COPD Treatment Landscape

I. Introduction

Chronic Obstructive Pulmonary Disease (COPD) is a common disease characterized by persistent respiratory symptoms like progressive breathlessness and cough. [Focus, 2023] In individuals with COPD, the lungs experience constant exposure to elevated levels of reactive oxygen species (ROS), resulting in oxidative stress. [Sharma, 2023] It's typically caused by long-term exposure to irritating gases or particulate matter, most often from cigarette smoke, but also other air pollution such as radon, dusts, chemicals and fumes in enclosed environments such as residences and workplaces. [Urrutia-Pereira, 2023] Inflammation is a major underlying cause and can be underpinned by mitochondrial dysfunction and oxidative imbalance. [Sharma, 2023] Genetic factors such as Alpha 1 antitrypsin deficiency may also play a role. [Alwadani, 2023]

The main symptoms of COPD are: [Focus, 2023]

• Shortness of breath, which gradually gets worse

• Shortness of breath during physical activity

• Frequent coughing, with or without sputum

• Wheezing

• Noisy breathing

• Tightness in the chest

• Tiredness

• Frequent infections of the lungs

• Change in appetite

• Weight loss

Severe symptoms that need emergency medical attention may include: [Focus, 2023]

• Bluish or gray fingernails or lips

• Trouble catching the breath

• Inability to speak

• Confusion

• Fainting

• Increased heart beat

• Swelling in ankles, feet, and legs

If uncontrolled, COPD may lead to complications, such as heart problems, respiratory infections such as pneumonia, lung cancer, depression, pneumothorax, bronchiectasis, and osteoporosis. [Zhang, 2023]

II. COPD treatments

COPD can be managed through a combination of medications, lifestyle changes, and in some cases, surgical interventions. Typical treatment options include:

1. Medications: [MedlinePlus, 2023]

Bronchodilators - (Albuterol, Levalbuterol, Glycopyrronium, Ipratropium, Tiotropium, Indacaterol, Vilanterol, Aclidinium, Umeclidinium) are used to relax the muscles of the airways and improve breathing.

Glucocorticosteroids - (Beclomethasone, Betamethasone, Budesonide, Cortisone, Dexamethasone) are used to reduce inflammation in the airways.

Antibiotics - (Azithromycin, Amoxicillin/Clavulanate) may be prescribed to avoid or cure lung infections.

Mucolytics - (N-acetylcysteine) are usually used in severe COPD attacks.

2. Therapy:

Oxygen therapy is used in exacerbations and sometimes as a therapy in long-term oxygen therapy required patients.

Pulmonary rehabilitation involves working with a team of specialists to learn, practice, and improve breathing and physical activity.

3. Surgical Interventions:

Bullectomy is advised in case other treatments fail to reduce symptoms. In this procedure, the enlarged air sacs are removed from the lungs.

Lung transplantation involves replacing diseased lungs with a healthy lung from a donor.

4. Personalized Approach:

Alpha-1 Antitrypsin Deficiency (AATD) is a genetic disorder caused by mutations in the SERPINA1 gene, which encodes alpha-1 antitrypsin (AAT), a protease inhibitor and contributes to COPD. AATD is an example of how a personalized genetic approach can be applied to the treatment of COPD.

AATD is caused by a single amino acid substitution of lysine for glutamic acid at position 342, E342K, named as the Protease Inhibitor (Pi)*Z phenotype. This mutation leads to misfolded and polymerized AAT protein aggregates which accumulate within the endoplasmic reticulum (ER) of the hepatocytes, impairing its secretion into the plasma. AATD can lead to chronic activation of neutrophils resulting in chronic lung inflammation. [Yetman, 2023]

Gene therapy is a long-term strategy for the treatment of AATD-lung disease, where the approach is to express the wild-type (WT) allele to drive production of the normal human M-AAT gene into cells that will secrete the protein into the blood, ultimately augmenting the lung levels of AAT and preventing alveolar proteolytic destruction. This approach is a long way from realization.

If lung function is declining quickly, patients may be eligible for alpha-1 antitrypsin protein replacement therapy. This treatment involves intravenous infusion of alpha-1 antitrypsin protein extracted from human donors.

5. Prevention:

Quitting smoking is considered the most essential step in any treatment plan for COPD. [De Luca, 2024]

Dietary changes can also help manage COPD. [Lai, 2023] It's recommended to eat whole foods like fruits, vegetables, whole grain breads, low-fat dairy products, beans, lean meat, and fish, and avoid processed food, food rich in sugar, caffeinated beverages, and alcoholic beverages.

COPD can be potentially prevented by maintaining a healthy lifestyle, and generally improving the quality of air, which can be measured using the commonly deployed Air Quality Index (AQI). [Zhang, 2020] Virus or bacterially induced COPD could be prevented by vaccinations such as for COVID-19, anti-virals, and antibiotics. [Yamaya, 2023]

III. What the Data Say

There are several exciting developments in the field of COPD pharmaceuticals:

1. Dupixent (dupilumab): Positive interim data from the Phase III NOTUS trial by Sanofi and Regeneron reveal a promising 34% reduction in exacerbations among COPD patients. This drug, functioning as an interleukin-4 receptor alpha antagonist monoclonal antibody, has earned breakthrough therapy designation from the FDA. Specifically designated as an add-on maintenance treatment for adult patients with uncontrolled COPD, associated with a history of exacerbations and an eosinophilic phenotype.

The NOTUS trial showcased a noteworthy 34% decrease in exacerbations and substantial enhancements in lung function among adults grappling with uncontrolled COPD and evidence of type 2 inflammation. These compelling findings have been published in the New England Journal of Medicine and are anticipated to underpin a supplemental Biologics License Application (BLA) submission by the close of 2023. [Hunter, 2023]

2. The 2023 GOLD Report: The Global Initiative for Chronic Obstructive Lung Disease (GOLD) has issued its latest report, featuring evidence-based strategies for the diagnosis, management, and prevention of COPD. The report includes updated guidelines for both initial and follow-up treatment, presents novel insights on the connection between pharmacological triple therapy and mortality reduction, and delves into considerations surrounding inhaler device selection and adherence to COPD medications. [GOLD, 2023]

3. Mucus Plugs: Researchers have identified mucus plugs, which clog airways in the lungs of many patients with COPD, as a new target that could potentially save more lives.

A study led by researchers from Brigham and Women's Hospital discovered a link between mucus plugs and increased mortality. Conducted as a retrospective analysis using patient data from the COPDGene study, which involved over 10,000 participants, the researchers examined chest CT scans from more than 4,000 of these individuals to identify those with mucus plugs. [Diaz, 2023]

These advancements represent significant progress in the research and development of treatments for COPD.

IV. Conclusion

In conclusion, the comprehensive management of Chronic Obstructive Pulmonary Disease (COPD) requires a multi-faceted approach encompassing medications, lifestyle adjustments, and surgical interventions. The severity of symptoms, ranging from shortness of breath to life-threatening complications, underscores the importance of effective and personalized treatments.

Exciting developments in COPD pharmaceuticals, such as the breakthrough results from the Phase III NOTUS trial of Dupixent, offer hope with a substantial reduction in exacerbations and improvements in lung function. This interleukin-4 receptor alpha antagonist monoclonal antibody, designated for add-on maintenance treatment, signifies a significant stride towards addressing uncontrolled COPD with a history of exacerbations.

The 2023 GOLD Report further contributes to the evolving landscape, providing evidence-based strategies, updated guidelines, and insights into pharmacological triple therapy's potential to reduce mortality. This invaluable resource emphasizes the importance of meticulous follow-up treatment and considerations for inhaler device choice and medication adherence.

Moreover, the identification of mucus plugs as a novel target highlights ongoing advancements. The study led by Brigham and Women's Hospital sheds light on the association between mucus plugs and increased mortality, offering a potential breakthrough in understanding and treating COPD.

As we embrace these advancements, it's crucial to acknowledge the pivotal role of preventative measures, such as smoking cessation, dietary changes, and maintaining good air quality. These efforts not only complement treatment but also contribute significantly to the prevention of COPD and overall respiratory health.

In summary, the convergence of cutting-edge pharmaceutical research, comprehensive guidelines, and innovative insights into COPD pathology promises a brighter future for patients. The collaborative efforts of researchers, healthcare professionals, and individuals committed to preventive measures collectively shape a landscape where COPD is not just managed but potentially prevented and, in some cases, even reversed.

V. REFERENCES

Alwadani, Fawaz A., et al. "Pulmonary Rehabilitation for Chronic Obstructive Pulmonary Disease Patients with Underlying Alpha-1 Antitrypsin Deficiency: A Systematic Review and Practical Recommendations." Chronic Obstructive Pulmonary Diseases, 2023, Oct 9. DOI: 10.15326/jcopdf.2023.0434. Online ahead of print.

Buttery, Sara C., et al. "Investigating the prognostic value of Digital Mobility Outcomes in patients with chronic obstructive pulmonary disease: A systematic literature review and meta-analysis." European Respiratory Review, vol. 32, no. 170, 2023, p. 230134, https://doi.org/10.1183/16000617.0134-2023.

De Luca, Simone N., and Ross Vlahos. "Targeting Accelerated Pulmonary Ageing to Treat Chronic Obstructive Pulmonary Disease-Induced Neuropathological Comorbidities." British Journal of Pharmacology, vol. 181, no. 1, 2024, pp. 3-20. DOI: 10.1111/bph.16263. Epub 2023 Nov 15.

Diaz, Alejandro A., et al. "Airway-Occluding Mucus Plugs and Mortality in Patients With Chronic Obstructive Pulmonary Disease." JAMA, vol. 329, no. 21, May 21, 2023, pp. 1832-1839. doi:10.1001/jama.2023.2065.

Focus Medica. Chronic Obstructive Pulmonary Disease, MSN, 8 Oct. 2023, www.msn.com/en-us/health/condition/Chronic-obstructive-pulmonary-disease/hp-Chronic-obstructive-pulmonary-disease?source=conditioncdx.

GOLD. "2023 Gold Report - Global Initiative for Chronic Obstructive Lung Disease." GOLD, 12 Nov. 2023, goldcopd.org/2023-gold-report-2/#.

Hunter, Erin. "Data from Phase 3 Trials Demonstrate Efficacy of Dupilumab for Treating COPD, Type 2 Inflammation." AJMC, AJMC, 1 Dec. 2023, www.ajmc.com/view/data-from-phase-3-trials-demonstrate-efficacy-of-dupilumab-for-treating-copd-type-2-inflammation.

Lai, Wei, et al. "Mendelian Randomization Study Reveals the Relationship Between Dietary Factors and Respiratory Diseases." Scientific Reports, vol. 13, no. 1, 2023, p. 22601. DOI: 10.1038/s41598-023-50055-x.

MedlinePlus. "Health Information from the National Library of Medicine." MedlinePlus, U.S. National Library of Medicine, medlineplus.gov/. Accessed 20 Dec. 2023.

Sharma, Gautam, et al. "Molecular Mechanisms and the Interplay of Important Chronic Obstructive Pulmonary Disease Biomarkers Reveals Novel Therapeutic Targets." ACS Omega, vol. 8, no. 49, 2023, pp. 46376-46389. DOI: 10.1021/acsomega.3c07480. Epub 2023 Dec 12.

Urrutia-Pereira, Marilyn, et al. "Radon Exposure: A Major Cause of Lung Cancer in Nonsmokers." J Bras Pneumol, vol. 49, no. 6, 2023, e20230210. DOI: 10.36416/1806-3756/e20230210. Epub 2023 Dec 4. [Article in English, Portuguese]

Yamaya, Mutsuo, et al. "Anti-inflammatory Effects of Medications Used for Viral Infection-Induced Respiratory Diseases." Respiratory Investigation, vol. 61, no. 2, 2023, pp. 270-283. DOI: 10.1016/j.resinv.2022.11.002. Epub 2022 Dec 19.

Yetman, Daniel. "Alpha-1 Antitrypsin Deficiency and COPD: The Connection." Edited by Roman Gokhman and Adithya Cattamanchi, Healthline, Healthline Media, www.healthline.com/health/alpha-1-antitrypsin-deficiency-copd. Accessed 21 Dec. 2023.

Zhang, Xu, et al. "When Chronic Obstructive Pulmonary Disease Meets Small Cell Lung Cancer: An Unusual Case Report of Rapid Progression." BMC Geriatrics, vol. 23, no. 1, 2023, p. 836. DOI: 10.1186/s12877-023-04508-7.

Zhang, Yi, et al. "Association Between Consecutive Ambient Air Pollution and Chronic Obstructive Pulmonary Disease Hospitalization: Time Series Study During 2015-2017 in Chengdu, China." Annual International Conference of the IEEE Engineering in Medicine and Biology Society, 2020, pp. 5378-5381. DOI: 10.1109/EMBC44109.2020.9176504.

About The Author

David  Orchard-Webb, Ph.D., is a technical writer with broad interests including  health & technology writing, plus extensive training and knowledge of  biomedicine and microbiology. My Ph.D. and postdoc were in oncology and  developing cancer medicines. I provide technical medical and other writing  services for projects ranging from “knowledge automation” to pure pharma, to  food safety, to the history of science, and everything in between. I also  provide white papers, ebooks, meta-analysis reviews, editing, consulting,  business, and market research-related activities in biomedicine, technology,  and health. In addition to its well-known role in the development of  medicines, I am a big believer in biotechnology’s ability to revolutionize  industries such as food-tech, agtech, textiles & fashion.