Аннотация (русский):
The purpose of the monograph, which contains a modern view of the problem of adaptation of children with extremely low body weight, is to provide a wide range of doctors with basic information about the clinical picture, functional activity of innate and adaptive immunity, prognostic criteria of postnatal pathology, based on their own research. The specific features of the immunological reactivity of premature infants of various gestational ages who have developed bronchopulmonary dysplasia (BPD) and retinopathy of newborns (RN) from the moment of birth and after reaching postconceptional age (37-40 weeks) are described separately. The mechanisms of their implementation with the participation of factors of innate and adaptive immunity are considered in detail. Methods for early prediction of BPD and RN with the determination of an integral indicator and an algorithm for the management of premature infants with a high risk of postnatal complications at the stage of early rehabilitation are proposed. The information provided makes it possible to personify the treatment, preventive and rehabilitation measures in premature babies. The monograph is intended for obstetricians-gynecologists, neonatologists, pediatricians, allergists-immunologists, doctors of other specialties, residents, students of the system of continuing medical education. This work was done with financial support from the Ministry of Education and Science, grant of the President of the Russian Federation No. MK-1140.2020.7.

Ключевые слова:
Children, extremely low body mass, neonatal pathology, immune system, weight, immunity, postnatal pathology, newborns

The problem of predicting outcomes in premature infants with ELBW remains relevant, which is due to both the lack of normative indicators and the absence of prognostic criteria that will allow differentiating various pathological conditions in the early postnatal period. It is not possible often to predict the severity and course of perinatal complications, since the clinical manifestations in a newborn may have a blurred picture and their delayed development. As the survival rate of infants born with ELBW increased. BPD began to exert a significant influence on the prognosis of their health and life, with outcomes ranging from clinical recovery to high mortality (11–36%) in the first year of life [1]. According to modern authors, the “new” or post-surfactant form of BPD in very premature infants is characterized by a more favorable course [2, 3, 4, 5]. However, severe forms of the disease are more typical for children with extreme immaturity in the presence of concomitant risk factors [6]. According to the classification formulated in 2001 by A.H. Jobe, E.H. Bancalari, distinguish several degrees of BPD severity: mild - oxygen support up to 28 days of life and older and with its termination up to 36 weeks of postconceptional age (PCA); of moderate severity - oxygen support up to 28 days of life and older with FiO2 <0.3 at 36 weeks of PCA; severe - the need for oxygen support at 36 weeks PCA with FiO2> 0.3. The development of complications (chronic and acute respiratory failure on the background of chronic, systemic arterial and pulmonary hypertension, osteoporosis, malnutrition, anemia) determine the severity and prognosis of BPD [7]. The incidence of BPD is higher in children with less birth weight and gestational age, which is confirmed by the results of various studies, for example, in deeply premature newborns with a birth weight of 500 to 750 grams, bronchopulmonary dysplasia is diagnosed in 35-67%, and in children from 1000 to 1500 grams does not exceed 3.6% of cases [8]. According to foreign authors, the frequency of BPD in very premature babies ranges from 29 to 49%, and in babies born at the time of very early preterm birth, it rises to 67% [9, 10, 11]. According to the studies of domestic authors, in newborns born at less than 32 weeks, a certain tendency towards a decrease in the incidence of BPD (15-30%) was noted, which is probably associated with the improvement of respiratory support and intensive care methods, as well as a change in diagnostic criteria. However, mortality in the first year of life remains quite high (11-36%) [12, 13]. By the time of discharge from the hospital, most of the children with severe BPD have concomitant diseases caused by perinatal damage to the central nervous system, vision, hearing and other organs and systems, and by the age of one. They have psychomotor development disorders and constitute a risk group for the formation of obstructive pulmonary disease [6, 14, 15, 112]. This fact gives the BPD problem a great medical and social significance, which served as the purpose of studying the relationship between immunological parameters and the severity of the disease. 4.1. Immunological reactivity of the immune system of children with bronchopulmonary dysplasia in the dynamics of the postnatal period Depending on the outcome of the disease in 38-40 weeks of PCA and taking into account the gestational age (from very early and early preterm birth), children who subsequently developed BPD were subdivided into groups during the study. Babies with BPD with GA of 22-27 weeks: Group 1A - severe BPD, n = 17; Group 1B - BPD of mild and moderate severity, n = 18; 1C group - without BPD, n = 7. Children with BPD with GA of 28-31 weeks: Group 2A - BPD of severe severity, n = 9; Group 2B - BPD of mild and moderate severity, n = 24; Group 2C - without BPD n = 9. Studies have shown that all children who subsequently developed severe BPD, regardless of gestational age, had a lower body weight than children with mild to moderate degrees. At the same time, very premature infants with GA of 28-31 weeks with severe BPD had the lowest body weight (781.11 ± 158.6 g versus 909.08 ± 84.9 g and 951.22 ± 51.48 g). However, infants from very early prematurities had a lower gestational age (25.4 ± 1.53 versus 26.2 ± 0.88 weeks with mild to moderate BPD). No significant differences were found between the severity of BPD and the incidence of sepsis and pneumonia in children from very early prematurity. In children from early preterm birth, this pathology was almost 1.7 times more likely to be diagnosed in children with severe BPD than in children with mild and moderate BPD. The etiology and pathogenesis of early anemia in premature infants are mainly determined by the physiological and biochemical characteristics of erythropoiesis and its regulation, as well as the gestational age of the child, since the most significant changes in hematopoiesis occur in the last 3 months of gestation [1]. It is known that the reserve fund of iron in premature infants is reduced and depends on the body weight at birth. Our studies have shown that anemia of prematurity was observed more often in children with ELBW of gestational age of 22-27 weeks. Moreover, severe anemia during the neonatal period in children with severe BPD, both from early and early preterm births, was 2.5 and 2.8 times more frequent than in children of the same gestational age with mild and moderate BPD, which required a greater number of repeated blood transfusions in newborns from very early preterm labor (4.3 ± 2.19 versus 2.2 ± 1.3 times, p <0.01). In children with GA of 28-31 weeks and severe BPD, repeated blood transfusions were 2 times more frequent (2.7 ± 1.75 versus 1.3 ± 1.5 times in children with mild to moderate BPD). However, no significant differences were found. When examining the umbilical cord blood of children with BPD who were born at the time of very early preterm labor, a significant increase in the absolute number of leukocytes was found (Table 31). Absolute lymphocytosis was significantly more frequent in children with severe BPD. Also in this group of children, the content of lymphocytes (CD3 - p1-2 = 0.047, p1-3 = 0.008, CD4 - p1-2 = 0.02, p1-3 = 0.05, CD19 - p1-2 = 0.02, p1-3 = 0.01) and NK cells (p1-2 = 0.05, p1-3 = 0.043) significantly exceeded the indicators of children with mild and moderate BPD and children without BPD, which indicated activation of the B-cell link immunity and increased cytotoxic potential. An increase in the number of regulatory cells with a receptor for IL-2, which is an activation marker (CD25+CD4+) (p1-2 = 0.05, p2-3 = 0.05) promotes the accelerated differentiation of regulatory lymphocyte populations and is the most important result of activation. Table 31 Population and subpopulation composition of umbilical cord blood lymphocytes from very early preterm labor that formed BPD, IU (P25-P75) Indicators Children of GA of 22-27 weeks Group 1А (n=17) Group 1В (n=18) Group 1С (n=7) Р Leukocytes, 109/l 7,0(6,4-12,0) 11,85(7,15-17,45) 5,0(3,78-6,4) 1А-1С=0,02 1В-1С=0,001 Lymphocytes, % 68,5(56,25-73,0) 78,0(70,3-81,50) 71,0(65,0-75,0) Lymphocytes, 109/l 5,1(3,83-9,2) 3,44(3,09-3,69) 3,38(2,38-3,55) 1А-1В=0,015 1А-1С =0,013 CD3+, % 46,0(35,0-51,0) 38,0(35,0-69,0) 37,0(33,5-40,0) CD3+, 109/l 2,24(1,85-3,94) 1,42(1,31-1,78) 1,31(1,02-1,36) 1А-1В=0,047 1А-1С =0,008 CD19+, % 12,0(7,0-19,0) 8,0(6,0-12,8) 12,0(8,5-130) CD19+, 109/l 1,06(0,25-1,46) 0,29 (0,22-0,44) 0,43(0,33-0,49) 1А-1В =0,02 1А-1С =0,01 CD4+, % 31,0(24,0-38,0) 41,5(28,3-56,0) 23,0(18,0-25,5) 1А-1В =0,01 1В-1С =0,001 CD4+, 109/l 1,7(0,8-2,3) 1,31(1,13-1,54) 0,78(0,63-0,93) 1А-1В =0,014 1В-1С =0,017 CD8+, % 11,0(9,0-13,0) 15,5 (11,8-16,0) 9,0(7,5-13,5) 1А-1В =0,06 1в-1С =0,048 CD8+, 109/l 0,54(0,3-1,34) 0,45(0,38-0,48) 0,28 (0,22-0,46) CD16+CD56+, % 8,0(4,0-10,0) 3(2,5-3,5) 2,0(2,0-3,0) 1А-1В =0,001 1А-1С =0,001 CD16+CD56+, 109/l 0,39(0,09-1,09) 0,11 (0,08-0,12) 0,09(0,06-0,12) 1А-1В =0,048 1А-1С =0,048 CD4/CD8 2,54(2,18-3,33) 3,43(2,91-4,15) 3,11(2,17-3,47) CD25/CD4+, % 3,0(2,0-5,0) 5,5(2,75-9,0) 2,0(1,0-3,0) 1А-1В =0,05 1В-1С =0,05 CD25/CD4+, 109/l 0,19(0,06-0,25) 0,19(0,10-0,28) 0,09(0,03-0,11) 1А-1С =0,01 1В-1С =0,01 Note. p - the significance of differences between the groups of children (Mann-Whitney test): group 1A - children with severe BPD III degree, group 1B - children with mild and moderate BPD, group 1C - children without BPD. In children from early preterm birth, who formed and did not form BPD, the indicators of cellular immunity were comparable (Table 32). Table 32 Population and subpopulation composition of umbilical cord blood lymphocytes of children from early preterm birth formed BPD, UI (P25-P75) Indicators Children of GA of 28-31 weeks Group 2А (n=9) Group 2В (n=25) Group 2С (n=9) Leukocytes, 109/l 6,6(4,7-6,9) 8,7(6,05-12,5) 9,0(5,5-9,9) Lymphocytes, % 75,5(68,8-80,3) 69,0(54,75-75,0) 65,5(60,5-70,5) Lymphocytes, 109/l 3,6(3,28-5,21) 3,77(2,95-6,86) 7,49(5,5-14,43) CD3+, % 47,0(44,5-50,5) 43,5(39,5-54,25) 37,0(35,0-45,5) CD3+, 109/l 1,74(1,43-2,15) 1,71(1,23-3,19) 3,2(3,23-7,26) CD19+, % 14(10-23) 14(9,25-17,25) 14(11,5-15) CD19+, 109/l 0,47(0,37-1,2) 0,59 (0,47-0,72) 0,83(0,59-2,86) CD4+, % 33,0(25,5-35,0) 32,5(26,75-38,0) 21,0(18,5-31,0) CD4+, 109/l 1,03(0,95-1,5) 1,25(0,92-2,42) 2,43(1,62-3,66) CD8+, % 12,0(10,5-16,5) 14,5(11,5-11,75) 13(11-14) CD8+, 109/l 0,6(0,31-0,69) 0,58(0,42-0,9) 0,89(0,69-1,82) CD16+56+, % 7,0(3,75-11,75) 5,5(3,0-10,5) 6,0(5,5-9,0) CD16+CD56+, 109/l 0,21(0,08-0,35) 0,23(0,09-0,59) 0,71(0,45-1,27) CD4/CD8 3,08(2,01-3,19) 2,07(1,73-3,31) 1,78(1,7-2,26) CD25+CD4+, % 4,0(2,5-5,5) 4,0(3,0-4,5) 2,5(1,75)4,0 CD25+CD4+, 109/l 0,18(0,13-0,28) 0,14(0,12-0,21) 0,3(0,15-0,54) Note. significance of differences between groups of children (Mann-Whitney test) in all cases, p> 0.05. By the end of the late neonatal period, an increase in the absolute number of T-cytotoxic CD8+ cells (p2-3 = 0.04) was observed at the level of a trend in the peripheral blood of children born at the time of very early preterm labor with mild and moderate BPD (Table 33). Table 33 Population and subpopulation composition of peripheral lymphocytes of premature babies at the age of 1 month of life, who formed BPD, IU (P25-P75) Indicators Children of GA of 22-27 weeks Group 1А (n=17) Group 1В (n=18) Group 1С (n=7) Р Leukocytes, 109/l 10,9(9,8-14,1) 10,21(7,95-11,42) 8,15(7,63-9,64) 1А-1С =0,06 Lymphocytes, % 50,5(43,75-58,0) 62,0(59,25-66,75) 60,0(58,0-63,0) Lymphocytes, 109/l 3,43(1,93-4,35) 4,42(3,35-6,12) 4,93(4,44-5,89) 1А-1В =0,08 1А-1С =0,03 CD3+, % 55(53-72) 54(48,5-67,0) 48(47-56) CD3+, 109/l 2,39(1,21-2,47) 2,12(1,56-3,14) 2,32(2,18-2,38) CD19+, % 22(14-30) 10(8-14) 16(13-17,5) CD19+, 109/l 0,26(0,22-0,5) 0,49(0,17-0,65) 0,77(0,57-0,81) CD4+, % 41(23-42) 39(28,5-48,5) 40(37-44,5) CD4+, 109/l 1,82(0,37-1,83) 1,24(1,18-2,21) 1,79(1,65-1,86) CD8+, % 21(20-28) 17(14,5-24) 14(11-16) CD8+, 109/l 0,72(0,54-0,83) 0,94(0,55-1,16) 0,62(0,50-0,64) 1В-1С=0,04 CD16+CD56+, % 17(10-18) 10(7-15,5) 11(10,5-11,0) CD16+CD56+, 109/l 0,44(0,27-0,46) 0,43(0,27-0,82) 0,48(0,44-0,49) CD4/CD8 2,1(0,44-2,52) 2,15(1,11-2,93) 2,72(2,57-3,86) CD25+CD4+, % 4(4-5) 6(4-7) 6(5,5-6,5) CD25+CD4+, 109/l 0,17(0,08-0,19) 0,21(0,17-0,42) 0,29(0,24-0,30) Note. p - the significance of differences between groups of children (Mann-Whitney test): group 1A - children who have formed severe BPD III degree, group 1B - children who have formed BPD mild and moderate degree, group 1C - children without BPD. In newborns with GA of 28-31 weeks, no significant differences in the parameters of the cellular component of immunity were found (Table 34). Table 34 Population and subpopulation composition of peripheral lymphocytes of premature babies at the age of 1 month of life, who formed BPD, IU (P25-P75) Indicators Children of GA of 28-31 weeks Group 2А (n=9) Group 2В (n=25) Group 2А (n=9) Leukocytes, 109/l 6,6(4,7-6,9) 8,7(6,05-12,5) 9,0(5,5-9,9) Lymphocytes, % 75,5(68,8-80,3) 69,0(54,75-75,0) 65,5(60,5-70,5) Lymphocytes, 109/l 3,6(3,28-5,21) 3,77(2,95-6,86) 7,49(5,5-14,43) CD3+, % 47,0(44,5-50,5) 43,5(39,5-54,25) 37,0(35,0-45,5) CD3+, 109/l 1,74(1,43-2,15) 1,71(1,23-3,19) 3,2(3,23-7,26) CD19+, % 14(10-23) 14(9,25-17,25) 14(11,5-15) CD19+, 109/l 0,47(0,37-1,2) 0,59 (0,47-0,72) 0,83(0,59-2,86) CD4+, % 33,0(25,5-35,0) 32,5(26,75-38,0) 21,0(18,5-31,0) CD4+, 109/l 1,03(0,95-1,5) 1,25(0,92-2,42) 2,43(1,62-3,66) CD8+, % 12,0(10,5-16,5) 14,5(11,5-11,75) 13(11-14) CD8+, 109/l 0,6(0,31-0,69) 0,58(0,42-0,9) 0,89(0,69-1,82) CD16+CD56+, % 7,0(3,75-11,75) 5,5(3,0-10,5) 6,0(5,5-9,0) CD16+CD56+, 109/l 0,21(0,08-0,35) 0,23(0,09-0,59) 0,71(0,45-1,27) CD4/CD8 3,08(2,01-3,19) 2,07(1,73-3,31) 1,78(1,7-2,26) CD25+CD4+, % 4,0(2,5-5,5) 4,0(3,0-4,5) 2,5(1,75)4,0 CD25+CD4+, 109/l 0,18(0,13-0,28) 0,14(0,12-0,21) 0,3(0,15-0,54) Note. the significance of differences between groups of children (Mann-Whitney test) in all cases, p> 0.05. An increased content of NK cells remained (p1-3 = 0.01) by 38-40 weeks of PCA in the peripheral blood of children born at the time of very early preterm labor who developed severe BPD, which is associated with the transferred infectious-inflammatory diseases (Table 35 ). Table 35 Population and subpopulation composition of peripheral blood lymphocytes of premature infants with BPD in 38-40 weeks of PCA, IU (P25-P75) Indicators Children of GA of 22-27 weeks Group 1А (n=17) Group1В (n=18) Group 1А (n=17) Р Leukocytes, 109/l 8,6(7,7-8,95) 7,11(5,57-8,54) 6,71(6,48-7,57) Lymphocytes, % 69,0(54,5-73,8) 68,5(64,8-79,3) 61,5(58,5-65,25) Lymphocytes, 109/l 4,19(3,24-4,74) 4,54(4,12-5,18) 4,32(3,95-4,67) CD3+, % 48,5(35,0-60,5) 50,0(45,5-55,0) 60,0(57,5-64,5) 1А-1С=0,04 CD3+, 109/l 1,74(1,52-2,53) 2,05(1,75-2,87) 2,36(2,32-2,41) 1А-1С =0,025 CD19+, % 34,0(18,0-38,75) 28,0(17,5-30,0) 20,0(16,0-23,5) CD19+, 109/l 1,07(0,49-1,48) 1,24(0,6-1,53) 0,68(0,6-0,91) CD4+, % 29,0(26-36) 34(24-37) 44(38,5-47) CD4+, 109/l 1,05(0,84-1,57) 1,44(1,13-1,72) 1,71(1,63-1,76) 1А-1С =0,010 CD8+, % 19,5(13,5-25,5) 15,0(12,5-20,5) 18,0(17,5-22,0) CD8+, 109/l 0,61(0,43-0,94) 0,67(0,53-0,78) 0,70(0,66-0,75) CD16+CD56+, % 22,0(10,5-24,5) 12,0(8,5-16,5) 8,5(7,3-10,0) 1А-1С =0,010 CD16+CD56+, 109/l 0,53(0,29-0,91) 0,58(0,33-0,68) 0,31(0,28-0,44) CD4/CD8 1,81(0,94-2,39) 2,11(1,65-2,5) 2,7(2,6-2,75) CD25+CD4+, % 4,5(3,3-5,0) 4,0(3,75-5,3) 5,0(4,8-5,25) CD25+CD4+, 109/l 0,19(0,11-0,24) 0,18(0,15-0,23) 0,19(0,18-0,21) Note. p - the significance of differences between groups of children (Mann-Whitney test): group 1A - children who have formed severe BPD III degree, group 1B - children who have formed BPD mild and moderate, group 1C - children without BPD. A decrease in the absolute and relative number of CD3 cells of the 1st group (p1-3 = 0.04, p1-3 = 0.03) testified to the insufficiency of the cellular effector link of immunity, and a decrease in CD4 lymphocytes (p1-3 = 0, 01) - disruption of the regulatory link of immunity. In children from early preterm labor with severe BPD, there was an increase in the number of leukocytes, and at the level of the trend in the percentage of CD16+CD56 + lymphocytes, no changes were found in other parameters of cellular immunity (Table 36). Table 36 Population and subpopulation composition of peripheral blood lymphocytes of premature infants with BPD in 38-40 weeks of PCA, IU (P25-P75) Indicators Children of GA of 28-31 weeks Group 2А (n=9) Group 2В (n=25) Group 2А (n=9) Р Leukocytes, 109/l 9,2(8,59-9,8) 6,78(6,4-8,63) 7,19(6,5-8,7) 2А-2В=0,025 2В-2С =0,03 Lymphocytes, % 73,5(65,75-80,0) 67,0(60-69,75) 79(71-79) Lymphocytes, 109/l 5,62(4,37-7,07) 4,65(4,05-4,84) 5,14(4,44-5,61) CD3+, % 51,0(44,25-53,75) 49,0(43,25-52,75) 50(50-51) CD3+, 109/l 2,35(2,27-2,73) 2,11(1,8-2,41) 2,62(2,47-2,64) CD19+, % 30,5(27,25-34,75) 27,5(19,5-34,0) 25,0(22,0-29,0) CD19+, 109/l 1,87(1,23-2,56) 1,23(0,85-1,49) 1,13(1,11-1,8) CD4+, % 32,5(24,5-38,75) 33,5(28,75-38,5) 37(32-43) CD4+, 109/l 1,74(1,52-1,93) 1,44(1,3-1,7) 1,91(1,63-2,21) CD8+, % 14,0(11,5-18,5) 13,5(13,0-18,5) 15(12-18) CD8+, 109/l 0,81(0,5-1,33) 0,62(0,59-0,76) 0,78(0,6-0,8) CD16+CD56+, % 17,0(14,5-19,25) 13,5(10,0-15,0) 12,0(7,0-12) 2А-2С =0,073 CD16+CD56+, 109/l 1,01(0,63-1,4) 0,63(0,34-0,69) 0,62(0,31-0,72) CD4/CD8 2,08(1,08-3,41) 2,17(1,88-2,38) 3,08(1,77-3,2) CD25+CD4+, % 4,0(3,0-5,5) 5(5-6) 4(4-5) CD25+CD4+, 109/l 0,23(0,22-0,25) 0,24(0,20-0,29) 0,20(0,18-0,26) Note. p - the level of significance of differences between groups of children (Mann-Whitney test): group 2A - children with severe BPD of III degree, group 2B - children who have formed BPD of mild and moderate degree, group 2C - children without BPD. When assessing the intracellular cytokines of the umbilical cord blood, there were no significant differences between the compared groups of children (Tables 37, 38) Table 37 Levels of intracellular cytokines in the umbilical cord blood of premature infants who have formed BPD, IU (P25-P75) Indicators Group 1А (n=17) Group 1В (n=18) Group 1С (n=7) CD4+CD3+IFN-γ self-existing, % 2,9(1,36-4,13) 2,31(1,74) 3,95(2,51-8,03) CD4+IFN-γ suscitate, % 3,83(2,86-6,17) 4,49(2,61-6,5) 4,58(2,52-6,0) CD4+IL-4 self-existing, % 2,47(1,32-3,06) 1,69(0,77-3,94) 0,9(0,9-1,38) CD4+IL-4 suscitate, % 3,84(2,43-5,7) 4,59(2,73-5,01) 4,9(3,35-4,9) CD4+IFN-γ+ / CD4+IL-4+ self-existing, c.u. 1,36(1,28-1,72) 1,54(1,28-1,75) 1,26(1,21-1,27) CD4+IFN-γ+ / CD4+IL-4+ suscitate, c.u. 1,8(1,04-1,54) 1,16(0,97-1,51) 1,22(1,21-1,3) Note. The level of significance of differences between groups of children (Mann-Whitney test) in all cases, p> 0.05. Table 38 Levels of intracellular cytokines in the umbilical cord blood of premature infants who have formed BPD, IU (P25-P75) Indicators Group 2А (n=9) Group 2В (n=25) Group 2С (n=9) CD4+CD3+IFN-γ self-existing, % 3,59(2,85-5,04) 3,18(2,78-4,5) 5,82(1,89-6,09) CD4+IFN-γ+ suscitate, % 5,44(4,63-6,11) 3,96(2,35-7,67) 6,5(4,58-9,06) CD4+IL-4+ self-existing, % 3,04(0,82-4,32) 1,25(0,82-3,17) 2,28(0,78-2,5) CD4+IL-4+ suscitate, % 3,22(2,88-4,5) 2,95(2,22-3,8) 3,6(2,6-4,32) CD4+IFN-γ+ / CD4+IL-4+ self-existing, c.u. 2,04(,184-3,13) 2,42(1,37-2,65) 2,55(1,43-2,8) CD4+IFN-γ+ / CD4+IL-4+ suscitate, c.u 1,58(1,32-1,84) 1,14(0,64-2,05) 1,9(1,68-2,1) Note. The level of significance of differences between groups of children (Mann-Whitney test) in all cases, p> 0.05. When assessing the intracellular cytokines of the peripheral blood of children of all groups, no significant differences were found (Tables 39, 40). Table 39 Intracellular cytokine levels in premature infants with BPD at 1 month of life, IU (P25-P75) Indicators Group 1А (n=17) Group 1В (n=18) Group 1С (n=7) CD4+CD3+IFN-γ+ self-existing, % 2,5(1,22-4,56) 1,93(1,24-3,91) 3,87(3,4-5,59) CD4+IFN-γ+ suscitate, % 3,55(2,51-5,05) 3,39(2,23-4,25) 7,84(6,2-10,18) CD4+IL-4+ self-existing, % 1,79(0,91-3,12) 1,55(1,02-2,44) 2,73(2,6-2,95) CD4+IL-4+ suscitate, % 2,71(1,7-3,49) 2,18(1,68-3,29) 3,28(3,1-4,81) CD4+IFN-γ+ / CD4+IL-4+ self-existing, c.u. 1,36(1,26-1,62) 1,29(1,15-1,46) 1,42(1,37-1,45) CD4+IFN-γ+ / CD4+IL-4+ suscitate, c.u. 1,63(1,52-2,45) 1,64(1,46-2,14) 2,21(1,86-2,57) Note. Significance of differences between groups of children (Mann-Whitney test) in all cases, p> 0.05. Table 40 Intracellular cytokine levels in premature infants with BPD at 1 month of life, IU (P25-P75) Indicators Group 2А (n=9) Group 2В (n=25) Group 2С (n=9) CD4+CD3+IFN-γ self-existing, % 1,71(1,1-2,37) 2,31(1,19-4,27) 2,56(2,09-3,2) CD4+IFN-γ+ suscitate, % 4,71(2,61-7,52) 5,19(2,43-6,66) 5,24(4,45-6,5) CD4+IL-4+ self-existing, % 1,12(0,89-2,41) 1,14(1,03-2,12)1,9 1,14-2,34() CD4+IL-4+ suscitate, % 2,93(1,28-3,02) 3,67(2,23-4,73) 4,04(3,55-4,5) CD4+IFN-γ+ / CD4+IL-4+ self-existing, c.u. 1,57(1,36-1,73) 1,68(1,39-1,98) 1,81(1,36-2,07) CD4+IFN-γ+ / CD4+IL-4+ suscitate, c.u. 1,59(1,33-2,06) 1,24(1,08-1,33) 1,46(1,19-4,24) Note. Significance of differences between groups of children (Mann-Whitney test) in all cases, p> 0.05. Analysis of intracellular cytokines showed that upon reaching 38-40 weeks of PCA, an increased number of CD4+IL-4+ cells in the stimulated test was observed in children who developed BPD regardless of severity (p1-3 = 0.06, p2-3 = 0.03) (Tables 41, 42). Table 41 Intracellular cytokine levels in premature infants with BPD at 38-40 weeks of PCA, IU (P25-P75) Indicators Group 1А (n=17) Group 1В (n=18) Group 1С (n=7) р CD4+CD3+IFN-γ+ self-existing, % 2,6(1,93-4,07) 3,08(1,27-4,05) 4,29(3,35-4,87) CD4+IFN-γ+ suscitate, % 5,63(4,82-6,44) 6,91(2,02-12,87) 6,1(6,0-7,49) CD4+IL-4+ self-existing, % 1,32(2,25-3,2) 1,43(0,9-3,2) 3,2(2,26-4,23) CD4+IL-4+ suscitate, % 2,22(2,01-3,21) 4,6(2,28-10,17) 5,9(4,95-6,05) Р1-3=0,06 Р2-3=0,03 CD4+IFN-γ+ / CD4+IL-4+ self-existing, c.u. 1,54(1,27-1,61) 1,37(1,23-1,82) 1,46(1,25-1,64) CD4+IFN-γ+ / CD4+IL-4+ suscitate, c.u. 2,45(2,1-3,01) 1,38(1,15-1,91) 1,43(1,27-2,48) Р1-3=0,045 Note. p - significance of differences between groups of children (Mann-Whitney test): group 1A - children with severe BPD of III degree, group 1B - children with BPD of mild and moderate degree, group 1C - children without BPD. Table 45c In all premature infants with severe BPD, the cell polarization index had a pro-inflammatory orientation, which is associated with antigenic stimulation with bacterial agents (p1-3 = 0.045, p4-6 = 0.09). Table 42 Intracellular cytokine levels in premature infants with BPD at 38-40 weeks of PCA, IU (P25-P75) Indicators Group 2А (n=9) Group 2В (n=25) Group 2С (n=9) р CD4+CD3+IFN-γ+ self-existing, % 2,37(2,26-3,68) 2,6(2,05-4,61) 3,81(2,45-4,19) CD4+IFN-γ+ suscitate, % 3,3(3,01-3,88) 3,58(2,58-5,54) 4,72(3,67-5,64) CD4+IL-4+ self-existing, % 1,19(1,02-1,41) 1,25(0,98-2,33) 1,91(1,4-2,3) CD4+IL-4+ suscitate, % 3,53(2,95-3,79) 3,62(2,53-5,26) 4,06(3,77-4,37) CD4+IFN-γ+ / CD4+IL-4+ self-existing, c.u. 1,82(1,72-1,93) 1,8(1,59-2,03) 1,66(1,43-1,74) CD4+IFN-γ+ / CD4+IL-4+ suscitate, c.u. 1,3(0,08-1,54) 1,04(0,93-1,93) 1,09(1,0-3,84) Р4-6=0,09 Р5-6=0,06 Note. p - significance of differences between groups of children (Mann-Whitney test): group 2A - children who have formed severe BPD of III degree, group 2B - children who have formed BPD of mild and moderate degree, group 2C - children without BPD. Thus, in all children with mild and moderate BPD, regardless of gestational age, there were no significant differences in the population composition of lymphocytes in the dynamics of the postnatal period in comparison with the indicators of children without BPD. Nevertheless, in children from very early preterm birth, an increase in the absolute number of leukocytes and the level of expression of the CD4+CD25+ receptor at birth was recorded. The greatest changes were noted in the indices of adaptive immunity during the formation of severe BPD in children with 22-27 weeks of GA. It was characterized by activation of the cellular link of the immune system, manifested by an increase in T- and B-lymphocytes, T-helpers, CD16+CD56+ cells and regulatory CD4+CD25+ lymphocytes with absolute leuko- and lymphocytosis at birth. Maintaining a high level of leukocytes and NK-cells, with a decrease in the number of T-lymphocytes and T-helpers - according to 38-40 weeks of GA. In children of gestational age of 28-31 weeks, regardless of the severity of BPD, there were no significant differences in the indicators of adaptive immunity. The first line of defense against foreign pathogens is innate immunity, which is the earliest defense mechanism in evolutionary terms and on response time. Pre-activation of innate immunity triggers adaptive responses. The implementation of innate immune responses is carried out through many types of cells. Cells of the myeloid series are a kind of effectors of innate immunity. Monocytes are the main component of the myeloid cell pool. The cells that cause congenital resistance - phagocytes in premature newborns are characterized by reduced activity. The transferrin receptor (CD71+) is a marker of early activation, and an increase in its expression level was observed on proliferating umbilical cord blood monocytes in children with 22-27 weeks of GA (p1-2 = 0.012) (Table 43). Table 43 Markers of activation of umbilical cord blood monocytes in children from very early preterm labor, which formed BPD, IU (P25-P75) Indicators Group 1А (n=17) Group 1В (n=18) Group 1С (n=7) Р CD11b+CD14+, % 20,0(15-36) 65,5(38,25-68) 21,5(10,5-45,25) CD11b+CD14+, abs. 0,13(0,07-0,16) 0,11(0,06-0,4) 0,08(0,03-0,13) CD64+CD14+, % 17,5(7,75-38,25) 17(12-32) 28,5(20,25-36,75) CD64+CD14+, 109/l 0,09(0,04-0,22) 0,05(0,04-0,15) 0,29(0,16-0,41) CD14+HLA-DR+, % 23,0(14,25-29,0) 21(10-61) 11(7-22) CD14+HLA-DR+, 109/l 0,10(0,09-0,31) 0,05(0,04-0,13) 0,06(0,04-0,19) CD71+CD14+, % 18(16,5-20,5) 11,0(7,75-15,5) 10,0(8,75-14,0) 1А-1С=0,012 CD71+CD14+, 109/l 0,15(0,05-0,22) 0,03(0,03-0,04) 0,02(0,02-0,09) 1А-1С=0,012 Note. p - significance of differences between groups of children (Mann-Whitney test): group 1A - children with severe BPD III degree, group 1B - children with mild and moderate degree of BPD, group 1C - children without BPD. In children with 28-31 weeks of GA with BPD, a statistically significant increase in the percentage of CD14/HLA-DR (p2A-2C = 0.01, p2B-2C = 0.023) was found in indicators of innate immunity of newborns, which, according to some authors, correlates with an increase risk of infectious pathology (Table 44). Postponed sepsis in the neonatal period was observed in newborns who subsequently developed BPD in 23.6% (17 of 72 children). Correlation analysis revealed a strong positive relationship between the amount of CD14+HLA-DR+ in cord blood with the development of sepsis in children born at the time of early preterm labor (r = 0.73, p = 0.004) and the formation of a severe form of BPD (r = 0, 52, p = 0.018). Table 44 Markers of activation of umbilical cord blood monocytes in children from early preterm labor that formed BPD, ME (P25-P75) Indicators Group 2А (n=9) Group 2В (n=25) Group 2С (n=9) Р CD11b+CD14+, % 39,0(30,5-60,0) 46,0(35,0-51,0) 21,0(15,0-27,0) CD11b+CD14+, abs. 0,16(0,10-0,25) 0,23(0,15-0,39) 0,06(0,06-0,07) CD64+CD14+, % 17,5(13,25-25,5) 42,0(38,0-44,0) 35(29,5-37,5) CD64+CD14+, 109/l 0,06(0,05-0,06) 0,19(0,09-0,32) 0,15(0,11-0,16) CD14+HLA-DR+, % 58(34-64,5) 33(21-47,5) 14(13-19,5) CD14+HLA-DR+, 109/l 0,16(0,10-0,29) 0,20(0,14-0,27) 0,07(0,06-0,07) 2А-2С=0,010 2В-2С=0,023 CD71+CD14+, % 17(14,5-24,0) 14(11,75-18,25) 16,0(14,25-22,5) 2В-2С=0,023 CD71+CD14+, 109/l 0,07(0,05-0,10) 0,10(0,08-0,12) 0,12(0,10-0,14) Note. p - significance of differences between groups of children (Mann-Whitney criterion): group 2A - children with severe BPD of III degree, group 2B - children who have formed BPD of mild and moderate degree, group 2C - children without BPD. A significant decrease in the absolute and relative amount of CD14/HLA-DR was revealed when comparing indicators of innate immunity of newborns from very early preterm birth, regardless of the severity of BPD. The number of CD14+CD64+ cells was reduced only in children with a severe form of the disease (p1-3 = 0.01, p2-3 = 0.01) (Table 45), which is associated with a high percentage of cases of infectious and inflammatory diseases in this group. (pneumonia - in 100% of cases). Table 45 Markers of activation of peripheral blood monocytes of premature infants at 1 month of life, who have formed BPD, ME (P25-P75) Indicators 1А group (n=17) 1В group (n=18) 1С group (n=7) Р CD11b+CD14+, % 65(59-67) 50(48-58,75) 71(66,25-76,25) CD11b+CD14+, abs. 0,85(0,76-1,07) 0,97(0,91-1,03) 0,74(0,58-0,87) CD64+CD14+, % 17,5(13,8-22,5) 39(20,3-55,0) 41(22-60) РА-С=0,007 РА-В=0,004 CD64+CD14+, 109/l 0,15(0,05-0,24) 0,31(0,28-0,48) 0,53(0,28-0,79) РА-В=0,04 РА-С=0,07 CD14+HLA-DR+, % 64(59-69) 65(44,5-77) 84(76,5-87,5) РА-С=0,01 РВ-С=0,01 CD14+HLA-DR+, 109/l 0,88(0,79-0,92) 0,9(0,67-0,97) 1,45(1,05-1,56) РА-С=0,06 CD71+CD14+, % 8(7-16) 14(6-18) 12(8-49,5) CD71+CD14+, 109/l 0,13(0,10-0,22) 0,11(0,07-0,24) 0,11(0,09-0,85) Note. p - significance of differences between groups of children (Mann-Whitney criterion): group 1A - children with severe BPD III degree, group 1B - children with mild and moderate BPD, group 1C - children without BPD. In children with at 28-31 weeks of GA, no significant differences were found in the indicators of the monocytic link of immunity (Table 46). Table 46 Activation markers of peripheral blood monocytes in premature infants at 1 month of age, who have formed BPD, IU (P25-P75) Indicators Group 2А (n=9) Group 2В (n=25) Group 2С (n=9) CD11b+CD14+, % 60(59-63) 79(66-82) 64(58,5-69) CD11b+CD14+, 109/l 0,63(0,53-0,68) 0,46(0,32-0,49) 0,49(0,43-0,54) CD64+CD14+, % 15(10-20) 30(18,75-51) 56(36-60) CD64+CD14+, 109/l 0,17(0,13-0,22) 0,22(0,06-0,34) 0,43(0,27-0,47) CD14+HLA-DR+, % 81,0(58,5-66,5) 67,5(50,5-76,0) 67,0(59,0-69,0) CD14+HLA-DR+, 109/l 0,53(0,43-0,73) 0,56(0,44-0,72) 0,57(0,40-0,80) CD71+CD14+, % 8,0(5,25-16,75) 15,0(8,0-20,23) 12(11-25) CD71+CD14+, 109/l 0,10(0,04-0,16) 0,11(0,07-0,22) 0,16(0,09-0,30) Note. Significance of differences between groups of children (Mann-Whitney test) in all cases, p> 0.05. When conducting a correlation analysis, it was found that a reduced content of CD14+HLA-DR+ monocytes in children with ELBW, born at the time of very early preterm labor, positively correlated with the presence of pneumonia at the age of 1 month of life (r = 0.48, p = 0.03). In the study of markers of activation of peripheral blood monocytes in newborns from very early preterm labor, which subsequently formed a severe BPD, a decrease in CD64+CD14+ (p1-2 = 0.01, p1-3 = 0.03) was noted in comparison with the indicators of children with mild and the average degree and children without BPD of the same gestational age (Table 45a). The relative number of CD14+HLA-DR+ monocytes in all children with BPD was reduced at the level of the tendency (p1-3 = 0.067, p 2-3 = 0.07) to at 38-40 weeks of PCA (Tables 47, 48). Table 47 Markers of peripheral blood monocyte activation in premature infants with BPD at 38-40 weeks of PCA, IU (P25-P75) Indicators Group 1А (n=17) Group 1В (n=18) Group 1С (n=7) Р CD11b+CD14+, % 77(75-78,5) 75,5(73,8-77,3) 75(67,5-77,5) CD11b+CD14+, abs. 0,50(0,39-0,58) 0,51(0,38-0,64) 0,41(0,33-0,47) CD64+CD14+, % 27(16,3-42,5) 50(35,3-65,0) 63,5(47,5-73,3) Р1А-1В=0,010 Р1А-1С=0,03 CD64+CD14+, 109/l 0,24(0,12-0,27) 0,27(0,12-0,41) 0,23(0,22-0,45) CD14+HLA-DR+, % 70,5(62,5-78,5) 74,0(64,8-83,0) 80,5(78,15-82,0) Р1А-1С =0,067 Р1В-1С =0,07 CD14+HLA-DR+, 109/l 0,49(0,39-0,56) 0,46(0,35-0,60) 0,4(0,38-0,57) Р1-2≥0,05 CD71+CD14+, % 18(13-23) 13(9,5-15,5) 19(17-21) Р1-2≥0,05 CD71+CD1, 109/l 0,12(0,07-0,22) 0,08(0,05-0,011) 0,12(0,10-0,14) Р1-2≥0,05 Note. p - significance of differences between groups of children (Mann-Whitney test): group 1A - children who have formed severe BPD III degree, group 1B - children who have formed BPD of mild and moderate degree, group 1C - children without BPD. Table 48 Markers of peripheral blood monocyte activation in premature infants with BPD at 38-40 weeks of PCA, IU (P25-P75) Indicators Group 2А (n=9) Group 2В (n=25) Group 2С (n=9) CD11b+CD14+,, % 83,5(81,12-85,8) 81,5(78,25-84,75) 86(84-88) CD11b+CD14+, abs. 0,9(0,8-1,0) 0,38(0,30-0,46) 0,72(0,64-0,80) CD64+CD14+,, % 80(72,5-83,5) 78(64,5-82,5) 75(70-80) CD64+CD14+, 109/l 0,58(0,58-0,63) 0,38(0,30-1,76) 0,50(0,47-0,52) CD14+HLA-DR+, % 82,5(70,5-90,25) 73,0(63,25-78,75) 76(74-78) CD14+HLA-DR+, 109/l 0,87(0,71-0,98) 0,58(0,34-0,74) 0,81(0,59-0,87) CD71+CD14+, % 15,5(12,0-26,5) 12,0(9,25-19,5) 15,0(8,0-16,0) CD71+CD14+, 109/l 0,19(0,14-0,27) 0,13(0,06-0,19) 0,12(0,11-0,14) Note. The significance of differences between groups of children (Mann-Whitney test) in all cases, p> 0.05. When studying the level of cytokines in the serum of umbilical cord blood, in children with 22-27 weeks of GA, who subsequently formed BPD, regardless of the severity of this pathology, there was a significant increase in the level of IL-6 and IL-8 (Table 49). Table 49 Levels of umbilical cord blood cytokines in children from very early preterm labor that formed BPD, IU (P25-P75) Indicators Group 1А (n=17) Group 1В (n=18) Group 1С (n=7) Р IFN- γ, pg/ml 12,23(9,72-13,9) 12,14(11,34-13,6) 10,42 (8,13-10,73) IL-6, pg/ml 120,43(12,6-160,78) 110,3(20,75-166,05) 16,5 (12,01-61,15) 1А-1С=0,03 1В-1С=0,05 IL-8, pg/ml 85,32(70,76-120,8) 131,1(79,42-172,4) 46,32 (39,03-53,29) 1А-1С=0,015 1В-1С=0,015 IL-4, pg/ml 0,74(0,48-0,87) 0,48(0,22-0,8) 0,61 (0,42-0,84) Note. p - significance of differences between groups of children (Mann-Whitney criterion): group 1A - children who have developed severe BPD III degree, group 1B - children who have formed BPD of mild and moderate degree, group 1C - children without BPD. Apparently, this is due to the fact that these mediators are markers of the development of the inflammatory process, an increase in the serum of the umbilical cord blood may be due to the presence of the transferred hypoxia, intrauterine infection. In children from early preterm labor, the concentration of IL-6 was comparable to the indicators of children without BPD, and the level of IL-8 significantly exceeded the indicators of children in the 1C group (Table 50). Table 50 Levels of umbilical cord blood cytokines in children from early preterm labor that formed BPD, IU (P25-P75) Indicators Group 2А (n=17) Group 2В (n=18) Group 2С (n=7) Р IFN- γ, pg/ml 8,11(4,06-10,09) 1,07(0,54-7,85) 11,22(11,03-11,4) IL-6, pg/ml 4,44(3,84-12,49) 5,86(4,07-13,81) 14,85(3,37-21,83) IL-8, pg/ml 126,16(25,9-272,0) 24,37(13,6-47,13) 25,9(19,1-37,94) 2А-2С=0,003 2А-2В=0,003 IL-4, pg/ml 0,93(0,49-1,13) 0,61(0,52-0,96) 0,93(0,71)0,95 Note. p - significance of differences between groups of children (Mann-Whitney criterion): group 2A - children who have developed severe BPD III degree, group 2B - children who have formed BPD of mild and moderate degree, group 2C - children without BPD. By the end of the neonatal period, the content of IL-8 in children who developed BPD decreased 2.8 and 4.8 times relative to the initial level (Tables 51, 52), but remained relevantly significant compared to newborns without BPD, probably at this stage of the examination may be a consequence of pneumonia suffered at birth (35.3% and 27.8%). Table 51 Levels of peripheral blood serum cytokines in premature infants at 1 month of age who subsequently formed BPD, IU (P25-P75) Indicators Group 1А (n=17) Group 1В (n=18) Group 1С (n=7) Р IFN- γ, pg/ml 2,21(1,1-3,87) 3,77 (0,28-13,12) 2,7(0,0-5,93) IL-6, pg/ml 4,69(4,35-10,29) 5,63(4,88-6,12) 5,1(4,2-5,94) IL-8, pg/ml 30,63(21,25-41,42) 27,07(25,56-31,33) 15,8(12,35-18,75) 1А-1С=0,010 1В-1С=0,03 IL-4, pg/ml 1,39(0,73-2,66) 1,74(1,42-1,79) 0,0(0,0-1,13) Note. p - significance of differences between groups of children (Mann-Whitney test): group 1A - children with severe BPD of III degree, group 1B - children with BPD of mild and moderate degree, group 1C - children without BPD. Table 52 Levels of peripheral blood serum cytokines in premature infants at 1 month of age who subsequently formed BPD, IU (P25-P75) Indicators Group 2А (n=9) Group 2В (n=25) Group 2С (n=9) Р IFN- γ, pg/ml 3,32(2,77-5,56) 2,21(0,83-4,44) 1,38(0,0-4,43) IL-6, pg/ml 3,04(2,46-35,08) 7,76(5,2-18,48) 4,95(3,08-8,5) IL-8, pg/ml 57,68(36,53-72,96) 19,77(15,96-25,44) 12,77(10,49-13,67) 2А-2В=0,012 2А-2С=0,010 2В-2С=0,010 IL-4, pg/ml 0,65(0,33-1,51) 1,96(1,91-2,05) 1,95(1,9-1,99) Note. p - significance of differences between groups of children (Mann-Whitney criterion): group 2A - children who have developed severe BPD III degree, group 2B - children who have formed BPD of mild and moderate degree, group 2C - children without BPD. A study of pro- and anti-inflammatory cytokines in peripheral blood serum showed that in all premature infants, regardless of gestational age, there were no significant differences in BPD (Tables 53, 54). Table 53 Levels of cytokines in the peripheral blood of premature infants with BPD at 38-40 weeks of PCA, IU (P25-P75) Indicators Group1А (n=17) Group 1В (n=18) Group 1С (n=7) IFN- γ, pg/ml 1,1(0,96-1,52) 0,0 (0,0-9,65) 0,0(0,0-0,9) IL-6, pg/ml 3,91(3,77-4,8) 3,78(2,46-4,35) 2,75(2,36-2,97) IL-8, pg/ml 16,72(10,75-31,18) 13,2(12,99-25,4) 15,5(12,8-17,75) IL-4, pg/ml 2,7(2,1-2,93) 1,82(1,72-2,1) 20,5(1,892,7) Note. The significance of differences between groups of children (Mann-Whitney test) in all cases, p> 0.05. Table 54 Levels of cytokines in the peripheral blood of premature infants with BPD at 38-40 weeks of PCA, IU (P25-P75) Indicators Group 2А (n=9) Group 2В (n=25) Group 2С (n=9) IFN- γ, pg/ml 0,55(0,55-2,21) 3,32(0,0-4,71) 8,95(1,66-9,51) IL-6, pg/ml 6,45(5,08-13,48) 5,39(2,93-11,27) 6,72(2,75-13,45) IL-8, pg/ml 13,54(11,87-17,73) 23,48(11,53-34,06) 13,47(12,9-80,54) IL-4, pg/ml 1,6(1,57-1,91) 2,1(2,0-2,4) 2,46(2,4-2,48) Note. Significance of differences between groups of children (Mann-Whitney test) in all cases, p> 0.05. Thus, it was found in the study of indicators of innate immunity that despite the increased level of proliferation of CD14+CD71+ monocytes at birth in children from very early preterm birth with severe BPD, which in the postnatal period of a child's life can have an anti-inflammatory effect [2]. A significant a decrease in the functional activity of monocytes according to the presentation of infectious pathogens of lymphocytes (CD14+HLA-DR+) in children with GA of 22-27 weeks with BPD at the age of 1 month of life and a decrease at the level of the tendency towards the outcome of the disease at 38-40 weeks of PCA were observed. It also indicates the past infectious pathology, most often detected in these children. According to Kanakoudi-Tsakalidou, the HLA-DR expression on monocytes may be critical in the presence of respiratory distress syndrome [3]. In addition, according to F. Genel et al. (2010), a decrease in the HLA-DR expression on circulating monocytes in newborns with sepsis was observed [4]. According to the results of a study by other authors, no significant differences were found in the HLA-DR expression by monocytes in infected and uninfected infants, as well as among healthy children [5]. Our study found a strong positive relationship between the level of CD14/HLA-DR in cord blood with the development of sepsis in children born at the time of early preterm labor (r = 0.73, p = 0.004) and the formation of a severe form of BPD (r = 0 , 52, p = 0.018). Currently, the role of adhesive molecules in the pathogenesis of respiratory disorders is being actively studied. There was a decrease in the number of CD14+CD64+ monocytes in children from very early preterm birth with severe BPD, both with the development of an active form of the disease and its outcome. It indicates a decrease in intracellular absorption opsonized microbes and is consistent with literature sources [6]. There are data on the formation of BPD as a result of an imbalance of pro-inflammatory and anti-inflammatory mechanisms, highlighting a large role for pro-inflammatory cytokines [7, 8] and emphasizing the insufficient activity of anti-inflammatory ones. Evaluation of the cytokine status showed that during the formation of BPD, regardless of the severity of this disease, increased production of IL-8 was noted in children from very early preterm birth during the neonatal period, in children with GA of 28-31 weeks - at the age of 1 month of life. A high level of IL-6 at birth was recorded only in children with GA of 22-27 weeks, which is due to infectious and inflammatory diseases in the neonatal period (sepsis, pneumonia), deaths in this group of children and is consistent with literature data. A number of foreign authors associate high levels of IL-6 in umbilical cord blood with an increased risk of morbidity and mortality in the newborn [9, 10], with RDS-associated inflammation and early peri / intraventricular hemorrhages [11]. Foreign studies have data on the high prognostic and diagnostic significance of IL-6 and IL-8 levels as predictors and early markers in severe bacterial infections and sepsis in premature infants [12]. To sum up, we can conclude that the state of the immune system of children from very early preterm birth, which subsequently developed severe BPD, is characterized by the activation of cellular (an increase in the number of lymphocytes and their subpopulations) and humoral immunity (an increase in the production of IL-6 and IL-8) at birth. It is characterized also in case of the disease development - a reduced ability of monocytes to present antigens, an increase in the level of IL-8 during the neonatal period, by 38-40 weeks of PCA - a decrease in the number of T-lymphocytes, T-helpers, a decrease in the effectiveness of monocyte phagocytosis, with an increased number of natural killer cells and leukocytes. In children from early preterm birth, which formed severe BPD, there is no change in the parameters of adaptive immunity throughout the entire examination period, an increase in the functional activity of CD14+ HLA-DR+ monocytes at birth, an increase in the synthesis of IL-8 in the neonatal period and NK- cells in 38-40 weeks of PCA. During the formation of mild and moderate degree of BPD in all children, regardless of gestational age, significant differences similar to the above were recorded in innate immunity indicators. 4.2. A method for predicting the development of severe bronchopulmonary dysplasia in premature infants with extremely low body weight in the neonatal period The urgency of the problem is determined by the fact that among premature infants who survived due to the use of artificial lung ventilation (ALV), there is an increase in morbidity and mortality at an early age and infancy, which is due to both severe perinatal pathology and the formation of postresuscitation complications, one of which is bronchopulmonary dysplasia. (BLD). According to various researchers, BLD occurs in 10–25% of premature infants who got extended ALV. Bronchopulmonary dysplasia continues to be one of the main causes of mortality and morbidity in extremely low body weight (ELBW) infants. The fatal outcome in BPD is up to 36% in children during the first 3 months of life, and up to 14.5% in the first year of life. Surviving children with BLD up to 5–6 years of age are prone to more frequent occurrence of respiratory dysfunctions, the development of severe chronic pathology, in particular, obstructive pulmonary disease, which leads to high financial costs for medical and rehabilitation measures. In children with GA of 22-27 weeks, a high incidence of severe BLD to PCA was diagnosed at 38-40 weeks. The incidence of BLD depends on birth weight, duration of ALV and is 40-45% in children with ELBW. Mortality in BLD varies from 14 to 36% during the first three months of life and then 11% during the first year of life. BLD is characterized by chronic respiratory failure (RF), long-term dependence on oxygen, recurrent broncho-obstructive syndrome, recurrent pneumonia. BLD is often transformed into obliterating bronchiolitis and bronchial asthma [66]. Establishment of the presence of clinical and radiological signs of BLD postpones the adoption of measures aimed at preventing this pathology. Treatment of bronchopulmonary dysplasia presents serious difficulties and is accompanied by high economic costs. Therefore, the most serious consideration should be given to the early prognosis of BLD. We have developed a method for predicting the development of severe bronchopulmonary dysplasia in children with ELBW in the neonatal period. It consists in determining the relative content of CD14+HLA-DR+ - monocytes and the absolute number of CD4+ CD25+ - lymphocytes in cord blood, taking into account the development of severe anemia, requiring blood transfusion and subsequent calculation of the prognostic index (PI). The method is as follows: venous blood is taken from the umbilical cord vein into a test tube with EDTA, which is used to determine the relative content of CD14+ HLA-DR+ - monocytes and the absolute number of CD4+CD25+ - lymphocytes in the umbilical cord blood of children with ELBW by flow cytometry. The obtained values, taking into account the data of the child's anamnesis (the presence of a severe degree of anemia in the neonatal period, requiring blood transfusion), are used to calculate the prognostic index (PI) according to the formula developed using the discriminant analysis method: PI1 = 0.074 × X1 + 6.72 × X2 + 3.27 × X3 - 5.31, where X1 - the relative content of CD14+HLA-DR+ - blood monocytes, %; X2 - the absolute number of CD4+ CD25+ - lymphocytes, 109/l; X3 - presence / absence of severe anemia in the neonatal period, requiring blood transfusion (1/0); 5.31- constanta. When PI1 <0, a high risk of severe bronchopulmonary dysplasia is predicted, and when PI1> 0, a low risk of developing a pathological condition in premature infants with ELBW. The sensitivity of the proposed method was calculated on the examination sample of additionally examined 47 premature infants with ELBW, is 90%, specificity - 88.9%. The efficiency of the method is 89.5%. Example 1. A newborn boy M. (labor and delivery record No. 53117) was born to a 24-year-old primary pregnant nicotine-dependent woman. The first real pregnancy proceeded against the background of chronic placental insufficiency, subcompensated form, 1st degree of uteroplacental blood flow disturbances, acute fetal hypoxia. Premature operative labor in cephalic presentation at GA of 26 weeks. Weight and body length at birth were 990 grams, 33 cm, 6/7 points on the Apgar scale. ALV from birth for 19 days, then respiratory support using the BNCPAP method for 5 days. He was transferred to the stage of rehabilitation at the age of 27 days of life. In the neonatal period, blood transfusions were not performed. When studying serum by umbilical cord blood flow cytofluorometry, the following data were obtained: CD14+HLA-DR+ - monocytes - 21%, CD4+CD25+ - lymphocytes - 0.07 × 109/l. The predictive index was calculated by the formula: PI = 0.074×21 + 6.72×0.07 + 3.27×0 - 5.31 = -3.2856, which indicates a high risk of developing severe BLD. At the age of 88 days of life in a satisfactory condition, the child was discharged with a body weight of 2536 g with a diagnosis of BLD, classical form, severe severity, stage of remission. Rd is of 0-I degree. Example 2. Newborn boy P. (labor and delivery record No. 52391) was born to a 35-year-old bipara woman, somatically weighed down by varicose veins of the lower extremities, myopia of the 1st degree. The anamnesis has 1 artificial termination of pregnancy, 1 urgent spontaneous delivery at full-term without any peculiarities, the child is healthy. This third present pregnancy proceeded against the background of a weighed down by obstetric history (medical abortion), chronic placental insufficiency, decompensated form, disorders of uteroplacental blood flow of II-III degree, oligohydramnios, moderate preeclampsia, progressive course. Labor premature operative at 28 weeks, foot presentation. Weight and body length at birth 790 grams, 33 cm, 4/6 points on the Apgar scale. There was ALV from birth for 2 days, then respiratory support using the BNCPAP method for 2 days. He was transferred to the stage of early rehabilitation at the age of 12 days of life. Blood transfusion was not performed in the neonatal period. In the study of serum by umbilical cord blood flow cytofluorometry, the following data were obtained: CD14+HLA-DR+ - monocytes - 61%, CD4+CD25+ - lymphocytes - 0.2816×109/l. The predictive index was calculated by the formula: PI = 0.074×61 + 6.72×0.2816 + 3.27×0 - 5.31 = 1.0963, which is more than 0 and predicts a low risk of severe bronchopulmonary dysplasia. At the age of 79 days of life in a satisfactory condition, the child was discharged home with a body weight of 2360 grams with a diagnosis of BPD, classical form, mild severity, stage of remission. RD is of 0 degree. Example 3. A newborn girl (labor and delivery record No. 52039) was born to a 33-year-old bipara woman. The anamnesis has 1 urgent delivery and 3 medical abortions at the request of the woman. Pregnancy 5 real proceeded against the background of a burdened obstetric history (3 medical abortions), bacterial vaginosis (without debridement), genital herpes, grade I anemia, fetal growth retardation syndrome (FGRS) of I-II degree. Delivery is quick premature at 29 weeks, occipital presentation. Weight and body length at birth were 840 grams, 32 cm, 4/6 points on the Apgar scale. There was ALV from birth for 6 days, then respiratory support using the BNCPAP method for 6 days. She was transferred to the stage of rehabilitation at the age of 25 days of life. Blood transfusion was performed in the neonatal period once. In the study of serum by umbilical cord blood flow cytofluorometry, the following data were obtained: CD14+HLA-DR+ - monocytes - 14%, CD4+CD25+ - lymphocytes - 0.13×109/l. The predictive index was calculated by the formula: PI = 0.074×14 + 6.72×0.13 + 3.27×1–5.31 = -0.1304, which is less than 0 and predicts a high risk of severe BLD. At the age of 94 days of life in a satisfactory condition, the child was discharged with a body weight of 2000 grams with a diagnosis of BLD, classical form, severe severity, stage of remission. RD is of 0-I degree. Example 4. Newborn girl B. (labor and delivery record No. 50427) was born to a 17-year-old primary primigravida mother with Klippel-Feil syndrome. The first real pregnancy proceeded against the background of chronic placental insufficiency, decompensated form, disorders of the uteroplacental blood flow of the III degree without centralization with the outcome in the FGRS of the I degree. Premature operative labor in breech presentation at 28 weeks. Weight and body length at birth were 890 grams, 34 cm, 5/6 points on the Apgar scale. There was ALV from birth for 18 days, then respiratory support using the BNCPAP method for 2 days. She was transferred to the stage of rehabilitation at the age of 22 days of life. Blood transfusion was performed in the neonatal period once. In the study of serum by umbilical cord flow cytofluorometry, the following data were obtained: CD14+HLA-DR+ - monocytes - 25%, CD4+CD25+ - lymphocytes - 0.42×109/l. The predictive index was calculated by the formula: PI = 0.074×25 + 6.72×0.42 + 3.27×1–5.31 = 2.6324, which is more than 0 and predicts a low risk of severe bronchopulmonary dysplasia. At the age of 74 days of life in a satisfactory condition, the child was discharged with a body weight of 2040 grams without a BLD diagnosis. Thus, the proposed method makes it possible to predict severe BLD in the neonatal period, which makes it possible to correct the tactics of managing premature infants at the stages of nursing. The inventive method for predicting the development of severe BPD in premature infants with ELBW has the following advantages in comparison with the existing ones: the method is simple to execute, includes an assessment of clinical and laboratory studies, and is minimally invasive (umbilical cord blood).

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