Influenza-associated Encephalopathy Research Articles

Identification of neurological complications in childhood influenza: a random forest model

BackgroundAmong the neurological complications of influenza in children, the most severe is acute necrotizing encephalopathy (ANE), with a high mortality rate and neurological sequelae. ANE is characterized by rapid progression to death within 1–2 days from onset. However, the knowledge about the early diagnosis of ANE is limited, which is often misdiagnosed as simple seizures/convulsions or mild acute influenza-associated encephalopathy (IAE).ObjectiveTo develop and validate an early prediction model to discriminate the ANE from two common neurological complications, seizures/convulsions and mild IAE in children with influenza.MethodsThis retrospective case-control study included patients with ANE (median age 3.8 (2.3,5.4) years), seizures/convulsions alone (median age 2.6 (1.7,4.3) years), or mild IAE (median age 2.8 (1.5,6.1) years) at a tertiary pediatric medical center in China between November 2012 to January 2020. The random forest algorithm was used to screen the characteristics and construct a prediction model.ResultsOf the 433 patients, 278 (64.2%) had seizures/convulsions alone, 106 (24.5%) had mild IAE, and 49 (11.3%) had ANE. The discrimination performance of the model was satisfactory, with an accuracy above 0.80 from both model development (84.2%) and internal validation (88.2%). Seizures/convulsions were less likely to be wrongly classified (3.7%, 2/54), but mild IAE (22.7%, 5/22) was prone to be misdiagnosed as seizures/convulsions, and a small proportion (4.5%, 1/22) of them was prone to be misdiagnosed as ANE. Of the children with ANE, 22.2% (2/9) were misdiagnosed as mild IAE, and none were misdiagnosed as seizures/convulsions.ConclusionThis model can distinguish the ANE from seizures/convulsions with high accuracy and from mild IAE close to 80% accuracy, providing valuable information for the early management of children with influenza.

Viral entry and translation in brain endothelia provoke influenza-associated encephalopathy

Influenza-associated encephalopathy (IAE) is extremely acute in onset, with high lethality and morbidity within a few days, while the direct pathogenesis by influenza virus in this acute phase in the brain is largely unknown. Here we show that influenza virus enters into the cerebral endothelium and thereby induces IAE. Three-weeks-old young mice were inoculated with influenza A virus (IAV). Physical and neurological scores were recorded and temporal-spatial analyses of histopathology and viral studies were performed up to 72 h post inoculation. Histopathological examinations were also performed using IAE human autopsy brains. Viral infection, proliferation and pathogenesis were analyzed in cell lines of endothelium and astrocyte. The effects of anti-influenza viral drugs were tested in the cell lines and animal models. Upon intravenous inoculation of IAV in mice, the mice developed encephalopathy with brain edema and pathological lesions represented by micro bleeding and injured astrocytic process (clasmatodendrosis) within 72 h. Histologically, massive deposits of viral nucleoprotein were observed as early as 24 h post infection in the brain endothelial cells of mouse models and the IAE patients. IAV inoculated endothelial cell lines showed deposition of viral proteins and provoked cell death, while IAV scarcely amplified. Inhibition of viral transcription and translation suppressed the endothelial cell death and the lethality of mouse models. These data suggest that the onset of encephalopathy should be induced by cerebral endothelial infection with IAV. Thus, IAV entry into the endothelium, and transcription and/or translation of viral RNA, but not viral proliferation, should be the key pathogenesis of IAE.

The effect of influenza A (H1N1) pdm09 virus infection on cytokine production and gene expression in BV2 microglial cells

Acute influenza infection has been reported to be associated with neurological symptoms such as influenza-associated encephalopathy (IAE). Although the pathophysiology of this condition remain unclear, neuroinflammation and associated alterations in the central nervous system (CNS) are usually induced. Microglia (MGs), CNS-resident macrophages, are generally the first cells to be activated in response to brain infection or damage. We performed reverse transcriptase droplet digital PCR (RT-ddPCR) and luminex assays to investigate virus proliferation and immune reactions in BV2 MGs infected with influenza A(H1N1)pdm09 virus. Furthermore, isobaric tags for relative and absolute quantitation (iTRAQ)-based quantitative proteomics methods were used to investigate the dynamic change in the protein expression profile in BV2 MGs to gain insight into the CNS response to influenza A (H1N1) pdm09 infection. Our results showed that the influenza A(H1N1)pdm09 virus was replicative and productive in BV2 MG cells, which produced cytokines such as interleukin (IL)-1β, IL-6, tumour necrosis factor (TNF)-α and monocyte chemoattractant protein (MCP)-1. The expression of osteopontin (OPN) in the influenza A (H1N1) pdm09-infected BV2 MGs was upregulated at 16 and 32 h post-infection (hpi) compared to that in the control group, resulting in aggravated brain damage and inflammation. Our study indicates that OPN signalling might provide new insights into the treatment of CNS injury and neurodegenerative diseases in IAE.

Influenza associated acute necrotizing encephalopathy and COVID-19 encephalopathy; a comparative review

Acute necrotizing encephalopathy (ANE) is influenza-associated encephalopathy (IAE) that mostly occurs in younger age groups following an acute viral illness with a very low recovery rate. It is a rare but rapidly progressive neurodegenerative disorder which pathogenesis is still not clear. There are some cases reported where the virus can directly invade the central nervous system (CNS) through the peripheral nervous system. Several pathogenic conditions like rising levels of proinflammatory cytokines, dissolving the blood-brain barrier (BBB), etc can trigger the viral infection. There are no specific treatments available but initial steroid therapy in combination with antivirals and hypothermia therapy were found efficacious in some cases. Similarly, coronavirus disease 2019 (COVID-19) encephalopathy is caused by a novel coronavirus SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2). Having a very low recovery rate, and still unknown pathophysiology, this condition is proved to be fatal for immunocompetent adults. Treatments are not available but drugs like remdesivir, hydroxychloroquine, tocilizumab, and losartan were used to reduce the viral infection. No recurrent cases have been reported so far, but reinfection of the virus can trigger hypoxic encephalopathy. This review mainly focuses on a comparative study to understand the pathophysiology to help for discovering a new area of drug development.

Risk Factors of Influenza-Associated Necrotizing Encephalopathy in Children

Objective: A case-control study of Influenza-Associated Necrotizing Encephalopathy (IANE) in children was conducted to explore the risk factors for the diagnosis of IANE, and to provide a predictive reference for the diagnosis of IANE. Methods: The children with IANE who received treatment in our hospital from January 2016 to December 2020 were selected as the study group, and the children with Influenza-Associated Encephalopathy (IAE) group who received treatment in the same period were selected as the control group. The blood biochemical, coagulation function and cerebrospinal fluid test results of the two groups were analyzed by univariate analysis. Receiver Operating Characteristic Curve (ROC) analysis was used to determine the optimal threshold point of each index for the indicators with statistically significant differences in univariate analysis results, and multivariate Logistic stepwise regression analysis was performed according to the optimal threshold points. Results: In the IANE group, there were 32 children, including 20 males and 12 females, aged 58 (23, 97) months. There were 40 children in IAE group, including 26 males and 14 females, aged 58 (23, 97) months. Univariate results showed that serum Lactate Dehydrogenase (LDH), Cerebrospinal Fluid Lactate Dehydrogenase (CSF LDH) and Cerebrospinal Fluid Protein (CSF Pro) in the IANE group were significantly higher than those in the IAE group, and the difference between the two groups was statistically significant (P <0.001). The optimal threshold points of blood LDH, CSF LDH and CSF Pro by ROC curve analysis were 535U/L, 67U/L and 0.49g/L, respectively. Further Multivariate Logistic stepwise regression analysis showed that LDH >535U/L (OR=31.264, 95% CI: 5.892-165.878, P <0.001) and CSF PRO >0.49g/L (OR=7.695, 95% CI: 1.052-56.305, P=0.044) were independent risk factors for IANE. Conclusion: For children with influenza whose neurological symptoms appear rapidly and persist in the early stages of the disease, blood LDH >535U/L and CSF PRO >0.49g/L are independent risk factors for IANE.

Characteristics and Mortality Risk Factors of Influenza-Associated Encephalopathy/Encephalitis in Children in a Tertiary Pediatric Hospital in China, 2016-2019

Objective: Seasonal influenza associated neurological complications had high mortality and morbidity rates in children. In this study, we aimed to investigate the clinical characteristics and mortality risk factors in children with influenza-associated encephalopathy. Methods: Retrospectively analyze the clinical data, laboratory tests, and imaging examinations of 68 children diagnosed with influenza-associated encephalopathy from January 2016 to December 2019 at Guangzhou Women and Children’s Medical Center, and the cases were divided into survival and non-survival groups by disease outcome and analyzed between two groups Results: Among the 68 children with influenza-associated encephalopathy, 40 were male, and 28 were female, aged from 3 months to 13 years, of which 66.18% (45/68) were under 5 years old. Pathogenetic tests showed that influenza virus type A accounted for 63.24% (43/68), and influenza virus type B accounted for 36.76% (25/68). Typical brain MRI changes in childhood influenza-associated encephalopathy were bilateral symmetrical lesions of the thalamus, basal ganglia, brainstem, and cerebellum. 68 patients had a mortality rate of 20.59% (14/68), with a significantly higher proportion of fever peak >39°C, Acute Disturbance Of Consciousness (ADOC), and cardiac arrest in the non-survival group than in the survival group (P<0.05). Laboratory tests showed significantly higher Alanine Aminotransferase (ALT), Aspartate Transaminase (AST), Creatinine Kinase (CK), and Lactate Dehydrogenase (LDH), Lactate, C-Reactive Protein (CRP), and CSF protein levels in the non-survival group compared with the survivor (P<0.05), and among them, elevated ALT, AST, LDH, and CSF protein were independent high-risk factors for death from influenzaassociated encephalopathy. Conclusions: Children under 5 years of age with influenza are prone to combine neurological complications and have a higher mortality rate. Significant elevations in ALT, AST, LDH, and CSF proteins predict death from influenzaassociated encephalopathy in children.

Neonatal Brain Injury From SARS-CoV-2: Fact or Fiction?

Neonatal Brain Injury From SARS-CoV-2: Fact or Fiction?

Clinical features and risk factors for severe influenza in children: A study from multiple hospitals in Shanghai

The incidence and mortality of influenza in children had risen, but data are limited on children with severe influenza virus infection in China. We conducted a retrospective case-control study and collected the patients' clinical data. Clinical data including demography, clinical presentation, laboratory findings, radiologic findings, treatment and outcomes were collected. Children were clinically confirmed to have virus infection in Shanghai in three hospitals from June 2014 to June 2019. During the study, 36,047 children were enrolled. Among them, 118 met the criteria for severe flu. Clinical symptoms such as fever, cough, gastrointestinal symptoms, coma and epilepsy were higher in the severe group. Complications such as pneumorrhagia, heart failure, septic shock, acute renal failure and influenza-associated encephalitis were higher in the severe influenza group than the death group. The laboratory findings including decreased hemoglobin, high alanine aminotransferase, high urea nitrogen and high lactate levels were risk factors for death in children with influenza. Influenza-associated encephalopathy (IAE), acute respiratory distress syndrome (ARDS) were the common clinical manifestations and complications for the severe influenza, and delayed use of oseltamivir was found to be associated with fatality.

Mortality and Neurologic Sequelae in Influenza-Associated Encephalopathy: Retrospective Multicenter PICU Cohort in France.

To describe and estimate the mortality rate of severe influenza-associated encephalopathy/encephalitis among children admitted to PICUs. Multicenter retrospective study. Twelve French PICUs. All children admitted for influenza-associated encephalopathy/encephalitis between 2010 and 2018 with no severe preexisting chronic neurologic disorders and no coinfection potentially responsible for the disease. None. We collected the clinical presentation; laboratory, electroencephalographic, and MRI findings; and treatments used in the PICU. The primary outcome was mortality. The secondary outcomes included sequelae at discharge and last follow-up. We included 41 patients with a median (interquartile range) age of 4.7 years (2.5-8.2 yr). The main reasons for admission were altered consciousness (59%) and status epilepticus (34%); 48% of patients had meningitis, and one third had acute necrotizing encephalopathy on MRI. Mechanical ventilation was required in 73% of patients and hemodynamic support in 24%. The use of specific treatments was variable; steroids were given to 49% of patients. Seven patients (17%) died in the PICU. Median (interquartile range) PICU stay length was 7 days (2-13 d), and total hospital length of stay was 23 days (7-33 d). On hospital discharge, 49% (n = 20) had neurologic sequelae, with 27% (n = 11) having severe disabilities defined by modified Rankin Score greater than or equal to 4. Children requiring PICU admission for influenza-associated encephalopathy/encephalitis have high mortality and morbidity rates. The management remains highly variable due to the lack of guidelines.

Parameters Indicating Development of Influenza-Associated Acute Necrotizing Encephalopathy: Experiences from a Single Center.

BackgroundInfluenza-associated acute necrotizing encephalopathy (IANE) can be lethal and disabling and have a sudden onset and deteriorate rapidly but lacks early diagnostic indicators. We aimed to examine the early clinical diagnostic indicators in children with IANE.Material/MethodsAcute influenza patients were grouped according to their clinical manifestations: flu alone (FA), flu with febrile seizure (FS), influenza-associated encephalopathy (IAE), and IANE. The clinical features, biomarkers, neuroelectrophysiological results, and neuroimaging examination results were compared.ResultsA total of 31 patients were included (FA (n=4), FS (n=8), IAE (n=14), and IANE (n=5)). The IANE group, whose mean age was 3.7 years, was more likely to show rapid-onset seizure, acute disturbance of consciousness (ADOC), Babinski’s sign, and death/sequela. More patients in the IANE group required tracheal intubation mechanical ventilation and received intravenous immunoglobulins (IVIG) and glucocorticoids. The alanine aminotransferase (ALT), aspartate transaminase (AST), and lactate dehydrogenase (LDH) levels in the IANE group were significantly higher than in the FS and IAE groups. The aquaporin-4 (AQP-4) antibody and malondialdehyde (MDA) levels in the serum and cerebrospinal fluid (CSF) were notably higher in IANE patients in the acute stage compared with FS and IAE patients. All patients in the IANE group had positive neuroimaging findings.ConclusionsEarly clinical warning factors for IANE include rapid-onset seizures in patients under 4 years of age, ADOC, and pathological signs. Increased AQP-4 antibodies and MDA levels in CSF might contribute to early diagnosis. Early magnetic resonance venography (MRV) and susceptibility-weighted imaging (SWI) sequences, or thrombelastography to identify deep vein thrombosis, might indicate clinical deterioration.

Characteristics and Mortality Risk Factors of Influenza-Associated Encephalopathy/Encephalitis in Children in a Tertiary Pediatric Hospital in China, 2016-2019

Background: Seasonal influenza associated neurological complications had high mortality and morbidity rates in children. In this study, we aimed to investigate the clinical characteristics and mortality risk factors in children with influenza-associated encephalopathy. Methods: Retrospectively analyze the clinical data, laboratory tests, and imaging examinations of 68 children diagnosed with influenza-associated encephalopathy from January 2016 to December 2019 at Guangzhou Women and Children’s Medical Center, and the cases were divided into survival and non-survival groups by disease outcome and analyzed between two groups. Chi-square test or Mann-Whitney rank sum test was used for comparison between groups, and multivariate Logistic regression analysis was used for the analysis of risk factors for death. Results: Among the 68 children with influenza-associated encephalopathy, 40 were male, and 28 were female, aged from 3 months to 13 years, of which 66.18% (45/68) were under 5 years old. Pathogenetic tests showed that influenza virus type A accounted for 63.24% (43/68), and influenza virus type B accounted for 36.76% (25/68). Typical brain MRI changes in childhood influenza-associated encephalopathy were bilateral symmetrical lesions of the thalamus, basal ganglia, brainstem, and cerebellum. 68 patients had a mortality rate of 20.59% (14/68), with a significantly higher proportion of fever peak > 39°C, Acute Disturbance of Consciousness (ADOC), and cardiac arrest in the non-survival group than in the survival group (P Conclusions: Children under 5 years of age with influenza are prone to combine neurological complications and have a higher mortality rate. Significant elevations in ALT, AST, LDH, and CSF proteins predict death from influenza-associated encephalopathy in children.

Risk Factors of Influenza-Associated Necrotizing Encephalopathy in Children

Objective: A case-control study of Influenza-Associated Necrotizing Encephalopathy (IANE) in children was conducted to explore the risk factors for the diagnosis of IANE, and to provide a predictive reference for the diagnosis of IANE. Methods: The children with IANE who received treatment in our hospital from January 2016 to December 2020 were selected as the study group, and the children with Influenza-Associated Encephalopathy (IAE) group who received treatment in the same period were selected as the control group. The blood biochemical, coagulation function and cerebrospinal fluid test results of the two groups were analyzed by univariate analysis. Receiver Operating Characteristic curve (ROC) analysis was used to determine the optimal threshold point of each index for the indicators with statistically significant differences in univariate analysis results, and multivariate Logistic stepwise regression analysis was performed according to the optimal threshold points. Results: In the IANE group, there were 32 children, including 20 males and 12 females, aged 60 (35, 84) months. There were 40 children in IAE group, including 26 males and 14 females, aged 58 (23, 97) months. Univariate results showed that serum Lactate Dehydrogenase (LDH), Cerebrospinal Fluid Lactate Dehydrogenase (CSF LDH) and Cerebrospinal Fluid Protein (CSF PRO) in the IANE group were significantly higher than those in the IAE group, and the difference between the two groups was statistically significant (P 535 U/L (OR = 31.264, 95% CI: 5.892 - 165.878, P 0.49 g/L (OR = 7.695, 95% CI: 1.052 - 56.305, P = 0.044) were independent risk factors for IANE. Conclusion: For children with influenza whose neurological symptoms appear rapidly and persist in the early stages of the disease, blood LDH > 535 U/L and CSF PRO > 0.49 g/L are independent risk factors for IANE.

Analysis of clinical characteristics and risk factors of influenza-related deaths in children

Objective: To explore the clinical characteristics and risk factors of influenza-related deaths in children and to raise awareness of the disease among clinicians. Methods: Clinical data of 31 influenza-related deaths hospitalized in Pediatric Intensive Care Unit (PICU) of Shenzhen Children's Hospital from January 2009 to December 2019 (death group) were retrospectively analyzed. A control group enrolled 188 patients with severe influenza who were successfully cured and hospitalized in PICU at the same time. Independent Student's t test, Mann-Whitney U test and chi square test were used to compare the general conditions, clinical manifestations, laboratory tests and antiviral therapy between two groups. Risk factors of mortality in children with severe influenza were identified by multivariate Logistic regression. Results: In a total of 219 cases with severe influenza, 31 cases progressed to influenza-related deaths, 19 males and 12 females, with age of (4.2±3.3) years; 29 cases had influenza A virus infection and 2 cases had influenza B virus infection. Deaths occurred more in winter and spring (23/31). Eight patients had underlying diseases. In 188 patients who were successfully cured, 138 were males and 50 females, with an average age of (3.4±2.7)years. There were 151 patients with influenza A virus infection, and 37 patients with influenza B virus infection. Twenty patients underlying diseases. None of the patients in the death group has received the influenza vaccine within 1 year before infection. Common symptoms were fever (n=31), cough (n=21), and seizures (n=17) in the death group. The complications were influenza associated encephalopathy (IAE) (n=17), pneumonia (n=17), plastic bronchitis (n=1), air leak syndrome (n=3), acute respiratory distress syndrome (ARDS) (n=8), and multiple organ dysfunction syndrome (n=24). In the death group, 13 patients had secondary infections, of whom 9 cases had gram-positive Cocci infection. Complete blood count of the patients showed that white blood cells count increased in 15 cases and the lymphocyte count decreased in 13 cases. Meanwhile, high sensitivity C-reactive protein increased in 18 patients. All the 31 patients in the death group were treated with neuraminidase inhibitors for antiviral therapy, of whom 24 cases received the first dose 48 h after fever (late neuraminidase inhibitor (NAI) treatment). The causes of death in 31 patients were further analyzed, including 23 cases died of influenza complications, 4 cases died of underlying diseases and 4 cases died of secondary infections. Compared with the control group, the death group had more underlying diseases (25.8% (8/31) vs. 10.6% (20/188), χ²=4.215, P=0.040), higher incidence of secondary infection (41.9% (13/31) vs. 20.2% (38/188), χ²=7.029, P=0.008), and more late NAI treatment (77.4% (24/31) vs. 53.7% (101/188), χ²=6.099, P=0.014). Logistic regression analysis showed that secondary infection, late NAI treatment, complicated with ARDS and IAE were risk factors for death of patients with severe influenza (all P<0.05). Conclusions: Influenza can cause multi-system disorder, especially lung infections and IAE. It can improve the success rate of treatment for children with severe influenza, identification and early treatment of secondary infection and complications, and timely administration of NAI treatment.

Influenza-Associated Encephalopathy and Acute Necrotizing Encephalopathy in Children: A Retrospective Single-Center Study.

BackgroundAlthough influenza primarily affects the respiratory system, it can cause severe neurological complications, especially in younger children, but knowledge about the early indicators of acute necrotizing encephalopathy (ANE) is limited. The main purpose of this article is to summarize the clinical characteristics, diagnosis, and treatment of neurological complications of influenza in children, and to identify factors associated with ANE.Material/MethodsThis was a retrospective study of children with confirmed influenza with neurological complications treated between 01/2014 and 12/2019 at Guangzhou Women and Children’s Medical Center. A receiver operating characteristics curve analysis was performed to determine the prognostic value of selected variables.ResultsSixty-three children with IAE (n=33) and ANE (n=30) were included. Compared with the IAE group, the ANE group showed higher proportions of fever and acute disturbance of consciousness, higher alanine aminotransferase, higher aspartate aminotransferase, higher creatinine kinase, higher procalcitonin, higher cerebrospinal fluid (CSF) protein, and lower CSF white blood cells (all P<0.05). The areas under the curve (AUCs) for procalcitonin and CSF proteins, used to differentiate IAE and ANE, were 0.790 and 0.736, respectively. The sensitivity and specificity of PCT >4.25 ng/ml to predict ANE were 73.3% and 100.0%, respectively. The sensitivity and specificity of CSF protein >0.48 g/L to predict ANE were 76.7% and 69.7%, respectively. Thirteen (43.3%) children with ANE and none with IAE died (P<0.0001).ConclusionsHigh levels of CSF protein and serum procalcitonin might be used as early indicators for ANE. All children admitted with neurological findings, especially during the influenza season, should be evaluated for influenza-related neurological complications.

Immune and epigenetic regulation through histone-lysine N-methyltransferase Setdb2 during severe influenza virus infection

Abstract Influenza virus causes acute respiratory infections that are highly contagious, and leads to significant morbidity and mortality in humans and animals. Especially, the main severe pathogenesis following influenza virus infection are secondary bacterial pneumonia (SBP) and influenza-associated encephalopathy (IAE). Thus, a better understanding of the molecular mechanisms of these diseases is essential. In our studies, microarray analysis demonstrated that influenza virus infected cells such as epithelial cells and macrophages upregulated SET domain, bifurcated 2 (Setdb2) expression following influenza virus infection via type-I IFN dependent manner. Setdb2 is a histone methyltransferase that methylates Lys-9 of histone H3 (H3K9), correlated with repression of transcription. Setdb2 expression in both influenza virus pneumonia and IAE models was significantly increased compared to control mice. Next, we investigated the role of Setdb2 in both SBP and IAE models. In SBP model, knocking down Setdb2 increased amphiregulin expression, which plays a critical role in tissue homeostasis of lungs and in decreased mortality of coinfection. In IAE model, the expression of Caveolin-1, one of the key proteins that correlate with protection of the blood-brain barrier, was significantly lower in brains from the IAE group compared with the control group. Furthermore, chromatin immunoprecipitation revealed that methylation of histone H3K9 was correlated with repression of the Caveolin-1 promoter region. These studies support the idea that an understanding of epigenetic change, especially via Setdb2, during influenza virus infection can provide mechanistic approaches for controlling and modifying the immune response in SBP and IAE.

Epidemiological changes of acute encephalopathy in Japan based on national surveillance for 2014–2017

BackgroundWe previously reported the nationwide, epidemiological data of acute encephalopathy in Japan during 2007–2010. Here we conducted the second national survey of acute encephalopathy during 2014–2017, and compared the results between the two studies to elucidate the trends in the seven years’ interval as well as the influence of changes in pediatric viral infections and guidelines for acute encephalopathy in Japan. MethodsThe Research Committee on Acute Encephalopathy supported by the Japanese Government sent a questionnaire to 507 hospitals throughout Japan, and collected the responses by mail. ResultsA total of 1115 cases from 267 hospitals reportedly had acute encephalopathy during April 2014–June 2017. In this study, the age at onset was younger, the ratios of recently established syndromes, such as acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) and clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS), were higher, and the ratio of influenza-associated encephalopathy was lower, than in the previous study. The age at onset of influenza-associated encephalopathy was lower, and that of HHV-6/7-associated encephalopathy higher, compared to the first survey. The outcomes of entire acute encephalopathy remained unchanged. ConclusionSome of these changes reflected the recent trends of viral infectious diseases including 2009 influenza pandemic, and others the standardization of the diagnosis of acute encephalopathy in Japan.

Central Brain Herniation Secondary to Influenza-Related Encephalopathy in a Pontocerebellar Hypoplasia Child: A Case Report and Review

Influenza-associated encephalopathy (IAE) can perform as varying patterns of neuroimaging. Central brain herniation (CBH) secondary to IAE is rare; it may be a bad prognosis. Here, we presented a 4-year-old girl with influenza who had a pontocerebellar hypoplasia (PCH) history; she performed the second Magnetic Resonance Imaging (MRI) on Day 6 from onset, showed the diffuse edema and the occurrence of central herniation; the medulla was “Z-like” folded and the basal cisterns were obliterated completely. Finally she was declared dead. The imbalance between supratentorial and infratentorial pressure can lead to the occurrence of CBH. Severe edema relates to IAE and unstable structure of the posterior fossa might be the main reason for the herniation. MRI is helpful in early diagnosis. Early treatment of cerebral edema in patients with congenital abnormalities of the posterior fossa is vital for their management.

Brain Complications with Influenza Infection in Children

Objectives: To summarize the characteristics and research progress of influenza-associated brain complications in children and provide references for early diagnosis and brain protection treatment. Methods: Studied published articles of influenza-associated neurocomplications in children from PubMed and summarizes them from epidemiology, clinical manifestations, diagnosis and treatment, and basic research progress. Results: Common brain complications in flu-children include febrile seizures, influenza-associated encephalopathy (IAE), acute or post-influenza encephalitis, and the most severe condition is acute necrotizing encephalopathy (ANE). However, the mechanism and relevant factors of influenza-associated brain damage have not been elucidated. Conclusion: Influenza could be accompanied by various brain lesion complications in dif ferent stages of the disease, some of which are life-threatening or leave severe neurological sequelae, such as ANE. Due to different brain injury mechanisms, specific early diagnosis and brain protection treatment for different complications are unclear or unanimous. Therefore, further classification and basic research are needed.

Characteristics and outcome of influenza-associated encephalopathy/encephalitis among children in a tertiary pediatric hospital in Italy, 2017\u20132019

BackgroundInfluenza is the most frequent cause of acute upper respiratory tract infections during winter season. Although rare, neurological manifestations are known to occur during influenza infection and approximatively three-quarters of cases are in children. In this study, we aimed to characterize the burden and clinical spectrum of influenza-associated encephalopathy and encephalitis in children admitted at a tertiary pediatric hospital in Italy over two influenza seasons (2017–2019).MethodsWe retrospectively analyzed clinical, laboratory, instrumental data and outcome of patients discharged with ICD9-CM 487.0 code.ResultsFifteen children (13.1% of those discharged with a diagnosis of influenza infection in the study period), had influenza-associated central nervous system (CNS) manifestations. Eight patients (53.3%) were diagnosed as influenza encephalitis, 7 (46.7%) as influenza encephalopathy. Median age was 27 months. In children under 2 years of age (40% of all cases) altered consciousness was the most frequent neurological manifestation while respiratory symptoms were present at admission in all cases. Younger children also required intensive care support more frequently. Five subjects (33.3%) presented comorbidity. None of the patients had received seasonal influenza vaccination. The median time from onset of respiratory signs to onset of neurological manifestations was 24 h. Cerebrospinal fluid (CSF) analysis was normal in most patients and polymerase chain reaction for influenza virus RNA on CSF, when performed, was negative in all samples. Neuroradiological investigations, performed in 5 children, reported cortical and subcortical white matter signal alterations. Oseltamivir was administered only in 2 cases. Fourteen patients recovered without sequelae, and only a 2-year-old girl had minimal impairment in fine motor skills at discharge.ConclusionsAll children presenting acute neurological features during influenza season should be evaluated for influenza-associated CNS complications even if the respiratory involvement is mild. Absence of underlying diseases or other risk factors are not protective factors against CNS influenza-associated complications. The lack of CSF pleocytosis does not exclude CNS involvement. Children under 2 years of age are at higher risk of requiring intensive care support.

Mortality risk factors in children with severe influenza virus infection admitted to the pediatric intensive care unit.

Some children hospitalized for severe influenza virus infection require intensive care or die because of disease progression, which may be combined with other complications. The objective of this study was to identify the mortality risk factors in the patients with severe influenza virus infection admitted to the pediatric intensive care unit (PICU).Seventy-seven pediatric patients with severe influenza virus infection who were admitted in the PICU at Guangzhou Women and Children's Medical Center between 2013 and 2017 were evaluated. Data were transcribed and analyzed.The patients’ median age was 3.0 years (interquartile range, 1.0–4.0 years), with 59.7% of the patients aged <3 years. The mortality was 16.9%, and patients aged >3 years accounted for 69.2% of the cases. Influenza A virus infection was found in 83.1% of the patients. Coinfection was detected in 58.7% of the patients. Haemophilus influenzae (11.7%) and adenovirus (9.1%) were the predominant bacterial and viral pathogens isolated, respectively. Older age, oxygen saturation level of <90% at admission, acute respiratory distress syndrome, pneumorrhagia, influenza-associated encephalopathy (IEA), septic shock, low ratio of partial pressure of oxygen in arterial blood (PaO2, <60 mm Hg) to the fraction concentration of oxygen in inspired air (FiO2; P/F), higher oxygenation index, increased alanine aminotransferase level (>100 IU/L), increased aspartate aminotransferase level (>100 IU/L), increased lactate dehydrogenase level (>500 IU/L), high fraction concentration of oxygen in inspired air (FiO2 > 60%), and positive end-expiratory pressure (>8 cmH2O) were associated with poor outcome. The deceased patients were more likely to have oxygen saturation levels of <90% at admission and IEA than those who survived. Higher P/F ratio was a protective factor against death in patients.The children with severe influenza virus infection who were admitted in the PICU were mainly aged <3 years. The presence of an oxygen saturation level of <90% at admission and IEA were the prognostic variables independently associated with mortality. Higher P/F ratio was a protective factor against death in patients.