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Treatment of seasonal influenza in adults
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Apr 2012. | This topic last updated: Mar 27, 2012.

INTRODUCTION — Seasonal influenza is an acute respiratory illness caused by influenza A or B viruses. Influenza occurs in outbreaks and epidemics worldwide, mainly during the winter season. Although acutely debilitating, influenza is usually a self-limited infection. However, it is associated with increased morbidity and mortality in certain high-risk populations.

Two classes of antiviral drugs are available for the treatment and prevention of influenza [1,2]:

  • The neuraminidase inhibitors, zanamivir and oseltamivir, which are active against both influenza A and B.
  • The adamantanes, amantadine and rimantadine, which are only active against influenza A. Due to a marked increase in resistant isolates, the Advisory Committee on Immunization Practices (ACIP) recommends that adamantanes not be used in the United States for the treatment of influenza, except in selected circumstances [2]. (See 'Choice of antiviral drug' below.)

The role of these drugs in the treatment of seasonal influenza will be reviewed here. Their role in the prevention of seasonal influenza, treatment and prevention of 2009 pandemic H1N1 influenza and avian influenza, and treatment and prevention of influenza in children are discussed separately; the pharmacologic characteristics of the antiviral drugs used for influenza are also presented elsewhere. (See "Prevention of seasonal influenza in adults" and "Treatment and prevention of pandemic H1N1 influenza ('swine influenza')" and "Treatment and prevention of avian influenza" and "Antiviral drugs for the prevention and treatment of seasonal influenza in children" and "Pharmacology of antiviral drugs for influenza".)

BENEFITS OF THERAPY — When initiated promptly, antiviral therapy can shorten the duration of influenza symptoms by one to three days; the benefit is greatest when given within the first 24 to 30 hours and in patients with fever at presentation [3-9]. Little to no benefit has been demonstrated when treatment is initiated two days or more after the onset of uncomplicated influenza. However, a patient survey found that only 13 percent of patients called their clinician within 48 hours of the onset of influenza-like symptoms [10].

Some studies have suggested that antiviral therapy reduces the severity and incidence of complications of influenza [4,8,11-13], the duration of hospitalization in patients with severe influenza [14], and influenza-associated mortality [15,16].

Studies of the use of antiviral therapy during the 2009 H1N1 influenza A pandemic are presented separately. (See "Treatment and prevention of pandemic H1N1 influenza ('swine influenza')", section on 'Efficacy'.)

NEURAMINIDASE INHIBITORS — Zanamivir and oseltamivir are moderately effective for the treatment of infections with susceptible viruses, reducing the duration and severity of symptoms particularly when treatment is initiated early after onset of symptoms. This was illustrated in a meta-analysis of 20 randomized trials that studied healthy adults in whom slight alleviation of influenza-like illness symptoms was reported for both oseltamivir and zanamivir use, provided that medication was started within 48 hours of symptom onset [9]. The neuraminidase inhibitors also reduce the duration of shedding and viral titer [17].

Neither oseltamivir nor zanamivir has been well studied in patients with severe seasonal influenza [3]. Studies of the use of neuraminidase inhibitors for the treatment of 2009 pandemic H1N1 influenza A infection are presented separately. (See "Treatment and prevention of pandemic H1N1 influenza ('swine influenza')", section on 'Treatment' and "Treatment and prevention of avian influenza", section on 'Treatment'.)

Investigational neuraminidase inhibitors are discussed below. (See 'Investigational approaches' below.)

Efficacy of oseltamivir — Oseltamivir is orally administered and is available as a capsule or powder for liquid suspension. It has good bioavailability and is widely distributed in the body.

Oseltamivir has been demonstrated to shorten the duration of influenza symptoms [5,6,11,18-23], and to reduce the duration of viral shedding [17]. Some studies have also shown that oseltamivir reduces illness severity and complication rates [11,12]. As discussed below, meta-analyses have provided contradictory results regarding reduction in influenza-related lower respiratory tract complications in healthy adults [13,23]. The role of oseltamivir in the prevention of lower respiratory tract infection complications in adults remains controversial.

Some studies have shown a mortality reduction [15,16] and shorter length of hospitalization in patients with severe influenza treated with oseltamivir [14].

In meta-analyses, treatment with oseltamivir reduced the median duration of symptoms by 0.9 days in otherwise healthy adults [23] and by 0.4 days in elderly adults or patients with comorbidities [5].

The range of findings in adults can be illustrated by the following observations:

  • A 60-center trial randomly assigned 627 healthy adults 18 to 65 years of age to oseltamivir (75 or 150 mg twice daily) or placebo for five days within 36 hours of the onset of suspected influenza [11]. Sixty percent had laboratory-confirmed influenza. Both doses of oseltamivir led to a statistically significant reduction in illness duration of approximately one day compared with placebo. Oseltamivir also reduced illness severity scores and the incidence of clinician-diagnosed secondary complications (pneumonia, bronchitis, sinusitis, and otitis media).
  • Comparable results were noted in a 51-center trial with 719 healthy adult patients [6]. Among the 66 percent of patients with laboratory-confirmed influenza, oseltamivir significantly reduced the duration of illness by approximately one day in patients treated 24 to 36 hours after illness onset, and by 1.5 to 2 days in those treated within 24 hours of illness onset.
  • A 2003 systematic review utilized data from 10 published and unpublished placebo-controlled trials to evaluate the effect of oseltamivir therapy on influenza-related lower respiratory tract complications [12]. Among patients with proven influenza, oseltamivir significantly reduced the incidence of lower respiratory tract complications that required antibiotic use compared with placebo (4.6 versus 10.3 percent in all patients, 12.2 versus 18.5 percent in patients at risk for complications).
  • In contrast to the 2003 systematic review described above [12], the authors of a 2012 meta-analysis deliberately did not assess a possible effect of oseltamivir on influenza-related lower respiratory tract complications because they believed that the unpublished data available to them lacked sufficient detail to address this question [23]. This meta-analysis was based upon unpublished clinical study reports of data from randomized trials and documents from regulatory agencies. However, a 2011 meta-analysis that reanalyzed the results from 11 randomized trials (including the 10 trials that were included in the 2003 systematic review and one trial that was published after the 2003 review) concluded that oseltamivir treatment reduces the risk of lower respiratory tract complications by 28 percent overall (95% CI 11-42%) and by 37 percent among patients with confirmed influenza infections (95% CI 18-52%) [13]. Although all 11 trials that were included in the analyses were funded by the manufacturer of oseltamivir, the 2011 meta-analysis was conducted by independent researchers who were given full access to the efficacy and safety data in the trials, access to the statisticians involved in the trials to answer data-related questions, and complete freedom to publish any results [13].
  • A 2012 meta-analysis evaluated the efficacy of antivirals for the treatment of influenza in 74 observational studies; only a small subset of these studies was used in each analysis since only those that adjusted for confounders were included [24]. In an analysis of three studies of hospitalized patients, oseltamivir appeared to reduce mortality (odds ratio [OR] 0.23, 95% CI 0.13-0.43). In an analysis of four studies, oseltamivir appeared to reduce hospitalization in outpatients (OR 0.75, 95% CI 0.66-0.89). In an analysis of six studies, oseltamivir appeared to reduce the duration of fever by 33 hours (95% CI 21-45 hours) compared with no antiviral therapy. Mortality, hospitalizations, intensive care unit admission, and respiratory failure were reduced when oseltamivir was started within 48 hours of onset of symptoms compared with later. The authors pointed out that the quality of the data in the observational studies was low or very low.
  • Some studies, but not others, have shown that oseltamivir may be less effective in reducing clinical symptoms related to influenza B. In a prospective, multicenter study conducted in Japan, influenza A was documented in 1818 patients and influenza B in 1485 patients [18]. The duration from treatment initiation to resolution of fever was significantly longer for patients with influenza B than for influenza A (mean duration 65 versus 48 hours, respectively). In addition, after four to six days of oseltamivir therapy, the resolution rate was higher for influenza B than for influenza A (52 versus 16 percent) in a subset of 75 patients in whom viral isolation was performed. In contrast, in a study of 64 children with influenza infections treated with oseltamivir (34 with influenza A subtype H3N2, 11 with influenza A subtype H1N1, 19 with influenza B), there were no differences in the reduction of viral shedding or time to clearance of virus among viral subtypes [25].

Studies during the 2009 H1N1 influenza A pandemic generally showed similar findings. The efficacy of oseltamivir during the 2009 H1N1 influenza A pandemic is discussed in greater detail separately. (See "Treatment and prevention of pandemic H1N1 influenza ('swine influenza')" and "Treatment and prevention of pandemic H1N1 influenza ('swine influenza')", section on 'Efficacy'.)

Efficacy of zanamivir — Zanamivir is administered by oral inhalation. Inhaled zanamivir is contraindicated in patients with underlying asthma or other chronic respiratory conditions. (See 'Adverse effects' below.)

An intravenous formulation of zanamivir is being evaluated in clinical trials [26-28], and is available for compassionate use.

In a 2003 meta-analysis of randomized trials, zanamivir reduced the median duration of symptoms of laboratory-confirmed influenza by 1.3 days in otherwise healthy adults ≤65 years of age and by two days in adults ≥65 years of age or patients with comorbidities [5]. Subsequent meta-analyses have shown similar benefits [9,22].

In one trial, 417 otherwise healthy adults presenting with suspected influenza of not more than 48 hours duration were randomly assigned to inhaled zanamivir (10 mg twice daily for five days), inhaled and intranasal zanamivir (6.4 mg twice daily for five days), or placebo [7]. Sixty-three percent of subjects had laboratory-confirmed influenza. The following findings were noted:

  • Among those with laboratory-confirmed influenza, zanamivir significantly shortened the median time to alleviation of all major symptoms by approximately one day compared with placebo (four versus five days).
  • Among the infected patients who were febrile at presentation, the median time to alleviation of all major symptoms was even more pronounced compared with placebo (four versus seven days).
  • Among the infected patients who began zanamivir within 30 hours of symptom onset, there was also a three day shortening of major symptoms (four versus seven days). In contrast, there was no benefit when zanamivir was started more than 30 hours after symptom onset.
  • There was no added benefit in the group that received intranasal zanamivir in combination with inhaled zanamivir.

In a separate trial, 455 previously healthy subjects who were at least 12 years old and presented with suspected influenza of ≤36 hours duration were randomly assigned to inhaled zanamivir (10 mg twice daily) or placebo for five days [8]. Eighty percent had laboratory-confirmed influenza. Among the patients with influenza who received zanamivir, the median duration of illness was significantly reduced by 1.5 days overall and by two days in those with fever at presentation. A subgroup of 39 patients, most of whom had mild asthma, was defined as high risk for complications of influenza. Zanamivir was associated with significantly fewer complications and a reduced need for antibiotics in this subgroup.

Another trial also demonstrated that zanamivir shortens the duration of illness and reduces the symptoms of influenza [29].

Adverse effects — Adverse effects of neuraminidase inhibitors are typically mild, although more serious side effects have been described [30]. Zanamivir can cause bronchospasm and a decline in respiratory function in patients with asthma and other chronic respiratory disorders. As a result, the manufacturer has issued a warning advising particular caution in patients with asthma or chronic obstructive pulmonary disease [31].

Zanamivir inhalation powder is not recommended for use in nebulizers or mechanical ventilators since the lactose carrier can clog ventilator tubing [2,32]. (See "Pharmacology of antiviral drugs for influenza", section on 'Adverse effects'.)

In November 2006, the manufacturer of oseltamivir notified healthcare professionals and the FDA of postmarketing reports of self-injury and delirium in patients (primarily children) receiving the drug for treatment of influenza. Most of these reports came from Japan, where the drug is used more commonly than in the United States [33]. However, a subsequent study has not demonstrated a causal association between neuraminidase inhibitors and abnormal behavior, and Japan's health ministry is considering whether to modify the warning [34]. (See "Antiviral drugs for the prevention and treatment of seasonal influenza in children", section on 'Rare adverse effects'.)

Oseltamivir can also cause nausea and vomiting, but these side effects have not generally resulted in discontinuation of therapy. (See "Pharmacology of antiviral drugs for influenza", section on 'Adverse effects'.)

ADAMANTANES — The adamantanes, amantadine and rimantadine, are active only against influenza A viruses, but high rates of resistance have developed and these drugs are infrequently indicated. These drugs prevent viral replication by blocking the viral M2 protein ion channel, which prevents fusion of the virus and host-cell membranes [35]. (See "Antiviral drug resistance among seasonal influenza viruses" and "Pharmacology of antiviral drugs for influenza", section on 'Mechanism of action'.)

The Advisory Committee on Immunization Practices (ACIP) recommends that adamantanes (M2 inhibitors) not be used for the treatment of influenza in the United States [2]. Oseltamivir or zanamivir should be used for most cases of influenza that require treatment. (See 'Neuraminidase inhibitors' above and 'Choice of antiviral drug' below.)

Efficacy — In a 2006 meta-analysis that included trials of the adamantanes from the 1960s through the 1980s, prior to the emergence of substantial rates of resistance, both amantadine and rimantadine reduced the duration of symptoms of influenza by about one day and reduced the severity of fever and other symptoms in patients with uncomplicated influenza A infections [4]. In recent years, high levels of resistance to these agents have emerged, initially in Asia and more recently in North America. (See "Antiviral drug resistance among seasonal influenza viruses", section on 'Adamantane resistance'.)

Adverse effects — Studies in young adults have reported a discontinuation rate of 13 to 17 percent with amantadine, largely attributable to central nervous system toxicity [36,37]. Rimantadine causes fewer central nervous system side effects than amantadine (13 versus 6 percent) [36] and has a discontinuation rate due to adverse effects that is similar to placebo [36,37]. (See "Pharmacology of antiviral drugs for influenza", section on 'Adverse effects'.)

RESISTANCE — Although antiviral drug resistance among influenza viruses has occurred during antiviral therapy, resistant influenza strains have spread widely in the absence of such drug pressure [38]. As examples, adamantane-resistant H3N2 influenza A viruses have circulated globally since 2003, oseltamivir-resistant seasonal H1N1 influenza A viruses since 2007 (the H274Y mutation), and adamantane-resistant pandemic H1N1 influenza A viruses since 2009 [38]. A mutation that confers low to moderate oseltamivir and zanamivir resistance, the S247N mutation, has been detected in the Asia Pacific region since December 2010 [39]. When combined with the H274N mutation, the dual S247N/H275Y mutant can cause high-level resistance to oseltamivir and zanamivir. (See "Antiviral drug resistance among seasonal influenza viruses".)

Since September 2009, 99 percent of influenza virus isolates tested in the US have been susceptible to neuraminidase inhibitors [2,40,41]. Information regarding antiviral resistance that emerges during the influenza season is available through the United States Centers for Disease Control and Prevention (www.cdc.gov/flu/professionals). Clinicians should review antiviral resistance patterns and the CDC’s website for updated antiviral recommendations should increased resistance emerge.

ANTIVIRAL THERAPY — The United States Advisory Committee on Immunization Practices (ACIP) published updated guidelines for the use of antivirals for patients with confirmed or suspected influenza virus infection (caused by either pandemic H1N1 or seasonal strains) in January 2011 [2], and a summary of antiviral recommendations was released by the CDC in August 2011 [42]. Our recommendations reflect those of the ACIP and CDC. See the CDC's website for updated recommendations (http://www.cdc.gov/flu/professionals/antivirals/index.htm). Clinicians in other countries should consult with their ministries of health and/or the World Health Organization for specific recommendations.

Target populations for treatment — Individuals with severe disease (requiring hospitalization or evidence of lower respiratory tract infection) or at high risk for complications should receive antiviral therapy. Antiviral therapy, when indicated, should be initiated as promptly as possible.

Definition of high risk — Adults at high risk for complications for influenza include (table 1) [2,43]:

  • Residents of nursing homes and other chronic care facilities
  • Adults ≥65 years of age
  • Pregnant women and women up to two weeks postpartum [44]. The risk of complicated influenza during pregnancy increases by trimester and with associated comorbidities [45,46]. (See 'Target populations for treatment' above and 'Pregnancy' below.)
  • Individuals with chronic medical conditions including:

  • Pulmonary disease, including asthma (particularly if systemic glucocorticoids have been required during the past year)
  • Cardiovascular disease, except isolated hypertension
  • Active malignancy
  • Chronic renal insufficiency
  • Chronic liver disease
  • Diabetes mellitus
  • Hemoglobinopathies such as sickle cell disease
  • Immunosuppression, including HIV infection (particularly if CD4 <200 cells/microL), organ or hematopoietic cell transplantation, inflammatory disorders treated with immunosuppressants
  • Any neurologic condition that can compromise handling of respiratory secretions (eg, cognitive dysfunction, spinal cord injuries, seizure disorders, neuromuscular disorders)

  • Native Americans and Alaska Natives
  • Individuals who are morbidly obese (body-mass index ≥40)

Of the groups described above, those at highest risk for influenza complications may be those with underlying lung disease and/or severe immunosuppression (eg, lung transplant recipients, individuals with advanced HIV infection [CD4 <200 cells/microL]).

Antiviral treatment should be considered in asplenic patients. Although there are no data regarding the risk for severe or complicated influenza among asplenic individuals, influenza is a risk factor for secondary bacterial infections that can cause severe disease among such patients [47].

Indications for treatment — In accordance with the ACIP’s guidelines, we recommend prompt initiation of antiviral therapy for individuals with suspected or confirmed influenza infection and any of the following features [2]:

  • Age ≥65 years
  • Pregnant women and women up to two weeks postpartum (including those who have had pregnancy loss) [44]. (See 'Pregnancy' below.)
  • Individuals with certain medical conditions (table 1) (see 'Definition of high risk' above)

All patients with the risk factors described above, including those with mild illness not requiring hospitalization, should be treated with antiviral therapy [2].

Adults with mild illness without high risk conditions who are younger than 65 years of age do not require testing or treatment [2]. If such individuals present within the first 48 hours of illness, antiviral treatment can be considered in order to reduce the duration of illness, but those who present >48 hours after illness onset should not be treated with antivirals since they are unlikely to benefit.

Patients who are recovering from influenza generally do not require antiviral therapy [2]. The decision of whether to initiate antiviral therapy for each patient should be based upon the clinician's judgment and on what is known about the potential benefits of therapy for seasonal influenza versus the potential risks. Given the concerning trends of increasing resistance with both the adamantanes and the neuraminidase inhibitors, the risk of promoting antiviral drug resistance should be considered when deciding which patients to treat. Overuse of the neuraminidase inhibitors, which are the agents of choice for the prevention and treatment of influenza, will promote further development of resistance that could lead to these agents becoming ineffective.

Timing of antiviral initiation — Treatment should be initiated as soon as possible since antiviral therapy is most likely to provide benefit when initiated within the first 48 hours of illness [2,48]. Treatment should not be delayed while awaiting the results of diagnostic testing, nor should it be withheld in patients with indications for therapy who present >48 after the onset of symptoms, particularly among patients requiring hospitalization. Furthermore, patients who have a negative rapid antigen test for influenza but in whom the clinical suspicion for influenza infection is high should be treated with antivirals since the sensitivity of these tests is generally low. (See "Diagnosis of seasonal influenza in adults".)

Patients with mild uncomplicated influenza infections who do not have risk factors for severe or complicated illness are not likely to benefit from antiviral therapy if it is initiated more than 48 hours after symptom onset [2].

Choice of antiviral drug — It is important to assess the risk of oseltamivir-resistant influenza before choosing therapy for patients with influenza. Clinicians should review local or state influenza surveillance data weekly to determine which types of influenza (A or B) and subtypes of influenza A (H1N1 or H3N2) are circulating [2]. (See 'Influenza activity' below and 'Oseltamivir resistance' below.)

In patients suspected of having influenza in whom treatment is indicated, we recommend treatment with a neuraminidase inhibitor (zanamivir or oseltamivir), provided that oseltamivir-resistant influenza is not suspected (table 2) [2].

Dosing — The usual dosing of oseltamivir for the treatment of influenza is 75 mg orally twice daily and of zanamivir is 10 mg [2 inhalations] twice daily (table 2). Since oseltamivir is primarily excreted by the kidneys, dosing must be modified for renal insufficiency.

Doubling the dose of oseltamivir to 150 mg orally twice daily has been suggested for some severely ill patients with H5N1 avian influenza and was also suggested for certain severely ill patients (eg, immunocompromised hosts) during the H1N1 influenza pandemic [49,50]. The effectiveness of increased dosing of oseltamivir for seasonal influenza has not been proven, but limited data suggest that it is well-tolerated and may be beneficial [2,51,52]. (See "Treatment and prevention of avian influenza", section on 'Treatment'.)

Duration — The recommended duration of antiviral therapy is five days [2]. However, a longer duration of therapy can be considered in severely ill patients or immunosuppressed individuals.

Oseltamivir resistance — Oseltamivir-resistant seasonal H1N1 influenza A viruses emerged in 2007 and were present at high rates worldwide during the 2008 to 2009 influenza season, prior to the onset of the 2009 H1N1 influenza A (“swine influenza”) pandemic. The pandemic strain of H1N1 influenza A was generally susceptible to oseltamivir, except for sporadic cases of oseltamivir resistance. Since September 2009, 99 percent of influenza virus isolates tested in the US have been susceptible to neuraminidase inhibitors [2,40,41]. (See "Antiviral drug resistance among seasonal influenza viruses", section on 'Oseltamivir resistance'.)

The IV formulation of zanamivir is being evaluated in clinical trials [28], and is available for compassionate use from its manufacturer through an emergency investigational new drug application to the Food and Drug Administration. IV zanamivir was the recommended antiviral treatment for severely ill patients with highly suspected or confirmed oseltamivir-resistant 2009 pandemic H1N1 influenza A infection [2]. IV zanamivir is also the most appropriate therapy for patients with non-pandemic strains of oseltamivir-resistant H1N1 influenza A infection who require treatment but cannot tolerate inhaled zanamivir.

Information regarding antiviral resistance that emerges during the influenza season is available through the US Centers for Disease Control and Prevention (www.cdc.gov/flu/professionals). Clinicians should review antiviral resistance patterns and the CDC’s website for updated antiviral recommendations should increased resistance emerge.

Pregnancy — Influenza causes more severe disease and an increased rate of mortality among pregnant women [44]. Oseltamivir and zanamivir are Pregnancy Category C drugs, reflecting that clinical studies have not been done to assess the safety of their use during pregnancy [53]. No adverse events have been shown to be caused by oseltamivir or zanamivir among women who received these agents during pregnancy or among infants who were exposed while in utero, although there are limited data [54]. (See "Pharmacology of antiviral drugs for influenza", section on 'Pregnancy'.)

Pregnant women who meet current case definitions for confirmed, probable, or suspected influenza A infection should receive antiviral therapy with oseltamivir, since the potential benefit outweighs the theoretical risk to the fetus [44]. Oseltamivir is recommended over zanamivir because only the former agent is systemically absorbed (table 2). In addition, zanamivir is relatively contraindicated in patients with asthma or chronic obstructive pulmonary disease.

Treatment should be initiated as early as possible, and should not be withheld while awaiting results of diagnostic testing or in situations in which testing is not performed [44]. Although the benefits of antiviral therapy are expected to be greatest when initiated within the first 48 hours following symptom onset, treatment should be administered even to pregnant women who present >48 hours after illness onset, particularly in those requiring hospitalization.

In addition to antiviral therapy, control of fever with antipyretic therapy is important when, since hyperthermia during the first trimester has been associated with neural tube defects and other birth defects [45,55]. In addition, fever during labor is a risk factor for neonatal seizures, encephalopathy, cerebral palsy, and neonatal death [45]. (See 'Symptom management' below.)

The management of influenza infection in pregnant women is discussed in greater detail separately. (See "Influenza and pregnancy", section on 'Treatment'.)

Hematopoietic cell transplantation — The use of antivirals in hematopoietic cell transplant (HCT) recipients has not been studied in randomized trials. A retrospective review of laboratory-confirmed influenza cases in HCT recipients found that 62 of 4797 patients (1.3 percent) were diagnosed with influenza within 120 days of undergoing HCT [56]. Of the 51 patients who were initially diagnosed with upper respiratory tract involvement and no signs or symptoms suggesting pneumonia, 6 of 34 untreated patients developed pneumonia, whereas none of nine patients treated with oseltamivir and one of eight patients treated with rimantadine developed pneumonia.

HCT recipients should be treated for influenza according to the recommendations for patients at high risk for influenza complications described above. (See 'Indications for treatment' above.)

INVESTIGATIONAL APPROACHES — There are several investigational approaches for the treatment of influenza. Some experts have called for the use of primary virologic endpoints in the evaluation of new influenza therapies, particularly in patients with severe influenza infection and/or in those at high risk of severe disease [57].

Parenteral formulations of zanamivir, oseltamivir, and another neuraminidase inhibitor, peramivir, have been developed and are considered investigational [26-28,58-61]. Although none of these agents have been approved by the US Food and Drug Administration (FDA) as an IV formulation, the FDA issued an emergency use authorization (EUA) for the use of peramivir during the 2009 H1N1 influenza A pandemic, and intravenous zanamivir was also available for compassionate use from its manufacturer through an emergency investigational new drug (IND) application. Although the EUA for IV peramivir expired in June 2010, IV zanamivir remains available for compassionate use. (See "Treatment and prevention of pandemic H1N1 influenza ('swine influenza')", section on 'Antiviral agents'.)

In a multinational trial, 1091 adults with seasonal influenza A or B virus infection were randomly assigned to receive either a single intravenous infusion of peramivir (300 or 600 mg) or oral administration of oseltamivir (75 mg twice a day for five days) [62]. The median duration of influenza symptoms was 78, 81, and 82 hours in the groups treated with 300 mg of peramivir, 600 mg of peramivir, or oseltamivir, respectively. Both doses of peramivir were considered to be noninferior to oseltamivir. The overall incidence of adverse drug reactions was significantly lower in the 300 mg peramivir group than in the other groups, but the incidence of severe reactions in either peramivir group was similar to that in the oseltamivir group.

Although this trial suggests that 300 mg of peramivir is as effective as 600 mg of peramivir, in a trial by the same group that compared different doses of peramivir (600 mg or 300 mg IV daily of peramivir for one to five days) in 37 high-risk patients (with immunocompromise, chronic respiratory disease, or diabetes) with influenza infection, the duration of illness was shorter among those who received the 600 mg dosing compared with the 300 mg dosing (median duration of 42 versus 114 hours; hazard ratio 0.50, 95% CI 0.25-0.98) [63]. This trial suggests that a 600 mg dose of peramivir may be more effective than a 300 mg dose in high-risk patients, although a larger trial is necessary to confirm these findings.

Long-acting neuraminidase inhibitors, which could allow a single dose to replace a five-day course, are also being developed, as illustrated by the following trials [60,64,65]:

  • In a randomized trial, a single inhalation of a long-acting neuraminidase inhibitor, laninamivir octanoate, was non-inferior to a five-day course of oral oseltamivir in adults with seasonal influenza [65]. The median time to alleviation of illness was 73 hours among those who received 40 mg of laninamivir compared with 86 hours among those who received 20 mg of laninamivir and 74 hours among those who received oseltamivir. The proportion of patients shedding influenza virus at day 3 was significantly lower among those who received 40 mg of laninamivir compared with oseltamivir.
  • Because peramivir has strong and prolonged affinity for influenza virus neuraminidase, the efficacy of a single dose of IV peramivir has been evaluated [66]. In a randomized trial that included 300 previously healthy adults with proven infection with seasonal influenza who presented within 48 hours of symptom onset, a single dose of 300 mg or 600 mg of IV peramivir significantly reduced the time to alleviation of symptoms compared with placebo (hazard ratio 0.68 and 0.67, respectively) [66].

Ribavirin is a nucleoside analog that has in vitro activity against both influenza A and B viruses. However, clinical data regarding its efficacy have been inconclusive; thus, it is not recommended for the treatment of influenza infection [67].

Other agents that have shown activity in animal models include conjugated sialidase, hemagglutinin inhibitors, small interfering RNA, polymerase inhibitors, protease inhibitors, monoclonal antibodies, and a sphingosine analog [26,60,68-72].

It has been hypothesized that the antiinflammatory effects of statins could reduce the severity of illness associated with influenza infection, although this has not been established. In a surveillance study of 3043 hospitalized patients with laboratory-confirmed seasonal influenza infection in the United States, the 1013 patients who were receiving a statin had a lower likelihood of dying than those who were not (adjusted odds ratio 0.59, CI 0.38-0.92) [73], although confounding factors may have been present. Randomized trials are necessary to determine whether statins result in a survival benefit in patients with influenza infection. (See "Mechanisms of benefit of lipid-lowering drugs in patients with coronary heart disease", section on 'Reduced inflammation'.)

SYMPTOM MANAGEMENT — Acetaminophen or nonsteroidal antiinflammatory drugs (NSAIDs) can be used to treat fever, headache, and myalgia associated with influenza. The use of salicylates should be avoided, particularly in children below 18 years of age, because of the association with Reye syndrome. (See "Acute toxic-metabolic encephalopathy in children", section on 'Reye syndrome'.)

Cough suppressants are generally not recommended, especially for children as the cough is self-limited in most cases and does not require specific therapy. Patients should be advised to maintain hydration. Activity may need to be modified, based on patient symptoms, but can be resumed as tolerated.

ANTIBIOTICS FOR SECONDARY COMPLICATIONS — Antibiotics are indicated only for bacterial complications of acute influenza such as bacterial pneumonia, otitis media, or sinusitis.

The choice of antibiotics for pneumonia should be guided by Gram stain and culture of sputum. If the etiology of the pneumonia is not clear from the sputum examination, empiric antibiotics effective against the most common bacterial pathogens following influenza (ie, Streptococcus pneumoniae, Streptococcus pyogenes, Staphylococcus aureus) should be used. Examples include a third-generation cephalosporin (eg, ceftriaxone) or an extended-spectrum quinolone (eg, levofloxacin or moxifloxacin) in combination with nafcillin, oxacillin, or vancomycin if the index of suspicion for S. aureus is high. (see "Treatment of community-acquired pneumonia in adults in the outpatient setting" and "Treatment of community-acquired pneumonia in adults who require hospitalization")

INFECTION CONTROL — Individuals with influenza who are managed as outpatients should remain home from work, school, and other populated environments until influenza signs and symptoms have abated. Infection control measures at home may be beneficial. A randomized trial found that the combination of hand hygiene and face masks, when implemented within 36 hours of symptom onset in the index patient, prevents the household transmission of seasonal influenza (adjusted odds ratio 0.33, 95% CI 0.13 to 0.87) [74].

Infection control measures for healthcare settings are discussed separately. (See "Infection control measures to prevent seasonal influenza in healthcare settings".)

INFLUENZA ACTIVITY — The Centers for Disease Control and Prevention (CDC), in collaboration with the World Health Organization and its reporting network, tracks influenza virus isolates throughout the world to monitor disease activity and antiviral resistance patterns, and to predict the appropriate components for the annual influenza vaccine. This information, which is updated weekly during influenza season, is available via the CDC through its website (www.cdc.gov/flu/weekly). In addition, FluNet, a database for global influenza virus surveillance, is available via the WHO website (http://www.who.int/influenza/gisrs_laboratory/flunet/en/). The typical trends of influenza activity in the United States are shown in the following figure (figure 1).

In 2011, H3N2 influenza A variant viruses caused by reassortment of swine-origin H3N2 influenza A viruses and pandemic H1N1 influenza A viruses were detected in 12 patients in the United States [75]. These viruses are susceptible to oseltamivir and zanamivir, but resistant to amantadine and rimantadine. The seasonal influenza vaccine is not expected to provide protection against these strains. (See "Epidemiology of influenza", section on 'H3N2 variant influenza'.)

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SUMMARY AND RECOMMENDATIONS

Target groups for therapy

  • Given the concerning trends of increasing resistance with both the adamantanes and the neuraminidase inhibitors, the risk of promoting antiviral drug resistance should be considered when deciding which patients to treat. Individuals with severe disease (requiring hospitalization or evidence of lower respiratory tract infection) or at high risk for complications should receive antiviral therapy. Antiviral therapy, when indicated, should be initiated as promptly as possible. (See 'Target populations for treatment' above.)
  • We recommend antiviral therapy (with zanamivir or oseltamivir) for all individuals with confirmed or suspected influenza virus infection who are severely ill, such as those with lower respiratory tract infection (eg, dyspnea, tachypnea, unexplained oxygen desaturation), and those who are showing signs of rapid clinical deterioration; we recommend treatment for such patients whether they present early in the course of infection (<48 hours after symptom onset) (Grade 1B), or later (Grade 1C). (See 'Indications for treatment' above.)
  • We recommend antiviral therapy for outpatients who present within 48 hours of symptom onset with confirmed or suspected influenza infection and who are at increased risk for complications (Grade 1A). We also recommend antiviral therapy for outpatients who present >48 hours after symptom onset with confirmed or suspected influenza infection and who are at increased risk for complications provided that they are not yet improving (Grade 1C). (See 'Indications for treatment' above.)
  • We suggest antiviral therapy for patients who present within 48 hours of symptom onset with mild illness and who are not at increased risk for complications (Grade 2C). There is high quality evidence for benefit to the individual patient; however, there is only low quality evidence regarding the magnitude of the risk of promoting resistance, which remains a major concern. Additionally, when supplies are limited, antivirals should be reserved for high-risk patients. (See 'Indications for treatment' above.)
  • We recommend that patients with uncomplicated influenza who have had more than 48 hours of influenza signs and symptoms not be treated with antivirals (Grade 1B). (See 'Indications for treatment' above.)
  • We suggest treating all pregnant women with suspected or confirmed influenza, even those who present >48 hours after onset of symptom onset provided that they are not yet improving (Grade 2C). (See 'Pregnancy' above and "Influenza and pregnancy", section on 'Treatment'.)

Choice of antiviral agent

  • Clinicians should review local or state influenza surveillance data during influenza season to determine which types of influenza (A or B) and subtypes of influenza A (H1N1 or H3N2) are circulating, as well as antiviral resistance patterns. (See 'Choice of antiviral drug' above and 'Influenza activity' above.)
  • A neuraminidase inhibitor (zanamivir or oseltamivir) is the recommended antiviral agent for the treatment of patients with influenza infection (table 2). (See 'Choice of antiviral drug' above.)
  • The recommended dose of zanamivir is 10 mg [two inhalations] twice daily; the recommended dose of oseltamivir is 75 mg twice daily. Since oseltamivir is primarily excreted by the kidneys, dosing must be modified in the setting of renal insufficiency. The recommended duration of therapy for either drug is five days. (See 'Choice of antiviral drug' above.)
  • Because of the high rates of influenza isolates resistant to adamantanes in the United States and in many other countries, amantadine and rimantadine are not recommended for the treatment of influenza. (See 'Choice of antiviral drug' above.)

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