We retrospectively analyzed 545 children with influenza in the PICU, 30 of whom developed neurological complications and were included in the study. Influenza infection is a serious threat to the health of children. In 2003–2004 influenza season, the average hospitalization rate was 36/100000 of American children, but up to 80% for children under 5 years of age [10]. A study on influenza-associated neurological diseases from Australia showed that seasonal influenza is an important cause of children’s neurological diseases in Australia. After extensive influenza vaccination, the mortality of children with influenza-associated encephalopathy was significantly reduced [11]. Data of influenza-associated encephalopathy reported through Japan’s National Infectious Disease Epidemiological Surveillance Database from 2010 to 2015 showed a total of 385 patients got with influenza-associated encephalopathy. The average incidence of influenza-associated encephalopathy in children and adults (age \(\geqslant \)18 years) was 2.83 and 0.19 per million, respectively. The median duration of fatal cases from the onset of influenza-associated encephalopathy to death was 1 day [12]. In China, the Beijing Children’s Hospital conducted an analysis of the cause of death of 19 children with influenza virus infection from November 2017 to April 2018, 8 children had flu-associated encephalopathy, and 7 of them died of flu-associated encephalopathy [13].
In addition to severe respiratory complications, which can rapidly progress to coma in some children, influenza-associated neurological complications are more severe in children and are the leading cause of influenza death [12, 14, 15]. Until now, the pathogenesis of influenza-associated neurological complications is still unclear. Autopsy of these patients showed necrosis and epithelial hemorrhage of thalamus and posterior cerebral cap of pons, pale myelin sheath in white matter of brain and cerebellum, and no clear obstruction of vascular endothelium and peripheral vascular edema [16]. Due to the acute onset of influenza-associated neurological diseases, severe brain dysfunction can occur quickly. The treatment time window is tight. Before the symptoms of nervous system appear, the children’s respiratory system disorder is not prominent or even no respiratory system performance, and lack of early warning indicators. Although immunization can reduce its incidence to a certain extent [11], most children are not actively vaccinated. Once the patient developed into an Influenza-associated neurological disease, treatment is extremely difficult, and some children develop cardiopulmonary failure within a short period of time. Many children have undergone cardiopulmonary resuscitation before admission, and showed pupil light loss or even brain herniation after admission, the brain failure will soon appear even if with active treatment. Even if they survived, some children will still have serious neurological complications. The mortality rate of acute necrotizing encephalopathy is 31.8%, and only 10% of patients make a full recovery, with many more surviving as neurological sequelae. The neurological sequelae recover very slowly and some patients received unacceptable long-term rehabilitation [17]. Therefore, effective treatment of influenza-associated neurological disease, especially acute necrotizing encephalopathy is a problem that we urgently need to solve. In this study, we found that the mortality of children in the CBP group was lower than that of the non-CBP group, and the neurological coma score (Glasgow score), PCIS score and PIM-2 score were improved compared with the non-CBP group. This suggests that CBP is associated with a reduction in mortality.
The pathogenesis of influenza-associated neurological disease is unclear. The current view is that influenza virus infection triggers a systemic inflammatory response syndrome, in particular, elevated cytokines (interleukin-6, -8, -10) are involved. The physiological states of IL-6 is knows to have a neuroprotective effect, but abnormal increase of IL-6 is found in serum of IAE patients with severe disability or death with serious adverse prognosis [17, 18]. This is consistent with the fact that IL-6 plays a more obvious role in nervous system diseases related to influenza reported in the literature [4]. Some people that the IL-6 overexpression subsequently induces or contributes to NMDA-mediated neurotoxicity, in pathological states [19]. Therefore, the elevated cytokines (interleukin-6, -8, -10), caused by systemic inflammatory response syndrome triggered by influenza virus infection, have been hypothesized to play an important role in the pathogenesis of neurological complications [14, 20]. However, there is no effective therapy for the “system cytokine storm” caused by influenza virus. Corticosteroid is the most commonly used and the effect is still controversial. The current treatment for influenza-associated neurological disease is symptomatic treatment and immune regulation. Kawashima [21] reported three children with influenza encephalopathy recovered from influenza after hormone and plasma exchange. The CBP model in this subject includes PE and CVVHDF, which can remove inflammatory factors between 0.5k-60 kDa from serum. IL-6 molecular weight is 24.385kD. In this study, the level of inflammatory factors,including CRP, PCT and IL-6, reduced in the CBP group after blood purification. Among them, the level of IL-6 decreased more significantly.
CBP can definitely reduce IL-6 levels significantly, and the survival rate of patients in the CBP group was improved. However, since this study is a retrospective study, all data are dependent on the records in the previous database. What’s more, due to the effective number of samples in this study, we don’t know if there is a relationship between the reduction of IL-6 levels and the survival rate. So, the mechanism and efficacy of CBP therapy in the treatment of Influenza-associated neurological disease require further research and discussion.
