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Abstract
Rationale: Acute cellular rejection (ACR) is common during the initial 3 months after lung transplant. Patients are monitored with spirometry and routine surveillance transbronchial biopsies. However, many centers monitor patients with spirometry only because of the risks and insensitivity of transbronchial biopsy for detecting ACR. Airway oscillometry is a lung function test that detects peripheral airway inhomogeneity with greater sensitivity than spirometry. Little is known about the role of oscillometry in patient monitoring after a transplant.
Objectives: To characterize oscillometry measurements in biopsy-proven clinically significant (grade ≥2 ACR) in the first 3 months after a transplant.
Methods: We enrolled 156 of the 209 double lung transplant recipients between December 2017 and March 2019. Weekly outpatient oscillometry and spirometry and surveillance biopsies at Weeks 6 and 12 were conducted at our center.
Measurements and Main Results: Of the 138 patients followed for 3 or more months, 15 patients had 16 episodes of grade 2 ACR (AR2) and 44 patients had 64 episodes of grade 0 ACR (AR0) rejection associated with stable and/or improving spirometry. In 15/16 episodes of AR2, spirometry was stable or improving in the weeks leading to transbronchial biopsy. However, oscillometry was markedly abnormal and significantly different from AR0 (P < 0.05), particularly in integrated area of reactance and the resistance between 5 and 19 Hz, the indices of peripheral airway obstruction. By 2 weeks after biopsy, after treatment for AR2, oscillometry in the AR2 group improved and was similar to the AR0 group.
Conclusions: Oscillometry identified physiological changes associated with AR2 that were not discernible by spirometry and is useful for graft monitoring after a lung transplant.
Little is known about the role of oscillometry in patient monitoring after lung transplant.
The findings reveal that oscillometry can detect changes in lung function associated with biopsy-proven acute graft rejection that are not detectable by spirometry. These oscillometry measurements improve after treatment of rejection. The data suggest that oscillometry can provide useful information for graft monitoring after lung transplantation.
Lung transplantation is an established therapy for end-stage lung diseases. However, long-term survival is limited by chronic lung allograft dysfunction (CLAD). Acute cellular rejection (ACR) is a well-known risk factor for CLAD and is common during the first year after a transplant, particularly in the initial 3 months (1–4). For these reasons, transplant centers monitor patients with frequent routine spirometry. Although both ACR and bronchiolitis obliterans syndrome, the most common form of CLAD, begin in the small airways and peripheral lung tissue, FEV1 primarily measures central airway function (5, 6). Some studies have found that obstruction of 75% of all the small airways must occur before changes are detected by FEV1 (7, 8). Unsurprisingly, spirometry has been found to have only a 60% sensitivity for detecting clinically significant grade 2 ACR (AR2) or higher (9).
Although histological assessment of lung tissue obtained from transbronchial biopsies remains the current gold standard diagnosis of ACR, it is an imperfect standard. Transbronchial biopsy is limited by the sampling of a small region of the lung and usually contains only a few small airways. Bronchoscopy and transbronchial biopsies also have associated risks, procedure-related morbidity, and costs (10–13). Routine surveillance bronchoscopy with transbronchial biopsies is not universally adopted by lung transplant centers. There is considerable debate within the lung transplant community regarding the value of routine surveillance biopsies versus clinically mandated bronchoscopy (14–23).
Airway oscillometry is a technique that directly assesses small airways and peripheral lung tissue using multifrequency pulse waves to measure respiratory impedance, a complex sum of respiratory resistance and reactance (24, 25). Respiratory resistance is a metric of airway diameter and tissue resistance; lower frequency signals (e.g., 5 Hz) are able to reach the smaller airways and periphery, whereas the high-frequency signals (19 Hz) only reach the proximal airways owing to the physical properties of the airways and lung parenchyma. Thus, although resistance at 5 Hz (R5) is reflective of total airway resistance, the difference in the resistance between 5 and 19 Hz (R5−19) is a measurement of small airway function and increases with small airway obstruction (26–30). Respiratory reactance measures inertance (i.e., the mass–inertance forces of the air column in the airways) and the capacitance (i.e., the elastic properties of the lung). At higher frequencies, reactance is dominated by inertance, whereas at lower frequencies (e.g., reactance at 5 Hz [X5]) capacitance predominates. X5 and AX (integrated area of reactance between X5 and the resonant frequency, the point where the magnitudes of inertance and capacitance are equal) are most reflective of the small airways and the soft tissue of the peripheral lung parenchyma. AX is more reproducible than X5 alone because it takes into account reactance at all frequencies from 5 Hz to the resonant frequency. X5 becomes more negative and AX increases with small airways derecruitment, and are observed in both obstructive and restrictive lung diseases (24, 31–34).
Although oscillometry was first described by Dubois and colleagues in 1956 (35), it was the recent introduction of commercially available devices that led to its increasing application as a diagnostic pulmonary function test (PFT). Currently, oscillometry is primarily used for monitoring common obstructive lung diseases, such as asthma and chronic obstructive pulmonary disease (COPD) (32, 36–48). Oscillometry has been found to detect lung function changes earlier in COPD (38, 43, 44, 49) and has demonstrated higher correlation with symptoms (50–52) than conventional PFTs. In asthma, oscillometry has been shown to be a more sensitive metric of disease control (39, 41, 53–55). A recent asthma cohort study of 177 patients, using airway models generated from computed tomography scans, demonstrated R5−19 to be a direct measurement of small airway obstruction, and that changes in R5−19 correlated with asthma control and quality of life (56).
Unlike spirometry, a forced maneuver that requires patient cooperation (5, 6), oscillometry is conducted during normal breathing and requires minimal patient cooperation. Thus, patient monitoring with oscillometry offers an advantage early after a lung transplant when physical deconditioning and chest discomfort may confound accurate measurement of FEV1. An early case report described oscillometry measurements in a patient with presumed rejection early after a transplant in which changes in respiratory impedance were found to correlate well with clinical symptoms before and after corticosteroid treatment (57). A recent study assessed the correlation of oscillometry with spirometry in 25 patients after lung transplants (58). Although the oscillometry measurements were confounded by presence of 12 single lung recipients in the cohort of 25, the authors concluded that oscillometry could be used in place of spirometry for lung function monitoring (58). However, no clinical outcomes were evaluated (58). The role of oscillometry for monitoring of ACR after lung transplant has not been studied.
We postulate that X5, AX, and R5−19 can measure physiological changes in the small airways that are associated with ACR after lung transplant that may not detected by spirometry. The aim of the current study is to characterize the oscillometry measurements of biopsy-proven grade A2 or higher ACR during the first 3 months after a lung transplant and compare them to biopsy-proven episodes of no ACR (i.e., grade A0 rejection).
Some of the results have been presented at the Montreal Oscillometry Symposium in 2019, but no abstract was distributed to meeting attendees.
The study was approved by the University Health Network (UHN) Research Ethics Board (REB# 17-5652). All double lung transplant recipients were eligible for enrollment. Single lung recipients and patients who died before enrollment remained hospitalized at 3 months after a transplant, and those with known anastomotic issues were excluded from the study. Spirometry and lung volumes were conducted in accordance with international guidelines (5, 6, 59). Oscillometry was performed before spirometry during each visit to the UHN Pulmonary Function Testing Laboratory, thus allowing for paired comparison of oscillometry with spirometry at each time point. Oscillometry was conducted according to European Respiratory Society guidelines (60) using the tremoflo device (Thorasys). Tests that did not meet quality control were rejected. A minimum of three 20-second recordings with a coefficient of variation of less than 15% was needed to pass quality control. Artifacts such as those due to cough or glottis closure were removed by automatic rejection.
In our clinical program, patients who underwent lung transplant are followed weekly with conventional PFTs at the UHN Pulmonary Function Testing Laboratory during the first 3 months after a lung transplant after being discharged from hospital. After 3 months, patients are monitored at their local PFT laboratory, returning to UHN only at routine assessment milestone visits at 6, 9, 12, 18, and 24 months after a lung transplant, and annually thereafter. Routine surveillance bronchoscopy with transbronchial biopsy is performed at 6 and 12 weeks, and at 6, 9, 12, 18, and 24 months at our center. According to our clinical protocol, patients with AR2 or higher are treated with high-dose methylprednisolone daily for 3 days regardless of symptoms after the tissue diagnosis was confirmed (usually 5–7 d after transbronchial biopsy). Demographic data and clinical parameters known to affect lung function and graft rejection, such as donor–recipient HLA match status, cytomegalovirus donor–recipient status, and respiratory infections, were prospectively collected at time of pulmonary testing and from the patients’ electronic clinical records.
Statistical analyses were performed using Prism 6.0 (GraphPad Software) and RStudio (The R Foundation). Comparisons between groups were conducted using one-way ANOVA for continuous variables and Pearson’s chi-square test for categoric variables. Mixed linear modeling was used to analyze the pulmonary function and oscillometry parameters to take into account the shared time effects and repeated sampling of patients. The data are shown as mean ± SD.
During the study time frame of December 2017 to March 2019, 258 patients underwent lung transplantation at our center, of which 209 were double lung transplants (Figure 1). Fourteen patients were excluded owing to early death (n = 6) or ongoing hospitalization at 3 months (n = 8). Eight patients were not approached for various reasons (e.g., anastomosis issues, psychosocial issues). Of the 187 patients who were approached for the study, 31 declined and 156 patients were enrolled (see Figure 1). Four patients were excluded from our analysis owing to early dropout (n = 3) or death (n = 1). Of the remaining 152 patients, 138 patients had completed 3 months of follow-up by March 2019 and formed the cohort for our analyses.
Figure 1. Patient recruitment, enrollment, and study cohort. Patient enrollment from December 2017 to March 2019 is shown. Stable AR0 = biopsy-proven grade 0 rejection (i.e., no rejection) and stable/improving spirometry; AR2 = grade 2 or higher acute cellular rejection; Others = no biopsy at Weeks 6 and 12, indeterminate biopsy (grade Ax), or grade A1 rejection. A1 = mild A grade; Ax = indeterminate A grade.
[More] [Minimize]In the first 3 months after a transplant, there were 16 episodes of AR2 in 15 patients and 64 episodes of grade A0 ACR (AR0) associated with stable or improving lung function in 44 patients. Eleven patients in the AR2 group had AR2 at 6 weeks after a lung transplant. The other five episodes of AR2 occurred at 12 weeks after a transplant. All episodes of AR2 were associated with improving or stable FEV1 and FVC, with the exception of one episode at 6 weeks in which spirometry detected a weekly FEV1 decline of 13% (140 ml) and 8% (80 ml) in the 2 weeks before transbronchial biopsy.
The primary indications for lung transplant were interstitial lung diseases (n = 47) and COPD (n = 43), followed by bronchiectasis (n = 24). Comparison of the 44 patients in the AR0 group, 15 patients in the AR2 group, and the 79 patients in the “other” category (defined by transbronchial biopsies as minimal or grade A1 ACR [n = 26], indeterminate or grade Ax [n = 21], or no transbronchial biopsy [n = 32]) revealed no significant differences in the baseline characteristics with respect to sex, age, height, weight, body mass index, or donor–recipient cytomegalovirus status. Assessment of immunological risk with respect to a panel of reactive antibodies, actual cytomegalovirus, and virtual cytomegalovirus HLA cross-match status at the time of transplant was also not significantly different among the three groups (Table 1).
| AR0 (n = 44) | AR2 (n = 15) | Others (n = 79) | P Value | |
|---|---|---|---|---|
| Sex, M/F | 29/15 | 11/4 | 39/40 | 0.09 |
| Age, yr | 55.14 ± 14.81 | 48.31 ± 15.32 | 55.00 ± 15.00 | 0.30 |
| Height, cm | 168.60 ± 9.28 | 169.30 ± 6.24 | 166.00 ± 9.50 | 0.30 |
| Weight, kg | 69.11 ± 13.54 | 70.03 ± 13.17 | 66.00 ± 15.00 | 0.40 |
| BMI, kg/m2 | 24.15 ± 3.16 | 24.33 ± 3.97 | 24.00 ± 4.20 | 0.40 |
| PRA, +/− | 29/15 | 8/7 | 57/22 | 0.33 |
| VCM, +/− | 7/37 | 1/14 | 15/64 | 0.50 |
| ACM, +/− | 6/38 | 0/15 | 16/63 | 0.1 |
| CMV match status | ||||
| CMV D−/R− | 13 | 3 | 16 | 0.48 |
| CMV R+ | 24 | 7 | 44 | 0.81 |
| CMV D+/R− | 7 | 5 | 19 | 0.33 |
| Underlying diagnoses | ||||
| Interstitial | 12 | 6 | 29 | 0.50 |
| Obstructive | 17 | 3 | 23 | 0.34 |
| Vascular | 2 | 2 | 5 | 0.49 |
| Bronchiectasis | 6 | 4 | 16 | 0.48 |
| Others | 7 | 0 | 6 | 0.13 |
The variability and trajectory of changes in weekly FEV1 and FVC during the first 3 months were similar in the AR0 and AR2 groups (Figure 2). In contrast, the pattern of the oscillometry parameters was different between the two groups (Figure 3). Patients in the AR2 group had abnormal measurements (61) of high R5, R5−19, and AX, and low X5 from 4 to 7 weeks after a transplant. At Week 7, the 11 patients who had AR2 detected by transbronchial biopsy at 6 weeks after a transplant (see Figures 2 and 3; denoted by the asterisks) were treated with pulsed high-dose methylprednisolone for 3 days (see Figures 2 and 3; denoted by the solid diamonds). By Week 8, the oscillometry parameters in AR2 group improved to the levels observed in the AR0 group. Furthermore, the variability of the oscillometry parameters was also less from Week 8 onwards. Five patients in the AR2 group had AR2 detected by transbronchial biopsy at Week 12 and were treated with pulsed corticosteroids at Week 13.
Figure 2. Spirometry during the first 3 months after lung transplant. Weekly monitoring of FEV1 and FVC for the 15 patients in the grade A2 acute cellular rejection (AR2) and 44 patients in the AR0 groups are shown as absolute values or percentage predicted normal FEV1 (%FEV1) and FVC (%FVC). Shown are means ± SD for each time point after a lung transplant. *Eleven patients had AR2 identified at 6 weeks after transbronchial biopsy. Five episodes of AR2 were detected at 12 weeks after transbronchial biopsy. The large diamonds indicate treatment with 3 days of high-dose corticosteroids. AR0 = grade A0 acute cellular rejection.
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Figure 3. Oscillometry parameters during the first 3 months after lung transplant. Weekly oscillometry for the 15 patients in the grade A2 acute cellular rejection (AR2) and 44 patients in the grade A0 acute cellular rejection (AR0) groups are shown as means ± SD for each time point after a lung transplant. In the AR2 group, there is wide variability in the difference in resistance between 5 and 19 Hz (R5−19), reactance at 5 Hz (X5), and area of reactance (AX) in the 3 weeks leading up to the 6 weeks after transbronchial biopsy (*) when 11 of 15 patients experienced biopsy-proven AR2. After treatment with augmented immunosuppression (large diamonds), R5−19, X5, and AX became less variable and improved to values that were similar to the AR0 group. Five episodes of AR2 occurred at week 12 after transplant. R5 = resistance at 5 Hz.
[More] [Minimize]We assessed the pulmonary function parameters at the time of and in the weeks before and after transbronchial biopsy. During the 2 weeks leading up to biopsy, the mean FEV1, FEV1% predicted, FVC, and FVC percentage predicted were stable or improving (see Figure 2 and Table E1 in the online supplement). No evidence of small airway obstruction as detected by forced expiratory flow, midexpiratory phase (FEF25–75) of FVC was observed at any time point in either group. All patients exhibited mild restriction during the first 3 months as detected by the TLC and TLC percentage predicted.
R5−19, X5, and AX were stable in the AR0 group in the weeks leading up to and following the biopsy (see Figure 3 and Table E2). In contrast, the AR2 group showed abnormally high R5−19 and AX values and abnormally low X5 values (61) in the 2 weeks before and the week of transbronchial biopsy. These values are compatible with airway obstruction despite the normal mean FEV1/FVC ratios (see Table E1) and are comparable with those measured in patients with established COPD (32, 62). By Week 2 after a biopsy, and one week after treatment with augmented immunosuppression (see Figure 3; denoted by the solid diamonds), all three parameters improved, with X5 becoming less negative and R5−19 and AX being lower.
A representative graph of the spirometry and oscillometry measurements of a 55-year-old man who was transplanted for idiopathic pulmonary fibrosis is shown in Figure 4. He was discharged at 3 weeks after lung transplant and reported to be feeling well with no respiratory symptoms on weekly clinical visits. His immunologic risk was low (i.e., panel of reactive antibodies negative, and virtual cytomegalovirus and actual cytomegalovirus negative). Routine transbronchial biopsy at 6 weeks after a lung transplant (see Figure 1; Week 0) identified AR2. He was treated with pulsed methylprednisolone for 3 days the following week (Week 1). Spirometry showed stable and marginally improving FEV1 (open triangles) and FVC (open diamonds) from Weeks −1 to 2 (dashed lines), whereas the oscillometry measurements improved after treatment of ACR. The abnormally high AX (solid diamonds) and R5−19 (solid circles) values and low X5 (solid triangles) at Weeks −1 and 0 improved by Week 2 (solid lines), with R5−19 and X5 improving (solid lines) to values that are within the normal range (61).
Figure 4. Changes in the spirometry and oscillometry values of a patient with grade A2 acute cellular rejection (AR2) in the weeks before and after transbronchial biopsy. The changes in the spirometry and oscillometry of a 55-year-old man who had a double lung transplant for idiopathic pulmonary fibrosis and was discharged 3 weeks after a transplant. He was clinically well when the routine six-week surveillance bronchoscopy with transbronchial biopsies (Week 0) identified AR2. He was treated with high-dose corticosteroids for 3 days at the onset of Week 1. The FEV1 (open triangles) and FVC (open diamonds) were stable before transbronchial biopsy with nonsignificant improvement after treatment. FEV1 (L): Week 0 = 0.88, Week 2 = 1.12; FVC (L): Week 0 = 1.93, Week 2 = 2.29; dashed lines. In contrast, the abnormally high area of reactance (AX; solid diamonds) and resistance between 5 and 19 Hz (R5−19) (solid circles) values at Weeks −1 and 0 improved after treatment at Week 1 (solid lines). Similarly, observations were made for reactance at 5 Hz (X5) (solid triangles), with the R5−19 and X5 improving (solid lines) to values that are within the normal range (61).
[More] [Minimize]To account for repeated sampling of each patient and shared time effects among the patients, we used a mixed linear effects model to compare the differences in the spirometry and oscillometry between the AR0 and AR2 groups at different time points relative to transbronchial biopsy (Figure 5). No differences were observed at any time point for FEV1, FVC, or FEF25–75. However, both AX and R5−19 were significantly higher in the AR2 group when compared with the AR0 group at Week 0 of transbronchial biopsy (P = 0.005 and P = 0.038, respectively) with the expiratory phase; R5−19 exhibiting greater difference between the groups.
Figure 5. Oscillometry detected significant changes between the grade A2 acute cellular rejection (AR2; solid circles) and grade A0 acute cellular rejection (AR0; open triangles) that were not discernable by spirometry. A mixed linear model was used to account for repeated testing in individual patients and shared time effects among participants. Comparison of the corrected mean values for oscillometry and spirometry revealed significant changes in the area of reactance (AX) and resistance between 5 and 19 Hz (R5−19) (top panels) at Week 0 of transbronchial biopsy (P < 0.05) but no difference in FEV1 or forced expiratory flow, midexpiratory phase (FEF25–75) (bottom panels). At the week before biopsy (Week −1), AX and R5−19 showed a trend to be higher in the AR2 group when compared with the AR0 group. After treatment with methylprednisolone in the week after biopsy, AX and R5−19 were similar in the two groups by Week 2 and Week 4. Episodes of AR2 rejection = 16; episodes of A0 rejection = 64. Shown are corrected means ± SD. AX is given in cm H2O/L; R5−19 is given in cm H2O ⋅ s/L; FEV1 is given in L; FEF25–75 is given in L/s.
[More] [Minimize]In this study, we focused on the characterization of the oscillometry measurements in biopsy-proven AR2 or higher during the first 3 months after lung transplant when the risk of ACR was highest, comparing these values to episodes of biopsy-proven AR0 or no ACR. In our cohort, 15 of the 16 episodes of AR2 or higher were spirometrically silent, underscoring the insensitivity of spirometry for identifying clinically significant ACR. These episodes would have been missed if patients were monitored with spirometry alone and clinically driven transbronchial biopsy prompted by drops in FEV1. The only patient who had incremental FEV1 drops of 13% (140 ml) and 8% (80 ml) in the 2 weeks before biopsy had just completed a 5-day course of ribavirin followed by 2 weeks of meropenem for lower respiratory tract respiratory syncytial virus infection and superimposed bacterial infection. If a decision to proceed with transbronchial biopsy had been based on clinical judgement and significant drops in FEV1, this episode of clinically significant ACR might also have been missed if the FEV1 had been ascribed to infection.
In contrast to spirometry, oscillometry was markedly abnormal in the AR2 group, and highly variable in Weeks 3 to 6 after lung transplant (see Figure 3) (i.e., during the 2 weeks before the 6-week transbronchial biopsy, when grade ≥2 ACR was detected in 11 of 15 patients). The tissue injury associated with ACR is known to be patchy, inhomogenously distributed, and evolves over time. It is possible that the variability observed in R5−19, X5, and AX in the weeks preceding the biopsies are reflective of the evolving tissue injury, inflammation, and edema in the peripheral tissue and small airways as ACR develops. For all episodes of AR2 (see Table E2), the R5−19 (0.46 ± 0.41 cm H2O · s/L) and X5 (−1.54 ± 0.64 cm H2O · s/L) improved by 2 weeks after a biopsy (i.e., 1 wk after treatment). These values were similar in the AR2 and AR0 groups, and comparable with the normal healthy subjects who were evaluated with different oscillometry devices as part of a multicenter study (61).
The AX improved but remained high after treatment in the AR2 group (8.81 ± 7.11 cm H2O/L; see Table E2) and did not approach those of normal healthy adults (1–6 cm H2O/L) (63). Similar measurements were observed in the AR0 group at all time points (see Table E2), with values approaching the proposed cut-off value of greater than or equal to 9 to 10 cm H2O/L for COPD (64). However, in the setting of lung transplant, the high Ax is likely reflective of the mild restrictive defects as a result of donor–recipient mismatch of lung size as evidenced by measurements of TLC (see Table E1) because AX also increases in restrictive defects owing to loss of volume and elastic properties of the lung (65). Although significant differences between the AR2 and AR0 were observed only for the AX and R5−19 at the week of transbronchial biopsy, both values were consistently higher in the preceding week. Differences in X5 between the AR2 and AR0 approached significance at Week 0 (P = 0.058) and was lower at in the AR2 group at Week −1 (see Figure E2). With increasing patient enrollment and longer patient follow-up, oscillometry may prove to be able to detect changes in lung function associated with ACR earlier in the future analysis.
Although it is not clear whether early treatment of ACR or, indeed, changes in immunosuppression, alter the course of progression to CLAD, the associations of ACR with CLAD are well documented (1–4). To date, our ability to track changes in the small airways and lung parenchyma have been limited by the lack of sensitive diagnostic tools. Our current findings of improved R5−19 and X5 after treatment of AR2 suggest that oscillometry is a sensitive tool that can track physiological changes associated with development of ACR and its resolution with treatment. These observations provide a cogent rationale for treating biopsy-proven AR2, even in the face of stable or improving FEV1. Ongoing patient monitoring with oscillometry will also allow us to address the value of treatment of ACR in modulating the progression to CLAD.
Oscillometry also has additional advantages over spirometry. Patients like the technique. In a survey conducted at 3 months after lung transplant (see Figure E1) and using a scale of 1 to 10, with 10 being most satisfied or most difficult, respectively, patients reported a significantly higher satisfaction with oscillometry compared with spirometry (9.09 ± 1.32 vs. 8.47 ± 2.06; n = 135; P = 0.004) and found oscillometry to be significantly easier to perform than spirometry (1.67 ± 1.39 vs. 4.20 ± 2.70; n = 135; P < 0.0001). The oscillometry device is portable, has a small footprint, and thus can be easily accommodated in most pulmonary function laboratories. Although stringent quality control is needed for accurate measurements (66), the technique is easy to learn and does not require specialized expertise.
Our observations and the ease of conducting oscillometry provide a solid and compelling rationale for incorporating oscillometry as an adjunct to spirometry for patient monitoring after lung transplant, particularly in centers that do not perform routine surveillance bronchoscopy with transbronchial biopsy. Oscillometry will facilitate identification of ACR and response to treatment, and could ultimately help stratify patient risks with respect to clinical outcomes.
| 1. | Yusen RD, Edwards LB, Kucheryavaya AY, Benden C, Dipchand AI, Goldfarb SB, et al. The registry of the International Society for Heart and Lung Transplantation: thirty-second official adult lung and heart-lung transplantation report 2015. Focus theme: early graft failure. J Heart Lung Transplant 2015;34:1264–1277. |
| 2. | Shino MY, Weigt SS, Li N, Derhovanessian A, Sayah DM, Huynh RH, et al. Impact of allograft injury time of onset on the development of chronic lung allograft dysfunction after lung transplantation. Am J Transplant 2017;17:1294–1303. |
| 3. | Hachem RR, Khalifah AP, Chakinala MM, Yusen RD, Aloush AA, Mohanakumar T, et al. The significance of a single episode of minimal acute rejection after lung transplantation. Transplantation 2005;80:1406–1413. |
| 4. | Hopkins PM, Aboyoun CL, Chhajed PN, Malouf MA, Plit ML, Rainer SP, et al. Association of minimal rejection in lung transplant recipients with obliterative bronchiolitis. Am J Respir Crit Care Med 2004;170:1022–1026. |
| 5. | Miller MR, Crapo R, Hankinson J, Brusasco V, Burgos F, Casaburi R, et al.; ATS/ERS Task Force. General considerations for lung function testing. Eur Respir J 2005;26:153–161. |
| 6. | Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al.; ATS/ERS Task Force. Standardisation of spirometry. Eur Respir J 2005;26:319–338. |
| 7. | Cosio M, Ghezzo H, Hogg JC, Corbin R, Loveland M, Dosman J, et al. The relations between structural changes in small airways and pulmonary-function tests. N Engl J Med 1978;298:1277–1281. |
| 8. | Burgel PR, Bergeron A, de Blic J, Bonniaud P, Bourdin A, Chanez P, et al. Small airways diseases, excluding asthma and COPD: an overview. Eur Respir Rev 2013;22:131–147. |
| 9. | Van Muylem A, Mélot C, Antoine M, Knoop C, Estenne M. Role of pulmonary function in the detection of allograft dysfunction after heart-lung transplantation. Thorax 1997;52:643–647. |
| 10. | Glanville AR. Bronchoscopic monitoring after lung transplantation. Semin Respir Crit Care Med 2010;31:208–221. |
| 11. | Glanville AR. The role of surveillance bronchoscopy post-lung transplantation. Semin Respir Crit Care Med 2013;34:414–420. |
| 12. | Sandrini A, Glanville AR. The controversial role of surveillance bronchoscopy after lung transplantation. Curr Opin Organ Transplant 2009;14:494–498. |
| 13. | Chhajed PN, Tamm M, Glanville AR. Role of flexible bronchoscopy in lung transplantation. Semin Respir Crit Care Med 2004;25:413–423. |
| 14. | Hopkins PM, Aboyoun CL, Chhajed PN, Malouf MA, Plit ML, Rainer SP, et al. Prospective analysis of 1,235 transbronchial lung biopsies in lung transplant recipients. J Heart Lung Transplant 2002;21:1062–1067. |
| 15. | Scott JP, Fradet G, Smyth RL, Mullins P, Pratt A, Clelland CA, et al. Prospective study of transbronchial biopsies in the management of heart-lung and single lung transplant patients. J Heart Lung Transplant 1991;10:626–636. [Discussion, pp. 636–637.] |
| 16. | Higenbottam T, Stewart S, Penketh A, Wallwork J. Transbronchial lung biopsy for the diagnosis of rejection in heart-lung transplant patients. Transplantation 1988;46:532–539. |
| 17. | Starnes VA, Theodore J, Oyer PE, Stinson EB, Moreno-Cabral CE, Sibley R, et al. Pulmonary infiltrates after heart-lung transplantation: evaluation by serial transbronchial biopsies. J Thorac Cardiovasc Surg 1989;98:945–950. |
| 18. | Sibley RK, Berry GJ, Tazelaar HD, Kraemer MR, Theodore J, Marshall SE, et al. The role of transbronchial biopsies in the management of lung transplant recipients. J Heart Lung Transplant 1993;12:308–324. |
| 19. | Kramer MR, Stoehr C, Whang JL, Berry GJ, Sibley R, Marshall SE, et al. The diagnosis of obliterative bronchiolitis after heart-lung and lung transplantation: low yield of transbronchial lung biopsy. J Heart Lung Transplant 1993;12:675–681. |
| 20. | Starnes VA, Theodore J, Oyer PE, Billingham ME, Sibley RK, Berry G, et al. Evaluation of heart-lung transplant recipients with prospective, serial transbronchial biopsies and pulmonary function studies. J Thorac Cardiovasc Surg 1989;98:683–690. |
| 21. | Valentine VG, Taylor DE, Dhillon GS, Knower MT, McFadden PM, Fuchs DM, et al. Success of lung transplantation without surveillance bronchoscopy. J Heart Lung Transplant 2002;21:319–326. |
| 22. | Valentine VG, Gupta MR, Weill D, Lombard GA, LaPlace SG, Seoane L, et al. Single-institution study evaluating the utility of surveillance bronchoscopy after lung transplantation. J Heart Lung Transplant 2009;28:14–20. |
| 23. | McWilliams TJ, Williams TJ, Whitford HM, Snell GI. Surveillance bronchoscopy in lung transplant recipients: risk versus benefit. J Heart Lung Transplant 2008;27:1203–1209. |
| 24. | Bhatawadekar SA, Leary D, Maksym GN. Modelling resistance and reactance with heterogeneous airway narrowing in mild to severe asthma. Can J Physiol Pharmacol 2015;93:207–214. |
| 25. | Bhatawadekar SA, Hernandez P, Maksym GN. Oscillatory mechanics in asthma: emphasis on airway variability and heterogeneity. Crit Rev Biomed Eng 2015;43:97–130. |
| 26. | Clément J, Làndsér FJ, Van de Woestijne KP. Total resistance and reactance in patients with respiratory complaints with and without airways obstruction. Chest 1983;83:215–220. |
| 27. | Wouters EF, Lándsér FJ, Polko AH, Visser BF. Impedance measurement during air and helium-oxygen breathing before and after salbutamol in COPD patients. Clin Exp Pharmacol Physiol 1992;19:95–101. |
| 28. | Grimby G, Takishima T, Graham W, Macklem P, Mead J. Frequency dependence of flow resistance in patients with obstructive lung disease. J Clin Invest 1968;47:1455–1465. |
| 29. | Cavalcanti JV, Lopes AJ, Jansen JM, de Melo PL. Using the forced oscillation technique to evaluate bronchodilator response in healthy volunteers and in asthma patients presenting a verified positive response. J Bras Pneumol 2006;32:91–98. |
| 30. | Cavalcanti JV, Lopes AJ, Jansen JM, Melo PL. Detection of changes in respiratory mechanics due to increasing degrees of airway obstruction in asthma by the forced oscillation technique. Respir Med 2006;100:2207–2219. |
| 31. | Leary D, Winkler T, Braune A, Maksym GN. Effects of airway tree asymmetry on the emergence and spatial persistence of ventilation defects. J Appl Physiol (1985) 2014;117:353–362. |
| 32. | Wei X, Shi Z, Cui Y, Mi J, Ma Z, Ren J, et al. Impulse oscillometry system as an alternative diagnostic method for chronic obstructive pulmonary disease. Medicine (Baltimore) 2017;96:e8543. |
| 33. | Bates JH, Maksym GN. Mechanical determinants of airways hyperresponsiveness. Crit Rev Biomed Eng 2011;39:281–296. |
| 34. | Dellacà RL, Aliverti A, Lutchen KR, Pedotti A. Spatial distribution of human respiratory system transfer impedance. Ann Biomed Eng 2003;31:121–131. |
| 35. | Dubois AB, Brody AW, Lewis DH, Burgess BF Jr. Oscillation mechanics of lungs and chest in man. J Appl Physiol 1956;8:587–594. |
| 36. | Dandurand R, Li P, Mancino P, Bourbeau J. Oscillometry from the CanCOLD Cohort: correlation with spirometry and patient reported outcomes. Presented at the European Respiratory Society International Congress. Paris, ON; 2018. p. PA3887. |
| 37. | Jabbal S, Manoharan A, Lipworth J, Lipworth B. Utility of impulse oscillometry in patients with moderate to severe persistent asthma. J Allergy Clin Immunol 2016;138:601–603. |
| 38. | Lipworth BJ, Jabbal S. What can we learn about COPD from impulse oscillometry? Respir Med 2018;139:106–109. |
| 39. | Manoharan A, Anderson WJ, Lipworth J, Lipworth BJ. Assessment of spirometry and impulse oscillometry in relation to asthma control. Hai 2015;193:47–51. |
| 40. | Manoharan A, Morrison AE, Lipworth BJ. Effects of adding tiotropium or aclidinium as triple therapy using impulse oscillometry in COPD. Hai 2016;194:259–266. |
| 41. | Manoharan A, von Wilamowitz-Moellendorff A, Morrison A, Lipworth BJ. Effects of formoterol or salmeterol on impulse oscillometry in patients with persistent asthma. J Allergy Clin Immunol 2016;137:727–733, e1. |
| 42. | Tse HN, Tseng CZ, Wong KY, Yee KS, Ng LY. Accuracy of forced oscillation technique to assess lung function in geriatric COPD population. Int J Chron Obstruct Pulmon Dis 2016;11:1105–1118. |
| 43. | Eddy RL, Westcott A, Maksym GN, Parraga G, Dandurand RJ. Oscillometry and pulmonary magnetic resonance imaging in asthma and COPD. Physiol Rep 2019;7:e13955. |
| 44. | Yamagami H, Tanaka A, Kishino Y, Mikuni H, Kawahara T, Ohta S, et al. Association between respiratory impedance measured by forced oscillation technique and exacerbations in patients with COPD. Int J Chron Obstruct Pulmon Dis 2017;13:79–89. |
| 45. | Kitaguchi Y, Yasuo M, Hanaoka M. Comparison of pulmonary function in patients with COPD, asthma-COPD overlap syndrome, and asthma with airflow limitation. Int J Chron Obstruct Pulmon Dis 2016;11:991–997. |
| 46. | Jetmalani K, Thamrin C, Farah CS, Bertolin A, Chapman DG, Berend N, et al. Peripheral airway dysfunction and relationship with symptoms in smokers with preserved spirometry. Respirology 2018;23:512–518. |
| 47. | Robinson PD, King GG, Sears MR, Hong CY, Hancox RJ. Determinants of peripheral airway function in adults with and without asthma. Respirology 2017;22:1110–1117. |
| 48. | Short PM, Anderson WJ, Manoharan A, Lipworth BJ. Usefulness of impulse oscillometry for the assessment of airway hyperresponsiveness in mild-to-moderate adult asthma. Ann Allergy Asthma Immunol 2015;115:17–20. |
| 49. | Ribeiro CO, Faria ACD, Lopes AJ, de Melo PL. Forced oscillation technique for early detection of the effects of smoking and COPD: contribution of fractional-order modeling. Int J Chron Obstruct Pulmon Dis 2018;13:3281–3295. |
| 50. | Frantz S, Nihlén U, Dencker M, Engström G, Löfdahl CG, Wollmer P. Impulse oscillometry may be of value in detecting early manifestations of COPD. Respir Med 2012;106:1116–1123. |
| 51. | Aarli BB, Calverley PMA, Jensen RL, Eagan TML, Bakke PS, Hardie JA. Variability of within-breath reactance in COPD patients and its association with dyspnoea. Eur Respir J 2015;45:625–634. |
| 52. | Dean J, Kolsum U, Hitchen P, Gupta V, Singh D. Clinical characteristics of COPD patients with tidal expiratory flow limitation. Int J Chron Obstruct Pulmon Dis 2017;12:1503–1506. |
| 53. | Shi Y, Aledia AS, Tatavoosian AV, Vijayalakshmi S, Galant SP, George SC. Relating small airways to asthma control by using impulse oscillometry in children. J Allergy Clin Immunol 2012;129:671–678. |
| 54. | Pisi R, Tzani P, Aiello M, Martinelli E, Marangio E, Nicolini G, et al. Small airway dysfunction by impulse oscillometry in asthmatic patients with normal forced expiratory volume in the 1st second values. Allergy Asthma Proc 2013;34:e14–e20. |
| 55. | Saadeh C, Saadeh C, Cross B, Gaylor M, Griffith M. Advantage of impulse oscillometry over spirometry to diagnose chronic obstructive pulmonary disease and monitor pulmonary responses to bronchodilators: an observational study. SAGE Open Med 2015;3:2050312115578957. |
| 56. | Foy BH, Soares M, Bordas R, Richardson M, Bell A, Singapuri A, et al. Lung computational models and the role of the small airways in asthma. Am J Respir Crit Care Med 2019;200:982–991. |
| 57. | Hamakawa H, Sakai H, Takahashi A, Zhang J, Okamoto T, Satoda N, et al. Forced oscillation technique as a non-invasive assessment for lung transplant recipients. Adv Exp Med Biol 2010;662:293–298. |
| 58. | Ochman M, Wojarski J, Wiórek A, Slezak W, Maruszewski M, Karolak W, et al. Usefulness of the impulse oscillometry system in graft function monitoring in lung transplant recipients. Transplant Proc 2018;50:2070–2074. |
| 59. | Wanger J, Clausen JL, Coates A, Pedersen OF, Brusasco V, Burgos F, et al. Standardisation of the measurement of lung volumes. Eur Respir J 2005;26:511–522. |
| 60. | Oostveen E, MacLeod D, Lorino H, Farré R, Hantos Z, Desager K, et al.; ERS Task Force on Respiratory Impedance Measurements. The forced oscillation technique in clinical practice: methodology, recommendations and future developments. Eur Respir J 2003;22:1026–1041. |
| 61. | Oostveen E, Boda K, van der Grinten CP, James AL, Young S, Nieland H, et al. Respiratory impedance in healthy subjects: baseline values and bronchodilator response. Eur Respir J 2013;42:1513–1523. |
| 62. | Young HM, Guo F, Eddy RL, Maksym G, Parraga G. Oscillometry and pulmonary MRI measurements of ventilation heterogeneity in obstructive lung disease: relationship to quality of life and disease control. J Appl Physiol (1985) 2018;125:73-85. |
| 63. | Boulay ME, Henry C, Bossé Y, Boulet LP, Morissette MC. Acute effects of nicotine-free and flavour-free electronic cigarette use on lung functions in healthy and asthmatic individuals. Respir Res 2017;18:33. |
| 64. | Lundblad LKA, Miletic R, Piitulainen E, Wollmer P. Oscillometry in chronic obstructive lung disease: in vitro and in vivo evaluation of the impulse oscillometry and tremoflo devices. Sci Rep 2019;9:11618. |
| 65. | Smith HJ, Reinhold P, Goldman MD. Forced oscillation technique and impulse oscillometry. Eur Respir Mon 2005;31:72–105. |
| 66. | Wu J, DeHaas E, Nadj R, Cheung A, Dandurand R, Hantos Z, et al. Development of quality assurance and quality control guidelines for respiratory oscillometry in clinical studies. Respir Care 2020 [online ahead of print]. DOI: https://doi.org/10.4187/respcare.07412. |
Supported by the Pettit Block Term Grant, University of Toronto and the Lung Association–Ontario, Grants-in-Aid (C.-W.C.), and a Canadian Graduate Scholarship (E.C.).
Author Contributions: E.C. conducted the research, compiled the clinical data, performed the data analysis, and drafted the manuscript. J.K.Y.W. coordinated the study, developed the standard operating procedures, and conducted regular quality control and assurance of the data. D.C.B. verified the clinical data and drafted the manuscript. J.M. developed the statistical analysis plan, and performed and oversaw data analysis. R.N. conducted the research, refined the standard operating procedures, and participated in the data analysis. E.D. conducted the research, refined the standard operating procedures, and participated in quality control and data analysis. Q.H., K.Y., A.B.C., L.N.W., and L.D. conducted the research and participated in quality control of the testing procedures and data collection. T.X. developed the data extraction and quality control and assurance methodologies. M.C. and J.T. provided feedback on study design and edited the manuscript. C.R. developed the research protocol, ensured quality control of the pulmonary function data, and edited the manuscript. C.-W.C. developed the concept, study protocol, and analysis, and oversaw all aspects of the project.
This article has an online supplement, which is accessible from this issue’s table of contents at www.atsjournals.org.
Originally Published in Press as DOI: 10.1164/rccm.201908-1539OC on March 5, 2020
Author disclosures are available with the text of this article at www.atsjournals.org.
