Influenza-associated Encephalopathy Research Articles

Acute necrotizing encephalopathy in adult patients with influenza: a case report and review of the literature

The neurological complications of influenza affect mainly the pediatric Asian population. In the category of influenza-associated encephalopathy, acute necrotizing encephalopathy (ANE) is a rapidly progressive and fulminant brain disorder associated with significant neurological sequelae and mortality. To date, only a few adult cases of influenza-associated ANE have been reported. We describe a 44-year-old woman who presented with rapid progression of consciousness impairment and recurrent generalized convulsions. Influenza was diagnosed three days prior to presentation, and infection with influenza A (H3N2) pdm09 was subsequently confirmed. A diagnosis of ANE was made based on the presence of characteristic brain MRI findings, the exclusion of central nervous system infection, and an elevated serum interleukin-6 level. Pulse steroid therapy followed by tocilizumab was initiated, which led to clinical stabilization and improvement. Genetic testing revealed that the patient carried heterozygous human leukocyte antigen DQB1 03:03 and DRB1 09:01 genotypes. An analysis of the adult cases of influenza-associated ANE in the literature and the present case revealed a wide range of ages (22–71 years), a short interval (median 3 days) between the clinical onset of influenza and ANE, and a high overall mortality rate (32%). The thalamus was the most frequent (91%) location of the lesions. Our report highlights the importance of identifying this devastating but treatable neurological complication of influenza in adults, especially those of Asian descent. As a cytokine storm is the most accepted pathogenic mechanism for ANE, cytokine-directed therapies may be promising treatments for which further investigation is warranted.

Mortality risk factors in children with influenza-associated encephalopathy admitted to the paediatric intensive care unit between 2009 and 2021.

The purpose of this study was to determine the risk factors for death in children with influenza-associated encephalopathy (IAE) in the paediatric intensive care unit (PICU). Forty-six paediatric patients with IAE admitted to the PICU at shenzhen Children's Hospital between December 2009 and December 2021 were evaluated. Their clinical characteristics were retrospectively analysed. A total of 46 patients were diagnosed with influenza A virus infection and encephalopathy. The cases were concentrated in children <5 years of age (27/46, 58.7%). Twenty-nine patients (63.0%) survived and 17 patients (37.0%) died, of which 70.6% (12/17) of the patients died within 1 week of hospitalisation. Thirty-two patients (69.6%) developed neurological symptoms within 1-2 days of fever onset. Common symptoms included fever (45/46, 97.8%), loss of consciousness (39/46, 84.8%), seizures (31/46, 67.4%), cough (19/46, 41.3%), and vomiting (16/46, 34.8%). Multivariate logistic regression analysis indicated that vomiting (odds ratio [OR], 11.005), loss of consciousness (AVPU score: P; OR, 15.871), lymphopenia (OR, 8.964), alanine aminotransferase (>80 IU/L; OR, 32.060) and serum sodium concentration (>145 mmol/L or <135 mmol/L; OR, 16.264) were related to mortality. The mortality in this study population was 37.0%. Children with IAE who have corresponding clinical manifestations and abnormal examination results in PICU should be warned of the high mortality rate.

Epidemiological, clinical characteristics and the association between influenza vaccination, oseltamivir treatment, and complications in children with seasonal influenza

Influenza, a historical and contemporary public health challenge, is an acute respiratory infection caused mainly by influenza A or B viruses. This descriptive case series describes 194 children treated for seasonal influenza at the Department of Pediatrics, 103 Military Hospital, Vietnam Military Medical University, from May 2022 to May 2023. Influenza primarily occurred during winter and early spring, peaking in December and January, 57.2% were aged 12-60 months, boys. Vaccination coverage was limited (36.3%), especially post-COVID-19. Complications were seen in 75.3% of the cases, including febrile seizures (42.3%), bronchopneumonia (40.2%), respiratory failure (8.2%), acute myocarditis, influenza-associated encephalopathy, and septic shock. The study reveals bacterial coinfections, affected 20% of the cases, mainly by Streptococcus pneumoniae and S. aureus, and atypical bacteria Mycoplasma pneumoniae. Non-vaccinated children faced significantly higher risks of complications, oseltamivir within 48 hours reducing the risks of complications. Influenza predominantly affects 12-60 month-olds, males, and peaks annually in winter. Severe conditions stem from bacterial coinfections, emphasizing the importance of vaccination and prompt antiviral treatment to mitigate complications. The study highlights a critical need for increased vaccination, especially in the post-COVID-19 era, to manage influenza in children effectively.

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.

Blindness Due to Severe Influenza B Infection: Case Report

Introduction: Influenza is an acute febrile infectious disease with respiratory manifestations, in a variable degree of severity, and a seasonal epidemic distribution. In healthy children, it usually presents as mild and self-limiting, but it can evolve into severe forms with significant morbidity and mortality. These include neurological manifestations such as influenza-associated encephalopathy and acute necrotizing encephalopathy. Objective: To report case of a previously healthy child who developed severe pneumonia due to influenza B and subsequent blindness associated with ANE. Case Report: previously healthy, five years old male, not vaccinated for seasonal influenza, was admitted with four days of fever and respiratory symptoms. Initial evaluation reveled respiratory impair and he was admitted to the critical care unit for respiratory distress syndrome. Influenza B antigen was detected in upper respiratory swab by immunochromatography. Initial laboratory: White blood count; 20300/L, C- protein reaction: 300mg/L, AST 176 U/L, LDH 2549 U/L. He required 11 days of invasive respiratory support due to severe hypoxemia. When support was withdrawn, severe bilateral visual impairment was observed without other neurological manifestations. Magnetic Resonance Image revels bilateral temporo-occipital cortico-subcortical lesions and in both cerebellar hemispheres, with a lacunar image in the left thalamus; no involvement of the optic nerve was observed. Close watching was workup without pharmacologic intervention. He starts recovering vision 5 month later. Discussion: influenza-associated encephalopathy and acute necrotizing encephalopathy are recognized as rare inflammatory complications associated with influenza and other virus infections. Cases of blindness associated with necrotizing encephalopathy are reported. Treatment with corticosteroids, intravenous immunoglobulin, hypothermia, and plasmapheresis are propose; roll of oseltamivir remain unknown. Tocilizumab represents a potentially rational approach to ANE management. Conclusion: Influenza infection could be severe, including neurological complication. Vaccination is the only primary prevention tool.

Clinical Features and Treatment Outcomes of Influenza-Associated Encephalitis and Encephalopathy: A Study on 16 Children in Vietnam.

Objectives. This study aims to report clinical features and treatment outcomes of 16 cases diagnosed with post-influenza encephalopathy/encephalitis. Methods. We recorded clinical characteristics of 16 pediatric patients diagnosed with post-influenza encephalopathy/encephalitis at the Vietnam National Children's Hospital from January 2019 to January 2021. Results. There were 87.5% infected with influenza A, with influenza A/H1pdm09 and influenza A/H3 accounting for 88.9% and 11.1% respectively, and 12.5% of participants infected with influenza B. The time from onset to the appearance of neurological symptoms was 3 days, of which perceptual changes (93.8%), hypertonia (75%), and seizures (43.8%) were prevalent neurological symptoms. The majority of cases had normal cerebrospinal fluid. Cranial CT/MRI imaging revealed abnormalities in 87.5% of patients. 56.3% of patients had sequelae, including epilepsy and cerebral palsy; 25% recovered, and 18.8% died after treatment. Conclusions. Influenza-associated encephalitis/encephalopathy is a complication occurring early in children, with high mortality and sequelae rates.

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 &lt;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 &gt;535U/L (OR=31.264, 95% CI: 5.892-165.878, P &lt;0.001) and CSF PRO &gt;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 &gt;535U/L and CSF PRO &gt;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 &gt;39°C, Acute Disturbance Of Consciousness (ADOC), and cardiac arrest in the non-survival group than in the survival group (P&lt;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&lt;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.