1. INTRODUCTION

As per Global initiative for Obstructive Lung Disease (GOLD) 2024, Chronic Obstructive Pulmonary Disease (COPD) is a heterogeneous lung condition characterized by chronic respiratory symptoms (Dyspnea, cough, sputum production and/or exacerbation) due to abnormalities of the airways (bronchitis, bronchiolitis) and/or alveoli (emphysema) that cause persistent, often progressive, airflow obstruction. The annual rate of COPD exacerbations has been estimated between 0.5 and 3.5 exacerbations per year.

Similarly, an exacerbation of COPD is defined as an event characterized by dyspnea and/or cough and sputum that worsen over < 14 days. Exacerbations of COPD are often associated with increased local and systemic inflammation caused by airway infection, pollution, or other insults to the lungs. As per GOLD 2024, frequent exacerbator phenotype of COPD is the occurrence of 2 or more exacerbations in a year 1,2. 

According to the traditional severity classification for E-COPD, Mild events are those treated with short-acting bronchodilators (SABDs), Moderate events require antibiotics, systemic corticosteroids or both Severe events are those requiring admission to an emergency room or hospitalization.1 Thus, severity of E COPD is usually graded post hoc, based on what medications were used to control symptoms and in what setting.

Frequent exacerbation of COPD is an important poor prognostication factor as it is associated with decreased lung function, poor quality of life and mortality. Similarly, presence of psychiatric comorbidities, (depressive symptoms) which further augment a decline in lung function leading to poorer quality of life, decreased physical activity, increased health care utilization, and up to a 3-fold increase in mortality.2 Prior year exacerbation history is the best predictor of future exacerbations and forms part of global clinical guidelines for management of COPD patients. They have a high risk of poor outcomes and may benefit from close monitoring and therapeutic interventions. Data regarding risk factors and predictors of frequent exacerbator-COPD is scarce. Hence we are conducting a cross sectional study to assess clinical profile, radiological status, pulmonary function and associated comorbidities. 

Review of Literature

Few national and international studies on frequent exacerbators subgroup of COPD were reviewed. 

Bhatia et al3 did a cross sectional study on search for covert precipitating clinical parameters in frequent exacerbators of chronic obstructive pulmonary disease at Lucknow in 2023. They recruited 98 patients with frequent exacerbations of COPD. They found that mean number of severe exacerbations were 2.42 per patient per year and predictors of frequent severe exacerbation were serum uric acid, serum total IgE, depression and anxiety. However, there was no description of radiological profile in the study which we tend to explore. 

Similarly, internationally, Uslu et al in 20224 conducted retrospective analysis on Chronic Obstructive Pulmonary Disease with Frequent exacerbator phenotype in institute of Germany. Evaluation of data of 299 participants showed that prevalence of frequent exacerbators was 35% and these patients are older, had emphysematous changes and lower eosinophil levels. The limitation of the study was that it was a retrospective study.

 Dayal et al in 20215 did a prospective study on defining the frequent exacerbator phenotype during a pandemic in COPD conducted in USA. They recruited 9781 participants in which prevalence of frequent exacerbators was found to be 15%. However, detailed radiological profile of these patients were not included in the study. 

Furthermore, Rouzic et al in 20176 also conducted a prospective study on defining the Frequent Exacerbator Phenotype in COPD in France with 464 participants. It showed frequent exacerbators patients have worse health-related quality of life impairment. The study did not include radiological profile. Miravittles et al7 underwent a cross sectional observation study on frequency and characteristics of different clinical phenotypes of chronic obstructive pulmonary disease in Barcelona in 2016 with 3125 participants. Prevalence of frequent exacerbators was found to be 19%. Exacerbators had more severe disease in terms of spirometry. Greater anxiety and depression were found among frequent exacerbators.

Prospective analysis of radiological profile of COPD patients was done in Congo in 2023 by Dikamba et al8, which showed thickening of bronchial walls, centrilobular emphysema dilatation of pulmonary artery were more frequent. 

A prospective analysis of the imaging spectrum of emphysema was conducted using chest X-ray and computed tomography (CT). The findings were correlated with the stages of chronic obstructive pulmonary disease (COPD) according to the GOLD guidelines, based on pulmonary function tests (PFTs), as reported by Sharma Y et al. in 2019.

Features Evaluated Using High-Resolution Computed Tomography (HRCT)

1. Hyperinflated Lung Fields: This is assessed by measuring the increased length of the anterior junctional line, which can indicate lung hyperinflation.

2. Bullae: Identified as areas of destroyed lung parenchyma that appear as thin-walled, air-filled spaces on HRCT scans.

3. Flattening of the Diaphragm: Noted as a sign of diaphragmatic dysfunction or lung hyperinflation.

4. Emphysematous Changes: These include various patterns of emphysema, such as:

• Centriacinar Emphysema: Affecting the central parts of the acinus.

• Panacinar Emphysema: Involving the entire acinus.

• Paraseptal Emphysema: Located near the lung edges and pleural surfaces.

5. Tracheal Index: This is the ratio of the transverse to the antero-posterior diameter of the trachea, measured 1 cm above the aortic arch. An index less than 2/3 (0.67) is indicative of a "Saber sheath" trachea.

6. Thoracic Cage Ratio: This ratio compares the antero-posterior diameter to the transverse diameter of the thoracic cage, measured at two levels:

• At the Carina: The carina is the point where the trachea bifurcates.

• 5 cm Below the Carina: The ratio is typically greater than 0.75 in emphysema.

7. Sterno-Aortic Distance: Measured from the posterior surface of the sternum to the anterior margin of the aorta at the level of the carina. In emphysema, this distance is usually less than or equal to 4 cm.

8. Mosaic Attenuation Pattern: This pattern shows non-uniform lung density, characterized by areas of relatively low attenuation (lucent) interspersed with regions of normal or increased density.

Lynch et al. conducted a prospective study in which they categorized emphysema based on visual assessment of CT scans. Their classification included mild centrilobular emphysema, affecting 5.0% of the lung zone, moderate centrilobular emphysema, involving more than 5% of the lung zone, and confluent emphysema. The study examined the association between these emphysema categories and mortality risk.

Since majority of these studies were done internationally and radiological parameters were not included in all studies. Hence we are conducting a cross sectional study to assess clinical profile, radiological status, pulmonary function and associated comorbidities. 

Lacunae of Literature 

• Limited data on clinical and radiological profile of frequent exacerbators of COPD in Indian population

• Limited data on spirometry parameters of frequent exacerbators

• Limited data on comorbidities associated with frequent exacerbators subgroup of COPD.

2. Aims and Objective

Aim: Assessment of clinical features, chest imaging parameters in frequent exacerbator patients of Chronic obstructive pulmonary disease

Primary Objective 

• To describe Clinical features and Chest radiology profile of frequent exacerbator patients of COPD

Secondary Objective 

• To describe the various risk factors associated with frequent exacerbator patients of COPD.

• To assess health related quality of life in frequent exacerbator patients of COPD.

3. Materials and Methods

1. Study Area: A study to be conducted in the Department of Pulmonary Medicine, All India Institute of Medical Sciences, Rishikesh.

2. Study Design: Descriptive, Cross-sectional study

3. Study Population: Outpatient and IPD (Ward & RICU), Department of Pulmonary,AIIMS Rishikesh

4. Study period : 15 months from the date of Ethical clearance

5. Sample Size: Time bound study 

6. Sampling method: Consecutive sampling.

                                     SAMPLE SIZE CALCULATION:

Time bound study (15-month duration) total of  90 patients to be included in my study.

In Pulmonary Medicine Department of AIIMS-Rishikesh, number of patients presenting with E COPD frequent exacerbator is about 6 patient /month,.

Calculated sample size : (15 x 6) = 90 patients

7. Patient Selection: Patients will be enrolled on the basis of the following inclusion and exclusion criteria:

Inclusion criteria for cases

• Subjects older than 18 years.

• Patients with 2 or more exacerbation of COPD in past one year.

Exclusion criteria for cases

• Patients with confounders of exacerbation

• Pneumothorax

• Myocardial Infarction

•  Pulmonary thromboembolism

• Left Heart failure

• Pneumonia

(5) Methodology

 Study Procedure: 

• We will enroll all consecutive patients fulfilling the inclusion criteria in study after taking informed consent. Patient/ relative will be informed about the study methodology. A proforma will be filled after detailed clinical interview and examination.

• Frequent exacerbators will be defined as patients having two or more exacerbations of COPD.

• Acute exacerbation of COPD is defined as dyspnea and/or cough and sputum that worsens in < 14 days which may be accompanied by tachypnea and/or tachycardia associated with rise in inflammatory parameters.

• Patient with COPD is defined as any patient who has dyspnea, chronic cough or sputum production, and/or a history of exposure to risk factors for the disease but forced spirometry that demonstrates the presence of a post-bronchodilator FEV1/FVC < 0.7. (GOLD 2024)     

  Patient who are frequent exacerbators of COPD will be enrolled and data will be collected (mentioned in the case record sheet).

(6) Statistical Analysis

Statistical analysis will be done in IBM SPSS version 26.0 statistical software. The normality of data testing Shapiro-Wilk test. Descriptive statistics will be done by the depiction of continuous variables by mean and standard deviation (for normally distributed data) and median and interquartile range (for non-normally distributed data). Categorical variables will be reported as frequencies and percentages. Inferential statistics will be done for the comparison of proportions using the Chi-square test and Fisher exact test as applicable. Comparison between means will be done by unpaired t-test for normally distributed variables and Mann-Whitney U test for non-normally distributed variables (between group analyses). For paired dependent sample (within group analyses) comparison of medians, Wilcoxon signed-rank test will be used..

Confidentiality of data

Sincere efforts would be taken to securely handle information collect from patients as well as medical records. Authorized healthcare workers would be given access to the information to be used for academic purposes only. Patient information would be withheld in such circumstances.

(7) Ethical consideration

Patients coming for routine clinical check-up and diagnostic evaluation to Pulmonary medicine department will be included in our study. All the patients will be enrolled only after an informed consent from the patients/relatives explaining the objective of the study. Every precaution will be taken to respect the privacy of the patient, confidentiality of the patient’s information and to minimize the impact of the study on his/her physical and mental integrity. There will be no extra economic burden on the patients. No harm is expected due to this study. Patients will have the option not to enroll in the study if they so desire without affecting their future treatment at the institute.

Budget Allocation

There is no requirement of any additional budget for this study. All investigations done are routinely done in the workup for COPD patients. 

   (8) References

1. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease [Internet]. 2024 [cited 2024 Aug 11]. Available from: https://goldcopd.org/2024-gold-report

2. Mirza S, Benzo R. Chronic obstructive pulmonary disease phenotypes: implications for care. Mayo Clin Proc. 2017 Jul;92(7):1104-12.

3. Bhatia A, Prakash V, Kant S, Verma A. A search for covert precipitating clinical parameters in frequent exacerbators of chronic obstructive pulmonary disease. Lung India. 2016;33(6):600-3.

4. Uslu B, Glsen A, Arpinar Yigitbas B. Chronic obstructive pulmonary disease with frequent exacerbator phenotype: what is different in these patients? Tanaffos. 2022 Mar;21(3):307-16. PMID: 37025319; PMCID: PMC10073954.

5. Dayal P, Dimond C, Yang X, Kent M, Rizzo S, Mohan D. Defining the frequent exacerbator phenotype during a pandemic in COPD. Chest. 2021 Oct;160(4):1786-87.

6. Le Rouzic O, Roche N, Cortot AB, Tillie-Leblond I, Masure F, Perez T, Boucot I, Hamouti L, Ostinelli J, Pribil C, Poutchnine C. Defining the “frequent exacerbator phenotype in COPD: a hypothesis-free approach. Chest. 2018 May;153(5):1106-15.

7. Miravitlles M, Barrecheguren M, Román-Rodríguez M. Frequency and characteristics of different clinical phenotypes of chronic obstructive pulmonary disease. Int J Tuberc Lung Dis. 2015 Aug;19(8):992-8.

8. Dikamba FF, Nkodila AN, Wembonyama SO. Clinical and radiological profile of chronic obstructive pulmonary disease in Kinshasa. Int J Health Sci Res. 2023 May 11;13(5):1-10.

9. Sharma Y, Bansal P, Saran S, Verma SR. Clinical and radiological evaluation of emphysematous chest: a prospective study [Internet]. IJCMR. 2019 Feb [cited 2024 Jan 19]. Available from: https://www.ijcmr.com/uploads/7/7/4/6/77464738/ijcmr_2361.pdf

10. Lynch DA, Moore CM, Wilson C, Nevrekar D, Jennermann T, Humphries SM, et al. CT-based visual classification of emphysema: association with mortality in the COPDGene study. Radiology. 2018 Sep;288(3):859-66.

Annexure I:

Case Record Form

Date:

      Home LTOT :

      Home NIV:

     Total distance covered:  

     Base line SpO2 (%): 

     Lowest SpO2 (%):

      Sputum culture :

 Emphysema: 

Health Related Quality of life questionnaire- EuroQol EQ-5D-5L questionnaire

Conclusion:

Annexure II:

Patient Information Sheet

Thesis Title: Descriptive cross – sectional study on clinical and radiological profile of frequent exacerbators of Chronic Obstructive Pulmonary Disease

Introduction: You are invited to participate in this research study. It is important that you read the description of the study & understand your role in it, including its nature & the risk of participation. Please give your consent to participate in this clinical study only if you have completely understood the nature and course of this study and if you are aware of your rights as a participant.

Purpose of the study: The primary aim of the study is to know the clinico-radiological profile of frequent exacerbator of COPD. It will be helpful for other people once we have sufficient research evidence.

Expected duration of the study: The study will span over 18 months while your participation will be only on a single day when you will undergo Chest x-ray, HRCT chest and PFT of standard management of your illness.

Study Procedure to Be Followed (Methodology): The study will be initiated only after obtaining permission from the Institutional Ethics committee. It is a cross-sectional observational study. Patients fulfilling the inclusion criteria will be enrolled at our institute. Your signature and consent will be taken at this stage. At any point of the study if you fall short of the laid criteria you will be omitted from the study. The study will include your routine blood investigations, spirometry, HRCT chest. It will just be a routine OPD visit and need not require hospital admission for the study.

Possible Benefits of the Study: There may not be any direct benefit to you from this study as your inclusion. Also, the data collected from the study will be of use in the management of other patients with similar parameters in the future.

Compensation for Participation: Participation in this study will not cost you anything. You will not be paid for participating in the study either.

Compensation for the Study Related Injury: There is no likely study related grave injuries warranting compensation.

Right to Withdraw from the Study: Participation in this study is entirely voluntary. You may choose not to take part or you may leave the study at any time. Your decision will not affect your further treatment at this institute.

Confidentiality: All study records will be kept confidential at all times. Your identity will not be revealed except as required by law. This result of your treatment may be published for scientific reasons. Your identity will not be revealed in these publications.

Contact for Further Information: Thank you for taking the time to read (or have read to you) the information about this study. Before you sign this document, you should ask questions about anything that you don’t understand. The study staff will answer your questions before, during and after the study. If you have questions about this study or how it is being run, side effects of the procedures involved or possible research related illness/injury, contact the study doctor.

Dr. Harshita, 

Junior Resident, 

Department of Pulmonary, Critical Care and Sleep Medicine, 

AIIMS Rishikesh 

+91-9971692975 

Annexure IV:

CONSENT:

I have read/have had read to me the information given in the informed consent document for the study titled “Descriptive cross sectional study on clinical and radiological profile of frequent exacerbators of Chronic Obstructive Pulmonary Disease

1. I have received an explanation of the nature, purpose, duration of the study and all my questions have been answered satisfactorily.

2. I understand that my participation in the trial is voluntary & that I may refuse to participate/withdraw from the trial at any time without any penalty/loss of benefits to which I am otherwise entitled.

3. I further understand that any information that becomes available during the course of study that may affect my willingness to take part will be informed to me.

4. Institutional review board authorities may wish to examine my medical records to verify the information collected. By signing this document, I give permission for this review of my records.

5. I understand that my identity will not be revealed in any report/publication.

6. I agree to take part in the above study.

Name of research participant:

Signature/Thumb Impression of research participant Name of the legally appointed representative Relation to research participant:

Signature/Thumb Impression Name of the Impartial witness:

Signature of the impartial witness

Name of the person administering consent:

Signature of the person administering consent:

Annexure VI: Abbreviations