Last Friday a new paper was made available:
Early and sustained innate immune response defines pathology and death in nonhuman primates infected by highly pathogenic influenza virus [available as open access, link here]. The scientific paper got a thoughtful write-up released to different media outlets Shades Of 1918? Comparing Avian Flu With A Notorious Killer From The Past, [an representative reprint here, at ScienceDaily.com]
A brief snip from the article:
In a new study, Carole Baskin, formerly assistant research professor at Arizona’s Biodesign Institute, currently with Science Foundation Arizona, and an interdisciplinary team of collaborators, compared the recent avian strain known in the scientific community as H5N1, with genetic ressortants of the 1918 virus—source of the most severe influenza pandemic in recorded history. The results, which appear in the latest issue of the Proceedings of the National Academy of Science, are sobering. H5N1 was found to replicate profusely within the first 24 hours, causing severe damage to respiratory tissues while sending the host’s innate immune response into a lethal overdrive, reminiscent of the trajectory of the original 1918 virus.
Fla_Medic, at A Flu Diary, has given us an understandable tour through the scientific paper, [Part I, Part II, and Part III], and since he’s done such a wonderful job of it there isn’t much for me to say. However, there are a few things about the paper that have been nagging at me for several days.
First, I must say [once again] that I am not a scientist, nor am I a medical professional, I am an average woman trying to understand all that is H5N1 and pandemic influenza.
Second, I believe H5N1 has the potential to be a catastrophic event should it manage to gain pandemic capability, though I do not believe is it guaranteed to gain that capability, nor do I believe it is guaranteed to be catastrophic if it does, only that the potential is real and significant.
Those two points are important for me to point out because of what follows.
Now a snip from the paper itself, [with minor editorial edits]:
Since 2003, the mortality for highly pathogenic avian influenza (HPAI) of the H5N1 virus subtype has been 63% of reported cases. Regardless of age or prior health, infected individuals have died within 10 days after onset of symptoms from a fast-progressing pneumonia, variably complicated by intestinal and CNS [central nervous system] symptoms, often leading to respiratory distress syndrome and multiorgan failure. Mild infections or asymptomatic seroconversion [blood testing positive for antibodies indication a prior infection] in high-risk groups, such as health-care or poultry workers, has been rare. The extreme virulence and rapidly fatal clinical outcomes of human H5N1 virus infections are reminiscent of the 1918 pandemic virus, which reportedly caused up to 100 million fatalities.
Yes, the mild infections and/or asymptomatic cases have been rare, known cases are indeed few. But, that is the problem: known cases. While attending the recent Pandemic and Seasonal Influenza Conference (and returning with some interloping pathogen of my own), it was again reiterated, as it was the year previous, that very few of these cases have been found.
The problem is, we don’t systematically look for them either. The few serological surveys of outbreak areas are years old now. The problem with aged data is the much wider geographic spread of the virus and the different clades circulating. Do the current viruses, in their new locations, still operate as the viruses from the original surveys? I don’t know, no one does, we just keep looking back to the old data and saying there is no evidence of any statistically meaningful occurrences. While probably true, it might not be.
We need new serological surveys in areas where the virus is entrenched, or we need the data released from studies that have been done. The published data from the original surveys were from outbreak areas, unfortunately, an outbreak is very different from endemnicity, where the virus is a constant presence, or nearly so.
More from the paper, and my major point of interest with this post:
[snip from the Discussion section, emphasis added]
Lack of affinity of avian influenza viruses for the most common receptor type (2–6-bound sialic acids) found in the human upper respiratory tract is believed to have thus far prevented person-to-person transmission and therefore the onset of an H5N1 pandemic. To overcome these affinity differences between avian- and human-adapted viruses, which most likely also exist in nonhuman primates, we inoculated the majority of the viruses directly into the lower respiratory tract. The H5N1 virus resulted in a more widespread lower respiratory tract infection than the other viruses, in particular there appeared to be a greater propensity to infect type II pneumocytes through day 7.
Another small snippet from the paper [emphasis added]:
Experimental Design. Animals assigned to 4 experimental groups (n8)
matched for age, weight, and sex, were inoculated by intratracheal, intranasal,
tonsillar, and conjunctival routes with a total of 10 million pfu of A/Vietnam/
1203/2004 (H5N1) virus….
Sadly, we do not have a thorough understanding of how people usually become infected with the influenza virus. Studies to fill in our gaps of knowledge are winding their way through the publication process, are ongoing, or are planned, but few are publicly available as yet.
We also don’t really know how much virus we have to take in before we become infected. Is it a few virus, a middling dose, or perhaps a whole whopping bunch? Very non-technical measurements because, well, as small as the influenza virus is, even a “whopping bunch” of them all clumped together would still be too small to image with anything less than an electron microscope.
I like this description from DrGreene:
Viruses are tiny geometric structures that can only reproduce inside a living cell. They range in size from 20 to 250 nanometers (one nanometer is one billionth of a meter)….
The average bacterium is 1,000 nanometers long. (If a bacterium were my size, a typical virus particle would look like a tiny mouse-robot. If an average virus were my size, a bacterium would be the size of a dinosaur over ten stories tall.
It gives an easy frame of reference for something too small to see with a standard microscope.
I am used to reading scientific papers that measure virus by “average infectious dose”, or “average fatal dose”, this paper is the only one I remember measuring viral load as “pfu”, which stands for “plaque forming unit”. Anyway, our researchers loaded the macaques with 10 million of these “pfu’s”, so my guess is that classifies the viral load as a “whopping bunch”. But, keep in mind, we are talking about viruses, so even 10 million of these “units”, which are comprised of some number of virus particles, though I could not find the number specific to influenza, is not a lot volume wise if you piled all those viruses into one neat little heap.
Now, finally, to the crux of my “issue” with this paper:
The researchers state that they “…inoculated the majority of the viruses directly into the lower respiratory tract.” Which, would be the “intratracheal” from the second snippet of the paper, or so I believe.
Most influenza infections start in the upper respiratory tract, and it is the primary reason we monitor the receptor binding domain [RBD] of H5N1’s hemagluttanin, the HA gene, or the part that “H5” designates in H5N1. Most of the receptor binding sites in the human upper respiratory tract are not “receptive” to H5N1, as stated in the paper, but if/when H5N1 gains those RBD’s it is believed the threat to human health will be more significant.
The point is worth laboring over. Since most influenza infections start in the upper respiratory tract, our innate and/or acquired immune systems have a bit of time to respond. By introducing a large viral load directly into the lower respiratory tract the researchers likely “bypassed” this small window of response time. Additionally, with such a [presumed] large viral load the lungs were more likely to be rapidly overwhelmed with replicating virus.
Although I believe this paper expands our understanding in very important and positive ways, it is probably useful to remember the conditions set up in this experiment are not likely to be what we, as non-lab experimental animals, would likely see if/when H5N1 gains the ability to easily infect us.
SZ