Immunogenicity of High-Dose Versus MF59-Adjuvanted Versus Standard Influenza Vaccine in Solid Organ Transplant Recipients: The Swiss/Spanish Trial in Solid Organ Transplantation on Prevention of Influenza (STOP-FLU Trial).

BACKGROUND: The immunogenicity of the standard influenza vaccine is reduced in solid-organ transplant (SOT) recipients, so new vaccination strategies are needed in this population. METHODS: Adult SOT recipients from 9 transplant clinics in Switzerland and Spain were enrolled if they were >3 months after transplantation. Patients were randomized (1:1:1) to a MF59-adjuvanted or a high-dose vaccine (intervention), or a standard vaccine (control), with stratification by organ and time from transplant. The primary outcome was vaccine response rate, defined as a ≥4-fold increase of hemagglutination-inhibition titers to at least 1 vaccine strain at 28 days postvaccination. Secondary outcomes included polymerase chain reaction-confirmed influenza and vaccine reactogenicity. RESULTS: A total of 619 patients were randomized, 616 received the assigned vaccines, and 598 had serum available for analysis of the primary endpoint (standard, n = 198; MF59-adjuvanted, n = 205; high-dose, n = 195 patients). Vaccine response rates were 42% (84/198) in the standard vaccine group, 60% (122/205) in the MF59-adjuvanted vaccine group, and 66% (129/195) in the high-dose vaccine group (difference in intervention vaccines vs standard vaccine, 0.20; 97.5% confidence interval [CI], .12-1); P < .001; difference in high-dose vs standard vaccine, 0.24 [95% CI, .16-1]; P < .001; difference in MF59-adjuvanted vs standard vaccine, 0.17 [97.5% CI, .08-1]; P < .001). Influenza occurred in 6% of the standard, 5% in the MF59-adjuvanted, and 7% in the high-dose vaccine groups. Vaccine-related adverse events occurred more frequently in the intervention vaccine groups, but most of the events were mild. CONCLUSIONS: In SOT recipients, use of an MF59-adjuvanted or a high-dose influenza vaccine was safe and resulted in a higher vaccine response rate. CLINICAL TRIALS REGISTRATION: Clinicaltrials.gov NCT03699839.

Post-transplant Inflammatory Bowel Disease Associated with Donor-Derived TIM-3 Deficiency.

Inflammatory bowel disease (IBD) occurring following allogeneic stem cell transplantation (aSCT) is a very rare condition. The underlying pathogenesis needs to be better defined. There is currently no systematic effort to exclude loss- or gain-of-function mutations in immune-related genes in stem cell donors. This is despite the fact that more than 100 inborn errors of immunity may cause or contribute to IBD. We have molecularly characterized a patient who developed fulminant inflammatory bowel disease following aSCT with stable 100% donor-derived hematopoiesis. A pathogenic c.A291G; p.I97M HAVCR2 mutation encoding the immune checkpoint protein TIM-3 was identified in the patient's blood-derived DNA, while being absent in DNA derived from the skin. TIM-3 expression was much decreased in the patient's serum, and in vitro-activated patient-derived T cells expressed reduced TIM-3 levels. In contrast, T cell-intrinsic CD25 expression and production of inflammatory cytokines were preserved. TIM-3 expression was barely detectable in the immune cells of the patient's intestinal mucosa, while being detected unambiguously in the inflamed and non-inflamed colon from unrelated individuals. In conclusion, we report the first case of acquired, "transplanted" insufficiency of the regulatory TIM-3 checkpoint linked to post-aSCT IBD.

Organ Dysfunction in Children With Blood Culture-Proven Sepsis: Comparative Performance of Four Scores in a National Cohort Study.

OBJECTIVES: Previous studies applying Sepsis-3 criteria to children were based on retrospective analyses of PICU cohorts. We aimed to compare organ dysfunction criteria in children with blood culture-proven sepsis, including emergency department, PICU, and ward patients, and to assess relevance of organ dysfunctions for mortality prediction. DESIGN: We have carried out a nonprespecified, secondary analysis of a prospective dataset collected from September 2011 to December 2015. SETTING: Emergency departments, wards, and PICUs in 10 tertiary children's hospitals in Switzerland. PATIENTS: Children younger than 17 years old with blood culture-proven sepsis. We excluded preterm infants and term infants younger than 7 days old. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We compared the 2005 International Pediatric Sepsis Consensus Conference (IPSCC), Pediatric Logistic Organ Dysfunction-2 (PELOD-2), pediatric Sequential Organ Failure Assessment (pSOFA), and Pediatric Organ Dysfunction Information Update Mandate (PODIUM) scores, measured at blood culture sampling, to predict 30-day mortality. We analyzed 877 sepsis episodes in 807 children, with a 30-day mortality of 4.3%. Percentage with organ dysfunction ranged from 32.7% (IPSCC) to 55.3% (pSOFA). In adjusted analyses, the accuracy for identification of 30-day mortality was area under the curve (AUC) 0.87 (95% CI, 0.82-0.92) for IPSCC, 0.83 (0.76-0.89) for PELOD-2, 0.85 (0.78-0.92) for pSOFA, and 0.85 (0.78-0.91) for PODIUM. When restricting scores to neurologic, respiratory, and cardiovascular dysfunction, the adjusted AUC was 0.89 (0.84-0.94) for IPSCC, 0.85 (0.79-0.91) for PELOD-2, 0.87 (0.81-0.93) for pSOFA, and 0.88 (0.83-0.93) for PODIUM. CONCLUSIONS: IPSCC, PELOD-2, pSOFA, and PODIUM performed similarly to predict 30-day mortality. Simplified scores restricted to neurologic, respiratory, and cardiovascular dysfunction yielded comparable performance.

Autoimmunity and immunodeficiency associated with monoallelic LIG4 mutations via haploinsufficiency.

BACKGROUND: Biallelic mutations in LIG4 encoding DNA-ligase 4 cause a rare immunodeficiency syndrome manifesting as infant-onset life-threatening and/or opportunistic infections, skeletal malformations, radiosensitivity and neoplasia. LIG4 is pivotal during DNA repair and during V(D)J recombination as it performs the final DNA-break sealing step. OBJECTIVES: This study explored whether monoallelic LIG4 missense mutations may underlie immunodeficiency and autoimmunity with autosomal dominant inheritance. METHODS: Extensive flow-cytometric immune-phenotyping was performed. Rare variants of immune system genes were analyzed by whole exome sequencing. DNA repair functionality and T-cell-intrinsic DNA damage tolerance was tested with an ensemble of in vitro and in silico tools. Antigen-receptor diversity and autoimmune features were characterized by high-throughput sequencing and autoantibody arrays. Reconstitution of wild-type versus mutant LIG4 were performed in LIG4 knockout Jurkat T cells, and DNA damage tolerance was subsequently assessed. RESULTS: A novel heterozygous LIG4 loss-of-function mutation (p.R580Q), associated with a dominantly inherited familial immune-dysregulation consisting of autoimmune cytopenias, and in the index patient with lymphoproliferation, agammaglobulinemia, and adaptive immune cell infiltration into nonlymphoid organs. Immunophenotyping revealed reduced naive CD4+ T cells and low TCR-Vα7.2+ T cells, while T-/B-cell receptor repertoires showed only mild alterations. Cohort screening identified 2 other nonrelated patients with the monoallelic LIG4 mutation p.A842D recapitulating clinical and immune-phenotypic dysregulations observed in the index family and displaying T-cell-intrinsic DNA damage intolerance. Reconstitution experiments and molecular dynamics simulations categorize both missense mutations as loss-of-function and haploinsufficient. CONCLUSIONS: This study provides evidence that certain monoallelic LIG4 mutations may cause human immune dysregulation via haploinsufficiency.

Structured Immune Workup in Healthy Children With a First Episode of Severe Bacterial Infection: A 7-year Single-Center Study.

BACKGROUND: Severe bacterial infections (SBIs) in otherwise healthy children are rare and may represent an underlying impairment of the immune system, including primary immunodeficiency. However, it is unclear whether and how children should be assessed. METHODS: We retrospectively analyzed data from hospital records of previously healthy children aged 3 days to 18 years with SBI, including pleuropneumonia, meningitis, and/or sepsis. Patients were diagnosed or immunologically followed up between 1 January 2013 and 31 March 2020. RESULTS: Among 432 children with SBI, findings could be analyzed in 360. Follow-up data were available for 265 children (74%), of whom 244 (92%) underwent immunological testing. Laboratory abnormalities were found in 51 of 244 patients (21%), with 3 deaths (1%). Fourteen children (6%) had immunodeficiency considered clinically relevant (3 complement deficiencies, 1 autoimmune neutropenia, 10 humoral immunodeficiencies), and 27 (11%) had milder humoral abnormalities or findings suggestive of delayed adaptive immune maturation. CONCLUSIONS: A substantial proportion of children with SBI may benefit from routine immunological testing, revealing (potentially) clinically relevant impaired immune function in 6%-17% of children. The identification of immune abnormalities allows for specific counseling of families and optimization of preventive measures, such as booster vaccinations, to avoid future SBI episodes.

Combinatorial host-response biomarker signature (BV score) and its subanalytes TRAIL, IP-10, and CRP in children with Mycoplasma pneumoniae community-acquired pneumonia.

BACKGROUND: Host-response biomarkers to differentiate bacterial from viral etiology in children with respiratory infections have shown high accuracies, but are understudied in Mycoplasma pneumoniae (Mp) infections. METHODS: We compared BV scores (0-34 indicating viral, and 66-100 indicating bacterial etiology), TRAIL (pg/mL), IP-10 (pg/mL), and CRP (mg/L) serum levels between Mp positive (Mp+) and negative (Mp-) community-acquired pneumonia (CAP). We performed receiver operating characteristic (ROC) curve analyses for clinical features and biomarkers. RESULTS: Of 80 CAP patients (median age 6.3 years, 57.5% male), 26 were Mp + CAP. By comparing Mp + CAP with Mp-CAP patients, BV scores were lower (median 14.0, IQR 3.0-27.8 vs. 54.0, IQR 12.0-84.8; P = 0.0008), TRAIL levels were higher (86.5, IQR 67.4-123.0 vs. 65.5, IQR 42.5-103.9; P = 0.025), CRP levels were lower (12.9, IQR 4.0-22.3 vs. 36.7, IQR 13.0-132.8; P = 0.0019), and IP-10 levels were comparable (366.0, IQR 150.2-603.8 vs. 331.0, IQR 154.3-878.8; P = 0.73). ROC analyses yielded a comparable discriminatory accuracy for the combination of age, fever duration, respiratory symptoms duration, with either procalcitonin or BV (AUC 0.87 vs. 0.86, P = 0.94). CONCLUSIONS: Children with Mp + CAP have atypically low, viral levels of the BV score, underscoring the complementary role of microbiological testing.

Immunologic and Genetic Contributors to CD46-Dependent Immune Dysregulation.

Mutations in CD46 predispose to atypical hemolytic uremic syndrome (aHUS) with low penetrance. Factors driving immune-dysregulatory disease in individual mutation carriers have remained ill-understood. In addition to its role as a negative regulator of the complement system, CD46 modifies T cell-intrinsic metabolic adaptation and cytokine production. Comparative immunologic analysis of diseased vs. healthy CD46 mutation carriers has not been performed in detail yet. In this study, we comprehensively analyzed clinical, molecular, immune-phenotypic, cytokine secretion, immune-metabolic, and genetic profiles in healthy vs. diseased individuals carrying a rare, heterozygous CD46 mutation identified within a large single family. Five out of six studied individuals carried a CD46 gene splice-site mutation causing an in-frame deletion of 21 base pairs. One child suffered from aHUS and his paternal uncle manifested with adult-onset systemic lupus erythematosus (SLE). Three mutation carriers had no clinical evidence of CD46-related disease to date. CD4+ T cell-intrinsic CD46 expression was uniformly 50%-reduced but was comparable in diseased vs. healthy mutation carriers. Reconstitution experiments defined the 21-base pair-deleted CD46 variant as intracellularly-but not surface-expressed and haploinsufficient. Both healthy and diseased mutation carriers displayed reduced CD46-dependent T cell mitochondrial adaptation. Diseased mutation carriers had lower peripheral regulatory T cell (Treg) frequencies and carried potentially epistatic, private rare variants in other inborn errors of immunity (IEI)-associated proinflammatory genes, not found in healthy mutation carriers. In conclusion, low Treg and rare non-CD46 immune-gene variants may contribute to clinically manifest CD46 haploinsufficiency-associated immune-dysregulation.

Prior polymyalgia rheumatica is associated with sonographic vasculitic changes in newly diagnosed patients with giant cell arteritis.

OBJECTIVES: To investigate the hypothesis that a history of polymyalgia rheumatica (PMR) is associated with a more severe and damaging disease course in newly diagnosed giant cell arteritis (GCA) patients. METHODS: Retrospective analysis of GCA patients diagnosed between 12/2006 and 05/2021. We compared vascular ultrasound findings (presence of vasculitis and vascular stenosis) in GCA patients with and without prior PMR. RESULTS: 49 of 311 GCA patients (15.8%) had prior PMR in median 30.6 (IQR 7.1-67.3) months before GCA diagnosis. Patients with prior PMR had more often large vessel vasculitis (LVV) (51.0% vs 25.0%, p< 0.001) and stenosis within the vasculitic segments (18.4% vs 3.1%, p< 0.001) on ultrasound. In multivariable analysis, prior PMR remained significantly associated with LVV (OR 7.65, 95% CI 2.72-23.97, p< 0.001). Polymyalgic symptoms at GCA diagnosis in the patients without prior PMR were not associated with a higher prevalence of LVV (p= 0.156). CONCLUSION: Patients with a diagnosis of PMR before GCA diagnosis had two times more often large vessel involvement and significant more vasculitic stenoses on ultrasound examination than patients without prior PMR. Pre-existing PMR is an independent risk factor for more extensive and advanced ultrasound findings at GCA diagnosis. The contribution of subclinical vasculitis to disease associated damage has to be further studied.

Chronic stage magnetic resonance imaging findings in patients with shoulder injury related to vaccine administration (SIRVA).

PURPOSE: Identify chronic shoulder MRI findings in patients with known shoulder injury related to vaccine administration (SIRVA). MATERIALS AND METHODS: Two fellowship-trained musculoskeletal radiologists retrospectively reviewed the MRI of nine patients with clinically established SIRVA. MRI was performed at least 4 weeks after vaccination and included intravenous contrast-enhanced sequences. MRI was reviewed for the presence of erosions, tendonitis, capsulitis, synovitis, bone marrow oedema, joint effusion, bursitis, cartilage defects, rotator cuff lesions, and lymphadenopathy. The number and location of focal lesions were recorded. RESULTS: Erosions of the greater tuberosity were present in 8/9 (89%), tendonitis of the infraspinatus muscle tendon in 7/9 (78%), capsulitis, synovitis, and bone marrow oedema in 5/9 (56%) cases, respectively. Effusion was found in three, and subdeltoid bursitis, rotator cuff lesions as well as cartilage defects in one patient, respectively. None of our included subjects showed axillary lymphadenopathy. CONCLUSION: In this case series, greater humeral tuberosity erosions, infraspinatus muscle tendonitis, capsulitis, synovitis, and bone marrow oedema were common MRI findings in chronic SIRVA.

Epidemiology and outcomes of medically attended and microbiologically confirmed bacterial foodborne infections in solid organ transplant recipients.

Food-safety measures are recommended to solid organ transplant (SOT) recipients. However, the burden of foodborne infections in SOT recipients has not been established. We describe the epidemiology and outcomes of bacterial foodborne infections in a nationwide cohort including 4405 SOT recipients in Switzerland between 2008 and 2018. Participants were prospectively followed for a median of 4.2 years with systematic collection of data on infections, and patient and graft-related outcomes. We identified 151 episodes of microbiologically confirmed bacterial foodborne infections occurring in median 1.6 years (IQR 0.58-3.40) after transplantation (131 [88%] Campylobacter spp. and 15 [10%] non-typhoidal Salmonella). The cumulative incidence of bacterial foodborne infections was 4% (95% CI 3.4-4.8). Standardized incidence rates were 7.4 (95% CI 6.2-8.7) and 4.6 (95% CI 2.6-7.5) for Campylobacter and Salmonella infections, respectively. Invasive infection was more common with Salmonella (33.3% [5/15]) compared to Campylobacter (3.2% [4/125]; p = .001). Hospital and ICU admission rates were 47.7% (69/145) and 4.1% (6/145), respectively. A composite endpoint of acute rejection, graft loss, or death occurred within 30 days in 3.3% (5/151) of cases. In conclusion, in our cohort bacterial foodborne infections were late post-transplant infections and were associated with significant morbidity, supporting the need for implementation of food-safety recommendations.

Reduced frequency of cytotoxic CD56dim CD16+ NK cells leads to impaired antibody-dependent degranulation in EBV-positive classical Hodgkin lymphoma.

Around 30-50% of classical Hodgkin lymphoma (cHL) cases in immunocompetent individuals from industrialized countries are associated with the B-lymphotropic Epstein-Barr virus (EBV). Although natural killer (NK) cells exhibit anti-viral and anti-tumoral functions, virtually nothing is known about quantitative and qualitative differences in NK cells in patients with EBV+ cHL vs. EBV- cHL. Here, we prospectively investigated 36 cHL patients without known immune suppression or overt immunodeficiency at diagnosis. All 10 EBV+ cHL patients and 25 out 26 EBV- cHL were seropositive for EBV antibodies, and EBV+ cHL patients presented with higher plasma EBV DNA levels compared to EBV- cHL patients. We show that the CD56dim CD16+ NK cell subset was decreased in frequency in EBV+ cHL patients compared to EBV- cHL patients. This quantitative deficiency translates into an impaired CD56dim NK cell mediated degranulation toward rituximab-coated HLA class 1 negative lymphoblastoid cells in EBV+ compared to EBV- cHL patients. We finally observed a trend to a decrease in the rituximab-associated degranulation and ADCC of in vitro expanded NK cells of EBV+ cHL compared to healthy controls. Our findings may impact on the design of adjunctive treatment targeting antibody-dependent cellular cytotoxicity in EBV+ cHL.

CD4 + T cells are found within endemic Burkitt lymphoma and modulate Burkitt lymphoma precursor cell viability and expression of pathogenically relevant Epstein-Barr virus genes.

Endemic Burkitt lymphoma (eBL) is an aggressive B cell cancer characterized by an IgH/c-myc translocation and the harboring of Epstein-Barr virus (EBV). Evidence accumulates that CD4 + T cells might contribute to eBL pathogenesis. Here, we investigate the presence of CD4 + T cells in primary eBL tissue and their potential dichotomous impact on an EBV-infected pre-eBL cell model using ex vivo material and in vitro co-cultures. In addition, we establish a novel method to study the effect of IgH/c-myc translocation in primary B cells by employing a CRISPR/Cas9 knock-in approach to introduce and tag de novo translocation. We unprecedently document that CD4 + T cells are present in primary eBL tumor tissue. Furthermore, we demonstrate that CD4 + T cells on the one hand suppress eBL development by killing pre-eBL cells lacking IgH/c-myc translocation in vitro and on the other hand indirectly promote eBL development by inducing crucial EBV Latency III to Latency I switching in pre-eBL cells. Finally, we show that while the mere presence of an IgH/c-myc translocation does not suffice to escape CD4 + T-cell-mediated killing in vitro, the CD4 + T-cell-mediated suppression of EBV's Latency III program in vivo may allow cells harboring an IgH/c-myc translocation and additional mutations to evade immune control and proliferate by means of deregulated c-myc activity, resulting in neoplasia. Thus, our study highlights the dichotomous effects of CD4 + T cells and the mechanisms involved in eBL pathogenesis, suggests mechanisms of their impact on eBL progression, and provides a novel in vitro model for further investigation of IgH/c-myc translocation.

Correction: Immunosuppressive FK506 treatment leads to more frequent EBV-associated lymphoproliferative disease in humanized mice.

[This corrects the article DOI: 10.1371/journal.ppat.1008477.].

Immunosuppressive FK506 treatment leads to more frequent EBV-associated lymphoproliferative disease in humanized mice.

Post-transplant lymphoproliferative disorder (PTLD) is a potentially fatal complication after organ transplantation frequently associated with the Epstein-Barr virus (EBV). Immunosuppressive treatment is thought to allow the expansion of EBV-infected B cells, which often express all eight oncogenic EBV latent proteins. Here, we assessed whether HLA-A2 transgenic humanized NSG mice treated with the immunosuppressant FK506 could be used to model EBV-PTLD. We found that FK506 treatment of EBV-infected mice led to an elevated viral burden, more frequent tumor formation and diminished EBV-induced T cell responses, indicative of reduced EBV-specific immune control. EBV latency III and lymphoproliferation-associated cellular transcripts were up-regulated in B cells from immunosuppressed animals, akin to the viral and host gene expression pattern found in EBV-PTLD. Utilizing an unbiased gene expression profiling approach, we identified genes differentially expressed in B cells of EBV-infected animals with and without FK506 treatment. Upon investigating the most promising candidates, we validated sCD30 as a marker of uncontrolled EBV proliferation in both humanized mice and in pediatric patients with EBV-PTLD. High levels of sCD30 have been previously associated with EBV-PTLD in patients. As such, we believe that humanized mice can indeed model aspects of EBV-PTLD development and may prove useful for the safety assessment of immunomodulatory therapies.

[18F]FDG uptake of axillary lymph nodes after COVID-19 vaccination in oncological PET/CT: frequency, intensity, and potential clinical impact.

OBJECTIVES: To assess the frequency, intensity, and clinical impact of [18F]FDG-avidity of axillary lymph nodes after vaccination with COVID-19 vaccines BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna) in patients referred for oncological FDG PET/CT. METHODS: One hundred forty patients referred for FDG PET/CT during February and March 2021 after first or second vaccination with Pfizer-BioNTech or Moderna were retrospectively included. FDG-avidity of ipsilateral axillary lymph nodes was measured and compared. Assuming no knowledge of prior vaccination, metastatic risk was analyzed by two readers and the clinical impact was evaluated. RESULTS: FDG PET/CT showed FDG-avid lymph nodes ipsilateral to the vaccine injection in 75/140 (54%) patients with a mean SUVmax of 5.1 (range 2.0 - 17.3). FDG-avid lymph nodes were more frequent in patients vaccinated with Moderna than Pfizer-BioNTech (36/50 [72%] vs. 39/90 [43%] cases, p < 0.001). Metastatic risk of unilateral FDG-avid axillary lymph nodes was rated unlikely in 52/140 (37%), potential in 15/140 (11%), and likely in 8/140 (6%) cases. Clinical management was affected in 17/140 (12%) cases. CONCLUSIONS: FDG-avid axillary lymph nodes are common after COVID-19 vaccination. The avidity of lymph nodes is more frequent in Moderna compared to that in Pfizer-BioNTech vaccines. To avoid relatively frequent clinical dilemmas, we recommend carefully taking the history for prior vaccination in patients undergoing FDG PET/CT and administering the vaccine contralateral to primary cancer. KEY POINTS: • PET/CT showed FDG-avid axillary lymph nodes ipsilateral to the vaccine injection site in 54% of 140 oncological patients after COVID-19 vaccination. • FDG-avid lymphadenopathy was observed significantly more frequently in Moderna compared to patients receiving Pfizer-BioNTech-vaccines. • Patients should be screened for prior COVID-19 vaccination before undergoing PET/CT to enable individually tailored recommendations for clinical management.

Development of the Swiss Database for dosing medicinal products in pediatrics.

In daily paediatrics, drugs are commonly used off-label, as they are not approved for children. Approval is lacking because the required clinical studies were limited to adults in the past. Without clinical studies, evidence-based recommendations for drug use in children are limited. Information on off-label drug dosing in children can be found in different handbooks, databases and scientific publications but the dosing recommendations can differ considerably. To improve safety and efficacy of drugs prescribed to children and to assist the prescribers, stakeholders in Swiss paediatrics started a pilot project, supported by the Federal Office of Public Health, with the aim to create a database, providing healthcare professionals with so called "harmonised" dosage recommendations based on the latest available scientific evidence and best clinical practice. A standardised process for dosage harmonisation between paediatric experts was defined, guided and documented in an electronic tool, developed for this purpose. As proof of principle, a total of 102 dosage recommendations for 30 different drugs have been nationally harmonised in the pilot phase considering the current scientific literature and the approval of the most experienced national experts in the field.Conclusion: This approach paved the way for unified national dosage recommendations for children. Reaching the project's milestones fulfilled the prerequisites for funding and starting regular operation of SwissPedDose in 2018. Since then, the database was extended with recommendations for 100 additional drugs. What is Known: • Prescribing off-label is a common practice among paediatricians, as many drugs are still not authorised for use in children. • Some countries developed national drug formularies providing off-label dosage recommendations. What is New: • Comparison of published dosage recommendations in known drug handbooks and online databases show substantial differences and heterogeneity, revealing the need for harmonisation. • The design of a tool for standardised harmonisation of dosage recommendations, based on information collected on currently applied dosages, latest scientific evidence and the approval of experts.

Fetal-Maternal Surgery for Spina Bifida in a HIV-Infected Mother.

INTRODUCTION: In select cases, in utero surgery for myelomeningocele (MMC) leads to better outcomes than postnatal repair. However, maternal HIV infection constitutes a formal exclusion criterion due to the potential of vertical HIV transmission. Encouraged by a previous case of a successful fetal spina bifida repair in a Hepatitis Bs antigen-positive woman, a plan was devised allowing for fetal surgery. CASE REPORT: In utero MMC repair was performed although the mother was HIV-infected. To minimize the risk of in utero HIV transmission, the mother was treated by highly active antiretroviral therapy throughout gestation as well as intravenous zi-dovudine administration during maternal-fetal surgery. The mother tolerated all procedures very well without any sequelae. The currently 20 month-old toddler is HIV negative and has significantly benefitted from fetal surgery. DISCUSSION/CONCLUSION: This case shows that maternal HIV is not a priori a diagnosis that excludes fetal surgery. Rather, it might be a surrogate for moving towards personalized medicine and away from applying too rigorous exclusion criteria in the selection of candidates for maternal-fetal surgery.

Association of antiviral prophylaxis and rituximab use with posttransplant lymphoproliferative disorders (PTLDs): A nationwide cohort study.

Posttransplant lymphoproliferative disorder (PTLD) is a serious complication of solid organ transplantation (SOT). Most PTLD cases are associated with Epstein-Barr virus (EBV) infection. The role of antiviral prophylaxis or rituximab therapy for prevention of PTLD in SOT recipients is controversial. In a nationwide cohort, we assessed the incidence, presentation, and outcome of histologically proven PTLD. We included 4765 patients with a follow-up duration of 23 807 person-years (py). Fifty-seven PTLD cases were identified; 39 (68%) were EBV positive (EBV+ PTLD). Incidence rates for EBV+ PTLD at 1, 2, and 3 years posttransplant were 3.51, 2.24, and 1.75/1000 py and 0.44, 0.25, and 0.29/1000 py for EBV- PTLD. We did not find an effect of antiviral prophylaxis on early and late EBV+ PTLD occurrence (early EBV+ PTLD: SHR 0.535 [95% CI 0.199-1.436], p = .264; late EBV+ PTLD: SHR 2.213, [95% CI 0.751-6.521], p = .150). However, none of the patients (0/191) who received a rituximab-containing induction treatment experienced PTLD, but 57 of 4574 patients without rituximab induction developed PTLD. In an adjusted restricted mean survival time model, PTLD-free survival was significantly longer (0.104 years [95% CI 0.077-0.131]) in patients receiving rituximab as induction treatment. This study provides novel data on the association of rituximab induction and reduced risk for PTLD.

Burden, epidemiology, and outcomes of microbiologically confirmed respiratory viral infections in solid organ transplant recipients: a nationwide, multi-season prospective cohort study.

Solid organ transplant (SOT) recipients are exposed to respiratory viral infection (RVI) during seasonal epidemics; however, the associated burden of disease has not been fully characterized. We describe the epidemiology and outcomes of RVI in a cohort enrolling 3294 consecutive patients undergoing SOT from May 2008 to December 2015 in Switzerland. Patient and allograft outcomes, and RVI diagnosed during routine clinical practice were prospectively collected. Median follow-up was 3.4 years (interquartile range 1.61-5.56). Six hundred ninety-six RVIs were diagnosed in 151/334 (45%) lung and 265/2960 (9%) non-lung transplant recipients. Cumulative incidence was 60% (95% confidence interval [CI] 53%-69%) in lung and 12% (95% CI 11%-14%) in non-lung transplant recipients. RVI led to 17.9 (95% CI 15.7-20.5) hospital admissions per 1000 patient-years. Intensive care unit admission was required in 4% (27/691) of cases. Thirty-day all-cause case fatality rate was 0.9% (6/696). Using proportional hazard models we found that RVI (adjusted hazard ratio [aHR] 2.45; 95% CI 1.62-3.73), lower respiratory tract RVI (aHR 3.45; 95% CI 2.15-5.52), and influenza (aHR 3.57; 95% CI 1.75-7.26) were associated with graft failure or death. In this cohort of SOT recipients, RVI caused important morbidity and may affect long-term outcomes, underlying the need for improved preventive strategies.

Support of BCP-ALL-cells by autologous bone marrow Th-cells involves induction of AID expression but not widespread AID off-target mutagenesis.

B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is the most common childhood malignancy. The two-step BCP-ALL pathogenesis requires in utero-induced chromosomal aberrations and additional mutagenic events for overt leukemia. In mouse models, activation-induced cytidine deaminase (AID/AICDA) was suggested to contribute to BCP-ALL pathogenesis by off-target mutagenic activity. The role of AID in patients, however, remains unclear. Moreover, AID is usually not expressed in precursor B-cells but in germinal center B-cells, where it is induced upon T-helper (Th) cell stimulation. We have previously demonstrated that autologous Th-cells supportively interacted with BCP-ALL-cells. Here, we hypothesize that this interaction additionally induces AID expression in BCP-ALL-cells, leading to off-target mutagenic activity. We show that co-culture with autologous bone marrow Th-cells induced high AICDA expression in primary BCP-ALL-cells. This induction was mediated by a mechanism similar to the induction in mature B-cells involving IL-13/Stat6, CD40L/NF-κB and TGFß/Smad2/3 signaling. Even though Th-cell-induced AID seemed to be active in vitro in a BCP-ALL reporter cell line, extensive mutational signature analysis revealed no major contribution of AID activity to the mutational landscape in BCP-ALL patients. AID activity was neither detected in mutation clusters nor in known AID targets. Moreover, no recurrently mutated gene showed a relevant enrichment of mutations in the AID motif. Together, the lack of AID-induced mutational consequences argues towards a Th-cell-promoted yet AID-independent BCP-ALL pathogenesis and favors therapeutic research focusing on Th-cell-derived support of BCP-ALL-cells rather than AID-induced effects.