Clinical presentation, immunologic features, and hematopoietic stem cell transplant outcomes for IKBKB immune deficiency.

IKBKB immune deficiency is a rare but life-threatening primary immunodeficiency disorder, involving activation defects in adaptive and innate immunity. We present sixteen cases of a homozygous IKBKB mutation (c.1292dupG) in infants characterized by early-onset bacterial, viral, fungal and Mycobacterial infections. In most cases, T- and B-cells were quantitatively normal, but phenotypically naïve, with severe hypogammaglobulinemia. T-cell receptor excision circles were normal, meaning newborn screening by TREC analysis would miss IKBKB cases. Although IKBKB immune deficiency does not meet traditional laboratory based definitions for SCID, this combined immune deficiency appears to be at least as profound. Urgent HSCT, performed in eight patients, remains the only known curative therapy, although only three patients are survivors. Ongoing infections after transplant remain a concern, and may be due to combinations of poor social determinants of health, secondary graft failure, and failure of HSCT to replace non-hematopoietic cells important in immune function and dependent upon IKK/NF-κB pathways.

Perforin and CD107a testing is superior to NK cell function testing for screening patients for genetic HLH.

Primary hemophagocytic lymphohistiocytosis (HLH) can be caused by biallelic mutations in PRF1, encoding perforin, or UNC13D, STXBP2, STX11, RAB27A, LYST, and AP3B1, encoding proteins involved in cytotoxic lymphocyte degranulation. Natural killer (NK)-cell cytotoxicity assays can quickly screen for all of these genetic diseases, facilitating treatment, but combining NK-cell perforin expression and CD107a upregulation tests can as well. To determine the relative diagnostic accuracies for each approach, we retrospectively reviewed screening test performance in 1614 patients referred for HLH evaluation. For each test, we generated a receiver operating characteristic (ROC) curve, and calculated area under the curve (AUC) and diagnostic parameters at optimal threshold. We generated an AUC for combining perforin and CD107a tests by creating a logistic regression model and applying model-generated coefficients to patient values. Sensitivities of NK-cell function, perforin mean channel fluorescence (MCF), and CD107a MCF to detect biallelic mutations were 59.5%, 96.6%, and 93.8%, with specificities of 72.0%, 99.5%, and 73%. AUCs for NK-cell cytotoxicity, perforin MCF, CD107a MCF, and combined perforin and CD107a MCFs were 0.690, 0.971, 0.860, and 0.838. Perforin and CD107a tests are more sensitive and no less specific compared with NK cytotoxicity testing for screening for genetic HLH and should be considered for addition to current HLH criteria.

Long-Term Outcomes of Hematopoietic Stem Cell Transplantation for ZAP70 Deficiency.

ZAP70 deficiency is a rare T + B + NK+ combined immunodeficiency with limited outcome data to help guide decisions around hematopoietic stem cell transplant (HSCT). We sought to understand the long-term clinical and immunologic outcomes of both conditioned and unconditioned HSCT for ZAP70 deficiency following transplant from a variety of graft sources. We performed a retrospective, single center review of all cases of HSCT for genetically confirmed ZAP70 deficiency since 1992. At a median of 13.5-year post-HSCT, 8/8 (100 %) patients are alive. Three received unconditioned bone marrow transplants from human leukocyte antigen (HLA)-matched siblings and achieved stable mixed donor-recipient T cell chimerism but low B cell (4-9 %) and absent to near-absent myeloid donor engraftment. Despite this, all three have normal immunoglobulin levels, have developed specific protective antibody responses to post-HSCT vaccinations, and have discontinued immunoglobulin replacement. Five patients received myeloablative conditioning (three T cell-depleted haploidentical and two unrelated cord blood) and have full donor chimerism for T and B cells and myeloid lineages. One patient experienced primary graft failure after serotherapy only. CD8 T cell count is normal in 5/8, high in 1/8, and low in 2/8. Infectious complications in 5/5 and autoimmune thrombocytopenia in one patient resolved post-HSCT. Mitogen proliferation to phytohemagglutinin was normal after HSCT in 8/8 patients. In total, seven have discontinued immunoglobulin replacement. In conclusion, HSCT using a variety of graft sources and approaches, including unconditioned matched sibling donor transplant, is a life-saving therapy for ZAP70 deficiency, providing excellent long-term immune function and resolution of clinical problems.

Delivery of subcutaneous immunoglobulin by rapid "push" infusion for primary immunodeficiency patients in Manitoba: a retrospective review.

BACKGROUND: Both intravenous and subcutaneous human immune globin G (IgG) replacement (IVIG and SCIG, respectively) reduce severe infection and increase serum IgG levels in primary immune deficiency disorder (PIDD) patients who require replacement. SCIG can be administered either with the aid of an infusion pump, or by patients or caregivers themselves, using butterfly needles and a syringe ("SCIG push"). SCIG offers advantages over IVIG, including higher steady state IgG levels, improved patient quality of life indicators, and decreased cost to the healthcare system, and for these reasons, SCIG has been increasingly used in Manitoba starting in 2007. We sought to determine the effectiveness of SCIG push in our local adult PIDD population. METHODS: We conducted a retrospective chart review of all adult patients enrolled in the SCIG push program in Manitoba, Canada from its inception in November 2007 through September 2018. We included patients who were naïve to IgG replacement prior to SCIG, and those who had received IVIG immediately prior. We collected data regarding serum IgG levels, antibiotic prescriptions, hospital admissions, and adverse events during a pre-defined period prior to and following SCIG initiation. Statistical significance was determined via two-tailed t-test. RESULTS: 62 patients met inclusion criteria, of whom 35 were on IVIG prior and 27 were IgG replacement naïve. SCIG push resulted in an increase in serum IgG levels in those naïve to IgG replacement, as well as in those who received IVIG prior. SCIG push also resulted in a statistically significant reduction in number of antibiotic prescriptions filled in the naïve subgroup, and no significant change in antibiotics filled in the IVIG prior group. 8/62 PIDD patients (12.9%) left the SCIG program during our review period for varying reasons, including side-effects. CONCLUSIONS: In a real-life setting, in the Manitoba adult PIDD population, SCIG push is an effective method of preventing severe infections, with most patients preferring to continue this therapy once initiated.

Development of a Population-Based Newborn Screening Method for Severe Combined Immunodeficiency in Manitoba, Canada.

The incidence of Severe Combined Immunodeficiency (SCID) in Manitoba, (1/15,000), is at least three to four times higher than the national average and that reported from other jurisdictions. It is overrepresented in two population groups: Mennonites (ZAP70 founder mutation) and First Nations of Northern Cree ancestry (IKBKB founder mutation). We have previously demonstrated that in these two populations the most widely utilized T-cell receptor excision circle (TREC) assay is an ineffective newborn screening test to detect SCID as these patients have normal numbers of mature T-cells. We have developed a semi-automated, closed tube, high resolution DNA melting procedure to simultaneously genotype both of these mutations from the same newborn blood spot DNA extract used for the TREC assay. Parallel analysis of all newborn screening specimens utilizing both TREC analysis and the high-resolution DNA procedure should provide as complete ascertainment as possible of SCID in the Manitoba population.