Concentration of serum cytokines in patients with various ages depending on the period and severity of hemorrhagic fever with renal syndrome

Introduction. The Republic of Bashkortostan occupies one of the leading places in the incidence of hemorrhagic fever with renal syndrome (HFRS) for many years with no tendency to reduce it. This is facilitated by the difficulty in diagnosing this disease, especially in the early stages, and the lack of effective methods for its prevention. A detailed and detailed study of the mechanisms of the pathological impact of hantavirus on the body is necessary for an accurate determination of the volume of pathogenetic therapy, which today is the main one in the treatment of HFRS. It is known that damage to the endothelium plays a key role in the pathogenesis of HFRS. However, hantavirus does not have a direct cytopathic effect on endotheliocytes, but serves only as an initiator of immune inflammation [1]. Cytokines occupy a leading role in the pathogenesis of many infectious diseases, including HFRS [3]. In the literature available to us, we have not encountered any publications on the study of the dynamics of cytokines in children with HFRS.

The purpose of our study was to conduct a comparative study of the dynamics of pro-inflammatory cytokines: interleukin-1β, tumor necrotizing factor-α, α-interferon and γ-interferon in patients with hemorrhagic fever with renal syndrome.

Materials and methods. The study included 47 children with HFRS who were hospitalized in the infectious clinical hospital No. 4 in Ufa. Patients were conditionally divided into 2 groups. The first group consisted of 25 patients who underwent treatment with the diagnosis: HFRS medium-heavy form. The second group included 22 patients diagnosed with severe HFRS. The age of those examined in these two groups was 5-17 years. The mean age in the first group was 11.1 ± 1.6 years, in the second group - 11.3 ± 1.3 years.

To compare the cytokine status, 24 healthy children aged 5 to 17 years were examined for the cytokine status, the mean age of this group was 11.2 ± 1.4 years.

The content of cytokines in patients studied in febrile, oliguric, polyuric periods and in the period of convalescence, 1 month after discharge from the hospital. A comparison of the results was performed with the indices of cytokines in a group of healthy children.

The cytokine content was determined by an enzyme immunoassay using commercial reagent kits of Protein Contour LLP (St. Petersburg).

Statistical processing of the research results was carried out using parametric and nonparametric statistics using statistical programs Statistica 7.0 for Windows. The mean value (M) and the mean value error (m) were calculated in Microsoft Excel.

Results and discussion. The content of cytokines in different periods of HFRS in the examined patients is presented in Table 1.

When analyzing the dynamics of the proinflammatory cytokines IL-1β and TNFα in the children examined, it appears that IL-1β and TNFα are increasing already during the febrile period. However, the increase in these cytokines was statistically significant only in severe HFRS (p <0.05). In the oligurical period, their increase is more pronounced. IL-1β increases with moderate and severe HFRS form 4 and 5 times, respectively. TNFα with a moderate form increased by 7 times, and in severe form 9 times. Thus, in the severe form of HFRS, the pro-inflammatory cytokines IL-1β and TNFα increase more severely than at moderate severity.

Table 1 - Cytokine content in children with HFRS, depending on the period and severity of the disease

p - reliability of differences with control, * - p <0,05.

During the reconvalescence period, a month after the disease, the level of proinflammatory cytokines was higher than in the control group, but no significant differences were noted. By this fact, the dynamics of proinflammatory cytokines in HFRS in children differs from the dynamics of proinflammatory cytokines in adults. Since even in the period of convalescence there is a significant increase in proinflammatory cytokines in comparison with the co[5]. Regarding INFα and INF-γ, we observed reverse dynamics, that is, a significant decrease in the level of INFα and INF-γ and already in the febrile period. The content of INFα and INF-γ in patients with severe HFRS was more dynamic than in the case of the moderate variant of the disease. So already in the feverish period, a significant deficit (p <0.05) of INFα and INF-γ was recorded. The development of the disease was accompanied by the preservation of a low level of INFα and INF-γ, even in the period of convalescence, with severe disease, these differences were statistically significant (p <0.05). Thus, in response to an antigenic attack, a massive release of pro-inflammatory cytokines occurs, the name of the "cytokine storm". It should be noted that the endothelium is both a source and a target for cytokines. There is a hyperproduction of TNF-α, IL-1β. In particular, TNF-α is one of the factors contributing to the increase in the permeability of capillaries and plasmorrhoea, the development of fever, the intensification of coagulation and stimulation of hemopoiesis [6]. However, a decrease in INFα and INF-γ is observed, which indicates a low activity of T-helpers and NK cells [2]. Activation of anti-inflammatory cytokines IL-10 is also taking place. That is, mutually opposite immunoregulation is carried out, which is protective in the "cytokine storm." When studying the dynamics of the anti-inflammatory cytokine IL-10, it was found that it increased in the feverish period of HFRS, and its growth continued until the polyuric period. In children, 1 month after discharge from hospital, the concentration of IL-10 was higher than in the control group, with both moderate and severe forms of HFRS, but the differences were not statistically significant. Unlike adult patients who had a significant increase in the anti-inflammatory cytokine IL-10 in the period of convalescence. [4]

Conclusions: 1. In children with HFRS, an increase in the concentration of proinflammatory cytokines IL-1β and TNFα has been observed since the febrile period. The peak in the growth of these cytokines is noted in the oligurical period. In the period of polyuria, the level of proinflammatory cytokines decreases. And in the period of convalescence, their difference from the control group is statistically not significant, in contrast to adult patients who have significantly increased concentrations of proinflammatory cytokines in the period of convalescence in comparison with the control group. 2. The level of INFα and INF-γ in children with HFRS decreases since the febrile period, the greatest decrease is noted in the oliguric period with severe HFRS form. In the polyuric period, the level of INFα and INF-γ is increased, but with a severe form of the disease their level is statistically significantly higher than in the control group even in the period of convalescence. 3. The concentration of anti-inflammatory cytokine IL-10 in the febrile period tends to increase, a statistically significant increase is noted in the oliguric period and continues to increase in the polyuric period. In the phase of convalescence, the level of IL-10 is not statistically different from the control group, while in adult patients the level of IL-10 in the period of convalescence is significantly higher than in the control group.

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