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January 23, 2019/Primary Care/News & Insights

Influenza Update 2018–2019: 100 Years After the Great Pandemic

A centennial year update on epidemiology, transmission and treatment of influenza.

Flu virus

by Sherif Mossad, MD


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This year marks the centennial of the 1918 influenza pandemic, which killed 50 million people worldwide. Three more influenza pandemics and annual epidemics have occurred since then, with other significant interim events.1 The 2017–2018 epidemic was particularly severe and long.2 This centennial year update focuses primarily on immunization, but also reviews epidemiology, transmission and treatment.

Medical Illustration of Flu Virus

2017–2018 was a bad season

The 2017–2018 influenza epidemic was memorable, dominated by influenza A(H3N2) viruses with morbidity and mortality rates approaching pandemic numbers. It lasted 19 weeks, killed more people than any other epidemic since 2010, particularly children, and was associated with 30,453 hospitalizations—almost twice the previous season high in some parts of the United States.2

Regrettably, 171 unvaccinated children died during 2017–2018, accounting for almost 80% of deaths.2 The mean age of the children who died was 7.1 years; 51% had at least 1 underlying medical condition placing them at risk for influenza-related complications, and 57% died after hospitalization.2

Recent estimates of the incidence of symptomatic influenza among all ages ranged from 3% to 11%, which is slightly lower than historical estimates. The rates were higher for children under age 18 than for adults.3 Interestingly, influenza A(H3N2) accounted for 50% of cases of non-mumps viral parotitis during the 2014–2015 influenza season in the United States.4

Influenza C exists but is rare. Influenza A and B account for almost all influenza-related outpatient visits and hospitalizations. Surveillance data from May 2013 through December 2016 showed that influenza C accounts for 0.5% of influenza-related outpatient visits and hospitalizations, particularly affecting children ages 6 to 24 months. Medical comorbidities and copathogens were seen in all patients requiring intensive care and in most hospitalizations.5 Diagnostic tests for influenza C are not widely available.

Dogs and cats: Factories for new flu strains? While pigs and birds are the major reservoirs of influenza viral genetic diversity from which infection is transmitted to humans, dogs and cats have recently emerged as possible sources of novel reassortant influenza A.6 With their frequent close contact with humans, our pets may prove to pose a significant threat.

Obesity a risk factor for influenza. Obesity emerged as a risk factor for severe influenza in the 2009 pandemic. Recent data also showed that obesity increases the duration of influenza A virus shedding, thus increasing duration of contagiousness.7

Influenza a cardiovascular risk factor.Previous data showed that influenza was a risk factor for cardiovascular events. Two recent epidemiologic studies from the United Kingdom showed that laboratory-confirmed influenza was associated with higher rates of myocardial infarction and stroke for up to 4 weeks.8,9

Which strain is the biggest threat? Predicting which emerging influenza serotype may cause the next pandemic is difficult, but influenza A(H7N9), which had not infected humans until 2013 but has since infected about 1,600 people in China and killed 37% of them, appears to have the greatest potential.10

National influenza surveillance programs and influenza-related social media applications have been developed and may get a boost from technology. A smartphone equipped with a temperature sensor can instantly detect one’s temperature with great precision. A 2018 study suggested that a smartphone-driven thermometry application correlated well with national influenza-like illness activity and improved its forecast in real time and up to 3 weeks in advance.11



Humidity may not block transmission. Animal studies have suggested that humidity in the air interferes with transmission of airborne influenza virus, partially from biologic inactivation. But when a recent study used humidity-controlled chambers to investigate the stability of the 2009 influenza A(H1N1) virus in suspended aerosols and stationary droplets, the virus remained infectious in aerosols across a wide range of relative humidities, challenging the common belief that humidity destabilizes respiratory viruses in aerosols.12

One sick passenger may not infect the whole plane. Transmission of respiratory viruses on airplane flights has long been considered a potential avenue for spreading influenza. However, a recent study that monitored movements of individuals on 10 transcontinental US flights and simulated inflight transmission based on these data showed a low probability of direct transmission, except for passengers seated in close proximity to an infectious passenger.13


Numerous studies have found anti-influenza medications to be effective. Nevertheless, in an analysis of the 2011–2016 influenza seasons, only 15% of high-risk patients were prescribed anti-influenza medications within 2 days of symptom onset, including 37% in those with laboratory-confirmed influenza.14 Fever was associated with an increased rate of antiviral treatment, but 25% of high-risk outpatients were afebrile. Empiric treatment of 4 high-risk outpatients with acute respiratory illness was needed to treat 1 patient with influenza. 14

Treatment with a neuraminidase inhibitor within 2 days of illness has recently been shown to improve survival and shorten duration of viral shedding in patients with avian influenza A(H7N9) infection.15 Antiviral treatment within 2 days of illness is associated with improved outcomes in transplant recipients16 and with a lower risk of otitis media in children.17

Appropriate anti-influenza treatment is as important as avoiding unnecessary antibiotics. Regrettably, as many as one-third of patients with laboratory-confirmed influenza are prescribed antibiotics.18

The US Food and Drug Administration warns against fraudulent unapproved over-the-counter influenza products.19

Baloxavir marboxil. Baloxavir marboxil is a new anti-influenza medication approved in Japan in February 2018 and anticipated to be available in the United States sometime in 2019.

This prodrug is hydrolyzed in vivo to the active metabolite, which selectively inhibits capdependent endonuclease enzyme, a key enzyme in initiation of messenger ribonucleic acid synthesis required for influenza viral replication.20

In a double-blind phase 3 trial, the median time to alleviation of influenza symptoms is 26.5 hours shorter with baloxavir marboxil than with placebo. One tablet was as effective as 5 days of the neuraminidase inhibitor oseltamivir and was associated with greater reduction in viral load 1 day after initiation and similar side effects.21 Of concern is the emergence of nucleic acid substitutions conferring resistance to baloxavir; this occurred in 2.2% and 9.7% of baloxavir recipients in the phase 2 and 3 trials, respectively.

Closing the Gaps

Several gaps in the management of influenza persist since the 1918 pandemic.1 These include gaps in epidemiology, prevention, diagnosis, treatment and prognosis.

  • Global networks wider than current ones are needed to address this global disease and to prioritize coordination efforts.
  • Establishing and strengthening clinical capacity is needed in limited resource settings. New technologies are needed to expedite vaccine development and to achieve progress toward a universal vaccine.
  • Current diagnostic tests do not distinguish between seasonal and novel influenza A viruses of zoonotic origin, which are expected to cause the next pandemic.
  • Current antivirals have been shown to shorten duration of illness in outpatients with uncomplicated influenza, but the benefit in hospitalized patients has been less well established.
  • In 2007, resistance of seasonal influenza A(H1N1) to oseltamivir became widespread.
  • In 2009, pandemic influenza A(H1N1), which is highly susceptible to oseltamivir, replaced the seasonal virus and remains the predominantly circulating A(H1N1) strain.
  • A small-molecule fragment, N-cyclohexyaltaurine, binds to the conserved hemagglutinin receptor-binding site in a manner that mimics the binding mode of the natural receptor sialic acid. This can serve as a template to guide the development of novel broad-spectrum small-molecule anti-influenza drugs.22
  • Biomarkers that can accurately predict development of severe disease in patients with influenza are needed.


This post is a shortened adaptation of a review article published in the November 2018 issue of Cleveland Clinic Journal of Medicine (2018;85:861-869).


  1. Uyeki TM, Fowler RA, Fischer WA. Gaps in the clinical management of influenza: a century since the 1918 pandemic. JAMA 2018; 320(8):755–756. doi:10.1001/jama.2018.8113
  2. Garten R, Blanton L, Elal AI, et al. Update: influenza activity in the United States during the 2017–18 season and composition of the 2018–19 influenza vaccine. MMWR Morb Mortal Wkly Rep. 2018; 67(22):634–642. doi:10.15585/mmwr.mm6722a4
  3. Tokars JI, Olsen SJ, Reed C. Seasonal incidence of symptomatic influenza in the United States. Clin Infect Dis. 2018; 66(10):1511–1518. doi:10.1093/cid/cix1060


  1. Elbadawi LI, Talley P, Rolfes MA, et al. Non-mumps viral parotitis during the 2014–2015 influenza season in the United States. Clin Infect Dis. 2018. Epub ahead of print. doi:10.1093/cid/ciy137
  2. Thielen BK, Friedlander H, Bistodeau S, et al. Detection of influenza C viruses among outpatients and patients hospitalized for severe acute respiratory infection, Minnesota, 2013–2016. Clin Infect Dis. 2018; 66(7):1092–1098. doi:10.1093/cid/cix931
  3. Chena Y, Trovãob NS, Wang G, et al. Emergence and evolution of novel reassortant influenza A viruses in canines in southern China. MBio. 2018; 9(3):e00909–e00918. doi:10.1128/mBio.00909-18
  4. Maier HE, Lopez R, Sanchez N, et al. Obesity increases the duration of influenza A virus shedding in adults. J Infect Dis. 2018. Epub ahead of print. doi:10.1093/infdis/jiy370
  5. Warren-Gash C, Blackburn R, Whitaker H, McMenamin J, Hayward AC. Laboratory-confirmed respiratory infections as triggers for acute myocardial infarction and stroke: a self-controlled case series analysis of national linked datasets from Scotland. Eur Respir J. 2018; 51(3):1701794. doi:10.1183/13993003.01794-2017
  6. Blackburn R, Zhao H, Pebody R, Hayward A, Warren-Gash C. Laboratory-confirmed respiratory infections as predictors of hospital admission for myocardial infarction and stroke: time-series analysis of English data for 2004–2015. Clin Infect Dis. 2018; 67(1):8–17. doi:10.1093/cid/cix1144
  7. Newsweek; Andrew S. What is disease X? Deadly bird flu virus could be next pandemic. www.newsweek.com/disease-x-bird-flu-deathspandemic-what-h7n9-979723. Accessed October 3, 2018.
  8. Miller AC, Singh I, Koehler E, Polgreen PM. A smartphone-driven thermometer application for real-time population- and individual-level influenza surveillance. Clin Infect Dis. 2018; 67(3):388–397. doi:10.1093/cid/ciy073
  9. 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(5):739–747. doi:10.1093/infdis/jiy221
  10. Hertzberg VS, Weiss H, Elon L, et. Behaviors, movements, and transmission of droplet-mediated respiratory diseases during transcontinental airline flights. Proc Natl Acad Sci U S A. 2018; 115(14):3623–3627. doi:10.1073/pnas.1711611115
  11. Stewart RJ, Flannery B, Chung JR, et al. Influenza antiviral prescribing for outpatients with an acute respiratory illness and at high risk for influenza-associated complications during 5 influenza seasons—United States, 2011–2016. Clin Infect Dis. 2018; 66(7):1035–1041. doi:10.1093/cid/cix922


  1. Zheng S, Tang L, Gao H, et al. Benefit of early initiation of neuraminidase inhibitor treatment to hospitalized patients with avian influenza A(H7N9) virus. Clin Infect Dis. 2018; 66(7):1054–1060. doi:10.1093/cid/cix930
  2. Kumar D, Ferreira VH, Blumberg E, et al. A five-year prospective multicenter evaluation of influenza infection in transplant recipients. Clin Infect Dis. 2018. Epub ahead of print. doi:10.1093/cid/ciy294
  3. 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(10):1492–1500. doi:10.1093/cid/cix1040
  4. Havers FP, Hicks LA, Chung JR, et al. Outpatient antibiotic prescribing for acute respiratory infections during influenza seasons. JAMA Network Open. 2018; 1(2):e180243. doi:10.1001/jamanetworkopen.2018.0243
  5. US Food and Drug Administration. FDA warns of fraudulent and unapproved flu products. www.fda.gov/newsevents/newsroom/pressannouncements/ucm599223.htm. Accessed October 3, 2018.
  6. Portsmouth S, Kawaguchi K, Arai M, Tsuchiya K, Uehara T. Capdependent endonuclease inhibitor S-033188 for the treatment of influenza: results from a phase 3, randomized, double-blind, placeboand active-controlled study in otherwise healthy adolescents and adults with seasonal influenza. Open Forum Infect Dis. 2017; 4(suppl 1):S734. doi:10.1093/ofi d/ofx180.001
  7. Hayden FG, Sugaya N, Hirotsu N, et al; Baloxavir Marboxil Investigators Group. Baloxavir Marboxil for uncomplicated influenza in adults and adolescents. N Engl J Med. 2018; 379(10):913–923. doi:10.1056/NEJMoa1716197
  8. Kadam RU, Wilson IA. A small-molecule fragment that emulates binding of receptor and broadly neutralizing antibodies to influenza A hemagglutinin. Proc Natl Acad Sci U S A. 2018; 115(16):4240–4245. doi:10.1073/pnas.1801999115

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