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4.
Cornea ; 41(5): 651-653, 2022 May 01.
Article in English | MEDLINE | ID: covidwho-1778963

ABSTRACT

PURPOSE: The purpose of this study was to report a case of "smoldering" keratolimbal allograft (KLAL) rejection in a patient with subtherapeutic levels of systemic immunosuppression in temporal association with BNT162b2 messenger RNA vaccination for severe acute respiratory syndrome coronavirus 2. METHODS: This was a case report. OBSERVATIONS: A 72-year-old man presented with circumferential perilimbal engorgement, stagnation, and tortuosity of vessels with mild chemosis in his right eye KLAL segments 1 month after receiving the BNT162b2 messenger RNA vaccine while his tacrolimus trough blood levels were subtherapeutic measuring <2 ng/mL. He had undergone KLAL 6.5 years before for total limbal stem cell deficiency from a chemical injury and had been stable without any history of rejection. The donor was blood type O, and the patient had no systemic comorbidities. The patient was treated with hourly difluprednate 0.05% and increasing of his oral tacrolimus dose to 2 mg twice a day with improvement of rejection signs. CONCLUSIONS: There may be a temporal association between KLAL rejection after immunization against severe acute respiratory syndrome coronavirus 2 in patients with subtherapeutic levels of systemic immunosuppression. Patients should be on alert for any ocular signs or symptoms postimmunization and present for treatment immediately.


Subject(s)
COVID-19 , Corneal Diseases , Limbus Corneae , Aged , Allografts , Corneal Diseases/diagnosis , Corneal Diseases/etiology , Graft Rejection/etiology , Humans , Male , Stem Cell Transplantation/adverse effects , Vaccines, Synthetic
5.
Transpl Infect Dis ; 24(2): e13813, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1699215

ABSTRACT

BACKGROUND: Assessing the composition of immune responses to SARS-CoV-2 vaccines is critical for our understanding of protective immunity, especially for immune compromised patients. The Pfizer (BNT162b2) vaccination showed >90% efficacy in protecting individuals from infection. However, these studies did not examine responses in immunocompromised kidney transplant patients (KT). Subsequent reports in KT have shown severe deficiencies in Spike-specific immunoglobin G (IgG) responses prompting booster vaccinations, but a broader understanding of T-cell immunity to vaccinating is lacking. METHODS: We examined SARS-CoV-2 Spike IgG and CD4+/CD8+ Spike-specific T-cell responses in 61 KT patients maintained on different immunosuppressive protocols (ISP) (Tac + mycophenolate mofetil + prednisone) versus (belatacept + MMF + prednisone) and compared to 41 healthy controls. We also examined cytomegalovirus-cytotoxic T-cell responses (CMV-Tc) in both groups to assess T-cell memory. RESULTS: Our data confirmed poor Spike IgG responses in vaccinated KT patients with both ISP (21% demonstrating Spike IgG 1M post-second dose of BNT162b2 vs. 93% in controls). However, 35% of Spike IgG (-) patients demonstrated CD4+ and/or CD8+ T-cell responses. All but one CMV-IgG+ patient demonstrated good CMV-Tc responses. No differences in T-cell immunity by ISP were seen. CONCLUSION: Immunocompromised KT recipients showed severe defects in humoral and T-cell immune response after vaccination. No differences in immune responses to SARS-CoV-2 Spike peptides were observed in KT patients by ISP post-vaccination. The detection of Spike-specific T-cell immunity in the absence of Spike IgG suggests that vaccination in immunocompromised KT patients may provide partial immunity, although not preventing infection, T-cell immunity may limit its severity.


Subject(s)
COVID-19 , Kidney Transplantation , Allografts , Antibodies, Viral , COVID-19/prevention & control , COVID-19 Vaccines , Humans , Immunity, Cellular , Immunity, Humoral , Kidney Transplantation/adverse effects , SARS-CoV-2 , Vaccination/methods
7.
Transpl Infect Dis ; 24(2): e13793, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1626700

ABSTRACT

We herein present a case of live related kidney transplant recipient who initially developed severe coronavirus (COVID-19) disease associated with E.coli related pyelonephritis and graft dysfunction, who improved over one week only to deteriorate in the second week, with fever, oligoanuria and refractory shock. A postmortem allograft biopsy revealed angioinvasive mucormycosis. With the resurgence of mucormycosis during the COVID-19 pandemic, the transplant team should add allograft mucormycosis as a rare differential for severe graft dysfunction and oligoanuria in the COVID-19-infected kidney transplant recipient.


Subject(s)
COVID-19 , Kidney Transplantation , Mucormycosis , Pyelonephritis , Allografts , COVID-19/complications , Humans , Kidney Transplantation/adverse effects , Mucormycosis/complications , Mucormycosis/drug therapy , Mucormycosis/microbiology , Pandemics , Pyelonephritis/complications
9.
EBioMedicine ; 75: 103789, 2022 Jan.
Article in English | MEDLINE | ID: covidwho-1587925

ABSTRACT

BACKGROUND: The long-term consequences of human umbilical cord-derived mesenchymal stem cell (UC-MSC) treatment for COVID-19 patients are yet to be reported. This study assessed the 1-year outcomes in patients with severe COVID-19, who were recruited in our previous UC-MSC clinical trial. METHODS: In this prospective, longitudinal, cohort study, 100 patients enrolled in our phase 2 trial were prospectively followed up at 3-month intervals for 1 year to evaluate the long-term safety and effectiveness of UC-MSC treatment. The primary endpoint was an altered proportion of whole-lung lesion volumes measured by high-resolution CT. Other imaging outcomes, 6 min walking distance (6-MWD), lung function, plasma biomarkers, and adverse events were also recorded and analyzed. This trial was registered with ClinicalTrials.gov (NCT04288102). FINDINGS: MSC administration improved in whole-lung lesion volume compared with the placebo with a difference of -10.8% (95% CI: -20.7%, -1.5%, p = 0.030) on day 10. MSC also reduced the proportion of solid component lesion volume compared with the placebo at each follow-up point. More interestingly, 17.9% (10/56) of patients in the MSC group had normal CT images at month 12, but none in the placebo group (p = 0.013). The incidence of symptoms was lower in the MSC group than in the placebo group at each follow-up time. Neutralizing antibodies were all positive, with a similar median inhibition rate (61.6% vs. 67.6%) in both groups at month 12. No difference in adverse events at the 1-year follow-up and tumor markers at month 12 were observed between the two groups. INTERPRETATION: UC-MSC administration achieves a long-term benefit in the recovery of lung lesions and symptoms in COVID-19 patients. FUNDING: The National Key R&D Program of China, the Innovation Groups of the National Natural Science Foundation of China, and the National Science and Technology Major Project.


Subject(s)
COVID-19/therapy , Mesenchymal Stem Cell Transplantation , Mesenchymal Stem Cells , Aged , Allografts , Double-Blind Method , Female , Follow-Up Studies , Humans , Male , Middle Aged , Patient Acuity
10.
J Heart Lung Transplant ; 41(4): 458-466, 2022 04.
Article in English | MEDLINE | ID: covidwho-1587721

ABSTRACT

BACKGROUND: As a marker of underlying lung allograft injury, donor-derived cell-free DNA (dd-cfDNA) may be used to identify episodes of acute allograft injury in lung transplant recipients. We investigated the utility of dd-cfDNA to monitor subjects at risk of acute rejection or infection in routine clinical practice. METHODS: This multicenter, retrospective cohort study collected data from lung transplant recipients within 3 years of transplant at 4 centers between March 24, 2020 and September 1, 2020. During this period, as part of routine care during the COVID-19 pandemic, these centers implemented a home-based surveillance program using plasma dd-cfDNA in preference to surveillance bronchoscopy. Dd-cfDNA was used to detect acute lung allograft dysfunction (ALAD) - a composite endpoint of acute rejection and infection. dd-cfDNA levels in patients with ALAD were compared to stable patients. The performance characteristics of dd-cfDNA ≥ 1.0% to detect ALAD were estimated. RESULTS: A total of 175 patients underwent 380 dd-cfDNA measurements, of which 290 were for routine surveillance purposes. dd-cfDNA was higher in patients with ALAD than stable patients (Median (IQR) 1.7% (0.63, 3.1) vs 0.35% (0.22, 0.79), p < 0.001). As an indication of underlying ALAD during surveillance testing, the estimated sensitivity of dd-cfDNA ≥1% was 73.9%, specificity of 87.7%, positive predictive value of 43.4% and negative predictive value of 96.5%. CONCLUSIONS: dd-cfDNA identified acute lung allograft dysfunction in asymptomatic lung transplant patients that may not have been identified by using a clinically indicated biopsy strategy alone. dd-cfDNA <1.0% may be useful in ruling out acute rejection and infection, supporting its use as a potential noninvasive marker for surveillance monitoring.


Subject(s)
COVID-19 , Cell-Free Nucleic Acids , Kidney Transplantation , Allografts , Graft Rejection/genetics , Humans , Lung , Pandemics , Retrospective Studies
11.
PLoS One ; 16(3): e0247251, 2021.
Article in English | MEDLINE | ID: covidwho-1574883

ABSTRACT

In the context of COVID-19 pandemic, we aimed to analyze the epidemiology, clinical characteristics, risk factors for mortality and impact of COVID-19 on outcomes of solid organ transplant (SOT) recipients compared to a cohort of non transplant patients, evaluating if transplantation could be considered a risk factor for mortality. From March to May 2020, 261 hospitalized patients with COVID-19 pneumonia were evaluated, including 41 SOT recipients. Of these, thirty-two were kidney recipients, 4 liver, 3 heart and 2 combined kidney-liver transplants. Median time from transplantation to COVID-19 diagnosis was 6 years. Thirteen SOT recipients (32%) required Intensive Care Unit (ICU) admission and 5 patients died (12%). Using a propensity score match analysis, we found no significant differences between SOT recipients and non-transplant patients. Older age (OR 1.142; 95% [CI 1.08-1.197]) higher levels of C-reactive protein (OR 3.068; 95% [CI 1.22-7.71]) and levels of serum creatinine on admission (OR 3.048 95% [CI 1.22-7.57]) were associated with higher mortality. The clinical outcomes of SARS-CoV-2 infection in our cohort of SOT recipients appear to be similar to that observed in the non-transplant population. Older age, higher levels of C-reactive protein and serum creatinine were associated with higher mortality, whereas SOT was not associated with worse outcomes.


Subject(s)
COVID-19/complications , Organ Transplantation/mortality , Adult , Aged , Aged, 80 and over , Allografts/physiology , Allografts/virology , COVID-19/epidemiology , COVID-19 Testing , Cohort Studies , Female , Hospitalization , Humans , Intensive Care Units , Male , Middle Aged , Organ Transplantation/adverse effects , Organ Transplantation/methods , Pandemics , Propensity Score , Risk Factors , SARS-CoV-2/pathogenicity , Spain/epidemiology , Transplant Recipients/statistics & numerical data , Treatment Outcome
12.
Cornea ; 41(4): 502-504, 2022 Apr 01.
Article in English | MEDLINE | ID: covidwho-1575618

ABSTRACT

PURPOSE: Our aim was to report the case of endothelial corneal allograft rejection after inactivated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine with an atypical presentation. METHODS: This was a case report. RESULTS: A 63-year-old woman with previous penetrating keratoplasty and laser in situ keratomileusis presented with clinical signs of endothelial corneal graft rejection 24 hours after CoronaVac (SinoVac Biotech, Beijing/China) vaccine. Slitlamp examination showed corneal edema and interface fluid accumulation. It was partially resolved after treatment with topical corticosteroids and polydimethylsiloxane. CONCLUSIONS: Corneal allograft rejection was already reported after another SARS-CoV-2 vaccine. This is the first report in the literature describing a possible association with inactivated SARS-CoV-2 vaccine and corneal allograft rejection, especially with laser in situ keratomileusis interface fluid accumulation presentation. Ophthalmologists should be aware of this potential complication.


Subject(s)
COVID-19 Vaccines/adverse effects , COVID-19/prevention & control , Graft Rejection/etiology , Keratoplasty, Penetrating , SARS-CoV-2/immunology , Vaccines, Inactivated/adverse effects , Allografts , Dexamethasone/therapeutic use , Dimethylpolysiloxanes/therapeutic use , Female , Glucocorticoids/therapeutic use , Graft Rejection/diagnosis , Graft Rejection/drug therapy , Humans , Keratomileusis, Laser In Situ , Middle Aged , Slit Lamp Microscopy
14.
Cornea ; 41(2): 252-253, 2022 Feb 01.
Article in English | MEDLINE | ID: covidwho-1505854

ABSTRACT

PURPOSE: The purpose of this study was to report a case of acute corneal epithelial rejection of living-related conjunctival limbal allograft (LR-CLAL) after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination. OBSERVATIONS: A 27-year-old woman developed acute epithelial rejection of LR-CLAL 2 weeks after receiving the SARS-CoV-2 vaccine. She received the LR-CLAL transplant 4 years and 7 months previously and had a stable clinical course with no history of rejection. She had an ABO blood group and human leukocyte antigen compatible donor, no systemic comorbidities, and no rejection risk factors. CONCLUSIONS: The novel SARS-CoV-2 vaccine upregulates the immune system to produce an adaptive immune response. The SARS-CoV-2 vaccine may potentially be associated with increased risk of rejection in those with ocular surface transplants.


Subject(s)
/adverse effects , Epithelium, Corneal/pathology , Graft Rejection/etiology , Limbus Corneae/cytology , Living Donors , Stem Cell Transplantation , Vaccination/adverse effects , Acute Disease , Administration, Ophthalmic , Administration, Oral , Adult , Allografts , COVID-19/prevention & control , Conjunctiva/cytology , Female , Glucocorticoids/therapeutic use , Graft Rejection/diagnosis , Graft Rejection/drug therapy , Humans , Immunosuppressive Agents/therapeutic use , Mycophenolic Acid/therapeutic use , Ophthalmic Solutions , Slit Lamp Microscopy , Tacrolimus/therapeutic use , Visual Acuity/physiology
15.
J Am Soc Nephrol ; 32(3): 708-722, 2021 03.
Article in English | MEDLINE | ID: covidwho-1496675

ABSTRACT

BACKGROUND: Late antibody-mediated rejection (ABMR) is a leading cause of transplant failure. Blocking IL-6 has been proposed as a promising therapeutic strategy. METHODS: We performed a phase 2 randomized pilot trial to evaluate the safety (primary endpoint) and efficacy (secondary endpoint analysis) of the anti-IL-6 antibody clazakizumab in late ABMR. The trial included 20 kidney transplant recipients with donor-specific, antibody-positive ABMR ≥365 days post-transplantation. Patients were randomized 1:1 to receive 25 mg clazakizumab or placebo (4-weekly subcutaneous injections) for 12 weeks (part A), followed by a 40-week open-label extension (part B), during which time all participants received clazakizumab. RESULTS: Five (25%) patients under active treatment developed serious infectious events, and two (10%) developed diverticular disease complications, leading to trial withdrawal. Those receiving clazakizumab displayed significantly decreased donor-specific antibodies and, on prolonged treatment, modulated rejection-related gene-expression patterns. In 18 patients, allograft biopsies after 51 weeks revealed a negative molecular ABMR score in seven (38.9%), disappearance of capillary C4d deposits in five (27.8%), and resolution of morphologic ABMR activity in four (22.2%). Although proteinuria remained stable, the mean eGFR decline during part A was slower with clazakizumab compared with placebo (-0.96; 95% confidence interval [95% CI], -1.96 to 0.03 versus -2.43; 95% CI, -3.40 to -1.46 ml/min per 1.73 m2 per month, respectively, P=0.04). During part B, the slope of eGFR decline for patients who were switched from placebo to clazakizumab improved and no longer differed significantly from patients initially allocated to clazakizumab. CONCLUSIONS: Although safety data indicate the need for careful patient selection and monitoring, our preliminary efficacy results suggest a potentially beneficial effect of clazakizumab on ABMR activity and progression.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Graft Rejection/therapy , Interleukin-6/antagonists & inhibitors , Kidney Transplantation/adverse effects , Adult , Allografts , Antibodies, Monoclonal, Humanized/adverse effects , Double-Blind Method , Female , Glomerular Filtration Rate , Graft Rejection/immunology , Graft Rejection/physiopathology , Humans , Infections/etiology , Interleukin-6/immunology , Isoantibodies/blood , Male , Middle Aged , Tissue Donors , Treatment Outcome , Young Adult
16.
J Am Soc Nephrol ; 32(2): 479-494, 2021 02.
Article in English | MEDLINE | ID: covidwho-1496663

ABSTRACT

BACKGROUND: Binding of donor-specific antibodies (DSAs) to kidney allograft endothelial cells that does not activate the classic complement cascade can trigger the recruitment of innate immune effectors, including NK cells. Activated NK cells contribute to microvascular inflammation leading to chronic antibody-mediated rejection (AMR). Recipient NK cells can also trigger antibody-independent microvascular inflammation by sensing the absence of self HLA class I molecules ("missing self") on allograft endothelial cells. This translational study investigated whether the condition of missing self amplifies DSA-dependent NK cell activation to worsen chronic AMR. METHODS AND RESULTS: Among 1682 kidney transplant recipients who underwent an allograft biopsy at Lyon University Hospital between 2004 and 2017, 135 fulfilled the diagnostic criteria for AMR and were enrolled in the study. Patients with complement-fixing DSAs identified by a positive C3d binding assay (n=73, 54%) had a higher risk of transplant failure (P=0.002). Among the remaining patients with complement-independent chronic AMR (n=62, 46%), those in whom missing self was identified through donor and recipient genotyping exhibited worse allograft survival (P=0.02). In multivariable analysis, only proteinuria (HR: 7.24; P=0.01) and the presence of missing self (HR: 3.57; P=0.04) were independent predictors for transplant failure following diagnosis of chronic AMR. Cocultures of human NK cells and endothelial cells confirmed that addition of missing self to DSA-induced NK cell activation increased endothelial damage. CONCLUSIONS: The assessment of missing self at the time of diagnosis of chronic AMR identifies patients at higher risk for kidney transplant failure.


Subject(s)
Allografts/pathology , Complement Activation/physiology , Graft Rejection/etiology , Histocompatibility Antigens Class I/blood , Kidney Transplantation/adverse effects , Killer Cells, Natural/physiology , Adult , Allografts/immunology , Cell Culture Techniques , Complement C3d/metabolism , Endothelial Cells/physiology , Female , Graft Rejection/blood , Graft Rejection/pathology , Graft Survival , Humans , Killer Cells, Natural/pathology , Male , Middle Aged , Young Adult
18.
Stem Cells Dev ; 30(19): 947-969, 2021 10 01.
Article in English | MEDLINE | ID: covidwho-1462261

ABSTRACT

Mesenchymal stem cell (MSC) therapy is considered one of the most promising treatments in the context of the coronavirus disease 2019 (COVID-19) pandemic. However, the safety and effectiveness of MSCs in the treatment of COVID-19-associated pneumonia patients need to be systematically reviewed and analyzed. Two independent researchers searched for relevant studies published between October 2019 and April 2021 in the PubMed, Embase, Cochrane Library, WAN FANG, and CNKI databases. All relevant randomized controlled trials, clinically controlled studies, retrospective studies, case reports, letters (with valid data), and case series were included in this meta-analysis. A fixed-effects model and 95% confidence interval (CI) were used to analyze the results. A total of 22 studies involving 371 patients were included in the present study. Allogeneic MSCs from umbilical cord, adipose tissue, menstrual blood, placental tissue, Wharton's jelly, or unreported sources were administered in 247 participants. Combined results revealed that MSC therapy significantly reduced the incidence of adverse events [AEs; odds ratio (OR) = 0.43, 95% CI = 0.22-0.84, P = 0.01] and mortality (OR = 0.17, 95% CI = 0.06-0.49, P < 0.01), and the difference compared with control group was statistically significant. No serious MSC treatment-related AEs were reported. Lung function, radiographic outcomes, and inflammation- and immunity-related biomarker levels all showed improving trends. Therefore, MSC therapy is an effective and safe method for the treatment of COVID-19-associated pneumonia and shows advantages in reducing AEs and mortality. However, a standard and effective MSC treatment program must be developed.


Subject(s)
COVID-19 , Mesenchymal Stem Cell Transplantation , Mesenchymal Stem Cells/metabolism , SARS-CoV-2/metabolism , Allografts , COVID-19/metabolism , COVID-19/mortality , COVID-19/therapy , Humans
19.
Blood Adv ; 5(23): 5140-5149, 2021 12 14.
Article in English | MEDLINE | ID: covidwho-1440899

ABSTRACT

We sought to evaluate the impact of cryopreservation of unrelated donor (URD) peripheral blood stem cell (PBSC) grafts on engraftment, chimerism, and immune reconstitution in the context of the COVID-19 pandemic. We reviewed stem cell product characteristics and clinical outcomes in 101 patients receiving cryopreserved PBSCs from URDs between January 1, 2019 and 31 December, 2020, compared with 203 patients receiving fresh URD PBSCs. We observed no differences in 6-month overall survival, progression-free survival, or nonrelapse mortality. Patients receiving cryopreserved PBSCs had delayed platelet engraftment and impaired reconstitution of white blood cells and T-cell subsets at day 30. Thirty-four percent of patients receiving cryopreserved grafts had CD3 chimerism <50% at day 30 after transplantation, compared with 14% of patients receiving fresh PBSCs (P = .0002). At day 100, this difference persisted (CD3+ chimerism <50%: 17% of cryopreserved cohort vs 6% of fresh cohort; P = .016). Greater product age at infusion was associated with increased graft failure, independent of cryopreservation. Receipt of grafts >48 hours old at time of cryopreservation or infusion significantly increased the risk of graft failure (subdistribution hazard ratio = 4.57; 95% confidence interval, 1.71-12.3; P = .0025). Our data indicate that cryopreservation is associated with similar overall short-term clinical outcomes compared with fresh PBSC. However, patients must be monitored closely for increased risk of other potentially adverse outcomes, including graft failure and poor immune recovery, particularly for grafts with older overall age at infusion. Longer-term follow-up is needed to determine impact on relapse and survival.


Subject(s)
COVID-19 , Hematopoietic Stem Cell Transplantation , Immune Reconstitution , Allografts , Cryopreservation , Hematopoietic Stem Cell Transplantation/adverse effects , Humans , Pandemics , SARS-CoV-2
20.
Am J Transplant ; 22(3): 786-800, 2022 03.
Article in English | MEDLINE | ID: covidwho-1434625

ABSTRACT

Studies are urgently needed to characterize immunogenicity, efficacy, and safety of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccines in kidney transplant (KT) recipients, excluded from major clinical trials. Complex ELISPOT and other cellular response techniques have been applied, but simpler tools are needed. An easy-to-use real-world monitoring of SARS-CoV-2 IgG antibodies against the Spike protein and QuantiFERON® SARS-CoV-2 IFNγ release assay (IGRA) were performed at baseline and 28 days after the second dose in KT recipients and controls (dialysis patients and healthy ones). All healthy controls and >95% dialysis controls became positive for anti-S IgG antibodies, while only 63.3% of KT patients seroconverted with a very low antibody level. A positive IGRA was documented in 96.9% of controls, 89.3% peritoneal dialysis, 77.6% hemodialysis, 61.3% of KT patients transplanted more than 1 year ago and only 36% of those transplanted within the previous 12 months. Overall, 100% of healthy controls, 95.4% of dialysis patients and 78.8% KT recipients developed any immune response (humoral and/or cellular) against SARS-CoV-2. KT patients showed low rates of immune responses to mRNA Coronavirus infectious disease 2019 vaccines, especially those with recent transplantations. Simple humoral and cellular monitoring is advisable, so that repeated doses may be scheduled according to the results.


Subject(s)
COVID-19 , Kidney Transplantation , Allografts , Antibodies, Viral , COVID-19/epidemiology , COVID-19/prevention & control , COVID-19 Vaccines , Humans , Immunity , Interferon-gamma Release Tests , Kidney Transplantation/adverse effects , RNA, Messenger/genetics , Renal Dialysis , SARS-CoV-2
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