55 results on '"Verschuuren EAM"'
Search Results
2. Kinetics of US28 gene expression during active human cytomegalovirus infection in lung-transplant recipients
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Boomker, JM, Verschuuren, EAM, Brinker, MGL, de Leij, LFMH, The, TH, Harmsen, MC, Groningen University Institute for Drug Exploration (GUIDE), Restoring Organ Function by Means of Regenerative Medicine (REGENERATE), Vascular Ageing Programme (VAP), and Groningen Institute for Organ Transplantation (GIOT)
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DYNAMICS ,CHEMOKINE RECEPTOR US28 - Abstract
Targeting viral proteins early during infection may limit exacerbation of human cytomegalovirus infection. The viral chemokine-receptor homologue US28 interferes with leukocyte trafficking and, possibly, viral replication. Because US28 molecules are abundant on the surface of infected cells, this homologue is a potential target for antiviral therapy. To assess the relationship between US28 and disease activity, we measured, by quantitative reverse-transcription polymerase chain reaction, the levels of US28 and immediate-early (IE) 1 gene transcripts in the blood of lung-transplant recipients. We found that, during primary and secondary infection, the IE1 and US28 genes have early transcription kinetics and are expressed at similar levels. This may render US28 an attractive target for antiviral therapy.
- Published
- 2006
3. Survival benefit of cardiopulmonary bypass support in bilateral lung transplantation for emphysema patients
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Hepkema, BG, Loef, BG, van der Bij, W, Verschuuren, EAM, Lems, SPM, Ebels, T, Faculteit Medische Wetenschappen/UMCG, Cardiovascular Centre (CVC), and Groningen Institute for Organ Transplantation (GIOT)
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surgical procedures, operative ,HEART ,REPERFUSION INJURY ,DYSFUNCTION - Abstract
Background. This study is designed to examine a possible association of cardiopulmonary bypass (CPB) support and outcome of lung transplantation in a well-balanced group of emphysema patients. Methods. We performed a retrospective analysis of 62 consecutive primary bilateral lung transplantations for emphysema. Risk factors for their possible association with patient survival were analyzed by multivariate logistic regression. Results. The use of CPB support was associated with improved survival (odds ratio=0.25; P=0.038). The actuarial survival at 1 year was 97% for patients treated with CPB and 77% for patients treated without CPB support. In 28 patients (45%), 2 human leukocyte antigen (HLA)-DR mismatches between donor and recipient occurred, whereas 34 patients had 0 or 1 HLA-DR mismatches. The use of CPB support in the group with two HLA-DR mismatches was associated with improved survival (odds ratio=0.06; P=0.020). This association was not present in the group with 0 or 1 HLA-DR mismatches. Conclusions. These results demonstrate a significant survival benefit of CPB support during bilateral lung transplantation in emphysema patients. The difference in survival benefit of CPB support between the patients with 0 or 1 HLA-DR mismatches and the patients with 2 HLA-DR mismatches indicates that the immunosuppressive effect of CPB support might be responsible for this survival benefit. The underlying immunological mechanism might be important in the future treatment of organ transplantation.
- Published
- 2002
4. Expression dynamics of human cytomegalovirus immune evasion genes US3, US6, and US11 in the blood of lung transplant recipients
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Greijer, AE, Verschuuren, EAM, Dekkers, CAJ, Adriaanse, HMA, van der Bij, W, The, TH, Middeldorp, JM, and Groningen Institute for Organ Transplantation (GIOT)
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I HEAVY-CHAINS ,PEPTIDE TRANSLOCATION ,ANTIGENEMIA ,MONOCYTES ,viruses ,INFECTION ,CELLS ,SEQUENCE-BASED AMPLIFICATION ,ENDOPLASMIC-RETICULUM ,LATENT ,virus diseases ,VIRUS ,biochemical phenomena, metabolism, and nutrition - Abstract
Delayed elimination of human cytomegalovirus (HCMV)-infected cells by the host immune system may contribute to viral dissemination and pathogenesis of HCMV infection. The mRNA expression dynamics of HCMV-encoded immune evasion genes US3, US6, and US11 expressed after active HCMV infection were analyzed in blood samples of lung transplant recipients by means of quantitative nucleic acid sequence-based amplification. The results were compared with the expression dynamics of IE1 mRNA and pp67 late mRNA, levels of pp65 antigenemia, and antiviral treatment. During acute infection, high levels of US3 and US6 RNA were detected before antigenemia, which were detected simultaneously with IE1 RNA. US11 RNA was detected simultaneously with antigenemia but before late pp67 RNA. These data suggest an active role of viral immune evasion during HCMV infection in vivo. Interestingly, immune evasion RNA remained detectable after clinical recovery, often independently of IE1 RNA expression, indicating persistent viral activity, which may have implications for long-term control of HCMV.
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- 2001
5. Direct quantification of human cytomegalovirus immediate-early and late mRNA levels in blood of lung transplant recipients by competitive nucleic acid sequence-based amplification
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Greijer, AE, Verschuuren, EAM, Harmsen, MC, Dekkers, CAJ, Adriaanse, HMA, The, TH, Middeldorp, JM, Restoring Organ Function by Means of Regenerative Medicine (REGENERATE), Vascular Ageing Programme (VAP), and Groningen Institute for Organ Transplantation (GIOT)
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EXPRESSION ,viruses ,virus diseases ,biochemical phenomena, metabolism, and nutrition ,POLYMERASE CHAIN-REACTION ,MARROW RECIPIENTS ,LATE TRANSCRIPT ,DISEASE ,IMMUNOCOMPROMISED PATIENTS ,VIRUS INFECTION ,EARLY ANTIGEN ,DIAGNOSTIC-VALUE ,parasitic diseases ,ALLOGRAFT-REJECTION - Abstract
The dynamics of active human cytomegalovirus (HCMV) infection was monitored by competitive nucleic acid sequence-based amplification (NASBA) assays for quantification of IE1 (UL123) and pp67 (UL65) mRNA expression levels In the blood of patients after lung transplantation. RNA was isolated from 339 samples of 13 lung transplant recipients and analyzed by the quantitative IE1 and pp67 NASBA in parallel with pp65 antigenemia and serology. Rapid increases in IE1 RNA exceeding 10(4) copies per 100 mul of blood were associated with active infection, whereas lower levels were suggestive for abortive, subclinical viral activity. Any positive value for pp67 RNA was indicative for active infection, and quantification of pp67 mRNA did not give additional diagnostic information. The onset of IE1-positive NASBA preceded pp67 NASBA and was earlier than the pp65 antigenemia assay, confirming previous studies with qualitative NASBA. Effective antiviral treatment was reflected by a rapid disappearance of pp67 mRNA, whereas IE1 mRNA remained detectable for longer periods. Quantification of IE1 might be relevant to monitor progression of HCMV infection but should be validated in prospective studies.
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- 2001
6. Vaginal delivery after lung transplantation
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Jongen, VHWM, Holm, JP, Verschuuren, EAM, van der Bij, W, and Groningen Institute for Organ Transplantation (GIOT)
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PREGNANCY ,pulmonary hypertension ,lung transplantation - Published
- 2000
7. Towards standardization of the human cytomegalovirus antigenemia assay
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Verschuuren, EAM, Harmsen, MC, Limburg, PC, van der Bij, W, van den Berg, AP, Meedendorp, AMKDB, van Son, WJ, Hauw, T, Restoring Organ Function by Means of Regenerative Medicine (REGENERATE), Groningen Institute for Organ Transplantation (GIOT), and Vascular Ageing Programme (VAP)
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standardization ,TRANSPLANTATION ,antigenemia ,INFECTION ,virus diseases ,VIRUS ,PERIPHERAL-BLOOD LEUKOCYTES ,VIREMIA ,cytomegalovirus ,IMMEDIATE EARLY ANTIGEN ,PP65 - Abstract
The Human Cytomegalovirus antigenemia (HCMV-Agemia) test has been accepted worldwide as a clinical tool in the diagnosis and management of HCMV-associated syndromes in immunocompromised patients. The many modifications proposed since the first description by our laboratory make standardisation of the HCMV-Agemia assay necessary to enable multicenter clinical trials. We report the initial work for standardization of the HCMV-Agemia ia assay. A sta nda rd protocol is proposed, the optimal distribution conditions are investigated and the results of the shipment of positive and negative test slides as well as of two sets of coded internal standard slides are discussed. The main conclusions are that standard slides can be distributed at room temperature and that the results of participating laboratories with the coded internal standard slides were strikingly similar in spite of differences in HCMV-Agemia protocols used by participating laboratories. Copyright (C) 2000 S. Karger AG, Basel.
- Published
- 1999
8. Recurrent Pulmonary Veno-Occlusive Disease after Lung Transplantation.
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Nossent EJ, Nossent GD, Meijboom LJ, Verschuuren EAM, Gan CT, Aman J, Bogaard HJ, Radonic T, Dorfmüller P, and Vonk Noordegraaf A
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- 2024
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9. Multiple indicators of gut dysbiosis predict all-cause and cause-specific mortality in solid organ transplant recipients.
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Swarte JC, Zhang S, Nieuwenhuis LM, Gacesa R, Knobbe TJ, De Meijer VE, Damman K, Verschuuren EAM, Gan TC, Fu J, Zhernakova A, Harmsen HJM, Blokzijl H, Bakker SJL, Björk JR, and Weersma RK
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- Humans, Female, Male, Middle Aged, Prospective Studies, Cause of Death, Transplant Recipients statistics & numerical data, Adult, Feces microbiology, Netherlands epidemiology, Metagenome, Aged, Dysbiosis mortality, Gastrointestinal Microbiome, Organ Transplantation adverse effects
- Abstract
Objective: Gut microbiome composition is associated with multiple diseases, but relatively little is known about its relationship with long-term outcome measures. While gut dysbiosis has been linked to mortality risk in the general population, the relationship with overall survival in specific diseases has not been extensively studied. In the current study, we present results from an in-depth analysis of the relationship between gut dysbiosis and all-cause and cause-specific mortality in the setting of solid organ transplant recipients (SOTR)., Design: We analysed 1337 metagenomes derived from faecal samples of 766 kidney, 334 liver, 170 lung and 67 heart transplant recipients part of the TransplantLines Biobank and Cohort-a prospective cohort study including extensive phenotype data with 6.5 years of follow-up. To analyze gut dysbiosis, we included an additional 8208 metagenomes from the general population of the same geographical area (northern Netherlands). Multivariable Cox regression and a machine learning algorithm were used to analyse the association between multiple indicators of gut dysbiosis, including individual species abundances, and all-cause and cause-specific mortality., Results: We identified two patterns representing overall microbiome community variation that were associated with both all-cause and cause-specific mortality. The gut microbiome distance between each transplantation recipient to the average of the general population was associated with all-cause mortality and death from infection, malignancy and cardiovascular disease. A multivariable Cox regression on individual species abundances identified 23 bacterial species that were associated with all-cause mortality, and by applying a machine learning algorithm, we identified a balance (a type of log-ratio) consisting of 19 out of the 23 species that were associated with all-cause mortality., Conclusion: Gut dysbiosis is consistently associated with mortality in SOTR. Our results support the observations that gut dysbiosis is associated with long-term survival. Since our data do not allow us to infer causality, more preclinical research is needed to understand mechanisms before we can determine whether gut microbiome-directed therapies may be designed to improve long-term outcomes., Competing Interests: Competing interests: The TransplantLines Biobank and Cohort study received funding from Astellas BV (TransplantLines Biobank and Cohort study) and Chiesi Pharmaceuticals BV (PA-SP/PRJ-2020-9136) and was cofinanced by the Dutch Ministry of Economic Affairs and Climate Policy by means of the PPP allowance made available by the Top Sector Life Sciences and Health to stimulate public–private partnerships. Sequencing of the kidney part of the TransplantLines cohort was funded by a grant from the Dutch NWO/TTW/DSM partnership programme Animal Nutrition and Health (project number 14939) to SJLB, RKW is supported by the Seerave Foundation, the Netherlands Organization for Scientific Research (NWO) and the EU Horizon Europe Programme grant miGut-Health: personalised blueprint of intestinal health (101095470). JF is supported by the Dutch Heart Foundation IN-CONTROL (CVON2018-27), the ERC Consolidator grant (grant agreement No. 101001678), NWO-VICI grant VI.C.202.022, the AMMODO Science Award 2023 for Biomedical Sciences from Stichting Ammodo and the Netherlands Organ-on-Chip Initiative, an NWO Gravitation project (024.003.001) funded by the Ministry of Education, Culture and Science of the government of The Netherlands., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2024
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10. The gut microbiome in end-stage lung disease and lung transplantation.
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Zhang S, Swarte JC, Gacesa R, Knobbe TJ, Kremer D, Jansen BH, de Borst MH, Harmsen HJM, Erasmus ME, Verschuuren EAM, Bakker SJL, Gan CT, Weersma RK, and Björk JR
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- Humans, Female, Male, Middle Aged, Adult, Lung Diseases microbiology, Lung Diseases surgery, Immunosuppressive Agents therapeutic use, Immunosuppressive Agents adverse effects, Feces microbiology, Aged, Lung Transplantation adverse effects, Gastrointestinal Microbiome, Dysbiosis microbiology
- Abstract
Gut dysbiosis has been associated with impaired outcomes in liver and kidney transplant recipients, but the gut microbiome of lung transplant recipients has not been extensively explored. We assessed the gut microbiome in 64 fecal samples from end-stage lung disease patients before transplantation and 219 samples from lung transplant recipients after transplantation using metagenomic sequencing. To identify dysbiotic microbial signatures, we analyzed 243 fecal samples from age-, sex-, and BMI-matched healthy controls. By unsupervised clustering, we identified five groups of lung transplant recipients using different combinations of immunosuppressants and antibiotics and analyzed them in relation to the gut microbiome. Finally, we investigated the gut microbiome of lung transplant recipients in different chronic lung allograft dysfunction (CLAD) stages and longitudinal gut microbiome changes after transplantation. We found 108 species (58.1%) in end-stage lung disease patients and 139 species (74.7%) in lung transplant recipients that were differentially abundant compared with healthy controls, with several species exhibiting sharp longitudinal increases from before to after transplantation. Different combinations of immunosuppressants and antibiotics were associated with specific gut microbial signatures. We found that the gut microbiome of lung transplant recipients in CLAD stage 0 was more similar to healthy controls compared to those in CLAD stage 1. Finally, the gut microbial diversity of lung transplant recipients remained lower than the average gut microbial diversity of healthy controls up to more than 20 years post-transplantation. Gut dysbiosis, already present before lung transplantation was exacerbated following lung transplantation.IMPORTANCEThis study provides extensive insights into the gut microbiome of end-stage lung disease patients and lung transplant recipients, which warrants further investigation before the gut microbiome can be used for microbiome-targeted interventions that could improve the outcome of lung transplantation., Competing Interests: The authors declare no conflict of interest.
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- 2024
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11. Management of infectious disease syndromes in thoracic organ transplants and mechanical circulatory device recipients: a Delphi panel.
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Luong ML, Nakamachi Y, Silveira FP, Morrissey CO, Danziger-Isakov L, Verschuuren EAM, Wolfe CR, Hadjiliadis D, Chambers DC, Patel JK, Dellgren G, So M, Verleden GM, Blumberg EA, Vos R, Perch M, Holm AM, Mueller NJ, Chaparro C, and Husain S
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- Humans, Surveys and Questionnaires, Heart-Assist Devices adverse effects, Consensus, Invasive Pulmonary Aspergillosis drug therapy, Mycobacterium Infections, Nontuberculous, Transplant Recipients, Lung Transplantation adverse effects, Anti-Bacterial Agents therapeutic use, Communicable Diseases, Delphi Technique
- Abstract
Purpose: Antimicrobial misuse contributes to antimicrobial resistance in thoracic transplant (TTx) and mechanical circulatory support (MCS) recipients. This study uses a modified Delphi method to define the expected appropriate antimicrobial prescribing for the common clinical scenarios encountered in TTx and MCS recipients., Methods: An online questionnaire on managing 10 common infectious disease syndromes was submitted to a multidisciplinary Delphi panel of 25 experts from various disciplines. Consensus was predefined as 80% agreement for each question. Questions where consensus was not achieved were discussed during live virtual live sessions adapted by an independent process expert., Results: An online survey of 62 questions related to 10 infectious disease syndromes was submitted to the Delphi panel. In the first round of the online questionnaire, consensus on antimicrobial management was reached by 6.5% (4/62). In Round 2 online live discussion, the remaining 58 questions were discussed among the Delphi Panel members using a virtual meeting platform. Consensus was reached among 62% (36/58) of questions. Agreement was not reached regarding the antimicrobial management of the following six clinical syndromes: (1) Burkholderia cepacia pneumonia (duration of therapy); (2) Mycobacterium abscessus (intra-operative antimicrobials); (3) invasive aspergillosis (treatment of culture-negative but positive BAL galactomannan) (duration of therapy); (4) respiratory syncytial virus (duration of antiviral therapy); (5) left ventricular assist device deep infection (initial empirical antimicrobial coverage) and (6) CMV (duration of secondary prophylaxis)., Conclusion: This Delphi panel developed consensus-based recommendations for 10 infectious clinical syndromes seen in TTx and MCS recipients., (© 2024 Wiley Periodicals LLC.)
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- 2024
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12. Tacrolimus Variability and Clinical Outcomes in the Early Post-lung Transplantation Period: Oral Versus Continuous Intravenous Administration.
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van Dommelen JEM, Grootjans H, Uijtendaal EV, Ruigrok D, Luijk B, van Luin M, Bult W, de Lange DW, Kusadasi N, Droogh JM, Egberts TCG, Verschuuren EAM, and Sikma MA
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- Humans, Male, Female, Administration, Oral, Middle Aged, Adult, Acute Kidney Injury epidemiology, Acute Kidney Injury etiology, Retrospective Studies, Length of Stay statistics & numerical data, Intensive Care Units statistics & numerical data, Treatment Outcome, Tacrolimus administration & dosage, Tacrolimus pharmacokinetics, Tacrolimus blood, Lung Transplantation adverse effects, Immunosuppressive Agents administration & dosage, Immunosuppressive Agents pharmacokinetics, Immunosuppressive Agents blood, Administration, Intravenous, Graft Rejection prevention & control, Graft Rejection epidemiology
- Abstract
Background and Objective: High variability in tacrolimus pharmacokinetics directly after lung transplantation (LuTx) may increase the risk for acute kidney injury (AKI) and transplant rejection. The primary objective was to compare pharmacokinetic variability in patients receiving tacrolimus orally versus intravenously early after LuTx., Methods: Pharmacokinetic and clinical data from 522 LuTx patients transplanted between 2010 and 2020 in two university hospitals were collected to compare orally administered tacrolimus to intravenous tacrolimus early post-transplantation. Tacrolimus blood concentration variability, measured as intrapatient variability (IPV%) and percentage of time within the therapeutic range (TTR%), was analyzed within the first 14 days after LuTx. Secondary outcomes were AKI, acute rejection, length of stay in the intensive care unit (ICU), and mortality in the ICU and during hospital admission., Results: We included 224 patients in the oral and 298 in the intravenous group. The mean adjusted IPV% was 10.8% (95% confidence interval [CI] 6.9-14.6; p < 0.001) higher in the oral group (27.2%) than the intravenous group (16.4%). The mean TTR% was 7.3% (95% CI - 11.3 to - 3.4; p < 0.001) lower in the oral group (39.6%) than in the intravenous group (46.9%). The incidence of AKI was 46.0% for oral and 42.6% for intravenous administration (adjusted odds ratio [OR] 1.2; 95% CI 0.8-1.8; p = 0.451). The frequencies of clinically diagnosed acute rejection in the oral and intravenous groups were nonsignificant (24.6% vs 17.8%; OR 1.5 [95% CI 1.0-2.3; p = 0.059]). ICU and hospital mortality rate and ICU length of stay were similar., Conclusions: Administering tacrolimus orally directly after LuTx leads to a higher variability in blood concentrations compared to intravenous administration. There was no difference in the occurrence of AKI or transplant rejection., (© 2024. The Author(s).)
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- 2024
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13. Humoral and cellular immune responses after COVID-19 vaccination of lung transplant recipients and patients on the waiting list: a 6-month follow-up.
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Hoek RAS, Liu S, GeurtsvanKessel CH, Verschuuren EAM, Vonk JM, Hellemons ME, Kool M, Wijbenga N, Bogers S, Scherbeijn S, Rugebregt S, van Gemert JP, Steenhuis WN, Niesters HGM, van Baarle D, de Vries RD, and Van Leer Buter C
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- Humans, COVID-19 Vaccines, Waiting Lists, Follow-Up Studies, Vaccination, Antibodies, Neutralizing, Immunity, Cellular, Lung, Transplant Recipients, COVID-19 prevention & control
- Abstract
Background: Data on cellular response and the decay of antibodies and T cells in time are scarce in lung transplant recipients (LTRs). Additionally, the development and durability of humoral and cellular immune responses have not been investigated in patients on the waitlist for lung transplantation (WLs). Here, we report our 6-month follow-up of humoral and cellular immune responses of LTRs and WLs, compared with controls., Methods: Humoral responses to two doses of the mRNA-1273 vaccination were assessed by determining spike (S)-specific IgG antibodies and neutralizing antibodies. Cellular responses were investigated by interferon gamma (IFN-γ) release assay (IGRA) and IFN-γ ELISpot assay at 28 days and 6 months after the second vaccination., Results: In LTRs, the level of antibodies and T-cell responses was significantly lower at 28 days after the second vaccination. Also, WLs had lower antibody titers and lower T-cell responses compared with controls. Six months after the second vaccination, all groups showed a decrease in antibody titers and T-cell responses. In WLs, the rate of decline of neutralizing antibodies and T-cell responses was significantly higher than in controls., Conclusion: Our results show that humoral and cellular responses in LTRs, if they develop, decrease at rates comparable with controls. In contrast, the inferior cellular responses and the rapid decay of both humoral and cellular responses in the WL groups imply that WLs may not be protected adequately by two vaccinations and repeat boostering may be necessary to induce protection that lasts beyond the months immediately post-transplantation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Hoek, Liu, GeurtsvanKessel, Verschuuren, Vonk, Hellemons, Kool, Wijbenga, Bogers, Scherbeijn, Rugebregt, van Gemert, Steenhuis, Niesters, van Baarle, de Vries and Van Leer Buter.)
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- 2024
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14. Successful Kidney Transplantation Despite Ongoing Chronic Norovirus Infection.
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Kremer D, Berger SP, Verschuuren EAM, Bakker SJL, and Knoester M
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- 2023
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15. Non-tuberculous mycobacteria disease pre-lung transplantation: A systematic review of the treatment regimens and duration pre- and post-transplant.
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van Gemert JP, Ravensbergen SJ, Verschuuren EAM, Kerstjens HAM, Willemse BWM, van Ingen J, Hoefsloot W, Gan T, and Akkerman OW
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- Child, Humans, Nontuberculous Mycobacteria, Anti-Bacterial Agents therapeutic use, Macrolides, Mycobacterium Infections, Nontuberculous complications, Mycobacterium Infections, Nontuberculous drug therapy, Mycobacterium Infections, Nontuberculous microbiology, Lung Diseases surgery, Lung Transplantation adverse effects
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Background: There is lack of consensus on non-tuberculous mycobacteria pulmonary disease (NTM-PD) treatment regimen and duration in patient listed for lung transplantation (LTx). We conducted a systematic review on treatment regimen and duration pre- and directly post-LTx, for patients with known NTM-PD pre-LTx. Additionally, we searched for risk factors for NTM disease development post-LTx and for mortality., Methods: Literature was reviewed on PubMed, Embase and the Cochrane Library, for articles published from inception to January 2022. Individual patient data were sought., Results: Sixteen studies were included reporting 92 patients. Most frequent used agents were aminoglycosides and macrolides for Mycobacterium abscessus (M. abscessus) and macrolides and tuberculostatic agents for Mycobacterium avium complex (M. avium complex). The median treatment duration pre-LTx was 10 months (IQR 6-17) and 2 months (IQR 2-8) directly post-LTx. Longer treatment duration pre-LTx was observed in children and in patients with M. abscessus. 46% of the patients with NTM-PD pre-LTx developed NTM disease post-LTx, related mortality rate was 10%. Longer treatment duration pre-LTx (p < 0.001) and sputum non-conversion pre-LTx (p = 0.003) were significantly associated with development of NTM-disease post-LTx. Longer treatment duration pre-LTx (p = 0.004), younger age (p < 0.001) and sputum non-conversion (p = 0.044) were risk factors for NTM related death., Conclusions: The median treatment duration pre-LTx was 10 months (IQR 6-17) and 2 months (IQR 2-8) directly post-LTx. Patients with longer treatment duration for NTM-PD pre-LTx and with sputum non-conversion are at risk for NTM disease post-LTx and for NTM-related death. Children were particularly at risk for NTM related death., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2023
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16. Three Decades Single Center Experience of Airway Complications After Lung Transplantation.
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van Pel R, Gan CT, van der Bij W, Verschuuren EAM, van Gemert JPA, Van De Wauwer C, Erasmus ME, and Slebos DJ
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- Humans, Constriction, Pathologic etiology, Constriction, Pathologic therapy, Retrospective Studies, Lung, Postoperative Complications etiology, Postoperative Complications therapy, Stents adverse effects, Bronchoscopy adverse effects, Lung Transplantation adverse effects
- Abstract
Post lung transplantation airway complications like necrosis, stenosis, malacia and dehiscence cause significant morbidity, and are most likely caused by post-operative hypo perfusion of the anastomosis. Treatment can be challenging, and airway stent placement can be necessary in severe cases. Risk factors for development of airway complications vary between studies. In this single center retrospective cohort study, all lung transplant recipients between November 1990 and September 2020 were analyzed and clinically relevant airway complications of the anastomosis or distal airways were identified and scored according to the ISHLT grading system. We studied potential risk factors for development of airway complications and evaluated the impact on survival. The treatment modalities were described. In 651 patients with 1,191 airway anastomoses, 63 patients developed 76 clinically relevant airway complications of the airway anastomoses or distal airways leading to an incidence of 6.4% of all anastomoses, mainly consisting of airway stenosis (67%). Development of airway complications significantly affects median survival in post lung transplant patients compared to patients without airway complication (101 months versus 136 months, p = 0.044). No significant risk factors for development of airway complication could be identified. Previously described risk factors could not be confirmed. Airway stents were required in 55% of the affected patients. Median survival is impaired by airway complications after lung transplantation. In our cohort, no significant risk factors for the development of airway complications could be identified., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 van Pel, Gan, van der Bij, Verschuuren, van Gemert, Van De Wauwer, Erasmus and Slebos.)
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- 2023
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17. Genomic profiling of post-transplant lymphoproliferative disorders using cell-free DNA.
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Veltmaat N, Zhong Y, de Jesus FM, Tan GW, Bult JAA, Terpstra MM, Mutsaers PGNJ, Stevens WBC, Mous R, Vermaat JSP, Chamuleau MED, Noordzij W, Verschuuren EAM, Kok K, Kluiver JL, Diepstra A, Plattel WJ, van den Berg A, and Nijland M
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- Humans, DNA Copy Number Variations, Epigenesis, Genetic, Herpesvirus 4, Human genetics, Genomics, Epstein-Barr Virus Infections genetics, Lymphoproliferative Disorders genetics, Cell-Free Nucleic Acids genetics
- Abstract
Diagnosing post-transplant lymphoproliferative disorder (PTLD) is challenging and often requires invasive procedures. Analyses of cell-free DNA (cfDNA) isolated from plasma is minimally invasive and highly effective for genomic profiling of tumors. We studied the feasibility of using cfDNA to profile PTLD and explore its potential to serve as a screening tool. We included seventeen patients with monomorphic PTLD after solid organ transplantation in this multi-center observational cohort study. We used low-coverage whole genome sequencing (lcWGS) to detect copy number variations (CNVs) and targeted next-generation sequencing (NGS) to identify Epstein-Barr virus (EBV) DNA load and somatic single nucleotide variants (SNVs) in cfDNA from plasma. Seven out of seventeen (41%) patients had EBV-positive tumors, and 13/17 (76%) had stage IV disease. Nine out of seventeen (56%) patients showed CNVs in cfDNA, with more CNVs in EBV-negative cases. Recurrent gains were detected for 3q, 11q, and 18q. Recurrent losses were observed at 6q. The fraction of EBV reads in cfDNA from EBV-positive patients was 3-log higher compared to controls and EBV-negative patients. 289 SNVs were identified, with a median of 19 per sample. SNV burden correlated significantly with lactate dehydrogenase levels. Similar SNV burdens were observed in EBV-negative and EBV-positive PTLD. The most commonly mutated genes were TP53 and KMT2D (41%), followed by SPEN, TET2 (35%), and ARID1A, IGLL5, and PIM1 (29%), indicating DNA damage response, epigenetic regulation, and B-cell signaling/NFkB pathways as drivers of PTLD. Overall, CNVs were more prevalent in EBV-negative lymphoma, while no difference was observed in the number of SNVs. Our data indicated the potential of analyzing cfDNA as a tool for PTLD screening and response monitoring., (© 2023. BioMed Central Ltd., part of Springer Nature.)
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- 2023
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18. A Joint Pharmacokinetic Model for the Simultaneous Description of Plasma and Whole Blood Tacrolimus Concentrations in Kidney and Lung Transplant Recipients.
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Koomen JV, Knobbe TJ, Zijp TR, Kremer D, Gan CT, Verschuuren EAM, Bakker SJL, Touw DJ, and Colin PJ
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- Humans, Transplant Recipients, Cohort Studies, Kidney, Lung, Tacrolimus pharmacokinetics, Immunosuppressive Agents pharmacokinetics
- Abstract
Background and Objective: Historically, dosing of tacrolimus is guided by therapeutic drug monitoring (TDM) of the whole blood concentration, which is strongly influenced by haematocrit. The therapeutic and adverse effects are however expected to be driven by the unbound exposure, which could be better represented by measuring plasma concentrations., Objective: We aimed to establish plasma concentration ranges reflecting whole blood concentrations within currently used target ranges., Methods: Plasma and whole blood tacrolimus concentrations were determined in samples of transplant recipients included in the TransplantLines Biobank and Cohort Study. Targeted whole blood trough concentrations are 4-6 ng/mL and 7-10 ng/mL for kidney and lung transplant recipients, respectively. A population pharmacokinetic model was developed using non-linear mixed-effects modelling. Simulations were performed to infer plasma concentration ranges corresponding to whole blood target ranges., Results: Plasma (n = 1973) and whole blood (n = 1961) tacrolimus concentrations were determined in 1060 transplant recipients. A one-compartment model with fixed first-order absorption and estimated first-order elimination characterised observed plasma concentrations. Plasma was linked to whole blood using a saturable binding equation (maximum binding 35.7 ng/mL, 95% confidence interval (CI) 31.0-40.4 ng/mL; dissociation constant 0.24 ng/mL, 95% CI 0.19-0.29 ng/mL). Model simulations indicate that patients within the whole blood target range are expected to have plasma concentrations (95% prediction interval) of 0.06-0.26 ng/mL and 0.10-0.93 ng/mL for kidney and lung transplant recipients, respectively., Conclusion: Whole blood tacrolimus target ranges, currently used to guide TDM, were translated to plasma concentration ranges of 0.06-0.26 ng/mL and 0.10-0.93 ng/mL for kidney and lung transplant recipients, respectively., (© 2023. The Author(s).)
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- 2023
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19. Is logistically motivated ex vivo lung perfusion a good idea?
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Van De Wauwer C, van Suylen V, Zhang ZL, Verschuuren EAM, van der Bij W, Gan CT, Ubbink R, and Erasmus ME
- Abstract
Ex vivo lung perfusion (EVLP) is a technique for reconditioning and evaluating lungs. However, the use of EVLP for logistical reasons is still under discussion. In this retrospective study, all EVLPs performed between July 2012 and October 2019 were analyzed for ventilation and perfusion data. After transplantation, primary graft dysfunction (PGD), lung function, chronic lung allograft dysfunction (CLAD)-free survival, and overall survival were analyzed. Fifty EVLPs were performed: seventeen logistic EVLPs led to 15 lung transplantations (LT) and two rejections (LR), and 33 medical EVLPs resulted in 26 lung transplantations (MT) and seven rejections (MR). Pre-EVLP PaO
2 was lower for MT than LT ( p < 0.05). Dynamic lung compliance remained stable in MT and LT but decreased in MR and LR. Plateau airway pressure started at a higher level in MR ( p < 0.05 MT vs. MR at T60) and increased further in LR. After transplantation, there were no differences between MT and LT in PGD, lung function, CLAD-free survival, and overall survival. In addition, the LT group was compared with a cohort group receiving standard donor lungs without EVLP (LTx). There were no significant differences between LT and LTx for PGD, CLAD-free survival, and overall survival. FVC was significantly lower in LT than in LTx after 1 year ( p = 0.005). We found that LT lungs appear to perform better than MT lungs on EVLP. In turn, the outcome in the LT group was comparable with the LTx group. Overall, lung transplantation after EVLP for logistic reasons is safe and makes transplantation timing controllable., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Van De Wauwer, van Suylen, Zhang, Verschuuren, van der Bij, Gan, Ubbink and Erasmus.)- Published
- 2022
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20. Chronic kidney disease after lung transplantation in a changing era.
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Grootjans H, Verschuuren EAM, van Gemert JP, Kerstjens HAM, Bakker SJL, Berger SP, and Gan CT
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- Humans, Quality of Life, Renal Insufficiency, Chronic surgery, Lung Transplantation adverse effects, Diabetes Mellitus
- Abstract
Lung transplant (LTx) physicians are responsible for highly complex post-LTx care, including monitoring of kidney function and responding to kidney function loss. Better survival of the LTx population and changing patient characteristics, including older age and increased comorbidity, result in growing numbers of LTx patients with chronic kidney disease (CKD). CKD after LTx is correlated with worse survival, decreased quality of life and high costs. Challenges lie in different aspects of post-LTx renal care. First, serum creatinine form the basis for estimating renal function, under the assumption that patients have stable muscle mass. Low or changes in muscle mass is frequent in the LTx population and may lead to misclassification of CKD. Second, standardizing post-LTx monitoring of kidney function and renal care might contribute to slow down CKD progression. Third, new treatment options for CKD risk factors, such as diabetes mellitus, proteinuria and heart failure, have entered clinical practice. These new treatments have not been studied in LTx yet but are of interest for future use. In this review we will address the difficult aspects of post-LTx renal care and evaluate new and promising future approaches to slow down CKD progression., Competing Interests: Declaration of Competing Interest CTG received funding from Chiesi pharmaceuticals, outside of the scope of this study. The other authors have nothing to declare. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2022
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21. Impact of COVID-19 social distancing measures on lung transplant recipients: decline in overall respiratory virus infections is associated with stabilisation of lung function.
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de Zwart AES, Riezebos-Brilman A, Lunter GA, Neerken ECU, van Leer-Buter CC, Alffenaar JC, van Gemert AP, Erasmus ME, Gan CT, Kerstjens HAM, Vonk JM, and Verschuuren EAM
- Subjects
- Humans, Transplant Recipients, Physical Distancing, Follow-Up Studies, Lung, Lung Transplantation, COVID-19, Viruses
- Abstract
Background: Coronavirus disease 2019 (COVID-19) social distancing measures led to a dramatic decline in non-COVID-19 respiratory virus infections, providing a unique opportunity to study their impact on annual forced expiratory volume in 1 s (FEV
1 ) decline, episodes of temporary drop in lung function (TDLF) suggestive of infection and chronic lung allograft dysfunction (CLAD) in lung transplant recipients (LTRs)., Methods: All FEV1 values of LTRs transplanted between 2009 and April 2020 at the University Medical Center Groningen (Groningen, The Netherlands) were included. Annual FEV1 change was estimated with separate estimates for pre-social distancing (2009-2020) and the year with social distancing measures (2020-2021). Patients were grouped by individual TDLF frequency (frequent/infrequent). Respiratory virus circulation was derived from weekly hospital-wide respiratory virus infection rates. Effect modification by TDLF frequency and respiratory virus circulation was assessed. CLAD and TDLF rates were analysed over time., Results: 479 LTRs (12 775 FEV1 values) were included. Pre-social distancing annual change in FEV1 was -114 (95% CI -133- -94) mL, while during social distancing FEV1 did not decline: 5 (95% CI -38-48) mL (difference pre-social distancing versus during social distancing: p<0.001). The frequent TDLF subgroup showed faster annual FEV1 decline compared with the infrequent TDLF subgroup (-150 (95% CI -181- -120) versus -90 (95% CI -115- -65) mL; p=0.003). During social distancing, we found significantly lower odds for any TDLF (OR 0.53, 95% CI 0.33-0.85; p=0.008) and severe TDLF (OR 0.34, 0.16-0.71; p=0.005) as well as lower CLAD incidence (OR 0.53, 95% CI 0.27-1.02; p=0.060). Effect modification by respiratory virus circulation indicated a significant association between TDLF/CLAD and respiratory viruses., Conclusions: During COVID-19 social distancing the strong reduction in respiratory virus circulation coincided with markedly less FEV1 decline, fewer episodes of TDLF and possibly less CLAD. Effect modification by respiratory virus circulation suggests an important role for respiratory viruses in lung function decline in LTRs., Competing Interests: Conflict of interest: The authors declare no competing interests., (Copyright ©The authors 2022. For reproduction rights and permissions contact permissions@ersnet.org.)- Published
- 2022
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22. Establishing an economical and widely accessible donation after circulatory death animal abattoir model for lung research using ex vivo lung perfusion.
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Zhang ZL, Moeslund N, Hu MA, Hoffmann R, Venema LH, Van De Wauwer C, Timens W, Okamoto T, Verschuuren EAM, Leuvenink HGD, Eiskjaer H, and Erasmus ME
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- Sheep, Animals, Abattoirs, Lung blood supply, Perfusion methods, Disease Models, Animal, Adenosine Triphosphate, Lung Transplantation methods
- Abstract
Background: Ex vivo lung perfusion (EVLP), is a platform that allows simultaneous testing and treatment of the lungs. However, use of EVLP is costly and requires access to lab animals and accompanying facilities. To increase the use of EVLP for research, we developed a method to perform EVLP using abattoir procured lungs. Furthermore, we were also able to significantly decrease costs., Methods: Six pair of lungs were procured from abattoir sheep. The lungs were then flushed and stored in ice for 3 h. A low-flow (20% of cardiac output) approach, a tidal volume of 6 ml/kg bodyweight and total perfusion time of 3 h were chosen. Perfusion fluids and circuits were self-made. Lung biopsies, perfusate collection, respiratory values, circulatory pressures were recorded and hourly blood gas analyses were performed., Results: Mean pO
2 remained stable from 60 min (49.3 ± 7.1 kPa) to 180 min (51.5 kPa ± 8.0), p = 0.66. Pulmonary artery pressure remained ≤15 mm Hg and the left atrial pressure remained between 3 and 5 mm Hg and peak respiratory pressures ≤20 cmH2 O. Lactate dehydrogenase increased from start (96.3 ± 56.4 U/L) to the end of perfusion (315.8 ± 85.0 U/L), p < 0.05. No difference was observed in ATP between procurement and post-EVLP, 129.7 ± 37.4 μmol/g protein to 132.0 ± 23.4 μmol/g, p = 0.92., Conclusions: Sheep lungs, acquired from an abattoir, can be ex vivo perfused under similar conditions as lab animal lungs with similar results regarding e.g., oxygenation and ATP restoration. Furthermore, costs can be significantly reduced by making use of this abattoir model. By increasing accessibility and lowering costs for experiments using lung perfusion, more results may be achieved in the field of lung diseases., (© 2022 The Authors. Artificial Organs published by International Center for Artificial Organ and Transplantation (ICAOT) and Wiley Periodicals LLC.)- Published
- 2022
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23. The effect of COVID-19 on transplant function and development of CLAD in lung transplant patients: A multicenter experience.
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Roosma E, van Gemert JP, de Zwart AES, van Leer-Buter CC, Hellemons ME, Berg EM, Luijk B, Hoek RAS, van Kessel DA, Akkerman OW, Kerstjens HAM, Verschuuren EAM, and Gan CT
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- Forced Expiratory Volume, Humans, Lung, Retrospective Studies, Spirometry, Vital Capacity, COVID-19, Lung Transplantation
- Abstract
Background: Concerns have been raised on the impact of coronavirus disease (COVID-19) on lung transplant (LTx) patients. The aim of this study was to evaluate the transplant function pre- and post-COVID-19 in LTx patients., Methods: Data were retrospectively collected from LTx patients with confirmed COVID-19 from all 3 Dutch transplant centers, between February 2020 and September 2021. Spirometry results were collected pre-COVID-19, 3- and 6-months post infection., Results: Seventy-four LTx patients were included. Forty-two (57%) patients were admitted, 19 (26%) to the intensive care unit (ICU). The in-hospital mortality was 20%. Twelve out of 19 ICU patients died (63%), a further 3 died on general wards. Patients with available spirometry (78% at 3 months, 65% at 6 months) showed a significant decline in mean forced expiratory volume in 1 second (FEV1) (ΔFEV1 138 ± 39 ml, p = 0.001), and forced vital capacity (FVC) (ΔFVC 233 ±74 ml, p = 0.000) 3 months post infection. Lung function improved slightly from 3 to 6 months after COVID-19 (ΔFEV1 24 ± 38 ml; ΔFVC 100 ± 46 ml), but remained significantly lower than pre-COVID-19 values (ΔFEV1 86 ml ± 36 ml, p = 0.021; ΔFVC 117 ± 35 ml, p = 0.012). FEV1/FVC was > 0.70., Conclusions: In LTx patients COVID-19 results in high mortality in hospitalized patients. Lung function declined 3 months after infection and gradually improved at 6 months, but remained significantly lower compared to pre-COVID-19 values. The more significant decline in FVC than in FEV1 and FEV1/FVC > 70%, suggested a more restrictive pattern., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2022
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24. Biological Characteristics of HLA-G and Its Role in Solid Organ Transplantation.
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Liu S, Bos NA, Verschuuren EAM, van Baarle D, and Westra J
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- Female, Humans, Immune Tolerance, Placenta immunology, Pregnancy immunology, Protein Isoforms, HLA-G Antigens immunology, Organ Transplantation
- Abstract
Organ transplantation is a lifesaving option for patients with advanced diseases. Rejection is regarded as one of the most severe risk factors post-transplantation. A molecule that contributes to immune tolerance and resisting rejection is human leukocyte antigen (HLA)-G, which belongs to the non-classical major histocompatibility complex class (MHC) I family. HLA-G was originally found to play a role during pregnancy to maintain immune tolerance between mother and child. It is expressed in the placenta and detected in several body fluids as soluble factor as well as different membrane isoforms on cells. Recent findings on HLA-G show that it can also play multifaceted roles during transplantation. This review will explain the general characteristics and biological function of HLA-G and summarize the views supporting the tolerogenic and other roles of HLA-G to better understand its role in solid organ transplantation (SOT) and its complications. Finally, we will discuss potential future research on the role of HLA-G in prevention, diagnosis, and treatment in SOT., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Liu, Bos, Verschuuren, van Baarle and Westra.)
- Published
- 2022
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25. Long-term outcome and bridging success of patients evaluated and bridged to lung transplantation on the ICU.
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Gan CT, Hoek RAS, van der Bij W, Van De Wauwer C, Erasmus ME, Oude Lansink-Hartgring A, Droogh JM, Seghers L, Mathot BJ, Mahtab EAF, Bekkers JA, Dos Reis Miranda D, Verschuuren EAM, and Hellemons ME
- Subjects
- Humans, Intensive Care Units, Lung, Retrospective Studies, Extracorporeal Membrane Oxygenation adverse effects, Lung Transplantation adverse effects
- Abstract
Background: Evaluating and bridging patients to lung transplantation (LTx) on the intensive care unit (ICU) remains controversial, especially without a previous waitlist status. Long term outcome data after LTx from ICU remains scarce. We compared long-term survival and development of chronic lung allograft dysfunction (CLAD) in elective and LTx from ICU, with or without previous waitlist status., Methods: Patients transplanted between 2004 and 2018 in 2 large academic Dutch institutes were included. Long-term survival and development of CLAD was compared in patients who received an elective LTx (ELTx), those bridged and transplanted from the ICU with a previous listing status (BTT), and in patients urgently evaluated and bridged on ICU (EBTT)., Results: A total of 582 patients underwent a LTx, 70 (12%) from ICU, 39 BTT and 31 EBTT. Patients transplanted from ICU were younger than ELTx (46 vs 51 years) and were bridged with mechanical ventilation (n = 42 (60%)), extra corporeal membrane oxygenation (n = 28 (40%)), or both (n = 21/28). Bridging success was 48% in the BTT group and 72% in the EBTT group. Patients bridged to LTx on ICU had similar 1 and 5 year survival (86.8% and 78.4%) compared to elective LTx (86.8% and 71.9%). This was not different between the BTT and EBTT group. 5 year CLAD free survival was not different in patients transplanted from ICU vs ELTx., Conclusion: Patients bridged to LTx on the ICU with and without prior listing status had excellent short and long-term patient and graft outcomes, and was similar to patients electively transplanted., Competing Interests: Disclosure statement The authors have no conflicts of interest to declare., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2022
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26. Lung transplantation for acute respiratory distress syndrome: A multicenter experience.
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Frick AE, Gan CT, Vos R, Schwarz S, Kraft F, Kifjak D, Neyrinck AP, Van Raemdonck DE, Klepetko W, Jaksch P, Verschuuren EAM, and Hoetzenecker K
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- Humans, Length of Stay, Lung, Respiration, Artificial, Lung Transplantation, Respiratory Distress Syndrome
- Abstract
Acute respiratory distress syndrome (ARDS) is a rapidly progressive lung disease with a high mortality rate. Although lung transplantation (LTx) is a well-established treatment for a variety of chronic pulmonary diseases, LTx for acute lung failure (due to ARDS) remains controversial. We reviewed posttransplant outcome of ARDS patients from three high-volume European transplant centers. Demographics and clinical data were collected and analyzed. Viral infection was the main reason for ARDS (n = 7/13, 53.8%). All patients were admitted to ICU and required mechanical ventilation, 11/13 were supported with ECMO at the time of listing. They were granted a median LAS of 76 (IQR 50-85) and waited for a median of 3 days (IQR 1.5-14). Postoperatively, median length of mechanical ventilation was 33 days (IQR 17-52.5), median length of ICU and hospital stay were 39 days (IQR 19.5-58.5) and 54 days (IQR 43.5-127). Prolongation of peripheral postoperative ECMO was required in 7/13 (53.8%) patients with a median duration of 2 days (IQR 2-7). 30-day mortality was 7.7%, 1 and 5-year survival rates were calculated as 71.6% and 54.2%, respectively. Given the lack of alternative treatment options, the herein presented results support the concept of offering live-saving LTx to carefully selected ARDS patients., (© 2021 The Authors. American Journal of Transplantation published by Wiley Periodicals LLC on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons.)
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- 2022
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27. A translational rat model for ex vivo lung perfusion of pre-injured lungs after brain death.
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van Zanden JE, Leuvenink HGD, Verschuuren EAM, Erasmus ME, and Hottenrott MC
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- Animals, Cytokines genetics, Cytokines metabolism, Extracorporeal Circulation, Lung metabolism, Lung pathology, Lung Transplantation, Male, Models, Biological, Rats, Rats, Inbred Lew, Tissue Donors, Brain Death, Lung physiopathology, Organ Preservation methods
- Abstract
The process of brain death (BD) detrimentally affects donor lung quality. Ex vivo lung perfusion (EVLP) is a technique originally designed to evaluate marginal donor lungs. Nowadays, its potential as a treatment platform to repair damaged donor lungs is increasingly studied in experimental models. Rat models for EVLP have been described in literature before, yet the pathophysiology of BD was not included in these protocols and prolonged perfusion over 3 hours without anti-inflammatory additives was not achieved. We aimed to establish a model for prolonged EVLP of rat lungs from brain-dead donors, to provide a reliable platform for future experimental studies. Rat lungs were randomly assigned to one of four experimental groups (n = 7/group): 1) healthy, directly procured lungs, 2) lungs procured from rats subjected to 3 hours of BD and 1 hour cold storage (CS), 3) healthy, directly procured lungs subjected to 6 hours EVLP and 4), lungs procured from rats subjected to 3 hours of BD, 1 hour CS and 6 hours EVLP. Lungs from brain-dead rats showed deteriorated ventilation parameters and augmented lung damage when compared to healthy controls, in accordance with the pathophysiology of BD. Subsequent ex vivo perfusion for 6 hours was achieved, both for lungs of healthy donor rats as for pre-injured donor lungs from brain-dead rats. The worsened quality of lungs from brain-dead donors was evident during EVLP as well, as corroborated by deteriorated ventilation performance, increased lactate production and augmented inflammatory status during EVLP. In conclusion, we established a stable model for prolonged EVLP of pre-injured lungs from brain-dead donor rats. In this report we describe tips and pitfalls in the establishment of the rat EVLP model, to enhance reproducibility by other researchers., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2021
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28. Recurrent fever 3 years post-lung transplantation: A treacherous case of Mycobacterium genavense.
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Eskandari SK, Jonkers SY, Almesned MAM, Akkerman OW, Verschuuren EAM, and Gan CT
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- Humans, Nontuberculous Mycobacteria, Lung Transplantation adverse effects, Mycobacterium, Mycobacterium Infections, Mycobacterium Infections, Nontuberculous diagnosis, Mycobacterium Infections, Nontuberculous drug therapy
- Published
- 2021
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29. Waiting List Dynamics and Lung Transplantation Outcomes After Introduction of the Lung Allocation Score in The Netherlands.
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Hoffman TW, Hemke AC, Zanen P, Luijk B, Hoek RAS, Verschuuren EAM, and van Kessel DA
- Abstract
The Netherlands was the third country to adopt the lung allocation score (LAS) for national allocation of donor lungs in April 2014. Evaluations of the introduction of the LAS in the United States and Germany showed mainly beneficial effects, including increased survival after transplantation., Methods: Data for transplant candidates from 2010 to 2019 were retrieved from the Dutch Transplant Foundation database. Diagnosis categories and outcomes were compared between the periods before and after the introduction of the LAS. Time-dependent Cox regression and Fine-Gray analyses were performed to compare the chance for transplantation before and after introduction of the LAS., Results: The cohort comprised 1276 patients. After introduction of the LAS, the annual number of transplantations and waiting list mortality did not change. The proportion of patients on the waiting list and transplanted patients with pulmonary fibrosis increased (25%-37%, P < 0.001; 22%-39%, P < 0.001). The chance of transplantation increased significantly for patients with pulmonary fibrosis after introduction of the LAS (hazard ratio 1.9 [95% confidence interval 1.4-2.9]). Patients who died on the waiting list had an increased LAS compared to the time of placement on the waiting list, reflecting clinical deterioration. This was not the case in patients with chronic obstructive pulmonary disease ( P < 0.001). Overall survival was similar after introduction of the LAS (5-y survival 68%, compared to 74% [ P = 0.171])., Conclusions: After the introduction of the LAS in The Netherlands, an increased proportion of transplantations was performed for patients with pulmonary fibrosis. Overall survival after transplantation did not change., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2021 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)
- Published
- 2021
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30. Ganciclovir therapeutic drug monitoring in transplant recipients.
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Märtson AG, Edwina AE, Burgerhof JGM, Berger SP, de Joode A, Damman K, Verschuuren EAM, Blokzijl H, Bakker M, Span LF, van der Werf TS, Touw DJ, Sturkenboom MGG, Knoester M, and Alffenaar JWC
- Subjects
- Drug Monitoring, Humans, Prospective Studies, Transplant Recipients, Continuous Renal Replacement Therapy, Ganciclovir therapeutic use
- Abstract
Background: The use of (val)ganciclovir is complicated by toxicity, slow response to treatment and acquired resistance., Objectives: To evaluate a routine therapeutic drug monitoring (TDM) programme for ganciclovir in a transplant patient population., Methods: An observational study was performed in transplant recipients from June 2018 to February 2020. Dose adjustments were advised by the TDM pharmacist as part of clinical care. For prophylaxis, a trough concentration (Cmin) of 1-2 mg/L and an AUC24h of >50 mg·h/L were aimed for. For treatment, a Cmin of 2-4 mg/L and an AUC24h of 80-120 mg·h/L were aimed for., Results: Ninety-five solid organ and stem cell transplant patients were enrolled. Overall, 450 serum concentrations were measured; with a median of 3 (IQR = 2-6) per patient. The median Cmin and AUC24h in the treatment and prophylaxis groups were 2.0 mg/L and 90 mg·h/L and 0.9 mg/L and 67 mg·h/L, respectively. Significant intra- and inter-patient patient variability was observed. The majority of patients with an estimated glomerular filtration rate of more than 120 mL/min/1.73 m2 and patients on continuous veno-venous haemofiltration showed underexposure. The highest Cmin and AUC24h values were associated with the increase in liver function markers and decline in WBC count as compared with baseline., Conclusions: This study revealed that a standard weight and kidney function-based dosing regimen resulted in highly variable ganciclovir Cmin and under- and over-exposure were observed in patients on dialysis and in patients with increased renal function. Clearly there is a need to explore the impact of concentration-guided dose adjustments in a prospective study., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.)
- Published
- 2021
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31. Machine Perfusion of Donation After Circulatory Death Liver and Lungs Before Combined Liver-lung Transplantation.
- Author
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van Leeuwen OB, Brüggenwirth IMA, de Kleine RHJ, van den Berg AP, Verschuuren EAM, Erasmus ME, and Porte RJ
- Abstract
Shortage of deceased donor organs for transplantation has led to the increased use of organs from donation after circulatory death (DCD) donors. There are currently no reports describing outcomes after multiorgan transplantation with DCD livers. The use of DCD organs for multiorgan transplantation can be enhanced if the detrimental effects of prolonged cold ischemia and subsequent ischemia-reperfusion injury are overcome. We present a case in which the liver and lungs of a DCD donor were preserved using ex situ machine perfusion for combined liver-lung transplantation. The recipient was a 19-year-old male patient requiring bilateral lung transplantation for severe progressive pleural parenchymal fibroelastosis and portal hypertension with portal vein thrombosis. The donor liver was preserved with dual hypothermic oxygenated machine perfusion, whereas the lungs were perfused using ex vivo lung perfusion. With ex vivo lung perfusion, total preservation time of right and left lung reached 17 and 21 h, respectively. Now, 2 y after transplantation, liver function is normal and lung function is improving. To conclude, we suggest that combined transplantation of DCD liver and lungs is feasible when cold ischemia is reduced with ex situ machine perfusion preservation., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)
- Published
- 2021
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32. Ex Vivo Perfusion With Methylprednisolone Attenuates Brain Death-induced Lung Injury in Rats.
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van Zanden JE, Leuvenink HGD, Verschuuren EAM, Veldhuis ZJ, Ottens PJ, Erasmus ME, and Hottenrott MC
- Abstract
The onset of brain death (BD) leads to the deterioration of potential donor lungs. Methylprednisolone is considered to increase lung oxygenation capacity and enhance the procurement yield of donor lungs, when applied in situ, during donor management. However, whether BD-induced lung damage is ameliorated upon treatment with methylprednisolone during acellular ex vivo lung perfusion (EVLP), remains unknown. We aimed to investigate whether the quality of lungs from brain-dead donors improves upon methylprednisolone treatment during EVLP., Methods: Rat lungs were randomly assigned to 1 of 3 experimental groups (n = 8/group): (1) healthy, directly procured lungs subjected to EVLP; (2) lungs from brain-dead rats subjected to cold storage and EVLP; and (3) lungs from brain-dead rats subjected to cold storage and EVLP with 40 mg methylprednisolone added to the perfusate. Ventilation and perfusion parameters, histology, edema formation, metabolic profile, and inflammatory status of lungs were investigated., Results: Methylprednisolone treated lungs from brain-dead donors improved positive inspiratory pressures needed to maintain tidal volumes of 7 mL/kg of body weight, which was 25.6 ± 5.8 cm H
2 O in untreated lungs and 18.0 ± 3.0 cm H2 O in methylprednisolone treated lungs, after 6 h EVLP. Furthermore, dynamic lung compliance increased upon methylprednisolone treatment, with values of 0.11 ± 0.05 mL/cm H2 O versus 0.18 ± 0.04 mL/cm H2 O after 6 h of EVLP. Methylprednisolone treatment ameliorated the amount of lung edema, as corroborated by a reduction of 0.7 in the wet/dry ratio. Although glucose consumption levels were comparable, the BD-induced cumulative lactate production decreased from 0.44 ± 0.26 to 0.11 ± 0.16 mmol/L upon methylprednisolone treatment. Finally, BD-induced inflammatory status was reduced upon methylprednisolone treatment compared to untreated lungs from brain-dead donors, as reflected by lower proinflammatory gene expression levels of IL-1β, IL-6 and MCP-1, and IL-6 perfusate levels., Conclusions: We showed that methylprednisolone treatment during EVLP attenuates BD-induced lung injury., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2021 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)- Published
- 2021
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33. Ageing of Immune System and Response to a Live-Attenuated Herpes Zoster Vaccine in Lung Transplant Candidates.
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Wang L, Verschuuren EAM, Paap D, Rondaan C, Raveling-Eelsing E, Liu S, Westra J, and Bos NA
- Abstract
The mean age of lung transplant recipients has significantly increased in recent decades. Elderly recipients have a higher risk of developing herpes zoster (HZ), and they have in general a worse response to vaccination than younger persons do. We investigated the relationship between the humoral and cellular immune response to a live-attenuated HZ vaccine (Zostavax
® , Merck Sharp and Dohme) and the frequencies of T and B cell subsets, especially aged cell subsets (CD28-T cells and age associated B cells, ABCs). In total, 37 patients awaiting lung transplantation received one dose of Zostavax® , and peripheral blood was collected before and within 6 months after vaccination. We observed a robust immune response after vaccination. The frequencies of CD28-T cells before vaccination had no impact on the subsequent immune response to HZ vaccination. However, a higher frequency of ABCs before vaccination correlated with a lower immune response especially regarding the cellular immune response. Cytomegalovirus seropositivity was associated with increased frequencies of CD28-T cells but not with frequencies of ABCs in the patients. In conclusion, increased levels of ABCs might disturb the cellular immune response to HZ vaccination, which could lower the efficacy of such vaccination in elderly transplant recipients.- Published
- 2021
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34. Evaluation of 10 years of parainfluenza virus, human metapneumovirus, and respiratory syncytial virus infections in lung transplant recipients.
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de Zwart AES, Riezebos-Brilman A, Alffenaar JC, van den Heuvel ER, Gan CT, van der Bij W, Kerstjens HAM, and Verschuuren EAM
- Subjects
- Antiviral Agents therapeutic use, Humans, Lung, Prospective Studies, Retrospective Studies, Ribavirin therapeutic use, Transplant Recipients, Lung Transplantation adverse effects, Metapneumovirus, Respiratory Syncytial Virus Infections drug therapy, Respiratory Syncytial Virus Infections epidemiology, Respiratory Syncytial Virus Infections etiology, Respiratory Tract Infections drug therapy, Respiratory Tract Infections epidemiology, Respiratory Tract Infections etiology
- Abstract
Respiratory tract infection with pneumoviruses (PVs) and paramyxoviruses (PMVs) are increasingly associated with chronic lung allograft dysfunction (CLAD) in lung transplant recipients (LTRs). Ribavirin may be a treatment option but its effectiveness is unclear, especially with respect to infection severity. We retrospectively analyzed 10 years of PV/PMV infections in LTRs. The main end points were forced expiratory volume in 1 second (FEV
1 ) at 3 and 6 months postinfection, expressed as a percentage of pre-infection FEV1 and incidence of new or progressed CLAD 6 months postinfection. A total of 139 infections were included: 88 severe infections (63%) (defined as >10% FEV1 loss at infection) and 51 mild infections (37%) (≤10% FEV1 loss). Overall postinfection CLAD incidence was 20%. Associations were estimated on postinfection FEV1 for ribavirin vs no ribavirin (+13.2% [95% CI: 7.79; 18.67]) and severe vs mild infection (-11.1% [95% CI: -14.76; -7.37]). Factors associated with CLAD incidence at 6 months were ribavirin treatment (odds ratio (OR [95% CI]) 0.24 [0.10; 0.59]), severe infection (OR [95% CI] 4.63 [1.66; 12.88]), and mycophenolate mofetil use (OR [95% CI] 0.38 [0.14; 0.97]). These data provide valuable information about the outcomes of lung transplant recipients with these infections and suggests possible associations of ribavirin use and infection severity with long-term outcomes. Well-designed prospective trials are needed to confirm these findings., (© 2020 The Authors. American Journal of Transplantation published by Wiley Periodicals LLC on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons.)- Published
- 2020
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35. Prophylactic vaccination with a live-attenuated herpes zoster vaccine in lung transplant candidates.
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Wang L, Verschuuren EAM, Paap D, Rondaan C, Raveling-Eelsing E, Westra J, and Bos NA
- Subjects
- Adult, Aged, Female, Follow-Up Studies, Humans, Male, Middle Aged, Primary Graft Dysfunction immunology, Retrospective Studies, Treatment Outcome, Vaccines, Attenuated, Young Adult, Herpes Zoster Vaccine pharmacology, Herpesvirus 3, Human immunology, Immunity, Cellular, Lung Transplantation, Preoperative Care methods, Primary Graft Dysfunction prevention & control, Respiratory Insufficiency surgery
- Abstract
Background: Herpes zoster (HZ) is caused by the reactivation of varicella-zoster virus (VZV). Patients with lung transplants are at high risk for HZ owing to their immunocompromised status and the need for lifelong immunosuppression. In this study, patients on the waiting list for lung transplantation were vaccinated by a live-attenuated HZ vaccine (Zostavax, Merck Sharp & Dohme), and the safety and immunogenicity of this vaccine were studied., Methods: In total, 105 patients with end-stage pulmonary disease (ESPD) were enrolled (68 participants received 1 dose of Zostavax and 37 participants were enrolled as unvaccinated controls). Among them, 43 patients underwent lung transplantation and were followed up for further analysis. VZV immunoglobulin G antibody titers and VZV-specific cell-mediated immunity (CMI) on multiple time points before and after vaccination and before and after transplantation were measured., Results: Immune response to Zostavax was higher in younger patients, highest within 3 months after vaccination, and not influenced by gender or type of ESPD. Age, cytomegalovirus serostatus, and immunity to VZV at baseline impacted the subsequent immune response to the vaccine. Short-term immunosuppressant treatment had strong effects on VZV CMI levels, which returned to a high level at 6 months after transplantation in vaccinated patients. Zostavax did not impact infection or rejection rate after transplantation., Conclusions: Zostavax was safe and induced a robust humoral and cellular response for patients awaiting lung transplantation regardless of the type of ESPD. Patients younger than the recommended vaccination age of over 50 years showed a strong response and could also benefit from pre-transplant immunization., (Copyright © 2020 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)
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- 2020
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36. Respiratory Syncytial Virus Infection Morbidity in the Elderly: Time for Repurposing of Ribavirin?
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de Zwart AES, Riezebos-Brilman A, Kerstjens HAM, Verschuuren EAM, and Alffenaar JC
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- Aged, Humans, Morbidity, Ribavirin therapeutic use, Influenza, Human, Respiratory Syncytial Virus Infections drug therapy, Respiratory Syncytial Virus Infections epidemiology, Respiratory Syncytial Virus, Human
- Published
- 2020
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37. Repurposed Oral Ribavirin for Respiratory Virus Infections Requires Pharmacokinetic-pharmacodynamic Dose Optimization.
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de Zwart AES, Riezebos-Brilman A, Kerstjens HAM, Verschuuren EAM, and Alffenaar JC
- Subjects
- Humans, Ribavirin therapeutic use, Transplant Recipients, Antiviral Agents therapeutic use, Hematopoietic Stem Cell Transplantation, Respiratory Syncytial Virus Infections drug therapy
- Published
- 2020
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38. Diagnostic performance of FDG-PET/CT of post-transplant lymphoproliferative disorder and factors affecting diagnostic yield.
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Montes de Jesus FM, Kwee TC, Kahle XU, Nijland M, van Meerten T, Huls G, Dierckx RAJO, Rosati S, Diepstra A, van der Bij W, Verschuuren EAM, Glaudemans AWJM, and Noordzij W
- Subjects
- Fluorodeoxyglucose F18, Herpesvirus 4, Human, Humans, Positron Emission Tomography Computed Tomography, Retrospective Studies, Epstein-Barr Virus Infections complications, Epstein-Barr Virus Infections diagnostic imaging, Lymphoproliferative Disorders diagnostic imaging, Lymphoproliferative Disorders etiology
- Abstract
Purpose: Post-transplant lymphoproliferative disorder (PTLD) is a serious complication after solid organ and hematopoietic stem cell transplantation, requiring a timely and accurate diagnosis. In this study, we evaluated the diagnostic performance of FDG-PET/CT in patients with suspected PTLD and examined if lactate dehydrogenase (LDH) levels, Epstein-Barr virus (EBV) load, or timing of FDG-PET/CT relate to detection performance of FDG-PET/CT., Methods: This retrospective study included 91 consecutive patients with clinical suspicion of PTLD and a total of 97 FDG-PET/CT scans within an 8-year period. Pathology reports and a 2-year follow-up were used as the reference standard. Diagnostic performance of FDG-PET/CT for detection of PTLD as well as logistic regression analysis for factors expected to affect diagnostic yield were assessed., Results: The diagnosis of PTLD was established in 34 patients (35%). Fifty-seven FDG-PET/CT scans (59%) were true negative, 29 (30%) were true positive, 6 (6%) false positive, and 5 (5%) false negative. Sensitivity of FDG-PET/CT for the detection of PTLD was 85%, specificity 90%, positive predictive value 83%, and negative predictive value 92%, with good inter-observer variability (k = 0.78). Of the parameters hypothesized to be associated with a true positive FDG-PET/CT result for the diagnosis of PTLD, only LDH was statistically significant (OR 1.03, p = 0.04)., Conclusion: FDG-PET/CT has a good diagnostic performance in patients suspected of PTLD, with a good inter-observer agreement. Only LDH levels seemed to influence the detection performance of FDG-PET/CT. EBV-DNA load and timing of FDG-PET/CT after transplantation did not affect FDG-PET/CT diagnostic yield.
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- 2020
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39. Torquetenovirus Serum Load and Long-Term Outcomes in Renal Transplant Recipients.
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Gore EJ, Gomes-Neto AW, Wang L, Bakker SJL, Niesters HGM, de Joode AAE, Verschuuren EAM, Westra J, and Leer-Buter CV
- Abstract
Following transplantation, patients must take immunosuppressive medication for life. Torquetenovirus (TTV) is thought to be marker for immunosuppression, and TTV-DNA levels after organ transplantation have been investigated, showing high TTV levels, associated with increased risk of infections, and low TTV levels associated with increased risk of rejection. However, this has been investigated in studies with relatively short follow-up periods. We hypothesized that TTV levels can be used to assess long term outcomes after renal transplantation. Serum samples of 666 renal transplant recipients were tested for TTV DNA. Samples were taken at least one year after renal transplantation, when TTV levels are thought to be relatively stable. Patient data was reviewed for graft failure, all-cause mortality and death due to infectious causes. Our data indicates that high TTV levels, sampled more than one year post-transplantation, are associated with all-cause mortality with a hazard ratio (HR) of 1.12 (95% CI, 1.02-1.23) per log
10 increase in TTV viral load, ( p = 0.02). Additionally, high TTV levels were also associated with death due to infectious causes (HR 1.20 (95% CI 1.01-1.43), p = 0.04). TTV levels decrease in the years following renal transplantation, but remain elevated longer than previously thought. This study shows that TTV level may aid in predicting long-term outcomes, all-cause mortality and death due to an infectious cause in renal transplant patients sampled over one year post-transplantation.- Published
- 2020
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40. Exploring failure of antimicrobial prophylaxis and pre-emptive therapy for transplant recipients: a systematic review.
- Author
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Märtson AG, Bakker M, Blokzijl H, Verschuuren EAM, Berger SP, Span LFR, van der Werf TS, and Alffenaar JC
- Subjects
- Adult, Clinical Trials as Topic standards, Cytomegalovirus Infections prevention & control, Documentation, Drug Resistance, Microbial, Humans, Invasive Fungal Infections prevention & control, Randomized Controlled Trials as Topic standards, Transplant Recipients, Treatment Failure, Antibiotic Prophylaxis adverse effects, Opportunistic Infections prevention & control, Organ Transplantation adverse effects, Stem Cell Transplantation adverse effects
- Abstract
Objectives: Infections remain a threat for solid organ and stem cell transplant recipients. Antimicrobial prophylaxis and pre-emptive therapy have improved survival of these patients; however, the failure rates of prophylaxis are not negligible. The aim of this systematic review is to explore the reasons behind failure of antimicrobial prophylaxis and pre-emptive therapy., Setting: This systematic review included prospective randomised controlled trials and prospective single-arm studies., Participants: The studies included were on prophylaxis and pre-emptive therapy of opportunistic infections in transplant recipients. Studies were included from databases MEDLINE, CENTRAL and Embase published until October first 2018., Primary and Secondary Outcome Measures: Primary outcome measures were breakthrough infections, adverse events leading to stopping of treatment, switching medication or dose reduction. Secondary outcome measures were acquired resistance to antimicrobials, antifungals or antivirals and death., Results: From 3317 identified records, 30 records from 24 studies with 2851 patients were included in the systematic review. Seventeen focused on prophylactic and pre-emptive treatment of cytomegalovirus and seven studies on invasive fungal infection. The main reasons for failure of prophylaxis and pre-emptive therapy were adverse events and breakthrough infections, which were described in 54% (13 studies) and 38% (9 studies) of the included studies, respectively. In 25%, six of the studies, a detailed description of patients who experienced failure of prophylaxis or pre-emptive therapy was unclear or lacking., Conclusions: Our results show that although failure is reported in the studies, the level of detail prohibits a detailed analysis of failure of prophylaxis and pre-emptive therapy. Clearly reporting on patients with a negative outcome should be improved. We have provided guidance on how to detect failure early in a clinical setting in accordance to the results from this systematic review., Prospero Registration Number: CRD42017077606., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)
- Published
- 2020
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41. Clinical application of a dried blood spot assay for sirolimus and everolimus in transplant patients.
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Veenhof H, Koster RA, Alffenaar JC, van den Berg AP, de Groot MR, Verschuuren EAM, Berger SP, Bakker SJL, and Touw DJ
- Subjects
- Adult, Biological Assay, Chromatography, Liquid methods, Dried Blood Spot Testing methods, Everolimus blood, Female, Humans, Immunosuppressive Agents blood, Internet, Male, Reproducibility of Results, Sirolimus blood, Software, Specimen Handling, Tandem Mass Spectrometry methods, Drug Monitoring methods, Everolimus analysis, Sirolimus analysis
- Abstract
Background Monitoring of immunosuppressive drugs such as everolimus and sirolimus is important in allograft rejection prevention in transplant patients. Dried blood spots (DBS) sampling gives patients the opportunity to sample a drop of blood from a fingerprick at home, which can be sent to the laboratory by mail. Methods A total of 39 sirolimus and 44 everolimus paired fingerprick DBS and whole blood (WB) samples were obtained from 60 adult transplant patients for method comparison using Passing-Bablok regression. Bias was assessed using Bland-Altman. Two validation limits were pre-defined: limits of analytical acceptance were set at >67% of all paired samples within 20% of the mean of both samples and limits of clinical relevance were set in a multidisciplinary team at >80% of all paired samples within 15% of the mean of both samples. Results For both sirolimus and everolimus, Passing-Bablok regression showed no differences between WB and DBS with slopes of 0.86 (95% CI slope, 0.72-1.02) and 0.96 (95% CI 0.84-1.06), respectively. Only everolimus showed a significant constant bias of 4%. For both sirolimus and everolimus, limits of analytical acceptance were met (76.9% and 81.8%, respectively), but limits or clinical relevance were not met (77.3% and 61.5%, respectively). Conclusions Because pre-defined limits of clinical relevance were not met, this DBS sampling method for sirolimus and everolimus cannot replace WB sampling in our center at this time. However, if the clinical setting is compatible with less strict limits for clinical relevance, this DBS method is suitable for clinical application.
- Published
- 2019
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42. Incidence of Massive Transfusion and Overall Transfusion Requirements During Lung Transplantation Over a 25-Year Period.
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Cernak V, Oude Lansink-Hartgring A, van den Heuvel ER, Verschuuren EAM, van der Bij W, Scheeren TWL, Engels GE, de Geus AF, Erasmus ME, and de Vries AJ
- Subjects
- Adult, Cohort Studies, Female, Humans, Incidence, Lung Transplantation adverse effects, Male, Middle Aged, Mortality trends, Retrospective Studies, Time Factors, Blood Transfusion mortality, Blood Transfusion trends, Lung Transplantation mortality, Lung Transplantation trends
- Abstract
Objective: To establish the incidence of massive transfusion and overall transfusion requirements during lung transplantation, changes over time, and association with outcome in relation to patient complexity., Design: Retrospective cohort study., Setting: University hospital., Participants: All 514 adult patients who underwent transplantation from 1990 until 2015., Interventions: None., Measurements and Main Results: Patient records and transfusion data, divided into 5-year intervals, were analyzed. The incidence of massive transfusion (>10 units of red blood cells [RBCs] in 24 h) was 27% and did not change over time, whereas the median (interquartile range) transfusion requirement in the whole cohort decreased from 8 (5-12) to 3 (0-10) RBCs (p < 0.001). In patients transplanted from the intensive care unit, the incidence of massive transfusion increased over time from 25% to 54% (p = 0.04) and median transfusion requirements from 4.5 (3-8.5) units to 14.5 (5-26) units of RBCs (p = 0.03). Multivariable analysis showed that circulatory support, pulmonary hypertension, re-transplantation, cystic fibrosis, Eisenmenger syndrome, bilateral transplantation, and low body mass index were associated with massive transfusion. Patients with massive transfusion had more primary graft dysfunction grade III at 0, 24, 48, and 72 hours (p < 0.001), higher 30-day mortality (13% v 4%; p < 0.001), and lower 5-year survival (hazard ratio 3.67 [95% confidence interval 1.72-7.85]; p < 0.001)., Conclusion: The incidence of massive transfusion did not change over time, whereas transfusion requirements in the whole cohort decreased. In patients transplanted from the intensive care unit, massive transfusion and transfusion requirements increased. Massive transfusion was associated with poor outcome., (Copyright © 2019 Elsevier Inc. All rights reserved.)
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- 2019
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43. Antiviral-resistant cytomegalovirus infections in solid organ transplantation in the Netherlands.
- Author
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Van Leer Buter CC, de Voogd DWK, Blokzijl H, de Joode AAE, Berger SP, Verschuuren EAM, and Niesters HGM
- Subjects
- Adult, Aged, Cytomegalovirus genetics, Female, Gene Frequency, Genotyping Techniques, Humans, Male, Microbial Sensitivity Tests, Middle Aged, Netherlands epidemiology, Prevalence, Retrospective Studies, Sequence Analysis, DNA, Young Adult, Cytomegalovirus drug effects, Cytomegalovirus Infections epidemiology, Cytomegalovirus Infections virology, Drug Resistance, Viral, Mutation, Organ Transplantation
- Abstract
Objectives: Antiviral resistance in cytomegalovirus (CMV) may result from mutations in the molecular targets of antiviral agents. The aim of this study was to investigate both the prevalence of resistance-associated mutations and the factors associated with antiviral resistance in solid organ transplant (SOT) patients with repeated high CMV loads during antiviral treatment., Methods: SOT patients were selected retrospectively, based on CMV loads of >30000 IU/mL at least twice in a period during which treatment was given. Patient samples were tested for antiviral resistance by Sanger sequencing the UL97 and UL54 genes of CMV, which code for the viral kinase and polymerase. Factors predisposing to and resulting from the development of antiviral resistance mutations were analysed., Results: Multiple samples from 113 SOT patients were tested, showing resistance-associated mutations in 25 patients (22%). A further 20 (18%) patients showed mutations that were not known to be associated with antiviral resistance. Several factors were associated with development of resistance-associated mutations in UL97 as well as UL54, including human leucocyte antigen (HLA) mismatch, which occurred more frequently in the group of patients with resistance mutations. High-level resistance mutations were most frequently seen in UL97., Conclusions: This study shows that by selecting patients solely on the basis of virological response to treatment, more patients with antiviral resistance mutations are identified. In this study we confirm findings by other groups that primary infections are associated with resistance development. Moreover, we show that HLA mismatch is associated with the development of antiviral resistance, which suggests a role for host immunity in the development of resistance., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2019
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44. Sofosbuvir Add-on to Ribavirin Treatment for Chronic Hepatitis E Virus Infection in Solid Organ Transplant Recipients Does Not Result in Sustained Virological Response.
- Author
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van Wezel EM, de Bruijne J, Damman K, Bijmolen M, van den Berg AP, Verschuuren EAM, Ruigrok GA, Riezebos-Brilman A, and Knoester M
- Abstract
Ribavirin is effective for treating immunocompromised patients with chronic hepatitis E virus infection. However, ribavirin treatment is not always successful. We describe 3 solid organ transplant recipients treated with sofosbuvir and ribavirin after failing ribavirin monotherapy. Complete elimination of hepatitis E virus could not be achieved., (© The Author(s) 2019. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)
- Published
- 2019
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45. 99m Tc-HYNIC-IL-2 scintigraphy to detect acute rejection in lung transplantation patients: a proof-of-concept study.
- Author
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Telenga ED, van der Bij W, de Vries EFJ, Verschuuren EAM, Timens W, Luurtsema G, Slart RHJA, Signore A, and Glaudemans AWJM
- Abstract
Rationale: Acute allograft rejection is one of the major complications after lung transplantation, and adequate and early recognition is important. Till now, the reference standard to detect acute rejection is the histopathological grading of transbronchial biopsies (TBBs). Acute rejection is characterised by high levels of activated T lymphocytes. Interleukin-2 (IL-2) binds specifically to high-affinity IL-2 receptors expressed on the cell membrane of activated T lymphocytes. The aim of this proof-of-concept study was to evaluate if non-invasive imaging with
99m Tc-HYNIC-IL-2 is able to detect acute rejection after lung transplantation., Methods:99m Tc-HYNIC-IL-2 scintigraphy (static, SPECT/CT of the lungs) was performed shortly before routine transbronchial biopsy (pathology as reference standard). Scans were scored as likely or unlikely for rejection, and semiquantitative analysis (target-to-background ratio) was performed., Results: Thirteen patients were included of which 3 showed acute rejection at transbronchial biopsy; in 2 of these patients (scored as graded 2-3 at pathology), the scan was scored likely for rejection, and in 1 patient (scored grade 1 at pathology), the scan was scored unlikely. No correlation was found between biopsy results and semiquantitative analysis., Conclusion:99m Tc-HYNIC-IL-2 scintigraphy proved to be a good technique to detect grade 2 and 3 acute rejection in a small sample population of patients after lung transplantation. Larger studies are necessary to really show the added value of this non-invasive specific imaging technique over transbronchial biopsy. Alternatively, imaging with the PET tracer18 F-IL-2 may be useful for this purpose.- Published
- 2019
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46. First experience with ex vivo lung perfusion for initially discarded donor lungs in the Netherlands: a single-centre study.
- Author
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Zhang ZL, van Suylen V, van Zanden JE, Van De Wauwer C, Verschuuren EAM, van der Bij W, and Erasmus ME
- Subjects
- Adult, Aged, Female, Humans, Male, Middle Aged, Netherlands, Primary Graft Dysfunction physiopathology, Retrospective Studies, Lung physiology, Lung surgery, Lung Transplantation adverse effects, Lung Transplantation methods, Lung Transplantation mortality, Reperfusion methods, Transplants physiology, Transplants transplantation
- Abstract
Objectives: Despite progress in lung transplantation (LTx) techniques, a shortage of donor lungs persists worldwide. Ex vivo lung perfusion (EVLP) is a technique that evaluates, optimizes and enables transplantation of the lungs that would otherwise have been discarded. Herein, we present our centre's first EVLP experiences between July 2012 and June 2016, when we performed 149 LTxs., Methods: It was a single-centre, retrospective analysis of a prospectively collected database. The EVLP group (n = 9) consisted of recipients who initially received discarded donor lungs that were reconditioned using EVLP. The non-EVLP (N-EVLP) group (n = 18) consisted of data-matched patients receiving conventional quality lungs in the conventional way. Both groups were compared on primary graft dysfunction (PGD) grades 0-3, pulmonary function, chronic lung allograft dysfunction and survival., Results: In the EVLP group, 33% (3/9) developed PGD1 at 72 h post-LTx. In the N-EVLP group, 11% (2/18) developed PGD1, 6% (1/18) PGD2 and 11% (2/18) PGD3 at 72 h post-LTx. At 3 and 24 months post-LTx, forced expiratory volume in 1 s as percentage of predicted was similar in the EVLP (78% and 92%) and N-EVLP groups (69% and 89%). Forced vital capacity as a percentage of predicted was comparable in the EVLP (77% and 93%) and N-EVLP groups (68% and 101%). Chronic lung allograft dysfunction was diagnosed in 1 N-EVLP patient at 2 years post-LTx. Three-year survival was 78% (7/9) (the EVLP group) vs 83% (15/18) (the N-EVLP group)., Conclusions: These results are in line with the existing literature suggesting that transplantation of the previously discarded lungs recovered by EVLP leads to equal outcomes compared to conventional LTx methods., (© The Author(s) 2018. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)
- Published
- 2019
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47. Population pharmacokinetics of ribavirin in lung transplant recipients and examination of current and alternative dosing regimens.
- Author
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Milliken E, de Zwart AES, Alffenaar JC, Marriott DJE, Riezebos-Brilman A, Schteinman A, Evans AM, Glanville AR, Verschuuren EAM, and Reuter SE
- Subjects
- Adult, Aged, Biological Variation, Individual, Female, Humans, Male, Middle Aged, Monte Carlo Method, Antiviral Agents administration & dosage, Antiviral Agents pharmacokinetics, Lung Transplantation adverse effects, Ribavirin administration & dosage, Ribavirin pharmacokinetics, Transplant Recipients
- Abstract
Background: Ribavirin is used in the treatment of respiratory paramyxovirus infection in lung transplant recipients; however, its pharmacokinetic profile in the transplant population is unknown despite the potential for alterations due to underlying pathology. Furthermore, the ability of current regimens to meet exposure targets has not been established., Objectives: This study examined the pharmacokinetics of ribavirin in a lung transplant population for which current and alternative dosing regimens were assessed., Methods: Population pharmacokinetic modelling was conducted in NONMEM using concentration-time data from 24 lung transplant recipients and 6 healthy volunteers. Monte Carlo simulation was used to assess the ability of dosing regimens to achieve pre-specified target concentrations., Results and Conclusions: A three-compartment model with first-order elimination most adequately described ribavirin concentration-time data, with CLCR and patient type (i.e. lung transplant) identified as significant covariates in the model. Simulations indicate that current regimens achieve efficacious concentrations within 24 h of treatment initiation that increase to supra-therapeutic levels over the treatment period. A regimen of 8 mg/kg q6h orally for 48 h followed by 8 mg/kg q24h orally for the remainder of the treatment period was predicted to result in >90% of patients exhibiting concentrations within the defined target range throughout the entire treatment course. Additional work to formally establish target therapeutic concentrations is required; however, this study provides a valuable first step in determining optimal ribavirin treatment regimens for paramyxovirus infections in the lung transplant population., (© The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2019
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48. Rationale and design of TransplantLines: a prospective cohort study and biobank of solid organ transplant recipients.
- Author
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Eisenga MF, Gomes-Neto AW, van Londen M, Ziengs AL, Douwes RM, Stam SP, Osté MCJ, Knobbe TJ, Hessels NR, Buunk AM, Annema C, Siebelink MJ, Racz E, Spikman JM, Bodewes FAJA, Pol RA, Berger SP, Drost G, Porte RJ, Leuvenink HGD, Damman K, Verschuuren EAM, de Meijer VE, Blokzijl H, and Bakker SJL
- Subjects
- Graft Survival, Humans, Netherlands, Observational Studies as Topic, Prospective Studies, Research Design, Time Factors, Tissue Banks, Tissue and Organ Procurement, Living Donors statistics & numerical data, Organ Transplantation mortality, Organ Transplantation statistics & numerical data, Transplant Recipients statistics & numerical data
- Abstract
Introduction: In the past decades, short-term results after solid organ transplantation have markedly improved. Disappointingly, this has not been accompanied by parallel improvements in long-term outcomes after transplantation. To improve graft and recipient outcomes, identification of potentially modifiable risk factors and development of biomarkers are required. We provide the rationale and design of a large prospective cohort study of solid organ transplant recipients (TransplantLines)., Methods and Analysis: TransplantLines is designed as a single-centre, prospective cohort study and biobank including all different types of solid organ transplant recipients as well as living organ donors. Data will be collected from transplant candidates before transplantation, during transplantation, at 3 months, 6 months, 1 year, 2 years and 5 years, and subsequently every 5 years after transplantation. Data from living organ donors will be collected before donation, during donation, at 3 months, 1 year and 5 years after donation, and subsequently every 5 years. The primary outcomes are mortality and graft failure. The secondary outcomes will be cause-specific mortality, cause-specific graft failure and rejection. The tertiary outcomes will be other health problems, including diabetes, obesity, hypertension, hypercholesterolaemia and cardiovascular disease, and disturbances that relate to quality of life, that is, physical and psychological functioning, including quality of sleep, and neurological problems such as tremor and polyneuropathy., Ethics and Dissemination: Ethical approval has been obtained from the relevant local ethics committee. The TransplantLines cohort study is designed to deliver pioneering insights into transplantation and donation outcomes. The study design allows comprehensive data collection on perioperative care, nutrition, social and psychological functioning, and biochemical parameters. This may provide a rationale for future intervention strategies to more individualised, patient-centred transplant care and individualisation of treatment., Trial Registration Number: NCT03272841., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2018
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49. Physical Activity, Sedentary Time, and Associated Factors in Recipients of Solid-Organ Transplantation.
- Author
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van Adrichem EJ, Dekker R, Krijnen WP, Verschuuren EAM, Dijkstra PU, and van der Schans CP
- Subjects
- Adult, Aged, Cross-Sectional Studies, Fear, Female, Health Behavior, Humans, Male, Middle Aged, Motivation, Socioeconomic Factors, Surveys and Questionnaires, Exercise, Organ Transplantation psychology, Patient Compliance, Sedentary Behavior
- Abstract
Background: Short-term survival after solid-organ transplantation has substantially improved, and the focus has shifted to long-term survival, including the role of physical activity (PA). Knowledge about PA and sedentary time in recipients of solid-organ transplantation is limited, and identification of the levels and associated factors is necessary for intervention development., Objective: The objectives of this study were to investigate the level of PA and sedentary time in recipients of solid-organ transplantation and to identify factors associated with these behaviors., Design: The design consisted of a cross-sectional survey., Methods: Questionnaires on PA level, sedentary time, and potential associated factors were used for recipients of solid-organ transplantation (kidney, liver, lung, and heart [N = 656]). Multiple regression analyses with a variable selection procedure were used., Results: Fewer than 60% of the recipients fulfilled the PA guideline. Factors significantly associated with a lower level of PA included being a woman, younger age (nonlinear), not actively working or being retired, physical limitations, and low expectations and self-confidence. Factors significantly associated with less sedentary time included exercise self-efficacy and not actively working or being retired. Significantly associated with more sedentary time were a high education level, fear of negative effects, physical limitations, and the motivator "health and physical outcomes." The type of transplantation did not significantly influence either of the outcome measures., Limitations: The design did not allow for causal inferences to be made. The studied associated factors were limited to individual and interpersonal factors. Self-reported measures of PA and sedentary time were used., Conclusions: In intervention development directed at increasing the level of PA and reducing sedentary time in recipients of solid-organ transplantation, attention should be paid to physical limitations, fear of negative effects, low expectations and self-confidence, health and physical outcomes, and exercise self-efficacy.
- Published
- 2018
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50. Donor Hypernatremia is Not Related with the Duration of Postoperative Mechanical Ventilation, Primary Graft Dysfunction, or Long-Term Outcome Following Lung Transplantation.
- Author
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Oude Lansink-Hartgring A, Hessels L, de Vries AJ, van der Bij W, Verschuuren EAM, Erasmus ME, and Nijsten MWN
- Subjects
- Adult, Female, Graft Survival, Humans, Male, Middle Aged, Postoperative Period, Primary Graft Dysfunction mortality, Prognosis, Retrospective Studies, Treatment Outcome, Donor Selection, Hypernatremia complications, Lung Transplantation mortality, Primary Graft Dysfunction etiology
- Abstract
BACKGROUND Donor hypernatremia has been associated with reduced graft and recipient survival after heart, liver, kidney, and pancreas transplantation. However, it is unknown what effect donor hypernatremia has on graft and recipient outcomes after lung transplantation. The aim of this study was to investigate the relation of donor hypernatremia with the duration of postoperative mechanical ventilation, the incidence of severe primary graft dysfunction, and survival following lung transplantation. MATERIAL AND METHODS We analyzed all consecutive lung transplantations performed in adult patients at our center between 1995 and 2016. During the study period, donor hypernatremia was not considered a reason to reject lungs for transplantation. Donors were classified into 3 groups: normonatremia (sodium <145 mmol/L), moderate hypernatremia (sodium 145-154 mmol/L), or severe hypernatremia (sodium ≥155 mmol/L). Short-term outcome was defined by the duration of mechanical ventilation and incidence of primary graft dysfunction; long-term outcome was defined by 10-year mortality. RESULTS Donor hypernatremia was recorded in 275 (58%) of the 474 donors. There were no differences in baseline characteristics between the 3 study groups. The duration of mechanical ventilation was similar for all groups (8±25, 7±17, and 9±15 days respectively, P=0.204). Severe primary graft dysfunction was not different between the 3 groups (29%, 26%, 28%, P=0.724). Donor hypernatremia was not associated with (graft) survival, or after correction for potential confounders. CONCLUSIONS Donor hypernatremia was not associated with a worse outcome in lung transplant recipients. Thus, in contrast to solid organ transplantation, donor hypernatremia is not a contraindication for lung transplantation.
- Published
- 2018
- Full Text
- View/download PDF
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