bubble_chart Overview

Influenza (commonly known as the flu) is an acute respiratory infectious disease caused by influenza viruses, with pathogens classified as types A, B, and C. It spreads through respiratory droplets and is clinically characterized by sudden high fever, fatigue, generalized muscle pain, and mild respiratory symptoms. The course of the illness is short and self-limiting, but middle-aged individuals and those with chronic respiratory diseases or heart conditions are prone to complications such as pneumonia. The influenza virus, particularly type A, is highly prone to mutation, often leading to outbreaks, epidemics, or pandemics. Since the beginning of this century, there have been five recorded global pandemics, occurring in 1900, 1918, 1957, 1968, and 1977, with the 1918 outbreak being the most severe, resulting in over 20 million deaths. In China, from 1953 to 1976, there were 12 moderate or larger influenza epidemics, all caused by type A influenza viruses. Since the 1980s, influenza cases have primarily been sporadic or small-scale outbreaks, with no significant epidemics occurring.

bubble_chart Epidemiology

The epidemiological characteristics of this disease are: sudden onset, high incidence rate, rapid spread, short epidemic process but capable of multiple recurrences.

(1) Pestilence source: The patient is the main pestilence source. They can transmit the pestilence from the end of the incubation period, with the highest pestilence potential in the first 2–3 days of illness. Viral shedding is rare after body temperature returns to normal, but can last up to 7 days after illness onset. The virus is present in the patient's nasal discharge, saliva, and sputum, and is expelled through coughing and sneezing. Due to partial immunity, infection may not lead to illness, resulting in asymptomatic infection. Although the duration of viral shedding is short, it can easily cause transmission in the population. To date, no long-term carriers have been confirmed.

(2) Transmission route: Mainly spread through airborne droplets. The virus is present in the respiratory secretions of patients or asymptomatic carriers and is dispersed into the air through talking, coughing, or sneezing, remaining viable for 30 minutes. Susceptible individuals can become infected upon inhalation. The speed of transmission depends on the degree of crowding in the population. Transmission can also occur through contact with contaminated utensils or toys.

(3) Susceptible population: People are generally susceptible to the influenza virus, regardless of age, gender, or occupation. Antibodies appear 1 week after infection, peak at 2–3 weeks, begin to decline after 1–2 months, and reach their lowest level after about 1 year. Antibodies are present in the blood and nasal secretions, but nasal secretion antibodies are only about 5% of those in the blood. There is no cross-immunity among the three types of influenza viruses, and post-infection immunity does not last long. Field observations indicate that even if antibodies are present in the blood 5 months after infection, reinfection with the same virus type can still occur. The respiratory tract produces secretory antibodies that can block viral invasion, but when local mucosal epithelial cells shed, this protective effect is lost. Therefore, local antibodies are more important than those in the blood.

bubble_chart Pathogen

The influenza virus belongs to the Orthomyxoviridae family and is an RNA virus. The viral particles are spherical or elongated in shape, with a diameter of 80–120 nm, and are enveloped by a lipid membrane. The membrane is studded with glycoprotein spikes composed of hemagglutinin (H) and neuraminidase (N) (Figure 11-5), both of which are antigenic. Hemagglutinin facilitates viral attachment to cells, and its antibodies can neutralize the virus, playing a major role in immunology. Neuraminidase acts on the release of viruses from cells, so its antibodies cannot neutralize the virus but can limit viral release, shortening the infection process.

The nucleic acid of the influenza virus consists of eight segments of single-stranded RNA. The nucleoprotein exhibits specificity and can be classified into types A, B, and C using complement fixation tests. Antibodies against the nucleoprotein do not protect against viral infection. In addition to the nucleoprotein, the viral core contains three polymerase proteins (P₁, P₂, P₃), the properties of which are unknown. The core is surrounded by membrane proteins (M₁, M₂) and a lipid envelope.

Variation in influenza A virus is a common natural phenomenon, primarily involving changes in hemagglutinin (H) and neuraminidase (N). Hemagglutinin subtypes include H₁, H₂, and H₃, while neuraminidase subtypes are limited to N₁ and N₂. Sometimes only one antigen undergoes variation, while other times both antigens change simultaneously. For example, the prevalent strain from 1946 to 1957 was (H₁N₁), and from 1957 to 1968, it was (H₂N₂). An influenza outbreak in Hong Kong in July 1968 was caused by the A(H₃N₂) strain. Since 1972, all subsequent outbreaks have been caused by influenza A (H₃N₂), with only minor antigenic variations compared to previous strains, all belonging to the (H₃N₂) lineage. Since 1976, the old strain (H₁N₁) re-emerged, referred to as the "Russian strain" (H₁N₁), causing outbreaks among young individuals (especially students). The variation in influenza A virus occurs when two different strains simultaneously infect a single cell, leading to viral gene reassortment. This results in changes in hemagglutinin and/or neuraminidase, giving rise to new strains—a phenomenon known as antigenic shift. For example, the hemagglutinin gene of a human epidemic strain may reassort with that of an avian influenza virus. Another mechanism, called antigenic drift, involves the emergence of epidemic strains through mutation and selection under immune pressure, primarily involving amino acid substitutions in hemagglutinin. All HN epidemic strains since 1968 have arisen this way.

Webster RG et al. reported in 1993: Phylogenetic analysis based on the nucleotide sequences of RNA segments from 8 strains of influenza A viruses indicated that human influenza A viruses originated from the avian influenza virus gene pool. The authors conducted phylogenetic studies on the classical H₁N₁ strains circulating in Italian swine populations, avian H₁N₁ strains, and human strains, revealing that genetic recombination occurred between avian and human viruses in European swine populations. The authors suggested that European pigs might serve as a mixing vessel for the genetic reassortment of influenza viruses from human and avian hosts, thus proposing that the next global pandemic could potentially originate in Europe.

bubble_chart Pathogenesis

Droplets containing influenza virus particles (generally less than 10μm in diameter) are inhaled into the respiratory tract, where the viral neuraminidase disrupts neuraminic acid, hydrolyzes mucoproteins, and exposes glycoprotein receptors. These receptors then bind to hemagglutinin (which contains glycoprotein components), a process known as specific adsorption. This binding is highly specific and can be inhibited by hemagglutinin antibodies. In human respiratory secretions, there is a soluble mucoprotein that also acts as an influenza virus receptor and can bind to hemagglutinin, thereby inhibiting viral entry into cells. However, this protective effect only becomes significant when respiratory mucus secretion increases after the onset of flu symptoms. When the virus enters the cell, its envelope is lost outside the cell. In the early stages of infection, influenza virus RNA is transported into the nucleus, where, with the participation of viral transcriptase and cellular RNA polymerase II, the viral RNA is transcribed to form complementary RNA, which serves as a template for viral RNA synthesis. The complementary RNA quickly binds to ribosomes to form messenger RNA, which, with the help of replicase, replicates viral RNA. This RNA then migrates to the cytoplasm for assembly. Nuclear proteins synthesized in the cytoplasm are rapidly transported to the nucleus, where they combine with viral RNA to form nucleocapsids. Before maturation, various viral components assemble on the cell surface, and the final assembly process, called budding, involves the local cell membrane protruding outward to envelop the nucleocapsids bound to the membrane, forming newly synthesized infectious virions. At this stage, neuraminidase hydrolyzes glycoproteins on the cell surface, releasing N-acetylneuraminic acid and facilitating the release of replicated viruses to infect nearby cells. This leads to widespread infection of respiratory ciliated epithelial cells, causing degeneration, necrosis, and shedding, and triggering an inflammatory response. Clinically, this manifests as systemic toxemia-like symptoms such as fever, muscle pain, and leukopenia, but viremia does not occur.

The pathological changes in uncomplicated influenza A primarily involve degeneration, necrosis, and shedding of respiratory ciliated epithelial cells. By days 4–5 of illness, the basal cell layer begins to proliferate, forming undifferentiated epithelial cells, and ciliated epithelial cells reappear and regenerate after about 2 weeks.

In influenza virus pneumonia, the lungs exhibit congestion and edema, with a dark red appearance on sectioning. Bloody secretions are present in the trachea and bronchi, and submucosal layers show focal hemorrhage, edema, and cellular infiltration. The alveolar spaces contain fibrin and exudate, presenting as serous hemorrhagic bronchopneumonia. Influenza virus can be detected using fluorescent antibody techniques.

If secondary Staphylococcus aureus infection occurs, the pneumonia may present as patchy consolidation or abscess formation, with a high risk of empyema or pneumothorax. Concurrent pneumococcal infection may lead to lobar or lobular consolidation. Secondary infections with Streptococcus or Klebsiella pneumoniae typically manifest as interstitial pneumonia.

bubble_chart Clinical Manifestations

The incubation period of this disease is generally 1 to 3 days (ranging from a few hours to 4 days). Clinically, it may present with sudden high fever, severe systemic symptoms but relatively mild respiratory symptoms, manifested as fear of cold, fever, headache, lack of strength, and general body aches. The body temperature can reach 39–40^°C, usually lasting 2–3 days before gradually subsiding. Systemic symptoms gradually improve, but upper respiratory symptoms such as stuffy nose, runny nose, sore throat, and dry cough become more pronounced. A few patients may experience epistaxis, loss of appetite, nausea, constipation, or diarrhea, which are grade I gastrointestinal symptoms. Physical examination reveals an acutely ill appearance, flushed cheeks, grade I conjunctival congestion and tenderness of the eyeballs, pharyngeal congestion, and possible herpes on the oral mucosa. Lung auscultation may only detect coarse breath sounds, occasionally with pleural friction sounds. After symptoms subside, patients may still feel weak, mentally fatigued, and slow to recover physically.

**(1) Pulmonary Complications** The following three types may occur:

**1. Primary Viral Pneumonia** This is relatively rare and was the main cause during the 1918–1919 pandemic. It is more common in patients with pre-existing heart or lung diseases (especially rheumatic heart disease or mitral stenosis) or pregnant women. The pulmonary lesions are primarily serous hemorrhagic bronchopneumonia, with red blood cell extravasation, fibrinous exudate, and hyaline membrane formation. Clinically, symptoms include persistent high fever, dyspnea, cyanosis, paroxysmal cough, and hemoptysis. Physical examination reveals diminished breath sounds in both lungs, widespread wheezing, but no signs of consolidation. The course can last 3–4 weeks, with low white blood cell counts and neutropenia. Chest X-rays show scattered flocculent shadows in both lungs. Patients may die from heart failure or peripheral circulatory failure. Sputum and blood cultures are negative, and the mortality rate is high.

**2. Secondary Bacterial Pneumonia** The illness begins as simple influenza but worsens after 2–4 days, with increased fever, shivering, and significant systemic toxicity. Cough intensifies, producing purulent sputum, and may be accompanied by chest pain. Physical examination reveals dyspnea, cyanosis, widespread rales in the lungs, and signs of consolidation or focal pneumonia. White blood cell and neutrophil counts are significantly elevated. Influenza virus is difficult to isolate, but pathogenic bacteria (commonly Staphylococcus aureus, Streptococcus pneumoniae, or Haemophilus) can be found in sputum.

**3. Mixed Viral and Bacterial Pneumonia** Influenza virus and bacterial pneumonia coexist. The onset is acute, with persistent high fever and severe illness, presenting as bronchopneumonia or lobar pneumonia. In addition to rising influenza antibody levels, pathogenic bacteria can also be identified.

**(2) Extrapulmonary Complications**

**1. Reye's Syndrome** This is a hepatic and neurological complication of influenza A and B, and can also occur with varicella-zoster virus infection. It is limited to children aged 2–16 and can occur in outbreaks related to influenza. Clinically, nausea and vomiting appear several days after acute respiratory infection subsides, followed by neurological symptoms such as drowsiness, unconsciousness, and convulsions. There is hepatomegaly but no jaundice. Cerebrospinal fluid examination is normal, with no signs of encephalitis. Blood ammonia is elevated, and there is grade I liver function impairment. Pathological findings show only cerebral edema and hypoxic neuronal degeneration, with fatty infiltration of hepatocytes. The cause is unknown, but recent studies suggest an association with aspirin use.

**2. Toxic Shock Syndrome** This often occurs after influenza, accompanied by respiratory failure. Chest X-rays may show adult respiratory distress syndrome (ARDS), but pneumonia lesions are not obvious. Influenza antibody levels may rise in the blood, and pathogenic bacteria (commonly Staphylococcus aureus) can be found in tracheal secretions.

**3. Rhabdomyolysis** This involves local or systemic skeletal muscle necrosis, presenting as myalgia and muscle weakness. Serum creatine phosphokinase (CPK) is elevated, with electrolyte imbalances, and may lead to acute renal failure.

bubble_chart Auxiliary Examination

(1) Blood Picture The total white blood cell count decreases, with a relative increase in lymphocytes and disappearance of eosinophils. In cases of concurrent bacterial infection, the total white blood cell count and neutrophils increase.

(2) Immunofluorescence or Immunoenzyme Staining for Antigen Detection A smear specimen of mucosal epithelial cells from the patient's nasal wash is stained with fluorescent or enzyme-labeled influenza virus immune serum to detect antigens. This method yields rapid results and has high sensitivity, aiding in early diagnosis. If monoclonal antibodies are used to detect antigens, it can differentiate between influenza types A, B, and C.

(3) Polymerase Chain Reaction (PCR) for Influenza Virus RNA Detection This method directly detects viral RNA from patient secretions and is a direct, rapid, and sensitive approach. Currently, an improved PCR-enzyme immunoassay (PCR-EIA) is used for direct influenza virus RNA detection, which is far more sensitive than viral culture and allows for rapid, direct measurement.

(4) Virus Isolation The gargle fluid from acute-phase patients is inoculated into the amniotic or allantoic sac of chicken embryos for virus isolation.

(5) Serological Tests Hemagglutination inhibition tests and complement fixation tests are used to measure antibodies in acute-phase and convalescent-phase sera. A fourfold or greater increase in antibody titer is considered positive. Neutralization immunoenzyme tests can measure neutralizing titers and detect neutralizing antibodies, which are useful for retrospective diagnosis and epidemiological investigations.

bubble_chart Diagnosis

During a flu epidemic, diagnosis is relatively easier and can be based on: ① exposure history and group onset; ② typical symptoms and signs. Sporadic cases are harder to diagnose. If a unit experiences a sudden increase in upper respiratory infections within a short period, the possibility of influenza should be considered, and further examinations should be conducted for confirmation. This disease should be differentiated from the following conditions.

bubble_chart Treatment Measures

Influenza patients should rest in bed early, drink plenty of water, and prevent secondary infections. For those with severe high fever and body pain, analgesic and antipyretic drugs can be used, but care should be taken to prevent collapse caused by excessive sweating. Aspirin is prohibited in children to prevent the occurrence of Reye's syndrome. For dry cough, medications such as carbetapentane, brown mixture, or codeine can be used. Patients with high fever and severe toxic symptoms should receive fluid infusion and physical cooling, with close monitoring of their condition and timely management of complications. If secondary bacterial infections occur, appropriate antibacterial drugs should be administered early based on the pathogen. Chinese medicinals such as common cold infusion granule and Isatis Root infusion granule, when used within the first 1–2 days of illness, can alleviate symptoms but have no antiviral effect.

Elderly influenza patients or nursing home residents should be given amantadine or rimantadine within the first 1–2 days of illness to reduce symptoms, shorten the course of the disease, and provide therapeutic effects. The adult dose of amantadine is 100–200 mg daily, divided into two doses, while the pediatric dose is 4.4–8.8 mg/kg daily, also divided into two doses. The treatment course lasts 5–7 days, and generally, there are no side effects. However, gastrointestinal and neurological reactions such as excessive excitement, slurred speech, tremor, insomnia, dizziness, lack of strength, mood disorders, and ataxia should be monitored. Rimantadine has fewer side effects than amantadine. Renal function decline or interactions with anion drugs (e.g., triamterene) can inhibit the tubular secretion of amantadine. Therefore, elderly patients over 65 years old with renal impairment should reduce the dose and be cautious of side effects. In about 30% of patients treated with amantadine or rimantadine, drug-resistant dermatitis medicamentosa strains can be isolated, whereas such strains are less frequently isolated in close contacts receiving prophylaxis. These resistant strains can emerge as early as 2–3 days into treatment and retain their medicinal property resistance after multiple laboratory passages, demonstrating genetic stability. During outbreaks in households and nursing homes, these resistant strains can spread among patients. Notably, even contacts who received drug prophylaxis may still develop typical influenza symptoms.

bubble_chart Prevention

(1) Early Detection and Rapid Diagnosis of Influenza Timely reporting, isolation, and treatment of patients are essential. Suspect an outbreak and report the epidemic promptly under the following circumstances: ① A continuous increase in outpatient upper respiratory infections for three consecutive days, with a sharp upward trend; ② The consecutive appearance of clinically typical influenza cases; ③ A continuous rise in households with two or more cases of fever or common cold. In such situations, take measures to isolate patients early and locally, collect specimens from acute-phase patients for virus isolation and antigen detection to confirm the diagnosis early, initiate early treatment, reduce transmission, lower incidence rates, and control the outbreak. During epidemics, reduce large gatherings and group activities, and contacts should wear masks.

(2) Drug Prevention Amantadine and rimantadine have some preventive effect against influenza A but are ineffective against influenza B. Therefore, it is crucial to identify the epidemic strain type early in the outbreak and administer prophylactic drugs to unprotected populations and nursing home residents. Chinese herbal medicine may also be tried for prevention.

(3) Vaccine Prevention Influenza vaccines can be divided into live attenuated vaccines and inactivated vaccines. After vaccination, serum and secretions develop anti-hemagglutinin antibodies, anti-neuraminidase antibodies, or T-cell cytotoxic responses. The former two prevent viral invasion, while the latter reduces disease severity (grade III) and accelerates recovery. Live attenuated vaccines administered via nasal spray induce local antibodies to block viral adsorption, providing protection against the same influenza strain for six months to a year, reducing incidence rates by 50–70%. Inactivated vaccines are administered subcutaneously as trivalent vaccines and are used for key populations during small to medium-sized outbreaks.

Due to frequent influenza virus mutations, the primary challenge in vaccine use is selecting the appropriate viral strain. The vaccine strain should closely match the epidemic strain. According to recommendations from the CDC's Advisory Committee on Immunization Practices in the U.S., the 1994–1995 trivalent influenza vaccine included the following strains: A/Texas/36/1 (H₁N₁), A/Shandong/9/93 (H₃N₂), and B/Panama/45/90 (influenza B). In addition to the influenza vaccine, elderly individuals should also receive pneumococcal vaccines to prevent lower respiratory complications. Mader R et al. reported three cases of systemic vasculitis following influenza vaccination, which, although rare, should be considered during large-scale vaccination campaigns.

bubble_chart Differentiation

(1) Respiratory tract infection: The onset is relatively slow, with mild symptoms and no obvious signs of toxicity. Diagnosis can be confirmed through serological and immunofluorescence tests.

(2) Epidemic cerebrospinal meningitis (meningococcal meningitis): Early symptoms of meningococcal meningitis often resemble influenza, but it has a distinct seasonal pattern and is more common in children. Early symptoms such as severe headache, meningeal irritation signs, petechiae, and herpes labialis can help differentiate it from influenza. Cerebrospinal fluid examination can confirm the diagnosis.

(3) Legionnaires' disease: This disease is more common in summer and autumn, clinically presenting as severe pneumonia with elevated total white blood cell count and complications involving the liver and kidneys. However, mild cases may resemble influenza. Antibiotics such as erythromycin, rifampin, and gentamicin are effective against this disease, and diagnosis can be confirmed through etiological tests.

(4) Mycoplasma pneumonia: Mycoplasma pneumonia has similar X-ray findings to primary viral pneumonia, but the former is milder in severity. Cold agglutination tests and MG streptococcus agglutination tests may yield positive results.