Severe Influenza Virus Infection Research Articles

MEK-inhibitor treatment reduces the induction of regulatory T cells in mice after influenza A virus infection.

Regulatory T cells (Tregs) play a crucial and complex role in balancing the immune response to viral infection. Primarily, they serve to regulate the immune response by limiting the expression of proinflammatory cytokines, reducing inflammation in infected tissue, and limiting virus-specific T cell responses. But excessive activity of Tregs can also be detrimental and hinder the ability to effectively clear viral infection, leading to prolonged disease and potential worsening of disease severity. Not much is known about the impact of Tregs during severe influenza. In the present study, we show that CD4+/CD25+FoxP3+ Tregs are strongly involved in disease progression during influenza A virus (IAV) infection in mice. By comparing sublethal with lethal dose infection in vivo, we found that not the viral load but an increased number of CD4+/CD25+FoxP3+ Tregs may impair the immune response by suppressing virus specific CD8+ T cells and favors disease progression. Moreover, the transfer of induced Tregs into mice with mild disease symptoms had a negative and prolonged effect on disease outcome, emphasizing their importance for pathogenesis. Furthermore, treatment with MEK-inhibitors resulted in a significant reduction of induced Tregs in vitro and in vivo and positively influenced the progression of the disease. Our results demonstrate that CD4+/CD25+FoxP3+ Tregs are involved in the pathogenesis of severe influenza and indicate the potential of the MEK-inhibitor zapnometinib to modulate CD4+/CD25+FoxP3+ Tregs. Thus, making MEK-inhibitors even more promising for the treatment of severe influenza virus infections.

Improving Influenza Vaccination Coverage in Patients with Cancer: A Position Paper from a Multidisciplinary Expert Group.

Patients with cancer can be immunocompromised because of their disease and/or due to anticancer therapy. In this population, severe influenza virus infections are associated with an elevated risk of morbidity and mortality. Influenza vaccination is therefore highly recommended in cancer patients, including those receiving anticancer therapy. However, vaccination coverage remains far below the recommended target for vulnerable subjects. Six specialists in oncology, hematology, immunology, and public health/vaccinology convened with the objective of developing strategies, based on evidence and clinical experience, for improving influenza vaccination coverage in cancer patients. This viewpoint provides an overview of current influenza vaccination recommendations in cancer patients, discusses barriers to vaccination coverage, and presents strategies for overcoming said barriers. New immunization issues raised by the COVID-19 pandemic are also addressed. Future directions include improving public education on influenza vaccination, providing the media with accurate information, improving knowledge among healthcare professionals, improving access to vaccines for cancer patients, co-administration of the influenza and COVID-19 vaccines, increased collaboration between oncologists and other health professionals, increased accessibility of digital vaccination registries to specialists, shared information platforms, and promoting immunization campaigns by healthcare systems with the support of scientific societies.

Attenuation of A(H7N9) influenza virus infection in mice exposed to cigarette smoke

Influenza A(H7N9) virus showed high pathogenicity in humans when it emerged in 2013. Cigarette smoke (CS) causes pulmonary diseases including bronchitis, emphysema, and lung cancer. Although habitual smoking is thought to increase the risk of severe seasonal influenza virus infection, its effect on A(H7N9) virus infection is poorly understood. Here, we employed a mouse model of long-term exposure to CS to investigate the effect of CS on the pathogenicity of A(H7N9) virus infection. Unexpectedly, body weight loss for mice exposed to CS was milder than that for mock-treated mice upon A(H7N9) virus infection. CS exposure improved the survival rate of A(H7N9) virus-infected mice even though virus titers and pathological changes in the lungs were not significantly different between CS-exposed and control mice. Microarray analysis showed that CS-exposure activates cytokine/chemokine activity, immune response, and cell cycle activities that resemble reactivities against A(H7N9) virus infection. Therefore, under conditions where cytokine and chemokine expression in the lungs is already high due to CS exposure, the enhanced expression of cytokines and chemokines caused by A(H7N9) virus infection might be less harmful to the organs compared to the rapid increase in cytokine and chemokine expression in the air-exposed mice due to the infection. CS may thus induce immunoregulatory effects that attenuate severe pulmonary disease during A(H7N9) virus infection. However, these findings do not support CS exposure due to its many other proven negative health effects.

Exposure to PM2.5 modulate the pro-inflammatory and interferon responses against influenza virus infection in a human 3D bronchial epithelium model

Epidemiological studies showed a positive association between exposure to PM2.5 and the severity of influenza virus infection. However, the mechanisms by which PM2.5 can disrupt antiviral defence are still unclear. From this perspective, the objective of this study was to evaluate the effects of PM2.5 on antiviral signalling in the respiratory epithelium using the bronchial Calu-3 cell line grown at the air-liquid interface. Pre-exposure to PM2.5 before infection with the influenza virus was investigated, as well as a co-exposure. Although a physical interaction between the virus and the particles seems possible, no effect of PM2.5 on viral replication was observed during co-exposure, although a downregulation of IFN-β release was associated to PM2.5 exposure. However, pre-exposure slightly increased the viral nucleoprotein production and the pro-inflammatory response. Conversely, the level of the myxovirus resistance protein A (MxA), an interferon-stimulated gene (ISG) induced by IFN-β, was reduced. Therefore, these results suggest that pre-exposure to PM2.5 could alter the antiviral response of bronchial epithelial cells, increasing their susceptibility to viral infection.

Analysis of viral pneumonia and risk factors associated with severity of influenza virus infection in hospitalized patients from 2012 to 2016

BackgroundInfluenza viruses cause pneumonia in approximately one-third of cases, and pneumonia is an important cause of death. The aim was to identify risk factors associated with severity and those that could predict the development of pneumonia.MethodsThis retrospective, observational study included all adult patients with confirmed influenza virus infection admitted to Son Espases University Hospital during four influenza seasons in Spain (October to May) from to 2012–2016.ResultsOverall, 666 patients with laboratory-confirmed influenza were included, 93 (14%) of which were severe; 73 (10.9%) were admitted to Intensive Care Unit (ICU), 39 (5.8%) died, and 185 (27.7%) developed pneumonia. Compared to less severe cases, patients with severe disease: were less vaccinated (40% vs. 28%, p = 0.021); presented with more confusion (26.9% vs. 6.8%), were more hypoxemic (Horowitz index (PaO2/FiO2) 261 vs. 280), had higher C-reactive protein (CRP) (12.3 vs. 4.0), had more coinfections (26.8% vs. 6.3%) and had more pleural effusion (14% vs. 2.6%) (last six all p < 0.001). Risk factors significantly associated with severity were pneumonia [OR (95% CI) = 4.14 (2.4–7.16)], history of heart disease (1.84, 1.03–3.28), and confusion at admission (4.99, 2.55–9.74). Influenza vaccination was protective (0.53, 0.28–0.98). Compared to those without pneumonia, the pneumonia group had higher CRP (11.3 vs. 4.0, p < 0.001), lower oxygen saturation (92% vs. 94%, p < 0.001), were more hypoxic (PaO2/FiO2 266 vs. 281, p < 0.001), and incurred more mechanical ventilation, septic shock, admission to the ICU, and deaths (all four p < 0.001). Higher CRP and lower oxygen saturation were independent variables for predicting the development of pneumonia.ConclusionsPneumonia, history of heart disease, confusion and no influenza vaccination were independent variables to present complications in patients admitted with influenza infection.

The critical role of RAGE in severe influenza infection: A target for control of inflammatory response in the disease

Controlling the excessive inflammatory response is one of the key ways to reduce the severity and mortality of severe influenza virus infections. RAGE is involved in inflammatory responses and acute lung injuries. Here, we investigated the role of RAGE and its potential application as a target for severe influenza treatment through serological correlation analysis for influenza patients, and treatment with the RAGE inhibitor FPS-ZM1 on A549 cells or mice with influenza A (H1N1) infection. The results showed high levels of RAGE were correlated with immunopathological injury and severity of influenza, and FPS-ZM1 treatment increased the viability of A549 cells with influenza A infection and decreased morbidity and mortality of influenza A virus infection in mice. The RAGE/NF-κb inflammatory signaling pathway is a major targeting pathway for FPS-ZM1 treatment in severe influenza. These findings provide further insights into the immune injury of severe influenza and a potential targeting candidate for the disease treatment.

Increasing HbA1c is associated with reduced CD8+ T cell functionality in response to influenza virus in a TCR-dependent manner in individuals with diabetes mellitus

Diabetes mellitus is on the rise globally and is a known susceptibility factor for severe influenza virus infections. However, the mechanisms by which diabetes increases the severity of an influenza virus infection are yet to be fully defined. Diabetes mellitus is hallmarked by high glucose concentrations in the blood. We hypothesized that these high glucose concentrations affect the functionality of CD8+ T cells, which play a key role eliminating virus-infected cells and have been shown to decrease influenza disease severity. To study the effect of hyperglycemia on CD8+ T cell function, we stimulated peripheral blood mononuclear cells (PBMCs) from donors with and without diabetes with influenza A virus, anti-CD3/anti-CD28-coated beads, PMA and ionomycin (PMA/I), or an influenza viral peptide pool. After stimulation, cells were assessed for functionality [as defined by expression of IFN-γ, TNF-α, macrophage inflammatory protein (MIP)-1β, and lysosomal-associated membrane protein-1 (CD107a)] using flow cytometry. Our results showed that increasing HbA1c correlated with a reduction in TNF-α production by CD8+ T cells in response to influenza stimulation in a TCR-specific manner. This was not associated with any changes to CD8+ T cell subsets. We conclude that hyperglycemia impairs CD8+ T cell function to influenza virus infection, which may be linked with the increased risk of severe influenza in patients with diabetes.

Harnessing Endogenous Peptide Compounds as Potential Therapeutics for Severe Influenza

Abstract Background Excessive pulmonary inflammation and damage are characteristic features of severe influenza virus infections. LAT8881 is a synthetic 16–amino acid cyclic peptide form of a naturally occurring C-terminal fragment of human growth hormone with therapeutic efficacy against influenza. Shorter linear peptides are typically easier to manufacture and formulate for delivery than larger cyclic peptides. A 6–amino acid linear peptide fragment of LAT8881, LAT9997, was investigated as a potential influenza therapy. Methods LAT9997 was evaluated for its potential to limit disease in a preclinical mouse model of severe influenza infection. Results Intranasal treatment of mice with either LAT8881 or LAT9997 from day 1 following influenza infection significantly improved survival outcomes. Initiating LAT9997 treatment at the onset of severe disease also significantly improved disease severity. Greater disease resistance in LAT9997-treated mice correlated with reduced lung immunopathology, damage markers, vascular leak, and epithelial cell death. Treatment reduced viral loads, cytokines, and neutrophil infiltration in the airways yet maintained protective alveolar macrophages in a dose-dependent manner. Sequential trimming of N- and C-terminal amino acids from LAT9997 revealed a structure-activity relationship. Conclusions These findings provide preclinical evidence that therapeutic LAT9997 treatment limits viral burden and characteristic features of severe influenza, including hyperinflammation and lung damage.

The Hybrid of Cu─TCPP@Mn3 O4 for Inflammation Relief by ROS Scavenging and O2 Production: An Efficient Strategy for Antiviral Therapy.

Seasonal influenza still greatly threatens public health worldwide, leading to significant morbidity and mortality. Antiviral medications for influenza treatment are limited and accompanied by increased drug resistance. In severe influenza virus infection, hyperinflammation and hypoxia may be the significant threats associated with mortality, so the development of effective therapeutic methods to alleviate excessive inflammation while reducing viral damage is highly pursued. Here, a multifunctional MOF-based nanohybrid of Cu─TCPP@Mn3 O4 as a novel drug against influenza A virus infection (MOF = metal-organic framework; TCPP = tetrakis (4-carboxyphenyl) porphyrin) is designed. Cu─TCPP@Mn3 O4 exhibits potent inhibitory capability against influenza A virus infection in vitro and in vivo. The mechanism study reveals that Cu─TCPP@Mn3 O4 inhibits the virus entry by binding to the HA2 subunit of influenza A virus hemagglutinin. In addition, the nanoparticles of Mn3 O4 in Cu─TCPP@Mn3 O4 can scavenge intracellular ROS with O2 generation to downregulate inflammatory factors and effectively inhibit cytokines production. By reconstructing the antioxidant microenvironment, Cu─TCPP@Mn3 O4 features as a promising nanomedicine with anti-inflammatory and anti-viral synergistic effects.

Influenza A virus replication has a stronger dependency on Raf/MEK/ERK signaling pathway activity than SARS-CoV-2.

The recent COVID-19 pandemic again highlighted the urgent need for broad-spectrum antivirals, both for therapeutic use in acute viral infection and for pandemic preparedness in general. The targeting of host cell factors hijacked by viruses during their replication cycle presents one possible strategy for development of broad-spectrum antivirals. By inhibiting the Raf/MEK/ERK signaling pathway, a central kinase cascade of eukaryotic cells, which is being exploited by numerous viruses of different virus phyla, the small-molecule MEK inhibitor zapnometinib has the potential to address this need. We here performed a side-by-side comparison of the antiviral efficacy of zapnometinib against IAV and SARS-CoV-2 to determine the concentration leading to 50% of its effect on the virus (EC50) and the concentration leading to 50% reduction of ERK phosphorylation (IC50) in a comparable manner, using the same experimental conditions. Our results show that the EC50 value and IC50 value of zapnometinib are indeed lower for IAV compared to SARS-CoV-2 using one representative strain for each. The results suggest that IAV's replication has a stronger dependency on an active Raf/MEK/ERK pathway and, thus, that IAV is more susceptible to treatment with zapnometinib than SARS-CoV-2. With zapnometinib's favorable outcome in a recent phase II clinical trial in hospitalized COVID-19 patients, the present results are even more promising for an upcoming phase II clinical trial in severe influenza virus infection.

Severe Influenza Virus and Respiratory Syncytial Virus Infections in Intensive Care Over the Last 15 Years.

Influenza virus is a common agent of pediatric infections. Most cases are mild, but severe illness and death can occur. We aimed to analyze severe cases associated the influenza virus and compare it with respiratory syncytial virus(RSV). This is a retrospective study of 0-17-year-old patients admitted to the intensive care unit (ICU) of Hospital Pediátrico, Centro Hospitalar e Universitário de Coimbra (Pediatric Hospital, Coimbra Hospital and University Center), a tertiary pediatric hospital in Coimbra, Portugal, over the last 15 years (2008-2022) due to influenza virus infection. Clinical presentation, severity, and evolution were analyzed. A comparison of children with RSV infection admitted in the same period was performed. We identified 47 cases of influenza virus infection (34% coinfection with other viruses), median age of 2.3 years (interquartile range (IQR) 6.1), and 38% had comorbidities. The median admissions were three/year (maximum 11 in 2019). Influenza A was identified in 96%. Ninety-six percent had respiratory symptoms, 38% had neurologic symptoms, and 28% had sepsis. The main reason for admission was respiratory failure (68%). The mean pediatric index of mortality 2 (PIM2) at admission was 9±15.9%. Ventilatory support was necessary in 66%, vasoactive support in 19%, and blood products in 17%. The median length of stay was four days (IQR 5). There were four (8.5%) deaths. During the same study period, there were 171 RSV-related admissions. When comparing influenza (group A, without RSV coinfection) and RSV (group B), the first had a higher PIM2 on admission, greater need of ventilatory support, more complications, and higher mortality (p=0.001). The number of influenza virus infections admitted to ICU was much lower than RSV. However, influenza was more severe and associated with all deaths registered.

Thoracic adipose tissue contributes to severe virus infection of the lung.

Obesity is an independent risk factor for severe influenza virus and COVID-19 infections. There might be an interplay between adipose tissue and respiratory pathogens, although the mechanism is unknown. Proinflammatory factors secreted by the adipose tissue are often discussed to serve as indirect contributor to virus infection. However, the direct potential of adipose tissue to serve as a viral niche has not yet been investigated. Two murine obesity models (DIO and ob/ob) were infected with influenza A virus (IAV) and monitored for 3 weeks. p.i. Lung and adipose tissue were harvested, and the viral load was analysed. Direct replication of IAV in vitro was investigated in human derived primary adipocytes and macrophages. The indirect impact of the secretory products of adipocytes during infection was analysed in a co-culture system with lung fibroblasts. Moreover, lung and adipose tissue was harvested from deceased patients infected with SARS-CoV-2 omicron variant. Additionally, replication of SARS-CoV-2 alpha, delta, and omicron variants was investigated in vitro in adipocytes and macrophages. Both murine obesity models presented high IAV titers compared to non-obese mice. Interestingly, adipose tissue adjacent to the lungs was a focal point for influenza virus replication in mice. We further detected IAV replication and antiviral response in human adipocytes. Co-cultivation of adipocytes and lung fibroblasts led to increased IL-8 concentration during infection. Though we observed SARS-CoV-2 in the thoracic adipose tissue of COVID-19 patients, no active replication was found in adipocytes in vitro. However, SARS-CoV-2 was detected in the macrophages and this finding was associated with increased inflammation. Our study revealed that thoracic adipose tissue contributes to respiratory virus infection. Besides indirect induction of proinflammatory factors during infection, adipocytes and macrophages within the tissue can directly support viral replication.

Transcriptomic profiles of multiple organ dysfunction syndrome phenotypes in pediatric critical influenza.

Influenza virus is responsible for a large global burden of disease, especially in children. Multiple Organ Dysfunction Syndrome (MODS) is a life-threatening and fatal complication of severe influenza infection. We measured RNA expression of 469 biologically plausible candidate genes in children admitted to North American pediatric intensive care units with severe influenza virus infection with and without MODS. Whole blood samples from 191 influenza-infected children (median age 6.4 years, IQR: 2.2, 11) were collected a median of 27 hours following admission; for 45 children a second blood sample was collected approximately seven days later. Extracted RNA was hybridized to NanoString mRNA probes, counts normalized, and analyzed using linear models controlling for age and bacterial co-infections (FDR q<0.05). Comparing pediatric samples collected near admission, children with Prolonged MODS for ≥7 days (n=38; 9 deaths) had significant upregulation of nine mRNA transcripts associated with neutrophil degranulation (RETN, TCN1, OLFM4, MMP8, LCN2, BPI, LTF, S100A12, GUSB) compared to those who recovered more rapidly from MODS (n=27). These neutrophil transcripts present in early samples predicted Prolonged MODS or death when compared to patients who recovered, however in paired longitudinal samples, they were not differentially expressed over time. Instead, five genes involved in protein metabolism and/or adaptive immunity signaling pathways (RPL3, MRPL3, HLA-DMB, EEF1G, CD8A) were associated with MODS recovery within a week. Thus, early increased expression of neutrophil degranulation genes indicated worse clinical outcomes in children with influenza infection, consistent with reports in adult cohorts with influenza, sepsis, and acute respiratory distress syndrome.

An IL-17-EGFR-TRAF4 axis contributes to the alleviation of lung inflammation in severe influenza

Excessive inflammation is a postulated cause of severe disease and death in respiratory virus infections. In response to severe influenza virus infection, adoptively transferred naïve hemagglutinin-specific CD4+ T cells from CD4+ TCR-transgenic 6.5 mice drive an IFN-γ-producing Th1 response in wild-type mice. It helps in virus clearance but also causes collateral damage and disease aggravation. The donor 6.5 mice have all the CD4+ T cells with TCR specificity toward influenza hemagglutinin. Still, the infected 6.5 mice do not suffer from robust inflammation and grave outcome. The initial Th1 response wanes with time, and a prominent Th17 response of recent thymic emigrants alleviates inflammation and bestows protection in 6.5 mice. Our results suggest that viral neuraminidase-activated TGF-β of the Th1 cells guides the Th17 evolution, and IL-17 signaling through the non-canonical IL-17 receptor EGFR activates the scaffold protein TRAF4 more than TRAF6 during alleviation of lung inflammation in severe influenza.

Molecular epidemiology and disease severity of influenza virus infection in patients with haematological disorders.

Influenza virus infection is a common cause of self-limiting respiratory tract infection (RTI), however immunocompromised patients are at an increased risk for a severe course of disease or fatal outcome. We therefore aimed to gain a better understanding of the molecular epidemiology of influenza viruses from patients with haematological disorders and their impact on the clinical course of disease. Molecular analysis using polymerase chain reaction (PCR) of nasopharyngeal swabs was performed for influenza virus in haematological patients at the Heidelberg University Hospital. Clinical data was evaluated to identify associated risk factors. For phylogenetic analysis, the hemagglutinin (HA) gene was sequenced. Out of 159 influenza positive patients, 117 patients developed upper RTI (influenza A: n = 73; influenza B: n = 44). Lower RTI was observed in n = 42 patients (26%), n = 22/42 patients developed severe disease and n = 16/159 (10.1%) patients died. Risk factors for lower RTI were nosocomial infection (p = 0.02), viral shedding for ≥14 days (p = 0.018), IgG levels <6 g/dL (p = 0.046), bacterial/fungal co-infections (p < 0.001). Risk factors for fatal outcome were age ≥65 years (p = 0.032), bacterial/fungal (p≤0.001) co-infections and high viral load (p = 0.026). Sequencing of the HA gene (n = 115) revealed subtype A(H3N2) (n = 46), A(H1N1)pdm09 (n = 24), B/Victoria (n = 34), B/Yamagata (n = 11). There was no correlation between influenza (sub)type and lower RTI. Influenza infection in haematological patients is associated with significant morbidity and mortality, the risk for aggravating co-infections, prolonged viral shedding and nosocomial transmission emphasizing the need for infection control.

Early peripheral blood lymphocyte subsets and cytokines in predicting the severity of influenza B virus pneumonia in children.

Children with influenza B virus infection have a higher susceptibility and higher severity of illness. The activation and disorder of immune function play an important role in the severity of influenza virus infection. This study aims to investigate whether early lymphocyte count and cytokines can provide predictive value for the progression in children with influenza B virus pneumonia. A retrospective cohort study was conducted to analyze the clinical data of children with influenza B virus pneumonia from December 1, 2021, to March 31, 2022, in the National Children's Regional Medical Center (Shengjing Hospital of China Medical University). According to the severity of the disease, the children were divided into a mild group and a severe group, and the clinical characteristics, routine laboratory examination, lymphocyte subsets, and cytokines were compared. A total of 93 children with influenza B virus pneumonia were enrolled, including 70 cases in the mild group and 23 cases in the severe group. Univariate analysis showed that drowsiness, dyspnea, white blood cell (WBC), lymphocytes, monocytes, procalcitonin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH), fibrinogen (FIB), Immunoglobulin M (IgM), lung consolidation, total T cell count, CD4+ T cell count, CD8+ T cell count, NK cell count, NK cell % and B cell % had statistical differences between the mild and severe groups (P<0.05). In multivariate logistic regression analysis, reduced ALT (OR = 1.016), FIB (OR = 0.233), CD8+ T cell count (OR = 0.993) and NK cell count (OR = 0.987) were independently associated with the development of severe influenza B virus pneumonia. The levels of T lymphocytes and NK cells were related to the progression of influenza B virus pneumonia in children, and the reduction of CD8+ T cell count and NK cell count can be used as independent risk factors for predicting the severity of influenza B virus pneumonia.

Th1-guided de novoTh17 response alleviates lung inflammation through IL-17-EGFR-TRAF4 signaling cascade in severe influenza

Abstract Excessive inflammation is a postulated cause of severe disease and death in respiratory virus infections. In response to severe influenza virus infection, adoptively transferred naïve hemagglutinin-specific CD4 +T cells from CD4 +TCR-transgenic 6.5 mice drive an IFN-γ-producing Th1 response in wild-type mice. It helps in virus clearance but also causes collateral damage and disease aggravation. The donor 6.5 mice have all the CD4 +T cells with TCR specificity toward influenza hemagglutinin. Still, the infected 6.5 mice do not suffer from robust inflammation and grave outcome. The initial Th1 response wanes with time, and a prominent Th17 response of recent thymic emigrants alleviates inflammation and bestows protection in 6.5 mice. The severe disease in older than younger adult 6.5 mice with aging-related thymic involution and waning Th17 response further supports the protective role of the de novo Th17 response in severe influenza. Our results suggest that viral neuraminidase-activated TGF-β of the Th1 cells guides the Th17 evolution. IL-17 up-regulates and phosphorylates the non-canonical IL-17 receptor EGFR, activates the scaffold protein TRAF4, and promotes the translocation of TRAF4 to the EGFR signaling complex. Taken together, Th1-guided de novo Th17 response alleviates lung inflammation through the IL-17-EGFR-TRAF4 signaling cascade in severe influenza. The Research Center for Emerging Viral Infections receives support from The Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education (MOE), Taiwan and NSTC 111-2634-F-182-001 from the National Science and Technology Council, Taiwan. This work was supported by Projects MOST 111-2314-B-182-029 (AD) and MOST-105-2321-B-182A-003-MY3 (AD) from the National Science and Technology Council, Taiwan, and by CMRPG3L1671 (CTH), CMRPVVJ0052 (CTH), and CMRPG3J1771 (CYH) from the Medical Research Project Fund, Chang Gung Memorial Hospital, Taiwan.

Influenza Vaccine Effectiveness Among Children: 2011-2020.

Infants and children are at increased risk of severe influenza virus infection and its complications. Influenza vaccine effectiveness (VE) varies by age, influenza season, and influenza virus type/subtype. This study's objective was to examine the effectiveness of inactivated influenza vaccine against outpatient influenza illness in the pediatric population over 9 influenza seasons after the 2009 A(H1N1) pandemic. During the 2011-2012 through the 2019-2020 influenza seasons at outpatient clinics at 5 sites of the US Influenza Vaccine Effectiveness Network, children aged 6 months to 17 years with an acute respiratory illness were tested for influenza using real-time, reverse-transcriptase polymerase chain reaction. Vaccine effectiveness was estimated using a test-negative design. Among 24 148 enrolled children, 28% overall tested positive for influenza, 3017 tested positive for influenza A(H3N2), 1459 for influenza A(H1N1)pdm09, and 2178 for influenza B. Among all enrollees, 39% overall were vaccinated, with 29% of influenza cases and 43% of influenza-negative controls vaccinated. Across all influenza seasons, the pooled VE for any influenza was 46% (95% confidence interval, 43-50). Overall and by type/subtype, VE against influenza illness was highest among children in the 6- to 59-month age group compared with older pediatric age groups. VE was lowest for influenza A(H3N2) virus infection. Analysis of multiple seasons suggested substantial benefit against outpatient illness. Investigation of host-specific or virus-related mechanisms that may result in differences by age and virus type/subtype may help further efforts to promote increased vaccination coverage and other influenza-related preventative measures.

K-medoids clustering of hospital admission characteristics to classify severity of influenza virus infection.

Patients are admitted to the hospital for respiratory illness at different stages of their disease course. It is important to appropriately analyse this heterogeneity in surveillance data to accurately measure disease severity among those hospitalized. The purpose of this study was to determine if unique baseline clusters of influenza patients exist and to examine the association between cluster membership and in-hospital outcomes. Patients hospitalized with influenza at two hospitals in Southeast Michigan during the 2017/2018 (n = 242) and 2018/2019 (n = 115) influenza seasons were included. Physiologic and laboratory variables were collected for the first 24 h of the hospital stay. K-medoids clustering was used to determine groups of individuals based on these values. Multivariable linear regression or Firth's logistic regression were used to examine the association between cluster membership and clinical outcomes. Three clusters were selected for 2017/2018, mainly differentiated by blood glucose level. After adjustment, those in C171 had 5.6 times the odds of mechanical ventilator use than those in C172 (95% CI: 1.49, 21.1) and a significantly longer mean hospital length of stay than those in both C172 (mean 1.5days longer, 95% CI: 0.2, 2.7) and C173 (mean 1.4days longer, 95% CI: 0.3, 2.5). Similar results were seen between the two clusters selected for 2018/2019. In this study of hospitalized influenza patients, we show that distinct clusters with higher disease acuity can be identified and could be targeted for evaluations of vaccine and influenza antiviral effectiveness against disease attenuation. The association of higher disease acuity with glucose level merits evaluation.

Successful Treatment of Complicated Influenza A(H3N2) Virus Infection and Rhabdomyolysis with Compassionate Use of IV Zanamivir

In 2019, EMA licensed intravenous (IV) zanamivir for severe influenza virus infection in children over 6 months as well as adults. Prior to that, it was possible via a compassionate use program. We present successful compassionate use of IV zanamivir in a 14-year-old female with severe influenza A(H3N2) and multi-organ failure, who had failed oral oseltamivir. Her illness was complicated by acute respiratory distress syndrome and rhabdomyolysis requiring extracorporeal membrane oxygenation and hemofiltration. Considering the broad safety margins with neuraminidase inhibitors, an adult dose of 600 mg IV BID was administered in this 60 kg patient. Influenza virus was cleared rapidly and undetectable on day 13. Creatine kinase (CK) values were dropping from 38,000 to 500 within nine days. Given the recent licensure of IV zanamivir, multi-center prospective observational studies in pediatric Intensive Care Unit patients would be beneficial to guide the most appropriate use of IV zanamivir in this vulnerable age group.