Influenza

Aka: Influenza

1. See Also
   1. Upper Respiratory Infection
   2. Avian Influenza
2. Epidemiology
   1. Annual Periodicity
      1. Temperate Climate
         1. Onset as early as October
         2. Peaks in late December to March
      2. Tropical Climate: Occurs year round
   2. Attack rate:
      1. Epidemics (antigenic drift): 20-30%
      2. Pandemics (antigenic shift): 50%
   3. Ages affected
      1. Children
         1. Highest attack rate
      2. Elderly (over age 65 years)
         1. Lowest attack rate
         2. Highest risk of complication
            1. Relative risk of hospitalization: 5-10
            2. Relative risk of mortality: 5
         3. Highest mortality (80% of deaths are in elderly)
   4. Incidence (worldwide)
      1. Severe Influenza: 3 to 5 million people annually
      2. Influenza-related deaths: Up to 500,000 annually
3. Course
   1. Incubation: 2-3 days (may be as long as 7 days)
   2. Infectivity (Viral load and shedding correlates with symptom severity)
      1. Begins 1 day prior to symptom onset
      2. Peaks with illness severity
      3. Declines over 4-5 days
      4. Absent after 10 days
   3. Acute symptoms resolve in 4-5 days
   4. Persistent symptoms may not clear for 3 or more weeks
      1. Fatigue or malaise
      2. Persistent non-productive cough
4. Pathophysiology
   1. Classification
      1. Single-stranded DNA virus in the Orthomyxovirus Family
   2. Transmission
      1. Small-large particle aerosol from cough and sneeze
      2. Receptors are primarily in nose (and to lesser extent in the lung)
   3. Vaccines directed at critical viral surface antigens
      1. Surface proteins typically change over successive Influenza generations, rendering prior Vaccines ineffective
         1. See antigenic drift and antigenic shift below
      2. Antigens (Influenza surface proteins)
         1. Hemagglutinin
         2. Neuraminidase
   4. Influenza A hosted in multiple species
      1. Migratory birds (main host)
         1. Typically carry Influenza asymptomatically
         2. Transmit Influenza to other species (especially pigs)
         3. Direct transmission of Avian Influenza to humans is uncommon
            1. Exception: H5N1 Avian flu is contracted by humans in sustained close contact with birds
      2. Horse
      3. Pigs
         1. Key to transmission to humans
         2. Receptors for both human and Avian Influenza
         3. Co-infection with avian and human Influenza can allow exchange of segmented genome components
            1. Allows for antigenic shift in human Influenza
            2. Swine flu (e.g. H3N2) is then transmitted to humans and can lead to pandemic
   5. Antigenic drift
      1. Minor genetic mutations result in epidemics
      2. Influenza A most commonly involved
   6. Antigenic shift
      1. Major genetic changes (surface protein changes) result in pandemic
         1. Typically results from co-infection in pigs (see above)
      2. Major Pandemics
         1. 1918: "Spanish flu" (H1N1) 50 Million deaths worldwide (500,000 in United States)
            1. Young, previously healthy adults were more likely to succumb in this pandemic (likely ARDS related)
         2. 1957: Asian Flu
         3. 1968: Hong Kong flu 34,000 deaths
      3. Recent Antigenic Shifts
         1. 1976: Swine flu isolated
         2. 1997: Hong Kong H5N1 (avian) Influenza
         3. 2009: H1N1 Novel Influenza
            1. Reported April 12, 2009 in Veracruz, Mexico and WHO declared pandemic by April 27, 2009
            2. Chimera of swine flu, avian flu, and human flu
            3. (2009) N Engl J Med 361:674-9
5. Types
   1. Influenza A
      1. Major outbreaks result from antigenic shifts
      2. See Avian Influenza
      3. Re-assortment of genomic expression
         1. Neuraminidase and Hemagglutinin
   2. Influenza B
      1. Less variation than Influenza A
      2. Outbreaks in Schools and Military camps
   3. Influenza C
6. Symptoms
   1. Abrupt illness onset
   2. Viral prodrome (cytokine response leads to primary symptoms)
      1. High fever to 104 F (fever lasts 4-5 days)
      2. Severe myalgias (lasts for first 3 days)
      3. Severe Headache (most severe in first 2 days)
      4. Chills
   3. Eye
      1. Photophobia
      2. Red, Burning eyes
   4. Nose
      1. Coryza or profuse Nasal discharge (lasts 6-7 days)
         1. Often onset with fever and no other symptoms
      2. Rhinitis
      3. Nasal congestion or "stuffiness"
   5. Throat
      1. Sore Throat or dry throat (lasts for first 3 days)
   6. Chest
      1. Severe dry cough (lasts for first 3 days)
      2. Chest discomfort
   7. Other Constitutional symptoms
      1. Anorexia (may persist for first week)
      2. Fatigue persists weeks
      3. Severe Malaise (may persist for more than a week)
   8. Less common symptoms (20-40%)
      1. Nausea or Vomiting
      2. Dizziness
7. Signs
   1. Fever up to 104 F (40 C)
   2. Non-exudative Pharyngitis
   3. Muscle tenderness
   4. Less Common Influenza signs
      1. Conjunctivitis
      2. Cervical adenopathy
8. Diagnosis
   1. Findings most suggestive of Influenza
      1. Sudden onset of classic Influenza symptoms
      2. High fever to 104 F with chills, sweats, rigors
      3. Severe malaise, Fatigue, and anorexia
      4. Severe myalgias
      5. Moderate to severe Headache
      6. Onset of symptoms within 3 days of office visit
   2. Findings most suggestive of other diagnosis
      1. Systemic symptoms absent
      2. Cough absent
      3. Not confined to bed
      4. Able to perform daily activities without difficulty
   3. References
      1. Ebell (2004) J Am Board Fam Pract 17:1-5
9. Differential Diagnosis
   1. Common Cold viruses
      1. Respiratory Syncytial Virus (RSV)
      2. Parainfluenza
      3. Adenovirus
   2. Factors suggesting Common Cold
      1. Findings suggestive of Influenza (see diagnosis above) are absent
      2. Gradual onset of more mild symptoms
      3. Upper respiratory symptoms predominate
10. Complications
    1. Primary Influenza Pneumonia (1% of adults)
       1. Increased risk with cardiac disease (Mitral Stenosis)
       2. Occurs 1 week after Influenza symptom onset
       3. Occasionally fatal even in young adults
    2. Bacterial tracheobronchitis (occurs in 30% of adults)
       1. Increased risk in Tobacco smoking
    3. Acute Sinusitis (5-10%)
    4. Secondary Bacterial Pneumonia
       1. Occurs one week after Influenza symptom onset
       2. Etiologies
          1. Streptococcal Pneumonia
          2. Staphylococcal Pneumonia
          3. Haemophilus Influenzae
       3. Risk factors
          1. Older than 65 years old
          2. Chronic renal disease
          3. Diabetes Mellitus and other endocrine disease
          4. Hematologic disease or Immunodeficiency
          5. Cardiopulmonary disease
    5. Rare Neurologic Complications
       1. Meningoencephalitis
       2. Transverse myelitis
       3. Reye's Syndrome
       4. Guillain-Barre Syndrome
       5. Myositis or Rhabdomyolysis
    6. Other rare complications
       1. Myoglobinuric Renal Failure
       2. Myocarditis
       3. Pericarditis
       4. Glomerulonephritis
       5. Parotitis
11. Labs: Diagnosis
    1. General
       1. Influenza diagnosis should be made clinically (lab testing is only needed in certain groups)
       2. Rapid Influenza Testing has poor Test Sensitivity and does not exclude Influenza if negative
       3. High risk groups should still be treated without delay if high clinical suspicion despite negative testing
    2. Indications for testing
       1. Influenza-like illness in patients or workers in the hospital, Nursing Home or daycare
    3. Initial testing at point of care
       1. Do not rely on Influenza testing to determine management (see above)
       2. Rapid Influenza Test (Influenza Immunoassay)
          1. Sample site varies between products
          2. Test Sensitivity 10-70% (very high false negative rate)
          3. Test Specificity >95%
    4. Confirmatory Testing
       1. Real Time Reverse Transcriptase PCR (RT-PCR) for RNA detection (preferred)
          1. Test Sensitivity: 86 to 100%
          2. Requires 24 hours to run test
          3. If Rapid Influenza Test negative despite high suspicion, consider PCR (especially in Nursing Home)
       2. Influenza Culture (48-72 hours required for isolation)
          1. Nasopharyngeal swab
          2. Throat swab
          3. Sputum
       3. Serology (diagnostic if four fold rise over 10-14 days)
          1. Hemagglutination inhibition
          2. Complement fixation titers
12. Labs: Other
    1. Complete Blood Count
       1. Leukopenia or slight Leukocytosis (up to 15,000)
       2. Relative Lymphopenia
13. Management
    1. Symptomatic treatment
       1. Acetaminophen
       2. Pharyngitis Symptomatic Treatment
       3. Cough Symptomatic Treatment
       4. Consider antiviral agent below if ill <48 hours
          1. Shorten course of illness (~1 day)
          2. No evidence that antivirals prevent complications
    2. Anti-viral agent indications
       1. Treat hospitalized or seriously ill patients with suspected Influenza regardless of time since onset (even >48 hours)
       2. Treat high risk populations who can start treatment within 48 hours
          1. Children under age 2 years old (some guidelines use under age 5 years)
          2. Elderly (over 65 years old)
          3. Chronic medical conditions (e.g. COPD, Asthma)
          4. Immunosuppressed patients
          5. Obese patients with BMI>40
          6. Pregnancy (despite Pregnancy category C due to higher risk of Influenza related morbidity)
    3. Influenza A
       1. Neuraminidase Inhibitors
          1. See Zanamivir (Relenza)
          2. See Oseltamivir (Tamiflu)
       2. Resistance to Adamantanes (Amantadine, Rimantadine) is common (esp. H1N1)
          1. CDC no longer recommends Amantadine or Rimantadine for Influenza management
          2. Consider using Rimantadine 100 mg daily for 5 days for treatment in combination with Neuraminidase Inhibitors in Nursing Home
          3. Due to resistance, not used for chemoprophylaxis or treatment
       3. Course: 5 days or 48 hours after symptoms resolve
    4. Influenza A or B: Neuraminidase Inhibitors
       1. See Zanamivir (Relenza)
       2. See Oseltamivir (Tamiflu)
    5. Avoid Salicylates in patients younger than 16 years
       1. Risk of Reye's Syndrome
14. Management: Hospitalization Indications (findings suggestive of severe case)
    1. Chest Pain
    2. Altered Level of Consciousness
    3. Seizures
    4. Severe weakness
    5. Hemoptysis
    6. Hypoxia, cyanosis, labored breathing or Shortness of Breath
    7. Decreased urine output, Hypotension or dehydration
    8. High fever or progressive worsening after first 72 hours
15. Complications
    1. Staphylococcal Pneumonia
    2. Acute Exacerbation of Chronic Bronchitis (AECB)
    3. Asthma Exacerbation
    4. Acute Respiratory Distress Syndrome (ARDS)
    5. Acute Sinusitis
    6. Acute Bronchitis
    7. Acute Otitis Media
16. Prevention
    1. Influenza Vaccine yearly
       1. Immunize all high risk groups
          1. CDC recommends immunizing everyone over age 6 months (as of 2012)
          2. See Influenza Vaccine for indications
          3. Nursing Home residents and staff
          4. Comorbid illness
          5. Pregnant women after first trimester
       2. Efficacy (depends on Vaccine components)
          1. Healthy younger patients: 70-90%
          2. Elderly: 30-40%
    2. Flumist
       1. Live virus intranasal Vaccine
       2. May be used in healthy patients aged 5 to 49 years
    3. Postexposure prophylaxis in high risk groups
       1. Start within 48 hours of exposure
       2. Nursing Home: Treat for at least 2 weeks and for at least 7 days after the last infected case
       3. Amantadine Or Rimantadine prophylaxis is no longer recommended for Influenza A due to resistance (use Neuraminidase Inhibitors)
       4. Neuraminidase Inhibitors
          1. See Zanamivir (Relenza)
          2. See Oseltamivir (Tamiflu)
    4. Other measures
       1. Respiratory isolate hospitalized Influenza patients
       2. Isolate Nursing Home residents with Influenza to room
       3. Isolate Nursing Home residents on prophylaxis to room
          1. Risk of virus shedding
17. Prevention: Pandemic Preparedness
    1. Federal, State and Local Planning
    2. Influenza Surveillance via WHO worldwide (CDC in US)
       1. Local Vital Statistics offices report deaths weekly
    3. Maximize Vaccine development and delivery
    4. Develop limited antiviral (Amantadine) indications
    5. Emergency medical, hospital and backup preparedness
    6. Ensure communication networks are in place
       1. Internet, Health Alert Network, Telephone
18. Resources
    1. Is it the cold or the flu
       1. http://www.naid.nih.gov/publications/cold/sick.htm
    2. CDC Influenza Surveillance
       1. http://www.cdc.gov/ncidod/diseases/flu/weekly.htm
    3. CDC Influenza Information
       1. http://www.cdc.gov/ncidod/diseases/flu
    4. CDC MMWR - ACIP Guidelines on antivirals in Influenza (2011)
       1. http://www.cdc.gov/mmwr/preview/mmwrhtml/rr6001a1.htm
    5. American Lung Association Influenza Information
       1. http://www.lungusa.org/diseases/luninfluenz.html
    6. National Foundation Infectious Disease on Influenza
       1. http://www.nfid.org/factsheets/inflfacts.html
19. References
    1. Takhar in Majoewsky (2012) EM:Rap 12(12): 11-12
    2. (1999) Preparing Next Influenza Pandemic Teleconf, CDC
    3. Hayden (2000) N Engl J Med 343:1282-9
    4. Welliver (2001) JAMA 285:748-54
    5. Erlikh (2010) Am Fam Physician 82(9):1087-95