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2018 is the 100th anniversary of one of the largest and most devastating flu pandemics in modern history in which more people died than in all of World War I. We offer this course as an annual review of the current and historical impact of influenza, seasonal and pandemic. It includes epidemiology, virus types and subtypes, how influenza viruses drift and shift, then review the impact the 1918–1919 influenza pandemic. We also discuss the goal of universal vaccination, diagnosis, and treatment, and the composition of the 2018–2019 influenza vaccines.
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This course will be reviewed every two years. It will be updated or discontinued on November 1, 2019.
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Fewer than 4 out of 10 adults in the United States got flu shots last winter, the lowest rate in seven seasons and one likely reason why the 2017-2018 season was the deadliest in decades.
Washington Post, October 25, 2018
Influenza is one of the deadliest viruses in the world, yet we take for granted that we are protected from its ill effects. We are deathly afraid of other viral infections, any of which kill only a fraction of the people that die each year from influenza. Yet many of us skip our annual flu shots, giving various excuses for forgoing the vaccine. This is despite the fact that the impact of influenza is enormous—estimated to be about 1 billion cases worldwide with death in nearly half a million people.
One hundred years ago the 1918 influenza pandemic devastated entire communities and took an estimated 675,000 American lives. It was the most severe pandemic in recent history, sweeping the globe quickly and killing more than 50 million people. Source: CDC.
The Flu I.Q. widget is an interactive quiz to test your flu knowledge. https://www.cdc.gov/flu/freeresources/widgets/fluiq/index.html
The 2017–2018 influenza season was severe, with high levels of outpatient clinic and emergency department visits for influenza-like illness (ILI), high influenza-related hospitalization rates, and elevated and geographically widespread influenza activity for an extended period. In 2017, the Centers for Disease and Prevention (CDC) began using new methodology to classify seasonal severity and applied the methodology to the 2003–2004 through 2016–2017 seasons. The 2017–2018 season was the first season to be classified as high severity across all age groups (CDC, 2018a).
Influenza is a clever virus—it shifts, drifts, and adapts, every so often mutating into a virus to which humans have little or no immunity. When this happens, a pandemic can occur, as in 1918 when a devastating influenza pandemic killed tens of millions of people throughout the world. Some of us lost grandparents, aunts, or uncles to the 1918 pandemic. All influenza A pandemics since that time, and almost all cases of influenza A worldwide, have been caused by descendants of the 1918 H1N1 virus (Taubenberger & Morens, 2006).
A 3D graphical representation of the biology and structure of a generic influenza virus. Source: CDC.
Even if you are not familiar with the 1918 pandemic, you may be aware of the 2009 H1N1 pandemic—the first global influenza pandemic in more than forty years. It was caused by the emergence of a novel* H1N1 influenza strain that reminded us just how serious an influenza pandemic can be. By the time the World Health Organization (WHO) declared the pandemic officially over in August 2010, the CDC estimated that 43 to 89 million people in the United States had become infected and more than 12,000 had died. It is estimated that worldwide between 151,700 and 575,400 people died from 2009 H1N1 virus infection during the first year the virus circulated (CDC, 2018b).
*Novel: New (novel) influenza viruses are different from those currently circulating. This can include highly pathogenic influenza A viruses (H1N1, H5N1, H7N3, and H7N9).
Influenza experts believe that another influenza pandemic will occur—likely caused by an influenza subtype to which there is little or no pre-existing immunity in the human population. Even though the H1N1 pandemic of 2009 is officially over, the H1N1 virus continues to circulate as a seasonal virus and is expected to do so for several years. Fortunately, most (although not all) countries have developed influenza vaccines that protect against the H1N1 virus.
Source: CDC (https://www.cdc.gov/flu/pandemic-resources/1918-commemoration/index.htm)
There are three kinds of influenza: A, B, and C. Influenza B and C aren’t much to worry about, at most causing minor illness. The influenza A viruses, by contrast, are highly variable and so have the potential to outwit the human immune system and cause a pandemic.
Pandemic Influenza: The Inside Story
It is helpful to understand a little bit about the influenza virus—the different types, how they are named, and how they mutate. The more you know, the better you will be able to protect your patients, friends, and family members from catching the flu.
Influenza viruses are categorized and named by type. There are three types of influenza viruses—A, B, and C. Type is determined by the material within the nucleus of the virus.
Left: The influenza virus. Copyright Zygote Media Group. Used with Permission. Right: Structure of the influenza virion. The hemagglutinin (HA) and neuraminidase (NA) proteins are shown on the surface of the particle. The viral RNAs that make up the genome are shown as red coils inside the particle and bound to ribonuclear proteins (RNPs). Source: NIH, public domain.
The nomenclature used to describe a specific influenza virus was established by the World Health Organization in 1980 and is expressed in this order:
For example, the 2009 H1N1 pandemic influenza virus was named as follows:
This is translated as: Influenza type A, isolated first in California, lineage (strain) number 04, year 2009, and type H1N1.
In the image below, a Fujian influenza virus that circulated in 2002 was named as follows:
This is translated as: Influenza type A, first isolated in Fujian (a province on the Southeast coast of mainland China), lineage number 411, year 2002, type H3N2.
Influenza virus nomenclature (for a Fujian flu virus). Source: Wikipedia.org
The Fujian H3N2 influenza of 2002 caused an unusually severe 2003–2004 flu season, partly because it spread rapidly and partly because the vaccine for that season had already been formulated when the Fujian H3N2 virus was identified.
Type A influenza viruses are divided into subtypes, based on the presence of two glycoproteins on the surface of the virus. These glycoproteins are called hemagglutinin (HA) and neuraminidase (NA). About 18 hemagglutinins have been identified, although generally, only H1, H2, and H3 are found in human influenza viruses. There are more than 100 types of neuraminidase, but only N1 and N2 have been positively linked to influenza epidemics in humans.
The above image shows the features of an influenza virus, including the surface proteins hemagglutinin (HA) and neuraminidase (NA). Following influenza infection or receipt of the influenza vaccine, the body’s immune system develops antibodies that recognize and bind to “antigenic sites,” which are regions found on an influenza virus’s surface proteins. By binding to these antigenic sites, antibodies neutralize flu viruses and prevent them from causing further infection. Source: CDC.
Hemagglutinin and neuraminidase are also called antigens, substances that, when introduced into the body, stimulate the production of an antibody. Currently, there are two subtypes of influenza A viruses found circulating among human populations: influenza A (H1N1) and influenza A (H3N2).
A reservoir is the place where a pathogen lives and survives. For all subtypes of influenza A viruses, wild birds are the primary natural reservoir and are thought to be the source of influenza A viruses in all other animals. Influenza A viruses are found in many different animals, including ducks, chickens, pigs, whales, horses, and seals.
Most influenza viruses cause asymptomatic or mild infection in birds; however, clinical signs in birds vary greatly depending on the virus. Infection with certain avian influenza A viruses (for example, some H5 and H7 viruses) can cause widespread, severe disease and death among some species of birds (CDC, 2018c).
In 2013 the ability to quickly identify the reservoir of a novel avian influenza A (H7N9) virus helped Chinese officials contain what started as an outbreak of “pneumonia of unknown cause” in the eastern coastal province of Zhejiang, China. During the outbreak, there were 135 confirmed human infections with H7N9, the vast majority during the month of April. Many of the people infected with H7N9 reported contact with poultry. By August 2013, 45 people had died (Chen et al., 2013). The H7N9 virus had previously been detected in birds but had never been seen in humans or any other animals prior to this outbreak.
Zhejiang province, China (in red). Shanghai, a city with a population of 24 million, is located on the northern tip of Zhejiang province. Source: Uwe Dedering, Wikipedia Commons.
Annual epidemics of sporadic human infections with Asian-lineage avian influenza A (H7N9) virus (“Asian H7N9”) in China have been reported since March 2013. In late 2016, China experienced its fifth epidemic of Asian H7N9 human infections. This was the largest annual epidemic to date. As of September 13, 2017, the World Health Organization reported 764 human infections with Asian H7N9 virus during the fifth epidemic. During epidemics one through four, about 40% of people confirmed with Asian H7N9 virus infection died (CDC, 2018c).
The eight genes of the H7N9 virus are closely related to avian influenza viruses found in domestic ducks, wild birds, and domestic poultry in Asia. The virus likely emerged from “reassortment,” a process in which two or more influenza viruses co-infect a single host and exchange genes. This can result in the creation of a new influenza virus. Source: CDC, 2014.
Pigs are susceptible to avian, human, and swine flu viruses and can potentially be infected with influenza viruses from different species at the same time. If this happens, it is possible for the genes of these viruses to mix (reassort) and create a new virus.
Influenza viruses that normally circulate in pigs are called “variant” viruses when they are found in people and denoted with a letter “v.” H3N2v viruses from the 2009 H1N1 pandemic virus were first detected in people in 2011 and were responsible for a multi-state outbreak in the summer of 2012 that resulted in 306 cases, including 16 hospitalizations and 1 fatality (CDC, 2016a).
Most cases of H3N2v identified during 2012 were associated with exposure to pigs at agricultural fairs. Many fairs have swine barns where pigs from different places come in close contact with each other and with people. These venues may allow the spread of influenza viruses both among pigs and between pigs and people. Infected pigs can spread influenza viruses even if they are not symptomatic. Although instances of limited person-to-person spread of this virus have been identified in the past, sustained or community-wide transmission of H3N2v has not occurred (CDC, 2016a).
Influenza type B viruses are separated into two genetic lineages (B/Yamagata and B/Victoria). They are not classified by subtype like influenza A viruses. Influenza B viruses from both the Yamagata and Victoria lineages have co-circulated in most recent influenza seasons. The trivalent influenza vaccines available in recent seasons have contained one influenza B virus, representing only the Yamagata lineage. The quadrivalent vaccine for 2018–2019 will contain both the Yamagata and Victoria lineages.
Influenza type B viruses are usually found only in humans, and can cause morbidity and mortality among humans, but in general are associated with less severe epidemics than influenza A viruses. Although influenza type B viruses can cause human epidemics, they have not caused pandemics. Influenza B viruses undergo genetic changes less rapidly than influenza A viruses.
Influenza type C is less common and less studied than influenza A and B. It can cause illness in humans and pigs, and it is thought that most people are exposed to influenza C during childhood. The influenza C virus lacks the multiple subtypes (hemagglutinin and neuraminidase) found in influenza A, which limits its ability to mutate. Influenza C is thought to be unlikely to cause a pandemic, although localized epidemics have occurred. As with type B influenza viruses, type C influenza viruses are not classified according to subtype.
Types of Influenza Virus
To successfully infect a person, the influenza virus must develop ways to evade a person’s immune system. Viruses do this through evolutionary processes called antigenic drift and antigenic shift. Influenza type A viruses undergo both kinds of changes, while influenza type B and C viruses change only by the gradual process of antigenic drift.
Antigenic drift involves continual small changes or mutations to a virus’s surface antigens (HA or NA). Think of a small boat drifting across the ocean or clouds drifting across the sky. These changes produce new viral strains that are fairly closely related to one another and may be recognized by the immune system (sometimes called “cross-protection”). Changes due to antigenic drift can nevertheless accumulate over time, straining the ability of a person’s immune system to recognize the new virus.
Like clouds drifting across the sky, antigenic drift involves small, continual changes to a virus’s surface antigens. Source: Wikipedia Commons.
In most years, one or two of the virus strains in the influenza vaccine are updated to keep up with the changes in the circulating flu viruses. Changes in viruses due to antigenic drift can cause widespread infection because the protection that remains from past exposures to similar viruses is incomplete. Drift occurs in all three types of influenza virus (A, B, C).
Antigenic shift is a major, abrupt change in one or both surface antigens (HA or NA). Shift occurs at varying intervals and likely is the result of reassortment (the exchange of a gene segment) between influenza A viruses, usually those that affect humans and birds.
Like this lightning storm near New Boston, Texas, antigenic shift involves major, abrupt changes in surface antigens (HA or NA). Source: Griffinstorm, Wikipedia Commons.
Antigenic shift results in a new influenza A subtype that is so different from previous subtypes in humans that most people do not have immunity to the new virus. An antigenic shift can lead to a worldwide pandemic if the virus is efficiently transmitted from person to person.
An example of a “shift” occurred in the spring of 2009, when a novel H1N1 virus with a new combination of genes (from American pigs, Eurasian pigs, birds, and humans) emerged in people and quickly spread, causing a pandemic. Since the late nineteenth century, four occurrences of antigenic shift have led to major influenza pandemics.
Although influenza viruses constantly and gradually change by antigenic drift, antigenic shift happens only occasionally. When a type A virus undergoes both kinds of changes, it is capable of evading host immunity, with profound implications for epidemiology and control. This is the main reason why seasonal influenza vaccines are updated frequently, to maintain protection in risk groups against currently circulating strains (Arinaminpathy & Grenfell, 2010).
Influenza Virus: Antigenic Changes
Antigenic drift vs. shift. Antigenic drift creates influenza viruses with slightly modified antigens, while antigenic shift generates viruses with entirely new antigens (shown in red). Source: Wikipedia Commons and USDA.
The 2009 influenza A (H1N1) virus was a new flu virus of swine origin that first caused illness in Mexico and the United States in March and April of 2009. This virus was originally referred to as “swine flu” because laboratory testing showed that many of the genes in this new virus were very similar to influenza viruses that normally occur in pigs in North America. Further study, however, showed that this new virus was very different from the one that formerly circulated in North American pigs. It has two genes from flu viruses that have circulated in pigs in Europe and Asia, plus bird (avian) genes and human genes. Scientists call this a quadruple reassortant virus (CDC, 2010).
Influenza occurs in two distinct patterns: pandemic and seasonal. Pandemic influenza results from the emergence of a new influenza A virus to which the population possesses little or no immunity and that can occur at any time of year. Seasonal influenza is usually caused by influenza A or B viruses and generally occurs each year during a specific time of the year.
While outbreaks of influenza may be traced as far back as 412 B.C.E., the first pandemic, or worldwide epidemic, that clearly fits the description of influenza occurred in 1580. It began in Asia and spread to most of the rest of the world, affecting nearly all of Europe in just six weeks. At least four influenza pandemics occurred in the nineteenth century, followed by three more in the twentieth century and one in this century.
In the twentieth century, the most devastating example of a new influenza subtype emerging in the human population occurred 1918. The virus contained a subtype 1 hemagglutinin protein (H1) and a subtype 1 neuraminidase protein (N1). After the 1918 pandemic, H1N1 variants circulated for 39 years before being replaced by an H2N2 virus in 1957. The H2N2 virus was prevalent for only 11 years until 1968, when it was replaced by an H3N2 virus (Palese & Wang, 2011). In 2009, a new strain of H1N1 influenza emerged and caused a worldwide pandemic in which as estimated 280,000 people died.
(A) H1N1 indicates virus with hemagglutinin subtype 1 and neuraminidase subtype 1. H2N2 and H3N2 indicate viruses with hemagglutinin subtype 2 and neuraminidase subtype 2 and hemagglutinin subtype 3 and neuraminidase subtype 2, respectively. pH1N1 indicates the novel swine origin virus first isolated in 2009. (B) Antibody response in the human population, which the authors propose to have contributed to the elimination of existing seasonal influenza virus strains. Source: Palese & Wang, 2011.
The influenza pandemic of 1918–1919 killed more people than the Great War, known today as World War I, at somewhere between 20 and 40 million people. It has been cited as the most devastating epidemic in recorded world history. More people died of influenza in a single year than in the four years of the Black Death Bubonic Plague from 1347 to 1351. Known as “Spanish Flu” or “La Grippe,” the influenza of 1918–1919 was a global disaster.
Molly Billings, 2005
The Influenza Pandemic of 1918
The 1918 influenza pandemic, caused by an H1N1 influenza subtype came on suddenly in March of 1918 and spread rapidly throughout the world. In the United States the first reports came from public health officials in Haskell County, Kansas, who reported “18 cases of influenza of a severe type.” By June the virus had spread from the United States to Europe, where it quickly moved from the military to the civilian population. From there, the disease circled the globe—to Asia, Africa, South America, and, back again, to North America.
The effect of the influenza epidemic was so severe that the average lifespan in the United States was depressed by 10 years (Billings, 2005). The “Spanish influenza” of 1918 is estimated to have hit nearly a third of the world’s population. Conditions at the end of World War I likely contributed to the mortality (Nicholls, 2006).
The 1918 pandemic occurred in three waves. The first wave was seen when mild influenza erupted in the late spring and summer of 1918. The second wave occurred with an outbreak of severe influenza in the fall of 1918 and the final wave hit in the spring of 1919. A physician stationed at Fort Devens, outside Boston, reported in late September 1918:
This epidemic started about four weeks ago, and has developed so rapidly that the camp is demoralized and all ordinary work is held up till it has passed. . . . These men start with what appears to be an ordinary attack of La Grippe or Influenza, and when brought to the Hosp. they very rapidly develop the most viscous type of Pneumonia that has ever been seen. Two hours after admission they have the Mahogany spots over the cheek bones, and a few hours later you can begin to see the Cyanosis extending from their ears and spreading all over the face, until it is hard to distinguish the coloured men from the white. It is only a matter of a few hours then until death comes, and it is simply a struggle for air until they suffocate. It is horrible. One can stand it to see one, two, or twenty men die, but to see these poor devils dropping like flies sort of gets on your nerves. We have been averaging about 100 deaths per day, and still keeping it up. There is no doubt in my mind that there is a new mixed infection here, but what I don’t know.
Source: Office of the Public Health Service Historian.
Unfortunately, few tools were available to either prevent the spread of influenza or treat patients during the 1918–1919 pandemic. A variety of remedies were tried, many of which could be found in local drugstores. Patent medicines (medicines whose ingredients were secret and trademarked) were still in widespread use in 1918. Among these medicines, Vicks Vapo-Rub, atropine capsules (belladonna), and a host of other treatments were especially common. In terms of curing or treating influenza symptoms, these remedies did little to nothing (HHS, 2009).
Drug advertisers routinely promised quick and painless cures. Source: National Library of Medicine.
At the time, most physicians believed that influenza was caused by a bacillus. Nevertheless, many practitioners resorted to treatments derived from older medical theories. These treatments included causing patients to sweat by wrapping them in blankets or cupping them to remove excess blood (HHS, 2009). People were also encouraged to wear masks, which had little effect.
Because patients experienced symptoms not traditionally associated with influenza, physicians found the disease especially difficult to diagnose in 1918. In the early stages of the pandemic, many physicians and scientists even claimed that influenza patients were suffering from cholera or bubonic plague, not influenza (HHS, 2009).
Drug advertisers routinely promised quick and painless cures. Source: National Library of Medicine.
During the fall of 1918, researchers from the Public Health Service began looking for a vaccine. They were joined by researchers in many other countries. These researchers developed a range of vaccines that were then tested in communities all over the world. None of these vaccines proved effective. While researchers placed their hope in vaccines, many politicians and physicians came to believe that the spread of the disease could be contained by quarantines and bans on public gatherings (HHS, 2009).
Across the United States, cities and counties began to require or recommend that citizens wear gauze masks. Unfortunately, while masks are highly effective at preventing diseases that are caused by bacteria, they are less effective in providing protection against viral diseases. As a result, even in communities where the wearing of masks was mandatory, influenza could not be contained. Public officials also sought to limit influenza by banning spitting in public places and demanding that those who sneezed covered their mouths.
Massachusetts had been drained of physicians and nurses due to calls for military service, and no longer had enough personnel to meet the civilian demand for healthcare during the 1918 flu pandemic. Governor McCall asked every able-bodied person across the state with medical training to offer their aid in fighting the epidemic. Boston Red Cross volunteers assembled gauze influenza masks for use at hard-hit, Camp Devens in Massachusetts. Source: CDC Historical Image Gallery.
During the 1918 pandemic, early symptoms included a temperature in the range of 102°F to 104°F. Patients experienced a sore throat, exhaustion, headache, aching limbs, bloodshot eyes, a cough, and occasionally a violent nosebleed. Some also suffered from digestive symptoms such as vomiting or diarrhea. Many patients who experienced these symptoms made a full recovery, only to suffer a relapse. Their temperatures, which had fallen, rose again and they now experienced serious respiratory problems. In some cases, these patients also experienced massive pulmonary hemorrhage. After death, pathologists found these victims to have swollen lungs and oversized spleens (HHS, 2009).
Chart showing mortality from the 1918 influenza pandemic in the United States and Europe, peaking in October and November 1918 and again in February and March of 1919. Source: Courtesy of the National Museum of Health and Medicine.
The 1918 pandemic strain of influenza is thought to have originated in China in a rare genetic shift of the influenza virus. The recombination of its surface proteins created a virus novel to almost everyone (Billings, 2005).
Lung from deceased influenza patient similar to that used to extract RNA from the 1918 killer strain. Source: Courtesy of the National Museum of Health and Medicine, Armed Forces Institute of Pathology, Washington, D.C.
In the late 1990s, researchers found isolates of the 1918 pandemic virus in the formalin-fixed, paraffin-embedded lungs of an American serviceman. They subsequently retrieved further samples of this deadly virus from a second soldier, and also from a flu victim exhumed from a frosty mass grave in Alaska. The genetic sequencing of the 1918 HIN1 virus was completed in 2005 (Nicholls, 2006).
The sequencing of the 1918 pandemic strain resulted in a key finding. Each segment is more similar to avian viruses than to segments from any human strains. This suggests that the virus did not emerge through reassortment of genetic material but evolved directly via mutation from an avian virus (Nicholls, 2006).
In the end, more than 50 million people throughout the world died as a result of the influenza pandemic. An estimated 675,000 people died in the United States. More people died from influenza than died during World War I.
Seasonal influenza differs from pandemic influenza in that it occurs each year, typically during a specific time of the year. Seasonal flu generally causes less illness because the population has some immunity leftover from previous, similar influenza strains. In the Northern Hemisphere, winter is the time for seasonal influenza, but the exact timing and duration of influenza seasons vary. While influenza outbreaks can happen as early as October, activity usually peaks in January or later.
The United States 2017–2018 influenza season was a high severity season with high levels of outpatient clinic and emergency department visits for influenza-like illness, high influenza-related hospitalization rates, and elevated and geographically widespread influenza activity across the country for an extended period (Garten et al., 2018).
During the 2017–2018 influenza season, influenza-like illness activity began increasing in November, reaching an extended period of high activity during January–February, and remaining elevated through March. Influenza A(H3N2) viruses predominated through February and were predominant overall for the season; influenza B viruses predominated from March onward (Garten et al., 2018).
The figure below shows peak seasonal flu activity for the United States by month for the 1982–1983 through 2017-2018 flu seasons. The “peak month of flu activity” is the month with the highest percentage of respiratory specimens testing positive for influenza virus infection during that influenza season. During this 36-year period, flu activity most often peaked in February (15 seasons), followed by December (7 seasons), March (6 seasons), and January (6 seasons) (CDC, 2018d).
Source: CDC, 2018d.
Influenza is a contagious respiratory illness caused by influenza viruses. It can cause mild to severe illness resulting in hospitalization or even death. “Classic” influenza is characterized by the abrupt onset of fever, myalgia, sore throat, nonproductive cough, and headache. The fever is usually 101°F to 102°F and accompanied by prostration (bedridden) (CDC, 2015PB).
The onset of fever is often so abrupt that the exact hour is recalled by the patient. Myalgias mainly affect the back muscles. Cough is believed to be a result of tracheal epithelial destruction. Additional symptoms may include runny nose, headache, substernal chest burning, and ocular symptoms such as eye pain and sensitivity to light (CDC, 2015PB).
The incubation period for influenza is usually 2 days, but can vary from 1 to 4 days. The severity of illness depends on whether the immune system has been exposed to related virus variants. Somewhat surprisingly, only about 50% of infected people will develop the classic clinical symptoms of influenza (CDC, 2015PB).
Systemic symptoms and fever usually last from 2 to 3 days, rarely more than 5 days. They may be decreased by such medications as aspirin* or acetaminophen. Recovery is usually rapid, but some patients may have lingering depression and lack of strength or energy for several weeks (CDC, 2015PB).
*Aspirin should NOT be used for infants, children, or teenagers because they may be at risk for contracting Reye syndrome following an influenza infection.
Symptoms of the Flu
People who have the flu often feel some or all of these symptoms:
* Not everyone with flu will have a fever.
The most frequent complication associated with influenza is pneumonia, especially secondary bacterial pneumonia (eg, Streptococcus pneumoniae, Haemophilus influenzae, or Staphylococcus aureus). Primary influenza viral pneumonia is an uncommon complication but has a high fatality rate. Reye syndrome is a complication that occurs almost exclusively in children taking aspirin, primarily in association with influenza B (or varicella zoster), and presents with severe vomiting and confusion, which may progress to coma due to swelling of the brain (CDC, 2015PB).
Other complications can include myocarditis and worsening of chronic bronchitis and other chronic pulmonary diseases. People with congestive heart failure may have a worsening of the condition triggered by the flu. Death is reported in less than 1 per 1,000 cases. The majority of deaths occur among individuals 65 years of age and older (CDC, 2015PB).
If vaccine supply is limited, vaccination efforts should focus on:
Influenza is primarily a community-based infection that is transmitted in households and community settings. In humans, influenza is primarily transmitted from person to person via large virus-laden droplets (particles more than 5 microns in diameter) that are generated when infected individuals cough or sneeze. These large droplets can then settle on the mucosal surfaces of the upper respiratory tracts of susceptible people who are nearby (within 3 feet).
This photograph captures a sneeze in progress, revealing the plume of salivary droplets as they are expelled in a large cone-shaped array from this man’s open mouth, thereby dramatically illustrating the reason for covering your mouth when coughing or sneezing, in order to protect others from germ exposure. Source: James Gathany, CDC PHIL, 2009.
Transmission can also occur through direct or indirect contact with respiratory secretions, such as when touching surfaces contaminated with influenza virus and then touching the eyes, nose, or mouth. Adults can transmit influenza from the day before symptom onset to approximately 5 days after symptoms begin. Children can transmit influenza to others for 10 or more days.
Healthy adults may be able to infect others beginning 1 day before symptoms develop and up to 5 to 7 days after becoming sick. Some people, especially young children and people with weakened immune systems, might be able to infect others for an even longer time.
A German study yielded information about how and when influenza spreads within a group of people. In the study involving 180 participants, evidence of pre-symptomatic shedding of the influenza virus was observed in 30% of samples 1 day prior to the onset of symptoms. Shedding of virus was greatest on days 1 to 3 of illness (Suess et al., 2012).
Other findings included:
Watch this fascinating 3-minute video showing how influenza is transmitted and replicated.
It has been well-established that influenza vaccination reduces influenza-associated illness. CDC estimates that tens of thousands of hospitalizations are averted because of vaccination each year and that vaccination prevents millions of influenza-related illnesses. This is despite that fact that fewer than half of those over the age of 6 months are vaccinated each year. Higher vaccination rates almost certainly would prevent a substantial number of additional cases and hospitalizations.
The estimated number of flu illnesses prevented by flu vaccination during the 2016–2017 season: 5.3 million, about the population of the Atlanta metropolitan area.
In the United States, goals for improving influenza vaccination rates are outlined in Healthy People 2020 (see table below). Since 2010 CDC has recommended that all people 6 months of age and older receive annual influenza vaccination. Despite substantial gains in the number of people vaccinated each year, we have yet to come close to the goal of universal influenza vaccination.
Influenza Vaccination Coverage 2017–2018 Season
All people (≥6 months)
Adults (≥18 years)
Children (6 months – 17 years)
Adults 65 and older
The College of Physicians of Philadelphia provides a fascinating look at the issues associated with vaccines on their History of Vaccines website (http://www.historyofvaccines.org/). It is well worth the time to look over this website and explore “the ways in which vaccines, toxoids, and passive immunization work, how they have been developed, and the role they have played in the improvement of human health.”
During the 2017–2018 season, flu vaccination coverage among adults was 37.1%, a decrease of 6.2% from the previous flu season. Vaccination coverage varied by age group and state, and coverage decreased in all age groups and in most states. However, interpretation of these results should take into account limitations of the survey, including reliance on self-report of vaccination status and decreasing response rates (CDC, 2018f).
During the 2016–2017 flu season, more than 53% of Americans did not receive a flu vaccination. The lowest rate of vaccination occurred in Nevada (36.1%) and the highest in South Dakota (53.9%). Vaccination rates increased slightly among adults compared to the previous influenza season but remained much the same for children (Black et al., 2017).
The same trends have been noted in European countries where surveys from five countries have shown consistently low coverage rates in the general population. During the 2009 H1N1 pandemic, vaccination campaigns were adopted in many countries; however, low acceptance of a vaccine or uptake rates against pandemic influenza were reported in many studies (25% among health workers in Beijing, 17% among a French adult population, and 8.9% among pregnant women in Turkey) (Wu et al., 2013).
Vaccination Rates Decline as Clinic Day Progresses
A retrospective, quality-improvement study of 11 primary care practices at the University of Pennsylvania Health System from September 1, 2014, to March 31, 2017 yielded interesting results. Researchers found that influenza vaccination rates significantly declined as the clinic day progressed.
Offering an “active choice” intervention in which medical assistants were prompted to make decisions on whether to template vaccinations orders in patients’ electronic health record for clinicians to review was associated with a significant increase in vaccination rates. Importantly, the active choice intervention was associated with a significant increase in influenza vaccination rates that were similar in magnitude throughout the day.
Source: Kim et al., 2018.
Influenza-associated deaths in children (less than 18 years) were added as a nationally notifiable condition in 2004. Of particular interest, for children in the United States, influenza vaccination rates are fairly high in young children but decrease with increasing age:
CDC analyzed data from the National Immunization Survey—Flu to estimate flu vaccination coverage for the U.S. population of children 6 months through 17 years during the 2017–2018 flu season. Receipt of flu vaccination was determined by parental report. Vaccination coverage with more than 1 dose of flu vaccine was 57.9%, a decrease of 1.1 percentage point from the previous flu season. Vaccination coverage varied by state and age group (CDC, 2018g).
During the 2017-2018 flu season, 180 lab-confirmed pediatric deaths were reported; for children eligible for vaccination and for whom vaccination status is known, 74% were not vaccinated. Common reasons parents give for not having their child receive a flu vaccination include: the child is unlikely to get the flu or get very sick from the flu, the child is not in a high risk group, and concern about side effects from the vaccine (CDC, 2018g).
The overall influenza vaccination coverage estimate among healthcare personnel was 78.4% during the 2017–2018 influenza season, a 15% increase since the 2010–2011 season, but similar to coverage during the previous four seasons. As in past seasons, the highest coverage was associated with workplace vaccination requirements. Reported coverage was consistently higher among healthcare personnel working in hospital settings than among those working in other settings; healthcare personnel working in hospital settings were also the most likely to report workplace vaccination requirements (Black et al., 2018).
Influenza vaccination coverage was higher among healthcare personnel with vaccination available at or promoted in their workplace than among those without any type of employer promotion of vaccination; however, coverage achieved through vaccine availability and promotion was still suboptimal in the absence of requirements. Neither vaccination coverage nor prevalence of employer vaccination requirements or promotion differed in the 2017–2018 season compared with the previous season, despite the severity of the 2017–2018 influenza season (Black et al., 2018).
Influenza vaccination coverage among healthcare personnel working in long-term care settings, the majority of whom work as assistants and aides, continues to be consistently lower than that among healthcare personnel working in all other healthcare settings. Influenza vaccination among healthcare personnel in long-term care settings is especially important because influenza vaccine efficacy is generally lowest among elders, who are at increased risk for severe disease (Black et al., 2018).
In contrast to healthcare personnel working in hospitals, a much lower proportion of survey respondents working in long-term care settings reported having a requirement for vaccination, and 23.5% reported that their employer did not require, make available on-site at no cost, or promote vaccination in any way. Implementing workplace vaccination programs that have been successful in increasing coverage in hospital settings, including vaccination requirements, could increase coverage in long-term care and other settings with historically lower vaccination coverage (Black et al., 2018).
Did You Know. . .
Workplace vaccination programs that have been successful in increasing coverage in hospital settings could be implemented in long-term care and other settings with lower vaccination coverage.
Employers can use the long-term care web-based toolkit developed by CDC and the National Vaccine Program Office to access resources, strategies, and educational materials for increasing influenza vaccination among healthcare personnel in long-term care settings (Black et al., 2017).
These low rates are certainly at least partly related to high staff turnover; it is not uncommon for a long-term facility’s staff to turn over completely every few years. Newly hired managers may not adhere to existing policies related to vaccinations, or they may decide to discard such policies and implement new ones (AHRQ, 2014).
Source: Morbidity and Mortality Weekly Report, 2018.
During the 2016–2017 season (earliest available statistics), flu vaccination coverage was highest among physicians (95.8%) and lowest among assistants and aides (69.1%), and highest overall among healthcare personnel who were required by their employer to be vaccinated (96.7%) (Black et al., 2017).
Among healthcare personnel working in settings where vaccination was neither required, promoted, nor offered onsite, vaccination coverage continued to be low (45.8%). An increased percentage of healthcare personnel reporting a vaccination requirement or onsite vaccination availability compared with earlier influenza seasons might have contributed to the overall increase in vaccination coverage during the past seven influenza seasons (Black et al., 2017).
Not surprisingly, vaccination rates among healthcare providers vary by work setting. During the 2016–2017 season, vaccination coverage continued to be higher among healthcare personnel working in hospitals (92.3%) and lower among healthcare personnel working in ambulatory (76.1%) and long-term care settings (68%) (Black et al., 2017).
Coverage was highest among physicians, nurse practitioners/physician assistants, nurses, pharmacists, and healthcare personnel working in hospital settings. Coverage was lowest among assistants and aides and personnel working in long-term care settings. Employer vaccination requirements and offering vaccination at the workplace at no cost were associated with higher vaccination coverage (Black et al., 2017).
Why is it so important to increase vaccination rates among healthcare personnel?
Because of their close proximity to sick patients, healthcare providers are more likely to get influenza and to pass it on, with more significant consequences than for any other group of workers. Paradoxically, when a healthcare provider gets sick, several studies have shown that more than 75% continue to work despite being infected with influenza (Riphagen-Dalhuisen et al., 2013).
A recent study conducted among nursing home workers in France suggest low rates of influenza vaccination there as well. Management and working environment appear to play a strong role and the authors suggest that: “To overcome vaccine ‘hesitancy,’ specific communication tools may be required to be adapted to the various NH professionals to improve influenza prevention” (Elias et al., 2017).
Each year, we must decide whether to get vaccinated against the flu. Many of us get the vaccine without a second thought, while a significant percentage of Americans either choose not to get vaccinated or simply never get around to it.
For many individuals, the health benefits associated with vaccination is not a sufficient reason to embrace vaccination wholeheartedly. They doubt the benefits of vaccines, worry over their safety, and question the need for them, an attitude referred to as vaccine hesitancy. An attitude of hesitancy differs from an action of vaccine refusal. Even those who are vaccinated can harbor hesitancy toward certain aspects of vaccination (Yaqub et al., 2014).
While coverage rates are helpful for identifying those who reject, it does little to help us understand hesitant attitudes, their origins, and how to change them. Maintaining high coverage rates helps to ensure that vaccination benefits are delivered widely, but the very act of delivering wide-scale vaccination can make vaccines “victims of their own success.” As the ravages of disease become less familiar to people, it may become more challenging to articulate the desirability of vaccination (Yaqub et al., 2014).
It is certainly reasonable to ask why so many people, both in and out of healthcare, decide not to get vaccinated against influenza each year. Studies that investigate why a segment of the population does not accept vaccination have highlighted lack of knowledge, misperceptions, and distrust of vaccines. Ironically, another reason cited is a low perceived risk because the incidence has declined as a result of vaccination programs (Herzog et al., 2013).
Surveys in Europe and the United States have found that low seasonal vaccination coverage rates are influenced by inadequate (or no) recommendation by general practitioners, poor public awareness of influenza and influenza vaccines, a lack of proactive reminder systems, and a fear of needles (Blank et al., 2012).
Examining misconceptions about vaccination provides some context about why many people forgo the influenza vaccine each year:
When looking at the reasons why a significant percentage of healthcare providers in the United States say they do not intend to get a seasonal flu vaccine, the most commonly reported reason was that they do not think the flu vaccine works. Other reasons included thinking they do not need a flu vaccine, fear of getting sick, fear of side effects from vaccination, being allergic to the vaccine, and thinking that flu vaccination is not good for you.
Source: CDC, 2016b.
Recently, researchers from the European Centre for Disease Prevention and Control (ECDC) analyzed the results of a study conducted by vaccine producers, which looked at the costs and benefits of influenza vaccination. Cautioning that the data on vaccine coverage, disease burden, and health costs are imprecise, the analysts nevertheless agreed that it is important to understand the reasons for low vaccine coverage in the 27 European countries included in the study (Ciancio & Rezza, 2014). The reasons for low vaccine coverage echo many of the findings in earlier studies:
When I first started work as a nurse, I never got a flu shot. If I got the flu, I went to work even though I was sick. One year I got the flu shot on a Friday morning and was sick as a dog by the evening. Now I know that I already had the flu when I got the shot—back then I blamed it on the vaccine and didn’t get a shot for several more years. One year I got the flu, missed several days of work, and coughed my lungs out for almost two weeks. After that I thought, this is ridiculous, the flu vaccine will stop all of this. It was a no-brainer. Now I get a shot every year.
ER Nurse, California, 2018
There are many good reasons for healthcare workers to get a flu vaccine, not least of which is they are less likely to become ill themselves and much less likely to pass the virus on to their patients and families. Among healthcare personnel who received the flu vaccine in 2016, protecting themselves from flu was the most common reason reported for receiving the flu vaccination. Employer requirement for flu vaccination was the second most commonly reported reason why vaccinated healthcare providers decided to get the flu vaccination (CDC, 2016b).
Source: CDC, 2016b.
During the 2009–2010 H1N1 influenza pandemic in France, Germany, and Mexico, the most common reason given to be vaccinated for A/H1N1 pandemic influenza was a physician’s advice or recommendation. In the United States, media advertising was the most important motivating factor, although a physician’s advice was nearly as important (Blank et al., 2012).
Influenza vaccination programs in healthcare facilities are most successful when they are multifaceted. Successful programs focus on the following:
In one innovative program initiated by the University of Pittsburgh Medical Center, 14 long-term care facilities ceded control of vaccination-related policies and processes to a regional pharmacy. The facilities worked collaboratively with the pharmacy to implement and enforce standardized policies and processes to boost influenza vaccination rates among facility workers. This policy change significantly increased worker vaccination rates in participating facilities, enabling all facilities to reach the Healthy People 2010 goal of vaccinating 60% of workers in long-term care settings and several facilities to exceed the Healthy People 2020 goal of vaccinating 90% (AHRQ, 2014).
When receiving the influenza vaccine is a condition for employment, vaccination rates can approach 100%. During the 2010–2011 influenza season, CDC found that approximately 13% of healthcare personnel reported that their employers required influenza vaccination as a condition of employment. Among this group, vaccination coverage was 98.1%, compared with 58.3% among those without an employer requirement (NVAC, 2013).
A national survey of acute care hospitals found that 55.6% of the hospitals surveyed had implemented an institutional requirement, but that vaccination coverage rates increased most significantly in hospitals that also enforced consequences for vaccine refusal. Consequences ranged in severity from mandatory masking to employee termination for noncompliance (NVAC, 2013).
The Influenza Antivirals I.Q. is an interactive quiz to test your flu knowledge. http://www.cdc.gov/flu/freeresources/widgets.htm
During the influenza season, when flu is circulating within the community, most people who get the flu will experience self-limiting symptoms. However, severe disease can occur in older adults, in those with underlying medical conditions, and in the very young.
Appropriate treatment of patients with respiratory illness depends on accurate and timely diagnosis. The diagnosis of influenza is usually suspected on the basis of characteristic clinical findings, particularly if influenza has been reported in the community (CDC, 2015PB).
Early diagnosis of influenza can reduce the inappropriate use of antibiotics and provide the option of using antiviral therapy. However, because certain bacterial infections can produce symptoms similar to influenza, bacterial infections should be considered and appropriately treated, if suspected. In addition, bacterial infections can occur as a complication of influenza.
The Infectious Diseases Society of America (2009, latest available) states that during flu season, consider influenza in the following patients, regardless of vaccination status:
Although summer influenza activity in the United States typically is low, influenza cases and outbreaks can occur during summer months. Clinicians should remain vigilant in considering influenza in the differential diagnosis of summer respiratory illnesses. Testing for seasonal influenza viruses and monitoring for novel influenza A virus infections should continue year-round (Blanton et al., 2017).
Healthcare providers also are reminded to consider novel influenza virus infections in persons with influenza-like illness and swine or poultry exposure, or with severe acute respiratory infection after travel to areas where avian influenza viruses have been detected. Providers should alert the local public health department if novel influenza virus infection is suspected (Blanton et al., 2017).
Annual influenza vaccination is recommended for all persons aged ≥6 months and remains the most effective way to prevent influenza illness. Antiviral medications are an important adjunct to vaccination in the treatment and prevention of influenza. Early treatment with neuraminidase-inhibitor antiviral medications is recommended for patients with severe, complicated, or progressive influenza illness and those at higher risk for influenza complications, including adults aged ≥65 years. Antiviral treatment should not be withheld from patients who are at high risk for complications or who are severely ill with suspected influenza infection, even if rapid antigen-detection influenza diagnostic test results are negative (Blanton et al., 2017).
The diagnosis of influenza is usually suspected on the basis of characteristic clinical findings, particularly if influenza has been reported in the community. Virus can be isolated from throat and nasopharyngeal swabs obtained within 3 days of onset of illness. Culture is performed by inoculation of chick embryos or certain cell cultures that support viral replication. A minimum of 48 hours is required to demonstrate virus, and 1 to 2 additional days to identify the virus type. Culture is helpful in defining the etiology of local epidemics, but not in individual case management (CDC, 2015PB).
Serologic confirmation of influenza requires demonstration of a significant rise in influenza immunoglobulin G (IgG). The acute-phase specimen should be taken less than 5 days from onset, and a convalescent specimen taken 10 to 21 days (preferably 21 days) following onset. Complement fixation (CF) and hemagglutination inhibition (HI) are the serologic tests most commonly used. The key test is HI, which depends on the ability of the virus to agglutinate erythrocytes and inhibition of this process by specific antibody. Diagnosis requires at least a fourfold rise in antibody titer (CDC, 2015PB).
Rapid diagnostic testing for influenza antigen is available, but because these tests fail to detect many patients with influenza, CDC recommends antiviral treatment with oseltamivir or zanamivir as early as possible for patients with confirmed or suspected influenza who have severe, complicated, or progressive illness; who require hospitalization; or who are at greater risk for serious influenza-related complications (CDC, 2015PB).
Influenza antiviral prescription drugs can be used to treat influenza or to prevent influenza. In the United States, five antiviral agents are licensed for preventing or treating influenza. A sixth “prodrug” (Xoflusa) was approved by the FDA on October 24, 2018:
Influenza virus replication inhibitor
Antiviral agents for influenza are an adjunct to vaccine and are not a substitute for vaccine. Vaccination remains the principal means for preventing influenza-related morbidity and mortality (CDC, 2015PB).
Three influenza antiviral medications approved by the U.S. Food and Drug Administration (FDA) are recommended for use in the United States during the 2017–2018 influenza season: oral oseltamivir (available as a generic version or under the trade name Tamiflu), inhaled zanamivir (trade name Relenza), and intravenous peramivir (trade name Rapivab). These drugs are chemically related antiviral medications known as neuraminidase inhibitors that have activity against both influenza A and B viruses. Generic oseltamivir was approved by the FDA in August 2016 and became available in December of 2016 (CDC, 2018h).
Amantadine and rimantadine are antiviral drugs in a class of medications known as adamantanes. These medications are active against influenza A viruses, but not influenza B viruses (CDC, 2018h).
As in recent past seasons, there continues to be high levels of resistance (>99%) to adamantanes among circulating influenza A(H3N2) and influenza A(H1N1)pdm09 (“2009 H1N1”) viruses. Therefore, amantadine and rimantadine are not recommended for antiviral treatment or chemoprophylaxis of currently circulating influenza A viruses (CDC, 2018h).
The Food and Drug Administration (FDA) approved a new prescription influenza antiviral drug, baloxavir marboxil (trade name Xofluza), on October 24, 2018. Xofluza is administered orally and is indicated for the treatment of acute, uncomplicated influenza in patients 12 years of age and older who have been symptomatic for no more than 48 hours (CDC, 2018h).
Baloxavir marboxil is a prodrug that is converted by hydrolysis to baloxavir, the active form that exerts anti-influenza virus activity. Baloxavir inhibits the endonuclease activity of the polymerase acidic (PA) protein, an influenza virus-specific enzyme in the viral RNA polymerase complex required for viral gene transcription, resulting in inhibition of influenza virus replication (CDC, 2018h).
Traditionally, influenza viruses have been thought to spread from person to person primarily through large-particle respiratory droplet transmission (eg, when an infected person coughs or sneezes near a susceptible person). Transmission via large-particle droplets requires close contact between source and recipient persons, because droplets generally travel only short distances (approximately 6 feet or less) through the air. Indirect contact transmission via hand transfer of influenza virus from virus-contaminated surfaces or objects to mucosal surfaces of the face (eg, nose, mouth) may also occur (CDC, 2018i).
Airborne transmission via small particle aerosols in the vicinity of the infectious individual may also occur; however, the relative contribution of the different modes of influenza transmission is unclear. Airborne transmission over longer distances, such as from one patient room to another, has not been documented and is thought not to occur. All respiratory secretions and bodily fluids, including diarrheal stools, of patients with influenza are considered to be potentially infectious; however, the risk may vary by strain. Detection of influenza virus in blood or stool in influenza infected patients is very uncommon (CDC, 2018i).
Healthcare settings include, but are not limited to, acute-care hospitals; long-term care facilities, such as nursing homes and skilled nursing facilities; physicians’ offices; urgent-care centers, outpatient clinics; and home healthcare (CDC, 2018i).
Preventing transmission of influenza within a healthcare setting requires a multi-faceted approach. Spread of influenza virus can occur among patients, healthcare personnel, and visitors; in addition, healthcare personnel may acquire influenza from people in their household or community (CDC, 2018i).
Core infection prevention strategies include:
Successful implementation of many, if not all, of these strategies is dependent on the presence of clear administrative policies and organizational leadership that promote and facilitate adherence to these recommendations among the various people within the healthcare setting, including patients, visitors, and healthcare personnel (CDC, 2018i).
Long-term care facilities are institutions, such as nursing homes and skilled nursing facilities, which provide healthcare to people (including children) who are unable to manage independently in the community. This care may represent custodial or chronic care management or short-term rehabilitative services (CDC, 2017).
Influenza can be introduced into a long-term care facility by newly admitted residents, healthcare workers, or visitors. Spread of influenza can occur between and among residents, healthcare providers, and visitors. Residents of long-term care facilities can experience severe and fatal illness during influenza outbreaks (CDC, 2017).
As in any healthcare setting, key prevention strategies in long-term care settings include:
If possible, all residents should receive trivalent inactivated influenza vaccine (TIV) annually before influenza season. In the majority of seasons, TIV will become available to long-term care facilities beginning in September, and influenza vaccination should begin as soon as vaccine is available. Informed consent is required to implement a standing order for vaccination, but this does not necessarily mean a signed consent must be present (CDC, 2017).
Since October 2005 the Centers for Medicare and Medicaid Services (CMS) has required nursing homes participating in Medicare and Medicaid programs to offer all residents influenza and pneumococcal vaccines and to document the results. Each resident is to be vaccinated unless contraindicated medically, the resident or legal representative refuses vaccination, or the vaccine is not available (CDC, 2017).
Even if it is not influenza season, influenza testing should occur when any resident of a long-term care facility has signs and symptoms that could be due to influenza, and especially when two residents or more develop respiratory illness within 72 hours of each other. Because of the high risk of morbidity and mortality in older adults, daily active surveillance is recommended for respiratory illness among ill residents, healthcare personnel, and visitors to the facility (CDC, 2017).
If influenza is already present in a long-term care facility, residents who are symptomatic should stay in their own rooms as much as possible. They should be restricted from participation in common activities and should have meals served in their rooms. If an outbreak is widespread, large-group activities should be limited and all meals should be offered in resident rooms. New admissions or transfers to wards with symptomatic residents should be avoided (CDC, 2017).
A posted notice should alert visitors to the presence of influenza in a facility. The spread of influenza can be reduced by restricting visitation and excluding ill people from visiting the facility during an outbreak. During community outbreaks of influenza, children should also be restricted from visiting residents (CDC, 2017).
Healthcare personnel with respiratory symptoms should be monitored and those with influenza-like symptoms should stay home until at least 24 hours after they no longer have a fever (CDC, 2017).
Influenza Prevention Recommendations for Long-Term Care Facilities
Healthcare personnel who get vaccinated help to reduce the following:
Influenza outbreaks in hospitals and long-term care facilities have been attributed to low influenza vaccination coverage among healthcare personnel. Higher vaccination levels among healthcare personnel have been associated with a lower risk of healthcare facility-associated influenza cases (CDC, 2017).
Current ACIP Influenza Recommendations
To access the current (2018–2019) ACIP influenza recommendations please see:
Prevention and Control of Seasonal Influenza with Vaccines: Recommendations of the Advisory Committee on Immunization Practices, United States, 2018–2019 Influenza Season
A vaccine is a substance (an antigen) made from a virus or bacterium that triggers the body’s immune system to develop antibodies. Substances are sometimes added to a vaccine to generate a stronger immune response so that less vaccine is needed for the body to recognize and fight the antigen. Influenza vaccines cause antibodies to develop about 2 weeks after vaccination.
Influenza vaccines are available in an inactivated form (IIV) and a live attenuated form (LAIV). Inactivated influenza vaccines have been available since the 1940s and have traditionally been administered intramuscularly or intradermally. Live attenuated vaccine was approved for use in the United States in 2003. Live attenuated influenza vaccines contain a version of the living microbe that has been weakened in the lab so it cannot cause disease.
Inactivated vaccines are produced by killing the disease-causing microbe in a virus or bacteria with chemicals, heat, or radiation. Inactivated vaccines are more stable and safer than live vaccines because the dead microbes cannot mutate back to their disease-causing state. However, most inactivated vaccines stimulate a weaker immune system response than do live vaccines (NIAID, 2012).
With one exception, U.S.-licensed inactivated influenza vaccines are manufactured through propagation of virus in eggs. The exception, the cell culture-based vaccine Flucelvax Quadrivalent contains vaccine viruses propagated in canine kidney cells although it is still not considered completely egg-free, as some of the initial vaccine viruses provided to the manufacturer by the World Health Organization are egg-derived (Grohskopf et al., 2017).
Influenza Vaccine Key Points
Inactivated influenza vaccine (IIV)
Live attenuated vaccine (LAIV)
For years, flu vaccines were designed to protect against three different flu viruses (trivalent vaccines). Standard dose trivalent vaccines include an influenza A (H1N1) virus, an influenza A (H3N2) virus and one influenza B virus. Because there are two distinct lineages of influenza B viruses—Victoria and Yamagata—immunization against a single influenza B virus provides only limited cross protection against strains in the other lineage.
The standard dose trivalent shots (IIV3), is manufactured using virus grown in eggs. This shot (Afluria) can be given either with a needle (for people aged 5 years and older) or with a jet injector (or people aged 18 through 64 years only) (CDC, 2018j).
A three-component (trivalent) inactivated flu vaccine called Fluzone High-Dose is licensed specifically for people 65 years and older. Fluzone High-Dose contains four times the antigen of standard-dose inactivated influenza vaccines. The higher dose of antigen in the vaccine is intended to give older people a better immune response, and therefore, better protection against flu (CDC, 2018j).
The high dose vaccine has been approved for use in the United States since 2009. Results from a clinical trial of more than 30,000 participants showed that adults 65 years and older who received the high dose vaccine had 24% fewer influenza infections as compared to those who received the standard dose flu vaccine (CDC, 2018k).
Fluzone, Fluzone High-Dose, Fluzone Intradermal Quadrivalent, and Fluzone Quadrivalent are all injectable vaccines. The intradermal flu vaccine is a shot that is injected into the skin instead of the muscle. The intradermal shot uses a much smaller needle than the regular flu shot, and it requires less antigen to be as effective as the regular flu shot. It may be used in adults 18-64 years of age.
Source: CDC, 2018k.
A trivalent flu shot made with adjuvant (Fluad) is approved for people 65 years and older. An adjuvant is an ingredient added to a vaccine to create a stronger immune response. The vaccine, FLUAD (allV3), was licensed in November 2015 and became available during the 2016–2017 flu season. It contains MF59 adjuvant, an oil-in-water emulsion of squalene oil. FLUAD is the first seasonal flu vaccine with adjuvant marketed in the United States. Squalene, a naturally occurring substance found in humans, animals, and plants, is highly purified for the vaccine manufacturing process (CDC, 2018j).
The quadrivalent flu vaccine is designed to protect against four different flu viruses: two influenza A viruses and two influenza B viruses. Adding another B virus to the vaccine aims to give broader protection against circulating flu viruses (CDC, 2018j).
Standard-dose quadrivalent flu shots are manufactured using virus grown in eggs. These include Afluria Quadrivalent, Fluarix Quadrivalent, FluLaval Quadrivalent, and Fluzone Quadrivalent. Different flu shots are approved for different age groups. There is a quadrivalent flu shot that can be given to children as young as 6 months of age. Other quadrivalent flu shots are approved for people 3 years and older (CDC, 2018i).
Most flu shots are given in the arm muscle with a needle. One quadrivalent flu shot (Afluria Quadrivalent) can be given either with a needle (for people aged 5 years and older) or with a jet injector (for people aged 18 through 64 years only) (CDC, 2018j).
A quadrivalent cell-based flu shot (Flucelvax Quadrivalent) containing virus grown in cell culture, is approved for people 4 years and older. A recombinant quadrivalent flu shot (Flublok Quadrivalent) is approved for people 18 years and older (CDC, 2018j).
For more information on approved flu vaccines for the 2018-2019 flu season, as well as age indications for each vaccine, please see CDC’s Table: U.S. Influenza Vaccine Products for the 2018-19 Season. (https://www.cdc.gov/flu/protect/vaccine/vaccines.htm)
2018 Flublok Recombinant Influenza Vaccine (RIV4)
In 2013 the U.S. Food and Drug Administration (FDA) announced its approval of Flublok, a trivalent inactivated influenza vaccine for the prevention of seasonal influenza in people 18 years and older. Flublok’s manufacturing process has the potential for faster startup of vaccine manufacturing, which can be useful in the event of a pandemic or vaccine supply shortage, mainly because it is not dependent on an egg supply or limited by the selection of vaccine viruses that are adapted for growth in eggs. Also, this vaccine is suitable for vaccinating people with egg allergies because it is not made using eggs.
Flublok Quadrivalent (RIV4) was made available for the 2018–2019 influenza season. RIV4 is indicated for persons aged ≥18 years. RIV4 is manufactured without the use of influenza viruses; therefore, similarly to IIVs, no shedding of vaccine virus will occur. RIV4 is produced without the use of eggs, and is egg-free. No preference is expressed for RIV4 versus IIVs within specified indications. RIV4 is administered by intramuscular injection (Grohskopf et al., 2018).
Live attenuated influenza vaccine (LAIV) was approved for use in the United States in 2003. LAIV contains the same influenza viruses as inactivated influenza vaccines. It does not contain thimerosal or any other preservative.
LAIV is provided in a single-dose sprayer unit; half of the dose is sprayed into each nostril. The nasal spray flu vaccine contains attenuated (weakened) live viruses that will not cause influenza illness. The weakened viruses are cold-adapted, which means they are designed to only multiply at the cooler temperatures found within the nose. The viruses cannot infect the lungs or other areas where warmer temperatures exist.
During previous flu seasons (2016–2017 and 2017–2018), the Advisory Committee on Immunization Practices (ACIP) recommended that LAIV4 not be used because of concerns about low effectiveness against influenza A(H1N1)pdm09-like viruses circulating in the United States during the 2013–2014 and 2015–2016 seasons (Grohskopf et al., 2018).
On February 21, 2018, ACIP recommended that LAIV4 be an option for influenza vaccination of persons for whom it is appropriate for the 2018–19 season. The nasal spray is approved for use in non-pregnant individuals, 2 years through 49 years of age. People with some medical conditions should not receive the nasal spray flu vaccine (Grohskopf et al., 2018). For more information, please see https://www.cdc.gov/flu/about/qa/nasalspray.htm
Immunity following inactivated influenza vaccine vaccination is less than 1 year due to waning of vaccine-induced antibodies and antigenic drift of circulating influenza viruses. Influenza vaccine efficacy varies by the similarity of the vaccine strain to circulating strains and the age and health of the recipient. When the vaccine strain is similar to the circulating strain, vaccines protect against illness in up to 90% of healthy recipients younger than 65 years of age.
Antibody against one influenza virus type or subtype confers limited or no protection against another type or subtype. Frequent emergence of antigenic variants through antigenic drift is the virologic basis for seasonal epidemics and necessitates consideration for adjustment of vaccine viruses each season (Grohskopf et al., 2018).
Pregnant and postpartum women are at higher risk for severe illness and complications from influenza, particularly during the second and third trimesters. ACIP and the American College of Obstetricians and Gynecologists recommend that all women who are pregnant or who might be pregnant during the influenza season receive influenza vaccine. Any licensed, recommended, and age-appropriate IIV or RIV4 may be used. LAIV4 should not be used during pregnancy. Influenza vaccine can be administered at any time during pregnancy, before and during the influenza season (Grohskopf et al., 2018).
Although there is substantial experience with the use of IIVs during pregnancy, data specifically reflecting administration of influenza vaccines during the first trimester are relatively limited. Most studies have not noted an association between influenza vaccination and adverse pregnancy outcomes (Grohskopf et al., 2018).
Immunocompromised states include a wide range of conditions. ACIP recommends that LAIV4 not be used for immunocompromised persons because of the uncertain but biologically plausible risk for disease attributable to the vaccine virus. In addition to potential safety issues, immune response to live or inactivated vaccines might be blunted in some clinical situations, such as for persons with congenital immune deficiencies, persons receiving cancer chemotherapy, and persons receiving immunosuppressive medications (Grohskopf, Sokolow, Broder et al., 2018).
The Infectious Diseases Society of America (IDSA) has published guidance for the selection and timing of vaccines for persons with specific immunocompromising conditions, including congenital immune disorders, stem cell and solid organ transplant, anatomic and functional asplenia, and therapeutic drug-induced immunosuppression, as well as for persons with cochlear implants or other conditions leading to persistent cerebrospinal fluid-oropharyngeal communication. Given the lack of safety data for LAIV in most of these populations, and the availability of alternative vaccines, IIV or RIV4 should be used instead of LAIV for these persons (Grohskopf et al., 2018).
Efforts should be made to vaccinate household and other close contacts of high-risk people. These include healthcare personnel, employees of long-term care facilities, and household contacts of high-risk people. These individuals may be younger and healthier and more likely to be protected from illness than are older adults. All healthcare providers should receive annual inactivated influenza vaccine (CDC, 2015PB).
Groups to be targeted include physicians, nurses, and other personnel in hospitals and outpatient settings who have contact with high-risk patients in all age groups, and providers of home care to high-risk people (CDC, 2015PB).
Because of the vulnerability of older adults to severe influenza illness, hospitalization, and death, efficacy and effectiveness of influenza vaccines among older adults is an area of active research. Recent comparative studies of vaccine efficacy/effectiveness against laboratory-confirmed influenza outcomes among older adults have focused on HD-IIV3 (Fluzone High-Dose), RIV4 (Flublok Quadrivalent), and aIIV3 (Fluad). Each of these three vaccines has been studied in comparison to a standard dose, unadjuvanted IIV (Grohskopf et al., 2018).
Although HD-IIV3 has been the most extensively studied, and evidence has accumulated for its superior efficacy and effectiveness compared with SD-IIV3 in this population, no preference is expressed for any one vaccine type. Vaccination should not be delayed if a specific product is not readily available. For persons aged ≥65 years, any age-appropriate IIV formulation (standard-dose or high-dose, trivalent or quadrivalent, unadjuvanted or adjuvanted) or RIV4 are acceptable options (Grohskopf et al., 2018).
Each year, experts from CDC, World Health Organization (WHO), and other institutions study virus samples collected from around the world to identify the influenza viruses that are the most likely to cause illness during the upcoming flu season. This information is used to create a vaccine.
Because flu viruses are constantly changing, it is not possible to predict with certainty which types of viruses will predominate during a given season. Flu viruses can change from one season to the next and can even change within the course of one flu season. Experts must pick which viruses to include in the vaccine many months in advance in order for vaccine to be produced and delivered on time. Because of these factors, there is always the possibility of a less-than-optimal match between circulating viruses and the viruses in the vaccine.
The 2018–2019 U.S. trivalent influenza vaccines contains the following:
The 2018–2-19 U.S. quadrivalent vaccines contain the same three antigens listed above and an additional influenza B virus component, a B/Phuket/3073/2013–like virus (Yamagata lineage). Compared with the 2017–18 season, the composition for 2018–2019 represents changes in the A(H3N2) and B (Victoria) components of both the trivalent and quadrivalent vaccines (Grohskopf et al., 2018).
For the 2018–2019 season, routine annual influenza vaccination of all people aged ≥6 months without contraindications continues to be recommended. A licensed, recommended, and age-appropriate vaccine should be used. (Grohskopf et al., 2018).
Recommendations for the use of LAIV4 (FluMist Quadrivalent) have been updated. Following the previous two seasons, during which ACIP recommended that LAIV4 not be used, for the 2018–2019 season, vaccination providers may choose to administer any licensed, age-appropriate influenza vaccine (IIV, RIV4, or LAIV4). LAIV4 is an option for those for whom it is appropriate (Grohskopf et al., 2018).
Persons with a history of egg allergy of any severity may receive any licensed, recommended, and age-appropriate influenza vaccine (IIV, RIV4, or LAIV4) (Grohskopf et al., 2018).
Recent licensures and labeling changes include expansion of the age indication for Afluria Quadrivalent (IIV4) from ≥18 years to ≥5 years and expansion of the age indication for Fluarix Quadrivalent (IIV4), previously licensed for ≥3 years, to ≥6 months (Grohskopf et al., 2018).
Balancing considerations regarding the unpredictability of timing of onset of the influenza season and concerns that vaccine-induced immunity might wane over the course of a season, it is recommended that vaccination should be offered by the end of October. Children aged 6 months through 8 years who require 2 doses should receive their first dose as soon as possible after vaccine becomes available, to allow the second dose (which must be administered ≥4 weeks later) to be received by the end of October (Grohskopf et al., 2018).
Community vaccination programs should balance maximizing likelihood of persistence of vaccine-induced protection through the season with avoiding missed opportunities to vaccinate or vaccinating after onset of influenza circulation occurs. Revaccination later in the season of persons who have already been fully vaccinated is not recommended (Grohskopf et al., 2018).
For a table of approved influenza vaccines for the 2018-2019 season, please see: https://www.cdc.gov/flu/protect/vaccine/vaccines.htm
Source: United States Navy. Public domain.
Influenza has been with us for a long time. More people died from influenza during the 1918–1919 influenza pandemic than died during World War I. Like all viruses, influenza is very good at finding ways to mutate and bypass our immune system defenses. We have been able to stay a step ahead by developing vaccines that stimulate our immune system to fight off these potentially deadly viruses.
Periodically however, influenza outsmarts us by mutating or shifting into a virus that our immune systems fail to recognize. When this happens, influenza pandemics can occur, as happened in 1918 with disastrous results. Although public health officials are rightly concerned about pandemics, seasonal influenza kills many thousands of people every year and many of these deaths can be prevented by getting a flu vaccination.
In past years CDC has emphasized the importance of increasing vaccination rates among high-risk groups, working toward a goal of universal vaccination. To that end, in 2010, in an attempt to simplify vaccination recommendations and increase vaccination rates, CDC issued guidelines stating all individuals aged 6 months or older should be vaccinated annually. This universal vaccination guideline reflects lessons learned from the 2009 H1N1 pandemic.
Despite these strong recommendations, more than half of the general public and about 25% of healthcare workers fail to get vaccinated against flu each year. The situation is particularly dire in long-term care settings, where some of our most vulnerable citizens are exposed to influenza by unvaccinated workers, visitors, and residents. Getting vaccinated each year protects high-risk populations from catching the flu from the people who are supposed to be helping and protecting them.
Vaccination is available in a live-attenuated (LAIV) and an inactivated (IIV) form. Knowing which one works best for you and your patients is important. The makeup of this year’s influenza vaccine is based on information about which influenza viruses are circulating, how they are spreading, and how well the previous season’s vaccine viruses protected against any that are being newly identified.
The overall vaccine effectiveness (VE) of the 2017-2018 flu vaccine against both influenza A and B viruses is estimated to be 40%. This means the flu vaccine reduced a person’s overall risk of having to seek medical care at a doctor’s office for flu illness by 40%. Protection by virus type and subtype was: 25% against A(H3N2), 65% against A(H1N1) and 49% against influenza B viruses (CDC, 2018a).
For the 2018–19 U.S. influenza season, providers may choose to administer any licensed, age-appropriate influenza vaccine (IIV, recombinant influenza vaccine, or LAIV4). LAIV4 is an option for those for whom it is otherwise appropriate. No preference is expressed for any influenza vaccine product (Grohskopf et al., 2018).
Vaccination should be offered as long as influenza viruses are circulating. To avoid missed opportunities for vaccination, providers should offer vaccination during routine healthcare visits and hospitalizations when vaccine is available.
Getting an annual influenza vaccine provides the best protection against influenza for virtually everyone.
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