Effects of donor smoking history on early post-transplant lung function measured by oscillometry.

Introduction: Prior studies assessing outcomes of lung transplants from cigarette-smoking donors found mixed results. Oscillometry, a non-invasive test of respiratory impedance, detects changes in lung function of smokers prior to diagnosis of COPD, and identifies spirometrically silent episodes of rejection post-transplant. We hypothesise that oscillometry could identify abnormalities in recipients of smoking donor lungs and discriminate from non-smoking donors. Methods: This prospective single-center cohort study analysed 233 double-lung recipients. Oscillometry was performed alongside routine conventional pulmonary function tests (PFT) post-transplant. Multivariable regression models were constructed to compare oscillometry and conventional PFT parameters between recipients of lungs from smoking vs non-smoking donors. Results: The analysis included 109 patients who received lungs from non-smokers and 124 from smokers. Multivariable analysis identified significant differences between recipients of smoking and non-smoking lungs in the oscillometric measurements R5-19, X5, AX, R5z and X5z, but no differences in %predicted FEV1, FEV1/FVC, %predicted TLC or %predicted DLCO. An analysis of the smoking group also demonstrated associations between increasing smoke exposure, quantified in pack years, and all the oscillometry parameters, but not the conventional PFT parameters. Conclusion: An interaction was identified between donor-recipient sex match and the effect of smoking. The association between donor smoking and oscillometry outcomes was significant predominantly in the female donor/female recipient group.

Center variability in the prognostic value of a cumulative acute cellular rejection "A-score" for long-term lung transplant outcomes.

The acute rejection score (A-score) in lung transplant recipients, calculated as the average of acute cellular rejection A-grades across transbronchial biopsies, summarizes the cumulative burden of rejection over time. We assessed the association between A-score and transplant outcomes in 2 geographically distinct cohorts. The primary cohort included 772 double lung transplant recipients. The analysis was repeated in 300 patients from an independent comparison cohort. Time-dependent multivariable Cox models were constructed to evaluate the association between A-score and chronic lung allograft dysfunction or graft failure. Landmark analyses were performed with A-score calculated at 6 and 12 months posttransplant. In the primary cohort, no association was found between A-score and graft outcome. However, in the comparison cohort, time-dependent A-score was associated with chronic lung allograft dysfunction both as a time-dependent variable (hazard ratio, 1.51; P < .01) and when calculated at 6 months posttransplant (hazard ratio, 1.355; P = .031). The A-score can be a useful predictor of lung transplant outcomes in some settings but is not generalizable across all centers; its utility as a prognostication tool is therefore limited.

Chronic lung allograft dysfunction is associated with an increased number of non-HLA antibodies.

BACKGROUND: Chronic lung allograft dysfunction (CLAD) is the major cause of adverse outcomes in lung transplant recipients. Multiple factors, such as infection, alloimmunity, and autoimmunity, may lead to CLAD. Here, we aim to examine the role of non-human leukocytes antigen (HLA) antibodies in CLAD in a large retrospective cohort. METHODS: We analyzed non-HLA antibodies in the pre- and post-transplant sera of 226 (100 CLAD, 126 stable) lung transplant recipients from 5 centers, and we used a separate cohort to confirm our findings. RESULTS: A panel of 18 non-HLA antibodies was selected for analysis based on their significantly higher positive rates in CLAD vs stable groups. The panel-18 non-HLA antibodies (n > 3) may be positive pre- or post-transplant; the risk for CLAD is higher in the latter. The presence of both non-HLA antibody and HLA donor-specific antibody (DSA) was associated with an augmented risk of CLAD (HR=25.09 [5.52-14.04], p < 0.001), which was higher than that for single-positive patients. In the independent confirmatory cohort of 61 (20 CLAD, 41 stable) lung transplant recipients, the risk for CLAD remained elevated in double-positive patients (HR=10.67 [0.98-115.68], p = 0.052). After adjusting for nonstandard immunosuppression, patients with double-positive DSA/Non-HLA antibodies had an elevated risk for graft loss (HR=2.53 [1.29-4.96], p = 0.007). CONCLUSIONS: Circulating non-HLA antibodies (n > 3) were independently associated with a higher risk for CLAD. Furthermore, when non-HLA antibodies and DSA were detected concomitantly, the risk for CLAD and graft loss was significantly increased. These results show that humoral immunity to HLA and non-HLA antigens may contribute to CLAD development.

The Initial Upper Paleolithic of the Altai: New radiocarbon determinations for the Kara-Bom site.

The Initial Upper Paleolithic (IUP) is one of the most important phases in the recent period of the evolution of humans. During a narrow period in the first half of Marine Isotope Stage 3 laminar industries, accompanied by developed symbolism and specific blade technology, emerged over a vast area, replacing different variants of the Middle Paleolithic. In western Eurasia, the earliest appearance of IUP technology is seen at the Boker Tachtit site, dated ca. 50 ka cal BP. The earliest evidence of IUP industries in the Balkans and Central Europe, linked to the spread of Homo sapiens, has been dated to around 48 ka cal BP. A key area of IUP dispersals are the mountains and piedmont of southern Siberia and eastern Central Asia. One of the reference assemblages here is Kara-Bom, an open-air site in the Siberian Altai. Three major settlement phases are distinguished in the sediment sequence. In this paper, we present the results of new radiocarbon determinations and Bayesian models. We find that the latest phase of the IUP, Upper Paleolithic 1 ('UP1') is bracketed between 43 and 35 ka cal BP (at 95.4% probability). The earliest IUP phase, 'UP2', begins to accumulate from ca. 49 ka cal BP and ends by ca. 45 ka cal BP. The Middle Paleolithic 'MP2' assemblages all fall prior to 50 ka cal BP. We can detect a spatial distribution of dates from the geographic core of the IUP beyond the Altai where it appears around 47-45 ka cal BP. The current distribution of dates suggests a west-east dispersal of the IUP technocomplex along the mountain belts of Central Asia and South Siberia.

Results of Lung Transplantation for Cystic Fibrosis With Selected Donors Over 65 Years Old.

Lung transplantation is limited by the shortage of suitable donors. Many programs have begun to use extended criteria donors. Donors over 65 years old are rarely reported, especially for young cystic fibrosis recipients. This monocentric study was conducted for cystic fibrosis recipients from January 2005 to December 2019, comparing two cohorts according to lung donor age (<65 years or ≥65 years). The primary objective was to assess the survival rate at 3 years using a Cox multivariable model. Of the 356 lung recipients, 326 had donors under 65 years, and 30 had donors over 65 years. Donors' characteristics did not differ significantly in terms of sex, time on mechanical ventilation before retrieval, and partial pressure of arterial oxygen/fraction of inspired oxygen ratio. There were no significant differences in post-operative mechanical ventilation duration and incidence of grade 3 primary graft dysfunction between the two groups. At 1, 3, and 5 years, the percentage of predicted forced expiratory volume in 1 s (p = 0.767) and survival rate did not differ between groups (p = 0.924). The use of lungs from donors over 65 years for cystic fibrosis recipients allows extension of the donor pool without compromising results. Longer follow-up is needed to assess the long-term effects of this practice.

Intra-subject variability in oscillometry correlates with acute rejection and CLAD post-lung transplant.

Background: Chronic lung allograft dysfunction (CLAD) is the major cause of death post-lung transplantation, with acute cellular rejection (ACR) being the biggest contributing risk factor. Although patients are routinely monitored with spirometry, FEV1 is stable or improving in most ACR episodes. In contrast, oscillometry is highly sensitive to respiratory mechanics and shown to track graft injury associated with ACR and its improvement following treatment. We hypothesize that intra-subject variability in oscillometry measurements correlates with ACR and risk of CLAD. Methods: Of 289 bilateral lung recipients enrolled for oscillometry prior to laboratory-based spirometry between December 2017 and March 2020, 230 had ≥ 3 months and 175 had ≥ 6 months of follow-up. While 37 patients developed CLAD, only 29 had oscillometry at time of CLAD onset and were included for analysis. These 29 CLAD patients were time-matched with 129 CLAD-free recipients. We performed multivariable regression to investigate the associations between variance in spirometry/oscillometry and the A-score, a cumulative index of ACR, as our predictor of primary interest. Conditional logistic regression models were built to investigate associations with CLAD. Results: Multivariable regression showed that the A-score was positively associated with the variance in oscillometry measurements. Conditional logistic regression models revealed that higher variance in the oscillometry metrics of ventilatory inhomogeneity, X5, AX, and R5-19, was independently associated with increased risk of CLAD (p < 0.05); no association was found for variance in %predicted FEV1. Conclusion: Oscillometry tracks graft injury and recovery post-transplant. Monitoring with oscillometry could facilitate earlier identification of graft injury, prompting investigation to identify treatable causes and decrease the risk of CLAD.

First use of imlifidase desensitization in a highly sensitized lung transplant candidate: a case report.

Lung transplant candidates who are highly sensitized against human leucocyte antigen present an ongoing challenge with regards to finding immunologically acceptable donors. Desensitization strategies aimed at reducing preformed donor-specific antibodies have a number of limitations. Imlifidase, an IgG-degrading enzyme derived from Streptococcus pyogenes, is a novel agent that has been used to convert positive crossmatches to negative in kidney transplant candidates, allowing transplantation to occur. We present the first case of imlifidase use for antibody depletion in a highly sensitized lung transplant candidate who went on to undergo a successful bilateral lung transplant.

Deep learning using multilayer perception improves the diagnostic acumen of spirometry: a single-centre Canadian study.

RATIONALE: Spirometry and plethysmography are the gold standard pulmonary function tests (PFT) for diagnosis and management of lung disease. Due to the inaccessibility of plethysmography, spirometry is often used alone but this leads to missed or misdiagnoses as spirometry cannot identify restrictive disease without plethysmography. We aimed to develop a deep learning model to improve interpretation of spirometry alone. METHODS: We built a multilayer perceptron model using full PFTs from 748 patients, interpreted according to international guidelines. Inputs included spirometry (forced vital capacity, forced expiratory volume in 1 s, forced mid-expiratory flow25-75), plethysmography (total lung capacity, residual volume) and biometrics (sex, age, height). The model was developed with 2582 PFTs from 477 patients, randomly divided into training (80%), validation (10%) and test (10%) sets, and refined using 1245 previously unseen PFTs from 271 patients, split 50/50 as validation (136 patients) and test (135 patients) sets. Only one test per patient was used for each of 10 experiments conducted for each input combination. The final model was compared with interpretation of 82 spirometry tests by 6 trained pulmonologists and a decision tree. RESULTS: Accuracies from the first 477 patients were similar when inputs included biometrics+spirometry+plethysmography (95%±3%) vs biometrics+spirometry (90%±2%). Model refinement with the next 271 patients improved accuracies with biometrics+pirometry (95%±2%) but no change for biometrics+spirometry+plethysmography (95%±2%). The final model significantly outperformed (94.67%±2.63%, p<0.01 for both) interpretation of 82 spirometry tests by the decision tree (75.61%±0.00%) and pulmonologists (66.67%±14.63%). CONCLUSIONS: Deep learning improves the diagnostic acumen of spirometry and classifies lung physiology better than pulmonologists with accuracies comparable to full PFTs.

Strongyloides hyper-infection in a lung transplant recipient: Case report and review of the literature.

CASE PRESENTATION: A 63-year-old man with a left single lung transplant for end-stage combined restrictive and obstructive lung disease developed persistent pulmonary infiltrates and recurrent gram-negative bacteremia post-transplant. Bronchoalveolar lavage fluid revealed a nematode on Papanicolau staining compatible with Strongyloides stercoralis larvae on day 50 post-transplant. Although Strongyloides serology performed post-transplant was negative, a retrospective review of the medical record revealed marked peripheral blood eosinophilia on several occasions before transplantation. Despite reduction in immunosuppression and treatment with albendazole and ivermectin, the patient developed another episode of Escherichia coli bacteremia. He died 3 months post-transplant from pulmonary and neurological complications. DIAGNOSIS: Strongyloides hyper-infection. DISCUSSION: Strongyloides hyper-infection syndrome is known to occur in immunocompromised patients, but it has only been reported once in a lung transplant recipient. This case illustrates the importance of screening for parasitic infections before transplantation in patients with marked eosinophilia, especially among immigrants from countries in which Strongyloides is endemic. Hyper-infection syndrome may appear years after infection in the context of immunosuppression or immunodeficiency. This case also highlights the association between Strongyloides hyper-infection and bacteremia with enteric organisms.

PRÉSENTATION DU CAS: Un homme de 63 ans ayant subi une transplantation du poumon gauche à cause d'une pneumopathie en phase terminale à la fois restrictive et obstructive a développé des infiltrats pulmonaires persistants et une bactériémie à Gram négatif récurrente après la transplantation. À la coloration de Papanicolau, le liquide du lavage bronchoalvéolaire a révélé un nématode compatible avec des larves de Strongyloides stercoralis le cinquantième jour après la transplantation. Même si la sérologie du Strongyloides effectuée après la transplantation était négative, une analyse rétrospective de son dossier médical a révélé une éosinophilie sanguine périphérique marquée à plusieurs occasions avant la transplantation. Malgré la diminution de l'immunodépression et un traitement à l'albendazole et à l'ivermectine, le patient a contracté une nouvelle bactériémie à Escherichia coli. Il est décédé de complications pulmonaires et neurologiques trois mois après la transplantation. DIAGNOSTIC: Hyperinfestation à Strongyloides. DISCUSSION: On sait que le syndrome d'hyperinfestation à Strongyloides se déclare chez des patients immunodéprimés, mais il n'a été signalé qu'une fois chez un transplanté du poumon. Ce cas démontre l'importance du dépistage d'infections parasitaires avant la transplantation chez des patients atteints d'éosinophilie marquée, notamment chez des immigrants de pays où le Strongyloides est endémique. Le syndrome d'hyperinfestation peut se manifester des années après l'infection en cas d'immunodépression ou d'immunodéficience. Ce cas fait également ressortir l'association entre l'hyperinfestation à Strongyloides et la bactériémie causée par des organismes entériques.

Characterization of chronic lung allograft dysfunction phenotypes using spectral and intrabreath oscillometry.

Background: Chronic lung allograft dysfunction (CLAD) is the major cause of death beyond 2 years after lung transplantation and develops in 50% of all patients by 5 years post-transplant. CLAD is diagnosed on the basis of a sustained drop of 20% for at least 3 months in the forced expiratory volume (FEV1), compared to the best baseline value achieved post-transplant. CLAD presents as two main phenotypes: bronchiolitis obliterans syndrome (BOS) is more common and has better prognosis than restrictive allograft syndrome (RAS). Respiratory oscillometry is a different modality of lung function testing that is highly sensitive to lung mechanics. The current study investigated whether spectral and intrabreath oscillometry can differentiate between CLAD-free, BOS- and RAS-CLAD at CLAD onset, i.e., at the time of the initial 20% drop in the FEV1. Methods: A retrospective, cross-sectional analysis of 263 double lung transplant recipients who underwent paired testing with oscillometry and spirometry at the Toronto General Pulmonary Function Laboratory from 2017 to 2022 was conducted. All pulmonary function testing and CLAD diagnostics were performed following international guidelines. Statistical analysis was conducted using multiple comparisons. Findings: The RAS (n = 6) spectral oscillometry pattern differs from CLAD-free (n = 225) by right-ward shift of reactance curve similar to idiopathic pulmonary fibrosis whereas BOS (n = 32) has a pattern similar to obstructive lung disease. Significant differences were found in most spectral and intrabreath parameters between BOS, RAS, and time-matched CLAD-free patients. Post-hoc analysis revealed these differences were primarily driven by BOS instead of RAS. While no differences were found between CLAD-free and RAS patients with regards to spectral oscillometry, the intrabreath metric of reactance at end-inspiration (XeI) was significantly different (p < 0.05). BOS and RAS were differentiated by spectral oscillometry measure R5, and intrabreath resistance at end expiration, ReE (p < 0.05 for both). Conclusion: Both spectral and intrabreath oscillometry can differentiate BOS-CLAD from CLAD-free states while intrabreath oscillometry, specifically XeI, can uniquely distinguish RAS-CLAD from CLAD-free. Spectral and intrabreath oscillometry offer complementary information regarding lung mechanics in CLAD patients to help distinguish the two phenotypes and could prove useful in prognostication.