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Clinical and immunological characteristics of moderate-to-severe forms of COVID-19 at different levels of the tissue damage marker (lactate dehydrogenase)

https://doi.org/10.21886/2219-8075-2021-12-4-108-115

Abstract

Objective: To study the features of the immune status in patients with a moderate-to-severe course of COVID-19, depending the levels of blood lactate dehydrogenase.

Materials and Methods: A total of 24 patients with a moderate-to-severe form of COVID-19 were examined. The control group consisted of 21 healthy volunteers. Methods: clinical, paraclinical (computed tomography of the lungs; complete blood count, blood biochemistry; immunological studies), statistical.

Results: Changes in complete blood count and blood biochemistry in patients with moderate-to-severe COVID-19 consist in granulocytosis, lymphopenia, monocytopenia, and an increase in the level of C-reactive protein, lactate dehydrogenase, with a simultaneous decrease in the total protein content. In patients with high levels of lactate dehydrogenase, a redistribution of lymphocyte populations towards B-cells was revealed with a decrease in the total number of T-cells. At the same time, there was a decrease in the production of IgM and IgG and a simultaneous increase in the synthesis of IgA.

Conclusions: The increase in blood LDH in COVID-19 patients is associated with a decrease in the content of T-cells due to severe lymphopenia, and a simultaneous increase in the content of B-cells without adequate enhancement of their antibody production function.

For citation:


Sizyakinа I.P., Zakurskayа V.Y., Skripkinа N.A., Antonova E.A., Sizyakin D.B. Clinical and immunological characteristics of moderate-to-severe forms of COVID-19 at different levels of the tissue damage marker (lactate dehydrogenase). Medical Herald of the South of Russia. 2021;12(4):108-115. (In Russ.) https://doi.org/10.21886/2219-8075-2021-12-4-108-115

Introduction

The new coronavirus SARS-CoV-2, designated COVID-19 by the World Health Organization (WHO) on February 11, 2020, is one of the highly pathogenic β-coronaviruses affecting humans [1]. The regular change of both diagnostic and therapeutic approaches to fight it is due to the gradual accumulation of more and more knowledge about the disease course. However, control over the course of the pandemic is still not achieved. Consequently, a more thorough study of the mechanisms underlying the COVID-19 pathogenesis is required. Most domestic and foreign works pay much attention to changes in clinical and biochemical blood tests, as well as the hemostasis and fibrinolysis system [2-4]. One such indicator used in clinical practice is lactate dehydrogenase (LDH). It is a zinc-containing intracellular enzyme that catalyzes the oxidation of lactic acid to pyruvate and is found in virtually all body cells. It is most active in skeletal muscle, heart muscle, kidneys, liver, and red blood cells [5]. In diseases with tissue damage and cell destruction, its activity in the blood increases. In this regard, LDH is a significant marker of tissue destruction [6]. Its increase associated with COVID-19 infection is evidence of increased cell death and may, according to some authors, indicate an unfavorable disease prognosis and its severity increase [7-10]. However, it is still unclear how stable is the nature of the relationship between LDH and complex dysregulatory processes in the immune system. Exactly what immune cells are the targets of the SARS-Cov-2 attack activity; what happens in the innate and adaptive parts of the immune system; what are the features of dysregulatory processes leading to the worsening of the infection process; and, in some cases, to its adverse outcome. Meanwhile, it is the identification of this relationship nature that can help to decipher the main pathogenetic mechanisms of this interaction and, consequently, find possible therapeutic intervention methods.

The study aims to analyze an immune status in patients with moderate COVID-19 course depending on different LDH levels.

Material and methods

The study included 24 patients with a moderate COVID-19 infection who were hospitalized in the monoinfectious hospital of the N.A. Semashko Central City Hospital with the diagnosis "New coronavirus infection COVID-19 (confirmed), moderate". The mean age of the subjects was 65 years [ 51.5, 68.5]. The distribution within the group by gender was 10 men and 14 women. Practically healthy subjects of comparable age (21 people) were taken as a comparison group. All patients signed voluntary informed consent to participate in the study. The clinical trial was retrospective and conducted under the World Medical Association Declaration of Helsinki – Ethical Principles for Medical Research Involving Human Subjects as amended (2000), WMA Declaration of Helsinki – Ethical Principles for Medical Research Involving Human Subjects (2013), Rules for Clinical Practice in the Russian Federation, approved by Order of the Russian Ministry of Health No. 266 from 19-Jun-2003. The patient's medical history was analyzed, identifying the patient's main complaints and the nature of the disease course. The pulmonary tissue damage was assessed by computed tomography (CT). On admission, blood was sampled for a full blood count (FBC), including estimation of RBC count, hemoglobin, hematocrit, thrombocrit, and total WBC count with WBC differential. Among the chemistry values, we determined C-reactive protein (CRP), ALT, AST, albumin, urea, creatinine, glucose, LDH, total protein, amylase, and bilirubin. The expression of species markers on the surface of the lymphocytes was determined by flow cytofluorimetry. The number of CD3+, CD4+, and CD8+ differentiation clusters for T cells, CD19+ for B cells, and CD16+ for natural killer cells was assessed. According to the Mancini method, the serum immunoglobulins of A, M, G classes were detected by radial immunodiffusion in a gel. Statistical analysis was performed using the STATISTICA 10 program (StatSoft Inc., USA). Descriptive statistics for the continuous character were presented as median and interquartile range (25th and 75th percentiles) central tendency, represented in the text as Me [LQ; UQ]. The medians in the groups were compared using Wilkinson's U-criterion.  Differences were considered statistically significant at the p < 0.05 level.

Results

On average, patients were admitted to the department on the 5th-6th day from the onset of the disease and remained in the department for 18.4±5.5 days. When evaluating the FBC results in patients with moderate COVID-19, changes were characterized by significant lymphopenia 10.75% [ 8; 18.6], as well as granulocytosis 86.85% [ 75; 90] and monocytopenia 1.7% [ 1.3; 2.6]. Significant changes in the patient blood chemistry value were expressed by increasing CRP, LDH with a simultaneous decrease of total protein (Table 1). In addition, there was an increase in blood transaminases and glucose.

Таблица / Table 1

Сравнительная характеристика биохимических показателей крови у пациентов со среднетяжёлой формой COVID-19 и контрольной группы

Comparative characteristics of blood biochemical parameters in patients with moderate form of COVID-19 and the control group

Показатель / Рarameter

Пациенты со среднетяжёлым течением COVID-19 / Patients with moderate form COVID - 19

Контрольная группа / Control group

U-критерий / U-criteria

Альбумин, г/л

Albumin, g/l

34,85 [ 32,6;35.5]

38 [ 34;41]

p >0,05

АЛТ, Ед/л

ALT, Unit /l

49.4* [ 29; 96]

22,4 [ 17.5;44,3]

p <0,05

АСТ, Ед/л

AST, Unit /l

45,7* [ 32,4; 57,4]

30 [ 19.7;41.6]

p <0,05

Мочевина, ммоль/л

Ureammol/l

8,2 [ 6,8; 10,9]

5.9 [ 3.1;7.4]

p >0,05

Креатинин, мкмоль/л

Creatininemmol/l

90,5 [ 77;95,5]

84 [ 61;101]

p >0,05

Глюкоза, ммоль/л

Glucosemmol/l

6,25* [ 4,95;10]

5.6 [ 4.8;6.0]

p <0,05

СРБ, мг/мл

CRPmg/ml

43,5* [ 8,3; 85,2]

1.5 [ 0.2;5]

p <0,05

Общий белок, г/л

Total proteing/l

62,6* [ 57,95; 67,5]

71.6 [ 64.7;78.5]

p <0,05

Амилаза, Ед/л

Amylase, Unit /l

38 [ 32;48]

45 [ 20;78.4]

p >0,05

Билирубин, мкмоль/л

Bilirubinmmol/l

7.2 [ 4.95;9.05]

9.4 [ 5.7;14.9]

p >0,05

ЛДГ, Ед/л

LDG, Unit/l

606* [ 392; 859]

191 [ 154; 310]

p <0,05

Примечание: * — статистическая значимость различий показателей между группами (p <0,05), рассчитанная с учётом U-критерия Вилкинсона; в таблице средние значения представлены в виде Медианы [Нижний квартиль; Верхний квартиль].
Note: * — the statistical significance of the differences in indicators between the groups (p <0.05) calculated taking into account the Wilkinson U-test; in the table, the average values are presented as Median [Lower quartile; Upper quartile].

When comparing the indices in the cellular arm of adaptive immunity, the relative indices are within the normal range, but when recalculated into absolute values, were significantly lower than similar indices in healthy donors. Such changes are explained by significant lymphopenia accompanying COVID-19 infection. A higher serum IgA level manifested significant differences in the humoral arm in COVID-19 patients (Table 2).

Таблица / Table 2

Сравнительная характеристика иммунологических показателей крови у пациентов со среднетяжёлой формой COVID-19 и контрольной группы

Comparative characteristics of blood immunological parameters in patients with moderate COVID-19 and the control group

Показатель / Рarameter

Пациенты со среднетяжёлым течением COVID-19 / Patients with moderate form COVID - 19

Контрольная группа / Control group

U-критерий / U-criteria

CD3+, %

CD3+,%

73[ 63,8;77]

71 [ 61;74]

p >0,05

CD3+, х109

CD3+, х109/l

0,6* [ 0,4;0,82]

1.6 [ 0.9;1.8]

p <0,05

CD3+CD4+, %

CD3+CD4+, %

43 [ 39; 47,8]

42 [ 36;44]

p >0,05

CD3+CD4+, х109

CD3+CD4+, х109/l

0,43*[ 0,24;0,52]

0.8 [ 0.6;1]

p <0,05

CD3+CD8+, %

CD3+CD8+, %

20 [ 16,3; 31,8]

25 [ 22;31]

p >0,05

CD3+CD8+, х109

CD3+CD8+, х109/l

0,16*[ 0,13;0,31]

0.46 [ 0.3;0.7]

p <0,05

ИРИ

IRI

2,18 [ 1,33;2,71]

1.8 [ 1.3;2.3]

p >0,05

СD16+,%

СD16+,%

10,5 [ 6;16]

12 [ 8;15.4]

p >0,05

СD16+, х109

СD16+, х109/l

0,1*[ 0,038;0,148]

0.22 [ 0.19;0.34]

p <0,05

CD19+, %

CD19+, %

15 [ 9,75;19,8]

14 [ 9;17.9]

p >0,05

CD19+, х109

CD19+, х109/l

0,131*[ 0,09;0,19]

0.28 [ 0.12;0.31]

p <0,05

IgA, г\л

IgA, g\l

2,6* [ 1,6;3,4]

2 [ 1.4; 2.5]

p <0,05

IgM, г\л

IgM, g\l

0,96 [ 0,79;1,18]

1.1 [ 0.89;1.4]

p >0,05

IgG, г\л

IgG, g\l

10 [ 8,9; 12]

11 [ 9.5;12.5]

p >0,05

Примечание: * — статистическая значимость различий показателей между группами (p <0,05), рассчитанная с учётом U-критерия Вилкинсона; в таблице средние значения представлены в виде Медианы [Нижний квартиль; Верхний квартиль].
Note: * — the statistical significance of the differences in indicators between the groups (p <0.05) calculated taking into account the Wilkinson U-test; in the table, the average values are presented as Median [Lower quartile; Upper quartile].

Although all patients were admitted to the department with the same disease severity, their laboratory values differed significantly according to the formulated diagnosis, as did their total time in the hospital. First of all, the difference between the blood LDH levels, which in some patients were significantly higher than the norm, while others remained within the reference values, was noteworthy. Given the proven role of LDH as a predictor of severe COVID-19 course, the study subjects were divided into two groups – those with high LDH (799 U/dL [ 624; 898], 14 subjects) and those with normal LDH (247 U/dL [ 117; 392], 10 subjects).

Analysis of the COVID-19 clinical course in patients with high LDH revealed that their hospitalization time was, on average, four days longer. In the FBC, significant changes change has involved greater lymphopenia and severe granulocytosis in patients in the high LDH group. We should note monocytopenia, equally characteristic of patients in both groups, which may indicate marked dysregulatory processes in the system of innate immunity (Table 3).

Таблица / Table 3

Сравнительная характеристика показателей ОАК у пациентов со среднетяжёлой формой COVID-19 в группах с высоким и нормальным уровнем ЛДГ

Comparative characteristics of UAC indicators in patients with moderate COVID-19 in groups with high and normal LDH levels

Показатель / Рarameter

Группа с высоким уровнем ЛДГ / High level LDG group

Группа с нормальным уровнем ЛДГ / Normal level LDG group

U-критерий / U-criteria

Лейкоциты, х109

 Leukocytes, х109/l

7,6 [ 5,6;9,5]

7,3 [ 4,35;8,3]

p >0,05

Эритроциты, х1012

Erythrocyteх1012/l

4,03 [ 3,7;4,4]

4,6[ 4,39;4,75]

p >0,05

Hb, г\л

Hb, g\l

125,5 [ 120,5;146,5]

143 [ 126,5;147,5]

p >0,05

Гематокрит, %

Hematocrit, %

35.5 [ 32.33;40.25]

36.5 [ 32.5;39.5]

p >0,05

Тромбоциты, х109

Plateletsх109/l

185,5 [ 162,5;291]

174 [ 156;220]

p >0,05

Гранулоциты, %

Granulocytes, %

89,95* [ 86,4;91]

76,6 [ 70;82]

p <0,05

Лимфоциты, %

Lymphocytes, %

8,9* [ 6,95;12]

19 [ 15;27]

p <0,05

Моноциты, %

Monocytes, %

1,7* [ 1,1;1,8]

2,7 [ 1,7;3,4]

p <0,05

Примечание: * — статистическая значимость различий показателей между группами (p <0,05), рассчитанная с учётом U-критерия Вилкинсона; в таблице средние значения представлены в виде Медианы [Нижний квартиль; Верхний квартиль].
Note: * — the statistical significance of the differences in indicators between the groups (p <0.05) calculated taking into account the Wilkinson U-test; in the table, the average values are presented as Median [Lower quartile; Upper quartile].

When assessing the blood chemistry values, significant differences between the two groups were in the CRP content (6-fold higher in the group with high LDH levels). In addition, significant hypoproteinemia was noted in the same group (Table 4).

Таблица / Table 4

Сравнительная характеристика биохимических показателей у пациентов со среднетяжёлой формой COVID-19 в группах с высоким и нормальным уровнем ЛДГ

Comparative characteristics of biochemical parameters in patients with moderate COVID-19 in groups with high and normal LDH levels

Показатель / Рarameter

Группа с высоким уровнем ЛДГ / High level LDH group

Группа с нормальным уровнем ЛДГ / Normal level LDH group

U-критерий / U-criteria

Альбумин, г/л

Albumin, g/l

34,8 [ 32,3; 35,2]

35,6[ 35; 38,4]

p >0,05

АЛТ, Ед/л

ALT, Unit /l

*69,5 [ 36,8; 103]

42,7 [ 14,9; 62,5]

p <0,05

АСТ, Ед/л

AST, Unit /l

48,3 [ 37,9; 57,4]

35,4 [ 19,2; 61,9]

p >0,05

Мочевина, ммоль/л

Ureammol/l

8,25 [ 6,9; 9,6]

8 [ 6,5; 13,8]

p >0,05

Креатинин, мкмоль/л

Creatininemmol/l

91 [ 81,5; 103,5]

71,5 [ 7,4;91,8]

p >0,05

Глюкоза, ммоль/л

Glucosemmol/l

6,4 [ 5,25;9,05]

5,75 [ 4,2;29]

p >0,05

СРБ, мг/мл

CRPmg/ml

*64,55 [ 22,43; 104,6]

11,8 [ 6; 41]

p <0,05

Общий белок, г/л

Total proteing/l

*59,3 [ 57,8; 66,4]

67,2 [ 64; 70]

p <0,05

Амилаза, Ед/л

Amylase, Unit /l

*35 [ 33,5;36,5]

48 [ 37;53,5]

p <0,05

Билирубин, мкмоль/л

Bilirubinmmol/l

*5,95 [ 4,9; 8,65]

17 [ 13;18]

p <0,05

Примечание: * — статистическая значимость различий показателей между группами (p <0,05), рассчитанная с учётом U-критерия Вилкинсона; в таблице средние значения представлены в виде Медианы [Нижний квартиль; Верхний квартиль].
Note: * — the statistical significance of the differences in indicators between the groups (p <0.05) calculated taking into account the Wilkinson U-test; in the table, the average values are presented as Median [Lower quartile; Upper quartile].

The results were interesting when comparing the immune status indices. Thus, it was found that moderate COVID-19 in patients with normal LDH are determined by the preservation of the maturation and differentiation of the cellular arm and are characterized by a higher CD3+, CD4+, and CD8+ T-lymphocytes in relative and in absolute values, which is explained by higher lymphocyte levels in the blood. The results obtained in the humoral arm of the adaptive immune response are quite interesting. Thus, the relative B-lymphocyte level was twice as high in the high LDH group. Furthermore, in absolute values, its level was significantly higher than in patients in the second group. These changes are exciting when considering the more significant lymphopenia observed in these patients. In addition, there were multidirectional changes in the serum immunoglobulin, such as a higher IgA and a lower LDH in the high LDH group (Table 5).

Таблица / Table 5

Сравнительная характеристика иммунологических показателей у пациентов со среднетяжёлой формой COVID-19 в группах с высоким и нормальным уровнем ЛДГ

Comparative characteristics of immunological parameters in patients with moderate COVID-19 in groups with high and normal LDH levels

Показатель / Рarameter

Группа с высоким уровнем ЛДГ / High level LDH group

Группа с нормальным уровнем ЛДГ / Normal level LDH group

U-критерий / U-criteria

CD3+, %

CD3+,%

*68[ 55,3;74]

76,5[ 75,8;77,3]

p <0,05

CD3+, х109

CD3+, х109/l

*0,42 [ 0,34;0,6]

1,04 [ 0,79;1,13]

p <0,05

CD3+CD4+, %

CD3+CD4+, %

*41,5 [ 33; 45,5]

48,5 [ 40,8; 55]

p <0,05

CD3+CD4+, х109

CD3+CD4+, х109/l

*0,28[ 0,21;0,42]

0,58[ 0,52;0,69]

p <0,05

CD3+CD8+, %

CD3+CD8+, %

*19 [ 13; 30]

23 [ 18,8; 32,8]

p <0,05

CD3+CD8+, х109

CD3+CD8+, х109/l

*0,14[ 0,1;0,17]

0,32[ 0,25;0,42]

p <0,05

ИРИ

IRI

1,95[ 1,44;2,7]

2,3 [ 1,23;2,66]

p >0,05

СD16+,%

СD16+,%

10,5 [ 4,5;15,75]

10 [ 6;17]

p >0,05

СD16+, х109

СD16+, х109/l

0,1[ 0,036;0,14]

0,12[ 0,1;0,18]

p >0,05

CD19+, %

CD19+, %

*19 [ 13,5;22]

11,5[ 6;14,25]

p <0,05

CD19+, х109

CD19+, х109/l

*0,14[ 0,11;0,21]

0,1[ 0,08;0,16]

p <0,05

IgA, г\л

IgA, g\l

*2,8 [ 2,1;3,4]

1,9 [ 1,4;3,6]

p <0,05

IgM, г\л

IgM, g\l

0,98 [ 0,76;1,18]

0,89[ 0,83;1,11]

p >0,05

IgG, г\л

IgG, g\l

*10 [ 8,9; 12]

12 [ 11;13]

p <0,05

Примечание: * — статистическая значимость различий показателей между группами (p <0,05), рассчитанная с учётом U-критерия Вилкинсона; в таблице средние значения представлены в виде Медианы [Нижний квартиль; Верхний квартиль].
Note: * — the statistical significance of the differences in indicators between the groups (p <0.05) calculated taking into account the Wilkinson U-test; in the table, the average values are presented as Median [Lower quartile; Upper quartile].

Discussion

As ongoing efforts to develop and introduce the SARS-CoV-2 vaccine move forward, there is an urgent need to characterize the immune responses to COVID-19 infection, especially adaptive immunity. The development of pathogenetic approaches to the therapy of new coronavirus infection is also impossible without understanding the interaction mechanisms between the virus and immune cells. Discovery of the fundamental mechanism of pathogenesis and assessing the nature of the relationship between biochemical changes and dysregulatory processes in the immune system will allow successful treatment and predict the likely outcome already in the early stages of the disease. As a result of this study, the identified biochemical shifts, such as an increase in LDH, CRP, and a simultaneous decrease in total protein levels in COVID-19 patients, are in complete agreement with previously published works [11]. Characterizing the changes in the adaptive parts of the immune function during the growth of LDH in these patients, we can note a general inhibition of T-cell defense mechanisms, manifested by a decrease in relative and absolute content of CD4+ T-helpers and CD8+ cytotoxic lymphocytes associated with total lymphopenia. These cells may be a target for the attack activity of the SARS-Cov-2 virus. In this context, recent reports detailing the contribution of T cells in the fight against SARS-CoV-2 confirm the importance of identified changes as a predictor of a more severe course of COVID-19 infection [12–14]. In the humoral arm, however, the opposite dynamics were observed. Thus, as LDH content increases, B-lymphocyte count increases in relative and absolute values. However, the expected increase in serum IgG of M and G class as a marker of active work of the humoral arm of the immune system was not observed. In contrast, IgG levels are significantly reduced compared to patients with lower LDH levels. At the same time, an increase in serum IgA was noted in severe patients. These changes are likely associated with an imbalance between different subpopulations of B-lymphocytes, reflected in a mismatch between the growing number of cells without adequately enhancing their antibody production function. The revealed shifts indicate the marked dysregulatory processes in the immune system, leading to the worsening of the COVID-19 infectious process.

Conclusion

The LDH increase in the blood of COVID-19 patients is associated with changes in the immune system, manifested by a significant decrease in relative and absolute T-lymphocytes count due to significant lymphopenia. And it is characterized by a simultaneous increase in B-lymphocytes without an adequate enhancement of their antibody production function. These changes appear to be due to the effect of SARS-CoV-2 on immunoregulatory mechanisms, which requires further study.

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About the Authors

I. P. Sizyakinа
Rostov State Medical University
Russian Federation

Lyudmila P. Sizyakina, Dr. Sci. (Med.), Professor, head of the Department of Clinical Immunology and Allergology

Rostov-on-Don



V. Ya. Zakurskayа
Rostov State Medical University
Russian Federation

Vita Ya. Zakurskaya, Assistant of the Department of Clinical Immunology and Allergology

Rostov-on-Don



N. A. Skripkinа
Semashko City Hospital No.1
Russian Federation

Nadezhda A. Skripkina, Infectious Disease Specialist at the monoinfective Hospital №1

Rostov-on-Don



E. A. Antonova
Semashko City Hospital No.1
Russian Federation

Elena A. Antonova, Head of the Laboratory Research Quality Department

Rostov-on-Don



D. B. Sizyakin
Rostov State Medical University; Semashko City Hospital No.1
Russian Federation

Dmitry V. Sizyakin, Dr. Sci. (Med.), Professor, Professor of the Department of urology, Rostov State Medical University; head of the Semashko City Hospital №1

Rostov-on-Don



Review

For citation:


Sizyakinа I.P., Zakurskayа V.Y., Skripkinа N.A., Antonova E.A., Sizyakin D.B. Clinical and immunological characteristics of moderate-to-severe forms of COVID-19 at different levels of the tissue damage marker (lactate dehydrogenase). Medical Herald of the South of Russia. 2021;12(4):108-115. (In Russ.) https://doi.org/10.21886/2219-8075-2021-12-4-108-115

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ISSN 2219-8075 (Print)
ISSN 2618-7876 (Online)