Introduction
In respiratory medicine one of the main points, other than clinical manifestations, is the lung pathophysiology. The lung is one of the more interesting organs that present a complex interaction between structures and function (anatomy and biophysics). Normally in clinical practice the evaluation of lung pathophysiology follow a functional and mechanic evaluation primarily through spirometry and plethysmography. The Small Airways (SAW) are one of the more important target for respiratory diseases and various studied underline their strict relations with chronic diseases like asthma or COPD, although it is nowadays recognized their role in a lot of other pathological entities [1]. SAW are defined as the peripheral airways having an internal diameter of less than 2 mm without cartilage [2]. The obstruction of the peripheral airways has proven to have little effect on the mechanical properties of the lung, though it has a guiding role in the ventilation distribution of the inhaled gases [3-5]. As because of the difficulty of reaching such a site, different and numerous techniques were developed in order to assess in vivo SAW physiopathological properties and to evaluate their changes in disease in a non-invasive manner, thus bringing light to the so called “silent zone” [1]. Next to the wellknown body-plethismography and Forced Oscillation Technique (FOT), other methods, like the nitrogen washout test, were lately re-descovered and re-interpreted, while new ones, like the Impulse Oscillometry (IOS), have been developed, gaining more approval in the respiratory pathophysiological landscape (Table 1). Is already clear, that until now there is no test that presents a widely accepted cut-off value that can be used to measure and assess the severity of small airways alterations and also there isn’t a test that represents the gold standard for clinical and experimental use. The objective of this review is to perform an overview of the actual major methods used to evaluate the SAW function and relative modifications in order to refresh the large instrumental options that pulmonologist have for their clinical and scientific use.
Table 1: Main tests to evaluate lung function.
Static and dynamic lung volumes
It is largely known that isolated SAW alterations haven’t measurable effect on the pressurevolume curve in experimental specimens [4] due to collateral alveolar ventilation [3] and that the peripheral airways have a marginal role in the total amount of pulmonary resistances [6], as it has been estimated that the obstruction of 75% of all SAW is required before an alterations can be identified by routine pulmonary functional tests [7].
Despite that, because of their physopathological characteristics, SAW represent the major site of airflow limitation [6] and of inhomogeneous ventilation distribution [3].
The + sign identifies the level of positive characteristics while – sign identify the level of negative characteristics. Three + represent the maximum level and one + the minimum, the same applies to -. Our score is a priority score; created by the authors during the drafting of the paper, and related only to real life applicability of reported tests /methodic.
Among the 31 different forced expiratory variables that can be measured from the Maximal Expiratory Flow Volume maneuver, the Forced Expiratory Flow between 75% and 25% (FEF25-75) of Vital Capacity (VC) and the forced expiratory flow at 50% of VC (FEF50) are considered the most sensitive in detecting SAW abnormalities [8,9]. Their measurement reflects the most effort independent portion of the flow-volume curve [7], and a close agreement between the two parameters should be evidenced in the case of monotonous emptying of the lung with a single time constant [10]. As reported by Bar-Yishay et al., patients with peripheral obstruction haven’t a linear relationship between flow and volume, thus implicating the presence of more than one time constant in order to describe the emptying of different zones of the lung [11]. The authors thus claim the independence of the FEF25- 75 and FEF50 from the peripheral airway obstruction and the lack of correlation with severity disease, putting the two parameters almost at the same level and indicating the preference towards the FEF50 because of it’s direct determination [11], while FEF25-75 appears to be more curve shape-dependent.
FEF25-75 is in fact calculated considering the 75% and 25% points of the Forced Vital Capacity (FVC) on flowvolume curve, thus being directly dependent on FVC and presenting great variability in case of air trapping and bronchodilation [12]. The lower limit of normality for FEF25-75 is considered to be the 60% of predicted value [13]. FVC in turn results a poor indicator of air trapping and appears to be underestimated in case of Total Lung Capacity (TLC) increase for a given increase of Residual Volume (RV). Taking in account the considerations made, modifications from normality of FEF25-75 should be considered and interpreted with caution as a reflection of SAW impairment, both due to its intrinsic variability and dependence on other spirometricvolumes. Cohen J et colleagues observed a significant reduction of the FVC/SVC (slow vital capacity) ratio independently of FEV1 (forced expiratory volume in 1 second) in patients with bronchiolitis obliterans that underwent lung transplantation suggesting the FVC/SVC as a parameter for detecting small airways obstruction [14]. A similar founding has been reported in subjects with eosinophilic versus non-eosinophilicsevere asthma [15].
The RV, obtained by body plethysmography through the modifications of mouth and airthight cabin pressure, appears to be elevated in case of premature airway closure and air trapping. It can be obtained through an easy-to-perform test, with a good reproducibility and low intra-patient variability [16]. Easy-to-perform has been referred to a real life and correlated to the possibility to have a good interaction between Doctor and Patients with a good result of the well done functional test. An elevation of RV/TLC ratio is considered the best measure of RV elevation and the first step of hyperinflation [12]. Stanescu in the past years described a new plethysmographic pattern characterized by a decrease in SVC and FEV1 , an increase in RV and RV/TLC and normal TLC and FEV1 /FVC [17].
This pattern has been proposed as an early detection of small airways disease. This alteration has been observed in the early stages of emphysema, elderly people and asymptomatic asthma [17]. Specific Airway Resistances (sRAW), also obtained by whole body-plethismography, appear not to be specifically related to SAW abnormalities [18]. The evaluation of static lung volumes as residual volume and total lung capacity permits only a quantitative characterization of hyperinflation and air trapping, without allowing a aren’t able to detect minor changes and defects in distal airways conductance and ventilation pattern, permitting only a general volumetric characterization of air trapping [12]. Recently has been published that also in clinical practice, with all the well-known limitations, the sRAW utilization could be an interesting methods to evaluate the bronchodilatory effect in COPD subjects [19].
Forced Oscillation Technique (FOT) and Impulse Oscillometry (IOS)
The Forced Oscillation Technique (FOT) and the Impulse Oscillometry (IOS) are two non-invasive versatile tests that imply little patient collaboration and represent one of most important current research lines in lung physiopathology. FOT, firstly studied by DuBois et al. in 1956 [20], measures the impedance of the respiratory system to forced pressure oscillations produced by a loudspeaker. The impedance includes in itself two parameters: Resistance (Rrs) and Reactance (Xrs).
Rrs is related to airway caliber, Xrs depends on the distributed inertance and stiffness of the respiratory system [21]. To derive its measures FOT uses the super-imposition of pressure fluctuations on the airway during subject’s tidal breathing [22]. Goldman et al. confirmed the hypothesis that Rrs at frequencies higher that than resonance reflects large airway mechanical properties, while that at frequencies below resonance reflects the added influence of SAW. So it appears simple to study peripheral airway effects by comparing low and high frequency resistance [23]. Low frequency reactance appeared to be a useful and sensitive index of peripheral airway function; in fact it has been seen to increase and decrease in according to clinical symptoms in asthmatic patients that used respectively less or more inhaled corticosteroids [23].
The functioning principle of IOS is similar to FOT, as it derives directly from it and delivers a regular square wave of pressure 5 times per second emitting a continuous spectrum of frequencies that allows the determination of the mechanical behavior of respiratory system [12,23,24]. The advantages of IOS include good time resolution and continuous resolution in the frequency domain because the calculation is based on the Fourier integral rather than a Fourier series [25,26].
The so-called frequency dependence, an increase of Rrs at lower frequencies (<10-15 Hz), has been demonstrated in various obstructive lung disease like asthma, as related to obstruction at SAW level [23,27,28]. The decrease of Xrs at 5 Hz during expiration, found during FOT evaluation of flow limitation in COPD [29], as described by Claverley and Koulouris, has allowedto differentiate between asthma and COPD [30]. An increase of Rrs at low frequencies has also been found to be strictly related to FEF25-75 in young asthmatics [31]. Takeda et al. reported that clinical symptoms and asthma control in asthmatics were strongly related with the parameters obtained by IOS [32]. Peripheral and proximal airway functions independently appear to contribute to health status, dyspnoea and disease control [32]. IOS results to be also a sensitive screening tool for the early detection of bronchial obstruction [33].
Oppenheimer et al., comparing the IOS technique with the dynamic compliance, observed that IOS can provide a non-invasive tool for assessment of distal airway function when spirometry is normal, which can be applied to various clinical settings including early diagnosis of COPD, asthma in clinical remission and occupational/ environmental irritant exposure [34].
There is no question that FOT and IOS keep the advantage on spirometry because of the ease with which these test can be performed , required little or no cooperation at all from the patients. This latter characteristic makes them feasible in pediatric environment too, were it has been demonstrated that with some technical refinements, the FOT measurement can reach the repeatability comparable to that of spirometry [21]. Moreover the amplitude of the oscillation do not alter the mechanical properties of the respiratory system, thus making this technique ideal in monitoring bronchoactive responses. The main weakness remains the inability to distinguish between obstructive and restrictive pattern [35].
Multiple and single breath nitrogen washout test
As deducted from previous studies, the SAW obstruction doesn’t play a great role in lung mechanics modifications, while, on the other side, it effects the distribution of inspired gases if there is collateral ventilation like in the human respiratory system [3,36]. In order to assess the presence of distal ventilation inhomogeneity, in the 60’s the Single Breath Nitrogen Washout Test (SBNW) was rediscovered and developed. It was firstly described by Fowler in 1949 [37], but largely ignored until Dolfuss et al. in ’67 used it to measure the Closing Volume (CV) [38]. The record originated is made by a first steep increase of N2 due to anatomical dead space of upper airways, than a plateau is reached reflecting the emptying of conductive and medium size airways (phase III) [38]. A final steep increase in N2 concentration (phase IV) that normally occurs at the 25% of VC represents the CV, the lung volume that reflects the complete occlusion of the gravity dependent small airways.
The CV is usually present near RV, being normal at about the 25% of VC. Although it has been seen a significant variation with age [39]. The SBNW represents a simple and sensible technique [40] to detect early closure of peripheral airwaysand while previously affected by poor reproducibility and predictivity [41], it is nowadays used in a lot of studies. The variability of CV can be ascribed to the incomplete filling or emptying of the lungs, the phase IV being influenced by expiratory flow and phase III by inspiratory flow [42,43]. In the last years the SBNW was used as a marker of airways dysfunction related to asthma severity [44] and to poor asthma control [45]. In the latter case Bourdin A and his colleagues found a relation between poor asthma control and an increase in CV and phase III slope [45]. Moreover J.C. In’t Veen et al. reported an increase of CV in severe asthmatics with frequent exacerbations and a relation between CV and RV/TLC ratio increase when compared to severe asthmatics patients with well-controlled disease [46].
When the RV is summed to CV, Closing Capacity (CC) is obtained. It is always referred as the percentage of TLC (CC/TLC%). In COPD subjects the increase of CC and phase III slope correlates with airflow limitation [47]. However Timmins et al. proved that in COPD patients, the modest changes in SAW mechanics that occur after an ICS/LABA (Inhaled Corticosteroids/ Long Acting Beta2 Agonists) combination therapy were detected by FOT technique and not by SBWT [48].
Moreover CC/TLC appears to be less reproducible when compared to FEV1 [49]. Recently, it was described a new way of assessing small airways alterations in a non-invasive way using the principles of Cosio et al. [7,50]: The Multiple Breath Nitrogen Wash-Out Test (MBWT). With respect to SBWT, MBWT has several major advantages as it is hardly affected by gravity [51], and it is not affected by airway closure below functional residual capacity, that is known to affect SBWT phase III [52].
Moreover it is capable of distinguishing the origin of ventilation heterogeneity, and so the implication of small airways. In fact in this case two different variables are detected, the Scond (index of conductive ventilation heterogeneity) and Sacin (index of acinar ventilation heterogeneity) [53,54]. It is important although to consider that age can play a role in the variability of detection of SAW abnormalities in lung diseases [55]. Both Sacin and Scond have been observed to increase in smokers and COPD patients [56], while a reversibility of Scond in relation to small airways was seen after smoking cessation in smokers without COPD [57]. In asthma, MBWT has been employed in airway challenging [58], and it showed a good relation in detecting SAW abnormalities independently of airway inflammation measured by Fractional Exhaled Nitric Oxide (FeNO) [59].
Due to the lack of the technique diffusion, nowadays is missing an international consensus standard of interpretation of SBWT and MBWT. However these non-invasive tests are capable of offering a reliable picture of small airways conditions both in asthma and COPD. The ability of interpretation of their numerous signals, next to other recent non-invasive techniques, has to bring novel insights in small airways pathophysiology.
Static/dynamic lung compliance and esophageal balloon
The esophageal balloon is perhaps at the same time the most invasive and most intriguing respiratory physiopathological technique of lung mechanics assessment. It represents still nowadays the gold standard for the measurement of transpulmonary pressure and permits the evaluation, when coupled with a pneumotacograph (flow and volume registration), of dynamic and static compliance. This test has been used principally for scientific scope and in intensive care unit as clinical test too. The pulmonary compliance is the result of the ratio between lung volume change and change in transpulmonary pressure (C=∆V/∆P) [60]. The esophageal balloon consists of a catheter linked to a pressure sampling equipment on one side, and the other extremity is represented by a soft balloon of 5-6 cm of length with a pressure transducer inside. The Pressure-Volume curve (PV curve) that is obtained is called “semi-static” because the test, when performed in conscious subjects, implies a minimal quote of muscle activity. The proper static PV curve is nowadays obtained only in emergency rooms and in invasively ventilated patients. It is not therefore a test that can be used in the everyday clinical practice.
It is known that the ratio between dynamic and static compliance decreases even in normal subjects when the breathing frequency exceeds 60/min. When small airway disease is present, both the dynamic compliance alone and the ratio are heavily reduced. This event is due to different time constants that characterize the uneven deflation of different lung zones, each with different and increased resistances. This ventilation heterogeneity increases more when breathing pattern changes [37,61,62]. A reduction in dynamic compliance is seen even when other lung functional parameters are in normal range [12]. The retractive pulmonary forces have been always studied by measuring the grade of the PV curve during tidal breathing. The S shape of the PV curve is due to the mechanical phenomena occurring at volumes close to RV and TLC. At low lung volumes this circumstance is thought to be related either to gas trapping secondary to the collapse of small airways [63] or to the balloon deformation by the mediastinal mass [64]. A closure of peripheral airways must be necessarily reflected by a modification in PV curve so the morphology of the curve at low lung volumes will not be influenced by artifacts but also by a closure of distal airways. Glaiser et al. confirmed that hypothesis in 1973 experimenting on animal models. Interestingly, the point at which the PV curve was leaving from the ideal exponential shape corresponded to the closing volume assessed with the 133Xenon washout [65].
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