Severe Influenza Patients Research Articles

Gene expression profile analysis of severe influenza-based modulation of idiopathic pulmonary fibrosis

BackgroundIt is known severe influenza infections and idiopathic pulmonary fibrosis (IPF) disease might stimulate each other. Till now, no associated mechanism has been reported.MethodWe collected the genetic pattern of expression of severe influenza (GSE111368) and IPF (GSE70866) from the Gene Expression Omnibus (GEO) database. Common differentially expressed genes (C-DEGs) were identified from the two datasets, and using this data, we conducted three forms of analyses, functional annotation, protein–protein interaction (PPI) network and module construction, and hub gene identification and co-expression analysis.ResultsIn all, 174 C-DEGs were selected for additional analyses. Based on our functional analysis, these C-DEGs mediated inflammatory response and cell differentiation. Furthermore, using cytoHubba, we identified 15 genes, namely, MELK, HJURP, BIRC5, TPX2, TK1, CDT1, UBE2C, UHRF1, CCNA2, TYMS, CDCA5, CDCA8, RAD54L, CCNB2, and ITGAM, which served as hub genes to possibly contribute to severe influenza patients with IPF disease as comorbidity. The hub gene expressions were further confirmed using two stand-alone datasets (GSE101702 for severe influenza and GSE10667 for IPF).ConclusionHerein, we demonstrated the significance of common pathways and critical genes in severe influenza and IPF etiologies. The identified pathways and genes may be employed as possible therapeutic targets for future therapy against severe influenza patients with IPF.

Profiling Bacteria in the Lungs of Patients with Severe Influenza Versus COVID-19 with or without Aspergillosis.

The influence of the lung bacterial microbiome, including potential pathogens, in patients with influenza- or COVID-19-associated pulmonary aspergillosis (IAPA or CAPA) is yet to be explored. To explore the composition of the lung bacterial microbiome and its association with viral and fungal infection, immunity and outcome in severe influenza versus COVID-19 with or without aspergillosis. We performed a retrospective study in mechanically ventilated influenza and COVID-19 patients with or without invasive aspergillosis in whom bronchoalveolar lavage (BAL) for bacterial culture (with or without PCR) was obtained within two weeks after ICU admission. Additionally, 16S rRNA gene sequencing data and viral and bacterial load of BAL samples from a subset of these patients, and of patients requiring non-invasive ventilation, were analyzed. We integrated 16S rRNA gene sequencing data with existing immune parameter datasets. Potential bacterial pathogens were detected in 20% (28/142) of influenza and 37% (104/281) of COVID-19 patients, while aspergillosis was detected in 38% (54/142) of influenza and 31% (86/281) of COVID-19 patients. A significant association between bacterial pathogens in BAL and 90-day mortality was found only in influenza patients, particularly IAPA patients. COVID-19 but not influenza patients showed increased pro-inflammatory pulmonary cytokine responses to bacterial pathogens. Aspergillosis is more frequently detected in lungs of severe influenza patients than bacterial pathogens. Detection of bacterial pathogens associates with worse outcome in influenza patients, particularly in those with IAPA, but not in COVID-19 patients. The immunological dynamics of tripartite viral-fungal-bacterial interactions deserve further investigation. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Platycodin D facilitates antiviral immunity through inhibiting cytokine storm via targeting K63-linked TRAF6 ubiquitination.

Influenza virus infection is a worldwide challenge that causes heavy burdens on public health. The mortality rate of severe influenza patients is often associated with hyperactive immunological abnormalities characterized by hypercytokinemia. Due to the continuous mutations and the occurrence of drug-resistant influenza virus strains, the development of host-directed immunoregulatory drugs is urgently required. Platycodon grandiflorum is among the top 10 herbs of traditional Chinese medicine used to treat pulmonary diseases. As one of the major terpenoid saponins extracted from Platycodon grandiflorum, Platycodin D (PD) has been reported to play several roles, including anti-inflammation, analgesia, anti-cancer, hepatoprotection, and immunoregulation. However, the therapeutic roles of PD to treat influenza virus infection remains unknown. Here, we show that PD can protect the body weight loss in severely infected influenza mice, alleviate lung damage, and thus improve the survival rate. More specifically, PD protects flu mice via decreasing the immune cell infiltration into lungs and downregulating the overactivated inflammatory response. Western blot and immunofluorescence assays exhibited that PD could inhibit the activation of TAK1/IKK/NF-κB and MAPK pathways. Besides that, CETSA, SPR and immunoprecipitation assays indicated that PD binds with TRAF6 to decrease its K63 ubiquitination after R837 stimulation. Additionally, siRNA interference experiments exhibited that PD could inhibit the secretion of IL-1β and TNF-α in TRAF6-dependent manner. Altogether, our results suggested that PD is a promising drug candidate for treating influenza. Our study also offered a scientific explanation for the commonly used Platycodon grandiflorum in many anti-epidemic classic formulas. Due to its host-directed regulatory role, PD may serve as an adjuvant therapeutic drug in conjunction with other antiviral drugs to treat the flu.

Bioinformatics analysis identifies a key gene HLA_DPA1 in severe influenza-associated immune infiltration

BackgroundSevere influenza is a serious global health issue that leads to prolonged hospitalization and mortality on a significant scale. The pathogenesis of this infectious disease is poorly understood. Therefore, this study aimed to identify the key genes associated with severe influenza patients necessitating invasive mechanical ventilation.MethodsThe current study utilized two publicly accessible gene expression profiles (GSE111368 and GSE21802) from the Gene Expression Omnibus database. The research focused on identifying the genes exhibiting differential expression between severe and non-severe influenza patients. We employed three machine learning algorithms, namely the Least Absolute Shrinkage and Selection Operator regression model, Random Forest, and Support Vector Machine-Recursive Feature Elimination, to detect potential key genes. The key gene was further selected based on the diagnostic performance of the target genes substantiated in the dataset GSE101702. A single-sample gene set enrichment analysis algorithm was applied to evaluate the participation of immune cell infiltration and their associations with key genes.ResultsA total of 44 differentially expressed genes were recognized; among them, we focused on 10 common genes, namely PCOLCE2, HLA_DPA1, LOC653061, TDRD9, MPO, HLA_DQA1, MAOA, S100P, RAP1GAP, and CA1. To ensure the robustness of our findings, we employed overlapping LASSO regression, Random Forest, and SVM-RFE algorithms. By utilizing these algorithms, we were able to pinpoint the aforementioned 10 genes as potential biomarkers for distinguishing between both cases of influenza (severe and non-severe). However, the gene HLA_DPA1 has been recognized as a crucial factor in the pathological condition of severe influenza. Notably, the validation dataset revealed that this gene exhibited the highest area under the receiver operating characteristic curve, with a value of 0.891. The use of single-sample gene set enrichment analysis has provided valuable insights into the immune responses of patients afflicted with severe influenza that have further revealed a categorical correlation between the expression of HLA_DPA1 and lymphocytes.ConclusionThe findings indicated that the HLA_DPA1 gene may play a crucial role in the immune-pathological condition of severe influenza and could serve as a promising therapeutic target for patients infected with severe influenza.

Comparison of the clinical features and outcomes of severe seasonal influenza and COVID-19 patients in Tunisia between 2021 and 2022.

We compared patients diagnosed at a SARI (severe acute respiratory infections) surveillance site with COVID-19 and those with seasonal influenza to investigate the clinical differences, common features, and outcomes. We conducted a descriptive, retrospective study in the Medical Intensive Care Unit (ICU) at Abderrahman Mami Hospital between September 2021 and April 2022. Demographic, clinical, and biological data as well as outcomes were recorded for all patients. Among 223 SARI patients, 83 were confirmed COVID-19, and 22 were influenza positive. The distribution according to gender was similar; but patients with influenza were younger than those suffering from COVID-19(mean age 60.36 SD 17.28 vs. 61.88 SD 17.91; P = 0.601). In terms of underlying chronic diseases, the frequency was 84.3% in the COVID-19 group and 72.7% in the influenza group. COVID-19 patients had a longer duration of hospitalization (mean [SD], 9.51 days [8.47 days] vs. 7.33 days [8.82 days]; P = 0.003), and a more frequent need for invasive ventilation (80 [97.4%] vs. 20 [92.3]). Case fatality was also higher among this group compared to the latter (39 [47%] vs. 6 [27.3%], P = 0.01). This exploratory study suggests higher severity of COVID-19 compared to seasonal influenza among SARI hospitalized patients even during the Omicron wave. Further research on higher sample sizes is required to confirm this conclusion.

Genetic analysis of cuproptosis subtypes and immunological features in severe influenza

The mechanisms regulating cuproptosis in severe influenza are still unknown. We aimed to identify the molecular subtypes of cuproptosis and immunological characteristics associated with severe influenza in patients requiring invasive mechanical ventilation (IMV). The expression of cuproptosis modulatory factors and immunological characteristics of these patients were analyzed using the public datasets (GSE101702, GSE21802, and GSE111368) from the Gene Expression Omnibus (GEO). Seven cuproptotic-associated genes (ATP7B, ATP7A, FDX1, LIAS, DLD, MTF1, DBT) related to active immune responses were identified in patients suffering from severe and non-severe influenza and two cuproptosis-associated molecular subtypes were discovered in severe influenza patients. Singe-set gene set expression analysis (SsGSEA) indicated that compared with subtype 2, subtype 1 was characterized by reduced adaptive cellular immune responses and increased neutrophil activation. Gene set variation assessment revealed that cluster-specific differentially expressed genes (DEGs) in subtype 1 were involved in autophagy, apoptosis, oxidative phosphorylation, and T cell, immune, and inflammatory responses, amongst others. The random forest (RF) model revealed the most differentiating efficiency with relatively small residual and root mean square error and an increased area under the curve value (AUC = 0.857). Lastly, a five-gene-based RF model (CD247, GADD45A, KIF1B, LIN7A, HLA_DPA1) was established, which showed satisfactory efficiency in the test datasets GSE111368 (AUC = 0.819). Nomogram calibration and decision curve analysis demonstrated its accuracy for the prediction of severe influenza. This study suggests that cuproptosis might be associated with the immunopathology of severe influenza. Additionally, an efficient model for the prediction of cuproptosis subtypes was developed which will contribute to the prevention and treatment of severe influenza patients needing IMV.

Co-expression network analysis identifies potential candidate hub genes in severe influenza patients needing invasive mechanical ventilation

BackgroundInfluenza is a contagious disease that affects people of all ages and is linked to considerable mortality during epidemics and occasional outbreaks. Moreover, effective immunological biomarkers are needed for elucidating aetiology and preventing and treating severe influenza. Herein, we aimed to evaluate the key genes linked with the disease severity in influenza patients needing invasive mechanical ventilation (IMV). Three gene microarray data sets (GSE101702, GSE21802, and GSE111368) from blood samples of influenza patients were made available by the Gene Expression Omnibus (GEO) database. The GSE101702 and GSE21802 data sets were combined to create the training set. Hub indicators for IMV patients with severe influenza were determined using differential expression analysis and Weighted correlation network analysis (WGCNA) from the training set. The receiver operating characteristic curve (ROC) was also used to evaluate the hub genes from the test set's diagnostic accuracy. Different immune cells' infiltration levels in the expression profile and their correlation with hub gene markers were examined using single-sample gene set enrichment analysis (ssGSEA).ResultsIn the present study, we evaluated a total of 447 differential genes. WGCNA identified eight co-expression modules, with the red module having the strongest correlation with IMV patients. Differential genes were combined to obtain 3 hub genes (HLA-DPA1, HLA-DRB3, and CECR1). The identified genes were investigated as potential indicators for patients with severe influenza who required IMV using the least absolute shrinkage and selection operator (LASSO) approach. The ROC showed the diagnostic value of the three hub genes in determining the severity of influenza. Using ssGSEA, it has been revealed that the expression of key genes was negatively correlated with neutrophil activation and positively associated with adaptive cellular immune response.ConclusionWe evaluated three novel hub genes that could be linked to the immunopathological mechanism of severe influenza patients who require IMV treatment and could be used as potential biomarkers for severe influenza prevention and treatment.

Super Dominant Pathobiontic Bacteria in the Nasopharyngeal Microbiota Cause Secondary Bacterial Infection in COVID-19 Patients.

ABSTRACTCoronavirus disease 2019 (COVID-19) is a respiratory infectious disease responsible for many infections worldwide. Differences in respiratory microbiota may correlate with disease severity. Samples were collected from 20 severe and 51 mild COVID-19 patients. High-throughput sequencing of the 16S rRNA gene was used to analyze the bacterial community composition of the upper and lower respiratory tracts. The indices of diversity were analyzed. When one genus accounted for >50% of reads from a sample, it was defined as a super dominant pathobiontic bacterial genus (SDPG). In the upper respiratory tract, uniformity indices were significantly higher in the mild group than in the severe group (P < 0.001). In the lower respiratory tract, uniformity indices, richness indices, and the abundance-based coverage estimator were significantly higher in the mild group than in the severe group (P < 0.001). In patients with severe COVID-19, SDPGs were detected in 40.7% of upper and 63.2% of lower respiratory tract samples. In patients with mild COVID-19, only 10.8% of upper and 8.5% of lower respiratory tract samples yielded SDPGs. SDPGs were present in both upper and lower tracts in seven patients (35.0%), among which six (30.0%) patients possessed the same SDPG in the upper and lower tracts. However, no patients with mild infections had an SDPG in both tracts. Staphylococcus, Corynebacterium, and Acinetobacter were the main SDPGs. The number of SDPGs identified differed significantly between patients with mild and severe COVID-19 (P < 0.001). SDPGs in nasopharyngeal microbiota cause secondary bacterial infection in COVID-19 patients and aggravate pneumonia.IMPORTANCE The nasopharyngeal microbiota is composed of a variety of not only the true commensal bacterial species but also the two-face pathobionts, which are one a harmless commensal bacterial species and the other a highly invasive and deadly pathogen. In a previous study, we found that the diversity of nasopharyngeal microbiota was lost in severe influenza patients. We named the genus that accounted for over 50% of microbiota abundance as super dominant pathobiontic genus, which could invade to cause severe pneumonia, leading to high fatality. Similar phenomena were found here for SARS-CoV-2 infection. The diversity of nasopharyngeal microbiota was lost in severe COVID-19 infection patients. SDPGs in nasopharyngeal microbiota were frequently detected in severe COVID-19 patients. Therefore, the SDPGs in nasopharynx microbiota might invade into low respiratory and be responsible for secondary bacterial pneumonia in patients with SARS-CoV-2 infection.

The Impacts of Aspergillosis on Outcome, Burden and Risks for Mortality in Influenza Patients with Critical Illness.

Previous studies have revealed higher mortality rates in patients with severe influenza who are coinfected with invasive pulmonary aspergillosis (IPA) than in those without IPA coinfection; nonetheless, the clinical impact of IPA on economic burden and risk factors for mortality in critically ill influenza patients remains undefined. The study was retrospectively conducted in three institutes. From 2016 through 2018, all adult patients with severe influenza admitted to an intensive care unit (ICU) were identified. All patients were classified as group 1, patients with concomitant severe influenza and IPA; group 2, severe influenza patients without IPA; and group 3, severe influenza patients without testing for IPA. Overall, there were 201 patients enrolled, including group 1 (n = 40), group 2 (n = 50), and group 3 (n = 111). Group 1 patients had a significantly higher mortality rate (20/40, 50%) than that of group 2 (6/50, 12%) and group 3 (18/11, 16.2%), p < 0.001. The risk factors for IPA occurrence were solid cancer and prolonged corticosteroid use in ICU of >5 days. Group 1 patients had significantly longer hospital stay and higher medical expenditure than the other two groups. The risk factors for mortality in group 1 patients included patients’ Charlson comorbidity index, presenting APACHE II score, and complication of severe acute respiratory distress syndrome. Overall, IPA has a significant adverse impact on the outcome and economic burden of severe influenza patients, who should be promptly managed based on risk host factors for IPA occurrence and mortality risk factors for coinfection with both diseases.

Risk Factors Associated with Invasive Pulmonary Mycosis Among Severe Influenza Patients in Beijing City, China.

ObjectiveInfluenza co-infection with fungal infection increases the risk of death. Our study was to estimate risk factors associated with invasive pulmonary mycosis (IPM) among severe influenza patients at a single center in Beijing, China.MethodsA retrospective chart review was carried out of all patients with severe influenza admitted to respiratory the department including the respiratory intensive care unit (RICU) during the 2014 to 2019 influenza seasons in Beijing Chao-yang hospital, China. We compared the differences of characteristics and examination outcomes between IPM patients and non-IPM patients, and explored the predictors of IPM by a multivariate logistic regression.ResultsInfluenza associated IPM was found in 65 of 131 (49.62%) patients. The average age of IPM patients was 57.28±14.56 years and 70.77% were male. The mortality rate was much higher in the IPM group than the non-IPM group (34.85% versus 18.46%, P=0.026). Older age, hypoimmunity, liver disease, hypertension, positive serum GM test, steroids using, gasping, gastrointestinal symptoms, high APECHEII, low oxygenation index, other viruses co-infection, bacterial co-infection, low lymphocyte counts, low CD4+ T-cell counts, low CD8+ T-cell counts, low RBC, low hemoglobin, low platelets, high N%, low total protein, high CRP, low albumin, low fibrinogen, high BUN, positive serum GM test, more mechanical ventilation requirement, and more renal replacement requirement were risk factors of influenza IPM co-infection.ConclusionIPM is a severe complication of influenza hospitalizations. It is associated with increasing mortality, longer hospital stays, and higher hospital charges compared with non-IPM patients. Clinicians caring for patients with severe influenza should consider IPM.

Influenza- and COVID-19-Associated Pulmonary Aspergillosis: Are the Pictures Different?

Invasive pulmonary aspergillosis (IPA) in intensive care unit patients is a major concern. Influenza-associated acute respiratory distress syndrome (ARDS) and severe COVID-19 patients are both at risk of developing invasive fungal diseases. We used the new international definitions of influenza-associated pulmonary aspergillosis (IAPA) and COVID-19-associated pulmonary aspergillosis (CAPA) to compare the demographic, clinical, biological, and radiological aspects of IAPA and CAPA in a monocentric retrospective study. A total of 120 patients were included, 71 with influenza and 49 with COVID-19-associated ARDS. Among them, 27 fulfilled the newly published criteria of IPA: 17/71 IAPA (23.9%) and 10/49 CAPA (20.4%). Kaplan–Meier curves showed significantly higher 90-day mortality for IPA patients overall (p = 0.032), whereas mortality did not differ between CAPA and IAPA patients. Radiological findings showed differences between IAPA and CAPA, with a higher proportion of features suggestive of IPA during IAPA. Lastly, a wide proportion of IPA patients had low plasma voriconazole concentrations with a higher delay to reach concentrations > 2 mg/L in CAPA vs. IAPA patients (p = 0.045). Severe COVID-19 and influenza patients appeared very similar in terms of prevalence of IPA and outcome. The dramatic consequences on the patients’ prognosis emphasize the need for a better awareness in these particular populations.

Severe Influenza With Invasive Pulmonary Aspergillosis in Immunocompetent Hosts: A Retrospective Cohort Study.

Background: Influenza was an independent risk factor for invasive pulmonary aspergillosis (IPA). In light of increasing incidence and mortality of influenza associated aspergillosis, our study summarized risk factors, clinical characteristics, and prognostic factors of developing aspergillosis in immunocompetent hosts with influenza to further screen high-risk population and improve outcome.Methods: We reviewed the patient characteristics, laboratory examinations, radiological imaging, and microbiology data of 72 influenza patients with IPA and 84 influenza patients without IPA admitted to West China Hospital.Result: Our study shown that aspergillosis co-infection increased overall mortality of severe influenza from 22.6 to 52.8%, along with higher white blood count (WBC) (10.9 ± 5.0 vs. 8.4 ± 3.3, P = 0.016), Neutrophiles (9.5 ± 5.0 vs. 7.0 ± 3.8, P = 0.023), procalcitonin (PCT) (8.6 ± 15.9 vs. 1.2 ± 2.1, P = 0.009), and a lower CD4+ T cell count (189.2 ± 135.3 vs. 367.1 ± 280.0, P = 0.022) in death group. No impact of age, gender, underlying diseases, immunosuppressive agents and steroids use, CD4+ T cell count on incidence of influenza associated aspergillosis was observed. But influenza associated aspergillosis cases mostly accompanied with more H1N1 subtype (91.7 vs. 79.8%, P = 0.037) and higher level of C-reactive protein (CRP) (117.6 ± 88.1 vs. 78.5 ± 75.2, P = 0.017) and interleukin 6 (IL-6) (133.5 ± 149.2 vs. 69.9 ± 100.0, P = 0.021) than those without aspergillosis.Conclusion: Aspergillosis co-infection in severe influenza patients can lead to a significant increased mortality, which was associated with severe respiratory failure due to mixed infection and immunosuppression. Pulmonary excessive inflammatory response was related with IPA co-infection.

Clinical Effectiveness of Intravenous Peramivir Compared With Oseltamivir in Patients With Severe Influenza A With Primary Viral Pneumonia: A Randomized Controlled Study.

BackgroundHigh-quality evidence confirms that the clinical efficacy of peramivir in severe influenza patients with primary viral pneumonia is lacking. To optimize clinical medication, we evaluate the different efficacy between peramivir and oseltamivir in the treatment of severe influenza A with primary viral pneumonia.MethodsA single-center, randomized, controlled trial was conducted during the Chinese influenza season from December 2018 to April 2019 in patients with severe influenza A with primary viral pneumonia. A total of 40 inpatients were enrolled and treated with either intravenous peramivir (300 mg, once daily for 5 days) or oral oseltamivir (75 mg, twice daily for 5 days).ResultsThe duration of influenza virus nucleic acid positivity in the oseltamivir group and the peramivir group was 2.95 days and 2.80 days, respectively. The remission times of clinical symptoms in the oseltamivir group and the peramivir group were 3.90 days and 3.25 days, respectively. In addition, the remission time of cough symptoms in the peramivir group (63.89 hours) was shorter than that in the oseltamivir group (75.53 hours). There was no significant difference between these values (P > .05). The remission time of fever symptoms in the oseltamivir group was 23.67 hours, which was significantly longer than that in the peramivir group (12.32 hours) (P = .034).ConclusionsPeramivir is no less effective than oseltamivir in the treatment of severe influenza A with primary viral pneumonia, and patients treated with peramivir had significantly shorter remission times of fever symptoms than those treated with oseltamivir.

Clinical characteristics and prognosis analysis of 37 patients with severe influenza

To explore the clinical characteristics and prognostic risk factors of severe influenza. Clinical data of severe influenza patients admitted to the department of respiratory and critical care medicine of the Second Affiliated Hospital of Anhui Medical University from March 2014 to June 2019 were retrospectively analyzed. General information, laboratory test results, and etiological test results of the hospitalization outcomes for survival group and death group during the 28-day follow-up were analyzed using Logistic regression analysis. Among the 37 patients, 29 were males and 8 were females. They aged 25-86 years old with an average of (59.59±15.16) years old. Twenty-one cases had chronic underlying diseases; 28 cases had co-infections, including 6 cases with bacterial infections, 7 cases with fungal infections, 3 case with other pathogens, and 12 cases with mixed infection. Among the 37 patients, 9 died during hospitalization and 5 died within 28-day of discharge. The overall mortality rate was 37.84%. Compared with the survival group, patients in the death group were older (years old: 66.57±3.94 vs. 55.35±14.53), British Thoracic Society's modified pneumonia score (CURB-65 score), acute physiology and chronic health evaluation II (APACHE II) score, neutrophil count, D-dimer, 48-hour C-reactive protein (CRP) and procalcitonin (PCT) were higher [CURB-65 score: 2 (2, 3) vs. 1 (0, 2), APACHE II: 16.00±4.62 vs. 11.00±4.22, neutrophil count (×109/L): 8.87 (5.42, 11.33) vs. 3.58 (2.55, 7.13), D-dimer (mg/L): 7.97 (5.19, 12.68) vs. 2.91 (1.19, 5.02), 48-hour CRP (mg/L): 127.83±92.24 vs. 87.01±57.00, 48-hour PCT (μg/L): 1.79 (0.59, 4.44) vs. 0.37 (0.13, 0.99)], oxygenation index (PaO2/FiO2) and creatinine clearance rate were lower [PaO2/FiO2 (mmHg, 1 mmHg = 0.133 kPa): 109.52±49.30 vs. 204.82±67.61, creatinine clearance rate (mL×min-1×1.73 m-2): 55.49±21.23 vs. 77.59±29.73], and the differences were statistically significant (all P < 0.05). There was no significant difference in gender, combined chronic underlying diseases, lymphocyte count, albumin, lactate dehydrogenase (LDH), prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (Fib), 24-hour CRP and PCT between the two groups. A total of 37 pathogens were cultured, including 17 Gram-negative bacteria (45.95%), 3 Gram-positive bacteria (8.10%), and 17 fungi (45.95%). The number of Acinetobacter baumannii infections in the death group was significantly higher than that in the survival group (cases: 7 vs. 2, P < 0.05). Logistic regression analysis showed that age, CURB-65 score, APACHE II score, PaO2/FiO2, neutrophil count, creatinine clearance rate, combined Acinetobacter baumannii infection, deep vein catheterization, catheterization, and stomach preservation during hospitalization were risk factors for the prognosis of patients with severe influenza [hazard ratios (HR) were 1.064, 4.920, 1.286, 0.975, 1.286, 0.965, 0.095, 0.083, 9.333, 0.089, respectively, all P < 0.05]. Multivariate analysis showed that low PaO2/FiO2 and Acinetobacter baumannii infection were risk factors for prognosis of severe influenza (HR were 0.834 and 0.000, respectively, both P < 0.05). Old age, high CURB-65 score, high APACHE II score, and co-infection are risk factors for the prognosis of patients with severe influenza.

The impact of early neuraminidase inhibitor therapy on clinical outcomes in patients hospitalised with influenza A-related pneumonia: a multicenter, retrospective study

BackgroundGuidelines emphasize prompt antiviral treatment in severe influenza patients. Although nearly a 50% of severe influenza present with pneumonia, the effect of early (≤ 2 days after illness onset) neuraminidase inhibitor (NAI) use on the clinical outcomes of influenza A-related pneumonia (FluA-p) has rarely been assessed. Furthermore, data about the administration of NAIs in the real-world management of Flu-p in China are limited.MethodsData of patients hospitalised with FluA-p from five teaching hospitals in China from 1 January 2013 to 31 December 2018 were reviewed retrospectively. The impact of early NAI therapy on the outcomes in FluA-p patients, and the indications of early NAI administration by clinicians were evaluated by logistic regression analysis.ResultsIn total, 693 FluA-p patients were included. Of these patients, 33.5% (232/693) were treated early. After adjusting for weighted propensity scores for treatment, systemic corticosteroid and antibiotic use, a multivariate logistic regression model showed that early NAI therapy was associated with decreased risk for invasive ventilation [odds ratio (OR) 0.511, 95% confidence interval (CI) 0.312–0.835, p = 0.007) and 30-day mortality (OR 0.533, 95% CI 0.210–0.807, p < 0.001) in FluA-p patients. A multivariate logistic regression model confirmed early NAI use (OR 0.415, 95% CI 0.195–0.858, p = 0.001) was a predictor for 30-day mortality in FluA-p patients and a positive rapid influenza diagnostic test was the only indication (OR 3.586, 95% CI 1.259–10.219, p < 0.001) related to the prescription of early NAI by clinicians.ConclusionsEarly NAI therapy is associated with better outcomes in FluA-p patients. Improved education and training of clinicians on the guidelines of influenza are needed.

Galectin-1 Ameliorates Influenza A H1N1pdm09 Virus-Induced Acute Lung Injury.

Influenza remains one of the major epidemic diseases worldwide. Acute lung injury mainly caused by excessive pro-inflammatory host immune responses leads to high mortality rates in severe influenza patients. Galectin-1, an animal lectin ubiquitously expressed in mammalian tissues, is reported to play important roles in viral diseases. Here, we established murine and A549 cell models to explore the potential roles of galectin-1 treatment in H1N1pdm09-induced acute lung injury. We found that galectin-1 protein level was elevated in A549 cell culture supernatants and mouse BALF after H1N1pdm09 challenge. In vivo experiments showed recombinant galectin-1 treatment reduced wet/dry weight ratio, inflammatory cell infiltration in mouse lungs and mediated the expression of cytokines and chemokines including IL-1β, IL-6, IL-10, IL-12(p40), IL-12(p70), G-CSF, MCP-1, MIP-1α and RANTES in serum and BALF of infected mice. Reduced apoptosis and viral titers in mouse lungs were also found after galectin-1 treatment. As expected, galectin-1 treated mice performed reduced body weight loss and enhanced survival rate against H1N1pdm09 challenge. In addition, in vitro experiments showed that viral titers decreased in a dose-dependent manner and cell apoptosis in A549 cells reduced after recombinant galectin-1 treatment. Taken together, our findings indicate a potentially positive effect of Gal-1 treatment on ameliorating the progress of H1N1pdm09-induced acute lung injury and recombinant galectin-1 might serve as a new agent in treating influenza.

Impact of corticosteroid treatment on clinical outcomes of influenza-associated ARDS: a nationwide multicenter study

BackgroundCorticosteroid treatment has been widely used in the treatment of septic shock, influenza, and ARDS, although some previous studies discourage its use in severe influenza patients. This multicenter retrospective cohort study conducted in the intensive care units (ICUs) of eight medical centers across Taiwan aims to determine the real-world status of corticosteroid treatment in patients with influenza-associated acute respiratory distress syndrome (ARDS) and its impact on clinical outcomes. Between October 2015 and March 2016, consecutive ICU patients with virology-proven influenza infections who fulfilled ARDS and received invasive mechanical ventilation were enrolled. The impact of early corticosteroid treatment (≥ 200 mg hydrocortisone equivalent dose within 3 days after ICU admission, determined by a sensitivity analysis) on hospital mortality (the primary outcome) was assessed by multivariable logistic regression analysis, and further confirmed in a propensity score-matched cohort.ResultsAmong the 241 patients with influenza-associated ARDS, 85 (35.3%) patients receiving early corticosteroid treatment had similar baseline characteristics, but a significantly higher hospital mortality rate than those without early corticosteroid treatment [43.5% (37/85) vs. 19.2% (30/156), p < 0.001]. Early corticosteroid treatment was independently associated with increased hospital mortality in overall patients [adjusted odds ratio (95% CI) = 5.02 (2.39–10.54), p < 0.001] and in all subgroups. Earlier treatment and higher dosing were associated with higher hospital mortality. Early corticosteroid treatment was associated with a significantly increased odds of subsequent bacteremia [adjusted odds ratio (95% CI) = 2.37 (1.01–5.56)]. The analyses using a propensity score-matched cohort showed consistent results.ConclusionsEarly corticosteroid treatment was associated with a significantly increased hospital mortality in adult patients with influenza-associated ARDS. Earlier treatment and higher dosing were associated with higher hospital mortality. Clinicians should be cautious while using corticosteroid treatment in this patient group.

Pathway mapping of leukocyte transcriptome in influenza patients reveals distinct pathogenic mechanisms associated with progression to severe infection

BackgroundInfluenza infections produce a spectrum of disease severity, ranging from a mild respiratory illness to respiratory failure and death. The host-response pathways associated with the progression to severe influenza disease are not well understood.MethodsTo gain insight into the disease mechanisms associated with progression to severe infection, we analyzed the leukocyte transcriptome in severe and moderate influenza patients and healthy control subjects. Pathway analysis on differentially expressed genes was performed using a topology-based pathway analysis tool that takes into account the interaction between multiple cellular pathways. The pathway profiles between moderate and severe influenza were then compared to delineate the biological mechanisms underpinning the progression from moderate to severe influenza.Results107 patients (44 severe and 63 moderate influenza patients) and 52 healthy control subjects were included in the study. Severe influenza was associated with upregulation in several neutrophil-related pathways, including pathways involved in neutrophil differentiation, migration, degranulation and neutrophil extracellular trap (NET) formation. The degree of upregulation in neutrophil-related pathways were significantly higher in severely infected patients compared to moderately infected patients. Severe influenza was also associated with downregulation in immune response pathways, including pathways involved in antigen presentation such as CD4+ T-cell co-stimulation, CD8+ T cell and Natural Killer (NK) cells effector functions. Apoptosis pathways were also downregulated in severe influenza patients compare to moderate and healthy controls.ConclusionsThese findings showed that there are changes in gene expression profile that may highlight distinct pathogenic mechanisms associated with progression from moderate to severe influenza infection.

Outcomes of patients with severe influenza infection admitted to intensive care units: a retrospective study in a medical centre.

This study assessed clinical manifestations and prognostic factors of critically ill patients with severe influenza admitted to the intensive care unit (ICU) in Taiwan's recent outbreak. Patients admitted to ICU for severe influenza between January 1, 2015, and March 31, 2016, were identified and their medical records were retrospectively reviewed. The primary endpoints were outcomes and predictors of in-hospital mortality. There were 125 patients with an average Acute Physiology and Chronic Health Evaluation II (APACHE II) score of 20.8. Hypertension (62.4 %) and diabetes mellitus (40.8 %) were the two most common underlying diseases. Ninety-eight (78.4 %) patients had at least one organ failure: the lungs were the most common (71.2 %), followed by the heart (53.6 %). Two of the most common symptoms of patients at ICU admission were fever (68.0 %) and cough (78.4 %). Thirty-three patients (26.4 %) died; most (40.9 %) were middle-aged (50-65 years old). A Cox regression analysis showed that multiple organ failure (MOF) [hazard ratio (HR)=3.618; 95 % CI=1.058-13.662] was significantly associated with higher risk of death. In contrast, a fluid-negative balance within 7 days of admission (HR=0.362; 95 % CI=0.140-0.934) was significantly associated with a lower risk of death. The mortality rate of severe influenza patients admitted to the ICU was high, especially in middle-aged adults. The risk of mortality was associated with ≥2 organ failures. A negative fluid balance predicts survival.

Higher mortality of severe influenza patients with probable aspergillosis than those with and without other coinfections.

Aspergillus-associated infection might comprise up to 23-29% of severe influenza patients from the community throughout stay in an intensive care unit (ICU). In Taiwan, cases of severe influenza with aspergillosis are increasingly reported. Therefore, we describe the relative risk of mortality among severe influenza patients with aspergillosis and other coinfections compared to severe influenza patients without Aspergillus coinfections. We retrospectively reviewed 124 adult patients with severe influenza in a tertiary medical center in southern Taiwan from January 2015 through March 2016. The definition of probable aspergillosis required abnormal radiological findings and positive Aspergillus galactomannan (GM) antigen and/or Aspergillus isolation. Probable aspergillosis (detected throughout the whole course) and other coinfections (only community-acquired) were diagnosed in 21 (17%) and 38 (31%) of all patients respectively. Klebsiella pneumoniae (36.8%), Pseudomonas aeruginosa (31.6%) and Staphylococcus aureus (31.6%) were the most frequent isolates of other coinfections. In-ICU mortality of Aspergillus group (66.7%) was significantly higher than other coinfections (23.7%, p=0.001) or control group without coinfections (15.4%, p<0.001), with significant odds ratios after adjusting for important variables. The factor of GM index ≥0.6 had a 19.82 (95% CI, 4.91 to 80.07, p<0.0001) odds of expiring in an ICU among the Aspergillus group. Dual Aspergillus and influenza infection is emerging in southern Taiwan. Meanwhile, community-acquired P. aeruginosa should be listed in the common copathogens with severe influenza. The 67% mortality linked to aspergillosis highlights the need for physicians to focus attention on patients with GM≥0.6.