Thinking about 1918 in 2018: A Review of Pale Rider

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There have been several books written over the past decades discussing the impact, scope, and origin of the 1918 influenza pandemic and each book takes the narrative a little farther and a little deeper while unraveling more of the mystery of the virus that possibly killed 100 million humans. Laurey Spinney's Pale Rider: The Spanish Flu of 1918 and How it Changed the World is the latest book to appear on this topic and it adds considerably to the understanding of the global catastrophic biological risk of influenza. 

In this book, Spinney blends tales of incomprehensible rates of illness with new data that peers back through the molecular clock to understand the origin of this deadly virus. Most people know the story of the utter calamity the flu pandemic and the futility of medical treatments in an era when the viral origin of the infection was not yet known. All of this is covered in great detail in the book but, to me, the chief value of the book was its discussion of how this outbreak started. I will just highlight this portion of the book's narrative in this post. 

"The Spanish Flu" was likely not Spanish at all and Spinney recounts three possible locations for its origin:

1. Camp Funston, Kansas: This is one of the most favored hypotheses. On March 4, 1918 an army cook fell ill with what sounds like a classic case of influenza. The camp was soon inundated with cases and the pandemic seems to follow a linear path from that time and location. It is speculated that the congregation of American solider recruits from rural areas around the country facilitated the emergence and global spread of this virus along WWI routes.  Haskell County in Kansas was noted to have a severe flu-like illness outbreak in January of 1918 and, perhaps, a recruit from this area made his way to Camp Funston. Molecular analysis shows that 7 of the 8 1918 flu genes come from a North American avian flu virus.

2.  China: Contemporaneous with the flu, there were reports attempting to link the outbreak to a prior appearance of what was believed to be pneumonic plague in the city of Harbin in China. This illness first appeared in 1910 and again in another city (Shansi) in the winter of 1917 and though it was reported that the plague bacilli was isolated from cases there is some doubt whether it actually was. Indeed some physicians at the time described it as a severe influenza-like illness. It is hypothesized that members of the Chinese Labor Corps (CLC), a secret Chinese effort to help the Allied war effort, brought the infection to the European front as well as to North America. 

3. The camp at Etaples: This hypothesis centers on a British military encampment in France near the Western Front of WWI where in December of 1916 an outbreak of
"purulent bronchitis" consistent with influenza occurred. According to this explanation, the virus moved through pockets of people, strengthening, until the major outbreak occurred over a year a later. 

The book contains a treasure of information that adds considerably and updates existing literature on this pandemic. It has been 100 years since the pandemic of 1918 and, since that time, there have been 3 subsequent pandemics yet 1918 dwarfs them all. For those of us in this field, the next flu pandemic (and probably the next and the next) are a foregone conclusion and understanding as much as possible about 1918 can only help us prepare. Pale Rider is a book that is highly valuable for that task and I unequivocally recommend it.

Why I'm a Liberal User of Tamiflu

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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

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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.

 

Understanding North Korea's Biological Weapons Potential

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There have been several stories recently published regarding the biological weapons capabilities possessed by the totalitarian regime of North Korea. Thus far, most of the media attention has been to situate this development, for good reason, in a general national security and defense context. However, biological weapons are a difference in kind when it comes to the tools of warfare and merit special attention because of their unique characteristics. Some of these characteristics include potential for contagiousness, induction of societal panic, and the need for special public health and medical preparedness.

To those in the field, it is no surprise that North Korea possesses biological weapons. Though they are a signatory of the Biological Weapons Convention (BWC), it matters little as the former Soviet Union operated an extensive biowarfare program despite being a party to the convention -- and they have demonstrated their prowess with deploying chemical agents such as VX in order to kill. 

The latest news surrounds the fact that a North Korean defector has antibodies to anthrax in his bloodstream. These antibodies are likely the result of prior vaccination which is somewhat routine for many militaries, including our own. It has also been reported that South Korea has purchased a small stockpile of anthrax vaccine (though this purchase seems to be linked to fears over the 2015 accidental shipment of live anthrax spores to Osan Air Base). 

Concern is focused on a "pesticide" factory (Pyongyang Bio-technical Institute) that may be a clandestine dual-use facility capable of producing large amounts of biological weapons that are rumored to be capable of being mounted on missiles (in the case of anthrax). Smallpox -- a disease vanquished from the planet to which many are susceptible due to suspension of the vaccination program -- has also been mentioned as a potential possession of North Korea. 

In the coming weeks, it will be important for those in the reach of North Korea to fortify and prepare hospitals and healthcare providers to recognize, diagnose, and treat conditions such as anthrax and smallpox. Such infectious disease emergency preparations were recently tested with South Korea's experience with MERS and hopefully improvements that will impact biodefense capacities were made. The US has made major gains in preparedness since the 2001 anthrax attacks but any biological attack -- particularly in today's political and societal context -- would be severely disruptive and stress the nations hospitals (especially given the current influenza season) as well as the biomedical enterprise that will be tasked with development vaccines and treatments.

It can be assumed that South Korean and American troops in the region are vaccinated against anthrax and smallpox.  Effective vaccines, both stockpiled in large numbers in the US, exist for both these agents and anthrax can be treated with several different antibiotics as well as with antibody-based treatments. 

A biological attack would unleash global pandemonium and the natural human response will be to panic, flee, and possibly shun the victims in fear of contagion (despite the fact that anthrax -- the most likely candidate weapon -- is not contagious). This is, in many ways, the opposite response to many other disasters. The use of smallpox would cross a line that, to many, is more serious than the use of a nuclear weapon and I suspect (and hope) would be met with a fierce response.

Biological weapons are not a fanciful threat and preparing for them is an important component of national security -- a core function of government. Whether or not North Korea possesses or will use such weapons, it is nevertheless important that the general public, politicians, and healthcare providers are apprised of the very real and dangerous threat they pose. 

Untangling the Fate of the Dengue Vaccine

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It can't be emphasized enough the dengue fever is a deadly viral infection that exacts a considerable burden on the world. Any tool to diminish this impact would be welcomed by the world. This mosquito-borne virus has a unique aspect about its pathophysiology that makes it especially intriguing and difficult to develop a vaccine against. There are 4 types or strains of dengue virus (maybe five) that circulate and it has been shown that antibody-based immunity to one strain enhances the severity of subsequent infections with the other strains. This phenomenon is known as antibody-dependent enhancement and is what accounts for severe dengue. 

Because of this capacity of dengue, it is essential that any vaccine not induce antibodies that lead to enhancement of infection. The only dengue vaccine on the market to seemingly clear this hurdle was Sanofi Pasteur's Dengvaxia which has been licensed in several countries (but not the US). This vaccine, based on a yellow fever vaccine platform, is protective against 4 strains of dengue.

Dengvaxia has been in the news because of new longer term data showing that in those with no prior immunity to dengue, the vaccine increases the chances that infection will lead to severe disease. Perhaps vaccine induced antibodies -- in the absence of any naturally formed antibodies -- are enhancing. Interestingly, in the clinical trials of this vaccine an increased rate of hospitalization and severe dengue was noted in children less than 9 years of age which restricted its use to those above 9.  I wonder if this is because those younger than 9 are more likely to have escaped natural dengue infection and be liable to develop severe dengue due to vaccine-induced antibodies. Of course, some people may reach 9 years of age and escape natural infection and have a similar risk as those below age 9.

It may be that restriction of the vaccine to those with laboratory confirmed dengue -- irrespective of age -- will be the best way to salvage this vaccine as a tool to prevent severe dengue. However, adding a lab test will considerably increase the costs and logistical difficulty of deployment. This finding also makes it very difficult to market the vaccine to travelers, most of whom will not have any natural dengue antibodies.

While this negative finding is clearly a setback for Sanofi, the dengue vaccine field, and for the countries using the vaccine it should be seen as a validation for the rigor of post-licensure vaccine safety testing in which this signal was uncovered and openly publicized. This finding should not be misinterpreted as some way to bolster the veracity of the anti-vaccine movement (which I am sure is inevitable) and be used to smear other vaccines to which this finding is wholly inapplicable.