Wang et al.

Nutrition Journal (2019) 18:80

https://doi.org/10.1186/s12937-019-0507-6

RESEARCH Open Access

Association between micronutrient

deficiency and acute respiratory infections
in healthy adults: a systematic review of
observational studies
Min Xian Wang, Jiayun Koh and Junxiong Pang*

Abstract
Background: Acute respiratory infections (ARI), including the common cold causes significant morbidity and
economical losses globally. Micronutrient deficiency may increase ARI incidence risk and its associated duration and
severity among healthy adults, but evidence are inconclusive. This study aims to systematically review all
observations on the association between single micronutrient deficiency and ARI incidence, duration and severity in
healthy adults.
Methods: Systematic literature searches were conducted in PubMed, Cochrane Library, Embase and Scopus
databases. Eligible studies were assessed for the reporting and methodological quality. Adjusted summary statistics
with their relevant 95% confidence intervals or interquartile ranges were extracted for the outcomes of interest.
Results: The literature search identified 423 unique studies. Of which, only eight studies were eligible and included
in the final review. Only vitamin D deficiency (VDD) was observed among these eight studies. There were no
eligible studies that focused on the association between other single micronutrient deficiency and ARI. The review
found mixed observations on ARI incidence, and a lack of evidence on its associated severity to conclude the
association between VDD and these outcomes. However, existing evidence consistently suggested that VDD is likely to
lead to longer ARI duration (median duration in days: deficient group, 4 to 13; non-deficient groups, 2 to 8).
Conclusion: This review found that VDD may be associated to longer ARI duration, but its effect on ARI incidence and
its associated severity among healthy adults remains inconclusive. This review also highlighted the lack of a consistent
regional and/or global definition for micronutrient sufficiency, and that future studies should explore and conclude the
association between other micronutrient deficiency and ARIs in healthy adults before considering supplementation for
ARI prevention and management.
Keywords: Micronutrients, Deficiency, Respiratory infections, Adults, Vitamin D

Introduction people were estimated to suffer from micronutrient defi-

Beneficial effects of micronutrients on the immune sys- ciency globally [4, 5]. Deficiencies commonly exist for
tem have long been established and well documented in zinc, iron, iodine and vitamins A, C and E, and are
many studies [1–3]. Micronutrients work to maintain prevalent in pregnant women and children due to higher
and strengthen one’s immune system through their ac- physiological demands [4–6]. Populations from develop-
tion on epithelial barriers, cellular immunity and anti- ing countries and the aged populations are also prone to
body production [1, 4]. However, approximately 2 billion micronutrient deficiency due to undernutrition, or a
lower dietary micronutrient density coupled with low
* Correspondence: [email protected]
use of dietary supplements [5, 7–9].
Centre for Infectious Disease Epidemiology and Research, Saw Swee Hock Micronutrients deficiencies are associated to varied ad-
School of Public Health, National University of Singapore, 12 Science Drive 2, verse health outcomes, including a weakened immune
Singapore 117549, Republic of Singapore

© The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
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Wang et al. Nutrition Journal (2019) 18:80 Page 2 of 12

system leading to higher risk for infections [1]. In the 1) Types of studies: Observational studies which
vulnerable population, the need of sufficient micronutri- included a comparator group in the study design i.e.
ents for proper immune function is evident. A cross- case-control, cross-sectional and cohort study de-
sectional study in elderly Ecuadorian population showed signs, and were reported in English.
that deficiency in folic acid, zinc, or vitamins C, D, B-6 2) Type of participants: Healthy subjects without
or B-12 was associated to recent episodes of the com- chronic conditions or comorbidities, or including
mon cold or pneumonia [10]. Lower zinc status was as- some subjects with chronic conditions with the
sociated with increased susceptibility to infectious diseases statistically adjusted for in analyses i.e. a
diseases such as malaria, diarrhea and acute lower re- population with solely healthy or healthy and
spiratory infection in children and pregnant women [11]. diseased subjects (mixed health status); a mean age
Indeed, decreased acute respiratory infection (ARI) epi- of 18–65 years old. Subjects may be infected with a
sodes and attenuation of its associated duration and se- naturally-acquired ARI or community-acquired
verity have been observed when children were pneumonia (CAP).
supplemented with zinc or vitamins E or A [4]. How- 3) Type of exposure: Deficiency in a single
ever, similar benefits on ARIs were absent when zinc or micronutrient of interest, including minerals
vitamins D or C supplements were given to a healthy (copper, iron, magnesium, selenium, zinc) and
population [2, 12] Nonetheless, a mild micronutrient de- vitamins (Vitamins A, B, D, E and K), compared to
ficiency can already cause negative effects on a normal a group without deficiency in the same
adult’s immune system [13]. micronutrient.
Despite the high economic burden for societies and 4) Types of outcome measures: Reported episodes,
impaired quality of life caused by ARIs, especially the duration (in days) and/or severity scores of ARI
common cold, in a healthy adult population [14, 15], no (primary outcome) or CAP episodes (secondary
systematic review has ever assessed the effects of micro- outcome).
nutrient deficiency on ARI, specifically the common cold
in this population. Thus, this review aims to systematic- On hindsight, we also allowed the inclusion of studies
ally search and summarise observations on the associ- which utilised a population with mixed health status,
ation between any single micronutrient deficiency and provided the outcomes reported adjusted for the in-
ARI incidence, duration and severity in healthy adults. cluded diseases. The micronutrients of interest in this
We hypothesise that deficiency in any single micronu- review include minerals (copper, iron, magnesium, selen-
trient is likely to increase the risk for common ARI epi- ium, zinc) and vitamins (Vitamins A, B, D, E and K).
sodes and its associated duration and severity. This review defines an ARI episode as any upper respira-
tory tract infection, acute respiratory tract infection, in-
fluenza, influenza-like illnesses and common cold
Methods episodes, regardless whether the illness was clinically di-
Study identification and selection agnosed, laboratory-confirmed or self-reported as de-
Four electronic databases (PubMed, Cochrane Library, fined by the study.
Embase and Scopus) were searched in January 2019 to The titles and abstracts of extracted studies were first
identify observational studies which measured micronu- screened for relevance; full texts of relevant studies were
trient status in healthy adults infected with ARI. Specific retrieved for further screening and validation according
search terms defined with the Population, Exposure, to the above criteria before final inclusion into the re-
Outcome and Study Design (PEOS) criteria and strat- view. A PRISMA flow diagram and checklist of the study
egies applied to each database are respectively provided selection process are shown in Fig. 1 and Additional file 2,
in Additional file 1: Tables S1 and Additional file 1: Ta- respectively.
bles S2. To identify additional studies, reference lists of
relevant reviews was searched and any year or language Data extraction
restrictions were not applied in the search strategy. Data extracted from selected studies were summarised
However, only studies published in English were eventu- in Tables 1, 2 and 3. When clarification or more infor-
ally selected as the reviewers were unable to accurately mation were required, we also contacted corresponding
interpret the five potentially eligible non-English studies. authors of included studies. The following data were ex-
This study was reported according to the Preferred tracted from each study: authors, year of publication,
Reporting Items for Systematic Reviews and Meta- study and population characteristics, the micronutrient
Analyses group (PRISMA) [16]. measured in that study, cut-off concentration values for
Studies extracted from the database search were in- micronutrient categories (deficiency, inadequacy and
cluded when the following criteria were satisfied: sufficiency in nmol/L), and outcomes. In the case where
Wang et al. Nutrition Journal (2019) 18:80 Page 3 of 12

Fig. 1 Flowchart of the process of study selection. *Only 4 studies clearly met the inclusion criteria [17–20]; the other 4 studies did not clearly
meet the inclusion criteria due to missing information [21–24] but were judged to be relevant and highly likely to meet the inclusion criteria
should missing information become available

concentrations of micronutrient categories were re- Quality assessment

ported in ng/mL, they were converted to nmol/L using Studies included in this review were assessed for their
the conversion factor of 1 ng/mL = 2.5 nmol/L. We also reporting quality and methodological quality using the
assessed the study design of the included studies based methods described in Additional file 3. Reporting
on their design features as recommended by the quality was assessed with the STrengthening the
Cochrane Handbook for Systematic Reviews and Meta- Reporting of OBservational studies in Epidemiology
analyses, in addition to extracting their reported study (STROBE) statement [26, 27]. The methodological
design [25]. Outcome measures extracted for each quality was assessed with the National Lung, Heart,
micronutrient category, when available, include 1) the and Blood Institute (NLHBI) Quality Assessment Tool
number of ARI episodes, 2) adjusted summary statistic for Observational Cohort, Cross-sectional and Case-
for ARI incidence (relative risk (RR) or odds ratio (OR)), Control Studies [28]. The tool examines the risk of
the median and interquartile ranges of 3) duration and biases in the domains of selection, misclassification,
4) severity of common ARI episodes, and 5) any other detection, confounding, attrition and inappropriate
key findings. The same outcome measures were also ex- sample sizes. The overall reporting and domain-
tracted for community-acquired pneumonia episodes. specific methodological quality ratings given to each
Table 1 Characteristics of included studies
Author, Year [Ref.] Reported Study Country of study; Population size and description (% Men); Micronutrient Cut-offs for different micronutrient categories, Outcome reported
Design follow-up duration Mean Age (years); in question as defined by study (nmol/L)
Wang et al. Nutrition Journal

Deficient Inadequate Sufficient Optimal

Met inclusion criteria clearly
Laaksi, 2007 [19] Prospective Finland; 6 months 756 Young Finnish military conscripts Vitamin D <40 – ≥40 – – • Clinical RTI incidence
cohort (100%); 18–29* • RTI duration
He, 2013 [17] Prospective UK; 4 months 225 healthy endurance exercise athletes Vitamin D 12 to 30 30 to 50 50 to ≥120 – • Self-reported upper RTI
(2019) 18:80

cohort with ≥3 h of total moderate/high-intensity 120 incidence

training per week (69.8%); 21 • Self-reported upper RTI
duration
• Subjective symptom
severity per episode
Jovanonich, 2014 Retrospective US; 3–15 months 132 patients hospitalised for pneumonia Vitamin D < 37 37 to 50 51 to 75 > 75 – • Laboratory-confirmed
[18] case-control (cases) or other reasons (controls) (29%); 60 pneumonia incidence
Rafiq, 2018 [20] Cross sectional Netherlands; 6138 men and women living in the greater Vitamin D < 50 50 to 75 ≥75 – – • Self-reported common
1 month prior area of Leiden with self-reported BMI cold incidence
to interview ≥27 kg/m2 (43.9%); 55 (deficient), 55.9
(inadequate), 55.7 (sufficient)
Highly likely to meet inclusion criteria
Sabetta, 2010 [24] Prospective US; 4 months 198 healthy adults (42.9%); 20–88* Vitamin D < 95 – ≥95 – – • Clinical acute viral RTI
cohort incidence
• Acute viral RTI duration
Berry, 2011 [21] Cross sectional UK; 3 weeks prior to 6789 non-pregnant free-living Caucasians Vitamin D < 25 25 to 49.9 50 to 75 to ≥100 • Self-reported influenza,
interview born in England, Scotland and Wales 74.9 99.9 pneumonia,
during a week in March 1958 (birth bronchitis or severe
cohort) (49.9%); 45 cold incidence
Nanri, 2017 [23] Nested Case- Japan; 6 months 532 employees from 4 companies in Vitamin D < 50 50 to < 75 ≥75 – – • Clinical influenza
control Kanto and Tokai regions (83.1%); 37.6 incidence
Lee, 2018 [22] Retrospective US; 1 year post- 437 Young, healthy US military members Vitamin D < 50 50 to 75 > 75 – – • Clinical influenza-like
cross sectional vaccination vaccinated with 2009 monovalent influenza illness incidence
A (H1N1) vaccine (50.3%); Not reported
by 90.6% of the population were
19–39 years old
RTI Respiratory tract infections, UK United Kingdom, US United States of America, *age range
Page 4 of 12
Table 2 Key findings on vitamin D deficiency on ARI incidence
Outcome Author, Year Population Outcome ascertainment Reported summary risk estimate: Odds Ratio (OR), Risk Ratio(RR) (95% Confidence Interval); % Population
Health infected (infected/population size)
Status
Deficient Inadequate Sufficient Optimal Per ↑ 10
nmol/L
Incidence of Laaksi, 2007 Healthy Clinically diagnosed episodes of sinusitis, 1.03 (0.90, 1.18)a,c; 88.9% (24/ – 1.00 (reference); – –
Wang et al. Nutrition Journal

ARI/pneumonia [19] tonsillitis, otitis, bronchitis, pneumonia, 27) 86.1% (628/729)

pharyngitis, and laryngitis
He, 2013 Healthy Symptom diary; URTI was deemed NR; 66.7% (12/18) NR; 39.7% (27/ NR; 43.8% (56/128) NR; 27.3% (3/11) –
[17] present when (i) total symptom score 68)
was ≥15 on any two consecutive days
and (ii) when a subject positively
(2019) 18:80

indicated suffering from a common

cold on ≥3 days
Jovanonich, Mixedb Laboratory confirmed CAP with chest 2.57 (1.08, 6.08)d; NR – 0.96 (0.35, 2.61)d; 1.03 (0.51, .09)d; NR –
2014 [18] radiograph NR
Rafiq, 2018 Mixedb Self-reported episodes of cold in the – – – – 1.00 (0.96,
[20] month prior to questionnaire 1.05)e; N/A
Sabetta, Healthy Self-reported, followed by clinical 1.00 (reference); 45.0% (81/180, – – 0.52 (0.25, 0.84)a; 16.7% (3/18; –
2010 [24] diagnosis of acute viral RTI, which 32 laboratory-confirmed cases) 1 laboratory-confirmed case)
may or may not be laboratory
confirmed
Berry, 2011 Supposedly Self-reported episodes of respiratory 1.00 (reference) 0.94 (0.7, 1.27)f 0.74 (0.54, 1.02)f 75–99.9 nmol/L: 0.66 (0.46, 0.93, (0.89,
[21] healthy infections (influenza, pneumonia, 0.96)f; NR 0.97)f; N/A
bronchitis, severe cold) in past ≥100 nmol/L: 0.57 (0.34,
3 weeks prior to questionnaire 0.94)e; NR
Nanri, 2017 Supposedly Self-reported to be clinically 1.00 (reference)g; 32.8% (59/ 1.11 (0.74, 1.68)g; 0.77 (0.37,1.59)g; – –
[23] healthy diagnosed with influenza, which 180) '28.6% (106/303) 28.6% (14/49)
may or may not be laboratory
confirmed
Lee, 2018 Healthy Clinical diagnosis of ILI (retrospective 1.43 (0.77, 2.67)h; NR 1.55 (0.84, 2.86)h; 1.00 (reference); – –
[22] retrieval from system) NR NR
RTI Respiratory tract infections, NR Not Reported, N/A Not Applicable, ILI Influenza-like illness
a
Relative risk reported, otherwise odds ratio was reported
b
Mixed health status refers to populations that with healthy and diseased subjects with chronic diseases, but statistically adjusted for these diseases in analyses.
c
Adjusted for smoking
d
Adjusted for diabetes, renal disease and peripheral vascular disease; Odds are compared against the cut-offs for the following serum 25(OH)D levels in the respective categories, i.e. Deficient (<37 nmol/L vs ≥37 nmol/
L), Sufficient (<50 nmol/L vs ≥50 nmol/L), optimal (<75 nmol/L vs ≥75 nmol/L)
e
Adjusted for age, sex, ethnicity, number of packyears, self-reported obstructive pulmonary disease, use of pulmonary and anti-inflammatory medication, educational level, season, physical activity, BMI, total body fat
and waist circumference
f
Adjusted for gender, lifestyle factor, BMI and waist circumference
g
Adjusted for influenza vaccination status, BMI, exercise and smoking statuses, living with schoolchildren, green tea intake and use of public bus or train for commuting
h
Adjusted for age, gender, time from vaccination to serum collection
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 Wang et al. Nutrition Journal

Table 3 Key findings on vitamin D deficiency on ARI duration and/or severity

(2019) 18:80

Outcome Author, Year Population Outcome ascertainment Median duration/severity per episode (Interquartile range)
Health Status
Deficient Inadequate Sufficient Optimal
Duration of ARI/ Laaksi, 2007 [19] Healthy Number of days absent from 4 (2,6) – 2 (0, 4)a –
pneumonia episode duty due to RTI
He, 2013 [17] Healthy Total number of days with a 13 (10, 17) 8 (5, 14)a 8 (6, 9)a 5 (5,7)a
symptom score of ≥5 in daily
symptom diary
Sabetta, 2010 [24] Healthy Symptom diary and follow-up by 6 (2, 8)Percentage of days ill – 6 (2, 27)Percentage of days ill –
clinician every 1–3 days until (days ill/days observed): 3.9% (days ill/days observed): 0.80%
asymptomatic (777/19763) (16/1994)
Severity of ARI/ He, 2013 [17] Healthy Symptom diary; total symptom 102 (67, 199) 62 (46, 74)a 47 (40, 69)a 43 (38, 52)a
pneumonia episode score for every subject each day
was calculated as a sum of
multiplied numbers of symptoms
experienced by the numerical
severity ratings (1 = mild,
2 = moderate, 3 = severe)
a
Significantly shorter than duration in deficient groups
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Wang et al. Nutrition Journal (2019) 18:80 Page 7 of 12

study were presented in Table 4, and a detailed control [18, 23] design. Design features of all but one
breakdown of the assessment can be found in Add- study matched their reported study design; the study
itional file 3: Table S3. had design features that suggested a retrospective co-
Study selection, data extraction and quality assessment hort design although it reported a retrospective cross-
were performed in duplicate by two independent re- sectional design [22]. Although we did not limit the
viewers. Differences in studies selected, data extracted or micronutrients in the search and found a variety of
quality assessments between reviewers were discussed micronutrients in the search results, the only micro-
and resolved by consensus at the end of each procedure. nutrient identified in the included studies was vitamin
D in the form of serum 25-hydroxyvitamin D. The
Results cut-off concentrations for the “deficiency”, insuffi-
Screening results and characteristics of included studies ciency” and “sufficient” vitamin D groups ranged from
Our literature searches identified 506 articles, of 12 nmol/L to 95 nmol/L, 25 nmol/L to 75 nmol/L, and
which 90 were duplicates. The articles covered vari- 40 nmol/L to 95 nmol/L respectively. Three studies
ous publication genres which were based on cells, were also observed to have an additional “Optimal”
animal and human populations. Of those based on category, with a cut-off concentration between 75
human populations, most focused on elderly or pa- nmol/L and 120 nmol/L [17, 18, 21], that was further
tient populations with various diseases (Fig. 1). Expo- stratified into subcategories at ≥100 nmol/L in 1 study
sures studied varied from the effects of a drug/ [21]. Outcomes were clinically diagnosed and/or la-
treatment, to the presence of risk factors for a disease boratory confirmed in five studies and self-reported in
and the measurement of micronutrient levels in the the remaining 3 studies.
study population. Micronutrients measured in the
identified articles included copper, zinc, magnesium, Outcomes
manganese, rubidium, phosphorus, selenium, calcium ARI incidence was reported in five studies [17, 19–21,
and vitamins A, B, C, D. E and K. Following the 24], whilst one study reported on the incidence of CAP
screening process, 415 unique articles were excluded [18]. Odd ratios (ORs), relative risks (RRs) and the per-
based on the inclusion criteria and eight articles were centage of population infected with ARI reported for the
selected for final inclusion into our review. A flow various vitamin D categories suggested that ARI inci-
chart of the screening process and the reasons for dence was either not associated to, or associated with a
article exclusion are presented in Fig. 1. It was also slight increase in probability or risk of incidence when
noted that no articles were excluded as they assessed Vitamin D deficiency (VDD) was present (Table 2).
the effects of multi-micronutrients deficiency on our Compared to the deficient group, reported ORs sug-
outcomes of interest. Of the eight articles included in gested that there was either no statistically significant
this review, only four articles were clearly eligible for difference in odds of ARI incidence (OR [95% CI]: 0.74
inclusion [17–20] while the other four articles did not [0.54, 1.02] to 1.11 [0.74, 1.68]) or a 43% reduction (OR
clearly meet the inclusion criteria due to missing in- [95% CI]: 0.57 [0.34,0.94]) in the non-deficient groups
formation [21–24]. Missing information from these [21, 23]. Nonetheless, a 48% lowered risk of ARI
studies include mean population age [22, 24] and an incidence was observed in the sufficient group (RR
explicit indication of a healthy population used [21– [95% CI]: 0.52 [0.25, 0.84], p < 0.001), compared to
23]. Nonetheless, these studies were deemed by the the deficient group [24]. However, when the sufficient
authors to be relevant and highly likely to meet the group was the reference group, the relative risk re-
inclusion criteria should the missing information be- duction was no longer significant (RR [95% CI]: 1.03
come available. Thus, these four studies were also in- [0.90, 1.18] to 1.55 [0.84, 2.86]) [19, 22]. During the
cluded in the review. follow-up period, a significantly bigger proportion of
The eight studies included in this review were the deficiency group reported ARI episodes (28.3%
mainly made up of Europeans and Americans (only [p = 0.015] to 39.4% [p = 0.039] higher) compared to
one study with Japanese) and involved 15,207 adult the optimal group [17, 24]. However, there was no
participants (Table 1). Health status of included sub- significant difference in the rate of ARI incidence be-
jects varied, with 1616 confirmed healthy subjects tween deficient and non-deficient groups (adjusted in-
from four studies [17, 19, 22, 24], 6270 subjects be- cidence rate ratio [95% CI]: 1.18 [0.988,1.40]) [19]. In
longing to populations of mixed health status in two addition, there was either a non-significant difference
studies [18, 20] and 7321 subjects with supposedly (OR [95% CI]: 1.00 [0.96, 1.05]) or a 7% reduction
healthy status due to limited descriptions in two (OR [95% CI] 0.93 [0.89, 0.97], p = 0.001) on ARI in-
other studies [21, 23]. The included studies reported cidence odds, with every 10 nmol/L increase in serum
a cohort [17, 19, 24], cross-sectional [20–22] or case- vitamin D levels [20, 21].
 Wang et al. Nutrition Journal

Table 4 Reporting and methodological quality

Quality Study Design Cohort & Cross sectional Studies Case-Control
Assessed
Author, Year Laaksi, 2007 He, 2013 Rafiq, 2018 Sabetta, 2010 Berry, 2011 Lee, 2018 Jovanovich, 2014 Nanri, 2017
(2019) 18:80

Section/ Domain
Reporting Title, Abstract and High Fair High Fair High High High High
Qualitya Introduction
Methods High High High High High High High High
Results Low High Low High High High High High
Discussion Fair Low High High High High High High
Other information High High High High High High High High
Overall Low Fair Fair High High High High High
Methodology Selection High High High High High High High High
Qualityb
Misclassification High High Low High High Low High High
Detection Fair Low Low High Low Low High High
Confounding Low Low High Low High High High High
Other (Inappropriate Low Low High Low Low Low Low Low
sample size, attrition)
Y Yes, N No, CT Can’t tell, N/A Not Applicable, P Partially reported
a
Assessed with the STROBE statement
b
Assessed by the NHLBI Quality Assessment Tool for Observational Cohort, Cross-Sectional and Case-control studies; a high quality indicates a low risk of bias in the assessed domain, and vice versa
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Wang et al. Nutrition Journal (2019) 18:80 Page 9 of 12

Across the non-deficient groups, i.e. those with insuffi- statistically. In contrast, cohort studies included displayed
cient, sufficient and optimal vitamin D status, conflicting varied risks of detection bias and a high risk of confounding
associations between vitamin D status and ARI incidence bias [17, 19, 24].
were also observed. One study reported no difference in
incidence between these groups (p = 0.062) [17], while an- Discussion and conclusion
other reported significantly different incidence (p < 0.001) This review provides a complete overview of current lit-
and adjusted ORs (p = 0.015) across these groups [21]. erature investigating the association between deficiency in
In the study reporting on CAP incidence, increased any single micronutrient and ARI, especially the common
likelihood for CAP incidence was associated with VDD, cold. The association assessment also included ARI-
where a 157% increase in odds was observed in deficient associated pneumonia incidence, duration and severity in
group compared to the non-deficient groups (OR [95% a healthy population. To the best of our knowledge, this is
CI]: 2.57 [1.08, 6.08]) [18]. the first review that attempts to systematically summarise
Duration of the ARI episodes was reported in three the association between these variables in a healthy popu-
studies, all of which consistently reported longer ARI lation. Nonetheless, the small number of studies included
durations or a higher percentage of total days ill in the in this review and identification of vitamin D as the sole
deficient group compared to the non-deficient groups micronutrient studied for the outcomes of interest in our
(median [IQR], total days ill (%): deficient group, 4 [2, 6] target population highlights the paucity of such studies in
to 13 [10, 25], 3.9%; non-deficient group, 2 [0, 4] to 8 [5, this population.
14], 0.80%) [17, 19, 24] (Table 3). The observations sug- Although small in number, the included studies
gested that ARI duration was associated to vitamin D already showed mixed results on the association be-
status, and that VDD could be associated with a longer tween VDD and ARI. The lack of association between
ARI duration. these variables, to a slight increase in odds and risk
Severity of the ARI episode was only reported in one of ARI or pneumonia with VDD persisted even when
study [17]. The study reported significantly higher sever- the findings were stratified according to health status
ity scores per ARI episode when in the deficient group of populations (confirmed healthy, mixed health status
compared to the non-deficient groups. The study also and supposedly healthy populations). This overlaps
observed that the median severity score was significantly with observations in the vulnerable populations where
different across the deficient, insufficient, sufficient and VDD was generally associated with increased preva-
optimal groups (p = 0.013), suggesting that vitamin D lence and/or incidence of respiratory diseases [29–31].
status is likely associated with ARI severity, but A meta-analysis revealed associations between low
remained inconclusive. serum vitamin D levels and a higher risk of active tu-
berculosis in healthy adults (pooled effect size: 0.68,
Reporting and methodological quality of included studies 95% C.I.: 0.43, 0.93) [32]. Another systematic review
Generally, most of the included studies had high overall found high VDD prevalence amongst those suffering
reporting quality [18, 21–24]. The remaining two studies from chronic lung diseases such as asthma, cystic fi-
were judged with fair overall quality [17, 20] and only brosis and chronic obstructive pulmonary disease, and
one study was judged with low overall quality [19] demonstrated the roles of VDD in the pathogenesis
(Table 4). While the reporting quality of the title, ab- of these diseases [33]. While the causal relationship
stract, introduction section were not included in the cri- between VDD and respiratory disease incidence can-
teria for rating the overall reporting quality, they were not be confirmed by randomised trials due to ethical
generally well reported with a fair [17, 24] or high qual- reasons, studies have explored this plausible relation-
ity [18–23] (Additional file 3; Table S1). It was interest- ship between these variables through supplementation
ing to note that the included studies were generally well trials. The protective effect of vitamin D supplemen-
reported, though none explicitly stated adherence to the tation against respiratory infections have been consist-
STROBE guidelines. ently demonstrated in susceptible populations [2, 4,
The eight studies were all of low risk of selection bias. All 7], hinting at the causality of VDD on ARI incidence.
but two studies [20, 22] were at low risk of misclassification However, this effect is unclear in the generally
bias, although it was generally unclear across the cohort healthy adult population [12, 34]. Nonetheless, a re-
and the cross-sectional studies whether the follow-up time- cent meta-analysis showed that vitamin D supplemen-
frame was sufficient to assess the association between vita- tation generally decreased the odds of an ARI episode
min D deficiency (VDD) and the outcomes. Case-control in humans (OR [95% C.I.], 0.88 [0.81, 0.96]). This
[18, 23] and cross-sectional studies [20–22] respectively protective effect is even more pronounced when one
showed low and high risk of detection biases, and all has vitamin D levels below 25 nmol/L (OR [95% C.I.],
adjusted for the key potential confounders identified 0.58 [0.40, 0.82]), but disappeared in all subgroups
Wang et al. Nutrition Journal (2019) 18:80 Page 10 of 12

when the population was stratified by the presence of domain-specific quality, is conservative, simplistic and
asthma or chronic obstructive pulmonary disease or may overestimate the risk of bias in each domain.
age, except in the 1–16 years old age group (OR [95% Nevertheless, it presents the risk of bias for each
C.I.], 0.60 [0.46, 0.77]) [34]. This observation supports assessed domain in a transparent manner, and does
the notion that a deficiency state may have more in- not misuse the NLHBI checklist [38].
fluence over ARI incidence (p-value for interaction
baseline 25-hydroxyvitamin D levels = 0.01) compared to an Strengths, limitations and future work
individual’s health status or age. The deficiency state A strength of this review was that it encompasses all
may have a relatively larger impact than health or age relevant literature published since inception of the elec-
on ARI incidence because vitamin D and its metabo- tronic databases searched, as there was no restriction on
lites act as powerful immunoregulators, with most im- publication year in the search strategy. This ensured that
mune cells expressing vitamin D receptors. Thus, this review presented a complete overview of all relevant
depleted serum vitamin D levels could have amplified research done in this area, in the healthy adult popula-
effects on all downstream pathways triggered by vita- tion. Another strength of this review was that it included
min D. This may expedite autoimmune development a more complete quality assessment of the included
and compromise the immune system to a larger ex- studies. “Quality” in research refers to both methodo-
tent than sickness or aging [35]. Therefore, separating logical and reporting quality of a study [37]. However,
our population into the confirmed, mixed and sup- only the former is generally assessed as part of the risk
posedly healthy status still yielded mixed findings on of biasness assessment for included studies in reviews.
the association between vitamin D status and ARI in- This could be because reporting quality assessment is
cidence as the health status has a relatively less pro- not included as part of the recommended systematic re-
nounced effect on ARI incidence. views and meta-analysis protocol by the Cochrane
In this review, we developed an approach to sum- Handbook [25]. Nonetheless, the reporting quality of a
marise the sectional and overall reporting quality study can affect the ease of assessing methodological
using the reporting qualities for the methods, results quality and hence, the confidence in the risk of bias gen-
and discussion sections. The quality of the remaining erated for the study [37]. As all but one of the included
sections assessed were omitted as they purely examine studies [19] in this review had fair to high reporting
the reporting transparency and do not affect the risk quality, we can have increased confidence in the given
of bias [36]. This is evident as the addition of those overall methodological quality rating.
sections into the framework did not change the over- It is worth noting some limitations of this review.
all reporting quality assigned to all but one study Firstly, a pooled risk estimate for the outcomes of
(Additional file 3: Table S3) [19]. The absence of a interest cannot be generated, and hence cannot assess
valid approach to summarise the reporting qualities the certainty of evidence presented in this review.
could be because the STROBE statement was The inability to statistically analyse the evidence was
intended to be a reporting guideline for observational due to missing data and the small number of studies
studies. However, the use of the STROBE statement reporting these outcomes. Furthermore, some of the
to assess reporting quality was not an inappropriate studies were included although they did not clearly
use of the guideline [36, 37]. The lack of a recom- meet the inclusion criteria or had some diseased sub-
mended quality assessment tool and approach to jects. This further decreases credibility of the conclu-
summarise the overall methodological quality of ob- sion drawn although these studies were highly likely
servational studies were also observed while perform- to meet the inclusion criteria, or the extracted study
ing this review. The Cochrane Handbook did results were statistically adjusted for diseases if
recommend using the Newcastle-Ottawa Scale (NOS) present. Secondly, 96.5% of the study populations
to assess quality of non-randomised studies. However, were Caucasian, limiting the external validity of our
we did not implement this tool as it was less compre- findings as it may not represent the effects of VDD
hensive and rigorous than the NLHBI checklist used on a ARI incidence, duration and severity in a healthy
in this review. In addition, the NOS manual was not Asian population. Due to a lack of studies investigat-
as clear and in-depth as that provided by NLHBI, ing the effect of other micronutrients deficiency on
resulting in difficulty in application of the tool. None- the outcomes of interest, our findings are limited to
theless, the NLHBI checklist also lacked an approach only VDD. Furthermore, multi-micronutrient deficien-
to summarise the overall reporting quality. The cies were more commonly observed than single
current approach adopted in this review i.e. using the micronutrient deficiencies, further limiting the gener-
majority of rating in each domain (or the lower rating alisabilty of our findings [5, 39]. Thirdly, publication
when there are 2 equal ratings for a domain) as the bias may exist as we searched only within published
Wang et al. Nutrition Journal (2019) 18:80 Page 11 of 12

literature and eventually only included those in Eng- simple solution to improve overall well-being of healthy
lish, although language was not restricted for in the individuals whilst reducing public health burden.
search strategy. Moreover, although included studies In conclusion, the association between VDD and ARI
generally adjusted for confounders, except for 3 studies incidence and severity remains inconclusive. However,
that either partially explored [19] or did not explore con- VDD is likely to increase the duration of ARI especially
founding entirely [17, 24], residual confounding may still common cold. More future studies are still required to
exist. Lastly, the observational nature of the studies limits strengthen these findings.
our assessment to whether an association exists between
VDD and the outcomes. Hence, we are unable to deter- Supplementary information
mine whether there is a direct or reverse causal relation- Supplementary information accompanies this paper at https://doi.org/10.
1186/s12937-019-0507-6.
ship between these variables.
Nonetheless, this review highlighted the need to de-
Additional File 1. Description of PICOS criteria for a systematic review
velop a consistent definition for “deficiency” and “suf- and search strategy. Table S1. Description of PICOS criteria for a
ficiency”, at least for each region to account for systematic review assessing the association of micronutrient deficiency
geographical, seasonal and ethnicity differences in with the incidence, duration and severity of common cold and
pneumonia. Table S2. Search strategy for micronutrient deficiency of
populations from different regions. Varying cutoff cold and/or pneumonia PubMED, Embase, Scopus and the Cochrane
concentrations for the vitamin D categories were Library.
observed in included studies, but US Institute of Additional File 2. PRISMA Checklist.
Medicine (IOM) and experts in the field suggested Additional File 3. Methods for methodological quality assessment & for
similar cutoff concentrations of 12 ng/mL and 12.5 reporting quality assessment. Table S1. Classification of risk of bias
domains assessed with published questions in NLHBI quality assessment
ng/mL to define the “deficiency” group. This suggests tool for observational cohort, cross-sectional and case-control studies.
a consistent increased risk for adverse health effects Table S2. Proposed framework for determining overall reporting quality
below these vitamin D levels [40, 41]. However, the based on title, abstract and introduction, methods, results and discussion
sections. Table S3. Breakdown of methodological and reporting quality
same experts mentioned that the IOM cutoff for “suf- assessment ratings given for each included study.
ficient” (≥20 ng/mL) was more applicable for popula-
tions most at risk for a true VDD, and overestimated Acknowledgements
the vitamin D levels required for normal cell and im- Not applicable.
mune functions in healthy individuals (approximately
Author contributions
15 ng/mL) [41, 42]. Instead, unnecessary supplementa- MXW: Conceptualisation, Methodology, Formal Analysis, Investigation, Data
tion of healthy individuals with vitamin D levels be- Curation, Writing – Original Draft, Review & Editing, Visualisation. JK:
tween 12.5 to 20 ng/mL may result in toxicity. Validation, Formal Analysis, Data Curation. JP: Conceptualisation,
Investigation, Interpretation, Supervision, Writing – Review & Editing. All
Toxicity occurs when vitamin D intake exceeds the authors read and approved the final manuscript.
tolerable upper intake level, resulting in vitamin D
levels of about 50 ng/mL [40, 41]. In light of these Authors’ information
considerations, the review authors propose cutoff con- MXW is a food science epidemiologist and JK is an infectious disease
epidemiologist of Centre for Infectious Disease Epidemiology and Research
centrations of <12.5 ng/mL (31.25 nmol/L) for “defi- (CIDER) under Saw Swee Hock School of Public Health (SSHSPH) at National
cient”, 12.5 to <50 ng/mL (31.25–125 nmol/L) for University of Singapore (NUS), who are keen in understanding the impact of
“sufficient” and > 50 ng/mL (>125 nmol/L) as “toxic” micronutrients on the risk of acute respiratory infections among healthy
adults. JP is Director of CIDER and Assistant Professor of SSHSPH at NUS who
for healthy children and adults in the western regions. is interested in understanding the risk factors for susceptibility and
However, the proposed cutoff concentrations will not transmission of a number of infectious diseases, including acute respiratory
be applicable to the Asian region, and more VDD infections.
studies conducted in Asian populations would be required Funding
to establish those values. This review also highlighted the This work was supported by Centre of Infectious Disease Epidemiology &
need for more studies on micronutrient deficiency on re- Research under Saw Swee Hock School of Public Health, an operational
research program funded Singapore Ministry of Defence (grant number N-
spiratory health, specifically ARIs, in a healthy adult popu- 608-000-065-001). The funder of the study had no role in study design, data
lation. This is required to substantiate and validate the collection, data analysis, data interpretation, or writing of the report.
need of supplementation, especially micronutrients shown
to improve or maintain respiratory health but were ex- Availability of data and materials
All data generated or analysed during this study are included in this
cluded from this review as no studies investigated the ef- published article and supplementary information files.
fect of its deficiency on ARI incidence, duration or
severity in a healthy adult population. More importantly, Ethics approval and consent to participate
Not applicable.
if there is a true association between micronutrient defi-
ciency and ARI incidence, duration and/or severity, then Consent for publication
micronutrient supplementation might be a viable and Not applicable.
Wang et al. Nutrition Journal (2019) 18:80 Page 12 of 12

Competing interests function, airway inflammation and common ARI in the general population.
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