Effectiveness and safety of Bufei granules in treatment of preserved ratio impaired spirometry: Study protocol for a randomized controlled trial

Preserved ratio impaired spirometry (PRISm) is prevalent within the general population. Increased mortality has been reported among subjects with PRISm, but the evidence has never been summarised. This systematic review aims to synthesise evidence on the association between PRISm and the risk of all-cause, cardiovascular and respiratory-related mortality. We systematically searched MEDLINE, Embase and Web of Science for population-based cohort studies from inception to April 2023 using the terms related to impaired spirometry and mortality. Titles and abstracts were screened to identify eligible studies that reported mortality estimates for individuals with PRISm. We excluded studies that adopted other definitions of impaired spirometry, had a specific study setting (e.g. HIV patients), had an insufficient follow-up period (<1 year) or reported duplicated data. Random-effects meta-analysis was used to produce pooled hazard ratio (HR) with 95% confidence intervals. Between-study heterogeneity was assessed with I2. Eight studies met the inclusion criteria involving 40 699 individuals with PRISm. All included studies reported increased risk of all-cause mortality among adults with PRISm. Meta-analysis showed that PRISm was associated with an increased risk of all-cause mortality (pooled HR 1.71, 95% CI 1.51-1.93; I2=64%), cardiovascular mortality (pooled HR 1.57, 95% CI 1.44-1.72; I2=35%) and respiratory-related mortality (pooled HR 1.97, 95% CI 1.55-2.49; I2=0%). Individuals with PRISm have a significantly increased risk of mortality compared with those with normal spirometry.

Risk of exacerbations, hospitalisation, and mortality in adults with physician-diagnosed chronic obstructive pulmonary disease with normal spirometry and adults with preserved ratio impaired spirometry in Sweden: retrospective analysis of data from a nationwide cohort study.

Concerns about PRISm

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RATIONALE: Preserved Ratio Impaired Spirometry (PRISm) is a heterogeneous condition linked to increased respiratory symptoms and elevated all-cause mortality. PRISm is characterized by a preserved FEV1/FVC ratio (≥70%) alongside a reduced FEV1 (&amp;lt;80% predicted), and its course is unstable, with some individuals reverting to normal lung function while others progress to chronic obstructive pulmonary disease (COPD). The long-term trajectory over decades and impact of PRISm have not been thoroughly assessed in the UK. Using data from a birth cohort study, we evaluated PRISm trajectories in ever-smokers over two decades and investigated its association with mortality. METHODS: We conducted a cohort analysis using data from the Medical Research Council National Survey of Health &amp; Development, a birth cohort initiated in 1946. Participants underwent regular clinical assessments, including pulmonary function tests (PFTs) at ages 43, 53, and 63. Associations with mortality were assessed using multivariable Cox proportional hazards models, adjusted for sex, smoking history (pack years), asthma diagnosis, and severity of airflow obstruction (classified by Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria). Mortality data were obtained through linked national death registries as of May 2024. RESULTS: 2,238 ever-smokers underwent PFTs at age 43 (47% female): 75% had normal spirometry, 16% had PRISm, and 9% exhibited COPD. At age 53, 1,877 ever-smokers were tested (48% female): 72% had normal spirometry, 18% had PRISm, and 10% had COPD. PRISm at age 43 was associated with increased all-cause mortality (Hazard Ratio (HR) = 1.31, 95%CI = 1.04-1.6, p = 0.020) and respiratory-specific mortality (HR = 2.5, 95%CI = 1.32-4.7, p = 0.005). PRISm at age 53 also predicted higher all-cause mortality (HR = 1.45, 95%CI = 1.11-1.89, p = 0.006). PRISm was unstable over time; of 196 participants with PRISm at age 43 who underwent repeat testing at ages 53 and 63, PRISm persisted in 72 (37%) at age 53, while 18 (9%) progressed to COPD and 106 (54%) reverted to normal spirometry. By age 63, of the 72 with persistent PRISm at age 53, 56 (78%) remained in the PRISm group, 5 (7%) developed COPD, and 11 (15%) reverted to normal spirometry. CONCLUSIONS: PRISm is an unstable condition over time, with a significant proportion of individuals reverting to normal lung function over a 10-20 year period. However, PRISm is linked to increased mortality as early as 43 years of age, highlighting its prognostic importance in high-risk populations.

Rationale: Subjects with preserved ratio impaired spirometry (PRISm) experience increased respiratory symptoms, although they present heterogeneous characteristics. However, the longitudinal changes in these symptoms and respiratory function are not well known. Objectives: To investigate PRISm from the viewpoint of respiratory symptoms in a longitudinal, large-scale general population study. Methods: The Nagahama study included 9,789 inhabitants, and a follow-up evaluation was conducted after 5 years. Spirometry and self-administered questionnaires regarding respiratory symptoms, including prolonged cough, sputum and dyspnea, and comorbidities were conducted. Results: In total, 9,760 subjects were analyzed, and 438 subjects had PRISm. Among the subjects with PRISm, 53% presented with respiratory symptoms; dyspnea was independently associated with PRISm. Follow-up assessment revealed that 73% of the subjects with PRISm with respiratory symptoms were consistently symptomatic, whereas 39% of the asymptomatic subjects with PRISm developed respiratory symptoms within 5 years. In addition, among subjects with respiratory symptoms without airflow limitation at baseline, PRISm was a risk factor for the development of airflow limitation independent of smoking history and comorbidities. Conclusions: This study demonstrated that 53% of the subjects with PRISm had respiratory symptoms; dyspnea was a distinct characteristic of PRISm. Approximately three-fourths of the symptomatic subjects with PRISm consistently complained of respiratory symptoms within 5 years. Together with our result that PRISm itself is an independent risk factor for the development of chronic obstructive pulmonary disease among subjects with respiratory symptoms, the clinical course of subjects with PRISm with symptoms requires careful monitoring.

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.

Background and Objectives: preserved ratio impaired spirometry (PRISm) is a common spirometric pattern that causes respiratory symptoms, systemic inflammation, and mortality. However, its impact on health-related quality of life (HRQOL) and its associated factors remain unclear. We aimed to identify these HRQOL-related factors and investigate the differences in HROOL between persons with PRISm and those with normal lung function. Materials and Methods: we reviewed the Korea National Health and Nutrition Examination Survey data from 2008 to 2013 to evaluate the HRQOL of persons with PRISm, as measured while using the Euro Quality of Life-5D (EQ-5D) and identify any influencing factors. PRISm was defined as pre-bronchodilator forced expiratory volume in 1 s (FEV1) <80% predicted and FEV1 to forced vital capacity (FVC) ratio (FEV1/FVC) ≥0.7. Individuals with FEV1 ≥80% predicted and FEV1/FVC ≥0.7 were considered as Controls. Results: of the 27,824 participants over the age of 40 years, 1875 had PRISm. The age- and sex-adjusted EQ-5D index was lower in the PRISm group than in the control group (PRISm, 0.930; control, 0.941; p = 0.005). The participants with PRISm showed a significantly higher prevalence of hypertension (p < 0.001), diabetes (p < 0.001), obesity (p < 0.001), low physical activity (p = 0.001), ever-smoker (p < 0.001), and low income (p = 0.034) than those in the control group. In participants with PRISm, lower EQ-5D index scores were independently associated with old age (p = 0.002), low income (p < 0.001), low education level (p < 0.001), and no economic activity (p < 0.001). Three out of five EQ-5D dimensions (mobility, self-care, and usual activity) indicated a higher proportion of dissatisfied participants in the PRISm group than the control group. Conclusions: the participants with PRISm were identified to have poor HRQOL when compared to those without PRISm. Old age and low socioeconomic status play important roles in HRQOL deterioration in patients with PRISm. By analyzing risk factors that are associated with poor HRQOL, early detection and intervention of PRISm can be done in order to preserve patients’ quality of life.

This study aimed to evaluate the prevalence, trends, and factors of preserved ratio with impaired spirometry (PRISm) by using a nationally representative sample. The datasets of the Korea National Health and Nutrition Examination Survey 2010-2019 were used: of total 32,949 participants aged ≥40 and no missing data on spirometry, 24,523 with normal, 4,623 with obstructive, and 3,803 with PRISm were identified. PRISm was defined as FEV1/FVC ≥70% and FEV1% of the predicted value (%pred) <80. PRISm-lower limit of normal (LLN) was defined when FEV1/FVC ≥LLN and FEV1 <LLN. The prevalence and trend of PRISm were estimated using the Joinpoint regression method. The trend was calculated for the periods 2010-2015 and 2017-2019, due to a change in spirometry device in June, 2016. A complex sample multivariable-adjusted regression model was used to identify factors associating PRISm. Estimated average prevalence of PRISm was 10.4% (PRISm-LLN 11.1%). Joinpoint regression analyses found a relatively stable trend of PRISm for both fixed ratio and LLN. The multivariable-adjusted logistic regression model showed female sex, BMI ≥25 kg/m2, metabolic syndrome, hypertriglyceridemia, abdominal obesity, low HDL-choleterol, hypertension, and diabetes were associated with the increased probability of PRISm. Whenever a PRISm pattern is identified in a clinical context, it may be necessary to measure absolute lung volumes to investigate underlying physiological abnormalities and to identify factors that is modifiable.

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.

The Association of Interstitial Lung Abnormalities and Preserved Ratio Impaired Spirometry With Mortality.

Background The pattern of preserved ratio impaired spirometry (PRISm) has gained increased attention in the last few years. While PRISm has been linked to increased morbidity and mortality, the underlying physiological causes remain unclear and the stability of PRISm over time remains uncertain. Methods We investigated 6571 individuals (≥25 years, 51.4% female) from the Austrian population-based, longitudinal LEAD study who underwent post-bronchodilator spirometry and body plethysmography twice within a 4-year interval. Individuals were classified into normal spirometry (FEV 1 /FVC≥0.7 and FEV 1 ≥80%predGLI); airflow limitation (AFL; FEV 1 /FVC&lt;0.7); and PRISm (FEV 1 /FVC≥0.7 and FEV 1 &lt;80%predGLI). Body composition was assessed by DXA scanning. Results PRISm was present in 2.6% of individuals (n=171) at baseline. Different subgroups of PRISm were identified: after 4 years, 45.6% had persistent PRISm, 37.4% PRISm-to-normal and 17.0% had PRISm-to-AFL. Persistent PRISm individuals were characterised by significantly lower total lung capacity (TLC), with two thirds meeting TLC criteria for restriction. PRISm-to-AFL had a higher TLC and lower airway conductance as well as a higher FEV 1 decline. Participants with new PRISm after 4 years (n=71) had the highest decline of vital capacity and TLC. Smoking status was not associated with PRISm progression or resolution as never- and ever- smokers with PRISm showed no difference in frequency of transitions after 4 years. Conclusion PRISm is primarily defined by low lung volumes and is characterised by a dynamic course, with more than two thirds demonstrating stable or improving lung function. Lung volume assessment in PRISm is mandatory for precise evaluation of pulmonary function. Similar transition patterns in smokers and never-smokers challenge the assumption of PRISm as an early smoking-related obstructive state and emphasize the importance of repeated lung function testing over time.

Preserved ratio impaired spirometry (PRISm) is a prevalent yet under-researched state of diminished lung function, which has been proposed as a pre-clinical abnormal spirometry associated with chronic obstructive pulmonary disease (COPD) or early-stage COPD. PRISm is closely associated with cardiovascular disease. Preventing and improving quality of life in PRISm subjects is important. We aimed to examined the relationship between American Heart Association’s Life’s Essential 8 (LE8) and PRISm. This cross-sectional study utilized data of 2,869 adults aged ≥ 20 years from the National Health and Nutrition Examination Survey (NHANES) in 2007–2012. Multivariable logistic regression models were employed to examine the association between LE8 score, health behavior score, health factor score, each component of LE8 score, and PRISm. Moreover, the study explored this correlation in greater depth using restricted cubic spline curves and subgroup analyses. Of the 2,869 participants, the mean age was 44.09 ± 0.44 years, and 316 (11.01%) were defined as having PRISm. In fully adjusted models, higher LE8 scores were associated with a reduced odds ratio for PRISm (OR = 0.97; 95% CI, 0.96–0.98). A linear relationship between the LE8 score and PRISm was observed. Similar patterns emerged for health behavior and health factor subscores, with a particularly stronger correlation between health factors and PRISm. In the subgroup analysis, the inverse association between LE8 and PRISm was significantly more pronounced among those with high income. A higher LE8 score was associated with a lower likelihood of developing PRISm. Promoting optimal adherence to the LE8 metrics may improve PRISm and offers a meaningful approach for its prevention and management.

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.

INTRODUCTIONPreserved ratio impaired spirometry (PRISm) is a new and variable phenotype of spirometry impairment that was first defined by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) in 2023. The identification of high-risk factors for the progression from PRISm to COPD remains insufficient at present.METHODSMendelian randomization (MR) analysis was conducted using genome-wide association study (GWAS) summary statistics. Genetic instruments for smoking behavior were derived from the GWAS & Sequencing Consortium of Alcohol and Nicotine use (GSCAN) (n=607291), while PRISm case-control data were sourced from the UK Biobank (n=296282). The inverse-variance weighted (IVW) method served as the primary analytical approach, supplemented by heterogeneity assessment, pleiotropy evaluation, and sensitivity analyses. For the meta-analysis, PubMed, Embase, Cochrane Library, and Web of Science were systematically searched from inception to 31 December 2024, to identify relevant studies that followed up on the changes in spirometry among individuals with PRISm or studies that reported the possible factors related to the changes in spirometry among individuals with PRISm. The risk of bias and the quality of the included studies were assessed using the Newcastle–Ottawa Scale (NOS).RESULTSThe MR analysis identified 85 SNPs as genetic instruments, revealing a modest causal link between cigarette smoking and PRISm prevalence (IVW: OR=1.01–1.02, p=0.048). The meta-analysis of 14 studies (n=7336 PRISm cases) shows 20.8% (95% CI: 15.6–25.9) progress to COPD at follow-up, with no significant difference by follow-up duration (<5 vs ≥5 years). Persistent PRISm occurs in 41.5% (95% CI: 35.8–47.2), more frequently in long-term follow-up subgroups. Baseline ‘chest distress/dyspnea’ (OR=3.81; 95% CI: 1.47–9.84) and ‘current smoking’ (OR=2.18; 95% CI: 1.14–4.15) significantly predict progression, while respiratory symptoms, FEV1/FVC ratio, TLC%, and FVC% show no association.CONCLUSIONSOur findings suggest a modest causal link between cigarette smoking and PRISm prevalence. The progression of PRISm to COPD within 5 years is approximately 20.8%. Among individuals with PRISm at the first visit, ‘chest distress or dyspnea’ and ‘current smoking’ are potential clinical risk factors for the progression of PRISm to COPD.