Type III interferons in community-acquired pneumonia in children

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Introduction.
Community-acquired pneumonia (VP) in children is a very urgent problem of pediatrics due to the high level of morbidity and mortality. To date, VP is considered one of the most common causes of death of children under the age of 5 everywhere [1, 2].
Community-acquired pneumonia is an infectious disease and in most cases has a viral-bacterial nature [3]. There are a large number of studies devoted to the study of the influence of immune defense factors involved in the pathogenesis of inflammation in the lung tissue. One of the significant factors of innate immunity in children are interferons, which, along with other cytokines, participate in protection against viral and bacterial infection [4, 5].
Interferons are a broad class of cytokines that are produced in the human body when various pathogens enter. Divided into three classes: type I, type II and type III, all interferons have a common ability to induce antiviral activity initiated by interaction with their related receptors [4].
There is information in the literature about the effect of type I, type II interferons on the clinical course and severity of the condition in children with VP [4, 5, 6]. In recent years, importance has been attached to type III interferons as factors affecting the severity of the course of the infectious process. Type III interferons (IFN-λ1, IFN-λ2 and IFN-λ3) are produced by epithelial cells of the respiratory tract in response to viral infection and play a role in eliminating viral infection and provides protection of the respiratory tract [7].
However, there are not enough studies on the study of type III interferons in children of different ages with VP in the available literature. There are also no studies reflecting changes in IFN-λ2, IFN-λ3 indicators in children with various degrees of severity of VP. Taking into account the role of interferons in antimicrobial protection, we determined the concentration of IFN –λ in the blood serum of children with community-acquired pneumonia of varying severity.
Objective: to determine the concentration of type III interferons in the blood serum of children of different ages with community-acquired pneumonia and to evaluate changes in indicators depending on the severity of the disease.
Materials and methods.
The work was carried out at the Department of Microbiology, Virology, Immunology, Clinical Laboratory Diagnostics, the Department of Propaedeutics of Childhood Diseases and Pediatrics and at the Research Institute of Immunology of the South Ural State Medical University of the Ministry of Health of the Russian Federation. The study included 117 children aged 1 to 18 years with an X-ray confirmed diagnosis of community-acquired pneumonia, hospitalized in the departments of respiratory infections of MBUZ DGKB No. 7 and MAUZ DGKB No. 8 in Chelyabinsk. All children were represented by 3 age groups according to the generally accepted critical periods of immune system development: children from 1 to 3 years old, from 4 to 7 years old and from 8 to 18 years old [8].
The comparison group was formed during routine medical examination of healthy children and consisted of 28 children who did not have signs of acute respiratory viral infection at the time of examination and were not registered at the dispensary for chronic pathology. All the children were comparable in gender and age.
During the statistical analysis, the children were divided into 2 clinical groups: children with mild VP (88 children) and children with severe VP (29 children). To assess the severity of patients with VP, the criteria of severity in children with community-acquired pneumonia, presented in the clinical recommendations of 2022, approved by the Union of Pediatricians of Russia, were used. The criteria for the severity of VP are considered to be: respiratory failure of grade II or higher, central cyanosis or SpO2< 90%, systemic dangerous signs, the presence of complications [1].
According to our study, 86.2% of children with severe pneumonia had signs of respiratory failure. The median saturation of peripheral capillaries with oxygen (SpO2) was 92% (80-97%). The median procalcitonin in children with severe VP was 4.0 ng/ml (1.2-8), 16 children (55.2%) had CRP ≥ 40 mg/l and 6 children (20.7%) had CRP ≥ 80 mg/l.
To determine the level of cytokines IFN-λ2 (IL-28A) and IFN-λ3 (IL-28B) in blood serum, the OmniKine ™ ELISA Kit test system (Assay Biotechnology Company, Inc. Fremont, United States of America) was used. The study was conducted according to the methods applied to the test systems. These test systems are based on the "sandwich" method of solid-phase ELISA using peroxidase as an indicator enzyme. The results were recorded on an ELISA analyzer. The results were expressed in pg/ml.
The results were processed using statistical programs in the IBM SPSS package (v. 23). In the course of statistical processing, medians and quartiles were calculated, and groups were compared using the Kraskel-Wallis criterion. The Dunn criterion with Bonferroni correction was used for a posteriori groups. The effects were considered statistically significant at p<0.05.
Results and discussion.
The results of a comparative analysis of the concentration of interferons in blood serum in children with VP and in the comparison group are presented in Table 1.
When comparing the concentrations of IFN-λ2 (IL-28A) and IFN-λ3 (IL-28B), it was revealed that the indicators were significantly increased regardless of the severity of pneumonia (rA-B, C). When comparing groups of children with mild and severe pneumonia, we found that the concentrations of IFN-λ2 (IL-28A) and IFN-λ3 (IL-28B) are significantly different (rV-C), which may reflect the severity of the course of the infectious process and is consistent with other studies in pneumonia [6].
Table 1

The concentration of cytokines (pg/ml) in the blood serum of children with

community-acquired pneumonia and in the comparison group. Me (Q1–Q3).

 

Цитокины (пг/мл)	Группа сравнения (A) (n=28)	Нетяжелая пневмония (B) (n=88)	Тяжелая пневмония (C) (n=29)
IFN-λ2 (IL-28A)	12,8 (6,7–379,9)	494,9 (5,4–8218,6) (pА-B,С<0,001)	1061,2 (4,05–3152,6) (рВ-С=0,012)
IFN-λ3 (IL-28B)	13,6 (5,4–21,6)	20,4 (10,1–2090,5) (рА-B,С<0,001)	26,3 (3,9–70,7) (рВ-С=0,004)

 

Note: statistically significant differences are highlighted in bold

р_А-В,С - differences between the studied indicators of group A from group B,С

р_B-C - differences between the studied indicators of group B from group C

 

Further, an analysis was carried out between the cytokine concentration indicators in children with VP and in the comparison group at different age periods (Table 2).
Table 2

The concentration of cytokines (pg/ml) in the blood serum of children

with community-acquired pneumonia and in the comparison

group at different age periods. Ме (Q₁–Q₃)

Возрастная группа, лет	Группа сравнения (А) (n= 6, 9, 13)	Нетяжелая пневмония (В) (n= 29, 21,  38)	Тяжелая пневмония (С) (n= 12, 10, 7)
IFN-λ2 (IL-28A)
1-3	12,8  (6,7–12,8)	506,7 (14,1–1506,7) (pА-B,С<0,001)	1025,1 (24,3–3152,6)
4-7	9,797 (6,7–12,73)	473,03 (12,8–8218,6) (pА-B,С<0,001)	1061,2  (240,9–2572,5)
8-18	379,9 (6,7–379,9)	463,6 (5,4–4550,6) (pА-B,С<0,001)	2332,06 (148,3–2637,4) (рВ-С=0,042)
IFN-λ3 (IL-28B)
1-3	5,4  (5,4–15,4)	22,8 (10,1–2090,5) (pА-B,С<0,001)	25,6 (15,8–36,9)
4-7	5,4  (5,4–15,4)	22,2 (12,3–410,9) (pА-B,С<0,001)	29,1 (22,8–53,7) (рВ-С=0,024)
8-18	21,6 (5,4–21,6)	19,5 (13,4–1722,6)	22,07 (5,4–70,7)

 

 

In the age group of children from 1 year to 3 years and from 4 to 7 years with VP, regardless of the severity, the concentration of IFN-λ2 (IL-28A) and IFN-λ3 (IL-28B) had much higher rates, whereas in older children from 8 to 18 years, the concentration of IFN changed-λ2 (IL-28A) (rA-B, C). When considering the interferon concentration indicators, depending on the severity of the disease, it was found that there were significant differences in the group of children from 4 to 7 years according to IFN-λ3 and in the group of children from 8 to 18 years according to IFN-λ2 (IL-28A) (rV-C).
Problems in interpreting interferon concentrations in children are the lack of established normal ranges and limited knowledge of age differences. According to some studies, there are significant differences in the concentration of cytokines in the blood plasma of young children and older age groups, which may be due to the peculiarity of the activation of the immune system in different age periods and the immaturity of the immune system in young children [9].
There is evidence in the literature that IFN-λ restricts the spread of the virus inside the body and is a powerful regulator of adaptive immune responses that are initiated in the tissues of the mucous membrane. IFN-λ, apparently, plays the same important role in protecting against pathogens as interferons of type I and II, and functions selectively on the surface of the mucous membranes of the respiratory tract. In these places, IFN-λ provides innate immunity and regulates the activity of the adaptive link of the immune system [10].
Conclusions:
Thus, according to the results of our study, it was revealed that the concentration of type III interferons in the blood serum, in particular, IFN-λ2 (IL-28A) and IFN-λ3 (IL-28B), increases with community-acquired pneumonia in children more pronounced with severe form of this pathology. A significant increase in the concentration of type III interferons depends on the age of patients. There was no increase in the concentration of IFN-λ2 (IL-28A) and IFN-λ3 (IL-28B) in the blood serum of children in the age group from 1 to 3 years, which, apparently, is associated with the immaturity of the immune system in young children compared with children from the older age group.

About the authors

Natalia V. Iziurova

South Ural Medical State University

Author for correspondence.
Email: Natusaz@live.ru
ORCID iD: 0000-0002-0049-2194
SPIN-code: 7970-7527

Assistant Professor, Department of Propaedeutics of Children’s Diseases and Pediatrics

Russian Federation, 64, Vorovsky str., Chelyabinsk, 454092

Albina Yu. Savochkina

South Ural Medical State University

Email: alina7423@mail.ru
ORCID iD: 0000-0002-0536-0924

PhD, MD (Medicine), Professor, Department of Clinical Laboratory Diagnostics

Russian Federation, 64, Vorovsky str., Chelyabinsk, 454092

Anna N. Uzunova

South Ural Medical State University

Email: propeddet@mail.ru

PhD, MD (Medicine), Professor, Department of Propaedeutics of Children’s Diseases and Pediatrics

Russian Federation, 64, Vorovsky str., Chelyabinsk, 454092

Karina V. Nikushkina

South Ural Medical State University

Email: knikushkina81@gmail.ru

PhD (Medicine), Leading Research Associate, Institute of Immunology

Russian Federation, 64, Vorovsky str., Chelyabinsk, 454092

References

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