Influenza Viruses/Influenza

Influenza viruses are members of the Orthomyxoviridae family and the causative organisms of influenza, a highly contagious febrile respiratory disease. There are 3 primary influenza viruses (A, B, and C) and various subtypes, which are classified based on their virulent surface antigens, hemagglutinin (HA) and neuraminidase (NA). Influenza typically presents with a fever, myalgia, headache, and symptoms of an upper respiratory infection. Symptoms of gastroenteritis may also commonly occur in children. Influenza is usually a self-limiting condition, though viral or secondary bacterial pneumonia may complicate the disease. Management is generally supportive, although NA inhibitors can be helpful if initiated within 48 hours of infection. Prevention relies on the annual vaccination of the public and practicing good hygiene.

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Classification

RNA virus identification:
Viruses can be classified in many ways. Most viruses, however, will either have a genome formed by DNA or RNA. Viruses with an RNA genome can be further characterized by whether that RNA is single or double-stranded. If the viruses are covered by a thin coat of cell membrane (usually taken from the host cell), they are called “enveloped” viruses. If that coat is absent, however, the viruses are called “naked” viruses. Viruses with single-stranded genomes are called “positive-sense” viruses if they employ their genome directly as messenger RNA, which is translated into proteins. “Negative-sense” single-stranded viruses employ the viral enzyme RNA-dependent RNA polymerase to transcribe their genome into messenger RNA.

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General Characteristics

Structure and basic features

The influenza virus is a member of the Orthomyxoviridae family.

  • Capsid: large, enveloped, helical
  • Genome:
    • ssRNA 
      • Linear
      • Negative sense
      • Segmented: 8 segments
    • Carries RNA-dependent RNA polymerase (RDRP)
    • Replicates within the nucleus
  • Viral proteins:
    • Virulent envelope glycoproteins:
      • Hemagglutinin (HA): attaches to sialic acid-containing receptors on respiratory epithelial cells 
      • Neuraminidase (NA): cleaves newly formed virions off the sialic acid-containing receptor, allowing the virus to exit cells
    • M1 protein: virion assembly
    • M2 protein: involved in viral uncoating within the respiratory epithelial cells
    • Nucleoprotein: helps distinguish between the 3 types of influenza viruses (A, B, and C)

A diagram of the structure of the Influenza virus

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Clinically relevant species and diseases

Influenza viruses cause a febrile respiratory disease known as influenza.
There are 3 distinct clinically relevant species of the virus:

  • Influenza virus A
  • Influenza virus B
  • Influenza virus C
Table: Characteristics and clinical manifestations of influenza viruses
CharacteristicsInfluenza AInfluenza BInfluenza C
Natural hosts
  • Humans
  • Swine
  • Birds
  • Equine
  • Marine mammals
Humans only
  • Humans
  • Swine
EpidemiologyAntigenic shift and driftAntigenic drift onlyAntigenic drift only
ManifestationsLarge epidemics and pandemics with significant mortalityNo pandemics; elderly and immunocompromised patientsMild disease without seasonality

Epidemiology

Epidemiology

  • Worldwide: 
    • 3–5 million cases of severe disease annually
    • 250,000–500,000 deaths annually 
    • Mortality rate: 4–8 per 100,000 annually 
  • Highest rates among individuals < 5 years of age and > 64 years of age
  • Most likely to be infected: children (approximately 9% develop symptomatic influenza annually)
  • Most likely to have severe disease:
    • Children
    • Elderly
    • Pregnant women
  • Mortality is highest among the elderly and individuals in less-developed countries:
    • 20–220 per 100,000 in patients ≥ 75 years of age
    • 4–40 per 100,000 in patients 65–74 years of age
    • 0.1–6 per 100,000 in patients < 65 years of age
  • Seasonality:
    • Temperate climates: annual epidemic
      • Begins in the fall
      • Peaks mid-February 
      • Ends late spring
    • Tropical areas: continually present

Outbreaks, epidemics, and pandemics

  • Outbreaks:
    • A single viral strain enters a single community → local outbreak
    • Begins abruptly in the fall or winter months
    • Peaks around 2–3 weeks and lasts 5–6 weeks
  • Epidemics: due to antigenic drift
    • Minor changes in the RNA, creating new antigenic sites in HA and/or NA spikes
    • Occur owing to a lack of error-checking mechanisms within the viral RNA polymerase
    • Gradual immunity develops in the population.
    • Severity of annual epidemic depends on the degree of antigenic drift.
  • Pandemics: due to antigenic shift
    • Radical changes in HA and/or NA spikes
    • Mixing and reassortment of different viral-genome segments occur within an intermediate host (often an animal) simultaneously infected with multiple strains.
    • Results in a completely new viral strain in humans
    • The entire population has limited or no prior immunity.

Pathogenesis

Reservoirs

  • Humans
  • Swine (pigs)
  • Birds
  • Equine
  • Marine mammals

Transmission

  • Transmission: 
    • Respiratory droplets:
      • Aerosols (remain suspended in air for hours)
      • Fomites
    • Direct contact with an infected person
    • Direct contact with infected animals (less common, lower human-to-human transmission)
  • Incubation period: 1–4 days
  • Viral shedding: 
    • Begins with or just before the onset of symptoms (0–24 hours)
    • Lasts 5–10 days 
    • Children and immunocompromised individuals tend to shed virus longer.

Host risk factors for severe disease

  • Cardiovascular disease (e.g., congestive heart failure)
  • Respiratory disease (e.g., asthma)
  • Chronic metabolic disease (e.g., diabetes mellitus)
  • Renal dysfunction
  • Immunosuppression
  • Pregnancy
  • Obesity

Disease process/pathophysiology

  1. Viral particles suspended in respiratory droplets enter the upper respiratory tract of a new host.
  2. The HA spike attaches to the sialic acid receptors on the wall of respiratory epithelial cells.
  3. The virus is internalized in an endosome (receptor-mediated endocytosis).
  4. M2 protein acts as an ion channel allowing the influx of hydrogen ions (H+) into the endosome.
  5. The virus uncoats, releasing viral RNA into the cellular cytoplasm.
  6. Viral gene segments move into the nucleus.
  7. Viral messenger RNA is synthesized. 
  8. Viral proteins are synthesized by cellular ribosomes.
  9. Viral copies are assembled at the cell surface.
  10. Neuraminidase cleaves off the virion from the sialic acid-containing receptor (otherwise it would stay bound to the cell surface by HA).
  11. A new viral copy is released from the cell, which can infect adjacent cells.
  12. Inflammation and necrosis of the infected respiratory epithelium
  13. Respiratory epithelium can be denuded (severe cases).
  14. Mucous and ciliated cells are lost, leaving the bronchial tree vulnerable to other infections.
  15. Secondary bacterial infection may lead to pneumonia.

Replication of the influenza virus:

1: A viral particle attaches its hemagglutinin (HA) spikes to sialic acid-containing receptors on the surface of respiratory epithelial cells.
2: The viral particle is internalized via receptor-mediated endocytosis.
3: Once inside the cell, the M2 protein acts as an ion channel, allowing an influx of hydrogen ions, which results in uncoating of the virus.
4: The viral RNA then moves into the nucleus of the cell, where it is replicated and messenger RNA is synthesized.
5: mRNA is translated into new viral proteins in the cell.
6: Viral particles and newly replicated RNA are brought to the cell surface and assembled into virions.
7: As the new virus buds off of the respiratory epithelial cells, HA binds to the sialic acid-containing receptors again. Neuraminidase (NA) then cleaves the new viral particle off of the respiratory epithelial cell, so that it can infect nearby cells.

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Clinical Presentation

Influenza A and B create the same disease patterns.

Severity

  • Mild-to-moderate, self-limiting disease: immunocompetent patients
  • Severe disease:
    • Immunodeficiency
    • Pregnancy
    • Cardiorespiratory disease

Prodrome (3–24 hours)

  • Myalgia (including extraocular muscles)
  • Malaise
  • Headache
  • Anorexia
  • Prostration in severe cases

Disease (7–10 days)

Adults:

  • Fever
    • Typically 37.8–40.0°C (100–104°F)
    • Lasts 1–5 days
  • Myalgias
  • Nonproductive/dry cough
  • Sore throat
  • Nasal congestion or rhinorrhea
  • Hyperemic nose and throat
  • Nonpurulent conjunctivitis
  • Mild cervical lymphadenopathy

Children:

  • High fever
  • Malaise
  • Headache
  • Laryngotracheobronchitis (croup)
  • Bronchiolitis
  • Otitis media 
  • Gastroenteritis symptoms:
    • Abdominal pain
    • Vomiting 
    • Diarrhea

Primary viral pneumonia

  • Dyspnea
  • Cyanosis
  • Inspiratory crackles
  • No consolidative findings

Secondary bacterial pneumonia

  • Recrudescent fever
  • Productive cough, possibly bloody
  • Hypoxemia
  • Consolidative findings:
    • Dullness to percussion
    • Bronchial breath sounds
    • Whispered pectoriloquy

Diagnosis

The diagnosis of influenza infection is typically made clinically; however, rapid diagnostic tests may be useful if the results will influence management.

Clinical diagnosis

  • Positive predictive value of clinical diagnosis once the virus has been documented in the community: 80%–90%
  • Key clinical findings:
    • Rapid onset of symptoms
    • Fever and symptoms of upper respiratory infection (URI)
    • Extraocular myalgias
    • GI symptoms and high fever in children

Laboratory and imaging

  • Gold standards:
    • Viral culture (3–7 days): detects virus in nasopharyngeal or throat samples
    • RT-PCR (24 hours): identification of viral genomes
  • Rapid diagnostic testing:
    • ELISA (15–20 minutes): detection of antigens in throat and nasal swabs
    • Specificity of up to 98%
    • Limited sensitivity and predictive values
  • Bloodwork:
    • CBC: 
      • Leukopenia (especially lymphopenia)
      • Mild thrombocytopenia
    • Basic metabolic panel (BMP): helpful in supportive care of hospitalized patients
  • Chest X-ray: 
    • 1st-line diagnosis for ruling out bacterial pneumonia
    • Should be obtained in the following cases:
      • Elderly
      • Patients at high risk due to medical comorbidities
      • Patients exhibiting signs/symptoms suggestive of pneumonia
    • Findings:
      • Bilateral symmetrical patch infiltrates
      • Ground-glass opacities
      • Focal infiltrates → bacterial pneumonia

Management

Treatment

The majority of patients require only supportive care and recover without complications. Antiviral medications are used in hospitalized or high-risk patients. 

  • General hospital management:
    • Contact precautions and isolation
    • O2 and IV fluids should be administered as needed.
  • NA inhibitors:
    • Options:
      • Oseltamivir (oral)
      • Zanamivir (oral inhalation)
      • Peramivir (IV)
    • Mechanism: blocks NA from cleaving the new viral copy off the sialic acid on respiratory epithelium → virus unable to leave the infected cell
    • Clinical uses and efficacy:
      • Active against influenza A and B viruses
      • Must be started within 48 hours of disease onset
  • M2 inhibitors:
    • Options:
      • Amantadine 
      • Rimantadine
    • Mechanism: inhibits M2 ion channels → virus cannot uncoat itself
    • Clinical uses and efficacy:
      • Active only against influenza A virus
      • Must be started within 24–48 hours to have full efficacy
      • Significant resistance to these drugs
  • Antibiotics
    • Indicated in cases of superimposed bacterial pneumonia
    • Empirical treatment for community-acquired pneumonia
    • Regimens based on age, risk factors, Gram stain, and/or culture results

Complications

  • Secondary bacterial pneumonia:
    • Streptococcus pneumoniae
    • Staphylococcus aureus
    • Haemophilus influenzae
  • Post-influenza encephalitis
  • Myositis
  • Aspirin-associated Reye syndrome (children)

Prevention

  • Recommendations to prevent transmission:
    • Cough etiquette
    • Use of facemasks
    • Frequent handwashing
    • Social isolation of infected individuals
  • Influenza vaccination (flu shot): 50%–90% efficacy
    • Different strains are included each year based on current circulating virus strains.
    • Inactivated vaccine: 70% efficacy
    • Live-attenuated vaccine: > 90% efficacy in children, 85% in adults
    • Recommended annually for all individuals ≥ 6 months of age who do not have contraindications
  • Chemoprophylaxis: 
    • To prevent outbreaks within a community (e.g., nursing home)
    • NA inhibitors
    • M2 inhibitors

Comparison With Similar Viruses

  • SARS-CoV-2: a novel coronavirus with a high rate of infection that causes the clinical disease known as coronavirus infectious disease 2019 (COVID-19). COVID-19 may be asymptomatic or mild with symptoms of only URI, or it can progress to more severe lower-respiratory disease, severe pneumonia, and multi-organ failure. Diagnosis is based on nucleic acid amplification tests. Treatment is primarily supportive and may involve glucocorticoids, remdesivir, and interleukin (IL)-6 inhibitors (e.g., tocilizumab). Vaccination, social isolation, and excellent hand and cough hygiene are key to prevention.
  • Respiratory syncytial virus (RSV): an enveloped ssRNA virus that causes infections of the lungs and respiratory tract. Respiratory syncytial viral infection is a leading cause of infections in infants and young children, and can also be spread by respiratory droplets. Complications include bronchiolitis, pneumonia, and otitis media. Respiratory syncytial viral infection is managed with supportive care. Although it may be difficult to distinguish RSV infections clinically from influenza, diagnostic testing may be helpful in more severe cases.
  • Human parainfluenza viruses (HPIVs): ssRNA viruses in the Paramyxoviridae family. Human parainfluenza viruses can cause both upper and lower respiratory tract diseases, including croup (laryngotracheobronchitis), bronchiolitis, and pneumonia. Management is primarily supportive care.
  • Adenoviruses: non-enveloped double-stranded DNA viruses that typically cause mild respiratory infections (the common cold), though they can also cause conjunctivitis, atypical pneumonia, gastroenteritis, and appendicitis. Transmission is through aerosols, fecal-oral route, fomites, and direct contact. Management is supportive.

Differential Diagnosis

  • Asthma: a chronic inflammatory airway disease that leads to luminal bronchial narrowing and airflow obstruction. Asthma is characterized by cough, wheezing, and dyspnea. Asthma has known triggers, and symptoms can be reversed with the use of bronchodilators. Asthma is not associated with fever and malaise like influenza.
  • Community-acquired bacterial pneumonia: an infection of the lower respiratory tract that results in acute exudative inflammation of the alveoli and lung parenchyma. Symptoms of community-acquired bacterial pneumonia include productive cough, fever, chills, dyspnea, and cyanosis. Management is with supportive care and antibiotics. Some forms of pneumonia can be prevented by vaccines. 
  • Gastroenteritis: inflammation of the stomach and intestines, commonly caused by bacterial, viral, and parasitic infections. Symptoms include abdominal pain, diarrhea, vomiting, fever, and dehydration. Stool analysis or culture is not required, but can help determine the etiology in certain circumstances. The majority of cases are self-limiting, and the only required treatment is supportive therapy. The presence of respiratory symptoms with gastroenteritis should prompt an evaluation for influenza.

References

  1. Ison, M.G., Hayden, F.G. (2020). Influenza. In L. Goldman MD, A.I. Schafer MD (Eds.), Goldman-Cecil Medicine (pp. 2156-2162.e3).
  2. Wright, P.F. (2018). Influenza. In J.L. Jameson, A.S. Fauci, D.L. Kasper, S.L. Hauser, D.L. Longo, J. Loscalzo (Eds.), Harrison’s Principles of Internal Medicine, 20e. New York, NY: McGraw-Hill Education.
  3. Dolin, R. (2020). Epidemiology of influenza. In Baron, E.L. (Ed.), UpToDate. Retrieved Feb 19, 2021, from https://www.uptodate.com/contents/treatment-of-seasonal-influenza-in-adults
  4. Dolin, R. (2020). Seasonal influenza in adults: Transmission, clinical manifestations, and complications. In Baron, E.L. (Ed.), UpToDate. Retrieved February 27, 2021, from https://www.uptodate.com/contents/seasonal-influenza-in-adults-transmission-clinical-manifestations-and-complications 
  5. Nguyen, H. (2020). Influenza Guidelines. Emedicine. Retrieved Feb 19, 2021, from https://emedicine.medscape.com/article/219557-guidelines#g3
  6. Nguyen, H. (2020). Influenza. Emedicine. Retrieved Feb 23, 2021, from https://emedicine.medscape.com/article/219557-overview#a3
  7. Boktor, S. (2020). Influenza. In: StatPearls. Retrieved February 27, 2021, from https://www.statpearls.com/articlelibrary/viewarticle/23512/

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