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Complications like acute cellular rejection (ACR) and infection are known risk factors for the development of chronic lung allograft dysfunction, impacting long-term patient and graft survival after lung transplantation (LTx). Differentiating between complications remains challenging and time-sensitive, highlighting the need for accurate and rapid diagnostic modalities. We assessed the ability of exhaled breath analysis using an electronic nose (eNose) to distinguish between ACR, infection, and mechanical complications in LTx recipients (LTR) presenting with suspected complications. LTR with suspected complications and subsequently proven diagnosis underwent exhaled breath analysis using an eNose. Supervised machine learning was used to assess the eNose's ability to discriminate between complications. Next, we determined the added value of the eNose measurement on top of standard clinical parameters. In 90 LTR, 161 measurements were performed during suspected complications, with 84 proven diagnoses. The eNose could distinguish between ACR, infection, and mechanical complications with 74% accuracy, and ACR and infection with 82% accuracy. Combining eNose measurements with standard clinical parameters improved diagnostic accuracy to 88% (P =.0139), with 94% sensitivity and 80% specificity. Exhaled breath analysis using eNose technology is a promising, noninvasive, diagnostic modality for distinguishing LTx complications, enabling timely diagnosis and interventions., Competing Interests: Declaration of competing interest The authors of this manuscript have conflicts of interest to disclose as described by the American Journal of Transplantation. Olivier C. Manintveld reports speaker engagement or advisory board fees from Astra Zeneca, Abbott, Boehringer Ingelheim, Daiichi Sankyo, Novartis, Novo Nordisk, Siemens, and Vifor. Nynke Wijbenga has no conflicts of interest to disclose. Bas J. Mathot has no conflicts of interest to disclose. Roel van Pel has no conflicts of interest to disclose. Leonard Seghers has no conflicts of interest to disclose. Catharina C. Moor has no conflicts of interest to disclose. Joachim G. J. V. Aerts has no conflicts of interest to disclose. Daniel Bos has no conflicts of interest to disclose. Merel E. Hellemons has no conflicts of interest to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

We present an exceptional case of a lung transplant recipient successfully treated by multiple courses of alemtuzumab for refractory acute cellular rejection (ACR). The patient experienced multiple episodes of ACR following the transplantation procedure. Alemtuzumab was initiated as a third-line rejection treatment and was repeated 6 times. Each treatment course resulted in complete recovery of the pulmonary function and depletion of T- and B-lymphocytes and natural killer cells (NK cells). The onset of rejection was consistently preceded by the recovery of NK cells, while T- and B-lymphocytes remained depleted. This suggests a rejection process mediated by NK cells. This case contributes to recent research findings suggesting that NK cells play a significant role in ACR in lung transplant recipients and stresses the importance to further investigate the role of NK cells in rejection. Furthermore, it demonstrates that ACR following lung transplantation can be repeatedly managed by treatment with alemtuzumab., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

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.)

Background: Bacterial colonization (BC) of the lower airways is common in lung transplant recipients (LTRs) and increases the risk of chronic lung allograft dysfunction. Diagnosis often requires bronchoscopy. Exhaled breath analysis using electronic nose (eNose) technology may noninvasively detect BC in LTRs. Therefore, we aimed to assess the diagnostic accuracy of an eNose to detect BC in LTRs., Methods: We performed a cross-sectional analysis within a prospective, single-center cohort study assessing the diagnostic accuracy of detecting BC using eNose technology in LTRs. In the outpatient clinic, consecutive LTR eNose measurements were collected. We assessed and classified the eNose measurements for the presence of BC. Using supervised machine learning, the diagnostic accuracy of eNose for BC was assessed in a random training and validation set. Model performance was evaluated using receiver operating characteristic analysis., Results: In total, 161 LTRs were included with 80 exclusions because of various reasons. Of the remaining 81 patients, 16 (20%) were classified as BC and 65 (80%) as non-BC. eNose-based classification of patients with and without BC provided an area under the curve of 0.82 in the training set and 0.97 in the validation set., Conclusions: Exhaled breath analysis using eNose technology has the potential to noninvasively detect BC., Competing Interests: J.G.J.V.A. reports personal fees and nonfinancial support from Merck Sharp & Dohme and personal fees from Bristol Myers Squibb's, Boehringer Ingelheim, Amphera, Eli Lilly, Takeda, Bayer, Roche, and Astra Zeneca outside the submitted work. In addition, J.G.J.V.A. has a patent on allogenic tumor cell lysate licensed to Amphera, a patent combination immunotherapy in cancer pending, and a patent biomarker for immunotherapy pending. O.M. reports personal fees from Astra Zeneca, Boehringer Ingelheim, and Novartis outside the submitted work. In addition, O.M. is Chair of the Working Group Heart Failure of the Dutch Society of Cardiology. The other authors declare no conflicts of interest., (Copyright © 2023 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)

In order to prevent long-term immunity-related complications after lung transplantation, close monitoring of immunosuppressant levels using therapeutic drug monitoring (TDM) is paramount. Novel electronic nose (eNose) technology may be a non-invasive alternative to the current invasive procedures for TDM. We investigated the diagnostic and categorization capacity of eNose breathprints for Tacrolimus trough blood plasma levels (TAC trough ) in lung transplant recipients (LTRs). We performed eNose measurements in stable LTR attending the outpatient clinic. We evaluated (1) the correlation between eNose measurements and TAC trough , (2) the diagnostic capacity of eNose technology for TAC trough , and (3) the accuracy of eNose technology for categorization of TAC trough into three clinically relevant categories (low: <7 µ g ml -1 , medium: 7-10 µ g ml -1 , and high: >10 µ g ml -1 ). A total of 186 measurements from 86 LTR were included. There was a weak but statistically significant correlation ( r = 0.21, p = 0.004) between the eNose measurements and TAC trough . The root mean squared error of prediction for the diagnostic capacity was 3.186 in the training and 3.131 in the validation set. The accuracy of categorization ranged between 45%-63% for the training set and 52%-69% in the validation set. There is a weak correlation between eNose breathprints and TAC trough in LTR. However, the diagnostic as well as categorization capacity for TAC trough using eNose breathprints is too inaccurate to be applicable in TDM., (© 2023 IOP Publishing Ltd.)

Background: There is a need for reliable biomarkers for the diagnosis of chronic lung allograft dysfunction (CLAD). In this light, we investigated the diagnostic value of exhaled breath analysis using an electronic nose (eNose) for CLAD, CLAD phenotype, and CLAD stage in lung transplant recipients (LTR)., Methods: We performed eNose measurements in LTR with and without CLAD, visiting the outpatient clinic. Through supervised machine learning, the diagnostic value of eNose for CLAD was assessed in a random training and validation set. Next, we investigated the diagnostic value of the eNose measurements combined with known risk factors for CLAD. Model performance was evaluated using ROC-analysis., Results: We included 152 LTR (median age 60 years, 49% females), of whom 38 with CLAD. eNose-based classification of patients with and without CLAD provided an AUC of 0.86 in the training set, and 0.82 in the validation set. After adding established risk factors for CLAD (age, gender, type of transplantation, time after transplantation and prior occurrence of acute cellular rejection) to a model with the eNose data, the discriminative ability of the model improved to an AUC of 0.94 (p = 0.02) in the training set and 0.94 (p = 0.04) in the validation set. Discrimination between BOS and RAS was good (AUC 0.95). Discriminative ability for other phenotypes (AUCs ranging 0.50-0.92) or CLAD stages (AUC 0.56) was limited., Conclusion: Exhaled breath analysis using eNose is a promising novel biomarker for enabling diagnosis and phenotyping CLAD. eNose technology could be a valuable addition to the diagnostic armamentarium for suspected graft failure in LTR., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Exhaled breath analysis using eNose technology holds promise as a point-of-care indicator of clinical status after lung transplantation. This case study invites further exploration of eNose technology in the field of lung transplantation. https://bit.ly/3wgQ3DE., Competing Interests: Conflict of interest: N. Wijbenga has no conflicts of interest to disclose. Conflict of interest: R.A.S. Hoek has no conflicts of interest to disclose. Conflict of interest: B.J. Mathot has no conflicts of interest to disclose. Conflict of interest: L. Seghers has no conflicts of interest to disclose. Conflict of interest: J.G.J.V. Aerts reports personal fees and nonfinancial support from MSD; and personal fees from BMS, Boehringer Ingelheim, Amphera, Eli Lilly, Takeda, Bayer, Roche and Astra Zeneca, outside the submitted work. In addition, he has a patent on allogenic tumour cell lysate licensed to Amphera, a patent combination immunotherapy in cancer pending, and a patent biomarker for immunotherapy pending. Conflict of interest: O.C. Manintveld has no conflicts of interest to disclose. Conflict of interest: M.E. Hellemons is an associate editor of this journal., (Copyright ©The authors 2022.)

Background: Serological responses to COVID-19 vaccination are diminished in recipients of solid organ transplants, especially in lung transplant recipients (LTR), probably as result of immunosuppressive treatment. There is currently no marker of immunosuppression that can be used to predict the COVID-19 vaccination response. Here, we study whether torque tenovirus (TTV), a highly prevalent virus can be used as an indicator of immunosuppression., Methods: The humoral response to the mRNA 1273 vaccine was assessed in 103 LTR, who received a transplant between 4 and 237 months prior to vaccination, by measuring Spike (S)-specific IgG levels at baseline, 28 days after first, and 28 days after the second vaccination. TTV loads were determined by RT-PCR and Pearson's correlation coefficient was calculated to correlate serological responses to TTV load., Results: Humoral responses to COVID-19 vaccination were observed in 41 of 103 (40%) LTR at 28 days after the second vaccination. Sixty-two of 103 (60%) were non-responders. Lower TTV loads at baseline (significantly) correlated with higher S-specific antibodies and a higher percentage of responders. Lower TTV loads also strongly correlated with longer time since transplantation, indicating that participants with lower TTV loads were longer after transplantation., Conclusions: This study shows a better humoral response to the SARS-CoV-2 vaccine in subjects with a lower TTV load pre-vaccination. In addition, TTV load correlates with the time after transplantation. Further studies on the use of TTV load in vaccination efficacy studies in immunocompromised cohorts should provide leads for the potential use of this marker for optimizing vaccination response., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Home spirometry after lung transplantation is common practice, to monitor graft function. However, there is little experience with online home monitoring applications with direct data transfer to the hospital. We evaluated the feasibility and patient experiences with a new online home monitoring application, integrated with a Bluetooth-enabled spirometer and real-time data transfer. Consecutive lung transplant recipients were asked to evaluate this home monitoring application for three months in a pilot study. Home spirometry measurements were compared with in-hospital lung function tests (the forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC)) at the end of the study. Ten patients participated. The home and hospital spirometry measurements showed a high correlation, for both the FEV1 ( r = 0.99, p < 0.01) and FVC ( r = 0.99, p < 0.01). The adherence and patient satisfaction were high, and the patients preferred the home monitoring application over the current home spirometer, with a difference of 1.4 ± 1.5 points on a scale from 0 to 10 ( p = 0.02). Online home monitoring with direct data transfer is feasible and reliable after lung transplantation and results in high patient satisfaction. Whether the implementation of online home monitoring enables the earlier detection of lung function decline and improves patient and graft outcomes will be the subject of future research.