A 48-Year-Old Man With Leukopenia, Jaundice, and Skin Rash After Lung Transplantation

A 48-year-old African-American male subject presented with progressive fatigue, jaundice, and new-onset leukopenia 12 weeks after undergoing bilateral lung transplantation for advanced pulmonary sarcoidosis. His transplant surgery and immediate posttransplantation course were uneventful. Induction immunosuppression included methylprednisolone 500 mg intraoperatively and basiliximab (anti-IL-2 monoclonal antibody) on days 0 and 4 after transplantation. His maintenance immunosuppression posttransplantation was prednisone 20 mg daily, tacrolimus with target tacrolimus levels 10 to 15 ng/mL, and mycophenolate mofetil 750 mg twice daily. Both the donor and recipient were seropositive for cytomegalovirus and Epstein-Barr virus. Infectious disease prophylaxis consisted of valganciclovir, trimethoprim/sulfamethoxazole, and voriconazole. Results of the surveillance bronchoscopy conducted after the lung transplant were negative for acute cellular rejection or infection at 4 and 12 weeks' posttransplantation. Findings on spirometry had continuously improved since transplantation

A 42-Year-Old Woman With Anemia, Shock, and Ischemic Stroke After Lung Transplantation

A 42-year-old woman with mixed connective tissue disease- associated interstitial lung disease underwent bilateral lung transplantation. She had an uneventful surgery and was extubated 3 h later. Induction immunosuppression therapy included methylprednisolone 500 mg intraoperatively, basiliximab (anti-IL-2 monoclonal antibody) on days 0 and 4 after transplantation, and methylprednisolone 125 mg intravenously bid for 2 days following surgery. Maintenance immunosuppression therapy consisted of prednisone 20 mg daily, mycophenolate mofetil 750 mg bid, and enteral tacrolimus 0.5 mg bid. Both the donor and the recipient were seropositive for cytomegalovirus. Infectious disease prophylaxis consisted of valganciclovir, trimethoprim- sulfamethoxazole, and voriconazole

Lung IFNAR1(hi) TNFR2(+) cDC2 promotes lung regulatory T cells induction and maintains lung mucosal tolerance at steady state

The lung is a naturally tolerogenic organ. Lung regulatory T cells (T-regs) control lung mucosal tolerance. Here, we identified a lung IFNAR1(hi)TNFR2(+) conventional DC2 (iR2D2) population that induces T-regs in the lung at steady state. Using conditional knockout mice, adoptive cell transfer, receptor blocking antibodies, and TNFR2 agonist, we showed that iR2D2 is a lung microenvironment-adapted dendritic cell population whose residence depends on the constitutive TNFR2 signaling. IFN beta-IFNAR1 signaling in iR2D2 is necessary and sufficient for T-regs induction in the lung. The Epcam(+)CD45(-) epithelial cells are the sole lung IFN beta producer at the steady state. Surprisingly, iR2D2 is plastic. In a house dust mite model of asthma, iR2D2 generates lung T(H)2 responses. Last, healthy human lungs have a phenotypically similar tolerogenic iR2D2 population, which became pathogenic in lung disease patients. Our findings elucidate lung epithelial cells IFN beta-iR2D2-T-regs axis in controlling lung mucosal tolerance and provide new strategies for therapeutic interventions

In vivo reprogramming of pathogenic lung TNFR2 + cDC2s by IFNβ inhibits HDM-induced asthma

Asthma is a common inflammatory lung disease with no known cure. Previously, we uncovered a lung TNFR2 conventional DC2 subset (cDC2s) that induces regulatory T cells (T ) maintaining lung tolerance at steady state but promotes T 2 response during house dust mite (HDM)-induced asthma. Lung IFNβ is essential for TNFR2 cDC2s-mediated lung tolerance. Here, we showed that exogenous IFNβ reprogrammed T 2-promoting pathogenic TNFR2 cDC2s back to tolerogenic DCs, alleviating eosinophilic asthma and preventing asthma exacerbation. Mechanistically, inhaled IFNβ, not IFNα, activated ERK2 signaling in pathogenic lung TNFR2 cDC2s, leading to enhanced fatty acid oxidation (FAO) and lung T induction. Last, human IFNβ reprogrammed pathogenic human lung TNFR2 cDC2s from patients with emphysema ex vivo. Thus, we identified an IFNβ-specific ERK2-FAO pathway that might be harnessed for DC therapy

Hyperammonemia After Lung Transplantation: Systematic Review and a Mini Case Series

Hyperammonemia after lung transplantation (HALT) is a rare but serious complication with high mortality. This systematic review delineates possible etiologies of HALT and highlights successful strategies used to manage this fatal complication. Seven biomedical databases and grey literature sources were searched using keywords relevant to hyperammonemia and lung transplantation for publications between 1995 and 2020. Additionally, we retrospectively analyzed HALT cases managed at our institution between January 2016 and August 2018. The systematic review resulted in 18 studies with 40 individual cases. The mean peak ammonia level was 769 μmol/L at a mean of 14.1 days post-transplant. The mortality due to HALT was 57.5%. In our cohort of 120 lung transplants performed, four cases of HALT were identified. The mean peak ammonia level was 180.5 μmol/L at a mean of 11 days after transplantation. HALT in all four patients was successfully treated using a multimodal approach with an overall mortality of 25%. The incidence of HALT (3.3%) in our institution is comparable to prior reports. Nonetheless, ammonia levels in our cohort were not as high as previously reported and peaked earlier. We attributed these significant differences to early recognition and prompt institution of multimodal treatment approach

Successful Preoperative Optimization for Lung Transplantation With Transcatheter Mitral Valve Repair

Surgically treatable valvular heart disease is common in patients with end-stage lung disease. Nevertheless, advanced lung disease is often seen as a contraindication to cardiac surgery, and severe valvular disease is seen as a contraindication to lung transplantation. This report describes the case of a patient presenting with very severe chronic obstructive pulmonary disease and severe mitral regurgitation who was managed with transcatheter mitral valve repair and who subsequently underwent successful lung transplantation. Critical valvular heart disease in patients with chronic respiratory failure may be amenable to transcatheter therapy, which may favorably affect lung transplantation candidacy

The Impact of Donor and Recipient Age: Older Lung Transplant Recipients Do Not Require Younger Lungs

Lung transplantation for patients with end-stage lung disease continues to grow worldwide. Increasing demand for this therapy generates significant waitlist mortality, indicating that alternative sources of donor lungs, such as older donors, are needed. The effect of the donor–recipient age relationship on outcomes remains unclear. A retrospective review of the United Network for Organ Sharing Standard Transplant Analysis and Research database was performed for adult lung recipients from 2005 to 2015. Variables examined included donor age, recipient age, listing diagnosis, episodes of acute cellular rejection in the first year, and survival. Both donors and recipients were stratified according to age ranges. Survival was compared with the log-rank test. Propensity score matching was done stratifying donors younger than 60 years versus older than 60 years for the recipient population of 60 to 69 years. From May 2005 to February 2015, 15,844 patients underwent lung transplantation. Unadjusted comparisons of donor-to-recipient age showed that older donor age appeared to be more relevant for recipients 60 to 69 years old (p = 0.002). Nevertheless, when propensity matching was done based on relevant covariates for recipients in this age range by donors younger or older than 60 years, there were no differences in survival. Our results suggest that even though donor and recipient age may be important in lung transplantation, the interplay between donor and recipient age alone is not an independent determinant of survival. Careful selection of lungs from donors older than 60 years old should be exercised, taking into consideration the totality of donor demographics and risk factors rather than dismissing lungs based on advanced age alone

Successful bridge to lung transplantation with transcatheter aortic valve replacement

End-stage lung disease and advanced cardiac conditions are frequently seen together and represent a clinical dilemma. Even though both issues may be amenable to surgical management, combining lung transplant with surgical valve repair is rarely done and theoretically associated with increased morbidity and mortality risks, especially in elderly patients. Here, we describe 2 patients presenting with end-stage lung disease and significant aortic stenosis who were successfully bridged to lung transplant via transcatheter aortic valve replacement. Patient 1 was a 66-year-old man who underwent a double lung transplant 56 days after transcatheter aortic valve replacement. Patient 2 was a 70-year-old man who underwent a single right lung transplant 103 days after transcatheter aortic valve replacement. Both patients had uneventful postoperative courses and are alive at the 1-year time point with excellent performance status. This report suggests that transcatheter aortic valve replacement may favorably impact lung transplant candidacy for patients with end-stage lung disease in the setting of severe aortic stenosis, likely representing a better alternative to concomitant aortic valve replacement and lung transplant in elderly patients

MicroRNA-206 antagomiR‒enriched extracellular vesicles attenuate lung ischemia‒reperfusion injury through CXCL1 regulation in alveolar epithelial cells

Our hypothesis is that the immunomodulatory capacities of mesenchymal stem cell‒derived extracellular vesicles (EVs) can be enhanced by specific microRNAs (miRNAs) to effectively attenuate post-transplant lung ischemia‒reperfusion (IR) injury. The expression of miR-206 was analyzed in bronchoalveolar lavage (BAL) fluid of patients on Days 0 and 1 after lung transplantation. Lung IR injury was evaluated in C57BL/6 mice using a left lung hilar-ligation model with or without treatment with EVs or antagomiR-206‒enriched EVs. Murine lung tissue was used for miRNA microarray hybridization analysis, and cytokine expression, lung injury, and edema were evaluated. A donation after circulatory death and murine orthotopic lung transplantation model was used to evaluate the protection by enriched EVs against lung IR injury. In vitro studies analyzed type II epithelial cell activation after coculturing with EVs. A significant upregulation of miR-206 was observed in the BAL fluid of patients on Day 1 after lung transplantation compared with Day 0 and in murine lungs after IR injury compared with sham. Treatment with antagomiR-206‒enriched EVs attenuated lung dysfunction, injury, and edema compared with treatment with EVs alone after murine lung IR injury. Enriched EVs reduced lung injury and neutrophil infiltration as well as improved allograft oxygenation after murine orthotopic lung transplantation. Enriched EVs significantly decreased proinflammatory cytokines, especially epithelial cell‒dependent CXCL1 expression, in the in vivo and in vitro IR injury models. EVs can be used as biomimetic nanovehicles for protective immunomodulation by enriching them with antagomiR-206 to mitigate epithelial cell activation and neutrophil infiltration in the lungs after IR injury