Rationale

Lung transplantation offers great promise for otherwise terminal lung diseases, but the development of bronchiolitis obliterans syndrome (BOS) continues to limit survival. Although acute rejection and lymphocytic bronchiolitis have been identified as risk factors for the development of BOS, it is unclear whether large-airway lymphocytic inflammation conveys the same risk.

Objectives

We evaluated lymphocytic bronchitis on endobronchial biopsies as a risk factor for BOS and mortality.

Methods

Endobronchial biopsies were collected and graded during surveillance after lung transplantation. We assessed samples with negative cultures collected in the first 90 days from 298 subjects and compared large-airway lymphocytic bronchitis assessed by a 0-2 "E-score" and with standard A and BR pathology scores for acute rejection and small-airway lymphocytic bronchiolitis, respectively.

Measurements and main results

We found surprisingly little association between large- and small-airway lymphocytic inflammation scores from a given bronchoscopy. Endobronchial lymphocytic bronchitis was more prevalent in subjects in BOS stage 0p and BOS stages 1-3 at the time of biopsy. Within 90 days after transplantation, increasing maximum E-score was associated with greater risk of BOS (adjusted hazard ratio, 1.76; 95% confidence interval, 1.11-2.78; P = 0.02) and in this analysis 90-day maximum E-scores were the only score type predictive of BOS (P < 0.01).

Conclusions

These results support a multicenter study to evaluate endoscopic biopsies for the identification of patients at increased risk for BOS. The association of endobronchial lymphocytic inflammation and BOS may have mechanistic implications.

BACKGROUND: The use of hydroxocobalamin following lung transplantation has not been previously reported. We present a series of 3 cases where hydroxocobalamin was used to treat postoperative vasoplegia. METHODS: We conducted a single-center, retrospective review of lung transplantation recipients from January 2016 to December 2020. We used cumulative vasopressor index to standardize vasopressor dose administered and mean arterial pressure at 2- and 24-hour time-points following hydroxocobalamin administration to assess treatment effectiveness. RESULTS: We identified 3 male patients aged 49 to 62, with lung allocation scores between 89.9 and 90.6, requiring extracorporeal membrane oxygenation support (pre- and post-transplant for 5, 5, 9 and 8, 2, 2 days, respectively). Each patient received hydroxocobalamin 5,000 mg infused over 15 minutes, with patient #3 receiving an additional 6 doses over the subsequent 4 days. At the 2-hour time-point, mean arterial pressure increased in all patients (+11%, +17%, and +13%, respectively), although cumulative vasopressor indexes were inconsistent. At 24 hours, patients #1 and #2 demonstrated a marked increase in mean arterial pressure (36% and 23%, respectively) and a decrease in cumulative vasopressor index, while patient #3 displayed stable with slight reduction in cumulative vasopressor index and mean arterial pressure values. No allergic reactions were observed. Patient #3 developed methemoglobinemia and a medication-related false increase in triglycerides. All 3 patients were discharged home. CONCLUSIONS: Hydroxocobalamin may be a valuable adjunct in managing refractory vasoplegia following lung transplantation.

Background

Pulmonary ischaemia-reperfusion injury (IRI) is a major contributor to poor lung transplant outcomes. We recently demonstrated a central role of airway-centred natural killer (NK) cells in mediating IRI; however, there are no existing effective therapies for directly targeting NK cells in humans.

Methods

We hypothesised that a depleting anti-CD94 monoclonal antibody (mAb) would provide therapeutic benefit in mouse and human models of IRI based on high levels of KLRD1 (CD94) transcripts in bronchoalveolar lavage samples from lung transplant patients.

Results

We found that CD94 is highly expressed on mouse and human NK cells, with increased expression during IRI. Anti-mouse and anti-human mAbs against CD94 showed effective NK cell depletion in mouse and human models and blunted lung damage and airway epithelial killing, respectively. In two different allogeneic orthotopic lung transplant mouse models, anti-CD94 treatment during induction reduced early lung injury and chronic inflammation relative to control therapies. Anti-CD94 did not increase donor antigen-presenting cells that could alter long-term graft acceptance.

Conclusions

Lung transplant induction regimens incorporating anti-CD94 treatment may safely improve early clinical outcomes.