Definitions of early COPD and predictors for disease a systematic review

Authors: Alastair Watson, Ross Davidson, Fu Chuen Kon, Arnav Sharma, Gbenga Adesoye, Bryan Chang, Kane Alexander, Mosea Song, Isobel Soper, Akhilesh Jha, Marie Fisk

Abstract

Introduction

Early chronic obstructive pulmonary disease (COPD) is considered to represent the initial phase of the disease. However, inconsistent terminology and lack of standardised definitions hinders research and clinical application. This systematic review examined clinical research on early COPD, analysed terms and definitions used, and evaluated predictors of disease progression. This serves as a platform to reach consensus and direct future research to target early disease states and improve patient outcomes.

Methods

Utilising a standardised protocol, we systematically screened all clinical studies on early COPD. Titles and abstracts were reviewed and compared against inclusion and exclusion criteria. Stage 1 assessed terminology and definitions and stage 2 evaluated predictors of progression. Two independent people reviewed studies at each stage. Study quality was appraised using a modified Downs and Black checklist.

Results

We identified 4871 articles, 1759 were screened after duplicate removal. The terms used included PRISm (preserved ratio impaired spirometry) (104 articles), GOLD 0 (Global Initiative for Chronic Obstructive Lung Disease stage 0) (63), early COPD (37), at-risk COPD (35) and pre-COPD (30). Definitions were heterogeneous and proposed early COPD definitions were not routinely used. Stage 2 included 43 full-text articles from cohort studies, of which 93% were of good quality. Predictors of progression included age (n=13 articles), smoking history (12), symptoms (12), exacerbations (one), lung function measures (20), computed tomography metrics (14), risk tools (three) and machine learning approaches (three).

Conclusion

We demonstrate an urgent need for consensus on clinically applicable definitions of the early disease course of COPD, prior to diagnosis. We highlight predictors of progression; these need validation to enable stratification of individuals early in their disease trajectory for targeted management to halt or modify progression.

Introduction

Chronic obstructive pulmonary disease (COPD) is a leading cause of death worldwide and contributes to substantial morbidity [1–4]. This heterogeneous disease is characterised by different pathological entities, including emphysema, chronic bronchitis and small airways disease. These can co-exist with varying degrees of severity and progress at different rates among individuals. Diagnosis is dependent on chronic airflow obstruction, which is dependent on disease progression to meet an arbitrary diagnostic threshold. Current diagnostic methods fail to capture the full spectrum of disease progression or guide effective management [5]. There is an urgent need to focus on earlier disease recognition and diagnosis, with an approach that stratifies patients based on risk prediction and trajectory, aiming to halt or modify disease mechanisms rather than treating complex intractable disease [6].

There has been growing interest in the concept of “early COPD”, which could help shift our current diagnostic approach [7–9]. Early COPD is considered to represent the initial disease phase rather than indicating its severity or potential future severity and so is not synonymous with “mild COPD”. However, studies have used these terms interchangeably, contributing to confusion in the literature and impeding research [10]. A clear widely adopted consensus definition of early COPD has not been established, limiting its translation into clinical practice. Two definitions have been proposed by Martinez et al. [8] and Siafakas et al. [11]. However, it is not clear that either of these are commonly used and other varied definitions continue to be employed [10]. Thus, interpreting, comparing and progressing the current evidence base for early COPD has been inadequate. More recently, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2026 COPD guidance advises use of the term early COPD to encompass the “biological” first steps of the disease in an experimental setting. However, what this means practically is uncertain [2, 8]. Furthermore, the use of various overlapping and synonymous terms has further complicated this; including pre-COPD, preclinical COPD, undiagnosed COPD, preserved ratio impaired spirometry (PRISm), at-risk COPD and GOLD stage 0 (box 1). Understanding which terms are used in the literature and achieving a consensus on their definition is thus essential.

In this systematic review we comprehensively reviewed the current clinical research related to early COPD to understand terms used and how they are defined. We further appraised the evidence for predictors of disease progression. This understanding will be critical to aid future research for the development of validated tools and new clinical pathways for stratifying patients with preclinical COPD based on their baseline risk and likely trajectory.

Methods and analysis

Systematic review overview

The literature on early COPD was systematically reviewed in two stages. Stage 1 of the review identified all clinical studies including participants with early COPD (or relevant related term) to understand the terms used and definitions for these terms. Relevant articles were taken forward to stage 2, which identified markers, biomarkers or tools with potential to predict early COPD progression. The inclusion and exclusion criteria for studies selected are listed in table 1. Comprehensive methodology for this systematic review protocol has been published in the form of a protocol [16] and is registered on PROSPERO (CRD42025645320). The protocol was written and performed with reference to the Cochrane methodology [17], JBI manual [18] and PRISMA-p (Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocol) (2015 guidelines) [19] and a PRISMA flow chart is given in figure 1.

Search strategy

Three independent people (A. Watson, R. Davidson and G. Adesoye) designed the search strategy and agreed on the following search “pre-COPD”, “preclinical COPD”, “prodromal COPD” “at-risk COPD”, “incipient COPD”, “early COPD”, “early-stage COPD”, “undiagnosed COPD”, “GOLD 0” OR “Preserved Ratio Impaired OR PRISm” OR “early diagnosis (and COPD OR chronic obstructive pulmonary disease)”. The full search strategy is given in the appendix.

A comprehensive search was performed on 20 February 2025 including all published articles. There were no restrictions on publication year (all publications up to the date of search were included) or language or publication or study type. Non-English studies were translated using Google Translate (https://translate.google.co.uk/). The ability for translated results to be adequately interpreted was assessed by two independent people (A. Watson and either R. Davidson, F.C. Kon, A. Sharma or G. Adesoye). If the translated article was deemed not able to be interpreted sufficiently it was excluded, disagreements were resolved by discussion. We searched the following CENTRAL (the Cochrane Library), Medline (Ovid), PubMed, Scopus and Web of Science. An additional complementary search was performed using Google Scholar with key terms. The first 1000 articles (ordered by relevance) were reviewed by title and where relevant abstract for consideration of inclusion. Reference lists from key original and review articles, as well as grey literature, were also identified. Corresponding authors of articles that could not be accessed were contacted where possible.

Inclusion and exclusion criteria

Inclusion and exclusion criteria are given in table 1 for stage 1 of this systematic review, with additional inclusion and exclusion criteria specified for stage 2.

Selection process

Search results were manually reviewed initially by two individuals (two from A. Watson, R. Davidson, F.C. Kon, G. Adesoye, K. Alexander and I. Soper) and those pertaining to a clinical study were considered for selection. At least two reviewers (two from the group of individuals listed above) independently evaluated the title and abstract of all articles and compared them against the inclusion and exclusion criteria. If inconsistencies occurred, a consensus was reached by discussion. Endnote, Word, Excel and online database libraries (listed above) were used to track references.

Outcomes measurement

Within this review, we looked at all definitions of early COPD. We used two proposed definitions by Martinez et al. [8] and Siafakas et al. [11] as reference points, but recorded all inclusion criteria within definitions. The primary outcomes

1. The frequency of each of the different terms used for early COPD (see terms in search strategy).2) The definitions used in the study of early COPD and related terms, and whether the following (taken from definitions proposed by Martinez et al. [8] or Siafakas et al. [11]) were a) Whether the study included the following individual parameters in their inclusion    i)  Age ≤50 years   ii)  Smoking history of ≥10 pack-years   iii) spirometry criteria of forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio (FEV1/FVC) <lower limit of normal (LLN)   iv) Spirometry criteria of FEV1/FVC >0.7   v)   Spirometry criteria FEV1 >80% pred   vi) Computer tomography (CT) abnormalities inclusion of compatible CT abnormalities   vii) Accelerated lung function decline defined by ≥60 mL or more FEV1 decline per year   viii) Compatible respiratory symptoms.b) Whether any other inclusion criteria were used in the study and if so what.c) Whether the study inclusion criteria met the Martinez et al. [8] inclusion criteria of age ≤50 years and smoking history of at least 10 pack-years and any one of FEV1/FVC less than LLN or compatible CT abnormalities or accelerated FEV1 decline of at least 60 mL·year^–1^.d) Whether the study inclusion criteria met the Siafakas et al. [11] inclusion criteria of FEV1/FVC >0.7 and FEV1 >80% predicted and presence of compatible respiratory symptoms.3) What predictors have been proposed for predicting the progression of early COPD and what is their effectiveness.4) What is the risk of bias/quality of these studies.

Data management and extraction

The methodology for data management, extraction and recorded variables are presented in the supplement. Due to the volume of data, studies reporting four or more different predictors of disease progression are grouped together, see the result tables. Where studies did not explicitly state criteria pertaining to definitions, where possible, it was interpreted from the study's inclusion/exclusion criteria, demographics or written text. For example, where pack-years were not explicitly stated, but a heavy smoking history or similar term/phrase was used, then patients were assumed to have a ≥10 pack-years history.

Critical appraisal of studies

The methodological quality of all studies included in stage 2 was assessed by two independent reviewers (M. Fisk and either A. Watson, G. Adesoye or B. Chang). Observational studies were appraised using a modified checklist from Downs and Black [20] (appendix). This was modified to encompass only questions related to cohort studies specifically. Questions relating to randomised controlled trials (RCTs) including adverse events, attempts to blind the study, compliance to the intervention and randomisation were excluded, yielding an assessment tool with 22-point total. Studies were appraised independently. Any discrepancies were resolved by discussion. Our search did not identify RCTs so the ROB2 tool was not required [21]. We used the Grading of Recommendation Assessment, Development and Evaluation (GRADE) methodology to assess evidence quality and strength.

Ethics and dissemination

As this protocol and systematic review used freely available data from the literature and did not directly involve human participants, ethical approval was therefore not required.

Patient public involvement

To ensure alignment with the needs and perspectives of patients, five COPD patients were sent a lay summary and questionnaire (supplement) and four responses were received. Feedback, questions and insights were reviewed and considered prior to completion of the protocol.

Results

Search results and article selection

Search results and articles included at each stage are given in figure 1. We identified 4871 articles, of which 1759 were taken forward for screening after duplicate removal. After review, 171 articles were included. A further 29 and 34 articles were identified through a supplementary Google Scholar search or searching reference lists and grey literature, respectively. This gave a total of 234 articles for stage 1 of the review. 88 additional articles used the term early COPD or other related terminology without providing rationale for such classification, rather than simply less severe COPD disease. To maintain a focused scope for the review, these articles were excluded.

Terms used for early COPD

The most commonly used term was PRISm (n=104 articles), then GOLD 0 (n=63), early COPD (n=37), at-risk COPD (n=35) and pre-COPD (n=30) (table S1). 15 articles used other terms, including functional small airways disease, nonspecific pulmonary function test pattern, early lung disease, subclinical respiratory dysfunction COPD, unclassified COPD and isolated small airways obstruction (table S1). 13 articles applied two or more terms for the same definitions, using these terms interchangeably, the most frequent combinations were early COPD/GOLD 0 (n=3), pre-COPD/at risk COPD (n=3), early COPD/at-risk COPD (n=2), GOLD 0/at-risk COPD (n=2) and pre-COPD/PRISm (n=2). In contrast, 43 articles used ≥2 definition terms to distinguish different participant groups within the same study, including PRISm/GOLD 0 (n=19), pre-COPD/PRISm (n=11) and at-risk COPD/PRISm (n=4). Five studies compared different definitions for the same term, including for PRISm [22], early COPD [23, 24], early lung disease [25] and GOLD-unclassified [26] (table S2).

Definitions for early COPD

Definitions which have been previously proposed or included in current or prior guidelines are given in box 1. Within this review, 97% of studies used the standard PRISm definition, comparatively 76% used the standard GOLD 0 definition. Common variations included using LLN values rather than fixed ratios or not stating COPD symptoms within their definition, for PRISm and GOLD 0, respectively.

Only 24% and 5% of the definitions used for early COPD met those proposed by Martinez et al. [8] or Siafakas et al. [11], respectively (table 2). For early COPD studies, 65% of studies used ≥10 pack-years and age <50 years, 19% used compatible symptoms, 11% used FEV1 decline ≥60 mL·year^–1^ and only 3% used CT abnormalities within the early COPD definition. By comparison, for at-risk COPD, 63% and 6% used pack-year history and age <50 years, 49% used symptoms, none used FEV1 decline, and 29% used other spirometry criteria besides those within the Martinez et al. [8] and Siafakas et al. [11] criteria. For pre-COPD, 27% and 3% used smoking and age criteria, 43% used COPD symptoms, 0% used FEV1 decline, 47% used other spirometry abnormalities and 20% used CT abnormalities. For “other” terms (table S1), 60% used smoking history, none used age <50 years, 13% used COPD symptoms, none used FEV1 accelerated decline and 20% used CT abnormalities (table 2).

Predictors of early COPD progression

Study characteristics and study quality

43 full-text articles met the stage 2 criteria to evaluate predictors for early COPD progression (figure 1). All studies were cohort studies or cohort studies nested within/followed-up after RCTs (four articles). These articles pertained to 23 different studies in total. 17 full-text articles came from the COPDGene study, six from SPIROMICS, three from the Lovelace Smokers’ Cohort and three from the NELSON study (table 3). Details of the 23 included studies are summarised in table 3, with further information including detailed demographics provided in table S3. 91% of the studies were prospective, 87% were either multicentre or population based. The size of the studies ranged from 176 to 11 922 participants, with longitudinal follow-up from 2 to 25 years. The quality of the cohort studies as described in each of the 43 publications was good in 40 studies, excellent in one study and fair in two studies, with median (interquartile range) modified Downs and Blacks scores of 16 (15–17) out of a possible total of 22 (table 4).

Predictors and tools

Various predictors were identified for predicting early COPD progression. A summary of results is given in figure 2, which shows the number of predictors within each predictor category and the outcome measures used. For the results of each individual predictor see tables 5 and 6. Due to the volume of data, studies reporting four or more different predictors of disease progression are grouped together in table 5 (additional details about studies, demographics, analytical methods and results are presented in table S3).

The reported predictors of early COPD progression included age (13 studies), with progression defined as either developing COPD (FEV1/FVC <0.7), gaining a medical diagnosis of COPD or having a reduction in FEV1/FVC (tables 5 and 6, summarised in figure 2). Lower body mass index (BMI) (six studies), having hypertension (two studies), having an asthma diagnosis (two studies) or having increased bronchodilator reversibility (one study) were all associated with an increased risk of early COPD progression (for progression definitions see tables 5 and 6, similarly for predictors detailed below). Males had an increased risk of developing COPD in three studies, whilst a study by Bhatt et al. [53] observed that females had a higher risk of FEV1 decline (table 6). Use of long-acting inhaled medication and being a manual worker were also associated with an increased risk of developing COPD (defined by FEV1/FVC <LLN or <0.7, respectively).

Smoking history was associated with early COPD progression both alone and within prediction tools (n=12), as well as indoor biomass exposure (n=1). The presence of various symptoms was associated with risk of early COPD progression (n=9), most commonly wheeze, sputum and chronic bronchitis, but also dyspnoea, chronic mucus hypersecretion, cough, exacerbation during follow-up, as well as lower six-minute walk distance, lower self-assessment of good health and higher St Georges Respiratory Questionnaire score (table 5).

Lung function measurement and CT predictors

Various studies (n=20) found that lung function measures were associated with increased risk of progression of early COPD (table 6), including low baseline FEV1, low FEV1/FVC ratio, increased FEV1 decline trajectory, increased total lung capacity (TLC), measures of hyperinflation (residual volume (RV)/TLC and RV/TLC% intrathoracic gas volume (ITGV)%), measures of small airways disease (forced expiratory flow at 25–75% of FVC (FEF25–75%), forced expiratory volume in 3 s (FEV3)/forced expiratory volume in 6 s (FEV6) and low forced expiratory flow at 50% of FVC) and reduced diffusion capacity for carbon monoxide (DLCO). Furthermore, presence of various CT features associated with early COPD progression (14 studies) (table 6), including emphysema (%low-attenuation areas (LAA) ≤–950 Hounsfield units (HU), 15th percentile point, parametric response mapping (PRM) or visually evident emphysema), small airways disease (%LAA ≤–856 HU, functional small airways disease (fSAD), upper lobe PRM^fSAD^ and disease probability measure-defined air trapping), airway wall thickness, hyperinflation (FVC/TLC), pulmonary vascular remodelling/loss (small vessel volume 0.75:total pulmonary vessel volume), bronchovascular prominence, ground glass opacity, TLC, vital capacity (VC) and inspiratory capacity.

Impulse oscillometry and breathe washout

We did not find any study that evaluated impulse oscillometry for early COPD progression. There are cross-sectional studies that have assessed the value of impulse oscillometry across different participant groups or in association with established COPD disease parameters [71, 72]. Similarly, studies have assessed the association of breath washout (single or multiple) to identify pre-COPD participants versus controls [73, 74]. Lung washout has also been shown to have utility in predicting incident COPD development in populations studies [75]. However, no studies were identified which evaluated the prognostic value of lung washout in early COPD subjects longitudinally and its utility for predicting early COPD progression.

Sputum and blood biomarkers

Only one study identified sputum biomarkers and no studies identified blood biomarkers to predict progression. Radicioni et al. [32] showed that mucin 5AC (MUC5AC) (a glycoprotein associated with epithelial goblet cells and mucus production) in sputum was higher in at-risk current smokers versus never-smokers. They further showed that increased MUC5AC predicted progression of worsening lung function and SAD across a mixed cohort of 90 at-risk patients and 201 patients with COPD; however, they did not report individual longitudinal analyses in the at-risk population alone.

Prediction tools and machine learning

We found three studies that presented prediction tools for early COPD progression to FEV1/FVC <0.7 with an area under the curve (AUC) between 0.72 and 0.85 (table 6). These incorporated varied parameters including lung function, smoking history or exposure, symptoms, asthma diagnosis, BMI, age, and CT measures including emphysema/SAD/airwall thickness. Three studies used machine learning to predict early COPD progression by visit-specific FEV1 decline or FEV1 and FEV1/FVC decline with an AUC between 0.62 and 0.80 (table 6).

Discussion

Our review comprehensively evaluated the current evidence base on early COPD and demonstrates a lack of consensus and the interchangeable use of terms and their definitions. This serves as a framework to allow the interpretation and comparison of current studies and the generation of a consensus to direct future research and clinical practice. We additionally synthesise the current research on predictors for early COPD disease progression. This understanding will be critical to aid future research for the development of validated tools and new clinical pathways, for stratifying patients with pre-COPD disease state based on likely trajectory.

The need for consensus on terms and definitions

This review highlights that further work is needed due to the use of widely differing terms and definitions, prohibiting comparison between studies. Early COPD has had two notable contrasting working definitions proposed by Martinez et al. [8] and Siafakas et al. [11], which differ to the definition recommended by GOLD guidelines [12]. We show that neither is routinely applied in research. Early COPD definitions most frequently included individual components of the Martinez et al. [8] definition, including age <50 years and ≥10 pack-year smoking history. Nevertheless, whether the Martinez et al. [8] definition generalises to all early-stage COPD patients is debatable. Martinez et al. [8] focus on a young COPD population which may skew towards those with genetic and early life environmental risk factors, with different disease trajectories than the broader early COPD population [76, 77]. Notably, their definition also excludes nonsmokers and lacks symptom inclusion [35]. Our review highlights that whilst the threshold for accelerated lung function decline (≥60 mL·year^–1^) based on multi-cohort analysis is useful [38], it is rarely used in definitions or reported in baseline demographics. Additionally, the Martinez et al. [8] definition includes a post-bronchodilator FEV1/FVC criteria below LLN, consistent with an established COPD diagnosis in the American Thoracic Society, European Respiratory Society and British Thoracic Society guidelines [78], which may identify a unique younger phenotype with established COPD representative of disproportionate cumulative risk factor exposures earlier in life, including cannabis or heroin smoking; this may limit its utility in identifying the earliest pre-disease stages.

In contrast, the Siafakas et al. [11] definition emphasises early compatible symptoms with normal spirometry, but does not include relevant exposures or other disease features. Moreover, the GOLD guidelines describe early COPD as the biological first steps of disease in an experimental setting rather than a specific clinical diagnosis. However, the practical implications of this definition and how to apply to standardised research remains unclear. Clearer guidelines and consensus definitions are urgently needed to advance this field and guide future studies.

The term GOLD 0, referring to “at-risk COPD” patients, was removed from more recent GOLD guidelines, due to a relatively low prevalence of COPD development in this population [79]. However, we demonstrate that these terms are still widely used without clear definition. Pre-COPD was also commonly used within the literature, a term which superseded at-risk COPD and GOLD 0 in recent GOLD guidelines. Yet, we observed that few studies applied the comprehensive definition (box 1) but rather included individual components. Future studies should state clear, standardised definitions of pre-COPD.

Many studies used the term early COPD to mean mild or sometimes moderate/severe disease. Likewise, numerous studies focused solely on ever-smokers but at times referred to early COPD without clear definitions [80]. Whilst these studies offer valuable insights, they do not necessarily capture the underlying early COPD disease processes [81, 82] and were therefore excluded. However, this misuse contributes unnecessary complexity and confusion and should be avoided. Many studies failed to report whether patients had relevant exposures or symptoms consistent with COPD, limiting the interpretability and comparability of findings. Differentiation of exposure types, such as occupational hazards, indoor biomass fuel exposure, pollutants, cigarette smoking, cannabis, electronic cigarettes and vaping, was often lacking. In addition, early life history relating to prematurity, childhood respiratory symptoms will also be important to record for full detailed understanding. This review highlights that a concerted effort is required to establish clear, standardised definitions and the statement of included patient characteristics and disease metrices to improve study interpretability, comparability, and to facilitate the design of future research. An international consensus agreement and statement in updated guidelines would help in this endeavour.

Validation of predictors of early COPD progression is required

Stratification of patients with preclinical disease will be key for effective targeted therapeutic interventions. We therefore appraised the current evidence around predictors for early COPD progression. Whilst studies were of good quality, cross-comparison was limited due to heterogeneity of cohorts, definitions of early COPD, clinical progression definitions and analytical methodologies used. We therefore highlighted key predictors that merit validation in future well-designed studies. Increased age and smoking history were common predictors of disease progression. Age as a risk factor for disease progression to COPD comes from large population or cohort studies and where the primary outcome assessed was a fixed ratio of FEV1/FVC <0.7. Given that normal ageing is associated with a higher probability of FEV1/FVC <0.7, the value of age alone as a risk factor in developing COPD needs to be considered.

The presence of increased COPD symptom burden, ranging from wheeze to sputum production, dyspnoea and cough were common predictors. Wheeze was highlighted in a recent study by Perret et al. [35] as present in the three most impaired lung trajectories, with the most impaired group having a wheeze predominant phenotype, even when excluding patients with self-reported asthma. This study highlights how typical early symptoms, particularly wheeze, could serve as a red flag for objective testing and diagnostic workup of individuals in their 30s and 40s. Exacerbations in the prior year were also shown to associate with emphysema progression in GOLD 0 and PRISm patients in the COPDgene study [52]. Other notable markers of progression included being a manual worker, African American and having shorter height, which associated with increased lung function decline [53].

There was a relative lack of blood, sputum, exhaled breath, impulse oscillometry or in vivo imaging markers which were investigated for predicting early COPD progression. Whilst in the SPIROMICS study, MUC5AC, which associates with type 2 asthma, predicted lung decline in a mixed population of health, at risk and COPD patients, this was not demonstrated to predict the progression to COPD in at risk individuals specifically. Further work investigating biomarkers in these modalities is desperately needed, with evaluation of the potential for translating emerging biomarkers from established COPD [32, 83, 84]. The SPIROMICS Source study and BEACON studies may hold promise in achieving this [85].

Notably, we show that numerous baseline lung function measures have the potential to predict early COPD progression. These included baseline FEV1/FVC ratios, FEV1 and FEV1 trajectories, DLCO, VC and TLC and measures of hyperinflation. However, although FEF25–75% and CT measures of small airways disease were identified as potential markers in studies, there was a lack of studies investigating the potential of oscillometry, which is becoming an increasingly available, convenient, non-invasive tool for assessing lung function and small airways disease dysfunction in COPD, especially for patients with difficulty performing traditional spirometry [72, 86]. Future studies which investigate the utility of oscillometry for patient stratification is indicated, as well as investigation of other emerging spirometry measures including FEV3/FEV6 or FEV1/FEV6, which is increasingly being included in handheld devices [33, 87]. Together, our study highlights the potential importance of early spirometric screening supported by advanced technologies.

Recent developments in CT metrics of disease are rapidly advancing our ability to detect early preclinical disease pathological changes, particularly with the use of artificial intelligence (AI) [88, 89]. Our study demonstrates how measures of emphysema, airway wall thickness, fSAD and hyperinflation predict either the development of airflow obstruction, progression of emphysema or lung function decline. The demonstration that air-trapping and small airways disease have potential in predicting progression highlights the importance of small airway remodelling and SAD as an early preclinical manifestation of COPD pathobiology. These imaging biomarkers enable the detection of spatially resolved, sensitive and reproducible pathological abnormalities which may have utility in predicting significant spirometry impairments. Stratification of patient endotypes based on the presence of early preclinical pathological features, rate of progression, spirometry and symptoms facilitated by machine learning approaches that can integrate multiple variables at scale is urgently required to identify early COPD progression; validating of those highlighted in this review is indicated.

Scope of the review and future prospects

Whilst we undertook a comprehensive review of the literature on early COPD, there are limitations. Studies without relevant terms or clear definitions of their populations (often including at-risk patients) and studies where early COPD populations could not be differentiated from established COPD populations were not included, but may hold additional insights about different endotypes of preclinical disease. There is also a wide seperate literature base on biomarkers/case-finding tools to identify undiagnosed COPD [90–92] but this was outside the scope of this study. We reviewed predictors of early COPD progression but excluded negative results on markers, which may represent reporting bias.

Following this review, the authors propose to use the term early COPD as an umbrella term to be used in an experimental or research setting to relate to detectable disease processes, biological mechanisms or manifestations that eventually may lead to COPD [12]. This will encompass early disease mechanisms and individuals with pre-COPD. Comparatively, pre-COPD may be a useful specific term which could be used in clinical practice and needs clearly defining (box 2). We view this paradigm as being analogous to diabetes, dyslipidaemia or hypertension. Diabetes, dyslipidaemia and hypertension diagnoses are based on arbitrary thresholds, but we recognise there is a period of elevated glycated haemoglobin, cholesterol or blood pressure readings where interventions may modify or halt disease progression, reduce risk and prevent established pathological complications. To this end, widely available lung health checks of spirometry and exposure risk factor identification are needed. Quality of spirometry tests has been an issue impeding roll-out and access to spirometry. A further consideration is what specific spirometric, impulse oscillometry or lung function measurement or variable is most useful in clinical practice to identify higher-risk individuals. With technological advances, lung health checks may become much easier to undertake. Unlike dyslipidaemia or hypertension, which often have no associated symptoms, respiratory symptoms in addition to spirometry may help identify pre-COPD.

Conclusion

Our review demonstrates the urgent need for standardised consensus definitions about early stages of pre-COPD disease in research and clinical settings. Furthermore, we highlight that there are currently few studies on biomarkers of early COPD disease progression and this is an area that with development could enable the stratification of patients to target disease mechanisms earlier in the natural history of disease. Further research is required to validate these predictors in well-characterised cohorts with clear cohort definitions. This review serves as a platform to help reach consensus and direct future research to aid the advancement of clinical practice to diagnose pre-disease states and stratify patients based on outcome. Capitalising on this opportunity will be essential for improving COPD outcomes.