Application of exchange transfusion in the treatment of hyperleukocytosis:a retrospective analysis

Background Few reports have described the application of exchange transfusion in patients with hyperleukocytosis. A retrospective clinical analysis of infants with exchange transfusion in the treatment of hyperleukocytosis was performed. A total of 13 patients were enrolled in the study.7 patients survived and 6 died after exchange transfusion.The incidence of pulmonary hypertension, heart failure, pertussis encephalopathy, Increased C-reactive protein, and increased PCT in the survival group were lower than those in the death group,The incidence of received Gamma globulin and received steroids were higher than those in the death group.The highest WBC count in the survival group was 74.15 ± 19.68*10^9/L, and in the death group patients was 86.29 ± 23.51*10^9/L.There were not signicant differences two groups(P = 0.332).


Abstract Background
Few reports have described the application of exchange transfusion in patients with hyperleukocytosis.

Methods
A retrospective clinical analysis of infants with exchange transfusion in the treatment of hyperleukocytosis was performed.

Results
A total of 13 patients were enrolled in the study.7 patients survived and 6 died after exchange transfusion.The incidence of pulmonary hypertension, heart failure, pertussis encephalopathy, Increased C-reactive protein, and increased PCT in the survival group were lower than those in the death group,The incidence of received Gamma globulin and received steroids were higher than those in the death group.The highest WBC count in the survival group was 74.15 ± 19.68*10^9/L, and in the death group patients was 86.29 ± 23.51*10^9/L.There were not signi cant differences two groups(P = 0.332). Decrease rate of WBC after the rst ET in the survival group was signi cantly higher than that of the death group (P 0.05).
In the survival group, there were 5 patients (71.42%) which decrease rate of WBC after the rst ET more than 50%, and the remaining 2 patients (28.58%) all exceeded 45%.In contrast, there was 1 patient which decrease rate of WBC exceeded 45% ,no patient exceed 50%. All patients with Decrease rate of WBC after the rst ET exceed 50% survived. In the death group, there were 4 patients (66.67%) which N/L exceeded 1, 3patients (50%) which N/L exceeded 2. In the survival group, only 3 patients (42.85%) which N/L exceeded 1, but there was no patient which N/L exceed 2.

Conclusion
Exchange transfusion is an effective method to reduce WBC count. Patient with Decrease rate of WBC after the rst ET exceed 50% were easier to survive. Patients with hyperleukocytoemia which N/L exceeding 2 predict death.

Background
Pertussis is a highly contagious respiratory illness. Increased peripheral WBC count is a common clinical manifestation in children with pertussis, especially hyperleukocytosis was an independent predictor of death [1] .Fatal cases had signi cantly higher peak WBC counts was more likely to have a WBC count ≥ 30 000 cells/µL [2] ;Children with WBC greater than 50,000 × 109/L had nearly a ten times higher risk of death [3] . And WBC count > 100_109/L] is strongly predicts mortality in cases of severe pertussis [4] Research indicates that elevated WBC counts are associated with increased mortality risk.
Hyperleukocytosis ultimately compromise pulmonary blood ow, exacerbate hypoxemia, and create a vicious cycle of refractory pulmonary hypertension [5][6] . Early leukopenia therapy has an important effect on severe pertussis complicated with hyperleukocytosis [7][8] Leukocyte reduction measures include ET, leukocyte apheresis, etc. Leukocyte apheresis requires high requirements and may have serious adverse reactions [9] ,ET may be preferable to leukocyte apheresis because it can remove PT and reduce the WBC count [2] . At present, there are scattered studies that have reported that ET is bene cial to improve the survival rate of patient [2,4] .It indicate that ET may be an effective method in severe hyperleukocytosis. ET has been widely used in hyperleukocytosis treatment, but there is no uni ed understanding of the effect and standard use of ET in patients with pertussis. Cherry suggested exchange blood transfusion and monitoring criteria for infants with pertussis who are ≤ 60 days of age [10] .But it has not been widely accepted and used clinically.
Based on previous reports and research, our hospital has formulated the ET standard for children with pertussis and hyperleukocytosis. According to this standard, there were 13 patients with hyperleukocytoemia received ET treatment. We wanted to analysis the clinical data of 13 patients with hyperleukocytoemia, and the role of exchange transfusion.

Patients
A total of 13 patients under 1 year old who were diagnosed with pertussis from January 2018 to October 2019 at the Children's Hospital of ChongQing Medical University were enrolled in this study. All patients received exchange transfusion treatment.The diagnosis of pertussis was based on clinical ndings and con rmed by PCR. Clinical data and laboratory data were collected and analyzed.
This study was approved by the Ethics Committee of Children's Hospital of ChongQing Medical University.

Statistical Analysis
Statistical analyses were performed using SPSS software version 25. Descriptive analyses for nonnormally distributed data are presented using the median (interquartile range); comparisons between two groups were calculated using the Mann-Whitney test and multigroup comparisons were conducted using the Kruskal-Wallis rank test. Count data are expressed as the rate (%), and the difference between groups was calculated using the chi-square test. Receiver operating characteristic curve (ROC) analyses and sensitivity and speci city values were calculated by using Med Calc version 14. A P value < 0.05 was considered statistically signi cant.

Study Population
During the study period, 13 patients were enrolled in this study. All patients had B pertussis DNA detected by PCR in nasopharyngeal secretions or in sputum. The clinical data of the study patients are shown in Table 1. 6 patients died after exchange transfusion (death group), and 7 patients survived after exchange transfusion (survival group). There were 3 females (42.85%) in the survival group and 5 females (83.33%) in the death group. 8 patients which age of onset within 90 days and 5 patients over 90 days. The incidence of pulmonary hypertension, heart failure, Pertussis encephalopathy, increased CRP, and increased PCT in the survival group were lower than those in the death group, and the use of hormones and gamma globulin were higher than those in the death group.

Peripheral blood cells and changes after exchange transfusion
The peripheral blood cell examination was perfected in 13 patients. The peripheral blood cells and changes after exchange transfusion of the study patients are shown in Table 2.The highest WBC count in the survival group was 74.15±19.68*10^9/L, and in the death group patients was 86.29±23.51*10^9/L.There were not signi cant differences two groups(P=0.332).In the death group, there were 4 patients (66.67%) which N/L exceeded 1, 3patients (50%)which N/L exceeded 2. In the survival group, only 3 patients (42.85%) which N/L exceeded 1, but there was no patient which N/L exceed 2.Decrease rate of WBC after the rst ET in the survival group was signi cantly higher than that of the death group (P 0.05).
3. The process and complications 10 patients received 1 exchange transfusion treatment, 3 patients received 2 exchange transfusion treatments. The process and complications of the study patients are shown in Table3. Complications occurred in 4 patients with exchange transfusion. there was 1 patient in the survival group which showed convulsions; there were 3 patients in the death group which showed convulsions(1patiten) and Cardiac arrest (2 patients).In the survival group, there were 5 patients (71.42%) which decrease rate of WBC after the rst ET more than 50%, and the remaining 2 patients (28.58%) all exceeded 45%.In contrast,there was 1 patient which decrease rate of WBC exceeded 45% ,no patient exceed 50%. All patients with Decrease rate of WBC after the rst ET exceed 50% survived.

Discussion
Hyperleukocytosis as a risk factor for death of pertussis patients has been con rmed in many previous studies [1][2][3] Early effective leukocyte-reducing treatment can reduce patient mortality and improve patient prognosis [7] .From now, many studies have focused on the application of exchange transfusion therapy in hyperleukocytosis. But there is no uni ed understanding of the effect and standard use of ET in patients with pertussis. Some scholars believe that it should be considered based on pulse, respiratory rate, total number of WBC and ascent speed, and the early incidence of pneumonia [11] .In our study, exchange transfusion criteria for infants with pertussis:1.  [4] .In our study, 7 cases survived, and the survival rate was 53.8% (7/13).TOur study is slightly lower than previous studies.
The incidence of pulmonary hypertension, heart failure, pertussis encephalopathy, Increased C-reactive protein, and increased PCT in the survival group were lower than those in the death group,The incidence of received Gamma globulin and received steroids were higher than those in the death group.We know that pulmonary hypertension, heart failure, and pertussis encephalopathy are risk factors for severe pertussis and death. However, it is not clear whether the use of hormones and gamma globulin has a clear meaning. Some scholars found that after 3 days of intravenous injection of pertussis immunoglobulin in children with pertussis, the white blood cell count was signi cantly reduced, the spastic cough was reduced, and the tachycardia improved [12] .But currently there is no pertussis immunoglobulin in our hospital After using gamma globulin, we found that the use rate of gamma globulin in the survival group was 71.42%, which was signi cantly higher than 16.67% in the death group, suggesting that gamma globulin use may also improve the prognosis of children. Hormones are used more in pertussis Kathleen Winter et al [2] found that steroid hormones were used in fatal cases more than non-fatal cases, suggesting that steroid hormones may be a risk factor for death from pertussis James D. Cherry et al [10] also believe that steroid hormones should not be used in patients with pertussis. However, the use rate of hormones in the survival group was higher than that in the death group in this study, suggesting that hormones may be meaningful for disease improvement. However, this study has a small sample size compared with previous studies, and the death of patients is related to many factors. Hormones play a role in the nal prognosis of patients. It may be inaccurate and needs further discussion The change in the level of WBC is an intuitive indicator that re ects the effect of exchange transfusion. Analyzing the level of WBC counts and the rate of WBC decline in the two groups of patient, The WBC counts of the two groups decreased signi cantly after exchange transfusion, but there was no signi cant difference in two groups(P = 0.636). It suggesting that exchange transfusion can effectively reduce the level of WBC.
Decrease rate of WBC after the rst ET in the survival group was signi cantly higher than that of the death group (P 0.05).
In the survival group, there were 5 patients (71.42%) which decrease rate of WBC after the rst ET more than 50%, and the remaining 2 patients (28.58%) all exceeded 45%.In contrast, there was 1 patient which decrease rate of WBC exceeded 45% ,no patient exceed 50%. All patients with Decrease rate of WBC after the rst ET exceed 50% survived. It shows that Decrease rate of WBC after the rst ET may have a certain effect on the prognosis of death.
The patient's blood exchange volume was 87.99 ± 17.36ml/kg, there was no signi cant difference between the two groups (P = 0.918). However, in the death group, only 3 (50%) patients had a blood exchange volume of more than 80ml/kg for the rst time of ET; In the survival group, 6 patients( 85.71%), it indicating that blood exchange volume may also have an impact on the prognosis of the disease At the same time, we also recommend that the rst exchange blood volume should exceed 80ml/kg. N/L ratio is an easily available biomarker that may help predict the severity of the disease in children with pertussis.
Clinical studies have shown that the proportion of lymphocytes in ordinary children with whooping cough is mainly increased, but in children with severe pertussis, the ratio of neutrophils to lymphocytes may be inverted. In patients with benign pertussis with leukocytosis, within 48 hours of admission, The median N/L were 0.33 and 0.39. In contrast, the median N/L of children with malignant pertussis within 48 hours of admission were 1.1 and 1.6, respectively [13] . In the death group, there were 4 patients (66.67%) which N/L exceeded 1, 3patients (50%)which N/L exceeded 2. In the survival group, only 3 patients (42.85%) which N/L exceeded 1, but there was no patient which N/L exceed 2. It indicate patients with hyperleukocytoemia which N/L exceeding 2 predict death.
Complications during or after transfusion are important factors affecting patient prognosis. In our study, complications occurred in 4 patients with exchange transfusion. There was 1 patient in the survival group which showed convulsions; there were 3 patients in the death group which showed convulsions(1patient) and Cardiac arrest (2 patients). It is suggested that the occurrence of complications may be a poor prognosis, especially the occurrence of cardiac arrest. At the same time, we found that patients with complications are mainly those with more than 100*10^9/L white blood cells. There were 3 patients with the highest white blood cell exceeding 100*10^9/L, all of which had complications during or after exchange transfusion, while only 1 case had complications in patients with white blood cell lower than 100*10^9/L. It suggests that white blood cells are signi cantly increased, especially patients with higher than 100*10^9/L are very prone to complications.

Conclusion
Taken together, exchange transfusion is an effective method to reduce WBC count. Patient with Decrease rate of WBC after the rst ET exceed 50% were easier to survive. Patients with hyperleukocytoemia which N/L exceeding 2 predict death. Blood exchange volume of more than 80ml/kg for the rst time of ET may have an impact on the prognosis of the disease. Declarations