While a postbronchodilator forced expiratory volume in 1 second and forced vital capacity (FEV1/FVC)ratio lower than 0.70 is required to confirm a diagnosis of chronic obstructive pulmonary disease (COPD), a substantial number of individuals with normal spirometry have a history of smoking or exposure to other COPD risk factors, along with the presence of symptoms including chronic cough and sputum production that may precede the development of COPD.1 In a 2001 report by the Global Initiative for Chronic Obstructive Lung Disease (GOLD), the authors proposed the addition of a “GOLD stage 0” category to identify these “at-risk” patients who may eventually progress to COPD and thus may benefit from early intervention such as inhaled therapies.2

Although GOLD ultimately declined to use this category because not all patients meeting these criteria progress to COPD, the authors of a recent review stated that perhaps the concept should not have been entirely abandoned.1 MeiLan K. Han, MD, MS, professor of internal medicine in the Division of Pulmonary and Critical Care Medicine at the University of Michigan Health System, and colleagues noted that other medical specialties recognize “pre-disease” states such as pre-cancer or pre-diabetes. Rather than implying certain disease progression, this approach helps to identify high-risk patients who warrant closer follow-up, they wrote.1

Han et al proposed the adoption of a similar category for patients at risk for COPD, explaining that these individuals may incur significant lung damage before FEV1 abnormalities can be detected. Some symptomatic patients with normal spirometry “may never develop spirometrically-defined airflow obstruction whereas others will experience rapid lung function decline and develop full blown disease” they stated.1 “Identifying individuals who will eventually develop airflow obstruction consistent with a diagnosis of COPD may enable therapeutic interventions with the potential to modify the course of disease.”


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Han et al pointed to a range of study results that may have implications regarding the value of a “pre-COPD” category. For example, in a longitudinal cohort study of 5002 young adults from 12 countries who had normal lung function, chronic cough and phlegm independently predicted incident COPD (incident rate ratio [IRR], 1.85).3 Additionally, a British cohort study of more than 4000 individuals linked chronic bronchitis symptoms at ages 36 and 43 years to a higher risk of airflow limitation (odds ratios, 3.70 [95% CI, 1.62-8.45] and 4.11 [95% CI, 1.85-9.13], respectively).4

An epidemiologic study of 1412 adults in the United States similarly showed that adults younger than 50 years with normal spirometry and chronic bronchitis had higher rates of subsequent airflow obstruction compared with participants without chronic bronchitis (42% vs 23%, respectively; P <.001), as well as increased mortality (adjusted hazard ratio, 1.31; 95% CI, 1.00-1.71).5

Han et al suggested that the pre-COPD category should expand beyond the symptom-based focus of the GOLD 0 concept by integrating further measures of physiologic abnormality such as low-normal FEV1 and diffusing capacity for carbon monoxide (DLco), along with radiographic findings such as airway abnormality and emphysema.1 Studies using CT have found airway wall thickening in individuals with chronic cough and phlegm despite normal spirometry, and patients with these symptoms “stand apart as a clear form of pre-COPD for several reasons,” according to the review.1 There may also be “other phenotypic subsets… that may or may not develop airflow obstruction but are clinically relevant subtypes due to significant symptoms, exacerbations or increased mortality.”1

However, study results on the topic are largely inconclusive, and there is scant evidence regarding the therapeutic implications such as the potential benefit of inhaled bronchodilator therapy in symptomatic smokers without spirometric obstruction. The Redefining Therapy in Early COPD (RETHINC) trial, funded by the National Heart, Lung, and Blood Institute and co-led by Dr Han, is currently enrolling with the aim of addressing this question (ClinicalTrials.gov Identifier: NCT02867761).6

While Dr Han and her colleagues acknowledged that the available data are currently insufficient to further refine the concept of pre-COPD, they emphasized that its use would be in line with the risk reduction approach used for other pre-disease states.1 Thus, although substantial research needs remain in this area, they believe that introducing the concept “would provide greater awareness within the medical community and general public of the fact that by the time spirometric obstruction develops, significant airway damage has already occurred.”

The Point/Counterpoint Q&A

The value of formally recognizing a pre-disease state for COPD is likely to remain a point of controversy for the foreseeable future. To explore opposing perspectives on the topic, we interviewed Dr Han and Paul Enright, MD, a pulmonary expert who is now retired from his professorship at the University of Arizona, College of Medicine in Tucson.

Dr Enright has written numerous papers pertaining to this issue over the years, including a 2020 editorial he coauthored with Carlos Vaz Fragoso, MD, from the Yale School of Medicine in New Haven, Connecticut.7,8

What are the potential benefits or drawbacks of using the term “pre-COPD” to describe certain patients? 

Dr Han: Introduction of the term is something the authors considered very carefully, but we wanted to acknowledge that there are some patients who do not fit classical criteria for COPD that have many of the same symptoms and even imaging abnormalities as patients with COPD. We also wanted to raise awareness that we need to figure out how best to identify such individuals so that they can be better studied and appropriate treatments may be developed.

Dr Enright: Inventing “pre-COPD” will sell sickness and drugs but will not help patients. Cigarette smoking causes up to 90% of clinically-important COPD.9 Telling a smoker that they have COPD does not prompt them to quit smoking.7 COPD inhalers have been proven not to reduce the morbidity and mortality of smoking, and they are expensive and risk serious side effects. 8

Prescribing an inhaler for a smoker with respiratory symptoms is much faster than motivational interviewing, so smokers are rarely helped by medical providers towards the decision to try to quit smoking. Sadly, the inexpensive drugs which have been proven to double or triple the success of smokers who are motivated to quit are rarely prescribed.10

At present, what are the relevant treatment implications for clinicians regarding this issue?

Dr Han: While many of these patients are already being treated with the same medications we use in COPD, unfortunately we have very little data regarding whether these therapies actually work in patients who do not demonstrate classical airflow obstruction. This is the type of data we really need so that we can understand how to help these patients. I am currently conducting the RETHINC trial with the NIH, which will complete enrolling soon. This study examines whether a dual bronchodilator improves symptoms among patients with pre-COPD, but more such data will be needed.

Dr Enright: During the past 3 decades since the GOLD guidelines were promoted by pharmaceutical giants, about one-fourth of adults who report a COPD diagnosis do not have the O in COPD (airway obstruction).11 The COPD inhalers prescribed for many of these patients are only bronchodilators which reduce obstruction. Bronchodilators do not reduce the airway inflammation that causes chronic bronchitis and exacerbations in almost all current smokers or in patients with asthma. Some COPD inhalers include a corticosteroid but substantially increase the risk of pneumonia.12

Because COPD inhalers create a great deal of profit each year, many smokers are enrolled in clinical trials of new inhalers with 2 or 3 drugs. However, one-half of them are continuing smokers who, even at the end of the study, are not offered help with the 1 intervention that could save their life: smoking cessation.13 I worry that many smokers who are prescribed a daily inhaler believe that they are taking a “cure” and thus do not need to try to quit smoking. 

We do not need a pre-COPD label given to patients with hyperinflation on a chest X-ray (which can also be due to asthma), emphysema or gas trapping on an expensive lung CT scan, or a mild “abnormality” from one of the dozens of values on a pulmonary function laboratory report. None of these have been shown to be better than a low FEV1 for predicting progression to clinically-important COPD when compared to simply knowing the patient’s smoking status and age, and no inhaler treats emphysema. 

What are additional remaining needs in this area in terms of research or practice?

Dr Han: While the RETHINC study is a good start, we are going to need a lot more research. Although we offered a working definition for pre-COPD, we did not provide specific thresholds to make it truly operational in clinical practice. Further, many such patients are not undergoing spirometry or imaging at all. We will need more data on the best measures to use for identifying such patients in addition to determining whether identification of these patients ultimately has any long-term impact. This is where testing interventions in the pre-COPD population becomes incredibly important.

Dr Enright: Defining COPD as a low postbronchodilator FEV1/FVC includes many patients with poorly controlled asthma — their spirometry does not normalize 5 minutes after inhaling albuterol. Many older current and former smokers have asthma but are falsely given a COPD diagnosis and thus denied asthma interventions which are much more effective than are COPD inhalers. 

Despite the guidelines which recommend using a low postbronchodilator FEV1/FVC, very few primary care providers take the extra time to repeat spirometry after the patient inhales albuterol. This greatly increases the proportion misdiagnosed as COPD instead of asthma.8 

COPD “risk reduction” is easy: reduce or eliminate inhalation of polluted air from smoking (active or secondhand), the workplace, and the environment. We do not need to sell sickness or inhalers to reduce COPD risk.

Disclosures: Dr Han reports various industry relationships as detailed here. Dr Enright has no conflicts of interest to report.

References

1. Han MK, Agusti A, Celli BR, et al. From GOLD 0 to Pre-COPD. Am J Respir Crit Care Med. 2021;203(4):414-423.

2. Pauwels RA, Buist AS, Calverley PM, Jenkins CR, Hurd SS; GOLD Scientific Committee. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) Workshop summary. Am J Respir Crit Care Med. 2001;163(5):1256-1276.

3. de Marco R, Accordini S, Cerveri I, et al. Incidence of chronic obstructive pulmonary disease in a cohort of young adults according to the presence of chronic cough and phlegm. Am J Respir Crit Care Med. 2007;175(1):32-39.

4. Allinson JP, Hardy R, Donaldson GC, Shaheen SO, Kuh D, Wedzicha JA. The presence of chronic mucus hypersecretion across adult life in relation to chronic obstructive pulmonary disease development. Am J Respir Crit Care Med. 2016;193(6):662-672.

5. Guerra S, Sherrill DL, Venker C, Ceccato CM, Halonen M, Martinez FD. Chronic bronchitis before age 50 years predicts incident airflow limitation and mortality risk. Thorax. 2009;64(10):894-900.

6. US National Library of Medicine. ClinicalTrials.gov. RETHINC: REdefining THerapy In Early COPD for the Pulmonary Trials Cooperative (RETHINC). Accessed online February 12, 2021. Last update posted July 29, 2020.https://clinicaltrials.gov/ct2/show/NCT02867761

7. Enright P, White P. Detecting mild COPD: Don’t waste resources. Prim Care Respir J. 2011;20(1):6-8.

8. Enright P, Fragoso CV. GPs should not try to detect mild COPD. NPJ Prim Care Respir Med. 2020;30(1):20.

9. American Lung Association. COPD causes and risk factors. Accessed online February 12, 2021.

10. van Eerd EA, van der Meer RM, van Schayck OC, Kotz D. Smoking cessation for people with chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2016;2016(8):CD010744.

11. Fisk M, McMillan V, Brown J, et al. Inaccurate diagnosis of COPD: the Welsh National COPD Audit. Br J Gen Pract. 2019;69(678):e1-e7. doi:10.3399/bjgp18X700385

12. Yang M, Du Y, Chen H, Jiang D, Xu Z. Inhaled corticosteroids and risk of pneumonia in patients with chronic obstructive pulmonary disease: A meta-analysis of randomized controlled trials. Int Immunopharmacol. 2019;77:105950. doi:10.1016/j.intimp.2019.105950

13. Tashkin DP. Smoking cessation in chronic obstructive pulmonary disease. Semin Respir Crit Care Med. 2015;36(4):491-507.