Kennedy, Cassie C

AbstractInvasive fungal infections threaten lung transplant outcomes with high associated morbidity and mortality. Pharmacologic prophylaxis may be key to prevent posttransplant invasive fungal infections, but cost, adverse effects, and absorption issues are barriers to effective prophylaxis. Trends in fungal infection diagnostic strategies utilize molecular diagnostic methodologies to complement traditional histopathology and culture techniques. While lung transplant recipients are susceptible to a variety of fungal pathogens, Candida spp. and Aspergillus spp. infections remain the most common. With emerging resistant organisms and multiple novel antifungal agents in the research pipeline, it is likely that treatment strategies will continue to evolve.

Background: Academic centers' and professional societies' top leadership representation and professional societies' award recipients remain disparate by gender in many fields. Little is known regarding leadership representation and recognition within pulmonary, critical care, and sleep medicine (PCCM), which has ∼22% women physicians. We sought to understand the landscape of female PCCM leaders. Methods: We abstracted gender of fellowship program directors (PDs), Department of Medicine (DOM) Chairs and Division Chiefs from academic medical centers with PCCM fellowship programs from 2018 and for comparison 2008. We abstracted leadership and recognition award recipients within four PCCM professional societies from 2013 to 2018 (American Thoracic Society [ATS], American Academy of Sleep Medicine [AASM], American College of Chest Physicians [CHEST], and Society of Critical Care Medicine [SCCM]). Results: In 2018, 29% of PCCM PD, 15% of PCCM Division Chiefs, and 15% of DOM Chairs were women. There were significantly more female PDs in 2018 (29%) compared with 2008 (16%, p = 0.04). On average, 25% of society presidents were women, with 28% of PCCM societal awards going to women, with significant difference between societies ( p = 0.04). Each society differed in average distribution of female board members over the 6-year period: ATS 38%, AASM 35%, CHEST 18%, and SCCM 44% ( p < 0.001). Conclusion: PCCM leadership and societal recognition are disparate by gender with few women holding top leadership roles and receiving societal recognition. Fortunately, the distribution notably is starting to reflect the specialty's demographics. Understanding why these inequalities exist will be essential to achieving gender parity in PCCM.

Abstract Rationale Many lung transplant centers prescribe antifungal medications after transplantation to prevent invasive fungal infections (IFIs); however, the effectiveness of antifungal prophylaxis at reducing the risk of all-cause mortality or IFI has not been established. Objectives We aimed to evaluate the effect of antifungal prophylaxis on all-cause mortality and IFI in lung transplant patients. Methods Using administrative claims data, we identified adult patients who underwent lung transplantation between January 1, 2005, and December 31, 2018. Propensity score analysis using inverse probability treatment–weighting approach was used to balance the differences in baseline characteristics between those receiving antifungal prophylaxis and those not receiving antifungal prophylaxis. Cox proportional hazards regression was used to compare rates of all-cause mortality and IFI in both groups. Results We identified 662 lung transplant recipients (LTRs) (387 received prophylaxis and 275 did not). All-cause mortality was significantly lower in those receiving antifungal prophylaxis compared with those not receiving antifungal prophylaxis (event rate per 100 person-years, 8.36 vs. 19.49; hazard ratio, 0.43; 95% confidence interval, 0.26–0.71; P = 0.003). Patients receiving antifungal prophylaxis had a lower rate of IFI compared with those not receiving prophylaxis (event rate per 100 person-years, 14.94 vs. 22.37; hazard ratio, 0.68; 95% confidence interval, 0.44–1.05; P = 0.079), but did not reach statistical significance. Conclusions In this real-world analysis, antifungal prophylaxis in LTRs was associated with reduced all-cause mortality compared with those not receiving antifungal prophylaxis. Rates of IFI were also lower in those receiving prophylaxis, but this was not statistically significant in our primary analysis.

AbstractBackgroundResilience represents the capacity to adapt to adversity. Resilience can improve following behavioral interventions. We examined lung transplant candidates’ resilience as a novel predictor using the Connor‐Davidson Resilience Scale (RISC‐10).MethodsWaitlisted candidates at six centers were mailed questionnaires from 9/16/2015 to 10/1/2019. Follow‐up surveys were collected annually and post‐transplant. Outcomes were recorded through February 17, 2020. Primary outcome was pre‐transplant death/delisting. Analyses included t test or chi‐square for group comparisons, Pearson's correlation coefficients for strength of relationships, and Cox proportional‐hazard models to evaluate associations with outcomes, adjusting for age, sex, and mood.ResultsParticipation was 55.3% (N = 199). Baseline RISC‐10 averaged 32.0 ± 5.6 and did not differ by demographics, primary transplant diagnosis, or disease severity markers. RISC‐10 did not correlate to the commonly utilized Psychosocial Assessment of Candidates for Transplant [PACT] or Stanford Integrated Psychosocial Assessment for Transplantation [SIPAT] tools. Scores < 26.3 (representing > 1 standard deviation below population average) occurred in 16% and were associated with pre‐transplant death or delisting, adjusted Hazard Ratio of 2.60 (95% Confidence Interval 1.23‐5.77; P = .01).ConclusionOne in six lung candidates had low resilience, predicting increased pre‐transplant death/delisting. RISC‐10 did not correlate with PACT or SIPAT; resilience may represent a novel risk factor.

AbstractBackgroundFrailty and decreased functional status are risk factors for adverse kidney transplant (KT) outcomes. Our objective was to examine the efficacy of an exercise intervention on frailty and decreased functional status in a cohort of patients with advanced chronic kidney disease (CKD).MethodsWe conducted a prospective study involving 21 adults with ≥stage 4 CKD who were (a) frail or pre‐frail by Fried phenotype and/or (b) had lower extremity impairment [short physical performance battery score ≤10]. The intervention consisted of two supervised outpatient exercise sessions per week for 8 weeks.ResultsAmong our cohort, median participant age was 62 years (interquartile range, 53‐67) and 85.7% had been evaluated for KT. Following the study, participants reported satisfaction with the intervention and multiple frailty parameters improved significantly, including fatigue, physical activity, walking time, and grip strength. Lower extremity impairment also improved (90.5%‐61.9%, P = .03). No study‐related adverse events occurred.ConclusionsPreliminary data from this study suggest that a supervised, outpatient exercise intervention is safe, acceptable, feasible, and associated with improved frailty parameters, and lower extremity function, in patients with advanced CKD. Further studies are needed to confirm these findings and determine whether this prehabilitation strategy improves KT outcomes.

AbstractBackgroundNo consensus exists regarding optimal strategy for antifungal prophylaxis following lung transplant.ObjectiveTo review data regarding antifungal prophylaxis on the development of fungal infections.Study selection/AppraisalWe searched MEDLINE, Embase, and Scopus for eligible articles through December 10, 2019. Observational or controlled trials published after January 1, 2001, that pertained to the prevention of fungal infections in adult lung recipients were reviewed independently by two reviewers for inclusion.MethodsOf 1702 articles screened, 24 were included. Data were pooled using random effects model to evaluate for the primary outcome of fungal infection. Studies were stratified by prophylactic strategy, medication, and duration (short term < 6 months and long term ≥ 6 months).ResultsWe found no difference in the odds of fungal infection with universal prophylaxis (49/101) compared to no prophylaxis (36/93) (OR 0.76, CI: 0.03‐17.98; I2 = 93%) and preemptive therapy (25/195) compared to universal prophylaxis (35/222) (OR 0.91, CI: 0.06‐13.80; I2 = 93%). The cumulative incidence of fungal infections within 12 months was not different with nebulized amphotericin (0.08, CI: 0.04‐0.13; I2 = 87%) compared to systemic triazoles (0.07, CI: 0.03‐0.11; I2 = 21%) (P = .65). Likewise, duration of prophylaxis did not impact the incidence of fungal infections (short term: 0.11, CI: 0.05‐0.17; I2 = 89%; long term: 0.06, CI: 0.03‐0.08; I2 = 51%; P = .39).ConclusionsWe have insufficient evidence to support or exclude a benefit of antifungal prophylaxis.

Background: We examined the association of adult lung transplant candidates’ self-reported affect with transplant-related outcomes, evaluating whether a positive (vs negative) frame of mind might be protective. Method: Consenting waitlisted candidates from 6 centers completed the questionnaires including the Positive and Negative Affect Schedule annually and posttransplant. Univariate logistic regression analysis was performed to determine the association of baseline affect with outcomes of death or delisting. Models were subsequently adjusted for age, marital status, and education. Results: Questionnaires were completed by 169 candidates (77.9% participation). Mean positive affect, negative affect, and positive-to-negative affect ratio (positivity ratio) were similar to expected norms. The scores of the questionnaire did not change significantly over time. Fifteen (8.9%) waitlisted participants died. Candidates who died while waiting had lower positivity ratios compared to those who survived (1.82 vs 2.45; P = .02). A more negative affect was associated with increased death on the waiting list (adjusted odds ratio [OR] 1.10; P = .021). Conversely, a higher positivity ratio was associated with decreased death while waiting (adjusted OR: 0.45; P = .027). Conclusion: Negative affect may represent a novel risk factor for death on the waitlist. Enhancing positive affect may represent a useful target for psychological optimization in lung transplant candidates.

Introduction: Short telomere syndromes (STS) are accelerated aging syndromes affecting hematopoietic, pulmonary, hepatobiliary and/or immunological systems. Clinical assessment of age-appropriate telomere length (TL) is performed using flow cytometry & fluorescence in-situ hybridization (flowFISH). Screening for germline variants in STS-related genes is guided by flowFISH-determined centile categories of TL, with screening recommended for TL <1st centile or 1-10th centile in lymphocytes (L) or granulocytes (G). However, the utility of genetic testing for patients with TL >10th centile and integration of clinical phenotype with flowFISH data in predictive algorithms is currently unclear. Methods: FlowFISH testing was done at reference laboratories in Vancouver (Repeat Diagnostics; Canada) & Johns Hopkins University (JHU, USA). Salient clinical features were pre-determined as, personal history of premature hair greying (onset at age < 30 years), idiopathic pulmonary fibrosis (IPF) or IPF/emphysema overlap (in smokers), cryptogenic cirrhosis or NRH, unexplained cytopenias &/or immunodeficiency, & family history of the above (in >1 1st or 2nd degree relatives). Clinical likelihood score (CLS) was assigned as low (1), intermediate (int, 2) or high (>2), based on the number of aforementioned clinical features present prior to flowFISH testing. Genetic testing was performed using either an in-house or commercial bone marrow failure-specific next generation sequencing (NGS) panel or whole exome sequencing (WES), and data for known variants affecting telomerase or telomeric function (TERT, TERC, DKC1, TINF2, NHP2, NOP10, TCAB1, NAF1, & RTEL1) was recorded. Results: One hundred forty-nine patients at our institution underwent TL assessment at Repeat diagnostics (n=38) and JHU (n=111) laboratories, respectively. Median age was 56 (range: 7-79) years; 88 (59%) being males. Significant family history was present in 40 (27%) patients, while premature greying of hair was present in 13 (9%) patients. Organ-specific clinical features included unexplained cytopenias (n=89, 60%) IPF (n=71, 48%), cryptogenic cirrhosis or NRH (n=21, 14%), & unexplained immunodeficiency (n=14, 9%). CLS stratification included low (n=74, 50%), int (n=54, 36%), & high (n=21, 14%), with higher CLS significantly correlating with lower delta TL for L (p=0.0005) but not G (p=0.3). Genetic testing was performed in 51 (35%) patients (NGS-51, WES-1) among which 13 (26%) patients had a telomere-associated variant; 5 (10%) pathogenic (pv, all TERT). CLS alone was unable to predict likelihood of finding a telomere-associated variant (p=0.4). Based on age-appropriate centile categorization of L & G TL (information for both available in 134 patients), patients were stratified into six groups (table 1). TL <1st centile in L: This group was further divided into two groups; TL<1st centile in both L & G [A1, n=7, CLS low-3 (43%), int-2 (29%), & high-2 (29%)] and TL <1st centile in L and 1-50th centile in G (A2, n=2, CLS low & high) patients. Among the 4 (57%) patients who underwent genetic (NGS-3, WES-1) testing, 3 (75%) had TERTpv in A1 subgroup and 1 A2 subgroup patient had a VUS in TERT.TL <1st centile in G, 1-10th centile in L (n=18): This group included 9 (50%) low, 8 (44%) int and 1 (6) high CLS patients, of which only 1 of 8 NGS-tested patients had TERTpv.TL 1-10th centile in L or G: This group was divided into; 1-10th centile in both L & G [C1, n=28, CLS low-3 (11%), int-14 (50%), high-11(39%)] of whom 8 (22%) underwent NGS with no pathogenic variants but 3 VUS in RTEL1, NAF1 & PARN genes, and 1-10th centile in L, >1-90th centile in G [C2, n=36, CLS low-19 (53%), 16 (44%), 1 (3%)] of whom 8 (22%) underwent NGS with 1 TERTpv and 2 VUS in TINF2TL >10th centile in L & 1-90th centile in G (n=43, 32%): CLS stratification in this group included 27 (63%) low, 12 (28%) int, 4 (9%) high. NGS testing was done in 13 (30%) patients [CLS low-9(69%), int 2(15%), high 2 (15%)], of whom only 2 (15%) had VUS in TINF2 and TERT gene, but no pathogenic variants (figure 1). Conclusion: Our study demonstrates the importance of using a flowFISH assay based predictive algorithm to screen patients with suspected STS for telomere-related genetic alternations, in comparison to a clinical likelihood score. We also demonstrate a limited role for genetic testing in patients with lymphocyte TL >10th centile, regardless of the clinical likelihood score. Disclosures Patnaik: Stem Line Pharmaceuticals.: Membership on an entity's Board of Directors or advisory committees.

Abstract BACKGROUND Respiratory failure syndromes are common after allogeneic hematopoietic cell transplantation (allo-HCT), and are associated with substantial morbidity and mortality. These syndromes are incompletely understood, and may be associated with histopathologic evidence of acute lung injury (ALI). The role of biopsy in this setting is controversial, with uncertain benefits and considerable procedural risk. We report the clinical, radiologic and histopathologic features of patients with biopsy-proven ALI following allo-HCT in a large multi-site retrospective series. METHODS The medical records of 1,864 consecutive adults who underwent allo-HCT at Mayo Clinic, Minnesota (n = 916), Arizona (n = 694), and Florida (n = 254) (Jan 2005-Dec 2017) were reviewed. A total of 152 patients underwent a lung biopsy: 126 bronchoscopic, 22 surgical, and 4 CT-guided biopsies (Figure 1). Patients with a histopathologic diagnosis of ALI were included in the study, and were classified into clinicopathologic subgroups per published American Thoracic Society guidelines (Am J Resp Crit Care Med, 2011). Patients whose diagnosis remained uncertain after a detailed review of the medical records were included in a separate subgroup as undifferentiated ALI. Transplant characteristics, radiologic features, pulmonary function test (PFT) results, treatments, and outcomes were compared between groups. RESULTS Clinicopathologic diagnoses in 62 patients with biopsy-proven ALI consisted of an infectious etiology in 15 (24%), cryptogenic organizing pneumonia (COP) in 15 (24%), idiopathic pneumonia syndrome (IPS) in 9 (15%), bronchiolitis obliterans syndrome (BOS) in 9 (15%), diffuse alveolar hemorrhage in 3 (5%), periengraftment respiratory distress syndrome in 2 (3%), and undifferentiated ALI in 9 (15%) patients (Figure 2). Transplant characteristics were comparable between groups. Infectious pneumonia and IPS were the most common diagnoses during the first 100 days post HCT (50% and 36%, respectively). Between 100 and 365 days, a range of diagnoses were seen including infectious pneumonia (20%), COP (23%), IPS (14%), BOS (23%), and undifferentiated ALI (20%) (Table 1). In 14/15 (93%) infectious pneumonia cases, biopsy did not change management and diagnosis was concurrently established by bronchoalveolar lavage (BAL) or non-invasive testing. Patients with IPS, BOS, and undifferentiated ALI more commonly had a pleural effusion (66%, 44%, and 44%, respectively). Nodular infiltrates were most commonly seen in patients with infectious pneumonia (55%). Other radiographic findings were not clearly discriminative. BOS and infectious pneumonia were more commonly associated with an obstructive PFT (78% and 33%, respectively), whereas restrictive pattern was more frequently seen in COP and IPS (50% and 57%, respectively) (Table 2). Despite a histopathologic diagnosis of ALI, 9 (15%) patients had clear clinical and radiographic evidence of BOS. Steroids were used commonly in noninfectious syndromes: 93% of patients with COP and in 100% of IPS patients. Of 4 patients with IPS who received Etanercept, 2 (50%) showed complete recovery, whereas the remaining 5 patients who did not receive Etanercept died from fulminant respiratory failure. Most common treatment response was complete recovery in COP (73%), fulminant respiratory failure leading to death in IPS (78%), and chronic respiratory failure in BOS (78%). Estimated OS was shortest in the group with IPS and undifferentiated ALI (median 5 and 17 mons, respectively), whereas patients with COP had the best prognosis (mOS not reached) followed by the infectious pneumonia and the BOS groups (mOS of 59 and 55 mons, respectively). Pulmonary complications were the most common cause of death in patients with non-infectious ALI. Lung biopsy was associated with post-procedural pneumothorax in 17 (27%) patients; 12 of whom required a chest tube. CONCLUSIONS In this largest case series to date of histopathologic ALI after allo-HCT, biopsy does not appear to meaningfully change management in the majority of patients, and is associated with substantial procedural risk. Histopathologic findings do not clearly correlate with the clinical and radiographic picture in a sizeable proportion of the patients. PFT results, BAL findings, the timing of the onset of respiratory failure after HCT, and the response to steroids seem to be of greater diagnostic and/or prognostic value. Disclosures No relevant conflicts of interest to declare.