A 57-year-old man with nonischemic cardiomyopathy who was dependent on venoarterial extracorporeal membrane oxygenation (ECMO) and was not a candidate for standard therapeutics, including a ...traditional allograft, received a heart from a genetically modified pig source animal that had 10 individual gene edits. Immunosuppression was based on CD40 blockade. The patient was weaned from ECMO, and the xenograft functioned normally without apparent rejection. Sudden diastolic thickening and failure of the xenograft occurred on day 49 after transplantation, and life support was withdrawn on day 60. On autopsy, the xenograft was found to be edematous, having nearly doubled in weight. Histologic examination revealed scattered myocyte necrosis, interstitial edema, and red-cell extravasation, without evidence of microvascular thrombosis - findings that were not consistent with typical rejection. Studies are under way to identify the mechanisms responsible for these changes. (Funded by the University of Maryland Medical Center and School of Medicine.).
Background
Solid organ transplant recipients (SOTR) have diminished humoral immune responses to COVID‐19 vaccination and higher rates of COVID‐19 vaccine breakthrough infection than the general ...population. Little is known about COVID‐19 disease severity in SOTR with COVID‐19 vaccine breakthrough infections.
Methods
Between 4/7/21 and 6/21/21, we requested case reports via the Emerging Infections Network (EIN) listserv of SARS‐CoV‐2 infection following COVID‐19 vaccination in SOTR. Online data collection included patient demographics, dates of COVID‐19 vaccine administration, and clinical data related to COVID‐19. We performed a descriptive analysis of patient factors and evaluated variables contributing to critical disease or need for hospitalization.
Results
Sixty‐six cases of SARS‐CoV‐2 infection after vaccination in SOTR were collected. COVID‐19 occurred after the second vaccine dose in 52 (78.8%) cases, of which 43 (82.7%) occurred ≥14 days post‐vaccination. There were six deaths, three occurring in fully vaccinated individuals (7.0%, n = 3/43). There was no difference in the percentage of patients who recovered from COVID‐19 (70.7% vs. 72.2%, p = .90) among fully and partially vaccinated individuals. We did not identify any differences in hospitalization (60.5% vs. 55.6%, p = .72) or critical disease (20.9% vs. 33.3%, p = .30) among those who were fully versus partially vaccinated.
Conclusions
SOTR vaccinated against COVID‐19 can still develop severe, and even critical, COVID‐19 disease. Two doses of mRNA COVID‐19 vaccine may be insufficient to protect against severe disease and mortality in SOTR. Future studies to define correlates of protection in SOTR are needed.
Hepatocellular carcinoma: a review Balogh, Julius; Victor, 3rd, David; Asham, Emad H ...
Journal of hepatocellular carcinoma,
01/2016, Letnik:
3
Journal Article
Recenzirano
Odprti dostop
Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and is a leading cause of cancer-related death worldwide. In the United States, HCC is the ninth leading cause of cancer ...deaths. Despite advances in prevention techniques, screening, and new technologies in both diagnosis and treatment, incidence and mortality continue to rise. Cirrhosis remains the most important risk factor for the development of HCC regardless of etiology. Hepatitis B and C are independent risk factors for the development of cirrhosis. Alcohol consumption remains an important additional risk factor in the United States as alcohol abuse is five times higher than hepatitis C. Diagnosis is confirmed without pathologic confirmation. Screening includes both radiologic tests, such as ultrasound, computerized tomography, and magnetic resonance imaging, and serological markers such as α-fetoprotein at 6-month intervals. Multiple treatment modalities exist; however, only orthotopic liver transplantation (OLT) or surgical resection is curative. OLT is available for patients who meet or are downstaged into the Milan or University of San Francisco criteria. Additional treatment modalities include transarterial chemoembolization, radiofrequency ablation, microwave ablation, percutaneous ethanol injection, cryoablation, radiation therapy, systemic chemotherapy, and molecularly targeted therapies. Selection of a treatment modality is based on tumor size, location, extrahepatic spread, and underlying liver function. HCC is an aggressive cancer that occurs in the setting of cirrhosis and commonly presents in advanced stages. HCC can be prevented if there are appropriate measures taken, including hepatitis B virus vaccination, universal screening of blood products, use of safe injection practices, treatment and education of alcoholics and intravenous drug users, and initiation of antiviral therapy. Continued improvement in both surgical and nonsurgical approaches has demonstrated significant benefits in overall survival. While OLT remains the only curative surgical procedure, the shortage of available organs precludes this therapy for many patients with HCC.
A 26-year-old otherwise healthy man died of fulminant myocarditis. Nasopharyngeal specimens collected premortem tested negative for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). ...Histopathological evaluation of the heart showed myocardial necrosis surrounded by cytotoxic T-cells and tissue-repair macrophages. Myocardial T-cell receptor (TCR) sequencing revealed hyper-dominant clones with highly similar sequences to TCRs that are specific for SARS-CoV-2 epitopes. SARS-CoV-2 RNA was detected in the gut, supporting a diagnosis of multisystem inflammatory syndrome in adults (MIS-A). Molecular targets of MIS-associated inflammation are not known. Our data indicate that SARS-CoV-2 antigens selected high-frequency T-cell clones that mediated fatal myocarditis.
Although the risk of SARS-CoV-2 transmission through lung transplantation from acutely infected donors is high, the risks of virus transmission and long-term lung allograft outcomes are not as well ...described when using pulmonary organs from COVID-19–recovered donors. We describe successful lung transplantation for a COVID-19–related lung injury using lungs from a COVID-19–recovered donor who was retrospectively found to have detectable genomic SARS-CoV-2 RNA in the lung tissue by multiple highly sensitive assays. However, SARS-CoV-2 subgenomic RNA (sgRNA), a marker of viral replication, was not detectable in the donor respiratory tissues. One year after lung transplantation, the recipient has a good functional status, walking 1 mile several times per week without the need for supplemental oxygen and without any evidence of donor-derived SARS-CoV-2 transmission. Our findings highlight the limitations of current clinical laboratory diagnostic assays in detecting the persistence of SARS-CoV-2 RNA in the lung tissue. The persistence of SARS-CoV-2 RNA in the donor tissue did not appear to represent active viral replication via sgRNA testing and, most importantly, did not negatively impact the allograft outcome in the first year after lung transplantation. sgRNA is easily performed and may be a useful assay for assessing viral infectivity in organs from donors with a recent infection.
Introduction
Advanced liver disease or cirrhosis is associated with an increased risk of infections; however, the impact of high pretransplant model for end‐stage liver disease (MELD) score on ...cytomegalovirus (CMV) viremia after liver transplantation is unknown.
Methods
This single‐center, retrospective, cohort study evaluated CMV high‐risk (CMV immunoglobulin G D+/R−) liver transplant recipients who received valganciclovir prophylaxis for 3 months between 2009 and 2019. Patients were stratified by pretransplant MELD score of <35 (low MELD) and ≥35 (high MELD). The primary outcome was 12‐month CMV viremia, and secondary outcomes included CMV resistance and tissue invasive disease, mortality, biopsy‐proven acute rejection (BPAR), leukopenia, and thrombocytopenia. Multivariable Cox proportional‐hazards modeling was used to assess the association of MELD score with the time to CMV viremia.
Results
There were 162 and 79 patients in the low and high MELD groups, respectively. Pretransplant MELD score ≥35 was associated with an increased risk of CMV viremia (hazard ratio HR 1.73; confidence interval 1.06–2.82, p = .03). CMV viremia occurred at 162 ± 61 days in the low MELD group and 139 ± 62 days in the high MELD group. Although BPAR occurred early at 30 days (13–59) in the low‐MELD group and at 18 days (11–66) in the high‐MELD group (p = .56), BPAR was not associated with an increased risk of CMV viremia (HR 1.55 0.93–2.60, p = .1).
Discussion
MELD scores ≥35 were associated with an increased hazards of CMV viremia. In liver transplant recipients with MELD scores ≥35 who are CMV high‐risk, additional CMV intervention may be warranted.
A genetically engineered pig cardiac xenotransplantation was done on Jan 7, 2022, in a non-ambulatory male patient, aged 57 years, with end-stage heart failure, and on veno-arterial extracorporeal ...membrane oxygenation support, who was ineligible for an allograft. This report details our current understanding of factors important to the xenotransplantation outcome.
Physiological and biochemical parameters critical for the care of all heart transplant recipients were collected in extensive clinical monitoring in an intensive care unit. To ascertain the cause of xenograft dysfunction, we did extensive immunological and histopathological studies, including electron microscopy and quantification of porcine cytomegalovirus or porcine roseolovirus (PCMV/PRV) in the xenograft, recipient cells, and tissue by DNA PCR and RNA transcription. We performed intravenous immunoglobulin (IVIG) binding to donor cells and single-cell RNA sequencing of peripheral blood mononuclear cells.
After successful xenotransplantation, the graft functioned well on echocardiography and sustained cardiovascular and other organ systems functions until postoperative day 47 when diastolic heart failure occurred. At postoperative day 50, the endomyocardial biopsy revealed damaged capillaries with interstitial oedema, red cell extravasation, rare thrombotic microangiopathy, and complement deposition. Increased anti-pig xenoantibodies, mainly IgG, were detected after IVIG administration for hypogammaglobulinaemia and during the first plasma exchange. Endomyocardial biopsy on postoperative day 56 showed fibrotic changes consistent with progressive myocardial stiffness. Microbial cell-free DNA testing indicated increasing titres of PCMV/PRV cell-free DNA. Post-mortem single-cell RNA sequencing showed overlapping causes.
Hyperacute rejection was avoided. We identified potential mediators of the observed endothelial injury. First, widespread endothelial injury indicates antibody-mediated rejection. Second, IVIG bound strongly to donor endothelium, possibly causing immune activation. Finally, reactivation and replication of latent PCMV/PRV in the xenograft possibly initiated a damaging inflammatory response. The findings point to specific measures to improve xenotransplant outcomes in the future.
The University of Maryland School of Medicine, and the University of Maryland Medical Center.
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