Effect of oseltamivir phosphate versus placebo on platelet recovery and plasma leakage in adults with dengue and thrombocytopenia; a phase 2, multicenter, double-blind, randomized trial

Background Thrombocytopenia, bleeding and plasma leakage are major complications of dengue. Activation of endogenous sialidases with desialylation of platelets and endothelial cells may underlie these complications. We aimed to assess the effects of the neuraminidase inhibitor oseltamivir on platelet recovery and plasma leakage in dengue. Methods We performed a phase 2, double-blind, multicenter, randomized trial in adult dengue patients with thrombocytopenia (<70,000/μl) and a duration of illness ≤ 6 days. Oseltamivir phosphate 75mg BID or placebo were given for a maximum of five days. Primary outcomes were the time to platelet recovery (≥ 100,000/μl) or discharge from hospital and the course of measures of plasma leakage. Results A total of 70 patients were enrolled; the primary outcome could be assessed in 64 patients (31 oseltamivir; 33 placebo). Time to platelet count ≥100,000/μl (n = 55) or discharge (n = 9) were similar in the oseltamivir and placebo group (3.0 days [95% confidence interval, 2.7 to 3.3] vs. 2.9 days [2.5 to 3.3], P = 0.055). The kinetics of platelet count and parameters of plasma leakage (gall bladder thickness, hematocrit, plasma albumin, syndecan-1) were also similar between the groups. Discussion In this trial, adjunctive therapy with oseltamivir phosphate had no effect on platelet recovery or plasma leakage parameters. Trial registration ISRCTN35227717.

Role of etiotropic therapy in the treatment and prevention of influenza complications amidst the COVID-19 pandemic

Influenza remains one of the most common respiratory viral diseases with a high risk of complications. In the context of the COVID-19 pandemic, there is a possibility of simultaneous circulation of two viruses, which makes it necessary to conduct a differential diagnosis. Influenza and COVID-19 have common pathways of transmission of the pathogen and similar symptoms, so the optimal differential diagnosis is the use of test systems for both viruses. Against the background of influenza and COVID-19, complications from various organs and systems can develop. The article describes in detail the complications of influenza from the cardiovascular system. After infection with the flu virus, there is a 6-to 10-fold increase in the risk of acute myocardial infarction and a 3 - to 8-fold increase in the risk of stroke. COVID-19 is associated with arterial hypertension, diabetes mellitus, cardiac arrhythmias, myocarditis, high risk of acute myocardial infarction, and heart failure. The article presents the data of our own research, indicating that the transferred COVID-19 disease increases the risk of acute coronary syndrome, regardless of the presence of risk factors for cardiovascular events. Prevention of the development of influenza complications is the early administration of etiotropic antiviral therapy. Numerous studies confirm the effectiveness of the neuraminidase inhibitor oseltamivir in the treatment of influenza. The use of oseltamivir reduces the severity of clinical manifestations, reduces the duration of the disease, reduces the risk of complications and death. The most effective measure to prevent influenza and COVID-19 is specific immunization. In some cases, chemoprophylaxis can be used. The article discusses studies on the effectiveness of influenza chemoprophylaxis with the use of neuraminidase inhibitors.

Prognostic Value of Elevated Levels of Plasma N-Acetylneuraminic Acid in Patients With Heart Failure

Background: Cardiac sialylation is involved in a variety of physiological processes in the heart. Altered sialylation has been implicated in heart failure (HF) mice. However, its role in patients with HF is unclear, and the potential effect of modulation of cardiac sialylation is worth exploring. Methods: We first assessed the association between plasma N-acetylneuraminic acid levels and the incidence of adverse cardiovascular events in patients with HF over a median follow-up period of 2 years. Next, immunoblot analysis and lectin histochemistry were performed in cardiac tissue to determine the expression levels of neuraminidases and the extent of cardiac desialylation. Finally, the therapeutic impact of a neuraminidase inhibitor was evaluated in animal models of HF. Results: Among 1699 patients with HF, 464 (27%) died of cardiovascular-related deaths or underwent heart transplantation. We found that the elevated plasma N-acetylneuraminic acid level was independently associated with a higher risk of incident cardiovascular death and heart transplantation (third tertile adjusted hazard ratio, 2.11 [95% CI, 1.67–2.66], P <0.001). In addition, in cardiac tissues from patients with HF, neuraminidase expression was upregulated, accompanied by desialylation. Treatment with oseltamivir, a neuraminidase inhibitor, in HF mice infused with isoproterenol and angiotensin II significantly inhibited desialylation and ameliorated cardiac dysfunction. Conclusions: This study uncovered a significant association between elevated plasma N-acetylneuraminic acid level and an increased risk of a poor clinical outcome in patients with HF. Our data support the notion that desialylation represents an important contributor to the progression of HF, and neuraminidase inhibition may be a potential therapeutic strategy for HF.

Zanamivir aqueous solution in severe influenza: A global Compassionate Use Program, 2009–2019

Background Zanamivir is a neuraminidase inhibitor effective against influenza A and B viruses. In 2009, GlaxoSmithKline (GSK) began clinical development of intravenous (IV) zanamivir, and initiated a global Compassionate Use Program (CUP) in response to the evolving H1N1 global pandemic. The goal of the CUP was to provide zanamivir to critically ill patients with limited treatment options. Methods Zanamivir was administered to patients with suspected or confirmed influenza infection, who were not suitable for other approved antiviral treatments. Reporting of serious adverse events (SAEs) was mandatory and recorded in the GSK safety database. A master summary tracking sheet captured requests and patient characteristics. A case report form was available for detailing medical conditions, dosing, treatment duration, and clinical outcomes. Results In total, 4033 requests were made for zanamivir treatment of hospitalized patients from 38 countries between 2009 and 2019. Europe had the highest number of requests (n=3051) followed by North America (n=713). At least 20 patients were aged ≤6 months, of whom 12 were born prematurely. The GSK safety database included 466 patients with ≥1 SAE, of whom 374 (80%) had a fatal outcome. Drug-related SAEs were reported in 41 (11%) patients, including hepatic failure (n=6 [2%]) and acute kidney injury (n=5 [1%)]. Conclusions The CUP fulfilled the need to provide global access to zanamivir prior to product approval. No new safety concerns were identified in the CUP compared with IV zanamivir clinical studies.

Analysis of the Genetic Diversity Associated With the Drug Resistance and Pathogenicity of Influenza A Virus Isolated in Bangladesh From 2002 to 2019

The subtype prevalence, drug resistance- and pathogenicity-associated mutations, and the distribution of the influenza A virus (IAV) isolates identified in Bangladesh from 2002 to 2019 were analyzed using bioinformatic tools. A total of 30 IAV subtypes have been identified in humans (4), avian species (29), and environment (5) in Bangladesh. The predominant subtypes in human and avian species are H1N1/H3N2 and H5N1/H9N2, respectively. However, the subtypes H5N1/H9N2 infecting humans and H3N2/H1N1 infecting avian species have also been identified. Among the avian species, the maximum number of subtypes (27) have been identified in ducks. A 3.56% of the isolates showed neuraminidase inhibitor (NAI) resistance with a prevalence of 8.50, 1.33, and 2.67% in avian species, humans, and the environment, respectively, the following mutations were detected: V116A, I117V, D198N, I223R, S247N, H275Y, and N295S. Prevalence of adamantane-resistant IAVs was 100, 50, and 30.54% in humans, the environment, and avian species, respectively, the subtypes H3N2, H1N1, H9N2, and H5N2 were highly prevalent, with the subtype H5N1 showing a comparatively lower prevalence. Important PB2 mutations such D9N, K526R, A588V, A588I, G590S, Q591R, E627K, K702R, and S714R were identified. A wide range of IAV subtypes have been identified in Bangladesh with a diversified genetic variation in the NA, M2, and PB2 proteins providing drug resistance and enhanced pathogenicity. This study provides a detailed analysis of the subtypes, and the host range of the IAV isolates and the genetic variations related to their proteins, which may aid in the prevention, treatment, and control of IAV infections in Bangladesh, and would serve as a basis for future investigations.

The severity and risk factors for mortality in immunocompromised adult patients hospitalized with influenza-related pneumonia

Objective To explore disease severity and risk factors for 30-day mortality of adult immunocompromised (IC) patients hospitalized with influenza-related pneumonia (Flu-p). Method A total of 122 IC and 1191 immunocompetent patients hospitalized with Flu-p from January 2012 to December 2018 were recruited retrospectively from five teaching hospitals in China. Results After controlling for confounders, multivariate logistic regression analysis showed that immunosuppression was associated with increased risks for invasive ventilation [odds ratio: (OR) 2.475, 95% confidence interval (CI): 1.511–4.053, p < 0.001], admittance to the intensive care unit (OR: 3.247, 95% CI 2.064–5.106, p < 0.001), and 30-day mortality (OR: 3.206, 95% CI 1.926–5.335, p < 0.001) in patients with Flu-p. Another multivariate logistic regression model revealed that baseline lymphocyte counts (OR: 0.993, 95% CI 0.990–0.996, p < 0.001), coinfection (OR: 5.450, 95% CI 1.638–18.167, p = 0.006), early neuraminidase inhibitor therapy (OR 0.401, 95% CI 0.127–0.878, p = 0.001), and systemic corticosteroid use at admission (OR: 6.414, 95% CI 1.348–30.512, p = 0.020) were independently related to 30-day mortality in IC patients with Flu-p. Based on analysis of the receiver operating characteristic curve (ROC), the optimal cutoff for lymphocyte counts was 0.6 × 109/L [area under the ROC (AUROC) = 0.824, 95% CI 0.744—0.887], sensitivity: 97.8%, specificity: 73.7%]. Conclusions IC conditions are associated with more severe outcomes in patients with Flu-p. The predictors for mortality that we identified may be valuable for the management of Flu-p among IC patients.

Behavior of hospitalized severe influenza cases according to the outcome variable in Catalonia, Spain, during the 2017–2018 season

Influenza is an important cause of severe illness and death among patients with underlying medical conditions and in the elderly. The aim of this study was to investigate factors associated with ICU admission and death in patients hospitalized with severe laboratory-confirmed influenza during the 2017–2018 season in Catalonia. An observational epidemiological case-to-case study was carried out. Reported cases of severe laboratory-confirmed influenza requiring hospitalization in 2017–2018 influenza season were included. Mixed-effects regression analysis was used to estimate the factors associated with ICU admission and death. A total of 1306 cases of hospitalized severe influenza cases were included, of whom 175 (13.4%) died and 217 (16.6%) were ICU admitted. Age 65–74 years and ≥ 75 years and having ≥ 2 comorbidities were positively associated with death (aOR 3.19; 95%CI 1.19–8.50, aOR 6.95, 95%CI 2.76–1.80 and aOR 1.99; 95%CI 1.12–3.52, respectively). Neuraminidase inhibitor treatment and pneumonia were negatively associated with death. The 65–74 years and ≥ 75 years age groups were negatively associated with ICU admission (aOR 0.41; 95%CI 0.23–0.74 and aOR 0.30; 95%CI 0.17–0.53, respectively). A factor positively associated with ICU admission was neuraminidase inhibitor treatment. Our results support the need to investigate the worst outcomes of hospitalized severe cases, distinguishing between death and ICU admission.

Interferon Lambda Delays the Emergence of Influenza Virus Resistance to Oseltamivir

Influenza viruses are a leading cause of morbidity and mortality worldwide. These air-borne pathogens are able to cross the species barrier, leading to regular seasonal epidemics and sporadic pandemics. Influenza viruses also possess a high genetic variability, which allows for the acquisition of resistance mutations to antivirals. Combination therapies with two or more drugs targeting different mechanisms of viral replication have been considered an advantageous option to not only enhance the effectiveness of the individual treatments, but also reduce the likelihood of resistance emergence. Using an in vitro infection model, we assessed the barrier to viral resistance of a combination therapy with the neuraminidase inhibitor oseltamivir and human interferon lambda against the pandemic H1N1 A/Netherlands/602/2009 (H1N1pdm09) virus. We serially passaged the virus in a cell line derived from human bronchial epithelial cells in the presence or absence of increasing concentrations of oseltamivir alone or oseltamivir plus interferon lambda. While the treatment with oseltamivir alone quickly induced the emergence of antiviral resistance through a single mutation in the neuraminidase gene, the co-administration of interferon lambda delayed the emergence of drug-resistant influenza virus variants. Our results suggest a possible clinical application of interferon lambda in combination with oseltamivir to treat influenza.