FVC to Slow Inspiratory Vital Capacity Ratio* A Potential Marker for Small Airways Obstruction

Original Research PSYCHOLOGICAL TESTING FVC to Slow Inspiratory Vital Capacity Ratio* A Potential Marker for Small Airways Obstruction Judith Cohen, MD; Dirkje S. Postma, MD, PhD; Karin Vink-Klooster; Wim van der Bij, MD, PhD; Erik Verschuuren, MD, PhD; Nick H. T. ten Hacken, MD, PhD; Gerard H. Koëter, MD, PhD; and W. Rob Douma, MD, PhD Background: The ratio of FVC to slow inspiratory vital capacity (SVC) has been reported to reflect small airways obstruction, but its validity as such is still unclear. The aim of this study was to assess the applicability of the FVC/SVC ratio as a marker of small airways function in patients with bronchiolitis obliterans syndrome (BOS) after lung transplantation (LTX), which is a disorder in which predominantly small airways obstruction causes progressive airflow limitation. Methods: The FVC/SVC ratio was analyzed both cross-sectionally and longitudinally in 39 patients (26 men) with BOS after bilateral LTX (median age, 47 years; interquartile range [IQR], 35 to 54 years), and 36 bilateral lung transplant recipients without BOS (14 men; median age, 46 years; IQR, 41 to 53 years). Results: The FVC/SVC ratio decreased significantly during follow-up in patients with BOS stages 1 and 2, by 2.2% and 4.4%, respectively, from baseline (p < 0.001). This decrease was not significantly associated with the decrease in FEV 1. The FVC/SVC ratio increased, though not significantly, in the group in which BOS did not develop by 1.1%, which is a significant difference from the average fall of 4.4% in the group in which BOS developed. Conclusions: Significant, yet small decreases in FVC/SVC ratio occur in patients in whom BOS develops, independent from changes in FEV 1. At a group level, FVC/SVC ratio is able to detect small airways changes. These results merit prospective studies to determine the sensitivity of FVC/SVC ratio to quantifying small airways dysfunction at an individual level and in other airway diseases. (CHEST 2007; 132:1198 1203) Key words: FVC; inspiratory vital capacity; small airways obstruction; spirometry Abbreviations: BOS bronchiolitis obliterans syndrome; FEF 25 75% forced expiratory flow between 25% and 75% of FVC; IQR interquartile range; LTX lung transplantation; SVC slow inspiratory vital capacity Over the last decade, there has been a renewed and increasing interest in the role of small airways in pulmonary disease. The so-called small airways (ie, those 2 mm in internal diameter) are not only affected in classic small airways diseases such as bronchiolitis obliterans, but are also important locations of inflammation in obstructive airways diseases such as asthma and COPD. 1 This understanding has led to the search for valid parameters that can identify, quantify, and evaluate small airways pathology. Small airways are a relatively inaccessible and therefore difficult area to investigate. Transbronchial biopsies and CT scans are being used as tools to assess small airways pathology. However, they are relatively invasive, burdening, and costly procedures; thus, noninvasive methods that can easily be repeated for follow-up reflecting small airways function are to be preferred. Pulmonary function testing via spirometry is such a method. FVC and slow inspiratory vital capacity (SVC) are parameters that may contain important information on the functioning of small airways. Factors that may limit the magnitude of FVC and SVC, as measured in an individual, are alveolar collapse, airway closure and elastic recoil of the chest wall, which diminishes with aging. 2 In asthma pa- 1198 Original Research

tients, it has been described that the difference between FVC and SVC is greater than in healthy control subjects and can be used as an index of small airways collapse. This difference increases when more airway obstruction is present and the disease is more severe. 2,3 Not only the difference between FVC and SVC but also the ratio between the two parameters has been applied in research as an indicator of small airways collapse and air trapping. 4,5 However, FVC/SVC ratio has not been fully validated so far. The few studies that have described the use of FVC/SVC ratio focus on obstructive airways diseases; thus, it is uncertain to what extent the small airways are affected, since larger airways have been demonstrated to contribute to airway obstruction as well. To further evaluate the applicability of FVC/SVC ratio as a marker of small airways function and to minimize the contribution of large airway narrowing, FVC/SVC ratio was evaluated in patients with bronchiolitis obliterans syndrome (BOS), which is a type of chronic allograft rejection occurring after lung transplantation (LTX) in which small airways become progressively obliterated leading to airway obstruction. 6 We hypothesized that FVC/SVC ratio, if it is a valid small airways parameter, should detect small airways changes in patients with BOS and tested this in a well-defined patient group after they had undergone LTX. Subjects Materials and Methods This particular study involves the use of anonymized data from human subjects and explicitly does not involve the use of human subjects. According to Dutch legislation, data analyses like the current study do not require review by local or central ethics committees. All patients (n 184) who underwent bilateral LTX between 1992 and 2002 at the University Medical Center Groningen (Groningen, the Netherlands) and in whom BOS developed at least up to stage 2 were included in the analysis. Patients who *From the Departments of Pulmonology (Drs. Cohen, Postma, ten Hacken, Koëter, and Douma), Pulmonary Function (Ms. Vink-Klooster), and Lung Transplantation (Drs. van der Bij and Verschuuren), University Medical Center Groningen, University of Groningen, Groningen, the Netherlands. The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Manuscript received June 14, 2006; revision accepted June 8, 2007. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal. org/misc/reprints.shtml). Correspondence to: W. Rob Douma, MD, PhD, Secretariaat Longziekten UMCG, PO Box 30001, 9700 RB Groningen, the Netherlands; e-mail: w.r.douma@int.umcg.nl DOI: 10.1378/chest.06-2763 39 LTX recipients WITH BOS Lung function data: 1. Baseline (median 188 days after transplantation) 2. BOS stage 1 (median 371 days after baseline) (also: Time point A) 3. BOS stage 2 (median 578 days after baseline) (also: Time point B) 184 bilateral LTX recipients 1992-2002 75 LTX recipients with complete lung function data (FVC, SVC, FEF 25-75 and FEV 1 ) 36 LTX recipients WITHOUT BOS Lung function data: 1. Baseline (median 226 days after transplantation) 2. Time point A (median 362 days after baseline) 3. Time point B (median 599 days after baseline) Figure 1. Selection of subjects and lung function data. underwent unilateral LTX were not included because of the possible interference of the remaining autologous lung with the measured lung function parameters. Thirty-nine patients were suitable for analysis and had a complete data set with regard to follow-up of FEV 1, forced expiratory flow between 25% and 75% of FVC (FEF 25 75% ), FVC, and SVC (median follow-up time from LTX to BOS stage 2, 912 days; interquartile range [IQR], 505 to 2,181 days). The control group consisted of 36 patients who had undergone bilateral LTX but in whom BOS of any stage did not develop (Fig 1). The lung function of these subjects was matched in time intervals with the median number of days in the BOS group (median follow-up time from LTX, 824 days; IQR, 809 to 842 days). Methods A routine clinical and spirometric follow-up took place in all post-ltx patients. Routine pulmonary function tests were performed two to three times weekly during hospitalization and weekly during the first 2 to 3 months after transplantation in the outpatient setting, and visits were tapered to a minimum frequency of once every 3 months. 7 Each stable post-ltx patient was classified as having BOS stage 0, based on their baseline FEV 1. The term baseline in this article represents the first measurement after LTX with the patient in the stable phase. Progressive BOS stages were defined based on an increasing decline in FEV 1 and or a decline in FEF 25 75% (Table 1) according to International Society for Heart and Lung Transplantation recommendations. 8 In the BOS group, the median number of days from the LTX date to the baseline phase and from the baseline phase to reaching BOS stages 1 and 2 were BOS Stage Table 1 Classifications of BOS* Decline in FEV 1 From Baseline Decline in FEF 25 75% From Baseline 0 10% and 25% 0-p (at risk) 10 19% and/or 25% 1 20 34% NA 2 35 49% NA 3 50% NA *Baseline values are determined in each stable post-lung transplant recipient according to International Society for Heart and Lung Transplantation recommendations. 8 NA not applicable. www.chestjournal.org CHEST / 132 / 4/ OCTOBER, 2007 1199

calculated. In the control group, which consisted of LTX recipients in whom BOS did not develop, pulmonary function measurements were selected to match time intervals similar to those in the BOS group reaching the consecutive baseline and BOS stages. These equivalent time intervals were named time interval A (an equivalent time interval from baseline to BOS stage 1 in the group with BOS) and time interval B (an equivalent time interval from baseline to BOS stage 2 in the group with BOS). Spirometric values were assessed with a pneumotachograph that was calibrated daily (Masterscreen Pneumo or Masterscreen IOS; Jaeger; Würzburg, Germany) and were obtained according to European Respiratory Society recommendations. 9 Subjects did not use bronchodilators if applicable within 12 h before the measurements. Statistical Analysis Pulmonary function data and baseline characteristics were investigated. Patients with BOS stage 0-p (indicating BOS at risk ) and BOS stage 3 were not included in the analysis. Descriptive statistics were applied to baseline characteristics. Declines in FEV 1, FVC, SVC, and FVC/SVC ratio from baseline were statistically tested for significant difference by means of a Wilcoxon signed rank test in both the BOS group and the control group. Differences in variables between groups with and without BOS were statistically tested with Mann-Whitney U tests. Correlations of the change in FVC/ SVC ratio with the change in FEV 1 and FEF 25 75% were calculated with Spearman nonparametric ranking tests. Since the variables used had a skewed distribution in this population, only nonparametric tests were used. To determine independent prognostic factors for baseline FVC/SVC ratio, a multivariate regression analysis in a stepwise algorithm was used (SPSS, version 12.0.2. for Windows; SPSS Inc; Chicago, IL). Results Baseline FVC/SVC Ratio Table 2 presents the baseline characteristics of 39 patients in whom BOS up to stage 2 developed and of 36 patients in whom BOS did not develop after bilateral LTX. There were significantly more men in the group with BOS than in the group without BOS (p 0.017) [Table 2]. There was no significant difference between the baseline FVC/SVC ratio in both groups, and there was also no significant gender difference in the baseline FVC/SVC ratio within each group. The diagnoses prior to LTX were comparable in both groups. A multivariate regression model with baseline FVC/SVC ratio as the dependent variable, and age at transplantation, gender, and height of both the donor and the recipient entered as covariates revealed no factors significantly influencing the baseline FVC/SVC ratio. Decrease in FVC/SVC Ratio In the BOS group, FVC/SVC ratio significantly decreased from baseline in patients with stage 1 and 2 BOS (Table 3). In the group of patients in whom BOS did not develop, FVC/SVC ratio did not decrease significantly after median periods of 362 days (time point A) and 599 days (time point B) from baseline but even increased by 1.2% and 1.1%, respectively, though not significantly. These time intervals correspond with the median time intervals from baseline to stage 1 and 2 BOS in the BOS group. The decline in FVC/SVC ratio from baseline was significantly larger in the BOS group than in the group without BOS (ie, a decrease of 2.2% vs an increase of 1.2%, respectively [p 0.001], and a decrease of 4.4% vs an increase of 1.1% [p 0.001], respectively) [Table 3, Fig 2]. The FVC/SVC ratios at time point A and time point B were significantly lower in the group with BOS than in the group without BOS (p 0.001) [Fig 2]. Within the BOS group, the median FVC/SVC ratio was significantly lower in patients with stage 2 BOS than in those with stage 1 BOS (96% [IQR, 92 to 100] vs 98% [IQR, 94 to 100], respectively; p 0.039). In the group without BOS, the FVC/SVC ratio was not significantly different at time point A and B (102% [IQR, 100 to 104] vs 102% [IQR, 99 to 105], respectively). Although there were significantly more men in the BOS group than in the group without BOS (p 0.017), the decline in FVC/SVC ratio per time interval was not significantly different in men and women (p 0.05) who had stage 1 and 2 BOS. The Table 2 Baseline Characteristics* Characteristics Patients With BOS (n 39) Patients Without BOS (n 36) p Value Gender, No. 0.017 Male 26 14 Female 13 22 Age at lung transplantation, yr 47.5 (35.4 53.7) 46.2 (41.2 52.9) 0.671 Age of donor, yr 38.0 (27.0 43.0) 37.0 (25.5 42.5) 0.709 Height of transplant recipient, cm 174 (169 183) 170 (165 177) 0.067 Height of transplant donor, cm 180 (170 180) 175 (165 180) 0.058 FEV 1 at baseline, L 3.17 (2.59 3.51) 2.87 (2.40 3.64) 0.335 FVC/SVC ratio at baseline, % 100.0 (98.2 100.5) 101.5 (98.8 103.6) 0.069 *Values are given as the median (IQR), unless otherwise indicated. Statistical differences between the group with BOS and the group without BOS were assessed with Mann-Whitney U tests. 1200 Original Research

Table 3 Lung Function Parameters in Patients With and Without BOS* Time Interval, % Change From Baseline Variables Baseline (Absolute Values) A B FEV 1,L Group with BOS 3.2 (2.6 3.5) 23.7 ( 22.0 to 26.2) 39.0 ( 36.4 to 42.1) Group without BOS 2.9 (2.4 3.6) 3.2 ( 5.5 to 8.9) NS 3.0 ( 2.9 to 7.6) FEF 25 75%, L/s Group with BOS 3.3 (2.4 4.0) 52.2 ( 44.6 to 61.8) 72.4 ( 63.6 to 77.3) Group without BOS 3.6 (2.6 4.5) 5.5 ( 13.5 to 8.6) NS 7.6 ( 28.3 to 1.9) FVC, L Group with BOS 3.8 (3.2 4.4) 9.2 ( 1.0 to 15.8) 18.3 ( 8.5 to 25.1) Group without BOS 3.2 (2.8 4.2) 5.7 ( 0.1 to 9.4) 7.7 (2.4 to 12.7) SVC, L Group with BOS 3.7 (3.1 4.4) 4.3 (3.0 to 13.5) 14.3 ( 3.7 to 21.5) Group without BOS 3.1 (2.7 4.1) 5.4 ( 1.1 to 8.8) 5.4 (2.9 to 11.6) FVC/SVC ratio, % Group with BOS 100.0 (98.2 100.5) 2.2 (0.0 to 6.5) 4.4 ( 1.2 to 7.5) Group without BOS 101.5 (98.8 103.6) 1.2 ( 1.6 to 3.0) NS 1.1 ( 1.7 to 2.5) NS *Values are given as the median (IQR). Time interval A corresponds with the time from baseline to BOS stage 1 (median time, 371 days after baseline) in the BOS group and for the group without BOS with an equivalent time interval (median time, 362 days after baseline). Time interval B corresponds with the time from baseline to BOS stage 2 (median time, 578 days after baseline) in the BOS group and for the group without BOS with an equivalent time interval (median time, 599 days after baseline). NS not significant. p 0.001. p 0.05. p 0.01. minimum and maximum values of the FVC/SVC ratio at all time points were 84% and 114%, respectively, in the total study group. In patients with stages 1 and 2 BOS, the decline in FVC/SVC ratio from baseline did not significantly correlate with the decline in FEV 1 from baseline ( 0.079 [p 0.637] vs 0.079 [p 0.672], respectively) or with FVC/SVC (%) * * 120 BOS group Group without BOS 110 * p<0.001 100 p = 0.039 90 80 70 * * Baseline 'A' 'B' Figure 2. FVC/SVC ratio at baseline, time point A, and time point B. Time interval A corresponds with the time from baseline to stage 1 BOS (median time, 371 days after baseline) in the BOS group and for the group without BOS with an equivalent time interval (median time, 362 days after baseline). Time interval B corresponds with the time from baseline to stage 2 BOS (median time, 578 days after baseline) in the BOS group and for the group without BOS with an equivalent time interval (median time, 599 days after baseline). FVC/SVC ratio is significantly lower in the BOS group at time points A and B (p 0.001 [Mann-Whitney U test]) than in the group without BOS. Within the BOS group, the FVC/SVC ratio at time points A and B is significantly lower than baseline (p 0.001 [Wilcoxon signed rank test]). Within the BOS group, FVC/SVC ratio at time point B is significantly lower than FVC/SVC ratio at time point A (p 0.039 [Wilcoxon signed rank test]). the decline in FEF 25 75% from baseline ( 0.039 [p 0.818] vs 0.109 [p 0.510], respectively). Discussion Our data show that FVC/SVC ratio decreases significantly with progressing BOS stages, which occurs independently from changes in FEV 1. These together may indicate that at a group level the FVC/SVC ratio assesses small airways changes. This study is one of the first to investigate the properties of the FVC/SVC ratio and its ability to reflect small airways obstruction. To our knowledge, Wenzel and colleagues 4 were the first to mention the use of FVC/SVC ratio in a biopsy study in patients with severe asthma. They demonstrated that a smaller FVC/SVC ratio was significantly associated with the presence of eosinophils in lung tissue. 4 In this population with severe asthma, the FVC/SVC ratio ranged between 71% and 100%, which is a different range than we demonstrated in our LTX population (range, 84 to 114%). Based on just two studies, it is difficult to pass judgement on this difference in ratios. Asthma and BOS are dissimilar airway diseases, which may partially account for the difference in FVC/SVC ratios. It seems likely that the contribution of larger airways to airflow limitation is more pronounced in patients with severe asthma than in those with stage 1 and 2 BOS, in which predominantly smaller airways are affected. A www.chestjournal.org CHEST / 132 / 4/ OCTOBER, 2007 1201

second explanation for the difference in FVC/SVC ratios may be that different types of inflammation exist in patients with severe asthma and BOS after LTX. In the study by Wenzel et al, 4 patients with severe asthma but without increased eosinophil numbers in lung tissue demonstrated FVC/SVC ratios that were similar to those of our BOS population (ie, 97%; range, 89 to 100%). This may indicate that eosinophilic inflammation in particular determines the level of FVC/SVC ratio more than the presence of small airway obstruction. A third explanation may be that stretch receptors play a role in the magnitude of the FVC/SVC ratio. In humans, a deep inspiration has been shown to stimulate stretch receptors in the lung, which may lead to bronchoconstriction 10 and thus to a lower FVC/SVC ratio. In LTX recipients, there is a loss of pulmonary stretch receptors, 11 which may explain why the FVC/SVC ratio is less attenuated in our patients with BOS after LTX than in the patients with severe asthma. 4 In patients with stage 1 and 2 BOS, the decline in FVC/SVC ratio was not associated with the decline in FEV 1. This may indicate that the FVC/SVC ratio reflects the functioning of different airway divisions than FEV 1. The observed decline in FVC/SVC ratio per BOS stage, which is independent of the decline in FEV 1, in combination with the absence of a decline in FVC/SVC ratio in the control group supports the hypothesis that the FVC/SVC ratio may serve as a parameter for detecting small airways changes. Nevertheless, the reduction in FVC/SVC ratio with progressive disease is fairly small and may prove to be too small to be of value in the monitoring of small airway disease in all individual patients. Whether FVC/SVC ratio is a sensitive parameter that will aid in elucidating early or pending stages of BOS on an individual level should therefore be assessed in future studies. In this retrospective study, patients with stages 0-p and 3 BOS were excluded from the analyses. BOS stage 0-p, indicating BOS at risk, was not included in the analysis because BOS does not actually develop in all patients classified as having BOS 0-p. Hence, there may be minimal small airways pathology in this group. In patients with stage 3 BOS, larger airways as well as small airways may be severely affected, and infections frequently play a role. For these reasons, we considered that BOS stages 0-p and 3 were not typical states for small airways disease, and they were thus unsuitable stages for evaluating the characteristics of the FVC/SVC ratio. Nevertheless, it is possible that some patients with BOS who were evaluated in this study have some extent of larger airway abnormalities as well. We evaluated the FVC/SVC ratio as an index of small airway obstruction in patients with BOS, which is a disease that is defined by especially small airway disease. It may be questioned whether the observed decline in FVC/SVC ratio is due to small airway obstruction or whether it is merely a logical result of the decline in FEV 1 since both parameters are extracted from the same flow volume maneuver. In that case, FVC/SVC ratio would only be a different way to express airway obstruction in general, rather than reflecting specific obstruction in the small airways. However, our results do not support this notion. There was no significant or clinically relevant correlation between the decline in FEV 1 and the decline in FVC/SVC ratio, indicating that the observed and significant decrease of FVC/SVC ratio in BOS is independent of the decrease in FEV 1. Some may state that a limitation of our study is that we did not correlate the decline in FVC/SVC ratio with changes in parameters other than lung function, such as radiologic or pathologic changes that may be observed in patients with BOS. However, current International Society for Heart and Lung Transplantation guidelines 8 state that the diagnosis of BOS is based purely on a decline in FEV 1. Therefore, irrespective of radiologic or pathologic data, the diagnosis of BOS would still be valid only if a decline in FEV 1 was observed. This would therefore not change the selection of the groups in this study and would also not change the outcomes. As mentioned before, in the absence of a valid small airway obstruction parameter BOS is still classified by the use of FEV 1. In the earlier developmental stages of BOS, small airways are relatively the most affected by disease, which is why the use of FEF 25 75% has been implemented in the classification of BOS stage 0-p, indicating patients who are at risk for the development of BOS. It is unclear whether FEF 25 75% is a reliable measure in classifying BOS stage 0-p since the relationship between FEF 25 75% and histologic changes is unknown. 12 Possibly, other small airway parameters such as FVC/SVC ratio, if proven feasible for detecting small airway pathology in the individual patient, may come of use in classifying the early stages of BOS. In conclusion, we have for the first time investigated the applicability of the FVC/SVC ratio as a parameter for small airway obstruction in a classic small airway disease. FVC/SVC ratio can demonstrate small airway dysfunction on a group level, when comparing patients with and without BOS at a matched time after bilateral LTX. Since the observed changes in FVC/SVC ratio with progressive small airway obstruction were fairly small, further prospective studies are needed to assess whether FVC/SVC ratio is an early signal of a pending BOS syndrome at an individual level. Future studies may also assess whether FVC/SVC ratio could be of value 1202 Original Research

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