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Background: Lung transplant recipients (LTRs) are at increased risk of morbidity and mortality from coronavirus disease 2019 (COVID-19); however, the disease course has changed as severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) variants have mutated. We compared COVID-19-related clinical outcomes in LTRs at different stages of the pandemic. We also identified risk factors for developing severe COVID-19 independent of the dominant SARS-CoV-2 variant., Methods: This single-center, retrospective cohort study of LTRs with COVID-19 used Cox regression analyses and bootstrapping to identify factors affecting COVID-19 severity., Results: Between March 2020 and August 2022, 195 LTRs were diagnosed with COVID-19, almost half (89 [45.6%]) during the Omicron period. A total of 113 (58.5%) LTRs were hospitalized and 47 (24.1%) died. Age >65 years increased the risk of hospitalization and death. Although infection with the Omicron variant was associated with a lower risk of hospitalization, the median length of hospital stay (10 days, [interquartile range, 5-19]) was similar between the variants. Intensive care unit (ICU) admission and death were more common with the Delta variant but comparable between the original, Alpha, and Omicron variants. Remdesivir and molnupiravir reduced the risk of hospitalization, and monoclonal antibody therapy reduced the risk of ICU admission, intubation, and death. Vaccination and pre-exposure prophylaxis (PrEP) with tixagevimab-cilgavimab did not significantly reduce COVID-19-related ICU admission, intubation, or mortality among LTRs., Conclusions: LTRs with COVID-19 continue to have high hospitalization rates and prolonged hospital stays, despite the reduced virulence of the Omicron variant. More effective PrEP and therapeutic interventions for COVID-19 among vulnerable patient groups are needed., (Copyright © 2023 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Humoral and cellular immune responses to SARS-CoV-2 and other coronaviruses in lung transplant recipients are unknown. We measured antibodies and T cell responses against the SARS-CoV-2 spike S2 and nucleocapsid antigens and spike antigens from common respiratory coronaviruses (229E, NL63, OC43, and HKU1) after vaccination or infection of LTxRs. 148 LTxRs from single center were included in this study: 98 after vaccination and 50 following SARS-CoV-2 infection. Antibodies were quantified by enzyme-linked immunosorbent assay. The frequency of T cells secreting IL2, IL4, IL10, IL17, TNFα, and IFNγ were enumerated by enzyme-linked immunospot assay. Our results have shown the development of antibodies to SARS-CoV-2 spike protein in infected LTxRs (39/50) and vaccinated LTxRs (52/98). Vaccinated LTxRs had higher number of T cells producing TNFα but less cells producing IFNγ than infected LTxRs in response to the nucleocapsid antigen and other coronavirus spike antigens. We didn't find correlation between the development of antibodies and cellular immune responses against the SARS-CoV-2 spike protein after vaccination. Instead, LTxRs have pre-existing cellular immunity to common respiratory coronaviruses, leading to cross-reactive immunity against SARS-CoV-2 which likely will provide protection against SARS-Cov-2 infection., Competing Interests: Declaration of Competing Interest Authors declare no conflict of interest. All authors have reviewed and approved the manuscript and have contributed in a substantial and intellectual manner to the work., (Copyright © 2023. Published by Elsevier B.V.)

Background: In the general population, prior infection with SARS-CoV-2 reduces the risk of severe COVID-19; however, studies in lung transplant recipients (LTRs) are lacking. We sought to describe the clinical course of COVID-19 recurrence and compare outcomes between the first and second episodes of COVID-19 in LTRs., Methods: We conducted a retrospective, single-center cohort study of LTRs with COVID-19 between January 1, 2022, and September 30, 2022, during the Omicron wave. We compared the clinical course of a second episode of COVID-19 to that of the patients' own first episode and to that of LTRs who developed a first episode during the study period., Results: During the study period, we identified 24 LTRs with COVID-19 recurrence and another 75 LTRs with a first episode of COVID-19. LTRs who survived the initial episode of COVID-19 had a similar disease course with recurrence, with a trend toward reduced hospitalization (10 (41.6%) vs. 4 (16.7%), p = .114). Furthermore, compared to LTRs with a primary infection during the Omicron wave, those with a reinfection had a non-statistically significant trend toward reduced hospitalizations (aOR .391, 95% CI [.115-1.321], p = .131), shorter lengths-of-stay (median, 4 vs. 9 days, p = .181), and reduced intensive care unit admissions, intubations, and COVID-19-related mortality., Conclusions: LTRs who survive the first episode of COVID-19 are likely to have a similar clinical course with recurrent episodes. Although recurrent COVID-19 may be milder, larger, well-powered studies are needed to confirm this observation. Ongoing precautions are warranted., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Hospitalized lung transplant (LT) recipients (LTRs) have higher post-LT morbidity and mortality than those who are well enough to wait for transplant at home. Outcomes after LT for COVID-19-associated acute respiratory distress syndrome (CARDS) may be even worse; thus, we compared post-LT outcomes between hospitalized LTRs transplanted for CARDS and those transplanted for restrictive lung disease (RLD)., Methods: Between 2014 and 2021, hospitalized LTRs ≥18 years old with CARDS or RLD were included. Primary and secondary outcomes were 1-year post-LT survival and postoperative morbidity. For each patient in the CARDS group, an analysis of 1-to-1 matched patients from the RLD group was performed using logistic regression modeling., Results: Of 764 LTRs, 163 (21.3%) were hospitalized at the time of LT; 132 met the inclusion criteria: 11 (8.3%) were transplanted for CARDS and 121 (91.7%) for RLD. LTRs with CARDS were younger with longer pre-LT hospitalization stays and higher rates of pretransplant mechanical ventilation, dialysis, and ECMO as a bridge to transplant. A propensity-matched analysis demonstrated comparable rates of intrathoracic adhesions, posttransplant duration of mechanical ventilation, PGD3 at 72 hours, and delayed chest closure. Compared to LTRs with RLD, those with CARDS had significantly longer posttransplant hospital stays and a higher prevalence of ACR ≥A2 and DSA >2000 MFI, but comparable 1-year survival rates., Conclusion: Even with careful selection, LT for patients with CARDS was associated with significant morbidity; however, 1-year survival of recipients with CARDS was comparable to that of matched hospitalized recipients with RLD., (Copyright © 2022 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Introduction: Evidence on new-onset endocrine dysfunction and identifying whether the degree of this dysfunction is associated with the severity of disease in patients with COVID-19 is scarce., Patients and Methods: Consecutive patients enrolled at PGIMER Chandigarh were stratified on the basis of disease severity as group I (moderate-to-severe disease including oxygen saturation <94% on room air or those with comorbidities) (n= 35) and group II (mild disease, with oxygen saturation >94% and without comorbidities) (n=49). Hypothalamo-pituitary-adrenal, thyroid, gonadal axes, and lactotroph function were evaluated. Inflammatory and cell-injury markers were also analysed., Results: Patients in group I had higher prevalence of hypocortisolism (38.5 vs 6.8%, p=0.012), lower ACTH (16.3 vs 32.1pg/ml, p=0.234) and DHEAS (86.29 vs 117.8µg/dl, p= 0.086) as compared to group II. Low T3 syndrome was a universal finding, irrespective of disease severity. Sick euthyroid syndrome (apart from low T3 syndrome) (80.9 vs 73.1%, p= 0.046) and atypical thyroiditis (low T3, high T4, low or normal TSH) (14.3 vs 2.4%, p= 0.046) were more frequent in group I than group II. Male hypogonadism was also more prevalent in group I (75.6% vs 20.6%, p=0.006) than group II, with higher prevalence of both secondary (56.8 vs 15.3%, p=0.006) and primary (18.8 vs 5.3%, p=0.006) hypogonadism. Hyperprolactinemia was observed in 42.4% of patients without significant difference between both groups., Conclusion: COVID-19 can involve multiple endocrine organs and axes, with a greater prevalence and degree of endocrine dysfunction in those with more severe disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Das, Dutta, Walia, Mukherjee, Suri, Puri, Mahajan, Malhotra, Chaudhary, Gupta, Jayant, Agrawal, Kumar, Sachdeva, Rastogi, Bhadada, Ram and Bhansali.)

Exosomes isolated from plasma of lung transplant recipients with allograft injury contain donor-derived lung self-antigens (collagen V and Kα1 tubulin) and human leukocyte antigen (HLA) molecules. We present a case of a 76-year-old, female lung transplant recipient treated for acute cellular rejection with methylprednisolone and anti-thymocyte globulin, who subsequently contracted SARS-CoV-2 and developed a sharp increase in the mean fluorescent intensity of anti-HLA antibodies. Analysis of circulating exosomes during rejection, but before SARS-CoV-2 infection, revealed the presence of lung self-antigens and HLA class II molecules. After the patient contracted SARS-CoV-2, exosomes with the SARS-CoV-2 spike protein were also found. After resolution of infectious symptoms, exosomes with SARS-CoV-2 spike protein were no longer detected; however, exosomes with lung self-antigens and HLA class II molecules persisted, which coincided with a progressive decline in spirometric flows, suggesting chronic lung allograft dysfunction. We propose that the analysis of circulating exosomes may be used to detect allograft injury mediated by both rejection and infection. Furthermore, the detection of exosomes containing viral proteins may be helpful in identifying allograft injury driven by viral pathogens., (© 2020 Wiley Periodicals LLC.)

Persistent detection of SARS-CoV-2 viral particles has been seen in the absence of symptoms in other solid organ transplant recipients. We report this unique phenomenon in lung transplant (LTx) recipients. We present the following cases of prolonged viral shedding in 3 LTx recipients: Patient A - 68-year-old female, bilateral LTx recipient for COPD (02/2020), Patient B - 65-year-old male, bilateral LTx recipient for IPF (07/2020), and Patient C - 64-year-old female, bilateral LTx recipient for COPD (08/2020). There were no major intraoperative complications, and the maintenance immunosuppression regimen was the same across patients. Patient A contracted COVID-19 at our center 10 months after transplant, reporting upper respiratory infection symptoms, after initially presenting with persistent headaches and diagnosed with posterior reversible encephalopathy syndrome. Patients B and C presented to clinic with myalgias and mild dyspnea at one and five months after transplant, respectively. SARS-CoV-2 was detected by RT-PCR of nasopharyngeal specimens in all patients. Chest CT demonstrated typical findings of COVID-19 pneumonia in all patients. Patients A and C received remdesivir and belatacept and were discharged home on days 5 and 7, respectively; Patient B received remdesivir and convalescent plasma and was discharged home on day 8. All were in stable clinical condition on room air. All 3 patients had persistently positive nasopharyngeal swab samples up to four weeks after hospitalization, despite absence of symptoms. We did not augment immunosuppression in these patients. Imaging findings during and after the infectious course are shown in Figure 1. Patient C has persistent lower lobe radiographic changes after COVID-19. LTx recipients may exhibit prolonged viral shedding up to at least 1 month despite resolution of symptoms. Well-established cohort studies are needed to elucidate the full duration of viral shedding in this group. [ABSTRACT FROM AUTHOR]

Patients with respiratory failure (RF) who are hospitalized at the time of lung transplant (LTx) have higher post-LTx morbidity and mortality than those who are well enough to remain at home. Complications may be even worse in patients transplanted for COVID-19 (C19), as they are commonly critically ill having endured prolonged mechanical ventilation, ECMO support, myopathy, malnutrition, and superimposed infections. In a retrospective cohort study, we compared inpatient lung transplant recipients (LTxRs) transplanted for C19 vs. other underlying restrictive lung diseases (RLDs) After IRB approval, patients who underwent inpatient LTx between 1/1/2014 and 8/31/2021 were categorized by indication: C19 or RLD. We excluded LTxRs <18 years old, a primary indication for LTx other than UNOS disease group D, and redo LTx. Primary outcomes were postoperative morbidity and 90-day survival. Out of 163 inpatient LTxRs, 141 met inclusion criteria: 11 (7.8%) with C19 and 130 (92.2%) with RLD. LTxRs with C19 were younger, had a longer pre-LTx hospital stay, and more likely needed pre-LTx mechanical ventilation and ECMO support. LTxRs with C19 were also more likely to have severe adhesions intraoperatively and their chest was more commonly left open after LTx due to a perceived risk of ongoing bleeding. In addition, LTxRs with C19 had a higher prevalence of PGD3 at 72 hours and longer post-LTx hospital stays and trended toward longer post-LTx mechanical ventilation and need for inpatient rehabilitation. The 2 groups had similar 90-day survival (C19, 100% vs. RLD, 95.4%, p=0.472), however, LTxRs with C19 had a higher incidence of acute cellular rejection and DSA production (>2,000 MFI) within 6 months of transplant. LTxRs with C19 are typically sicker and have more post-LTx complications than LTxRs with RLD hospitalized at the time of LTx. However, 90-day survival is comparable and high in both groups. Long-term follow-up is needed. [ABSTRACT FROM AUTHOR]

Vaccination reduces COVID-19-related morbidity and mortality in the general population, however, the response to vaccination is attenuated among immunosuppressed lung transplant recipients (LTR). Boyarski et al noted that 61% of LTR had no serologic response to the first or second dose of mRNA vaccines, with an additional 31% only responding to the second dose. We sought to compare the impact of vaccination status on COVID-19-related morbidity and mortality in LTR. We conducted a retrospective chart review of LTR with COVID-19 that did not receive Tixagevimab-Cilgavimab (Tix-Cil) prophylaxis. We compared outcomes based on vaccination status using chi-square and binomial exact tests. Between March 2020 and August 2022, 195 LTR developed COVID-19, 24 received Tix-Cil and were excluded from the analysis. The median age was 66.6 (58.8-71.9), 100 (58.5%) were male, 166 (97.1%) had a bilateral lung transplant, 91 (53.2%) had diabetes, 55 (32.2%) were obese, and 126 (73.7%) had chronic kidney disease with an eGFR <60. The most common immunosuppressive regimen included mycophenolate mofetil, tacrolimus, and prednisone (124 (72.5%)). The median percent predicted FEV1 was 78% (IQR 62, 94) and the median time from LT to COVID-19 diagnosis was 38.3 months (IQR 20.3, 66.9). LTR with COVID-19 that received at least 2 doses of the mRNA vaccines were less likely to be hospitalized compared to their unvaccinated counterparts. However, 2 vaccine doses alone did not reduce ICU admission, intubation, or mortality. LTR with COVID-19 that received >2 vaccines were less likely to be hospitalized, admitted to the ICU, or intubated, and had a lower mortality. Two doses of mRNA vaccines reduced COVID-19-related hospitalization among LTR with COVID-19; additional vaccine doses were needed to reduce risk of ICU admission, intubation, and death. [ABSTRACT FROM AUTHOR]

Multiple variants of SARS-CoV-2 have been documented throughout the COVID-19 pandemic. Mutations that lead to these variants can affect viral spread, disease severity, and the efficacy of vaccines and therapeutics. Lung transplant (LT) recipients (LTRs) are at high risk of COVID-19-related morbidity and mortality; however, disease severity may differ between SARS-CoV-2 variants. We sought to describe the clinical outcomes of LTRs with COVID-19 at different stages of the pandemic. We performed a retrospective chart review of LTRs with COVID-19 and categorized them into 4 groups according to the prevalent variant on the date of the positive test. Chi-square and non-parametric binomial exact tests were used for comparative analyses. Since March 2020, 195 LTRs at our institute developed COVID-19; the median age was 66.6 years (58.7-72); 114 (58.5%) were male; 190 (97.4%) had received a bilateral LT; 106 (54.4%) had diabetes; 63 (32.3%) were obese; and 145 (74.4%) had chronic kidney disease with an eGFR <60. The most common immunosuppressive regimen included mycophenolate mofetil, tacrolimus, and prednisone (n=142; 72.8%). The median percent predicted FEV1 was 81% (IQR 63-96) and the median time from LT to COVID-19 diagnosis was 37.3 months (IQR 18.5-66.7). Rates of hospitalization, ICU admission, need for mechanical ventilation, and death were significantly lower for the Omicron variant than the original strain, the Alpha variant, and the Delta variant. However, there was no difference in length of hospital stay, development of extrapulmonary end-organ dysfunction, or persistent drop in spirometric flows (Table 1). Lastly, the utilization of vaccination and monoclonal antibodies grew over time and likely contributed to reduced COVID-19 severity in the latter part of the pandemic. COVID-19 continues to drive morbidity and mortality among LTRs; however, the severity of disease is lower with the omicron variant. [ABSTRACT FROM AUTHOR]

Tixagevimab-cilgavimab (Tix-Cil) is a long-acting monoclonal antibody combination granted Emergency Use Authorization approval for COVID-19 pre-exposure prophylaxis (PrEP) in immunocompromised patients, due to their suboptimal response to vaccination. We sought to determine whether Tix-Cil reduces COVID-19 severity among lung transplant recipients (LTRs) who develop breakthrough infection. After IRB approval, we conducted a retrospective chart review of LTRs who developed COVID-19 during the Omicron surge (December 2021 to August 2022). We performed comparative analyses using Fisher's exact test and logistic regression to control for vaccination and other monoclonal antibodies. A total of 89 LTRs with COVID-19 were included. The median time from LT to COVID-19 diagnosis was 38.3 months (IQR 20.3, 66.9). The median age was 67.4 years (59.5-72.4), 49 (55.1%) were male, 87 (97.8%) had undergone bilateral LT, 48 (53.9%) had diabetes, 25 (28.0%) were obese (body mass index ≥30 kg/m2), and 67 (75.3%) had chronic kidney disease (eGFR <60 mL/min/1.73m2). The most common immunosuppressive regimen included mycophenolate mofetil, tacrolimus, and prednisone (64; 71.9%), and the median percent predicted FEV1 was 87% (IQR 64.5, 99.5). The overwhelming majority of patients received at least 2 doses of an mRNA vaccine (84 (94.3%)) and 60 (67.4%) were treated with monoclonal antibodies, 51 (57.3%) with antivirals, and 82 (92.1%) with increased corticosteroids upon COVID-19 diagnosis. Despite Tix-Cil prophylaxis, 24 LTRs contracted COVID-19 during the Omicron surge. The median time from Tix-Cil to COVID-19 diagnosis was 90.5 days (60.3, 119.0). PrEP with Tix-Cil did not reduce hospitalization, ICU admission, need for mechanical ventilation or death among LTRs. Pre-exposure prophylaxis with Tix-Cil may not reduce COVID-19 severity among LTRs that develop breakthrough infection. [ABSTRACT FROM AUTHOR]

Critically ill patients with COVID-19 are at high risk of morbidity and mortality. This risk may be even higher among lung transplant recipients (LTxRs) as they are immunosuppressed and typically older with multiple co-morbidities. The aim of this study was to characterize the outcomes of critically ill LTxRs with COVID-19. LTxRs with COVID-19 hospitalized in the ICU between 06/01/2020 and 02/28/2021 were included and classified as alive or deceased. Baseline clinical characteristics, laboratory results, and complications were reviewed. Death due to COVID-19 was the primary outcome. Descriptive statistics were used. Twenty-five LTxRs (13 men; 8 alive, 17 deceased) were included. Median (IQR) age, interval between LTx and COVID-19 diagnosis, and duration of ICU stay was 66 years (56, 71), 27 months (10, 51), and 19 days (10, 28), respectively. Pre-existing diabetes and chronic kidney disease were common (68%, 68%). Although statistical significance was not reached due to small sample size, survivors trended toward lower levels of CRP, ferritin, and D-Dimer at ICU admission. Fewer survivors had a stroke (0% vs 6%), hemorrhage requiring transfusion (14% vs 18%), new-onset heart failure (14% vs 29%), venous thromboemboli (24% vs 33%), and renal failure requiring dialysis (25% vs 53%). At a median of 8 days after COVID-19 diagnosis, 18 (72%) LTxRs required intubation. The need for mechanical ventilation increased the risk of death 4.327-fold (p=0.054) and lowered the probability of 60-day survival (16.7% vs 71.4%, p=0.035; Figure 1). The median survival of deceased subjects was 23 days (17, 34). Most LTxRs received corticosteroids, convalescent plasma, remdesevir, and reduced immunosuppression. Among LTxRs that survived to hospital discharge, 38% (3) were discharged home, 50% (4) required acute rehabilitation, and 75% (6) were supplemental oxygen dependent. Critically ill LTxRs with COVID-19 have high morbidity and mortality. The need for mechanical ventilation portends a poor prognosis. [ABSTRACT FROM AUTHOR]

Immunosuppressed patients, particularly solid organ transplant recipients, are at an increased risk of death from COVID-19. We report a large single-center experience with COVID-19 in lung transplant recipients (LTRs). This is a retrospective cohort study of 91 LTRs diagnosed with COVID-19 between March 1, 2020 and August 31, 2021. Patients were classified as alive (n=61) or deceased (n=30). The Kruskal-Wallis and Chi-squared tests were used for data analysis. Mortality from COVID-19 was high (n=30, 33%). There was no difference in baseline clinical characteristics between alive and deceased patients; age, medical co-morbidities, body mass index, and lung function were similar (Table 1). The vast majority of patients were hospitalized (n=79, 86%), not only for severe illness but also to receive remdesivir, an infusion available only to inpatients. Patients that died were more commonly hypoxemic and admitted to the ICU, more likely to require mechanical ventilation, and had a longer hospital stay. Of the 24 intubated patients, only 4 survived (16.7%); 2 patients were placed on ECMO and both died. Deceased patients had higher peak levels of D-dimer, ferritin, procalcitonin, and lactate dehydrogenase. The vast majority of patients received corticosteroids; deceased patients were more likely to be treated with remdesivir and tocilizumab. Extrapulmonary complications were more common in deceased patients: 33% developed renal failure requiring hemodialysis and 19.2% developed multi-organ system dysfunction. The median time to death was 1.1 (0.63, 3.70) months; 3 patients survived the acute illness but died several months later of complications from post-adult respiratory distress syndrome-fibrosis. The COVID-19 pandemic has had catastrophic consequences for lung transplant recipients. We hope that high vaccination rates, reduction of immunosuppression in the early disease period, and more effective antiviral therapies can reduce mortality. [ABSTRACT FROM AUTHOR]

COVID-19 promotes inflammation and a hypercoagulable state. Antithrombotic therapies may be administered for thromboprophylaxis in those with severe infection requiring hospitalization. Spontaneous bleeding is an infrequent, yet life-threatening complication in patients receiving systemic anticoagulation. Two bilateral lung transplant recipients - 77-year-old female with idiopathic pulmonary fibrosis (patient A) and 69-year-old male with chronic obstructive pulmonary disease (patient B) - each presented with several days' history of dyspnea, cough, and fatigue at 29-months and 11-months post-transplant, respectively; RT-PCR was positive for SARS-CoV-2 infection in both. Over the course of the next few days, patient A rapidly deteriorated with need for intubation despite initial treatment with antibiotics and corticotherapy. Patient B experienced gradual worsening of respiratory symptoms, which required high-flow oxygen supplementation and IV antibiotics. Inflammatory markers were elevated in both patients, and CT of the chest was consistent with atypical pneumonia in each. Patient A received convalescent plasma as a rescue therapy, and patient B received remdesivir with convalescent plasma. Given the hypercoagulable state in each, patient A and B received enoxaparin and IV heparin, respectively. Slowly, hemoglobin and platelet counts dropped in both patients, with need for transfusion and hemodynamic support. CT of the abdomen revealed a left gluteal intramuscular hematoma in patient A; CT of the chest, abdomen, and pelvis revealed a spontaneous chest wall hematoma and small area of retroperitoneal bleeding in patient B (Figure 1A and B). These cases raise awareness for the viral-induced hypercoagulable state observed during the disease course. Clinicians should be cautious to avoid any hemorrhagic complications associated with thromboprophylaxis in selected cases, particularly in at-risk immunosuppressed patients. [ABSTRACT FROM AUTHOR]