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Influenza

Essential Evidence


Authors:
Mark H. Ebell, MD, MS, Professor, College of Public Health, University of Georgia

Editors:
Randall Forsch, MD, MPH, Assistant Professor, University of Michigan
Mark H. Ebell, MD, MS, Professor, College of Public Health, University of Georgia
Kenny Lin, MD, MPH, Professor of Family Medicine, Georgetown University

Last updated: 2022-06-24 © 2022 John Wiley & Sons, Inc.

Overall Bottom Line

  • Yearly influenza vaccination is recommended by ACIP (US) for persons over the age of 6 months. A
  • Patients classically present with rapid onset of fever, cough, chills or rigors, sore throat, and myalgias. A clinical decision rule can be used to identify patients at low, moderate or high risk of influenza. B
  • Rapid antigen tests are most useful during the beginning and end of the flu season. C
  • Treatment is largely supportive; antiviral medications are recommended only if the likelihood of influenza is high and the patient presents within 24 hours of symptom onset. There is no evidence that they reduce serious complications or hospitalization. A
  • Predictors of adverse outcome in the elderly include increased age, previous hospitalization, comorbidities, gender, and number of outpatient visits in the previous year (Table 1). A

Background

Influenza is an acute lower respiratory tract infection with systemic manifestations caused by influenza virus and occurring most frequently in epidemics during the winter months.

Incidence

  • Onset of the flu season varies but typically begins at about week 40 of the year in the northern hemisphere (early October) and peaks in January. 45

Other Impact

  • Pneumonia and influenza typically cause between 6% and 8% of deaths in the United States but may exceed that during epidemic conditions. 45

Causes of the Condition

  • Influenza A (typically 70%-98%).
  • Influenza B (typically 2%-30%).
  • Balance between influenza A and B varies from year to year. During 2006/2007 season, 79% were influenza A and 21% were influenza B. 45

Pathophysiology

  • Influenza is caused by single-stranded RNA viruses of the family Orthomyxoviridae.
  • Hemagglutinin and neuraminidase are surface proteins important in diagnosis and treatment. The subtype is used to describe the virus, that is, H5N1 (avian flu) is hemagglutinin 5 and neuraminidase 1. The so-called "swine flu" is H1N1. Avian flu is discussed in more detail in a separate chapter.
  • Influenza A typically causes a more severe clinical illness than influenza B.
  • Persons are infectious from just before the onset of symptoms until 5 to 10 days after the onset of symptoms. Shedding is prolonged in children.

Screening and Prevention

Bottom Line

  • ACIP (United States) recommends influenza vaccination for all persons over the age of 6 months. A424313
  • While zanamivir and oseltamivir prevent flu in close contacts and family members (NNT = 25-36), the cost and concerns about developing resistance argue against routine or widespread use for this indication, particularly in vaccinated individuals. A3637383940

Primary prevention

  • Influenza vaccination is recommended by ACIP (US) for all persons over the age of 6 months.13 A Cochrane review found a 3% absolute risk reduction in the likelihood of influenza symptoms (1% vs. 4%) when there was a good match to the circulating virus, but only a 1% reduction when the match was poor.
  • Vaccination reduced time off work but there is no evidence of an impact on hospitalization or complications.56 Overall, there is good evidence that immunization is cost-effective.84
  • Vaccination is usually recommended for anyone living in a nursing home or chronic care facility and anyone who lives with or cares for patients at high risk of complications.4243 However, it is unclear if offering vaccination to health care workers in long-term care facilities improves outcomes for residents.68
  • Vaccination is recommended by the CDC and ACIP for pregnant women, and is not associated with any subsequent illness in offspring based on a Canadian registry study.82
  • An RCT of 31,989 adults 65 years and older compared a standard dose influenza vaccine (15 mcg hemagglutinin) with a high dose vaccine (60 mcg hemagglutinin) over two flu seasons. Laboratory confirmed influenza was less likely in the high dose group (1.4% vs. 1.9%, p < 0.05, NNT = 220). This small benefit must be balanced against a possibly higher risk of serious adverse events (3 vs. 0) and higher cost.65
  • A trial randomized 9003 healthy adults 50 and older to a recombinant quadrivalent flu vaccine or inactivated quadrivalent flu vaccine. The recombinant vaccine provided a small advantage in terms of preventing flu (NNT = 100) in the study year.75
  • Influenza vaccination of healthy working adults under age 65 years can reduce the rates of febrile illness, lost workdays, and physician visits if there is a good match between the vaccine and the circulating virus.56 However, it does not reduce overall cost to society.35
  • Live attenuated intranasal vaccine is approved for persons aged between 5 and 50 years. Some studies have shown that it may be safe and effective for younger children.323334 However, it is not currently recommended due to evidence of poor effectiveness against H1N1 during the 2013-2014 and 2015-2016 influenza seasons.7378
  • Flu vaccine does not prevent asthma flares or acute otitis media in children.3031
  • Although baloxavir,90 zanamivir63 and oseltamivir prevent flu in close contacts and family members (NNT = 25-51), the cost and concerns about developing resistance argue against use for this indication, particularly in vaccinated individuals.3637383940
  • CDC guidelines recommend that persons with egg allergy who have had only hives after exposure to egg should receive the flu vaccine. Recombinant hemagglutinin influenza vaccine is egg-free and is recommended for adults 18 to 49 years. Many persons can safely receive influenza vaccination containing less than 1.2 mcg/ml egg protein, but appropriate precautions should still be taken and it should only be administered in a setting where patients can be observed for at least 30 minutes and emergency systems are in place in the event of a severe reaction.4828 Live attenuated vaccine does contain egg protein. A cohort study in 779 persons age 2 to 18 years with egg allergy in the UK found no systemic reactions (95% CI, 0%-0.47% in all, 0%-1.4% in those with previous anaphylaxis). However, 8.1% experienced lower RTI symptoms, including 29 persons with wheeze.72
  • Statins may impair the immune response to the vaccine, but the clinical implications of this are uncertain.70
  • A vaccine to H7N9 (avian influenza) is under development.71
  • High-Risk Groups
  • A Cochrane review found no benefit of influenza vaccination in persons with cystic fibrosis, but the analysis was limited by a very small sample size (n = 179).57
  • Another Cochrane review of influenza vaccine for patients with hematologic malignancies found a reduction in the likelihood of lower respiratory tract infection and hospitalization with vaccination.59
  • For patients diagnosed with COPD, a Cochrane review found that influenza vaccine reduces the number of exacerbations (WMD −0.37; 95% CI, −0.64 to −0.11).61
  • In children undergoing chemotherapy given the flu vaccine, they are able to generate an immune response (although weaker than in healthy children). Evidence of clinical effectiveness in this population is lacking.83
  • A meta-analysis found that flu vaccine was associated with a lower risk of cardiovascular events in adults with coronary disease, particularly those with a history of acute coronary syndrome within the past 6 months (NNT = 8).53
  • No trials were found in a Cochrane review of influenza vaccine for persons with bronchiectasis.60
  • An RCT in South Africa found that trivalent inactivated influenza vaccine significantly reduced the attack rates of influenza among HIV negative women (1.8% vs. 3.6%), the infants of HIV negative women (1.9% vs. 3.6%), and among HIV infected women (7.0% vs. 17.0%).66 Other Interventions Patient reminder and recall systems improve immunization rates (OR 2.2 for childhood influenza vaccination, 1.7 for adult influenza vaccination). 27 58 Antibacterial household products do not reduce the risk of infectious symptoms.26   Handwashing (especially around young children), isolation and social distancing may be effective at preventing the spread of influenza.46  A Cochrane review identified four studies of interventions to improve hand hygiene in healthcare settings, but only limited evidence of effectiveness.41 A systematic review found no evidence that N95 respirators are more effective than surgical masks at preventing influenza transmission. While N95 masks have theoretical advantages, they are also less comfortable which may impair usage.69 This was confirmed in a subsequent trial in 2862 healthcare personnel (8.2% vs 7.2%) laboratory confirmed flu.86
  • There is no increase in flares when patients with rheumatoid arthritis, lupus, or spondylarthritis are given the flu vaccine.85

Diagnosis

Bottom Line

  • Patients classically present with rapid onset of fever, cough, chills or rigors, sore throat, and myalgias. B6
  • Overall, physician judgment is useful with early but not late onset of symptoms. B
  • Rapid antigen tests are most useful during the shoulder season (beginning and end of the flu season), when the pretest probability of influenza is 5% to 10%. Their accuracy varies, with older tests having approximately 55% sensitivity compared to 80% to 95% for newer molecular tests.77B44

Differential Diagnosis

DiagnosisFeatures
PneumoniaEvidence of consolidation on physical examination and CXR
Pulmonary embolismHypoxia, tachycardia, and pleuritic chest pain common; fever uncommon
Other viral lower respiratory tract infectionsDifficult to distinguish without laboratory investigation
Dengue, chikungunya, and Zika virusProminent myalgias and joint pains; conjunctivitis and rash with Zika

Using the History and Physical

Selecting Diagnostic Tests

  • A systematic review identified 162 studies (130 of rapid influenza diagnostic tests [RIDTs], 19 of digital immunoassays [DIAs], and 13 of rapid nucleic acid amplification tests [NAATs]). The older RIDTs had lower sensitivity (55%) than the newer DIAs (80%) and NAATs (92%); all tests had excellent specificity (98% or higher). This corresponds to very high positive likelihood ratios to rule-in influenza when any test is positive (LR+ 27-46), but varying negative likelihood ratios to rule-out flu when negative (0.46 for RIDT, 0.20 for DIA, and 0.08 for NAAT).77
  • Rapid antigen tests are most useful during the shoulder season (beginning and end of the flu season) when the pretest probability of influenza is 5% to 10%. During flu season, patients with a negative rapid antigen test still have a significant likelihood of flu, so the test is less useful (see Figure 1).44
  • Rapid antigen tests for H1N1 pandemic influenza has been shown to have reasonable sensitivity and specificity.50
  • Confirmatory testing with PCR or culture is generally done only for disease surveillance.
  • A procalcitonin value <0.25 ng/ml (especially if <0.1) makes bacterial infection unlikely and during an influenza epidemic makes influenza correspondingly more likely.24
  • Order CXR to rule out pneumonia in patients with lower respiratory tract findings or significant tachypnea or hypoxia. Two studies with approximately 2000 patients found no evidence that CXR improves clinical outcomes in patients with respiratory infection, though.15
  • Consider pulmonary embolism in any patient with dyspnea, although fever makes it less likely.
  • Consider Dengue fever in areas where the disease is endemic (including southern Florida and the Keys), especially in patients with leukopenia and thrombocytopenia.67 Also consider Chikungunya in Puerto Rico and Central and South America, and Zika Virus infection.

Clinical Decision Rules

  • A "FluScore" decision rule has been developed and internally validated to classify patients at low, moderate, or high risk of influenza. It uses four patient reported symptoms: Fever + cough (2 points), Myalgias (2 points), Chills or sweats (1 point) or Sudden onset (1 point). The risk of influenza was 8% for 0 to 2 point, 30% for 3 points, and 59% for 4 or more points. Two-thirds of patients fell into the low or high risk groups, and required no further testing.51
  • A decision rule has been developed and validated to predict the need for hospitalization and mortality in patients presenting with acute respiratory infection. While not validated in an epidemic, it could be useful in such a setting.2

Approach to the Patient

History and Physical Tests

  • Influenza suspected -> influenza
  • Influenza suspected (pediatric) -> influenza
  • Diagnostic Tests

  • Influenza suspected (all ages) -> influenza
  • Influenza suspected (child) -> influenza
  • Influenza suspected (adult) -> influenza
  • Treatment

    Bottom Line

    • Treatment is largely supportive with analgesics, antipyretics, rest, adequate (but not excessive) hydration, and reevaluation if symptoms worsen. C
    • Antiviral medications (oseltamivir, baloxavir, or zanamivir) are recommended only if the probability of influenza is high (see Figure 1) and patients present within 24 or at most 36 hours of symptoms onset. It is also recommended for pregnant patients and for hospitalized patients.80A192021222388
    • Oseltamivir has not been shown in RCTs to reduce the likelihood of hospitalization or the likelihood of complications requiring antibiotics.64 Studies in patients with cardiopulmonary disease or in patients over age 65 years did not find a signficant reduction in the duration of symptoms. A52

    Drug Therapy

    • When given within 24 hours of the onset of symptoms, antiviral agents such as oseltamivir or zanamivir reduce the duration of symptoms by about 30 hours and may reduce the intensity somewhat. 27 63 64 When given at 24 to 36 hours, it reduces duration by 14 hours. The overall reduction in the ITT population was 21 hours.18202252  A Cochrane review using ITT data also found a 21 hour reduction in symptoms.54
    • There is no evidence from RCTs that oseltamivir reduces the likelihood of hospitalization5452 or the likelihood of complications requiring antibiotics, once acute bronchitis is excluded as a complication.52 The likelihood of pneumonia was reduced by 0.9%, but only in patients with PCR or culture confirmed influenza, and not in the intention to treat population. Studies in patients with cardiopulmonary disease or in patients over age 65 years did not find a signficant reduction in the duration of symptoms. Much of these data were initially unpublished and analysis was based on unpublished clinical trial reports.52 The drugs are associated with an increased risk of nausea (NNH = 28) and vomiting (NNH = 22).54
    • 2 RCTs comparing baloxavir with oseltamivir or placebo found a similar reduction in symptoms between oseltamivir and baloxavir compared to placebo (about 20-24 hours), with a greater benefit if given in the first 24 hours (33 hours fewer symptoms) than at 24 to 48 hours (13 hours). This is also similar to oseltamivir. Complications were not reported.8088
    • Usual dosing in adults is oseltamivir 75 mg po twice daily for 5 days, baloxavir 40 mg (< 80 kg) or 80 mg (> 80 kg) in a single dose, or zanamivir 10 mg by MDI bid for 5 days.
    • A study randomized 366 hospitalized patients with severe influenza to baloxavir plus oseltamivir, zanamivir or peramivir, or to oseltamivir, zanamivir, or peramivir alone. There was no difference in time to symptom improvement (97.5 vs 100 hours) or any other outcomes.89
    • A Cochrane review found that amantadine and rimantadine were both effective for the prevention and treatment of influenza symptoms. However, the drugs have significant adverse effects (especially amantadine) and widespread resistance exists.55 They should not be used routinely in practice, based on current CDC recommendations.
    • A Cochrane review identified one RCT and 29 observational studies of corticosteroids for influenza. The RCT was too small to provide useful information. In the observational studies, there was an association with increased mortality but this could represent residual confounding and confounding by indication, as sicker patients and patients with ARDS or other complications were preferentially given corticosteroids.79
    • In hospitalized patients with flu and a pulmonary infiltrate, an RCT found that adding clarithromycin and naproxen reduced 30 day mortality (0.9% vs. 8.2%; p = 0.01; NNT = 14) and 90-day mortality.74
    • A randomized trial randomized 633 patients with influenza who were at inreased risk of complications to either the combination of oseltamivir, amantadine, and ribavrin or to oseltamivir alone. There was some reduction in viral shedding with the combination therapy, but no reduction in influenza symptom severity or duration. There was no difference in adverse events.76

    Complementary/Alternative Therapy

    • Two poor-quality RCTs provide insufficient evidence to recommend "Ganmao" or "E Shu You" Chinese herbal medicines for influenza.17
    • Two poor-quality RCTs found a small benefit to the homeopathic drug oscillococcinum; current evidence is insufficient to recommend this intervention routinely.16

    Other Treatment

    • Treatment generally includes rest, fluids, and antipyretics. "Forcing fluids" is not supported by any clinical studies and may lead to hyponatremia, especially in infants and the elderly.14
    • Supplemental oxygen or mechanical ventilation may be needed for hospitalized patients.

    Management of Complications

    • In a cohort study of 343 Welsh patients with influenza, complications included bronchitis (19%; 95% CI, 15%-23%), pneumonia (2.9%; 95% CI, 1.4%-5.4%), otitis media (2.3%; 95% CI, 1.0%-4.6%).12 See those chapters for management of those conditions.
    • Influenza may also worsen cardiac disease and diabetes mellitus control in affected individuals.11In a U.S. cohort study, up to 12% of adults hospitalized with laboratory-confirmed influenza from 2000 to 2018 experienced acute heart failure or acute coronary syndrome.87

    Prognosis

    Bottom Line

    • In a case-control study of 119 hospitalized patients and 196 matched controls, risk factors for hospitalization included COPD, more than one significant comorbidty, polypharmacy, more than 5 GP consultations in the previous year, and previous hospitalizations in patients aged 18 to 64 years. B11
    • In the same study, risk factors for patients over age 65 years were all of the above plus CHF and minus previous hospitalizations. B11
    • A clinical decision rule was developed in 16,280 patients and validated in over 11,000 patients to predict the likelihood of hospitalization or pneumonia or death from any cause during flu season in community-dwelling elderly (aged 65 years and older). Key factors include age, previous hospitalization, comorbidities, gender, and number of outpatient visits in the previous year (Table 1). A10

    Management of Special Populations

    The Elderly

    • Oseltamivir provided very little benefit as prophylaxis for older patients who had received influenza vaccine.38

    Infants and Children

    • Likelihood of hospitalization for flu was 7 per 10,000 child-years in an urban cohort. A history of cardiac and neuromuscular conditions was an independent predictor for hospitalization. Median age of hospitalization was 1.8 years.9
    • Oseltamivir is approved for children over age 1 year. Dosing is 75 mg bid if >40 kg or 13 years old, 60 mg bid if 23 to 40 kg, 45 mg bid if 15 to 23 kg, and 30 mg bid if ≤5 kg.
    • Zanamivir is approved for children aged 7 years and older is 10 mg by metered-dose inhaler twice daily.
    • Rimantadine is not FDA approved for treatment of influenza in children.

    References and Additional Resources

    References

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    Practice Guidelines

      Influenza

      Tools, Tables, and Images

      Tools

      Tables

      Table 1: Model to Predict Probability of Hospitalization With Pneumonia or Influenza or Death From Any Cause During Flu Season.

      Symptom Score
      Age  
      70-74 years 14
      75-79 years 28
      80-89 years 42
      >89 years 56
      Male 9
      Outpatient visits during the previous year  
      1-6 11
      7-12 22
      >12 33
      Previous hospitalization for pneumonia or influenza 63
      Pulmonary disease 18
      Heart disease 6
      Renal disease or transplant 12
      Dementia or stroke 22
      Cancer 48
      Total  
      Score Probability*
      <40 0.3%
      40 to <60 1.2%
      60 to <100 3.0%
      ≥100 15.4%
      *Hospitalization for pneumonia or influenza, or all-cause mortality during flu season. From Hak E, Wei F, Nordin J, Mullooly J, Poblete S, Nichol KL. Development and validation of a clinical prediction rule for hospitalization due to pneumonia or influenza or death during influenza epidemics among community-dwelling elderly persons. J Infect Dis 2004;189:50-58.10