Lung size mismatch in bilateral lung transplantation is associated with allograft function and bronchiolitis obliterans syndrome.

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 FEV(1)/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.

Parameters of donor-recipient size mismatch and survival after bilateral lung transplantation.

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.

Supranormal expiratory airflow after bilateral lung transplantation is associated with improved survival.

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.

Perception of airflow obstruction in patients hospitalized for acute asthma.

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.

The structural basis of airways hyperresponsiveness in asthma.

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.

Inhaled corticosteroids and the beneficial effect of deep inspiration in asthma.

Deep inspiration-induced bronchoprotection and bronchodilation are impaired in asthma. We evaluated the effect of inhaled glucocorticosteroids on these phenomena. Two groups of subjects with asthma, 9 with moderate/severe hyperresponsiveness to methacholine, and 12 with mild/borderline hyperresponsiveness to methacholine, received inhaled fluticasone (880 microg daily) for 12 weeks. Serial bronchoprovocations were performed at Weeks 0, 6, and 12. The impact of deep inspirations on the airway response to methacholine was evaluated on the basis of inspiratory vital capacity and FEV(1). Fluticasone produced a wide spectrum of changes in the beneficial effects of deep inspiration, but the mean changes were not significant. The magnitude of the steroid-induced changes in bronchoprotection by deep inspiration correlated with baseline log PC(20) (the provocative concentration of methacholine causing a 20% fall in FEV(1); higher log PC(20) predicted improvement of the deep inspiration effect). The steroid-induced changes led to the emergence of strong positive correlations between the effects of deep inspiration and the methacholine log PC(20) that did not exist at baseline. We conclude that deep inspiration-induced bronchoprotection can be restored by inhaled glucocorticosteroids only in individuals with mild hyperresponsiveness. After steroid treatment, the beneficial effects of deep inspiration become significant determinants of the magnitude of airway hyperresponsiveness.

Decreased exhaled nitric oxide in pulmonary arterial hypertension: response to bosentan therapy.

RATIONALE: Decreased nitric oxide (NO) is considered an important pathogenetic mechanism in pulmonary arterial hypertension (PAH), but clear evidence is lacking. OBJECTIVES: We used multiple techniques to assess endogenous NO in 10 patients with untreated PAH (8 idiopathic and 2 anorexigen-associated PAH) and 12 control subjects. METHODS: After a nitrite/nitrate-restricted diet, NO metabolites (NOx) were assayed in 24-hour urine collections and exhaled NO (FE(NO)) determined at multiple expiratory flows. Analysis of the relation between FE(NO) and flow allowed derivation of three flow-independent parameters: airway wall concentration (C(W)), diffusing capacity (D(NO)), and alveolar concentration (C(A)). Seven patients underwent follow-up testing after 3 months of bosentan treatment. RESULTS: At baseline, FE(NO) was markedly decreased at the two lowest expiratory flows in PAH: 21 +/- 4 versus 36 +/- 4 ppb at 18 ml/second and 11 +/- 2 versus 17 +/- 2 ppb at 50 ml/second, for subjects with PAH and control subjects, respectively (p < 0.05). C(W) was 33 +/- 11 ppb in subjects with PAH versus 104 +/- 34 in control subjects (p = 0.04). Urinary NOx was also reduced in PAH (42 +/- 6 microM NOx/mM creatinine versus 62 +/- 7 in control subjects; p = 0.04). After bosentan, FE(NO), C(W), and urine NOx increased to control values (p < 0.05). Exclusion of the two anorexigen cases did not alter these results. CONCLUSIONS: FE(NO) at low expiratory flows was decreased in PAH due to reduced C(W). Bosentan reversed these abnormalities, suggesting that suppression of NO in PAH may have been caused by endothelin.

Effects of tidal volume and respiratory frequency on lung lymph flow.

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.

Role of nasal nitric oxide in the resolution of experimental rhinovirus infection.

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.

Modeling pulmonary nitric oxide exchange.

Nitric oxide (NO) was first detected in the exhaled breath more than a decade ago and has since been investigated as a noninvasive means of assessing lung inflammation. Exhaled NO arises from the airway and alveolar compartments, and new analytical methods have been developed to characterize these sources. A simple two-compartment model can adequately represent many of the observed experimental observations of exhaled concentration, including the marked dependence on exhalation flow rate. The model characterizes NO exchange by using three flow-independent exchange parameters. Two of the parameters describe the airway compartment (airway NO diffusing capacity and either the maximum airway wall NO flux or the airway wall NO concentration), and the third parameter describes the alveolar region (steady-state alveolar NO concentration). A potential advantage of the two-compartment model is the ability to partition exhaled NO into an airway and alveolar source and thus improve the specificity of detecting altered NO exchange dynamics that differentially impact these regions of the lungs. Several analytical techniques have been developed to estimate the flow-independent parameters in both health and disease. Future studies will focus on improving our fundamental understanding of NO exchange dynamics, the analytical techniques used to characterize NO exchange dynamics, as well as the physiological interpretation and the clinical relevance of the flow-independent parameters.

Absence of deep inspiration-induced bronchoprotection against inhaled allergen.

Deep inspiration-induced bronchoprotection appears to be a major mechanism through which airway obstruction by spasmogens is avoided. Loss of bronchoprotection is associated with airway hyper-responsiveness. Individuals with allergic rhinitis and no airway hyperresponsiveness develop obstruction after allergen inhalation. To test the hypothesis that deep inspiration-induced bronchoprotection is not active against allergic reactions, we performed four single-dose bronchial challenges, two with methacholine and two with allergen, on 10 subjects with allergic rhinitis. Without deep inspirations, the methacholine-induced reduction in FEV1 from baseline was 36.9 +/- 3.6% (mean +/- SEM); this was attenuated to 15.0 +/- 2.0 when five deep inspirations preceded methacholine inhalation (p = 0.0001). When allergen was inhaled, the reduction in FEV1 was 24.7 +/- 2.9% and 28.8 +/- 6.4% without and with deep inspirations, respectively. We conclude that bronchoprotection by deep inspirations is absent against allergic reactions. Understanding the cause of this phenomenon may shed light into the pathogenesis of airway hyperresponsiveness in allergic asthma.

Improvement in spirometry following lung volume reduction surgery: application of a physiologic model.

According to a previously published theoretical model of emphysema, the ratio of RV to TLC (RV/TLC) reflects the size mismatch between the hyperinflated lungs in the disease and the surrounding chest. The model suggests that RV/TLC is an important predictor of improvement in FVC and that increased FVC is an important determinant of increased FEV(1) after lung volume reduction surgery (LVRS). We tested these predictions in 13 patients undergoing LVRS, in whom we made detailed measurements of lung mechanics. Using stepwise regression, we found that RV/TLC was the only preoperative independent predictor of the increase in FVC. Seventy percent of the increase in FEV(1) was attributable to increased FVC, with the remainder due to increased FEV(1)/FVC. In a separate group of 78 LVRS patients evaluated with standard preoperative pulmonary function tests, RV/TLC again was found to correlate with the increase in FVC, and changes in FEV(1) were also due largely to changes in FVC. However, RV/TLC was not predictive of the increase in FEV(1) among the group of 78 patients, because FEV(1)/FVC in patients with a low preoperative RV/TLC often increased despite little change in FVC. These findings support the proposed mechanism for increased FVC following LVRS. They also illustrate the limitations of the model, and suggest further hypotheses for selecting patients who may benefit from surgery.