COPD

Mehmet Kesimer, PhD, on Mucin Abnormalities in Early COPD

To reduce the long-term societal impact of chronic obstructive pulmonary disease (COPD), there has been a call to focus intervention efforts on not only the reduction of symptoms and exacerbations in advanced disease, but also the prevention of pathological progression in early disease.

Mucin abnormalities may be a key factor in predicting the risks and rates of progression to more severe disease, according to a presentation1 that Mehmet Kesimer, PhD, gave during the American Thoracic Society’s 2020 Virtual Meeting.

Dr Kesimer is a professor of pathology and laboratory medicine at the University of North Carolina’s School of Medicine, where he also works at the Marsico Lung Institute. He answered our questions about the importance of identifying a sensitive and specific laboratory biomarker for early bronchitis, how mucin abnormalities may serve as a noninvasive biomarker in early COPD, and how the research in this area may impact the future of clinical practice.

PULMONOLOGY CONSULTANT: In your presentation, you said that a sensitive and specific laboratory biomarker for early bronchitis is a key requirement to elucidate early COPD pathogenesis. What is the importance behind identifying such a marker?

Mehmet Kesimer: Recent efforts have focused on earlier stages of COPD to predict the risks and rates of progression to more severe disease. At this early stage of the disease, the involved pathobiological factors, which cause small airway obstruction and damage, are less complicated and perhaps reversable. Therefore, it is essential to find an objective biological indicator that sensitively and specifically tracks the pathogenesis of muco-obstructive lung disease for subsequent interventions. Currently, it is almost impossible to predict which subjects among the at-risk group (ever smokers with no airway obstruction) will progress to more severe chronic conditions because we do not have the biological underpinnings of the disease-causing pathways in hand. Spirometric lung function tests, such as FEV1 and FEV1/FVC, lack the sensitivity to detect the early pathological changes occurring in “early” airway disease even if these individuals are symptomatic and have rapidly declining lung health. In turn, spirometry is not sufficiently sensitive to diagnose early disease and cannot tell us which subjects will progress from the “at risk” group to COPD. Therefore, there is a need for an objective laboratory metric to identify this population and intervene in a timely manner. 

PULM CON: How can mucin abnormalities be used as a noninvasive biomarker and help identify progressive COPD early? 

MK: Gel-forming mucins are the major macromolecular components of the airway mucus, a gel layer that covers and protects surfaces of our lungs. Too much of a good thing, however, could be equally bad. Our data indicated that increased total mucin concentrations are closely related to many manifestations of COPD2 including lung function decline, exacerbation frequency, etiological factors such as cigarette smoking and asthma, phlegm production, increased symptoms and impact scores, and small airway abnormalities.3 We also found that the mucin/mucus compositions are altered in responses to cigarette smoke-induced early chronic bronchitic changes and COPD symptoms such as cough and phlegm production; computed tomography abnormalities of small airways, such as air trapping and airway thickening; and lung function decline. These novel observations can be utilized to assess disease initiation and progression as a more sensitive, objective, noninvasive biomarker and can be used as a biological endpoint.  

PULM CON: How do you envision clinicians implementing these findings into their approach to COPD prevention and management? 

MK: In 2020, we do not have enough information regarding the pathobiological pathways that cause the mucus accumulation that produces chronic bronchitis symptoms, which are the first indicators that a patient will develop COPD, the only current way to diagnose chronic bronchitis is based on subjective questionnaires (i.e. what patients tell a clinician). There is a need for an objective marker to diagnose such conditions, just like the blood glucose level for diabetes diagnosis and serum cholesterol level for cardiovascular risk assessment. So, our work can fill this gap by proposing airway mucin concentration measurements from clinically-obtained samples to diagnose chronic bronchitis, including in the early stages of the disease. Now we are learning that the onset of small airway disease in the lung occurs much earlier than emphysema in the lung on the way to developing COPD. Both in the early stages of the disease and in established COPD, clinicians tell patients to stop smoking, but to really convince patients to stop smoking, it is key to have a clear understanding of what drives their conditions and to have an objective laboratory metric to say, “Look, this is abnormal.”

PULM CON: What knowledge gaps still exist regarding mucin abnormalities in early COPD, and what are the next steps to bridge those gaps?

MK: We are really only beginning to study such populations. Currently, the number of longitudinal studies in the United States and in the United Kingdom are working with people aged younger than 50 years and with under a 20 pack/year cigarette smoking history. We need to extensively characterize such populations to understand the biological underpinnings of the early disease and which pathways are dominant in the beginning before a patient develops COPD. In that context, the role of my laboratory is to understand the close correlation between  increased mucin concentrations and the initiation and progression of the disease in order to improve understanding of the early pathogenesis and provide a possible prognostic/diagnostic biomarker, as well as to guide selection of novel targets in mucin-producing pathways for future therapies.   

References:

  1. Kesimer M. Mucin abnormalities in early COPD. Video presented at: ATS 2020 Virtual; August 5-10, 2020. Accessed August 10, 2020. https://cattendee.abstractsonline.com/meeting/8998/presentation/4215
  2. Kesimer M, Ford AA, Ceppe A, et al. Airway mucin concentration as a marker of chronic bronchitis. N Engl J Med. 2017;377(10):911-922. doi:10.1056/NEJMoa1701632  
  3. Kesimer M, Smith BM, Ceppe A, et al; SPIROMICS Investigative Group. Mucin concentrations and peripheral airway obstruction in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2018;198(11):1453-1456. doi:10.1164/rccm.201806-1016LE