Pathogenesis

There are three serotypes - A, B and C. Influenza A and B viruses cause most clinical disease:

• A is the more frequent and the cause of major influenza outbreaks.
• B tends to circulate with A in yearly outbreaks and causes less severe illness.
• C tends to cause a mild or asymptomatic illness akin to the common cold.

Influenza A serotypes are further categorised by their surface antigens:

• H: haemagglutinin - facilitates entry of the virus into the host respiratory cell.
• N: neuraminidase - facilitates release of virions from the infected host cells.

There are 15 H and 9 N subtypes of the A virus in aquatic birds, which together with pigs (often termed the 'mixing vessel' for scrambling human and avian virus genetic material) are the natural reservoir of the virus. Many of the newer types of influenza are thought to have arisen in China because of the often close co-habitation there of pigs, fowl and humans. Swine flu is an influenza A virus most frequently of subtype H1N1, usually found in pigs but able to be transferred to humans.

The influenza virus undergoes minor mutations to one or both of its surface antigens - antigenic drift. This causes seasonal epidemics where people have only partial immunity from previous infection.

In influenza A alone, major and sudden changes in the H and N antigens produce a new virus subtype - antigenic shift. There is little population immunity to the new form and a major epidemic may ensue.

There is evidence emerging that humans can serve as the 'mixing vessel' for at least some of the 15 avian subtypes circulating in bird populations.

Epidemiology

Incidence

Cases peak:

• From December to March in temperate regions of the Northern hemisphere.
• From May to September in the Southern hemisphere.
• Throughout the year in tropical areas.

Up to 15% of the population can develop influenza in any year. There is a 10-20% seroconversion rate with or without symptoms. In an average year, there are 50-200 GP consultations for influenza, or flu-like illnesses, per 100,000 population per week.^[1] It is highly infectious with a ratio of infections to clinical cases of between 3:1 and 9:1.

An epidemic can be declared when the GP consultation rate for new cases of influenza or flu-like illness is >400 per 100,000 population per week. This occurred in the UK in 1989/1990.

The World Health Organization (WHO) has defined the criteria for a pandemic:

• The disease must be new to the population - or at least a disease that had not surfaced for a long time.
• This disease must be caused by disease-causing agents that infect humans, causing serious illness.
• The agents must spread easily and sustainably among humans.

There have been four pandemics in the last 100 years. The effects can be devastating; the 1918 outbreak killed around 21 million worldwide (that is 6 x more casualties than the First World War):^[2]

• The most recent was swine influenza virus (H1N1v) reaching pandemic proportions in June 2009 in the UK.^[3] Swine influenza A virus was quite different to previous viruses. The human community initially had little immunity to it. The young were at most risk and those aged over 60 years at least risk.^[4] Epidemics occurred worldwide in 209 countries with considerable morbidity and at least 14,142 deaths.^[5]
• The National Pandemic Flu Service (NPFS) was established in the UK at the height of the pandemic, but this was disbanded in February 2010 as the number of cases fell.
• Continuing WHO surveillance reveals that in the winter of 2011-12 the majority of cases in Europe were associated with influenza A(H3N2),^[6] although H1N1 was over-represented in severe cases compared with the other 2 circulating viruses in France, Ireland, Spain and the UK.
• Vaccines developed for 2012-13 will primarily be against serotypes H3N2, H1N1 and influenza B.^[7]

Risk factors

• Closed environments, eg residential homes, schools and prisons.
• Advanced age.
• Pre-existing cardiac or respiratory illness.

Presentation

Transmission is either by:

• Droplet due to coughing/sneezing.
• Direct nasal or eye contact with hands carrying the virus.

After an incubation period of around two days the patient commonly presents with rapid onset of:

• Anorexia.
• Malaise.
• Headache (retro-orbital).
• Fever.
• Myalgia.
• Non-productive cough and sore throat.

Nasal discharge/obstruction and sneezing can occur but are not usually prominent features of the illness.^[2] Fever may not be seen in older patients. Gastrointestinal symptoms are not usual but may occur in a minority of patients.

Swine flu is similar to the usual human seasonal influenza infection, with most cases in adults and children being mild. Clinicians are encouraged to diagnose swine flu based on symptoms if there is a pyrexia (≥38°C), fever or history of fever and flu-like illness (two or more of the following symptoms: cough, sore throat, rhinorrhoea, widespread muscle and joint aches, headache). There may also be any of the following: fatigue, loss of appetite and sometimes diarrhoea, nausea, vomiting, otitis media and, rarely, cerebral irritability ± seizures.^[4]

Most symptoms typically last for 3-5 days but cough, tiredness and malaise may last for 1-2 weeks. Infectivity continues for five days from onset, although children can remain infectious for two weeks, and the severely immunocompromised can shed virus for weeks.

Atypical symptoms in children

In H1N1 influenza these include haematemesis, photophobia, chest pain, epistaxis, croup, apnoea, and rigors. Very young children and babies can present with apnoea, reduced tone and poor feeding (without classical influenza features) and may exhibit a sudden severe collapse (apparent life-threatening episode).^[4]

With all influenzas, neonates and infants may present with lethargy, poor feeding, apnoea or fever, pneumonia or otitis media. Drowsiness occurs in 50% of children aged <4 years, and in around 10% of children aged 4-15 years. It is uncommon in adults.

Differential diagnosis

The most important are listed below:

• Common cold/upper respiratory tract infection.
• Pharyngitis - multiple aetiologies.
• Meningitis.
• Bacterial or viral pneumonia/lower respiratory tract infection.
• Malaria or dengue fever in returning travellers.
• Infectious mononucleosis.
• Cytomegalovirus.
• Acute HIV seroconversion illness.

In pregnant women, always consider pulmonary embolus (chest pain, tachypnoea and tachycardia) and pre-eclampsia (epigastric pain, headaches and elevated blood pressure).

Investigations

The diagnosis is a clinical one so investigations are usually reserved for community surveillance purposes. Available tests include:

• Direct viral culture of nasopharyngeal swabs/aspirates.
• Immunofluorescence of nasopharyngeal swabs/aspirates.
• Acute and convalescent sera, 10-14 days apart.
• Polymerase chain reaction.
• Rapid bedside antigen tests. These currently have low positive predictive values.^[8]

Management

General measures

In otherwise healthy individuals with uncomplicated illness, self-management is recommended, including resting at home, increased fluid intake, analgesics and antipyretics.

NB: Aspirin should be avoided in children aged <16 years due to the danger of Reye's syndrome.

Pharmacological

Three antiviral drugs are licensed for the treatment of influenza. GPs can prescribe antivirals to susceptible individuals if considered at risk.^[9] These are covered in detail in the separate article Antivirals for Influenza.

Please remember to endorse prescriptions 'SLS'; otherwise, community pharmacies will not be able to dispense on the NHS.

Post-exposure prophylaxis

This is covered in detail in the separate Antivirals for Influenza article.

Complications

Respiratory complications include:

• Acute bronchitis (about 20% of cases, with increased risk in the elderly and those with chronic disease).
• Secondary bacterial pneumonia (especially Staphylococcus aureus).
• Primary viral pneumonia.
• Exacerbations of asthma and chronic obstructive pulmonary disease (COPD).
• Empyema.
• Pulmonary aspergillosis.
• Sinusitis.

Non-respiratory complications include:

• Febrile convulsions.
• Otitis media.
• Toxic shock syndrome.
• Myositis and myoglobinaemia.
• Heart failure.
• Myocarditis.^[4]
• Reye's syndrome.
• Guillain-Barré syndrome.
• Transverse myelitis.
• Encephalitis.

Risk of complications with hospitalisation and death are higher among:

• Those aged >65 years.
• Very young children.
• Those with at-risk factors shown above.

Residents of nursing homes are particularly at risk of serious complications because of their age, high rate of chronic disease and living in a closed community. In pregnant women there is a slight increase in perinatal mortality rate as well as early and late fetal deaths.

Prognosis

Each year more than 20,000 deaths worldwide are attributed to influenza.^[2] During epidemics this can be much higher. Typically seasonal influenza (H3N2) has a greater effect on mortality rates in the elderly, but H1N1 tended to affect children and young adults.^[10]

Prevention

See separate article Influenza Vaccination.