Study of Blood Eosinophils and Plasma Periostin as Biomarkers for Response of COPD Patients to ICS/LABA Treatment

doi:10.21203/rs.3.rs-4892123/v1

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Study of Blood Eosinophils and Plasma Periostin as Biomarkers for Response of COPD Patients to ICS/LABA Treatment

https://doi.org/10.21203/rs.3.rs-4892123/v1

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Background: Eosinophilic airway inflammation has been detected in up to 40% of chronic obstructive pulmonary disease (COPD) patients during stable periods of the disease and increased sputum eosinophil count was associated with better lung function, more future exacerbations, and symptoms that responded better to treatment with inhaled and oral corticosteroids.

The aim of this work was to investigate the relationship of blood eosinophils and plasma Periostin with lung function changes related to ICS and long-acting beta2- agonist combination treatment in stable COPD patients for three months.

Methods: This prospective experimental study was carried out on 50 COPD patients with post bronchodilator FEV1/ FVC ratio <70%. Patient collected from outpatient clinics of Chest Department Tanta University Hospitals, Tanta Chest Hospital and Mansoura Chest Hospital from February 2020 to February 2022.Patients subjected to complete history taking, clinical examinations including general and local examinations and laboratory investigations [complete blood count to assess eosinophilic count, arterial blood gases and plasma periostin] and spirometry were done for all patients pre and post treatment. All patients received three months of treatment with a fixed dose of combined inhalers of ICS and LABA and then they were classified into FEV1 responder and FEV1 non-responder according to improvement in FEV1 at least 12% and 200ml from base line of three months of combined treatment with ICS/LABA.

Results: Blood eosinophil count had a significant positive correlation with smoking index (pack/year), negative correlations with FEV1% of predicted, FEV1 actual value (L), FEV1/FVC ratio. Plasma periostin concentration had significant positive correlation with blood eosinophil count, COPD grade, FVC actual value (L) and significant negative correlations with FEV1% of predicted, FEV1 actual value (L) and FEV1/FVC. Cut off values of blood eosinophil count >265cell/ µL, plasma Periostin concentration >15.747 ng/ml and FEV1% < 40.5% were associated with post treatment FEV1 response.

Conclusions: COPD patients with poor lung functions regarding FEV1/FVC ratio, FEV1 actual value (L) and FEV1% of predicted as well as high blood eosinophil count and high plasma periostin concentration are predicted to have FEV1 response with fixed dose ICS/LABA combination treatment.

Blood eosinophils

Plasma Periostin

COPD

ICS/LABA combination Treatment

Chronic Obstructive Pulmonary Disease (COPD) is a complex pulmonary disorder characterized by persistent and often progressive obstruction of airflow due to abnormalities in the alveoli (emphysema) and/or airway (bronchitis, bronchiolitis). These abnormalities cause respiratory symptoms including dyspnea, cough, and sputum production, as well as exacerbations ^[1].

Pathological changes in the airways, lung parenchyma, and pulmonary vasculature are observed in patients with COPD. These changes encompass both structural and inflammatory modifications, which worsen in severity as airflow obstruction persists despite smoking cessation ^[2]. Eosinophilia and T helper type 2 (Th2) inflammation may also play a significant role in the development of COPD in a subset of patients, despite the widespread belief that neutrophils are the primary factor. Furthermore, a Th2-high signature has been observed in approximately 20% of smokers with COPD ^[3].

Elevated levels of eosinophils in the bloodstream are correlated with heightened eosinophil counts in the lungs and the prevalence of more pronounced indicators of type-2 inflammation in the airways among patients with COPD. These variations in airway inflammation may account for the differential response to ICS based on eosinophil count in the blood ^{[4, 5]}

Patients with frequent or severe exacerbations (two or more moderate exacerbations annually, or at least one exacerbation requiring hospitalization) and a blood eosinophil count of 300 cells/µl4 should receive initial treatment with ICS (as LAMA/LABA/ICS; triple therapy), according to the 2023 GOLD strategy. Furthermore, patients who exhibit persistent exacerbations despite receiving LAMA/LABA therapy and have blood eosinophil counts below 100 cells/µl may undergo triple therapy subsequent to a thorough evaluation of the anticipated benefits and associated risks. Although the recommendation has shifted away from LABA/ICS usage in patients with COPD and concurrent asthma, the administration of ICS remains obligatory ^[1]. Additionally, a number of studies have demonstrated a correlation among elevated sputum eosinophil counts and ameliorated lung function in patients with COPD who received ICS in conjunction with LABA ^{[6, 7]}

In recent trail, a significant correlation has been established not only among eosinophils in the sputum and those in the blood (8), but also among eosinophils and serum periostin, which can serve as an additional blood surrogate marker for eosinophilic airway inflammation ^{[8, 9]}.

Aim of the work:

The purpose of this trail was to examine the correlation among plasma periostin and blood eosinophils and alterations in lung function associated with LABA and ICS combination therapy in stable COPD patients over a three-month period.

Fifty patients who were clinically stable COPD as defined by the Global Initiatives for Chronic Obstructive Lung Disease (GOLD 2020) ^[10] and had a post-bronchodilator FEV1/FVC ratio of less than 70% at the time of follow-up in the outpatient clinics of the Chest Department Tanta University Hospitals, Tanta Chest Hospital, and Mansoura Chest Hospital participated in this prospective experimental study. The trail was conducted from February 2020 to February 2022 with the authorization of the Ethical Committee of the Faculty of Medicine, Tanta University in Tanta, Egypt (approval code: 33652/1/20). Written informed assent was obtained from each patient. Patients who meet the following inclusion criteria: age exceeding 40 years, a history of cigarette consumption exceeding 10 pack years, and a post-bronchodilator FEV1/FVC ratio below 70%. Pregnant women, patients with a recent history of COPD exacerbation within one month, and those with concurrent lung diseases including interstitial lung disease, pneumonia, active pulmonary tuberculosis, pulmonary embolism, or lung cancer were excluded from the study. Every individual underwent the following procedures: comprehensive history taking, clinical examination encompassing general and local chest examinations, radiological assessment (chest x-ray), and laboratory investigations (including eosinophilic count assessment via arterial blood gases (ABG), complete blood count (CBC) and plasma periostin). Regarding eosinophilic count and plasma periostin concentration, blood samples about (3cm,2cm for doing CBC and assessing eosinophilic count and 1cm to detect plasma Periostin concentration) were collected after 2 weeks of washout period ( After cessation of ICS for 2 weeks, an inhaled LABA, or LAMA for 2 days, an inhaled short acting B2 for 12 hours) and recollected again after 3 months of treatment with a fixed dose of combined inhalers of ICS and LABA (50mcg salmetrol/500mcg fluticasone or 9mcg formotrol/320mcg budesonide, twice daily) when they separated into their components and transferred to the Clinical Pathology Department; Tanta University Hospitals on dry ice, and kept in -80°c freezers until use. plasma samples were thawed for periostin and measured using a commercially available ELISA kit according to the manufactors instructions. The Human Periostin ELISA (Enzyme-Linked Immunosorbent Assay) kit is an in vitro enzyme-linked immunosorbent assay for the quantitative measurement of Human Periostin in Cell Culture Supernatants, Serum, Plasma. from Biokit for Scientific Research ^[11].

Procedure of Spirometry

Spirometry was done according to ATS guidelines 2019 ^[12]. The procedure was explained to the patients who were informed about the activities that should be avoided before the technique. Without shoes on, the subjects' age and gender were documented, their weight was estimated to the nearest kilogram, and their height was measured to the nearest centimeter. The hands of the physician were cleansed. The patient was situated in a seated position, maintaining a modest elevation of the head. A nose clip was utilized to close the patient's nose, and a mouthpiece was inserted into his oral cavity. He was instructed to firmly clasp his lips around the mouthpiece. At total lung capacity (TLC), the patient was instructed to inhale maximally with a pause of less than one second, followed by an exhalation of maximal force in a single continuous sequence until no further air was emitted for a minimum of six seconds. The procedure step was repeated as necessary for a minimum of three satisfied maneuvers and rest among every trial for 10 minutes. The patient was prepared 10–15 minutes before the procedure by inhalation of 400 mcg of salbutamol. The presence of a post-bronchodilator FEV1/FVC ratio less than 0.70 confirm non fully reversible airflow obstruction ^[13].

Then patients were subdivided into 4 subgroups according to post bronchodilator FEV1%. FEV1% ≥ 80% predicted; GOLD 1 – mild airflow obstruction, 50% ≤ FEV1 < 80% predicted; GOLD 2 – moderate airflow obstruction, 30% ≤ FEV1 < 50% predicted GOLD 3 – severe airflow obstruction, FEV1% < 30% predicted; GOLD 4 - very severe airflow obstruction). After three months of treatment with a fixed dose of ICS/LABA, spirometry was repeated again, and patients were classified into two groups according to improvement in FEV1 of at least 12% and 200ml from baseline into: FEV1 non- responders who did not record this criterion and FEV1 responders who recorded this criterion.

Statistical analysis

For statistical analysis, SPSS v26 (IBM Inc., Chicago, IL, USA) was utilized. Histograms and the Shapiro-Wilks test were utilized to assess the normality of the data distribution. The quantitative parametric variables were expressed as the mean and standard deviation (SD), and the unpaired Student's t-test was utilized to compare the two groups. Quantitative non-parametric data were analyzed using the Mann Whitney test and were presented as the median and interquartile range (IQR). Frequency and percentage (%) were used to present qualitative variables, which were analyzed utilizing the chi-square test or Fisher's exact test. The Spearman Correlation Test (rs) was employed to examine the direction and strength of the relationship among two nonparametric variables. The area under the curve (AUC) gauged the efficacy of the test as a whole. A p-value less than 0.05 was deemed to be statistically significant.

The included 50 patients were subdivided at the end of the trail into two groups according to improvement in FEV1 of at least 12% and 200ml from baseline into: FEV1 non- responders included 39 (78%) patients and FEV1 responders included 11 (22%) patients.

Regarding demographic data, age, sex, BMI, smoking status, smoking index (pack/year) and co morbidities were insignificantly different among the two studied groups. COPD grade differed significantly among the two groups (p = 0.009) with regard to baseline COPD criteria Table 1

Table 1

Comparison between FEV1 non- responder and FEV1 responder groups regarding demographic data and baseline COPD criteria
		FEV1 non-responder (n = 39)	FEV1 responder (n = 11)	P
Age (years)		60.0 (50.0–67.0)	61.0 (53.0–66.0)	0.879
Gender	Male	30 (76.9%)	9 (81.8%)	1.000
Gender	Female	9 (23.1%)	2 (18.2%)	1.000
BMI (kg/m2)		22.4 (20.8–28.0)	23.0 (20.8–26.0)	0.963
Smoking status	Passive smoker	6 (15.4%)	2 (18.2%)	0.393
	Active smoker	21 (53.8%)	8 (72.7%)
	Ex- smoker	12 (30.8%)	1 (9.1%)
Smoking index (pack/ year)		45.0 (39.0–54.0)	47.0 (39.0–55.0)	0.760
Comorbidities	HTN	9 (45.0%)	2 (33.3%)	0.897
	DM	7 (35.0%)	2 (33.3%)
	IHD	3 (15.0%)	1 (16.7%)
	CKD	1 (5.0%)	1 (16.7%)
Baseline COPD criteria
COPD grade	Moderate	17 (43.6%)	0 (0.0%)	0.009*
COPD grade	Severe	22 (56.4%)	11 (100.0%)	0.009*
mMRC dyspnea scale		3.0 (2.0–3.0)	3.0 (2.0–3.0)	0.663
Rate of exacerbation in last year		3.0 (2.0–4.0)	3.0 (2.0–4.0)	0.932
Number of COPD related hospitalization in last year		2.0 (1.0–3.0)	2.0 (1.0–3.0)	0.668
Data were presented as mean ± SD or frequency (%) or median (IQR). *Significant p value < 0.05, FEV1: forced expiratory volume in first second, BMI: Body mass index, HTN: hypertension, DM: diabetes mellitus, IHD: ischemic heart disease, CKD: chronic kidney disease, COPD: Chronic obstructive pulmonary disease .mMRC: modified medical research council

In relation to baseline spirometric data, the responder group exhibited substantially lower values for FEV1%, FEV1 (L), and the FEV1/FVC ratio in comparison to the non-responder group (P = 0.001). However, no significant differences were observed in FVC% and FVC (L) among the two groups under investigation. The ABG parameters (pH, PaCO2, PaO2, HCO3) exhibited negligible variation among the two groups under investigation. The responder group exhibited significantly higher levels of plasma periostin and baseline blood eosinophil count compared to the non-responder group (p < 0.001). There was statistical significance in this difference. Table 2

Table 2

Comparison between FEV1 non- responder and FEV1 responder groups regarding baseline spirometry, ABG, WBC count, blood eosinophil count and plasma periostin concentration
	FEV1-non-responder (n = 39)	FEV1 responder (n = 11)	P
Baseline Spirometry
FVC % of predicted	79.0 (78.0–81.0)	78.0 (78.0–80.0)	0.328
FVC actual value (L)	3.5 (3.3–3.6)	3.5 (3.5–3.6)	0.300
FEV1% of predicted	48.0 (43.0–52.0)	34.0 (31.0–39.0)	< 0.001*
FEV1 actual value (L)	1.7 (1.5–1.8)	1.2 (1.1–1.4)	< 0.001*
FEV1/FVC ratio (%)	48.0 (43.0–51.0)	33.0 (31.0–38.0)	< 0.001*
Baseline ABG
pH	7.4 (7.39–7.43)	7.44 (7.39–7.45)	0.376
PaCO₂ (mmHg)	41.0 (38.0–45.0)	40.0 (36.0–44.0)	0.359
PaO₂ (mmHg)	66.0 (60.0–72.0)	65.0 (60.0–70.0)	0.596
HCO₃ (mmol/ L)	37.0 (31.0–40.0)	37.0 (29.0–45.0)	0.907
White blood cell count (cell /µL)	7000.0 (6500.0–8000.0)	7500.0 (7300.0–8200.0)	0.360
Neutrophil count (cell/µL)	4000.0 (3600.0–4553.0)	3900.0 (3289.0–4230.0)	0.227
Eosinophil count (cell/µL)	200.0 (180.0–220.0)	300.0 (290.0–320.0)	< 0.001*
Plasma periostin concentration (ng/mL)	8.732 (7.968–9.87)	23.88 (19.43–35.31)	< 0.001*
Data were presented as mean ± SD or median (IQR). *Significant p value < 0.05,, FVC: Forced vital capacity, FEV1: forced expiratory volume in first second, ABG: arterial blood gases, WBC: white blood cell count

Regarding post treatment spirometric data, blood eosinophil and plasma Periostin concentration: FVC% of predicted, FVC actual value(L), FEV1/FVC ratio, change in FEV1% of predicted, change in FEV1 actual value (L), blood eosinophil count, plasma Periostin concentration and plasma Periostin concentration change showed statistically significant difference among two groups (p;<0.001) but FEV1 actual value (L), FEV1% of predicted, blood eosinophil count change showed non statistically significant difference among two groups. Table 3

Table 3

Comparison between FEV1 non-responder and FEV1 responder groups regarding post treatment spirometric data, blood eosinophil count and plasma Periostin concentration
	FEV1-non-responder (n = 39)	FEV1 responder (n = 11)	P
FVC % of predicted	81.0 (78.0–82.0)	89.0 (84.0–91.0)	< 0.001*
FVC actual value (L)	3.6 (3.5–3.7)	4.0 (3.8–4.1)	< 0.001*
FEV1%of predicted	53.0 (48.0–54.0)	48.0 (46.0–54.0)	0.338
FEV1 actual value (L)	1.8 (1.7–1.9)	1.7 (1.6–1.9)	0.574
FEV1/FVC ratio	50.0 (47.0–53.0)	45.0 (42.0–46.0)	0.001*
Change in FEV1% of predicted	3.0 (0.0–6.0)	15.0 (14.0–17.0)	< 0.001*
Change in FEV1 actual value (L)	0.1 (0.01 − 0. 2)	0.5 (0.5–0.6)	< 0.001*
Blood eosinophil count ₍cell/µL)	190.0 (170.0–208.0)	290.0 (279.0–308.0)	< 0.001*
Blood eosinophil count change (cell/µL)	10.0 (5.0–15.0)	11.0 (8.0–20.0)	0.236
Plasma Periostin concentration (ng/mL)	7.23 (6.166–8.008)	12.676 (8.208–18.818)	< 0.001*
Plasma Periostin concentration change (ng/mL)	1.713 (1.028–3.18)	14.562 (6.749–19.532)	< 0.001*

Data were presented as median (IQR). *Significant p value < 0.05, FVC: Forced vital capacity, FEV1: forced expiratory volume in first second.

Regarding correlation between blood eosinophil count, plasma Periostin concentration and other variables at baseline

At baseline, blood eosinophil count had a significant positive correlation with and plasma periostin concentration and smoking index (pack/year) (rs = 0.454, P = 0.001), (r_s; 0,299 P = 0.035) respectively but had significant negative correlations with FEV1 actual value (L), FEV1% of predicted and FEV1/FVC ratio (r_s=-0.503, P = < 0.001), (r_s;-0.435, P = 0.002) and (r_s=-.434, P = 0.002) respectively. Also, plasma periostin concentration had significant positive correlations with COPD grade and FVC actual value (L) (r_s=.410; P = .003) (r_s=.290, P = 0.041) respectively but had significant negative correlations with FEV1/FVC ratio, FEV1% of predicted and FEV1 actual value (L) (r_s = − .648; P = < 0.001), (r_s=- 0.630; P = < 0.001) and (r_s = − .579; P = < 0.001) respectively. Table 4

Table 4

Correlation between baseline blood eosinophil count, plasma Periostin concentration and other variables at baseline:
Variables	Blood eosinophil count		Plasma Periostin concentration
Variables	r_s	P	r_s	P
Age	0.013	0.928	0.057	0.693
Sex	0.008	0.954	0.008	0.954
BMI	-0.122	0.400	0.139	0.335
Smoking index (pack/ year)	0.299	0.035*	0.059	0.682
Comorbidities	0.220	0.281	0.189	0.356
No. of COPD related hospitalization in last year	-0.054	0.711	0.072	0.619
Rate of exacerbation in last year	-0.265	0.063	0.084	0.563
mMRC dyspnea scale	-0.061	0.676	0.074	0.610
COPD grade	0.179	0.214	0.410	0.003*
Neutrophil count	0.078	0.589	-0.236	0.099
Plasma Periostin concentration	0.454	0.001*	--	---
pH	0.152	0.293	0.063	0.666
PaCO₂	0.085	0.557	-0.049	0.734
PaO₂	-0.159	0.269	-0.094	0.516
HCO₃	0.072	0.617	-0.057	0.692
FVC % of predicted	-0.023	0.874	-0.067	0.646
FVC actual value (L)	-0.051	0.723	0.290	0.041*
FEV1% of predicted	-0.435	0.002*	-0.630	< 0.001*
FEV1 actual value (L)	-0.503	< 0.001*	-0.579	< 0.001*
FEV1/FVC ratio	-0.434	0.002*	-0.648	< 0.001*
rs: Spearman correlation, *significant p value < 0.05, BMI: Body mass index, HTN: hypertension, DM: diabetes mellitus, IHD: ischemic heart disease, CKD: chronic kidney disease, COPD: Chronic obstructive pulmonary disease, MRC: Medical Research Council, FVC: Forced vital capacity, FEV1: forced expiratory volume in first second, ABG: arterial blood gases, WBC: white blood cell count

In order to ascertain cutoff values for plasma periostin concentration, blood eosinophil count, and FEV1% as predictors of post-treatment FEV1 response, a Roc curve was constructed. It was found, baseline blood eosinophil count, cut off value count > 265cell/ µL, plasma periostin concentration > 15.747 ng/ml and FEV1% predicted < 40.5% (sensitivity, specificity, PPV, NPV and accuracy were 100% for all) were associated with post treatment FEV1 response with (AUC = 1, 95% C. I = 1.00–1.00),P < 0.001 for all .Table 5, Fig. 1

Table 5

ROC curve for sensitivity and specificity of baseline blood eosinophil count, plasma periostin concentration and FEV1% of predicted for prediction of post treatment FEV1 response:
	AUC	P	95% C.I	Cut off	Sensitivity	Specificity	PPV	NPV	Accuracy
Baseline blood eosinophil count (cells/µL)	1.00	< 0.001*	1.00–1.00	> 265.0	100.0	100.0	100.0	100.0	100.0
Baseline Plasma periostin concentration (ng/mL)	1.00	< 0.001*	1.00–1.00	> 15.747	100.0	100.0	100.0	100.0	100.0
Baseline FEV1% of predicted	1.00	< 0.001*	1.00–1.00	< 40.5	100.0	100.0	100.0	100.0	100.0
*p ≤ 0.05 statistically significant
AUC = 1.00 (Excellent predictor)

Although eosinophilic inflammation is frequently observed in individuals with asthma, it is also present in a subset of patients with COPD. Although serum periostin is commonly administered to patients with asthma, it is seldom studied in patients with COPD ^[14].

Periostin, an extracellular matrix protein, has been identified in the airway subepithelial layer of patients with COPD IL-4 and IL-13 induce an upregulation of periostin expression in airway epithelial cells ^[15]. Produced by bronchial epithelial cells and pulmonary fibroblasts, this biomarker is linked to type 2 eosinophilic inflammation ^{[16, 17]}.

Plasma periostin and Blood eosinophils were examined in this trail as biomarkers of COPD patients' response to ICS/LABA therapy.

In relation to demographic characteristics, there were no statistically significant difference observed among the two groups under investigation, including age, gender, BMI, smoking status, smoking index (pack/year), and comorbidities, when comparing FEV1-non-responder and FEV1 responder groups. In agreement with this study, Park et al., ^[18] who conducted a trial on 130 COPD patients, demonstrated that 42 subjects (32 percent) were classified as FEV1 responders after three months of treatment with ICS and LABA. Sexual orientation, smoking history, and body mass index did not differ significantly among FEV1 responders and non-responders.In the context of baseline COPD criteria, this trail compared FEV1-non-responder and FEV1 responder groups as follows: of the non-responder group, 17 (43.6%) patients had moderate COPD (GOLD II), while 22 (56.4%) patients had severe COPD (GOLD III). In contrast, the responder group comprised 11 (100%) patients with severe COPD (GOLD III). Although a statistically significant difference was observed among the two groups (p;0.009), the former group utilized the mMRC dyspnea scale, rate of exacerbation in the previous year, and number of patients with severe COPD (GOLD III). In agreement with present study, Park et al. ^[18] found comparable results and there were non significant difference in mMRC dyspnea scale, exacerbation rate among FEV1 responders and FEV1 non-responders.

In relation to the comparison of baseline spirometric data among the two groups, the findings of this research indicated that the responder group exhibited significantly lower values for FEV1% of predicted, FEV1 actual value (L), and FEV1/FVC ratio (P = 0.001). On the contrary, there was no statistically significant difference observed among the two groups with regard to the FVC% of predicted value and the FVC actual value (L). In agreement with present study, Park et al. ^[18] distinguished among FEV1 responders and non-responders by demonstrating that the former had a higher likelihood of having a baseline FEV1 less than 50% pred, while the latter had higher FVC (L) and (% pred) values than the former.

The FEV1 responder group had significantly higher baseline blood eosinophil count and plasma Periostin concentration than the FEV1 non-responder group (p0.001), whereas the differences among the two groups in terms of white blood cell count and neutrophil count were not statistically significant. Pascoe et al. ^[19], Siddiqui et al. ^[20] and Barnes et al. ^[21] reported that elevated eosinophil concentrations have been found to predict response to ICS in COPD patients.

FVC% of predicted, FVC actual value (L), change in FEV1% of predicted, and change in FEV1 actual value (L) were all significantly higher in the FEV1 responder group compared to the FEV1 non-responder group in this trail (p0.001). In contrast to the FEV1 non-responder group, the FEV1 actual value (L), FEV1% of predicted value, and FEV1/FVC ratio were all significantly lower in the FEV1 responder group. These findings were anticipated given that responders had reduced FEV1%, FEV1 (L), and FEV1/FVC ratios at baseline than non-responders. Brightling et al. ^[7] and Brightling et al. ^[22] demonstrated that COPD patients with high eosinophil count had a greater forced expiratory volume in first second (FEV1) improvement after corticosteroid treatment.

In this study, post treatment blood eosinophil count, plasma periostin concentration and change in plasma periostin concentration were significantly higher in responder group compared to non-responder group (p < 0.001) while change in blood eosinophil count was not statistically significant different among two groups. Compatible with these findings, Park et al. ^{[18] observed} that the blood eosinophil count and plasma Periostin concentration were most significantly elevated in the FEV1 responders compared to the FEV1 non-responders among COPD patients undergoing ICS/LABA treatment. Fingleton et al., ^[23], recorded in their trail on 386 patients with obstructive airway diseases, among them (17 patients were diagnosed as COPD) that ICS responsiveness patients, showed reduction in serum periostin after 12 weeks of ICS treatment.

Regarding correlation among baseline blood eosinophil count, plasma periostin concentration and other variables: blood eosinophil count had significant positive correlations with plasma periostin concentration and smoking index (pack/year) but had significant negative correlations with FEV1 actual value (L), FEV1% of predicted, FEV1/FVC ratio. Other variables; age, sex, BMI, comorbidities, number of COPD related hospitalization, rate of exacerbation, mMRC dyspnea scale, neutrophil count, pH, PaCO₂, PaO₂, HCO3, FVC%, FVC (L) were insignificantly correlated with blood eosinophil count. Consistent with the findings of this study, Jensen et al. ^[24] examined a relation among lung functions and blood eosinophil and monocyte counts. They discovered that individuals with a history of heavy smoking had a higher blood eosinophil count compared to light smokers, but a lower monocyte count. These findings suggested that smoking does indeed impact blood eosinophil and monocyte counts, which may have a marginally detrimental effect on lung functions. Additionally, the relation among eosinophil blood count and lung function differed among smokers and nonsmokers..

Plasma periostin concentration had significant positive correlations with COPD grade and FVC actual value (L) but had significant negative correlations with FEV1/FVC ratio, FEV1% predicted and FEV1 actual value (L) .Other variables: age, sex, BMI, smoking index (pack/ year), comorbidities, number of COPD related hospitalization, rate of exacerbation, mMRC dyspnea scale, neutrophil count, pH, PaCO₂, PaO₂, HCO₃ and FVC % were insignificantly correlated with plasma periostin concentration. In agreement with these findings, Fingleton et al., ^[23] provided evidence of a statistically significant association among the logarithm of serum periostin and blood eosinophil count in individuals diagnosed with obstructive airway diseases. A minor negative association was observed among serum periostin and predicted FEV1%, while a weak positive correlation was observed among serum periostin and functional residual capacity%. However, no statistically significant associations were found among serum periostin and FEV1/FVC ratio. Additionally, a small negative association was observed among body mass index and serum periostin. Also, Clarenbach et al., ^[25] who investigated relation among blood periostin levels and exacerbation rates on 26 COPD patients demonstrated that there is no significant correlation among exacerbation rate and periostin levels in blood. Conversely, Shirai et al. ^[26] demonstrated a mild positive correlation (p = 0.24) among serum periostin and FEV1/FVC in patients with COPD, as well as a moderate correlation (p = 0.41) among serum periostin and FEV1. Eosinophil counts were greater in COPD patients with elevated serum periostin concentrations; however, no correlation was observed among periostin and body mass index (BMI) in this subset of patients.

In this study, regarding cut off values, baseline blood eosinophil count > 265cell/ µL, plasma periostin concentration > 15.747 ng/ml and FEV1% predicted < 40.5% (sensitivity, specificity, PPV, NPV and accuracy were 100% for all) were associated with post treatment FEV1 response with (AUC = 1, 95% C. I = 1.00–1.00), P < 0.001 for all. In agreement with these findings, Park et al., ^[18] conducted the initial investigation into the relationship among plasma periostin and blood eosinophils and alterations in lung function associated with the combination therapy of ICS and LABA in stable COPD patients. They discovered that elevated levels of plasma periostin (> 23 ng/mL) and blood eosinophils (> 260/µL) were significantly related with a 50% improvement in FEV1 following 12 weeks of treatment with ICS and LABA in patients with COPD who had a baseline FEV1 below 50% predilection. Also, Tashkin et al., ^[27] reported that elevated blood eosinophil counts could potentially serve as a suitable substitute for airway eosinophilia and function as a readily available biomarker to assess the response of COPD patients to ICS treatment.

Limitations: The sample size was relatively small. The short follow up period didn't allow detection of long-term outcomes of treatment on COPD exacerbation and related hospitalization and decline in lung functions. The trail did not assess the correlations among blood eosinophils, bronchoalveolar lavage fluid cells, airway inflammatory markers (e.g., sputum eosinophil), or bronchoalveolar lavage fluid cells; consequently, the relationship among airway and blood inflammatory markers was not investigated. COPD Assessment Test (CAT) was not included in analysis of these findings as it was not obtained at initial evaluation.

COPD patients with poor lung functions regarding FEV1/FVC ratio, FEV1 actual value (L) and FEV1% of predicted as well as high blood eosinophil count and high plasma periostin concentration are predicted to have FEV1 response with fixed dose ICS/LABA combination treatment. Baseline cut off values of blood eosinophil count > 265cell/ µL, plasma periostin concentration > 15.747 ng/ml and FEV1% < 40.5% may be used for selection of COPD patients who will show benefit from ICS/LABA treatment.

COPD:	Chronic Obstructive Pulmonary Disease
Th2:	T Helper Type 2
GOLD 2020:	Global Initiatives for Chronic Obstructive Lung Disease
ABG:	Arterial Blood Gases
CBC:	Complete Blood Count
FEV1:	Forced Expiratory Volume in First Second
FVC:	Forced Vital Capacity
MRC:	Medical Research Council
IHD:	Ischemic Heart Disease
CKD:	Chronic Kidney Disease
CAT:	COPD Assessment Test

Ethics approval and consent to participate

It was approved by the ethics committee of Faculty of medicine, Tanta University Hospitals, Tanta Chest Hospital and Mansoura Chest Hospital from February 2020 to February 2022. An informed written consent was obtained from the participants. approval No. 33652/1/20.

Consent for publication: All authors give their consent for publication in the journal.

Availability of data and material: Data and material are available on a reasonable request from the author.

Competing interests: The authors declare no conflict of interest.

Funding: Nil.

Authors' contributions: SAA and MSH conceived and supervised the study; HAH and AAE were responsible for data collection. GAE and SAA analysed and interpreted the data. All authors provided comments on the manuscript at various stages of development. All authors read and approved the final manuscript.

Acknowledgements: Nil

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No competing interests reported.

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Study of Blood Eosinophils and Plasma Periostin as Biomarkers for Response of COPD Patients to ICS/LABA Treatment

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Introduction

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Patients and Methods

Procedure of Spirometry

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Regarding correlation between blood eosinophil count, plasma Periostin concentration and other variables at baseline

Discussion

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Version 1