Leo C. Ginns

Severe alpha-1-antitrypsin deficiency is the only proven genetic risk factor for chronic obstructive pulmonary disease (COPD). We have assembled a cohort of 44 probands with severe, early-onset COPD, who do not have severe alpha-1-antitrypsin deficiency. A surprisingly high prevalence of females (79.6%) was found. Assessment of the risk to relatives of these early-onset COPD probands for airflow obstruction and chronic bronchitis was performed to determine whether significant familial aggregation for COPD, independent of alpha-1-antitrypsin deficiency, could be demonstrated. First- degree relatives of early-onset COPD probands had significantly lower FEV1 and FEV1/FVC values than control subjects (p < 0.01), despite similar pack-years of smoking. Reduced spirometric values in first-degree relatives of early-onset COPD probands were found only in current or ex-cigarette smokers. The mean FEV1 in current or ex-smoking first-degree relatives was 76.1 +/- 20.9% predicted compared to 89.2 +/- 14.4% predicted in current or ex-smoking control subjects (p < 0.01); in lifelong nonsmokers, the mean FEV1 was 93.4% predicted for both control subjects and first-degree relatives of early-onset COPD probands. Generalized estimating equations, adjusting for age and pack-years of smoking, demonstrated increased odds of reduced FEV1 and chronic bronchitis in current or ex-smoking first-degree relatives of early-onset COPD probands. Using a new method to estimate relative risk from relative odds, we estimate that the relative risks for FEV1 below 60%, FEV1 below 80%, and chronic bronchitis are each approximately three in current or ex-smoking first-degree relatives of early-onset COPD probands. The increased risk to relatives of early-onset COPD probands for reduced FEV1 and chronic bronchitis, limited to current or ex-smokers, suggests genetic risk factor(s) for COPD that are expressed in response to cigarette smoking.

Men have higher prevalence rates of chronic obstructive pulmonary disease (COPD) than women, which has been attributed to the historically higher rates of cigarette smoking in males. However, the increased rates of cigarette smoking in females within the last several decades have been associated with steadily increasing rates of COPD in women. As part of a study of the genetics of severe, early-onset COPD, we assembled a group of 84 probands with severe, early-onset COPD (without severe alpha(1)-antitrypsin deficiency) and 348 of their first-degree relatives. We found a markedly elevated prevalence (71.4%) of females among the early-onset COPD probands. Among the entire group of first-degree relatives of early-onset COPD probands, univariate analysis demonstrated similar spirometric values and bronchodilator responsiveness in males and females; however, among current or ex-smokers, female first-degree relatives had significantly lower FEV(1)/ FVC (81.4 +/- 17.2% in females versus 87.0 +/- 12.9% in males, p = 0.009) and significantly greater bronchodilator responsiveness (expressed as percentage of baseline FEV(1)) (7.7 +/- 9.4% pred in females versus 4.1 +/- 6.4% pred in males, p = 0.002). Female smoking first-degree relatives were significantly more likely to demonstrate profound reductions in FEV(1) (< 40% pred) than male smoking first-degree relatives (p = 0. 03). Multivariate analysis, performed with generalized estimating equations, demonstrated that current or ex-smoking female first-degree relatives had significantly greater risk of FEV(1) < 80% pred (OR 1.91, 95% CI 1.03- 3.54), FEV(1) < 40% pred (OR 3.56, 95% CI 1.08-11.71), and bronchodilator response greater than 10% of baseline FEV(1) (OR 4.74, 95% CI 1.91-11.75). These results suggest that women may be more susceptible to the development of severe COPD.

We characterized T-lymphocyte subsets in peripheral blood of smokers (N = 60) and nonsmokers (N = 35). Total T-lymphocytes and T cell subsets were similar to nonsmokers in light and moderate smokers. In heavy smokers, total OKT3+ cells were increased, the percentage of OKT4+ cells was decreased, and percentage and total number of OKT8+ cells were increased. The ratio of OKT4+ to OKT8+ lymphocytes was decreased in heavy smokers. The percentage of OKT8+ cells and the OKT4+/OKT8+ ratio returned to normal in heavy smokers six weeks after they stopped smoking. These findings suggest that cigarette smoking causes reversible alterations in immunoregulatory T cells.

<h3>Study objective</h3> To assess the relationship of distance amhulated during the 6-min walk test (6'WT) to maximal oxygen consumption ( <mml:math>V<mml:mo>˙</mml:mo></mml:math>o₂ max). <h3>Design</h3> Multivariate analysis of patient characteristics to <mml:math>V<mml:mo>˙</mml:mo></mml:math>o₂ max. <h3>Setting</h3> Pre-lung transplant evaluation. <h3>Patients</h3> 60 patients (22 men, 38 women; mean age, 44 years) with end-stage lung disease (mean FEV₁ and forced vital capacity of 0.97 and 1.93, respectively). <h3>Measurements and results</h3> The 6'WT was performed on a level hallway surface, and <mml:math>V<mml:mo>˙</mml:mo></mml:math>o₂ max was obtained during maximal cycle ergometry exercise testing with respiratory gas analysis. Multivariate analysis of patient characteristics (age, sex, weight, FEV₁, FVC, diffusing capacity for carbon monoxide (DCO), 6'WT distance ambulated, number of rests per 6'WT, and the maximal heart rate, blood pressure, rate-pressure product, respiratory rate, oxygen saturation, rating of perceived exertion, and amount of supplemental oxygen used during the 6'WT) was performed on two groups of 30 patients each (group A or B) who were randomly assigned to either group by a process of random selection using a computer-generated random numbers program. Distance ambulated was the strongest independent predictor of <mml:math>V<mml:mo>˙</mml:mo></mml:math>o₂ max (r=0.73; p<0.0001) in both groups, and adding age, weight, and pulmonary function test results (FVC, FEV₁, and DCO) to the regression equation increased the correlation coefficient to 0.83. Because of the significant correlation of distance ambulated during the 6'WT to <mml:math>V<mml:mo>˙</mml:mo></mml:math>o₂ max, the prediction equation obtained from the multivariate analysis of group A, <mml:math>V<mml:mo>˙</mml:mo></mml:math>o₂ max=0.006×distance (feet) +3.38, was used to estimate the <mml:math>V<mml:mo>˙</mml:mo></mml:math>o₂ max of the group B patients. No significant difference was observed between the estimated (x±SD= 8.9±2.4 mL/kg/min) and observed (x±SD=9.4±3.8 mL/kg/min) <mml:math>V<mml:mo>˙</mml:mo></mml:math>o₂ max (mean difference, 0.5 mL/kg/min; SD of the difference=2.88). <h3>Conclusions</h3> The distance ambulated during a 6'WT can predict <mml:math>V<mml:mo>˙</mml:mo></mml:math>o₂ max in patients with end-stage lung disease. The addition of several patient characteristics can increase the ability to predict <mml:math>V<mml:mo>˙</mml:mo></mml:math>o₂ max and account for more of the variability. Such information is valuable when assessing patient response to therapeutic intervention if respiratory gas analysis is unavailable or impractical. <i>(CHEST 1995; 108:452-59)</i>

Chronic obstructive pulmonary disease (COPD) is a common, complex disease associated with substantial morbidity and mortality. COPD is defined by irreversible airflow obstruction; airflow obstruction is typically determined by reductions in quantitative spirometric indices, including forced expiratory volume at 1 s (FEV(1)) and the ratio of FEV(1) to forced vital capacity (FVC). To identify genetic determinants of quantitative spirometric phenotypes, an autosomal 10-cM genomewide scan of short tandem repeat (STR) polymorphic markers was performed in 72 pedigrees (585 individuals) ascertained through probands with severe early-onset COPD. Multipoint variance-component linkage analysis (using SOLAR) was performed for quantitative phenotypes, including FEV(1), FVC, and FEV(1)/FVC. In the initial genomewide scan, significant evidence for linkage to FEV(1)/FVC was demonstrated on chromosome 2q (LOD score 4.12 at 222 cM). Suggestive evidence was found for linkage to FEV(1)/FVC on chromosomes 1 (LOD score 1.92 at 120 cM) and 17 (LOD score 2.03 at 67 cM) and to FVC on chromosome 1 (LOD score 2.05 at 13 cM). The highest LOD score for FEV(1) in the initial genomewide scan was 1.53, on chromosome 12, at 36 cM. After inclusion of 12 additional STR markers on chromosome 12p, which had been previously genotyped in this population, suggestive evidence for linkage of FEV(1) (LOD score 2.43 at 37 cM) to this region was demonstrated. These observations provide both significant evidence for an early-onset COPD-susceptibility locus on chromosome 2 and suggestive evidence for linkage of spirometry-related phenotypes to several other genomic regions. The significant linkage of FEV(1)/FVC to chromosome 2q could reflect one or more genes influencing the development of airflow obstruction or dysanapsis.

Bilateral volume reduction surgery (VRS) improves lung function for selected patients with emphysema. However, predictors of outcome are not well defined. We reviewed the preoperative characteristics of the first 47 consecutive patients who underwent bilateral VRS at the Massachusetts General Hospital in order to define potential predictors of unacceptable outcome. Preoperative data included spirometry, plethysmography, diffusion of carbon monoxide (DCO), maximum inspiratory pressure (MIP), maximum expiratory pressure, resting arterial blood gases (ABG), cardiopulmonary exercise testing with ABG and lactate sampling, and radionuclide ventriculography. Prepulmonary and postpulmonary rehabilitation 6-min walk tests (6MWT), and preoperative chest CT scans were also obtained. Twenty-two subjects were male and 17 of the subjects were on the lung transplant list. Patient characteristics included age of 60.5 ± 7.5 years, FEV1 of 0.67 ± 0.20 L, total lung capacity of 7.56 ± 1.7 L, DCO of 7.40 ± 4.1 mL/min/mm Hg, and PaCO2 of 41.6 ± 6.4 mm Hg (mean±SD). The FEV1, vital capacity, MIP, resting room air PaCO2, prepulmonary and postpulmonary rehabilitation 6MWT, and PaCO2 at maximum oxygen consumption correlated with length of hospitalization (p<0.05). Based on analysis of 41 of 47 patients for whom there were complete data, the inability to walk more than 200 m on the 6MWT before or after preoperative pulmonary rehabilitation, and resting PaCO2≥45 mm Hg were the best predictors of an unacceptable outcome. If either of these characteristics was present, six of 16 vs zero of 25 died (Fisher's Exact Test, p=0.0025, one-tailed) and 11 of 16 vs four of 25 had hospital courses >21 days (p<0.002). Both the 6MWT <200 m and resting PaCO2 ≥45 mm Hg alone correlated with death (p=0.004 and p=0.012, respectively) and the resting PaCO2 ≥45 mm Hg correlated with hospital days >21 (p=0.0002). In conclusion, the data suggest that the inability to walk at least 200 m in 6 min before or after pulmonary rehabilitation and a resting room air PaCO2≥45 mm Hg are excellent preoperative predictors of unacceptable postoperative outcomes. Bilateral volume reduction surgery (VRS) improves lung function for selected patients with emphysema. However, predictors of outcome are not well defined. We reviewed the preoperative characteristics of the first 47 consecutive patients who underwent bilateral VRS at the Massachusetts General Hospital in order to define potential predictors of unacceptable outcome. Preoperative data included spirometry, plethysmography, diffusion of carbon monoxide (DCO), maximum inspiratory pressure (MIP), maximum expiratory pressure, resting arterial blood gases (ABG), cardiopulmonary exercise testing with ABG and lactate sampling, and radionuclide ventriculography. Prepulmonary and postpulmonary rehabilitation 6-min walk tests (6MWT), and preoperative chest CT scans were also obtained. Twenty-two subjects were male and 17 of the subjects were on the lung transplant list. Patient characteristics included age of 60.5 ± 7.5 years, FEV1 of 0.67 ± 0.20 L, total lung capacity of 7.56 ± 1.7 L, DCO of 7.40 ± 4.1 mL/min/mm Hg, and PaCO2 of 41.6 ± 6.4 mm Hg (mean±SD). The FEV1, vital capacity, MIP, resting room air PaCO2, prepulmonary and postpulmonary rehabilitation 6MWT, and PaCO2 at maximum oxygen consumption correlated with length of hospitalization (p<0.05). Based on analysis of 41 of 47 patients for whom there were complete data, the inability to walk more than 200 m on the 6MWT before or after preoperative pulmonary rehabilitation, and resting PaCO2≥45 mm Hg were the best predictors of an unacceptable outcome. If either of these characteristics was present, six of 16 vs zero of 25 died (Fisher's Exact Test, p=0.0025, one-tailed) and 11 of 16 vs four of 25 had hospital courses >21 days (p<0.002). Both the 6MWT <200 m and resting PaCO2 ≥45 mm Hg alone correlated with death (p=0.004 and p=0.012, respectively) and the resting PaCO2 ≥45 mm Hg correlated with hospital days >21 (p=0.0002). In conclusion, the data suggest that the inability to walk at least 200 m in 6 min before or after pulmonary rehabilitation and a resting room air PaCO2≥45 mm Hg are excellent preoperative predictors of unacceptable postoperative outcomes.

Coronavirus disease 2019 (COVID-19) is a disease caused by severe acute respiratory syndrome-coronavirus-2. Consensus suggestions can standardise care, thereby improving outcomes and facilitating future research.An International Task Force was composed and agreement regarding courses of action was measured using the Convergence of Opinion on Recommendations and Evidence (CORE) process. 70% agreement was necessary to make a consensus suggestion.The Task Force made consensus suggestions to treat patients with acute COVID-19 pneumonia with remdesivir and dexamethasone but suggested against hydroxychloroquine except in the context of a clinical trial; these are revisions of prior suggestions resulting from the interim publication of several randomised trials. It also suggested that COVID-19 patients with a venous thromboembolic event be treated with therapeutic anticoagulant therapy for 3 months. The Task Force was unable to reach sufficient agreement to yield consensus suggestions for the post-hospital care of COVID-19 survivors. The Task Force fell one vote shy of suggesting routine screening for depression, anxiety and post-traumatic stress disorder.The Task Force addressed questions related to pharmacotherapy in patients with COVID-19 and the post-hospital care of survivors, yielding several consensus suggestions. Management options for which there is insufficient agreement to formulate a suggestion represent research priorities.

Abnormal fibrogenic repair response upon alveolar injury is believed to play an important role in the pathogenesis of idiopathic pulmonary fibrosis (IPF). PRM-151 (recombinant human pentraxin-2, also known as serum amyloid P), has been shown to reduce fibrosis in preclinical lung fibrosis models, and was well tolerated with a favourable pharmacokinetic profile in an earlier single-dose phase I study. A randomised, double-blind, placebo-controlled, multiple ascending dose trial was performed to assess the tolerability and pharmacokinetic and pharmacodynamic characteristics of multiple doses of PRM-151 in IPF patients. Subjects in three successive cohorts (1, 5, or 10 mg·kg −1 versus placebo) received intravenous study drug on days 1, 3, 5, 8 and 15, and were followed-up to day 57. PRM-151 was well tolerated at all dose levels, with no serious adverse reactions. Administration of PRM-151 resulted in two- to eight-fold dose-dependent increases in circulating pentraxin-2 levels. Forced vital capacity and 6-min walk test showed trends towards improvement in the combined PRM-151 dose groups. On high-resolution computed tomography scans, stable or improved lung volume unoccupied by interstitial lung abnormality was noted in some PRM-151 subjects compared to placebo subjects on day 57. The efficacy of PRM-151 in IPF remains to be investigated in dedicated future trials.

<h3>Importance</h3> Alteration in lung microbes is associated with disease progression in idiopathic pulmonary fibrosis. <h3>Objective</h3> To assess the effect of antimicrobial therapy on clinical outcomes. <h3>Design, Setting, and Participants</h3> Pragmatic, randomized, unblinded clinical trial conducted across 35 US sites. A total of 513 patients older than 40 years were randomized from August 2017 to June 2019 (final follow-up was January 2020). <h3>Interventions</h3> Patients were randomized in a 1:1 allocation ratio to receive antimicrobials (n = 254) or usual care alone (n = 259). Antimicrobials included co-trimoxazole (trimethoprim 160 mg/sulfamethoxazole 800 mg twice daily plus folic acid 5 mg daily, n = 128) or doxycycline (100 mg once daily if body weight &lt;50 kg or 100 mg twice daily if ≥50 kg, n = 126). No placebo was administered in the usual care alone group. <h3>Main Outcomes and Measures</h3> The primary end point was time to first nonelective respiratory hospitalization or all-cause mortality. <h3>Results</h3> Among the 513 patients who were randomized (mean age, 71 years; 23.6% women), all (100%) were included in the analysis. The study was terminated for futility on December 18, 2019. After a mean follow-up time of 13.1 months (median, 12.7 months), a total of 108 primary end point events occurred: 52 events (20.4 events per 100 patient-years [95% CI, 14.8-25.9]) in the usual care plus antimicrobial therapy group and 56 events (18.4 events per 100 patient-years [95% CI, 13.2-23.6]) in the usual care group, with no significant difference between groups (adjusted HR, 1.04 [95% CI, 0.71-1.53;<i>P</i> = .83]. There was no statistically significant interaction between the effect of the prespecified antimicrobial agent (co-trimoxazole vs doxycycline) on the primary end point (adjusted HR, 1.15 [95% CI 0.68-1.95] in the co-trimoxazole group vs 0.82 [95% CI, 0.46-1.47] in the doxycycline group;<i>P</i> = .66). Serious adverse events occurring at 5% or greater among those treated with usual care plus antimicrobials vs usual care alone included respiratory events (16.5% vs 10.0%) and infections (2.8% vs 6.6%); adverse events of special interest included diarrhea (10.2% vs 3.1%) and rash (6.7% vs 0%). <h3>Conclusions and Relevance</h3> Among adults with idiopathic pulmonary fibrosis, the addition of co-trimoxazole or doxycycline to usual care, compared with usual care alone, did not significantly improve time to nonelective respiratory hospitalization or death. These findings do not support treatment with these antibiotics for the underlying disease. <h3>Trial Registration</h3> ClinicalTrials.gov Identifier:NCT02759120

Breathing low concentrations of nitric oxide (NO) produces selective pulmonary vasodilatation and increases exercise capacity in patients with pulmonary hypertension of various etiologies, 1 Frostell C.G. Blomqvist H. Hedenstierna G. Lundberg J. Zapol W.M. Inhaled nitric oxide selectively reverses human hypoxic pulmonary vasoconstriction without causing systemic vasodilation. Anesthesiology. 1993; 78: 427-435 Crossref PubMed Scopus (401) Google Scholar , 2 Hasuda T. Satoh T. Shimouchi A. Sakamaki F. Kyotani S. Matsumoto T. Goto Y. Nakanishi N. Improvement in exercise capacity with nitric oxide inhalation in patients with precapillary pulmonary hypertension. Circulation. 2000; 101: 2066-2070 Crossref PubMed Scopus (44) Google Scholar and an acute pulmonary vasodilator response to NO inhalation has been used as a predictor of response to oral vasodilators. 3 Cockrill B.A. Kacmarek R.M. Fifer M.A. Bigatello L.M. Ginns L.C. Zapol W.M. Semigran M.J. Comparison of the effects of nitric oxide, nitroprusside, and nifedipine on hemodynamics and right ventricular contractility in patients with chronic pulmonary hypertension. Chest. 2001; 119: 128-136 Crossref PubMed Scopus (60) Google Scholar Continuous or intermittent NO inhalation has been proposed as chronic pulmonary vasodilator therapy; 4 Channick R.N. Newhart J.W. Johnson F.W. Williams P.J. Auger W.R. Fedullo P.F. Moser K.M. Pulsed delivery of inhaled nitric oxide to patients with primary pulmonary hypertension an ambulatory delivery system and initial clinical tests. Chest. 1996; 109: 1545-1549 Crossref PubMed Scopus (174) Google Scholar however, many patients with pulmonary hypertension do not have a pulmonary vasodilator response to inhaled NO, and in patients who do respond, the duration of vasodilatation after cessation of NO inhalation is brief. Inhaled NO exerts its pulmonary vasodilator effects by diffusing into pulmonary vascular smooth muscle cells and stimulating the production of cyclic guanosine 3′-5′ monophosphate, a mediator of vasodilatation. 5 Steudel W. Hurford W.E. Zapol W.M. Inhaled nitric oxide basic biology and clinical applications. Anesthesiology. 1999; 91: 1090-1121 Crossref PubMed Scopus (139) Google Scholar One approach to augment and prolong the pulmonary vasodilator effects of inhaled NO is the concomitant administration of an inhibitor of cyclic guanosine 3′-5′ monophosphate metabolism. Sildenafil is a selective inhibitor of type 5 phosphodiesterase, a phosphodiesterase isoenzyme that metabolizes cyclic guanosine 3′-5′ monophosphate specifically and is present in pulmonary vascular smooth muscle cells. 6 Corbin J.D. Francis S.H. Cyclic GMP phosphodiesterase-5 target of sildenafil. J Biol Chem. 1999; 274: 13729-13732 Crossref PubMed Scopus (467) Google Scholar Our laboratory has recently reported that sildenafil is a selective pulmonary vasodilator in lambs with experimental pulmonary hypertension. 7 Weimann J. Ullrich R. Hromi J. Fujino Y. Clark M.W. Bloch K.D. Zapol W.M. Sildenafil is a pulmonary vasodilator in awake lambs with acute pulmonary hypertension. Anesthesiology. 2000; 92: 1702-1712 Crossref PubMed Scopus (205) Google Scholar Several case reports have suggested that sildenafil has pulmonary vasodilator effects in humans, 8 Prasad S. Wilkinson J. Gatzoulis M.A. Sildenafil in primary pulmonary hypertension. N Engl J Med. 2000; 343: 1342 Crossref PubMed Scopus (313) Google Scholar , 9 Zhao L. Mason N.A. Morrell N.W. Kojonazarov B. Sadykov A. Maripov A. Mirrakhimov M.M. Aldashev A. Wilkins M.R. Sildenafil inhibits hypoxia-induced pulmonary hypertension. Circulation. 2001; 104: 424-428 Crossref PubMed Scopus (431) Google Scholar , 10 Wilkens H. Guth A. Konig J. Forestier N. Cremers B. Hennen B. Bohm M. Sybrecht G.W. Effect of inhaled iloprost plus oral sildenafil in patients with primary pulmonary hypertension. Circulation. 2001; 104: 1218-1222 Crossref PubMed Scopus (373) Google Scholar that it can augment the pulmonary vasodilator effects of inhaled NO, 11 Bigatello L.M. Hess D. Dennehy K.C. Medoff B.D. Hurford W.E. Sildenafil can increase the response to inhaled nitric oxide. Anesthesiology. 2000; 92: 1827-1829 Crossref PubMed Scopus (64) Google Scholar and that it can prevent rebound pulmonary hypertension after cessation of NO inhalation. 12 Atz A.M. Wessel D.L. Sildenafil ameliorates effects of inhaled nitric oxide withdrawal. Anesthesiology. 1999; 91: 307-310 Crossref PubMed Scopus (317) Google Scholar , 13 Mychaskiw G. Sachdev V. Heath B.J. Sildenafil (Viagra) facilitates weaning of inhaled nitric oxide following placement of a biventricular-assist device. J Clin Anesth. 2001; 13: 218-220 Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar In this report, we describe hemodynamic effects of sildenafil administered alone and in combination with inhaled NO in a series of adult patients with primary pulmonary hypertension.

Analysis of peripheral blood T cells and T cell subsets by immunofluorescence and flow cytometry is employed commonly in studies of normal individuals and in certain disease states. Methods for separating T cells from granulocytes and erythrocytes vary. We have sought to determine whether or not such procedures alter the composition of cells being analyzed. In this communication, we report that, in normal individuals, Ficoll-Hypaque separation of lymphocytes selectively decreases the OKT8+ subset compared to the whole blood lysis technique (P less than 0.01). The decrease in the OKT8+ subset results in a significant increase (P less than 0.01) in the OKT4/OKT8 ratio. This disparity appears to be due to a selective loss of OKT8+ cells during centrifugation over Ficoll-Hypaque. With the Ficoll-Hypaque method, we have also found that the fixation of lymphocytes reacted with monoclonal antibodies is less stable than cells prepared by the whole blood lysis method. The interpretation of measurements of T cell subsets is influenced by the method by which these cells are isolated.

Dyspnea and exercise intolerance are commonly reported post-acute sequelae of SARS-CoV-2 infection (PASC), but routine diagnostic testing is often normal. Cardiopulmonary exercise testing (CPET) offers comprehensive assessment of dyspnea to characterize pulmonary PASC.We performed a retrospective cohort study of CPET performed on patients reporting dyspnea and/or exercise intolerance following confirmed Covid-19 between August 1, 2020 and March 1, 2021, and compared them to age- and sex-matched patients with unexplained dyspnea referred for CPET at the same center in the pre-Covid-19 era.Compared to matched unexplained dyspnea comparators, PASC patients shared similar medical comorbidities and subjective dyspnea at referral (mMRC score 1.6 ± 0.9 vs. 1.4 ± 0.9, P = 0.5). Fifteen (83.3%) PASC patients underwent high resolution computed tomography of the chest, of which half (46.7%) were normal, and 17 (94.4%) patients had pulmonary function testing, of which the majority (76.5%) were normal. All patients underwent CPET, and 12 (67%) had normal findings. Compared to matched comparators, PASC patients had similar peak oxygen consumption, oxygen consumption at ventilatory anaerobic threshold, and ventilatory efficiency measured by the minute ventilation to carbon dioxide production (VE/VCO2) slope.Despite prominent dyspnea, physiological abnormalities on CPET were mild across a range of initial Covid-19 severity and similar to matched comparators referred for dyspnea without antecedent SARS-CoV-2.The project was supported by the NHLBI (R01HL131029, R01HL151841, U10HL110337, T32HL116275) and a KL2 award (5KL2TR002542-02) from Harvard Catalyst.

We tested the hypothesis that breathing 100% oxygen could result in selective pulmonary vasodilatation in patients with pulmonary hypertension, including those patients who would not meet current Health Care Finance Administration guidelines for long-term oxygen therapy.From 1996 to 1999, 23 adult patients (mean +/- SEM age, 51 +/- 4 years) with pulmonary arterial hypertension without left-heart failure underwent cardiac catheterization in a university teaching hospital while breathing air and then 100% oxygen.Treatment with 100% oxygen increased arterial oxygen saturation (91 +/- 1% to 99 +/- 0.1%, p < 0.05) and PaO(2) (64 +/- 3 to 309 +/- 28 mm Hg, p < 0.05). Treatment with 100% oxygen also decreased mean pulmonary artery pressure (56 +/- 3 to 53 +/- 2 mm Hg, p < 0.05) and increased cardiac index (2.1 +/- 0.1 to 2.5 +/- 0.2 L/min/m(2), p < 0.05). Calculated mean pulmonary vascular resistance (PVR) decreased from 14.1 +/- 1.4 to 10.6 +/- 1.0 Wood units (p < 0.05). Vasodilatation with 100% oxygen occurred preferentially in the pulmonary circulation (PVR/systemic vascular resistance, 0.53 +/- 0.04 to 0.48 +/- 0.03; p < 0.05). The magnitude of the PVR response to oxygen therapy was correlated only with decreasing patient age (r = 0.45, p < 0.05).Treatment with 100% oxygen is a selective pulmonary vasodilator in patients with pulmonary hypertension, regardless of primary diagnosis, baseline oxygenation, or right ventricular function. Development of disease-specific oxygen prescription guidelines warrants consideration.

The purpose of this work was to determine whether cross-sectional area and coronal and sagittal diameter measurements of the trachea between inspiration and end-expiration on CT are significantly different between patients with acquired tracheomalacia and those without this condition.Inspiratory and end-expiratory CT scans of the trachea of 23 normal patients and 10 patients with acquired tracheomalacia were analyzed. Percent changes in cross-sectional area, coronal, and sagittal diameters were calculated.For patients with tracheomalacia, mean percent changes in the upper and middle trachea between inspiration and expiration were 49 and 44%; mean changes in the coronal and sagittal diameters in the upper and middle tracheal were 4 and 10% and 39 and 54%, respectively. Control group mean percent changes in the upper and middle tracheal area were 12 and 14%, respectively, and mean changes in the coronal and sagittal diameters in the upper and middle trachea were 4 and 4% and 11 and 13%, respectively. Significant differences were calculated for changes in cross-sectional area and sagittal diameter between groups (p < 10-5). Based on receiver operator curve analysis, a > 18% change in the upper trachea and 28% change in the midtrachea between inspiration and expiration were observed; the probability of tracheomalacia was 89-100%. The probability of tracheomalacia was > 89%, especially if the change in sagittal diameter was > 28%.By measuring changes in tracheal cross-sectional area and sagittal diameters between inspiratory and end-expiratory CT, a significant difference can be identified between normal patients and those with acquired tracheomalacia.

Although lung transplantation improves exercise capacity by removal of a ventilatory limitation, recipients' postoperative maximum oxygen uptake (VO2max) remains markedly abnormal. To determine if abnormal skeletal muscle oxidative capacity contributes to this impaired aerobic capacity, nine lung transplant recipients and eight healthy volunteers performed incremental quadriceps exercise to exhaustion with simultaneous measurements of pulmonary gas exchange, minute ventilation, blood lactate, and quadriceps muscle pH and phosphorylation potential by 31P-magnetic resonance spectroscopy (31P-MRS). Five to 38 mo after lung transplantation, peak VO2 was decreased compared with that of normal control subjects (6.7 +/- 0.4 versus 12.3 +/- 1.0 ml/min/kg, p < 0.001), even after accounting for differences in age and lean body weight. Neither ventilation, arterial O2 saturation nor mild anemia could account for the decrease in aerobic capacity. Quadriceps muscle intracellular pH (pH(i)) was more acidic at rest (7.07 +/- 0.01 versus 7.12 +/- 0.01 units, p < 0.05) and fell during exercise from baseline values at a lower metabolic rate (282 +/- 21 versus 577 +/- 52 ml/min, p < 0.001). Regressions for pH(i) versus VO2, phosphocreatine/inorganic phosphate ratio (PCr/Pi) versus VO2, and blood lactate versus pH(i) were not different. Among transplant recipients, the metabolic rate at which pH(i) fell correlated closely with VO2max (r = 0.87, p < 0.01). The persistent decrease in VO2max after lung transplantation may be related to abnormalities of skeletal muscle oxidative capacity.

Rationale and Objectives. The purpose of the study was to determine the relationship between pulmonary artery (PA) size at computed tomography (CT) and PA pressures, to develop a noninvasive CT method of PA pressure measurement, and to determine a PA diameter that can enable differentiation of normal subjects from those with ptfimonary hypertension. Methods. PA vessel diameters in 55 candidates for lung and heart-lung transplantation were measured at CT and correlated with PA pressures with both linear and stepwise multiple regression. The multiple regression equations were then tested prospectively in 35 pretransplantation patients. Results. Combined main and left main PA cross-sectional area corrected for body surface area showed the best correlation with mean PA pressure (r = .87). The multiple regression equations helped predict mean PA pressure within 5 mm Hg in 50% of patients with chronic lung disease and in only 8% of patients with pulmonary vascular disease. Conclusion. There was a very good correlation between main and left main PA size and mean PA pressure. At present, however, CT has not demonstrated sufficient accuracy to be used clinically. The purpose of the study was to determine the relationship between pulmonary artery (PA) size at computed tomography (CT) and PA pressures, to develop a noninvasive CT method of PA pressure measurement, and to determine a PA diameter that can enable differentiation of normal subjects from those with ptfimonary hypertension. PA vessel diameters in 55 candidates for lung and heart-lung transplantation were measured at CT and correlated with PA pressures with both linear and stepwise multiple regression. The multiple regression equations were then tested prospectively in 35 pretransplantation patients. Combined main and left main PA cross-sectional area corrected for body surface area showed the best correlation with mean PA pressure (r = .87). The multiple regression equations helped predict mean PA pressure within 5 mm Hg in 50% of patients with chronic lung disease and in only 8% of patients with pulmonary vascular disease. There was a very good correlation between main and left main PA size and mean PA pressure. At present, however, CT has not demonstrated sufficient accuracy to be used clinically.

"Dynamic Contrast-Enhanced MRI Demonstrates Pulmonary Microvascular Abnormalities Months After SARS-CoV-2 Infection ." American Journal of Respiratory and Critical Care Medicine, 0(ja), pp.

Multiple risk factors for mortality in patients with COPD have been described, but most studies have involved older, primarily male subjects. The purpose of this study was to determine the mortality rate and predictors of survival in subjects with severe, early onset COPD.The cohort of 139 probands in the Boston Early-Onset COPD Study was recruited from lung transplant and general pulmonary clinics between September 1994 and July 2002. Subjects were < 53 years old, had an FEV(1) of < 40% of predicted, did not have severe alpha(1)-antitrypsin deficiency, and had not undergone lung transplantation. The initial evaluation included a standardized respiratory questionnaire, spirometry, and a blood sample. A follow-up telephone interview was conducted between May and December 2002.Subjects were young (mean age at enrollment, 47.9 years) and had severe airflow obstruction (mean baseline FEV(1), 19.4% predicted). A total of 72.7% of the subjects were women (p < 0.0001 [comparison to equal gender distribution]). The median estimated survival time was 7.0 years from the time of study enrollment, determined by the Kaplan-Meier method. The majority of deaths were due to cardiorespiratory illness. In a multivariable Cox proportional hazards model, adjusting for age, gender, and baseline FEV(1), lifetime cigarette consumption (hazard ratio [HR], 1.20 [per 10 pack-years]; 95% confidence interval [CI], 1.02 to 1.40) and recent smoking status (HR, 2.50; 95% CI, 1.03 to 6.05) were both significant predictors of mortality.In this cohort, recent smoking status predicted increased mortality independent of the effects of lifetime smoking intensity. Smoking cessation may confer a survival benefit even among patients with very severe COPD.

Leukotriene B4 is a lipid mediator that recently has been shown to have potent chemotactic activity for effector T lymphocytes mediated through its receptor, BLT1. Here, we developed a novel murine model of acute lung rejection to demonstrate that BLT1 controls effector CD8+ T cell trafficking into the lung and that disruption of BLT1 signaling in CD8+ T cells reduces lung inflammation and mortality in the model. In addition, we used BLT1-deficient mice and a BLT1 antagonist in two tracheal transplant models of lung transplantation to demonstrate the importance of BLT1 for the recruitment of T cells into tracheal allografts. We also show that BLT1-mediated CD8+ T cell recruitment plays an important role in the development of airway fibroproliferation and obliteration. Finally, in human studies of lung transplant recipients, we found that BLT1 is up-regulated on T lymphocytes isolated from the airways of patients with obliterative bronchiolitis. These data demonstrate that BLT1 contributes to the development of lung rejection and obliterative bronchiolitis by mediating effector T lymphocyte trafficking into the lung. This is the first report that describes a pathologic role for BLT1-mediated T lymphocyte recruitment in disease and identifies BLT1 as a potential therapeutic target after lung transplantation.

Thymus-dependent (T) lymphocytes may contribute to the pathogenesis of human interstitial lung disease. In order to determine whether alterations of immunoregulatory T cells occur in patients with idiopathic pulmonary fibrosis (IPF) and sarcoidosis, we characterized T lymphocytes in peripheral blood (n = 8 and 11, respectively) and lung lavage (n = 4 and 6, respectively) in untreated patients with these diseases. In IPF, we found a decreased percentage, but normal total count of circulating OKT3+ (mature) and OKT4+ (inducer/helper) cells compared to normal controls. We observed a normal percentage and total count of circulating OKT8+ (cytotoxic/suppressor) cells. The ratio of OKT4+ to OKT8+ (48) lymphocytes, reflecting the balance of immunoregulatory cells, was normal in peripheral blood. Comparing peripheral blood to lung lavage, we noted a lower proportion of OKT4+ cells and a higher proportion of OKT8+ cells in lung lavage. The 48 ratio in lung lavage tended to be low compared to blood. In contrast, we found in sarcoidosis patients a decrease in both percentage and total circulating OKT3+, OKT4+, and OKT8+ cells as compared to normal. In lung lavage, there was an increase in OKT3+ cells, due to an increase in the OKT4+ subset. The percentage of OKT8+ cells in lung lavage was low. Compared to blood the 48 ratio was high in lung lavage. Thus, a number of alterations in circulating and lavage T cells were found both in patients with IPF and sarcoidosis. These results suggest that immunoregulatory abnormalities contribute to pathogenesis of these disorders.

Influenza causes significant morbidity and mortality in lung transplant recipients and likely predisposes to obliterative bronchiolitis. Neuraminidase inhibitors shorten the duration of symptoms and virus shedding and the number of antibiotic-requiring complications in ambulatory immunocompetent patients, although the efficacy of these agents in lung transplant recipients has not been assessed previously.In this study, 9 lung transplant patients who were treated with oseltamivir for influenza infections were identified and analyzed retrospectively.Oseltamivir was well tolerated. Infection resolved in all patients and there were no deaths. Two patients developed pneumonia shortly after their influenza infection and both responded to antibiotic therapy. None of the patients had persistent abnormalities noted on chest imaging and most did not show significant changes on pulmonary function testing. Two patients with the lowest pulmonary function test (PFT) values pre-infection had persistent defects after infection.Oseltamivir is well tolerated in lung transplant recipients and may reduce the risk of complications, although further studies are warranted.

The effects of inhaled nitric oxide (NO) on hemodynamics and right ventricular (RV) contractility were compared with those of nitroprusside and nifedipine in 14 patients with severe chronic pulmonary hypertension.Micromanometer and balloon-tipped right heart catheterization were performed. Inhaled NO, IV nitroprusside, and sublingual nifedipine were administered sequentially while patients breathed > 90% oxygen.Cardiac catheterization laboratory in a tertiary care teaching hospital.Fourteen patients with severe pulmonary hypertension unrelated to left ventricular dysfunction.During NO inhalation, mean systemic arterial pressure (MAP) was unchanged, but pulmonary artery (PA) pressure ([mean +/- SEM] 49 +/- 2 mm Hg vs 44 +/- 2 mm Hg; p < 0.01), pulmonary vascular resistance (PVR; 829 +/- 68 vs 669 +/- 64 dyne x s x cm(-5); p < 0.01) and RV end-diastolic pressure (RVEDP; 12 +/- 1 vs 10 +/- 1 mm Hg; p < 0.01) decreased. Stroke volume index (SVI; 31 +/- 2 vs 35 +/- 3 mL/m(2); p < 0.05) increased, and the first derivative of RV pressure at 15 mm Hg developed pressure (RV +dP/dt at DP15) was unchanged. During nitroprusside administration, MAP decreased (105 +/- 5 vs 76 +/- 5 mm Hg; p < 0.01), PA was unchanged (48 +/- 2 vs 45 +/- 3 mm Hg; p = not significant), and PVR decreased (791 +/- 53 vs 665 +/- 53 dyne x s x cm(-5); p < 0.01). RV +dP/dt at DP15 increased (425 +/- 22 vs 465 +/- 29 mm Hg/s; p < 0.05), but SVI was unchanged. Nifedipine decreased MAP (103 +/- 5 vs 94 +/- 5 mm Hg; p < 0.01), PA and PVR were unchanged, RVEDP increased (12 +/- 1 vs 14 +/- 2 mm Hg; p < 0.01), and RV +dP/dt at DP15 decreased (432 +/- 90 vs 389 +/- 21 mm Hg/s; p < 0.05).Inhaled NO is a selective pulmonary vasodilator in patients with chronic pulmonary hypertension that improves cardiac performance without altering RV contractility. Nitroprusside caused a similar degree of pulmonary vasodilation. In contrast to inhaled NO, nitroprusside caused systemic hypotension associated with an increase in RV contractility. Acute administration of nifedipine did not cause pulmonary vasodilation, but RVEDP increased and RV contractility decreased.

We report here our experience in achieving remission in a 20-year-old man with pulmonary capillary hemangiomatosis (PCH) with atypical endotheliomatosis following therapy with doxycycline. PCH is a rare disorder characterized by proliferating capillaries that invade the pulmonary interstitium and alveolar septae, and occlude the pulmonary vasculature. The patient's symptoms, lung function, and radiographic findings had worsened despite treatment with both prednisone and alpha-interferon. He was considered to be a candidate for transplantation. Given the elevated levels of basic fibroblast growth factor (bFGF) in urine and the capillary proliferation noted on biopsy specimens, we elected to treat the patient with doxycycline, a matrix metalloproteinase and angiogenesis inhibitor. Following several weeks of therapy, a gradual resolution of symptoms was noted, with normalization of pulmonary function test results and urine bFGF levels. After 18 months of therapy, the patient remains in complete remission.

Blunted maximum cardiac output and systemic O2 extraction could constitute primary limits to exercise in severe chronic obstructive pulmonary disease (COPD) or they could simply reflect cessation of exercise because of abnormal pulmonary mechanics. To determine which is the case, eight consecutive patients with severe COPD (FEV1 = 0.56 ± 0.04 L, mean ± SEM), five of whom had α 1-antiprotease deficiency, performed two incremental cycling tests while breathing N2-O2 or He-O2. Expired gases and V˙ e were measured, and radial and pulmonary arterial blood was simultaneously sampled each minute. Peak exercise V˙ e was higher with He-O2 than with N2-O2 (25.5 ± 2.2 versus 19.3 ± 1.5 L/min, p = 0.002) and PaCO2 was lower (42 ± 2 versus 46 ± 2 mm Hg, p = 0.0003). V˙ o 2max improved only modestly (594 ± 75 versus 514 ± 54 ml/min, p = 0.04), and was accompanied by an increase in peak exercise CaO2 (18.7 ± 0.9 versus 17.6 ± 0.9 ml/dl, p = 0.02). Peak Fick cardiac output was decreased (39 ± 3% pred) and CvO2 was elevated (130 ± 10% pred), and neither improved with He-O2 (p > 0.05 for each). Abnormal peak exercise cardiac output and systemic O2 extraction in severe COPD cannot be fully accounted for by limiting pulmonary mechanics and may contribute to exercise intolerance.

Background Because of the shortage of donor lungs, liberalization of donor selection criteria in terms of age, gas exchange, and smoking history has been proposed. Methods We evaluated a single-institution population of lung transplant recipients (n = 98) for donor—recipient gender matching. We measured overall survival, time to acute allograft rejection, and time to development of obliterative bronchiolitis (OB). Results We found significant improvement in overall survival for gender-mismatched donor and recipient pairs (p = 0.078) and a significantly shorter OB-free period for male donor and female recipient pairs (p = 0.017). Conclusion These findings suggest that donor organ allocation based on gender may affect long-term survival and other outcomes after lung transplantation.

Lung transplantation remains the only effective therapy for patients with end-stage lung disease, but survival is limited by the development of obliterative bronchiolitis (OB). The chemokine receptor CXCR3 and two of its ligands, CXCL9 and CXCL10, have been identified as important mediators of OB. However, the relative contribution of CXCL9 and CXCL10 to the development of OB and the mechanism of regulation of these chemokines has not been well defined. In this study, we demonstrate that CXCL9 and CXCL10 are up-regulated in unique patterns following tracheal transplantation in mice. In these experiments, CXCL9 expression peaked 7 days posttransplant, while CXCL10 expression peaked at 1 day and then again 7 days posttransplant. Expression of CXCL10 was also up-regulated in a novel murine model of lung ischemia, and in bronchoalveolar lavage fluid taken from human lungs 24 h after lung transplantation. In further analysis, we found that 3 h after transplantation CXCL10 is donor tissue derived and not dependent on IFN-gamma or STAT1, while 24 h after transplantation CXCL10 is from recipient tissue and regulated by IFN-gamma and STAT1. Expression of both CXCL9 and CXCL10 7 days posttransplant is regulated by IFN-gamma and STAT1. Finally, we demonstrate that deletion of CXCR3 in recipients reduces airway obliteration. However, deletion of either CXCL9 or CXCL10 did not affect airway obliteration. These data show that in this murine model of obliterative bronchiolitis, these chemokines are differentially regulated following transplantation, and that deletion of either chemokine alone does not affect the development of airway obliteration.

The proportion of cystic fibrosis (CF) patients dying while on the lung transplant wait list remains high; identification of such patients remains difficult. The breathing reserve index (BRI = minute ventilation/maximal voluntary ventilation) at the lactate threshold (LT) is a predictor of a pulmonary mechanical limit to incremental exercise. We hypothesized that an elevated BRI at the LT in patients with CF awaiting lung transplantation would be a predictor of wait list mortality. Forty-five consecutive patients with CF completed cardiopulmonary exercise testing as part of their pretransplant assessment. We evaluated BRI at LT, baseline demographic characteristics, pulmonary function, and other exercise parameters via Cox proportional hazards modeling. Fifteen patients died while awaiting transplant. Twenty one were transplanted, and nine still awaited transplantation. Relative risks from the multivariate model included (95% confidence interval in parentheses) BRI at LT, 17.52 (2.45-123.97); resting Pa(CO(2)), 1.29 (1.10-1.49); resting Pa(O(2)), 0.97 (0.90-1.05); and forced expiratory volume at one second as a percent of predicted, 1.19 (1.05-1.34). BRI at LT not only provided the highest point estimate of risk for wait list mortality but also identified a physiologically significant threshold value (0.70 or more) for those at risk. This measurement may allow improved timing of listing for transplantation, including consideration for living donor transplantation.

In order to determine whether abnormalities of immunoregulatory T-cells occur in patients with lung cancer, we characterized peripheral T-lymphocytes in 26 patients with untreated lung cancer. The results in patients with primary squamous cancer (SC) (n = 10), primary adenocarcinoma (AC) (n = 7), and secondary lung metastases (M) (n = 9) were compared with each other and to subjects without cancer (n = 48), including nonsmokers (n = 29) and smokers (n = 19). We found that OKT3+ (mature, peripheral (T-lymphocytes, including both OkT4+ (inducer/helper) and OKT8+ (cytotoxic/suppressor) lymphocytes, were increased in light-to-moderate smokers, but that OKT4+ cells were decreased n heavy smokers (p less than 0.05). The ratio of OKT4+ to OKT8+ (4/8) lymphocytes, reflecting the balance of immunoregulatory cells, was normal in light-to-moderate smokers, but was decreased in heavy smokers (p less than 0.05). The profile of circulating T-cells in patients with SC was similar to the smokers. In contrast, in patients with AC, we found a decreased percentage of OKT8+ cells (p less than 0.05). The 4/8 ratio was elevated in patients with AC (p less than 0.05). In patients with M, there was a decreased percentage of OKT3+ cells reflected in both OKT4+ and OKT8+ subsets. The 4/8 ratio in patients with M was low. Thus, a number of abnormalities in circulating T-cells was found both in smokers and in patients with lung cancer. These results suggest that immunoregulatory abnormalities contribute to the pathogenesis of lung cancer.

A 32-year-old man with progressive dyspnea and congenital lymphedema was transferred to our hospital for evaluation as a lung transplant candidate with the suspected diagnosis of primary pulmonary hypertension. Evaluation revealed the additional history of previous limb-shortening procedures for the left leg, the presence of syndactyly, long-standing bilateral (left to right) lower extremity varices, as well as soft tissue asymmetry with the left leg and arm larger than the right-sided counterparts. A diagnosis of Klippel-Trénaunay syndrome was made on the basis of these findings. Because of the deep venous malformations known to occur in this syndrome, we sought evidence of recurrent pulmonary emboli as an explanation for the patient's progressive dyspnea, despite negative pulmonary arteriography and ventilation-perfusion scanning results at another institution. Repeat pulmonary arteriography demonstrated evidence of chronic and subacute pulmonary emboli. The patient is presently being treated with warfarin anticoagulation, with plans for placement of a caval filter if anticoagulation alone is insufficient to prevent further embolism. Klippel-Trénaunay syndrome is a rare cause of chronic pulmonary emboli, and this entity should be considered when the characteristic historical and physical findings are present. A case report and review of the syndrome, with particular focus on the aspects relevant to the vascular surgeon, are presented. (J VASC SURG 1995;21:686-90.)

The purpose of our study was to evaluate CT findings during respiratory syncytial virus (RSV) infection in lung transplant recipients and to identify sequelae.Thirty-nine CT scans prior to, during, and following acute infection in 10 lung transplant recipients were reviewed. Abnormalities that were new from baseline observations and occurred within 4 weeks of diagnosis were defined as acute. Chronic findings were defined as those present >4 weeks after diagnosis.Findings in nine patients were ground-glass (seven), air-space (five), and tree-in-bud (four) opacities and acute bronchial dilatation (four) and wall thickening (four). Patients lacked pleural effusions or lymph node enlargement. Five of seven patients with follow-up exams had new air trapping (three), persistent bronchial dilatation (three), and thickening (two). Three and 2 of the 10 patients developed bronchiolitis obliterans syndrome and obliterative bronchiolitis, respectively.During acute infection, patients commonly had ground-glass opacities but lacked pleural effusions and lymph node enlargement. There can be chronic sequelae after infection.

OKT3 monoclonal antibody therapy results in an acute clinical syndrome (ACS) associated with the release of tumor necrosis factor and sequestration of neutrophils in the lungs. We have previously shown that inhibition of tumor necrosis factor does not completely eliminate OKT3-ACS, suggesting that other factors also contribute to the ACS. The current studies analyzed complement activation in vivo during the first hour after OKT3 administration.Renal (n=4) and lung (n=4) transplant recipients received OKT3 as treatment for rejection and induction therapy, respectively. Complement activation products C4d, Bb, iC3b, and SC5b-9 were measured by ELISA. Hemodynamic parameters were also monitored in the lung transplant recipients. Neutrophil expression of CD11a, CD11b, and CD18 was monitored by flow cytometry. Controls included patients receiving methylprednisolone for rejection (n=4), two adults with adult respiratory distress syndrome who received extracorporeal membrane oxygenation, and normal volunteers (n=5). P values less than 0.05 (*) were considered significant.Increases in the plasma levels of C4d, Bb, iC3b, and SC5b-9 were observed in seven of eight patients after OKT3 administration. Mean values (n=8) at 0, 15, and 60 min (in microg/ml) were as follows-C4d: 1.865, 2.644*, and 2.607*; Bb: 0.245, 0.411, and 0.385; iC3b: 10.881, 17.242*, and 15.145*; and SC5b-9: 0.232, 0.269, and 0.302*. An increase in CD11b and CD18 and a decrease of CD11a on neutrophils in parallel with complement activation was observed. In lung transplant recipients, C3 activation correlated with increases in mean pulmonary and central venous pressures (P<0.05). As compared with extracorporeal membrane oxygenation, which activated classical and alternative pathways, OKT3 predominantly activated complement by the classical pathway. Methylprednisolone pulses did not activate complement.Complement activation is an early event after OKT3 administration and is associated with the increased expression of adhesion molecules on neutrophils and with pulmonary hemodynamic changes. Effective therapeutic approaches to the control of early monoclonal antibody side effects may require measures that limit complement activation in addition to reducing cytokine activity.

Although respiratory syncytial virus (RSV) infection is known to cause severe pulmonary infections in bone marrow transplant recipients, less is known concerning its clinical course, diagnosis, and treatment in solid organ transplant recipients.We have conducted a retrospective review of seven cases of RSV infection in adult recipients of solid organ transplants. Four patients received lungs, two received kidneys, and one received a heart.The most common presenting complaints were dyspnea (100%), cough (86%), and purulent sputum (57%). Physical findings included fever (43%), rales (100%), and wheezing (29%). Admission studies were significant for leukocytosis (29%), a left shift in the white blood cell differential (86%), and hypoxemia (mean PaO2 = 64). Chest radiographs were unchanged in 29% and showed infiltrates that were bilateral in 43% and unilateral in 29%. Pulmonary function tests in lung transplant recipients showed a mean fall in forced expiratory volume in 1 second of 26% and a fall in diffusion capacity for carbon monoxide of 24%. Five patients were treated with aerosolized ribavirin. Adverse events associated with treatment included wheezing (80%) and mild dyspnea (20%). The conditions of three of five treated patients were believed by their physicians to have improved 7 days after the initiation of therapy. One of the five treated patients died, and both untreated patients survived.RSV infection in this population has an extremely variable severity and clinical course, usually dominated by lower respiratory symptoms and obstructive airway disease. Ribavirin therapy is well tolerated, but its efficacy remains unknown.

Lung transplantation has become a viable treatment option for patients with end-stage lung disease. Donor selection and organ allocation must follow specific guidelines. Single, bilateral, and living-donor lobar transplantation have all been performed successfully for a variety of diseases. Complications include reimplantation response and airway complications. Rejection may occur in the hyperacute, acute, or chronic settings and requires judicious management with immunosuppression. Infection and malignancy remain potential complications of the commitment to lifelong systemic immunosuppression. Survival statistics have remained encouraging and continue to improve with experience. Improved exercise tolerance and quality of life have been demonstrated in the years following transplantation. Remaining obstacles include limited donor organ availability, long-term graft function, and patient survival. However, ongoing advances in immune tolerance and standardized training of physicians in the care of transplant patients should carry lung transplant forward in the twenty-first century.

Background: The risk of death for patients with end-stage cystic fibrosis awaiting lung transplantation remains high and most patients succumb to respiratory failure. This study was conducted to evaluate the usefulness of ventilation-perfusion scintillation scans, obtained during the pre-transplant period, to identify patterns that predict prognosis while on the waiting list. These patterns were compared with other pulmonary physiologic markers of ventilation and perfusion obtained from pulmonary function and cardiopulmonary exercise tests. Methods: From November 1990 to January 1999, 46 patients with cystic fibrosis were listed for bilateral lung transplantation. Fourteen (30.4%) died while waiting for a transplant (Group 1), whereas 32 were transplanted successfully or remain alive and waiting (Group 2). Mean arterial blood gas values, Brasfield radiograph scores, cardiopulmonary exercise data and the degree of scintillation scan abnormalities between lungs were compared for each group. Results: Mean survival for Group 1 was 10.2 ± 1.7 months, and for Group 2 was 23.5 ± 3.0 months (p < 0.001). The right upper lung zone was the most severely affected segment. The Cox proportional hazards model revealed an increased perfusion disparity and resting hypercapnia as the main predictors of death while on the transplant list. The Kaplan-Meier analysis indicated greater survival for the groups with <30% disparity between lungs on the pre-transplant scintillation scans. Conclusions: The results suggest that severe, unilateral perfusion abnormalities seen on scintillation scans in patients with cystic fibrosis are associated with an increased risk of dying while on the lung transplant waiting list and may be helpful in identifying patients who should be considered for early or living-donor transplantation.

To assess left ventricular systolic and diastolic function in adult patients with cystic fibrosis using radionuclide ventriculography.Although myocardial fibrosis has been described in autopsy specimens of patients with cystic fibrosis, the possibility that myocardial dysfunction may occur during life in adult patients with cystic fibrosis has not been explored.To assess the possibility of cardiac dysfunction occurring in cystic fibrosis, we studied 40 patients with advanced cystic fibrosis with first-pass radionuclide ventriculography and compared them to 9 patients with advanced bronchiectasis and 18 normal control subjects.Indexes of right ventricular systolic function were similarly impaired in patients with cystic fibrosis and patients with bronchiectasis. Left ventricular ejection fraction of patients with cystic fibrosis, patients with bronchiectasis, and normal control subjects did not differ. Fractional left ventricular filling at 50% of diastole, an index of diastolic function, was significantly lower in patients with cystic fibrosis (54 +/- 13%, mean +/- SD) in comparison to patients with bronchiectasis (66 +/- 4%, p = 0.009) or normal control subjects (69 +/- 14, p = 0.0002). The contribution of atrial systole to total diastolic left ventricular filling was greater in patients with cystic fibrosis (38 +/- 18%) than in patients with bronchiectasis (21 +/- 4%, p = 0.01) or normal control subjects (25 +/- 12%, p = 0.01).Patients with advanced cystic fibrosis demonstrate impaired left ventricular distensibility when compared to normal control subjects and patients with bronchiectasis. Patients with cystic fibrosis may be at risk of heart failure due to right ventricular dysfunction or left ventricular diastolic dysfunction.

Soluble interleukin-2 receptor (sIL-2R) levels in cigarette smokers and in patients with lung cancer were measured using an enzyme immunoassay. The rationale for our study was based on the fact that activation of T-cells is dependent upon the T-cell growth factor, interleukin-2, which may be regulated by its receptor, IL-2R. Measurements of circulating sIL-2R might be useful in the immune assessment of certain conditions. This study assessed elevated concentrations of circulating sIL-2R in smokers and in patients with lung cancer. The data show that healthy smokers, as a group, have an elevated level of sIL-2R compared with that in nonsmokers. Significantly higher than normal levels were found among light, moderate, and heavy smokers. Patients with lung cancer (squamous cell carcinoma [SSC] or adenocarcinoma [AC]) also have abnormally high sIL-2R levels. In the SCC group, the highest level of sIL-2R was among asymptomatic patients with well-differentiated tumors. Similarly, patients with SCC whose tumors were < 3 cm in diameter had a significantly higher mean level of sIL-2R than did patients whose tumors exceeded 3 cm. The sIL-2R level in the SCC group also correlated with the tumor stage, with the highest level found among Stage I patients. In patients with SCC, but not in those with AC, the sIL-2R level was indicative of the extent of malignancy. These data support the concept that sIL-2R may be important in the pathogenesis of immune alterations associated with smoking and lung cancer.

Opportunistic fungal infections remain a significant complication in immunosuppressed patients, especially those having undergone solid-organ transplantation. We report a 39-year-old patient who represents the second case of cutaneous Aspergillus ustus infection in a solid-organ transplant recipient, and the first documented case after lung transplantation. The patient's cutaneous lower extremity aspergillosis responded to a combination of intravenous liposomal amphotericin B, caspofungin and topical terbinafine cream, with a concomitant reduction in immunosuppression. A. ustus is an emerging opportunistic fungal pathogen in transplant recipients.

Abstract Compared to healthy volunteers, participants with post‐acute sequelae of SARS‐CoV‐2 infection (PASC) demonstrated increased plasma levels of the prothrombotic protein NEDD9, which associated inversely with indices of pulmonary vascular function. This suggests persistent pulmonary vascular dysfunction may play a role in the pathobiology of PASC.

During the past two decades, lung transplantation has become a viable option for end-stage pulmonary disease. Advances in surgical techniques and immunosuppression and standardization of preoperative and postoperative care have contributed to improved survival and quality of life. Chronic rejection and limited allograft availability remain the two most important issues to resolve in the coming years. As indicated in Figure 1, from approximately 1985 until 1994, the number of lung transplants (single and double) from cadaveric donors increased. Yet, by 1994, the rate of increase in the annual number of transplants appeared to slow, despite increased numbers of patients with end-stage lung disease listed and waiting for lung transplantation. This trend has persisted despite the use of increasingly older donors and the initiation of living donor transplants. As of April 2001, 76,124 people are awaiting solid organ transplantation in the United States. Of this number, 3748 are awaiting lung transplantation and 215 are awaiting heart-lung transplants (United Network Organ Sharing Critical Data, http://www.unos.org). Figure 1: International statistics regarding the number of lung transplants performed since 1985. The numbers increased until 1994, at which time the rate of increase appears to have reached a plateau. (From ISHLT Registry Report 2000, http://www.ishlt.org, accessed April 15, 2001.)The majority of single lung transplants are performed for individuals with end-stage chronic obstructive pulmonary disease; cystic fibrosis accounts for the majority of bilateral/double lung transplants. Improvements in the management of selected patients with emphysema via lung volume reduction surgery, the antibiotic management of patients with cystic fibrosis, and the use of long-term prostacyclin therapy in patients with pulmonary hypertension may alter organ allocation trends in the future. RECIPIENT SELECTION Referral and listing of potential candidates for lung transplantation must consider a waiting period of 1 to 2 years after the completion of screening. During this waiting time, it is imperative that patients maintain adequate nutrition and conditioning. Guidelines for referral timing consider the rate of progression of specific diseases, but each patient must be considered individually. These guideline are listed in Table 1(1). Table 1: Disease-specific guidelines for adult lung transplantationThe use of standardized criteria is essential to the selection of candidates for lung transplantation. Age criteria include limits of 55 years for heart-lung transplantation candidates, 60 years for candidates for bilateral lung transplantation, and 65 years for candidates for single lung transplantation. The relative contraindications have changed as management of the lung transplantation patients has improved over time. For example, corticosteroid usage, once an absolute contraindication, is not necessarily prohibitive at moderate doses. Coronary disease, if treated, is no longer an absolute contraindication, especially if left ventricular function is preserved (2). Osteoporosis and fractures are common in both the preoperative and postoperative settings and remain a relative concern, mandating aggressive management before transplantation (3,4). A history of active malignancy of any organ is considered an absolute contraindication for lung transplantation. Of note, lung transplantation for bronchioalveolar carcinoma has been performed, but tumor recurrence in the donor lung occurred in four of seven patients within 10 to 48 months posttransplantation (5). Guidelines for listing for transplantation are included in Table 2(1). Table 2: Indications and contraindications for lung transplantationOne actively debated issue relevant to disease-specific considerations for lung transplantation has been the transplantation of patients with multiple or pan-resistant bacterial organisms. International guidelines suggest that the presence of pan-resistant bacteria is not an absolute contraindication, but multiple centers limit offering lung transplantation to patients with cystic fibrosis with Burkholderia cepacia(6,7). The management issues associated with this organism have been reviewed (8). One group has suggested that triple antimicrobial therapy can be bactericidal when B cepacia has a multi-resistant profile (9). The presence of B cepacia has been associated with higher mortality before and after transplantation in individuals with cystic fibrosis. Yet, some suggest that alterations in medical management after transplantation may improve outcomes for this subgroup (10). B cepacia species represent distinct genomic categories named genomovars, with the majority of the genomovar types being II or III (11). To date, seven genomovars have been identified (12). Ultimately, the decision to transplant patients with B cepacia is made by individual centers. Hopefully, in the future this decision will be aided by knowing more about the genetic epidemiology of the genomovars and their association with short- and long-term outcomes. DONOR SELECTION Before brain death and organ procurement, the lung may be exposed to injury from gastric aspiration or bacterial infection, potentially limiting organ use. These injuries may be compounded by the trauma of mechanical ventilation, further compromising the suitability for lung donation without compromising donation of other solid organs. Suitable allografts are generally characterized by Pao2 greater than 300 mmHg while mechanically ventilated with an Fio2 of 1.0 and positive end-expiratory pressure of 5 cm of water. Unilateral pneumonia or trauma does not preclude donation of the contralateral lung. Guidelines suggest that donor age should be less than 60 years, with a smoking history of no greater than 20 to 30 pack-years. Age and smoking criteria may be more flexible, however, when a waiting recipient’s survival is precarious. Liberalized smoking criteria have resulted in comparable outcomes (13–15). In this setting, the potential benefit outweighs the risk from the use of “marginal” or “extended” donors. In addition to more flexible criteria for age, smoking history, and gas exchange, the use of lungs from non–heart beating donors may help reduce the donor shortages (14–16). Successful transplantation of organs from non–heart beating donors has been described (17). One group suggests that careful in situ preservation techniques will protect the anatomic and physiologic attributes of these cadaveric lungs as they are prepared for implantation (18). In rodent and porcine models of non–heart beating cadaveric donors, research has demonstrated healing of the bronchial anastomosis without parenchymal abnormalities and with acceptable function (19–22). Consideration must be given to the proinflammatory gene activation that occurs in solid organs as a consequence of brain death and the idea that long-term organ dysfunction might be programmed even before allografting (23). As such, cytokine profiling represents a significant advance for identification of organs suitable for transplantation. The inflammatory cascade and the consequent pulmonary dysfunction associated with massive irreversible brain injury and brain death have been implicated as preventing approximately 75% of potential organs from ever being considered for lung donation (24). One group has demonstrated an increase in interleukin 8 in the lungs of potential organ donors after brain death. Donor lungs with high interleukin 8 levels had decreased graft oxygenation and early graft failure; these patients had shorter survival times (25). Cytokine profiles should be considered during donor selection given the relevance to short- and long-term outcomes. SURGICAL CONSIDERATIONS: PRESERVATION ISSUES The vascular endothelium of the lung is most susceptible to ischemic injury, potentially leading to an increase in permeability with resultant pulmonary edema. Hypothermic flush perfusion of the pulmonary vasculature (with Euro-Collin’s solution or University of Wisconsin Solution) is most commonly used to prevent this problem. A number of studies have been performed on potential additives that enhance the efficacy of flush solutions. Nitroprusside, dimethylurea, and pentoxifylline have been tested as agents to improve preservation and limit pulmonary edema in the early postoperative state (26,27). An alternative solution of low-potassium dextran has been found to decrease both severity and incidence of reperfusion injury and to improve survival and graft function. The administration of prostanoids into the pulmonary circulation improves lung preservation by dilating the pulmonary vasculature and decreasing leukocyte adhesiveness, thus facilitating more extensive distribution of solution. Relevant to the development of ischemic injury is the eventuality of reperfusion injury. Leukocyte adhesion to the endothelium and production of oxygen-derived free radicals contribute to this response. Prostanoid use and infusion of donor leukocytes and inhaled nitric oxide use and inclusion of superoxide dismutase or catalase as free radical scavengers may help diminish some reperfusion injury (28–31). As research in the field of lung preservation continues, it should be underscored that graft ischemic time may be an independent predictor of survival, with the negative effects being most pronounced after 5 hr (32). As such, transportation of patients and organization of surgical and medical staff should be coordinated closely once donor organs become available. Once procured, the lung poorly tolerates more than 6 hr of ischemic time, which limits cross-matching of HLA antigens and geography of organ donation. However, a recent study suggests viable extension of approved ischemic time to 5 to 8 hr from 4 to 5 hr without change in short-term outcomes (33). One study reports that it is not graft time alone that portends a poor survival after transplantation, but the interaction between donor age and ischemic time. This is especially true if donor age exceeds 55 years and ischemic time exceeds 6 to 7 hr (34). SINGLE LUNG TRANSPLANTATION Single lung transplantation is most commonly used for non-septic lung diseases. The lung to be extracted is determined preoperatively as that having the poorest pulmonary function. This is typically delineated via ventilation/perfusion scanning. The use of only one lung optimizes allograft availability, providing a lung for a second recipient. In patients with pulmonary hypertension, there has been some concern over the use of single lung transplantation, secondary to preferential perfusion of the allograft in the setting of high-native vascular resistance and perfusion of the cardiac output almost fully through the allograft. However, no difference has been found perioperatively, and postoperative survival is similar with either double versus single lung transplantation (35). There are some accounts that the use of extracorporeal membrane oxygenation, intraoperatively and into the postoperative setting, may reduce some of the reperfusion injury encountered in single lung transplantation for pulmonary hypertension (36). Single lung transplantation is an option in patients with end-stage emphysema. Occasionally, selective lung ventilation has been used to manage overinflation of the native lung after transplant (37). However, a recent review notes that despite radiographic evidence of native lung hyperinflation, there is little compromise of the allograft in most patients. These data suggest that routine lung volume reduction, isolated lung ventilation, or bilateral transplant is not necessary, despite the risk for native lung hyperinflation (38). In some cases, however, native lung hyperinflation may result in severe allograft compromise, acutely and chronically, secondary to compressive atelectasis. Hyperinflation of the native lung may occur many months postoperatively and, in this setting, native lung volume reduction has been used to preserve allograft volume and function (39–41). As a way in which to limit this potentially preventable cause of allograft compromise, measurements of patients’ static lung compliance have been advocated as a screening technique to select patients who might benefit from lung volume reduction surgery after transplantation (42). BILATERAL LUNG TRANSPLANTATION Bilateral sequential lung transplantation has surpassed en bloc resection and implantation as the procedure of choice for septic lung disease and other diseases in which bilateral transplantation is preferred. Advantages of the sequential procedure include a lower incidence of bronchial anastomotic complications and less technical difficulty to perform. Cardiopulmonary bypass is not always necessary in the sequential procedure because selective lung ventilation may adequately preserve oxygenation and ventilation. Indications for adult lung transplantation by procedure are provided in Figure 2. Figure 2: Indications for adult lung transplantation. Emphysema is the predominating indication for single lung transplantation, with cystic fibrosis as the predominating indication for double lung transplantation. (From ISHLT Registry Report 2000, http://www.ishlt.org, accessed April 15, 2001.)HEART-LUNG TRANSPLANTATION As isolated lung transplantation has evolved and more diseases have been successfully treated with this technique, the number of heart-lung transplants has decreased. The number of centers that perform this operation decreased from 62 in 1993 to 30 in 1998 (43). Right ventricular function typically improves after isolated lung transplantation, and the presence of cor pulmonale is neither an absolute exclusion criteria for lung transplantation nor an indication necessarily for heart-lung transplantation (44–46). Presently, heart-lung transplantation is best reserved for patients with end-stage pulmonary disease with concomitant irreversible cardiac failure. LIVING-DONOR LOBAR TRANSPLANTATION Living-donor lobar transplantation is now a realistic option for carefully selected patients. As of December 2000, 139 living-donor lobar transplants have been performed in the United States (United Network Organ Sharing Critical Data, http://www.unos.org). Blood group compatibility is the only matching performed; HLA matching is not a prerequisite. In adults, outcomes have been similar to cadaveric transplantation. However, results have been reported to be superior to cadaveric lung transplants in children (47). Improved function and less obliterative bronchiolitis have been noted in pediatric recipients of lobar donation (48). In both children and adults, the procedure has been considered safe for the donor; donation of a lobe was associated with only a 15% decrease in lung volume without change in functional capacity (49). However, one group has noted that 61.3% of living donors had postoperative complications, including pleural effusions, bronchial stump fistulas, phrenic nerve injury, and bronchial stricture (50). Morbidity and mortality data that concern living donors should continue to be monitored closely in the coming years. COMPLICATIONS OF LUNG TRANSPLANTATION Complications of lung transplantation include complications secondary to the surgery itself; hyperacute, acute, and chronic rejection; and complications of the immunosuppressive agents. Reimplantation Response The morbidity and mortality in the first weeks after single or double lung transplant are due mainly to the reimplantation response and airway anastomotic complications. The reimplantation response manifests as worsening gas exchange in the hours to days after transplant. There is decreased lung compliance, and there are also perihilar infiltrates. This diagnosis should be considered after the exclusion of volume overload, rejection, pneumonia, or vascular compromise. A recent retrospective study found that pulmonary reimplantation response occurred 57% of the time after lung transplantation. In this series, there was no association with a prolonged ischemic time, pulmonary hypertension, age, gender, type of lung transplant, or underlying pulmonary disease. However, cardiopulmonary bypass was associated with an increased incidence and severity of the reimplantation response (51). In 15% of lung transplantation recipients, severe lung injury may develop, which is attributable to the reperfusion injury and lymphatic disruption associated with the perioperative period (52). Development of this pattern of lung injury, if unilateral, may dictate the need for selective lung ventilation; nitric oxide or extracorporeal membrane oxygenation also may be considered (31,53,54). On a clinical continuum with the reimplantation response is acute graft dysfunction, in which early abnormalities of lung function and lung compliance after implantation are associated with pulmonary hypertension and rapidly progressive pulmonary edema. Aspiration, contusion, or inadequate lung preservation may account for acute graft dysfunction. Acute graft dysfunction is associated with a mortality up to 60%, although some patients who have survived have gained adequate graft function (53,55). Airway Complications Airway complications have decreased, as the years of successful lung transplantation accumulate. Graft failure, secondary to bronchial dehiscence, occurred early in the transplant experience. Telescoping of the donor bronchus into that of the recipient has promoted long-term integrity of the donor-recipient airway connection. This technique diminished allograft failure secondary to dehiscence but resulted in a higher incidence of anastomotic stenosis and postoperative pneumonia when compared to end-to-end anastomosis (56–60). Anastomotic stenosis is now the most common large airway complication; rates of anastomotic complications vary with technique and center (58,60–64). Anastomotic complications are diagnosed with direct visualization with bronchoscopy or by suggestive decrements in spirometry (65–67). Symptoms include dyspnea with chest tightness and wheezing. The narrowing because of strictures may be managed with balloon dilation or with stent placement; granulation tissue may be removed via surgical or laser ablation (68). Rejection Immunosuppression remains the key to successful solid organ transplantation. Hyperacute rejection is an uncommon cause of lung allograft dysfunction. Although current immunosuppressive combinations may control acute rejection, chronic rejection still accounts for the majority of long-term morbidity and mortality. Hyperacute Rejection Preformed antibodies against allograft antigens, including HLA and ABO blood group antigens, target the donor vascular endothelium and may lead to hyperacute rejection within minutes to hours after transplantation. The antibodies bind to the vascular endothelium, activate inflammatory and coagulation cascades, thus causing extensive thrombosis of graft vessels and graft failure. Clinically, hyperacute rejection in the pulmonary allograft has been associated with a positive T-cell cross-match and diffuse alveolar damage (69). Another case of hyperacute rejection is described as characterized by interstitial neutrophilic infiltration, with platelet and fibrin thrombi and antibody deposition on the endothelial surface and vessel walls (70). Hyperacute rejection, which is extremely rare, must be distinguished clinically from ischemia-reperfusion injury, which is likely present in most lung transplant recipients. Fulminant hyperacute rejection is almost uniformly fatal and reinforces the importance of ongoing research in graft preservation and cross-matching to help attenuate this contribution to mortality. Acute Rejection Acute rejection typically occurs in the first 3 to 6 months after transplantation. Most recipients have at least one episode. The risk remains after this time, and later episodes of rejection are not uncommon. The acute rejection response includes both a cellular response and soluble mediators, whereas hyperacute rejection is considered primarily a humoral response. The degree of HLA mismatching, especially at HLA-DR and HLA-B loci, appears to be a risk factor for acute rejection (71,72). Transbronchial biopsy has been of use in the asymptomatic patients with rejection, in which routine surveillance biopsies have revealed histologic evidence of minimal to mild grade rejection. Not infrequently, radiography is unrevealing (73). When rejection is symptomatic, patients may complain of fever, cough, dyspnea, or anorexia. Spirometry is a useful adjunct; declines in home spirometry of 10% to 15% usually prompt a search for acute rejection. A decrease in FEV1, vital capacity, and diffusion capacity have a sensitivity of greater than 80% to detect acute rejection or infection episodes (74). However, specificity is low because deterioration in pulmonary function parameters does not point to an etiology of pulmonary dysfunction (75). Bronchoscopy with biopsy aids in the diagnosis of rejection. The key histologic finding is perivascular lymphocytic infiltrates, which may be in association with lymphocytic bronchitis or bronchiolitis. Eosinophilic alveolitis has been associated with allograft rejection (76). Despite characteristic pathology and spirometry suggestive of acute rejection, infection and rejection do not infrequently occur together. Infection should be excluded before an augmentation of immunosuppression. Competitive reverse transcription–polymerase chain reactions of cytotoxic lymphocyte effector molecules such as perforin, granzyme B, granulysin, and Fas ligand are being investigated as tools to assist differential diagnosis of graft dysfunction. A recent report suggests that the transcription of cytotoxic lymphocyte effector molecules is increased in both rejection and infection, but it is highest in infection with cytomegalovirus. Novel noninvasive methods for diagnosing acute rejection have been suggested, but they remain experimental. For example, exhaled nitric oxide levels reportedly correlate with acute lung rejection and may serve as a future noninvasive way to monitor allograft function and rejection (77). Tumor necrosis factor levels, gamma interferon levels, and soluble interleukin-2 receptor levels are also elevated during episodes of acute rejection, but they lack sensitivity and specificity. Treatment of acute rejection usually includes a brief course of high-dose corticosteroids (methylprednisolone 7–15 mg/kg daily for 3 days). Ganciclovir prophylaxis is indicated preemptively during the steroid therapy for patients at risk for cytomegalovirus. Symptomatic improvement usually occurs within 48 hr of steroid initiation, although surveillance biopsies may demonstrate persistent rejection in one third of patients who symptomatically respond to treatment (78,79). After the pulse of steroids, a higher dose is maintained for several weeks. If symptoms persist, a second pulse of steroids may be indicated. If a response does not occur, cytolytic therapy should be considered. Total lymphoid irradiation has been used in cases of refractory acute rejection (80). Persistent symptoms and spirometric decline should prompt a search for an alternative diagnosis such as airway stenosis, infection, or chronic rejection. Chronic Rejection Chronic rejection usually occurs 6 months to 1 year after transplantation. It is characterized as graft dysfunction secondary to airflow limitations. It may be present in up to 40% of patients at 2 years (6,81) and in 60% to 70% of patients who survive for 5 years (82). The target of the immune response in chronic rejection is the bronchial epithelium, manifested histologically as obliterative bronchiolitis. Airway injury stimulates fibroproliferation in the small airways, leading to narrowing and ultimately luminal obliteration. Graft dysfunction may develop more than 3 months posttransplant, with a mean time to formal diagnosis of 16 to 20 months (83,84). For diagnosis, transbronchial biopsy has a sensitivity of only 17% in some series (85). Home spirometry helps detect a bronchiolitis syndrome (suggested by a sustained decrease in the FEV1 by 20% upon consecutive measures) (86) and may do so before it is revealed by laboratory testing (87). Similar to acute rejection, symptoms are nonspecific and include insidious onset of cough and dyspnea, although dyspnea is a later symptom and may portend more extensive disease (88). Chest radiographic findings are nonspecific and may include volume loss, subsegmental atelectasis, linear opacities, and bronchiectasis (89,90). Air trapping and bronchial wall thickening on high-resolution computed tomography scanning can help support the diagnosis, and, in one study, they were the most sensitive and specific findings for obliterative bronchiolitis (91). The etiology of chronic rejection is obscure, but prior acute rejection, cytomegalovirus infection, airway ischemia, and HLA mismatching have all been implicated (82,92–95). One group found that late acute rejection, lymphocytic bronchitis, or bronchiolitis and decreased immunosuppression were all risk factors for bronchiolitis obliterans syndrome (96). Another group has found that ongoing neutrophilic inflammation, as reflected by increased polymorphonuclear cells in bronchoalveolar lavage, was a significant predictor for mortality (97). Cytokines and adhesion molecules have been a focus of investigation in the realm of obliterative bronchiolitis, yet it is unclear if these factors are a causal contributor or a response to chronic rejection. There are some data that suggest neutrophilia and consequent interleukin-8 elevations antedate the development of obliterative bronchiolitis (98). These data also suggest that the level of elevation may correlate with the severity and rapidity of the development of obliterative bronchiolitis. Transforming growth factor (TGF)-β has been demonstrated to localize to the airway and lung parenchyma in patients with obliterative bronchiolitis, with expression greater in patients with bronchiolitis obliterans syndrome as opposed to those without. TGF-β positivity in tissue preceded the diagnosis of bronchiolitis obliterans by 6 to 18 months and increased expression was associated with its development (99,100). Corticosteroid therapy, inhaled cyclosporine, cytolytic therapy, tacrolimus, and mycophenolate mofetil have all been used in the management of bronchiolitis obliterans. Extracorporeal photopheresis has been applied by some groups to manage refractory rejection (101,102). In the majority of patients, the problem is difficult to resolve, and the mortality rate at 3 years after diagnosis is 40% or higher. Treatments may slow, but not terminate, functional decline (103,104). Late-stage management is largely palliative. Retransplantation has been performed for some patients with bronchiolitis obliterans. Early results were notable for an increased morbidity and mortality when compared to first time transplantation (105). However, more recent experience suggests that retransplantation outcomes approximate those of initial transplantation (106). Future research must focus upon the etiology of chronic rejection given the progressive and often fatal nature of its course. Understanding the genesis of bronchiolitis obliterans, with a goal of prevention, is key. Immunosuppression Induction of an immunosuppressed state is critical to the success of solid organ transplants. Extensive reviews of immunosuppression regimens for the lung transplant patient have been published (107,108). At most centers, a triple-drug regimen is standard and includes steroids, cyclosporine, and azathioprine. Despite aggressive multi-drug therapy, acute rejection is still common in the first weeks to months after transplantation. In this setting, tacrolimus and mycophenolate mofetil are sometimes substituted for cyclosporine and azathioprine, respectively. A prospective randomized study of tacrolimus versus cyclosporine demonstrated that acute rejection occurred less frequently in the tacrolimus group (89% vs. 100% in the cyclosporine group) (109). Another prospective trial reported a reduced incidence of biopsy-proven obliterative bronchiolitis in the group that had received tacrolimus versus cyclosporine (21.7% vs. 38%) (110). Although tacrolimus use has been associated with lower rates of rejection, with similar infection rates, a higher incidence of new onset diabetes has been observed (111). Tacrolimus has been demonstrated as efficacious in reversing refractory rejection (112). Tacrolimus has been used as a rescue therapy in bronchiolitis obliterans, in which patients treated with tacrolimus have a slowed rate of decline (104). Some have suggested the use of tacrolimus as a primary immunosuppressant after lung transplantation (113). Guidelines have been published for the use of tacrolimus (114). Antilymphocyte preparations are the mainstay of induction therapy in some centers. They were introduced initially, in part, to help avoid steroids in the early perioperative period. Cytolytic therapy is also used in steroid-resistant rejection. Polyclonal antilymphocyte globulin, antithymocyte globulin, and murine monoclonal antibody to CD3 (OKT3) all have been used in these circumstances. A recent, randomized prospective study in 44 lung recipients found that induction with rabbit antithymocyte globulin reduced the incidence of acute allograft rejection (115). Others have suggested that the use of OKT3 is as safe and effective as induction immunosuppressive regimen. When used as such, it is associated with a lower incidence of acute rejection in the immediate postoperative period and, potentially, a decreased incidence of obliterative bronchiolitis in the long term (116). Infection Immunosuppressive agents necessary to prevent and treat rejection diminish host defenses and predispose to infection. The rate of infectious

The study hypothesis was that asbestos exposure and asbestos-related pleural plaques and interstitial disease are associated with (1) immune imbalances favoring helper-inducer T-cell subsets in blood and bronchoalveolar lavage (BAL) and (2) T-lymphocyte accumulation in BAL. One hundred twenty-two asbestos-exposed subsets (AES), including 27 nonsmokers (NS), were evaluated and compared with 10 unexposed normal subjects. Data were collected on medical, smoking, and occupational histories, physical examination, spirometry, lung volumes, single-breath DlCO, chest films read by a “B” reader, and T-lymphocyte characterization in blood and BAL using flow cytometry analysis of monoclonal-antibody-treated cells. On average, AES were 47 yr of age and had 23 yr of asbestos exposure. Fifty-eight (48%) had pleural thickening, and seven (6%) had profusion ⩾ 1/0. In blood, asbestos-exposed NS had lower total and percent CD8 and lower total CD3 than did normal subjects. In BAL, asbestos-exposed NS had higher total CD3 than did normal subjects. Among AES, increased asbestos exposure was associated with increased percent CD8 in BAL and decreases in both percent lymphocytes and total CD8 in blood. Increases in CD4/CD8 ratio in BAL were associated with pleural thickening. In those seven with profusion ⩾ 1/0, there was increased percent CD4 in blood and decreased percent CD8 in BAL. These results suggest immune imbalance favoring helper-inducer T-cell subsets in association with asbestos exposure systemically and with pleural plaques in BAL. In addition, our results suggest possible redistribution of T-lymphocytes and CD8 from blood to lungs in association with asbestos exposure. Longitudinal studies will determine whether these imbalances signal later asbestos-related diseases such as asbestosis, lung cancer, or mesothelioma.

In order to evaluate the effects of cigarette smoking and asbestos exposure on cellular immunity, we tested a group of cigarette smokers and asbestos workers for natural killer (NK) activity in the peripheral blood. The mean NK activity in cigarette smokers was lower than in normal subjects (13.7 +/- 1.6 versus 29.0 +/- 3%; p less than 0.05). As a group, the mean NK activity for the asbestos-exposed group was also reduced compared with that of the nonsmoking control group (22.6 +/- 3.2%; p less than 0.05). When divided according to the smoking status, the asbestos workers who were nonsmokers or ex-smokers showed similar decreases in NK activity compared with normal subjects (19.5 +/- 6.2 and 21.2 +/- 4.5%, respectively; p less than 0.05). A subgroup of asbestos-exposed subjects who currently smoked showed no decrease in NK activity. The data show that NK activity is reduced in the peripheral blood of cigarette smokers and asbestos workers. The relatively normal NK activity found in asbestos workers who also smoked is unexplained. Impairment of NK activity is a potential mechanism for the increased incidence of infection and cancer in smokers and neoplasia in asbestos workers.

Living donor lobar lung transplantation is a viable therapy for carefully selected patients with end-stage pulmonary disease. Its success is largely dependent upon donor outcome, including both physical and emotional factors. To date, there has been little focus on psychosocial outcomes of lobar lung donors.Retrospective evaluation of 15 of 20 living lobar lung transplant donors was performed. Donors underwent evaluation of pulmonary function after recovery from donor lobectomy. Participants completed two self-report questionnaires, the SF-36 Health Survey (SF-36) and the Beck Depression Inventory (BDI), as well as an open-ended psychiatric interview.After lobar donation, mean forced expiratory volume in 1 second (FEV(1)) decreased by 21 +/- 2%, forced vital capacity (FVC) decreased by 16 +/- 3%, total lung capacity (TLC) decreased by 15 +/- 3%, and single-breath diffusing capacity (DLCO) decreased by 14 +/- 4%. All subjects scored higher than the national average on both the physical and mental health components of the SF-36. The BDI scores showed no evidence of clinical depression. However, the subjective interviews elicited two common complaints: (1) a decline in exercise performance, not accounted for by resting lung function measurements; and (2) a dissatisfaction with the degree of acknowledgment of their donation.Living lobar lung transplant donors enjoy generally satisfactory physical and emotional health. Donors report positive feelings about donation, but wish to be recognized and valued by the transplant team and by the recipient. Despite preservation of lung function within the normal range, some donors also experience a subjective decline in exercise tolerance. Long-term medical and psychologic follow-up appears warranted to monitor symptoms of exercise impairment and to enhance the donor experience.

In order to determine whether abnormalities of immunoregulatory T-cells occur in patients with lung cancer, we characterized peripheral T-lymphocytes in 26 patients with untreated lung cancer. The results in patients with primary squamous cancer (SC) (n = 10), primary adenocarcinoma (AC) (n = 7), and secondary lung metastases (M) (n = 9) were compared with each other and to subjects without cancer (n = 48), including nonsmokers (n = 29) and smokers (n = 19). We found that OKT3+ (mature, peripheral) T-lymphocytes, including both OKT4+ (inducer/helper) and OKT8+ (cytotoxic/suppressor) lymphocytes, were increased in light-to-moderate smokers, but that OKT4+ cells were decreased in heavy smokers (p < 0.05). The ratio of OKT4+ to OKT8+ (4/8) lymphocytes, reflecting the balance of immunoregulatory cells, was normal in light-to-moderate smokers, but was decreased in heavy smokers (p < 0.05). The profile of circulating T-cells in patients with SC was similar to the smokers. In contrast, in patients with AC, we fo...

To determine if fiberoptic bronchoscopy (FOB) with bronchoalveolar lavage impairs pulmonary function in normal subjects or those with sarcoidosis, we measured flow-volume loops, thoracic gas volume, and single breath carbon monoxide diffusing capacity before, one half hour and 24 hours after lavage. We studied 12 normal subjects; six underwent a large volume lavage (approximately 500 ml saline instilled), and six underwent a small volume lavage (approximately 175 ml). Five subjects with sarcoidosis also had a small volume lavage. Six control subjects underwent FOB without lavage. The FOB alone produced no significant changes in pulmonary function one half hour after the procedure. Small volume lavage in normal subjects produced no change except for a 16.3 ±5.1 percent (mean± SEM) decline in peak expiratory flow rate (p<.05) one half hour postlavage which returned to normal by 24 hours. This contrasts with sarcoidosis subjects in whom forced expiratory volume in one second, peak expiratory flow rate, and vital capacity declined by 20±4.8 percent, 26.7±7.3 percent, and 15.2 ±4.1 percent, respectively, (all p<0.05) one half hour postlavage. No change occurred in total lung capacity or diffusing capacity. Only with large volume lavage did decrements in lung function occur in normal patients that were comparable to those seen in the sarcoidosis subjects. Our findings suggest that bronchoalveolar lavage in normal patients can be associated with a significant and volume-related decline in pulmonary function and that in subjects with sarcoidosis, the deterioration is more pronounced. To determine if fiberoptic bronchoscopy (FOB) with bronchoalveolar lavage impairs pulmonary function in normal subjects or those with sarcoidosis, we measured flow-volume loops, thoracic gas volume, and single breath carbon monoxide diffusing capacity before, one half hour and 24 hours after lavage. We studied 12 normal subjects; six underwent a large volume lavage (approximately 500 ml saline instilled), and six underwent a small volume lavage (approximately 175 ml). Five subjects with sarcoidosis also had a small volume lavage. Six control subjects underwent FOB without lavage. The FOB alone produced no significant changes in pulmonary function one half hour after the procedure. Small volume lavage in normal subjects produced no change except for a 16.3 ±5.1 percent (mean± SEM) decline in peak expiratory flow rate (p<.05) one half hour postlavage which returned to normal by 24 hours. This contrasts with sarcoidosis subjects in whom forced expiratory volume in one second, peak expiratory flow rate, and vital capacity declined by 20±4.8 percent, 26.7±7.3 percent, and 15.2 ±4.1 percent, respectively, (all p<0.05) one half hour postlavage. No change occurred in total lung capacity or diffusing capacity. Only with large volume lavage did decrements in lung function occur in normal patients that were comparable to those seen in the sarcoidosis subjects. Our findings suggest that bronchoalveolar lavage in normal patients can be associated with a significant and volume-related decline in pulmonary function and that in subjects with sarcoidosis, the deterioration is more pronounced.

During each transplantation passage of a line of mouse myeloma tumor MOPC-315 through syngeneic (BALB/c) hosts, the tumor cells lose reactivity with cytotoxic thymus-derived lymphocytes directed against products of the BALB/c major histocompatibility complex (H-2d) and regain reactivity on transfer to fresh hosts. In contrast to this cyclical change, the tumor cells remain uniformly reactive with anti-H-2d alloantisera throughout the transplantation cycle.

Bronchodilator responsiveness has been associated with a subsequent accelerated decline in forced expiratory volume in one second (FEV1). Therefore, bronchodilator responsiveness and total serum immunoglobulin E(IgE) levels were assessed in 184 adult first-degree relatives of probands with severe early-onset chronic obstructive pulmonary disease (COPD) and a control group. Greater bronchodilator responsiveness was found among current smokers or exsmokers who were first-degree relatives of early-onset COPD probands than in currently or exsmoking controls, expressed as increase in FEV1 as a percentage of baseline (5.8+/-8.1 versus 2.9+/-5.1%, p<0.01), absolute increase in FEV1 from baseline (120+/-130 versus 60+/-110 mL, p<0.05), and increase in FEV1 as a percentage of the predicted value (3.6:4.1 versus 2.2+/-3.9%, p<0.05). However, elevated total serum IgE levels were not found in first-degree relatives of early-onset COPD probands compared with control subjects. The increased bronchodilator responsiveness among currently smoking/exsmoking first-degree relatives of early-onset COPD probands suggests that these individuals may have enhanced susceptibility to the detrimental effects of cigarette smoking.

Abstract Preliminary tests of three BALB/c myeloma tumors for ability to elicit immune responses in BALB/c mice showed that the only highly immunogenic one was MOPC-167. BALB/c mice immunized with this tumor developed cytotoxic T lymphocytes (CTLs) that lysed MOPC-167 cells specifically. When challenged with 5 × 105 MOPC-167 cells (about 1000 times the LD50 dose) labeled with 131I-iododeoxyuridine, tumors failed to develop in immunized animals and whole-body counts showed that the labeled MOPC-167 cells were rapidly eliminated. The cross-reactions of these CTL were unusual: they caused essentially no lysis of eight other BALB/c tumors, including three myeloma tumors, but they lysed extensively six out of nine tumors of DBA/2 mice (a seventh was lysed weakly). In contrast, the CTL elicited by MOPC-167 in (BALB/c × DBA/2)F1 hybrids did not lyse P815, the most sensitive of the DBA/2 tumors, and had less lytic activity against MOPC-167. CTL elicited by MOPC-167 in other BALB/c hybrids (BALB/c × NZB and BALB/c × C57BL/6) had the same reactions and cross-reactions as those elicited in purebred BALB/c mice. All of these observations suggest that MOPC-167 expresses an alloantigen that normally is absent in BALB/c mice but present in DBA/2 mice and in many DBA/2 tumors. The possibility that CTL elicited by immunization with a syngeneic tumor might be directed to inappropriately expressed alloantigens on the tumor cells was supported by observations with L5178Y: this lymphoma was one of the DBA/2 tumors not lysed by BALB/c anti-MOPC-167 CTL, but it was lysed by the CTL elicited in DBA/2 mice with MOPC-167 or with normal BALB/c spleen cells. Hence L5178Y, although of DBA/2 origin, appears to express antigens that are the same or strongly cross-reactive with an alloantigen that is absent in DBA/2 mice and present on normal BALB/c spleen cells and on a BALB/c myeloma tumor (MOPC-167).

The use of OKT3, an anti-CD3 monoclonal antibody, for immunosuppressive therapy for lung transplantation has been restricted because of concerns regarding infectious risk and cardiopulmonary instability after its administration.Fifty-two patients received OKT3 (5 mg/d intravenously for 10 days) for induction of immunosuppressive therapy, along with azathioprine (1.5 mg x kg(-1) x d(-1) intravenously) and enteral cyclosporine (12 mg x kg(-1) x d(-1)). Maintenance steroid therapy was begun on postoperative day 8. Prophylactic antifungal therapy (fluconazole or amphotericin B) and ganciclovir was used in all patients. Serial transbronchial biopsy and measurements of pulmonary function were used to assess patients for evidence of infection or rejection. Cytomegalovirus infection was diagnosed by biopsy or the presence of cytomegalovirus antigenemia.The 30-day mortality rate was 4%; the in-hospital mortality rate was 8%. Acute graft failure was seen in 6 patients. The median length of intubation was 5 days, and the median hospital stay was 30 days. Systemic and pulmonary artery systolic pressures, cardiac index, and ratio of arterial partial oxygen pressure to fraction of inspired oxygen showed no significant alteration after OKT3 dosage. Gram-negative pulmonary infections were identified in 12 patients. Aspergillus infection was seen in 7 patients. Cytomegalovirus infection in 8 patients responded to ganciclovir and did not affect mortality. Respiratory syncytial viral infection was seen in 7 patients. Acute rejection was never seen during OKT3 administration. No episodes of acute rejection were identified in 14 patients at any time postoperatively. In the remainder, episodes of acute rejection responded to steroid or antithymocyte globulin therapy. At a median length of follow-up of 31 months, freedom from obliterative bronchiolitis was 69%+/-9% at 36 months. The overall survival rate was 88%+/-5% at 12 months, 82%+/-6% at 24 months, and 74%+/-7% at 36 months after transplantation.OKT3 is a safe and effective agent for induction immunosuppressive therapy in lung transplant recipients that limits the incidence of acute rejection and may decrease the incidence of obliterative bronchiolitis.

A bstract : Effector T cells significantly contribute to inflammatory diseases. These cells are recruited into tissue, where they orchestrate an inflammatory response that can either protect against infection or sometimes stimulate human disease. The recruitment of T cells into tissue from the blood and lymphoid compartments is an active process controlled by chemokines and the chemokine receptors expressed on distinct effector T‐cell subsets. Thus, the chemokines secreted in the tissue will determine the specific types of T lymphocyte recruited into that tissue based on the chemokine receptors expressed on these cells. It follows that the chemokine receptor profile on T cells isolated from the lungs of patients with inflammatory pulmonary disease will define the subtype of pathogenic T lymphocytes mediating the disease process and will identify the mechanisms that recruit these cells into the lung. This article reviews data from both human and animal studies that define the chemokine receptors involved in the recruitment of T lymphocytes into the lung in various inflammatory pulmonary diseases, including asthma, obliterative bronchiolitis, sarcoidosis, and chronic eosinophilic pneumonia. We then speculate on the potential role of these chemokine receptors in the pathogenesis of these disorders and potential novel therapeutic approaches suggested by these data.

α1-antitrypsin

Peripheral blood lymphocytes were analysed from 40 subjects with occupational asbestos exposure and 40 controls matched for age and smoking habits. Patients were classified by duration of exposure as short or long, and by chest radiograph as normal, pleural plaques or interstitial changes. As a group, subjects with asbestos exposure had decreased percentages of OKT3+ and OKT8+ cells and increased OKT4+/OKT8+ ratio compared to controls. Correcting for age and smoking, those with short exposure were similar to controls, while those with long exposure had decreased percentages OKT3+ and OKT8+ cells and an increased OKT4+/OKT8+ ratio. Among radiographic subgroups, those with normal radiographs were similar to controls, but those with plaques had increased circulating OKT4+ cells, and those with interstitial changes had decreased percentages OKT3+ and OKT8+ cells and OKT8+ cells/mm3, with an increased OKT4+/OKT8+ ratio. There were no differences between subjects and controls in OKT10+ cells and OKIa+ cells. There appears to be a progressive decrease in percentage OKT8+ cells and increase in OKT4+/OKT8+ ratio with increasing exposure to asbestos, as determined by length of exposure and by radiographic abnormalities.

The prevalence of coronary artery disease in potential lung transplant recipients has not been extensively studied. Given the limited donor supply, a high degree of sensitivity for detecting occult disease is essential.This retrospective study examined both the clinical indications for coronary angiography and the extent of coronary arteriosclerotic disease in 105 consecutive potential lung transplant candidates.Fifty-one patients (49%) underwent angiography to either exclude asymptomatic atherosclerosis (n = 46) or define the extent of known symptomatic ischemic heart disease (n = 5). The perceived risk of occult disease according to a semiquantitative coronary risk assessment score that included hypertension, hyperlipidemia, diabetes, smoking, a family history of coronary artery disease, and electrocardiographic or echocardiographic abnormalities influenced the decision to perform angiography: 4 of 44 patients (9%) with two or fewer risk factors underwent angiography versus 42 of 56 patients (75%) with more than two risk factors (p < or = 0.05). A higher risk factor score also correlated with angiographic evidence of coronary artery disease. In the 46 patients without symptoms who were studied, two hemodynamically significant but unsuspected coronary lesions were identified. Six other patients without symptoms had noncritical (< 50%) lesions. Among the five patients with angina or a prior myocardial infarction, coronary angiography showed either minimal atherosclerosis (n = 2) or non-life threatening anatomy (n = 3). Angiographic findings did not exclude any patient from transplant listing.Coronary angiography appears most useful in patients without symptoms with multiple coronary risk factors and in a subset of patients who might otherwise be excluded from lung transplantation because of a history of symptomatic cardiovascular disease.

A 65-year-old man with a history of emphysema and inflammatory colitis was admitted to this hospital because of dyspnea, hypoxemia, and progressively worsening lung disease. Chest imaging revealed diffuse ground-glass opacities. Diagnostic tests were performed.

Single lung transplantation for chronic obstructive pulmonary disease relieves a ventilatory limit to incremental exercise, but maximum oxygen uptake remains abnormal. The purpose of this study was to define the relative contributions of Fick principle variables to abnormal aerobic capacity after lung transplantation.Twelve paired incremental cardiopulmonary exercise test results obtained before and 3 to 6 months after single lung transplantation for chronic obstructive pulmonary disease were compared.Maximum workload nearly doubled after operation (42.5+/-4.2 vs 25.5+/-4.7 watts, P < .05). Peak exercise minute ventilation increased (32.8+/-3.3 vs 21+/-2.4 L/min, n = 11, P < .05), but maximum oxygen uptake remained markedly abnormal after transplantation (46.6%+/-4.4% vs 32.1%+/-2.9% predicted, P < .05, n = 8). Peak exercise cardiac output was normal (11.0+/-1.4 L/min, 89% predicted), but arterial-mixed venous oxygen content difference at peak exercise was only half of normal (7.2+/-0.61 mL/dL), as a result in part of the failure of mixed venous oxygen saturation to fall normally (peak exercise SvO2 = 49.8%+/-2.8%).Lung transplantation for chronic obstructive pulmonary disease relieves a ventilatory limit to exercise, but maximum aerobic capacity remains abnormal, in part because of abnormal systemic O2 extraction.

In single lung transplantation (SLT) recipients, a "plateau" of the maximal expiratory flow volume curve (MEFV) and a "biphasic" MEFV have been reported to reflect anastomosis pathology. A plateau is defined as constant airflow over a large expired volume early in the MEFV. A biphasic MEFV has an initial period of high flow followed by a terminal low flow phase. Models of expiratory flow limitation by wave speed, however, predict that the MEFV of SLT recipients with emphysema should both be biphasic and demonstrate a plateau even without anastomosis pathology. Review of the spirometries and clinical courses of our first ten patients receiving SLT for emphysema demonstrated a biphasic MEFV, and a plateau of the MEFV in all patients. No patient showed evidence of anastomosis pathology. Independent lung spirometries, generated by a novel technique, revealed that the initial high flow phase of the MEFV came from the transplanted lung and the terminal low flow from the native emphysematous lung. The location of the flow limitation was demonstrated to be immediately downstream from the anastomosis. Therefore, the MEFV of SLT recipients with emphysema routinely demonstrates both a biphasic pattern and a plateau, neither of which necessarily reflect anastomosis pathology.

We have previously found that NK cell activity is present in rat lung lavage and inhibited by lidocaine. The purpose of this report is to characterize further the inhibition by lidocaine on NK activity. Peripheral blood lymphocytes from normal human volunteers were assayed in a four-hour 51chromium release assay in the presence of varying concentrations of lidocaine during or prior to the lytic assay. During the assay, increasing concentrations of lidocaine inhibited NK activity. This effect was not related to pH and at high concentrations was unrelated to methylparaben found in topical lidocaine. Preincubation of effector cells for one hour with different concentrations of lidocaine produced similar results which were temperature dependent and related to incubation time. Preincubation of effector cells in lidocaine (0.5g%) for one to ten minute intervals at 37°C resulted in 60 to 92% inhibition, respectively. The lidocaine did not alter effector cell viability nor did it affect the phenotypes of the effector cells as determined by flow cytometry. Lidocaine's inhibition of NK activity remained the same for cells which were further purified by plastic adherence, nylon wool filtration and percoll density centrifugation. The effect was not reversed by a 16 hour incubation in tissue culture medium. In a single cell assay, we determined that the inhibition was at the level of cell lysis.

Study Objective Our objective was to determine the extent to which patterns of diagnostic and therapeutic practice differ among hospitals caring for acutely ill hospitalized asthmatic patients in a single city. Design Our study comprised a retrospective review of the records of patients admitted to the hospital for the treatment of acute asthma. Setting Three large teaching hospitals in Boston were the setting. Patients One hundred twenty-seven patients between 18 and 50 years of age who were admitted to the medical services specifically for the treatment of asthma were studied. Interventions There were no interventions. Measurements and Main Results For this group of patients with similar histories of asthma, clinical presentation, and severity of asthma, the diagnostic tests used within 12 hours of admission and the frequency and volume of diagnostic laboratory testing throughout the admission differed significantly among the three hospitals. Spirometry, the test bearing most directly on the severity of the asthmatic attack, was not used routinely as a criterion for admission or discharge at any of the hospitals. Other tests of uncertain efficacy, such as chest x-ray films, were used frequently at some of the hospitals. Patients at all three hospitals were treated similarly with intensive combined regimens of methylxanthines, sympathomimetics, and corticosteroids and had similar mean lengths of stay. The use of chest physical therapy, which has not yet been demonstrated to be effective in acute asthma, differed significantly among the three hospitals. Conclusions We conclude that considerable variability exists in the diagnostic evaluation acutely ill hospitalized asthmatic patients in the three hospitals; little variability exists in the pharmacologic treatment of these patients. In the absence of data on outcome regarding functional improvement and reductions in morbidity, we are unable to recommend a preferred pattern of practice from this study. Our objective was to determine the extent to which patterns of diagnostic and therapeutic practice differ among hospitals caring for acutely ill hospitalized asthmatic patients in a single city. Our study comprised a retrospective review of the records of patients admitted to the hospital for the treatment of acute asthma. Three large teaching hospitals in Boston were the setting. One hundred twenty-seven patients between 18 and 50 years of age who were admitted to the medical services specifically for the treatment of asthma were studied. There were no interventions. For this group of patients with similar histories of asthma, clinical presentation, and severity of asthma, the diagnostic tests used within 12 hours of admission and the frequency and volume of diagnostic laboratory testing throughout the admission differed significantly among the three hospitals. Spirometry, the test bearing most directly on the severity of the asthmatic attack, was not used routinely as a criterion for admission or discharge at any of the hospitals. Other tests of uncertain efficacy, such as chest x-ray films, were used frequently at some of the hospitals. Patients at all three hospitals were treated similarly with intensive combined regimens of methylxanthines, sympathomimetics, and corticosteroids and had similar mean lengths of stay. The use of chest physical therapy, which has not yet been demonstrated to be effective in acute asthma, differed significantly among the three hospitals. We conclude that considerable variability exists in the diagnostic evaluation acutely ill hospitalized asthmatic patients in the three hospitals; little variability exists in the pharmacologic treatment of these patients. In the absence of data on outcome regarding functional improvement and reductions in morbidity, we are unable to recommend a preferred pattern of practice from this study.

The morbidity and mortality rates of lung transplantation have been decreasing, partly because of improvements in the prevention, recognition, and treatment of transplant-related complications. These complications can be classified into three broad categories: (1) complications of the operation itself, (2) complications of transplantation (i.e., rejection), and (3) complications of the immunosuppressive agents used to prevent rejection, including infection, malignancy, and direct toxicities of the medications. In each of these categories, this article describes the clinical presentations of the major transplant-related complications and strategies for their prevention, early diagnosis, and treatment.

Donor to recipient matching is based primarily on ABO blood group compatibility. Median sternotomy is the standard approach for heart transplantation. Although the surgical technique of heart transplantation is simple, there are certain specific circumstances in which the operation can be technically demanding and require careful planning to get the best outcome. Ventricular assist devices (VADs) are more commonly used as a bridge to transplantation, and many patients wait for heart transplantation with a functioning VAD or are listed for urgent procedure due to VAD-related complications. Heart-lung transplantation and domino heart transplantation have largely been superseded by bilateral sequential lung transplantation. Heterotopic transplantation allows much more leniency on the donor and recipient mismatching. Careful consideration should be given to the adequacy of cardiac output in maintaining oxygen delivery to the tissues, bleeding, collections, pneumothorax, and position of the monitoring lines.

Natural killer (NK) cells play an important role in defense against tumors and certain infected cells. Although NK activity is present in cells recovered from lung parenchyma, its demonstration in cells retrieved from normal bronchoalveolar lavage (lung lavage) has been difficult. In this study, we report that NK cells are present and active in normal rat lung lavage. Purified effector cells retrieved from lung lavage and peripheral blood mononuclear cells were compared for NK activity. NK activity was tested in a four hour 51-chromium release assay against radiolabeled Yac-1 target cells and expressed as lytic units (LU). There was no difference in NK activity between the blood and lung (80 ± 10 LU vs. 62±15 LU). Since lidocaine is used in lung lavage for topical anaesthesia in humans and to increase the cell yield in animals, we also sought to determine if it could affect NK activity. We found that lidocaine inhibited NK activity in a dose dependent manner when it was instilled into the airways prior to performance of lavage. Lidocaine did not affect the yield of cells recovered from lavage, their relative proportions, nor their viability. Lung macrophages (93 ± 1% nonspecific esterase positive) inhibited blood NK activity, an effect significantly augmented by lidocaine. In sum, we report that NK activity in lung lavage is similar to that found in blood and may be regulated by alveolar macrophages and that topical lidocaine inhibits NK activity, an effect which needs to be considered in studies of these cells from lung lavage.

Presentation of CaseA 62-year-old woman was admitted to the hospital because of a question of pneumonia.She was well until 19 months earlier, when she noticed a lump in the left breast. A mammographie study was reported to be negative. Five months before admission another mammographie examination disclosed an abnormal density in the left breast, and a biopsy of the lesion was performed elsewhere. Microscopical examination of the excised specimen revealed infiltrating ductal carcinoma. The patient was referred to this hospital.There was a history of smoking more than two packs of cigarettes daily for many years, with recent . . .

Presentation of CaseA 59-year-old man was admitted to the hospital because of hemoptysis.The patient was a commercial fisherman who was well until five years earlier, when the onset of arthralgia in the knees, ankles, feet, and elbows caused him to retire from his work. Aspirin gave partial relief. Ten days before admission the arthralgia worsened, and he coughed up a small amount of pink sputum. A physician prescribed indomethacin, without benefit. On the day before entry he coughed up obvious blood. On the following day hemoptysis recurred, and he came to this hospital.The patient had smoked two . . .

Abstract In sarcoidosis and idiopathic pulmonary fibrosis, it has been reported that lymphocyte proportions in lung lavage predict the subsequent clinical course. Recent evidence has suggested that lymphocytes are important in the alveolitis of asbestosis. We hypothesized that a greater relative proportion of T‐lymphocytes in lung lavage of asbestos‐exposed subjects is associated with immune activation and may predict the subsequent clinical course. We assessed lymphocyte subsets in lung lavage and peripheral blood (PB) of 97 asbestos‐exposed subjects and 10 unexposed normals, using flow cytometry analysis of monoclonal antibody‐treated cells. T‐cell alveolitis was defined as follows: [%lymphocytes in lavage × %CD3 in lavage] &gt; 2 SD above that product in normals. Eighteen subjects had T‐cell alveolitis (group 1) and 79 did not (group 2). There were no significant differences between the groups in age, smoking status, duration of exposure, lung function results, or frequency of plaques or profusion ≥ 1/0. Percent CD2 was higher in lavage of group 1 compared with group 2. There was a trend for higher %Ia in lavage of group 1 compared with group 2. These results identify a subgroup of asbestos‐exposed subjects with T‐cell alveolitis but no present excess of asbestos‐related disease who may be at risk for future asbestos‐related disease.

Genetic epidemiology studies of end-stage lung disease are potentially hindered by low numbers of participants due to early death of patients from the underlying disease, or due to exclusion from studies after patients have had lung transplants, because of concern about bias of genotype data due to chimerism.The number of participants enrolled in genetic studies of end-stage lung disease could be increased by including those individuals who have undergone lung transplant.We hypothesized that individuals who have had lung transplants can be included in genetic epidemiology studies that use single nucleotide polymorphism and short tandem repeat marker data, without confounding due to chimerism.Ten probands with severe, early-onset chronic obstructive pulmonary disease were included in this analysis.Pre-and post-lung transplant DNA samples were used in the investigation of concordance of genotype results for 12 short tandem repeat markers and 23 single nucleotide polymorphisms.Concordance was observed for all genotypes before and after lung transplant.We conclude that the risk of biasing genetic epidemiology studies due to donor lung-related DNA microchimerism is low, and that the inclusion of post-lung transplantation participants will allow for larger genetic epidemiology studies of individuals with end-stage lung disease.

Background: Lung transplantation can increase quality of life and survival in patients with end-stage lung disease. However, long-term success is limited by obliterative bronchiolitis (OB). Although the exact pathogenic mechanisms leading to OB have not been fully delineated, lymphocyte recruitment into the lung allograft plays a crucial role in its development. Chemokines are a large family of chemotactic cytokines that control inflammatory cell recruitment into the lung and are markedly elevated in the lung in patients with OB and acute rejection.

We appreciate Dr. Venuta’s interest in our report and concur with the importance of identifying markers of disease progression, given the heterogeneous nature of cystic fibrosis (CF) lung disease involvement. We observed that substantial disparity in ventilation/perfusion abnormalities identified a group of CF patients at risk for dying on the transplant list. In addition, we confirmed earlier reports that an elevated Pco2 is associated with greater risk of mortality while waiting. Although not directly measured in every patient at the time of transplant evaluation, pulmonary arterial pressure estimates via echocardiogram (right ventricular systolic pressure) were not significantly different between the study groups. Trends toward higher dead space ventilation (Vds/Vt), Ve/Vco2 and lower maximal oxygen uptake during exercise were observed in the group of patients who died while on the lung transplant waiting list, suggesting greater exercise-induced impairment of pulmonary vascular reserve. However, these differences were not statistically significant. A subsequent analysis comparing the observed estimate of pulmonary arterial pressure to disparity in both ventilation and perfusion between lungs revealed no substantial correlation (mean R2 = 0.05). One possible explanation is that heterogeneous abnormalities seen on ventilation/perfusion scans may not always accompany an important change in PA pressure, considered a global estimate of the entire pulmonary vascular bed. Variability of pulmonary vascular reserve among different lung regions may lead to relatively normal mean values through compensatory dilation of the normal vascular beds. Nonetheless, we do not dispute that, if significant pulmonary hypertension is identified, then it represents an independent risk factor for early death while waiting for a lung transplant.

Living donor lobar transplantation is a viable option for carefully selected recipients with end-stage pulmonary disease. Successful results depend, in part, on the donor outcome. In this study we report long-term donor follow-up for ten living donor transplants performed between 1995 and 2000. Prior to donation all twenty donors had normal pulmonary function tests. No major post-operative complications occurred among the donors. To date, we have evaluated the pulmonary function and psychological state of nine donors. Following donation, pulmonary function tests remained within the normal range, but showed mean decrements of 20 +/- 3% in FEV1, 13 +/- 4% in FVC, 17 +/- 4% in TLC, 20+/-9% in RV, and 7 +/- 5% in DLCO. Psychological well being was assessed with the Beck Depression Inventory and the MOS 36-Item Short-Form Health Survey, as well as an open-ended psychiatric interview. On the structured interviews all donors denied formal psychiatric symptoms. However, on private interview, they expressed some dissatisfaction; all wished for greater acknowledgement of their role in the process. In addition, the donors perceived a decrease in their exercise tolerance– out of proportion to measured spirometry. The findings underscore the limitations of structured surveys and highlight the importance of open-ended psychiatric interviews for lobar donors.

155 Background: OKT3 monoclonal antibody therapy results in an acute clinical syndrome (ACS) associated with the release of cytokines such as tumor necrosis factor (TNF) and sequestration of neutrophils in the lungs. We have previously shown that inhibition of TNF does not eliminate OKT3-ACS, suggesting that other factors also contribute to the ACS. We analyzed the mechanisms of complement (C) activation in vivo, during the first hour following OKT3 administration. Methods: Renal transplant (Tx) recipients (n=4) with steroid-resistant rejection and lung Tx recipients (n=4) received OKT3 as treatment for rejection and induction therapy, respectively. Blood samples were obtained in Nafamostat-EDTA tubes. C activation products C4d (classical pathway), Bb (alternative pathway), iC3b (C3 cleavage product) and SC5b-9 (terminal pathway) were measured using ELISA kits (QUIDEL Corporation, San Diego, CA). Hemodynamic parameters were monitored using a Swan-Ganz catheter in lung Tx recipients in the ICU. Neutrophil CD11a, CD11b, and CD18 were monitored in two patients by flow cytometry. Controls included patients receiving 500mg i.v. methylprenisolone (MP) pulses for rejection, adults with acute respiratory distress syndrome who received extracorporeal membrane oxygenation (ECMO) in the ICU and normal individuals. Data were analyzed using the student's t-test and correlated by regression analysis. Results: An increase in the levels of C4d, Bb, iC3b, and SC5b-9 was observed in 7/8 OKT3-treated patients. No significant differences in C activation were found between lung and Table kidney Tx recipients. Total WBC and neutrophil counts at 60 minutes were 65% and 70% of their pre-OKT3 values. A marked increase in the expression of CD11b and CD18 and a decrease of CD11a on neutrophils in parallel with C activation was observed. In lung Tx recipients C4d and iC3b production correlated with increases in central venous pressure (p = 0.023, p = 0.003) and iC3b production correlated with increases in mean pulmonary arterial pressure (p = 0.024). As compared to ECMO (silicone membrane), OKT3 induced activation of C occurred predominantly by the classical pathway, whereas ECMO activated C by the alternative pathway and MP pulses did not activate C.TableConclusions: C activation is an early event after OKT3 administration and is associated with activation of neutrophils and pulmonary hemodynamic changes. In addition to cytokine production, C activation should be studied to delineate potential side-effects of new monoclonal antibodies used in organ transplantation.

96 Background: In contrast to a single chronological list as used by most lung transplant programs nationally, the programs in UNOS Region 1 rank recipients by illness severity using hospitalization as a surrogate marker. Potential recipients are listed chronologically within categories ranked according to the level of support currently being received as an inpatient (status 1-3) or outpatient (status 4). We sought to determine the effect of this strategy on waiting time and post-transplant survival. Methods: Recipients of 100 consecutive lung transplant operations from 3/94 to 4/98 were reviewed as to diagnosis, transplant type, active listed time, number of status elevations, status at transplant, and survival. Results: Waiting time was 14.0 ± 11.8 months (mean ± SD) for 25 recipients transplanted from status 1-3 and 20.4 ± 12.7 months for 75 recipients transplanted from status 4 (p <0.05). While 4 of 44 single lung recipients (9%) had a single elevation in status at some point during the waiting period, only 1 underwent transplantation while at an elevated status. In contrast, 35 of 56 bilateral lung recipients (63%) had an average of 2.3 (range 1 to 12, median 2) elevations in status and 24 (43%) underwent transplantation while at an elevated status. Emphysema and COPD were the diagnoses in 33 of the 44 single lung recipients and Cystic Fibrosis accounted for 37 of the 56 bilateral lung recipients. Of those with Cystic Fibrosis, 28 of 37 (76%) had an elevation in status and 18 (49%) underwent transplantation while at an elevated status. Survival following bilateral lung transplantation (status 1-3 vs. status 4 at time of transplant) was 92% vs. 88% at 30 days and 70% vs. 90% at 1 year (p value not significant by log-rank analysis). Survival for Cystic Fibrosis recipients was 100% vs. 79% (status 1-3 vs. 4) at 30 days and 79% vs. 82% at 1 year (p = not significant). Conclusions: Prioritization of recipients using hospitalization as a surrogate marker for illness severity significantly shortens waiting times for "sicker" patients without altering short-term outcome. Recipients most likely to benefit from this strategy are those with diseases such as Cystic Fibrosis who require repeated hospitalization.

In a prospective study, from 1983 to 1986, circulating T-lymphocyte subsets were measured in patients with lung cancer who received thoracic radiation therapy (RT) as either primary or postoperative treatment. Samples were collected from new and follow-up patients, either before and/or after RT. A total of 230 samples from 131 patients were analyzed. T-cell determinations were made using subset-specific monoclonal antibodies and flow cytometry. RT portals typically included the area of primary disease, the ipsilateral hilum, the mediastinum and the supraclavicular fossae. The mean dose for all patients was 57 Gy (range 36-70 Gy). Post RT samples were arbitrarily divided into the following time groups: O-3 months, 3-6 months 6-12 months, 12-24 months, 24-59 months and 160 months. Statistical significance was determined using Student’s T-test for comparisons of 2 groups and analysis of variance for comparisons of 3 or more groups. All described changes were statistically significant at the 95% confidence limit, unless otherwise stated (ie. n.s.). Analysis of data collected before and after RT showed a decrease in CD4 cells from 48% before RT to 32% at O-3 months post-RT and remained depressed beyond 60 months. CD8 cells increased from 24% before RT to 31% at O-3 months postRT. As a result of these changes, the mean CD4/CD8 ratio decreased from 2.33 to 1.41 at O-3 months after RT and stayed depressed beyond 60 months. This phenomenon was observed for all histologies. In 18 patients who had at least one sample drawn before and after RT, the individual CD4/CD8 ratio was observed to decrease in 16. CD3 cells were also observed to decrease from 69% before RT to 64% at O-3 months post-RT (n.s.) and to 55% at 3-6 months after RT and remained significantly below the pre-RT value beyond 60 months. Similarly, the %llA cells decreased following RT and remained significantly below pre-RT values beyond 60 months. Conversely, the %CDlO and %IA cells increased following RT, both peaking at 3-6 months post-RT. The total number of WBCs did not significantly change following treatment while the mean total number of lymphocytes decreased from 1832 before treatment to 1186 at O-3 months post-RT, and increased to 1400 at 12-24 months. In 49 patients who had 52 T-cell profiles measured prior to RT, we analyzed CD4/CD8 ratios with regard to histology, stage of disease and survival. There were 18 cases of adenocarcinoma, 15 squamous cell carcinomas, 11 small cell carcinomas, 3 large cell carcinomas and 2 cases of undifferentiated carcinoma. Within this group, there was no significant difference between small cell, adenocarcinoma and squamous histologies. In general, CD4/CD8 ratio increased with extent of disease. For T2 versus T3 tumors, CD4/CD8 ratios were 2.08 and 2.26 respectively (n.s.). For NO-l versus N2 CD4/CD8 ratios were 1.77 and 2.52, respectively. For MO versus Ml patients, CD4/CD8 ratios were 2.16 and 3.09, respectively. Patients with pretreatment CD4/CD8 ratios 2.00 had an average survival of 15.9 months. Similarly, patients with an absolute CD4 900 survived 14.9 months. No other T-cell subsets were significantly prognostic. These data indicate that low CD4 values and low CD4KD8 ratios are associated with a better prognosis and that thoracic RT may produce favorable redistribution of CD4/CD8 ratios.

Upright exercise in normals is accompanied by an increase in indexed left ventricular end-diastolic volume (LVEDVI) which is felt to enhance cardiac output via the Frank-Starling mechanism. To assess whether an inability to increase LVEDVI during exercise may exist in pts with pulmonary hypertension (PHTN), we examined data from right heart catheterization and rest and exercise first-pass radionuclide ventriculography (RVG) in 55 pts referred for lung transplantation (LTX) evaluation. Grp 1 (n = 16; 46 ± 3 yrs. mean ± SEM) had pulmonary vascular resistance (PVR) ≥ 250 dynes-sec/cm5 (mean 452 ± 44); Grp 2 (n = 39; 48 ± 2 yrs) had PVR &lt; 250 dynes-sec/cm5 (mean 179 ± 6). Pulmonary capillary wedge pressure did not differ between groups (8.2 ± 1.0 vs. 7.2 ± 0.6 mmHg). Right ventricular ejection fraction (RVEF) at rest (0.35 ± 0.02 vs. 0.39 ± 0.01; P &lt; 0.05) and exercise (0.36 ± 0.02 vs. 0.42 ± 0.01; p &lt; 0.005) were lower in Grp 1. All pts reached a pulmonary limit to exercise; exercise capacity. as determined by maximal oxygen consumption or watts achieved. did not differ between groups. Rest and exercise heart rate. indexed LV stroke volume. and LVEF did not differ between groups. Rest Ire) and exercise (ex) LVEDVI. and the change in LVEDVI with exercise. were as follows:Empty CellGrp1Grp2Empty CellreLVEDVI (ml/m2)69.9 ± 4.469.6 ± 2.2 NSexLVEDVI (ml/m2)70.5 ± 3.482.2 ± 2.6*ΔLVEDVI (ml/m2)0.5 ± 2.512.6 ± 2.1*Grp 1 vs. Grp 2*p &lt; 0.01 Grp 1 vs. Grp 2 p &lt; 0.01 19 pts (11 Grp 1.8 Grp 2) underwent LTX with follow-up rest and exercise RVG 15 ± 2 mos later. Following LTX. there was no difference between the groups in exercise capacity or LVEF. and no longer a difference in RVEF or in the ability to increase LVEDVI with exercise. Pts with PHTN have an abnormal LVEDVI response to upright exercise which may contribute to their exercise intolerance. This abnormality resolves following LTX.