Vitamin D and Influenza1,2
Maria E. Sundaram and Laura A. Coleman
Marshfield Clinic Research Foundation, Marshfield, WI
Vitamin D has become increasingly recognized in the literature for its extra-skeletal roles, including an effect on inflammation and the immune
response to infection. Our goal was to describe the role of vitamin D in the immune response and implications for the risk of influenza infection
in humans. In this review, we first consider literature that provides molecular and genetic support to the idea that vitamin D is related to the
adaptive and innate immune responses to influenza infection in vitro and in animal models. We then discuss observational studies and
randomized controlled trials of vitamin D supplementation in humans. Finally, we consider some of the knowledge gaps surrounding vitamin D
and immune response that must be filled. Adv. Nutr. 3: 517–525, 2012.
Vitamin D is a fat-soluble vitamin, unique in that it is pri-
marily produced in the skin during sun exposure rather
than absorbed from the diet (1). Vitamin D has long been
known to play a role in the skeletal system and calcium ho-
meostasis; vitamin D deficiency is known to be a cause of
rickets and osteoporosis (2). Recently, cells of the immune
system have been found to possess vitamin D receptors
(VDR)3and are capable of metabolizing the active form of
vitamin D [also known as calcitriol, 1,25-dihydroxyvitamin
D, or 1,25(OH)2D] (1), suggesting that this nutrient may be
an important factor in the immune response to infection
(3). Forexample, activated T- and B-cells can convert the in-
active form of vitamin D [also known as 25-hydroxyvitamin
D, or 25(OH)D] to 1,25(OH)2D in human cells in vitro (4);
locally produced 1,25(OH)2D then acts on immune cells in
an autocrine or paracrine fashion. VDR have also been iden-
tified on peripheral blood mononuclear cells (PBMC) in hu-
man cells in vitro (5), lending support for a potential role of
vitamin D in the regulationof the immune system and infec-
tious diseases (6).
Further investigation has revealed that vitamin D plays
important roles in signaling during both the adaptive and
innate immune response to viral and bacterial infection
(3,7). 25(OH)D can be converted to 1,25(OH)2D in human
respiratory epithelium cells in vitro (8), and 1,25(OH)2D
and 25(OH)D have both been implicated in the immune re-
sponse to several types of respiratory infections, including
respiratory syncytial virus and tuberculosis, in vitro (8–
10). Studies have also found associations between either
25(OH)D or 1,25(OH)2D deficiency and clinical illnesses,
including influenza (11–14), tuberculosis (15–19), respira-
tory syncytial virus (9,20), and other respiratory illnesses
(21–24), in observational studies. An estimate provided
by data from the NHANES states that more than one-
half of U.S. adults have 25(OH)D <30 mg/L (23), a status
defined as vitamin D insufficient (1). However, an Institute
of Medicine report suggests that vitamin D deficiency be
defined as 25(OH)D <10 mg/L (25), a condition shared
by only 2% of Americans (23). No matter the cutoff, 25
(OH)D levels have been found to be significantly lower
among children with respiratory illnesses, older adults,
women, and individuals with darker skin pigmentation
In this review, we will describe evidence for the role of vi-
tamin D in modulating the adaptive and innate immune re-
sponse. We will then consider how those aspects of the
immune system respond to influenza infection. We will
also consider observational studies and randomized con-
trolled trials of vitamin D supplementation in humans and
the concurrent seasonality of poor vitamin D status and in-
creased risk of influenza infection. Finally, we will note the
problems in accurately assessing vitamin D and consider
the next steps for assessing vitamin D in the context of res-
1Supported by funding from the Marshfield Clinic Research Foundation in Marshfield, WI.
2Author disclosures: M. Sundaram and L. Coleman, no conflicts of interest.
3Abbreviations used: 25(OH)D, 25-hydroxyvitamin D; 1,25(OH)2D, 1,25-dihydroxyvitamin D;
PBMC, peripheral blood mononuclear cell; Th, T helper cell; Treg, T regulatory cell; VDR,
vitamin D receptor.
*To whom correspondence should be addressed. E-mail: sundaram.maria@marsheldclinic.
ã2012 American Society for Nutrition. Adv. Nutr. 3: 517–525, 2012; doi:10.3945/an.112.002162.
by guest on December 31, 2015
Current status of knowledge
Vitamin D and adaptive immune response to infection
The adaptive immune response to infection is complex and
multi-faceted and involves a diverse population of cell types
and other factors such as cytokines, chemokines, enzymes,
and hormones (3,30,31) (Fig. 1). Additionally, the immune
response to an infectious insult is not static; characteristics
of the response (measured by serum cytokines in human
adults) change from the initial period of antigenic stimula-
tion to the later stage of disease clearance (32). Vitamin D
may therefore affect one component of an immune system
response but not other components, meaning that the net
effect of vitamin D on immune function and clinical illness
is difficult to characterize. This also suggests that evidence of
vitamin D’s role in the immune system in vitro may not ap-
ply to vitamin D’s role in vivo. Nevertheless, vitamin D [in
particular, 1,25(OH)2D] has been found to act on specific
cell parameters of the adaptive immune response, most no-
tably T- and B-cells (Fig. 1A).
The T-cell profile shift
Vitamin D [espcially 1,25(OH)2D] is widely acknowledged
to shift the T-cell response profile from a T helper cell
(Th) 1- to a Th2-mediated response by inhibiting cells of
the Th1 profile (3,31,33-43) in vitro in mouse fibroblasts,
pancreatic islets, cultured splenocytes, and host serum;
and in vivo in mouse dendritic cells. Vitamin D also pro-
motes cells of the Th2 profile (31,39,41,42,44,45) in mouse
fibroblasts (Fig. 1A). This bias is thought to reduce in-
flammation and promote an immunosuppressive state (31).
1,25(OH)2D inhibits the proliferation of Th1 helper cells
in mouse lymphocytes and human T-cell clones in vitro in
part by inhibiting IFNg and IL-2, cytokines that promote
Th1 production and recruitment and macrophage pro-
duction (3,46–48). 1,25(OH)2D also reduces IL-12 (another
cytokine that promotes Th1 production and recruitment)
in vitro in human PBMC (15); it is thought to accomplish
this by downregulating molecules in human dendritic
cells, which produce IL-12 (3,15,47,49), and by promoting
IL-10, a cytokine thought to inhibit production of IL-12
(39,50,51). 1,25(OH)2D suppresses an additional Th1-
mediated cytokine, TNFa, in vitro in human monocytes,
further pushing immune response to a Th2 profile (52,53).
1,25(OH)2D has also been found to suppress the production
and recruitment of Th17 cells in mice in vivo by down-
regulating Th17-mediated cytokines IL-23 and IL-6 (3,50)
(Fig. 1B). In contrast, 1,25(OH)2D has been shown to upre-
gulate IL-4, IL-5, and IL-10 in mouse lymphocytes in vitro;
these cytokines promote a Th2 response profile (3,46). IL-10
also promotes the proliferation of T regulatory (Treg) cells
Th0 cells by inhibiting IL-2, IFNg, and TNFa; vitamin D promotes the production of Treg cells by facilitating production of IL-10. (B)
Vitamin D promotes a Th2-mediated immune response profile by promoting IL-4, IL-5, and IL-10. Vitamin D inhibits a Th17-mediated
immune response profile (and thus inhibits IL-17) by inhibiting IL-6 and IL-23. (C) Vitamin D inhibits the production of B-cells, the
differentiation of B-cells into plasma cells, and the production of antibodies by B-cells. (D) Vitamin D promotes nuclear factor of kappa
light polypeptide gene enhancer in B-cells inhibitor, a in respiratory epithelial cells, which inhibits NF-kB, in turn promoting antiviral
and immunomodulatory interferon signaling. Th, T helper cell; Treg, T regulatory cell.
Vitamin D and its various actions in the immune system. (A) Vitamin D inhibits the production and proliferation of Th1 and
518Sundaram and Coleman
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in mouse colon cells in vivo; these Treg cells inhibit the Th1
response profile (3,50) (Fig. 1A).
Despite overwhelming invitro evidence that 1,25(OH)2D
biases the immune system response toward a Th2-dominated
profile, it has been shown to repress both Th1 and Th2
response profiles in human cord blood cells in vitro (54).
This suggests that the effects of 1,25(OH)2D on Th helper
cell selection are more complex in vivo and in differing
molecular and cellular environments (44). A study on the
immune response to allergy stimulus in mice in vivo sug-
gested that vitamin D supplementation [100 ng 1,25(OH)2D
injection] given after the initial period of sensitization pre-
vented high levels of eosinophils associated with reduced
local inflammatory response in bronchoalveolar lavage fluid
and lung tissue. However, constant vitamin D supplementa-
tion [100 ng 1,25(OH)2D injection every other day during
the study] did not protect against a high eosinophil count
in mice respiratory epithelia (38). The proposal that the
effect of vitamin D is time-sensitive is further bolstered by
a study that showed that low vitamin D [measured by serum
25-hydroxy-(ergocalciferol + cholecalciferol] was common
among patients with tuberculosis (35.6 mg/L compared
with 37.2 mg/L in patients without tuberculosis; P < 0.05)
but was not associated with the initial, acute-phase response
to infection (measured by levels of a1-antichymotrypsin, an
acute-phase protein) (19). A 3-mo prospective, randomized
controlled trial investigating whether vitamin D has an effect
on cytokine levels in humans showed that supplementation
of 2000 IUcholecalciferol in ambulatory adults does not have
asignificanteffect on the association between levels of serum
25(OH)D and IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-13,
IFNg, and TNFa, although this study did not take into ac-
count infection status and there was no difference between
25(OH)D levels pre- and postsupplementation in the group
randomized to receive cholecalciferol (55).
In contrast, another study found that many of the cyto-
kines inhibited by 1,25(OH)2D in humans (IL-2, IL-12,
IFNg, IL-6, TNFa, IL-17, and IL-23) are produced in signif-
icantly greater quantities in individuals with pandemic
H1N1 influenza compared with healthy controls; some cyto-
kines that are promoted by 1,25(OH)2D (IL-5, IL-10) are
also produced in significantly greater quantities in those in-
dividuals (3,56) (measured by serum cytokine levels) (Fig.
1A,B). Early secretion of Th1- and Th17-mediated cytokines
was also found to be significantly increased in individuals
infected with severe novel H1N1 influenza (37), suggesting
that serum 25(OH)D may play a role in inflammatory re-
sponse during influenza infection, even if it does not affect
levels of inflammatory cytokines in a noninfectious state.
1,25(OH)2D inhibits proliferation and promotes apoptosis
of activated human B-cells in vitro, although the initial pro-
duction of B-cells remains unaffected (4). 1,25(OH)2D is
thought to thereby inhibit the differentiation of B-cells
into plasma cells (4) (Fig. 1C). B-cell deficiency in mice
and ferrets has been associated with decreased heterologous
immunity between seasonal and pandemic H1N1 influenzas
(57) and memory B-cells against influenza infection have
persisted for >5 mo after infection in lung epithelial cells
in vitro (58). Although there is relatively little evidence link-
ing influenza infection to B-cell levels in humans, a small
study involving 15 children aged 2–14 y with pandemic or
seasonal H1N1 influenza showed that a significantly higher
percentage of B-cells were found in children infected with
any strain of influenza, compared with controls (59).
Vitamin D and innate immune response
Inflammation and cell signaling. Both the active form of
vitamin D [1,25(OH)2D] and a fluorescent vitamin D an-
alogue have been found to decrease proinflammatory che-
mokine production during infection in vitro in human
respiratory epithelial cells (for the active form of vitamin D)
and mouse pancreatic islets (for the vitamin D analogue)
(9,35). Additionally, 1,25(OH)2D has been found to down-
regulate proinflammatory cytokines such as IL-1, IL-6,
IL-8, and TNFa in many different cell types in vitro (60).
Significantly higher serum levels of IL-6, IL-8, IL-17, and
TNFa were found in patients hospitalized with pandemic
H1N1 influenza in a case control study (37) and have
elsewhere been implicated in influenza infection (32,56).
In human lymphocytes in vitro, the antiinflammatory ef-
fect of vitamin D is carried out in part through inhibition of
NF-kB (61) (Fig. 1C). NF-kB is a protein complex that is as-
sociated with the transcription of inflammatory proteins
during infection (62), including cytokines and chemokines,
acute phase proteins, adhesion molecules, and inducible
effector enzymes (63). 1,25(OH)2D induces nuclear fac-
tor of k light polypeptide gene enhancer in B-cells inhib-
itor, a, the inhibitor of NF-kB, in human airway epithelial
cells in vitro during infection with respiratory syncytial
virus (9). NF-kB itself has been found to modulate T-cell
response profiles in various types of mouse cells (64) and
to downregulate antiviral and immunomodulatory inter-
feron signaling involved against influenza infection in mouse
embryonic fibroblasts (65,66). 1,25(OH)2D inhibits NF-kB
in vitro in human promyelotic leukemia HL-60 cells during
the early infection period (67) (Fig. 1D) but promotes it
later on (67).
Monocytes and differentiation. 1,25(OH)2D has been
shown to promote the differentiation of monocytes into
macrophages in both mouse and human cells in vitro (47)
and suppress the differentiation of human monocytes into
dendritic cells (49) (Fig. 2). 1,25(OH)2D (10 nmol/L) has
also been found to induce a tolerogenic state in human my-
eloid (but not plasmacytoid) dendritic cells in vitro (68) and
has an effect on the trafficking and translocation of differen-
tiated but immature dendritic cells in mice (69). Mouse den-
dritic cells exposed to 1,25(OH)2D in vivo for 24 h were able
to retain antigen-presenting abilities and avoid sequestration
in lymph nodes. However, mouse dendritic cells that were
differentiated in the constant presence of 1,25(OH)2D in vi-
tro did not retain these capabilities (69), a result that supports
Vitamin D and influenza 519
by guest on December 31, 2015
the idea that immune system involvement of active vitamin
D is modulated by infection time frame as well as the type of
immune cell involved. In older adults, loss of dendritic cell
function (including reduction in dendritic cell-mediated cy-
tokines, such as TNFa) is associated with poor influenza
vaccine response (70) and impaired response to influenza
infection as a result of decreased induction of dendritic
cell-stimulated CD8+ T-cells (71). Notably, infection with
influenza A virus induced human blood monocytes to rap-
idly differentiate into mature dendritic cells in vitro (72).
However, it has been found that plasmacytoid dendritic
cells, which are unaffected by 1,25(OH)2D, may be respon-
sible for dendritic cell-mediated protection to influenza in-
fection in mice (73).
1,25(OH)2D is also thought to suppress IFNg-mediated
activation of macrophages through inhibition of the Th1 re-
sponse profile (3); the deactivation of IFNg-activated mac-
rophages is contingent upon a functional VDR in vitro in
mouse macrophages (74). However, macrophages are capa-
ble of responding to and producing 1,25(OH)2D in human
alveolar macrophages in vitro (75), and 1,25(OH)2D in-
creases the production of cathelicidin in human macro-
phages in vitro by increasing expression of the VDR (76).
Antimicrobial properties. 1,25(OH)2D is associated with
increased bactericidal activity in human PBMC (15) and
the innate antibacterial response in human trophoblasts in
vitro (77). VDR expression is upregulated by the activation
of toll-like receptors in human macrophages and tropho-
blasts; this upregulation leads to the transcription of cathe-
licidin, which kills intracellular Mycobacterium tuberculosis
(42,77) (Fig. 2). This finding has been corroborated by in
vivo evidence: vitamin D supplementation (a single oral
mega-dose of 100,000 IU ergocalciferol) has been found
to improve antimycobacterial immunity in humans (78).
Because cathelicidin’s main mechanism of action is the de-
struction of envelope proteins of foreign agents, it may also
be implicated in the destruction of influenza virus, which
possesses an envelope protein (2,79).
Additionally, 1,25(OH)2D has been found to upregulate
human b-defensin 2 in a variety of human cells (80); human
b-defensin 2 is thought to act as a chemoattractant for mon-
ocytes during viral infection (7). 1,25(OH)2D also induces
hydrogen peroxide production in human monocytes in vitro
(81). However, serum 25(OH)D was not associated with
levels of serum cathelicidin or b-defensin-2 in patients
with community-acquired pneumonia (82).
In total, the literature describing vitamin D’s role in the
adaptive and innate immune systems suggests that vitamin
D is involved in reducing inflammation during infection. Al-
though 1,25(OH)2D suppresses the response of Th1 cells
and proinflammatorycytokines, it promotesantimycobacte-
rial factors such as cathelicidin and human b-defensin 2.
Additionally, the literature suggests that vitamin D’s role in
modulating immune system response to infection is not
constant over time and changes according to the host and
state of infection; 25(OH)D deficiency has been shown to
be related to tuberculosis but not the acute phase of infec-
tion in humans (19): 1,25(OH)2D has been shown to have
a positive effect on infection only when given after the initial
phase of infection in mice (38); 1,25(OH)2D has been
shown to affect NF-kB in different ways at different time
points of infection in human leukemia cells (67) and pre-
vents mouse dendritic cells from presenting antigens and
differentiating only at certain time points (69).
Vitamin D and respiratory diseases in humans. Due to
the complexity of adaptive and innate immune responses
to antigenic stimulation, it is difficult to pinpoint the over-
all effect of vitamin D during infection. This complexity
dendritic cells and promotes the differentiation of monocytes into macrophages. When toll-like receptors are activated by circulating
LPS, they promote vitamin D-mediated transcription of cathelicidin, an antimicrobial peptide that kills Mycobacterium tuberculosis.
Vitamin D activation and mycobacterial immune response. Vitamin D inhibits the differentiation of monocytes into
520 Sundaram and Coleman
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Randomized controlled trials investigating the association between vitamin D supplementation and increased risk of respiratory illness as an outcome
Dose and duration
Strength of association
et al. (93)
n = 569 adults
32–84 y old
1111–6800 IU/d cholecalciferol
for at least 12 wk during
Risk of influenza-like illness,
measured by self-report
RR of influenza-like illness1:
0.88 (95%CI: 0.58–1.32)
Median increased duration
of ILI2: 3 d (P , 0.01)
et al. (12)
n = 334
One 200-IU tablet
3 times/d for 120 d
PCR-confirmed influenza A
RR of infection1: 0.58
et al. (22)
n = 162 adults
18–80 y old
2000 IU cholecalciferol/ d
for 12 wk
Risk of URTI
RR of URTI1: 0.96
et al. (100)
n = 281 adults
100,000 IU of cholecalciferol at
inclusion and again at 5 and
8 mo after TB treatment
Clinical severity and mortality
RR of mortality1: 1.19
n = 208 postmenopausal
African American women
800 IU cholecalciferol/d for 2 y,
then increased to 2000 IU/d for
an additional year (3 y total)
Risk of self-reported cold
RR of cold or influenza1: 0.31
et al. (92)
n = 3444
adults $70 y old
800 IU/d cholecalciferol,
1000 mg calcium, both, or
placebo, for 24–62 mo
Risk of any infection,
Relative odds of any infection1:
0.90 (95%CI: 0.76–1.07)
et al. (78)
n = 131
adults .17 y old
Single dose of 100,000 IU
ergocalciferol at beginning
Immunity to TB
mycobacteriameasured by BCG-lux
luminescence ratio at
24 h postinfection
Relative increase in immunity3:
20.4% (95%CI: 1–25%)
et al. (17)
n = 67 TB
patients 15–59 y
old with moderately
advanced TB lesions
10,000 IU vitamin D
Rate of sputum
Relative odds of conversion4:
1.32 (95%CI: 1.09–1.60)
et al. (18)
n = 24 children
with TB, 1–13 y old
1000 IU cholecalciferol/d for
the length of tuberculosis treatment
Concentration of serum
vitamin D in supplementedvs. unsupplemented
Difference in vitamin D (pg/mL)
between supplemented and
unsupplemented groups was not
significant (data not shown)
n = 47 children
3–12 y old
60,000 IU vitamin D
6 wk, plus 650 mg
Frequency of any infection
No difference in frequency seen
between supplemented and
control groups (data not shown)
1RR refers to the risk of illness while being supplemented with vitamin D compared with being supplemented with placebo. TB, tuberculous; URTI, upper respiratory tract infection.
2“Relative increase in duration” refers to the extra number of days that participants in the placebo group reported experiencing ILI symptoms, compared with the number of days that supplemented participants reported; P-value is a chi-square
value comparing the 2 proportions.
3“Relative increase” refers to the increase in immunity in vitamin D-supplemented compared with placebo-supplemented participants.
4“Relative conversion” refers to the conversion proportion of vitamin D-supplemented compared with conversion proportion of placebo-supplemented participants.
Vitamin D and influenza521
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sometimes results in different results in in vitro compared
with in vivo studies. In several observational studies, lower
25(OH)D serum levels have been associated with increased
risk of respiratory infection in adults (21,23,83,84), children
(26,85,86), and infants (20). A robust, dose-response associ-
ation was found between lower levels of 25(OH)D and
increased risk of upper respiratory infection in large, popu-
lation-based studies in the United States (23) and Great Brit-
ain (21). 25(OH)D deficiency has also been connected to
increased severity of acute lower respiratory infection in
children (27,86) and mortality from pneumonia in adults
(82). Furthermore, children with VDR gene polymorphisms
(specifically, the FokI ff or TaqI polymorphisms) are more
likely to have acute lower respiratory infections (87). The
FokI ff polymorphism results in a downregulation of the vi-
tamin D target gene, CYP24A1, which codes for an enzyme
that degrades 1,25(OH)2D (88); the TaqI polymorphism is
associated with lower VDR protein levels (89).
However, randomized controlled trials supplementing vi-
tamin D have yielded mixed results; a summary of these re-
sults can be found in Table 1. No significant effect was
found for 1,25(OH)2D supplementation as an adjuvant to
increase the efficacy of an influenza vaccine in the general
adult population (90) or in HIV-positive (91) adults, and
supplementation with oral cholecalciferol did not signifi-
cantly reduce the risk of infection in an elderly population
(92). General vitamin D supplementation (median daily
dose of 2000 IU/d, or 50 mg/d) was not associated with im-
proved serologic response to an influenza vaccine (measured
by a $1:40 hemagglutinin antibody inhibition titer ratio or
4-fold increase in hemagglutinin antibody inhibition titer at
3-mo postvaccination) in prostate cancer patients (13).
However, the baseline 25(OH)D serum concentration in
the same population was associated with an improved re-
sponse to influenza vaccine (P = 0.045) (13). Supplementa-
tionwith cholecalciferol (1200 IU/d for 4 mo) was also found
to be associated with a reduced risk of seasonal influenza A
in Japanese schoolchildren (P = 0.04) (12), but the study did
not measure serum concentrations of 25(OH)D or serum
antibody concentrations to influenza. An additional study
found a lower rate of upper respiratory infection and in-
fluenza in participants taking a cholecalciferol supplement
(2000 IU or 50 mg/d), but this analysis was based on self-
reported illness (14) and the results were not reproduced
(93). A systematic review of randomized controlled trials
supplementing vitamin D for the prevention or treatment
of infectious disease found that the strongest evidence for
the effectiveness of vitamin D in prevention or treatment
of infectious diseases is for the reduction of risk of acute
respiratory illness and influenza (45).
Influenza and vitamin D: seasonality. EdgarHope-Simpson
(94) was the first to make the argument that the seasonality of
researchers have corroborated the finding that influenza is
more prevalent in the winter during times of less sunlight
and therefore less available vitamin D (40,95,96). Healthy
volunteers inoculated with live attenuated influenza virus in
northern latitudes of Russia during different seasons of the
year were 8 times more likely to have influenza infection dur-
ing the winter than summer (97). However, another study re-
cently found that model simulations of vitamin D seasonal
fluctuation are not able to consistently reproduce observed
seasonal patterns in influenza; the authors concluded that sea-
sonal variation in vitamin D is unlikely to be the main factor
affecting the seasonality of influenza (98). Because there are
other important environmental factors that could affect viru-
lence of influenza that are synchronous with periods of less
sunlight (e.g., colder temperatures and lower humidity), it
enza and vitamin D seasonality.
Problems in assessing vitamin D. Lee (99) has pointed out
several problems in assessing vitamin D. First, a consensus
has not yet been reached on what level of vitamin D is con-
sidered “deficient” (1), and studies with different definitions
of deficiency may not have comparable results. Additionally,
there is no consensus on biologically relevant doses of vita-
min D for use in randomized controlled trials; studies cited
in this paper supplemented vitamin D in a broad range of
forms, from 200 IU cholecalciferol 3 times/d (12 to 2000
IU/d (22), and including one-time supplements of cholecal-
ciferol in 100,000-IU doses (78,100). Second, concentrations
of 25(OH)D obtained from serum vary depending on the
method of assay and reproducibility is poor (99,101). Third,
concentrations of 25(OH)D are subject to change depending
on levels of binding proteins and rapid fluid shifts, factors of
concern in critically ill patients (99).
In 8 of 10 supplementation studies cited in this review
that looked at respiratory illness as an outcome, serum vita-
min D pre- and postsupplementation was not reported
(12,14,17,22,92,93,100,102). Lack of vitamin D measure-
ment in these studies makes interpretation of the results
more difficult, because there is no way to demonstrate that
participants in the supplementation group had significantly
higher serum vitamin D than participants in the control
group. In such studies, determining the biological relevance
of a particular dose of vitamin D is also difficult. One study
that supplemented vitamin D and measured vitamin D se-
rum status postsupplementation found no significant differ-
ence in respiratory illness between the supplementation and
control groups (18); one study found a significant difference
in the level of mean 25(OH)D after a single mega-dose of
Limitations of current literature. Evidence from in vitro,
invivo animal, and invivo human studies has been accumu-
lating over the past decade, suggesting that vitamin D may
influence the risk of respiratory infections, including influ-
enza. However, much work remains to be done: there
must be a focus on the application of laboratory and animal
findings to human populations, because it has already been
observed that the results of in vitro studies are not always
replicated in vivo and the results of animal studies are not
522Sundaram and Coleman
by guest on December 31, 2015
always replicated in humans. It is important to note that sev-
eral of the studies listed here were done in mouse models.
Although mouse models are accepted for studying influenza
infection, they are not ideal; mice do not possess avitamin D
response element for the production of cathelicidin (3) and
other differences in cell signaling have been observed between
mouse and human cells (42,103). However, a “humanized”
ful in studying this mechanism more closely (39).
Several of the studies onvitamin D and respiratory illness
cited herewereconducted insettingswhereothermicronutrient
It is possible that other nutrient deficiencies act as effect mod-
ifiers or confounders for respiratory illness outcomes in such
settings. Additionally, other infectious diseases with a higher
prevalence in these settings than in other settings (e.g., ma-
laria, multi-drug–resistant tuberculosis, and HIV/AIDS) may
affect the outcome measurement. It is therefore important
to keep in mind that such different settings limit generalizabil-
ity of results.
The difference between the role of vitamin D during the
acute initial infection state and after the initial infection state
must be considered in future studies, because it is possible
that the effects of vitamin D on the immune system change
over time and between immune cell types. It is also impor-
tant to differentiate between the effect of vitamin D status on
influenza incidence and influenza severity, taking into spe-
cial consideration the possibility that the serum 25(OH)D
levels of critically ill patients may be subject to change
more rapidly than in healthy individuals. Furthermore, a
distinction must be made between “deficient” and “subopti-
mal” vitamin D status. Analyses considering not only vita-
min D deficiency but the continuous range of serum
vitamin D values will add to the literature. Finally, rigorous
methodology, including a standardized serum vitamin D as-
say, consistent reporting of specific types of vitamin D [e.g.,
1,25(OH)2D as opposed to 25(OH)D] and other measures
of immune response in addition to hemagglutinin antibody
inhibition titers, such as cell-mediated immunity, are needed.
PCR confirmation of influenza diagnosis is the gold standard
for measuring outcome; if other methods are used, these
methods should be clearly reported.
influenza infection exists, albeit mainly in in vitro and animal
tive immunity. Observationalhuman studies of 25(OH)D de-
ficiency and randomized controlled trials supplementing
various formsof vitaminD have yielded mixed but promising
results. More rigorous research studies with large populations
and outcome measures including 25(OH)D serostatus post-
supplementation are needed to further elucidate the possible
relationships between vitamin D and risk of influenza infec-
tion. The establishment of a clear link between vitamin D
status and influenzainfection has broad implications for influ-
enza research, especially in groups that are likely to have low
vitamin D levels, as well as the formulation of policy regarding
vitamin D supplementation.
All authors read and approved the final manuscript.
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