At the end of 2018, we remember and respect Influenza, 100 years after the great pandemic

The Mother of All Pandemics
In the 1918-1919 calendar year, the world experienced the worst influenza pandemic in modern times. Coming on the heels of WWI, the H1N1 pandemic occurred in three waves – in the spring of 1918, fall 1918 and spring 1919. Estimates suggest that the pandemic infected a third of the world’s population, with 50 million people dying worldwide, including 675,000 Americans. Mortality was high at extremes of ages, but what sets this particular pandemic apart was the significant mortality (over half of all deaths) in young, healthy 20-40yr olds. Why such devastating morbidity and mortality? Perhaps a combination of war-ravaged, crowded conditions, malnourishment, inadequate healthcare resources (many doctors/nurses were deployed at war), and poor hygiene. In the early 20th century, there were no influenza vaccines to prevent flu or lessen its symptoms; no antivirals to help reduce transmission; no antibiotics to treat post-influenza bacterial pneumonia. The Smithsonian National Museum estimated that the total death toll of the 1918 pandemic outnumbered military deaths in both World War I and II. You can watch a video created by the CDC about the 1918 pandemic here. This avian-origin H1N1 pandemic has been called “The Mother of All Pandemics”, setting the stage for all of the subsequent epidemic and pandemic strains of influenza we have experienced.

After 1918: Influenza still deadly, though not as devastating
In 1957-1958 an H2N2 avian influenza virus caused a pandemic resulting in 1.1 million deaths worldwide including 116,000 Americans. 10 years later, another avian-based virus H3N2 triggered a similar sized pandemic with 1 million deaths worldwide and 100,000 Americans. The H3N2 still circulates as a seasonal flu virus and is included in seasonal vaccines. The next major pandemic was triggered by a novel influenza A virus called H1N1pdm09 in 2009, originating in the United States. By this time, seasonal influenza vaccines had included H1N1 but this variant was completely different from the seasonal flu vaccine, resulting in an estimated over half million deaths worldwide and up to 18,000 Americans.

Today: There is still work to be done
Since 2009's pandemic, seasonal influenza is still prevalent, with an estimate of over 291,000-645,000 deaths from seasonal influenza worldwide. The highest mortality rates are in poorer, developing countries, with individuals at extremes of age being most vulnerable to death from seasonal influenza. We still do not have a universal influenza vaccine, though research is moving in that direction. The 2017-2018 influenza season brought a serious influenza epidemic, with 48.8 million illnesses, 959,000 hospitalizations and 79,400 deaths estimated in the United States alone. This week, the Infectious Diseases Society of America (IDSA) released updated guidelines for diagnosis, and management of seasonal influenza. In the guidelines, they recommend testing for influenza in upper respiratory specimens of high risk patients, when testing can reduce unnecessary additional testing/inappropriate antibiotics, or when testing can influence chemoprophylaxis for high-risk household contacts. Annual seasonal flu vaccination reduces the risk of influenza by 40-60% and is still recommended as the best way to mitigate the impact of seasonal influenza, but antiviral prophylaxis may be necessary in outbreaks or for certain at-risk populations. Other ways to prevent spread include hand hygiene, limiting contact with people who have influenza-like illness, and if you have such an illness yourself, STAY HOME. 

More than 166.6Million influenza vaccines have been distributed in the US as of December 20, 2018.The influenza vaccine may not always be a 100% match to all circulating strains, as we saw with last year's flu season.  This year’s vaccine contains an influenza A H1N1pdm09-like strain, an influenza A H3N2-like strain, and influenza B strains from the Victoria and Yamagata lineages. Updated this year, the Advisory Committee on Immunization Practices (ACIP) also recommends the live-attenuated influenza vaccine (FluMist); however, the American Academy of Pediatrics suggests this only be used if the alternative would be no flu shot at all. The CDC can explain the types of vaccines available and who should get them. 

Final thoughts about the flu 

Regardless of which vaccine is more appropriate, our ancestors would probably encourage us to just get ANY vaccine if it would help avoid recreating the influenza pandemic of 1918. There's still time - it's not too late so if you haven't gotten your flu shot, consider getting it today!

Pushing the Needle on Influenza Vaccination

Despite continued debates about the use of influenza vaccination mandates in healthcare settings (see prior discussions just on this blog here, here, here, here, and here), facilities continue to move toward implementing some form of ‘mandatory’ program to ensure sustained high levels of influenza vaccination coverage among their staff.  A new article published in JAMA Network Open documents this increase with an update to a multi-year survey project asking about facility infection prevention practices.  I use the word ‘mandatory’ in quotes above on purpose because, as I detailed in an accompanying editorial, the definition of a mandate, when it comes to vaccination policy, is not standardized.

“…Most importantly, it does not appear that mandate was defined. Among respondents who reported having a vaccination mandate, only 74% reported having penalties for noncompliance and 13% allowed declination without a specified reason. Of those reporting no mandate, 21% reported penalties for noncompliance with hospital policy on influenza vaccination and 41% reported requirements for wearing masks if unvaccinated. An article in a bioethics journal⁵ offers the following criteria for using the term mandate in this setting: limiting acceptable reasons for refusal, penalizing nonparticipation, and enforcing these expectations. By these criteria, it is not clear how many programs described in this survey should appropriately be referred to as mandatory—the number may be higher or lower than that reported, although an increase over time seems likely.”

The authors of the survey article also note that the VA is moving to a mandatory vaccine or mask policy this year, which will again increase the number of facilities using some type of mandate.  Hopefully, the VHA will take advantage of their more comprehensive healthcare delivery system to evaluate the impact of the program on both inpatient AND outpatient influenza among their patients, something that has been a persistent gap in prior reports.

ALSO, did you appreciate how easy it was to click the link and access the whole article?  Note that the article and the accompanying editorial are in JAMA Network Open, a new, fully open access journal “in which all content is made freely available to all readers immediately on publication. ….[they] will publish online only, every Friday.” Read more here.

New evidence supports high-dose influenza vaccines

People older than 65 years are at particularly high risk for influenza-related medical complications including hospitalizations and death. In 2009, the FDA approved a trivalent inactivated vaccine with four-times the hemagglutinin antigen per strain, which was thought to improve immune response in seniors.

Background data has largely supported high-dose vaccination among seniors. In a multicenter, randomized controlled trial of high vs standard dose vaccine that included almost 32,000 patients during 2011/12 and 2012/13, 1.4% of high-dose and 1.9% standard-dose patients had an influenza-confirmed influenza-like illness, resulting in a relative efficacy of 24%. Adverse events were slightly, but significantly lower in the high-dose group but 3 high-dose recipients had serious vaccine-related events (which all resolved) vs none in the standard-dose group. A very large Medicare study during 2012/13 and 2013/14 reported similar benefits but only during 2012/13 when H3N2 was more common. Perhaps it is difficult to measure a benefit during more mild, H1N1 seasons? There have been other studies supporting the effectiveness and cost-effectiveness (at least during the 2011/12 and 2012/13 H3N2 seasons) of high-dose vaccine.

One of the larger groups of seniors in the US are patients in the Veterans Health Administration (VHA) system, so it makes sense to measure the benefits of high-dose vaccine using the VHA integrated EMR. In the June 1st JID, authors reported results of a large (industry-funded) retrospective cohort study completed using data from the 2015/16 influenza season (an H1N1 year) that included seniors with at least one inpatient or outpatient visit during the prior year (2014/15). The primary outcome was any hospitalization for pneumonia or influenza. The study used a number of nice methods to adjust for confounding including matching on baseline characteristics and the Care Assessment Need (CAN) score, that is a proxy for frailty. They also adjusted for residual confounding using the prior event rate ratio (PERR) method, which you can read more about here. Basically, PERR adjusts for outcome rates in the baseline period (before vaccination) by dividing the relative rate post-vaccination by the relative rate pre-vaccination (in the baseline period).

The final cohort (before matching) included 104,965 standard-dose and 125,776 high-dose recipients during the 2015/16  influenza season. The matched cohort had 49,091 standard-dose and 24,682  high-dose patients. Using the unmatched and matched cohorts, and using the PERR method with each, the relative vaccine effectiveness of high-dose influenza vaccine was 23% and 25%, respectively. This suggests that high-dose vaccine was effective in preventing influenza or pneumonia-associated hospitalizations among VHA patients.

These results are encouraging since they were from a more mild H1N1 season. Even more encouraging, the authors plan to automate the data extraction process and report vaccine effectiveness within 3 months of the end of each influenza season. But one note of caution, having a high-dose vaccine that is 25% more effective isn't a huge improvement, since influenza vaccines in general aren't very effective. So high-dose influenza vaccine is a small step in the right direction - but more research and new influenza vaccines are needed.

Working while sick

A few days ago, I learned about visual abstracts, a great way to encapsulate the essence of a paper. You can read more about visual abstracts here. Here's my first attempt using a recent paper in the American Journal of Infection Control.

This paper tells us that hospitals can't just mandate influenza vaccine for their workers and think that they have done their job. Preventing the transmission of respiratory illnesses requires a more comprehensive approach that makes a real attempt at keeping sick healthcare workers at home. Of note, the rate of vaccination in the survey participants was 45%, and vaccine effectiveness that season was only 19%.

Bottom line: Influenza like illness (ILI) has many causes, influenza vaccine is modestly to moderately effective against three of those, and healthcare workers continue to place patients at risk by coming to work when sick with ILI.

How much more stupid can it get?

Forbes.com recently reported on a psychologist at an academic medical center in New York who was fired because she didn't receive the influenza vaccine this year. Followers of this blog know how I feel about mandatory flu vaccine policies, which are not grounded in high-level evidence. But this case is worse. Much worse. The psychologist is unpaid, occasionally gives lectures, but doesn't see patients. The hospital epidemiologist defended the termination decision on the basis that the psychologist may expose other healthcare workers in the medical library. Wow! All of us come into contact with unvaccinated humans on a daily basis, and many of those contacts are likely more intense than those that occur in a library. What's next? Firing healthcare workers who have unvaccinated family members at home? Where does this end? This is what happens when you enact a misguided policy. One stupid decision just leads to the next more stupid decision. Fortunately for the poor psychologist, a more enlightened medical school offered her library privileges.

When a dead horse is your only horse...

I’d like to thank Tom Talbot and Hilary Babcock, two of the authors of SHEA’s position paper on mandatory influenza vaccination of healthcare workers, for their response to my recent post on why I think this policy is misguided. Hilary and Tom are excellent hospital epidemiologists that I respect. Nonetheless, on this issue, I remain unconvinced by their arguments.

They point out that that I mischaracterized SHEA’s position being based on four nursing home cluster randomized trials, when in fact the position paper has 63 references. There are, indeed, 63 references, the majority of which do not address the impact of vaccinating healthcare workers on patients. In fact, most of the references lay out the biologic plausibility that vaccinating healthcare workers should have an impact on patients, as well as other issues, such as the impact of mandatory programs on vaccine rates. The biologic plausibility arugment is very nicely laid out in their blog post, and I agree with it completely. So, I’ll be more precise: SHEA’s best evidence for their policy is contained in the four cRCTs.

Tom and Hilary go on to cite newer studies that they believe support SHEA’s position, one of which is a cluster randomized trial from the Netherlands. I was not familiar with this paper so I reviewed it. In this trial, 6 hospitals were randomized—3 had an intervention to increase vaccination rates in HCWs and 3 did not. Significantly higher vaccination rates were demonstrated in the intervention hospitals. The patient outcomes were divided into adult and pediatric patients and the outcomes reported for patients were influenza and/or pneumonia and pneumonia. Influenza was not an outcome. Thus, the influenza rates cannot be determined. If the two outcomes are mutually exclusive, then the influenza rate is actually higher in the intervention hospitals (though not likely significantly so). For children, there was no difference between the intervention and control hospitals. And interestingly, the intervention hospitals had significantly higher HCW absenteeism rates, a metric Hilary and Tom argue as important for demonstrating the effect of employee vaccination. Thus, I don’t think this paper in any way supports mandatory vaccination.

Despite the studies published in the seven years since the SHEA position paper was published, there remains an irrefutable fact: there is no high level evidence demonstrating that vaccinating healthcare workers reduces influenza in hospitalized patients. I agree with Hilary and Tom that the four nursing home studies are a dead horse. Unfortunately, however, that dead horse is their only horse.

Everyone has opinions about infection prevention interventions biased by their own experiences and perceptions, and I’m glad that Tom and Hilary pointed out one of mine—bare below the elbows. As I write this post while on service, I’m, you guessed it, bare below the elbows! There’s clearly biologic plausibility that clothing can transmit pathogens to patients, but there is no evidence that following a bare below the elbows approach to patient care lowers infection rates, and in every talk I give on this topic I make that very clear. I would never argue that HCWs wearing white coats should be fired; otherwise, Tom and Hilary would have to be fired (based on their photos). And unfortunately, they missed the entire point of my post. I’m not arguing against vaccination of HCWs. My point is that you can’t mandate an intervention (and in this case threaten a person’s livelihood) when the intervention is not supported by high level evidence. In other words, you can’t mandate on opinion, but that’s exactly what SHEA did. Expectations for compliance with an intervention must be correlated with the strength of the evidence. 

SHEA made a huge mistake when they published this position. And seven years later, there’s still no published evidence that can bail it out. It was wrong seven years ago, and it’s still wrong. Healthcare workers in the US deserve better, especially from a professional society that prides itself on using science to guide practice.

It's time to finally fix this

In 2010, the Society for Healthcare Epidemiology (SHEA) published a position paper that stated that annual influenza vaccination of healthcare workers should be a condition of employment on the basis of four studies performed in nursing homes. In other words, SHEA advised hospitals to fire HCWs who refused to get a flu shot. Other professional societies jumped on this insane bandwagon, and CMS made vaccine compliance rates publicly reportable and a metric in their hospital Star Rating program.

From the beginning, I have argued on this blog that SHEA's position was misguided for a number of reasons that I won't rehash in this post (see here, here, and here). Moreover, the Cochrane group evaluated the same four papers on which SHEA based its recommendation and determined there was no conclusive evidence that vaccinating HCWs was effective in reducing influenza in patients. But SHEA didn't back down. Another systematic review by another group came to the same conclusion. But SHEA didn't back down. CDC significantly downgraded the effectiveness of influenza vaccination to worse than placebo in some years. But SHEA didn't back down. And there's even a lack of evidence that influenza vaccine of healthcare workers reduces influenza in healthcare workers.

Now comes a 21-page paper (free full text here) in PLoS One by a group of Canadian epidemiologists that decimates those four nursing home studies. And all I can say is: SHEA better back down.

According to these investigators, all four studies violate the principle of dilution by reporting greater percentage reductions with less specific outcomes (i.e., the studies report percentage reductions in all-cause mortality > influenza-like illness (ILI) > laboratory-confirmed influenza). The principle of dilution requires that vaccine efficacy must be lower when non-targeted events (non-flu illnesses) are included in the study outcome than when only the target (confirmed influenza) contributes. The authors give the simple analogy of using an item-specific coupon at the grocery store--the percentage reduction in price on that item will always be much greater than the percentage reduction on your entire purchase that includes multiple other items. It's an irrefutable law of mathematics.

They also note several sources of bias. Depending on the study, there were differences in mortality between the control and intervention groups accrued before influenza arrived in the community, and there were issues with the definition of ILI. Estimates of numbers need to vaccinate were so flawed (off by as much as 4,000-fold) that if extrapolated to all healthcare workers in the US, more deaths would be averted than occurred in the 1918 influenza pandemic.

Here's the bottom line per the authors: Each of the four cluster RCTs used to champion compulsory HCW influenza vaccination policies reports benefits that are mathematically impossible under any reasonable hypothesis of indirect vaccine effect. It's hard to imagine a stronger conclusion.

If you don't read the entire paper, please read the discussion. Here's the concluding paragraph:

Through this detailed critique and quantification of the evidence we conclude that policies of enforced influenza vaccination of HCWs to reduce patient risk lack a sound empirical basis. In that context, an intuitive sense that there may be some evidence in support of some patient benefit is insufficient scientific basis to ethically override individual HCW rights. While HCWs have an ethical and professional duty not to place their patients at increased risk, so also have advocates for compulsory vaccination a duty to ensure that the evidence they cite is valid and reliable, particularly in the absence of good scientific estimates of patient impact. The diversion of resources from more evidence-based efforts and other important but less tangible costs related to loss of trust and credibility also need to be considered, including the implications for other immunization programs and workplace policies. Although current data are inadequate to support enforced HCW influenza vaccination, they do not refute approaches to support voluntary vaccination or other more broadly protective practices such as staying home or masking when acutely ill.

And if that's not enough, there's a commentary in the same journal, responding to the Canadian study written by the lead author of one of the nursing home studies. He defends his study, but importantly he states that the findings should not be extrapolated beyond the nursing home setting.

As I see it, unless SHEA cites alternative facts, it has three choices: change its position to recommending (not mandating) annual influenza vaccine for healthcare workers, articulate a damn good reason to support its current policy despite the evidence (hard to imagine what that would be), or simply retire the guideline (as it has quietly done for the 2003 highly controversial MRSA/VRE search and destroy recommendation). Given the assault on science that we are likely to see over the next four years in the US, SHEA must lead by ensuring that all of its recommendations are solidly based in evidence and that expectations for compliance with interventions correlate with the strength of the evidence. Just as we must defend vaccines from false claims of adverse effects, we must also truthfully acknowledge their limitations and shape our policy on science not opinion.

The almighty influenza vaccine

A recent study in Clinical Infectious Disease that analyzed the effectiveness of the influenza vaccine for the 2014-15 season was sent to me by a colleague. Wow. Overall effectiveness (for influenza A and B combined) was a whopping 19%, but for influenza A was 6%. Honestly, placebo is more effective than that. For the 2015-16 season, overall effectiveness was 47%, and 55% for influenza A.

CDC used to cite that the flu vaccine was 70-90% effective, but more recently they have revised that significantly. I was quite surprised when I looked at the CDC website today and I made the graph below from their data.

In 12 consecutive flu seasons, effectiveness hit 60% just once. If you average those 12 seasons, the effectiveness was 41%. We are sorely in need of a better vaccine. The CDC analysis begs many questions: Should hospitals make this weakly effective vaccine a condition of employment? Should SHEA take another look at its guideline? Does anyone still believe that we should fire healthcare workers that are not vaccinated with a vaccine that provides such poor protection? How many hospitals fire employees who come to work sick with influenza? Would you rather be hospitalized at a hospital with a mandatory flu vaccine policy or a hospital that makes a serious attempt to minimize presenteeism?

You better not cough!

I have to thank Eli for rekindling my interest in the mandatory influenza vaccination controversy. I had resigned myself to it being water under the bridge and had not thought much about it until the last week. What I didn't realize is that another Cochrane review was published last year on influenza vaccination of healthy adults. This is very useful to our discussion since most healthcare workers fall into the category of healthy adults. A free full-text version of the review can be found here. This review examined 69 clinical trials involving 70,000 participants, 27 cohort studies with 8 million subjects, and 20 case control studies with 25,000 participants. The bottom line is that the parenteral vaccine was 60% efficacious in preventing influenza, which didn't seem surprising to me. However, the absolute difference in influenza infections between the vaccinated and unvaccinated groups was only 1.3%. That knocked my socks off! All of the energy and resources consumed and ill will created in trying to increase vaccination rates in healthcare workers, including firing people, for a vaccine that reduces infection by 1% is about as stupid as it gets. Merry Christmas!

Photo: NBC News

Festivus Grievances: Are Mandatory Influenza Vaccination Policies and Banning White Coat Ceremonies Ethically Equivalent?

"Welcome, new comers. The tradition of Festivus begins with the airing of grievances. I got a lot of problems with you people! And now you're gonna hear about it!"  - Frank Costanza

BB8 is for BBE

(Warning: Mild Star Wars spoiler at the end, although I surveyed folks here and no one complained)

Outside my recent posts on influenza vaccine mandates, I have very few infection control grievances to air this year. To start, 2015 saw the return of original science to the annual SHEA spring meeting, a tradition that will continue in the May 2016 meeting chaired by Silvia Munoz-Price and Tom Talbot. And the year ended with NIH planning to spend $461 million in FY 2016 on antimicrobial resistance research, an increase of $100 million over FY 2015. On a personal note, University of Iowa was selected as one of CDC's new Prevention Epicenters. Our team is honored and excited to join the other 5 new centers for the kick-off meeting this January. Thus, things are truly looking up in our fight against antimicrobial resistant bacteria. If we can convince congress, NIH and CDC to continue to gradually increase research funding over the next decade, we should have many things to celebrate in 2025. That is, if we can fix the ID fellowship match and the reimbursement issues that have plagued us the past 10+ years.

...but back to influenza vaccine mandates. Several folks have wondered how we bloggers could support banning white coats and at the same time question influenza vaccine mandates, especially since both interventions have similar levels of evidence (i.e. biological plausibility, math models, observational data, limited RCT data). This is an interesting question. Just to clarify, Mike is against compulsory influenza vaccine policies and I grudgingly support them and neither of us wants to ban white coats - we favor voluntary policies that make it OK not to wear a white coat - which is exactly what Mike instituted at VCU and plans here at Iowa, starting in 2016.

Yet ignoring our policy stances, the assertion that bare below elbow policies are somehow equivalent to vaccine mandates from an ethical standpoint is incorrect. Let's consider the current situation in the US with white coat ceremonies and the pressure that medical students, housestaff and faculty are under to wear white coats. If white coats are harmful (and many would agree that it is equally likely that white coats harm patients as influenza vaccines protects patients), then the current situation would be the ethical equivalent of forcing healthcare workers to not get vaccine.

That is, white coat ceremonies force healthcare workers to cause harm to their patients, which is not morally or ethically the same as requesting healthcare workers to help protect themselves and their patients by receiving an influenza shot. In a Star Wars context, forcing FN-2187 to murder villagers on Jakku (wearing white coats) is not ethically equivalent to requesting that Finn defend the people of Takodana from a First Order attack (influenza vaccine). 

Forcing healthcare workers to wear white coats that they deem to be harmful is wrong. We need to eliminate white coat ceremonies and stop coercing healthcare workers into wearing white coats.

Clarification: I'm in favor of mandating influenza vaccination of healthcare workers (for now)

There's been some misunderstanding of the motivation behind my recent posts offering suggestions for improving the implementation of compulsory influenza vaccination policies and acknowledging the limitations of the existing data supporting vaccine mandates. Most of the snark was on twitter where folks challenged my commitment to infection prevention and my interpretation of the data. If I can dish it, I better be able to take it. With that being said, however, I still feel a need to clarify my support for mandatory influenza vaccination policies in both acute care and long-term care settings. But...

1) I will only support such policies for 4-5 years. If those that push these policies can't come up with better clinical trial data during that time, I'm going to call BS. There is simply no excuse for stretching the existing data to drive change now and not validating your claims. Recommend the mandate, but then do the proper studies.

2) CDC and others must fund studies evaluating the benefits of mandatory vaccine policies in acute care settings. There is never going to be a better time than now, when hospitals are implementing mandatory vaccination programs, to fund the necessary cluster-randomized and quasi-experimental studies. Wouldn't it be great if we could find 50 or more hospitals planning to implement an influenza vaccine mandate and then fund a mixed-methods, stepped-wedge cluster randomized trial as those hospitals implemented the policy over the next 3-4 years? I think it can happen and SHEA, IDSA, PIDS and APIC need to demand such a study.

3) As Sara Cosgrove and I wrote in the 2007 SHEA Business-Case Guideline: "Most hospital epidemiologists or infection control specialists want to increase the resources available for infection control activities, but it is important to avoid overestimating benefits or underestimating staff and time costs. Overestimation in an initial analysis may improve the situation in the short term, but it will hinder efforts and necessary trust in the long term after actual resource audits are performed." There's simply no excuse for hand waiving and over promising the benefits of healthcare worker influenza vaccination. It erodes trust and prevents the necessary validation studies from being funded. Please take the long view and don't be afraid to challenge dogma.

Happy holidays!

Root causes underlying the emergence of influenza vaccine mandates

Those that follow me on twitter or the blog have probably noticed my recent focus on trying to understand the emergence of compulsory influenza vaccination of healthcare workers. Before moving on from this topic, I wanted to share what I've learned in the process.

(1) There doesn't appear to be any estimate of the burden of nosocomial influenza in the US. We know healthcare-associated influenza does occur, but we don't have estimates for the proportion of influenza cases that occur in hospitals. Even if we did know the incidence, we don't have reliable estimates for what proportion is acquired from healthcare workers vs. visitors or family members. It seems like we'd need those numbers before pushing for a mandate.

(2) There is no data supporting the benefits of healthcare worker vaccination in acute care hospital settings. If we look at the CDC systematic review everyone quotes, there were only 4 randomized trials and all 4 were from long-term care settings. If we generously include the observational studies, 3 were from long-term care and only one was from a hospital setting. We are basing acute-care hospital policy on one observational study.

(3) Again from the CDC systematic review, "HCP vaccination rates ranged from 48% to 70% in the intervention arms and 5% to 32% in the control arms." Thus, there is no evidence that raising vaccination above 48% or 70% is beneficial in long-term care settings. Thus, if we have vaccination rates near 50%, do we need a mandate?

The last two things I learned are that none of the above matters. Science is not what is driving the push for mandates, unless you consider the studies showing mandates raise influenza vaccination rates among healthcare workers. Probably didn't need a study to show that.

(4) Yesterday, I wrote a post trying to bias the respondents of a twitter survey in favor of being cared for by a masked unvaccinated healthcare worker over a vaccinated one. As you can see by the results (below), despite my efforts, the large majority want their healthcare worker to be vaccinated. This is critical - despite the science, we just want people to be vaccinated. A huge driver behind influenza vaccine mandates must be this desire. Additionally, it's likely that masks are viewed negatively by patients. Vaccine mandates make folks feel safe and masks don't - very patient centered.

(5) The finally bit that occurred to me is that the reason vaccine mandates exist is because CMS and other governing bodies require hospitals to collect and report influenza vaccine coverage among their workers. There is also a target of 90% coverage that must be met. Thus, we have a QI target that exists despite minimal scientific evidence that it protects patients but we have to meet the target. And the only way to meet such an arbitrary target is through mandates. QED

Influenza Vaccine Mandate Math

Last week, I described five steps individual hospitals, systems and society should take when implementing compulsory influenza vaccination of healthcare workers. One component of many influenza vaccine policies is mandatory surgical masks for healthcare workers who refuse or otherwise cannot receive the vaccine. Does masking unvaccinated healthcare workers even make sense? Or rather, who is more likely to spread influenza in hospitals - an unmasked, vaccinated healthcare worker or an unvaccinated, masked healthcare worker? Let's look at the numbers.

Let's assume influenza vaccine is 50% effective. In 2014-15, overall effectiveness was 19% while in 2012-13 and 2013-14 it was 49% and 51%, respectively. I'll give the vaccine a mulligan last year since during the prior decade, vaccines were far more effective. Let's further assume with vaccine mandates, 90% of healthcare workers receive the vaccine and 10% do not.

If 90% receive a vaccine that is 50% effective, we will have 45% of healthcare workers in our hospital protected and 45% unprotected. The tricky thing is that we won't know who is protected or unprotected. And what if the 45% vaccinated but non-immune healthcare workers assume they are immune and work while sick? You can imagine them saying - "I'm sick, but it's not influenza because I was vaccinated, so I'll do my ICU shift." Any mandatory vaccination policy should consider that scenario or it's possible that the mandate could make hospitals less safe. But what of the 10% required to wear masks? I suspect they'd be more likely to stay home if sick, but even if they don't they'll be wearing a mask!

Finally, if I had a choice between being cared for by a vaccinated, unmasked healthcare worker or a masked, unvaccinated healthcare worker, I'd chose the mask. That is, until we implement influenza prevention bundles that focus on presenteeism.

Note: Mike wrote a fantastic quantitative post (in 2010!!) comparing a vaccine mandate to a presenteeism reduction policy. His conclusion: "Reducing presenteeism by 1 percentage point (from 70% to 69%) would have the same impact as increasing vaccination from 70% to 98%." It's too bad not many read the blog back in 2010...

Mandatory Influenza Vaccination of Healthcare Workers: The end or just the beginning?

"Just don't let the human factor fail to be a factor at all" - Andrew Bird, Tables and Chairs

We are all in favor of protecting patients from preventable harm. No question. With that aim, the intervention du jour (in the US) is mandatory influenza vaccination of healthcare workers. SHEA, IDSA and PIDS support such a policy, yet a recent Cochrane review stated "there is no evidence that only vaccinating healthcare workers prevents laboratory-proven influenza or its complications (lower respiratory tract infection, hospitalization or death due to lower respiratory tract infection) in individuals aged 60 or over in LTCIs and thus no evidence to mandate compulsory vaccination of healthcare workers."

Yet given the inevitability of mandatory influenza vaccine policies in the US, what can we do to protect our patients from healthcare-acquired influenza and other viral illnesses since mandates would be expected to have minimal or even negative effects on nosocomial influenza transmission? To explain this further, compulsory vaccination policies are technical interventions which are relatively simple to implement. But we have seen over and over that ignoring the human equation or socio-adaptive factors behind infection prevention initiatives leads to failure. As Sanjay Saint and Sarah Krein have written eloquently in their recent book: "Our research has shown that the principle reason is the failure of the hospitals to win their staff's active support of the infection prevention initiatives. In their focus on the technical aspects of an initiative, these hospitals have give short shrift to the human aspects." (You can read my Doody review of their book at Barnes & Noble here)

What are the additional components that we need to consider when implementing an influenza vaccine mandate? Some suggestions:

1) First, acknowledge that we know the vaccine is imperfect through the develop of communication strategies that highlight the proven benefits of the influenza vaccine to the individual health care worker. Since the data supporting direct benefits to patients is more theoretical at this point, highlighting the protective effects for the individual receiving the vaccine - including reduced risks of cardiovascular outcomes could improve acceptance of the mandate.

2) Next, mandate additional components in our influenza prevention bundle, especially those highlighted in the Cochrane review which included "hand-washing, masks, early detection of influenza with nasal swabs, antivirals, quarantine, restricting visitors and asking healthcare workers with an influenza-like illness not to attend work."

3) Offer additional sick leave to healthcare workers required to receive the vaccine. Policies that include bans on presenteeism (working while sick), should be accompanied by additional paid sick leave. In this specific instance, influenza vaccine is associated with fever (especially high-dose vaccines that are associated with benefits in older adults). Providing additional sick leave shows our understanding of vaccine side-effects, demonstrates support for staying home sick and most importantly, respects the individual health care worker.

4) Include in the mandate bundle a plan to de-implement the vaccine mandate if future studies demonstrate that they're ineffective. Doing this will gain more trust with our healthcare workers, which may, counterintuitively, improve the effectiveness of the mandate.

5) Finally, fund large studies evaluating the efficacy, effectiveness and implementation (i.e. barriers) of influenza vaccine mandates in our health care systems. Funding research acknowledges that the data around vaccine mandates isn't perfect, but we are doing the best we can to protect patients now, while simultaneously validating the safety and efficacy of this policy to protect future generations of patients AND our healthcare workers.

There are many things we need to consider as we implement mandatory influenza vaccine policies. The mandate is just the beginning. We have a long road ahead before we can state convincingly that our hospitals are safe from hospital-acquired influenza.

"And how 

How I wish 

I, I had talked to them 

And I wish they fit into the plan"

-Andrew Bird, Tables and Chairs

Evidence, schmevidence! Occupational medicine edition

The LA Times reports today that another porn star has become infected with HIV. This brings the total of infections to three in the past year. Although porn workers are required to be HIV tested every 14 days, condoms are not mandated. The lack of mandate is unfortunate given that we have great evidence for the effectiveness of condoms in reducing HIV transmission.

Now let’s switch gears and talk about healthcare workers. Increasingly, hospitals are mandating influenza vaccination. A new paper in the latest issue of the American Journal of Preventive Medicine by investigators at Johns Hopkins describes a systematic review of the literature on mandatory influenza vaccination for healthcare workers. One key finding was that mandating influenza vaccination increased compliance (imagine that!). But (and it’s a very big but) there was either no demonstrated statistically significant reduction in sick leave after mandating vaccination or no evaluation was performed in the studies reviewed. Moreover, none of the studies evaluated the impact on patients. At the end of the day, we still have no evidence that vaccinating healthcare workers reduces influenza in hospitalized patients. That doesn’t mean vaccination is not a good idea. I would argue that bare below the elbows is a good idea, but I’m quick to acknowledge that we don’t have data that it reduces infections, and therefore I don't support a mandate.

So here we have two industries struggling with evidence: one won’t mandate a proven prophylactic strategy, and the other seems quite comfortable mandating a prophylactic strategy that isn't proven. The root cause in both cases appears to be the same—an attempt to please the customer. It’s a whole lot easier for hospitals to mandate flu vaccine and publicly pat themselves on the back and tout how they are serious about patient safety than to develop and enforce policies and practices that keep healthcare workers home when they are sick.

Photo: Francine Orr, Los Angeles Times

Here come the maskers

Recently, the New York State Health Department mandated that all healthcare workers either be vaccinated against influenza or wear a mask. This week’s JAMA has a commentary by the ethicist Art Caplan and New York’s Commissioner of Health, Dr. Nirav Shah. In the JAMA piece they argue the ethical imperative underlying the mask ruling. You can read about the ruling here and the JAMA commentary here (free full text). Unvaccinated HCWs will be required to wear the mask during periods of widespread influenza activity. It’s important to note that over the past 6 years, the period of widespread activity in New York varied from 11 to 22 weeks. That’s a long time to wear a mask, which is required in any area where patients are typically present. The document notes that this includes the cafeteria, though the unvaccinated worker is allowed to be mask-free when eating.

For many reasons, I dislike mandatory influenza vaccination. But I despise the mask regulation. I have to question the rationale. It seems to me to be less about ethics and more about being coercive and punitive. It’s wasteful. There have been periods of time when masks were in short supply with the shortage being made worse by the maskers. Most importantly, wearing a mask for prolonged periods of time is impractical—it’s uncomfortable and distracting. If we are going to argue for masking on an ethical basis, since influenza vaccination is only 60% effective at best, wouldn’t it be consistent to argue that all healthcare workers, vaccinated and unvaccinated, should wear a mask? It's also laughable that the ethicist doesn't mention that it's unethical to come to work while sick with influenza, which studies tell us is quite common. Presenteeism remains the elephant in the middle of the room, and reducing it is likely far more important than mandating influenza vaccine or masks to prevent transmission of infectious diseases in the healthcare setting.

Photo: REUTERS/Yuri Maltsev

Influenza Vaccine Has Miracle Powers After All*

This blog hasn't always been kind to the humble influenza vaccine. So in fairness to our trusty old vaccine friend, I'd like to highlight a recent study published in Lancet ID by Jeffrey Kwong and colleagues in Toronto. They utilized 19 years of data (1993-2011) from the universal health care system databases in Ontario Canada to assess the risk of Guillane-Barré Syndrome (GBS) after influenza vaccination and after influenza infection. They accomplished this using a self-controlled, risk-interval design. This design compares the risk of GBS in a predefined risk interval after exposure to the vaccine or infection and compares it to the risk in the control period outside the selected exposure period. In this case, the exposure period was the first 6 weeks post exposure and the control period was weeks 9-42. Importantly, the patients were conditioned on having GBS in either the risk or control period and each patient served as their own control, which eliminates selection bias. Outcome of GBS was determined using ICD-9 or ICD-10 primary billing codes, which have reported positive predictive values in the 60% range. This is a limitation of the study.

They identified 2831 patients with GBS.  Within the 42 week period, 330 cases were preceded by influenza vaccination and 109 cases were preceded by influenza infection.  The risk of GBS was 1.5 times higher in the initial 6 weeks post vaccination compared to weeks 9-42. The risk peaked in the third week post vaccination with twice the risk. The risk was higher in patients ages 18-64 compared to older adults. Importantly, even this increased risk adds up to one GBS admission per 1 million vaccinated. I also don't think we can rule of influenza infection causing this post vaccine risk since people are more likely to receive vaccine when influenza virus is circulating in the community.

In the 6 weeks post influenza-coded healthcare encounter, the risk of GBS was 15 times higher than baseline and peaked at 61 times higher in the first week post infection. Pending a formal competing risk analysis, patients should continue to be informed of a small increased absolute risk of GBS associated with the vaccine, but also a large risk associated with the infection. Of course, there other benefits associated with influenza vaccination, which should also be discussed with patients. To be clear, influenza vaccine IS a miracle when it's compared to influenza infection.

Image source: wikipedia

*Title is just playing off the title of one of our prior posts on influenza vaccine. Nothing in medicine has miracle powers, since medicine is a science. However, if there is anything close to a miracle it would be vaccines. Antibiotics would be a close second.

We’re doing it wrong—influenza vaccine edition

This prospective cohort study out of University of Michigan demonstrated that influenza vaccine didn’t protect against PCR-documented influenza illness, influenza transmission in households, or medically-attended influenza. Given the good match between vaccine and circulating viruses during the 2010-11 season, and given that the population studied was predominantly healthy young adults and children, these results are pretty shocking (even in the context of other underwhelming data on the effectiveness of influenza vaccination). As John Treanor and Peter Szilagyi opine in the excellent accompanying editorial, “the apparent failure of influenza vaccine under optimal conditions seen in this study is indeed troubling.”

One of the more intriguing findings of this study is that receipt of flu vaccine the previous year seemed to reduce the effectiveness of the vaccine, a finding that is not new. What struck me most after reading these two papers, though, was this statement in the editorial:

"It is frequently stated that evaluation of influenza vaccines in randomized controlled trials is “unethical”, but given that the effectiveness of the vaccine is unclear, the subjects in such studies are typically at extremely low risk of serious disease, and that effective antiviral therapy is available, perhaps this statement should be reconsidered."

When a vaccine’s effectiveness causes experts to consider a return to randomized controlled trials, it’s safe to say that the vaccine in question is pretty awful. We desperately need something better.

Influenza Vaccine Effectiveness Study Author Responds

Late last week, Dr. Jackson, one of the co-authors of the recent MMWR influenza vaccine effectiveness report, sent me an email response to my posts discussing how and why they measure influenza vaccine effectiveness the way they do. I thought that in the interest of fairness, I should post his full email, rather than pasting his response into a largely hidden comment section. I will likely post a follow-up to this at some point. Additionally, I want to thank Dr. Jackson publicly for responding in this fashion, both professionally and academically. The intent of my posts was academic, and I am pleased that he responded the way he did.

Dear Dr. Perencevich,

I am one of the co-authors on the MMWR article on influenza vaccine effectiveness, and I read your blog posts about that article. I believe I can clear up some of your questions. I tried posting this as a comment on the blog, but the website wouldn't let me, so my apologies for e-mailing you instead. Feel free to post this as comment on the website if you are able.

 (1) Regarding your first point, this study used what is known as a “test-negative” design. In the test-negative design, we enroll patients with a medically attended acute respiratory illness (MAARI). We then test these enrollees for influenza, and assess who was previously vaccinated and who was not. The test-negative design is based on an assumption that the rate of MAARI caused by pathogens other than influenza is the same in both vaccinated and unvaccinated persons. If this assumption is true, than our test-negative subjects are representative of the population from which the influenza-positive cases came, and our study does give an estimate of how well the vaccine reduces the risk of getting sick enough to visit the doctor.

 Although the paper refers to cases and controls, this is not a true case-control study, since a true case-control study requires that we know who is a case and who is not before we sample them. The design is closer to the “indirect cohort” method proposed by Claire Broome for studying pneumococcal vaccine effectiveness [NEJM 1980; 303:549-52]. The real advantage of the test-negative design is that it controls for differences in healthcare-seeking behavior. If we did the full cohort study you proposed, there would be variation among the cohort members in how often they seek healthcare, and these variations would be related both to their likelihood of being vaccinated and to their likelihood of going to the doctor if they got influenza. By only sampling people who come to the doctor, we control for those differences.

(2) Regarding your second point and third points, the relative risk (RR) is not an appropriate measure of association for this study design. The RR is (obviously) a measure of risk, which would be based on the cumulative incidence of disease in some defined cohort. In this study, we do not sample the full cohort; we simply use the influenza negative subjects to estimate the frequency of vaccination in the cohort. Using the RR in this setting would give a biased estimate of vaccine effectiveness, which is seen in the sample calculations you provided.

Sampling in a test-negative design is conceptually similar to incidence density sampling in a case-control study. When using incidence density sampling, the exposure odds ratio is a direct estimate of the incidence rate ratio and not an approximation to the RR. 

(3) Finally, regarding your final question about including the flu B cases in the estimate of VE against flu A: As mentioned above, the test-negative design assumes that the rate of non-flu MAARI is the same in vaccinated and unvaccinated persons. If we included flu B in the non-case group, we would be violating this assumption, because the vaccine does protect against B, and the rate of non-flu A MAARI would no longer be the same in vaccinated and unvaccinated persons.

 I hope this clears up your questions!
~Mike Jackson, Group Health Research Institute

Part 2: Influenza Vaccine Effectiveness - The Test-Negative Control Design

Before going further, I want to highlight the purpose of yesterday's and today's post. Occasionally, it is important to question standard practice in epidemiology when something doesn't make sense to you. I've experienced this first hand 3-4 times in infectious disease epidemiology and consider it an important exercise and critically important to our field. You can read this post if you want to read more about how we've questioned the ID epidemiology dogma around control-group selection, quasi-experimental design methodology and inappropriately controlling for intermediates in the causal-pathway of outcomes studies. Of course, this doesn't prove anything in this instance but rather explains my motive.

Yesterday, I posted my initial thoughts on how the CDC calculated the preliminary influenza vaccine effectiveness for the 2012-2013. I've now had several informal discussions on the phone and in person with several vaccine experts and am starting to understand how/why they conducted the study the way they did. I'm even more convinced now that design considerations (e.g. which patients are included in the cohort) are influencing the statistical analysis, which should be separate considerations. I will explain this further below.

It appears that the current standard study design in vaccine effectiveness (VE) is called the "test-negative" control design. This design is a modified case-control design where controls are required to have been tested for influenza but have been found "test negative". This appears to be a useful design when the specificity of the diagnostic test for influenza is low (Orenstein EW 2007), which is not the case in the current MMWR report. Another reason mentioned for selecting this design is that it is thought to reduce the bias, since vaccinated individuals may be more like to seek medical care vs. unvaccinated individuals. However, this benefit would apply to any patient seen in the outpatient clinic and not necessarily require diagnostic testing for influenza. 

In favor of cohort studies over case-control or test-negative designs, is the fact that "if specificity was 100%, the cohort method VE estimate was equivalent to the true VE, regardless of test sensitivity or ARs of influenza- and non-influenza-ILIs." (Orenstein EW 2007) The Orenstein paper's stated purpose was to study the impact of sensitivity and specificity of influenza testing on VE estimates across these study designs. Any benefits for the test-negative approach appear to evaporate when using a great diagnostic test, like the rt-PCR used in the MMWR report.

From what I can tell, the Orenstein paper is frequently cited to justify the test-negative design, but given current conditions, the design doesn't seem to be as useful as it once was. I also remain unconvinced that a cohort of patients already being seen in a doctor's office can tell us anything about risk factors for "medically attended" influenza. More importantly, I'm still very concerned with how the cohort was analyzed. Even if there are very good reasons to enroll a cohort of patients who presented to a clinic in order to avoid bias from vaccinated patients presenting differentially to clinics and even if all were tested for influenza, it doesn't follow that you need to use an odds-ratio approach to measure vaccine effectiveness when the relative-risk approach is more accurate. It appears that correcting one wrong (differential medical care seeking in vaccinated vs unvaccinated) is leading to a countervailing wrong when the analysis is done incorrectly. If they had just called this a cohort of tested patients or a "tested cohort", perhaps this wouldn't have happened.

Oh, and I'm still not sure why they are excluding influenza B positive patients from their VE calculation  for influenza A. Shouldn't they have to look at each A strain separately then? Well, that's another post for another day.