Why I'm a Liberal User of Tamiflu

In the midst of the current flu season -- which is likely one of the worst in over a decade with the exception of the pandemic in 2009-10 -- there has been a lot of discussion regarding the benefits of Tamiflu (oseltamivir), the only oral antiviral indicated for the treatment of influenza in the US (the adamantane class of antivirals is virtually obsolete due to widespread resistance). Thus far there have been at least 37 pediatric deaths with more sure to come. 

I am a liberal user of Tamiflu and I hope to help people understand why in this post. Tamiflu, which was FDA approved in 1999, is an antiviral that blocks the ability of the virus to release from cells -- it inhibits the viral neuraminidase enzyme. It is given twice daily, for 5 days. In multiple randomized clinical trials, such as this one,  it has been shown in healthy adults to diminish the duration and severity of symptoms when given within 48 hours of symptom onset. This type of clinical use is non-controversial and very well accepted.

However, the controversy begins -- and it is impossible to describe all its nuances in a simple blog post -- when treatment is done outside of the 48 hour window or when the purpose is to diminish complications of influenza such as otitis media, pneumonia, hospitalization, ICU admission, the need for mechanical ventilation, and death or to diminish contagiousness. 

What fuels the controversy? To me, I think there are several reasons. One is the fact that people fail to realize that a trial in healthy adults with uncomplicated flu isn't designed to study the cascading impact of influenza -- they were designed, primarily, to look at symptom duration and severity in uncomplicated flu in low-risk patients. is the fact that people are trying to extrapolate trial results and trial populations outside of their proper realm. The 48 hour window cannot be applied with the same confidence to a pregnant woman, an immunocompromised person, an infant too young to be vaccinated, or a person with chronic illness such as asthma, COPD, or the like. 

During 2009 H1N1, it was shown in retrospective analysis (which may fall short of the gold standard randomized control trial but is nevertheless something that still provides valuable information) that receipt of Tamiflu correlated with outcome in severe influenza in multiple studies such as this one.

Because of this data the CDC has recommended antiviral therapy be used in the following high-risk groups (irrespective of any 48 hour window and irrespective of a confirmed laboratory diagnosis):

• children less than 2 years of age
• adults aged 65 years and older;
• persons with chronic pulmonary, cardiovascular , renal, hepatic, hematological, and metabolic disorders (including diabetes), or neurologic and neurodevelopment conditions 
• persons with immunosuppression, including that caused by medications or by HIV infection;
• women who are pregnant or postpartum 
• persons aged younger than 19 years who are receiving long-term aspirin therapy;
• American Indians/Alaska Natives;
• persons who are morbidly obese 
• residents of nursing homes and other chronic care facilities.

Ideally, these people should be treated as soon as possible but benefit may still accrue with later treatment. Unfortunately, many healthcare providers don't know these risk groups well and many people who could benefit from antiviral therapy are overlooked. Those without risk factors can also benefit from Tamiflu, especially if given early in the course of illness.

The side effects of Tamiflu, in my experience, are generally mild and involve nausea and vomiting and are outweighed by the benefits of treatment in most cases (and can be treated anti-nausea medications). However, I have seen some parents complain that children do not like the taste of the suspension and question the need for Tamiflu. If taste is the issue, capsules can be substituted and, if the child cannot swallow them, they can be opened and the contents put into a substance of choice (ice cream, pudding, etc). 

Optimizing the treatment of seasonal influenza is an important task that is all the more important in a moderately severe season. It will be of enormous importance during the next pandemic and familiarity and comfort among the patients, parents, and healthcare providers is essential for the population to be best equipped for that eventuality. 

Thank You Joseph Lister: A Review of The Butchering Art

One of the ways in which a correct revolutionary idea changes the world is when it becomes integrated into other fields allowing those new fields to leap forward via a shimmering green light provided by the original idea. This is how I think about the germ theory of disease as articulated by Louis Pasteur. Pasteur's pathbreaking identification, which stemmed from Pasteur's work with industrial concerns such as the manufacture of silk and the manufacture of wine, is arguably the most important idea in medicine. While it is obvious how such an idea would impact the diagnosis and control of infectious diseases -- an impressive feat in its own right -- the impact the germ theory had on surgery is also inestimable. 

The idea transmission belt, in this case, begins with Pasteur and ends with Joseph Lister. This topic is expertly explored by medical historian Lindsey Fitzharris in her book The Butchering Art: Joseph Lister's Quest to Transform the Grisly World of Victorian Medicine. In this book, Fitzharris engrosses the reader with gruesome tales of what surgery was like in the 19th century: scary, dangerous, and often restricted to external maladies (as opposed to internal medicine which non-surgically treated diseases of the organs) because of these insurmountable facts about the profession. As she writes of Lister:

“He knew that for thousands of years, the ever-looming threat of infection had restricted the extent of a surgeon’s reach. Entering the abdomen, for instance, had proven almost uniformly fatal because of it.”

Today, entering the abdomen is routine...because of Lister.

Fitzharris makes it clear why it was Lister who was almost predestined for this task given his relentless interest in microscopy (his father was a renowned microscopist) and his effort to incorporate the microscope into clinical medicine. When one is about to do battle with invisible organisms that many don't believe exist, having an active mind that is familiar with the tools needed to see them as well as the existence of a microscopic world is essential.

Lister was faced with the seemingly unsolvable problem of surgical site infections -- something we still struggle with today -- and  worked to understand what caused surgical wounds to become inflamed and then rancid from some unknown source (e.g. spontaneous generation, the air). This mystery all unraveled when, in 1864, Lister was introduced to the ideas of Louis Pasteur via a chemistry professor, and "picked up the baton." Lister read Pasteur's works with the idea of extracting principles and findings that could help him explain the problem of surgical infections.

Pasteur, who was not a physician, recognized the enormous synergy that would result from such a man as Lister who could apply and test Pasteur's ideas. As Pasteur wrote: “How I wish I had … the special knowledge I need to launch myself wholeheartedly into the experimental study of one of the contagious diseases." Lister, when it came to surgical infections, was the one with special knowledge that Pasteur needed.

What followed was the application of carbolic acid, a chemical used to ward off putrid smells by sanitation workers, to surgical sites with success, the predictable backlash from the world, and the ultimate victory (Lister was eventually named Queen Victoria's personal surgeon after treating a severe abscess she developed) that we all benefit incalculably from.

All of this and much more, including the use of catgut sutures, is covered by Fitzharris in what is a very valuable book.

My favorite elements are the interactions between Pasteur and Lister -- just to witness two giants and heroes of mankind together is unimaginable to me. For example, in an effusive letter to Lister, Pasteur wrote: “I do not think that another instance of such a prodigy could be found amongst us here." While at a tribute honoring Pasteur, Lister said of Pasteur who he credited with "raising the dark curtain" which loomed over medicine:

“You have changed Surgery … from being a hazardous lottery into a safe and soundly-based science...You are the leader of the modern generation of scientific surgeons, and every wise and good man in our profession—especially in Scotland—looks up to you with respect and attachment as few men receive.” 

The occasion was described as “the living picture of the brotherhood of science in the relief of humanity.”

Lindsey Fitzharris deserves great praise for bringing this important and inspiring story to life. She clearly recognizes and values the achievements of these great minds and the importance of ideas in changing the world. This line of hers is one which will stick with me for a while: “But for all the opposition Lister faced, he was fighting the battle with like-minded people who recognized the revolutionary nature of his work.” 

Recognizing the revolutionary nature of Lister's -- or any other bold thinker's ideas -- is one way to give a reward to those whose value is priceless and Fitzharris, through this book, has helped our species to do that to Lister.