Burnout Syndrome in Lung Transplant Physicians.

Objective: Burnout syndrome is common in physicians, but little is known about burnout in lung transplant physicians specifically. The purpose of this study was to explore burnout and its relationship to job factors and depression in lung transplant physicians.Design: A cross-sectional study that included lung transplant pulmonologists and surgeons was performed via electronic survey.Setting: The lung transplant physicians surveyed practiced worldwide.Methods: The survey incorporated questions about demographics and job characteristics as well as the Maslach Burnout Inventory and Patient Health Questionnaire-2. Burnout was defined by high emotional exhaustion or depersonalization.Participants: Ninety physicians worldwide completed the survey.Results: Of the 90 physicians who completed the entire survey, 44 (48.9%) had burnout with 38 (42.2%) having high emotional exhaustion, 15 (16.7%) having high depersonalization, and 9 (10.0%) with both. Of the respondents, 14 (15.6%) had high risk of depression, and of these, 13 also had high emotional exhaustion. There was a positive correlation between depression score and emotional exhaustion score (P=0.67, P<0.001). Depression was more common in surgeons compared with pulmonologists (35.7% versus 11.8%, P=0.02). There was a trend toward more burnout by emotional exhaustion in physicians with more versus less work experience (68.4% versus 31.6%, P=0.056).Conclusions: Emotional exhaustion is common in lung transplant physicians and is associated with depression and a negative impact on life.

Need for anticoagulation and use of direct oral anticoagulants in lung transplant recipients.

Limited information is available about use of direct oral anticoagulants (DOACs) in lung transplant recipients (LTRs). The purpose of this study is to describe the indications and use of long-term anticoagulation, including the safety and tolerability of DOACs, in LTRs. This was a single-center retrospective study. LTRs who received therapeutic anticoagulation were identified. Patient characteristics, indications for treatment, and complications of therapy were obtained. A total of 203 patients underwent lung transplantation of which 118 patients (58.1%) had an indication for anticoagulation. Patients with an indication for anticoagulation were older than those without (59 ± 14 years versus 48 ± 17 years, p < 0.001) and were more likely to be male (72.0% versus 50.6%, p = 0.002). Of the patients with indication for anticoagulation, 74 (62.7%) received it. Fifty-one (68.9%) of patients receiving anticoagulation were treated with DOACs. In the patients receiving anticoagulation, there were 14 major bleeding events in 13 patients, of which 3 were receiving DOACs and the remainder were receiving heparin or warfarin. The need for anticoagulation is common in LTRs for both atrial arrhythmias and venous thromboembolism. However, many patients with atrial arrhythmias do not receive anticoagulation. The use of DOACs is well tolerated and safe in LTRs.

The impact of fungal allergic sensitization on asthma.

PURPOSE OF REVIEW: Fungal sensitization may contribute to the development of asthma as well as asthma severity. The purpose of this review is to summarize existing knowledge about the pathophysiology, diagnosis, and management of fungal sensitization in asthma and highlight unmet needs and target areas for future investigation. RECENT FINDINGS: Fungal sensitization may occur by a normal or aberrant immune response. Allergic sensitization to fungi is mediated by the adaptive immune response driven by TH2 cells and the innate immune response driven by the innate lymphoid cells group 2. Diagnosis of fungal sensitization can be made by either skin prick testing or measurement of fungal-specific serum IgE. Fungal sensitization in asthma has been associated with worse disease severity, including reduced lung function, increased risk of hospitalizations, and life-threatening asthma. A spectrum of disease related to fungal sensitization has been described in asthma including allergic bronchopulmonary mycosis and severe asthma with fungal sensitization (SAFS). The role of antifungals and targeted biologic therapy in asthma with fungal sensitization need further investigation. SUMMARY: There is increasing awareness of the contribution of fungal sensitization to asthma severity. However, there are no therapies with proven efficacy. Randomized clinical trials are needed to further investigate the role of biologics.

Tacrolimus monitoring parameters are not associated with acute cellular rejection following lung transplantation.

PURPOSE: The purpose of this study was to evaluate the impact of tacrolimus drug monitoring parameters on the incidence of acute cellular rejection (ACR) in lung transplant recipients (LTRs). METHODS: This was a retrospective study of patients who underwent lung transplantation at a single center. LTRs who were given tacrolimus during the first 6 months after transplantation and who underwent at least one bronchoscopy with biopsy were included. Tacrolimus time in therapeutic range (TTR) was calculated using Rosendaal's method. Time to therapeutic level, coefficient of variance (CoV), and median trough concentrations were also determined. RESULTS: The study included 157 LTRs. ACR ≥ A1 grade was present in 46.5% of patients, and ACR ≥ A2 grade was present in 17.2%. There was no difference between tacrolimus TTR in patients with ACR ≥ A1 compared with those without ACR (47.4 ± 16.1 versus 46.2 ± 18.9%, p = 0.67) or in patients with ACR ≥ A2 grade compared with those with A0 or A1 ACR (46.0 ± 16.3 versus 47.0 ± 17.9%, p = 0.81). When comparing patients with any ACR grade A1 or higher with those without ACR, there was no difference in tacrolimus CoV (42.7 ± 11.0 versus 44.6 ± 12.4, p = 0.30), median tacrolimus trough concentration (9.9 ± 1.3 versus 9.8 ± 1.4 ng/mL, p = 0.66), or days to therapeutic level (9 versus 12 days, p = 0.057). CONCLUSIONS: The results suggest that tacrolimus TTR, time in therapeutic range, and variability are not related to the presence of ACR in LTRs.

Detection, classification, and management of rejection after lung transplantation.

Rejection is a major complication following lung transplantation. Acute cellular rejection, lymphocytic bronchiolitis, and antibody-mediated rejection (AMR) are all risk factors for the subsequent development of chronic lung allograft dysfunction (CLAD). Acute cellular rejection and lymphocytic bronchiolitis have well defined histopathologic diagnostic criteria and grading. Diagnosis of AMR requires a multidisciplinary approach. CLAD is the major barrier to long-term survival following lung transplantation. The most common phenotype of CLAD is bronchiolitis obliterans syndrome (BOS) which is defined by a persistent obstructive decline in lung function. Restrictive allograft dysfunction (RAS) is a second phenotype of CLAD and is associated with a worse prognosis. This article will review the diagnosis, staging, clinical presentation, and treatment of acute rejection, AMR, and CLAD following lung transplantation.

Postoperative management of lung transplant recipients.

Despite advances in surgical technique, lung transplantation is associated with worse survival when compared with other solid organ transplantations. Graft dysfunction and infection are the leading causes of mortality in the first 30 days following transplantation. Primary graft dysfunction (PGD) is a form of reperfusion injury that occurs early after transplantation. Management of PGD is mainly supportive with use of lung protective ventilation. Inhaled nitric oxide (iNO) and extracorporeal membrane oxygenation may be used in severe cases. Bacterial pneumonias are the most common infectious complication in the immediate post transplant period, but invasive fungal infections may also occur. Other potential complications in the postoperative period include atrial arrhythmias and neurologic complications such as stroke. There is a lack of multicenter, randomized trials to guide ventilation strategies, infection prophylaxis, and treatment of atrial arrhythmias, therefore prevention and management of post-transplant complications vary by transplant center.

Pleural catheter placement and intrapleural fibrinolysis following lung transplantation.

BACKGROUND: This study aimed to investigate the characteristics of lung transplant recipients requiring additional pleural drainage catheters early post-lung transplantation and to determine the safety and efficacy of intrapleural fibrinolytics in these patients. METHODS: A retrospective review of lung transplant recipients at a single center was performed. Patient and transplant characteristics, placement of pleural drainage catheters within 90 days of transplant, and use of intrapleural fibrinolytics were determined. RESULTS: Out of 128 patients who underwent lung transplantation, 54 patients required 86 additional chest tubes, the majority of which were size 14 French or smaller. Pleural effusion was the most common indication for tube placement. Patients who required additional chest tubes were more likely to have chronic obstructive pulmonary disease than those who did not. Use of intrapleural fibrinolytics led to radiographic improvement in 77.8% of patients and was not associated with bleeding, pneumothorax, or mortality within 30 days. CONCLUSIONS: Use of small-bore chest tubes and intrapleural fibrinolytics can be safe and effective in lung transplant recipients with persistent pleural effusions.

Spotlight on fevipiprant and its potential in the treatment of asthma: evidence to date.

Asthma is a heterogeneous disease, which may be classified into phenotypes and endotypes based on clinical characteristics and molecular mechanisms. The best described endotype of severe asthma is type 2 (T2)-high asthma, characterized by release of inflammatory cytokines by T helper 2 (TH2) cells and type 2 innate lymphoid cells cells. Prostaglandin D2 contributes to T2 inflammation through binding of the G-protein-coupled receptor chemoattractant receptor-homologous molecule expressed on TH2 cells (CRTH2). Fevipiprant is an oral competitive antagonist of CRTH2. Early-phase trials have demonstrated safety and potential efficacy in patients with asthma, specifically, improvement in FEV1 and eosinophilic airway inflammation. However, no clear biomarker identified patients who responded favorably to fevipiprant, although patients with moderate-to-severe asthma and evidence of T2 inflammation may be more likely to respond to treatment. Additional studies are needed to determine the efficacy and target population for use of this drug in patients with asthma.

Targeting the interleukin-4 and interleukin-13 pathways in severe asthma: current knowledge and future needs.

PURPOSE OF REVIEW: Severe asthma is a heterogeneous disease that can be classified into phenotypes and endotypes based upon clinical or biological characteristics. Interleukin (IL)-4 and IL-13 play a key role in type 2 (T2) asthma. This article reviews the signaling pathway of IL-4 and IL-13 and highlights its targeted therapy in severe asthma. RECENT FINDINGS: Several clinical trials of biologics targeting the IL-4/IL-13 pathway have recently been completed. In patients with severe, uncontrolled asthma, targeting IL-13 alone with biologics including lebrikizumab and tralokinumab has not shown consistent reduction in asthma exacerbations. Simultaneous targeting of both IL-4 and IL-13 by blocking IL-4 receptor α using dupilumab has yielded more consistent results in reducing asthma exacerbations and improving lung function, especially in patients with increased blood eosinophils. Other biomarkers of T2 inflammation such as exhaled nitric oxide and serum periostin may also predict response to biologics targeting the IL-4/IL-13 pathway. SUMMARY: No biologic targeting the IL-4/IL-13 pathway is currently available for treatment of asthma, but emerging data suggest that biologics targeting IL-4 and IL-13 together may benefit patients with T2 high asthma. Additional data are needed about long-term efficacy and safety prior to incorporating these drugs into routine clinical practice.

Examining the Effects of Age on Health Outcomes of Chronic Obstructive Pulmonary Disease: Results From the Genetic Epidemiology of Chronic Obstructive Pulmonary Disease Study and Evaluation of Chronic Obstructive Pulmonary Disease Longitudinally to Identify Predictive Surrogate Endpoints Cohorts.

RATIONALE: The prevalence of chronic obstructive pulmonary disease (COPD) and its associated comorbidities increase with age. However, little is understood about differences in the disease in patients over 65 years of age compared with younger patients. OBJECTIVES: To determine disease characteristics of COPD and its impact in older patients compared with younger patients. METHODS: We examined baseline characteristics of patients with COPD (global obstructive lung disease stage II-IV) in 2 large cohorts: Genetic Epidemiology of COPD Study (COPDGene) and Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE). We compared demographics, indices of disease severity, prevalence of comorbidities, exacerbation frequency, and quality of life scores in patients ≥65 years of age vs patients <65 years of age. We also tested for associations of age with disease characteristics and health outcomes. RESULTS: In the COPDGene cohort, older patients (n = 1663) had more severe disease as measured by forced expiratory volume in 1 second (1.22 vs 1.52 L, P < .001), use of long-term oxygen therapy (35% vs 22%, P < .001), 6-minute walk distance (355 vs 375 m, P < .001), and radiographic evidence of emphysema (14% vs 8%, P < .001) and air trapping (47% vs 36%, P < .001) and were more likely to have comorbidities compared with younger patients (n = 2027). Similarly, in the ECLIPSE cohort, older patients (n = 1030) had lower forced expiratory volume in 1 second (1.22 vs 1.34 L, P < .001), greater use of long-term oxygen therapy (7% vs 5%, P = .02), shorter 6- minute walk distance (360 vs 389 m, P < .001), and more radiographic evidence of emphysema (17% vs 14%, P = .009) than younger patients (n = 1131). In adjusted analyses of both cohorts, older age was associated with decreased frequency of exacerbations [odds ratio = 0.52, 95% confidence interval (CI) = 0.43-0.64 in COPDGene, odds ratio = 0.79, 95% CI = 0.64-0.99 in ECLIPSE] and a better quality of life (lower St. Georges respiratory questionnaire score) (ß = -8.7, 95% CI = -10.0 to -7.4 in COPDGene, ß = -4.4, 95% CI = -6.1 to -3.2 in ECLIPSE). CONCLUSIONS: Despite greater severity of illness, older patients with COPD had better quality of life and reported fewer exacerbations than younger patients. Although this observation needs to be explored further, it may be related to the fact that older patients change their expectations and learn to adapt to their disease.

Determinants of pre-transplantation pectoralis muscle area (PMA) and post-transplantation change in PMA in lung transplant recipients.

BACKGROUND: This study aimed to determine predictors of pectoralis muscle area (PMA) and assess change in PMA following lung transplantation and its relationship to outcomes. METHODS: A retrospective review of 88 lung transplant recipients at a single center was performed. PMA was determined on a single axial slice from chest computerized tomography. Pectoralis muscle index (PMI) was calculated from the PMA divided by the height squared. RESULTS: PMI decreased post-transplantation (8.1±2.8 cm2 /m2 pre-transplantation, 7.5±2.9 cm2 /m2 at 6 months, and 7.6±2.7 cm2 /m2 at 12 months, P<.05). Chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD) were predictors of pre-transplant PMI (ß=-2.3, P=.001 for COPD; ß=2.1, P<.001 for ILD) and percent change in PMI at 12 months post-transplantation relative to baseline (ß=19.2, P=.04 for COPD; ß=-20.1, P=.01 for ILD). Patients in the highest quartile for PMI change at 12 months had fewer ventilator days compared with patients in the other quartiles (P=.03). CONCLUSIONS: Underlying diagnosis was a significant predictor of both pre-transplantation PMI and change in PMI post-transplantation. Further studies of PMI are needed to determine its clinical utility in predicting outcomes following lung transplantation.

Fungal Sensitization Is Associated with Increased Risk of Life-Threatening Asthma.

BACKGROUND: Fungal sensitization in patients with asthma has been associated with severe asthma and worse asthma outcomes. OBJECTIVE: The purpose of this study was to determine the relationship between fungal and nonfungal sensitization, asthma severity, and clinical outcomes. METHODS: A retrospective review of patients with asthma evaluated in an urban pulmonary subspecialty clinic in the United States was performed. Patients with fungal and nonfungal allergen sensitization were identified based on serum-specific immunoglobulin E (sIgE) testing. Demographic, clinical, laboratory, and spirometric data were obtained. The relationship between fungal sensitization and asthma outcomes was examined. RESULTS: Of 390 patients with asthma identified, 307 had sIgE testing, of whom 53 (17.3%) had fungal sensitization, 117 (38.1%) had nonfungal sensitization, and 137 (44.6%) had no sensitization. Patients with fungal sensitization were more likely to be sensitized to ≥5 allergens than patients with nonfungal sensitization (66% for fungal vs 29% for nonfungal, P < .001). Serum IgE concentrations were highest in patients with fungal sensitization compared with patients with no sensitization or nonfungal sensitization (median, 825, 42, and 203 IU/mL, respectively, P < .001). Fungal sensitized patients were more likely to require intensive care unit (ICU) admission and mechanical ventilation than those with no sensitization or nonfungal sensitization (13.2%, 3.7%, and 3.4%, respectively, for ICU admission, P = .02; 11.3%, 1.5%, and 0.9%, respectively, for ventilation, P < .001). CONCLUSIONS: Fungal sensitization is common in patients with asthma in an urban setting and is associated with greater sensitization to nonfungal allergens and increased risk of life-threatening asthma.

Predictors and patterns of weight gain during treatment for tuberculosis in the United States of America.

OBJECTIVES: Patients with tuberculosis (TB) often present with weight loss. Lack of weight gain with TB treatment has been associated with treatment failure. The purpose of this study was to examine patterns of weight gain in patients with TB and determine the disease characteristics that predict weight gain. METHODS: This was a retrospective cohort study of adults with TB treated in a county health system in the USA. Demographic, clinical, radiographic, and microbiological data were recorded in addition to monthly weights during treatment. RESULTS: Overall, patients had a significant change in weight over the course of treatment (p<0.0001). After 2 months of treatment, 31.9% of patients had gained at least 5% body weight; by the end of treatment, 62.4% of patients had gained at least 5% weight. Patients who gained weight did so in a linear fashion throughout treatment. Cavitary and extensive disease, a positive smear, and a positive culture were predictors of weight gain (p<0.05). No patients had relapses during the time period of the study. CONCLUSIONS: Only a subset of patients treated for TB gain significant weight. A greater burden of disease was predictive of weight gain.

Increased mitochondrial arginine metabolism supports bioenergetics in asthma.

High levels of arginine metabolizing enzymes, including inducible nitric oxide synthase (iNOS) and arginase (ARG), are typical in asthmatic airway epithelium; however, little is known about the metabolic effects of enhanced arginine flux in asthma. Here, we demonstrated that increased metabolism sustains arginine availability in asthmatic airway epithelium with consequences for bioenergetics and inflammation. Expression of iNOS, ARG2, arginine synthetic enzymes, and mitochondrial respiratory complexes III and IV was elevated in asthmatic lung samples compared with healthy controls. ARG2 overexpression in a human bronchial epithelial cell line accelerated oxidative bioenergetic pathways and suppressed hypoxia-inducible factors (HIFs) and phosphorylation of the signal transducer for atopic Th2 inflammation STAT6 (pSTAT6), both of which are implicated in asthma etiology. Arg2-deficient mice had lower mitochondrial membrane potential and greater HIF-2α than WT animals. In an allergen-induced asthma model, mice lacking Arg2 had greater Th2 inflammation than WT mice, as indicated by higher levels of pSTAT6, IL-13, IL-17, eotaxin, and eosinophils and more mucus metaplasia. Bone marrow transplants from Arg2-deficient mice did not affect airway inflammation in recipient mice, supporting resident lung cells as the drivers of elevated Th2 inflammation. These data demonstrate that arginine flux preserves cellular respiration and suppresses pathological signaling events that promote inflammation in asthma.

Arginine metabolic endotypes in pulmonary arterial hypertension.

Decreased synthesis of nitric oxide (NO) by NO synthases (NOS) is believed to play an important role in the pathogenesis of pulmonary arterial hypertension (PAH). Multiple factors may contribute to decreased NO bioavailability, including increased activity of arginase, the enzyme that converts arginine to ornithine and urea, which may compete with NOS for arginine; inadequate de novo arginine production from citrulline; and increased concentration of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NOS. We hypothesized that PAH patients with the lowest arginine availability secondary to increased arginase activity and/or inadequate de novo arginine synthesis might have a slower rate of NO synthesis and greater pulmonary vascular resistance. Nine patients with group 1 PAH and 10 healthy controls were given primed, constant intravenous infusions of (15)N2-arginine, (13)C,(2)H4-citrulline, (15)N2-ornithine, and (13)C-urea in the postabsorptive state. The results showed that, compared with healthy controls, PAH patients had a tendency toward increased arginine clearance and ornithine flux but no difference in arginine and citrulline flux, de novo arginine synthesis, or NO synthesis. Arginine-to-ADMA ratio was increased in PAH patients. Two endotypes of patients with low and high arginase activity were identified; compared with the low-arginase group, the patients with high arginase had increased arginine flux, slower NO synthesis, and lower plasma concentrations of ADMA. These results demonstrate that increased breakdown of arginine by arginase occurs in PAH and affects NO synthesis. Furthermore, there is no compensatory increase in de novo arginine synthesis to overcome this increased utilization of arginine by arginase.

Indian women of childbearing age do not metabolically conserve arginine as do American and Jamaican women.

BACKGROUND: In a previous study in pregnant American women, we reported that arginine flux and nitric oxide synthesis increased in trimester 2. More recently, we reported that Indian women do not increase arginine flux during pregnancy as their American or Jamaican counterparts do. OBJECTIVE: The purpose of this study was to determine whether Indian women of childbearing age are producing less arginine and/or catabolizing more arginine and therefore have less available for anabolic pathways than do Jamaican and American women. METHODS: Thirty healthy women aged 28.3 ± 0.8 y from the United States, India, and Jamaica (n = 10/group) were given 6 h primed, constant intravenous infusions of guanidino-¹5N2-arginine, 5,5-²H2-citrulline, ¹5N2-ornithine, and ring-²H5-phenylalanine, in addition to primed, oral doses of U-¹³C6-arginine in both the fasting and postprandial states. An oral dose of deuterium oxide was also given to determine fat-free mass (FFM). RESULTS: Compared with American women, Indian and Jamaican women had greater ornithine fluxes (µmol · kg fat FFM⁻¹ · h⁻¹) in the fasting and postprandial states (27.3 ± 2.5 vs. 39.6 ± 3.7 and 37.2 ± 2.0, respectively, P = 0.01), indicating greater arginine catabolism. However, Jamaican women had a higher endogenous arginine flux than did Indian and American women in the fasting (66.1 ± 3.1 vs. 54.2 ± 3.1 and 56.1 ± 2.1, respectively, P = 0.01) and postprandial (53.8 ± 2.2 vs. 43.7 ± 4.9 and 42.8 ± 3.1, respectively, P = 0.06) states. As a consequence, Indian women had lower arginine bioavailability (µmol · kg FFM⁻¹ · h⁻¹) in the fasting state (42.0 ± 2.6) than did American (49.9 ± 1.3, P = 0.045) and Jamaican (55.5 ± 3.5, P = 0.004) women, as well as in the postprandial state (40.7 ± 3.5 vs. 51.8 ± 1.2 and 57.5 ± 3.2, respectively, P = 0.001). CONCLUSION: Compared with American and Jamaican women, Indian women of childbearing age have a decreased arginine supply because of increased arginine catabolism without an increase in arginine flux.

The Microbiome, Intestinal Function, and Arginine Metabolism of Healthy Indian Women Are Different from Those of American and Jamaican Women.

BACKGROUND: Indian women have slower arginine flux during pregnancy compared with American and Jamaican women. Arginine is a semi-essential amino acid that becomes essential during periods of rapid lean tissue deposition. It is synthesized only from citrulline, a nondietary amino acid produced mainly in the gut. The gut is therefore a key site of arginine and citrulline metabolism, and gut microbiota may affect their metabolism. OBJECTIVE: The objective of this study was to identify differences in the gut microbiota of nonpregnant American, Indian, and Jamaican women and characterize the relations between the gut microbiota, gut function, and citrulline and arginine metabolism. METHODS: Thirty healthy American, Indian, and Jamaican women (n = 10/group), aged 28.3 ± 0.8 y, were infused intravenously with [guanidino-15N2]arginine, [5,5-2H2]citrulline, and [15N2]ornithine and given oral [U-13C6]arginine in the fasting and postprandial states. Fecal bacterial communities were characterized by 16S rRNA gene sequencing. RESULTS: In the fasting state, Indian women had lower citrulline flux than did American and Jamaican women [7.0 ± 0.4 compared with 9.1 ± 0.4 and 8.9 ± 0.2 µmol ⋅ kg fat-free mass (FFM)-1 ⋅ h-1, P = 0.01] and greater enteral arginine conversion to ornithine than did American women (1.4 ± 0.11 compared with 1.0 ± 0.08 µmol ⋅ kg FFM-1 ⋅ h-1, P = 0.04). They also had lower mannitol excretion than American and Jamaican women (154 ± 37.1 compared with 372 ± 51.8 and 410 ± 39.6 mg/6 h, P < 0.01). Three dominant stool community types characterized by increased abundances of the genera Prevotella, Bacteroides, and Bacteroides with Clostridium were identified. Indian women had increased mean relative abundances of Prevotella (42%) compared to American and Jamaican women (7% and < 1%, P = 0.03) which were associated with diet, impaired intestinal absorptive capacity, and arginine flux. CONCLUSIONS: These findings suggest that dysregulated intestinal function and a unique gut microbiome may contribute to altered arginine metabolism in Indian women.

Glucose and pyruvate metabolism in severe chronic obstructive pulmonary disease.

The mechanisms leading to weight loss in patients with chronic obstructive pulmonary disease (COPD) are poorly understood but may involve alterations in macronutrient metabolism. Changes in muscle oxidative capacity and lactate production during exercise suggest glucose metabolism may be altered in COPD subjects. The objective of this study was to determine differences in the rates of glucose production and clearance, the rate of glycolysis (pyruvate production), and oxidative and nonoxidative pyruvate disposal in subjects with severe COPD compared with healthy controls. The in vivo rates of glucose production and clearance were measured in 14 stable outpatients with severe COPD (seven with low and seven with preserved body mass indexes) and 7 healthy controls using an intravenous infusion of [(2)H(2)]glucose. Additionally, pyruvate production and oxidative and non-oxidative pyruvate disposal were measured using intravenous infusions of [(13)C]bicarbonate and [(13)C]pyruvate. Endogenous glucose flux and glucose clearance were significantly faster in the combined COPD subjects (P = 0.002 and P < 0.001, respectively). This difference remained significant when COPD subjects were separated by body mass index. Pyruvate flux and oxidation were significantly higher in the combined COPD subjects than controls (P = 0.02 for both), but there was no difference in nonoxidative pyruvate disposal or plasma lactate concentrations between the two groups. In subjects with severe COPD, there are alterations in glucose metabolism leading to increased glucose production and faster glucose metabolism by glycolysis and oxidation compared with controls. However, no difference in glucose conversion to lactate via pyruvate reduction is observed.