Diaphragmatic plication among lung transplant patients: A single-center experience.

BACKGROUND: There is lack of data reporting outcomes among patients needing diaphragmatic plication (DP) during or after lung transplantation (LT). We sought to assess the association of DP with post-transplant spirometry among other outcomes. METHODS: We included all patients who underwent LT between 2012 and 2016 (n = 324, mean age 56.3±13.4 years; M:F 198:126). We compared early and late outcomes based on the need for DP. RESULTS: The frequency of diaphragmatic dysfunction (DD) on pre-transplant fluoroscopy was 52.2%. A total of 38 DP procedures were performed among 37 patients (11.4% of LT patients). DP was done for anatomic (sizing or spacing issues) or functional indications (symptomatic DD). While patients with DP had significantly lower spirometry throughout the 3-year follow-up period, their slope of decline, functional assessments at the first annual visit, the risk of CLAD, and mortality were similar to patients without DP. A sub-group analysis limited to patients with restrictive lung diseases as the transplant indication had similar findings. CONCLUSIONS: Pre-transplant DD is common among LT candidates although it did not predict the need for DP. DP may be performed for functional or anatomic indications especially for addressing the donor-recipient size mismatch. Despite the lack of favorable effect on post-transplant spirometry, patients undergoing DP have acceptable and comparable early and late outcomes.

Predictors and outcomes of respiratory failure among lung transplant patients with COVID-19.

BACKGROUND: There is limited data on the predictors and outcomes of new or worsening respiratory failure among lung transplant (LT) patients with Coronavirus disease 2019 (COVID-19). METHODS: We included all the LT patients diagnosed with COVID-19 during a 1-year period (March 2020 to February 2021; n = 54; median age: 60, 20-73 years; M:F 37:17). Development of new or worsening respiratory failure (ARF) was the primary outcome variable. RESULTS: The overall incidence of ARF was 48.1% (n = 26). More than 20% of patients (n = 11) needed intubation and mechanical ventilation. Body mass index > 25 Kg/m2 (adjusted OR: 5.7, .99-32.93; P = .05) and peak D-dimer levels > .95 mcg/ml (adjusted OR: 24.99, 1.77-353.8; P = .017) were independently associated with ARF while anticoagulation use prior to COVID-19 was protective (adjusted OR: .024, .001-.55; P = .02). Majority patients survived the acute illness (85.2%). Pre-infection chronic lung allograft dysfunction (CLAD) was an independent predictor of mortality (adjusted HR: 5.03, 1.14-22.25; P = .033). CONCLUSIONS: COVID-19 is associated with significant morbidity and mortality among LT patients. Patients on chronic anticoagulation seem to enjoy favorable outcomes, while higher BMI and peak D-dimer levels are associated with development of ARF. Pre-infection CLAD is associated with an increased risk of death from COVID-19.

Characteristics and outcomes among vaccinated lung transplant patients with breakthrough COVID-19.

BACKGROUND: Despite multiple studies evaluating the immunological responsiveness to vaccines, the clinical effectiveness of the two-dose mRNA vaccine schedule among lung transplant (LT) patients has not been evaluated. METHODS: We included LT patients who tested positive for SARS-CoV-2 on a nasopharyngeal swab between March 1, 2020, and August 25, 2021 (n = 70). The study group was divided based on their vaccination status. RESULTS: During the study period, 14 fully vaccinated LT patients with one of the mRNA vaccines tested positive for COVID-19 (median age 54, range 30-62 years, M:F 9:5). The vaccinated cohort was younger with bilateral LT, have suppurative conditions as the transplant indication, and present with milder symptoms. However, pulmonary parenchymal involvement was seen among all 12 patients where computed tomography (CT) of chest was available. The laboratory profile indicated a more subdued inflammatory response among the vaccinated group. A lower proportion of vaccinated patients developed respiratory failure, needed ICU admission or ventilator support, although none of the differences achieved statistical significance. None of the vaccinated patients succumbed to COVID-19 during the study period, while the 4-week mortality among unvaccinated patients was nearly 15% (8/56). CONCLUSIONS: In this cohort of vaccinated LT patients who developed breakthrough COVID-19, the clinical course, risk of complications, and outcomes trended better than unvaccinated patients. However, universal involvement of the allograft demonstrates the continued vulnerability of these patients to significant sequelae from COVID-19. Future studies may evaluate the incremental protection of vaccination after the completion of the third dose of mRNA vaccines among LT patients.

Characteristics and outcomes among patients with community-acquired respiratory virus infections during the first year after lung transplantation.

BACKGROUND: The current study describes the spectrum of community-acquired respiratory infections (CARV) during the first year after lung transplantation (LT). Additionally, we elucidate variables associated with CARV, management strategies utilized, and impact on early and late outcomes. METHODS: This was a retrospective study among patients transplanted between 2012 and 2015 (n = 255, mean age 55.6 ± 13.5 years, M: F 152:103). The diagnosis of CARV was based on the multiplex PCR on nasopharyngeal swab samples. Baseline characteristics, post-transplant variables, and outcomes were compared among patients with and without CARV. RESULTS: Eighty CARV infections developed among a quarter of the study group (n = 62, 24.3%). Rhinovirus/enterovirus was the most commonly isolated CARV (n = 24) followed by coronavirus (n = 17) and RSV (n = 9). A significant proportion of episodes (43.8%) required hospitalization. The use of nasal corticosteroids and left single LT was independently associated with an increased risk of CARV. CARV infections did not impact the lung functions during the first year or the CLAD-free survival at 3 years. CONCLUSIONS: There is a significant burden of CARV infections during the first year after LT. The use of nasal corticosteroids may increase the risk of CARV infection. CARV infections did not impact outcomes.

Characteristics and outcomes among lung transplant patients with respiratory syncytial virus infection.

BACKGROUND: To describe characteristics and outcomes among lung transplantation (LT) patients with respiratory syncytial virus (RSV) infection and elucidate the predictors of 1-year survival after RSV infection. METHODS: This was a retrospective chart review study among LT patients with RSV infection between 2013 and 2018 (90 episodes among 87 patients; mean age 56.3 ± 13.1 years, M:F 52:35). A contemporaneous control group consisting of LT patients without RSV infection (n = 183) was included. One-year survival after the RSV infection was the primary endpoint. RESULTS: Median time from LT to RSV infection was 30 (1-155) months. Before RSV infection, the median decline in forced vital capacity (FVC) was 9.7 cc (-17.8 to 83 cc) or 0.29% (-1.4% to 4.6%) per month, while the forced expiratory volume (FEV1 ) decline was 7.5 cc (-8.8 to 58 cc) or 0.3% (-0.57% to 4.3%) per month with no statistically significant change after RSV infection. One-year survival among patients with RSV infection was 86.2% (75/87). Pre-infection diagnosis of chronic lung allograft dysfunction (CLAD; adjusted HR: 4.29, 1.08-17.0; P = .038) and FVC or FEV1 decline >10% during 6 months post infection (adjusted HR: 35.1, 3.26-377.1; P = .003) were independently associated with worse survival. On propensity score matched analysis, RSV infection was not associated with worse post-transplant survival (HR with 95% CI: 0.79, 0.47-1.34; P = .38). CONCLUSIONS: A majority of LT patients in the current cohort did not experience an alteration in the trajectory of FVC or FEV1 decline after developing RSV infection, and their post-transplant survival was not adversely impacted. Established CLAD at the time of RSV infection and post infection >10% decline in FVC or FEV1 are independently associated with worse survival after RSV infection.

Post-infection pulmonary sequelae after COVID-19 among patients with lung transplantation.

BACKGROUND: There is limited data on outcomes among lung transplant (LT) patients who survive Coronavirus disease 2019 (COVID-19). METHODS: Any single or bilateral LT patients who tested positive for SARS-CoV-2 between March 1, 2020, to February 15, 2021 (n = 54) and survived the acute illness were included (final n = 44). Each patient completed at least 3 months of follow-up (median: 4.5; range 3-12 months) after their index hospitalization for COVID-19. The primary endpoint was a significant loss of lung functions (defined as > 10% decline in forced vital capacity (FVC) or forced expiratory volume in 1 s (FEV1 ) on two spirometries, at least 3 weeks apart compared to the pre-infection baseline). RESULTS: A majority of the COVID-19 survivors had persistent parenchymal opacities (n = 29, 65.9%) on post-infection CT chest. Patients had significantly impaired functional status, with the majority reporting residual disabilities (Karnofsky performance scale score of 70% or worse; n = 32, 72.7%). A significant loss of lung function was observed among 18 patients (40.9%). Three patients met the criteria for new chronic lung allograft dysfunction (CLAD) following COVID-19 (5.6%), with all three demonstrating restrictive allograft syndrome phenotype. An absolute lymphocyte count < 0.6 × 103 /dl and ferritin > 150 ng/ml at the time of hospital discharge was independently associated with significant lung function loss. CONCLUSIONS: A significant proportion of COVID-19 survivors suffer persistent allograft injury. Low absolute lymphocyte counts (ALC) and elevated ferritin levels at the conclusion of the hospital course may provide useful prognostic information and form the basis of a customized strategy for ongoing monitoring and management of allograft dysfunction. TWEET: Twitter handle: @AmitBangaMD Lung transplant patients who survive COVID-19 suffer significant morbidity with persistent pulmonary opacities, loss of lung functions, and functional deficits. Residual elevation of the inflammatory markers is predictive.

Insult to Injury: Development of Alveolar Hemorrhage after Initiation of Extracorporeal Membrane Oxygenation.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) is associated with complications that are separate from the underlying diagnoses that require its use. One of the foremost complications of ECMO is a high incidence of bleeding, including alveolar hemorrhage (AH), which is believed to be due to both prophylactic anticoagulation and critical illness-induced systemic coagulopathy. However, akin to systemic inflammatory response syndrome after cardiopulmonary bypass, ECMO causes widespread systemic inflammation and acute lung injury, which likely further predisposes patients to AH. The burden of clinically significant AH among patients on ECMO for advanced lung disease remains unknown. PATIENTS AND METHODS: Charts of patients with advanced lung disease who required ECMO at a single institution were reviewed. The clinical course and variables of patients who developed AH and those who did not were compared. RESULTS: This report describes five patients who developed AH after initiation of venovenous ECMO for refractory hypoxemia. Clinical and laboratory variables did not predict the development or the prognosis of AH. Two of these patients with refractory hypoxemia and AH were treated with pulse-dose corticosteroids, with a dramatic response in one case. CONCLUSION: The acute decompensation of the patients and response to corticosteroids suggest AH was mediated by a systemic inflammatory process, as opposed to coagulopathy alone. Judicious use of steroids may be considered among select patients who develop AH without symptoms of systemic coagulopathy after initiation of ECMO. HOW TO CITE THIS ARTICLE: Williams S, Batra K, Mohanka M, Bollineni S, Kaza V, Torres F, et al. Insult to Injury: Development of Alveolar Hemorrhage after Initiation of Extracorporeal Membrane Oxygenation. Indian J Crit Care Med 2020;24(12):1201-1205.

Incidence and variables associated with 30-day mortality after lung transplantation.

BACKGROUND: With the introduction of the lung allocation score (LAS), sicker patients are prioritized for lung transplantation (LT). There is a lack of data regarding variables independently associated with 30-day mortality after LT. METHODS: We queried the UNOS database for adult patients undergoing LT between 1989 and 2014. Patients with dual organ or previous transplantation and those with missing survival data were excluded. Mortality during the first 30 days after LT was the primary outcome variable. RESULTS: The yearly trends indicate a statistically significant reduction in the 30-day mortality during the study period (P < 0.001, overall mortality: 5.5%) which has continued in the post-LAS era (P = 0. 014, overall mortality: 3.6%). Among patients with 30-day mortality, "primary non-function" (n = 118, 72.8%) was reported as the most common etiology. Transplant indication of vascular diseases, history of non-transplant cardiac or lung surgery, mean pulmonary pressures >35 mm Hg, disabled functional status, ECMO support, high LAS, ischemic time >6 hours, and blunt injury as the mechanism of donor death are independently associated with 30-day mortality. CONCLUSION: The incidence of early mortality after LT continues to decline in the post-LAS era. Apart from the mechanism of donor death and ischemic time, early mortality appears to be primarily driven by the recipient characteristics.

Evaluation of current strategies for surveillance and management of donor-specific antibodies: Single-center study.

BACKGROUND: Although the presence of donor-specific antibodies (DSA) is known to impact lung allograft, limited data exist regarding DSA management. METHODS: We did a retrospective study at our center evaluating DSA management in adult lung transplant recipients undergoing lung transplantation between January 1, 2010 and June 30, 2014. Study follow-up was completed through October 2017. All recipients were stratified into 2 groups based on the presence or absence of DSA. Those with DSA were evaluated for the impact of treatment of DSA. The primary outcomes were postlung transplant survival and freedom from bronchiolitis obliterans syndrome (BOS), subset of chronic lung allograft dysfunction (CLAD). Simon-Makuch method was used to estimate overall survival and BOS-free survival to account for DSA as time-dependent covariate. Survival differences between the groups were analyzed using time-dependent Cox proportional hazards model. RESULTS: Sixty-four percent of 194 total subjects developed post-lung transplant DSA. Overall survival was different with worse survival in the DSA positive group that never cleared DSA (P = .002). BOS-free survival was lower, but did not reach significance in this group. Response to treatment was poor, with only 12 of 47 (25.5%) who received treatment demonstrating clearance of DSA. CONCLUSIONS: Donor-specific antibodies prevalence is high after lung transplantation. Clearance of DSA correlated with improved outcomes. Current therapeutic strategies against DSA are relatively ineffective. Multicenter collaborative studies will be required to evaluate current treatment strategies and other innovative modalities.

Characteristics and outcomes among patients with need for early dialysis after lung transplantation surgery.

BACKGROUND: With the introduction of lung allocation score (LAS), increasingly sicker patients are undergoing lung transplantation (LT). This study was conducted to determine the time trends in need for dialysis after LT, identify variables independently associated with need for dialysis, and evaluate its association with 1- and 5-year mortality. METHODS: We queried the United Network of Organ Sharing database for adult patients undergoing LT between 1994 and 2014. We excluded patients with simultaneous dual organ transplantation and where data regarding the need for dialysis were not available. RESULTS: Time trends in the yearly incidence of the need for dialysis showed a gradual increase (P = .012). In the post-LAS era, ethnicity, underlying diagnosis, estimated GFR <90 mL/min/1.73 m2 and mean pulmonary pressures>35 mm Hg, ventilator or extracorporeal membrane oxygenation support at LT, and >20% increase in serum creatinine between listing and match were independently associated with the need for dialysis. Patients with need for dialysis had significantly increased hazard of 1-year (n = 13 849; adjusted hazard ratio, 95% CI:7.23, 6.2-8.4, P < .001) and 5-year mortality (n = 7287; adjusted hazard ratio, 95% CI:3.96, 3.43-4.56, P < .001). CONCLUSIONS: There is a gradual increase in the incidence of the need for early dialysis after LT, and these patients have significantly worse early and late survival. Several pre-transplant recipient characteristics are independently associated with the need for dialysis.

Association of pretransplant kidney function with outcomes after lung transplantation.

PURPOSE: There is a lack of data regarding the independent association of pretransplant kidney function with early and late outcomes among lung transplant (LT) recipients. METHODS: We queried the United Network for Organ Sharing database for adult patients (≥18 years of age) undergoing LT between 1987 and 2013. Glomerular filtration rate (GFR) was estimated using the modification of diet in renal disease (MDRD) and the Chronic kidney disease epidemiology collaboration (CKD-EPI) equations. The study population was split into four groups (>90, 60-90, 45-59.9, and <45 mL/min/1.73 m2 ) based on the estimated GFR at the time of listing. RESULTS: Overall, there was a good correlation between the GFR estimated from the two equations (n=17884, Pearson r=.816, P<.001). There was a consistent and independent association of worse early and late outcomes with declining GFR throughout the spectrum including those above 60 mL/min/1.73 m2 (P<.001 for overall comparisons). Although GFR<45 mL/min/1.73 m2 was associated with worse early and late survival, patients with GFR 45-59.9 mL/min/1.73 m2 do not appear to have survival advantage beyond 3 years post-transplant. CONCLUSION: There is a good correlation between GFR estimated using MDRD and CKD-EPI equations among patients being considered for LT. Early and late outcomes after LT worsen in a linear fashion with progressively lower pretransplant GFR.

Predictors of outcome among patients on extracorporeal membrane oxygenation as a bridge to lung transplantation.

BACKGROUND: There is a lack of data regarding clinical variables associated with successful bridge to lung transplantation (LT) using extracorporeal membrane oxygenation (ECMO) support. METHODS: We reviewed the institutional database for patients supported with veno-venous (VV) or veno-arterial ECMO as a bridge to LT (n=25; mean age: 50.6±14.2 years). We recorded clinical and laboratory variables, findings on echocardiogram and development of organ dysfunction along with hospital and one-year survival. Variables were compared between patients successfully bridged to LT versus those who were not. RESULTS: The most common diagnostic group was interstitial lung disease (18/25, 72%). VV-ECMO was used in the majority (84%). Fifteen patients (60%) were successfully bridged to LT, and the majority were alive at 1 year (14/15, 93.3%). The presence of right ventricular systolic dysfunction on pre-ECMO echocardiogram was associated with increased risk of unsuccessful bridging (OR, 95% CI: 2.67, 1.01-6.99, P=.041). While on ECMO, trough albumin levels <2.5 gm%, peak blood urea nitrogen levels >35 mg/dL and positive fluid balance were also associated with failure to bridge to LT. CONCLUSIONS: Among patients awaiting LT, the presence of RV systolic dysfunction before ECMO initiation along with worsening renal functions, low albumin levels, and volume overload is associated with poor outcomes.

Mast cell phenotypes in the allograft after lung transplantation.

BACKGROUND: The burden of mast cell (MC) infiltration and their phenotypes, MC-tryptase (MCT ) and MC-tryptase/chymase (MCTC ), after lung transplantation (LT) has not been evaluated in human studies. METHODS: We reviewed 20 transbronchial lung biopsy (TBLB) specimen from patients with early normal allograft (<6 months post-LT, n=5), late normal allograft (>6 months, n=5), A2 or worse acute cellular rejection (ACR, n=5), and chronic lung allograft dysfunction (CLAD, n=5). Slides were immunostained for tryptase and chymase. Total MC, MCT , MCTC and MCTC to-MCT ratio were compared between the four groups using a generalized linear mixed model. RESULTS: Irrespective of clinicopathologic diagnosis, MC burden tends to increase with time (r(2) =.56, P=.009). MCTC phenotype was significantly increased in the CLAD group (8.2±4.9 cells per HPF) in comparison with the other three groups (early normal: 1.6±1.7, P=.0026; late normal: 2.5±2.3, P=.048; ACR: 2.7±3.5, P=.021). Further, the ratio of MCTC to MCT was significantly increased in CLAD group as compared to the other three groups (P<.001 for all comparisons). CONCLUSIONS: The burden of MC may increase in the allograft as function of time. Patients with CLAD have an increased relative and absolute burden of MCTC phenotype MC. Future studies are needed to confirm these findings and evaluate the potential pathologic role of MCTC in allograft dysfunction.

Tracheobronchial smooth muscle atrophy and separation.

We report a case series involving 4 patients with chronic obstructive pulmonary disease who were on an appropriate medical regimen including a high dose of inhaled corticosteroids (ICS). During bronchoscopy, patients were found to have an excessive dynamic collapse of the posterior wall and its separation from the ends of the adjacent cartilaginous rings. This was causing a near-total occlusion of the tracheal and bronchial lumen during exhalation, thereby presenting with an obstructive pattern on the pulmonary functions. We suspect that this was caused by the atrophy of the smooth muscles of the tracheobronchial wall. We reviewed the literature to explore the mechanisms causing atrophy of the bronchial smooth muscle, focusing on the potential role of long-term ICS use.

The natural history of lung function after lung transplantation for α(1)-antitrypsin deficiency.

RATIONALE: Lung transplantation (LT) is an established treatment for end-stage lung diseases, including chronic obstructive pulmonary disease (COPD) associated with α1-antitrypsin deficiency (AATD). OBJECTIVES: We sought to compare the post-transplantation course of patients with AATD and AAT-replete COPD. METHODS: Between June 1991 and January 2008, a total of 231 patients with AAT-replete COPD and 45 with AATD underwent LT at Cleveland Clinic. Data reviewed included baseline recipient, donor, and surgical data; all spirometry evaluations; acute cellular rejection (ACR) events; and survival data. Endpoints included temporal change in FEV1, severity of ACR, and survival. A longitudinal temporal decomposition model was used for analysis. MEASUREMENTS AND MAIN RESULTS: Comparison of overall rates of FEV1 decline in AATD and AAT-replete patients with COPD showed no significant differences (P > 0.09). However, although the single LT patients had similar trends in FEV1 in both groups, patients with AATD with double LT declined faster (P < 0.002) than the AAT-replete patients. No differences in the frequency or severity of ACR episodes were observed (P = 0.32). Furthermore, there was no difference in early or late mortality between patients with AATD and patients with AAT-replete COPD (P > 0.09). CONCLUSIONS: Although overall the post-LT FEV1 slope, severity of ACR, and survival among patients with AATD is similar to that of AAT-replete patients with COPD, patients with AATD with double LT have a faster rate of FEV1 decline. These findings support the eligibility of patients with AATD for LT, and suggest the need for additional studies to better understand the difference between single and double LT in AATD.

Outpatient management of Post-COVID syndrome - single center experience.

BACKGROUND: COVID patients continue to experience unremitting symptoms that extend far beyond the initial illness. While there is rapid accumulation of data on acute COVID treatment in hospitalized patients, little is known regarding post-COVID management. OBJECTIVES: To describe our center's experience treating post-COVID sub-syndromes encountered in Post-COVID Lung Clinic. METHODS: We retrospectively reviewed data on 98 post-COVID patients evaluated in our clinic between 07/01/2020-12/31/2022. We encountered three distinct post-COVID subtypes: 1) respiratory complaints associated with increased O2 requirements and abnormal CT findings (post-COVID interstitial lung disease [ILD]), 2) respiratory complaints associated with tachycardia (post-COVID dyspnea-tachycardia syndrome [DTS]). Post-COVID ILD patients (n = 28) received steroids in combination with cell cycle inhibitor (mycophenolate mofetil-MMF). Post-COVID DTS patients (n = 16) were treated with metoprolol. 3) A third, undifferentiated group presented with mild respiratory complaints and normal spirometry (n = 17) and was followed in clinic without initiation of a specific treatment. RESULTS: In treated post-COVID ILD patients, mean oxygen requirements at rest (1.96 ± 1.79 L/NC) decreased to 0.89 ± 1.29 L/NC at 6 months follow-up, p = 0.005. In patients with post-COVID DTS, mean heart rate at rest decreased (98 ± 15 bpm to 79 ± 11 bpm) at 6 months follow-up, p = 0.023. 60 % of patients reported an improvement in exertional dyspnea. CONCLUSIONS: Our descriptive study presents a single center outpatient COVID-19 clinic experience. We encountered 3 post-COVID sub-syndromes and describe their treatments: post-COVID interstitial lung disease [ILD] treated with a novel regimen of MMF and steroids, post COVID dyspnea-tachycardia syndrome [DTS] treated with metoprolol, and a third subgroup with mild undifferentiated symptoms without specific treatment.

Alterations in Pulmonary Physiology with Lung Transplantation.

Lung transplant is a treatment option for patients with end-stage lung diseases; however, survival outcomes continue to be inferior when compared to other solid organs. We review the several anatomic and physiologic changes that result from lung transplantation surgery, and their role in the pathophysiology of common complications encountered by lung recipients. The loss of bronchial circulation into the allograft after transplant surgery results in ischemia-related changes in the bronchial artery territory of the allograft. We discuss the role of bronchopulmonary anastomosis in blood circulation in the allograft posttransplant. We review commonly encountered complications related to loss of bronchial circulation such as allograft airway ischemia, necrosis, anastomotic dehiscence, mucociliary dysfunction, and bronchial stenosis. Loss of dual circulation to the lung also increases the risk of pulmonary infarction with acute pulmonary embolism. The loss of lymphatic drainage during transplant surgery also impairs the management of allograft interstitial fluid, resulting in pulmonary edema and early pleural effusion. We discuss the role of lymphatic drainage in primary graft dysfunction. Besides, we review the association of late posttransplant pleural effusion with complications such as acute rejection. We then review the impact of loss of afferent and efferent innervation from the allograft on control of breathing, as well as lung protective reflexes. We conclude with discussion about pulmonary function testing, allograft monitoring with spirometry, and classification of chronic lung allograft dysfunction phenotypes based on total lung capacity measurements. We also review factors limiting physical exercise capacity after lung transplantation, especially impairment of muscle metabolism. © 2023 American Physiological Society. Compr Physiol 13:4269-4293, 2023.

Delayed-Onset Psychosis Secondary to Tacrolimus Neurotoxicity After Lung Transplant: A Case Report and Systematic Review.

BACKGROUND: Tacrolimus is the most common immunosuppressant used after transplant, yet it can result in moderate-to-severe neurotoxicity in up to 32% of patients. Signs of neurotoxicity can vary from mild (tremor or headache) to severe (posterior reversible encephalopathy syndrome or psychosis. Prompt recognition and management is needed to lead to symptom resolution. OBJECTIVE: The objective of this study is to describe the clinical presentation of tacrolimus-induced psychosis, a type of tacrolimus-inducted neurotoxicity, and distinguish it from other central nervous system disturbances, including delirium. METHODS AND RESULTS: We present a case of delayed onset tacrolimus-induced psychosis with focus on unique clinical features and management strategies. We conducted a systematic review of cases of tacrolimus-induced psychosis using the PubMed database and included 15 manuscripts in our review. CONCLUSIONS: Tacrolimus-induced psychosis is a unique presentation of tacrolimus-related neurotoxicity and can present without the cardinal symptoms of delirium. The data on isolated psychotic symptoms are limited with current literature focusing on more common presentations of tacrolimus-induced neurotoxicity, such as delirium and tremor. Development of psychosis can occur later in the treatment course and at normal tacrolimus serum levels. It can improve with antipsychotic therapies, but primary management should include cross-titration to an alternate immunosuppressant regimen.

A Randomized, Multicenter, Blinded Pilot Study Assessing the Effects of Gaseous Nitric Oxide in an Ex Vivo System of Human Lungs.

INTRODUCTION: Normothermic ex vivo lung perfusion (EVLP) is used to evaluate and condition donor lungs for transplantation. The objective of this study was to determine whether administration of exogenous nitric oxide during EVLP contributes to improvement of lung health. METHODS: A multicenter, blinded, two-arm, randomized pilot study evaluated the effect of gaseous nitric oxide (gNO) administered during EVLP on donor lungs rejected for transplantation. gNO introduced into the perfusate at 80 parts per million (ppm) was compared with perfusate alone (P). An open-label substudy assessed inhaled nitric oxide gas (iNO) delivered into the lungs at 20 ppm via a ventilator. Primary endpoints were an aggregate score of lung physiology indicators and total duration of stable EVLP time. Secondary endpoints included assessments of lung weight and left atrium partial pressure of oxygen (LAPO2). RESULTS: Twenty bilateral donor lungs (blinded study, n = 16; open-label substudy, n = 4) from three centers were enrolled. Median (min, max) total EVLP times for the gNO, P, and iNO groups were 12.4 (8.6, 12.6), 10.6 (6.0, 12.4), and 12.4 (8.7, 13.0) hours, respectively. In the blinded study, median aggregate scores were higher in the gNO group compared to the P group at most time points, suggesting better lung health with gNO (median score range [min, max], 0-3.5 [0, 7]) vs. P (0-2.0 [0, 5] at end of study). In the substudy, median aggregate scores did not improve for lungs in the iNO group. However, both the gNO and iNO groups showed improvements in lung weight and LAPO2 compared to the P group. CONCLUSIONS: The data suggest that inclusion of gNO during EVLP may potentially prolong duration of organ stability and improve donor lung health, which warrants further investigation.

Crossroads between Autoimmunity and COVID-19 in Lung Transplant Recipients.

The presence of a certain group of auto-antibodies (AAbs) is known to correlate with the severity of COVID-19. It is, however, unknown if such AAbs are prevalent and impact COVID-19-related outcomes in lung transplant recipients (LTRs) who are immunosuppressed. We performed a retrospective study of LTRs with COVID-19 and analyzed samples before and after COVID-19 for IgG AAbs. AAbs analysis was carried out using autoimmune and coronavirus microarray and the resulting cross-sectional differences in Ab-scores and clinical variables were analyzed using Fischer's Exact test for categorical variables and a paired t-test for continuous variables. Linear regression was used to analyze the differences in Ab-scores and COVID-19 severity. LTRs with non-severe [NS gp (n = 10)], and severe [S gp (n = 8)] COVID-19 disease were included. Ferritin and acute respiratory failure were higher in the S group (p = 0.03; p < 0.0001). Among the AAbs analyzed, interferon-related AAbs (IFN-alpha2, IFN-beta, IFN lamba, IFN-epsilon), eight interleukin-related AAbs, and several tissue-related AAbs were also found to be changed significantly from pre- to post-COVID-19 (p < 0.05). IFN-lambda (p = 0.03) and IL-22 (p = 0.002) were significantly associated with COVID-19 severity and remained significant in linear regression analysis while controlling for other variables. AAbs are common in LTRs, and certain groups of antibodies are particularly enhanced in LTRs with severe COVID-19. Preliminary observations of this study need to be confirmed by a larger sample size.