Lung function trajectories and exacerbation risks in preserved ratio impaired spirometry (PRISm) patients

Abstract

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.

Supplementary Information

The online version contains supplementary material available at 10.1038/s41598-026-40025-4.

Introduction

Chronic Obstructive Pulmonary Disease (COPD) is a leading global cause of mortality and disease burden, with its prevalence rising due to air pollution, smoking exposure, and rapid population aging^1,2. COPD is characterized by persistent airflow limitation, often associated with chronic bronchitis and emphysema³. In recent years, growing research has highlighted the importance of identification and management of early COPD⁴. Preserved Ratio Impaired Spirometry (PRISm), defined by a forced expiratory volume in 1 s (FEV1) below 80% of the predicted value while maintaining an FEV1/forced vital capacity (FVC) ratio > 0.7, does not meet the diagnostic criteria for COPD. However, accumulating evidence suggests that PRISm may represent an early warning stage in COPD progression⁵.

Emerging evidence indicates that PRISm patients may experience acute exacerbation of respiratory symptoms comparable to COPD, with similar exacerbation frequencies⁶. While landmark cohorts such as COPDGene and Nagahama have advanced PRISm research, they predominantly treat PRISm as a relatively static phenotype based on single-time-point or multi-year interval follow-up data, and rely on retrospective recall of exacerbation history that introduces recall bias. Existing studies also focus primarily on stable or exacerbated COPD states, with scarce attention to longitudinal lung function trajectory changes in PRISm patients and their clinical implications^7,8. Existing evidence demonstrated the potential for progressive lung function decline in PRISm patients, suggesting increased COPD risk that correlates with disease progression and all-cause mortality^9,10. However, critical knowledge gaps persist: (1) lack of identification of dynamic PRISm subtypes (e.g., normalization, persistence, or COPD progression) beyond static definitions; and (2) absence of subtype-specific exacerbation risk analysis to establish targeted trajectory-outcome associations.

Inflammatory response represents a key mechanism in COPD exacerbations, with biomarkers such as C-reactive protein and eosinophils playing significant roles in severity assessment^11,12. While PRISm patients typically exhibit milder inflammatory responses compared to COPD, emerging evidence suggests that progressive lung function deterioration may intensify systemic inflammation, potentially triggering symptom exacerbations¹³. However, the role of systemic inflammation in linking longitudinal lung function deterioration to acute exacerbations remains insufficiently explored. Furthermore, PRISm patients present with multiple comorbidities (e.g., cardiovascular disease, diabetes), whose potential impact on exacerbation susceptibility warrants further investigation^14–16.

We hypothesize that PRISm is a heterogeneous entity with distinct lung function trajectory patterns, and that worse trajectory (e.g., progression to COPD), systemic inflammation, and specific comorbidities are associated with increased exacerbation risk. This study aims to: (1) characterize clinical features and exacerbation risk in PRISm patients; (2) compare annual exacerbation rates among distinct lung function trajectory subgroups; (3) elucidate associations between lung function decline and exacerbation risk; and (4) identify independent risk factors for exacerbations. These findings will provide evidence-based insights for developing early intervention strategies for PRISm patients.

Methods

Study design

This study combined a retrospective cohort analysis with a subsequent prospective cohort follow-up. Firstly, we retrospectively enrolled PRISm patients and individuals with normal lung function from Henan Provincial People’s Hospital. For all participants, we retrospectively collected data on the demographic characteristics, clinical features, and the rates of moderate or severe exacerbations over the past year. Subsequently, the same PRISm patients were prospectively followed for 1 year and stratified into three distinct subgroups based on longitudinal lung function trajectories: (1) PRISm-Normal, (2) persistent PRISm, and (3) PRISm-COPD. We systematically analyzed between-group differences in: (a) acute exacerbation events (including annualized rates of moderate or severe exacerbations and proportions of frequent exacerbators [defined as ≥ 2 events/year]), and (b) annual lung function changes (quantified as ΔFEV1 (ml/y), ΔFVC (ml/y), and ΔFEV1/FVC).

According to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2023 criteria, PRISm was defined as post-bronchodilator FEV1/FVC ≥ 0.7 and FEV1% predicted < 80%, COPD was defined as post-bronchodilator FEV1/FVC < 0.7, accompanied by chronic respiratory symptoms (e.g., dyspnea, chronic cough). PRISm-Normal: For PRISm patients, this transition was defined as post-bronchodilator spirometric results meeting both “FEV1/FVC ≥ 0.7” and “FEV1 predicted ≥ 80%” after 1-year of follow-up. PRISm transition to COPD (PRISm-COPD): For PRISm patients, this transition was defined as post-bronchodilator spirometric results meeting “FEV1/FVC < 0.7” after 1-year of follow-up, accompanied by chronic respiratory symptoms. To minimize single-test variability, two independent spirometric assessments (interval ≥ 2 weeks) were required.

Participants

We enrolled 204 PRISm patients and 501 control subjects with normal lung function from Henan Provincial People’s Hospital between January 2021 and December 2023. Inclusion criteria for PRISm group: (1) aged 18 years or older; (2) spirometric results consistent with the definition of PRISm; (3) no acute respiratory tract infection, acute exacerbation, or airway-related treatment regimen within 4 weeks before enrollment; (4) informed consent. Inclusion criteria for controls: (1) aged 18 years or older; (2) post-bronchodilator spirometric results meeting both “FEV1/FVC ≥ 0.7” and “FEV1 predicted  ≥  80%”; (3) no acute respiratory tract infection, acute exacerbation, or airway-related treatment regimen within 4 weeks before enrollment; (4) informed consent.

Participants and controls with any of the following conditions were excluded from this study: (1) established COPD diagnosis; (2) neurological disorders (e.g., dementia); (3) pregnancy/lactation; (4) incomplete spirometry data that do not meet the quality control standard; (5) contraindications for spirometry (such as prior lung volume reduction surgery or lung transplantation); (6) poor protocol compliance.

Pulmonary function tests

Spirometry was conducted by trained technicians using a Jaeger MasterScreen pulmonary function instrument (CareFusion, Hochberg, Germany). All tests were performed following volume calibration and strict quality control procedures in accordance with the American Thoracic Society/European Respiratory Society (ATS/ERS) guidelines. Each participant completed at least three technically acceptable maneuvers, and the best result was recorded for analysis. For the bronchodilator responsiveness test, spirometry was repeated 30 min after inhalation of 400 µg salbutamol, with the same quality control criteria applied to post-bronchodilator measurements.

Data collection

For the study, data were extracted from the Hospital Information System (HIS), involving demographic characteristics (e.g. age, sex, body mass index and smoking history), clinical symptoms related to respiratory diseases (COPD assessment test (CAT)), laboratory blood tests (e.g. white blood cell, neutrophils and neutrophil percentage, eosinophils and eosinophil percentage, red blood cell counts, hemoglobin, and C-reactive protein, CRP) and post-bronchodilator pulmonary function parameters (e.g. FEV1, FVC and FEV1/FVC). An acute exacerbation is defined as a clinically significant worsening of respiratory symptoms requiring additional therapeutic intervention, and is classified as moderate (necessitating treatment with oral antibiotics and/or corticosteroids) or severe (requiring hospitalization or emergency department visit). Patients experiencing ≥ 2 moderate or severe exacerbations annually were categorized as frequent exacerbators, with annualized rates of acute exacerbation calculated as the total number of acute exacerbation events divided by the total patient-years of follow-up. Furthermore, we documented patients’ comorbidities, including cardiovascular diseases, diabetes, asthma, emphysema, and interstitial lung diseases, then used the validated Charlson Comorbidity Index (CCI) scoring system to evaluate comorbidity burden¹⁷. The proportion of missing data for laboratory blood tests was 3%, and for CRP it was 9%. For missing values, we employed multiple imputation to better preserve the sample size.

Statistical analyses

Statistical analyses were conducted using SPSS 26.0. Outcome measures were summarised as means with SDs or median with quartiles [M (Q1, Q3)] for continuous variables or numbers with percentages n (%) for categorical variables. The differences in variables between the two study groups were analysed using independent samples t-test, Wilcoxon U test, and chi-square test and the Fisher exact method. Bonferroni correction was used for multiple pairwise comparisons between groups. Linear regression was conducted to analyse the risk factors influencing the decreased lung function. For binary variables, logistic regression analysis was conducted to analyse the risk factors influencing the exacerbation outcomes (acute exacerbation and frequent acute exacerbation of respiratory symptoms). Variables that demonstrated an association with the outcome in univariate analyses (p < 0.05) or were considered clinically relevant were included in the multivariate model. Variance inflation factor (VIF) was employed to assess multicollinearity. Statistical significance was defined as p < 0.05.

Results

Participants’ characteristics

This study included a total of 705 patients, with 204 PRISm patients and 501 subjects with normal lung function (shown in Table 1). Demographic characteristics, including age, sex, and body mass index, showed no statistically significant differences between groups (p > 0.05). However, the PRISm group demonstrated a higher prevalence of smoking history (38.2% vs. 26%, p < 0.05) and greater comorbidity burden, with significantly elevated rates of cardiovascular diseases (28.1% vs. 20.2%), asthma (15.2% vs. 7.4%), emphysema (21.6% vs. 5.6%), and interstitial lung disease (14.7% vs. 1%), along with higher CCI scores compared to controls (p < 0.05). Notably, PRISm patients exhibited significantly greater symptom burden, as evidenced by CAT scores > 10 points (17.2% vs. 61.2%, p < 0.05).

Table 1.

Patients characteristics between PRISm and control subjects.

	PRISm (n = 204)	Control (n = 501)	χ2/t/ Z	p value
Age, M(Q1,Q3), y	56.50 (48.50, 67.00)	58.40 (50.80, 68.50)	– 1.12	0.263
Sex, n (%)			2.8	0.094
Male	131 (64.20)	285 (56.90)
Female	73 (35.80)	216 (43.10)
BMI, mean (SD), kg/m2	24.90 (4.50)	25.20 (3.70)	0.672	0.502
Smoking history, n (%)	78 (38.20)	130 (26.00)	10.76	< 0.001
Comorbidities, n (%)
Cardiovascular disease	57 (28.10)	101 (20.20)	8.21	< 0.05
Diabetes	21 (10.30)	40 (8.00)	1.35	0.245
Asthma	31 (15.20)	37 (7.40)	12.45	< 0.001
Emphysema	44 (21.60)	28 (5.60)	40.37	< 0.001
Interstitial lung disease	30 (14.70)	6 (1.00)	57.737	< 0.001
CCI, M(Q1, Q3)	2.00 (1.00, 3.00)	1.00 (0.50, 1.50)	4.21	< 0.001
Spirometry, mean (SD)
FEV1, predicted	0.73 (0.03)	0.97 (0.06)	– 50.2	< 0.001
FVC, predicted	0.72 (0.04)	1.06 (0.07)	– 50.2	< 0.001
FEV1/FVC	0.79 (0.04)	0.76 (0.05)	6.83	< 0.001
Blood tests, M(Q1, Q3)
White blood cell counts, ×109/L	6.82(6.10, 9.63)	6.59 (5.52, 8.57)	2.41	0.016
Neutrophil counts, ×109/L	4.67 (4.11, 10.70)	4.05 (3.18, 5.60)	5.12	< 0.001
Neutrophil percentage	62.00 (55.00, 71.00)	59.00 (55.00, 75.00)	1.23	0.219
Eosinophil counts, ×109/L	0.17 (0.90, 2.93)	1.25 (0.70, 2.58)	1.44	0.150
Eosinophil percentage	2.30 (1.40, 3.43)	1.85 (1.13, 3.60)	0.04	0.971
C-reactive protein, mg/L	5.78 (1.61, 15.88)	3.26 (0.13, 10.46)	1.73	0.084
Red blood cell counts, mean (SD), ×1012/L	4.20 (0.54)	4.37 (0.60)	– 3.43	< 0.001
Hemoglobin, mean (SD), g/L	128.00 (16.00)	132.00 (18.00)	– 2.381	0.018
Symptom burden, n (%)
CAT score > 10	35 (17.20)	6 (1.20)	98.6	< 0.001

Notes: PRISm preserved ratio impaired spirometry, BMI body mass index, CCI charlson comorbidity index, FEV1 forced expiratory volume in 1 s, FVC forced vital capacity, COPD chronic obstructive pulmonary disease, CAT COPD assessment test.

The PRISm group demonstrated significantly lower FEV1% predicted and FVC% predicted values compared to the normal lung function group (73% vs. 97%, 72% vs. 106%, both p < 0.05). Hematological analysis revealed that PRISm patients had significantly elevated white blood cell and neutrophil counts, along with significantly reduced red blood cell counts and hemoglobin levels relative to controls (all p < 0.05). Although eosinophil counts (both absolute and percentage) and CRP levels showed higher trends in the PRISm group, these differences did not reach statistical significance (p > 0.05).

Annualized rates of acute exacerbation

The PRISm group exhibited significantly higher annual acute exacerbation rates compared to controls, with 1.8-fold (0.35 vs. 0.19, p < 0.001) and 2.1-fold (0.17 vs. 0.08, p < 0.05) increases in moderate and severe exacerbations, respectively. Frequent exacerbations were 2.7 times more prevalent in PRISm patients (10.30% vs. 3.80%, p < 0.001). During the 1-year follow-up of 201 PRISm cases, longitudinal analysis revealed that 45 patients reverted to normal lung function (PRISm-normal subgroup), 142 maintained PRISm status (persistent PRISm subgroup), and 17 progressed to COPD (PRISm-COPD subgroup). Subgroup analyses demonstrated statistically significant differences in both the incidence of moderate and severe exacerbations and the proportion of frequent exacerbators when comparing PRISm subgroups with the controls (all p < 0.05). Notably, the PRISm-COPD subgroup demonstrated particularly elevated exacerbation risks, exhibiting 3.7-fold (0.71 vs. 0.19) and 5.9-fold (0.47 vs. 0.08) higher annualized rates of moderate and severe exacerbations, respectively, compared to controls, along with a 7.7-fold greater proportion of frequent exacerbators (29.4% vs. 3.8%). Interestingly, the PRISm-normal subgroup showed lower annualized exacerbation rates for both moderate and severe events compared to not only the normal lung function group but also the persistent PRISm and PRISm-COPD subgroups, suggesting a potential protective effect associated with lung function recovery (p < 0.001, shown in Table 2).

Table 2.

Comparison of acute exacerbation events between the group with normal lung function and PRISm subgroups.

Annualized rates of AE, Mean (SD)	Control (n = 501)	PRISm (n = 204)	p value	PRISm-normal (n = 45)	Persistent PRISm (n = 142)	PRISm-COPD (n = 17)	p value
Moderate	0.19 (0.02)	0.35 (0.02)	< 0.001	0.11 (0.10)	0.43 (0.26)	0.71 (0.27)	< 0.001
Severe	0.08 (0.01)	0.17 (0.01)	0.001	0.03 (0.02)	0.16 (0.11)	0.47 (0.25)	< 0.001
Frequent AE, n (%)	19 (3.80)	21 (10.30)	< 0.001	1 (2.20)	13 (9.20)	5 (29.40)	0.001

Notes: PRISm preserved ratio impaired spirometry, COPD chronic obstructive pulmonary disease, AE acute exacerbation, SD standard deviation.

Risk factors for frequent acute exacerbations of PRISm

Univariate analysis demonstrated that compared to the normal lung function group, the odds ratios (ORs) for frequent acute exacerbations were 0.58 (95%CI: 0.22–1.37, p > 0.05), 2.56 (95%CI: 1.23–5.31, p < 0.05) and 10.57 (95%CI: 3.38–33.03, p < 0.001) of the PRISm-normal, persistent PRISm, and PRISm-COPD subgroups, respectively. After adjustment for age, smoking, CCI score, CAT > 10, cardiovascular disease, asthma, emphysema, interstitial lung abnormalities, baseline lung function (FEV1%pred, FVC%pred, and FEV1/FVC ratio), neutrophil counts, red blood cell counts, white blood cell counts and C-reactive protein levels, the PRISm-COPD subgroup maintained a significantly elevated risk (adjusted OR = 4.2, 95%CI: 1.57–21.06, p < 0.05). In contrast, neither the PRISm-normal nor persistent PRISm subgroups demonstrated statistically significant associations (p > 0.05), indicating that progression to COPD confers an independent and clinically relevant increase in frequent exacerbation risk (shown in Table 3).

Table 3.

Risk analysis for frequent acute exacerbations in the group with normal lung function and PRISm subgroups.

	Univariate analysis		Multivariate analysis
	OR (95%CI)	p value	OR (95%CI)	p value
Control	Ref		Ref
PRISm-normal	0.58 (0.22, 1.37)	0.354	0.67 (0.21, 1.05)	0.912
Persistent PRISm	2.56 (1.23, 5.31)	0.012	1.66 (0.47, 5.87)	0.430
PRISm-COPD	10.57 (3.38, 33.03)	< 0.001	4.20 (1.57, 21.06)	0.011

Notes: PRISm preserved ratio impaired spirometry, COPD chronic obstructive pulmonary disease, AE acute exacerbation, OR odds ratio, CI confidence interval.

Risk factors for lung function changes of PRISm

The annual changes in FEV1 and FVC showed significant variations among PRISm-normal, persistent PRISm, and PRISm-COPD subgroups (shown in Table 4). Longitudinal analysis revealed an annual decline in FEV1, FVC, and FEV1/FVC ratio in all the normal lung function group, persistent PRISm, and PRISm-COPD groups. Notably, significantly greater declines were observed in persistent PRISm and PRISm-COPD groups compared to controls. On the contrary, the PRISm-normal subgroup exhibited annual improvements in FEV1, FVC, and FEV1/FVC ratio, suggesting partial lung functional recovery. Importantly, the PRISm-COPD group showed the most pronounced annual deterioration in FEV1/FVC ratio among all subgroups (p < 0.05).

Table 4.

Risk factors analysis for lung function changes in the group with normal lung function and PRISm subgroups.

	Univariate analysis			Multivariate analysis
	β ± SE	95% CI	p value	β ± SE	95% CI	p value
ΔFEV1, ml/y
Control	−8.41 ± 2.99	−16.24, − 2.35	0.005	−6.82 ± 2.83	−14.32, − 2.17	0.016
PRISm-normal	16.40 ± 5.40	5.24, 26.46	0.003	18.14 ± 4.72	5.89, 28.32	< 0.001
Persistent PRISm	−15.90 ± 7.18	−29.47, − 4.78	0.028	−13.10 ± 5.34	−24.24, − 2.52	0.015
PRISm-COPD	−27.20 ± 14.50	−49.53, − 8.34	0.061	−30.50 ± 10.10	−51.29, − 11.74	0.003
ΔFVC, ml/y
Control	−6.31 ± 2.49	−12.19, − 1.56	0.012	−5.80 ± 2.83	−11.32, − 1.22	0.041
PRISm-normal	17.24 ± 5.41	11.04, 27.32	0.003	18.95 ± 4.23	12.63, 28.32	< 0.001
Persistent PRISm	−14.60 ± 6.77	−25.46, − 2.33	0.031	−18.10 ± 5.23	−29.26, − 8.56	0.008
PRISm-COPD	−8.20 ± 2.56	−16.22, − 4.18	0.001	−6.54 ± 5.12	−14.34, − 3.54	0.202
ΔFEV1/FVC
Control	− 0.04 ± 0.03	− 0.11, − 0.01	0.184	− 0.02 ± 0.01	− 0.05, 0.00	0.046
PRISm-normal	0.11 ± 0.08	− 0.01, 0.27	0.169	0.13 ± 0.09	− 0.01, 0.32	0.150
Persistent PRISm	−0.01 ± 0.02	−0.05, 0.01	0.617	−0.00 ± 0.01	−0.01, 0.02	0.150
PRISm-COPD	−0.15 ± 0.06	−0.32, −0.07	0.013	−0.14 ± 0.05	−0.29, −0.06	0.019

Notes: PRISm preserved ratio impaired spirometry, COPD chronic obstructive pulmonary disease, FEV1 forced expiratory volume in 1 s, FVC forced vital capacity, SE standard error, CI confidence interval.

After adjustment for age, smoking, CCI score, CAT > 10, cardiovascular disease, asthma, emphysema, interstitial lung abnormalities, baseline lung function (FEV1%pred, FVC%pred, and FEV1/FVC ratio) and C-reactive protein levels, the PRISm-COPD subgroup demonstrated a significantly accelerated annual decline in FEV1 (30.5 ml/y) compared with the pre-adjusted estimate (27.2 ml/y, p < 0.001), establishing PRISm-COPD progression as an independent predictor of lung function deterioration. Conversely, the PRISm-normal subgroup showed a significantly greater annual improvement in FEV1 (16.40 ml/y vs. 18.14 ml/y) and FVC (17.24 ml/y vs. 18.95 ml/y) compared with the pre-adjusted estimate (both p < 0.001), suggesting potential pulmonary functional recovery in this population.

Risk factors for acute exacerbations of PRISm

Compared to the normal lung function group, PRISm patients demonstrated significantly elevated risks for both moderate and severe acute exacerbations, suggesting that PRISm status represents a distinct clinical phenotype with inherent vulnerability to acute respiratory symptom deterioration (shown in Table 5).

Table 5.

Risk factors analysis for acute exacerbations of PRISm patients.

	Moderate acute exacerbations		Severe acute exacerbations
	β (95% CI)	p value	β (95% CI)	p value
PRISm (vs normal)	0.15 (0.06, 0.23)	< 0.001	0.18 (0.13, 0.25)	< 0.001
Age	0.01 (0.00, 0.03)	0.124	0.02 (– 0.01, 0.06)	0.385
Smoking history	0.02 (– 0.01, 0.04)	0.213	0.01 (0.00, 0.03)	0.256
CAT>10	0.21 (0.15, 0.29)	< 0.001	0.23 (0.18, 0.31)	< 0.001
Exacerbation in previous year	0.53 (0.39, 0.69)	< 0.001	0.51 (0.36, 0.67)	< 0.001
Comorbidities
Cardiovascular disease	0.02 (– 0.01, 0.06)	0.367	0.04 (0.01, 0.09)	0.032
Asthma	0.08 (0.04, 0.14)	< 0.001	0.09 (0.05, 0.15)	< 0.001
Interstitial lung disease	0.13 (0.11, 0.17)	< 0.001	0.16 (0.14, 0.20)	< 0.001
Emphysema	0.02 (– 0.01, 0.07)	0.115	0.06 (0.01, 0.12)	0.048
CCI score	0.03 (0.00, 0.06)	0.034	0.03 (0.00, 0.06)	0.027
Spirometry
ΔFEV1, ml/y	– 0.21 (– 0.34, – 0.11)	< 0.001	– 0.25 (– 0.37, – 0.17)	< 0.001
FEV1, predicted	– 0.03 (– 0.07, – 0.01)	< 0.001	– 0.03 (– 0.07, – 0.01)	< 0.001
C-reactive protein	0.07 (0.03, 0.13)	< 0.001	0.09 (0.05, 0.15)	< 0.001
Red blood cell	– 0.03 (– 0.05, 0.01)	0.286	– 0.01 (– 0.04, 0.01)	0.314

Notes: PRISm preserved ratio impaired spirometry, COPD chronic obstructive pulmonary disease, CAT COPD assessment test, CCI Charlson comorbidity Index, FEV1 forced expiratory volume in 1 s, CI confidence interval.

We further evaluated the risk factors for the acute exacerbations of PRISm, and found that comorbidity burden (as quantified by CCI score) was significantly correlated with the risk of acute exacerbation, with concurrent asthma and interstitial lung disease demonstrating particularly strong associations with moderate (β = 0.08 ± 0.02, 95%CI: 0.04 to 0.14 and β = 0.13 ± 0.02, 95%CI: 0.11 to 0.17) and severe (β = 0.09 ± 0.02, 95%CI: 0.05 to 0.15 and β = 0.16 ± 0.02, 95%CI: 0.14 to 0.20) acute exacerbations, both p < 0.001. And the annual variation amplitude of FEV1 (ΔFEV1, ml/y) was significantly negatively correlated with moderate (β=− 0.21 ± 0.05, 95%CI: − 0.34 to − 0.11, p < 0.001) and severe (β=− 0.25 ± 0.04, 95%CI: − 0.37 to − 0.17, p < 0.001) acute exacerbations in patients, suggesting that lung function deterioration is a critical risk factor for acute exacerbation. At the same time, lower baseline FEV1% predicted was independently associated with higher risks of both moderate and severe acute exacerbations (both p < 0.001). Furthermore, our analysis demonstrated a significant positive correlation between elevated CRP levels and the risk of both moderate and severe acute exacerbations (p < 0.001), indicating that the elevated inflammatory level is an independent risk factor for acute exacerbation. The remaining variables were not statistically significant (all p > 0.05, shown in Table 5 and Fig. 1).

Fig. 1.

Risk factors analysis for moderate (left) and severe (right) acute exacerbations of PRISm patients. Notes: Red lines respresent the risk factors, blue lines respresent the protective factors. PRISm preserved ratio impaired spirometry, COPD chronic obstructive pulmonary disease, CAT COPD assessment test, CCI charlson comorbidity index, FEV1 forced expiratory volume in 1 s, CI confidence interval.

Discussion

This study focuses on PRISm, a critical transitional stage in COPD, by evaluating its demographics, clinical manifestations, inflammatory status, longitudinal lung function trajectories, exacerbation risk and association with the development of COPD, highlighting its potential value in the early identification and intervention of COPD. Our findings substantiate the pathogenic contributions of lower baseline FEV1% predicted, progressive lung function decline, chronic systemic inflammation, and specific comorbidities (notably asthma and interstitial lung disease) to acute exacerbation susceptibility in PRISm patients.

By identifying these modifiable high-risk features, this study provides valuable insights to inform the development of more targeted screening and intervention strategies in clinical practice. Specifically, for PRISm patients with asthma or interstitial lung disease, enhanced control of airway inflammation and monitoring of pulmonary fibrosis progression are essential to prevent exacerbations triggered by disease overlap. For those with a lower or rapidly declining FEV1, it is recommended to shorten follow-up intervals and dynamically adjust treatment regimens to delay disease progression. Elevated CRP levels should prompt further assessment of systemic inflammation and consideration of anti-inflammatory therapies. These findings highlight the need for precision interventions in the PRISm population. Effective early management not only contributes to reducing healthcare utilization such as emergency visits and hospitalizations but also improves patients’ quality of life and lowers long-term mortality risk, emphasizing the public health significance of integrating PRISm management into COPD prevention and control.

This study demonstrates that PRISm patients exhibit a greater comorbidity burden than individuals with normal lung function, especially interstitial lung disease, cardiovascular diseases, and asthma. Consistent with Hancock et al., who reported lung interstitial abnormalities in 23% of PRISm cases, suggesting that interstitial pathology may contribute to restrictive ventilatory dysfunction via alveolar-capillary disruption and fibrotic remodeling¹⁸. Furthermore, asthma and interstitial lung disease are identified as independent risk factors for exacerbations in PRISm. Subgroup analysis reveals a higher asthma prevalence in PRISm-COPD (41.2%) compared with PRISm-normal (24.4%) and persistent PRISm (16.2%) subgroup (Supplementary Table 1). Existing evidence indicates that the coexistence of these comorbidities substantially increases exacerbation risk potentially through heightened inflammatory burden, accelerated lung function decline, immune dysregulation, and greater therapeutic complexity^19,20. Thus, comprehensive evaluation and targeted management of comorbidities are crucial in the clinical care of PRISm.

In this 1-year follow-up study of 204 PRISm patients, participants were classified into three subgroups based on lung function trajectories: 22.1% reverted to normal (PRISm-normal), 69.6% maintained PRISm status (persistent PRISm), and 8.3% progressed to COPD (PRISm-COPD). The lower COPD conversion rate in this study compared to previous ones may be attributable to shorter follow-up duration, population heterogeneity, or therapeutic interventions⁷. The PRISm-COPD subgroup showed the highest-risk profile, with greater comorbidity burden, higher smoking rates, and worse lung function. This subgroup also showed the greatest FEV1 decline and higher exacerbation risk. Despite multivariable adjustment, PRISm-COPD remained a significant independent risk factor for frequent exacerbations, consistent with COPDGene Study findings²¹. These results support viewing PRISm as an early stage in the COPD continuum. This trajectory-based classification can aid in personalized management, emphasizing early identification of high-risk PRISm individuals and timely interventions—such as airway inflammation control, smoking cessation, and lifestyle improvement—to delay or prevent COPD progression.

The mechanisms underlying the progression from PRISm to COPD likely involve multiple biological processes. Elevated leukocyte and neutrophil counts observed in PRISm indicate a persistent low-grade inflammatory state, which may drive FEV1 decline. Though CRP and eosinophil counts changes were not statistically significant, their upward trends may still hold clinical relevance. Distinct inflammatory phenotypes of PRISm, such as eosinophilic subtypes, may exhibit distinct disease trajectories and treatment responses. Future studies should adopt more refined biomarkers (e.g., IL-6 and fibrinogen) and larger cohorts to elucidate inflammatory dysregulation from a more systemic perspective. Beyond inflammation, airway remodeling and impaired lung tissue repair may accelerate PRISm progression, especially under systemic pro-inflammatory conditions, which may predispose patients to frequent exacerbations and heightened risk of associated comorbidities and complications^11,22,23. Therefore, integrative molecular profiling, quantitative imaging, and multi-omics analyses will be essential to uncover PRISm’s biological basis and guide early precision interventions.

Our study also found that the PRISm-normal subgroup exhibited significant improvements in both FEV1 and FVC, which may be associated with a reduced risk of acute exacerbations. Previous studies have demonstrated that inhaled corticosteroid therapy can enhance lung function and lower exacerbation risk in PRISm patients^24–26, suggesting that early interventions might reverse subclinical inflammation and establish a positive link between lung function improvement and optimized outcomes^11,27,28. The independent predictive value of FEV1 and FVC further highlights the central role of preserved pulmonary structure and function^29,30. Moreover, although the FEV1/FVC ratio in PRISm individuals is only mildly reduced compared to normal, the restrictive ventilatory pattern is already evident, indicating that structural and functional impairments may have occurred earlier. Future studies should consider incorporating comprehensive lung volume assessments (e.g., total lung capacity, TLC) and advanced imaging techniques (e.g., high-resolutioncomputed tomography, HRCT), which would help enhance diagnostic accuracy and phenotyping capability in this population³¹.

Although this study provides empirical support for PRISm’s dynamic evolution and potential progression to COPD, several limitations should also be acknowledged. First, the 1-year follow-up may be insufficient to capture long-term lung function changes, extended observation is needed to clarify the natural course of PRISm and its potential causal link with COPD. Second, the single-center design and small sample size in the PRISm-COPD subgroup may limit generalizability and statistical power. Nevertheless, the baseline data and effect size estimates presented here offer valuable references for future large-scale investigations. Additionally, although some confounders were adjusted for, variables such as medication adherence, smoking cessation, occupational exposure, air pollution, and socioeconomic status were not systematically assessed, potentially introducing bias. Future studies should adopt multicenter, large-sample, and long-term follow-up designs, with comprehensive environmental and socioeconomic indicators, and enhanced control of confounders. Lastly, the requirement for standardized lung function testing may have excluded individuals unable to complete assessments, introducing compliance-related selection bias. Improving test completion during follow-up would strengthen future findings.

In conclusion, PRISm represents a pivotal stage in the early progression of COPD, characterized by notable heterogeneity and dynamic disease trajectories. These features underscore the need to focus on elucidating the underlying molecular mechanisms and identifying reliable biomarkers, thereby facilitating targeted interventions.

Supplementary Information

Below is the link to the electronic supplementary material.

Author contributions

Xiangsong Cheng, Xingru Zhao and Yi Yu contributed to data collection, analytical strategy design and data interpretation. Xiaoju Zhang contributed to the study conception and design. Linqi Diao directed the study’s implementation. Xiangsong Cheng and Yi Yu contributed to data curation and literature review. Quncheng Zhang and Yunxia An contributed to the study’s quality control. The original draft was written by Xingru Zhao, all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. Xiaoju Zhang is responsible for the overall content as the guarantor. Xiangsong Cheng, Xingru Zhao and Yi Yu contributed equally to the work.

Funding

This work was supported by Henan Provincial Key Research and Development Project [251111311600] and Henan Provincial Science and Technology Research Project [242102311142].

Data availability

Researchers interested in further information are invited to contact the corresponding authors via e-mail to: XJZ [zhangxiaoju@zzu.edu.cn].

Declarations

Competing interests

The authors declare no competing interests.

Ethical statement

This study was approved by the Ethics Review Committee of Henan Provincial People’s Hospital (No. 2022042). Participates gave informed consent to participate in the study before taking part. All methods were performed in accordance with the relevant guidelines and regulations. Due to the observational nature of this study, clinical trial registration was not conducted.

Consent for publication

Not applicable.