Neuraminidase Inhibitor Treatment Research Articles

Effect of neuraminidase inhibitor (oseltamivir) treatment on outcome of hospitalised influenza patients, surveillance data from 11 EU countries, 2010 to 2020.

BackgroundTimely treatment with neuraminidase inhibitors (NAI) can reduce severe outcomes in influenza patients.AimWe assessed the impact of antiviral treatment on in-hospital deaths of laboratory-confirmed influenza patients in 11 European Union countries from 2010/11 to 2019/20.MethodsCase-based surveillance data from hospitalised patients with known age, sex, outcome, ward, vaccination status, timing of antiviral treatment, and hospitalisation were obtained. A mixed effect logistic regression model using country as random intercept was applied to estimate the adjusted odds ratio (aOR) for in-hospital death in patients treated with NAIs vs not treated.ResultsOf 19,937 patients, 31% received NAIs within 48 hours of hospital admission. Older age (60-79 years aOR 3.0, 95% CI: 2.4-3.8; 80 years 8.3 (6.6-10.5)) and intensive care unit admission (3.8, 95% CI: 3.4-4.2) increased risk of dying, while early hospital admission after symptom onset decreased risk (aOR 0.91, 95% CI: 0.90-0.93). NAI treatment initiation within 48 hours and up to 7 days reduced risk of dying (0-48 hours aOR 0.51, 95% CI: 0.45-0.59; 3-4 days 0.59 (0.51-0.67); 5-7 days 0.64 (0.56-0.74)), in particular in patients 40 years and older (e.g. treatment within 48 hours: 40-59 years aOR 0.43, 95% CI: 0.28-0.66; 60-79 years 0.50 (0.39-0.63); ≥80 years 0.51 (0.42-0.63)).ConclusionNAI treatment given within 48 hours and possibly up to 7 days after symptom onset reduced risk of in-hospital death. NAI treatment should be considered in older patients to prevent severe outcomes.

Sterilization of Drug‐Resistant Influenza Virus through Genetic Interference Inspired by Unnatural Amino Acid‐Engineered Particles (Adv. Therap. 10/2022)

In article number 2200069, Xuesheng Wu and co-workers demonstrate an novel antiviral method that utilizes unnatural amino acid-engineered drug-resistant (UAA-DR) virus generated through genetic code expansion to combat emerging drug-resistant viruses through genomic segment reassortment to produce sterilized progenies, and antiviral effect could be enhanced combined neuraminidase (NA) inhibitors treatment in mice.

Risk factors for lower respiratory tract disease and outcomes in allogeneic hematopoietic stem cell transplantation recipients with influenza virus infection

IntroductionInfluenza virus infection (IVI) is frequent in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients, and reports from several countries indicate high morbidity and mortality from progression to lower respiratory tract disease (LRTD). However, there have been no reports on IVI clinical characteristics, treatment outcomes, and risk factor for progression to LRTD among allo-HSCT recipients in Japan. MethodsWe retrospectively reviewed the medical charts of allo-HSCT recipients who developed IVI between 2012 and 2019. ResultsForty-eight cases of IVI following allo-HSCT were identified at our institution. The median age was 42 years, and median time from allo-HSCT to IVI was 25 months. Thirty-seven patients (77.1%) were administered neuraminidase inhibitors (NAIs) as antiviral therapy within 48 h of symptom onset (early therapy), whereas 11 (22.9%) received NAI over 48 h after onset (delayed therapy). Subsequently, 12 patients (25.0%) developed LRTD after IVI. Multivariate analysis identified older age (hazard ratio [HR], 7.65; 95% confidence interval [CI], 2.22–26.3) and bronchiolitis obliterans (HR, 5.74; 95% CI, 1.57–21.0) as independent risk factors for progression to LRTD. Moreover, land-mark analysis showed that early therapy prevented progression to LRTD (11.8% vs. 45.5%, P = 0.013). The IVI-related mortality rate was 2.1%. ConclusionsEarly NAI treatment is recommended for reducing the risk of LRTD progression due to IVI in allo-HSTC recipients, particularly for older patients and those with bronchiolitis obliterans.

Neuraminidase inhibitor treatment is associated with decreased mortality in COVID-19 patients: a retrospective analysis.

AimsThe aim of this study was to investigate the effects of Neuraminidase inhibitors (NI) on COVID-19 in a retrospective study.Methods and resultsThe study included an overall COVID-19 patients (n = 3267) and a 1:1 propensity score-matched patients (n = 972). The levels of plasma N-acetylneuraminic acid and neuraminidase expression were further evaluated in a panel of hospitalized and 1-month post-infection recovered COVID-19 subjects. The mortality rate in the overall patients was 9.6% (313/3267) and 9.2% (89/972) in the propensity-score matched patients. The NI treatment lowered the mortality rate (5.7% vs. 10.3%) and the critically ill conversion rate (14.1% vs. 19.7%) compare to those in the non-NI group in the overall patients and evaluated in the propensity score-matched patients when applying the multivariate Cox model for adjusting imbalanced confounding factors. Furthermore, NI treatment was associated with attenuated cytokine storm levels and acute heart injury but not liver or kidney injuries. Further analysis in a small panel of patients found the levels of N-acetylneuraminic acid and neuraminidase (dominantly the NEU3 isoform) were elevated in the hospitalized COVID-19 subjects and recovered at the 1-month post-infection stage, suggesting increasing desialylation in COVID-19 patients.ConclusionThese results suggest that NI treatment is associated with decreased mortality in COVID-19 subjects, especially for those subjects with acute heart injury.

Influenza Antiviral Therapy and Length of Hospitalization

Source: Campbell AP, Tokars JI, Reynolds S, et al. Influenza antiviral treatment and length of stay. Pediatrics. 2021;148(4):e2021050417; doi:10.1542/peds.2021-050417Investigators from multiple institutions conducted a retrospective study to assess the effect of treatment with neuraminidase inhibitors (NAIs) on length of hospital stay (LOS) in children with influenza. Study data were abstracted from the Influenza Hospitalization Surveillance Network (FluServ-NET), a population-based surveillance network with data from 10 counties in different states and 5 entire states. Information on patients in the surveillance system, including demographics, patient characteristics, treatment with NAIs, symptom onset, and details on hospitalization were collected. Study participants were children <18 years old with laboratory-identified influenza who were divided into 2 cohorts for analysis. Cohort 1 included children with ≥1 medical condition and not admitted or transferred to an ICU who were hospitalized during the 2012–2013 influenza season. Cohort 2 were children with or without an underlying medical condition who were admitted to an ICU during 3 consecutive influenza seasons (2010–2011, 2011–2012, and 2012–2013). Exclusion criteria included missing information on receipt of NAIs, LOS <1 day, and symptom onset on or after ≥3 days prior to admission. Receipt of NAIs was classified as never, ≤2 days after onset of symptoms (early), or ≥3 days after symptoms (late). The primary study outcome was LOS, and the association of treatment with NAIs on LOS was evaluated using Cox regression after controlling for confounders.During the 2012–2013 influenza season, data on 1,924 children hospitalized with influenza were collected in FluServ-NET; 1,039 (54%) had ≥1 underlying medical condition. After applying exclusions, cohort 1 consisted of 309 children, of whom 199 (64.4%) received early NAI ≤2 days after treatment, 37 (12.0%) were treated ≥3 days after symptom onset, and 73 (23.6%) had no treatment with NAIs. After controlling for confounders, a shorter LOS was statistically associated with early NAI treatment (hazard ratio [HR], 1.37; 95% confidence interval [CI], 1.05, 1.80), but not late treatment (HR, 1.02; 95% CI, 0.67, 1.54). There were 299 children admitted to an ICU, included in cohort 2 analyses, with a median LOS of 5 days. NAIs were started ≤2 days after symptom onset in 168 (56%), ≥3 days after onset of symptoms in 45 (15%), and never in 86 (29%). In this cohort, early NAI treatment also was associated with shorter LOS (HR, 1.46; 95% CI, 1.11, 1.92), and late NAI treatment was not (HR, 1.20; 95% CI, 0.85, 1.69).The authors conclude that early treatment with NAIs in children with influenza was associated with shorter hospitalizations.Dr Doolittle has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.Treatment with NAIs has been shown to reduce hospitalization among high-risk adults and children with influenza.1 NAIs also have been shown to reduce mortality among hospitalized adults when given ≤2 days after symptom onset but have not been associated with a reduction in mortality among children <16 years.2 Because of these studies and others, treatment with NAIs has been recommended for patients of all ages with influenza since 2009.3 However, since most studies of NAIs were performed on outpatients and adults, the experience among hospitalized children is limited.4 The current investigators close that gap.The investigators employed a large data set, controlled for confounding variables, and were careful to reject participants for whom NAI use was not known. Further, they studied children who would benefit the most from NAIs: those with ≥1 chronic illness and those admitted to the ICU. The most common chronic medical conditions included chronic lung and cardiac diseases such as asthma, neurologic diseases, prematurity, immunocompromise, and chronic metabolic or blood disorders. Interestingly, 48% of the chronic illness cohort and 37% of the ICU cohort were vaccinated for influenza. Vaccination status was not associated with LOS.The results of the current study affirm the Centers for Disease Control and Prevention (CDC) position to start early empiric treatment with NAIs on all patients suspected of influenza.3 Interestingly, the CDC also recommends NAIs in all hospitalized patients with influenza regardless of time of onset due to potential reduction in viral shedding and LOS.5Among children with influenza admitted to the ICU or with ≥1 chronic conditions, treatment with NAIs within ≤2 days of symptom onset is associated with a shorter LOS compared to those treated ≥3 days after symptom onset or not at all. (See AAP Grand Rounds. 2021;46[4]:39).6

Reverse transcription recombinase-aided amplification assay for rapid detection of the influenza A(H1N1)pdm09 H275Y mutation that confers oseltamivir resistance

The emergence of the influenza A(H1N1)pdm09 virus with the NA-H275Y mutation, which confers oseltamivir resistance, must be monitored, especially in patients undergoing neuraminidase inhibitor treatment. In this study, we developed a reverse transcription recombinase-aided amplification assay that has high sensitivity (detection limit: 1.0 × 101 copies/μL) and specificity for detecting the oseltamivir-resistant H275Y mutation; the assay is performed within 30 min at a constant temperature of 39° Celsius using an isothermal device. This method is suitable for the clinical application of targeted testing, thereby providing technical support for precision medicine in individual drug applications for patients with severe infection or immunosuppression.

The aminoshikimic acid pathway in bacteria as source of precursors for the synthesis of antibacterial and antiviral compounds.

The aminoshikimic acid (ASA) pathway comprises a series of reactions resulting in the synthesis of 3-amino-5-hydroxybenzoic acid (AHBA), present in bacteria such as Amycolatopsis mediterranei and Streptomyces. AHBA is the precursor for synthesizing the mC7N units, the characteristic structural component of ansamycins and mitomycins antibiotics, compounds with important antimicrobial and anticancer activities. Furthermore, aminoshikimic acid, another relevant intermediate of the ASA pathway, is an attractive candidate for a precursor for oseltamivir phosphate synthesis, the most potent anti-influenza neuraminidase inhibitor treatment of both seasonal and pandemic influenza. This review discusses the relevance of the key intermediate AHBA as a scaffold molecule to synthesize diverse ansamycins and mitomycins. We describe the structure and control of the expression of the model biosynthetic cluster rif in A. mediterranei to synthesize ansamycins and review several current pharmaceutical applications of these molecules. Additionally, we discuss some relevant strategies developed for overproducing these chemicals, focusing on the relevance of the ASA pathway intermediates kanosamine, AHAB, and ASA.

Behavior of hospitalized severe influenza cases according to the outcome variable in Catalonia, Spain, during the 2017\u20132018 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.

Complications of Cardiovascular Events in Patients Hospitalized with Influenza-Related Pneumonia.

PurposeInfluenza virus infections are a key cause of community-acquired pneumonia (CAP). Cardiovascular events (CVEs) are common among CAP and influenza patients, but there have been few population-based studies of influenza-related pneumonia (Flu-p) patients published to date.MethodsA retrospective analysis of 1191 immunocompetent hospitalized adult Flu-p patients from January 2012 to December 2018 in five teaching hospitals in China was conducted.ResultsA total of 24.6% (293/1191) of patients developed at least one form of CVE-related complication while hospitalized. In a multivariate logistic regression analysis, hypertension, cerebrovascular disease, coronary artery disease, preexisting heart failure, systolic blood pressure <90 mmHg, respiratory rates ≥30 breaths/min, a lymphocyte count <0.8×109/L, PaO2/FiO2 <300 mmHg, and systemic corticosteroid administration were independently associated with the incidence of CVEs; while early neuraminidase inhibitor treatment and angiotensin converting enzyme inhibitors/angiotensin II receptor blocker treatment were associated with a lower risk of CVEs. After controlling for potential confounding variables, we determined that CVEs were linked to a higher risk of 30-day mortality (OR 3.307, 95% CI 2.198–4.975, p < 0.001) in Flu-p patients.ConclusionCVE-related complications are common among hospitalized Flu-p patients and are associated with negative patient outcomes. Clarifying these CVE-related risk factors can aid in their clinical prevention and management.

Association of baloxavir marboxil prescription with subsequent medical resource utilization among school-aged children with influenza.

Baloxavir marboxil is a novel antiviral agent for influenza, introduced into clinical practice in 2018. A concern remains about the variant virus with reduced susceptibility after baloxavir exposure and its clinical consequences such as healthcare-seeking behavior. Using a healthcare database in Japan, we compared the medical resource use following baloxavir and neuraminidase inhibitors (NAIs) treatment among children aged 7-15 years. The study period was from December 2018 to March 2019. The primary endpoint was the composite of hospitalization, laboratory and radiological tests, and antibiotic use over 1-9 days of antiviral treatment. As exploratory analyses, secondary outcomes being each single component of the primary composite were assessed and subgroup analyses comparing baloxavir with each NAI were done. Data from 115 867 prescriptions in 115 238 children were analyzed (median age: 10 years; severe influenza risk in 26%; baloxavir accounting for 43%). Overall, baloxavir use did not increase subsequent medical resource utilization in the composite endpoint (adjusted odds ratio [aOR]: 1.04; 95% confidence interval [CI]: 0.99-1.09; P = 0.14), as were likelihoods of other secondary outcomes. In the subgroup analysis, baloxavir use was associated with higher medical resource use than oseltamivir (aOR: 1.21; 95% CI: 1.13-1.31; P < 0.001) and lower resource use than zanamivir (aOR: 0.93; 95% CI 0.86-1.00; P = 0.040). Based on a single-year experience in Japan, prescribing baloxavir rather than NAIs did not increase medical resource utilization within 9 days of treatment, except in one exploratory comparison with oseltamivir.

Low rate of oseltamivir prescription among adults and children with confirmed influenza illness in France during the 2018-19 influenza season.

Oseltamivir shows effectiveness in reducing influenza-related symptoms, morbidity and mortality. Its prescription remains suboptimal. We aim to describe oseltamivir prescription in confirmed cases of influenza and to identify associated factors. A prospective monocentric observational study was conducted between 1 December 2018 and 30 April 2019. All patients with a virologically confirmed influenza diagnosis were included. Factors associated with oseltamivir prescription were studied. Influenza was confirmed in 755 patients (483 children and 272 adults), of which 188 (25.1%) were hospitalized and 86 (11.4%) had signs of severity. Oseltamivir was prescribed for 452 patients (59.9%), more frequently in children than in adults [329/483 (68.1%) versus 123/272 (45.2%), P < 0.001]. Factors associated with oseltamivir prescription were evaluated in 729 patients (246 adults and 483 children). Patients with at least one risk factor for severe influenza received oseltamivir less frequently (50%, 137/274) than those without risk factors (70%, 315/452) (P < 0.001). Pregnant women received oseltamivir in 81% of cases (17/21). Severe influenza cases were treated with oseltamivir in only 45.3% (39/86). The median duration of symptoms was 24 h (IQR 12-48) in treated patients versus 72 h (IQR 48-120) in untreated patients (P < 0.01). Oseltamivir should be administered as early as possible, preferably within 24-48 h after illness onset, for the best benefits. It is, however, very important to promote the use of neuraminidase inhibitor ('NAI') treatment beyond 48 h in some specific patient populations.

Neuraminidase inhibitors are effective and safe in reducing influenza complications: meta-analysis of randomized controlled trials.

BackgroundThere is scarce evidence verifying the impact of neuraminidase inhibitors (NAIs) in reducing influenza complications. The aim was to evaluate the available evidence from randomized-controlled trials (RCT) regarding the efficacy and safety of NAIs in reducing influenza complications. MethodsA systematic search of the literature was performed in the Cochrane Library, PubMed and Web of Science databases (2006–2019). Eligibility criteria were RCT that enrolled patients of any age or clinical severity with seasonal influenza (H1N1, H3N2, or B) or influenza-like syndrome and receiving NAIs comparing to placebo therapy. ResultsEighteen RCTs (9004 patients) were included: nine focused on oral oseltamivir, six on inhaled zanamivir, and three on intravenous peramivir. Administration of NAIs therapy significantly decreased the time to clinical resolution (median difference: -17.7 hours; and total influenza-related complications (OR: 0.64, 95%CI: 0.51–0.82). In addition, NAIs significantly decreased acute otitis media complication (OR: 0.50, 95%CI: 0.31–0.82) and need for antibiotic treatment (OR: 0.64, 95%CI: 0.46–0.90); and showed a trend towards a reduced occurrence of pneumonia (OR: 0.44, 95%CI: 0.10–2.00), bronchitis (OR: 0.80, 95%CI: 0.43–1.48), sinusitis (OR: 0.73, 95%CI: 0.40–1.32), asthma exacerbations (OR: 0.57, 95%CI: 0.28–1.16), and hospitalizations (OR: 0.57, 95%CI: 0.24–1.38). The overall proportion of AEs tend to increase with NAIs treatment (OR: 1.16, 95%CI: 0.92–1.47). Use of NAIs was associated with a significant increase of nausea and vomiting (OR: 1.61, 95%CI: 1.04–2.50) and a decrease on diarrhea (OR: 0.81, 95%CI: 0.65–1.00). ConclusionsNAIs are effective in reducing time to clinical resolution, total influenza-related complications, otitis media, and need of antibiotic administration. Reductions on mortality, pneumonia, asthma exacerbations or hospitalization rates only did demonstrate a trend benefit in favor of NAIs. The only significant AE is the increased occurrence of nausea and vomiting.

Analysis of clinical characteristics and risk factors of influenza-related deaths in children

Objective: To explore the clinical characteristics and risk factors of influenza-related deaths in children and to raise awareness of the disease among clinicians. Methods: Clinical data of 31 influenza-related deaths hospitalized in Pediatric Intensive Care Unit (PICU) of Shenzhen Children's Hospital from January 2009 to December 2019 (death group) were retrospectively analyzed. A control group enrolled 188 patients with severe influenza who were successfully cured and hospitalized in PICU at the same time. Independent Student's t test, Mann-Whitney U test and chi square test were used to compare the general conditions, clinical manifestations, laboratory tests and antiviral therapy between two groups. Risk factors of mortality in children with severe influenza were identified by multivariate Logistic regression. Results: In a total of 219 cases with severe influenza, 31 cases progressed to influenza-related deaths, 19 males and 12 females, with age of (4.2±3.3) years; 29 cases had influenza A virus infection and 2 cases had influenza B virus infection. Deaths occurred more in winter and spring (23/31). Eight patients had underlying diseases. In 188 patients who were successfully cured, 138 were males and 50 females, with an average age of (3.4±2.7)years. There were 151 patients with influenza A virus infection, and 37 patients with influenza B virus infection. Twenty patients underlying diseases. None of the patients in the death group has received the influenza vaccine within 1 year before infection. Common symptoms were fever (n=31), cough (n=21), and seizures (n=17) in the death group. The complications were influenza associated encephalopathy (IAE) (n=17), pneumonia (n=17), plastic bronchitis (n=1), air leak syndrome (n=3), acute respiratory distress syndrome (ARDS) (n=8), and multiple organ dysfunction syndrome (n=24). In the death group, 13 patients had secondary infections, of whom 9 cases had gram-positive Cocci infection. Complete blood count of the patients showed that white blood cells count increased in 15 cases and the lymphocyte count decreased in 13 cases. Meanwhile, high sensitivity C-reactive protein increased in 18 patients. All the 31 patients in the death group were treated with neuraminidase inhibitors for antiviral therapy, of whom 24 cases received the first dose 48 h after fever (late neuraminidase inhibitor (NAI) treatment). The causes of death in 31 patients were further analyzed, including 23 cases died of influenza complications, 4 cases died of underlying diseases and 4 cases died of secondary infections. Compared with the control group, the death group had more underlying diseases (25.8% (8/31) vs. 10.6% (20/188), χ²=4.215, P=0.040), higher incidence of secondary infection (41.9% (13/31) vs. 20.2% (38/188), χ²=7.029, P=0.008), and more late NAI treatment (77.4% (24/31) vs. 53.7% (101/188), χ²=6.099, P=0.014). Logistic regression analysis showed that secondary infection, late NAI treatment, complicated with ARDS and IAE were risk factors for death of patients with severe influenza (all P<0.05). Conclusions: Influenza can cause multi-system disorder, especially lung infections and IAE. It can improve the success rate of treatment for children with severe influenza, identification and early treatment of secondary infection and complications, and timely administration of NAI treatment.

Development of an Ordinal Scale Treatment Endpoint for Adults Hospitalized With Influenza.

An obstacle in influenza therapeutics development is the lack of clinical endpoints, especially in hospitalized patients. A single time-point binary outcome measure is limited by patients' diverse clinical trajectories and low event rates. A 6-point ordinal scale with ascending clinical status severity (scoring: discharged; subacute care; acute care without/with respiratory failure; intensive care unit [ICU]; death) was proposed to study outcomes of adults hospitalized with influenza. Individual patient data from 2 active surveillance cohorts' datasets (2015/2016-2017/2018; Edmonton, Hong Kong) was used for evaluation. The impact of neuraminidase inhibitor (NAI) treatment on longitudinal ordinal outcome changes over 30 days was analyzed using mixed-effects ordinal logistic regression and group-based trajectory models. Patient (n = 1226) baseline characteristics included age (mean 68.0 years), virus-type (A 78.1%, B 21.9%), respiratory failure (57.2%), ICU admittance (14.4%), and NAI treatment within 5 days of illness (69.2%). Outcomes at 30 days included discharged (75.2%), subacute care (13.7%), acute care (4.5%), and death (6.6%). Two main clinical trajectories were identified, predictive by baseline scoring (mean ± SD, 4.3 ± 0.6 vs 3.5 ± 0.6, P < .001). Improved outcomes with NAI treatment within 5 days were indicated by significantly lower clinical status scores over time (unadjusted odds ratio [OR], 0.53; 95% confidence interval [CI], .41-.69; P < .001; adjusted OR, 0.62; 95% CI, .50-.77; P < .001, for baseline score, age, and within-patient correlations). In subanalysis, influenza vaccination was also associated with lower scores (adjusted OR, 0.67; 95% CI, .50-.90; P = .007). Analyses of binary endpoints showed insignificant results. The ordinal outcome scale is a potentially useful clinical endpoint for influenza therapeutic trials, which could account for the diverse clinical trajectories of hospitalized patients, warranting further development.

Baloxavir for the treatment of Influenza in allogeneic hematopoietic stem cell transplant recipients previously treated with oseltamivir

Seasonal influenza causes significant morbidity and mortality in allogeneic stem cell transplant (SCT) recipients. In this population, influenza virus can replicate for prolonged periods, despite neuraminidase inhibitor treatment, leading to resistance and treatment failure. Baloxavir targets the influenza polymerase and may be an effective treatment option in these patients. We used baloxavir to treat five allogeneic SCT recipients that were still symptomatic and shedding influenza virus after completing one or more treatment courses of oseltamivir and characterized the viral isolates before and during treatment. Two patients were infected with influenza A/H1pdm09 carrying a neuraminidase variant (H275Y) linked to oseltamivir resistance. Both these two patients were successfully treated with baloxavir. Of the three patients infected with wild-type influenza virus, two cleared the virus after baloxavir treatment, while the third patient developed the polymerase I38T variant linked to baloxavir resistance. Our data suggest that baloxavir treatment can be effective in treating neuraminidase inhibitor-resistant influenza in profoundly immunocompromised patients. Randomized clinical trials are needed to define the role of baloxavir alone and combined with oseltamivir for the treatment of influenza in SCT recipients and other immunocompromised populations.

Impact of early neuraminidase inhibitor treatment on clinical outcomes in patients with influenza B-related pneumonia: a multicenter cohort study.

The aim of this study is to evaluate the impact of early (within 2days after disease onset) neuraminidase inhibitor (NAI) administration on clinical outcomes in patients with laboratory-confirmed influenza B-related pneumonia (FluB-p). This was a multicenter study conducted from 1 January 2013 to 1 May 2019. Data of immunocompetent adult and adolescent FluB-p patients hospitalized at five different teaching hospitals in China were retrospectively collected, including demographic and clinical features as well as clinical and treatment outcomes. Univariate and multivariate logistic regression analyses were performed to assess the effects of early NAI administration on clinical outcomes in FluB-p patients. In total, 386 hospitalized patients with community-onset FluB-p were included in this study, of whom 39.6% (153/386) were treated with NAI early. After adjusting for the weighted propensity scores of treatment, systemic corticosteroid, and antibiotic uses, the results of multivariate logistic regression model indicated that early NAI treatment was associated with the decreased risks of invasive ventilation [odd ratio (OR) 0.325, 95% confidence interval (CI) 0.123-0.858; p = 0.023), admittance to intensive care unit (OR 0.425, 95% CI 0.204-0.882; p = 0.022), and 30-day mortality (OR 0.416, 95% CI 0.184-0.944, p = 0.036)] in FluB-p patients. In addition, the multivariate logistic regression analysis revealed that early NAI treatment (OR 0.306, 95% CI 0.063-0.618; p = 0.010) was an independent predictor for 30-day mortality in patients with FluB-p. Early NAI treatment was associated with better clinical outcomes in FluB-p patients, which supports the recommendations of its use in severe influenza illness.

Pragmatic multicentre randomised controlled trial evaluating the impact of a routine molecular point-of-care ‘test-and-treat’ strategy for influenza in adults hospitalised with acute respiratory illness (FluPOC): trial protocol

BackgroundInfluenza infections often remain undiagnosed in patients admitted to hospital due to lack of routine testing. When tested for, the diagnosis and treatment of influenza are often delayed due to...

Influenza A virus hemagglutinin mutations associated with use of neuraminidase inhibitors correlate with decreased inhibition by anti-influenza antibodies

BackgroundVaccination and the use of neuraminidase inhibitors (NAIs) are currently the front lines of defense against seasonal influenza. The activity of influenza vaccines and antivirals drugs such as the NAIs can be affected by mutations in the influenza hemagglutinin (HA) protein. Numerous HA substitutions have been identified in nonclinical NAI resistance-selection experiments as well as in clinical specimens from NAI treatment or surveillance studies. These mutations are listed in the prescribing information (package inserts) for FDA-approved NAIs, including oseltamivir, zanamivir, and peramivir.MethodsNAI treatment-emergent H1 HA mutations were mapped onto the H1N1 HA1 trimeric crystal structure and most of them localized to the HA antigenic sites predicted to be important for anti-influenza immunity. Recombinant A/California/04/09 (H1N1)-like viruses carrying HA V152I, G155E, S162 N, S183P, and D222G mutations were generated. We then evaluated the impact of these mutations on the immune reactivity and replication potential of the recombinant viruses in a human respiratory epithelial cell line, Calu− 3.ResultsWe found that the G155E and D222G mutations significantly increased viral titers ~ 13-fold compared to the wild-type virus. The hemagglutination and microneutralization activity of goat and ferret antisera, monoclonal antibodies, and human serum samples raised against pandemic A(H1N1)pdm09 viruses was ~ 100-fold lower against mutants carrying G155E or D222G compared to the wild-type virus.ConclusionsAlthough the mechanism by which HA mutations emerge during NAI treatment is uncertain, some NAI treatment-emergent HA mutations correlate with decreased immunity to influenza virus.

Antibody dynamics in Japanese paediatric patients with influenza A infection treated with neuraminidase inhibitors in a randomised trial

Neuraminidase inhibitors (NAIs) complement influenza virus infection management by helping to clear virus, alleviate symptoms, and reduce transmission. In a previous randomised study, we examined the effect of 4 NAIs on virus clearance and influenza symptoms in Japanese paediatric patients. In this second analysis, we examined the effects of NAI treatment on antibody responses and virus clearance, and the relationships between antibody responses and patients’ infection histories (previous infection; asymptomatic infection via household members of same virus type/subtype; vaccination), and between infection histories and viral kinetics. Haemagglutination inhibition (HI) antibody responses produced HI titres ≥40 by Day 14 of NAI treatment, in parallel with virus clearance (trend test P = 0.001). Comparing patients with and without influenza infection histories (directly or asymptomatic infection via household members) showed that infection history had a marked positive effect on HI antibody responses in patients vaccinated before the current influenza season (before enrolment). Current virus clearance was significantly faster in patients previously infected with the same virus type/subtype than in those not previously infected, and clearance pattern depended on the NAI. Assessment of anti-influenza effects of antiviral drugs and vaccines should consider virus and antibody dynamics in response to vaccination and natural infection histories.

Neuraminidase Inhibitors and Hospital Length of Stay: A Meta-analysis of Individual Participant Data to Determine Treatment Effectiveness Among Patients Hospitalized With Nonfatal 2009 Pandemic Influenza A(H1N1) Virus Infection

BackgroundThe effect of neuraminidase inhibitor (NAI) treatment on length of stay (LoS) in patients hospitalized with influenza is unclear.MethodsWe conducted a one-stage individual participant data (IPD) meta-analysis exploring the association between NAI treatment and LoS in patients hospitalized with 2009 influenza A(H1N1) virus (A[H1N1]pdm09) infection. Using mixed-effects negative binomial regression and adjusting for the propensity to receive NAI, antibiotic, and corticosteroid treatment, we calculated incidence rate ratios (IRRs) and 95% confidence intervals (CIs). Patients with a LoS of <1 day and those who died while hospitalized were excluded.ResultsWe analyzed data on 18 309 patients from 70 clinical centers. After adjustment, NAI treatment initiated at hospitalization was associated with a 19% reduction in the LoS among patients with clinically suspected or laboratory-confirmed influenza A(H1N1)pdm09 infection (IRR, 0.81; 95% CI, .78–.85), compared with later or no initiation of NAI treatment. Similar statistically significant associations were seen in all clinical subgroups. NAI treatment (at any time), compared with no NAI treatment, and NAI treatment initiated <2 days after symptom onset, compared with later or no initiation of NAI treatment, showed mixed patterns of association with the LoS.ConclusionsWhen patients hospitalized with influenza are treated with NAIs, treatment initiated on admission, regardless of time since symptom onset, is associated with a reduced LoS, compared with later or no initiation of treatment.