Textbook of Influenza

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Respiratory Tract Infections: Influenza Virus – Respiratory Medicine - Lecturio

Webster Robert G. The Textbook of Influenza is a comprehensive resource covering all aspects of influenza, from the genetic and molecular biology of the virus through to clinical aspects of the disease and the latest drug developments and treatments. This new edition has been completely revised and reflects the integration of disciplines concerning the emergence, evolution, pathogenesis and control of influenza viruses in the field of human and veterinary public health. Textbook of Influenza examines the lessons learnt from the latest pandemic and provides the current state of knowledge for many yet unresolved issues related to virus origin, spread, pathogenesis and disease severity to better prepare for future pandemics.

Because of its essential role in viral replication, NA represents a potential target for antiviral therapy. By analysing its crystallographic structure and interaction with sialic acid, selective reverse competitive inhibitors have been developed All three compounds are highly active against a broad range of influenza A of human and avian origin and B viruses, including all nine NA subtypes in the avian reservoir. They tend to be less active in vitro against influenza B than influenza A neuraminidase.


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All three compounds inhibit amantadine and rimantadine resistant strains of influenza A. Zanamivir has poor oral bioavailability and consequently has been administered topically. The licensed formulation is administered as a dry-powder aerosol. Deposition studies have not been conducted in subjects with influenza or patients with obstructive airways disease.

Proton channels of influenza A and B viruses

Nonetheless, the data from the lung deposition studies suggest that the concentration of zanamivir throughout the airways is far in excess of the median inhibitory concentration IC50 values for zanamivir against the viral neuraminidases. Given the wide safety margin of zanamivir the possible increased exposure to zanamivir in patients with renal failure does not indicate a reduction in dosage during administration by oral inhalation.

Animal studies suggest good distribution throughout the respiratory tract. Both zanamivir and oseltamivir have been found to be effective in prevention and treatment of experimental influenza A infection in healthy volunteers 86 — Intravenous zanamivir was found to significantly reduce the cytokine and chemokine proinflammatory response seen in influenza infection A double-blind, placebo controlled study of aerosolized zanamivir, with or without intranasal delivery, was conducted during the — season in North America and Europe The antiviral spectrum and clinical effectiveness of zanamivir included both influenza A and B virus infections.

Self-administered inhaled zanamivir was used for a period of 5 days following enrolment. There was a mean reduction of 1. For afebrile patients, no benefit was observed and there was no difference between influenza A and B virus infections. There was a median reduction of 2.

Sixty-six per cent of patients enrolled had laboratory confirmed influenza. Zanamivir showed a clinically and statistically significant benefit with a 1-day reduction in the time to alleviation of symptoms in the healthy group and a 1. No dose difference between the oseltamivir treatment arms was noted Patients who received oseltamivir had significantly lower viral titres in nose and throat swabs without impairing humoral haemagglutinin inhibition immune response to infection No significant adverse effects were associated with drug prophylaxis.

Both once-daily and twice-daily administration of oseltamivir were effective against influenza infection.


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  • There was a higher rate of gastrointestinal side effects in those receiving oseltamivir, although the frequency of drug discontinuation was similar in both treatment and placebo groups There are limited data of neuraminidase inhibitors in the elderly and patients with high risk conditions including underlying cardiorespiratory disease.

    A small number of high risk patients included in two treatment studies of zanamivir were shown to have significant symptom benefit and reductions in complications and prescribed antibiotic treatment 91 , Results from studies of NA inhibitors in the immunocompromised, infants, and the frail elderly are awaited. No animal tetratogenicity has been reported but neuraminidase inhibitors pass through the placenta and also into breast milk and their use is best avoided in pregnancy unless there is life-threathening infection for the mother.

    Influenza viruses with reduced susceptibility to NA inhibitors have been isolated following sequential tissue culture passage of the virus in the presence of drugs. Two mechanisms of resistance have been identified. Firstly, resistant viruses may involve multiple mutations clustered close to or around the binding site of the viral haemagglutinin with its sialic acid receptors, thereby reducing efficiency of virus binding and decreasing dependence on NA function.

    Resistance may also arise from single amino acid substitutions in the highly conserved active site of neuraminidase in the central cleft of the global head There are differences in cross-resistance, e. NA mutant variants replicate in cell culture, but have reduced virulence in animal models Emergence of clinical resistance requires further study but appears rare.

    A study of over samples collected from oseltamivir-treated patients found five resistant variants by genotypic and neuraminidase assays, but these patients did not have a poorer clinical outcome Attempts to select in vitro influenza B mutants resistant to NA inhibitors have failed. However a zanamivir resistant influenza B virus was recovered from a bone-marrow transplant recipient following two weeks of treatment Most clinical trials of zanamivir and oseltamivir were performed in healthy volunteers and the drugs have low acute toxicity.

    There have been a number of post marketing reports of transient acute bronchospasm and reductions in spirometric lung volumes in some patients However, more serious deteriorations in respiratory function have been reported in some patients with pre-existing respiratory disease Oseltamivir has been well tolerated with no serious adverse effects reported in clinical treatment or prophylaxis trials.

    Textbook of Influenza : Robert G. Webster :

    It is associated with mild and transient gastrointestinal disturbance during the first two days of administration. In clinical trials, dropout rates were low and similar between treatment and placebo arms 95 , 96 , 98 — Neuraminidase inhibitors offer advances in treatment and chemoprophylaxis over M2 inhibitors due to their broader antiviral spectrum, proven efficacy with reduction of symptoms and complications, less potential for emergence of clinically resistant strains and for combating emerging influenza strains such as avian H5 and H9 for which vaccination is unavailable There may also be benefits in terms of delaying the emergence of drug resistance by decreasing unnecessary prescriptions 91 , There is however, a need to assess direct comparative studies between the drugs available, and to consider the effect of combination treatment.

    Several concerns have been raised regarding the prescription of NA inhibitors. Recommendations for their use in symptomatic patients of all age groups could theoretically overwhelm primary care physicians during outbreaks of influenza and other pathogens such as respiratory syncytial virus RSV.

    In addition, unexpected adverse effects such as possible exacerbations of pre-existing respiratory disease are always a potential problem with new therapies as they become more widely used. Delivery issues and compliance with intranasal administration in the frail elderly and young children may be problematic. Although no clinical resistance appeared in trial settings, careful surveillance is required, particularly in populations in whom delivery and compliance are suboptimal. A formal health-economic study is needed to address these concerns It remains to be seen if the neuraminidase inhibitors fulfil their clinical potential.

    Adapted from Influenza vaccine effectiveness in preventing pneumonia and influenza hospitalizations in the elderly.

    Textbook of Influenza, 2nd Edition

    Summary of trials in treatment of naturally acquired or experimentally induced influenza infection. Summary of seasonal and post contact prophylaxis with neuraminidase inhibitors. Chlamydia pneumoniae and the lung. Eur Respir J ; — Severity assessment in community-acquired pneumonia. Fungal infections in transplant recipients.

    watch Burkholderia cepacia : current clinical issues, environmental controversies and ethical dilemmas. Microbial investigation in ventilator-associated pneumonia. Bacteria, antibiotics and COPD. NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address. Skip to main content. Influenza: vaccination and treatment I. Stephenson , K. Abstract Few conditions exert such an enormous toll of absenteeism, suffering, medical consultations, hospitalization, death and economic loss as influenza.

    Structure and classification Influenza viruses are enveloped ribonucleic acid RNA viruses with a segmented genome belonging to the family of Orthomyxoviridae. Antigenic shift and drift Pandemics and epidemics arise as a result of changes in the HA. Inactivated vaccines Vaccination represents the mainstay for influenza prevention. Safety of inactivated vaccines Many millions of doses of split product and purified surface antigen vaccines are administered throughout the world each year and the overall rate of adverse reactions is low. Live cold-adapted reassortant vaccines The highest annual attack rates for influenza occur in children and observations suggest that schoolchildren are central to the spread of influenza within the community 33 , Other vaccines and vaccine developments The serum HAI antibody response to split and subunit influenza vaccines is generally lower in older people.

    Antiviral therapy M2 ion channel inhibitors The adamantanes, amantadine and rimantadine were discovered in the s to inhibit strains of influenza A. Neuraminidase inhibitors The enzyme neuraminidase NA sialidase is a tetramer composed of a cytoplasmic tail, transmembrane domain, stalk region and globular head. Clinical efficacy Both zanamivir and oseltamivir have been found to be effective in prevention and treatment of experimental influenza A infection in healthy volunteers 86 — Zanamivir A double-blind, placebo controlled study of aerosolized zanamivir, with or without intranasal delivery, was conducted during the — season in North America and Europe Use in special groups There are limited data of neuraminidase inhibitors in the elderly and patients with high risk conditions including underlying cardiorespiratory disease.

    Resistance Influenza viruses with reduced susceptibility to NA inhibitors have been isolated following sequential tissue culture passage of the virus in the presence of drugs. Adverse effects Most clinical trials of zanamivir and oseltamivir were performed in healthy volunteers and the drugs have low acute toxicity. Current status Neuraminidase inhibitors offer advances in treatment and chemoprophylaxis over M2 inhibitors due to their broader antiviral spectrum, proven efficacy with reduction of symptoms and complications, less potential for emergence of clinically resistant strains and for combating emerging influenza strains such as avian H5 and H9 for which vaccination is unavailable View this table: View inline View popup.

    Other Titles by Robert G. Webster & Arnold S. Monto & Thomas J. Braciale & Robert A. Lamb

    Table 1— Summary of trials in treatment of naturally acquired or experimentally induced influenza infection. Table 2— Summary of seasonal and post contact prophylaxis with neuraminidase inhibitors. Clinical features of influenza. Semin Respir Infect ; 7 : 26 — OpenUrl PubMed. Glezen WP. Serious morbidity and mortality associated with influenza epidemics.

    Epidemiol Review ; 4 : 25 — Survey of underlying conditions of persons hospitalised with acute respiratory disease during influenza epidemics in Houston — Am Rev Respir Dis ; : — Hay AJ. Functional properties of the virus ion channels. Textbook of Influenza Oxford, Blackwell, ;, pp. Influenza in pigs and their role as the intermediate host.

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    Antigenic drift and efficacy of influenza virus vaccines. J Infect Dis ; : — Clinical features and rapid diagnosis of human disease associated with avian influenza H5N1 virus. Lancet ; : — Human infection with influenza H9N2. Determinants of immunity to influenza infection in man. Br Med Bull ; 35 : 69 — Meiklejohn G. Viral respiratory disease at Lowry Air Force base in Denver — A clinical trial of influenza vaccine in Canberra. Med J Aust ; 2 : 6 — The efficacy of influenza vaccination in elderly individuals. A randomised double blind placebo-controlled trial.