HLA-C mismatching improves outcomes following lung transplantation.

HLA (HLA) are a major barrier to transplant success, as HLA-A and -B molecules are principal ligands for T-cells, and HLA-C for Killer cell Immunoglobulin-like Receptors (KIR), directing Natural Killer (NK) cell function. HLA-C molecules are designated "C1" or "C2" ligands based on residues 77 and 80, which determine the NK cell responses. Here, we investigated donor/recipient HLA-C mismatch associations with the development of chronic lung allograft dysfunction (CLAD) following lung transplantation (LTx). 310 LTx donor/recipient pairs were Next Generation Sequenced and assessed for C1 and C2 allotypes. PIRCHE scores were used to quantify HLA mismatching between donor/recipients at amino acid level and stratify recipients into low, moderate or highly mismatched groups (n = 103-104). Associations between C ligands and freedom from CLAD was assessed with Cox regression models and survival curves. C2/C2 recipients (n = 42) had less CLAD than those with C1/C1 (n = 138) or C1/C2 genotypes (n = 130) (p < 0.05). Incidence of CLAD was lower in C2/C2 recipients receiving a mismatched C1/C1 allograft (n = 14), compared to matched (n = 8) or heterozygous (n = 20) allografts. Furthermore, ~80% of these recipients (C2/C2 recipients receiving C1/C1 transplants) remained CLAD-free for 10 years post-LTx. Recipients with higher HLA-C mismatching had less CLAD (p < 0.05) an observation not explained by linkage disequilibrium with other HLA loci. Our data implicates a role for HLA-C in CLAD development. HLA-C mismatching was not detrimental to LTx outcome, but potentially beneficial, representing a paradigm shift in assessing donor/recipient matching. This may inform better selection of donor/recipient pairs and potentially more targeted approaches to treating CLAD.

How do we expand the lung donor pool?

PURPOSE OF REVIEW: Lung transplantation activity continues to be limited by the availability of timely quality donor lungs. It is apparent though that progress has been made. The steady evolution of clinical practice, combined with painstaking scientific discovery and innovation are described. RECENT FINDINGS: There have been successful studies reporting innovations in the wider use and broader consideration of donation after circulatory death donor lungs, including an increasing number of transplants from each of the controlled, uncontrolled and medically assisted dying donor descriptive categories. Donors beyond age 70 years are providing better than expected long-term outcomes. Hepatitis C PCR positive donor lungs can be safely used if treated postoperatively with appropriate antivirals. Donor lung perfusion at a constant 10 degrees appears capable of significantly improving donor logistics and ex-vivo lung perfusion offers the potential of an ever-increasing number of novel donor management roles. Bioartificial and xenografts remain distant possibilities only at present. SUMMARY: Donor lungs have proved to be surprisingly robust and combined with clinical, scientific and engineering innovations, the realizable lung donor pool is proving to be larger than previously thought.

COVID-19 infection is mild and has minimal impact on lung function in well vaccinated and widely treated lung transplant recipients.

BACKGROUND: COVID-19 has become a common infection affecting lung transplant recipients (LTR), who are at high risk for poor outcomes. Outcomes early in the pandemic were poor, but since the rollout of vaccination and novel COVID-19 treatments, outcomes of LTR have not been well described. Our aim was to evaluate the effect of COVID-19 on the clinical course and lung function trajectory in an Australian cohort of LTR. METHODS: Data were retrospectively collected from LTR with confirmed COVID-19 managed at Alfred Health, between August 2020 and December 2022. Baseline demographics, COVID-19 disease details (including severity) and spirometry pre- and postinfection have been analyzed. RESULTS: A total of 279 LTR were included. The cohort was comorbid, but well vaccinated, with 275/279 (98.6%) having ≥2 COVID-19 vaccines at symptom onset. Severe disease occurred in only 17 cases (6%) and overall mortality was very low (4%). Prompt treatment with antivirals, particularly remdesevir (OR 0.18, 95% CI 0.04-0.81, p = 0.02) and vaccination (OR 0.24, CI 0.08-0.81, p = 0.01), was protective. There was not a clinically significant drop in lung function post-COVID-19 with the median absolute decline in forced expiratory volume (FEV1) being 40 ml (IQR 5-120 ml, p < 0.001), with a decline of >10% occurring in only 42 patients (17%). After multivariate adjustment, only rejection before COVID-19 was significantly associated with FEV1 decline afterward (OR 3.74, 1.12-11.86, p = 0.03). CONCLUSIONS: In our highly COVID-19 vaccinated, promptly treated LTR, the majority of COVID-19 infections were mild and did not result in a clinically significant decline in lung function.

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.

Oscillometry in Stable Single and Double Lung Allograft Recipients Transplanted for Interstitial Lung Disease: Results of a Multi-Center Australian Study.

Peak spirometry after single lung transplantation (SLTx) for interstitial lung disease (ILD) is lower than after double lung transplantation (DLTx), however the pathophysiologic mechanisms are unclear. We aim to assess respiratory mechanics in SLTx and DLTx for ILD using oscillometry. Spirometry and oscillometry (tremoflo® C-100) were performed in stable SLTx and DLTx recipients in a multi-center study. Resistance (R5, R5-19) and reactance (X5) were compared between LTx recipient groups, matched by age and gender. A model of respiratory impedance using ILD and DLTx data was performed. In total, 45 stable LTx recipients were recruited (SLTx n = 23, DLTx n = 22; males: 87.0% vs. 77.3%; median age 63.0 vs. 63.0 years). Spirometry was significantly lower after SLTx compared with DLTx: %-predicted mean (SD) FEV1 [70.0 (14.5) vs. 93.5 (26.0)%]; FVC [70.5 (16.8) vs. 90.7 (12.8)%], p < 0.01. R5 and R5-19 were similar between groups (p = 0.94 and p = 0.11, respectively) yet X5 was significantly worse after SLTx: median (IQR) X5 [-1.88 (-2.89 to -1.39) vs. -1.22 (-1.87 to -0.86)] cmH2O.s/L], p < 0.01. R5 and X5 measurements from the model were congruent with measurements in SLTx recipients. The similarities in resistance, yet differences in spirometry and reactance between both transplant groups suggest the important contribution of elastic properties to the pathophysiology. Oscillometry may provide further insight into the physiological changes occurring post-LTx.