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Treatment of pandemic H1N1 influenza ('swine influenza')

Last literature review version 17.3: September 2009  |  This topic last updated: February 1, 2010   (More)

INTRODUCTION — In late March and early April 2009, an outbreak of H1N1 influenza A virus infection was detected in Mexico, with subsequent cases observed in many other countries, including the United States [1,2]. On June 11, 2009, the World Health Organization raised its pandemic alert level to the highest level, phase 6, indicating widespread community transmission on at least two continents [3]. (See "Epidemiology, clinical manifestations, and diagnosis of pandemic H1N1 influenza ('swine influenza')", section on 2009 pandemic.)

The pandemic that began in March 2009 was caused by an H1N1 influenza A virus that represents a quadruple reassortment of two swine strains, one human strain, and one avian strain of influenza. (See "Epidemiology, clinical manifestations, and diagnosis of pandemic H1N1 influenza ('swine influenza')", section on 'Genetic and antigenic characterization'.)

The treatment of pandemic H1N1 influenza A virus infection will be reviewed here. The epidemiology, clinical manifestations, diagnosis, and prevention of pandemic H1N1 influenza A virus infection, and the treatment and prevention of seasonal and avian (H5N1) influenza virus infections, are discussed separately. (See "Epidemiology, clinical manifestations, and diagnosis of pandemic H1N1 influenza ('swine influenza')" and "Prevention of pandemic H1N1 influenza ('swine influenza')" and "Treatment of seasonal influenza in adults" and "Antiviral drugs for the prevention and treatment of influenza in children" and "Prevention of seasonal influenza in adults" and "Treatment and prevention of avian influenza".)

DEFINITIONS

Case definitions — The following case definitions have been provided by the United States Centers for Disease Control and Prevention [4]:

  • Influenza-like illness (ILI) is defined as fever (temperature of 100ºF [37.8ºC] or greater) with cough or sore throat in the absence of a known cause other than influenza.
  • A confirmed case of pandemic H1N1 influenza A is defined as an individual with an ILI with laboratory-confirmed H1N1 influenza A virus detected by real-time reverse transcriptase (rRT)-PCR or culture.
  • Pandemic H1N1 influenza A may be suspected in an individual who does not meet the definition of confirmed pandemic H1N1 influenza A, but has an ILI and an epidemiologic link.

High risk groups — High risk groups for the development of complications of pandemic H1N1 influenza A are thought to be similar to those defined for seasonal influenza. The target groups for vaccination against pandemic H1N1 influenza A are discussed separately. (See "Prevention of pandemic H1N1 influenza ('swine influenza')", section on 'Target groups'.)

High risk groups include [5-11]:

  • Children younger than 5 years of age, but especially those younger than 2

  • - The United States Centers for Disease Control and Prevention recommends that early empiric treatment be considered in children <2 years of age. Children from 2 to 4 years of age with mild illness who do not have high risk conditions do not necessarily require antiviral therapy [10]. (See 'Indications for therapy' below.)

  • Individuals 65 years of age or older

  • Pregnant women and women up to two weeks postpartum (including those who have had pregnancy loss)
  • Individuals younger than 19 years of age who are receiving long-term aspirin therapy and who therefore might be at risk for Reye syndrome after influenza virus infection
  • Individuals of any age with chronic medical conditions requiring ongoing medical care, including:

  • - Chronic 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 stem cell transplantation, inflammatory disorders treated with immunosuppressants
  • - Certain rheumatologic diseases, such as rheumatoid arthritis, systemic lupus erythematosus, psoriatic arthritis, antiphospholipid syndrome, systemic sclerosis/scleroderma, spondyloarthropathies, Sjogren's syndrome, polymyositis/dermatomyositis, vasculitis (eg, giant cell arteritis), necrotizing arteritis, sarcoidosis, and polyarteritis nodosa [12]
  • - Individuals who have any condition that can compromise handling of respiratory secretions (eg, cognitive dysfunction, spinal cord injuries, seizure disorders, neuromuscular disorders, cerebral palsy, metabolic conditions)
  • - Children with an underlying metabolic disorder, such as medium-chain acyl-CoA dehydrogenase deficiency, who are unable to tolerate prolonged fasting

Obesity has not been recognized as a risk factor for severe seasonal influenza, but cases of severe pandemic H1N1 influenza A, including pneumonia and acute respiratory distress syndrome, have been reported in obese individuals without known underlying conditions [10,13-15]. (See 'Indications' below.)

A disproportionately high percentage of the indigenous populations of Australia, New Zealand, and Canada have been affected by severe pandemic H1N1 influenza infection. (See "Epidemiology, clinical manifestations, and diagnosis of pandemic H1N1 influenza ('swine influenza')", section on Range of complications.)

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. (See "Prevention of seasonal influenza in adults", section on 'Definition of high risk' and "Antiviral drugs for the prevention and treatment of influenza in children".)

In the United States, 40 percent of children and 20 percent of adults requiring hospitalization for pandemic H1N1 influenza have had no known risk factors for severe disease [16].

Infectious period — The infectious period is considered to be one day before fever begins until 24 hours after fever ends [10].

Close contacts — Close contacts are defined by the United States Centers for Disease Control and Prevention as individuals who have had any of the following types of exposure to someone infected with influenza [10]:

  • Droplet exposure of mucosal surfaces (eg, nose, mouth, eyes) by respiratory secretions from coughing or sneezing
  • Contact, usually of hands, with an infectious patient or surface that is contaminated with secretions, followed by self-inoculation of virus onto mucosal surfaces
  • Small particle aerosols in the vicinity of an infectious individual
  • In a healthcare setting, being within 6 feet of a confirmed or suspected case of pandemic H1N1 influenza A or entering into a small enclosed airspace of such an individual, such as a typical patient room [17]

Close contact does not typically include such activities as walking by an infected individual or sitting across from a symptomatic patient in a waiting room.

MEDICAL CARE FOR SUSPECTED CASES — Not all individuals with suspected pandemic H1N1 influenza A infection need to be seen by a health care provider or treated [5,18]. Patients with severe illness and those at high risk of complications from influenza should contact their health care provider or seek medical care. (See 'High risk groups' above and 'Indications' below.)

ANTIVIRAL THERAPY — The United States Centers for Disease Control and Prevention (CDC) has released guidelines for the use of antivirals for patients with confirmed or suspected influenza virus infection (caused by either pandemic H1N1 or seasonal strains), which were updated most recently on October 14, 2009 [10]. Our recommendations reflect those of the CDC. Guidelines may change as more information becomes available. See the CDC's website for updated recommendations (http://www.cdc.gov/h1n1flu/). Clinicians in other countries should consult with their ministries of health and/or the World Health Organization (http://www.who.int/csr/resources/publications/swineflu/clinical_management/en/index.html) for specific recommendations.

Efficacy — Therapy should be started as soon as possible, since evidence of benefit is strongest for seasonal influenza when treatment is started within 48 hours of illness onset [10]. Some studies of hospitalized patients have demonstrated benefit even when therapy for seasonal influenza is started >48 hours after onset of illness. (See "Treatment of seasonal influenza in adults" and "Antiviral drugs for the prevention and treatment of influenza in children".)

The following observational studies of hospitalized patients with pandemic H1N1 influenza A have suggested that treatment with a neuraminidase inhibitor (most commonly oseltamivir) may reduce disease severity and mortality [19]:

  • In a study of 272 patients requiring hospitalization for pandemic H1N1 influenza A in the United States between April and mid-June 2009, the receipt of antiviral drugs within two days after the onset of illness was significantly associated with a positive outcome in a multivariable model [20].
  • Among critically ill patients in Mexico with confirmed, probable, or suspected pandemic H1N1 influenza A infection, after excluding patients who died within 72 hours of presentation who may have had less opportunity to be exposed to antiviral therapy, survivors were more likely than non-survivors to have received treatment with a neuraminidase inhibitor (odds ratio 7.4, 95% CI 1.8-31) [21].

In patients who are more than mildly ill, we would initiate therapy even past 48 hours of symptoms [10]. (See 'Timing of antiviral initiation' below.)

Resistance patterns — The vast majority of strains of pandemic H1N1 influenza A virus circulating in 2009 appear sensitive in vitro to the neuraminidase inhibitors, oseltamivir and zanamivir, but all strains tested have been resistant to amantadine and rimantadine [13,22-24]. However, there are no reported studies yet on the clinical benefits of antiviral therapy.

As of early December, >99 percent of influenza isolates circulating in the United States have been pandemic H1N1 influenza A, the vast majority of which have been susceptible to oseltamivir [25]. A notable difference between pandemic and seasonal strains of H1N1 influenza A is the resistance pattern to oseltamivir. The low rate of oseltamivir resistance among pandemic H1N1 influenza A strains to date contrasts with the extremely high rate among seasonal H1N1 influenza A strains. This is discussed in detail separately. (See "Treatment of seasonal influenza in adults", section on 'Neuraminidase inhibitor resistance'.)

A small minority of isolates of pandemic H1N1 influenza virus with resistance to oseltamivir have been detected from patients in several countries, including Japan, the United States, China, Hong Kong, Singapore, Vietnam, Denmark, and Canada [24,26-34]. No tested isolates have been resistant to zanamivir [33]. Among 32 cases in one series, 7 occurred in immunosuppressed patients and 13 occurred in individuals receiving oseltamivir prophylaxis; thus, both features appear to be risk factors for the development of oseltamivir resistance [33].

Two nosocomial clusters of oseltamivir-resistant pandemic H1N1 influenza A infection have been identified in Wales and the US; both clusters involved individuals with significant underlying conditions, some of whom were severely immunocompromised patients in a cancer unit [35]. Most of the patients whose clinical courses have been reported recovered without complications [24,28,32], although some immunocompromised patients have died [35]. A community cluster of oseltamivir-resistant pandemic H1N1 influenza infection occurred in 7 train passengers in Vietnam, 6 of whom shared a carriage; 4 other passengers in the carriage did not become ill [34]. None of the individuals in this cluster had received oseltamivir prophylaxis.

The neuraminidase mutation, H274Y, that caused widespread oseltamivir resistance among seasonal H1N1 influenza A isolates beginning in 2007 has also been detected in isolates from patients with oseltamivir-resistant pandemic H1N1 influenza A infection [32,33]. (See "Treatment of seasonal influenza in adults", section on 'Neuraminidase inhibitor resistance'.)

Adults — Our recommendations reflect those of the CDC. Guidelines may change as more information becomes available. See the CDC's website for updated recommendations (http://www.cdc.gov/h1n1flu/). Clinicians in other countries should consult with their ministries of health and/or the World Health Organization for specific recommendations.

Indications — Based on the guidelines of the United States Centers for Disease Control and Prevention, we recommend prompt initiation of antiviral therapy for individuals with suspected or confirmed influenza infection and any of the following features [6,10]:

  • Illness requiring hospitalization

Progressive, severe, or complicated illness, regardless of previous health status (see "Epidemiology, clinical manifestations, and diagnosis of pandemic H1N1 influenza ('swine influenza')" section on Severity of illness.)

  • Risk factors for influenza complications, including:

  • - Children <5 years of age, particularly those <2 years of age
  • - Adults ≥65 years of age
  • - Pregnant women and women up to two weeks postpartum (including those who have had pregnancy loss) [6]. (See 'Pregnant and postpartum women' below.)
  • - Individuals with certain medical conditions (see 'High risk groups' above)

Individuals with obesity (particularly those with morbid obesity) may be at increased risk of hospitalization and death due to pandemic H1N1 influenza infection; many obese persons have underlying conditions that increase the risk of influenza complications, such as diabetes mellitus, asthma, chronic respiratory illness, or liver disease [15]. Thus, patients with morbid obesity (BMI >40) and possibly those with obesity (BMI 30 to 39) with suspected or confirmed influenza virus infection should be carefully evaluated for the presence of conditions that confer an increased risk of influenza complications. If any such conditions are present, treatment should be given.

Severely immunosuppressed patients (eg, those receiving treatment for malignancies, hematopoietic or solid organ transplant recipients) with influenza infection may not have a fever or other typical signs and symptoms; if such patients present with an acute respiratory illness, influenza should be suspected [36]. During the current pandemic period, antiviral therapy should be started as soon as possible and respiratory specimens should be sent for real-time reverse transcriptase PCR.

Definitions of suspected and confirmed influenza infection are provided above. (See 'Case definitions' above.)

During the current pandemic, patients with mild illness without high risk conditions who are older than 2 years and younger than 65 years of age do not require testing or treatment [10]. 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 [10]. On the other hand, antiviral therapy should be considered among outpatients who are not improving after several days [16]. 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 benefits of therapy for seasonal influenza.

Since no vaccine is 100 percent effective, individuals who have been vaccinated against pandemic H1N1 influenza A who have signs and/or symptoms of influenza infection and have indications for treatment should be treated [10].

The World Health Organization's recommendations for the management of patients with pandemic H1N1 influenza can be accessed at: http://www.who.int/csr/resources/publications/swineflu/clinical_management/en/index.html.

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 [10]. 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. 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 "Epidemiology, clinical manifestations, and diagnosis of pandemic H1N1 influenza ('swine influenza')" and "Clinical manifestations and diagnosis of seasonal influenza in adults".)

Steps should be taken to reduce delays in treatment initiation, including [10]:

  • Informing patients at increased risk for complications of the signs and symptoms of infection and the importance of early initiation of therapy
  • Ensuring rapid access to telephone consultation and clinical evaluation for patients at high risk for complications and those with severe illness
  • Considering empiric treatment of patients at high risk for complications based on telephone contact
  • Counseling patients at increased risk for complications to contact their provider if signs or symptoms of influenza develop, and obtain medication and initiate treatment as soon as possible if prescribed
  • Counseling patients about influenza antiviral benefits and adverse effects
  • Close monitoring for signs or symptoms and early treatment as an alternative to prophylaxis among individuals exposed to influenza

Choice of antiviral — For patients requiring treatment, we recommend either zanamivir or oseltamivir [10]. Peramivir, an investigational neuraminidase inhibitor that is administered intravenously, is recommended under certain very specific circumstances, as discussed below. Zanamivir is contraindicated in patients with asthma or chronic obstructive pulmonary disease. (See "Pharmacology of antiviral drugs for influenza".)

During this pandemic, in patients suspected to have influenza, we recommend treatment with a neuraminidase inhibitor (zanamivir or oseltamivir) [10]. As of early December 2009, >99 percent of influenza isolates circulating in the United States were pandemic H1N1 influenza A, the vast majority of which are sensitive to oseltamivir [25]. However, if surveillance data indicate that oseltamivir-resistant seasonal H1N1 influenza A virus is circulating, we suggest that the neuraminidase inhibitor be zanamivir rather than oseltamivir. In such a setting, for patients who are unable to take zanamivir, we suggest the addition of rimantadine (or, less preferably, amantadine) to oseltamivir [10].

Of note, prior to the emergence of pandemic H1N1 influenza A, the majority of seasonal H1N1 influenza A isolates in the United States were resistant to oseltamivir. Clinicians will need to be aware of local surveillance data and updated recommendations from the US Centers of Disease Control and Prevention as the 2009 to 2010 influenza season evolves (http://www.cdc.gov/h1n1flu/). (See "Treatment of seasonal influenza in adults".)

The US Food and Drug Administration (FDA) has issued emergency use authorization for peramivir, an investigational neuraminidase inhibitor that is administered intravenously, for the treatment of certain patients with suspected or confirmed pandemic H1N1 influenza A infection [37,38]. Although peramivir has not been evaluated in large clinical trials, preliminary data suggest that it is as effective as oseltamivir [39,40]. Patients infected with a strain of influenza virus that is highly suspected or proven to be resistant to oseltamivir should not be treated with peramivir because of likely cross-resistance [38].

Peramivir may be used in hospitalized and critically ill adults who meet any of the following criteria:

  • Unresponsiveness to either oral or inhaled antiviral therapy OR
  • Enteral oseltamivir or inhaled zanamivir is not expected to be dependably absorbed or is not feasible OR
  • The clinician judges intravenous therapy is appropriate due to other circumstances

Clinicians who want to administer peramivir should call 1-800-CDC-INFO (1-800-232-4636); further information can be found on the CDC's website (http://www.cdc.gov/h1n1flu/eua/peramivir.htm). If peramivir is initiated, the patient should continue to receive oseltamivir or zanamivir until the first dose of peramivir has been administered. There is no role for combination therapy with oseltamivir or zanamivir with peramivir since they have the same mechanism of action.

The recommended dosing of peramivir is discussed below. (See 'Dosing' below.)

Limited quantities of intravenous zanamivir are also available for compassionate use from its manufacturer through an emergency investigational new drug application to the FDA [37].

Bacterial coinfections should be considered in individuals with pneumonia. (See 'Antibacterial therapy' below.)

Dosing — The dosing of antivirals for the treatment of pandemic H1N1 influenza A infection in adults is the same as that for seasonal influenza (table 1). Since oseltamivir is primarily excreted by the kidneys, dosing must be modified for renal insufficiency. Zanamivir inhalation powder should not be reconstituted in any liquid formulation and is not recommended for use in nebulizers or mechanical ventilators since the lactose sugar carrier can interfere with proper functioning of such equipment [10,41]. (See "Treatment of seasonal influenza in adults" and "Pharmacology of antiviral drugs for influenza".)

Antiviral therapy should be continued for five days, as with seasonal influenza [10]. The US Centers for Disease Control and Prevention note that some experts have advocated increased (doubled) doses of oseltamivir and that hospitalized patients with severe infections might require longer treatment courses (10 days) [10,36,42], although the possible benefit of these approaches has not been adequately studied.

The recommended dose of the investigational agent, peramivir, for adults with normal renal function is 600 mg intravenously once daily for 5 to 10 days [43]. Dose adjustment is necessary for patients with renal insufficiency; information about renal dosing can be found on the CDC's website (http://www.cdc.gov/h1n1flu/eua/Final%20HCP%20Fact%20sheet%20Peramivir%20IV_CDC.pdf).

The United States Food and Drug Administration (FDA) has issued a warning for patients to use extreme caution when purchasing products claiming to diagnose, treat, or prevent influenza infection; the FDA analyzed several products claiming to be oseltamivir purchased via the internet; one of the products did not contain oseltamivir, whereas others contained varying concentrations of the active ingredient [44].

Pregnant and postpartum women — Seasonal and pandemic strains of influenza cause more severe disease and an increased rate of mortality among pregnant women [6]. Cases of severe pandemic H1N1 influenza A have been reported in pregnant women. (See "Epidemiology, clinical manifestations, and diagnosis of pandemic H1N1 influenza ('swine influenza')".)

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 [10]. 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 [45]. (See "Pharmacology of antiviral drugs for influenza", section on 'Pregnancy'.)

Pregnant women (and women who are up to two weeks postpartum, even if pregnancy loss has occurred) who meet current case definitions for confirmed or suspected pandemic H1N1 influenza A infection should receive antiviral therapy with oseltamivir, since the potential benefit outweighs the theoretical risk to the fetus [6,10]. Oseltamivir is recommended over zanamivir because only the former agent is systemically absorbed (table 1). In addition, zanamivir is relatively contraindicated in patients with asthma or chronic obstructive pulmonary disease. Intravenous peramivir, which has received emergency use authorization from the US Food and Drug Administration, is appropriate under certain circumstances. Intravenous zanamivir is also available for compassionate use from its manufacturer through an emergency Investigational New Drug application to the FDA. (See 'Choice of antiviral' above.)

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 [6,10]. 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 and women in the early postpartum period (up to two weeks following delivery) who present >48 hours after illness onset, particularly in those requiring hospitalization. (See 'Timing of antiviral initiation' above.)

The recommended dosing of antivirals in pregnant women is the same as in non-pregnant individuals. However, the Infectious Diseases Society of America has stated that it is reasonable to use a higher dose of oseltamivir (150 mg twice daily) in critically ill pregnant women, particularly during the third trimester [46]. The rationale for this is that the serum concentration of oseltamivir is likely to be moderately reduced during the third trimester of pregnancy as a result of an increase in total body water and renal filtration. In addition, the higher dose of oseltamivir has been shown to be safe in non-pregnant individuals in clinical trials, and teratogenicity is unlikely during the third trimester. In the absence of further data, the higher dose of oseltamivir should not be used in pregnant women who are not critically ill.

In addition to antiviral therapy, use of acetaminophen is important when fever is present, since hyperthermia during the first trimester has been associated with neural tube defects and other birth defects [6,47,48]. In addition, fever during labor is a risk factor for neonatal seizures, encephalopathy, cerebral palsy, and neonatal death [6,47].

Bacterial coinfections should be considered in individuals with pneumonia. (See 'Antibacterial therapy' below.)

Children

Indications for therapy — Early empiric antiviral therapy is recommended for children and adolescents of any age with suspected or confirmed influenza infection who meet any of the following criteria [9]:

  • Illness requiring hospitalization
  • Progressive, severe, or complicated illness, regardless of previous health status
  • Risk factors for severe illness, including age <5 years (and especially age <2 years) (see 'High risk groups' above.

Children who are not at increased risk for complications may not require treatment, but antiviral therapy can be considered in those who present for medical care within the first 48 hours of illness in order to shorten the duration of illness [9]. Individuals without risk factors for complications who have mild illness are unlikely to benefit from antiviral therapy that is initiated >48 hours after the onset of symptoms.

Choice of agent — Oseltamivir is approved in the United States for the treatment of influenza A and B viral infections in individuals ≥1 year of age. In addition, the US Food and Drug Administration has issued an emergency use authorization for clinicians to administer oseltamivir to children <1 year of age, when indicated, during the current pandemic [9,49,50]. Limited safety data on oseltamivir treatment in infants <1 year of age suggest that severe adverse reactions are rare [10]. Zanamivir is approved for the treatment of influenza A and B viral infections in individuals ≥7 years of age. Zanamivir inhalation powder should not be reconstituted in any liquid formulation and is not recommended for use in nebulizers or mechanical ventilators [41].

Therapy should be started as soon as possible. (See 'Timing of antiviral initiation' above.)

The US Food and Drug Administration has issued emergency use authorization for peramivir, an investigational neuraminidase inhibitor that is administered intravenously, for the treatment of certain patients with suspected or confirmed pandemic H1N1 influenza A infection [37,38]. Patients infected with a strain of influenza virus that is suspected or proven to be resistant to oseltamivir should not be treated with peramivir because of likely cross-resistance.

Peramivir may be used in hospitalized and critically ill children who meet either of the following criteria [9]:

  • Unresponsiveness to either oral or inhaled antiviral therapy OR
  • Enteral oseltamivir or inhaled zanamivir is not expected to be dependably absorbed or is not feasible

Clinicians who want to administer peramivir should call 1-800-CDC-INFO (1-800-232-4636); further information can be found on the CDC's website (http://www.cdc.gov/h1n1flu/eua/peramivir.htm). If peramivir is initiated, the patient should continue to receive oseltamivir or zanamivir until the first dose of peramivir has been administered. There is no role for combination therapy with oseltamivir or zanamivir with peramivir since they have the same mechanism of action.

Limited quantities of intravenous zanamivir are available for compassionate use from its manufacturer through an emergency Investigational New Drug application to the FDA [38].

Bacterial coinfections should be consiered in individuals with pneumonia. (See 'Antibacterial therapy' below.)

Children and adolescents under age 18 who may have influenza infection should not take aspirin or aspirin-containing products, such as bismuth subsalicyclate (PeptoBismol), due to the increased risk of Reye syndrome [9,10]. Children under 4 years of age should not take over the counter cold medications unless recommended by a healthcare provider.

Antiviral dosing — The dosing of antivirals for pandemic H1N1 influenza A infection in children >1 year of age is the same as that for seasonal influenza (table 2) [9]. Since oseltamivir is primarily excreted by the kidneys, dosing must be modified for renal insufficiency. Zanamivir inhalation powder should not be reconstituted in any liquid formulation and is not recommended for use in nebulizers or mechanical ventilators since the lactose sugar carrier can interfere with proper functioning of such equipment [10,41]. (See "Antiviral drugs for the prevention and treatment of influenza in children" and "Pharmacology of antiviral drugs for influenza".)

Weight-based dosing of oseltamivir (3 mg/kg per dose twice daily) is recommended for full-term infants under one year of age [9]. This dosing is not intended for premature infants, who may have slower clearance of oseltamivir due to immature renal function; since inadequate data exist, specific doses cannot be recommended for such individuals.

If weight is not known, dosing should be determined by age as follows:

  • Age 0 to 3 months - 12 mg (1 mL of commercial suspension) twice daily
  • Age 3 to 5 months - 20 mg (1.6 mL of commercial suspension) twice daily
  • Age 6 to 11 months - 25 mg (2 mL of commercial suspension) twice daily

The dosing regimens recommended above are not intended for premature infants, who may have slower clearance of oseltamivir due to immature renal function; since inadequate data exist, specific doses cannot be recommended for such individuals [9].

Antiviral therapy should be continued for five days, as with seasonal influenza.

When the commercially-available oseltamivir oral suspension is not available, oseltamivir 75 mg capsules can be compounded into a suspension at most retail pharmacies [9]. It is important to note that the commercially-available oseltamivir oral suspension concentration is 12 mg/mL, whereas the compounded suspension concentration is 15 mg/mL. Thus, the concentration of the oral suspension should always be specified.

When dispensing the oral suspension of oseltamivir to children <1 year of age, providers and pharmacists must take care to provide a dosing device that matches the units of measure on the prescription [51,52]. Health care providers should write doses in mg if the dosing dispenser with the drug is in mg [52]. As an alternative, the oral dosing dispenser that is provided in the package (which has markings for 30 mg, 45 mg, and 60 mg) can be removed and pharmacists or health care personnel should provide an oral syringe that can accurately measure the prescribed milliliter (mL) dose [10,51]. The caregiver should also be counseled regarding proper administration.

If the oral suspension of oseltamivir is not available and the 75 mg capsules cannot be compounded at a pharmacy in a timely manner, the children's formulation of oseltamivir capsules (available as 30 mg, 45 mg, and 75 mg capsules) may be opened and mixed with sweetened liquids such as chocolate syrup by the child's caregiver [9,53]. If this is done, caution should be used to ensure that the correct dose is administered.

The recommended dose of the investigational agent, peramivir, for infants and children with normal renal function is [43]:

  • Age 0 through 30 days - 6 mg/kg IV once daily
  • Age 31 through 90 days - 8 mg/kg IV once daily
  • Age 91 through 180 days - 10 mg/kg IV once daily
  • Age 181 days through 5 years - 12 mg/kg IV once daily
  • Age 6 through 17 years - 10 mg/kg IV once daily

The maximum daily dose of peramivir is 600 mg once daily. Dose adjustment is necessary for patients with renal insufficiency; information about renal dosing can be found on the CDC's website (http://www.cdc.gov/h1n1flu/eua/Final%20HCP%20Fact%20sheet%20Peramivir%20IV_CDC.pdf).

The recommended duration of peramivir is 5 to 10 days.

Antivirals after vaccination — Since the protective capacity of current vaccines against pandemic H1N1 has not yet been firmly established and since it takes some time for protective antibodies to be produced following pandemic H1N1 influenza vaccination, individuals who have been vaccinated but are suspected of having influenza infection should be treated if they have an indication for antiviral therapy. (See 'Indications' above and 'Pregnant and postpartum women' above and 'Indications for therapy' above.)

If an individual who received the live attenuated intranasal vaccine is treated with an antiviral drug within 48 hours before or up to two weeks after vaccination, the vaccine dose should be repeated [10]; this is not necessary in individuals who received the inactivated intramuscular vaccine.

Adverse effects — Postmarketing reports have identified rare, but serious neuropsychiatric events in children with influenza who are taking oseltamivir. (See "Antiviral drugs for the prevention and treatment of influenza in children", section on 'Rare adverse effects'.)

Bronchospasm may occur in individuals with underlying asthma or chronic obstructive pulmonary disease who are receiving zanamivir. Thus, this agent is generally avoided in such patients. (See "Pharmacology of antiviral drugs for influenza", section on 'Adverse effects'.)

The most common adverse effects associated with peramivir are diarrhea, nausea, vomiting, and reduced neutrophil count; less common adverse effects include dizziness, headache, somnolence, insomnia, and agitation [43].

Other adverse effects are discussed in detail separately. (See "Pharmacology of antiviral drugs for influenza".)

INVESTIGATIONAL THERAPIES — Investigational therapies for pandemic H1N1 influenza include the intravenous neuraminidase inhibitors, peramivir and zanamivir, which are discussed above. (See 'Choice of antiviral' above.)

Although ribavirin has some in vitro activity against influenza viruses, clinical data regarding its efficacy have been inconclusive; thus, it is not recommended for the treatment of influenza [54].

There has also been interest in the possible benefit of statins in patients with influenza infection. In a surveillance study of 3921 hospitalized patients with laboratory-confirmed seasonal influenza infection in the United States, the 1019 patients who were receiving a statin had a lower likelihood of dying than those who were not (adjusted odds ratio 0.34, CI 0.16-0.70) [55], although confounding factors may have been present. It has been hypothesized that the antiinflammatory effects of statins could have reduced the severity of illness associated with influenza infection, although this has not been established. Randomized trials are necessary to determine whether statins result in a mortality benefit in patients with influenza infection. (See "Mechanisms of benefit of lipid lowering drugs in patients with coronary heart disease", section on 'Reduced inflammation'.)

Other investigational agents for the treatment of influenza infection are discussed separately. (See "Treatment of seasonal influenza in adults", section on 'Investigational approaches'.)

ANTIBACTERIAL THERAPY — Secondary bacterial pneumonia has been detected in patients with pneumonia caused by pandemic H1N1 influenza A, particularly in those with severe disease. (See "Epidemiology, clinical manifestations, and diagnosis of pandemic H1N1 influenza ('swine influenza')", section on Range of complications.)

Clinical findings that are suggestive of secondary bacterial pneumonia in patients with influenza pneumonia include the following [56]:

  • Secondary fever after a period of defervescence
  • Sputum gram stain and/or culture showing a predominant organism (eg, Streptococcus pneumoniae, Staphylococcus aureus, Streptococcus pyogenes, Haemophilus influenzae, Moraxella catarrhalis)
  • Lobar consolidation on chest imaging rather than the diffuse pattern that is typical of viral pneumonia
  • Leukocytosis rather than a normal or low white blood cell count, the latter two more common with influenza infection
  • Onset of respiratory compromise occurring four to seven days after initial symptoms rather than one to two days after initial symptoms, the latter more suggestive of primary influenza pneumonia
  • A lower rate of positive diagnostic tests for influenza virus compared with patients with primary influenza pneumonia because secondary bacterial pneumonia occurs later in the course of illness, when viral shedding may have ceased

Patients with pandemic H1N1 influenza A who develop pneumonia should be treated empirically for community-acquired pneumonia (CAP) [10,46], given the risk of secondary bacterial pneumonia with organisms such as Streptococcus pneumoniae and Staphylococcus aureus.

In hospitalized patients with severe CAP requiring intensive care unit admission who also have either necrotizing/cavitary infiltrates or empyema, methicillin-resistant Staphylococcus aureus (MRSA) infections should be suspected and treated in addition to other potential causes [5]. (See "Treatment of community-acquired pneumonia in adults who require hospitalization" and "Inpatient treatment of pneumonia in children".)

Some authors have different recommendations for when and how to initiate antibacterial therapy for secondary pneumonia [56].

BREASTFEEDING — Infants who are ill with pandemic H1N1 influenza A should continue to breastfeed [6].

Recommendations regarding breastfeeding when the infant's mother has influenza are presented separately. (See "Prevention of pandemic H1N1 influenza ('swine influenza')", section on 'Breastfeeding'.)

SUMMARY AND RECOMMENDATIONS — In late March and early April 2009, an outbreak of H1N1 influenza A virus infection was detected in Mexico, with subsequent cases observed in many other countries including the United States. On June 11, 2009, the World Health Organization raised its pandemic alert level to the highest level, phase 6, indicating widespread community transmission on at least two continents. (See 'Introduction' above.)

Case definitions of pandemic H1N1 influenza

  • Influenza-like illness (ILI) is defined as fever (temperature of 100ºF [37.8ºC] or greater) with cough or sore throat in the absence of a known cause other than influenza.
  • A confirmed case of pandemic H1N1 influenza A is defined as an individual with an ILI with laboratory-confirmed H1N1 influenza A virus detected by real-time reverse transcriptase (rRT)-PCR or culture.
  • Pandemic H1N1 influenza A may be suspected in an individual who does not meet the definition of confirmed pandemic H1N1 influenza A, but has an ILI and an epidemiologic link. (See 'Case definitions' above.)

Treatment

  • The vast majority of strains of pandemic H1N1 influenza A virus circulating in 2009 appear sensitive in vitro to the neuraminidase inhibitors, oseltamivir and zanamivir, but all strains tested have been resistant to amantadine and rimantadine. (See 'Resistance patterns' above.)

  • Not all individuals with suspected pandemic H1N1 influenza A infection need to be seen by a health care provider or treated. During the current pandemic, patients with mild illness do not need to be tested or treated unless they have risk factors for complications. Patients with severe illness and those at high risk for complications from influenza should contact their health care provider or seek medical care. (See 'High risk groups' above and 'Indications' above.)

  • We recommend prompt initiation of antiviral therapy (with zanamivir or oseltamivir) for individuals with suspected or confirmed influenza infection and any of the following features (Grade 1B):

  • - Illness requiring hospitalization
  • - Progressive, severe, or complicated illness, regardless of previous health status (see "Epidemiology, clinical manifestations, and diagnosis of pandemic H1N1 influenza ('swine influenza')" section on Severity of illness.) .
  • - Risk factors for influenza complications, including children <5 years of age (particularly those <2 years of age), adults ≥65 years of age, pregnant women and women up to two weeks postpartum (including those who have had pregnancy loss), and individuals with certain medical conditions (see 'Indications' above)

  • Peramivir, an investigational neuraminidase inhibitor that is administered intravenously, is recommended for the treatment of certain hospitalized and critically ill patients with suspected or confirmed pandemic H1N1 influenza A infection. Limited quantities of intravenous zanamivir are also available for compassionate use from its manufacturer through an emergency investigational new drug application to the FDA. (See 'Choice of agent' above.)

  • Antiviral therapy should be considered for outpatients with confirmed or suspected influenza virus infection who are at increased risk for complications. (See 'Indications' above.)

  • As of early December 2009, >99 percent of influenza isolates circulating in the United States were pandemic H1N1 influenza A, the vast majority of which are sensitive to oseltamivir. However, if local surveillance data indicate that oseltamivir-resistant seasonal H1N1 influenza A virus is circulating, zanamivir is the preferred antiviral. Patients who are unable to take zanamivir in such a setting can be given the combination of rimantadine and oseltamivir. As the 2009 to 2010 influenza season evolves, clinicians will need to be aware of local surveillance data and updated recommendations from the US Centers for Disease Control and Prevention (http://www.cdc.gov/h1n1flu/). (See 'Choice of antiviral' above and "Treatment of seasonal influenza in adults".)

  • Treatment should be initiated as soon as possible. In patients who are more than mildly ill, we would initiate therapy even past 48 hours of symptoms. (See 'Timing of antiviral initiation' above.)

  • The duration of therapy is typically five days. (See 'Dosing' above.)

  • Patients with pandemic H1N1 influenza A who develop pneumonia should be treated empirically for community-acquired pneumonia (CAP), given the risk of secondary bacterial pneumonia. In hospitalized patients with severe CAP requiring intensive care unit admission who also have either necrotizing/cavitary infiltrates or empyema, methicillin-resistant Staphylococcus aureus (MRSA) infections should be suspected and treated in addition to other potential causes. (See 'Antibacterial therapy' above.)

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