Maximal Forced Inspiratory Flow Dynamics and Acute Exacerbation in Chronic Obstructive Pulmonary Disease Patients with Exacerbation History
Article information
Abstract
Background
Chronic obstructive pulmonary disease (COPD), characterized by progressive airflow obstruction and frequent exacerbations, is a significant global health burden. COPD severity has traditionally been assessed using expiratory flow measurements, like forced expiratory volume in 1 second. However, the role of inspiratory flow, specifically maximal forced inspiratory flow (FIFmax), in predicting exacerbation risk is gaining attention.
Methods
This retrospective cohort study evaluated COPD patients with a history of exacerbations who were receiving inhaled therapy. The eligible patients were followed up for 3 years with spirometric assessments. Patients were categorized into quartiles based on the annual change in FIFmax, from the greatest decrease (Q1) to the greatest increase (Q4). Primary outcome was acute exacerbation, stratified by severity as moderate-to-severe and severe exacerbation.
Results
In total, 180 patients were followed up for 3 years. A greater increase in FIFmax was linearly associated with lower rates of both moderate-to-severe and severe exacerbations (p-value for trend <0.001 for both), but time-to-event analysis revealed no significant association between FIFmax changes and moderate-to-severe exacerbations. In contrast, a significant association with severe exacerbations was observed (log-rank p=0.005). Even after adjusting for confounders, FIFmax remained an independent predictor of severe exacerbations (Q3: hazard ratio, 0.506 [95% confidence interval, 0.306 to 0.836], p=0.008; Q4: hazard ratio, 0.491 [95% confidence interval, 0.291 to 0.830], p=0.008).
Conclusion
Changes in FIFmax were not significantly associated with moderate-to-severe exacerbations, but were related to a reduced risk of severe exacerbations in COPD patients receiving inhaled therapy. These findings indicate that FIFmax may serve as a valuable prognostic marker for severe exacerbations in high-risk COPD patients.
Introduction
Chronic obstructive pulmonary disease (COPD), characterized by progressive airflow obstruction, persistent respiratory symptoms, and associated comorbidities, is a significant global health burden [1]. Since COPD predominantly affects the small airways and alveoli during the expiratory phase of respiration, the severity and progression of COPD have traditionally been assessed using expiratory flow measurements, such as forced expiratory volume in 1 second (FEV1) [2]. However, the clinical management and understanding of COPD are evolving beyond the traditional reliance on FEV1, recognizing that a complex interplay of pulmonary and extrapulmonary factors influence the manifestations and prognosis of the disease [3,4]. In particular, inspiratory flow, including peak inspiratory flow (PIF) and maximal forced inspiratory flow (FIFmax), is gaining attention for its potential implications for COPD pathophysiology. While PIF, which is typically measured using devices such as the In-Check Dial, is commonly used to assess inhaler device suitability, FIFmax, obtained during spirometry, provides additional aerodynamic insights that may reflect disease progression and therapeutic response.
An exacerbation is defined as an acute worsening of symptoms that necessitates additional therapy [5]. Patients with a history of exacerbations are known to have a higher risk of mortality [6]. Increased frequency of past exacerbations, especially severe exacerbations, is associated with higher long-term mortality risk [7,8]. Consequently, patients with a history of exacerbations are considered a high-risk group with poor prognosis. However, biomarkers that can reliably assess COPD progression and exacerbation risk in these patients remain insufficiently explored.
Inspiratory flow can be associated with the clinical outcomes of COPD patients, especially in managing exacerbations [9]. PIF or FIFmax, defined as the maximum speed at which air is inhaled into the lungs, reflects the complex interaction between airway resistance, lung compliance, lung volume, and respiratory muscle strength [10,11]. PIF has become a crucial factor in choosing appropriate drug delivery methods or inhaler devices for stable COPD management [12,13]. However, a significant concern is that approximately 22% to 42% of Korean COPD patients using dry powder inhalers had suboptimal PIF [14,15].
FIFmax is a biomarker for inspiratory flow in COPD patients, and provides additional aerodynamic information beyond traditional expiratory flow measurements [16]. Unlike PIF, which varies depending on device resistance, FIFmax is obtained from standard spirometry, making it more consistent across measurements. Improving FIFmax is related to reduced exacerbation risk and attenuated lung function decline in COPD patients [17]. However, there is limited evidence of whether in COPD patients who are at high risk of future exacerbations, increased inspiratory flow is associated with the efficacy of inhaled therapy.
In this study, we specifically focused on COPD patients with a history of exacerbations, as they represent a high-risk group for future exacerbations, and are likely to benefit most from optimized inspiratory function. Our study aimed to elucidate the association between changes in FIFmax and the risk of acute exacerbations in COPD patients with a history of exacerbations who are receiving inhaled therapy. To capture potential prognostic implications and account for the absence of an established clinical cut-off for FIFmax, we stratified patients by quartiles of FIFmax change, to enable a more granular assessment of its impact on clinical outcomes.
Materials and Methods
1. Study design and participants
The present retrospective cohort study evaluated patients with COPD who had a documented history of acute exacerbation, and were receiving inhaled treatment. Patients were selected from those who visited a teaching hospital between January 2004 and December 2020. The diagnosis of COPD was confirmed based on clinical presentation, including chronic respiratory symptoms and spirometric evidence of non-fully reversible airflow limitation, as defined by a ratio of post-bronchodilator FEV1 to forced vital capacity (FVC) of less than 0.7.
Inclusion criteria for the study required that patients have: (1) a history of at least one moderate or severe exacerbation; (2) ongoing inhaled treatment with long-acting bronchodilators and/or inhaled corticosteroids; and (3) complete spirometric assessments available at multiple follow-up visits over a 3-year observation period. Patients with incomplete data regarding demographic characteristics, clinical information, or exacerbation events between clinic visits, were excluded from the study.
Eligible patients were categorized into quartiles based on the annual change in PIF (FIFmax), with quartiles ranging from the greatest decrease in FIFmax (Q1), to the greatest increase in FIFmax (Q4).
2. Variables
Data collected included demographic characteristics (age, sex, body mass index [BMI], and smoking history), and clinical data, such as the Charlson comorbidity index (CCI), history of exacerbations, symptom burden (COPD assessment test and modified Medical Research Council dyspnea scale scores), blood tests, pulmonary function test results, and inhaled therapy.
3. Measurements
FIFmax, representing the PIF during spirometry, was obtained during spirometric assessments with minimal airflow resistance. Spirometry was performed by certified pulmonary function technologists in accord with the American Thoracic Society guidelines. The longitudinal changes in FIFmax were analyzed using a linear mixed-effect model, which accounted for multiple FIFmax values obtained from repeated spirometry assessments during follow-up.
4. Outcomes
The primary outcome was moderate-to-severe exacerbation of COPD. The severity of exacerbations was defined based on previously established criteria [18]. Moderate exacerbations were defined as episodes of acute worsening of respiratory symptoms requiring intervention with oral corticosteroids or antibiotics. Severe exacerbations were specifically defined as exacerbations that necessitated hospitalization or an emergency room visit.
5. Statistical analysis
Comparisons of continuous variables between quartiles were conducted using the t-test or the Wilcoxon signed-rank test, depending on the distribution of the data. Categorical variables were compared using the chi-squared test or Fisher’s exact test. Survival analysis was performed to evaluate the time to the first moderate-to-severe exacerbation using Kaplan-Meier curves, with the log-rank test being used to assess differences between the quartiles. To assess the adjusted impact of changes in FIFmax on the rates of severe exacerbations, multivariable Cox regression analyses were performed, incorporating clinically relevant variables that were known to influence exacerbation risk.
Statistical significance was determined with a p-value threshold under 0.05. All statistical analyses were conducted using R statistical software version 4.1.2 (R Foundation, Vienna, Austria).
6. Ethics approval and consent to participate
This study was conducted according to the principles of the Declaration of Helsinki. The Institutional Review Board of Seoul Metropolitan Government-Seoul National University Boramae Medical Center waived the requirement for written informed consent, and approved this study (30-2023-79).
7. Data sharing
The data used in this research cannot be shared publicly to maintain patient confidentiality and comply with ethical guidelines. However, researchers interested in accessing the data for scientific collaboration or verification purposes may contact the corresponding author and submit a formal request. The release of data will be subject to ethical approval, ensuring that privacy and confidentiality standards are upheld in accordance with institutional policies and regulations.
Results
A total of 180 patients were followed up for 3 years. The median annual change in FIFmax was 1.6 L/min (interquartile range [IQR], −3.6 to 8.1). Figure 1 summarizes the distribution of the annual change in FIFmax. Patients were categorized into quartiles (Q1 to Q4) based on the degree of change in FIFmax, with each quartile consisting of 45 patients. Q1 represented the group with the greatest decrease in FIFmax, with a median change of −8.4 L/min (IQR, −12.6 to −4.9). Q2 had a median change of −0.3 L/min (IQR, −1.8 to 0.8), indicating minimal change. Q3 showed a moderate increase in FIFmax, with a median change of 4.9 L/min (IQR, 3.2 to 6.6). Finally, Q4 represented the group with the greatest increase in FIFmax, with a median change of 22.2 L/min (IQR, 15.3 to 48.6).
Distribution of annual change in maximum forced inspiratory flow. (A) Histogram showing the overall distribution of annual changes in maximum forced inspiratory flow among all patents. (B) Distribution of patients categorized into four quartiles (Q1–Q4) based on the change in maximum forced inspiratory flow.
1. Baseline characteristics
Baseline characteristics were well balanced across the quartiles (Table 1). The mean age of patients ranged 60.3 to 65.8 years in Q4 to Q3. The proportion of males was slightly higher in Q4 than Q2 at 95.6% to 77.8%, though this difference did not reach statistical significance. Other variables, such as BMI, smoking history, and CCI, showed no significant variations among the quartiles.
Baseline characteristics according to FIFmax change
In blood tests, there were no significant differences across the quartiles (Table 2). The mean white blood cell count, neutrophil count, and lymphocyte count were similar among the groups, nor did the neutrophil-to-lymphocyte ratio and eosinophil counts differ significantly. The pulmonary function tests showed significant differences between the quartiles, particularly in post-bronchodilator FEV1 and FVC. Patients in Q4 compared to Q1 showed a significantly higher mean post-bronchodilator response (BDR) FEV1 of 1.67 to 1.32 L. Similarly, the mean post-BDR FVC was significantly higher in Q4 than Q1 at 3.16 to 2.86 L (p=0.011). However, no significant differences were observed in the post-BDR FEV1/FVC ratio or forced expiratory flow at 25%−75% of vital capacity.
Clinical features according to FIFmax change
2. Exacerbation events
A significant difference was shown in exacerbation rates across the quartiles of changes in FIFmax (Table 3). Patients in Q2 showed the highest annual rate of moderate-to-severe exacerbations, with a mean of 1.36 exacerbations per year. In contrast, those in Q4 had the lowest rate of moderate-to-severe exacerbations, with a mean of 0.50 exacerbations per year (p<0.001). A significant trend of linear relationship between the quartiles of FIFmax changes and exacerbation rates was observed (p-value for trend <0.001). The annual rate of severe exacerbations was highest in Q1 and lowest in Q4, with a mean rates of 0.76 and 0.29 severe exacerbations per year, respectively (p=0.002). A significant trend of linear relationship between the quartiles of FIFmax changes and exacerbation rates was observed (p-value for trend <0.001).
Annual rate of exacerbation event according to FIFmax change
The Kaplan-Meier curve did not show a statistically significant difference across the quartiles in the time to first moderate-to-severe exacerbation. However, compared to other groups, the patients in Q1 had a significantly shorter time to their first severe exacerbation (log-rank p=0.005) (Figure 2).
Kaplan-Meier curve according to maximum forced inspiratory flow (FIFmax) change. (A) Kaplan-Meier curves for time to first moderate-to-severe exacerbation by quartiles of FIFmax change. (B) Kaplan-Meier curves for time to first severe exacerbation by quartiles of FIFmax change. Q1–Q4: quartiles 1 through 4.
3. Univariable and multivariable Cox regression model
Univariable and multivariable Cox regression analyses showed that the quartiles of FIFmax change were not significantly associated with moderate-to-severe exacerbations. However, univariable Cox regression analysis identified FIFmax change as a significant predictor of severe exacerbations (Table 4). Patients in Q3 and Q4 showed significantly lower hazard ratios (HRs) for severe exacerbations compared to those in Q1, with unadjusted HRs of 0.525 (95% confidence interval [CI], 0.331 to 0.833) for Q3, and 0.461 (95% CI, 0.282 to 0.754) for Q4. Multivariable Cox regression analysis, adjusting for potential confounders, confirmed that FIFmax change is a significant independent factor that is associated with severe exacerbations. The adjusted HR for severe exacerbations was as follows: Q4 had an adjusted HR of 0.510 (95% CI, 0.308 to 0.843), compared to Q1. Another significant independent predictor was a history of severe exacerbation (adjusted HR, 3.655; 95% CI, 1.770 to 7.548).
Cox regression model for severe exacerbation
Discussion
This study examined the relationship between changes in FIFmax and the risk of acute exacerbations in COPD patients with a history of exacerbations, and found that FIFmax changes were not significantly associated with moderate-to-severe exacerbations. However, a greater increase in FIFmax over time was associated with a lower incidence of severe exacerbations. This finding indicates that improvements in inspiratory flow may play a significant role in reducing exacerbation risk. Furthermore, even after adjusting for potential confounders, FIFmax remained a significant predictor of exacerbation outcomes. These results indicate that inspiratory flow parameters can provide additional clinical information beyond traditional expiratory measures, like FEV1. While FEV1 has been the standard to evaluate COPD severity, FIFmax could offer complementary insights, particularly in assessing the risk of exacerbations in the patients who have already experienced acute exacerbations. Consequently, inspiratory metrics, like FIFmax, may be valuable spirometric biomarkers to manage and prognosticate COPD, especially in patients at high risk of exacerbations.
Previous studies have predominantly focused on expiratory measures, such as FEV1 decline or FEV1/FVC decline, to assess disease progression and prognosis in COPD [19,20]. These studies have established FEV1 or the FEV1/FVC ratio as a key metric in characterizing the severity of airflow limitation and its relationship to clinical outcomes. However, our study contributes to the growing evidence that supports the inclusion of inspiratory flow measurements, such as PIF or FIFmax, in the comprehensive assessment of COPD. Although recent studies have not consistently showed an association between PIF and expiratory measures, such as FEV1 [21,22], our study found that higher post-BDR FEV1 was significantly associated with increased FIFmax measured via spirometry. Similarly, previous studies have shown inconsistent correlations between spirometric PIF (FIFmax) and device-specific PIF [22-25]. In line with our findings, individuals in the increased FIFmax group experienced a slower rate of FEV1 decline, compared to those in the decreased FIFmax group [17].
Assessing PIF typically necessitates the use of specialized devices with specific resistance settings, which increases both the time and complexity of the procedure, thereby limiting its routine application in clinical practice. In contrast, FIFmax can be measured with minimal resistance during standard spirometry, allowing its integration into routine assessments. While PIF has been widely studied in the context of inhaler device suitability, its direct association with long-term COPD outcomes has not been well investigated. In a prospective study, suboptimal PIF was linked to an increased risk of exacerbations, but substantial differences in baseline characteristics between the suboptimal and optimal PIF groups limited the interpretability of the findings [26]. In contrast, FIFmax provides a standardized inspiratory flow measure that is independent of device resistance, offering a more reproducible metric to assess airway function and disease progression. Furthermore, unlike PIF, which varies depending on the resistance settings of the device for the same patient, FIFmax, when measured using a standardized spirometry protocol, can offer a consistent and reproducible value, providing an advantage for standardization [27,28]. In fact, when measured at least three times, the correlation coefficient for FIFmax reached 0.981, highlighting its high reliability [29]. In our study, to ensure the reliability of FIFmax, patients performed at least three maximal inspiratory efforts during spirometry, with the highest value recorded as FIFmax. Among patients with a history of exacerbations, after adjustment for clinically important confounding factors, those with decreased FIFmax were found to be at greater risk of future severe exacerbations. Consequently, FIFmax may serve as a repeatable marker to assess exacerbation risk, particularly in COPD patients with a history of exacerbations.
Several physiological mechanisms may explain the observed relationship between increased FIFmax and a reduced risk of severe exacerbations. First, FIFmax represents the complex interaction between airway resistance, lung compliance, and lung volume [10]. Enhancements in these factors can improve inspiratory flow, thereby decreasing the likelihood of airflow limitation or acute exacerbation events. Second, FIFmax may serve as an indicator of respiratory muscle strength. In COPD patients, sarcopenia caused by malnutrition and other factors can lead to respiratory muscle weakness and reduced exercise capacity, which may be associated with worse clinical outcomes [30-32]. A previous study found that respiratory muscle strength was reduced in patients experiencing acute exacerbations of COPD, compared to those with stable COPD [33]. Reduced inspiratory muscle strength can lead to diminished inspiratory flow [34]. Meanwhile, inspiratory muscle training has been shown to enhance inspiratory muscle strength [35], which in turn improves inspiratory power output in COPD patients by increasing inspiratory flow [36] and may also enhance PIF [37]. Third, improved inspiratory flow may facilitate a more efficient delivery of inhaled medications, potentially leading to better treatment outcomes. In a prospective study, suboptimal PIF was associated with an increased risk of moderate-to-severe exacerbation [26]. Inspiratory flow has been recognized to be important when choosing an inhalation device for COPD patients [38]. Moreover, recent growing evidence indicates that inspiratory flow serves as a predictive therapeutic biomarker for COPD patients [11]. Fourth, higher FIFmax values could also indicate better overall lung health, reflecting more preserved lung function, and a lower susceptibility to exacerbations. These potential mechanisms warrant further investigation to clarify the causal pathways underlying these associations. Our findings align with recent studies that suggest that inspiratory parameters can offer additional insights into the pathophysiology of COPD and patient prognosis. Notably, the significance of this study lies in its evaluation of COPD progression and the risk of severe exacerbations in high-risk COPD patients with a history of previous exacerbations.
Several limitations should be acknowledged. First, the retrospective design may introduce selection bias, and the findings may not be generalizable to all COPD populations, in particular, those with different phenotypes or comorbidities. Second, although the study controlled for several confounding variables, there could be unmeasured factors that might influence the relationship between FIFmax and exacerbation risk. Third, the relatively small sample size may limit the statistical power and robustness of the findings. Fourth, the reliance on spirometric measurements for FIFmax may introduce variability, especially if the tests are not conducted under standardized conditions. Future studies should aim to validate these findings in larger, more diverse populations, and explore the impact of potential confounders in greater detail.
In conclusion, this study found that changes in FIFmax were not significantly associated with moderate- to-severe exacerbations. However, an increase in FIFmax was significantly correlated with a lower risk of severe exacerbations in COPD patients receiving inhaled therapy, underscoring the importance of monitoring inspiratory flow. Integrating FIFmax measurements may enhance therapeutic strategies for COPD, particularly in patients at high risk of severe exacerbations. Further research is needed to validate these findings, and to establish FIFmax as a standard measure in COPD care.
Notes
Authors’ Contributions
Conceptualization: Park H, Lee HW. Methodology: Lee JK, Heo EY, Kim DK, Lee HW. Formal analysis: all authors. Data curation: Park H, Lee HW. Project administration: Lee HW. Investigation: Park H, Lee HW. Writing - original draft preparation: Park H, Lee HW. Writing - review and editing: Lee JK, Heo EY, Kim DK, Lee HW. Approval of final manuscript: all authors.
Conflicts of Interest
Hyun Woo Lee is an early career editorial board member and Deog Kyeom Kim is an editor of the journal, but they were not involved in the peer reviewer selection, evaluation, or decision process of this article. No other potential conflicts of interest relevant to this article were reported.
Funding
No funding to declare.