Risk Factors for and Outcomes Following Early Acquisition of Mycobacterium abscessus Complex After Lung Transplantation.

Background: Lung transplant recipients are at increased risk of Mycobacterium abscessus complex (MABC) acquisition and invasive infection. We analyzed risk factors and outcomes of early post-lung transplant MABC acquisition. Methods: We conducted a retrospective matched case-control study of patients who underwent lung transplant from 1/1/2012 to 12/31/2021 at a single large tertiary care facility. Cases had de novo MABC isolation within 90 days post-transplant. Controls had no positive MABC cultures and were matched 3:1 with cases based on age and transplant date. Recipient demographics and pre-/peri-operative characteristics were analyzed, and a regression model was used to determine independent risk factors for MABC acquisition. We also assessed 1-year post-transplant outcomes, including mortality. Results: Among 1145 lung transplants, we identified 79 cases and 237 matched controls. Post-transplant mechanical ventilation for >48 hours was independently associated with MABC acquisition (adjusted odds ratio, 2.46; 95% CI, 1.29-4.72; P = .007). Compared with controls, cases required more days of hospitalization after the MABC index date (28 vs 12 days; P = .01) and had decreased 1-year post-transplant survival (78% vs 89%; log-rank P = .02). One-year mortality appeared highest for cases who acquired M. abscessus subsp. abscessus (31% mortality) or had extrapulmonary infections (43% mortality). Conclusions: In this large case-control study, prolonged post-transplant ventilator duration was associated with early post-lung transplant MABC acquisition, which in turn was associated with increased hospital-days and mortality. Further studies are needed to determine the best strategies for MABC prevention, surveillance, and management.

Nonspecific oral medications versus anti-calcitonin gene-related peptide monoclonal antibodies for migraine: A systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: To compare calcitonin gene-related peptide monoclonal antibodies (CGRP mAbs) versus nonspecific oral migraine preventives (NOEPs). BACKGROUND: Insurers mandate step therapy with NOEPs before approving CGRP mAbs. METHODS: Databases were searched for class I or II randomized controlled trials (RCTs) comparing CGRP mAbs or NOEPs versus placebo for migraine prevention in adults. The primary outcome measure was monthly migraine days (MMD) or moderate to severe headache days. RESULTS: Twelve RCTs for CGRP mAbs, 5 RCTs for topiramate, and 3 RCTs for divalproex were included in the meta-analysis. There was high certainty that CGRP mAbs are more effective than placebo, with weighted mean difference (WMD; 95% confidence interval) of -1.64 (-1.99 to -1.28) MMD, which is compatible with small effect size (Cohen's d -0.25 [-0.34 to -0.16]). Certainty of evidence that topiramate or divalproex is more effective than placebo was very low and low, respectively (WMD -1.45 [-1.52 to -1.38] and -1.65 [-2.30 to -1.00], respectively; Cohen's d -1.25 [-2.47 to -0.03] and -0.48 [-0.67 to -0.29], respectively). Trial sequential analysis showed that information size was adequate and that CGRP mAbs had clear benefit versus placebo. Network meta-analysis showed no statistically significant difference between CGRP mAbs and topiramate (WMD -0.19 [-0.56 to 0.17]) or divalproex (0.01 [-0.73 to 0.75]). No significant difference was seen between topiramate or divalproex (0.21 [-0.45 to 0.86]). CONCLUSIONS: There is high certainty that CGRP mAbs are more effective than placebo, but the effect size is small. When feasible, CGRP mAbs may be prescribed as first-line preventives; topiramate or divalproex could be as effective but are less well tolerated. The findings of this study support the recently published 2024 position of the American Headache Society on the use of CGRP mAbs as the first-line treatment.

Whole Blood Resuscitation for Injured Patients Requiring Transfusion: A Systematic Review, Meta-Analysis, and Practice Management Guideline from the Eastern Association for the Surgery of Trauma.

INTRODUCTION: Whole blood resuscitation has reemerged as a resuscitation strategy for injured patients. However, the effect of whole blood-based resuscitation on outcomes has not been established. The primary objective of this guideline was to develop evidence-based recommendations on whether whole blood should be considered in civilian trauma patients receiving blood transfusions. METHODS: An EAST working group performed a systematic review and meta-analysis utilizing the GRADE methodology. One PICO question was developed to analyze the effect of whole blood resuscitation in the acute phase on mortality, transfusion requirements, infectious complications, and ICU length of stay. English language studies including adult civilian trauma patients comparing in-hospital whole blood to component therapy were included. Medline, Embase, Cochrane CENTRAL, CINAHL Plus, and Web of Science were queried. GRADEpro was used to assess quality of evidence and risk of bias. The study was registered on PROSPERO (#CRD42023451143). RESULTS: A total of 21 studies were included. Most patients were severely injured and required blood transfusion, massive transfusion protocol activation, and/or a hemorrhage control procedure in the early phase of resuscitation. Mortality was assessed separately at the following intervals: early (i.e., ED, 3-, or 6-hour), 24-hour, late (i.e., 28- or 30-day), and in-hospital. On meta-analysis, whole blood was not associated with decreased mortality. Whole blood was associated with decreased 4-hour RBC (mean difference -1.82, 95% CI -3.12 to -0.52), 4-hour plasma (mean difference -1.47, 95% CI -2.94 to 0), and 24-hour RBC transfusions (mean difference -1.22, 95% CI -2.24 to -0.19) compared to component therapy. There were no differences in infectious complications or ICU length of stay between groups. CONCLUSION: We conditionally recommend WB resuscitation in adult civilian trauma patients receiving blood transfusions, recognizing that data are limited for certain populations, including women of childbearing age, and therefore this guideline may not apply to these populations. LEVEL OF EVIDENCE: Level III, Guidelines.

Efficacy of Botulinum Toxin in the Treatment of Cutaneous Flushing: A Systematic Review and Meta-Analysis.

BACKGROUND: Flushing is a common dermatologic complaint and can be resistant to many treatments. As the utility of botulinum toxin continues to expand, recent data suggest that it may also be a therapeutic option for flushing. OBJECTIVE: To evaluate the efficacy of botulinum toxin for the treatment of cutaneous flushing. MATERIALS AND METHODS: A systematic search of Medline, Embase, Cochrane CENTRAL, CINAHL, Scopus, and Web of Science databases was conducted to identify studies evaluating the effect of botulinum toxin on flushing 1 month after treatment. Prespecified outcome measures included a clinical flushing score, dermatology life quality index (DLQI), and erythema index (EI). Meta-analysis was performed to calculate the mean differences in these outcomes before and after treatment at 1-month follow-up. RESULTS: Nine studies (132 patients) were included in the analysis of this study (2 randomized controlled trials and 7 nonrandomized studies). All studies had a low risk of bias (high quality). The most frequent outcome reported was a clinical flushing score, which significantly decreased by 1.25 points overall (95% confidence interval [CI]: -2.47; -0.04) 1 month after treatment with botulinum toxin. Mean DLQI scores decreased (i.e., improved) by 9.02 points (95% CI: -19.81; 1.77) 1 month after botulinum toxin injections. The EI (measured by Mexameter) before and after botulinum toxin was evaluated in 2 studies; however, not enough statistical information was provided to analyze with meta-analytic techniques. CONCLUSION: Based on this meta-analysis, botulinum toxin significantly improves clinical flushing scores 1 month after treatment.

Risk factors, management, and clinical outcomes of invasive Mycoplasma and Ureaplasma infections after lung transplantation.

Mollicute infections, caused by Mycoplasma and Ureaplasma species, are serious complications after lung transplantation; however, understanding of the epidemiology and outcomes of these infections remains limited. We conducted a single-center retrospective study of 1156 consecutive lung transplants performed from 2010-2019. We used log-binomial regression to identify risk factors for infection and analyzed clinical management and outcomes. In total, 27 (2.3%) recipients developed mollicute infection. Donor characteristics independently associated with recipient infection were age ≤40 years (prevalence rate ratio [PRR] 2.6, 95% CI 1.0-6.9), White race (PRR 3.1, 95% CI 1.1-8.8), and purulent secretions on donor bronchoscopy (PRR 2.3, 95% CI 1.1-5.0). Median time to diagnosis was 16 days posttransplant (IQR: 11-26 days). Mollicute-infected recipients were significantly more likely to require prolonged ventilatory support (66.7% vs 21.4%), undergo dialysis (44.4% vs 6.3%), and remain hospitalized ≥30 days (70.4% vs 27.4%) after transplant. One-year posttransplant mortality in mollicute-infected recipients was 12/27 (44%), compared to 148/1129 (13%) in those without infection (P <.0001). Hyperammonemia syndrome occurred in 5/27 (19%) mollicute-infected recipients, of whom 3 (60%) died within 10 weeks posttransplant. This study highlights the morbidity and mortality associated with mollicute infection after lung transplantation and the need for better screening and management protocols.

Short-term outcomes after third-time lung transplantation: A single institution experience.

BACKGROUND: Reoperative lung transplantation (LTx) survival has improved over time such that a growing number of patients may present for third-time LTx (L3Tx). To understand the safety of L3Tx, we evaluated perioperative outcomes and 3-year survival after L3Tx at a high-volume US LTx center. METHODS: This retrospective study included all patients who underwent bilateral L3Tx at our institution. Using an optimal matching technique, a primary LTx (L1Tx) cohort was matched 1:2 and a second-time LTx (L2Tx) cohort 1:1. Recipient, operative, and donor characteristics, perioperative outcomes, and 3-year survival were compared among L1Tx, L2Tx, and L3Tx groups. RESULTS: Eleven L3Tx, 11 L2Tx, and 22 L1Tx recipients were included. Among L3Tx recipients, median age at transplant was 37 years and most (73%) had cystic fibrosis. L3Tx was performed median 6.0 and 10.6 years after L2Tx and L1Tx, respectively. Compared to L1Tx and L2Tx recipients, L3Tx recipients had greater intraoperative transfusion requirements, a higher incidence of postoperative complications, and a higher rate of unplanned reoperation. Rates of grade 3 primary graft dysfunction at 72 hours, extracorporeal membrane oxygenation at 72 hours, reintubation, and in-hospital mortality were similar among groups. There were no differences in 3-year patient (log-rank p = 0.61) or rejection-free survival (log-rank p = 0.34) after L1Tx, L2Tx, and L3Tx. CONCLUSIONS: At our institution, L3Tx was associated with similar perioperative outcomes and 3-year patient survival compared to L1Tx and L2Tx. L3Tx represents the only safe treatment option for patients with allograft failure after L2Tx; however, further investigation is needed to understand the long-term survival and durability of L3Tx.

Overamped: Stimulant Use and HIV Pathogenesis.

PURPOSE OF REVIEW: In the era of HIV treatment as prevention (TasP), more clarity is needed regarding whether people with HIV who use stimulants (i.e., methamphetamine, powder cocaine, and crack cocaine) display elevated HIV viral load and greater immune dysregulation. RECENT FINDINGS: Although rates of viral suppression have improved in the TasP era, stimulant use was independently associated with elevated viral load in 23 of 28 studies included in our review. In the 12 studies examining other HIV disease markers, there was preliminary evidence for stimulant-associated alterations in gut-immune dysfunction and cellular immunity despite effective HIV treatment. Studies generally focused on documenting the direct associations of stimulant use with biomarkers of HIV pathogenesis without placing these in the context of social determinants of health. Stimulant use is a key barrier to optimizing the effectiveness of TasP. Elucidating the microbiome-gut-brain axis pathways whereby stimulants alter neuroimmune functioning could identify viable targets for pharmacotherapies for stimulant use disorders. Examining interpersonal, neighborhood, and structural determinants that could modify the associations of stimulant use with biomarkers of HIV pathogenesis is critical to guiding the development of comprehensive, multi-level interventions.

Real-world Experiences in the Transplantation of Hepatitis C-NAAT-positive Organs.

Background: Hepatitis C virus (HCV) nucleic acid amplification test (NAAT)-positive donors have increased the organ pool. Direct-acting antivirals (DAAs) have led to high rates of treatment success and sustained virologic response (SVR) in recipients with donor-derived HCV infection without significant adverse effects, although variability remains in the timing and duration of antivirals. Methods: This retrospective study analyzed all adult HCV-NAAT-negative transplant recipients who received an organ from HCV-NAAT-positive donors from November 24, 2018, to March 31, 2022, at Duke University Medical Center with protocolized delay of DAA initiation until after hospital discharge, with at least 180-d follow-up on all patients. Transplant and HCV-related outcomes were analyzed. Results: Two hundred eleven transplants (111 kidneys, 41 livers, 34 hearts, and 25 lungs) were performed from HCV-NAAT-positive donors to HCV-NAAT-negative recipients. Ninety percent of recipients became viremic within 7 d posttransplant. Ninety-nine percent of recipients were initiated on pangenotypic DAAs in the outpatient setting a median of 52 d posttransplant, most commonly with 12-wk courses of sofosbuvir-velpatasvir (lungs) and glecaprevir-pibrentasvir (heart, kidney, and liver). Ninety-seven percent of recipients had SVR after a first-line DAA; all ultimately achieved SVR at 12 wk after subsequent treatment courses. The median peak HCV RNA for all organ systems was 2 436 512 IU/mL; the median time from antiviral to undetectable RNA was 48 d, although differences were noted between organ groups. No patient deaths or graft losses were directly attributable to HCV infection. Conclusions: One hundred percent of transplant recipients of HCV-NAAT-positive organs ultimately developed SVR without significant adverse effects when HCV antivirals were initiated in the outpatient setting after transplant hospitalization, suggesting that this real-world treatment pathway is a viable option.

Voxelotor as a Treatment of Persistent Hypoxia in the ICU.

Hypoxia is encountered frequently in the ICU as a result of a wide range of pathologic characteristics. The oxygen-hemoglobin dissociation curve describes hemoglobin's affinity for a given Po2 and factors affecting uptake and offload. Research in manipulating this relationship between hemoglobin and oxygen is sparing. Voxelotor is a hemoglobin oxygen-affinity modulator that is approved by the US Food and Drug Association for use in the management of sickle cell disease. We present two patients without sickle cell disease who underwent treatment with this novel agent to assist with chronic hypoxia and weaning of mechanical support.

Preemptive immune globulin therapy in sensitized lung transplant recipients.

BACKGROUND: Sensitized lung transplant recipients are at increased risk of developing donor-specific antibodies, which have been associated with acute and chronic rejection. Perioperative intravenous immune globulin has been used in sensitized individuals to down-regulate antibody production. METHODS: We compared patients with a pre-transplant calculated panel reactive antibody ≥25% who did not receive preemptive immune globulin therapy to a historical control that received preemptive immune globulin therapy. Our cohort included 59 patients, 17 patients did not receive immune globulin therapy and 42 patients received therapy. RESULTS: Donor specific antibody development was numerically higher in the non-immune globulin group compared to the immune globulin group (58.8% vs 33.3%, respectively, odds ratio 2.80, 95% confidence interval [0.77, 10.79], p = 0.13). Median time to antibody development was 9 days (Q1, Q3: 7, 19) and 28 days (Q1, Q3: 7, 58) in the non-immune globulin and immune globulin groups, respectively. There was no significant difference between groups in the incidence of primary graft dysfunction at 72 h post-transplant or acute cellular rejection, antibody-mediated rejection, and chronic lung allograft dysfunction at 12 months. CONCLUSION: These findings are hypothesis generating and emphasize the need for larger, randomized studies to determine association of immune globulin therapy with clinical outcomes.

Early posttransplant reductions in club cell secretory protein associate with future risk for chronic allograft dysfunction in lung recipients: results from a multicenter study.

BACKGROUND: Chronic lung allograft dysfunction (CLAD) increases morbidity and mortality for lung transplant recipients. Club cell secretory protein (CCSP), produced by airway club cells, is reduced in the bronchoalveolar lavage fluid (BALF) of lung recipients with CLAD. We sought to understand the relationship between BALF CCSP and early posttransplant allograft injury and determine if early posttransplant BALF CCSP reductions indicate later CLAD risk. METHODS: We quantified CCSP and total protein in 1606 BALF samples collected over the first posttransplant year from 392 adult lung recipients at 5 centers. Generalized estimating equation models were used to examine the correlation of allograft histology or infection events with protein-normalized BALF CCSP. We performed multivariable Cox regression to determine the association between a time-dependent binary indicator of normalized BALF CCSP level below the median in the first posttransplant year and development of probable CLAD. RESULTS: Normalized BALF CCSP concentrations were 19% to 48% lower among samples corresponding to histological allograft injury as compared with healthy samples. Patients who experienced any occurrence of a normalized BALF CCSP level below the median over the first posttransplant year had a significant increase in probable CLAD risk independent of other factors previously linked to CLAD (adjusted hazard ratio 1.95; p = 0.035). CONCLUSIONS: We discovered a threshold for reduced BALF CCSP to discriminate future CLAD risk; supporting the utility of BALF CCSP as a tool for early posttransplant risk stratification. Additionally, our finding that low CCSP associates with future CLAD underscores a role for club cell injury in CLAD pathobiology.

Efficacy and Safety of Bezafibrate Alone or in Combination with Ursodeoxycholic Acid in Primary Biliary Cholangitis: Systematic Review and Meta-Analysis.

BACKGROUND: Bezafibrate (BZF) alone or in combination with ursodeoxycholic acid (UDCA) has been used to slow disease progression in patients with primary biliary cholangitis (PBC). We performed a systematic review and meta-analysis to assess the efficacy and harms of BZF monotherapy or combination therapy. METHODS: We performed a systematic search of PubMed, EMBASE, Cochrane Library, Scopus, ClinicalTrials.gov, and WHO ICTRP from inception until January 2020, for randomized controlled clinical trials assessing BZF + UDCA versus UDCA monotherapy or BZF monotherapy versus UDCA monotherapy in PBC patients. Additionally, we systematically evaluated data on harms using seven observational studies. Pooled effect estimates were calculated for the outcomes of interest. The certainty of evidence was assessed using GRADE (Grading of Recommendations Assessment, Development and Evaluation). RESULTS: We identified 7 randomized controlled trials with a total of 279 participants. Comparing BZF + UDCA to UDCA alone, a clinically significant improvement was observed in serum ALP with a mean difference (MD) of - 159.04 U/L (95% CI - 186.45 to - 131.62) and a reduction in gamma-glutamyltransferase (GGT) (MD - 106.94 IU/L; 95% CI - 151.99 to - 61.89), but not in total bilirubin (TB) or IgM levels. A statistically significant reduction in ALP levels was also noticed with BZF monotherapy compared to UDCA monotherapy. The effect of BZF + UDCA versus UDCA on mortality remains unclear. Across 5 observational studies including 106 patients, one death was reported due to advanced liver disease in an incomplete responder getting treatment with BZF + UDCA. Analysis of observational studies demonstrated improvement in pruritus intensity with BZF. CONCLUSIONS: Use of BZF alone or in combination with UDCA improved liver biochemistries in patients with PBC, but its effect on mortality, liver-related complications or quality of life remains unknown.

Prognostic implications of and clinical risk factors for acute lung injury and organizing pneumonia after lung transplantation: Data from a multicenter prospective cohort study.

We determined prognostic implications of acute lung injury (ALI) and organizing pneumonia (OP), including timing relative to transplantation, in a multicenter lung recipient cohort. We sought to understand clinical risks that contribute to development of ALI/OP. We analyzed prospective, histologic diagnoses of ALI and OP in 4786 lung biopsies from 803 adult lung recipients. Univariable Cox regression was used to evaluate the impact of early (≤90 days) or late (>90 days) posttransplant ALI or OP on risk for chronic lung allograft dysfunction (CLAD) or death/retransplantation. These analyses demonstrated late ALI/OP conferred a two- to threefold increase in the hazards of CLAD or death/retransplantation; there was no association between early ALI/OP and these outcomes. To determine risk factors for late ALI/OP, we used univariable Cox models considering donor/recipient characteristics and posttransplant events as candidate risks. Grade 3 primary graft dysfunction, higher degree of donor/recipient human leukocyte antigen mismatch, bacterial or viral respiratory infection, and an early ALI/OP event were significantly associated with increased late ALI/OP risk. These data from a contemporary, multicenter cohort underscore the prognostic implications of ALI/OP on lung recipient outcomes, clarify the importance of the timing of these events, and identify clinical risks to target for ALI/OP prevention.

Full-face motorcycle helmets to reduce injury and death: A systematic review, meta-analysis, and practice management guideline from the Eastern Association for the Surgery of Trauma.

BACKGROUND: While motorcycle helmets reduce mortality and morbidity, no guidelines specify which is safest. We sought to determine if full-face helmets reduce injury and death. METHODS: We searched for studies without exclusion based on: age, language, date, or randomization. Case reports, professional riders, and studies without original data were excluded. Pooled results were reported as OR (95% CI). Risk of bias and certainty was assessed. (PROSPERO #CRD42021226929). RESULTS: Of 4431 studies identified, 3074 were duplicates, leaving 1357 that were screened. Eighty-one full texts were assessed for eligibility, with 37 studies (n = 37,233) eventually included. Full-face helmets reduced traumatic brain injury (OR 0.40 [0.23-0.70]); injury severity for the head and neck (Abbreviated Injury Scale [AIS] mean difference -0.64 [-1.10 to -0.18]) and face (AIS mean difference -0.49 [-0.71 to -0.27]); and facial fracture (OR 0.26 [0.15-0.46]). CONCLUSION: Full-face motorcycle helmets are conditionally recommended to reduce traumatic brain injury, facial fractures, and injury severity.

Running with Scissors: a Systematic Review of Substance Use and the Pre-exposure Prophylaxis Care Continuum Among Sexual Minority Men.

PURPOSE OF REVIEW: Patterns of sexualized drug use, including stimulants (e.g., methamphetamine) and chemsex drugs, are key drivers of HIV incidence among sexual minority men (SMM). Although pre-exposure prophylaxis (PrEP) mitigates HIV risk, there is no consensus regarding the associations of substance use with the PrEP care continuum. RECENT FINDINGS: SMM who use substances are as likely or more likely to use PrEP. Although SMM who use stimulants experience greater difficulties with daily oral PrEP adherence, some evidence shows that SMM who use stimulants or chemsex drugs may achieve better adherence in the context of recent condomless anal sex. Finally, SMM who use substances may experience greater difficulties with PrEP persistence (including retention in PrEP care). SMM who use stimulants and other substances would benefit from more comprehensive efforts to support PrEP re-uptake, adherence, and persistence, including delivering behavioral interventions, considering event-based dosing, and providing injectable PrEP.

Plasma CXCL9 and CXCL10 at allograft injury predict chronic lung allograft dysfunction.

Histopathologic lung allograft injuries are putative harbingers for chronic lung allograft dysfunction (CLAD). However, the mechanisms responsible are not well understood. CXCL9 and CXCL10 are potent chemoattractants of mononuclear cells and potential propagators of allograft injury. We hypothesized that these chemokines would be quantifiable in plasma, and would associate with subsequent CLAD development. In this prospective multicenter study, we evaluated 721 plasma samples for CXCL9/CXCL10 levels from 184 participants at the time of transbronchial biopsies during their first-year post-transplantation. We determined the association between plasma chemokines, histopathologic injury, and CLAD risk using Cox proportional hazards models. We also evaluated CXCL9/CXCL10 levels in bronchoalveolar lavage (BAL) fluid and compared plasma to BAL with respect to CLAD risk. Plasma CXCL9/CXCL10 levels were elevated during the injury patterns associated with CLAD, acute rejection, and acute lung injury, with a dose-response relationship between chemokine levels and CLAD risk. Importantly, there were strong interactions between injury and plasma CXCL9/CXCL10, where histopathologic injury associated with CLAD only in the presence of elevated plasma chemokines. We observed similar associations and interactions with BAL CXCL9/CXCL10 levels. Elevated plasma CXCL9/CXCL10 during allograft injury may contribute to CLAD pathogenesis and has potential as a minimally invasive immune monitoring biomarker.

Cytomegalovirus prevention in thoracic organ transplantation: A single-center evaluation of letermovir prophylaxis.

BACKGROUND: Cytomegalovirus (CMV) infection is common following thoracic organ transplantation and causes substantial morbidity and mortality. Letermovir is a novel antiviral agent used off-label in this population for CMV prevention. Our goal was to understand patterns of letermovir use and effectiveness when applied for CMV prophylaxis after thoracic transplantation. METHODS: We retrospectively evaluated letermovir use among thoracic transplant recipients at an academic transplant center who initiated letermovir from January 2018 to October2019 for CMV prophylaxis. We analyzed indication, timing, and duration of prophylaxis; tolerability; and occurrence of breakthrough CMV DNAemia and disease. RESULTS: Forty-two episodes of letermovir prophylaxis occurred in 41 patients, including 37 lung and 4 heart transplant recipients. Primary prophylaxis (26/42, 61.9%) was utilized mainly due to myelosuppression (25/26, 96.2%) and was initiated a median of 315 days post-transplant (interquartile range [IQR] 125-1139 days). Sixteen episodes of secondary prophylaxis (16/42, 38.1%) were initiated a median of 695 days post-transplant (IQR 537-1156 days) due to myelosuppression (10/16, 62.5%) or prior CMV resistance (6/16, 37.5%). Median duration of letermovir prophylaxis was 282 days (IQR 131-433 days). Adverse effects required letermovir cessation in 5/42 (11.9%) episodes. Only one episode (2.4%) was complicated by clinically significant breakthrough CMV infection. Transient low-level CMV DNAemia (<450 IU/ml) occurred in 15 episodes (35.7%) but did not require letermovir cessation. CONCLUSIONS: Letermovir was well tolerated and effective during extended prophylactic courses with only one case of breakthrough CMV infection in this cohort of thoracic transplant recipients. Further prospective trials of letermovir prophylaxis in this population are warranted.

Inhaled Pulmonary Vasodilator Therapy in Adult Lung Transplant: A Randomized Clinical Trial.

Importance: Inhaled nitric oxide (iNO) is commonly administered for selectively inhaled pulmonary vasodilation and prevention of oxidative injury after lung transplant (LT). Inhaled epoprostenol (iEPO) has been introduced worldwide as a cost-saving alternative to iNO without high-grade evidence for this indication. Objective: To investigate whether the use of iEPO will lead to similar rates of severe/grade 3 primary graft dysfunction (PGD-3) after adult LT when compared with use of iNO. Design, Setting, and Participants: This health system-funded, randomized, blinded (to participants, clinicians, data managers, and the statistician), parallel-designed, equivalence clinical trial included 201 adult patients who underwent single or bilateral LT between May 30, 2017, and March 21, 2020. Patients were grouped into 5 strata according to key prognostic clinical features and randomized per stratum to receive either iNO or iEPO at the time of LT via 1:1 treatment allocation. Interventions: Treatment with iNO or iEPO initiated in the operating room before lung allograft reperfusion and administered continously until cessation criteria met in the intensive care unit (ICU). Main Outcomes and Measures: The primary outcome was PGD-3 development at 24, 48, or 72 hours after LT. The primary analysis was for equivalence using a two one-sided test (TOST) procedure (90% CI) with a margin of 19% for between-group PGD-3 risk difference. Secondary outcomes included duration of mechanical ventilation, hospital and ICU lengths of stay, incidence and severity of acute kidney injury, postoperative tracheostomy placement, and in-hospital, 30-day, and 90-day mortality rates. An intention-to-treat analysis was performed for the primary and secondary outcomes, supplemented by per-protocol analysis for the primary outcome. Results: A total of 201 randomized patients met eligibility criteria at the time of LT (129 men [64.2%]). In the intention-to-treat population, 103 patients received iEPO and 98 received iNO. The primary outcome occurred in 46 of 103 patients (44.7%) in the iEPO group and 39 of 98 (39.8%) in the iNO group, leading to a risk difference of 4.9% (TOST 90% CI, -6.4% to 16.2%; P = .02 for equivalence). There were no significant between-group differences for secondary outcomes. Conclusions and Relevance: Among patients undergoing LT, use of iEPO was associated with similar risks for PGD-3 development and other postoperative outcomes compared with the use of iNO. Trial Registration: ClinicalTrials.gov identifier: NCT03081052.

Intragraft Hyaluronan Increases in Association With Acute Lung Transplant Rejection.

BACKGROUND: Acute perivascular rejection (AR) is common in lung recipients and increases the risk for chronic lung allograft dysfunction (CLAD). Hyaluronan (HA), an extracellular matrix constituent, accumulates in experimental AR and can act as an innate immune agonist, breaking tolerance and potentiating alloimmunity. We previously demonstrated HA accumulates in CLAD after human-lung transplantation. We sought to determine if HA accumulates in the bronchoalveolar lavage fluid (BALF) concurrent with AR in lung recipients. METHODS: The cohort consisted of 126 first adult lung recipients at 5 transplant centers with a total of 373 BALF samples collected within the first posttransplant year. All samples were paired with a lung biopsy from the same bronchoscopy. BALF HA (ng/mL) was quantified by ELISA and log-transformed for analysis. Linear-mixed effect models, adjusted for potential confounders, were used to estimate the association between BALF HA concentration and the presence of AR on biopsy. The association between early posttransplant BALF HA levels and the development of CLAD was explored utilizing tertiles of maximum BALF HA level observed within the first 6 months of transplant. RESULTS: In analyses adjusted for potential confounders, BALF HA concentration was significantly increased in association with AR (change in means on log-scale 0.31; 95% CI, 0.01-0.60; P = 0.044). When considered on the original scale (ng/mL), BALF HA concentrations were 1.36 times (36%) higher, on average, among samples with, versus without, AR. The cumulative incidence of CLAD was numerically higher in individuals in the highest tertiles of BALF HA level within the first 6 months after transplant, as compared with those in the lowest tertile; however, this difference was not statistically significant (P = 0.32). CONCLUSIONS: These results demonstrate accumulation of HA in clinical AR and suggest a mechanism by which innate and adaptive immune activation might interact in the development of AR and CLAD.