Authors: Jin Hwa Song, Youlim Kim
Categories: Review, Chronic Obstructive Pulmonary Disease, Respiratory Function Tests, Oscillometry, Plethysmography, Ultrasonography
Source: Tuberculosis and Respiratory Diseases
Authors: Jin Hwa Song, Youlim Kim
Spirometry can play a critical role as a gold standard in the diagnosis and treatment of patients with chronic obstructive pulmonary disease (COPD). While the criteria for diagnosis have advanced over time, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) standard of the forced expiratory volume in 1 second/forced vital capacity ratio <0.7 remains the most universally employed metric. However, spirometry cannot be utilized in all situations, and test execution can be difficult for some patients, often showing normal values in the early diagnosis of COPD. Therefore, research on new diagnostic methods is underway. Techniques include whole-body plethysmography for measurement of residual volume and inspiratory capacity and airway resistance, diffusing capacity of carbon monoxide or nitric oxide, impulse oscillometry, infrared time-offlight depth image sensor, diaphragm ultrasonography, which can enable early diagnosis and multifaceted assessment of patients with COPD.
Chronic obstructive pulmonary disease (COPD) presents a significant global health challenge, affecting millions with this progressive lung condition [1]. Although spirometry is the cornerstone of COPD diagnosis [2], its effectiveness is limited in the early detection of the disease and in patients with performance limitations [2]. Consequently, the integration of complementary pulmonary function tests (PFTs) is essential. Measurements such as the diffusing capacity of the lungs for carbon monoxide (DLCO) [3], airway resistance [4], and respiratory oscillometry [5] offer crucial insights into the manifestations of COPD, including static lung hyperinflation, airway obstruction, and small airway dysfunction, which spirometry alone cannot fully assess [6].
The introduction of these sophisticated diagnostic tools enables a more comprehensive evaluation of lung function, particularly beneficial for characterizing precursor conditions like preserved ratio impaired spirometry (PRISm) [2] and the phenotype of asthma-COPD overlap (ACO). These tools support the development of tailored strategies [7]. Utilizing these modalities can also improve our understanding of disease severity and progression, facilitating personalized management approaches.
The increasing recognition of comprehensive methods for evaluating lung function, given traditional spirometry’s limitations, necessitates clinicians’ knowledge of these constraints and the potential of emerging diagnostic techniques.
The purpose of this review is to examine the role of recently introduced diagnostic tools (Table 1 and Figure 1) [8-30], including hyperinflation quantified by residual volume (RV), single-breath washout (SBW) nitrogen test, airway resistance (Raw) measured by body plethysmography or respiratory oscillometry, infrared timeof-flight (ToF) depth image sensor, ultrasonography of the diaphragm, and respiratory muscle strength. These tools provide valuable insights into gas exchange, airway obstruction, and small airway function, which are critical components of the disease. Enhanced knowledge of spirometry’s limitations and the capabilities of these novel diagnostic modalities can lead to more thorough assessments of patients with COPD, offering guidance on appropriate treatment and management strategies.
During the assessment or treatment of patients with COPD, spirometric data is valuable for diagnosing COPD and for gauging the severity of airflow limitation using forced expiratory volume in 1 second (FEV1). Patients with irreversible airflow obstruction (post-bronchodilator FEV1/forced vital capacity [FVC] ratio <0.7) [31], respiratory symptoms, and risk factors such as smoking, occupational exposure, and environmental pollutants are typically diagnosed with COPD [2].
Spirometric data remains an essential tool for healthcare professionals in assessing airflow obstruction and confirming the diagnosis of COPD [2]. Expressing FEV1 as a percentage of the predicted value in a patient can effectively determine the condition’s severity. Lower FEV1 [32,33], rapid decline of FEV1 [34] are considered predictors of a higher risk of COPD exacerbation. Additionally, a lower FEV1/FVC ratio [35] is associated with all-cause mortality.
Airway obstruction was initially defined by the European Community for Steel and Coal and the European Respiratory Society (ERS) as a condition where the FEV1/FVC ratio falls below the lower fifth percentile of a relatively large healthy reference group, a threshold known as the lower limit of normal (LLN) [36]. A FEV1/FVC ratio of 0.75 was later established as the cut-off by the American Thoracic Society (ATS) in 1987 [37], and a FEV1/FVC ratio of 0.70 with FEV1 <80% was predicted by the British Thoracic Society in 1997 [38]. In 2007, COPD was redefined by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) as a fixed FEV1/FVC ratio of less than 0.7, a standard unaffected by factors such as age and gender, and with no limitation on FEV1 [39]. Despite the potential for a significant number of false-positive results in older non-smokers and false-negative results in younger patients when using the fixed FEV1/FVC ratio instead of the LLN [40,41], this method has advantages in identifying populations at increased risk of COPD [42].
COPD encompasses several phenotypes beyond the traditional classification of emphysema and chronic bronchitis, including the frequent exacerbator phenotype (two or more acute exacerbations per year) [43], ACO [7], and small airway disease (SAD) [44,45]. These phenotypes play a vital role in predicting patient prognosis and guiding treatment strategies [46]. However, their differential diagnosis using only spirometry remains challenging. Spirometry does not correlate with arterial blood gas, a key predictor of survival in patients with COPD, thus limiting its efficacy [47,48].
Whole body plethysmography (WBP) enables clinicians to measure spirometric parameters such as total lung capacity (TLC), RV, inspiratory capacity (IC), and inspiratory reserve volume (IRV). Typically, the normal ranges for TLC, functional residual capacity (FRC), and RV fall between 80% and 120% of the predicted value [4].
Early pathophysiological manifestations of COPD may include air trapping due to limited expiratory airflow, evidenced by an increased FRC or RV (>140% of predicted). Additionally, limited expiratory airflow can lead to lung hyperinflation, denoted by a higher RV/TLC ratio, and reductions in both IC and IRV [4].
Data from two Korean COPD cohorts, the Korean Obstructive Lung Disease (KOLD) Cohort Study and the Korea COPD Subgroup Study (KOCOSS), also indicate a positive correlation between acute exacerbations and RV/TLC [8,9]. COPD patients with a change from a normal to an abnormal RV/TLC exhibited worsened lung function and more severe emphysematous changes on chest computed tomography (CT) [9]. A study found that in chronic hypercapnic COPD patients undergoing noninvasive ventilation (NIV), an increased RV/TLC ratio was a risk factor for all-cause mortality [10].
A reduction in the resting IC or IC/TLC ratio is considered a sensitive indicator of hyperinflation. IC is negatively correlated with FEV1 [11], suggesting flow limitation in early stages of COPD with preserved FEV1. An IC/TLC ratio below 25% is associated with decreased exercise capacity, higher mortality, and increased exacerbations in GOLD stage II–III [12], and IC/TLC independently predicted mortality beyond the Body mass index, airflow Obstruction, Dyspnea, and Exercise capacity (BODE) index in a USA and Spanish COPD cohort [11].
While measurements of RV/TLC and IC/TLC can offer significant insights into static lung hyperinflation, they are not as readily performed or practical as spirometry, especially for patients who are unsuitable for traditional spirometry.
The helium dilution method, involving the inhalation of helium mixed with oxygen and allowing it to equilibrate in the lungs, accurately measures FRC—the gas volume remaining in the lungs at the end of a passive expiration [49,50]. This method has been utilized in studies to quantify air trapping in COPD.
A study of 65 COPD patients disclosed that those at higher GOLD stages, indicating more advanced disease, displayed significantly higher FRC values using the single-breath helium dilution method [51]. In another study of 55 COPD patients, D’Ascanio et al. [13] reported that RV/TLC ratios measured by the helium dilution method correlated with those from WBP. The study also linked these measurements to reactance at 5 Hz (X(5)) from oscillometry data, which will be further discussed [13].
Closing volume (CV) is the lung volume at which small airways begin to close during expiration, impairing gas exchange by trapping air; closing capacity (CC) is measured as CV+RV [52]. Two methods are used to measure the CV: the xenon gas bolus measurement [53] and the interstitial gas washout method. Due to radiation exposure concerns, the latter is now the most frequently used and is known as the SBW method. In this method, the subject exhales to the RV, inhales pure oxygen up to the TLC, and then exhales through the nitrogen (N2) sensor. An expirogram comprises four distinct phase I, the absolute dead space; phase II, the bronchial phase; phase III, the alveolar phase; and phase IV [54]. In phase I, N2 is not detected, but its concentration rises as the phase advances. At the end of expiration (phase IV), nitrogen released from the upper lobe causes an upward shift in N2 concentration, indicating the point where CC can be measured [14]. In emphysema, structural changes in the lungs lead to increased values of both CV and CC, which correlate with disease severity [55,56].
DLCO, or the lung’s capacity to diffuse carbon monoxide (CO), serves as a marker for gas exchange between the alveolar epithelium and the bloodstream [15,57]. In COPD, a reduced DLCO is often linked with the emphysematous type of the disease [15] and diminished exercise capacity [16]. This reduction is typically seen in patients with more severe COPD and is used to predict exercise intolerance [17], elevated risk of mortality [58,59], development of pulmonary hypertension [60], and frequency of exacerbations [59].
An analysis of data from the Genetic Epidemiology of COPD (COPDGene) study revealed a correlation between a 10% predicted decrease in DLCO and worsened symptoms, along with reduced quality of life in COPD patients [57]. This assessment utilized the COPD Assessment Test (CAT) and St. George’s Respiratory Questionnaire (SGRQ), as well as an evaluation of exercise performance through the 6-minute walk distance (6MWD) test. Furthermore, a decline in DLCO was associated with an increased rate of severe exacerbations [57]. A retrospective cohort study involving patients with GOLD stage I COPD from Spain and Canada identified a correlation between a predicted DLCO cut-off value of less than 60% and a higher rate of all-cause mortality. Also reported were worsening symptoms and a decline in 6MWD, a lower IC/TLC ratio, and a higher BODE index in patients with a DLCO <60% [58].
DLCO can decrease as a result of reduced alveolar volume (VA) post-lung resection, indicating that more precise measurement may be achievable by utilizing the DLCO/VA ratio [61]. The CO transfer coefficient (KCO) is determined by the ratio of hemoglobin-adjusted DLCO to VA [61]. KCO serves as an indicator of changes in functional lung volume and impediments to gas exchange across the alveolar-capillary membrane [61]. A decrease in KCO is typically linked to the destruction of lung parenchyma, SAD, and damage to the microvascular system [61].
A study by Shimizu et al. [62], assessed emphysema volumes (lung attenuation volume [%LAV]) and the percentage of cross-sectional area of small pulmonary vessels smaller than 5 mm (%CSA [<5]) via chest CT scans in non-smokers, smokers with asthma, and COPD patients. According to the study’s findings, %KCO demonstrated a stronger correlation with %LAV and %CSA than %DLCO [62]. Data from KOLD also indicated a lower FEV1/FVC% and a higher emphysema index at baseline for individuals who experienced the most rapid decline in KCO. This group exhibited an increased risk of acute exacerbations [18].
Unlike DLCO, the measurement of nitric oxide diffusing capacity (DLNO), which assesses the diffusion of nitric oxide (NO), does not depend on capillary blood volume [63,64]. Measurement of DLNO is more sensitive to changes in alveolar structure than DLCO, which is influenced by blood flow and anemia [64-66]. The barrier to CO uptake primarily occurs within the red blood cell (RBC), while the barrier to NO diffusion primarily exists between the alveolar membrane and the RBC membrane [67]. DLNO is minimally affected by variations in hemoglobin concentration [68] or oxygenation conditions [69] and serves as an indicator of the diffusing state of the alveolar membrane [70]. Research by van der Lee et al. [19] also found that KNO (DLNO/VA) displays greater sensitivity in diagnosing CT-based emphysema compared to KCO (DLCO/VA) and FEV1/FVC. However, because of technical challenges, DLNO’s clinical application has been restricted [64,71].
The nitrogen SBW test was briefly mentioned in the CC section. The phase III slope, or slope of the alveolar plateau (ΔN2), reflects changes in nitrogen concentration during the nitrogen SBW test. Normally in healthy individuals, this process is uniform, ensuring effective gas exchange [14,72]. In COPD patients, a rapid increase in nitrogen, or a higher ΔN2, signifies residual N2 in the lungs at the end of expiration, illustrating air trapping and uneven ventilation [73].
A study conducted by Mikamo et al. [74] reported significant correlations between ΔN2 and various lung function and structural parameters, including FVC (% predicted), resonant frequency, and emphysema score. Additionally, the Po River Delta epidemiological study, which involved an 8-year longitudinal follow-up, demonstrated a significant association between ΔN2 measured by the SBW test and the rate of FEV1 decline, as well as the risk of developing COPD as defined by the GOLD and ATS-ERS criteria [20]. Olofson et al. [75] reported that a steep N2 slope along with multiple respiratory symptoms, such as dyspnea and wheezing, effectively predicted hospital admissions and mortality in COPD patients.
Increased airway resistance is a key pathological component in COPD, and a major site for the development of heightened airway resistance is the small airways [44,76,77].. Technically, airway resistance (Raw) is calculated from the ratio of driving pressure to airflow rate, indicating the alveolar pressure required to achieve a flow rate of 1 L/sec [4]. Using WBP, Raw can be determined by dividing the specific resistance loops (sRaw), which represent the inverse slope of the flow versus box pressure plot, by the FRC measured by plethysmography (FRCpleth) during the occlusion maneuver [4]. In cases of hyperinflation with increased FRC, Raw registers as normal while sRaw is elevated, allowing discrimination from early obstructive lung disease, characterized by increases in both values [4,21].
Impulse oscillometry (IOS), a forced oscillation technique (FOT), represents a significant advancement in the measurement of airway resistance, aiming to overcome existing limitations [78]. IOS, a noninvasive technique, employs sound waves to evaluate respiratory mechanics (Figure 2) [79]. Using IOS eliminates the need for forced expiratory maneuvers and requires minimal patient cooperation, making it a suitable tool for as sessing lung function in populations such aspediatric and elderly patients, for whom traditional spirometry may not be feasible [22,80].
FOT provides detailed insights into the resistive properties of the lungs, such as changes in elastance and lung parenchyma structure. It offers estimations of the impedance of the respiratory system (Zrs), encompassing both resistance (Rrs) and reactance (Xrs) [81]. The principle of IOS involves delivering waves at a consistent and repetitive frequency through a loudspeaker during respiration. The analysis of resultant pressure and flow responses alongside resistance and reactance is achieved using Fourier transformation methods. These responses, reflecting both the forces ahead of the sound wave (resistance) and those produced in response to wave pressure (reactance), reveal the impedance of the entire respiratory system, enabling a passive evaluation of lung mechanics [5].
Several studies [22,80,82,83] have described the clinical utility of IOS in smokers and patients with COPD. One study involving asymptomatic smokers with normal spirometry detected a significant inverse relationship between the values of decreased resistance from 5 to 20 Hz (R5–R20) and the ratio of forced expiratory volume in 3 and 6 seconds (FEV3/FEV6) [22]. Another investigation involving subjects with chronic respiratory symptoms and preserved pulmonary function (PRISm) found that IOS parameters correlated better with symptom scores than spirometric data [23]. There was also a noted increase in R5, R5–R20, the integrated area of low-frequency reactance (AX), and resonance frequency (Fres) in subjects diagnosed with SAD. These findings suggest that IOS might be more sensitive than spirometry in detecting SAD in individuals with chronic respiratory symptoms and preserved pulmonary function; therefore, it could serve as an additional method to identify early-stage SAD [23]. The Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE) cohort study evaluated the efficacy of IOS in determining COPD severity [24], revealing that abnormalities in AX, R5, and emphysema grades detected by CT scans were more frequently observed in patients categorized as GOLD 2, 3, and 4 [24]. Another study indicated good agreement between values obtained from the FOT and spirometric data in COPD patients. Particularly, reactance (X) values showed high correlation with specific spirometric measures like FEV1, the forced mid-expiratory flow, and RV/TLC, which are markers of airflow obstruction, SAD, and air trapping. Using Fres and frequency dependence (FDep) allowed for the accurate diagnosis of severe COPD, and varying severities of air trapping could be stratified by X values [82].
The non-contact early airflow limitation screening system (EAFL-SS), an innovative non-contact screening tool that does not require individual calibration with a spirometer, employs an infrared ToF depth image sensor—a technology widely used in smartphones for applications like photography focusing (Figure 3). The 850 nm infrared ToF sensor, featuring 224×171 pixels, is coupled with custom-designed data processing algorithms to provide real-time, three-dimensional visualization of the anterior-thorax movements [25]. This method, fundamentally akin to photoplethysmography using a remote sensor, does not require separate calibration when adjusted for anthropometric data [84,85].
Calculation of FVCEAFL-SS is conducted using multiple linear regression analysis, utilizing ToF-derived anterior-thorax FVC, height, and body mass index as explanatory variables, with spirometer-derived FVC as the objective variable. The EAFL-SS system enables tracking of respiration during forced exhalation while in a stationary position, referencing a spirometer. Similar to diagnosing COPD, an FEV1EAFL-SS/FVCEAFL-SS ratio below 0.7 suggests airflow obstruction [25]. EAFL-SS demonstrates a sensitivity of 81% and a specificity of 90% in diagnosing COPD and correlates well with spirometric data. The system is user-friendly and universally applicable for initial diagnosis [25].
Since the 1970s, M-mode or two-dimensional mode has been employed to study diaphragmatic function for assessing changes in the diaphragm’s thickness during exhalation and deep inhalation. This method is valuable for measuring inspiratory thickening, providing insights into diaphragmatic function quality, and identifying diaphragmatic paralysis or diminished function [86,87].
Some studies have noted inconsistencies in diaphragmatic thickness and variations in the thickening fraction in COPD [88-90]. However, a decrease in diaphragmatic displacement during deep breathing, associated with air trapping and correlated with RV and the RV/TLC, has been observed in moderate to severe cases [90]. This reduction has also been linked to decreased exercise capacity, which typically improves post-rehabilitation [91].
Other studies have assessed the M-mode index of obstruction (MIO) using M-mode ultrasound to examine the right diaphragm during maximal expiratory effort. An MIO lower than 77, calculated as the ratio of maximum expiratory diaphragmatic excursion to the diaphragmatic excursion in the first second of expiration, is associated with obstructive lung disease [26].
The diagnostic potential of diaphragm ultrasonography (DUS) for distinguishing between acute exacerbations of COPD and stable conditions has been acknowledged. A study by An et al. [27] observed reduced thickening fraction and decreased diaphragm excursion in the COPD exacerbation group compared to the stable group. Another study found that approximately 24.3% (10 out of 41) of COPD patients with acute exacerbations exhibited diaphragmatic dysfunction, characterized by a change in diaphragmatic thickness of less than 20% during spontaneous respiration. This dysfunction was significantly associated with clinical failure of NIV, extended intensive care unit stays, pro-longed mechanical ventilation, and the need for tracheostomy [28].
Diaphragm sonography performed during PFT using a mouthpiece and nose clip has been reported to increase excursions, which may differ from the patient’s natural breathing pattern and should be interpreted with caution [86].
Respiratory muscle strength declines with age [92], a phenomenon also observed in individuals with COPD [93]. Nishimura and colleagues, in their study of 24 male COPD patients, found a significant positive correlation between respiratory muscle strength, as indicated by maximal inspiratory mouth pressure and maximal expiratory mouth pressure, and vital physical parameters such as lean body mass and body weight [94]. In another retrospective study by Kim et al. [29], the COPD group experiencing acute exacerbations exhibited statistically lower maximal inspiratory pressure (MIP) compared to the COPD group without exacerbations. Additionally, as the COPD stage progressed, the MIP values decreased [29].
In a study involving 61 COPD veterans, it was observed that sustained maximal inspiratory pressure (SMIP) correlated better with FEV1, IC, and the IC/TLC ratio than MIP. Moreover, the SMIP group with less than 427 pressure time units exhibited lower FEV1, higher RV, higher modified Medical Research Council Dyspnea Scale scores, higher Hospital Anxiety and Depression Scale depression scores, and a higher frequency of previous acute exacerbations [95].
Respiratory muscle strength, as measured by MIP, maximal expiratory pressure (MEP), and SMIP, not only shows a relationship with lung function and acute exacerbations in COPD patients but has also been shown to improve with rehabilitation therapy. In a study of 32 COPD patients, a home-based rehabilitation program led to improvements in MIP and MEP, as well as a reduction in the perception of dyspnea [96].
The traditional view of COPD as a single disease entity has evolved with the recognition of distinct subtypes and phenotypes within the broader spectrum of COPD. These subtypes may include SAD, emphysema, and overlapping conditions such as ACO. Key pathognomonic changes, including structural lung lesions like emphysema or SAD, and physiological changes such as declines in FEV1, air trapping, hyperinflation, and a decrease in lung diffusing capacity, are crucial for understanding the disease processes and tailoring treatment strategies for individual patients [2].
The concept of ‘multiple faces’ encompasses the systemic effects of COPD, including muscle dysfunction, systemic inflammation, and metabolic dysfunction, which contribute to the disease’s heterogeneity [97,98]. Moreover, the patient’s experience of living with COPD, which involves chronic breathlessness and the challenges encountered by patients and their caregivers, underscores the diverse and complex nature of the disease. Although beyond the scope of this article, we recognize the considerable potential for nutritional and morphotypic evaluations in the COPD context.
In conclusion, various diagnostic modalities such as infrared ToF depth image sensor, WBP, DLCO measurement, airway resistance assessment using body plethysmography, respiratory oscillometry, and DUS provide comprehensive insights into the diagnosis and evaluation of COPD patients. These techniques are valuable for early detection, quantifying airflow obstruction, distinguishing airway resistance, and assessing risk, thereby enhancing the understanding of disease presentations and optimizing patient management strategies. Ultimately, this leads to improved quality of life for individuals with COPD and paves the way for developing more effective treatments and interventions in the future.