Clinical, physiological, and radiological different phenotypes of COPD patients

COPD is a heterogeneous lung disorder with multiple phenotypes and endotypes. This study aimed to identify the diverse clinical, physiological, and radiological phenotypes of COPD. Moreover, to provide whether there was a possible relation between FEV1%, FVC%, and FEV1/FVC ratio, [both before and after broncho-dilation with the diameters of the airway at three diverse levels throughout both inspiratory and expiratory phases of respiration]. This study included 50 cases, that were classified according to the radiological phenotypes into 5 groups [29 cases (58%) were mild [centrilobular emphysema) CLE)], 8 cases (16%) were moderate CLE, 5 cases (10%) were [confluent emphysema (CON)], 5 cases (10%) were [advanced destructive emphysema (ADE)] and 3 cases (6%) were [para septal emphysema (PSE)]. There was no considerable variance in the frequency of COPD clinical phenotypes among the diverse radiological phenotypes. There was a moderate positive correlation between the predicted FEV1% and the corresponding inter-luminal diameter at the selected levels (RB1, and LB3) in the inspiratory phase of respiration (P < 0.001 and p = 0.001 respectively) (r = 0.58, 0.46 respectively). and there was a moderate positive correlation in the expiratory phase of respiration between the predicted FEV1% and the equivalent inter-luminal diameter at the selected levels (RB1, and LB3) (P < 0.001 respectively) (r = 0.62, 0.51 respectively). We confirmed that COPD is a highly heterogeneous illness, with multiple diverse clinical, physiological, and radiological phenotypes. Furthermore, HRCT can well be allied with pulmonary function tests (PFT).


Introduction
COPD is a heterogeneous lung disorder categorized by chronic respiratory complaints (shortness of breath, cough, sputum, exacerbations) due to a diversity of the airway's anomalies (bronchitis, bronchiolitis) and/or alveolar (emphysema) that cause constant, commonly progressive airflow limitation [1].and is nowadays considered as a heterogeneous illness with multiple phenotypes and endotypes [2].
The term phenotype has been presented to aid physicians in the documentation of the diverse types of COPD sub-groups.The description for "phenotype" is considered as [the physical appearance or bio-chemical criteria as a consequence of interaction amid the genotype and environment].Furthermore, the definition clearly states that a phenotype has to be a subgroup with a great impact on the prognosis (complaints, exacerbations, response to medications, rate of disease progression, or death) [3].
Spirometry was the main evaluation technique in diagnosing the severity of airway obstruction because it is simple, non-invasive, and easily applied.The diagnosis of COPD was built mostly on pulmonary function tests.However, the constant variations in parenchymal and airway pathology added a more diverse analytical urge [4].
CT imaging has arisen as a non-invasive measure in the phenotyping of COPD, aiming to investigate the changes in the airway wall, lumen, and lung parenchyma, as well as calculations of emphysema degree (EM) and load of small airways illness [5].
This study aimed to identify the diverse clinical, physiological, and radiological phenotypes of COPD.Moreover, to provide whether there was a possible relation between FEV1%, FVC%, and FEV1/FVC ratio, [both before and after broncho-dilation with the diameters of the airway at 3 diverse levels throughout both inspiratory and expiratory phase of respiration].

Study design
It is a prospective cross-sectional study that was accomplished in the Chest Department, Faculty of Medicine, Aswan University, during the period from October 2021 till October 2022.

Ethical consideration
This study was approved by the ethical committee of the Faculty of Medicine, Aswan University (IBR 522/3/21), and all subjects gave written informed consent prior to participating in the study.

Inclusion criteria
• All COPD cases that are clinically stable (at least 30 days after being recovered from the most recent exacerbation) • Smoker or former smoker (minimum of 10 packs each year) • Post-bronchodilator [FEV1/FVC ratio < 0.7 and FEV1 < 80% or pre-bronchodilator FEV1/FVC ratio < 0.7 and FEV1 < 80%] • Capability to complete the MSCT

Exclusion criteria
• Cases with other chest illnesses: for example, collapse, consolidation, effusion, malignancy, and thoracic cage deformity which have an impact on lung volumes.

• Uncooperative cases.
All eligible participants were subjected to the following: 1) A thorough history is taken, comprising the following information: age, gender, BMI, occupation, smoking status, smoking index, other special habits (such as experience with biomass fuel), the existence of comorbid conditions, chest complaints, healthrelated quality of life (HRQoL) evaluation, frequency of exacerbations, requirement for hospitalization in the preceding year, clinical phenotypes of COPD, and GOLD staging.
The patients' breathlessness was categorized according to the modified Medical Research Council scale [6].
With minimal assistance from the researchers, the patients were instructed to complete the CAT and SGRQ-c questionnaires independently in order to evaluate their HRQoL.Eight questions make up the CAT questionnaire: a cough (CAT 1), phlegm (CAT 2), tightness in the chest (CAT 3), dyspnea (CAT 4), activity restriction (CAT 5), confidence in leaving the house (CAT 6), sleep (CAT 7), and energy (CAT 8).Each of these items receives a score between 0 and 5, while the overall score ranges from 0 to 40.A healthy subject's overall CAT score is less than six, with a higher score indicating a stronger or worse impact of COPD on HRQoL [7].Fourteen questions make up the SGRQ-c questionnaire, with questions 1 through 7 focusing on the symptom component, questions 9 and 12 on the activity component, and questions 8, 10, 11, 13, and 14 on the impact component.Each component's score as well as the overall score ranges from 0 to 100%, with a higher score indicating worse HRQoL.The total score in healthy subjects is (6%), the symptom component is (12%), the activity component is (9%), and the effect component is (2%) [8].
Exacerbations in the last year: only moderate and severe exacerbations were taken into account when calculating the total number of exacerbations.A moderate exacerbation was defined as one that required outpatient therapy, whilst a severe exacerbation was classified as one that needed hospital admission [9].
The following clinical phenotypes of COPD were identified using the GesEPOC guidelines: a non-exacerbator phenotype (NON-AE) is one in which there have been no severe exacerbations in the preceding year and less than two episodes of moderate exacerbation.The presence of two or more episodes of mild exacerbation or an event of severe exacerbation in the preceding year was used to identify the exacerbator phenotype (AE).Without taking into account the frequency of exacerbations, the presence of bronchial asthma criteria (ACOS) was used to establish the asthma-COPD phenotype [10].

2) Six-minutes walking test:
The patients were asked to walk along a 30-m hallway at sea level for approximately 6 min before the walking distance was measured.Using a pulse oximeter, oxygen saturation was assessed both before and right after the 6MWT [11].

• HRCT of the lung
In a supine posture and without the use of contrast material, all cases underwent MSCT chest during both the inspiratory and expiratory phases.A diagnostic radiologist reviewed each CT scan film and watched them all on the same viewer system, a GE Lightspeed Ultra 160 slice CT scanner (GE Healthcare, Milwaukee, WI, USA).The following CT parameters are used: gantry rotation speed of 0.75 s, pitch 0.875, B31f reconstruction kernel, section thickness 1-1.25 mm, collimator width 1 mm, and scan range from lung apex to diaphragm.Additionally, a common technique was used to reconstruct the CT raw data to 1.25 mm section thicknesses.
We distinguished firstly the visually based patterns of COPD as shown in Fig. 1.Moreover, we measured airway internal diameters in some selected zones: the apical bronchus (RB1) of the right upper lobe, the posterior basal bronchus (RB10) of the right lower lobe, and the anterior bronchus (LB3) of the left upper lobe, all of which were upright to the long airway axis.After that, we manually traced it, allowing us to assess the bronchial internal diameters (L) by standard.

Statistical analysis
Data analysis was done using SPSS (Statistical Package for Social Science) software program version 21.0 (SPSS Inc., Chicago, IL, USA).
There was considerable variance between the 5 radiological phenotypes regarding both the smoking index (p = 0.046) and the need for hospitalization in the last year (p = 0.001) as shown in Table 1.
Fig. 1 Visually defined forms of COPD at CT [7].Abbreviations: CLE: centrilobular emphysema; ADE: advanced destructive emphysema; CON: confluent emphysema; PSE: parastatal emphysema Table 2 illustrates the frequency of COPD clinical phenotypes among the diverse radiological phenotypes with no considerable variance between them (p = 0.65).
The clinical characteristics of the COPD patients according to their CT phenotypes, where there was considerable variance between the diverse groups regarding   as displayed in Table 3. Table 4 illustrates the intra-luminal diameters at selected levels (RB1, RB10, and LB3) during both inspiration and expiration among the diverse radiological phenotypes where there was statically considerable variance between groups in both [Insp-RB1, Exp-RB1, and EXP-LB3] (P = 0.044, 0.046 and 0.043 respectively).
Table 5 displays the pulmonary function tests among the diverse radiological phenotypes where there was considerable variance between the included groups in FEV1 values in both pre-and post-broncho-dilator tests (p = 0.001, p = 0.043 respectively).
Table 6 disclosed that there was a moderate positive correlation between the predicted FEV1% and the corresponding inter-luminal diameter at the selected levels (RB1, and LB3) in the inspiratory phase of respiration (P = < 0.001, and p = 0.001 respectively) (r = 0.58, 0.46 respectively).While there was a mild positive correlation in the inspiratory phase of respiration between the predicted FEV1% and the corresponding inter-luminal diameter at the selected levels (RB10) (p = 0.007) (r = 0.38).
There was a moderate positive correlation in the expiratory phase of respiration between the predicted FEV1% and the equivalent inter-luminal diameter at the selected levels (RB1 and LB3) (P = < 0.001 respectively) (r = 0.62, 0.51 respectively) while there was a strong positive correlation in expiratory phase of respiration between the predicted FEV1% and the equivalent inter-luminal diameter at the selected levels (RB10) (P = < 0.001) (r = 0.72) as demonstrated in Table 7.

Discussion
A variety of different phenotypes make up the complicated, heterogeneous disorder known as COPD, which has varied clinical characteristics.The prevalence of COPD among hazardous personnel in Egypt was assessed to be about 10% according to GOLD, as well as cumulative disease and morbidity rates [13].
This study included 50 cases with stable GOLD stage I or II COPD, which was categorized according to the visual CT findings into five radiological phenotypes comprising [mild CLE, moderate CLE, CON, ADE, and PSE] based on Fleischner Society and inspiratory HRCT [14,15], that was classified rendering to the percent of the lung's overall emphysematous zone.Among the five radiological phenotypes examined in this study, mild CLE was the most frequent phenotype.In harmony with our study, earlier research has shown that the most prevalent type of emphysema in smokers with COPD, particularly in the right upper lobe, is centrilobular emphysema [16].
We found that there was considerable variance between the five radiological phenotypes regarding the need for hospitalization in the previous year.When compared to patients who are not hospitalized, individuals who are hospitalized may also have more severe disease, which is manifested by more severe blockage, more impaired gas exchange, higher muscle weakness, increased anxiety, and social isolation [17].In contrast, a previous study had reported, that there were no substantial variances in respiratory-related hospitalizations between the diverse CT-based groups [18].
In this study, concerning the clinical features of the COPD cases rendering to their CT phenotypes, there was a substantial variance between the diverse groups regarding the following: the frequency of severe exacerbations, 6-min walking test distance, mMRC score, and CAT Questionnaire.In accordance, several studies have reported that there was a relationship between emphysema and the hazard of exacerbation [14,19,20].Similarly, Zhu et al. disclosed that there were significant variances in age, gender, body mass index (BMI), mMRC score, acute exacerbation frequency, and PFTs between enrolled patients of the diverse sub-groups (all p < 0.01) [21], which is reliable with the prior results [14,22,23].However, Han et al. reported a non-linear relation between emphysema and exacerbation [24].Furthermore, Karayama et al. reported that there is an unfortunate association between exacerbation and emphysema [16].
In accordance with this study, Chen et al. reported that the 6MWT walking distance was inversely correlated with the HRCT emphysema score, indicating that morphological and airflow limitations affect walking performance [25].
We found that there was considerable variance between the frequency of COPD clinical phenotypes among the diverse radiological phenotypes.However, Miravitlles et al. reported that AE were highly observed in mild-tomoderate CLE patients, ADE, and PSE; however, ACO and NON-AE were less common among patients, consequently; clinical phenotypes were highly allied with radiological results] [26].
In harmony with this study, Bafadhel et al. disclosed that patients with EM on CT scan had worsened lung function, airflow obstruction, and larger increases in residual lung volume, compared with patients with radiologic evidence of BE [bronchiectasis phenotype] or BWT [bronchial wall thickening phenotype], although the clinical features of airway inflammation, health status, and microbiologic inflammation are vague between these radiologic phenotypes [27].Correspondingly, in a prior study, the patients were categorized into emphysemapredominant and airway-predominant sub-groups and displayed that emphysema cases had lower FEV1 and were more functionally restricted, with higher BODE scores and minor BMI [22].However, Shaikh et al. did not find any statistically considerable alliance between FEV1 and emphysema percent in any particular lung lobe [28].
Calverley et al. reported that both FEV 1 and FVC increased considerably after inhaling salbutamol in COPD patients [29] and we confirmed similar results.
In our study, we disclosed there was a moderate positive correlation between the predicted FEV1% and the corresponding inter-luminal diameter at the selected    levels (RB1 and LB3) in the inspiratory phase of respiration and there was a positive correlation in the expiratory phase of respiration between the predicted FEV1% and the equivalent inter-luminal diameter at the selected levels (RB1, LB3, and RB10).Recently, Mahros et al. demonstrated that there was a considerable positive relation between CT noticed airway inter-luminal area at the expiratory stage of respiration and the FEV1%, while the equivalent correlation at the inspiratory stage was not ominous.Later, the thickness of the airway wall provides further restriction force during expiration.moreover, the narrowing in the expiratory phase was more pronounced than in the inspiratory one owing to the thickness of the airway wall and the collapsibility of the bronchi.Furthermore, with diminishing the size of the airway luminal area as sloping from the third generation level to the fifth one, the link was improved which confirms the present theory that the sub-segmental bronchus affects the obstruction level of COPD rather than the segmental bronchus [30].Moreover, a recent study disclosed that quantitative CT parameters are ominously allied with lung function among COPD cases [31].However, previous studies disclosed opposite results [32,33].
Several factors may help to explain these differences between studies: Individual differences come first, followed by airway heterogeneity in COPD patients, and last, patients' diversity.Traditional pulmonary functions are unable to provide the same level of regional information that a quantitative CT scan does [34,35].Finally, despite the fact that the FEV1 parameter was a crucial factor in determining airflow restriction in COPD research, its function became flawed since it had little ability to distinguish between regional variations in lung diseases in addition to airway anomalies.Several airway troubles, comprising loss of bronchiolar tethering with alveolar obliteration, fibrosis, mucous metaplasia, inflammation, and smooth muscle hypertrophy, need more quantitative analysis utilizing MDCT, which helps in differentiating diverse COPD phenotypes [21].
Finally, we argue that additional studies are necessary to prove quantitative CT analysis as an imaging biomarker of illness that may be applied practically to COPD patients and considered a useful research tool to give insights into the disease.The results of CT analysis must be compared to outcome indicators and disease activity indicators.Few long-term studies have been conducted thus far, and those that have produced inconsistent findings.
Our research faced a number of limitations; The first is the small sample size, the second is the inter-observer variability in CT interpretation, and the third is that we only use visual scoring for COPD and don't use any additional automated techniques like [CT densitometry: it is a computerized identification of the lung attenuation area (LAA)] that were developed to segment the lung parenchyma and quantify emphysema.Fourth, there were only three bronchial levels that we could find: B1, B3, and B10.Fifth: the frightening radiation exposure levels were noticed while examining the relation between the inspiratory and expiratory phases.In addition to the severity of COPD and its distribution, the pathogenicity of the condition meant that the level of obstruction may be at a diverse bronchial lobe rather than what we defined in our study.

Conclusion
We confirmed that COPD is a highly heterogeneous illness, with multiple variable clinical, physiological, and radiological phenotypes.Phenotyping COPD patients is crucial to accomplishing a more tailored management.Furthermore, HRCT can well be allied with the PFT parameters.

Fig. 2
Fig. 2 Distribution of the diverse emphysema phenotypes identified among the study population based on MSCT examination

Table 1
Demographic and clinical characteristics of the study population (n = 50) CLE centrilobular emphysema, ADE advanced destructive emphysema, Con confluent emphysema, PSE paraseptal emphysema * Pearson Monte Carlo test; ¥ ANOVA test

Table 2
Frequency of COPD clinical phenotypes among the diverse radiological phenotypes in the study group Row percent was used * Pearson Monte Carlo test ACOS Asthma-COPD overlap syndrome phenotype, AE exacerbator phenotype, NON-AE non-exacerbator phenotype, CLE centrilobular emphysema, ADE advanced destructive emphysema, CON confluent emphysema, PSE paraseptal emphysema

Table 3
Clinical characteristics of the COPD patients according to their CT phenotypes (n = 50) GOLD Global Initiative on Obstructive Lung Disease, BODE body mass index, airflow Obstruction, Dyspnea and Exercise capacity, CAT COPD assessment test, SGRQ St. George's Respiratory Questionnaire, CLE centrilobular emphysema, ADE advanced destructive emphysema, CON confluent emphysema, PSE paraseptal emphysema Row percent was used * Pearson Monte Carlo test; ¥ ANOVA test

Table 4
The CT intra-luminal diameters at selected levels of all the included cases (N = 50) Row percent was used ¥ ANOVA test.Continues data represented as mean, SD; SD standard deviation, RB1 apical bronchus of the right upper lobe, RB10 the posterior basal bronchus of the right lower lobe, LB3 the anterior bronchus of the left upper lobe, CLE centrilobular emphysema; ADE advanced destructive emphysema, CON confluent emphysema, PSE paraseptal emphysema

Table 5
Pulmonary function test parameters of the study population stratified according to CT diverse phenotype groups (n = 50)

Table 6
Correlation between FEV1% and inter-luminal diameter during the inspiratory phase

Table 7
Correlation between FEV1% and inter-luminal diameter during the expiratory phase RB1 apical bronchus of the right upper lobe, RB10 the posterior basal bronchus of the right lower lobe, LB3 the anterior bronchus of the left upper lobe *