2018-2019 Influenza Season and Recommendations for Clinicians
Moderator: Ibad Khan
Presenters: Alicia P. Budd, MPH; Angela Campbell, MD, MPH
Date/Time: February 5, 2019, 2:00 – 3:00 pm ET
Ibad Khan:
Good afternoon. I am Commander Ibad Khan and I’m representing the Clinician Outreach and Communication Activity, COCA, with the Emergency Risk Communication Branch at the Centers for Disease Control and Prevention. I would like to welcome you to today’s COCA Call: 2018-2019 Influenza Season and Recommendations for Clinicians.
You may participate in today’s presentation via webinar or you may download the slides if you are unable to access the webinar. The PowerPoint slides and the webinar link can be found on our COCA webpage at emergency.cdc.gov/coca. Again, the web address is emergency.cdc.gov/coca. Free continuing education is offered for this webinar. Instructions on how to earn the continuing education will be provided at the end of the call. In compliance with continuing education requirements, CDC, our planners, our presenters and their spouses/partners wish to disclose they have no financial interests or other relationships with the manufacturers of commercial products, suppliers of commercial services, or commercial supporters.
Planners have reviewed content to ensure there is no bias. Content will not include any discussion of the unlabeled use of a product or a product under investigational use, except Dr. Angela Campbell will discuss off-label use of antiviral medications for treatment of influenza. CDC did not accept commercial support for this continuing education activity.
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At the conclusion of today’s session participants will be able to accomplish the following: summarize the current status of influenza activity in the United States; discuss the circulating influenza strains seen this season and the implications for clinicians; and describe the antiviral treatment recommendations for patients with influenza.
Today’s first presenter is Ms. Alicia Budd. Ms. Budd is an epidemiologist in CDC’s Influenza Division. Ms. Budd has been at CDC for more than 13 years and has worked on national influenza surveillance for most of that time. She also has experience in infection control having spent six years at the Johns Hopkins Hospital in the Hospital Epidemiology and Infection Control Department. Our second presenter is Dr. Angela Campbell. Dr. Campbell is a Medical Officer in CDC’s Influenza Division. Her projects focus on studies of influenza antiviral treatment and antiviral effectiveness, vaccine effectiveness, pandemic preparedness, and development of CDC clinical guidance related to treatment and prevention of seasonal and novel influenza viruses. She is an Adjunct Associate Professor of Pediatrics at Emory University School of Medicine and has a professional staff appointment at Children’s Healthcare of Atlanta.
Thank you all for joining us today. I will now turn over the presentation to Ms. Alicia Budd.
Alicia Budd:
Thank you. So, today I’m going to be talking about influenza activity this season. This update is going to cover activity that occurred through January 26th and its data that was reported to CDC as of February 1st, so some of these data may be changing slightly as more data come in. So, before I launch, oops. Sorry, I need to, Ibad can you take it back one slide for me? Thank you, and if you wouldn’t mind, I’ll just say next slide and have you advance for me. But, before I launch into an actual update of our activity, I just wanted to briefly give you an overview of how we track flu activity at the national level and really it is a collaborative effort between staff here at CDC and our public health partners at the state and local level as well as numerous other data providers. And at CDC our role is really to coordinate the systems that these other providers and public health professionals make possible.
So we get data in five categories that come from eight components or eight systems that we use. Three have to do with the virus itself, two have to do with influenza-related mortality, and then we have one each that has to do with outpatient visits to physicians, hospitalizations, and then the geographic spread of activity. The data are reported to CDC at least weekly and then we analyze the data and summarize it and feed the information back out to public health partners and to the general public in the form of Flu View and Flu View Interactive, and then there’s some additional data that we make available to the public health partners that reported the information to us. Next slide, please.
So, Flu View is the static report that we put out each week and it’s basically a text summary with some graphics and a high level interpretation of what’s going on. The focus is primarily national level activity, but there is some discussion of regional and state level activity, as well. And then we have what we call Flu View Interactive, which is an online application that really lets you look into a lot more depth at the data that’s presented in the static report. You can look at data from the current season as well as data from past seasons, you can look at data on different geographic levels, national, regional, and in most cases, state level data as well, and you can also find more information, for instance, on some of the pediatric death data or the hospitalization data that we’re able to put out in the static report. But both of these are updated every Friday morning year-round, usually by 11:00 a.m. Eastern time and you can see the website there for accessing these tools. Next slide, please.
So, the National Influenza Surveillance System was initially constructed many years ago to provide information about what viruses are circulating, to certainly be able to identify any that have pandemic potential, to let us know when the season is starting, how long it’s lasting, where activity is occurring geographically, to monitor the severity of activity, and to help us understand better about who is getting infected, who is at highest risk, and all of this information really is to help guide decisions for intervention. And the system has been modified quite substantially over the years but these are still the goals that we’re trying to accomplish. Next slide, please.
So now I’m going to move on to what we’re actually seeing this year. So this slide shows data that we get reported to CDC by laboratories across the country. We get data from about 250 clinical laboratories and about 85 public health labs. And the clinical labs are primarily testing specimens for diagnostic purposes and the data from these labs lets us calculate the percent of specimens that they tested that are positive for flu and we use this, what we call percent positivity, to help us understand the timing and the intensity of flu activity. So, you can see in the top part of this slide, that activity was low during October and November, it began to increase in December, and has continued to increase over the past three weeks. We did see a little bit of a decrease in percent positivity in early January and that could be due to an actual true decline in flu virus circulation around and just after the holidays while the kids were out of school and transmission may have actually slowed down a little bit. Or, it could be that what we’re seeing here is sort of changes in healthcare-seeking behavior over the holidays and that sort of self-corrected since then. But either way we have seen steady increases during the last three weeks.
From the public health labs we get information on specimens that they test primarily for surveillance purposes but they let us know what proportion of circulating viruses belong to each of the influenza A subtype, H1 or H3, and influenza B lineages, either Victoria or Yamagata. And this year we are seeing primarily an H1 predominant season, so that’s the most commonly reported virus nationwide and that’s true in nine of the 10 surveillance regions as well; however, the Southeastern part of the country which is shown there highlighted in blue, the Southeastern region, is actually seeing more H3 viruses than H1 viruses this season, though they are seeing significant H1 as well. Also of note, we have seen very little influenza B activity this season. Only about 1% of the viruses reported by the public health labs are influenza B viruses this year and the majority of those are Yamagata lineage viruses. Next slide, please.
So the public health labs send a subset of their influenza positives on to CDC for genetic and antigenic testing and for testing related to antiviral susceptibility. The genetic and antigenic data are used so we can monitor whether the circulating viruses, how they’re changing and how similar they are to the reference viruses that were used for developing the flu vaccine. So the pie chart on the left part of this slide shows the same data that we saw on the bottom graph of the previous slide which is the overall distribution of influenza subtypes and lineages reported by the public health labs this season. And the pies on the right-hand side show the results of the genetic characterization for each subtype and lineage. On the very far right two pie charts you can see that all of the influenza A H1 viruses and all of the influenza B Yamagata lineage viruses belong to a single genetic group or clade. But we do see a little bit more genetic diversity when we look at the H3 viruses and the B Victoria viruses. So, the predominant H3 genetic group is what we call 3C.2a1 and that accounts for about 43% of the characterized viruses so far this season. The other groups that we’re seeing are 3C.2a and 3C.3a, roughly equally split between those two. And then the B Victoria lineage viruses, all of them belong to what’s called the V1A clade but we know within that clade that there are some viruses, different groups of viruses, that have specific genetic changes that are also making those viruses behave differently antigenically so we are tracking those on this graph, as well. We have them separated out as V1A.1 and V1A-3DEL. Next slide, please.
So, this next slide shows the results of the antigenic characterization of flu viruses. And this testing is performed in addition to the genetic testing that I just talked about because it gives us some more information about how the vaccine might protect against circulating viruses based on how similar the circulating viruses are antigenically to the vaccine reference viruses. And this is important because we know that there can be times when the virus has genetic changes that do not affect the virus’ antigenicity so it may be still similar to the vaccine antigenically. So in this graph you can see that all or nearly all of the H1, H3 and B Yamagata lineage viruses collected in the U.S. this season that have been antigenically characterized are similar to their respective cell-grown vaccine reference viruses. There’s a little bit more diversity when you look at the B Victoria viruses but even so more than 71% of those viruses that have been tested are antigenically similar to the vaccine virus. So these data tell us that at this point the vaccine is well matched to the currently circulating strains that have been tested at CDC. And I don’t have a graphic for it but I did also want to mention the results of the antiviral susceptibility testing of U.S. viruses this season. All the viruses tested, it’s been around 700 viruses, all of those have shown susceptibility to zanamivir and more than 99% of them also showed susceptibility to oseltamivir and peramivir. We’ve had a very small number of H1 viruses that have been found to have reduced or highly reduced susceptibility to oseltamivir and/or peramivir. Next slide, please.
So now I’m going to turn from the virologic surveillance to how we track influenza-related morbidity and mortality. So this slide shows data from our ILI-like system which is a network of about 2,500 outpatient providers that report information on ILI visits each week. And so this season’s percentage of outpatient visits for ILI are shown in red along with other prior seasons so you can see where we are in comparison. So the percent of influenza-like illness or ILI this season has been at or above the national baseline for ten consecutive weeks starting since the middle of November and was at 3.8% during the week ending January 26th. All of the regions are also above their region-specific baselines and have been for several weeks. And we see a similar dip in these data that we saw in the clinical lab data just after the holidays and the possible explanations are the same. That there actually was a reduction in transmission in that time or that it reflects changes in healthcare-seeking behavior and we’ve since seen sort of a self-correction there. Next slide, please.
And in addition to looking at the ILI data on a national and regional level, we also look at it on a state level and classify a state’s level of ILI intensity from minimal up to high, and you can see here for the most recent week data that we have, we had 23 states experiencing high ILI activity, ten at moderate and 17 at either low or minimal activity. Next slide, please.
We track influenza-associated hospitalizations as well and we do this through a multistate population-based surveillance system that operates in select areas of thirteen states and covers about 9% of the U.S. population. I just want to point out that these data are presented a little bit differently than our other components in that it’s weekly data but each week the data that’s shown there is for the season cumulative up until that point in time. So this slide is showing that cumulative laboratory-confirmed hospitalization rates for the current season, and you can see our most recent week there circled in red and comparing it to the past eight seasons. This season’s rate as of the week ending January 26th was 15.3 hospitalizations per 100,000 population, and this graph here shows all ages combined but we also have the data broken out by age group. The 65 years and older age group had the highest rates at 40 per 100,000, followed by a hospitalization rate of about 27 per 100,000 for the zero to four year olds who were the next highest rate age group.
The two most recent H1 predominant seasons, which were the 2015-16 and 2013-14 seasons, had final end-of-the-season hospitalization rates of around 31 and 35 per 100,000, respectively, and you can see that where we are right now is nowhere close to that, yet. So we do expect these hospitalization rates to continue to increase as the season progresses, but we certainly don’t expect to see rates anywhere near the record breaking rates we saw in the H3 predominant season we had last year. Next slide, please.
We have two systems for monitoring flu-related mortalities. The graph on the left shows data from the National Center for Health Statistics Mortality Surveillance System which captures data on nearly all the deaths in the U.S. by pulling information from death certificates. And from these data we calculate the percent of deaths in a given week that have pneumonia or influenza listed anywhere on the death certificate and this season’s data is there on the far right of the screen, of the graph rather. And the percent of P&I has been slowly increasing this season and has been either at or just slightly above the epidemic threshold during the past three weeks. And on the right-hand side of the graph, you see data about laboratory-confirmed influenza-associated pediatric deaths. So far this season 24 pediatric deaths have been reported to CDC. All but one of those have been an influenza A virus infection and the majority of the subtype influenza A viruses have been due to H1 infections as we would expect in the H1 predominant season. Next slide, please.
The last component of the National Surveillance System is one that consists of reports from state and territorial epidemiologists about the spread of activity across their state. This indicator has nothing to do with the intensity or the severity of the activity, only about the geographic spread within the state. During the week ending January 26th we were seeing widespread flu activity across most of the country, with 45 states reporting widespread activity, three reporting regional, and two reporting local activity. Next slide.
So, in addition to the surveillance updates that we have historically put out each week, this season we are also starting to put out weekly updates on the severity classification for the season as well as preliminary burden estimates. So, I just really briefly wanted to walk through what each of these assessments of flu activity tells us, very briefly how they’re generated, and then of course where we are in the season with respect to each one.
So we’ve already talked about the surveillance data, that’s the update I’ve given you in detail up until this point. The severity assessment is based on a couple of those surveillance system components and it’s how we are objectively classifying the severity of the season. Basically, we take data from a couple of these components and compare where we are right now to different threshold indicators of severity based on data that we’ve had from past seasons. We used to only do this at the end of the season but this year we’re starting to put out that information on a weekly basis sort of as the season unfolds.
And similarly, with the burden estimates this used to be something that was only put out at the end of the season when all of the surveillance data were final, and basically what this is, is using mathematical models to translate some of our surveillance data into estimated numbers of illnesses, hospitalizations and deaths. We do this because we know the surveillance system cannot provide those actual counts. It does a great job of tracking activity but not providing those numbers of cases, and we know that that information is helpful for folks for a number of reasons. Next slide, please.
So, this graph shows the severity assessments going back to 2003-2004. As I’m sure we all remember way too vividly last season was a high severity season. Overall, it was a high severity season for all three of the age groups that we broke the data down into, and it was the first time that we’ve had a season where all three age groups were at a level of high severity. Thankfully, so far this season all of our indicators are still at this sort of threshold of low level of activity and that’s based on our outpatient ILI and pneumonia and influenza mortality data at this point. Next slide, please.
And while this you know classified as a low severity season, I think it’s important to remember that even low severity flu seasons can have significant impact on morbidity and mortality, and our preliminary midseason burden estimates as of January 26th based on this mathematical model shows that flu this season in what we’re calling a low severity season has caused at least 10.1 million illnesses, so far. About half of those individuals have sought medical care and at least 118,000*(correction from verbal number given in recording) have been hospitalized. So these numbers are cumulative for the season. We expect them each week when the new updates come out. They will continue to grow because they are cumulative, and just to point out we don’t yet at this point in the season have enough data that are sufficient to allow us to estimate the number of deaths, but we do anticipate that that information will be available later in the season.
And I included the portion of the slide on the left there, that includes the ranges of the burden of flu during the past several years just for comparison purposes so you can see where we are this season compared to the range of prior seasons and we’re clearly at the low end for now and we’ll have to continue to see how things progress with the season. Next slide, please.
So just in summary, in terms of activity so far, activity is elevated across the U.S. and we do expect significant flu activity to continue for several more weeks. So far this season, and I emphasize so far because we are still in the middle of the season, but so far this season has been mild compared to recent seasons as is evidenced by all the severity indicators still being at that low threshold mark, but even as I pointed out in the last slide, even with a low severity season we are seeing significant morbidity and mortality. H1 is the predominate virus this season except in the southeastern part of the country where they are seeing H3 viruses most commonly, and so far the viruses do seem to be antigenically and genetically similar to the cell grown reference viruses from the Northern Hemisphere vaccine.
So that concludes the activity update that I had. I’m going to turn the presentation over to my colleague, Dr. Angela Campbell, who is going to address some of the clinical issues about influenza virus infection.
Angela Campbell:
Thank you Alicia. Ibad let me know if you can’t hear me, I think that I have control of the slides so let’s see.
Ibad Khan:
Dr. Campbell, we’re able to hear you just fine.
Angela Campbell:
Great. I may not be able to advance the slides myself and if not that’s okay. Did I do that?
Ibad Khan:
Dr. Campbell, you can also use the directional arrows on your keypad, right left, to navigate.
Angela Campbell:
Great, that’s working! Apologies audience. We weren’t able to practice that because of the system beforehand, but I think I have it now. So, in this next section of the presentation I’m going to briefly review the clinical manifestations of influenza. As you probably know, influenza can cause a spectrum of illness. This can range from asymptomatic infection to a more typical upper respiratory tract illness consisting of abrupt onset of fever and typically cough, with other symptoms which may include chills, muscle aches, fatigue, headache, sore throat, runny nose. I should note that rhinorrhea or runny nose and nasal congestion tend to occur with other more common cold viruses but may occur in young children with flu. Likewise, GI symptoms such as abdominal pain, vomiting and diarrhea are also more common in children. Infants may not actually have respiratory symptoms at all and may present with fever alone or often with irritability. And on the other end of the age spectrum, elderly people as well as people who are immunosuppressed may have atypical symptoms and may not have fever. So all of these manifestations can occur with what we would generally call uncomplicated illness. However, as we know all too well, flu can also cause complications.
So, this is a list of groups of people considered at increased risk for influenza complications and severe illness. This includes children under the age of five but especially those less than two years old, adults 65 and older, people with immunosuppression or chronic medical conditions such as pulmonary, cardiovascular and other conditions, pregnant and postpartum women, children who are on long term aspirin therapy, American Indians, Alaska Natives, people who are extremely obese, and residents of nursing homes and other long term care facilities.
So, this slide is a graphic from FluView, from the hospitalization surveillance system that Alicia mentioned. This is showing the underlying medical conditions among influenza hospitalizations in the current season, and the small blue bar on the bottom means that about 10% of adults hospitalized with flu were previously healthy, whereas 90% of hospitalized adults have some sort of underlying medical conditions with the most common being cardiovascular disease, metabolic disorders including diabetes, and obesity. Among children, the most common conditions have been asthma, neurologic disorders, and obesity; however, I do want to emphasize the point that more than half of children hospitalized with flu actually have no underlying, no previously known underlying medical conditions and, unfortunately, we know that every year previously healthy children and adults can get severe illness from flu.
So, moving to the complications. A common complication is otitis media, which can develop in up to 40% of children under the age of three. Influenza can also cause sinusitis. Those are I think probably what we would call mild to moderate complications. Influenza can also exacerbate chronic underlying conditions such as asthma or heart disease. Other common causes of hospitalization with flu actually include the dehydration that goes along with it, or pneumonia, and this pneumonia can be primary viral pneumonia or secondary bacterial pneumonia. Flu can also cause other respiratory syndromes such as croup, bronchiolitis, even acute respiratory failure, as well as a number of extra-pulmonary complications including renal failure, myocarditis, pericarditis, myositis, rhabdomyolysis, encephalopathy and encephalitis which tend to be more common in children, Guillain-Barre Syndrome, ADEM or acute disseminated encephalomyelitis, sepsis, and multi-organ failure. And sepsis, in fact, has been found to be listed as a complication in up 30% of pediatric death reports. This was recently published in a review of the pediatric mortality flu surveillance. And lastly, the most common bacteria found in coinfections with flu are S. aureus, S. pneumoniae, and S. pyogenes, which is group A strep.
So, now I just want to move on to talk about vaccination. We all know that it’s the best way to prevent flu, but let’s talk a little bit about that and about vaccine effectiveness. So, the Advisory Committee on Immunization Practices, or ACIP, and CDC recommend annual vaccination for everyone six months of age and older who do not have contraindications, and this has been recommended for everyone six months and older since the 2010-11 season. This is recommended generally to be received by the end of October, but as long as influenza viruses are circulating, vaccinations should continue through flu season; and as Alicia said, we expect to have several more weeks of flu season.
This slide lists the vaccine formulations available this season. Those highlighted in blue are available for children as well as adults. These include inactivated trivalent, quadrivalent, and quadrivalent cell-culture-based vaccine. In addition, for adults 65 years and over we have trivalent high dose and trivalent adjuvanted vaccines. Recombinant protein vaccine is available in a quadrivalent formulation for people eighteen years and over. And then lastly, LAIV, live attenuated influenza vaccine, is available this season for ages two through 49.
I included a brief review on the history of LAIV. As you will likely remember, LAIV had not been recommended for 2016-17 or 2017-18 seasons and this was because of low effectiveness versus influenza A(H1N1)pdm09 (that was the new H1N1 virus that emerged during the 2009 pandemic)—low effectiveness against that virus among children during the 2013-14 and 2015-16 seasons. This was thought to be due to poor fitness of the H1N1 virus in the vaccine. So, in February of 2018, ACIP reviewed additional data, just last year, and they reviewed two analyses of previous seasons’ data from observational studies and manufacturer’s data on shedding and immunogenicity of the new H1N1 vaccine virus and it indicated improved fitness. And so based on this review, for 2018-19, LAIV was voted to be an option for those for whom it is appropriate.
And I just want to note that you’re likely aware there was a difference in the ACIP and AAP recommendations in that ACIP makes no preferential recommendations for any one vaccine type when more than one is appropriate. However, AAP recommends IIV (inactivated influenza vaccine) as the primary choice for children. I think what is important to keep in mind and share with patients is that both recommendations share the same principle that flu vaccination is an important preventive strategy for children.
And I thought that this recent publication is really interesting. It’s from the Immunization Services Division at CDC, regarding whether parents prefer inactivated or live attenuated flu vaccine for their children. This study used parent-reported data from the National Immunization Survey Flu, or NIS-Flu, from the 2014-15 and 15-16 seasons. So, if you remember, this was when there were still both vaccines available, and for the 2014-15 and 2015-16 seasons, 55% and 53.7% of vaccinated children had parents who actually reported no preference for either IIV or LAIV. In 2014-15, 22.7% preferred LAIV and 22.1% preferred IIV, and the following season this actually switched a little and the LAIV was preferred by 21.7% and 24.7% preferred IIV. So, I think this study is helpful by showing that most parents do not have a vaccine type preference for their children, and really this lack of preference as advantageous for the maintenance of vaccination coverage levels during times when one vaccine type is not available or not recommended.
And so in this next slide, I wanted to give you a look at estimates of early season flu vaccination coverage as of mid-November 2018. This was also based on the NIS-Flu Survey for kids and the National Internet Flu Survey for adults. Flu vaccination coverage among children age six months to seventeen years was 45.6(%) at the time of the survey, which was actually an increase of 6.8 percentage points compared with the same time period last flu season, and flu vaccination coverage among adults was 44.9%, an increase of 6.4 percentage points compared with the same time period last flu season. So this is also encouraging.
And last, I will review some effectiveness data to support why we say that annual seasonal influenza vaccination is the best way to protect against influenza outpatient visits, hospitalizations, and deaths. In 2017-18, you may remember that influenza vaccination reduced the odds of outpatient medical visits by 40% overall, and then below that is the number for each age group shown, with the lowest among older adults, and the highest being 53% vaccine effectiveness among children six months to eight years old.
This figure shows overall vaccine effectiveness and VE for six months to eight-year-old children and nine year to seventeen-year-old children from the past eight seasons back to 2010-11. In general, we see that overall VE against any flu virus among all ages—those are the red bars—to be between about 40 to 60 percent. I will comment that the (20)14-15 season was the year that the (“vaccine virus” corrected to “circulating virus”) that the circulating virus drifted and was not a good match—the vaccine virus did not well match the circulating virus—but in general VE is about 40 to 60 percent for overall. And for children, the VE is generally similar to the overall VE although you will see that in 2016-17 and 2017-18, six month to eight-year-old children had higher vaccine effectiveness point estimates compared with the lower vaccine effectiveness in nine to seventeen-year-old children, although this difference did not reach statistical significance. And I just did want to mention before I move on that we expect our interim vaccine effectiveness estimates from our outpatient flu VE network to be out in mid-February, so probably within the next couple of weeks.
Moving from outpatient illness, I just wanted to show some data for influenza vaccine effectiveness in preventing severe disease. First in adults, a recent publication reported a 50% reduction in risk of influenza-associated hospitalization among adults of all ages. This was 65% in the youngest eighteen to 49 year age group, 46% among 50 to 64 year olds, and 50% in age 65 and up. This study also found an 81% reduction in influenza requiring ICU admission.
In children, various studies have shown 50 to 80 percent reduction in flu-associated hospitalizations, and another study found that vaccination was associated with a 74 percent reduction in flu requiring PICU admission. And then lastly, this was a recent study from 2017 that evaluated vaccine effectiveness in preventing death in children, and found it to be 51 percent effective in reducing the likelihood of death in children with high risk conditions and 65 percent for children without underlying high risk conditions. Unfortunately, in our pediatric mortality surveillance system, we consistently see that about 75 to 80 percent of the children who die with flu are not vaccinated.
So, although we all know that vaccination is important, we also know that communicating influenza vaccine effectiveness is challenging. And as I have shown, the VE can vary by population, as well as by circulating virus type and vaccine type, and—you may be aware, but I wanted to point out—that CDC has developed a model to translate VE into number of influenza-related outcomes prevented by vaccination. So another way to say this is the burden averted by flu vaccination, and we make a graphic every year. This was just came out for the 2017-18 season. It shows that approximately 40% of the U.S. population chose to get a flu vaccine last season and this prevented an estimated seven million flu illnesses, about the population of New York City; 109,000 flu hospitalizations, about the number of vehicles crossing the Golden Gate Bridge each day; and 8,000 flu deaths, twice the number of hospitals in the United States. So we try to make this something that people can kind of grasp onto. And then it says: “Imagine the impact if more Americans chose to get a flu vaccine. Many more flu illnesses, flu hospitalizations, and flu deaths could be prevented.”
So, I just want to close this vaccination section by reminding you of factors associated with higher level of flu vaccination in patients—and this has been found in studies of children, pregnant women, and other adults. Consistently having received a provider recommendation for flu vaccination is significantly associated with higher vaccination coverage. In pregnant women, educational materials were also shown to be beneficial, and in a study of all adults 18 and over, these were some of the other factors associated with likelihood of vaccination. But please know that your flu vaccine recommendation makes a difference to your patients.
So, now I’m just going to move on to talk a little bit about the diagnosis of flu. I wanted to make sure you are all aware of the recent IDSA Clinical Practice Guidelines that were published in December, the 2018 Update on Diagnosis, Treatment, Chemoprophylaxis, and Institutional Outbreak Management of Seasonal Influenza. I also want to draw your attention to the main CDC page on flu virus diagnostics. And I’m not going to go into a lot of detail on diagnostics, but I do want to remind you that influenza testing should be performed when results are likely to influence clinical management—in that they may decrease unnecessary laboratory testing for other etiologies, they may decrease unnecessary use of antibiotics, facilitate implementation of infection prevention and control measures, increase appropriate use of influenza antiviral medications, and potentially decrease length of stay. Testing should also be performed if results will influence a public health response such as for outbreak identification and interventions, for example, in a long term care facility.
This is an algorithm from the IDSA guidance and our web pages. It’s a guide for considering influenza testing when flu is circulating in the community, and this should be regardless of flu vaccination history. It starts by asking: “Does the patient have signs and symptoms suggestive of flu?” And it reminds that some may have atypical presentations as I’ve discussed. If no, it then asks about those atypical presentations such as immunocompromised patients or also about whether underlying chronic conditions or are experiencing exacerbation. And if the answer is still no, then testing is not indicated. But now moving to the left of this diagram, if a patient with suspected flu is being admitted to the hospital, testing is recommended along with empiric antiviral treatment while results are pending. If not being admitted but if results will influence clinical management, the same recommendation applies; and if results will not influence management, testing is not necessary. For example, if flu can be clinically diagnosed, empiric treatment can simply be initiated and empiric treatment is recommended if the patient is in a high-risk group or has progressive disease, and we’ll talk a little bit more about that in the next section.
So, if testing is performed, what test should be used? The main point of this entire slide is that molecular assays are the most sensitive. So for outpatients, rapid molecular assays exist now that have high sensitivity, and will improve detection over rapid influenza diagnostic tests, or RIDTs, that use antigen detection. And for hospitalized patients, molecular assays including RT-PCR or other multiplex molecular assays should be used to improve detection of influenza, and for immunocompromised patients, specifically, multiplex molecular panels are recommended.
So, the last topic I will cover with you today is antiviral treatment recommendations. Influenza antiviral medications are an important adjunct to vaccination. We still recommend vaccination as the first line. The focus of CDC as well as actually AAP and IDSA influenza treatment guidance is really on prevention of severe outcomes and that means that we focus on treatment of those with severe disease and in persons at high risk of severe influenza complications. And as I mentioned, antiviral recommendations that CDC puts out are common to IDSA and the American Academy of Pediatrics.
So in this one slide—it’s almost too much to put in one slide—but I’m providing just a brief overview of a lot of data regarding the efficacy and effectiveness of antivirals. But I need to preface by saying that no antiviral is specifically approved for severe influenza. So that gets to my, the disclosure that Ibad gave at the beginning—really, all influenza antivirals are FDA approved for treatment of uncomplicated flu of less than 48 hours duration. So that being said, we do have observational data that support an effect on reduction of flu complications and most experts support use. And so what we know is that clinical trials and observational data show that early antiviral treatment can shorten the duration of fever and flu symptoms. Meta-analyses of randomized controlled trials have demonstrated that early treatment reduces risk of otitis media in children, and lower respiratory tract complications requiring antibiotics and hospital admission in adults. Observational studies and meta-analyses of observational data have reported that among high risk outpatient children and adults, early antiviral treatment reduced risk of hospital admission. Early treatment of hospitalized adult flu patients with oseltamivir reduced the likelihood of death and shortened hospitalization, and in hospitalized children early antiviral treatment with oseltamivir shortened duration of hospitalization. So it’s a lot of data packed into one slide.
And now to get to the actual recommendations. Antiviral treatment is recommended as early as possible for any patient with suspected or confirmed flu who is hospitalize; has severe, complicated, or progressive illness; or is at high risk for influenza complications.
And here’s a reminder of those at high risk. I won’t read them all again but I will note that children less than two years old are considered at the highest risk. We know that clinical benefit is greatest when antiviral treatment is initiated as close to illness onset as possible, so treatment shouldn’t be delayed while awaiting test results. There are some data to suggest that antiviral treatment initiated after 48 hours can still be beneficial. There have been observational studies of hospitalized patients and in pregnant women that have suggested that treatment might still be beneficial when initiated three, four or five days after symptom onset.
So I mentioned that these are the three categories for whom treatment is recommended, but also we note that antiviral treatment can certainly be considered for any previously healthy, symptomatic outpatient not at high risk with suspected or confirmed flu on the basis of clinical judgment, if treatment can be initiated within 48 hours of illness onset.
So there are four approved FDA antivirals this season for use in the U.S. That includes the three neuraminidase inhibitors that we’ve had, and a new cap-dependent endonuclease inhibitor which is baloxavir. So this table summarizes these and some of their differences. Oseltamivir and baloxavir are oral. I should also note that peramivir and zanamivir are single dose. You only receive them once for outpatient flu. Zanamivir is administered using this diskhaler device shown in the picture at the bottom, and peramivir is intravenous. Oseltamivir can be given to anyone of any age. I would note that FDA approval is for children two weeks of age and older, but CDC, AAP, and IDSA support its use from birth in both term and pre-term infants. Zanamivir is approved and recommended for age seven and up, peramivir two and up, Baloxavir twelve and up, and two of these drugs are approved and recommended for chemoprophylaxis: oseltamivir and zanamivir.
And then the most common adverse events are listed here. Oseltamivir is GI: nausea and vomiting. These symptoms can be lessened if the medication is able to be taken with food. Zanamivir can cause bronchospasm, and is therefore not recommended for anyone with underlying airway disease. Peramivir has been shown in clinical trials to cause more diarrhea than placebo, and baloxavir has actually not had adverse events reported more commonly than placebo in clinical trials. It seems to have a fairly favorable profile.
So just a little bit more on baloxavir. The full name is baloxavir marboxil. This is a new mechanism of action. It actually blocks viral replication by acting on the polymerase whereas the neuraminidase inhibitors block release of virions from the cell. Baloxavir was FDA approved in October of last year, again, for treatment of acute uncomplicated flu in patients twelve to 64 years old. It’s given orally as a single dose. It’s based on the weight and the age. Basically, it’s a 40 mg dose for people between 40-80 kilos and an 80 mg dose for people 80 kilos and above. In clinical trials and in this Fred Hayden paper that I’ve shown in the insert, baloxavir was associated with significantly shorter time to alleviation of symptoms than placebo, and significantly more rapid declines in viral load and shorter duration of infectious virus detection than either oseltamivir or placebo. Just like the other antivirals, it showed the most benefit when initiated earliest after illness onset. And lastly, the emergence of viral escape mutants with reduced susceptibility has been observed in clinical trials and it will be really important to monitor this in future trials and in clinical use.
So in my last two slides, I want to review principles of treatment in hospitalized patients and pregnant women. For hospitalized patients, treatment with oral or enterically-administered oseltamivir is recommended as soon as possible. Inhaled zanamivir and oral baloxavir are not recommended because of the lack of data in hospitalized flu patients, and really there are also insufficient data for treatment of hospitalized flu patients with IV peramivir. However, for patients who can’t tolerate or absorb oral or enterically-administered oseltamivir—maybe they have malabsorption or a GI bleed—the use of IV peramivir should be considered. And also keep in mind that the optimal duration and dosing of treatment for hospitalized patients is uncertain and likely longer than for outpatients with uncomplicated flu.
And for pregnant women, oral oseltamivir is the preferred medication because it has the most studies available to suggest that it’s safe and beneficial. Baloxavir is not recommended right now for treatment of pregnant women or breastfeeding mothers, and that’s because we really have no available efficacy or safety data in pregnant women. And there’s no available data on the presence of baloxavir in human milk or effects on the breastfed infant or effects on milk production. So, a lot of data that we wait for on baloxavir.
And then at the end we’ve just included links to the main webpage references in our presentation today. We thank all of you so much for your attention and we’re happy to take questions.
Ibad Khan:
Thank you so much, Ms. Budd and Dr. Campbell, for sharing such valuable and timely guidance with our audience. We will now go into our Q&A session. Please remember, you may submit questions through the webinar system by clicking the Q&A button at the bottom of your screen, then typing your question. If we are not able to get to your questions today, please note that you can also send your questions to coca@cdc.gov.
Our first question as to do with the antigenicity and the good match comments that Alicia made. The question is, this inquirer often gets questions from clinicians as well as members of the public to ask about if this year’s vaccine is a good match and this individual would like to know is it safe to so based on the antigenicity results that were shared?
Alicia Budd:
Yes. This is Alicia. So, yes, based on the antigenic and genetic characterization that we’ve done of the viruses so far it does look like this season’s vaccine is well matched to the circulating strains, so that gives us an indication of how well the vaccine might perform and then we use the vaccine effectiveness data that Dr. Campbell mentioned will be available—preliminary data be available in the next couple of weeks—to see how it’s actually playing out in terms of effectiveness against in that case preventing outpatient medically attended illness. So, yes, right now it does look like the viruses are well matched with the vaccine and we’ll wait and see what that means clinically with the coming data.
Ibad Khan:
Thank you for that. The next question is semi-related to this as well as to a theme of questions we have received in the system and that is when do you expect to see flu activity decline and does it tend to decline earlier if the vaccine is a good match?
Alicia Budd:
I wish I had a crystal ball to know when it was going to decline. We don’t know when we’re going to see the peak yet. That’s why we love to run our surveillance data each week. But I can say while we don’t know for sure when it’s going to start to decline, we do know that we’re going to have still several more weeks of significant flu activity. And then to the part of the question about whether we see activity decline quicker or have a less intense season when there’s a good vaccine match. I think in order for us to see something like that we’d have to have a lot higher vaccine coverage than we currently have so that’s not typically something that we see. Now, on the flipside I will say we do see a lot more severe illness, or it appears that we see more severe illness, when we have a season with an unmatched vaccine but do we see overall a shorter season and that type of thing—no, not that we’re able to discern at this point.
Ibad Khan:
Thank you for that. The next question focuses mainly on specific patient population when it comes to vaccination. The question states generally that does the vaccine, even in cases where it may not prevent influenza in high risk elderly, will it still mitigate the severity if the patient contracts influenza?
Angela Campbell:
This is Angie Campbell. We actually do have some studies in recent years that have been performed by a couple, in particular by Sofia Arriola in our Flu Division looking at hospitalized adults that does suggest that even if they were ill enough to be hospitalized, that vaccination prevented them from having severe disease such as ICU admission or other complications while in the hospital. And there have been a couple of other recent studies that have actually helped us have evidence to support when we say that, yes, it’s probably true that even if you get flu after being vaccinated, not just for elderly, that the vaccine should mitigate your disease.
Ibad Khan:
Thank you for that. We have a few questions regarding either comorbidities or adverse effects that I would like to ask next. Our first question states are there considerations when using antivirals with chronic kidney disease?
Angela Campbell:
Ok, that’s a good point and I didn’t show specific dosing information at all actually in this presentation, but that is present on our website as well as in the IDSA guidelines. Both oseltamivir and peramivir need to be adjusted for renal impairment. I don’t actually think that baloxavir does but I would want to—yeah I feel pretty confident but there’s no adjustment for baloxavir but the other, oseltamivir and peramivir, both need to have adjustment for renal failure and renal impairment.
Ibad Khan:
Thank you. And for our audience, you will be able to find these resources in the web links that were just referenced when you download the slides from our call page. The next question is regarding patients in septic shock that may be on multiple pressors. Would there be concern about the use of oseltamivir and adequate absorption, or would peramivir be recommended in such patients?
Angela Campbell:
I think that’s a really good question. I think certainly these are probably patients where clinicians feel like their gut is not working very well and they’re unlikely to absorb and it’s a very reasonable patient to use IV peramivir in. I would think we’re pretty general in the recommendation of saying “GI bleed or malabsorption or suspicion that an oral drug may not be absorbed” and I think that’s up to clinical judgment but, yeah, I think that’s a really good point.
Ibad Khan:
Thank you. While we’re discussing antivirals, could you reiterate some important information about when to prescribe and the availability of baloxavir, the newer antiviral you mentioned?
Angela Campbell:
Ok sure. So it is FDA approved for outpatients twelve and over and I don’t think I said this—but it’s actually for people with and without underlying chronic medical conditions, so it can be used in anyone twelve and older. Aside from pregnant women, there’s really no condition that would preclude from it. It is now available in the market. It’s not yet covered by all insurance companies is my understanding, because some have policies in place that require a six-month waiting period before they can add new products that have entered the market onto their formulary. The other thing that I’m aware of is that the manufacturer is offering a coupon that can be found online on the manufacturer’s website to offset the drug costs and I think the manufacturer has ongoing activities to increase clinician awareness of the drug in the market. So it is out there. We don’t even have a full sense of how much it’s being used. I’ve talked to some providers that have used it, others that have had trouble finding it, but I think it’s starting to be more and more available.
Ibad Khan:
Thank you. Next question asks is there data you can share that would compare the effectiveness of high dose Flu Zone and FLUAD vaccine?
Angela Campbell:
So that is a good question, and as far as I’m aware we have data that compare these new vaccines to standard dose but not to each other. And my understanding is that’s partly why there really isn’t a preferential recommendation, because we don’t have all those comparative studies.
Ibad Khan:
Thank you. Our last question asks about some more information about hallucinations and other psychiatric adverse effects that may be experienced with oseltamivir, if they are specific only to that medication or other antivirals as well, if that is a concern.
Angela Campbell:
Thank you for that question. I had a footnote on my table of antiviral drugs but didn’t feel that I had too much time to mention—but really all of the neuraminidase inhibitors do include a note in the package insert about post marketing reports of delirium and abnormal behavior leading to injury, in some cases fatal outcomes, in patients who received mostly oseltamivir and Relenza which is the inhaled zanamivir. Most of these were in Japan, and most of these events were reported voluntarily, and most of them were among pediatric patients. But I think that what I’m aware of is that the contribution of the drug itself to these events has not truly been established. The manufacturers just are being clear that there have been post marketing reports from Japan of this behavior. And also I would remind people that influenza itself can be associated with a variety of neurologic and behavioral symptoms, including hallucinations and abnormal behavior, and so it’s hard to tease out the connection between drug versus disease but the package inserts do advise about this and about monitoring for it.
Ibad Khan:
Thank you very much for providing insight and perspective on that. So this concludes our Q&A session. I would like to thank our audience because it seems we have an abundance of questions that were not answered. However, please feel free to email your questions to coca@cdc.gov and we will be happy to get you answers from our presenters. And on behalf of COCA I would like to thank everyone for joining us today with a special thank you to our presenters, Ms. Budd and Dr. Campbell.
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