Influenza

See Also

Epidemiology

Annual Periodicity
1. Temperate Climate
  1. Onset as early as October
  2. Peaks in late December to March
2. Tropical Climate: Occurs year round
Attack rate:
1. Epidemics (Antigenic drift): 20-30%
2. Pandemics (Antigenic shift): 50%
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)
Incidence (worldwide)
1. Severe Influenza: 3 to 5 million people annually
2. Influenza-related deaths: Up to 500,000 annually

Pathophysiology
Orthomyxovirus (Orthomyxoviridae)

Influenza is a negative single-stranded RNA virus in the Orthomyxovirus Family
Orthomyxovirus (Orthomyxoviridae) family includes genera Influenza A, B, C
1. Influenza A and B are the primary Influenza pathogens in humans
2. Influenza A infects other animals (e.g. birds, pigs), while Influenza B and C only infect humans
  1. Broad types of animal hosts allows Influenza A to develop significant Antigenic shifts (see below)
3. Influenza C is Antigen stable (no significant drift/shift or epidemic), and causes mild URI symptoms
4. One final Orthomyxovirus, Thogotovirus is a rare tick-borne zoonotic virus causing Encephalitis
Orthomyxoviridae are spherical virions
1. Nucleocapsid Protein (NP) bands 8 negative-stranded RNA together into a helical symmetry nucleocapsid
2. Outer viral lipid bilayer membrane is studded with 2 Glycoprotein types
  1. Each Glycoprotein is anchored to M-Proteins in the viral outer membrane
Glycoproteins on surface of virion
1. Hemagglutinin Activity (HA)
  1. Binds sialic acid receptors (SIAs) on RBCs and upper respiratory tract
  2. HA allows the virion to bind target its target, and release its necleocapsid into the host cell
  3. After reproduction within the host cell, new virions bud to the host cell surface, bound by HA-SIA
2. Neuraminidase Activity (NA)
  1. NA lyses neuraminic acid, a key component in the mucin protective coat of the respiratory tract
  2. NA breaks apart the mucin layer and exposes the sialic acid receptors for binding by HA
  3. New budded virions at the surface of host cells, are released from HA-SIA binding by NA

Pathophysiology
Infleunza Infectivity and Antigenic Shift/Drift

See Viral Infection for general pathophysiology
Transmission
1. Small particle respiratory aerosol from cough and sneeze
2. Receptors are primarily in nose (and to lesser extent in the lung)
Antibodies and Vaccines are directed at critical viral surface Antigens
1. Antigens (Influenza surface Glycoproteins)
  1. Hemagglutinin Activity (HA)
  2. Neuraminidase Activity (NA)
2. Surface Proteins typically change over successive Influenza generations, rendering prior Vaccines ineffective
  1. See Antigenic drift and Antigenic shift below
Influenza A hosted in multiple species
1. Horse
2. 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
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
Antigenic drift
1. Minor genetic mutations in HA and NA Glycoproteins result in epidemics
2. Influenza A most commonly involved
Antigenic shift
1. Major genetic changes in HA and NA surface Glycoproteins, resulting in pandemic
  1. Typically results from co-infection in pigs (see above)
  2. Various Influenza strains may coinfect the same human host cells and share nucleocapsid RNA
    1. Allows for different RNA combinations, some with higher virulence
2. Major Pandemics (31 pandemics described since 1580)
  1. 1918: "Spanish flu" (H1N1) 21 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 [PubMed]
  4. 2013: Avian Influenza A (H7N9)
    1. First reported in China

Types

Influenza A
1. Major outbreaks result from Antigenic shifts (including pandemics)
2. See Avian Influenza
3. Re-assortment of genomic expression
  1. Neuraminidase and Hemagglutinin
Influenza B
1. Less variation than Influenza A
2. Outbreaks in Schools and Military camps
3. Less virulent than Influenza A in most cases (although children have a higher rate of complications)
Influenza C
1. Influenza C is Antigen stable (no significant drift/shift or epidemic)
2. Causes mild upper repsiratory symptoms

Symptoms

Abrupt illness onset
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
Eye
1. Photophobia
2. Red, Burning eyes
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"
Throat
1. Sore Throat or dry throat (lasts for first 3 days)
Chest
1. Severe dry cough (lasts for first 3 days)
2. Chest discomfort
Gastrointestinal Symptoms (present in 30% of children, uncommon in adults)
1. Nausea or Vomiting
2. Abdominal Pain
Other Constitutional symptoms
1. Anorexia (may persist for first week)
2. Fatigue persists weeks
3. Severe Malaise (may persist for more than a week)
4. Dizziness

Signs

Fever up to 104 F (40 C)
Non-Exudative Pharyngitis
Muscle tenderness
Less Common Influenza signs
1. Conjunctivitis
2. Cervical adenopathy

Course

Incubation: 2-3 days (may be as long as 7 days)
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. Ceases with fever resolution
5. Absent after 10 days
Acute symptoms resolve in 4-5 days
Persistent symptoms may not clear for 3 or more weeks
1. Fatigue or malaise
2. Persistent non-productive cough

Diagnosis

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
Classic triad (Test Sensitivity 80-85% in adults, 60% in children; Test Specificity >75% in adults)
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
References
1. Ebell (2004) J Am Board Fam Pract 17:1-5 [PubMed]

Differential Diagnosis

Common Cold Viruses
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

Complications

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
Bacterial tracheobronchitis (occurs in 30% of adults)
1. Increased risk in Tobacco Smoking
Secondary Bacterial Pneumonia
1. Occurs one week after Influenza symptom onset
2. Etiologies
  1. Streptococcal Pneumonia
  2. Staphylococcal Pneumonia (and empyema risk)
  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
Other respiratory complications
1. Acute Sinusitis (5-10%)
2. Acute Otitis Media
3. Acute Exacerbation of Chronic Bronchitis (AECB)
4. Asthma Exacerbation
5. Acute Respiratory Distress Syndrome (ARDS)
  1. More common with H5N1 and other pandemic strains
Neurologic Complications
1. Seizures
  1. Most common neurologic complication
2. Other rare neurologic complications
  1. Meningoencephalitis
  2. Transverse Myelitis
  3. Guillain-Barre Syndrome
  4. Myositis or Rhabdomyolysis
  5. Reye's Syndrome
    1. Encephalopathy and Liver failure in children with Influenza (or VZV) who are given Aspirin
Other rare complications
1. Myoglobinuric Renal Failure
2. Myocarditis
  1. ECMO has been required in some cases
3. Pericarditis
4. Glomerulonephritis
5. Parotitis

Labs
Diagnosis

General
1. Influenza diagnosis should be made clinically (lab testing is only needed in certain groups)
2. Rapid Influenza Testing has poor Test Sensitivity (50%) and does not exclude Influenza if negative
3. High risk groups should still be treated without delay if high clinical suspicion despite negative testing
Indications for testing
1. Influenza-like illness in patients or workers in the hospital, Nursing Home or daycare (limit spread)
2. Alternative diagnosis evaluation subjects patient to extensive testing (e.g. Sepsis work-up)
3. Serious underlying comorbidity (e.g. oxygen dependent COPD) for which diagnosis might alter disposition
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%
Confirmatory Testing
1. Real Time Reverse Transcriptase PCR (RT-PCR) for RNA detection (preferred)
  1. Test Sensitivity: 86 to 100%
  2. Requires 1 hour to run test (but often delayed 1 day if sent to outside lab)
  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

Labs
Other

Complete Blood Count
1. Leukopenia or slight Leukocytosis (up to 15,000)
2. Relative Lymphopenia

Management

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
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, hematologic disorders)
  4. Immunosuppressed patients
  5. Obese patients with BMI>40
  6. Alaskan natives and native americans
  7. Pregnancy (despite Pregnancy category C due to higher risk of Influenza related morbidity)
Influenza A
1. Neuraminidase Inhibitors
  1. Oseltamivir (Tamiflu)
    1. First-line agent for high risk patients (e.g. hospitalized or severe illness, immunosuppressed)
  2. Baloxavir Marboxil (Xofluza)
    1. One single dose, but no evidence of benefit in high risk patients
    2. Consider in non-severe, outpatient Influenza with moderate risks (e.g. diabetes, coronary disease)
  3. Zanamivir (Relenza)
  4. Peramivir (Rapivab)
    1. IV Antiviral with no better efficacy than Oseltamivir (Tamiflu), at 10 times the cost
    2. Indicated in hospitalized Influenza patients unable to take oral Oseltamivir (Tamiflu)
    3. Dose 600 mg IV as single dose in adults >18 years old (Category C in pregnancy, adjust for CKD)
    4. May cause Diarrhea (common), Anaphylaxis, skin reactions, transient neuropsychiatric events
2. Resistance to Adamantanes (Amantadine, Rimantadine) is common (esp. H1N1)
  1. CDC no longer recommends Amantadine or Rimantadine for Influenza management
    1. Due to resistance, not used for chemoprophylaxis or treatment
  2. Consider combination therapy in the Nursing Home
    1. Rimantadine 100 mg daily for 5 days AND
    2. Neuraminidase Inhibitors
3. Course: 5 days or 48 hours after symptoms resolve
Influenza A or B: Neuraminidase Inhibitors
1. See Oseltamivir (Tamiflu)
2. See Zanamivir (Relenza)
Avoid Salicylates in patients younger than 16 years
1. Risk of Reye's Syndrome
Avoid herbal preparations
1. Elderberry and Oscillococcinum (unlikely to be helpful)
  1. Oscillococcinum is homeopathic and unlikely to contain any active ingredient (but unlikely to be harmful)
  2. Elderberry (e.g. Sambucol) may be helpful in first 48 hours, but available doses are likely too low
  3. (2018) Presc Lett 25(3)

Management
Hospitalization Indications (findings suggestive of severe case)

Chest Pain
Altered Level of Consciousness
Seizures
Severe weakness
Hemoptysis
Hypoxia, Cyanosis, labored breathing or Shortness of Breath
Decreased Urine Output, Hypotension or Dehydration
High fever or progressive worsening after first 72 hours

Prevention

Influenza Vaccine yearly
1. Immunize everyone over 6 months of age (and especially 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
  1. Varies by year, selected Vaccine components, Antigenic drifts and shifts
    1. Predominant strain in 2014/15 was H3N2
    2. Influenza Vaccine was 55% effective in 2013/14, but only 23% effective in 2014/15
  2. Healthy younger patients: 70-90%
  3. Elderly: 30-40%
Flumist
1. Was not recommended in U.S. in 2016 due to lower efficacy, but offered again in 2018 as alternative
2. Alternative to standard injectable Influenza Vaccine who otherwise refuse Influenza Vaccine
3. Live virus intranasal Vaccine
4. May be used in healthy, non-pregnant patients aged 2 to 49 years
Postexposure Prophylaxis
1. Indications
  1. Influenza exposure from 1 day prior to symptom onset to resolution of fever
  2. High risk groups (for serious Influenza related complication)
  3. Nursing Home or other high risk institutional outbreaks
2. Start within 48 hours of exposure
3. Nursing Home: Treat for at least 2 weeks and for at least 7 days after the last infected case
4. Amantadine Or Rimantadine prophylaxis is no longer recommended for Influenza A due to resistance (use Neuraminidase Inhibitors)
5. Neuraminidase Inhibitors
  1. See Zanamivir (Relenza)
  2. See Oseltamivir (Tamiflu)
6. May consider single dose Baloxavir (not FDA approved)
  1. May prevent up to 1 case in 9 contacts
  2. Ikematsu (2020) N Engl J Med 383:309-20 [PubMed]
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

Prevention
Pandemic Preparedness

Federal, State and Local Planning
Influenza Surveillance via WHO worldwide (CDC in US)
1. Local Vital Statistics offices report deaths weekly
Maximize Vaccine development and delivery
Develop limited Antiviral (Amantadine) indications
Emergency medical, hospital and backup preparedness
Ensure communication networks are in place
1. Internet, Health Alert Network, Telephone

Resources

Is it the cold or the flu
1. http://www.naid.nih.gov/publications/cold/sick.htm
CDC Influenza Surveillance
1. http://www.cdc.gov/ncidod/diseases/flu/weekly.htm
CDC Influenza Information
1. http://www.cdc.gov/ncidod/diseases/flu
CDC MMWR - ACIP Guidelines on Antivirals in Influenza (2011)
1. http://www.cdc.gov/mmwr/preview/mmwrhtml/rr6001a1.htm
American Lung Association Influenza Information
1. http://www.lungusa.org/diseases/luninfluenz.html

References

(2020) Presc Lett 27(10): 55-6
(1999) Preparing Next Influenza Pandemic Teleconf, CDC
Claudius and Zangwill in Herbert (2018) EM:Rap 18(12): 17-8
Takhar in Herbert (2012) EM:Rap 12(12): 11-12
Hayden (2000) N Engl J Med 343:1282-9 [PubMed]
Welliver (2001) JAMA 285:748-54 [PubMed]
Erlikh (2010) Am Fam Physician 82(9):1087-95 [PubMed]