Solid-organ Recipients Research Articles

Therapeutic Drug Monitoring of Ganciclovir in Cytomegalovirus-Infected Patients With Solid Organ Transplants and Its Correlation to Efficacy and Toxicity.

Cytomegalovirus causes morbidity and mortality, especially in immunocompromised patients, and is treated with (val)ganciclovir. Therapeutic drug monitoring of ganciclovir is often performed; however, clinically established target trough levels corresponding to efficacy are lacking. In 2021, our clinic increased the target trough level for ganciclovir from 1 to 2 mg/L to 2-4 mg/L. This study aims to compare both target trough levels in efficacy, toxicity, and occurrence of resistance. A retrospective cohort study was performed in adult solid organ recipients treated for cytomegalovirus infection with (val)ganciclovir. Clinical efficacy was defined as the absence of treatment failure, defined as > 1 log 10 increase in viral load within 2 weeks of treatment initiation, therapy switch to foscarnet, and/or request for resistance analysis. A total of 46 patients were involved in the study, with 200 ganciclovir trough levels obtained. The composite endpoint was recorded in 23 (69.7%) and 10 (76.9%) patients in the 1-2 mg/L and the 2-4 mg/L group, respectively ( P = 0.18). No association was found between ganciclovir trough levels and the composite endpoint ( P = 1.0). However, a correlation was found between ganciclovir trough levels and the occurrence of lymphopenia ( P = 0.02). Our study could not establish a difference in clinical efficacy or toxicity between target trough levels of 1-2 mg/L or 2-4 mg/L because of the lack of clinical differences between the compared groups. However, a correlation was found between ganciclovir trough levels and lymphopenia, which warrants further investigation.

Remdesivir in Solid Organ Recipients for COVID-19 Pneumonia

Solid organ transplant (SOT) recipients represent a vulnerable patient population and are of high risk for airborne viral infections, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV2). Treatment of COVID-19 is still challenging, as no proven therapeutic regimen is available for immunocompromised patients. Our aim was to evaluate the efficacy and safety of remdesivir (RDV) therapy in infected hospitalized SOT patients. All transplanted recipients (N=25; lung: 19; kidney: 3, liver: 2, heart: 1) who needed hospital care were reviewed in the time period between September 2020 and May 2021 out of the 945 patients treated at the Department. Case control matched patients receiving RDV (all in need of supplementary oxygen) and standard of care (SOC) were included as controls. Among the 25 SOT patients (female:male=11:14; average age=53.2 ± 12.7 years), 15 received RDV medication (RDV-TX), and in 10 cases SOC treatment was used (SOC-TX). Significantly worse clinical score was noted in RDV patients compared with RDV-TX; however, transfer to a higher intensity care unit as well as 60-day survival of RDV-TX patients were significantly worse. All SOT fatalities within 60 days of follow-up were lung transplant recipients (6 out of 19 lung transplant patients). No adverse events were noted related to RDV therapy. In SOT patients, especially lung transplant recipients, with severe COVID-19 needing supplementary oxygen, RDV treatment was safe; however, outcome was significantly worse as compared with nontransplanted individuals with initially worse clinical parameters.

Risks and ways of preventing kidney dysfunction in drug-induced immunosuppression in solid organ recipients

Immunosuppressive therapy (IMT) is the cornerstone of treatment after transplantation. The goal of immunosuppression is to prevent acute and chronic rejection while maximizing patient survival and long-term graft function. However, the expected effects of IMT must be balanced against the major adverse effects of these drugs and their toxicity. The purpose of this review is to summarize world experience on current immunosuppressive strategies and to assess their effects on renal function.

Case Report: Renal relapse after heart transplantation, induction, and autologous stem cell transplantation in a patient with AL amyloidosis with exclusive cardiac involvement

There is no recommendation on what salvage therapy is optimal in the solid organ recipient with AL amyloidosis, such as a heart transplant. With this case, we illustrate how treatment with daratumumab may be effective and safe in a patient with AL amyloidosis with renal involvement at the relapse after heart transplantation and autologous stem cell transplantation.

Machine learning, antimicrobial stewardship, and solid organ transplantation: Is this the future?

The use of machine learning (ML) in infectious diseases is expanding. This review aims to provide an overview of the literature on ML for clinical decision support in antimicrobial stewardship in the particular context of solid organ transplantation (SOT). References for this review were identified through searches of MEDLINE/PubMed and Google Scholar databases up to July 2022. ML may improve the prediction of infectious complications and the diagnosis and treatment of infectious diseases in SOT recipients. One of the most studied applications for antimicrobial stewardship is the individual prediction of antimicrobial resistance that could guide the empiric use of anti-infective treatments. ML may also guide the choice of antimicrobial dose taking into account the interactions with immunosuppressive drugs. The main challenge to the development of ML clinical decision support systems (CDSSs) in SOT is the development of large clinical databases, accessible to all, with good quality, comprehensive, and diversified data. ML-driven CDSSs are still at an experimental stage, and the education of clinicians about the benefits and limits of ML is essential. ML could improve antimicrobial stewardship for SOT, but literature on that specific topic is scarce. Future studies are needed to design ML-CDSS in the particular population of solid organ recipients and report clinical outcomes following use in routine practice.

420.1: Successful Transplantation From Selected SARS-CoV-2 RNA Positive Deceased Donors

Introduction: In the UK, the SARS-CoV-2 status of deceased donors is assessed by specific questionnaire and by universal Nucleic Acid Test (NAT) for SARS-CoV-2 RNA in nose and throat swabS (NTS) and endotracheal aspirateS (ETA). Initially, only asymptomatic and NAT-negative donors were accepted. Improved understanding of the relationship of SARS-CoV-2 replication to viral RNA detection as well as a more detailed testing approach have enabled consideration of NAT-positive donors. Methods: Donor information and detailed SARS-CoV-2 RNA screening results were collected in real-time. SARS-CoV-2 NAT positivity triggered repeat sampling for the clarification of significance. Laboratory-proven diagnosis of SARS-CoV-2 infection in deceased donors or recipients of solid organs in England were captured by data linkage between the organ transplant registry and the National laboratory reporting system. Recipient infection within 14 days from organ transplantation was reviewed for the possibility of donor-transmitted infection. Results: Between 1st March 2020 and 9th February 2022, 3537 potential donors were assessed in the UK. Thirty-seven tested NAT positive during donor assessment, with 17 not proceeding to donation due to the result (15) or due to other reasons (2). Of the remaining 20, the majority had a result profile indicating previous resolved infection, with detection of residual viral RNA; in the absence of evidence of previous infection some of the very weakly reactive NAT results might have been due to false positivity. Two donors had results compatible with current but resolving asymptomatic infection. Organs from these 20 donors were offered for transplantation, resulting in 57 organ transplants into 53 recipients (3 heart, 14 liver, 3 pancreas, 31 kidney). Six lungs were transplanted from donors with NAT negative ETA and whose positive NTS results were at the limit of assay detection and not repeatable upon re-sampling. No donor-transmission of virus has been identified, with good transplant outcomes achieved. Conclusion: SARS-CoV-2 RNA positivity should be verified and interpreted in conjunction with clinical, epidemiological and virological information. In an asymptomatic individual, other than a current infection, positivity could also be due to previous, resolved infection with detection of residual viral RNA; current, resolving infection; or a false-positive result. This enables consideration of organs that would otherwise be deemed unsafe for transplantation. Our preliminary results suggest that organs other than lungs can be safely transplanted, without SARS-CoV-2 transmission, from selected NAT-positive deceased donors in whom SARS-CoV-2 infection is considered either historical or non-evolving.

P16.11: Decreased Immunogenicity After SARS-CoV-2 Vaccination in Liver and Kidney Transplant Recipients

Background: Recently published studies have found an impaired immune response after SARS-CoV-2 vaccination in solid organ recipients. However, most of these studies have not assessed immune cellular responses in solid organ transplant recipients. And no studies have yet demonstrated the efficacy of a booster (third) dose of SARS-CoV-2 vaccination in these patients. In this study, a prospective double-arm cohort study was performed to evaluate the humoral and the cellular immune response to SARS-CoV-2 vaccination in solid organ transplant recipients compared to healthy staff members with the normal function of the immune system. Methods: A total of 64 transplant patients and an age-matched control group of 103 healthy staff members were included. Blood samples were obtained and analyzed after the second dose and the boosting (third) dose, respectively. For evaluation of the virus-neutralization capacity of each group, serum was analyzed using a surrogate SARS-CoV-2 neutralization test to quantify the functional inhibitory capacity of neutralizing antibodies (Genscript) against SARS-CoV-2 spike protein. Inhibition scores of under 30% was considered negative. Results: Except the vaccination subgroup of the initial two dosages of AstraZeneca followed by Pfizer was significantly higher in the healthy control group, another prime-booster combination subgroup proportions were similar between the group. After the standard two doses of vaccination, only 28.3% of the transplant recipients demonstrated positive functional inhibition of neutralizing antibodies, significantly lower than 70.9% of the healthy control group (p <0.001). Even after the booster (third) dose of vaccination, 43.2% of the transplant recipients showed positive functional inhibition of neutralizing antibodies, significantly lower than 100% of the healthy control group (p <0.001). No other immune-associated complications such as acute rejection has occurred after SARS-CoV-2 vaccination in the transplant recipient group. Conclusion: Our data strongly suggest revised vaccination approaches in immunocompromised patients, including individual immune monitoring for the protection of this vulnerable group at risk of developing severe COVID-19. It urges for a review of future vaccine strategies in these patients.

210.12: Booster Shots and Additional Doses for COVID-19 in Solid Organ Recipients

Introduction: Vaccination against SARS-CoV-2 reduces COVID-19 mortality and complications in solid organ transplant recipients. We evaluated the associated antibody responses and breakthrough infections following vaccination with inactivated SARS-CoV-2 vaccine (CoronaVac, Sinovac) or BNT162b2 mRNA vaccine (Comirnaty, Pfizer-BioNTech) in this high-risk population. Method: This prospective observational study (April 2021-Febbruary 2022) included 10 liver and 38 kidney transplant recipients who received 2 vaccine doses (Sinovac, n = 31; or BioNTech, n = 17) as primary series all of whom provided blood samples (4-6 weeks after second dose) for quantitative antibody tests (Abbott Quant assay forimmunoglobulin G antibodies against SARS-CoV-2 spike protein). Following the end of the primary series, all patients were monitored for the development of infection for 9 months. The booster doses given to the patients throughout the follow-up were also documented. Type I error was α =.05 in all statistical analyses (SPSS, version 25). Results: We analyzed demographic data, antibody responses after 2 doses of SARSCoV-2 vaccine as primary series, booster doses and development of breakthrough infection. Median age was 36.5 and 35 (73%) of them were male. Five patients developed COVID-19 in the first six months after the primary series were completed, four of them had received two doses of Sinovac and one had received two doses of BioNTech. Only one patient has needed hospitalization vaccinated with two doses of Sinovac and her antibody level was 0 AU/mL. The median antibody level in patients who developed COVID-19 was 41,9 AU/mL, while it was 312,0 AU/mL in those who did not. However the difference was not statistically significant (p=0,092). Between the 6th and 9th months, 11 participants tested positive for SARS CoV-2 PCR, with all isolates being Omicron variant. While the rate of positivity was 17% in patients who had at least two booster doses of mRNA vaccine after two consecutive doses of primary series, it was 27% in patients who received just one dose or no booster. Conclusion: Solid-organ transplant recipients demonstrated inadequate vaccine responses. In addition, with the decrease in the immune response developed with the vaccine over time, it is seen that the newly emerged variants significantly increase the need for additional doses. In solid organ transplant patients, the CDC recommends a primary series of three doses at one-month intervals with a booster dose three months later. Despite the small amount of data, the findings of our study support this requirement.

216.14: Validating a Cut-off of IgG Hypogammaglobulinemia as a Risk Factor of Severe Infection in Solid Organ Transplantation

Backgound and aims: Severe infection is a leading cause of morbidity and mortality in solid organ transplantation. IgG hypogammaglobulinemia has been previously investigated in single and multicenter studies in distinct solid organ transplantations as a predictor of infection. We aimed to validate the IgG cut-off of 600 mg/dl as a risk factor of severe infection in solid organ transplantation. The potential utility of this biomarker is that this can be modulated by therapeutic intervention. Materials and Methods: 538 heart, liver or kidney recipients were analysed in a prospective study performed in 2 centers. During a follow-up during the first 6 months after solid organ transplantation 298 (55.4%) patients developed at least one episode of severe infection the majority of which were bacterial infections. As a secondary outcome we retrospectively analysed the impact of IgG hypogammaglobulinemia early after transplantation on the rate of death. Survival analysis was performed by Kaplan-Meier. Risk for development of severe infection was also performed by logistic regression analysis. Results: The rate of decrease of IgG after transplantation was similar in both participating centers. Cumulative survival without severe infection during the first 6 months after transplantation was lower in solid organ transplantation recipients with IgG hypogammaglobulinemia defined as IgG < 600 mg/dl at days 7 or 30 after transplantation (Log Rank 5.22, p=0.022). IgG hypogammaglobulinemia was associated with higher rates of death after solid organ transplantation (Log Rank 5.75, p=0.017). In logistic regression analysis IgG hypogammaglobulinemia was significantly associated with risk of severe infection (OR 1.635, p=0.040, 95%CI 1.022-2.615). IgG hypogammaglobulinemia was a risk factor of death (OR 1.078, p= 0.011, 95%CI 1.180 – 3.668). We performed an immunological score for development of severe infection composed of pre transplant monocytes < 7% (2 points), IgG hypogammaglobulinemia (2 points), CD4 <400 cells/uL at day 30 (2 points), C3 < 60 mg/dl at day 30 (2 points) and CRP > 3 mg/dl at day 30 (2 points). In those patients with 4 or more points, OR for development of infection was 2.89 (95% CI 1.641 – 5.123; p<0.001). Conclusion: IgG hypogammaglobulinemia (defined as IgG < 600 mg/dL early after transplantation) is associated with risk of severe infection in solid organ transplantation. This cut-off should be taken into account in future clinical trials that evaluate the impact of the modification of this risk factor by adding intravenous immunoglobulin to these patients to prevent severe infection. An immunological score combining IgG hypogammaglobulinemia and other innate and acquired immunity parameters could be a better way to identify the risk for development of severe infection in solid organ recipients.

Notifiable Infectious Diseases Among Organ Transplant Recipients: A Data-Linked Cohort Study, 2000-2015.

BackgroundInfections, including common communicable infections such as influenza, frequently cause disease after organ transplantation, although the quantitative extent of infection and disease remains uncertain.MethodsA cohort study was conducted to define the burden of notifiable infectious diseases among all solid organ recipients transplanted in New South Wales, Australia, 2000–2015. Data linkage was used to connect transplant registers to hospital admissions, notifiable diseases, and the death register. Standardized incidence ratios (SIRs) were calculated relative to general population notification rates, accounting for age, sex, and calendar year. Infection-related hospitalizations and deaths were identified.ResultsAmong 4858 solid organ recipients followed for 39 183 person-years (PY), there were 792 notifications. Influenza was the most common infection (532 cases; incidence, 1358 [95% CI, 1247–1478] per 100 000 PY), highest within 3 months posttransplant. Next most common was salmonellosis (46 cases; incidence, 117 [95% CI, 87–156] per 100 000 PY), then pertussis (38 cases; incidence, 97 [95% CI, 71–133] per 100 000 PY). Influenza and invasive pneumococcal disease (IPD) showed significant excess cases compared with the general population (influenza SIR, 8.5 [95% CI, 7.8–9.2]; IPD SIR, 9.8 [95% CI, 6.9–13.9]), with high hospitalization rates (47% influenza cases, 68% IPD cases) and some mortality (4 influenza and 1 IPD deaths). By 10 years posttransplant, cumulative incidence of any vaccine-preventable disease was 12%, generally similar by transplanted organ, except higher among lung recipients. Gastrointestinal diseases, tuberculosis, and legionellosis had excess cases among transplant recipients, although there were few sexually transmitted infections and vector-borne diseases.ConclusionsThere is potential to avoid preventable infections among transplant recipients with improved vaccination programs, health education, and pretransplant donor and recipient screening.

New Perspectives on Antimicrobial Agents: Maribavir.

Maribavir was approved by the U.S. Food and Drug Administration in November 2021 for the treatment of adult and pediatric patients with post-transplant cytomegalovirus (CMV) infection/disease that is refractory to treatment (with or without genotypic resistance) with ganciclovir, valganciclovir, cidofovir, or foscarnet. Maribavir is an oral benzimidazole riboside with potent and selective multimodal anti-CMV activity. It utilizes a novel mechanism of action which confers activity against CMV strains that are resistant to traditional anti-CMV agents, and also offers a more favorable safety profile relative to the dose-limiting side effects of previously available therapies. Maribavir was initially studied as an agent for CMV prophylaxis in solid organ and hematopoietic stem cell recipients, but initial phase III trials failed to meet clinical efficacy endpoints. It has been more recently studied as a therapeutic agent at higher doses for refractory-resistant (R-R) CMV infections with favorable outcomes. After an overview of maribavir's chemistry and clinical pharmacology, this review will summarize clinical efficacy, safety, tolerability, and resistance data associated with maribavir therapy.

CMV Infection Following mRNA SARS-CoV-2 Vaccination in Solid Organ Transplant Recipients.

CMV Infection Following mRNA SARS-CoV-2 Vaccination in Solid Organ Transplant Recipients.

Pulmonary toxicity of mTOR inhibitors. Comparisons of two populations: Solid organ recipients and cancer patients

Mammalian target of rapamycin (mTOR) inhibitors-associated pneumonitis (mTOR-IP) has long been described in solid organ recipients (T) patients but more recently in cancer (K) patients. Its overall characteristics have never been compared between these 2 populations. The aim of this study was to compare them in terms of presentation, severity and outcome in T and in K patients. We carried out a retrospective study in a single French tertiary center. Four databases were used to ensure the exhaustive collection of all mTOR-IP cases between 2001 and 2020. All clinical, biological, radiological, pathological and outcome data were reviewed. Thirty-nine patients with mTOR-IP were diagnosed during this period, 24T and 15K patients. The average dosage of everolimus and sirolimus was 2,65mg (±1,78) and 2,75mg (±0,96) in T patients, respectively, versus 8,75mg (±2,26) for everolimus in K patients. The overall prevalence of mTOR-IP was 6.4% with a median time of occurrence of 7 months [IQR 3-35 months]. mTOR-IP were significantly more frequent (P<0.001) and occurred earlier (P<0.001) in cancer patients. No clinical, functional, radiological, pathological nor outcome differences were otherwise observed between the 2 groups. Average everolimus blood levels at the time of mTOR-IP diagnosis were in the range of recommended therapeutic values. Our study shows that mTOR-IP is comparable in terms of presentation in T and in K patients but that it occurs significantly earlier after drug introduction in the latter. This raises questions as to the potential role of the higher doses used in K patients as well as that of co-treatments in the pathogeny of the disease.

Pediatric EBV-negative monomorphic post–solid organ transplant lymphoproliferative disorders [EBV(-)M-PTLD]: Characteristics, treatment, and outcome from 11 pediatric academic centers.

10012 Background: Pediatric EBV(-)M-PTLD comprises &lt; 15% of M-PTLD. Two-year-overall survival of pediatric EBV(+) PTLD is 83%. No large multi-institution pediatric-specific reports are available for EBV(-)M-PTLD. Methods: Retrospective study of characteristics, treatment, and outcome of pediatric solid organ recipients diagnosed with EBV(-)M-PTLD at age ≤21 years (y) in 11 pediatric transplant centers in US and UK. Results: Thirty-three patients transplanted with solid organs between 1991-2017 developed EBV(-)M-PTLD. Twenty-two (66%) were male. Median age (range) at organ transplantation was 2.6y(0.1-17), diagnosis of EBV(-)M-PTLD 14y(3-20), interval from transplant to PTLD 8.3y (2.3-18). Transplanted organs were heart (n = 10), kidney (n = 17), liver (n = 4), small bowel (n = 1), liver and small bowel (n = 1). Immunosuppressive therapy at the time of diagnosis of PTLD was available on 31 patients. All were receiving a calcineurin inhibitor except one who was on sirolimus alone. Tacrolimus was given in 27 patients, alone (n = 3), or in various combination with mycophenolate (n = 8), azathioprine (n = 9), prednisone (n = 8), or everolimus (n = 1). Four of these receiving tacrolimus received 3 immunosuppressive drug combinations. Cyclosporine was given in 3 patients, with mycophenolate (n = 1), prednisone (n = 1), or both (n = 2). Murphy stages were I (n = 1), II (n = 7), III (n = 22), and IV (n = 3). Lactate dehydrogenase was elevated in 19/31 (61%) and &gt; 2X upper limit of normal in 10/31 (32%) tested. Pathological diagnoses were diffuse large B-cell lymphoma (n = 30) and B-NHL NOS (n = 3). Treatment included: rituximab alone (n = 1), low-dose cyclophosphamide, prednisone, and rituximab (CPR; n = 9), pediatric mature B-NHL-specific regimen [FAB/LMB with (n = 12) or without (n = 1) rituximab], EPOCH-R (n = 2), R-CHOP (n = 3), modified R-CHOP (n = 2), COP (n = 1), and R-COP (n = 2). At a median 2.9y (0.3-11y) from diagnosis, 26/33 (79%) were alive and in complete remission (CR). Three experienced relapses at 1, 3, and 6.5y after CPR, rituximab alone, and B-NHL therapy, respectively. All achieved a sustained second CR with additional B-NHL therapy. Of the 7 deaths: 6 were from progressive disease despite escalation to intensive B-NHL therapy following initial COP (n = 1), R-COP (n = 1), CPR (n = 2), and B-NHL therapy (n = 2), and one cardiac transplant recipient from presumed cardiotoxicity. There was one graft rejection that was successfully treated. Conclusions: This collaboration represents the first multi-institution series of pediatric EBV(-)M-PTLD. Overall survival was comparable to that reported for pediatric EBV(+) PTLD, but inferior to DLBCL in immunocompetent children. These preliminary data reflect a wide range of therapeutic regimens used over 20 years and strongly support an organized collaborative effort to collect data prospectively.

An explanatory analytics model for identifying factors indicative of long- versus short-term survival after lung transplantation

Due to the shortage of available organs compared to the number of patients on waitlists, the organ allocation process has always been challenging and calls for an equitable and optimized allocation system. This system demands minimizing the waitlist mortality and improving transplantation benefits (e.g., survival time and quality of life). According to prior research, lung recipients’ long-term survival time is lower than other solid organs recipients. This paper proposes and implements an explanatory analytics framework to study the most prominent factors contributing to long-term survival after lung transplantation. We collect data from the United Network for Organ Sharing registry database. It contains more than 44 thousand unique patients undergoing lung transplantation in the US since 1987. In our proposed framework, we first employ several machine learning (ML) algorithms for classification and choose the best-performing one for further analysis of factors. Then, we utilize a state-of-the-art explainable artificial intelligence method with the chosen ML algorithm for the model explanation and interpretation. The proposed framework lists the most critical factors influencing long-term survival after lung transplantation and their corresponding importance measures. For instance, our results suggest that Hepatitis B surface antibody (HBV_SURF) and forced expiratory volume in one second (FEV1) are among the important factors but have not been well examined by lung transplant researchers. Our framework is also able to provide the main contributing factors for each patient individually. Medical scholars and practitioners can use our findings for further analysis and improvement of the lung allocation system.

Approaches to vaccination against the new coronavirus infection in solid organ recipients

Solid organ recipients represent a high risk group for all adverse outcomes associated with SARS-CoV-2 infection due to the immunosuppressive treatment and the presence of comorbidities such as cardiovascular disease, diabetes mellitus, and arterial hypertension.The aim of the study was to assess the ability of solid organ recipients to form immune response after vaccination against a new coronavirus infection and safety of the vaccines in this population.Conclusion. An analysis of the literature and the results obtained in Russia show that vaccines against SARS-CoV-2 do not cause unusual clinical events in recipients of solid organs. Levels of post-vaccination antibodies in these patients, especially in the elderly patients shortly after transplantation who take antimetabolites, are lower than in the general population. This group of patients needs alternative immunization schemes against the new coronavirus infection, which may include more than two booster doses or a combination of different types of vaccines, as well as doubling the vaccine dose.

Predictors of impaired SARS-CoV-2 immunity in healthcare workers after vaccination with BNT162b2

Healthcare workers are at substantially increased risk for infection with SARS-CoV-2. Successful vaccination constitutes a crucial prerequisite to protect this group during the pandemic. Since post vaccination antibody monitoring is not standard of care in all healthcare institutions, data on risk factors of impaired vaccine induced immune response are urgently required. Moreover, there are no data on cellular immune responses in humoral low responders so far. Anti-SARS-CoV-2 spike IgG was assessed after vaccination with BNT162b2 in 1386 employees of three hospitals of a German healthcare provider. Concentrations were compared to those of 45 convalescent employees. Vaccine-induced cellular immunity was measured in employees with reduced humoral response by assessment of frequencies of SARS-CoV-2-reactive CD4+ and CD8+ T cell. Anti-SARS-CoV-2 spike IgG were detected in 99.9% of 1386 healthcare workers after completed vaccination. The median antibody concentration was significantly higher after vaccination than after infection with SARS-CoV-2 (p = 0.0001). 10 subjects (0.7%) generated an IgG concentration < 100 IU/ml, and only two persons (0.1%, solid organ recipients) did not produce detectable antibodies at all. T cell responses of those subjects with submaximal or lacking humoral response were comparable to employees with maximal antibody titers. 50% of those individuals with impaired or lacking humoral immune response were on immunosuppression. Vaccination to SARS-CoV-2 with BNT162b2 is very effective in healthcare workers yielding a seroconversion rate of 99.9%. Immunosuppression is the most important risk factor of an impaired immune response. There was no case of vaccination failure without immunosuppression. Thus, post vaccination antibody monitoring is highly recommendable in those employees with immunosuppression.

Posttransplantation Diabetes Mellitus Among Solid Organ Recipients in a Danish Cohort.

Post-transplant diabetes mellitus (PTDM) is associated with a higher risk of adverse outcomes. We aimed to describe the proportion of patients with diabetes prior to solid organ transplantation (SOT) and post-transplant diabetes mellitus (PTDM) in three time periods (early-likely PTDM: 0–45 days; 46–365 days and >365 days) post-transplant and to estimate possible risk factors associated with PTDM in each time-period. Additionally, we compared the risk of death and causes of death in patients with diabetes prior to transplant, PTDM, and non-diabetes patients. A total of 959 SOT recipients (heart, lung, liver, and kidney) transplanted at University Hospital of Copenhagen between 2010 and 2015 were included. The highest PTDM incidence was observed at 46–365 days after transplant in all SOT recipients. Age and the Charlson Comorbidity Index (CCI Score) in all time periods were the two most important risk factors for PTDM. Compared to non-diabetes patients, SOT recipients with pre-transplant diabetes and PTDM patients had a higher risk of all-cause mortality death (aHR: 1.77, 95% CI: 1.16–2.69 and aHR: 1.89, 95% CI: 1.17–3.06 respectively). Pre-transplant diabetes and PTDM patients had a higher risk of death due to cardiovascular diseases and cancer, respectively, when compared to non-diabetes patients.

Secondary Pulmonary Alveolar Proteinosis Due to Sirolimus

Introduction Pulmonary alveolar proteinosis (PAP) is a rare, progressive lung disease characterized by the accumulation of lipoproteinaceous material in alveoli due to impaired clearance by alveolar macrophages. Although most cases are due to the disruption of granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling, secondary PAP from immunodeficiency is described in solid organ recipients. We present a treatment conundrum in a heart transplant (OHT) patient with a history of graft rejection who develops secondary PAP while on sirolimus. Case Report A 63-year-old male 6 years post re-do OHT, initially transplanted for ischemic cardiomyopathy then re-do for antibody mediated rejection presented with new hypoxia requiring 2L O2. His immunosuppression regimen included myfortic, prednisone, sirolimus, and tacrolimus. A CT scan demonstrated central and basilar ground glass opacities with “crazy paving”. He underwent a bronchoscopy with bronchoalveolar lavage (BAL) showing 90% macrophages, negative cultures, and cytology with hemosiderin pigment and proteinaceous material. He was empirically placed on levofloxacin and weaned to room air. At 5-month follow-up a repeat CT re-demonstrated similar findings. Repeat BAL, performed for concern for PAP, was Periodic acid-Schiff (PAS) stain positive for proteinaceous material. Serum GM-CSF antibodies were absent and the patient was diagnosed with secondary PAP due to sirolimus. Given the patient's prior history of graft failure, his sirolimus dose was unchanged and he was treated with inhaled sargramostim. Summary PAP is a rare disease caused by disorders in surfactant homeostasis further divided into three distinct etiologies: autoimmune (90%), secondary (5-10%), and congenital (2%). Secondary PAP is due to functional impairment in alveolar macrophages from immunodeficiency and is well-described in kidney and lung transplant recipients. To our knowledge, this is the first case described in a heart transplant recipient. The prognosis of transplant-associated secondary PAP is difficult to establish due to the limited number of published cases, though resolution is typically observed 2-4 months after removal of the offending agent. We present a case treated with GM-CSF due to difficulties reducing immunosuppression. Pulmonary alveolar proteinosis (PAP) is a rare, progressive lung disease characterized by the accumulation of lipoproteinaceous material in alveoli due to impaired clearance by alveolar macrophages. Although most cases are due to the disruption of granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling, secondary PAP from immunodeficiency is described in solid organ recipients. We present a treatment conundrum in a heart transplant (OHT) patient with a history of graft rejection who develops secondary PAP while on sirolimus. A 63-year-old male 6 years post re-do OHT, initially transplanted for ischemic cardiomyopathy then re-do for antibody mediated rejection presented with new hypoxia requiring 2L O2. His immunosuppression regimen included myfortic, prednisone, sirolimus, and tacrolimus. A CT scan demonstrated central and basilar ground glass opacities with “crazy paving”. He underwent a bronchoscopy with bronchoalveolar lavage (BAL) showing 90% macrophages, negative cultures, and cytology with hemosiderin pigment and proteinaceous material. He was empirically placed on levofloxacin and weaned to room air. At 5-month follow-up a repeat CT re-demonstrated similar findings. Repeat BAL, performed for concern for PAP, was Periodic acid-Schiff (PAS) stain positive for proteinaceous material. Serum GM-CSF antibodies were absent and the patient was diagnosed with secondary PAP due to sirolimus. Given the patient's prior history of graft failure, his sirolimus dose was unchanged and he was treated with inhaled sargramostim. PAP is a rare disease caused by disorders in surfactant homeostasis further divided into three distinct etiologies: autoimmune (90%), secondary (5-10%), and congenital (2%). Secondary PAP is due to functional impairment in alveolar macrophages from immunodeficiency and is well-described in kidney and lung transplant recipients. To our knowledge, this is the first case described in a heart transplant recipient. The prognosis of transplant-associated secondary PAP is difficult to establish due to the limited number of published cases, though resolution is typically observed 2-4 months after removal of the offending agent. We present a case treated with GM-CSF due to difficulties reducing immunosuppression.

Memory B Cell Deficiency and Disseminated Nocardiosis in a Pediatric Patient with Congenital Single Ventricle Physiology and Heart Transplantation

IntroductionNocardiosis is infrequently described in solid organ transplant recipients. Children born with single ventricle physiology may be at increased risk due to impairments of T- and B-cell immunity from early thymectomy and other factors. We report the case of a patient born with hypoplastic left heart syndrome (HLHS), who underwent palliative surgery followed by 2 heart transplants (HT) and later contracted disseminated and incurable Nocardiosis.Case ReportA 16-year old male with HLHS underwent Norwood and Glenn palliations, followed by HT in 2008 and retransplant in 01/2021 for coronary allograft vasculopathy. Immunosuppression consisted of prednisone, tacrolimus, and mycophenolate mofetil. He presented in 07/2021 with fever and cough, found to have rhinovirus/enterovirus and multicentric pulmonary nodules on chest CT. Despite treatment for presumed bacterial pneumonia, he re-presented with persistent cough, headache, dizziness, and a seizure-like episode. Brain MRI demonstrated multifocal intracranial abscesses with ventriculitis. Chest CT showed persistent multifocal nodules. He developed hydrocephalus requiring bilateral external ventricular drains. Nocardia farcinica was detected in bronchial and cerebrospinal fluid. Immune cell profiling conducted prior to his acute illness demonstrated decreased CD31+ recent thymic emigrants and near absence of CD27+ memory B cells. Despite 6 weeks of antibiotics and IVIG, his symptoms and brain MRI findings worsened, and he ultimately passed away.SummaryDisseminated Nocardia is rare, even in solid organ recipients. In this case, T-cell immunodeficiency from neonatal thymectomy and a lack of memory B cell response likely contributed to illness severity. Immune system profiling should be considered in HT patients, especially in those with a history of infant heart surgery. The use of proper prophylaxis may prevent severe opportunistic infections. Nocardiosis is infrequently described in solid organ transplant recipients. Children born with single ventricle physiology may be at increased risk due to impairments of T- and B-cell immunity from early thymectomy and other factors. We report the case of a patient born with hypoplastic left heart syndrome (HLHS), who underwent palliative surgery followed by 2 heart transplants (HT) and later contracted disseminated and incurable Nocardiosis. A 16-year old male with HLHS underwent Norwood and Glenn palliations, followed by HT in 2008 and retransplant in 01/2021 for coronary allograft vasculopathy. Immunosuppression consisted of prednisone, tacrolimus, and mycophenolate mofetil. He presented in 07/2021 with fever and cough, found to have rhinovirus/enterovirus and multicentric pulmonary nodules on chest CT. Despite treatment for presumed bacterial pneumonia, he re-presented with persistent cough, headache, dizziness, and a seizure-like episode. Brain MRI demonstrated multifocal intracranial abscesses with ventriculitis. Chest CT showed persistent multifocal nodules. He developed hydrocephalus requiring bilateral external ventricular drains. Nocardia farcinica was detected in bronchial and cerebrospinal fluid. Immune cell profiling conducted prior to his acute illness demonstrated decreased CD31+ recent thymic emigrants and near absence of CD27+ memory B cells. Despite 6 weeks of antibiotics and IVIG, his symptoms and brain MRI findings worsened, and he ultimately passed away. Disseminated Nocardia is rare, even in solid organ recipients. In this case, T-cell immunodeficiency from neonatal thymectomy and a lack of memory B cell response likely contributed to illness severity. Immune system profiling should be considered in HT patients, especially in those with a history of infant heart surgery. The use of proper prophylaxis may prevent severe opportunistic infections.