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.

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.

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.

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.

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.

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.

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.

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.

Role of T2 inflammation biomarkers in severe asthma.

PURPOSE OF REVIEW: Severe asthma is a heterogeneous syndrome. Classification of asthma into phenotypes and endotypes can improve understanding and treatment of the disease. Identification and utilization of biomarkers, particularly those linked to T2 inflammation, can help group patients into phenotypes, predict those who will respond to a specific therapy, and assess the response to treatment. RECENT FINDINGS: Biomarkers are present in sputum, exhaled breath, and blood of patients with asthma. These include sputum eosinophils and neutrophils, fractional excretion of nitric oxide, blood eosinophilia, IgE, and periostin. Many of these biomarkers are associated with eosinophilic inflammation propagated mainly by T2 cytokines such as IL-5 and IL-13, which are released from Th2 cells and Type 2 innate lymphoid cells. Biomarkers have been utilized in recent trials of novel biologic agents targeted at T2 inflammation and may contribute to the defining population who would respond to these therapies. SUMMARY: Despite advances in the identification and utilization of asthma biomarkers, further studies are needed to better clarify the role of biomarkers, individually or in combination, in the diagnosis and treatment of severe asthma. Future therapeutic trials should include the use of biomarkers in their design, which may lead to a more personalized approach to therapy and improved outcomes.

Antifungals in severe asthma.

PURPOSE OF REVIEW: Despite guideline-based treatment, many patients with severe asthma continue to have uncontrolled disease. Fungal allergy is being increasingly recognized in the pathogenesis of severe asthma. Limited data exist on the approach to treatment of fungal asthma. This review summarizes existing evidence on the use of antifungal agents in allergic bronchopulmonary aspergillosis (ABPA) and severe asthma with fungal sensitization (SAFS), and highlights needed areas of future investigation. RECENT FINDINGS: Recent studies evaluating oral triazole therapy in ABPA appear to support triazole use in a carefully considered clinical setting, whereas studies assessing triazole use in SAFS have yielded mixed results. Despite early encouraging findings that oral triazole use may improve asthma symptoms, stabilize lung function, decrease inhaled and systemic corticosteroid requirements, and alter serum biomarkers, overall data are limited. Appropriate patient selection, as well as choice of the optimal drug, dose, frequency, and duration of therapy, remains poorly defined. SUMMARY: The role of antifungal therapy in severe asthma remains unclear. Early studies have suggested a possible benefit of some antifungal agents, such as oral triazoles in ABPA and SAFS; however, routine clinical use of these agents in severe asthma without ABPA is not currently recommended. Further research is needed to better delineate the potential utility of antifungal medications in severe asthma and identify the asthma populations who benefit from such treatment.

The asthma COPD overlap syndrome (ACOS).

Asthma and chronic obstructive pulmonary disease (COPD) have traditionally been viewed as distinct clinical entities. Recently, however, much attention has been focused on patients with overlapping features of both asthma and COPD: those with asthma COPD overlap syndrome (ACOS). Although no universal definition criteria exist, recent publications attempted to define patients with ACOS based on differences in clinical features, radiographic findings, and diagnostic tests. Patients with ACOS make up a large percentage of those with obstructive lung disease and have a higher overall health-care burden. Identifying patients with ACOS has significant therapeutic implications particularly with the need for early use of inhaled corticosteroids and the avoidance of use of long-acting bronchodilators alone in such patients. However, unlike asthma and COPD, no evidence-based guidelines for the management of ACOS currently exist. Future research is needed to improve our understanding of ACOS and to achieve the best management strategies.

Periostin, a novel biomarker of TH2-driven asthma.

PURPOSE OF REVIEW: Asthma is a heterogeneous disease with multiple, overlapping phenotypes. Biomarkers are currently being investigated to better characterize the disease phenotypes and to identify the responders to specific targeted therapies. This review focuses on the emerging data surrounding the use of one such biomarker for T helper 2 (TH2)-driven asthma: periostin. RECENT FINDINGS: Periostin is an extracellular matrix protein that is induced by interleukin (IL)-4 and IL-13 in airway epithelial cells and lung fibroblasts. It has proven to be an important biomarker of TH2-associated airway inflammation and a potential predictor of airway eosinophilia. It has also been shown to predict response to treatment with inhaled corticosteroids in patients with these characteristics. Furthermore, recent asthma clinical trials have established that serum periostin may have value in predicting the response to targeted therapy with biologic agents such as lebrikizumab and omalizumab. SUMMARY: Emerging data suggest a role for periostin in refining asthma phenotypes and predicting the response to targeted therapy. Although early data are promising, further investigations are needed to confirm these findings and to identify other clinical applications in which periostin may be valuable.

A randomized controlled trial to evaluate inhibition of T-cell costimulation in allergen-induced airway inflammation.

RATIONALE: T lymphocytes are important in the pathogenesis of allergic asthma. Costimulation through CD28 is critical for optimal activation of T cells, and inhibition of this pathway with CTLA4Ig has been shown to be effective in preventing airway inflammation and hyperresponsiveness in animal models of asthma. Abatacept, a humanized version of CTLA4Ig, has been approved for treatment of rheumatoid arthritis, providing the opportunity to test whether inhibition of costimulation is an effective strategy to treat people with asthma. OBJECTIVES: To determine if 3 months of treatment with abatacept reduced allergen-induced airway inflammation in people with mild atopic asthma. METHODS: Randomized, placebo-controlled, double-blinded study. Bronchoscopically directed segmental allergen challenge was performed on 24 subjects followed by bronchoalveolar lavage 48 hours later. Subjects were randomized 1:1 to receive abatacept or placebo, followed by a second allergen challenge protocol after 3 months of study drug. MEASUREMENTS AND MAIN RESULTS: There was no significant reduction in allergen-induced eosinophilic inflammation in the abatacept-treated group compared with placebo (17.71% ± 17.25% vs. 46.39% ± 29.21%; P = 0.26). In addition, we did not detect an effect of abatacept on FEV1, provocative concentration of methacholine sufficient to induce a 20% decline in FEV1, or asthma symptoms. Subjects treated with abatacept had an increased percentage of naive and a corresponding decrease in memory CD4(+) T cells in the blood compared with placebo. CONCLUSIONS: Inhibition of CD28-mediated costimulation with abatacept does not seem to alter the inflammatory response to segmental allergen challenge or clinical measures of asthma symptoms in people with mild atopic asthma. Clinical trial registered with ClinicalTrials.gov (NCT 00784459).

Asthma outcomes revisited.

PURPOSE OF REVIEW: Asthma outcomes constitute the cornerstone of asthma clinical research. Despite their known importance, it has been difficult for researchers to standardize these outcomes in large part because of the heterogeneity of the disease. This review seeks to provide an overview of recent recommendations for standardization of asthma outcomes in clinical trials, as well as discuss areas of future interest. RECENT FINDINGS: Several outcome measures have been recommended and are used in evaluating different interventions in asthma clinical trials. Such outcomes include lung function, asthma control measures, symptoms, exacerbations, quality of life, biomarkers, healthcare utilization and cost of care. More recently, recommendations for core measures, supplemental measures and future areas of interest for all future asthma clinical trials have been recommended by the Asthma Outcomes Workshop supported by the National Institute of Health (NIH) and the Agency for Healthcare Research and Quality (AHRQ) in the US. SUMMARY: Standardization of asthma outcomes allows the comparison of results across multiple studies and centers. The recommendations of the Asthma Outcomes Workshop constitute an excellent first step in standardizing the way in which asthma outcomes are assessed. The asthma research community is now charged with implementing these recommendations and expanding upon them.

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.

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.