‘Oversimplified’ asthma and COPD classifications miss important subgroups: NOVELTY study

The value of conventional asthma and COPD classifications has again been called into question as findings from a global real-world study show the labels do little to differentiate between clinically important phenotypes, potentially leading to unsuitable or unsafe treatment decisions. 

Respiratory clinicians involved in the Australian-led NOVELTY study say their analysis of baseline characterisers in more than 11,200 patients from 19 countries demonstrated marked heterogeneity within, and considerable overlap between, clinician assigned diagnoses of asthma and/or COPD, including by clinician-assessed severity.

 Speaking to the limbic, Professor Helen Reddel, international co-chair of the NOVELTY study and research leader at the Woolcock Institute of Medical Research at the University of Sydney, said NOVELTY is one of the few studies that looks at patients across the spectrum of asthma and COPD despite increasing recognition that there are numerous phenotypes of asthma and COPD, and that conventional diagnostic criteria for the two diseases overlap.

“It’s an increasing concern because the clinical trials that form the basis of guideline recommendations have been conducted in patients who have very precisely defined disease. It has  been shown across a number of studies that only about 5% of patients with asthma or COPD in the community would satisfy the criteria for regulatory studies.”

Professor Reddel, who has for a number of years been advocating for pragmatic trials with broader eligibility to complement the randomised controlled trial evidence base, says the NOVELTY study was designed to look at people with asthma and COPD in the community without applying the regulatory-type criteria that exclude significant amounts of real-world patients.

“We deliberately recruited patients who had a diagnosis of asthma or COPD or both, but we didn’t give clinicians any instructions about the criteria they should use for diagnosis or assessment of severity. We didn’t want to miss patients who had important airway disease but didn’t necessarily satisfy the pre specified criteria.” 

Just over half of the cohort (52.8%) had clinician-assigned asthma, 12.4% had asthma+COPD and 34.8% had COPD. Over half of patients were recruited from primary care.

Symptoms, health-related quality of life and spirometry showed substantial heterogeneity and overlap between asthma, asthma+COPD and COPD. One important finding was that only 64% of patients with COPD, and 62% of those with diagnoses of both asthma and COPD, had persistent airflow limitation as indicated by post-bronchodilator FEV1/FVC <lower limit of normal, which in guidelines is essential for diagnosis of COPD. Further, of patients with an asthma diagnosis, 23% had persistent airflow limitation, indicating that spirometry is not sufficient to distinguish between asthma and COPD.

Symptoms and exacerbations increased with greater physician-assessed severity, and were higher in asthma+COPD, but 24.3% with mild asthma and 20.4% with mild COPD had experienced ≥1 exacerbation in the past 12 months. Meanwhile medication records suggested both under-treatment and over-treatment relative to severity. Together the findings suggests that the criteria used by physicians to assess severity – and on which they make treatment decisions – do not adequately identify patients at risk of adverse outcomes, including death, say investigators. 

Meanwhile blood eosinophil counts varied little across diagnosis and severity groups, but blood neutrophil counts increased with severity across all diagnoses. Also, features such allergic rhinitis and nasal polyposis, and smoking and emphysema, that are commonly associated with asthma and COPD, respectively, were found to be present across all diagnoses. 

Oversimplified classifications

The findings support the emerging view that “conventional diagnostic categories in asthma and COPD are over-simplified and generalise complex and heterogeneous conditions”, investigators stated.

For Professor Reddel, the study emphasises the importance of identifying and validating biomarkers to identify target populations, particularly those characterised by different trajectories over time, from which molecular endotypes of asthma and/or COPD can be elucidated, and more precise clinical classification and treatment decisions can be made.

“There are some conditions in which you can find an underlying mechanism that clearly translates into a particular treatment, but that’s not the case with asthma and COPD so the long-term goal is to identify these underlying mechanisms. So far, we’ve reported the baseline characteristics to describe the population and there is a lot more work to be done, but it certainly confirms what we were expecting to find – that there is a lot of heterogeneity and that it is both within and between the diagnostic labels.”

But are we ready to ditch such labels in obstructive airway disease? Professor Reddel argues against it – at least for now. 

“Some people will call for abandoning the labels for asthma and COPD, and there have been a lot of calls for that, but I strongly resist this at the moment because these labels provide clinically important information about risks of some treatment options, that we don’t have from anything else. The key difference is that several community-based studies have found that if you treat someone who has a diagnosis of asthma (with or without a diagnosis of COPD) with a long-acting bronchodilator alone, they are more likely to die or be hospitalised than if they are also treated with inhaled corticosteroids. 

This doesn’t apply in patients who have a diagnosis only of COPD. At the moment we do not know the explanation for this, or how to identify the patients who can be safely treated with bronchodilators alone and those who must not, but to investigate differences like these, you need a study that recruits a broad population of patients, rather than only the highly selected patients who are eligible for clinical trials.”

While NOVELTY will continue to systematically collect and analyse real-world data from patients with asthma and COPD with the end goal of identifying clinal phenotypes and molecular endotypes to aid more personalised targeted treatment, Professor Reddel identified several immediate implications for practice.

“The take-home message regarding use of inhaled corticosteroids is that if a patient has a diagnosis of asthma, they should be on at least some corticosteroids – that message has not been overridden by anything that we’ve seen in this study.”

Measuring lung function serially over time has also been flagged as critical in helping to determine underlying mechanisms and phenotypes that might one day inform more targeted treatment.  

“Measuring lung function when patients first present, even if it doesn’t clearly distinguish between asthma and COPD, does allow you to identify patients who are progressively getting worse over time. It’s not perfect but it will help identify patients who have a different clinical pattern from others.”

“Finally, it is important to take multimorbidity into account when looking after patients with asthma and/or COPD, because these other conditions contribute to poor quality of life and the potential for treatment interactions.”


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