On the Epidemiology of Influenza - x

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On the epidemiology of influenza

John J Cannell,  Michael Zasloff,  Cedric F Garland,  Robert Scragg  &  Edward Giovannucci

Introduction

It is useful, at times, to question our assumptions. Arguably, the most universally accepted assumption about influenza is that it is a highly infectious virus spread by the sick. Edgar Hope-Simpson not only questioned that assumption, he went much further. Realizing that solar radiation has profound effects on influenza, he added an unidentified "seasonal stimulus" to the heart of his radical epidemiological model 1. Unfortunately, the mechanism of action of the "seasonal stimulus" eluded him in life and his theory languished. Nevertheless, he parsimoniously used latent asymptomatic infectors and an unidentified "season stimulus" to fully or partially explain seven epidemiological conundrums 2.

1. Why is influenza both seasonal and ubiquitous and where is the virus between epidemics?

2. Why are the epidemics so explosive?

3. Why do epidemics end so abruptly?

4. What explains the frequent coincidental timing of epidemics in countries of similar latitudes?

5. Why is the serial interval obscure?

6. Why is the secondary attack rate so low?

7. Why did epidemics in previous ages spread so rapidly, despite the lack of modern transport?

An eighth conundrum – one not addressed by Hope-Simpson – is the surprising percentage of seronegative volunteers who either escape infection or develop only minor illness after being experimentally inoculated with a novel influenza virus. The percentage of subjects sickened by iatrogenic aerosol inoculation of influenza virus is less than 50% 3, although such experiments depend on the dose of virus used. Only three of eight subjects without pre-existing antibodies developed illness after aerosol inhalation of A2/Bethesda/10/63 4. Intranasal administration of various wild viruses to sero-negative volunteers only resulted in constitutional symptoms 60% of the time; inoculation with Fort Dix Swine virus (H1N1) – a virus thought to be similar to the 1918 virus – in six sero-negative volunteers failed to produce any serious illness, with one volunteer suffering moderate illness, three mild, one very mild, and one no illness at all 5. Similar studies by Beare et al on other H1N1 viruses found 46 of 55 directly inoculated volunteers failed to develop constitutional symptoms 6. If influenza is highly infectious, why doesn't direct inoculation of a novel virus cause universal illness in seronegative volunteers?

A ninth conundrum evident only recently is that epidemiological studies question vaccine effectiveness, contrary to randomized controlled trials, which show vaccines to be effective. For example, influenza mortality and hospitalization rates for older Americans significantly increased in the 80's and 90's, during the same time that influenza vaccination rates for elderly Americans dramatically increased 7,8. Even when aging of the population is accounted for, death rates of the most immunized age group did not decline 9. Rizzo et al studying Italian elderly, concluded, "We found no evidence of reduction in influenza-related mortality in the last 15 years, despite the concomitant increase of influenza vaccination coverage from ~10% to ~60%" 10. Given that influenza vaccinations increase adaptive immunity, why don't epidemiological studies show increasing vaccination rates are translating into decreasing illness?

After confronting influenza's conundrums, Hope-Simpson concluded that the epidemiology of influenza was not consistent with a highly infectious disease sustained by an endless chain of sick-to-well transmissions 2. Two of the three most recent reviews about the epidemiology of influenza state it is "generally accepted" that influenza is highly infectious and repeatedly transmitted from the sick to the well, but none give references documenting such transmission 11-13. Gregg, in an earlier review, also reiterated this "generally accepted" theory but warned:

"Some fundamental aspects of the epidemiology of influenza remain obscure and controversial. Such broad questions as what specific forces direct the appearance and disappearance of epidemics still challenge virologists and epidemiologists alike. Moreover, at the most basic community, school, or family levels of observation, even the simple dynamics of virus introduction, appearance, dissemination, and particularly transmission vary from epidemic to epidemic, locale to locale, seemingly unmindful of traditional infectious disease behavioral patterns." 14 (p. 46)

Questioning a generally accepted assumption means asking anew, "What does the evidence actually show?..."
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Vitamin D, innate immunity, and influenza
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Discussion
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8. Why does experimental inoculation of seronegative humans fail to cause consistent illness?
   
   If influenza is highly infectious, one would expect most, if not all, human volunteers iatrogenically inoculated with a novel virus to fall ill. Although the rate of illness depends on the virus used and the dose of the inoculum, variations in the innate immunity of the volunteers also explain such variable illness response. We propose individual variations in 25(OH)D levels explain some degree of the variations in illness response.
   
   
9. Over the last 20 years, why has influenza mortality in the aged not declined with increasing vaccination rates?
   
   Given that influenza vaccines effectively improve adaptive immunity, the most likely explanation is that the innate immunity of the aged declined over the last 20 years due to medical and governmental warnings to avoid the sun. While the young usually ignore such advice, the elderly often follow it 87,88. We suggest that improvements in adaptive immunity from increased vaccination of the aged are inadequate to compensate for declines in innate immunity the aged suffered over that same time.

Conclusion
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x - On the Epidemiology of Influenza

x - Safety & Two MD Recommendations: "How Much Vitamin D Should I Take?"