Clinical Drug Investigation

, Volume 21, Issue 6, pp 443–452 | Cite as

New Approaches for Managing Influenza in Primary Care

  • Martin Ehlers
  • Chris Silagy
  • Douglas Fleming
  • Daryl Freeman
Review Article

Abstract

Influenza outbreaks occur annually on a seasonal basis, usually in the winter, and are responsible for substantial global morbidity and mortality, particularly amongst patients at high risk of complications. Influenza also places a significant clinical and economic burden on the healthcare system and management is largely the responsibility of primary-care practitioners (PCPs), who are often the first point of contact for patients. Diagnosis is usually made on clinical grounds, which is 60 to 70% accurate when influenza is known to be circulating locally. Vaccination remains the cornerstone for influenza management and protects the majority of at-risk patients, but vaccine effectiveness depends on correct prediction of the circulating strain and it is reduced in immunosuppressed and elderly patients. Until recently the options for treatment of influenza were very limited, with the primary recommendations being bedrest and treatment of symptoms only. In some countries the amantadine and rimantadine antiviral drugs have been available to treat influenza for some years, but use of these agents is limited by the incidence of adverse events, rapid development of resistance, and the fact that their activity is restricted to influenza A. Zanamivir (Relenza™, Glaxo Wellcome) is the first neuraminidase inhibitor to be approved for use in the treatment of influenza A and B. Oseltamivir (Tamiflu™, F. Hoffmann-La Roche) is similarly active against influenza A and B, and in clinical trials both drugs were shown reduce the median time to alleviation of influenza symptoms by 1 to 2.5 days (zanamivir) and 1.2 to 1.3 days (oseltamivir). Both agents were well tolerated, zanamivir having a safety profile similar to placebo and oseltamivir producing mild nausea and vomiting in some patients. Zanamivir is administered by oral inhalation delivering the drug directly to the respiratory tract, and oseltamivir, a prodrug, is taken in the form of a pill. In short-term use, no resistance to zanamivir has been seen so far, while resistance to oseltamivir is reported to be 3% in adults and 8% in children, although resistant viruses have low infectivity. While vaccines will continue to be the mainstay of the influenza pre-season management programme, the advent of neuraminidase inhibitors presents a new opportunity to manage influenza within the primary-care setting and will allow PCPs to plan ahead for their increased workload during the influenza season. Education is essential to ensure that patients consult within 48 hours, and possible practical measures to reduce the PCP’s workload include developing the role of nurses to make the initial diagnosis.

Keywords

Chronic Obstructive Pulmonary Disease Influenza Oseltamivir Amantadine Influenza Season 

Notes

Acknowledgements

This review is loosely based on material presented at a Glaxo Wellcome-sponsored satellite symposium held on 5 July 2000 at the 6th European Conference on General Practice and Family Medicine (WONCA 2000), in Vienna, Austria.

References

  1. 1.
    Nguyen-Van-Tam J. Epidemiology of influenza. In: Nicholson KG, Webster RG, Hay AJ, editors. Textbook of Influenza. Oxford: Blackwell Science, 1998: 181–206Google Scholar
  2. 2.
    Chew FT, Doraisingham S, Ling AE, et al. Seasonal trends of viral respiratory tract infections in the tropics. Epidemiol Infect 1998; 121: 121–8PubMedCrossRefGoogle Scholar
  3. 3.
    Nicholson KG. Managing influenza in primary care. Oxford: Blackwell Science, 1999Google Scholar
  4. 4.
    Fleming DM. The contribution of influenza to combined acute respiratory infections, hospital admissions, and deaths in winter. Commun Dis Public Health 2000; 3: 32–8PubMedGoogle Scholar
  5. 5.
    Connolly AM, Salmon RL, Lervy B, Williams DH. What are the complications of influenza and can they be prevented? Experience from the 1989 epidemic of H3N2 influenza A in general practice. BMJ 1993; 306: 1452–4PubMedCrossRefGoogle Scholar
  6. 6.
    Teichtahl H, Buckmaster N, Pertnikovs E. The incidence of respiratory tract infection in adults requiring hospitalization for asthma. Chest 1997; 112: 591–6PubMedCrossRefGoogle Scholar
  7. 7.
    Philit F, Etienne J, Calvet A, et al. Infectious agents associated with exacerbations of chronic obstructive bronchopneumopathies and asthma attacks. Rev Mal Respir 1992; 9: 191–6PubMedGoogle Scholar
  8. 8.
    Roldaan AC, Masural N. Viral respiratory infections in asthmatic children staying in a mountain resort. Eur J Respir Dis 1982; 63: 140–50PubMedGoogle Scholar
  9. 9.
    Brocklebank JT, Court SD, McQuillin J, et al. Influenza-A infection in children. Lancet 1972; 2: 497–500PubMedCrossRefGoogle Scholar
  10. 10.
    Nicholson KG. Human influenza. In: Nicholson KG, Webster RG, Hay AJ, editors. Textbook of Influenza. Oxford: Black-well Science, 1998: 219–66Google Scholar
  11. 11.
    Carrat F, Flahault A, Boussard E, et al. Surveillance of influenza-like illness in France. The example of the 1995/1996 epidemic. J Epidemiol Community Health 1998; 52Suppl. 1: 32S–8SPubMedGoogle Scholar
  12. 12.
    Barker WH, Mullooly JP. Impact of epidemic type A influenza in a defined adult population. Am J Epidemiol 1980; 112: 798–811PubMedGoogle Scholar
  13. 13.
    Cox NJ, Bender CA. The molecular epidemiology of influenza viruses. Semin Virol 1995; 6: 359–70CrossRefGoogle Scholar
  14. 14.
    Scholtissek C. Genetic reassortaient of human influenza viruses in nature. In: Nicholson KG, Webster RG, Hay AJ, editors. Textbook of Influenza. Oxford: Blackwell Science, 1998: 120–5Google Scholar
  15. 15.
    Scholtissek C, Hinshaw VS, Olsen CW. Influenza in pigs and their role as the intermediate host. In: Nicholson KG, Webster RG, Hay AJ, editors. Textbook of Influenza. Oxford: Black-well Science, 1998: 137–45Google Scholar
  16. 16.
    Cox NJ, Brammer TL, Regnery HL. Influenza: global surveillance for epidemic and pandemic variants. Eur J Epidemiol 1994; 10: 467–70PubMedCrossRefGoogle Scholar
  17. 17.
    Recommended composition of influenza virus vaccines for use in 2000. Wkly Epidemiol Rec 1999; 74: 321–5Google Scholar
  18. 18.
    Zambon M. Laboratory diagnosis of influenza. In: Nicholson K, Webster R, Hay A, editors. Textbook of Influenza. Oxford: Blackwell Science, 1998: 291–313Google Scholar
  19. 19.
    Cram P, Blitz S, Monto A, et al. Diagnostic testing for influenza: review of current status and implications of newer treatment options. Am J Managed Care 1999; 5(12): 1555–61Google Scholar
  20. 20.
    The MIST (Management of Influenza in the Southern Hemisphere Trialists) Study Group. Randomised trial of efficacy and safety of inhaled zanamivir in treatment of influenza A and B virus infections. Lancet 1998; 352: 1877–81CrossRefGoogle Scholar
  21. 21.
    Mäkelä MJ, Pauksens K, Rostila T, et al. Clinical efficacy and safety of the orally inhaled neuraminidase inhibitor zanamivir in the treatment of influenza: a randomized, double-blind, placebo-controlled European study. J Infect 2000; 40: 42–8PubMedCrossRefGoogle Scholar
  22. 22.
    Monto A, Ohmit S. The evolving epidemiology of influenza infection and disease. In: Brown L, Hampson A, Webster R, editors. Options for the control of influenza III. Amsterdam: Excerpta Medica, 1996: 45–9Google Scholar
  23. 23.
    Monto AS, Gravenstein S, Elliott M, et al. Clinical signs and symptoms predicting influenza positivity. Arch Intern Med 2000; 160: 3243–7PubMedCrossRefGoogle Scholar
  24. 24.
    Nichol KL, Lind A, Margolis KL, et al. The effectiveness of vaccination against influenza in healthy, working adults. N Engl J Med 1995; 333: 889–93PubMedCrossRefGoogle Scholar
  25. 25.
    Nichol KL, Goodman M. The health and economic benefits of influenza vaccination for healthy and at-risk persons aged 65 to 74 years. Pharmacoeconomics 1999; 16: 63–71PubMedCrossRefGoogle Scholar
  26. 26.
    Nichol KL, Wuorenma J, von Sternberg T. Benefits of influenza vaccination for low-, intermediate-, and high-risk senior citizens. Arch Intern Med 1998; 158: 1769–76PubMedCrossRefGoogle Scholar
  27. 27.
    Bridges CB, Thompson WW, Meltzer MI, et al. Effectiveness and cost-benefit of influenza vaccination of healthy working adults: a randomized controlled trial. JAMA 2000; 284: 1655–63PubMedCrossRefGoogle Scholar
  28. 28.
    Snacken R. Control of influenza. Public health policies. Vaccine 1999; 17: S61–3PubMedCrossRefGoogle Scholar
  29. 29.
    Bernstein E, Kaye D, Abrutyn E, et al. Immune response to influenza vaccination in a large healthy elderly population. Vaccine 1999; 17: 82–94PubMedCrossRefGoogle Scholar
  30. 30.
    Levine M, Beattie B, McLean D, et al. Characterization of the immune response to trivalent influenza vaccine in elderly men. J Am Geriatr Soc 1987; 35: 609–15PubMedGoogle Scholar
  31. 31.
    Uptake of influenza vaccine in high risk patients. Commun Dis Rep Wkly 1997; 7: 401, 404Google Scholar
  32. 32.
    Wang C, Takeuchi K, Pinto LH, et al. Ion channel activity of influenza A virus M2 protein: characterization of the amantadine block. J Virol 1993; 67: 5585–94PubMedGoogle Scholar
  33. 33.
    Hayden FG, Gwaltney JM Jr, Van de Castle RL, et al. Comparative toxicity of amantadine hydrochloride and rimantadine hydrochloride in healthy adults. Antimicrob Agents Chemo-ther 1981; 19: 226–33CrossRefGoogle Scholar
  34. 34.
    Keyser LA, Karl M, Nafziger AN, et al. Comparison of central nervous system adverse effects of amantadine and rimantadine used as sequential prophylaxis of influenza A in elderly nursing home patients. Arch Intern Med 2000; 160: 1485–8PubMedCrossRefGoogle Scholar
  35. 35.
    Guay DR. Amantadine and rimantadine prophylaxis of influenza A in nursing homes. A tolerability perspective. Drugs Aging 1994; 5: 8–19PubMedCrossRefGoogle Scholar
  36. 36.
    Hayden FG, Hay AJ. Emergence and transmission of influenza A viruses resistant to amantadine and rimantadine. Curr Top Microbiol Immunol 1992; 176: 119–30PubMedCrossRefGoogle Scholar
  37. 37.
    Aoki FY. Amantadine and rimantadine. In: Nicholson KG, Webster RG, Hay AJ, editors. Textbook of Influenza. Oxford: Blackwell Science, 1998: 457–46Google Scholar
  38. 38.
    Zambon M. Epidemiology and pathogenesis of influenza. J Antimicrob Chemother 1999; 44: 3–9PubMedCrossRefGoogle Scholar
  39. 39.
    Colman PM, Varghese JN, Laver WG. Structure of the catalytic and antigenic sites in influenza virus neuraminidase. Nature 1983; 303: 41–4PubMedCrossRefGoogle Scholar
  40. 40.
    Cass LM, Brown J, Pickford M, et al. Pharmacoscintigraphic evaluation of lung deposition of inhaled zanamivir in healthy volunteers. Clin Pharmacokinet 1999; 36: 21–31PubMedCrossRefGoogle Scholar
  41. 41.
    Silagy C, Watts R. Zanamivir, a new targeted therapy in the treatment of influenza —a patient perspective assessed by questionnaire. Clin Drug Invest 2000; 19: 111–21CrossRefGoogle Scholar
  42. 42.
    Johnson R, Schweinle J, Burroughs S. Zanamivir for the treatment of influenza in clinical practice: results of the Valuable-Insights-from-Patients study. Clin Drug Invest 2000; 20(5): 327–36CrossRefGoogle Scholar
  43. 43.
    He G, Massarella J, Ward P. Clinical pharmacokinetics of the prodrug oseltamivir and its active metabolite Ro 64-0802. Clin Pharmacokinet 1999; 37: 471–84PubMedCrossRefGoogle Scholar
  44. 44.
    Lalezari J, Klien T, Stapleton J, et al. The efficacy and safety of inhaled zanamivir in the treatment of influenza in otherwise healthy and ‘high risk’ individuals in North America. J Antimicrob Chemother 1999; 44: 42Google Scholar
  45. 45.
    Hayden FG, Osterhaus AD, Treanor JJ, et al. Efficacy and safety of the neuraminidase inhibitor zanamivir in the treatment of influenza virus infections. N Engl J Med 1997; 337: 874–80PubMedCrossRefGoogle Scholar
  46. 46.
    Monto AS, Fleming DM, Henry D, et al. Efficacy and safety of the neuraminidase inhibitor zanamivir in the treatment of influenza A and B virus infections. J Infect Dis 1999; 180: 254–61PubMedCrossRefGoogle Scholar
  47. 47.
    Treanor JJ, Hayden FG, Vrooman PS, et al. Efficacy and safety of the oral neuraminidase inhibitor oseltamivir in treating acute influenza: a randomized controlled trial. US Oral Neuraminidase Study Group. JAMA 2000; 283: 1016–24PubMedCrossRefGoogle Scholar
  48. 48.
    Nicholson KG, Aoki FY, Osterhaus AD, et al. Efficacy and safety of oseltamivir in treatment of acute influenza: a randomised controlled trial. Neuraminidase Inhibitor Flu Treatment Investigator Group. Lancet 2000; 355: 1845–50PubMedCrossRefGoogle Scholar
  49. 49.
    The MIST (Management of Influenza in the Southern Hemisphere Trialists) Study Group. Randomised trial of efficacy and safety of inhaled zanamivir in treatment of influenza A and B virus infections. Lancet 1998; 352: 1877–81CrossRefGoogle Scholar
  50. 50.
    Monto AS, Webster A, Keene O. Randomised, placebo-controlled studies of inhaled zanamivir in the treatment of influenza A and B: pooled efficacy analysis. J Antimicrob Chemother 1999; 44: 23–9PubMedCrossRefGoogle Scholar
  51. 51.
    Fleming DM, Moult AB, Keene O. Indicators and significance of severity in influenza patients. Options for the control of influenza IV. Crete, Greece: Hersonissos, 2000. Elsevier Science BV. In pressGoogle Scholar
  52. 52.
    Lalezari J, Campion K, Keene O, et al. Zanamivir for the treatment of influenza A and B infection in high-risk patients: a pooled analysis of randomized controlled trials. Arch Intern Med 2001; 161: 212–7PubMedCrossRefGoogle Scholar
  53. 53.
    Zaug M, Mahoney P, Ward P. Effective treatment of influenza with oral oseltamivir in a vaccinated population of high risk patients. Options for the control of influenza IV. Crete, Greece: Hersonissos, 2000. Elsevier Science BV. In pressGoogle Scholar
  54. 54.
    Murphy KR, Eivindson A, Pauksens K, et al. The efficacy and safety of inhaled zanamivir for the treatment of influenza in patients with asthma or chronic obstructive pulmonary disease: a double-blind, randomised, placebo-controlled, multicentre study. Clin Drug Invest 2000; 20(5): 337–49CrossRefGoogle Scholar
  55. 55.
    Freund B, Gravenstein S, Elliott M, Miller I. Zanamivir: a review of clinical safety. Drug Saf 1999; 21: 267–81PubMedCrossRefGoogle Scholar
  56. 56.
    Hayden FG, Treanor JJ, Fritz RS, et al. Use of the oral neuraminidase inhibitor oseltamivir in experimental human influenza: randomized controlled trials for prevention and treatment. JAMA 1999; 282: 1240–6PubMedCrossRefGoogle Scholar
  57. 57.
    Glaxo Wellcome. Relenza: European summary of product characteristics, 2000Google Scholar
  58. 58.
    Tamiflu®. Technical information of the Swiss Medicines Compendium: F. Hoffman-La Roche, 1999Google Scholar
  59. 59.
    Webster A, Boyce M, Edmundson S, et al. Coadministration of orally inhaled zanamivir with inactivated trivalent influenza vaccine does not adversely affect the production of antihaemagglutinin antibodies in the serum of healthy volunteers. Clin Pharmacokinet 1999; 36: 51–8PubMedCrossRefGoogle Scholar
  60. 60.
    Tisdale M. Monitoring of viral susceptibility: new challenges with the development of influenza NA inhibitors. Rev Med Virol 2000; 10: 45–55PubMedCrossRefGoogle Scholar
  61. 61.
    Gubareva LV, Matrosovich MN, Brenner MK, et al. Evidence for zanamivir resistance in an immunocompromised child infected with influenza B virus. J Infect Dis 1998; 178: 1257–62PubMedCrossRefGoogle Scholar
  62. 62.
    McKimm-Breschkin JL, Sahasrabudhe A, Blick TJ, et al. Mutations in a conserved residue in the influenza virus neuraminidase active site decreases sensitivity to Neu5Ac2en-derived inhibitors. J Virol 1998; 72: 2456–62PubMedGoogle Scholar
  63. 63.
    Varghese JN, Smith PW, Sollis SL, et al. Drug design against a shifting target: a structural basis for resistance to inhibitors in a variant of influenza virus neuraminidase. Structure 1998; 6: 735–46PubMedCrossRefGoogle Scholar
  64. 64.
    Zambon M, Hayden FG, on behalf of the Global Neuraminidase Inhibitor Susceptibility Network. Position statement: Global Neuraminidase Inhibitor Susceptibility Network January 8, 2001. Antiviral Res. In pressGoogle Scholar

Copyright information

© Adis International Limited 2001

Authors and Affiliations

  • Martin Ehlers
    • 1
  • Chris Silagy
    • 2
  • Douglas Fleming
    • 3
  • Daryl Freeman
    • 4
  1. 1.Schmoller and EhlersHamburgGermany
  2. 2.Monash Institute of Public Health and Health Services ResearchMonash Medical CentreClaytonAustralia
  3. 3.Northfield Health CentreBirminghamUK
  4. 4.The Glenfield SurgeryLeicesterUK

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