Browsing by Subject "Lung Transplantation"
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Item Open Access A novel injury site-natural antibody targeted complement inhibitor protects against lung transplant injury.(American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons, 2021-06) Li, Changhai; Patel, Kunal; Tu, Zhenxiao; Yang, Xiaofeng; Kulik, Liudmila; Alawieh, Ali; Allen, Patterson; Cheng, Qi; Wallace, Caroline; Kilkenny, Jane; Kwon, Jennie; Gibney, Barry; Cantu, Edward; Sharma, Ashish; Pipkin, Mauricio; Machuca, Tiago; Emtiazjoo, Amir; Goddard, Martin; Holers, V Michael; Nadig, Satish; Christie, Jason; Tomlinson, Stephen; Atkinson, CarlComplement is known to play a role in ischemia and reperfusion injury (IRI). A general paradigm is that complement is activated by self-reactive natural IgM antibodies (nAbs), after they engage postischemic neoepitopes. However, a role for nAbs in lung transplantation (LTx) has not been explored. Using mouse models of LTx, we investigated the role of two postischemic neoepitopes, modified annexin IV (B4) and a subset of phospholipids (C2), in LTx. Antibody deficient Rag1-/- recipient mice were protected from LTx IRI. Reconstitution with either B4 or C2nAb restored IRI, with C2 significantly more effective than B4 nAb. Based on these information, we developed/characterized a novel complement inhibitor composed of single-chain antibody (scFv) derived from the C2 nAb linked to Crry (C2scFv-Crry), a murine inhibitor of C3 activation. Using an allogeneic LTx, in which recipients contain a full nAb repertoire, C2scFv-Crry targeted to the LTx, inhibited IRI, and delayed acute rejection. Finally, we demonstrate the expression of the C2 neoepitope in human donor lungs, highlighting the translational potential of this approach.Item Open Access Development of New Donor-Specific and Human Leukocyte Antigen Antibodies After Transfusion in Adult Lung Transplantation.(Journal of cardiothoracic and vascular anesthesia, 2023-09) Stoker, Alexander; Hicks, Anne; Wright, Mary Cooter; Ali, Azfar; Klapper, Jacob; Poisson, Jessica; Zaffiri, Lorenzo; Chen, Dongfeng; Hartwig, Matthew; Ghadimi, Kamrouz; Welsby, Ian; Bottiger, BrandiObjectives
The development of new human leukocyte antigens (HLAs) and donor-specific antibodies (DSAs) in patients are associated with worse outcomes following lung transplantation. The authors aimed to examine the relationship between blood product transfusion in the first 72 hours after lung transplantation and the development of HLA antibodies, including DSAs.Design
A retrospective observational study.Setting
At a single academic tertiary center.Participants
Adult lung transplant recipients who underwent transplantation between September 2014 and June 2019.Interventions
None.Measurements and main results
A total of 380 patients were included in this study, and 87 (23%) developed de novo donor-specific antibodies in the first year after transplantation. Eighty-five patients (22%) developed new HLA antibodies that were not donor-specific, and 208 patients (55%) did not develop new HLA antibodies in the first year after transplantation. Factors associated with increased HLA and DSA development included donor pulmonary infection, non-infectious indication for transplant, increased recipient body mass index, and a preoperative calculated panel reactive antibody value above 0. Multivariate analysis identified platelet transfusion associated with an increased risk of de novo HLA antibody development compared to the negative group (odds ratio [OR; 95% CI] 1.18 [1.02-1.36]; p = 0.025). Cryoprecipitate transfusion was associated with de novo DSA development compared to the negative group (OR [95% CI] 2.21 [1.32-3.69] for 1 v 0 units; p = 0.002).Conclusions
Increased perioperative transfusion of platelets and cryoprecipitate are associated with de novo HLA and DSA development, respectively, in lung transplant recipients during the first year after transplantation.Item Open Access Donor pretreatment with nebulized complement C3a receptor antagonist mitigates brain-death induced immunological injury post-lung transplant.(American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons, 2018-10) Cheng, Qi; Patel, Kunal; Lei, Biao; Rucker, Lindsay; Allen, D Patterson; Zhu, Peng; Vasu, Chentha; Martins, Paulo N; Goddard, Martin; Nadig, Satish N; Atkinson, CarlDonor brain death (BD) is an inherent part of lung transplantation (LTx) and a key contributor to ischemia-reperfusion injury (IRI). Complement activation occurs as a consequence of BD in other solid organ Tx and exacerbates IRI, but the role of complement in LTx has not been investigated. Here, we investigate the utility of delivering nebulized C3a receptor antagonist (C3aRA) pretransplant to BD donor lungs in order to reduce post-LTx IRI. BD was induced in Balb/c donors, and lungs nebulized with C3aRA or vehicle 30 minutes prior to lung procurement. Lungs were then cold stored for 18 hours before transplantation into C57Bl/6 recipients. Donor lungs from living donors (LD) were removed and similarly stored. At 6 hours and 5 days post-LTx, recipients of BD donor lungs had exacerbated IRI and acute rejection (AR), respectively, compared to recipients receiving LD lungs, as determined by increased histopathological injury, immune cells, and cytokine levels. A single pretransplant nebulized dose of C3aRA to the donor significantly reduced IRI as compared to vehicle-treated BD donors, and returned IRI and AR grades to that seen following LD LTx. These data demonstrate a role for complement inhibition in the amelioration of IRI post-LTx in the context of donor BD.Item Open Access Emphysema-associated Autoreactive Antibodies Exacerbate Post-Lung Transplant Ischemia-Reperfusion Injury.(American journal of respiratory cell and molecular biology, 2019-06) Patel, Kunal J; Cheng, Qi; Stephenson, Sarah; Allen, D Patterson; Li, Changhai; Kilkenny, Jane; Finnegan, Ryan; Montalvo-Calero, Valeria; Esckilsen, Scott; Vasu, Chentha; Goddard, Martin; Nadig, Satish N; Atkinson, CarlChronic obstructive pulmonary disease-associated chronic inflammation has been shown to lead to an autoimmune phenotype characterized in part by the presence of lung autoreactive antibodies. We hypothesized that ischemia-reperfusion injury (IRI) liberates epitopes that would facilitate preexisting autoantibody binding, thereby exacerbating lung injury after transplant. We induced emphysema in C57BL/6 mice through 6 months of cigarette smoke (CS) exposure. Mice with CS exposure had significantly elevated serum autoantibodies compared with non-smoke-exposed age-matched (NS) mice. To determine the impact of a full preexisting autoantibody repertoire on IRI, we transplanted BALB/c donor lungs into NS or CS recipients and analyzed grafts 48 hours after transplant. CS recipients had significantly increased lung injury and immune cell infiltration after transplant. Immunofluorescence staining revealed increased IgM, IgG, and C3d deposition in CS recipients. To exclude confounding alloreactivity and confirm the role of preexisting autoantibodies in IRI, syngeneic Rag1-/- (recombination-activating protein 1-knockout) transplants were performed in which recipients were reconstituted with pooled serum from CS or NS mice. Serum from CS-exposed mice significantly increased IRI compared with control mice, with trends in antibody and C3d deposition similar to those seen in allografts. These data demonstrate that pretransplant CS exposure is associated with increased IgM/IgG autoantibodies, which, upon transplant, bind to the donor lung, activate complement, and exacerbate post-transplant IRI.Item Embargo Evaluating Humoral Immune Responses Against HLA and Cytomegalovirus in Human Lung Transplantation(2024) Harnois, MelissaIn the past 30 years, the global prevalence of chronic respiratory diseases has increased by 40%. Importantly, lung transplantation remains the only definitive treatment for patients with advanced lung disease. Despite the rapidly growing need for lung transplantation, lung transplant recipients have by far the worst survival rates among all solid organ transplant types, with a current median survival of only 6 years post transplantation. Chronic lung allograft dysfunction (CLAD) is the leading cause of limited long-term survival of lung transplant recipients, affecting approximately 50% of patients within 5 years post-transplantation. Previous studies have identified humoral alloimmune responses against mismatched donor HLA and cytomegalovirus (CMV) infection as primary independent risk factors for chronic deterioration of the transplanted allograft and the fatal diagnosis of CLAD. This dissertation is comprised of work that aims to address critical gaps in knowledge in the fields of transplant immunology and infectious disease. The first component focuses on CMV-specific humoral immunity in naturally infected healthy blood donors (Chapter 2) and in CMV seropositive lung transplant recipients (Chapter 3). The second area of study focuses on humoral alloimmune responses and current methods used to evaluate and characterize donor HLA-specific alloantibodies (Chapter 4), as well as factors contributing to HLA-DQ immunogenicity (Chapter 5). These projects utilized clinical data and longitudinally collected human plasma samples from the completed multicenter Clinical Trials in Organ Transplantation (CTOT)-20 and CTOT-22 consortium studies. The findings from Chapter 2 contribute to our knowledge of naturally acquired immunity against CMV, which informs strategies for antibody-based therapeutics to help treat CMV infection as well as CMV vaccine development. The results from Chapter 3 indicate that CMV-specific antibodies have the potential to be used as novel biomarkers for viremia risk, possibly in combination with other known risk factors for viremia including CMV-specific T cell responses. These tools may help inform antiviral treatment duration in clinical practice. Chapter 4 of this dissertation represents the first in-depth technical comparison across traditional and modified single antigen bead Luminex assays using IgG enriched sera for donor-HLA specific post-transplant monitoring. These findings may be useful for clinical workflows to help improve efficiency and cost by stratifying patient samples that may benefit from additional testing in modified assays. Finally, Chapter 5 of this dissertation examines the specificity and timing of donor HLA-specific antibodies (DSA), as well as other risk factors for DSA development. In this project, we detail novel strategies for calculating HLA-DQ mismatch by accounting for trans-encoded DQ heterodimer formation. The results from this study also reveal elevated risk for developing DSA among patients with high-risk epitope mismatches and suggest that different organs may require different HLA mismatch calculation strategies. Overall, the results from these projects advance our understanding of the human immune response to alloantigens and cytomegalovirus in lung transplantation and push the field forward to help improve patient outcomes.
Item Open Access Frailty in the End-Stage Lung Disease or Heart Failure Patient: Implications for the Perioperative Transplant Clinician.(Journal of cardiothoracic and vascular anesthesia, 2019-05) Bottiger, Brandi A; Nicoara, Alina; Snyder, Laurie D; Wischmeyer, Paul E; Schroder, Jacob N; Patel, Chetan B; Daneshmand, Mani A; Sladen, Robert N; Ghadimi, KamrouzThe syndrome of frailty for patients undergoing heart or lung transplantation has been a recent focus for perioperative clinicians because of its association with postoperative complications and poor outcomes. Patients with end-stage cardiac or pulmonary failure may be under consideration for heart or lung transplantation along with bridging therapies such as ventricular assist device implantation or venovenous extracorporeal membrane oxygenation, respectively. Early identification of frail patients in an attempt to modify the risk of postoperative morbidity and mortality has become an important area of study over the last decade. Many quantification tools and risk prediction models for frailty have been developed but have not been evaluated extensively or standardized in the cardiothoracic transplant candidate population. Heightened awareness of frailty, coupled with a better understanding of distinct cellular mechanisms and biomarkers apart from end-stage organ disease, may play an important role in potentially reversing frailty related to organ failure. Furthermore, the clinical management of these critically ill patients may be enhanced by waitlist and postoperative physical rehabilitation and nutritional optimization.Item Open Access Gastroesophageal reflux symptoms are not sufficient to guide esophageal function testing in lung transplant candidates.(Diseases of the esophagus : official journal of the International Society for Diseases of the Esophagus, 2018-05) Posner, S; Zheng, J; Wood, RK; Shimpi, RA; Hartwig, MG; Chow, S-C; Leiman, DAGastroesophageal reflux disease and esophageal dysmotility are prevalent in patients with advanced lung disease and are associated with graft dysfunction following lung transplantation. As a result, many transplant centers perform esophageal function testing as part of the wait-listing process but guidelines for testing in this population are lacking. The aim of this study is to describe whether symptoms of gastroesophageal reflux correlate with abnormal results on pH-metry and high-resolution manometry and can be used to identify those who require testing. We performed a retrospective cohort study of 226 lung transplant candidates referred for high-resolution manometry and pH-metry over a 12-month period in 2015. Demographic data, results of a standard symptom questionnaire and details of esophageal function testing were obtained. Associations between the presence of symptoms and test results were analyzed using Fisher's exact tests and multivariable logistic regression. The most common lung disease diagnosis was interstitial lung disease (N = 131, 58%). Abnormal pH-metry was seen in 116 (51%) patients and the presence of symptoms was significantly associated with an abnormal study (p < 0.01). Dysmotility was found in 98 (43%) patients, with major peristaltic or esophageal outflow disorders in 45 (20%) patients. Symptoms were not correlated with findings on esophageal high-resolution manometry. Fifteen of 25 (60%) asymptomatic patients had an abnormal manometry or pH-metry. These results demonstrate that in patients with advanced lung disease, symptoms of gastroesophageal reflux increase the likelihood of elevated acid exposure on pH-metry but were not associated with dysmotility. Given the proportion of asymptomatic patients with abnormal studies and associated post-transplant risks, a practice of universal high-resolution manometry and pH-metry testing in this population is justifiable.Item Open Access Human Leukocyte Antigen Sensitization in Solid Organ Transplantation: A Primer on Terminology, Testing, and Clinical Significance for the Apheresis Practitioner.(Therapeutic apheresis and dialysis : official peer-reviewed journal of the International Society for Apheresis, the Japanese Society for Apheresis, the Japanese Society for Dialysis Therapy, 2017-10) Abbes, Sarah; Metjian, Ara; Gray, Alice; Martinu, Tereza; Snyder, Laurie; Chen, Dong-Feng; Ellis, Matthew; Arepally, Gowthami M; Onwuemene, OluwatoyosiThe human leukocyte antigen (HLA) system is an important immunologic barrier that must be considered for successful solid organ transplantation. Formation of donor-specific HLA antibodies in solid organ transplantation is an important cause of allograft injury and may contribute to recipient morbidity and mortality. Therapeutic plasma exchange is often requested to lower HLA antibody levels prior to or after transplantation and for management of HLA antibodies in the context of organ rejection. In this review, we summarize the current terminology, laboratory testing, and clinical significance of HLA sensitization in the solid organ transplant population. Furthermore, to illustrate applications of HLA testing in clinical practice, we summarize our own lung and kidney institutional protocols for managing HLA antibodies in the peri-transplant setting.Item Open Access Inhaled Pulmonary Vasodilator Therapy in Adult Lung Transplant: A Randomized Clinical Trial.(JAMA surgery, 2022-01) Ghadimi, Kamrouz; Cappiello, Jhaymie; Cooter-Wright, Mary; Haney, John C; Reynolds, John M; Bottiger, Brandi A; Klapper, Jacob A; Levy, Jerrold H; Hartwig, Matthew G; INSPIRE-FLO InvestigatorsImportance
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.Item Open Access Lung Transplantation and the Era of the Sensitized Patient.(Frontiers in immunology, 2021-01) Young, Katherine A; Ali, Hakim A; Beermann, Kristi J; Reynolds, John M; Snyder, Laurie DLong term outcomes in lung transplant are limited by the development of chronic lung allograft dysfunction (CLAD). Within the past several decades, antibody-mediated rejection (AMR) has been recognized as a risk factor for CLAD. The presence of HLA antibodies in lung transplant candidates, "sensitized patients" may predispose patients to AMR, CLAD, and higher mortality after transplant. This review will discuss issues surrounding the sensitized patient, including mechanisms of sensitization, implications within lung transplant, and management strategies.Item Open Access Prevalence and Etiology of Community-acquired Pneumonia in Immunocompromised Patients.(Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2019-04) Di Pasquale, Marta Francesca; Sotgiu, Giovanni; Gramegna, Andrea; Gramegna, Andrea; Radovanovic, Dejan; Terraneo, Silvia; Reyes, Luis F; Rupp, Jan; González Del Castillo, Juan; Blasi, Francesco; Aliberti, Stefano; Restrepo, Marcos I; GLIMP InvestigatorsBackground
The correct management of immunocompromised patients with pneumonia is debated. We evaluated the prevalence, risk factors, and characteristics of immunocompromised patients coming from the community with pneumonia.Methods
We conducted a secondary analysis of an international, multicenter study enrolling adult patients coming from the community with pneumonia and hospitalized in 222 hospitals in 54 countries worldwide. Risk factors for immunocompromise included AIDS, aplastic anemia, asplenia, hematological cancer, chemotherapy, neutropenia, biological drug use, lung transplantation, chronic steroid use, and solid tumor.Results
At least 1 risk factor for immunocompromise was recorded in 18% of the 3702 patients enrolled. The prevalences of risk factors significantly differed across continents and countries, with chronic steroid use (45%), hematological cancer (25%), and chemotherapy (22%) the most common. Among immunocompromised patients, community-acquired pneumonia (CAP) pathogens were the most frequently identified, and prevalences did not differ from those in immunocompetent patients. Risk factors for immunocompromise were independently associated with neither Pseudomonas aeruginosa nor non-community-acquired bacteria. Specific risk factors were independently associated with fungal infections (odds ratio for AIDS and hematological cancer, 15.10 and 4.65, respectively; both P = .001), mycobacterial infections (AIDS; P = .006), and viral infections other than influenza (hematological cancer, 5.49; P < .001).Conclusions
Our findings could be considered by clinicians in prescribing empiric antibiotic therapy for CAP in immunocompromised patients. Patients with AIDS and hematological cancer admitted with CAP may have higher prevalences of fungi, mycobacteria, and noninfluenza viruses.Item Open Access Pulmonary dysfunction after lung transplantation: the dilemma of coexisting mitral regurgitation.(J Cardiothorac Vasc Anesth, 2014-12) McCartney, Sharon L; Colin, Brian J; Duane Davis, R; Del Rio, J Mauricio; Swaminathan, MadhavA case of MR progression after single-lung transplant as a significant contributor to postoperative respiratory failure is reported. Pre-existing MR may progress due to the decompressive effects of lung transplantation on RV dimension and consequent alteration of MV geometry. This case highlights the importance of intraoperative TEE findings, especially pertaining to valvulopathies in the setting of lung transplantation. Postoperative surveillance of significant findings is imperative when any new symptoms are being investigated.Item Open Access Two Cases of Late Shone Syndrome With Pulmonary Hypertension: Heart-Lung Transplant or Valve Surgery?(World J Pediatr Congenit Heart Surg, 2016-01) Robich, Michael P; Stewart, Robert D; Zahka, Kenneth G; Krasuski, Richard A; Hanna, Mazen; Blackstone, Eugene H; Pettersson, Gosta BTwo cases of Shone syndrome with severe mitral and aortic valve problems and pulmonary hypertension were referred for heart-lung transplantation. Severely elevated pulmonary vascular resistance (PVR) was confirmed as was severe periprosthetic mitral and aortic regurgitation. Based on the severity of the valve lesions in both patients, surgery was decided upon and undertaken. Both experienced early pulmonary hypertensive crises, one more than the other, that gradually subsided, followed by excellent recovery and reversal of pulmonary hypertension and PVR. These cases illustrate Braunwald's concept that pulmonary hypertension secondary to left-sided valve disease is reversible.