Evaluation of Vitamin D , IL 6 and Hs-CRP in Different Stages of Chronic Obstructive Pulmonary Disease and Their Correlation with Severity of Disease and Frequency of Exacerbations

C l i n M e d International Library Citation: Menon B, Kaur C, Vardhan H, Gopi A, Md Yousoof D (2016) Evaluation of Vitamin D, IL6 and Hs-CRP in Different Stages of Chronic Obstructive Pulmonary Disease and Their Correlation with Severity of Disease and Frequency of Exacerbations. Int J Aller Medications 2:020 Received: July 28, 2016: Accepted: September 26, 2016: Published: September 30, 2016 Copyright: © 2016 Menon B, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Menon et al. Int J Aller Medications 2016, 2:020 Volume 2 | Issue 2

In the past, COPD was regarded solely as a lung disease.However, it is now accepted as a multi-component disease characterized by extra-pulmonary effects that contribute to disease severity [6].The characteristic pathological changes of COPD are due to inflammatory cells & inflammatory mediators, oxidative stress & proteases & antiproteases imbalance [7].
An exacerbation is defined as an event in the natural course of the disease characterized by a change in the patient's baseline dyspnoea, cough, and/or sputum that is beyond normal day-to-day variations, is acute in onset, and may warrant a change in regular medication in a patient with underlying COPD [7].It is the major cause of deterioration of functional capacity of a COPD subject causing debilitation and death.
Recent studies have shown association of COPD with systemic inflammation [8].This is associated with activation of circulating inflammatory cells & increased level of pro-inflammatory cytokines such as IL-6 & inflammatory mediators such as CRP.Studies show that reduced lung function is associated with elevated systemic inflammatory factors that increase during exacerbations & these factors may contribute to the co-morbidities associated with COPD [8].

Introduction
Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity & mortality worldwide & results in an economic vitamin D have been shown in COPD [11,12].However, Current studies have failed to prove that low vitamin D levels predispose to increased exacerbations in COPD [13,14].Based on the data from the previous studies we hypothesized that baseline 25(OH)D, hs-CRP & IL-6 levels should correlate to the severity of disease & frequency of acute exacerbations in COPD.

Materials and Methods
This was a prospective study conducted at the Clinical Research Centre, Vallabhbhai Patel Chest Institute (VPCI), University of Delhi over a period of one year.A total of 182 consecutive patients with the diagnosis of COPD as per GOLD guidelines attending the outpatient department of pulmonary medicine were recruited.The diagnosis of COPD was based on clinical history consistent with COPD and Pulmonary function test showing irreversible bronchial obstruction.Patients having acute respiratory infection during the past 4 weeks or those treated with antibiotics, steroids or vitamin D during the past 4 weeks were excluded.Subjects with other systemic illness were also excluded.
These patients were subjected to detailed history & clinical examination.All subjects were then subjected to baseline investigations to rule out any associated co-morbidity.Once patients were recruited in the study, a written informed consent was taken.And baseline initial assessment was done that includes Spirometry with reversibility.hs-CRP, IL-6 & 25-hydroxy vitamin D levels were performed on patient serum samples on TECAN automated ELISA reader using respective ELISA kits based on Quantitative sandwich immunoassay.
All subjects were classified as per GOLD stages I, II, III, IV based on PFT & as grade A, B, C, D based on history & spirometry was done as per GOLD guidelines.6 min walk test was done & BODE index was calculated.All subjects were asked to fill CCQ at initial presentation & then at weekly intervals that was recorded & assessed at monthly followups.All subjects then received standard inhalational therapy as per the GOLD guidelines.Subjects were followed up at monthly intervals for 6 months.Subjects also reported if exacerbations occurred.
The data was examined for distribution and homogeneity of variance.Multiple groups were compared using analysis of variance and Kruskal Wallis test.Groups were compared using student's t test, Wilcoxon sign rank test and Mann Whitney U test.For comparing proportions of patients, chi square test were used.Correlations were computed using Pearson/Spearman's test.Multivariate analysis (logistic/linear) were used to identify factors determining outcomes after adjustment for cofactors.A conventional value of p < 0.05 was used for statistical clinical significance of the study.20 healthy disease free volunteers were also recruited to establish normal values of test parameters.

Study population
Study group included 158 (87%) males & 24 (13%) females with age ranged between 45 to 77 years with a mean age of 57.42 ± 7.37 years.Mean BMI of subjects was 24.26 ± 5.17 kg/m 2 .Out of 182 subjects, 37 were current smokers, 129 were former smokers.33 had history of significant exposure to biomass fuel smoke while 12 had history of both smoking as well as biomass fuel smoke exposure.Mean smoking index amongst the smokers was 739.81 ± 427.39.
Duration of disease ranged from 1 year to 17 years with mean of 7.614 ± 8.33 years.History of persistent cough & sputum along with progressive dyspnea & wheezing was present in all the subjects.Chest tightness was present as presenting symptoms in 87 (47.80%) cases.Nasal symptoms were present in 70 (38.46%)cases.Family history suggestive of COPD was present in 51 (28.02%) cases.

Vitamin D, IL6 and hs-CRP
IL-6 & hs-CRP were higher in study group than the normal controls and the difference was statistically significant with 'p' value of 0.024 & < 0.01 respectively whereas vitamin D was significantly lower in study group (p < 0.01) (Table 1).

Discussion
COPD is a systemic illness associated with enhanced chronic inflammatory response in airways & is a leading cause of morbidity and mortality worldwide.Despite the best treatment, to date none of the existing medications for COPD has been conclusively shown to modify the long term decline in lung function in clinical trials [7].
Vitamin D deficiency has been linked to respiratory diseases like asthma [15], tuberculosis [16], and influenza [17].Also, low levels of vitamin D have been seen in patients of COPD in recent studies [18][19][20].IL6 [21,22] & hs-CRP [23][24][25] have also been linked as an inflammatory marker in COPD.CRP has been shown to be increased in COPD in stable condition and during exacerbations.IL6 has been linked as an inflammatory marker in COPD and acute exacerbations of COPD have been shown to be accompanied by elevation of IL-6 levels.
Vitamin D was considered deficient at levels < 20 ng/ml and insufficient when between 20-29 ng/ml.If vitamin D levels are found to be low, supplementation may be required.However, it is still not clear if the deficiency of vitamin D levels is the cause of severe COPD or a result of it.Further studies with supplementation of vitamin D along with pharmacologic therapy are required to further validate the benefit of supplementing vitamin D in poorly controlled cases of COPD having vitamin D deficiency.Till further results are available such deficiency should be treated in accordance to endocrine society guidelines for vitamin D deficiency due to multiple ill effects of vitamin D deficiency independent of COPD.
This study indicates that patients with COPD has lower mean value of vitamin D and there is a modest correlation of vitamin D with severity of COPD as assessed by functional scores like mMRC and 6MWD, lung function test scores i.e.FEV1% & stage on PFT, composite assessment scores like GOLD group and BODE index, health related quality of life scores i.e.CCQ scores and exacerbation risk i.e. frequency of exacerbations in the past & exacerbation during 6 month follow up.
In contrast to previous studies, our study has shown lower vitamin D levels in patients with frequent exacerbations.Also vitamin D deficiency was more prevalent in severe stages of COPD with mean value of vitamin D being lower in severe stages COPD than less severe stages as assessed by PFT & GOLD group.Mean IL-6 levels were higher in patients of COPD than normal subjects & could be correlated only to BODE index, exacerbation during follow up, FEV1% & PFT stage.This was a weak correlation.It failed to achieve correlation with other markers of severity.This is in contrast to our previous hypothesis where correlation of IL-6 with severity of disease & frequency of exacerbations in COPD was proposed.
Mean hs-CRP levels were higher in patients of COPD than normal subjects & could be correlated to all parameters except exacerbations during follow up.BODE index & baseline CCQ were modestly correlated to hs-CRP & rest all other parameters had a weak correlation with hs-CRP.

Conclusion
We therefore suggest that vitamin D levels be estimated in poorly controlled COPD cases especially those who are having severe disease, more functional limitation or having frequent exacerbations.
Mean distance in six minute walk test was 328.42 ± 101.73 meter with 18 cases failed to walk more than 150 m in 6 minutes.Mean value of BODE index calculated in the study group was 3.47 ± 1.54.The mean value of baseline CCQ score in study group was 1.98 ± 0.73 with mean & standard deviation of mental, symptom, & functional score being 0.46 ± 0.22, 0.69 ± 0.32 & 0.87 ± 0.57 respectively.

Table 1 :
D deficiency was present in 33.33%, 39.13%, 47.62%, & 84.37% of patients with GOLD group A, B, C & D respectively with group C & D having lower mean values than A & B (Table 2).Mean values of vitamin D, IL6 & hs-CRP are shown in relation to PFT staging in table 3, GOLD grouping in table 4 and to exacerbation during follow-up in table 5.The differences in values were found to be significant.Mean value of vitamin D, hs-CRP & IL-6.

Table 2 :
Vitamin D deficiency in relation to stage of COPD.
PFT stage Total no. of patients vitamin D ( < 20 ng/ml) PercentageGOLD group Total no. of patients vitamin D ( < 20 ng/ml) Percentage

Table 3 :
Mean value of vitamin D, hs-CRP & IL-6 in relation to PFT stage.

Table 4 :
Mean value of vitamin D, hs-CRP & IL-6 in relation to GOLD group.

Table 5 :
Mean value of vitamin D, hs-CRP & IL-6 in relation to exacerbations during follow-up.