27th August 2023, Dr Chee L Khoo
I thought I knew how to diagnose COPD when I see one. I thought I knew everything I need to know as a GP in managing COPD. I mean, how hard can it be? LABA, LAMA +/- ICS. If in doubt, put them on a triple puffer. Might be a bit of an overkill but what is the harm? Most of these patients are smokers or at least, ex-smokers. Stop smoking will be nice but that’s not always easy. I understand that. I knew there was a Global Initiative for Chronic Obstructive Lung Disease (GOLD) report published annually and issue some guidance on diagnosis and management like all good guidelines do. Haven’t got around reading the report all these years but finally did read the 2023 report which span only 205 pages (1). This is my take for practising GPs.
Naturally, I won’t go through what we already know about COPD but what is new that was a surprise to me which I am sure will be a surprise to many of you.
Prevalence
Prevalence data vary widely due to differences in survey methods, diagnostic criteria, and analytical approaches. There is obviously a lot of under-recognition and under-diagnosis but also mis- diagnosis. As the diagnosis is not just based on symptoms alone, the availability of spirometry also affects prevalence data. Nonetheless, there is emerging data that have enable more accurate estimates of prevalence. Based on the Burden of Obstructive Lung Diseases (BOLD) and other large epidemiological studies, it is thought that the global prevalence is about 10.3% although with the increasing prevalence of smoking in LMICs, and aging populations in high-income countries, the prevalence of COPD is expected to rise.
The diagnosis
A diagnosis of COPD should be considered in any patient who has dyspnoea, chronic cough or sputum production and/or a history of exposure to risk factors for the disease (see below). The dyspnoea is persistent, worse with exercise and tends to be progressive. Typically, COPD patients describe their dyspnoea as a sense of increased effort to breathe, chest heaviness, air hunger, or gasping. However, the terms used to describe dyspnoea may vary both individually and culturally.
Forced spirometry that demonstrates the presence of a post-bronchodilator FEV1/FVC < 0.7 is mandatory to establish the diagnosis of COPD. This has not changed.
The Pathogenesis
COPD is the end-result of complex, cumulative and dynamic gene-environment interactions over the lifetime that can damage the lungs and/or alter their normal developmental or aging processes. There are interactions between the genetic (G) background of the host and varied environmental (E) risk factors over the lifetime (T). This is coined GET’onmics and requires further investigation.
Genetic
The best documented genetic risk factor for COPD are mutations in the SERPINA1 gene that leads to the hereditary deficiency of α-1 antitrypsin, a major circulating inhibitor of serine proteases. Hundreds of genetic variants associated with reduced lung function and risk of COPD have also been identified but their individual effect size is small. It remains uncertain whether these genes are directly responsible for COPD or are merely markers of other causal genes.
Environmental
While cigarette smoking is a major risk factor for COPD, there must be genetic and other risk factors involved. Cigarette smokers have a higher prevalence of respiratory symptoms and lung function abnormalities, a greater annual rate of decline in FEV1, and a greater COPD mortality rate than non-smokers. Yet fewer than 50% of heavy smokers develop COPD and it is estimated that half of all COPD cases worldwide are due to risk factors other than tobacco so other pathogenic factors beyond smoking need to be considered. Exposure to other tobacco and marijuana and passive exposure (including smoking during pregnancy) are also risk factors.
Whilst tobacco smoking remains the leading risk factor for COPD in high income countries, accounting for over 70% of the cases, in low to middle income countries (LMIC), tobacco smoking contributes to around 30 – 40% of the total burden. Wood, animal dung, crop residues, and coal, typically burned in open fires or poorly functioning stoves, may lead to very high levels of household air pollution but there is limited data about household pollution related COPD.
Occupational exposures, including organic and inorganic dusts, chemical agents and fumes, are an under-appreciated environmental risk factor for COPD. Individuals with exposure to inhalation of high doses of pesticides have a higher incidence of respiratory symptoms, airways obstruction and COPD. Workers in occupations including sculptors, gardeners, warehouse workers and fire fighters have an increased COPD risk among never-smokers without asthma.
Air pollution typically consists of particulate matter, ozone, oxides of nitrogen or sulphur, heavy metals, and other greenhouse gases is responsible for ~50% of the attributable risk for COPD in LMICs.
Time (Ageing)
At birth, the lung is not fully developed. It grows and matures until about 20-25 years of age (earlier in females), when lung function reaches its peak. This is followed by a relatively short plateau and a final phase of mild lung function decline due to physiological lung ageing. This normal lung function trajectory can be altered by processes occurring during gestation, birth, childhood, and adolescence that affect peak lung function.
A large study and meta-analysis confirmed a positive association between birthweight and FEV1 in adulthood. Factors in early life termed “childhood disadvantage factors” are key determinants of lung function in adult life. It is thought that approximately 50% of patients developed COPD due to accelerated decline in FEV1 over time while the other 50% developed COPD due to abnormal lung growth and development (2).
Asthma and COPD
Asthma may also be a risk factor for the development of chronic airflow obstruction and COPD. In a longitudinal cohort of the Tucson Epidemiological Study of Airway Obstructive Disease, adults diagnosed with asthma were found to have a 12-X higher risk of developing COPD compared to those without asthma, after adjusting for smoking (3). The pathology of chronic airflow obstruction in asthmatic non-smokers and non-asthmatic smokers is markedly different, suggesting that the two disease entities may remain different even when presenting with similarly reduced lung function. However, separating asthma from COPD in adults can sometimes be clinically difficult.
There are differences in the inflammatory cells and mediators involved in the two diseases, albeit some patients with COPD have an inflammatory pattern with increased eosinophils and ILC2 cells, similar to that of asthma.
Infections and Inflammation
In patients with COPD pathological changes can be found in the airways, lung parenchyma, and pulmonary vasculature. These include inflammatory and structural changes which increase with the severity of airflow obstruction and can persist even with smoking cessation. There are increased numbers of macrophages in peripheral airways, lung parenchyma and pulmonary vessels, together with increased activated neutrophils and increased lymphocytes. The inflammation seen in COPD appears to be an amplification of the normal response to chronic irritants (including smoking). The mechanism of this amplification is still not fully understood.
Oxidative stress can also contribute to COPD. Oxidants are both generated by cigarette smoke and other inhaled particulates and released from activated inflammatory cells such as macrophages and neutrophils. Oxidative stress is further increased during exacerbations.
In summary, our understanding of the pathogenesis of COPD have come a long way. It’s not just smoking that is the root of all evils in COPD. Other environmental causes including household pollutants and air pollution are major culprits too.
Not everyone develop their lungs to the full potential. Up to 50% of patients developed COPD because they did not have adult peak lung function when they get to 25 years of age. These people are at much higher risk of developing COPD whether they take up cigarette smoking on not. This opens up avenues in general practice to identify these at risk groups. Perhaps, this will reduce the under-diagnosis and may promote preventative activities that slow down the decline in lung function.
Next fortnight, we will look at the new understanding of the structural changes in COPD which will aid our understanding of the management of COPD.
References:
- https://goldcopd.org/2023-gold-report-2/. Accessed on 22nd August 2023.
- Fletcher C, Peto R. The natural history of chronic airflow obstruction. Br Med J 1977; 1(6077): 1645-8.
- Silva GE, Sherrill DL, Guerra S, Barbee RA. Asthma as a risk factor for COPD in a longitudinal study. Chest 2004; 126(1):59-65.