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.

Comparison of four commercial EBV DNA quantitative tests to a new test at an early stage of development.

BACKGROUND: Regular screening for Epstein-Barr virus (EBV) DNA using quantitative RT-PCR is recommended for early intervention in at-risk patients. Harmonization of quantitative RT-PCR assays is critical to avoid misinterpretation of results. Here, we compare quantitative results of the cobas® EBV assay to four commercial RT-qPCR assays. METHODS: The cobas EBV, EBV R-Gene, artus EBV RG PCR, RealStar EBV PCR kit 2.0 and Abbott EBV RealTime assays were compared for analytic performance using a 10-fold dilution series of EBV reference material, normalized to the WHO standard. For clinical performance, their quantitative results were compared using anonymized, leftover EBV-DNA-positive EDTA plasma samples. RESULTS: For analytic accuracy, the cobas EBV deviated -0.0097 log10 from target values. The other tests showed deviations between 0.0037 and -0.12 log10. For clinical performance, accuracy and linearity of cobas EBV data from both study sites were excellent. Bland-Altman bias and Deming regression analyses showed statistical correlation for cobas EBV to both EBV R-Gene and Abbott RealTime assays but an offset of cobas EBV to artus EBV RG PCR and RealStar EBV PCR kit 2.0. CONCLUSION: The cobas EBV showed the closest correlation to the reference material, followed closely by EBV R-Gene and Abbott EBV RealTime. Values obtained are stated in IU/mL, facilitating comparison across testing sites and potentially improving utilization of guidelines for diagnosis, monitoring, and treatment of patients.

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.

Frailty and aging-associated syndromes in lung transplant candidates and recipients.

Many lung transplant candidates and recipients are older and frailer compared to previous eras. Older patients are at increased risk for pre- and posttransplant mortality, but this risk is not explained by numerical age alone. This manuscript represents the product of the American Society of Transplantation (AST) conference on frailty. Experts in the field reviewed the latest published research on assessment of elderly and frail lung transplant candidates. Physical frailty, often defined as slowness, weakness, low physical activity, shrinking, and exhaustion, and frailty evaluation is an important tool for evaluation of age-associated dysfunction. Another approach is assessment by cumulative deficits, and both types of frailty are common in lung transplant candidates. Frailty is associated with death or delisting before transplant, and may be associated with posttransplant mortality. Sarcopenia, cognitive dysfunction, depression, and nutrition are other important components for patient evaluation. Aging-associated inflammation, telomere dysfunction, and adaptive immune system senescence may also contribute to frailty. Developing tools for frailty assessment and interventions holds promise for improving patient outcomes before and after lung transplantation.

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.

Lung Procurement After Cardiac Death in a Donor With Previous Median Sternotomy.

The shortage of lungs for organ donation is problematic, and meeting the demand by expanding the donor pool in lung transplantation is critical. Donation after cardiac death (DCD) is an under-used approach that could be a valuable source of organs. However, procuring lungs from donors with a previous median sternotomy is technically difficult and is usually avoided. Here, we describe the procurement of lungs from a DCD patient with a previous median sternotomy.

Predictive Biomarkers for Asthma Therapy.

PURPOSE OF REVIEW: Asthma is a heterogeneous disease characterized by multiple phenotypes. Treatment of patients with severe disease can be challenging. Predictive biomarkers are measurable characteristics that reflect the underlying pathophysiology of asthma and can identify patients that are likely to respond to a given therapy. This review discusses current knowledge regarding predictive biomarkers in asthma. RECENT FINDINGS: Recent trials evaluating biologic therapies targeting IgE, IL-5, IL-13, and IL-4 have utilized predictive biomarkers to identify patients who might benefit from treatment. Other work has suggested that using composite biomarkers may offer enhanced predictive capabilities in tailoring asthma therapy. Multiple biomarkers including sputum eosinophil count, blood eosinophil count, fractional concentration of nitric oxide in exhaled breath (FeNO), and serum periostin have been used to identify which patients will respond to targeted asthma medications. Further work is needed to integrate predictive biomarkers into clinical practice.

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.

Role of biologics targeting type 2 airway inflammation in asthma: what have we learned so far?

PURPOSE OF REVIEW: Severe asthma is a heterogeneous syndrome that can be classified into distinct phenotypes and endotypes. In the type 2 (T2)-high endotype, multiple cytokines are produced that lead to eosinophilic inflammation. These cytokines and their receptors are targets for biologic therapies in patients with severe asthma who do not respond well to standard therapy with inhaled corticosteroids. RECENT FINDINGS: In the last decade, an increasing number of biologic therapies have been developed targeting T2 inflammation. Clinical trials of therapies targeting immunoglobulin E as well as the T2 cytokines interleukin (IL)-4, IL-5, and IL-13 have demonstrated that these treatments improve asthma-related clinical outcomes and/or have steroid-sparing properties. The use of biomarkers of T2 inflammation can help to identify the subset of patients in whom these therapies may be most efficacious. Multiple biologic agents that are directed at other targets are currently in development, including thymic stromal lymphopoietin (TSLP), prostaglandin (PG)D2 receptor, IL-25, and IL-33. SUMMARY: Biologics are emerging as a key component of severe asthma management. In patients with T2-high severe asthma, the addition of treatments targeting immunoglobulin E and IL-5 to standard therapy may lead to improvement in clinical outcomes. Other biologic therapies have shown promising preliminary results and need to be studied in further clinical trials. These biologic therapies in conjunction with biomarkers will lead to tailored therapy for asthma.

Lebrikizumab in the treatment of asthma.

INTRODUCTION: Severe asthma continues to be a major clinical problem despite the availability of effective asthma medications such as inhaled corticosteroids. Several targeted biologic therapies are emerging to treat patients with severe asthma. Areas Covered: This review provides an update of information on lebrikizumab, a novel monoclonal antibody that targets IL-13 and is currently in advanced stages of development. It describes the role of IL-13, a key effector cytokine in Type 2 (T2) airway inflammation in asthma and discusses the results of recent phase 2 trials investigating lebrikizumab's efficacy and safety in patients with severe asthma. Furthermore, it provides insight into the current ongoing trials with lebrikizumab and outlines future research needs. Expert Opinion: Several emerging therapeutic targets have been identified for patients with severe asthma. By specifically targeting IL-13, lebrikizumab has the potential to block several downstream signals that play a role in disease progression including airway inflammation, mucous hypersecretion and airway remodeling. The effects of lebrikizumab have been more marked in individuals with high serum periostin levels which reflect underlying IL-13 activity and T2 airway inflammation. Ongoing trials with lebrikizumab aim to further examine its long-term safety and efficacy in a larger population and explore its effects on airway inflammation and function.