Influenza_Review_2022.pdf

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...

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. 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-respiratorytract 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 inhospital 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 www.thelancet.com Vol 400 August 27, 2022 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 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 [email protected] 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. 693 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 (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 Molecular assay (45–80 min to results; up to 4–6 h for some assays) done in clinical laboratories Influenza viral RNA detection using nucleic acid amplification; some assays require complex machinery, preanalytical nucleic-acid extraction, and downstream analysis High sensitivity (>95%) and high specificity (>99%) 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 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 Virus culture (1–10 days to results); requires qualified personnel, usually done at public health laboratories Isolation of viable influenza virus using tissue cell culture High sensitivity and high specificity 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 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 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 upperrespiratory-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 696 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 www.thelancet.com Vol 400 August 27, 2022 Seminar 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 Hospitalacquired 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 www.thelancet.com Vol 400 August 27, 2022 Complications Considerations Upper-respiratory complications Otitis media, parotitis, sinusitis, and laryngotracheobronchitis Otitis media, parotitis, and laryngotracheobronchitis are more common in children than adults 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 Cardiac complications Myocardial infarction, myocarditis, pericarditis, and heart failure Influenza might precipitate myocardial infarction or heart failure in people with coronary artery disease; cardiac complications can result in critical illness with fatal outcomes Gastrointestinal complications Hepatitis, pancreatitis, and severe acute abdomen-like pain Hepatic failure is rare Musculoskeletal complications Myositis, rhabdomyolysis, and compartment syndrome Severe myositis (soleus and gastrocnemius) can occur in schoolage children; myoglobinuria can cause acute kidney injury Renal complications Acute kidney injury and kidney failure Can occur with severe pneumonia Neurological complications Encephalopathy, encephalitis, meningoencephalitis, febrile seizures, cerebrovascular accident, transverse myelitis, acute demyelinating encephalomyelitis, Reye syndrome with salicylate exposure, and Guillain-Barré syndrome 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 Co-infections Pneumonia, ventilator-associated pneumonia, tracheitis, and meningitis Invasive bacterial, viral, and fungal coinfections can cause critical illness and fatal outcomes Other complications 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 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) Adapted from Uyeki and colleagues.26 Table 2: Complications associated with influenza 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 697 Seminar Dosing Mechanism of action Considerations Oseltamivir (oral suspension or capsule) Duration of treatment, 5 days; age 40 kg, 75 mg twice per day; and adults, 75 mg twice per day Inhibits influenza viral neuraminidase; blocks release of progeny virions from infected respiratory epithelial cells 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 Zanamivir* (inhaled powder) Inhibits influenza viral Duration of treatment, 5 days; age ≥7 years, 10 mg (two inhalations) twice neuraminidase; blocks release of progeny virions from infected per day respiratory epithelial cells Peramivir (intravenous) 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 Inhibits influenza viral neuraminidase; blocks release of progeny virions from infected respiratory epithelial cells Less available than oseltamivir; insufficient data for patients who are hospitalised Baloxavir (oral suspension or capsule) Duration of treatment, single dose; age ≥5 years and weight