Bilateral Lung Transplantation Research Articles

Invasive Aspergillosis Resistant to Double-Coverage of Antifungal Therapy in a Very Immunosuppressed Lung Transplant Recipient

<h3>Introduction</h3> Lung transplant (LT) recipients require intensive immunosuppressive regimens, which raises the risk of invasive fungal disease that can be challenging to clear. <h3>Case Report</h3> The patient is an 18-year-old male, bilateral LT (04/2021) recipient for cystic fibrosis, complicated by immediate posttransplant <i>de novo</i> DSA requiring plasma exchange and IVIG. At his 1-month post-discharge visit, significant DSA to multiple class I and class II alleles was found requiring augmented immunosuppression and admission for repeat inpatient plasma exchange and IVIG. Lavage cultures were remarkable for MDR-<i>Pseudomonas</i> with multiple subtypes, sensitive only to cefiderocol. Pulmonary function had not completely recovered since LT as FEV₁ had peaked at 1.5 L (47%) before dropping to 1.1 L (35%) in the current admission. Due to the ongoing DSA burden, we began treatment with antithymocyte globulin (ATG) to prevent the sequalae of antibody-mediated rejection. Additional imaging was remarkable for multiple, confluent, mass-like structures concerning for post-LT lymphoproliferative disorder, prompting biopsies that revealed angioinvasive <i>Aspergillus</i> (<b>Figure 1</b>). We started IV isavuconazole and continued cefiderocol, linezolid, and micafungin given his infectious history. The patient was symptomatic for dyspnea, which did not resolve despite the above antimicrobial coverage, prompting us to substitute voriconazole with some subjective improvement. Serial chest imaging showed worsening markings with new cavitation. Repeat lavage cultures were now significant for <i>Aspergillus terreus</i> and <i>Pseudomonas spp</i> superinfection. After nearly 2 months of ongoing IV antimicrobial therapy, we observed radiographic and symptomatic resolution. <h3>Summary</h3> Early DSA burden with decreasing pulmonary function justified treatment with ATG, but increased the risk of severe fungal infections, which required lengthy double-coverage antifungal therapy.

Unexpected High-Grade Neuroendocrine Carcinoma in Lung Explant

<h3>Introduction</h3> Rarely, malignancies are incidentally detected in lung transplant (LT) explants. These can remain unidentified before LT due to significant architectural distortion of the lung parenchyma, despite appropriate radiographic surveillance. <h3>Case Report</h3> We present the case of a 74-year-old man with history of bilateral LT (03/2021), complicated by grade 2 primary graft dysfunction, for fibrotic hypersensitivity pneumonitis after which a high-grade neuroendocrine carcinoma was unexpectedly found in the right explanted lung. The tumor was 2.1 cm and 3/11 peribronchial lymph nodes were positive for metastatic carcinoma. The left lung explant was negative for malignancy. The tumor was strongly positive for TTF-1 and synaptophysin (<b>Figure 1</b>) with dot-like positivity of the pancytokeratin (AE1/AE3) and CAM 5.2 stains. Tumor cells were negative for CD45, PHH3 demonstrated >50 mitoses/10 high-power fields, and MIB-1 highlighted approximately 60% of tumor nuclei. Whole-body imaging was negative for other masses or acute processes. Maintenance immunosuppression was decreased, and the patient was discharged after LT in stable condition with need for outpatient oncology follow-up. Given the aggressive nature of the explant tumor, the patient decided to pursue adjuvant chemotherapy after recovery from the early post-LT period. The patient received 2 cycles of carboplatin/etoposide, but further treatment was stopped due to severe pancytopenia and need for blood products including platelets. At 6 months post-LT, allograft function is stable - FEV₁ at 2.56 L (88%) - with no evidence of acute cellular rejection or antibody-mediated rejection. There is no evidence of cancer recurrence. <h3>Summary</h3> This is a rare case of high-grade neuroendocrine carcinoma in a lung explant after LT. Recommended etoposide/platinum-based chemotherapy may be limited by adverse effects. Prognosis and feasibility of adjuvant chemotherapy after LT is insufficiently understood.

The Diagnostic Dilemma of a Nodule Appearing as a Mass

<h3>Introduction</h3> Posttransplant lymphoproliferative disorder (PTLD) after lung transplantation (LT) occurs due to immunosuppressant therapy that limits antiviral host immunity and permits Epstein-Barr viral (EBV) replication and transformation of B cells. <h3>Case Report</h3> We present the case of a 61-year-old man with history of bone marrow transplant (08/2009) for non-Hodgkin's lymphoma and bilateral LT (04/2021) for idiopathic pulmonary fibrosis - EBV status: D+/R+. The transplant was complicated by prolonged duration of ECMO and a lengthy post-LT hospital stay for renal failure, significant deconditioning, and acute on chronic respiratory failure requiring tracheostomy and fiberoptic bronchoscopic airway stent placement to limit atelectasis. He also required a muscle flap for right bronchial anastomotic dehiscence in this time course. After 4 months, he was finally discharged to home with tracheostomy in place, requiring oxygen supplementation based only on physical demands. On his return to clinic, an inspection bronchoscopy was performed to assess the airway stent, which was found to have purulent secretions concerning for infection. Bronchoalveolar lavage was positive for pan-sensitive <i>Pseudomonas</i> requiring intravenous antibiotic therapy. At the same time, a chest CT revealed multiple pulmonary nodules in the right lung base, the largest measuring 2.8 cm in diameter. A CT-guided biopsy confirmed EBV-positive polymorphic PTLD. Immunostaining yielded positive results for CD20, CD138, CD79a, MUM1, and EBV-encoded RNAs (EBER) (<b>Figure 1</b>). Notably, this patient never had a positive EBV-viral load. Given his undetectable EBV levels, a decision was made to reduce immunosuppression and follow imaging and blood counts as appropriate. <h3>Summary</h3> EBV-positive PTLD with negative EBV viremia is an unusual combination in an EBV-seropositive recipient with donor non-mismatch. The patient's tenuous respiratory status requiring intensive corticotherapy likely contributed significant risk for PTLD in this case.

Esophageal Cancer Requiring Multiple Biopsies in a Lung Transplant Recipient with Previously Normal Objective Studies

<h3>Introduction</h3> Esophageal cancer is a relatively rare malignancy in lung transplant (LT) recipients. <h3>Case Report</h3> We report the case of a 61-year-old man with a history of bilateral LT (08/2017) for COPD who presented 4 years after transplant with a 1-month complaint of dysphagia to solids (mainly large pills) only. He had no history of reflux disease; routine, prior esophagram, EGD, and gastric emptying studies were grossly normal; no evidence of Barrett's esophagus. We performed an EGD that found a 2-cm long focal stricture in the proximal/mid-esophagus. A biopsy from the region confirmed atypical squamous epithelium but not dysplasia or malignancy. A chest CT showed scattered, bilateral solid and ground-glass sub-centimeter pulmonary nodules and circumferential thickening of the proximal/mid-esophagus. At this time, the primary concern was esophageal stricture possibly related to gastroduodenal aspiration. Meanwhile, surveillance bronchoscopies showed no evidence of ACR, granulomatous inflammation, or malignancy. We performed a second EGD with limited ultrasound assessment for esophageal stent placement at the stricture. Unfortunately, biopsy at this time revealed moderately differentiated, keratinizing, invasive squamous cell carcinoma. Given this finding, we performed robotic bronchoscopy with EBUS-guided FNA of the right upper lobe and right lower lobe pulmonary nodules; pathology was non-diagnostic. An abdomen/pelvis CT showed no intraabdominal or intrapelvic malignancy concerns. A follow-up PET/CT showed increased metabolic activity in the proximal esophagus surrounding the esophageal stent and in the distal esophagus. There was no focal uptake involving the previously identified pulmonary nodules. The patient was informed and shared the decision to start definitive chemoradiotherapy with weekly carboplatin and paclitaxel. <h3>Summary</h3> Suspicion for this malignancy was particularly low given no previous history of reflux disease, grossly normal objective studies to date, and a first biopsy not diagnostic for dysplasia or malignancy. Nonetheless, esophageal stricturing with complaint of dysphagia to solids only should raise concern for malignancy.

A Fatal Case of Nocardia Bacteremia in a Lung Transplant Recipient

<h3>Introduction</h3> <i>Nocardia</i> bacteremia is an extremely rare disease. Although closely associated with immunocompromised states, only a few cases have been reported after lung transplant (LT). <h3>Case Report</h3> We present a case of <i>Nocardia</i> bacteremia in a 75-year-old man after bilateral LT (11/2017) for combined pulmonary fibrosis and emphysema. Nearing 3 years posttransplant, pulmonary function tests (PFTs) revealed an obstructive pattern with downtrending FEV₁ from baseline; work-up for acute cellular rejection, infection, and antibody-mediated rejection was unremarkable. Serial PFTs ultimately suggested CLAD-BOS phenotype, and he received photopheresis with some stabilization. However, over the next 2 months, he required 2 hospital admissions with need for high-dose intravenous steroids given hypercapnia in the setting of underlying rejection. At 38 months posttransplant, he developed lower extremity cellulitis and new-onset anorexia, generalized weakness, and rapid decline in mental status with need for a third hospitalization and mechanical ventilation with vasopressor support. Infectious work-up and empiric broad-spectrum antibiotic coverage were initiated. Within 12 hours, both blood cultures were positive for <i>Nocardia cyriacigeorgica</i> (Gram stain, <b>Figure A</b>). Meropenem and trimethoprim/sulfamethoxazole were substituted without clinical improvement over the next several days. Brain MRI ruled out cerebral nocardiosis; chest CT showed bibasilar consolidations with air space opacities. An echocardiogram estimated a left ventricular ejection fraction between 20-25% with severe diffuse hypokinesis, likely stress-induced cardiomyopathy, with no evidence of vegetations. Bronchoscopy revealed superinfection with pan-sensitive <i>Pseudomonas</i> spp, without isolation of <i>Nocardia</i> spp. The patient deteriorated and died 39 months after transplant. <h3>Summary</h3> <i>Nocardia</i> bacteremia, scarcely reported in LT recipients, portends a poor prognosis despite aggressive combination antimicrobial therapy.

Small Anastomotic Dehiscence Identified Late After Lung Transplant

<h3>Introduction</h3> Anastomotic airway complications, such as necrosis with dehiscence of the anastomotic site, may cause morbidity after lung transplant (LT). In rare cases, sloughing and necrosis of the anastomotic site can mask partial, asymptomatic dehiscence. <h3>Case Report</h3> We present the case of a masked, partial anastomotic dehiscence in a 71-year-old man after bilateral LT (06/2021) for COPD. His postoperative course was complicated by PGD grade 1 and positive crossmatch with the donor, requiring plasma exchange and IVIG. During the transplant stay, he also required frequent bronchoscopies given thick secretions in the bilateral anastomotic sites. We initiated inhaled antibiotics with tobramycin and amphotericin; donor cultures were positive for MRSA, for which the recipient was also adequately covered. Chest CT showed small, bilateral pneumothoraces, more pronounced on the right (<b>Figure 1A</b>), but no evidence of dehiscence (<b>Figure 1B</b>). At 2 weeks posttransplant, secretions were slowing, but a fifth bronchoscopy showed continued sloughing (<b>Figure 1C</b>) with need for forceps to remove the necrotic debris. He was ultimately discharged in stable condition, without bronchoscopic findings of dehiscence. Two months later, surveillance bronchoscopy showed resolution of sloughing. However, a small hole near the anastomotic site was seen, suspicious for partial dehiscence. Because there was no evidence of allograft dysfunction or pneumothorax, we lowered his steroid dose and monitored healing with frequent bronchoscopies. Alongside aggressive antibiotic therapy and airway clearance, a repeat bronchoscopy performed 10 days later showed pseudomembrane formation and healed dehiscence (<b>Figure 1D</b>). Fortunately, the patient had no issues with initial chest tube removal after transplant. <h3>Summary</h3> Partial, asymptomatic anastomotic dehiscence can be masked in the immediate posttransplant period. Careful inspection of the bilateral anastomosis with repeat bronchoscopies may be necessary to rule out dehiscence with certainty.

Prediction of Chronic Lung Allograft Dysfunction by Monitoring Serum KL-6 Levels

<h3>Purpose</h3> Chronic lung allograft dysfunction (CLAD) is the main cause of long-term mortality in lung transplantation (LT). The main phenotypes of CLAD are bronchiolitis obliterans syndrome (BOS), restrictive allograft syndrome (RAS) and mixed. Biomarkers for early identification of CLAD are needed. KL-6, an antigen produced mainly by damaged type II pneumocytes, has been described as a RAS-biomarker. The aim of our study was to assess the utility of serum KL-6 levels as a CLAD biomarker. <h3>Methods</h3> This was a longitudinal study in which KL-6 levels were measured in 52 bilateral LT patients at 3, 6, 9, 12, 18 and 24 months after LT. At the same time-points, clinical features and pulmonary function were determined. CLAD diagnosis was assessed during a three years follow-up. <h3>Results</h3> Seventeen out of 52 patients developed CLAD (11 BOS and 6 patients RAS or mixed). No differences in demographics were found, but patients with RAS or mixed phenotypes had a higher incidence of positive Donor-Specific Antibodies (DSA). Also, serum KL-6 levels before CLAD diagnosis were higher in the patients who developed RAS-mixed (563 [439.7-752.8 U/ml]) compared to patients diagnosed with BOS (356.7 [265.7-492.2 U/ml]) or those without CLAD (372.8 [274.8-606.9 U/ml]) at 6 months after LT, although not statistically significant (p=0.187). However, a KL-6 cut-off of 520.4 U/ml at 6-month post-transplant was able to differentiate RAS-mixed from non- RAS-mixed patients with a sensitivity of 80% (IC95 28.36-99.49%) and specificity of 72.73% (IC95 57.21-85.04%). When analyzing serum KL-6 levels in all samples, even those obtained after CLAD diagnosis, RAS patients had higher levels which progressively increase along follow-up (see table). <h3>Conclusion</h3> Serum KL-6 could be a useful biomarker for RAS prediction.

Lung Transplantation in COVID-19 Induced End Stage Lung Disease

IntroductionIn a subset of patients COVID-19 induced lung injury progresses to irreversible lung damage and pulmonary fibrosis. Bilateral orthotopic lung transplant (BOLT) has been used as a rescue therapy in these patients. We describe four patients who were bridged to BOLT using venovenous extracorporeal membrane oxygenation (VV-ECMO).Case ReportBetween October 13, 2020 and February 14, 2021, four patients with SARS-CoV-2 infection underwent BOLT for end-stage pulmonary fibrosis demonstrated on computed tomography. Median age was 42 years and three were male. One patient had a prior history of undifferentiated interstitial lung disease managed with chronic steroids. Pre-transplant hospital course was complicated by right ventricular failure due to pulmonary hypertension in two patients and ventilator-associated pneumonia in one. One patient developed heparin-induced thrombocytopenia requiring anticoagulation with bivalirudin perioperatively. Three patients were non-ambulatory and bedridden for a median of 54 days prior to surgery. Timing of transplantation ranged from hospital day 26 - 68 with a median of 48 days. At the time of transplant, three patients were mechanically ventilated via tracheostomy, while all were on VV-ECMO a median of 27 (IQR 11 - 42) days. All patients underwent BOLT via clamshell exposure utilizing cardiopulmonary bypass (CPB) with aortic and right atrial cannulation. VV-ECMO was discontinued intraoperatively in all cases after initiating CPB. All patients required intraoperative blood transfusion with a median of 3 units. The three patients with tracheostomy prior to transplant were liberated from the ventilator a median of 9 days postoperatively and decannulated from their tracheostomy a median of 11 days postoperatively. Aside from one patient requiring short courses of hemodialysis, there were no significant postoperative complications. Patients were discharged a median of 17 (14 - 20) days following surgery. After a median follow-up of 226.5 (223 - 257.75) days, all four patients were alive with no supplemental oxygen requirement.SummaryPulmonary fibrosis secondary to COVID-19 pneumonia can be successfully treated with VV-ECMO and subsequent lung transplantation in select patients. Special consideration should be given to this patient population as they may not meet traditional listing requirements. We report a 100% oxygen-free survival rate at six months.

Initial Case Series with a Novel Cold Storage System for Lung Transplantation

<h3>Purpose</h3> Hypothermia is used to slow the metabolic rate and degradation of donor organs. However, the most commonly used method, ice storage, assures neither a uniform nor an optimal preservation temperature for the organ. Although a recent report suggests that 10 ºC storage prolongs cellular preservation and prevents grade 3 primary graft dysfunction (PGD) in lungs transplanted following <i>ex vivo</i> lung perfusion assessment, these resources are not available at all centers. We report an early case series with a new FDA-approved device that provides temperature-regulated 4 ºC transport of donor lungs and an 8-hour storage time. <h3>Methods</h3> We retrospectively examined the outcomes of 9 patients who underwent bilateral lung transplantation over a 4-month period at our institution. Three patients received donor lungs transported using the novel preservation device (novel group), while 6 patients received donor lungs preserved in ice (standard group). PGD at 24, 48, and 72 hours was the primary outcome. Secondary outcomes included post-reperfusion P/F ratios, ventilation hours, days in ICU, length of stay (LOS), and death. <h3>Results</h3> The standard group recipients were older than the patients in the novel group (standard 64.0 ± 2.4 vs novel 59.3 ± 1.2 years, p = 0.004). Donor characteristics were similar between the two groups. There were no differences in either the total (397.5 ± 59.0 vs 352.7 ± 27.0 minutes, p = 0.16) or warm (46.9 ± 15.3 vs 45.0 ± 13.5 minutes, p = 0.79) ischemic times. Ten minutes after reperfusion, the median intraoperative P/F ratio was markedly better in the novel group (432.4, IQR 341.9-516.2) than the standard group (243.2, IQR 190.2-363.9). No PGD was observed in the novel group. In the standard group, grade 2 or 3 PGD was seen in 4 patients after 24 hours, 2 patients after 48 hours, and 3 patients after 72 hours. The novel group had a shorter LOS (38.0 ± 16.2 vs 16.3 ± 6.1 days, p = 0.04). There was 1 death in the standard ice group and no deaths in the novel device group (<i>n.s.</i>). <h3>Conclusion</h3> The novel preservation system regulates the temperature of donor lungs during transport and until implantation. Our early experience suggests that the novel device may minimize PGD, improve post-reperfusion P/F ratios, and shorten LOS. Analysis of larger cohorts in a randomized controlled study is recommended to validate these results.

Phaeohyphomycoses in Lung Transplant Recipient

<h3>Introduction</h3> Phaeohyphomycoses are fungal infections caused by dematiaceous fungi, mold with dark colored walls due to the presence of melanin, which are found in soil around the world. The melanin acts as a virulent factor contributing to pathogenesis. Despite ubiquity of these organisms and more than 100 causative species known, infection remains rare with increased frequency noted in solid organ transplant recipients (SOTR) due to immunosuppression and their opportunistic nature. The spectrum of disease is wide, ranging from localized skin/soft tissue infection to disseminated disease with high mortality. <h3>Case Report</h3> A 34 year old male with occupational lung disease requiring bilateral lung transplant 1 year prior, on a standard immunosuppressive regimen with no previous augmentation, presented with small, non-erythematous nodules on his right arm (RUE) and lower leg (RLL). Lesions were painful initially at onset 6 months ago; the tenderness resolved but the nodules persisted and enlarged in size with associated development of new onset dyspnea. Imaging revealed mild scattered ground glass opacities with right lower lobe bronchial wall thickening. Bronchoalveolar lavage fungal culture grew Bipolaris spp. RUE nodule punch biopsy was obtained with septate hyphae on KOH prep and Phialemonium spp. on culture. Excisional biopsy of both nodules revealed seropurulent drainage grossly and invasive filamentous fungal forms on pathology. KOH prep of both again demonstrated septate hyphae, with Phialemonium spp. from RUE and Colletotrichum spp. from RLE. There were no signs of hematogenous spread. He was started on a prolonged course of posaconazole and temporary decrease in immunosuppression with clinical improvement and no return of nodules after excision. <h3>Summary</h3> Phaeohyphomycoses remain rare though occur with increased incidence in SOTR. Here we present a case of multifocal, but not disseminated, phaeohyphomycoses caused by 3 distinct dematiaceous fungi in a lung transplant recipient and avid gardener. Diagnosis occurs histologically and microbiologically in setting of high clinical suspicion. We suspect inhalation and two separate instances of direct inoculation during time spent gardening resulting in concomitant pneumonia and subcutaneous infection by multiple causative dematiaceous fungi. Infection at non-contiguous sites presented as diagnostically challenging with social history as key.

Fulminant Antibody-Mediated Rejection in a Stable Lung Transplant Recipient Post COVID-19 Vaccination

IntroductionVaccination against COVID-19 in immunocompetent individuals has demonstrated high efficacy in disease prevention while significantly reducing severe infections and hospitalizations. COVID-19 vaccination is endorsed in immunosuppressed recipients of solid organ transplant. Trials have examined safety data in this population, with no published reports of increased risk of antibody-mediated rejection (AMR). We present a case of probable mRNA vaccine induced AMR in a previously stable lung transplant recipient.Case ReportA 27-year-old bilateral lung transplant recipient for cystic fibrosis related lung had grade 2 rejection with class II antibodies 2 months post-transplant that was treated with methylprednisolone with good response. He was then event free for over two years. He developed acute onset of dyspnea, dry cough, non-pleuritic chest pain, and general malaise 24 hours after receiving his second dose of the Pfizer mRNA vaccine. Over the subsequent 3 weeks, he deteriorated with worsening exertional dyspnea and desaturation. He was admitted to hospital with rapidly progressive type 1 respiratory failure. A CT angiogram of the chest demonstrated findings consistent with organizing pneumonia versus opportunistic infection. Bronchoscopy was negative for infectious etiology. He was treated with a methylprednisolone pulse to treat the organizing pneumonia seen on imaging and potential AMR. He required intubation and mechanical ventilation on post admission day (PAD) 4. Human leukocyte antigen testing demonstrated de novo class II donor specific antibody (DR12) and possible weak class I reactivity. With declining status and refractory hypoxemia, 5 cycles plasma exchange (PLEX) alternating with thymoglobulin were administered. He became dependent on extracorporeal membrane oxygenation with poor lung compliance. Antibody levels decreased but remained elevated. Subsequent therapy included thymoglobulin (total dose 7mg/kg), 5 additional cycles of PLEX, and intravenous immunoglobulin and Daratumumab on PAD 38. He died PAD 47 when life sustaining measures were removed due complications from Clostridium difficile infection.SummaryThis case of probable AMR post mRNA vaccination in a lung transplant recipient raises clinical suspicion for a serious adverse event and contributes to safety data for this select population.

Airway Complications After Lung Transplant for Post Coronaviral Disease (COVID-19) Acute Respiratory Distress Syndrome (ARDS) Related End Stage Lung Disease: Single Centre Experience

PurposeSevere COVID-19 ARDS related end stage lung fibrosis with irreversible changes is a newer indication for lung transplantation with acceptable survival rate. Airway complication post lung transplant is a major source of morbidity and mortality with incidence as high as 25 to 49 percent. Patients with end stage COVID-19 fibrosis are likely to be clinically deconditioned with long duration of extracorporeal oxygenator (ECMO) support, high burden of sepsis and prolonged respiratory support which may affect the airways post lung transplantation.MethodsThis is a retrospective observational study after obtaining institutional ethical clearance. We reviewed electronic medical data of patients who underwent lung transplantation for post COVID-19 ARDS related fibrosis. We evaluated the incidence and type of airway complications and the various therapeutic interventions applied for its management.ResultsBetween May 2020 and September 2021 our centre performed 23 bilateral lung transplants for end stage COVID-19 ARDS related fibrosis. 22 patients were on ECMO support with mean duration of 50.9 days before transplantation. All patients underwent lung transplantation with central Veno-Arterial ECMO support with mean organ ischaemia time of 360±154 minutes. The incidence of airway complication in our study group was 56%. We observed anastomotic narrowing in 3(13%), distal airway narrowing in 4(17%) and sloughing/coating of anastomotic site in 5(22%) patients. Nonspecific inflammatory polypi around the bronchial anastomotic site were noticed in 4(17%) and mild airway anastomotic dehiscence in 2 subjects. 8(34%) patients required serial bronchoscopy and balloon dilatation; 2 among them mandated additional cautery usage. 2 cases underwent polypectomy, further 4 subjects needed bronchial stent placement. 5 (21%) recipients were discharged with Tracheostomy while rest were successfully decannulated in the ward.ConclusionWe observed a high incidence of airway complications in post lung transplant for COVID-19 ARDS related fibrosis. Early detection, timely management and serial follow up is of paramount importance in this subset of patients.

Hyperammonemia Refractory to Continuous Renal Replacement Therapy, a Fatal Complication Post-Lung Transplant

<h3>Introduction</h3> Post-lung transplant hyperammonemia is a rare complication associated with high mortality. Incidence is about 1-4% usually presenting within 2 weeks post-lung transplant. We describe a rare case of delayed-onset hyperammonemia post-lung transplant refractory to Continuous Renal Replacement Therapy (CRRT). <h3>Case Report</h3> A 30-year-old female underwent re-do bilateral lung transplantation for bronchiolitis obliterans syndrome. Her initial lung transplant was done for interstitial lung disease secondary to radiation-induced lung injury following treatment for childhood acute lymphocytic leukemia. Her first-week Bronchoalveolar lavage was positive for MRSA, <i>Pseudomonas</i> & <i>Ureaplasma</i> which were treated with antibiotics. Her postoperative course was complicated by prolonged hospitalization and need for ventilator support. She required Veno-venous Extra Corporeal Membrane Oxygenation support and CRRT. On POD 140, she was found to have decreased responsiveness. Workup revealed ammonia levels 353mmol/l. Her liver function was normal and repeat BAL cultures were negative for Ureaplasma & Mycoplasma. She was treated with lactulose, polyethylene glycol, levocarnitine, rifaximin, acarbose & sodium benzoate. Despite being on CRRT & this regimen, her ammonia levels continued to rise and peaked at 493 mmol/l. On continuous EEG, seizure-like activity was seen with features suggestive of metabolic encephalopathy. MRI revealed cerebral edema and findings consistent with hyperammonemic encephalopathy. MARS therapy (Molecular Adsorbent Recirculating System) was started, which resulted in a rapid decline in ammonia levels and some improvement in her mental status. In spite of improved ammonia levels, given her poor overall prognosis, the patient & family chose to transition to comfort measures and she subsequently passed away. <h3>Summary</h3> Post-lung transplant hyperammonemia is a poorly understood relatively uncommon condition associated with poor outcomes. Ammonia is a small molecule that does not bind to proteins & is amenable to removal by dialysis. Therefore, significantly elevated ammonia levels despite being on CRRT & medical management, so late following the lung transplant in the absence of any definitive etiology makes this rare. MARS has been proven to successfully treat refractory hyperammonemia post lung transplantation.

Selective Loss of Donor Specific HLA Antibodies in a Highly Sensitized Patient After Lung Transplantation

<h3>Introduction</h3> Lung transplantation in the presence of donor specific antibodies (DSA) is safe with peri-operative desensitization, although persistence of DSA is common. Herein, we present a unique case of a highly sensitized lung transplant recipient with selective loss of DSA post-transplantation. <h3>Case Report</h3> A 65-year-old female with a calculated PRA (cPRA) value of of 17% (class I) and 100% (class II), underwent bilateral lung transplantation for chronic obstructive pulmonary disease. Virtual crossmatch (VCM) was positive, involving DPB1*04:01, DR17, and DR52. The subsequent flow cytometry B-cell crossmatch was strongly positive (median channel shift 296). She received peri-operative desensitization protocol for VCM positive patients, which includes intra-operative and post-operative plasmapheresis, intravenous immune globulin, and anti-thymocyte globulin. Maintenance immunosuppression included cyclosporine (target trough 250-350 umol/L), mycophenolic acid 900mg BID and prednisone 20 mg OD. An increase in DSA reactivity was observed one month after transplant (DPB1*04:01 (MFI=17639), DR17 (MFI=17812), and DR52 (MFI=19414). Repeat HLA testing at 3, 4, and 6 months post-transplant showed sequential reduction of DSAs to below the laboratory cut-off for positivity point despite persistence of non-DSA alloantibodies. The patient continues to maintain good lung function with an FEV1 of 2L (86% of predicted) at 6 months post-transplant. Surveillance transbronchial biopsies at 3 and 6 months were free of cellular rejection. <h3>Summary</h3> Despite initial rebound of pre-formed DSA following peri-operative desensitization, sustained selective clearance of the DSA subsequently occurred in this case, which likely benefited graft function. Similar cases have been reported after combined kidney-liver transplant. Robust laboratory research and prospective studies are required to understand the mechanism of selective DSA elimination in organ transplantation.

SARS-CoV-2 Vaccination Efficacy & Safety in Lung Transplantation Recipients: A Single Centre Study

PurposeSolid Organ Transplant recipients (SOT) are at higher risk of SARS-CoV-2 infection. Mortality rates reported between 13 to over 30% in SOT recipients. SARS‐CoV‐2 vaccination may help reduce the morbidity and mortality of COVID‐19 among SOT. There is paucity of literature of SARS-CoV-2 vaccination efficacy in lung transplantation recipients . The purpose of the study was 1) to evaluate SARS-CoV-2 vaccination efficacy & safety in lung transplantation recipients and 2) to assess the need for 3rd booster dose.MethodsA retrospective study (from Jan 2021 till Oct 2021) of lung transplantation recipients receiving 2 doses of SARS-CoV-2 vaccination available in India i.e. ChAdOx1 nCoV- 19 Corona Virus Vaccine (Recombinant) or Whole-Virion Inactivated Vero Cell vaccine, was done to evaluate vaccination efficacy and safety. SARS-CoV-2 spike COVID antibodies levels were checked 4 weeks after 2nd dose of vaccination. Local and Systemic reactions to vaccination were notedResults11 Bilateral lung transplantation recipients and 4 Combined Heart-Lung transplantation recipients received SARS-CoV-2 vaccination. Out of 15 recipients, 11 recipients received ChAdOx1 nCoV- 19 Corona Virus Vaccine (Recombinant) and 4 recipients received Whole-Virion Inactivated Vero Cell vaccine. 12 recipients developed mild pain at vaccination site, 2 recipients developed local tenderness and 1 recipient developed redness at vaccination site as part of local reaction . 5 recipients developed fever, 5 recipients experienced fatigue/bodypain, 2 recipients had vomiting, 2 recipients experienced headache & 1 recipient developed abdominal pain as part of systemic reactions. 8 (53.3%) out of 15 recipients developed significant SARS-CoV-2 spike antibodies level demonstrating vaccination efficacy. 7 (46.6%) recipients demonstrated lower SARS-CoV-2 antibodies titre (Less than cut off values) indicating no significant vaccination efficacy. 1 recipient developed vaccine breakthrough mild infection after 2nd dose.ConclusionOur experience has shown that SARS-CoV-2 vaccination efficacy was demonstrated in nearly 50 % of lung transplantation recipients. The study also showed safety of SARS-CoV-2 vaccines in such immunocompromised subset. However, for those recipients with no vaccination efficacy, utility of 3rd booster dose and at what interval needs more research.

Diagnosis of Pulmonary Veno-Occlusive Disease in the Absence of Hemodynamic Abnormalities

<h3>Introduction</h3> Sarcoidosis is a granulomatous disorder of unknown etiology that can lead to pulmonary hypertension (PH). Pulmonary veno-occlusive disease (PVOD) is a subset of PH characterized by intimal proliferation and obliteration of the intralobular veins. We present this case of a patient with sarcoidosis, who had symptoms and imaging consistent with PVOD, which preceded hemodynamic manifestations. <h3>Case Report</h3> A 52-year-old male nonsmoker presented with progressive shortness of breath, dry cough, and mild wheezing over the preceding seven months. He had no hypoxemia. He had a history of neurosarcoidosis, diagnosed nine years prior, for which he was in remission and off all immunosuppression. Physical examination was pertinent only for minimal lower extremity edema. Spirometry, diffusing capacity, 6-minute-walk-test, B-type Natriuretic Peptide (BNP), sarcoid markers, and infectious workup were normal. Chest computed tomography (CT) scan revealed interlobular septal thickening, ground glass opacities (GGOs), and lymphadenopathy, concerning for PVOD. Transthoracic echo (TTE) was normal. His right heart catheterization (RHC) was notable for a mean pulmonary artery pressure of 28 mmHg, a pulmonary capillary wedge pressure of 15 mmHg, and a pulmonary vascular resistance of 1.71 Woods units. The clinical picture was felt to represent PVOD, with imaging findings preceding hemodynamic changes. He was referred to the lung transplant program. Patient's symptoms rapidly progressed before he could undergo lung biopsy and he developed progressive hypoxemia. He underwent a successful bilateral lung transplant two weeks later. The explanted lung pathology revealed granulomatous PVOD. <h3>Summary</h3> In prior reports of sarcoidosis-associated PVOD, PH was noted on TTE or RHC correlating with symptoms well before diagnosis of PVOD. Additionally, in patients with hemodynamic or biopsy proven diagnoses of PH, the combination of GGOs, interlobular septal thickening, and mediastinal lymphadenopathy is 95% sensitive and 89% specific for PVOD. Our case suggests that CT imaging findings should raise the index of suspicion for PVOD, even in the absence of objective evidence of pulmonary vascular changes on TTE and RHC. In patients with symptoms of dyspnea, progressive hypoxemia, and these imaging findings, delayed evaluation for transplant may miss an opportunity for early intervention.

Detectable Serum Concentration with Prophylactic Inhaled Tobramycin in Lung Transplant Recipients

<h3>Purpose</h3> Inhaled tobramycin (iTOBI) is used in bilateral lung transplant recipients (LTRs) to prevent PsA colonization. Pharmacokinetic studies show that iTOBI is not systemically absorbed, making it an alternative to intravenous formulations. Case reports exist of LTRs on iTOBI developing renal failure with detectable tobramycin troughs (DTTs). The purpose of this review is to describe the incidence of DTT in LTRs receiving iTOBI immediately post-transplant. <h3>Methods</h3> This single-center, retrospective review included patients in their index lung transplant admission who received iTOBI with a DTT (≥ 0.5 mg/L). All LTRs received iTOBI 300 mg q12hr prophylaxis for at least one month with levels drawn for cause when concerned for accumulation. Primary outcome was the number of LTRs with DTTs. Secondary outcomes included duration of therapy and incidence of SCr increase ≥ 0.3 mg/dL within 48 hours (AKI). Descriptive statistics were used to analyze baseline characteristics and outcomes. <h3>Results</h3> We reviewed 211 LTRs from January 2014 to August 2021. Twenty patients (9.5%) met inclusion criteria with 32 DTTs and 4 were excluded due to undetectable troughs. Median time to initial DTT was 10 (2-34) days of therapy. AKI occurred within a week prior to 84% of DTT, with a median of 3 days to elevated trough. Median time to DTT clearance (undetectable level or resumption of therapy) was 2 days. Therapy was discontinued in 10% of patients due to concern for nephrotoxicity (Table 1). <h3>Conclusion</h3> iTOBI therapy may cause systemic drug levels in the early post-transplant phase. Given known association of systemic tobramycin with nephrotoxicity, particularly in the presence of nephrotoxic medications, iTOBI trough surveillance may be prudent to guide therapy. Rapid DTT clearance may render repeat levels unnecessary. Larger studies are needed to assess the renal risk, timing of iTOBI accumulation in LTRs and thresholds for serum monitoring.

IgM Antibodies to Tropoelastin in Serum Prior to the Onset of Chronic Allograft Dysfunction

<h3>Purpose</h3> Non- Human Leukocyte Antigen (non-HLA) antibodies have been identified as a risk factor for chronic allograft dysfunction (CLAD). Using a two-colour fluorescent antigen microarray with 152 unique antigens, we previously observed that lung transplant recipients who developed CLAD exhibited persisting serum IgM reactivity to several tissue antigens. Among these we observed heightened reactivity to tropoelastin, a precursor of elastin, a major component of the lung extracellular matrix. Here we tested the hypothesis that higher reactivity to tropoelastin is associated with risks for de novo donor-specific antibodies (DSA) and CLAD <h3>Methods</h3> In a single center retrospective study, we measured IgG and IgM reactivities in pre-transplant and six months post-transplant serum samples of 96 flow crossmatch negative bilateral lung transplant recipients. Log2- transformed mean fluorescent intensities (MFIs) were determined for each antigen. Significance analysis of microarrays was used to analyze the results (false discovery rate of 0.05). CLAD was determined using published definitions. A univariate Cox proportional hazards model was performed to examine whether increases in anti-tropoelastin IgM reactivity post-transplant were associated with CLAD risk <h3>Results</h3> Samples were available for 93 patients: 36 (38.7%) patients developed CLAD and 57 (61.3%) patients remained CLAD-free by 5 years post-transplant. Patients with high pre-transplant IgM reactivity to tropoelastin had increased risk for the development of de novo donor specific antibodies (DSA) to HLA antigens post-transplant (Fig 1). A univariate Cox proportional hazards model showed that patients with an above-the-median pre-to-post-transplant increase in tropoelastin IgM reactivity had a shorter time to CLAD (Fig 2, HR 2.2, CI 1.1-4.5) <h3>Conclusion</h3> Serum IgM anti-tropoelastin antibodies present pre- and at 6 months post-transplant may enhance risks for DSA and CLAD. Further work will be required to validate this observation

Case Report of Donor Transmitted SARS-CoV-2 Infection During Lung Transplantation

IntroductionAvoiding SARS-CoV-2 infection in the peri-operative period is a challenge for lung transplantation during the COVID19 pandemic. Testing donor lung BAL samples for SARS-CoV-2 as part of pre-transplant workup may avoid donor-derived infections.Case ReportA 36-year-old woman with interstitial lung disease secondary to desquamatous interstitial pneumonia during infancy underwent bilateral lung transplant. She was highly allosensitized (cPRA >89%, ccPRA 97%) prompting intra-operative plasmapheresis (PLEX) and rabbit thymoglobulin induction immunosuppression. Post-operatively, her immunosuppression consisted of institution-standard tacrolimus, mycophenolate, and methylprednisolone. For HLA desensitization belatacept, rituximab, intravenous immunoglobulin (IVIG), and carfilzomib regimens were added. She was extubated post-op day 2. Her course was complicated by worsening hypercarbia, hypoxia and respiratory secretions. Post-op day 11, she was reintubated with tracheostomy placement. Chest imaging showed bilateral heterogeneous pulmonary opacities. BAL sampling was positive for SARS-CoV-2 with concern for donor transmission given adherent hospital precautions. Pre-transplant donor and recipient nasopharyngeal (NP) SARS-CoV-2 screenings were negative. Donor transmission was confirmed by positive PCR testing of banked pre-operative donor lung BAL samples. Dexamethasone and remdesivir were started. Tacrolimus and mycophenolate were continued for immunosuppression. She developed acute antibody-mediated rejection (AMR) with new donor specific antigens (DSA) likely related to her SARS-CoV-2 infection. Her AMR was managed with IVIG and PLEX x 10 with PLEX followed by SARS-CoV-2 convalescent plasma. Her DSA's resolved and ventilatory support was weaned. She was discharged home post-op day 56 and was doing well on room air 6 months out.SummaryThis case emphasizes a potential to miss donor SARS-CoV-2 infection in standard pre-operative evaluation. Despite absence from the NP mucosa viable SARS-CoV-2 virions may be present in donor lung tissue, increasing risk of infection to recipients. Peri-transplant SARS-CoV-2 infection carries a high risk of morbidity. Of note, our case occurred prior to the UNOS mandate for donor lung SARS-CoV-2 screening by lower respiratory sampling. This mandate will decrease risk for similar cases in the future.

Assessment of Cardiac Contribution to Exercise Intolerance in Pediatric Bilateral Lung Transplant Recipients

<h3>Purpose</h3> Exercise intolerance is common among lung transplant (LTx) recipients. However, there is limited data in pediatrics. Since the heart and lungs work in concert with each other, we aim to assess the cardiac contribution to exercise intolerance in pediatric LTx recipients by examining the prevalence of traditional cardiac risk factors (CRFs) and their performance on cardiopulmonary exercise testing (CPET). <h3>Methods</h3> All pediatric LTx recipients followed at a single center who had a resting echocardiogram (echo), were able to exercise, and had a routine CPET in the last 2 years were included. CRFs including hypertension, hyperlipidemia, diabetes mellitus (DM), body mass index (BMI), activity level, and smoking history were assessed. CPET-derived maximal oxygen consumption (VO2_max) and % predicted peak VO2 (ppVO2_max) were used to assess exercise tolerance. Left ventricular (LV) systolic and diastolic function were also assessed on resting echo. <h3>Results</h3> 11 bilateral LTx patients (7M, 4F, and median age 21 years, range 17-28 years) formed the cohort. Median time since LTx is 6 years, range 2-10 years. The majority of patients (8, 73%) had multiple CRFs: 7 (64%) had hypertension, 7 (64%) hyperlipidemia, 6 (55%) DM, 2 with BMI ≥25 kg/m², and 6 (55%) sedentary lifestyle. None had a smoking history. On resting echo, all had normal LV systolic function. 5 (45%) had LV diastolic dysfunction. On CPET, 9 (82%) had abnormal ppVO2_max ≤85%, even with maximal patient effort. None had ischemia. Surprisingly, only 2 of the 9 had a pulmonary limitation to exercise with abnormal breathing reserve (<25%) to account for abnormal ppVO2_max. 6 had a cardiac limitation to exercise attributed to inability to augment stroke volume (decreased % predicted peak O2 pulse). 1 had an abnormal respiratory exchange ratio (RER <1.10), with a normal % predicted peak O2 pulse and a chronotropic deficit (achieving 60% predicted peak heart rate). Of note, 2 patients had normal exercise tolerance with ppVO2_max >85%. <h3>Conclusion</h3> Despite maximal effort, low exercise tolerance is common among pediatric LTx recipients. The high prevalence of CRFs, diastolic dysfunction, and inability to augment stroke volume suggest a potential cardiac contribution to exercise intolerance for this cohort. Further studies are needed to define potential cardiac issues in exercise tolerance in pediatric LTx recipients.