Influenza is a highly contagious airborne viral disease that is characterized by an abrupt onset of symptoms. Vaccination remains the key effort in preventing the development of this illness and possible influenza-related complications.
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Despite a history of influenza vaccination, it does not rule out the possibility that an individual has been infected by the influenza virus. The potential to acquire the virus therefore supports the need for ill individuals to seek immediate treatment, even before the results of diagnostic tests are available.
To this end, The United States Centers for Disease Control and Prevention (CDC) recommends that treatment should be initiated as soon as possible after the onset of symptoms in patients meeting certain criteria. The CDC also recommends antiviral prophylaxis for all individuals in close contact with an infected person during the infectious period. Treatment of patients with severe influenza, particularly those who require hospitalization, presents multiple challenges.
Both clinical trials and observational data have shown that early antiviral treatment can shorten the duration of fever and other symptoms of influenza, as well as reduce the risk of complications. The benefit is greatest when treatment is initiated early, preferably within 48 hours of illness onset. Two classes of antiviral drugs that can be used against influenza are neuraminidase inhibitors and M2 ion channel inhibitors such as adamantanes.
Neuraminidase inhibitors block the viral neuraminidase function, which is critical in releasing virions from the infected host's cells. By blocking this function, this class of drugs effectively stops the spread and reinfection of both influenza A and B. Although four neuraminidase inhibitors have been approved for use in humans including oseltamivir, zanamivir, laninamivir, and peramivir, only oseltamivir and zanamivir are broadly used in most countries.
Oseltamivir, which is marketed under the trade name Tamiflu, is an oral agent approved for the treatment of uncomplicated acute influenza in patients one year and older who have been symptomatic for no more than two days, as well as for influenza prophylaxis in patients one year and older. Influenza virus mutants with resistance genes have been characterized from cell culture and particularly well-studied for this drug.
Zanamivir, which is marketed under the trade name Relenza, is an oral inhalation agent approved for influenza prophylaxis in patients five years and older, as well as for the treatment of influenza in patients seven years and older who have not been symptomatic with the illness for more than two days. Since inhaled zanamivir can worsen pulmonary status in patients with underlying pulmonary pathology, it should not be administered in these individuals.
M2 ion channel inhibitors
Adamantanes, which include both amantadine and rimantadine, are M2 ion channel blockers that are characterized by three condensed cyclohexane rings fused in the chair conformation. These drugs interfere with hydrogen ion channel activity of the influenza virus, blocking its entry into a host’s cell. Although M2 ion channel inhibitors were previously widely used against influenza, they are now largely discontinued and replaced by neuraminidase inhibitors.
The reduced use of these drugs is largely do to their limited efficacy, as adamantanes are only effective against influenza A, as influenza B viruses lack M2. Furthermore, almost all influenza strains have now developed significant resistance against both amantadine and rimantadine. This has primarily been attributed to their over-the-counter availability in densely populated nations such as Russia and China, as well as their large-scale use in the poultry.
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Other antiviral agents
Ribavirin and arbidol have long been acknowledged as broad-spectrum antiviral agents against viruses from diverse families. The clinical effectiveness of ribavirin on influenza is inferior to that of adamantanes or NA inhibitors and more reliant on the delivery manner. Guidelines set by the World Health Organization (WHO) therefore recommend that ribavirin should only be used to treat influenza in an approved research protocol.
Symptomatic relief and approach during pregnancy
Symptomatic measures can also help patients with influenza, particularly those who sought seek medical treatment after 48 hours of symptom onset. Over-the-counter antipyretic drugs and anti-inflammatory agents are most often used for this purpose. However, medications containing acetylsalicylic acid should be avoided in children because of the risk of Reye syndrome, which is an extremely rare but serious illness that can affect the liver and the brain. The development of complications or bacterial coinfection may require the use of antimicrobial drugs in patients with influenza.
Pregnant and postpartum women, including those with pregnancy loss, are at significant risk of severe influenza-related complications, mostly due to the changes in the respiratory, cardiovascular, and immune systems that occur during pregnancy. During previous influenza outbreaks, pregnant women who were otherwise healthy were more likely to become very sick or even die, when compared to non-pregnant women. In addition, pregnant women who develop high fever or pneumonia are at higher risk for pre-term labor and other complications.
The official CDC recommendations are that neuraminidase inhibitors should be prescribed for pregnant women and for those up to two weeks postpartum with suspected or confirmed influenza disease. Women can continue to breastfeed while being treated with antivirals. Since pregnancy is a particularly vulnerable period for influenza, vaccination should be an integral element of preconception, prenatal and postpartum care.
- Nicholson KG, Webster RG, Hay AJ. Textbook of Influenza. Blackwell Science, Oxford, 1998.
- Lamb RA, Krug RM. Orthomyxoviridae: The viruses and their Replication. In: Fields Virology fourth edition, Knipe DM, Howley PM eds, Lippincott, Philadelphia 2001, pp 1487-1531.