ArticlePDF AvailableLiterature Review

On the epidemiology of influenza

Authors:
  • Vitamin D Council, Inc.

Abstract and Figures

The epidemiology of influenza swarms with incongruities, incongruities exhaustively detailed by the late British epidemiologist, Edgar Hope-Simpson. He was the first to propose a parsimonious theory explaining why influenza is, as Gregg said, "seemingly unmindful of traditional infectious disease behavioral patterns." Recent discoveries indicate vitamin D upregulates the endogenous antibiotics of innate immunity and suggest that the incongruities explored by Hope-Simpson may be secondary to the epidemiology of vitamin D deficiency. We identify - and attempt to explain - nine influenza conundrums: (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 they end so abruptly? (4) What explains the frequent coincidental timing of epidemics in countries of similar latitude? (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? (8) Why does experimental inoculation of seronegative humans fail to cause illness in all the volunteers? (9) Why has influenza mortality of the aged not declined as their vaccination rates increased? We review recent discoveries about vitamin D's effects on innate immunity, human studies attempting sick-to-well transmission, naturalistic reports of human transmission, studies of serial interval, secondary attack rates, and relevant animal studies. We hypothesize that two factors explain the nine conundrums: vitamin D's seasonal and population effects on innate immunity, and the presence of a subpopulation of "good infectors." If true, our revision of Edgar Hope-Simpson's theory has profound implications for the prevention of influenza.
Content may be subject to copyright.
BioMed Central
Page 1 of 12
(page number not for citation purposes)
Virology Journal
Open Access
Review
On the epidemiology of influenza
John J Cannell*
1
, Michael Zasloff
2
, Cedric F Garland
3
, Robert Scragg
4
and
Edward Giovannucci
5
Address:
1
Department of Psychiatry, Atascadero State Hospital, 10333 El Camino Real, Atascadero, CA 93423, USA,
2
Departments of Surgery and
Pediatrics, Georgetown University, Washington, D.C., USA,
3
Department of Family and Preventive Medicine, University of California San Diego,
La Jolla, CA, USA,
4
Department of Epidemiology and Biostatistics, University of Auckland, Auckland, New Zealand and
5
Departments of Nutrition
and Epidemiology, Harvard School of Public Health, Boston, MA, USA
Email: John J Cannell* - jcannell@ash.dmh.ca.gov; Michael Zasloff - maz5@georgetown.edu; Cedric F Garland - cgarland@ucsd.edu;
Robert Scragg - r.scragg@auckland.ac.nz; Edward Giovannucci - egiovann@hsph.harvard.edu
* Corresponding author
Abstract
The epidemiology of influenza swarms with incongruities, incongruities exhaustively detailed by the
late British epidemiologist, Edgar Hope-Simpson. He was the first to propose a parsimonious
theory explaining why influenza is, as Gregg said, "seemingly unmindful of traditional infectious
disease behavioral patterns." Recent discoveries indicate vitamin D upregulates the endogenous
antibiotics of innate immunity and suggest that the incongruities explored by Hope-Simpson may
be secondary to the epidemiology of vitamin D deficiency. We identify – and attempt to explain –
nine influenza conundrums: (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 they end so
abruptly? (4) What explains the frequent coincidental timing of epidemics in countries of similar
latitude? (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? (8)
Why does experimental inoculation of seronegative humans fail to cause illness in all the
volunteers? (9) Why has influenza mortality of the aged not declined as their vaccination rates
increased? We review recent discoveries about vitamin D's effects on innate immunity, human
studies attempting sick-to-well transmission, naturalistic reports of human transmission, studies of
serial interval, secondary attack rates, and relevant animal studies. We hypothesize that two factors
explain the nine conundrums: vitamin D's seasonal and population effects on innate immunity, and
the presence of a subpopulation of "good infectors." If true, our revision of Edgar Hope-Simpson's
theory has profound implications for the prevention of influenza.
Introduction
It is useful, at times, to question our assumptions. Argua-
bly, 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 mecha-
nism of action of the "seasonal stimulus" eluded him in
life and his theory languished. Nevertheless, he parsimo-
niously used latent asymptomatic infectors and an uni-
Published: 25 February 2008
Virology Journal 2008, 5:29 doi:10.1186/1743-422X-5-29
Received: 9 February 2008
Accepted: 25 February 2008
This article is available from: http://www.virologyj.com/content/5/1/29
© 2008 Cannell et al; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0
),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Virology Journal 2008, 5:29 http://www.virologyj.com/content/5/1/29
Page 2 of 12
(page number not for citation purposes)
dentified "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 epi-
demics 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 adminis-
tration 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 constitu-
tional 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 epidemi-
ological studies question vaccine effectiveness, contrary to
randomized controlled trials, which show vaccines to be
effective. For example, influenza mortality and hospitali-
zation rates for older Americans significantly increased in
the 80's and 90's, during the same time that influenza vac-
cination 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 eld-
erly, 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 vaccina-
tions increase adaptive immunity, why don't epidemio-
logical studies show increasing vaccination rates are
translating into decreasing illness?
After confronting influenza's conundrums, Hope-Simp-
son 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 reit-
erated 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 chal-
lenge 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 particu-
larly 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 ask-
ing anew, "What does the evidence actually show? Thus,
we asked, are there any controlled human studies that
attempted sick-to-well influenza transmission? Do natu-
ralistic 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 Brit-
ain 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 succes-
sive 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]?
Virology Journal 2008, 5:29 http://www.virologyj.com/content/5/1/29
Page 3 of 12
(page number not for citation purposes)
Review of Jordan's sobering monograph of the 1918 pan-
demic leaves little room to doubt that close human inter-
action 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 epidemiologi-
cal 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 com-
municability 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 natu-
ralistic 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. Obvi-
ously, A preceding B does not prove A causes B.
Vitamin D, innate immunity, and influenza
Hope-Simpson's model theorized that an unidentified
"seasonal stimulus," inextricably bound to solar radia-
tion, substantially controlled the seasonality of influenza.
Recent evidence suggests the "seasonal stimulus" may be
seasonal impairments of the antimicrobial peptide
(AMPs) systems crucial to innate immunity [22], impair-
ments caused by dramatic seasonal fluctuations in 25-
hydroxy-vitamin D [25(OH)D] levels [23]. (Figure 1) The
evidence that vitamin D has profound effects on innate
immunity is rapidly growing [24].
In fact, Aloia and Li-Ng presented evidence of a dramatic
vitamin D preventative effect from a randomized control-
led trial (RCT) [25]. In a post-hoc analysis of the side effect
questions of their original three-year RCT, they discovered
104 post-menopausal African American women given
vitamin D were three times less likely to report cold and
flu symptoms than 104 placebo controls. A low dose (800
IU/day) not only reduced reported incidence, it abolished
the seasonality of reported colds and flu. A higher dose
(2000 IU/day), given during the last year of their trial, vir-
tually eradicated all reports of colds or flu. (Figure 2)
Recent discoveries about vitamin D's mechanism of
action in combating infections [26] led Science News to
suggest that vitamin D is the "antibiotic vitamin" [27] due
primarily to its robust effects on innate immunity.
Unlike adaptive immunity, innate immunity is that
branch of host defense that is "hard-wired" to respond
rapidly to microorganisms using genetically encoded
effectors that are ready for activation by an antigen before
the body has ever encountered that antigen. Activators
include intact microbes, Pathogen Associated Molecular
Patterns (PAMPS), and host cellular constituents released
during tissue injury. Of the effectors, the best studied are
the antimicrobial peptides (AMPs) [28].
Both epithelial tissues and phagocytic blood cells produce
AMPs; they exhibit rapid and broad-spectrum antimicro-
Geometric mean monthly variations in serum 25-hydroxyvi-tamin D [25)OH)D] concentration in men (dark shade, n = 3723) and women (light shade, n = 3712) in a 1958 British birth cohort at age 45Figure 1
Geometric mean monthly variations in serum 25-
hydroxyvitamin D [25)OH)D] concentration in men
(dark shade, n = 3723) and women (light shade, n =
3712) in a 1958 British birth cohort at age 45.
25(OH)D levels are in ng/ml; to convert to nmol/L, multiply
by 2.5. Adapted from: Hypponen E, Power C: Hypovitamino-
sis D in British adults at age 45 y: nationwide cohort study of
dietary and lifestyle predictors. Am J Clin Nutr 2007, 85: 860–
868. Reproduced with kind permission of the American Soci-
ety for Nutrition.
Sept
July
June
May
Apr
Mar
Feb
Jan
Dec
Nov
Aug
Oct
34
30
28
24
20
16
12
8
4
0
Sept
Mar
Feb
Jan
Dec
Nov
Oct
Virology Journal 2008, 5:29 http://www.virologyj.com/content/5/1/29
Page 4 of 12
(page number not for citation purposes)
bial activity against bacteria, fungi, and viruses [29]. In
general, they act by rapidly and irreversibly damaging the
lipoprotein membranes of microbial targets, including
enveloped viruses, like influenza [30]. Other AMPs, such
as human beta-defensin 3, inhibit influenza haemaggluti-
nin A mediated fusion by binding to haemagglutinin A
associated carbohydrates via a lectin-like interaction [31].
AMPs protect mucosal epithelial surfaces by creating a
hostile antimicrobial shield. The epithelia secrete them
constitutively into the thin layer of fluid that lies above
the apical surface of the epithelium but below the viscous
mucous layer. To effectively access the epithelium a
microbe, such as influenza, must penetrate the mucous
barrier and then survive damage inflicted by the AMPs
present in the fluid that is in immediate contact with the
epithelial surface. Should this constitutive barrier be
breached, the binding of microbes to the epithelium and/
or local tissue injury rapidly provokes the expression of
high concentrations of specific inducible AMPs such as
human beta-defensin 2 and cathelicidin, that provide a
"back-up" antimicrobial shield. These inducible AMPs
also act as chemo-attractants for macrophages and neu-
trophils that are present in the immediate vicinity of the
site of the microbial breach [28-30]. In addition, catheli-
cidin plays a role in epithelial repair by triggering epithe-
lial growth and angiogenesis [32].
The crucial role of vitamin D in the innate immune system
was discovered only very recently [33,34]. Both epithelial
cells and macrophages increase expression of the antimi-
crobial cathelicidin upon exposure to microbes, an
expression that is dependent upon the presence of vita-
min D. Pathogenic microbes, much like the commensals
that inhabit the upper airway, stimulate the production of
a hydroxylase that converts 25(OH)D to 1,25(OH)
2
D, a
seco-steroid hormone. This in turn rapidly activates a suite
of genes involved in defense [35].
In the macrophage, the presence of vitamin D also
appears to suppress the pro-inflammatory cytokines,
Interferon γ, TNFα, and IL12, and down regulate the cel-
lular expression of several PAMP receptors. In the epider-
mis, vitamin D induces additional PAMP receptors,
enabling keratinocytes to recognize and respond to
microbes [36]. Thus, vitamin D appears to both enhance
the local capacity of the epithelium to produce endog-
enous antibiotics and – at the same time – dampen certain
arms of the adaptive immune response, especially those
responsible for the signs and symptoms of acute inflam-
mation, such as the cytokine storms operative when influ-
enza kills quickly.
Of particular note is that not all animals appear to depend
on vitamin D for their innate immune circuitry. The cathe-
licidin genes of mouse, rat, and dog, lack a vitamin D
receptor-binding site, and do not require vitamin D for
expression [34]. Therefore, one cannot extrapolate the
role vitamin D plays in human infections from studies of
such animals.
Plasma levels of vitamin 25(OH)D in African Americans,
known to be lower than white skinned individuals, are
inadequate to fully stimulate the vitamin D dependent
antimicrobial circuits operative within the innate
immune system. However, the addition of 25(OH)D
restored the dependent circuits and greatly enhanced
expression of AMPs [37]. High concentrations of melanin
in dark-skinned individuals shield the keratinocytes from
the ultraviolet radiation required to generate vitamin D in
skin [38]. In addition, the production of vitamin D in skin
diminishes with aging [39]. Therefore, relative – but easily
correctable – deficiencies in innate immunity probably
exist in many dark-skinned and aged individuals, espe-
cially during the winter.
Because humans obtain most vitamin D from sun expo-
sure and not from diet, a varying percentage of the popu-
lation is vitamin D deficient, at any time, during any
season, at any latitude, although the percentage is higher
in the winter, in the aged, in the obese, in the sun-
deprived, in the dark-skinned, and in more poleward pop-
ulations [40,41]. However, seasonal variation of vitamin
D levels even occur around the equator [42] and wide-
spread vitamin D deficiency can occur at equatorial lati-
tudes [43], probably due to sun avoidance [44], rainy
Incidence of reported cold/influenza symptoms according to seasonFigure 2
Incidence of reported cold/influenza symptoms
according to season. The 104 subjects in the placebo
group (light shade) reported cold and flu symptoms year
around with the most symptoms in the winter. While on 800
IU per day (intermediate shade) the 104 test subjects were
as likely to get sick in the summer as the winter. Only one of
the 104 test subjects had cold/influenza symptoms during the
final year of the trial, when they took 2,000 IU of vitamin D
per day (dark shading). Adapted from: Aloia JF, Li-Ng M: Epi-
demic influenza and vitamin D. Epidemiol Infect 2007; 135:
1095–1096. (Reproduced with permission, Cambridge Uni-
versity Press).
25
20
15
10
5
0
Winter Spring Summer
Placebo 800 IU/d 2000 IU/d
Autumn
Virology Journal 2008, 5:29 http://www.virologyj.com/content/5/1/29
Page 5 of 12
(page number not for citation purposes)
seasons [45], and air pollution [46]. For example, a study
of Hong Kong infants showed about half had 25(OH)D
levels less than 20 ng/ml in the winter [47]. Even in the
summer, few of the infants had levels higher than 30 ng/
ml, which many experts now think are below the lower
limit of the optimal range [40,41,48,49]. As 25(OH)D
levels affect innate immunity, then a varying percentage of
most populations – even equatorial ones – will have
impaired innate immunity at any given time, together
with distinct seasonal variations in that percentage. The
effects such impairments have on influenza transmission
are unknown.
Human studies attempting sick-to-well human
transmission
In 2003, Bridges et al reviewed influenza transmission and
found "no human experimental studies published in the
English-language literature delineating person-to-person
transmission of influenza. This stands in contrast to sev-
eral elegant human studies of rhinovirus and RSV trans-
mission ..." [50]. (p. 1097)
However, according to Jordan's frightening monograph
on the 1918 pandemic, there were five attempts to dem-
onstrate sick-to-well influenza transmission in the desper-
ate days following the pandemic and all were "singularly
fruitless" [19]. (p. 441) Jordan reports that all five studies
failed to support sick-to-well transmission, in spite of hav-
ing numerous acutely ill influenza patients, in various
stages of their illness, carefully cough, spit, and breathe on
a combined total of >150 well patients [51-55].
Rosenau's work was the largest of the studies, illustrative
of the attempts, and remarkable for the courageousness of
the volunteers [52]. In 1919 – in a series of experiments –
he and six colleagues at the U.S. Public Health Service
attempted to infect 100 "volunteers obtained from the
Navy." He reports all volunteers were "of the most suscep-
tible age," and none reported influenza symptoms in
1918. That is, "from the most careful histories that we
could elicit, they gave no account of a febrile attack of any
kind," during the previous year. The authors then selected
influenza donors from patients in a "distinct focus or out-
break of influenza, sometimes an epidemic in a school
with 100 cases, from which we would select typical cases,
in order to prevent mistakes in diagnosis of influenza."
Rosenau made every attempt to get donors who were early
in their illness, "A few of the donors were in the first day
of the disease. Others were in the second or third day of
the disease."
"Then we proceeded to transfer the virus obtained
from cases of the disease; that is, we collected the
material and mucous secretions of the mouth and
nose and bronchi from (19) cases of the disease and
transferred this to our volunteers. We always obtained
the material in the following way: The patients with
fever, in bed, has a large, shallow, traylike arrange-
ment before him or her, and we washed out one nos-
tril with some sterile salt solution, using perhaps 5 c.c.,
which is allowed to run into this tray; and that nostril
is blown vigorously into the tray. That is repeated with
the other nostril. The patient then gargles the solution.
Next we obtain some bronchial mucous through
coughing, and then we swab the mucous surface of
each nares and also the mucous membranes of the
throat."
Then they mixed all the "stuff" together and sprayed 1 cc
of the mixture in each of the nostrils of 10 volunteers, and
"into the throat, while inspiring, and on the eye" and
waited 10 days for the volunteers to fall ill. However,
"none of them took sick in any way." Undaunted,
Rosenau conducted another experiment in which ten
acutely ill influenza patients coughed directly into the
faces of each ten well volunteers. Again, "none of them
took sick in any way."
Perhaps Rosenau's and similar experiments failed because
all the well volunteers had contracted infections in 1918
and were immune from further infection. While possible,
none of the volunteers reported symptoms in 1918, even
a fever. Furthermore, adaptive immunity to influenza is
relative to the immune response that infection generates
and to the time since infection; it is seldom absolute and
abiding.
Another explanation is that all of the influenza patients
had passed their time of infectivity although Rosenau
obtained donors in the first, second, or third day of their
illnesses. As no laboratory confirmation was possible, per-
haps the ill did not have influenza, but we doubt U.S.
Public Health Service physicians had much trouble mak-
ing accurate clinical diagnosis of influenza in 1919. Fur-
thermore, all the donors were symptomatic; peak viral
shedding occurs 24–72 hours after infection, and the
amount of virus shed is associated with symptoms [56].
Perhaps peak viral shedding is not associated with peak
infectivity. Perhaps – although Rosenau does not report
the date or season of the experiments – all the naval vol-
unteers had adequate innate immunity from sun expo-
sure. Obviously, another explanation is that sick-to-well
transmission is not the usual mode of contagion.
Naturalistic reports of sick-to-well transmission
A number of naturalistic studies suggest influenza is trans-
mitted from the sick to the well [57-59]. They all assume
the first case was the index case. The best-known case is an
airliner in Alaska, where an extensive outbreak of influ-
enza occurred after an infected patient appeared among
Virology Journal 2008, 5:29 http://www.virologyj.com/content/5/1/29
Page 6 of 12
(page number not for citation purposes)
well, and the airliner subsequently malfunctioned, caus-
ing a four-hour delay in which passengers breathed re-cir-
culated air [60].
Although her influenza culture was negative, the authors
hypothesized their "index case" infected 37 well passen-
gers within a mean of 38 hours after she boarded the
plane. However, 30 other passengers boarded the Alaskan
plane at the same time as the sick passenger, and other
passengers were already onboard, any of whom could
have been the common source. The airline study, like
other naturalistic studies, is very suggestive of a common
source and aerosol transmission, but offers no proof that
the common source was the suspected index case, other
than the logic that if A preceded B then A must have
caused B.
Experts frequently cite an experience at an "irradiated"
Livermore, California, VA hospital during the 1957–58
influenza epidemic as naturalistic evidence of sick-to-well
aerosol influenza transmission. McLean (as part of a gen-
eral discussion in a paper by Jordan) [61] reported an
entire hospital building unit, housing approximately 150
patients with chronic pulmonary disease, was "totally
radiated" in an attempt to reduce TB contagion through
the air. There remained, nonradiated, another 250 control
patients. He reported a two percent influenza attack rate
for the "radiated patients" compared to a 19 percent attack
rate for the "nonradiated patients." (p. 37).
However, Maclean's description of the Livermore hospi-
tal's irradiation procedures is inadequate to know if
patients were being directly irradiated, thus triggering vita-
min D production in their skin. However, careful inspec-
tion of another 1957 publication about a similarly
irradiated Baltimore VA hospital – co-authored by
McLean – is illuminating [62]. The Baltimore hospital
wing apparently used a similar irradiation set-up with
"standard ultraviolet light fixtures." (p. 421) Illustrations
clearly show – despite text stating that only upper air was
irradiated – that the rooms and hallways were all
equipped with UV lights that either shone directly or indi-
rectly on patients, apparently 24 hours per day, seven days
a week (see pp. 422–423 for illustrations). If the irradia-
tion processes were similar in Livermore and Baltimore
hospitals, they would have significantly raised the
25(OH)D levels of the irradiated, and relatively influenza-
free, patients.
Furthermore, if irradiation of the air destroyed viral aero-
sols and was responsible for the lower attack rate, such
results should be reproducible. In a carefully controlled
trial, Gelperin et al directly investigated the possibility of
transmission of viral respiratory illness by aerosols [63].
For four months during the height of the flu season, the
authors carefully irradiated only the upper air in half the
classrooms in eight New Haven schools with ultraviolet
light, and, unlike the Livermore VA hospital, the research-
ers took great care not to irradiate the students, either
directly or indirectly. When they compared absenteeism
in irradiated classrooms to non-irradiated control
schools, they found no effect from upper air irradiation.
Two other large field studies in schools likewise showed
no effect from UV air irradiation on viral diseases trans-
mitted via the respiratory tract [64,65].
These last three studies do not disprove aerosol transmis-
sion. Such transmission could have occurred at lower
room levels and the schoolchildren were free to contract
infections outside of the classroom. However, one might
have expected some decrease in infection rates. Further-
more, their negative results stand in stark contrast to the
dramatic effects seen in the irradiated patients in Liver-
more, leading us conclude the irradiated Livermore
patients were the beneficiaries of more than just cleaner
air.
What is the serial interval for influenza?
The generally accepted theory of sick-to-well transmission
demands direct epidemiological measurement (not calculation
from the incubation period) of a serial interval between causal
and resultant cases (time between successive cases in a chain of
transmission) as has been amply demonstrated for other respi-
ratory infectious diseases. In families, where the virus infects
one member outside the home and that member then
infects others inside the family, a serial interval should be
easy to demonstrate if the virus is propagating itself via
sick-to-well transmission. Unfortunately, when the World
Health Organization Writing Group reported that "the
serial interval ... is 2 – 4 days" (p. 83) for influenza, they
failed to give a reference and apparently meant the incu-
bation period is 2 – 4 days [56]. While the incubation
period of influenza is well documented, if anyone has suc-
cessfully documented a serial interval for influenza in
families, we have yet to locate their work.
In contrast, Hope-Simpson, using viral isolates obtained
over 8 years, found low attack rates within households, a
high proportion of affected households with only one
influenza case (70%), and no demonstrable serial interval
[66]. A five-year serological surveillance study found that
73% of family members who get influenza get it on the
first day and are apparent index cases [67]. They could not
identify a serial interval. Jordan et al followed 60 families
during the Asian epidemic of 1957, isolating the virus
from 86% of the families [68]. They found no evidence of
a serial interval. Jordan later reviewed similar studies and
reported, "No peak occurred at the expected incubation
period when secondary cases in families were plotted by
intervals from the index case" [61]. (p. 32).
Virology Journal 2008, 5:29 http://www.virologyj.com/content/5/1/29
Page 7 of 12
(page number not for citation purposes)
Viboud et al did not say so, but they apparently could not
demonstrate a serial interval in families, as secondary
cases did not peak at any particular interval after the first
case in the family [69]. Remarkably, in 116 families, two
family members developed symptoms simultaneously. Of
the 131 family members who developed a flu-like illness
within five days of the 543 serologically confirmed first
cases, it appears that 38 of 131 occurred on day one, 40 on
day two, 30 on day three, 28 on day four, and nine on day
five.
If influenza is highly contagious, a serial interval should
be evident – easily observed and directly measured – as
sick family members infect the well. The large percentage
of family members that sicken on the first day and the lack
of a demonstrable serial interval, despite numerous
attempts to measure one, seems more consistent with a
limited number of infectors, usually outside the family,
than with all the sick being infectors.
What is the secondary attack rate for influenza?
The reproductive number, R
0
, an estimation of the average
number of new cases of influenza produced by each infec-
tious case in a fully susceptible population, has replaced
secondary attack rates in most epidemiological models.
However, the R
0
for influenza has been "notoriously hard
to estimate" [70] (p. 11146). While the estimated R
0
remains obscure, epidemiologists have directly measured
its father, secondary attack rates, for more than 5 decades.
For a highly infectious virus, secondary attack rates for
influenza are surprisingly low.
Secondary attack rates for influenza cannot be accurately
determined without knowing the serial interval and are
thus actually subsequent attack rates. Subsequent attack
rates inflate the rate because they include all co-primary,
tertiary, and later cases as secondaries. The subsequent
attack rate for rhinovirus among non-immune family
members is 58% [71]. The rate for unvaccinated house-
hold contacts is 70% for measles [72] and 71% for vari-
cella [73]. If influenza is highly contagious and spread by
the sick, then secondary attack rates should reflect that
contagiousness.
However, 80% of household members with an infected
family member escaped the first outbreak of Hong Kong
influenza in Great Britain despite it being a new antigenic
variant in a non-immune population [74]. Thus, even if
one assumes all subsequent cases were secondaries, the
secondary attack rate was only 20%. Neuzil et al found
that 22% of household members became ill within three
days of a child in the family being absent from school due
to illness but did not report how many family members
became ill on the same day as the child [75]. Using a spe-
cific clinical definition in secondary cases, Viboud et al
found a subsequent attack rate of 18% [69].
Longini et al analyzed data from four large family studies,
reporting the apparent secondary attack rates varied from
13 to 30% [76]. After taking the community infection rate
into account, they concluded the actual secondary attack
rate among family members was 15%. Later, Longini et al
estimated the secondary attack rate for adults and children
with low levels of preexisting viral specific antibodies was
18 percent and 37%, respectively, while the secondary
attack rate in adults and children with high levels of such
antibodies was 1.6% and 3.4%, respectively [77].
For a review of all studies on subsequent attack rates up to
1986, see Thacker [78]. Of the eight household studies he
analyzed, four showed a subsequent attack rate in the
teens (14%, 15%, 15%, 17%), two in the twenties (21%
and 27%), one was 31%, while one was 58% (H
3
N
2
in
New Zealand in 1973). The weighted mean of subsequent
attack rates in all 870 households was 22%.
A recent review combining the data from four controlled
household studies of antiviral effectiveness in the control
households found a combined subsequent attack rate of
13% for symptomatic laboratory confirmed infections
(136 of 1061 contacts) and 23% for any laboratory con-
firmed infections (246 of 1061 contacts) [79].
Such low subsequent attack rates in families seem incon-
sistent with a highly infectious virus sustaining itself by
sick-to-well transmission. They seem more consistent
with large intrafamilial variations in immunity and family
members contracting the infection, usually outside the
home, from a common source.
Animal studies
Ironically, the strongest evidence for sick-to-well trans-
mission in man comes from studies of ferrets. Unlike
human studies, studies show infected ferrets readily trans-
mit influenza to well animals and those newly sickened
animals readily infect a third animal and so on [80].
Recently, similar experiments with guinea pigs were able
to sustain a chain of eight successive transmissions but the
animals do not become ill (written communication with
Lowen A., Palese Laboratory). Likewise, hamsters can
transmit influenza but apparently do not become ill [81].
Schulman and Kilbourne were able to infect about 50% of
secondary mice after caging them with a two experimen-
tally infected animals [82]. However, they were unable to
get the newly sickened mice to transmit, that is, instigate
a chain of transmission from sick to well mice.
Schulman and Kilbourne did demonstrate that some
infector mice are "good transmitters" while other mice
Virology Journal 2008, 5:29 http://www.virologyj.com/content/5/1/29
Page 8 of 12
(page number not for citation purposes)
will not transmit the virus, it spite of inoculation with the
same dose of virus. That is, for unknown reasons, some
infected mice readily transmit the disease to their litterma-
tes and some will not. As all infector mice received an
identical inoculum of virus, it is reasonable to hypothe-
size that good transmitters have an unidentified inade-
quacy in innate immunity that facilitate their ability to
transmit the virus.
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.
Discussion
After a 20 year search for parsimony, Hope-Simpson
hypothesized that influenza is mainly transmitted by a
limited number of highly infectious latent carriers – carri-
ers infected the prior season – who are called into infectiv-
ity by a "seasonal stimulus" inextricably bound to
sunlight and who remain highly infective for brief peri-
ods, thus explaining the waves of influenza that abruptly
end despite a wealth of non-immune potential victims
[2]. Nevertheless, to our knowledge, researchers have
never demonstrated latency for influenza, as expected
with a constantly replicating RNA virus.
However, significant seasonal and population variations
in innate immunity make it unnecessary to postulate
latency to explain the bizarre epidemiology of influenza.
While any theory of influenza must take into account four
factors: transmissibility, virulence, adaptive immunity,
and innate immunity, it has been easy to ignore innate
immunity as it lacked demonstrable seasonal variations,
population variations, and a mechanism of action.
To make sense of influenza's epidemiology, we revise
Hope-Simpson theory, hypothesizing marked variation in
the infectivity of the infected (the good infectors demon-
strated in rats by Schulman and Kilbourne in 1963) and
that vitamin D deficiency is Hope-Simpson's seasonal
stimulus. Adding these two factors to transmissibility, vir-
ulence, and adaptive immunity, solves a number of influ-
enza's mysteries.
1. Why is influenza both seasonal and ubiquitous and
where is the virus between epidemics?
If influenza were surviving in an endless chain of
transmissions from good transmitters to the well – the
good transmitters being generally asymptomatic dur-
ing times of enhanced innate immunity – the disease
would be widely seeded in the population, explaining
its ubiquity. Seasonal impairments in innate immu-
nity would allow seasonal epidemics in temperate lat-
itudes and less predictable epidemics in tropical
zones, depending on viral novelty, transmissibility,
virulence, and the innate immunity of the population.
Non-seasonal isolated outbreaks would usually only
appear in nursing homes [85] or prisons [86] where
lack of sunlight impaired innate immunity; such iso-
lated outbreaks would seldom lead to community out-
breaks. More extensive out-of-season outbreaks, as
occurred in 1918, would arise when novel antigenic
viruses with significantly greater infectivity and viru-
lence overwhelm innate immunity.
2. Why are influenza epidemics so explosive?
Predictable fall and winter impairments in innate
immunity in temperate latitudes – and less predictable
recurrent impairments in subequatorial and equato-
rial latitudes – would cause a percentage of the non-
immune population to become suddenly susceptible
to background influenza virus. The size of that suscep-
tible subpopulation would vary, not only by the size
of their impairments in innate immunity, but with the
transmissibility and virulence of the virus, and the per-
centage of the population with competent adaptive
immunity. Abrupt deficiencies in innate immunity,
especially when large segments of the population also
have inadequate adaptive immunity, would allow qui-
escent influenza to erupt.
3. Why do epidemics end so abruptly?
The rapid depletion of the population with both
impaired innate and inadequate adaptive immunity
may explain the abrupt disappearance of influenza.
Impairments in innate immunity may also increase
transmission, in effect, turning more infectors, symp-
tomatic or not, into good transmitters. Furthermore, if
only a small population of good transmitters – and
not all the sick – usually spread the virus, and their
transmission period is limited, the epidemic would
end shortly after the good transmitters lose their infec-
tivity.
4. What explains the frequent coincidental timing of epi-
demics in countries of similar latitudes?
Virology Journal 2008, 5:29 http://www.virologyj.com/content/5/1/29
Page 9 of 12
(page number not for citation purposes)
Simultaneous impairments of innate immunity at
similar latitudes – due to seasonal sunlight depriva-
tion – explain the almost simultaneous eruption of
influenza at sites of different longitude but similar lat-
itude. If the virus had already imbedded itself in a pop-
ulation and a subgroup of the infected became good
transmitters when their innate immunity declines to a
critical threshold, such transmitters would coinciden-
tally infect populations at similar latitudes made sus-
ceptible by those same impairments in innate
immunity.
5. Why is the serial interval obscure?
Good transmitters explain the difficulty identifying
influenza's serial interval especially since influenza's
incubation period is well known. If only subpopula-
tions of infected persons are good transmitters, and if
their infectious period is limited, then the serial inter-
val would remain obscure until we identified the good
transmitters. Vitamin D induced variations in natural
immunity may also affect influenza's incubation
period, further obfuscating the serial interval.
6. Why is the secondary attack rate so low?
The studies we identified found a secondary attack rate
of around 20%, impossibly low for a highly infectious
virus spread from the sick to the well. If only a subpop-
ulation of the infected, the good transmitters, are
infective, this would explain the surprisingly low sec-
ondary attack rates. Current estimates of secondary
attack rates assume the first case in the family is the
index case and is spreading the disease. However, if
only a subpopulation of infected persons transmit the
disease, the true secondary attack rate could not be
accurately determined until we identify the good
infectors.
7. Why did epidemics in previous ages spread so rapidly,
despite the lack of modern transport?
If influenza were embedded in the population, only to
erupt when impairments in innate immunity create a
susceptible subpopulation, the disease would only
give the appearance of spreading. Instead, it would
appear in large segments of the population seasonally,
and almost simultaneously, as long as good transmit-
ters were available. Furthermore, as good transmitters
traveled, populations with neither adequate innate
immunity nor competent adaptive immunity may suc-
cumb. That is, the disease would actually spread, as
good transmitters traveled and subsequently infected
well subpopulations with impaired immunity.
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 inoc-
ulated 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
Kilbourne once wrote the "student of influenza is con-
stantly looking back over his shoulder and asking 'what
happened?' in the hope that understanding of past events
will alert him to the catastrophes of the future" [89]. That
is all we are attempting.
Certainly, without factoring in the effects of innate immu-
nity, we must contort our logic to make sense of influ-
enza's bewildering epidemiological contradictions. When
seasonal and population variations in innate immunity
are considered in context with the novelty, transmissibil-
ity, and virulence of the attacking virus, the conundrums
are fewer. A subpopulation of good transmitters among
the infected further clarifies influenza's confusing epide-
miology. The addition of both variables would improve
current epidemiological models of influenza.
Compelling epidemiological evidence indicates vitamin
D deficiency is the "seasonal stimulus" [22]. Furthermore,
recent evidence confirms that lower respiratory tract infec-
tions are more frequent, sometimes dramatically so, in
those with low 25(OH)D levels [90-92]. Very recently,
articles in mainstream medical journals have emphasized
the compelling reasons to promptly diagnose and ade-
quately treat vitamin D deficiency, deficiencies that may
be the rule, rather than the exception, at least during flu
season [40,41]. Regardless of vitamin D's effects on innate
Virology Journal 2008, 5:29 http://www.virologyj.com/content/5/1/29
Page 10 of 12
(page number not for citation purposes)
immunity, activated vitamin D is a pluripotent pleiotropic
seco-steroid with as many mechanisms of action as the
1,000 human genes it regulates [93]. Evidence continues
to accumulate of vitamin D's involvement in a breathtak-
ing array of human disease and death. [40,41]
In 1992, Hope-Simpson predicted that, "understanding
the mechanism (of the seasonal stimulus) may be of crit-
ical value in designing prophylaxis against the disease."
Twenty-five years later, Aloia and Li-Ng found 2,000 IU of
vitamin D per day abolished the seasonality of influenza
and dramatically reduced its self-reported incidence [25].
(Figure 2) Hence, we propose this modification of Hope-
Simpson's theory. We do not expect our revisions to prove
invincible, nor do we delude ourselves that influenza is
now comprehensible. Rather, we build on Hope-Simp-
son's theory so that it "may be corroborated, corrected, or
disproved." (Hope-Simpson, 1992, p. 191)
Abbreviations
AMPs: antimicrobial peptides; RCT: randomized control-
led trial; Pathogen Associated Molecular Patterns: PAMPS
Competing interests
Dr. Cannell heads the non-profit educational group, 'The
Vitamin D Council'.
Authors' contributions
JJC conceived of the project, consulted with EG, and wrote
each new draft. MZ added material on innate immunity.
CFG and RS revised the first and subsequent drafts and
expanded the article's scope. EG revised and reviewed all
drafts and added additional material to each draft. All
authors read and approved the final manuscript.
Acknowledgements
The authors wish to thank Dr. Brian Mahy of the Centers for Disease Con-
trol and Dr. Cecile Viboud of the National Institutes of Health for reviewing
the manuscript and making many useful suggestions.
References
1. Hope-Simpson RE, Golubev DB: A new concept of the epidemic
process of influenza A virus. Epidemiol Infect 1987, 99:5-54.
2. Hope-Simpson RE: The transmission of epidemic influenza New York:
Plenum Press; 1992.
3. Brankston G, Gitterman L, Hirji Z, Lemieux C, Gardam M: Trans-
mission of influenza A in human beings. Lancet Infect Dis 2007,
7:257-265.
4. Alford RH, Kasel JA, Gerone PJ, Knight V: Human influenza result-
ing from aerosol inhalation. Proc Soc Exp Biol Med 1966,
122:800-804.
5. Beare AS, Craig JW: Virulence for man of a human influenza-A
virus antigenically similar to "classical" swine viruses. Lancet
1976, 2:4-5.
6. Beare AS, Kendal AP, Craig JW: Further studies in man of
Hsw1N1 influenza viruses. J Med Virol 1980, 5:33-38.
7. Thompson WW, Shay DK, Weintraub E, Brammer L, Cox N, Ander-
son LJ, Fukuda K: Mortality associated with influenza and res-
piratory syncytial virus in the United States. JAMA 2003,
289:179-186.
8. Thompson WW, Shay DK, Weintraub E, Brammer L, Bridges CB,
Cox NJ, Fukuda K: Influenza-associated hospitalizations in the
United States. JAMA 2004, 292:1333-1340.
9. Simonsen L, Reichert TA, Viboud C, Blackwelder WC, Taylor RJ,
Miller MA: Impact of influenza vaccination on seasonal mor-
tality in the US elderly population. Arch Intern Med 2005,
165:265-272.
10. Rizzo C, Viboud C, Montomoli E, Simonsen L, Miller MA: Influenza-
related mortality in the Italian elderly: no decline associated
with increasing vaccination coverage. Vaccine 2006,
24:6468-6475.
11. Cox NJ, Subbarao K: Influenza. Lancet 1999, 354:1277-1282.
12. Stephenson I, Zambon M: The epidemiology of influenza. Occup
Med (Lond) 2002, 52:241-247.
13. Cox NJ, Subaru K: Global epidemiology of influenza: past and
present.
Annu Rev Med 2000, 51:407-421.
14. Gregg MB: The epidemiology of influenza in humans. Ann N Y
Acad Sci 1980, 353:45-53.
15. Miller DL, Pereira MS, Clarke M: Epidemiology of the Hong
Kong-68 variant of influenza A2 in Britain. BMJ 1971,
1:475-479.
16. Hope-Simpson RE: The method of transmission of epidemic
influenza: further evidence from archival mortality data. J
Hyg (London) 1986, 96(2):353-375.
17. Hope-Simpson RE: Age and secular distributions of virus-
proven influenza patients in successive epidemics 1961–1976
in Cirencester: epidemiological significance discussed. J Hyg
(London) 1984, 92(3):303-336.
18. Viboud C, Boëlle PY, Pakdaman K, Carrat F, Valleron AJ, Flahault A:
Influenza epidemics in the United States, France, and Aus-
tralia, 1972–1997. Emerg Infect Dis 2004, 10:32-39.
19. Jordan EO: Epidemic influenza, a survey Chicago: American Medical
Association; 1927.
20. Tellier R: Review of aerosol transmission of influenza A virus.
Emerg Infect Dis 2006, 12:1657-1662.
21. Kilbourne ED: Influenza New York: Plenum Press; 1987.
22. Cannell JJ, Vieth R, Umhau JC, Holick MF, Grant WB, Madronich S,
Garland CF, Giovannucci E: Epidemic influenza and vitamin D.
Epidemiol Infect 2006, 134:1129-1140.
23. Hypponen E, Power C: Hypovitaminosis D in British adults at
age 45 y: nationwide cohort study of dietary and lifestyle pre-
dictors. Am J Clin Nutr 2007, 85:860-868.
24. Adams JS, Hewison M: Unexpected actions of vitamin D: new
perspectives on the regulation of innate and adaptive immu-
nity. Nat Clin Pract Endocrinol Metab 2008, 4:80-90.
25. Aloia J, Li-Ng M: Re: epidemic influenza and vitamin D. Epide-
miol Infect 2007, 135(7):1095-1096.
26. Zasloff M: Inducing endogenous antimicrobial peptides to bat-
tle infections. Proc Natl Acad Sci USA 2006, 103:8913-4.
27. Raloff J: The Antibiotic Vitamin. Science News 2006, 170:312-317
[http://www.sciencenews.org/articles/20061111/bob9.asp
].
28. Zasloff M: Antimicrobial peptides of multicellular organisms.
Nature 2002, 415:389-95.
29. Schutte BC, McCray PB Jr: [beta]-defensins in lung host defense.
Annu Rev Physiol 2002, 64:709-748.
30. Laube DM, Yim S, Ryan LK, Kisich KO, Diamond G: Antimicrobial
peptides in the airway. Curr Top Microbiol Immunol 2006,
306:153-182.
31. Leikina E, Delanoe-Ayari H, Melikov K, Cho MS, Chen A, Waring AJ,
Wang W, Xie Y, Loo JA, Lehrer RI, Chernomordik LV: Carbohy-
drate-binding molecules inhibit viral fusion and entry by
crosslinking membrane glycoproteins. Nature Immunol 2005,
6(10):995-1001. Epub 2005 Sep 11.
32. Tjabringa GS, Aarbiou J, Ninaber DK, Drijfhout JW, Sørensen OE,
Borregaard N, Rabe KF, Hiemstra PS: The Antimicrobial Peptide
LL-37 Activate Innate Immunity at the Airway Surface by
Transactivation of the Epithelial Growth Factor Receptor. J
Immunol 2003, 171:6690-6696.
33. Wang TT, Nestel FP, Bourdeau V, Nagai Y, Wang Q, Liao J, Tavera-
Mendoza L, Lin R, Hanrahan JW, Mader S, White JH: Cutting edge:
1,25-dihydroxyvitamin D3 is a direct inducer of antimicrobial
peptide gene expression. J Immunol 2004, 173:2909-2912.
34. Gombart AF, Borregaard N, Koeffler HP: Human Cathelicidin
Antimicrobial Peptide Gene is a Direct Target of the Vita-
min D Receptor and is Strongly Upregulated in Myeloid Cells
by 1,25 dihydroxy Vitamin D3. FASEB J 2005, 19:1067-1077.
Virology Journal 2008, 5:29 http://www.virologyj.com/content/5/1/29
Page 11 of 12
(page number not for citation purposes)
35. Zasloff M: Fighting Infections with Vitamin D. Nat Med 2006,
12:388-390.
36. Schauber J, Dorschner RA, Coda AB, Büchau AS, Liu PT, Kiken D,
Helfrich YR, Kang S, Elalieh HZ, Steinmeyer A, Zügel U, Bikle DD,
Modlin RL, Gallo RL: Injury Enhances TLR2 Function and Anti-
microbial Peptide Expression Through a Vitamin D Depend-
ent Mechanism. J Clin Invest 2007, 117:803-811.
37. Liu PT, Stenger S, Li H, Wenzel L, Tan BH, Krutzik SR, Ochoa MT,
Schauber J, Wu K, Meinken C, Kamen DL, Wagner M, Bals R, Stein-
meyer A, Zügel U, Gallo RL, Eisenberg D, Hewison M, Hollis BW,
Adams JS, Bloom BR, Modlin RL: Toll like receptor triggering of
a vitamin D mediated human antimicrobial response. Science
2006, 311:1770-1773.
38. Clemens TL, Adams JS, Henderson SL, Holick MF: Increased skin
pigment reduces the capacity of skin to synthesise vitamin
D3. Lancet 1982, 1:74-76.
39. MacLaughlin J, Holick MF: Aging decreases the capacity of
human skin to produce vitamin D3. J Clin Invest 1985,
76:1536-1538.
40. Holick MF: Vitamin D deficiency. N Engl J Med 2007, 357:266-281.
41. Cannell J, Hollis B, Zasloff M, Heaney R: Diagnosis and treatment
of vitamin D deficiency. Expert Opin Pharmacother 2008,
9:107-118.
42. MacDonald D, Swaminathan R: Seasonal variation in 25-OH vita-
min D in plasma of Hong Kong Chinese. Clin Chem 1988,
34:2375.
43. Levis S, Gomez A, Jimenez C, Veras L, Ma F, Lai S, Hollis B, Roos BA:
Vitamin D deficiency and seasonal variation in an adult
South Florida population. J Clin Endocrinol Metab 2005,
90:1557-1562.
44. Kung AW, Lee KK: Knowledge of vitamin D and perceptions
and attitudes toward sunlight among Chinese middle-aged
and elderly women: a population survey in Hong Kong. BMC
Public Health 2006, 6:226.
45. Shek LP, Lee BW: Epidemiology and seasonality of respiratory
tract virus infections in the tropics. Paediatr Respir Rev 2003,
4:105-111.
46. Agarwal KS, Mughal MZ, Upadhyay P, Berry JL, Mawer EB, Puliyel JM:
The impact of atmospheric pollution on vitamin D status of
infants and toddlers in Delhi, India. Arch Dis Child 2002,
87:111-113.
47. Leung SS, Lui S, Swaminathan R: Vitamin D status of Hong Kong
Chinese infants. Acta Paediatr Scand 1989, 78:303-306.
48. Vieth R: What is the optimal vitamin D status for health? Prog
Biophys Mol Biol 2006, 92:26-32.
49. Hollis BW: Circulating 25-hydroxyvitamin D levels indicative
of vitamin D sufficiency: implications for establishing a new
effective dietary intake recommendation for vitamin D. J
Nutr 2005, 135:317-322.
50. Bridges CB, Kuehnert MJ, Hall CB: Transmission of Influenza:
Implications for Control in Health Care Settings. Clin Infect
Dis 2003, 37:1094-1101.
51. McCoy GW, Richey D: II. Series of experiments at San Fran-
cisco, November and December, 1918. Hygienic Laboratory
U.S.P.H.S. Bulletin 1921, 123:42-53.
52. Rosenau MJ: Experiments to determine mode of spread of
influenza. JAMA 1919, 73:311-313.
53. Rosenau MJ: I. Series of experiments at Boston, November
and December, 1918. Hygienic Laboratory U.S.P.H.S. Bulletin 1921,
123:5-41.
54. Rosenau MJ: III. Series of experiments at Boston, February
and March, 1919. Hygienic Laboratory U.S.P.H.S. Bulletin 1921,
123:54-102.
55. Leake JP: The transmission of influenza. Boston Med Surg J 1919,
181:675-679.
56. World Health Organization Writing Group: Nonpharmaceutical
Interventions for Pandemic Influenza, International Meas-
ures. Emerg Infect Dis 2006, 12:81-87.
57. Olson JG, Ksiazek TG, Irving GS, Rendin RW: An explosive out-
break of influenza caused by A/USSR/77-like virus on a
United States naval ship. Mil Med 1979, 144:743-745.
58. Taylor R, Nemaia H, Tukuitonga C, Kennett M, White J, Rodger S,
Levy S, Gust I: An epidemic of influenza in the population of
Niue. J Med Virol 1985, 16:127-136.
59. Blumenfeld HL, Kilbourne ED, Louria DB, Rogers DE: Studies on
influenza in the pandemic of 1957–1958. I. An epidemiologic,
clinical and serologic investigation of an intrahospital epi-
demic, with a note on vaccination efficacy. J Clin Invest 1959,
38:199-212.
60. Moser MR, Bender TR, Margolis HS, Noble GR, Kendal AP, Ritter
DG: An outbreak of influenza aboard a commercial airliner.
Am J Epidemiol 1979, 110:1-6.
61. Jordan WS Jr: The mechanism of spread of Asian influenza. Am
Rev Respir Dis 1961, 83(2):29-40.
62. Riley RL, Wells WF, Mills CC, Nyka W, Mclean RL: Air hygiene in
tuberculosis: quantitative studies of infectivity and control in
a pilot ward. Am Rev Tuberc 1957, 75:420-431.
63. Gelperin A, Granoff MA, Linde JI: The effect of ultraviolet light
upon absenteeism from upper respiratory infections in New
Haven schools. Am J Pub Health Nations Health 1951,
41(7):796-805.
64. Kingston D, Lidwell OM, Williams RE: The epidemiology of the
common cold. III. The effect of ventilation, air disinfection
and room size. J Hyg (London) 1962, 60:341-352.
65. Medical Research Council: Air disinfection with ultraviolet irra-
diation: its effect on illness among school children. London:
Her Majesty's Stationary Office, 1954. Special Report Series No. 283 .
66. Hope-Simpson RE: Epidemic mechanisms of type A influenza.
J Hyg (London) 1979, 83(1):11-26.
67. Mann PG, Pereira MS, Smith JW, Hart RJ, Williams WO: A five-year
study of influenza in families. Joint Public Health Laboratory
Service/Royal College of General Practitioners working
group. J Hyg (Lond) 1981, 87:191-200.
68. Jordan WS Jr, Denny FW Jr, Badger GF, Curtiss C, Dingle JH, Osea-
sohn R, Stevens DA: A study of illness in a group of Cleveland
families. XVII. The occurrence of Asian influenza. Am J Hyg
1958, 68:190-212.
69. Viboud C, Boëlle PY, Cauchemez S, Lavenu A, Valleron AJ, Flahault A,
Carrat F: Risk factors of influenza transmission in households.
Br J Gen Prac 2004, 54(506):684-689.
70. Gog JR, Rimmelzwaan GF, Osterhaus AD, Grenfell BT: Population
dynamics of rapid fixation in cytotoxic T lymphocyte escape
mutants of influenza A. Proc Nat Acad Sci USA 2003,
100:11143-11147.
71. Fox JP, Cooney MK, Hall CE: The Seattle virus watch. V. Epide-
miologic observations of rhinovirus infections, 1965–1969, in
families with young children. Am J Epidemiol 1975, 101:122-143.
72. Narain JP, Khare S, Rana SR, Banerjee KB: Epidemic measles in an
isolated unvaccinated population, India. Int J Epidemiol 1989,
18:952-958.
73. Seward JF, Zhang JX, Maupin TJ, Mascola L, Jumaan AO: Contagious-
ness of varicella in vaccinated cases: a household contact
study. JAMA 2004, 292:704-708.
74. Hope-Simpson RE: First outbreak of Hong Kong influenza in a
general practice population in Great Britain. A field and lab-
oratory study. Br Med J 1970, 3:74-77.
75. Neuzil KM, Hohlbein C, Zhu Y: Illness among schoolchildren
during influenza season: effect on school absenteeism,
parental absenteeism from work, and secondary illness in
families. Arch Pediatr Adolesc Med 2002, 156:986-991.
76. Longini IM Jr, Koopman JS, Monto AS, Fox JP: Estimating house-
hold and community transmission parameters for influenza.
Am J Epidemiol 1982, 115:736-751.
77. Longini IM Jr, Koopman JS, Haber M, Cotsonis GA: Statistical infer-
ence for infectious diseases. Risk-specific household and
community transmission parameters. Am J Epidemiol 1988,
128:845-859.
78. Thacker SB: The persistence of influenza A in human popula-
tions. Epidemiol Rev 1986, 8:129-142.
79. Halloran ME, Hayden FG, Yang Y, Longini IM Jr, Monto AS:
Antiviral
effects on influenza viral transmission and pathogenicity:
observations from household-based trials. Am J Epidemiol 2007,
165:212-221.
80. Herlocher ML, Elias S, Truscon R, Harrison S, Mindell D, Simon C,
Monto AS: Ferrets as a transmission model for influenza:
sequence changes in HA1 of type A (H3N2) virus. J Infect Dis
2001, 184:542-546.
81. Ali MJ, Teh CZ, Jennings R, Potter CW: Transmissibility of influ-
enza viruses in hamsters. Arch Virol 1982, 72:187-197.
82. Schulman JL, Kilbourne ED: Experimental transmission of influ-
enza virus infection in mice. I. The period of Transmissibility.
J Exp Med 1963, 118:257-266.
Publish with BioMed Central and every
scientist can read your work free of charge
"BioMed Central will be the most significant development for
disseminating the results of biomedical research in our lifetime."
Sir Paul Nurse, Cancer Research UK
Your research papers will be:
available free of charge to the entire biomedical community
peer reviewed and published immediately upon acceptance
cited in PubMed and archived on PubMed Central
yours — you keep the copyright
Submit your manuscript here:
http://www.biomedcentral.com/info/publishing_adv.asp
BioMedcentral
Virology Journal 2008, 5:29 http://www.virologyj.com/content/5/1/29
Page 12 of 12
(page number not for citation purposes)
83. Young GA, Underdahl NR, Carpenter LE: Vitamin D intake and
susceptibility of mice to experimental swine influenza virus
infection. Proc Soc Exp Biol Med 1949, 72:695-697.
84. Underdahl NR, Young GA: Effect of dietary intake of fat-soluble
vitamins on intensity of experimental swine influenza virus
infection in mice. Virology 1956, 2:415-429.
85. Ferson MJ, Morgan K, Robertson PW, Hampson AW, Carter I, Raw-
linson WD: Concurrent summer influenza and pertussis out-
breaks in a nursing home in Sydney, Australia. Infect Control
Hosp Epidemiol 2004, 25:962-966.
86. Young LC, Dwyer DE, Harris M, Guse Z, Noel V, Levy MH: Summer
outbreak of respiratory disease in an Australian prison due
to an influenza A/Fujian/411/2002(H3N2)-like virus. Epidemiol
Infect 2005, 133:107-112.
87. Hall HI, May DS, Lew RA, Koh HK, Nadel M: Sun protection
behaviors of the U.S. white population. Prev Med 1997,
26:401-407.
88. Robinson JK, Rigel DS, Amonette RA: Trends in sun exposure
knowledge, attitudes, and behaviors: 1986 to 1996. J Am Acad
of Dermatol 1997, 37:179-186.
89. Kilbourne ED: The molecular epidemiology of influenza. J
Infect Dis 1973, 127:478-487.
90. Wayse V, Yousafzai A, Mogale K, Filteau S: Association of subclin-
ical vitamin D deficiency with severe acute lower respiratory
infection in Indian children under 5 y. Eur J Clin Nutr 2004,
58:563-567.
91. Laaksi I, Ruohola JP, Tuohimaa P, Auvinen A, Haataja R, Pihlajamäki H,
Ylikomi T: An association of serum vitamin D concentrations
< 40 nmol/L with acute respiratory tract infection in young
Finnish men. Am J Clin Nutr 2007, 86:714-7.
92. Karatekin G, Kaya A, Saliho&#x011F;lu O, Balci H, Nuho&#x011F;lu
A: Association of subclinical vitamin D deficiency in new-
borns with acute lower respiratory infection and their moth-
ers. Eur J Clin Nutr in press. 2007 Nov 21
93. Tavera-Mendoza LE, White JH: Cell defenses and the sunshine
vitamin. Sci Am 2007, 297:62-5. 68–70, 72
... Infectious disease transmission occurs in four major ways: direct contact, indirect contact, droplet transmission, and airborne transmission [32]. COVID-19 virus is being transferred between people via respiratory droplets and contact pathways, according to current evidence [33]. ...
Article
Full-text available
Responding to the events surrounding the COVID-19 pandemic, this study explores how to improve health and wellbeing and reduce infections in outdoor open spaces on university campuses to maximize their potential as a response to future crises. The study identifies the relationship between human behavior (social) and the various physical and environmental elements of these spaces. A case study and mixed-methods approach were undertaken, comprising four modes of inspection: user analysis layer using questionnaires and observations to survey students’ needs and behavior; context analysis layer using space syntax and CFD to examine the space’s physical and environmental conditions; design solutions reflecting an understanding of virus transmission; and a performance analysis layer to test the performance of ‘anti-virus’ courtyards. The findings demonstrated that students are willing to use the open spaces that they used before the pandemic, at the same frequency. This indicates a need to redesign the current spaces to prevent the spread of viruses. The study highlights the social, physical, and environmental implications to be considered in designs for outdoor anti-virus spaces. It provides a comprehensive process for transforming outdoor spaces on university campuses into anti-virus spaces that meet users’ needs. These findings have implications for the designing and retrofitting of open spaces to reduce infection.
... [7] Multiple studies have shown that low solar UVB levels, which are directly linked to vitamin D concentrations, might be one of the reasons why seasonal influenza infections rise over the winter months, another fact firmly linking hypovitaminosis D with RTIs and probably COVID-19. [8] COVID-19 arrived in the northern hemisphere at the end of 2019 in winter, when levels of vitamin D are at rock bottom. The northern hemisphere suffered maximally in terms of cases and mortality. ...
Article
Full-text available
Background: The COVID-19 pandemic has become a global threat, with an inexplicable course of action and suboptimal response to the multitudes of therapies being tried. Vitamin D's pleiotropic effects (immunomodulatory, anti-inflammatory, and antiviral) have lately received considerable attention in the scientific community, and it has been shown to be helpful in the defense against viral respiratory infections. Aim: To find out the association between vitamin D and COVID-19. Methods: Overall, 360 (156 COVID-19 +ve and 204 COVID-19 −ve) subjects were investigated in this hospital-based case-control study. The study participants were taken from the COVID-19 wards and Flu clinic of a dedicated COVID hospital between August 1 and September 15, 2020. The demographics and clinical data including alcohol and smoking history along with serum vitamin D levels were recorded. Binary logistic regression analysis was performed to assess the association between age, gender, alcohol intake, smoking history, vitamin D status, and COVID-19. Results: There was no significant difference in the mean vitamin D levels between cases and controls. Bivariate analysis of predictors and COVID-19 revealed that predictors such as advanced age, BMI, alcohol intake, smoking habit, diabetes, hypertension, and vitamin D deficiency were significantly associated with COVID-19. Conclusions: This study showed that serum vitamin D status might be able to reduce the impact of COVID-19, although more studies are required to establish clear causality.
... In the past decade, several studies have demonstrated a potential link between vitamin D deficiency and various diseases, including systemic infections [6][7][8]. Various clinical studies have reported associations of low serum vitamin D levels with acute respiratory tract infections, including epidemic influenza [9][10][11]. Vitamin D, a steroid hormone, whose biosynthesis begins with solar ultraviolet radiation in bare skin exposed to strong sunlight, and shows multidimensional effects beyond calcium and bone metabolism. ...
Article
Full-text available
Objectives: Extensive evidence has linked low vitamin D status and comorbidities with COVID-19 outcomes, but the results from published studies till date are contradictory. We hypothesized that lower level of vitamin D in the blood is linked to a high risk of COVID-19 infection. Therefore, we aimed to determine the association of lower levels of vitamin D and comorbidities with the risk of COVID-19 infection. Method: We searched Medline (via PubMed), Cochrane registry and ClinicalTrials.gov for articles published until August 20, 2021. A total of 16 eligible studies were found. Results: The pooled estimate showed significantly lower levels of vitamin D in COVID-19 positive patients (mean difference [MD]= -1.70, 95% confidence interval [CI]= -2.74 to -0.66, p = 0.001), however, varies by study designs (case-control: -4.08 [95% CI -5.98 to -2.10], p<0.001; cohort: -0.39 [95% CI -1.62 to 0.84], p=0.538). The subgroup analysis revealed lower levels of vitamin D in female patients (MD= -2.18; 95% CI -4.08 to -0.28; p=0.024) when compared to male patients (MD= -1.74; 95% CI -3.79 to 0.31; p=0.096). Male patients showed higher odds of having low vitamin D levels (OR=2.09; 95% CI 1.38 to 3.17; p<0.001) compared to females (OR=1.17; 95% CI 0.74 to 1.86; p=0.477). Conclusions: To conclude, low serum vitamin-D levels are significantly associated with a high risk of COVID-19 infection. Female gender with the COVID-19 showed lower level of serum vitamin-D compared to male patients. Limited evidence was found between reported comorbidities and acquiring COVID-19 infection and therefore, large population-based studies are needed.
... Vitamin D insufficiency has been linked to increased risk of respiratory tract infections including SARS-CoV2 in a large number of association studies [21][22][23][24][25][26][27][28][29], whereas vitamin D supplementation appears to be protective especially in those with low levels of 25OHD at baseline and treated with modest doses at daily or weekly intervals [28,30,31]. Similarly, certain vitamin D receptor (VDR) polymorphisms have been associated with increased risk of acute lower respiratory tract infections [32]. ...
Article
Full-text available
Covid-19 has to date infected a confirmed 275 million people with 5.4 million, now dead, with the count rising every day. Although the virus, SARS-CoV2, causing Covid-19 infects many cells in the body, its infection of the upper and lower respiratory tract (upper airway epithelia and pulmonary alveolar pneumocytes and macrophages) causing what is now called a cytokine storm in the lungs is the major cause of morbidity and mortality. This results from a dysregulation of the innate immune system with an outpouring of proinflammatory cytokines and chemokines leading to abnormal activation of the adaptive immune pathway. Airway epithelia constitutively expresses CYP27B1, the enzyme producing the active vitamin D metabolite, 1,25(OH)2D, and the vitamin D receptor (VDR) for which 1,25(OH)2D is the ligand. Pulmonary alveolar macrophages, on the other hand, are induced to express both CYP27B1 and VDR by various pathogens including viruses and cytokines released from infected epithelia and other immune cells. Although not demonstrated for corona viruses like SARS-CoV2, for other viruses and other respiratory pathogens activation of innate immunity leading to increased local 1,25(OH)2D production has been shown to enhance viral neutralization and clearance while modulating the subsequent proinflammatory response. Whether such will be the case for SARS-CoV2 remains to be seen, but is currently being proposed and investigated. This mini review will discuss some of the mechanisms by which vitamin D may help reduce morbidity and mortality in this devastating pandemic.
... From three types of influenza viruses (A, B, and C), the latter two produce relatively mild seasonal outbreaks and are confined mainly to humans. In contrast, A viruses as the most virulent pathogens are associated with several well-known human pandemics during the last century and an increasing number of epizootics in domestic birds (Cannell et al., 2008;Michaelis et al., 2009;Suzuki, 2009). Influenza A viruses are further classified into subtypes according to the combinations of the proteins on the surface of the virus: hemagglutinin (HA) and neuraminidase (NA). ...
Article
The rapid emergence of influenza virus A resistance to current antivirus drugs has raised an urgent need for developing safe and effective remedies based on plants. Hairy roots are considered an efficient system for the large-scale production of valuable compounds with potent antiviral activity. We have evaluated for the first time an antivirus activity in Astragalus penduliflorus Lam. hairy roots (APHRs) lines obtained from cotyledons (APHR 2), primary shoots (APHR 5), and hypocotyls (APHR 6) against influenza A/Aichi/2/68 (H3N2) and A/chicken/Kurgan/05/2005 (H5N1) subtypes. Estimation of the antiviral activity was based on the analysis of cytotoxic activity, selectivity and neutralization indexes. All tested samples demonstrated low toxicity for MDCK cell culture corresponding to the modern requirement for antiviral drugs. Index neutralization (IN) was 2.50 in APHR 2, 28 d extract against H3N2 subtype, whereas the highest IN against H5N1 (2.25) was detected for line APHR 5 56 d The levels of selectivity index observed in APHR 5, and APHR 6 were higher in comparison with APHR 2, corresponding to the level of antioxidants, determined by the DPPH radical scavenging assay and total antioxidant activities by amperometric method. Major phenolic compounds identified in APHRs lines extracts by HPLC analysis, including flavonoids, hydroxybenzoic, hydroxicinnamic acids, could be responsible for the antiviral activities.
... Пик острых респираторных вирусных инфекций (ОРВИ) чаще всего приходится на осенне-зимний период [59]. Вклад в сезонность ОРВИ вносит снижение инсоляции и, следовательно, падение концентраций витамина D в сыворотке крови [60,61]. В пользу этой гипотезы выступают, например, W. Grant и cоавт., которые выявили наличие сильной обратной корреляции между уровнем ультрафиолетового облучения в регионе и смертностью от пандемии испанки в 1918-1919 гг. ...
Article
Full-text available
Due to global spread of COVID-19, the search for new factors that could influence its clinical course becomes highly important. This review summarize the relevant publications on the association between immune system and the main regulators of mineral homeostasis including. In addition, we have highlighted the various aspects of phosphorus-calcium metabolism related to the acute respiratory diseases and in particular to COVID-19. The data about the calcium-phosphorus metabolism in SARS-CoV-2 infection is required to understand the possible clinical implications and to develop new therapeutic and preventive interventions.
Article
Full-text available
Several human pathogens exhibit distinct patterns of seasonality and circulate as pairs. For instance, influenza A virus subtypes oscillate and peak during winter seasons of the world’s temperate climate zones. Alternation of dominant strains in successive influenza seasons makes epidemic forecasting a major challenge. From the start of the 2009 influenza pandemic we enrolled influenza A virus infected patients (n = 2980) in a global prospective clinical study. Complete hemagglutinin sequences were obtained from 1078 A/H1N1 and 1033 A/H3N2 viruses. We used phylodynamics to construct high resolution spatio-temporal phylogenetic hemagglutinin trees and estimated global influenza A effective reproductive numbers (R) over time (2009–2013). We demonstrate that R oscillates around R = 1 with a clear opposed alternation pattern between phases of the A/H1N1 and A/H3N2 subtypes. Moreover, we find a similar alternation pattern for the number of global viral spread between the sampled geographical locations. Both observations suggest a between-strain competition for susceptible hosts on a global level. Extrinsic factors that affect person-to-person transmission are a major driver of influenza seasonality. The data presented here indicate that cross-reactive host immunity is also a key intrinsic driver of influenza seasonality, which determines the influenza A virus strain at the onset of each epidemic season.
Article
Full-text available
Purpose of Review To review the mechanisms by which vitamin D and its metabolites regulate the immune system to facilitate the ability of the body to prevent and/or treat SARS-CoV2 and other respiratory infections and encourage further research into the role that vitamin D supplementation plays in preventing/treating such infections. Recent Findings Vitamin D deficiency is associated with an increased risk of SARS-CoV2 and other respiratory infections. Clinical trials in general demonstrate that correction of vitamin D deficiency reduces the risk of hospitalization, ICU admission, and death from SARS-CoV2 infection. The airway epithelium and alveolar macrophages express the enzyme, CYP27B1, that produces the active metabolite of vitamin D, 1,25(OH) 2 D, and the vitamin D receptor, VDR. Vitamin D and its metabolites promote the innate immune response, which provides the first line of defense against viral and bacterial infections while restricting the adaptive immune response, which if unchecked promotes the inflammatory response leading to the acute respiratory distress syndrome and death. Summary The rationale for treating vitamin D deficiency to reduce the risk of SARS-CoV2 infection and supplementing patients with vitamin D early in the course of SARS-CoV2 infection rests primarily on the ability of vitamin D metabolites to promote an effective immune response to the infection.
Article
In 2020 North Italy suffered the SARS-CoV-2-related pandemic with a high number of deaths and hospitalization. The effect of atmospheric parameters on the amount of hospital admissions (temperature, solar radiation, particulate matter, relative humidity and wind speed) is studied through about 8 months (May–December). Two periods are considered depending on different conditions: a) low incidence of COVID-19 and very few regulations concerning personal mobility and protection (“free/summer period”); b) increasing incidence of disease, social restrictions and use of personal protections (“confined/autumn period”). The “hospitalized people in medical area wards/100000 residents” was used as a reliable measure of COVID-19 spreading and load on the sanitary system. We developed a chemometric approach (multiple linear regression analysis) using the daily incidence of hospitalizations as a function of the single independent variables and of their products (interactions). Eight administrative domains were considered (altogether 26 million inhabitants) to account for relatively homogeneous territorial and social conditions. The obtained models very significantly match the daily variation of hospitalizations, during the two periods. Under the confined/autumn period, the effect of non-pharmacologic measures (social distances, personal protection, etc.) possibly attenuates the virus diffusion despite environmental factors. On the contrary, in the free/summer conditions the effects of atmospheric parameters are very significant through all the areas. Particulate matter matches the growth of hospitalizations in areas with low chronic particulate pollution. Fewer hospitalizations strongly correspond to higher temperature and solar radiation. Relative humidity plays the same role, but with a lesser extent. The interaction between solar radiation and high temperature is also highly significant and represents surprising evidence. The solar radiation alone and combined with high temperature exert an anti-SARS-CoV-2 effect, via both the direct inactivation of virions and the stimulation of vitamin D synthesis, improving immune system function.
Article
The severe acute respiratory syndrome coronavirus 2 is spreading like wildfire with no specific recommended treatment in sight. While some risk factors such as the presence of comorbidities, old age, and ethnicity have been recognized, not a lot is known about who the virus will strike first or impact more. In this hopeless scenario, exploration of time-tested facts about viral infections, in general, seems to be a sound basis to prop further research upon. The fact that immunity and its various determinants (e.g., micronutrients, sleep, and hygiene) have a crucial role to play in the defense against invading organisms, may be a good starting point for commencing research into these as yet undisclosed territories. Herein, the excellent immunomodulatory, antiviral, and anti-inflammatory roles of Vitamin D necessitate thorough investigation, particularly in COVID-19 perspective. This article reviews mechanisms and evidence suggesting the role Vitamin D plays in people infected by the newly identified COVID-19 virus. For this review, we searched the databases of Medline, PubMed, and Embase. We studied several meta-analyses and randomized controlled trials evaluating the role of Vitamin D in influenza and other contagious viral infections. We also reviewed the circumstantial and anecdotal evidence connecting Vitamin D with COVID-19 emerging recently. Consequently, it seems logical to conclude that the immune-enhancing, antiviral, anti-inflammatory, and lung-protective role of Vitamin D can be potentially lifesaving. Hence, Vitamin D deserves exhaustive exploration through rigorously designed and controlled scientific trials. Using Vitamin D as prophylaxis and/or chemotherapeutic treatment of COVID-19 infection is an approach worth considering. In this regard, mass assessment and subsequent supplementation can be tried, especially considering the mechanistic evidence in respiratory infections, low potential for toxicity, and widespread prevalence of the deficiency of Vitamin D affecting many people worldwide.
Article
A general practice population of around 3900, under continuous clinical and laboratory surveillance, experienced 20 outbreaks of influenza between March 1960 and March 1976. Four epidemics were caused by subtype H2N2 type A viruses, seven by subtype H3N2 type A viruses and nine outbreaks by type B viruses. The age of every person proved virologically to have influenza is related to the age structure of the community and to the phase of the epidemic in which the virus-positive specimens were collected. Children 0–15 years old suffered a higher incidence rate than adults 16–90±. Pre-school children 0–4 suffered the highest rate of infection by viruses of both influenza A subtypes, whereas older schoolchildren 10–15 suffered the highest rate of type B infections. Despite these high incidence rates neither pre-school nor schoolchildren appear to have been the major disseminators of any of these influenza viruses in the community. Adults of all ages suffered a high rate of infection even into extreme old age, and the indiscriminate age distribution among adults was sustained in the successive epidemics. Such age-patterns are not those caused by a highly infectious immunizing virus surviving by means of direct transmissions from the sick, whose prompt development of the disease continues endless chains of transmissions. An alternative epidemic mechanism – whereby the virus does not spread from the sick but becomes latent in them, reactivating seasonally so that they later infect their companions – would produce age patterns similar to those recorded here for influenza patients. The suggested mechanism is illustrated by a simple conceptual model and the influenzal age patterns are discussed in relation to the recycling of influenza A subtypes.
The experiments here described were performed on an island in Boston Harbor, on volunteers obtained from the Navy. The work was conducted by a group of officers detailed for that purpose, from the U. S. Navy and the U. S. Public Health Service, consisting of Dr. G. W. McCoy, director of the Hygienic Library, Dr. Joseph Goldberger, Dr. Leake, and Dr. Lake, all on the part of the U. S. Public Health Service; and cooperating with those medical officers, was a group also detailed for this purpose on the part of the U. S. Navy, consisting of Dr. J. J. Keegan, Dr. De Wayne Richey and myself.The work itself was conducted at Gallops Island, which is the quarantine station of the Port of Boston, and peculiarly well fitted for operations of this kind, serving adequately for the purposes of isolation, observations, and maintenance of the large group of volunteers