Management of Influenza

Am Fam Physician. 2010 Nov 1;82(9):1087-1095.

  Patient information: See related handout on influenza, written by the authors of this article.

Influenza is a contagious airborne viral illness characterized by abrupt onset of symptoms. Fever, myalgia, headache, rhinitis, sore throat, and cough are commonly reported symptoms. The diagnosis should be made clinically, and the decision to begin antiviral therapy should not be delayed for laboratory confirmation of influenza. The 2009 pandemic influenza A (H1N1) virus is expected to continue to circulate during the 2010–2011 season, but it is not certain whether it will replace or cocirculate with seasonal influenza A subtypes that have been circulating since 1977. The 2009 H1N1 virus is largely resistant to adamantanes, but it is sensitive to neuraminidase inhibitors such as oseltamivir. Neuraminidase inhibitors have modest effectiveness in reducing influenza-related symptoms in patients at low risk of complications. Patients at high risk of complications, including pregnant women, should be treated with antiviral agents, preferably within 48 hours of symptom onset. Family physicians should follow guidelines from the World Health Organization and the Centers for Disease Control and Prevention when treating patients with influenza or influenza-like symptoms.

Influenza is a highly contagious airborne viral illness. The virus enters the respiratory tract cells of the host and, if not neutralized by antibodies, begins proliferating.1 Systemic symptoms, such as fever, myalgia, headache, malaise, rhinitis, sore throat, and cough, are thought to result from the release of inflammatory mediators in response to viral activity.1 The incubation period is 18 to 72 hours, but viral shedding may occur up to 24 hours before symptom onset and continue for five to 10 days.1,2 Influenza is typically uncomplicated and self-limited in otherwise healthy patients. However, severe complications, such as pneumonia, encephalitis, respiratory failure, multiorgan failure, and death, can occur.3,4 According to estimates from the World Health Organization (WHO), 3 to 5 million cases of severe influenza-related illness and 250,000 to 500,000 influenza-related deaths occur worldwide every year.5

SORT: KEY RECOMMENDATIONS FOR PRACTICE

Clinical recommendation Evidence rating References

The decision to begin antiviral treatment should be based on the clinical diagnosis of influenza, not on test results.

C

4, 16, 20, 21

Patients at risk of complications from influenza should begin antiviral treatment within 48 hours of symptom onset.

C

3, 4, 8, 16, 20, 21

The choice of antiviral agent should be based on local patterns of virus activity and susceptibility.

C

3, 4, 8, 16, 20, 21


A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, go to http://www.aafp.org/afpsort.xml.

SORT: KEY RECOMMENDATIONS FOR PRACTICE

View Table

SORT: KEY RECOMMENDATIONS FOR PRACTICE

Clinical recommendation Evidence rating References

The decision to begin antiviral treatment should be based on the clinical diagnosis of influenza, not on test results.

C

4, 16, 20, 21

Patients at risk of complications from influenza should begin antiviral treatment within 48 hours of symptom onset.

C

3, 4, 8, 16, 20, 21

The choice of antiviral agent should be based on local patterns of virus activity and susceptibility.

C

3, 4, 8, 16, 20, 21


A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, go to http://www.aafp.org/afpsort.xml.

Influenza viruses are single-stranded RNA viruses belonging to the Orthomyxovirus family. They can mutate quickly, which makes development of effective vaccines and antiviral agents a challenge.6 Influenza A viruses cause most outbreaks and are more pathogenic than other types of influenza viruses.1,3,7 In the spring of 2009, a triple-reassortant strain of influenza A (H1N1) that contained swine, avian, and human genes caused several outbreaks in Mexico and the United States; new cases were soon reported worldwide.2,4,812 On June 11, 2009, WHO declared a global pandemic based on 30,000 cases of H1N1 influenza in 74 countries.9 The Centers for Disease Control and Prevention (CDC) estimates that by April 19, 2010, about 61 million persons in the United States had been infected with 2009 H1N1 influenza, 274,000 had been hospitalized, and 12,470 had died.13 WHO declared an end to the pandemic on August 10, 2010.14

Typically, persons at risk of influenza-related complications include older adults, young children, persons with chronic medical conditions, and pregnant women3,4,8  (Table 1 4,8,15,16). However, during the 2009–2010 influenza season, about one third of patients with complicated influenza who were admitted to intensive care units were previously healthy and had no identifiable risk factors.3,8

Table 1.

Persons at Risk of Complications from Influenza

Persons with coexisting medical conditions

Any condition that may compromise the handling of respiratory secretions (e.g., neuromuscular diseases, cerebral palsy, stroke, seizure disorder, dementia)

Asthma or other chronic pulmonary disease

Chronic liver disease

Chronic renal disease

Heart disease (acquired or congenital)

Immunosuppression (e.g., human immunodeficiency virus infection, cancer, transplant recipients, use of immunosuppressive medications)

Long-term aspirin therapy in patients younger than 19 years

Metabolic disorders (acquired [e.g., diabetes mellitus] or inherited [e.g., mitochondrial disorders])

Morbid obesity

Sickle cell anemia and other hemoglobinopathies

Special groups

Adults 65 years and older

Children younger than 5 years (particularly those younger than 2 years)

Institutionalized adults (e.g., those living in long-term care facilities, prisons, or college dormitories)

Pregnant and postpartum women (up to 2 weeks postpartum, including pregnancy loss)


Information from references 4, 8, 15 and 16.

Table 1.   Persons at Risk of Complications from Influenza

View Table

Table 1.

Persons at Risk of Complications from Influenza

Persons with coexisting medical conditions

Any condition that may compromise the handling of respiratory secretions (e.g., neuromuscular diseases, cerebral palsy, stroke, seizure disorder, dementia)

Asthma or other chronic pulmonary disease

Chronic liver disease

Chronic renal disease

Heart disease (acquired or congenital)

Immunosuppression (e.g., human immunodeficiency virus infection, cancer, transplant recipients, use of immunosuppressive medications)

Long-term aspirin therapy in patients younger than 19 years

Metabolic disorders (acquired [e.g., diabetes mellitus] or inherited [e.g., mitochondrial disorders])

Morbid obesity

Sickle cell anemia and other hemoglobinopathies

Special groups

Adults 65 years and older

Children younger than 5 years (particularly those younger than 2 years)

Institutionalized adults (e.g., those living in long-term care facilities, prisons, or college dormitories)

Pregnant and postpartum women (up to 2 weeks postpartum, including pregnancy loss)


Information from references 4, 8, 15 and 16.

Influenza caused by 2009 H1N1 is expected to continue during the 2010–2011 influenza season and in the future, but it is not known whether this virus will replace or cocirculate with one or more of the two seasonal influenza A viruses (seasonal H1N1 and H3N2) that have circulated since 1977. The CDC Web site (http://www.cdc.gov/flu) provides regular updates on influenza activity and resistance patterns in the United States. Local public health authorities provide similar information, which can help physicians make treatment decisions for patients with suspected influenza.

Prevention

The CDC recommends that all persons six months and older receive influenza vaccination this season.17,18 The trivalent (seasonal) vaccine will protect against 2009 H1N1 influenza and contains the same strain used in the 2009–2010 monovalent H1N1 vaccine, plus an H3N2 virus and influenza B virus.17,18 A complete discussion of the different influenza vaccine types is available on the CDC Web site (http://www.cdc.gov/flu/professionals/acip/index.htm).17

Treatment of Patients with Influenza-Like Illness

When influenza cases are reported in the community, most patients presenting with symptoms suggestive of uncomplicated influenza should be diagnosed clinically.3 Patients should be instructed to return for follow-up if their symptoms worsen or do not improve within 72 hours.3  During the 2009 H1N1 pandemic, prompt empiric antiviral treatment was recommended for certain high-risk groups (children younger than two years, adults 65 years and older, pregnant women, and persons with certain medical conditions; see Table 1 4,8,15,16).3,15 All patients with signs of severe, progressive illness should be promptly referred for hospitalization3,16  (Table 23). Telephone triage of persons with influenza-like symptoms helps prevent the exposure of these patients to other patients in waiting rooms.19

Table 2.

Signs and Symptoms of Complicated Progressive Influenza

Cardiovascular

Chest pain

Hypotension

Central nervous system

Altered mental status

Lethargy

Seizures

Severe weakness or paralysis

Respiratory

Cyanosis

Hemoptysis or colored sputum

Hypoxia (measured by pulse oximetry)

Labored breathing (on examination)

Shortness of breath (exertional or resting, as reported by the patient)

Other

Decreased urine output

Dehydration

Persistence or worsening of initial symptoms beyond 72 hours

Persistent high fever (longer than 72 hours)


Information from reference 3.

Table 2.   Signs and Symptoms of Complicated Progressive Influenza

View Table

Table 2.

Signs and Symptoms of Complicated Progressive Influenza

Cardiovascular

Chest pain

Hypotension

Central nervous system

Altered mental status

Lethargy

Seizures

Severe weakness or paralysis

Respiratory

Cyanosis

Hemoptysis or colored sputum

Hypoxia (measured by pulse oximetry)

Labored breathing (on examination)

Shortness of breath (exertional or resting, as reported by the patient)

Other

Decreased urine output

Dehydration

Persistence or worsening of initial symptoms beyond 72 hours

Persistent high fever (longer than 72 hours)


Information from reference 3.

Diagnosis

Sudden onset of symptoms is a telltale sign of influenza.1,7 Common symptoms include high fever, headache, sore throat, myalgia, cough, rhinorrhea, and fatigue. Patients with 2009 H1N1 influenza often had gastrointestinal symptoms, suggesting viral replication in the gastrointestinal tract.1,4

The CDC, WHO, and the Infectious Diseases Society of America recommend that physicians diagnose influenza clinically and perform testing only in the following groups: hospitalized patients with influenza-like illness; patients who died of an influenza-like illness (to clarify etiology); and patients for whom decisions about infection control and treatment of close contacts is a concern (e.g., child care and health care workers, nursing home residents).3,4,16,20,21  Several diagnostic tests for influenza are available (Table 3).4,20,21 Rapid influenza diagnostic tests have variable sensitivities (10 to 70 percent); therefore negative results do not rule out influenza.4,21 The specificities of rapid tests are generally high (greater than 95 percent).4,21 Although many physicians use rapid influenza tests, clinical judgment should prevail, especially in view of the limitations of such tests.20,21 Real-time reverse transcriptase polymerase chain reaction tests and viral cultures have much higher sensitivities than rapid tests, but results generally take more than 24 hours. Both are definitive when diagnostic testing for influenza is indicated.3,4,20

Table 3.

Diagnostic Tests for Influenza

Test Type of test Sensitivity for 2009 pandemic influenza A (H1N1)* Distinguishes 2009 H1N1 influenza from other influenza A viruses?

Direct and indirect immunofluorescence assays

Antigen detection

47 to 93 percent

No

Rapid influenza diagnostic test

Antigen detection

10 to 70 percent

No

Real-time reverse transcriptase polymerase chain reaction tests

RNA detection

86 to 100 percent†

Yes

Viral culture

Virus isolation and identification

NA

Yes


NA = not applicable.

*—Compared with real-time reverse transcriptase polymerase chain reaction testing.

—Sensitivity compared with other real-time reverse transcriptase polymerase chain reaction tests.

Information from references 4, 20, and 21.

Table 3.   Diagnostic Tests for Influenza

View Table

Table 3.

Diagnostic Tests for Influenza

Test Type of test Sensitivity for 2009 pandemic influenza A (H1N1)* Distinguishes 2009 H1N1 influenza from other influenza A viruses?

Direct and indirect immunofluorescence assays

Antigen detection

47 to 93 percent

No

Rapid influenza diagnostic test

Antigen detection

10 to 70 percent

No

Real-time reverse transcriptase polymerase chain reaction tests

RNA detection

86 to 100 percent†

Yes

Viral culture

Virus isolation and identification

NA

Yes


NA = not applicable.

*—Compared with real-time reverse transcriptase polymerase chain reaction testing.

—Sensitivity compared with other real-time reverse transcriptase polymerase chain reaction tests.

Information from references 4, 20, and 21.

Antiviral Therapy

Treatment should not be delayed until the results of diagnostic tests are available.3,4,20,21 The CDC recommends initiating treatment as soon as possible after the onset of influenza-like symptoms in patients meeting certain criteria15  (Table 4 3,4,8,15,16,2023). The CDC also recommends antiviral prophylaxis for persons who have had close contact with an infected person during the infectious period.15

Table 4.

Indications and Contraindications for Influenza Chemoprophylaxis and Treatment

Consider antiviral chemoprophylaxis if close contact* has occurred with an infected person during the infectious period

Health care workers

Persons at risk of complications from influenza

Pregnant women

Do not prescribe antiviral chemoprophylaxis

Healthy children and adults

Persons who had close contact* with an infected person outside the infectious period

Persons whose last close contact* with an infected person was more than 48 hours before presentation

Prescribe antiviral treatment

Hospitalized patients with severe, complicated influenza-like illness (see Table 2) or laboratory-confirmed influenza

Outpatients with influenza-like illness or laboratory-confirmed influenza who are at risk of complications (see Table 1)

Outpatients with severe, complicated influenza-like illness (see Table 2) or laboratory-confirmed influenza‡


*—Close contact refers to droplet exposure of mucosal surfaces by respiratory secretions from coughing or sneezing; or contact with an infectious person or fomite, followed by self-inoculation onto mucosal surfaces.

—The infectious period for influenza is one day before fever until 24 hours after defervescence.

—Antiviral treatment may be considered in outpatients with suspected or laboratory-confirmed influenza who are not at risk of complications, whose symptoms began less than 48 hours earlier, and who wish to shorten the duration of illness and potentially decrease the risk of complications (or who are in close contact with persons at risk of complications, such as persons who work in child care centers or nursing homes). However, antiviral treatment in these patients is not recommended by the Centers for Disease Control and Prevention, and the benefits in these patients have not been proven. 4,22,23 Patients whose symptoms began more than 48 hours before presentation may benefit from treatment; however, the effectiveness of antiviral treatment in these patients has not been well studied. 4,22,23

Information from references 3, 4, 8, 15, 16, and 20 through 23.

Table 4.   Indications and Contraindications for Influenza Chemoprophylaxis and Treatment

View Table

Table 4.

Indications and Contraindications for Influenza Chemoprophylaxis and Treatment

Consider antiviral chemoprophylaxis if close contact* has occurred with an infected person during the infectious period

Health care workers

Persons at risk of complications from influenza

Pregnant women

Do not prescribe antiviral chemoprophylaxis

Healthy children and adults

Persons who had close contact* with an infected person outside the infectious period

Persons whose last close contact* with an infected person was more than 48 hours before presentation

Prescribe antiviral treatment

Hospitalized patients with severe, complicated influenza-like illness (see Table 2) or laboratory-confirmed influenza

Outpatients with influenza-like illness or laboratory-confirmed influenza who are at risk of complications (see Table 1)

Outpatients with severe, complicated influenza-like illness (see Table 2) or laboratory-confirmed influenza‡


*—Close contact refers to droplet exposure of mucosal surfaces by respiratory secretions from coughing or sneezing; or contact with an infectious person or fomite, followed by self-inoculation onto mucosal surfaces.

—The infectious period for influenza is one day before fever until 24 hours after defervescence.

—Antiviral treatment may be considered in outpatients with suspected or laboratory-confirmed influenza who are not at risk of complications, whose symptoms began less than 48 hours earlier, and who wish to shorten the duration of illness and potentially decrease the risk of complications (or who are in close contact with persons at risk of complications, such as persons who work in child care centers or nursing homes). However, antiviral treatment in these patients is not recommended by the Centers for Disease Control and Prevention, and the benefits in these patients have not been proven. 4,22,23 Patients whose symptoms began more than 48 hours before presentation may benefit from treatment; however, the effectiveness of antiviral treatment in these patients has not been well studied. 4,22,23

Information from references 3, 4, 8, 15, 16, and 20 through 23.

MANAGEMENT OF INFLUENZA DURING PREGNANCY

Pregnant and postpartum women (including those who have had pregnancy loss) are at risk of severe influenza-related complications because of the changes in immune, respiratory, and cardiovascular systems that occur during pregnancy.3,2427 The CDC recommends that neuraminidase inhibitors be prescribed for pregnant women and for those up to two weeks postpartum who have suspected or confirmed influenza.26 Women can continue to breastfeed while being treated with antivirals.14

ANTIVIRAL AGENTS

Neuraminidase Inhibitors. Neuraminidase inhibitors block the viral neuraminidase enzyme, which is critical in releasing virions from the infected host's cells.28 These drugs are active against influenza A and B.6,7,29 As of April 2010, more than 99 percent of the 2009 H1N1 viruses were susceptible to oseltamivir (Tamiflu) and zanamivir (Relenza).15,29 None of the H3N2 or influenza B viruses tested were resistant to oseltamivir.17

Oseltamivir is an oral agent that is approved for influenza prophylaxis in patients one year and older, and for treatment of uncomplicated acute influenza in patients one year and older who have been symptomatic for no more than two days22  (Table 5).3,4,6,8,15,16,2023,2932

Table 5.

Antiviral Agents for Influenza Chemoprophylaxis and Treatment

Drug/available formulations Dosage FDA-approved indications FDA pregnancy category and contraindications Possible adverse effects

Oseltamivir (Tamiflu)

Children 1 to 12 years Prophylaxis

Influenza prophylaxis in patients 1 year and older Treatment of uncomplicated acute influenza in patients 1 year and older who have been symptomatic for no more than 2 days

Category C (preferred treatment in pregnancy) Contraindicated in patients with known serious hypersensitivity to oseltamivir or any component of the product

Nausea, vomiting, allergic reactions (rash, facial swelling) Rarely, serious skin reactions (toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme) and transient neuropsychiatric events(self-injury or delirium; causal relationship has not been established)

Capsules (30, 45, and 75 mg) Intravenous form (in clinical trials) Powder for oral suspension

≤ 33 lb (≤ 15 kg): 30 mg once daily for 10 days* > 33 to 51 lb (> 15 to 23 kg): 45 mg once daily for 10 days* > 51 to 88 lb (> 23 to 40 kg): 60 mg once daily for 10 days* > 88 lb (> 40 kg): adult dosage

Treatment

≤ 33 lb (= 15 kg): 30 mg twice daily for 5 days

> 33 to 51 lb (> 15 to 23 kg): 45 mg twice daily for 5 days

> 51 to 88 lb (> 23 to 40 kg): 60 mg twice daily for 5 days

> 88 lb (> 40 kg): adult dosage

Adults and children 13 years and older

Prophylaxis

75 mg once daily for at least 10 days*

Patients with impaired renal function: 75 mg every other day for at least 10 days*

Treatment

75 mg twice daily for 5 days

Patients with impaired renal function: 75 mg once daily for5 days

Zanamivir (Relenza)

Children

Influenza prophylaxis in patients 5 years and older Treatment of influenza in patients 7 years and older who have been symptomatic for no more than 2 days

Category C Contraindicated in patients with milk allergy or history of allergic reaction to zanamivir or any component of the product Not recommended in patients with underlying reactive airways disease (e.g., asthma, chronic obstructive pulmonary disease); may worsen pulmonary status in these patients

Cough, nasal and throat discomfort, bronchospasm, worsening of pulmonary status, allergic reactions(including anaphylaxis)

Intravenous form (not FDA approved) Powder for inhalation, supplied in blister packs of 10 5-mg doses and packaged with a Diskhaler (should not be used with any other inhalation device)

Prophylaxis

5 years and older: adult dosage

Treatment

7 years and older: adult dosage

Adults

Prophylaxis

10 mg (2 5-mg inhalations) once daily for 10 days

Treatment

10 mg (2 5-mg inhalations) twice daily for 5 days

Peramivir‡

NA

NA

NA

Diarrhea, nausea, vomiting, neutropenia

Intravenous form (single-use vials)

Amantadine

Children

Prophylaxis and treatment of influenza A virus infection in patients 1 year and older Treatment of parkinsonism and drug-induced extrapyramidal reactions

Category C Contraindicated in patients with known hypersensitivity to amantadine or rimantadine

Central nervous system effects (e.g., insomnia, lightheadedness, difficulty concentrating, delirium, seizures, hallucinations) Suicidal ideation has been reported (more common in patients taking other agents with central nervous system effects)

Capsules and tablets (100 mg) Oral solution

Prophylaxis

1 to 9 years of age: 5 mg per kg per day (up to 150 mg per day) in 2 divided doses for at least 10 days after exposure§

10 years and older (≥ 88 lb [≥ 40 kg]): adult dosage

Treatment

1 to 9 years of age: 5 mg per kg per day (up to 150 mg per day) in 2 divided doses for 5 days

10 years and older (≥ 88 lb [≥ 40 kg]): adult dosage

Adults

Prophylaxis

100 mg twice daily for at least 10 days after exposure§

Creatinine clearance less than 50 mL per minute: 100 mg once daily for 10 days after exposure

Treatment

100 mg twice daily for 5 days

65 years and older: 100 mg once daily for 5 days

Creatinine clearance less than 50 mL per minute: 100 mg once daily for 5 days

Rimantadine (Flumadine) Tablets (100 mg)

Children

Influenza A virus prophylaxis in children 1 to 16 years of age Prophylaxis and treatment of influenza A virus infection in adults and adolescents 17 years and older

Category C Contraindicated in patients with known hypersensitivity to amantadine or rimantadine

Similar to amantadine, but less common

Prophylaxis∥

1 to 9 years of age: 5 mg per kg per day (up to 150 mg per day) in 2 divided doses for 5 to 7 days after exposure

10 years and older: adult dosage

Adults

Prophylaxis∥

100 mg twice daily for 5 to 7 days after exposure

65 years and older: 100 mg once daily for 5 to 7 days after exposure

Treatment

100 mg twice daily for 5 days

65 years and older: 100 mg once daily for 5 days

Ribavirin

As specified in an approved research protocol

Approved for use only in patients with respiratory syncytial virus infection and in those with hepatitis C (in combination with other agents), but has been used in hospitalized immunocompromised patients with influenza Should be used only in critical patients and on a case-by-case basis as part of an approved research protocol

Category X See package insert for contraindications and FDA boxed warnings

Cardiovascular events, arrhythmias, hematologic derangements, seizures, asthenia, worsening of pulmonary status

Intravenous form (available through the FDA as part of an approved research protocol)

Powder for nebulizer solution (Virazole)

Capsules and tablets (for treatment of hepatitis C)


note: The choice of antiviral agent should be based on local patterns of virus activity and susceptibility.

FDA = U.S. Food and Drug Administration; NA = not available.

*—Oseltamivir may be used prophylactically for up to six weeks during community outbreaks of influenza.

—Zanamivir may be used prophylactically for four weeks during community outbreaks of influenza.

—Peramivir is an investigational neuraminidase inhibitor that was used during the 2009–2010 influenza season under an emergency use authorization by the FDA. The authorization expired in June 2010.

§—Amantadine may be used prophylactically for two to four weeks during community outbreaks of influenza.

—For control of influenza outbreaks in hospitals and long-term care facilities, the Centers for Disease Control and Prevention recommends chemoprophylaxis for a minimum of two weeks, and for up to one week after the last case is identified.

Information from references 3, 4, 6, 8, 15, 16, 20 through 23, and 29 through 32.

Table 5.   Antiviral Agents for Influenza Chemoprophylaxis and Treatment

View Table

Table 5.

Antiviral Agents for Influenza Chemoprophylaxis and Treatment

Drug/available formulations Dosage FDA-approved indications FDA pregnancy category and contraindications Possible adverse effects

Oseltamivir (Tamiflu)

Children 1 to 12 years Prophylaxis

Influenza prophylaxis in patients 1 year and older Treatment of uncomplicated acute influenza in patients 1 year and older who have been symptomatic for no more than 2 days

Category C (preferred treatment in pregnancy) Contraindicated in patients with known serious hypersensitivity to oseltamivir or any component of the product

Nausea, vomiting, allergic reactions (rash, facial swelling) Rarely, serious skin reactions (toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme) and transient neuropsychiatric events(self-injury or delirium; causal relationship has not been established)

Capsules (30, 45, and 75 mg) Intravenous form (in clinical trials) Powder for oral suspension

≤ 33 lb (≤ 15 kg): 30 mg once daily for 10 days* > 33 to 51 lb (> 15 to 23 kg): 45 mg once daily for 10 days* > 51 to 88 lb (> 23 to 40 kg): 60 mg once daily for 10 days* > 88 lb (> 40 kg): adult dosage

Treatment

≤ 33 lb (= 15 kg): 30 mg twice daily for 5 days

> 33 to 51 lb (> 15 to 23 kg): 45 mg twice daily for 5 days

> 51 to 88 lb (> 23 to 40 kg): 60 mg twice daily for 5 days

> 88 lb (> 40 kg): adult dosage

Adults and children 13 years and older

Prophylaxis

75 mg once daily for at least 10 days*

Patients with impaired renal function: 75 mg every other day for at least 10 days*

Treatment

75 mg twice daily for 5 days

Patients with impaired renal function: 75 mg once daily for5 days

Zanamivir (Relenza)

Children

Influenza prophylaxis in patients 5 years and older Treatment of influenza in patients 7 years and older who have been symptomatic for no more than 2 days

Category C Contraindicated in patients with milk allergy or history of allergic reaction to zanamivir or any component of the product Not recommended in patients with underlying reactive airways disease (e.g., asthma, chronic obstructive pulmonary disease); may worsen pulmonary status in these patients

Cough, nasal and throat discomfort, bronchospasm, worsening of pulmonary status, allergic reactions(including anaphylaxis)

Intravenous form (not FDA approved) Powder for inhalation, supplied in blister packs of 10 5-mg doses and packaged with a Diskhaler (should not be used with any other inhalation device)

Prophylaxis

5 years and older: adult dosage

Treatment

7 years and older: adult dosage

Adults

Prophylaxis

10 mg (2 5-mg inhalations) once daily for 10 days

Treatment

10 mg (2 5-mg inhalations) twice daily for 5 days

Peramivir‡

NA

NA

NA

Diarrhea, nausea, vomiting, neutropenia

Intravenous form (single-use vials)

Amantadine

Children

Prophylaxis and treatment of influenza A virus infection in patients 1 year and older Treatment of parkinsonism and drug-induced extrapyramidal reactions

Category C Contraindicated in patients with known hypersensitivity to amantadine or rimantadine

Central nervous system effects (e.g., insomnia, lightheadedness, difficulty concentrating, delirium, seizures, hallucinations) Suicidal ideation has been reported (more common in patients taking other agents with central nervous system effects)

Capsules and tablets (100 mg) Oral solution

Prophylaxis

1 to 9 years of age: 5 mg per kg per day (up to 150 mg per day) in 2 divided doses for at least 10 days after exposure§

10 years and older (≥ 88 lb [≥ 40 kg]): adult dosage

Treatment

1 to 9 years of age: 5 mg per kg per day (up to 150 mg per day) in 2 divided doses for 5 days

10 years and older (≥ 88 lb [≥ 40 kg]): adult dosage

Adults

Prophylaxis

100 mg twice daily for at least 10 days after exposure§

Creatinine clearance less than 50 mL per minute: 100 mg once daily for 10 days after exposure

Treatment

100 mg twice daily for 5 days

65 years and older: 100 mg once daily for 5 days

Creatinine clearance less than 50 mL per minute: 100 mg once daily for 5 days

Rimantadine (Flumadine) Tablets (100 mg)

Children

Influenza A virus prophylaxis in children 1 to 16 years of age Prophylaxis and treatment of influenza A virus infection in adults and adolescents 17 years and older

Category C Contraindicated in patients with known hypersensitivity to amantadine or rimantadine

Similar to amantadine, but less common

Prophylaxis∥

1 to 9 years of age: 5 mg per kg per day (up to 150 mg per day) in 2 divided doses for 5 to 7 days after exposure

10 years and older: adult dosage

Adults

Prophylaxis∥

100 mg twice daily for 5 to 7 days after exposure

65 years and older: 100 mg once daily for 5 to 7 days after exposure

Treatment

100 mg twice daily for 5 days

65 years and older: 100 mg once daily for 5 days

Ribavirin

As specified in an approved research protocol

Approved for use only in patients with respiratory syncytial virus infection and in those with hepatitis C (in combination with other agents), but has been used in hospitalized immunocompromised patients with influenza Should be used only in critical patients and on a case-by-case basis as part of an approved research protocol

Category X See package insert for contraindications and FDA boxed warnings

Cardiovascular events, arrhythmias, hematologic derangements, seizures, asthenia, worsening of pulmonary status

Intravenous form (available through the FDA as part of an approved research protocol)

Powder for nebulizer solution (Virazole)

Capsules and tablets (for treatment of hepatitis C)


note: The choice of antiviral agent should be based on local patterns of virus activity and susceptibility.

FDA = U.S. Food and Drug Administration; NA = not available.

*—Oseltamivir may be used prophylactically for up to six weeks during community outbreaks of influenza.

—Zanamivir may be used prophylactically for four weeks during community outbreaks of influenza.

—Peramivir is an investigational neuraminidase inhibitor that was used during the 2009–2010 influenza season under an emergency use authorization by the FDA. The authorization expired in June 2010.

§—Amantadine may be used prophylactically for two to four weeks during community outbreaks of influenza.

—For control of influenza outbreaks in hospitals and long-term care facilities, the Centers for Disease Control and Prevention recommends chemoprophylaxis for a minimum of two weeks, and for up to one week after the last case is identified.

Information from references 3, 4, 6, 8, 15, 16, 20 through 23, and 29 through 32.

Zanamivir is an oral inhalation agent that is approved for influenza prophylaxis in patients five years and older, and for treatment of influenza in patients seven years and older who have been symptomatic for no more than two days.23 Inhaled zanamivir can worsen pulmonary status in patients with underlying pulmonary disorders, and should not be used in these patients.23,29 Relenza is a mixture of zanamivir and lactose drug carrier; therefore milk allergy is a contraindication.23

The effectiveness of oseltamivir and zanamivir in outpatient populations was evaluated in a 2009 systematic review that included trials involving healthy adults and trials involving persons at risk of influenza-related complications.33 Oseltamivir reduced the duration of symptoms by 0.55 days among healthy adults (1,410 participants) and by 0.74 days in persons at risk of complications (1,472 participants). For zanamivir, time to symptom alleviation was reduced by 0.57 days in healthy adults (2,701 participants) and by 0.98 days in persons at risk of complications (1,252 participants).33 A 2010 Cochrane review concluded that inconsistencies in the available studies, as well as unavailability of data from other studies, preclude any firm conclusions to be made about the effectiveness of oseltamivir in preventing influenza-related complications in healthy adults, and that its effectiveness in reducing influenza-related symptoms is modest.34,35 A 2009 systematic review and meta-analysis of oseltamivir and zanamivir use in children concluded that treatment of influenza with either agent produced faster resolution of symptoms by 0.5 to 1.5 days.36 Most of the data about the use of neuraminidase inhibitors in outpatient settings was derived from studies of seasonal influenza and influenza-like illnesses. Whether these conclusions can be extrapolated to patients with 2009 H1N1 influenza is not clear.16,34

In hospitalized patients, early treatment with oseltamivir is associated with increased survival rates in critically ill patients with 2009 H1N1 influenza.10,12,25 Reduced dosages are recommended for patients with impaired renal function.22,29 No dosage adjustment is needed for patients with renal disease who are taking zanamivir.23

Neuropsychiatric adverse events (self-injury and delirium) have been reported in adolescents taking oseltamivir, but these events are rare (one per 100,000 prescriptions).15,29,37,38 It is not clear whether these events are associated with oseltamivir use, influenza infection, or some other factor. Similar events have been reported in adults taking oseltamivir.39

Peramivir is a neuraminidase inhibitor formulated for intravenous administration.29,40 It is an investigational product and is currently being evaluated in clinical trials.8 In October 2009, the U.S. Food and Drug Administration issued an emergency use authorization allowing peramivir to be used in the treatment of hospitalized patients with H1N1 influenza; this authorization expired in June 2010.15

Adamantanes. Adamantanes are M2 ion channel blockers; they interfere with hydrogen ion channel activity of the influenza A virus, thus blocking its entry into the host cells. Adamantanes are active only against influenza A viruses.6,7,28,29 During the 2009–2010 influenza season, more than 99 percent of circulating influenza viruses in the United States were H1N1 viruses that were resistant to adamantanes.15 However, surveillance data from the CDC show that isolates resistant to oseltamivir may remain susceptible to amantadine, rimantadine (Flumadine), and zanamivir.15 Although adamantanes currently have no role in the management of influenza, emerging resistance patterns may necessitate re-evaluation of their use.15,16

Ribavirin. Ribavirin, an antiviral drug with in vitro activity against DNA and RNA viruses, is approved for the treatment of respiratory syncytial virus infection and for the treatment of hepatitis C in combination with other agents.6,41 It has been used to treat critically ill patients with influenza, although data are limited.6,42,43 WHO guidelines recommend that ribavirin be used to treat influenza only as part of an approved research protocol.16

Additional Considerations

Over-the-counter antipyretics and anti-inflammatory agents can be used for symptomatic relief in patients with influenza; aspirin or aspirin-containing medications should not be used in children because of the risk of Reye syndrome.16 Bacterial coinfection or development of complications may necessitate the use of antibiotics in patients with influenza.16

Many patients with influenza-like illnesses use supplements such as homeopathic Oscillococcinum, vitamin C, zinc, echinacea, elderberry, garlic, ginseng, and olive leaf to alleviate symptoms.7,4447 Most clinical trials of complementary and alternative medicine in influenza-like illnesses have methodologic flaws that prevent conclusions to be made about the effectiveness of these preparations.

The Authors

IRINA V. ERLIKH, MD, is an associate program director in the Department of Family Medicine and the Family Medicine Residency Program at the Brooklyn Hospital Center in Brooklyn, NY.

SHERLY ABRAHAM, MD, is a program director in the Department of Family Medicine and the Family Medicine Residency Program at the Brooklyn Hospital Center.

VASANTHA K. KONDAMUDI, MD, is chairperson of the Department of Family Medicine at the Brooklyn Hospital Center.

Address correspondence to Irina V. Erlikh, MD, Department of Family Medicine, Brooklyn Hospital Center, 121 DeKalb Ave., Brooklyn, NY 11201 (e-mail: ire9001@nyp.org). Reprints are not available from the authors.

Author disclosure: Nothing to disclose.

The authors thank Dahlia Davidson for assistance with preparation of the manuscript.

REFERENCES

1. Derlet RW, Sandrock CE, Nguyen HH, Lawrence R. Influenza. http://emedicine.medscape.com/article/219557-overview. Accessed October 14, 2010.

2. Dawood FS, Jain S, Finelli L, et al.; Novel Swine-Origin Influenza A (H1N1) Virus Investigation Team. Emergence of a novel swine-origin influenza A (H1N1) virus in humans [published correction appears in N Engl J Med. 2009;360(25):2667–2668]. N Engl J Med. 2009;360(25):2605–2615.

3. World Health Organization. Clinical management of human infection with pandemic (H1N1) 2009: revised guidance. http://www.who.int/csr/resources/publications/swineflu/clinical_management_h1n1.pdf. Accessed October 14, 2010.

4. Harper SA, Bradley JS, Englund JA, et al.; Expert Panel of the Infectious Diseases Society of America. Seasonal influenza in adults and children—diagnosis, treatment, chemoprophylaxis, and institutional outbreak management: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis. 2009;48(8):1003–1032.

5. World Health Organization. Fact sheet no. 211. Influenza (seasonal). http://www.who.int/mediacentre/factsheets/fs211/en/. Accessed October 14, 2010.

6. Glezen WP. Clinical practice. Prevention and treatment of seasonal influenza. N Engl J Med. 2008;359(24):2579–2585.

7. Roxas M, Jurenka J. Colds and influenza: a review of diagnosis and conventional, botanical, and nutritional considerations. Altern Med Rev. 2007;12(1):25–48.

8. Bautista E, Chotpitayasunondh T, Gao Z, et al.; Writing Committee of the WHO Consultation on Clinical Aspects of Pandemic (H1N1) 2009 Influenza. Clinical aspects of pandemic 2009 influenza A (H1N1) virus infection [published correction appears in N Engl J Med. 2010;362(21):2039]. N Engl J Med. 2010;362(18):1708–1719.

9. World now at the start of 2009 influenza pandemic [news release]. World Health Organization Media Centre; June 11, 2009. http://www.who.int/mediacentre/news/statements/2009/h1n1_pandemic_phase6_20090611/en/index.html. Accessed October 14, 2010.

10. Domínguez-Cherit G, Lapinsky SE, Macias AE, et al. Critically ill patients with 2009 influenza A (H1N1) in Mexico. JAMA. 2009;302(17):1880–1887.

11. Rello J, Rodríguez A, Ibañez P, et al.; H1N1 SEMICYUC Working Group. Intensive care adult patients with severe respiratory failure caused by influenza A (H1N1)v in Spain. Crit Care. 2009;13(5):R148.

12. Lee EH, Wu C, Lee EU, et al. Fatalities associated with the 2009 H1N1 influenza A virus in New York City. Clin Infect Dis. 2010;50(11):1498–1504.

13. Centers for Disease Control and Prevention. Updated CDC estimates of 2009 H1N1 influenza cases, hospitalizations and deaths in the United States, April 2009 – April 10, 2010. http://www.cdc.gov/h1n1flu/. Accessed October 14, 2010.

14. Centers for Disease Control and Prevention. 2009 H1N1 flu. Situation update. http://www.cdc.gov/h1n1flu/. Accessed October 14, 2010.

15. Centers for Disease Control and Prevention. Updated interim recommendations for the use of antiviral medications in the treatment and prevention of influenza for the 2009–2010 season. http://www.cdc.gov/H1N1flu/recommendations.htm. Accessed October 14, 2010.

16. World Health Organization. WHO guidelines for pharmacological management of pandemic influenza A (H1N1) 2009 and other influenza viruses. Revised February 2010. Part I: recommendations. http://www.who.int/csr/resources/publications/swineflu/h1n1_guidelines_pharmaceutical_mngt.pdf. Accessed October 14, 2010.

17. Fiore AE, Uyeki TM, Broder K, et al.; Centers for Disease Control and Prevention (CDC). Prevention and control of influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2010 [published correction appears in MMWR Recomm Rep. 2010;59(31):993]. MMWR Recomm Rep. 2010;59(RR-8):1–62. http://www.cdc.gov/mmwr/pdf/rr/rr5908.pdf. Accessed October 14, 2010.

18. CDC's Advisory Committee on Immunization Practices (ACIP) recommends universal annual influenza vaccination [news release]. Centers for Disease Control and Prevention Online Newsroom; February 24, 2010. http://www.cdc.gov/media/pressrel/2010/r100224.htm. Accessed October 14, 2010.

19. Temte JL. Telephone triage of patients with influenza. Am Fam Physician. 2009;79(11):943–945.

20. Centers for Disease Control and Prevention. Interim recommendations for clinical use of influenza diagnostic tests during the 2009–10 influenza season. http://www.cdc.gov/h1n1flu/guidance/diagnostic_tests.htm. Accessed October 14, 2010.

21. Centers for Disease Control and Prevention. Interim guidance for the detection of novel influenza A virus using rapid influenza diagnostic tests. http://www.cdc.gov/h1n1flu/guidance/rapid_testing.htm. Accessed October 14, 2010.

22. Oseltamivir [package insert]. Nutley, N.J.: Roche; 2008. http://www.rocheusa.com/products/tamiflu/pi.pdf. Accessed October 14, 2010.

23. Zanamivir [package insert]. Philadelphia, Pa.: GlaxoSmithKline; 2008. http://us.gsk.com/products/assets/us_relenza.pdf. Accessed October 14, 2010.

24. Jamieson DJ, Honein MA, Rasmussen SA, et al.; Novel Influenza A (H1N1) Pregnancy Working Group. H1N1 2009 influenza virus infection during pregnancy in the USA. Lancet. 2009;374(9688):451–458.

25. Jain S, Kamimoto L, Bramley AM, et al.; 2009 Pandemic Influenza A (H1N1) Virus Hospitalizations Investigation Team. Hospitalized patients with 2009 H1N1 influenza in the United States, April–June 2009. N Engl J Med. 2009;361(20):1935–44.

26. Centers for Disease Control and Prevention. Updated interim recommendations for obstetric health care providers related to use of antiviralmedications in the treatment and prevention of influenza for the 2009–2010 season. http://www.cdc.gov/h1n1flu/pregnancy/antiviral_messages.htm. Accessed October 14, 2010.

27. Louie JK, Acosta M, Jamieson DJ, Honein MA; California Pandemic (H1N1) Working Group. Severe 2009 H1N1 influenza in pregnant and postpartum women in California. N Engl J Med. 2010;362(1):27–35.

28. Govorkova EA, Fang HB, Tan M, Webster RG. Neuraminidase inhibitor-rimantadine combinations exert additive and synergistic anti-influenza virus effects in MDCK cells. Antimicrob Agents Chemother. 2004;48(12):4855–4863.

29. Antiviral drugs for influenza. Med Lett Drugs Ther. 2009;51(1325):89–92.

30. Centers for Disease Control and Prevention. Influenza. Table: recommended daily dosage of seasonal influenza antiviral medications for treatment and chemoprophylaxis for the 2008–09 season—United States. http://www.cdc.gov/flu/professionals/antivirals/dosagetable.htm. Accessed October 14, 2010.

31. Symmetrel (amantadine hydrochloride) [package insert]. Chadds Ford, Pa.: Endo Pharmaceuticals; 2009. http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/016023s041,018101s016lbl.pdf. Accessed October 14, 2010.

32. Flumadine (rimanatadine hydrochloride) [package insert]. St. Louis, Mo.: Forest Laboratories; 2010. http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/019649s015lbl.pdf. Accessed October 14, 2010.

33. Burch J, Corbett M, Stock C, et al. Prescription of anti-influenza drugs for healthy adults: a systematic review and meta-analysis. Lancet Infect Dis. 2009;9(9):537–545.

34. Jefferson T, Jones M, Doshi P, Del Mar C. Neuraminidase inhibitors for preventing and treating influenza in healthy adults: systematic review and meta-analysis. BMJ. 2009;339:b5106.

35. Jefferson T, Jones M, Doshi P, Del Mar C, Dooley L, Foxlee R. Neuraminidase inhibitors for preventing and treating influenza in healthy adults. Cochrane Database Syst Rev.. 2010;(2):CD001265.

36. Shun-Shin M, Thompson M, Heneghan C, Perera R, Harnden A, Mant D. Neuraminidase inhibitors for treatment and prophylaxis of influenza in children: systematic review and meta-analysis of randomised controlled trials. BMJ. 2009;339:b3172.

37. U.S. Food and Drug Administration. Tamiflu (oseltamivir phosphate). http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm150758.htm. Accessed October 14, 2010.

38. Toovey S, Rayner C, Prinssen E, et al. Assessment of neuropsychiatric adverse events in influenza patients treated with oseltamivir: a comprehensive review. Drug Saf. 2008;31(12):1097–1114.

39. McGeer AJ, Lee W, Loeb M, et al. Adverse effects of amantadine and oseltamivir used during respiratory outbreaks in a center for developmentally disabled adults. Infect Control Hosp Epidemiol. 2004;25(11):955–961.

40. Uyeki T. Antiviral treatment for patients hospitalized with 2009 pandemic influenza A (H1N1). N Engl J Med. 2009;361(23):e110.

41. Chan-Tack KM, Murray JS, Birnkrant DB. Use of ribavirin to treat influenza. N Engl J Med. 2009;361(17):1713–1714.

42. Wilson SZ, Gilbert BE, Quarles JM, et al. Treatment of influenza A (H1N1) virus infection with ribavirin aerosol. Antimicrob Agents Chemother. 1984;26(2):200–203.

43. Rodriguez WJ, Hall CB, Welliver R, et al. Efficacy and safety of aerosolized ribavirin in young children hospitalized with influenza: a double-blind, multicenter, placebo-controlled trial. J Pediatr. 1994;125(1):129–135.

44. Barnes PM, Bloom B, Nahin RL. Complementary and alternative medicine use among adults and children: United States, 2007. In: National Health Statistics Reports. No. 12. Hyattsville, Md.: National Center for Health Statistics; 2008. http://nccam.nih.gov/news/2008/nhsr12.pdf. Accessed October 14, 2010.

45. Zakay-Rones Z, Varsano N, Zlotnik M, et al. Inhibition of several strains of influenza virus in vitro and reduction of symptoms by an elderberry extract (Sambucus nigra L.) during an outbreak of influenza B Panama. J Altern Complement Med. 1995;1(4):361–369.

46. Zakay-Rones Z, Thom E, Wollan T, Wadstein J. Randomized study of the efficacy and safety of oral elderberry extract in the treatment of influenza A and B virus infections. J Int Med Res. 2004;32(2):132–140.

47. Guo R, Pittler MH, Ernst E. Complementary medicine for treating or preventing influenza or influenza-like illness. Am J Med. 2007;120(11):923–929.


Copyright © 2010 by the American Academy of Family Physicians.
This content is owned by the AAFP. A person viewing it online may make one printout of the material and may use that printout only for his or her personal, non-commercial reference. This material may not otherwise be downloaded, copied, printed, stored, transmitted or reproduced in any medium, whether now known or later invented, except as authorized in writing by the AAFP. Contact afpserv@aafp.org for copyright questions and/or permission requests.

Want to use this article elsewhere? Get Permissions


Article Tools

  • Download PDF
  • Print page
  • Share this page
  • AFP CME Quiz

Information From Industry

More in Pubmed

Navigate this Article