Read With A Grain of Salt: A Review of Jeremy Brown's Influenza


It is not surprising to see books being released at the centenary of the 1918 influenza pandemic, arguably the greatest infectious disease threat the human race has ever encountered. I have devoured many books on this event, covering many different facets of what was a global catastrophic biological event like no other in which up to 100 million people perished and cascading effects impacted every aspect of human civilization.

A new book focused on this topic was recently released and, unlike many other books I have read on this topic, was decidedly mixed and at times veered towards a conspiratorial tone. Books on infectious diseases are not immune from conspiratorial speculation but I was surprised it was present in one authored by an NIH physician.

Influenza: The Hundred Year Hunt to Cure the Deadliest Disease in History by Dr. Jeremy Brown is a book that delves in depth into the origins of the pandemic virus and the quest to unlock its secrets. This is the book’s strong suit. Dr. Brown, fittingly begins his book with an anecdote set in Pittsburgh recounting the harrowing experience of a young woman ravaged with influenza who required extra-corporeal support. (This patient, coincidently was taken care of at UPMC and I think I was one of the physicians who initially saw her.) Dr. Brown’s book has many positive attributes that include:

  • A discussion of early treatments of influenza (including blood-letting)

  • An exploration of hypotheses regarding the extraordinary impact of the 1918 virus

  • The resurrection, via science, of the 1918 influenza virus

I found his discussion of the cascading impact of flu on the life insurance and pension industries particularly illuminated as it illustrated how economically important pandemics and severe influenza seasons can be (good for the pension industry bad for life insurance companies).

Brown also explores the differences in how flu is conceptualized in different countries. In the US, there is an aggressive approach to influenza with universal vaccination as a goal and a stress on the complications of flu while in the UK a decidedly different approach is taken. In the UK, cost-effectiveness analysis (necessitated by their socialized, single-payer healthcare system) has found that the optimal targets for vaccination are children, the elderly, and those at risk for complications — the cost-effectiveness analysis is restricted to direct healthcare costs and does not account for absenteeism, lost income, and other costs. Interestingly, Brown also draws attention to the British “keep calm and carry on” attitude towards influenza which is thought of as just “a bit of a nuisance” with no mention of the severe complications such as death that are highlighted on the CDC website but not the NHS.

Where I depart with Dr. Brown is on his position on flu antivirals and flu testing. With respect to flu testing, Dr. Brown, who works as an emergency medicine physician, is of the mind that it does not change treatment and the epidemiological value gained by specifically diagnosing cases does not justify the expense and the effort of reporting cases to public health authorities. Dr. Brown tends to treat patients with over-the-counter medications and the test does not change his treatment. However, multiple studies have shown that many flu patients are inappropriately prescribed antibacterial treatments and flu testing enhances antibiotic stewardship. Moreover, some hospitals collect flu data and use it to trigger specific actions from infection control and hospital administration when the season is in effect. This anathema to testing also likely derives from Dr. Brown’s position on antiviral therapy for influenza.

There is a group of individuals, of which I believe Dr. Brown is a part, that doubt the efficacy of antiviral medications to make meaningful impacts on influenza. Drawing on the studies in healthy individuals with flu which revealed a modest decrement in symptoms, this group eschews the use of flu in high risk patients for whom the drug is considered life-saving based on observational data. Indeed, such a position of liberal use of antivirals in those at high risk for complications is embraced by the Infectious Disease Society of America (IDSA) guidelines. Dr. Brown also engages in speculation regarding the pandemic stockpiling of Tamiflu and the lobbying efforts of Roche, tying them to a suicide of a wealthy lobbyist who worked to raise awareness of the threat of avian influenza.

Overall, I recommend this book to those interested in influenza and the 1918 pandemic. The book is well-written and easily accessible however I do believe non-medical readers should approach the book with an active mind but could still have time grappling with the arguments made regarding antiviral therapy and diagnostic testing. For those with more knowledge of influenza, it is a good read that will challenge you to dissect arguments while learning more about flu.

Thinking about 1918 in 2018: A Review of Pale Rider


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


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. 

FluBlok: Not Your Father's Flu Vaccine

There are very good reasons why many infectious disease experts spend a lot of time focused on the threat of influenza. This virus is a known pandemic threat and has producing such devastating phenomenon at regular intervals throughout human history. 

Our chief means of defense against this threat -- as it is with almost all infectious disease threats -- is vaccination. However, as I and many others have written, we largely battle flu with a vaccine technology from the 1940s that has many limitations and at best is possibly about 60% protective and its worst not so protective at all.

Influenza is a tricky virus and has the capacity to drift, shift, mutate, and reassort in a manner that renders vaccines obsolete and requires an intensive process of regular reformulation (because we do not have a universal evergreen flu vaccine). This process is further complicated because the vaccine is grown in chicken eggs -- a cumbersome process that not only is dependent on a supply of chicken eggs but can itself mutate the vaccine strain during growth further handicapping the vaccine.

One solution to this problem is to move out of chicken eggs altogether and to cell lines -- something that is the norm for many other vaccines. To date, however, only one totally cell-based vaccine is available (there is another partial cell-based vaccine as well which relies on an egg derived viral reference strains that is then grown in MDCK cells): Flublok, a recombinant vaccine grown in insect cells through a baculovirus vector.

It's no secret that I am a huge fan of this vaccine, insisted on receiving it this season, recommend it to my friends, and even got to tour their vaccine plant. The value of FluBlok is not only that it frees flu vaccine production from the tyranny of eggs from a production standpoint, but that its recombinant nature results in a better vaccine. A recent study, published in The New England Journal of Medicine, illustrates this latter point. 

During the 2014-2015 influenza season -- a season  characterized by influenza A/H3N2 dominance and vaccine mismatch-- a randomized clinical trial was conducted on 9000 individuals aged 50 years of age and older. Participants were randomized to quadrivalent FluBlok vs. a standard quadrivalent GSK flu vaccine. The primary endpoint was PCR confirmed influenza-like illness.

Fully 30% less participants randomized to FluBlok experienced PCR-positive influenza reaching statistical superiority. In subgroup analysis, this appeared to be derived from enhanced protection against influenza A. Since no influenza A/H1N1 was detected in the study, the result was driven from enhanced efficacy against A/H3N2 -- a usually more severe strain of seasonal flu. No safety concerns arose.

This trial is very significant and should help physicians and the public understand that moving away from eggs in vaccine production will have many important effects including rapid scale up, flexibility in plugging in new strains of flu and other viruses (e.g. Zika), and no susceptibility to egg supply shocks (a real concern during an avian flu outbreak that could make chicken egg supplies dwindle), less mutation of vaccine strains induced by adaptation to egg growth, and -- as this trial illustrates -- better protection during seasonal flu.




Kiss A Frog, Fight the Flu

There is always speculation about particular compounds that exist naturally in the wild that may have benefits for human health. Indeed, history is full of stories like this from quinine to aspirin. New research from Emory shows that frog mucus contains a potentially flu-fighting antimicrobial peptide. 

For the study peptides contained in the mucus from Hydrophylax bahuvistara frogs were screening for both anti-influenza activity and non-toxicity to human cells. Of these screens, one peptide, named urumin, emerged as the leading candidate. Urumin was noted to interact directly with the influenza virus at an important site: the conserved stalk area of the H1 hemagglutinin. Because it is a "conserved" region (i.e. one not highly mutable) the frog peptide retained activity against drug-resistant variants. This region is one of the targets of the long sought after universal flu vaccine. In the study, urumin worked not only in vitro but also in a mouse model.  The peptide was specific for just H1 variant influenza A viruses.

I found the paper to be very interesting and the discoveries may have wide-ranging implications not only for novel antivirals but for understanding influenza. As the authors note, innate defense mechanisms are less likely to be prone to resistance because they presumably were selected  via natural selection for their durability against their target. It is unclear what role amphibians have with influenza A epidemiology but it appears they can be infected and perhaps urumin is one of its natural defenses against the virus. Future studies with ferrets will be important to perform as they are important surrogates for humans.