Unpredictability remains the one constant with seasonal influenza

Seasonal influenza epidemics occur each year, but any prediction about the severity of upcoming influenza seasons is often conjecture, at best.

We know that flu strikes in the winter, but other than that, flu has no real pattern. That is especially evident in the 2014-2015 flu season, which has been exceptionally severe, thanks to the predominant circulating strain — a drifted H3N2 strain — that was not included in this year’s vaccine. It first was detected in the United States just a few weeks after the strains for the vaccine were selected.

Every year, careful consideration goes into determining the strains to be included in the next flu vaccine. Sometimes, the strains are right on the mark. But other times, like this year, experts are blindsided. 

“The best characterization of flu is that it’s predictably unpredictable,” Kathleen M. Neuzil, MD, MPH, director of PATH’s Vaccine Access and Delivery, Seattle, and clinical professor of allergy and infectious diseases and global health at the University of Washington, told Infectious Disease News. “People always want to know if it will be a bad year, but really, you’re going to lose if you bet on flu.”

Flu affects many different species. In order to survive in humans, it has to adapt regularly to continue to be infectious, and these sometimes subtle changes to the virus can cause significant illness. Infectious Disease News spoke with several experts to learn exactly what makes flu so volatile and how these regular changes affect the population.

Antigenic drift

This year, the primary circulating flu strain is close to the A/Switzerland/9715293/2013 H3N2 strain, which is a component of the 2015 flu vaccine for the Southern Hemisphere. However, the strain is antigenically and genetically different from the H3N2 component in this season’s Northern Hemisphere flu vaccine, A/Texas/50/2012.

This antigenic drift means the virus has changed just enough that it makes people susceptible to the virus, even if they have had flu before or received the vaccine.

“Some viruses are very, very stable and don’t mutate,” Jorge P. Parada, MD, MPH, professor of medicine at Loyola University Medical Center, told Infectious Disease News. “Take measles, for instance. There is a two-shot vaccine series, and you have immunity for life because measles is a stable virus. Flu, on the other hand, is inherently unstable and develops quite a few mutations. Antigenic drifts involve smaller mutations that are just enough to make a person susceptible to flu again.”

Influenza A viruses are the ones that experience bigger and more frequent changes, Parada said, because influenza A viruses can infect many other species. Influenza B viruses, however, only cause human infection. Another, lesser known flu type is influenza C, but this is a minor strain that causes very few, usually mild, infections, Parada said.

According to Pedro A. Piedra, MD, professor in the department of molecular virology and microbiology and the department of pediatrics at Baylor College of Medicine, every virus has developed ways to gain a better foothold and infect more efficiently. Flu does this by allowing changes in the surface proteins that induce immune response.

If these antigenic areas change, the virus becomes less recognizable and can evade the immune system.

“As population immunity increases to a particular strain, it makes it sufficiently hard for that strain to be infectious,” Piedra said. “Viruses need to infect in order to survive, so they find different ways to adapt. Over time, influenza viruses drift so the progeny viruses can infect later on.”

Dominating strains

According to the CDC, flu infects millions of people each year and causes thousands of deaths. The most severe seasons are ones in which H3N2 strains dominate, because these strains are associated with more severe illness and mortality, particularly in older adults and young children.

This year’s drifted strain also is the predominant strain in Europe and other areas in the Northern Hemisphere, according to Brendan Flannery, PhD, a CDC epidemiologist. The Southern Hemisphere flu season starts in the spring, and at that time, researchers will be able to determine if the same strain is the dominant one.

The presence of this particular strain increased throughout the 2014 flu season in the Southern Hemisphere, and by the start of the Northern Hemisphere season it made up half of the H3N2 viruses received at CDC, Flannery said.

“Flu is highly contagious and how strains become dominant is not really clear,” Flannery said. “It’s not likely a case of one person bringing the strain back after traveling. New flu strains are not something you can prevent with really good surveillance. When a strain starts circulating, it circulates on a global wave very, very quickly.”

The dominant circulating influenza A strain can change yearly. In the 2009-2010 season, the novel pandemic H1N1 strain dominated, and again in the 2013-2014 season. In the 2010-2011 flu season, the H3N2 strain emerged and was the dominant circulating strain for 3 consecutive years. Over the four flu seasons from 2010-2011 to 2013-2014, the circulating H3N2 strain was similar.

“The changes seen across flu seasons, including the antigenic changes to individual strains and the changes in the dominating virus, do not happen on a predictable time scale,” Flannery said. “It’s always a bit of a guess in terms of how related the vaccine strain will be to the actual circulating virus.”

Vaccine effectiveness

This year the interim reported effectiveness of the flu vaccine was 23%, according to the CDC. In some age groups the vaccine effectiveness was as low as 12%. When the vaccine and the circulating strains are well-matched, the average vaccine effectiveness is about 60%, Flannery said.

Flu vaccine effectiveness is never guaranteed. Regardless, it is the best protection against flu. When the circulating strain is not a match for the strain in the vaccine, the vaccine still will provide cross-immunity that leads to a slightly less severe disease, Parada noted. Even if the vaccine is not perfect, it is not a total miss.

“Two-thirds of the circulating H3N2 strains do not match the vaccine strain, but the other third do,” Parada said. “The vaccine is also a match for the H1N1 strain and the predominant B strain. It’s an overstatement to say this year’s flu vaccine was a total waste.”

There is a universal recommendation for the flu vaccine: Everyone aged 6 months and older without contraindications should receive it annually. Children who are receiving the flu vaccine for the first time need two doses, Piedra said.

The flu vaccine is especially important for children and pregnant women because they face a high risk for developing severe flu complications.

“Children don’t have immunologic experience with flu or other respiratory viruses because of their young age, so they are particularly vulnerable to having more severe disease,” Susan E. Coffin, MD, MPH, attending physician in the division of infectious diseases at The Children’s Hospital of Philadelphia and professor of pediatrics at the Perelman School of Medicine, University of Pennsylvania, told Infectious Disease News. “For that reason, every child aged 6 months and older should be vaccinated. Pregnant women should receive it for two reasons: to pass on immune protection to the baby before it’s delivered, and to protect themselves.”

Differences in immunity

Flu typically has the biggest impact on young children and adults aged older than 65 years. In the 2009 H1N1 pandemic, however, children and adults aged 18 to 49 years were the hardest hit population, while older adults were not affected as much as usual.

That scenario was atypical, Parada said. It was caused by an antigenic shift. In an antigenic drift, there are small mutations to the existing flu strain. In an antigenic shift, there is essentially a new strain of flu that is often much more aggressive and lethal due to a lack of crossover immunity. These shifts are the cause of flu pandemics.

The “Spanish Flu” pandemic of 1918-1919 is a well-known antigenic shift. It turned out to be a very lethal strain that caused millions of people to die, Parada said. There were other important pandemics such as the “Asian Flu” pandemic of 1957-1958, the “Hong Kong Flu” pandemic of 1968-1969, and then the 2009 “Swine Flu” pandemic.

“The novel 2009 H1N1 virus emerged as a mutant combination of flu viruses from North American and Eurasian pigs, with a dollop of North American bird flu and a pinch of human flu virus,” Parada said.

The virus was not as severe for older adults because they may have had exposure to other swine flus over the course of their lifetimes.

“They had a partial crossover immunity to the swine flu variant, but it provoked a much more robust immune response in younger people, who were ‘firing on all cylinders’ trying to fight the virus,” he said.

Susceptible populations

In general, despite the potential crossover immunity, older adults will be more susceptible to flu complications because they have a lower effective immune response and an increased prevalence of chronic diseases.

“During the H1N1 pandemic, young adults were less likely to have immunity to H1N1, but they also had healthier bodies that were more able to tolerate infection,” Neuzil said. “The body’s reaction to flu is an interplay between the immune system and the overall health of the body.”

Children also bear a large amount of the flu burden. In a normal year, the flu attack rate can be as high as 50% in children, according to Piedra. Although children with comorbid conditions, such as lung disease or congenital heart disease, are at a higher risk for severe disease compared with healthy children, the majority of children with severe disease, by numbers alone, are otherwise healthy children.

“It’s often very difficult to predict who is going to develop severe disease, but even a mild disease that doesn’t require hospitalization still has a significant impact on the child and the parent,” he said.

In both children and adults, flu viruses can lead to secondary bacterial infections, Piedra noted, because flu viruses depress the immune response and make the environment easier for bacteria to invade.

Children are susceptible to many respiratory viruses, not only because they are young, but also because they attend school or preschool — an environment that allows for easy virus transmission, he said. Young children also are susceptible to respiratory syncytial virus, parainfluenza, enterovirus and rhinoviruses, and it is difficult to distinguish flu clinically from these other viruses.

Identifying flu

According to Edward T. Dickinson III, MD, professor of emergency medicine at the University of Pennsylvania Perelman School of Medicine, there is no question that there has been an increase of flu cases presenting to the ED this season. In addition, those patients with flu have generally been sicker than in previous years.

“This is anecdotal, but this year, I’ve seen more patients presenting with flu-related pneumonia who have been sick for several days,” Dickinson told Infectious Disease News. “Many of the patients I’ve seen with flu complications like pneumonia and respiratory failure are otherwise healthy. Some patients have been so ill with flu that they’ve needed ventilators.”

A bad flu outbreak is like a double-edged sword, he said. While a physician can be confident in knowing a moderately ill person with a fever and dry cough likely has the flu, it is important to ensure that other, more serious circulating illnesses are not overlooked.

“Sometimes, the process is to look at all the other nooks and crannies and exclude non-flu illnesses,” he said. “In patients with a high fever, we need to exclude meningitis and other serious infections first.”

There have been many efforts and projects to develop clinical prediction rules that might help clinicians identify patients with flu based on symptoms. However, none of the potential rules has consistently performed well, according to Coffin.

“These other viruses can co-circulate and masquerade as influenza,” she said. “But as a pediatrician, influenza concerns me the most. Every year, children in the U.S. die of influenza despite our best efforts to prevent it.”

Treatment options

Vaccination is the best defense against flu, but it is not perfect. Some people do not respond well to vaccines because they are immunocompromised. Some just do not get vaccinated. Other times, like this year, the circulating strain does not match the vaccine strain.

When people do get flu, there is a second line of defense: neuraminidase inhibitors. These include the oral agents Tamiflu (oseltamivir, Genentech) and Relenza (zanamivir, GlaxoSmithKline), and the IV agent Rapivab (peramivir, BioCryst Pharmaceuticals), which was approved by the FDA in December.

The CDC recommends that all high-risk or severely ill patients with suspected flu receive a neuraminidase inhibitor, even before flu is confirmed, since antivirals work best when given within 2 days of illness onset.

According to Piedra, there is no controversy regarding the use of antivirals in patients who are hospitalized with flu. Controversy does exist, however, regarding when to prescribe them in the outpatient setting. Antivirals are recommended for patients with comorbid conditions or those who are likely to develop severe disease, he said.

However, it is difficult to determine who will develop severe disease. In addition, the patient would need to be evaluated and receive the prescription on time.

“All of those factors make the use of antivirals in the outpatient setting more difficult for adults who sometimes can’t see their physicians in a timely manner,” Piedra said. “In pediatrics, if you become ill today, you can be seen today. These factors add to some of the complexities with the use of antivirals.”

Effectiveness of antivirals

There is some debate about whether antivirals have any significant benefit. In a Cochrane review published in British Medical Journal last year, researchers found no evidence that the drugs reduce hospitalizations or serious complications. In a meta-analysis published earlier this year in The Lancet, however, researchers found the opposite: The drugs shortened the length of symptoms and reduced the risk for complications, including pneumonia.

Piedra said the difference between the studies is that Cochrane reviews only include randomized, placebo-controlled studies. The review in The Lancet included unpublished, patient-level data, including epidemiological studies that demonstrated the worth of antivirals.

Coffin said that although the ability of antivirals to lessen disease severity may be lower than physicians would like, their impact is still significant, especially because they decrease the need for hospitalization. Approximately 1.5% of people with flu need to be hospitalized, she said. That number goes down to 0.6% with the use of antivirals.

“We’re talking about numbers far down the numeric spectrum, but it’s reducing the likelihood of needing hospitalization by 50%,” Coffin said. “When you look at it from that perspective, it has a big impact.”

Regardless of their benefit, antivirals are underprescribed in the U.S. Coffin said it may be that the general public simply does not believe flu to be a serious disease.

Public perception

Flu affects millions of people each year and it can be deadly, but the general public does not seem to regard it as a dangerous disease.

“Flu is pretty well known, and people think they know what the symptoms are and when the flu season is, but overall, they don’t regard it as a serious disease,” Flannery said. “They don’t realize that there are people who are at especially high risk for severe disease, and everyone should be vaccinated to help that high-risk group.”

Neuzil said public perception of flu is something that physicians have struggled with, and one reason may be that the word “flu” is often used in a generic sense to describe any similar illness.

“This definitely works against us, and it’s something we have to explain to patients when we give them the flu vaccine,” Neuzil said. “There are other viruses that can make you feel bad this winter. What makes flu different is its high attack rates and severity. Those make it absolutely worth preventing.”

Flu happens every year. It is expected, and it is difficult to bring people’s attention to a predictable problem, especially one that has symptoms that make the disease seem like any other cold.

Parada said his primary argument when discussing the importance of the flu vaccine with patients is to remember that sometimes, it is not all about you.

“If you’re in your 20s and 30s, and you catch the flu, the truth is, while nobody likes to be sick, you will probably get over it,” Parada said. “But when you’re sick and in line at the grocery store, and the person in front of you is immunocompromised for any reason, he or she may not get over it.” – by Emily Shafer

References:

Dobson J, et al. Lancet. 2015;doi:10.1016/S0140-6736(14)62449-1.
Flannery B, et al. MMWR. 2015;64:10-15.
Jefferson T, et al. BMJ. 2014;doi:10.1136/bmj.g2545.

For more information:

Susan E. Coffin, MD, MPH, can be reached at coffin@email.chop.edu.
Edward T. Dickinson III, MD, can be reached at edward.dickinson@uphs.upenn.edu.
Brendan Flannery, PhD, can be reached through the CDC media office at media@cdc.gov.
Kathleen M. Neuzil, MD, MPH, can be reached at kneuzil@path.org.
Jorge P. Parada, MD, MPH, can be reached at  jparada@lumc.edu.
Pedro A. Piedra, MD, can be reached at ppiedra@bcm.edu.