Review ArticleSelf-Care for Common Colds: The Pivotal Role ofVitamin D, Vitamin C, Zinc, and Echinacea in Three MainImmune Interactive Clusters (Physical Barriers, Innate andAdaptive Immunity) Involved during an Episode of CommonColds—Practical Advice on Dosages and on the Time to TakeThese Nutrients/Botanicals in order to Prevent or TreatCommon Colds

Mariangela Rondanelli ,1 Alessandra Miccono,1 Silvia Lamburghini,1

Ilaria Avanzato,1 Antonella Riva ,2 Pietro Allegrini,2 Milena Anna Faliva,1

Gabriella Peroni,1 Mara Nichetti,1 and Simone Perna 1

1Department of Applied Health Sciences, Azienda di Servizi alla Persona (ASP) di Pavia, University of Pavia, Pavia, Italy2Research and Development Unit, Indena, Milan, Italy

Correspondence should be addressed to Simone Perna; simoneperna@hotmail.it

Received 20 November 2017; Revised 6 March 2018; Accepted 26 March 2018; Published 29 April 2018

Academic Editor: Roland Schoop

Copyright © 2018 Mariangela Rondanelli et al. This is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properlycited.

Maintaining a normal healthy immune defense system lowers the incidence and/or the severity of symptoms and/or the durationof common cold (CC). Physical barriers and innate and adaptive immunity have been involved during a CC episode. Vitamins Cand D, zinc, and Echinacea have evidence-based efficacy on these immune system barriers. This review includes 82 eligible studiesto consider the preventive role of these nutrients in immune clusters and in CC to provide advice on dosage and assumption ofthese nutrients. Regarding vitamin C, regular supplementation (1 to 2 g/day) has shown that vitamin C reduces the duration (inadults by 8%, in children by 14%) and the severity of CC. Considering zinc, the supplementation may shorten the duration ofcolds by approximately 33%. CC patients may be instructed to try zinc within 24 hours of onset of symptoms. As for vitamin D, thesupplementation protected against CC overall, considering baseline levels and age. Patients with vitaminD deficiency and those notreceiving bolus doses experienced the most benefit. Regarding Echinacea, prophylactic treatment with this extract (2400mg/day)over 4months appeared to be beneficial for preventing/treatingCC. In conclusion, the current evidence of efficacy for zinc, vitaminsD and C, and Echinacea is so interesting that CC patients may be encouraged to try them for preventing/treating their colds,although further studies are needed on this topic.

1. IntroductionCommon cold (CC) is a conventional term used for mildupper respiratory illnesses, which comprises a heterogeneousgroup of self-limited diseases caused by numerous virusesand is the most frequently encountered human diseasesworldwide [1].

In European populations, adults have from 2 to 5 infec-tions annually, children typically present 6 to 12 “colds” peryear, and rates of symptomatic infections increase in theelderly [2]. A seasonal variation is present withmore episodesin winter and fall [1] and, on average, episodes of commoncolds last around 10 days [3].

HindawiEvidence-Based Complementary and Alternative MedicineVolume 2018, Article ID 5813095, 36 pageshttps://doi.org/10.1155/2018/5813095

2 Evidence-Based Complementary and Alternative Medicine

Beyond impairing the quality of life [4], common coldshave a tremendous economic burden on societies due toworkabsenteeism [5, 6].

Thus, treatments that reduce the incidence of infectionand/or lessen the severity of symptoms and/or shorten theduration of common colds are of high interest both for theindividual and for the whole society.

Maintaining the immune defense systemwithin a normalhealthy state lowers the incidence of infection and/or lessensthe severity of symptoms and/or shortens the duration ofcommon colds. Natural killer cell (NK cell) activity andsalivary immunoglobulin A (IgA) are considered importantin the prevention of common colds [7]. However, severalenvironmental factors, including a stressful lifestyle, are likelyto weaken the immune defense system [8], which mayresult in an increased risk of common cold. Lifestyles andmental health status are associated with natural killer cell andlymphokine-activated killer cell activities [8]. The immunesystem is an intricate network of specialized tissues, organs,cells, and chemicals protecting the host from infectiousagents and other noxious insults. Although these defensemechanisms are very complex, they can be described as beingorganized in threemain interactive clusters: physical barriers,and innate and adaptive immunity [9, 10].

The first barrier against “invaders” consists of physicalbarriers (low pH caused by various fatty acids and enzymes;it can limit the growth of most bacteria), mucus secretion (itcontains proteins that can destroy pathogens), and the acidityof the stomach. Innate immunity is the second barrier andincludes immune system cells, such as NK cells, cytokines(such as interferon-𝛾), macrophages, and neutrophil granu-locytes. In addition, zinc shows its antiviral effects throughthe Intercellular Adhesion Molecule 1 (ICAM-1). Adaptiveimmunity is the third barrier to infection and is acquiredlater in life, such as after an immunization or successfullyfighting off an infection. It retains a memory of all theinvaders it has faced and this accelerates antibody production[11]. It includes lymphocytes T (e.g., regulatory T cells) andlymphocytes B.

1.1. Mechanism of Innate Immunity (Physical Barriers andImmune Cells) during Common Cold. When a respiratoryvirus is inhaled it first binds to nonspecific receptors on therespiratory epithelium, usually glycolipids or glycoproteins.Membrane fusion or endocytosis follows, thus internalizingthe virus and enabling subsequent replication, transcription,and translation of new viruses which can then be releasedto infect new cells. Once a cell has been infected, pathogen-associated molecular patterns (PAMPs) on the virus canbe recognized by various intracellular innate pathogenrecognition receptors (PRRs) such as the toll-like receptors(TLRs), retinoic-acid-inducible gene-I- (RIG-I-) like recep-tors (RLRs), and nucleotide binding-oligomerization domain(NOD-) like receptors (NLRs) [12]. Pulmonary epithelialcells have been shown to express all of the known humanTLRs and RLRs that detect viruses, and ligands for thesePRRs activate epithelial cells in order to initiate a rapidimmune response against viral invasion [13]. In addition to

direct infection of epithelial cells, intraepithelial dendriticcells (DCs) residing just below the respiratory epithelium andtissue-resident macrophages continually sample particles inthe airway lumen and can internalize them by phagocytosisandmacropinocytosis, thus activating PRRs and initiating animmune response [14, 15].

Features of the induced antiviral state include resistanceto viral replication in all cells, induction of apoptotic celldeath in infected cells, increased major histocompatibil-ity complex (MHC) class I expression to enhance anti-gen presentation, activation of dendritic cells (DCs) andmacrophages, and stimulation of natural killer (NK) cellsto enhance their cytolytic activity [16]. The inflammatorycytokines TNF-𝛼, IL-1𝛽, IL-6, and IL-12 are also producedat an early stage of the innate immune response. Thesecytokines promote leukocyte extravasation by increasingendothelial expression of adhesion molecules increasing vas-cular permeability, induce synthesis of acute phase proteins,and contribute to recruitment and activation of cells of theadaptive immune response [12]. Other antimicrobial vitaminD dependent peptides, such as cathelicidins and defensins,are involved in the second barrier.

1.2. Mechanism of Adaptive Immunity (Antibodies) dur-ing Common Cold. Around 72 h after infection, DCs withantigen-MHC complexes migrate through the afferent lymphvessels to secondary lymph nodes where they form inter-actions with naive CD4 and CD8 T lymphocytes. TheseT lymphocytes activate, proliferate, and differentiate intoeffector T cells and migrate via efferent lymph vessels intothe circulation. Multiple chemokines are expressed in therespiratory epithelium and result in changes in integrinaffinity, allowing effector T cells to bind to the endotheliumand migrate into the infected tissue [17–19]. For efficientand effective viral clearance Th1 effector T cells are required,which produce IL-2, TNF-𝛼, and IFN-𝛾 to activate NK cellsand induce generation of cytolytic molecules. CD8 effector Tcells and NK cells can then induce apoptosis of infected cells[17]. B cells have also been demonstrated to play an importantrole in the immune response to highly pathogenic viralinfections. Contact between CD4 T cells and naive B cellsin secondary lymphoid tissues results in their proliferationand antibody class-switching, with neutralizing virus-specificantibodies crucial for optimal viral clearance. Additionally,viral components expressed on infected cells allow antibodiesto bind, thus initiating antibody-dependent cell-mediatedcytotoxicity (ADCC), whereby CD16 on NK cells recognizesthe Fc portion of antibodies bound to the surface and kills thetarget cell [12, 17, 20, 21].

1.3. Self-Care for Common Colds: Role of Nutrition and Botan-icals and Their Interaction in Three Main Immune InteractiveClusters: Physical Barriers, Innate and Adaptive Immunity. Ascommon colds have a self-limited course and resolve withouttreatment, studies on self-care have shown that commoncolds are the most frequent cause for self-care [22–24]. Avariety of alternative and nonpharmacologic treatments ofthe common cold are proposed [25, 26]. Between these

Evidence-Based Complementary and Alternative Medicine 3

numerous nonpharmacological approaches for preventionand treatment of the common cold, there are the intakesof some nutrients, such as zinc, selenium, iron, copper, b-carotene, vitamins A, D, C, and E, folic acid, and botanicals,such as Echinacea [26]. The proposed biologic mechanismsare that these nutrients can significantly influence severalcomponents of immunity [10]. But among these numerousnutrients, which have proven to have evidence-based efficacyon all three immune system barriers? The nutrients arevitamin C, vitamin D, and zinc, because all three nutrientshave specific EFSA (European Food Safety Authority) scien-tific opinion on the substantiation of health claims relatedto vitamin D [27], vitamin C [28], zinc [29], and normalfunction of the immune system. Moreover, there is EFSAscientific opinion on the substantiation of health claimsrelated to zinc [30] and to vitamin C [31] and maintenance ofnormal physical barriers, the first immune system barriers.Finally, for vitamin C [32] and Echinacea [33] there areCochrane reviews regarding the use of these two nutrients forpreventing and treating the common cold.

Given this background, the purpose of this narrativereview is to consider the pivotal role of vitamin D, vitaminC, zinc, and Echinacea on three main immune interactiveclusters (physical barriers, innate and adaptive immunity) interms of prevention and treatment (shortening the durationand/or lessening the severity of symptoms) of common coldsin order to provide practice advice on the dosages and on thetime to take these nutrients.

2. Methods

The present systematic review was performed following thesteps by Egger et al. as follows [34]: (1) A working group wasconfigured as follows : three operators skilled in endocrinol-ogy and clinical nutrition, of whom one acting as a method-ological operator and two participating as clinical operators.(2)The revision question on the basis of considerations madein the abstract was formulated as follows: “the state of the arton role of vitamin D, vitamin C, zinc, and Echinacea in threemain immune clusters (physical barriers, innate and adaptiveimmunity) in terms of prevention and treatment (shorteningthe duration and/or lessening the severity of symptoms)of common colds.” (3) Relevant studies were identifiedas follows: a research strategy was planned, on PubMed[PublicMedline run by the National Center of BiotechnologyInformation (NCBI) of the National Library of Medicine ofBethesda (USA)], as follows: (a) definition of the key words(common cold, Echinacea, immunity, nutrients, vitamin C,vitamin D, and zinc), allowing the definition of the interestfield of the documents to be searched, grouped in quotationmarks (“. . .”), and used separately or in combination; (b) useof the Boolean AND operator that allows the establishmentof logical relations among concepts; (c) research modalities:advanced search; (d) limits: time limits: papers publishedin the last 30 years; languages: English; (e) manual searchperformed by the senior researchers experienced in clinicalnutrition through revision of reviews and individual articleson role of vitamin D, vitamin C, zinc, and Echinacea in three

main immune interactive clusters (physical barriers, innateand adaptive immunity) in terms of prevention and treatment(shortening the duration and/or lessening the severity ofsymptoms) of common colds published in journals qualifiedin the Index Medicus. (4) The analysis was carried out in theform of a narrative review of the reports.

3. Results

3.1. Zinc and the Three Main Immune Interactive Clusters(Physical Barriers, Innate and Adaptive Immunity) Involvedduring an Episode of Common Colds. This research has beencarried out based on the following keywords: “zinc” OR “zincsupplementation” AND “immune response” AND “innateimmunity” AND “adaptive immunity” AND “respiratorytract infections” AND “common cold” AND “Immunodefi-ciency.”

Figure 1 shows the study selection process.Table 1 summarizes the studies presented in the narrative

review.

3.1.1. First Barrier: Physical Barrier. In the present era,approximately two billion people in developing countriessuffer from Zn deficiency (ZnD), mainly due to malnutritionand manifest clinical characteristics of growth retardationand compromised immune systems [35].

Adequate zinc intake helps to maintain physical barriersand mucosal membrane integrity and unbound zinc ionsexert a direct antiviral effect on rhinovirus replication [10].Supplementation of Zn improves immune functions, includ-ing delayed cutaneous hypersensitivity in children (10–20mgof Zn) [36, 37], but other authors do not completely agree[38, 39]. It improves delayed-type hypersensitivity (DTH) inchildren supplemented with 10mg/day [40].

3.1.2. Second Barrier: Cellular Natural Immunity. Zinc sup-plementation increases cellular components of innate immu-nity (e.g., phagocytosis by macrophages and neutrophils,natural killer cell activity, and generation of oxidative burst)[10].

(1) Neutrophil granulocytes, macrophages: largeamounts of oral zinc significantly impaired polymor-phonuclear leukocytes (PMNL) function and, invitro, zinc potentiated the neutrophil response againstStaphylococcus aureus [11]. Zn supplementation(150mg/d) in elderly also induces a decrease in gran-ulocyte zinc that has implications in phagocytosisand chemotaxis [41].

(2) Natural killer: a supplementation of zinc (in vitrostudies or 100mg/d in elderly) improves natural killer(NK) cells activity, as argued by a lot of authors [9,11, 39, 42]. Zinc administration decreased peripheralblood NK cell activity in vitro in patients with thatinflammatory disease [11].

(3) Cytokine: common cold viruses increase oxidativestress, which activates macrophages and mono-cytes and results in increased production of both

4 Evidence-Based Complementary and Alternative Medicine

Table1:Stud

ieso

nzinc,immun

ity,and

common

cold

presentedin

then

arrativ

ereview.

Authors

Type

ofstu

dySubjects

Dosage

Results

Type

ofim

mun

ityInvolved

Mechanism

ofactio

n

Turner;2001

Clinicalstu

dy,

rand

omized

Ninety-on

evolunteers

41tre

ated

with

activ

emedication

(con

sistedof

33mM

zinc

glucon

ate)and

50tre

ated

with

placebofor3

days

were

inoculated

with

rhinoviru

sand

then

were

treated

with

study

medicationfora

nadditio

nal6

days,singlen

asalsprayof

120m

Lpern

ostril,at∼4-hintervals,5

times

each

day

Zinc

treatmenth

adno

effecto

ntotalsym

ptom

score,rhinorrhea,

nasalobstructio

n,or

thep

ropo

rtion

ofinfected

volunteerswho

developedclinicalcolds

Mahalanabis

etal.;2004

Rand

omized,

doub

le-blin

d,placebo-

controlled

clinicaltria

l

153child

ren

aged

2–24

Four

treatment:(1)zinca

cetate(10m

gelem

entalZ

ntwiced

ailyfor5

d)plus

aplaceboforv

itamin

A,(2)

vitamin

Aas

retin

ylpalm

itate[10,000𝜇

gretin

olequivalents(RE

)twiced

ailyfor4

d]plus

aplacebo

forz

inc,(3)zincp

lusv

itamin

Aaccordingto

thea

bove

schedu

le,or

(4)

placeboforz

inca

ndforv

itamin

A

Zinc

treatmentsignificantly

redu

ces

duratio

nof

fevera

ndvery

illsta

tus

inbo

ys,but

notingirls,w

ithsevere

acutelow

errespira

tory

infection

(ALR

I)

Zinc

asam

icronu

trient

playsa

keyroleat

thec

atalyticsites

ofaw

ider

ange

ofenzymes

andiscriticaltohu

man

grow

th,

metabolism

,and

immun

efun

ction.

The

dietso

fchildrenin

manydeveloping

coun

triesa

reoft

endeficient

inzinc

anda

high

phytate:zinc

ratio

intheird

iet

redu

cesz

incb

ioavailability

Barnettetal.;

2016

Arand

omized

doub

le-blin

d,placebo-

controlled

trial

53nu

rsingho

me

elderly(aged

≥65

y)

Supp

lementatio

nwith

30mgZn

/dfor

3mo

Theincreaseinserum

zinc

concentrationisassociated

with

the

enhancem

ent

ofTcellfunctio

n

Adaptiv

eim

mun

ity

Mainlybecauseo

fanincrease

inthe

numbero

fTcells

andZn

improves

Tcell-mediatedfunctio

nby

increasin

gthe

numbero

ffun

ctionalT

cells

inthe

perip

hery

Prasad

etal.;

2007

Rand

omized,

doub

le-blin

d,placebo-

controlled

trial

Fifty

healthy

subjectsof

both

sexesa

ged

55–87y

Each

dayfor12mo,subjectsin

the

zinc-sup

plem

entedgrou

preceived

1capsuleo

fzincg

luconate(15m

gelem

entalzinc)orally

Them

eanincidenceo

finfectio

nspersub

jectin

12mowas

significantly

lower

inthe

zinc-sup

plem

entedgrou

pthan

inthep

lacebo

grou

p.Asig

nificantly

lower

incidenceo

ffever

anda

nonsignificanttrend

towardalow

erincidenceo

fthe

common

cold

were

observed

inthez

inc-supp

lemented

grou

pthan

inthep

lacebo

grou

p

Innate

immun

ity

Zinc

supp

lementatio

ndecreasedno

tonly

thep

rodu

ctionof

inflammatory

cytokinesb

utalso

thatof

oxidatives

tress

marker:theincreaseo

fIL-2prod

uctio

nin

zinc-deficientelderlysubjectsby

increasin

gtheg

enee

xpressionof

IL-2

andby

adecreaseinIL-10prod

uctio

n

Pinn

aetal.;

2002

Clinicalstu

dy8healthymen

Thes

ubjectsw

ereg

iven

acon

trolled3-d

rotatin

gdietthatcontained4.6m

gZn

/d.

Znintakesw

erea

djustedby

giving

Znglucon

ates

upplem

ents.

Duringbaselin

eperio

dsandrepletionperio

ds,sub

jects’

Znintakestotaled

13.7mg/d.During

restric

tionperio

d,thes

ubjectsc

onsumed

4.6m

gof

high

lyavailableZ

n

Changesinlymph

ocyte

proliferatio

nandIL-2Rexpressio

nmay

beearly

markersof

mild

zinc

deficiency

Innate

immun

ity

Zinc

restr

ictio

nredu

cedperip

heralblood

mon

onuclear

cells

(PBM

NC)

proliferatio

natallm

itogen

concentrations

teste

dexcept

10mg/L.

Dietary

zinc

restric

tionredu

cedIL-2R

secretionby

PBMNCstim

ulated

ata

subo

ptim

alPH

Aconcentration.

Thes

ecretio

nof

IFN-𝛾

andTN

F-𝛼was

unchangedthroug

hout

thes

tudy

Evidence-Based Complementary and Alternative Medicine 5

Table1:Con

tinued.

Authors

Type

ofstu

dySubjects

Dosage

Results

Type

ofim

mun

ityInvolved

Mechanism

ofactio

n

Maggini

etal.;2012

Datafrom

two

prelim

inary,

doub

le-blin

d,rand

omized,

placebo-

controlledtrials,

parallel-g

roup

Stud

y1included

30patie

nts:13

males

and17

females

Stud

y2enrolled

64patie

nts:25

males

and39

females

1000

mgvitamin

Cplus

10mgzinc

Supp

lementatio

nwith

vitamin

Candzinc

may

representan

efficaciou

smeasure

Prasad

etal.;

2008

Rand

omized,

doub

le-blin

d,placebo-

controlled

trial

Fifty

ambu

latory

volunteerswere

recruitedwith

in24

hof

developing

symptom

softhe

common

cold

1lozenge

containing

13.3mgof

zinc

(as

zinc

acetate)or

placeboevery2-3h

while

beingaw

ake

Meandu

ratio

nsof

cold

symptom

s,coug

h,nasald

ischarge,andmuscle

ache

weres

ignificantly

decreasedin

thez

incg

roup

comparedwith

the

placebogrou

pthanks

toits

anti-inflammatoryandantio

xidant

prop

ertie

s

Innate

immun

ity

Thed

ecreaseinsIL-1raa

ndsTNF-R1

levelsin

thez

incg

roup

onlysuggeststhat

zinc

decreasedtheo

xidativ

estre

ss,

resulting

indecreasedactiv

ationof

mon

ocytes

andmacroph

ages

Zinc

decreasesICA

M-1levelsandindu

ces

thez

inc-depend

enttranscriptio

nfactor

A20

inmon

ocytes

andmacroph

ages,

which

inhibitsNF-kB

activ

ationviathe

TNF-R-associated

factor

pathway

Zinc

isan

inhibitoro

fNADPH

oxidase,

anenzymethatinitia

testhe

generatio

nof

freer

adicals;itisessentialfor

superoxide

dism

utasea

ndforg

enerationof

metallothionein,

redu

cedthec

oncentratio

nof

the

oxidatives

tressmarkers,and

inhibited

thee

xvivo

indu

ctionof

TNF-𝛼andIL-1𝛽

mRN

Ain

mon

onuclear

cells;and

itprovided

protectio

nagainst

TNF-𝛼-in

ducedNF-kB

activ

ationin

isolatedperip

heralblood

mon

onuclear

cells

Bhandariet

al.;2002

Dou

blem

asked,

rand

omized

placebo-

controlled

trial

2482

child

ren

aged

6to

30mon

ths

Dailyele

mentalzinc,10mgto

infantsa

nd20

mgto

olderc

hildrenor

placebofor

four

mon

ths.Zinc

glucon

ate

Zinc

supp

lementatio

nsubstantially

redu

cedtheincidence

ofpn

eumon

iain

child

renwho

had

received

vitamin

A

Skin

Innate

immun

ityandadaptiv

eim

mun

ity

Supp

lementatio

nim

proves

immun

efunctio

ns,including

delay

edcutaneou

shypersensitivity,and

increasesthe

numbero

fCD4(help

er)lym

phocytes

Inexperim

entalm

odelsz

incd

eficiency

hasb

eenshow

nto

impaircellu

lara

ndhu

moralim

mun

efun

ction

6 Evidence-Based Complementary and Alternative Medicine

Table1:Con

tinued.

Authors

Type

ofstu

dySubjects

Dosage

Results

Type

ofim

mun

ityInvolved

Mechanism

ofactio

n

Bogden

etal.;

1990

Dou

ble-blind

partialcrossover

desig

n

63subjects(age

60–89)

3–6mon

thsupp

lyof

placebo,15mgof

Zn,or100

mgZn

-capsules

Zinc

hadpo

sitivee

ffectso

non

emeasure

ofcellu

larimmun

efunctio

nbu

tatthe

sametim

ehad

anadversee

ffecton

another

measure

ofcellu

larimmun

ity

Innate

immun

ity

NKcellactiv

itywas

enhanced,but,except

forthisc

ellularimmun

efun

ctions,w

ere

notsignificantly

improved

Dela

yedderm

alhypersensitivity

(DDH)

increasedin

thes

tudy

inplacebogrou

pandthes

uppressio

nof

theincreasein

DDHby

zinc

persisted

McD

onaldet

al.;2015

Arand

omized,

doub

le-blin

d,placebo-

controlled

clinicaltria

l

2400

infants

who

were6

wk

ofagea

ndbo

rnto

HIV-negative

mothersin

alow-m

alaria

setting

,Tanzania

Oralsup

plem

entatio

nof

MVs(vitamin

Bcomplex

andvitaminsC

andE),zinc,

zinc

+MVs,or

placebofor18m

o.From

thetim

eofrando

mizationto

6mo

ofage,infantsreceived1capsule/d,and

from

7moof

agetothee

ndof

follo

w-up,

2capsules

werep

rovideddaily

The

capsulec

ontained

5mgof

zinc

Acuteu

pper

respira

tory

infections

weres

ignificantly

lower

forinfants

supp

lementedwith

zinc

than

for

thosew

hodidno

treceive

zinc

Adaptiv

eim

mun

ity

MeanCD

4Tcellpercentage

was

slightly

butsignificantly

high

eram

ongchild

ren

who

received

zinc

andMVsin

comparis

onwith

placebo

Isbaniah

etal.;2010

Dou

ble-blind,

rand

omized,

placebo-

controlled

trial

Chronic

obstr

uctiv

epu

lmon

ary

disease(CO

PD)

patie

ntsw

ithacuteu

pper

respira

tory

tract

infection

(URT

I)—108

mostly

male

patie

nts(age

40–81)

Treatm

ent:EP

(Echinacea

purpurea)o

rEP

+zinc,sele

nium

,and

ascorbicacid

orplacebozinc

=10mg

Thec

ombinatio

nof

EP—zinc,

selenium

,and

ascorbic

acid—alleviates

exacerbatio

nsymptom

scausedby

URT

Iin

COPD

Innateand

adaptiv

erespon

se

Itseem

sthatb

othselen

ium

andzinc

act

onTlymph

ocytes,throu

ghmod

ulating

IL-2

secretion,

itsreceptor

expressio

n,andsensitivity,asw

ellasthe

thym

ulin

activ

itywhich

isrequ

iredforthe

differentiatio

nof

CD4+

Tcells.

Zinc

isinclu

dedin

theb

iosynthesis

ofleuk

otrie

neB4

.Finally,the

transcrip

tionalrepressor

Gfi1,

azingerfi

nger

protein,

was

identifi

edas

aregulator

oftheinn

ateimmun

erespo

nse

andto

beessentialfor

thed

evelo

pmento

fmacroph

ages-dependent

cytokine

prod

uctio

nandgranulocytes

Fieldetal.;

1987

Clinicalstu

dy15

female

patie

nts

Zinc

supp

lements(50,100,150m

g)Ev

idence

inplasmaa

ndleucocyte

zinc

concentrations

inan

elderly

popu

latio

n

Innate

immun

ity

Decreaseingranulocytew

ithhigh

zinc

dosesp

robablythanks

tothed

iminish

edph

agocyticandchem

otactic

activ

ityof

polymorph

onuclear

cells

Evidence-Based Complementary and Alternative Medicine 7

Table1:Con

tinued.

Authors

Type

ofstu

dySubjects

Dosage

Results

Type

ofim

mun

ityInvolved

Mechanism

ofactio

n

Wintergerst

etal.;2005

Review

:alarge

numbero

frand

omized

controlled

interventio

ntrials

Hum

anDailyintakeso

f10–

30mgof

zinc

for

child

renwith

infectious

diseases

Thea

utho

rsexplainthatzinc

and

vitamin

Cplay

anim

portantrolein

immun

esystem:adequ

ateintakes

amelioratesymptom

sand

shorten

thed

urationof

respira

tory

tract

infection,

inclu

ding

thec

ommon

cold,but

therea

rediscrepanciesin

trialsthathave

been

considered

Innateand

adaptiv

eim

mun

ity

Zinc

isessentialfor

theintracellu

lar

bind

ingof

tyrosin

ekinasetoTcell

receptors,which

arer

equiredforT

lymph

ocyted

evelo

pmentand

activ

ation—

lowered

zinc

status

impairs

cellu

larm

ediatorsof

innateim

mun

itysuch

asph

agocytosisby

macroph

ages

and

neutroph

ils,naturalkillerc

ellactivity,

generatio

nof

theo

xidativ

eburst,

and

complem

entactivity

Sancheze

tal.;

2014

Rand

omized

triple-blin

dcommun

itytrial

301children,

2–5yearso

fage

Child

renwered

istrib

uted

inthreeg

roup

sreceivingzinc

aminoacid

chelate,zinc

sulfate,and

placebofived

aysa

weekfor

16weeks

7mgof

zinc

forc

hildrenwith

2-3years

and9,4

5mgof

zinc

forc

hildrenwith

4-5

years

Zinc

aminoacid

chelateh

adab

etter

effecto

nredu

cing

theincidence

ofacuter

espiratory

infectionin

child

ren

Innate

immun

ity

Prob

ablythanks

tothep

rodu

ctionof

interfe

ronandthem

odulationof

inflammatorycytokines

Martin

ez-

Esteveze

tal.;

2016

12-m

onth

rand

omized

controlledtrial,

triple-blin

d

355child

ren

underw

ent

rand

omization,

with

174

assig

nedto

the

zinc

supp

lemen-

tatio

ngrou

pand

181tothe

controlgroup

Child

renin

thea

ctives

upplem

entatio

ngrou

preceived

5mgof

zinc

oxidep

lus

525m

gof

calcium

carbon

atep

lus7

0UIo

fvitamin

D3(K

idCa

l),andchild

renin

the

nonsup

plem

entedcontrolgroup

received

525m

gof

calcium

carbon

atep

lus7

0UIo

fvitamin

D3

Decreased

theincidence

ofURT

IInnate

immun

ity

Amon

gthev

arious

mechanism

sinvolved

inthea

ntivira

leffectso

fzinc,theICA

M-1

receptor

blocking

hasb

eenconsidered

ason

eofthe

mostimpo

rtantactions

Broo

ksetal.;

2004

Dou

ble-blind

placebo-

controlled

trial

270child

ren

(age

2–23

mon

ths)

Elem

entalzinc,20

mgperd

ay,orp

lacebo

Zinc

acceleratesrecoveryfro

msevere

pneumon

iain

child

renand

couldhelpredu

ceantim

icrobial

resis

tanceb

ydecreasin

gmultip

leantib

iotic

expo

suresa

ndles

sen

complications

anddeaths

where

second

lined

rugs

areu

navailable

Innate

immun

ity

Zinc

hasroleinthea

cuteph

aser

espo

nse

mediatedby

cytokinesd

uringacute

infection,

helpingto

boostthe

body’s

immun

erespo

nsethrou

ghad

efense

cascade,beginn

ingwith

mob

ilizatio

nand

sequ

estrationof

zinc

tometallothionein-richtissue,rapid

upregulationof

immun

edefense

specific

proteinsynthesis

,activationof

immun

edefensea

ctivity

such

asmacroph

ages,

lymph

ocytes,and

NKcells

and

antib

ody-depend

entcytotoxicity

8 Evidence-Based Complementary and Alternative Medicine

Table1:Con

tinued.

Authors

Type

ofstu

dySubjects

Dosage

Results

Type

ofim

mun

ityInvolved

Mechanism

ofactio

n

Sazawaletal.;

1997

Ado

uble-blin

d,rand

omized

controlledtrial

Child

ren(zinc

38,con

trol48)

Zinc

glucon

atetoprovidee

lementalzinc

10mgdaily

and20

mgdu

ringdiarrhea

Zinc

supp

lementatio

nim

proves

cellu

larimmun

estatus:regarding

cell-mediatedim

mun

ity(C

MI),the

percentage

ofanergico

rhypoergic

child

ren(usin

gindu

ratio

nscore)

decreasedfro

m67%to

47%in

the

zinc

grou

p.Th

ezincg

roup

hadas

ignificantly

high

erris

eintheg

eometric

means

ofCD

3,CD

4,andCD

4/CD

8ratio

with

nodifferenceinCD

8and

CD20.Th

erise

inCD

4was

significantly

high

erin

thez

inca

scomparedto

thec

ontro

lgroup

Adaptiv

eim

mun

ity

Theo

bservatio

nof

anincrease

inthe

numbero

fcirc

ulatingTlymph

ocytes,

especiallyCD

4cells,afte

rzinc

supp

lementatio

nmay

beexplainedby

directeffecto

fzincion

onthelym

phocyte

mem

branea

ffectingmaturationand

differentiatio

nof

Tlymph

ocytes

orby

astim

ulationof

thym

usendo

crine

functio

n.OnceT

lymph

ocytes

leavethe

thym

ustheird

ifferentia

tionand

maturationaretho

ught

tobe

regu

latedby

zinc-th

ymulin

anddeficiencyof

zinc-th

ymulin

hasb

eenassociated

with

second

arycellu

larimmun

edeficiency

andwith

immun

esenescence.Th

usterm

inaldeoxynucleotidyltransfe

rase

orzinc-th

ymulin

hasb

eensuggestedas

possiblemechanism

bywhich

zinc

may

beaffectin

gTcelldevelopm

entand

functio

n

Sempertegui

etal.;1996

Arand

omized

doub

le-blin

dplacebo-

controlled

trial

50child

ren(age

12–59mon

ths

old)

10mgof

zinc

sulfateor

placebo

Afte

rtreatment(on

day60),the

cutaneou

sdelayed-ty

pehypersensitivity

(DTH

)was

high

erin

treated

grou

p;theincidence

offever,coug

h,andup

perrespiratory

tractssecretions

was

lower

inS

grou

p,bu

tafte

r120

days

the

incidenceo

ffever

andup

per

respira

tory

tractssecretions

was

the

sameinbo

thgrou

ps,but

the

incidenceo

fcou

ghwas

high

erin

Sgrou

p

Innate

immun

ityTh

emechanism

isno

tclear,probably

improvingcellu

larimmun

ity

Bogden

etal.;

1988

Clinicalstu

dy103eld

erly

subjects(age

60–89years)

Threetreatments:

placebo,or

15mg

zinc/day

or100m

g/dayfor3

mon

ths

Inas

ubgrou

p(34,3%

),Zn

administratio

nenhanced

delay

edderm

alhypersensitivity

(DDH)

Skin,inn

ate

immun

ity

cellu

larimmun

itywill

notb

eenh

anced

byZn

supp

lementatio

n,bu

ttheyargued

thatcellu

larimmun

ityin

subgroup

sof

elderly

peop

lewill

beim

proved

byZn

supp

lementatio

n

Evidence-Based Complementary and Alternative Medicine 9Ta

ble1:Con

tinued.

Authors

Type

ofstu

dySubjects

Dosage

Results

Type

ofim

mun

ityInvolved

Mechanism

ofactio

n

Fortes

etal.;

1998

Ado

uble-blin

d,rand

omized,

controlledtrial

178eld

erly

patie

nts

4tre

atments:

(1)v

it.A(800𝜇gretin

olpalm

itate),(2)zinc(25

mgas

zinc

sulfate),(3)zinc+

vit.A(800𝜇gretin

olpalm

itateand25

mgof

zinc

sulfate),(4)

placebo

Zinc

supp

lementatio

nim

proves

cell-mediatedim

mun

erespo

nse,

becauseitincreases

then

umbero

fCD

4+DR+

Tcells

andcytotoxicT

lymph

ocytes

Immun

eand

adaptiv

erespon

se

Effecto

nthym

ulin

levelsthatprom

otes

Tcells

functio

ns,including

supp

ressor

functio

nandinterle

ukin-2

prod

uctio

n.Zn

preventsthen

egativity

effectsof

vit.A

onim

mun

ity

Turk

etal.;

1998

Clinicalstu

dy

26patie

ntsin

hemod

ialysis

and11healthy

patie

nts(HP)

werev

accinated

with

multiv

alent

influ

enza

vaccine(MIV

)

Supp

lementatio

nwith

120m

gof

ZnSO

4

Znsupp

lementatio

ncouldno

tresto

retheimmun

eparam

etersa

ndenhancea

ntibod

yrespon

seto

MIV

inHP

Wierin

gaet

al.;2010

Rand

omized,

doub

le-blin

d,controlledtrial

229pregnant

wom

enwith

agesta

tionalage

<20

weeks,and

infantsa

ndwom

enwere

follo

wed

upmon

thlyun

tiltheinfantswere

6mon

thso

ld

Inadditio

nto

iron(30m

gas

ferrou

sfumarate)andfolic

acid

(0,4mg),one

grou

pof

wom

enreceived𝛽-c

arotene

(4,5mg),one

grou

pzinc

(30m

gas

zinc

sulfate),andon

egroup𝛽-c

arotenep

lus

zinc

(4,5and30

mg,resp.)

Maternalsup

plem

entatio

nwith

zinc

and𝛽-carotenea

ffected

the

newbo

rn’sim

mun

edevelo

pment,

buto

nlyzinc

supp

lementatio

naffectsmorbidityin

theinfants

Innate

immun

ityZinc

givesh

igherinterleuk

in-6

prod

uctio

n

Erickson

etal.;2000

Review

Hum

ans

Supp

lementatio

nsuch

aszinc,sele

nium

,iro

n,copp

er,b-carotene,vitaminsA

,C,

andE,

andfolic

acid

Micronu

trientsh

avea

nim

portant

rolein

immun

ityInnate

immun

ity

Zinc

enhances

naturalkiller

cell

functio

ns;

zinc

supp

lementatio

ndirectlyindu

ced

cytokine

prod

uctio

n,predom

inantly

IL-1,

IL-6,and

TNF-a,by

mon

onuclear

cells

invitro

Maggini

etal.;2007

Review

Hum

ans

Inadequateintake

andsta

tuso

fvitaminsa

ndtracee

lementsmay

lead

tosupp

ressed

immun

ity,w

hich

predisp

oses

toinfections

and

aggravates

undernutrition.

Therefore,supp

lementatio

nwith

theses

electedmicronu

trients

(inclu

ding

zinc)can

supp

ortthe

body’snaturald

efense

syste

mby

enhancingallthree

levelsof

immun

ity

Skin

innate

andadaptiv

eim

mun

ity

Itisinvolved

inthec

ytosolicdefense

againsto

xidativ

estre

ss(sup

eroxide

dism

utasea

ctivity

)and

isan

essential

cofactor

forthymulin

which

mod

ulates

cytokine

releasea

ndindu

ces

proliferatio

n.Ithelpstomaintainskin

andmucosalmem

braneintegrityand

increasesc

ellularc

ompo

nentso

finn

ate

immun

ity(e.g.,ph

agocytosisby

macroph

ages

andneutroph

ils,N

Kcell

activ

ity,generationof

oxidativeb

urst,

DTH

activ

ity),antib

odyrespon

ses,and

then

umbersof

cytotoxicC

D8þTcells

(Th1respo

nse)

10 Evidence-Based Complementary and Alternative MedicineTa

ble1:Con

tinued.

Authors

Type

ofstu

dySubjects

Dosage

Results

Type

ofim

mun

ityInvolved

Mechanism

ofactio

n

Calder

and

Kew;2002

Review

Increasin

gintakeso

fsom

enutrie

nts

aboveh

abitu

alandrecommended

levelscanenhances

omea

spectsof

immun

efun

ction;

lowplasmaZ

nlevelspredictedthes

ubsequ

ent

developm

ento

flow

errespira

tory

tractinfectio

ns

Skin

innateand

adaptiv

eim

mun

ity

Inpatie

ntsw

ithZn

deficiencyrelated

tosic

kle

celldisease,naturalkiller

cellactiv

ityis

decreased.

Zinc

supp

lementatio

nincreasesthymus

size,

andtopicalapp

licationof

Znim

proves

the

DTH

respon

sein

thea

reao

fskinon

which

the

applicationwas

made

Znadministratio

nto

preterm-lo

w-birth-weightinfantsincreasesthe

numbero

fcirc

ulatingTlymph

ocytes

andtheir

proliferatio

nanda5

mgZn

/dincreases

measureso

fcell-m

ediatedim

mun

efun

ction

Sing

hand

Das;2013

Review

Hum

ans

Thereisa

significantreductio

nin

the

duratio

nof

cold

atad

oseo

f≥75

mg/day

Zinc

administered

with

in24

hours

ofon

seto

fsym

ptom

sreduces

the

duratio

nof

common

cold

symptom

sinhealthypeop

le

Enhancem

ent

ofinnateas

wellas

acqu

ired

immun

ity

Not

clear

Hojyo

and

Fukada;2016

Review

Znhasroleindend

riticcells

(that

areimpo

rtanttopresentthe

peptide-MHC-

IIcomplex

ontheir

cellsurfa

ceto

antig

en-specific

CD4+

helper

T(Th

)cellsto

initiate

immun

erespo

nses)b

ecause

aredu

ctionin

Znisrequ

iredfor

prop

erantig

enpresentatio

nvia

MHC-

IIto

elicitadaptiv

eimmun

erespon

ses

Zndeficiencyischaracteriz

edby

immun

odeficiency

with

thym

icatroph

yandlymph

openia

Zncontrolsantib

ody-mediated

humoralim

mun

erespo

nses

and

ZIP10-Zn

hasa

rolein

early

B-cell

developm

entand

them

aintenance

ofmatureB

cells

ZIP10-Zn

signalin

gmay

controlfate

decisio

nsin

lymph

ocytep

rogenitors

underp

hysio

logicalcon

ditio

nsand

exacerbatemalignancyun

der

pathologicalcond

ition

s,according

totheh

ighlyregu

latedpatte

rnof

ZIP10expressio

n

Innateand

adaptiv

eim

mun

ity

Znfacilitates

thee

ndocytosisof

MHC-

IIbu

tinhibitsthetraffickingof

MHC-

IIfro

mthe

lysosome/endo

somec

ompartmentsto

the

plasmam

embrane

theZ

nD-in

ducedthym

icatroph

ycouldresult

from

thec

ombinatio

nof

increased

glucocortic

oidlevels,

anim

pairm

ento

fthym

ulin

activ

ity,and

impaire

dcell-intrinsic

survivalfunctio

nZIP10-Zn

signalin

gregulates

thee

xpressionof

CD45Rwhilesim

ultaneou

sly(and

indirectly)

enhancingtheC

D45RPT

Pase

activ

itythroug

haZ

n-depend

entp

rocessrather

than

byad

irect

effecto

nPT

Pase

activ

ityTh

eeffecton

developm

entcou

ldbe

explained

byglucocorticoids

andZIP10maintains

mature

Bcells

throug

haL

YN-in

depend

entm

echanism

ZIP10-Zn

signalin

ginhibitsthea

poptosis

indu

cedby

activ

ated

caspases

andprom

otes

pro-B-cellsurvivalin

acell-a

uton

omou

smanner

Cytokine

stim

ulation(th

efirstsignal)activ

ates

theJAK-

STAT

pathway

(thes

econ

dsig

nal),

which

furtherind

uces

ZIP10expressio

nand

eventuallygeneratesZ

IP10-Znsig

nals(th

ethird

signal)

Evidence-Based Complementary and Alternative Medicine 11

Records identified through database

[n = 152]

Records excluded [n = 48]

Reasons:(i) Not pertinent, n = 18

(ii) Other manuscript type, n = 27(iii) Duplicates, n =3

Records screened[n = 104]

Full-text articles assessed for eligibility[n = 104]

(i) Zinc = 35(ii) Vitamin D = 33

(iii) Vitamin C = 22(iv) Echinacea = 14

Studies included in the review[n = 82]

Identifi

catio

nScreening

Eligibility

Inclu

ded

Records excluded [n = 22]

Reasons:(i) Not pertinent, n = 11

(ii) Other manuscript type, n = 10(iii) Duplicates, n = 1

(i) Zinc = 28(ii) Vitamin D = 26

(iii) Vitamin C = 14(iv) Echinacea = 14Note. Some articles are included in all three topics.

(PUBMED) searching

Figure 1: Flow chart of the study selection process.

the inflammatory cytokine IL-1𝛼 and the anti-inflammatory product IL-1ra [43]. After zinc restric-tion, there was reduction in the in vitro secretion ofinterleukin-2 receptor (IL-2R) [44]. Zinc is involvedin the cytosolic defense against oxidative stress(superoxide dismutase activity) [10]. Recently, thetranscriptional repressor Gfi1, a zinc finger protein,was identified as a regulator of immune response[45]. Inflammatory cytokines, such as tumor necrosisfactor 𝛼 and interleukin (IL) 1, are also known togenerate greater amounts of reactive oxygen speciesand these parameters significantly decrease after zincsupplementation in the elderly (45mg) [46]. Zn couldnormalize the production of interleukins, such asIL-2 [9], but also IL-1, IL-6, and tumor necrosisfactor 𝛼 (TNF-a), by mononuclear cells in vitro [11].It modulates cytokine release by peripheral bloodnuclear cells [26]. Il-6 increased in infants born tomothers that received Zn supplementation [47]. Mostimportant, the ex vivo generation of TNF-𝛼 fromisolated mononuclear cells (MNCs) is significantlydecreased in elderly subjects after zinc supplemen-tation [46]. Finally, Zn has role in the productionof interferon-𝛾 [48]. Zinc is involved also in thebiosynthesis of leukotriene B4, which is implicated in

a variety of acute and chronic inflammation, includ-ing chronic-obstructive pulmonary disease (COPD)[45]. The antiviral effects of zinc (5mg), through theIntercellular Adhesion Molecule 1 (ICAM-1) receptorblocking, have been considered as one of the mostimportant actions for impacting on incidence and/orduration of upper respiratory tract infections (URTI)[49].

3.1.3. Third Barrier: Adaptive Immunity. Zn is required forproper antigen presentation via MHC-II to elicit adaptiveimmune responses [35]. Zinc deficiency in experimentalanimals is associated with low thymic weight and pro-gressive loss of T lymphocytes (T cells) because zinc isan essential cofactor for the thymic hormone thymulin.Thymulin induces several T cell markers and promotes T cellfunction, including allogenic cytotoxicity, suppressor func-tions, and interleukin-2 production [26]. Zn supplementation(30mg/day) is required in order to enhance functions of Tcells, thanks to an increase in the production of T cells and/ora decrease in the loss of T cell precursors via apoptosis [50].It increases the number of CD4 (helper) lymphocytes in chil-dren with a 10–20mg of supplementation [36] or with 5mg ofzinc [51] and also CD8 [9, 26]. Since it is an essential cofactor

12 Evidence-Based Complementary and Alternative Medicine

for thymulin [10], a possible explanation of these effects onT cells is related to thymulin levels, which is required for thedifferentiation of CD4+ T cells [45, 52]. Another explanationis a direct effect of zinc ion on the lymphocyte membraneaffecting maturation and differentiation of T lymphocytes[37]. Zinc acts on T lymphocytes through modulating IL-2 secretion, receptor expression, and sensitivity [45]. Zncontrols antibody-mediated humoral immune responses, anda zinc cell-membrane-localized transporter (ZIP10-Zn) hasa role in early B-cell development and the maintenance ofmature B cells [35].

3.1.4. Zinc Supplementation for Common Colds. Many stud-ies have agreed that supplementation of zinc is helpful inreducing the risk of pneumonia and common cold and theincidence of respiratory tract infection, specifically in theelderly and in children [9, 33, 36, 50, 53, 54]. Zinc sup-plementation (20mg/day) accelerates recovery from severepneumonia in children [42]. (However, two articles werefound which do not support a role for intranasal zinc(gluconate) in prevention or treatment of the common coldor immune parameters [55, 56], but in these two studies theway of administration is intranasal.) Very recently two meta-analyses demonstrated that zinc may shorten the duration ofcolds by approximately 33% [57]. However, there are sometopics about zinc and common cold that are still not clear.In particular, high dosage of zinc in clinical trials has causedadverse effects, such as bad taste, and the variation in the totaldaily dose of zinc.

In conclusion, given the discreet evidence of efficacyon shortening the duration of colds by approximately 33%,common cold patientsmay be instructed to try zinc within 24hours of onset of symptoms [57]. However, since controlledtrials that have examined the effect of zinc on the commoncold have diverged, the optimal composition and dosage ofzinc should be better investigated in addition to the optimumfrequency of their administration.

3.2. Vitamin D and Three Main Immune Interactive Clusters(Physical Barriers, Innate and Adaptive Immunity) Involvedduring an Episode of Common Colds. This research has beencarried out based on the following keywords: “vitamin D”OR “vitamin D supplementation” AND “immune response”AND “innate immunity” AND “adaptive immunity” AND“respiratory tract infections” AND “common cold” AND“immunodeficiency.”

Figure 1 shows the study selection process.Table 2 summarizes the studies presented in the narrative

review.

3.2.1. First Barrier: Physical Barrier. The active hormone1,25(OH)2D is important in upregulating genes via the 1a-hydroxylase enzyme, which then encode proteins requiredfor tight junctions (e.g., occludin), gap junctions, andadherens junctions (e.g., E-cadherin) [58].

Vitamin D supplementation increases cathelicidin pro-duction and it is involved in the production of defensins [59].

These antimicrobial peptides are also involved in the secondbarrier.

3.2.2. Second Barrier: Cellular Natural Immunity. A review byHewison et al. shows that vitamin D supplementation is suc-cessful in raising serum levels of 25OHD in TB patients and itmay also play a role in promoting innate immune responsesto enhance monocyte phagocytosis and degradation of b-amyloid.

The effects of vitamin D3 on macrophage phagocyto-sis may be related to the ability of that vitamin to altermonocyte maturation. Thus, D3 enhances immunoglobulinand complement-mediated phagocytosis by human mono-cytes through its stimulation of monocyte maturation tomacrophages [11].

Enhancing protective innate immune responses,1,25(OH)2D helps maintain self-tolerance by dampeningoverly zealous adaptive immune responses.

In addition, oral supplementation with HyD (25(OH)D3metabolite) at a dose of 20𝜇g per day may explain the benefitof HyD on systolic blood pressure reduction, improvementin lower extremity function, and the more pronouncedreduction in several markers of innate immunity amonghealthy postmenopausal women [60].

3.2.3. Third Barrier: Adaptive Immunity. Human epidemio-logical studies indicate supplementation with 1,25(OH)2D3as an independent protective factor influencing the occur-rence of Th-1 mediated autoimmunity [10]. The effectsof 1,25(OH)2D on the immune system include decreasingTh1/Th17 CD4+ T cells and cytokines, increasing regulatoryT cells, downregulation of T cell-driven IgG production, andinhibition of dendritic cell differentiation [61]. The adaptiveimmune effects of vitamin D are not restricted to effector Tcells and also include actions on suppressor or regulatory Tcells (Treg), a group of CD4+ T cells known for inhibiting theproliferation of other CD4+T cells. Treatment of naive CD4+T cells with 1,25(OH)2D potently induces the developmentof Treg, and this may exert beneficial effects in autoimmunedisease and host-graft rejection [62].

A short term high-dose vitD3 supplementation(140.000 IU) significantly increased the frequency ofregulatory T cells (Tregs) but did not further improve 𝛽-cellfunction in apparently healthy subjects.

VitD3 may be a useful therapeutic agent in autoimmunediseases exerting immunemodulatory effects involving stim-ulatory actions on Tregs [63].

Vitamin D deficiency or insufficiency has immuno-logical implications in patients with recurrent miscarriage(RM). The percentage of B cells, the percentage of TNF-𝛼-producing Th cells, and NK cytotoxicity are significantlyreduced under 0.5 𝜇g/day of 1,25(OH)2D supplementationfor 2 months [64]. Treatment with 4000 IU vitamin D3 sig-nificantly reduced CD4+ T cell activation compared to low-dose vitamin D3, providing human evidence that vitamin Dcan influence cell-mediated immunity [65].

Vitamin D associated with upper respiratory tract infec-tions (URI) burden probably involves lymphocytes and their

Evidence-Based Complementary and Alternative Medicine 13

Table2:Stud

ieso

nvitamin

D,immun

ity,and

common

cold

presentedin

then

arrativ

ereview.

Authors

Type

ofstu

dySubjects

Dosage

Results

Type

ofim

mun

ityinvolved

Mechanism

ofactio

n

Bergman

etal.;

2015

Arand

omized,

placebo-

controlled,and

doub

le-blin

ded

study

Thep

erprotocol

popu

latio

n(𝑛=124

patie

ntsa

ged18

to75

years),w

hocompleted

thes

tudy,con

sistedof

𝑛=62

vitamin

Dtre

ated

and𝑛=62

placebo

treated

patie

nts.

𝑛=62

oralvitamin

D3

(400

0IU/day

for1

year)

treated

and𝑛=62

oil

(Miglyol)p

lacebo

treated

patie

nts.

Follo

w-up:12

mon

ths.

Vitamin

Dsupp

lementatio

nincreasedthe

prob

abilityof

staying

freeo

frespiratory

tract

infections

(RTI)d

uringthes

tudy

year

(RR

0.64

,95%

CI0.43–0

.94).Further,the

total

numbero

fRTIsw

asalso

redu

cedin

the

vitamin

Dgrou

p(86R

TIs)versus

placebo

(120

RTIs;𝑝=0.05).Finally,the

timetothe

firstRT

Iwas

significantly

extend

edin

the

vitamin

Dgrou

p(H

R1.6

8,95%CI

1.03–2.68,

𝑝=0.0376).

Ther

oleo

fvitamin

Din

respira

tory

tractinfectio

nsisstillno

tclear,despite

severallarge

RCTs

inthe

area.Th

iscanprob

ablybe

explainedby

thelarge

heterogeneity

inthese

rand

omized

controlled

trials(RCT

s).

Bock

etal.;2011

Ado

uble-blin

d,placebo-

controlled

trial

59healthyadultsub

jects

(49%

females).

Subjectsreceived

oral

vitD

3(14

0,00

0IU

oleovitD

3,mon

thly)o

rplacebo(alm

ondoil)for

aperiodof

3mon

ths.

%regu

latory

Tcells

(Tregs)increased

significantly

onlyin

thev

itDgrou

p.Ashort

timeh

igh-do

sevitD

3supp

lementatio

nsig

nificantly

increasedthefrequ

ency

ofTregs,

butd

idno

tfurther

improve𝛽

-cellfun

ctionin

apparentlyhealthysubjects.

Adaptiv

eim

mun

ity:T

cells

and𝛽cellfunctio

n

Theimmun

omod

ulatory

potentialofvitDmight

bean

impo

rtantm

echanistic

linkforthe

associationof

vitD

andT1D.

Goo

dalletal.;

2014

Dou

ble-blind

clinicaltria

l

600participants(≥17

years),471

(78.5%

)completed

allsurveys

while43

(7.2%

)completed

none.

Participantswere

rand

omized

toreceivea

containerw

itheight

capsules

ofeither

10,000

IUof

activ

evitamin

D3or

identic

alplacebo.Stud

entsare

rand

omized

into

4tre

atmentarm

s:(1)

vitamin

D3andgarglin

g,(2)p

lacebo

andgarglin

g,(3)v

itamin

D3andno

garglin

g,and(4)p

lacebo

andno

garglin

g.

Of6

00participants,

471(78.5%)com

pleted

all

surveysw

hile43

(7.2%

)com

pleted

none;150

(25.0%

)reportedclinicalU

RTI.Seventy

participants(23.3%

)rando

mized

tovitamin

D3

repo

rted

clinicalU

RTIcom

paredto

80(26.7%

)rand

omized

toplacebo(RR:

0.79,C

I95:

0.61–1.03,𝑝=0.09).Eighty-five

participants

(28.3%

)rando

mized

togarglin

grepo

rted

clinicalupp

errespira

tory

tractinfectio

n(U

RTI)comparedto

65participants(21.7

%)

rand

omized

tothen

ogarglin

garm

(RR:

1.3,

CI95:0.92–1.5

7,𝑝=0.19).Labo

ratory

testing

identifi

ed70

infections

(46.7per100

URT

Is).

Vitamin

D3tre

atmentw

asassociated

with

asig

nificantly

lower

riskforlaboratory

confi

rmed

URT

I(RR

:0.54,CI

95:0.34–

0.84,

𝑝=0.007)

andwith

asignificantly

lower

mean

viralloadmeasuredas

log10viralcop

ies/mL

(meandifference:−0.89,C

I95:−1.7,−

0.06,

𝑝=0.04).Fewer

studentsa

ssignedto

garglin

gexperie

nced

labo

ratory

confi

rmed

URT

I;ho

wever

thiswas

notstatisticallysig

nificant

(RR:

0.82,C

I95:0.53–1.26,𝑝=0.36).

Vitamin

D3isap

romising

interventio

nforthe

preventio

nof

URT

I.Vitamin

D3sig

nificantly

redu

cedther

iskof

labo

ratory

confi

rmed

URT

Iandmay

redu

cether

iskof

clinicalinfectio

ns.

14 Evidence-Based Complementary and Alternative Medicine

Table2:Con

tinued.

Authors

Type

ofstu

dySubjects

Dosage

Results

Type

ofim

mun

ityinvolved

Mechanism

ofactio

n

Camargo

etal.;

2012

Dou

ble-blind

clinicaltria

l

744Mon

golian

child

renfro

m21

third

-andfourth-grade

classroom

s(9-10

years

old),but

thisanalysis

focusedon

asub

seto

f247child

renwho

were

assig

nedto

daily

ingestionof

unfortified

regu

larm

ilkor

milk

fortified

with

300I

Uof

vitamin

D3.

50%of

child

ren,

who

drankmilk

,werem

ale.

54%of

child

ren,

who

drankmilk

vitamin

Dfortified

werem

ale.

TheB

lueS

kyStud

yexam

ined

5approaches

toim

provethe

vitamin

Dsta

tuso

fMon

golian

scho

olchild

ren:

(1)3

00IU

ofvitamin

D3

daily

inMon

golianmilk

(𝑛=143);(2)

300I

Uof

vitamin

D3daily

inUS

milk

(𝑛=143);(3)

300I

Uof

vitamin

D3

daily

inam

ilksubstitute

(𝑛=147);(4)

300I

Uof

vitamin

D3in

adailypill

(𝑛=112);and

(5)a

total

of13,700

IUof

vitamin

D3in

pills

givenover

the

first7days

ofstu

dy(𝑛=95).

Follo

w-up:winter

(Janu

ary–March).

Atbaselin

e,them

edianserum

25(O

H)D

level

was

7ng/mL(in

terquartile

range:5–10ng

/mL).

Atthee

ndof

thetria

l,follo

w-upwas

99%

(𝑛=244),and

them

edian25(O

H)D

levelsof

child

renin

thec

ontro

lversusv

itamin

Dgrou

psweres

ignificantly

different

(7versus

19ng

/mL;

𝑝=0.001).C

omparedwith

controls,

child

ren

receivingvitamin

Drepo

rted

significantly

fewer

ARIsd

uringthes

tudy

perio

d(m

ean:

0.80

versus

0.45;𝑝=0.047),w

ithar

ater

atio

of0.52

(95%

confi

denceinterval:0.31–0

.89).

Adjustingfora

ge,gender,andhisto

ryof

wheezing,vitamin

Dcontinuedto

halvethe

riskof

ARI

(rater

atio:0.50[95%

confi

dence

interval:0.28–0.88]).Sim

ilarresultswere

foun

dam

ongchild

reneither

belowor

above

them

edian25(O

H)D

levelatb

aseline

(rate

ratio

:0.41v

ersus0

.57;pforinteractio

n=.27).

Vitamin

Dsupp

lementatio

nsig

nificantly

redu

cedthe

riskof

ARIsinwinter

amon

gMon

golianchild

ren

with

vitamin

Ddeficiency.

Urashim

aetal.;

2010

Amultic

enter,

rand

omized,

doub

le-blin

d,placebo-

controlled,

parallel-g

roup

trial

430scho

olchild

ren(56%

werem

ale)aged

6–15y,

with

orwith

out

underly

ingdiseases,

weree

ligibleandasked

toparticipateinthe

study

bythe

pediatric

ians

incharge

oftheo

utpatie

ntclinics.

Thep

articipantswere

askedto

take

3tablets

twiced

aily,

total:1200

IUvitamin

D3(217

child

ren)

orplacebo(213

child

ren).

Thea

ccrualperio

dwas

from

Decem

ber1,2008,

toMarch

31,200

9.

Influ

enza

Aoccurred

in18

of167(10.8%

)child

renin

thev

itamin

D3grou

pcompared

with

31of

167(18.6%

)childrenin

thep

lacebo

grou

p[rela

tiver

isk(RR),0.58;95%CI

:0.34,

0.99;𝑝=0.04].Th

ereductio

nin

influ

enza

Awas

morep

rominentinchild

renwho

hadno

tbeen

taking

otherv

itamin

Dsupp

lements(RR:

0.36;95%

CI:0.17,0.79;𝑝=0.006)

andwho

startednu

rseryscho

olaft

erage3

y(RR:

0.36;

95%CI

:0.17,0.78;𝑝=0.005).Inchild

renwith

apreviou

sdiagn

osisof

asthma,asthmaa

ttacks

asas

econ

dary

outcom

eoccurredin

2child

ren

receivingvitamin

D3comparedwith

12child

renreceivingplacebo(RR:

0.17;95%

CI:

0.04,0.73;𝑝=0.006).

Vitamin

D3

supp

lementatio

ndu

ringthe

winterm

ayredu

cethe

incidenceo

finfl

uenzaA

,especiallyin

specific

subgroup

sof

scho

olchild

ren.

Evidence-Based Complementary and Alternative Medicine 15

Table2:Con

tinued.

Authors

Type

ofstu

dySubjects

Dosage

Results

Type

ofim

mun

ityinvolved

Mechanism

ofactio

n

Sism

anlare

tal.;

2016

Clinicaltrial

Sixty-threec

hildren

aged

betweensix

mon

ths

andfivey

earswith

lower

respira

tory

infections

and59

age-matched

child

renwho

hadno

histo

ryof

respira

tory

symptom

sinthelast

mon

thandno

accompanyingchronic

disease.

Follo

w-up:Decem

ber

2010

andFebruary

2011.

25(O

H)v

itamin

Dlevel

of<20

ng/m

Lwas

considered

vitamin

Ddeficiency,alevelof

20–30n

g/mLwas

considered

vitamin

Dinsufficiency,a

levelof

>30

ng/m

Lwas

considered

norm

al,and

alevelof

>150–

200n

g/mLwas

considered

intoxicatio

n.

Nosig

nificantcorrelationwas

foun

dbetween

vitamin

Dlevelsandlower

respira

tory

tract

infectionin

term

sofd

iseasea

ndits

severity.

How

ever,itw

asfoun

dthatvitamin

Ddeficiency/insufficiency

was

observed

with

ahigh

ratein

allchildreninclu

dedin

thes

tudy.

Alth

ough

nocorrelation

was

foun

dbetweenvitamin

Dleveland

lower

respira

tory

tractinfectio

n,itisrecommendedthat

vitamin

Dlevelsho

uldbe

measuredin

child

renwith

lower

respira

tory

tract

infectionandvitamin

Dsupp

lementatio

nshou

ldbe

givento

allchildren

especiallyin

winterm

onths

basedon

thefactthatthe

levelofvitamin

Dwas

lower

than

norm

alin

approxim

ately

halfof

the

child

reninclu

dedin

the

study

andconsideringthe

effectsof

vitamin

Don

infections,pulmon

ary

functio

ns,and

immun

ity.

Li-ngetal.;2009

A3-mon

thprospective,

rand

omized,

doub

le-blin

d,placebo-

controlledtrial

ofvitamin

D3

supp

lementa-

tionin

ambu

latory

adults

162adults(18–80

years

old)

werer

ando

mized.

Male:17

activ

e,13

placebo.

Female:61

activ

e,57

placebo.

84patie

ntsreceived

50𝜇g/dvitamin

D3and

78patie

ntsreceived

placebo.

Follow-up:March–Jun

e2007.

Therew

eren

osig

nificantd

ifferencesb

etween

thea

ctivea

ndplacebopatie

ntsa

tbaseline.Th

ebaselin

e25-OHDlevelsranged

from

16to

156n

mol/lwith

meanlevelof63.7±28.7nm

ol/l

inthes

tudy

popu

lation.

Atbaselin

e,23%of

the

activ

epatientse

xceeded75

nmol/l.

16 Evidence-Based Complementary and Alternative Medicine

Table2:Con

tinued.

Authors

Type

ofstu

dySubjects

Dosage

Results

Type

ofim

mun

ityinvolved

Mechanism

ofactio

n

Bischo

ff-Ferrariet

al.;2012

Clinicaltrial

20white

postm

enop

ausalw

omen,

50to

70yearso

fage,in

generalgoo

dhealth

with

anaverage2

5(OH)D

levelof13.2±3.9ng

/mL

(mean±SD

)and

amean

ageo

f61.5±7.2years

werer

ando

mized

toeither

20mgof

HyD

or20

mg(800

IU)o

fvitamin

D3perd

ayin

ado

uble-blin

dmanner.

Participantsattend

edon

escreening

visit

and

14clinicalvisitsdu

ringa

4-mon

thtrialp

eriod.

Wom

enwho

passed

eligibilitycriteria

signed

inform

edconsentand

werer

ando

mlyassig

ned

toon

eoffou

rgroup

s:20

mgHyD

daily,20m

g(800

IU)v

itamin

D3

daily,140

mgHyD

weekly,or

140m

g(560

0IU)v

itamin

D3

weekly.Allsupp

lements

weretaken

orally.

We

rand

omized

five

participantsto

each

treatmentg

roup

.The

dose

ofvitamin

D3was

chosen

tocompare

tothec

urrent

stand

ardfor

vitamin

D3

(20m

g(1/4)800I

U/d).

Mean25(O

H)D

levelsincreasedto

69.5ng

/mL

intheH

yDgrou

p.Th

isris

ewas

immediateand

susta

ined.M

ean25(O

H)D

levelsincreasedto

31.0ng

/mLwith

aslowincrease

inthev

itamin

D3grou

p.Wom

enon

HyD

comparedwith

vitamin

D3had2.8-fold

increasedod

dsof

maintainedor

improved

lower

extre

mity

functio

n(odd

sratio

[OR](1/4)2.79;95%

confi

denceinterval[CI

],1.18–6.58)a

nda

5.7-mmHgdecrease

insysto

licbloo

dpressure

(𝑝(1/4)0.0002).B

othtypeso

fvitamin

Dcontrib

uted

toad

ecreaseinfiveo

utof

seven

markersof

innateim

mun

ity,significantly

more

pron

ounced

with

HyD

fore

otaxin,IL-12,

MCP

-1,and

MIP-1b.Th

erew

eren

ocaseso

fhypercalcemiaatanytim

epoint.Twenty

microgram

s(20

mg)

ofHyD

perd

ayresultedin

asafe,im

mediate,and

susta

ined

increase

in25(O

H)D

serum

levelsin

allp

artic

ipants,

which

may

explainits

significantb

enefito

nlower

extre

mity

functio

n,systo

licbloo

dpressure,and

innateim

mun

erespo

nse

comparedwith

vitamin

D3.

innateim

mun

erespon

se

Thes

tudy

show

sthat2

0mg

HyD

issig

nificantly

more

efficientand

morer

apid

inshiftinghealthy

postm

enop

ausalw

omen

into

adesira

ble2

5(OH)D

serum

levelofatleast

30ng

/mLcomparedto

800I

U(20m

g)vitamin

D3.

Charan

etal.;2012

Asyste

matic

review

and

meta-analysis

Hum

ans

Adults(18–80

year,

18–28men,and

postm

enop

ausal

wom

en)a

ndchild

ren

(1–3

year,6–15year).

Thep

opulationnu

mber

isno

treported.

Doseo

fvitamin

Dused

inthesec

linicaltrials

ranged

from

400I

U/day

to2000

IU/day.Inon

eclinicaltria

lsingle

parenteraldo

seof

vitamin

Dwas

given

(100

000I

U).

Eventsof

respira

tory

tractinfectio

nswere

significantly

lower

invitamin

Dgrou

pas

comparedto

controlgroup

[odd

sratio

=0.582

(0.417–0

.812)𝑝=0.001]

accordingto

rand

ommod

el.Onseparateanalysisof

clinicaltria

lsdealingwith

grou

psof

child

renandadults,

beneficialeffectof

vitamin

Dwas

observed

inbo

th,according

tofixed

mod

el[odd

sratio

=0.579(0.416–0

.805),𝑝=0.001andod

dratio

=0.653(0.472–0

.904

0),𝑝=0.010resp.].

Innateand

adaptiv

eim

mun

ity

Itisbelievedthatvitamin

Dincreasesthe

prod

uctio

nof

naturalantibod

ies.Vitamin

Disalso

know

nto

streng

then

theimmun

ityby

indu

cing

mon

ocyte

differentiatio

nand

inhibitin

glymph

ocyte

proliferatio

n.Itisalso

postu

latedthatvitamin

Denhances

thep

hagocytic

activ

ityof

macroph

ages.

Evidence-Based Complementary and Alternative Medicine 17

Table2:Con

tinued.

Authors

Type

ofstu

dySubjects

Dosage

Results

Type

ofim

mun

ityinvolved

Mechanism

ofactio

n

Chen

etal.;2016

Clinicaltrial

99wom

enwith

ahistory

oftwoor

more

successiv

emisc

arria

ges.

Atotalof35patie

nts

constituted

thev

itamin

Dno

rmalgrou

p(V

DN)

(age

33.6y±3.9),and

51patie

ntsw

ereincludedin

thev

itamin

Dinsufficiency

grou

p(V

DI)(age

32.4y±3.9),

and13

vitamin

Ddeficiencypatie

ntsin

VDD(age

33.0y±4.4).

Patie

ntsw

ithrecurrent

misc

arria

ge(RM)w

ere

supp

lementedwith

0.5𝜇

g/dayof

1,25(OH)2Dfor2

mon

thsa

ndthen

perip

heralblood

cells.

Thep

ercentageo

fCD19+Bcells

andNK

cytotoxicityatan

effector-to-ta

rgetcell(E

:T)

ratio

of50

:1,25:

1,and12.5:1weresignificantly

high

erin

thev

itamin

Dinsufficiency

grou

p(V

DI)than

inthev

itamin

Dno

rmalgrou

p(V

DN)(𝑝<.05each).Th

epropo

rtionof

TNF-𝛼-expressingTh

cells

was

significantly

high

erin

thev

itamin

Ddeficiencygrou

p(V

DD)thanin

VDN(𝑝<.05).H

owever,there

weren

osig

nificantd

ifferencesb

etweenVDI

andVDD.Th

isdysregulationwas

significantly

redu

cedwith

1,25(OH)2Dsupp

lementatio

n.

Innateand

adaptiv

eim

mun

ity:

cell-mediated

immun

ity

Itwas

foun

dthatthe

percentage

ofperip

heral

bloo

dCD

19+Bcells,the

percentage

ofTN

F-𝛼-

prod

ucingTh

cells,and

NK

cytotoxicityatallE

:Tratio

swered

ramatically

redu

cedun

der1,25(OH)2D

supp

lementatio

n.ithas

been

show

nthat

1,25(OH)2Dcould

downregulates

everalgenes

associated

with

TNF-𝛼,

inclu

ding

proteins

involved

inthetranscriptio

nof

TNF-𝛼,one

ofits

prim

ary

receptors,andTN

F-𝛼itself.

Vitamin

Dwas

also

ableto

depo

lariz

eperforin

expressio

nin

the

cytoplasm,w

hich

redu

ced

theN

Kcytotoxicityin

RMpatie

nts.

Dankersetal.;

2017

Review

Ther

eviewdiscussedthee

ffectof

vitamin

Dwhich

isthem

odulationof

theimmun

esystem.

Ther

eviewdiscussesthe

currentk

nowledge

abou

tthe

molecular

mechanism

sund

erlying

theimmun

omod

ulatoryeffectsof

vitamin

Dandho

wthesea

dvancesc

anbe

used

inthe

treatmento

fautoimmun

edise

ases.

Autoim

mun

ity,

innateandadaptiv

eim

mun

ity

18 Evidence-Based Complementary and Alternative Medicine

Table2:Con

tinued.

Authors

Type

ofstu

dySubjects

Dosage

Results

Type

ofim

mun

ityinvolved

Mechanism

ofactio

n

DeG

ruijland

Pavel;2012

Rand

omized

clinicalstudy

105stu

dent

volunteers

(18–30

yearso

fage)

divide

in3grou

ps.

Thep

articipantswere

rand

omized

to3grou

ps:

(A)sub

jected

to3tim

esaw

eeksub-sunb

urn

sunb

edexpo

sure

(𝑛=35),(B)d

aily

vitamin

Dsupp

lementatio

n,1000

IU(𝑛=37),and

(C)a

controlgroup

with

outany

interventio

n(𝑛=33).Th

emean

serum

levelof

25-hydroxy

vitamin

D(25(OH)D

)dropp

edfro

m62

to55

nmoll−1

ingrou

pC,

whilethese

levelsrose

from

62to

109

andfro

m58

to93

nmol

l−1in

grou

psAandB.

Alth

ough

fewer

coldso

ccurredin

theg

roup

s(A

)and

(B)com

paredwith

controlgroup

(C),

thed

ifference

was

notsignificant.Th

einitia

l25(O

H)D

levelsin

thev

olun

teersthatcaughta

cold

(𝑛=61)w

eren

otsig

nificantly

different

from

thosew

hodidno

t(𝑛=44):meanof

61(SD21)v

ersus6

1(SD

20)n

moll−1

(nor

were

thefi

nallevelsd

ifferent:meanof

86(SD31)

versus

86(SD32)n

moll−1

).

Innateim

mun

ityandskin

barrier

Thes

tudy

show

ssub-sunb

urnsunb

edtre

atmenttobe

effectiv

ein

tann

ingandin

increasin

gthe2

5(OH)D

serum

level,

mores

othan

oralvitamin

Dsupp

lementatio

nby

1000

IUperd

ay.D

espite

earlier

results

suggestin

ga

possiblebeneficialeffecton

colds,this8-week

mid-w

interc

ourseo

fsunb

edexpo

suresh

as,

however,noappreciable

effecto

ncolds.

deSa

DelFiolet

al.;2015

Review

Hum

ans.

Thisstu

dyaimed

toreview

recent

clinicaland

epidem

iologicalstudies

cond

uctedin

adults

andchild

renandto

evaluatethefun

ctionalrole

ofvitamin

Din

respira

tory

infections.Th

eevaluatedstu

dies

show

anim

portant

immun

omod

ulatoryroleof

vitamin

D,w

hich

redu

cesthe

incidencea

ndris

kof

URT

Is(upp

errespira

tory

tractinfectio

ns),bo

thin

child

ren

andin

adults.

Com

batin

gURT

Iscanbe

done

prop

hylactically,

associatingtheu

seof

vaccines

againstStre

ptococcusp

neum

oniaew

ithstreng

theningtheimmun

esystem

throug

hsupp

lementatio

nwith

vitamin

D.

Innateand

adaptiv

eimmun

esyste

m

Vitamin

Dappearsto

combatinfectio

nvia

multip

lemechanism

s.It

hasa

directinflu

ence

onthep

rodu

ctionof

cathelicidin,w

hich

may

lead

toincreased

susceptib

ilityto

virusesa

ndbacteria,and

itinflu

ences

cytokine

profi

lesd

uring

infectionviathe

innateand

adaptiv

eimmun

esystem.

Evidence-Based Complementary and Alternative Medicine 19Ta

ble2:Con

tinued.

Authors

Type

ofstu

dySubjects

Dosage

Results

Type

ofim

mun

ityinvolved

Mechanism

ofactio

n

Denlin

gere

tal.;

2016

Aclinicaltria

l:theA

sthm

aNet

VID

A(V

itamin

DAd

d-on

Therapy

Enhances

Corticosteroid

Respon

siveness)

trial

408adult

patie

nts.

Patie

ntsa

rerand

omized

toreceivep

lacebo

orcholecalciferol

(100,000

IUload

plus

4,00

0IU/d)for

28weeks

asadd-on

therapy.

Atotalof203

participantsexperie

nced

atleasto

necold.

Despiteachieving25-hydroxy

vitamin

Dlevelsof

41.9ng

/ml(95%confi

denceinterval[CI

],40

.1–43.7ng

/ml)by

12weeks,vitamin

Dsupp

lementatio

nhadno

effecto

nthep

rimaryou

tcom

e:thea

verage

peak

WURS

S-21

scores

(62.0[95%

CI,

55.1–

68.9;placebo

]and

58.7[95%

CI,52.4–

65.0;vitamin

D];𝑝=0.39).Th

erateo

fcolds

didno

tdiffer

between

grou

ps(rater

atio

[RR],1.2;95%

CI,0.9–1.5);ho

wever,

amon

gAfrican

Americans,thoser

eceiving

vitamin

Dversus

placebohadan

increasedrateof

colds(RR

,1.7;

95%CI

,1.1–

2.7;𝑝=0.02).Th

iswas

also

observed

ina

respon

dera

nalysis

ofallsub

jectsa

chieving

vitamin

Dsufficiency,regardlesso

ftreatmentassignm

ent(RR

,1.4;

95%CI

,1.1–

1.7;𝑝=0.009).

Epith

elium

innate

immun

ity

Thea

utho

rshypo

thesized

butd

idno

tobserve

that

achievingvitamin

Dsufficiency

wou

ldallowfor

enhanced

respon

sivenessto

ICS(th

edailydo

seof

inhaledcorticosteroid)

with

respecttolung

functio

now

ingto

the

abilityof

vitamin

Dto

influ

ence

steroid

metabolism

.Con

versely

,it

isalso

possiblethatthe

change

inICSdo

sesd

uring

thep

rotocolinfl

uenced

vitamin

Dmetabolism

and/or

thee

xpressionof

thev

itamin

Dreceptor

and

bind

ingprotein,

soitis

possiblethatwed

idno

tgive

enou

ghvitamin

Dand

that25(O

H)D

levelsin

the

serum

dono

treflectthe

changesrele

vant

toairw

ayepith

elium

innate

immun

ity.

Erickson

etal.;

2000

Review

Micronu

trientssuchas

zinc,selenium,iron,

copp

er,

b-carotene,vitaminsA

,C,and

E,andfolic

acid

can

influ

ence

severalcom

ponentso

finn

ateimmun

ity.

Selected

micronu

trientsp

layan

impo

rtantrolein

alteratio

nof

oxidant-m

ediatedtissueinjury,and

phagocyticcells

prod

ucer

eactiveo

xidantsa

sparto

fthe

defensea

gainstinfectious

agents.

Innateim

mun

ity

Deficiencies

inzinc

and

vitaminsA

andDmay

redu

cenaturalkiller

cell

functio

n,whereas

supp

lementalzinco

rvitamin

Cmay

enhance

theira

ctivity.

Hew

ison;

2012

Overview

Itisno

wcle

arthatcells

from

theimmun

esystem

contain

allthe

machinery

needed

toconvert2

5-hydroxyvitamin

Dto

activ

e1,25-

dihydroxyvitamin

D,and

forsub

sequ

ent

respon

sesto1,2

5-dihydroxyvitamin

D.Suchmechanism

sareimpo

rtantfor

prom

otingantim

icrobialrespon

sesto

pathogensinmacroph

ages

andforregulatingthe

maturationof

antig

en-presentingdend

riticcells.Th

elatterm

aybe

akey

pathway

bywhich

vitamin

Dcontrols

Tlymph

ocyte(Tcell)

functio

n.How

ever,T

cells

also

exhibitd

irectrespon

sesto1,2

5-dihydroxyvitamin

D,

notablythed

evelo

pmento

fsup

pressorregulatoryTcells.

Innateand

adaptiv

eim

mun

ity

Vitamin

Disak

eyfactor

linking

innateandadaptiv

eim

mun

ity,and

both

ofthesefun

ctions

may

becomprom

isedun

der

cond

ition

sofvitamin

Dinsufficiency.

20 Evidence-Based Complementary and Alternative MedicineTa

ble2:Con

tinued.

Authors

Type

ofstu

dySubjects

Dosage

Results

Type

ofim

mun

ityinvolved

Mechanism

ofactio

n

Gup

taetal.;2016

Arand

omized

controltria

l

38adultswith

vitamin

Ddeficiencyandun

treated

pre-

orearly

stage

Ihypertensio

nwere

inclu

ded.

Participantsare

rand

omized

toeither

low-(40

0IUdaily)o

rhigh

-(40

00IU

daily)

dose

oralvitamin

D3for

6mon

ths.

Treatm

entw

ith40

00IU

ofvitamin

D3

decreasedintracellularC

D4+

ATPreleaseb

y95.5ng

/ml(interquartile

range,−219.5

to105.8).

Incontrast,

400I

Uof

vitamin

D3decreased

intracellularC

D4+

ATPreleaseb

y0.5n

g/ml

(interquartile

range,−69.2to

148.5).Ina

prop

ortio

nalodd

smod

el,high

-dosev

itamin

D3was

morelikely

than

low-dosev

itamin

D3

todecrease

CD4+

ATPrelease(od

dsratio

,3.43;95%

confi

denceinterval,1.0

6–1.11).

Adaptiv

eim

mun

ity:

cell-mediated

immun

ity

Treatm

entw

ithhigh

-dose

vitamin

D3redu

cesC

D4T

cellactiv

ation,

providing

directhu

man

datathat

vitamin

Dmay

influ

ence

cell-mediatedim

mun

ity(C

MI).Th

esefi

ndings

offer

amechanisticcorrelation

forthe

potentialinfl

uence

ofvitamin

Don

thec

ourse

ofim

mun

e-mediated

disorders.

Laaksietal.;2010

Aplacebo-

controlled

doub

le-blin

ded

study

164voluntaryyoun

gFinn

ishmen

(18–28

yearso

fage).

Thes

ubjectsw

ere

rand

omlyassig

nedto

theinterventiongrou

p,which

received

400I

U(10m

g)vitamin

D3d

aily,

orthec

ontro

lgroup

,which

received

placebo

for6

mon

ths.

Afterd

ailysupp

lementatio

n,them

eanserum

25(O

H)D

concentrations

(±SD

)were

71.6±22.9nm

ol/L

(𝑛=58)intheintervention

grou

pand51.3±15.5nm

ol/L

(𝑛=50)inthe

placebogrou

p(𝑝<.001).Th

enum

bero

fdays

ofabsencefrom

dutydu

etorespira

tory

tract

infectiondidno

tdiffer

betweengrou

ps.M

ean

numbero

fabsence

days

(±SD

)was2.2±3.2

days

intheinterventiongrou

pand3.0±4.0

days

inthep

lacebo

grou

p(𝑝<096).Th

erew

asan

effectd

uringthefi

rst6

weeks

ofthes

tudy,

with

amean(±SD

)of0.7±2.1absenced

aysin

theinterventiongrou

pand1.4±2.6absence

days

inthep

lacebo

grou

p(𝑝<060).

Innateim

mun

ity

Maggini

etal.;

2007

Review

Thev

itaminsA

,B6,B12,C,

D,and

E;folic

acid;

andthetrace

elem

entsiro

n,zinc,cop

per,and

selenium

workin

synergyto

supp

ortthe

protectiv

eactivities

oftheimmun

ecells.

Finally,allthesem

icronu

trients,with

the

exceptionof

vitamin

Candiro

n,aree

ssentia

lfora

ntibod

yprod

uctio

n.Overall,inadequate

intake

andsta

tuso

fthese

vitaminsa

ndtrace

elem

entsmay

lead

tosupp

ressed

immun

ity,

which

predisp

oses

onetoinfections

and

aggravates

malnu

trition

.

Innate,adaptive

immun

ityand

autoim

mun

ity

Vitamin

Dandespecially

itsbiologicallyactiv

emetabolite

1,25-

dihydroxycho

lecalciferol

(1,25(OH)2D3)

actas

powerful

immun

oregulators.Th

ediscoveryof

significant

quantitieso

fvitamin

Dreceptorsinmon

ocytes,

macroph

ages,and

thym

ustissues

uggests

aspecific

roleof

vitamin

Dandits

metabolitesintheimmun

esyste

m.M

ostcellsof

the

immun

esystem

except

Bcells

expressv

itamin

Dreceptors.

Evidence-Based Complementary and Alternative Medicine 21Ta

ble2:Con

tinued.

Authors

Type

ofstu

dySubjects

Dosage

Results

Type

ofim

mun

ityinvolved

Mechanism

ofactio

n

Martin

eauetal.;

2017

Syste

matic

review

and

meta-analysisof

individu

alparticipantd

ata

(IPD

)from

rand

omized

controlledtrials

Total11321

participants,aged0to

95years.

Benefit

was

greaterin

thoser

eceiving

daily

orweeklyvitamin

Dwith

outadd

ition

albo

lus

doses(NNT=20),and

thep

rotectivee

ffects

againstacuterespira

tory

tractinfectio

nin

this

grou

pweres

trongestin

thosew

ithprofou

ndvitamin

Ddeficiencyat

baselin

e(NNT=4).

Vitamin

Dsupp

lementatio

nredu

cedther

iskof

acuter

espiratory

tractinfectio

nam

ongall

participants(adjustedod

dsratio

0.88,95%

confi

denceinterval0.81to0.96;𝑝

for

heterogeneity<0.001).Insubgroup

analysis,

protectiv

eeffectsw

eres

eenin

thoser

eceiving

daily

orweeklyvitamin

Dwith

outadd

ition

albo

lusd

oses

(adjustedod

dsratio

0.81,0.72to

0.91)b

utno

tinthoser

eceiving

oneo

rmore

bolusd

oses

(adjustedod

dsratio

0.97,0.86to

1.10;𝑝forinteractio

n=0.05).Amon

gthose

receivingdaily

orweeklyvitamin

D;protective

effectsweres

tronger

inthosew

ithbaselin

e25-hydroxy

vitamin

Dlevels<25

nmol/L

(adjustedod

dsratio

0.30,0.17

to0.53)thanin

thosew

ithbaselin

e25-hydroxyvitamin

Dlevels≥25

nmol/L

(adjustedod

dsratio

0.75,

0.60

to0.95;𝑝

forinteractio

n=0.00

6).

Mayan

etal.;2015

Clinicaltrial

82adolescent

swim

mersfor

serum

25(O

H)D

andTR

EC(T

cellreceptor

excisio

ncircles)

concentrations;itw

asfoun

dthat55

had

vitamin

Dinsufficiency.

Fifty

-five

participants

(67%

)had

vitamin

Dinsufficiency

and

comprise

dan

interventio

nalstudy

grou

p,where

subjects

werer

ando

mized

toreceives

upplem

entatio

nof

either

vitamin

D3

(200

0IU/day)inliq

uid

drop

sora

placebo.

Subjectswho

were

vitamin

Dsufficientd

idno

treceive

any

supp

lementatio

nor

treatment.Ra

ndom

ized

supp

lementatio

nof

either

vitamin

D3or

placebowas

givenfor12

winterw

eeks.

TREC

concentrations

decreasedwith

the

participants’

age(𝑟=−0.346,𝑝=0.003),w

ithno

significantb

etween-gend

erdifference.

TREC

concentrations

didno

tmaterially

differ

amon

gsubjectswith

norm

al,insuffi

cient,or

deficient

vitamin

Dsta

tusa

ndweren

otaffected

byvitamin

Dsupp

lementatio

n.Nosig

nificant

correlations

werefou

ndbetweenTR

EClevels,

ortheirc

hanges

durin

gthes

tudy

perio

d,and

meanup

perrespiratory

infections

(URI)

severityor

duratio

n.

Adaptiv

eimmun

ity

Thea

utho

rsfoun

dno

significantcorrelation

betweenvitamin

DandTR

EClevels,

either

before

oraft

ersupp

lementatio

n,suggestin

gthattheimmun

omod

ulatory

effectsof

vitamin

Daren

otexerteddirectlyon

thethymus

gland.Indeed,severalother

mechanism

sbywhich

vitamin

Dmay

influ

ence

Tcell

functio

nhave

been

prop

osed,

inclu

ding

directendo

crine

effectson

Tcells

mediatedvia

syste

miccalcitriol,direct

intracrin

econ

versionof

25(O

H)D

tocalcitriolbyT

cells,dire

ctparacrinee

ffectso

fcalcitriolonTcells

follo

wing

conversio

nof

25(O

H)D

tocalcitriolbymon

ocytes

ordend

riticcells,and

indirect

effectson

antig

enpresentatio

nto

Tcells

mediatedvia

localized

antig

en-presenting

cells

affectedby

calcitriol.

22 Evidence-Based Complementary and Alternative Medicine

Table2:Con

tinued.

Authors

Type

ofstu

dySubjects

Dosage

Results

Type

ofim

mun

ityinvolved

Mechanism

ofactio

n

Schw

alfenb

erg;

2011

Review

Thisreview

looksa

tthe

criticalroleo

fvitamin

Din

improvingbarrierfun

ction,

prod

uctio

nof

antim

icrobialpeptides

inclu

ding

cathelicidin

andsomed

efensin

s,andim

mun

emod

ulation.

Thefun

ctionof

vitamin

Din

theinn

ate

immun

esystem

andin

thee

pithelialcellsof

the

oralcavity,lun

g,gastrointestinalsyste

m,

genitourinarysyste

m,skin,

andsurfa

ceof

the

eyeisd

iscussed.

Epith

elialbarrier

andinnate

immun

ity

Murdo

chetal.;

2012

Dou

ble-blind,

placebo-

controlled

trial

322healthyadults.

Participantswere

rand

omlyassig

nedto

receivea

ninitialdo

seof

200,000I

Uoralvitamin

D3,then

200,00

0IU1

mon

thlater,then

100,00

0IUmon

thly

(𝑛=161),orp

lacebo

administered

inan

identic

aldo

singregimen

(𝑛=161),for

atotalof

18mon

ths.

Them

eanbaselin

e25-OHDlevelof

participantswas

29(SD,9)n

g/mL.Vitamin

Dsupp

lementatio

nresultedin

anincrease

inserum

25-O

HDlevelsthatwas

maintainedat

greaterthan48

ng/m

Lthroug

hout

thes

tudy.

Therew

ere5

93up

perrespiratory

tract

infections

(URT

I)episo

desinthev

itamin

Dgrou

pand611inthep

lacebo

grou

p,with

nostatisticallysig

nificantd

ifferencesinthe

numbero

fURT

Isperp

articipant(mean,

3.7

perp

ersonin

thev

itamin

Dgrou

pand3.8per

person

inthep

lacebo

grou

p;ris

kratio

,0.97;

95%CI

,0.85–1.11),num

bero

fdayso

fmiss

edworkas

aresulto

fURT

Is(m

ean,

0.76

days

ineach

grou

p;ris

kratio

,1.03;95%CI

,0.81–1.3

0),

duratio

nof

symptom

sper

episo

de(m

ean,

12days

ineach

grou

p;ris

kratio

,0.96;95%CI

,0.73–1.25),orseverity

ofURT

Iepisodes.

Bartley;2010

Review

Vitamin

Disinvolved

inthep

rodu

ctionof

defensinsa

ndcathelicidin-antim

icrobial

peptides

thatprovidea

naturald

efense

against

potentialm

icrobiologicalpathogens.Vitamin

Dsupp

lementatio

nincreasesc

athelicidin

prod

uctio

n.Lo

wvitamin

Dlevelsare

associated

with

anincreasedincidenceo

fup

perrespiratory

tractinfectio

ns.

Innateim

mun

ity

Evidence-Based Complementary and Alternative Medicine 23

Table2:Con

tinued.

Authors

Type

ofstu

dySubjects

Dosage

Results

Type

ofim

mun

ityinvolved

Mechanism

ofactio

n

Jordee

tal.;2016

Rand

omized

controlledtrial

Five

hund

redandele

ven

subjectswith

prediabetes.

Participantsare

rand

omized

tovitamin

D3(20,00

0IUperw

eek)

versus

placeboforfi

veyears.Tw

ohu

ndredand

fifty-six

subjectsreceived

vitamin

Dand255

placebo.One

hund

red

andsix

teen

subjectsin

thev

itamin

Dand111in

thep

lacebo

grou

pcompleted

thefi

ve-year

study.

Meanbaselin

eserum

25-hydroxy

vitamin

D(25(OH)D

)levelwas

60nm

ol/.Eighteen

subjectsin

thev

itamin

Dgrou

pand34

subjects

inthep

lacebo

grou

prepo

rted

urinarytract

infections

(UTI)d

uringthes

tudy

(𝑝<0.02),

whereas

nosig

nificantd

ifferencesw

eres

eenfor

respira

tory

tractinfectio

ns(RTI).Th

eeffecton

UTI

was

mostp

rono

uncedin

males.Th

eeffect

ofvitamin

Don

UTI

was

unrelated

tobaselin

eserum

25(O

H)D

level.

Kamen

and

Tang

pricha;2010

Review

Theimpo

rtance

ofvitamin

Din

ther

egulation

ofcells

oftheimmun

esystem

hasg

ained

increasedappreciatio

nover

thep

astd

ecade

with

thed

iscoveryof

thev

itamin

Dreceptor

(VDR)

andkeyvitamin

Dmetabolizing

enzymes

expressedby

cells

oftheimmun

esyste

m.

Innateand

adaptiv

eimmun

ity

Theh

ormon

alform

ofvitamin

Dup

regu

lates

antim

icrobialpeptides,

namely

,cathelicidin,to

enhancec

learance

ofbacteriaatvario

usbarrier

sites

andin

immun

ecells.

Vitamin

Dmod

ulates

the

adaptiv

eimmun

esystem

bydirecteffectson

Tcell

activ

ationandon

the

phenotypea

ndfunctio

nof

antig

en-presentingcells

(APC

s),partic

ularlyof

DCs

.Thep

urpo

seof

this

manuscriptistoreview

the

molecular

andclinical

evidence

forv

itamin

Das

amod

ulator

oftheinn

atea

ndadaptiv

eimmun

esystem.

24 Evidence-Based Complementary and Alternative Medicine

Table2:Con

tinued.

Authors

Type

ofstu

dySubjects

Dosage

Results

Type

ofim

mun

ityinvolved

Mechanism

ofactio

n

Bolland

etal.;2017

Edito

rial

Authorsc

onsid

erthat

currentevidenced

oes

notsup

porttheu

seof

vitamin

Dsupp

lementatio

nto

preventd

isease,except

fortho

seathigh

riskof

osteom

alacia,currently

defin

edas

25-hydroxy

vitamin

Dlevelsles

sthan

25nm

ol/L.

Inabsoluteterm

s,thep

rimaryresultisa

redu

ctionfro

m42%to

40%in

thep

ropo

rtion

ofparticipantsexperie

ncingatleasto

neacute

respira

tory

tractinfectio

n.Itseem

sunlikely

thattheg

eneralpo

pulatio

nwou

ldconsider

a2%

absoluteris

kredu

ctionsufficient

justificatio

nto

take

supp

lements.

Furtherm

ore,

thed

efinitio

nof

acuter

espiratory

tract

infectionvarie

dbetweenstu

dies,con

sistin

gof

amixture

ofdiversec

onditio

nssuch

asacute

otitism

edia,laboratoryconfi

rmed

influ

enza,

self-repo

rted

colds,parent

repo

rted

coldso

rchestinfectio

ns,orradiographconfi

rmed

pneumon

ia.

Khaksho

uretal.;

2015

Cross-sectional

study

90child

renbelow5y

ears

ofages

ufferingfro

mrespira

tory

infections.

Intheg

roup

ofchild

renwith

respira

tory

disorders,9(42.9%

)exh

ibitedvitamin

Ddeficiency.Vitamin

Ddeficiencyshow

edno

meaning

fulstatistic

alrelationwith

acute

respira

tory

infections

(𝑝>0.05).

Itisassumed

thatthelack

ofsig

nificantd

ifferencesin

vitamin

Disdu

etothe

gesta

tionalage

andother

factorse

xceptthatvitamin

Ddeficiencyplaysc

rucial

rolesinrespira

tory

syste

minfections.

Zitte

rmannetal.;

2016

Review

Regardingacuter

espiratory

tractinfectio

n,RC

Tsindicateas

ignificantrisk

redu

ctionby

vitamin

Dsupp

lements[O

R=0.65;95%

confi

denceinterval(CI

)0.50–

0.85].Th

ereis

evidence

thatdaily

administratio

nismore

effectiv

ethanhigh

-doseb

olus

administratio

n[O

R=0.48

(95%

CI0.30–0

.77)

versus

OR=

0.87

(95%

CI0.67–1.14

)]andthatindividu

als

with

deficient

orinsufficient(30–50n

mol/l)

circulating25-hydroxy

vitamin

Dlevelsbenefit

most.

Innateand

adaptiv

eim

mun

ity

Evidence-Based Complementary and Alternative Medicine 25

activity. However, thymus activity, represented by higher Tcell receptor excision circles (TREC,markers of thymus activ-ity) levels, is not related to vitamin D concentrations or statusand is not affected by 2000 IU/d vitamin D supplementationin adolescent swimmers [66].

3.2.4. Vitamin D and Common Colds. Clinical trials demon-strate that 400 IU/d vitamin D supplementation is needed forthe prevention of respiratory infections [67, 68]. Vitamin Dsupplementation decreases the events related to respiratorytract infections. In particular, vitamin D is useful in preven-tion of these types of infections, assuming dosage of vitaminD ranging from 400 IU/day to 2000 IU/day [68]. Epidemio-logic studies have foundhigh vitaminD levels to be associatedwith lower risk of infections of the upper respiratory tract(colds). 4000 IE/day vitamin D supplementation is foundto significantly increase the probability of staying infectionfree during the study period. This finding further supportsthe notion that vitamin D status should be monitored inadult patients with frequent respiratory tract infections, andpatients with vitamin D deficiency must be supplemented[69].Themore vitamin D is reserved within the infants’ bod-ies, the more they will be immune to respiratory infections. Itis assumed that the lack of significant differences in vitaminD is due to the gestational age and other factors except thatvitamin D deficiency plays crucial roles in respiratory systeminfections [70]. Supplementation with vitamin D in childrenseems to be a strong ally in fighting the onset of respiratoryinfections. The combination of vaccines and vitamin Dsupplementation can significantly reduce the appearance ofURTIs and the use of antibiotics, with a consequent decreaseof global indicators of bacterial resistance [71]. In Mongolianchildren, who received milk fortified with 300 IU of vitaminD3, vitamin D supplementation significantly reduced therisk of acute respiratory infections (ARIs) in winter amongchildren with vitamin D deficiency [72]. Finally, 1200 IU/dvitamin D3 supplementation during the winter may reducethe incidence of influenza A and enhance innate immunityby upregulating antimicrobial peptides, especially in specificsubgroups of schoolchildren [73]. Weekly supplementationwith 10,000 IU of vitamin D3 is preventive for URTI in youngadults [74].

Vitamin D supplementation is safe and protected againstacute respiratory tract infection overall, but patients whoare very deficient in vitamin D and those not receivingbolus doses experienced the most benefit, as demonstratedvery recently in a meta-analysis that considered 25 eligiblerandomized controlled trials (total 11,321 participants, aged 0to 95 years) [75].

On the other hand, some evidence shows no significantcorrelation between vitamin D levels and lower respiratorytract infections in terms of the disease and its severity [76],despite a 50𝜇g vitamin D3 (2000 IU) daily supplementation[77]. The sub-sunburn sunbed treatment is effective intanning and increasing the 25(OH)D serum level, more sothan 1000 IU per day, but had no appreciable effect on colds[78]. In patients with mild to moderate asthma undergoingan inhaled corticosteroid dose reduction, the use of vitamin

D supplementation (100,000 IU load plus 4,000 IU/d) isnot supported for the purpose of reducing cold severityor frequency [79]. In addition, monthly administration of100,000 IU of vitamin D does not reduce the incidence orseverity of URTIs in healthy adults [80]. It is reasonableand safe to take approximately 1000 IU of vitamin D daily,as suggested by Zittermann et al., in order to optimizenonspecific immunity and prevent infection. It is importantto start supplementation in early autumn in order to ensurean adequate vitamin D level in winter [81].

In conclusion, vitamin D supplementation was safe and itmay protect against acute respiratory tract infections overall,although there are numerous studies that do not support thisindication and therefore it is necessary that further researchwill be conducted on the dosage of intake of vitamin Dand prevention/treatment of common cold. Baseline levelsof vitamin D, age, and dose of vitamin D need to be takenunder consideration in order to personalize therapy. Patientswho were very deficient in vitamin D and those not receivingbolus doses experienced the most benefit, and it is importantto start supplementation in early autumn in order to ensurean adequate vitamin D level in winter.

3.3. Vitamin C and Three Main Immune Interactive Clusters(Physical Barriers, Innate and Adaptive Immunity) Involvedduring an Episode of Common Colds. This research has beencarried out based on the following keywords: “vitamin D”OR “vitamin D supplementation” AND “immune response”AND “innate immunity” AND “adaptive immunity” AND“respiratory tract infections” AND “common cold” AND“immunodeficiency.”

Figure 1 shows the study selection process.Table 3 summarizes the studies presented in the narrative

review.

3.3.1. First Barrier: Physical Barrier. 1 study was focusedonly on the physical barriers [82] and the aim of this studywas to measure changes in the radical-scavenging activity ofhuman physical barriers in vivo due to supplementation withdifferent doses of vitamin C (100 or 180mg) and at differenttime points.The study shows that orally administered vitaminC can have a significant radical-scavenging effect on physicalbarriers.

3.3.2. Second Barrier: Cellular Natural Immunity. 5 studiesobserved an improvement in the innate immune function[83–87].

Specifically, Schertling et al., 1990 [84] used a highdose of ascorbic acid (5 g/die) and observed that additionaladministration of ascorbic acid and over a longer periodof time may be expected to provide a therapeutic effectin the presence of increased activity of the pulmonaryinflammatory cells (e.g., alveolarmacrophages, granulocytes)with bronchial asthma. Harper et al., 2002, have selected,as an outcome, the reduction in spontaneous generation ofsuperoxide and total antioxidant capacity observing reducedneutrophil generation of superoxide [85]. In the study of Duet al., 2003, two different doses (10 g/day or 1 g/day) have

26 Evidence-Based Complementary and Alternative Medicine

Table3:Stud

ieso

nvitamin

C,im

mun

ity,and

common

cold

presentedin

then

arrativ

ereview.

Authors

Type

ofstu

dySubjects

Dosage

Results

Type

ofim

mun

ityinvolved

Mechanism

ofactio

n

Hem

ilaetal.;

2010

Review

and

meta-analysis

11306

men,

wom

anand

child

ren

0.2g

daily

fora

single

dayor

fora

perio

d

Twenty-ninec

omparis

onse

xamined

thee

ffectof

prop

hylacticvitamin

Con

common

cold

duratio

n(9649episo

des).Inadultsthed

urationof

coldsw

asredu

cedby

8%(3%

to12%),andin

child

renby

13%

(6%

to21%).Th

eseverity

ofcoldsw

assig

nificantly

redu

cedin

thep

roph

ylaxistrials.

Seventrial

comparis

onse

xamined

thee

ffectof

therapeutic

vitamin

C(3249episo

des).N

oconsistentd

ifferences

from

thep

lacebo

grou

pweres

eenin

thed

urationor

severityof

colds.

Allim

mun

ity

Regu

laringestio

nof

vitamin

Chadno

effect

oncommon

cold

incidenceintheo

rdinary

popu

lation.

How

ever,ith

adam

odestb

utconsistenteffectin

redu

cing

thed

urationand

severityof

common

cold

symptom

s.In

trials

with

participantsexpo

sedto

shortp

eriods

ofextre

mep

hysic

alstr

ess(inclu

ding

maratho

nrunn

ersa

ndskiers)v

itamin

Chalved

the

common

cold

risk.

Maggini

etal.;

2012

Dou

ble-blind,

rand

omized,

placebo-controlled

pilotstudy

94patients

1000

mgvitamin

Cplus

10mgzinc

Rateof

defin

iterelieffrom

rhinorrhoeaw

assig

nificantly

high

erin

thea

ctivetreatmentg

roup

than

inthep

lacebo

grou

pover

the5

-day

assessment

perio

d(𝑝=0.03,C

oxprop

ortio

nalh

azardmod

el).

Allim

mun

ity

Inview

ofthefrequ

ency

ofthec

ommon

cold,

coup

ledwith

ther

elated

socialandecon

omic

costs

andthelim

itedtre

atmento

ptions,

supp

lementatio

nwith

vitamin

Candzinc

may

representaneffi

caciou

smeasure,w

ithag

ood

safetyprofi

le,to

helpam

elioratethe

symptom

sof

thisinfectious

virald

isease.

Penn

etal.;1991

Rand

omized

controlledtrial

Thirtyeld

erly

30100m

gfor2

8days

Percentage

ofcells

(mean±SD

)inperip

heralblood

Tcells:6.58±6.3(before)

69.1±9.7

(afte

r)𝑝=NS

T4cells:45.2±4.5(before)

50.3±8.8(afte

r)𝑝<0.05

T8cells:24.7±5.3(before)

19.7±7.6

(afte

r)𝑝<0.05

T4:T

8:1.92±0.49(before)

2.88±1.2(afte

r)𝑝<0.01

Proliferativeresponseo

flym

phocytestothem

itogen

PHA,

atconcentra

tions

of1/2

00and1/4

00,m

easured

indecays

perm

inute(dpm)

PHA1/2

00:9562±11(before)

15,690±11,577

(afte

r)𝑝<0.02

PHA1/4

00:3355±3662(before)

12,863±11,872(after)

𝑝<0.01.

Innateim

mun

ity

Improvem

entinsomea

spectsof

cell-mediated

immun

efun

ction.

Inparticular

then

umbero

fTcells,T

4cells,and

theT

4:T8

ratio

increased

significantly.Th

erespo

nsivenesso

flymph

ocytes

tothem

itogenPH

Aalso

increasedsig

nificantly

andindepend

ently

ofthec

oncentratio

nsof

them

itogenused.Th

eresults

suggestthatsup

plem

entatio

nwith

physiologicald

oses

ofvitaminsA

,C,and

Ein

combinatio

ncanim

provec

ell-m

ediated

immun

ity.

Evidence-Based Complementary and Alternative Medicine 27

Table3:Con

tinued.

Authors

Type

ofstu

dySubjects

Dosage

Results

Type

ofim

mun

ityinvolved

Mechanism

ofactio

n

Schertlin

get

al.;1990

Rand

omized

crossovertria

l24

men

and

wom

en5g

/diefor3

5days

Thed

ifference

betweenthetwogrou

ps(placebo

perio

d,ascorbicacidperio

d)isstatisticallysig

nificant

forthe

peak

heights(𝑝∼0.03).Th

echang

esin

the

alveolar

macroph

agea

ctivity

measuredon

theb

asis

oftheformationof

ROM

dono

tcorrelateor

only

weaklycorrela

tewith

thec

hanges

inpeak

flowvalues

andsymptom

scores

(|𝑟|<0.04in

allcases).

Innateim

mun

ity

Inthep

resenceo

fincreased

activ

ityof

the

pulm

onaryinflammatorycells

(e.g.,alveolar

macroph

ages,granu

locytes)with

bron

chial

asthma,thee

quilibrium

betweenoxidativea

ndantio

xidativ

ecapacity

inthelun

gsmay

bedisplacedin

favoro

fthe

oxidativep

rocess,

such

thatadditio

naladm

inistratio

nof

ascorbic

acid

atah

ighdo

se(5g/day)

andover

alon

ger

perio

dof

timem

aybe

expected

toprovidea

therapeutic

effect.

Lauere

tal.;

2013

placebo-controlled

trial

33healthy

volunteerswith

skin

typesII

andIII

accordingto

theF

itzpatrick

classificatio

n

100or

180m

gfor

4weeks

Carotenoid

valuesbeforeandaft

er4we

ekso

fvita

min

Csupplem

entatio

nmeasuredon

theinn

erforearm

and

thep

alm

(Δ=10–4AU

)Vitamin

Cdo

se100m

gTo

talcarotenoids

Palm

:1.5(𝑝

=NS)

Forearm:0.5(𝑝

=NS)

Lycopene

Palm

:0.3(𝑝

=NS)

Forearm:−

0.1(𝑝<0.05)

Vitamin

Cdo

se180m

gTo

talcarotenoids

Palm

:0.6(𝑝

=NS)

Forearm:0.8(𝑝<0.05)

Lycopene

Palm

:−0.1(𝑝<0.05)

Forearm:−

0.1(𝑝=NS).

Skin

Vitamin

Cincreasesthe

antio

xidativ

eactivity

ofthes

kin,

andthereisa

nincrease

incutaneou

scarotenoids

thou

ghitwas

not

significant.Th

eincreaseincutaneou

santio

xidativ

eactivity

occurred

fastaft

ersupp

lementatio

nandwas

enhanced

with

high

erdo

seso

fvitamin

C.Th

estudy

show

sthatd

ietary

supp

lementatio

nwith

vitamin

Ccanhasa

significanteffecton

skin

radicalscaveng

ing.

Sasazukietal.;

2006

Ado

uble-blin

d,5-year

rand

omized

controlledtrial

244men

and

wom

en

50mg(lo

w-doseg

roup

)or

500m

g(high-do

segrou

p)

Whenthec

ommon

cold

was

defin

edas

occurring

threeo

rmoretim

esdu

ringthes

urveyperio

d,an

approxim

ately

70%

redu

ctionin

relativer

isks(RR

)was

observed

(0.34,95%

CI:0.12

–0.97,𝑝=0.04).Th

ecorrespo

ndingvaluefor

thec

ommon

cold

defin

edas

occurringfour

ormoretim

eswas

0.28

(95%

CI:

0.06–1.28,𝑝=0.10),forw

hich

only10

eventswere

observed.Th

eresultsweree

ssentia

llythes

ameinthe

intention-to-tr

eatg

roup

s.

Allim

mun

ity

Vitamin

Csupp

lementatio

nsig

nificantly

redu

cesthe

frequ

ency

ofthec

ommon

cold

but

hadno

apparent

effecto

nthed

urationor

severityof

thec

ommon

cold.

28 Evidence-Based Complementary and Alternative Medicine

Table3:Con

tinued.

Authors

Type

ofstu

dySubjects

Dosage

Results

Type

ofim

mun

ityinvolved

Mechanism

ofactio

n

Harpere

tal.;

2002

Case

serie

sstudy

12men

and

wom

en1g/day

for10days

Redu

ctionin

spon

taneou

sgenerationof

superoxide

(pretre

atment8.41±0.7nm

ol/106cells;

posttreatment5.64±0.6nm

ol/106;𝑝<0.05).

Totalantioxidant

capacityincreasedsig

nificantly

follo

wingtre

atmentw

ithvitamin

C(555.4±142

versus668.6±186𝜇mol/ltro

loxequivalent;

𝑝=0.01)a

sdid

vitamin

Cconcentration(56.5±27

versus137.7±64𝜇mol/l;𝑝=0.002).

Innateim

mun

ity

Thetreatmento

fpatientsw

ithantio

xidants

redu

cedneutroph

ilgeneratio

nof

superoxide

andsuggestedthatantio

xidantsm

ayhave

anim

portantrolea

sadjuvanttherapy.

Nieman

etal.;

2002

Rand

omized

study

28men

and

wom

en1500

mg/diefor

7days

Plasmaa

scorbica

cidwas

markedlyhigh

erin

the

vitamin

Ccomparedwith

placebogrou

ppreracea

ndrose

mores

trong

lyin

thev

itamin

Cgrou

pdu

ringthe

race

(postrace:3.21±0.29and1.28±0.12𝜇g/100𝜇

l,resp.,𝑝<0.001).Nosig

nificantg

roup

orinteraction

effectswerem

easuredforlipid

hydrop

eroxide,

F2-isop

rostane,im

mun

ecell

coun

ts,plasma

interle

ukin

(IL)-6,IL-10,IL-1-r

eceptora

ntagon

ist,or

IL-8

concentrations,orm

itogen-stimulated

lymph

ocytep

roliferationandIL-2

andIFN-𝛾

prod

uctio

n.

Innateim

mun

ity

Vitamin

Csupp

lementatio

ndo

esno

tserve

asa

coun

term

easure

topo

straceo

xidativ

eand

immun

echang

esin

carboh

ydratefed

ultram

aratho

nrunn

ers.Statisticalcorrelations

suggestthato

xidativ

estre

sshadlittle

influ

ence

ontheimmun

echanges

thattake

placed

uring

oraft

erac

ompetitiveu

ltram

aratho

nrace.

Daviso

nand

Gleeson

.;2006

Sing

leblind,

rand

omized

crossoverd

esign

9men

1000

mgfor2

weeks

Maineffects𝑝values

(trial;tim

e;interaction)

ACTH

(adrenocorticotroph

icho

rmon

e)(pgml−1)

0.303;0.002;0.276

IL-6

(pgml−1)0

.818;0.000;0.795

Cortisol(nM)0

.097;0.004

;0.039.

Therew

asas

ignificant

trial-tim

einteractio

neffectfor

plasmac

ortisol

concentration(𝑝=0.039).

Therew

asas

ignificantly

lower

poste

xercise

neutroph

ilia(𝑝<0.014)intheV

Ctrial,

comparedwith

theP

LAtrial.

Innateim

mun

ity

Vitamin

C(V

C)was

effectiv

eatincreasing

antio

xidant

defence,mod

ulatingthe

leuk

ocytosisandneutroph

iliar

espo

nses

and

possiblyhadsomes

malleffectso

nthep

lasm

acortiso

lrespo

nse.

Thissuggeststhatsupp

lementatio

nwith

VCalon

efor

aperiodof

upto

2we

eksp

rovides

very

limitedor

noprotectio

nagainstthe

depressio

nof

neutroph

ilfunctio

nwhich

istypically

observed

after

prolon

gedexercise.

Evidence-Based Complementary and Alternative Medicine 29

Table3:Con

tinued.

Authors

Type

ofstu

dySubjects

Dosage

Results

Type

ofim

mun

ityinvolved

Mechanism

ofactio

n

Duetal.;2003

Rand

omized

controlledstu

dy84

men

and

wom

en

Treatm

entg

roup

:vitC

(10g

/day)w

asgiven

intra

veno

uslyfor5

days

controlgroup

:vitC

(1g/day)

was

given

intra

veno

uslyfor5

days

Ther

atioso

fCD4/CD8andCD4po

sitivec

ellswere

decreased,especiallyin

severe

acutep

ancreatitis

(SAP)

patie

nts(𝑝<0.05.C

D4/CD8,𝑝=0.041;C

D4,

𝑝=0.019).Afte

rtreatment,thea

verage

valueo

fconcentrationof

plasmav

itamin

C(P-VC)

was

significantly

high

erandthev

alueso

fSIL-2R,

TNF-𝛼,

IL-6,and

IL-8

weres

ignificantly

lower

inthe

treatmentg

roup

than

inthec

ontro

lgroup

(𝑝<0.05P-VC

,𝑝=0.045;SIL-2R,𝑝=0.012;

TNF-𝛼,𝑝=0.030;IL-6,𝑝=0.015;and

IL-8,

𝑝=0.043).

Innateim

mun

ity

High-do

sevitamin

Chastherapeuticeffi

cacy

onacutep

ancreatitis.

Com

paredwith

the

norm

algrou

p,CD3andCD4po

sitivec

ellsin

acutep

ancreatitis(A

P)patie

ntsw

ere

significantly

decreased.Th

epotentia

lmechanism

sinclude

prom

otionof

antio

xidizing

abilityof

APpatie

nts,blocking

oflip

idperoxidatio

nin

thep

lasm

a,and

improvem

ento

fcellularimmun

efun

ction.

Dun

stanetal.;

2007

Arand

omized

controlledtrial

54allergic

adults

1500

mg/dayfor4

weeks

Antioxidant

supp

lementatio

nresultedin

significant

increasesinserum

levelsof

vitamin

C,vitamin

E,𝛽-carotene,andselenium

levels,

comparedwith

the

placebogrou

p(𝑝<0.001).Th

erew

asno

change

inserum

antio

xidativ

ecapacity

(AC)

,plasm

aF2-isop

rostanes,exh

aled

nitricoxide(eN

O),or

immun

erespo

nses

follo

wingsupp

lementatio

nwith

antio

xidantsc

omparedwith

placebo.

Acqu

iredim

mun

ity

Alth

ough

thed

ietary

supp

lementachieved

changesinantio

xidant

levels,

itdidno

tresult

inanysig

nificantchanges

inestablish

edim

mun

erespo

nses

over

thes

tudy

perio

d.

Hun

tere

tal.;

2012

Rand

omized

crossoverstudy

32older

individu

als

362.4m

gfor4

weeks

Nochangestoinnateim

mun

efun

ction(natural

killerc

ellactivity,phagocytosis

)orinfl

ammation

markers(high-sensitivityC-

reactiv

eprotein,

homocysteine)wered

etected.

𝑝=0.03(significantvalue

was

defin

edap

rioriat

𝑝<0.001).

Innateim

mun

ity

Con

sumptionof

gold

kiwifruitenh

ancedthe

concentrations

ofseverald

ietary

plasma

analytes,w

hich

may

contrib

utetoredu

ced

duratio

nandseverityof

selected

URT

I(up

per

respira

tory

tractinfectio

ns)sym

ptom

s,off

eringan

oveltoolforreducingtheb

urdenof

URT

Iinolderind

ividuals.

30 Evidence-Based Complementary and Alternative MedicineTa

ble3:Con

tinued.

Authors

Type

ofstu

dySubjects

Dosage

Results

Type

ofim

mun

ityinvolved

Mechanism

ofactio

n

Vojdanietal.;

2000

Rand

omized

clinical

trial

20men

and

wom

en500,1000,or5

000m

gfor2

weeks

Intra

cellu

larlevels

ofascorbicacid

inhu

man

leukocytes

(𝜇g/5×106cells)

Dosage5

00mg:

(mean±SD

)Day

0:6.8±2.1

Day

1:9.1±1.1𝑝=0.03(𝑝

from

day0to

day1)

Day

7:10±1.4𝑝=0.01(𝑝

from

day1today7)

Day

15:10.1±1.2𝑝=0.01(𝑝

from

day7to

day15)

Day

21:7.2±1.7𝑝=0.18(𝑝

from

day15

today21)

Dosage1000m

g:(m

ean±SD

)Day

0:7.4±2.4

Day

1:10±2.6𝑝=0.01(𝑝

from

day0to

day1)

Day

7:10.3±2.7𝑝=0.01(𝑝

from

day1today7)

Day

15:10.7±2.8𝑝=0.01(𝑝

from

day7to

day15)

Day

21:7.3±2.3𝑝=0.26(𝑝

from

day15

today21)

Dosage5

000m

g:(m

ean±SD

)Day

0:7±2.3

Day

1:9.1±1.8𝑝=0.01(𝑝

from

day0to

day1)

Day

7:9.2±1.7𝑝=0.03(𝑝

from

day1today7)

Day

15:9.5±1.9𝑝=0.01(𝑝

from

day7to

day15)

Day

21:7±2.6𝑝=0.91(𝑝

from

day15

today21)

NKcellcytotoxica

ctivity

(LU)

Dosage5

00mg:

(mean±SD

)Day

0:35.6±27.6

Day

1:55.8±18.8𝑝=0.07(𝑝

from

day0to

day1)

Day

7:50.6±12.8𝑝=0.19(𝑝

from

day1today7)

Day

15:52.4±24.4𝑝=0.05(𝑝

from

day7to

day15)

Day

21:39.6±26.4𝑝=0.01(𝑝

from

day1

5today2

1)Dosage1000m

g:(m

ean±SD

)Day

0:34.2±22.5

Day

1:72.6±39.12𝑝=0.04(𝑝

from

day0to

day1)

Day

7:82±46.4𝑝=0.04(𝑝

from

day1today7)

Day

15:77.6±36.4𝑝=0.04(𝑝

from

day7to

day15)

Day

21:43.2±29.6𝑝=0.17(𝑝

from

day1

5today2

1)Dosage5

000m

g:(m

ean±SD

)Day

0:33.4±28.8

Day

1:67.4±39𝑝=0.19(𝑝

from

day0to

day1)

Day

7:56.6±29.5𝑝=0.21(𝑝

from

day1today7)

Day

15:58.8±26.2𝑝=0.24(𝑝

from

day7to

day15)

Day

21:35±24.9𝑝=0.60(𝑝

from

day15

today21).

Innateim

mun

ity

Wec

onclu

dedthatascorbicacid

inan

antio

xidant

anddo

sesu

pto

5000

mgneith

erindu

cemutageniclesio

nno

rhaven

egative

effectson

NKcellactiv

ity.

McC

omseyet

al.;2003

Pilottria

ls8men

and

wom

en1000

mg/diefor

24weeks𝐶𝐷

4+cellcoun

t(cell/mm

3 )(m

ean±SD

)Stud

yentry:627±316

Week24:605±460(𝑝=0.49).

Innateim

mun

ityTh

ereisa

ratio

nalefortestin

gof

antio

xidant

butthere

isno

statisticalsig

nificance.

Evidence-Based Complementary and Alternative Medicine 31

been used in patients with pancreatitis and have demon-strated therapeutic efficacy [86]. The potential mechanismsinclude promotion of antioxidizing ability of pancreatitispatients, blocking of lipid peroxidation in the plasma, andimprovement in cellular immune function. Vojdani et al.,2000, using three different doses of ascorbic acid (500, 1000,or 5000mg), did not observe adverse effects on the activity ofNK cells even at high doses (5000mg) [87]. In four studiesan improvement in the innate immune function was notobserved [88–91]. Nieman et al., 2002, used a dose of 1500mgand focused on immune changes after an ultramarathon,showing that supplementation of vitamin C does not serve asa countermeasure to postoxidative race and immune changesin carbohydrate fed ultramarathon runners [88]. Davison andGleeson [89] used a dose of 1000mg, and the aim of studywas to determine the effect of 2 weeks of supplementationwith vitamin C on cortisol, adrenocorticotrophic hormone,interleukin-6, oxidative stress, and neutrophil responses toa single bout of endurance exercise. The authors concludedthat supplementation with vitamin C for a maximum periodof two weeks provides very limited or no protection againstdepression neutrophil function that is typically seen after pro-longed exercise. The study of Hunter et al., 2012, [90] aimedto assess whether regular consumption of gold kiwifruitreduces upper respiratory tract infections (URTI) symptomsin older people and determined the effect it has on plasmaantioxidants and markers of oxidative stress, inflammation,and immune function. The results showed that no changesto innate immune function (natural killer cell activity,phagocytosis) or inflammation markers (high-sensitivity C-reactive protein, homocysteine) were detected. The resultsof the pilot study of McComsey et al., 2003, conducted inHIV-infected subjects with lipoatrophy demonstrated thatantioxidant supplementation did not change significantlyimmunity [91].

3.3.3. Third Barrier: Adaptive Immunity. Only one study inallergic adults was focused on the acquired immunity [92]and used a dose of 1500mg; the aim was to determine theeffects of dietary antioxidants on allergen-specific immuneresponses in sensitized individuals. The study found thatantioxidant supplementation resulted in significant increasesin serum levels of vitamin C, vitamin E, 𝛽-carotene, andselenium levels, compared with the placebo group, buthere there was no change in serum antioxidative capacity(AC), plasma F2-isoprostanes, exhaled nitric oxide (eNO), orimmune responses following supplementation with antioxi-dants compared with placebo.

Penn et al., 1991, have used a dose of 100mg by observingan improvement in the immune function cell-mediatedimmunity, in particular T lymphocyte [83].

3.3.4. Vitamin C and Common Colds. The Cochrane reviewby Hemila et al., 2011, encompassing twenty-nine trials with11,306 research participants, concluded that regular ingestionof vitamin C had no effect on common cold incidence inthe ordinary population [32]. However, it had a modest butconsistent effect in reducing the duration and severity of

common cold symptoms: in adults the duration of colds wasreduced by 8% (3% to 12%) and in children by 14% (7% to21%); moreover, in children, 1 to 2 g/day vitamin C shortenedcolds by 18%. Maggini et al., 2012, used a dosage of 1000mgplus 10mg zinc and showed that supplementation withvitamin C and zinc may represent an efficacious measure,with a good safety profile, to help ameliorate the symptomsof this infectious viral disease [54].

A particular category of subjects that may need vitaminC supplements is athletes who engage in heavy physicalactivity, as these athletes’ vitamin C status may be depleted.A review demonstrated that in trials with participantsexposed to short periods of extreme physical stress (includingmarathon runners and skiers), supplementationwith vitaminC (0.6–1.0 g/day) halved the common cold risk [93]; theresults of this review suggest that vitamin C supplementationmay be beneficial for some of the subjects doing heavyexercise who have problems with frequent upper respiratoryinfections. An important point to consider is that overdosingvitamin Cmight be negative for immune defense as it inhibitsoxidative processes that are needed for first line defenseagainst bacteria or viruses [94–96].

In conclusion, regular supplementation (1 to 2 g/day) hasshown that vitamin C may reduce the duration (in adults by8%, in children by 14%) and the severity of CC. Therefore,given the low cost and safety, it may be also worthwhile forcommon cold patients to test on an individual basis whethertherapeutic vitamin C is beneficial for them, considering thatunder certain conditions vitamin C can act as a prooxidant,potentially contributing to oxidative damage.

3.4. Echinacea and Three Main Immune Interactive Clusters(Physical Barriers, Innate and Adaptive Immunity) Involvedduring an Episode of Common Colds. This research hasbeen carried out based on the following keywords: “Echi-nacea” AND “immune response” OR “innate immunity” OR“adaptive immunity” OR “respiratory tract infections” OR“common cold” OR “immunodeficiency.”

3.4.1. First Barrier: Physical Barrier. Echinacea extracts havethe immunomodulatory potency to promote both pheno-typic and functional maturation of murine dendritic cellsvia modulating the activation of JNK, p38-MAPK, and NF-𝜅B pathways [97]. A similar effect has been demonstrated inhuman dendritic cells [98].

3.4.2. Second Barrier: Cellular Natural Immunity. Echinaceasignificantly normalized the restraint stress-induced reduc-tion in splenocyte proliferation and splenic natural killer(NK) cell activity in rats [99]. E. purpurea extract reducedthe risk of respiratory complications by preventing virus-induced bacterial adhesion because it significantly reducedthe expression of ICAM-1, fibronectin, and platelet activatingfactor receptor (PAFr) and consequently the adhesion of bothbacterial strains [100]. E. purpurea extract reduced the risk ofrespiratory complications through the inhibition of inflam-mation superstimulation (cytokine storms) by suppressingthe expression of NFkB and possibly TLR-4 [100]. Moreover,

32 Evidence-Based Complementary and Alternative Medicine

in animal models, Echinacea restored serum cytokine levels,including interleukin-6 (IL-6), interleukin-10 (IL-10), andinterleukin-17 (IL-17), as well as the mRNA expressions ofthese cytokines in the spleen [99]. This immunomodulatoryeffect of Echinacea has also been confirmed in a pilot studyin healthy subjects considering the expression levels of thecytokines IL-2, IL-8, IL-6, and TNF- alfa in lymphomono-cytes and in plasma samples measuring the mRNA andprotein levels [101].

3.4.3.Third Barrier: Adaptive Immunity. Echinacea treatmentsignificantly increased the percentages of CD4+ and CD8+T lymphocytes in the blood of rats [99]. Moreover, water-soluble extract from Echinacea purpurea (L.) Moench hasdose-related adjuvant effects on human T cell cytokineresponses characterized by enhancing and suppressive effectsthat are regulated by T cell density [102]. The mechanismof action involved modulatory effects indicating a possiblerole for water-soluble extract from Echinacea purpurea (L.)Moench (EchNWA) in enhanced Ca2+ mobilization and Tcell activation. The authors underline that only the polysac-charide fraction was responsible for the immune modulatoryeffects described.

3.4.4. Echinacea and Common Colds. A double-blind, ran-domized, placebo-controlled trial demonstrated that thecombination of Echinacea purpurea, zinc, selenium, and vita-min C may alleviate exacerbation symptoms in 108 chronic-obstructive pulmonary disease (COPD) patients with acuteupper respiratory tract infections (URTI) [45]. Echinaceaalso seems to have the same synergistic effect in combina-tion with Justicia adhatoda and Eleutherococcus senticosus,as demonstrated in a parallel-group, randomized, double-blinded, placebo-controlled trial, in which this combinationof extracts exerted significant antitussive effects in acuteupper respiratory tract infections (URI) [103].

Regarding RCT with Echinacea supplementation alone,various studies demonstrated that use of this plant maybe a complementary treatment of respiratory tract infec-tions. In a randomized, double-blind, placebo-controlledtrial, Echinacea reduced the total number of cold episodes,cumulated episode days within the group, and pain-killermedicated episodes; inhibited virally confirmed colds; andespecially prevented enveloped virus infections. It showedmaximal effects on recurrent infections, and preventiveeffects increased with therapy compliance and adherence tothe protocol [104]. The authors suggest a prophylactic intakeof E. purpurea over 4 months to provide a positive riskto benefit ratio [104]. In 2012, a study demonstrated that ahighly standardized extract from roots of Echinacea angus-tifolia with a specific phytochemical profile (presence of thecomplex polysaccharide IDN5405, the phenylethanoid echi-nacoside, and substantial lack of alkamides) could enhancethe immune response subsequent to the influenza vaccination[105]. Another randomized, double-blind, double-dummy,multicenter, controlled clinical trial compared a new Echi-nacea formulation with a neuraminidase inhibitor, the goldstandard treatment for influenza, and demonstrated the same

effect [106]. The same authors explain other possible benefitsof this natural treatment, such as lack of induction of drugresistance and complications [106]. A recent meta-analysis ofrandomized controlled trials indicated that Echinacea lowersthe risk of recurrences and development of complicationsof respiratory tract infection, through antiviral and anti-inflammatory effects and the modulation of immune system[107]. However, in 2014 a Cochrane review on Echinacea forpreventing and treating the common cold was published,demonstrating that results of individual prophylaxis trialsconsistently show positive (if nonsignificant) trends [33].

In conclusion, the use of this plant represents a comple-mentary treatment of respiratory tract infections. Prophylac-tic treatment with Echinacea extracts (2400mg/day for pre-vention and 4000mg/day during acute stages of colds) over 4months appeared to be beneficial for preventing/treating CC.

4. Conclusion

In European populations, adults have between 2 and 5 infec-tions annually and children typically present 6 to 12 “colds”per year, and rates of symptomatic infections increase in theelderly [2]. Maintaining the immune defense system within anormal healthy state lowers the incidence of infection and/orlessens the severity of symptoms and/or shortens the durationof common colds.The immune system is an intricate networkof specialized tissues, organs, cells, and chemicals protectingthe host from infectious agents and other noxious insults.Although these defensemechanisms against invaders are verycomplex, they can be described as being organized in threemain interactive clusters: physical barriers, and innate andadaptive immunity [9, 10]. The intakes of some nutrients andbotanicals can significantly influence several components ofimmunity [26]. There are three nutrients that have specificEFSA scientific opinion on the substantiation of health claimsrelated to vitamin D [27], vitamin C [28], zinc [29], andnormal function of the immune system. Moreover, there isEFSA scientific opinion on the substantiation of health claimsrelated to zinc [30] and to vitamin C [31] and maintenanceof normal physical barriers, that is, the first immune systembarriers. Finally, for vitamin C [32] and Echinacea [33], thereare Cochrane reviews regarding the use of these two nutrientsfor preventing and treating the common cold.

Therefore, vitamin D, vitamin C, zinc, and Echinaceahave pivotal roles of three main immunoreactive clusters(physical barriers, innate and adaptive immunity) in termsof prevention and treatment (shortening the duration and/orlessening the severity of symptoms) of common colds. Thepresent narrative review demonstrated that current evidenceof efficacy for zinc, vitamins D and C, and Echinacea is quitestrong that CC patients may be encouraged to try them forpreventing/treating their colds.

Regarding vitamin C, regular supplementation (1 to2 g/day) has shown that vitamin C may reduce the duration(in adults by 8%, in children by 14%) and the severity of CC.

Considering zinc, supplementation may shorten theduration of colds by approximately 33%. CC patients may beinstructed to try zinc within 24 hours of onset of symptoms.

Evidence-Based Complementary and Alternative Medicine 33

Regarding vitamin D, the supplementation protectedagainst CC overall. Baseline levels and age need to beconsidered. Patients who were deficient in vitamin D andthose not receiving bolus doses experienced the most benefit.

As for Echinacea, the use of this plant represents acomplementary treatment of respiratory tract infections.Prophylactic treatment with Echinacea extracts (2400mg/dayfor prevention and 4000mg/day during acute stages ofcolds) over 4 months appeared to be beneficial for prevent-ing/treating CC.

Conflicts of Interest

The authors declare no conflicts of interest regarding thepublication of this article.

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