The Impact of Donor Smoking on Primary Graft Dysfunction and Mortality after Lung Transplantation.

Rationale: Primary graft dysfunction (PGD) is the leading cause of early morbidity and mortality after lung transplantation. Prior studies implicated proxy-defined donor smoking as a risk factor for PGD and mortality. Objectives: We aimed to more accurately assess the impact of donor smoke exposure on PGD and mortality using quantitative smoke exposure biomarkers. Methods: We performed a multicenter prospective cohort study of lung transplant recipients enrolled in the Lung Transplant Outcomes Group cohort between 2012 and 2018. PGD was defined as grade 3 at 48 or 72 hours after lung reperfusion. Donor smoking was defined using accepted thresholds of urinary biomarkers of nicotine exposure (cotinine) and tobacco-specific nitrosamine (4-[methylnitrosamino]-1-[3-pyridyl]-1-butanol [NNAL]) in addition to clinical history. The donor smoking-PGD association was assessed using logistic regression, and survival analysis was performed using inverse probability of exposure weighting according to smoking category. Measurements and Main Results: Active donor smoking prevalence varied by definition, with 34-43% based on urinary cotinine, 28% by urinary NNAL, and 37% by clinical documentation. The standardized risk of PGD associated with active donor smoking was higher across all definitions, with an absolute risk increase of 11.5% (95% confidence interval [CI], 3.8% to 19.2%) by urinary cotinine, 5.7% (95% CI, -3.4% to 14.9%) by urinary NNAL, and 6.5% (95% CI, -2.8% to 15.8%) defined clinically. Donor smoking was not associated with differential post-lung transplant survival using any definition. Conclusions: Donor smoking associates with a modest increase in PGD risk but not with increased recipient mortality. Use of lungs from smokers is likely safe and may increase lung donor availability. Clinical trial registered with www.clinicaltrials.gov (NCT00552357).

Infectious complications associated with bronchial anastomotic dehiscence in lung transplant recipients.

INTRODUCTION: Bronchial anastomotic dehiscence (AD) is an uncommon complication following lung transplantation that carries significant morbidity and mortality. The objective of this study was to characterize fungal and bacterial infections in ADs, including whether infections following AD were associated with progression to bronchial stenosis. METHODS: This was a single-center study of 615 lung transplant recipients between 6/1/2015 and 12/31/2021. Airway complications were defined according to ISHLT consensus guidelines. RESULTS: 22 of the 615 recipients (3.6%) developed an AD. Bronchial ischemia or necrosis was common prior to dehiscence (68.1%). Fourteen (63.6%) recipients had bacterial airway infections, most commonly with Gram-negative rods, prior to dehiscence. Thirteen (59.1%) recipients had an associated pleural infection, most commonly with Candida species (30.8%). Post-dehiscence Aspergillus species were isolated in 4 recipients, 3 of which were de novo infections. Eleven had bacterial infections prior to dehiscence resolution, most commonly with Pseudomonas aeruginosa. Eleven recipients developed airway stenosis requiring dilation and/or stenting. Development of secondary infection prior to AD resolution was not associated with progression to stenosis (OR = .41, 95% CI = .05-3.30, p = .41). CONCLUSIONS: Gram-negative bacterial infections are common before and after AD. Pleural infection should be suspected in most cases. Infections prior to healing were not associated with subsequent development of airway stenosis.

Collaborative leadership in transplantation: Blending clinical, business, and regulatory roles.

Transplantation is a high-risk, high-cost treatment for end-stage diseases and is the most strictly regulated area of healthcare in the United States. Thus, achieving success for patients and the program requires skillful and collaborative leadership. Various factors, such as outcomes, volume, and financial health, may measure the success of a transplant program. Strong collaboration between clinical and administrative leaders is key to achieving and maintaining success in those three categories. Clinical leaders of adult programs, such as medical and surgical directors, bear the primary responsibility for a program's volume, outcomes, and patient safety, while administrative directors are focused on business intelligence and regulatory compliance. This paper aims to provide readers with insights into the critical role of collaborative leadership in running a successful program, with a focus on clinical, business, and regulatory perspectives.

Managing connective tissue disease: how to select and facilitate successful transplantation.

PURPOSE OF REVIEW: Lung transplant (LTx) evaluation and selection of candidates with connective tissue disease (CTD) remains controversial and varies between centers, and the optimal candidate selection is still controversial. RECENT FINDINGS: Recent United States and European publications have reported reasonable short-term and long-term LTx outcomes in patients with CTD to other lung fibrosis patients without CTD. This article discusses the recently published International Society for Heart and Lung Transplantation (ISHLT) consensus document recommendations to evaluate and select CTD candidates, the importance of early referral, posttransplant management, and the involvement of a multidisciplinary team. SUMMARY: Future standardized practices among centers adapting the 2021 ISHLT consensus recommendations to evaluate and select CTD candidates will allow risk stratification, determine the best candidates, and facilitate the most successful long-term LTx outcomes.

COVID-19 in hospitalized lung and non-lung solid organ transplant recipients: A comparative analysis from a multicenter study.

Lung transplant recipients (LTR) with coronavirus disease 2019 (COVID-19) may have higher mortality than non-lung solid organ transplant recipients (SOTR), but direct comparisons are limited. Risk factors for mortality specifically in LTR have not been explored. We performed a multicenter cohort study of adult SOTR with COVID-19 to compare mortality by 28 days between hospitalized LTR and non-lung SOTR. Multivariable logistic regression models were used to assess comorbidity-adjusted mortality among LTR vs. non-lung SOTR and to determine risk factors for death in LTR. Of 1,616 SOTR with COVID-19, 1,081 (66%) were hospitalized including 120/159 (75%) LTR and 961/1457 (66%) non-lung SOTR (p = .02). Mortality was higher among LTR compared to non-lung SOTR (24% vs. 16%, respectively, p = .032), and lung transplant was independently associated with death after adjusting for age and comorbidities (aOR 1.7, 95% CI 1.0-2.6, p = .04). Among LTR, chronic lung allograft dysfunction (aOR 3.3, 95% CI 1.0-11.3, p = .05) was the only independent risk factor for mortality and age >65 years, heart failure and obesity were not independently associated with death. Among SOTR hospitalized for COVID-19, LTR had higher mortality than non-lung SOTR. In LTR, chronic allograft dysfunction was independently associated with mortality.

Lung transplantation outcomes after crossing low-level donor specific antibodies without planned augmented immunosuppression.

It is unknown whether some donor specific antibodies (DSA) can be crossed at the time of lung transplant without desensitization or augmented induction immunosuppression. This study assessed whether crossing low-level pre-transplant DSA (defined as mean fluorescence intensity [MFI] 1000-6000) without augmented immunosuppression is associated with worse retransplant-free or chronic lung allograft dysfunction (CLAD)-free survival. Of the 458 included recipients, low-level pre-transplant DSA was crossed in 39 (8.6%) patients. The median follow-up time was 2.2 years. There were 15 (38.5%) patients with Class I DSA and 24 (61.5%) with Class II DSA. There was no difference in adjusted overall retransplant-free survival between recipients where pre-transplant DSA was and was not crossed (HR: .98 [95% CI = .49-1.99], P = .96). There was also no difference in CLAD-free survival (HR: .71 [95% CI = .38-1.33], P = .28). There was no difference in Grade 3 PGD at 72 h (OR: 1.13 [95% CI = .52-2.48], P = .75) or definite or probable AMR (HR: 2.22 [95% CI = .64-7.61], P = .21). Lung transplantation in the presence of low-level DSA without planned augmented immunosuppression is not associated with worse overall or CLAD-free survival among recipients with intermediate-term follow-up.

Human polyomavirus 7-associated pruritic rash and viremia in transplant recipients.

Human polyomavirus 7 (HPyV7) is one of 11 HPyVs recently discovered through genomic sequencing technologies. Two lung transplant recipients receiving immunosuppressive therapy developed pruritic, brown plaques on the trunk and extremities showing a distinctive epidermal hyperplasia with virus-laden keratinocytes containing densely packed 36-45-nm icosahedral capsids. Rolling circle amplification and gradient centrifugation testing were positive for encapsidated HPyV7 DNA in skin and peripheral blood specimens from both patients, and HPyV7 early and capsid proteins were abundantly expressed in affected tissues. We describe for the first time that HPyV7 is associated with novel pathogenicity in some immunosuppressed individuals.

Simkania negevensis and acute cellular rejection in lung transplant recipients.

Simkania negevensis infection has been hypothesized to play a role in lung transplant rejection. The incidence of S. negevensis infection and its association with acute cellular rejection (ACR) were determined in a prospective cohort study of 78 lung transplant recipients (LTRs) in Toronto, Canada, and Pittsburgh, USA, from July 2007 to January 2010. Simkania negevensis testing was detected by quantitative polymerase chain reaction (PCR) on bronchoalveolar lavage fluid. The relationship between S. negevensis and ACR was examined using Cox proportional hazards models and generalized linear and latent mixed models. Cumulative incidence estimates for time-to-ACR in S. negevensis PCR-positive vs. PCR-negative LTRs were 52.7% vs. 31.1% at six months and 68.9% vs. 44.6% at one yr, respectively. Although not statistically significant, there was a trend toward a higher risk of ACR among S. negevensis PCR-positive vs. PCR-negative LTRs in all statistical models.

Ganciclovir-resistant cytomegalovirus infections among lung transplant recipients are associated with poor outcomes despite treatment with foscarnet-containing regimens.

Ganciclovir-resistant cytomegalovirus (CMV) infections are reported infrequently among lung transplant recipients receiving extended valganciclovir prophylaxis. We performed a single-center, retrospective review of ganciclovir-resistant CMV infections in a program that employed valganciclovir prophylaxis for ≥6 months after lung transplant. CMV infections were diagnosed in 28% (170/607) of patients. UL97 mutations were detected in 9.4% (16/170) of CMV-infected patients at a median of 8.5 months posttransplant (range, 5 to 21) and despite prophylaxis for a median of 7 months (range, 4 to 21). UL97 mutations were canonical; 25% (4/16) of strains carried concurrent UL54 mutations. Ganciclovir-resistant CMV was more likely with breakthrough infections (75% [12/16] versus 19% [30/154]; P = 0.00001) and donor positive/recipient negative (D+/R-) serostatus (75% versus 45% [69/154]; P = 0.03). The median whole-blood CMV load was 4.13 log10 copies/cm(3) (range, 2.54 to 5.53), and 93% (14/15) of patients had low-moderate immune responses (Cylex Immunoknow). Antiviral therapy was successful, failed, or eradicated viremia followed by relapse in 12% (2/16), 31% (5/16), and 56% (9/16) of patients, respectively. Eighty-seven percent (14/16) of patients were treated with foscarnet-containing regimens; toxicity developed in 78% (11/14) of these. Median viral load half-life and time to viremia eradication among foscarnet-treated patients were 2.6 and 23 days, respectively, and did not correlate with protection from relapse. Sixty-nine percent (11/16) of patients developed CMV pneumonitis, and 25% (4/16) died of it. Serum viral load was independently associated with death among foscarnet-treated patients (P = 0.04). In conclusion, ganciclovir-resistant CMV infections remained a major cause of morbidity and mortality following lung transplantation. Foscarnet-based regimens often eradicated viremia rapidly but were ineffective in the long term and limited by toxicity.

Lung transplantation for COVID-2019 respiratory failure in the United States: Outcomes 1-year posttransplant and the impact of preoperative extracorporeal membrane oxygenation support.

OBJECTIVE: Patients with end-stage respiratory failure after severe coronavirus disease 2019 (COVID-19) infection may benefit from lung transplant; however, data on transplant outcomes and the impact of prolonged circulatory support before transplant in these patients are limited. METHODS: We assessed survival, postoperative complications, and the impact of pretransplant extracorporeal membrane oxygenation (ECMO) in patients undergoing lung transplant in the United States from August 2020 through March 2022 using records validated by United Network for Organ Sharing experts and extracted from the United Network for Organ Sharing database. RESULTS: In 305 patients with COVID-19-related respiratory failure and validated data, survival for up to 1-year posttransplant did not differ between 188 patients with COVID-19-related acute respiratory distress syndrome and 117 patients with post-COVID-19 pulmonary fibrosis (P = .8). Pretransplant ECMO support (median 66 days) was required in 191 patients (63%), and venovenous ECMO was used in 91.2% of patients. One-, 6-, and 12-month survival was not significantly different between patients requiring ECMO and patients without ECMO (95.8% vs 99.1%, 93.1% vs 96.4%, 84.8% vs 90.9%, P = .2) In addition, 1-year survival was similar in recipients requiring ECMO for COVID-19 lung failure and recipients requiring ECMO for non-COVID-19 restrictive lung failure (84.8% vs 78.0%, P = .1). CONCLUSIONS: These findings suggest that lung transplant in patients with COVID-19 respiratory failure yields acceptable 1-year outcomes. Despite an often more complex postoperative course, prolonged ECMO pretransplant in well-selected patients was associated with adequate clinical and functional status.

Reevaluating Rehabilitation Practice for Patients Who Were Critically Ill After COVID-19 Infection: An Administrative Case Report.

OBJECTIVE: The goal of this case report is to describe the process, challenges, and opportunities of implementing rehabilitation for individuals who were critically ill and required both mechanical ventilation (MV) and extracorporeal membrane oxygenation (ECMO) support following a coronavirus 2019 (COVID-19) infection in an academic medical center. METHODS: This administrative case report is set in a heart and vascular intensive care unit, a 35-bed critical care unit that provides services for patients with various complex cardiovascular surgical interventions, including transplantation. Patients were admitted to the heart and vascular intensive care unit with either COVID-19 acute respiratory distress syndrome or pulmonary fibrosis for consideration of bilateral orthotropic lung transplantation. The authors describe the process of establishing rehabilitation criteria for patients who, by previously established guidelines, would be considered too ill to engage in rehabilitation. RESULTS: The rehabilitation team, in coordination with an interprofessional team of critical care providers including physicians, respiratory care providers, perfusionists, and registered nurses, collaborated to implement a rehabilitation program for patients with critical COVID-19 being considered for bilateral orthotropic lung transplantation. This was accomplished by (1) reviewing previously published guidelines and practices; (2) developing an interdisciplinary framework for the consideration of rehabilitation treatment; and (3) implementing the framework for patients in our heart and vascular intensive care unit. CONCLUSION: In response to the growing volume of patients admitted with critical COVID-19, the team initiated and developed an interprofessional framework and successfully provided rehabilitation services to patients who were critically ill. While resource-intensive, the process demonstrates that rehabilitation can be implemented on a case-by-case basis for select patients receiving extracorporeal membrane oxygenation and MV, who would previously have been considered too critically ill for rehabilitation services. IMPACT: Rehabilitating patients with end-stage pulmonary disease on extracorporeal membrane oxygenation and MV support is challenging but feasible with appropriate interprofessional collaboration and knowledge sharing.

Lung transplant outcomes after acute respiratory distress syndrome requiring extracorporeal life support: Lessons from the COVID-19 pandemic.

OBJECTIVE: Lung transplant for acute respiratory distress syndrome in patients supported with extracorporeal membrane oxygenation was rare before 2020, but was rapidly adopted to rescue patients with COVID-19 with lung failure. This study aims to compare the outcomes of patients who underwent lung transplant for COVID-associated acute respiratory distress syndrome and non-COVID acute respiratory distress syndrome, and to assess the impact of type and duration of extracorporeal membrane oxygenation support on survival. METHODS: Using the United Network for Organ Sharing database, we identified 311 patients with acute respiratory distress syndrome who underwent lung transplant from 2007 to 2022 and performed a retrospective analysis of the patients who required extracorporeal membrane oxygenation preoperatively, stratified by COVID-associated acute respiratory distress syndrome and non-COVID acute respiratory distress syndrome listing diagnoses. The primary outcome was 1-year survival. Secondary outcomes included the effect of type and duration of extracorporeal membrane oxygenation on survival. RESULTS: During the study period, 236 patients with acute respiratory distress syndrome and preoperative extracorporeal membrane oxygenation underwent lung transplant; 181 patients had a listing diagnosis of COVID-associated acute respiratory distress syndrome (77%), and 55 patients had a listing diagnosis of non-COVID acute respiratory distress syndrome (23%). Patients with COVID-associated acute respiratory distress syndrome were older, were more likely to be female, had higher body mass index, and spent longer on the waitlist (all P < .02) than patients with non-COVID acute respiratory distress syndrome. The 2 groups had similar 1-year survival (85.8% vs 81.1%, P = .2) with no differences in postoperative complications. Patients with COVID-associated acute respiratory distress syndrome required longer times on extracorporeal membrane oxygenation pretransplant (P = .02), but duration of extracorporeal membrane oxygenation support was not a predictor of 1-year survival (P = .2). CONCLUSIONS: Despite prolonged periods of pretransplant extracorporeal membrane oxygenation support, selected patients with acute respiratory distress syndrome can undergo lung transplant safely with acceptable short-term outcomes. Appropriate selection criteria and long-term implications require further analysis.

Percutaneous Venopulmonary Extracorporeal Membrane Oxygenation as Bridge to Lung Transplantation.

Mechanical circulatory support (MCS) as a bridge to lung transplant is an infrequent but accepted pathway in patients who have refractory end-stage pulmonary failure. The American Association of Thoracic Surgeons Expert Consensus Guidelines, published in 2023, recommends venovenous (VV) extracorporeal membrane oxygenation (ECMO) as the initial configuration for those patients who have failed conventional medical therapy, including mechanical ventilation, while waiting for lung transplantation and needing MCS. Alternatively, venoarterial (VA) ECMO can be used in patients with acute right ventricular failure, hemodynamic instability, or refractory respiratory failure. With the advancement in percutaneous venopulmonary (VP) ECMO cannulation techniques, this option is becoming an attractive configuration as bridge to lung transplantation. This configuration enhances stability of the right ventricle, prevents recirculation with direct introduction of pulmonary artery oxygenation, and promotes hemodynamic stability during mobility, rehabilitation, and sedation-weaning trials before lung transplantation. Here, we present a case series of eight percutaneous VP ECMO as bridge to lung transplant with all patients mobilized, awake, and successfully transplanted with survival to hospital discharge.

Vascular endothelial-derived SPARCL1 exacerbates viral pneumonia through pro-inflammatory macrophage activation.

Inflammation induced by lung infection is a double-edged sword, moderating both anti-viral and immune pathogenesis effects; the mechanism of the latter is not fully understood. Previous studies suggest the vasculature is involved in tissue injury. Here, we report that expression of Sparcl1, a secreted matricellular protein, is upregulated in pulmonary capillary endothelial cells (EC) during influenza-induced lung injury. Endothelial overexpression of SPARCL1 promotes detrimental lung inflammation, with SPARCL1 inducing 'M1-like' macrophages and related pro-inflammatory cytokines, while SPARCL1 deletion alleviates these effects. Mechanistically, SPARCL1 functions through TLR4 on macrophages in vitro, while TLR4 inhibition in vivo ameliorates excessive inflammation caused by endothelial Sparcl1 overexpression. Finally, SPARCL1 expression is increased in lung ECs from COVID-19 patients when compared with healthy donors, while fatal COVID-19 correlates with higher circulating SPARCL1 protein levels in the plasma. Our results thus implicate SPARCL1 as a potential prognosis biomarker for deadly COVID-19 pneumonia and as a therapeutic target for taming hyperinflammation in pneumonia.

Development and validation of primary graft dysfunction predictive algorithm for lung transplant candidates.

BACKGROUND: Primary graft dysfunction (PGD) is the leading cause of early morbidity and mortality after lung transplantation. Accurate prediction of PGD risk could inform donor approaches and perioperative care planning. We sought to develop a clinically useful, generalizable PGD prediction model to aid in transplant decision-making. METHODS: We derived a predictive model in a prospective cohort study of subjects from 2012 to 2018, followed by a single-center external validation. We used regularized (lasso) logistic regression to evaluate the predictive ability of clinically available PGD predictors and developed a user interface for clinical application. Using decision curve analysis, we quantified the net benefit of the model across a range of PGD risk thresholds and assessed model calibration and discrimination. RESULTS: The PGD predictive model included distance from donor hospital to recipient transplant center, recipient age, predicted total lung capacity, lung allocation score (LAS), body mass index, pulmonary artery mean pressure, sex, and indication for transplant; donor age, sex, mechanism of death, and donor smoking status; and interaction terms for LAS and donor distance. The interface allows for real-time assessment of PGD risk for any donor/recipient combination. The model offers decision-making net benefit in the PGD risk range of 10% to 75% in the derivation centers and 2% to 10% in the validation cohort, a range incorporating the incidence in that cohort. CONCLUSION: We developed a clinically useful PGD predictive algorithm across a range of PGD risk thresholds to support transplant decision-making, posttransplant care, and enrich samples for PGD treatment trials.

Malignancies incidentally detected at lung transplantation: radiologic and pathologic features.

OBJECTIVE: The purpose of this study was to assess the CT-pathologic features of cancer incidentally detected at lung transplantation. MATERIALS AND METHODS: Our lung transplant registry was reviewed over 7 years for incidental malignancy. Patient demographics, diffuse lung disease, surgical procedure, histopathology, and chest CT were recorded. We correlated lesion size, morphology, multiplicity, and location with surgical and pathology reports and histopathology. Cancers were pathologically staged. RESULTS: Of 759 lung transplant recipients, cancer was incidentally detected in 22 (2.9%). Half (11 of 258) or 4.3% were detected within the past 2 years. Four patients had a history of treated malignancy, and three had recurrence. Patients had emphysema (chronic obstructive pulmonary disease [COPD]) (n = 10), fibrosis (n = 10), or combined COPD and fibrosis (n = 2). Histopathology revealed 13 solitary lung carcinomas, four multifocal adenocarcinomas, three metastases, and two lymphoproliferative diseases. Lung cancer (n = 17) stages were I or II (n = 13), IIIA (n = 2), or IV (n = 2). Metastases (n = 3) and lymphoproliferative disease (n = 2) represented advanced disease. The interval between CT and surgery was a mean of 4 months. CT-positive cases (n = 10) represented lung cancer (n = 9) and posttrans-plantation lymphoproliferative disease (n = 1). Cases with no CT findings of malignancy (n = 12) included lung cancer (n = 8), metastases (n = 3), and lymphoma (n = 1). Ten cases (45%) had other histologically benign CT abnormalities that mimicked cancer. CONCLUSION: Detection of incidental malignancy at lung transplantation has increased over the past 2 years. Malignancies were typically stage I or II lung cancers that were occult or indeterminate on CT. Diffuse lung disease, multiple CT abnormalities, and a delay between CT and transplantation compromise the preoperative diagnosis of cancer.

Rehabilitation Characteristics and Outcomes for Lung Transplantation for COVID-19: A Case Series.

OBJECTIVE: Severe coronavirus disease 2019 (COVID-19) can result in irreversible lung damage, with some individuals requiring lung transplantation. The purpose of this case series is to describe the initial experience with the rehabilitation and functional outcomes of 9 patients receiving a lung transplant for COVID-19. METHODS: Nine individuals, ranging in age from 37 to 68 years, received bilateral orthotopic lung transplantation (BOLT) for COVID-19 between December 2020 and July 2021. Rehabilitation was provided before and after the transplant, including in-hospital rehabilitation, postacute care inpatient rehabilitation, and outpatient rehabilitation. RESULTS: Progress with mobility was limited in the pretransplant phase despite rehabilitation efforts. Following transplantation, 2 individuals expired before resuming rehabilitation, and 2 others had complications that delayed their progress. The remaining 5 experienced clinically important improvements in mobility and walking capacities. CONCLUSION: Considerable rehabilitation resources are required to care for individuals both before and after BOLT for COVID-19. Rehabilitation can have a profound impact on both functional and clinical outcomes for this unique patient population. IMPACT: There is limited literature on the rehabilitation efforts and outcomes for patients who received BOLT for COVID-19. Occupational therapists and physical therapists play an important role during the pretransplant and posttransplant recovery process for this novel patient population. LAY SUMMARY: Patients with a bilateral orthotopic lung transplant due to COVID-19 require a unique rehabilitation process. They have significant difficulties with activities of daily living and functional mobility across the pretransplant and posttransplant continuum of care, but progressive gains in functional performance may be possible with a comprehensive multidisciplinary rehabilitation program.

The SHELTER Trial of Transplanting Hepatitis C Virus-Infected Lungs Into Uninfected Recipients.

SHELTER is a trial of transplanting lungs from deceased donors with hepatitis C virus (HCV) infection into HCV-negative candidates (sponsor: Merck; NCT03724149). Few trials have reported outcomes using thoracic organs from HCV-RNA+ donors and none have reported quality of life (QOL). Methods: This study is a single-arm trial of 10 lung transplants at a single center. Patients were included who were between 18 and 67 y of age and waitlisted for lung-only transplant. Patients were excluded who had evidence of liver disease. Primary outcome was HCV cure (sustained virologic response 12 wk after completing antiviral therapy). Recipients longitudinally reported QOL using the validated RAND-36 instrument. We also applied advanced methods to match HCV-RNA+ lung recipients to HCV-negative lung recipients in a 1:3 ratio at the same center. Results: Between November 2018 and November 2020, 18 patients were consented and opted-in for HCV-RNA+ lung offers in the allocation system. After a median of 37 d (interquartile range [IQR], 6-373) from opt-in, 10 participants received double lung transplants. The median recipient age was 57 y (IQR, 44-67), and 7 recipients (70%) had chronic obstructive pulmonary disease. The median lung allocation score at transplant was 34.3 (IQR, 32.7-86.9). Posttransplant, 5 recipients developed primary graft dysfunction grade 3 on day 2 or 3, although none required extracorporeal membrane oxygenation. Nine patients received elbasvir/grazoprevir, whereas 1 patient received sofosbuvir/velpatasvir. All 10 patients were cured of HCV and survived to 1 y (versus 83% 1-y survival among matched comparators). No serious adverse events were found to be related to HCV or treatment. RAND-36 scores showed substantial improvement in physical QOL and some improvement in mental QOL. We also examined forced expiratory volume in 1 s-the most important lung function parameter after transplantation. We detected no clinically important differences in forced expiratory volume in 1 s between the HCV-RNA+ lung recipients versus matched comparators. Conclusions: SHELTER adds important evidence regarding the safety of transplanting HCV-RNA+ lungs into uninfected recipients and suggests QOL benefits.

Vascular Endothelial-derived SPARCL1 Exacerbates Viral Pneumonia Through Pro-Inflammatory Macrophage Activation.

Inflammation upon infectious lung injury is a double-edged sword: while tissue-infiltrating immune cells and cytokines are necessary to control infection, these same factors often aggravate injury. Full appreciation of both the sources and targets of inflammatory mediators is required to facilitate strategies to maintain antimicrobial effects while minimizing off-target epithelial and endothelial damage. Recognizing that the vasculature is centrally involved in tissue responses to injury and infection, we observed that pulmonary capillary endothelial cells (ECs) exhibit dramatic transcriptomic changes upon influenza injury punctuated by profound upregulation of Sparcl1 . Endothelial deletion and overexpression of SPARCL1 implicated this secreted matricellular protein in driving key pathophysiologic symptoms of pneumonia, which we demonstrate result from its effects on macrophage polarization. SPARCL1 induces a shift to a pro-inflammatory "M1-like" phenotype (CD86 + CD206 - ), thereby increasing associated cytokine levels. Mechanistically, SPARCL1 acts directly on macrophages in vitro to induce the pro-inflammatory phenotype via activation of TLR4, and TLR4 inhibition in vivo ameliorates inflammatory exacerbations caused by endothelial Sparcl1 overexpression. Finally, we confirmed significant elevation of SPARCL1 in COVID-19 lung ECs in comparison with those from healthy donors. Survival analysis demonstrated that patients with fatal COVID-19 had higher levels of circulating SPARCL1 protein compared to those who recovered, indicating the potential of SPARCL1 as a biomarker for prognosis of pneumonia and suggesting that personalized medicine approaches might be harnessed to block SPARCL1 and improve outcomes in high-expressing patients.

Prospective, observational study of voriconazole therapeutic drug monitoring among lung transplant recipients receiving prophylaxis: factors impacting levels of and associations between serum troughs, efficacy, and toxicity.

Voriconazole prophylaxis is common following lung transplantation, but the value of therapeutic drug monitoring is unknown. A prospective, observational study of lung transplant recipients (n = 93) receiving voriconazole prophylaxis was performed. Serum voriconazole troughs (n = 331) were measured by high-pressure liquid chromatography. The median initial and subsequent troughs were 1.91 and 1.46 µg/ml, respectively. The age of the patient directly correlated with initial troughs (P = 0.005). Patients that were ≥ 60 years old and cystic fibrosis patients were significantly more likely to have higher and lower initial troughs, respectively. In 95% (88/93) of patients, ≥ 2 troughs were measured. In 28% (25/88) and 32% (28/88) of these patients, all troughs were ≤ 1.5 µg/ml or >1.5 µg/ml, respectively. Ten percent (10/93) and 27% (25/93) of the patients developed invasive fungal infection (tracheobronchitis) and fungal colonization, respectively. The median troughs at the times of positive and negative fungal cultures were 0.92 and 1.72 µg/ml (P = 0.07). Invasive fungal infections or colonization were more likely with troughs of ≤ 1.5 µg/ml (P = 0.01) and among patients with no trough of >1.5 µg/ml (P = 0.007). Other cutoff troughs correlated less strongly with microbiologic outcomes. Troughs correlated directly with aspartate transferase levels (P = 0.003), but not with other liver enzymes. Voriconazole was discontinued due to suspected toxicity in 27% (25/93) of the patients. The troughs did not differ at the times of suspected drug-induced hepatotoxicity, central nervous system (CNS) toxicity, or nausea/vomiting and in the absence of toxicity. Voriconazole prophylaxis was most effective at troughs of >1.5 µg/ml. A cutoff for toxicity was not identified, but troughs of >4 µg/ml were rare. The data support a target range of >1.5 to 4 µg/ml.