Respiratory viruses: New frontiers-a Keystone Symposia report.

Respiratory viruses are a common cause of morbidity and mortality around the world. Viruses like influenza, RSV, and most recently SARS-CoV-2 can rapidly spread through a population, causing acute infection and, in vulnerable populations, severe or chronic disease. Developing effective treatment and prevention strategies often becomes a race against ever-evolving viruses that develop resistance, leaving therapy efficacy either short-lived or relevant for specific viral strains. On June 29 to July 2, 2022, researchers met for the Keystone symposium "Respiratory Viruses: New Frontiers." Researchers presented new insights into viral biology and virus-host interactions to understand the mechanisms of disease and identify novel treatment and prevention approaches that are effective, durable, and broad.

Induction of pulmonary HLA-G expression by SARS-CoV-2 infection.

The non-classical human leukocyte antigen (HLA)-G exerts immune-suppressive properties modulating both NK and T cell responses. While it is physiologically expressed at the maternal-fetal interface and in immune-privileged organs, HLA-G expression is found in tumors and in virus-infected cells. So far, there exists little information about the role of HLA-G and its interplay with immune cells in biopsies, surgical specimen or autopsy tissues of lung, kidney and/or heart muscle from SARS-CoV-2-infected patients compared to control tissues. Heterogeneous, but higher HLA-G protein expression levels were detected in lung alveolar epithelial cells of SARS-CoV-2-infected patients compared to lung epithelial cells from influenza-infected patients, but not in other organs or lung epithelia from non-viral-infected patients, which was not accompanied by high levels of SARS-CoV-2 nucleocapsid antigen and spike protein, but inversely correlated to the HLA-G-specific miRNA expression. High HLA-G expression levels not only in SARS-CoV-2-, but also in influenza-infected lung tissues were associated with a high frequency of tissue-infiltrating immune cells, but low numbers of CD8+ cells and an altered expression of hyperactivation and exhaustion markers in the lung epithelia combined with changes in the spatial distribution of macrophages and T cells. Thus, our data provide evidence for an involvement of HLA-G and HLA-G-specific miRNAs in immune escape and as suitable therapeutic targets for the treatment of SARS-CoV-2 infections.

3D Ex vivo tissue platforms to investigate the early phases of influenza a virus- and SARS-CoV-2-induced respiratory diseases.

Pandemic outbreaks of viruses such as influenza virus or SARS-CoV-2 are associated with high morbidity and mortality and thus pose a massive threat to global health and economics. Physiologically relevant models are needed to study the viral life cycle, describe the pathophysiological consequences of viral infection, and explore possible drug targets and treatment options. While simple cell culture-based models do not reflect the tissue environment and systemic responses, animal models are linked with huge direct and indirect costs and ethical questions. Ex vivo platforms based on tissue explants have been introduced as suitable platforms to bridge the gap between cell culture and animal models. We established a murine lung tissue explant platform for two respiratory viruses, influenza A virus (IAV) and SARS-CoV-2. We observed efficient viral replication, associated with the release of inflammatory cytokines and the induction of an antiviral interferon response, comparable to ex vivo infection in human lung explants. Endolysosomal entry could be confirmed as a potential host target for pharmacological intervention, and the potential repurposing potentials of fluoxetine and interferons for host-directed therapy previously seen in vitro could be recapitulated in the ex vivo model.

Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation.

COVID survivors frequently experience lingering neurological symptoms that resemble cancer-therapy-related cognitive impairment, a syndrome for which white matter microglial reactivity and consequent neural dysregulation is central. Here, we explored the neurobiological effects of respiratory SARS-CoV-2 infection and found white-matter-selective microglial reactivity in mice and humans. Following mild respiratory COVID in mice, persistently impaired hippocampal neurogenesis, decreased oligodendrocytes, and myelin loss were evident together with elevated CSF cytokines/chemokines including CCL11. Systemic CCL11 administration specifically caused hippocampal microglial reactivity and impaired neurogenesis. Concordantly, humans with lasting cognitive symptoms post-COVID exhibit elevated CCL11 levels. Compared with SARS-CoV-2, mild respiratory influenza in mice caused similar patterns of white-matter-selective microglial reactivity, oligodendrocyte loss, impaired neurogenesis, and elevated CCL11 at early time points, but after influenza, only elevated CCL11 and hippocampal pathology persisted. These findings illustrate similar neuropathophysiology after cancer therapy and respiratory SARS-CoV-2 infection which may contribute to cognitive impairment following even mild COVID.

Bilateral Avid Axillary Nodes on FDG PET/CT Due to Concurrent Booster COVID-19 Immunization and Seasonal Influenza Vaccination.

ABSTRACT: In an attempt to protect the high-risk demographic and reduce burden on health care systems, concomitant administration of COVID-19 and influenza vaccines has been recommended by health bodies. The ComFluCOV trial indicates this is well tolerated with no reduction in immune response to either vaccine. A 48-year-old woman with right oropharyngeal squamous cell carcinoma underwent postradiotherapy FDG PET/CT, which demonstrated complete metabolic response. Incidental avid bilateral axillary lymphadenopathy of benign configuration was noted and concluded to be reactive in response to recent Pfizer-BioNTech booster and influenza vaccination. This is expected to be seen more frequently over the coming months.

COVID-19 and obesity: the confrontation of two pandemics.

In 2009, obesity was identified for the first time as a risk factor for increased disease severity and mortality in patients infected with the H1N1 influenza A virus. During the current COVID-19 pandemic, overweight and obesity have been described as independent risk factors of disease severity and mortality due to COVID-19. Excess visceral fat is associated with systemic chronic microinflammation, changes in adipokine release, and oxidative stress. These disturbances result in an impaired immune response, including dysfunction in lymphocyte action and antibody production. Moreover, obesity is a cause of endothelial dysfunction, pro-coagulation state, and enhanced expression of angiotensin-converting enzyme 2 (ACE-2), which contributes to the infection itself and the severity of the disease. We analyzed both the impact of obesity on the severity of COVID-19 and the potential mechanism that influences this severity. Moreover, we discuss the effect of obesity complications on the severity of disease and mortality of patients with COVID-19. Furthermore, we summarize the effectiveness of COVID-19 vaccination in patients with obesity. Finally, we analyzed the effect of the COVID-19 pandemic on mood disturbances and emotional eating and, as a consequence, the development of obesity or an increase in its severity. In summary, the studies conducted during the COVID-19 pandemic indicate that effective obesity treatment should be initiated at once. In addition, the data confirm the need to organize efficient obesity treatment systems for the sake of not only the individual but also society.

System-wide transcriptome damage and tissue identity loss in COVID-19 patients.

The molecular mechanisms underlying the clinical manifestations of coronavirus disease 2019 (COVID-19), and what distinguishes them from common seasonal influenza virus and other lung injury states such as acute respiratory distress syndrome, remain poorly understood. To address these challenges, we combine transcriptional profiling of 646 clinical nasopharyngeal swabs and 39 patient autopsy tissues to define body-wide transcriptome changes in response to COVID-19. We then match these data with spatial protein and expression profiling across 357 tissue sections from 16 representative patient lung samples and identify tissue-compartment-specific damage wrought by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, evident as a function of varying viral loads during the clinical course of infection and tissue-type-specific expression states. Overall, our findings reveal a systemic disruption of canonical cellular and transcriptional pathways across all tissues, which can inform subsequent studies to combat the mortality of COVID-19 and to better understand the molecular dynamics of lethal SARS-CoV-2 and other respiratory infections.

Greasing the inflammatory pathogenesis of viral pneumonias in diabetes.

Type 2 diabetes (T2D) and obesity are independent risk factors for increased morbidity and mortality associated with influenza and SARS-CoV-2 infection. Skewed cellular metabolism shapes immune cell inflammatory responsiveness and function in obesity, T2D, and infection. However, altered immune cell responsiveness and levels of systemic proinflammatory mediators, partly independent of peripheral immune cell contribution, are linked with SARS-CoV-2-associated disease severity. Despite such knowledge, the role of tissue parenchymal cell-driven inflammatory responses, and specifically those dominantly modified in obesity (e.g., adipocytes), in influenza and SARS-CoV-2 infection pathogenesis remain poorly defined. Whether obesity-dependent skewing of adipocyte cellular metabolism uncovers inflammatory clades and promotes the existence of a 'pathogenic-inflammatory' adipocyte phenotype that amplifies SARS-CoV-2 infection diseases severity in individuals with obesity and individuals with obesity and T2D has not been examined. Here, using the knowledge gained from studies of immune cell responses in obesity, T2D, and infection, we highlight the key knowledge gaps underlying adipocyte cellular functions that may sculpt and grease pathogenic processes associated with influenza and SARS-CoV-2 disease severity in diabetes.

COVID-19: Immunohistochemical Analysis of TGF-ß Signaling Pathways in Pulmonary Fibrosis.

Acute respiratory distress syndrome (ARDS) followed by repair with lung remodeling is observed in COVID-19. These findings can lead to pulmonary terminal fibrosis, a form of irreversible sequelae. There is evidence that TGF-ß is intimately involved in the fibrogenic process. When activated, TGF-ß promotes the differentiation of fibroblasts into myofibroblasts and regulates the remodeling of the extracellular matrix (ECM). In this sense, the present study evaluated the histopathological features and immunohistochemical biomarkers (ACE-2, AKT-1, Caveolin-1, CD44v6, IL-4, MMP-9, α-SMA, Sphingosine-1, and TGF-ß1 tissue expression) involved in the TGF-ß1 signaling pathways and pulmonary fibrosis. The study consisted of 24 paraffin lung samples from patients who died of COVID-19 (COVID-19 group), compared to 10 lung samples from patients who died of H1N1pdm09 (H1N1 group) and 11 lung samples from patients who died of different causes, with no lung injury (CONTROL group). In addition to the presence of alveolar septal fibrosis, diffuse alveolar damage (DAD) was found to be significantly increased in the COVID-19 group, associated with a higher density of Collagen I (mature) and III (immature). There was also a significant increase observed in the immunoexpression of tissue biomarkers ACE-2, AKT-1, CD44v6, IL-4, MMP-9, α-SMA, Sphingosine-1, and TGF-ß1 in the COVID-19 group. A significantly lower expression of Caveolin-1 was also found in this group. The results suggest the participation of TGF-ß pathways in the development process of pulmonary fibrosis. Thus, it would be plausible to consider therapy with TGF-ß inhibitors in those patients recovered from COVID-19 to mitigate a possible development of pulmonary fibrosis and its consequences for post-COVID-19 life quality.

No evidence of SARS-CoV-2 in hospitalized patients with severe acute respiratory syndrome in five Italian hospitals from 1st November 2019 to 29th February 2020.

BACKGROUND: On 9th January 2020, China CDC reported a novel coronavirus (later named SARS-CoV-2) as the causative agent of the coronavirus disease 2019 (COVID-19). Identifying the first appearance of virus is of epidemiological importance to tracking and mapping the spread of SARS-CoV-2 in a country. We therefore conducted a retrospective observational study to detect SARS-CoV-2 in oropharyngeal samples collected from hospitalized patients with a Severe Acute Respiratory Infection (SARI) enrolled in the DRIVE (Development of Robust and Innovative Vaccine Effectiveness) study in five Italian hospitals (CIRI-IT BIVE hospitals network) (1st November 2019 - 29th February 2020). OBJECTIVES: To acquire new information on the real trend in SARS-CoV-2 infection during pandemic phase I and to determine the possible early appearance of the virus in Italy. MATERIALS AND METHODS: Samples were tested for influenza [RT-PCR assay (A/H1N1, A/H3N2, B/Yam, B/Vic)] in accordance with the DRIVE study protocol. Subsequently, swabs underwent molecular testing for SARS-COV-2. [one-step real-time multiplex retro-transcription (RT) PCR]. RESULTS: In the 1683 samples collected, no evidence of SARS-CoV-2 was found. Moreover, 28.3% (477/1683) of swabs were positive for influenza viruses, the majority being type A (358 vs 119 type B). A/H3N2 was predominant among influenza A viruses (55%); among influenza B viruses, B/Victoria was prevalent. The highest influenza incidence rate was reported in patients aged 0-17 years (40.3%) followed by those aged 18-64 years (24.4%) and ≥65 years (14.8%). CONCLUSIONS: In Italy, some studies have shown the early circulation of SARS-CoV-2 in northern regions, those most severely affected during phase I of the pandemic. In central and southern regions, by contrast no early circulation of the virus was registered. These results are in line with ours. These findings highlight the need to continue to carry out retrospective studies, in order to understand the epidemiology of the novel coronavirus, to better identify the clinical characteristics of COVID-19 in comparison with other acute respiratory illnesses (ARI), and to evaluate the real burden of COVID-19 on the healthcare system.

IFP35 as a promising biomarker and therapeutic target for the syndromes induced by SARS-CoV-2 or influenza virus.

Previous studies have shown that the high mortality caused by viruses such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza virus primarily results from complications of a cytokine storm. Therefore, it is critical to identify the key factors participating in the cytokine storm. Here we demonstrate that interferon-induced protein 35 (IFP35) plays an important role in the cytokine storm induced by SARS-CoV-2 and influenza virus infection. We find that the levels of serum IFP35 in individuals with SARS-CoV-2 correlates with severity of the syndrome. Using mouse model and cell assays, we show that IFP35 is released by lung epithelial cells and macrophages after SARS-CoV-2 or influenza virus infection. In addition, we show that administration of neutralizing antibodies against IFP35 considerably reduces lung injury and, thus, the mortality rate of mice exposed to viral infection. Our findings suggest that IFP35 serves as a biomarker and as a therapeutic target in virus-induced syndromes.

Comparison of clinical and biochemical features of hospitalized COVID-19 and influenza pneumonia patients.

Both severe acute respiratory syndrome coronavirus 2 and influenza viruses cause similar clinical presentations. It is essential to assess severely ill patients presenting with a viral syndrome for diagnostic and prognostic purposes. We aimed to compare clinical and biochemical features between pneumonia patients with coronavirus disease 2019 (COVID-19) and H1N1. Sixty patients diagnosed with COVID-19 pneumonia and 61 patients diagnosed with influenza pneumonia were hospitalized between October 2020-January 2021 and October 2017-December 2019, respectively. All the clinical data and laboratory results, chest computed tomography scans, intensive care unit admission, invasive mechanical ventilation, and outcomes were retrospectively evaluated. The median age was 65 (range 32-96) years for patients with a COVID-19 diagnosis and 58 (range 18-83) years for patients with influenza (p = 0.002). The comorbidity index was significantly higher in patients with COVID-19 (p = 0.010). Diabetes mellitus and hypertension were statistically significantly more common in patients with COVID-19 (p = 0.019, p = 0.008, respectively). The distribution of severe disease and mortality was not significantly different among patients with COVID-19 than influenza patients (p = 0.096, p = 0.049).). In comparison with inflammation markers; C-reactive protein (CRP) levels were significantly higher in influenza patients than patients with COVID-19 (p = 0.033). The presence of sputum was predictive for influenza (odds ratio [OR] 0.342 [95% confidence interval [CI], 2.1.130-0.899]). CRP and platelet were also predictive for COVID-19 (OR 4.764 [95% CI, 1.003-1.012] and OR 0.991 [95% CI 0.984-0.998], respectively. We conclude that sputum symptoms by itself are much more detected in influenza patients. Besides that, lower CRP and higher PLT count would be discriminative for COVID-19.

Atypical response to bacterial coinfection and persistent neutrophilic bronchoalveolar inflammation distinguish critical COVID-19 from influenza.

Neutrophils are recognized as important circulating effector cells in the pathophysiology of severe coronavirus disease 2019 (COVID-19). However, their role within the inflamed lungs is incompletely understood. Here, we collected bronchoalveolar lavage (BAL) fluids and parallel blood samples of critically ill COVID-19 patients requiring invasive mechanical ventilation and compared BAL fluid parameters with those of mechanically ventilated patients with influenza, as a non-COVID-19 viral pneumonia cohort. Compared with those of patients with influenza, BAL fluids of patients with COVID-19 contained increased numbers of hyperactivated degranulating neutrophils and elevated concentrations of the cytokines IL-1ß, IL-1RA, IL-17A, TNF-α, and G-CSF; the chemokines CCL7, CXCL1, CXCL8, CXCL11, and CXCL12α; and the protease inhibitors elafin, secretory leukocyte protease inhibitor, and tissue inhibitor of metalloproteinases 1. In contrast, α-1 antitrypsin levels and net proteolytic activity were comparable in COVID-19 and influenza BAL fluids. During antibiotic treatment for bacterial coinfections, increased BAL fluid levels of several activating and chemotactic factors for monocytes, lymphocytes, and NK cells were detected in patients with COVID-19 whereas concentrations tended to decrease in patients with influenza, highlighting the persistent immunological response to coinfections in COVID-19. Finally, the high proteolytic activity in COVID-19 lungs suggests considering protease inhibitors as a treatment option.

Prognostic value of neutrophil-to-lymphocyte ratio in COVID-19 compared with Influenza and respiratory syncytial virus infection.

A high neutrophil to lymphocyte ratio (NLR) is considered an unfavorable prognostic factor in various diseases, including COVID-19. The prognostic value of NLR in other respiratory viral infections, such as Influenza, has not hitherto been extensively studied. We aimed to compare the prognostic value of NLR in COVID-19, Influenza and Respiratory Syncytial Virus infection (RSV). A retrospective cohort of COVID-19, Influenza and RSV patients admitted to the Tel Aviv Medical Center from January 2010 to October 2020 was analyzed. Laboratory, demographic, and clinical parameters were collected. Two way analyses of variance (ANOVA) was used to compare the association between NLR values and poor outcomes among the three groups. ROC curve analyses for each virus was applied to test the discrimination ability of NLR. 722 COVID-19, 2213 influenza and 482 RSV patients were included. Above the age of 50, NLR at admission was significantly lower among COVID-19 patients (P < 0.001). NLR was associated with poor clinical outcome only in the COVID-19 group. ROC curve analysis was performed; the area under curve of poor outcomes for COVID-19 was 0.68, compared with 0.57 and 0.58 for Influenza and RSV respectively. In the COVID-19 group, multivariate logistic regression identified a high NLR (defined as a value above 6.82) to be a prognostic factor for poor clinical outcome, after adjusting for age, sex and Charlson comorbidity score (odds ratio of 2.9, P < 0.001). NLR at admission is lower and has more prognostic value in COVID-19 patients, when compared to Influenza and RSV.

Differentiating coronavirus disease 2019 (COVID-19) from influenza and dengue.

The novel coronavirus disease 2019 (COVID-19) presents with non-specific clinical features. This may result in misdiagnosis or delayed diagnosis, and lead to further transmission in the community. We aimed to derive early predictors to differentiate COVID-19 from influenza and dengue. The study comprised 126 patients with COVID-19, 171 with influenza and 180 with dengue, who presented within 5 days of symptom onset. All cases were confirmed by reverse transcriptase polymerase chain reaction tests. We used logistic regression models to identify demographics, clinical characteristics and laboratory markers in classifying COVID-19 versus influenza, and COVID-19 versus dengue. The performance of each model was evaluated using receiver operating characteristic (ROC) curves. Shortness of breath was the strongest predictor in the models for differentiating between COVID-19 and influenza, followed by diarrhoea. Higher lymphocyte count was predictive of COVID-19 versus influenza and versus dengue. In the model for differentiating between COVID-19 and dengue, patients with cough and higher platelet count were at increased odds of COVID-19, while headache, joint pain, skin rash and vomiting/nausea were indicative of dengue. The cross-validated area under the ROC curve for all four models was above 0.85. Clinical features and simple laboratory markers for differentiating COVID-19 from influenza and dengue are identified in this study which can be used by primary care physicians in resource limited settings to determine if further investigations or referrals would be required.

Effects of human immunodeficiency virus status on symptom severity in influenza-like illness in an otherwise healthy adult outpatient cohort.

The impact of HIV on influenza-like illness (ILI) has been incompletely described in the era of combination antiretroviral therapy, particularly in the post-H1N1 pandemic period. This analysis informs on ILI in an otherwise healthy, predominantly outpatient cohort of adults with HIV in the USA. From September 2010 to March 2015, this multisite observational cohort study enrolled otherwise healthy adults presenting to a participating US military medical center with ILI, a subset of whom were HIV positive. Demographics, clinical data, and self-reported symptom severity were ascertained, and enrollees completed a daily symptom diary for up to 10 days. 510 men were included in the analysis; 50 (9.8%) were HIV positive. Subjects with HIV were older and less likely to be on active duty. Rhinovirus and influenza A were the most commonly identified pathogens. Moderate-severe diarrhea (p<0.001) and fatigue (p=0.01) were more frequently reported by HIV-positive men. HIV positivity was associated with higher gastrointestinal scores, but not other measures of ILI symptom severity, after controlling for age, race, military status, and influenza season. Few were hospitalized. HIV-positive subjects had more influenza B (p=0.04) and were more likely to receive antivirals (32% vs 6%, p<0.01). Antiviral use was not significantly associated with symptom scores when accounting for potential confounders. In this predominantly outpatient cohort of adult men, HIV had minimal impact on ILI symptom severity. Despite similar illness severity, a higher percentage of subjects with HIV reported undergoing antiviral treatment for ILI, likely reflecting differences in prescribing practices.Trial registration number: NCT01021098.

Adipocyte inflammation and pathogenesis of viral pneumonias: an overlooked contribution.

Epidemiological evidence establishes obesity as an independent risk factor for increased susceptibility and severity to viral respiratory pneumonias associated with H1N1 influenza and SARS-CoV-2 pandemics. Given the global obesity prevalence, a better understanding of the mechanisms behind obese susceptibility to infection is imperative. Altered immune cell metabolism and function are often perceived as a key causative factor of dysregulated inflammation. However, the contribution of adipocytes, the dominantly altered cell type in obesity with broad inflammatory properties, to infectious disease pathogenesis remains largely ignored. Thus, skewing of adipocyte-intrinsic cellular metabolism may lead to the development of pathogenic inflammatory adipocytes, which shape the overall immune responses by contributing to either premature immunosenescence, delayed hyperinflammation, or cytokine storm in infections. In this review, we discuss the underappreciated contribution of adipocyte cellular metabolism and adipocyte-produced mediators on immune system modulation and how such interplay may modify disease susceptibility and pathogenesis of influenza and SARS-CoV-2 infections in obese individuals.

Interleukin-13: A pivotal target against influenza-induced exacerbation of chronic lung diseases.

Non-communicable, chronic respiratory diseases (CRDs) affect millions of individuals worldwide. The course of these CRDs (asthma, chronic obstructive pulmonary disease, and cystic fibrosis) are often punctuated by microbial infections that may result in hospitalization and are associated with increased risk of morbidity and mortality, as well as reduced quality of life. Interleukin-13 (IL-13) is a key protein that regulates airway inflammation and mucus hypersecretion. There has been much interest in IL-13 from the last two decades. This cytokine is believed to play a decisive role in the exacerbation of inflammation during the course of viral infections, especially, in those with pre-existing CRDs. Here, we discuss the common viral infections in CRDs, as well as the potential role that IL-13 plays in the virus-induced disease pathogenesis of CRDs. We also discuss, in detail, the immune-modulation potential of IL-13 that could be translated to in-depth studies to develop IL-13-based therapeutic entities.

Cytokine/Chemokine Expression Is Closely Associated Disease Severity of Human Adenovirus Infections in Immunocompetent Adults and Predicts Disease Progression.

Increasing human Adenovirus (HAdV) infections complicated with acute respiratory distress syndrome (ARDS) even fatal outcome were reported in immunocompetent adolescent and adult patients. Here, we characterized the cytokine/chemokine expression profiles of immunocompetent patients complicated with ARDS during HAdV infection and identified biomarkers for disease severity/progression. Forty-eight cytokines/chemokines in the plasma samples from 19 HAdV-infected immunocompetent adolescent and adult patients (ten complicated with ARDS) were measured and analyzed in combination with clinical indices. Immunocompetent patients with ARDS caused by severe acute respiratory disease coronavirus (SARS-CoV)-2, 2009 pandemic H1N1 (panH1N1) or bacteria were included for comparative analyses. Similar indices of disease course/progression were found in immunocompetent patients with ARDS caused by HAdV, SARS-CoV-2 or panH1N infections, whereas the HAdV-infected group showed a higher prevalence of viremia, as well as increased levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and creatine kinase (CK). Expression levels of 33 cytokines/chemokines were increased significantly in HAdV-infected patients with ARDS compared with that in healthy controls, and many of them were also significantly higher than those in SARS-CoV-2-infected and panH1N1-infected patients. Expression of interferon (IFN)-γ, interleukin (IL)-1ß, hepatocyte growth factor (HGF), monokine induced by IFN-γ (MIG), IL-6, macrophage-colony stimulating factor (M-CSF), IL-10, IL-1α and IL-2Ra was significantly higher in HAdV-infected patients with ARDS than that in those without ARDS, and negatively associated with the ratio of the partial pressure of oxygen in arterial blood/fraction of inspired oxygen (PaO2/FiO2). Analyses of the receiver operating characteristic curve (ROC) showed that expression of IL-10, M-CSF, MIG, HGF, IL-1ß, IFN-γ and IL-2Ra could predict the progression of HAdV infection, with the highest area under the curve (AUC) of 0.944 obtained for IL-10. Of note, the AUC value for the combination of IL-10, IFN-γ, and M-CSF reached 1. In conclusion, the "cytokine storm" occurred during HAdV infection in immunocompetent patients, and expression of IL-10, M-CSF, MIG, HGF, IL-1ß, IFN-γ and IL-2Ra was closely associated with disease severity and could predict disease progression.

Influenza co-infection associated with severity and mortality in COVID-19 patients.

BACKGROUND: In COVID-19 patients, undetected co-infections may have severe clinical implications associated with increased hospitalization, varied treatment approaches and mortality. Therefore, we investigated the implications of viral and bacterial co-infection in COVID-19 clinical outcomes. METHODS: Nasopharyngeal samples were obtained from 48 COVID-19 patients (29% ICU and 71% non-ICU) and screened for the presence of 24 respiratory pathogens using six multiplex PCR panels. RESULTS: We found evidence of co-infection in 34 COVID-19 patients (71%). Influenza A H1N1 (n = 17), Chlamydia pneumoniae (n = 13) and human adenovirus (n = 10) were the most commonly detected pathogens. Viral co-infection was associated with increased ICU admission (r = 0.1) and higher mortality (OR 1.78, CI = 0.38-8.28) compared to bacterial co-infections (OR 0.44, CI = 0.08-2.45). Two thirds of COVID-19 critically ill patients who died, had a co-infection; and Influenza A H1N1 was the only pathogen for which a direct relationship with mortality was seen (r = 0.2). CONCLUSIONS: Our study highlights the importance of screening for co-infecting viruses in COVID-19 patients, that could be the leading cause of disease severity and death. Given the high prevalence of Influenza co-infection in our study, increased coverage of flu vaccination is encouraged to mitigate the transmission of influenza virus during the on-going COVID-19 pandemic and reduce the risk of severe outcome and mortality.