Spirometric Transition of at Risk Individuals and Risks for Progression to Chronic Obstructive Pulmonary Disease in General Population

Increasing awareness of the prevalence and significance of Preserved Ratio Impaired Spirometry (PRISm), alternatively known as restrictive or Global Initiative for Chronic Obstructive Lung Disease (GOLD)-unclassified spirometry, has expanded the body of knowledge on cross-sectional risk factors. However, longitudinal studies of PRISm remain limited. To examine longitudinal patterns of change in lung function, radiographic characteristics, and mortality of current and former smokers with PRISm. Current and former smokers, aged 45 to 80 years, were enrolled in COPDGene (phase 1, 2008-2011) and returned for a 5-year follow-up (phase 2, 2012-2016). Subjects completed questionnaires, spirometry, chest computed tomography scans, and 6-minute-walk tests at both study visits. Baseline characteristics, longitudinal change in lung function, and mortality were assessed by post-bronchodilator lung function categories: PRISm (FEV1/FVC < 0.7 and FEV1 < 80%), GOLD0 (FEV1/FVC > 0.7 and FEV1 > 80%), and GOLD1-4 (FEV1/FVC < 0.7). Although the prevalence of PRISm was consistent (12.4-12.5%) at phases 1 and 2, subjects with PRISm exhibited substantial rates of transition to and from other lung function categories. Among subjects with PRISm at phase 1, 22.2% transitioned to GOLD0 and 25.1% progressed to GOLD1-4 at phase 2. Subjects with PRISm at both phase 1 and phase 2 had reduced rates of FEV1 decline (-27.3 ± 42.1 vs. -33.0 ± 41.7 ml/yr) and comparable proportions of normal computed tomography scans (51% vs. 52.7%) relative to subjects with stable GOLD0 spirometry. In contrast, incident PRISm exhibited accelerated rates of lung function decline. Subjects with PRISm at phase 1 had higher mortality rates relative to GOLD0 and lower rates relative to the GOLD1-4 group. PRISm is highly prevalent, is associated with increased mortality, and represents a transitional state for significant subgroups of subjects. Additional studies to characterize longitudinal progression in PRISm are warranted.

Concerns about PRISm

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Preserved ratio impaired spirometry (PRISm), defined as a forced expiratory volume in 1s (FEV1) to forced vital capacity (FVC) ratio ≥0.70 and a predicted FEV1 <80%, is associated with increased morbidity and mortality. However, determinants of PRISm, particularly in younger populations, remain poorly characterised. We aimed to address this knowledge gap. We conducted a cross-sectional analysis of 12,350 participants from a Japanese community-based cohort using data from the Tohoku Medical Megabank Project. Participants underwent spirometry, blood pressure measurement, laboratory testing, and completed standardised questionnaires. Multivariate logistic regression was used to identify factors associated with PRISm across three age groups: 20-39, 40-59, and ≥60 years. Interactions between age groups and other explanatory variables were assessed. In the 20-39-year group, PRISm was independently associated with being men, diabetes mellitus, hypothyroidism, and low body mass index (BMI <18.5kg/m2), and inversely associated with age. Among participants aged ≥60 years, PRISm was significantly associated with increasing age, overweight status (BMI ≥25.0-<30.0kg/m2), being men, current smoking, hypertension, diabetes mellitus, bronchial asthma, elevated eosinophil counts (≥300cells/μL), and birth weight ≥2000-<2500g. Significant interactions were observed between age and BMI, bronchial asthma, and thyroid dysfunction. Our findings indicate that PRISm in younger adults is associated with hypothyroidism and underweight status, whereas in older adults, it is more closely related to constitutional and lifestyle-related factors. These results highlight the heterogeneity of PRISm and indicate that its pathophysiology and optimal management may vary by age group.

Preserved ratio impaired spirometry (PRISm) is a heterogeneous, clinically relevant pre-chronic obstructive pulmonary disease (pre-COPD) state that remains incompletely understood. Recurrent exacerbations link to poor outcomes, but data on subtype-specific (lung function trajectory) exacerbation risk is scarce. This study assessed lung function trajectory changes and exacerbation risk in PRISm. We enrolled 204 PRISm patients and 501 individuals with normal lung function. Demographics, clinical features, and exacerbation events over the past year were evaluated. 204 PRISm patients were subsequently followed for one year, and categorized into three subgroups: PRISm-normal, persistent PRISm, and PRISm-COPD. Exacerbation events and lung function changes were analyzed. Univariate and multivariate logistic regression analyses were used to identify risk factors for exacerbation. PRISm patients had higher smoking prevalence, comorbidities, and symptom burden than controls (p < 0.05). The incidence of moderate and severe exacerbations and frequent exacerbations in PRISm patients were 1.8-fold (0.35 vs. 0.19, p < 0.001), 2.1-fold (0.17 vs. 0.08, p < 0.05), and 2.7-fold (10.3% vs. 3.8%, p < 0.001) higher than the normal group. The PRISm-COPD subgroup had the highest risk, with rates 3.7- to 7.7-fold higher than the normal group. Furthermore, persistent PRISm and PRISm-COPD subgroups showed significantly greater declines in forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and FEV1/FVC. After adjusting for confounders, the PRISm-COPD subgroup had a more pronounced FEV1 decline (− 27.2 ml/y vs. −30.5 ml/y, p < 0.001). Multivariate analysis showed that FEV1 decline was inversely associated with exacerbations in PRISm patients, whereas elevated C-reactive protein levels were positively correlated with exacerbation risk (p < 0.001). PRISm patients exhibit worse lung function and more frequent acute exacerbations, with the PRISm-COPD subtype predicting faster lung function decline. Worsening lung function and inflammation levels significantly increase exacerbation risk in PRISm patients.

Low lung function and Preserved Ratio Impaired Spirometry (PRISm) have been associated with increased co-morbid cardiovascular disease. However, the association of abnormal lung function and PRISm with imaging markers of cardiovascular dysfunction has not been well elucidated. Participants from the Jackson Heart Study who had spirometry measurements at baseline and underwent cardiac magnetic resonance (CMR) were included. Multivariable adjusted associations between forced expiratory volume in the first second (FEV1) and forced vital capacity (FVC) and markers of aortic (pulse wave velocity, aPWV, wall thickness) and cardiac function (left ventricular (LV) stroke volume, and indexed LV mass) as measured on CMR were examined using linear regression models. Study participants were then divided into three groups (normal spirometry: FEV1/FVC ≥ 0.70, FEV1 ≥ 80%, airflow obstruction: FEV1/FVC < 0.70, and PRISm: FEV1/FVC ≥ 0.70, FEV1 < 80%). We then examined the associations of spirometry pattern and markers of structure and function as dichotomous outcomes using multivariable adjusted logistic regression models. A total of 1278 participants (788 women [63%]; 375 (29%) ever smokers, 612 (48%) with hypertension, 1033 [81%] with normal spirometry, 80 [6%] with airflow obstruction, and 165 (13%) with PRISm met criteria for inclusion. In a multivariable model adjusting for age, sex, BMI, smoking status, and systolic blood pressure, aPWV was significantly associated with FEV1% (-0.20 ± 0.03, p = 0.04) and those with airflow obstruction had significantly higher odds of an increased aPWV (OR 2.25, 95% CI 1.29-3.93) compared to controls with a normal spirometry pattern. In the multivariable adjusted model, those with PRISm had a higher likelihood of a reduced LV stroke volume compared to controls (OR 1.69, 95% CI 1.14-2.56). The PRISm pattern is associated with decreased LV stroke volume. This may be a potential mechanism between PRISm pattern and incident heart failure.

Physician diagnosed COPD with normal spirometry (dnsCOPD) (sometimes labeled pre-COPD) and Preserved Ratio Impaired Spirometry (PRISm) has been studied in population-based cohorts, but not in physician diagnosed COPD (dCOPD) patients from routine clinical practice. The Swedish National Airway Register (SNAR) is a large nationwide register including data from dCOPD patients from over 1000 clinics across all regions of Sweden and is representative of the COPD care in Sweden. We aimed to identify and characterize patients with dnsCOPD, PRISm and spirometrically confirmed COPD (sCOPD) from dCOPD patients in SNAR, stratify them further according to symptoms and exacerbations risk using the Global Initiative for Chronic Obstructive Lung Disease (GOLD) A/B/E classification, and assess differences in risk for exacerbations, cause-specific hospitalisations and mortality. We enrolled patients aged ≥30 years with dCOPD in the SNAR from 1 January 2014 to 30 June 2022 with complete spirometry i.e., postbronchodilator values for both forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) (index date). Patients with concomitant asthma were excluded. Patients were stratified into dnsCOPD (FEV1/FVC ≥0.7 and FEV1 ≥80% predicted), PRISm (FEV1/FVC ≥0.7 and FEV1 <80% predicted) and sCOPD (FEV1/FVC <0.7). Further substratification was based on GOLD A/B/E (A: COPD assessment test (CAT) score <10 points and <2 moderate, 0 severe exacerbations within 1 year before the index date, B: CAT-score ≥10 points and <2 moderate, 0 severe exacerbations, E: ≥2 moderate or ≥1 severe exacerbation(s)). Patients were followed until 31 November 2022. Competing risk regression was used to calculate subdistribution hazard ratios (SHR)s with 95% confidence intervals (CIs) for exacerbation, hospitalisation and mortality. Of 45,653 patients with dCOPD, 5.4% had dnsCOPD, 11.4% had PRISm and 83.3% had sCOPD. Smoking history was similar between groups (ever smoker: dnsCOPD: 79% PRISm: 82% sCOPD: 86%) and inhalation therapy was common in all groups (any inhaler: 75%, 80% and 80%, triple combination: 22%, 28% and 35%). Patients with PRISm had a high prevalence of obesity (dnsCOPD: 30%, PRISm: 43%, COPD: 22%), cardiovascular disease (dnsCOPD: 39%, PRISm: 48%, COPD: 41%) and diabetes (dnsCOPD: 10%, PRISm: 17%, COPD: 9%). Baseline GOLD group B or E were highly prevalent in dnsCOPD (B: 54%, E: 11%), PRISm (B: 59%, E: 14%), as well as in COPD (B: 54%, E: 17%). DnsCOPD and PRISm patients had lower risk of exacerbations (SHR 0.69, 95%CI 0.64-0.74 and 0.85, 95%CI 0.81-0.89), respiratory hospitalisation (0.40, 95%CI 0.34-0.46 and 0.68, 95%CI 0.62-0.73), and respiratory mortality (0.22, 95%CI 0.13-0.37 and 0.60, 95%CI 0.48-0.75) compared to sCOPD. Cardiovascular mortality was lower in dnsCOPD (0.41, 95%CI 0.19-0.86), but similar in PRISm (0.73, 95%CI 0.49-1.08) compared to sCOPD. The A/B/E classification was predictive for all outcomes in dnsCOPD and PRISm. DnsCOPD and PRISm group E patients had higher risks for all outcomes than sCOPD group A or B. DnsCOPD and PRISm are prevalent in a real-life cohort of patients with a physician diagnosis of COPD. These patients are symptomatic, might suffer from exacerbations and are commonly treated with inhaled therapy, equally to sCOPD. Patients with PRISm had a high prevalence of obesity, diabetes and cardiovascular disease. DnsCOPD and PRISm had generally lower overall risks of exacerbation or respiratory events, although PRISm patients showed similar cardiovascular risk to sCOPD. The A/B/E classification predicted future events, even in dnsCOPD and PRISm patients. This study is performed with support from The Swedish Heart-Lung Foundation (20200150) and the Swedish government and country council ALF grant (ALFGBG-824371).

Increased Levels of Airways Responsiveness as a Risk Factor for Development of Chronic Obstructive Lung Disease: What Are The Issues?

Background: Preserved ratio impaired spirometry (PRISm) is defined as a FEV₁ of less than 80% predicted and a FEV₁/forced vital capacity (FVC) ratio of 0·70 or higher. Previous research has indicated that PRISm is associated with respiratory symptoms and is a precursor of chronic obstructive pulmonary disease (COPD). However, these findings are based on relatively small selective cohorts with short follow-up. We aimed to determine the prevalence, risk factors, clinical implications, and mortality of PRISm in a large adult general population. Methods: For this cohort analysis, we used data from the UKBiobank to assess PRISm prevalence, risk factors and associated symptoms, and associated comorbidities in a large adult population. Participants with spirometry deemed acceptable by an investigator (best measure FEV₁ and FVC values) at baseline were included. Participants were excluded if they did not have acceptable spirometry or were missing data on body-mass index or smoking status. Control spirometry was defined as a FEV₁ of 80% or more predicted and a FEV₁/FVC ratio of 0·70 or higher. Airflow obstruction was defined as a FEV₁/FVC ratio of less than 0·70. We used multivariable regression to determine risk factors for PRISm and associated comorbidities. Individuals who lived within close proximity to an assessment centre were invited for follow-up, with repeat spirometry. Only participants who had been included at baseline were examined in follow-up. This allowed for a longitudinal analysis of PRISm over time and risk factors for transition to airflow obstruction. We also did the survival analysis for a 12-year period. Findings: Participants were recruited by UK Biobank between Dec 19, 2006, and Oct 10, 2010. We included 351 874 UK Biobank participants (189 247 women and 162 627 men) in our study, with a median follow-up of 9·0 years (IQR 8·0–10·0). 38 639 (11·0%) of 351 874 participants had PRISm at baseline. After adjustment, PRISm was strongly associated with obesity (odds ratio [OR] 2·40 [2·26–2·55], p < 0·0001), current smoking (1·48 [1·36–1·62], p < 0·0001), and patient reported doctor-diagnosed asthma (1·76 [1·66–1·88], p < 0·0001). Other risk factors identified included female sex, being overweight, trunk fat mass, and trunk fat percentage. PRISm was strongly associated with symptoms and comorbidity including increased risk of breathlessness (adjusted OR 2·0 [95% CI 1·91–2·14], p < 0·0001) and cardiovascular disease (adjusted OR 1·71 [1·64–1·83], p < 0·0001 for heart attack). Longitudinal analysis showed that 241 (12·2%) of 1973 participants who had PRISm at baseline had transitioned to airflow obstruction consistent with COPD. PRISm was associated with increased all-cause mortality (adjusted hazard ratio 1·61 [95% CI 1·53–1·69], p < 0·0001) versus control participants. Interpretation: PRISm was associated with breathlessness, multimorbidity, and increased risk of death, which does not seem to be explained by smoking, obesity, or existing lung disease. Although for many patients PRISm is transient, it is important to understand which individuals are at risk of progressive lung function abnormalities. Further research into the genetic, structural and functional pathophysiology of PRISm is warranted. Funding: UK Medical Research Council and University of Bristol.

Prevalence, risk factors, and clinical implications of preserved ratio impaired spirometry: a UK Biobank cohort analysis

Trajectory and mortality of preserved ratio impaired spirometry: the Rotterdam Study.

The association between obstructive sleep apnea (OSA) and preserved ratio impaired spirometry (PRISm) has not been well studied. This prospective cohort study enrolled 3408 adults aged 20-79 years without airflow obstruction. The median follow-up time was 11.8 years. Probable OSA (pOSA) was defined based on symptoms (snore, snort/stop breathing, sleepy) and was divided into a normal lung function group (FEV1 ≥ 80% predicted) and a PRISm group (FEV1 < 80% predicted) according to spirometry. Multivariable regression was used to analyze the association between pOSA and PRISm, and Cox regression and Kaplan-Meier analysis were used to assess the effects of pOSA alone, PRISm alone, and both on the risk of mortality. All analyses used survey weights. At baseline, 28.5% of participants presented with pOSA, and 11.4% had PRISm. Multivariable analysis showed an independent association between pOSA and PRISm (adjusted OR = 1.40, 95% CI 1.01-1.94, p = 0.04). Individuals with comorbid pOSA and PRISm had the highest risk of death (adjusted HR = 2.34, 95% CI 1.55-3.55) compared with individuals with PRISm alone (adjusted HR = 1.78, 95% CI 1.3-2.44), while individuals with pOSA alone were not significantly associated with death (adjusted p = 0.893). Kaplan-Meier analysis confirmed significant survival differences between the groups (p < 0.0001). Our results show that individuals with suspected OSA are associated with a higher prevalence of PRISm and individuals with comorbid OSA and PRISm have a higher risk of all-cause death. Although the limitations of the observational study do not allow us to determine causality, it emphasizes that the association between OSA and PRISm deserves further in-depth study.

Preserved ratio impaired spirometry (PRISm), which identifies a population at high risk for COPD, has drawn increasing attention. However, definitions for PRISm vary across studies, and researches comparing these definitions are limited. We aim to assess the agreement, the clinical features, and the prevalence of PRISm defined by restrictive spirometric pattern (RSP) method [that is forced vital capacity (FVC) method] versus forced expiratory volume in the first second (FEV1) method and by fixed values versus the lower limit of normal (LLN). All 1862 participants from the ECOPD study underwent questionnaire investigation, spirometry, biphasic CT, and impulse oscillometry. Participants were categorized into control and two targeted groups (RSP fixed and PRISm fixed excluding RSP fixed) based on FVC and FEV1 fixed definitions. Similar categorizations were conducted for RSP LLN versus PRISm LLN and PRISm fixed versus PRISm LLN. We assessed the agreement, the clinical features, and the prevalence of PRISm among these various definitions, repeating all analyses using Global Lung function Initiative (GLI) equation. Significant overlap with merely moderate agreement (Kappa coefficient = 0.706, P value <0.001) existed between RSP fixed and PRISm fixed definitions. Participants identified as PRISm by both definitions exhibited lower lung function, higher airway reactance, and increased airway resistance compared to the control group. Similar findings were observed in RSP LLN versus PRISm LLN and PRISm fixed versus PRISm LLN. Our sensitivity analysis verified the consistency of these results. Furthermore, the prevalence of PRISm varied from 2.0% to 12.5% depending on the definitions and predicted equations, with the Chinese equation, LLN definition in Chinese equation and fixed definition in GLI equation yielding higher prevalence rates. Our findings highlight concerns about the comparability of studies and the interchangeability of various definitions and reference equations for PRISm.

BackgroundIt has been known that smoking and various lung diseases including lung cancer can cause lung function impairment. However, the impact of different types of lung function impairments, such as...

Preserved ratio impaired spirometry (PRISm) is a heterogeneous disease entity. Limited data are available regarding its prevalence, clinical course, or prognosis. We aimed to evaluate the longitudinal clinical course of patients with PRISm compared with chronic obstructive pulmonary disease (COPD). A retrospective study enrolled PRISm and COPD patients who underwent chest computed tomography and longitudinal pulmonary function tests between January 2013 and December 2020. We compared the incidence of acute exacerbations and lung function changes between PRISm and COPD patients. Of the 623 patients, 40 and 583 had PRISm and COPD, respectively. Compared to COPD patients, PRISm patients were younger, more likely to be female and have a history of tuberculosis, and less likely to be smokers. They also had less severe comorbidities, lower forced vital capacity (FVC) and diffusing capacity of the lungs for carbon monoxide (DLCO). The clinical course was not significantly different between the PRISm and COPD patients in terms of the risk of moderate-to-severe acute exacerbations or proportion of frequent exacerbators. During follow-up, PRISm patients had a significantly slower annual decline of forced expiratory volume in 1 second, FVC, and DLCO than COPD patients. PRISm patients had no significant difference in the risk of acute exacerbations, but a significantly slower decline of lung function during longitudinal follow-up, compared with COPD patients.