Non specific pattern of lung function in a respiratory physiology unit: causes and prevalence: results of an observational cross-sectional and longitudinal study

An obstructive ventilatory defect is a disproportionate reduction in maximal airflow from the lung in relation to the maximal volume (i.e. vital capacity, VC) that can be displaced from the lung [1]. It is defined by a reduced Forced Expiratory Volume in 1 second (FEV₁)/VC ratio below the 5^th percentile of the predicted value. As stated by the ATS/ERS task force [1], “special attention must be paid when FEV₁ and forced VC (FVC) are concomitantly decreased and the FEV₁/FVC ratio is normal or almost normal […]. A possible cause of this pattern is patchy collapse of small airways early in exhalation. Under these conditions, total lung capacity (TLC) may be normal, but residual volume (RV) is ordinarily increased. ” This pattern has been named as small airways obstruction syndrome by Stanescu [2], and has initially been described in small series of adults with emphysema, small airways diseases, bronchial asthma [2] and also in asthmatic children [3]. Hyatt and colleagues identified more recently the medical conditions associated with this pattern from a database of lung function tests (LFT) results and medical records [4]. These authors showed that 68% of the patients were suffering from airway disease (including asthma, chronic obstructive pulmonary disease [COPD] and bronchiectasis), while the others suffered from restricted expansion of the thorax or the lung [4]. Consequently, they preferred to define this pattern as a non specific pattern (NSP).

The objective of our observational study using routinely collected data were to confirm the results of Hyatt and colleagues (main lung diseases associated with this syndrome), to further assess the prevalence of this syndrome in these diseases and to describe the follow-up of this NSP as done by the same research group [5]. These objectives have practical consequences for lung function testing units because if the prevalence of the syndrome is “significant” it is a plea for systematic absolute lung volume measurement when a reduction of FEV₁ with a normal FEV₁/FVC ratio is evidenced.

Reporting is in accordance with STROBE Statement (http://​www.​strobe-statement.​org/​). Unfortunately, the statements of the REporting of studies Conducted using Observational Routinely collected Data (RECORD, http://​www.​strobe-statement.​org/​) are not available.

In the presence of a normal TLC, a decrease in VC, and therefore of FEV₁, is the consequence of an increase in RV. Pathologic conditions associated with intrinsic and extrinsic obstruction of small airways, together with expiratory muscle weakness, will lead to an increased RV. Dynamic expiratory airflow obstruction could also produce an increase in RV and a decrease in FVC. However, measuring a slow VC instead of a forced one would avoid the rise in RV, which was not observed in our study. Consequently, the pattern of NSP may effectively be related to patchy collapse of small airways early in exhalation, and does not seem to be related to a bronchoconstrictor effect of deep inspiration [16] that would be associated with normal slow inspiratory vital capacity.

To our best knowledge, only one study evaluated the main lung diseases that are associated with this pattern [4]. In the retrospective study of Hyatt and colleagues, NSP was observed in 7702/80 929 subjects (9.5%), and a random sample of 100 patients allowed to define the medical conditions associated with this pattern [4]. The authors showed that 52 patients had some degree of airway responsiveness (positive response to bronchodilator or methacholine) including 26 asthmatics, 16 were suffering from chronic lung disease (including 11 with COPD and 3 with bronchiectasis), 7 were obese only and 25 were suffering from various conditions (prevalence ≤5% for each condition). Overall, in their study, obesity (BMI ≥ 30 kg/m²) was very prevalent (50 subjects equally distributed between the sexes) and they highlighted the association of NSP with obesity and hyperresponsiveness (31%). Obesity has also been associated with propensity of distal airway closure/hyperresponsiveness [17]. We similarly observed that asthmatic patients in our series were often obese, even if obesity prevalence was lower in our series (26%), which may further explain our lower prevalence of NSP. These authors emphasized that some patients had no evidence of airway disease. Restricted expansion of the thorax or lung may have explained the NSP in most of these subjects since the conditions were suggestive of restriction despite the low normal TLC. Interestingly, some of these conditions have also been associated with increased airway responsiveness [18, 19], which may have favoured the occurrence of this NSP.

Our design had both similarities and differences. Large databases were used in the two studies that used body plethysmography for absolute lung volumes measurements. We deliberately decided not to include all medical conditions associated with NSP (30 patients were excluded) because one objective was to provide confident prevalences of the functional pattern in the various medical conditions. The prevalence of NSP was thus described for seven conditions associated with the pattern, over 360 patients. Then we further selected 185 patients in order to describe the functional abnormalities and to evaluate whether the severity of the pattern varied among the seven conditions. To this end, we selected only Caucasian (to use only one set of predicted values) and non or light smokers in non COPD/emphysema conditions (to exclude overlapping conditions). In agreement with the study of Hyatt and colleagues, a moderate impairment was evidenced (FEV₁ 68 ± 9% predicted in their study) [4].

A large series of patients has been obtained with indisputable diagnoses and, besides lung diseases already associated with NSP [4], we further show that some conditions as interstitial pneumonia, pulmonary hypertension or bilateral lung transplantation are associated with low to moderate prevalence of the syndrome. Interestingly, in patients with bronchiolitis obliterans syndrome after allogeneic hematopoietic stem cell transplantation [20], Bergeron and colleagues identified two functional phenotypes: a typical obstructive lung defect and an atypical obstructive lung defect with a concomitant decrease in the FEV₁ and FVC with a normal total lung capacity (31% of the patients, 95% CI: 21 to 42%). Consequently, this latter prevalence is similar to ours, and one may hypothesize that this high prevalence is specifically related to obliterative bronchiolitis [21] rather than to biases related to the presence of lung size mismatching between donor and recipient, and/or inaccurate predicted values for donor lungs.

Before the more recent ATS/ERS Task Force recommendations [1], previous international guidelines did not formally classified this functional phenotype as an obstructive defect, as pointed out by Stanescu [2]. In patients with established airway diseases, as COPD or asthma, a reduction in FEV₁ would be regarded by most physicians as indicative of airway obstruction whatever the FVC value. On the other hand, when the diagnosis has not been established or in presence of a patient with pulmonary hypertension, a “restrictive” pattern observed after the sole spirometry may lead to misdiagnosis, accordingly with the low predictive value of spirometry for lung restriction [22]. Furthermore, measurement of absolute volumes by dilution technique may lead to misdiagnosis (restrictive pattern), as suggested by the reduction of alveolar volume as compared to TLC, which would lead to restrictive defect diagnosis in 85% of the patients (see Table 1).

Some authors prefer to label this pattern as non specific due to the normalcy of the FEV₁/VC ratio and of the TLC [4, 5]. Nevertheless, it has to be emphasized that small airway (bronchiolar) involvement is a characteristic or can occur in all these diseases. For instance in pulmonary hypertension, a mild obstructive pattern is well-described that can be associated with exercise-induced dynamic hyperinflation [23]. Small airway disease is also well demonstrated in interstitial pneumonias [24], suggesting a mixed defect when an additional restrictive defect occurs as observed in our study. The mild to moderate lung air trapping that was evidenced in our study together with an increase in airway resistance further suggest distal airway obstruction. Along this line we showed that both airway resistance and specific airway resistance can augment in the presence of peripheral airway obstruction [25, 26].

Finally, the observed prevalence of this syndrome in selected conditions may seem relatively high, but we previously demonstrated that isolated hyperinflation is not infrequent in asthmatic children (7-11%) [3]. Logically, due to this prevalence in common respiratory diseases, the overall prevalence in our LFT unit (6.6%) is in agreement with the results of Hyatt and colleagues (9.5%) and with those of Aaron and colleagues (15%, 95% CI: 13 to 17% patients with low FVC and normal absolute lung volumes) [22]. Unfortunately, the diagnoses associated with this specific functional pattern were not described in this latter study [22].

Our study has inherent limitations due to its design. Data extraction was based on the actual recording of NSP by the physician in charge of the LFT report made in the routine practice; consequently, the observed prevalences could have been underestimated. These prevalences are only indicative because some patients had several LFT that may have facilitated the detection of NSP, which can be a transient functional phenotype [5]. Reversibility of airway limitation was not systematically assessed because patients are tested while taking their usual respiratory treatment. Finally, our study was not designed to evaluate all lung diseases associated with NSP, since only concordant and indisputable diagnoses were retrieved for functional description. Whether NSP is associated with specific clinical phenotypes warrants further studies.

In conclusion, NSP can be observed in asthma, COPD/emphysema, bronchiectasis, sarcoidosis, interstitial pneumonias, pulmonary hypertension and after bilateral lung transplantation. Thus, the measurement of static lung volumes by body plethysmography can be helpful in presence of FEV₁ and FVC reduction, depending on previous measurements, lung imaging, and clinical judgment.