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Background Outcomes after lung retransplantation (LRT) remain inferior compared with primary lung transplantation (PLT). This study examined the impact of center volume on 1-year survival after LRT. Methods Using the United Network for Organ Sharing database, the study abstracted patients undergoing PLT and LRT between January 2006 and December 2017, excluding combined heart-lung transplants and multiple retransplants. One-year survival rates after PLT and LRT were compared using propensity score matching. In the LRT cohort, multivariable Cox models with and without time-dependent coefficients were fitted to examine association between transplant center volume and 1-year survival. Center volume was categorized on the basis of inspection of restricted cubic splines. Results A total of 20,675 recipients (PLT 19,853 [96.0%] vs LRT 822 [4.0%]) were included. One-year survival was lower for LRT recipients in the matched cohort (PLT 84.8% vs LRT 76.7%). There was steady improvement in 1-year survival after LRT (2006 to 2009 72.1% vs 2010 to 2013 76.6% vs 2014 to 2017 80.1%). Higher center volume was associated with better 1-year survival after LRT. This survival difference was noted in the initial 30 days after transplantation (intermediate vs low volume hazard ratio, 0.282 [95% confidence interval, 0.151 to 0.526]; high vs low volume hazard ratio, 0.406 [95% confidence interval, 0.224 to 0.737]), but it became insignificant after 30 days. Conclusions Superior 1-year survival after LRT at higher-volume centers is predominantly the result of better 30-day outcomes. This finding suggests that LRT candidates may be referred to higher-volume centers for surgery.

The complement component C3 is a fundamental plasma protein for host defense, produced largely by the liver. However, recent work has demonstrated the critical importance of tissue-specific C3 expression in cell survival. Here, we analyzed the effects of local versus peripheral sources of C3 expression in a model of acute bacterial pneumonia induced by Pseudomonas aeruginosa . Whereas mice with global C3 deficiency had severe pneumonia-induced lung injury, those deficient only in liver-derived C3 remained protected, comparable to wild-type mice. Human lung transcriptome analysis showed that secretory epithelial cells, such as club cells, express high levels of C3 mRNA. Mice with tamoxifen-induced C3 gene ablation from club cells in the lung had worse pulmonary injury compared with similarly treated controls, despite maintaining normal circulating C3 levels. Last, in both the mouse pneumonia model and cultured primary human airway epithelial cells, we showed that stress-induced death associated with C3 deficiency parallels that seen in Factor B deficiency rather than C3a receptor deficiency. Moreover, C3-mediated reduction in epithelial cell death requires alternative pathway component Factor B. Thus, our findings suggest that a pathway reliant on locally derived C3 and Factor B protects the lung mucosal barrier.

BACKGROUND: Mechanical ventilation immediately after lung transplantation may impact the development of primary graft dysfunction (PGD), particularly in cases of donor-recipient size mismatch as ventilation is typically based on recipient rather than donor size. METHODS: We conducted a retrospective cohort study of adult bilateral lung transplant recipients at our center between January 2010 and January 2017. We defined donor-based lung protective ventilation (dLPV) as 6 to 8 ml/kg of donor ideal body weight and plateau pressure

Background Pulmonary embolism (PE) is unexpectedly detected in some donor lungs during organ procurement for lung transplantation. Anecdotally, such lungs are usually implanted; however, the impact of this finding on recipient outcomes remains unclear. We hypothesized that incidentally detected donor PE is associated with adverse short-term and long-term outcomes among lung transplant recipients. Methods We analyzed a prospectively maintained database of all lung donors procured by a single surgeon and transplanted at our institution between 2009 and 2018. A standardized approach was used for all procurements and included antegrade and retrograde flush. Pulmonary embolism was defined as macroscopic thrombus seen in the pulmonary artery during the donor procurement operation. Results A total of 501 consecutive lung procurements were performed during the study period. The incidence of donor PE was 4.4% (22 of 501). No organs were discarded owing to PE. Donors with PE were similar to donors without PE in baseline characteristics and Pa o 2. Recipients in the two groups were also similar. Pulmonary embolism was associated with a higher likelihood of acute cellular rejection grade 2 or more (10 of 22 [45.5%] vs 120 of 479 [25.1%], P = .03). Multivariable Cox modeling demonstrated an association between PE and the development of chronic lung allograft dysfunction (hazard ratio 2.02; 95% confidence interval, 1.23 to 3.30; P = .005). Conclusions Lungs from donors with incidentally detected PE may be associated with a higher incidence of recipient acute cellular rejection as well as reduced chronic lung allograft dysfunction-free survival. Surgeons must use caution when transplanting lungs with incidentally discovered PE. These preliminary findings warrant corroboration in larger data sets.

PURPOSE OF REVIEW: The aim of this study was to provide a critical appraisal of the literature on the effects of the COVID-19 pandemic on organ transplantation, with a specific focus on lung transplantation given the predominant pulmonary involvement of the virus. RECENT FINDINGS: There was a significant decrease in lung transplant volumes during the first wave of the COVID-19 pandemic due to a combination of reduced availability of donors and an imbalance between waitlist additions and inactivations. SARS-CoV-2 infection was subsequently associated with an exuberant immune response that can lead to the development of postinfectious fibrotic lung disease. Few lung transplants have been performed in previously infected recipients and long-term outcomes remain unknown. Although the lung transplant volume rebounded during the second wave, it is unclear what the long-term effects of healthcare resource limitation and public health measures will have on transplant volumes in the future. Outcomes after SARS-CoV-2 infection in previous lung transplant recipients appear to be worse than the general public, and, although an immunosuppressed state likely contributes to these outcomes, whether immunosuppression should be altered in those exposed to or infected with SARS-CoV-2 remains unanswered in the absence of unequivocal data. SUMMARY: The COVID-19 pandemic has presented a number of challenges for lung transplant programs across the globe. Multiple research questions remain to be answered in order to optimally manage lung transplant recipients in the context of this pandemic.

The life-saving benefits of organ transplantation can be thwarted by allograft dysfunction due to both infectious and sterile inflammation post-surgery. Sterile inflammation can occur after necrotic cell death due to the release of endogenous ligands (such as damage associated molecular patterns [DAMPs] and alarmins), which perpetuate inflammation and ongoing cellular injury via various signaling cascades. Ischemia-reperfusion injury (IRI) is a significant contributor to sterile inflammation after organ transplantation and is associated with detrimental short- and long-term outcomes. While the vicious cycle of sterile inflammation and cellular injury is remarkably consistent amongst different organs and even species, we have begun understanding its mechanistic basis only over the last few decades. This understanding has resulted in the developments of novel, yet non-specific therapies for mitigating IRI-induced graft damage, albeit with moderate results. Thus, further understanding of the mechanisms underlying sterile inflammation after transplantation is critical for identifying personalized therapies to prevent or interrupt this vicious cycle and mitigating allograft dysfunction. In this review, we identify common and distinct pathways of post-transplant sterile inflammation across both heart and lung transplantation that can potentially be targeted.

Rationale: Complement is crucial for host defense but may also drive dysregulated inflammation. There is limited understanding of alternative complement function, which can amplify all complement a...

Acute interstitial pneumonia (AIP), also known as Hamman-Rich syndrome, is a rare and rapidly progressive idiopathic interstitial lung disease with a high mortality rate. Treatment is limited to supportive care and empirical high-dose steroids; however, outcomes are generally poor. There are few reports of lung transplantation (LTx) in patients with AIP.We retrospectively identified patients with AIP among those who underwent LTx at our center between January 2008 and December 2020.During the study period, 4 patients with AIP underwent bilateral LTx: 3 men and 1 woman, between 30 and 57 years of age. The lung allocation score ranged between 71 and 89. Of the 4 patients, 2 needed extracorporeal membrane oxygenation and mechanical ventilation (MV) and 1 needed MV preoperatively. Time of onset to transplant ranged from 1 to 3 months. None of the patients had primary graft dysfunction after LTx; 2 had acute cellular rejection and 1 had chronic lung allograft dysfunction. The 4 patients are alive with survival ranging between 1 and 12 years after LTx.AIP should be considered in patients with acute respiratory failure without a clear etiology. Our study showed that LTx led to good outcomes and should be considered as a treatment option in appropriate candidates.

The complement component C3 is a fundamental plasma protein for host defense. However, recent work has demonstrated the critical importance of local C3 expression in cell survival. Here we analyzed the effects of local versus peripheral sources of C3 expression in a model of bacterial pneumonia. While mice with global C3 deficiency had severe pneumonia-induced lung injury, those deficient in liver-deficient C3 remain protected, comparable to wildtype mice.Human lung transcriptome analysis showed secretory epithelial cells are a major source of C3. Mice with a C3 gene ablation from lung epithelial cells had worse pulmonary injury compared to wild type, despite maintaining normal circulating C3 levels. Finally, in human cellular and mouse pneumonia models, we show that C3 reduces epithelial cell death mediated through the alternative pathway component Factor B. Thus, our findings suggest that a locally-derived C3-Factor B pathway protects the lung mucosal barrier.One Sentence SummaryLung-derived C3 mitigates severe bacterial pneumonia suggesting a novel cytoprotective role at mucosal barrier surfaces independent of circulating C3.

With advancements in basic science and clinical medicine, lung transplantation (LT) has evolved rapidly over the last three decades. However, it is unclear if significant regional variations exist in long-term outcomes after LT.To investigate potential differences, we performed a retrospective, comparative cohort analysis of adult patients undergoing deceased donor single or double LT in North America (NA) or Europe between January 2006 and December 2016. Data up to April 2019 were abstracted from the International Society for Heart and Lung Transplantation (ISHLT) Thoracic Organ Registry. We compared overall survival (OS) between North American and European LT centers in a propensity score matched analysis.In 3,115 well-matched pairs, though 30-day survival was similar between groups (NA 96.2% vs Europe 95.4%, p = 0.116), 5-year survival was significantly higher in European patients (NA 60.1% vs Europe 70.3%, p0.001).This survival difference persisted in a sensitivity analysis excluding Canadian patients. Prior observations suggest that these disparities are at least partly related to better access to care via universal healthcare models prevalent in Europe. Future studies are warranted to confirm our findings and explore other causal mechanisms. It is likely that potential solutions will require concerted efforts from healthcare providers and policymakers.

Rationale: Allosensitization may be a barrier to lung transplant. Currently, consideration is not given to allosensitization when assigning priority on the lung transplant waiting list. Objectives: We aimed to examine the association between allosensitization and waiting list outcomes. Methods: We conducted a retrospective single-center cohort study of adults listed for lung transplant at our center between January 1, 2006, and December 31, 2016. We screened candidates for human leukocyte antigen antibodies before listing and examined the association between allosensitization and waiting list outcomes, including likelihood of transplant and death on the waiting list, using a competing risk model. Calculated panel-reactive antibody (CPRA) was used as a continuous measure of allosensitization. Results: Among 746 candidates who were listed for lung transplant during the study period, 263 (35%) were allosensitized, and 483 (65%) were not. In unadjusted analysis, allosensitized candidates had a decreased likelihood of transplant compared with nonallosensitized candidates (subhazard ratio [sHR], 0.71; 95% confidence interval [CI], 0.60–0.83; P

Primary graft dysfunction (PGD) is a major limitation in short- and long-term lung transplant survival. Recent work has shown that mitochondrial damage-associated molecular patterns (mtDAMPs) can promote solid organ injury, but whether they contribute to PGD severity remains unclear. We quantitated circulating plasma mitochondrial DNA (mtDNA) in 62 patients, before lung transplantation and shortly after arrival to the intensive care unit. Although all recipients released mtDNA, high levels were associated with severe PGD development. In a mouse orthotopic lung transplant model of PGD, we detected airway cell-free damaged mitochondria and mtDNA in the peripheral circulation. Pharmacologic inhibition or genetic deletion of formylated peptide receptor 1 (FPR1), a chemotaxis sensor for N-formylated peptides released by damaged mitochondria, inhibited graft injury. An analysis of intragraft neutrophil-trafficking patterns reveals that FPR1 enhances neutrophil transepithelial migration and retention within airways but does not control extravasation. Using donor lungs that express a mitochondria-targeted reporter protein, we also show that FPR1-mediated neutrophil trafficking is coupled with the engulfment of damaged mitochondria, which in turn triggers reactive oxygen species (ROS)-induced pulmonary edema. Therefore, our data demonstrate an association between mtDAMP release and PGD development and suggest that neutrophil trafficking and effector responses to damaged mitochondria are drivers of graft damage.

The complement system has historically been entertained as a fluid-phase, hepatically-derived system, which protects the intravascular space from encapsulated bacteria. However, there has been an increasing appreciation for its role in protection against non-encapsulated pathogens. Specifically, we have an improved understanding of how pathogens are recognized by specific complement proteins, as well as how they trigger and evade them. Additionally, we have an improved understanding of locally-derived complement proteins, many of which promote host defense. Moreover, intracellular complement proteins have been identified that facilitate local protection and barrier function despite pathogen invasion. Our review aims to summarize these advances in the field, as well as provide an insight into the pathophysiological changes occurring when the system is dysregulated in infection.

The decision to perform single lung transplants or double lung transplants is usually made before the operation. We have previously reported that a proportion of single lung transplants were unexpectedly performed in the setting of an aborted double lung transplant, and these patients may be at a higher risk of worse short-term outcomes. Long-term outcomes in unplanned single lung transplants remain unknown.We analyzed a single-center database of lung transplants from 2000 to 2020. Single lung transplants were classified into planned and unplanned groups after reviewing operative notes. Root cause analysis was performed for unplanned single lung transplants.Of the 1326 lung transplants, 1265 (95%) were double lung transplants and 61 (5%) were single lung transplants (22 planned [36%], 39 unplanned [64%]). Underlying indications for transplant were significantly different; planned single lung transplant: chronic obstructive pulmonary disease (55%) and idiopathic pulmonary fibrosis (45%); unplanned single lung transplants: chronic obstructive pulmonary disease (23%), idiopathic pulmonary fibrosis (39%), and bronchiolitis obliterans syndrome (13%). The primary reasons for unplanned single lung transplant were donor-related (3, 7.7%), recipient-related (31, 80%), and donor and recipient-related factors (5, 13%). Unplanned single lung transplants were more likely to require cardiopulmonary bypass during the operation (planned: 4/22, 18% vs unplanned: 20/39, 51%) but had shorter ischemic times (planned: 251 ± 58 minutes vs unplanned: 221 ± 48 minutes). The 5-year overall survival was 53% in the planned and 58% in the unplanned groups, respectively (P = .323). No difference in chronic lung allograft dysfunction-free survival (P = .995) was observed.Unplanned single lung transplants in the setting of aborted double lung transplant may be associated with acceptable long-term outcomes.

Background Studies in lung transplantation have shown variable association between hospital volume and clinical outcomes. We aimed to identify the pattern of effect of hospital volume on individual patient survival after lung transplantation. Methods We performed a retrospective analysis using the United Network for Organ Sharing national thoracic organ transplantation database. Adult patients who underwent lung transplantation between January 2013 and December 2017 were included. The association between mean annual center volume and 1-year overall survival was examined using restricted cubic splines in a random effects multivariable Cox model. The volume threshold for optimal 1-year overall survival was subsequently approximated by the maximum likelihood approach using segmented linear splines in the same model. Results The study included 10,007 patients at 71 transplant centers. Median annual center volume was 22 cases (interquartile range, 10.6 to 38). A center volume threshold was identified at 33 cases per year (95% confidence interval, 28 to 37). Higher center volume, to 33 cases per year, was associated with better 1-year survival (hazard ratio 0.989, 95% confidence interval, 0.980 to 0.999 every additional case). Further increase in center volume above 33 cases per year showed no additional benefit (hazard ratio 1.000, 95% confidence interval, 0.996 to 1.003 every additional case). Twenty-three centers (32.4%) reached the volume threshold of 33 cases per year. Conclusions One-year survival after lung transplantation improved with increasing center volume to as many as 33 cases per year. Low volume centers below the 33 cases per year threshold had large variations in their outcomes and had a higher risk of performing poorly, although many of them maintained good performance.

Complement activation has been implicated in the pathogenesis of severe SARS-CoV-2 infection. However, it remains to be determined whether increased complement activation is a broad indicator of critical illness (and thus, no different in COVID-19). It is also unclear which pathways are contributing to complement activation in COVID-19, and if complement activation is associated with certain features of severe SARS-CoV-2 infection, such as endothelial injury and hypercoagulability. To address these questions, we investigated complement activation in the plasma from patients with COVID-19 prospectively enrolled at two tertiary care centers: Washington University School of Medicine (n=134) and Yale School of Medicine (n=49). We compared our patients to two non-COVID cohorts: (a) patients hospitalized with influenza (n=54), and (b) patients admitted to the intensive care unit (ICU) with acute respiratory failure requiring invasive mechanical ventilation (IMV, n=22). We demonstrate that circulating markers of complement activation are elevated in patients with COVID-19 compared to those with influenza and to patients with non-COVID-19 respiratory failure. Further, the results facilitate distinguishing those who are at higher risk of worse outcomes such as requiring ICU admission, or IMV. Moreover, the results indicate enhanced activation of the alternative complement pathway is most prevalent in patients with severe COVID-19 and is associated with markers of endothelial injury (i.e., angiopoietin-2) as well as hypercoagulability (i.e., thrombomodulin and von Willebrand factor). Our findings identify complement activation to be a distinctive feature of COVID-19, and provide specific targets that may be utilized for risk prognostication, drug discovery and personalized clinical trials., Increased complement activation is observed in COVID-19 compared to non-COVID respiratory illness, and is a key marker of organ failure.

Objectives:. To describe the infectious complications and interleukin-6 trajectories in mechanically ventilated patients with coronavirus disease 2019. Design:. Retrospective cohort study. Setting:. ICUs at Washington University-Barnes Jewish Hospital in St. Louis, MO. Participants:. All consecutive patients admitted to the medical ICU and requiring mechanical ventilation from March 12, 2020, to April 21, 2020, were included. Interventions:. Tocilizumab, an interleukin-6 receptor blocker, was prescribed at the discretion of the treating physicians to patients with a clinical picture compatible with cytokine release syndrome. Measurements:. All the patients were followed to death or hospital discharge. Demographic and laboratory data were collected retrospectively from the electronic medical record. Interleukin-6 levels were measured at days 0, 3, 7, 14, and 21. Infections were divided into culture positive and culture negative (clinically suspected and treated). The main outcomes were infectious complications and interleukin-6 levels at different points in time. Results:. Forty-three patients with respiratory failure secondary to coronavirus disease 2019 were on mechanical ventilation during the study period. Twenty-seven (68%) were male, and 31 (72.1%) were African-American. Median Charlson score was 2 (interquartile range, 0–4). Median Pao2/Fio2 was 171.5 (122–221) on the day of mechanical ventilation initiation, and 13 patients (30.2%) required vasopressors. C-reactive protein was 142.7 (97.7–213.7), d-dimer 1,621 (559–13,434), and Acute Physiology and Chronic Health Evaluation-II 11 (9–15). Interleukin-6 levels at admission were 61 pg/mL (interquartile range, 28.6–439 pg/mL). Patients treated with tocilizumab had higher levels of interleukin-6 at each measurement (days 0, 3, 7, 14, and 21) compared with patients receiving standard of care. Both groups reached peak interleukin-6 levels at day 7. Administration of tocilizumab was associated with a trend toward increased risk of infection. Conclusions:. Interleukin-6 levels peak at day 7 in patients with severe coronavirus disease 2019 pneumonia requiring mechanical ventilation and follows a similar trajectory in patients with coronavirus disease 2019 pneumonia requiring mechanical ventilation irrespective of treatment with interleukin-6R blockers. Interleukin-6 levels continued to rise in nonsurvivors, in comparison with survivors, where the rise in interleukin-6 levels was followed by a decline.

Drug overdoses have tripled in the United States over the last two decades. With the increasing demand for donor organs, one potential consequence of the opioid epidemic may be an increase in suitable donor organs. Unfortunately, organs from donors dying of drug overdose have poorer utilization rates than other groups of brain-dead donors, largely due to physician and recipient concerns about viral disease transmission. During the study period of 2011 to 2016, drug overdose donors (DODs) account for an increasingly greater proportion of the national donor pool. We show that a novel model of donor care, known as specialized donor care facility (SDCF), is associated with an increase in organ utilization from DODs compared to the conventional model of hospital-based donor care. This is likely related to the close relationship of the SDCF with the transplant centers, leading to improved communication and highly efficient donor care.

Coronavirus disease 2019 (COVID-19), the disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has resulted in a global pandemic and a disruptive health crisis. COVID-19–related morbidity and mortality have been attributed to an exaggerated immune response. The role of complement activation and its contribution to illness severity is being increasingly recognized. Here, we summarize current knowledge about the interaction of coronaviruses with the complement system. We posit that (a) coronaviruses activate multiple complement pathways; (b) severe COVID-19 clinical features often resemble complementopathies; (c) the combined effects of complement activation, dysregulated neutrophilia, endothelial injury, and hypercoagulability appear to be intertwined to drive the severe features of COVID-19; (d) a subset of patients with COVID-19 may have a genetic predisposition associated with complement dysregulation; and (e) these observations create a basis for clinical trials of complement inhibitors in life-threatening illness.

The purpose of this study was to recognize clinically meaningful differences in lung transplant outcomes based on local or distant lung procurement. This could identify if the lung allocation policy change would influence patient outcomes.This single-center retrospective cohort study analyzed adult patients who underwent lung transplant from 2006 to 2017. Donor and recipient data were abstracted from a collaborative, prospective registry shared by our local organ procurement organization, and tertiary medical center. Short-term outcomes, 1-year survival, and hospitalization costs were compared between local and distant lung transplants defined by donor service area.Of the 722 lung transplants performed, 392 (54%) had local donors and 330 (46%) had distant donors. Donors were similar in age and cause of death. Recipients were significantly different in diagnosis and local recipients had lower median lung allocation scores (local, 37.3 and distant, 44.9; P .01). Distant lung transplants had longer total ischemic times (local, 231 ± 52 minutes and distant, 313 ± 48 minutes; P .01). The rate of major complications, length of hospital stay, and 1-year survival were similar between groups. Distant lung transplants were associated with higher median overall cost (local, $183,542 and distant, $229,871; P .01). Local lung transplants were more likely to be performed during daytime (local, 333 out of 392 [85%] and distant, 291 out of 330 [61%]; P .01).Local lung transplants are associated with shorter ischemic times, lower cost, and greater likelihood of daytime surgery. Short- and intermediate-term outcomes are similar for lung transplants from local and distant donors. The new lung allocation policy, with higher proportion of distant lung transplants, is likely to incur greater costs but provide similar outcomes.

A key component of both innate and adaptive immunity, new understandings of the complement system are expanding its roles beyond that traditionally appreciated. Evidence is accumulating that complement has an intracellular arsenal of components that provide not only immune defense, but also assist in key interactions for host cell functions. Although early work has primarily centered on T cells, the intracellular complement system likely functions in many if not most cells of the body. Some of these functions may trace their origins to the primitive complement system that began as a primeval form of C3 likely tasked for protection from intracellular pathogen invasion. This later expanded to include extracellular defense as C3 became a secreted protein to patrol the vasculature. Other components were added to the growing system including regulators to protect host cells from the indiscriminate effects of this potent system. Contemporary cells may retain some of these vestigial remnants. We now know that a) C3 serves as a damage-associated molecular pattern (in particular by coating pathogens that translocate into cells), b) most cells store C3 and recycle C3(H2O) for immediate use, and c) C3 assists in cellular survival and metabolic reprogramming. Other components also are part of this hidden arsenal including C5, properdin, factors H and B, and complement receptors. Importantly, better definition of the intracellular complement system may translate into new target discovery to assist in creating the next generation of complement therapeutics.

An intracellular complement system (ICS) has recently been described in immune and nonimmune human cells. This system can be activated in a convertase-independent manner from intracellular stores of the complement component C3. The source of these stores has not been rigorously investigated. In the present study, Western blotting identified a band corresponding to C3 in freshly isolated human peripheral blood cells that was absent in corresponding cell lines. One difference between native cells and cell lines was the time absent from a fluid-phase complement source; therefore, we hypothesized that loading C3 from plasma was a route of establishing intracellular C3 stores. We found that many types of human cells specifically internalized C3(H2O), the hydrolytic product of C3, and not native C3, from the extracellular milieu. Uptake was rapid, saturable, and sensitive to competition with unlabeled C3(H2O), indicating a specific mechanism of loading. Under steady-state conditions, approximately 80% of incorporated C3(H2O) was returned to the extracellular space. These studies identify an ICS recycling pathway for C3(H2O). The loaded C3(H2O) represents a source of C3a, and its uptake altered the cytokine profile of activated CD4+ T cells. Importantly, these results indicate that the impact of soluble plasma factors should be considered when performing in vitro studies assessing cellular immune function.

Factors contributing to donor-specific HLA antibody (DSA) development after lung transplantation have not been systematically evaluated. We hypothesized that the isolation of Pseudomonas aeruginosa in respiratory specimens would increase the risk of DSA development. Our objective was to determine the risk of DSA development associated with the isolation of Pseudomonas aeruginosa after lung transplantation. We conducted a single-center retrospective cohort study of primary lung transplant recipients and examined risk factors for DSA development using Cox regression models. Of 460 recipients, 205 (45%) developed DSA; the majority developed Class II DSA (n = 175, 85%), and 145 of 205 (71%) developed DSA to HLA-DQ alleles. Univariate time-dependent analyses revealed that isolation of Pseudomonas from respiratory specimens, acute cellular rejection, and lymphocytic bronchiolitis are associated with an increased risk of DSA development. In multivariable analyses, Pseudomonas isolation, acute cellular rejection, and lymphocytic bronchiolitis remained independent risk factors for DSA development. Additionally, there was a direct association between the number of positive Pseudomonas cultures and the risk of DSA development. Our findings suggest that pro-inflammatory events including acute cellular rejection, lymphocytic bronchiolitis, and Pseudomonas isolation after transplantation are associated with an increased risk of DSA development.

Background Previous studies in the field of organ transplantation have shown a possible association between nighttime surgery and adverse outcomes. We aim to determine the impact of nighttime lung transplantation on postoperative outcomes, long-term survival, and overall cost. Methods We performed a single-center retrospective cohort analysis of adult lung transplant recipients who underwent transplantation between January 2006 and December 2017. Data were extracted from our institutional Lung Transplant Registry and Mid-America Transplant services database. Patients were classified into 2 strata, daytime (5 AM to 6 PM) and nighttime (6 PM to 5 AM), based on time of incision. Major postoperative adverse events, 5-year overall survival, and 5-year bronchiolitis obliterans syndrome–free survival were examined after propensity score matching. Additionally we compared overall cost of transplantation between nighttime and daytime groups. Results Of the 740 patients included in this study, 549 (74.2%) underwent daytime transplantation and 191 (25.8%) underwent nighttime transplantation (NT). Propensity score matching yielded 187 matched pairs. NT was associated with a higher risk of having any major postoperative adverse event (adjusted odds ratio, 1.731; 95% confidence interval, 1.093-2.741; P = .019), decreased 5-year overall survival (adjusted hazard ratio, 1.798; 95% confidence interval, 1.079-2.995; P = .024), and decreased 5-year bronchiolitis obliterans syndrome–free survival (adjusted hazard ratio, 1.556; 95% confidence interval, 1.098-2.205; P = .013) in doubly robust multivariable analyses after propensity score matching. Overall cost for NT and daytime transplantation was similar. Conclusions NT was associated with a higher risk of major postoperative adverse events, decreased 5-year overall survival, and decreased 5-year bronchiolitis obliterans syndrome–free survival. Our findings suggest potential benefits of delaying NT to daytime transplantation.

BACKGROUND Chronic lung allograft dysfunction (CLAD) is the leading cause of death beyond the first year after lung transplantation. Several treatments have been used to prevent the progression or reverse the effects of CLAD. Cytolytic therapy with rabbit antithymocyte globulin (rATG) has previously shown to be a potential option. However, the effect on patients with restrictive allograft syndrome (RAS) versus bronchiolitis obliterans syndrome (BOS) and the effect of cumulative dosing are unknown. METHODS The charts of lung transplant patients treated with rATG at Barnes-Jewish Hospital from 2009 to 2016 were retrospectively reviewed. The primary outcome was response to rATG; patients were deemed responders if their FEV1 improved in the 6 months after rATG treatment. Safety endpoints included incidence of serum sickness, cytokine release syndrome, malignancy, and infectious complications. RESULTS 108 patients were included in this study; 43 (40%) patients were responders who experienced an increase in FEV1 after rATG therapy. No predictors of response to rATG therapy were identified. Serum sickness occurred in 22% of patients, 15% experienced cytokine release syndrome, and 19% developed an infection after therapy. CONCLUSION 40% of patients with CLAD have an improvement in lung function after treatment with rATG although the improvement was typically minimal.

Despite the increasing numbers of heart and lung transplants within the United States and worldwide and an increased awareness regarding organ donation, there remains a global shortage of donor organs. As a result, the waitlist mortality rate for lung transplantation is approximately 15.3% for all diagnoses in the United States despite introduction of the lung allocation score (1,2), and is higher among those patients listed in areas of low local lung availability (3).

Single-nucleotide polymorphisms (SNPs) in genes involved in mycophenolic acid (MPA) metabolism have been shown to contribute to variable MPA exposure, but their clinical effects are unclear. We aimed to determine if SNPs in key genes in MPA metabolism affect outcomes after lung transplantation. We performed a retrospective cohort study of 275 lung transplant recipients, 228 receiving mycophenolic acid and a control group of 47 receiving azathioprine. Six SNPs known to regulate MPA exposure from the SLCO, UGT and MRP2 families were genotyped. Primary outcome was 1-year survival. Secondary outcomes were 3-year survival, nonminimal (≥A2 or B2) acute rejection, and chronic lung allograft dysfunction (CLAD). Statistical analyses included time-to-event Kaplan–Meier with log-rank test and Cox regression modeling. We found that SLCO1B3 SNPs rs4149117 and rs7311358 were associated with decreased 1-year survival [rs7311358 HR 7.76 (1.37–44.04), p = 0.021; rs4149117 HR 7.28 (1.27–41.78), p = 0.026], increased risk for nonminimal acute rejection [rs4149117 TT334/T334G: OR 2.01 (1.06–3.81), p = 0.031; rs7311358 GG699/G699A: OR 2.18 (1.13–4.21) p = 0.019] and lower survival through 3 years for MPA patients but not for azathioprine patients. MPA carriers of either SLCO1B3 SNP had shorter survival after CLAD diagnosis (rs4149117 p = 0.048, rs7311358 p = 0.023). For the MPA patients, Cox regression modeling demonstrated that both SNPs remained independent risk factors for death. We conclude that hypofunctional SNPs in the SLCO1B3 gene are associated with an increased risk for acute rejection and allograft failure in lung transplant recipients treated with MPA.

Pattern recognition receptors (PRRs) are germline-encoded sensors best characterized for their critical role in host defense. However, there is accumulating evidence that organ transplantation induces the release or display of molecular patterns of cellular injury and death that trigger PRR-mediated inflammatory responses. There are also new insights that indicate PRRs are able to distinguish between self and non-self, suggesting the existence of non-clonal mechanisms of allorecognition. Collectively, these reports have spurred considerable interest into whether PRRs or their ligands can be targeted to promote transplant survival. This review examines the mounting evidence that PRRs play in transplant-mediated inflammation. Given the large number of PRRs, we will focus on members from four families: the complement system, toll-like receptors, the formylated peptide receptor, and scavenger receptors through examining reports of their activity in experimental models of cellular and solid organ transplantation as well as in the clinical setting.

The complement system is a key player in innate immunity and a major effector arm of humoral immunity. Its activating components are a group of plasma proteins, whose triggering consists of a series of sequential protease-based steps similar to the coagulation, fibrinolytic, and contact pathways. Complement activation is linked to cellular responses by the recognition of cleaved complement protein fragments by receptors on leukocytes and vascular cells. The three primary roles of complement in host defense against infection are to (1) activate an inflammatory response; (2) opsonize microbial pathogens for immune adherence; and (3) damage membranes, including lysis of susceptible organisms. The complement cascade is amplified at several steps so that it has the potential to induce a rapid and massive opsonic and inflammatory response. Complement activation is normally highly targeted and strictly regulated to focus this response. However, complement activation also contributes to tissue injury in infectious, autoimmune, and acute and chronic inflammatory diseases. This chapter gives an overview of the “workings” of the complement system, a brief review of complement deficiency, and discussion of the role of complement in diseases of inflammation, autoimmunity, and debris disposal.

Purpose Antibody mediated rejection (AMR) has become an increasingly recognized form of lung transplant rejection. Our group recently identified Pseudomonas aeruginosa infection as a risk factor for clinical AMR but whether infection is sufficient for donor specific antibody (DSA) production and AMR remains unknown. Here we ask in a mouse model of orthotopic lung allograft transplantation whether airway infection with P. aeruginosa promotes DSA generation and AMR. Methods Balb/c lungs were transplanted into the following recipients: B6 WT (wildtype), uMT KO (No B cells), AID/uS KO (Have B cells but are unable to secrete Ig), CD19 Cre , CD19 Cre x TLR4fl/fl and CD19 Cre x MyD88fl/fl. Lung recipients were immunosuppressed with costimulatory blockade on post-operative day (POD) 0 (CD40L Ab) and POD 2 (CTLA4Ig) to induce allograft acceptance. On POD 21 recipients received intratracheal saline or 2 x 105 pfu/g body weight of live P. aeruginosa (clinical isolate M57-15) and then treated with ciprofloxacin from POD 22 to 25. On POD 42 peripheral blood was assessed for DSA and graft tissue evaluated for C4d deposition or quantitated for plasma cells (PC) by flow cytometric analysis (FACS). Results P. Aeruginosa infection stimulated high amounts of DSA generation and marked C4d deposition. In contrast, C4d deposition was nearly absent in uMT and AID/uS KO recipients. Infected recipients with TLR4 or MyD88 targeted-deficiency in B cells had sharply lower DSA when compared to WT controls. P. aeruginosa infection drove a 4-fold expansion of allograft resident PCs that was largely dependent on maintaining B cell TLR4-MyD88 signaling. In contrast, the spleen and bone marrow had only modest changes in PC abundance despite infection. Surprisingly, re-transplantation of P. aeruginosa-infected lung allografts into secondary uMT KO recipients revealed that lung allograft-resident PCs are capable of producing large amounts of DSA. Conclusion Collectively, these data show that P. aeruginosa infection abrogates established lung transplant tolerance through engaging innate immune signaling pathways within the B cell compartment. Additionally, we make the novel observation that the lung is a suitable environment for PC development with implications for clinical AMR.

Purpose It is unclear whether mechanical ventilator settings impact the risk of primary graft dysfunction (PGD) after lung transplantation. Importantly, ventilator settings are typically based on recipient rather than donor weight and height. In this study, we examined the relationship between lung protective ventilation based on donor size and PGD. Methods We analyzed 373 adult bilateral lung transplant recipients at our center between 1/2010 and 1/2017. We collected recipient, donor, and ventilator data after transplantation. We defined PGD as PGD 3 between 24 and 72 hours after transplantation and lung protective ventilation as a maximum tidal volume Results In univariate analysis, maximum tidal volume expressed as ml/kg of donor ideal body weight was associated with a significantly increased risk of PGD 3, (OR=1.42; 95%CI = 1.12-1.72, p>0.001). Similarly, lack of lung protective ventilation was associated with a significantly increased risk of PGD 3 (OR=5.56; 95%CI = 1.89-16.34, p=0.002). PGD risk factors that were significant in the univariate analysis were included in the multivariate analysis. In multivariate analysis, maximum tidal volume remained an independent predictor of PGD 3. Similarly, lack of lung protective ventilation remained an independent predictor of PGD 3. Conclusion Higher tidal volumes and not receiving lung protective ventilation were associated with an increased risk of PGD 3 between 24 and 72 hours. This suggests that adjusting ventilator settings based on donor size and lung protective ventilation after transplantation may mitigate the risk of PGD.

BACKGROUND: Lung transplant (LTx) recipients have low long-term survival and a high incidence of bronchiolitis obliterans syndrome (BOS). However, few long-term, multicenter, and precise estimates of BOS-free survival (a composite outcome of death or BOS) incidence exist. METHODS: This retrospective cohort study of primary LTx recipients (1994–2011) reported to the International Society of Heart and Lung Transplantation Thoracic Transplant Registry assessed outcomes through 2012. For the composite primary outcome of BOS-free survival, we used Kaplan-Meier survival and Cox proportional hazards regression, censoring for loss to follow-up, end of study, and re-LTx. Although standard Thoracic Transplant Registry analyses censor at the last consecutive annual complete BOS status report, our analyses allowed for partially missing BOS data. RESULTS: Due to BOS reporting standards, 99.1% of the cohort received LTx in North America. During 79,896 person-years of follow-up, single LTx (6,599 of 15,268 [43%]) and bilateral LTx (8,699 of 15,268 [57%]) recipients had a median BOS-free survival of 3.16 years (95% confidence interval [CI], 2.99–3.30 years) and 3.58 years (95% CI, 3.53–3.72 years), respectively. Almost 90% of the single and bilateral LTx recipients developed the composite outcome within 10 years of transplantation. Standard Registry analyses “overestimated” median BOS-free survival by 0.42 years and “underestimated” the median survival after BOS by about a half-year for both single and bilateral LTx (p < 0.05). CONCLUSIONS: Most LTx recipients die or develop BOS within 4 years, and very few remain alive and free from BOS at 10 years post-LTx. Less inclusive Thoracic Transplant Registry analytic methods tend to overestimate BOS-free survival. The Registry would benefit from improved international reporting of BOS and other chronic lung allograft dysfunction (CLAD) events.