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.

Deus ex machina: duabus partibus (Part Two) - Tiny Magnets

With infectious diseases, there is always another miracle around the corner.  The problem is that the miracle typically stays around the corner. Come on down...The next contestants in the search for a miracle cure are..."tiny magnets."

Researchers in Switzerland are developing nanomagnets that could remove harmful compounds (e.g. bacteria) from the blood. The technology involves magnetized nanoparticles coated with carbon and pathogen-directed antibodies. The plan is that the antibodies attach to the pathogens and then the whole compound is removed from the blood with hemodialysis. Sounds pretty exciting. Probably exciting enough to hold off on further investments in infection prevention research, not!

Source: Technology Review (MIT): 11/28/2011

It's a vaccine, not a miracle

There apparently was a recent rumor causing quite a stir in some segments of the infectious diseases community that a paper was about to be published that would show that influenza vaccine doesn't work. Well, the paper was published yesterday and the results don't quite match the rumor. Osterholm and colleagues have published a systematic review and meta-analysis on the efficacy and effectiveness of influenza vaccine in Lancet Infectious Diseases. The major finding was that the pooled efficacy of the vaccine is 59%. This is somewhat lower than that found by the Cochrane group (73% in years when the vaccine and circulating strains were well matched); however, there were some differences in methodology that are well outlined in an editorial that accompanies the paper.

Shocking? I don't think so. I have never thought that influenza vaccine was a great vaccine. It's a good vaccine; certainly good enough to widely recommend its use. But clearly not so good as to fire healthcare workers who refuse to take it.

Two years ago I blogged about the interview in the Atlantic with Tom Jefferson, the head of the Cochrane influenza group. Here's the money quote from that interview:

"For a vaccine to reduce mortality by 50 percent and up to 90 percent in some studies means it has to prevent deaths not just from influenza, but also from falls, fires, heart disease, strokes, and car accidents. That's not a vaccine, that's a miracle."

The Rise of the MIC: Microbiological Industrial Complex

Mike "Alexander" Edmond

Note: This is the post I wanted to write regarding the NIH Clinical Center KPC outbreak last week until I noticed the posts and comments blaming the front line infection prevention staff.

"...we must guard against the acquisition of unwarranted influence, whether sought or unsought, by the military-industrial complex (MIC). The potential for the disastrous rise of misplaced power exists and will persist....As we peer into society's future, we-you and I, and our government-must avoid the impulse to live only for today, plundering, for our own ease and convenience, the precious resources of tomorrow. We cannot mortgage the material assets of our grandchildren without risking the loss also of their political and spiritual heritage." - President Eisenhower's Farewell Address January 17, 1961

In microbiology and clinical medicine, the MIC is the "lowest concentration of an antimicrobial that will inhibit the visible growth of a microorganism after overnight incubation."  I think it's time to recognize a new definition for MIC: the Microbiological Industrial Complex. The MIC encompasses the industry, associated lobbying efforts and government agencies that most benefit from the adoption of expensive and unproven testing and treatment. The MIC has had a tremendous impact on infection prevention practice through economic forces pushing for MRSA active surveillance mandates and perhaps mandatory flu vaccinations of health care workers. This MIC leads to the utilization of expensive (and largely unproven) interventions at great cost both economically and to the well-being of patients.  The more we spend on expensive sequencing, the less we can spend on actual prevention. Hand hygiene might not be sexy, but it does more to prevent the spread of resistant infections than any PCR test.

The latest evidence of the insidious rise of the MIC is the initial discussion surrounding the NIH Clinical Center KPC outbreak. So far, the only paper describing the outbreak covered the miracle of whole-genome sequencing and how it helped halt the outbreak, which it most certainly did not. The outbreak was halted using a grab bag of unproven and expensive interventions including the hiring of 9 hand hygiene "police" that monitored infection control practice 24-7.  Even NIH's Henry Masur speaking today on the Diane Rehm show said that sequencing "didn't conclusively prove" (what caused the outbreak).  Both he and Jule Segre suggested they only stepped up their infection control efforts because of the whole genome sequencing evidence, which is almost certainly not true. They would have used infection control escalation even without expensive testing. (listen to the Diane Rehm show segment here)

To understand the power of the MIC, you don't have to look further than a recent MSNBC report, which noted that the NIH sequencing cost $40,000 and suggested that this technique could spawn a $1 billion industry in the US alone. In discussing the whole genome technique, Dr. Segre was noted to say "When you have patients in your ICU who just paid $100,000 for an organ transplant,"...spending a few thousand dollars to protect them from an outbreak of deadly bacterial infections "doesn't seem like too much to ask."

It seems to me that since there is no evidence that whole genome identified the source of transmission here or elsewhere and even if it did it wouldn't have altered the course of the outbreak, we might better spend our infection control research and clinical dollars elsewhere.  Unfortunately, the MIC has more money and more NIH backing. The NIH has a National Human Genome Research Institute but it doesn't have a "National Infection Prevention Institute", for example.

Almost a year ago, Mike peered through his crystal ball and accurately predicted the future of KPC prevention in the US.  The NIH outbreak and report starts the countdown, and much like MRSA before it, the prevention efforts will be focused on expensive DNA surveillance efforts backed by large industry lobbying efforts and not investments in the research and expansion of basic and simple infection control efforts. It is easy to blame the healthcare worker for not washing their hands and look for a quick scientific panacea (DNA). Sadly, given that there have been only four high-quality hand hygiene improvement studies since 1980, we haven't provided clinicians with the proven tools to improve hand hygiene. If we continue to bow to the pressure of the MIC and avoid the harder tasks of infection prevention, we will be squandering our precious resources of tomorrow (antibiotics), as Eisenhower warned 50 years ago.

Further Reading:
(1) Maryn McKenna: The ‘NIH Superbug’: This Is Happening Every Day
(2) Ed Yong:  Genome detectives unravel spread of stealthy bacteria in a hospital
(3) Dr. Judy Stone: The NIH Superbug Story-A Missing Piece
(4) Mike the Mad Biologist: Some thoughts on the CRE Superbugs

Image source: wikimedia commons

Intrigued by the plot of Kent Sepkowitz’ perspective piece on antibiotic stewardship in the NEJM

This is a guest-authored piece by Dr. Tom Gottlieb (Senior Specialist in Microbiology and Infectious Diseases, Concord Hospital, New South Wales, Australia), wherein he discusses Kent Sepkowitz's latest commentary in the NEJM.

This is writ in the genre of a thriller in which a new generation of ID physician villains (the previous heroic ID generation’s illegitimate offspring, it seems ) abound as ‘fervent’ ‘chastisers of antibiotic overuse and abuse’. These ‘self-pitying’, ‘inept’, ‘feckless’ ‘prohibitionists’, ‘gnawed with regret’, indeed ‘deranged’, threaten to undermine and disenfranchise the orderly world of antibiotic prescribing, by seeking to banish miracle antibiotics forever from the world. Indeed their quest, (in cahoots with the loonies of the anti-vaccination lobby), is so dangerous, it is spelt out in the more sophisticated French; “an idée fixe”. These antibiotic nihilists cannot appreciate the true contribution antibiotic chemotherapy has made to individual patient care and also to the global well being of humanity.

Now I too enjoy debunking zealotry, and would not deny that there is plenty about antibiotic stewardship that is worth challenging in a balanced discourse. And stewardship, (or is it shepherd-ship?) can be clearly problematic. As ID physicians, we are frequently left in a schizoid situation where, as on one hand we attempt to control unnecessary use, on the other, in individual care we often contribute to broad-spectrum prescribing. Moreover some clever contrarianism never goes astray. But Sepkowitz’ pendulum swings beyond healthy scepticism, past contrarianism, to something akin to denialism.

Damn it, I too need to reach for the French dictionary. Un agent provocateur? Peut-être, saboteur? Because there is significant damage caused when worthwhile attempts, not as suggested by Sepkowitz to deny antibiotics for patients, but to preserve antibiotics into an uncertain future, are derided by ID doyens. But without him providing us with any cogent examples of groups or policies that would support the existence of these villanous ‘antibiotic prohibitionists’. And the very simplistic, polemical, good versus evil like vision he paints, creates a disservice to the antibiotic debate. (Or is it that for the sake of a good argument, as Oscar Wilde wrote, Sepkowitz feels that “in matters of great importance, style, not sincerity is the vital thing”)

I agree with Sepkowitz that “just in case” prescribing, often saves the day in settings of uncertainty. But one of the banes of our clinical existence is ‘just in case’ prolonged orthopedic prophylaxis, ‘just in case’ ceftriaxone in heart failure, ‘just in case’ stat gentamicin dose pre catheter removal, just in case treatment in case confusion is caused by a urine infection, or a few more days of treatment ‘just in case’, etc..; situations in which antibiotics are used to treat the prescribers’ anxieties rather than the patient’s condition.

I find Sepkowitz’s piece in the NEJM more a diatribe than a commentary. But it is a very useful piece too. It is a wake-up call that if we fail to convince other ID physicians regarding the merits of prudent antibiotic use, we have a long way to go to change attitudes amongst medical peers or in the community.

Image: Nicolas Poussin's Adoration of the Golden Calf. "The Golden calf of Stewardship" paraded in front of idolatrous ID physicians?

Flu vaccine: Too good to be true?

There's a well written, provocative article in the November issue of The Atlantic on influenza vaccination and how the evidence for its effectiveness is overstated. In the article Tom Jefferson, the head of the Vaccines Field at the Cochrane Collaboration, says "For a vaccine to reduce mortality by 50 percent and up to 90 percent in some studies means it has to prevent deaths not just from influenza, but also from falls, fires, heart disease, strokes, and car accidents. That's not a vaccine, that's a miracle." The writers describe how Jefferson has been shunned by the vaccine research community. The article has been branded by some as anti-science and anti-vaccine, but I didn't sense that. I still think the benefits of influenza vaccine outweigh the risks and continue to promote vaccination of healthcare workers, but I don't believe the evidence for effectiveness is strong enough to mandate vaccination.

On penicillin

Today, we have a guest post by Philip Lederer, an Infectious Disease fellow at Massachusetts General Hospital and Brigham and Women’s Hospital, and a former Epidemic Intelligence Service Officer at the Centers for Disease Control and Prevention (CDC). His views do not represent any of those organizations.

Bright and alert, the elderly woman sat in a chair in the corner of her hospital room. Snow fell lightly outside. An IV ran into her arm, giving her antibiotics for a bloodstream infection. Meanwhile, she told me her story:

“I started nursing school in 1943 and soon after we first started giving penicillin. I don’t remember my first patient who got it, but we ended up giving it to many people. We didn’t realize at the time that penicillin would turn out to be so amazing. What I remember most clearly was the size of the 18-gauge needle we used. It was so big. We had to inject intramuscularly, into the patients’ buttocks, every four hours. It would turn their buttocks black. And the injections were so painful. 

When I would walk into a patient’s room, I would think, ‘Oh God, do I really have to do this again?’ 

But before penicillin, people died, and afterwards, they lived. The patients loved it and hated it at the same time. It was wonderful and horrible.”

Now, more than seventy years later, we are heading towards an era of untreatable bacterial infections. The penicillin miracle may someday be a memory. As an infectious disease physician-in-training, I see antibiotic resistant bacterial infections every day. I believe the writing is on the wall.

While the Centers for Disease Control and Prevention (CDC) and the White House have issued reports and launched initiatives, little is changing in the trenches, our hospitals and clinics. Antibiotics are prescribed widely and often carelessly. There are no easy solutions, other than a wholesale change in the practice of medicine and an emphasis on antibiotic stewardship.

Digging in the Dirt - For Antibiotics

Not a week goes by without some claim of a new miracle antibiotic. Usually, when I read the press releases I yawn and go back to washing my hands. It's not like any of these magical compounds will ever make it to human studies. However, today's article in the NY Times describing a "powerful new antibiotic" piqued my interest. Dr. Kim Lewis from Northeastern University in Boston and her team just reported (Nature 7 January 2015) the discovery of a novel cell wall inhibitor called teixobactin. What was unique about their discovery was that they identified the compound by screening soil from a "grassy field in Maine." This is a big deal since 99% of environmental bacteria can't be cultured under typical laboratory conditions, so their method of "tricking the bacteria" into thinking they are back in their native 'dirt' is important.

Once the authors identified the compound teixobactin from the uncultured bacteria, they showed that it had excellent in-vitro activity against Gram-positive bacteria including enterococci, C. difficile, B. anthracis, and S. aureus (including VISA strains). (Table 1, below) They also tested the in-vivo efficacy against MRSA and S. pneumoniae in a mouse model and reported excellent results. Intriguingly, the authors said that "resistance has not developed...suggesting that the target is not a protein" and since there exists a similar lack of resistance development to vancomycin through mutations, they postulated "that teixobactin could be acting against the same (lipid II) target."

I agree with Dr. William Schaffner's comments in the NY Times as he called the study/method “ingenious” yet also cautioned that "it’s at the test-tube and the mouse level, and mice are not men or women, and so moving beyond that is a large step, and many compounds have failed.” I would add one additional caveat  - teixobactin had little activity against most Gram-negative bacteria including E coli, Klebsiella and Pseudomonas. (Table 1, above) Since the real resistance crisis is in multi drug-resistant Gram-negatives (think CRE, NDM-1), we better get back to digging in the dirt.

Shocking: Another review of the evidence finds flu vaccine has no miracle powers

The Science section of the New York Times this week had an article on a new report regarding influenza vaccination. This report (free full text here) from the University of Minnesota is the kingdaddy of all analyses on influenza vaccination--a 3-year project funded by the Alfred P. Sloan Foundation that reviewed 12,000 papers back to 1936 and involved interviewing 88 influenza experts. The report is 123 pages without appendices and includes over 500 references. 

Here's my summary of the chapter on vaccine performance of the two major vaccines (trivalent inactivated influenza vaccine [TIV] and live attenuated influenza vaccine [LAIV]):

Population	TIV	LAIV
Children	Inconsistent evidence of protection	High level of protection (83%)
Healthy adults	Moderate protection (59%)	Lack of evidence of protection
Elderly	Paucity of evidence for protection	Inconsistent evidence of protection

What about use of the vaccine in healthcare workers? This can be found on pages 57-58 of the report and I have pasted below the important discussion of the HICPAC recommendation regarding offering influenza vaccine to healthcare workers):

The 2006 statement on influenza vaccination of healthcare personnel (HCP) from the Healthcare Infection Control Practices Advisory Committee (HICPAC) and ACIP illustrates potential concerns with using a grading scale.[63] This recommendation used the HICPAC grading scale, which is similar to the GRADE criteria in that it provides a structure for ranking the evidence. All recommendations were approved by the HICPAC and the ACIP. This document has been used widely as evidence to support HCP vaccination policies, including mandating vaccination. It offers six recommendations, and one was deemed to have the highest possible evidence, category IA. Category IA recommendations are “strongly supported by well-designed experimental, clinical, or epidemiological studies.”[63] The recommendation in the HICPAC document that received a category IA rating states:  “Offer influenza vaccine annually to all eligible HCP to protect staff, patients, and family members and to decrease HCP absenteeism. Use of either available vaccine (inactivated and live, attenuated influenza vaccine [LAIV]) is recommended for eligible persons. During periods when inactivated vaccine is in short supply, use of LAIV is especially encouraged when feasible for eligible HCP.”[63]

This recommendation is supported in part by this key summary statement in the HICPAC document: “Vaccination of HCP reduces transmission of influenza in healthcare settings, staff illness and absenteeism, and influenza-related morbidity and mortality among persons at increased risk for severe influenza illness.[64-67]” In the first study cited, the authors did
not find a statistically significant reduction in patient mortality associated with HCP vaccination, after adjusting for covariates.[64] In the second study, the authors concluded that “we do not have any direct evidence that the reductions in rates of patient mortality and influenza-like illness that were associated with HCW vaccination were due to prevention of influenza.”[65] In the third study, vaccination did not reduce the episodes of self-reported respiratory infection or the number of days ill with a respiratory infection, but it did reduce the time employees were 58 unable to work because of a respiratory infection.[66] In the fourth study, the authors reported reductions in absenteeism and illness among HCP that were not statistically significant.[67] The authors did, however, report serologically confirmed vaccine effectiveness of 88% for H3N2 and 89% for influenza B across three influenza seasons.[67] Since only two of the four studies cited provide some support for the HICPAC statement and the others no support, it is unclear how the quality of evidence in these studies received a category IA evidence grade. Another review conducted in the same time frame by the Cochrane Collaboration noted that the two RCTs cited in this recommendation were at “moderate risk of bias.”[68] They concluded that “both elderly people in institutions and the healthcare workers who care for them could be vaccinated for their own protection, but an incremental benefit of vaccinating healthcare workers for elderly people has yet to be proven in well-controlled clinical trials.”[68]

So this report questions the evidence base for even recommending influenza vaccination to healthcare workers. Yet, SHEA's position is so over-reaching that it calls for mandating vaccination and firing noncompliant healthcare workers. This is now the fourth independent analysis that does not support the SHEA position statement (read about the others here, here and here).

I continue to be fascinated by the post-modern disdain for evidence. A marvelous example from this week is the shock and utter disbelief suffered by Mitt Romney and his staff on learning that Barack Obama won the presidential election, despite nearly every poll indicating that Romney would lose. I guess I naively thought that somehow epidemiologists were immune to such bias but SHEA's flu vaccine position suggests otherwise.

One of the recommendations in the Minnesota report is that "scientifically sound estimates of influenza vaccines’ efficacy and effectiveness must become the cornerstone of policy recommendations." Amen. And it's time for SHEA to retract its policy!