RATIONALE:flow volume loops (FVL) in some bilateral lung transplant (BLT) and heart-lung transplant (HLT) patients suggest variable extrathoracic obstruction in the absence of identifiable causes. These FVLs usually have supranormal expiratory and normal inspiratory flow rates (SUPRA pattern).OBJECTIVES:characterize the relationship of the SUPRA pattern to predicted donor and recipient lung volumes, airway size, and survival.METHODS:we performed a retrospective review of adult BLT/HLT patients. We defined the SUPRA FVL pattern as: (1) mid-vital capacity expiratory to inspiratory flow ratio (Ve50:Vi50) > 1.0, (2) absence of identifiable causes of extrathoracic obstruction, and (3) Ve50/FVC ≥ 1.5 s(-1). We calculated predicted total lung capacity (pTLC) ratio by dividing the donor pTLC by the recipient pTLC. We measured airway luminal areas on thoracic computer tomographic scans. We compared survival in patients with and without the SUPRA pattern.MEASUREMENTS AND MAIN RESULTS:the SUPRA FVL pattern occurred in 56% of the 89 patients who qualified for the analysis. The pTLC ratio of SUPRA and non-SUPRA patients was 1.11 and 0.99, respectively (P = 0.004). A higher pTLC ratio was correlated with increased probability of the SUPRA pattern (P = 0.0072). Airway luminal areas were larger in SUPRA patients (P = 0.009). Survival was better in the SUPRA cohort (P = 0.009).CONCLUSIONS:the SUPRA FVL pattern was frequent in BLT/HLT patients. High expiratory flows in SUPRA patients could result from increased lung elastic recoil or reduced airway resistance, both of which could be caused by the pTLC mismatch. Improved survival in the SUPRA cohort suggests potential therapeutic approaches to improve outcomes in BLT/HLT patients.

BACKGROUND: The purpose of this study was to investigate the relationship between donor recipient height, gender and predicted estimates of total lung capacity (pTLC) mismatches and post-transplant survival.METHODS: The lung transplant databases at three programs were reviewed. The pTLC ratios (donor pTLC/recipient pTLC) and height ratios (donor height/recipient height) were calculated retrospectively. Patients were grouped according to pTLC ratio <= 1.0 or >1.0 and height ratio <= 1.0 or >1.0, and according to gender (mis-)matching. A time-to-event analysis was performed for risk of death after transplantation conditional on 30-day survival using Kaplan-Meier survival and Cox proportional hazard models.RESULTS: There were 211 adult bilateral lung transplant recipients who qualified for the analysis. Mean follow-up was comparable for all cohorts (range 2.21 to 3.85 years). In the univariate Cox proportional hazard models, a pTLC ratio >1.0 (HR 0.43, p = 0.002) and a height ratio >1.0 (HR 0.61, p = 0.03) were associated with better survival, and a female-donor-to-male-recipient gender mismatch (F-to-M) was associated with worse survival (HR 2.35, p = 0.01). In the multivariate Cox proportional hazard model accounting for F-to-M gender mismatch and height ratio >1.0, a pTLC ratio >1.0 remained associated with survival (HR 0.38, p = 0.015). However, accounting for a pTLC ratio >1.0, a height ratio of >1.0 and F-to-M mismatch were not associated with survival.CONCLUSIONS: A pTLC ratio >1.0 is associated with improved survival after bilateral lung transplantation. The pTLC ratio might better reflect allograft thorax mismatch than the height ratio, as it also accounts for effects of gender on lung and thoracic volumes. J Heart Lung Transplant 2012;31:1207-13 (C) 2012 International Society for Heart and Lung Transplantation. All rights reserved.

Background Size mismatch between donor lungs and a recipient thorax could affect the major determinants of maximal expiratory airflow: airway resistance, propensity of airways to collapse, and lung elastic recoil. Methods A retrospective review of 159 adults who received bilateral lung transplants was performed. The predicted total lung capacity (pTLC) for donors and recipients was calculated based on sex and height. Size matching was represented using the following formula: pTLC ratio = donor pTLC / recipient pTLC. Patients were grouped according to those with a pTLC ratio > 1.0 (oversized) or those with a pTLC ratio ≤ 1.0 (undersized). Allograft function was analyzed in relation to the pTLC ratio and to recipient and donor predicted function. Results The 96 patients in the oversized cohort had a mean pTLC ratio of 1.16 ± 0.13 vs 0.89 ± 0.09 in the 63 patients of the undersized group. At 1 to 6 months posttransplant, the patients in the oversized cohort had higher FEV1/FVC ratios (0.895 ± 0.13 vs 0.821 ± 0.13, P < .01) and lower time constant estimates of lung emptying (0.38 ± 0.2 vs 0.64 ± 0.4, P < .01) than patients in the undersized cohort. Although the FVCs expressed as % predicted for the recipient were not different between cohorts, the FVCs expressed as % predicted for the donor organ were lower in the oversized cohort compared with the undersized cohort (at 1-6 months, 52.4% ± 17.1% vs 65.3% ± 18.3%, P < .001). Kaplan-Meier estimates for the occurrence of bronchiolitis obliterans syndrome (BOS) showed that patients in the oversized cohort had a lower probability of BOS (P < .001). Conclusions A pTLC ratio > 1.0, suggestive of an oversized allograft, is associated with higher expiratory airflow capacity and a less frequent occurrence of BOS.

BACKGROUND:Little is known about the perception of airflow obstruction in patients hospitalized for acute asthma. OBJECTIVES:To evaluate patient perception of airflow obstruction at hospital discharge and at a 2-week follow-up visit and to determine whether symptom control and/or severity of airflow obstruction identified patients at risk for acute asthma after discharge. METHODS:In a prospective cohort study of inner-city adults hospitalized for acute asthma from April 1, 2001, through October 31, 2002, symptom control (Asthma Control Questionnaire) and airflow obstruction (forced expiratory volume in 1 second [FEV1] percentage predicted) were evaluated at discharge and 2 weeks after discharge. We evaluated perception of airflow obstruction (symptom control vs FEV1 percentage predicted) and perception of change in airflow obstruction (change in symptom control vs percentage change in FEV1) between the 2 visits. Acute asthma after discharge was defined as an emergency department visit or hospitalization for asthma within 90 days of discharge. RESULTS:In fifty-one participants, symptom control was not significantly associated with airflow obstruction at hospital discharge (P = .30), indicating poor perception of airflow obstruction. Among the 41 participants (80.4% of those enrolled) who completed the follow-up visit, change in symptom control was not significantly associated with change in airflow obstruction (P = .20), indicating poor perception of change in airflow obstruction. Greater airflow obstruction at follow-up (P = .02) and a smaller improvement in airflow obstruction (P = .03), but not symptom control, were associated with a higher risk of acute asthma after discharge. CONCLUSIONS:Patients hospitalized for acute asthma have poor perception of airflow obstruction and change in airflow obstruction. Objective measurements of lung function should guide treatment decisions after discharge in this population.

LETTERS TO THE EDITORLast Word on Viewpoint “The role of the large airways on smooth muscle contraction in asthma”Solbert PermuttSolbert PermuttPublished Online:01 Oct 2007https://doi.org/10.1152/japplphysiol.00822.2007MoreSectionsPDF (28 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInEmailWeChat To the Editor: Macklem (3) and Pellegrino and Brusasco (4) suggest that the change in lung volume from the baseline smooth muscle tone (BSMT) might be largely an artifact. Whatever proportion of the increase in FRC from the BSMT was due to an artifact had no significant effect on the results of our study (2). The artifact causes an equal overestimation of the change in RV and FRC, but it is the change in FRC relative to the change in RV, as reflected by the FRCratio, that was the major determinant of the magnitude of the hyperresponsiveness to the BSMT (1). We recalculated the FRCratio with the assumption that there was an increase in FRC from an artifact proportional to the resistance of the large airways that averaged nearly 80% of the measured increase in FRC. None of the effects of FRCratio on lung volumes or hyperresponsiveness was significantly altered.The points that were raised by Thompson et al. (6) that the methods used in our study were not sufficiently sensitive to detect an effect of small airways on the increase in RV from BSMT are certainly valid. Nevertheless, the methods we used were sufficiently sensitive to detect a highly significant decrease from BSMT in the diameter of the small airways of 15% that was nearly fourfold greater than the decrease in the diameter of the large airways (1). While the significant changes in the diameter of the small airways had no effect on the variance of the change in RV, the ratio of the wall thickness to the diameter of the large airways and the diameter of the medium airways accounted for more than 70% of the variance of the increase in RV (1).Perhaps the most surprising and important finding in our study is that the magnitude of the structural response of the airways to smooth muscle tone was not a determinant of the magnitude of the response in pulmonary function. Thus hyperresponsiveness of the change in FVC or FEV1 to smooth muscle tone occurred with the same degree of airways narrowing; and it is, therefore, a nonsequitur to consider the exaggerated response in pulmonary function as a manifestation of airways hyperresponsiveness. These findings are compatible with the study of Schueller et al. (5) who found that the difference in airway luminal area between baseline and postalbuterol or between baseline and histamine challenge was the same for three groups: a group of healthy volunteers and two groups of asthmatic subjects, those with or without a significant decrease in FEV1 with the histamine challenge.We suggest that the hyperresponsiveness of the change in pulmonary function is determined by the attenuation of the compensatory response in FRC and TLC to the change in RV that, in turn, is a function of the degree of dynamic hyperinflation that results from narrowing of the relaxed large airways.REFERENCES1 Brown RH, Pearse DB, Pyrgos G, Liu MC, Togias A, Permutt S. The structural basis of airways hyperresponsiveness in asthma. J Appl Physiol 101: 30–39, 2006.Link | ISI | Google Scholar2 Brown RH, Pearse DB, Pyrgos G, Liu MC, Togias A, Permutt S. Reply from Drs. Brown, Pearse, Pyrgos, Liu, Togias, and Permutt. J Appl Physiol 101: 1813, 2006.Link | ISI | Google Scholar3 Macklem P. Commentary on “The role of large airways on smooth muscle contraction in asthma.” J Appl Physiol; doi:10.1152/japplphysiol.00646.2007.Google Scholar4 Pellegrino R, Brusasco V. Commentary on “The role of large airways on smooth muscle contraction in asthma.” J Appl Physiol; doi:10.1152/japplphysiol.00684.2007.Google Scholar5 Schueller G, Neumann K, Helbich T, Riemer H, Backfrieder W, Sertl K, Herold CJ. Bronchial reactivity in hyperresponsive patients and healthy individuals: demonstration with high resolution computed tomography. Eur J Radiol 52: 151–156, 2004.Crossref | ISI | Google Scholar6 Thompson B, King G, Harding R. Commentary on “The role of large airways on smooth muscle contraction in asthma.” J Appl Physiol; doi:10.1152/japplphysiol.00696.2007.Google ScholarAUTHOR NOTESAddress for reprint requests and other correspondence: S. Permutt, 5501 Hopkins Bayview Circle, Baltimore, MD 21224 (e-mail: [email protected]) Download PDF Previous Back to Top Next FiguresReferencesRelatedInformation More from this issue > Volume 103Issue 4October 2007Pages 1466-1466 Copyright & PermissionsCopyright © 2007 the American Physiological Societyhttps://doi.org/10.1152/japplphysiol.00822.2007History Published online 1 October 2007 Published in print 1 October 2007 Metrics

We hypothesized that structural airway remodeling contributes to airways hyperresponsiveness (AHR) in asthma. Small, medium, and large airways were analyzed by computed tomography in 21 asthmatic volunteers under baseline conditions (FEV1 = 64% predicted) and after maximum response to albuterol (FEV1 = 76% predicted). The difference in pulmonary function between baseline and albuterol was an estimate of AHR to the baseline smooth muscle tone (BSMT). BSMT caused an increase in residual volume (RV) that was threefold greater than the decrease in forced vital capacity (FVC) because of a simultaneous increase in total lung capacity (TLC). The decrease in FVC with BSMT was the major determinant of the baseline FEV1 (P < 0.0001). The increase in RV correlated inversely with the relaxed luminal diameter of the medium airways (P = 0.009) and directly with the wall thickness of the large airways (P = 0.001). The effect of BSMT on functional residual capacity (FRC) controlled the change in TLC relative to the change in RV. When the FRC increased with RV, TLC increased and FVC was preserved. When the relaxed large airways were critically narrowed, FRC and TLC did not increase and FVC fell. With critical large airways narrowing, the FRC was already elevated from dynamic hyperinflation before BSMT and did not increase further with BSMT. FEV1/FVC in the absence of BSMT correlated directly with large airway luminal diameter and inversely with the fall in FVC with BSMT. These findings suggest that dynamic hyperinflation caused by narrowing of large airways is a major determinant of AHR in asthma.

Ventilation (V) increases lung lymph flow (Ql), but the separate effects of tidal volume (Vt) and frequency (f) and the role of V-induced changes in edema formation are poorly understood. An isolated, in situ sheep lung preparation was used to examine these effects. In eight sheep with f = 10 min(-1), results obtained during 30-min periods with Vt = 5 or 20 ml/kg were compared with values obtained during bracketed 30-min control periods (Vt = 12.5 ml/kg). Eight other sheep with constant Vt (12.5 ml/kg) were studied at f = 5 or 20 min(-1) and compared with f = 10 min(-1). Three additional groups of six sheep were perfused for 100 min with control V (10 ml/kg, 10 min(-1)). Vt was then kept constant or changed to 20 or 3 ml/kg during a second 100-min period. Increases in Vt or f increased Ql and vice versa, without corresponding effects on the rate of edema formation. For the same change in V, changing Vt had a greater effect on Ql than changing f. The change in Ql caused by an increase in Vt was significantly greater after the accumulation of interstitial edema. The change in Ql caused by a sustained increase in Vt was transient and did not correlate with the rate of edema formation, suggesting that V altered Ql through direct mechanical effects on edema-filled compartments and lymphatic vessels rather than through V-induced changes in fluid filtration.

BACKGROUND:Human rhinovirus (HRV) infections are associated with exacerbations of asthma, chronic obstructive pulmonary disease, and sinusitis. Nitric oxide (NO) might play an important role in host defense through its potent antiviral properties. Previous studies have shown that HRV infection in human subjects increased nasal epithelial expression of type 2 nitric oxide synthase (NOS2), an isoform of the enzyme that produces NO.OBJECTIVE:We sought to investigate whether increases in exhaled NO (eNO) would accompany the increased NOS2 expression and would be associated with clearance of the virus.METHODS:Six human subjects were infected with HRV-16 intranasally. eNO from nasal and lower airways was measured by means of direct measurement at multiple controlled flow rates. eNO was monitored at baseline (day 1) and on days 2 to 5, 8, 14, and 42 after infection. Nasal lavages were performed on days 1 to 5 and 8, and nasal scrapings were performed on days 1 to 4. NOS2 mRNA expression in nasal cells was measured by using quantitative real-time RT-PCR. Viral shedding in nasal lavage fluid was monitored by using real-time RT-PCR and bioassay.RESULTS:Peak HRV titers and symptom scores were correlated on day 3, and HRV persisted until day 5 (n=4) or day 8 (n=2). Infection was associated with transient but significant increases in lymphocytes and monocytes in nasal lavage fluid. Significant increases in both nasal and lower airway eNO concentrations accompanied HRV infection and were positively correlated. Increased nasal eNO concentrations on day 3 were associated with increased expression of NOS2 mRNA in nasal scrapings. Symptom scores on day 4 were inversely correlated with the increases in nasal eNO concentration.CONCLUSIONS:We conclude that increased production of NO occurs as part of the host response to HRV infection and speculate that NO plays a beneficial role in viral clearance.

Interest has recently been renewed in lung volume reduction surgery (LVRS) for end-stage emphysema. However, numerous questions about its role in the treatment of emphysema remain, including the clinical characteristics of optimal candidates and its mechanism of improvement in pulmonary function. In this report, we develop a mathematical analysis and graphic depiction of the mechanism of improvement in expiratory airflow and vital capacity. This analysis is based on consideration of the interaction between lung function and respiratory muscle function. We also reexamine previously published pulmonary mechanics in patients with alpha1-antitrypsin deficiency, chronic obstructive pulmonary disease, and asthma. We find a major determinant of airflow limitation common to these diseases is the ratio of residual volume to total lung capacity (RV/TLC). Moreover, RV/TLC is found to be the single most important determinant of the improvement in pulmonary function after LVRS. Regardless of the specific underlying lung disease, the impairment of airflow is due primarily to mismatch between the sizes of the lung and the chest wall, and the effects of LVRS are almost exclusively due to improvement of that match. This analysis can be used to develop testable hypotheses to guide patient selection for this procedure.