Functional SARS-CoV-2-specific T cells of donor origin in allogeneic stem cell transplant recipients of a T-cell-replete infusion: A prospective observational study.

In the current post-pandemic era, recipients of an allogeneic hematopoietic stem cell transplant (HCT) deserve special attention. In these vulnerable patients, vaccine effectiveness is reduced by post-transplant immune-suppressive therapy; consequently, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19) is often associated with elevated morbidity and mortality. Characterizing SARS-CoV-2 adaptive immunity transfer from immune donors to HCT recipients in the context of immunosuppression will help identify optimal timing and vaccination strategies that can provide adequate protection to HCT recipients against infection with evolving SARS-CoV-2 variants. We performed a prospective observational study (NCT04666025 at ClinicalTrials.gov) to longitudinally monitor the transfer of SARS-CoV-2-specific antiviral immunity from HCT donors, who were either vaccinated or had a history of COVID-19, to their recipients via T-cell replete graft. Levels, function, and quality of SARS-CoV-2-specific immune responses were longitudinally analyzed up to 6 months post-HCT in 14 matched unrelated donor/recipients and four haploidentical donor/recipient pairs. A markedly skewed donor-derived SARS-CoV-2 CD4 T-cell response was measurable in 15 (83%) recipients. It showed a polarized Th1 functional profile, with the prevalence of central memory phenotype subsets. SARS-CoV-2-specific IFN-γ was detectable throughout the observation period, including early post-transplant (day +30). Functionally experienced SARS-CoV-2 Th1-type T cells promptly expanded in two recipients at the time of post-HCT vaccination and in two others who were infected and survived post-transplant COVID-19 infection. Our data suggest that donor-derived SARS-CoV-2 T-cell responses are functional in immunosuppressed recipients and may play a critical role in post-HCT vaccine response and protection from the fatal disease. Clinical trial registration: clinicaltrials.gov, identifier NCT04666025.

High-titer post-vaccine COVID-19 convalescent plasma for immunocompromised patients during the first omicron surge.

BACKGROUND: Transplant and hematologic malignancy patients have high Coronavirus disease 2019 (COVID-19) mortality and impaired vaccination responses. Omicron variant evades several monoclonal antibodies previously used in immunocompromised patients. Polyclonal COVID-19 convalescent plasma (CCP) may provide broader neutralizing capacity against new variants at high titers. Vaccination increases severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) titer in convalescent donors. METHODS: We conducted a retrospective chart review of hospitalized immunocompromised patients with COVID-19 who received high-titer CCP during the first omicron surge, collected from vaccinated donors within 6 months of pre-omicron COVID-19. Data on safety and outcomes were extracted. RESULTS: A total of 44 immunocompromised patients were included, 59.1% with solid organ transplant, 22.7% with hematopoietic cell transplant, 11.4% with hematologic malignancy, and 6.8% with autoimmune disease. Overall, 95% of CCP units transfused were from recently recovered and vaccinated donors and had SARS-CoV-2 antibody results 8- to 37-fold higher than the Food and Drug Administration's cutoff for high-titer CCP. There were two mild transfusion reactions. A total of 30-day mortality was 4.5%. There were no differences in 100-day mortality by underlying diagnosis, levels of immunosuppression, and timing of CCP administration. Patients with higher immunosuppression had significantly higher mean World Health Organization clinical progression scores at 30-day post-CCP compared to those with lower immunosuppression. CONCLUSIONS: CCP is a safe, globally available treatment for immunocompromised patients with COVID-19. Mortality was lower in our cohort than that of COVID-19 patients with similar immunocompromising conditions. Post-vaccine CCP with very high titers should be prioritized for study in immunocompromised patients. Post-vaccine CCP has the potential to keep pace with new variants by overcoming mutations at sufficiently high titer.

Prior COVID-19 infection may increase risk for developing endothelial dysfunction following hematopoietic cell transplantation.

Endothelial dysfunction underlies many of the major complications following hematopoietic cell transplantation (HCT), including transplant-associated thrombotic microangiopathy (TA-TMA), veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS), and engraftment syndrome (ES). Emerging evidence similarly implicates endothelitis and microangiopathy in severe COVID-19-related multi-system organ dysfunction. Given the overlap in these two illness states, we hypothesize that prior COVID-19 infection may increase risk for HCT-related endotheliopathies. This retrospective, multicenter study included patients aged 0-25 years who underwent autologous or allogeneic HCT for any indication between January 1, 2020 and September 21, 2021, with close attention to those infected with COVID-19 in either the six months prior to transplant or twelve months following transplant. Incidences of TA-TMA, VOD/SOS, and ES were compared among patients with COVID-19 infection pre-HCT and post-HCT, as well as with historical controls who were never infected with SARS-CoV-2. Those who underwent HCT following COVID-19 infection displayed significantly increased rates of TA-TMA compared to those who were never infected. Additionally, our data suggests a similar trend for increased VOD/SOS and ES rates, although this did not reach statistical significance. Therefore, a history of COVID-19 infection prior to undergoing HCT may be a nonmodifiable risk factor for endothelial-related complications following HCT. Further studies are warranted to better clarify this relationship among larger cohorts and in the era of the Omicron SARS-CoV-2 variants.

Frequently Asked Questions on Coronavirus Disease 2019 Vaccination for Hematopoietic Cell Transplantation and Chimeric Antigen Receptor T-Cell Recipients From the American Society for Transplantation and Cellular Therapy and the American Society of Hematology.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), disproportionately affects immunocompromised and elderly patients. Not only are hematopoietic cell transplantation (HCT) and chimeric antigen receptor (CAR) T-cell recipients at greater risk for severe COVID-19 and COVID-19-related complications, but they also may experience suboptimal immune responses to currently available COVID-19 vaccines. Optimizing the use, timing, and number of doses of the COVID-19 vaccines in these patients may provide better protection against SARS-CoV-2 infection and better outcomes after infection. To this end, current guidelines for COVID-19 vaccination in HCT and CAR T-cell recipients from the American Society of Transplantation and Cellular Therapy Transplant Infectious Disease Special Interest Group and the American Society of Hematology are provided in a frequently asked questions format.

Respiratory viruses

Respiratory viruses are commonly detected in both healthy and immunocompromised children. In most healthy children, respiratory viruses are associated with self-limited upper respiratory tract infections and are not accompanied by significant morbidity. In immunocompromised hosts, including hematopoietic cell transplant recipients, solid organ transplant recipients, and oncology patients, respiratory viruses can be associated with significant clinical manifestations, including prolonged viral shedding, lower respiratory tract disease, the need for supplemental oxygen, late airflow obstruction, and even death. This chapter reviews the major respiratory viruses, including respiratory syncytial virus, human metapneumovirus, influenza, parainfluenza viruses, human rhinoviruses, and human coronaviruses. Other viruses can manifest as pulmonary infection;however, these viruses are discussed elsewhere (see Chapter 17 for discussion of cytomegalovirus and Chapter 22 for discussion of adenoviruses). © 2021 Elsevier Inc. All rights reserved.

A Portrait of SARS-CoV-2 Infection in Patients Undergoing Hematopoietic Cell Transplantation: A Systematic Review of the Literature.

The management of COVID-19 in hematopoietic cell transplant (HCT) recipients represents a special challenge given the variable states of immune dysregulation and altered vaccine efficacy in this population. A systematic search (Ovid Medline and Embase on 1 June 2021) was needed to better understand the presenting features, prognostic factors, and treatment options. Of 897 records, 29 studies were identified in our search. Most studies reporting on adults and pediatric recipients described signs and symptoms that were typical of COVID-19. Overall, the mortality rates were high, with 21% of adults and 6% of pediatric HCT recipients succumbing to COVID-19. The factors reported to be associated with increased mortality included age (HR = 1.21, 95% CI 1.03-1.43, p = 0.02), ICU admission (HR = 4.42, 95% CI 2.25-8.65, p < 0.001 and HR = 2.26, 95% CI 1.22-4.20, p = 0.01 for allogeneic and autologous HCT recipients), and low platelet count (OR = 21.37, 95% CI 1.71-267.11, p = 0.01). Performance status was associated with decreased mortality (HR = 0.83, 95% CI 0.74-0.93, p = 0.001). A broad range of treatments was described, although no controlled studies were identified. The risk of bias, using the Newcastle-Ottawa scale, was low. Patients undergoing HCT are at a high risk of severe morbidity and mortality associated with COVID-19. Controlled studies investigating potential treatments are required to determine the efficacy and safety in this population.

Vaccine-Associated Measles in a Hematopoietic Cell Transplant Recipient: Case Report and Comprehensive Review of the Literature.

Measles is a worldwide viral disease that can cause fatal complications in immunocompromised hosts such as hematopoietic cell transplant (HCT) recipients. The live attenuated measles, mumps, and rubella (MMR) vaccine is generally contraindicated post-HCT due to the risk for vaccine-associated measles. This, combined with decreasing vaccination rates due to vaccine hesitancy and the coronavirus disease 2019 pandemic, raises significant concerns for a measles resurgence that could portend devastating consequences for immunocompromised hosts. Multiple guidelines have included criteria to determine which HCT recipients can safely receive the MMR vaccine. Here, we report a case of vaccine-associated measles in a HCT recipient who met guideline-recommended criteria for MMR vaccination. The objective of this article is to query these criteria, highlight the importance of MMR vaccination, and comprehensively review the literature.

How Do We Manage Hematopoietic Cell Transplant during the SARS-CoV-2 Pandemic?

Patients receiving a hematopoietic cell transplant are thought to be at increased risk of infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and coronavirus infectious disease 2019. Transplant activities at our center continue, and notably, no patient has been infected with SARS-CoV-2. Indeed, social distancing, masking, and education for patients and donors are major pillars of prevention. We recommend potential transplant recipients and donors to be tested for SARS-CoV-2 with qRT-PCR, serum antibody detection, and a lung CT scan pretransplant. If possible, stem cells from HLA-matched unrelated donors by local processing laboratories should be cryopreserved and shipped before initiating pretransplant conditioning. An alternative HLA-haplotype-matched related donor should be identified and evaluated as a backup. The interval immediately after discharge is the time of greatest risk for SARS-CoV-2 infection because of travel and exposure to infected persons. We recommend self-isolation and minimal contact with family members. Nonessential clinic visits should be deferred or substituted with telemedicine consultations if possible. These recommendations are based on our experience at a major transplant center in China. Although some recommendations are evidence based, other recommendations are not and warrant validation in controlled trials.

COVID - 19 post Hematopoietic Cell Transplant, a Report of 11 Cases from a Single Center.

In late 2019 the coronavirus disease - 2019 (COVID - 19) pandemic caused by SARS Coronavirus 2 (SARS - CoV - 2) started in Wuhan, China. Life has changed radically since then. Data emerging from the first hit countries show a tendency for a complicated course and higher mortality in some subgroups of infected patients. Cancer patients are immunosuppressed from their disease and the therapy they receive. Hematopoietic cell transplant (HCT) recipients are a subgroup of patients that are severely immunocompromised and may be at an even higher risk of a complicated course during this infection. Reports describing the course of these patients with COVID-19 disease are limited. We herein report the onset, progression, and outcome of 11 sequential cases of HCT recipients infected by SARS - CoV - 2 treated in our center. The patients' age ranged from 17 to 60 years, the duration from transplant to infection ranged from day +5 to 192 months, six patients were post-allo-HCT, four post-auto-HCT, and one had both allo and auto-HCT. The presenting symptoms were not different from other viral illnesses. The majority (seven patients) had mild COVID-19 stage, while 3 had a moderate stage on presentation. None of the patients required oxygen supplementation nor mechanical ventilation.