Influenza World Health Care Professionals

A key element of preparing for an influenza pandemic is the development and implementation of prevention and treatment strategies.

Vaccines

In the event of an influenza pandemic, it could take 9–12 months to develop and market a new vaccine that is effective against the circulating strain. However, because of the complex and time-consuming manufacturing process required for influenza vaccines, there is not sufficient capacity to produce the number of doses needed to meet the expected demand.

Vaccines that will potentially protect humans against pandemic influenza are being developed and tested. [1] These pre-pandemic vaccines contain strains of H5N1 that have been isolated from humans with the disease; however, they may not exactly match the strain of virus that may eventually cause a pandemic. The vaccines available in the early stages of a pandemic may, therefore, rely on cross-protection against different virus strains to prevent serious illness, and may not be fully protective.
Should another avian influenza virus, for example an H9N2 or H7N7 strain emerge as the pandemic virus, then these vaccines will not offer protection.

Antivirals

During the period where a pandemic influenza vaccine is being developed, millions of people could be infected with the influenza virus worldwide. The WHO recognise that during this time antivirals are likely to be the only influenza-specific medical intervention available and recommends their use to help contain the spread of the virus. [2] Antivirals will continue to be important commodities even when vaccination against the pandemic influenza strain becomes an option because vaccines are not 100% effective. 

Antiviral agents, oseltamivir (Tamiflu®) and zanamivir (Relenza®), belong to a class of drugs called neuraminidase inhibitors (NAIs). They are potent and selective drugs that, if administered early enough following onset of symptoms, have activity against both influenza A and B viruses and have two principal roles in the management of seasonal influenza:

• prophylaxis – aimed at reducing the likelihood of developing influenza symptoms following suspected exposure to the virus
• treatment – aimed at reducing the duration of influenza illness by approximately one-third if given within 48 hours after the onset of symptoms. [3]

Research has demonstrated the effectiveness of antivirals when used for both purposes.

The WHO recommends neuraminidase inhibitors for pandemic influenza [2]

The WHO considers NAIs to be the preferred class of antiviral drugs for the treatment of influenza during a pandemic rather than M2 inhibitors or adamantanes. [2] This is because NAIs have a lower risk of adverse events and much lower levels of drug resistance compared with these other classes of antivirals. Additionally, NAIs possess undoubted therapeutic value in reducing the incidence of lower respiratory tract infections. [2]

NAIs inhibit neuraminidase, an enzyme that promotes the release of influenza virus from infected cells and facilitates viral spread within the respiratory tract. [4, 5] NAIs prevent the influenza virus from spreading to and infecting other cells in the body by inhibiting neuraminidase activity, thus greatly reducing the impact of the disease. 

NAIs are expected to be effective against human illness caused by the pandemic influenza strain. [2, 6] Animal studies and clinical reports have shown survival in H5N1 infections treated with oseltamivir (Tamiflu®). [7–9] To date, there has been no reported use of zanamivir (Relenza®) in the management of human H5N1 infections. However, it is anticipated that wide-scale application of zanamivir in a pandemic situation will be limited by both poor bioavailability and administration of the drug via an inhaler device. [2] 
Antivirals form a key component of the WHO pandemic plan and measures are being taken by the WHO and individual countries to stockpile osteltamivir (Tamiflu®) in case a pandemic situation should arise. [10]

The WHO have made the following recommendations for the treatment and prophylaxis of patients infected or exposed to H5N1 virus. [10]

Recommendations for treatment of patients with confirmed or strongly suspected human infection with the H5N1 virus:

• Clinicians should administer oseltamivir treatment (strong recommendation); zanamivir might be used as an alternative (weak recommendation). The quality of evidence if considered on a continuum is lower for the use of zanamivir compared to oseltamivir.
• Clinicians should not administer amantadine or rimantadine alone as a first-line treatment (strong recommendation).
• Clinicians might administer a combination of a neuraminidase inhibitor and an M2 inhibitor if local surveillance data show that the H5N1 virus is known or likely to be susceptible (weak recommendation), but this should only be done in the context of prospective data collection.

Recommendations for prophylaxis

• In high risk exposure groups, including pregnant women, oseltamivir should be administered as prophylaxis, continuing for 7–10 days after the last exposure (strong recommendation); zanamivir could be used in the same way (strong recommendation) as an alternative.
• In moderate risk exposure groups, including pregnant women, oseltamivir might be administered as prophylaxis, continuing for 7–10 days after the last exposure (weak recommendation); zanamivir might be used in the same way (weak recommendation).
• In low risk exposure groups, oseltamivir or zanamivir should probably not be administered for prophylaxis (weak recommendation). Pregnant women in the low risk group should not receive oseltamivir or zanamivir for chemoprophylaxis (strong recommendation).
• Amantadine or rimantadine should not be administered as prophylaxis (strong recommendation).

Moreover, the WHO has issued a revised assessment of the utility of oseltamivir in the management of avian influenza, based upon case reports from patients treated with H5N1 to date. [11] The main points are as follows:

• Experiences with early oseltamivir treatment suggest its usefulness in reducing H5N1-associated mortality. In addition, evidence of prolonged H5N1 virus replication indicates that treatment is warranted even with late presentation.
• Modified regimens of oseltamivir treatment, including two-fold higher dosage, longer duration and possibly combination therapy with amantadine (in countries where the H5N1 virus is susceptible to amantadine) may be considered on a case by case basis, especially in patients with pneumonia or progressive disease. Ideally this should be done in the context of prospective data collection.
• Corticosteroid therapy has, so far, failed to show effectiveness, and prolonged or high dose corticosteroids can result in serious adverse events in patients infected with H5N1, including opportunistic infection. Corticosteroids should not be used routinely, except for persistent septic shock with suspected adrenal insufficiency.
• Antibiotic prophylaxis should not be used. When pneumonia is present, antibiotic treatment is appropriate initially for community-acquired pneumonia according to published evidence-based guidelines. When available, the results of microbiologic studies should be used to guide antibiotic usage in patients with (H5N1) infection.
• Therapy for H5N1-associated acute respiratory distress syndrome (ARDS) should be based upon published evidence-based guidelines for sepsis-associated ARDS, specifically including lung protective mechanical ventilation with low tidal volume.

Improved hygiene measures

Informing patients about simple hygiene practices – such as wearing a protective mask, regular hand-washing and covering the mouth and nose with a tissue when coughing and sneezing – may reduce the spread of a pandemic virus.

1. Treanor JJ, Campbell JD, Zangwill KM, et al. Safety and immunogenicity of an inactivated subvirion influenza A (H5N1) vaccine. N Engl J Med 2006; 354: 1343–51.
2. World Health Organization. Antivirals – their use and availability. Available here.
3. 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: 1016–24.
4. Jackson HC, Roberts N, Wang M, et al. Management of influenza: use of new antivirals and resistance in perspective. Clin Drug Invest 2000; 20(6): 447–54.
5. Moscona A. Neuraminidase inhibitors for influenza. N Engl J Med 2005; 353: 1363–73.
6. Hurt AC, Selleck P, Komadina N, et al. Susceptibility of highly pathogenic A (H5N1) avian influenza viruses to the neuraminidase inhibitors and adamantanes. Antiviral Res 2007; 73: 228–31
7. Govorkova EA, Ilyushina NA, Boltz DA, et al. Efficacy of oseltamivir therapy in ferrets inoculated with different clades of H5N1 influenza virus. Antimicrob Agents Chemother 2007; 51: 1414–24.
8. Oner AF, Bay A, Arslan S, et al. Avian influenza A (H5N1) infection in eastern Turkey in 2006. N Engl J Med 2006; 355: 2179–85.
9. Yen HL, Monto AS, Webster RG, et al. Virulence may determine the necessary duration and dosage of oseltamivir treatment for highly pathogenic A/Vietnam/1203/04 influenza virus in mice. J Infect Dis 2005; 192: 665–72.
10. World Health Organization. WHO rapid advice guidelines on pharmacological management of humans infected with avian influenza A (H5N1) virus. Available here.
11. World Health Organization. Summary of the second WHO consultation on clinical aspects of human infection with avian influenza A (H5N1) virus Available here.