Introduction

Summary of the National Advisory Committee on Immunization’s Seasonal Influenza Statement and the Association of Medical Microbiology and Infectious Disease Canada’s Treatment Recommendations for frontline healthcare practitioners and public health vaccine providers to help guide their practice.

Dr. Ian Gemmill presented on prevention of seasonal influenza, types of vaccines available and their effectiveness, new indications and available internet resources. Dr. Gerald Evans presented on the burden of seasonal influenza, the trends in recent years and the antiviral treatment recommendations.

Published: 2018

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TRANSCRIPT


Dr. Theresa Tam, Chief Public Health Officer of Canada:
Bonjour, hello. I’m really pleased to have this opportunity to introduce this webinar. The National Advisory Committee on Immunization, NACI, and the Association for Medical Microbiology and Infectious Disease, AMMI Canada, provide foundational guidance to our overall efforts to reduce the burden of influenza in Canada.

Shortly, you will be provided with an overview of NACI’s 2018 and ’19 statement on seasonal influenza vaccine. You’ll also hear about recommendations on the treatment of influenza using antiviral drugs from AMMI Canada.

At this time of the year we all need to be prepared with up-to-date information to answer the questions that are top of mind for our patients. So, today’s webinar is an important opportunity to ask questions and discuss best practices for the prevention and control of influenza and its complications.

We all know that, in addition to sound hygienic practices, vaccination is the best layer of protection for preventing influenza infection. Influenza vaccine helps reduce illness and hospitalizations, protect pregnant women during and after pregnancy and is life-saving in children. Influenza is not a trivial illness, the fact that it results in over 12,000 hospitalizations and 3,500 deaths every year in Canada.

As well, a recent study found an association between influenza and heart attacks, particularly within the first seven days of the illness. In severe influenza seasons we also see an increased burden on the healthcare system, with ERs filling up and the cancellation of elective surgeries.

As you know, given the tendency for influenza viruses to undergo an antigenic drift, we cannot ascertain which strains will predominate in advance. For this year, based on global surveillance data, new influenza A H3N2 and B/Victoria components were selected for this season’s northern hemisphere vaccine.

While we won’t know what vaccine effectiveness will be until well into the season, even an underperforming vaccine still provides benefits. While vaccine efforts in most for preventing infection may be suboptimal, the vaccine can still reduce the severity of influenza symptoms and outcomes.

So now we come to your part. A recommendation for vaccination from a healthcare provider remains one of the most important factors in a patient’s decision to vaccinate. You play a key role in educating your patients on the importance of vaccination and prescribing antiviral treatments.

This webinar aims to equip you with the material you need to act as a trusted source of information on influenza prevention and treatment. I hope you find this information useful. Be sure to have your burning questions answered by our influenza experts.

Finally, I would like to thank the National Collaborating Centre for Infectious Disease and the team at the Public Health Agency of Canada for collaborating on this event. And thank you for your participation. Merci.

Alexandra Wierzbowski, NCCID: Thank you very much, Dr. [Tam], for introducing today’s webinar. Without further ado, I welcome our speakers and ask Dr. Evans to take the microphone to start our presentation.

Dr. Gerald Evans: Thanks very much, Alexandra. I’m just waiting for the first slide to come up. There we go. So I’m going to just start off today’s talk by talking a little bit about the burden of seasonal influenza in Canada. I’m sure many of the people who are participating today in today’s webinar are aware of this, but we certainly recognize that seasonal influenza creates a significant burden to society in general, and certainly to the healthcare system.

Influenza is a respiratory illness caused by influenza viruses. Although it can be mild in some patients, particularly people who have either been exposed to strains or have been vaccinated, much more commonly it produces a severe illness, very commonly resulting in significant school absenteeism and workdays lost.

Influenza occurs with a striking degree of regularity. It is seasonal in Canada, occurring during the late fall into winter and the early spring in an unpredictable fashion. And epidemics do occur in Canada every year, and certainly outbreaks in certain regions can be quite profound. It is typically in the northern hemisphere where Canada lies low in activity during spring and summer and it begins to rise as the colder months ensue. And of course, conversely, in the southern hemisphere it typically is in the middle months of the year; June, July and August.

The graph you can see on this slide indicates the seasonal activity from last year, along with a sort of average. And this based on influenza-like illness reports and visits to practitioners and [unintelligible] organizations. Last year, in 2017/2018, was a particularly difficult year. I think many of you who were working last year know it was a year predominated by H3N2 and there were substantial impacts in terms of mortality and healthcare utilization.

The spectrum of influenza illness, as I mentioned, can be mild to more severe and complicated. For most seasoned clinicians it’s very easy to spot influenza. It usually typically occurs with a sudden onset of a fever, cough and myalgias, which is fairly dramatic enough that many people can actually tell you within an hour of when their illness started.

Other common symptoms include headache, chills, marked fatigue and lassitude, loss of appetite and on occasion sore throat. And when one sees influenza, it’s very easy to see how that is different from the usual kinds of respiratory illnesses that frequently occur during the winter season in Canada.

So, is influenza serious? It is very serious. This is an illness that lasts much longer than a typical upper respiratory tract infection caused by cold viruses, and can last upwards of a week and a half to two weeks in some cases. And severe illness can occur.

We recognize that serious complications related to influenza can occur in groups that are at particular high risk, and those include pregnant women and women in the immediate postpartum period, infants and young children, particularly those under age five, older adults over age 65, and adults and children who don’t fit those age criteria but suffer from a number of chronic health conditions, probably the most typical one that is commonly seen is diabetes.

Those that reside in nursing homes and other chronic care facilities are at risk, not just because of comorbid illnesses and age but because of their proximity to each other. And then lastly, we recognize – and this has occurred throughout the world – that Indigenous peoples suffer significant more morbidity with influenza illness than non-Indigenous individuals.

So that susceptibility and the risk for serious illness can be related to a number of those host factors, which include their living conditions as well as just the risk of serious infection. And it’s estimated in any given season on average there are over 12,000 hospitalizations in Canada per year, and deaths that are close to 3,500.

So when it comes to differentiating influenza and common cold, this is a useful sort of table to look at. Recognizing that in influenza this is a more serious illness. It typically is characterized with a high fever, a significant cough which is often non-productive and which can become severe, and with significant other phenomenon such as headache and myalgias that are very prominent features of the illness. And some patients may in fact, even after recovering from influenza, go on to have significant fatigue and weakness for upwards of two or three weeks.

This is very different from a cold, which almost everybody on this call and on this webinar would be familiar with, which is a mild illness in which there may or may not be fever, a mild cough, some degree of systemic manifestations, but usually things that are relatively mild and easy to deal with. Most people would agree that being off work for a day or two with a cold is actually kind of fun because you get to do other things. But being off work with influenza usually makes you want to be able to be back at work, because you would rather face that than actually have the influenza.

A nice way to look at it is this little thing I put together which shows the difference between influenza and a cold using trains. One of them is clearly a real locomotive and the other one is simply Thomas the tank engine. So influenza is a particularly severe illness. And when people get influenza, they then begin to understand why we take it so seriously and why it’s an important disease to prevent.

Influenza certainly burdens particular age groups. I’ve already mentioned those over age 65 as well as children under the age of five. And what we recognize even amongst groups is that certain strengths of influenza, including influenza A H3N2 strains which circulate seasonally, preferentially seem to affect with significant more morbidity and mortality those over age 65.

Influenza B also occurs in varying patterns which I’m going to talk about in a second, and they have a particular problem in terms of the burden of illness being higher in younger children. And what you can see in this graph is sort of the last three seasonal influenza seasons, and what sort of happened in terms of the rates of hospitalizations amongst those age groups. And you can see that in the 2015/’16 season it was an H1N1-predominant strain. In 2016/17 it was H3N2, and then last year it was a mixed season of B and H3N2.

So how can influenza be prevented? Well, what we know is that annual influenza vaccination is the least-expensive, longest-lasting and most-effective way to prevent influenza and/or its complications, and certainly can decrease the severity of symptoms. In addition, there are lots of good health practices which I think many of you, especially those who work in public health and infection prevention and control know about, proper hand washing, cough etiquette, making sure that when people are sick they stay home and don’t come to work and transmit it to others, as well as some things like the control of infectious particles which may be on touch surfaces, less of an issue with influenza and more so with other viruses.

Dr. Gemmill is going to expand more on the influenza vaccine, but we know that the influenza vaccine can be effective. Its effectiveness however varies with a number of things, which Dr. Gemmill’s going to talk about. And I’ve included in here the last bullet point about mutations that arise during vaccine production.

There may or may not be questions related to the fact that we are really looking for the technology to improve our influenza vaccination. But for now, this is our chief strategy and the most important strategy in terms of preventing influenza illness and/or serious outcomes that has a public health benefit.

This is just sort of a schematic, for those of you who are unfamiliar, that any given season there can be a mix of viruses, influenza viruses that are causing seasonal influenza. This graph shows that, for instance, back in 1990/’91 it was primarily an influenza B season. In ‘93/’94 it was mainly an H1N1 season.

And then in other seasons they may be mixed where there’s a contribution from a number of different viruses, like initiative ‘92/’92, if you look at the UK data, all three viruses were playing a role. And that’s part of what makes it a little bit difficult to sort of predict or expect what’s going to happen, because than can change. And although we learned from the southern hemisphere’s experience, that can sometimes be different in the northern hemisphere.

This results in differences between what is in an influenza vaccine in the way of an antigen, and that can result in some problems with mismatches. And this is a graph that shows data from way back to 1980 all the way up to about 1998 that shows, if you assume that that horizontal line is about 70% effectiveness, in the seasons where it matches it works well and in seasons where it doesn’t match it doesn’t work well.

So on that point, it’s a good segue into further discussion. I’m going to turn it over to my co-presenter, Dr. Gemmill, who’s going to talk about the NACI recommendations on seasonal influenza vaccine.

Dr. Ian Gemmill: Well thank you, Dr. Evans, and I trust that everybody can hear me alright. I want to thank the National Collaborating Centre for Infectious Diseases for the opportunity to present on the recommendations from the National Advisory Committee on Immunization for the 2018/2019 influenza season.

I’ll be presenting the main changes that are going to be listed in the document that can be found on the website for the Public Health Agency of Canada and NACI’s website. And also, please note that the vaccines that are available through provincial programs may not include all of the vaccines that I mention today, depending upon the East Provinces’ Program.

So NACI has been providing rigorous expert and evidence-based advice on vaccines for over 50 years. It’s an external advisory body to the Public Health Agency of Canada that makes recommendations on the optimal use of vaccines to protect Canadians. It’s a diverse expert committee comprising a number of different specialists that are listed for you there, and representatives from national professional associations, as you can see.

Recommendations are made based on NACI’s evidence-based process which broadly involves evidence gathering, synthesis and translation of evidence to guidance. And every year NACI issues a statement on seasonal influenza vaccine that helps healthcare providers understand the optimal use of this vaccine, the various formulations that are available in Canada based on the most up-to-date data available. And please note that the chapter on influenza in the Canadian Immunization Guide and this statement are one and the same document.

So what’s new for 2018/2019? The first issue that has been identified is the literature review that’s been conducted for people with neurological conditions. Based on an updated literature review, NACI has reaffirmed its recommendation that children and adults with neurological and neurodevelopmental conditions are groups for whom influenza immunization is particularly recommended. So they joint that list of people with chronic diseases.

This literature review found that the body of evidence is suggestive of a relatively high burden of pre-existing neurological conditions in children and adults who experience serious pandemic and seasonal influenza-related complications, such as hospitalization, admission to ICUs and death. And these neurological conditions include neuromuscular, neurovascular, neurodegenerative, neurodevelopmental and [senior’s] disorders.

What’s not included in the group of neurological conditions are conditions such as migraines and psychiatric conditions without neurological impairment. And this literature review was published in May of 2018 and the web link is provided for you on this slide.

The second issue is the choice of vaccine formulations for persons age 65 and older. And this group is important because they are more like to – as you all know – to develop the complications of influenza, and yet the vaccine often has a lower efficacy in this population.

Manufacturers have focused some of their efforts on developing a vaccine that provides better protection. And there are a number of vaccines that have been developed for this purpose, but the new one for this year is Sanofi’s high-dose vaccine, which contains 60 mcg of each of the components. This is a trivalent vaccine so it’s against two As and one B, as recommended by the WHO.

So these recommendations are based on the updated literature review, and through that NACI concluded that there is no substantial change in the conclusions to be drawn from the scientific literature. But what is different is that NACI has updated it recommendation wording on the choice of vaccine for this group. And it’s going to, as you’ll see in a moment or two, depend upon how the vaccine is being used or provided, whether it’s through individual recommendation to an individual patient or through programmatic situations where the provinces are providing vaccine to the population.

So, NACI has updated its recommendation, and it’s based on how this vaccine is provided, as I mentioned. For the programmatic level, that’s provinces and territories making decisions for publicly-funded immunization programs, as opposed to the individual level. So this is an individual wishing to prevent influenza in themselves or a clinician wishing to advise an individual patient. And these two recommendations are different because the cost benefit of vaccines must always be considered in provincial programs but may be less relevant when an individual is deciding, for example if the high-dose vaccine is not provided in their province, they’re deciding whether they are going to buy it for themselves.

Further, without data on the relative efficacy and effectiveness between high-dose trivalent vaccine, MF59-adjuvanted trivalent vaccine and quadrivalent vaccine, there’s insufficient evidence to make a comparative recommendation on the use of these vaccines at the programmatic level. And that’s a Grade I recommendation, IE, insufficient evidence. And therefore, at a programmatic level NACI recommends that any of the four vaccines available for use in adults age 65 years of age and older may be used. That’s standard-dose TIV, high-dose TIV, MF59-adjuvanted TIV or QIV.

This process allows provinces to decide which vaccine to purchase for their population. Some provinces will decide to pay perhaps a premium for a vaccine that they believe may provide a higher relative vaccine efficacy, while others may stay with a standard dose. And, for example, in Ontario they have decided to offer high-dose TIV exclusively for people aged 65 years of age and over.

So the choice of vaccine here, as mentioned, high-dose TIV is expected to provide superior protection to standard-dose TIV, based on the evidence that NACI has reviewed on this. So for individuals NACI recommends that high-dose TIV should be offered over standard-dose TIV to persons aged 65 years of age or older.

In provinces in which high-dose TIV is not offered in the publicly-funded program, individuals may decide to pay for a vaccine that probably will have a higher VE but which is trivalent rather than quadrivalent in its formulation. The difference in these two approaches allows provinces to make decisions based on their populations, taking into consideration their assessment of the cost benefit, while for individuals the data suggests that there may be better protection but only against these three above-mentioned strains.

So here are the general recommendations for the use of influenza vaccine for 2018/’19 which have not changed except for the addition of, or the comments I’ve already made on neurological conditions. NACI recommends influenza vaccination for everyone aged six months of age and older who does not have a contraindication to the vaccine, and also for the standard groups that are particularly identified for this vaccine, including those with a risk of complications or hospitalization, people capable of transmitting influenza to those at risk, that’s household contacts of infants for example, or care providers of young children or people who have high risk of influenza complications, people who provide essential communities services and people in direct contact with poultry infected with avian influenza during culling operations.

So just to summarize, anyone who wishes to reduce their risk of influenza should consider receiving their vaccine. The rationale for people who provide essential services is that the community does not want to have too few people to provide those services in a large outbreak. And the rationale for those who cull poultry is to prevent the theoretical risk of a reassortment of a seasonal virus in a human with a new strain of poultry which then may lead to the emergence of an aggressive strain.

So, this is a list of chronic medical conditions that are indications for influenza vaccine, and they have not changed except for the neurological conditions already mentioned. And it’s really important to understand the influenza infection can lead to the worsening of these pre-existing conditions.

Why pregnant women? There is now good evidence that women who have influenza during pregnancy have worse outcomes than women who are not pregnant. The risks are not great, but they are true relative risks. In addition, infants born to women who have had influenza in pregnancy do worse than other infants. Therefore not only is influenza vaccine safe at all stages of pregnancy, but pregnancy is in fact an indication for immunization.

In addition to protecting the pregnant mother against influenza, these women who are vaccinated against influenza will pass on antibodies that will help to protect their newborns in utero. Antibodies provided to the newborn via breast milk will also help. And if the mother does not contract influenza she will not transmit it to a newborn. And therefore NACI recommends the inclusion of all pregnant women at any stage of pregnancy to be recipients of influenza vaccine.

Why older adults? Well, due to immunosenescence – so that’s the aging of our immune system – adults age 65 years of age and older are at greater risk for serious influenza-related complications. While the severity of influenza varies from season to season, the burden of severe influenza disease, including hospitalization and death, is greatest in this group, as you all are aware. And in particular, influenza A, the N3N2 strain, disproportionately affects older adults in terms of hospitalizations and death compared to younger age groups. And so, therefore, persons over the age 65 have been recommended to have influenza vaccine for decades for this reason.

And why young children? Well, children younger than the age of five, particularly those younger than two, are at increased risk of influenza-associated complications, as has been demonstrated in the literature. Children younger than age two account for about a third of the hospitalizations reported by IMPACT, the monitoring program run through the Canadian Paediatric Society.

And although pediatric deaths due to influenza remain mercifully rare, some children still die from influenza infection every year in Canada. For all of these reasons, influenza vaccine continues to be recommended for younger children. Finally, influenza vaccine is less immunogenic in infants less than six months of age and does not provide sufficient protection against influenza, which is why the vaccine is not indicated for or recommended in this group.

So, there are two important reasons why annual influenza immunization is needed. First, the body’s immune response when vaccination diminishes within a year, and the circulating influenza viruses change frequently necessitating annual change in influenza strains. Children age six months to nine years of age receiving seasonal vaccine for the first time in their life should be given two doses with a minimum interval of four weeks in between the doses. And the reason for that is that children under the age of nine need priming, and once the priming has been done it need not be repeated.

And so, therefore, children who have been previously immunized with seasonal influenza vaccine, and adults, need receive just one dose of influenza vaccine each year. So, older adults do not need to be primed as it is assumed that they will have been exposed to influenza naturally by age nine.

As mentioned by Dr. Evans, over time antigenic drift of strains occurs within influenza A subtypes or B lineage. And this constant changing of circulating viruses requires seasonal influenza vaccines to be reformulated annually. And just to remind you, antigenic drift are the minor antigenic alterations to the influenza virus surface proteins, hemagglutinin and neuraminidase, which can lead to decreased efficacy.

The influenza vaccines in Canada for this season contain strains recommended by the World Health Organization last February. And in the trivalent vaccine there will be A/Michigan for H1N1, A/Singapore for H3N2 and B/Colorado for the B/Victoria lineage. And in the quadrivalent vaccine is added the B/Phuket-like virus which is from the Yamagata lineage. This year there will continue to be trivalent formulations of influenza vaccine, although the movement is towards quadrivalent formulations.

So anyway, just going back to the influenza vaccines available in Canada, the second column are the various products of each type that are licensed and marketed. And in the third column are the indications by age for each vaccine formulation, which may vary by product.

In addition to the regular vaccines, such as the TIVs and the QIVs, there are specialized vaccines, as we’ve already mentioned, for those over 65, the adjuvanted and high-dose, and also special formulations for nasal spray as an example. This table is for your reference.

And please note that not all products will be made available in all jurisdictions, and that the availability of some products may be limited. The decision to include specific influenza vaccines is part of a publicly-funded program. It depends on a variety of factors in each province that we have already talked about.

And this chart, also for your reference, shows the recommended formulations for each age group. For children, NACI recommends quadrivalent vaccine or trivalent vaccine as there is a greater burden of influenza B in this age group, and we’ve already mentioned the mismatches that have occurred.

For adults age 65 years of age and over, due to the increased burden with H3N2 in particular, and good evidence of better efficacy of high-dose TIV compared to the standard dose, NACI is recommending that the high-dose TIV for individuals should be offered over the standard dose.

And for LAIV for children age two to 17 years, after careful review of the available vaccine efficacy data from various countries, including Canada, over the last several seasons, NACI has concluded that the current evidence is consistent with LAIV’s providing comparable protection against influenza to that afforded by inactivated influenza vaccines. Previous studies and clinical experience also indicate LAIV to be safe, but the current evidence does not support a recommendation for preferential use of that vaccine in these children.

A word about contraindications; all influenza vaccines are contraindicated for people who have had an anaphylactic reaction to a previous dose or to any component, with the exception of egg. Egg allergy is not a contraindication for influenza vaccine with any formulation. Allergy to egg protein was considered a contraindication on theoretical grounds until recent when it was shown, first of all, that the amount of egg protein in the vaccine is insufficient to cause as severe allergic reaction.

And then, observations in persons, over the last several seasons, with severe allergic reaction to egg protein did not have a reaction to the vaccine that was severe or life-threatening. And several seasons of post-marketing safety surveillance in Canada have shown that egg allergy does not appear to be associated with a greater proportion of spontaneous reports of anaphylaxis or allergic adverse events following immunization with influenza vaccine.

LAIV is contraindicated for children less than 24 months of age, and that’s because of the increased risk of wheezing, individuals with severe asthma or those with medically-attended wheezing in the seven days prior to immunization. And severe asthma is defined as currently on oral or high-dose inhaled glucocorticosteroids or active wheezing. But LAIV is not contraindicated in people with stable asthma or recurrent wheezing.

Next, pregnant women, because it’s a live attenuated vaccine and there’s a lack of safety data at this time, and the same for people with immune-compromising conditions.

So, a word about influenza vaccine safety; these vaccines are safe and well tolerated. With the I’m administration injection site reactions are common but generally mild and transient. With a nasal spray, commonly there is rhinitis and congestion, which again are more trivial types of events following immunization. Serious adverse events are rare, and in most cases data are insufficient to determine a causal association. And the safety of influenza vaccines in Canada is continuously monitored by the Canadian Adverse Events Following Immunization Surveillance System. It’s important to understand that any medical intervention has risks, but the vaccines, including influenza vaccines, are monitored carefully and they are amongst the safest of interventions that people are offered.

The risk of potential adverse events associated with influenza vaccination again must be balanced against the risk of influenza infection itself, and all the other benefits of the immunization. So, for example, the risk of Guillain-Barré syndrome following influenza vaccine is approximately one additional case per million doses of vaccine administered. But Jeff Kwong and his group in Toronto have shown that the risk of GBS following immunization infection itself is 10-fold greater.

So what can you do as healthcare providers? To help prevent the spread of influenza it is recommended that we all receive our annual influenza vaccine to help to prevent transmission to patients. Use every opportunity to vaccinate people at risk, even after activity has been documented in the community to discuss the risks and benefits of the vaccine with patients, as well as the risk of not being vaccinated, and then to remind people about all those other good things that Dr. Evans has previously mentioned.

Do remember that as a healthcare provider your patients trust your recommendations. You are a key driver for vaccine uptake. And the recommendation of a healthcare provider is one of the most important reasons that people are immunized. Being immunized ourselves not only decreases our own risk but also demonstrates to our patients that we believe in this vaccine.

Finally, just a word about the implications and low vaccine effectiveness; existing influenza vaccines are by no means perfect but they are, as Dr. Evans has said, currently the best available line of defence against influenza. And even when there’s a less-than-ideal match or a lower VE against circulating strains, the possibility of that lower VE should not preclude vaccination, particularly for people at high risk of complications.

There have been some reports about decreased efficacy of the vaccine, and even that the receipt of vaccine in one season may lead to decreased efficacy in the following year’s vaccine. It’s still important to remember that people who are immunized are still more likely to be protected against influenza for those who are unvaccinated, and that the protections against several different strains and that in milder illness may occur even if one does contract influenza.

And then the other protective measures such as antiviral treatment and the non-pharmaceutical practices you’ve already heard about. And that mention of antiviral treatment then is a nice segue back to Dr. Evans who is going to tell you more about antivirals. Thank you.

Dr. Evans: Thanks very much, Ian. So I’m going to just kind of quickly go through a little bit of our antiviral recommendations for seasonal influenza. And many of you know that we have been, as a specialty society of ID specialists and microbiologists, have been producing guidelines a fair bit.

Back in 2005 we started to look at the whole role of antiviral therapy for seasonal influenza and ended up publishing a guideline that next year. And then we’ve been revising and updating it and eventually in 2013 we created a foundation document. And right now we’re working on actually revamping the foundation document and that’s currently in review for publication. And many of you know we’ve also issued some statements to sort of back it up.

This is just a membership of a committee I want to acknowledge, my AMMI colleagues who have worked on this committee. We this year brought in a couple of new members, Dr. Mubareka from Sunnybrook and Dr. Papenburg from McGill, to sort of help us expand on the development of a new guideline document.

I’m going to really quickly go over the general principles from our antiviral guidance. I’m going to talk about treatment of non-pregnant adults, and talk about the difference between those with mild or uncomplicated disease and those who have moderate progressive severe or complicated; same thing for the treatment of infants, children and youth. And then we’ll talk about what you do with immunocompromised patients, pregnant women obviously, and then I think into the areas that I get most of the questions about, or our group gets most of the questions about, which is what to do in terms of chemoprophylaxis, post-exposure prophylaxis early versus early therapy, and even a little bit about pre-exposure prophylaxis.

So our document used a grade system to sort of look at where we made recommendations, strong recommendations, what we call an option, and sort of looked at the issue of either preponderance or balance of benefit or harm to make those decisions. So you can put those into context and you can see the quality of evidence that was used to support these recommendations.

So, general principles about antiviral therapy for influenza is that, if you’re going to use an antiviral you should initiate that treatment as rapidly as possible. Initiation at less total hip arthroplasty 12 hours is probably even better at less than 48 hours. And 48 hours is the typical cut off that’s used for most of the manufacturer-approved regulatory requirements. And that’s because it works better when you start it earlier.

However, antiviral therapy should be initiated even if the interval is longer than 48 hours if you’re dealing with someone whose influenza illness is severe enough to require hospitalization, if they have what appears to be progressive severe or complicated influenza, regardless of their previous health status, and/or if it’s an individual from the group that’s at high risk. So, and you’ve seen the list of the people who are at high risk for serious progressive or complicated influenza.

In healthy people, there’s not really likely to be a benefit from using the current neuraminidase inhibitors that are out there. So we are not advocating that all people with influenza should be treated. And if it’s mild, self-limited and that person’s healthy, you could really argue that it’s probably not going to be of benefit, and particularly should not be initiated if it’s more than 48 hours of illness onset.

If you don’t give your patient antiviral therapy, we advise that you talk to them and speak to them about symptoms and signs of worsening illness that may warrant a reassessment. And generally speaking, treatment duration for the current neuraminidase inhibitors for antivirals should be five days and not longer. There was a lot of discussion during 2009 about longer courses of therapy for people who are hospitalized, but that data has not really suggested that that had any appreciable benefit for the added cost or exposure to antiviral drugs.

So very quickly, in non-pregnant adults with mild or uncomplicated disease you can consider using an antiviral for their influenza if it’s less than 48 hours’ duration. But if it’s more than 48 hours since their illness started it is not generally recommended you treat them.

If they have risk factors however, even with mild disease, we suggest that you consider giving them, initiate antiviral therapy immediately if their illness duration is less than 48 hours. If it’s more than 48 hours you can consider it sort of on a case-by-case basis, and we’re still a little bit iffy in the setting of a mild influenza illness in somebody with risk factors.

This is a little algorithm that just kind of lays out what I just finished saying. And you can see that basically, in a non-pregnant adult with mild or uncomplicated disease you’re really looking at the risk factor initiation and the time interval.

If we look at non-pregnant individuals however who have moderate, progressive, severe or complicated illness, there’s a number of things that we recommend. One is the consideration for hospitalization and, if necessary, admission to an Intensive Care Unit. Also, Tamivir should be started immediately. That should be started even if the interval between symptom onset and that administration is greater than 48 hours.

Using Zanamivir, inhaled Zanamivir instead of oral Oseltamivir should be considered just in the settings where we might expect to see Oseltamivir resistance. And so those would be people who are not responding to Oseltamivir, people who have been on prophylaxis and are still ill, or if influenza B is present, simply because Zanamivir’s activity against influenza B is greater than that of Oseltamivir.

This kind of lays what we’re talking about in the non-pregnant adult with moderate, progressive, severe or complicated disease. And you can see the recommendations there that I’ve just summarized.

In infants, children and youth again with mild or uncomplicated influenza, it’s important to recommend that neuraminidase inhibitors are not currently approved in Canada for those under age one year. And consideration of use in them should be made on a case-by-case basis, and you may wish to consult either a neonatologist, pediatrician or a pediatric ID person if you’re considering that, and they can help to provide advice.

In those under five, because they’re classified as a high-risk group, if they are otherwise healthy and have mild disease that doesn’t require hospitalization, we’re not routinely requiring antiviral therapy and we consider it an option. And for those over age five who are otherwise healthy with mild disease not needing hospitalization it is not routinely recommended, principally because they are the group that usually do reasonably well.

In terms of timing, if the illness duration is less than 48 hours, Oseltamivir or, if they’re able to take it, inhaled Sanamivir – it does require a person or a child or a youth who can work the inhaled device – can be considered. If it’s over 48 hours it should be considered on a case-by-case basis.

For infants, children and youth with moderate or progressive illness, with or without risk factors, again it’s very much like the adult recommendations around hospitalization, potential admission to ICU if its warranted. Treatment should be started immediately with either Oseltamivir or Zanamivir, and even if the interval is greater than 48 hours. Again with the same recommendations around treatment with Zanamivir if you’re dealing in a circumstance where you expect there is a small possibility that Oseltamivir resistance may be present, because Zanamivir is effective in those influenza viruses which have mutations which confer Oseltamivir resistance. And the last bullet point is already on the previous slide.

This is our algorithm. And when it’s published we’ll certainly let people know. It is in our foundation document if you go back and look at that reference to look at this table, because it doesn’t come across well obviously on a slide, being slightly bigger.

For immunocompromised patients, our recommendation is to treat as soon as possible without any regard to the duration of illness. So this 48-hour window is kind of thrown out the window here. It’s simply because we know, at least based on our experience from the 2009 pandemic, that these patients did seem to benefit if they were started on treatment and given antivirals.

Early initiation therapy is preferred in immunocompromised patients over post-exposure prophylaxis. So, although prophylaxis is effective with neuraminidase inhibitors, we feel that it’s probably better to consider just, if you have a patient who’s been exposed to influenza who is immunocompromised and you have concerns about initiation, that they should just be informed and perhaps given a prescription, which they can initiate should they develop symptoms early, rather than just giving them post-exposure prophylaxis.

The other issue has been presumptive therapy. If you have an exposed, susceptible and profoundly immunosuppressed individual who is at very high risk of complications, you may want to consider presumptive therapy even before they develop the symptoms of illness. But the evidence to support that is not very good and it’s really considered an option.

For pregnant women, as has already been stated by Dr. Gemmill, the association between pregnancy and the immediate four-week postpartum periods with an increased risk for severe influenza has been well documented. We know that Oseltamivir is a safe drug inherently given to pregnant women, at least based on observational data from the 2009 pandemic. So Oseltamivir in the standard doses that you would use is recommended for the treatment of women who develop influenza during pregnancy, or up to four weeks postpartum. And that’s a fairly strong recommendation with not the greatest evidence but some good evidence.
Pre-exposure prophylaxis versus early therapy; early therapy is preferred over any kind of routine seasonal pre-exposure prophylaxis. Any early treatment strategy should involve counselling with arrangements for contacts to have medication on hand, so that’s the sort of presumptive prescription that a physician or other prescriber could give the patient along with instructions.

Selective prep – that is giving pre-exposure prophylaxis – can be considered in an attempt to bridge people who may have problems with vaccine-induced immunity, because there’s about a two-week period or so until the vaccine’s effectiveness kind of comes on board. In people who are high-risk where vaccination is contraindicated, protection of patients at high risk and their close contacts, if there’s a poor seasonal influenza match. Sometimes we have that data by the time we get them to the mid part of the season. And then very rarely for protection of family members or healthcare workers in whom influenza immunization is contraindicated, Dr. Gemmill’s pointed out that’s an uncommon event and are likely to have ongoing close exposure to unimmunized persons at risk.

Post-exposure prophylaxis, as I’ve already mentioned, early therapy is preferred over PEP in this circumstance due to the concerns about drug resistance. There are some times when you can consider post-exposure prophylaxis. Probably the one with the strongest recommendation is about controlling outbreaks in closed facilities combined with treatment and vaccine administration.

Early treatment or PEP should not be prescribed to groups of healthy individuals who may have an exposure in the community if that close contact occurred but did not occur during the infectious period or more than four days have elapsed since that last infectious contact. Again, we have an algorithm which lays out what I’ve just said in a sort of algorithmic form that some people may find useful, and I’ve highlighted in red those recommendations.

Lastly, I’m just going to finish by talking about what do you do with antiviral drugs in the potentially low vaccine efficacy season. And antiviral therapy we still believe can be considered for individuals at high risk of serious influenza complications in a season where there’s a poor match. But the evidence to support that is not particularly strong, and we are incorporating our recommendation by grade in the new document.

Where influenza is clinically suspected, antiviral treatment of high-risk individuals should be initiated as soon as possible, ideally within the first 24 hours, even if they have received influenza immunization. And that’s because of that issue of potential mismatch.

And then finally, antiviral prophylaxis for the control of influenza outbreaks in healthcare facilities, long-term care, nursing homes etcetera should be done at the discretion of the local medical officer of health, and could include staff, simply because we may not be as confident about the protection that we’re getting when an outbreak occurs in that particular setting.

So I’m just going to turn it over to Dr. Gemmill for a last summary of key messages and some resources about seasonal influenza prevention and control.

Dr. Gemmill: Well thanks, Dr. Evans. And in the interest of time, we have some questions that have been posted, so I just want to say very quickly that influenza vaccine is the most effective way to prevent influenza. You’ve already heard that from both of us. Everyone six months of age and older may get the vaccine, but particularly if they’re at high risk for complications. It’s important to get immunized every year because of the lack of effectiveness probable after one year, and the change in the virus.

This vaccine protects against several different flu viruses, three in the case of trivalent and four in the case of quadrivalent. And even when there’s lower effectiveness against one strain, the vaccine can still provide protection against the remaining strains. And you’ve already head several times about the other ways of preventing influenza.

So I just want to provide you with this list of resources, NACI’s Statement of Seasonal Influenza Vaccine which the material I’ve taken has come from, AMMI’s guidance on antiviral drugs. Then there’s the Seasonal Influenza Awareness resources at Canada.ca and the weekly flu watch Influenza Surveillance Reports, which I guess we all should be having a look at every week to see what’s going on.

So thank you very much, and I guess it’s time for questions and back to Alexandra.

Alexandra: Thank you very much, Dr. Gemmill and Dr. Evans. We have a few minutes for questions. So a number of questions have been posted in our chat pod. If you still have a burning question for our experts, please do post your question right now and we will try to get to them.

A first question that I would like to pose is why was high-dose TIV made as opposed to high-dose QIV?

Dr. Gemmill: It’s Dr. Gemmill here. I’m looking in the chat box and I think Dr. Evans did answer this quite accurately, which is to say Sanofi did their clinic trials using a trivalent vaccine, and that’s why it’s the one that’s licensed. I haven’t heard from Sanofi whether they’re going to be doing a quadrivalent vaccine. But since we’re moving to quadrivalent vaccines in general – and this is to guard against the mismatches in disease that have occurred regularly over the last decade or so – I would not be at all surprised if we will see a QIV high-dose vaccine at some point in the near future.

Wierzbowski: Okay, thank you very much. A similar question, if an adult 65 years or older already received a QIV, should they go back and get a high-dose TIV?

Dr. Gemmill: Well, I think the answer to that question is, for most provincial programs, for those people over 65, you’re allowed one dose of vaccine. And this is an interesting question because one could argue let’s get as much protection as we can with a quadrivalent vaccine against four, and then the high-dose against the three remaining since it’s not a quadrivalent.

I think that the idea here is that one should get an influenza vaccine. and it would not be, I think, generally recommended that people who have had a dose, a legitimate dose of influenza vaccine should go back now. If you’ve had the quadrivalent vaccine you won’t get necessarily that relative vaccine efficacy. It might be as much as 30%, so that’s a little bit you’ve lost there. And if you get the high dose only, which is trivalent, then you may have a risk of being exposed to the influenza B, the B-Phuket that’s not in the vaccine.

And I think these are basically risks that we take. So my suggestion would be that people should not be going back for a supplementary dose.

Wierzbowski: Okay, great. Thank you very much. A question for Dr. Evans, you spoke about who should be prescribed antiviral medication, but a question came up about resistance. Should clinicians be concerned about antiviral resistance?

Dr. Evans: At this point, absolutely not. The incidents of Oseltamivir resistance in seasonal influenza strains – and this is looked for prospectively – is still very, very low. The mutations that confer resistance Oseltamivir we know can be present, but they’re not currently circulating amongst the N3N2 and H1N1 strains that cause most of our seasonal influenza.

So at the moment, your probably biggest clue to the presence of Oseltamivir resistance and when you should be worried is somebody who maybe got the flu while they were receiving Oseltamivir, and/or someone who you have on Oseltamivir who doesn’t appear to be responding and you don’t have another reason why things are getting badly, or they’re not doing well in the ICU or in the hospital.

So don’t worry about resistance at the moment. It’s still not a big problem. We really worry resistance mostly in potential pandemic strains, which fortunately have remained quiescent.

Wierzbowski: Okay great, thank you. A subsequent question is regarding prophylaxis. Should healthcare workers be prophylaxed if significantly exposed and refuse vaccination?

Dr. Evans: Well, this is probably one of the most controversial questions. So, if you’re a healthy person and you’ve been exposed to influenza and you don’t have risk factors etcetera, you may develop a milder, uncomplicated influenza illness. So the benefit personally of taking prophylaxis may not be huge.

The issue does come up though, what do you do with people who refuse influenza immunization and they may have had an exposure. And again, I think this underscores where we sort of cross over into the line of what is our personal responsibility as healthcare workers to make sure we do everything we can to protect ourselves.

Certainly during the 2009 pandemic we were using antiviral agents for post-exposure prophylaxis in that setting so we could maintain healthcare workers interest he environment. But that’s, you know, something that, you know, when you actually have an available vaccine, why would you sort of necessarily do that? If the healthcare worker though has risk factors then, yeah, post-exposure prophylaxis is probably warranted, but not because they’re a healthcare worker but simply because they’re at risk for more severe, progressive influenza.

It’s a tough question to really answer because it tends to sort of give an out for the idea that this is an alternative to immunization. And I would still really push the idea that immunization is the best mechanism for prevention. The reasons to not take it that are I would say scientifically or medically legitimate are very few, and so in most cases I would still encourage them to get immunization.

Post-exposure prophylaxis, if it’s going to happen it’s going to happen probably with their own payment or pocketbook. I don’t know that the system should necessarily provide that. That might be a controversial statement, but that’s my opinion.

Wierzbowski: Okay, great. A further one more question regarding prophylaxis. Could you please speak to the duration of prophylaxis in the event of a closed facility outbreak?

Dr. Evans: Great question, another one that we get asked very frequently. So typically, if there’s an outbreak in a closed facility, people are being given post-exposure prophylaxis because they haven’t had time to, you know, get all the immunizations on board. It’s typically done for about a period of 10 to 14 days, assuming that the person, at the same time that the post-exposure prophylaxis is initiated, they’re given their immunization, because that should give them protection, bridging protection while we wait for vaccine efficacy to kick in.

Wierzbowski: Okay great, thank you. I have a question regarding child’s first vaccination. If in a child’s first vaccination season they are not provided with two doses for priming but only one dose, would it be recommended for them to receive two doses in the next influenza season, or continue to receive a single dose?

Dr. Gemmill: My understanding is that first dose will count as a priming, so that they could get the one dose the next season. And so I think that is the way to manage it. But the best way of doing it of course is to provide the two doses in the same season because there may be a slight change in the vaccine, as we’re all aware.

Wierzbowski: Okay, thank you very much. Well, this is all the time we have for today. There are many questions that unfortunately we’re not going to be able to get to. On behalf of NCCID and the Public Health Agency of Canada, I would like to thank all our speakers for an informative presentation.

Questions and Answers

1. Is there a specific influenza vaccine recommended for pregnant women?

a. NACI recommends that all pregnant women be immunized against influenza, regardless of the stage of pregnancy

b. Pregnant women may receive any of the formulations that are licensed for adults aged 18-59, except that LAIV (live, nasal spray) is contraindicated because it is a live vaccine. Live vaccines are normally contraindicated in pregnancy because of the theoretical risk to the foetus.

c. The vaccines that may be used are any inactivated TIV or QIV

2. If an adult 65 and older already received a QIV, should they go back and get high-dose TIV?

a. Individuals normally should receive a single dose of influenza vaccine each year. The exception is children < 9, who have never received influenza vaccine and who therefore need to be primed

b. While there is likely no harm in receiving more than one dose of vaccine, NACI has not made the recommendation for seniors to receive both QIV & HD TIV, and provincial programmes are based on one dose per person.

c. Older adults need to decide with her or his physician which vaccine (HD giving somewhat better protection against three strains, or QIV giving standard protection against four strains) is better for that individual. There are arguments for both, but NACI suggests for individuals to use the HD TIV for older adults.

3. Why was a High Dose TIV made as opposed to a High Dose QIV?

This is a question for the manufacturer; presumably the formulation is based on the clinical trials that they designed, which may not have included a formulation with four components.

4. Can you clarify the recommendation for influenza vaccination for poultry workers – is it recommended for all poultry workers who work in culling operations regardless of presence of avian influenza?

a. This recommendation is made only for poultry workers who are culling flocks in which a novel avian strain has been identified. Other poultry workers should be considered along with other adults.

b. The purpose of this recommendation is to prevent the theoretical risk that a poultry worker who is culling a flock with a novel avian strain may have seasonal influenza, and thus a re-assortment to create an aggressive strain that it infectious to humans may occur. The recommendation is highly precautionary & theoretical.

5. How often is Influenza resistant to oseltamivir?

Oseltamivir resistance in seasonal influenza strains is < 1%

6. Should health care workers be prophylaxed if significantly exposed and refused vaccination?

If involved in direct patient care, particularly with patients who are high-risk for severe or complicated influenza, PEP for a HCW following exposure is an option. An alternative is to reassign them to work that does not involve direct patient care of patients at risk.

7. Could you speak to the duration of prophylaxis in the event of a closed facility outbreak? Should it be for the duration of the outbreak or for 10-14 days as per the drug product monograph?

It should be no longer than 14 days; shorter if an outbreak resolves in less time than that.

8. During Influenza Season in a LTC facility, should we wait until we get a positive lab prior to starting treatment and prophylaxis?

Treatment should be started on clinical grounds during influenza season once there is lab confirmation that influenza is circulating in the community. Prophylaxis should only occur, if needed, again when there is confirmation of influenza cases in a facility.

9. Some Long-Term care homes obtain creat cl before prescribing oseltamivir. Is there evidence to support or not support this practice with the elderly in long-term care settings?

Absolutely. Oseltamivir dosing requires modification in the presence of renal insufficiency. The AMMI Canada Influenza Antiviral guideline has a table showing dose modifications in the patients with renal impairment.

10. If, in a child’s first vaccination season, they are not provided with 2 doses for priming but only 1 dose, would it be recommended for them to receive 2 doses in their next influenza season, or continue to receive a single dose without having this priming in place?

a. Any child < 9 years of age who has never received influenza vaccine should receive 2 doses, with a minimal interval of four weeks

b. Although more study is needed on the protection provided when there is a change in the B lineage in the subsequent season, NACI currently recommends that children under 9 years of age who have properly received one or more doses of seasonal influenza vaccine in the past should receive one dose per influenza vaccination season thereafter. Therefore, one dose in a previous season, which is not recommended but may occur, would count as the priming, and the child would need just one dose annually thereafter.

11. Why is the high dose flu vaccine not recommended for people below 65 at high risk? Is it just because studies were not done in this group?

a. Yes, the clinical trials were done on people over the age of 65, as the vaccine efficacy (VE) of the standard vaccine in this age group tends to be lower.

b. Some people have suggested that trials with this vaccine be conducted on younger age groups, as improved VE is needed generally. That decision is up to the manufacturer, as trials have a cost and they likely will pursue it only if there is a reasonable business case for it.

12. Are there more side effects being reported by age 65 and older with high efficiency vaccine?

a. Yes, HD vaccine has more reports of adverse events following immunisation, but they are still deemed acceptable, considering the increased relative VE or this age group.

b. High-dose TIV has been observed to produce a higher rate of some systemic reactions than the comparator standard-dose TIV. Studies have reported higher rates of malaise, myalgia, and moderate to severe fever. Most systemic reactions were mild and resolved within three days. Serious adverse events were rare, and similar in frequency between the standard-dose and high-dose vaccine.

c. Refer to the annual statement on influenza vaccine, section IV (Vaccine Preparations Available for Use in Canada) for the references.

13. Are there any stats on how effective this year’s vaccination is across Canada?

a. The recommendation for vaccine constituents for a given influenza season in the northern hemisphere is made in the February preceding the season by an exert committee at the WHO.

b. It is based on surveillance of the circulating strains worldwide, and is the best guess at what will be circulating in the following season.

c. The licensure of the vaccine in Canada is based on the demonstration of immunogenicity (the ability to induce antibodies) of the current season’s vaccine, as studies on efficacy (how well it prevents illness) cannot be undertaken in the short time frame between manufacture and the start of the season.

d. Whether the vaccine is effective against circulating strains can be demonstrated only during the season, as patients are assessed. It depends on a number of factors, including changes in the organism in the wild, and on the characteristics of the specific vaccine formulation by the specific companies. The VE cannot be determined in advance, and we are to some degree going on faith, based on immunogenicity.

14. Any word on baloxavir becoming available in Canada?

Not yet licenced in Canada. I believe a file is being submitted for NOC.

15. Has there been any more discussion of giving the elderly two doses of vaccine 4 months apart due to their poor uptake or is the high dose TIV the answer to that?

a. The provision of two doses of vaccine to age groups that may have a less than adequate response has been discussed for years. In fact, that recommendation has been made for children < 9 years of age who have never received a previous dose.

b. For practical reasons, this recommendation has not been made for the elderly. First, duration of protection may be variable, and protection may last longer in some seasons. Second, the effort to get just one dose into all of the people at higher risk of complications has to be done every year, and already is a major undertaking.

c. Other strategies, such as immunising people around the elderly has been preferred.

d. If such a recommendation is undertaken, it will have to be based on research that will need to be conducted to support or refute such an innovation.

16. Interested in your thoughts on mandatory health care worker immunization.

Dr. Gemmill:

a. Some people believe that there is an ethical and professional obligation for all persons working in health and long-term care settings should be immunised to prevent transmission from HCWs to their patients. Others believe that HCWs should have control over this issue, and should not be compelled to be immunised.

b. There is demonstrated benefit in long-term care, and probable benefit in acute care settings, which makes the argument more compelling.

c. What makes it less compelling is the variable vaccine efficacy each year. Some HCWs argue that the vaccine does not always work well, so why should they take it. We need a vaccine that has better VE, has activity against all variations in the strains of influenza, and lasts longer.

d. There are benefits to the HCW (decreased risk to self and family from infection from patients), and the vaccine is safe, so there are many good reasons to take it. Some HCWs, however, don’t want to be compelled to take it, despite the benefit to them as well.

e. Some argue that we need to have enough HCWs to provide care in an epidemic year, and one way to ensure it is to require HCWs to be immunised. The vaccine reduces the risk of incapacity of HCWs, thereby maintaining the workforce. Therefore, some believe that the vaccine should be mandated.

f. This issue has been debated for several years; Ontario tried to make it mandatory by regulation, but relented when they were challenged by ambulance workers. Mandating the vaccine is mostly done by institutional policy and not by law or regulation. Arbitrators have largely sided with the employer, but not in every case.

Dr. Evans:

I am personally in favour, but recognize that there are legal and human right issues that make it a problem.

17. When was the last vaccine effectiveness study done & will there be another one done anytime soon?

a. Studies on the vaccine efficacy of annual vaccines are done every year, in many countries, and in several centres in Canada. They are used in considering changes to vaccine formulations for subsequent years. For example, Astro Zenaca spent a lot of effort to increase the VE of LAIV, when it was found to be extremely poor in the USA and the vaccine was removed from the list of recommended vaccines for children.

18. Are you saying if a LTC resident was vaccinated and in an outbreak but have not developed symptoms, then they should be prophylaxed ?

No. Early initiation of antivirals is preferred over PrEP or PEP.

19. What are the side effects ofoseltamavir and zanamivir?

Oseltamivir primarily causes GI AEs, primarily nausea & vomiting in about 10-15% of individuals. Neurologic AEs (i.e. seizures, abnormal behaviour, etc.) are described, but more frequently in children < 2 years of age. Zanamivir can cause dizziness, cough and wheezing, which can lead to exacerbations of asthma or COPD in about 5% of patients.