Simon Urschel

Relevance of biallelic versus monoallelic TNFRSF13B mutations in distinguishing disease-causing from risk-increasing TNFRSF13B variants in antibody deficiency syndromes

TNFRSF13B encodes transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), a B cell- specific tumor necrosis factor (TNF) receptor superfamily member. Both biallelic and monoallelic TNFRSF13B mutations were identified in patients with common variable immunodeficiency disorders. The genetic complexity and variable clinical presentation of TACI deficiency prompted us to evaluate the genetic, immunologic, and clinical condition in 50 individuals with TNFRSF13B alterations, following screening of 564 unrelated patients with hypogammaglobulinemia. We identified 13 new sequence variants. The most frequent TNFRSF13B variants (C104R and A181E; n=39; 6.9%) were also present in a heterozygous state in 2% of 675 controls. All patients with biallelic mutations had hypogammaglobulinemia and nearly all showed impaired binding to a proliferation-inducing ligand (APRIL). However, the majority (n=41; 82%) of the pa-tients carried monoallelic changes in TNFRSF13B. Presence of a heterozygous mutation was associated with antibody deficiency (P< .001, relative risk 3.6). Heterozygosity for the most common mutation, C104R, was associated with disease (P< .001, relative risk 4.2). Furthermore, heterozygosity for C104R was associated with low numbers of IgD(-)CD27(+) B cells (P= .019), benign lymphoproliferation (P< .001), and autoimmune complications (P= .001). These associations indicate that C104R heterozygosity increases the risk for common variable immunodeficiency disorders and influences clinical presentation.

Common Variable Immunodeficiency Disorders in Children: Delayed Diagnosis Despite Typical Clinical Presentation

OBJECTIVE To characterize common variable immunodeficiency disorder (CVID) in childhood. STUDY DESIGN We retrospectively investigated clinical findings in 32 children with primary CVID by questionnaire and file review. RESULTS Clinical presentation included recurrent or chronic respiratory tract infections (88%), sinusitis (78%), otitis media (78%), and intestinal tract infections (34%), mainly with encapsulated bacteria. Meningitis was found in 25%, sepsis in 16%, and pyelonephritis in 16% of patients. Poliomyelitis after vaccination occurred in 2 patients and opportunistic infections occasionally. Allergic disorders were present in 38%, and autoimmune disease in 31% of patients. Eighty percent of the patients underwent surgical procedures because of recurrent infections. Growth retardation was seen in 28% of patients, and 16% showed retarded mental development. Bronchiectasis developed in 34%, and lymphoid proliferative disease in 13%. Incidence of allergic and autoimmune diseases was increased in first-degree relatives with normal immunologic findings. Mean time between symptoms and induction of immunoglobulin substitution therapy was 5.8 years (0.2-14.3). CONCLUSIONS CVID in children presents with comparable symptoms and disorders as in adults. We found a significant influence on growth and development. The marked delay of diagnosis may be due to overlap with common pediatric disorders, while also reflecting insufficient awareness of these disorders.

Randomized Controlled Trial of High-Dose Intradermal Versus Standard-Dose Intramuscular Influenza Vaccine in Organ Transplant Recipients

The immunogenicity of standard intramuscular (IM) influenza vaccine is suboptimal in transplant recipients. Also, recent studies suggest that alloantibody may be upregulated due to vaccination. We evaluated a novel high‐dose intradermal (ID) vaccine strategy. In conjunction, we assessed alloimmunity. Transplant recipients were randomized to receive IM or high‐dose ID vaccine. Strain‐specific serology and HLA alloantibody production was determined pre‐ and postimmunization. In 212 evaluable patients (105 IM, 107 ID), seroprotection to H1N1, H3N2 and B strains was 70.5%, 63.8% and 52.4% in the IM group, and 71.0%, 70.1%, 63.6% in the ID group (p = ns). Seroconversion to ≥1 antigen was 46.7% and 51.4% in the IM and ID groups respectively (p = 0.49). Response was more likely in those ≥6 months posttransplant (53.2% vs. 19.2%; p = 0.001). Use of mycophenolate mofetil was inversely associated with vaccine response in a dose‐dependent manner (p < 0.001). Certain organ subgroups had higher response rates for influenza B in the ID vaccine group. Differences in anti‐HLA antibody production were detected in only 3/212(1.4%) patients with no clinical consequences. High‐dose intradermal vaccine is an alternative to standard vaccine and has potential enhanced immunogenicity in certain subgroups. In this large cohort, we also show that seasonal influenza does not result in significant alloantibody production.

ABO-incompatible heart transplantation in early childhood: An international multicenter study of clinical experiences and limits

BACKGROUND Intentional blood group (BG)-incompatible (ABOi) heart transplantation in childhood is emerging in many centers. Safety limits remain undetermined. In this multicenter study we have compiled experience on clinical and immunologic boundaries. METHODS Data from six centers in Europe and North America on ABOi transplantation were collected in a standardized survey. RESULTS Fifty-eight ABOi transplants were performed in 57 patients. Median age at transplant was 6.8 months (0.03 to 90 months); post-transplant follow-up was 37.7 months (0.46 to 117 months), accumulating 188 patient-years. Forty-seven percent of the patients received pretransplant mechanical circulatory support. Donors were either blood group A (n = 25), B (n = 18) or AB (n = 15). The median peak antibody titer to the donor BG pretransplant was 1:8 (0 to 1:64) for anti-A and 1:4 (0 to 1:32) for anti-B. Titers against the donor BG were lower post- than pretransplant in B recipients (p = 0.02), whereas third-party antibodies in BG O recipients developed normally post-transplant. Induction immunosuppression included anti-thymocyte globulin (61%), basiliximab (32%) or none (7%). All patients received calcineurin inhibitors, including 62% with mycophenolate mofetil, 10% with azathioprine, 2% with everolimus and 24% with steroids. There were 4 episodes of cellular rejection (Grade≥2R) and 7 antibody-mediated rejections. Five patients underwent antibody removal post-transplant. One patient developed severe graft vasculopathy. Freedom from death or retransplantation was 100%/96%/69% at 1/5/10 years. No graft loss was attributed to BG antibodies. CONCLUSIONS Successful ABOi heart transplantation can be performed at an older age and with higher isohemagglutinin titers than initially assumed and using similar immunosuppressive regimens as for ABO-compatible transplants. Rejection and graft vasculopathy are rare. Persistently low titers of antibodies to the donor BG post-transplant suggest elements of tolerance and/or accommodation.

Infection and malignancy after pediatric heart transplantation: The role of induction therapy

BACKGROUND Variable rates of malignancy and early infection have previously been reported in heart transplant (HTx) recipients who received induction therapy. This study hypothesized that induced pediatric patients would have an increased risk of these events compared with non-induced patients. METHODS Data from a prospective, multicenter event-driven registry of outcomes after HTx listing in patients aged < 18 years was used to analyze risks of infection and malignancy and their association with induction between January 1993 and December 2007. RESULTS Of 2,374 patients, 1,258 (53%) received induction and more frequently from 1999 to 2008 compared with 1993 to 1998 (70.8% vs 57.5%, p < 0.001). At HTx, induced patients were more likely to have congenital heart disease (56.9% vs 48.1%, p < 0.001) but no more likely to be positive for Epstein-Barr virus (50.3% vs 51.4%, p = 0.67). Post-transplant lymphoproliferative disease (PTLD) was the most common malignancy (n = 92) within 5 years of HTx. Patients who received induction had a lower risk for PTLD (hazard ratio [HR], 0.5; 95% confidence interval [CI], 0.3-0.84; p = 0.009) and early fungal infections (HR, 0.60; 91% CI, 0.40-0.91; p = 0.016). Among induction agents used, OKT3 was associated with lowest freedom from PTLD and fungal/cytomegalovirus infection. CONCLUSIONS Induction use has increased since 1999 and has not been associated with an increased risk of malignancy (predominantly PTLD) or overall infection. Because these adverse events occurred with higher rates in non-induced patients, it is likely that induction alone is not the primary risk determinant for PTLD and infection.

Differences of humoral and cellular immune response to an acellular pertussis booster in adolescents with a whole cell or acellular primary vaccination

To study the pertussis-specific immune response of adolescents with different prevaccination schedules, we measured the humoral and cell-mediated immunity (CMI) to pertussis antigens before and after a five-component Tdap booster vaccination in 78 adolescents, who had previously received either five doses of a two-component acellular pertussis vaccine (aP; last dose age 4-6 years), four doses of aP (last dose age 18-24 months), or four doses of whole cell pertussis vaccine (wcP; last dose age 18-24 months). The proportion of participants with a twofold rise in titre was 79% against pertussis toxin (PT), 94% against filamentous hemagglutinin (FHA), and 99% against pertactin (PRN) without significant differences between the three groups. However, participants with primary wcP vaccination showed higher postvaccination titres to pertussis toxin (geometric mean titre, GMT 50.3EU/ml) than those with either four (GMT 17.1EU/ml) or five (GMT 16.4EU/ml) previous aP doses. CMI indices to PT, FHA, PRN and fimbriae (FIM) increased after vaccination and were similar between groups. The current adolescent Tdap booster immunization induced good humoral and cellular immune response to pertussis. The higher antibody titres to pertussis toxin may indicate a more effective priming of B cell memory after primary whole-cell vaccination.

Absence of Donor-Specific Anti-HLA Antibodies after ABO-Incompatible Heart Transplantation in Infancy – Altered Immunity or Age?

Specific B‐cell tolerance toward donor blood group antigens develops in infants after ABO‐incompatible heart transplantation, whereas their immune response toward protein antigens such as HLA has not been investigated. We assessed de novo HLA‐antibodies in 122 patients after pediatric thoracic transplantation (28 ABO‐incompatible) and 36 controls. Median age at transplantation was 1.7 years (1 day to 17.8 year) and samples were collected at median 3.48 years after transplantation. Antibodies were detected against HLA‐class I in 21 patients (17.2%), class II in 18 (14.8%) and against both classes in 10 (8.2%). Using single‐antigen beads, donor‐specific antibodies (DSAs) were identified in six patients (all class II, one additional class I). Patients with DSAs were significantly older at time of transplantation. In patients who had undergone pretransplant cardiac surgeries, class II antibodies were more frequent, although use of homografts or mechanical heart support had no influence. DSAs were absent in ABO‐incompatible recipients and class II antibodies were significantly less frequent than in children with ABO‐compatible transplants. This difference was present also when comparing only children transplanted below 2 years of age. Therefore, tolerance toward the donor blood group appears to be associated with an altered response to HLA beyond age‐related effects.

Advanced Therapies for Congenital Heart Disease: Ventricular Assist Devices and Heart Transplantation

Improvement in pre-, peri-, and postoperative management of congenital heart disease (CHD) has significantly increased long-term survival in children with CHD. However, there is a subset of patients with CHD who are either poor candidates for surgical palliation or in whom surgical intervention has failed and require advanced cardiac support. Heart transplant (HT) as a therapy for CHD has undergone tremendous evolution. Though transplantation remains the standard of care to improve survival and quality of life when conventional medical and surgical therapies have failed, it remains limited by the scarcity and unpredictability of donor organ availability. As such, the use of ventricular assist devices (VADs) as a bridge to transplant is gaining increasing popularity. Because of improvement in device technology, and reduced rate of VAD-related complications, the use of these devices is expanding to smaller children and more complex congenital anatomy. Challenges with VAD support and HT in the congenital heart population will be addressed in this review with focus on: (1) reasons for VAD implantation; (2) VAD support in Fontan circulation; (3) challenges with human leukocyte antigen (HLA) sensitization in HT; and (4) effect of VAD support on HT in CHD.

Acellular pertussis booster in adolescents induces Th1 and memory CD8+ T cell immune response.

In a number of countries, whole cell pertussis vaccines (wcP) were replaced by acellular vaccines (aP) due to an improved reactogenicity profile. Pertussis immunization leads to specific antibody production with the help of CD4+ T cells. In earlier studies in infants and young children, wcP vaccines selectively induced a Th1 dominated immune response, whereas aP vaccines led to a Th2 biased response. To obtain data on Th1 or Th2 dominance of the immune response in adolescents receiving an aP booster immunization after a wcP or aP primary immunization, we analyzed the concentration of Th1 (IL-2, TNF-α, INF-γ) and Th2 (IL-4, IL-5, IL-10) cytokines in supernatants of lymphocyte cultures specifically stimulated with pertussis antigens. We also investigated the presence of cytotoxic T cell responses against the facultative intracellular bacterium Bordetella pertussis by quantifying pertussis-specific CD8+ T cell activation following the aP booster immunization. Here we show that the adolescent aP booster vaccination predominantly leads to a Th1 immune response based on IFNgamma secretion upon stimulation with pertussis antigen, irrespective of a prior whole cell or acellular primary vaccination. The vaccination also induces an increase in peripheral CD8+CD69+ activated pertussis-specific memory T cells four weeks after vaccination. The Th1 bias of this immune response could play a role for the decreased local reactogenicity of this adolescent aP booster immunization when compared to the preceding childhood acellular pertussis booster. Pertussis-specific CD8+ memory T cells may contribute to protection against clinical pertussis.

Withdrawal of Pneumocystis jirovecii prophylaxis in HIV-infected children under highly active antiretroviral therapy.

Objective:In HIV-infected adults Pneumocystis jirovecii pneumonia (PCP) prophylaxis can be safely withdrawn after immune reconstitution due to the introduction of highly active antiretroviral therapy (HAART). With regard to children only a small amount of data has been published. The present study investigated whether the withdrawal of PCP prophylaxis after immune reconstitution is safe in HIV-infected children. Methods:A retrospective analysis at 10 European centers belonging to the Pediatric European Network on the treatment of AIDS (PENTA) using a standardized questionnaire. Results:A total of 113 questionnaires were received. In 82 children the indication for PCP prophylaxis was provided following Centers for Disease Control (CDC) guidelines (72 primary and 10 secondary). Prophylaxis was withdrawn after the CD4 cell count increased above the age-related CDC thresholds. The observation period off prophylaxis was 335 years (300 years for primary and 35 years for secondary prophylaxis) and the median time per patient off prophylaxis was 4.1 years (range, 0.3–7.7 years). No episode of PCP occurred during the study period. In comparison with the incidence rate from historical data before the introduction of PCP prophylaxis and HAART, this was a significant reduction (P < 0.05). Conclusions:The increase in CD4 cell count provides functional reconstitution of the immune system in children. Our data suggests that the risk of developing a PCP after immune reconstitution is sufficiently low to withdraw PCP prophylaxis.