Influenza Virus

Virology

  • Member of Orthomyxovirus Family (Orthomyxoviridae)

Epidemiology

  • Incidence
    • 3-5 million patients develop severe influenza annually
    • 250k-500k patients die of influenza-related causes annually
  • Peak Season:
  • Prior Exposure: epidemiological and laboratory serology indicate that older people (age >65 y/o) may have pre-existing immunity to the novel H1N1 virus due to a prior exposure to a related virus
  • Risk Factors for H1N1

Epidemiology of Avian Influenza H7N9 Infection in China (NEJM, 2014) [MEDLINE]

  • Median Age: 61 y/o
  • Sex: 71% of cases were male
  • Exposure: 82% of cases had exposure to chickens
    • Transmission: in four family clusters, human-to-human transmission could not be ruled out
    • Excluding these family clusters, only 1% of close contacts of case patients developed respiratory symptoms
  • Clinical Severity
    • 90% of cases had pneumonia or respiratory failure
    • 63% of cases were admitted to an ICU
  • Mortality Rate: 34% (with median duration of illness: 21 days)

Risk Factors for Influenza Complications (MMWR Recomm Rep, 2011 from Epidemiologic Studies of Seasonal Influenza or 2009 H1N1) [MEDLINE]

  • American Indian/Alaskan Native Race
  • Adults ≥65 y/o
  • Children <5 y/o: highest in children <2 y/o
  • Aspirin (see Acetylsalicylic Acid, [[Acetylsalicylic Acid]]): chronic aspirin therapy in patients ≤18 y/o
    • Chronic Aspirin Therapy with Superimposed Influenza Increases the Risk of Reye’s Syndrome
  • Chronic Cardiovascular Disease: excluding hypertension alone
  • Chronic Hematologic Disease
  • Chronic Kidney Disease (CKD) (see Chronic Kidney Disease, [[Chronic Kidney Disease]])
  • Chronic Lung Disease
  • Cirrhosis (see Cirrhosis, [[Cirrhosis]])
  • Diabetes Mellitus (DM) (see Diabetes Mellitus, [[Diabetes Mellitus]])
  • Immunosuppression
  • Morbid Obesity with BMI ≥40 (see Obesity, [[Obesity]])
  • Neurologic/Neurodevelopmental Disease
    • Cerebral Palsy
    • Developmental Delay
    • Epilepsy (see Seizures, [[Seizures]])
    • Mental Retardation
    • Muscular Dystrophy
    • Spinal Cord Injury (see Spinal Cord Injury, [[Spinal Cord Injury]])
    • Stroke
  • Nursing Home/Chronic Care Facility Residents
  • Pregnancy/Post-Partum (Within 2 Weeks of Delivery) (see Pregnancy, [[Pregnancy]])

Physiology

Transmission of Influenza Virus

  • Transmission Occurs Predominantly Via Large (>5 Micron) Particle Droplets
    • Large Amounts of Influenza Virus are Present in Respiratory Secretions of Infected Influenza Patients
    • Large Particles Travel a Limited (Short) Distance: approximately 6 feet
    • While Small Particles (Which Can Become Aerosolized and Remain Suspended in the Air) Contain Influenza Virus, Their Contribution to Transmission of Influenza is Unclear
    • While Contact with Surfaces Which Have Been Contaminated by Respiratory Droplets is a Potential Source of Transmission, These are Not an Established Mode of Transmission
    • Trans-Ocular Transmission of Influenza Virus Has Also Been Documented in Studies (J Infect Dis, 2011) [MEDLINE]

Incubation

  • Incubation Period: 1-4 days (average: 2 days)

Viral Shedding

  • Viral Shedding in Otherwise Healthy Adults Infected with Influenza Virus Can Be Detected 24-48 hrs Before the Onset of Illness: however, this shedding is at much lower titers than those observed during the symptomatic period
  • Viral Shedding Increases 12-24 hrs Following Exposure, Peaks at 2 Days, and Then Rapidly Declines (Am J Epidemiol, 2008) [MEDLINE]
    • Average Duration of Viral Shedding: 4.8 days (range: 4.3-5.3 days)
    • Shedding Generally Ceases After 6-7 Days (Although May Persist Up to 10 Days in Some Cases)
    • Longer Periods of Viral Shedding May Occur in Children, Older Adults, Patients with Chronic Diseases, and Immunocompromised Patients

Virology

  • Over 99% of Influenza Infections are Due to Influenza A
    • Influenza A-H3N2: most common circulating influenza A serotype in the US in the past decades
      • Leads to more severe disease and higher rates of hosptilization/death than influenza B
      • Generally associated with higher viral loads
    • Influenza A-H1N1: lowest severity index (lowest morbidity/mortality)
      • Generally associated with lower viral loads

Diagnosis

Recommendations (Infectious Diseases Society of America, IDSA/American Thoracic Society, ATS 2007 Consensus Guidelines for the Management of CAP) (Clin Infect Dis, 2007) [MEDLINE]

  • Patients with Illness Compatible with Influenza and Known Exposure to Poultry in Areas with Previous H5N1 Infection Should be Tested for H5N1 (Moderate Recommendation, Level III Evidence)
  • In Patients with Suspected H5N1 Infection, Droplet Precautions and Careful Routine Infection Control Measures Should Be Used Until H5N1 Infection is Ruled Out (Moderate Recommendation, Level III Evidence)

Recommendations (Infectious Diseases Society of America Clinical Practice Guidelines for Seasonal Influenza, 2009) (Clin Infect Dis, 2009) [MEDLINE]

  • Patients Who Should Be Tested for Influenza During Influenza Season (if Testing Will Influence Clinical Management)
    • Outpatient Immunocompetent Patients of Any Age at High Risk of Developing Influenza Complications (Hospitalization, Death) Presenting with Acute Febrile Respiratory Symptoms, Within 5 Days After Onset of Illness
      • Five Days Corresponds to Period of Time When Influenza Virus is Usually Being Shed in Immunocompetent Patients
    • Outpatient Immunocompromised Patients of Any Age Presenting with Febrile Respiratory Symptoms, Irrespective of Time Since Onset of Illness
      • Immunocompromised Patients Can Shed Influenza Virus for Weeks-Months
    • Hospitalized Patients of Any Age (Immunocompetent or Immunocompromised) with Fever and Respiratory Symptoms (Including Those with a Diagnosis of Community-Acquired Pneumonia), Irrespective of Time Since Onset of Illness
    • Elderly Patients and Infants Presenting with Suspected Sepsis or Fever of Unknown Origin, Irrespective of Time Since Onset of Illness
    • Children with Fever and Respiratory Symptoms Presenting for Medical Evaluation, Irrespective of Time Since Onset of Illness
    • Patients of Any Age Who Develop Fever and Respiratory Symptoms After Hospital Admission, Irrespective of Time Since Onset of Illness
    • Immunocompetent Persons with Acute Febrile Respiratory Symptoms Who are Not at High Risk of Developing Complications Secondary to Influenza Infection May Be Tested for Purposes of Obtaining Local Surveillance Data
  • Patients Who Should Be Tested for Influenza at Any Time of the Year
    • Health Care Personnel, Residents or Visitors in an Institution Experiencing an Influenza Outbreak Who Present with Febrile Respiratory Symptoms, Within 5 Days After Onset of Illness
    • Persons Who are Epidemiologically Linked to an Influenza Outbreak (Household and Close Contacts of Patients with Suspected Influenza, Returning Travelers from Countries Where Influenza Viruses May Be Circulating, Participants in International Mass Gatherings, and Cruise Ship Passengers), Who Present Within 5 Days After Onset of Illness

Immunochromatographic Assay (Rapid Influenza Diagnostic Tests = RIDT)

  • Clinical Utility
    • RIDT’s are Useful to “Rule In” Influenza (Due to Higher Specificity), But Not Useful to “Rule Out” Influenza (Due to Highly Variable Sensitivity): due to lower sensitivity, a negative RIDT result should be followed by RT-PCR testing (Clin Infect Dis, 2009) [MEDLINE]
    • Cost: inexpensive ($15-20 per assay)
    • Sensitivity
      • Sensitivity of 70-90% in Children: perform better in children due to higher viral loads and longer period of viral shedding in children
      • Sensitivity of <40-60% in Adults
      • Performance of RIDT’s Depends Heavily on Patient Age, Duration of Illness, Sample Type, and Perhaps Viral Type
        • RIDT’s Have Higher Sensitivity in Detecting Influenza A than Influenza B
    • Specificity: typically >90%
  • Technique
    • Specimen Quality: probably, nasopharygneal > nasal > throat (although some studies do not cite a difference in quality between these specimen sites)
    • Common Assays
      • Binax Tests: BinaxNOW Flu A and Flu B and Binax-NOW Influenza A + B (Inverness Medical Innovations, Portland, Maine)
      • Directigen Tests: Directigen Flu A and Directigen Flu A + B (Becton, Dickinson and Company, Franklin Lakes, New Jersey)
      • QuickVue Tests: QuickVue Influenza and QuickVue Influenza A + B (Quidel Corporation, San Diego, California)
    • Laboratory Turnaround Time: 15-30 min (may be used at the point of care)

Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR)

  • Clinical Utility
    • RT-PCR is the Gold Standard Test
    • RT-PCR is the Most Sensitive and Specific Test for Influenza (Clin Infect Dis, 2009) [MEDLINE]: it has a 2-13% higher detection rate than viral culture
    • RT-PCR Has Very High Specificity for Influenza
    • RT-PCR is Useful for Differentiating Between Influenza Types/Subtypes
    • RT-PCR is the Preferred Test for Patients with a History of Exposure to Animals with Possible Influenza
      • Influenza A-H5N1 in Poultry in Eurasia or Africa
      • Swine Influenza in Any Part of the World (Including North America)
    • RT-PCR is the Least Widely Available Test: due to need for specialized expertise
    • Cost: RT-PCR is the most expensive diagnostic test
  • Technique
    • Specimen: upper or lower respiratory tract specimen
      • Endotracheal Aspirate or Bronchoalveolar Lavage (BAL) Specimens Have Higher Yields in Patients with Lower Respiratory Tract Illness
    • Methods
      • Conventional Gel-Based PCR
      • Real-Time RT-PCR
      • Multiplex PCR
    • Laboratory Turnaround Time: 2 hrs (although if samples are run in batches in clinical labs, delayed testing may occur)

Immunofluorescence

  • Clinical Utility
    • Slightly Lower Sensitivity and Specificity than Viral Isolation in Cell Culture
  • Technique
    • Specimen: must contain respiratory epithelial cells to achieve reasonable quality of assay result
    • Methods: performance of assay depends on heavily on laboratory expertise and quality of the specimen collected
      • Direct Fluorescent Antibody Staining: detects and distinguishes between influenza A and B and between A/B and other respiratory viruses
      • Indirect Fluorescent Antibody Staining: detects and distinguishes between influenza A and B and between A/B and other respiratory viruses
    • Laboratory Turnaround Time: 2-4 hrs

Neuraminidase Detection Assay

  • Clinical Utility
    • Neuraminidase Detection Assay Detects But Does Not Distinguish Between Influenza A and B
  • Technique
    • Laboratory Turnaround Time: 20-30 min

Influenza Viral Culture

  • Clinical Utility
    • Historical Viral Culture was the Gold Standard Diagnostic Test: but has recently been replaced by RT-PCR
    • Sensitivity: moderately high
    • Specificity: highest of all influenza assays (this makes viral culture important for confirming screening test results and for public health surveillance, but not useful for timely clinical management)
  • Technique
    • Method
      • Shell Vial Culture: 48-72 hr laboratory turnaround time
      • Isolation in Cell Culture: 3-10 day laboratory turnaround tim

Serologic Tests

  • Clinical Utility
    • Recommended Only for Retrospective Diagnosis, Surveillance, or Research Purposes
  • Technique
    • Methods
    • Hemagglutinin Inhibition
    • ELISA
    • Complement Fixation
    • Neutralization

Clinical Manifestations

General Comments

Onset of Illness

  • Usually Abrupt Onset of Fever, Headache, Myalgias, and Malaise
    • Associated with Dry Cough, Pharyngitis, and Nasal Discharge

Patient Groups with the Highest Mortality and Hospitalization Rates

  • Groups with Highest Risk of Mortality and Serious Morbidity (Hospitalization) (Clin Infect Dis, 2009)[MEDLINE]
    • Severely Immunocompromised Patients (Hematopoietic Stem Cell Transplant, etc)
    • Very Elderly (Age >85 y/o) Nursing Home Residents
    • Infants <24 Months Old: this group has higher hospitalization rate, but lower case-fatality rate than the first two groups

Constitutional Manifestations

Fever(see Fever, [[Fever]])

  • Clinical
    • Fever is Typically 37.8-40.0°C (100-104°F)
    • Fever is Frequently Higher in Children than in Adults

Cardiovascular Complications

Acute Pericarditis (see Acute Pericarditis, [[Acute Pericarditis]])

  • Epidemiology: uncommon

Electrocardiographic (EKG) Changes (see Electrocardiogram, [[Electrocardiogram]])

  • Epidemiology: may be due to underlying cardiac disease or due to influenza infection itself (observed in some cases of influenza in young previously healthy patients) (Clin Infect Dis, 2005) [MEDLINE]
  • Clinical: absence of elevated troponin or echocardiographic abnormalities (in cases due to influenza virus infection itself) (Clin Infect Dis, 2005) [MEDLINE]

Exacerbation of Underlying Cardiovascular Disease

Increased Risk of Myocardial Infarction (see Coronary Artery Disease, [[Coronary Artery Disease]])

  • Epidemiology: increased risk has been identified in epidemiological studies of seasonal influenza outbreaks
  • Physiology: influenza may act as a trigger for acute coronary syndromes

Myocarditis (see Myocarditis, [[Myocarditis]])

  • Epidemiology: has been identified in autopsy series
  • Physiology: likely not directly due to the influenza virus itself (due to lack of viral antigens in myocardial tissue)

Gastrointestinal Manifestations

Nausea/Vomiting/Diarrhea (see Nausea and Vomiting, [[Nausea and Vomiting]] and Diarrhea, [[Diarrhea]])

  • Epidemiology: uncommon in adults, but can occur in 10-20% of childhood cases

Infectious Manifestations

Staphylococcal Toxic Shock Syndrome (see Staphylococcal Toxic Shock Syndrome, [[Staphylococcal Toxic Shock Syndrome]])

  • Epidemiology: has been reported with influenza (most commonly influenza B) and Staphylococus Aureus co-infection (Clin Infect Dis, 1993) [MEDLINE]

Neurologic Manifestations

Aseptic Meningitis (see Meningitis, [[Meningitis]])

  • Epidemiology: has been reported

Encephalitis (see Encephalitis, [[Encephalitis]])

  • Epidemiology: has been reported

Encephalopathy (see Delirium, [[Delirium]])

  • Epidemiology: has been reported

Febrile Seizures (see Seizures, [[Seizures]])

  • Epidemiology: reported in 6-20% of children hosptalized with influenza

Guillain-Barre Syndrome (see Guillain-Barre Syndrome, [[Guillain-Barre Syndrome]])

  • Epidemiology: has been reported

Transverse Myelitis (see Transverse Myelitis, [[Transverse Myelitis]])

  • Epidemiology: has been reported

Otolaryngologic Manifestations

Pulmonary Manifestations

Cough (see Cough, [[Cough]])

  • Epidemiology: common
  • Clinical
    • Dry Cough

Acute Respiratory Distress Syndrome (ARDS) (see Acute Respiratory Distress Syndrome, [[Acute Respiratory Distress Syndrome]])

  • Epidemiology: may occur

Exacerbation of Underlying Lung Disease

Pleural Effusion (see Pleural Effusion-Exudate, [[Pleural Effusion-Exudate]])

  • Epidemiology:

Primary Influenza Pneumonia (see Pneumonia, [[Pneumonia]] and Interstitial Lung Disease, [[Interstitial Lung Disease]])

  • Epidemiology: may occur in patients without other underlying disease
  • Risk Factors
    • Chronic Lung Disease
    • Increased Left Atrial Pressure
  • Diagnosis
    • Chest X-Ray (see Chest X-Ray, [[Chest X-Ray]])
      • Bilateral reticular/reticulonodular infiltrates with lower-lobe predominance: most common pattern
      • Consolidation: may be present with/without reticulonodular infiltrates
    • Chest CT (see Chest Computed Tomography, [[Chest Computed Tomography]])
      • Bilateral reticular/reticulonodular infiltrates with lower-lobe predominance: most common pattern
      • Consolidation: may be present with/without reticulonodular infiltrates
    • High-Resolution Chest CT (HRCT) (see High-Resolution Chest Computed Tomography, [[High-Resolution Chest Computed Tomography]]): multifocal peribronchovascular or subpleural consolidations and/or ground glass opacities

Secondary Bacterial Pneumonia (Superinfection)

  • Epidemiology: contributes to morbidity/mortality in patients >65 y/o
  • Microbiology
    • Streptococcus Pneumoniae (see Streptococcus Pneumoniae, [[Streptococcus Pneumoniae]]): accounts for 48% of cases
    • Staphylococcus Aureus (see Staphylococcus Aureus, [[Staphylococcus Aureus]]): accounts for 19% of cases
      • Community-Acquired Methicillin-Resistant Staphylococcus Aureus (CA-MRSA): associated with severe outbreaks of influenza-associated severe pneumonia in previously healthy patients
    • Haemophilus Influenzae (see Haemophilus Influenzae, [[Haemophilus Influenzae]])
  • Physiology
    • Influenza Virus Damages Tracheobronchial Epithelium with Loss of Cilia and Decrease in Cell Size
    • Influenza Virus Also Enhances the Attachment of Streptococcus Pneumoniae to Nasopharyngeal Epithelial Cells, Enhancing Colonization (J Infect Dis, 2014) [MEDLINE]
  • Diagnosis
  • Clinical: occurs after initial period of clinical improvement

Pneumothorax (see Pneumothorax, [[Pneumothorax]])

  • Epidemiology: may occur

Rheumatologic Manifestations

Myalgias (see Myalgias, [[Myalgias]])

  • Epidemiology: common

Viral Myositis/Rhabdomyolysis (see Viral Myositis, [[Viral Myositis]]) and Rhabdomyolysis, [[Rhabdomyolysis]])

  • Epidemiology: reported most commonly in children
  • Physiology: presence of influenza virus in muscles
  • Clinical: muscle tenderness (especially in the lower extremities)
    • In Severe Cases, Myositis May Result in Markedly Elevated Creative Kinase (CK) with Myoglobinuria and Acute Kidney Injury (AKI)

Prevention and Infection Control

Annual Influenza Vaccination

General Comments

  • Annual Influenza Vaccination is Recommended for All Patients ≥6 mo Who Do Not Have Contraindications
    • Annual Influenza Vaccination Should Occur Before the Onset of Seasonal Influenza Activity in the Community: vaccination should continue to be offered as long as there are influenza viruses circulating in the community

Standard-Dose Quadrivalent Live Attenuated Influenza Vaccine (LAIV4)-Intranasal (FluMist Quadrivalent)

  • Pharmacology: live, attenuated vaccine against both influenza A + B
    • Prepared in Embryonated Chicken Eggs
  • Indications
    • Healthy, Non-Pregnant Adults 2-49 y/o and Without High-Risk Medical Conditions
      • Children 2-8 y/o Group: there is evidence that nasal vaccine provides better protection in this group
  • Contraindications
    • Children 2-4 y/o with History of Wheezing/Asthma in Past 12 mo
    • Concomitant Aspirin Use in Children and Adolescents: due to risk of Reye syndrome
    • Egg Allergy
    • Immunosuppression
    • Pregnancy
    • Use of Oral Influenza Antiviral Medication in Past 48 hrs
    • Not Recommended for Use During the 2016-2017 Influenza Season
  • Administration
    • Intranasal
  • Precautions: immunosuppressed patients should avoid contact with patients vaccinated with the LAIV4 vaccine for at least 7 days after receipt of the vaccine (due to the theoretical risk of influenza transmission)

Standard-Dose Inactivated Influenza Vaccine, Trivalent (IIV3)/Quadrivalent (IIV4) (Multiple Brands)

  • Pharmacology: standard-dose inactivated vaccine against both influenza A + B
    • Prepared in Embryonated Chicken Egs
  • Indications
    • Patients ≥6 mo Old
  • Contraindications
    • Egg Allergy
  • Administration
    • Intramuscular (IM)

Standard-Dose Inactivated Influenza Vaccine, Trivalent (ccIIV3) (Flucelvax)

  • Pharmacology: standard-dose inactivated vaccine against both influenza A + B
    • Prepared in Cell Culture
  • Indications
    • Patients ≥18 y/o
  • Administration
    • Intramuscular (IM)

Standard-Dose Recombinant Influenza Vaccine, Trivalent (RIV3) (Flublok)

  • Pharmacology: standard-dose inactivated vaccine against both influenza A + B
    • Prepared Using a Recombinant Baculovirus Expression System
  • Indications
    • Patients ≥18 yo/
  • Administration
    • Intramuscular (IM)

High-Dose Inactivated Influenza Vaccine, Trivalent (IIV3) (Fluzone High Dose)

  • Pharmacology: high-dose inactivated vaccine against both influenza A + B
  • Indications
    • Patients ≥65 y/o
  • Contraindications
    • Egg Allergy
  • Administration
    • Intramuscular (IM)

Vaccination in Patients with Egg Sensitivity/Allergy

  • Egg Allergy Consists of Only Hives
    • Either Inactivated Influenza Vaccine (IIV) (Egg or Cell Culture-Based) or Recombinant Influenza Vaccine, Trivalent (RIV3) Vaccine May Be Administered: patient should be observed for ≥30 min after vaccination
  • Egg Allergy with History of Angioedema/Respiratory Distress/Lightheadedness/Recurrent Emesis
    • Recombinant Influenza Vaccine, Trivalent (RIV3) Vaccine May Be Administered in Patients ≥18 y/o if There are No Other Contraindications
  • Egg Sensitivity with Ability to Eat Lightly-Cooked (Scrambled) Eggs without Reaction: these patients are unlikely to be allergic

Post-Influenza Exposure Prophylaxis

  • Influenza Vaccine + Consider Antivirals x 2 wks Following Exposure

Influenza Infection Control

  • Droplet Precautions/Isolation
    • Half of Health Care Worker Seroconversion is Due to Workplace Exposure and the Other Half is Due to Community Exposure to Virus
    • Randomized Effectiveness Trial Comparing Surgical Masks to N95 Respirators in the 2008 Season Demonstrated that Surgical Masks were Equally Efficacious (JAMA, 2009) [MEDLINE]: influenza infection occurred in 23.6% of nurses wearing regular masks compared to 22.9% wearing the N95 masks

Treatment

Recommendations (Infectious Diseases Society of America Clinical Practice Guidelines for Seasonal Influenza, 2009) (Clin Infect Dis, 2009) [MEDLINE]

  • Patients at High Risk for Influenza Complications, in Whom Antiviral Therapy Should Be Considered
    • Unvaccinated Infants 12–24 Mo Old
    • Patients with Chronic Lung Disease
    • Patients with Hemodynamically Significant Cardiac Disease
    • Patients Who Have Immunosuppressive Disorders or Who are Receiving Immunosuppressive Therapy
    • HIV-Infected Patients (see Human Immunodeficiency Virus, [[Human Immunodeficiency Virus]])
    • Patients with Hemoglobinopathies
      • Sickle Cell Disease (see Sickle Cell Disease, [[Sickle Cell Disease]])
      • Other Hemoglobinopathies
    • Patients with Diseases that Require Long-Term Aspirin Therapy
    • Patients with Chronic Kidney Disease (see Chronic Kidney Disease, [[Chronic Kidney Disease]])
    • Patients with Cancer
    • Patients with Chronic Metabolic Disease
    • Patients with Neuromuscular Disorders, Seizure Disorders, or Cognitive Dysfunction Which May Compromise the Handling of Respiratory Secretions
    • Adults >65 y/o
    • Residents of Any Age of Nursing Homes or Other Long-Term Care Institutions

Anti-Viral Agents

General Indications for Antiviral Treatment

  • Patient with Suspected/Confirmed Influenza with Severe, Complicated, or Progressive Disease or Who Requires Hospitalization: see risk factors above for patients with increased risk of influenze complications

Amantadine (Symmetrel, Symadine) (see Amantadine, [[Amantadine]])

  • Mechanism: M2 ion channel blocker (adamantane) -> not currently recommended by the CDC for Influenza A (due to resistance) [MEDLINE]
    • Activity Against Influenza A
  • Cost: inexpensive
  • Administration: PO
  • Clinical Efficacy of Influenza Treatments
    • Systematic Review and Meta-Analysis of Influenza Treatments (Annals Int Med, 2012) [MEDLINE]
      • In High-Risk Populations, Oral Oseltamivir Decreased Mortality Rate (Odds Ratio: 0.23), Hospitalization (Odds Ratio: 0.75), and Duration of Symptoms (From 45 hrs -> 33 hrs)
      • Earlier Treatment with Oseltamivir (Within 48 hrs) was Associated with Better Outcomes
      • Inhaled Zanamivir Decreased Symptom Duration (From 28 hrs -> 23 hrs) and Hospitalization (Odds Ratio: 0.66), But Had More Complications
      • No Differences Between Oseltamivir and Zanamivir
      • Oral Amantadine Decreased Mortality and Pneumonia: data from single study only
  • Indications
    • Treatment
    • Prophylaxis: for patients >1 y/o
      • Given x 2 wks during epidemic, during which time vaccine will induce antibody response
      • Given during facility outbreak, to all exposed regardless of vaccination status, until 1 wk after end of outbreak
  • Contraindications: pregnancy
  • Metabolism: renal clearance
  • Adverse Effects
    • Mild Central Nervous System Effects: insominia, anxiety, or difficulty concentrating occur in 13% of cases
    • Seizures (see Seizures, [[Seizures]]): usually in those with history of seizures
    • Delirium (see Delirium, [[Delirium]]): usually in those with psychiatric history

Rimantadine (Flumadine) (see Rimantadine, [[Rimantadine]])

  • Mechanism: M2 ion channel blocker (adamantane) -> not currently recommended by the CDC for Influenza A (due to resistance) [MEDLINE]
    • Activity Against Influenza A
  • Cost: inexpensive
  • Administration
  • Clinical Efficacy
    • Early treatment (within 48 hrs) is probably better than later treatment
    • Probably decreases the duration of fever and symptoms by 1-2 days
  • Indications
    • Treatment: patients >13 y/o
    • Prophylaxis: patients >1 y/o
      • Given x 2 wks during epidemic, during which time vaccine will induce antibody response
      • Given during facility outbreak, to all exposed regardless of vaccination status, until 1 wk after end of outbreak
  • Contraindications: pregnancy
  • Metabolism: hepatic clearance
  • Adverse Effects
    • Mild Central Nervous System Effects: insominia, anxiety, or difficulty concentrating occur in 6% of cases
    • Seizures (see Seizures, [[Seizures]]): usually in those with history of seizures
    • Delirium (see Delirium, [[Delirium]]): usually in those with psychiatric history

Oseltamivir (Tamiflu) (see Oseltamivir, [[Oseltamivir]])

  • Indications
    • Treatment: patients >1 y/o
      • Oseltamivir and Zanamivir are Not Recommended for Uncomplicated Influenza with Symptoms Which Have Been Present for >48 hrs (Level I Recommendation), But these Agents May Be Used to Decrease Viral Shedding in Hospitalized Patients or for Patients with Influenza Pneumonia (Moderate Recommendation, Level III Evidence) (Infectious Diseases Society of America, IDSA/American Thoracic Society, ATS 2007 Consensus Guidelines for the Management of CAP) (Clin Infect Dis, 2007) [MEDLINE]
      • Patients with Suspected H5N1 Avian Influenza Infection Should be Treated with Oseltamivir (Level II Evidence) and Antibacterial Agents Targeting Streptococcus Pneumoniae and Staphylococcus Aureus (Level III Evidence) (Infectious Diseases Society of America, IDSA/American Thoracic Society, ATS 2007 Consensus Guidelines for the Management of CAP) (Clin Infect Dis, 2007) [MEDLINE]
    • Prophylaxis: patients >13 y/o
      • Given x 2 wks during epidemic, during which time vaccine will induce antibody response
      • Given during facility outbreak, to all exposed regardless of vaccination status, until 1 wk after end of outbreak
  • Mechanism: neuraminidase inhibitor
    • Activity Against Influenza A + B
  • Cost: more expensive than older agents
  • Administration (Oral)
    • Prophylaxis: 75 mg PO BID (adult)
    • Treatment: 75 mg PO BID (adult)
      • Therapy Should Be Started Within 48 hrs of Onset of Symptoms of Influenza A (Strong Recommendation, Level I Evidence) (Infectious Diseases Society of America, IDSA/American Thoracic Society, ATS 2007 Consensus Guidelines for the Management of CAP) (Clin Infect Dis, 2007) [MEDLINE]
  • Oseltamivir Resistance
    • Sporadic Oseltamivir-Resistant 2009 H1N1 Has Been Reported
    • Oseltamivir Resistance was Associated with the H275Y (Histidine->Tyrosine) Substitution in Neuraminidase in H1N1 During 2007-2008: this strain was spread worldwide, but has not been prominent in later influenza seasons -> nearly all cases are sensitive to zanamivir
  • Adverse Effects
    • Acute Kidney Injury (AKI) (see Acute Kidney Injury, [[Acute Kidney Injury]]): unclear association
    • Nausea/Vomiting (see Nausea and Vomiting, [[Nausea and Vomiting]]): occurs in 19% of cases (decreased when taken with food)
    • Psychiatric Effects: psychiatric adverse effects appear to be dose-related (Cochrane Database Syst Rev, 2014) [MEDLINE]
  • Clinical Efficacy of Influenza Treatments
    • Systematic Review and Meta-Analysis of Influenza Treatments (Annals Int Med, 2012) [MEDLINE]
      • In High-Risk Populations, Oral Oseltamivir Decreased Mortality Rate (Odds Ratio: 0.23), Hospitalization (Odds Ratio: 0.75), and Duration of Symptoms (From 45 hrs -> 33 hrs)
      • Earlier Treatment with Oseltamivir (Within 48 hrs) was Associated with Better Outcomes
      • Inhaled Zanamivir Decreased Symptom Duration (From 28 hrs -> 23 hrs) and Hospitalization (Odds Ratio: 0.66), But Had More Complications
      • No Differences Between Oseltamivir and Zanamivir
      • Oral Amantadine Decreased Mortality and Pneumonia: data from single study only
    • Hong Kong Prospective Study of High-Dose Oseltamivir in Hospitalized Adult Patients with Influenza A + B (Clin Infect Dis, 2013) [MEDLINE]
      • No Benefit of High-Dose Oseltamivir in Influenza A
      • Improved Virologic Response in Influenza B
    • Cochrane Database Systematic Review of Efficacy of Neuraminidase Inhibitors in Influenza (Cochrane Database Syst Rev, 2014) [MEDLINE]
      • Time to First Symptom Alleviation
        • Oseltamavir Decreased the Time to First Alleviation of Symptoms in Adults by 16.8 hrs (Time to First Alleviation of Symptoms Decreased From 7.0 -> 6.3 Days): effect was observed in healthy children, but no effect was observed in asthmatic children
        • Zanamivir Decreased the Time to First Alleviation of Symptoms in Adults by 0.60 days (Mean Duration of Symptoms Decreased From 6.6 -> 6.0 Days): no effect was observed in children
      • Hospitalizations
        • Oseltamavir Had No Effect on Hospitalization Rate in Adults/Children: prophylaxis also had no no effect on hospitalizations
        • Zanamivir Hospitalization Rate was Not Reported
      • Serious Influenza Complications
        • Oseltamavir Did Not Decrease Serious Influenza Complications in Adults/Children: insufficient data to determine effect of oseltamavir prophylaxis on serious complications
        • Zanamivir Did Not Decrease Serious Influenza Complications in Adults: prophylaxis also had no no effect on serious complications
      • Pneumonia
        • Oseltamavir Decreased the Investigator-Reported, Unverified Pneumonia Rate: however, effect was not significant in trials which used more detailed diagnostic form for pneumonia (and no trials reported effect on radiologically-confirmed pneumonia)
        • Oseltamavir Prophylaxis Had No Effect on Self-Reported, Investigator-Mediated, Unverified Pneumonia Rate in Adults
        • Zanamivir Had No Effect on Self-Reported or Radiologically-Confirmed Pneumonia
        • Zanamivir Prophylaxis Decreased the Self-Reported, Investigator-Mediated, Unverified Pneumonia Rate in Adults
      • Bronchitis/Sinusitis/Otitis Media
        • Oseltamavir Had No Effect on the Risk of Bronchitis in Adults
        • Zanamivir Decreased the Risk of Bronchitis in Adults
        • Neither Oseltamavir/Zanamivir Decreased Rates of Sinusitis/Otitis Media in Adults/Children
      • Prophylaxis
        • Oseltamavir/Zanamivir Prophylaxis Decreased the Risk of Symptomatic Influenza
      • Conclusions
        • Oseltamavir/Zanamivir Have Small, Non-Specific Effects on Decreasing the Time to Alleviation of Symptoms in Adults, But Not in Asthmatic Children
        • Oseltamavir/Zanamivir Prophylaxis Decrease the Risk of Symptomatic Influenza
        • Trials Do Not Settle the Question of Whether Influenza Complications of Influenza (Pneumonia) are Reduced, Because of a Lack of Diagnostic Definitions
        • The Lower Bioavailability of Zanamivir May Explain its Lower Toxicity, as Compared to Oseltamivir
    • Study of High-Dose Oseltamivir in Adults Hospitalized with Influenza A and B (Clin Infect Dis, 2013) [MEDLINE]
      • High-Dose Oseltamivir Demonstrated No Benefit in Influenza A, But Improved the Virologic Response in Influenza B

Zanamivir (Relenza) (see Zanamivir, [[Zanamivir]])

  • Indications
    • Treatment: patients >7 y/o
      • Oseltamivir and Zanamivir are Not Recommended for Uncomplicated Influenza with Symptoms Which Have Been Present for >48 hrs (Level I Recommendation), But these Agents May Be Used to Decrease Viral Shedding in Hospitalized Patients or for Patients with Influenza Pneumonia (Moderate Recommendation, Level III Evidence) (Infectious Diseases Society of America, IDSA/American Thoracic Society, ATS 2007 Consensus Guidelines for the Management of CAP) (Clin Infect Dis, 2007) [MEDLINE]
    • Prophylaxis
  • Mechanism: neuraminidase inhibitor
    • Activity Against Influenza A + B
  • Cost: more expensive than older agents
  • Administration
    • Inhalation (Treatment): 10 mg (2 Inhalations) BID (child >13 y/o and adult)
    • Inhalation (Propylaxis): 10 mg (2 Inhalations) qday (child >13 y/o and adult)
    • Intravenous (IV)
  • Adverse Effects
    • Bronchospasm (see Obstructive Lung Disease, [[Obstructive Lung Disease]]): associated with inhaled zanamivir
      • Use with Caution in COPD and Asthma
  • Clinical Efficacy of Influenza Treatments
    • Systematic Review and Meta-Analysis of Influenza Treatments (Annals Int Med, 2012) [MEDLINE]
      • In High-Risk Populations, Oral Oseltamivir Decreased Mortality Rate (Odds Ratio: 0.23), Hospitalization (Odds Ratio: 0.75), and Duration of Symptoms (From 45 hrs -> 33 hrs)
      • Earlier Treatment with Oseltamivir (Within 48 hrs) was Associated with Better Outcomes
      • Inhaled Zanamivir Decreased Symptom Duration (From 28 hrs -> 23 hrs) and Hospitalization (Odds Ratio: 0.66), But Had More Complications
      • No Differences Between Oseltamivir and Zanamivir
      • Oral Amantadine Decreased Mortality and Pneumonia: data from single study only
    • Hong Kong Prospective Study of High-Dose Oseltamivir in Hospitalized Adult Patients with Influenza A + B (Clin Infect Dis, 2013) [MEDLINE]
      • No Benefit of High-Dose Oseltamivir in Influenza A
      • Improved Virologic Response in Influenza B
    • Cochrane Database Systematic Review of Efficacy of Neuraminidase Inhibitors in Influenza (Cochrane Database Syst Rev, 2014) [MEDLINE]
      • Time to First Symptom Alleviation
        • Oseltamavir Decreased the Time to First Alleviation of Symptoms in Adults by 16.8 hrs (Time to First Alleviation of Symptoms Decreased From 7.0 -> 6.3 Days): effect was observed in healthy children, but no effect was observed in asthmatic children
        • Zanamivir Decreased the Time to First Alleviation of Symptoms in Adults by 0.60 days (Mean Duration of Symptoms Decreased From 6.6 -> 6.0 Days): no effect was observed in children
      • Hospitalizations
        • Oseltamavir Had No Effect on Hospitalization Rate in Adults/Children: prophylaxis also had no no effect on hospitalizations
        • Zanamivir Hospitalization Rate was Not Reported
      • Serious Influenza Complications
        • Oseltamavir Did Not Decrease Serious Influenza Complications in Adults/Children: insufficient data to determine effect of oseltamavir prophylaxis on serious complications
        • Zanamivir Did Not Decrease Serious Influenza Complications in Adults: prophylaxis also had no no effect on serious complications
      • Pneumonia
        • Oseltamavir Decreased the Investigator-Reported, Unverified Pneumonia Rate: however, effect was not significant in trials which used more detailed diagnostic form for pneumonia (and no trials reported effect on radiologically-confirmed pneumonia)
        • Oseltamavir Prophylaxis Had No Effect on Self-Reported, Investigator-Mediated, Unverified Pneumonia Rate in Adults
        • Zanamivir Had No Effect on Self-Reported or Radiologically-Confirmed Pneumonia
        • Zanamivir Prophylaxis Decreased the Self-Reported, Investigator-Mediated, Unverified Pneumonia Rate in Adults
      • Bronchitis/Sinusitis/Otitis Media
        • Oseltamavir Had No Effect on the Risk of Bronchitis in Adults
        • Zanamivir Decreased the Risk of Bronchitis in Adults
        • Neither Oseltamavir/Zanamivir Decreased Rates of Sinusitis/Otitis Media in Adults/Children
      • Prophylaxis
        • Oseltamavir/Zanamivir Prophylaxis Decreased the Risk of Symptomatic Influenza
      • Conclusions
        • Oseltamavir/Zanamivir Have Small, Non-Specific Effects on Decreasing the Time to Alleviation of Symptoms in Adults, But Not in Asthmatic Children
        • Oseltamavir/Zanamivir Prophylaxis Decrease the Risk of Symptomatic Influenza
        • Trials Do Not Settle the Question of Whether Influenza Complications of Influenza (Pneumonia) are Reduced, Because of a Lack of Diagnostic Definitions
        • The Lower Bioavailability of Zanamivir May Explain its Lower Toxicity, as Compared to Oseltamivir

Prognosis

Natural History/Prognosis

  • Disease Course: most cases of influenza are self-limited

Epidemiology of Avian Influenza H7N9 Infection in China [MEDLINE]

  • Mortality Rate: 34% (with median duration of illness: 21 days)

References

General

  • Toxic shock syndrome complicating influenza A in a child: case report and review. Clin Infect Dis. 1993;17(1):43 [MEDLINE]
  • Cardiac findings during uncomplicated acute influenza in ambulatory adults. Clin Infect Dis. 2005;40(3):415 [MEDLINE]
  • Time lines of infection and disease in human influenza: a review of volunteer challenge studies. Am J Epidemiol. 2008;167(7):775 [MEDLINE]
  • Preparing for the sickest patients with 2009 influenza A (H1N1). JAMA, Published online October 12, 2009 [MEDLINE]
  • Canadian Critical Care Trials Group H1N1 Collaborative. Critically ill patients with 2009 influenza A (H1N1) infection in Canada [published online October 12, 2009]. JAMA doi:10.1001/jama.2009.1496 [MEDLINE]
  • Critically ill patients with 2009 influenza A (H1N1) in Mexico [published online October 12, 2009]. JAMA. doi:10.1001/jama.2009.1536 [MEDLINE]
  • Surgical mask vs N95 respirator for preventing influenza among health care workers: a randomized trial [published online October 1, 2009]. JAMA doi:10.1001/jama.2009.1466 [MEDLINE]
  • Seasonal Influenza in Adults and Children— Diagnosis, Treatment, Chemoprophylaxis, and Institutional Outbreak Management: Clinical Practice Guidelines of the Infectious Diseases Society of America. Clin Infect Dis. 2009 Apr 15;48(8):1003-32. doi: 10.1086/598513 [MEDLINE]
  • Antiviral agents for the treatment and chemoprophylaxis of influenza—recommendations of the Advisory Committee on Immunization Practices (ACIP).  MMWR Recomm Rep.  2011;60(1):1–24 [MEDLINE]
  • Transocular entry of seasonal influenza-attenuated virus aerosols and the efficacy of n95 respirators, surgical masks, and eye protection in humans. J Infect Dis. 2011;204(2):193 [MEDLINE]
  • Accuracy of Rapid Influenza Diagnostic Tests: A Meta-analysis. Ann Intern Med. 2012;156:500–511 [MEDLINE]
  • High nasopharyngeal pneumococcal density, increased by viral coinfection, is associated with invasive pneumococcal pneumonia. J Infect Dis. 2014 Nov 15;210(10):1649-57. doi: 10.1093/infdis/jiu326. Epub 2014 Jun 6 [MEDLINE]
  • Epidemiology of human infections with avian influenza A (H7N9) virus in China. N Engl J Med 2014;370:520-532 [MEDLINE]
  • Prevention and Control of Influenza with Vaccines: Recommendations of the Advisory Committee on Immunization Practices, United States, 2015-16 Influenza Season. MMWR Morb Mortal Wkly Rep. 2015 Aug 7;64(30):818-25 [MEDLINE]

Treatment

  • Infectious Diseases Society of America/American Thoracic Society Consensus Guidelines on the Management of Community-Acquired Pneumonia in Adults. Clin Infect Dis. 2007 Mar 1;44 Suppl 2:S27-72 [MEDLINE]
  • Antiviral agents for the treatment and chemoprophylaxis of influenza—recommendations of the Advisory Committee on Immunization Practices (ACIP).  MMWR Recomm Rep.  2011;60(1):1–24 [MEDLINE]
  • A prospective intervention study on higher-dose oseltamivir treatment in adults hospitalized with influenza a and B infections. Clin Infect Dis. 2013 Dec;57(11):1511-9. doi: 10.1093/cid/cit597. Epub 2013 Sep 17 [MEDLINE]
  • Antivirals for Treatment of Influenza: A Systematic Review and Meta-analysis of Observational Studies. Ann Intern Med. 2012;156:512-524 [MEDLINE]
  • Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children. Cochrane Database Syst Rev. 2014 Apr 10;4:CD008965. doi: 10.1002/14651858.CD008965.pub4 [MEDLINE]