Anti-Thymocyte Globulin as a Therapy for Chronic Lung Allograft Dysfunction: A Single-Center Experience.

INTRODUCTION: Anti-thymocyte globulin (ATG) is a polyclonal antibody formulation which has been used as a second-line therapy for chronic lung allograft dysfunction (CLAD). Limited data exist evaluating its efficacy; however, several single-center retrospective studies have variably demonstrated either improvement or stabilization of spirometry parameters after administration of ATG. ATG has been in use at UT Southwestern for treatment of CLAD since at least 2010; here, we seek to evaluate the effectiveness of this intervention at our center.  METHODS: A retrospective chart review was conducted of a total of 136 patients who underwent lung transplantation at UT Southwestern Medical Center between 2010 and 2022. Of these, 72 patients had received ATG specifically for treatment of CLAD, and the remaining 64 had never received ATG. Two separate analyses were performed: in the first, among those who received ATG for CLAD, spirometry data from the 6 months preceding and following ATG administration were reviewed and rates of change in FEV1 were calculated for each time period. Descriptive statistics were performed to summarize the baseline clinical characteristics and outcomes after ATG, with patients classified as having either a full response (positive rate of change in FEV1) or partial response (>20% attenuation in rate of FEV1 decline) to ATG.  In the second analysis, survival was described among those who received ATG for CLAD and comparison was provided between propensity-score matched cohorts from the ATG and non-ATG groups. RESULTS: Of the 63 patients who received ATG for treatment of CLAD (and had adequate spirometry measurements available to trend FEV1), 49 (77.8%) had at least a partial response to therapy; 8 (12.7%) experienced an overall improvement in FEV1. Response to ATG was found to be associated with a more rapid rate of pre-ATG decline in FEV1; no other baseline parameters were found to be predictive of a response to ATG. Median post-CLAD graft survival was 31.7 months among those who received ATG, and only baseline absolute neutrophil count was found to be associated with worse post-CLAD graft survival among this group. CONCLUSION: Anti-thymocyte globulin therapy, when given for CLAD, was associated with at least a modest attenuation in rate of FEV1 decline in most patients but only rarely preceded an absolute improvement in FEV1. Further study is warranted to better define the role for ATG in treatment of CLAD, a challenging disease state with limited therapeutics available.

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.

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.

Management of donor-specific antibodies in lung transplantation.

The formation of antibodies against donor human leukocyte antigens poses a challenging problem both for donor selection as well as postoperative graft function in lung transplantation. These donor-specific antibodies limit the pool of potential donor organs and are associated with episodes of antibody-mediated rejection, chronic lung allograft dysfunction, and increased mortality. Optimal management strategies for clearance of DSAs are poorly defined and vary greatly by institution; most of the data supporting any particular strategy is limited to small-scale retrospective cohort studies. A typical approach to antibody depletion may involve the use of high-dose steroids, plasma exchange, intravenous immunoglobulin, and possibly other immunomodulators or small-molecule therapies. This review seeks to define the current understanding of the significance of DSAs in lung transplantation and outline the literature supporting strategies for their management.

A Case Report of Breakthrough Infections With 2 SARS-CoV-2 Variants in a Lung Transplant Patient.

A lung transplant (LT) patient developed 2 distinct episodes of COVID-19, confirmed by whole-genome sequencing, which was caused by the Delta, and then followed 6 weeks later, by the Omicron variant. The clinical course with Omicron was more severe, leading us to speculate that Omicron may not be any milder among LT patients. We discuss the potential mechanisms behind the Omicron not being any milder among LT patients and emphasize the need for outcomes data among these patients. Until such data become available, it may be prudent to maintain clinical equipoise as regards the relative virulence of the newer variants among LT patients.

COVID-19 Vaccination is Associated With Favorable Outcomes Among Lung Transplant Patients With Breakthrough Infections.

BACKGROUND: There are limited data regarding the clinical efficacy of COVID-19 vaccines among lung transplant (LT) patients. METHODS: We included all LT patients diagnosed with COVID-19 between March 1, 2020, and December 10, 2021 (n = 84; median age 55, range, 20-73 years; males 65.5%). The study group was divided into 3 groups based on the vaccination status (patients who did not complete the primary series for any of the vaccines: n = 58; those with 2 doses of messenger RNA (mRNA) or 1 dose of the adenoviral vector vaccine, vaccinated group: n = 16; those with at least 1 additional dose beyond the primary series, boosted group: n = 10). RESULTS: Pulmonary parenchymal involvement on chest computed tomography scan was less common among the boosted group (P = .009). The proportion of patients with new or worsening respiratory failure was significantly lower among the vaccinated and boosted groups and these patients were significantly more likely to achieve the composite endpoint of oxygen-dependence free survival (P = .02). On multivariate logistic regression analysis, higher body mass index, restrictive lung disease as the transplant indication, and preinfection chronic lung allograft dysfunction were independently associated with acute or acute on chronic respiratory failure while being on therapeutic dose anticoagulation and having received the booster dose had a protective effect. CONCLUSION: COVID-19 vaccines appear to have several favorable effects among LT patients with breakthrough infections including lower likelihood of allograft involvement on imaging (among boosted patients), need of hospitalization, and complications such as new or worsening respiratory failure.

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.

ECMO Long Haulers: A Distinct Phenotype of COVID-19-Associated ARDS With Implications for Lung Transplant Candidacy.

BACKGROUND: Studies indicate that the recovery from coronavirus disease 2019 (COVID-19)-associated acute respiratory distress syndrome may be slower than other viral pneumonia. There are limited data to guide decisions among patients who need extracorporeal membrane oxygenation (ECMO) support, especially the expected time of recovery and considering lung transplantation (LT). METHODS: This was a retrospective chart review of patients with COVID-19-associated acute respiratory distress syndrome placed on ECMO between March 1, 2020, and September 15, 2021 (n = 20; median age, 44 y; range, 22-62 y; male:female, 15:5). We contrasted the baseline variables and clinical course of patients with and without the need for ECMO support >30 d (ECMO long haulers, n = 10). RESULTS: Ten patients met the criteria for ECMO long haulers (median duration of ECMO, 86 d; range, 42-201 d). The long haulers were healthier at baseline with fewer comorbidities but had worse pulmonary compliance and higher partial pressure of CO2. They had a significantly higher number of membrane oxygenator failures, changes to their cannulation sites, and suffer more complications on ECMO. One of the long hauler was bridged to LT while another 6 patients recovered and were discharged. Overall survival was better among the ECMO long haulers (70% versus 20%; 9.3, 1.2-73; P = 0.03). CONCLUSIONS: Despite worse pulmonary physiology, frequent complications, and a tortuous hospital course that may appear to portend a poor prognosis, ECMO long haulers have the potential to recover and be weaned off ECMO without the need for LT. A customized approach comprising a more conservative timeline for the consideration of LT may be prudent among these patients.

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.

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.

Clinical characteristics, management practices, and outcomes among lung transplant patients with COVID-19.

BACKGROUND: There are limited data on management strategies and outcomes among lung transplant (LT) patients with Coronavirus disease 2019 (COVID-19). We implemented management protocols based on the best available evidence and consensus among multidisciplinary teams. The current study reports our experience and outcomes using this protocol-based management strategy. METHODS: We included single or bilateral LT patients who tested positive for SARS-CoV-2 on nasopharyngeal swab between March 1, 2020, to December 15, 2020 (n = 25; median age: 60, range 20-73 years; M: F 17:8). A group of patients with Respiratory Syncytial Virus (RSV) infection during 2016-18 were included to serve as a comparator group (n = 36). RESULTS: As compared to RSV, patients with COVID-19 were more likely to present with constitutional symptoms, spirometric decline, pulmonary opacities, new or worsening respiratory failure, and need for ventilator support. Patients with SARS-CoV-2 infection were less likely to receive a multimodality treatment strategy, and they experienced worse post-infection lung function loss, functional decline, and three-month survival. A significant proportion of patients with COVID-19 needed readmission for worsening allograft function (36.4%), and chronic kidney disease at initial presentation was associated with this complication. Lower pre-morbid FEV1 appeared to increase the risk of new or worsening respiratory failure, which was associated with worse outcomes. Overall hospital survival was 88% (n = 22). Follow-up data was available for all discharged patients (median: 43.5 days, range 15-287 days). A majority had persistent radiological opacities (19/22, 86.4%), with nearly half of the patients with available post-COVID-19 spirometry showing > 10% loss in lung function (6/13, median loss: 14.5%, range 10%-31%). CONCLUSIONS: Despite similar demographic characteristics and predispositions, LT patients with COVID-19 are sicker and experience worse outcomes as compared to RSV. Despite the availability of newer therapeutic agents, COVID-19 continues to be associated with significant morbidity and mortality.