Cytokines are soluble low-molecular-weight proteins that are produced and secreted by a variety of cells, including lymphocytes, macrophages, natural killer cells, mast cells, and stromal cells. Cytokines participate in the body's immune response and play an important role in immune regulation. Cytokines can be divided into proinflammatory factors including IL-1 interleukins, IL-6, IL-8, IL-12, TNF-, and INF, which tend to stimulate immune cells. In contrast, anti-inflammatory cytokines such as IL-4, IL-6, IL-10, IL-11, IL-13, IL-1, and TGF- betas in the system inhibit inflammation and suppress immune cells. Some cytokines such as IL-6 have both pro-inflammatory and anti-inflammatory properties [3].The levels of cytokines in the human body can be affected by a variety of factors, and the external pathogen infection often leads to changes in the levels of cytokines. Therefore, in order to verify the differences in serum cytokines caused by different pathogen infection, this study analyzed the cytokines in children with CAP caused by five different respiratory pathogens. In addition, the disorder of cytokines such as inflammatory factor storm can lead to organ failure and death. To further verify the influence of cytokines on disease outcome, this study further analyzed the predictive value of cytokines for severe pneumonia.
The results of this study showed that the levels of cytokines in children with CAP caused by different respiratory pathogens were different. For example, the level of IL-2 in Mycoplasma pneumoniae 0.42(0,1.34) was higher than that in RSV 0(0,0.18), P < 0.01. Mycoplasma pneumoniae 0.42(0,1.34) was higher than Streptococcus pneumoniae 0(0,0.3), P < 0.01. IL-2 plays an integral role in the maintenance and homeostasis of innate and adaptive immune responses. In response to antigen stimulation, effector T cells produce IL-2, which in turn promotes the survival or expansion of a variety of lymphocytes, including effector T cells and memory T cells, natural killer (NK) cells and regulatory T cells. IL-2 regulates the balance between immune stimulation and immunosuppression through a variety of ways [4]。In terms of IL-4, Mycoplasma pneumoniae 0(0,0.92) was higher than that of RSV 0(0,0), P < 0.01. IL-4 is an anti-inflammatory cytokine that plays a pleiotropic regulatory role in many inflammatory response processes. It is normally secreted by type 2 helper T lymphocytes, mast cells, eosinophils, and basophils, and especially plays a protective role in nerve injury, IL-4 exerts anti-inflammatory effects by inhibiting the production and release of proinflammatory cytokines, chemokines, proteases, and reactive oxygen species [5]. In terms of IL-6, Mycoplasma pneumoniae 21.76(12.04,50.76) was higher than that of RSV 7.06(3.57,20.14), P < 0.001. Adenovirus 29.08(7.15,48.92) was higher than RSV 7.06(3.57,20.14), P < 0.05. Streptococcus pneumoniae 25.69(5.51,39.45) was higher than RSV 7.06(3.57,20.14),P < 0.05. IL-6 is a pleiotropic cytokine produced by different cells and tissues, which has a wide range of physiological and pathological effects. It has pro-inflammatory and anti-inflammatory effects, and stimulates B lymphocytes to produce antibodies [6]. In the level of IL-10, Mycoplasma pneumoniae 3.82(2.08,6.17) was lower than adenovirus 9.82(3.2,18.38), P < 0.01; Mycoplasma pneumoniae 3.82(2.08,6.17) was lower than RSV 11.58(5.05,27.26), P < 0.001; Haemophilus influenzae 4.62(1.87,15.57) was lower than RSV 11.58(5.05,27.26), P < 0.05. IL-10 is an important anti-inflammatory cytokine. IL-10 inhibits the ability of Th1 cells to produce cytokines, so that the host is protected from the excessive response of pathogens and microbiota, and pathogens also undergo immune escape [7]. In IL-17A, Mycoplasma pneumoniae 0.95(0,4.39) was higher than that of RSV 0(0,0.09), P < 0.01. Mycoplasma pneumoniae 0.95(0,4.39) was higher than Haemophilus influenzae 0(0,0), P < 0.01; Mycoplasma pneumoniae 0.95(0,4.39) was higher than Streptococcus pneumoniae 0(0,0), P < 0.05; IL-17A is a member of the IL-17 family of cytokines. It is produced mainly by T helper 17 cells, but also by epithelial cells, neutrophils, NK cells, etc. In response to antigen stimulation, these cells secrete IL-17A, which in turn activates downstream signaling pathways to promote the recruitment of phagocytes and the production of antimicrobial peptides. IL-17A also has the side effect of promoting inflammatory responses [8]. There was no significant difference in TNF-α among the pathogens. Tnf-α is a proinflammatory factor, and by binding to TNF receptors, Tnf-α can induce apoptosis, regulate innate immune responses to inhibit viral replication, and promote the infiltration of macrophages, dendritic cells, natural killer cells, and neutrophils to suppress infection {[9]. In terms of IFN-γ, Mycoplasma pneumoniae 4.92(2,9.81) was higher than RSV 3.01(0.8,6.85), P < 0.05. Mycoplasma pneumoniae 4.92(2,9.81) was higher than Haemophilus influenzae 0.52(0,2.47), P < 0.001; Mycoplasma pneumoniae 4.92(2,9.81) was higher than Streptococcus pneumoniae 0.83(0.3,5.73), P < 0.01; Adenovirus 4.93(0.15,21.62) was higher than Haemophilus influenzae 0.52(0,2.47), P < 0.05; RSV 3.01(0.8,6.85) was higher than Haemophilus influenzae 0.52(0,2.47), P < 0.01. IFN is one of the first immune pathways activated in the human body after viral infection and is essential for the control of viral replication and spread, especially on the mucosal surface of the host exposed to pathogens. IFN-γ has been associated with antiviral responses, but it is now more generally accepted that it plays an important role in immunity against fungi and bacteria. Ifn-γ provides important support for the function of type I IFN, especially in regulating cell-mediated immune responses, promoting macrophage activation and enhancing antigen presentation [10]. Therefore, in the overall comparison of single pathogen, it was found that the levels of IL-2, IL-6, IL-17A, IFN-γ and other pro-inflammatory factors in Mycoplasma pneumoniae group were higher than those in respiratory syncytial virus group, P < 0.05. When Mycoplasma pneumoniae was compared with Streptococcus pneumoniae and Haemophilus influenzae, it was found that in IL-17A, INF-γ and other pro-inflammatory factors, Mycoplasma pneumoniae was higher than that of Streptococcus pneumoniae and Haemophilus influenzae, P < 0.05. This indicated that the expression of pro-inflammatory factors in Mycoplasma pneumoniae was higher than that in RSV, Streptococcus pneumoniae and Haemophilus influenzae. However, the anti-inflammatory factor IL-10 of Mycoplasma pneumoniae was lower than that of RSV and adenovirus (P < 0.05), indicating that Mycoplasma pneumoniae was lower than that of viral pneumonia in inhibiting the expression of inflammatory factors. Therefore, Mycoplasma pneumoniae is more likely to cause the disorder of cytokines and inflammatory response than other pathogens to a greater extent. When bacteria and viruses were compared, Streptococcus pneumoniae was higher than RSV in IL-6, while RSV was higher than Haemophilus influenzae in IL-10. On INF-γ, adenovirus and RSV were higher than Haemophilus influenzae, indicating that INF-γ expression was higher in viral infections. As a viral pneumonia, it was found that the level of IL-6 in adenovirus was higher than that in RSV, indicating that adenovirus could cause stronger inflammatory response than RSV. As bacterial pneumonia, there was no significant difference in the levels of cytokines between Streptococcus pneumoniae and Haemophilus influenzae caused pneumonia.
This study further analyzed the predictive value of different cytokines in severe pneumonia caused by different pathogens. According to the ROC curve analysis, IL-6, IL-10 and IFN-γ had certain diagnostic value for severe mycoplasma pneumonia, and the area under the ROC curve, 95% confidence interval and boundary value were 0.759 (95%CI:0.624, 0.895, P < 0.01; Cut-off value 20.87), 0.714 (95%CI: 0.560, 0.867, P < 0.05, cut-off value 4.765), 0.732 (95%CI: 0.598, 0.865, P < 0.01, 3.4) and IL − 6, IL − 10, IFN - gamma hemophilies influenzae in severe pneumonia has certain diagnostic value. The area under the ROC curve, 95% confidence interval and cut-off value were 0.868 (95%CI: 0.717, 1, P < 0.01, cut-off value 23.325), 0.891 (95%CI: 0.778, 1, P < 0.001, cut-off value 5.175) and 0.761 (95%CI: 0.778, 1, P < 0.001, cut-off value 5.175). 0.582 vs 0.941, P < 0.05, cut-off value 0.56). These results indicate that IL-6, IL-10 and IFN-γ have certain predictive value for severe Mycoplasma pneumoniae pneumonia and severe Haemophilus influenzae pneumonia. Marthe S. Paats et al. showed that the levels of IL-6, IL-10 and IFN-γ in peripheral blood of severe CAP patients were significantly higher than those of non-severe CAP patients[11]. But the study did not identify the cause。In addition, studies have shown that IL-6 and IL-10 have high predictive value for severe COVID-19 [12]. However, this study did not find the diagnostic value of cytokines in severe adenovirus pneumonia, severe respiratory syncytial virus pneumonia, and severe Streptococcus pneumoniae pneumonia, so more studies are needed to verify. Therefore, the predictive value of serum cytokines for severe pneumonia caused by different pathogens is also different. This can also provide reference value for future studies, and the relationship between severe pneumonia with a single pathogen and cytokines should be discussed separately.