Influenza

• Influenza ("flu") is an acute respiratory infection caused by influenza A and B viruses, which infect the nose, throat and lungs.
• It starts suddenly, usually with fever, chills, aching muscles, headache and a dry cough, and most people recover in 3 to 7 days. ^[4]
• The important dangers are not the cough itself but complications: viral pneumonia, secondary bacterial pneumonia (often with Streptococcus pneumoniae or Staphylococcus aureus), and worsening of heart or lung disease.
• A nucleic acid (PCR) test confirms the diagnosis reliably; rapid antigen tests are fast but miss many cases, especially outside peak season.
• Antivirals (oseltamivir, baloxavir, zanamivir) shorten illness if started within 48 hours, and benefit is greatest for people at high risk of complications; antibiotics do not treat flu. ^[9]
• An annual flu vaccine for everyone 6 months and older is the best prevention, with antiviral post-exposure prophylaxis reserved for selected high-risk people.

By the end of this page you should be able to:

1. Describe the influenza virus, its two surface proteins, and how antigenic drift and shift change it over time.
2. Explain seasonality, transmission and the approximate burden of disease.
3. Recognise the typical presentation of uncomplicated influenza and its complications.
4. Choose the right test and interpret a negative result correctly.
5. Decide who should receive antiviral treatment, which drug, at what dose, and within what time window, and who benefits from chemoprophylaxis.
6. Plan vaccination, infection control and low-resource management.

Most people experience "seasonal influenza": self-limited infection during winter epidemics. "Novel" influenza A viruses of animal origin (for example avian or swine viruses) are a different and potentially pandemic threat. The viral RNA is segmented, which is why antigenic shift can happen.

Influenza viruses are RNA viruses with a genome split into eight segments. Two proteins dominate the surface and the immune response:

• Hemagglutinin (HA, H) binds to sialic acid on respiratory epithelial cells and allows the virus to enter the cell.
• Neuraminidase (NA, N) cleaves new virus particles free from infected cells so they can spread.

The subtypes of influenza A are named by their H and N proteins (for example, H1N1 and H3N2). Influenza B has no comparable subtype system and evolves more slowly.

Antigenic drift is the slow accumulation of small mutations in the HA and NA genes. The new virus is related to the old one but different enough that existing antibodies bind less well; this is why the same person can catch flu more than once and why vaccine composition is reviewed every year. ^[2]

Antigenic shift is an abrupt, major change in an influenza A virus, producing new HA or new HA and NA combinations in a virus that infects humans. It can occur when a virus of animal origin gains the ability to infect people. Most people have little immunity to the new virus, so shift can start a pandemic. ^[2] The 2009 H1N1 pandemic began this way: an H1N1 virus with genes from swine, human and avian influenza viruses emerged and spread rapidly. ^[2] Flu pandemics have been rare, with four in the past 100 years. ^[2]

Seasonal influenza A and B epidemics return every year. In the United States, one estimate found that about 8% of all ages (range 3% to 11%) had symptomatic influenza each season during 2010 to 2016. ^[8] Earlier U.S. estimates assigned 4.3 to 23 million medical visits, 140,000 to 960,000 hospitalisations and 12,000 to 79,000 respiratory and circulatory deaths to seasonal epidemics each year during 2010 to 2018. ^[8] A modelling study estimated 291,243 to 645,832 seasonal influenza-associated respiratory deaths worldwide each year. ^[8]

The virus spreads from person to person by respiratory droplets, aerosols and contaminated hands. Transmission surges in autumn and winter in temperate regions; in the tropics, influenza circulates year round with less distinct peaks.

About 9 out of 10 people hospitalised with influenza had at least one underlying health condition in recent seasons. ^[3] This is why the same virus causes a mild illness in one person and respiratory failure in another.

Severe disease and death concentrate in the very young, the very old, pregnant women, nursing-home residents and people with chronic pulmonary, cardiac, metabolic, renal, hepatic, haematological or neurologic disease, or impaired immunity. ^[3][8] Young children, especially those under 2 years, have much higher hospitalisation rates than older children and young adults, plausibly because of an immature immune response and lack of prior exposure to circulating viruses. ^[8]

Influenza infects ciliated epithelial cells of the upper and lower airways. HA binds to sialic acid residues on the cell surface, the virus is taken up, and viral replication begins within hours. Infected cells release virus and inflammatory cytokines (including IL-6 and TNF-alpha), producing fever, myalgia and malaise; damaged epithelium and inflamed airways produce cough and sore throat. Neuraminidase then releases new virions to spread deeper into the lung and to the next host.

Most damage is mediated by the host inflammatory response and by the loss of mucociliary clearance, which sets the scene for secondary bacterial infection.

Uncomplicated influenza is recognised by its abrupt onset:

• fever and chills
• generalised myalgia and headache
• malaise and marked fatigue
• non-productive cough
• sore throat and rhinitis

Many people with influenza, especially older or immunosuppressed people, do not develop a fever. ^[4] Frail, institutionalised older adults may present with mental status changes, behavioural changes or loss of appetite rather than classic symptoms. ^[4] In young children, nausea, vomiting and diarrhoea may accompany the respiratory illness. ^[4]

Symptoms usually resolve in 3 to 7 days for most people, but cough and malaise can persist for more than two weeks, particularly in older adults and those with chronic lung disease. ^[4]

The IDSA guideline lists the major problems to watch for:

• Lower respiratory tract: primary influenza viral pneumonia and secondary invasive bacterial pneumonia, most commonly with Streptococcus pneumoniae, Staphylococcus aureus (methicillin-sensitive or methicillin-resistant) and group A streptococcus. ^[8] This bacterial coinfection was a major cause of death in the 1918 and 2009 pandemics. ^[8]
• Extrapulmonary: myocarditis and pericarditis, rhabdomyolysis, encephalitis and encephalopathy, acute disseminated encephalomyelitis, transverse myelitis, Guillain-Barre syndrome, and cerebrovascular events. ^[8] Neurological complications may be driven by cytokine dysregulation rather than direct viral invasion of the brain. ^[8]
• Reye syndrome: a rare neurologic complication associated with influenza (more common with influenza B than A) and salicylate exposure. It has been very rare since aspirin use in children with influenza was discouraged from 1982. ^[4]
• Exacerbation of chronic disease (coronary artery disease, heart failure, asthma, COPD), dehydration, and invasive meningococcal infection following influenza. ^[4][8]

Influenza is not the only winter virus. Consider:

• COVID-19 and other respiratory viruses (respiratory syncytial virus, adenovirus, parainfluenza)
• Bacterial pneumonia or sinusitis that may need antibiotics
• Streptococcal pharyngitis
• Malaria or dengue in travellers returning from endemic areas
• A bacterial coinfection on top of flu, which changes management

Clinical and epidemiological clues help (abrupt onset, fever with myalgia in winter, local circulation). Confirmation requires a test, because neither clinician judgement nor symptoms alone are specific.

A test is not needed for an uncomplicated outpatient if it will not change management. ^[5] Testing is recommended for all patients admitted with acute respiratory illness. ^[8]

• Molecular assays (PCR, other NAATs) are the most accurate: sensitivity 90 to 95% and high specificity. ^[5] Results take minutes to a few hours. IDSA recommends rapid molecular assays for outpatients and RT-PCR or other molecular assays for hospitalised patients. ^[5][8]
• Rapid influenza diagnostic tests (RIDTs) detect viral antigen in 10 to 15 minutes but have only 50 to 70% sensitivity (up to 75 to 80% with a reader device, and FDA requires 80% sensitivity). ^[5] A negative RIDT is commonly false negative, particularly at the peak of the season, so negative results should be confirmed with a molecular test. ^[5]
• Immunofluorescence and viral culture are reserved for specific situations; viral culture takes days and is a public-health rather than clinical tool.
• Serology is not recommended for clinical management.

The cycle threshold difference between laboratories does not change the basic rule: the post-test probability depends on how much influenza is circulating in the community, and a negative result in a high-risk patient with classic illness should not delay treatment. IDSA also sets specimen and timing rules: upper respiratory samples (best a nasopharyngeal swab, or a combined nasal-throat swab) taken as soon as possible, ideally within 4 days of symptom onset, with lower respiratory samples for patients on ventilation. ^[8]

Full blood count, renal function, oxygen saturation, chest radiography and procalcitonin (to help exclude bacterial coinfection) are guided by severity. ^[8]

• Start antiviral treatment as soon as possible for people who meet the criteria below; benefit is greatest within 48 hours of symptom onset, but hospitalised and high-risk patients may still benefit later. ^[1][8]
• Antibiotics do not treat influenza and should not be started for uncomplicated flu. ^[1]
• Corticosteroids are not recommended for influenza unless there is another indication (for example, an asthma exacerbation). ^[8]
• Supportive care: rest, fluids, antipyretics, oxygen, and intravenous fluids if dehydrated. Note that aspirin (and other salicylates) should not be given to children or adolescents with influenza, because of the risk of Reye syndrome. ^[4]
• Patients with suspected or confirmed influenza who are hospitalised need isolation precautions (see infection control below).

IDSA 2018 recommends starting antiviral treatment as soon as possible, regardless of vaccination status, for:

• anyone hospitalised with influenza, regardless of illness duration before admission
• outpatients with severe or progressive illness, regardless of duration
• outpatients at high risk of complications, including those with chronic medical conditions and immunocompromised patients
• children younger than 2 years and adults 65 years and older ^[8]
• pregnant women and those within 2 weeks after delivery ^[8]

Antiviral treatment can also be considered for otherwise healthy outpatients with symptom onset no more than 2 days before presentation, and for symptomatic household contacts or health-care workers caring for highly immunocompromised patients. ^[8]

Risk of severe disease rises in people with asthma, COPD, heart, kidney, liver, blood and metabolic disease, neurological conditions, obesity (BMI of 40 kg/m2 or higher), diabetes, immunosuppression, pregnancy, nursing-home residence, and in children under 2 and adults 65 and older. ^[3] During recent U.S. seasons, an estimated 9 out of 10 people hospitalised with influenza had at least one underlying condition. ^[3]

All three current antivirals inhibit neuraminidase (oseltamivir and zanamivir) or a different viral enzyme (baloxavir); use one drug, not combinations. ^[8]

• Oseltamivir (oral, 75 mg twice daily for 5 days for adults and adolescents 13 years and older). ^[9] It has the widest evidence base and is the preferred option in pregnancy. ^[1] Dose reduction is needed in renal impairment, as set out in the label. ^[9]
• Zanamivir (inhaled, 10 mg twice daily for 5 days; each dose is two 5 mg inhalations). ^[11] It is not suitable for people with underlying airways disease (asthma or COPD), because of bronchospasm. ^[11]
• Baloxavir (single oral dose, weight-based: 40 mg for 20 to less than 80 kg, 80 mg for 80 kg or more; 2 mg/kg as oral suspension for those under 20 kg), approved for uncomplicated influenza in people 5 years and older. ^[10] It is not recommended in pregnancy or breastfeeding and should not be used in hospitalised patients because of limited data. ^[1][10]
• Peramivir is a single intravenous dose used when the oral or inhaled route is not practical. ^[1]

Treatment is usually for 5 days; longer courses (10 days or more) may be considered in immunocompromised patients or severe pneumonia, because viral replication there is often prolonged, although robust randomised evidence for high doses is lacking. ^[8]

For pessimal evidence-based context: the high-quality trials supporting neuraminidase inhibitors enrolled mostly healthy outpatients within 36 to 48 hours of illness onset and showed symptom reduction of about 1 to 2 days. ^[8] Starting within 6 hours reduced symptoms by roughly 4 days. ^[8] In hospitalised patients, many observational studies report benefit even when treatment starts more than 48 hours after onset. ^[8]

IDSA emphasises that empiric antiviral treatment should be started as soon as possible for critically ill patients with suspected or confirmed influenza, because the drug is absorbed adequately even when given through a nasogastric tube. ^[8] Very low plasma oseltamivir concentrations are a concern with severe illness, but most studies show adequate exposure. ^[8] Patients on extracorporeal membrane oxygenation generally need no oseltamivir dose adjustment, while dose reduction is generally needed for patients on continuous renal replacement therapy. ^[8] Inhaled zanamivir must never be nebulised or used in mechanically ventilated patients: the lactose in the commercial formulation can obstruct ventilator equipment, and there have been severe and fatal cases reported. ^[8] Patients who are significantly hypoxaemic but not ventilated may not be able to use the diskhaler device reliably. ^[8]

Viral replication in the lower respiratory tract can be prolonged in severe influenza. Continuing antiviral therapy beyond 5 days may be beneficial in patients who are not improving, even though the optimal duration has not been defined and higher oseltamivir doses have not shown benefit in randomised trials. ^[8]

Secondary bacterial pneumonia can follow influenza and is dangerous. It should be investigated and empirically treated when a patient presents with severe disease (extensive pneumonia, respiratory failure, hypotension, fever) or deteriorates after initial improvement, and considered if there is no improvement after 3 to 5 days of antiviral treatment. ^[8] Empiric coverage must include activity against S. aureus, including MRSA, in critically ill patients. ^[8]

Prevention of complications is the reason antivirals are used. Secondary bacterial pneumonia is the classic reason for late deterioration: a patient who begins to recover, then spikes a new fever with productive cough and focal signs, has bacterial pneumonia until proven otherwise. ^[8] Myocarditis, stroke and rhabdomyolysis are less common but life-threatening. ^[8]

Most seasonal influenza is self-limited and resolves without specific treatment. The variables that matter are age, the presence of chronic illness, vaccination status and how quickly antivirals are started. High-risk adults, pregnant women, young children and immunocompromised patients account for most hospitalisations and deaths. ^[8] Early antiviral treatment in hospitalised patients is associated with better survival in most, although not all, observational studies. ^[8]

Annual influenza vaccination is the best prevention. CDC recommends it for everyone 6 months and older who does not have a contraindication. ^[7] Pregnant women should receive the injectable vaccine, which protects both mother and newborn; the nasal spray vaccine is not used in pregnancy. ^[7] Vaccine composition accounts for antigenic drift and is reviewed each season. ^[2]

Antivirals are not a substitute for vaccination. ^[1]

Routine or widespread use of antiviral drugs outside institutional outbreaks is not recommended. ^[8] Selected uses:

• For the whole influenza season in people at very high risk for whom vaccination is contraindicated or ineffective (for example, severely immunocompromised patients): oseltamivir or zanamivir. ^[8]
• Post-exposure prophylaxis within 48 hours of exposure, and continued for 7 days after the last contact, for selected high-risk or unvaccinated household contacts of a high-risk person. ^{[8] [10]}
• During outbreaks in long-term care facilities or hospitals: all exposed residents or patients receive chemoprophylaxis alongside outbreak control measures, for at least 14 days and continuing until 7 days after the last case's symptom onset. ^[8]
• Short-term pairing with vaccination for unvaccinated high-risk people during active circulation. ^[8]

Post-exposure prophylaxis should not be given once-daily if more than 48 hours have elapsed since exposure; instead, full-dose empiric treatment is started as soon as symptoms occur. ^[8]

Influenza spreads by droplets, aerosols and contaminated surfaces. In health care facilities, follow CDC infection-control guidance: standard and transmission-based (droplet/airborne as indicated) precautions, single rooms or cohorting, respiratory hygiene, surgical masks on the patient during transport, and scrupulous hand hygiene. ^[6] IDSA notes that specific institutional outbreak measures are detailed on the CDC website. ^[8]

• Pregnancy. Pregnant women are at higher risk of severe influenza and should receive the injectable vaccine; oseltamivir is recommended if treatment is needed. ^[1][7]
• Children. Children under 2 years are at high risk; zanamivir is limited to those 7 years and older for treatment and 5 years and older for prophylaxis. ^[4][11] Baloxavir is not approved under 5 years of age because of higher rates of treatment-emergent resistance. ^[10]
• Older adults. Adults 65 and older are at high risk; vaccination every year and early antiviral treatment are the anchors. ^[3][8]
• Immunocompromised patients. They may have prolonged viral shedding and require longer treatment; prophylaxis over the whole season can be justified. ^[8]
• Asthma and COPD. Zanamivir is avoided in these patients because of bronchospasm. ^[11]

Where molecular tests or antivirals are limited, the diagnosis is clinical: acute onset of fever, cough and myalgia in season is influenza until proven otherwise. ^[5] IDSA explicitly allows a clinical diagnosis in hospitalised patients when testing is unavailable, guiding empiric antiviral decisions. ^[8] Antipyretics, fluids, oxygen and early recognition of bacterial pneumonia save lives when drugs are not available. Priorities are to direct the available antiviral (usually oseltamivir) to hospitalised and high-risk patients and to keep infection-control measures (cohorting, masking, hand hygiene) even where private rooms are not available.

• Influenza is a febrile respiratory illness of abrupt onset; recovery usually takes 3 to 7 days.
• People can be infectious slightly before and for several days after symptoms begin; older adults and those with chronic disease may have no fever.
• The serious complications are viral pneumonia, secondary bacterial pneumonia (often S. pneumoniae or S. aureus), myocarditis, encephalitis, Reye syndrome and Guillain-Barre syndrome.
• Nucleic acid tests are the reliable diagnostic; rapid antigen tests miss many cases and negatives should be confirmed.
• Neuraminidase inhibitors (oseltamivir 75 mg twice daily for 5 days, zanamivir inhaled, baloxavir single dose) work best started within 48 hours, but hospitalised and high-risk patients may benefit later. ^[8]
• Antibiotics do not treat flu, but secondary bacterial pneumonia must be recognised and treated.
• Aspirin is avoided in children with influenza to prevent Reye syndrome.
• Annual vaccination for everyone 6 months and older is the single best prevention measure.
• Antiviral chemoprophylaxis is reserved for the very high risk and for outbreak settings; it is not mass prophylaxis.

• Community-acquired pneumonia and secondary bacterial pneumonia
• Sepsis and respiratory failure
• Vaccination in adults and in pregnancy
• Infection control and outbreak management in long-term care
• Aspirin and Reye syndrome in children
• Asthma and COPD exacerbations