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Last Updated: 4/23/2014  

Influenza

Prevention
  • Recommend annual influenza vaccination to all patients, and ensure vaccination of those at high risk for complications of influenza.

  • Note that patients at high risk for complications include: children aged 6 months to 4 years, adults over age 65, patients with chronic medical conditions such as cardiac disease, CKD, diabetes or other endocrine disorders, hematologic disorders, or neurologic disease, patients with immunodeficiencies, and institutionalized adults.

  • Use TIV in patients aged 6 months and over; use either TIV or intranasal LAIV in healthy non-pregnant patients aged 2 to 49.

  • Give two doses of influenza vaccine at least 4 weeks apart to some children under the age of 9 years.

  • Provide antiviral agents to residents of institutions during institutional outbreaks of influenza.

  • Consider antiviral prophylaxis for high-risk patients or close contacts of high-risk patients who are exposed to influenza.

Diagnosis
  • Suspect influenza in adults and children who present with the typical symptoms, particularly the acute onset of fever and cough, during influenza season.

  • Use specific diagnostic tests in patients with suspected influenza when there is diagnostic uncertainty, to investigate outbreaks, or to make decisions about treatment, beginning with PCR or a rapid test depending on the situation.

Therapy
  • Institute antiviral therapy with oseltamivir, zanamivir, or an amantadine in hospitalized patients with influenza and in patients at risk for severe disease who present within 48 hours of symptom onset.

  • Consider use of antiviral agents such as oseltamivir, zanamivir, or an amantadine in adults and children with influenza who present within 48 hours of symptom onset during influenza outbreaks in order to shorten the duration of illness.

Recommend annual influenza vaccination to all patients, and ensure vaccination of those at high risk for complications of influenza. 
  • Recommend annual vaccination against seasonal influenza for all persons aged 6 months and older, unless specifically contraindicated.

  • Place particular emphasis on vaccinating persons at high risk for severe disease and complications, including

    • All children aged 6 months to 4 years

    • All persons aged 50 years and older

    • Children and adolescents (aged 6 months to 18 years) receiving long-term aspirin therapy who therefore might be at risk for experiencing Reye syndrome after influenza virus infection

    • Women who will be pregnant during the influenza season

    • Adults and children with chronic pulmonary disorders, including asthma; cardiovascular disease, with the exception of hypertension; and renal, hepatic, hematologic, or metabolic disorders, including diabetes mellitus

    • Adults and children with immunosuppression, including that caused by medications or by HIV

    • Residents of nursing homes and other chronic care facilities

    • Close contacts of those at high risk for complications, including

      • Health care workers involved in direct patient care

      • Out-of-home caregivers and household contacts of children under 59 months (especially those under 6 months) or adults over 50 years

      • Out-of-home caregivers and household contacts of persons in high-risk groups

    • Any persons who want to reduce the risk for becoming ill with influenza or of transmitting influenza to others

  • Know that certain groups of individuals respond poorly to influenza vaccine, including the elderly, HIV-infected patients, patients with hematologic malignancy or receiving chemotherapy, and patients with organ transplantation.

  • If vaccine is in short supply, prioritize its use to individuals at high risk and their close contacts.

  • Consult the CDC for guidelines during vaccine shortages and for other updated information and recommendations.

  • Check the CDC's Seasonal Influenza Web site frequently for updated information and recommendations.

Evidence
  • The 2012 recommendations from the CDC Advisory Committee on Immunization Practices for the prevention and control of seasonal influenza with vaccines recommended universal vaccination of all individuals over the age of 6 months who do not have contraindications and discussed options regarding specific vaccines (1).

  • The 2010 recommendations from the CDC Advisory Committee on Immunization Practices for the prevention and control of seasonal influenza with vaccines identified high-risk populations who should be targeted for vaccination or who should preferentially receive vaccine in times of shortage (2).

  • A 2012 systematic review of the effect of influenza vaccination on confirmed cases of influenza included a total of 17 randomized trials and 14 observational trials. TIV had a pooled efficacy of 59% (CI, 51% to 67%) in adults aged 18 to 65; no trials of children or the elderly met inclusion criteria. LAIV had a pooled efficacy of 83% (CI, 69% to 91%) in children aged 6 months to 7 years. Pandemic H1N1 vaccine had an efficacy of 69% (CI, 60% to 93%) (3).

  • A 2010 Cochrane review of influenza vaccination in healthy adults included 50 reports. During seasons when vaccine strains match circulating strains, vaccination lowered rates of symptomatic influenza from 4% to 1% of the population; when strains do not match, vaccination lowered rates of symptomatic influenza from 2% to 1% (4).

  • A 2010 Cochrane review of the efficacy of influenza vaccination in the elderly included 75 studies, of which only one was a randomized trial. Evidence was of poor quality but appeared to show that vaccination decreased symptoms of influenza (5).

  • A 2011 systematic review addressed the effectiveness of the inactivated influenza vaccine in preventing laboratory-confirmed influenza among healthy adults (16 to 65 years) and children (6 years or older). The review found that vaccine was generally effective but was limited by little good-quality evidence of the effectiveness of influenza vaccination on complications such as pneumonia, hospitalization, and influenza-specific and overall mortality, and in certain groups such as children under 6 years, individuals with chronic obstructive pulmonary disease, institutionalized elderly (65 years or older), elderly with comorbidities, and health care workers in homes for the elderly (6).

  • A 2012 systematic review of the effect of influenza vaccination in immunocompromised patients included 209 studies. There were 13 studies of patients with HIV, of which 2 were appropriate for inclusion in the meta-analysis. Despite heterogeneity, those studied showed that vaccination reduced influenza-like illness (pooled OR, 0.20 [CI, 0.05 to 0.88]). Studies in HIV patients found few significant adverse effects. Similarly, influenza vaccination reduced influenza-like illness in patients with cancer (pooled OR, 0.26 [CI, 0.15 to 0.46]) and in patients with transplants (pooled OR, 0.27 [CI, 0.11 to 0.66]), with few adverse effects (7).

  • A 2012 Cochrane review of influenza vaccination in healthy children included 17 randomized, controlled trials, 19 cohort studies, and 11 case-control studies. Overall, influenza vaccination prevented cases of influenza in children 2 years or older, with an NNT of 6 for children under age 6 and an NNT of 28 for those over age 6. There was little evidence for children under age 2. There was no evidence of effect of the vaccine on secondary cases, lower respiratory tract disease, drug prescriptions, otitis media and its consequences, and socioeconomic impact (8).

  • A 2010 Cochrane review of the effect of health care worker vaccination on rates of influenza in long-term care facilities included 4 randomized trials and 1 cohort study. Health care worker vaccination did not affect rates of confirmed influenza (OR, 0.87 [CI 0.38 to 1.99]), pneumonia (OR, 0.71 [CI 0.29 to 1.71]), or death from pneumonia (OR, 0.87 [CI 0.47 to 1.64]), although it did reduce influenza-like illness (RR, 0.71 [CI 0.58 to 0.88]) (9).

  • A 2009 Cochrane review of one randomized, controlled trial of influenza vaccination in children receiving chemotherapy for cancer included eight trials. Immune responses in children receiving chemotherapy were consistently weaker (four-fold rise of 25% to 52%) than in children who had completed chemotherapy (50% to 86%) and in healthy children (71% to 89%) (10).

  • A randomized, controlled trial including a total of 1340 healthy subjects aged 18 years and older showed that a single dose of the 3.75-mcg hemagglutinin AS03(A)-adjuvanted H1N1 2009 influenza vaccine induced the strongest immune responses in subjects aged 18 to 64 years, as well as in subjects over age 64, compared with 1.9-mcg hemagglutinin AS03(B) or nonadjuvanted vaccine formulation (11).

  • A prospective, randomized, open, blinded end-point study enrolled 439 patients who had been admitted due to acute coronary syndrome within 8 weeks and randomly assigned to receive either TIV or no treatment. The study showed that TIV was associated with reduction of major cardiovascular events, including death, hospitalization from acute coronary syndrome, hospitalization from heart failure, and hospitalization from stroke (12).

  • In a randomized trial, healthy adults aged 18 to 44 years, 45 to 64 years, and 65 years and older received two doses of pandemic H1N1 vaccine given 21 days apart: either 7.5 mcg of hemagglutinin formulated as whole-virion vaccine or 3.75 mcg of hemagglutinin formulated as split-virion vaccine with AS03(A) oil-in-water adjuvant. The study showed that AS03(A)-adjuvanted vaccine was more immunogenic against pandemic influenza A H1N1 virus than whole-virion vaccine. The immunogenic response was better with two doses of the vaccine than one in older adults (13).

  • A randomized, controlled trial among 117 participants aged 22 to 62 years showed that previous vaccination with the seasonal trivalent influenza vaccine was associated with a weak antibody response to the pandemic H1N1 2009 vaccine. The authors recommended that the pandemic H1N1 2009 vaccine be administered before vaccination with the seasonal trivalent influenza vaccine (14).

  • A multicenter clinical trial to evaluate the immunogenicity and safety of H1N1 vaccine in young adults (18 to 64 years) and the elderly (65 years or older) using a two-dose regimen, with the doses administered 21 days apart, showed that the increase in hemagglutination inhibition titers was higher with MF59-adjuvanted vaccine than with nonadjuvanted vaccine. In the elderly, on day 21 after the first dose, the rates of seroprotection and seroconversion were significantly higher for the 7.5-mcg dose of MF59-adjuvanted vaccine than for the 3.75-mcg dose (58.0% versus 44.3% [P=0.03] and 53.7% versus 37.2% [P<0.01], respectively) (15).

  • A randomized, blinded, controlled trial among 261 healthy adults aged 18 to 60 years showed that AS03(A)-adjuvanted H1N1 vaccine containing 3.75 mcg was more immunogenic than nonadjuvanted H1N1 vaccine containing 15 or 3.75 mcg of hemagglutinin (16).

  • A randomized trial including 150 HIV patients aged 20 to 59 years demonstrated that a single dose of a single-antigen, inactivated, split, AS03(A)-adjuvanted H1N1 influenza vaccine induced high-level immunogenicity. Seroprotection and seroconversion were further improved in those patients randomly assigned to booster dosing at day 21 compared with a single-dose vaccination (17).

  • A randomized trial compared TIV with placebo in 506 HIV-infected adults in South Africa. The efficacy of TIV against confirmed influenza illness was 75.5%. Seroconversion, measured by hemagglutination inhibition titers, was evident in 52.6% for H1N1, 60.8% for H3N2, and 53.6% for influenza B virus (18).

  • A randomized, controlled trial included 340 pregnant women in Bangladesh who received either inactivated influenza vaccine or 23-valent pneumococcal polysaccharide vaccine (control). During the period with circulating influenza virus, there was a substantial reduction in the incidence per 100 person-months of respiratory illness with fever among the mothers and infants who had received the influenza vaccine (influenza vaccine: 3.7; control: 7.2; P=0.0003). Furthermore, the proportion of infants who were small for gestational age was lower in the influenza vaccine group than in the control group (25.9% vs. 44.8%; P=0.03) (19).

  • A randomized trial enrolled 120 pregnant women who received an inactivated 2009 H1N1 influenza vaccine containing either 25 mcg or 49 mcg of hemagglutinin in a two-dose series with a 21-day period between administration of the first and second doses. The study showed that one dose of an inactivated 2009 H1N1 influenza vaccine containing 25 mcg of hemagglutinin elicited an antibody response (hemagglutination inhibition titers of ≥1:40) typically associated with protection against influenza infection in both the mother and the cord blood (20).

  • A randomized trial compared influenza vaccination to pneumococcal vaccination in 340 pregnant women. There were fewer cases of documented influenza in the infants of vaccinated mothers compared with infants of unvaccinated women, with an effectiveness of 63% (CI, 5% to 85%) (21).

  • A prospective, multicenter trial demonstrated the immunogenicity and reactogenicity of two doses of AS03(B)-adjuvanted pandemic influenza vaccine in 302 children aged 6 months to 12 years (22).

  • A randomized, double-blind, active-controlled, phase III study confirmed a new trivalent inactivated split-virus influenza vaccine to be immunogenic and safe in 283 healthy children aged 6 months to less than 18 years (23).

  • A randomized, observer-blinded, multicenter trial in 474 children aged 6 to 35 months or 3 to 9 years confirmed the immunogenicity and safety of two doses of a monovalent inactivated pandemic (H1N1) 2009 vaccine containing 7.5 or 15 mcg of hemagglutinin. The first dose of either H1N1 vaccine formulation was more immunogenic in children over 3 years than in younger children (24).

  • An immunization registry showed that one dose of 2009 influenza A (H1N1) vaccine was effective in preventing hospitalization due to pandemic H1N1 influenza in children aged 7 months to 9 years (25).

  • In a multicenter, randomized, head-to-head trial, vaccination with two doses of an AS03(B)-adjuvanted split-virion H1N1 influenza vaccine was more effective in inducing protective antibodies than a nonadjuvanted whole-virion H1N1 influenza vaccine among 318 children. A single dose of trivalent seasonal influenza vaccine was found to be immunoprotective among 302 children (26).

  • A randomized, controlled trial confirmed that two age-appropriate doses of TIV with the MF59 adjuvant was more effective than TIV without the MF59 adjuvant against PCR-confirmed influenza in 4707 healthy children aged 6 months to under 72 months who had not previously been vaccinated against influenza (27).

  • A randomized, open-label trial among 392 children showed similar immunogenicity of one dose of nonadjuvanted A/H1N1 vaccine, one dose of MF59-adjuvanted vaccine, or two doses of nonadjuvanted vaccine in 9- to 17-year-olds. However, in children aged 3 to 8 years, only one dose of the adjuvanted vaccine or two doses of nonadjuvanted vaccine achieved protective titers (28).

  • A randomized, controlled trial showed that the 2009 pandemic influenza A/H1N1 MF59-adjuvanted vaccine is as immunogenic, safe, and well tolerated in 36 HIV-infected children and adolescents as in 36 age- and gender-matched healthy controls (29).

  • A prospective study of 199 patients with autoimmune diseases confirmed the safety and efficacy of seasonal TIV and A/H1N1 influenza vaccines where 80% and 65% of study subjects achieved seroprotection, respectively (30).

  • In a randomized, controlled trial that included 81 young patients with type 1 diabetes, one dose of MF59-adjuvanted influenza A(H1N1) vaccine, simultaneously with a single dose of a virosome-adjuvanted TIV was as seroprotective and safe as two doses of the same vaccines (31).

  • In an open, prospective trial, two doses, not one dose, of the 2009 AS03-adjuvanted influenza H1N1 vaccine in allogeneic, hematopoietic stem-cell transplant recipients elicited comparable responses to a single dose in healthy individuals. Transplant-to-vaccination interval and active graft-versus-host disease were the most powerful predictors of poor antibody responses to vaccine (32).

  • A randomized, controlled trial comparing the immunogenicity of the TIV seasonal 2008-2009 influenza vaccine containing either 6 mcg (intradermal) or 15 mcg (intramuscular) of hemagglutinin per viral strain in 85 lung-transplant recipients showed poor response (14.6% vs. 18.6% in the intradermal and the intramuscular group, respectively; P=0.77) (33).

  • A randomized, controlled trial that included 38 breast cancer patients on chemotherapy and 21 healthy controls showed that patients on chemotherapy had significantly lower responses to TIV compared with healthy controls. Vaccination early during the chemotherapy cycle induced better responses than did vaccination at day 16 of the cycle (34).

  • In a randomized, controlled trial, the immune response to the pandemic influenza A/H1N1 MF59-adjuvanted and seasonal virosomal-adjuvanted influenza vaccines was lower in pediatric kidney-transplant recipients than in healthy controls. Furthermore, the simultaneous administration of the two vaccines seems to increase immune response to both pandemic and seasonal A/H1N1 and A/H3N2 antigens (35).

  • A controlled trial that included 555 patients with systemic lupus erythematosus and 170 healthy controls showed pandemic influenza A H1N1/2009 vaccine response was diminished in SLE under immunosuppressive therapy (such as prednisone >20 mg and other drugs), and antimalarials (chloroquine) seemed to restore this immunogenicity (36).

Rationale
  • Influenza vaccines are safe and effective.

  • The current strategy for controlling influenza by vaccination is designed to reduce the overall incidence of influenza, with a special emphasis on reducing the incidence in individuals at highest risk for complications (e.g., hospitalizations and deaths).

  • Pregnant women are at high risk for severe disease and for complications from typical seasonal strains and especially the 2009 H1N1; vaccination of the mother may also provide some protection for newborn infants who cannot be vaccinated.

  • High-risk persons may be protected from exposure to influenza virus by immunizing persons with whom they have frequent, close contact.

  • Protection of caregivers from influenza may also reduce interruptions in care during influenza epidemics.

Comments
  • On February 23, 2012, the WHO recommended that the Northern Hemisphere's 2012-2013 seasonal influenza vaccine be made from the following three vaccine viruses: an A/California/7/2009 (H1N1)pdm09-like virus; an A/Victoria/361/2011 (H3N2)-like virus; and a B/Wisconsin/1/2010-like virus.

  • Vaccination should optimally occur before onset of influenza activity in the community and also should continue to be offered throughout the influenza season.

  • Note that the TIV is classed by the FDA as pregnancy category C. However, multiple clinical trials, as well as the Vaccine Adverse Events Reporting System database, have shown no significant differences in pregnancy outcome (37; 38; 39; 40).

  • Influenza vaccination of international travelers with high-risk conditions is complex because seasonal influenza activity varies with geography. Detailed recommendations are given in Prevention and Control of Seasonal Influenza with Vaccines: Recommendations of the Advisory Committee on Immunization Practices (37).

  • Note that the TIV is safe for mothers who are breastfeeding and their infants. Breastfeeding is not a contraindication for vaccination of infants.

  • TIV can be given with 13-valent pneumococcal conjugate vaccine in adults aged 65 years or older with acceptable immunogenicity and safety (41).

  • In a Danish cohort study that included 53,432 infants and 54,585 pregnancies, exposure to an adjuvanted influenza A(H1N1)pdm09 vaccine during pregnancy was not associated with a significantly increased risk for major birth defects, preterm birth, or fetal growth restriction (42; 43).

Use TIV in patients aged 6 months or older; use either TIV or intranasal LAIV in healthy, non-pregnant patients aged 2 to 49. 
  • Use intramuscular TIV in any person aged 6 months or older who does not have a specific contraindication.

  • Do not administer TIV to

    • Children under 6 months

    • Adults or children with severe hypersensitivity to eggs or any of the vaccine components (includes persons experiencing angioedema, respiratory distress, lightheadedness, or recurrent emesis, or persons who required epinephrine or other emergency medical intervention, particularly those that occurred immediately or within minutes to hours after egg exposure or vaccination)

    • Adults or children with a moderate or severe acute febrile illness of moderate or greater severity

    • Anyone with a history of Guillain-Barré syndrome occurring within 6 weeks after influenza vaccine

  • Reserve intranasal LAIV for healthy persons aged 2 to 49 years who are not pregnant.

    • When TIV is in short supply, use LAIV preferentially in this group to preserve TIV supplies for those in whom LAIV is not indicated

    • If nasal congestion that could impede delivery of vaccine is present, defer vaccination until the illness resolves

  • Do not administer LAIV to

    • Persons under age 2 or over age 49

    • Persons with asthma, reactive airways disease, or other chronic disorders of the pulmonary or cardiovascular systems

    • Persons with other underlying medical conditions, such as diabetes mellitus, renal dysfunction, hemoglobinopathies, or an immune deficiency disorder

    • Persons who are receiving immunosuppressive therapy

    • Children or adolescents taking aspirin or other salicylates

    • Persons with a history of Guillain-Barré syndrome

    • Pregnant women

    • Persons with known hypersensitivity, including anaphylaxis, to any vaccine component or to eggs

    • Persons receiving antiviral agents active against influenza

    • Health care workers or close contacts of severely immunocompromised patients in special care units (e.g., stem-cell transplant recipients in protective isolation)

  • Do not consider minor acute illnesses, such as diarrhea or minor respiratory illness with or without fever, as a contraindication to LAIV.

  • Use TIV rather than LAIV in persons who have experienced only hives following exposure to egg, and observe them for a reaction for at least 30 minutes after vaccination.

Evidence
  • The 2012 recommendations from the CDC Advisory Committee on Immunization Practices for the prevention and control of seasonal influenza with vaccines recommended universal vaccination of all individuals over the age of 6 months who do not have contraindications. The guideline recommended that TIV be given intramuscularly and recommended LAIV for healthy, non-pregnant persons aged 2 to 49 (1).

  • A randomized trial compared LAIV with TIV in 8352 children aged 6 to 59 months. There were fewer cases of culture-confirmed influenza in the group that received LAIV (3.9%) than in the group that received TIV (8.6%) (P<0.0001) (44).

  • A randomized trial compared TIV with LAIV in 52 children with cancer aged 2 to 21 years. TIV induced significantly higher postvaccination titers against influenza A viruses (P<0.001), greater seroprotection against influenza A/H1N1 (P=0.01), and greater seroconversion against A/H3N2 (P=0.004) compared with LAIV. There were no differences in titers against influenza B viruses (45).

  • A randomized, open-label, multicenter trial compared LAIV with TIV in 3009 community-dwelling ambulatory adults aged 60 to 95 years. Influenza illness caused by vaccine-matched strains was detected in 0.8% (12 of 1494) and 0.5% (8 of 1488) of LAIV and TIV recipients. There was a trend toward less feverishness and fever among LAIV recipients who developed influenza compared with TIV recipients with influenza. Runny nose and nasal congestion, cough, sore throat, lethargy, and decreased appetite were reported by more LAIV than TIV recipients. Serious adverse events were reported by a similar proportion of LAIV and TIV recipients (9% vs. 8%) (46).

  • A randomized, controlled trial of 1592 previously healthy subjects aged 18 to 64 years were randomly assigned to one of four TIV vaccine groups: standard, 15 mcg of hemagglutinin per strain of TIV, intramuscularly; either 9 mcg or 6 mcg of hemagglutinin per strain of TIV, intradermally, given using a new microinjection system (BD Soluvia™ Microinjection System); or 3 mcg of hemagglutinin per strain of TIV, intradermally, given by the Mantoux technique. The reduced doses (6 mcg and 9 mcg) of TIV delivered intradermally using a novel microinjection system stimulated comparable hemagglutination inhibition antibody responses to standard TIV given intramuscularly. The reduced 3-mcg dose administered intradermally by needle and syringe, as well as the 6-mcg intradermal dose for subjects aged 50 to 64 years generated poorer immune responses as compared with the standard TIV given intramuscularly (47).

  • An integrated analysis of randomized, controlled trials of LAIV compared with standard TIV or placebo in children aged 2 to 17 years confirmed the safety of LAIV. The majority of adverse events were mild and included runny or stuffy nose, headache, tiredness or decreased activity, and decreased appetite (48).

Rationale
  • Advantages of LAIV include the potential for inducing both mucosal and systemic immunity, ease of administration, and the fact that the intranasal route may be preferred by some patients over intramuscular injection, which is required for administration of inactivated vaccine.

  • The rationale for giving inactivated vaccine to individuals in close contact with severely immunocompromised people is the theoretical risk for transmission of vaccine virus to these hosts, with the subsequent development of disease.

  • No preference exists for inactivated influenza vaccine use by health care workers or others in contact with persons with lesser degrees of immunosuppression, including HIV infection, or by health care workers and others in contact with all other high-risk groups.

  • There are few contraindications to vaccination, but because the vaccine is produced in eggs, it should not be used in those with anaphylactic reactions to eggs; desensitization techniques are available.

Comments
  • Three kinds of TIV are on the market in the U.S. The regular trivalent inactivated vaccine, which is given intramuscularly, is approved for people aged 6 months and older, including healthy persons, those with chronic medical conditions, and pregnant women. A “high-dose” trivalent inactivated vaccine, also given intramuscularly and containing four times the amount of antigen as the regular TIV, is approved for use in people 65 years and older. An intradermal trivalent inactivated vaccine, which is injected into the dermal layer of the skin via a single-dose, prefilled microinjection syringe and that contains less antigen than the intramuscular TIV formulations, was approved in 2011 for use in persons aged 18 to 64 years.

  • Intradermal influenza vaccine has been shown to foster a broader immune response than TIV (49) and was as safe and acceptable as intramuscular influenza vaccine in elderly patients in an observational, multicenter trial (50).

  • In February 2012, the FDA approved the intranasal quadrivalent live influenza vaccine (FluMist® Quadrivalent) for use in individuals aged 2 to 49 years for the prevention of both influenza A and B viruses.

  • LAIV should not be given concurrently with influenza antiviral medications; vaccine can be given 48 hours after antivirals have been stopped, and antivirals should not be given for 2 weeks after LAIV has been administered.

  • LAIV must be stored at 2° to 8°C (35° to 40°F). Manufacturer's recommendations for storage should be reviewed and followed.

  • TIV is classified as pregnancy category C; however, data from the Vaccine Adverse Event Reporting System and other sources show no major adverse events attributable to TIV in pregnant women or their fetuses (37).

  • Note that TIV is safe for mothers who are breastfeeding and their infants. Breastfeeding is not a contraindication for vaccination of infants.

Give 2 doses of influenza vaccine at least 4 weeks apart to some children under the age of 9 years and consider giving high-dose vaccine in some other high-risk populations.  
  • Give 2 doses of influenza vaccine at least 4 weeks apart to children aged 6 months through 8 years if

    • It is their first season of influenza vaccination or

    • They have not received at least 2 doses of influenza vaccine after July 1, 2010

  • Note that not all TIV formulations are licensed for use in children; check the package insert for FDA approval and dosing in children.

  • Note that a high-dose vaccine (Fluzone High-Dose®) has been licensed for persons aged 65 years and older and has been proposed as a way to optimize immunity in immunocompromised patients.

Evidence
  • The 2012 recommendations from the CDC Advisory Committee on Immunization Practices for the prevention and control of seasonal influenza with vaccines recommended universal vaccination of all individuals over the age of 6 months who do not have contraindications. The guideline recommended two doses of influenza vaccine at least 4 weeks apart in children aged 6 months to 8 years who are either undergoing their first season of influenza vaccination or who have received fewer than two influenza vaccines since July 1, 2010 (1).

  • Extensive trials of inactivated influenza vaccines conducted in advance of the 1977 Russian (H1N1) epidemic showed that a two-dose schedule was required in persons without previous immunologic exposure to H1N1 viruses, but those with previous exposure achieved adequate titers with one dose (51).

  • Accumulating data indicate that two doses are required for protection of children aged 6 months to 8 years who were not previously vaccinated with either LAIV or TIV (52; 53).

  • A randomized, double-blind, study compared high-dose (60 mcg of hemagglutinin per strain) to standard-dose vaccine in 3837 elderly persons and found higher rates of seroconversion and mean hemagglutination inhibition titers with high-dose vaccine (54).

  • A randomized trial comparing standard-dose TIV (15 mcg of hemagglutinin per virus strain) to a high-dose vaccine (60 mcg of hemagglutinin per virus strain) enrolled 49 healthy, independently living elderly (65 years or older) volunteers and 15 young adults (18 to 40 years). The high-dose vaccine induced greater hemagglutination inhibition and virus neutralization antibody titers than the standard-dose vaccine in the elderly, but hemagglutinin inhibition and virus neutralization remained lower than in young adults receiving standard-dose vaccine (55).

  • In a randomized trial in previously unimmunized infants and toddlers, participants were separately and randomly assigned to receive two full (0.5-mL) or two half (0.25-mL) doses of 2008-2009 split TIV. In the toddlers, postimmunization seroprotection rates exceeded 85% for all three vaccine components without significant difference by dose. In the infants, the full dose induced higher responses for the H3N2 and B/Yamagata components but not H1N1 (56).

  • A randomized trial compared high-dose (60 mcg antigen/strain) and standard-dose (15 mcg antigen/strain) influenza vaccine in 195 patients with HIV infection. Rates of seroprotection were higher with high-dose vaccine for H1N1 strains (96% vs. 87%, p=0.029) and influenza B (91% vs. 80%, p=0.030). Adverse effects were similar in the groups (57).

  • A randomized trial among 192 HIV-infected individuals aged 18 to 64 years showed a higher immune response with two doses of 30-mcg hemagglutinin 2009 H1N1 vaccine compared with two doses of 15-mcg hemagglutinin 2009 H1N1 vaccine (58).

  • A randomized trial compared one or two doses of the 2009 monovalent pandemic influenza A/H1N1 MF59-adjuvanted vaccine coadministered with one dose of the seasonal 2009-2010 trivalent nonadjuvanted influenza vaccine in 66 HIV-infected patients aged 9 to 26 years. The immune response triggered by a single dose of H1N1 vaccine was similar to that obtained with a double dose and was associated with long-term antibody response (59).

  • A multicenter, patient-blinded, randomized trial in a cohort of 306 HIV-infected adults showed that two doses of the AS03(A)-adjuvanted H1N1 vaccine containing 3.75 mcg of hemagglutinin yielded a higher immune response than did two doses of the nonadjuvanted vaccine containing 15 mcg of hemagglutinin (60).

  • A randomized, controlled trial among 298 HIV-infected patients showed that neither higher nor booster dosing with nonadjuvanted influenza vaccine was associated with increased immunogenicity compared with standard dosing (61).

  • A randomized, open-label trial compared 15-mcg and 30-mcg doses of an unadjuvanted, inactivated 2009 H1N1 vaccine in patients with asthma. In patients with mild to moderate asthma, those receiving low- and high-dose vaccines had similar levels of seroprotection, while in patients with severe asthma, higher-dose vaccine offered better seroprotection (94.1% vs. 77.9% at day 21; P=0.004) (62).

Rationale
  • A two-dose schedule may be needed to elicit antibody in unprimed persons, but multiple doses do not improve antibody responses in adults already primed immunologically by previous vaccination or exposure to influenza.

Comments
  • Vaccinate adults and older children with TIV in the deltoid muscle. Consider a needle length >1 inch (>25 mm) because shorter needles may be of insufficient length to penetrate muscle tissue in certain adults and older children. Use a needle length of 7/8 to 1.25 inches when injecting into the deltoid muscle in children with adequate deltoid muscle mass. Vaccinate infants and younger children in the anterolateral thigh.

Prioritize vaccination based on the patient's risk of disease and the supply of vaccine. 
  • Offer vaccine to high-risk patients and their close contacts during hospital admission or routine office visits as soon as the vaccine is available in order to avoid missed or delayed opportunities.

  • For children who require two doses, offer the first dose in September; try to complete the series before the onset of influenza season.

  • Begin most routine vaccination in October and continue to offer vaccine throughout the influenza season for as long as the supply lasts.

  • Consider delaying routine vaccination in the nursing-home setting before October because the duration of antibody levels may be shorter in this population and may not last through the influenza season if vaccine is given too early.

  • If vaccine supplies are limited or delayed, target vaccination primarily at high-risk patients and their close contacts as soon as vaccine becomes available.

  • If vaccine supplies are limited, consult the CDC and local health departments for strategy and availability.

Evidence
  • The 2010 CDC recommendations for influenza vaccination discussed prioritization of vaccine for high-risk patients during times of vaccine shortage (37).

Rationale
  • Timing of vaccine is based on the usual chronology of influenza activity in the U.S., the duration of antibody levels, and the supply of vaccine.

Provide antiviral agents to residents of institutions during institutional outbreaks of influenza. 
  • Vaccinate staff members and residents not already immunized, and give chemoprophylaxis for at least 2 weeks following immunization with inactivated vaccine.

  • Give all residents chemoprophylaxis, even if they have been vaccinated earlier in the season with the current vaccine.

  • Continue prophylaxis for at least 2 weeks and for 1 week longer than the duration of the outbreak if surveillance indicates continued new cases.

  • Consider giving chemoprophylaxis to staff members who decline vaccine or when vaccine is unavailable.

  • Consider chemoprophylaxis for all employees in an outbreak caused by a strain that is not included in the vaccine.

  • Seek information from the CDC and local health department on currently circulating influenza strains to determine the best choice of antiviral agent (or combination) for prophylaxis in the community; the CDC provides periodic updates to guide antiviral therapy and weekly surveillance reports that include the geography of prevailing strains.

  • Review CDC guidelines frequently for additional details regarding management of institutional outbreaks.

  • See table Drug Treatment for Influenza.

Evidence
  • A 2009 guideline from the Infectious Diseases Society of America addressed the diagnosis, treatment, chemoprophylaxis and institutional outbreak management of influenza. The guideline recommended antiviral chemoprophylaxis for all residents of institutions with influenza outbreaks, including residents who have been previously vaccinated (63).

  • A 2014 Cochrane review of neuraminidase inhibitors for the prevention and treatment of influenza in healthy children and adults included 107 studies, many of which were at high risk for bias. In adults, oseltamivir (difference, 16.8 hours [CI, 8.4 to 25.1 hours]) and zanamivir (difference, 0.60 days [CI, 0.39 to 0.81 days]) resulted in faster symptom relief. Oseltamivir did not prevent hospitalization compared with placebo. Oseltamivir treatment reduced self-reported pneumonia (rate difference 1.00% [CI, 0.22% to 1.49%]) but did not reduce rates of verified pneumonia; zanamivir treatment did not reduce pneumonia but prophylaxis reduced self-reported pneumonia (rate difference, 0.32% [CI, 0.09% to 0.41%]). Benefits were generally less in children. Oseltamivir reduced diarrhea (rate difference, 2.33% [CI, 0.14% to 3.81%]) and cardiac events (rate difference, 0.68% [CI, 0.4% to 1.0%]) compared to placebo. Prophylaxis with oseltamivir and zanamivir decreased rates of symptomatic influenza, with rate difference of 3.05% (CI, 1.83% to 3.88%) for oseltamivir in individuals and 13.6% (CI, 9.52% to 15.47%) in households, and 1.98% (CI, 0.98% to 2.54%) for zanamivir in individuals and 14.84% (CI, 12.18% to 16.55%) in households. Oseltamivir increased rates of headache (risk difference, 3.15% [CI, 0.88% to 5.78%]) and nausea (risk difference, 4.15% [CI, 0.86% to 9.51%]) compared with placebo (64).

  • A 2009 systematic review of chemoprophylaxis for influenza with neuraminidase inhibitors included 7 trials with 7021 participants. Chemoprophylaxis lowered rates of symptomatic influenza (RR, 0.26 [CI, 0.18 to 0.37]) with no overall increase in adverse events (RR, 1.01 [CI, 0.94 to 1.08]). Nausea and vomiting were more common in patients receiving oseltamivir (RR, 1.48, [CI 1.86 to 2.33]) (65; 66).

  • A randomized trial compared prophylactic oseltamivir with placebo for 6 weeks beginning at the start of influenza season in 548 nursing-home residents. Rates of laboratory-confirmed clinical influenza (0.4% vs. 4.4%; P=0.02) and complications of influenza (0.4% vs. 2.6%; P=0.037) were lower in the oseltamivir group. Adverse events were similar in the groups (67).

  • A randomized trial compared inhaled zanamivir with placebo for influenza outbreak control in 494 residents of long-term care facilities over 3 influenza seasons. Residents were randomly assigned at the start of an outbreak to receive 14 days of either zanamivir or placebo. Rates of the primary outcome of symptomatic, laboratory-confirmed influenza were not significantly lower in the zanamivir group (6% vs. 9%; P=0.355). Rates of secondary outcomes were marginally lower in the zanamivir group, including symptomatic influenza confirmed by culture (2% vs. 6%, p=0.052) and laboratory-confirmed influenza with fever (2% vs. 6%; P=0.043) (68).

  • A randomized trial compared inhaled zanamivir with oral rimantadine for influenza A outbreak control in residents of long-term care facilities. Residents were randomly assigned at the start of an outbreak and were treated for 14 days. Symptomatic, laboratory-confirmed influenza (the primary outcome) was less common in patients who received zanamivir (3% v. 8%; P=0.038) (69).

  • An observational study of influenza outbreaks in long-term care facilities in Ontario included 11 outbreaks in the 1999-2000 season. Prophylactic medications included oseltamivir and amantadine, and protocols differed across facilities. Oseltamivir was associated with termination of outbreaks (in the 8 that could be evaluated) (70).

Rationale
  • Despite high vaccination levels, outbreaks of influenza occur in nursing homes and long-term care facilities and occasionally in acute care facilities, all of which are unusual settings of high-intensity virus exposure in a closed environment with a high-risk population; therefore, every effort should be made to stop virus transmission.

  • Use of antiviral agents even in previously vaccinated residents is recommended because of concern that elderly and chronically ill patients may not generate optimal immunity.

Comments
  • The duration of prophylactic administration depends on the situation: generally 10 to 14 days when combined with late-season immunization, 7 to 10 days for postexposure prophylaxis in households, and at least 1 week after the last case in outbreak control.

  • Other infection control measures, such as limiting visitors, use of droplet precautions, and placing infected patients in cohorts, should also be implemented in the event of an outbreak.

  • Oseltamivir is licensed for use as chemoprophylaxis in persons aged 1 year and older, and zanamivir is licensed for use as chemoprophylaxis in persons aged 5 years and older.

  • LAIV cannot be administered in conjunction with antiviral prophylaxis; however, it generates immunity more rapidly than TIV and, in some circumstances, may be an appropriate vaccine to use in controlling outbreaks (e.g., in a healthy health care worker).

Consider antiviral prophylaxis for high-risk patients or close-contacts of high-risk patients who are exposed to influenza. 
  • Consider short-term antiviral prophylaxis for persons at the onset of community influenza activity if they

    • Received vaccine that has not yet become protective, including

      • Adults and children who were previously vaccinated and who received seasonal vaccine within 2 weeks of an outbreak

      • Children under 9 years who were not previously vaccinated and who received only one dose of vaccine or the second dose within 2 weeks of an outbreak

    • Cannot be adequately vaccinated due to

      • Unavailability of vaccine

      • Intolerance to vaccine

      • Poor expected response to vaccine

  • Offer postexposure prophylaxis in conjunction with TIV if possible.

  • If a patient at high risk for complications of influenza has a known close contact with influenza,

    • Offer short-term prophylaxis to the high-risk patient

    • Offer short-term prophylaxis to other close contacts of the high-risk patient (i.e., other household members)

  • Consider short-term prophylaxis for travelers, especially those with risk conditions, if they are traveling in large groups or to areas with influenza activity.

  • Consider those at high risk to be

    • Children under age 2

    • Adults over age 65

    • Persons with chronic pulmonary disease, including asthma

    • Persons with cardiovascular (excluding hypertension) disease, CKD, hemoglobinopathy, neurologic, or metabolic (including diabetes) diseases

    • Persons with HIV infection or immunosuppression or those receiving immunosuppressive medication

    • Women who are pregnant or who have delivered within the previous 2 weeks

    • Persons with inflammatory conditions requiring chronic aspirin therapy

    • Residents of nursing homes and other chronic care facilities

  • Consider prophylaxis for the duration of the season for health care workers who have direct patient care responsibilities and who have been unable to obtain vaccine or when the prevailing strain does not match the vaccine.

  • Provide postexposure prophylaxis for unimmunized health care workers and other first responders who have had unprotected, close contact with suspected or confirmed influenza.

  • Seek information from the CDC and local health department on currently circulating influenza strains to determine the best choice of antiviral agent (or combination) for prophylaxis in the community; the CDC provides periodic updates to guide antiviral therapy and weekly surveillance reports that include the geography of prevailing strains.

  • See table Drug Treatment for Influenza.

Evidence
  • A 2009 guideline from the Infectious Diseases Society of America recommended antiviral prophylaxis in high-risk patients with insufficient vaccination and in close contacts of high-risk exposed patients (63).

  • A 2012 Cochrane review of neuraminidase inhibitors for influenza prophylaxis and treatment in healthy adults and children included 15 studies of oseltamivir and 10 of zanamivir; most studies were of adults and all were industry funded. There was little evidence about prophylaxis, but oseltamivir shortened the duration of influenza symptoms by 21 hours (CI, 12.9 to 29.5 hours) and did not decrease hospitalizations (OR, 0.95 [CI, 0.57 to 1.61]). Zanamivir did not show similar benefit (71; 72).

  • A 2012 Cochrane review of neuraminidase inhibitors for influenza prophylaxis and treatment in children included three prophylaxis trials with 863 participants exposed to influenza. Prophylaxis with either zanamivir or oseltamivir was associated with an 8% absolute reduction in the risk for developing influenza (NNT, 12) after the introduction of a case into a household (73).

  • A 2009 systematic review of chemoprophylaxis for influenza with neuraminidase inhibitors included 7 trials with 7021 participants. Chemoprophylaxis lowered rates of symptomatic influenza (RR, 0.26 [CI, 0.18 to 0.37]) with no overall increase in adverse events (RR, 1.01 [CI, 0.94 to 1.08]). Nausea and vomiting were more common in patients receiving oseltamivir (RR, 1.48 [CI, 1.86 to 2.33]) (65; 66).

  • A randomized trial compared zanamivir with placebo in 3363 adolescents and adults at high risk for complications from influenza. The study drug was begun within 5 days of local influenza activity. Fewer patients receiving zanamivir developed laboratory-confirmed symptomatic influenza (the primary outcome), with an NNT of 100 (P<0.01), and fewer patients receiving zanamivir had complications of influenza, with an NNT of 244 (P=0.042) (74).

  • In a randomized, controlled pilot study among 56 adult health care workers, the incidence of symptomatic laboratory-confirmed influenza was similar for participants in both the seasonal influenza vaccine arm and the arm that received prophylaxis with oseltamivir, 75 mg once daily (17% and 24%, respectively; P=0.71). Twenty-two percent of study subjects developed symptomatic laboratory-confirmed influenza (75).

  • An observational trial described an influenza outbreak in a summer camp. Campers with known influenza were sent home, and all cabin mates of children with infection received antiviral prophylaxis with oseltamivir. In addition, comprehensive hand sanitation and surface decontamination were performed. The subsequent rate of new influenza cases was 1.8% (76).

Rationale
  • Antiviral prophylaxis provides immediate protection (unlike vaccine).

  • Influenza occurs from April through September in the Southern Hemisphere and year-round in the tropics. Vaccine appropriate to the season may not be available in the U.S.

  • Outbreaks may occur when unimmunized travelers mix with others from areas currently experiencing the yearly influenza season.

  • Widespread resistance to some antiviral agents has been reported among circulating strains.

Comments
  • The duration of prophylactic administration depends on the situation: generally 10 to 14 days when combined with late-season immunization, 7 to 10 days for postexposure prophylaxis in households, and 2 weeks or at least 1 week after the last case in outbreak control.

  • LAIV cannot be administered in conjunction with antiviral prophylaxis.

  • A randomized, controlled trial showed that chloroquine did not prevent infection with influenza among 1496 healthy adults (77).

Suspect influenza during periods of local epidemic activity. 
  • Consider the diagnosis of influenza

    • In patients with a compatible clinical illness who present during the months of November to April if cases of laboratory-confirmed illness are occurring in the community

    • Outside of the usual seasonal time frame in recent travelers or their close contacts and in institutional outbreaks of febrile respiratory illness

Evidence
  • A 2009 guideline from the Infectious Diseases Society of America recommended suspecting influenza during influenza season (63).

  • Pandemic disease due to the emergence of a new virus is often characterized by appearance outside of the usual influenza season (78).

Rationale
  • Outbreaks have occurred during summer months in semi-closed nursing-home populations and in groups of travelers, especially in association with influenza A/H3N2 viruses.

Comments
Suspect influenza in adults and children who present with the typical symptoms, particularly the acute onset of fever and cough. 
  • Ask patients about contact with persons with febrile respiratory illness.

  • Ask about the sudden onset of typical symptoms, including

    • Fever

    • Myalgias

    • Malaise

    • Headache

    • Rhinitis

    • Sore throat

    • Cough, usually nonproductive

  • Note that children may additionally present with nausea, vomiting, irritability, or otitis media.

  • Note that the combination of fever and cough of acute onset is most predictive, especially in older patients.

  • Recognize that the clinical presentation of influenza may be more subtle in the elderly, with less fever and myalgia.

  • See table Diagnostic Accuracy of Symptoms of Influenza.

Evidence
  • A 2005 systematic review of the diagnostic accuracy of signs and symptoms of influenza included 6 studies. The absence of fever (LR, 0.40), cough (LR, 0.42), or nasal congestion (LR, 0.49) made influenza moderately less likely. In patients over age 60, the presence of the combination of acute onset of fever and cough was the strongest predictor of influenza, with an LR of 5.4 (79).

  • A 2007 systematic review of the diagnostic accuracy of symptoms of influenza included 6 studies with 7105 participants. There were no symptoms that could reliably rule in or rule out influenza, but the most helpful was the combination of fever and cough of acute onset, which had a positive LR of 5.4 in patients aged 60 or older (80).

  • A retrospective study evaluated the diagnostic accuracy of symptoms of influenza in 3744 participants in clinical trials of antiviral medication, using laboratory confirmation as the diagnostic reference standard. The most sensitive symptoms were cough (sensitivity, 93%) and fever (sensitivity, 68%); the most specific symptoms were fever and cough of acute onset (specificity, 81%) and fever, cough, and nasal congestion (specificity, 74%) (81).

  • In a prospective sample of 128 children who were suspected of having influenza infection based on predetermined criteria, the triad of cough, headache, and pharyngitis had a sensitivity of 80% (CI, 69% to 91%), a specificity of 78% (CI, 67% to 89%), and an LR for a positive viral culture for influenza of 3.7 (CI, 2.3 to 6.3) (82).

  • In a prospective, observational study of 420 patients with suspected RSV illness, 197 of 251 were tested for RSV and influenza A. One hundred twenty-four (63%) were positive for RSV, and 33 (17%) were positive for influenza A. Patients with influenza A were more likely to have temperatures ≥39°C (101.2°F) than were patients with RSV (36% vs. 15%; P=0.01). Patients with RSV were more tachypneic (54 vs. 43 breaths/min; P<0.0001) and more often had wheezing (90% vs. 8%; P<0.0001) (83).

  • In a retrospective study of 15,420 Finnish children, 683 nasal aspirates were positive for influenza A or B antigen. High fever, cough, and rhinorrhea were the most frequently recorded symptoms. Acute otitis media developed in 24% of the children, and pneumonia developed in 9% of the children (84).

  • A prospective study of 789 U.S. military family members aged 3 to 80 years and presenting for care with influenza-like illness from November 2007 to April 2008 found that the independent predictors of laboratory-confirmed influenza included fever, cough, acute onset, body aches, and vaccination status among 6- to 49-year-olds; only vaccination among 3- to 5-year-olds; and only fever among 50- to 80-year-olds. However, no combination of clinical and demographic predictors had a sensitivity over 60% (85).

Rationale
  • Determining the presence of fever and cough can help differentiate influenza from other viral respiratory illnesses.

  • Virus is spread from person to person through large-particle respiratory droplets, and the incubation period is short (average, 2 days; range, 1 to 4 days).

Use specific diagnostic tests in patients with suspected influenza when there is diagnostic uncertainty, to investigate outbreaks, or to make decisions about treatment, beginning with PCR or a rapid test depending on the situation. 
  • Obtain nasopharyngeal swabs, aspirates, or washings for diagnostic testing in persons with atypical presentation or to monitor influenza in the community.

    • Consider using rapid diagnostic tests, but be aware that sensitivity is low so there may be many false-negative results

    • Note that PCR testing is more sensitive than immunofluorescence testin

  • Consider viral culture if it is outside of influenza season or to determine strain characteristics.

  • See table Accuracy of Diagnostic Tests for Influenza.

  • See the CDC's information on rapid diagnostic testing.

Evidence
  • A 2009 guideline from the Infectious Diseases Society of America recommended that diagnostic testing be tailored to the specific situation, but generally recommended PCR as the first-line test and suggested considering further testing to confirm negative rapid test results (63).

  • A 2012 meta-analysis of 159 studies evaluating the accuracy of 26 rapid influenza diagnostic tests with a reference standard of either reverse transcriptase PCR (first choice) or viral culture in adults and children with influenza-like illness showed that the pooled sensitivity and specificity were 62.3% (CI, 57.9% to 66.6%) and 98.2% (CI, 97.5% to 98.7%), respectively. The positive and negative LRs were 34.5 (CI, 23.8 to 45.2) and 0.38 (CI, 0.34 to 0.43), respectively. Sensitivity of rapid influenza diagnostic tests was higher in children than in adults (66.6% vs. 53.9%, respectively) and for influenza A than for influenza B (64.6% vs. 52.2%, respectively) (86).

  • A 2003 systematic review of studies of the accuracy of diagnostic tests for influenza in children found that direct immunofluorescence tests had moderate (57% to 74%) sensitivity and good (97% to 100%) specificity (87).

  • A prospective study determined the sensitivity of tests for influenza in hospitalized patients. Cytospin-enhanced direct immunofluorescence had a sensitivity of 96.2% and reverse transcriptase PCR had a sensitivity of 100% (88).

  • In a prospective study of 222 children with respiratory tract infections, a panviral DNA microarray platform (Virochip) was superior in performance to conventional direct fluorescent antibody testing and similar to virus-specific PCR (sensitivity, 85% to 90%; specificity, ≥99%; positive predictive value, 94% to 96%; negative predictive value, 97% to 98%) in the detection of RSV, influenza A, and rhinoviruses or enteroviruses (89).

Rationale
  • Rapid tests are helpful for individual patients when the results contribute to diagnostic and treatment decisions.

  • Knowledge of local influenza activity improves clinical diagnostic accuracy.

  • Tests to detect influenza add cost to care and currently do not have sufficient sensitivity and, in some cases, specificity for routine management of individual adult outpatients. However, the results can be useful to recognize an outbreak and to guide care in complicated cases.

Comments
  • Viral culture has increasingly been replaced by molecular assays as the modality of choice for influenza diagnosis in most clinical laboratories; however, it is required for antiviral susceptibility testing and vaccine preparation.

  • The sensitivity of current rapid diagnostic tests is generally higher with nasal and sputum samples than with throat samples, and higher during the first few days of illness; therefore, samples should be collected in the first 4 days of illness (86).

  • Some rapid tests detect both influenza A and B viruses, but a few detect only one. None of the commercially available rapid tests distinguishes between different subtypes of influenza A.

Consider the possibility of complications in patients who remain ill, worsen, or have acute onset of high fever and malaise. 
  • In persons whose condition deteriorates rapidly, consider the possibility of bacterial infection (e.g., meningococcal disease, bacterial pneumonia), institute appropriate work-up, and administer empiric antibacterial antibiotics.

  • In persons who remain febrile for more than 3 to 5 days or develop new fever, consider diagnostic work-up to exclude secondary bacterial complications (such as sinusitis, bronchitis, or pneumonia).

  • See module Meningococcal Disease.

  • See module Community Acquired Pneumonia.

  • See table Differential Diagnosis of Influenza.

Evidence
  • In a retrospective and prospective cohort study conducted in 35 U.S. adult intensive care units over the course of 1 year, 207 of 683 (30.3%) critically ill adults with confirmed or probable 2009 influenza A had bacterial coinfection (with Staphylococcus aureus and Streptococcus pneumoniae) within 72 hours of admission (90).

  • A prospective, observational, multicenter study conducted in 148 Spanish intensive care units found that of the women of reproductive age who were admitted to intensive care, more than 20% were pregnant, and pregnancy was significantly associated with primary viral pneumonia (91).

  • In active surveillance of severe influenza cases in pediatric intensive care units in all German pediatric hospitals during the prepandemic seasons 2005 to 2008, the most frequent diagnoses were influenza-associated pneumonia (60%), bronchitis/bronchiolitis (30%), encephalitis/encephalopathy (25%), secondary bacterial pneumonia (25%), and acute respiratory distress syndrome (25%) (92).

Rationale
  • Although rare, some serious, systemic bacterial infections may present initially with influenza-like symptoms.

  • Fever in adults generally lasts about 3 days, by which time most adults should be clearly recovering; however, symptoms, such as cough, malaise, and asthenia, may persist for 7 to 14 days even in uncomplicated disease.

Comments
  • Rare presentations of influenza include encephalopathy, transverse myelitis, myocarditis, and pericarditis.

Obtain consultation from an appropriate subspecialist in patients with a clinically severe influenza-like illness. 
  • Consider consultation for help in making the diagnosis in patients with

    • Severe enough illness to require hospitalization in whom the diagnosis of influenza is in doubt

    • Documented influenza who are not responding to therapy

Evidence
  • Consensus.

Rationale
  • Patients with illness serious enough to require hospitalization may have an alternative diagnosis, bacterial complications, severe exacerbation of an underlying condition, or a resistant strain of influenza.

  • Because the approach to treatment of patients with viral and bacterial diseases is radically different, accurate diagnosis is obviously critical, particularly in severely ill subjects.

  • Management of hypoxemia and bronchospasm may require intensive care unit support and monitoring.

Obtain consultation from public health authorities for suspected cases of avian influenza or other new strains. 
  • Obtain consultation if a laboratory identifies a viral isolate as avian strain.

  • Obtain consultation when the history indicates epidemiologic exposure to a proven case of avian influenza or exposure in a geographic area with known cases.

  • Consider consultation if new resistance patterns appear to be emerging.

Evidence
  • The CDC provides information on avian influenza and on other emerging strains of epidemic or pandemic potential.

Rationale
  • Public health authorities carefully monitor outbreaks of avian influenza to determine the source of the outbreak, the mechanism of transmission, and the occurrence of human-to-human transmission, which is reported rarely. This information guides determination of the need for controls.

  • Public health authorities conduct surveillance of circulating influenza strains to detect the emergence of new strains and new resistance patterns.

Obtain infectious disease and/or pulmonary consultation in complicated cases of influenza. 
  • Obtain infectious disease consultation for guidance on the use of antiviral agents and potential need for antibacterial antibiotics in patients with complicated influenza.

  • Consider consulting an infectious disease specialist for help in selecting appropriate antiviral agents if multiple resistant strains are circulating.

  • Obtain pulmonary consultation for help in managing severe pneumonia and respiratory insufficiency or bronchospasm, especially when intensive care and mechanical ventilatory support are needed.

Evidence
  • Consensus.

Rationale
  • There are currently no data showing efficacy of specific antiviral therapy in patients hospitalized with influenza; the decision to initiate antiviral therapy should be made by an expert.

  • Progression of viral pneumonia, particularly in persons with significant underlying cardiopulmonary disease, can be rapid.

  • Therapy of patients on mechanical ventilatory support can be especially difficult, because there are no available intravenous formulations of anti-influenza drugs. Nebulized zanamivir and oral liquid formulations of oseltamivir can be considered in these cases.

Obtain infectious disease and/or pulmonary consultation for patients suspected of having avian influenza; consultation with public health officials at the outset is critical. 
  • Obtain infectious disease consultation for decisions on antiviral management and isolation.

  • Obtain pulmonary consultation for respiratory insufficiency or bronchospasm, especially when intensive care and mechanical ventilatory support are needed.

Evidence
Rationale
  • Data on susceptibility and clinical efficacy are limited. Experts should guide the decision to use antiviral therapy and selection of appropriate treatment.

  • Public health authorities monitor outbreaks of avian influenza closely, assessing the source; the need for controls, including killing of poultry flocks; and the occurrence of human-to-human transmission.

Consider hospitalization in severely ill patients with influenza and/or its complications. 
  • Consider hospitalization for the following clinical situations in patients with

    • Significant dehydration and inadequate fluid intake

    • Respiratory distress (dyspnea, wheezing) or significant hypoxia (e.g., O2 saturation <90%)

    • An uncertain clinical course, in which close observation is important

    • Underlying medical conditions, including diabetes, obesity, heart and lung diseases, and pregnancy

  • Recognize that pregnant women and those who have delivered recently have substantial risk for complications and death; close vigilance is required.

Evidence
  • Consensus.

Rationale
  • There are no consensus criteria for hospitalization that are specific for influenza, but common sense should prevail.

Comments
  • A 2004 study evaluated rates of hospitalization for influenza across several seasons. People aged 85 and older had the highest rates of hospitalization for influenza (93).

Institute antiviral therapy in hospitalized patients with influenza and in patients at risk for severe disease who present within 48 hours of symptom onset.  
  • Institute antiviral therapy in patients at high risk for complications if they present within 48 hours of the onset of symptoms.

  • Consider instituting antiviral therapy in patients at risk for severe disease or complications, even if presentation occurs after 48 hours of illness, especially if no improvement is seen or if the novel H1N1 strain is suspected to be the etiologic virus.

  • Select a drug based on seasonal and local resistance patterns.

    • Treat influenza A with oseltamivir, zanamivir, or an adamantine, depending on the specific strain

    • In general, treat influenza B with oseltamivir or zanamivir

  • Consider those at high risk to be

    • Children under age 2

    • Adults over age 65

    • Persons with chronic pulmonary disease, including asthma

    • Persons with cardiovascular disease (excluding hypertension), CKD, hemoglobinopathy, or neurologic or metabolic (including diabetes) diseases

    • Women who are pregnant or who have delivered within the previous 2 weeks

    • Patients with HIV infection or other immunosuppression

    • Persons receiving chronic aspirin therapy for an inflammatory condition

    • Residents of nursing homes and other chronic care facilities

  • See information on selecting an antiviral regimen.

Evidence
  • A 2009 guideline from the Infectious Diseases Society of America recommended that patients with influenza who have had symptoms for less than 48 hours be treated with antiviral medication if they are at high risk for complications (including those who are hospitalized), are in close contact with patients at high risk for complications, or wish to shorten the duration of their illness. In addition, the guideline recommended treatment in patients with symptoms for more than 48 hours who are at high risk for complications and whose symptoms are not improving (63).

  • A 2014 Cochrane review of neuraminidase inhibitors for the prevention and treatment of influenza in healthy children and adults included 107 studies, many of which were at high risk for bias. In adults, oseltamivir (difference, 16.8 hours [CI, 8.4 to 25.1 hours]) and zanamivir (difference, 0.60 days [CI, 0.39 to 0.81 days]) resulted in faster symptom relief. Oseltamivir did not prevent hospitalization compared with placebo. Oseltamivir treatment reduced self-reported pneumonia (rate difference 1.00% [CI, 0.22% to 1.49%]) but did not reduce rates of verified pneumonia; zanamivir treatment did not reduce pneumonia but prophylaxis reduced self-reported pneumonia (rate difference, 0.32% [CI, 0.09% to 0.41%]). Benefits were generally less in children. Oseltamivir reduced diarrhea (rate difference, 2.33% [CI, 0.14% to 3.81%]) and cardiac events (rate difference, 0.68% [CI, 0.4% to 1.0%]) compared to placebo. Prophylaxis with oseltamivir and zanamivir decreased rates of symptomatic influenza, with rate difference of 3.05% (CI, 1.83% to 3.88%) for oseltamivir in individuals and 13.6% (CI, 9.52% to 15.47%) in households, and 1.98% (CI, 0.98% to 2.54%) for zanamivir in individuals and 14.84% (CI, 12.18% to 16.55%) in households. Oseltamivir increased rates of headache (risk difference, 3.15% [CI, 0.88% to 5.78%]) and nausea (risk difference, 4.15% [CI, 0.86% to 9.51%]) compared with placebo (64).

  • A 2012 Cochrane review of neuraminidase inhibitors for influenza prophylaxis and treatment in children included 6 treatment trials with 2356 participants with influenza. Oseltamivir reduced the duration of illness by 36 hours (P<0.001) and reduced otitis media in children aged 1 to 5 years. In children with influenza A/H1N1 resistant to oseltamivir, laninamivir reduced the duration of illness by 2.8 days (P<0.001). Zanamivir reduced the duration of illness by 1.3 days (P<0.001) (73).

  • A 2012 systematic review and meta-analysis of antivirals for influenza included 74 observational studies. In studies of high-risk populations that adjusted for confounders, oral oseltamivir reduced symptom duration (33 hours; CI, 21 to 45 hours), hospitalization (OR, 0.75 [CI, 0.66 to 0.89]), and mortality (OR, 0.23 [CI, 0.13 to 0.43]). Inhaled zanamivir reduced symptom duration (23 hours; CI, 17 to 28 hours) but had side effects. A single study of oral amantadine found possible reductions in mortality and pneumonia associated with influenza A. No included study evaluated rimantadine (94).

  • A retrospective cohort study of 1257 children with influenza infection admitted to a pediatric intensive care unit during six consecutive winter seasons (2001-2007) showed that treatment with oseltamivir within 24 hours of hospital admission was associated with an 18% reduction in total hospital days but not with in-hospital mortality or readmission rate (95).

  • A prospective cohort study of 538 adults hospitalized with laboratory-confirmed influenza A(H1N1) showed that time from onset of symptoms to oseltamivir administration (+ 1-day increase) was associated with a prolonged duration of fever, prolonged length of stay, and higher mortality (96).

Rationale
  • Treatment is generally well tolerated and, even if started late, may improve outcome in critically ill or high-risk patients.

  • Treatment reduces viral shedding and, therefore, may reduce transmissibility of infection to staff and other patients in the hospital setting.

Comments
  • Oseltamivir and zanamivir are both pregnancy category C drugs, but in 2010 the CDC advised that pregnancy not be considered a contraindication to treatment (37).

  • The standard dose of oseltamivir (75 mg by mouth twice daily) can be used in obese patients with a body mass index ≥40 kg/m2 (97).

  • Reduce dosages of amantadine and oseltamivir in patients with CKD and those over age 65.

Consider use of antiviral agents in adults and children with influenza who present within 48 hours of symptom onset during influenza outbreaks in order to shorten the duration of illness.  
  • Consider treating patients who are not at increased risk for complications with antiviral medications if they present within 48 hours of symptom onset and wish to shorten the duration of illness.

  • Select a drug based on seasonal and local resistance patterns.

    • Treat influenza A with oseltamivir, zanamivir, or an adamantine, depending on the specific strain

    • In general, treat influenza B with oseltamivir or zanamivir

  • Monitor reports of influenza activity from the CDC and from local diagnostic laboratories; the CDC provides periodic updates to guide antiviral therapy and weekly surveillance reports that include the geography of prevailing strains.

  • Consider using diagnostic tests that differentiate between influenza A and B.

  • If there is significant uncertainty regarding the identity and sensitivity pattern of the prevailing local strain or if the patient is severely ill, use zanamivir alone, if tolerated, or a combination of oseltamivir and rimantadine.

  • Do not use a combination of oseltamivir and zanamivir for the treatment of seasonal influenza.

  • See table Drug Treatment for Influenza.

Evidence
  • A 2009 guideline from the Infectious Diseases Society of America recommended that patients with influenza with symptoms for less than 48 hours be treated with antiviral medication if they are at high risk for complications (including those who are hospitalized), are in close contact with patients at high risk for complications, or wish to shorten the duration of their illness. In addition, the guideline recommended treatment in patients with symptoms for more than 48 hours who are at high risk for complications and whose symptoms are not improving (63).

  • A 2014 Cochrane review of neuraminidase inhibitors for the prevention and treatment of influenza in healthy children and adults included 107 studies, many of which were at high risk for bias. In adults, oseltamivir (difference, 16.8 hours [CI, 8.4 to 25.1 hours]) and zanamivir (difference, 0.60 days [CI, 0.39 to 0.81 days]) resulted in faster symptom relief. Oseltamivir did not prevent hospitalization compared with placebo. Oseltamivir treatment reduced self-reported pneumonia (rate difference 1.00% [CI, 0.22% to 1.49%]) but did not reduce rates of verified pneumonia; zanamivir treatment did not reduce pneumonia but prophylaxis reduced self-reported pneumonia (rate difference, 0.32% [CI, 0.09% to 0.41%]). Benefits were generally less in children. Oseltamivir reduced diarrhea (rate difference, 2.33% [CI, 0.14% to 3.81%]) and cardiac events (rate difference, 0.68% [CI, 0.4% to 1.0%]) compared to placebo. Prophylaxis with oseltamivir and zanamivir decreased rates of symptomatic influenza, with rate difference of 3.05% (CI, 1.83% to 3.88%) for oseltamivir in individuals and 13.6% (CI, 9.52% to 15.47%) in households, and 1.98% (CI, 0.98% to 2.54%) for zanamivir in individuals and 14.84% (CI, 12.18% to 16.55%) in households. Oseltamivir increased rates of headache (risk difference, 3.15% [CI, 0.88% to 5.78%]) and nausea (risk difference, 4.15% [CI, 0.86% to 9.51%]) compared with placebo (64).

  • A 2012 Cochrane review of neuraminidase inhibitors for influenza prophylaxis and treatment in children included six treatment trials with 2356 participants with influenza. Oseltamivir reduced the duration of illness by 36 hours (P<0.001) and reduced otitis media in children aged 1 to 5 years. In children with influenza A/H1N1 resistant to oseltamivir, laninamivir reduced the duration of illness by 2.8 days (P<0.001). Zanamivir reduced the duration of illness by 1.3 days (P<0.001) (73).

  • A 2012 systematic review and meta-analysis of antivirals for influenza included 74 observational studies. In studies of high-risk populations that adjusted for confounders, oral oseltamivir reduced symptom duration (33 hours [CI, 21 to 45 hours]), hospitalization (OR, 0.75 [CI, 0.66 to 0.89]), and mortality (OR, 0.23 [CI, 0.13 to 0.43]). Inhaled zanamivir reduced symptom duration (23 hours [CI, 17 to 28 hours]) but had side effects. A single study of oral amantadine found possible reductions in mortality and pneumonia associated with influenza A. No included study evaluated rimantadine (94).

  • In persons with mild to moderate asthma or COPD and acute influenza, inhaled zanamivir shortens the duration of illness, reduces ancillary medication use, and is generally well tolerated compared with placebo (98).

  • In a randomized, controlled trial that included 19 patients with oseltamivir-resistant seasonal influenza A (H1N1) infections, early treatment with oseltamivir was associated with faster symptom resolution or reduction and negative viral culture compared with late treatment or placebo (99).

  • A randomized, controlled trial of 300 pediatric patients presenting to three university hospitals with an influenza-like illness (129 had confirmed influenza by reverse transcriptase PCR) showed that early treatment with oseltamivir (within 48 hours of the onset of symptoms) was associated with shorter duration of symptoms and earlier recovery compared with placebo (100).

  • A randomized trial compared oseltamivir with maxingshigan-yinqiaosan (Chinese traditional therapy) and the combination of both with placebo in 410 persons aged 15 to 69 years with laboratory-confirmed H1N1 influenza. Median time to fever resolution was reduced compared with placebo in all groups, but symptom scores did not differ from placebo (101).

  • A randomized, blinded, placebo-controlled trial among 541 adult outpatients presenting with influenza-like illness for less than 36 hours and having a positive influenza A rapid-test diagnosis showed that the oseltamivir-zanamivir combination was less effective than oseltamivir monotherapy and not significantly more effective than zanamivir monotherapy (both virologically and clinically) (102).

Rationale
  • Information about local influenza activity is often available from hospital or health department diagnostic labs.

  • Neuraminidase inhibitor therapy has been shown to reduce respiratory complications and associated antibiotic use and has been associated with rapid recovery from illness and return to work or normal activities.

Comments
  • Oseltamivir and zanamivir may be effective in treating avian influenza. If avian influenza is suspected, the WHO recommends early treatment with oseltamivir and consultation with public health authorities.

  • Postmarketing reports include several cases of delirium and abnormal behavior in patients taking oseltamivir and zanamivir. Postmarketing reports on zanamivir suggest rare cases of bronchospasm, and this drug should be used with caution in patients with known underlying airway disease.

  • Information on local influenza virus isolations may be obtained from a variety of Web sites, including CDC: Seasonal Influenza (Flu), American Lung Association: Influenza, WHO: Global Alert and Response (GAR): Influenza, National Institute of Allergy and Infectious Diseases: Flu (Influenza), and Immunize Canada: Influenza.

  • Recognize that oseltamivir is approved for treatment of influenza A and B in adults and children aged 1 year and older.

  • Note that zanamivir is approved for treatment of influenza A and B in adults and children aged 7 years and older.

  • Note that some clinicians use a higher dose of oseltamivir (150 mg twice daily for adults) in seriously ill or immunosuppressed patients, particularly those with influenza B.

  • Reduce dosages of amantadine and oseltamivir in patients with CKD and those over age 65.

Consider antipyretic therapy in patients with high fever. 
  • Administer acetaminophen or ibuprofen as needed to control fevers causing significant discomfort.

  • Avoid the use of aspirin or aspirin-containing medications in persons with acute respiratory illness.

  • See table Drug Treatment for Influenza.

Evidence
  • Consensus.

Rationale
  • There is no convincing evidence that antipyretic therapy either prolongs or reduces the course of illness, but some patients may derive benefit because the chills and discomfort associated with fever can be relieved.

  • Aspirin use has been linked with the development of Reye's syndrome.

Comments
  • There is no beneficial effect of corticosteroids in patients with influenza pneumonia and acute respiratory distress (103).

Maintain adequate hydration in patients with influenza. 
  • Encourage patients with influenza to drink fluids.

Evidence
  • Consensus.

Rationale
  • Rates of insensible fluid loss are higher in patients with fever.

Monitor patients with influenza for clinical deterioration. 
  • Instruct patients with influenza to contact a health care provider if they experience

    • More than 4 days of fever or recurrent fever

    • Increasing cough or change in character of cough

    • Hemoptysis or purulent sputum

    • Increasing shortness of breath, wheezing, pleuritic chest pain

    • Severe earache

    • Facial pain, purulent nasal discharge

    • New symptoms that were not present initially

Evidence
  • A 2008 narrative review discussed complications of influenza (104).

  • Host factors that increase the likelihood of complications include presence of chronic medical conditions of the cardiopulmonary system and older age (105).

Rationale
  • Influenza complications, such as bacterial pneumonia, sinusitis, or otitis media, may manifest as worsening after an initial period of improvement.

  • Patients who are thought to have influenza but who actually have some other condition will usually deteriorate, while those with influenza will generally improve.

Provide information on measures to prevent the spread of influenza to household members and the community.  
  • Remind patients to use proper respiratory hygiene, which consists of covering coughs and sneezes with a hand or a tissue, discarding the tissue, and washing hands.

  • Suggest a face mask, if it can be tolerated, to help prevent the spread of infection to other household members.

  • Inform patients of the potential for the spread of influenza by contaminated surfaces and the need to wash hands frequently and to avoid touching the mouth, nose, and eyes with unwashed hands.

  • Instruct patients not to return to school or work until afebrile without antipyretics for 24 hours.

Evidence
  • A 2010 Cochrane review of interventions to reduce the spread of respiratory viruses included 60 studies, of which 4 were randomized trials. Randomized trials suggested that hand washing can reduce the spread of viruses. The impact of antiseptics or virucidal agents in addition to usual hand washing was unclear (106).

Rationale
  • Influenza is spread in close contact (6 feet or less), primarily through droplets, but other known routes include surface contamination and aerosol transmission.

Base decisions on follow-up on the age of the patient and the presence of underlying diseases that may require monitoring. 
  • Reevaluate patients with underlying diseases as appropriate for that particular disease.

  • Ensure immunization against influenza in subsequent years according to accepted guidelines.

  • Provide immunization for those in contact with high-risk patients.

  • Ensure pneumococcal vaccination as appropriate.

Evidence
  • Consensus.

  • A 2012 recommendation from the CDC's Advisory Committee on Immunization Practices recommends both 13-valent and 23-valent pneumococcal vaccination in patients with cerebrospinal fluid leaks or cochlear implants and those who are immunocompromised from conditions including hemoglobinopathy, asplenia, immunodeficiencies, HIV infection, CKD, hematologic malignancy, nephrotic syndrome, organ transplantation, and the use of immunosuppressive medication (107).

Rationale
  • Appropriate management of underlying disease and prophylaxis against recurrent influenza will reduce morbidity and mortality.

Table Grahic Jump Location
 Differential Diagnosis of Influenza

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DiseaseCharacteristics
InfluenzaFever, cough, and upper respiratory symptoms, with myalgias and general malaise and fatigue.
Generally occurs during influenza season or after possible exposure
Common coldUpper respiratory symptoms dominated by rhinitis, usually fever absent or mild
Fever is a negative predictor of rhinovirus infection in adults
Streptococcal pharyngitisSore throat with accompanying nasal symptoms is typical of viral pharyngitis. Presence of tender unilateral adenopathy and exudate is typical of streptococcal pharyngitis
Severe sore throat is evidence against influenza
Acute mononucleosisPresence of elevated liver function test results, splenomegaly, and atypical lymphocytes on peripheral smear, positive monospot test
Bacterial pneumoniaClassic association with pleuritic chest pain and productive sputum
Bacterial pneumonia may be concurrent with viral pneumonia or may occur up to 2 weeks after recovery from influenza
Bacterial meningitisIn general, will present with clouded sensorium and prominent headache, but early presentation may be confused with influenza
Patients with influenza should have some improvement within 48 hours. Influenza is associated with increased risk for invasive meningococcal disease
EncephalitisFever, change in mental status, stiff neck, headache
Febrile seizuresGeneralized seizure activity associated with rising body temperatures. Lasts <15 minutes without residual weakness or mental changes
Other diseasesA large list of relatively rare conditions can present with influenza-like symptoms
Inhalational anthrax can present initially with influenza-like illness
Table Grahic Jump Location
 Drug Treatment for Influenza

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Drug or Drug ClassDosingSide EffectsPrecautionsClinical Use
Zanamivir (Relenza)Prophylaxis: 2 oral inhalations (5 mg/inhalation) qd. Duration depends on clinical situation. Treatment: 2 oral inhalations bid for 5 daysHeadache, dizziness, rash, sore throat, diarrhea, nauseaNo data with high-risk underlying medical conditions. Avoid with milk allergy. Caution with asthma, COPDInfluenza A and B
Oseltamivir (Tamiflu)Prophylaxis: 75 mg PO qd. Duration depends on clinical situation. Treatment: 75 mg PO bid for 5 daysNausea, diarrhea, dizzinessNo data with severe hepatic disease, severe CKD. Decrease dose with CrCl 10-30Influenza A and B
Rimantadine (Flumadine)Prophylaxis or treatment: 200 mg PO total daily dose, dosed qd-bid. Decrease to 100 mg qd with elderly. Treat for 5 days. Duration of prophylaxis depends on clinical situationNausea, insomnia, dizziness, anxietyUse 100 mg qd with severe hepatic disease, CrCl 10-30. Caution with seizure disorderInfluenza A; however, resistance has increased significantly. Preferred over amantadine. Combine with oseltamivir when strain is not known
AmantadineProphylaxis or treatment: 200 mg PO total daily dose, dosed qd-bid. Decrease to 100 mg qd with elderly. Treat for 5 days. Duration of prophylaxis depends on clinical situationDizziness, insomnia, confusion, anticholinergic effects, suicidal ideation, hypotension, peripheral edema, nauseaAvoid with untreated closed-angle glaucoma. Caution with hepatic disease, seizure disorder, cardiac disease, psychiatric disorder. Decrease dose with CrCl<50Influenza A; however, resistance has increased significantly. Combine with oseltamivir when strain is not known

bid = twice daily; CKD = chronic kidney disease; CNS = central nervous system; COPD = chronic obstructive pulmonary disease; CrCl = creatinine clearance; GI = gastrointestinal; IM = intramuscular; IV = intravenous; PO = oral; qd = once daily; qid = four times daily; SC = subcutaneous; tid = three times daily

ACP Smart Medicine provides key prescribing information for practitioners but is not intended to be a source of comprehensive drug information.

Table Grahic Jump Location
 Diagnostic Accuracy of Symptoms of Influenza

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SymptomSensitivity (%)Specificity (%)
Fever6860
Cough84-987-29
Myalgias60-946-38
Malaise7326
Headache70-9111-43
Sore throat75-8416-33
History of vaccination2-1282-83
Sneezing33-5059-69
Fever and cough6467
Fever and cough for ≤ 36 hours6368
Fever and cough for > 36 hours5081
Fever, cough, and nasal congestion5974
Fever, cough, and weakness6072
Fever, cough, and myalgias6269
Fever, cough, and poor appetite6168
Fever, cough, and sore throat5671
Fever, cough, and headache6069

Adapted from 81 and 79.

Table Grahic Jump Location
 Accuracy of Diagnostic Tests for Influenza

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TestSensitivity (%)Specificity (%)Notes
Rapid influenza tests6298Results in 10-30 minutes; may vary based on specific test
Direct immunofluorescence antibody test (DFA)96 (adults)
57-62 (children)
98-100 (children)Results in several hours
Indirect immunofluorescence antibody test (IFA)74 (children)97 (children)Results in several hours
Reverse transcriptase PCR100Results in several hours. May be more sensitive than culture
Viral cultureReference standardReference standardNot commonly used clinically. Results in several days

Data from 86; 87; and 88.

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McGeer A. ACP Journal Club. Review: Extended-duration chemoprophylaxis with neuraminidase inhibitors prevents symptomatic influenza. Ann Intern Med. 2010;152:JC3-3. [Full Text] (PMID: 20231557)
 
Peters PH Jr, Gravenstein S, Norwood P, De Bock V, Van Couter A, Gibbens M, et al. Long-term use of oseltamivir for the prophylaxis of influenza in a vaccinated frail older population. J Am Geriatr Soc. 2001;49:1025-31. (PMID: 11555062)
 
Ambrozaitis A, Gravenstein S, van Essen GA, Rubinstein E, Balciuniene L, Stikleryte A, et al. Inhaled zanamivir versus placebo for the prevention of influenza outbreaks in an unvaccinated long-term care population. J Am Med Dir Assoc. 2005;6:367-74. (PMID: 16286057)
 
Gravenstein S, Drinka P, Osterweil D, Schilling M, Krause P, Elliott M, et al. Inhaled zanamivir versus rimantadine for the control of influenza in a highly vaccinated long-term care population. J Am Med Dir Assoc. 2005;6:359-66. (PMID: 16286056)
 
Bowles SK, Lee W, Simor AE, Vearncombe M, Loeb M, Tamblyn S, et al. Use of oseltamivir during influenza outbreaks in Ontario nursing homes, 1999-2000. J Am Geriatr Soc. 2002;50:608-16. (PMID: 11982659)
 
Jefferson T, Jones MA, Doshi P, Del Mar CB, Heneghan CJ, Hama R, et al. Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children. Cochrane Database Syst Rev. 2012;(1):CD008965. (PMID: 22258996)
 
Smieja M. ACP Journal Club. Review: oseltamivir relieves symptoms but does not reduce hospitalizations in influenza. Ann Intern Med. 2012;157:JC3-5. [Full Text] (PMID: 22986397)
 
Wang K, Shun-Shin M, Gill P, Perera R, Harnden A. Neuraminidase inhibitors for preventing and treating influenza in children (published trials only). Cochrane Database Syst Rev. 2012;(4):CD002744. (PMID: 22513907)
 
LaForce C, Man CY, Henderson FW, McElhaney JE, Hampel FC Jr, Bettis R, et al. Efficacy and safety of inhaled zanamivir in the prevention of influenza in community-dwelling, high-risk adult and adolescent subjects: a 28-day, multicenter, randomized, double-blind, placebo-controlled trial. Clin Ther. 2007;29:1579-90; discussion 1577-8. (PMID: 17919541)
 
Coleman BL, Boggild AK, Drews SJ, Li Y, Low DE, McGeer AJ. Respiratory illnesses in Canadian health care workers: a pilot study of influenza vaccine and oseltamivir prophylaxis during the 2007/2008 influenza season. Influenza Other Respi Viruses. 2011;5:404-8. (PMID: 21668681)
 
Kimberlin DW, Escude J, Gantner J, Ott J, Dronet M, Stewart TA, et al. Targeted antiviral prophylaxis with oseltamivir in a summer camp setting. Arch Pediatr Adolesc Med. 2010;164:323-7. (PMID: 20124132)
 
Paton NI, Lee L, Xu Y, Ooi EE, Cheung YB, Archuleta S, et al. Chloroquine for influenza prevention: a randomised, double-blind, placebo controlled trial. Lancet Infect Dis. 2011;11:677-83. (PMID: 21550310)
 
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Call SA, Vollenweider MA, Hornung CA, Simel DL, McKinney WP. Does this patient have influenza? JAMA. 2005;293:987-97. (PMID: 15728170)
 
Eskin B, Levy R. Evidence-based emergency medicine/rational clinical examination abstract. Does this patient have influenza? Ann Emerg Med. 2007;49:103-5. (PMID: 17203543)
 
Monto AS, Gravenstein S, Elliott M, Colopy M, Schweinle J. Clinical signs and symptoms predicting influenza infection. Arch Intern Med. 2000;160:3243-7. (PMID: 11088084)
 
Friedman MJ, Attia MW. Clinical predictors of influenza in children. Arch Pediatr Adolesc Med. 2004;158:391-4. (PMID: 15066881)
 
Friedman MJ, Attia MW. Influenza a in young children with suspected respiratory syncytial virus infection. Acad Emerg Med. 2003;10:1400-3. (PMID: 14644795)
 
Peltola V, Ziegler T, Ruuskanen O. Influenza A and B virus infections in children. Clin Infect Dis. 2003;36:299-305. (PMID: 12539071)
 
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Chartrand C, Leeflang MM, Minion J, Brewer T, Pai M. Accuracy of rapid influenza diagnostic tests: a meta-analysis. Ann Intern Med. 2012;156:500-11. [Full Text] (PMID: 22371850)
 
Uyeki TM. Influenza diagnosis and treatment in children: a review of studies on clinically useful tests and antiviral treatment for influenza. Pediatr Infect Dis J. 2003;22:164-77. (PMID: 12586981)
 
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AIDS

acquired immunodeficiency syndrome

AS03

Adjuvant System 03

bid

twice daily

CD4

cluster designation 4

CDC

Centers for Disease Control and Prevention

CI

confidence interval

CKD

chronic kidney disease

CNS

central nervous system

COPD

chronic obstructive pulmonary disease

CrCl

creatinine clearance

DNA

deoxyribonucleic acid

FDA

Food and Drug Administration

FLUCAD

Influenza Vaccination in Prevention from Acute Coronary Events in Coronary Artery Disease (study)

HIV

human immunodeficiency virus

IgA

immunoglobulin A

LAIV

live, attenuated influenza vaccine

LR

likelihood ratio

NNT

number needed to treat

OR

odds ratio

PCR

polymerase chain reaction

po

oral

qd

once daily

RR

relative risk

RSV

respiratory syncytial virus

SLE

systemic lupus erythematosus

TIV

trivalent inactivated influenza vaccine

WHO

World Health Organization


Guidelines

Immunization and the prevention of influenza and pneumococcal disease in people with diabetes

Recommendations of the Advisory Committee on Immunization Practices (ACIP): Influenza Prevention and Control Recommendations

Influenza and pneumococcal vaccination coverage among persons aged ≥65 years—United States, 2004-2005

Adult immunization schedules—United State

Seasonal Influenza in Adults and Children—Diagnosis, Treatment, Chemoprophylaxis, and Institutional Outbreak Management: Clinical Practice Guidelines of the Infectious Diseases Society of America

Systematic Reviews

Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children

Evidence-based emergency medicine/rational clinical examination abstract. Does this patient have influenza?

Accuracy of rapid influenza diagnostic tests: a meta-analysis

Antivirals for treatment of influenza: a systematic review and meta-analysis of observational studies

Meta-analysis: convalescent blood products for Spanish influenza pneumonia: a future H5N1 treatment?

Systematic review: safety and efficacy of extended-duration antiviral chemoprophylaxis against pandemic and seasonal influenza

Neuraminidase inhibitors for treatment and prophylaxis of influenza in children: systematic review and meta-analysis of randomised controlled trials

Influenza vaccination in children being treated with chemotherapy for cancer (Cochrane review)

Influenza vaccination for healthcare workers who work with the elderly (Cochrane review)

Neuraminidase inhibitors for preventing and treating influenza in children (published trials only) (Cochrane review)

Vaccines for preventing influenza in the elderly (Cochrane review)

Vaccines for preventing influenza in healthy children (Cochrane review)

Vaccines for preventing influenza in people with asthma (Cochrane Review)

Amantadine and rimantadine for influenza A in adults (Cochrane Review)

Vaccines for preventing influenza in healthy adults (Cochrane Review)

Vaccines for preventing influenza in people with cystic fibrosis (Cochrane Review)

Influenza vaccine for patients with chronic obstructive pulmonary disease (Cochrane Review)

Neuraminidase inhibitors for preventing and treating influenza in healthy adults (Cochrane Review)

Does this patient have influenza?

Influenza vaccination for immunocompromised patients: systematic review and meta-analysis by etiology

Efficacy and effectiveness of influenza vaccines: a systematic review and meta-analysis

Assessment of the efficacy and effectiveness of influenza vaccines in healthy children: systematic review

Efficacy and effectiveness of influenza vaccines in elderly people: a systematic review

Influenza diagnosis and treatment in children: a review of studies on clinically useful tests and antiviral treatment for influenza

A systematic review of the evidence on the effectiveness and risks of inactivated influenza vaccines in different target groups

FDA Drug Safety Communication: Important safety changes to the influenza drug Tamiflu (oseltamivir phosphate) for oral suspension

FDA Safety Alert for Tamiflu (oseltamivir phosphate) for Oral Suspension: Label Change-New Concentration (6 mg/mL)

Guidance for clinicians on the use of rapid influenza diagnostic tests for the 2010-2011 influenza season

Seasonal Influenza A (H3N3) Virus Infections

FDA Safety Alert for Afluria (CSL Ltd.) Influenza Virus Vaccine: Label Change - Risk of Fever and Febrile Seizure

FDA Safety Alert for Tamiflu: Counterfeit Product Sold on Internet

FDA MedWatch Safety Alert for Relenza (zanamivir) Inhalation Powder

FDA MedWatch Safety Alert for Tamiflu (oseltamivir) for Oral Suspension: Potential Medication Errors

ACP advises public to get seasonal flu vaccine

CDC advisory committee recommends an influenza vaccine option for persons with egg allergy

CDC: Interim Guidance on the Use of Antiviral Agents for Treatment of Human Infections with Avian Influenza A (H7N9)

FDA approves vaccines for the 2012-2013 influenza season

Antiviral Agents for the Treatment and Chemoprophylaxis of Influenza. Recommendations of the Advisory Committee on Immunization Practices (ACIP)

New HCPCS Q-codes for 2010-2011 Seasonal Influenza Vaccines

FDA Approves Vaccines for the 2010-2011 Influenza Season

CDC's Advisory Committee on Immunization Practices (ACIP) recommends universal annual influenza vaccination

Recommended viruses for influenza vaccines for use in the 2010-2011 northern hemisphere influenza season

FDA approves a high dose seasonal influenza vaccine specifically intended for people ages 65 and older

Non-safety-related voluntary recall of certain lots of Sanofi Pasteur H1N1 pediatric (0.25 mL, for 6-35 month olds) vaccine in pre-filled syringes questions and answers

Despite Early Uptake, Seasonal Flu Vaccination Rates are Similar to Last Year

CDC: Deaths Related to 2009 Pandemic Influenza A (H1N1) Among American Indian/Alaska Natives—12 States, 2009

CDC: Updated Interim Recommendations for the Use of Antiviral Medications in the Treatment and Prevention of Influenza for the 2009-2010 Season

New England Journal of Medicine: When to Consider the Use of Antibiotics in the Treatment of 2009 H1N1 Influenza-Associated Pneumonia

FDA Authorizes Emergency Use of Intravenous Antiviral Peramivir for 2009 H1N1 Influenza for Certain Patients, Settings

WHO Pandemic (H1N1) 2009 briefing note 13: Clinical features of severe cases of pandemic influenza

FDA Approves Vaccines for 2009 H1N1 Influenza Virus

ACP News: H1N1 Swine Flu Update

Updated Interim Recommendations for the Use of Antiviral Medications in the Treatment and Prevention of Influenza for the 2009-2010 Season

The CDC has published provisional guidelines for use of the H1N1 vaccine when it becomes available.

CDC Advisors Make Recommendations for Use of Vaccine Against Novel H1N1

FDA Approves Vaccine for 2009-2010 Seasonal Influenza

ACP Foundation HEALTH TiPS: Flu

American Lung Association: Influenza

Immunize Canada: Influenza (seasonal)

Centers for Disease Control and Prevention: What You Should Know about Flu Antiviral Drugs

Centers for Disease Control and Prevention: Children, the Flu, and the Flu Vaccine

Centers for Disease Control and Prevention: Cover Your Cough

Centers for Disease Control and Prevention: Key Facts About Influenza (Flu) and Flu Vaccine

Centers for Disease Control and Prevention: Flu Symptoms and Severity

Centers for Disease Control and Prevention: The Nasal-Spray Flu Vaccine (Live Attenuated Influenza Vaccine [LAIV]): Questions & Answers

Centers for Disease Control and Prevention: Seasonal Influenza: Flu Basics

Centers for Disease Control and Prevention: CDC Says “Take 3” Actions to Fight the Flu

National Institute on Aging: Flu—Get the Shot

National Institute of Allergy and Infectious Diseases: Flu (Influenza): Understanding Flu

National Institute of Allergy and Infectious Diseases: Is It a Cold or the Flu?

Nemours Foundation: Kidshealth: The Flu

World Health Organization: Health Topics: Influenza

ACP Foundation HEALTH TiPS: Flu (Spanish)

Immunize Canada: Influenza (seasonal) (French)

Public Health Agency of Canada: FluWatch

Centers for Disease Control and Prevention: Cover Your Cough in Chinese

Centers for Disease Control and Prevention: CDC Flu Resources in Spanish

Centers for Disease Control and Prevention: Cover Your Cough in Tagalog

Centers for Disease Control and Prevention: Cover Your Cough in Vietnamese

National Institute of Allergy and Infectious Diseases: Is It a Cold or the Flu? (Spanish)

DOI: 10.7326/d193
The information included herein should never be used as a substitute for clinical judgment and does not represent an official position of ACP.
Disclosures:
John Treanor, MD University of Rochester Medical Center
Rochester, NY
received grants from Protein Sciences Corporation, Merck, GlaxoSmithKline, has pending grant through EpiVax.
Fred Hayden, MD has no financial relationships with pharmaceutical companies, biomedical device manufacturers, or health-care related organizations. Margaret Trexler Hessen, MD, FACP has no financial relationships with pharmaceutical companies, biomedical device manufacturers, or health-care related organizations. Mazen Bader, MD has no financial relationships with pharmaceutical companies, biomedical device manufacturers, or health-care related organizations.
Deborah Korenstein, MD, FACP, Editor in Chief, ACP Smart Medicine, has no relationships with any entity producing, marketing, re-selling, or distributing health care goods or services consumed by, or used on, patients. Richard B. Lynn, MD, FACP, Editor, ACP Smart Medicine, has no relationships with any entity producing, marketing, re-selling, or distributing health care goods or services consumed by, or used on, patients.
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