Clinical and virological impact of single and dual infections with influenza A (H1N1) and SARS-CoV-2 in adult inpatients

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mimics the influenza A (H1N1) virus in terms of clinical presentation, transmission mechanism, and seasonal coincidence. Comprehensive data for the clinical severity of adult patients co-infected by both H1N1 and SARS-CoV-2, and, particularly, the relationship with PCR cycle threshold (Ct) values are not yet available. All participants in this study were tested for H1N1 and SARS-CoV-2 simultaneously at admission. Demographic, clinical, treatment, and laboratory data were extracted from electronic medical records and compared among adults hospitalized for H1N1 infection, SARS-CoV-2 infection and co-infection with both viruses. Ct values for viral RNA detection were further compared within SARS-CoV-2 and co-infection groups. Score on seven-category ordinal scale of clinical status at day 7 and day 14 were assessed. Among patients with monoinfection, H1N1 infection had higher frequency of onset symptoms but lower incidence of adverse events during hospitalization than SAR-CoV-2 infection (P < 0.05). Co-infection had an increased odds of acute kidney injury, acute heart failure, secondary bacterial infections, multilobar infiltrates and admittance to ICU than monoinfection. Score on seven-category scale at day 7 and day 14 was higher in patients with coinfection than patients with SAR-CoV-2 monoinfection (P<0.05). Co-infected patients had lower initial Ct values (referring to higher viral load) (median 32) than patients with SAR-CoV-2 monoinfection (median 36). Among co-infected patients, low Ct values were significantly and positively correlated with acute kidney injury and ARDS (P = 0.03 and 0.02, respectively). Co-infection by SARS-CoV-2 and H1N1 caused more severe disease than monoinfection by either virus in adult inpatients. Early Ct value could provide clues for the later trajectory of the co-infection. Multiplex molecular diagnostics for both viruses and early assessment of SAR-CoV-2 Ct values are recommended to achieve optimal treatment for improved clinical outcome.

Influenza A H1N1 Induced Disturbance of the Respiratory and Fecal Microbiome of German Landrace Pigs – a Multi-Omics Characterization

Here, we used swine as a biomedical model to elucidate the impact of influenza A H1N1 infection on structure and function of the respiratory and gastrointestinal tract microbiome by employing a multi-omics analytical approach. To our knowledge, this is the first study to investigate the temporal development of the porcine microbiome and to provide insights into the functional capacity of the gastrointestinal microbiome during influenza A virus infection.

Oseltamivir and acute hepatitis, reality association or coincidence?

Oseltamivir is an orally administered antiviral medication that selectively inhibits the influenza neuraminidase enzymes that are essential for viral replication and it is active against both influenza A and B viruses. Oseltamivir is indicated for therapy or post-exposure prevention of influenza A and B. Side effects are uncommon and include mild nausea, gastrointestinal upset, dizziness, and headache. Despite widespread use, oseltamivir has not been associated with clinically apparent liver injury; however, there is growing evidence of possible toxic liver involvement during oseltamivir therapy. To the best of our knowledge, this is the first reported case in Italy linking the development of acute hepatitis and oseltamivir therapy, in a patient suffering from influenza H1N1 infection. We also present a review of the literature on cases of oseltamivir hepatotoxicity, through the consultation of PubMed database, the bibliographical references of various articles and an extensive search using Google. In view of the analyzed results, we suggest that experts should carefully consider the need for inclusion of potential serious liver reactions be added to the oseltamivir product label.

Influenza A Virus (H1N1) Infection Induces Glycolysis to Facilitate Viral Replication

Viruses depend on host cellular metabolism to provide the energy and biosynthetic building blocks required for their replication. In this study, we observed that influenza A virus (H1N1), a single-stranded, negative-sense RNA virus with an eight-segmented genome, enhanced glycolysis both in mouse lung tissues and in human lung epithelial (A549) cells. In detail, the expression of hexokinase 2 (HK2), the first enzyme in glycolysis, was upregulated in H1N1-infected A549 cells, and the expression of pyruvate kinase M2 (PKM2) and pyruvate dehydrogenase kinase 3 (PDK3) was upregulated in H1N1-infected mouse lung tissues. Pharmacologically inhibiting the glycolytic pathway or targeting hypoxia-inducible factor 1 (HIF-1), the central transcriptional factor critical for glycolysis, significantly reduced H1N1 replication, revealing a requirement for glycolysis during H1N1 infection. In addition, pharmacologically enhancing the glycolytic pathway further promoted H1N1 replication. Furthermore, the change of H1N1 replication upon glycolysis inhibition or enhancement was independent of interferon signaling. Taken together, these findings suggest that influenza A virus induces the glycolytic pathway and thus facilitates efficient viral replication. This study raises the possibility that metabolic inhibitors, such as those that target glycolysis, could be used to treat influenza A virus infection in the future.

Influenza A virus (H1N1) infection induces microglia activation and temporal dysbalance in glutamatergic synaptic transmission.

Influenza A virus (IAV) causes respiratory tract disease and is responsible for seasonal and reoccurring epidemics affecting all age groups. Next to typical disease symptoms such as fever and fatigue, IAV infection has been associated with behavioral alterations presumably contributing to the development of major depression. Previous experiments using IAV/H1N1 infection models have shown impaired hippocampal neuronal morphology and cognitive abilities, but the underlying pathways have not been fully described. In this study, we demonstrate that infection with a low dose non-neurotrophic H1N1 strain of IAV causes ample peripheral immune response followed by a temporary blood-brain barrier disturbance. Although histological examination did not reveal obvious pathological processes in the brains of IAV-infected mice, detailed multidimensional flow cytometric characterization of immune cells uncovered subtle alterations in the activation status of microglia cells. More specifically, we detected an altered expression pattern of major histocompatibility complex class I and II, CD80, and F4/80 accompanied by elevated mRNA levels of CD36, CD68, C1QA, and C3, suggesting evolved synaptic pruning. To closer evaluate how these profound changes affect synaptic balance, we established a highly sensitive multiplex flow cytometry-based approach called Flow Synaptometry. The introduction of this novel technique enabled us to simultaneously quantify the abundance of pre- and postsynapses from distinct brain regions. Our data reveal a significant reduction of VGLUT1 in excitatory presynaptic terminals in the Cortex and Hippocampus, identifying a subtle dysbalance in glutamatergic synapse transmission upon H1N1 infection in mice. In conclusion, our results highlight the consequences of systemic IAV-triggered inflammation on the central nervous system and the induction and progression of neuronal alterations.

Six-Month Outcomes of Post-ARDS Pulmonary Fibrosis in Patients With H1N1 Pneumonia

Background: Influenza virus is a common pathogen causing community-acquired pneumonia. After H1N1 infection, some patients present with rapid disease progression and various respiratory complications, especially immunocompromised patients and pregnant women. However, most patients have a favorable prognosis. Influenza viruses infect respiratory epithelial cells, leading to diffuse alveolar damage (DAD), which could induce secondary bacterial or fungal infections that could lead to serious complications, such as acute respiratory failure, severe pneumonia, pneumothorax, mediastinal emphysema, acute respiratory distress syndrome (ARDS) and post-ARDS fibrosis.Objective: The short-term mortality rate of ARDS is decreasing, and understanding survivors’ posthospitalization outcomes is very important. Our aim was to evaluate the outcomes of 69 patients who survived H1N1 pneumonia with severe respiratory complications and abnormal CT findings and developed post-ARDS pulmonary fibrosis.Materials and methods: The 280 inpatients included in this trial had been diagnosed with H1N1 infection that was confirmed by pharyngeal sputum or swab tests. The data were collected from January 2018 to January 2020 in the First Affiliated Hospital of Zhengzhou University and the Sixth People's Hospital of Zhengzhou. Of these patients, 232 had CT findings indicating pulmonary fibrosis after H1N1 infection, and 69 survived and consented to participate in this study. 6°months after diagnosis, the 69 surviving patients were interviewed and underwent physical examinations, CT scans, 6°min walk tests, and quality-of-life evaluations (SF-36). We analyzed the baseline variables and six-month outcomes of post-ARDS pulmonary fibrosis in patients with H1N1 pneumonia.Results: Of the 69 surviving patients with post-ARDS pulmonary fibrosis, there were 24 females and 45 males, with a mean age of 53.7 ± 16.8°years; 18 patients (26%) had no underlying disease, and 14 (20%) patients had more than one underlying disease. The distance walked in 6°min increased from an average of 451.9°m at 3°months to 575.4°m at 6°months; the mean 36-Item Short Form Survey (SF-36) physical function score increased from an average of 75.3 at 3°months to 77.5 at 6°months; and the average CT score decreased from 31.3 at 3°months to 14.8 at 6°months. Treatment with systemic corticosteroids and the presence of an underlying disease were related to the CT score and the distance walked in 6°min.Conclusion: Among the survivors with pulmonary fibrosis after H1N1 influenza, the 6°min walk test and CT scores continued to be affected after 6°months. The 6°min walk distance and imaging findings improved during the first 6°months. The health-related QoL (HRQoL) scores of H1N1 pneumonia survivors were lower than those of sex- and age-matched controls.