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 A 2 /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 (H 1 N 1 ) – 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 H 1 N 1 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? Thus, we asked, are there any controlled human studies that attempted sick-to-well influenza transmission? Do naturalistic studies of outbreaks in confined spaces prove sick-to-well transmission or are they compatible with another mode of dissemination? Is there an easily measurable serial interval (the median time between the index case and the secondary cases), so crucial to establishing sick-to-well transmission? Are measured secondary attack rates in families (the percentage of family members sickened after a primary case) suggestive of a highly infectious virus? What do animal models of influenza tell us?

Do current theories explain the explosive onset and then abrupt disappearance of epidemics, epidemics that cease despite a wealth of potential victims lacking adaptive immunity [15]? Why have epidemic patterns in Great Britain not altered in four centuries, centuries that have seen great increases in the speed of human transport [16]? If each successive epidemic increases herd immunity and children born since the last epidemic are non-immune, why doesn't the average age of persons infected in successive epidemics become progressively lower[17]? Why did the peak of 25 consecutive epidemics in France and the USA occur within a mean of four days of each other [18]?

Review of Jordan's sobering monograph of the 1918 pandemic leaves little room to doubt that close human interaction propagates influenza [19]. Furthermore, laboratory evidence leaves no doubt that droplets or aerosols can transmit influenza; droplets containing a high dose of virus, or aerosols containing a much lower dose, both can result in iatrogenic human infection [20].

Subjects that sicken do so two to four days after being iatrogenically infected; that is, the incubation period is about three days. However, it is crucial to remember that the incubation period only tells us what the serial interval should be, not what it is. Furthermore, induction of human infection in the laboratory only tells us such infection is possible; it does not tell us who is infecting the well in nature.

The obvious candidate is the sick. However, Edgar Hope-Simpson contended that the extant literature on serial interval, secondary attack rates, and other epidemiological aspects of influenza are not compatible with sick-to-well transmission as the usual mode of contagion. In his 1992 book, after considering all known epidemiological factors, he presented a comprehensive, parsimonious – and radically different – model for the transmission of influenza, one heavily dependent on a profound, even controlling, effect of solar radiation. Furthermore, while agreeing the sick could infect the well, Hope-Simpson's principal hypothesis was that epidemic influenza often propagates itself by a series of transmissions from a small number of highly infectious – but generally symptomless – latent carriers, briefly called into contagiousness by the "seasonal stimulus."

In contrast, Kilbourne's 1987 text – without mentioning serial interval or secondary attack rates in his chapter on epidemiology – concluded, "Any doubt about the communicability of influenza from those ill with the disease is dispelled by studies in crowded, confined, or isolated populations" [21]. (p. 269) As discussed below, the naturalistic studies Kilbourne refers to certainly indicate human interaction facilitates transmission of influenza. However, these naturalistic studies simply assume that the first person with identified illness is the index case. Obviously, A preceding B does not prove A causes B.