Ongoing Challenges in the Management of Influenza

Complete author affiliations and disclosures are at the end of this activity.

Release Date: November 30, 2007



Influenza and its associated costs represent a huge worldwide burden to the healthcare system and to society at large. Intensive efforts are under way to find universal vaccines that will protect against seasonal influenza and, more recently, avian influenza. Until such time, treatment with effective antiviral agents is crucial, both to alleviate the symptoms associated with these highly contagious viruses and to prevent or at least contain their spread. Antiviral drugs will be essential for dealing with a pandemic caused by a new influenza virus of any origin, and will remain important as new vaccination approaches are being developed.

It has been estimated that annual influenza epidemics result in 3.1 million days of hospitalization, 31.4 million outpatient visits, direct medical costs averaging $10.4 billion, and projected lost earnings of $16.3 billion.[1]

Epidemiology of Influenza


Every year, roughly 20% of the world's population is infected by influenza, which is associated with significant morbidity and mortality. School-age children have the highest attack rates, estimated at nearly 50%, and act as a reservoir of the virus for the community by introducing influenza into households. Older adults, however, have the highest influenza-associated mortality rates.[2]

The 3 influenza types -- A, B, and C -- infect humans, although influenza C infection rarely results in disease. Only type A influenza undergoes antigenic shift, which occurs when a novel and significantly different subtype of hemagluttin (HA) or NA that circulates in an animal reservoir enters a human population without preexisting immunity. Worldwide influenza pandemics occur as a result of this major mechanism of antigenic variation.

The incubation period of influenza ranges from 24 to 72 hours. The onset of illness is sudden and is characterized by fever, chills, rigor, headache, prostration, and malaise. As the disease progresses, respiratory symptoms, such as cough, sore throat, nasal congestion, and retrosternal pain, become more pronounced. Some patients also experience vomiting, abdominal pain, myositis, and central nervous system (CNS) manifestations. Pulmonary complications, including bronchitis and pneumonia, have been estimated to occur in up to 25% of cases, and are especially common among immunocompromised children and other high-risk populations. Influenza is associated with otitis media in 20% to 50% of previously healthy preschool children.[3] In neonates, influenza can present as a sepsislike syndrome associated with high morbidity and mortality.

Avian Influenza

The first human cases of infections with avian influenza strain were documented in Hong Kong in 1997 and were attributed to subtype A/H5N1. Infection with H5N1 avian influenza in humans is a severe disease with a high fatality rate, characterized by rapid progression to respiratory failure and manifestations of acute respiratory distress syndrome. In the past 10 years, the World Health Organization (WHO) has confirmed more than 370 human cases of infections with avian influenza and approximately 160 deaths due to this pathogen.[4] The diffuse presence of receptors on endothelial cells may account for the multiple organ involvement in H5N1 influenza.[5] Thus far, the human infections that have been reported have been sporadic. Although there have been several probable incidences of human-to-human transmission,[6] at this time there is no documented sustained transmission between people. It is unclear why human transmission of avian virus is so rare, but the relative lack of avian influenza receptors in the upper airway has been proposed as one of the factors preventing efficient human-to-human transmission.[5] However, it is possible that, with time, the H5N1 virus will adapt to humans to the extent that it will cause the next influenza pandemic.

Recently developed guidelines for the pharmacologic management (treatment and prevention) of avian influenza A H5N1 virus infections in humans highlight the complexity of preparing for an avian flu pandemic, given the dearth of clinical data pertaining to human infection and the limited availability of effective treatments.[7]



To make the diagnosis of influenza, rapid laboratory assays are performed that employ antigen, enzyme, or nucleic acid detection methods. Sensitivities range from 60% to 70% and specificities range from 93% to 100%,[8] depending on the test. Results are often available in less than an hour, and the assays are generally inexpensive. Optimal application of antiviral agents requires early, accurate diagnosis.

Treatment of Influenza

A key aim of therapy is to maintain adequate hydration and temperature control. The use of acetaminophen or other fever-reducing agents is particularly important in younger patients because they are at increased risk for febrile seizures. Aspirin should be avoided in patients with suspected or documented influenza infection. Antiviral agents should be started as soon as possible after the onset of symptoms of illness, and have been shown to be useful when started up to 48 hours after the onset of symptoms.[9]

Antiviral Agents: NA Inhibitors and Adamantanes


Despite the introduction of CDC guidelines for their use,[2] antiviral medications for influenza remain underutilized, partly because patients are generally not well educated about the benefits of antiviral medications or have preconceived notions about the risks that they confer. The costs of antivirals also represent a barrier to treatment. It has been suggested that, in advance of influenza season, clinicians should discuss antiviral medications with patients who are at high risk for complications from influenza, and that education programs for both healthcare providers and patients should be developed.[10] Populations at increased risk for complications from influenza include:

Adamantanes (amantadine and rimantadine) and NA inhibitors are antiviral agents that can be used for the treatment of influenza, but NA inhibitors are currently the only reliable antiviral option for treating seasonal influenza infection because the development of widespread resistance to the adamantanes has rendered their use problematic.[9] Table 1 describes the antiviral medications currently licensed for the prophylaxis and treatment of influenza.

Table 1. Antiviral Agents for Treatment and Prophylaxis of Influenza

Antiviral Compound When to Initiate Duration of Administration Indications

(amantadine, rimantadine)
Currently not recommended, due to incidence of resistance. If these become useful in the future, use within 48 hrs of onset of illness. Currently not recommended, due to incidence of resistance. If these become useful in the future, use for 3-5 days, or 24-48 hrs after symptomatic improvement, whichever is shorter. Currently not recommended, due to incidence of resistance. If these become useful in the future: Amantadine prophylaxis may be used for the entire influenza season in individuals with immunodeficiency who may not respond to vaccination, high-risk patients who cannot receive vaccine due to allergy, unimmunized caretakers of high-risk patients, and for any child in addition to vaccine for whom the prevention of influenza is highly desirable (eg, children with underlying chronic medical [cardiac, respiratory, or immunodeficiency] conditions). It may be used for treatment or prophylaxis in children over 1 year of age.

If these become useful in the future: Rimantadine is indicated for treatment only over 13 years of age, and prophylaxis over 1 year of age.
Neuraminidase inhibitors

(zanamivir, oseltamivir)
Within 30-48 hrs of onset of illness Treatment:
-Zanamivir: 10 mg (= 2 inhalations) BID for 5 days
-Oseltamivir (based on age/weight):
< 15 kg: 30 mg BID for 5 days
> 15-23 kg: 45 mg BID for 5 days
> 23-40 kg: 60 mg BID for 5 days
> 40 kg: 75 mg BID for 5 days

-Zanamivir: 10 mg (= 2 inhalations) once a day for 10 days (household setting) or 28 days (community outbreak)
-Oseltamivir (based on age/weight):
< 15 kg: 30 mg once daily for 10 days
> 15-23 kg: 45 mg once daily for 10 days
> 23-40 kg: 60 mg once daily for 10 days
> 40 kg: 75 mg once daily for 10 days
Zanamivir is licensed for treatment of influenza A and B infections in adults and children ≥ 7 years of age who have had symptoms of influenza for less than 48 hours, and for prophylaxis of influenza in adults and children 5 years of age and older.

Oseltamivir may be used for treatment or for prophylaxis of influenza in adults and children aged 1 year and older.
BID = twice daily


Adamantanes inhibit uncoating of viral RNA inside infected cells by blocking an ion channel formed by the influenza M2 protein, thereby preventing viral replication. They are effective against influenza A, but not against the other types of virus, and are associated with several toxicities, particularly of the CNS. They are also associated with rapid emergence of drug-resistant variants during the course of therapy. This drug resistance is thought to have come about because of widespread inappropriate use of adamantanes, which needs to be controlled if the use of these compounds is going to continue.

The CDC instructed clinicians not to prescribe adamantanes for prevention or treatment of influenza during the 2005-2006 influenza season, after finding that 91% of samples of the dominant circulating strain of human influenza were adamantane-resistant.[2,11,12]

Several new adamantane derivative compounds[13] and more distantly structurally related compounds[14] have demonstrated in vitro activity against influenza A and may prove to be useful against resistant variants. Although these compounds offer promise as potential alternatives to amantadine and rimantadine, studies in animal models and in humans are needed to confirm their benefit.

Amantadine. In healthy adolescents and adults, amantadine has been shown to be 91% efficacious in preventing influenza illness and 74% efficacious in preventing laboratory-confirmed influenza infections. Amantadine is well absorbed following oral administration. Over 90% of the drug is excreted unchanged by the kidneys, necessitating close monitoring and dosage adjustment that are based on creatinine clearance in patients with renal disease. Administration of amantadine in combination with antihistamines or anticholinergic medications has been noted to increase the risk for CNS toxicity.[8]

The use of amantadine is associated with the development of viral resistance occurring as soon as 3 days after starting a course of the drug in up to 30% of patients. Amantadine-resistant isolates of influenza A can be transmitted to susceptible contacts, and can be shed for prolonged periods of time in immunocompromised patients taking the drug. Therefore, amantadine therapy of long duration should be avoided whenever possible to minimize the potential for development of resistant virus.[8]

Rimantadine. Rimantadine is essentially equivalent to amantadine in terms of efficacy, with reported efficacy rates of 85% in healthy adolescents and 66% in young adults. The drug, delivered by oral administration, provides a 1-day benefit in the relief of the signs and symptoms of influenza illness.[8]

Rimantadine is well absorbed and is highly metabolized by the liver prior to renal excretion. Dosage adjustments are required only in patients with severe renal disease or severe liver dysfunction. Rimantadine is associated with significantly lower rates of CNS toxicity but poses risk in patients with a prior history of seizure disorders. Emergence and transmission of rimantadine-resistant isolates of influenza A virus occur about as frequently as amantadine-resistant isolates of influenza A virus, and use of the 2 drugs may be further limited by the fact that they share cross-resistance.[8]

NA Inhibitors: Zanamivir and Oseltamivir

NA inhibitors achieve their effect by preventing viral enzyme from cleaving sialic acid receptor moieties, a necessary step in release of virus from infected cells. The inhibitors thus interfere with the release of progeny influenza viruses from infected host cells in the respiratory tract, preventing infection of new host cells and halting the spread of infection. Two licensed NA inhibitors are currently available: zanamivir and oseltamivir. Their effectiveness against influenza A and B in humans and against avian influenza in animal models has been demonstrated.[15] NA inhibitors are associated with very little toxicity and are less prone to selecting for resistant influenza viruses compared with the adamantanes.[16,17]

Several large treatment trials in widely diverse geographic areas showed that when otherwise healthy adults with influenza were treated with zanamivir or oseltamivir within 36-48 hours after the onset of illness, a 1- to 2-day decrease in the length of symptomatic illness occurred.[16,18,19] The earlier after the onset of illness the NA inhibitor is administered, the shorter the duration of the fever and the faster the patient's return to baseline health.[20] Secondary complications of influenza, such as pneumonia, bronchitis, sinusitis, and otitis media, are also significantly reduced by timely treatment. Children aged 1-12 years receiving oseltamivir exhibited a 1.5-day decrease in the duration of illness and a 43% reduction in the incidence of otitis media.[8]

Zanamivir and oseltamivir have demonstrated 70% to 90% effectiveness in preventing clinical influenza in healthy adults, when used either as postexposure prophylaxis for close contacts, such as household members, or as seasonal prophylaxis in the community.[16] A 92% reduction in the incidence of influenza was observed with the use of oseltamivir in a senior residential facility, even though the majority of the elderly residents had been appropriately vaccinated.[21] NA inhibitors are effective for postexposure prophylaxis in children as young as 1 year of age,[22] although the inhaler device limits the use of zanamivir to children 5 years and older.

Zanamivir and oseltamivir are the drugs of choice for the treatment and prevention of avian influenza. The WHO guideline recommendations specify that individuals at risk for serious infection should be given chemoprophylaxis with either oseltamivir or zanamivir in the event of exposure to H5N1 influenza.[5] It is currently thought that higher doses of oseltamivir and/or zanamivir, given for longer periods, may be needed for treatment of H5N1 infection than for other types of influenza.[23] This is an area of active investigation.

Parents of children taking oseltamivir should be aware that use in children aged 10-19 years in Japan and use in teenagers in Korea has been discontinued due to reports of a link between oseltamivir use and abnormal neurologic/behavioral episodes.[24] During the most recent safety review by the US Food and Drug Administration (FDA), 596 reports of neuropsychiatric events in children and adults administered oseltamivir, including 25 deaths, were examined. Additionally, 115 reports of neuropsychiatric events in patients taking zanamivir were also examined, although no reports of death have occurred in users of this agent. According to FDA staff, "These cases provide conflicting evidence as to whether these events are drug-related only, disease manifestation alone, or a combination of drug-disease expression.[25]"

Zanamivir. Zanamivir is a sialic acid transition-state analog that acts as a specific inhibitor of the viral NA enzyme. The active site of this protein is highly conserved among all strains of influenza A and B, making it an ideal target for antiviral drug development.[8] Zanamivir is licensed for the treatment of influenza A and B infections in adults, adolescents, and children ≥ 7 years of age who have had symptoms of influenza for less than 48 hours.

The drug is well tolerated, with a similar incidence of adverse events to that seen with placebo -- primarily minor transient upper respiratory and gastrointestinal complaints.

Some postlicensure reports indicated that zanamivir may cause cough, bronchospasm, and a reversible decrease in pulmonary function in some patients.[26] On the other hand, a well-controlled trial demonstrated that the recommended dosages of zanamivir did not adversely affect pulmonary function in patients with respiratory disorders.[27] If patients with pulmonary dysfunction do receive zanamivir, it is recommended that they have a fast-acting bronchodilator available and discontinue zanamivir if respiratory difficulty develops.

The drug is administered by oral inhalation as a dry powder, and is delivered directly to the respiratory tract. Roughly 10% to 20% of the active compound reaches the lungs, whereas the rest is deposited in the oropharynx; 5% to 15% of the total dose is absorbed and excreted in the urine. No dosage adjustment is necessary in patients with renal failure.

No virus resistant to zanamivir has yet been isolated after the treatment of immunocompetent individuals, with the possible exception of partially resistant influenza B viruses isolated recently in Japan.[28,29]

Oseltamivir. Oseltamivir was developed through modifications to the sialic acid analog framework, including the addition of a lipophilic side chain, that allow the drug to be orally available.[30]

Oseltamivir may be currently used to treat influenza in children 1 year of age and older, and may be used for prophylaxis in persons over 12 years of age. The drug has shown excellent tolerability in pediatric studies.[31] Of note, oseltamivir is much less effective as a treatment for influenza B than for influenza A virus infection, especially in young children.[32,33]

Oseltamivir is administered orally, and a liquid preparation has been developed for use in children. The half-life is 6-10 hours, and it is predominantly excreted through the kidneys. Dosing needs to be modified in patients with a creatinine clearance of < 30 mL/minute. Food does not interfere with the absorption of oseltamivir and, in limited studies, has been shown to reduce the nausea and vomiting that are associated with the use of this medication[30]

The drug is generally well tolerated; the most frequent side effects are transient nausea, vomiting, and abdominal pain, occurring in 5% to 10% of patients. Taking the drug with meals may alleviate the nausea and vomiting.[8]

Although oseltamivir is associated with benefits, such as an expanded spectrum of activity that includes influenza A and B viruses, minimal drug toxicity, good oral bioavailability, and favorable pharmacokinetics (allowing for twice-daily administration), the recent emergence of oseltamivir-resistant variants is a matter of grave concern. Structural analysis performed several years ago predicted that aspects of the chemical structure of oseltamivir -- not present in zanamivir -- could facilitate the development of resistance mutations that would permit NA function, allowing drug-resistant virus to survive and propagate.[34] A growing body of clinical data has emerged to support this hypothesis.

Peramivir. The NA inhibitor peramivir is being developed in intravenous and intramuscular formulations, but it is not yet licensed for use. This compound is highly protective against influenza A infection -- seasonal (H1N1) -- as well as H5N1 in mice[35]; however, its efficacy in humans is currently under investigation. The availability of an NA inhibitor that can be intravenously administered could be important for treating patients hospitalized with severe influenza, and for cases in which neither oral nor inhaled routes are an option. Long-acting NA inhibitors are being developed that may, in the future, offer the option of single-dose treatment of influenza symptoms or once-weekly administration for prevention of infection.[36]

Summary: Resistance to NA Inhibitors in Seasonal and Avian Influenza

Little spontaneous resistance to NA inhibitors has been documented, and no spontaneously resistant influenza viruses were identified prior to the introduction of the drugs. Furthermore, no virus resistant to zanamivir has yet been isolated after the treatment of immunocompetent individuals. The recent emergence of oseltamivir-resistant variants is therefore a matter of great concern. Beginning in 2004, resistance to oseltamivir in strains of influenza A has been gradually rising.[28,37] Recently, influenza B viruses in Japan with decreased sensitivity to oseltamivir and zanamivir were isolated from individuals who had not been treated with antiviral medications, and the pattern of virus isolation strongly suggested that person-to-person transmission of these resistant viruses had occurred, either within families or in the community.[28,29] The evidence that some NA inhibitor-resistant influenza virus variants are indeed transmissible and are aggressive pathogens underscores the threat of epidemic or pandemic influenza and may necessitate a change in treatment guidelines.

Resistant strains mandate a new approach to the issue of resistance. Although resistant viruses may be somewhat less infectious and require more time to replicate in the individual, they eventually may cause disease that is equal in severity to the parent strain.[28,29] Over time, viral resistance may develop to any single antiviral agent, or even to multiple agents simultaneously. Therefore, ongoing investigation of antiviral therapies that use alternative mechanisms of action and target different points in the viral life cycle is needed.

Treatment with 2 or more compounds that act at different stages of the viral life cycle would be more effective and make it less likely for single mutations in the viral genome to confer drug resistance. Research is currently being conducted to develop combinations of adamantanes and NA inhibitors that can be effectively used to reduce replication of influenza A.[38] In preliminary studies, this combination has been shown to provide enhanced protection against lethality in H5N1-infected mice.[39]

Prevention of Influenza


Although considerable progress has been made in the research of influenza pandemic vaccines, it is expected that production can only start once the pandemic virus has been recognized. Therefore, at least during the first phase of the potential influenza pandemic, the limitations on vaccine capacity will necessitate vaccine prioritization strategies.[40]

One strategy under consideration by the US Department of Health & Human Services (DHHS) is to induce immunity in individuals prior to the start of national epidemics using a prepandemic vaccine targeted against current avian influenza strains by allocating vaccine supplies to states in proportion to the size of their population, with plans to vaccinate predefined priority groups (eg, healthcare workers, the elderly, pregnant women, and infants).[41] The WHO also recommends developing preliminary priorities for pandemic vaccine use.[40] Table 2 lists the priority populations identified by the DHHS and WHO.

Table 2. Priority Groups Targeted for Vaccination in the Early Weeks of an Influenza Pandemic

US Department of Health & Human Services[53] World Health Organization[54]
Individuals essential to the pandemic response and who provide care for persons who are ill Military personnel
Individuals who maintain essential community services Medical workers
Children Emergency workers
Workers who are at greater risk for infection as a result of their jobs Pregnant women
Individuals who maintain homeland and national security Babies

A study was conducted to assess pandemic vaccine prioritization concepts in the 27 European Union (EU) member states and the 4 non-EU countries of the Global Health Security Action Group. Data collected for each country between September and December 2006 revealed that 26 countries (84%) had established at least 1 vaccine priority group that will be the first to receive the vaccine in the event of a pandemic. The most commonly reported vaccine priority groups were healthcare workers (100%), essential service providers (92%), and high-risk individuals (92%).[40]


Influenza Vaccines: Active Immunization

In the United States, 2 types of influenza vaccine are currently licensed: trivalent inactivated influenza vaccine (TIV) and live attenuated influenza vaccine (LAIV). Their safety and effectiveness in the populations for which they are approved for use have been demonstrated.[42] However, despite long-standing recommendations for the routine vaccination of persons in high-priority groups, US vaccination rates remain below desired target levels across all age groups.

Trivalent inactivated split influenza virus vaccine has been used for more than 35 years, and is currently licensed in over 100 countries. Arnoux and colleagues[43] evaluated the vaccine-preventable influenza burden in different populations and geographic regions by reviewing studies of vaccine effectiveness against nonspecific outcomes, such as upper respiratory infection, hospitalization, and death, in addition to microbiologically confirmed influenza. They found that the vaccine-preventable disease incidence was high in most of the studies, regardless of the outcome or population evaluated. The study authors concluded from these results that routine influenza vaccination can improve overall population health under a broad range of circumstances.

Inactivated influenza vaccine is recommended for all persons 6-59 months and ≥ 50 years old, as well as persons of any age who are at increased risk for complications from influenza, healthcare workers, pregnant women, and close contacts of children < 59 months old. The currently available preparations include a "whole virus" vaccine made from inactivated highly purified intact viral particles grown in embryonated chicken eggs. The "subvirion" vaccine adds a further step in which the lipid-containing viral envelope has been disrupted. In addition, a purified surface antigen vaccine is also available. These last 2 preparations, known as "split" vaccines, should be given to children younger than 13 years of age because the other vaccines are associated with a higher incidence of adverse effects in the younger age group.[3]

LAIV (FluMist, MedImmune), has been available in the United States since 2003 and is currently approved for use in healthy, nonpregnant persons 2-49 years old. It should not be used in patients who are immunosuppressed or those with chronic cardiovascular, pulmonary, renal, or metabolic disease. The LAIV appears to be more effective, at least in children, and may offer some cross-protection against antigenic drift.

Development of a vaccine against potentially pandemic strains is an essential part of the strategy to control and prevent a pandemic outbreak. Approaches currently being tested include subvirion inactivated vaccines and cold-adapted, live attenuated vaccines.[42]

The overall effectiveness of influenza vaccine depends on the age, immunocompetence of the patient, and on the similarity between the viruses contained in the vaccine and those in circulation that season. The protection when challenged with a homologous virus is approximately 70% to 80%, and is estimated to last only briefly, usually around 1 year.[3]

Specific Recommendations for the Use of Influenza Vaccine

The Advisory Committee on Immunization Practices (ACIP) recommends administration of the influenza vaccine to any person older than 6 months who is at increased risk for complications due to the illness.[44] Healthcare workers and persons in close contact with high-risk groups, including household contacts, should be vaccinated to reduce the risk for transmission, as should women who may be pregnant during the influenza season. Travelers to areas where influenza outbreaks will be occurring should be recommended for vaccination. The optimal time for vaccination in the United States is in early fall, from the beginning of October through mid-November. However, when vaccine shortages occur, immunization should be continued further into the influenza season as vaccine becomes available.[2]

Among previously unvaccinated children younger than 9 years of age, 2 intramuscular doses administered at least 1 month apart are recommended, with the second dose administered before December, if possible.[44] The effectiveness, efficacy, and safety of the current inactivated vaccine have not been established for infants younger than 6 months of age.

Adverse events are mild and infrequent, and are usually limited to fever, malaise, myalgias, and other systemic manifestations. Because inactivated influenza vaccine contains noninfectious killed viruses, it cannot cause influenza. Administration of influenza vaccine is not recommended in persons with acute febrile illness, although minor illnesses with or without fever, particularly among children, are not a contraindication.[2]

Inactivated influenza vaccine should not be given to individuals with a history of anaphylactic hypersensitivity to any of its components. Egg allergy is the most frequent food allergy that occurs during childhood. Influenza vaccines grow in chicken eggs, and the final product contains egg proteins. The Food Allergy Committee of the Spanish Society of Clinical Immunology and Pediatric Allergy reported in its recommendations for the safe administration of influenza vaccines in patients with egg allergy that influenza vaccine is contraindicated in patients with severe anaphylactic reaction after egg ingestion. Those without such hypersensitivity can receive influenza vaccine in a 2-dose protocol with a vaccine that contains no more than 1.2 micrograms (mcg) of egg protein per milliliter.[45]

The development of LAIV, as outlined above, has generated a great deal of enthusiasm. These vaccines contain live viruses that replicate in the upper respiratory tract but are unable to replicate efficiently at temperatures found in the lower respiratory tract. Potential advantages of cold-adapted influenza vaccines include ease of administration, intranasal delivery of the vaccine (nose drops), and their ability to elicit a broad mucosal and systemic immune response, with minimal symptoms. In pediatric trials, their efficacy in preventing influenza infection has been approximately 90%.[3] These vaccines have also shown efficacy in preventing febrile otitis media.[3] The currently licensed LAIV is approved for use in individuals aged 2-49 years.

Vaccination in the Elderly

The long-term benefits of influenza vaccine among persons 65 years of age and older are a matter of debate, and attempts by investigators to determine the long-term effects of vaccination in the elderly are ongoing. Nichol and colleagues[46] pooled data from 18 cohorts of community-dwelling elderly members of a US health maintenance organization (HMO) for 1990-1991 through 1999-2000 and of 2 other HMOs for 1996-1997 through 1999-2000, representing 713,872 person-years of observation. They used logistic regression to estimate the effectiveness of the vaccine for the prevention of hospitalization for pneumonia or influenza and death after adjustment for important covariates. Most high-risk medical conditions that were measured were more prevalent among vaccinated than among unvaccinated persons. Vaccination was associated with a 27% reduction in the risk for hospitalization for pneumonia or influenza (adjusted odds ratio, 0.73; 95% confidence interval [CI], 0.68-0.77) and a 48% reduction in the risk for death (adjusted odds ratio, 0.52; 95% CI, 0.50-0.55). During 10 seasons, influenza vaccination was associated with significant reductions in the risk for hospitalization for pneumonia or influenza and in the risk for death among community-dwelling elderly persons.

Vaccination Against Avian Influenza

On April 17, 2007 the FDA approved the first vaccine against the avian influenza virus H5N1 for humans at high risk. However, more research is needed to develop a more effective and affordable vaccine that can be given at lower doses.[47]

Phase 1 trials of 2 vaccines against the H5N1 virus constructed from the NIBRG-14 vaccine strain, obtained from the WHO, have recently been completed. Results indicated that both vaccines were safe, well tolerated, and characterized by low reactogenicity. They are expected to be entering phase 2 trials in the near future.[48]

Ichinohe and colleagues[49] assessed the ability of currently licensed seasonal influenza vaccine to confer cross-protection against highly pathogenic H5N1 influenza virus in mice. BALB/c mice were inoculated 3 times, either intranasally or subcutaneously, with the TIV licensed in Japan for the 2005-2006 season. Compared with noninoculated mice, those inoculated intranasally manifested cross-reactivity of mucosal immunoglobulin (Ig)A and serum IgG with H5N1 virus, as well as a reduced H5N1 virus titer and increased survival, after challenge with H5N1 virus. Subcutaneous inoculation did not induce a cross-reactive IgA response and did not afford protection against H5N1 viral infection.[49] The question about the degree, if any, of cross-protection afforded humans remains unanswered.

In order to develop effective vaccines against avian influenza, further research is needed to elucidate the clinical and virologic course of the H5N1 virus in humans, its response to therapy, and its susceptibility to the development of resistance. The incubation period may be longer than that for other influenza viruses, potentially increasing the period of transmissibility before patients become aware that they are ill.[23]

New Influenza Vaccines


The potential threat of person-to-person transmissibility of the H7N2 virus, documented in poultry in 2002 and 2003, has led to the development of prepandemic vaccines for any potential pandemic virus, such as a high-growth reassortant virus (H7N2-PR8) containing the genes for HA and NA from a low pathogenic (H7N2) virus strain and the remaining 6 genes from a human vaccine strain (H1N1). Results of antigenicity studies with ferret antibodies raised against H7N2-PR8 indicated that this virus confers broad cross-reactivity with divergent H7 viruses of different years and lineages. Mice and chickens inoculated with high doses of H7N2-PR8 supported virus replication but survived, indicating that this virus is comparable to other avian viruses of low pathogenicity. Mice immunized with 2 doses of formalin-inactivated A/H7N2-PR8, alone or with alum, that were subsequently challenged with highly pathogenic viruses from homologous and heterologous lineages exhibited pronounced reduction of wild-type virus replication. These studies indicated that A/H7N2-PR8 is immunogenic, safe, and protective in animal models, thus qualifying them for study in phase 1 human clinical trials as a prepandemic vaccine.[50]

Recent work has focused on improving the efficacy of vaccine adjuvants, which are the materials injected together with the antigens in a vaccine to help stimulate the human immune response. MF59 has been found to be a safe and potent vaccine adjuvant that has been licensed in more than 20 countries.[51] It has had a significant impact on the immunogenicity of influenza vaccines in the elderly and in adults who are chronically ill, and has also been shown to have a significant impact on the immunogenicity of pandemic influenza vaccines. It allows for broader cross-reactivity against viral strains not included in the vaccine, and has been shown to be more potent for both antibody and T-cell responses compared with aluminum-based adjuvants. Thus, investigators have concluded that MF59 has broad potential to be used as a safe and effective vaccine adjuvant for a wide range of vaccine types.[51]

Approaches to Improving Vaccination Rates

A number of strategic interventions have been implemented in an attempt to improve influenza vaccination rates. In one study of interventions implemented in clinics and private practices targeting a total of 18,866 high-risk children, the most frequently implemented change concepts were posters in the office, walk-in clinics, or same-day appointments and reminder phone calls. The interventions deemed most helpful were weekend or evening "flu shot only" sessions, walk-in or same-day appointments, reminder calls, and special mailings to families. Implementation of the strategies resulted in higher immunization rates than typically reported in the medical literature, especially for the community-based primary care practices.[52]



It is expected that influenza virus will go the way of other infectious agents, ie, it will evolve to evade any single drug. Mutation and reassortment have resulted in newer viruses, such as H5N1, with new resistance against antiviral medications, and the fear is that this may lead to the emergence of a fully transmissible strain, such as those that emerged in the 1957 and 1968 pandemics. The H5N1 avian influenza virus can cause severe human infection involving multiple organs, with a mortality rate exceeding 50%. The case death rate of H5N1 avian influenza infection is 20 times higher than that of the 1918 infection (50% vs 2.5%), which killed 675,000 people in the United States and almost 40 million people worldwide.[48]

Oseltamivir resistance in H5N1 influenza is no longer just a theoretical threat, but has become a real issue of grave concern. Greater understanding of how and when resistance to the NA inhibitors develops, and continued development of effective antiviral drugs, are urgently needed.

By targeting several points in the viral life cycle simultaneously with different medications, we are more likely to discourage the emergence of viruses that can resist all drugs at once.

Post-Assessment: Measuring Educational Impact

Thank you for participating in the CME activity. Please take a few moments to read the following cases and complete the questions that follow to help us assess the effectiveness of this medical education activity.

Self-assessment Case Studies


Case #1: It is the end of March and a 55-year-old woman, who is accompanied by her daughter, presents with headache, fever, chills, sore throat, and runny nose that have been progressive since last night. She also complains of nausea, dry cough, severe fatigue, and weakness. Her medical history is remarkable for stage I hypertension controlled by hydrochlorothiazide. She neither smokes nor drinks alcohol. She had her last influenza immunization 3 years ago. She is retired and lives with her daughter and grandson.

On physical exam her temperature is 39.2?C; blood pressure is 140/88 mm Hg; pulse rate is 95 beats per minute; respiratory rate is 22 breaths per minute; and there is mucosal congestion in the upper airways. A rapid influenza test is positive.

Self-assessment Case Studies (Continued)


Case #2: A 31-year-old mother and her 5-year-old daughter present to the clinic early in November to establish care and ask about influenza vaccination. They are generally in good health, and although up-to-date on immunization, have had no prior flu vaccination. You discuss the benefits of flu vaccination and agree upon vaccination during the current visit.


Clinical Pearls

Supported by an independent educational grant from GlaxoSmithKline


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Anne Moscona, MD

Professor, Weill Medical College of Cornell University, New York, NY

Disclosure: Anne Moscona, MD, has disclosed that she has served as an advisor or consultant to GlaxoSmithKline, Merck, Roche, and MedImmune.


Peggy Keen, PhD, RNC

Editorial Director, New York, NY

Disclosure: Peggy Keen, PhD, FNP, has disclosed no relevant financial relationships.