HHV-8-associated diseases in transplantation: A case report and narrative review focused on diagnosis and prevention.

BACKGROUND: Human herpes virus 8 (HHV-8) or Kaposi sarcoma herpesvirus (KSHV) is an opportunistic oncovirus that causes multiple pathologic entities. METHODS: We present a case of fatal HHV-8-associated multisystem illness with disseminated Kaposi sarcoma and HHV8-associated lymphoproliferative disorder with systemic inflammation. We conducted a narrative review of the literature on HHV-8 in transplantation with a goal of illuminating the spectrum of HHV-8-associated diseases in this vulnerable population, modes of disease transmission, and the potential role for donor and recipient screening. RESULTS: HHV-8-associated KS, primary effusion lymphoma (PEL), multicentric Castleman disease (MCD), and KSHV inflammatory cytokine disorder (KICS) may affect transplant recipients; with the exception of KS, these conditions are rare but carry high morbidity and mortality. CONCLUSION: HHV-8-associated diseases have diverse and protean manifestations in transplant recipients, with potentially fatal outcomes. HHV-8 seroprevalence among organ donors and the magnitude of risk for donor-derived HHV-8 infection or clinically significant disease remain unknown and require further study.

What Does Disability Justice Require of Antimicrobial Stewardship?

This commentary on a case argues that antimicrobial stewardship requires an intersectional disability justice approach if it is to be equitable, particularly for multiply marginalized patients with disabilities residing in nursing homes, who are more susceptible to antibiotic under- and overtreatment. Disability justice concepts emphasize resistance to structural and capitalist roots of ableism and prioritize leadership by disabled persons. A disability justice perspective on antimicrobial stewardship means prioritizing clarification of presumptive diagnoses of infection in vulnerable patients, clinician education led by disabled persons, and data collection.

A Brief History of Antimicrobial Resistance.

Despite mounting attention in recent years, health threats posed by antimicrobial resistance are not new. Antimicrobial resistance has dogged infectious disease treatment processes since the first modern antimicrobials were discovered.

Research involving the recently deceased: ethics questions that must be answered.

Research involving recently deceased humans that are physiologically maintained following declaration of death by neurologic criteria-or 'research involving the recently deceased'-can fill a translational research gap while reducing harm to animals and living human subjects. It also creates new challenges for honouring the donor's legacy, respecting the rights of donor loved ones, resource allocation and public health. As this research model gains traction, new empirical ethics questions must be answered to preserve public trust in all forms of tissue donation and in the practice of medicine while respecting the legacy of the deceased and the rights of donor loved ones. This article suggests several topics for immediate investigation to understand the attitudes and experiences of researchers, clinical collaborators, donor loved ones and the public to ensure research involving the recently deceased advances ethically.

Attenuated immunogenicity of SARS-CoV-2 vaccines and risk factors in stem cell transplant recipients: a meta-analysis.

Immunogenicity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination is diminished in hematopoietic stem cell transplant (HSCT) recipients. To summarize current evidence and identify risk factors for attenuated responses, 5 electronic databases were searched since database inceptions through 12 January 2023 for studies reporting humoral and/or cellular immunogenicity of SARS-CoV-2 vaccination in the HSCT population. Using descriptive statistics and random-effects models, extracted numbers of responders and pooled odds ratios (pORs) with 95% confidence intervals (CIs) for risk factors of negative immune responses were analyzed (PROSPERO: CRD42021277109). From 61 studies with 5906 HSCT recipients, after 1, 2, and 3 doses of messenger RNA (mRNA) SARS-CoV-2 vaccines, the mean antispike antibody seropositivity rates (95% CI) were 38% (19-62), 81% (77-84), and 80% (75-84); neutralizing antibody seropositivity rates were 52% (40-64), 71% (54-83), and 78% (61-89); and cellular immune response rates were 52% (39-64), 66% (51-79), and 72% (52-86). After 2 vaccine doses, risk factors (pOR; 95% CI) associated with antispike seronegativity were male recipients (0.63; 0.49-0.83), recent rituximab exposure (0.09; 0.03-0.21), haploidentical allografts (0.46; 0.22-0.95), <24 months from HSCT (0.25; 0.07-0.89), lymphopenia (0.18; 0.13-0.24), hypogammaglobulinemia (0.23; 0.10-0.55), concomitant chemotherapy (0.48; 0.29-0.78) and immunosuppression (0.18; 0.13-0.25). Complete remission of underlying hematologic malignancy (2.55; 1.05-6.17) and myeloablative conditioning (1.72; 1.30-2.28) compared with reduced-intensity conditioning were associated with antispike seropositivity. Ongoing immunosuppression (0.31; 0.10-0.99) was associated with poor cellular immunogenicity. In conclusion, attenuated humoral and cellular immune responses to mRNA SARS-CoV-2 vaccination are associated with several risk factors among HSCT recipients. Optimizing individualized vaccination and developing alternative COVID-19 prevention strategies are warranted.

Ribavirin treatment for respiratory syncytial virus infection in patients with haematologic malignancy and haematopoietic stem cell transplant recipients: a systematic review and meta-analysis.

BACKGROUND: Ribavirin use for respiratory syncytial virus (RSV) infection in patients with haematologic malignancies (HM) and haematopoietic stem cell transplant (HSCT) recipients remains controversial. OBJECTIVES: To summarize the current evidence of ribavirin treatment in association with mortality and progression to lower respiratory tract infection (LRTI) among patients with HM/HSCT with RSV infection. DATA SOURCES: MEDLINE, Embase, and the Institute for Scientific Information Web of Science. STUDY ELIGIBILITY CRITERIA: Randomized controlled trials and observational studies investigating the effects of ribavirin, compared with treatment without ribavirin, for RSV infection. PARTICIPANTS: Patients with HM/HSCT. INTERVENTIONS: Ribavirin versus no ribavirin. ASSESSMENT OF RISK OF BIAS: The risk of bias in non-randomized studies of exposure (ROBIN-E). METHODS OF DATA SYNTHESIS: The random-effects model was used to calculate the pooled OR (pOR) with 95% CI for the pooled effect estimates of ribavirin benefits. Grading of recommendation assessment, development, and evaluation was used to evaluate the certainty of evidence. RESULTS: One randomized controlled trial and 14 observational studies were included, representing 1125 patients with HM/HSCT. Ribavirin use was not associated with lower all-cause or RSV-associated mortality with pORs [95% CI] of 0.81 [0.40, 1.66], I2 = 55% (low certainty of evidence) and 0.48 [0.11, 2.15], I2 = 64% (very low certainty of evidence), respectively. In subgroup analyses, ribavirin use was associated with lower mortality in patients with HM/HSCT with LRTI with pOR [95% CI] of 0.19 [0.07, 0.51], I2 = 0% (moderate certainty of evidence). In subgroup analyses among studies providing adjusted OR, ribavirin use was associated with lower all-cause mortality with pOR of 0.41 [0.23, 0.74], I2 = 0% (moderate certainty of evidence). In addition, aerosolized ribavirin was associated with lower progression to LRTI with pOR [95% CI] of 0.27 [0.09, 0.80], I2 = 71% (low certainty of evidence). CONCLUSIONS: Ribavirin may be a reasonable option to treat RSV in patients with HM/HSCT in the absence of other effective antiviral agents.

Prevalence of Ocular Candidiasis and Candida Endophthalmitis in Patients With Candidemia: A Systematic Review and Meta-Analysis.

BACKGROUND: Infectious diseases and ophthalmology professional societies have disagreed regarding ocular screening in patients with candidemia. We aimed to summarize the current evidence on the prevalence of ocular candidiasis (OC) and Candida endophthalmitis (CE) according to the standardized definitions. METHODS: A literature search was conducted from the inception date through 16 October 2022 using PubMed, Embase, and SCOPUS. Pooled prevalence of ocular complications was derived from generalized linear mixed models (PROSPERO CRD42022326610). RESULTS: A total of 70 and 35 studies were included in the meta-analysis for OC and concordant CE (chorioretinitis with vitreous involvement), respectively. This study represented 8599 patients with candidemia who underwent ophthalmologic examination. Pooled prevalences (95% CI) of OC, overall CE, concordant CE, and discordant CE were 10.7% (8.4-13.5%), 3.1% (2.1-4.5%), 1.8% (1.3-2.6%), and 7.4% (4.5-12%) of patients screened, respectively. Studies from Asian countries had significantly higher concordant CE prevalence (95% CI) of patients screened (3.6%; 2.9-4.6%) compared with studies from European countries (1.4%; .4-5%) and American countries (1.4%; .9-2.2%) (P <.01). Presence of total parenteral nutrition and Candida albicans was associated with CE, with pooled odds ratios (95% CI) of 6.92 (3.58-13.36) and 3.02 (1.67-5.46), respectively. CONCLUSIONS: Prevalence of concordant CE overall and among Asian countries was 2 and 4 times higher than the prevalence previously reported by the American Academy of Ophthalmology (AAO) of <0.9%, respectively. There is an urgent need to study optimal screening protocols and to establish joint recommendations by the Infectious Diseases Society of America and AAO.

Disseminated Tuberculosis With an Atypical Cutaneous Manifestation in a Hematopoietic Cell Transplant Patient in the Early Posttransplant Period: Case Report and Review of the Literature.

We describe an unusual case of posttransplant tuberculosis reactivation in a man who underwent allogeneic hematopoietic cell transplant. Concomitant with disseminated adenovirus infection, reactivation of tuberculosis manifested as disseminated, nonfollicular pustules on day +49. Skin biopsy was obtained on day +50. Initial histopathologic evaluation did not suggest mycobacterial infection, but tissue stain showed acid-fast organisms, which were subsequently identified as Mycobacterium tuberculosis. Shortly after the cutaneous presentation of tuberculosis, the patient died on day +52. Our case is among a paucity of reports describing tuberculosis reactivation in hematopoietic cell transplant patients in the early posttransplant period. It highlights the difficulty of diagnosing contemporaneous systemic infections, and it presents a rare and atypical cutaneous manifestation of tuberculosis in a hematopoietic cell transplant patient. Our case and review of the literature emphasize the need for further research to elucidate risk factors associated with early posttransplant reactivation of tuberculosis, and the importance of remaining vigilant for active tuberculosis in hematopoietic cell transplant patients with epidemiologic risk factors.

Immunogenicity of SARS-CoV-2 vaccines in patients with multiple myeloma: a systematic review and meta-analysis.

Patients with multiple myeloma (MM) have a diminished immune response to coronavirus disease 2019 (COVID-19) vaccines. Risk factors for an impaired immune response are yet to be determined. We aimed to summarize the COVID-19 vaccine immunogenicity and to identify factors that influence the humoral immune response in patients with MM. Two reviewers independently conducted a literature search in MEDLINE, Embase, ISI Web of Science, Cochrane library, and Clinicaltrials.gov from existence until 24 May 24 2022. (PROSPERO: CRD42021277005). A total of 15 studies were included in the systematic review and 5 were included in the meta-analysis. The average rate (range) of positive functional T-lymphocyte response was 44.2% (34.2%-48.5%) after 2 doses of messenger RNA (mRNA) COVID-19 vaccines. The average antispike antibody response rates (range) were 42.7% (20.8%-88.5%) and 78.2% (55.8%-94.2%) after 1 and 2 doses of mRNA COVID-19 vaccines, respectively. The average neutralizing antibody response rates (range) were 25% (1 study) and 62.7% (53.3%-68.6%) after 1 and 2 doses of mRNA COVID-19 vaccines, respectively. Patients with high-risk cytogenetics or receiving anti-CD38 therapy were less likely to have a humoral immune response with pooled odds ratios of 0.36 (95% confidence interval [95% CI], 0.18, 0.69), I2 = 0% and 0.42 (95% CI, 0.22, 0.79), I2 = 14%, respectively. Patients who were not on active MM treatment were more likely to respond with pooled odds ratio of 2.42 (95% CI, 1.10, 5.33), I2 = 7%. Patients with MM had low rates of humoral and cellular immune responses to the mRNA COVID-19 vaccines. Further studies are needed to determine the optimal doses of vaccines and evaluate the use of monoclonal antibodies for pre-exposure prophylaxis in this population.

Approaches to pretransplant vaccination.

PURPOSE OF REVIEW: The aim of this study was to summarize new data and perspectives in pretransplant vaccination, with a particular focus on COVID-19 vaccination and vaccination requirements. RECENT FINDINGS: Pretransplant vaccination produces superior markers of immunity and is expected to have greater clinical benefit, compared with posttransplant vaccination. As such, efforts are underway to identify and characterize barriers to pretransplant vaccination, with a particular focus on COVID-19 vaccine hesitancy. Unfortunately, vaccine hesitancy is common in transplant patients, often motivated by individual side effect and safety concerns. COVID-19 vaccination requirements have been implemented in some centres, informed by ethical principles, including beneficence, utility and justice. SUMMARY: Barriers to pretransplant vaccination can be understood in three categories: hard stops, including issues of vaccine availability, eligibility, safety and feasibility; soft stops, including issues of convenience, prioritization and care coordination; and volitional stops related to vaccine hesitancy and refusal. All of these barriers present opportunities for improvement based on recent data.

Immunogenicity and Risk Factors Associated With Poor Humoral Immune Response of SARS-CoV-2 Vaccines in Recipients of Solid Organ Transplant: A Systematic Review and Meta-Analysis.

Importance: Recipients of solid organ transplant (SOT) experience decreased immunogenicity after COVID-19 vaccination. Objective: To summarize current evidence on vaccine responses and identify risk factors for diminished humoral immune response in recipients of SOT. Data Sources: A literature search was conducted from existence of database through December 15, 2021, using MEDLINE, Embase, Web of Science, Cochrane Library, and ClinicalTrials.gov. Study Selection: Studies reporting humoral immune response of the COVID-19 vaccines in recipients of SOT were reviewed. Data Extraction and Synthesis: Two reviewers independently extracted data from each eligible study. Descriptive statistics and a random-effects model were used. This report was prepared following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. Data were analyzed from December 2021 to February 2022. Main Outcomes and Measures: The total numbers of positive immune responses and percentage across each vaccine platform were recorded. Pooled odds ratios (pORs) with 95% CIs were used to calculate the pooled effect estimates of risk factors for poor antibody response. Results: A total of 83 studies were included for the systematic review, and 29 studies were included in the meta-analysis, representing 11 713 recipients of SOT. The weighted mean (range) of total positive humoral response for antispike antibodies after receipt of mRNA COVID-19 vaccine was 10.4% (0%-37.9%) for 1 dose, 44.9% (0%-79.1%) for 2 doses, and 63.1% (49.1%-69.1%) for 3 doses. In 2 studies, 50% of recipients of SOT with no or minimal antibody response after 3 doses of mRNA COVID-19 vaccine mounted an antibody response after a fourth dose. Among the factors associated with poor antibody response were older age (mean [SE] age difference between responders and nonresponders, 3.94 [1.1] years), deceased donor status (pOR, 0.66 [95% CI, 0.53-0.83]; I2 = 0%), antimetabolite use (pOR, 0.21 [95% CI, 0.14-0.29]; I2 = 70%), recent rituximab exposure (pOR, 0.21 [95% CI, 0.07-0.61]; I2 = 0%), and recent antithymocyte globulin exposure (pOR, 0.32 [95% CI, 0.15-0.71]; I2 = 0%). Conclusions and Relevance: In this systematic review and meta-analysis, the rates of positive antibody response in solid organ transplant recipients remained low despite multiple doses of mRNA vaccines. These findings suggest that more efforts are needed to modulate the risk factors associated with reduced humoral responses and to study monoclonal antibody prophylaxis among recipients of SOT who are at high risk of diminished humoral response.

Delayed mortality among solid organ transplant recipients hospitalized for COVID-19.

INTRODUCTION: Most studies of solid organ transplant (SOT) recipients with COVID-19 focus on outcomes within one month of illness onset. Delayed mortality in SOT recipients hospitalized for COVID-19 has not been fully examined. METHODS: We used data from a multicenter registry to calculate mortality by 90 days following initial SARS-CoV-2 detection in SOT recipients hospitalized for COVID-19 and developed multivariable Cox proportional-hazards models to compare risk factors for death by days 28 and 90. RESULTS: Vital status at day 90 was available for 936 of 1117 (84%) SOT recipients hospitalized for COVID-19: 190 of 936 (20%) died by 28 days and an additional 56 of 246 deaths (23%) occurred between days 29 and 90. Factors associated with mortality by day 90 included: age > 65 years [aHR 1.8 (1.3-2.4), p =<0.001], lung transplant (vs. non-lung transplant) [aHR 1.5 (1.0-2.3), p=0.05], heart failure [aHR 1.9 (1.2-2.9), p=0.006], chronic lung disease [aHR 2.3 (1.5-3.6), p<0.001] and body mass index ≥ 30 kg/m 2 [aHR 1.5 (1.1-2.0), p=0.02]. These associations were similar for mortality by day 28. Compared to diagnosis during early 2020 (March 1-June 19, 2020), diagnosis during late 2020 (June 20-December 31, 2020) was associated with lower mortality by day 28 [aHR 0.7 (0.5-1.0, p=0.04] but not by day 90 [aHR 0.9 (0.7-1.3), p=0.61]. CONCLUSIONS: In SOT recipients hospitalized for COVID-19, >20% of deaths occurred between 28 and 90 days following SARS-CoV-2 diagnosis. Future investigations should consider extending follow-up duration to 90 days for more complete mortality assessment.

Ethical review of COVID-19 vaccination requirements for transplant center staff and patients.

Transplant centers seeking to increase coronavirus disease 2019 (COVID-19) vaccine coverage may consider requiring vaccination for healthcare workers or for candidates. The authors summarize current data to inform an ethical analysis of the harms, benefits, and individual and societal impact of mandatory vaccination, concluding that vaccine requirements for healthcare workers and transplant candidates are ethically justified by beneficence, net utility, and fiduciary duty to patients and public health. Implementation strategies should mitigate concerns about respect for autonomy and transparency for both groups. We clarify how the same arguments might be applied to related questions of caregiver vaccination, allocation of other healthcare resources, and mandates for non-COVID-19 vaccines. Finally, we call for effort to achieve global equity in vaccination as soon as possible.

Changing trends in mortality among solid organ transplant recipients hospitalized for COVID-19 during the course of the pandemic.

Mortality among patients hospitalized for COVID-19 has declined over the course of the pandemic. Mortality trends specifically in solid organ transplant recipients (SOTR) are unknown. Using data from a multicenter registry of SOTR hospitalized for COVID-19, we compared 28-day mortality between early 2020 (March 1, 2020-June 19, 2020) and late 2020 (June 20, 2020-December 31, 2020). Multivariable logistic regression was used to assess comorbidity-adjusted mortality. Time period of diagnosis was available for 1435/1616 (88.8%) SOTR and 971/1435 (67.7%) were hospitalized: 571/753 (75.8%) in early 2020 and 402/682 (58.9%) in late 2020 (p < .001). Crude 28-day mortality decreased between the early and late periods (112/571 [19.6%] vs. 55/402 [13.7%]) and remained lower in the late period even after adjusting for baseline comorbidities (aOR 0.67, 95% CI 0.46-0.98, p = .016). Between the early and late periods, the use of corticosteroids (≥6 mg dexamethasone/day) and remdesivir increased (62/571 [10.9%] vs. 243/402 [61.5%], p < .001 and 50/571 [8.8%] vs. 213/402 [52.2%], p < .001, respectively), and the use of hydroxychloroquine and IL-6/IL-6 receptor inhibitor decreased (329/571 [60.0%] vs. 4/492 [1.0%], p < .001 and 73/571 [12.8%] vs. 5/402 [1.2%], p < .001, respectively). Mortality among SOTR hospitalized for COVID-19 declined between early and late 2020, consistent with trends reported in the general population. The mechanism(s) underlying improved survival require further study.