First uterine transplant case at the Royal Prince Alfred Hospital.

Uterine transplantation (UT) is an emerging medical treatment for women affected by absolute uterine factor infertility (AUFI). To date there have been over 90 documented cases of UT performed worldwide, with over 50 live births. UT allows women affected by AUFI the opportunity to carry and deliver a childd. The Royal Prince Alfred Hospital (RPAH) introduced a UT study in 2019; however, due to the impacts of the COVID pandemic the study was placed on hold for two years. In February 2023, RPAH performed the centre's first UT from a living unrelated donor to a 25-year-old woman with Mayer-Rokitansky-Küster-Hauser syndrome. The donor and recipient surgeries were uncomplicated and both are recovering well in the early post-operative period.

Influenza Virus Infection and Transplantation.

Influenza infection poses significant risk for solid organ transplant recipients who often experience more severe infection with increased rates of complications, including those relating to the allograft. Although symptoms of influenza experienced by transplant recipients are similar to that of the general population, fever is not a ubiquitous symptom and lymphopenia is common. Annual inactivated influenza vaccine is recommended for all transplant recipients. Newer strategies such as using a higher dose vaccine or multiple doses in the same season appear to provide greater immunogenicity. Neuraminidase inhibitors are the mainstay of treatment and chemoprophylaxis although resistance may occur in the transplant setting. Influenza therapeutics are advancing, including the recent licensure of baloxavir; however, many remain to be evaluated in transplant recipients and are not yet in routine clinical use. Further population-based studies spanning multiple influenza seasons are needed to enhance our understanding of influenza epidemiology in solid organ transplant recipients. Specific assessment of newer influenza therapeutics in transplant recipients and refinement of prevention strategies are vital to reducing morbidity and mortality.

Gravité de la COVID-19 chez les receveurs d'une transplantation d'organe plein au Canada, 2020­2021 : étude de cohorte prospective multicentrique.

CONTEXTE: La forme grave de COVID-19 semble affecter de manière disproportionnée les gens immunovulnérables, même si les données canadiennes dans ce contexte sont limitées. Nous avons voulu déterminer quels facteurs sont associés aux paramètres de la forme grave de COVID-19 chez les receveurs de transplantations au Canada. MÉTHODES: Nous avons procédé à une étude de cohorte multicentrique prospective regroupant tous les receveurs d'une transplantation d'organe plein ayant reçu un diagnostic de COVID-19 suivis dans 9 programmes de transplantation au Canada entre mars 2020 et novembre 2021. Les données ont été analysées afin de dégager les facteurs de risque à l'égard du recours à l'oxygénothérapie et autres critères de la gravité de la maladie. Nous avons comparé les paramètres selon le type d'organe transplanté et suivi l'évolution des paramètres au fil du temps. Nous avons procédé à une analyse multivariée pour déterminer quelles variables sont associées au recours à l'oxygénothérapie. RÉSULTATS: En tout, 509 patients ayant reçu une transplantation d'organe plein ont contracté la COVID-19 durant la période de l'étude. Les facteurs de risque associés au recours à l'oxygénothérapie (n = 190) ou non (n = 319) incluaient l'âge (âge médian 62,6 ans, intervalle interquartile [II] 52,5­69,5 ans c. âge médian 55,5 ans, II 47,5­66,5; p < 0,001) et le nombre de comorbidités (nombre médian 3, II 2­3 c. nombre médian 2, II 1­3; p < 0,001), de même que les paramètres concernant l'immunosuppression. Les receveurs d'une transplantation pulmonaire (n = 48) étaient plus susceptibles de souffrir d'une forme grave de la maladie, avec un taux de mortalité élevé (n = 15, 31,3 %) comparativement aux receveurs d'autres organes, y compris le rein (n = 48, 14,8 %), le cœur (n = 1, 4,4 %), le foie (n = 9, 11,4 %) et le rein­pancréas (n = 3, 12,0 %) (p = 0,02). Les facteurs protecteurs contre le recours à l'oxygénothérapie incluaient le fait d'avoir subi une transplantation hépatique et de recevoir de l'azathioprine. Le fait d'avoir reçu 2 doses de vaccin anti-SRAS-CoV-2 n'a pas eu d'influence appréciable sur le recours à l'oxygénothérapie. L'analyse multivariée a montré que l'âge avancé (rapport des cotes [RC] 1,04, intervalle de confiance [IC] de 95 % 1,02­1,07) et le nombre de comorbidités (RC 1,63, IC de 95 % 1,30­2,04), entre autres facteurs, étaient associés au recours à l'oxygénothérapie. La gravité de la maladie n'a pas considérablement diminué au fil du temps. INTERPRÉTATION : Malgré les progrès thérapeutiques et la vaccination des receveurs d'une transplantation d'organe plein, les signes de gravité accrue de la COVID-19, en particulier chez les receveurs d'une transplantation pulmonaire, justifient le maintien des mesures de santé publique pour protéger ces personnes à risque, et l'utilisation hâtive de traitements contre la COVID-19 chez les receveurs d'une transplantation d'organe plein.

Severity of COVID-19 among solid organ transplant recipients in Canada, 2020-2021: a prospective, multicentre cohort study.

BACKGROUND: Severe COVID-19 appears to disproportionately affect people who are immunocompromised, although Canadian data in this context are limited. We sought to determine factors associated with severe COVID-19 outcomes among recipients of organ transplants across Canada. METHODS: We performed a multicentre, prospective cohort study of all recipients of solid organ transplants from 9 transplant programs in Canada who received a diagnosis of COVID-19 from March 2020 to November 2021. Data were analyzed to determine risk factors for oxygen requirement and other metrics of disease severity. We compared outcomes by organ transplant type and examined changes in outcomes over time. We performed a multivariable analysis to determine variables associated with need for supplemental oxygen. RESULTS: A total of 509 patients with solid organ transplants had confirmed COVID-19 during the study period. Risk factors associated with needing (n = 190), compared with not needing (n = 319), supplemental oxygen included age (median 62.6 yr, interquartile range [IQR] 52.5-69.5 yr v. median 55.5 yr, IQR 47.5-66.5; p < 0.001) and number of comorbidities (median 3, IQR 2-3 v. median 2, IQR 1-3; p < 0.001), as well as parameters associated with immunosuppression. Recipients of lung transplants (n = 48) were more likely to have severe disease with a high mortality rate (n = 15, 31.3%) compared with recipients of other organ transplants, including kidney (n = 48, 14.8%), heart (n = 1, 4.4%), liver (n = 9, 11.4%) and kidney-pancreas (n = 3, 12.0%) transplants (p = 0.02). Protective factors against needing supplemental oxygen included having had a liver transplant and receiving azathioprine. Having had 2 doses of SARS-CoV-2 vaccine did not have an appreciable influence on oxygen requirement. Multivariable analysis showed that older age (odds ratio [OR] 1.04, 95% confidence interval [CI] 1.02-1.07) and number of comorbidities (OR 1.63, 95% CI 1.30-2.04), among other factors, were associated with the need for supplemental oxygen. Over time, disease severity did not decline significantly. INTERPRETATION: Despite therapeutic advances and vaccination of recipients of solid organ transplants, evidence of increased severity of COVID-19, in particular among those with lung transplants, supports ongoing public health measures to protect these at-risk people, and early use of COVID-19 therapies for recipients of solid organ transplants.

The role of real-time, on-site, whole-genome sequencing of severe acute respiratory coronavirus virus 2 (SARS-CoV-2) in guiding the management of hospital outbreaks of coronavirus disease 2019 (COVID-19).

OBJECTIVE: We aimed to demonstrate the role of real-time, on-site, whole-genome sequencing (WGS) of severe acute respiratory coronavirus virus 2 (SARS-CoV-2) in the management of hospital outbreaks of coronavirus disease 2019 (COVID-19). DESIGN: This retrospective study was undertaken at our institutions in Sydney, New South Wales, Australia, between July 2021 and April 2022. We included SARS-CoV-2 outbreaks due to SARS-CoV-2 δ (delta) and ο (omicron) variants. All unexpected SARS-CoV-2-positive cases identified within the hospital were managed by the infection control team. An outbreak was defined as 2 or more cases acquired on a single ward. We included only outbreaks with 2 or more suspected transmission events in which WGS was utilized to assist with outbreak assessment and management. RESULTS: We studied 8 outbreaks involving 266 patients and 486 staff, of whom 73 (27.4%) and 39 (8.0%), respectively, tested positive for SARS-CoV-2 during the outbreak management. WGS was used to evaluate the source of the outbreak, to establish transmission chains, to highlight deficiencies in infection control practices, and to delineate between community and healthcare acquired infection. CONCLUSIONS: Real-time, on-site WGS combined with epidemiologic assessment is a useful tool to guide management of hospital SARS-CoV-2 outbreaks. WGS allowed us (1) to establish likely transmission events due to personal protective equipment (PPE) breaches; (2) to detect inadequacies in infection control infrastructure including ventilation; and (3) to confirm multiple viral introductions during periods of high community SARS-CoV-2 transmission. Insights gained from WGS-guides outbreak management directly influenced policy including modifying PPE requirements, instituting routine inpatient SARS-CoV-2 surveillance, and confirmatory SARS-CoV-2 testing prior to placing patients in a cohort setting.

Homotypic and heterotypic immune responses to Omicron variant in immunocompromised patients in diverse clinical settings.

Immunocompromised patients are predisposed to severe COVID-19. Here we compare homotypic and heterotypic humoral and cellular immune responses to Omicron BA.1 in organ transplant patients across a diverse clinical spectrum. We perform variant-specific pseudovirus neutralization assays for D614G, and Omicron-BA.1, -BA.2, and Delta variants. We also measure poly-and monofunctional T-cell responses to BA.1 and ancestral SARS-CoV-2 peptide pools. We identify that partially or fully-vaccinated transplant recipients after infection with Omicron BA.1 have the greatest BA.1 neutralizing antibody and BA.1-specific polyfunctional CD4+ and CD8+ T-cell responses, with potent cross-neutralization against BA.2. In these patients, the magnitude of the BA.1-directed response is comparable to immunocompetent triple-vaccinated controls. A subset of patients with pre-Omicron infection have heterotypic responses to BA.1 and BA.2, whereas uninfected transplant patients with three doses of vaccine demonstrate the weakest comparative responses. These results have implications for risk of infection, re-infection, and disease severity among immune compromised hosts with Omicron infection.

Successful liver transplantation for hepatitis B-related acute liver failure in a patient with active COVID-19.

The emergence of coronavirus disease 19 (COVID-19) has significantly disrupted liver transplantation worldwide. Despite significant, collective experience in treating liver transplant recipients with COVID-19, there remains a paucity of data to guide the management of transplant candidates with acute COVID-19 who require urgent transplantation. We present the case of an otherwise well, 39-year-old female presenting for urgent liver transplantation for acute liver failure secondary to hepatitis B, with concomitant acute, mild COVID-19 due to Omicron BA.2. COVID-19 antivirals were not administered pre-transplant as the potential risk of hepatotoxicity precipitating further deterioration of liver function was not felt to outweigh the small, potential benefit of antiviral therapy. No effective SARS-CoV-2 monoclonal antibodies were available; however, the patient was previously vaccinated against SARS-CoV-2 with evidence of anti-spike antibodies at the time of COVID-19. Transplantation surgery and recovery were uncomplicated with no progression of COVID-19 post-transplant, hospital discharge was at day 14. At 30 days post-transplant the patient had recovered, with normal liver function and SARS-CoV-2 was not detectable on nasopharyngeal PCR. While the safety of transplantation of patients with acute COVID-19 cannot be assured by a single case, ours highlights the complex decision-making process undertaken and competing priorities that need to be balanced when assessing patients with acute COVID-19 who require urgent transplantation.

Outcomes of SARS-CoV-2 Infection in Unvaccinated Compared With Vaccinated Solid Organ Transplant Recipients: A Propensity Matched Cohort Study.

BACKGROUND: Solid organ transplant (SOT) recipients are at high risk for complications from coronavirus disease 2019 (COVID-19). Vaccination may mitigate this risk; however, immunogenicity appears to be significantly impaired, with reports of increased risk of breakthrough infection. It is unknown if vaccine breakthrough infections are milder or as severe as infections in unvaccinated patients. METHODS: We performed a multicenter matched cohort study between March 2020 and September 2021 to assess influence of COVID-19 vaccination on outcomes of COVID-19 infection. Treatment characteristics and disease severity outcomes were compared on the basis of vaccine status; breakthrough infections versus unvaccinated infections. Variable ratio propensity score matching based on age, sex, transplant type, and number of comorbidities, was used to develop the analytic cohort. Logistic regression was used to assess the influence of vaccination status on the selected outcomes. RESULTS: From a cohort of 511 SOT patients with COVID-19, we matched 77 partially or fully vaccinated patients with 220 unvaccinated patients. Treatment characteristics including use of dexamethasone, remdesivir, and antibiotics did not differ. Vaccinated participants were more likely to receive tocilizumab, 15 of 77 (19.5%) versus 5 of 220 (2.3%), P < 0.001. Disease severity outcomes including oxygen requirement, mechanical ventilation, and mortality were similar among medically attended vaccine breakthroughs compared with unvaccinated patients. CONCLUSIONS: SOT recipients who develop medically attended COVID-19 following 1- or 2-dose vaccination seem to have similar disease severity to unvaccinated patients who develop infection. This is consistent with the requirement that SOT recipients need 3 or more vaccine doses and emphasizes the importance of alternate strategies for this population.

Severe Acute Respiratory Syndrome Coronavirus 2 Infection Induces Greater T-Cell Responses Compared to Vaccination in Solid Organ Transplant Recipients.

T-cell immunity associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or vaccination in solid organ transplant recipients (SOTRs) is poorly understood. To address this, we measured T-cell responses in 50 SOTRs with prior SARS-CoV-2 infection. The majority of patients mounted SARS-CoV-2-specific CD4+ T-cell responses against spike (S), nucleocapsid, and membrane proteins; CD8+ T-cell responses were generated to a lesser extent. CD4+ T-cell responses correlated with antibody levels. Severity of disease and mycophenolate dose were moderately associated with lower proportions of antigen-specific T cells. Relative to nontransplant controls, SOTRs had perturbations in both total and antigen-specific T cells, including higher frequencies of total PD-1+ CD4+ T cells. Vaccinated SOTRs (n = 55) mounted significantly lower proportions of S-specific polyfunctional CD4+ T cells after 2 doses, relative to unvaccinated SOTRs with prior coronavirus disease 2019. Together, these results suggest that SOTRs generate robust T-cell responses following natural infection that correlate with disease severity but generate comparatively lower T-cell responses following mRNA vaccination.

Humoral and cellular immune response and safety of two-dose SARS-CoV-2 mRNA-1273 vaccine in solid organ transplant recipients.

Solid organ transplant recipients are at high risk of severe disease from COVID-19. We assessed the immunogenicity of mRNA-1273 vaccine using a combination of antibody testing, surrogate neutralization assays, and T cell assays. Patients were immunized with two doses of vaccine and immunogenicity assessed after each dose using the above tests. CD4+ and CD8+ T cell responses were assessed in a subset using flow-cytometry. A total of 127 patients were enrolled of which 110 provided serum at all time points. A positive anti-RBD antibody was seen in 5.0% after one dose and 34.5% after two doses. Neutralizing antibody was present in 26.9%. Of note, 28.5% of patients with anti-RBD did not have neutralizing antibody. T cell responses in a sub-cohort of 48 patients showed a positive CD4+ T cell response in 47.9%. Of note, in this sub-cohort, 46.2% of patients with a negative anti-RBD, still had a positive CD4+ T cell response. The vaccine was safe and well-tolerated. In summary, immunogenicity of mRNA-1273 COVID-19 vaccine was modest, but a subset of patients still develop neutralizing antibody and CD4+T- cell responses. Importantly polyfunctional CD4+T cell responses were observed in a significant portion who were antibody negative, further highlighting the importance of vaccination in this patient population. IRB Statement: This study was approved by the University Health Network Research Ethics Board (CAPCR ID 20-6069).

Prospective Clinical, Virologic, and Immunologic Assessment of COVID-19 in Transplant Recipients.

BACKGROUND: Several studies have described the clinical features of COVID-19 in solid-organ transplant recipients. However, many have been retrospective or limited to more severe cases (hospitalized) and have not routinely included serial virological sampling (especially in outpatients) and immunologic assessment. METHODS: Transplant patients diagnosed with COVID-19 based on a respiratory sample PCR were prospectively followed up to 90 d. Patients provided consent for convalescent serum samples and serial nasopharyngeal swabs for SARS-CoV-2 antibody (antinucleoprotein and anti-RBD) and viral load, respectively. RESULTS: In the 161 SOT recipients diagnosed with COVID-19, the spectrum of disease ranged from asymptomatic infection (4.3%) to hospitalization (60.6%), supplemental oxygen requirement (43.1%), mechanical ventilation (22.7%), and death (15.6%). Increasing age (OR, 1.031; 95% CI, 1.001-1.062; P = 0.046) and ≥2 comorbid conditions (OR, 3.690; 95% CI, 1.418-9.615; P = 0.007) were associated with the need for supplemental oxygen. Allograft rejection was uncommon (3.7%) despite immunosuppression modification. Antibody response at ≥14 d postsymptoms onset was present in 90% (anti-RBD) and 76.7% (anti-NP) with waning of anti-NP titers and stability of anti-RBD over time. Median duration of nasopharyngeal positivity was 10.0 d (IQR, 5.5-18.0) and shedding beyond 30 d was observed in 6.7% of patients. The development of antibody did not have an impact on viral shedding. CONCLUSIONS: This study demonstrates the spectrum of COVID-19 illness in transplant patients. Risk factors for severe disease are identified. The majority form antibody by 2 wk with differential stability over time. Prolonged viral shedding was observed in a minority of patients. Reduction of immunosuppression was a safe strategy.