Noninvasive monitoring of infection and rejection after lung transplantation

The survival rate following lung transplantation is among the lowest of all solid-organ transplants, and current diagnostic tests often fail to distinguish between infection and rejection, the two primary posttransplant clinical complications. We describe a diagnostic assay that simultaneously monitors for rejection and infection in lung transplant recipients by sequencing of cell-free DNA (cfDNA) in plasma. We determined that the levels of donor-derived cfDNA directly correlate with the results of invasive tests of rejection (area under the curve 0.9). We also analyzed the nonhuman cfDNA as a hypothesis-free approach to test for infections. Cytomegalovirus is most frequently assayed clinically, and the levels of CMV-derived sequences in cfDNA are consistent with clinical results. We furthermore show that hypothesis-free monitoring for pathogens using cfDNA reveals undiagnosed cases of infection, and that certain infectious pathogens such as human herpesvirus (HHV) 6, HHV-7, and adenovirus, which are not often tested clinically, occur with high frequency in this cohort.

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Cytomegalovirus in Lung Transplant

OBM Transplantation ◽

10.21926/obm.transplant.2102145 ◽

2021 ◽

Vol 05 (02) ◽

pp. 1-1

Author(s):

Justin P. Rosenheck ◽

◽

Mena M B otros ◽

David R Nunley ◽

◽

...

Keyword(s):

Lung Transplantation ◽

Lung Transplant ◽

Therapeutic Option ◽

Organ Transplant ◽

Solid Organ ◽

Transplant Recipients ◽

Ongoing Research ◽

Complex Patients ◽

Lung Transplant Recipients ◽

New Generation

Lung transplantation is a therapeutic option for patients with advanced lung diseases. Lung transplant outcomes have improved over time with improvements in the management of these complex patients. Cytomegalovirus is a common opportunistic organism affecting all solid organ transplant recipients. Characteristics unique to lung transplantation can make this virus difficult to manage, with myriad complications including graft failure and death. Ongoing research into and understanding of cytomegalovirus has opened exciting new avenues of management. We discuss the various manifestations of CMV related pathologies in the lung transplant recipient. We discuss current mainstays of risk stratification, diagnosis, and treatment, as well as present new and evolving concepts. Current medications are highly effective at preventing and treating CMV manifestations, but may be poorly tolerated. A new generation of therapies carry the promise of efficacy, with a greater safety profile and improved tolerance of adverse effects. We discuss host-virus immune interactions, specifically how these can be utilized in clinical practice to individualize the cytomegalovirus related care of lung transplant recipients. Finally, we turn our attention to the near horizon as we continue to evolve the care of this unique population.

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Low-Dose Valganciclovir for CMV Prophylaxis after Lung Transplantation

ISRN Transplantation ◽

10.5402/2013/680589 ◽

2013 ◽

Vol 2013 ◽

pp. 1-6

Author(s):

Hargobind S. Khurana ◽

Alison Kole ◽

Jeremy Falk ◽

Sara Ghandehari ◽

Guy Soohoo ◽

...

Keyword(s):

Lung Transplantation ◽

Lung Transplant ◽

Low Dose ◽

Solid Organ ◽

Transplant Recipients ◽

Female Ratio ◽

Oral Valganciclovir ◽

Lung Transplant Recipients ◽

Cmv Disease ◽

Cmv Prophylaxis

Purpose. Cytomegalovirus (CMV) remains an important pathogen following solid organ transplantation (SOT). Universal prophylaxis for CMV is adopted by most centers after lung transplantation. Various combinations studied for CMV prophylaxis include intravenous and oral ganciclovirs, oral valganciclovir, and CMV immunoglobulins. We present our experience with a low-dose of oral valganciclovir for CMV prophylaxis following lung transplantation. Methods and Materials. Our center started using 450 mg of daily oral valganciclovir for CMV prophylaxis in lung transplant recipients in Jan, 2001. A retrospective chart analysis of patients who underwent lung transplantation from January 2001 to December 2006 was done. Of 46 patients, 4 were excluded as they died within 30 days of transplant from postop complications. The mean age at transplant was 64 years, mostly single lung transplants (36/6) with a male-to-female ratio of 25/17. COPD was the most common reason for transplant (65%), and the serological CMV status of donors (D) and recipients (R) was as follows: D+/R+ 28, D+/R− 5, D−/R+ 5, and D−/R− 4. Valganciclovir was given for a total of 6 months posttransplant except for D−/R+ patients who received it for 12 months. Results. Five patients (12%) developed CMV disease with an average followup of 26 months. Only 2 (4.7%) developed CMV disease within six months of completing valganciclovir prophylaxis. This incidence is not significantly different from the best-reported results of CMV prophylaxis in lung transplant recipients. The remaining 3 patients developed the disease later in their course, one as late as 32 months posttransplant. The main side effects noted include leucopenia, neutropenia, and GI disturbances. However, the number of patients who had to temporarily stop or discontinue the medication (9.5%) was significantly lower than that reported in previous studies. Conclusions. Our experience suggests that low-dose valganciclovir is an effective method of prophylaxis for CMV disease in high-risk patients. It is a simple regimen that seems to have a better side effect profile and to improve patient compliance.

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Antibody-Mediated Rejection Management Following Lung Transplantation

Annals of Pharmacotherapy ◽

10.1177/10600280211012410 ◽

2021 ◽

pp. 106002802110124

Author(s):

Kristen Neuhaus ◽

Benjamin Hohlfelder ◽

Jessica Bollinger ◽

Marcus Haug ◽

Heather Torbic

Keyword(s):

Lung Transplantation ◽

Lung Transplant ◽

Management Strategies ◽

Organ Transplant ◽

Outcome Analysis ◽

Solid Organ ◽

Transplant Recipients ◽

Antibody Mediated Rejection ◽

Patient Admissions ◽

Lung Transplant Recipients

Background Although antibody-mediated rejection (AMR) is described in other solid organ transplant populations, the literature describing the management following lung transplantation is limited. Objective The purpose of this study is to evaluate the management strategies of AMR in lung transplant recipients. Methods This single-center, retrospective study described the management of AMR in adult lung transplant recipients who received treatment with rabbit antithymocyte globulin, bortezomib, rituximab, intravenous immune globulin (IVIG), and/or plasmapheresis between September 2015 and June 2019. Results A total of 270 medication orders for 55 patient admissions were included in the primary outcome analysis. The most commonly used regimen consisted of IVIG, plasmapheresis, and rituximab (49.1%; n = 27), followed by IVIG and plasmapheresis alone (27.3%, n = 15). A total of 51 patients (93%) received plasmapheresis as part of their AMR treatment, with a median of 4 [3, 5] sessions per encounter; 86% of patients with positive donor-specific antibodies (DSAs) had a reduction in DSAs following AMR treatment. Overall, 23.5% of patients had noted allograft failure or need for retransplantation. A total of 10 patients died during the AMR treatment hospital admission, and an additional 11 patients died within 1 year of the initial encounter. Conclusion and Relevance This represents the largest report describing management strategies of AMR in lung transplant recipients. Although practice varied, the most commonly used regimen consisted of plasmapheresis, IVIG, and rituximab.

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A systematic review of post-transplant lymphoproliferative disorder after lung transplant.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e19046 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e19046-e19046

Author(s):

Mobeen Zaka Haider ◽

Zarlakhta Zamani ◽

Fnu Kiran ◽

Hasan Mehmood Mirza ◽

Muhammad Taqi ◽

...

Keyword(s):

Lymphoproliferative Disorder ◽

Lung Transplant ◽

Late Onset ◽

Adult Population ◽

Solid Organ Transplantation ◽

Chemotherapeutic Agents ◽

Solid Organ ◽

Transplant Recipients ◽

Post Transplant ◽

Lung Transplant Recipients

e19046 Background: Post-transplant lymphoproliferative disorder (PTLD) is a serious complication after solid organ transplantation. This study aims to explore the association of PTLD diagnosed after lung transplant with infectious agents and immunosuppression regimen, explore types of PTLD, and their outcome. Methods: Following the PRISMA guideline, we searched the literature on PubMed, Cochrane, Embase, and clinicaltrials.gov. 1741 articles were screened and included five studies. Results: We analyzed data from five studies, n=13,643 transplant recipients with n=287 (2.10%) developed PTLD. Four studies showed that 32/63 (51%) PTLD patients were male and 31 (49%) were female. Three studies reported 53/55 (96.4%) patients were EBV positive at PTLD diagnosis. Courtwright. et al, reported that 217/224 (97%) PTLD was associated with either EBV positive donor or recipient. Four studies showed that the monomorphic B cell type 48/63 (76%) was the most common histological type of PTLD diagnosed with DLBCL the most common subtype 31/48 (64.6%). Data from 3 studies showed that the onset of PTLD following lung transplant varies with a median duration of 18.3 months (45 days to 20.2 years). Three studies showed that 26/55 (47.3%) patients had early-onset (≤ 1 yr of Tx) and 29/55 (52.7%) patients had late-onset PTLD (> 1 yr of Tx). Management of PTLD included a reduction in immunosuppression including corticosteroids, CNI, purine synthesis inhibitors, Rituximab, and chemotherapeutic agents. Three studies showed a mortality rate of 30/45 (66.7%) and 13/30 (43.3%) deaths were PTLD related. Conclusions: Our review concludes that PTLD is a serious complication, only 2% of lung transplant recipients developed PTLD. EBV seropositivity is the most factor associated with PTLD diagnosis. Monomorphic PTLD was reported as the most common type in the adult population and no association between gender and PTLD was found. The analysis shows that there is a slightly lower incidence of early (≤ 1 yr of Tx) than late-onset (> 1 yr of Tx) PTLD. Table 1 PTLD after a Lung transplant in adults - a review. [Table: see text]

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Detrimental Association of Hypogammaglobulinemia With Chronic Lung Allograft Dysfunction and Death Is Not Mitigated by On-Demand Immunoglobulin G Replacement After Lung Transplantation

Progress in Transplantation ◽

10.1177/1526924818817028 ◽

2018 ◽

Vol 29 (1) ◽

pp. 18-25

Author(s):

Alicia B. Lichvar ◽

Christopher R. Ensor ◽

Adriana Zeevi ◽

Matthew R. Morrell ◽

Joseph M. Pilewski ◽

...

Keyword(s):

Lung Transplantation ◽

Immunoglobulin G ◽

Lung Transplant ◽

Primary Outcome ◽

Transplant Recipients ◽

Chronic Lung Allograft Dysfunction ◽

On Demand ◽

Allograft Dysfunction ◽

Group 2 ◽

Lung Transplant Recipients

Background: Hypogammaglobulinemia (HGG), immunoglobulin G (IgG) <700 mg/dL, is associated with infections, chronic lung allograft dysfunction, and death following lung transplantation. This study evaluates the use of on-demand intravenous IgG in lung transplant recipients with HGG. Materials and Methods: This single-center retrospective cohort study of adult lung recipients evaluated 3 groups, no, untreated (u), or treated (t) HGG at first IgG administration or a matched time posttransplant. Primary outcome was freedom from allograft dysfunction. Secondary outcomes included development of advanced dysfunction, rejection, infection burden, and mortality. Results: Recipients included 484 (no HGG: 76, uHGG: 192, tHGG: 216). Freedom from chronic allograph dysfunction was highest in the non-HGG group 2 years post-enrollment (no HGG 77.9% vs uHGG 56.4% vs tHGG 52.5%; P = .002). Freedom from advanced dysfunction was significantly different 2 years post-enrollment (no HGG 90.5% vs uHGG 84.7% vs tHGG 75.4%; P = .017). Patients without HGG and those with uHGG had less mortality at 2 years post-enrollment (no HGG 84.2% vs uHGG 81.3% vs tHGG 64.8%; P < .001). Gram-negative pneumonias occurred more often in the tHGG group ( P = .02). Conclusions: Development of chronic lung allograft dysfunction, patient survival, rejection burden, and key infectious outcomes in lung transplant recipients were still problematic in the context of on-demand IgG therapy. Prospective studies are warranted.

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Viral load Guided Immunosuppression after Lung Transplantation (VIGILung) – study protocol for a randomized controlled trial

10.21203/rs.3.rs-38454/v1 ◽

2020 ◽

Author(s):

Jens Gottlieb ◽

Alexander Reuss ◽

Konstantin Mayer ◽

Karin Weide ◽

Carmen Schade-Brittinger ◽

...

Keyword(s):

Therapeutic Drug Monitoring ◽

Lung Transplantation ◽

Drug Monitoring ◽

Lung Transplant ◽

Controlled Trial ◽

Therapeutic Drug ◽

Transplant Recipients ◽

Randomized Controlled ◽

Lung Transplant Recipients ◽

Trough Levels

Abstract Background:Immunosuppression including high dose calcineurin-inhibitors (CNI) is essential after lung transplantation. Dosing is usually guided by therapeutic drug monitoring adjusted to target trough levels of CNIs to keep the balance between over-dose causing severe toxicity and increased risk of infections or under-dose with risk of graft-injury.Adaptation of CNI-based immunosuppression by monitoring of Torque-Teno-Virus (TTV) – a latent nonpathogenic DNA virus, measured in whole blood in addition to conventional therapeutic drug monitoring may reduce toxicity of immunosuppression with similar efficacy.Methods/Design:An open-label, randomized, controlled, parallel-group, multicenter trial in lung transplant recipients will be conducted to investigate the safety and efficacy of immunosuppression guided by TTV monitoring as add-on to conventional therapeutic drug monitoring. Adult lung transplant recipients 21 - 42 days after transplantation are eligible to participate. Patients (N = 144) will be randomized 1:1 to the experimental intervention (Arm 1: Immunosuppression guided by TTV monitoring in addition to conventional therapeutic drug monitoring of tacrolimus trough levels) and control intervention (Arm 2: conventional therapeutic drug monitoring). Outcomes will be assessed 12 months after randomization with the change in glomerular filtration rate as the primary endpoint. Secondary endpoints will be additional measurements on renal function, allograft function, incidence of acute rejections, incidence of chronic lung allograft dysfunction, graft loss and infections.Discussion:The results of this randomized controlled trial may reduce toxicity of immunosuppression after lung transplantation while maintaining efficacy of immunosuppression. Study results are transferable to all other solid organ transplantations.Trial registration: ClinicalTrials.gov, NCT04198506. Registered 12 December 2019, https://www.clinicaltrials.gov/show/NCT04198506

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Providing post-lung transplant care during the time of COVID-19

British Journal of Nursing ◽

10.12968/bjon.2021.30.16.976 ◽

2021 ◽

Vol 30 (16) ◽

pp. 976-980

Author(s):

Sara Winward ◽

Iain Lawrie ◽

Susan Talbot Towell ◽

Nina Sheridan ◽

Patricia Ging

Keyword(s):

Lung Transplant ◽

Organ Transplant ◽

Solid Organ ◽

Transplant Recipients ◽

Model Of Care ◽

Community Based Interventions ◽

Community Based ◽

Solid Organ Transplant Recipients ◽

Remote Monitoring Systems ◽

Lung Transplant Recipients

The COVID-19 pandemic is a public health emergency of international concern. Solid organ transplant recipients have been identified as being at high risk of acquiring the virus SARS-CoV-2 and having a more severe COVID-19 disease. This article describes the experience of the National Lung Transplant Centre in Ireland in changing established care pathways for lung transplant recipients during the pandemic. The innovations which were put in place to protect this clinically vulnerable group are discussed. With the advancement of technology and remote monitoring systems available, patient-focused strategies and community-based interventions were implemented. Additional strategies have been implemented so that the new model of care can be safely maintained.

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Postoperative Management of Lung Transplant Recipients in the Intensive Care Unit

Anesthesiology ◽

10.1097/aln.0000000000004054 ◽

2021 ◽

Author(s):

Matteo Di Nardo ◽

Jussi Tikkanen ◽

Shahid Husain ◽

Lianne G. Singer ◽

Marcelo Cypel ◽

...

Keyword(s):

Intensive Care Unit ◽

Intensive Care ◽

Lung Transplantation ◽

Lung Transplant ◽

Postoperative Management ◽

Transplant Recipients ◽

Complex Interplay ◽

Hemodynamic Management ◽

Lung Transplant Recipients ◽

Evidence Based Guidelines

The number of lung transplantations is progressively increasing worldwide, providing new challenges to interprofessional teams and the intensive care units. The outcome of lung transplantation recipients is critically affected by a complex interplay of particular pathophysiologic conditions and risk factors, knowledge of which is fundamental to appropriately manage these patients during the early postoperative course. As high-grade evidence-based guidelines are not available, the authors aimed to provide an updated review of the postoperative management of lung transplantation recipients in the intensive care unit, which addresses six main areas: (1) management of mechanical ventilation, (2) fluid and hemodynamic management, (3) immunosuppressive therapies, (4) prevention and management of neurologic complications, (5) antimicrobial therapy, and (6) management of nutritional support and abdominal complications. The integrated care provided by a dedicated multidisciplinary team is key to optimize the complex postoperative management of lung transplantation recipients in the intensive care unit.

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Isavuconazole Is as Effective as and Better Tolerated Than Voriconazole for Antifungal Prophylaxis in Lung Transplant Recipients

Clinical Infectious Diseases ◽

10.1093/cid/ciaa652 ◽

2020 ◽

Cited By ~ 4

Author(s):

Palash Samanta ◽

Cornelius J Clancy ◽

Rachel V Marini ◽

Ryan M Rivosecchi ◽

Erin K McCreary ◽

...

Keyword(s):

Risk Factors ◽

Lung Transplantation ◽

Lung Transplant ◽

Fungal Infections ◽

Oral Intake ◽

Antifungal Prophylaxis ◽

Red Blood Cell Transfusion ◽

Transplant Recipients ◽

Independent Risk Factors ◽

Lung Transplant Recipients

Abstract Background Invasive fungal infections (IFIs) are common following lung transplantation. Isavuconazole is unstudied as prophylaxis in organ transplant recipients. We compared effectiveness and tolerability of isavuconazole and voriconazole prophylaxis in lung transplant recipients. Methods A single-center, retrospective study of patients who received isavuconazole (September 2015–February 2018) or voriconazole (September 2013–September 2015) for antifungal prophylaxis. IFIs were defined by EORTC/MSG criteria. Results Patients received isavuconazole (n = 144) or voriconazole (n = 156) for median 3.4 and 3.1 months, respectively. Adjunctive inhaled amphotericin B (iAmB) was administered to 100% and 41% of patients in the respective groups. At 1 year, 8% of patients receiving isavuconazole or voriconazole developed IFIs. For both groups, 70% and 30% of IFIs were caused by molds and yeasts, respectively, and breakthrough IFI (bIFI) rate was 3%. Outcomes did not significantly differ for patients receiving or not receiving iAmB. Independent risk factors for bIFI and breakthrough invasive mold infection (bIMI) were mold-positive respiratory culture and red blood cell transfusion >7 units at transplant. Bronchial necrosis >2 cm from anastomosis and basiliximab induction were also independent risk factors for bIMI. Isavuconazole and voriconazole were discontinued prematurely due to adverse events in 11% and 36% of patients, respectively (P = .0001). Most common causes of voriconazole and isavuconazole discontinuation were hepatotoxicity and lack of oral intake, respectively. Patients receiving ≥90 days prophylaxis had fewer IFIs at 1 year (3% vs 9%, P = .02). IFIs were associated with increased mortality (P = .0001) and longer hospitalizations (P = .0005). Conclusions Isavuconazole was effective and well tolerated as antifungal prophylaxis following lung transplantation.

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Early protein expression profile in bronchoalveolar lavage fluid and clinical outcomes in primary graft dysfunction after lung transplantation

European Journal of Cardio-Thoracic Surgery ◽

10.1093/ejcts/ezaa043 ◽

2020 ◽

Vol 58 (2) ◽

pp. 379-388

Author(s):

Anna E Frick ◽

Stijn E Verleden ◽

Sofie Ordies ◽

Annelore Sacreas ◽

Robin Vos ◽

...

Keyword(s):

Bronchoalveolar Lavage ◽

Lung Transplantation ◽

Lung Transplant ◽

Bronchoalveolar Lavage Fluid ◽

Lavage Fluid ◽

Enzyme Linked Immunosorbent Assay ◽

Transplant Recipients ◽

Primary Graft Dysfunction ◽

Graft Dysfunction ◽

Lung Transplant Recipients

Abstract OBJECTIVES Primary graft dysfunction (PGD) remains a major post-transplant complication and is associated with increased morbidity and mortality. Mechanisms evoking PGD are not completely clear, but inflammation plays a central role. We investigated the association between PGD and inflammatory proteins present in immediate postoperative bronchoalveolar lavage. METHODS All double-lung recipients transplanted at our institution from 2002 to 2018 were included in our study. We retrospectively selected 80 consecutive lung transplant recipients with different PGD grades (n = 20 for each PGD grades 0–1 to 2–3). In bronchoalveolar lavage performed within the first 24 h after donor aortic cross-clamping following lung transplantation, concentrations of 30 cytokines, chemokines and growth factors were assessed by enzyme-linked immunosorbent assay (ELISA) and correlated with donor and recipient demographics and outcomes. For analysis, 2 groups were defined: ‘mild’ PGD (grade 0–1) and ‘severe’ PGD (grades 2–3). RESULTS Significant differences between mild and severe PGD were found in 8 biomarkers [interleukin (IL)-6, IL-10, IL-13, eotaxin, granulocyte colony-stimulating factor, interferon γ, macrophage inflammatory protein 1α, surfactant protein D (SP-D); P < 0.05]. Increased IL-10 and IL-13, but none of the other proteins, were associated with short-term outcome (longer time to extubation; P = 0.005 and P < 0.0001; increased intensive care unit stay; P = 0.012 and P < 0.0001; and hospital stay; P = 0.041 and P = 0.002). There were no significant differences in donor and recipient characteristics between the groups. CONCLUSIONS Expression profiles of key inflammatory mediators in bronchoalveolar lavage fluid differed significantly between lung transplant recipients with severe versus mild PGD and correlated with clinical outcome variables. Further research should focus on the early mechanisms leading to PGD.

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