Antiviral Therapy For Influenza Research Articles

Diagnosis, treatment, and prevention of community-acquired pneumonia in children: an evidence-based clinical practice guideline adapted for the use in Egypt using ‘Adapted ADAPTE’

BackgroundWe recently adapted a guideline for Community-Acquired Pneumonia (CAP) in children to the Egyptian health system. Adaptation of evidence-based clinical practice guidelines to the local healthcare context is a valid alternative to de novo development that can upgrade their application without enforcing a major burden on resources. The objective of this manuscript is to elucidate diagnosis, treatment, and prevention of CAP as well as methods used for the adaptation process to produce the 1st National Guideline for Community-Acquired Pneumonia in children in Egypt using Adapted ADAPTE method. The full process was described extensively with all three phases of set up, adaptation, and finalization. An adaptation group and an external review including clinical content experts and methodologists conducted the process.ResultsThe authors adapted 10 principal categories of recommendations from three source Clinical Practice Guidelines. Recommendations incorporate; common clinical manifestations, indications for hospitalization and intensive care unit admission, indications for laboratory investigations and radiology in diagnosis, choice of empiric antibiotic therapy in the outpatient and hospitalized children with non-complicated CAP and the duration of therapy, the role of influenza antiviral therapy, follow-up anticipated response to therapy, management of non-responding pneumonia, criteria of safe discharge, and prevention of CAP. Many tools were gathered and established to improve implement ability containing two clinical algorithms for management of non-complicated CAP and for non-responding pneumonia in children, pathway for assessment of severity of CAP in primary care facilities, medication tables, simplified Arabic patient information, PowerPoint slide presentation lecture for management of CAP, and online resources.ConclusionThe final clinical guideline supports pediatricians and related healthcare workers with evidence-based applicable guidance for managing community-acquired pneumonia in Egypt. This work demonstrated the efficiency of Adapted ADAPTE and highlighted the importance of a cooperative clinical and methodological professional group for adaptation of national guidelines.

Unveiling New Druggable Pockets in Influenza Non-Structural Protein 1: NS1-Host Interactions as Antiviral Targets for Flu.

Influenza viruses are responsible for significant morbidity and mortality worldwide in winter seasonal outbreaks and in flu pandemics. Influenza viruses have a high rate of evolution, requiring annual vaccine updates and severely diminishing the effectiveness of the available antivirals. Identifying novel viral targets and developing new effective antivirals is an urgent need. One of the most promising new targets for influenza antiviral therapy is non-structural protein 1 (NS1), a highly conserved protein exclusively expressed in virus-infected cells that mediates essential functions in virus replication and pathogenesis. Interaction of NS1 with the host proteins PI3K and TRIM25 is paramount for NS1's role in infection and pathogenesis by promoting viral replication through the inhibition of apoptosis and suppressing interferon production, respectively. We, therefore, conducted an analysis of the druggability of this viral protein by performing molecular dynamics simulations on full-length NS1 coupled with ligand pocket detection. We identified several druggable pockets that are partially conserved throughout most of the simulation time. Moreover, we found out that some of these druggable pockets co-localize with the most stable binding regions of the protein-protein interaction (PPI) sites of NS1 with PI3K and TRIM25, which suggests that these NS1 druggable pockets are promising new targets for antiviral development.

Comparative Analysis of Clinical and Epidemiological Characteristics in Patients with SARI Confirmed as Influenza or COVID-19 Admitted in a Tertiary Care Hospital in Bucharest, Romania

The COVID-19 pandemic has influenced the epidemiology of other respiratory pathogens, and this was most evident in the 2020–2021 season, which was characterized by a low circulation of influenza viruses. We aim to present a comparative analysis of clinical and epidemiological characteristics of 2018–2019 influenza cases and 2020–2021 COVID-19 cases, hospitalized at a tertiary infectious diseases hospital in Bucharest. We used data collected from patients admitted for severe acute respiratory infection (SARI) and subsequently confirmed with either influenza or COVID-19. During the 2018–2019 season, 208 patients over 18 years of age were confirmed with influenza (median age = 53 years, 59.6% were female) and 6.7% had been vaccinated against influenza. The most frequent symptoms were fever (97.1%) and cough (94.7%), and 77.4% had at least one chronic condition. 90.4% received influenza antiviral therapy. During the 2020–2021 season, 191 patients were confirmed with COVID-19 (median age = 56 years, 67% were male). The most frequent symptoms were cough (85.9%) and fever (80.6%), and 75.9% had at least one chronic condition. This analysis highlights the main similarities and differences between influenza and COVID-19 and could help to optimize the management of cases.

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

Factors Affecting the Incidence of Hospitalized Pneumonia after Influenza Infection in Korea Using the National Health Insurance Research Database, 2014-2018: Focusing on the Effect of Antiviral Therapy in the 2017 Flu Season.

BackgroundThis study aimed to investigate the effect of antiviral therapy following influenza outpatient episodes on the incidence of hospitalized pneumonia episodes, one of secondary complications of influenza.MethodsIn the National Health Insurance Research Database, data from July 2013 to June 2018 were used. All of the claim data with diagnoses of influenza and pneumonia were converted to episodes of care after applying 100 days of window period. With the 100-day episodes of care, the characteristics of influenza outpatient episodes and antiviral therapy for influenza, the incidence of hospitalized pneumonia episodes following influenza, and the effect of antiviral therapy for influenza on hospitalized pneumonia episodes were investigated.ResultsThe crude incidence rate of hospitalized pneumonia after influenza infection was 0.57% in both males and females. Factors affecting hospitalized pneumonia included age, income level except self-employed highest (only in females), municipality, medical institution type, precedent chronic diseases except hepatitis (only in females) and antiviral therapy. In the 2017 flu season, the relative risk was 0.38 (95% confidence interval [CI], 0.29–0.50) in males aged 0–9 and 0.43 (95% CI, 0.32–0.57) in females aged 0–9 without chronic diseases, and it was 0.51 (95% CI, 0.42–0.61) in males aged 0–9 and 0.42 (95% CI, 0.35–0.50) in females aged 0–9 with one or more chronic diseases in the aspect of the effect of antiviral therapy on pneumonia. It suggests that antiviral therapy may decrease the incidence of pneumonia after influenza infection.ConclusionAfter outpatient episode incidence of influenza, antiviral treatment has been shown to reduce the incidence of hospitalized pneumonia, especially in infants and children, during pandemic season 2017. Antiviral therapy for influenza is recommended to minimize burden caused by influenza virus infection and to reduce pneumonia. In addition, medical costs of hospitalization may decrease by antiviral therapy, especially in infants and children.

Utility of Rapid Influenza Molecular Testing in an Outpatient Hemodialysis Unit: A Prospective Cohort Study.

Background:Early initiation of antiviral therapy for individuals at risk for severe influenza infection is important for improving patient outcomes. Current guidelines recommend empiric antiviral therapy for patients with end-stage kidney disease presenting with suspected influenza infection. Rapid molecular influenza assays may reduce diagnostic uncertainty and improve patient outcomes by providing faster diagnostics compared to traditional batched polymerase chain reaction (PCR) testing.Objective:To determine the utility of implementing a rapid influenza PCR assay compared to the standard of care in a hemodialysis unit.Design:This is a prospective cohort study.Setting:A hospital-based dialysis unit in a tertiary care hospital.Patients:Adult patients with end-stage kidney disease on intermittent hemodialysis.Measurements:Patient characteristics, influenza PCR swab results, antibiotic prescriptions, antiviral prescriptions, emergency room visits and hospitalizations.Methods:From November 1, 2017 to March 31, 2018, we assigned samples collected from a single center, hemodialysis unit to be processed using a rapid influenza PCR (cobas® Influenza A/B & respiratory syncytial virus assay) or the standard of care (in-house developed multiplex PCR). Samples were assigned to the rapid PCR if the patient received dialysis treatment in the morning dialysis shift, while the remainder were processed as per standard of care. Study outcomes included the time from collection to result of nasopharyngeal swab, prescription of influenza antiviral therapy, time to receiving prescription, and the need for emergency department visit or hospitalization within 2 weeks of presentation.Results:During the study period, 44 patients were assessed (14 with the rapid PCR and 30 with the standard of care assay). Compared to conventional testing, the time to result was shorter using rapid PCR compared to conventional testing (2.3 vs 22.6 hours, P < .0001). Individuals who were tested using the rapid PCR had a tendency to shorter time to receiving antiviral prescriptions (0.7 days vs 2.1 days, P = .11), and fewer emergency department visits (7.1% vs 30%, P = .13) but no difference in hospitalizations (14.3% vs 30%, P = .46) within 2 weeks of testing.Limitations:This is a single center non-randomized study with a relatively small sample size. Patients who were tested using the standard of care assay experienced a delay in the prescription of antiviral therapy which deviates from recommended clinical practice.Conclusions:Rapid influenza molecular testing in the hemodialysis unit was associated with a shorter time to a reportable result and with a tendency to reduced time to prescription of antiviral therapy. Rapid molecular testing should be compared with standard of care (empiric therapy) in terms of economic costs, adverse events, and influenza-related outcomes.

Incidence of antiviral drug resistance markers among human influenza A viruses in the Eastern Mediterranean Region, 2005–2016

BackgroundTwo classes of antiviral drugs are available for influenza antiviral therapy: the adamantanes and the neuraminidase inhibitors (NAIs). Due to the emergence of adamantane-resistant variants, the use of these drugs has been largely limited in the world. The NAIs became the drugs of choice for treatment of influenza A infections. However, amino acid substitutions in the NA protein might lead to reduced sensitivity to NAIs. MethodsThe frequency and distribution of matrix protein 2 (M2) and neuraminidase (NA) variants which confer resistance to antiviral drugs was investigated in the Eastern Mediterranean Region (EMR) between 2005 and 2016. A total of 314 M2 and 1209 NA protein sequences from influenza A/H1N1, A/H1N1pdm09, A/H3N2, and A/H5N1 available in the public database were analyzed. ResultsEighty-six percent of the influenza A viruses detected in the EMR were resistant to adamantanes, among which, H3 strains exhibited the highest (95.32%) level of adamantane resistance. Approximately 98.51% (265/269) of influenza A/H1N1 and H3N2 resistant viruses had the S31N substitution in their M2 sequences. The V27A mutation was the only resistance marker found in A/H5N1 viruses and was detected at a frequency of 7.40% among the investigated viruses. Other resistant mutations L26F, A30T, G34E, and L38F were not detected in any of the variants. We found that 2.81% (n = 34) of the detected NA sequences from influenza A viruses possessed at least one NAI-resistant mutation and the vast majority of resistant viruses 79.41% (27/34) bear the H274Y mutation. The frequency of NAI-resistant viruses was 3.29% (24/729) for the H1N1pdm09, 10.64% (5/47) for the seasonal H1N1, and 4.06% (5/123) for H5N1 viruses. None of the H3N2 viruses analyzed during the study period were resistant to NAIs. ConclusionOur study reveals the emergence and spread of antiviral drug resistant influenza A viruses in the EMR and emphasizes the importance of continuous surveillance to maintain the effective use of the current antivirals.

Etiological structure and clinical manifestations of influenza in Khanty-Mansiysk autonomous District-Ugra

The aim of the study was to examine the incidence of influenza in epidemic seasons from 2000 to 2017 in Khanty-Mansi Autonomous Okrug — Yugra, analysis of selected pathogens flu, clinical course, outcomes, risk and contingent. Used by the Russian Agency management database Khanty-Mansijsky autonomous region-Yugra weekly influenza morbidity, hospitalization, deaths, results of antigenic analysis of selected influenza viruses (1203 biosample) various age groups of the population from 22-x administrative territories district. Clinical-Laboratory conducted a survey of 133 hospitalized patients, of whom 70 patients over 18 years and 63 child aged 7 months to 9 years. Results: when analyzing the highest rates of flu were reported in the period 2000-2007, with a significant reduction in the beyond. The incidence of flu is caused by a prior distribution of influenza A (H1N1-pdm), seasonal influenza A (H1N1) and influenza A (H3N2). Epidemic season 2016/17, due to the simultaneous circulation of influenza A virus (N3N2) (52.1%), influenza A (H1N1) (39.6%) and influenza virus B (8.3%), was the longest. High proportion of flu registered among children under 6 years (79%), as well as in non-immunized population (95%). Compared with adults, children with influenza A (H1N1-pdm) is characteristic fever lasting more than 3 febrile-x days (100%), a combination of intoxic index with qatar syndrome of the upper respiratory tract, 2 times more likely to develop viral and bacterial pneumonia (23.8%). See influenza antiviral therapy high efficiency drug oseltamivir (Tamiflu) in children and adults.

Clinical and pharmacological approaches to present-day influenza anti-viral therapy

Up to 646,000 people worldwide die from seasonal influenza-related respiratory illnesses each year. According to new estimates by WHO, the prevalence of three strains of the influenza virus is expected in the 2017-2018 epidemic season: Influenza A (H1N1), A (H3N2), and influenza B viruses. In this regard, the issue of prescribing rational etiotropic antiviral therapy becomes particularly topical. Neuraminidase inhibitors are currently the first line drugs that are recommended by WHO for the treatment and prevention of influenza.

Cell culture-based production of defective interfering particles for influenza antiviral therapy

Defective interfering particles (DIPs) lack an essential portion of the virus genome, but retain signals for replication and packaging, and therefore, interfere with standard virus (STV) replication. Due to this property, DIPs can be potential antivirals. The influenza A virus DIP DI244, generated during propagation in chicken eggs, has been previously described as a potential candidate for influenza antiviral therapy. As a cell culture-based manufacturing process would be more suitable to fulfill large-scale production needs of an antiviral and enables full process control in closed systems, we investigated options to produce DI244 in the avian cell line AGE1.CR.pIX in chemically defined suspension culture. With a DI244 fraction of 55.8% compared to STV, the highest DI244 yield obtained from 50 million cells was 4.6 × 109 vRNA copies/mL at 12 h post infection. However, other defective genomes were also detected. Since these additionally produced defective particles are non-infectious, they might be still useful in antiviral therapies. In case they would interfere with quality of the final product, we examined the impact of virus seeds and selected process parameters on DI244 yield and contamination level with other defective particles. With a DI244 fraction of 5.5%, the yield obtained was 1.7 × 108 vRNA copies/mL but now without additional defective genomes. Although the DI244 yield might be decreased in this case, such controlled manufacturing conditions are not available in chicken eggs. Overall, the application of these findings can support design and optimization of a cell culture-based production process for DIPs to be used as antivirals.

The PA Endonuclease Inhibitor RO-7 Protects Mice from Lethal Challenge with Influenza A or B Viruses.

Current influenza treatment relies on a single class of antiviral drugs, the neuraminidase inhibitors (NAIs), raising concern over the potential emergence of resistant variants and necessitating the development of novel drugs. In recent years, investigational inhibitors targeting the endonuclease activity of the influenza acidic polymerase (PA) protein have yielded encouraging results, although there are only limited data on their in vivo efficacy. Here, we examined the antiviral potential of the PA endonuclease inhibitor RO-7 in prophylactic and therapeutic regimens in BALB/c mice inoculated with influenza A/California/04/2009 (H1N1)pdm09 or B/Brisbane/60/2008 viruses, which represent currently circulating antigenic variants. RO-7 was administered to mice intraperitoneally twice daily at dosages of 6, 15, or 30 mg/kg/day for 5 days, starting 4 h before or 24 or 48 h after virus inoculation, and showed no adverse effects. Prophylactic administration completely protected mice from lethal infection by influenza A or B virus. The level of therapeutic protection conferred depended upon the time of treatment initiation and RO-7 dosage, resulting in 60 to 100% and 80 to 100% survival with influenza A and B viruses, respectively. RO-7 treatment significantly decreased virus titers in the lung and lessened the extent and severity of lung damage. No PA endonuclease-inhibitor resistance was observed in viruses isolated from lungs of RO-7-treated mice, and the viruses remained susceptible to the drug at nanomolar concentrations in phenotypic assays. These in vivo efficacy results further highlight the potential of RO-7 for development as antiviral therapy for influenza A and B virus infections.

Burden of influenza B virus infections in Scotland in 2012/13 and epidemiological investigations between 2000 and 2012.

We describe the burden of influenza B infections in Scotland during a 13-year study period. Influenza A and B viruses cocirculated throughout the period, with numbers of influenza B cases approaching or exceeding those of influenza A during six influenza seasons. Influenza B viruses of both Victoria and Yamagata lineage were detected in two of six seasons investigated. For the 2012/13 season, influenza B accounted for 44.4% of all influenzas, with the highest incidence in those under the age of five years. Influenza B virus infections led to fewer admissions to an intensive care unit (ICU) and a lower mortality rate than influenza A (37 vs 81 ICU admissions and three vs 29 deaths) during the 2012/13 season. However, a quarter of those admitted to ICU with influenza B had not been immunised and 60% had not received specific influenza antiviral therapy. This highlights the need for consistent influenza vaccination and prompt usage of antiviral treatment for identified risk groups. Combining the newly introduced vaccination programme for children with the use of a tetravalent vaccine may provide the opportunity to improve the control of influenza B in those with the highest influenza B burden, children and young adolescents.

Analyzing the relationship of QT interval and exposure to Nitazoxanide, a prospective candidate for influenza antiviral therapy—A formal TQT study

In this randomized, double-blind, placebo controlled study, the safety of therapeutic (675 mg) and supra-therapeutic (2,700 mg) doses of nitazoxanide was evaluated in accordance with the ICH E14 guidelines. Fifty six (56) subjects participated in four treatment periods and received single doses of nitazoxanide 675 mg, nitazoxanide 2,700 mg, moxifloxacin 400 mg, or placebo. For 675 mg nitazoxanide, the largest change in QTcF from baseline was observed at 12 hours post-dose with a peak value of 1.6 ms (two-sided 90% CI: -0.3, 3.6 ms). The largest negative change in QTcF was observed at 1 hour post-dose (-2.7 ms with two-sided 90% CI: -4.5, -0.8 ms). The largest change in QTcF from baseline for 2,700 mg nitazoxanide was observed at 24 hours post-dose with a peak value of 3.4 ms (two-sided CI: 1.4, 5.4 ms). These findings demonstrate that neither a single dose of 675 mg nor 2,700 mg nitazoxanide prolonged the QT interval in healthy male and female volunteers. The safety results also demonstrate that all four treatments were well-tolerated and the most frequently reported adverse events in the nitazoxanide and moxifloxacin treatment groups were gastrointestinal disorders which were as expected according to the reference safety information.

FLU IN PREGNANT WOMEN

It is shown that in addition to increased susceptibility in pregnant women to influenza virus in them more often severe and complicated forms of the infection are recorded. The frequency of mortality from influenza, complicated by pneumonia, in the mothers during the pandemic period in 2009 was 2.5% and perinatal loss amounted to 8.3%. There are presented data on the relationship of the disease of pregnant women with influenza with developmental malformations in their offsprings. Obstetric tactic is determined individually for each pregnant depending on the period of parturition. Antiviral therapy of influenza A (H1N1) pdm09 in pregnant with arbidol drugs, oseltamivir, viferon reduced the rate of preterm labors, congenital pneumonia and cerebral ischemia in newborns. The main methods of preventing influenza is vaccination, which is allowed from the II trimester of gestation. Post-exposure antiviral chemoprophylaxis in pregnants is expedient to perform with zanamivir. There are listed all the errors in the management of pregnant women with influenza, which significantly reduced the effectiveness of treatment and increased incidence of adverse outcomes.

HIV-Infected Hospitalized Patients with 2009 Pandemic Influenza A (pH1N1)—United States, Spring and Summer 2009

We describe the clinical findings of HIV-infected patients hospitalized with 2009 pandemic influenza A (pH1N1). Data were derived from 3 separate case series in the United States. Among 911 adults hospitalized with pH1N1 influenza, 31 (3.4%) were HIV infected compared with an HIV prevalence of 0.45% in the general US adult population. HIV-infected influenza patients experienced similar rates of intensive care unit admission (29% vs 34%) and death (13% vs 13%) compared with non-HIV-infected patients. Among HIV-infected patients with available data, 14 (50%) of 28 patients had a CD4 cell count <200 cells/μL, which was not associated with an increased risk of an intensive care unit admission or death. Overall, 25 (81%) HIV-infected patients received influenza antiviral therapy, but treatment was initiated within 48 h of illness onset in only 33% of cases. Clinicians should consider early empiric influenza antiviral treatment in HIV-infected patients presenting with suspected influenza.

Clinical presentation and prognosis of the 2009 H1N1 influenza A infection in HIV-1-infected patients: a Spanish multicenter study

The aim of the study was to describe the clinical presentation and prognosis in HIV-1-infected patients with hospital admission and pandemic influenza A 2009 (H1N1) confirmed, and compare this data with those of a general population. : This is a prospective study in nature. All adult patients admitted to 13 hospitals in Spain with confirmed influenza A 2009(H1N1) virus infection by real-time reverse transcriptase PCR assay or culture from June 12 to November 10, 2009 were recruited and followed up until 1 month after discharge. In the HIV group risk factors for HIV infection, AIDS criteria, last CD4 cell count and viral load, and antiretroviral therapy and pneumococcal vaccines were collected. Five hundred and eighty-five patients were recruited, 26 with HIV-1 infection and 559 non-HIV. The HIV patients had a long-term well controlled infection with a median CD4 cell count 503 cells/μl and 84% with undetectable viral load, although more frequently they had chronic liver and chronic obstructive pulmonary disease. No significant differences were observed about reported symptoms and physical findings on hospital admission. About 50% of patients in both groups present radiological infiltrates and 30% present respiratory failures. Practically all the patients in both groups received influenza antiviral therapy and in each group 80% received antibacterial therapy. No differences were observed in clinical outcomes. In HIV patients, well controlled on HAART, the pandemic influenza virus AH1N1 had a similar clinical outcome and prognosis to that of non-HIV patients.

Oseltamivir Treatment Prevents the Increased Influenza Virus Disease Severity and Lethality Occurring in Chronic Ethanol Consuming Mice

Chronic consumption of ethanol (EtOH) is well recognized to lead to defective innate and adaptive immune responses and increase the severity of pulmonary infections. Our own studies have demonstrated that chronic EtOH consumption decreases CD8 T-cell immunity to influenza virus infections (IAV) leading to severe infections and mortality. Interestingly, antiviral treatment of IAVs has been shown to be compromised in mice and humans that are immuno-deficient. It is known that EtOH can alter the pharmacokinetics of antivirals. Therefore, the effectiveness of influenza antiviral therapy during chronic ethanol consumption remains in question. BALB/c mice were placed on 18% (w/v) EtOH in their drinking water for 8 weeks. Chronic EtOH consuming and water controls were then treated with 10 mg/kg oseltamivir orally and infected intranasally with influenza virus 4 hours post-oseltamivir treatment. The mice were then treated with oseltamivir twice daily until day 7 postinfection. Influenza disease severity was measured by morbidity and mortality, pulmonary viral titers, and histology. Chronic EtOH consuming mice infected with IAV and treated with oseltamivir have decreased morbidity and mortality, pulmonary viral titers, and pulmonary pathology compared to untreated EtOH mice. Despite the severe immune defect seen in chronic EtOH mice as well as the potential for EtOH to inhibit the conversion of oseltamivir into an active form, treatment with oseltamivir reduces viral shedding as well as disease severity. These data suggest that the combination of a limited adaptive immune response plus the anti-IAV drug oseltamivir is sufficient to curb high mortality and mediate resolution of IAVs in mice chronically consuming ethanol.

Kinetics of Influenza A Virus Infection in Humans

Currently, little is known about the viral kinetics of influenza A during infection within an individual. We utilize a series of mathematical models of increasing complexity, which incorporate target cell limitation and the innate interferon response, to examine influenza A virus kinetics in the upper respiratory tracts of experimentally infected adults. The models were fit to data from an experimental H1N1 influenza A/Hong Kong/123/77 infection and suggest that it is important to include the eclipse phase of the viral life cycle in viral dynamic models. Doing so, we estimate that after a delay of approximately 6 h, infected cells begin producing influenza virus and continue to do so for approximately 5 h. The average lifetime of infected cells is approximately 11 h, and the half-life of free infectious virus is approximately 3 h. We calculated the basic reproductive number, R(0), which indicated that a single infected cell could produce approximately 22 new productive infections. This suggests that antiviral treatments have a large hurdle to overcome in moderating symptoms and limiting infectiousness and that treatment has to be initiated as early as possible. For about 50% of patients, the curve of viral titer versus time has two peaks. This bimodal behavior can be explained by incorporating the antiviral effects of interferon into the model. Our model also compared well to an additional data set on viral titer after experimental infection and treatment with the neuraminidase inhibitor zanamivir, which suggests that such models may prove useful in estimating the efficacies of different antiviral therapies for influenza A infection.

Pharmacoeconomics of Antiviral Therapy for Influenza in a Japanese Hospital Setting

We constructed a cost-effectiveness decision model to determine a hypothetical 'best treatment' pathway for patients presenting at our institution with influenza virus infection when the choice of treatment was either oseltamivir, zanamivir or a control therapy not active against influenza. The decision model was constructed using DATA 3.5 for evaluating the cost-effectiveness analysis of neuraminidase inhibitors from the perspective of the healthcare payer. The time horizon was set at 14 days based on the general duration of influenza infection in Japan. Clinical outcomes were mainly derived from reports and guidance published by the National Institute for Clinical Excellence in the UK. Japan-specific cost parameters incorporated into the decision model were taken from the Medical Fee Point Survey conducted at St Luke's International Hospital in accordance with medical fee receipts kept at our institution. The study included four professionals and a supporter who gathered information required for the analysis. In otherwise healthy adults, cost savings of yen831.6 (approximately $US6.72; 2002 values) in the oseltamivir group and an increment in cost of yen40.5 (approximately $US0.33) in the zanamivir group were achieved in comparison with the control group. In contrast, an incremental cost of yen288.4 (approximately $US2.33) was incurred in the oseltamivir group versus the control group when at-risk patients were assessed, but cost savings of yen159.8 (approximately $US1.29) were achieved in the zanamivir group. As a result of cost-effectiveness and cost-utility analyses in otherwise healthy adults, oseltamivir dominated the control therapy because cost savings in the oseltamivir group were made. In the zanamivir group the cost was incremental and the Incremental Cost-Utility Ratio (ICUR) compared with the control group was about yen13 000 (approximately $US107.34)/quality-adjusted life-year (QALY) gained. As a result of cost-effectiveness and cost-utility analyses in at-risk patients, in the oseltamivir group the cost was incremental and the ICUR compared with the control group was about yen230 000 (approximately $US2138.77)/QALY gained. As cost savings were made, zanamivir dominated the control therapy. While the cost effectiveness (from the perspective of a healthcare payer) of the neuraminidase inhibitors was superior to that of the control group in the treatment of otherwise healthy adults with influenza in our study, it seemed necessary to take other factors into consideration before recommending one agent over the other as a first-line therapy. On the other hand, we suggest that zanamivir is the drug of choice for use in at-risk patients, and we recommend, in the light of our results, that if zanamivir is not available another therapy should be given rather than oseltamivir. Since with influenza infections deaths and hospitalisations of at-risk patients impact on the Japanese community, decision-making on the appropriate therapy should take into account the particular patient group involved.

Combination anti-inflammatory and antiviral therapy of influenza in a cotton rat model.

The cotton rat was evaluated as a model for anti-inflammatory and antiviral influenza therapy. Beginning 3 days after intranasal infection with 10(7) tissue culture infectious doses-50% (TCID)(50) of an H3N2 human influenza, animals were treated topically via intranasal lavage with a range of doses of triamcinolone acetonide (1, 4, or 16 mg/kg), alone or in combination with a neuraminidase inhibitor or anti-influenza convalescent serum. Pulmonary histopathologic changes were dramatically decreased in animals treated with 4 or 16 mg/kg of triamcinolone, with little additional benefit from addition of a neuraminidase inhibitor or topical serum, agents which were much less effective when used alone. A high degree of suppression of IFN-gamma levels was observed in all combinations where 4 or 16 mg/kg of triamcinolone were used. Viral replication was not prolonged by corticosteroid therapy. Tissue damage during influenza infection may be greatly reduced by combination antiviral and anti-inflammatory therapy.