Vitamin D deficiency contributes directly to the acute respiratory distress syndrome (ARDS)

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DOI: 10.1136/thoraxjnl-2014-206680 · Source: PubMed
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Abstract
Vitamin D deficiency has been implicated as a pathogenic factor in sepsis and intensive therapy unit mortality but has not been assessed as a risk factor for acute respiratory distress syndrome (ARDS). Causality of these associations has never been demonstrated. To determine if ARDS is associated with vitamin D deficiency in a clinical setting and to determine if vitamin D deficiency in experimental models of ARDS influences its severity. Human, murine and in vitro primary alveolar epithelial cell work were included in this study. Vitamin D deficiency (plasma 25(OH)D levels <50 nmol/L) was ubiquitous in patients with ARDS and present in the vast majority of patients at risk of developing ARDS following oesophagectomy. In a murine model of intratracheal lipopolysaccharide challenge, dietary-induced vitamin D deficiency resulted in exaggerated alveolar inflammation, epithelial damage and hypoxia. In vitro, vitamin D has trophic effects on primary human alveolar epithelial cells affecting >600 genes. In a clinical setting, pharmacological repletion of vitamin D prior to oesophagectomy reduced the observed changes of in vivo measurements of alveolar capillary damage seen in deficient patients. Vitamin D deficiency is common in people who develop ARDS. This deficiency of vitamin D appears to contribute to the development of the condition, and approaches to correct vitamin D deficiency in patients at risk of ARDS should be developed. UKCRN ID 11994. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
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ORIGINAL ARTICLE
Vitamin D deciency contributes directly to the
acute respiratory distress syndrome (ARDS)
Rachel C A Dancer,
1
Dhruv Parekh,
1
Sian Lax,
1
Vijay DSouza,
1
Shengxing Zheng,
1
Chris R Bassford,
1
Daniel Park,
1
D G Bartis,
1
Rahul Mahida,
1
Alice M Turner,
1
Elizabeth Sapey,
1
Wenbin Wei,
2
Babu Naidu,
1
Paul M Stewart,
3
William D Fraser,
4
Kenneth B Christopher,
5
Mark S Cooper,
6
Fang Gao,
1
David M Sansom,
7
Adrian R Martineau,
8
Gavin D Perkins,
9
David R Thickett
1
Additional material is
published online only. To view
please visit the journal online
(http://dx.doi.org/10.1136/
thoraxjnl-2014-206680).
For numbered afliations see
end of article.
Correspondence to
Professor David Thickett,
Centre for Translational
Inammation and Fibrosis
Research, Queen Elizabeth
Hospital, University
of Birmingham, Birmingham
B15 2TH, UK;
d.thickett@bham.ac.uk
RCAD and DP are joint rst
author of this paper.
Received 10 December 2014
Revised 10 March 2015
Accepted 2 April 2015
To cite: Dancer RCA,
Parekh D, Lax S, et al.
Thorax Published Online
First: [please include Day
Month Year] doi:10.1136/
thoraxjnl-2014-206680
ABSTRACT
Rationale Vitamin D deciency has been implicated as
a pathogenic factor in sepsis and intensive therapy unit
mortality but has not been assessed as a risk factor for
acute respiratory distress syndrome (ARDS). Causality of
these associations has never been demonstrated.
Objectives To determine if ARDS is associated with
vitamin D deciency in a clinical setting and to
determine if vitamin D deciency in experimental models
of ARDS inuences its severity.
Methods Human, murine and in vitro primary alveolar
epithelial cell work were included in this study.
Findings Vitamin D deciency ( plasma 25(OH)D levels
<50 nmol/L) was ubiquitous in patients with ARDS and
present in the vast majority of patients at risk of
developing ARDS following oesophagectomy. In a
murine model of intratracheal lipopolysaccharide
challenge, dietary-induced vitamin D deciency resulted
in exaggerated alveolar inammation, epithelial damage
and hypoxia. In vitro, vitamin D has trophic effects on
primary human alveolar epithelial cells affecting >600
genes. In a clinical setting, pharmacological repletion of
vitamin D prior to oesophagectomy reduced the
observed changes of in vivo measurements of alveolar
capillary damage seen in decient patients.
Conclusions Vitamin D deciency is common in
people who develop ARDS. This deciency of vitamin D
appears to contribute to the development of the
condition, and approaches to correct vitamin D
deciency in patients at risk of ARDS should be
developed.
Trial registration UKCRN ID 11994.
INTRODUCTION
Acute respiratory distress syndrome (ARDS) occurs
due to either direct or indirect proinammatory
insults. However, only a proportion of at-risk
patients develop ARDS, with research suggesting
that genetic, age, social and other factors play a
role in determining who develops ARDS.
1
More than 1 billion people worldwide are
believed to have vitamin D deciency.
2
Vitamin D
has important functions besides bone and calcium
homeostasis
3
with cells of the innate and adaptive
immune system responding to vitamin D. Vitamin
Ddeciency may therefore increase the risk of bac-
terial and viral infection.
Vitamin D deciency is associated with an
increased risk of intensive care admission and mor-
tality in patients with pneumonia.
4
Deciency is
common in critically ill patients and associated
with adverse outcome.
3
Gram-positive bacteria,
invasive pneumococcal disease and meningococcal
disease are more common when 25(OH)D
3
levels
are low.
5
Recent data from an Austrian study in
critically ill decient patients suggests that when
treatment with vitamin D is successful in raising
levels >75 nmol/L there is a mortality benet.
6
Vitamin D may improve outcomes by reducing
both local and systemic inammatory responses as a
result of modulating cytokine responses.
7
In a mouse
model of lethal endotoxaemia, survival post intraven-
ous lipopolysaccharide (LPS) was signicantly poorer
in the vitamin D receptor knockout mice.
8
Our aim was to dene the prevalence and sever-
ity of vitamin D deciency in patients with ARDS
and to establish whether vitamin D deciency is a
risk factor for and/or a driver of the exaggerated
and persistent inammation that is a hallmark of
ARDS. To achieve these aims, we employed transla-
tional clinical studies and in vitro primary cell
work and murine models.
Key messages
What is the key question?
Is vitamin D deciency a risk factor for the
development of acute respiratory distress
syndrome (ARDS)?
What is the bottom line?
Patients with and at risk of ARDS are highly
likely to be decient, and severity of vitamin D
deciency relates to increased epithelial
damage, the development of ARDS and
survival.
Why read on?
We present evidence that an easily treatable
vitamin deciency may increase the risk of
ARDS in patients at risk.
Dancer RCA, et al.Thorax 2015;0:18. doi:10.1136/thoraxjnl-2014-206680 1
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METHODS
Patient cohorts
Patient cohort details are outlined in the online supplement but
consisted of 52 patients with ARDS, 57 patients undergoing
oesophagectomy (at risk of ARDS) and 8 patients undergoing
oesophagectomy who had high-dose vitamin D supplementation
prior to surgery.
Patients with ARDS: 52 patients who were recruited into the
rst beta agonist lung injury trial (BALTI-1) study
9
and the
translational sub-study of BALTI-2.
10
There was no difference in
age, sex, pre-enrolment Lung Injury score or acute physiology
and chronic health evaluation (APACHE) II in these two groups
of patients. Vitamin D levels were determined from ARDS
patient plasma collected on the day of enrolment. In the oeso-
phagectomy cohort, blood was collected on the day of the oper-
ationpre any intervention.
Aetiology of ARDS is outlined in table 1. As these cohorts of
patients were diagnosed prior to the Berlin criteria, throughout
the paper we have used ARDS to indicate patients meeting cri-
teria for acute lung injury or ARDS according to the denition
of the American European Consensus Conference.
11
Pulse Contour Cardiac Output Monitoring (PiCCO)
Extravascular lung water (EVLW) was measured using the single-
indicator transpulmonary thermodilution system (PiCCO-II;
Pulsion) as described previously.
12
In our study, the coefcient
of variance for this system was <7% for all parameters.
Vitamin D status: 25(OH)D
3
was measured by tandem mass
spectroscopy using appropriate Vitamin D External Quality
Assessment Scheme control. 1,25(OH)
2
D and vitamin D binding
protein (VDBP) were measured by ELISA. Denition of vitamin
D status is controversial, with different gures used throughout
the literature, but for this study we have considered plasma
25-OH vitamin D
3
levels <50 nmol/L as decient and levels
<20 nmol/L as severe deciency.
13 14
In addition, patients in the
at-risk cohort with 25(OH) vitamin D
3
<20 nmol/L had signi-
cantly lower 1,25(OH)
2
vitamin D than patients with higher
levels (<20 nmol/L 74 pmol/L vs >20 nmol/L 90 pmol/L,
p=0.029).
Murine cytokines were measured by multiplex array (R&D,
UK) or ELISA as per the manufacturers instruction.
ATII cell isolation and culture
ATII cells were extracted from lung resection specimens accord-
ing to the methods described previously
15
(see online supple-
mentary material).
Microarray analysis is outlined in the online supplementary
material.
Wound repair, proliferation and cell death assays were per-
formed as described previously.
16
Mouse methods
Wild-type (WT) C57Bl/6 mice were obtained from Harlan UK,
Oxford, UK, and maintained at BMSU, Birmingham University,
UK. Once weaned, vitamin D deciency was induced in WT
pups by feeding them a vitamin D-decient chow (Harlan, USA)
for 6 weeks pre-intra-tracheal (IT) LPS. 25(OH)-vitamin D was
assessed by direct ELISA (ImmunDiagnostik, Germany). The
LPS challenge model was performed as described previously.
17
Briey, mice are anaesthetised and 50 mg LPS (Sigma, UK)
instilled by IT route as a model of direct lung injury. Mice were
sacriced at neutrophilic peak, 48 h post-LPS instillation, and
bronchoalveolar lavage (BAL) performed with two washes of
0.6 mL phosphate buffered saline (PBS)/EDTA (200 nM) instal-
lations to determine the local effects on inammation.
Untreated controls were also analysed to determine lung para-
meters in vitamin D-decient mice. BAL uid (BALF) was
assessed for cellular inammation by cell count, neutrophilia
and neutrophil apoptosis (ow cytometry), markers of epithelial
damage BALF receptor for glycosylated endpoints (BALF
RAGE), protein permeability index (ratio of BALF protein:
plasma protein) as well as cytokines by luminex array (R&D
systems, UK). Results represent mice from three separate experi-
ments with at least four replicates per group. Oxygen satura-
tions were measured at 48 h post-LPS and compared with WT
mice given PBS by MouseOx II Plus (n=8 for each condition).
All experiments were performed in accordance with UK laws
with approval of local animal ethics committee.
Statistics Data were analysed using SPSS for Windows 16.0
(SPSS, Chicago, Illinois, USA). Data were tested for normality
and analysed by unpaired t tests or MannWhitney U test. Data
are expressed as mean (SD) unless otherwise indicated. A χ
2
or
Fishers exact test was used to compare proportions.
Table 1 Comparison of demographics between ARDS and at-risk patients who were undergoing oesophagectomy
ARDS (n=52) At risk (n=65) p Value
Male, n (%) 30 (57) 57 (87.6) <0.001
Age (years), mean (SD) 61.3 (16.7) 62.8 (10.8) 0.560
Predisposing condition, n (%) Pneumonia 18 (35)
Other sepsis 24 (46)
Aortic aneurysm repair 3 (6)
Chest trauma 2 (3.8)
Pancreatitis 1 (1.9)
Transfusion-related lung injury 1 (1.9)
Other 3 (6)
Oesophagectomy 65 (100) n/a
LIS, median (IQR) 2.75 (2.503.19) 1.5 (1.02.0) <0.001
APACHE II median (IQR) 24 (1928) 12 (814) <0.001
Worst P/F ratio during admission, mean (SD) 14.9 (5.2) 31.5 (9.9) <0.001
Hospital survival, n (%) 16 (30.8) 62 (95.4) <0.001
Length of hospital stay for survivors (days), median (IQR) 35 (1649) 17 (1028) 0.025
Statistical tests used are χ
2
t test where data is normally distributed and KruskalWallis for non-parametric data.
APACHE, acute physiology and chronic health evaluation; ratio of arterial oxygen tension to the fraction of inspired oxygen (Pao
2
:Fio
2
), arterial oxygen tension: fractional inspired
oxygen; ARDS, acute respiratory distress syndrome; LIS, lung injury score.
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To test the hypothesis that low 25(OH)D levels are associated
with the development of ARDS in the at-risk oesophagectomy
cohort (N=65), we performed multivariable logistic regression
with the exposure of interest being 25(OH)D
3
level <20 nmol/L
and ARDS as the outcome. Adjusted ORs were estimated by multi-
variable logistic regression models with inclusion of covariate
terms chosen, a priori, thought to be plausibly associated with
both 25(OH)D
3
level and ARDS in the oesophagectomy patient
cohort. We sought to build a parsimonious model that did not
unnecessarily adjust for covariates that did not affect bias or the
causal relation between exposure and outcome. Model calibration
was assessed using the HosmerLemeshow (HL) χ
2
goodness-of-t
test and the accompanying p value. Bayesian information criterion
and Akaike information criterion were also used to determine
global model t. Covariates included in the logistic regression
model were age, gender, diagnosis, staging and pack-years
smoked. The discriminatory ability for ARDS was quantied using
the c-statistic. In all analyses, p values are two-tailed and values
below 0.05 were considered statistically signicant.
RESULTS
Plasma vitamin D status in patients with or at risk of ARDS
Patients with ARDS (100%) were vitamin D-decient ( plasma
25(OH)D
3
<50 nmol/L). In total, 55 (96%) out of 57
unsupplemented oesophagectomy patients at risk of ARDS were
decient preoperatively but levels were higher than in patients
with ARDS. Both patients at risk and patients with ARDS had
signicantly lower levels of 25(OH)D
3
than normal controls
(see gure 1). Demographics of patients groups based on
vitamin D levels are illustrated in table 2.
In at-risk patients, preoperative median plasma levels of 25
(OH)D
3
were signicantly lower in those patients who were ven-
tilated with ARDS postoperatively (ARDS 16.97 nmol/L vs no
ARDS 25.46 nmol/L, p=0.014). Oesophagectomy patients with
severe vitamin D deciency (plasma 25(OH)D
3
<20 nmol/L)
had a 37.5% risk of postoperative lung injury as opposed to a
15% risk with vitamin D levels >20 nmol/L (gure 2).
In the at-risk oesophagectomy cohort, preoperative vitamin D
status was the only measure to have a signicant difference in
oesophagectomy patients who develop lung injury postopera-
tively (see table 3).
The odds of ARDS in patients with 25(OH)D
3
<20 nmol/L
was 3.5-fold that of patients with 25(OH)D
3
20 nmol/L
(OR=3.5 (95% CI 1.06 to 11.6; p=0.040)). Following adjust-
ment for gender, age, diagnosis, staging data, and pack-years,
patients with 25(OH)D
3
<20 nmol/L had a 4.2-fold higher
odds of ARDS than patients with 25(OH)D <20 nmol/L
(OR=4.2 (95% CI 1.13 to 15.9; p=0.032)). The adjusted
model showed good calibration (HL χ
2
11.10, p=0.20) and dis-
crimination for ARDS (area under the curve 0.73). When 25
(OH)D was analysed with logistic regression as a continuous
Figure 1 Plasma 25(OH)D
3
levels in acute respiratory distress
syndrome (ARDS) versus at risk and normal controls. The horizontal bar
represents the median, and the boxes represent IQRs. Vertical lines
show minimummaximum range. Fifty-two patients with ARDS, 57
at-risk patients undergoing oesophagectomy, 18 healthy controls.
Table 2 Comparison of demographics between patients with severe deficiency, moderate deficiency and vitamin D supplemented at-risk
patients undergoing oesophagectomy
Patients with severe
25-OH vitamin D
3
deficiency (n=25)
Patients with moderate
25-OH vitamin D
3
deficiency (n=32)
Patients who received
vitamin D supplementation
(n=8) p Value
Male, n (%) 21 (84) 28 (87.5) 8 (100) 0.706
Age, years
median (IQR)
60.0 (52.068.5) 65.5 (54.572.0) 68.0 (63.871.3) 0.122
BMI median (IQR) 24.3 (20.627.9) 25.4 (21.728.3) 24.1 (22.026.6) 0.698
ASA median (IQR) 2.0 (2.02.0) 2.0 (2.02.0) 2.0 (2.02.75) 0.950
Postoperative P/F ratio 41.0 (34.353.3) 39.8 (32.052.0) 47.8 (39.450.8) 0.476
Preoperative plasma 25-OH vitamin D
3
level (nmol/L)
median (IQR)
13.7 (10.916.7) 27.6 (22.534.9) 66.9 (42.592.6) <0.001
All p values shown are KruskalWallis tests from SPSS.
ASA, American Society of Anaesthesiologists physical status classification system; BMI, body mass index.
Figure 2 Risk of postoperative acute respiratory distress syndrome in
severe 25(OH)D
3
deciency versus less severe deciency. Severe
deciency (n=25), less severe (n=32).
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exposure in 1 nmol/L increments, the odds of ARDS decreases
by 17% for every 1 nmol/L decrease in 25(OH)D (OR 0.83
(95% CI 0.69 to 0.98; p=0.033)), adjusted for age, gender,
diagnosis, staging and pack-years smoked.
Plasma levels of 1,25(OH)
2
D are lowest in ITU non-survivors
Median plasma 1,25(OH)
2
D levels were also signicantly lower
in patients with ARDS (35.5 pmol/L) than in at-risk patients
(85 pmol/L, p=0.0001). Plasma 1,25(OH)
2
D was lower at
admission to intensive therapy unit (ITU) in patients who died
than survivors (gure 3). Plasma levels of 1,25(OH)
2
D were
lower in oesophagectomy patients at risk of ARDS who subse-
quently went on to be ventilated for ARDS (68 pmol/L (IQR
4791)) than those who did not get postoperative ARDS
(89 pmol/L (IQR 76109), p=0.007).
Plasma VDBP levels are lower in patients with ARDS.
25(OH)D
3
circulates tightly bound to the VDBP (also known as
Gc-actin).
18
VDBP levels were 40 mg/dL in normal controls,
19 mg/dL in ARDS and 28.7 mg/mL in the at-risk patients at the
beginning of oesophagectomy (gure 4).
Vitamin D levels and perioperative changes in epithelial
integrity in patients at risk of ARDS
We measured perioperative changes in an in vivo measure of the
integrity of the alveolarcapillary barrier, namely EVLW accu-
mulation (extravascular lung water index (EVLWI)) and pulmon-
ary vascular permeability index (PVPI) using a PiCCO
2
catheter
1922
and related this to the patients vitamin D status.
Severe vitamin D deciency (25-(OH)D
3
<20 nmol/L) was
associated with an increased accumulation of EVLW as assessed
by PiCCO EVLWI and evidence of increases of PVPI, a marker
of alveolar capillary permeability. Patients supplemented with
Table 3 Univariate analysis of predictors of postoperative ARDS in patients undergoing oesophagectomy
Patients with ARDS (n=15) Patients without ARDS (n=50) p Value
Male, n (%) 14 (93) 43 (86) 0.448
Age (years), median (IQR) 61 (5366) 66 (5671) 0.304
BMI (kg/cm
2
), median (IQR) 25.2 (23.929.1) 24.8 (21.628.1) 0.460
FEV
1
(L), median (IQR) 2.69 (2.283.50) 2.85 (2.383.3) 0.901
FVC (L), median (IQR) 4.3 (3.45.2) 4.1 (3.54.7) 0.450
Tumour type=adenocarcinoma, n (%) 12 (80) 35 (70) 0.511
Tumour stage, n (%)*
T2 4 (27) 12 (24) 0.865
T3 11 (73) 37 (76)
N0 3 (20) 12 (24) 0.719
N12 12 (80) 37 (76)
Smoker, n (%)
Current 6 (40) 11 (22) 0.304
Former 7 (47) 34 (68)
Never 2 (13) 5 (10)
Pack-years, median (IQR) 30 (2040) 30 (1545) 0.740
Plasma 25-OH vitamin D
3
(nmol/L), Median (IQR) 16.97 (12.9822.46) 25.46 (17.3539.77) 0.014
Plasma 1,25(OH)
2
vitamin D (pmol/L), median (IQR) 68 (4791) 89 (76109) 0.007
Only preoperative 25(OH)D
3
and 1,25(OH)
2
D vitamin D were significantly different in univariate analysis.
*No lung function available for seven patients, pack-years not available for two patients. One patient (without lung injury) had a benign tumournot included in staging data.
ARDS, acute respiratory distress syndrome; BMI, body mass index.
Figure 3 Plasma 1,25(OH)
2
D was signicantly higher in patients with
acute respiratory distress syndrome who survived at least 28 days
following admission than those who died. The horizontal bar represents
the median, and the boxes represent IQRs. Vertical lines show
minimummaximum range. Died (n=32), survived (n=20).
Figure 4 Plasma vitamin D binding protein measured by ELISA in
acute respiratory distress syndrome (ARDS) versus at risk and normal
controls. Fifty-two patients with ARDS, 57 at-risk patients undergoing
oesophagectomy, 18 healthy controls.
4 Dancer RCA, et al.Thorax 2015;0:18. doi:10.1136/thoraxjnl-2014-206680
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vitamin D prior to oesophagectomy had signicantly reduced
changes in PiCCO EVLWI and PVPI than unsupplemented
patients (gures 5 and 6).
Vitamin D deciency is a determinant of inammation and
epithelial injury in the intratracheal LPS murine model of
ALI/ARDS
We studied the response to 50 mg of IT LPS in WT or mice
made vitamin D decient by dietary manipulation. Decient
mice were fed a vitamin D-free diet for 6 weeks and had
median plasma vitamin 25(OH)D
3
levels of 8 nmol/L (SEM
1.15 nmol/L) vs 42 nmol/L (SEM 2.17 nmol/L) in WT
(p=0.001). Untreated vitamin D-decient mice had no observed
lung damage or inammation (gure 7, and data not shown).
Following LPS challenge, vitamin D-decient mice had
increased evidence of alveolar epithelial damage as measured by
BALF RAGE and BALF permeability index (gure 7A). Cellular
inammation and neutrophil apoptosis in BALF were also ele-
vated in vitamin D-decient mice, along with release of proin-
ammatory cytokines tumour necrosis factor-α, CXCL1/KC and
vascular endothelial growth factor (gure 7B and C, respect-
ively). These changes resulted in signicantly lower oxygen sat-
uration as measured by pulse oximetry (gure 7C), which we
have previously demonstrated as a physiological measure of
murine lung function.
15
Vitamin D is trophic for alveolar epithelial cells in vitro
ATII cells were treated with 100 nmol/L of 25(OH)D
3
for 24 h.
Microarray analysis revealed that vitamin D treatment caused a
sustained activation or inhibition of 660 genes that included
pathways involved in vitamin metabolism as well as regulators
of cell growth, differentiation and response to wounding
(GEOSET record GSE46749). The online supplementary table
SA and SB outline the top 25 genes up-regulated and down-
regulated by vitamin D and a heat map illustrating up-regulated
and down-regulated genes. Table 4 outlines the biological pro-
cesses and molecular functions modied by vitamin D treat-
ment. Several of the identied pathways had signicant
relevance to proliferation, wound repair and apoptosis, so we
tested the functional effects of vitamin D upon these important
repair/protective processes.
Effect of physiologically relevant doses of 25(OH)D
3
upon
primary human alveolar type II cells
25(OH)D
3
at physiologically relevant concentrations stimulated
scratch wound repair, cell proliferation and attenuated soluble
Fas ligand (sFasL)-mediated cell death (see gures 810).
DISCUSSION
We have assessed the vitamin D status of a large cohort of
patients with ARDS and a well-characterised group of patients
at risk of ARDS, namely patients undergoing oesophagectomy.
In ARDS cases, vitamin D deciency was ubiquitous. Survivors
of ARDS had signicantly higher levels of vitamin D than
non-survivors.
Our nding of a 30% reduction in VDBP in patients with
ARDS supports a role for either reduced production or
increased losses as an explanation for some of the degree of
deciency seen. Equally the low observed levels of circulating
1,25(OH)
2
D in patients with ARDS suggests a problem with
renal metabolism as this is probably the major source of circulat-
ing 1,25(OH)
2
D.
23
Several studies have suggested that vitamin D deciency may
be a risk factor for adverse outcome in pneumonia
24
and lower
respiratory tract infections in neonates.
25
Other studies have
suggested patients with sepsis have signicant vitamin D de-
ciency.
26 27
Our data suggests in the high-risk oesophagectomy
group that vitamin D status is also a pre-existing risk factor for
ARDSespecially when deciency is severe. Patients undergo-
ing oesophagectomy with severe preoperative vitamin D de-
ciency had greater risk of postoperative ARDS and increases in
PiCCO measures of alveolar permeability than those with less
severe deciency.
In our animal model of LPS-induced lung injury, vitamin D
deciency was associated with greater BALF cellular inamma-
tion and cytokine release at 48 h. Increased epithelial damage
and accumulation of apoptotic neutrophils was also evident.
Mice that were vitamin D decient became more hypoxic, sug-
gesting physiologically worse lung injury.
Our animal data is in keeping with recently published data in
hamsters treated with LPS.
28
In contrast, Klaff et al found
reduced neutrophil chemotactic potential to the chemokine KC
ex vivo in mice decient in vitamin D but no differences in
LPS-induced BALF neutrophilia. They used a 72 h time point
Figure 5 Changes in extravascular lung water index (EVLWI) at the
end of oesophagectomy and on the morning of postoperative day 1.
EVLWI was measured using Pulse Contour Cardiac Output Monitoring II
catheter at the end of the operation and on the morning after the
operation (day 1). Severe decient (n=25), moderate (n=32) and
supplemented (n=8).
Figure 6 Changes in Pulse Contour Cardiac Output Monitoring
pulmonary vascular permeability index (PVPI) at the end of
oesophagectomy and the morning of postoperative day 1. Severe
decient (n=25), moderate (n=32) and supplemented (n=8).
Dancer RCA, et al.Thorax 2015;0:18. doi:10.1136/thoraxjnl-2014-206680 5
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and a much lower dose of LPS (2.5 mg), which we suggest
accounts for the differences with our study.
In both our human at-risk patients and the murine model, we
have demonstrated evidence of increased permeability of the
alveolar capillary barrier in response to one lung ventilation
(EVLWI and PVPI) and LPS challenge respectively (PPI) when
severe deciency is present, suggesting that vitamin D might
have protective effects on the alveolar epithelium as well as
being anti-inammatory. 1,25(OH)
2
D has been shown to induce
DNA incorporation in human alveolar type II cells,
29
but the
effects of physiologically relevant doses of 25(OH)D have not
been addressed upon type II cells previously. To address
whether 25(OH)D
3
has effects on ATII cells, we demonstrated
considerable functional activity of a physiological dose of 25
(OH)D
3
by microarray analysis. Physiologically relevant doses
of 25(OH)D
3
stimulated wound repair, cellular proliferation
and reduced sFasL-induced cell death. These in vitro experi-
ments suggest that 25(OH)D
3
may play a trophic role on adult
human alveolar epithelial cells.
This study has limitations. First, although we obtained blood
from patients with ARDS as soon as possible following admis-
sion to ITU, we are unable to be sure that levels of 25(OH)D
3
were low prior to the development of ARDS in that cohort or
whether levels fall because of the development of ARDS.
Second, our at-risk data from oesophagectomy patients has to
be divided into severe deciency and moderate deciency
because of the severity of vitamin D deciency observed in that
patient group. Third, our data in oesophagectomy patients
needs validating in an additional signicant cohort as well as in
other patient groups at risk of ARDS. Finally, our comparison of
EVLWI between our patients in BALTI prevention cohort versus
our oesophagectomy patients in the open label vitamin D
replacement study is a potential limitation. However, the trans-
lational protocol of assessments and the two centres in which
those assessments were performed was the same between the
two studies.We are currently conducting a randomised placebo
controlled trial to conrm these results due to nish recruitment
in mid-2015, which should further address this question.
30
Figure 7 Lung injury and inammation was signicantly higher in vitamin D-decient mice compared with wild-type (WT) following intra-tracheal
(IT)-lipopolysaccharide (LPS). Levels of tumour necrosis factor-αand CXCL1/KC in UTCs were below the detection threshold of the assays performed.
UTC, untreated control; N.D., not detected.
6 Dancer RCA, et al.Thorax 2015;0:18. doi:10.1136/thoraxjnl-2014-206680
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Taken together, these data suggest that vitamin D deciency is
ubiquitous in patients with ARDS and relates to adverse
outcome. In patients undergoing oesophagectomy, severe pre-
operative deciency is associated with evidence of increased
alveolar epithelial damage and EVLW accumulation as well as an
increased risk of postoperative lung injury. Novel in vitro data
further suggest a trophic and antiapoptotic role of physiologic-
ally relevant doses of 25(OH)D
3
upon primary adult human
alveolar epithelial cells. Finally, preoperative restoration of
vitamin D levels in patients with oesophageal cancer who are at
risk of ARDS resulted in signicantly less accumulation of
EVLW than in unsupplemented patients postoperatively.
In conclusion, we suggest that clinical strategies should be
developed to replete vitamin D levels in patients at risk of
ARDS and this approach might also have value as a treatment
for established ARDS.
Table 4 List of 30 statistically significant gene ontology (GO)
terms implicated by differential expression of genes in day 3
epithelial (type II like) cells treated with vitamin D
3
100 nM relative
to untreated cells
GO
Annotated
genes Total p Value
587 2230
Immune response 48 76 0.00000
Immune system process 58 103 0.00000
Cytokine activity 25 36 0.00001
Extracellular process 45 86 0.00003
Signal transducer activity 75 173 0.00008
Molecular transducer activity 75 173 0.00008
Plasma membrane 133 356 0.00013
DNA replication 20 29 0.00015
Receptor activity 57 124 0.00015
Defence response 42 83 0.00015
Monoxygenase activity 12 13 0.00018
ATPase activity, coupled to transmembrane
movement of substances
6 107 (0.00018)
Primary active transmembrane transporter
activity
6 107 (0.00018)
Hydrolase activity, acting on acid
anhydrides, catalysing transmembrane
movement of substances
6 107 (0.00018)
P-P-bond-hydrolysis-driven transmembrane
transporter activity
6 107 (0.00018)
ATPase activity, coupled to movement of
substances
6 107 (0.00018)
Cell surface receptor linked signal
transduction
69 162 0.00025
Chemotaxis 14 17 0.00027
Taxis 14 17 0.00027
Response to external stimulus 50 108 0.00030
Response to wounding 38 76 0.00043
Heme binding 12 14 0.00060
Tetrapyrrole binding 12 14 0.00060
Cellular biosynthetic process 15 145 (0.00105)
Biosynthetic process 29 214 (0.00121)
Extracellular region part 58 137 0.00168
Nucleotide biosynthetic process 1 61 (0.00168)
Cell cycle process 44 97 0.00208
Nucleobase-containing small molecule
metabolic process
3 69 (0.00412)
Nucleotide metabolic process 3 68 (0.00466)
p values of underrepresented GO terms are denoted in parentheses.
Figure 8 Scratch wound repair response of primary human alveolar
type II cells to 25(OH)D
3
. Wound area after 24 h was compared with
baseline and expressed as fold change in wound area. Data represents
experiments using cells from six separate lung resection specimens.
Analysis of variance p=0.001.
Figure 9 Proliferation of primary human ATII cells in response to
physiological doses of 25(OH)D
3
by bromodeoxyuridine incorporation.
Experiments were performed using cells from four donors. Analysis of
variance p=0.001.
Figure 10 Cellular response to soluble Fas ligand (sFasL) 10 ng/mL
induced cell death. Experiments were performed using ATII cells from
four donors. 100 nmol/L 25(OH)D
3
was added at the time of addition
of sFasL.
Dancer RCA, et al.Thorax 2015;0:18. doi:10.1136/thoraxjnl-2014-206680 7
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Author afliations
1
Centre for Translational Inammation and Fibrosis Research, School of Clinical and
Experimental Medicine, University of Birmingham, Birmingham, UK
2
School of Cancer Sciences, University of Birmingham, Birmingham, UK
3
Centre for Endocrinology, Diabetes and Metabolism, School of Clinical and
Experimental Medicine, University of Birmingham, Birmingham, UK
4
Norwich Medical School, University of East Anglia, Norwich, UK
5
Renal Division, Brigham and Womens Hospital, Harvard Medical School, Boston,
Massachusetts, USA
6
Department of Medicine, Concord Medical School, University of Sydney, Sydney,
New South Wales, Australia
7
Institute of Immunity and Transplantation, University College London, London, UK
8
Blizard Institute, Queen Mary University of London, London, UK
9
Warwick Clinical Trials Unit, Warwick Medical School, University of Warwick,
Coventry, UK
Correction notice This article has been corrected since it was published Online First.
The authorsnameWilliam M Fraser was incorrect and should be William D Fraser.
Acknowledgements We would like to thank the staff and patients of the Queen
Elizabeth Hospital Birmingham and Heart of England NHS trust for their help in
recruiting to and taking part in these studies. We would like to thank Teresa Melody
and Amy Bradley for trial nurse support for the study.
Contributors RCAD and DP are joint rst authors. DRT, FG, ARM, PMS, MSC,
WMF and GDP designed the study. SL, VD, SZ, CRB, DP, BN, RM, AMT and ES
recruited the patients and undertook lab analysis/animal work. WW, PMS, WMF,
KBC and MSC provided expert advice in their specialist areas. All authors
contributed to the writing of the paper. DT is the guarantor of the data.
Funding These studies were funded by the Wellcome trust (DRT, PMS, MSC, SL),
QEHB charities (RCAD, VD, DRT), the Medical Research Council UK (DRT, DP, RCAD)
and the NIHR (DP, DRT, GDP). DB was funded by an ERS long-term training
fellowship and a Marie Curie Intra-European Fellowship.
Competing interests None declared.
Patient consent Obtained
Ethics approval NHS LREC West midlands and all clinical investigations were
conducted according to Declaration of Helsinki principles.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement The microarray dataset outlined in this paper is freely
available to search on PubMed GEOSET.
Open Access This is an Open Access article distributed in accordance with the
terms of the Creative Commons Attribution (CC BY 4.0) license, which permits
others to distribute, remix, adapt and build upon this work, for commercial use,
provided the original work is properly cited. See: http://creativecommons.org/
licenses/by/4.0/
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(ARDS)
the acute respiratory distress syndrome
Vitamin D deficiency contributes directly to
Thickett
David M Sansom, Adrian R Martineau, Gavin D Perkins and David R
William D Fraser, Kenneth B Christopher, Mark S Cooper, Fang Gao,
Turner, Elizabeth Sapey, Wenbin Wei, Babu Naidu, Paul M Stewart,
Zheng, Chris R Bassford, Daniel Park, D G Bartis, Rahul Mahida, Alice M
Rachel C A Dancer, Dhruv Parekh, Sian Lax, Vijay D'Souza, Shengxing
published online April 22, 2015Thorax
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Supplementary resource

May 2015
Rachel C A Dancer · Dhruv Parekh · Sian Lax · Vijay D'Souza · David R Thickett
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    Importance Low vitamin D status is linked to increased mortality and morbidity in patients who are critically ill. It is unknown if this association is causal.Objective To investigate whether a vitamin D3 treatment regimen intended to restore and maintain normal vitamin D status over 6 months is of health benefit for patients in ICUs.Design, Setting, and Participants A randomized double-blind, placebo-controlled, single-center trial, conducted from May 2010 through September 2012 at 5 ICUs that included a medical and surgical population of 492 critically ill adult white patients with vitamin D deficiency (≤20 ng/mL) assigned to receive either vitamin D3 (n = 249) or a placebo (n = 243).Interventions Vitamin D3 or placebo was given orally or via nasogastric tube once at a dose of 540 000 IU followed by monthly maintenance doses of 90 000 IU for 5 months.Main Outcomes and Measures The primary outcome was hospital length of stay. Secondary outcomes included, among others, length of ICU stay, the percentage of patients with 25-hydroxyvitamin D levels higher than 30 ng/mL at day 7, hospital mortality, and 6-month mortality. A predefined severe vitamin D deficiency (≤12 ng/mL) subgroup analysis was specified before data unblinding and analysis.Results A total of 475 patients were included in the final analysis (237 in the vitamin D3 group and 238 in the placebo group). The median (IQR) length of hospital stay was not significantly different between groups (20.1 days [IQR, 11.1-33.3] for vitamin D3 vs 19.3 days [IQR, 11.1-34.9] for placebo; P = .98). Hospital mortality and 6-month mortality were also not significantly different (hospital mortality: 28.3% [95% CI, 22.6%-34.5%] for vitamin D3 vs 35.3% [95% CI, 29.2%-41.7%] for placebo; hazard ratio [HR], 0.81 [95% CI, 0.58-1.11]; P = .18; 6-month mortality: 35.0% [95% CI, 29.0%-41.5%] for vitamin D3 vs 42.9% [95% CI, 36.5%-49.4%] for placebo; HR, 0.78 [95% CI, 0.58-1.04]; P = .09). For the severe vitamin D deficiency subgroup analysis (n = 200), length of hospital stay was not significantly different between the 2 study groups: 20.1 days (IQR, 12.9-39.1) for vitamin D3 vs 19.0 days (IQR, 11.6-33.8) for placebo. Hospital mortality was significantly lower with 28 deaths among 98 patients (28.6% [95% CI, 19.9%-38.6%]) for vitamin D3 compared with 47 deaths among 102 patients (46.1% [95% CI, 36.2%-56.2%]) for placebo (HR, 0.56 [95% CI, 0.35-0.90], P for interaction = .04), but not 6-month mortality (34.7% [95% CI, 25.4%-45.0%] for vitamin D3 vs 50.0% [95% CI, 39.9%-60.1%] for placebo; HR, 0.60 [95% CI, 0.39-0.93], P for interaction = .12).Conclusions and Relevance Among critically ill patients with vitamin D deficiency, administration of high-dose vitamin D3 compared with placebo did not reduce hospital length of stay, hospital mortality, or 6-month mortality. Lower hospital mortality was observed in the severe vitamin D deficiency subgroup, but this finding should be considered hypothesis generating and requires further study.Trial Registration clinicaltrials.gov Identifier: NCT01130181
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    Background Acute lung injury occurs in approximately 25% to 30% of subjects undergoing oesophagectomy. Experimental studies suggest that treatment with vitamin D may prevent the development of acute lung injury by decreasing inflammatory cytokine release, enhancing lung epithelial repair and protecting alveolar capillary barrier function. Methods/Design The ‘Vitamin D to prevent lung injury following oesophagectomy trial’ is a multi-centre, randomised, double-blind, placebo-controlled trial. The aim of the trial is to determine in patients undergoing elective transthoracic oesophagectomy, if pre-treatment with a single oral dose of vitamin D3 (300,000 IU (7.5 mg) cholecalciferol in oily solution administered seven days pre-operatively) compared to placebo affects biomarkers of early acute lung injury and other clinical outcomes. The primary outcome will be change in extravascular lung water index measured by PiCCO® transpulmonary thermodilution catheter at the end of the oesophagectomy. The trial secondary outcomes are clinical markers indicative of lung injury: PaO2:FiO2 ratio, oxygenation index; development of acute lung injury to day 28; duration of ventilation and organ failure; survival; safety and tolerability of vitamin D supplementation; plasma indices of endothelial and alveolar epithelial function/injury, plasma inflammatory response and plasma vitamin D status. The study aims to recruit 80 patients from three UK centres. Discussion This study will ascertain whether vitamin D replacement alters biomarkers of lung damage following oesophagectomy. Trial registration Current Controlled Trials ISRCTN27673620
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    Acute Lung Injury (ALI) and the more severe form Acute Respiratory Distress Syndrome (ARDS) remain a significant cause of morbidity and mortality in the critically ill patient. It is characterised by a severe inflammatory process resulting in diffuse alveolar damage, influx of neutrophils, macrophages and a protein rich exudate in the alveolar spaces caused by endothelial and epithelial injury. Improvements in outcomes are in part due to restrictive fluid management and protective lung ventilation however successful therapeutic strategies remain elusive with promising therapies failing to translate positively in human studies. The evidence for the role of vitamin D in lung disease is growing - deficiency has been associated with impaired pulmonary function, increased incidence of viral and bacterial infections and inflammatory disease including asthma and COPD. Studies have also reported a high prevalence of vitamin D deficiency in the critically ill and an association with adverse outcomes. Although exact mechanisms are yet to be discerned, vitamin D appears to impact on a variety of inflammatory and structural cells within the lung including macrophages, lymphocytes and epithelial cells. To date there are few directly supportive clinical studies in ALI; this review explores the compelling evidence suggesting arole for vitamin D in ALI and the mechanisms by which it could contribute to pathogenesis.
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    Objective: To determine the relationship between cord blood 25-hydroxyvitamin D [25 (OH) D] concentrations and the subsequent risk of acute lower respiratory tract infection (ALRI) in the first 2 years of life. Patients and methods: Cord blood from 206 newborns was tested for 25 (OH) D. Medical records covering the first 2 years of life were reviewed, and the diagnosis of ALRI was recorded. Results: Sixty-two (30.1%) infants developed ALRI in their first 2 years of life, of whom 49 (79%) infants had bronchiolitis and 13 (21%) infants had pneumonia. Concentrations of 25 (OH) D were lower in infants who developed ALRI compared with those did not (p < 0.0001). Vitamin D deficiency was associated with increased risk of ALRI (p = 0.000). Conclusion: Low cord blood 25 (OH) D levels are associated with increased risk of ALRI in the first 2 years of life.