Vascular endothelial-derived SPARCL1 exacerbates viral pneumonia through pro-inflammatory macrophage activation.

Inflammation induced by lung infection is a double-edged sword, moderating both anti-viral and immune pathogenesis effects; the mechanism of the latter is not fully understood. Previous studies suggest the vasculature is involved in tissue injury. Here, we report that expression of Sparcl1, a secreted matricellular protein, is upregulated in pulmonary capillary endothelial cells (EC) during influenza-induced lung injury. Endothelial overexpression of SPARCL1 promotes detrimental lung inflammation, with SPARCL1 inducing 'M1-like' macrophages and related pro-inflammatory cytokines, while SPARCL1 deletion alleviates these effects. Mechanistically, SPARCL1 functions through TLR4 on macrophages in vitro, while TLR4 inhibition in vivo ameliorates excessive inflammation caused by endothelial Sparcl1 overexpression. Finally, SPARCL1 expression is increased in lung ECs from COVID-19 patients when compared with healthy donors, while fatal COVID-19 correlates with higher circulating SPARCL1 protein levels in the plasma. Our results thus implicate SPARCL1 as a potential prognosis biomarker for deadly COVID-19 pneumonia and as a therapeutic target for taming hyperinflammation in pneumonia.

Inflammatory and tissue injury marker dynamics in pediatric acute respiratory distress syndrome.

BACKGROUNDThe molecular signature of pediatric acute respiratory distress syndrome (ARDS) is poorly described, and the degree to which hyperinflammation or specific tissue injury contributes to outcomes is unknown. Therefore, we profiled inflammation and tissue injury dynamics over the first 7 days of ARDS, and associated specific biomarkers with mortality, persistent ARDS, and persistent multiple organ dysfunction syndrome (MODS).METHODSIn a single-center prospective cohort of intubated pediatric patients with ARDS, we collected plasma on days 0, 3, and 7. Nineteen biomarkers reflecting inflammation, tissue injury, and damage-associated molecular patterns (DAMPs) were measured. We assessed the relationship between biomarkers and trajectories with mortality, persistent ARDS, or persistent MODS using multivariable mixed effect models.RESULTSIn 279 patients (64 [23%] nonsurvivors), hyperinflammatory cytokines, tissue injury markers, and DAMPs were higher in nonsurvivors. Survivors and nonsurvivors showed different biomarker trajectories. IL-1α, soluble tumor necrosis factor receptor 1, angiopoietin 2 (ANG2), and surfactant protein D increased in nonsurvivors, while DAMPs remained persistently elevated. ANG2 and procollagen type III N-terminal peptide were associated with persistent ARDS, whereas multiple cytokines, tissue injury markers, and DAMPs were associated with persistent MODS. Corticosteroid use did not impact the association of biomarker levels or trajectory with mortality.CONCLUSIONSPediatric ARDS survivors and nonsurvivors had distinct biomarker trajectories, with cytokines, endothelial and alveolar epithelial injury, and DAMPs elevated in nonsurvivors. Mortality markers overlapped with markers associated with persistent MODS, rather than persistent ARDS.FUNDINGNIH (K23HL-136688, R01-HL148054).

Benefits of Aeroallergen Testing on Oral Corticosteroid Bursts in Adults with Asthma.

BACKGROUND: Aeroallergen testing can improve precision care for persistent asthma and is recommended by the U.S. clinical guidelines. How testing benefits diverse populations of adults with asthma, and the importance of the testing modality used, are not fully understood. OBJECTIVE: We sought to evaluate whether receipt of aeroallergen testing was associated with a reduction in oral corticosteroid (OCS) bursts. METHODS: We used electronic health record data to conduct a retrospective, observational cohort study of adults with asthma who were prescribed an inhaled corticosteroid and had an Allergy/Immunology visit in a large health system between 1/1/2017-6/30/2022. Negative binomial regression models were used to evaluate whether OCS bursts in the 12-month period after an initial visit were reduced for patients who received aeroallergen testing. We also measured differences in benefit after excluding patients with chronic obstructive pulmonary disease (COPD) and smoking histories, and whether testing receipt was via skin prick or serum. RESULTS: 668/1,383 (48.3%) patients received testing. Receipt of testing was not associated with fewer bursts in all patients (incidence rate ratio (IRR)=0.83 versus no testing, p=0.059), but it was among never smokers without COPD (417/844 tested, IRR=0.68, p=0.004). The receipt of skin testing was associated with fewer bursts in all patients (418/1,383 tested, IRR=0.77, p=0.02) and among never smokers without COPD (283/844 tested, IRR=0.59 versus no testing, p=0.001). CONCLUSION: Guideline-concordant aeroallergen testing in the context of Allergy/Immunology care was associated with clinical benefit in a real-life, diverse cohort of adults with asthma. This benefit varied according to patient comorbidities and the testing modality.

Characterizing proximity and transfers of deceased organ donors to donor care units in the United States.

Some United States organ procurement organizations transfer deceased organ donors to donor care units (DCUs) for recovery procedures. We used Organ Procurement and Transplantation Network data, from April 2017 to June 2021, to describe the proximity of adult deceased donors after brain death to DCUs and understand the impact of donor service area (DSA) boundaries on transfer efficiency. Among 19 109 donors (56.1% of the cohort) in 25 DSAs with DCUs, a majority (14 593 [76.4%]) were in hospitals within a 2-hour drive. In areas with DCUs detectable in the study data set, a minority of donors (3582 of 11 532 [31.1%]) were transferred to a DCU; transfer rates varied between DSAs (median, 27.7%, range, 4.0%-96.5%). Median hospital-to-DCU driving times were not meaningfully shorter among transferred donors (50 vs 51 minutes for not transferred, P < .001). When DSA boundaries were ignored, 3241 cohort donors (9.5%) without current DCU access were managed in hospitals within 2 hours of a DCU and thus potentially eligible for transfer. In summary, approximately half of United States deceased donors after brain death are managed in hospitals in DSAs with a DCU. Transfer of donors between DSAs may increase DCU utilization and improve system efficiency.

Provider beliefs and practices regarding the management of obesity in lung transplant recipients.

Obesity at the time of lung transplant is associated with decreased survival. How providers manage obesity after lung transplantation is unknown. We performed an international survey of lung transplant providers to assess beliefs and practices regarding post-transplant obesity management. Eighty-one providers initiated the survey and 73 (90%) completed the full survey. Respondents were primarily North American-based pulmonary physicians. Nearly all providers believe treating obesity improves quality of life (99%) and survival (95%) after lung transplantation, but that only 41% of patients attempting weight loss are successful. While respondents nearly always recommend diet (96%), exercise (92%), and dietician consultation (89%), they less frequently recommend prescription weight loss medications (29%) or bariatric surgery (11%). Lung transplant providers are motivated to treat obesity in transplant recipients. However, there is a gap between general obesity treatment guidelines and lung transplant practice. Additional training, education, and trials in this population could address this gap.

Development and validation of primary graft dysfunction predictive algorithm for lung transplant candidates.

BACKGROUND: Primary graft dysfunction (PGD) is the leading cause of early morbidity and mortality after lung transplantation. Accurate prediction of PGD risk could inform donor approaches and perioperative care planning. We sought to develop a clinically useful, generalizable PGD prediction model to aid in transplant decision-making. METHODS: We derived a predictive model in a prospective cohort study of subjects from 2012 to 2018, followed by a single-center external validation. We used regularized (lasso) logistic regression to evaluate the predictive ability of clinically available PGD predictors and developed a user interface for clinical application. Using decision curve analysis, we quantified the net benefit of the model across a range of PGD risk thresholds and assessed model calibration and discrimination. RESULTS: The PGD predictive model included distance from donor hospital to recipient transplant center, recipient age, predicted total lung capacity, lung allocation score (LAS), body mass index, pulmonary artery mean pressure, sex, and indication for transplant; donor age, sex, mechanism of death, and donor smoking status; and interaction terms for LAS and donor distance. The interface allows for real-time assessment of PGD risk for any donor/recipient combination. The model offers decision-making net benefit in the PGD risk range of 10% to 75% in the derivation centers and 2% to 10% in the validation cohort, a range incorporating the incidence in that cohort. CONCLUSION: We developed a clinically useful PGD predictive algorithm across a range of PGD risk thresholds to support transplant decision-making, posttransplant care, and enrich samples for PGD treatment trials.

The Impact of Donor Smoking on Primary Graft Dysfunction and Mortality after Lung Transplantation.

Rationale: Primary graft dysfunction (PGD) is the leading cause of early morbidity and mortality after lung transplantation. Prior studies implicated proxy-defined donor smoking as a risk factor for PGD and mortality. Objectives: We aimed to more accurately assess the impact of donor smoke exposure on PGD and mortality using quantitative smoke exposure biomarkers. Methods: We performed a multicenter prospective cohort study of lung transplant recipients enrolled in the Lung Transplant Outcomes Group cohort between 2012 and 2018. PGD was defined as grade 3 at 48 or 72 hours after lung reperfusion. Donor smoking was defined using accepted thresholds of urinary biomarkers of nicotine exposure (cotinine) and tobacco-specific nitrosamine (4-[methylnitrosamino]-1-[3-pyridyl]-1-butanol [NNAL]) in addition to clinical history. The donor smoking-PGD association was assessed using logistic regression, and survival analysis was performed using inverse probability of exposure weighting according to smoking category. Measurements and Main Results: Active donor smoking prevalence varied by definition, with 34-43% based on urinary cotinine, 28% by urinary NNAL, and 37% by clinical documentation. The standardized risk of PGD associated with active donor smoking was higher across all definitions, with an absolute risk increase of 11.5% (95% confidence interval [CI], 3.8% to 19.2%) by urinary cotinine, 5.7% (95% CI, -3.4% to 14.9%) by urinary NNAL, and 6.5% (95% CI, -2.8% to 15.8%) defined clinically. Donor smoking was not associated with differential post-lung transplant survival using any definition. Conclusions: Donor smoking associates with a modest increase in PGD risk but not with increased recipient mortality. Use of lungs from smokers is likely safe and may increase lung donor availability. Clinical trial registered with www.clinicaltrials.gov (NCT00552357).

Factors associated with aeroallergen testing among adults with asthma in a large health system.

Background: Aeroallergen testing informs precision care for adults with asthma, yet the epidemiology of testing in this population remains poorly understood. Objective: We sought to identify factors associated with receiving aeroallergen testing, the results of these tests, and subsequent reductions in exacerbation measures among adults with asthma. Methods: We used electronic health record data to conduct a retrospective, observational cohort study of 30,775 adults with asthma who had an office visit with a primary care provider or an asthma specialist from January 1, 2017, to August 26, 2022. We used regression models to identify (1) factors associated with receiving any aeroallergen test and tests to 9 allergen categories after the index visit, (2) factors associated with positive test results, and (3) reductions in asthma exacerbation measures in the year after testing compared with before testing. Results: Testing was received by 2201 patients (7.2%). According to multivariable models, receiving testing was associated with having any office visit with an allergy/immunology specialist during the study period (odds ratio [OR] = 91.3 vs primary care only [P < .001]) and having an asthma emergency department visit (OR = 1.62 [P = .004]) or hospitalization (OR = 1.62 [P = .03]) in the year before the index visit. Age 65 years or older conferred decreased odds of testing (OR = 0.74 vs age 18-34 years [P = .008]) and negative test results to 6 categories (P ≤ .04 for all comparisons). Black race conferred increased odds of testing (OR =1.22 vs White race [P = .01]) and positive test results to 8 categories (P < .04 for all comparisons). Exacerbation measures decreased after testing. Conclusion: Aeroallergen testing was performed infrequently among adults with asthma and was associated with reductions in asthma exacerbation measures.

Readmission Rates After Acute Respiratory Distress Syndrome in Children.

Importance: An increasing number of children survive after acute respiratory distress syndrome (ARDS). The long-term morbidity affecting these survivors, including the burden of hospital readmission and key factors associated with readmission, is unknown. Objective: To determine 1-year readmission rates among survivors of pediatric ARDS and to investigate the associations of 3 key index hospitalization factors (presence or development of a complex chronic condition, receipt of a tracheostomy, and hospital length of stay [LOS]) with readmission. Design, Setting, and Participants: This retrospective cohort study used data from the commercial or Medicaid IBM MarketScan databases between 2013 and 2017, with follow-up data through 2018. Participants included hospitalized children (aged ≥28 days to <18 years) who received mechanical ventilation and had algorithm-identified ARDS. Data analysis was completed from March 2022 to March 2023. Exposures: Complex chronic conditions (none, nonrespiratory, and respiratory), receipt of tracheostomy, and index hospital LOS. Main Outcomes and Measures: The primary outcome was 1-year, all-cause hospital readmission. Univariable and multivariable Cox proportional hazard models were created to test the association of key hospitalization factors with readmission. Results: One-year readmission occurred in 3748 of 13 505 children (median [IQR] age, 4 [0-14] years; 7869 boys [58.3%]) with mechanically ventilated ARDS who survived to hospital discharge. In survival analysis, the probability of 1-year readmission was 30.0% (95% CI, 29.0%-30.8%). One-half of readmissions occurred within 61 days of discharge (95% CI, 56-67 days). Both respiratory (adjusted hazard ratio [aHR], 2.69; 95% CI, 2.42-2.98) and nonrespiratory (aHR, 1.86; 95% CI, 1.71-2.03) complex chronic conditions were associated with 1-year readmission. Placement of a new tracheostomy (aHR, 1.98; 95% CI, 1.69-2.33) and LOS 14 days or longer (aHR, 1.87; 95% CI, 1.62-2.16) were associated with readmission. After exclusion of children with chronic conditions, LOS 14 days or longer continued to be associated with readmission (aHR, 1.92; 95% CI, 1.49-2.47). Conclusions and Relevance: In this retrospective cohort study of children with ARDS who survived to discharge, important factors associated with readmission included the presence or development of chronic medical conditions during the index admission, tracheostomy placement during index admission, and index hospitalization of 14 days or longer. Future studies should evaluate whether postdischarge interventions (eg, telephonic contact, follow-up clinics, and home health care) may help reduce the readmission burden.

Association of delivery risk phenotype with early-onset sepsis in preterm infants.

OBJECTIVE: To determine delivery risk phenotype-specific incidence of early-onset sepsis (EOS) among preterm infants. STUDY DESIGN: Retrospective cohort study of infants born <35 weeks' gestation at four perinatal centers during 2017-2021. Infants were classified into one of six delivery risk phenotypes incorporating delivery mode, presence of labor, and duration of rupture of membranes (ROM). The primary outcome was EOS incidence within the overall cohort and each risk phenotype. RESULTS: Among 2937 preterm infants, 21 had EOS (0.7%, or 7.1 cases/1000 preterm infants). The majority of EOS cases (13/21, 62%) occurred in the setting of prolonged ROM ≥ 18 h, with a phenotype incidence of 23.8 cases/1000 preterm infants. There were no EOS cases among infants born by cesarean section without ROM (with or without labor), nor via cesarean section with ROM < 18 h without labor. CONCLUSION: Delivery risk phenotyping may inform EOS risk stratification in preterm infants.

Poor functional status at the time of waitlist for pediatric lung transplant is associated with worse pretransplant outcomes.

BACKGROUND: Whether functional status is associated with survival to pediatric lung transplant is unknown. We hypothesized that completely dependent functional status at waitlist registration, defined using Lansky Play Performance Scale (LPPS), would be associated with worse outcomes. METHODS: Retrospective cohort study of pediatric lung transplant registrants utilizing United Network for Organ Sharing's Standard Transplant Analysis and Research files (2005-2020). Primary exposure was completely dependent functional status, defined as LPPS score of 10-40. Primary outcome was waitlist removal for death/deterioration with cause-specific hazard ratio (CSHR) regression. Subdistribution hazard regression (SHR, Fine and Gray) was used for the secondary outcome of waitlist removal due to transplant/improvement with a competing risk of death/deterioration. Confounders included: sex, age, race, diagnosis, ventilator dependence, extracorporeal membrane oxygenation, year, and listing center volume. RESULTS: A total of 964 patients were included (63.5% ≥ 12 years, 50.2% cystic fibrosis [CF]). Median waitlist days were 95; 20.1% were removed for death/deterioration and 68.2% for transplant/improvement. Completely dependent functional status was associated with removal due to death/deterioration (adjusted CSHR 5.30 [95% CI 2.86-9.80]). This association was modified by age (interaction p = 0.0102), with a larger effect for age ≥12 years, and particularly strong for CF. In the Fine and Gray model, completely dependent functional status did not affect the risk of removal due to transplant/improvement with a competing risk of death/deterioration (adjusted SHR 1.08 [95% CI 0.77-1.49]). CONCLUSIONS: Pediatric lung transplant registrants with the worst functional status had worse pretransplant outcomes, especially for adolescents and CF patients. Functional status at waitlist registration may be a modifiable risk factor to improve survival to lung transplant.

Development and validation of a population pharmacokinetic model to guide perioperative tacrolimus dosing after lung transplantation.

Background: Tacrolimus therapy is standard of care for immunosuppression after lung transplantation. However, tacrolimus exposure variability during the early postoperative period may contribute to poor outcomes in this population. Few studies have examined tacrolimus pharmacokinetics (PK) during this high-risk time period. Methods: We conducted a retrospective pharmacokinetic study in lung transplant recipients at the University of Pennsylvania who were enrolled in the Lung Transplant Outcomes Group (LTOG) cohort. We derived a model in 270 patients using NONMEM (version 7.5.1) and examined validity in a separate cohort of 114 patients. Covariates were examined with univariate analysis and multivariable analysis was developed using forward and backward stepwise selection. Performance of the final model in the validation cohort was examined with calculation of mean prediction error (PE). Results: We developed a one-compartment base model with a fixed rate absorption constant. Significant covariates in multivariable analysis were postoperative day, hematocrit, transplant type, CYP3A5 genotype, total body weight, and time-varying postoperative day, hematocrit, and CYP inhibitor drugs. The strongest predictor of tacrolimus clearance was postoperative day, with median predicted clearance increasing more than threefold over the 14 day study period. In the validation cohort, the final model showed a mean PE of 36.4% (95%CI 30.8%-41.9%) and a median PE of 7.2% (IQR -29.3%-70.53%). Conclusion: Postoperative day was the strongest predictor of tacrolimus exposure in the early post-lung transplant period. Future multicenter studies employing intensive sampling to examine a broad set of variables related to critical illness physiology are needed to understand determinants of clearance, volume of distribution and absorption in this population.

Exposure to ambient air pollutants and acute respiratory distress syndrome risk in sepsis.

PURPOSE: Exposures to ambient air pollutants may prime the lung enhancing risk of acute respiratory distress syndrome (ARDS) in sepsis. Our objective was to determine the association of short-, medium-, and long-term pollutant exposures and ARDS risk in critically ill sepsis patients. METHODS: We analyzed a prospective cohort of 1858 critically ill patients with sepsis, and estimated short- (3 days), medium- (6 weeks), and long- (5 years) term exposures to ozone, nitrogen dioxide (NO2), sulfur dioxide (SO2), carbon monoxide (CO), particulate matter < 2.5 µm (PM2.5), and PM < 10 µm (PM10) using weighted averages of daily levels from monitors within 50 km of subjects' residences. Subjects were followed for 6 days for ARDS by the Berlin Criteria. The association between each pollutant and ARDS was determined using multivariable logistic regression adjusting for preselected confounders. In 764 subjects, we measured plasma concentrations of inflammatory proteins at presentation and tested for an association between pollutant exposure and protein concentration via linear regression. RESULTS: ARDS developed in 754 (41%) subjects. Short- and long-term exposures to SO2, NO2, and PM2.5 were associated with ARDS risk (SO2: odds ratio (OR) for the comparison of the 75-25th long-term exposure percentile 1.43 (95% confidence interval (CI) 1.16, 1.77); p < 0.01; NO2: 1.36 (1.06, 1.74); p = 0.04, PM2.5: 1.21 (1.04, 1.41); p = 0.03). Long-term exposures to these three pollutants were also associated with plasma interleukin-1 receptor antagonist and soluble tumor necrosis factor receptor-1 concentrations. CONCLUSION: Short and long-term exposures to ambient SO2, PM2.5, and NO2 are associated with increased ARDS risk in sepsis, representing potentially modifiable environmental risk factors for sepsis-associated ARDS.

Vascular Endothelial-derived SPARCL1 Exacerbates Viral Pneumonia Through Pro-Inflammatory Macrophage Activation.

Inflammation upon infectious lung injury is a double-edged sword: while tissue-infiltrating immune cells and cytokines are necessary to control infection, these same factors often aggravate injury. Full appreciation of both the sources and targets of inflammatory mediators is required to facilitate strategies to maintain antimicrobial effects while minimizing off-target epithelial and endothelial damage. Recognizing that the vasculature is centrally involved in tissue responses to injury and infection, we observed that pulmonary capillary endothelial cells (ECs) exhibit dramatic transcriptomic changes upon influenza injury punctuated by profound upregulation of Sparcl1 . Endothelial deletion and overexpression of SPARCL1 implicated this secreted matricellular protein in driving key pathophysiologic symptoms of pneumonia, which we demonstrate result from its effects on macrophage polarization. SPARCL1 induces a shift to a pro-inflammatory "M1-like" phenotype (CD86 + CD206 - ), thereby increasing associated cytokine levels. Mechanistically, SPARCL1 acts directly on macrophages in vitro to induce the pro-inflammatory phenotype via activation of TLR4, and TLR4 inhibition in vivo ameliorates inflammatory exacerbations caused by endothelial Sparcl1 overexpression. Finally, we confirmed significant elevation of SPARCL1 in COVID-19 lung ECs in comparison with those from healthy donors. Survival analysis demonstrated that patients with fatal COVID-19 had higher levels of circulating SPARCL1 protein compared to those who recovered, indicating the potential of SPARCL1 as a biomarker for prognosis of pneumonia and suggesting that personalized medicine approaches might be harnessed to block SPARCL1 and improve outcomes in high-expressing patients.

Transplanting candidates with stacked risks negatively affects outcomes.

BACKGROUND: Lung transplant (LT) centers are increasingly evaluating patients with multiple risk factors for adverse outcomes. The effects of these stacked risks remains unclear. Our aim was to determine the relationship between the number of comorbidities and post-transplant outcomes. METHODS: We performed a retrospective cohort study using the National Inpatient Sample (NIS) and UNOS Starfile (USF). We applied a probabilistic matching algorithm using 7 variables (transplant: month, year, and type; recipient: age, sex, race, payer). We matched recipients in the USF to transplant patients in the NIS between 2016 and 2019. The Elixhauser methodology was used to identify comorbidities present on admission. We determined the associations between mortality, length of stay (LOS), total charges, and disposition with comorbidity numbers using penalized cubic splines, Kaplan-Meier, and linear and logistic regression methods. RESULTS: From 28,484,087 NIS admissions, we identified 1,821 LT recipients. Matches were exact in 76.8% of the cohort. While the remaining cohort had a probability match of ≥0.94. Penalized splines of Elixhauser comorbidity number identified 3 knots defining 3 groups of stacked risk: low (<3), medium (3-6), and high risk (>6). Inpatient mortality increased from low to medium to high-risk categories: (1.6%, 3.9%, and 7.0%; p < 0.001), as did LOS (16, 21, 29 days, p < 0.001), total charges ($553,057, $666,791, $821,641.5; p = 0.004) and discharge to a skilled nursing facility (15%, 20%, 31%; p < 0.001). CONCLUSIONS: Stacked risks adversely affect post-LT mortality, LOS, charges, and discharge disposition. Further study to understand the details of specific stacked risks is warranted.

Acute respiratory failure-related excess mortality in pediatric sepsis.

Excess mortality risk imparted by acute respiratory failure in children is unknown. We determined excess mortality risk associated with mechanically ventilated acute respiratory failure in pediatric sepsis. Novel ICD10-based algorithms were derived and validated to identify a surrogate for acute respiratory distress syndrome to calculate excess mortality risk. Algorithm-identified ARDS was identified with specificity of 96.7% (CI 93.0 - 98.9) and sensitivity of 70.5% (CI 44.0 - 89.7). Excess risk of mortality for ARDS was 24.4% (CI 22.9 - 26.2). Development of ARDS requiring mechanical ventilation imparts modest excess risk of mortality in septic children.

Cryoablation in lung transplantation: Its impact on pain, opioid use, and outcomes.

Objective: To assess the effect of intraoperative cryoablation on postoperative patient-reported pain, opioid use, and clinical outcomes in lung transplantation. Methods: We performed a single-center retrospective cohort study of adult lung transplant recipients from August 2017 to September 2018. We compared outcomes of patients who received intraoperative cryoablation of the intercostal nerves with those who did not. Primary outcomes were postoperative patient-reported pain scores and opioid use. Secondary outcomes included postoperative sedation and agitation levels and perioperative outcomes. Data were abstracted from patients' electronic health records. Results: Of the 102 patients transplanted, 45 received intraoperative cryoablation (intervention group) and 57 received the standard of care, which did not include intercostal or serratus blocks or immediate postoperative epidural placement (control group). The intervention group had significantly lower median and maximum postoperative pain scores at days 3 and 7 and significantly lower oral opioid use at days 3, 7, and 14 compared with the control group. Chronic opioid use at 3 and 6 months' posttransplant was lower in the intervention group. Differences in perioperative outcomes, including length of mechanical ventilation, sedation and agitation levels, and hospital stay, were not clinically meaningful. Survival at 30 days and 1 year was superior in the intervention compared with the control group. Conclusions: Findings suggest that use of intraoperative cryoablation is an effective approach for treating pain and reducing opioid use in patients who undergo lung transplant, but a randomized study across multiple institutions is needed to confirm these findings.

Pseudomonas-dominant microbiome elicits sustained IL-1ß upregulation in alveolar macrophages from lung transplant recipients.

BACKGROUND: Isolation of Pseudomonas aeruginosa (PsA) is associated with increased BAL (bronchoalveolar lavage) inflammation and lung allograft injury in lung transplant recipients (LTR). However, the effect of PsA on macrophage responses in this population is incompletely understood. We examined human alveolar macrophage (AMΦ) responses to PsA and Pseudomonas dominant microbiome in healthy LTR. METHODS: We stimulated THP-1 derived macrophages (THP-1MΦ) and human AMΦ from LTR with different bacteria and LTR BAL derived microbiome characterized as Pseudomonas-dominant. Macrophage responses were assessed by high dimensional flow cytometry, including their intracellular production of cytokines (TNF-α, IL-6, IL-8, IL-1ß, IL-10, IL-1RA, and TGF-ß). Pharmacological inhibitors were utilized to evaluate the role of the inflammasome in PsA-macrophage interaction. RESULTS: We observed upregulation of pro-inflammatory cytokines (TNF-α, IL-6, IL-8, IL-1ß) following stimulation by PsA compared to other bacteria (Staphylococcus aureus (S.Aur), Prevotella melaninogenica, Streptococcus pneumoniae) in both THP-1MΦ and LTR AMΦ, predominated by IL-1ß. IL-1ß production from THP-1MΦ was sustained after PsA stimulation for up to 96 hours and 48 hours in LTR AMΦ. Treatment with the inflammasome inhibitor BAY11-7082 abrogated THP-1MΦ IL-1ß production after PsA exposure. BAL Pseudomonas-dominant microbiota elicited an increased IL-1ß, similar to PsA, an effect abrogated by the addition of antibiotics. CONCLUSION: PsA and PsA-dominant lung microbiota induce sustained IL-1ß production in LTR AMΦ. Pharmacological targeting of the inflammasome reduces PsA-macrophage-IL-1ß responses, underscoring their use in lung transplant recipients.