Episode 011 marks our official foray into microbiology and infectious disease.

Resources

I mentioned that I really find a particular clinic-oriented textbook (Wright’s Essentials of Clinical Infectious Disease) to be quite useful for at-a-glance info on which meds and tests to use for common complaints. Alex mentioned This Podcast Will Kill You for medium-yield micro learning in your spare time.

Vocab

Lexicon of Orthopaedic Etymology, 1999

Our vocab word for this episode is ‘felon,’ which refers to an infection of the pulp of the fingertip. Paronychia is another finger infection to be aware of (located more in the cuticle area). The etymology of felon as it refers to finger infections was a little difficult to get to the bottom of, but eventually we sorted it out using this reference.

Vaccine reactions?

I mentioned that propofol is in a suspension with soy and egg ingredients, meaning that technically it’s contraindicated for patients with sensitivities to those things. Soy is probably a hard contraindication(?), and some consider it not the best idea for folks with egg allergies, but in practical terms, at least according to Rosen, it’s likely safe. Here’s what Rosen says:

“Propofol is delivered in a soybean oil and lecithin vehicle and should not be used for patients with allergies to these substances. Although propofol has traditionally been avoided in patients with egg allergy, it is likely safe unless a history of anaphylaxis to egg protein exists.”

I mentioned a random article I found (referenced from here) while we were talking, from 1980, that says out of 48 million influenza vaccinations, there were just 11 episodes of anaphylaxis.

Oseltamivir & the BMJ

We did a quick run-through of some of the micro concepts related to influenza and then launched into a discussion of the evidence for and against use of oseltamivir (aka Tamiflu). This was a difficult undertaking to prepare for, because there’s just so much on this topic that it’s hard to reduce it to a podcast format. If you take a look at the dedicated portion of their website the BMJ has had to develop to house all of the evidence on the ‘oseltamivir controversy’ you can get a quick sense of what we mean. In the end, the two papers we used to try to give an overview of this were both from the BMJLENZER, 2015 + DOSHI, ET AL, 2012.

  • 22,000+ pgs of clinical study reports, 2700+ pgs of regulatory comments
  • Data review: equivalent of two full-time researchers for 14 months
  • Published papers: “there were no drug-related serious adverse events,” VS trials data: 3 serious adverse events possibly related to treatment
  • “…complications like pneumonia lacked a standardised definition”
  • Placebos that were colored differently from the drug and had unexplained ingredients
    • “We lost faith in the idea that the many trials reported as “placebo controlled” were in fact controlled by inert, visually indistinguishable placebos”
  • “Although participants had been randomised in the expected proportions (usually 1:1), those receiving oseltamivir had a 21% reduced odds of showing a fourfold increase in influenza antibody titre, suggesting that oseltamivir may inhibit the body’s ability to mount a normal immune response to influenza. This raises questions regarding oseltamivir’s true mode of action and probably makes all analyses of the population thought to be infected with influenza (the primary efficacy analysis population) as invalid because the groups are no longer comparable.”

To include just a few more references, here’s a second paper in which Doshi is an author:

The Imperative to Share Clinical Study Reports: Recommendations from the Tamiflu Experience, PLoS Med → Prior to the global outbreak of H1N1 influenza in 2009, the United States alone had stockpiled nearly US$1.5 billion dollars worth of the antiviral. As the only drug in its class (neuraminidase inhibitors) available in oral form, Tamiflu was heralded as the key pharmacologic intervention for use during the early days of an influenza pandemic when a vaccine was yet to be produced. It would cut hospitalizations and save lives, said the US Department of Health and Human Services (HHS). The Advisory Committee on Immunization Practices (ACIP, the group the US Centers for Disease Control and Prevention [CDC] uses to form national influenza control policy) said it would reduce the chances of developing complications from influenza. So, too, did the Australian Therapeutic Goods Administration and the European Medicines Agency (EMA).

Most (perhaps all) of these claims can be traced back to a single source: a meta-analysis published in 2003 that combined ten randomized clinical trials conducted during the late 1990s by the manufacturer prior to US registration of the drug. This analysis, conducted by Kaiser and colleagues, proposed that oseltamivir treatment of influenza reduced both secondary complications and hospital admission. In contrast, the Food and Drug Administration (FDA), which approved Tamiflu in 1999 and was aware of these same clinical trials, concluded that Tamiflu had not been shown to reduce complications, and required an explicit statement in the drug’s label to that effect. FDA even cited Roche, Tamiflu’s manufacturer, for violation of the law for claims made to the contrary.

A NY Times article:

https://www.nytimes.com/2012/04/11/opinion/drug-data-shouldnt-be-secret.html → In the fall of 2009, at the height of fears over swine flu, our research group discovered that a majority of clinical trial data for the anti-influenza drug Tamiflu — data that proved, according to its manufacturer, that the drug reduced the risk of hospitalization, serious complications and transmission — were missing, unpublished and inaccessible to the research community. From what we could tell from the limited clinical data that had been published in medical journals, the country’s most widely used and heavily stockpiled influenza drug appeared no more effective than aspirin.

After we published this finding in the British Medical Journal at the end of that year, Tamiflu’s manufacturer, Roche, announced that it would release internal reports to back up its claims that the drug was effective in reducing the complications of influenza. Roche promised access to data from 10 clinical trials, 8 of which had not been published a decade after completion, representing more than 4,000 patients from every continent except Antarctica. Independent verification of the data seemed imminent. But more than two years later, and despite repeated requests, we have yet to receive even a single full trial report. Instead, the manufacturer released portions of the reports, most likely a very small percentage of the total pages. This is entirely within Roche’s rights. After all, regulators have never required drug or medical device manufacturers to share their data with independent researchers or academics. They are required to show the information only to the regulators themselves, who treat the data as secret.

Some may argue that, because the Food and Drug Administration approves drugs for the United States market based on these data, this is not a major cause for concern. But the actual use of drugs is often driven by assumptions about drug safety and effectiveness put forth by articles in peer-reviewed journals (sometimes written by doctors affiliated with the drug manufacturers) and clinical practice guidelines that can be entirely inconsistent with the F.D.A.’s assessments.

In the case of Tamiflu, some of these assumed properties led to stockpiling at great taxpayer expense — more than $1.5 billion. The F.D.A. approved Tamiflu for the treatment of influenza (on the basis that it could reduce the duration of flu symptoms by about a day); not for the prevention of transmission. But other agencies are far more enthusiastic about Tamiflu’s benefits. The Centers for Disease Control and Prevention has argued that it reduces the duration of hospitalizations and serious complications like pneumonia, citing Roche-authored papers. The Department of Health and Human Services, also citing Roche, assumed in its national influenza pandemic plan that Tamiflu would cut complications. And the World Health Organization’s pandemic planning assumed that the drug would cut transmission of the virus. But here’s the rub: none of these organizations have vetted the original trial data

And commentary from Cochrane:

https://www.cochrane.org/news/tamiflu-and-relenza-getting-full-evidence-picture → Since 2002, governments around the world have spent billions of dollars stockpiling neuraminidase inhibitors (NIs) such as Tamiflu® (oseltamivir) and Relenza® (zanamivir) in anticipation of an influenza pandemic. This trend increased dramatically following the outbreak of the H1N1 virus (swine flu) in April 2009. It was initially believed that NIs would reduce hospital admissions and complications of influenza, such as pneumonia, during influenza pandemics. However, the original evidence presented to government agencies around the world was incomplete, raising questions about the accuracy of these claims and the efficacy of both preparations. An international team of researchers, based in Australia, Italy, Japan, the UK, and the US, working with the Cochrane Acute Respiratory Infections Group, expanded their research beyond the typical systematic review analysis, which focused on using published trial reports available in scientific journals. [Public trials] reported on only a small percentage of the research carried out on the effectiveness of NIs. Over the last six years, following publication of the first Cochrane Reviews of oseltamivir and zanamivir, the Cochrane NI Research Group has accessed and reviewed more than 160,000 pages of regulatory documents in order to examine the full evidence picture.
The latest updated Cochrane Review, published on 10 April 2014, is based on full internal reports of 20 Tamiflu and 26 Relenza trials. These trials involved more than 24,000 people and the findings challenge the historical assumption that NIs are effective in combating influenza. The review confirms small benefits on symptom relief, namely shortening duration of symptoms by half a day on average. However, there is little evidence to support any belief that use of NIs reduces hospital admission or the risk of developing confirmed pneumonia. The evidence also suggests that there are insufficient grounds to support the use of NIs in preventing the person-to-person spread of influenza.
This latest Cochrane Review has benefited from access to more complete reports of the original research, now made available by the manufacturers, Roche and GlaxoSmithKline. Along with documenting evidence of harms from use of NIs, the review raises the question of whether global stockpiling of the drugs is still justifiable given the lack of reliable evidence to support the original claims of its benefits.  
Dr David Tovey, Editor-in-Chief of The Cochrane Library, commenting on the release of the updated Cochrane Review, said: “We now have the most robust, comprehensive review on neuraminidase inhibitors that exists. Initially thought to reduce hospitalisations and serious complications from influenza, the review highlights that [NIs are] not proven to do this, and it also seems to lead to harmful effects that were not fully reported in the original publications. This shows the importance of ensuring that trial data are transparent and accessible.”

Dissuading folks who demand prescriptions

I mentioned having planned ahead for the possibility that a patient might demand antibiotics for an illness where they aren’t warranted. One can fight a patient over this, but that doesn’t seem likely to create a good outcome (or really be in the spirit of partnering with patients). Rather, it might be better to try to demonstrate to the patient that you’re aligned with their interests. One idea is mentioning the downsides of taking antibiotics. Namely, for something like amoxicillin clavulanate, there’s a 1-in-4 or 1-in-5 rate of antibiotic associated diarrhea.

Appendicitis: surgery or abx?

Kim told a story of a relative being misdiagnosed as having gastroenteritis rather than appendicitis and only getting the correct diagnosis two weeks later after becoming septic. I mentioned that antibiotic therapy is increasingly seen as a viable alternative to surgery in appendicitis. While this is a topic we will dig a lot more into during a future episode, I figured I’d provide at least a couple links to back that up. Here’s a randomized trial published in JAMA in 2015 in which 530 patients were randomized to either surgery or antibiotics. The trial did not meet its ‘noninferiority’ outcome measure, since 27.3% of the antibiotic patients needed surgery within one year (pre-specified outcome threshold for noninferiority was 24%). But it’s worth noting the antibiotic arm had a lower complication rate (2.8% for antibiotics versus 20.5% for surgery) and needed fewer sick days to recover (7 vs 19). Also, 0.7% of those who received surgery were found not to have appendicitis (based on histologic criteria). Finally, in this 5-year-followup study of the same trial, also published in JAMA, they found by the end of the fifth year after the antibiotic intervention that 60+% were still appendicitis-free (end of: Y1 72.7%, Y2 66%, Y3 64.8%, Y4 62.9%, Y5 60.9%).

Apology laws

If you want to read the WA apology law for yourself, it’s located here. For a bit more insight into how Washington stands out in this regard, checkout this 2010 Health Affairs article. To excerpt just a bit of it:

Six of the nine states with mandatory or discretionary disclosure laws provide legal protection for the communication in subsequent litigation. In five of those states, the protected communication is limited to a statement that an unanticipated outcome occurred, such as, “During the operation, your ureter was injured.” Only one state, Washington, also protects explanations and expressions of sympathy such as, “I’m sorry your ureter was injured during the surgery.” All six of the states whose disclosure laws provide legal protection also have separate apology laws that may be relevant.

Among the nine states with mandatory or discretionary disclosure laws, Washington’s approach is unique, offering the most comprehensive protection of disclosure conversations for health care providers. It adopted what reads like a combination disclosure-and-apology law. The statute explicitly provides protection for an explanation of the event and an expression of sympathy offered as part of a voluntary disclosure conversation with the patient, such as, “I’m sorry your ureter was injured when a surgical tool malfunctioned during the operation.” Washington also has a separate apology law that could extend protection to an admission of fault.

Isopropyl alcohol for nausea?!

We had a semi-impromptu discussion of the 2018 Annals of Emergency Medicine article, “Aromatherapy Versus Oral Ondansetron for Antiemetic Therapy Among Adult Emergency Department Patients: A Randomized Controlled Trial.” This was an RCT with three arms, looking at placebo, inhaled isopropyl alcohol aroma, and ondansetron in treatment of nausea and vomiting. Each arm had two of the interventions → placebo + alcohol, placebo + ondansetron, alcohol + ondansetron. Ondansetron + alcohol performed best, although only marginally better than alcohol alone, with ondansetron doing poorly by itself. This is counter to my own observations of ondansetron’s effectiveness, which leads me to wonder if the 30 minute measurement threshold gave an advantage to alcohol.

EBM

To round out our earlier discussion of a problematic meta-analysis related to Tamiflu, we decided to briefly discuss the paper, “The Mass Production of Redundant, Misleading, and Conflicted Systematic Reviews and Meta-analyses” by Ioannidis in Millbank Quarterly. The main take-away is that there has been a huge increase in junk papers being published, particularly those that don’t require trials (etc), and so one should approach the evidence skeptically rather than simply replying on heuristics like “meta-analyses are better than expert opinion.” If the meta-analysis was poorly conducted and funded by industry it may in fact be less informative than expert opinion.

 


— Episode credits —

Hosted by Addie, Kim, and Alex. Audio production and editing by Addie. Show notes written by Addie. Railway sound by Satish Madiwale. Theme music compositions (Too Cool, and Laserpack) by Kevin MacLeod of incompetech.com, licensed under Creative Commons: By Attribution 3.0 License.