Bp can produce many virulence factors after infection, and its pathogenic core is pertussis endotoxin (PT) function [13] . By interfering with the immune regulation of the body, PT causes lymphocytes from immune organs such as lymph nodes to be released in large numbers with extravascular overflow to peripheral blood [14] , and inhibits lymphocyte recycling, resulting in abnormal accumulation of lymphocytes in peripheral blood and finally causing the total number of white blood cells (mainly lymphocytes) to increase significantly [15] . Hyperleukocytosis has been identified as an independent risk factor and predictor of severe pertussis in contemporary studies [16] [17] .

Many studies [18] have shown that WBC ≥ 20 × 10⁹/L has significance in the diagnosis of severe pertussis. Florence et al. [19] found that WBC > 30 × 10⁹/L significantly increases the risk of severe pertussis in children, and serious complications such as apnea, cyanosis, and bacteremia could occur. Wang Caiying et al. [20] retrospectively analyzed 184 cases of pertussis. It was found that when the white blood cell count (WBC) was > 50 × 10⁶/L, severe leukocytosis could occur. A large number of white blood cells aggregated in the pulmonary capillary network and lymphatic vessels. Due to the poor deformability of white blood cells, white blood cell clumps were likely to form emboli at these sites, increasing the pressure in the pulmonary vessels, reducing pulmonary blood flow, decreasing oxygen delivery, and resulting in hypoxemia and pulmonary hypertension. In severe cases, heart failure could occur, increasing the risk of death in children. Meanwhile, Helen et al. [21] found that when WBC > 50 × 10⁹/L, the death risk of children may be tenfold higher, and speculated that WBC elevation is related to mechanical ventilation demand, pulmonary hypertension, and death risk. Lynda et al. [22] further analyzed 16 cases of pertussis death and found that WBC > 55 × 10⁹ was present in all cases. Foreign related studies [21] showed that when WBC > 100 × 10⁹/L, if white blood cell count reduction measures were taken, the mortality rate of children could be as high as 100%.

At present, leukapheresis is mainly used for hyperleukocytemia, including exchange transfusion therapy. Because leukapheresis requires high-level operational skills, vascular access status, and blood volume, it is often combined with extracorporeal membrane lung (ECMO) [22] [23] . In the reported cases treated with leukapheresis [23] [24] , the children all had adverse reactions of different degrees, such as anemia, hypoalbuminemia, hemodynamic instability, and even death. Exchange transfusion therapy was safer and more applicable than that, especially for infants with severe pertussis aged ≤ 60 days [23] [25] . In the case reports at home and abroad [26] [27] , the prognosis was better after exchange transfusion therapy was performed early in the WBC surge stage. However, it is not advocated to actively implement this treatment for children with severe whooping cough in China at present. Leukapheresis can be tried when the WBC is excessively elevated or when the WBC is increased with cardiovascular complications.

The peripheral blood cell count of children with pertussis shows an increase in total white blood cells, mainly lymphocytes [11] . Lymphocytes are often used in conjunction with white blood cells to predict the malignant progression of pertussis and the probability of adverse prognosis. Ganeshalingham et al. [28] suggested that when WBC > 25 × 10⁹/L and lymphocyte ratio > 50%, there is a high probability of malignant progression of pertussis; some researchers [29] also pointed out that when WBC > 20 × 10⁹/L and lymphocyte ratio > 60%, the prognosis of children is poor; Liu Juan et al. [8] believed that WBC > 20 × 10⁹/L and LY > 14 × 10⁹/L could be used as specific indicators for the diagnosis of severe pertussis. Ratio of neutrophil to lymphocyte count. Neutrophil-to-lymphocyte ratio (NLR) can effectively suggest that WBC > 20 × 10⁹/L and LY > 14 × 10⁹/L could be used as specific indicators for the diagnosis of severe pertussis. The neutrophil-to-lymphocyte ratio (NLR) refers to the ratio of neutrophils to lymphocytes in peripheral blood [30] . It is a new type of inflammatory response indicator derived from white blood cell subsets. It can reflect the relative relationship of reciprocal changes between the body’s inflammatory response and immune status. That is, there is an interactive and relative change relationship between the body’s inflammatory response and immune status, where an increase in one may lead to a decrease in the other [31] . It also plays a clinical predictive role in various systems such as infectious diseases, cardiovascular diseases, autoimmune diseases, and tumors. The study [32] indicates that the normal range of NLR is 1 - 2. When the value of NLR is less than 0.7, it is common among patients with viral infections, neutropenia, or tumors [33] . An NLR > 1 indicates a more pronounced increase in neutrophil count than lymphocyte count, which may be related to the presence of an excessive and abnormal host response after infection with Bp [34] . In foreign studies, NLR inversion occurs earlier than clinical deterioration in children [34] , and NLR > 1 within 48 hours of hospital admission in children with pertussis is often indicative of severe pertussis [28] . The study by Wu Xiaoying et al. [35] found that children with pertussis with significantly increased NLR are more likely to have severe respiratory involvement, indicating that NLR can be used as a predictor of severe pertussis pneumonia.

Cytokine imbalance and inflammatory storm can promote the malignant evolution of pertussis, and abnormal expression of some cytokines can be used as a key reference to judge severity risk, assess the degree of injury, and guide intervention. After BP infection, the body is first infected by innate immune cells (macrophages, dendritic cells, neutrophils, etc.), initiating an immune response and secreting cytokines to facilitate phagocytosis and killing [36] . For example, NK cells enhance the antibacterial activity of macrophages by secreting IFN-γ and induce the production of Th1 cells; dendritic cells induce T cells to proliferate and differentiate into Th1 and Th17 cells secreting IFN-γ and IL-17, further activating neutrophils and macrophages, while PT regulates T cell differentiation and thus affects cytokine expression levels [21] [36] - [38] .

Pro-inflammatory factors’ “explosive increase” directly drives syste Pro-inflammatory factors’ explosive rise directly drives systemic inflammation and organ damage. On the one hand, IL-6 can damage bronchial epithelial tissue, directly stimulate airway mucosal epithelial cells to release mucus, aggravate airway stenosis, promote pneumonia, and the progression of severe disease is positively correlated with the IL-6 level [39] [40] . On the other hand, IL-6 can also activate the systemic inflammatory response through excessive secretion, causing SIRS. The higher the IL-6 level, the higher the risk of adverse prognosis and death in children [41] . Related experiments [42] showed that TNF can be significantly secreted after BP infection and induces a peak response after 1 hour. When the level of TNF-α in serum is too high, it will seriously damage bodily functions and even cause death [43] . Cytokine bias towards the ‘Th2 response’ will weaken the clearance ability. Li Xiaomei et al. [44] pointed out that the risk of immune function decline in children with pertussis increased 1.255-fold for each unit of IL-5 and 0.886-fold for each unit of IFN-γ. Tao Meiting et al. [45] believed that the reduction in IFN-λ expression level after BP infection could lead to a reduction in the local mucosal immune response, which was not conducive to infection control.

Macrolides are the first-line drugs for the treatment and prevention of pertussis [46] . However, with the immune selection pressure induced by vaccines [47] and the widespread use of macrolides in clinical treatment in recent years, the number of pertussis-resistant strains is increasing. The A2047G point mutation of the 23SrRNA gene is the main molecular mechanism for generating pertussis-resistant strains. Erythromycin-resistant strains in China have increased rapidly since 2008 and have high levels of drug resistance [48] [49] . Guo Mengyang et al. [50] found that ptxP1 and ptxP3 pertussis-resistant strains were highly resistant to erythromycin, and studies [51] showed that ptxP3 pertussis-resistant strains secreted more PT and were more toxic. Some domestic scholars also found that children infected with resistant strains were more likely to be infected with other pathogens during the course of the disease, resulting in lower respiratory symptoms [52] .