Chronic lung allograft dysfunction: Definition, diagnostic criteria, and approaches to treatment―A consensus report from the Pulmonary Council of the ISHLT

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Cystic fibrosis physicians’ perspectives on the timing of referral for lung transplant evaluation: a survey of physicians in the United States

Abstract Background Prior studies reveal that a significant proportion of patients with cystic fibrosis (CF) and advanced lung disease are not referred for lung transplant (LTx) evaluation. We sought to assess expert CF physician perspectives on the timing of LTx referral and investigate their LTx knowledge. Methods We developed an online anonymous survey that was distributed by the Cystic Fibrosis Foundation (CFF) to the medical directors of all CFF-accredited care centers in the United States in 2015. The survey addressed only adult patients (≥18 years old) and was sent to 119 adult CF physicians, 86 CFF-affiliated CF physicians (who see adults and children, but have smaller program sizes than adult or pediatric centers), and 127 pediatric CF physicians (who see some adults, but mostly children). The focus of the questions was on CFF-care center characteristics, physician experience and indications/contraindications to referral for LTx evaluation. Results There were 114/332 (34%) total responses to the survey. The response rates were: 57/119 (48%) adult physicians, 12/86 (14%) affiliate physicians and 43/127 (34%) pediatric physicians; 2 physicians did not include their CFF center type. Despite the poor ability of FEV1 < 30% to predict death within 2 years, 94% of responding CF physicians said they would refer an adult patient for LTx evaluation if the patient’s lung function fell to FEV1 < 30% predicted. Only 54% of respondents report that pulmonary hypertension would trigger referral. Pulmonary hypertension is an internationally recommended indication to list a patient for LTx (not just for referral for evaluation). Very few physicians (N = 17, 15%) employed components of the lung allocation score (LAS) to determine the timing of referral for LTx evaluation. Interestingly, patient preference not to undergo LTx was “often” or “always” the primary patient-related reason to defer referral for LTx evaluation for 41% (47/114) of respondents. Conclusions Some potential barriers to timely LTx referral for patients with CF include physician knowledge regarding non-lung function-based recommendations related to timing of referral and listing for LTx, and patient preference not to undergo LTx. Further exploration of physician-level and CF patient-level barriers to timely LTx referral is warranted

β-D-glucan Surveillance with Preemptive Anidulafungin for Invasive Candidiasis in Intensive Care Unit Patients: A Randomized Pilot Study

<div><h3>Background</h3><p>Invasive candidiasis (IC) is a devastating disease. While prompt antifungal therapy improves outcomes, empiric treatment based on the presence of fever has little clinical impact. Β-D-Glucan (BDG) is a fungal cell wall component detectable in the serum of patients with early invasive fungal infection (IFI). We evaluated the utility of BDG surveillance as a guide for preemptive antifungal therapy in at-risk intensive care unit (ICU) patients.</p> <h3>Methods</h3><p>Patients admitted to the ICU for ≥3 days and expected to require at least 2 additional days of intensive care were enrolled. Subjects were randomized in 3∶1 fashion to receive twice weekly BDG surveillance with preemptive anidulafungin in response to a positive test or empiric antifungal treatment based on physician preference.</p> <h3>Results</h3><p>Sixty-four subjects were enrolled, with 1 proven and 5 probable cases of IC identified over a 2.5 year period. BDG levels were higher in subjects with proven/probable IC as compared to those without an IFI (117 pg/ml vs. 28 pg/ml; p<0.001). Optimal assay performance required 2 sequential BDG determinations of ≥80 pg/ml to define a positive test (sensitivity 100%, specificity 75%, positive predictive value 30%, negative predictive value 100%). In all, 21 preemptive and 5 empiric subjects received systemic antifungal therapy. Receipt of preemptive antifungal treatment had a significant effect on BDG concentrations (p< 0.001). Preemptive anidulafungin was safe and generally well tolerated with excellent outcome.</p> <h3>Conclusions</h3><p>BDG monitoring may be useful for identifying ICU patients at highest risk to develop an IFI as well as for monitoring treatment response. Preemptive strategies based on fungal biomarkers warrant further study.</p> <h3>Trial Registration</h3><p>Clinical Trials.gov <a href="http://www.clinicaltrials.gov/ct2/show/NCT00672841">NCT00672841</a></p> </div

1,3-β-D Glucan (BDG) Test Characteristics.

<p>SN = sensitivity; SP = specificity; PPV = positive predictive value; NPV = negative predictive value; LR (+) = positive likelihood ratio; LR (−) = negative likelihood ratio.</p

Study Demographics^*.

*<p>Subject characteristics and baseline invasive candidiasis (IC) risk factors were assessed beginning the week prior to study enrollment, percentages (%) are displayed unless otherwise specified. N = number, SICU = surgical intensive care unit; Colonization was defined as the isolation of <i>Candida</i> from any non-sterile site (e.g. oral wash, respiratory tract or urine) in the absence of clinical signs/symptoms of invasive disease; Broad spectrum antibiotic = systemic receipt of a drug with activity against both gram positive and gram negative organisms; Blood products = transfusion of packed red blood cells, platelets, cryoprecipitate, and/or fresh frozen plasma; ANC = absolute neutrophil count; LOS = length of ICU stay; IC = invasive candidiasis.</p

Case Definitions for Proven and Probable Invasive Candidiasis (IC).

<p>Case Definitions for Proven and Probable Invasive Candidiasis (IC).</p

Study Subject Disposition.

<p>Abbreviations: RX = treatment; TX = transplant; LFTs = liver function tests; ULN = upper limit of the normal reference range; IC = invasive candidiasis; IFI = invasive fungal infection; IA = invasive aspergillosis; BDG = β-D-Glucan; medical vs. surgical = ICU location.<b>*</b>5 subjects in the preemptive group had a positive BDG test(s) but did not receive anidulafungin; 2 were BDG positive only at baseline/screening, 2 were transitioned to comfort care and 1 was treated empirically with antifungal therapy before development of a single positive test. All 5 subjects in the empiric therapy group that received systemic antifungal therapy had at least 1 positive BDG test around the time antifungal treatment.</p

β-D-Glucan Concentrations Over Time in Subjects Receiving Preemptive versus No Antifungal Therapy.

<p>The antifungal treatment effect on glucan concentration over time was modeled as a linear trend. Abbreviations: 0 = subjects in the standard care group with at least one positive BDG test, but no systemic antifungal treatment; 2 = subjects in active surveillance group that were treated with preemptive anidulafungin; SE = standard error of the estimated glucan concentration slope.</p

Bronchiolitis obliterans syndrome after lung or haematopoietic stem cell transplantation: current management and future directions

Bronchiolitis obliterans syndrome (BOS) may develop after either lung or haematopoietic stem cell transplantation (HSCT), with similarities in histopathological features and clinical manifestations. However, there are differences in the contributory factors and clinical trajectories between the two conditions. BOS after HSCT occurs due to systemic graft-versus-host disease (GVHD), whereas BOS after lung transplantation is limited to the lung allograft. BOS diagnosis after HSCT is more challenging, as the lung function decline may occur due to extrapulmonary GVHD, causing sclerosis or inflammation in the fascia or muscles of the respiratory girdle. Treatment is generally empirical with no established effective therapies. This review provides rare insights and commonalities of both conditions, which are not well elaborated elsewhere in contemporary literature, and highlights the importance of cross disciplinary learning from experts in other transplant modalities. Treatment algorithms for each condition are presented, based on the published literature and consensus clinical opinion. Immunosuppression should be optimised, and other conditions or contributory factors treated where possible. When initial treatment fails, the ultimate therapeutic option is lung transplantation (or re-transplantation in the case of BOS after lung transplantation) in carefully selected candidates. Novel therapies under investigation include aerosolised liposomal cyclosporine, Janus kinase inhibitors, antifibrotic therapies and (in patients with BOS after lung transplantation) B-cell-directed therapies. Effective novel treatments that have a tangible impact on survival and thereby avoid the need for lung transplantation or re-transplantation are urgently required