Original Article

Chronic Respiratory Disease

2015, Vol. 12(1) 24–30
A test of vitamin D benefits on ª The Author(s) 2014
Reprints and permission:
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respiratory health mediated DOI: 10.1177/1479972314556086
crd.sagepub.com
through inflammatory markers

Michael Hendryx1 and Juhua Luo2

Abstract
Previous studies have shown that vitamin D has beneficial effects on respiratory health. The role of
inflammation as a possible mediator between vitamin D and respiratory health is not well understood. We
used National Health and Nutrition Examination Survey 2001–2006 data (unweighted N ¼ 12,856) to
examine the mediating effects of biomarkers of inflammation on associations between vitamin D and
respiratory health. Vitamin D was measured by serum 25 hydroxy vitamin D test. Respiratory health was
measured by self-reported respiratory symptoms and chronic obstructive pulmonary disease (COPD). Bio-
markers included C-reactive protein (CRP), alkaline phosphatase (AP), and five leukocyte measures. Models
controlled for season, age, sex, race/ethnicity, body mass index, and current and former smoking. Lower levels
of vitamin D were significantly associated with respiratory symptoms (linear trend p < 0.01) and with COPD
(linear trend p < 0.0002) after adjusting for covariates. Adding biomarkers to the models to test for mediation,
the vitamin D effect on respiratory health was not a consequence of any single marker but was partially atte-
nuated as a combined result of leukocytes, AP, and CRP. Vitamin D is beneficial to improve respiratory health.
Its benefits do not appear to be mediated by any single biomarker examined in this study; rather, benefits of
vitamin D may act broadly through multiple mediating mechanisms.

Keywords
Vitamin D, lung disease, inflammation, NHANES, COPD

Introduction The specific mechanisms by which vitamin D sup-

Vitamin D is essential for bone mineralization and
calcium homeostasis. Evidence more recently has
established that vitamin D has beneficial effects
on immune function and control of inflammation1,2
and that it is related to lower risks of cancer, dia-
betes, cardiovascular disease, and infectious dis-
ease.3–5 The benefits of vitamin D extend to
improve respiratory health as well.6–8 For example,
vitamin D has been found to correlate inversely
with inflammatory forms of respiratory disease.9,10
Black and Scragg7 analyzed National Health and
Nutrition Examination Survey (NHANES) 1988–
1994 data and found significant associations
between vitamin D and spirometry measures of
lung function. In a controlled trial, Laaksi et al.11
found that vitamin D supplementation was effec-
tive in prevention of acute respiratory tract infec-
tion in a sample of healthy men.
ports respiratory health are unclear. One explanation
for the respiratory health benefits of vitamin D is
found in its anti-inflammatory properties.2,12–16 Vita-
min D is thought to regulate many cellular processes
including immunomodulating the activity of mono-
cytes, macrophages, lymphocytes, and epithelial
cells.10 Both acute and chronic forms of respiratory
disease occur in conjunction with inflammation.17–19
In an analysis of NHANES III data, Mannino
1
Department of Applied Health Science, School of Public Health,
Indiana University, Bloomington, IN, USA
2
Department of Epidemiology and Biostatistics, School of Public
Health, Indiana University, Bloomington, IN, USA
Corresponding author:
Michael Hendryx, Department of Applied Health Science, School
of Public Health, Indiana University, Bloomington, IN 47405, USA.
Email: hendryx@indiana.edu
Hendryx and Luo
et al.20 found higher levels of C-reactive protein
(CRP) and fibrinogen in persons with restrictive or
obstructive lung disease.
There is evidence to support each of the three
hypothesized links. Studies have found associations
between (A) vitamin D and respiratory health,7,13
(B) vitamin D and various biomarkers of inflamma-
tion,15,16,21,22 and (C) biomarkers and respiratory
health.20 However, a direct test of the mediating role
of inflammatory biomarkers in the vitamin D–respira-
tory health link within a single study has not been
undertaken. There have been recent calls for research
to understand how the relationship between vitamin D
and respiratory health may be mediated through sys-
temic inflammation.23,24 The purposes of this study
were to test for relationships between vitamin D and
respiratory health using recent survey years from the
NHANES and to determine whether there was evi-
dence that the effect of vitamin D on respiratory
health may be mediated through a set of tested
biomarkers.
Methods
Design
The study was a cross-sectional analysis of NHANES
data.25 We included three survey periods conducted
over 6 years (2001–2002, 2003–2004, and 2005–
2006). Each sampling period included different per-
sons, and each person was measured on all variables
at one time observation. These years were selected
because they are the most recent years in which the
vitamin D status has been assessed in the NHANES.
Variables from the laboratory, examination, demo-
graphic, and questionnaire data were combined for
analysis. Pregnant women and persons less than
20 years of age were excluded.
Dependent variables
The primary dependent variables of interest were self-
report measures of respiratory symptoms and chronic
respiratory disease. Participants were asked if they
had ever been told by a doctor or health-care profes-
sional that they had emphysema or chronic bronchitis;
these two conditions were combined to form a dichot-
omous measure of the presence or absence of chronic
obstructive pulmonary disease (COPD).
Symptoms of respiratory illness included eight
items regarding cough and wheezing. All participants
were asked two questions, whether or not they had
25
experienced a dry cough at night in the past year and
whether or not they had experienced wheezing or
whistling in the chest during the past year. Partici-
pants who said yes to the wheezing question were
asked follow-up questions regarding the number of
such attacks in the last year (dichotomized for this
study into one versus more than one) and whether the
wheezing episodes resulted in medical attention, chest
sounds, sleep disturbance, medications being pre-
scribed, or activity limitations. Participants received
a score from 0 to 8 based on the number of symptoms;
this distribution was positively skewed and was
dichotomized into persons who reported 0 to 2 symp-
toms versus persons who reported more than 2
symptoms.
Independent variables and mediators
The primary independent variable of interest was vita-
min D measured by serum 25 hydroxy vitamin D
(25(OH)D) test in nanomoles per liter. The vitamin
D distribution was divided into quintiles consistent
with a previous NHANES study of vitamin D and
lung function.7
Seven blood biomarkers were included based on
their availability from the same persons as the data
on vitamin D and respiratory symptoms. Markers
included CRP (milligrams per deciliter), alkaline
phosphatase (AP; units per liter), and five leukocytes
measured as 1000 cells/mL including basophils, lym-
phocytes, monocytes, eosinophils, and segmented
neutrophils. The distributions of biomarkers were
examined and were found to be positively skewed;
we converted all biomarkers to natural log values for
analysis.
Covariates
We included covariates to control for possible con-
founding influences on the relationships among vari-
ables. Covariates included season, sex, age, race/
ethnicity, smoking, and overweight and obesity. Sea-
son was recorded as fall–winter (November 1 through
April 30) or spring–summer (May 1 through October
31) according to the time when the laboratory samples
were obtained. Age in years was categorized into ages
20–39 (used as the referent), 40–59, and 60 and over.
Race/ethnicity was categorized into non-Hispanic
White (used as the referent), non-Hispanic Black, and
other. Smoking was categorized into lifetime never
smokers (used as the referent), former smokers, and
current smokers. Body mass index (BMI) was used
26 Chronic Respiratory Disease 12(1)

to distinguish participants who were normal weight Table 1. Summary of unweighted (N ¼ 12,856) study vari-
(BMI < 25; used as the referent), overweight (25– able descriptive statistics.
29.9), and obese (30 and over.) Variable Number Percentage

Analysis COPD
Yes 950 7.4
We conducted an analysis based on Baron and No 11859 92.6
Kenny26 guidelines to determine whether associations Three or more respiratory
between vitamin D and respiratory health may be symptoms
mediated by the biomarkers in the study. Evidence for Yes 1351 10.5
mediation is observed in multiple regression analysis No 11,504 89.5
if a significant vitamin D–respiratory outcome coeffi- Vitamin D quintiles
(nmol/L)
cient becomes nonsignificant when a significant bio- I (<33) 2568 20.0
marker–respiratory outcome coefficient is added to II (33 to <45) 2369 18.4
the model. Partial mediation could occur if the vita- III (45 to <58) 2889 22.5
min D effect remained significant but the magnitude IV (58 to <72) 2451 19.1
of the effect was reduced. In the mediation models, V (72) 2579 20.1
we first examined the effect of biomarkers individu- Sex
ally and then examined whether there was evidence Male 6547 50.9
Female 6309 49.1
for mediation when biomarkers were combined.
Age (years)
Data were analyzed using SAS software version 20–39 4173 32.5
9.3. The procedures ‘surveyreg’ and ‘surveylogistic’ 40–59 4103 31.9
were used depending on the response variable scale. 60 and over 4580 35.6
Strata and cluster variables as provided in the BMI
NHANES data were used to account for the sampling <25 3926 31.5
design, and the data were weighted according to 25–29.9 4458 35.7
NHANES guidelines.27 30 and over 4086 32.8
Smoking
Lifetime never smoker 6455 50.2
Results Former smoker 3439 26.8
Current smoker 2962 23.0
A descriptive summary of unweighted study variables
Race
is provided in Table 1. The total N was 12,856; miss- Non-Hispanic White 6773 52.7
ing values reduced available sample sizes by less than Non-Hispanic Black 3495 27.2
1%. COPD was reported by 7.4% of the sample and Other 2588 20.0
three or more respiratory symptoms by 11.7%. The Season
mean value for vitamin D was 58.5 nmol/L (SD ¼ Fall–winter 5928 46.1
22.4); the values that approximated a quintile split are Spring–summer 6928 53.9
shown in Table 1. Standard
Bivariate correlations between the markers of Biomarkers N Mean deviation
inflammation and oxidative stress were examined.
The highest correlation was r ¼ 0.38 between CRP 12,844 0.47 0.93
monocyte and neutrophil counts; monocytes and AP 12,780 71.41 28.3
Monocytes 12,796 0.56 0.20
lymphocytes were correlated at r ¼ 0.32. Other Lymphocytes 12,796 2.14 1.43
correlations were smaller. We interpreted these Eosinophils 12,796 0.21 0.17
correlations to mean that multicollinearity was not Neutrophils 12,796 4.26 1.64
a serious concern and we therefore included multi- Basophils 12,796 0.04 0.06
ple markers as separate independent variables in
COPD: chronic obstructive pulmonary disease; BMI: body mass
final models. index; CRP: C-reactive protein; AP: alkaline phosphatase.
The relationships between respiratory health mea-
sures as the dependent variables and vitamin D as the associated with respiratory symptoms (p < 0.01) and
primary independent variable are summarized in with COPD (p < 0.0002). The effects were strongest
Table 2. Lower levels of vitamin D were significantly for the lower vitamin D quintiles.
Hendryx and Luo 27

Table 2. ORs, 95% CIs, and p values for linear trends test- for vitamin D when it was included in the models with
ing the associations between vitamin D and respiratory each of the five biomarkers individually. The findings
health measures.a indicated little difference between the significant vita-
Symptoms COPD min D effects before adding the biomarkers and the
effects when adding each marker individually; vita-
OR 95% CI OR 95% CI min D ORs remained almost identical. There was
Vitamin Db some evidence for a partial mediating effect through
I 1.35 (1.07–1.69) 1.36 (1.11–1.66) AP for both respiratory symptoms and COPD.
II 1.24 (1.02–1.50) 1.51 (0.78–2.90) The last model results in Tables 4 and 5 show the
III 1.08 (0.92–1.27) 1.34 (1.05–1.71) vitamin D ORs when adding all five markers simulta-
IV 0.94 (0.75–1.19) 1.11 (0.98–1.25) neously. In each of these final models (one for respira-
p ¼ 0.01c p ¼ 0.0002c tory symptoms and one for COPD), the vitamin D
COPD: chronic obstructive pulmonary disease; OR: odds ratio; effect appeared to be partially attenuated. The ORs
CI: confidence interval. were altered in particular for vitamin D levels at the
a
Models adjusted for covariates. Covariates include gender, age, lowest quintiles. For respiratory symptoms, the p val-
race/ethnicity, overweight, obesity, current smoking, former
ues for the linear trends for the vitamin D effects
smoking, and season.
b
ORs are relative to the highest vitamin D quintile as the referent. changed from p ¼ 0.01 without biomarkers to p ¼
c
p Value for linear trend. 0.07 with combined biomarkers. For COPD, the cor-
responding change in the linear trend was from p ¼
0.0002 without biomarkers to p ¼ 0.03 with combined
Table 3. ORs, 95% CIs, and p values for linear trends,
testing the associations between biomarkers, respiratory biomarkers. Although not shown in the table, the bio-
symptoms, and COPD. Models adjusted for covariates.a markers in the final model with the strongest associa-
tions to COPD were CRP and AP; the biomarkers
Symptoms COPD with the strongest associations to respiratory symp-
OR 95% CI OR 95% CI toms were CRP, AP, and eosinophil count.

(log) CRP 1.22 (1.15–1.29) 1.26 (1.17–1.36)

(log) AP 1.84 (1.37–2.45) 2.13 (1.68–2.71) Discussion
(log) Monocytes 1.34 (1.05–1.71) 1.57 (1.17–2.12)
(log) Lymphocytes 0.97 (0.82–1.15) 0.94 (0.75–1.19) The results of this study add to the research evidence
(log) Basophils 0.94 (0.61–1.45) 0.92 (0.52–1.62) that vitamin D is correlated to better respiratory
(log) Eosinophils 8.36 (5.27–13.27) 2.44 (1.23–4.85) health. We observed significant linear trends from the
(log) Neutrophils 1.32 (1.04–1.67) 1.67 (1.28–2.18) highest to the lowest quintile levels between vitamin
D and increased risk for reported COPD and respira-
COPD: chronic obstructive pulmonary disease; OR: odd ratio; CI:
confidence interval; CRP: C-reactive protein; AP: alkaline tory symptoms.
phosphatase. Results of the mediation analysis suggest that the
a
Covariates include gender, age, race/ethnicity, overweight, obe- apparent respiratory benefits of vitamin D occur
sity, current smoking, former smoking, and season. broadly and at best could be partially mediated
through anti-inflammatory mechanisms that are
Table 3 confirms that most tested biomarkers were expressed through leukocyte counts, CRP, and AP.
significantly associated with respiratory measures. Two Any one indicator could not account for the benefits
of the leukocytes, basophils and lymphocytes, were not of vitamin D, but combined, they appeared to partially
related to the measures of respiratory health and so, per mediate the vitamin D–respiratory health relation-
Baron and Kenny26 guidelines, were not used in the ships. Even with this partial mediation, the benefits
mediation analysis. All remaining biomarkers were sig- of vitamin D appeared to be broader than those that
nificantly related to vitamin D level (data not shown). we could capture with the biomarkers under study.
Tables 4 and 5 show the final mediation analysis AP is an enzyme that dephosphorylates endotoxins
results for respiratory symptoms and COPD, respec- and counters pro-inflammatory responses. It has been
tively. The top lines of each table show the vitamin proposed as a possible therapeutic agent for such con-
D effect before adding biomarkers; this is copied from ditions as sepsis, acute kidney injury, or brain
Table 2 but is repeated for ease of comparison. The injury.28–30 It has also been examined as a diagnostic
next lines show the odds ratios (ORs) and linear trends tool for pulmonary tuberculosis31 and as a marker of
28 Chronic Respiratory Disease 12(1)

Table 4. ORs, 95% CIs, and p values for linear trends testing the associations between vitamin D and respiratory symp-
toms before and after inclusion of biomarkers.a
Vitamin D quintileb
p value
I II III IV V for trend
Vitamin D only 1.35 (1.07–1.69) 1.24 (1.02–1.50) 1.08 (0.92–1.27) 0.94 (0.75–1.19) 1.00 0.01
Vitamin D (with CRP 1.33 (1.06–1.67) 1.22 (1.01–1.48) 1.09 (0.92–1.28) 0.95 (0.75–1.20) 0.02
Vitamin D (with AP) 1.29 (1.02–1.62) 1.19 (0.98–1.45) 1.05 (0.89–1.25) 0.93 (0.74–1.17) 0.05
Vitamin D (with monocytes) 1.32 (1.05–1.67) 1.23 (1.02–1.49) 1.08 (0.92–1.27) 0.94 (0.75–1.18) 0.02
Vitamin D (with neutrophils) 1.31 (1.04–1.64) 1.22 (1.02–1.48) 1.07 (0.91–1.26) 0.94 (0.75–1.18) 0.02
Vitamin D (with eosinophils) 1.31 (1.03–1.67) 1.23 (1.02–1.49) 1.07 (0.91–1.27) 0.93 (0.74–1.17) 0.02
Vitamin D (with all) 1.25 (0.98–1.61) 1.18 (0.97–1.43) 1.05 (0.88–1.25) 0.91 (0.72–1.16) 0.07
CI: confidence interval; OR: odds ratio; CRP: C-reactive protein; AP: alkaline phosphatase.
a
Models adjusted for covariates. Covariates include gender, age, race/ethnicity, overweight, obesity, current smoking, former smoking,
and season.
b
ORs are relative to the highest vitamin D quintile as the referent.

Table 5. Odds ratios, 95% CIs, and p values for linear trends testing the associations between vitamin D and COPD
before and after inclusion of biomarkers.a
Vitamin D quintileb
p value
I II III IV V for trend
Vitamin D only 1.36 (1.11–1.66) 1.51 (0.78–2.90) 1.34 (1.05–1.71) 1.11 (0.98–1.25) 1.00 0.0002
Vitamin D (with CRP) 1.32 (1.01–1.73) 1.48 (1.10–2.01) 1.35 (1.06–1.71) 1.11 (0.85–1.46) 0.005
Vitamin D (with AP) 1.26 (0.97–1.64) 1.44 (1.06–1.96) 1.31 (1.04–1.65) 1.10 (0.84–1.42) 0.01
Vitamin D (with monocytes) 1.36 (1.05–1.76) 1.49 (1.11–2.01) 1.32 (1.06–1.66) 1.10 (0.85–1.43) 0.004
Vitamin D (with neutrophils) 1.32 (1.02–1.72) 1.48 (1.10–1.99) 1.32 (1.05–1.65) 1.10 (0.85–1.43) 0.006
Vitamin D (with eosinophils) 1.36 (1.05–1.77) 1.51 (1.11–2.04) 1.33 (1.06–1.67) 1.10 (0.85–1.44) 0.004
Vitamin D (with all) 1.24 (0.94–1.65) 1.40 (1.03–1.89) 1.30 (1.03–1.63) 1.09 (0.84–1.42) 0.03
COPD: chronic obstructive pulmonary disease; CI: confidence interval; CRP: C-reactive protein; AP: alkaline phosphatase; OR: odds
ratio.
a
Models adjusted for covariates. Covariates include gender, age, race/ethnicity, overweight, obesity, current smoking, former smoking,
and season.
b
ORs are relative to the highest vitamin D quintile as the referent.

fibrosis in chronic interstitial lung disorders.17 Our
evidence suggests that AP is elevated in persons who
report more frequent respiratory symptoms or COPD
and that vitamin D may operate to help control serum
levels of this enzyme.
CRP is a pro-inflammatory cytokine. It is synthe-
sized primarily in the liver and kidney in response
to interleukins and other agents and can increase rap-
idly in concentration in the blood after infection or
inflammation.32 CRP plays a powerful and broad role
in anti-inflammatory, anti-infection, and immune
responses in a wide variety of disease states. CRP may
also be produced at lower levels in response to
ongoing chronic conditions including subclinical
inflammation.32 Some studies have suggested that
exposure to particulate matter air pollution causes
increases in CRP, which lends support to its potential
role as a marker in respiratory disease.33,34
It appears, however, that vitamin D may impact
measures of respiratory health through control of sys-
temic inflammation broadly, or possibly through
other mechanisms, rather than through these specific
markers as isolated paths. It is an oversimplification
to attempt to treat inflammatory markers as though
they acted independently of each other. Leukocytes
and CRP, for example, are interdependent.32
Our findings are limited by the particular biomar-
kers that were available for study. The NHANES
Hendryx and Luo
data did not include measures of some markers that
have been found to be related to vitamin D levels
in prior research, particularly the cytokine tumor
necrosis factor a (TNF-a) and interleukins (ILs) such
as IL-1 and IL-6.
Other limitations of the study concern the cross-
sectional design, the self-report nature of the outcome
data, and the limited covariate data included in the
analysis. The cross-sectional design restricts the abil-
ity to test for temporal relationships between vitamin
D, biomarker response, and subsequent occurrence of
symptoms and disease. This may be especially limit-
ing when considering that self-reported COPD diag-
nosis took place prior to NHANES data collection,
and respiratory symptoms were asked for occurrence
within the previous year. However, the fact that we
observed significant associations between vitamin D
and these respiratory measures, and between many
biomarkers and the respiratory measures, makes it
plausible to examine whether there may be evidence
for mediation. Nevertheless, we cannot exclude the
possibility of reverse causation. Independent assess-
ments of lung function such as through spirometry
were not available during the 2001–2006 period when
vitamin D was assessed. Respiratory symptom self-
report measures were restricted to the eight available
items. Measures of respiratory symptoms may repre-
sent persons with a variety of respiratory diseases
such as COPD, asthma, or other clinical or subclinical
lung disorders. For example, the relationships
observed between vitamin D, eosinophils, and
respiratory symptoms may reflect effects for persons
with asthma. Measures of dietary variables or medica-
tions that might influence vitamin D levels, media-
tors, or outcome measures were not included;
medications, for example, that work to improve
respiratory symptoms may obscure the impacts of
vitamin D, or diets high in anti-inflammatory proper-
ties may affect measures of biomarkers independently
of vitamin D.
Further research is necessary to better understand
how vitamin D exerts beneficial effects on respira-
tory health. The broad physiological importance of
vitamin D to autoimmune, infectious, and inflamma-
tory processes across multiple organ systems is
increasingly recognized but, as yet, incompletely
understood. Although this study did not isolate sin-
gle biomarkers that might account for links between
vitamin D and respiratory health, it would perhaps
have been more surprising had we found such evi-
dence, and instead, the results are perhaps more
29
properly reflective of the broader roles that vitamin
D plays in maintaining optimal health through its
impact on multiple processes.
Funding
This research received no specific grant from any funding
agency in the public, commercial, or not-for-profit sectors.
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