, autoimmune and oncological diseases put these patients at high risk of severe COVID-19. Domestic experience in managing adults and children with COVID-19 is described in detail in the current temporary guidelines “Prevention, diagnosis and treatment of new coronavirus infection (COVID-19)” [Temporary guidelines “Prevention, diagnosis and treatment of new coronavirus infection (COVID-19)” " Version 18 dated 10/26/2023].

In children with immunodeficiency conditions, immunobiological therapy is widely used in modern medical practice, consisting mainly of the use of monoclonal antibodies and cell therapy [Immunotherapy for infectious diseases in haematological immunocompromise / M.T. Cutino-Moguel, C. Eades, K. Rezvani, D. Armstrong-James // British Journal of Haematology. 2017. Vol. 177, No. 3. P 348-356].

In the absence of etiotropic treatment with evidence-based effectiveness, doctors turned to the experience of previous pandemics, namely transfusion of convalescent plasma. Passive immunization has been successfully used in outbreaks of viral diseases caused by SARS-CoV-1 in 2002-2003, MERS-CoV in 2011, and the pandemic H1N1 influenza strain in 2009 [Hosseini P, Rahimi H, Najafabadi MM, Ghorbani A , Najafabadi SK, Faridzadeh A, Arabpour J, Khormali E, Deravi N. Convalescent Plasma Therapy for COVID-19: Lessons from SARS-CoV, MERS-CoV, and H1N1 Infection. Acta Med Indonesia. 2021 Jan; 53(1): 86-95. PMID: 338184112]. For the first time, transfusion of anti-Covid plasma in adults was used in the People's Republic of China, Wuhan. Anti-Covid plasma was first used in children on September 4, 2020 in Philadelphia, USA [Diorio, C, Anderson, EM, McNerney, KO, et al. Convalescent plasma for pediatric patients with SARS-CoV-2-associated acute respiratory distress syndrome. Pediatr Blood Cancer. 2020; 67:e28693. https://doi.org/10.1002/pbc.28693]. 4 children with laboratory-confirmed COVID-19 complicated by severe ARDS received convalescent plasma therapy. Anti-Covid plasma has become widely used around the world, including in Russia [Baklaushev V.P., Averyanov A.V., Sotnikova A.G., Perkina A.S., Ivanov A.V., Yusubalieva G.M. ., Novikova O.N., Shikina V.E., Dupik N.V., Kedrova A.G., Sanzharov A.E., Shirshova E.V., Balionis O.I., Valuev-Elliston V.T. ., Zakirova N.F., Glazov Ya.N., Panyukhina I.A., Solovyov N.A., Vinokurov A.G., Ivanov Yu.V., Vasiliev V.N., Klypa T.V., Troitsky A.V. Preliminary results of a study of the safety and effectiveness of convalescent plasma in the treatment of COVID-19 // Clinical practice. 2020. No. 2. URL: https://cyberleninka.ru/article/n/predvaritelnye-itogi-issledovaniya-bezopasnosti-i-effektivnosti-plazmy-rekonvalestsentov-v-terapii-covid-19 (date of access: 10/11/2021).].

Given the conflicting research results, as well as the high risks of complications associated with the use of blood plasma, the task of developing new treatment strategies for COVID-19 has not lost its relevance.

In medical practice, passive immunization of the patient is used using drugs containing class G immunoglobulins, which have antibody activity to SARS-CoV-2.

Thus, there is a known method for obtaining immunoglobulin G against COVID-19 [EA patent No. 044535, date of publication and issue of the patent 08/31/2023] from donor plasma, which uses plasma containing antibodies to the SARS-CoV-2 virus with a positivity rate of more than 2 established using the enzyme-linked immunosorbent assay method using test systems for which the correlation coefficient between the results of determining the antibody content by ELISA with the activity established in the virus neutralization reaction is at least 0.9.

Based on the mentioned method, the drug “Human Immunoglobulin against COVID-19” (COVID-globulin) was developed and registered in Roszdravnadzor [https://nacimbio.ru/deliveries/kovid-globulin]. The use of this drug is based on the concept of passive immunization. COVID globulin is administered intravenously, drip, without dilution, once, at a dose of 1 ml/kg body weight. The initial rate of administration is from 0.01 to 0.02 ml/kg body weight per minute for 30 minutes. If the drug is well tolerated, the rate of administration can be gradually increased to a maximum of 0.12 ml/kg body weight per minute. The drug is administered only in a hospital setting, subject to all aseptic rules.

A foreign analogue of COVID-globulin is COVID-19 hyperimmune globulin, anti-SARS-CoV-2 hyperimmune globulin. [Potent Anti-SARS-CoV-2 Efficacy of COVID-19 Hyperimmune Globulin from Vaccine-Immunized Plasma; Ding Yu, Yu-Feng Li, Hong Liang, Jun-Zheng Wu, Yong Hu, Yan Peng, Tao-Jing Li, Ji-Feng Hou, Wei-Jin Huang, Li-Dong Guan, Ren Han, Yan-Tao Xing, Yong Zhang, Jia Liu, Lu Feng, Chun-Yan Li, Xiao-Long Liang, Ya-Ling Ding, Zhi-Jun Zhou, De-Ming Ji, Fei-Fei Wang, Jian-Hong Yu, Kun Deng, Dong-Mei Xia, De-Mei Dong, Heng-Rui Hu, Ya-Jie Liu, Dao-Xing Fu, Yan-Lin He, Dong-Bo Zhou, Hui-Chuan Yang, Rui Jia, Chang-Wen Ke, Tao Du, Yong Xie , Rong Zhou, Ce-Sheng Li, Man-Li Wang, Xiao-Ming Yangcorresponding; Published online 2022 Apr 11. doi: 10.1002/advs.202104333]. It is COVID-19 hyperimmune globulin (COVID-HIG), a passive immunotherapy drug that is prepared from the plasma of healthy donors vaccinated with BBIBP-CorV (Sinopharm COVID-19 Vaccine).

The prescription of Human Immunoglobulin against COVID-19 to patients at high risk of severe disease is provided for by the Temporary Guidelines “Prevention, diagnosis and treatment of new coronavirus infection (COVID-19). Version 18 (10.26.2023)", approved by the Russian Ministry of Health) (https://static-0.minzdrav.gov.ru/system/attachments/attaches/000/064/610/original/%D0%92%D0%9C %D0%A0_COVID-19_V18.pdf). However, this document contains contraindications for the use of the mentioned drug in persons under 18 years of age and over 60 years of age due to the lack of data on effectiveness and safety.

A single intravenous injection of 1 ml/kg of human immunoglobulin against COVID-19 (COVID-globulin) to patients with moderate, severe and extremely severe disease is provided for by the Clinical Protocol for the treatment of children with a new coronavirus infection (COVID-19) who are hospitalized in medical organizations state healthcare system of the city of Moscow (Osmanov I.M., Alekseeva E.I., Mazankova L.N., Zakharova I.N. [et al.]; edited by A.I. Khripun. - M.: GBU "NIIOZMM DZM", 2021. - 92 s). At the same time, this protocol contains an indication that contraindications for use are age under 18 years and over 60 years (due to the lack of data on effectiveness and safety).

The decision to use Human Immunoglobulin against COVID-19 (COVID-globulin) at the rate of 1 ml per 1 kg of the child’s body weight intravenously, drip, and once was made exclusively by the medical commission upon admission to the SKP GBUZ “Children's City Clinical Hospital named after. BEHIND. Bashlyaeva Department of Health" of a child with risk factors for the development of a severe course of the new coronavirus infection (COVID-19) [Clinical protocol for providing medical care to children with risk factors for the development of a severe course of the new coronavirus infection (COVID-19) in medical organizations of the state healthcare system of the city of Moscow (Osmanov I.M., Alekseeva E.I., Mazankova L.N., Zakharova I.N. and others; Edited by A.I. Khripun. - M.: GBU "NIIOZMM DZM", 2021. - p. . 19].

The instructions for medical use of the drug COVID-globulin contain a direct indication that due to the lack of data on the effectiveness and safety of the drug, children under 12 years of age are a contraindication to its use [https://nacimbio.ru/upload/iblock/c86 /p94crzpltrnosky7sc6uygn8yjwdmrfq/KOVID_globulin-Instruktsiya-29.12.21.pdf].

Despite the fact that it is currently known that passive immunization is effectively used with the drug Human immunoglobulin against COVID-19 (COVID-globulin) in adult patients, information on practice confirms the effectiveness and safety of this drug in the treatment of children, including children from groups There is no risk of severe disease. All major studies conducted and currently being conducted do not have clear results, and the data obtained differ from each other. The use of immunomodulators in high doses leads to the frequent development of side effects, most pronounced in comorbid patients suffering from diseases of cardiology, rheumatology, nephrology, hematology, immunology, pulmonology, endocrinology, oncology and other immunodeficiency conditions of various origins.

However, taking into account the peculiarities of the course of the new coronavirus infection in children with comorbid diseases, including immunocompromising diseases (oncological, hematological, autoimmune, etc.), the lack of effect of standard therapy to eliminate SARS-CoV2 and the weak production of specific antibodies to the pathogen, in Currently, the development of effective methods of immunotherapy for COVID-19 in children with immunosuppression and prolonged viral shedding is becoming an urgent problem.

The purpose of the proposed solution is to develop a new effective method for treating the new coronavirus infection COVID-19 in children at risk of severe disease, which has a minimal number of side effects, and is aimed at reducing the duration and preventing complications of the disease.

This goal is achieved due to the fact that in the method of treating COVID-19, including antiviral, symptomatic, antibacterial, interference therapy against the background of therapy for the underlying disease prescribed before infection with COVID-19, the patient - a child - is additionally administered the drug Human Immunoglobulin against COVID-19. 19 at a dose of 0.3-1.1 mg/kg body in the amount of 1-3 infusions. Infusions are carried out at intervals of 24-72 hours in the presence of a positive IgG control result for SARS-CoV-2. IgG testing for SARS-CoV-2 is carried out using a PCR test or a rapid test for SARS-CoV-2. Treatment according to the claimed method is carried out when viral shedding of SARS-CoV-2 lasts more than 10 days, regardless of the severity of the disease and the manifestation of syndromes.

In comorbid patients suffering from diseases in the field of cardiology, rheumatology, nephrology, hematology, immunology, pulmonology, endocrinology, oncology and other immunodeficiency conditions of various origins, treatment must be carried out taking into account the compromise of the immune system, aimed at eliminating the virus, restoring the immune status and preventing bacterial infections. and fungal complications.

Acute respiratory distress syndrome (ARDS) is the most common cause of death among patients infected with one of the three highly pathogenic human coronaviruses (COVs), namely SARS-COV-1, Middle East respiratory syndrome (MERS)-CoV, and the current SARSCoV-2 [7 - Channappanavar, R., Perlman, S. Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology. Semin Immunopathoi 39, 529-539 (2017). https://doi.org/10.1007/s00281-017-0629-x].

Drugs such as tocilizumab and other targeted monoclonal antibodies may work well to block the specific cytokine they are designed to target. However, ARDS is a hyperinflammatory condition involving multiple proinflammatory cytokines, and targeting a single cytokine may be a poor therapeutic approach.

Human immunoglobulin against COVID-19 (COVID-globulin) is a drug whose active principle is class G immunoglobulins, which have antibody activity to SARS-CoV-2. The distribution of immunoglobulin G (IgG) subclasses in the preparation is close to that in natural plasma and has all the properties characteristic of a healthy person. During the preparation of the drug, IgG molecules do not undergo changes due to chemical or enzymatic action. Antibody activity is completely preserved. The specific activity of antibodies to SARS-CoV-2 in ELISA is at least 160 anti-Covid units (ACU). The drug increases the body's nonspecific resistance.

With intravenous infusion, the drug immediately enters the systemic circulation, bioavailability is 100%. Pharmacokinetic parameters are linearly dependent on the activity of the drug. The pharmacokinetic parameters of the drug COVID-globulin are given after infusion into healthy individuals at a maximum dose of 4 ml/kg and for patients with moderate COVID-19 disease at an optimal dose of 1 ml/kg. After intravenous infusion to healthy individuals, the time values for IgG antibodies to the SARS-CoV-2 virus at maximum concentration vary from 25 minutes to 6 hours. The values of the maximum concentration of IgG antibodies to the SARS-CoV-2 virus in patients with moderate COVID-19 disease depend on the time of drug administration after the onset of the disease and the values of endogenous IgG antibodies to the SARS-CoV-2 virus at the time of initiation of treatment and can be from 8.77 AKE/ml to 7860 AKE/ml during the first 12 hours after infusion. The median time to reach the maximum concentration of antibodies against the SARS-CoV-2 virus during the first 12 hours after the infusion was 1 hour. The average maximum concentration of antibodies against the SARS-CoV-2 virus in healthy individuals is 21-26 AKE/ml. The areas under the concentration-time curve from zero to time t and from zero to infinity (AUC0-t and AUC0-∞) in healthy volunteers are 4100-4900 AKE*h/ml and 6000-6800 AKE*h/ml, respectively . In patients with moderate COVID-19 disease, the average value for the 0-12 hour interval AUC0-t was 3900 AKE*h/ml. The average values of the volume of distribution of the drug correspond to Vd = 4-6 l. Specific IgG antibodies to the SARS-CoV-2 virus are eliminated from the blood plasma of healthy individuals with an average T1/2 value of 11 days; for patients with moderate COVID-19 disease, the corresponding T1/2 value was 4 days. The drug is redistributed between the plasma and the extravascular space, after which immunoglobulin G and IgG complexes are utilized by the cells of the reticuloendothelial system.

However, known areas and methods of application could not indicate to the specialist in what dose and at what point in the treatment of a new coronavirus infection, the drug Human Immunoglobulin against COVID-19 will be able to reduce the activity of the body’s systemic inflammatory response to coronavirus infection and shorten the recovery period.

From November 2021 to April 2022, under supervision at the State Budgetary Institution “Children's City Clinical Hospital named after. BEHIND. Bashlyaeva Department of Health" there were 56 patients at risk for severe COVID-19, 45 of whom received treatment with Human Immunoglobulin against COVID-19 (Covid-globulin). The age structure of the patients was presented as follows - 5 (2-11) years.

The structure of comorbid pathology in children at risk of severe course of COVID 19 is presented in Table 1.

13 (29%) children with palliative status had communications (tracheostomy, gastrostomy, VPS, positive pressure ventilation, not related to COVID-19).

Clinical forms of the disease were distributed as follows: monoforms were identified in 34 children (75.6%), mixed forms in 11 (24.4%) children. Among the monoforms, pneumonia predominated - 24 children (70.6%), of which 19 children (79.2%) had respiratory failure. Gastrointestinal monoform was detected in 2 (5.9%) children. The clinical picture of ARVI with COVID-19 was identified in 8 (23.5%) children and manifested itself as symptoms of nasopharyngitis in 6 (75%) children, pharyngitis in 1 (12.5%) child, bronchitis in 1 (12.5%) child. Among the mixed forms, combinations of nasopharyngitis + viral pneumonia with DN (6 children; 54.5%) and gastrointestinal form + viral pneumonia with DN (5 children; 45.5%) were equally common. In the structure of pneumonia in children with COVID-19 and comorbid pathology, lung lesions predominated: CT 1 - 10%, CT 2 - 20%, CT-3 - 46.7%, CT 4 - 23.3%.

Clinical manifestations of COVID-19 in children: catarrhal syndrome and symptoms of intoxication in 37 (82.2%) children, febrile fever in 38 (84.4%), low-grade fever in 7 (15.6%) and diarrheal syndrome in 11 ( 24.4%) and abdominal syndrome in 8 (17.8%) children. The duration of clinical symptoms from the moment of use of Human Immunoglobulin against COVID-19 until the relief of symptoms was: duration of catarrhal syndrome - 3; (1-5) days, fever - 2; (1-10) days, respiratory failure - 4; (3-9), There were no significant differences in the duration of diarrheal and abdominal syndrome.

In 36 (80%) children, the condition was noted as severe and critical, treatment was received in the ICU; the course of coronavirus infection COVID-19 in 23 (51.1%) children with immunodeficiency conditions was complicated by the development of generalized bacterial and fungal complications with multiple organ failure and the need carrying out mechanical ventilation due to the progression of respiratory failure and the development of ARDS.

The drug was administered at a dose of 0.3-1.1 ml/kg body weight with mandatory control of IgG to SARS-CoV-2 on days 1-3. If the test result was positive for SARS-CoV-2, the infusion was repeated.

The infusion was carried out strictly in a hospital setting under the supervision of the attending physician. The drug was administered intravenously, drip-wise, slowly, once, without dilution. To ensure an accurate rate of administration, dosing devices such as infusion pumps were used. The initial rate of administration is 0.01-0.02 ml/kg body weight/min for 30 minutes. The patient was observed for 30 minutes; if the drug was well tolerated, the administration rate was increased to a maximum of 0.12 ml/kg body weight per minute.

When studying biochemical blood parameters and coagulograms over time, a decrease in the level of inflammatory markers CRP and D-dimer was observed, which indicated the relief of systemic inflammation (Table 2).

With intravenous infusion of Human Immunoglobulin against COVID-19, the content of specific IgG antibodies to the SARS-CoV-2 virus was 21-26 anti-Covid units per 1 ml (AUC/ml), which are eliminated from blood plasma with an average T1 _/2 of 11 days.

In addition, both before treatment with Immunoglobulin against COVID-19 and on day 11 in the dynamics of treatment, the level of IgM and IgG antibodies to SARS-CoV-2 was assessed by ELISA. In 100% on day 11, a high level of IgG was detected - 132 (42-239) PFU/ml, which was significantly significant compared to the initial IgG antibodies to SARS-CoV-2 - 1.3 (0.3-4.8) PFU /ml.

For comparison, 11 children at risk of severe COVID-19 received anti-Covid plasma; the children’s age was 9±4; 8; (7-12) years old. The majority of children were patients with primary immunodeficiencies - 4 (36.4%) and oncological diseases: acute myeloid leukemia (1), Burkitt's lymphoma (1), brain tumors (2) - 4 (36.4%), chronic kidney disease 5 tbsp. - 2 (18.2%) children and 1 (9%) child with cerebellar hemorrhage, IVH, occlusive hydrocephalus. In the structure of pneumonia in children with COVID-19 and comorbid pathology who received anti-Covid plasma, lung lesions with DN predominated: CT 1 - 40%, CT-3 - 60%. In all children, the condition was noted as severe and critical, treatment was received in the ICU, the course of coronavirus infection COVID-19 in children with immunodeficiency was complicated by generalized bacterial and fungal complications with the development of multiple organ failure, 4 children were on mechanical ventilation due to the progression of respiratory failure and the development of ARDS . When studying biochemical blood parameters and coagulograms, high markers of acute-phase inflammation were observed over time during the entire period of treatment in the hospital.

A single dose of anti-Covid plasma was 270 ml with virus inactivated activity 1/160-1/320, the interval between administration was 3-5 days. Detection of IgG to the receptor binding domain (RDB) in anti-Covid plasma amounted to an RBD titer of 2.37, which allows us to judge the presence of protective immunity, which could have formed both after the disease and after vaccination. Noteworthy is the persistence of a positive nasopharyngeal smear for the SARS-CoV-2 RNA virus in 63.6% of children up to 3 days after the administration of anti-Covid plasma, in 36.4% of children the positive smear remained up to 7 days and in 9.1% of patients over 11 days. The average duration of viral shedding of SARS-CoV-2 RNA was 32 (23-40) days. In addition, both before treatment with anti-Covid plasma and on day 11 in the dynamics of treatment, the level of IgM and IgG antibodies to SARS-CoV-2 was assessed by ELISA. In 100%, on day 11, an IgG level was detected - 119 (72-165) PFU/ml, which is significantly significant compared to the initial IgG antibodies to SARS-CoV-2 - 11.9 (0.9-29.6) PFU/ ml, but significantly lower than after the use of human immunoglobulin against COVID-19.

Thus, the use of plasma from COVID-19 survivors turned out to be less effective, the duration of treatment in bed days exceeded the treatment period for children compared to children who received Human Immunoglobulin against COVID-19, bacterial complications of COVID-19 and deaths were recorded.

The claimed solution makes it possible to determine the optimal dose of use of Human Immunoglobulin against COVID-19 with a positive therapeutic effect. Children treated according to the proposed method showed significant improvement in the course of the disease, rapid recovery and no mortality in this group of patients.

The inventive method is illustrated by examples of its practical application, but is not limited to them.

Clinical example No. 1.

Child V., 1 year 2 months with clinical diagnosis:

Main diagnosis: U07.1 Coronavirus infection caused by the COVID-19 virus, the virus has been identified (confirmed by laboratory testing regardless of the severity of clinical signs or symptoms: COVID-19 PCR from 04/01/2022 - positive, from 04/09/22 - negative; ELISA COVID- 19 from 04/01/22 - IgM 0.2 IgG 0.15; from 04/09/2022 - IgM 0.4 IgG 153.21 FU/ml), nasopharyngitis, mild form.

Accompanying illnesses:

Delayed psychomotor and speech development. organic damage to the central nervous system. Combined structural epilepsy. Secondary microcephaly.

Z92.8 biological therapy human immunoglobulin against COVID-19 No. 1 dated 04/06/2021.

The patient stayed from 04/03/2022 to 04/16/2022 - Infectious diseases department No. 1 (13 bed days).

History of the disease: sick since March 27, 2022, all days the body temperature increased to 37.1°C. On 04/01/2022, he was examined by a pediatrician, a rapid COVID-19 antigen test was performed - positive, influenza and symptomatic therapy were prescribed. 04/03/2022 in the morning - rhinitis, lethargy, loss of appetite; she was taken to the hospital via ambulance.

Diseases of the nervous system: delayed psychomotor and speech development. organic damage to the central nervous system. Epilepsy. He constantly takes Depakine Chronosphere 125 mg 2 times a day.

Upon receipt of a complaint of lethargy, rhinitis. Body temperature 37.1°C. Body weight: 7.6 kg. BMI: 14.2 Consciousness: clear. The skin color is pale and clear. Cutaneous dermographism: mixed. The mucous membrane of the oropharynx is clearly hyperemic, with follicular hyperplasia of the posterior pharyngeal wall. NPV: 24 /min; Breathing independently: naturally. Participation of the chest in breathing: uniform. SPO ₂ 98%. Breathing is puerile, no wheezing. Percussion sound is clear. No cough. Nasal breathing is difficult, the secretion is mucous. Hemodynamics: stable. Heart rate 122/min; Heart rhythm: rhythmic. Heart sounds: clear. The area of the heart and border is not changed.

The abdomen is soft and painless on palpation. Symptoms of peritoneal irritation are negative. The stool is regular, without pathological changes. The liver and spleen do not protrude from under the edge of the costal arch. Urination is not impaired. Urine unchanged. Diuresis is preserved. There are no meningeal or focal symptoms.

In accordance with the VK dated 04/06/2022, a child at risk of severe coronavirus infection COVID-19 with prolonged viral release of SARS-CoV-2 RNA from the upper respiratory tract was given an infusion of Human Immunoglobulin against COVID-19 in a dose of 0.3 ml on the 11th day / kg (2.3 ml). Instrumental studies:

X-ray of the lungs 04/03/2022: Focal and infiltrative changes in the lungs were not reliably identified.

The results of laboratory tests are shown in tables 3 and 4.

Drug treatment:

1. Interferon alpha-2b 150,000 IU. Per rectally, 2 times a day from 04/03/2022 to 04/12/2022.

2. Dextrose 150 ml. Heparin sodium 1000 IU. IV, 1 time per day during the day, 1 day, Start date: 04/03/2022 (1 day).

3. Bifidobacterium bifidum 5 doses. Inside, 2 times a day during the day, at night, Start date: from 04/03/2022 to 04/16/2022.

4. Potassium chloride + Sodium bicarbonate + Sodium chloride 150 ml. intravenous drip from 04/03/2022.

5. Dextrose 300 ml with aminophylline 0.7 ml, (35 ml/kg) from 04/04/2022 to 04/07/2022.

6. Human immunoglobulin against COVID-19 2.3 ml. at a dose of 0.3 ml/kg body weight, intravenously once, 04/06/2022.

7. Oxymetazoline 0.01%, 2 drops 3 times a day in the nose from 04/03/22 to 04/09/22.

8. Protargol 2%, 2 drops 3 times a day from 04/03/22 to 04/09/22.

9. Depakine Chronosphere 125 mg 2 times a day constantly.

Against the background of immunobiological therapy, positive dynamics were noted - body temperature steadily returned to normal on the 2nd day, catarrhal symptoms stopped on the 3rd day after application, the level of laboratory markers of inflammation decreased to the reference values on the 3-5th day after the introduction of biological therapy. A child of 1 year 2 months with a comorbid disease due to a mild form of coronavirus infection COVID-19, who was admitted to the hospital on the 8th day of illness, received Human Immunoglobulin against COVID-19 at a dose of 0.3 ml/kg on the 11th day of treatment in the hospital. As a result of treatment, elimination of SARS-CoV-2 RNA from the upper respiratory tract was achieved on day 3 after the use of human immunoglobulin against COVID-19 and IgG to SARS-CoV-2 increased from 0.15 to 153.21 PFU/ml. The child was discharged home under the supervision of a pediatrician, neurologist, cardiologist and pulmonologist.

Clinical example No. 2

Child K., 11 years old. with a diagnosis: Main diagnosis: U07.1 Coronavirus infection caused by the COVID-19 virus, the virus has been identified (PCR from 10/29/2021 - positive, SARS-CoV-2 RNA PCR from 11/03/2021 - positive, from 11/05/2021 positive, from 11/07/2021 - negative, COVID-19 PCR from 11/08/2021 negative; COVID-19 ELISA from 10/29/2021 - IgM 0.53 IgG: 0.23, from 11/04/2021 - IgM 21.23 IgG 87.16; from 11/08/2021 - IgM 20.68 IgG 142.42 PFU/ml). Bilateral pneumonia, CT-4 (according to MSCT dated October 27, 2021). Complications of the underlying disease: Respiratory failure, stage 2.

Associated diseases: Q90.9 Down syndrome. UPS. Condition after transluminal balloon angioplasty of coarctation of the aorta from 08/14/2019, after plastic surgery of the anterior mitral valve leaflet, suturing of multiple ventricular septal defects under cardiopulmonary bypass from 08/21/2019. Recoarctation of the aorta. Resection of aortic recoarctation with end-to-end anasmotosis surgery from 10/20/2021. N39.0 Urinary tract infection. Cicatricial phimosis.

Z92.8 Transfusion of human immunoglobulin against COVID-19 No. 3 dated 11/02/2021, 11/04/2021, 11/06/2021.

From 01.11.2021 to 16.11.2021 in ICU No. 2, from 16.11.2021 to 17.12.2021 - Infectious diseases department No. 1.

History of life and illness:

A child from the 2nd pregnancy, which occurred against the background of toxicosis in the first trimester, the second spontaneous birth at 38 weeks. Birth weight 2200 g, height 48 cm. Down syndrome and congenital heart disease were diagnosed immediately at birth. Over the past 6 months, the condition has deteriorated in the form of persistent arterial hypertension and worsening headaches. In connection with the diagnosed coarctation of the aorta, at the first stage on August 14, 2019, it was carried out at the Federal State Budgetary Institution National Medical Research Center for Cardiovascular Surgery named after. A.N. Bakulev of the Ministry of Health of the Russian Federation, transdymal balloon angioplasty of the aortic coarctation zone. 08/21/2019: plastic surgery of the anterior leaflet of the mitral valve, suturing of multiple ventricular septal defects under conditions of bypass, hypothermia and FCP. The early postoperative period was complicated by hyperthermia, hydrothorax, hydropericardium and a long rehabilitation period.

Since October 15, 2021, the child has been in routine hospitalization for coarctation of the aotra. Resection of aortic recoarctation was performed on October 20, 2021, with end-to-end anastomosis from October 20, 2021. In the department, a decrease in saturation to 65% was noted, and the supply of an oxygen-air mixture in a volume of 5 l/min was established. Despite the ongoing therapy, the child’s condition showed negative dynamics, bilateral pneumonia was diagnosed based on the results of a CT scan of the OGK dated 10/23/21 with a lesion volume of 84% (CT-4).

Upon admission, the condition was severe due to DN, severe oxygen dependence, NK, intoxication syndrome, and symptoms of dehydration. Body temperature 38.1°C. Body weight: 47 kg. BMI: 22.3 kg/sq.m. Consciousness: clear. ShKG 15 b. pSOFA 4. Conscious, reacts to examination calmly and adequately, is communicative. There are no meningeal or focal symptoms. Pupils D=S, photoreaction is live.

The skin color is pale. Microcirculation is moderately impaired. Diffuse cyanosis without O ₂ subsidy. Visible mucous membranes are gray and dry. The skin is distinctly pale and dry. Lymph nodes are not enlarged.

Breathing on your own. SPO ₂ 77%. O ₂ subsidy through face mask 12 l/min. Auscultation is hard. The breathing rhythm is regular. NPV 35 per minute. Breathing through the nose is somewhat difficult, there is no discharge, he breathes through the mouth. The excursion is sufficient and symmetrical. Dyspnea is mixed, the inspiratory component predominates, and worsens with activity. Auscultation is carried out evenly over all fields, weakened in the left fields, posteriorly on the right. Crepitating rales on the left, more along the posterior surface. No cough.

Hemodynamics: stable. Blood pressure 151/63 mmHg. Heart rate 114/min; Heart rhythm: not disturbed. Heart sounds: muffled. Rhythm description: sinus according to the monitor. Presence of heart murmur: yes. Characteristics of noise: systolic rough.

The abdomen is soft and painless on palpation. On auscultation, peristalsis is sluggish. No vomiting. Symptoms of peritoneal irritation: negative. The liver and spleen are palpated at the edge of the costal arch. There was no stool upon admission. Urination: independently. The color of urine is yellow.

Considering the absence of an increase in saturation indicators in a child on O ₂ subsidy through a face mask with a flow of 12 l/min over several hours of intensive care in the ICU, the child was transferred to NIV on the same day, saturation indicators were 94-95%; mechanical ventilation; FIO ₂ : 60%; SPO ₂ : 94%; Ventilation mode: Spont (Pressure support, ASB). Support pressure level: 5 mbar; PEEP: 2 mbar; MOD: 10.1 l/min; Tidal volume: 354 ml; Respiratory rate 41 per minute.

In accordance with the decision of the Supreme Court dated November 2, 2021, a child with a comorbid disease and a severe form of coronavirus infection COVID-19 with a disease duration of more than ≥10 days was given an infusion of Human Immunoglobulin against COVID-19 at a dose of 1.1 ml/kg (51.7 ml ) No. 3.

Transferred on 11/07/21 to spontaneous breathing with O ₂ subsidy with a flow of 6 l/min through a face mask, SPO ₂ 96%. Spontaneous breathing is carried out evenly across all fields, weakened along the posterior lower fields on both sides. No wheezing can be heard. Nasal breathing is free. The excursion is sufficient and symmetrical. Inspiratory dyspnea, moderate, insignificant during sleep. The cough is infrequent and non-productive.

Instrumental studies:

Ultrasound examination of the abdominal organs 11/02/2021: Echo signs of hepatomegaly, moderate diffuse changes in the pancreas. Ultrasound examination of the pleural cavity 11/02/2021: The pleural line is compacted, mobility is not impaired. In the right pleural cavity along the posterior surface at the level of the lower angle of the scapula, free fluid 7 mm thick is determined, in the right axillary line at the level of the anterior axillary line 4 mm. Conclusion: Echo signs of a small amount of free fluid in the pleural cavities.

Echocardiography 11/02/2021: Condition after transluminal balloon angioplasty of aortic coarctation from 08/14/2019; plastic surgery of the anterior cusp of the mitral valve, suturing of multiple ventricular septal defects on 08/21/2019, resection of aortic recoarctation with end-to-end anastomosis on 10/20/2021. The residual gradient on the aorta in the projection of the anastomosis is 18 mm Hg. The ventricular septal defect is perimembranous (3.8 mm) with left-to-right shunting. Left ventricular myocardial hypertrophy. Transverse trabeculae, ectopic chords in the left ventricle.

Computed tomography of the chest organs 11/02/2021: In both lungs, diffuse compactions of the lung tissue of the “ground glass” type in combination with linear compactions of the pulmonary interstitium. The volume of damage to the right lung is about 85%, the left - 80%. The intrathoracic lymph nodes are multiple, with a diameter of 8 mm. X-ray picture of bilateral pneumonia (CT-4).

ECG 11/05/2021: Atrial rhythm. Heart rate 71-77 beats. in a minute. Horizontal position of the electrical axis of the heart. Violation of intraventricular conduction.

X-ray of the chest organs 11/08/2021: X-ray signs of infiltrative changes on both sides of the lungs (apparently viral etiology), more pronounced in the lower sections.

ECG 11/09/2021: Atrial rhythm, arrhythmia. Heart rate 68-86 beats. in a minute. Normal position of the electrical axis of the heart. Violation of intravenous conductivity. Left ventricular overload. Changes in the ventricular myocardium. Compared to the ECG dated 11/04/21 - negative dynamics.

Ultrasound examination of the abdominal organs 11/15/2021: Echo signs of hepatomegaly, diffuse changes in the pancreas.

Echocardiography 11/15/2021: Residual gradient on the aorta in the projection of the anastomosis is 14 mm Hg. Left ventricular myocardial hypertrophy. Transverse trabeculae, ectopic chords in the left ventricle. Indicators of left ventricular systolic function were within normal limits. There is no effusion in the pericardial cavity. CDR=30 mm, FI=80%. ECG 11/15/2021: heart rate 56-72 beats/min. Average heart rate 63 beats/min (normal 61-107). PQ 135 ms (normal 100-170). QRS 100 ms, QT 393 ms, QTc 402 ms. Horizontal position of the EOS. Sinus rhythm. Signs of left ventricular enlargement.

Computed tomography of the OGK 11/12/2021: Compared to 11/02/2021, the intensity and extent of “frosted glass” changes has decreased. The volume of damage to the right lung is about 50%, the left - 45%. X-ray picture of the course of bilateral pneumonia (CT-2), with positive dynamics compared to 11/02/2021. Hilar lymphadenopathy.

Ultrasound examination of the kidneys, bladder and urinary tract November 19, 2021: Sonographic signs of a 2-sided megaureter, dilation of the renal collecting system.

Echocardiography 11/24/2021: Condition after transluminal balloon angioplasty of aortic coarctation from 08/14/2019; plastic surgery of the anterior leaflet of the mitral valve, suturing of multiple defects of the interventricular septum 08/21/2019; resection of aortic recoarctation with end-to-end anastomosis from 10/20/2021. The residual gradient on the aorta in the projection of the anastomosis is 17 mm Hg. Left ventricular myocardial hypertrophy. Transverse trabeculae, ectopic chords in the left ventricle. Indicators of left ventricular systolic function were within normal limits. There is no effusion in the pericardial cavity.

ECG 11/25/2021: Sinus rhythm. Heart rate 81-85 beats. in a minute. Horizontal position of the electrical axis of the heart.

The results of laboratory tests are shown in tables 5-7.

Drug treatment:

1. Antibacterial therapy:

2. Cefoperazone + Sulbactam IV, 2 times a day, from 11/02/2021 to 11/14/2021.

3. Vancomycin 470 mg. IV, 4 times a day, from 11/02/2021 to 11/14/2021.

4. Levofloxacin from November 15, 2021 to November 29, 2021, 500 mg 1 time/day

5. Imipenem + Cilastatin 0.5 fl. IV, 4 times a day from 12/01/2021 to 12/13/2021.

6. Human immunoglobulin against COVID-19 at a dose of 1 ml/kg (51.7 ml) No. 3 intravenously, 11/02/2021, 11/04/2021, 11/06/2021.

7. Antifungal therapy: Fluconazole 200 mg. IV, 1 time per day, from 11/02/2021 to 11/12/2021.

8. Inhalation therapy: Budesonide 0.5 mg. Inhalations through a nebulizer, 2 times a day in the morning, in the evening from November 20, 2021 to December 16, 2021.

9. Salbutamol 2.5 mg. Inhalation, 2 times a day, from 11/02/2021 to 11/30/2021.

10. Hormonal therapy: Dexamethasone 10 mg IV, 2 times a day, with gradual withdrawal, from 11/02/2021 to 11/30/2021.

11. Heparin therapy: Heparin 10 units/kg/hour around the clock, intravenously from 11/01/2021 to 12/16/2021.

12. Infusion therapy: Sodium chloride 200 ml. Dextrose 400 ml. IV, in order to replenish the physiological need in a volume of 600 ml, from 11/19/2021 to 11/21/2021.

13. Dextrose Amino acids for parenteral nutrition + Other preparations [Fat emulsions for parenteral nutrition + Dextrose + Minerals] 960 ml. IV, 1 time per day, from 11/10/2021 to 11/16/2021.

During treatment in the ICU, the child was transferred to infectious diseases department No. 1 on November 10, 2021 in a condition of moderate severity. No fever, no additional oxygen therapy, oxygenation was satisfactory. Conscious, contactable. He reacts calmly and adequately to examination. Active within the bed. Spontaneous motor activity was fully preserved. SPO2 98%. Breathing through natural airways. NPV 21 per minute. Nasal breathing is free. The chest excursion is sufficient and symmetrical. There is no shortness of breath at rest. The cough is infrequent and non-productive. On auscultation, breathing is harsh and carried out evenly across all fields. No wheezing can be heard. Hemodynamics are stable. Blood pressure 112/63 mmHg. Heart rate 77/min.

MSCT dated 12/17/21: Convalescent of a bilateral polysegmental interstitial process in the lungs (CT-0). The child was discharged home under the supervision of a pediatrician, cardiologist and pulmonologist.

Against the background of immunobiological therapy, positive dynamics were noted in an 11-year-old child with a comorbid disease and coronavirus infection COVID-19, an extremely severe form, who was admitted to the hospital on the 11th day of illness. On the 2nd day of treatment in the hospital, he began receiving a course of Human Immunoglobulin against COVID-19 at a dose of 1.1 ml/kg No. 3 every other day. As a result of treatment on the 3rd day after the use of human immunoglobulin against COVID-19, DN was stopped, SARS-CoV-2 RNA was eliminated from the discharge of the upper respiratory tract 24 hours after the third infusion of human immunoglobulin against COVID-19 and IgG to SARS-CoV increased -2 from 0.23 to 142.42 FU/ml.

Clinical example No. 3

Child K., 2 years 5 months with a clinical diagnosis: Main diagnosis: U07.1 Coronavirus infection caused by the COVID-19 virus, the virus has been identified (confirmed by laboratory testing, regardless of the severity of clinical signs or symptoms: COVID-19 PCR from 05/26/2020 - positive, from 06/04/20 - negative, 11/27/20, 11/30/20, 12/04/20, 12/09/20, 12/13/20, 12/17/20, 12/21/20, 12/25/20, 12/29/20, 01/01/21, 06/01 .21, 01/10/21 - positive, from 01/14/21 - negative, from 01/16/2021, 01/20/21, 01/25/21, 01/29/21, 02/04/21, 02/08/21, 02/10/21, 02/15/21, 19/02 .21, 02/22/21 - positive; from 02/25/21, 02/28/21 - negative; COVID-19 ELISA from 12/09/20 - IgM 0.04, IgG 1.74; from 01/25/2021 - IgM 0.06, IgG 0.5; from 02/25/2021 - IgM 0.08, IgG 0.12, Ig G S1-0.06; from 02/28/2021 - IgM 2.26, IgG 1.51, Ig G S1-0.97 OE /ml.

Complications: Generalized infection of mixed etiology Staphylococcus sp, Candida sp.): bilateral polysegmental pneumonia, enterocolitis, bacteremia. Multiple organ failure syndrome: stage 3 DN. NC stage 3. Acute rhythm disturbance (ventricular tachycardia). Acute renal failure. Brain swelling. Anemia of mixed origin (correction dated February 21, 2021). Itsenko-Cushing syndrome. Secondary arterial hypertension. Cardiopulmonary resuscitation from 02/28/2021.

Concomitant diseases: D82.8 Primary immunodeficiency. Dysregulation syndrome associated with mutation in the STAT3 gene. Congenital hypothyroidism with antibodies to TPO. Agranulocytosis. Autoimmune drug-resistant enteropathy. Severe malabsorption syndrome. Permanent carrier of the port of Broviak. Severe delay in psychomotor development.

Z92.8 Biological therapy: anti-Covid plasma from 02/24/2021.

Was in infectious diseases department No. 1 from 12/04/2020 - 02/19/2021.

02/20/2021 - 02/28/2021 in ICU No. 2 (87 bed days).

History of the disease: from November 20, 2020, the child was examined at the Russian Children's Clinical Hospital of the Russian National Research Medical University named after N.I. Pirogov Ministry of Health of the Russian Federation. From November 23, 2020, there was an increase in temperature to 38.5°C, there was no cough, no vomiting. On November 26, 2020, the temperature returned to normal, but drowsiness and lethargy persisted. PCR for COVID-19 from 11/27/2020 and 11/30/2020 was positive, in the KLA from 12/23/2020 agranulocytosis, leukocytes 0.53×10/l, neutrophils 0. Due to the positive results of PCR for COVID-19, the child was transferred to the Children's City Clinical Hospital named after . BEHIND. Bashlyaeva, to infectious diseases department No. 1 with a diagnosis of coronavirus infection COVID-19, laboratory confirmed. Bilateral pneumonia (coronavirus associated? autoimmune pneumonitis? DN, stage 1. Primary immunodeficiency, unspecified. Anemia of mixed origin (autoimmune, parvovirus-associated, chronic diseases) stage 3. Thrombocytopenia, unspecified, autoimmune? Fisher-Evans syndrome? Autoimmune enteropathy, severe refractory course, exacerbation. Enterocolitis associated with Candida albicans, Stenotrophomonas maltophilia, Enterobacter cloacae, long-term. Malabsorption syndrome, protein-energy deficiency stage 2. Sepsis associated with Candida albicans, parapsilosis (May-June 2020). Thrombosis of the superior vena cava and right atrium (07/10/2020). Congenital hypothyroidism with antibodies to TPO. Agranulocytosis. During her stay in the RCCH she received vancomycin, meronem, dexamethasone, heptral, L-thyroxine, without effect.

Previously, the child's development was delayed; by the time of hospitalization, the child was sitting with support, rolling over, and attempting to crawl. Over the past 4 days, the mother noticed a decrease in the child’s motor activity, a setback in motor skills: he does not sit, does not roll over.

Upon admission, the condition was serious. Complaints of fever, lethargy, loss of appetite. Consciousness: clear. Body temperature 36.6°C. Body weight 12 kg. The child is lethargic and capricious. A Broviak central venous catheter was installed for parenteral nutrition. The color of the skin is pale pink, with a reticulated crimson marble pattern. Drug-induced Itsenko-Cushing syndrome. Breathing is puerile, spontaneous. NPV 26 per minute. The breathing rhythm is regular. No wheezing. Nasal breathing: free. Heart rate 120/min. Heart rhythm: arrhythmic. Heart sounds are muffled. The abdomen is soft and painless on palpation. Stool without pathological changes, tendency to diarrhea. There is no vomiting. The liver and spleen are not palpable. Urination is painless. Urine color: yellow (normal). The kidney area is not changed. There are no focal or meningeal signs.

Instrumental studies:

X-ray of the OGK 12/05/2020: There is no convincing radiological evidence for pneumonia, radiological signs of a viral infection.

Ultrasound examination of the abdominal organs 12/27/2020: Echo signs of hepatosplenomegaly, free fluid in the right lateral canal.

Ultrasound examination of the abdominal organs 01/03/2021: Echo signs of hepatosplenomegaly, moderate diffuse changes in the pancreas, severe flatulence.

Ultrasound examination of the thyroid gland and parathyroid glands 01/07/2021: Echo signs of thyroid hypoplasia.

Computed tomography of the chest organs 02/20/2021: CT picture of bilateral polysegmental pneumonia, the volume of lung tissue damage on both sides is about 75%.

Ultrasound examination of the abdominal organs and kidneys 02/27/2021: Echo signs of hepatosplenomegaly, diffuse changes in the pancreas, dynamic intestinal disorders, severe flatulence. Echo signs of diffuse changes in the walls of the kidneys.

X-ray of the chest organs 02/27/2021: X-ray signs of the course of bilateral pneumonia with negative dynamics. Reaction of the pleura on the left.

Ultrasound examination of the abdominal organs 02/28/2021: Echo signs of hepatosplenomegaly, dyscholia. Intestinal paresis. Flatulence. Lymphadenopathy.

Chest X-ray 02/28/2021: X-ray signs of the course of bilateral pneumonia, without significant X-ray changes compared to chest X-ray from 02/27/2021.

Echocardiography 02/28/2021: The study was conducted against the backdrop of resuscitation measures. An ultrasound examination does not detect heart contraction.

The results of laboratory tests are shown in tables 8-11.

Interpretation of results: For Index S/CO - Ig G (antibodies to nucleocapsid protein): <0.49 - not detected; ≥0.49 - <1.40 - gray zone (borderline result); ≥1.40 - detected.

For Index S/CO - Ig G S1 (neutralizing antibodies to the receptor-binding domain (RBD) of the S1 protein): ≤0.80 - not detected; >0.80 - <1.00 - gray zone (borderline result); ≥1.00 - detected.

For Index S/CO - Ig M: <1.00 - not detected; ≥1.00 - detected.

Results of bacteriological studies:

from 01/11/21 blood culture - Staphylococcus epidermidis;

from 01/22/21 blood culture - Staphylococcus epidermidis;

from 02.24.21 urine culture - Candida sp.;

from 02.24.21 culture from the anus - Candida albicans, Enterobacter cloacae ssp. Cloacae;

from 02.24.21 blood culture - microflora growth was not detected;

from 02/26/21 blood culture - Staphylococcus intermedius;

from 02.28.21 sputum culture - Staphylococcus ntermedius, Candida albicans.

During his stay in the infectious diseases department No. 1, the condition remained stably severe; despite the ongoing therapy, the administration of dexamethasone, there was a progressive weight gain of up to 2 kg, which required a dose reduction. The stool is liquefied up to 4-5 times a day with an area of water, and bloating persists. IVIG therapy was carried out, and antibacterial therapy was adjusted based on the results of biological media cultures. When re-examined for coronavirus, the PCR test is positive. Over the next 10 days of observation, the child had a persistent low-grade fever, with a one-time increase in body temperature to 38.1°C, which was associated with bacterial and fungal complications. Antibacterial therapy was adjusted, and the dose of dexamethasone was gradually reduced. Against this background, the child’s stool became more frequent up to 8 times a day, the liquid part increased (large circle of water), periodically there was a decrease in the level of total protein and albumin from 32 to 28 g/l, which required albumin transfusion, and repeated administration of IVIG was also carried out. Repeated PCR swabs for COVID-19 are positive, ELISA COVID-19 is negative. During the period from 60 to 70 days, negative dynamics were observed in the form of increased diarrhea syndrome (stools became watery up to 8-11 times a day), appetite worsened, an increase in tachycardia and tachypnea, anxiety, and grade 2 anemia (Hb - 92 g/l) was noted. , a decrease in albumin levels is noted again. The results of the immune status were obtained - humoral immunity IgM IgG IgA - no. IVIG and albumin are administered again. A consultation was held with the Russian Children's Clinical Hospital of the Federal State Autonomous Institution VShch Russian National Research Medical University named after. N.I. Pirogov Ministry of Health of the Russian Federation and Federal State Budgetary Institution "National Medical Research Center for Dogs named after. Dmitry Rogachev" of the Ministry of Health of the Russian Federation. For a child with primary immunodeficiency and a low level of antibodies to SARS-CoV-2, it is recommended for health reasons to receive anti-Covid non-quarantine plasma. However, it was decided to refrain from introducing it in the future. In the following days, intoxication syndrome increases, fever reaches febrile levels over the next 4 days, stool becomes thin and frequent up to 12-14 times a day, the child is lethargic, adynamic, weight gain progresses, and he eats poorly. Since 02/13/2020, the condition worsened, she became lethargic, inactive, refused to eat, shortness of breath and O2 dependence appeared. A CT scan of the chest was performed and pneumonia was detected with a lesion volume of 75% (CT-3). On 02/20/21, due to negative dynamics for subsequent treatment and observation, he was transferred to ICU No. 2 on the 78th day of treatment.

The severity of the condition of a child 2 years 4 months old with an immunodeficiency state, autoimmune gastroenteropathy, protein-energy deficiency, repeated episodes of sepsis in history, a carrier of the Broviac venous port, is due to symptoms of persistent intoxication, stage 1-2 DN, water-electrolyte imbalance, gastrointestinal insufficiency 1 -2 degrees, anemia, coagulopathy, against the background of bilateral pneumonia of mixed etiology. New coronavirus infection COVID-19, persistent viral carriage.

Consilium dated 12/08/2020: Considering viral-induced leukopenia and agranulocytosis, high-dose therapy with 10% normal human immunoglobulin for intravenous administration at a dose of 2 g/kg body weight (5 g) No. 3 and G-CSF preparations (filgrastim, lenograsim) is indicated for the therapy. at a starting dose of 5 mcg/kg/administration under the control of leukocyte and granulocyte levels.

Conclusion of the consultation dated 02/24/2021: a patient with primary immunodeficiency, persistence of COVID-19, has a deterioration in her condition in the form of progression of lung damage of mixed viral-bacterial origin. The tactics recommend:

1. Considering the persistent viral release of SARS-CoV-2 RNA, consider administering plasma from a donor who has had COVID-19 according to scheme: No. 3 with an interval of 3-4 days.

2. Consider remdesivir therapy. Considering deep leukopenia, mainly due to neutropenia, therapy with GCSF drugs is recommended, starting with 5 mg/kg, then individually at a selected dose, in order to maintain granulocytes of at least 1000 cells per μl. Drug treatment:

1. Infusion therapy with glucose-saline solutions according to the clinical situation.

2. Parenteral nutrition Aminoven 15% 55 ml + Smoflipid 20% 25 ml from 12/04/2020 to 02/20/2021, Aminoven 15% 3 g/kg/day 229 ml + Smoflipid 20% 3.5 g/kg/day 200 ml with 02/21/2021 - 02/28/2021.

3. Transfusion therapy with blood products:

- Er. mass O(I)Rh positive 100 ml 02/20/2021,

- FFP O(I)Rh positive 100 ml 02/25/2021,

- Albumin 20% 50 ml 01/15/2021, 50 ml 01/16/2021, 25 ml 01/23/2021, 25 ml 01/24/2021, 100 ml 02/16/2021.

4. Immunoreplacement therapy:

- Prividgen 50 ml No. 3 (12-14.12.2020), 50 ml No. 1 12.25.2020,

- Gabriglobin 25 ml 01/15/2021, 25 ml 01/16/2021, 100 ml 02/08/2021, 100 ml 02/16/2021, 50 ml 02/21/2021, 50 ml 02/28/2021.

5. Therapy with G-CSF drugs.

6. Antibacterial therapy:

- Biseptol 10 mg/kg/day, 120 mg × 2 times from 12/05/2020, from 02/26/2021 20 mg/kg to 02/28/2021.

- Meronem 150 mg × 3 times from 12/05/2020 to 12/20/2020,

- Vancomycin 150 mg × 3 times from 12/05/2020 to 12/20/2020,

- Baktsefort 600 mg × 2 times from 12/21/2020 to 01/08/2021,

- Ciprofloxacin 100 mg × 2 times from 01/08/2021 to 02/08/2021,

- Vancomycin 100 mg × 4 times from 01/16/2021 to 02/08/2021,

- Linezolid 110 mg × 3 times from 02/09/2021 to 02/16/21, per os from 02/17/2021 to 02/24/2021, IV 02/25/2021,

- Imipenem 165 mg × 4 times from 02/09/2021 to 02/20/2021,

- Piperacillin-tazobactam 360 mg/kg/day, 1030 mg × 4 times from 02/21/2021 to 02/26/2021,

- Polymyxin 12 mg 2 times from 02/24/2021 to 02/28/2021,

- Meropenem 230 mg × 3 times from 02/27/2021 -02/28/2021.

7. Hormonal therapy: Dexamethasone - 1 mg morning and evening from 12/04/2020 to 01/06/2021; 1 mg morning and 0.5 mg evening from 01/07/2021 to 01/09/2021; 0.5 mg morning and evening from 01/10/2021 to 01/16/2021; 0.5 mg morning from 01/17/2021 - 02/28/2021.

8. Antifungal therapy:

- Voriconazole 50 mg × 2 times from 12/05/2020 to 12/08/2020,

- Diflucan 50 mg × 2 times from 12/09/2020 to 12/24/2020,

- Voriconazole 50 mg × 2 times from 12/24/2020 to 02/20/2021,

- Mikamin 55 mg × × 1 time from 02/21/2021 to 02/28/2021.

9. L-thyroxine 75 mg from 12/05/2020.

10. Heparin therapy: Heparin 12-15 U/kg/hour under APTT control from 02/20/202128/02/2021.

11. Omeprozole 10 mg × 1 time from 12/07/2020 - 02/28/2021.

12. Ursofalk 1 mg × 1 time from 12/05/2020 - 02/28/2021.

13. Heptral 100 mg × 2 times from 12/05/2020 to 01/03/2021.

14. Bifidumbacterin 5 doses × 2 times from 12/25/2020 - 02/28/2021.

15. Panzinorm U2 tablet × 4 times from 12/05/2020 to 02/20/2021.

16. Reamberin 50 ml × 1 time from 02/27/2021 - 02/28/2021.

17. Midazolam 0.5% 4 mcg/kg/min from 02/27/2021 - 02/28/2021.

18. Croiron 0.2 mg/kg/hour from 02/28/2021 - 02/28/2021.

19. Neoton 1 g/day from 02/21/2021 - 02/28/2021.

20. Veroshpiron 23 mg × 2 times from 02/24/2021 - 02/28/2021.

21. Biological therapy: anti-Covid plasma 300 ml No. 1 dated 02/24/2021.

22. Mechanical ventilation 02/27/2021 - 02/28/2021.

During observation in ICU No. 2, the child’s condition remained serious. Collectively, with the involvement of specialized specialists, treatment tactics were developed. Anti-Covid plasma was administered once. However, on the 84th day there was an increase in fever and worsening cardiopulmonary failure, and therefore the child was transferred to controlled ventilation (8th day in the ICU). On 02/28/2021, a disturbance in heart rhythm, a progressive decrease in saturation, and a decrease in blood pressure were noted. Despite the full range of resuscitation measures, biological death was confirmed at 14.20 on 02/28/2021.

A patient aged 2 years and 5 months with persistent COVID-19 against the background of primary immunodeficiency, despite complex treatment with anti-Covid plasma, died due to the progression of respiratory failure and bacterial and fungal complications. After the use of anti-Covid plasma, the immunocompromised child did not experience an increase in IgG to SARS-CoV-2, from 1.74 FU/ml to 1.51 FU/ml. SARS-CoV-2 RNA from upper respiratory tract secretions persisted for more than 90 days. Immunocompromised children with COVID-19 require more effective and safe immunobiological therapy to treat the new coronavirus infection COVID-19.

The declared solution expands the arsenal of methods for treating coronavirus infection COVID-19 in children. Promotes a more favorable course of the disease and is an effective and safe treatment method that can prevent the progression of the disease in children at risk of severe COVID-19 and eliminate the SARS-CoV-2 virus from the body in immunocompromised children.

Claims (3)

1. A method of treating COVID-19 in children at risk of severe disease with viral shedding of SARS-CoV-2 lasting more than 10 days, including antiviral, symptomatic, antibacterial therapy against the background of therapy for the underlying disease prescribed before infection with COVID-19, Additionally, the drug Human Immunoglobulin against COVID-19 is administered at a dose of 0.3-1.1 ml/kg body and an amount of 1-3 infusions at intervals of 24-72 hours if the result of SARS-CoV-2 is positive. 2. The method of treating COVID-19 according to claim 1, characterized in that before each administration of Human Immunoglobulin against COVID-19, the patient is tested for IgG to SARS-CoV-2, and the infusion is carried out if there is a positive result of such control. 3. The method of treating COVID-19 according to claim 1, characterized in that infusions of Human Immunoglobulin against COVID-19 are carried out regardless of the severity of the disease.