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Treatments for influenza include a range of medications and therapies that are used in response to disease influenza. Treatments may either directly target the influenza virus itself; or instead they may just offer relief to symptoms of the disease, while the body's own immune system works to recover from infection.
The two main classes of antiviral drugs used against influenza are neuraminidase inhibitors, such as zanamivir and oseltamivir, or inhibitors of the viral M2 protein, such as amantadine and rimantadine. These drugs can reduce the severity of symptoms if taken soon after infection and can also be taken to decrease the risk of infection. However, virus strains have emerged that show drug resistance to both classes of drug.
The United States authority on disease prevention, the Centers for Disease Control and Prevention (CDC), recommends that persons suffering from influenza infections:
Warning signs are symptoms that indicate that the disease is becoming serious and needs immediate medical attention. These include:
In children other warning signs include irritability, failing to wake up and interact, rapid breathing, and a blueish skin color. Another warning sign in children is if the flu symptoms appear to resolve, but then reappear with fever and a bad cough.
Antiviral drugs directly target the viruses responsible for influenza infections. Generally, anti-viral drugs work optimally when taken within a few days of the onset of symptoms. Certain drugs are used prophylactically, that is they are used in uninfected individuals to guard against infection.
Four licensed influenza antiviral agents are available in the United States: amantadine, rimantadine, zanamivir, and oseltamivir. They are available through prescription only. These drugs fall into categories as either M2-inhibitors (admantane derivatives) or neuraminidase inhibitors as illustrated in the following table.
|Class||Effective Against||Drug Name (INN)||Brand Name||Year Approved||Manufacturer|
|Influenza A||Amantadine||Symmetrel||1976||Endo Pharmaceuticals|
|Neuraminidase inhibitors||Influenza A & B||Zanamivir||Relenza||1999||GlaxoSmithKline|
|Note: Neuraminidase inhibitors are approved for prophylaxis use in children and adults.|
The efficacy of neuraminidase inhibitors was highly debated in recent years. The benefits of neuraminidase inhibitors in those who are otherwise healthy do not appear to outweigh its risks. The combination of diagnostic uncertainty, the risk for virus strain resistance, possible side effects and financial cost outweigh the small benefits of oseltamivir or zanamivir for the prophylaxis and treatment of healthy individuals. No benefit of treatment, on hospitalization, complications or risk of death has been found in randomized trials in those people at high risk for complications or the elderly. The United States Centers for Disease Control continues to recommend the use of oseltamavir treatment for people at high risk for complications and the elderly and those at lower risk who present within 48 hours of first symptoms of infection.
Peramivir, an experimental anti-influenza drug, developed by BioCryst Pharmaceuticals has not yet been approved for sale in the United States. This drug can be given as an injection, so could be particularly useful in serious cases of influenza where the patient is unconscious and oral or inhaled drug administration is therefore difficult. In October 2009, it was reported in the news that the experimental antiviral drug Peramivir had been effective in treating 6 serious cases of swine flu. On October 23, the U.S. Food and Drug Administration (FDA) issued an Emergency Use Authorization for Peramivir (now expired), leading to wider and faster availability for patients.
According to the U.S. Centers for Disease Control and Prevention, 100% of seasonal H3N2 and 2009 pandemic flu samples tested have shown resistance to adamantanes, and amantadine is no longer recommended for treatment of influenza in the United States since 2009. A cochrane review of trials found that both adamantane drugs are similarly helpful in relieving the symptoms of influenza A in adults, but only when there is a high probability that the cause of the flu is influenza A (a known epidemic, for example). It is likely that neither drug will interrupt the spread of influenza A. Resistance of influenza viruses to amantadine is a serious worldwide problem as shown by recent surveys. Both drugs have adverse gastrointestinal (stomach and gut) effects, but amantadine can also have serious effects on the nervous system. They should only be used in an emergency when all other measures fail.
Interferons are cellular signalling factors produced in response to viral infection. Research into the use of interferons to combat influenza began in the 1960s in the Soviet Union, culminating in a trial of 14,000 subjects at the height of the Hong Kong Flu of 1969, in which those treated prophylactically with interferon were more than 50% less likely to suffer symptoms, though evidence of latent infection was present. In these early studies leukocytes were collected from donated blood and exposed to a high dose of Newcastle disease, causing them to release interferons. Although interferon therapies became widespread in the Soviet Union, the method was doubted in the United States after high doses of interferon proved ineffective in trials. Though the 1969 study used 256 units of interferon, subsequent studies used up to 8.4 million units. It has since been proposed that activity of interferon is highest at low concentrations. In one trial healthy volunteers were enrolled to take low dose oral interferon or placebo lozenges once daily for 16 weeks. Overall, the incidence of serologically confirmed viral infections (influenza and non-influenza) was the same in both the interferon-alpha and placebo groups.
According a 2010 WHO statement about intranasal interferons in vitro data indicated no major cytokine dysregulation due to pandemic (H1N1)2009 virus. Therefore, whether immunomodulators such as interferons were useful as an adjunctive therapy was uncertain, with the possible exception of individual severe cases. One study demonstrated the sensitivity of pandemic (H1N1) 2009 virus to the antiviral effects of interferons. Other influenza viruses varied in their in vitro interferon sensitivity. Thus, uncertainty remains regarding the potential value of interferons for treatment of influenza. Animal data show constraint of viral replication and prevention of transmission by intranasal interferons. There are no published clinical randomized controlled trials or observational studies of current intranasal interferon preparations for the treatment of influenza. One interferon alfa-2b medicine, "Grippferon", nasal drops, is used for treatment and emergency prevention of Influenza and cold.
Interferons have also been investigated as adjuvants to enhance to effectiveness of influenza vaccines. This work was based on experiments in mice that suggested that type I interferons could enhance the effectiveness of influenza vaccines in mice. However, a clinical trial in 2008 found that oral dosing of elderly patients with interferon-alpha actually reduced their immune response to an influenza vaccine.
Another interferon alfa-2b medicine Viferon is a suppository of (non-pegylated) interferon alpha-2b, ascorbic acid (vitamin C), and tocopherol (vitamin E) which was reported in two small studies to be as effective as arbidol.
In Russia and China a drug called arbidol is also used as a treatment. Testing of the drug has predominantly occurred in these countries and, although no clinical trials have been published demonstrating this is an effective drug, some data suggest that this could be a useful treatment for influenza. A review by Boriskin et al. (2008) provided a summary of the studies of arbidol. The WHO found while the results described by Boriskin reported some efficacy and safety of arbidol, the lack of information regarding trial design, trial numbers, and comparative analyses indicated the results should be interpreted with caution.
Influenza viruses can show resistance to anti-viral drugs. Like the development of bacterial antibiotic resistance, this can result from over-use of these drugs. For example, a recent study published in the June 2009 Issue of Nature Biotechnology emphasized the urgent need for augmentation of oseltamivir (Tamiflu) stockpiles with additional antiviral drugs including zanamivir (Relenza) based on an evaluation of the performance of these drugs in the scenario that the 2009 H1N1 'Swine Flu' neuraminidase (NA) were to acquire the tamiflu-resistance (His274Tyr) mutation which is currently widespread in seasonal H1N1 strains. On the other hand, a few strains resistant to neuraminidase inhibitors have emerged and circulated in the absence of much use of the drugs involved, and the frequency with which drug resistant strains appears shows little correlation with the level of use of these drugs. However, laboratory studies have shown that it is possible for the use of sub-optimal doses of these drugs as a prophylactic measure might contribute to the development of drug resistance.
During the United States 2005–2006 influenza season, increasing incidence of drug resistance by strain H3N2 to amantadine and rimantadine led the CDC to recommend oseltamivir as a prophylactic drug, and the use of either oseltamivir or zanamivir as treatment.  In the case of the amantadines treatment may lead to the rapid production of resistant viruses, and over-use of these drugs has probably contributed to the spread of resistance. In particular, this high-level of resistance may be due to the easy availability of amantadines as part of over-the-counter cold remedies in countries such as China and Russia, and their use to prevent outbreaks of influenza in farmed poultry.
Antiviral drugs are prescription-only medication in the United States. Readily available over-the-counter medications do not directly affect the disease, but they do provide relief from influenza symptoms, as illustrated in the table below.
|fever, aches, pains, sinus pressure, sore throat||analgesics|
|nasal congestion, sinus pressure||decongestants|
|sinus pressure, runny nose, watery eyes, cough||antihistamines|
|sore throat||local anesthetics|
Children and teenagers with flu symptoms (particularly fever) should avoid taking aspirin as taking aspirin in the presence of influenza infection (especially Influenzavirus B) can lead to Reye's syndrome, a rare but potentially fatal disease of the brain.
Malnutrition can reduce the ability of the body to resist infections and is a common cause of immunodeficiency in the developing world. For instance, in a study in Ecuador, micronutrient deficiencies were found to be common in the elderly, especially for vitamin C, vitamin D, vitamin B-6, vitamin B-12, folic acid, and zinc, and these are thought to weaken the immune system or cause anemia and thus place people at greater risk of respiratory infections such as influenza. Seasonal variation in sunlight exposure, which is required for vitamin D synthesis within the body, has been proposed as one of the factors accounting for the seasonality of influenza. A meta-analysis of 13 studies indicated some support for adjunctive vitamin D therapy for influenza, but called for more rigorous clinical trials to settle the issue conclusively.
A recent review discussing herbal and alternative medicines in influenza treatment details evidence suggesting that N-acetylcysteine, elderberry, or a combination of Eleutherococcus senticosus and Andrographis paniculata may help to shorten the course of influenza infection. The article cites more limited evidence including animal or in vitro studies to suggest possible benefit from vitamin C, DHEA, high lactoferrin whey protein, Echinacea spp., Panax quinquefolium, Larix occidentalis arabinogalactans, elenolic acid (a constituent of olive leaf extract), Astragalus membranaceus, and Isatis tinctoria or Isatis indigotica.  Another review assessed the quality of evidence for alternative influenza treatments, it concluded that there was "no compelling evidence" that any of these treatments were effective and that the available data on these products is particularly weak, with trials in this area suffering from many shortcomings, such as being small and poorly designed and not testing for adverse effects.
The activity of N-acetylcysteine (NAC) against influenza was first suggested in 1966. In 1997 a randomized clinical trial found that volunteers taking 1.2 grams of N-acetylcyteine daily for six months were as likely as those taking placebo to be infected by influenza, but only 25% of them experienced clinical symptoms, as contrasted with 67% of the control group. Seroconversion towards A/H1N1 Singapore 6/86 influenza virus was similar in the two groups. The authors concluded that resistance to flu symptoms was associated with a shift in cell mediated immunity from anergy toward normoergy, as measured by the degree of skin reactivity to seven common antigens such as tetanus and Candida albicans. A 2005 review didn't find more trials abouts its use in influenza.
Several animal studies found that in a mouse model of lethal infection with a high dose of influenza A virus APR/8, oral supplementation with one gram of N-acetylcysteine per kilogram of body weight daily increased the rate of survival, either when administered alone or in combination with the antiviral drugs ribavirin or oseltamivir. NAC alone did not show any antiviral action. There was found antiviral in vitro activity with H5N1 strains. But an in vivo mouse study, found n-acetylcysteine unable to alter the course of a fatal influenza pneumonia caused by inoculation of a murinized swine H1N1 influenza virus. Therefore, susceptibility of influenza viruses to n-acetylcysteine appears to be strain-dependent and not universal.
A few news reports have suggested the use of an elderberry (Sambucus nigra) extract as a potential preventative against the 2009 flu pandemic. The preparation has been reported to reduce the duration of influenza symptoms by raising levels of cytokines. However, the use of the preparation has been described as "imprudent" when an influenza strain causes death in healthy adults by cytokine storm leading to primary viral pneumonia. The manufacturer cites a lack of evidence for cytokine-related risks, but labels the product only as an antioxidant and food supplement.
The mixture of Eleutherococcus senticosus ("Siberian ginseng") and Andrographis paniculata, sold under the trade name Kan Jang, was reported in the Journal of Herbal Pharmacotherapy to outperform amantadine in reducing influenza-related sick time and complications in a Volgograd pilot study of 71 patients in 2003. Prior to this, an extract of Eleutherococcus senticosus was shown to inhibit replication of RNA but not DNA viruses in vitro. Among nine Chinese medicinal herbs tested, Andrographis paniculata was shown to be most effective in inhibiting RANTES secretion by H1N1 influenza infected cells in cell culture, with an IC50 for the ethanol extract of 1.2 milligrams per liter.
High dietary intake of Green Tea (specifically, catechins and theanine that is found in tea products) has been correlated with reduced risk of contracting influenza, as well as having an antiviral effect upon types A and B. Specifically, the high levels of epigallocatechin gallate, epicatechin gallate, and epigallocatechin present in green tea were found to inhibit influenza virus replication. Additionally, topical application has been suggested to possibly act as a mild disinfectant. Regular dietary intake of green tea has been associated with stronger immune response to infection, through the enhancement of T-Cell function.
A systematic review containing 18 Chinese herbal trials showed a similar effect to antiviral drugs in preventing or treating influenza. However, since these included studies were of poor quality, the evidence does not support or reject the use of any Chinese herbal preparations for influenza. High-quality trials are required.
An alternative to vaccination used in the 1918 flu pandemic was the direct transfusion of blood, plasma, or serum from recovered patients. Though medical experiments of the era lacked some procedural refinements, eight publications from 1918 to 1925 reported that the treatment could approximately halve the mortality in hospitalized severe cases with an average case-fatality rate of 37% when untreated. A preliminary study found a lower mortality by transfusion with convalescent serum of AH1N12009 patients.
Human T lymphocytes can be expanded in vitro using beads holding specific antigens to activate the cells and stimulate growth. Clonal populations of CD8+ cytotoxic T cells have been grown which carry T cell receptors specific to influenza. These work much like antibodies but are permanently bound to these cells. (See cellular immunity). High concentrations of N-acetylcysteine have been used to enhance growth of these cells. This method is still in early research.
|title=(help)|title=Amarillo Biosciences. Clinical trials