I normally write the first draft of this blog the weekend before it is due, and this is no exception. However, I am ill this weekend. Headache, myalgia, painful cough, but only mildly ill. The worst part is the interferon induced brain fog; my thoughts flow with all the speed of pudding and I was not appreciably better as the week progressed, although no cracks about how you can’t tell any difference in my writing over baseline.

I doubt the cause of my symptoms is influenza. According to the CDC site and Google flu trends there is little influenza activity in the US at the moment, so it is probably one of the innumerable viruses that can cause a flu-like illness. I am also not ill enough to think I have influenza, but I could be having a modified course as I was vaccinated a month ago. Of course, the doctor who treats herself has a fool for a patient and an idiot for a doctor. Flu season approaches, so from my interferon-addled brains, flu thoughts.

Flu vaccine efficacy

The flu vaccine has a bad reputation in part because it is not the best of our vaccines for preventing illness and those who need vaccination the most are the least likely to respond. Still, I was happy to see the Lancet meta-analysis this month on the efficacy of the influenza vaccine, although it breaks no new ground. It was a nice paper in that they only included studies where influenza confirmed by culture or real-time polymerase chain reaction, not the clinical diagnosis of influenza:

We screened 5707 articles and identified 31 eligible studies (17 randomised controlled trials and 14 observational studies). Efficacy of TIV was shown in eight (67%) of the 12 seasons analyzed in ten randomised controlled trials (pooled efficacy 59% [95% CI 51—67] in adults aged 18—65 years). No such trials met inclusion criteria for children aged 2—17 years or adults aged 65 years or older. Efficacy of LAIV was shown in nine (75%) of the 12 seasons analysed in ten randomised controlled trials (pooled efficacy 83% [69—91]) in children aged 6 months to 7 years. No such trials met inclusion criteria for children aged 8—17 years. Vaccine effectiveness was variable for seasonal influenza: six (35%) of 17 analyses in nine studies showed significant protection against medically attended influenza in the outpatient or inpatient setting. Median monovalent pandemic H1N1 vaccine effectiveness in five observational studies was 69% (range 60—93).
Influenza vaccines can provide moderate protection against virologically confirmed influenza, but such protection is greatly reduced or absent in some seasons. Evidence for protection in adults aged 65 years or older is lacking. LAIVs consistently show highest efficacy in young children (aged 6 months to 7 years). New vaccines with improved clinical efficacy and effectiveness are needed to further reduce influenza-related morbidity and mortality.”

Seems on an order of efficacy with seat belts, which decrease death by 70% and injuries by 40%. Neither the seat belt nor the flu vaccine is perfect, but both are better than no intervention at all. The largest problem with the vaccine is the difficulty in choosing the correct strains every year to be in the vaccine. If the JREF ever has a million dollar winner, I hope the new millionaire would use their powers for good and predict the upcoming years influenza strains.

A universal flu vaccine

There is ongoing work to improve the flu vaccine, which is what we really need. The problem with influenza is that it mutates. In the argot of the field it has antigenic drift, so that the organism at the end of the flu season does not antigenically resemble the strain at the beginning of the season and antigenic shift, where there is a whole new strain unknown to world, as happened with H1N1.

There are sections of protein of the virus that do not mutate, regions that are highly conserved, and if those proteins could be isolated perhaps there would be a universal vaccine against all influenza strains. And someone is on track to do just that:

To answer that question, Corti et al. screened 104,000 peripheral-blood plasma cells from eight recently infected or vaccinated donors for antibodies that recognize each of three diverse influenza strains: H1N1 (swine-origin influenza) and H5N1 and H7N7 (highly pathogenic avian influenzas). From one donor, they isolated four plasma cells that produced an identical antibody, which they called FI6. This antibody binds all 16 HA subtypes, neutralizes infection, and protects mice and ferrets from lethal infection. The most broadly reactive antibodies that had previously been discovered recognized either one group of HA subtypes or the other, highlighting how remarkable FI6 is in its ability to target the gamut of influenza subtypes.

That was a lot of work, but now that they have discovered the key to neutralizing all influenza, the challenge is to develop a vaccine that promote a reaction to that antigenic site and, viola, a universal flu vaccine. I hope we see it in my lifetime. It explains why if there is poor match between the vaccine and circulating influenza there is still efficacy, although decreased, from the vaccine. The lucky few will make antibody to the conserved areas common to all viruses and develop protective antibody in a mismatch year. Vaccine response is always more subtle than one antigen/one antibody.

It really surprises me that this advance is coming from basic science work on the immunology of influenza, I would have anticipated this kind of breakthrough would have come from NCAAM, which has been on the cutting edge of improving patient care and quality initiatives. Like, um, er, well, the brain fog is preventing me from recalling the advances.

Flu stats

Humans always have difficulties comprehending large numbers. Politics, and life, is small and local. If an event did not happen to you and yours then often it wasn’t important. I am used to thinking about large numbers and influenza, but they do not have the same impact compared to what happened in my own ICU with the initial H1N1 outbreak: all beds filled, all ventilators in use and no place to put the next case which, by some random luck, never occurred. The pandemic affected millions; I remember my 30 cases.

The CDC released estimates (and they are estimates, based to best data and models; if the CDC develops a better technique and changes the numbers, they are not “backing away” from the prior estimates, a phrase that always identifies someone who is both against vaccines and does not understand the tentative nature of all data) on both the effect of the H1N1 pandemic on the US:

43 million to 89 million cases, 195,000 to 403,000 hospitalizations, and 8,900 to 18,300 deaths, including 910 to 1,880 deaths among children aged <18 years, during April 2009–April 2010.

As well as the estimates for what the vaccine accomplished:

713,000 to 1.5 million cases, 3,900 to 10,400 hospitalizations, and 200 to 520 deaths were averted as a result of the vaccination campaign.

Not bad prevention considering 61 million Americans received the vaccine, a paltry 1 in 5.

Flu and pregnancy

There are people who have a marked increased risk of dying from influenza, including the obese and pregnant women (not pregnant men, I hasten to add living in Oregon). 1% of the population is pregnant, but in 2009 pregnancy accounted for 5% of H1N1 deaths.

It is difficult to convince pregnant women to get the vaccine, since people have an understandable fear of anything that could adversely affect the pregnancy. The data available suggests that not only is the vaccine safe in pregnancy but maternal vaccination protects the child against influenza. There is no data to suggest that the flu vaccine increases the risk of miscarriage and some reports suggest that influenza is associated with premature delivery. The effect of influenza infections on pregnancy outcomes has had little evaluation.

There was an interesting epidemiological study this month in JID on the 1919 pandemic that suggested that about 1 in 10 pregnant women had a first trimester miscarriage from influenza:

…documented an unusual 5%–15% decline in natality with a trough 6.1–6.8 months after the peak of the severe autumn 1918 pandemic wave in several Scandinavian countries and the United States. On average, 2.2 births per 1000 persons were missing during spring 1919, corresponding to an excess of ~1 in 10 pregnant women infected with influenza during their first trimester having miscarried in autumn 1918. We argue that the most parsimonious explanation for this unusual and temporal birth depression is substantial pregnancy losses following influenza infection in autumn 1918 among women who were then in their first trimester of pregnancy.

Whether vaccination would prevent miscarriage is unknown, but there is strong biologic plausibility to suggest it could. Vaccination benefits often extend beyond the simple concept of one vaccine preventing or ameliorating one infection. There is also all the positive consequences of not having an infection, from potentially avoiding a miscarriage to not having a heart attack.

Moral imperative

I am an Infectious Disease blogger over at Medscape and every October I publish a deliberately obnoxious essay on the flu vaccine. The essay is addressed to fellow Health Care Workers (HCW), and does somewhat come from the heart.

Here is my opinion.

Patients in the hospital are particularly vulnerable. They are a population at risk from their care providers. About 1 in 5 cases of influenza are subclinical, hospitalized patients are more susceptible to acquiring influenza from HCWs than the general population, and 27% of nosocomial-acquired H1N1 die.

As HCWs, it is our responsibility to our patients to maximize their safety when under our care. While not perfect, the influenza vaccine is a reasonable intervention to prevent the spread of flu from HCW to patient. Since HCWs have ready access to the worlds literature and the best minds in medicine, if HCWs use any of the standard excuses to avoid the flu vaccine and increase the risk of their patients they are, well, a Dumb Ass. We owe it to our patients to keep them safe.

There was a program a few years back to try an increase the hand hygiene rates in the hospital by enlisting the patients help. It is “OK to ask” if your HCW had washed their hands. I thought from the beginning the idea was bankrupt, and would anyone fly on an airline where it was “OK to ask” if the wheels are down when landing? I took an informal poll of patients on a medical unit and it was unanimous. Everyone understood what “It’s OK to ask” referred to, and not a one would ever ask their doctor or nurse if they washed their hands for fear of making them angry. And really, who wants to piss off the person responsible for their morphine?

Be that as it may, I would suggest that, during flu season, if you or someone you love is in the hospital, ask if their providers are vaccinated against the flu. Remember that being in the hospital probably means you are one of the groups unlikely to benefit from the flu vaccine and that your best protection is to not acquire influenza from others. If your HCW has not received the vaccine, ask for a new provider or, at a minimum, request they wear a mask while involved with your care. I know it will never happen, but there is a lot to be said for public pressure to alter behavior. I have been half thinking about starting a web site to promote the idea, but I haven’t the time.

Dumb associations

While a blog aimed at medical providers, Medscape apparently has a fair number of Dunning-Kruger amateurs who have taken offense at my suggestion that the vaccine is a good thing for health care providers and their excuses for avoiding vaccination are not grounded in reality. Again, the blog was not directed towards patients, but HCWs, and since the comments are anonymous, there is no way of really knowing who is commenting.

There are two broad themes as to why people refuse the vaccine. One is straight from Bizarro World: there is a cabal of government, pharma, and doctors whose sole purpose in giving the vaccine is to line the pockets of big pharma and keep people ill. This is a delusional state so at odds with the reality to which I am accustomed, and evidently so common, I am surprised there is no DSM entry for the disorder and there are no clinical descriptions of the phenomena. Most articles that address vaccine refusal have similar reasons:

Predictors of vaccine noncompliance were fear of needles (P ≤ 0.042), fear of getting sick from the vaccine (P ≤ 0.000), disbelief that the vaccine is effective (P ≤ 0.000), ignoring vaccination as a healthy behavior (P ≤ 0.000), and younger age (P ≤ 0.026).

And do not mention the paranoid medical-industrial conspiracy delusion that seems to be at the heart of a vocal subset of vaccine refusers. I make no money from giving the flu vaccine or from promoting the flu vaccine. Promoting the flu vaccine, like much of my professional life, is counter-productive to making money. I make money, and can prescribe with abandon to line the pockets of my corporate masters, only when people are admitted with the flu. At least, in the other Bizarro world where people have health insurance. Not always my world. The last thing I would want to do financially is prevent influenza.

Association is not causation

The other theme is that they, or someone they knew, had the vaccine and shortly thereafter had some adverse reaction attributed to the vaccine. Like the paranoid conspirators, the idea that the vaccine caused the subsequent disease is not amenable to logical refutation. It is a motto in the skeptical world that association is not causation, but it is a concept that is paid little attention.

Humans underestimate the role of randomness in their life and I recommend the Drunkards Walk as an excellent book on the topic. You have to know the background rate of events to know if there is an increased rate associated with a vaccine as a hint that the vaccine is potentially causative. For example:

On the basis of the reviewed data, if a cohort of 10 million individuals was vaccinated in the UK, 21·5 cases of Guillain-Barré syndrome and 5·75 cases of sudden death would be expected to occur within 6 weeks of vaccination as coincident background cases. In female vaccinees in the USA, 86·3 cases of optic neuritis per 10 million population would be expected within 6 weeks of vaccination. 397 per 1 million vaccinated pregnant women would be predicted to have a spontaneous abortion within 1 day of vaccination.

Random badness happens and it takes an immense, and for some impossible, effort of will to ignore what appears to be an association. Take, as example, death. People die. People get the vaccine. A hefty segment of those who get the vaccine are at risk of dying from underlying diseases. So you would predict that there would be a cluster of people who will die shortly after receiving the vaccine, but not due to the vaccine, as if anyone would be convinced otherwise:

In October 2006, four deaths occurred in Israel shortly after influenza immunization, resulting in a temporary halt to the vaccination campaign. After an epidemiologic investigation, the Ministry of Health concluded that these deaths were not related to the vaccine itself and the campaign resumed; however, vaccine uptake was markedly reduced. Estimates of true background mortality in this high-risk population would aid in public education and quell unnecessary concerns regarding vaccine safety. We used data from a large HMO to estimate mortality in influenza vaccine recipients aged 55 and over during four consecutive winters (2003, 2004, 2005 and 2006). Date of immunization was ascertained from patient treatment files, vital status through Israeli National Insurance Institute data. We calculated crude death rates within 7, 14 and 30 days of influenza immunization, and used a Cox Proportional Hazards Model to estimate the risk of death within 14 days of vaccination, adjusting for age and comorbid conditions (age over 75, history of diabetes or cardiovascular disease, status as homebound patient) in 2006. The death rate among influenza vaccine recipients ranged from 0.01 to 0.02% within 7 days and 0.09-0.10% at 30 days. Influenza immunization was associated with a decreased risk of death within 14 days after adjustment for comorbidities (Hazard ratio, 0.33, 95% CI, 0.18-0.61). Our findings support the assumption that influenza vaccination is not associated with increased risk of death in the short term.”

Yet I know, and you know, that any event after a vaccine will be credited to the vaccine, even, as with death, the preponderance of data points to the influenza vaccine decreasing mortality.

It was better back in the day

As a grumpy old fart who thinks that medical training was better back in my day, I have one piece of data in support of that assertion. An abstract at IDSA, and reported in Medscape suggests:

…that more recent graduates were 15% less likely than older graduates to believe that vaccines are effective. The younger graduates were also less likely to believe that inactivated or oral polio, measles, mumps, rubella, and varicella vaccines are safe.

Great. I suppose that my initial hypothesis was wrong. Having access to the world’s literature and the best minds in medicine is not so conducive to understanding the benefits of vaccines. Given the other nonsense taught in medical schools that is given the patina of respectability, what should I expect?

Posted by Mark Crislip

Mark Crislip, MD has been a practicing Infectious Disease specialist in Portland, Oregon, since 1990. He has been voted a US News and World Report best US doctor, best ID doctor in Portland Magazine multiple times, has multiple teaching awards and, most importantly,  the ‘Attending Most Likely To Tell It Like It Is’ by the medical residents at his hospital. His multi-media empire can be found at edgydoc.com.