Death Takes a Vacation
Scott McPherson
in influenza and infectious diseases
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OR: It's time to rediscover the theories of R. Edgar Hope-Simpson.
One of the most intriguing questions regarding seasonal influenza is just that: Why is influenza seasonal? Why is it that the virus only seems to move in the winter and spring seasons? Why doesn't it move year-round? It certainly isn't for a lack of hosts and victims.
This phenomenon is so prevalent that people have simply taken to shrug their shoulders and take the information as immutable fact and have ceased to question it.
All, save for some intrepid researchers at Penn State University (Go Nittany Lions!), plus some researchers at NIAID and NIH. http://pathogens.plosjournals.org/archive/1553-7374/3/9/pdf/10.1371_journal.ppat.0030131-L.pdf
They are (perhaps unknowingly, perhaps knowingly) continuing the work started three decades ago by the late R. Edgar Hope-Simpson, a British doctor. Dr. Hope-Simpson challenged the Conventional Wisdom of influenza researchers by claiming the existing theories about the spread of influenza were flawed in many places. He speculated (bear with me: I am only reading his book "The Transmission of Epidemic Influenza" just now, after eighteen months' worth of scouring the Internet for an affordable used copy) that influenza moves between humans all the time, but there is some significant event surrounding the autumnal equinox that seems to activate the virus and may also account for antigenic drift and shift.
Do not make the mistake of dismissing Dr. Hope-Simpson's work summarily. He was the first individual to postulate that shingles was caused by the chicken pox virus. Years later, someone else won a Nobel Prize off his research. A simple country doctor from Gloucestershire, he became one of Britain's most respected physician-researchers. I quote directly from his obituary in the prestigious British Medical Journal: http://www.bmj.com/cgi/content/full/327/7423/1111?ck=nck
The bulk of his interest was in infectious diseases. He was self taught and without any formal epidemiological or research training, but he learnt fast. He established a small epidemiological research unit around his practice in 1946 and chaired a Medical Research Council committee.He started to write papers, particularly on chickenpox and herpes zoster, in the 1940s and 1950s, which were published in the Lancet and the BMJ, and he produced a series of publications of which many professors would be proud.
Chickenpox and shingles were known to be related, but how? Experts at the time were suggesting that two different viruses existed. Hope-Simpson increasingly believed there was only one, but how to prove it? In the end, he took his small team of research colleagues to the Island of Yell in the Shetlands in 1953 and literally followed up every known case in a much closed community. He was empowered by local islanders' memories for occurrences and dates. By 1962, new microbiological techniques enabled him to prove his point.
Only a great intellect could have conceived this possibility—that, remarkably, a virus could commonly lie dormant in the human body, for years, indeed decades, and then reappear in another form. Only an unusually determined researcher could have pursued the idea through fieldwork in the natural history tradition.
Hope-Simpson delivered his conclusion in the Albert Wander lecture of 1965, very properly and modestly describing it as his "hypothesis." His report became one of the most cited general practitioner publications. This was world class research in clinical medicine and Hope-Simpson made probably the most important clinical discovery in general practice in the 20th century.
Later the virus, now known as the varicella zoster virus (VZV), was identified and isolated, and the researcher responsible received a Nobel prize. Later still, a therapy for herpes zoster was developed and that research worker, too, received a Nobel prize.
Hope-Simpson never stopped thinking and reading, made many observations, and wrote a textbook on influenza. He retained his faculties until just before he died, saying how much he loved life, even in his final week.
What a selfless visionary! Self-taught, and free to make observations without the impediment of rigid scientific poo-pooing and inability to challenge the CW. And a man who would clearly be uncomfortable with the accolades afforded him in this blog.
Hope-Simpson's work has been latched onto by a posse that I call the "Vitamin D Gang," a group of doctors and researchers who believe strongly that Hope-Simpson's missing catalyst is none other than The Sun Vitamin. And there is some evidence to support that claim, but the jury is still out on the role Vitamin D plays in arresting influenza in the offseason.
Now back to the study, published in the Public Library of Science. The theory is that seasonal influenza heads for a vacation in the tropics, where it does all the things you would expect randy influenzas to do while on vacation: To frolic with other influenzas and engage in a shameless display of reassortment, over and over again. Then, when the vacation's up, these influenzas pack up and board the plane for each hemisphere until the Autumnal Equinox strikes and the viruses let go of their payloads.
Here are some key passages from the study:
Our large-scale phylogenetic analysis of A/H3N2 influenza virus populations from opposite geographic hemispheres provides evidence for regular bi-directional cross-hemisphere viral migration between seasons, even among localities as distantly separated as New York state and Australia and as relatively geographically isolated as New Zealand's South Island. Multiple genetic variants of influenza virus co-circulate each season, even in geographically remote areas, and many of these viral clades are more closely related to isolates from the opposite hemisphere than to isolates from either the previous or following season in the same location. Thus, viral populations do not appear to “over-summer” locally, where they would evolve in situ and give rise to the next season's epidemic. Rather, cycles of viral migration and recurrent introduction have clearly played a significant role in generating the genetic diversity that characterizes influenza A virus in both hemispheres. Importantly, given the sample composition of our sequence data set, the extent of cross-hemisphere migration observed here undoubtedly represents a conservative estimate. Hence, including data from more populated areas could only reveal more instances of cross-hemisphere migration.
In addition, our finding that the virus migrates globally between epidemics and is reintroduced is clearly compatible with tropical regions, including Southeast Asia, playing a key role in the genesis of new clades and the global spread of these novel influenza virus variants. Thus, while limitations in global genome sampling necessarily means that the current study is directed toward testing hypotheses of viral migration versus latency, equivalent data from tropical regions would undoubtedly enable us to conduct a more refined analysis of global migration patterns and their determinants. Specifically, if tropical regions serve as year-long influenza reservoirs, we would expect to observe phylogenies in which tropical isolates display the greatest genetic diversity and are positioned basal to viruses sampled from temperate regions. Consequently, complete genome sampling from tropical regions where influenza viruses circulate year-round, including a record of the precise date of collection, is of key importance for understanding the global epidemiology of the influenza virus.
Notably, the viral migration we observe does not appear to follow any clear pattern, but rather occurs in all directions, involves all genes, and involves clades of all sizes and geographic compositions. This argues against a role of immune selection in determining which viral clades are able to migrate among localities, although it does not preclude a role for natural selection as the sieve that determines which clades are able to survive in specific host populations. Similarly, the observation that migration patterns vary to some extent among the HA, NA, and concatenated non-surface glycoproteins must reflect the effect of widespread genomic reassortment [7,20]. Frequent reassortment complicates the analysis of migration patterns, as individual viruses can carry genomic segments with differing phylogenetic, and hence geographical, histories. Consequently, the analysis of migration patterns based on single gene segments may paint a misleading picture.
Similarly, the seasonal importation of multiple global isolates appears to be a greater contributor to the genetic diversity of the influenza virus population in New York state from 1997 to 2005 than local in situ evolution [7]. While our findings confirm that human population movements play a role in introducing new viral variants at the start of an epidemic, some aspect of climate is clearly of importance in triggering epidemics. Additional research is required to define how human susceptibility to infection and viral transmissibility fluctuate under varying climate conditions and why influenza virus is absent in summer in temperate climates but exists year-round in tropical zones.
The traditional focus on epidemic influenza may detract from the equally important epidemiological question of why influenza A virus does not circulate in humans for so many months of the year in temperate areas, especially given its apparent ability to infect humans in tropical areas year-round. Attempts to predict, model, or contain the spread of the influenza virus require a unified understanding of how the virus's spatial-temporal dynamics, antigenic evolution, and seasonal emergence interrelate [27]. (Bold type all mine).
OK, pretty fascinating stuff. Short form: Influenza takes a holiday in the tropics. The virus reassorts and then heads to the Four Corners, where some trigger changes either the virus, or changes us, and we become susceptible. But why people can get the flu in the tropics year-round, and others only get it in the fall and winter, is still unknown. The study, as one would imagine, calls for (among other things) a strenuous tropical surveillance effort.
Dr. Hope-Simpson died in November, 2003. Let's hope others keep his legacy and his spirit alive.
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