Pre-transplant vaccination compliance in adult heart and lung transplant recipients.

BACKGROUND: Vaccine preventable diseases can affect solid organ transplant recipients post-transplant. Therefore, the administration of vaccines and assessment of serologic response should be prioritized in the pre-transplant period. METHODS: This single-center, retrospective study included 349 adult heart or lung transplant candidates between December 1, 2017 and November 30, 2019. We describe vaccination or serologic status for hepatitis A, hepatitis B, tetanus, pneumococcal, influenza, and other recommended vaccinations among heart or lung transplant candidates. RESULTS: Eighty-two heart transplant candidates (91%) and 77 lung transplant candidates (30%) received an ID consult prior to transplant. More patients completed the pneumococcal series (66.7% vs. 28.6%, P = .045) in the heart transplant group that received an ID consult. In the lung transplant group, patients with an ID consult demonstrated higher rates of immunity to hepatitis A (84.4% vs. 72.9%, P = .047), hepatitis B (75.3% vs. 56.9%, P = .005), and measles (71.4% vs. 52.5%, P = .005) compared to those without. CONCLUSIONS: Our results demonstrate the value of consulting ID and administering vaccinations in the early evaluation phase, prior to transplant listing. Opportunities remain to better optimize vaccination rates prior to transplant in heart and lung transplant candidates.

Perspectives on donor lung allocation from both sides of the Atlantic: The United States.

Donor lung allocation in the United States focuses on decreasing waitlist mortality and improving recipient outcomes. The implementation of allocation policy to match deceased donor lungs to waitlisted patients occurs through a unique partnership between government and private organizations, namely the Organ Procurement and Transplantation Network under the Department of Health and Human Services and the United Network for Organ Sharing. In 2005, the donor lung allocation algorithm shifted toward the prioritization of medical urgency of waitlisted patients instead of time accrued on the waitlist. This led to the Lung Allocation Score, which weighs over a dozen clinical variables to predict a 1-year estimate of survival benefit, and is used to prioritize waitlisted patients. In 2017, the use of local allocation boundaries was eliminated in favor of a 250 nautical mile radius from the donor hospital as the first unit of distance used in allocation. The next upcoming iteration of donor allocation policy is expected to use a continuous distribution algorithm where all geographic boundaries are eliminated. There are additional opportunities to improve donor lung allocation, such as for patients with high antibody titers with access to a limited number of donors.

Evaluating resilience as a predictor of outcomes in lung transplant candidates.

BACKGROUND: Resilience represents the capacity to adapt to adversity. Resilience can improve following behavioral interventions. We examined lung transplant candidates' resilience as a novel predictor using the Connor-Davidson Resilience Scale (RISC-10). METHODS: Waitlisted candidates at six centers were mailed questionnaires from 9/16/2015 to 10/1/2019. Follow-up surveys were collected annually and post-transplant. Outcomes were recorded through February 17, 2020. Primary outcome was pre-transplant death/delisting. Analyses included t test or chi-square for group comparisons, Pearson's correlation coefficients for strength of relationships, and Cox proportional-hazard models to evaluate associations with outcomes, adjusting for age, sex, and mood. RESULTS: Participation was 55.3% (N = 199). Baseline RISC-10 averaged 32.0 ± 5.6 and did not differ by demographics, primary transplant diagnosis, or disease severity markers. RISC-10 did not correlate to the commonly utilized Psychosocial Assessment of Candidates for Transplant [PACT] or Stanford Integrated Psychosocial Assessment for Transplantation [SIPAT] tools. Scores < 26.3 (representing > 1 standard deviation below population average) occurred in 16% and were associated with pre-transplant death or delisting, adjusted Hazard Ratio of 2.60 (95% Confidence Interval 1.23-5.77; P = .01). CONCLUSION: One in six lung candidates had low resilience, predicting increased pre-transplant death/delisting. RISC-10 did not correlate with PACT or SIPAT; resilience may represent a novel risk factor.

A single-institution study of concordance of pathological diagnoses for interstitial lung diseases between pre-transplantation surgical lung biopsies and lung explants.

BACKGROUND: By comparing diagnoses made by pre-transplant surgical lung biopsy (SLB) and the final pathologic diagnosis of the explanted pathology (EP), we aimed to study the factors that could impact pathologic diagnoses in patients with interstitial lung disease (ILD). METHODS: We retrospectively reviewed the lung transplant database at Cleveland Clinic [01/01/2006-12/31/2013] to include all lung transplant recipients with a prior diagnosis of ILD. Two pulmonary pathologists independently reviewed each SLB and lung explant. The diagnoses were labeled as concordant (same diagnosis on SLB and explant) or discordant (diagnosis on SLB and explant were different) by consensus. RESULTS: Of 389 patients transplanted for ILD, 217 had an SLB before transplant. Pathological diagnoses were concordant in 190 patients (87.6%) [165 UIP (86.8%), 13 NSIP (6.8%), 8 CHP (4.2%) and 4 other diagnoses (2.1%). In 27 cases (12.4%), the diagnosis on SLB differed from EP. 8/27 were diagnosed with UIP on SLB and of these, 5 were re-classified as NSIP. 14/19 (73.7%) patients with a SLB diagnosis "other than UIP" were re-categorized as UIP based on explant. Discordant cases had a greater time between SLB and EP than concordant cases (1553 days vs 1248 days). CONCLUSIONS: The pathologic diagnosis of ILD by SLB prior to lung transplant is accurate in most patients, but may be misleading in a small subset of patients. The majority of discordant cases that were reclassified as UIP could be due to a sampling error, or perhaps, an increased time from the date of the SLB to transplant. Future studies examining how multidisciplinary consensus diagnosis affects this discordance are necessary.

Human leukocyte antigens antibodies after lung transplantation: Primary results of the HALT study.

Donor-specific antibodies (DSA) to mismatched human leukocyte antigens (HLA) are associated with worse outcomes after lung transplantation. To determine the incidence and characteristics of DSA early after lung transplantation, we conducted a prospective multicenter observational study that used standardized treatment and testing protocols. Among 119 transplant recipients, 43 (36%) developed DSA: 6 (14%) developed DSA only to class I HLA, 23 (53%) developed DSA only to class II HLA, and 14 (33%) developed DSA to both class I and class II HLA. The median DSA mean fluorescence intensity (MFI) was 3197. We identified a significant association between the Lung Allocation Score and the development of DSA (HR = 1.02, 95% CI: 1.001-1.03, P = .047) and a significant association between DSA with an MFI ≥ 3000 and acute cellular rejection (ACR) grade ≥ A2 (HR = 2.11, 95% CI: 1.04-4.27, P = .039). However, we did not detect an association between DSA and survival. We conclude that DSA occur frequently early after lung transplantation, and most target class II HLA. DSA with an MFI ≥ 3000 have a significant association with ACR. Extended follow-up is necessary to determine the impact of DSA on other important outcomes.

Increased Intraoperative Fluid Administration Is Associated with Severe Primary Graft Dysfunction After Lung Transplantation.

BACKGROUND: Severe primary graft dysfunction (PGD) is a major cause of early morbidity and mortality in patients after lung transplantation. The etiology and pathophysiology of PGD is not fully characterized and whether intraoperative fluid administration increases the risk for PGD remains unclear from previous studies. Therefore, we tested the hypothesis that increased total intraoperative fluid volume during lung transplantation is associated with the development of grade-3 PGD. METHODS: This retrospective cohort analysis included patients who had lung transplantation at the Cleveland Clinic between January 2009 and June 2013. We used multivariable logistic regression with adjustment for donor, recipient, and perioperative confounding factors to examine the association between total intraoperative fluid administration and development of grade-3 PGD in the initial 72 postoperative hours. Secondary outcomes included time to initial extubation and intensive care unit length of stay. RESULTS: Grade-3 PGD occurred in 123 of 494 patients (25%) who had lung transplantation. Patients with grade-3 PGD received a larger volume of intraoperative fluid (median 5.0 [3.8, 7.5] L) than those without grade-3 PGD (3.9 [2.8, 5.2] L). Each intraoperative liter of fluid increased the odds of grade-3 PGD by approximately 22% (adjusted odds ratio, 1.22; 95% confidence interval [CI], 1.12-1.34; P <0.001). The volume of transfused red blood cell concentrate was associated with grade-3 PGD (1.1 [0.0, 1.8] L for PGD-3 vs 0.4 [0.0, 1.1 for nongrade-3 PGD] L; adjusted odds ratio, 1.7; 95% CI, 1.08-2.7; P = 0.002). Increased fluid administration was associated with longer intensive care unit stay (adjusted hazard ratio, 0.92; 97.5% CI, 0.88-0.97; P < 0.001) but not with time to initial tracheal extubation (hazard ratio, 0.97; 97.5% CI, 0.93-1.02; P = 0.17). CONCLUSIONS: Increased intraoperative fluid volume is associated with the most severe form of PGD after lung transplant surgery. Limiting fluid administration may reduce the risk for development of grade-3 PGD and thus improve early postoperative morbidity and mortality after lung transplantation.

Immune aging: biological mechanisms, clinical symptoms, and management in lung transplant recipients.

While chronologic age can be precisely defined, clinical manifestations of advanced age occur in different ways and at different rates across individuals. The observed phenotype of advanced age likely reflects a superposition of several biological aging mechanisms which have gained increasing attention as the world contends with an aging population. Even within the immune system, there are multiple age-associated biological mechanisms at play, including telomere dysfunction, epigenetic dysregulation, immune senescence programs, and mitochondrial dysfunction. These biological mechanisms have associated clinical syndromes, such as telomere dysfunction leading to short telomere syndrome (STS), and optimal patient management may require recognition of biologically based aging syndromes. Within the clinical context of lung transplantation, select immune aging mechanisms are particularly pronounced. Indeed, STS is increasingly recognized as an indication for lung transplantation. At the same time, common aging phenotypes may be evoked by the stress of transplantation because lung allografts face a potent immune response, necessitating higher levels of immune suppression and associated toxicities, relative to other solid organs. Age-associated conditions exacerbated by lung transplant include bone marrow suppression, herpes viral infections, liver cirrhosis, hypogammaglobulinemia, frailty, and cancer risk. This review aims to dissect the molecular mechanisms of immune aging and describe their clinical manifestations in the context of lung transplantation. While these mechanisms are more likely to manifest in the context of lung transplantation, this mechanism-based approach to clinical syndromes of immune aging has broad relevance to geriatric medicine.

The Past, Present, and Near Future of Lung Allocation in the United States.

The first official donor lung allocation system in the United States was initiated by the United Network of Organ Sharing in 1990. The initial policy for lung allocation was simple with donor lungs allocated based on ABO match and the amount of time the candidates accrued on the waiting list. Donor offers were first given to candidates' donor service area. In March 2005, the implementation of the lung allocation score (LAS) was the major change in organ allocation. International adoption of the LAS-based allocation system can be seen worldwide.

Mechanical thrombectomy for acute pulmonary embolism in lung transplant recipients.

The rates of pulmonary embolism (PE) are high among lung transplant (LT) recipients. Management is challenging because of elevated bleeding risks and inadequacy of conventional PE risk stratification tools. New percutaneous large bore mechanical thrombectomy catheters are being increasingly used effectively to debulk thrombus and restore flow immediately. We describe the use of mechanical thrombectomy (MT) in 8 LT recipients. All patients were diagnosed with intermediate/high-risk proximal PE involving the allograft and underwent successful MT within 30 hours of diagnosis. Estimated blood loss was between 200 and 450 cc, with 3 patients requiring blood transfusions. Improvement in heart rate and oxygenation was seen in all 8 patients after the procedure. In the 30 days after MT, 7 of 8 patients survived. One patient died from major bleeding occurred 16 days after MT and 5 days after venoarterial extracorporeal membrane oxygenator decannulation. Mechanical thrombectomy may provide a feasible management strategy in select LT recipients with pulmonary embolism.

Anti-fibrotic therapy and lung transplant outcomes in patients with idiopathic pulmonary fibrosis.

BACKGROUND: It is unclear whether continuing anti-fibrotic therapy until the time of lung transplant increases the risk of complications in patients with idiopathic pulmonary fibrosis. OBJECTIVES: To investigate whether the time between discontinuation of anti-fibrotic therapy and lung transplant in patients with idiopathic pulmonary fibrosis affects the risk of complications. METHODS: We assessed intra-operative and post-transplant complications among patients with idiopathic pulmonary fibrosis who underwent lung transplant and had been treated with nintedanib or pirfenidone continuously for ⩾ 90 days at listing. Patients were grouped according to whether they had a shorter (⩽ 5 medication half-lives) or longer (> 5 medication half-lives) time between discontinuation of anti-fibrotic medication and transplant. Five half-lives corresponded to 2 days for nintedanib and 1 day for pirfenidone. RESULTS: Among patients taking nintedanib (n = 107) or pirfenidone (n = 190), 211 (71.0%) had discontinued anti-fibrotic therapy ⩽ 5 medication half-lives before transplant. Anastomotic and sternal dehiscence occurred only in this group (anastomotic: 11 patients [5.2%], p = 0.031 vs patients with longer time between discontinuation of anti-fibrotic medication and transplant; sternal: 12 patients [5.7%], p = 0.024). No differences were observed in surgical wound dehiscence, length of hospital stay, or survival to discharge between groups with a shorter versus longer time between discontinuation of anti-fibrotic therapy and transplant. CONCLUSION: Anastomotic and sternal dehiscence only occurred in patients with idiopathic pulmonary fibrosis who discontinued anti-fibrotic therapy < 5 medication half-lives before transplant. The frequency of other intra-operative and post-transplant complications did not appear to differ depending on when anti-fibrotic therapy was discontinued. REGISTRATION: clinicaltrials.gov NCT04316780: https://clinicaltrials.gov/ct2/show/NCT04316780.

Reflux Surgery in Lung Transplantation: A Multicenter Retrospective Study.

BACKGROUND: Aspiration has been associated with graft dysfunction after lung transplantation, leading some to advocate for selective use of fundoplication despite minimal data supporting this practice. METHODS: We performed a multicenter retrospective study at 4 academic lung transplant centers to determine the association of gastroesophageal reflux disease and fundoplication with bronchiolitis obliterans syndrome and survival using Cox multivariable regression. RESULTS: Of 542 patients, 136 (25.1%) underwent fundoplication; 99 (18%) were found to have reflux disease without undergoing fundoplication. Blanking the first year after transplantation, fundoplication was not associated with a benefit regarding freedom from bronchiolitis obliterans syndrome (hazard ratio [HR], 0.93; 95% CI, 0.58-1.49) or death (HR, 0.97; 95% CI, 0.47-1.99) compared with reflux disease without fundoplication. However, a time-dependent adjusted analysis found a slight decrease in mortality (HR, 0.59; 95% CI, 0.28-1.23; P = .157), bronchiolitis obliterans syndrome (HR, 0.68; 95% CI, 0.42-1.11; P = .126), and combined bronchiolitis obliterans syndrome or death (HR, 0.66; 95% CI, 0.42-1.04; P = .073) in the fundoplication group compared with the gastroesophageal reflux disease group. CONCLUSIONS: Although a statistically significant benefit from fundoplication was not determined because of limited sample size, follow-up, and potential for selection bias, a randomized, prospective study is still warranted.

Early posttransplant reductions in club cell secretory protein associate with future risk for chronic allograft dysfunction in lung recipients: results from a multicenter study.

BACKGROUND: Chronic lung allograft dysfunction (CLAD) increases morbidity and mortality for lung transplant recipients. Club cell secretory protein (CCSP), produced by airway club cells, is reduced in the bronchoalveolar lavage fluid (BALF) of lung recipients with CLAD. We sought to understand the relationship between BALF CCSP and early posttransplant allograft injury and determine if early posttransplant BALF CCSP reductions indicate later CLAD risk. METHODS: We quantified CCSP and total protein in 1606 BALF samples collected over the first posttransplant year from 392 adult lung recipients at 5 centers. Generalized estimating equation models were used to examine the correlation of allograft histology or infection events with protein-normalized BALF CCSP. We performed multivariable Cox regression to determine the association between a time-dependent binary indicator of normalized BALF CCSP level below the median in the first posttransplant year and development of probable CLAD. RESULTS: Normalized BALF CCSP concentrations were 19% to 48% lower among samples corresponding to histological allograft injury as compared with healthy samples. Patients who experienced any occurrence of a normalized BALF CCSP level below the median over the first posttransplant year had a significant increase in probable CLAD risk independent of other factors previously linked to CLAD (adjusted hazard ratio 1.95; p = 0.035). CONCLUSIONS: We discovered a threshold for reduced BALF CCSP to discriminate future CLAD risk; supporting the utility of BALF CCSP as a tool for early posttransplant risk stratification. Additionally, our finding that low CCSP associates with future CLAD underscores a role for club cell injury in CLAD pathobiology.

Advanced Circulatory Support and Lung Transplantation in Pulmonary Hypertension.

Pulmonary arterial hypertension (PAH) is a progressive fatal disease. Although medical therapies have improved the outlook for these patients, there still exists a cohort of patients with PAH who are refractory to these therapies. Lung transplantation (LT), and in certain cases heart-lung transplantation (HLT), is a therapeutic option for patients with severe PAH who are receiving optimal therapy yet declining. ECMO may serve as a bridge to transplant or recovery in appropriate patients. Although, the mortality within the first 3 months after transplant is higher in PAH recipients than the other indications for LT, and the long-term survival after LT is excellent for this group of individuals. In this review, we discuss the indications for LT in PAH patients, when to refer and list patients for LT, the indications for double lung transplant (DLT) versus HLT for PAH patients, types of advanced circulatory support for severe PAH, and short and long-term outcomes in transplant recipients with PAH.

Infectious Complications in Lung Transplant Recipients.

Infection remains a common cause of death throughout the lifespan of a lung transplant recipient. The increased susceptibility of lung transplant recipients is multifactorial including exposure of the graft to the external environment, impaired mucociliary clearance, and high levels of immunosuppression. Long-term outcomes in lung transplant recipients remain poor compared with other solid organ transplants largely due to deaths from infections and chronic allograft dysfunction. Antibacterial, antifungal, and antiviral prophylaxis may be used after lung transplantation to target a number of different opportunistic infections for varying durations of time. The first-month posttransplant is most commonly characterized by nosocomial infections and donor-derived infections. Following the first month to the first 6 months after transplant-a period of intense immunosuppression-is associated with opportunistic infections. While immunosuppression is reduced after the first year posttransplant, infection remains a risk with community-acquired and rarer infectious agents. Clinicians should be vigilant for infection at all time points after transplant. The use of patient-tailored prophylaxis and treatments help ensure graft and patient survival.

Clinical significance of donor lung weight at procurement and during ex vivo lung perfusion.

BACKGROUND: Elevated donor lung weight may adversely affect donor lung transplant suitability and post-transplant outcomes. The objective of this study is to investigate the impact of lung weight after procurement and ex vivo lung perfusion (EVLP) on transplant suitability, post-transplant graft dysfunction, and clinical outcomes and define the donor lung weight range most relevant to clinical outcomes. METHODS: From February 2016 to August 2020, 365 human lung donors to a single transplant center were retrospectively reviewed. 239 were transplanted without EVLP, 74 treated with EVLP (50 went on to transplant), and 52 declined for transplant without EVLP consideration. Donor lung weights were measured immediately after procurement and, when performed, after EVLP. Lung weights were adjusted by donor height and divided into 4 quartiles. RESULTS: Donor lungs in the highest weight quartile at donor hospital had a significantly lower transplant suitability rate after EVLP, higher rates of primary graft dysfunction grade 3 at 72 hours, and longer intensive care unit/hospital stay. For lungs treated with lung perfusion, the highest lung weight quartile at the end of lung perfusion was associated with a significantly lower transplant suitability rate, higher incidence of primary graft dysfunction grade 3 at 72 hours, and longer intensive care unit/hospital stay, compared to the other categories. CONCLUSIONS: Donor lung weight stratified by quartile categories can assist decision-making regarding need for EVLP at the donor hospital as well as during EVLP evaluation. Caution should be used when considering donor lungs in the highest weight quartile for transplantation.

Evolution of Recipient Characteristics Over 3 Decades and Impact on Survival After Lung Transplantation.

BACKGROUND: Lung transplantation (LTx) is a definitive treatment for end-stage lung disease. Herein, we reviewed our center experience over 3 decades to examine the evolution of recipient characteristics and contemporary predictors of survival for LTx. METHODS: We retrospectively reviewed the data of LTx procedures performed at our institution from January 1990 to January 2019 (n = 1819). The cohort is divided into 3 eras; I: 1990-1998 (n = 152), II: 1999-2008 (n = 521), and III: 2009-2018 (n = 1146). Univariate and multivariate analyses of survival in era III were performed. RESULTS: Pulmonary fibrosis has become the leading indication for LTx (13% in era I, 57% in era III). Median recipient age increased (era I: 46 y-era III: 61 y) as well as intraoperative mechanical circulatory support (era I: 0%-era III: 6%). Higher lung allocation score was associated with primary graft dysfunction (P < 0.0001), postoperative extracorporeal mechanical support (P < 0.0001), and in-hospital mortality (P = 0.002). In era III, hypoalbuminemia, thrombocytopenia, and high primary graft dysfunction grade were multivariate predictors of early mortality. The 5-y survival in eras II (55%) and III (55%) were superior to era I (40%, P < 0.001). Risk factors for late mortality in era III included recipient age, chronic allograft dysfunction, renal dysfunction, high model for end-stage liver disease score, and single LTx. CONCLUSIONS: In this longitudinal single-center study, recipient characteristics have evolved to include sicker patients with greater complexity of procedures and risk for postoperative complications but without significant impact on hospital mortality or long-term survival. With advancing surgical techniques and perioperative management, there is room for further progress in the field.

COVID-19 and lung transplant patients.

COVID-19 is a novel respiratory disease leading to high rates of acute respiratory failure requiring hospital admission. It is unclear if specific patient populations such as lung transplant patients are at higher risk for COVID-19. Some reports suggest that transplant patients may not be at higher risk if proper social distancing and preventive measures are employed. Efforts to ensure the safety of wait-listed patients, transplant recipients, and healthcare workers are underway. Recommendations for the care of lung transplant patients during the COVID-19 pandemic are discussed and will likely change as the pandemic evolves.

Accuracy of the physical examination in evaluating pleural effusion.

A careful physical examination is a valuable and noninvasive means of assessing pleural effusion and should be routinely performed in every patient in whom this condition is suspected. Although physical examination is less accurate than ultrasonography or computed tomography in detecting a pleural effusion, the sensitivity and specificity of the different physical signs of pleural effusion may be comparable to those of conventional chest radiography.

Extracorporeal Membrane Oxygenation as a Bridge to Lung Transplantation in the United States: A Multicenter Survey.

The clinical use of extracorporeal membrane oxygenation (ECMO) as a bridge to lung transplantation (LTx) has greatly increased in recent years. However, clinical practices for ECMO as a bridge to LTx vary widely between LTx centers. To better define the current practice of ECMO as a bridge to LTx, we surveyed pre-LTx ECMO practices among all adult LTx programs in the United States. All US LTx centers were surveyed (n = 57) between January and December 2014. Responses were received from 33 of 57 centers (58%). Of 33 responding centers, six (18%) performed ≥50 LTxs per year (defined as high volume) and two (6%) performed <10 LTxs per year (low volume). Two-third of responding centers, 22/33 (67%), reported use of ECMO as a bridge to LTx. Of these 22 centers, 18 (82%) successfully used venovenous (VV) ECMO as a bridge to LTx using the dual-lumen Avalon cannula. Patient >65 years of age was judged an ECMO contraindication in 15/33 (45%) of responding centers, but 12/33 (36%) centers, including the six high-volume centers, had no official age cutoff for ECMO candidacy. There was no consensus on the maximum acceptable duration of pre-LTx ECMO therapy; although 18/33 (55%) of programs had no defined maximal duration of ECMO pre-LTx, 10/33 (30%) considered >10 days on ECMO support contraindicated. Our survey suggests that in the United States, ECMO is used frequently pre-LTx, particularly VV ECMO at high-volume centers. However, criteria for ECMO initiation, age eligibility, bedside care, and maximum duration of support varied significantly between survey respondents.