The End of Endomyocardial Biopsy?: A Practical Guide for Noninvasive Heart Transplant Rejection Surveillance.

Noninvasive heart transplant rejection surveillance using gene expression profiling (GEP) to monitor immune activation is widely used among heart transplant programs. With the new development of donor-derived cell-free DNA (dd-cfDNA) assays, more programs are transitioning to a predominantly noninvasive rejection surveillance protocol with a reduced frequency of endomyocardial biopsies. As a result, many practical questions arise that potentially delay implementation of these valuable new tools. The purpose of this review is to provide practical guidance for clinicians transitioning toward a less invasive acute rejection monitoring protocol after heart transplantation, and to answer 10 common questions about the GEP and dd-cfDNA assays. Evidence supporting GEP and dd-cfDNA testing is reviewed, as well as guidance on test interpretation and future directions.

A multicentre, patient- and assessor-blinded, non-inferiority, randomised and controlled phase II trial to compare standard and torque teno virus-guided immunosuppression in kidney transplant recipients in the first year after transplantation: TTVguideIT.

BACKGROUND: Immunosuppression after kidney transplantation is mainly guided via plasma tacrolimus trough level, which cannot sufficiently predict allograft rejection and infection. The plasma load of the non-pathogenic and highly prevalent torque teno virus (TTV) is associated with the immunosuppression of its host. Non-interventional studies suggest the use of TTV load to predict allograft rejection and infection. The primary objective of the current trial is to demonstrate the safety, tolerability and preliminary efficacy of TTV-guided immunosuppression. METHODS: For this purpose, a randomised, controlled, interventional, two-arm, non-inferiority, patient- and assessor-blinded, investigator-driven phase II trial was designed. A total of 260 stable, low-immunological-risk adult recipients of a kidney graft with tacrolimus-based immunosuppression and TTV infection after month 3 post-transplantation will be recruited in 13 academic centres in six European countries. Subjects will be randomised in a 1:1 ratio (allocation concealment) to receive tacrolimus either guided by TTV load or according to the local centre standard for 9 months. The primary composite endpoint includes the occurrence of infections, biopsy-proven allograft rejection, graft loss, or death. The main secondary endpoints include estimated glomerular filtration rate, graft rejection detected by protocol biopsy at month 12 post-transplantation (including molecular microscopy), development of de novo donor-specific antibodies, health-related quality of life, and drug adherence. In parallel, a comprehensive biobank will be established including plasma, serum, urine and whole blood. The date of the first enrolment was August 2022 and the planned end is April 2025. DISCUSSION: The assessment of individual kidney transplant recipient immune function might enable clinicians to personalise immunosuppression, thereby reducing infection and rejection. Moreover, the trial might act as a proof of principle for TTV-guided immunosuppression and thus pave the way for broader clinical applications, including as guidance for immune modulators or disease-modifying agents. TRIAL REGISTRATION: EU CT-Number: 2022-500024-30-00.

Corneal Allograft Endothelial Rejection after Sinopharm COVID-19 Vaccination; Report of Six Cases.

AIM: To report the clinical characteristics of six patients with corneal allograft endothelial rejection after COVID-19 vaccination with Sinopharm and to review the literature. METHODS: This is a prospective case series describing corneal allograft rejection among subjects having received Sinopharm (BBIBP-CorV) vaccine, coming to cornea clinic at a university-based hospital (Rassoul Akram Hospital, Tehran, Iran) from September 2021 to March 2022 for regular follow-up examinations. Data on demographics, vaccination (based on vaccine card), and graft condition (based on recent examination and previous medical documents) were recorded. RESULTS: Out of 54 eyes (46 patients), 6 eyes (6 patients) had corneal allograft endothelial rejection after 3 to 117 days, post-vaccination. Three out of six rejections occurred within two weeks following vaccination. All of them were male with the mean age of 53.00 ± 19.66 years. The graft type of all patients was penetrating keratoplasty (PKP). The adverse event developed on average at 40.67 ± 34.33 months after surgery. Four patients were under maintenance treatment by topical steroid at the time of vaccination. One also received systemic immunomodulatory medication. Four grafts ended up with partial or complete graft failure. One case had received two doses of vaccine before undergoing the second corneal graft transplantation. CONCLUSION: COVID-19 vaccination with Sinopharm may trigger corneal allograft endothelial rejection even in individuals with low-risk graft and under maintenance topical and/or systemic immunomodulatory medications.

Donor Derived Cell Free DNA in Kidney Transplantation: The Circa 2020-2021 Update.

The routine surveillance of kidney transplant allografts has relied on imperfect non-invasive biomarkers such as creatinine and urinary indices, while the gold standard allograft biopsy is associated with risk of bleeding, organ injury and sampling errors. Donor derived cell free DNA (dd-cfDNA) is being employed as a biomarker that addresses limitations of these surveillance methods, albeit has inherent drawbacks. This review provides an update on the enhanced understanding of dd-cfDNA and its expanded use beyond the conventional indication of detecting allograft rejection.

A case of acute endothelial corneal transplant rejection following immunization with ChAdOx1 nCoV-19 coronavirus vaccine.

A 28-year-old female who underwent an uneventful femtosecond laser enabled keratoplasty (FLEK) in her left eye presented with pain, redness, and blurring of vision in the operated eye two weeks after getting immunized with COVID-19 vector vaccine (ChAdOx1 nCoV19 Vaccine Recombinant COVISHIELD, AstraZeneca). Slit-lamp examination showed donor stromal edema with Descemet's membrane folds and Khodadoust line (KP's on endothelium) with anterior chamber cells and flare. The patient was diagnosed with acute corneal graft rejection and advised hourly topical steroids with cycloplegics and oral steroids. The patient responded to treatment and there was progressive reversal of graft rejection with the patient achieving best spectacle-corrected visual acuity (BSCVA) of 20/30 after five weeks of treatment. Our case highlights possible immune corneal graft rejection after COVID19 vaccination and the need to step up topical steroids before vaccination.

Five Cases of Corneal Graft Rejection After Recent COVID-19 Vaccinations and a Review of the Literature.

PURPOSE: The purpose of this study was to report 5 cases of acute corneal graft rejection after COVID-19 vaccination and perform a review of the literature. METHODS: This was a case series and review of literature dated on the October 10, 2021. RESULTS: We describe 5 cases-2 patients with Descemet stripping automated endothelial keratoplasty (for Fuchs endothelial dystrophy) who presented with acute corneal graft rejection after their first dose of mRNA (BNT162) vaccine. The other 3 patients who had penetrating keratoplasty performed more than 10 years ago for keratoconus presented with acute graft rejection-2 patients after their second dose of adenovirus vector (AZD1222) vaccine and 1 patient after first dose of mRNA (BNT162) vaccine. Three patients were not using any topical steroid treatment at the time of diagnosis of graft rejection. The mean duration between vaccination and onset of symptoms was 16.86 ± 6.96 days for the mRNA vaccine and 17 ± 11.89 days for the adenovirus vector vaccine. CONCLUSIONS: Corneal graft rejection has recently been reported after COVID-19 vaccination. Patients with keratoplasty need to be advised regarding the risk of corneal graft rejection and warning symptoms of rejection after COVID-19 vaccination. Seeking early referral to the emergency department and increasing topical steroids pre-COVID-19 and post-COVID-19 vaccination may reduce the risk of rejection.

Non-Invasive Monitoring for Rejection in Kidney Transplant Recipients After SARS-CoV-2 mRNA Vaccination.

Introduction: Studies have shown reduced antiviral responses in kidney transplant recipients (KTRs) following SARS-CoV-2 mRNA vaccination, but data on post-vaccination alloimmune responses and antiviral responses against the Delta (B.1.617.2) variant are limited. Materials and methods: To address this issue, we conducted a prospective, multi-center study of 58 adult KTRs receiving mRNA-BNT162b2 or mRNA-1273 vaccines. We used multiple complementary non-invasive biomarkers for rejection monitoring including serum creatinine, proteinuria, donor-derived cell-free DNA, peripheral blood gene expression profile (PBGEP), urinary CXCL9 mRNA and de novo donor-specific antibodies (DSA). Secondary outcomes included development of anti-viral immune responses against the wild-type and Delta variant of SARS-CoV-2. Results: At a median of 85 days, no KTRs developed de novo DSAs and only one patient developed acute rejection following recent conversion to belatacept, which was associated with increased creatinine and urinary CXCL9 levels. During follow-up, there were no significant changes in proteinuria, donor-derived cell-free DNA levels or PBGEP. 36% of KTRs in our cohort developed anti-wild-type spike antibodies, 75% and 55% of whom had neutralizing responses against wild-type and Delta variants respectively. A cellular response against wild-type S1, measured by interferon-γ-ELISpot assay, developed in 38% of KTRs. Cellular responses did not differ in KTRs with or without antibody responses. Conclusions: SARS-CoV-2 mRNA vaccination in KTRs did not elicit a significant alloimmune response. About half of KTRs who develop anti-wild-type spike antibodies after two mRNA vaccine doses have neutralizing responses against the Delta variant. There was no association between anti-viral humoral and cellular responses.

Stromal rejection in penetrating keratoplasty following COVID-19 vector vaccine (Covishield) - A case report and review of literature.

Endothelial rejection has been described following both m-RNA and vector-based vaccines for COVID-19. There is one case report of a stromal rejection described following influenza vaccination. We report a case of stromal rejection following vector-based COVID-19 vaccination, which might be the first case reported so far.

Corneal Graft Rejection After Inactivated SARS-CoV-2 Vaccine: Case Report.

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.

Acute graft rejection in a high-risk corneal transplant following COVID-19 vaccination: A case report.

As COVID-19 vaccination is being undertaken all over the world, its side effects are materializing slowly. One such emerging side effect is acute graft rejection in corneal transplant (CT) cases post COVID-19 vaccination. We report a case of left eye (LE) repeat penetrating keratoplasty presenting with diminished vision in LE within 2 days of COVID-19 vaccination (ChAdOx1 nCoV-19 Corona Virus Vaccine Recombinant, COVISHIELD™). The patient was diagnosed with acute graft rejection post vaccination and was treated with topical and systemic immunosuppression therapy with successful outcome in terms improvement of visual acuity and corneal graft clarity. Timely presentation, diagnosis, and management may help to survive acute rejection episodes post vaccination.

Acute Corneal Epithelial Rejection of LR-CLAL After SARS-CoV-2 Vaccination.

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.

Acute Corneal Transplant Rejection After Severe Acute Respiratory Syndrome Coronavirus 2 mRNA-1273 Vaccination.

PURPOSE: The purpose of this article was to report a case of full-thickness corneal transplant rejection 3 days after immunization with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Moderna mRNA-1273 vaccine. METHODS: Case Report. RESULTS: A 51-year-old man with a history of keratoconus and penetrating keratoplasty underwent repeat penetrating keratoplasty for graft failure. The patient had an uncomplicated intraoperative and postoperative course with improved vision and a healthy graft. The patient received the SARS-CoV-2 Moderna vaccine on postoperative week 3, and within 3 days, the patient began developing eye pain, photophobia, and blurred vision. The patient was found to have graft rejection with corneal edema and endothelial keratic precipitates. The rejection did not improve despite a trial of increased topical steroids and ultimately evolved into graft failure. CONCLUSIONS: To the best of our knowledge, this case of full-thickness graft rejection after the Moderna SARS-CoV-2 mRNA vaccination is the first to be reported worldwide. The temporal relationship between vaccination and subsequent rejection is highly suggestive of causation due to the short interval (3 days) between vaccination and rejection and the lack of other inciting factors in an otherwise healthy graft. Patients with corneal transplants who plan to take the COVID-19 vaccinations should be counseled on symptoms and closely monitored, and an individualized plan should be made in discussion with the ophthalmologist.

Acute Corneal Transplant Rejection After COVID-19 Vaccination.

PURPOSE: The purpose of this report was to describe 4 cases of acute corneal transplant rejection occurring in association with coronavirus disease 2019 (COVID-19) mRNA vaccination. METHODS: Four patients with prior keratoplasty developed presumed immunologic rejection after the mRNA-1273 vaccination for coronavirus 2 (SARS-CoV-2). Case 1 had received Descemet membrane endothelial keratoplasty 6 months ago and presented with endothelial graft rejection 3 weeks after the first vaccine dose. Case 2 had undergone penetrating keratoplasty 3 years previously and presented with acute endothelial rejection 9 days after the second vaccine dose. Case 3 had prior Descemet stripping automated endothelial keratoplasty (DSAEK) and began experiencing symptoms of endothelial graft rejection 2 weeks after the second vaccine dose. Case 4 presented with endothelial rejection of the penetrating keratoplasty graft 2 weeks after the second vaccine dose. RESULTS: Frequent topical corticosteroids alone were initiated in all 4 cases. In case 1, the endothelial rejection line appeared fainter with improvement in visual acuity and corneal edema 5 weeks after diagnosis. Case 2 experienced complete resolution of corneal stromal edema and rejection line 6 weeks after diagnosis. Cases 3 and 4 have both experienced initial improvement with steroid treatment as well. CONCLUSIONS: These cases suggest acute corneal endothelial rejection may occur soon after either dose of the COVID-19 mRNA vaccine. Prompt initiation of aggressive topical steroid therapy may result in complete resolution of clinical signs and symptoms. Further studies are needed to elucidate the causal mechanism of corneal graft rejection after COVID-19 vaccination.

Acute graft rejection in a COVID-19 patient: Co-incidence or causal association?

A 32-year-old man with a clear and compact graft following a penetrating keratoplasty 6 years back, developed an episode of acute graft rejection, coinciding with the COVID-19 disease. Subsequent to the infection with the novel coronavirus, he developed symptoms of acute graft rejection concurrent with the development of respiratory distress and peak systemic symptoms. This was the phase of cytokine storm as evidenced by the raised inflammatory markers in his blood tests. Such a case of acute corneal graft rejection coinciding with SARS-CoV-2 infection has been reported only once in the literature and this unique association needs to be researched further.

Chronic Active Antibody-Mediated Rejection Following COVID-19 Infection in a Kidney Transplant Recipient: A Case Report.

Kidney transplant recipients who develop coronavirus disease 2019 (COVID-19) are at increased risk of life-threatening illness, which often requires reducing immunosuppression despite the potential risk of causing an allograft rejection. Herein, we describe the clinical presentation and course of a kidney transplant recipient who acquired COVID-19 and was hospitalized with severe symptoms and hypoxemia. Upon admission, the patient was found to have elevated de novo donor-specific antibodies (DSA) yielding a positive cytotoxicity crossmatch and concurrent elevated plasma donor-derived cell-free DNA (dd-cfDNA) level, indicating a possible ongoing rejection despite improvement in his serum creatinine. Because of persistent positive COVID-19 tests and stable serum creatinine, a kidney allograft biopsy was initially deferred and his dd-cfDNA and DSA were monitored closely postdischarge. Three months later, because of persistent elevated dd-cfDNA and positive DSA, a kidney allograft biopsy was performed, which showed chronic active antibody-mediated rejection. Accordingly, the patient was treated with intravenous immunoglobulin and his maintenance immunosuppressive regimen was increased.

Acute Corneal Endothelial Graft Rejection With Coinciding COVID-19 Infection.

PURPOSE: To report a case of acute corneal endothelial graft rejection with the concurrent onset of coronavirus disease 2019 (COVID-19) symptoms. METHODS: Case report. RESULTS: A 31-year-old African American woman with a history of asthma, sleep apnea, obesity (body mass index of 40), and bilateral keratoconus was noted to have acute corneal endothelial graft rejection 3 months after uncomplicated penetrating keratoplasty of the left eye. The patient developed dysgeusia and subjective fever on the same day as ocular discomfort, and she was subsequently diagnosed with COVID-19 with only these 2 classic symptoms of the viral infection. CONCLUSIONS: Severe acute respiratory syndrome coronavirus 2 is known to cause conjunctivitis and has demonstrated transmissibility through ocular secretions. Acute immune and inflammatory dysregulations have been seen in cases of COVID-19 through various mechanisms. COVID-19 infection may potentially compromise ocular immune privilege contributing to acute corneal graft rejection.

Use of Donor-Derived Cell-Free DNA for Assessment of Allograft Injury in Kidney Transplant Recipients During the Time of the Coronavirus Disease 2019 Pandemic.

BACKGROUND: Kidney allograft biopsy is the gold standard for diagnosis of rejection. Under the current extraordinary circumstances of the coronavirus disease 2019 (COVID-19), in which social distancing is key to limiting the spread of the virus, the model used to provide care to transplant recipients has undergone a very rapid transformation. In the spirit of medical distancing, we have been using the donor-derived cell-free DNA (dd-cfDNA) test for screening for rejection. METHODS: This article describes our experience with this approach between March 15th and May 20th, 2020. RESULTS: This test was obtained for-cause in 23 patients and for monitoring in 9 patients. Normal results aided in forgoing biopsy in 63% of the patients for whom the test was obtained in the outpatient setting. The test is neither 100% sensitive nor specific for rejection; however, when used in combination with the available clinical information, it can be used for determining whether bringing in a transplant recipient into a medical facility is necessary. CONCLUSIONS: In the event COVID-19 becomes a long-term challenge for our community, noninvasive biomarkers such as the dd-cfDNA may become more relevant than ever in enhancing our ability to care for our transplant patients while maximizing the distancing measures.