Иммуноопосредованные заболевания у постковидных пациентов и их связь с нарушением активности системы комплемента

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Аннотация

Пандемия новой коронавирусной инфекции COVID-19, вызванная вирусом SARS-CoV-2, привела к далеко идущим последствиям. Вызываемые им изменения в макроорганизме могут сохраняться более 6-12 месяцев после окончания острой фазы заболевания, формируя постковидные нарушения иммунной системы. Пациенты, перенесшие острый COVID-19 как в легкой, так и в тяжелой форме, страдают от различных проявлений постковидного синдрома. Однако выраженность этих проявлений весьма вариабельна. Целью настоящего исследования стала оценка влияния степени поражения легких в остром периоде COVID-19 на выраженность клинических проявлений постковидного синдрома на примере иммуноопосредованных симптомокомплексов: аутоиммунного, пролиферативного и аллергопатологии. Обследован 131 пациент, перенесший инфекцию SARS-CoV-2. Для исследования использованы анамнестические данные из амбулаторных карт пациентов. С помощью метода ИФА-диагностики определялись IgA, IgM, IgG, специфичные к SARS-CoV-2, фрагменты комплемента C1q, C3a, C5a. В ходе исследований выявлена связь между тяжестью постковидного синдрома и тяжестью острого течения COVID-19. Вирус SARS-CoV-2 способен активировать комплемент, и активация эта сохраняется длительно (более полугода), что объясняет наличие клинических проявлений постковидного синдрома у лиц, перенесших легкую острую форму COVID-19 без поражения легких по данным компьютерной томографии и не имеющих выявленных нами ранее фенотипов поражения иммунной системы (врожденного звена – снижение экспрессии CD46 на Т-лимфоцитах и снижение экспрессии CD46 на NK-клетках, и приобретенного – снижение уровня Т-цитотоксических лимфоцитов и нарушение уровня В-клеток CD45+CD3-CD19+CD5+CD27+). Полученные данные свидетельствуют о том, что обследование пациентов, имеющих постковидный синдром, должно проводиться не только путем оценки их клинических характеристик, но и путем изучения состояния иммунной системы таких пациентов с целью постановки правильного диагноза и назначения этиологической и патогенетической терапии, в том числе иммунотерапии. Аутоиммунные, пролиферативные и аллергические заболевания напрямую связаны с нарушениями иммунной системы. Обобщая результаты данного исследования, можно сделать следующие выводы: 1. Тяжесть аутоиммунных нарушений в постковидный период напрямую не связана с тяжестью заболевания, а в большей степени связана с базисной кортикостероидной терапией (ГКС) как для лечения аутоиммунных процессов, так и для лечения COVID-19. Если ГКС не используются при аутоиммунном тиреоидите, то их применение в остром периоде инфекции впоследствии снижало количество рецидивов. Тогда как при ревматоидном артрите ситуация обратная: применение ГКС в остром периоде инфекции у пациентов, уже находящихся на базисной кортикостероидной терапии, впоследствии приводит к увеличению количества рецидивов у пациентов, перенесших ковидный. 2. У пациентов, перенесших COVID, выявлена тенденция к увеличению наиболее клинически тяжелой аллергопатологии: во-первых, во всех группах (52%) в постковидный период участились обострения таких патологий, как отек Квинке, крапивница, анафилаксия, васкулит, альвеолит, бронхиолит. Все это свидетельствует о том, что на ухудшение состояния этих пациентов в постковидный период повлияла перенесенная инфекция, вызванная вирусом SARS-CoV-2. Аллергические поражения кожи оказались на втором месте по частоте обострений – около 28%. 3. Отмечается тенденция к увеличению частоты обострений пролиферативных заболеваний у пациентов с более тяжелыми формами острой инфекции COVID-19. Также следует отметить, что процент таких пациентов достаточно высок – от 31,6% до 48%. 4. Вирус SARS-CoV-2 может влиять на активацию системы комплемента, что объясняет наличие клинических проявлений постковидного синдрома у лиц, перенесших острую форму COVID-19 в легкой форме без поражения легких по данным компьютерной томографии и не имеющих выявленных нами ранее фенотипов поражения иммунной системы. Полученные данные свидетельствуют о том, что обследование постковидных больных должно проводиться не только путем оценки их клинических характеристик, но и путем исследования состояния иммунной системы таких пациентов с целью постановки правильного диагноза и назначения этиологической и патогенетической терапии, в том числе иммунотерапии.

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The work is completed on the topic of State assignments FBIS Federal Scientific Research Institute of Viral Infections “VIROM” Federal Service for Supervision of Consumer Rights Protection and Human Consumption “Study of the mechanisms of chronic viral infection formation in patients with post-COVID syndrome and impaired immune system functions. Development of pathogenetic approaches to effective prevention and immunocorrection of identified disorders in patients with “post-COVID syndrome” No. state registration 124031800093-5.

Introduction

The COVID-19 coronavirus pandemic caused by the SARS-CoV-2 virus has had far-reaching consequences. According to case histories, patients with post-COVID syndrome experience severe fatigue, increased fatigability, an increase in the incidence of acute respiratory viral infections per year, an increase in the recurrence of skin diseases, allergy pathologies, an increase in the recurrence of chronic infectious and non-infectious diseases of various organs and systems. Patients were examined at least six months after recovery from acute COVID-19. Such persistent post-infectious consequences are known as post-COVID syndrome [7]. When assessing post-COVID syndrome, it is necessary to reveal the main clinical symptoms of multiorgan pathology characteristic of post-COVID patients according to the literature [3]. For example, 410 participants in a Swiss study were assessed for complaints 7-9 months after being diagnosed with COVID-19, of which 39.0% of patients reported long-term symptoms such as fatigue (20.7%), loss of taste or smell (16.8%), shortness of breath (11.7%), and headache (10.0%), including among young, previously healthy people [6]. In another study by Chinese scientists, 1,733 patients were examined 6 months after acute COVID-19, in which 9% reported a long-term sensation of palpitations and 5% reported chest pain [2]. Cognitive impairments were noted, manifested by difficulty concentrating, deteriorating memory, perception, and/or speech reproduction [8]. In a study by Chinese scientists, approximately a quarter of patients reported anxiety, depression, and sleep disturbances 6 months after COVID-19 [2]. However, reports of similar complaints after mild COVID-19 suggest a contribution to their development by dysfunction of the autonomic nervous system [1]. Long-term cognitive impairment has been noted in studies aimed at assessing the condition of patients who have suffered critical illnesses; it occurs in 20-40% of patients hospitalized with COVID-19 [10]. Ruggeri R.M. et al. (2021) write about subacute thyroiditis with clinical manifestations of thyrotoxicosis weeks after the disappearance of respiratory symptoms [9]. COVID-19 can lead to the manifestation of latent autoimmune thyroiditis in the form of new-onset Hashimoto’s thyroiditis [11] or Graves’ disease [5]. Endocrine manifestations of post-COVID syndrome can be a consequence of direct damage by the virus, immunological and inflammatory damage, as well as iatrogenic complications.

Thus, in the literature there are indications of various clinical pathological manifestations of post-covid syndrome, but at the same time, there is no systematization of these studies, and there is no data on the pathogenesis of the formation of clinical manifestations of post-covid syndrome. In addition, if the immune system of patients with acute coronavirus infection has been studied quite well, then the state of the immune system of post-covid patients remains practically unstudied. All this served as the basis for our studies of post-covid patients.

The aim of the study was to assess the impact of the degree of lung damage in the acute period of COVID-19 on the severity of clinical manifestations of post-COVID syndrome using the example of immune-mediated symptom complexes – autoimmune, proliferative, and allergopathology.

Materials and methods

A total of 131 patients who had recovered from SARS-CoV-2 infection were examined. Of these, 48 were men aged 20 to 76 years (mean age 55.3 years) and 83 were women aged 21 to 79 years (mean age 53.4 years). The inclusion criteria in the study groups were: confirmed diagnosis of SARS-CoV-2 infection by polymerase chain reaction (PCR), the presence of IgA, IgM to the SARS-CoV-2 virus in the acute and post-acute periods of infection and IgG to the SARS-CoV-2 virus during the recovery period, computed tomography data of the lungs on the presence or absence of changes of the “ground glass” type. This study was conducted at least 6-12 months after the infection caused by SARS-CoV-2. All patients were preliminarily examined by a general practitioner and an immunologist-allergist in order to identify concomitant diseases, as well as by doctors of other specialties before COVID-19 to establish concomitant diagnoses. The groups were randomized by gender, age, concomitant diseases according to the χ2 criterion. All studies were approved by the Independent Local Ethics Committee at the State Autonomous Healthcare Institution of the Republic of Chelyabinsk “City Clinical Hospital No. 1” of Chelyabinsk (protocol No. 8 dated 04/11/2022), on the basis of which these studies were conducted, and by the Independent Local Ethics Committee at the Federal Research Institute of Virology and Infection “Virom” of Rospotrebnadzor of Yekaterinburg, protocol No. 1 dated 03/22/2024, on the basis of which these studies were conducted.

Clinical research methods

  • dentification of persons with post-COVID syndrome after examination by doctors: therapist, allergist-immunologist, pulmonologist, ENT doctor.
  • Filling out the immunological examination card.
  • Physical, laboratory and instrumental examinations for diagnosis.

Immunological research methods

ELISA diagnostic methods. Determination of the level of specific IgA, IgM, IgG to the SARS-CoV-2 coronavirus, C1 inhibitor, C3a and C5a complement components by enzyme immunoassay and immunofluorescence analysis on a Multiscan FC Thermoscientific enzyme immunoassay analyzer (China). The study was conducted using generally accepted standardized enzyme immunoassay methods (test systems of VectorBest, Russia; Cytokine LLC, Russia).

Statistical research methods

Based on the study results, a database was created in Excel (MS Office 2007). Data processing and analysis were performed using R 3.1.1 12 (RFoundation for Statistical Computing, Vienna, Austria) and Microsoft Excel version 14.0. Student’s t-tests were used for parametric data; differences were considered significant at p < 0.05.

Equipment

The following equipment was used: Multiscan FC Thermoscientific enzyme immunoassay analyzer (China), Mindray SL-1200 A immunochemiluminometer (China), related equipment (centrifuges, shakers, thermostats, etc.), computers with software packages required for mathematical and statistical analysis of the results.

Results and discussion

According to the data presented in Table 1, reliable differences were obtained between groups KT0 and KT1-2, as well as KT0 and KT3-4 – the frequency of exacerbations of rheumatoid arthritis in the post-COVID period is significantly higher in the group with lung damage of less than 50% in the acute period of COVID-19 compared to the group of patients without lung damage, while the frequency of exacerbations of autoimmune thyroiditis is significantly higher in patients without lung damage in the acute period of COVID-19 compared to the other groups.

 

Table 1. Severity of clinical manifestations of the autoimmune symptom complex in post-COVID patients depending on the degree of lung damage in the acute period of COVID-19

Diseases with increased incidence of relapses or first identified after clinical recovery from acute COVID-19 infection/degree of lung damage according to CT data

Total number of patients examined (n = 131)

Group 1

CT 0 (n = 38)

Group 2

CT 1-2 (n = 68)

Group 3

CT 3-4 (n = 25)

Abs.

%

Abs.

%

Abs.

%

Abs.

%

Rheumatoid arthritis

30

22.9

4

10.2

19

27.9

p1-2 < 0.05

7

28.0

Autoimmune thyroiditis

20

15.3

11

29.0

7

10.3

p1-2 < 0.05

2

8.0

p1-3 < 0.05

Note. Reliability of differences between groups p1-p2, p1-p3, p2-p3. Differences p < 0.05 (Student’s T-test) were considered reliable.

 

When analyzing the effect of the degree of lung damage in the acute period of COVID-19 infection on the increase in the frequency of exacerbations of allergic diseases in the post-COVID period (Table 2), no dependence was found. However, at the same time, a tendency towards an increase in the most clinically severe allergopathology was revealed in post-COVID patients: firstly, in all groups (52%), exacerbations of such pathologies as Quincke’s edema, urticaria, anaphylaxis, vasculitis, alveolitis, and bronchiolitis became more frequent in the post-COVID period. All this indicates that the deterioration of the condition of these patients in the post-COVID period was influenced by the infection caused by the SARS- CoV- 2 virus. Allergic skin lesions were in second place in terms of exacerbation frequency – about 28%.

 

Table 2. Severity of clinical manifestations of the symptom complex of allergopathology in post-COVID patients depending on the degree of lung damage in the acute period of COVID-19

Diseases with increased incidence of relapses or first identified after clinical recovery from acute COVID-19 infection/degree of lung damage according to CT data

Total number of patients examined (n = 131)

Group 1

CT 0 (n = 38)

Group 2

CT 1-2 (n = 68)

Group 3

CT 3-4 (n = 25)

Abs.

%

Abs.

%

Abs.

%

Abs.

%

Eczema, contact dermatitis, psoriasis

36

27.5

11

29.0

18

26.7

7

28.0

Quincke’s edema, urticaria, anaphylaxis, vasculitis, alveolitis, bronchiolitis

68

51.9

20

52.3

35

51.5

13

52.0

Seasonal rhinitis, conjunctivitis

32

24.4

10

26.3

17

25.0

5

20.0

Bronchial asthma

19

14.5

4

10.5

14

20.6

1

4.0

Note. As for Table 1.

 

The frequency of exacerbations of proliferative diseases did not show significant differences between patient groups depending on the degree of lung damage in the acute period of infection (Table 3), but there was a tendency for the frequency of exacerbations to increase in patients with more severe forms of acute COVID-19 infection. It should also be noted that the percentage of such patients is quite high – from 31.6% to 48%. These data further indicate that post-COVID patients develop multiple organ pathology.

 

Table 3. Severity of clinical manifestations of the proliferative symptom complex in post-COVID patients depending on the degree of lung damage in the acute period of COVID-19

Diseases with increased incidence of relapses or first identified after clinical recovery from acute COVID-19 infection/degree of lung damage according to CT data

Total number of patients examined (n = 131)

Group 1

CT 0

(n = 38)

Group 2

CT 1-2

(n = 68)

Group 3

CT 3-4

(n = 25)

Abs.

%

Abs.

%

Abs.

%

Abs.

%

Frequent lymphadenitis

41

31.3

13

34.2

20

29.4

8

32.0

Benign tumors: fibroids, cysts, polyps, fibroadenomas, endometriosis

54

41.2

12

31.6

30

44.1

12

48.0

Note. As for Table 1.

 

One of the key indicators of immune status is the complement system. Disturbances in the activity of the complement system can lead to serious consequences for various organs and tissues – the central nervous system, liver, lungs, and the immune system as a whole [4]. Therefore, the next stage of the study was to compare the level of complement system indicators in post-COVID patients depending on the severity of acute coronavirus infection (Table 4).

 

Table 4. Analysis of complement system parameters in post-COVID patients depending on the degree of lung damage according to computed tomography data in the acute period of COVID-19

Degree of lung damage according to CT data / Level of complement system indicators

Group 1

CT0

(n = 38)

M±m, р

Group 2

CT 1-2

(n = 68)

M±m, р

Group 3

CT 3-4

(n = 25)

M±m, р

Group 4

Conditionally healthy individuals who have not had COVID-19 (n = 16)

M±m, p

C1q, mcg/mL

273.9±31.7

275.5±27.9

199.1±20.3

p1-3 < 0.05

p2-3 < 0.05

p3-4 < 0.05

287.2±31.2

C3a, ng/mL

109.7±6.4

115.3±6.9

106.3±13.0

119.7±18.3

C5a, ng/mL

27.2±3.5

p1-4 < 0.05

25.2±2.6

p2-4 < 0.05

27.1±5.9

p3-4 < 0.05

15.1±2.7

Note. As for Table 1.

 

As can be seen from Table 4, all patients who have had COVID-19 have increased activity of the complement fragment C5a, which indicates long-term (at least six months) stimulation of the classical complement activation pathway. Also noteworthy is the persistent decrease in the activity of C1q, which is responsible for the normalization of activated complement, in the most clinically severe patients.

Conclusions

Autoimmune, proliferative and allergic diseases are directly related to disorders of the immune system. Summarizing the results of this study, we can make the following conclusions:

  1. The severity of autoimmune disorders in the post-COVID period is not directly related to the severity of the disease, but is more associated with basic corticosteroid therapy (GCS) both for the treatment of autoimmune processes and for the treatment of COVID-19. If GCS are not used for autoimmune thyroiditis, then their use in the acute period of infection subsequently reduced the number of relapses. Whereas with rheumatoid arthritis, the situation is the opposite: the use of GCS in the acute period of infection in patients already on basic corticosteroid therapy subsequently leads to an increase in the number of relapses in post-COVID patients.
  2. In post-COVID patients, a tendency towards an increase in the most clinically severe allergopathology was revealed: firstly, in all groups (52%) in the post-COVID period, exacerbations of such pathologies as Quincke’s edema, urticaria, anaphylaxis, vasculitis, alveolitis, and bronchiolitis became more frequent. All this indicates that the deterioration of the condition of these patients in the post-COVID period was influenced by the past infection caused by the SARS-CoV-2 virus. Allergic skin lesions were in second place in terms of the frequency of exacerbations – about 28%.
  3. There is a tendency towards an increase in the frequency of exacerbations of proliferative diseases in patients with more severe forms of acute COVID-19 infection. It should also be noted that the percentage of such patients is quite high – from 31.6% to 48%.
  4. The SARS-CoV-2 virus can affect the activation of the complement system, which explains the presence of clinical manifestations of post-COVID syndrome in individuals who have had an acute form of COVID-19 in a mild form without lung damage according to computed tomography data and who do not have the phenotypes of immune system damage that we have previously identified. The data obtained indicate that the examination of post-COVID patients should be carried out not only by assessing their clinical characteristics, but also by examining the state of the immune system of such patients in order to make a correct diagnosis and prescribe etiological and pathogenetic therapy, including immune therapy.
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Об авторах

Мария Александровна Добрынина

ФБУН «Федеральный научно-исследовательский институт вирусных инфекций “Виром”» Роспотребнадзора

Автор, ответственный за переписку.
Email: info@niivirom.ru

к.м.н., старший научный сотрудник лаборатории трансмиссивных вирусных инфекций

Россия, г. Екатеринбург

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