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8FEATURES OF IMMUNE RESPONSE IN CHILDREN WITH IRON DEFICIENCY ANEMIA WHO HAVE RECOVERED FROM CORONAVIRUS INFECTION.
Jiemuratova G.K., 2Kamalov Z.S., 3Ahmedjanova Z.I., 4Kalandarova A.N., 5Ahmedjanov
R.I.
1,2,3,4,5Institute of Immunology and Human Genomics, Academy of Sciences of the Republic of
Uzbekistan. https://doi.org/10.5281/zenodo. 8358498
Abstract. The review presents data on the causative agent of coronavirus infection, its impact on the bodies of children with iron deficiency anemia, and describes the peculiarities of children's immune response to the virus. All of this data indicates that the study of the peculiarities of COVID-19 progression and immune response in children with anemia is a relevant issue in modern medicine. Finding a solution to this issue will help understand the pathogenesis of this condition and develop effective approaches to the diagnosis and treatment of the disease, taking into account the age-specific characteristics of children.
Keywords: COVID-19; children; iron deficiency anemia (IDA); ferritin; immune indicators.
Аннотация. В данном обзоре представлены данные, касающиеся возбудителя коронавирусной инфекции и его влияния на организм детей с железодефицитной анемией. Также описаны особенности иммунного ответа у детей при воздействии вируса. Эти данные подчеркивают важность изучения особенностей протекания COVID-19 и иммунного ответа у детей с анемией в современной медицине. Решение этой проблемы поможет лучше понять патогенез данного состояния и разработать эффективные подходы к диагностике и лечению заболевания, учитывая возрастные особенности детей.
Ключевые слова: COVID-19; дети; железодефицитная анемия (ЖДА); ферритин; иммунные показатели.
Introduction. The novel coronavirus infection, SARS-CoV-2, presents new challenges to specialists and continues to be the subject of intense scrutiny. Special attention is being given to active research related to the role of various bioactive substances in assessing the severity and likelihood of adverse outcomes in this disease. At the beginning of the pandemic, it was noted that COVID-19 primarily affected the adult population, while children were rarely affected. As more empirical data on this infection accumulated, it became clear that children of all ages, including newborns and infants, are susceptible to SARS-CoV-2 infection, but they develop the disease much less frequently, with only 1-5% of cases [2,7]. The majority of children experience mild illness, with involvement limited to the upper respiratory tract or asymptomatic presentation \[3,10\]. From an epidemiological standpoint, children have a reduced risk of infection due to fewer travel, contact, and mobility opportunities [6]. Furthermore, certain age-related characteristics, such as a higher level of angiotensin-converting enzyme 2 (ACE2) enzyme circulation and, therefore, lower receptor expression, as well as some innate immune system characteristics, including immaturity, may play a role in the lower frequency of illness among children. Anemia affects a quarter of the world's population, including children under 5 years of age and women, with iron-deficiency anemia (IDA) being the most common form, accounting for approximately 90% of all anemia cases [12].
Normal iron (Fe) levels in the body are necessary for efficient phagocytosis, high natural killer cell activity, bactericidal capacity of serum, sufficient synthesis of properdin, complement, lysozyme, interferon, IgA, and for the body's resistance to adverse environmental conditions. Children with iron deficiency may experience increased susceptibility to respiratory infections [14].
Mechanisms of action of SARS-CoV-2 based on the hypothesis of the virus's hemotoxic effects leading to erythrocyte hemolysis and release of free iron into the bloodstream continue to be discussed in the literature. One of the biomarkers that has gained attention is ferritin, whose levels in the blood, especially in severe cases ofCOVID-19, are significantly elevated [13].
In clinical practice, measurement of serum ferritin (F) levels has been used to assess iron stores in the body. It is well known that ferritin is the most sensitive, early, and reliable indicator of iron deficiency in tissues preceding the development of iron-deficiency anemia [9].
However, it is important to consider that serum ferritin (SF) is an acute-phase protein of inflammation, and its levels increase during infectious and neoplastic processes, as well as liver diseases. This limits its diagnostic value in detecting iron deficiency (ID) in such cases. To overcome this issue, measuring serum ferritin levels in combination with other acute-phase inflammation markers (C-reactive protein, procalcitonin) is recommended [11].
The aforementioned points emphasize the need to study the peculiarities of COVID-19 progression and immune response in children with iron-deficiency anemia (IDA) in Karakalpakstan. Addressing this issue will help understand the pathogenesis of this condition and develop effective approaches to the diagnosis and treatment of the disease, taking into account the characteristics of the pediatric population.
To achieve this, it is necessary to start with a description of the novel coronavirus and the specific immune response of the human body to it. Without this knowledge, it is impossible to fully comprehend the pathogenesis of COVID-19, correctly apply therapeutic and rehabilitative approaches for recovery after the illness, and assess the effectiveness and prospects of various preventive methods.
Main Part: The role of the innate immune system is crucial in the interaction between the body and viral infections. The innate immune system is the oldest mechanism of defense against various pathogens. It is genetically inherited, provides protection from birth, and persists throughout life, although its activity may change with age [9]. The innate immune system plays a primary role in protecting the body from genetically foreign microbial factors through receptors that recognize conservative molecular structures of microorganisms known as pathogen-associated molecular patterns (PAMPs). This leads to instant activation of the body's immune system and subsequent elimination of the pathogen. However, not all innate immune cells are capable of completely neutralizing the action of the invading microorganism, and in such cases, the adaptive (specific) immune system is activated, with lymphocytes being its main representatives. Lymphocytes express T-cell receptors (TCRs) or B-cell receptors (BCRs) that possess high specificity and recognize one or several antigenic determinants [10]. The precise biological and genetic factors determining the wide range of possible scenarios for the development of the new coronavirus disease, ranging from completely asymptomatic carriage to severe cases involving various organs and systems and fatal outcomes, are still unknown. A deeper understanding of the features of humoral and cellular immunity will help develop more effective approaches to the prevention and treatment of this disease [3].
Destruction of erythrocytes and the development of anemia are the results of COVID-19 infection. Additionally, anemia is a predictor of severe disease progression [1,18]. Firstly, COVID-19 infection is associated with pronounced hypoxia. Secondly, a decrease in the quantity and quality of erythrocytes leads to the development of oxygen insufficiency [2,16]. In children infected with COVID-19, there is often an increase in erythrocyte sedimentation rate (ESR) (greater than 20 mm/h), which is associated with a reduction in the number of functional erythrocytes responsible for gas exchange [7,17]. Deficiency of folates and other B-group vitamins contributes to the decrease in the quantity and quality of erythrocytes [4]. Thirdly, children with anemia experience depletion of iron stores and develop iron-deficiency anemia (IDA). Therefore, COVID-19 infection in children, especially in the presence of IDA, leads to a more severe course of the coronavirus infection [12]. In children with IDA, in addition to iron deficiency, there is also a deficiency of trace elements that slow down the development of acute and chronic inflammatory processes, prevent the formation of a cytokine storm [15], and contribute to maintaining oxygen exchange during COVID-19 and iron-deficiency anemia. For example, microcytosis of erythrocytes, which occurs in folate deficiency and other B-group vitamin deficiencies, exacerbates the course of IDA and leads to the accumulation of iron in lung tissues due to the penetration of small-sized erythrocytes through capillaries and their subsequent destruction [10]. It should be noted that iron metabolism disorders in COVID-19, including IDA, are not always associated with an increased level of ferritin. Although ferritin is a protein involved in iron homeostasis, it is also an acute-phase protein of inflammation, similar to C-reactive protein (CRP). Ferritin is produced in cells of various organs, so tissue destruction during inflammation can be one of the reasons for the elevation of ferritin levels in the blood [8].
It is known that ferritin has specific physiological functions in the human body. On one hand, it is responsible for iron accumulation and deposition, and on the other hand, it is considered an acute-phase protein of inflammation, along with C-reactive protein (CRP). Ferritin is produced in cells of various organs, hence tissue damage during inflammation can be one of the causes for increased ferritin levels in the blood [8,16].
In 2020, a review article authored by Y.P. Orlov et al. was published in the journal "Vestnik Anesteziologii i Reanimatologii" [6]. This article discussed the negative impact of excessive iron content on the outcomes of COVID-19 based on the role of this element in the replication and virulence of RNA viruses. The literature continues to discuss the pathogenetic model of the systemic effects of SARS-CoV-2, which is based on the hypothesis of the hemotoxic effect of the virus, leading to hemolysis of erythrocytes and the release of free iron into the bloodstream [5,9]. There are several publications that suggest ferritin as a humoral factor in regeneration processes, an inhibitor of lipid oxidation, and an element that enhances the body's resistance to infectious agents. There may be complex feedback interactions between ferritin and cytokines in the control of anti-inflammatory and pro-inflammatory mediators, as cytokines can stimulate the expression of ferritin, and ferritin, in turn, can influence the expression of anti-inflammatory and pro-inflammatory cytokines.
Our analysis of the literature reveals that many authors often confuse true iron overload in cells and tissues (histologically confirmed hemosiderosis of the liver, lungs, etc., marked elevation of iron levels in the blood) with hyperferritinemia. In doing so, they fail to consider other indicators of iron homeostasis, such as hemoglobin, transferrin, erythrocyte size, shape, and color. Ignoring such obvious facts leads to incorrect conclusions, for example, that "removal of iron from the
blood could be an effective therapeutic measure to reduce coronavirus survival" [14,16]. Indeed, COVID-19 is associated with disruptions in the regulation of iron homeostasis, such as low hemoglobin levels, low iron content in the blood, microcytosis and anisocytosis of erythrocytes, elevated levels of lactate and LDH [13,17]. In one study involving 50 patients with confirmed COVID-19 by PCR, abnormally low concentrations of iron in the blood (<7.8 ^mol/L) were found in 45 of them. The decrease in iron levels was associated with an increased risk of severe disease progression and mortality from COVID-19 [2,18]. Another clinical study demonstrated that systemic hypoferremia is associated with the severity of hypoxia in COVID-19. Patients with severe hypoxemia had significantly lower blood iron levels (2.3 ^mol/L, 95% CI = 1.7-2.6 ^mol/L) compared to patients with milder hypoxemia (4.3 ^mol/L, 95% CI = 3.3-5.2; p \< 0.001). Blood iron levels were directly dependent on oxygen partial pressure and lymphocyte count [8,11]. A meta-analysis of 35 studies involving 5,912 patients with severe COVID-19 confirmed that more severe disease progression is associated not only with increased levels of inflammatory markers (CRP by 3.04 times, D-dimers by 2.74 times, leukocytes by 1.2 times, neutrophils by 1.33 times, ESR by 1.44 times) but also with decreased hemoglobin levels (by 1.53 times) [7,8].
It is important to note that hemoglobin levels depend on the patient's constitution, not just iron status. For example, a study by S.H. Cai et al. found an inverse correlation between lymphocyte count (r = -0.23, p = 0.027) and platelet count (r = -0.44, p< 0.001) with body mass index (BMI), and a direct correlation between hemoglobin levels (r = 0.267, p = 0.008) and BMI [12]. The existing data on reduced hemoglobin and iron levels in the blood lead to the conclusion that COVID-19 infection is associated with the development of iron deficiency.
Iron, along with other micronutrients such as zinc, magnesium, manganese, calcium, selenium, folate, and vitamins A and niacin, plays an important role in inhibiting various stages of the life cycle of single-stranded RNA viruses. For example, iron- and niacin-dependent cholesterol 25-hydroxylase affects viruses at early stages of cell infection (virion fusion with cell membrane) and viral protein "maturation" (including post-translational modifications of the viral envelope M protein). The iron/folate-dependent protein viperin inhibits viral replication and release from the plasma membrane [7, 12]. In cases of iron deficiency, the activity of these proteins inevitably decreases, reducing the effectiveness of interferon-dependent antiviral protection. Thus, existing research indicates that COVID-19 is characterized by elevated levels of the acute-phase protein ferritin, rather than iron overload. Moreover, the available data support the development of iron deficiency in the context of COVID-19. Therefore, the presence of signs of iron-deficiency anemia in a pregnant woman suffering from COVID-19 warrants the prescription of iron supplements or continuation of previously prescribed ones. For the prevention and treatment of iron-deficiency anemia, it is recommended to use iron-based pharmaceutical formulations supplemented with synergistic vitamins [7].
The obtained data confirm the previously established link between the severity of COVID-19 and ferritin levels. In this context, an immunological mechanism underlying the observed dependency has been elucidated. Patients with moderate to severe forms of COVID-19 and high ferritin levels exhibit more pronounced disruptions in the regulation of the immune system, primarily manifested by impaired maturation processes of the T-cell component and enhanced proliferation of B lymphocytes without a corresponding increase in antibody production.
Conclusion: The newly acquired knowledge about the immunopathogenesis of SARS-CoV-2 infection provides researchers and healthcare professionals with a basis for understanding
the reasons behind unfavorable disease outcomes, despite adherence to guidelines and standard treatment methods according to clinical protocols.
The data presented in the review indicate that hypoxia in children resulting from COVID-19 and anemia leads to decreased blood oxygen levels and contributes to overall hypoxia development. Latent iron deficiency caused by unbalanced nutrition or increased iron requirements creates conditions for the development of hypoxic and immunodeficient states, increasing the risk of severe coronavirus infections. Therefore, special attention needs to be given to children with COVID-19 in the presence of anemia.
Indeed, the deficient state in children exacerbates the characteristic inflammation of COVID-19 and increases the risk of cytokine storms and erythrocyte hemolysis, which can lead to iron-deficiency anemia. In light of the coronavirus pandemic, timely prevention and treatment of anemia in children become particularly relevant.
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