The Association of Serum Vitamin D
Levels with Lung Function, Symptom Severity, and Exacerbations in Stable COPD
Patients
Nurrahmah Yusuf*, Chelsy Mekasari, Sri Dianova, Herry Priyanto, Budi
Yanti
Faculty of Medicine, Universitas
Syiah Kuala, Banda Aceh, Indonesia
*Corresponding author: rahmah_ys@yahoo.com
Submitted: 15.08.2024 Accepted: 14.09.2024 Published: 16.09.2024
Keywords: COPD,
Lung Function, Vitamin D Deficiency
Introduction
Chronic obstructive pulmonary disease (COPD) is characterized
by persistent respiratory symptom and airflow limitation caused by airway
and/or alveolar abnormalities. This chronic disease has a substantial impact on
patient's quality of life and progresses slowly. An elevated chronic
inflammatory response of the airways caused by specific irritating gases or
particles is associated with COPD
COPD can be prevented and treated but is among the diseases
with the highest health burden. Global Initiative for Chronic Obstructive Lung
Disease (GOLD) reports that health costs account for 56% of the total paid for
respiratory diseases. COPD has high mortality and morbidity throughout the
world
The hallmark of stable COPD is variable degrees of
inflammation in the alveoli as well as large and small airways, leading to
mucus hypersecretion, airway constriction, and alveolar destruction. Symptom
that arise in patients with stable COPD can shift to acute exacerbation and
increase the incidence of death. Increased severity will further reduce the
quality of life. An acute worsening of COPD known as an acute exacerbation
necessitates further treatment, negatively affects health, and accelerates the
course of the disease. Respiratory tract infections are one of the most common
causes of exacerbation, although there are other causes. Narrowing of the
airways and excessive mucus production leads to decreased lung function and
results in an increased incidence of respiratory failure
The respiratory system greatly benefits from vitamin D and
patients with COPD frequently have deficiency. Lung function can be disrupted
by low vitamin D levels, particularly in patients with coexisting respiratory
conditions in the past. Male COPD patients have a high incidence of deficiency,
according to recent studies. Furthermore, low levels of vitamin D have been
connected to reduced severity of COPD, frequency of exacerbation, and forced
expiratory volume in one second (FEV1)
COPD assessment aims to ascertain the degree of airflow
restriction, the effect on the state of health, and the prognosis for upcoming
events, including hospitalizations, exacerbation, and death. When estimating
significant clinical outcomes for COPD patients, such as death and
hospitalizations, or deciding the possibility of non-pharmacological therapy,
FEV1 must be considered at the population level. Acute exacerbation and
decreased lung function are linked to vitamin D deficiency, which is frequently
the cause of symptom in COPD patients
Patients frequently have vitamin D deficiency but is still
unclear whether vitamin D concentration and the risk of COPD exacerbation are
consistently associated. Three studies found no effect and one reported vitamin
D had a protective effect on the risk of exacerbation, according to four
double-blind randomized control trials. Vitamin D supplementation was found to
have no effect in patients experiencing moderate to severe COPD exacerbation,
but it clinically and statistically had a significant protective effect at
concentrations less than 25 nmol/L
Method
This cross-sectional study was conducted among stable COPD
patients treated at RSUDZA, Banda Aceh. Inclusion criteria were patients aged ≥
40, diagnosed with COPD based on anamnesis, physical exam, and spirometry
assessment after administration of bronchodilator based on GOLD criteria
(FEV1/FVC). Meanwhile, exclusion criteria were patients with acute exacerbation
COPD, had comorbidity that can affect the metabolism of vitamin D (e.g.,
Diabetes mellitus, Asthma, chronic kidney disease, chronic liver disease), had
malabsorption syndrome (chron’s disease, inflammatory bowel syndrome,
gastrectomy or Jejunoileostomy) and vitamin D supplementation in the last 3
months. This study used primary data from serum vitamin D levels as well as
past medical history and secondary data from records to collect information on
patient characteristics.
Data collection started from May – July 2023 using
questionnaire data and interviews conducted physically face to face. After data
collection was carried out, 30 patients with stable COPD who met the study
criteria were included as subjects.
Vitamin D levels in patients with stable COPD were obtained
by examination in the laboratory using a venepuncture procedure in the cubital
fossa with an aseptic technique. About 3 ccs of blood were collected and the
measurement was carried out using the Enzyme-linked immunosorbent assay
(ELISA). The blood samples were taken by laboratory staff of a private
laboratory in, Banda Aceh based on a memorandum of cooperation with the clinic.
The results of vitamin D levels were categorized as sufficient (> 30 ng/mL),
insufficient (20-30 ng/mL), and deficient (< 20 ng/mL).
Lung function was obtained by spirometry examination in the
form of FEV1. Based on the results, subjects were grouped into four GOLD
groups, namely GOLD 1, GOLD 2, GOLD 3 and GOLD 4. Symptom assessment was
conducted using CAT and mMRC questionnaires. Furthermore, mMRC is the sum of
the scores obtained from subjects based on questionnaires submitted to assess
the severity of shortness of breath. There are five points (0-4) based on the
severity of dyspnea. The mMRC scale is divided into two categories, namely mMRC
with a value of 0-1 (mild symptom) and ≥ 2 (severe symptom). The CAT score
consists of two categories, namely CAT < 10 (mild symptom) and ≥ 10 (severe
symptom). This score was obtained during an interview using the CAT
questionnaire.
Exacerbation assessed by anamnesis results include severe
shortness of breath, productive cough, and purulent sputum. The number of
exacerbation recurrences was calculated in the last 1 year and categorized into
0–1 (non-exacerbation) and ≥ 2 (exacerbation).
SPSS was then used to examine the data while univariate
analysis was used to analyse frequency distribution, proportion of variables,
and sample characteristics. Bivariate analysis was used to assess the
correlation between serum vitamin D level, lung function (FEV1) and the number
of exacerbations.
Results
It was found that most subjects were male (86.7%), had no
history of allergies (83.3%), and had no history of consuming alcohol (76.7%).
The youngest was 45 years old and the oldest was 78 years old, with a mean age
of 66 years. The mean Body Mass Index (BMI) was 22.47 or in the normal
category. Regarding occupation, some of the subjects were retirees (43.3%)
others were in the labour profession (26.7%), while some were farmers (20%).
The education level was mostly elementary school (30%) and detailed
characteristics of the subjects are presented in Table 1.
Table 1. Socio-demographic
characteristics of study participants
|
Characteristic |
Frequency |
Percentage |
|
|
(n=30) |
(%) |
||
|
Gender |
|||
|
Male |
26 |
86,7 |
|
|
Female |
4 |
13,3 |
|
|
Marrital Status |
|||
|
Married |
30 |
100 |
|
|
Allergy history |
|||
|
No |
25 |
83,3 |
|
|
Yes |
5 |
16,7 |
|
|
Alcohol history |
|||
|
No |
23 |
76,7 |
|
|
Yes |
7 |
23,3 |
|
|
Smoking History |
|||
|
No |
4 |
13,3 |
|
|
Yes |
26 |
86,7 |
|
|
Brinkman Index, median
: 720 (0 - 3200) |
|||
|
None |
4 |
13,33 |
|
|
Mild |
2 |
6,67 |
|
|
Moderate |
3 |
10 |
|
|
Severe |
21 |
70 |
|
|
Age, mean±SD (66 ±
7,73) |
|||
|
45-59 |
5 |
16,67 |
|
|
60-69 |
16 |
53,33 |
|
|
≥ 70 |
9 |
30 |
|
|
BMI, mean±SD (22,47 ±
4,42) |
|||
|
< 18,5 |
6 |
20 |
|
|
18,5-24,9 |
18 |
60 |
|
|
25,0-29,9 |
4 |
13,33 |
|
|
≥ 30 |
2 |
6,67 |
|
|
Job |
|||
|
Civil servant |
1 |
3,3 |
|
|
Private employee |
1 |
3,3 |
|
|
Retirees |
13 |
43,3 |
|
|
Labourer |
8 |
26,7 |
|
|
Farmer |
6 |
20 |
|
|
Housewives |
1 |
3,3 |
|
|
Education |
|||
|
Primary school |
9 |
30 |
|
|
Junior Highschool |
5 |
16,7 |
|
|
Senior Highschool |
7 |
23,3 |
|
|
Diploma |
3 |
10 |
|
|
Bachelor |
6 |
20 |
|
It was found that 23.3% of patients had normal serum vitamin
D levels (sufficiency), 56.7% had insufficiency, and 20% had deficiencies.The
FEV1 values for lung function were classified into four categories: mild (≥
80%), moderate (50-79.9%), severe (30-49.9%), and very severe, with 26.7%,
36.7%, 36.7%, and 0 subjects in each category, respectively. Furthermore, the
majority were in category GOLD 2 and 3, which included 11 subjects each
(36.7%). COPD grouping based on GOLD ABE assessment tools was also conducted,
showing two groups namely B and E. A total of 20 subjects (66, 7%) were in
Group B, and the other 33.3% were in E with a total of 10 subjects. Detail of
Physical assessment, Laboratory, and spirometry result can be found in Table 2.
Tabel. 2 Physical
assessment, Laboratory, and spirometry results
|
Examination |
Frequency
(n) |
Percentage |
|
Vitamin D Status |
||
|
Deficiency |
6 |
20 |
|
Insufficiency |
17 |
56,7 |
|
Sufficiency |
7 |
23,3 |
|
FEV1 |
||
|
≥ 80 % |
8 |
26,7 |
|
50-79,9% |
11 |
36,7 |
|
30-49,9% |
11 |
36,7 |
|
GOLD Classification |
||
|
GOLD 1 |
8 |
26,7 |
|
GOLD 2 |
11 |
36,7 |
|
GOLD 3 |
11 |
36,7 |
|
CAT Score |
||
|
Oct-15 |
11 |
36,67 |
|
16-20 |
10 |
33,33 |
|
21-25 |
6 |
20 |
|
26-30 |
2 |
6,67 |
|
>30 |
1 |
3,33 |
|
Group COPD based on GOLD ABE assessment
tools |
||
|
Grup B |
20 |
66,7 |
|
Grup E |
10 |
33,3 |
|
mMRC scale |
||
|
1 |
1 |
3,33 |
|
2 |
7 |
23,33 |
|
3 |
19 |
63,34 |
|
4 |
3 |
10 |
|
Exacerbation |
||
|
0 |
16 |
53,33 |
|
1 |
9 |
30 |
|
2 |
5 |
16,67 |
Interviews were conducted to assess symptom of the subjects
and the results showed that all 30 had severe symptom or CAT ≥ 10. The highest
number of subjects with a CAT score of 10-15 was 11 (36.37%) then followed by
those with a score of 16-20, namely 10 people (33.33%). Meanwhile, only 1
subject (3.33%) had a score > 30 (CAT score = 35). For mMRC assessment, 1
subject had mild symptom (mMRC = 1) and 29 others had severe symptom or in the
percentage of 3.33% and 96.67% respectively. The majority obtained mMRCs score
of 3 (19 subjects; 63.34%). Furthermore, a significant proportion of subjects
did not experience exacerbation (25; 83,33%). Among the 25 subjects who did not
experience exacerbation, 16 (53.33%) had a value = 0. Meanwhile for the other 9
subjects (30%) the value = 1.
Subjects with sufficient vitamin D levels had lung function
at GOLD 3 (42.86%). Meanwhile, those with insufficient vitamin D levels had
lung function at GOLD 3 and 2 (41.18%) and the majority with vitamin D
deficiency were in GOLD 1 group (50,0%). No association between serum vitamin D
levels and Gold classification in stable COPD subjects was found. Furthemore, all
subjects (100%) had a CAT score ≥ 10 and there was no CAT < 10. The analysis
showed no significant correlation between serum vitamin D levels and CAT(p =
0,12). Subjects in the mMRC ≥ 2 or severe symptom group had vitamin D
insufficiency and sufficiency levels of 100% respectively. Meanwhile, for
subjects with vitamin D deficiency levels, it was 83.33%. No statistically
significant difference between mMRC score and Vitamin D status was found.
Table 3. Association of serum Vitamin D level toward Lung Function, Symptom
Assessment, and Number of Exacerbation of patients with Stable COPD
|
Variable |
Vitamin D Status |
X2 |
P-value |
|||||||
|
Deficiency |
Insufficiency |
Sufficiency |
Total |
|||||||
|
n |
% |
n |
% |
n |
% |
n |
% |
|||
|
Pulmonary
Function |
|
|
|
|
|
|
|
|
2.8 |
0,58 |
|
GOLD 1 |
3 |
50,0 |
3 |
17,65 |
2 |
28,57 |
8 |
26,67 |
||
|
GOLD 2 |
2 |
33,33 |
7 |
41,18 |
2 |
28,57 |
11 |
36,67 |
||
|
GOLD 3 |
1 |
16,67 |
7 |
41,18 |
3 |
42,86 |
11 |
36,67 |
||
|
mMRC scale |
|
|
|
|
|
|
|
|
4,1 |
0,12 |
|
0-1 |
1 |
16,7 |
0 |
0,0 |
0 |
0,0 |
1 |
3,3 |
||
|
≥2 |
5 |
83,33 |
17 |
100,0 |
7 |
100,0 |
29 |
96,67 |
||
|
Exacerbation |
|
|
|
|
|
|
|
|
0,04 |
0,98 |
|
No |
5 |
83,33 |
14 |
82,35 |
6 |
85,71 |
25 |
83,33 |
||
|
Yes |
1 |
16,67 |
3 |
17,65 |
1 |
14,29 |
5 |
16,67 |
||
Exacerbation was found in 17.65% of subjects showing Vitamin
D insufficiency, 16,6% of those with deficiency levels, and 14.29% of subjects
who had sufficiency status. The analysis results also showed no association
between vitamin D status and exacerbation. Detail of the association of serum
Vitamin D level toward lung function, ymptom assessment, and number of exacerbation
of patients with stable COPD is presented in Table 3.
Despite the availability of prevention and treatment
measures, COPD is among the diseases with the highest health burden. GOLD
reports that medical costs due to COPD account for approximately 56% of the
total costs paid for respiratory diseases. This disease has high mortality and
morbidity throughout the world
After data collection was carried out, a total of 30 stable
COPD patients who met the inclusion criteria participated as subjects. Selected
subjects received an explanation regarding the aims and benefits of the study
and were asked to sign an agreement. A 3cc vein puncture procedure was
performed in the cubital fossa using an aseptic technique to determine serum
vitamin D levels through the Enzyme-linked immunosorbent assay (ELISA).
Subsequently, FEV1 assessment was carried out using spirometry. The frequency
of exacerbation within 1 year was determined through patient's history. Symptom
assessment was carried out using the CAT and mMRC checklists, then all data
obtained were tabulated for further processing and analysis.
The subjects had a mean age of 66 years and BMI within normal
limits. Easter et al (2020) reported that aging negatively impacted the
structure and function of lungs
The subjects were predominantly males, including 26 (86.7%),
with only 4 females (13.3%). A meta-analysis of 156 studies worldwide by
Ntritsos et al (2018) found that the prevalence of COPD was 9.23% in males and
6.16% in females. When the analysis was restricted to subjects aged 40 years or
older, the prevalence increased to 11.55% in men and 7.47% in women
BMI of the subjects was within normal limits and according to
Huber et al. (2020), BMI and health-related quality of life (HRQoL) in COPD
patients have a non-linear relationship. After losing weight, the HRQoL of
patients with mild to severe COPD may improve. BMI between 30–40 is not
associated with a worsening of subjective complaints for very severe COPD.
Therefore, unless there are other medical indications, this metric is not the
primary goal of treatment
Referring to vitamin D status, about 23.33% showed normal
serum levels (sufficiency), 56.67% had insufficiency and 20% had deficiencies.
According to the Indonesian Ministry of Health, serum vitamin D can be
categorized as sufficiency (> 30 ng/mL), insufficiency (20-30 ng/mL), and
deficiency (< 20 ng/mL). This value is slightly higher (geographic impact)
compared to WHO which defines vitamin D insufficiency as serum
25-hydroxyvitamin D [25(OH)D] below 20 ng/ml (50 nmol/liter)
Divakar et al., (2020) examined the prevalence of vitamin D
deficiency among indoor workers in Singapore. The results showed the mean serum
vitamin D concentration of the subjects was under the optimal level and a third
were classified as deficient
The mean serum vitamin D level was 26.25 ng/mL and FEV1 was
54.55. Statistically, there was no significant correlation between serum
vitamin D levels and FEV1 (p=0.577). A previous study assessed the relationship
between serum vitamin D levels and FEV1 in patients with stable COPD in
Indonesia (Soeroto et al., 2021). A total of 30 subjects had a mean age of 62
years and vitamin D of 20.17 ng/mL with 50% having low levels (<20ng/mL).
Furthermore, there was no significant correlation between vitamin D levels and
VEP1
Janssens et al (2010) found a significant correlation between
two factors, namely vitamin D deficiency and disease severity measured by FEV1.
The association between serum vitamin D levels and COPD
assessment test (CAT) in patients with stable COPD in Indonesia was assessed by
Soeroto et al (2021). The results showed that vitamin D levels were negatively
correlated with CAT scores, suggesting low vitamin D levels were associated
with increasing CAT scores
Furthermore, we found that the mean serum vitamin D level in
COPD group B group was slightly lower than in group E with a mean difference of
0.79 ng/mL. Statistically, there was no difference in serum vitamin D levels
based on symptom severity groups (p > 0.05). We also assessed the
relationship between serum vitamin D levels and the number of exacerbation.
Although the correlation between serum vitamin D levels and the number of
exacerbation was not statistically significant, the coefficient value was very
weak and negative. This implies that an increase in serum vitamin D levels is
inversely proportional to the number of exacerbation.
Soeroto et al., (2021) found that vitamin D levels were
negatively correlated with the number of exacerbation. This implied that low
levels of vitamin D were associated with more frequent exacerbation
In conclusion, there was no correlation between serum vitamin
D levels and lung function, symptom assessment, and number of exacerbations in
patients with stable COPD. More studies are needed, ideally with a bigger
sample size and a longer follow-up period.
The authors are grateful to the medical record staff,
laboratory staff, and colleagues who helped with data collection.
The authors declare that there is no conflict of interest
The authors funded this study
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