Abstract
The aim of the present study was to determine whether the combination of low forced expiratory volume in 1 s (FEV1)/vital capacity (VC) ratio with normal FEV1 represents a physiological variant or a sign of early airflow obstruction.
We studied 40 subjects presenting with low FEV1/VC, but FEV1 within the range of normality predicted by European Respiratory Society reference equations, and 10 healthy controls. All subjects completed two questionnaires and underwent comprehensive pulmonary function testing, which included methacholine challenge and single-breath nitrogen wash-out.
According to the questionnaires, the subjects were assigned to three groups, i.e. rhinitis (n = 8), bronchial asthma (n = 13) and chronic obstructive pulmonary disease (COPD; n = 12). Subjects with negative responses to questionnaires were assigned to an asymptomatic group (n = 7). Airway hyperresponsiveness was found in four subjects of the rhinitis group, all of the asthma group, and 10 of the COPD group; in the last two groups, it was associated with signs of increased airway closure and gas trapping. Bronchodilator response to salbutamol was positive in only a few individuals across groups. In the asymptomatic group, no significant functional changes were observed, possibly suggesting dysanaptic lung growth.
In subjects with low FEV1/VC and normal FEV1, questionnaires on respiratory symptoms together with additional pulmonary function tests may help to clarify the nature of this pattern of lung function.
- Atopic rhinitis
- bronchial asthma
- chronic obstructive pulmonary disease
- dysanaptic lung growth
- methacholine challenge
- single-breath nitrogen wash-out
The assumption that a decrease in forced expiratory volume in 1 s (FEV1) and its ratio to vital capacity (VC) below the fifth percentile of the predicted normal value indicates an obstructive pulmonary abnormality is a useful simple approach 1. However, in some individuals with VC normal or higher than normal, the FEV1/VC ratio may lie below the normal range while the FEV1 is still above the lower limit of normality 2–5. Whether this spirometric pattern represents a physiological variant, possibly due to dysanaptic lung growth 6–8, or an early sign of airflow obstruction, possibly due to increased airway resistance 9 or loss of elastic recoil 10, is unknown. As the treatment of obstructive pulmonary diseases is based on proper recognition of airflow obstruction 11, 12, the interpretation of this functional pattern is of practical relevance.
The present study was designed to investigate whether a careful assessment of respiratory symptoms, combined with tests sensitive to abnormalities of airway function, may help to interpret the pattern of low FEV1/VC ratio with normal FEV1. For this purpose, 40 subjects were studied who presented with an FEV1/VC ratio below and an FEV1 above their lower limits of normality according to the European Respiratory Society (ERS) predicting equations 13. Symptoms were assessed by questionnaires and lung function by additional tests, including measurement of lung volumes, single-breath diffusing capacity of the lung for carbon monoxide (DL,CO), bronchodilator response to salbutamol, methacholine (MCh) bronchial challenge and single-breath nitrogen wash-out (SBN2W-O).
MATERIALS AND METHODS
Subjects
Forty consecutive Caucasian subjects presenting with an FEV1/VC ratio below the lower limit of normality and FEV1 within the ERS predicted normal range 13 were recruited from 1,386 workers (1,136 males and 250 females, 76% white-collar workers) referred to the Unit of Preventive and Occupational Medicine of San Martino University Hospital (Genoa, Italy) to be spirometrically tested for pre-employment or surveillance purposes. Of the remaining subjects, 1,269 showed a normal spirometry, 72 an obstructive and five a restrictive abnormality confirmed by lung volume measurements. None of the 40 subjects suffered from known cardiopulmonary or systemic diseases. 10 healthy volunteers with both FEV1/VC and FEV1 within the normal range were recruited from the hospital staff to serve as control group. The study was approved by the institutional ethics committee of San Martino University Hospital and written informed consent was obtained prior to the study.
Study design
At the first visit, the selected subjects completed two questionnaires (see online supplementary material). One was administered by an occupational physician and focused on work-related air pollution 14 and habitual physical activity 15; the other was self-administered and focused on symptoms of atopic rhinitis, bronchial asthma 16, 17 and chronic obstructive pulmonary disease (COPD) 18. A total score was computed for each disease by grading symptoms according to their temporal frequency. Grading ranged from 0 to 30 for asthma, 0 to 6 for COPD and 0 to 9 for atopic rhinitis, with the higher numbers indicating higher frequency. Control subjects (with normal FEV1/VC ratio and FEV1) showed a total score equal to zero for all the three sections of the self-administered questionnaire. Subjects with a score ≤2 for all questionnaire sections were assigned to an asymptomatic group, subjects with a score ≥3 for asthma to an asthma group, smokers ≥20 pack-yrs and a score ≥3 for COPD to a COPD group, and subjects with scores ≥3 for rhinitis but <3 for asthma and COPD to a rhinitis group.
Absolute lung volumes and spirometry were measured before and after inhaling 400 μg of salbutamol through a valved-holding chamber 19. Approximately 1 week after the first visit, the subjects underwent a bronchial challenge with MCh.
Lung function measurements
Standard spirometry was obtained by a mass flowmeter (VIASYS-SensorMedics Inc., Yorba Linda, CA, USA) with numerical integration of the flow signal 19. DL,CO was measured (Vmax22D; VIASYS-SensorMedics Inc.) at least in duplicate 20.
Absolute lung volumes were measured by a transmural whole-body plethysmograph (V62J; VIASYS-SensorMedics Inc.) 21. Following thoracic gas volume measurement, the subjects resumed regular breathing and performed a forced expiration from ∼70% forced vital capcity (FVC; partial expiratory manoeuvre). Soon after and without disconnecting from the circuit, they took a fast deep breath to total lung capacity (TLC) and, without hesitation, performed a maximal forced expiratory manoeuvre of ≥6 s until a flat volume-time plateau was achieved (maximal expiratory manoeuvre) 22, 23. Then, without coming off the mouthpiece, they resumed tidal breathing and performed a slow inspiratory VC (IVC) manoeuvre. From this set of manoeuvres functional residual capacity, TLC, residual volume (RV), and maximal (V′max) and partial (V′part) forced expiratory flows at 40% control FVC were measured (fig. 1⇓) 24. The reported value of FEV1/VC is the one calculated by using the largest of the technically acceptable IVCs or FVCs 19.
Representative tidal, partial and maximal flow–volume curves at baseline in a subject with low forced expiratory volume in 1 s (FEV1)/vital capacity ratio and normal FEV1. ------: 40% forced vital capacity indicating the point where instantaneous maximal and partial expiratory flows were measured.
An SBN2W-O test 25 was performed by using a Vmax22D (VIASYS-SensorMedics Inc.). After at least four regular breaths, the subjects were asked to fully expire to RV and then to take an IVC of 100% oxygen. This was followed, without breath-hold, by a full expiration to RV at a rate of 0.30–0.50 L·s−1. Expiratory nitrogen concentration was plotted against VC and the slope of nitrogen alveolar plateau (phase III) calculated by drawing the best-fit line. The first departure from this straight line exceeding cardiogenic oscillations was taken as the onset of phase IV. The open capacity (OC) was calculated as the difference between TLC and the volume at which phase IV (closing capacity) began 26. The slope of phase III and OC were measured at least in triplicate, and the mean value retained for analysis. The results were expressed as % predicted (% pred) 25.
MCh challenge
Aerosols of MCh chloride solutions (0.2%, 1% and 6%) were delivered via a DeVilbiss 646 nebuliser attached to a KoKo (Rosenthal–French) breath-activated dosimeter (Ferraris, Louisville, CO, USA). Aerosols were inhaled during quiet tidal breathing in the sitting position 27. Increasing doses of MCh from 40 to 4,800 μg were inhaled until a decrease of FEV1 ≥20% from control was achieved. FVC, FEV1, V′max and V′part were measured only once at each step to avoid the effects of full lung inflation on airway calibre. The provocative dose of MCh causing an FEV1 decrease of 20% (PD20) was determined by interpolating between two adjacent points of the log dose–response curve. If the FEV1 decrease was <20% of control, the last dose (4,800 μg) was retained as PD20. The extent of gas trapping during induced bronchoconstriction was estimated from slope and y-intercept of the simple regression analysis of all FVC values plotted against the corresponding FEV1 values 28, 29. The effects of deep inspiration (DI) during constriction were estimated by the slope and y-intercept of simple regression analysis of V′max values plotted against the corresponding V′part values 23. As opposed to the V′max/V′part ratio, the regression of V′max versus V′part is independent of thoracic gas compression volume 30.
Statistical analysis
PD20 values were log-transformed before analysis. Data are presented as mean±sd. A generalised linear model was used for comparisons of the data between the 40 subjects with a low FEV1/VC ratio and normal FEV1 and controls.
A mixed between-within-groups ANOVA with Duncan's post hoc comparisons was used to assess the significance of differences between categories of subjects with abnormally low FEV1/VC and controls. Chi-squared and Fisher's exact test were used in the analysis of categorical data. Values of p<0.05 were considered statistically significant.
RESULTS
Baseline condition
The main anthropometric and life-style parameters were not significantly different between the whole group (n = 40) with a low FEV1/VC ratio and normal FEV1, and the control group. In the former, the % pred FEV1 and DL,CO were slightly less than in controls (98±11% versus 113±9%, p<0.001; and 105±19% versus 118±11%, p = 0.048, respectively).
Based on questionnaires, only seven subjects with a low FEV1/VC ratio and normal FEV1 did not reach the pre-set minimum threshold of symptoms score to be considered abnormal and were included in the asymptomatic group (table 1⇓). Of the remaining 33 subjects, eight were assigned to the rhinitis group, 12 to the bronchial asthma group and 13 to the COPD group. Of the 13 subjects assigned to the COPD group, 12 had also a score of 3 for asthma, but the COPD score was prevalent. Four subjects from the asthma group and five subjects of the COPD group also had positive rhinitis scores.
Main anthropometric, life-style parameters and symptoms of the groups of subjects
Anthropometric characteristics, life-style habits, work-related airborne irritants, or aerobic physical activity were similar between groups. The FEV1 % pred was slightly, though significantly, less (ranging from 102±7% to 97±12%, p = 0.006) than in the control group (113±9%), while all other spirometric parameters were not significantly different (p = 0.61 and p = 0.81 for IVC and FVC % pred, respectively; table 2⇓). The RV/TLC ratio in COPD group was slightly, but significantly, higher (0.34±0.06, p<0.001) than in any other group. The slope of phase III was significantly (p = 0.001) higher (207±97%) in COPD than in other groups, whereas OC was less in both asthma and COPD (94±8 and 90±8%, respectively, p = 0.011), thus suggesting a greater tendency for airway closure (fig. 2⇓).
Slope of a) phase III and b) open capacity (OC) as % predicted (% pred) of the single-breath nitrogen wash-out. Asymp: asymptomatic; COPD: chronic obstructive pulmonary disease. #: p = 0.011 versus rhinitis; ¶: p = 0.011 versus control, asymptomatic and rhinitis; ***: p = 0.001 versus all other groups.
Main spirometric and volumetric data of the five groups of subjects
Bronchodilator response
On average, the FEV1, IVC, FVC and lung volumes remained unchanged after inhaling salbutamol in all groups. Exceptions were observed in one subject of the control and asymptomatic groups, two of the asthma group, and three of the COPD group, in whom the FEV1 increased by >12% and 200 mL of baseline. Interestingly, the FEV1/VC ratio was normalised after salbutamol in four subjects from each of rhinitis, asthma and COPD groups, and in two of the asymptomatic group. Post-bronchodilator changes in V′max were not significantly different among groups (p = 0.91), whereas V′part % showed a tendency (p = 0.070) to increase more after salbutamol in rhinitis (56±29%) and asthma (64±52%) groups of subjects as compared with those in the COPD group (30±41%).
MCh challenge
At the second visit, the FEV1/VC at presentation was still below the normal range in all subjects, thus confirming the repeatability of the parameter. All subjects of the asthma group had a cumulative PD20 <800 μg (range 31–300 μg) consistent with airway hyperresponsiveness (fig. 3⇓). This was also observed in four subjects with rhinitis and 10 with COPD. In the latter, the slope of FVC versus FEV1 was significantly >1 (p = 0.048) and steeper (1.24±0.40, p = 0.002) than in any other groups (fig. 4⇓), suggesting that all of the fall in FEV1 was due to the decrease in FVC, i.e. to trapping of air. Moreover, the y-intercept was lower (1.19±0.82, p = 0.013) than in asymptomatic and rhinitis groups. Similarly, the y-intercept of V′max versus V′part in COPD was lower (0.28±0.14, p = 0.006) than in the control and rhinitis groups, suggesting a reduced bronchodilator effect of DI.
Mean±sd of log-transformed dose of methacholine causing a 20% decrease of forced expiratory volume in 1 s (MCh PD20). COPD: chronic obstructive pulmonary disease. ***: p<0.001 versus all other groups.
Mean linear regression analysis of a) absolute values (L) of forced vital capacity (FVC) versus forced expiratory volume in 1 s (FEV1) and b) of instantaneous maximal (V′max) and partial (V′part) flows (L·s−1) at 40% of control FVC at each step of methacholine challenge in the five groups. By regressing FVC against FEV1 values, an increase of slope or a decrease of y-intercept suggests enhanced gas trapping and vice versa. Similarly, an increase of slope or a decrease of y-intercept of V′max versus V′part values suggests a reduced bronchodilator effect of deep inspiration. ▪: control; ▵: asymptomatic; ⨐: rhinitis; ○: asthma; □: chronic obstructive pulmonary disease. -----: line of identity. See text for statistical differences among groups.
DISCUSSION
The present study was conceived to investigate whether a low FEV1/VC ratio with an FEV1 within the predicted normal range may represent a physiological variant or an early sign of obstructive abnormalities. Our findings suggest that routine lung function tests are of little help to resolve this issue. In contrast, in most (33 out of 40) of these individuals, the use of clinical questionnaires of symptoms with additional tests of airway mechanics, such as bronchodilator and bronchoconstrictor responses and SBN2W-O, revealed abnormalities consistent with early airflow obstruction. In the remaining few subjects (seven out of 40), who were classified as asymptomatic by respiratory questionnaires, the results of additional lung function tests were within normal ranges and indistinguishable from those of the control group, except for a borderline airway hyperresponsiveness to MCh in one subject with a symptoms score of zero.
In agreement with current guidelines 11, 12, an obstructive respiratory disease is diagnosed when symptoms are confirmed by appropriate functional tests. If, in theory, such a statement is sound and represents the basis of our daily clinical practice, things may be not so straightforward when the disease is at its initial stage and/or the functional tests show borderline values. This is exactly the case in our study. In an attempt to shed light on this problem, we combined the results of clinical questionnaires with additional pulmonary function tests.
As for the choice of the functional tests, we used lung volumes, DL,CO, and the response to the bronchodilator and bronchoconstrictor agents. The latter was slightly modified to examine the response of the airways to DI, as repeatedly reported in bronchial asthma 31, 32 and COPD 22, 23, 33. We also included the SBN2W-O by virtue of its high sensitivity to detect inhomogeneous distribution of ventilation 34.
The DL,CO measurements did not reveal any significant differences between groups with low FEV1/VC ratio. The MCh challenge documented the presence of airway hyperresponsiveness in all subjects with a history of bronchospasm, thus confirming the results of the questionnaire. Surprisingly, however, we did not see significantly different responses to the DI in these asthmatics, as previously reported 31, 32. In an attempt to explain such an unexpected finding, we postulate that at the transition from health to disease, and with normal or near normal lung function, the bronchodilator effect of DI may still be preserved 31, 32. In COPD, we observed a high rate of airway hyperresponsiveness and evidence of increased airway closure with gas trapping both at rest (increased RV/TLC and decreased OC) and after exposure to MCh (increased slope and decreased y-intercept of the FVC versus FEV1 regression), as well as signs of impaired bronchodilation either with salbutamol (low ΔFEV1 and ΔV′part as % of control) or DI during the bronchial challenge (reduced y-intercept of the V′max versus V′part regression). With the assumption that these subjects were properly assigned to the COPD group, our findings would suggest that increased airway closure with gas trapping and impaired response to large inflation or bronchodilator agents are already part of the early stages of the disease 22, 23.
Finally, we observed an increase in airway responsiveness in about half of the rhinitis group with no other functional alterations. This is consistent with the early stages of asthma being associated with an increased response to a constrictor agent without necessarily causing respiratory symptoms 35.
No abnormalities were observed in functional tests in the group with a low FEV1/VC ratio but normal FEV1 and without any history of respiratory diseases or symptoms, except for one subject in whom the response to MCh and salbutamol was slightly abnormal. If our examination reasonably excludes the presence of early obstructive lung diseases in these subjects, it does not help to explain the pattern observed. For instance, we could not see any differences between the control group for sex, age, height, body mass index, occupation and exercise activity. The pattern may have been caused by an asynchronous development of airways and air spaces during the early stages of life, as previously described as dysanaptic lung growth 6–8. That is, in some individuals, during growth, the lung parenchyma could increase disproportionately to the airways as a result of various natural events or disease conditions occurring before definite maturation of the respiratory system.
As for the rhinitics with increased airway responsiveness, the functional pattern could have been caused by an imbalance between increased force generation capacity of the airway smooth muscle 35 and basal membrane thickness as a result of persistent allergen exposure 36. Even though this is likely to be part of a remodelling process, there is no evidence suggesting that this might be a risk factor for exaggerated lung function decline. As for the rhinitics with normal response to MCh, the pattern could have been due to the same mechanisms discussed for the asymptomatic subjects. In fact, six out of eight subjects of rhinitis group may have been undergoing an excessive exercise-induced stress or strain imposed on the alveolar septa during growth 37.
The clinical interpretation of the reduced FEV1/VC ratio and normal FEV1 in the asthma and COPD subjects appears to be more complicated. Under these conditions, the possibility exists that the decrease in FEV1 was a sign of accelerated decline in lung function in subjects with initial spirometric values higher than normal. In smokers, Corbin et al. 10 found a significant increase in TLC and VC due to loss of lung elastic recoil, while FEV1 only tended to decrease, thus resulting in a decrease in FEV1/VC preceding the decrease of FEV1. In the absence of pressure–volume measurements, we can only speculate that this mechanism might have contributed to our findings in the COPD group.
We recognise that our study has some limitations. First, we used the predicting equations published by the European Respiratory Society 13, 38, mainly because they are still the most frequently used in Europe 1. The values of VC and FEV1 obtained in our control group were mostly >100% pred, suggest<2?show=[to]?>ing that the predicted values were somehow underestimated. Supposedly, the use of different reference equations might have resulted in an FEV1 falling below normal range in some of our subjects, thus leading to a diagnosis of airflow obstruction without qualification. When predicted values were recalculated using predicting equations recently derived from a large Caucasian-American population 39 and a local population of northern Italy 40, only one subject from the COPD group had an FEV1 slightly below the lower limits of normality (9 and 6%, respectively). Exclusion of this subject did not abolish the significance of differences between groups. Secondly, we used questionnaires that had already been validated 14–18, but a cut-off of more than two for positive responses was arbitrarily chosen. This was done to seek for high specificity, but could have resulted in a low sensitivity. However, only one subject assigned to the asymptomatic group had a symptom score for asthma of two, but the disease was reasonably excluded by a lack of response to MCh. Thirdly, there were overlaps of either symptoms or lung function, particularly between the asthma and COPD groups, but this does not invalidate the conclusion that the low FEV1/VC ratio in these subjects may be a marker of airflow obstruction, despite FEV1 still being normal.
In summary, in subjects with a reduction of FEV1/VC as the only spirometric abnormality, lung volume measurement, reversibility or challenge tests, SBN2W-O and appropriate questionnaires may help to assist in detecting an early obstructive abnormality. In the case of positive history for bronchial asthma and significant responses to bronchodilator and/or bronchoconstrictor agents or in heavy smokers with signs of airway closure either at baseline or after induced bronchoconstriction, the pattern is highly suggestive of airflow obstruction. By contrast, in subjects with rhinitis or no respiratory symptoms, and normal or slightly increased bronchodilator or bronchoconstrictor responses, the pattern is presumably due to either initial airway remodelling or dysanaptic lung growth.
Statement of interest
A statement of interest for V. Brusasco can be found at www.erj.ersjournals.com/misc/statements.dtl
Footnotes
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This article has supplementary material accessible from www.erj.ersjournals.com
- Received December 3, 2008.
- Accepted January 19, 2009.
- © ERS Journals Ltd
References
