Introduction
Influenza is an acute viral respiratory disease caused by infection of the respiratory tract with influenza viruses (seasonal influenza A and B viruses) that circulate among people worldwide. Seasonal influenza refers to disease in humans caused by infection with seasonal influenza A or B viruses and is the focus of this Seminar. Annual influenza epidemics of variable severity typically occur during colder periods in temperate climates worldwide.1 Year-round influenza activity can be observed in tropical and subtropical areas, peaking at different times.1 Most people with influenza have self-limited upper-respiratory- tract symptoms with or without systemic signs and symptoms that temporarily affect daily activities, including missing work or school, and some might access medical care. Some individuals with influenza, particularly young children, older adults, pregnant people, and those with certain underlying conditions, can have complications resulting in medical care visits, hospital admissions, or in- hospital and community deaths.2
Virology
Of the four types of influenza viruses (A–D) within the Orthomyxoviridae family, three types (A, B, and C) infect and cause disease in humans. Type A and B viruses that cause epidemics worldwide are referred to as seasonal influenza viruses. Influenza viruses are enveloped viruses encoded by segmented negative-sense RNA genomes. The eight viral RNA segments of influenza A and B viruses are translated into 12 proteins. Influenza A viruses infect many avian and some mammalian species and can cause rare pandemics in humans; influenza B viruses primarily infect humans.2 Influenza C viruses infect humans and pigs and dogs.3 Influenza D viruses primarily infect cattle with spillover to other animals. Whether influenza D viruses can infect and cause disease in people is unclear, but detection of antibodies to influenza D virus has been reported in people exposed to cattle.4 Influenza A viruses are divided into subtypes on the basis of the haemagglutinin and neuraminidase surface glycoproteins. Currently, influenza A(H1N1)pdm09 and A(H3N2) viruses circulate among people worldwide. The haemagglutinin protein is
the major antigen that contains the sialic-acid-receptor binding site, and the neuraminidase aids in release of viral particles from infected cells. Influenza B viruses circulating among humans are divided into two lineages, B/Victoria/2/87 and B/Yamagata/16/88, but B/Yamagata viruses have not been detected since March, 2020.
Of the 18 haemagglutinin and 11 neuraminidase subtypes identified to date, 16 haemagglutinin (H1–16) and nine neuraminidase (N1–9) subtypes are enzootic in avian species, primarily wild waterfowl, and these viruses periodically infect animals such as poultry and pigs and establish enzootic and endemic lineages. The high error rate of the RNA-dependent RNA polymerase (RDRP) and reassortment of RNA segments during co-infections provide influenza A viruses with evolutionary power and can facilitate circulation among a new host. Both intrasubtype and intersubtype genetic reassortment occur and can rapidly select for influenza A viruses with
Seminar
Influenza
Timothy M Uyeki, David S Hui, Maria Zambon, David E Wentworth, Arnold S Monto
Annual seasonal influenza epidemics of variable severity caused by influenza A and B virus infections result in substantial disease burden worldwide. Seasonal influenza virus circulation declined markedly in 2020–21 after SARS-CoV-2 emerged but increased in 2021–22. Most people with influenza have abrupt onset of respiratory symptoms and myalgia with or without fever and recover within 1 week, but some can experience severe or fatal complications. Prevention is primarily by annual influenza vaccination, with efforts underway to develop new vaccines with improved effectiveness. Sporadic zoonotic infections with novel influenza A viruses of avian or swine origin continue to pose pandemic threats. In this Seminar, we discuss updates of key influenza issues for clinicians, in particular epidemiology, virology, and pathogenesis, diagnostic testing including multiplex assays that detect influenza viruses and SARS-CoV-2, complications, antiviral treatment, influenza vaccines, infection prevention, and non-pharmaceutical interventions, and highlight gaps in clinical management and priorities for clinical research.
Lancet 2022; 400: 693–706
Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USA (T M Uyeki MD,
D E Wentworth PhD); Division of Respiratory Medicine and Stanley Ho Centre for Emerging Infectious Diseases, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong Special Administrative Region, China (Prof D S Hui MD); Virology Reference Department, UK Health Security Agency, London, UK (M Zambon PhD); Center for Respiratory Research and Response, Department of Epidemiology, University of Michigan, Ann Arbor, MI, USA (Prof A S Monto MD)
Correspondence to:
Dr Timothy M Uyeki, Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA 30329, USA tmu0@cdc.gov
Search strategy and selection criteria
We searched PubMed for articles on influenza published in English from May 1, 2016, to April 31, 2022, on the topics included in the Seminar using the search terms “influenza”, “influenza and systematic reviews”, “influenza and diagnosis”, “influenza and therapy”, “influenza and prevention and control”, “influenza and pandemic”, “influenza and epidemiology”, “influenza and complications”, “influenza
and clinical”, “influenza clinical management”, “influenza and vaccines”, “influenza vaccine effectiveness”, “influenza and pandemic”, “influenza and transmission”, and “influenza
and risk factors”, “influenza surveillance”, “influenza disease burden”, “influenza hospitalizations”, “influenza mortality”, “influenza and diagnostic testing”,
“influenza virology”, “influenza pathogenesis”, “influenza complications”, “influenza treatment”, “influenza and antiviral treatment”, “influenza and COVID-19”, “zoonotic influenza”, “novel influenza A”, and “influenza pandemic preparedness”. The most relevant and recently published references were prioritised for inclusion. Relevant key articles older than 5 years were included when indicated.
http://www.thelancet.com Vol 400 August 27, 2022
693

694
http://www.thelancet.com Vol 400 August 27, 2022
Seminar
See Online for appendix
improved fitness. H17N10 and H18N11 virus subtypes were identified in new-world bats;5 however, these viruses use different receptors and have other features not common to influenza A viruses.6
Seasonal influenza A and B viruses primarily evolve to escape human humoral immunity via amino-acid substitutions, insertions, or deletions coding for haemag- glutinin and neuraminidase epitopes that enable the viruses to escape key antibodies induced through previous infections, vaccinations, or both. This evolutionary process is known as antigenic drift and drives annual influenza epidemics. Antigenic shift refers to human infection with a novel influenza A virus containing a haemagglutinin that is antigenically and genetically different from circulating seasonal influenza A viruses. Interspecies transmission in animals can result in genetic reassortment of viral RNA segments during co-infections with different influenza A viruses and this is central to the emergence of novel influenza A viruses, typically through zoonotic transmission. Host species-specific determinants affect the pandemic potential of influenza A viruses circulating among animals.7 Crucial determinants are the ability for a viral haemagglutinin to efficiently bind α2,6-linked sialic acids (highly expressed by epithelial cells in the upper respiratory tract of humans),8–10 and for the RDRP to transcribe and replicate the RNA genome efficiently.10 If the novel influenza A virus has the ability for sustained human-to-human transmission and most of the population does not have immunity to the novel virus, a pandemic can occur. Global surveillance for influenza viruses is crucial to monitoring antigenic drift and emergence of novel influenza A viruses (appendix pp 1–2).
Transmission dynamics and modalities
The basic reproduction number for seasonal influenza is estimated to be approximately 1·3,11 with mean serial intervals for symptomatic influenza A virus infections of 2·2 and 2·8 days.12 A systematic review estimated the median incubation period to be 1·4 days for influenza A and 0·6 days for influenza B.13 Slightly longer incubation periods have generally been considered; for example, in human challenge studies, symptoms scores peak 2–3 days after influenza A virus inoculation.14 Seasonal influenza A and B viruses are generally believed to be transmitted at a short range (1–2 metres) from person to person through large (≥5 μm) droplets and small-particle (<5 μm) droplet nuclei (aerosols) that are expelled by infected people through coughing.15 Detection of infectious virus from exhaled breath of symptomatic individuals suggests potential for aerosol transmission.16 Influenza viruses in aerosols and droplets can remain infectious for several hours at low and high relative humidity under experimental conditions.17,18 The role of contact transmission and fomite spread is not well understood but is theoretically possible because animal studies have detected viral aerosolisation from fomites,19 demonstrated efficient aerosol transmission,20 and
influenza viral RNA has been detected on surfaces,21 including recovery of infectious virus from mobile phones of people with influenza.22
Influenza virus concentrations in the upper respiratory tract are highest at illness onset or 1–2 days after illness onset and then decline substantially within 3 days for influenza A but can remain higher for influenza B in immunocompetent individuals.23,24 Young infants can shed influenza virus for more than 1 week and severely immunocompromised people can have prolonged viral shedding for weeks to months.25,26 Duration of influenza- virus detection increases with severity of illness.27 Influenza viruses can be detected in the upper respiratory tract of some people who are infected before symptom onset,24 but the contribution of transmission from presymptomatic and asymptomatic people who are infected is unclear. Influenza viral RNA concentrations in the upper respiratory tract are lower, and duration of viral RNA detection is shorter, for individuals who are asymptomatic or paucisymptomatic, versus those with more influenza symptoms.28 A systematic review of influenza-virus transmission in households reported a wide range (1–38%) of secondary infection risk.29 A study of households in South Africa reported that secondary transmission was highest from symptomatic index cases with two or more symptoms and from children aged 1–4 years; among households with asymptomatic index cases, influenza virus infection was identified in 6% of household contacts, accounting for 27% of all secondary household infections.30
Epidemiology and disease burden
Influenza epidemics occur annually during relatively cooler and lower humidity periods in temperate climates of the northern and southern hemispheres, whereas in tropical and subtropical climates, one or more peaks in influenza activity during higher absolute humidity or higher precipitation months and year-round influenza activity can occur.1,31 Influenza outbreaks can occur during interepidemic periods among people who are epidemiologically linked to travel to areas with influenza activity, including people in congregate settings. In the USA, annual incidence of symptomatic influenza is estimated to vary from 3% to 11%.32 Household-based and community-based studies in different countries have shown that influenza virus infections and illness rates are highest in children and decrease with increasing age, approximately 20–40% of symptomatic people can manifest influenza-like illness (fever and cough or sore throat), whereas up to half of people with symptomatic illnesses can experience acute upper-respiratory-tract symptoms without fever, and the asymptomatic proportion can range from 14% to more than 50%.24,28,30,33
The severity of influenza epidemics varies widely. Because of limitations in influenza testing and the small percentage of people with influenza who are tested, modellingstudiesbasedonsurveillancedataareusedto

estimate disease burden. In the USA, in 2010–20, estimated influenza-related symptomatic illnesses, medical visits, hospitalisations, and deaths ranged from 9·3 to 41·0 million, 4·3 to 21·0 million, 140000 to 710 000, and 12 000 to 52 000, respectively, per year.34 A systematic review and meta-analysis estimated that more than 32 million cases and 5·7 million hospitalisations occur from influenza-associated lower-respiratory-tract disease in adults worldwide each year, with the highest hospitalisation rates in people aged 65 years or older.35 A systematic review estimated that among nearly 110 million influenza illnesses, 870 000 hospitalisations, more than 15 000 in-hospital deaths, and approximately 35 000 deaths caused by acute lower-respiratory-tract disease worldwide occurred in children younger than 5 years in 2018, with most influenza in-hospital deaths occurring in low-income and middle-income countries.36 Epidemics caused by influenza A(H3N2) viruses are associated with higher morbidity and mortality in older adults and epidemics caused by antigenically drifted A(H3N2) viruses can also cause higher morbidity and mortality in children.37
In the USA, hospitalisation rates for laboratory- confirmed influenza are typically highest among people aged 65 years and older, children younger than 5 years, and people aged 50–64 years, with the highest mortality rate in people aged 65 years and older. Among US children, incidence of hospitalisation and in-hospital mortality rates are highest in infants younger than 6 months.38 It has been estimated that approximately 300000 influenza-associated respiratory deaths occur worldwide each year, with the highest estimated regional influenza-associated mortality rates in sub-Saharan Africa and southeast Asia.39 However, the numbers of influenza-related respiratory hospital admissions and deaths underestimate non-respiratory complications, such as exacerbation of underlying chronic conditions or major adverse cardiovascular events associated with influenza,40 particularly in older adults, and limited influenza testing can underestimate both mild and severe influenza-associated illnesses. For example, in a small Spanish study that tested respiratory specimens from deceased older adults in morgues, 10 of 57 were positive for influenza A(H3N2) virus infection, of whom only one had been diagnosed with influenza before death.41
In the USA, children younger than 5 years, people aged 65 years or older, pregnant people up to 2 weeks post partum, immunocompromised people, people with certain chronic comorbidities (eg, pulmonary, cardiac, neurological, metabolic, haematological, and extreme obesity), and long-term care-facility residents are considered to be at increased risk for influenza compli- cations that might require hospital admission or lead to death (appendix p 8).42 Among women of reproductive age hospitalised with influenza over nine seasons in the USA, nearly 28% were pregnant, and 62% were in their third trimester.43 Pregnant people can have premature labour
and fetal loss, and severe pneumonia with influenza, particularly in the third trimester up to about 2 weeks post partum,44,45 although a meta-analysis reported that pregnant people were at higher risk of hospitalisation, but not intensive-care-unit (ICU) admission or death compared with non-pregnant people.46 Non-Hispanic Black people younger than 75 years are more likely to be hospitalised and admitted to an ICU for influenza-related complications than White people in the USA.47 Similarly, people who are American Indian or Alaska Native younger than 50 years are more likely to be hospitalised or admitted to an ICU than White people, and hospitalisation rates for those younger than 5 years are higher for Black, Hispanic, American Indian or Alaska Native, and Asian or Pacific Islander children than for White children in the USA.47 The average economic cost associated with annual influenza epidemics in the USA was estimated to be US$11·2 billion, with indirect costs (eg, absenteeism from paid employment) substantially higher than direct medical-care costs.48
Diagnostic testing
Clinical diagnosis of influenza is often inaccurate because of overlapping symptoms from infections with other cocirculating respiratory pathogens, including SARS-CoV-2. Influenza testing can aid clinical decisions, but results, especially negative results, should be properly interpreted in the context of predictive values that consider the prevalence of influenza viruses in the tested population, test sensitivity, and specificity.26 Upper- respiratory-tract specimens from outpatients should ideally be collected within 4 days of illness onset, but viral RNA might be detectable for longer periods, particularly in young children and immunocompromised people. Nasopharyngeal specimens have the highest yield for influenza viruses, but a mid-turbinate nasal swab or combined nasal and throat swabs are acceptable specimens, depending upon the test. In patients hospitalised with respiratory failure, lower-respiratory- tract specimens should be tested if upper-respiratory- specimens are negative.26
Several diagnostic tests detect influenza viruses in respiratory specimens (table 1). Point-of-care (PoC) rapid antigen-detection tests detect influenza viral proteins in upper-respiratory specimens, are simple, and can produce quick results, but have lower sensitivity and lower negative predictive values than RT-PCR.26,49 Nucleic-acid amplifi- cation assays (molecular assays), including RT-PCR and loop isothermal amplification, have high sensitivity and high specificity, can detect influenza viruses for longer periods than antigen tests and can produce prompt results within 15–20 min (for PoC use) or up to several hours.26,50 Multiplex antigen tests and molecular assays can detect and distinguish influenza A, influenza B, and SARS-CoV-2 infections (and identify co-infections), and can be very useful when SARS-CoV-2 and influenza viruses are cocirculating for testing of outpatients and patients who
http://www.thelancet.com Vol 400 August 27, 2022
695
Seminar

Seminar
Rapid antigen test (10–15 min to results)
Molecular assay (45–80 min to results; up to 4–6 h for some assays) done in clinical laboratories
Virus culture (1–10 days to results); requires qualified personnel, usually done at public health laboratories
Method
Influenza viral antigen detection by antibodies using a lateral flow immunoassay or rapid immunofluorescent assay, often with a digital analyser device
Influenza viral RNA detection using nucleic acid amplification; some assays require complex machinery, preanalytical nucleic-acid extraction, and downstream analysis
Isolation of viable influenza virus using tissue cell culture
Accuracy*
Low-to-moderate sensitivity (40–80%) and high specificity
High sensitivity (>95%) and high specificity (>99%)
High sensitivity and high specificity
Comments
Can detect and distinguish influenza A and B virus infection; sensitivity is higher for tests that use an analyser device; available for point-of- care use; and multiplex tests can detect and distinguish among SARS- CoV-2 and influenza A and B virus infections
Can detect and distinguish influenza A and B virus infection; must be done in a certified clinical laboratory or public health laboratory; requires qualified laboratory personnel; multiplex assays can detect and distinguish among SARS-CoV-2 and influenza A and B virus infections; and some multiplex assays can also identify influenza A virus subtypes and other respiratory virus and bacterial pathogens
Can detect and distinguish influenza A and B virus infection; requires complex laboratory space suitable for virus propagation; shell-vial cell culture can yield results in 1–3 days; and standard tissue cell culture might require 3–10 days
Rapid molecular assay (15–40 min to results)
Influenza viral RNA detection using nucleic acid amplification; requires a small-footprint machine with an embedded analyser device
High sensitivity (>95%) and high specificity (>99%)
Can detect and distinguish influenza A and B virus infection; some assays are available for point-of-care use; multiplex tests can detect and distinguish among SARS-CoV-2 and influenza A and B virus infections; and some assays can also detect RSV
Immunofluorescence assay (1–4 h to results)
Influenza viral antigen detection by antibodies using immunofluorescent staining; requires collection of upper-respiratory-tract cells and fluorescent microscope
Moderate sensitivity and high specificity
Can detect and distinguish influenza A and B virus infection; must be done in a certified clinical laboratory or public health laboratory; requires qualified laboratory personnel; requires skilled staff; sensitivity depends upon sample preparation; and less commonly used
For respiratory specimens. Adapted from the Centers for Disease Control and Prevention.49 RSV=respiratory syncytial virus. *Compared with RT-PCR. Negative results do not necessarily rule out influenza virus infection; results should be interpreted in the context of influenza prevalence in the population being tested and the signs and symptoms of the patient, underlying medical conditions, specimen source, and test characteristics (sensitivity and specificity).
Table 1: Influenza diagnostic tests
696
http://www.thelancet.com Vol 400 August 27, 2022
were hospitalised presenting with acute respiratory illness (appendix pp 9–10). Tissue-cell viral culture of respiratory specimens does not yield timely results for clinical decision making, but is essential for antigenic characterisation and candidate vaccine development. Serology can establish a retrospective diagnosis of influenza, but requires collection of acute and convalescent sera, must be done at specialised laboratories, cannot produce timely results to inform clinical management, and is not recommended except for vaccine studies and epidemiological investigations.26
Use of PoC influenza tests outside of health-care facilities such as at pharmacies can facilitate prompt initiation of antiviral treatment.51 Home self-collection of nasal swabs can yield similar influenza testing results to swab collection by trained research staff.52 Influenza rapid-antigen tests and molecular assays that use smartphone technology are under development for home use with self-collected nasal swabs; ideally, results are transmitted in real time to a physician to facilitate rapid prescription of antiviral treatment and are included in the patient’s electronic health record.53 Other diagnostic innovations are in development (appendix p 5).
Clinical spectrum and clinical complications
The clinical spectrum of seasonal influenza ranges from asymptomatic infection, uncomplicated upper- respiratory-tract symptoms with or without fever, to complications that can result in severe disease (table 2). Fever might not be present in many people who are symptomatic, particularly in older adults and people who are immunocompromised. Systemic signs and
symptoms, such as fever, chills, myalgia, malaise, and headache typically occur abruptly with respiratory symptoms such as dry cough, sore throat, and nasal discharge.2 Gastrointestinal symptoms such as nausea, vomiting, diarrhoea, and abdominal pain can occur in children. Ocular symptoms such as lacrimation, conjunctivitis, photophobia, and painful eye movement are less common.54 Rashes have been described but are uncommon. Older adults might present with general symptoms such as malaise, anorexia, dizziness, and weakness without fever, sore throat, and myalgia. Signs and symptoms of uncomplicated influenza typically resolve after 3–7 days for most people,2 although cough and malaise can persist for more than 2 weeks, especially in older adults and those with chronic lung disease.
Respiratory complications
Influenza is associated with a wide range of respiratory complications. In children, croup, bronchiolitis, tracheitis, and otitis media can occur. In all ages, both primary influenza viral pneumonia (appendix p 6) and influenza viral co-infection with community-acquired bacterial pneumonia (appendix p 7; most commonly with Streptococcus pneumoniae or Staphylococcus aureus, methicillin-sensitive or methicillin-resistant staphylococcus aureus [MRSA], including Panton Valentine leucocidin-producing MRSA) can lead to respiratory failure, acute respiratory distress syndrome (ARDS), septic shock, and multiorgan failure.26,55,56 Community-acquired secondary bacterial pneumonia is more common with influenza than with COVID-19 in

patients requiring hospitalisation.57,58 Influenza-virus infection can exacerbate asthma, chronic obstructive pulmonary disease, and cystic fibrosis.
Co-infection with other respiratory viruses can occur, particularly in children, and influenza virus and SARS-CoV-2 co-infection can result in more severe disease in adults than either SARS-CoV-2 or influenza virus infection alone.59,60 Invasive fungal co-infection can also result in critical illness and high mortality, particularly in patients treated with corticosteroids and people who are immunocompromised, and has been reported with widely variable frequency in different countries.61 Hospital- acquired infection with multidrug-resistant bacteria causing ventilator-associated pneumonia is a severe com- plication in patients who are critically ill with influenza.
Non-respiratory complications
Patients of all ages with influenza can experience dehydration and exacerbation of underlying chronic disease (eg, heart failure, coronary artery disease, cerebrovascular disease, and diabetes). Cardiac compli- cations of influenza that can result in critical illness and fatal outcomes include acute ischaemic heart disease, myocardial infarction, and heart failure in people with pre-existing cardiovascular disease, and myocarditis and pericarditis without underlying cardiac disease.40,62 Musculoskeletal complications include mild-to-severe myositis, and uncommonly, rhabdomyolysis. Elevation of hepatic aminotransferases, can occur with severe disease, but hepatic failure is rare. A wide range of neurological complications have been described shortly after influenza symptom onset or with onset in the second week or later; encephalopathy, encephalitis, transverse myelitis, and acute disseminated encephalomyelitis are more common in children than in adults.63,64 Influenza can precipitate febrile seizures in young children and status epilepticus in people with seizure disorders. Transient altered mental status, encephalopathy with full recovery, and fulminant acute necrotising encephalitis with neurological sequelae or brain death can occur.65 Uncommon neurological complications include Guillain-Barré syndrome,66 and Reye syndrome (with salicylate exposure in children more commonly associated with influenza B than influenza A). Severe illness from toxic shock syndrome associated with S aureus or group A Streptococcus has been reported with influenza, and an association of influenza and meningococcal disease has been reported.67 Acute kidney injury requiring renal replacement therapy can complicate respiratory failure. Sepsis and septic shock can occur with influenza, with or without invasive bacterial co-infection.
Pathogenesis
Host factors (eg, age, genetics, overall health, immune history with influenza virus, and immunological function) influence severity of influenza virus infections. Severe disease can occur among infants and young children who do not have immunity from infection or
vaccination, whereas immunosenescence occurs in older adults and people who are immunocompromised. Influenza virus infection might exacerbate chronic conditions such as coronary artery disease and chronic obstructive pulmonary disease. Pregnancy (ie, third trimester), cardiovascular disease, diabetes, and obesity can impair T-cell responses that induce chronic inflammation with persistently elevated concentrations of proinflammatory cytokines such as interleukin (IL)-1, IL-6, IL-8, and tumor necrosis factor α.
Immunity resulting from first exposure to influenza viruses (termed original antigenic sin)68 has an important effect on pathogenesis because the first influenza A virus infection experienced in childhood can generate lifelong immunological memory to many different epitopes on several viral proteins, providing protection from antigenically similar influenza A viruses, although not necessarily against infection by antigenically drifted or novel influenza A viruses, but protection might be conferred against severe disease.69 During the 1918 H1N1 pandemic, young adults without previous exposure to
Seminar
Upper-respiratory complications
Cardiac complications
Musculoskeletal complications
Neurological complications
Other complications
Complications
Otitis media, parotitis, sinusitis, and laryngotracheobronchitis
Myocardial infarction, myocarditis, pericarditis, and heart failure
Myositis, rhabdomyolysis, and compartment syndrome
Encephalopathy, encephalitis, meningoencephalitis, febrile seizures, cerebrovascular accident, transverse myelitis, acute demyelinating encephalomyelitis, Reye syndrome with salicylate exposure, and Guillain-Barré syndrome
Exacerbation of chronic disease, dehydration, sepsis, toxic shock syndrome, sepsis-like syndrome or sudden death in young infants, premature labour, and fetal loss in pregnant people
Considerations
Otitis media, parotitis,
and laryngotracheobronchitis are more common in children than adults
Influenza might precipitate myocardial infarction or heart failure in people with coronary artery disease; cardiac complications can result in critical illness with fatal outcomes
Severe myositis (soleus
and gastrocnemius) can occur in school- age children; myoglobinuria can cause acute kidney injury
Encephalopathy and encephalitis are more common in young children, can be acute or postinfectious with full neurological recovery, sequelae, or fatal outcomes; Reye syndrome is rare in children without salicylate exposure, and Guillain Barre syndrome is uncommon
People of all ages with chronic disease can experience worsening of underlying conditions (eg, chronic obstructive pulmonary disease exacerbation in adults, acute chest syndrome with sickle cell disease, worsening of asthma, and heart failure)
Lower-respiratory complications
Bronchiolitis, bronchitis, reactive airway disease, pneumonia, respiratory failure, and acute respiratory distress syndrome
Bronchiolitis is more common in young children than in adults
Gastrointestinal complications
Hepatitis, pancreatitis, and severe acute abdomen-like pain
Hepatic failure is rare
Renal complications
Acute kidney injury and kidney failure
Can occur with severe pneumonia
Co-infections
Pneumonia, ventilator-associated pneumonia, tracheitis, and meningitis
Invasive bacterial, viral, and fungal coinfections can cause critical illness and fatal outcomes
Adapted from Uyeki and colleagues.26
Table 2: Complications associated with influenza
http://www.thelancet.com Vol 400 August 27, 2022
697

Seminar
Oseltamivir (oral suspension or capsule)
Peramivir (intravenous)
Dosing
Duration of treatment, 5 days; age
40 kg, 75 mg twice per day; and adults, 75 mg twice per day
Duration of treatment, single dose via intravenous infusion; age 6 months to 12 years, 12 mg/kg up to 600 mg; and age ≥13 years, 600 mg
Mechanism of action
Inhibits influenza viral neuraminidase; blocks release of progeny virions from infected respiratory epithelial cells
Inhibits influenza viral neuraminidase; blocks release of progeny virions from infected respiratory epithelial cells
Considerations
Widely available in generic formulation; can be administered enterically via orogastric or nasogastric tubes; recommended for pregnant people; recommended for patients who are hospitalised; no completed fully enrolled placebo-controlled trials; increased risk of nausea or vomiting; dosage should be adjusted for patients with reduced creatinine clearance or receiving dialysis; can be given for prophylaxis after exposure once per day for 7 days; and might have lower effectiveness against influenza B virus infections
Less available than oseltamivir; insufficient data for patients who are hospitalised
Zanamivir* (inhaled powder)
Duration of treatment, 5 days; age
≥7 years, 10 mg (two inhalations) twice per day
Inhibits influenza viral neuraminidase; blocks release of progeny virions from infected respiratory epithelial cells
Less available than oseltamivir; contraindicated in people with chronic airway disease because of increased risk of bronchospasm; insufficient data for patients who are hospitalised; intravenous zanamivir might be available in some countries; and laninamivir (single inhalation) is a related long-acting inhaled neuraminidase inhibitor approved for treatment of influenza in Japan
Baloxavir (oral suspension or capsule)
Duration of treatment, single dose; age ≥5 years and weight <20 kg, 2mg/kg; weight 20 kg to <80 kg, 40 mg; and weight ≥80 kg, 80 mg
Inhibits cap-dependent endonuclease within the polymerase acidic-protein subunit of viral polymerase; blocks viral replication in infected cells
Similar clinical benefit to 5 days of oseltamivir; significantly reduces influenza viral RNA concentrations in the upper respiratory tract after single dose; greater efficacy against influenza B virus infection than oseltamivir; reduces some complications in patients at high risk; not recommended for pregnant people; not recommended as monotherapy in people who are severely immunocompromised; single dose can be given as prophylaxis after exposure
Check national recommendations for the availability of antivirals and differences in age approvals and duration of treatment, including in patients who are immunocompromised. Greatest clinical benefit is when treatment is started within 2 days of illness onset in outpatients with uncomplicated influenza. The information here is partially obtained from the Centers for Disease Control and Prevention.80 *Intravenous zanamivir might be available in some countries. For example, intravenous zanamivir received marketing authorisation in the EU in 2019 for the treatment of patients aged 6 months or older with complications and potentially life-threatening influenza caused by influenza virus with known or suspected resistance to antivirals other than zanamivir, and, or when other antivirals, including inhaled zanamivir, are not suitable. Consult national recommendations for availability and indicated use.
Table 3: Antiviral medications for treatment of influenza
698
http://www.thelancet.com Vol 400 August 27, 2022
A(H1N1) viruses had high mortality rates. During the 2009 H1N1 pandemic, relatively lower disease severity was observed in older adults previously exposed in childhood to an A(H1N1) virus with antigenic similarity to the pandemic virus, and many B cells induced by infection or vaccination were derived from B-cell memory.70 Certain genetic alleles of genes encoding proteins can increase disease severity risk, such as interferon-induced transmembrane protein 3,71 transmembrane protease serine 2,72 or pulmonary-surfactant-associated proteins.73,74
In most symptomatic influenza virus infections, the innate immune response triggered is balanced, cellular immunity is activated, and recovery is associated with adaptive immune responses. However, in some individuals, the immune response to influenza virus infection can be dysregulated, with activation of proinflammatory cytokines (especially IL-6) and chemokines that can cause pulmonary inflammation and acute lung injury, acute respiratory distress syndrome, sepsis, and multiorgan failure.75 Influenza virus infection can activate host type 1 interferon-related pathways early in the clinical course of severe influenza, but this response can be diminished by activation of inflammatory neutrophilic and cell stress or apoptotic responses in
patients who are critically ill.76 Proinflammatory cytokines (eg, IL-6, IL-8, monocyte chemoattractant protein 1, and monokine-induced γ interferon) are higher in the lower respiratory tracts of patients with severe influenza compared to those with moderate disease.77 Coagulation pathway abnormalities can be provoked by activation of endothelial cells and result in critical illness from vascular leak and disseminated intravascular coagulation, further contributing to inflammatory injury.78 Bacterial co- infections and the microbiome further contribute to the pathogenesis and severity caused by influenza viruses.55,76,79
Treatment
The clinical benefit of antiviral treatment of influenza is greatest when started soon after illness onset. Antiviral drugs with activity against influenza A and B viruses include neuraminidase inhibitors, and a polymerase inhibitor (table 3). The neuraminidase inhibitors oseltamivir, zanamivir, laninamivir, and peramivir, differ by approved ages and availability in different countries, duration of treatment, routes of administration, and contraindications. By inhibiting the function of viral neuraminidase, neuraminidase inhibitors block release of progeny virions from infected respiratory epithelial cells,

reducing viral spread in the respiratory tract. Oseltamivir is the most widely prescribed neuraminidase inhibitor globally. Meta-analyses of randomised controlled trials (RCTs) reported that oseltamivir treatment of uncomplicated laboratory-confirmed influenza started within 2 days of symptom onset reduces illness duration by approximately 18 h overall and 30 h in those without asthma, and risk of otitis media by 34% versus placebo, but increases vomiting in children,81 and in adults when started within 36 h of symptom onset, reduces the median time to alleviation of symptoms by 25 h, reduces by 44% the risk of lower-respiratory-tract complications occurring more than 48 h after starting oseltamivir treatment that requires antibiotic treatment, and reduces the risk of hospital admission for any cause by 63%, but increases the risk of nausea and vomiting versus placebo.82
A meta-analysis of individual participants’ data reported that neuraminidase inhibitor treatment of influenza in outpatients at high risk of complications reduced the odds of hospital admission by 76% versus no treatment.83 Oseltamivir is recommended for treatment of outpatients at higher risk for complications or who have progressive disease, even if more than 2 days from illness onset.26 One dose of the polymerase inhibitor, baloxavir, a cap- dependent endonuclease inhibitor, blocks viral replication and rapidly reduces upper-respiratory-tract viral concentrations when started within 2 days of illness onset, has similar clinical benefit to 5 days of oseltamivir treatment, including in adolescents and adults at increased risk of complications, has greater efficacy against influenza B than oseltamivir, and can reduce the risk of some complications.84,85 Baloxavir is not recommended in pregnant people because of the scarcity of efficacy and safety data, whereas abundant safety data exist for oseltamivir in pregnancy.86 Meta-analyses have reported that treatment with oseltamivir, zanamivir, peramivir, or baloxavir is associated with shorter time to alleviation of symptoms of uncomplicated influenza versus placebo,87 and treatment with neuraminidase inhibitors (primarily oseltamivir) or baloxavir significantly reduces antibiotic prescriptions compared with placebo.88 Antiviral drug exposure can result in a low frequency of emergence of influenza viral variants with reduced drug susceptibility. Emergence of oseltamivir resistance with treatment is generally uncommon in immunocompetent patients, appears to occur slightly more frequently in influenza A(H1N1)pdm09 virus infections than A(H3N2) virus infections,89 but is higher for patients who are severely immunocompromised and who have prolonged influenza viral replication,25 and transmission to close contacts is possible.90 Resistance to baloxavir can emerge rapidly at low frequency, more commonly with treatment of A(H3N2) virus infections than A(H1N1)pdm09 virus infections,82 but is more frequent in young children.91 Infrequent transmission of baloxavir-resistant virus to household contacts has been reported.92,93 Combination therapy using antivirals with different mechanisms of
action in people who are immunocompromised could reduce the risk of emergence of resistant viruses, but results from RCTs are not available.
The adamantane antivirals amantadine and rimantadine that block the M2-channel of influenza A viruses, with no activity against influenza B viruses, are not recommended because of the high prevalence of resistance to these drugs among circulating influenza A viruses.26 Other antivirals with activity against influenza A and B viruses include the haemagglutinin inhibitor umifenovir, approved in Russia and China, which has shown clinical benefit in an RCT in adult outpatients, and the polymerase inhibitor favipiravir, approved in Japan for treatment of novel or re-emerging influenza viruses.94,95 Other agents with antiviral activity against influenza viruses, including immunotherapeutics, are under investigation and have been reviewed elsewhere.95
Although there are no completed fully enrolled RCTs of antivirals versus placebo for treatment of patients hospitalised with influenza, prompt empiric oseltamivir treatment has been recommended in many countries on the basis of potential delays in receiving results of influenza testing at clinical laboratories and observational studies that reported survival benefit (18% reduction in mortality) of neuraminidase inhibitor treatment versus no treatment, and reduced hospital duration (19% reduction and median 1·1 day reduction) with neuraminidase inhibitor treatment started promptly after hospital admission in adults, compared with later initiation or no treatment.96–98 An observational study reported that neuraminidase inhibitor treatment (nearly all oseltamivir) started within 2 days of illness onset in children hospitalised with influenza and underlying medical conditions or in those admitted to the ICU was associated with shorter length of stay compared to later initiation or no treatment.99 An RCT of antiviral treatment versus placebo would clarify the role of antivirals in patients hospitalised with influenza. One RCT of combination neuraminidase inhibitor (primarily oseltamivir) and baloxavir treatment of patients hospitalised with influenza aged 12 years or older did not find clinical benefit compared with neuraminidase inhibitor and placebo, but the addition of baloxavir significantly reduced influenza viral RNA concentrations,100 and has implications for infection prevention and control measures.
Clinical management
Management of influenza in patients who are not admitted to hospital consists of starting antiviral treatment as soon as possible after illness onset, especially in people at high risk for complications or those with progressive disease, and supportive care.26,101 In addition to prompt initiation of antiviral treatment and implementation of infection prevention-and-control measures to prevent health-care-associated influenza, clinical management of influenza in patients who are hospitalised includes supportive care of complications (eg, antibiotics for bacterial co-infection or low-flow supplemental oxygen)
http://www.thelancet.com Vol 400 August 27, 2022
699
Seminar

700
http://www.thelancet.com Vol 400 August 27, 2022
Seminar
and exacerbation of chronic medical conditions, and providing critical care and advanced organ support (eg, high-flowsupplementaloxygen,non-invasiveorinvasive mechanical ventilation, renal replacement therapy, vasopressors, and extracorporeal membrane oxygenation for refractory hypoxaemia). The utility of prognostic scoring systems, such as those developed for community- acquired pneumonia, to inform management of severe influenza is unclear. The value of biomarkers, including markers of inflammation, to inform clinical management andprognosisofsevereinfluenzaalsoneedstobedefined.
The role of immunomodulatory therapy in severe influenza complications is unclear. Observational studies have reported that corticosteroids might prolong influenza viral replication and viral RNA detection.26 A meta-analysis of 21 observational studies reported that corticosteroid treatment of influenza was associated with increased mortality, but risk-of-bias assessment was consistent with potential confounding by indication.102 Another meta-analysis of a small subgroup from one RCT and 18 observational studies reported that corticosteroid treatment of influenza-related pneumonia or ARDS was associated with significantly higher mortality, but among patients from studies with adjusted analyses, there was no significant difference in mortality between corticosteroid recipients and controls.103 Both meta-analyses reported that corticosteroid treatment of influenza increased the risk of hospital-acquired infections. One single centre, open-label RCT in adults hospitalised with influenza reported that clarithromycin, naproxen, and oseltamivir significantly reduced length of hospital stay, and 30-day and 60-day mortality compared with oseltamivir and placebo.104 RCTs of low-dose or moderate-dose corticosteroids or other immunomodulators are needed to inform their roles in treating severe influenza complications.
Prevention and control interventions
Community settings
Before the COVID-19 pandemic, evidence for the community effectiveness of non-pharmaceutical interven- tions (NPIs) for prevention and control of influenza was scarce.105,106 After emergence of SARS-CoV-2, cocirculation with influenza viruses was observed in some countries, and some co-infections occurred with these viruses.59 From the early spring of 2020 to late 2021, influenza activity declined substantially and generally remained low after implementation of NPIs and behavioural changes (eg, school closures with online instruction, workplace closures and telework, wearing face masks in public settings, physical distancing, indoor dining restrictions, travel restrictions, isolation of people who were ill and the quarantine of those who were exposed, and border control measures) to control the spread of SARS-CoV-2.107–110 Increases in influenza activity were observed after relaxation of control measures in some southeast Asian countries in 2020,111 and influenza activity increased in late 2021 as NPIs were reduced.112
Health-care settings
Engineering and environmental controls can reduce exposures from infectious respiratory aerosols or contaminated surfaces and inanimate objects to health- care personnel (HCP) and patients.113 The Centers for Disease Control and Prevention (CDC) recommends a minimum room ventilation rate of six air changes per hour in an existing facility and a higher ventilation of 12 air changes per hour for new or renovated construction are required to prevent room contamination, especially when managing patients receiving mechanical ventilation and during aerosol-generating procedures.113
Source control with a face mask is recommended for outpatients and patients with acute respiratory symptoms in emergency departments, including suspected seasonal influenza, ideally with placement in a single patient isolation room for evaluation. Use of influenza PoC assays can inform decisions to initiate antiviral treatment and infection prevention-and-control measures. If single isolation rooms are not available, patients with influenza who are hospitalised can be grouped together (cohorting). Standard and droplet precautions (face mask, gown, gloves, and hand hygiene before and after patient contact) for HCP are recommended for routine management of patients with suspected or confirmed seasonal influenza.113 A cluster randomised, pragmatic, effectiveness study among outpatient HCP found no significant difference in laboratory-confirmed influenza between people who wore N95 respirators versus medical masks.114 The risk of influenza virus infection of the upper respiratory tract from virus-laden droplets deposited on conjunctivae and spread through the nasolacrimal duct is unknown, and whether routine eye protection for HCP is indicated needs to be defined. The COVID-19 pandemic has highlighted the absence of consensus on what constitutes an aerosol- generating procedure, including which procedures present high risk of SARS-CoV-2 transmission to HCP.115,116 Further studies are also needed to better define aerosol- generating procedures that present a risk of influenza virus transmission. Current CDC guidance recommends that when performing aerosol-generating procedures (eg, bronchoscopy, sputum induction, elective intubation, and extubation) on patients with severe influenza, ideally the patient should be placed in a negative-pressure airborne isolation room, and HCP should wear a fitted N95 filtering-facepiece respirator or equivalent respiratory protection with eye protection (face shield or goggles).113 Influenza viral RNA has been detected infrequently in the stool of patients with seasonal influenza, but virus has very rarely been isolated from faecal specimens;117 the risk of transmission from stool is unknown but likely to be very low. Similarly, influenza viral RNA has been detected infrequently in blood in patients with seasonal influenza, particularly in those who are critically ill,118 but has rarely ever been isolated from blood.119 The risk of transmission of influenza viruses from respiratory secretions, fomites, stool, or blood is unknown but is likely to be very low.

Seminar
Inactivated, split or subunit, at standard dose
Inactivated, split or subunit, at standard dose
Recombinant
Inactivated, split or subunit, at high dose
Haemagglutinin concentration per virus antigen
7·5 μg or 15 μg (varies by manufacturer and country)
15 μg
45 μg
60 μg
Administration
Intramuscular
Intramuscular
Intramuscular
Intramuscular
Manufacturing process
Egg-grown viruses; inactivated
Tissue cell-culture grown; inactivated
Recombinant haemagglutinin DNA expressed in insect-cell culture and purified
Egg-grown viruses; inactivated
Approved age group recommendations*
6 months to 35 months (two doses recommended for previously unvaccinated children)
≥2 years; ≥9 years in some countries (two doses recommended for previously unvaccinated children aged 6 months to 8 years)
≥18 years
≥65 years
Inactivated, split or subunit, at standard dose
15 μg
Intramuscular
Egg-grown viruses; inactivated (aluminum phosphate adjuvant might be used in some countries)
≥6 months (two doses recommended for previously unvaccinated children aged 6 months to 8 years)
Live attenuated, at standard dose
15 μg
Intranasal
Egg-grown viruses that replicate in nasal passages, but do not replicate at internal body temperature (cold adapted), and express virus antigens
2 years to 49 years (for non-pregnant, non-high- risk conditions; 2 doses recommended for previously unvaccinated children aged 6 months to 8 years)
Inactivated, split or subunit, at standard dose, and adjuvanted
15 μg
Intramuscular
Egg-grown viruses; inactivated; administered with MF59 adjuvant
≥65 years
Adapted from Grohskopf and colleagues.120 Vaccines might be available in trivalent or more commonly quadrivalent formulations depending on country and manufacturer. Trivalent vaccines contain antigens for three virus strains; one influenza A(H1N1)pdm09 strain, one influenza A(H3N2) strain, and either one influenza B or Yamagata lineage or one B/Victoria lineage. Quadrivalent vaccines contain antigens for one representative of both type B lineages in addition to the A(H1N1)pdm09 and A(H3N2) virus strains. *Check national guidance for differences in recommended age groups.
Table 4: Characteristics of generally available seasonal influenza vaccines
Nevertheless, contact precautions and hand hygiene are indicated for HCP caring for patients with influenza; standard cleaning and disinfection of surfaces in health- care settings, including areas in which aerosol-generating procedures are done, are thought to be adequate for influenza-virus environmental control in health-care settings.113
When health-care-associated influenza is suspected or confirmed, particularly in congregate settings such as long-term-care facilities, implementation of a bundle of NPIs is recommended, as is influenza vaccination of unvaccinated people, antiviral treatment of people who are symptomatic, and antiviral chemoprophylaxis of exposed individuals.26 Both oseltamivir and baloxavir can be used for prophylaxis after exposure, but should be administered within 1–2 days of exposure to a close contact with influenza.26,101
Influenza vaccines and vaccine effectiveness
Annual influenza vaccination is recommended because of waning immunity over time and antigenic drift among circulating influenza viruses that requires annual updating of vaccine antigens. Most influenza vaccines used worldwide are manufactured using influenza viruses propagated in eggs and formalin inactivated, with antigens presented as split or subunit, without adjuvant (table 4).121 Standardisation is based on haemagglutinin content, with most vaccines containing 15 μg of each haemagglutinin antigen. Most available vaccines worldwide are quadriva- lent, containing an A(H3N2) and an A(H1N1)pdm09 virus strain, and a representative of each of the Victoria and Yamagata lineages of influenza B viruses, or trivalent in
some countries, containing the two influenza A virus strains and one influenza B virus lineage.
Because immunogenicity of standard dose vaccines is reduced in older adults, vaccines with higher antigen content (eg, a recombinant vaccine containing three times [45 μg] the antigen content for each component or a high-dose vaccine containing four times [60 μg] the antigen content for each component) or an adjuvanted vaccine with standard amounts of egg-derived antigens120 are available in some countries for use in this population. Given that adaptation of influenza viruses to eggs for vaccine production might render the vaccine less protective,122 vaccines are available that are either propagated in cell culture or produced by molecular technology from genetic sequences and manufactured using insect-cell culture. Live attenuated influenza vaccines have been available since 2003 in an increasing number of countries and are licensed in the USA for non-pregnant people aged 2–49 years without chronic medical conditions,120 but are mainly used in children in most countries and represent only approximately 5% of influenza vaccines produced worldwide.121
The vaccine viral antigens are updated regularly because of antigenic drift among circulating influenza viruses. WHO makes recommendations on vaccine composition twice per year for the northern and southern hemispheres following review of antigenic and molecular characteristics of circulating strains worldwide (appendix p 1). Recommendations for vaccine use vary greatly internationally. In the USA, annual influenza vaccination is recommended for all people aged 6 months and older, and vaccine coverage is approximately 50–60% among children
http://www.thelancet.com Vol 400 August 27, 2022
701

702
http://www.thelancet.com Vol 400 August 27, 2022
Seminar
and adults. However, disparities in influenza vaccination exist in the USA, with the lowest vaccination coverage among people younger than 18 years in Black children, and among people aged 18 years or older in Black and Hispanic adults.123–125 HCP and older adults are the priority groups for annual vaccination in many countries. Attempts have been made to modify outbreaks by vaccinating children to protect others, but evidence for indirect protection might be difficult to identify or modest.126–128 WHO has identified pregnant people as a priority target for vaccination with the goal of protecting them and their newborn children on the basis of RCTs.127 Influenza vaccines have shown safety in pregnant and non-pregnant people,129,130 especially in terms of the many millions of vaccine doses administered worldwide each year. Influenza vaccine can be coadministered with COVID-19 vaccine.120
Influenza vaccine effectiveness is typically estimated by comparing vaccine history in those meeting an influenza case definition who test positive or negative for influenza (test-negative design).131 Influenza vaccine effectiveness can vary depending upon the antigenic match between circulating influenza virus strains and vaccine components, time since vaccination because of waning immunity, and host factors such as age, immune function, earlier exposure to influenza viruses, and vaccination history.132–134 Vaccine effectiveness might also be reduced by molecular changes arising from egg adaption for vaccines that use viruses grown in embryonated eggs, such as in the influenza A(H3N2) vaccine component.122 The test- negative design has shown that the A(H1N1)pdm and type B components are generally more protective than A(H3N2), particularly in older adults, but can still provide moderate protection against influenza-related compli- cations requiring hospitalisation in children and adults.135,136 Influenza vaccination of people with cardiovascular disease can reduce mortality and major adverse cardiovascular events.137 During 2004–20, influenza vaccine effectiveness against medically attended influenza among outpatients in the USA ranged from 10% to 60% and varied by antigenic match to circulating virus strains.138
Major efforts are underway to develop more effective influenza vaccines of greater breadth and duration of protection. The goal is a vaccine that will provide extended immune protection against pandemic viruses or antigenically drifted viruses causing epidemics, and without requiring annual vaccination, often referred to as a universal vaccine.139 The term supraseasonal has been used for a more broadly protective vaccine for seasonal influenza. Strategies being studied include stimulating antibodies directed against the haemagglutinin stem or other conserved epitopes, and standardising neuraminidase content for improved response or more reliance on adjuvants.140 A standardised human influenza-virus challenge model can contribute insights into the effectiveness of more broadly protective vaccines.141,142 The mRNA technology used for some COVID-19 vaccines was originally developed for influenza
vaccines and both mRNA influenza vaccines and combined mRNA COVID-19-influenza vaccines are under development.143 In addition, an adjuvanted nanoparticle vaccine is under development for older individuals.144 Nevertheless, even with the modest vaccine effectiveness of currently available influenza vaccines against medically attended influenza, vaccination is effective in preventing some severe influenza outcomes, such as ICU admission (26% risk reduction) and mortality (31% risk reduction) among adults with influenza-associated hospital admission.145,146
Lessons from COVID-19 for prevention and control of influenza
The effect of community-wide and national use of NPIs to control SARS-CoV-2 transmission on reducing influenza virus circulation suggests that such measures combined with influenza vaccination could be important public health tools during severe influenza epidemics and pandemics. Supplies of personal protective equipment must be ensured for HCP. Inequities in the global availability of COVID-19 vaccines highlight the need to expand efforts to increase influenza vaccine manufacturing capacity worldwide and increase influenza vaccine access and use in low-income and middle-income countries,147 which will also improve pandemic vaccine response.
Regional and multinational clinical research networks were invaluable in rapidly implementing adaptive clinical trials to identify therapeutics that led to significant improvements in the care and survival of patients hospitalised with COVID-19,148–150 and can be used to identify interventions that improve care for patients with influenza.151 Oxygen shortages for patients with COVID-19 highlighted the urgency to increase capacity and expand access to oxygen and monitoring for patients with hypoxaemia worldwide. Surges of patients severely ill with COVID-19 overburdened hospitals in low-resource and high-resource settings with resultant patient harm,152 emphasising that more efforts are needed to prevent illness or avert progression to severe disease during severe influenza epidemics and pandemics, and there is a need to increase critical care capacity worldwide. Wider global availability of highly sensitive influenza assays and effective, affordable oral antiviral medications can facilitate prompt influenza diagnosis and early initiation of treatment to avert severe disease. Novel influenza A virus infections of humans present ongoing pandemic threats (appendix pp 1–2, 11).
Conclusions
Influenza vaccines with much higher effectiveness are greatly needed, especially for older adults, ideally conferring broader and longer duration of protective immunity than current vaccines. Many gaps and questions in the clinical management of influenza need to be addressed, particularly to optimise supportive care of patients who are hospitalised.153,154 Prospective observational

studies with serial respiratory sampling and integrated analyses of virological, genetic sequencing, clinical, immunological, transcriptomics, proteomics, and host genomics can yield insights for targeting therapies in select patients with influenza who are hospitalised. Priorities for multinational clinical research networks are clinical trials of immunomodulators (eg, IL-6 receptor blockers and low-to-moderate dose corticosteroids) and combined antiviral and immunomodulator treatments in patients with severe influenza (appendix p 12). Although more effective therapeutics and targeted interventions are needed, a logistical challenge in almost all countries is how to implement prompt influenza diagnostic testing and initiation of treatment soon after illness onset with available antivirals, particularly in people at high risk for complications, for the greatest clinical benefit.
Contributors
All authors did literature reviews for the sections they drafted.
TMU drafted the Summary and Introduction, and the sections on Transmission dynamics and modalities, Epidemiology and disease burden, Treatment, Prevention and control interventions community settings, and Lessons from COVID-19 for prevention and control of influenza, and contributed to the tables and edited all sections. DSH drafted the sections on Clinical spectrum and clinical complications, Clinical management, and Prevention and control interventions health- care settings, and contributed to the figures. DEW drafted the Virology and Pathogenesis sections. MZ drafted the sections on Influenza surveillance and Diagnostic testing, and contributed to the figures. ASM drafted the section on Influenza vaccines and vaccine effectiveness, contributed to the tables, and coedited all sections
and tables. All authors approved of the final draft.
Declaration of interests
DSH reports grant support unrelated to contributions to the Clinical spectrum and clinical complications, Clinical management, and Prevention and control interventions health-care settings sections, and, outside the submitted work support, from F Hoffmann-La Roche for a research nurse to enrol participants in a phase 3, randomised, double-blind, placebo- controlled, multicentre study to evaluate the efficacy and safety of baloxavir marboxil in combination with standard-of-care neuraminidase inhibitor in hospitalised patients with severe influenza. DEW reports research unit support (CRADA) from Seqirus for evaluation of virus isolation and propagation of viruses for the implementation of cell-based vaccines (US$200 000 per year) unrelated to contributions to the virology and pathogenesis sections and outside the submitted work. MZ reports being a member of the WHO Strategic Advisory Group of Experts on Immunization, the J Craig Venter Institute, and the UK New and Emerging Respiratory Virus Threats Advisory Group, and is Chair of the International Society of Influenza and Respiratory Viruses, unrelated to contributions to the influenza surveillance and diagnosis sections
and outside the submitted work. ASM reports serving on a Roche advisory board unrelated to the contributions to the Influenza vaccines and vaccine effectiveness sections and outside the submitted work. TMU declares no competing interests. The views expressed are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention or the UK Health Security Agency.
References
1 Azziz Baumgartner E, Dao CN, Nasreen S, et al. Seasonality, timing, and climate drivers of influenza activity worldwide. J Infect Dis 2012; 206: 838–46.
2 Paules C, Subbarao K. Influenza. Lancet 2017; 390: 697–708.
3 Sederdahl BK, Williams JV. Epidemiology and clinical
characteristics of influenza C virus. Viruses 2020; 12: E89.
4 Liu R, Sheng Z, Huang C, Wang D, Li F. Influenza D virus.
Curr Opin Virol 2020; 44: 154–61.
5 Tong S, Zhu X, Li Y, et al. New world bats harbor diverse
influenza A viruses. PLoS Pathog 2013; 9: e1003657.
http://www.thelancet.com Vol 400 August 27, 2022
6 Ciminski K, Schwemmle M. Bat-borne influenza A viruses:
an awakening. Cold Spring Harb Perspect Med 2021; 11: a038612.
7 Long JS, Mistry B, Haslam SM, Barclay WS. Host and viral determinants of influenza A virus species specificity.
Nat Rev Microbiol 2019; 17: 67–81.
8 Connor RJ, Kawaoka Y, Webster RG, Paulson JC. Receptor specificity in human, avian, and equine H2 and H3 influenza virus isolates. Virology 1994; 205: 17–23.
9 Shinya K, Ebina M, Yamada S, Ono M, Kasai N, Kawaoka Y. Avian flu: influenza virus receptors in the human airway. Nature 2006; 440: 435–36.
10 Carrique L, Fan H, Walker AP, et al. Host ANP32A mediates the assembly of the influenza virus replicase. Nature 2020; 587: 638–43.
11 Biggerstaff M, Cauchemez S, Reed C, Gambhir M, Finelli L. Estimates of the reproduction number for seasonal, pandemic, and zoonotic influenza: a systematic review of the literature. BMC Infect Dis 2014; 14: 480.
12 Vink MA, Bootsma MC, Wallinga J. Serial intervals of respiratory infectious diseases: a systematic review and analysis.
Am J Epidemiol 2014; 180: 865–75.
13 Lessler J, Reich NG, Brookmeyer R, Perl TM, Nelson KE, Cummings DA. Incubation periods of acute respiratory viral infections: a systematic review. Lancet Infect Dis 2009; 9: 291–300.
14 Carrat F, Vergu E, Ferguson NM, et al. Time lines of infection and disease in human influenza: a review of volunteer challenge studies. Am J Epidemiol 2008; 167: 775–85.
15 Leung NHL. Transmissibility and transmission of respiratory viruses. Nat Rev Microbiol 2021; 19: 528–45.
16 Yan J, Grantham M, Pantelic J, et al. Infectious virus in exhaled breath of symptomatic seasonal influenza cases from a college community. Proc Natl Acad Sci USA 2018; 115: 1081–86.
17 Kormuth KA, Lin K, Prussin AJ 2nd, et al. Influenza virus infectivity is retained in aerosols and droplets independent of relative humidity. J Infect Dis 2018; 218: 739–47.
18 Kormuth KA, Lin K, Qian Z, Myerburg MM, Marr LC, Lakdawala SS. Environmental persistence of influenza viruses is dependent upon virus type and host origin. MSphere 2019;
4: e00552–19.
19 Asadi S, Gaaloul Ben Hnia N, Barre RS, Wexler AS, Ristenpart WD, Bouvier NM. Influenza A virus is transmissible via aerosolized fomites. Nat Commun 2020; 11: 4062.
20 Mubareka S, Lowen AC, Steel J, Coates AL, García-Sastre A, Palese P. Transmission of influenza virus via aerosols and fomites in the guinea pig model. J Infect Dis 2009; 199: 858–65.
21 Fong MW, Leung NHL, Xiao J, et al. Presence of influenza virus on touch surfaces in kindergartens and primary schools. J Infect Dis 2020; 222: 1329–33.
22 Xiao J, de Mesquita JB, Leung NHL, et al. Viral RNA and infectious influenza virus on mobile phones of influenza patients in
Hong Kong and the United States. J Infect Dis 2021; 224: 1730–34.
23 Ip DKM, Lau LLH, Chan KH, et al. The dynamic relationship between clinical symptomatology and viral shedding in naturally acquired seasonal and pandemic influenza virus infections.
Clin Infect Dis 2016; 62: 431–37.
24 Lau LL, Cowling BJ, Fang VJ, et al. Viral shedding and clinical illness in naturally acquired influenza virus infections. J Infect Dis 2010; 201: 1509–16.
25 Memoli MJ, Athota R, Reed S, et al. The natural history of influenza infection in the severely immunocompromised vs nonimmunocompromised hosts. Clin Infect Dis 2014; 58: 214–24.
26 Uyeki TM, Bernstein HH, Bradley JS, et al. Clinical practice guidelines by the Infectious Diseases Society of America: 2018 update on diagnosis, treatment, chemoprophylaxis, and institutional outbreak management of seasonal influenza. Clin Infect Dis 2019; 68: e1–47.
27 Fielding JE, Kelly HA, Mercer GN, Glass K. Systematic review of influenza A(H1N1)pdm09 virus shedding: duration is affected by severity, but not age. Influenza Other Respir Viruses 2014; 8: 142–50.
28 Ip DK, Lau LL, Leung NH, et al. Viral shedding and transmission potential of asymptomatic and paucisymptomatic influenza virus infections in the community. Clin Infect Dis 2017; 64: 736–42.
29 Tsang TK, Lau LLH, Cauchemez S, Cowling BJ. Household transmission of influenza virus. Trends Microbiol 2016; 24: 123–33.
Seminar
703

704
http://www.thelancet.com Vol 400 August 27, 2022
Seminar
30
31
32 33
34 35
36
37 38
39 40 41 42 43
44 45 46 47
48 49 50
51
Cohen C, Kleynhans J, Moyes J, et al. Asymptomatic transmission and high community burden of seasonal influenza in an urban and a rural community in South Africa, 2017-18 (PHIRST): a population cohort study. Lancet Glob Health 2021; 9: e863–74.
Ali ST, Cowling BJ, Wong JY, et al. Influenza seasonality and its environmental driving factors in mainland China and Hong Kong. Sci Total Environ 2022; 818: 151724.
Tokars JI, Olsen SJ, Reed C. Seasonal incidence of symptomatic influenza in the United States. Clin Infect Dis 2018; 66: 1511–18. Hayward AC, Fragaszy EB, Bermingham A, et al. Comparative community burden and severity of seasonal and pandemic influenza: results of the Flu Watch cohort study. Lancet Respir Med 2014; 2: 445–54.
Centers for Disease Control and Prevention. Disease burden of flu. 2021. https://www.cdc.gov/flu/about/burden/index.html (accessed May 16, 2022).
Lafond KE, Porter RM, Whaley MJ, et al. Global burden of influenza-associated lower respiratory tract infections and hospitalizations among adults: a systematic review and meta- analysis. PLoS Med 2021; 18: e1003550.
Wang X, Li Y, O’Brien KL, et al. Global burden of respiratory infections associated with seasonal influenza in children under
5 years in 2018: a systematic review and modelling study.
Lancet Glob Health 2020; 8: e497–510.
Bhat N, Wright JG, Broder KR, et al. Influenza-associated deaths among children in the United States, 2003-2004. N Engl J Med 2005; 353: 2559–67.
Kamidani S, Garg S, Rolfes MA, et al. Epidemiology, clinical characteristics, and outcomes of influenza-associated hospitalizations in U.S. children over 9 seasons following the 2009 H1N1 pandemic. Clin Infect Dis 2022; published online April 19. https://doi.org/10.1093/cid/ciac296.
Iuliano AD, Roguski KM, Chang HH, et al. Estimates of global seasonal influenza-associated respiratory mortality: a modelling study. Lancet 2018; 391: 1285–300.
Kwong JC, Schwartz KL, Campitelli MA, et al. Acute myocardial infarction after laboratory-confirmed influenza infection.
N Engl J Med 2018; 378: 345–53.
Navascués A, Casado I, Pérez-García A, et al. Detection of respiratory viruses in deceased persons, Spain, 2017.
Emerg Infect Dis 2018; 24: 1331–34.
Centers for Disease Control and Prevention. Who is at higher risk of flu complications. 2021. https://www.cdc.gov/flu/highrisk/index. htm (accessed May 16, 2022).
Holstein R, Dawood FS, O’Halloran A, et al. Characteristics and outcomes of hospitalized pregnant women with influenza,
2010 to 2019: a repeated cross-sectional study. Ann Intern Med 2022; 175: 149–58.
Wen T, Arditi B, Riley LE, et al. Influenza complicating delivery hospitalization and its association with severe maternal morbidity in the United States, 2000–2018. Obstet Gynecol 2021; 138: 218–27. Louie JK, Acosta M, Jamieson DJ, Honein MA. Severe 2009 H1N1 influenza in pregnant and postpartum women in California.
N Engl J Med 2010; 362: 27–35.
Mertz D, Lo CK, Lytvyn L, Ortiz JR, Loeb M. Pregnancy as a risk factor for severe influenza infection: an individual participant data meta-analysis. BMC Infect Dis 2019; 19: 683.
O’Halloran AC, Holstein R, Cummings C, et al. Rates of influenza- associated hospitalization, intensive care unit admission, and in- hospital death by race and ethnicity in the United States from 2009 to 2019. JAMA Netw Open 2021; 4: e2121880.
Putri WCWS, Muscatello DJ, Stockwell MS, Newall AT. Economic burden of seasonal influenza in the United States. Vaccine 2018;
36: 3960–66.
Centers for Disease Control and Prevention. Influenza virus testing methods. https://www.cdc.gov/flu/professionals/diagnosis/table- testing-methods.htm (accessed May 16, 2022).
Merckx J, Wali R, Schiller I, et al. Diagnostic accuracy of novel and traditional rapid tests for influenza infection compared with reverse transcriptase polymerase chain reaction: a systematic review and meta-analysis. Ann Intern Med 2017; 167: 394–409.
Hardin R, Roberts P, Hudspeth B, et al. Development and implementation of an influenza point-of-care testing service
in a chain community pharmacy setting. Pharmacy (Basel) 2020;
8: E182.
52
53 54 55 56
57
58
59 60
61
62 63 64 65 66 67
68 69 70
71 72
73 74
Malosh RE, Petrie JG, Callear AP, Monto AS, Martin ET.
Home collection of nasal swabs for detection of influenza in the Household Influenza Vaccine Evaluation Study.
Influenza Other Respir Viruses 2021; 15: 227–34.
Heimonen J, McCulloch DJ, O’Hanlon J, et al. A remote household-based approach to influenza self-testing and antiviral treatment. Influenza Other Respir Viruses 2021; 15: 469–77.
Belser JA, Lash RR, Garg S, Tumpey TM, Maines TR. The eyes have it: influenza virus infection beyond the respiratory tract.
Lancet Infect Dis 2018; 18: e220–27.
Klein EY, Monteforte B, Gupta A, et al. The frequency of influenza and bacterial coinfection: a systematic review and meta-analysis. Influenza Other Respir Viruses 2016; 10: 394–403.
MacIntyre CR, Chughtai AA, Barnes M, et al. The role of pneumonia and secondary bacterial infection in fatal and serious outcomes of pandemic influenza a(H1N1)pdm09. BMC Infect Dis 2018; 18: 637.
Hedberg P, Johansson N, Ternhag A, Abdel-Halim L, Hedlund J, Nauclér P. Bacterial co-infections in community-acquired pneumonia caused by SARS-CoV-2, influenza virus and respiratory syncytial virus. BMC Infect Dis 2022; 22: 108.
Rouze A, Martin-Loeches I, Povoa P, et al. Early bacterial identification among intubated patients with COVID-19 or influenza pneumonia: a European multicenter comparative cohort study. Am J Respir Crit Care Med 2021; 204: 546–56.
Stowe J, Tessier E, Zhao H, et al. Interactions between SARS-CoV-2 and influenza, and the impact of coinfection on disease severity:
a test-negative design. Int J Epidemiol 2021; 50: 1124–33.
Zheng J, Chen F, Wu K, et al. Clinical and virological impact of single and dual infections with influenza A (H1N1) and SARS-CoV-2 in adult inpatients. PLoS Negl Trop Dis 2021;
15: e0009997.
Verweij PE, Rijnders BJA, Brüggemann RJM, et al. Review of influenza-associated pulmonary aspergillosis in ICU patients and proposal for a case definition: an expert opinion. Intensive Care Med 2020; 46: 1524–35.
Chow EJ, Rolfes MA, O’Halloran A, et al. Acute cardiovascular events associated with influenza in hospitalized adults: a cross- sectional study. Ann Intern Med 2020; 173: 605–13.
Frankl S, Coffin SE, Harrison JB, Swami SK, McGuire JL. Influenza-associated neurologic complications in hospitalized children. J Pediatr 2021; 239: 24–31.e1.
Sellers SA, Hagan RS, Hayden FG, Fischer WA 2nd. The hidden burden of influenza: a review of the extra-pulmonary complications of influenza infection. Influenza Other Respir Viruses 2017; 11: 372–93. Mizuguchi M. Influenza encephalopathy and related neuropsychiatric syndromes. Influenza Other Respir Viruses 2013;
7 (suppl 3): 67–71.
Grisanti SG, Franciotta D, Garnero M, et al. A case series of parainfectious Guillain-Barré syndrome linked to influenza A (H1N1) virus infection. J Neuroimmunol 2021; 357: 577605.
Salomon A, Berry I, Tuite AR, et al. Influenza increases invasive meningococcal disease risk in temperate countries.
Clin Microbiol Infect 2020; 26: 1257.e1–e7.
Francis T. On the doctrine of original antigenic sin.
Proc Am Philos Soc 1960; 104: 572–78.
Yewdell JW, Santos JJS. Original antigenic sin: how original?
How sinful? Cold Spring Harb Perspect Med 2021; 11: a038786.
Li GM, Chiu C, Wrammert J, et al. Pandemic H1N1 influenza vaccine induces a recall response in humans that favors broadly cross-reactive memory B cells. Proc Natl Acad Sci USA 2012;
109: 9047–52.
Everitt AR, Clare S, Pertel T, et al. IFITM3 restricts the morbidity and mortality associated with influenza. Nature 2012; 484: 519–23. Cheng Z, Zhou J, To KK, et al. Identification of TMPRSS2 as a susceptibility gene for severe 2009 pandemic A(H1N1) influenza and A(H7N9) influenza. J Infect Dis 2015; 212: 1214–21.
To KKW, Zhou J, Song YQ, et al. Surfactant protein B gene polymorphism is associated with severe influenza. Chest 2014;
145: 1237–43.
Herrera-Ramos E, López-Rodríguez M, Ruíz-Hernández JJ, et al. Surfactant protein A genetic variants associate with severe respiratory insufficiency in pandemic influenza A virus infection. Crit Care 2014; 18: R127.

75 Morris G, Bortolasci CC, Puri BK, et al. The cytokine storms of COVID-19, H1N1 influenza, CRS and MAS compared. Can one sized treatment fit all? Cytokine 2021; 144: 155593.
76 Dunning J, Blankley S, Hoang LT, et al. Progression of whole-blood transcriptional signatures from interferon-induced to neutrophil- associated patterns in severe influenza. Nat Immunol 2018;
19: 625–35.
77 Reynolds D, Vazquez Guillamet C, Day A, et al. Comprehensive immunologic evaluation of bronchoalveolar lavage samples from human patients with moderate and severe seasonal influenza and severe COVID-19. J Immunol 2021; 207: 1229–38.
78 Yang Y, Tang H. Aberrant coagulation causes a hyper-inflammatory response in severe influenza pneumonia. Cell Mol Immunol 2016; 13: 432–42.
79 Kaul D, Rathnasinghe R, Ferres M, et al. Microbiome disturbance and resilience dynamics of the upper respiratory tract during influenza A virus infection. Nat Commun 2020; 11: 2537.
80 Centers for Disease Control and Prevention. Influenza antiviral medications: summary for clinicians. https://www.cdc.gov/flu/ professionals/antivirals/summary-clinicians.htm (accessed May 16, 2022).
81 Malosh RE, Martin ET, Heikkinen T, Brooks WA, Whitley RJ, Monto AS. Efficacy and safety of oseltamivir in children: systematic review and individual patient data meta-analysis of randomized controlled trials. Clin Infect Dis 2018; 66: 1492–500.
82 Dobson J, Whitley RJ, Pocock S, Monto AS. Oseltamivir treatment for influenza in adults: a meta-analysis of randomised controlled trials. Lancet 2015; 385: 1729–37.
83 Venkatesan S, Myles PR, Leonardi-Bee J, et al. Impact of outpatient neuraminidase inhibitor treatment in patients infected with influenza A(H1N1)pdm09 at high risk of hospitalization:
an individual participant data metaanalysis. Clin Infect Dis 2017;
64: 1328–34.
84 Hayden FG, Sugaya N, Hirotsu N, et al. Baloxavir marboxil for
uncomplicated influenza in adults and adolescents. N Engl J Med
2018; 379: 913–23.
85 Ison MG, Portsmouth S, Yoshida Y, et al. Early treatment with
baloxavir marboxil in high-risk adolescent and adult outpatients with uncomplicated influenza (CAPSTONE-2): a randomised, placebo-controlled, phase 3 trial. Lancet Infect Dis 2020; 20: 1204–14.
86 Chow EJ, Beigi RH, Riley LE, Uyeki TM. Clinical effectiveness and safety of antivirals for influenza in pregnancy. Open Forum Infect Dis 2021; 8: ofab138.
87 Liu JW, Lin SH, Wang LC, Chiu HY, Lee JA. Comparison of antiviral agents for seasonal influenza outcomes in healthy adults and children: a systematic review and network meta-analysis. JAMA Netw Open 2021; 4: e2119151.
88 Tejada S, Tejo AM, Peña-López Y, Forero CG, Corbella X, Rello J. Neuraminidase inhibitors and single dose baloxavir are effective and safe in uncomplicated influenza: a meta-analysis of randomized controlled trials. Expert Rev Clin Pharmacol 2021; 14: 901–18.
89 Roosenhoff R, Reed V, Kenwright A, et al. Viral kinetics and resistance development in children treated with neuraminidase inhibitors: the Influenza Resistance Information Study (IRIS). Clin Infect Dis 2020; 71: 1186–94.
90 Hurt AC, Chotpitayasunondh T, Cox NJ, et al. Antiviral resistance during the 2009 influenza A H1N1 pandemic: public health, laboratory, and clinical perspectives. Lancet Infect Dis 2012; 12: 240–48.
91 Omoto S, Speranzini V, Hashimoto T, et al. Characterization of influenza virus variants induced by treatment with the endonuclease inhibitor baloxavir marboxil. Sci Rep 2018; 8: 9633.
92 Imai M, Yamashita M, Sakai-Tagawa Y, et al. Influenza A variants with reduced susceptibility to baloxavir isolated from Japanese patients are fit and transmit through respiratory droplets.
Nat Microbiol 2020; 5: 27–33.
93 Takashita E, Ichikawa M, Morita H, et al. Human-to-human transmission of influenza A(H3N2) virus with reduced susceptibility to baloxavir, Japan, February 2019. Emerg Infect Dis 2019; 25: 2108–11.
94 Shiraki K, Daikoku T. Favipiravir, an anti-influenza drug against life- threatening RNA virus infections. Pharmacol Ther 2020; 209: 107512.
95 Beigel JH, Hayden FG. Influenza therapeutics in clinical practice challenges and recent advances. Cold Spring Harb Perspect Med 2021; 11: a038463.
96 Venkatesan S, Myles PR, Bolton KJ, et al. Neuraminidase inhibitors and hospital length of stay: a meta-analysis of individual participant data to determine treatment effectiveness among patients hospitalized with nonfatal 2009 pandemic influenza A(H1N1) virus infection. J Infect Dis 2020; 221: 356–66.
97 Katzen J, Kohn R, Houk JL, Ison MG. Early oseltamivir after hospital admission is associated with shortened
hospitalization: a 5-year analysis of oseltamivir timing and clinical outcomes. Clin Infect Dis 2019; 69: 52–58.
98 Muthuri SG, Venkatesan S, Myles PR, et al. Effectiveness of neuraminidase inhibitors in reducing mortality in patients admitted to hospital with influenza A H1N1pdm09 virus infection: a meta-analysis of individual participant data. Lancet Respir Med 2014; 2: 395–404.
99 Campbell AP, Tokars JI, Reynolds S, et al. Influenza antiviral treatment and length of stay. Pediatrics 2021; 148: e2021050417.
100 Kumar D, Ison MG, Mira JP, et al. Combining baloxavir marboxil with standard-of-care neuraminidase inhibitor in patients hospitalised with severe influenza (FLAGSTONE): a randomised, parallel-group, double-blind, placebo-controlled, superiority trial. Lancet Infect Dis 2022; 22: 718–30.
101 Centers for Disease Control and Prevention. For clinicians: antiviral medication. 2021. https://www.cdc.gov/flu/professionals/antivirals/ summary-clinicians.htm (accessed May 16, 2022).
102 Lansbury LE, Rodrigo C, Leonardi-Bee J, Nguyen-Van-Tam J,
Shen Lim W. Corticosteroids as adjunctive therapy in the treatment of influenza: an updated Cochrane systematic review and meta- analysis. Crit Care Med 2020; 48: e98–106.
103 Zhou Y, Fu X, Liu X, et al. Use of corticosteroids in influenza- associated acute respiratory distress syndrome and severe pneumonia: a systemic review and meta-analysis. Sci Rep 2020; 10: 3044.
104 Hung IFN, To KKW, Chan JFW, et al. Efficacy of clarithromycin- naproxen-oseltamivir combination in the treatment of patients hospitalized for influenza A(H3N2) infection: an open-label randomized, controlled, phase IIb/III trial. Chest 2017;
151: 1069–80.
105 Xiao J, Shiu EYC, Gao H, et al. Nonpharmaceutical measures for
pandemic influenza in nonhealthcare settings: personal protective
and environmental measures. Emerg Infect Dis 2020; 26: 967–75. 106 Ryu S, Gao H, Wong JY, et al. Nonpharmaceutical measures for
pandemic influenza in nonhealthcare settings: international travel-
related measures. Emerg Infect Dis 2020; 26: 961–66.
107 Cowling BJ, Ali ST, Ng TWY, et al. Impact assessment of non-
pharmaceutical interventions against coronavirus disease 2019 and influenza in Hong Kong: an observational study.
Lancet Public Health 2020; 5: e279–88.
108 Feng L, Zhang T, Wang Q, et al. Impact of COVID-19 outbreaks and interventions on influenza in China and the United States. Nat Commun 2021; 12: 3249.
109 Olsen SJ, Azziz-Baumgartner E, Budd AP, et al. Decreased influenza activity during the COVID-19 pandemic: United States, Australia, Chile, and South Africa, 2020.
MMWR Morb Mortal Wkly Rep 2020; 69: 1305–09.
110 Qi Y, Shaman J, Pei S. Quantifying the impact of COVID-19 nonpharmaceutical interventions on influenza transmission in the United States. J Infect Dis 2021; 224: 1500–08.
111 Mott JA, Fry AM, Kondor R, Wentworth DE, Olsen SJ. Re-emergence of influenza virus circulation during 2020 in parts of tropical Asia: implications for other countries.
Influenza Other Respir Viruses 2021; 15: 415–18.
112 Melidou A, Ködmön C, Nahapetyan K, et al. Influenza returns with a season dominated by clade 3C.2a1b.2a.2 A(H3N2) viruses, WHO European Region, 2021/22. Euro Surveill 2022;
27: 2200255.
113 Centers for Disease Control and Prevention. Guidelines for healthcare settings. 2021. https://www.cdc.gov/flu/professionals/ infectioncontrol/healthcaresettings.htm (accessed May 16, 2022).
114 Radonovich LJ Jr, Simberkoff MS, Bessesen MT, et al. N95 respirators vs medical masks for preventing influenza among health care personnel: a randomized clinical trial. JAMA 2019; 322: 824–33.
115 Hamilton F, Arnold D, Bzdek BR, et al. Aerosol generating procedures: are they of relevance for transmission of SARS-CoV-2? Lancet Respir Med 2021; 9: 687–89.
http://www.thelancet.com Vol 400 August 27, 2022
705
Seminar

706
http://www.thelancet.com Vol 400 August 27, 2022
Seminar
116 117
118
119 120
121 122
123 124
125 126 127
128
129
130 131 132
133
134
135
Klompas M, Baker M, Rhee C. What Is an aerosol-generating procedure? JAMA Surg 2021; 156: 113–14.
Minodier L, Charrel RN, Ceccaldi PE, et al. Prevalence of gastrointestinal symptoms in patients with influenza, clinical significance, and pathophysiology of human influenza viruses in faecal samples: what do we know? Virol J 2015; 12: 215.
Campbell AP, Jacob ST, Kuypers J, et al. Respiratory failure caused by 2009 novel influenza A/H1N1 in a hematopoietic stem-cell transplant recipient: detection of extrapulmonary H1N1 RNA
and use of intravenous peramivir. Ann Intern Med 2010; 152: 619–20. Likos AM, Kelvin DJ, Cameron CM, Rowe T, Kuehnert MJ,
Norris PJ. Influenza viremia and the potential for blood-borne transmission. Transfusion 2007; 47: 1080–88.
Grohskopf LA, Alyanak E, Ferdinands JM, et al. Prevention and control of seasonal influenza with vaccines: recommendations of the advisory committee on immunization practices, United States, 2021-22 influenza season. MMWR Recomm Rep 2021; 70: 1–28. Sparrow E, Wood JG, Chadwick C, et al. Global production capacity of seasonal and pandemic influenza vaccines in 2019. Vaccine 2021; 39: 512–20.
Zost SJ, Parkhouse K, Gumina ME, et al. Contemporary H3N2 influenza viruses have a glycosylation site that alters binding of antibodies elicited by egg-adapted vaccine strains.
Proc Natl Acad Sci USA 2017; 114: 12578–83.
Kawai K, Kawai AT. Racial/ethnic and socioeconomic disparities in adult vaccination coverage. Am J Prev Med 2021; 61: 465–73.
Lu PJ, Hung MC, Srivastav A, et al. Surveillance of vaccination coverage among adult populations—United States, 2018.
MMWR Surveill Summ 2021; 70: 1–26.
Centers for Disease Control and Prevention. Racial and ethnic
minority groups. 2021. https://www.cdc.gov/flu/highrisk/disparities- racial-ethnic-minority-groups.html (accessed May 16, 2022).
Malosh RE, Petrie JG, Callear A, et al. Effectiveness of influenza vaccines in the HIVE household cohort over 8 years: is there evidence of indirect protection? Clin Infect Dis 2021; 73: 1248–56. Benjamin-Chung J, Arnold BF, Kennedy CJ, et al. Evaluation
of a city-wide school-located influenza vaccination program in Oakland, California, with respect to vaccination coverage, school absences, and laboratory-confirmed influenza: a matched cohort study. PLoS Med 2020; 17: e1003238.
Mertz D, Fadel SA, Lam PP, et al. Herd effect from influenza vaccination in non-healthcare settings: a systematic review of randomised controlled trials and observational studies. Euro Surveill 2016; 21: 30378.
Omer SB, Clark DR, Madhi SA, et al. Efficacy, duration of protection, birth outcomes, and infant growth associated with influenza vaccination in pregnancy: a pooled analysis of three randomised controlled trials. Lancet Respir Med 2020; 8: 597–608. Giles ML, Krishnaswamy S, Macartney K, Cheng A. The safety of inactivated influenza vaccines in pregnancy for birth outcomes:
a systematic review. Hum Vaccin Immunother 2019; 15: 687–99. Chua H, Feng S, Lewnard JA, et al. The use of test-negative controls to monitor vaccine effectiveness: a systematic review of methodology. Epidemiology 2020; 31: 43–64.
Okoli GN, Racovitan F, Abdulwahid T, Righolt CH, Mahmud SM. Variable seasonal influenza vaccine effectiveness across geographical regions, age groups and levels of vaccine antigenic similarity with circulating virus strains: a systematic review and meta-analysis of the evidence from test-negative design studies after the 2009/10 influenza pandemic. Vaccine 2021; 39: 1225–40.
Ohmit SE, Thompson MG, Petrie JG, et al. Influenza vaccine effectiveness in the 2011-2012 season: protection against each circulating virus and the effect of prior vaccination on estimates. Clin Infect Dis 2014; 58: 319–27.
Ferdinands JM, Gaglani M, Martin ET, et al. Waning vaccine effectiveness against influenza-associated hospitalizations among adults, 2015–2016 to 2018–2019, United States Hospitalized Adult Influenza Vaccine Effectiveness Network. Clin Infect Dis 2021;
73: 726–29.
Rondy M, El Omeiri N, Thompson MG, Levêque A, Moren A, Sullivan SG. Effectiveness of influenza vaccines in preventing severe influenza illness among adults: a systematic review and meta-analysis of test-negative design case-control studies. J Infect 2017; 75: 381–94.
136 Boddington NL, Pearson I, Whitaker H, Mangtani P, Pebody RG. Effectiveness of influenza vaccination in preventing hospitalization due to influenza in children: a systematic review and meta-analysis. Clin Infect Dis 2021; 73: 1722–32.
137 Yedlapati SH, Khan SU, Talluri S, et al. Effects of influenza vaccine on mortality and cardiovascular outcomes in patients with cardiovascular disease: a systematic review and meta-analysis.
J Am Heart Assoc 2021; 10: e019636.
138 Centers for Disease Control and Prevention. Vaccine effectiveness studies. 2021. https://www.cdc.gov/flu/vaccines-work/effectiveness- studies.htm (accessed May 16, 2022).
139 Erbelding EJ, Post DJ, Stemmy EJ, et al. A universal influenza vaccine: the strategic plan for the National Institute of Allergy and Infectious Diseases. J Infect Dis 2018; 218: 347–54.
140 Paules CI, Fauci AS. Influenza vaccines: good, but we can do better. J Infect Dis 2019; 219 (suppl 1): S1–4.
141 Innis BL, Berlanda Scorza F, Blum JS, et al. Meeting report: convening on the influenza human viral challenge model for universal influenza vaccines, part 1: value; challenge virus selection; regulatory, industry and ethical considerations; increasing standardization, access and capacity. Vaccine 2019; 37: 4823–29.
142 Innis BL, Scorza FB, Blum JS, et al. Convening on the influenza human viral challenge model for universal influenza vaccines, part 2: methodologic considerations. Vaccine 2019; 37: 4830–34.
143 Dolgin E. mRNA flu shots move into trials. Nat Rev Drug Discov 2021; 20: 801–03.
144 Shinde V, Cho I, Plested JS, et al. Comparison of the safety and immunogenicity of a novel Matrix-M-adjuvanted nanoparticle influenza vaccine with a quadrivalent seasonal influenza vaccine in older adults: a phase 3 randomised controlled trial. Lancet Infect Dis 2022; 22: 73–84.
145 Thompson MG, Pierse N, Sue Huang Q, et al. Influenza vaccine effectiveness in preventing influenza-associated intensive care admissions and attenuating severe disease among adults in New Zealand 2012-2015. Vaccine 2018; 36: 5916–25.
146 Ferdinands JM, Thompson MG, Blanton L, Spencer S, Grant L,
Fry AM. Does influenza vaccination attenuate the severity of breakthrough infections? A narrative review and recommendations for further research. Vaccine 2021; 39: 3678–95.
147 Bresee JS, Lafond KE, McCarron M, et al. The partnership for influenza vaccine introduction (PIVI): supporting influenza vaccine program development in low and middle-income countries through public-private partnerships. Vaccine 2019; 37: 5089–95.
148 Gordon AC, Mouncey PR, Al-Beidh F, et al. Interleukin-6 receptor antagonists in critically ill patients with COVID-19. N Engl J Med 2021; 384: 1491–502.
149 Horby P, Lim WS, Emberson JR, et al. Dexamethasone in hospitalized patients with Covid-19. N Engl J Med 2021; 384: 693–704.
150 Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the treatment of COVID-19—final report. N Engl J Med 2020; 383: 1813–26.
151 Angus DC, Berry S, Lewis RJ, et al. The REMAP-CAP (Randomized Embedded Multifactorial Adaptive Platform for Community- acquired Pneumonia) study. Rationale and design.
Ann Am Thorac Soc 2020; 17: 879–91.
152 Kadri SS, Sun J, Lawandi A, et al. Association between caseload surge and COVID-19 survival in 558 U.S. hospitals, March to August 2020. Ann Intern Med 2021; 174: 1240–51.
153 WHO. Optimizing the treatment of patients. 2017. https://apps. who.int/iris/bitstream/handle/10665/259887/WHO-WHE-IHM- GIP-2017.7-eng.pdf?sequence=1&isAllowed=y (accessed
May 16, 2022).
154 Uyeki TM, Fowler RA, Fischer WA. Gaps in the clinical management of influenza: a century since the 1918 pandemic. JAMA 2018; 320: 755–56.
Copyright © 2022 Elsevier Ltd. All rights reserved.