Prevention and treatment of influenza in the primary care office
ABSTRACTInfluenza, a common respiratory infection, is a source of significant rates of illness, death, and loss of productivity. Annual vaccination is safe and effective in preventing disease and in reducing its severity. Yet a majority of eligible US adults do not receive the annual vaccine, at least in part because of misunderstandings about adverse reactions and clinical effectiveness.
KEY POINTS
- Influenza vaccination is effective at preventing influenza-associated disease.
- Influenza vaccine is safe in people with a history of mild egg allergy.
- Many new vaccine formulations exist and may offer benefits to different patient groups.
- Neuraminidase inhibitors are recommended for treatment and postexposure prophylaxis in patients at high risk of influenza-related complications; however, they are not a substitute for vaccination.
NEW VACCINE FORMULATIONS
Recent years have seen a dramatic expansion in influenza vaccine options (Table 1).
Quadrivalent vaccines
Quadrivalent vaccines protect against two strains of influenza A and two strains of influenza B, whereas earlier formulations included only one influenza B strain. Vaccination against either influenza B strain offers only limited cross-protection against the other B strain, and previous formulations involved assumptions about which strain would predominate in any given year. The CDC estimates that switching to quadrivalent vaccines will prevent up to 970,000 cases of influenza, 8,200 hospitalizations, and 485 deaths per year.37
Intradermal vaccine
The newly available Fluzone Intradermal vaccine contains smaller doses of hemagglutinin but is still effective because antigen-presenting dendritic cells in the skin reduce the required amount of vaccine antigen necessary for inducing protection.38 This may provide an advantage in the event of vaccine shortage. Also, since it is given in needles only 1.5 mm long, it may appeal to people who are afraid of needles.
The stronger immune reaction with intradermal administration causes more redness, induration, and tenderness at the injection site than with intramuscular administration.39 Patients should not be surprised by this reaction and can be advised to apply ice packs for symptomatic relief.
High-dose vaccine
A high-dose vaccine was approved in 2009 for use in adults age 65 and older. It contains 60 μg of hemagglutinin, compared with 15 μg in standard-dose vaccines, and has been shown to improve seroconversion rates. It remains to be seen if this translates into better clinical outcomes in older adults.40 Further studies will be necessary before we can recommend high-dose vaccines to other people with weakened immune response, such as those undergoing chemotherapy or those infected with human immunodeficiency virus (HIV).
Cell-based vaccines
Flucelvax was the first cell-based influenza vaccine. However, unlike the recombinant trivalent influenza vaccine, which uses no eggs in its manufacturing process, Flucelvax production starts with egg-derived influenza strains that are subsequently propagated in liquid culture of animal cells. It may therefore contain traces of egg protein, and it has not been studied in people with egg allergy.41
An advantage of the cell-based production technique is the use of fewer or no eggs at all, which may result in greater manufacturing efficiency. Also, it is a closed process that reduces the risk of bacterial contamination as well as reliance on antibiotics or preservatives, such as thimerosal, in the manufacturing process.42
CHEMOPROPHYLAXIS WITH NEURAMINIDASE INHIBITORS
The mainstays of influenza prevention are seasonal vaccination and appropriate infection-prevention practices. In addition, in patients at high risk of influenza-related complications (Table 2),43 postexposure chemoprophylaxis with a neuraminidase inhibitor, ie, oseltamivir (Tamiflu) or zanamivir (Relenza), is an effective preventive strategy, especially in years when the match between vaccine and circulating virus strains is suboptimal.44,45
Neuraminidase inhibitors are competitive inhibitors of the active site of the influenza glycoprotein neuraminidase, responsible for viral release from infected respiratory epithelial cells. Rates of resistance to neuraminidase inhibitors have been less than 1% in the United States in recent years, while resistance to the adamantanes amantadine (Symmetrel) and rimantadine (Flumadine) can be as high as 92%, depending on the virus isolate. Thus, their use for treatment or prophylaxis of influenza is not currently recommended by the CDC.46
Chemoprophylaxis with any agent may promote emergence of resistant strains, can cause adverse reactions, and should never be considered a substitute for vaccination.
ANTI-INFLUENZA AGENTS
Two neuraminidase inhibitors, oseltamivir and zanamivir, are approved by the FDA for preventing and treating uncomplicated influenza. Treatment must be instituted within 2 days of onset of symptoms to be effective.
Oseltamivir is available as an oral capsule or powder for liquid suspension. Its most common adverse effects are gastrointestinal upset including diarrhea, nausea, and vomiting.44
Zanamivir is only available in the form of a dry powder inhaler because of the drug’s poor oral bioavailability, and only 4% to 17% of the inhaled dose is systemically absorbed.45 There is a theoretical benefit in targeted delivery of zanamivir to the primary organ affected by influenza, and gastrointestinal side effects are less common with this drug.44,45 Unfortunately, the zanamivir inhaler requires complicated assembly and dexterity for administration (see the video on YouTube47), which may make it unreliable in certain patient groups, especially handicapped and elderly patients. Administration has been associated with bronchospasm, resulting in a more than 20% reduction in the forced expiratory volume in 1 second, and it is contraindicated in patients with underlying reactive airway disease such as chronic obstructive pulmonary disease or asthma.45
Table 3 lists the doses and duration of therapy for oseltamivir and zanamivir in adults with normal renal function, as well as approximate costs. No generic formulations of neuraminidase inhibitors are currently available, and outpatient use may not be covered by medical insurance. Several other neuraminidase inhibitors are either under development or at various stages in the FDA approval process.
EFFECTIVENESS OF ANTI-INFLUENZA DRUGS
Treatment with oseltamivir has been shown to reduce the duration of symptoms by approximately 1 day if initiated within 36 hours of onset of illness and 1.5 to 2 days if initiated within 24 hours.48,49 Trials and meta-analyses of zanamivir show similar effectiveness, though some suggest that symptoms were alleviated as much as 3 days sooner than in controls in a subgroup of patients who were febrile at presentation.50,51 Dual neuraminidase inhibitor therapy in an attempt to prevent emergence of resistance seems logical but was actually found to be less effective than monotherapy, according to a 2010 study.52
The effectiveness of neuraminidase inhibitors in reducing influenza-related complications and mortality rates has been controversial in recent years, as these outcomes were not addressed in initial studies that secured FDA approval. Several meta-analyses differ in their assessments of available data quality and conclusions. A 2009 Cochrane review questioned the completeness and the veracity of the data from manufacturer-funded trial data, much of which was unpublished and not made available to reviewers, and it concluded that a reduction of complications could not be supported by the available data.53 Hernán and Lipsitch,54 in a 2011 review, calculated that oseltamivir reduces the risk of lower respiratory tract complications by 28% in patients with influenza-like symptoms and by 37% in patients with confirmed influenza infection.
Additional trials and better access to available data are needed to settle the question of the effectiveness of neuraminidase inhibitors in reducing complications of influenza. Meanwhile, they remain strongly recommended by major health organizations, including the CDC and the WHO, which lists oseltamivir on its “model list of essential medicines.”
