The influenza virus is a member of the Orthomyxoviridae family with a single-stranded segmented negative-sense RNA genome. In general, the viruses appear as spherical, enveloped particles 80-120 nm in diameter. Filamentous virions are usually seen in new isolates, and can measure up to several micrometers long. Influenza viruses are classified as types A, B and C, identified by antigenic differences in nucleocapside proteins (NP) and matrix proteins (MP). Influenza virus types A and B contain eight RNA segments, while type C contains only seven with the one that encodes neuraminidase missing (5). The genomes of influenza A and B strains encode at least 10 and 11 proteins, respectively. As these genomes are segmented rather than a single piece of nucleic acids, gene re-assortment among viral strains of a same species appears more likely to occur, and so does gene mutation in a higher frequency compared with other viruses, since RNA proofreading enzymes are absent in the process of influenza virus RNA replication (5,6). Influenza A viruses are further classified, based on structures and genetic properties of surface hemagglutinin (HA or H) and neuraminidase (NA or N). Currently, 16 HA subtypes (H 1 to 16) and 9 NA subtypes (N 1 to 9) of influenza A virus have been identified (7). For each new isolate of influenza A virus, the full nomenclature includes the type of virus, the host of origin (except for human), geographical site of isolation, number of isolate, and year of isolation followed by description of HA and NA subtypes in parentheses, eg. A/Brisbane/10/2006(H3N2). Types B and C viruses follow the similar nomenclature but without subtype classification. Influenza viruses are widespread in animals. All known subtypes of the type A virus, including the 16 HA and 9 NA subtypes, have been identified in avians, waterfowls in particular, and may also infect other animals such as pigs, horses, seals, whales, and minks. So far, humans are the only natural host for influenza B viruses. Influenza C viruses can infect both humans and pigs. All influenza viruses are readily inactivated by ultraviolet and heat (usually at 56 degree Celsius for 30 minutes). A pH of less than 5 or greater than 9 may quickly attenuate the communicability of the virus. Like other enveloped viruses, influenza viruses are susceptible to all membrane-perturbing reagents, including ionic and non-ionic detergents, chlorine-based disinfectants and organic solvents (7).

Over the past 300 years, there might have been at least six pandemics of influenza, including four with detailed records in the 20th century, and the one caused by reassortant H1N1 influenza A viruses in 2009. Of those events, the 1918 influenza pandemic known as Spanish flu (H1N1) probably originated in the United States; the 1957 Asian flu (H2N2) in China's Guizhou Province; the 1968 influenza pandemic (H3N2) in Hong Kong; the 1977 influenza pandemic, also called Russia influenza (H1N1), probably in Dandong, a north-eastern city of China; and the 2009 novel influenza A (H1N1) pandemic in Mexico and the United States (10). Previous pandemics of influenza encircled the globe in 6 to 9 months, with a speed apparently constrained by patterns of human travel and not accounting for seasonal factors. Given the amount and velocity of international traffics today, spread of influenza viruses can conceivably be much faster.

Subjects with clinical or subclinical infections are the major reservoir of influenza viruses, and remain contagious from late in the incubation period through the acute phase of the disease. Typically, the mean duration for sustained viral shedding from airway discharge is 3 to 6 days in adults and older children with uncomplicated seasonal influenza. Hospitalized adults may steadily transmit the infectious virus to others throughout one week or longer after onset. Long-term shedding (for 1 to 3 weeks) of viruses can be frequent in infants and young children with seasonal influenza or in patients with H5N1 avian influenza. Immunodeficient patients, including those with AIDS, may also show a prolonged period of viral shedding (10).

Influenza is mainly spread through air droplets, or by direct or indirect contact with mucosa of the mouth, nose, eyes, and so on. Infection is also possible through contact with airway discharges and body fluids from patients, or with surfaces or materials that have been contaminated with the virus. The probable transmission through airborne aerosols from the airways is yet to be further confirmed.

People are susceptible to influenza infection throughout their lives. Moreover, influenza viruses mutate frequently. For example, novel antigenic variants of influenza A viruses with epidemiological significance will emerge every two or three years as a result of immune pressure from the host population, and the highest infection rate is usually observed among young people.

Major pathological changes include degeneration of respiratory ciliated epithelial cells, epithelial cell metaplasia, and edema and congestion of mucosal lamina propria cells with mononuclear cell infiltrates in the lamina propria. In fatal influenza viral pneumonia, the gross pathological findings include bleeding, severe tracheal bronchitis and pneumonia, characterized by widespread bronchial and bronchiolar cell necrosis with ciliated epithelial cell loss, fibrin exudation, inflammatory cell infiltration, hyaline membrane formation, congestion of alveolar and bronchial epithelial cells, interstitial edema and mononuclear cell infiltration. Later changes include diffuse alveolar damage, lymphocytic alveolitis, metaplastic epithelial cell regeneration, or even extensive tissue fibrosis. Severe cases may be complicated with pneumonia as a result of secondary bacterial infection, mostly diffuse, and sometimes localized. In general, influenza patients will have a normal or slightly low peripheral complete blood cell count with increased lymphocytes, whereas total WBC and lymphocytes usually decrease in a few severe.In severe patients, chest x-ray may suggest unilateral or bilateral pneumonia, with pleural effusions in a few cases. The severity of pneumonitis relates to cell-mediated immune response, though its significance in the pathological process is still unclear. Patients with fatal cases of influenza often show pathological changes in other organs. In one autopsy study, diffuse brain tissue hyperemia, edema, and myocardial cell swelling, interstitial hemorrhage, lymphocytic infiltration, necrosis and other inflammatory reactions have been found in one-third autopsies (5).

A typical incubation period of influenza is 1 to 7 days, 2 to 4 days in most of the times.

This is the most common type of influenza, manifested by a sudden onset, high fever (39-40 degree Celsius), chills or rigors, and in many cases, other systemic symptoms such as headache, muscle and joint pain, extreme fatigue, and loss of appetite. Sore throat, dry cough, nasal congestion, runny nose and retrosternal discomfort are commonly present. Typical patients may have facial flushing and mild conjunctival hyperemia at the lateral canthus. In uncomplicated and self-limited cases, the fever will resolve and general symptoms subside in 3 to 4 days after the onset, although disappearance of coughing and physical recovery usually takes 1 to 2 weeks. Mild cases of influenza may seem like common cold, often have fewer symptoms and can recover in 2 to 3 days.

An extremely rare type of influenza. Typical patients can have high fever, shock and disseminated intravascular coagulation (DIC) or other serious symptoms. The case fatality is high.

Apart from fever, vomiting and diarrhea feature this type of influenza. More likely affects children rather than adults. Typical patients can recover in 2 to 3 days.

During flu seasons, more than 40% of preschool and 30% of school-age children can contract influenza. An average child infected with influenza viruses may present with mild symptoms like fever, cough, runny nose, nasal congestion, sore throat, headache, and less frequently, muscle pain, vomiting and diarrhea. Quite often, influenza in infants manifests in atypical symptoms, and sometimes may lead to febrile seizures. Influenza in neonates is rare, but often gives rise to pneumonia and signs of sepsis, such as lethargy, milk refusal, and apnea. In children, influenza-induced viral laryngitis, tracheitis, bronchitis, bronchiolitis, pneumonia and gastrointestinal symptoms are more common than in adults.

This group refers to patients at the age of 65 or above. As a result of respiratory and cardiovascular co-morbidities, influenza in the elderly may present with more severe conditions, faster progression, and higher incidence of pneumonia as compared with the younger. Damage to other organs may result in abnormalities due to influenza-related viral myocarditis in ECG, heart failure, acute myocardial infarction, and even encephalitis or poor blood sugar control.

In addition to fever and cough, female patients in the second and third trimesters of pregnancy are prone to pneumonia with rapid onset of dyspnea, hypoxemia or even acute respiratory distress syndrome (ARDS), which may lead to miscarriage, premature birth, intrauterine fetal distress and death. Influenza infection during these periods may cause worsening of the underlying diseases, which is sometimes fatal. Failure to deliver a proper antiviral therapy within two days after onset is associated with a significant increase in the mortality for this population.

Immunodeficient individuals, including recipients of organ transplantation, HIV/AIDS patients and long-term users of immunosuppressant, are at a significantly higher risk of severe influenza once infected. Predisposed to influenza-related viral pneumonia, they may experience rapid onset of fever, cough, dyspnea and cyanosis, which contributes to a high mortality.

Viral pneumonia associated with seasonal influenza A (H1N1, H2N2, H3N2, etc.) occurs mainly in infants, young children, the elderly, the immunocompromised group and those with chronic cardiopulmonary conditions. The 2009 influenza A (H1N1) even caused severe viral pneumonia in young adults, obese people, pregnant women and those with chronic underlying diseases, as well as refractory hypoxemia in a few (19). Infection with highly pathogenic avian influenza can often evolve into acute lung injury (ALI) or ARDS, which is potentially fatal (20,21).

Secondary bacterial pneumonia is reported in 5-15% of patients, usually manifested by deterioration of the general conditions in 2 to 4 days after onset of influenza or worsening of the illness even after the a period of convalescence, high fever, bouts of violent coughs, purulent sputum, dyspnea, moist rales and signs of pulmonary consolidation. There is a noticeable increase in peripheral white blood cells and neutrophils. Pathogens involved in this condition mainly includes Staphylococcus aureus [esp. methicillin-resistant Staphylococcus aureus (MRSA)], Streptococcus pneumoniae or Haemophilus influenzae.

These may be associated with chlamydia, mycoplasma, Legionella pneumophila, fungi (Aspergillus), and so on. When influenza-related pneumonia does not respond to conventional anti-infective therapy, a fungal nature should be suspected.

Common viruses include rhinovirus, coronavirus, respiratory syncytial virus and human parainfluenza viruses. This type of pneumonia often affects patients with chronic obstructive pulmonary disease (COPD) and may aggravate their conditions. Differentiation from influenza-induced pneumonia is clinically difficult and should depend on pathogenic and serological studies.

Occasionally seen in children aged 14 or younger, particularly those on aspirin or other analgesic and antipyretic agents that contain salicylic acid.

Most patients have normal chest X-ray. Those with pneumonia may show patchy, multilobar infiltrates that can rapidly progress into diffuse exudative lesions or consolidation of both lungs. Pleural effusion can be seen in individual cases.

Peripheral hemogram: usually normal or lowered WBC count. Blood biochemistry: some patients may have hypokalemia, and a few have elevated levels of creatine kinase, aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, and creatinine.

Etiological investigations may be ordered, if available, for a definite diagnosis in the cases described hereinabove. Etiological investigations should be proactively accessed in those cases for which the clinical management depends substantially on a definite diagnosis. These cases may include: critical patients for whom timely initiation of antiviral therapy is to be decided on, patients in whom a confirmed diagnosis determines the use of subsequent investigations, patients for whom antibiotic treatment is pending, patients awaiting a definite diagnosis to justify subsequent infection control measures, and patients involved in an epidemiological sampling survey.

Patients who are symptomatic and test positive for at least one of the following etiological investigations can be diagnosed with influenza: Nucleic acids of influenza viruses (using either real-time or classical RT-PCR); Rapid antigen test (using either immunofluorescence or colloidal gold assay), interpreted with reference to epidemiological history; Influenza virus isolation and culture; and a four-fold or greater rise in virus-specific IgG antibody in paired acute and convalescent sera.

Patients who meet diagnostic criteria for influenza and have at least one of the following are classified as severe cases: Altered states of consciousness: confused, somnolent, irritable or convulsive; Difficulty breathing and/or increased respiratory rate ( > 30 times per minute in adults and children aged five or older; > 40 times per minute in young children aged between 1 and 5; > 50 times per minute in infants aged 2 to 12 months; > 60 times per minute in neonates or infants during the first two months of their life); Severe vomiting and diarrhea with signs of dehydration; Oliguria (urine output 2 in infants, < 300 ml/m² in pre-school children, < 400 ml/m² in school-age children, 2) < 60 mmHg (1 mmHg = 0.133 kPa), or oxygenation index (PaO₂/FiO₂) < 300; Bilateral or multilobar infiltrates on chest X-ray, or ≥ 50% extension of pulmonary infiltrates within 48 hours of admission; and a rapid elevation in levels of cardiac enzymes, including creatine kinase (CK) and MB-type isoenzyme of CK (CK-MB).

Influenza is non-specific by clinical symptoms and therefore can be readily mislabeled as common cold. Typically, influenza causes more systemic symptoms than does common cold. Retrieval of epidemiological history may be helpful in differential diagnosis. Patients with common cold are negative for influenza virus detection, or may show evidence of infection with other pathogens. Key points in the differential diagnosis (25-29) are listed in Table 1.

These include acute pharyngitis, tonsillitis, rhinitis and sinusitis, usually with localized symptoms of the infection. Discharges from the affect site are negative for influenza viruses.

Influenza should be differentiated from acute tracheobronchitis when complicated by cough or tracheobronchitis, and from other types of pneumonia (bacterial, chlamydial, mycoplasmal, viral, fungal) and tuberculosis when complicated by influenza-related viral pneumonia. A preliminary diagnosis may be determined based on clinical manifestations, followed by confirmation with etiological investigations.

Influenza should also be differentiated from non-infectious diseases which are complicated with fever and particularly lung shadows, such as in connective tissue diseases, pulmonary thromboembolism and lung cancer.

The principles of treatment of severe cases are aggressive management of primary diseases, prevention of complications, and delivery of effective organ support.

Severe pneumonia is the most common of serious, sometimes fatal, complications in influenza. About 30% of deaths from severe pneumonia are associated with secondary bacterial infections. Common causes of death include respiratory failure, refractory shock and multiple organ failure.

Severe cases of influenza can deteriorate rapidly. The time from symptom onset to hospital admission is usually 2-7 days, and 10-30% of hospitalized patients need referral to an intensive care unit (ICU) on the same day of or in 1-2 days after admission. In these severe cases, disorders of the lung as one of the most frequently involved organs are usually manifested by rapidly progressive severe pneumonia which may develop into acute lung injury occurs (ALI) or even acute respiratory distress syndrome (ARDS) (40,41). For patients in need of mechanical ventilation, relevant guideline recommendations for ventilation in the ARDS can be followed (42-44).

There is much controversy surrounding the use of ECMO in adult patients with ARDS. However, ECMO may be useful as a life-saving or life-sustaining measure in patients with severe ARDS resulting from influenza-induced pneumonia where mechanical ventilation has failed to improve the oxygenation; in particular, ECMO can be more valuable as an alternative for patients in whom acute respiratory failure is caused by correctable causes. There have been domestic and international reports on successful rescue of critical cases of severe oxygenation dysfunction with ECMO during the pandemic of 2009 influenza A (H1N1).

Refractory shock is one of the most common causes of death in influenza patients. While the shock in influenza is frequently of a septic nature, cardiogenic shock may sometimes be noted. Influenza viruses rarely cause direct damages to the heart, but they have been linked to myocarditis and pericarditis. Moreover, the viruses may activate release of proinflammatory cytokines which in turn impose indirect damages to the heart and lead to deterioration of the underlying heart disorders. In cases of severe influenza, both direct and indirect factors may contribute to the development of a cardiogenic shock.

The strategies include maintenance of the airway, breathing and circulation (ABC principles) (50), fluid replacement, use of vasoactive and inotropic agents, and mechanical circulatory support (such as intraaortic balloon pump counterpulsation).

The use of glucocorticoids in patients with severe influenza is not evidence-based by far. Low-dose glucocorticoids may be considered for patients with septic shock who need administration of vasopressors (51). High doses of systemic glucocorticoids may be associated with serious side effects (such as secondary infection or increased viral replication) in patients infected with influenza viruses, and are thus used only when hemodynamic instability is complicated. Dosage: hydrocortisone 200-300 mg/d (for adults) or 5-10 mg/kg.d (for children) i.v.; methylprednisolone 80-120 mg/d (for adults) or 1-2 mg/kg.d (for children), i.v.

Apart from the lungs, heart and kidneys, influenza viruses may also affect other organs such as meninges, nerves and muscles. In addition, the systemic inflammation induced by influenza viruses can lead to multiple organ dysfunction syndrome (MODS), which is one of the leading causes of death. Signs of probable damages to other organs should be handled with proper supportive treatments. Pay attention to nutritional support, prevent and treat gastrointestinal failure in patients with severe influenza. Restore the homostasis, particularly, correct electrolyte imbalance and metabolic acidosis.

People having definite contact with influenza patients: Prescription for children, young adults, and other healthy people: honeysuckle 6g, folium isatidis 6g, Wild Mint Herb 3g, unprocessed licorice 3g, decocted with water and administered once per day for 5 consecutive days; Prescription for the frail elderly: codonopsis pilosula 6g, Herba Periliae 6g, Fineleaf Schizonepeta Herb 6g, decocted with water and administered once per day for 5 consecutive days.

Seasonal influenza spreads very fast from person to person, making proactive prevention and control more necessary than effective yet limited treatment measures.

Maintain good indoor ventilation, and avoid gathering places during influenza epidemic; Cover coughing and sneezing with a tissue to avoid spraying droplets; Wash hands frequently and keep dirty hands away from the mouth, eyes and nose; and go to the doctor's office as soon as possible when influenza-like symptoms are present during epidemic period, stay home and minimize contact with others.

When there is an influenza epidemic in the community and two or more people in one facility have presented with influenza-like symptoms within 72 hours, pathogen detection should be performed as soon as possible to identify the cause. Once diagnosed, patients are required to be hospitalized or staying at home while maintaining good personal hygiene and minimizing contact with others. Once an intra-facility outbreak is identified, the Infectious Diseases Prevention Law and the Public Health Emergency Response Guide shall be observed. In the case of a nosocomial outbreak, protective isolation measures shall be performed in accordance with the National Influenza Surveillance Technology Guide (56).

Drug prevention is no substitute for vaccination. It serves only as an temporary preventive measure under emergency for high-risk groups who have not been immunized or have not established full immunity after inoculation. Antiviral drugs to which pandemic strains are sensitive should be the choice of preventive agents. Depending on the physician, the course of administration may generally be 1 to 2 weeks. A decision should also be made by the physician as to whether, when, and how long an additional administration will be needed and at what dose for those in whom effective immunity is not likely to establish due to immunosuppression despite vaccination.

The English full-text of these Guidelines was translated by Guangqiao Zeng (Professor of Editology and Consultant physician at State Key Laboratory of Respiratory Disease Guangzhou, First Affiliated Hospital of Guangzhou Medical College. zgqiao@vip.163.com). Dr Zeng declared no conflict of interests therein.