Influenza is a highly contagious respiratory transmitted disease with a high prevalence in winter and spring. Influenza in children is a major cause of morbidity and mortality worldwide, with higher incidence rates each year. Influenza viruses, belonging to the family Orthomyxoviridae, primarily affect the respiratory system. And influenza A and B viruses are the main prevalent viruses of influenza. The typical clinical manifestations of influenza-infected persons are acute fever, muscle pain, headache, accompanied by respiratory symptoms. Some patients may not have any typical clinical features. Symptoms in young children are even characterized by high fever, and gastrointestinal complaints such as nausea, vomiting, diarrhea, and loss of appetite.

Influenza viruses usually invade the respiratory tract, but can also affect other systems such as digestive, nervous, cardiovascular and so on. Although the infection is usually self-limiting, children have a higher risk of complications when involving the neurological and cardiovascular systems, causing complications such as IANE, multiple organ dysfunction syndrome, and septic shock, leading to death in children [1] [2]. There are various neurological complications of influenza, including febrile convulsion, encephalopathy, encephalitis, aseptic meningitis, acute cerebellar ataxia, myelitis, Guillain Barre syndrome, acute disseminated encephalomyelitis (ADEM), occasional cerebrovascular diseases and so on, some of which can be life-threatening or leave severe neurological sequelae. Neurological complication, often defined as IANE, is rare but is an important complication of influenza infection with approximate three-quarters of cases regarding children and leading up to 30% of mortality in children [3] [4]. The current lack of characteristic clinical manifestations or effective biomarkers of IANE and the exact pathogenesis and risk factors are not clear, have made early diagnosis relatively difficult [5] [6] [7]. In this study, we review and compare the demographic data, clinical manifestations, and laboratory findings of a total of 25 cases hospitalized with a diagnosis of IANE and 57 cases diagnosed with FS from January 2016 to January 2020 in Guangzhou Women’s and Children’s Medical Center, aiming to explore the characteristic clinical manifestations and available biomarkers of IANE.

Influenza is a common infectious disease worldwide. While mainly invading the respiratory tract, influenza viruses can cause neurological damage in some cases, leading to a series of neurological syndromes. The morbidity and mortality rates of neurological damages due to influenza are high, especially in children [4] [10]. Among them, IANE can progress rapidly and even cause death or leave permanent neurological sequelae in the short term [11]. The mortality rate of IANE in this study was as high as 40%. However, there is still a lack of specific clinical manifestations and laboratory indices for the diagnosis of IANE, and there are relatively few reports on it [5] [6] [7]. The diagnostic criteria of IANE suggested by Mizuguchi et al. [8] are now used as the main reference standard, among which cranial imaging is vitally important in the diagnosis and assessment of prognosis. However, cranial imaging has not been effectively performed in all children due to various factors such as medical condition, medical conditions and patients’ wishes. Therefore, we need some simple and easy predictors with rapid results to enable early and rapid identification of IANE.

In this study, there was no significant difference in the prevalence between males and females in the IANE group, with ages ranging from 8 months to 11 years and a mean age of 4.4 years, which is consistent with the literature reporting that IANE occurs from 24 d - 13 years of age and is more common in children under 5 years of age [5] [10] [12]. Surana P et al. [13] reported that influenza-associated encephalopathy (IAE) and IANE are caused primarily by influenza virus type A, of which H1N1 was the most common. In contrast, FA and FB accounted for 36.00% and 40.00% of IANE cases in this study, with no significant difference between them, suggesting that although FB causes relatively minor neurological damage, it can also lead to severe cases and even cause death. The clinical presentation of IANE lacks specificity and is reported in the literature [5] [7] [14] to be characterized by rapid progression to encephalopathy, coma, or death within 1 - 2 days after the onset of the disease. In this study, the main clinical manifestations of children in the IANE group were acute impairment of consciousness (64.00%, 16/25) and convulsions (72.00%, 18/25), of which 33.33% (6/18) could have more than two convulsions. In contrast, no child in the FS group had more than two convulsions (0.00%, 0/57), while alterations in consciousness were rarely seen (3.51%, 2/57). In addition, children in both the IANE and FS groups developed neurological symptoms within 2 - 3 days of the onset of the disease, which is consistent with literature reports. This suggests that children with influenza need to be on high alert for IANE when they present with frequent convulsions and rapid consciousness impairment at an early stage.

IANE patients lack specific laboratory indicators, but some studies have reported that most IANE patients have significant changes in biochemical indicators within about 48 hours of admission [6]. In this study, we found that children in the IANE group showed changes in ALT, AST, CK, PCT, LDH, and PLT after admission, which were similar to the results of the above study. Consistent with the results reported in previous literature [6] [8] [14] [15], ALT, AST, CK, blood LDH and CSF LDH and CSF protein levels were significantly higher in children in the IANE group compared with the FS group in this study. Some studies [16] [17] [18] reported that the mechanisms of neurological injury in influenza include endothelial damage. In this study, platelets were found to be below the reference range in all cases of IANE deaths, suggesting a high possibility of concomitant neurological symptoms and poor prognosis in children with influenza with reduced platelets. In addition, logistic regression analysis showed that LDH ≥ 348.5 U/L predicted a significantly higher risk of IANE, suggesting that elevated LDH could be an important reference for the diagnosis of IANE. Consistent with previous reports [19] [20], the results of this study showed that the early appearance of elevated AST, LDH, CK, and reduced platelets were associated with the development of IANE and poor prognosis, so influenza patients with neurological symptoms followed by abnormalities in the above indicators need to be highly alert for the development of IANE.

In summary, in children under 5 years of age admitted to the hospital with neurological symptoms of influenza, if they present early with acute impairment of consciousness, with or without convulsive seizures, and the first biochemical indexes AST, LDH, and CSF protein and CSF lactate dehydrogenase are elevated and platelets are decreased within 48 h after admission, especially when blood LDH ≥ 348.5 U/L, they need to be closely evaluated and alerted to the ANE, the possibility of occurrence, improve neurological related examinations as soon as possible, and give relevant interventions as early as possible to reduce the occurrence of death and sequelae. This study was conducted in only one hospital, with limited sample size and limitations, and the ability of early identification of IANE needs to be improved. Future larger studies and further validation and analysis of these biochemical indicators in future clinical cases may be needed.

The authors declare no conflicts of interest regarding the publication of this paper.

Chen, Q.L., Qiu, T.X., Liu, G.M., Li, Q.P. and Lu, H. (2021) Early Identification of Influenza Related Acute Necrotizing Encephalopathy by Clinical Manifestations and Laboratory Index. Journal of Behavioral and Brain Science, 11, 227-238. https://doi.org/10.4236/jbbs.2021.119018