Influenza-induced Acute Respiratory Distress Syndrome Research Articles

Mitigation of influenza-mediated inflammation by immunomodulatory matrix-bound nanovesicles.

Cytokine storm describes a life-threatening, systemic inflammatory syndrome characterized by elevated levels of proinflammatory cytokines and immune cell hyperactivation associated with multi-organ dysfunction. Matrix-bound nanovesicles (MBV) are a subclass of extracellular vesicle shown to down-regulate proinflammatory immune responses. The objective of this study was to assess the efficacy of MBV in mediating influenza-induced acute respiratory distress syndrome and cytokine storm in a murine model. Intravenous administration of MBV decreased influenza-mediated total lung inflammatory cell density, proinflammatory macrophage frequencies, and proinflammatory cytokines at 7 and 21 days following viral inoculation. MBV decreased long-lasting alveolitis and the proportion of lung undergoing inflammatory tissue repair at day 21. MBV increased the proportion of activated anti-viral CD4+ and CD8+ T cells at day 7 and memory-like CD62L+ CD44+, CD4+, and CD8+ T cells at day 21. These results show immunomodulatory properties of MBV that may benefit the treatment of viral-mediated pulmonary inflammation with applicability to other viral diseases such as SARS-CoV-2.

Comparing Clinical Outcomes of COVID-19 and Influenza-Induced Acute Respiratory Distress Syndrome: A Propensity-Matched Analysis.

Acute respiratory distress syndrome (ARDS) is one the leading causes of mortality and morbidity in patients with COVID-19 and Influenza, with only small number of studies comparing these two viral illnesses in the setting of ARDS. Given the pathogenic differences in the two viruses, this study shows trends in national hospitalization and outcomes associated with COVID-19- and Influenza-related ARDS. To evaluate and compare the risk factors and rates of the adverse clinical outcomes in patients with COVID-19 associated ARDS (C-ARDS) relative to Influenza-related ARDS (I-ARDS), we utilized the National Inpatient Sample (NIS) database 2020. Our sample includes 106,720 patients hospitalized with either C-ARDS or I-ARDS between January and December 2020, of which 103,845 (97.3%) had C-ARDS and 2875 (2.7%) had I-ARDS. Propensity-matched analysis demonstrated a significantly higher in-hospital mortality (aOR 3.2, 95% CI 2.5-4.2, p < 0.001), longer mean length of stay (18.7 days vs. 14.5 days, p < 0.001), higher likelihood of requiring vasopressors (aOR 1.7, 95% CI 2.5-4.2) and invasive mechanical ventilation (IMV) (aOR 1.6, 95% CI 1.3-2.1) in C-ARDS patients. Our study shows that COVID-19-related ARDS patients had a higher rate of complications, including higher in-hospital mortality and a higher need for vasopressors and invasive mechanical ventilation relative to Influenza-related ARDS; however, it also showed an increased utilization of mechanical circulatory support and non-invasive ventilation in Influenza-related ARDS. It emphasizes the need for early detection and management of COVID-19.

Potential mechanisms by which impaired ketogenesis links metabolism to T-cell dysfunction in patients with severe COVID-19.

Potential mechanisms by which impaired ketogenesis links metabolism to T-cell dysfunction in patients with severe COVID-19.

Impaired ketogenesis ties metabolism to T cell dysfunction in COVID-19.

Anorexia and fasting are host adaptations to acute infection, and induce a metabolic switch towards ketogenesis and the production of ketone bodies, including β-hydroxybutyrate (BHB)1–6. However, whether ketogenesis metabolically influences the immune response in pulmonary infections remains unclear. Here we show that the production of BHB is impaired in individuals with SARS-CoV-2-induced acute respiratory distress syndrome (ARDS) but not in those with influenza-induced ARDS. We found that BHB promotes both the survival of and the production of interferon-γ by CD4+ T cells. Applying a metabolic-tracing analysis, we established that BHB provides an alternative carbon source to fuel oxidative phosphorylation (OXPHOS) and the production of bioenergetic amino acids and glutathione, which is important for maintaining the redox balance. T cells from patients with SARS-CoV-2-induced ARDS were exhausted and skewed towards glycolysis, but could be metabolically reprogrammed by BHB to perform OXPHOS, thereby increasing their functionality. Finally, we show in mice that a ketogenic diet and the delivery of BHB as a ketone ester drink restores CD4+ T cell metabolism and function in severe respiratory infections, ultimately reducing the mortality of mice infected with SARS-CoV-2. Altogether, our data reveal that BHB is an alternative source of carbon that promotes T cell responses in pulmonary viral infections, and highlight impaired ketogenesis as a potential confounding factor in severe COVID-19.

Effect of oxidative stress response in acute respiratory distress syndrome caused by influenza

Influenza virus is one of the common pathogens causing acute respiratory infectious diseases, and is easy to cause acute respiratory distress syndrome (ARDS) after infecting human body, which is an important cause of death of influenza patients. Influenza-induced ARDS results from a combination of overwhelming inflammation and immune response, causing tissue damage and apoptosis. Furthermore, virus-mediated oxidative stress is another important mechanism. Viral infection can produce excessive reactive oxygen species, which damage the epithelial-endothelial barrier with pulmonary edema. In this content, numerous studies have highlighted the importance of antioxidants as a new therapy aimed at blocking both viral replication and virus-induced inflammation. Therefore, this paper summarizes the epidemiology and mechanisms of influenza-induced ARDS, the role of oxidative stress in the occurrence and development of influenza-related ARDS and the role of antioxidants in anti influenza virus infection, in order to provide reference for effective treatment of influenza patients, reducing mortality, developing new anti influenza drugs and preventing and controlling influenza epidemic.

Dysregulation of ion transport in the lung epithelium infected with SARS-CoV-2.

Dysregulation of ion transport in the lung epithelium infected with SARS-CoV-2.

Postexposure Liponucleotide Prophylaxis and Treatment Attenuates Acute Respiratory Distress Syndrome in Influenza-infected Mice.

There is an urgent need for new drugs for patients with acute respiratory distress syndrome (ARDS), including those with coronavirus disease (COVID-19). ARDS in influenza-infected mice is associated with reduced concentrations of liponucleotides (essential precursors for de novo phospholipid synthesis) in alveolar type II (ATII) epithelial cells. Because surfactant phospholipid synthesis is a primary function of ATII cells, we hypothesized that disrupting this process could contribute significantly to the pathogenesis of influenza-induced ARDS. The goal of this study was to determine whether parenteral liponucleotide supplementation can attenuate ARDS. C57BL/6 mice inoculated intranasally with 10,000 plaque-forming units/mouse of H1N1 influenza A/WSN/33 virus were treated with CDP (cytidine 5'-diphospho)-choline (100 μg/mouse i.p.) ± CDP -diacylglycerol 16:0/16:0 (10 μg/mouse i.p.) once daily from 1 to 5 days after inoculation (to model postexposure influenza prophylaxis) or as a single dose on Day 5 (to model treatment of patients with ongoing influenza-induced ARDS). Daily postexposure prophylaxis with CDP-choline attenuated influenza-induced hypoxemia, pulmonary edema, alterations in lung mechanics, impairment of alveolar fluid clearance, and pulmonary inflammation without altering viral replication. These effects were not recapitulated by the daily administration of CTP (cytidine triphosphate) and/or choline. Daily coadministration of CDP-diacylglycerol significantly enhanced the beneficial effects of CDP-choline and also modified the ATII cell lipidome, reversing the infection-induced decrease in phosphatidylcholine and increasing concentrations of most other lipid classes in ATII cells. Single-dose treatment with both liponucleotides at 5 days after inoculation also attenuated hypoxemia, altered lung mechanics, and inflammation. Overall, our data show that liponucleotides act rapidly to reduce disease severity in mice with severe influenza-induced ARDS.

Critical Care Considerations in Adult Patients With Influenza-Induced ARDS.

Acute respiratory distress syndrome is a complex respiratory disease that can be induced by influenza virus infection. Critical care providers are uniquely positioned to manage this pathological progression in adult patients through evidence-based practice. Influenza and subsequent acute respiratory distress syndrome are associated with extremely high morbidity and mortality in adult patients in the United States. Although evidence-based medical management strategies can alter the clinical trajectory of acute respiratory distress syndrome and improve outcomes, critical care providers do not always implement these measures. To provide critical care providers with an overview of the pathological progression of influenza-induced acute respiratory distress syndrome and the current evidence-based strategies for management. This article reviews the epidemiology and pathophysiology associated with influenza-induced acute respiratory distress syndrome, the criteria for diagnosis, and the evidence-based medical management.

Influenza-induced acute respiratory distress syndrome during the 2010-2016 seasons: bacterial co-infections and outcomes by virus type and subtype

ObjectivesWe aimed to describe bacterial co-infections and acute respiratory distress (ARDS) outcomes according to influenza type and subtype. MethodsA retrospective observational study was conducted from 2012 to 2016 in patients admitted to the respiratory intensive care unit (ICU) of Marseille university hospital for influenza-induced ARDS. Microbiological investigations, including multiplex molecular respiratory panel testing and conventional bacteriological cultures, were performed as part of the routine ICU care on the bronchoalveloar lavage collected at admission. Bacterial co-infections, ICU mortality and respiratory function were investigated according to virus type and subtype. ResultsAmong the 45 ARDS patients included, A(H1N1)pdm09 was the most frequent influenza virus identified (28/45 A(H1N1)pdm09, eight out of 45 A(H3N2) and nine out of 45 influenza B). Bacterial co-infections involving a total of 23 bacteria were diagnosed in 16/45 patients (36%). A(H1N1)pdm09 patients presented fewer bacterial co-infections (17.9% vs. 50.0% for A(H3N2) patients and 77.8% for B patients; p < 0.01). Overall, mortality at 90 days post admission was 33.3% (15/45), and there was no significant difference between influenza type and subtype. The need for extracorporeal membrane oxygenation was more frequent for A(H1N1)pdm2009 (20/28, 71.4%) and B patients (7/9, 77.8%) than the A(H3N2) subtype (1/8, 12.5%; p < 0.01). A(H1N1)pdm09-ARDS patients were associated with fewer ventilation-free days at day 28 (median (IQR): 0 (0–8) days) compared with other influenza–ARDS patients (15 (0–25) days, p < 0.05). DiscussionIn a population of influenza-induced ARDS, A(H1N1)pdm09 was associated with fewer bacterial co-infections but poorer respiratory outcomes. These data underline the major role of A(H1N1)pdm09 subtype on influenza disease severity.

Timing of ECMO Initiation Impacts Survival in Influenza-Associated ARDS.

In the past decade, extracorporeal membrane oxygenation (ECMO) has emerged as an innovative therapy for influenza-associated acute respiratory distress syndrome (ARDS). Despite its promising results, the ideal timing of ECMO initiation for these patients remains unclear. Retrospective analysis of a single institution experience with venovenous ECMO for influenza-induced ARDS was performed. Twenty-one patients were identified and categorized into early (0-2 days), standard (3-6 days), or late (more than 7 days) cannulation cohorts. Patients cannulated within 48 hours of admission had 80% survival rate at 90 days. Comparatively, the standard and late cannulation cohorts had an observed 90-day survival rate of 60 and 16.7%, respectively.

ATP catabolism by tissue nonspecific alkaline phosphatase contributes to development of ARDS in influenza-infected mice.

Influenza A viruses are highly contagious respiratory pathogens that are responsible for significant morbidity and mortality worldwide on an annual basis. We have shown previously that influenza infection of mice leads to increased ATP and adenosine accumulation in the airway lumen. Moreover, we demonstrated that A1-adenosine receptor activation contributes significantly to influenza-induced acute respiratory distress syndrome (ARDS). However, we found that development of ARDS in influenza-infected mice does not require catabolism of ATP to adenosine by ecto-5'-nucleotidase (CD73). Hence, we hypothesized that increased adenosine generation in response to infection is mediated by tissue nonspecific alkaline phosphatase (TNAP), which is a low-affinity, high-capacity enzyme that catabolizes nucleotides in a nonspecific manner. In the current study, we found that whole lung and BALF TNAP expression and alkaline phosphatase enzymatic activity increased as early as 2 days postinfection (dpi) of C57BL/6 mice with 10,000 pfu/mouse of influenza A/WSN/33 (H1N1). Treatment at 2 and 4 dpi with a highly specific quinolinyl-benzenesulfonamide TNAP inhibitor (TNAPi) significantly reduced whole lung alkaline phosphatase activity at 6 dpi but did not alter TNAP gene or protein expression. TNAPi treatment attenuated hypoxemia, lung dysfunction, histopathology, and pulmonary edema at 6 dpi without impacting viral replication or BALF adenosine. Treatment also improved epithelial barrier function and attenuated cellular and humoral immune responses to influenza infection. These data indicate that TNAP inhibition can attenuate influenza-induced ARDS by reducing inflammation and fluid accumulation within the lung. They also further emphasize the importance of adenosine generation for development of ARDS in influenza-infected mice.

Pathogenesis of influenza-induced acute respiratory distress syndrome

Acute respiratory distress syndrome (ARDS) is a fatal complication of influenza infection. In this Review we provide an integrated model for its pathogenesis. ARDS involves damage to the epithelial-endothelial barrier, fluid leakage into the alveolar lumen, and respiratory insufficiency. The most important part of the epithelial-endothelial barrier is the alveolar epithelium, strengthened by tight junctions. Influenza virus targets these epithelial cells, reducing sodium pump activity, damaging tight junctions, and killing infected cells. Infected epithelial cells produce cytokines that attract leucocytes--neutrophils and macrophages--and activate adjacent endothelial cells. Activated endothelial cells and infiltrated leucocytes stimulate further infiltration, and leucocytes induce production of reactive oxygen species and nitric oxide that damage the barrier. Activated macrophages also cause direct apoptosis of epithelial cells. This model for influenza-induced ARDS differs from the classic model, which is centred on endothelial damage, and provides a rationale for therapeutic intervention to moderate host response in influenza-induced ARDS.

Contribution of neutrophil‐derived myeloperoxidase in the early phase of fulminant acute respiratory distress syndrome induced by influenza virus infection

Because the pathogenesis of acute respiratory distress syndrome (ARDS) induced by influenza virus infection remains unknown, we can only improve on existing therapeutic interventions. To approach the subject, we investigated immunological etiology focused on cytokines and an acute lung damage factor in influenza-induced ARDS by using a PR-8 (A/H1N1)-infected mouse model. The infected mouse showed fulminant severe pneumonia with leukocyte infiltration, claudin alteration on tight junctions, and formation of hyaline membranes. In addition to interferon (IFN)-α, plenty of keratinocyte-derived chemokines (KC), macrophage inflammatory protein 2 (MIP-2), regulated on activation normal T-cell expressed and secreted (RANTES), and monocyte chemotactic protein 1 (MCP-1) were significantly released into bronchoalveolar lavage fluid (BALF) of the model. We focused on neutrophil myeloperoxidase (MPO) as a potent tissue damage factor and examined its contribution in influenza pneumonia by using mice genetically lacking in MPO. The absence of MPO reduced inflammatory damage with suppression of leakage of total BALF proteins associated with alteration of claudins in the lung. MPO(-/-) mice also suppressed viral load in the lung. The present study suggests that MPO-mediated OCl(-) generation affects claudin molecules and leads to protein leakage and viral spread as a damage factor in influenza-induced ARDS.