Influenza, commonly known as flu, is an acute respiratory infectious disease caused by the influenza virus. It has a sudden onset, characterized by pronounced systemic symptoms such as high fever, headache, fatigue, conjunctivitis, and generalized muscle aches, while respiratory catarrhal symptoms are relatively mild. The virus is mainly transmitted through contact and airborne droplets. Influenza exhibits seasonal patterns, occurring mostly in winter and spring. Due to its high mutation rate, the population is generally susceptible. With a high incidence rate, influenza has caused multiple global outbreaks, posing a significant threat to human life. Notable pandemics include the 2009 H1N1 influenza and the 2013 H7N9 avian influenza, which led to severe cases involving pneumonia and acute respiratory distress syndrome (ARDS), resulting in fatalities and drawing significant public attention.
Pathogen
The influenza virus belongs to the Orthomyxoviridae family and is an RNA virus. It has a lipid envelope on its surface, with glycoprotein spikes composed of hemagglutinin (HA) and neuraminidase (NA). Based on the antigenic properties of its nucleoprotein, the influenza virus is classified into three types that infect humans—Type A, B, and C—and Type D, which infects animals. Further classification of Type A influenza is based on the antigenic differences in hemagglutinin (H) and neuraminidase (N). Antigenic variation is the most notable characteristic of the influenza virus.
Type A influenza virus is highly prone to mutations, primarily in its hemagglutinin (H) and neuraminidase (N). To date, 18 subtypes of hemagglutinin (H1-H18) and 11 subtypes of neuraminidase (N1-N11) have been identified. The influenza virus undergoes two types of antigenic changes: antigenic drift and antigenic shift. Antigenic drift involves point mutations in the genes encoding surface antigens (HA and NA), resulting in minor changes in antigenic sites, which are gradual and quantitative. Antigenic shift, on the other hand, involves genomic reassortment, leading to the emergence of new subtypes, which are abrupt and qualitative changes. Cross-species transmission among animals can result in genetic reassortment, creating new viral strains, such as the H7N9 avian influenza virus identified in 2013.
Type A influenza virus can exhibit large-scale mutations (both H and N mutate), subtype mutations (major changes in H, with little or no change in N), or strain mutations (minor changes in both H and N). Depending on the extent of antigenic variation, pre-existing immunity in humans may be completely or partially ineffective against the new virus, leading to influenza epidemics. Type B influenza virus is also prone to strain mutations, whereas Type C influenza virus rarely mutates. The spread of influenza viruses is closely related to factors such as the binding efficiency of viral hemagglutinin to α2,6-sialic acid expressed on respiratory epithelial cells and the transcription efficiency of the virus within host cells.
Type A influenza virus is often associated with pandemics and tends to cause more severe disease. Type B and C influenza viruses typically result in localized outbreaks or sporadic cases with milder illness. Due to the rapid antigenic changes of influenza viruses, humans cannot acquire long-lasting immunity. Influenza pandemics lack clear seasonality, whereas sporadic outbreaks are more common in winter and spring. Children and older adults are more commonly affected. Recent influenza outbreaks have shown distinct patterns: H5N1 primarily affects older adults, H1N1 is more common in children, and H7N9 predominantly affects older individuals, especially those with diabetes or chronic obstructive pulmonary disease (COPD).
Pathogenesis and Pathology
Influenza viruses are transmitted primarily through airborne viral particles or close contact. The virus infects ciliated columnar epithelial cells in the respiratory tract, where it replicates. After the influenza virus's RNA enters the host cell nucleus, viral RNA transcription occurs with the involvement of viral RNA polymerase and host cell RNA polymerase. Complementary RNA (mRNA) is formed, which binds to ribonucleoproteins. Viral RNA is then replicated using host nucleotides and transported to the cytoplasm for assembly. Finally, through the action of neuraminidase, the virus is released from the cell to infect other epithelial cells, causing further damage.
In cases of pneumonia, pathological changes include pulmonary congestion, edema, and fibrinous exudates in the alveoli, resembling bronchopneumonia. Some influenza patients may develop severe pneumonia that rapidly progresses to acute respiratory distress syndrome (ARDS).
Clinical Manifestations
Influenza can be classified into four clinical types: simple influenza, gastrointestinal influenza, pneumonic influenza, and infective influenza. The incubation period is 1-3 days. Influenza is characterized by pronounced outbreaks and epidemics. The onset is acute, with symptoms such as chills, high fever, headache, dizziness, generalized muscle aches, and fatigue, indicative of systemic infection. Nasopharyngeal symptoms are mild, and appetite may be reduced.
Gastrointestinal influenza is accompanied by abdominal pain, abdominal distention, emesis, and diarrhea, which is more common in children than adults.
Pneumonic influenza presents with pneumonia and may progress to respiratory failure.
Infective influenza involves systemic toxemia, which in severe cases can lead to shock, disseminated intravascular coagulation (DIC), circulatory failure, and even death.
Laboratory Tests
Peripheral blood tests typically show normal or decreased total white blood cell (WBC) counts, with a reduction in lymphocytes.
Nasopharyngeal secretions, lower respiratory tract secretions, or oral gargle fluid can be used to isolate the influenza virus.
A fourfold or greater increase in influenza virus antibody titers between paired serum samples taken during the acute and convalescent phases can aid in retrospective diagnosis.
Rapid nasopharyngeal swab tests or serum viral PCR testing are helpful for early diagnosis, offering high sensitivity and specificity. These methods are widely used in the clinical diagnosis of influenza and other respiratory viruses.
Influenza diagnosis should take into account the epidemiological context of the disease and consider the potential for false positives and false negatives in viral antigen detection.
Treatment
The key points in the treatment of influenza are as follows:
Isolation
Suspected and confirmed patients should be isolated to prevent further spread.
Symptomatic Treatment
Medications such as antipyretic, analgesic, and anti-inflammatory drugs, nasal decongestants, and cough suppressants/expectorants can be used to relieve symptoms.
Antiviral Therapy
Antiviral treatment should ideally be initiated within 48 hours of symptom onset.
Baloxavir marboxil, A novel cap-dependent endonuclease inhibitor that suppresses influenza virus mRNA transcription, renders the virus unable to replicate. A single dose (40-80 mg) taken within 48 hours after onset can effectively inhibit viral replication.
Neuraminidase inhibitors inhibit viral replication, reduce pathogenicity, alleviate symptoms, shorten the disease course, and decrease complications. They have low toxicity, minimal resistance, and good tolerability.
The adult dosage of oseltamivir is 75 mg twice daily for at least 5 days. For severe cases, treatment should continue until two consecutive negative viral tests are obtained.
Peramivir can be administered as a 300-600 mg intravenous infusion once daily.
Zanamivir can be administered via inhalation at 5 mg twice daily for 5 days. It is suitable for adults and adolescents aged 12 years and older.
Arbidol, a hemagglutinin inhibitor, can be used for the treatment of influenza.
Ion channel M2 blockers amantadine and rimantadine are no longer widely used due to high resistance and significant side effects.
Supportive care and prevention of complications:
- Encourage rest, increased fluid intake, and a nutrient-rich, easily digestible diet.
- Correct water and electrolyte imbalances.
- Closely monitor and prevent complications.
- Provide respiratory support in cases of respiratory failure. Extracorporeal membrane oxygenation (ECMO) may be used if necessary.
- Administer antibiotics promptly in cases of secondary bacterial infection.
Prognosis and Prevention
The prognosis of influenza depends on the virulence of the virus and the patient’s immune status. Older and frail individuals are more prone to pneumonia-related influenza, with a higher mortality rate. Simple influenza generally has a favorable prognosis.
Influenza vaccination should be actively promoted, especially for young children and older adults. Vaccination can alleviate secondary symptoms of influenza to some extent.
Early administration of antiviral drugs in patients diagnosed with or suspected of influenza based on exposure history and epidemiological context can reduce the risk of severe influenza.