Egyptian Journal of Chest Diseases and Tuberculosis (2015) 64, 67–73

HO ST E D BY

The Egyptian Society of Chest Diseases and Tuberculosis

Egyptian Journal of Chest Diseases and Tuberculosis

www.elsevier.com/locate/ejcdtwww.sciencedirect.com

ORIGINAL ARTICLE

Vitamin D and chronic obstructive pulmonary

disease

* Corresponding author. Tel.: +20 01001862270.

E-mail address: azza20022@yahoo.com (A.F. Said).

Peer review under responsibility of The Egyptian Society of Chest

Diseases and Tuberculosis.

http://dx.doi.org/10.1016/j.ejcdt.2014.11.0330422-7638 ª 2014 Production and hosting by Elsevier B.V. on behalf of The Egyptian Society of Chest Diseases and Tuberculosis.

Azza Farag Said a,*, Emad Allam Abd-Elnaeem b

a Chest Diseases Department, Minia University, Egyptb Clinical Pathology Department, Minia University, Egypt

Received 22 August 2014; accepted 30 November 2014Available online 5 January 2015

KEYWORDS

Chronic obstructive

pulmonary disease;

Vitamin D;

Pulmonary function tests;

COPD outcomes

Abstract Background: Evidence is increasing that suggests an expanded role of vitamin D in

health outcomes apart from its classic actions on the bone and calcium homeostasis. Vitamin D

deficiency has been associated with some chronic respiratory illnesses; one of them is chronic

obstructive pulmonary disease (COPD).

Objective: This study was designed to detect vitamin D level among stable COPD patients. The

effect of vitamin D supplements (200,000 IU monthly for 6 months) with regular therapy of COPD

on COPD outcomes was also evaluated.

Patients and methods: Pulmonary function test (PFT), COPD assessment test (CAT), 6 min walk

test (6MWT), serum 25-hydroxyvitamin D (25-OHD) and ionized calcium were performed on 61

COPD patients (50 males and 11 females, mean age 61.1 years). PFT and clinical assessment were

carried out at the start and completion of 6 month treatment among those with vitamin D defi-

ciency. Twenty healthy age-matched and sex matched volunteers were also studied as a control

group.

Results: The distribution of vitamin D status including vitamin D deficiency, vitamin D insuffi-

ciency and vitamin D sufficiency was 16.4%, 34.4% and 49.2% respectively among COPD patients.

There was no significant improvement of 6MWT, CAT score and PFT among those treated with

vitamin D supplements in addition to standard therapy of COPD.

Conclusion: Low serum level of vitamin D was less common among COPD patients than other

studies and correlates with severity of COPD. 6 month supplementation of standard treatment with

200,000 IU monthly of vitamin D did not provide additional clinical benefit among COPD patients.ª 2014 Production and hosting by Elsevier B.V. on behalf of The Egyptian Society of Chest Diseases and

Tuberculosis.

Introduction

Cholecalciferol (vitamin D3) is synthesized upon exposure ofthe skin to (ultraviolet) UV radiation resulting in the conver-sion of endogenous 7-dehydrocholesterol to previtamin D3,which isomerizes to vitamin D3. To a lesser extent, vitamin

68 A.F. Said, E.A. Abd-Elnaeem

D can be sourced in the diet from foods such as fortified dairyproducts and cereals, oily fish and fish liver oils [1]. Synthesizedor dietary vitamin D, from the skin and the gut, respectively,

are hydroxylated in the liver to form 25-hydroxyvitamin D[25-OHD] through the action of cytochrome P450 enzymes),which is converted to the biologically active form of vitamin

D, 1,25-dihydroxyvitamin D [1,25(OH)2D], in the kidneyand other tissues by the 1a-hydroxylase [2].

The concentration of 25-hydroxyvitamin D in blood is

regarded as the best indicator of vitamin D status, because itis quantitatively related to the supply of vitamin D over theweeks preceding blood sample collection. The concentrationof 25-OHD reflects the supply of vitamin D from both the diet

and from cutaneous synthesis under the influence of solarultraviolet light [3].

Conventionally, vitamin D is known for its actions in bone

mineralization and calcium homeostasis. Some studies havehighlighted the role of vitamin D, vitamin D receptor (VDR)in regulation of several genes involved in inflammation, immu-

nity, cellular proliferation, differentiation, and apoptosis. So,vitamin D may play a role in multiple chronic diseases suchas cancer, autoimmune diseases, infections, and cardiovascular

disorders [4,5].Vitamin D may also have a role in several diseases involving

the respiratory system such as asthma, chronic obstructive pul-monary disease, cystic fibrosis, and respiratory infections.

These studies have demonstrated a high prevalence of vitaminD deficiency in their participants [6–9]. Patients with chronicobstructive pulmonary disease have a high prevalence of vita-

min D deficiency, ranging from approximately 30% in mildCOPD to over 75% in severe COPD [9–11]. Particularly forCOPD, vitamin D deficiency may enhance chronic airway and

systemic inflammation, reduce bacterial clearance, and increasethe risk for infectious exacerbations at the same time [12].

Some intervention studies are being undertaken to study

the impact of adequate vitamin D supplementation in chronicdiseases. COPD is a candidate disease for which vitamin Dsupplementation might be beneficial. Epidemiological studiesrevealed a dose-dependent association between serum

25-OHD levels and pulmonary function so that adequate vita-min D supplementation may extend beyond its protectionagainst osteoporotic fractures. In line with the novel insights

into the immune function of vitamin D, it is tempting to spec-ulate that vitamin D may down-regulate the inflammatoryimmune response in the airways while boosting innate immune

defense against different microorganisms. Apart from itseffects on osteoporosis, vitamin D may also interfere withother comorbidities of COPD such as skeletal muscle weak-ness, cardiovascular disease, and cancer. Because respiratory

treatments in COPD fail to reverse disease progression,interventional trials that may exploit the broader potential ofvitamin D are warranted [12].

Aim of the work

We undertook this study to assess serum level of vitamin D

among patients with stable COPD. In addition the role of sup-plementation of vitamin D (200,000 IU cholecalciferol permonth for 6 months) among COPD patients with vitamin D

deficiency plus standard therapy of COPD on exercise capac-ity, clinical response and spirometry was assessed.

Patients and methods

Sixty-one cases of stable COPD were recruited from thoseattending the outpatient chest clinic at Minia University hospi-

tal from January 2011 to December 2013. The study alsoincluded 20 healthy controls.

This study was approved by the ethics committee of Faculty

of Medicine, Minia University and consent was obtained frompatients and controls.

Patients were diagnosed according to the Global

Initiative for Chronic Obstructive Lung Disease (GOLD)definition (postbronchodilator FEV1/FVC ratio <0.7). Sta-ble COPD was defined by the lack of hospitalizations,

urgent care visits, antibiotics, or changes in medicationswithin 4 weeks prior to study. Patients were excluded if theyhad a past history of TB, asthma, active cancer, diabetes,hypertension, ischemic heart disease, chronic kidney disease,

liver failure, history of upper or lower respiratory tractinfections or use of oral steroid within 1 month prior tostudy, as all these conditions are associated with a low

serum level of vitamin D [4].All the patients and healthy controls had been subjected to

the following:

- Full detailed history taking including (age, sex, smokingstatus, patient’s medications, CAT score and GOLD stage).

- Clinical examination, body mass index (BMI), and 6 min

walk test were also determined and 6 min walk distance(6MWD) was detected.

- Local chest examination.

- Investigations included:1. Plain chest X-ray (PA view).2. Complete blood count was done by automated cell

counter (Sysmex KX 21N, Cole, Japan).3. The liver, renal function tests and random blood sugar

were determined using Flexor 200ELI, Tech, France

apparatus.4. Serum ionized calcium (Ca) was determined by ion

selective electrode (AVL, USA).5. Electrocardiogram (ECG).

6. Pulmonary function tests (PFTs) using 2130 spirometer(Vmax, Sensormedics, USA), which was calibrateddaily. Patient’s maximum effort had been used in per-

forming the test so as to avoid any expected error indiagnosis. Results were obtained for forced vital capac-ity (FVC), forced expiratory volume in 1st second

(FEV1), and FEV1/FVC percentage. Subjects whohad FEV1/FVC <70% underwent post – bronchodila-tor spirometry test, 20 min following 2 puffs of salbuta-mol 200 mcg.

7. Blood samples were collected, centrifuged within 2 hof sampling, and the serum was frozen and stored at�40 �C until analyzed for measurement of serum

25-hydroxyvitamin D (25-OHD) by enzyme immuno-assay kits supplied by Immunodiagnostic AG,Germany.

Role of vitamin D among patients with COPD 69

Assay of serum 25-OHD by EIA

- This test kit is a competitive protein binding assay for the

measurement of 25-OH Vit D. It is based on competitionof 25-OH Vit D present in the sample with 25-OH Vit Dtracer, for the binding pocket of vitamin D binding protein

(VDBP, Gc-globulin). Since all circulating 25-OH Vit D isbound to VDBP in vivo, samples have to be precipitatedwith precipitation reagent to extract the analyte.

- 25-OH Vit D present in the sample competes with thetracer, coated on the well for the specific binding site ofthe binding protein and the VDBP-antibody is bound tothe vitamin binding protein. Hence, with increasing

concentrations of 25-OH Vit D in the sample, the amountof binding protein immobilized to the well via the tracer,is reduced. After a washing step to remove unbound

components, the quantitation of VDBP is achieved by incu-bation with a host specific peroxidase labeled antibodyusing TMB (tetramethylbenzidine) as enzyme substrate.

An acidic stopping solution is then added to stop thereaction. The color converts to yellow. The intensity ofthe yellow color is indirectly proportional to the concentra-

tion of 25-OH Vit D in the sample.

According to Endocrine Society Clinical PracticeGuidelines, vitamin D deficiency is defined by most experts

[13–15] as a 25-hydroxyvitamin D level of less than 20 ng permilliliter (50 nmol per liter). A level of 25-hydroxyvitamin Dof 21–29 ng per milliliter (52–72 nmol per liter) can be consid-

ered to indicate an insufficiency of vitamin D, and a level of30 ng per milliliter or greater (>75 nmol per liter) can be con-sidered to indicate sufficient vitamin D.

According to this level of vitamin D, 61 COPD patientswere divided into the following groups:

Group (A): Included 31 COPD patients who had animpaired vitamin D level, 10 of them had vitamin D defi-ciency and 21 had vitamin D insufficiency.Group (B): Included 30 COPD patients with a sufficient

level of vitamin D.Control group (group C): Included 20 apparently healthyindividuals matched in age and sex with the other 2 groups

and their serum level of 25-OHD was >30 ng/ml.

Those with vitamin D deficiency received their usual treat-

ment of COPD supplemented with a high-dose of vitamin D(cholecalciferol 200,000 IU ampoule) intramuscular injectionevery 4 weeks for 6 months. The outcome parameters usedfor the study after 6 months were spirometry, 6MWT and

CAT score. Serum ionized calcium level at the end of 6 monthswas re-assessed among 10 patients who received vitamin Dsupplements to detect if any of them developed hypercalcemia

as a sign of vitamin D overdose. None of these patients devel-oped hypercalcemia.

Statistical analysis

Data entry and analysis were all done using the software SPSSversion 13. Quantitative data were presented by mean and

standard deviation; qualitative data were presented asfrequency distribution. A one way ANOVA, Student’s t-test,

correlation and chi square tests were used. Correlation wasdone using Pearson correlation. A value of P< 0.05 was con-sidered to be statistically significant.

Results

Table 1 shows the general characteristics of all studied groups,

it was found that there was a significant difference in smokingand mean pack-year among COPD patients (groups A & B)and the control group (group C) (P = 0.03 and 0.01 respec-

tively). Considering BMI, there was no significant differencein BMI among all of the COPD patients and healthy controls(P= 0.7). There was a significant difference in 6MWD, post-

bronchodilator values of FVC%, FEV1% and FEV1/FVCamong COPD patients and the control group (P = 0.001).Besides, FVC% predicted and FEV1% predicted were signifi-

cantly lower in the group A than the group B (P = 0.01 and0.03 respectively). It was found that those with impaired vita-min D level (group A) had a significantly higher CAT scoreand GOLD stage than those with sufficient level of vitamin

D (group B) (P= 0.004 and 0.04 respectively).Fig. 1 shows mean 25-hydroyvitamin D and ionized cal-

cium levels among the studied groups. It was found that 10

COPD patients out of 31 in the group A had vitamin D defi-ciency with a mean value of 12.0 ± 4.5 ng/ml and the remain-ing 21 had vitamin D insufficiency with a mean value of

24.4 ± 3.7 ng/ml. The difference of 25-OHD mean valuebetween the group A (20.4 ± 6.6) and both of the group B(47.1 ± 18.8) and group C (44.4 ± 9.1) was significant(P= 0.001). In addition, the mean value of serum ionized cal-

cium was significantly lower among the group A (0.79 ± 0.1)versus groups B and C (0.9 ± 0.1 & 1.1 ± 0.05 respectively)(P= 0.01).

It was found that there was a significant positive correlationbetween serum 25-OHD and FVC% predicted, FEV1% pre-dicted, FEV1/FVC and GOLD stage and a negative correla-

tion with CAT score among patients with COPD. On theother hand, there was no correlation between both of clinicalvariables and pulmonary function test among the control

group (Table 2 and Fig. 2).Table 3 shows that in spite of minor improvement in CAT

score, 6MWD, FVC% predicted and FEV1% predicted, thisimprovement was not statistically significant (P > 0.05 in all

of them).

Discussion

Vitamin D deficiency is more common than previouslythought. The Centers for Disease Control and Preventionhas reported that the percentage of adults achieving vitamin

D sufficiency as defined by 25-OHD of at least 30 ng/mL hasdeclined from about 60% in 1988–1994 to approximately30% in 2001–2004 in whites and from about 10% to approxi-

mately 5% in African Americans during this same time. Sohypovitaminosis D is as an important public health problemin the United States and worldwide [16].

Few studies have assessed the relevance of vitamin D defi-ciency in COPD by measuring serum levels of 25-hydroxyvita-min D which is the principal circulating vitamin D metaboliteand recognized as the best short-term biomarker of total expo-

sure to vitamin D [17].

Table 1 Descriptive data of the studied groups.

Character Group A

No. = 31

Group B

No. = 30

Group C

No. = 20

P

Age 59.9 ± 8.1 62.3 ± 7.2 56.1 ± 8.17 0.075

Sex

Male 23 (74.2%) 27 (90%) 16 (80%) 0.2

Female 8 (25.8%) 3 (10%) 4 (20%)

Smoking

Current smoker 10 (32.3%) 10 (33.3%) 4 (20%) 0.03

Ex smoker 12 (38.7%) 16 (53.3%) 5 (25%)

Non smoker 9 (29%) 4 (13.3%) 11 (55%)

Pack-year 21 ± 4.5 28.8 ± 10.2 16.2 ± 4.7 0.01

BMI 24.1 ± 4.9 23.2 ± 4.1 23.8 ± 1.6 0.7

Medications

ICS + short acting B2 agonist 19 (61.3%) 17 (56.7%) – 0.4

Short acting B2 agonist 6 (19.5%) 0

Long acting B2 agonist 3 (9.6%) 0

Theophylline + short acting B2 agonist 3 (9.6%) 13 (43.3%) 0.001

6MWD (meter) 266.8 ± 93.8 272.4 ± 133.1 384.7 ± 53.1 0.001

FVC% pred. 56.1 ± 17.9 68.6 ± 10.5 85.1 ± 4.6 0.001

FEV1% pred. 33.7 ± 10.8 40.8 ± 13.6 83.1 ± 3.7 0.001

FEV1/FVC 46.7 ± 12.7 50.7 ± 8.3 74.7 ± 2.1 0.001

CAT score 26.2 ± 5.1 22.6 ± 4.4 – 0.004

GOLD stage 3.1 ± 0.6 2.8 ± 0.6 – 0.04

Data are represented as number and percentages or mean ± SD, P < 0.05 = significant.

ICS = inhaled corticosteroids.

12

0.6

24.4

0.88

47.1

0.94

44.4

1.10

5

10

15

20

25

30

35

40

45

50

Mea

n

less than 20 20

Group A Group B Group C

25 hydro vitamin D (ng/ml) Ca (mmol/L)

Figure 1 Serum level of 25-OHD and ionized calcium among all

the studied groups.

Table 2 Correlation coefficient between serum 25-OHD and

clinical data among all of the studied groups.

Variable COPD groups Control group

r P r P

Age �0.01 0.8 0.18 0.4

BMI �0.01 0.6 0.01 0.9

6MWD 0.10 0.4 0.15 0.5

FVC% pred. 0.61 0.001 0.1 0.6

FEV1% pred. 0.79 0.008 0.09 0.6

FEV1/FVC 0.61 0.001 0.05 0.8

GOLD stage 0.80 0.05 – –

CAT score �0.24 0.04 – –

r=0.61 p=0.001

25-OHD

706050403020100

FVC

% p

rede

cted

100

90

80

70

60

50

40

30

20

Figure 2 Correlation coefficient between serum 25-OHD and

FVC% predicted among COPD patients.

Table 3 Comparison of clinical variables and pulmonary

function test before and after 6 months of vitamin D supple-

ments among patients with vitamin D deficiency.

Character Before therapy After therapy P

CAT score 25.5 ± 6.4 24.9 ± 7.7 0.08

6MWD 260.4 ± 116.4 284.8 ± 71.4 0.3

FEV1% pred. 32.4 ± 14.1 33.5 ± 17.2 0.1

FVC% pred. 55.9 ± 10.4 56.4 ± 15.6 0.4

70 A.F. Said, E.A. Abd-Elnaeem

Role of vitamin D among patients with COPD 71

The present study was designed to detect firstly, vitamin Dlevel among stable COPD patients. It was found that vitaminD was impaired among 50.8% of the studied COPD patients,

16.4% of them had vitamin D deficiency and 34.4% had vita-min D insufficiency.

Forli et al. [18] reported that in a small sample of patients

with advanced COPD awaiting lung transplantation, themajority (>50%) suffered from vitamin D deficiency (25-OHD <20 ng/ml). In an outpatient study on patients with

COPD in Denmark, 68% of the participants had osteoporosisor osteopenia [19].

The cause of lower percentage of vitamin D deficiency inour study than these reported studies could be attributed to

the fact that most of the studied patients with vitamin D defi-ciency are farmers exposed to the sun most of the day and milkand cheese are main constitutes of daily foods.

Impaired vitamin D in COPD can be due to that patientswith COPD suffered from reduction of outdoor activity, areduced capacity of aging skin for vitamin D synthesis, a lower

food intake, increased glucocorticoids-induced catabolism,impaired activation as a consequence of renal dysfunction,and a lower storage capacity in muscle and fat due to wasting

[12]. Franco et al. [20] found that patients with COPD, evenwithout chronic use of systemic glucocorticoids, haveincreased risk for osteoporosis and low levels of vitamin D,which is correlated with the severity of disease.

Regarding correlation of vitamin D with other clinical vari-ables, the present study showed that serum 25-OHD correlatedsignificantly in a positive direction with pulmonary function

test parameters among COPD patients, while there was no cor-relation among healthy controls. On the other hand, 25-OHDcorrelated negatively with CAT score. This finding was in

accordance with Janssens et al. [9] who found that 25-OHDserum levels were correlated significantly with FEV1 in theCOPD subgroup (r= 0.28, P < 0.0001) with no correlation

with FEV1 in the subgroup of healthy controls. EL-Shafeyand EL-Srougy [21] found also that a significant correlationwas found between serum 25-OHD and FEV1 (r = 0.896,P = 0.001).

However, another study reported by Shaheen et al. [22] inan older adult UK population (the Hertfordshire Cohortstudy) did not show a positive correlation between serum

25(OH)D concentrations and lung function in spirometricallydefined COPD patients. This study concluded that vitamin Dis not an important determinant of adult lung function in

COPD.The mechanisms by which vitamin D levels might affect

lung function are unclear. Potential explanations could dependon the calcemic effects of vitamin D. The vital capacity and

total lung capacity were found to decline with an increasingnumber of thoracic vertebral fractures as a direct consequenceof vitamin D deficiency [23]. Kyphosis related to osteoporosis

caused limitation in rib mobility and inspiratory muscle func-tion and correlated with a reduction in FEV1 and FVC [24].The altered properties of the thoracic skeleton could result in

failure of the respiratory muscles contributing to the patho-physiology of COPD.

An important systemic consequence of COPD is muscle

weakness, and this is associated with an increased risk ofmortality.

Vitamin D plays a role in influencing skeletal muscle func-tion, with deficiency resulting in muscle weakness, and VDRs

are present in the muscles [25]. It has been reported that poly-morphisms in the VDR can influence muscle weakness in bothhealthy individuals and patients with COPD [26], suggesting

that the VDR has a significant influence on one of the impor-tant complications of this disease.

Vitamin D may also interact with stress, tobacco smoke,

and air pollutants through an oxidative/antioxidative imbal-ance, influencing lung inflammation and consequently lungfunction [27] .

Chronic obstructive pulmonary disease is a progressive anddisabling disorder. Unfortunately, the treatment, mostly com-prising bronchodilators of different groups, is entirely symp-tomatic. Findings of some epidemiological observations

demonstrating benefits with dietary supplements and somevitamins have therefore raised the hope of managing COPDwith an additional approach to currently available therapy

[28–31].Vitamin D therapy in COPD is an intriguing consideration.

Given that vitamin D is inexpensive and safe, it would be a

desirable treatment option if proven to be effective [32]. Inaddition to preserving skeletal health, vitamin D may haveother health benefits, including improving both respiratory

muscle and skeletal muscle function.Vitamin D may play a beneficial role in improving the

innate immune system against chronic respiratory infectionsby up-regulating specific antimicrobial peptides (human cath-

elicidin antimicrobial peptide (hCAP-18) [33]. In addition, ameta-analysis of randomized controlled trials concluded thatuse of vitamin D supplements is associated with a decrease

in total mortality rates [34].The second aim of the present study was to evaluate the

effect of vitamin D supplements in addition to the regular

therapy among COPD patients. Unfortunately, pulmonaryfunction test, exercise capacity as evidenced by 6MWD, andCAT score did not improve significantly after 6 months among

COPD patients who took vitamin D supplements. This lack ofclinical improvement could be attributed to the fact that, thestudied COPD patients who took vitamin D supplementshad a severe airflow limitation as their mean post-bronchodila-

tor FEV1% predicted was 33.7 ± 10.8, in addition their CATscore was >10 and they had a severe COPD stage (GOLDstage = 3.1 ± 0.6). Intervention in the earlier stages of COPD

might therefore be more effective, which is consistent with theidea that such milder stages are also more sensitive to diseasemodification [35].

There are limited studies on the use of vitamin D supple-ments in COPD patients, one study [36] evaluated a monthlydose of 100,000 IU of vitamin D for 1 year in addition to reg-ular therapy among COPD patients and they found that addi-

tion of vitamin D did not reduce the time to first exacerbationor the rate of exacerbations in patients with moderate to verysevere COPD. Secondary outcomes in the same study, such as

FEV1, quality of life, and death, were also not affected. How-ever, a post hoc analysis in 30 participants with severe vitaminD deficiency (serum 25-[OH]D levels <10 ng/mL) at baseline

showed a significant reduction in exacerbations in the vitaminD group (rate ratio, 0.57 [CI, 0.33–0.98]; P = 0.042).

In conclusion, our study revealed that hypovitaminosis D

was less common than western studies among stable COPDpatients. We also found a direct relationship between serumlevel of vitamin D and pulmonary function test parameters.The long term use of vitamin D supplements in addition to

72 A.F. Said, E.A. Abd-Elnaeem

usual treatment of COPD had no significant effects on COPDoutcomes.

We recommend further studies to assess vitamin D level

among a bigger number of COPD patients and to judge onthe use of vitamin D supplements on a large sample size thanthe current one. Finally, we recommend comparing COPD

outcomes in vitamin D sufficient patients who take usual treat-ment of COPD versus those with vitamin D deficiency and onvitamin D supplements to detect the usual progress of the

disease.

Conflict of interest

Both authors approved on the conception and design of thestudy. The authors report no conflicts of interest. The authorsalone are responsible for the contents and writing of the paper.

None of the authors had a financial support for this paper.

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