Fc-optimized antibodies elicit CD8 immunity to viral respiratory infection.

Antibodies against viral pathogens represent promising therapeutic agents for the control of infection, and their antiviral efficacy has been shown to require the coordinated function of both the Fab and Fc domains1. The Fc domain engages a wide spectrum of receptors on discrete cells of the immune system to trigger the clearance of viruses and subsequent killing of infected cells1-4. Here we report that Fc engineering of anti-influenza IgG monoclonal antibodies for selective binding to the activating Fcγ receptor FcγRIIa results in enhanced ability to prevent or treat lethal viral respiratory infection in mice, with increased maturation of dendritic cells and the induction of protective CD8+ T cell responses. These findings highlight the capacity for IgG antibodies to induce protective adaptive immunity to viral infection when they selectively activate a dendritic cell and T cell pathway, with important implications for the development of therapeutic antibodies with improved antiviral efficacy against viral respiratory pathogens.

Mortality Rates of the Spanish Flu and Coronavirus Disease 2019 in the Netherlands: A Historical Comparison.

The coronavirus disease 2019 (COVID-19) pandemic has been called the deadliest disease event in history. In this study, we compared the cause-specific mortality rate of the Spanish flu (1918-1920) with that of COVID-19 (2020-2022) in the Netherlands. During the periods of exposure, about 50 000 people died of COVID-19 and 32 000 people of the Spanish flu. In absolute numbers, COVID-19 seems to be deadlier than Spanish flu. However, the crude mortality rates for COVID-19 and Spanish flu were 287 and 486 per 100 000 inhabitants, respectively. Comparing age-standardized mortality rates, there would have been 28 COVID-19- and 194 Spanish flu-related deaths in 1918-1920, or 214 Spanish flu- and 98 COVID-19-related deaths in 2020-2022 per 100 000 inhabitants per year. Thus, taking the population differences into account, the Spanish flu would have been deadlier than COVID-19.

Association between influenza vaccination and one-year all-cause and cardiovascular mortality risk: A self-controlled case series and matched case-control study.

Debates surrounding the efficacy of influenza vaccination for survival benefits persist, and there is a lack of data regarding its duration of protection. A self-controlled case series (SCCS) and a 1:4 matched case-control study were conducted using the National Health Interview Survey (NHIS) and public-use mortality data from 2005 to 2018 in the United States. The SCCS study identified participants who received influenza vaccination within 12 months before the survey and subsequently died within 1 year of postvaccination. The matched case-control study paired participants who died during the influenza season at the time of survey with four survivors. Among 1167 participants in the SCCS study, there was a 46% reduction in all-cause mortality and a 43% reduction in cardiovascular mortality within 29-196 days of postvaccination. The greatest protection was observed during days 29-56 (all-cause mortality: RI: 0.19; 95% CI: 0.12-0.29; cardiovascular mortality: RI: 0.28; 95% CI: 0.14-0.56). Among 626 cases and 2504 controls included in the matched case-control study, influenza vaccination was associated with a reduction in all-cause mortality (OR: 0.74, 95% CI: 0.60-0.92) and cardiovascular mortality (OR: 0.64, 95% CI: 0.44-0.93) during the influenza season. This study highlights the importance of influenza vaccination in reducing the risks of all-cause and cardiovascular mortality, with effects lasting for approximately 6 months.

The Hospital Burden of Flu in Italy: a retrospective study on administrative data from season 2014-2015 to 2018-2019.

BACKGROUND: Every year in Italy, influenza affects about 4 million people. Almost 5% of them are hospitalised. During peak illness, enormous pressure is placed on healthcare and economic systems. This study aims to quantify the clinical and economic burden of severe influenza during 5 epidemic seasons (2014-2019) from administrative claims data. METHODS: Patients hospitalized with a diagnosis of influenza between October 2014, and April 2019, were analyzed. Clinical characteristics and administrative information were retrieved from health-related Administrative Databases (ADs) of 4 Italian Local Health Units (LHUs). The date of first admission was set as the Index Date (ID). A follow-up period of six months after ID was considered to account for complications and re-hospitalizations, while a lookback period (2 years before ID) was set to assess the prevalence of underlying comorbidities. RESULTS: Out of 2,333 patients with severe influenza, 44.1% were adults ≥ 65, and 25.6% young individuals aged 0-17. 46.8% had comorbidities (i.e., were at risk), mainly cardiovascular and metabolic diseases (45.3%), and chronic conditions (24.7%). The highest hospitalization rates were among the elderly (≥ 75) and the young individuals (0-17), and were 37.6 and 19.5/100,000 inhabitants/year, respectively. The average hospital stay was 8 days (IQR: 14 - 4). It was higher for older individuals (≥ 65 years, 11 days, [17 - 6]) and for those with comorbidities (9 days, [16 - 6]), p-value < 0.001. Similarly, mortality was higher in elderly and those at risk (p-value < 0.001). Respiratory complications occurred in 12.7% of patients, and cardiovascular disorders in 5.9%. Total influenza-related costs were €9.7 million with hospitalization accounting for 95% of them. 47.3% of hospitalization costs were associated with individuals ≥ 65 and 52.9% with patients at risk. The average hospitalisation cost per patient was € 4,007. CONCLUSIONS: This retrospective study showed that during the 2014-2019 influenza seasons in Italy, individuals of extreme ages and those with pre-existing medical conditions, were more likely to be hospitalized with severe influenza. Together with complications and ageing, they worsen patient's outcome and may lead to a prolonged hospitalization, thus increasing healthcare utilization and costs. Our data generate real-world evidence on the burden of influenza, useful to inform public health decision-making.

A Pathology-based Case Series of Influenza- and COVID-19-associated Pulmonary Aspergillosis: The Proof Is in the Tissue.

Rationale: Invasive pulmonary aspergillosis has emerged as a frequent coinfection in severe coronavirus disease (COVID-19), similarly to influenza, yet the clinical invasiveness is more debated. Objectives: We investigated the invasive nature of pulmonary aspergillosis in histology specimens of influenza and COVID-19 ICU fatalities in a tertiary care center. Methods: In this monocentric, descriptive, retrospective case series, we included adult ICU patients with PCR-proven influenza/COVID-19 respiratory failure who underwent postmortem examination and/or tracheobronchial biopsy during ICU admission from September 2009 until June 2021. Diagnosis of probable/proven viral-associated pulmonary aspergillosis (VAPA) was made based on the Intensive Care Medicine influenza-associated pulmonary aspergillosis and the European Confederation of Medical Mycology (ECMM) and the International Society for Human and Animal Mycology (ISHAM) COVID-19-associated pulmonary aspergillosis consensus criteria. All respiratory tissues were independently reviewed by two experienced pathologists. Measurements and Main Results: In the 44 patients of the autopsy-verified cohort, 6 proven influenza-associated and 6 proven COVID-19-associated pulmonary aspergillosis diagnoses were identified. Fungal disease was identified as a missed diagnosis upon autopsy in 8% of proven cases (n = 1/12), yet it was most frequently found as confirmation of a probable antemortem diagnosis (n = 11/21, 52%) despite receiving antifungal treatment. Bronchoalveolar lavage galactomannan testing showed the highest sensitivity for VAPA diagnosis. Among both viral entities, an impeded fungal growth was the predominant histologic pattern of pulmonary aspergillosis. Fungal tracheobronchitis was histologically indistinguishable in influenza (n = 3) and COVID-19 (n = 3) cases, yet macroscopically more extensive at bronchoscopy in influenza setting. Conclusions: A proven invasive pulmonary aspergillosis diagnosis was found regularly and with a similar histological pattern in influenza and in COVID-19 ICU case fatalities. Our findings highlight an important need for VAPA awareness, with an emphasis on mycological bronchoscopic work-up.

Effect of a Structured Multilevel Telehealth Service on Hospital Admissions and Mortality During COVID-19 in a Resource-Limited Region in Brazil: Retrospective Cohort Study.

BACKGROUND: The COVID-19 pandemic represented a great stimulus for the adoption of telehealth and many initiatives in this field have emerged worldwide. However, despite this massive growth, data addressing the effectiveness of telehealth with respect to clinical outcomes remain scarce. OBJECTIVE: The aim of this study was to evaluate the impact of the adoption of a structured multilevel telehealth service on hospital admissions during the acute illness course and the mortality of adult patients with flu syndrome in the context of the COVID-19 pandemic. METHODS: A retrospective cohort study was performed in two Brazilian cities where a public COVID-19 telehealth service (TeleCOVID-MG) was deployed. TeleCOVID-MG was a structured multilevel telehealth service, including (1) first response and risk stratification through a chatbot software or phone call center, (2) teleconsultations with nurses and medical doctors, and (3) a telemonitoring system. For this analysis, we included data of adult patients registered in the Flu Syndrome notification databases who were diagnosed with flu syndrome between June 1, 2020, and May 31, 2021. The exposed group comprised patients with flu syndrome who used TeleCOVID-MG at least once during the illness course and the control group comprised patients who did not use this telehealth service during the respiratory illness course. Sociodemographic characteristics, comorbidities, and clinical outcomes data were extracted from the Brazilian official databases for flu syndrome, Severe Acute Respiratory Syndrome (due to any respiratory virus), and mortality. Models for the clinical outcomes were estimated by logistic regression. RESULTS: The final study population comprised 82,182 adult patients with a valid registry in the Flu Syndrome notification system. When compared to patients who did not use the service (n=67,689, 82.4%), patients supported by TeleCOVID-MG (n=14,493, 17.6%) had a lower chance of hospitalization during the acute respiratory illness course, even after adjusting for sociodemographic characteristics and underlying medical conditions (odds ratio [OR] 0.82, 95% CI 0.71-0.94; P=.005). No difference in mortality was observed between groups (OR 0.99, 95% CI 0.86-1.12; P=.83). CONCLUSIONS: A telehealth service applied on a large scale in a limited-resource region to tackle COVID-19 was related to reduced hospitalizations without increasing the mortality rate. Quality health care using inexpensive and readily available telehealth and digital health tools may be delivered in areas with limited resources and should be considered as a potential and valuable health care strategy. The success of a telehealth initiative relies on a partnership between the involved stakeholders to define the roles and responsibilities; set an alignment between the different modalities and levels of health care; and address the usual drawbacks related to the implementation process, such as infrastructure and accessibility issues.

Beyond the sine wave: unveiling climate-driven baseline mortality cycles.

The relationship between temperature and mortality is well-established, with higher mortality rates occurring in moderate climates during winter. Studies on COVID-19 and influenza-related excess deaths often assume a sine-like wave pattern for baseline mortality. This study aims to assess the accuracy of this approximation in capturing the observed mortality pattern and explore its linkage with climate. Weekly mortality data from European regions (2000-2019) were modeled using the seasonal-trend decomposition procedure based on Loess. Cycles were grouped into clusters, and underlying trends were extracted using principal component analysis. Generalized linear models assuming a sine-like pattern were used to test predictive value. Cluster analysis divided the regional cycles approximately into continental and temperate climate regions, further subdivided into oceanic and Mediterranean. While the continental region exhibited a sine-like mortality pattern, it displayed modest deviations that compounded further south. The period of elevated winter mortality became shorter but more intense, while decreased summer mortality became more pronounced yet delayed. This study improves weekly estimations of excess mortality models by providing enhanced baselines. The deviation from the sine-like approximation mirrors the idealized outbreak pattern from epidemiological models with sharper surges and more gradual declines. The results point to winter infections, impacted by acquired immunity and weather conditions, as the primary drivers of fluctuations in mortality. In warmer regions, there is an apparent shift toward a lower number of overall infections within a compressed time span.

Low-Dose Corticosteroids for Critically Ill Adults With Severe Pulmonary Infections: A Review.

Importance: Severe pulmonary infections, including COVID-19, community-acquired pneumonia, influenza, and Pneumocystis pneumonia, are a leading cause of death among adults worldwide. Pulmonary infections in critically ill patients may cause septic shock, acute respiratory distress syndrome, or both, which are associated with mortality rates ranging between 30% and 50%. Observations: Corticosteroids mitigate the immune response to infection and improve outcomes for patients with several types of severe pulmonary infections. Low-dose corticosteroids, defined as less than or equal to 400 mg hydrocortisone equivalent daily, can reduce mortality of patients with severe COVID-19, community-acquired pneumonia, and Pneumocystis pneumonia. A randomized clinical trial of 6425 patients hospitalized with COVID-19 who required supplemental oxygen or noninvasive or invasive mechanical ventilation reported that dexamethasone 6 mg daily for 10 days decreased 28-day mortality (23% vs 26%). A meta-analysis that included 7 randomized clinical trials of 1689 patients treated in the intensive care unit for severe bacterial community-acquired pneumonia reported that hydrocortisone equivalent less than or equal to 400 mg daily for 8 days or fewer was associated with lower 30-day mortality compared with placebo (10% vs 16%). In a meta-analysis of 6 randomized clinical trials, low-dose corticosteroids were associated with lower mortality rates compared with placebo for patients with HIV and moderate to severe Pneumocystis pneumonia (13% vs 25%). In a predefined subgroup analysis of a trial of low-dose steroid treatment for septic shock, patients with community-acquired pneumonia randomized to 7 days of intravenous hydrocortisone 50 mg every 6 hours and fludrocortisone 50 µg daily had decreased mortality compared with the placebo group (39% vs 51%). For patients with acute respiratory distress syndrome caused by various conditions, low-dose corticosteroids were associated with decreased in-hospital mortality (34% vs 45%) according to a meta-analysis of 8 studies that included 1091 patients. Adverse effects of low-dose corticosteroids may include hyperglycemia, gastrointestinal bleeding, neuropsychiatric disorders, muscle weakness, hypernatremia, and secondary infections. Conclusions and Relevance: Treatment with low-dose corticosteroids is associated with decreased mortality for patients with severe COVID-19 infection, severe community-acquired bacterial pneumonia, and moderate to severe Pneumocystis pneumonia (for patients with HIV). Low-dose corticosteroids may also benefit critically ill patients with respiratory infections who have septic shock, acute respiratory distress syndrome, or both.

Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19.

BACKGROUND: Progressive respiratory failure is the primary cause of death in the coronavirus disease 2019 (Covid-19) pandemic. Despite widespread interest in the pathophysiology of the disease, relatively little is known about the associated morphologic and molecular changes in the peripheral lung of patients who die from Covid-19. METHODS: We examined 7 lungs obtained during autopsy from patients who died from Covid-19 and compared them with 7 lungs obtained during autopsy from patients who died from acute respiratory distress syndrome (ARDS) secondary to influenza A(H1N1) infection and 10 age-matched, uninfected control lungs. The lungs were studied with the use of seven-color immunohistochemical analysis, micro-computed tomographic imaging, scanning electron microscopy, corrosion casting, and direct multiplexed measurement of gene expression. RESULTS: In patients who died from Covid-19-associated or influenza-associated respiratory failure, the histologic pattern in the peripheral lung was diffuse alveolar damage with perivascular T-cell infiltration. The lungs from patients with Covid-19 also showed distinctive vascular features, consisting of severe endothelial injury associated with the presence of intracellular virus and disrupted cell membranes. Histologic analysis of pulmonary vessels in patients with Covid-19 showed widespread thrombosis with microangiopathy. Alveolar capillary microthrombi were 9 times as prevalent in patients with Covid-19 as in patients with influenza (P<0.001). In lungs from patients with Covid-19, the amount of new vessel growth - predominantly through a mechanism of intussusceptive angiogenesis - was 2.7 times as high as that in the lungs from patients with influenza (P<0.001). CONCLUSIONS: In our small series, vascular angiogenesis distinguished the pulmonary pathobiology of Covid-19 from that of equally severe influenza virus infection. The universality and clinical implications of our observations require further research to define. (Funded by the National Institutes of Health and others.).

PPARα exacerbates necroptosis, leading to increased mortality in postinfluenza bacterial superinfection.

Patients infected with influenza are at high risk of secondary bacterial infection, which is a major proximate cause of morbidity and mortality. We have shown that in mice, prior infection with influenza results in increased inflammation and mortality upon Staphylococcus aureus infection, recapitulating the human disease. Lipidomic profiling of the lungs of superinfected mice revealed an increase in CYP450 metabolites during lethal superinfection. These lipids are endogenous ligands for the nuclear receptor PPARα, and we demonstrate that Ppara-/- mice are less susceptible to superinfection than wild-type mice. PPARα is an inhibitor of NFκB activation, and transcriptional profiling of cells isolated by bronchoalveolar lavage confirmed that influenza infection inhibits NFκB, thereby dampening proinflammatory and prosurvival signals. Furthermore, network analysis indicated an increase in necrotic cell death in the lungs of superinfected mice compared to mice infected with S. aureus alone. Consistent with this, we observed reduced NFκB-mediated inflammation and cell survival signaling in cells isolated from the lungs of superinfected mice. The kinase RIPK3 is required to induce necrotic cell death and is strongly induced in cells isolated from the lungs of superinfected mice compared to mice infected with S. aureus alone. Genetic and pharmacological perturbations demonstrated that PPARα mediates RIPK3-dependent necroptosis and that this pathway plays a central role in mortality following superinfection. Thus, we have identified a molecular circuit in which infection with influenza induces CYP450 metabolites that activate PPARα, leading to increased necrotic cell death in the lung which correlates with the excess mortality observed in superinfection.

[Risk of mortality of severe SARS-CoV-2 infection and other causes of viral pneumonia in Chile]. / Mortalidad a 30 días en neumonías adquiridas en la comunidad graves por SARS-COV-2 y otros virus respiratorios en Chile.

INTRODUCTION: Severe community-acquired pneumonia (CAP) due to respiratory viruses is highly prevalent in Chile. Common etiologies include Influenza A and B, respiratory syncytial virus (RSV), Hantavirus, and SARS-CoV-2 since 2020. OBJECTIVE: To identify clinical and laboratory features associated with 20-day mortality in severe viral CAP in a high complexity health care center in southern Chile. METHODS: The observational study included two cohorts of patients with severe CAP according to IDSA/ATS criteria: the years 2013-2018 (No COVID-19) and the year 2020 (COVID-19). Sociodemographic, clinical, laboratory, and 30-day mortality data were collected. We used Chi-square and Student's T for categorical and continuous variables. We used a binary logistic regression model for mortality analysis, reporting the results as Odd ratios (ORs). RESULTS: Mortality at 30 days was: Hantavirus 54.4%, Influenza H1N1 36.8%, other influenza 30.4%, RSV 25%, and COVID-19 23.6%. We found no significant difference regarding type of virus (COVID-19 or NO COVID-19). Mortality was associated with older age (OR: 4.6; p-value < 0.01), immunosuppression (OR: 5.8; p-value 0.01), and cyanosis (OR: 3.8, p-value 0.02). CONCLUSION: COVID-19 was not associated with an increased risk of 30-day mortality compared to other common respiratory viruses in our study. Older age, immunosuppression, and cyanosis were associated with higher risk among patients with severe viral CAP.

Influenza outcomes in patients with inflammatory joint diseases and DMARDs: how do they compare to those of COVID-19?

OBJECTIVES: To estimate absolute and relative risks for seasonal influenza outcomes in patients with inflammatory joint diseases (IJDs) and disease-modifying antirheumatic drugs (DMARDs). To contextualise recent findings on corresponding COVID-19 risks. METHODS: Using Swedish nationwide registers for this cohort study, we followed 116 989 patients with IJD and matched population comparators across four influenza seasons (2015-2019). We quantified absolute risks of hospitalisation and death due to influenza, and compared IJD to comparators via Cox regression. We identified 71 556 patients with IJD on active treatment with conventional synthetic DMARDs and biological disease-modifying antirheumatic drugs (bDMARDs)/targeted synthetic disease-modifying antirheumatic drug (tsDMARDs) at the start of each influenza season, estimated risks for the same outcomes and compared these risks across DMARDs via Cox regression. RESULTS: Per season, average risks for hospitalisation listing influenza were 0.25% in IJD and 0.1% in the general population, corresponding to a crude HR of 2.38 (95% CI 2.21 to 2.56) that decreased to 1.44 (95% CI 1.33 to 1.56) following adjustments for comorbidities. For death listing influenza, the corresponding numbers were 0.015% and 0.006% (HR=2.63, 95% CI 1.93 to 3.58, and HR=1.46, 95% CI 1.07 to 2.01). Absolute risks for influenza outcomes were half (hospitalisation) and one-tenth (death) of those for COVID-19, but relative estimates comparing IJD to the general population were similar. CONCLUSIONS: In absolute terms, COVID-19 in IJD outnumbers that of average seasonal influenza, but IJD entails a 50%-100% increase in risk for hospitalisation and death for both types of infections, which is largely dependent on associated comorbidities. Overall, bDMARDs/tsDMARDs do not seem to confer additional risk for hospitalisation or death related to seasonal influenza.

The pneumococcal two-component system SirRH is linked to enhanced intracellular survival of Streptococcus pneumoniae in influenza-infected pulmonary cells.

The virus-bacterial synergism implicated in secondary bacterial infections caused by Streptococcus pneumoniae following infection with epidemic or pandemic influenza A virus (IAV) is well documented. However, the molecular mechanisms behind such synergism remain largely ill-defined. In pneumocytes infected with influenza A virus, subsequent infection with S. pneumoniae leads to enhanced pneumococcal intracellular survival. The pneumococcal two-component system SirRH appears essential for such enhanced survival. Through comparative transcriptomic analysis between the ΔsirR and wt strains, a list of 179 differentially expressed genes was defined. Among those, the clpL protein chaperone gene and the psaB Mn+2 transporter gene, which are involved in the stress response, are important in enhancing S. pneumoniae survival in influenza-infected cells. The ΔsirR, ΔclpL and ΔpsaB deletion mutants display increased susceptibility to acidic and oxidative stress and no enhancement of intracellular survival in IAV-infected pneumocyte cells. These results suggest that the SirRH two-component system senses IAV-induced stress conditions and controls adaptive responses that allow survival of S. pneumoniae in IAV-infected pneumocytes.

Administration of a CXC Chemokine Receptor 2 (CXCR2) Antagonist, SCH527123, Together with Oseltamivir Suppresses NETosis and Protects Mice from Lethal Influenza and Piglets from Swine-Influenza Infection.

Excessive neutrophil influx, their released neutrophil extracellular traps (NETs), and extracellular histones are associated with disease severity in influenza-infected patients. Neutrophil chemokine receptor CXC chemokine receptor 2 (CXCR2) is a critical target for suppressing neutrophilic inflammation. Herein, temporal dynamics of neutrophil activity and NETosis were investigated to determine the optimal timing of treatment with the CXCR2 antagonist, SCH527123 (2-hydroxy-N,N-dimethyl-3-[2-([(R)-1-(5-methyl-furan-2-yl)-propyl]amino)-3,4-dioxo-cyclobut-1-enylamino]-benzamide), and its efficacy together with antiviral agent, oseltamivir, was tested in murine and piglet influenza-pneumonia models. SCH527123 plus oseltamivir markedly improved survival of mice infected with lethal influenza, and diminished lung pathology in swine-influenza-infected piglets. Mechanistically, addition of SCH527123 in the combination treatment attenuated neutrophil influx, NETosis, in both mice and piglets. Furthermore, neutrophils isolated from influenza-infected mice showed greater susceptibility to NETotic death when stimulated with a CXCR2 ligand, IL-8. In addition, CXCR2 stimulation induced nuclear translocation of neutrophil elastase, and enhanced citrullination of histones that triggers chromatin decondensation during NET formation. Studies on temporal dynamics of neutrophils and NETs during influenza thus provide important insights into the optimal timing of CXCR2 antagonist treatment for attenuating neutrophil-mediated lung pathology. These findings reveal that pharmacologic treatment with CXCR2 antagonist together with an antiviral agent could significantly ameliorate morbidity and mortality in virulent and sublethal influenza infections.

Severe influenza virus infection in children admitted to the PICU: Comparison of influenza A and influenza B virus infection.

Although the influenza virus usually causes a self-limiting disease, deaths are reported even in children without risk factors. We aimed to identify the clinical features, mortality associated with severe influenza A and B virus infections of children admitted to the pediatric intensive care unit (PICU). We conducted a retrospective study of children with confirmed influenza infection between 2012 and 2019 who were admitted to the PICU. Demographic features, risk factors, clinical data, microbiological data, complications, and outcomes were collected. Over seven influenza seasons (2012-2011 to 2015-2016), 713 children diagnosed with laboratory-confirmed influenza-related LRTI, and PICU admission was needed in 6% (46/713) of the patients. Thirty-one patients (67.4%) were diagnosed with influenza A and 15 patients were diagnosed with influenza B. Epidemiologic and clinical characteristics were similar in both influenza types, lactate dehydrogenase levels were significantly higher for influenza A than for influenza B infections. Although the influenza A to B ratio among the patients admitted to the PICU was 2.06, the percentage of cases requiring PICU admission was nearly two times higher in influenza B cases. There was no statistically significant difference in disease severity and complications in patients with influenza A and influenza B.

An application of slow feature analysis to the genetic sequences of coronaviruses and influenza viruses.

BACKGROUND: Mathematical approaches have been for decades used to probe the structure of DNA sequences. This has led to the development of Bioinformatics. In this exploratory work, a novel mathematical method is applied to probe the DNA structure of two related viral families: those of coronaviruses and those of influenza viruses. The coronaviruses are SARS-CoV-2, SARS-CoV-1, and MERS. The influenza viruses include H1N1-1918, H1N1-2009, H2N2-1957, and H3N2-1968. METHODS: The mathematical method used is the slow feature analysis (SFA), a rather new but promising method to delineate complex structure in DNA sequences. RESULTS: The analysis indicates that the DNA sequences exhibit an elaborate and convoluted structure akin to complex networks. We define a measure of complexity and show that each DNA sequence exhibits a certain degree of complexity within itself, while at the same time there exists complex inter-relationships between the sequences within a family and between the two families. From these relationships, we find evidence, especially for the coronavirus family, that increasing complexity in a sequence is associated with higher transmission rate but with lower mortality. CONCLUSIONS: The complexity measure defined here may hold a promise and could become a useful tool in the prediction of transmission and mortality rates in future new viral strains.

Systemic administration of glucocorticoids, cardiovascular complications and mortality in patients hospitalised with COVID-19, SARS, MERS or influenza: A systematic review and meta-analysis of randomised trials.

BACKGROUND: Administration of glucocorticoids might reduce mortality in patients with severe COVID-19 but have adverse cardiometabolic effects. OBJECTIVES: to investigate the effect of systemic administration of glucocorticoids on cardiovascular complications and all-cause mortality in patients hospitalised with respiratory viral infections, including COVID-19, SARS, MERS and influenza. METHODS: We identified randomised trials published prior to July 28th, 2021. The Mantel-Haenszel random effects method and the Hartung and Knapp adjustment were used to obtain pooled estimates of treatment effect with 95% confidence intervals. RESULTS: No randomised trials of glucocorticoids for SARS, MERS or influenza reported relevant outcomes. We included eleven COVID-19 randomised trials (8109 patients). Overall, compared to placebo or standard care, glucocorticoids were not associated with a reduction of in-hospital mortality (p = 0.09). In a pre-specified sub-analysis, in-hospital mortality was reduced by 19% when follow-up was restricted to 14 days from randomisation (5/11 trials, 1329 patients, p = 0.02). With longer follow-up (9/11 trials, 7874 patients), administration of glucocorticoids was associated with a trend to benefit for those requiring mechanical ventilation (RR 0.86; 95% CI 0.57-1.27) but possible harm for those not receiving oxygen at randomisation (RR 1.27; 95% CI 1.00 - 1.61), an effect that was significantly different amongst subgroups (p = 0.0359). Glucocorticoids reduced the risk of worsening renal function by 37% (4/11 trials); reported rate of other cardiovascular complications was low. CONCLUSIONS: Administration of systemic glucocorticoids to patients hospitalised with COVID-19 does not lower mortality overall but may reduce it in those requiring respiratory support and increase it in those who do not.

Estimating the cumulative incidence of COVID-19 in the United States using influenza surveillance, virologic testing, and mortality data: Four complementary approaches.

Effectively designing and evaluating public health responses to the ongoing COVID-19 pandemic requires accurate estimation of the prevalence of COVID-19 across the United States (US). Equipment shortages and varying testing capabilities have however hindered the usefulness of the official reported positive COVID-19 case counts. We introduce four complementary approaches to estimate the cumulative incidence of symptomatic COVID-19 in each state in the US as well as Puerto Rico and the District of Columbia, using a combination of excess influenza-like illness reports, COVID-19 test statistics, COVID-19 mortality reports, and a spatially structured epidemic model. Instead of relying on the estimate from a single data source or method that may be biased, we provide multiple estimates, each relying on different assumptions and data sources. Across our four approaches emerges the consistent conclusion that on April 4, 2020, the estimated case count was 5 to 50 times higher than the official positive test counts across the different states. Nationally, our estimates of COVID-19 symptomatic cases as of April 4 have a likely range of 2.3 to 4.8 million, with possibly as many as 7.6 million cases, up to 25 times greater than the cumulative confirmed cases of about 311,000. Extending our methods to May 16, 2020, we estimate that cumulative symptomatic incidence ranges from 4.9 to 10.1 million, as opposed to 1.5 million positive test counts. The proposed combination of approaches may prove useful in assessing the burden of COVID-19 during resurgences in the US and other countries with comparable surveillance systems.

Comparison of influenza type A and B with COVID-19: A global systematic review and meta-analysis on clinical, laboratory and radiographic findings.

We compared clinical symptoms, laboratory findings, radiographic signs and outcomes of COVID-19 and influenza to identify unique features. Depending on the heterogeneity test, we used either random or fixed-effect models to analyse the appropriateness of the pooled results. Overall, 540 articles included in this study; 75,164 cases of COVID-19 (157 studies), 113,818 influenza type A (251 studies) and 9266 influenza type B patients (47 studies) were included. Runny nose, dyspnoea, sore throat and rhinorrhoea were less frequent symptoms in COVID-19 cases (14%, 15%, 11.5% and 9.5%, respectively) in comparison to influenza type A (70%, 45.5%, 49% and 44.5%, respectively) and type B (74%, 33%, 38% and 49%, respectively). Most of the patients with COVID-19 had abnormal chest radiology (84%, p < 0.001) in comparison to influenza type A (57%, p < 0.001) and B (33%, p < 0.001). The incubation period in COVID-19 (6.4 days estimated) was longer than influenza type A (3.4 days). Likewise, the duration of hospitalization in COVID-19 patients (14 days) was longer than influenza type A (6.5 days) and influenza type B (6.7 days). Case fatality rate of hospitalized patients in COVID-19 (6.5%, p < 0.001), influenza type A (6%, p < 0.001) and influenza type B was 3%(p < 0.001). The results showed that COVID-19 and influenza had many differences in clinical manifestations and radiographic findings. Due to the lack of effective medication or vaccine for COVID-19, timely detection of this viral infection and distinguishing from influenza are very important.

Current views on the potentials of convalescent plasma therapy (CPT) as Coronavirus disease 2019 (COVID-19) treatment: A systematic review and meta-analysis based on recent studies and previous respiratory pandemics.

Convalescent plasma therapy (CPT) has been investigated as a treatment for COVID-19. This review evaluates CPT in COVID-19 and other viral respiratory diseases, including severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS) and influenza. PubMed and Google scholar databases were used to collect eligible publications until 8 December 2020. Meta-analysis used Mantel-Haenszel risk ratio (RR) with 95% confidence interval (CI) and pooled analysis for individual patient data with inverse variance weighted average. The study is registered at PROSPERO with the number of CRD4200270579. Forty-four studies with 36,716 participants were included in the pooled analysis and 20 studies in the meta-analysis. Meta-analysis showed reduction of mortality (RR 0.57, 95% CI [0.43, 0.76], z = 3.86 [p < 0.001], I2  = 44% [p = 0.03]) and higher number of discharged patients (RR 2.53, 95% CI [1.72, 3.72], z = 4.70 [p < 0.001], I2  = 3% [p = 0.39]) in patients receiving CPT compared to standard care alone. A possible mechanism of action is prompt reduction in viral titre. Serious transfusion-related adverse events were reported to be less than 1% of cases, suggesting the overall safety of CPT; nevertheless, the number of patients participating in the studies was still limited. It is also important to notice that in all the studies, the majority of patients were also given other medications, such as antivirals, antibiotics and corticosteroid; furthermore, randomized controlled studies involving more patients and in combination with other treatment modalities are urgently needed.