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The mystery of asymptomatic influenza
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?
"It is worth noting that one animal study indicated vitamin D, when added to the diet of rats, prevented influenza but a subsequent paper reported it did not [83, 84]. Young et al also reported that a Japanese researcher, Midzuno, was able to reproduce influenza in rats simply by maintaining them on diets deficient in vitamin D, apparently part of Japan's World War II biological weapons research. (The American CIA confiscated Midzuno's papers after the war.) As vitamin D does not upregulate AMPs in murine mammals, it is unclear what these studies mean. If researchers can identify an influenza susceptible species in which vitamin D increases expression of AMPs, it would be useful to know if vitamin D deficiency promotes the pathology of influenza."
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Heterogeneous and Dynamic Prevalence of Asymptomatic Influenza Virus Infections
Influenza infection manifests in a wide spectrum of severity, including symptomless pathogen carriers. We conducted a systematic review and meta-analysis of 55 studies to elucidate the proportional representation of these asymptomatic infected persons. We observed extensive heterogeneity among these studies. The prevalence of asymptomatic carriage (total absence of symptoms) ranged from 5.2% to 35.5% and subclinical cases (illness that did not meet the criteria for acute respiratory or influenza-like illness) from 25.4% to 61.8%. [Emph. mine - rjs] Statistical analysis showed that the heterogeneity could not be explained by the type of influenza, the laboratory tests used to detect the virus, the year of the study, or the location of the study. Projections of infection spread and strategies for disease control require that we identify the proportional representation of these insidious spreaders early on in the emergence of new influenza subtypes or strains and track how this rate evolves over time and space.
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