Vaccination with >2 Doses of Mrna Vaccines is Needed to Reduce Mortality Among Lung Transplant Recipients with Covid-19

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] Copyright of Journal of Heart & Lung Transplantation is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Pre-Exposure Prophylaxis with Tixagevimab-Cilgavimab May Not Reduce Covid-19 Severity Among Lung Transplant Recipients That Develop Breakthrough Infection

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] Copyright of Journal of Heart & Lung Transplantation is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Covid-19 is Less Severe with the Omicron Variant Compared to Prior Variants and the Original Sars-Cov-2 Strain in Lung Transplant Recipients

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] Copyright of Journal of Heart & Lung Transplantation is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Clinical Outcomes of Lung Transplant Recipients with Covid-19 That Received Pre-Exposure Prophylaxis with Tixagevimab-Cilgavimab: A Single Center Experience

Lung transplant recipients (LTRs) are at risk of significant morbidity and mortality due to COVID-19. The neutralizing antibody response to vaccination among LTRs is reduced, particularly in those treated with anti-proliferative agents. Tixagevimab-cilgavimab (Tix-Cil) is a SARS-CoV-2 spike protein-directed attachment inhibitor that is authorized under Emergency Use Authorization (EUA) to reduce the risk of COVID-19 in immunocompromised adults. We describe the clinical outcomes of LTRs who contracted COVID-19 despite Tix-Cil therapy. After IRB approval, we conducted a retrospective chart review and used descriptive statistics. Following EUA approval, 203 LTRs received Tix-Cil, and 24 (11.8%) subsequently contracted COVID-19. All 24 had undergone bilateral LT;14 (58.3%) were male;23 (95.8%) were vaccinated;and 23 (95.8%) were ≥6 months out from LT. The median age at COVID-19 diagnosis was 68.6 years, and most (75%) were on a standard 3-drug immunosuppressive regimen with tacrolimus, mycophenolate mofetil, and prednisone. The median time from Tix-Cil to COVID-19 diagnosis was 90.5 days (62.75-118.25). Five LTRs (20.8%) were hospitalized;3 (12.5%) required ICU level of care;and 2 (8.3%) were intubated. Two LTRs (8.3%) died;both were male, >70 years old, vaccinated, >2 years out from LT, and had co-morbidities. Both were treated with corticosteroids and tocilizumab;1 received anti-viral and monoclonal antibody therapy with remdesevir and sotrovimab, respectively. Both were critically ill, and 1 was intubated. LTRs that contracted COVID-19 despite pre-exposure prophylaxis with Tix-Cil had significant rates of hospitalization, critical illness, and mortality. More effective therapies are needed to reduce the risk of COVID-19 in this vulnerable patient population. [ABSTRACT FROM AUTHOR] Copyright of Journal of Heart & Lung Transplantation is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Guillain-Barré Syndrome after Mrna-1273 Covid-19 Vaccine Booster in an Immunosuppressed Double Lung Transplant Recipient

Guillain-Barré Syndrome (GBS) is an immune-mediated neurological disorder with an estimated incidence of 1 to 2 per 100,000 person-years. GBS is characterized by progressive and symmetric ascending muscle weakness, areflexia, sensory symptoms, and dysautonomia. Antecedent infection or vaccination may trigger GBS;however, there are few reports of GBS after either mRNA-1273 (Moderna) or mRNA-BNT-162b2 (Pfizer-BioNTech) COVID-19 vaccines (1.21 and 1.05 GBS reports per million doses, respectively). A 2021 analysis of the Vaccine Safety Datalink found no increased risk of GBS after vaccination with either of the vaccines. We report a case of GBS after a third dose of mRNA-1273 in a lung transplant recipient (LTxR). A 38-year-old LTxR on standard 3-drug immunosuppression presented to clinic complaining of back pain 2 weeks after receiving a third dose of mRNA-1273. His pain was treated with analgesics;however, a week later he presented to the Emergency Department (ED) with worsening back pain, myalgias, and lower extremity weakness. Neurology was consulted and he underwent an extensive work-up including screening serologies for vasculitis and myasthenia gravis and blood tests for B12, folate, and creatinine kinase (CK) levels. Viral and bacterial infections were ruled out. A spinal MRI showed no evidence of nerve root enhancement;a lumbar puncture revealed albuminocytologic dissociation with a high protein level of 113 mg/dL and cell count of 1/uL. Autoimmune and paraneoplastic panels as well as oligoclonal bands were negative. He was diagnosed with GBS and completed a 5-day IVIG course which led to transient symptomatic improvement. Four weeks later, he reported to the ED in a wheel chair after multiple falls and an inability to stand or walk. His neurological exam showed symmetric ascending weakness of lower extremities that was worse distally, reduced hand-grip strength, and areflexia. Electromyography showed evidence of acute inflammatory demyelinating polyneuropathy, confirming the GBS diagnosis. An additional 2-day IVIG course and intensive outpatient physical therapy led to neurologic improvement. Although current data does not suggest an increased risk of GBS after mRNA COVID-19 vaccines, GBS should be considered in LTxRs who develop symmetric motor and sensory deficits after vaccination. [ABSTRACT FROM AUTHOR] Copyright of Journal of Heart & Lung Transplantation is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Molnupiravir vs Remdesivir for Treatment of Covid-19 in Lung Transplant Recipients

Three SARS-CoV-2-directed anti-viral therapies are currently accessible in the United States: remdesivir (REM), molnupiravir (MOL), and nirmatrelvir+ritonavir. The latter has significant drug-drug interactions and is typically not used in lung transplant recipients (LTRs). We compared the efficacy between early REM and MOL treatment of LTRs with COVID-19. LTRs who contracted COVID-19 between 3/2020 and 8/2022 were identified. LTRs with COVID-19 that were well enough to remain outpatient were treated with either REM or MOL, depending on drug availability;REM became available in 10/2020 and MOL in 12/2021. The primary outcome was hospitalization and the secondary outcome was mortality. The analysis was adjusted for SARS-CoV-2 strain, vaccination status, pre-exposure prophylaxis with tixagevimab-cilgavimab, and COVID-19 therapies, eg, monoclonal antibodies and modification of anti-proliferative agent. Of 195 LTRs that developed COVID-19 during the study period, 54 were included and divided into groups: REM (n=25) or MOL (n=29). The baseline characteristics of the two groups were comparable (Table 1). On unadjusted analysis, LTRs treated with MOL were less likely to be hospitalized, admitted to the ICU, or to die from COVID-19;on adjusted analysis, only reduced likelihood of hospitalization remained statistically significant (p=0.035). One-year survival probability was comparable between the groups, but trended lower among LTRs treated with REM (REM: 64% vs MOL: 93.1%, p=0.081, Figure 1). LTRs with COVID-19 treated with MOL were less likely to be hospitalized due to COVID-19 than those treated with REM. [ABSTRACT FROM AUTHOR] Copyright of Journal of Heart & Lung Transplantation is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Progressive Multifocal Leukoencephalopathy Presenting as Expressive Aphasia in a Lung Transplant Recipient

Introduction: Progressive multifocal leukoencephalopathy (PML) is a demyelinating brain disease caused by reactivation of JC virus in immunocompromised patients. PML typically manifests with subacute neurologic deficits including altered mental status, motor deficits, limb ataxia, gait ataxia, and visual symptoms. We report an atypical presentation of PML in a lung transplant recipient (LTR). Case Report: A 71-year-old LTR received rituximab induction followed by a combination of mycophenolate mofetil, tacrolimus, and prednisone. He had a single episode of minimal acute cellular rejection early after LT, but never required significantly augmented immunosuppression. Notably, he had mild leukopenia throughout his post-LT course (WBC count 3-4 thousand/µL), and he had no response to 4 doses of the Pfizer SARS-CoV-2 vaccine, suggesting advanced immunosuppression. At 14 months after LT, the patient reported progressive anomia and aphasia, but no other neurologic deficits. MRI showed an abnormal increased T2/FLAIR signal in the left posterior parieto-occipital subcortical white matter, involving subcortical U fibers, characteristic of PML (Figure A, C). Serum JC virus PCR showed low-level viremia, but CSF from 2 lumbar punctures was PCR negative. Thus, he was diagnosed with possible PML, and immunosuppression was narrowed to a combination of tacrolimus (goal trough 4-6) and prednisone, 5 mg daily. Despite reduced immunosuppression, a repeat MRI 2 months after the initial diagnosis showed worsening PML (Figure B, D) and his symptoms progressed to severe anomia, aphasia, and cortical blindness, but still no motor deficits. PML is a rare, albeit well described, complication of LT, but presentation with only anomia and aphasia is unusual. Without CSF viral isolation, a definitive diagnosis requires brain tissue;however, MRI changes involving subcortical U fibers in the parieto-occipital area are highly characteristic. Early recognition allows for expeditious management.

Lung transplant recipients with severe acute respiratory syndrome-coronavirus 2 infection and asymptomatic carriers waiting for lung transplantation induce circulating exosomes with severe acute respiratory syndrome-coronavirus 2 spike protein s2

Purpose: Exosomes are vesicles released by cells into body fluids. We demonstrated increased circulating exosomes with lung self-antigens (Collagen V, Kα1 Tubulin) and viral antigens in lung transplant recipients (LTxRs) undergoing rejection. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2), an important risk factor for LTxRs in immunosuppression and patients with diseased lungs waiting for transplantation. Our goal is to determine that exosomes from LTxRs with SARSCoV2 infection carry SARS-CoV2 spike protein. Methods: We analyzed 30 patients waiting for LTx with no clinical symptoms and 7 LTxRs with SARS-CoV2 infection and symptoms. Exosomes were isolated from plasma by precipitation kit, 0.2 micron filtration and size determination by Nanosight300. Eluted protein from gel was analyzed by mass spectrometry and peptides were aligned with SARS-CoV2. Transmission electron microscopy of exosomes was performed for spike and nucleocapsid antigen. Exosomes were also characterized by western blot for immune and molecular markers. Serum cytokines were analyzed using 25 Plex on Luminex. Results: Exosomes from symptomatic (7/7) and 7/30 (23.3%) asymptomatic LTxRs contained SARS-CoV2 spike protein S2 and increased levels of SARS-CoV2 RNA. SARS-CoV2 spike protein in exosomes was confirmed by mass spectroscopy. Transmission electron microscopy from symptomatic and asymptomatic LTxRs revealed spike protein and nucleocapsid antigen on exosomes. Exosomes contained macrophage stimulating factor 1, GRAnzyme B and angiotensin type II receptor 1 proteins. Increased levels of CXCL10 in sera were detected in SARS-CoV2 positive symptomatic patients, agreeing with the reports that CXCL10 levels correlate with disease severity. Conclusions: SARS-CoV2 infected LTxRs symptomatic and asymptomatic induced circulating exosomes having spike protein, nucleic acid and antigens related to viral entry (angiotensin type II receptor), infection (macrophage stimulating factor 1) and cytotoxic molecule (GRAnzyme B) suggesting that the exosomes induced by SARS-CoV2 will have functional consequences. Exosomes also contained increased levels of viral RNA and antigens suggesting that circulating exosomes may provide a noninvasive tool for detection of SARS-CoV2 infection.

Two Cases of Spontaneous Bleeding in Lung Transplant Recipients Treated with Systemic Anticoagulation for COVID-19

Introduction 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. Case Report 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). Summary 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.

SARS-CoV-2 Re-Infection in a Lung Transplant Recipient

Introduction Since the onset of the SARS-CoV-2 pandemic, increasing evidence has shown waning immunity after initial SARS-CoV-2 infection, and re-infection in patients with a prior history of COVID-19 has been reported. We report a case of SARS-CoV-2 re-infection in a lung transplant recipient 3 months after initial illness. Case Report The patient is a 56-year-old man with a history of bilateral lung transplant in August 2018 for idiopathic pulmonary fibrosis. His post-transplant course was complicated by insulin-dependent diabetes mellitus (HbA1c 5.8%), chronic renal insufficiency (eGFR nadir 48 mL/min/1.73m2), and peripheral arterial disease requiring bilateral below-knee amputations. At the time of transplant, he was induced with basiliximab and remained on standard 3-drug immunosuppression with mycophenolate mofetil (500 mg BID), prednisone (5 mg daily), and tacrolimus. He contracted SARS-CoV-2 from his wife and tested positive for the virus on July 2, 2020 after presenting to the emergency department (ED) with headache, chills, nausea, body aches, shortness of breath, and generalized weakness. His oxygen saturation and chest X-ray were normal, and he was therefore discharged from the ED to recover at home. His symptoms resolved 17 days after diagnosis and serial SARS-CoV-2 testing via nasal washing were positive on July 16, 2020 and negative on July 30, 2020 and August 11, 2020. In addition, on October 21, 2020, he tested positive for SARS-CoV-2 antibodies (3.41, positive: index ≥1.4). On October 23, 2020, he presented to the ED with generalized chest pain, low-grade fever (100.1F), dyspnea, and weakness. His nasal swab was positive for SARS-CoV-2 and CT of the chest showed bibasilar ground-glass opacities consistent with atypical infection vs. atelectasis. His labs were notable for a CRP of 132 mg/L, ferritin of 2,307 ng/mL, LDH 304 units/L, D-dimer 240 ng/mL, and procalcitonin of 0.05 ng/mL. He was admitted for monitoring and treated with remdesivir, corticosteroids, and anticoagulation. Summary We present a case of SARS-CoV-2 re-infection 3 months after initial illness in a lung transplant recipient living in a high-incidence area. Unexpectedly, recurrent infection occurred despite development of SARS-CoV-2 antibodies. This case speaks to the vulnerability of this patient population to COVID-19 and the need for ongoing precautions to prevent infection even among patients who have seroconverted.