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Common variable immunodeficiency (CVID) is the most common primary immunodeficiency in adults. It is associated with hypogammaglobulinemia, recurring infections and autoimmune phenomena. Treatment includes immunoglobulin substitution and immunosuppressants. Autoimmune neurological manifestations of CVID are rare and occur predominantly as granulomatous disease. We report the case of a 35-year-old woman with CVID who developed autoimmune encephalitis as demonstrated by double cerebral biopsy. Infectious or malignant causes could be excluded. Despite intensive immunosuppressive therapy with common regimens no significant improvement could be achieved. Ultimately, an autologous hematopoietic stem cell transplantation (HSCT) was performed, resulting in lasting complete remission of the encephalitis. To our knowledge, this is the first report of refractory autoimmune phenomena in CVID treated by autologous HSCT., (Copyright © 2020 Froehlich, Schwaneck, Gernert, Gadeholt, Strunz, Morbach, Tony and Schmalzing.)

Background: Patients with common variable immunodeficiency show higher incidence of sinopulmonary and gastrointestinal infections, as well as lymphoproliferative and autoimmune diseases. The treatment of choice is replacement therapy with human gamma-globulin. Hematopoietic stem cell transplantation is a non-conventional therapeutic modality., Case Report: Twenty-six-year old woman with no family or hereditary history of primary immune deficiencies or consanguinity, with repeated episodes of otitis, sinusitis, gastroenteritis and bronchitis since childhood. At adolescence, she was diagnosed with common variable immunodeficiency; she was prescribed intravenous gamma-globulin, broad-spectrum antimicrobials and macrolides. At 22 years of age, she underwent hematopoietic stem cell transplantation owing to continued severe infections. At 4 months, post-transplantation she was diagnosed with hypothyroidism and ovarian insufficiency. During the following 3 years, she had no infections, but at 25 years of age she had immune thrombocytopenic purpura diagnosed, which persists together with Raynaud's disease and upper respiratory tract persistent infections. At the moment of this report she is being treated with intravenous gamma-globulin and receiving prophylaxis with clarithromycin, without steroids or danazol., Conclusions: Given the high rate of morbidity and mortality associated and immune reconstitution failure, hematopoietic stem cell transplantation should be carefully evaluated in patients with treatment-unresponsive infections or lymphoproliferative disorders.

Purpose: Autosomal recessive mutations in LRBA, encoding for LPS-responsive beige-like anchor protein, were described in patients with a common variable immunodeficiency (CVID)-like disease characterized by hypogammaglobulinemia, autoimmune cytopenias, and enteropathy. Here, we detail the clinical, immunological, and genetic features of a patient with severe autoimmune manifestations., Methods: Whole exome sequencing was performed to establish a molecular diagnosis. Evaluation of lymphocyte subsets was performed for immunological characterization. Medical files were reviewed to collect clinical and immunological data., Results: A 7-year-old boy, born to consanguineous parents, presented with autoimmune hemolytic anemia, hepatosplenomegaly, autoimmune thyroiditis, and severe autoimmune gastrointestinal manifestations. Immunological investigations revealed low immunoglobulin levels and low numbers of B and NK cells. Treatment included immunoglobulin replacement and immunosuppressive therapy. Seven years after disease onset, the patient developed severe neurological symptoms resembling acute disseminated encephalomyelitis, prompting allogeneic hematopoietic stem cell transplantation (HSCT) with the HLA-identical mother as donor. Whole exome sequencing of the patient uncovered a homozygous 1 bp deletion in LRBA (c.7162delA:p.T2388Pfs*7). Importantly, during 2 years of follow-up post-HSCT, marked clinical improvement and recovery of immune function was observed., Conclusions: Our data suggest a beneficial effect of HSCT in patients with LRBA deficiency.

Acute graft-versus-host disease (aGVHD) is mediated by allogeneic T cell responses. We hypothesized that increases of peripheral blood-activated CD8+ effector memory T (TEM) cells would be observed after hematopoietic stem cell transplantation (HSCT) before onset of aGVHD symptoms. Blood was collected twice weekly after HSCT for 7 weeks in 49 consecutive pediatric and adult HSCT recipients. Samples were incubated with fluorochrome-conjugated antibodies against CD45, CD3, CD8, CD38, CD45RA, and CCR7 and analyzed using flow cytometry. TEM cells were defined as CD3+ CD8+ CCR7- CD45RA(-) lymphocytes. CD38 expression was used as a marker of T cell activation. Patients were followed for 100 days for development of aGVHD. Twenty-three patients developed grade 1 to 4 aGVHD at a median of 37 days (range, 15 to 79 days) after HCST. Absolute CD38 bright CD8+ TEM of > 35 cells/μL predicted aGVHD at a median of 8 days (range, 1 to 34) before aGVHD onset with a sensitivity of 82.6% and specificity of 91.6%. The cumulative incidence of aGVHD was 90% in patients with absolute CD38 bright CD8+ TEM >35 cells/μL and 15% in patients without (P < .0001). Quantification of CD38 bright CD8+ TEM cells may predict aGVHD in children and young adult HSCT recipients., (Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Common variable immunodeficiency (CVID) is usually well controlled with immunoglobulin substitution and immunomodulatory drugs. A subgroup of patients has a complicated disease course with high mortality. For these patients, investigation of more invasive, potentially curative treatments, such as allogeneic hematopoietic stem cell transplantation (HSCT), is warranted., Objective: We sought to define the outcomes of HSCT for patients with CVID., Methods: Retrospective data were collected from 14 centers worldwide on patients with CVID receiving HSCT between 1993 and 2012., Results: Twenty-five patients with CVID, which was defined according to international criteria, aged 8 to 50 years at the time of transplantation were included in the study. The indication for HSCT was immunologic dysregulation in the majority of patients. The overall survival rate was 48%, and the survival rate for patients undergoing transplantation for lymphoma was 83%. The major causes of death were treatment-refractory graft-versus-host disease accompanied by poor immune reconstitution and infectious complications. Immunoglobulin substitution was stopped in 50% of surviving patients. In 92% of surviving patients, the condition constituting the indication for HSCT resolved., Conclusion: This multicenter study demonstrated that HSCT in patients with CVID was beneficial in most surviving patients; however, there was a high mortality associated with the procedure. Therefore this therapeutic approach should only be considered in carefully selected patients in whom there has been extensive characterization of the immunologic and/or genetic defect underlying the CVID diagnosis. Criteria for patient selection, refinement of the transplantation protocol, and timing are needed for an improved outcome., (Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Purpose of Review: Primary immunodeficiencies (PIDs) constitute a heterogeneous group of inherited disorders affecting the development and/or function of the immune system. This review focuses on the recent advances in hematopoietic stem cell transplantation (HSCT) for PIDs, as it remains the only potentially curative option for many of these diseases., Recent Findings: We report on the most recent HSCT European results and suggest some opportunities for better treatment of certain PIDs. Progress on gene therapy is also discussed, as it emerges as an interesting option for PIDs management., Summary: Progress in the treatment of primary immune deficiency with HSCT requires a better understanding of the pathophysiology and specificity of each of these diseases, allowing us to determine the best options in terms of donor, conditioning regimen, modification of the allograft and immunosuppressive therapy. Alternative therapies - such as gene therapy - emerge as an interesting option for some PIDs.

Purpose of Review: This review describes recent studies on outcomes after allogeneic hematopoietic cell transplantation for primary immunodeficiency in North America, including severe combined immunodeficiency (SCID), Wiskott-Aldrich syndrome and chronic granulomatous disease., Recent Findings: Using uniform diagnostic criteria, the Primary Immune Deficiency Treatment Consortium described the baseline characteristics of newly diagnosed infants with SCID in North America. Analysis of outcomes of hematopoietic cell transplantation for SCID in North America from 2000 to 2009 showed that young infants, and older infants without active infection, had excellent survival irrespective of type of donor or transplant approach with regard to conditioning. Although pretransplant conditioning with chemotherapy had a clear and strong negative impact on survival in infants with active infection at the time of transplant, among survivors, conditioning was associated with improved immune reconstitution. However, the potential late effects of conditioning in these infants remain to be characterized. Advances in transplant outcomes for Wiskott-Aldrich syndrome and chronic granulomatous disease support the strategy of early transplantation before the onset of severe complications; additional multicenter studies are needed to fully define optimal approaches., Summary: The formation of the Primary Immune Deficiency Treatment Consortium, a multiinstitutional North American consortium, has contributed to our understanding of outcomes after transplant for primary immunodeficiency.

Graft failure may contribute to increased morbidity and mortality after allogeneic hematopoietic SCT (allo-HSCT). Here, we present risk factors for graft failure in all first allo-HSCTs performed at our center from 1995 to mid-2010 (n=967). Graft failure was defined as >95% recipient cells any time after engraftment with no signs of relapse, or re-transplantation because of primary or secondary neutropenia (<0.5 × 10(9)/L) and/or thrombocytopenia (<30 × 10(9)/L). Fifty-four patients (5.6%) experienced graft failure. The majority were because of autologous reconstitution (n=43), and only a few patients underwent re-transplantation because of primary (n=6) or secondary (n=5) graft failures. In non-malignant disorders, graft failure had no effect on survival, whereas in malignant disease graft failure was associated with reduced 5-year survival (22 vs 53%, P<0.01). In multivariate analysis, ex vivo T-cell depletion (relative risk (RR) 8.82, P<0.001), HLA-mismatched grafts (RR 7.64, P<0.001), non-malignant disorders (RR 3.32, P<0.01) and reduced-intensity conditioning (RR 2.58, P<0.01) increased the risk for graft failure, whereas graft failures were prevented by total nucleated cell doses of ≥ 2.5 × 10(8)/kg (RR 0.36, P<0.01). In conclusion, graft failure was only associated with inferior survival in malignant disease. Non-malignant disorders, HLA match, conditioning intensity, immunosuppression regimen and cell dose all influenced graft failure risk.

Background: Hemophagocytic lymphohistiocytosis (HLH) is associated with hypercytokinemia in children. Although HLH can be also observed after hematopoietic stem cell transplantation (HSCT), the incidence and clinical features of HLH after HSCT remain obscure., Procedure: The clinical features of HLH after HSCT (post-HSCT HLH) were investigated in children with malignancies, immune deficiencies, or aplastic anemia. The HLH/Langerhans Cell Histiocytosis (LCH) Committee of the Japanese Society of Pediatric Hematology (JSPH) sent questionnaires to hospitals with JPSH members asking for details of cases in which HLH occurred after HSCT between 1998 and 2008., Results: Among 42 children who were diagnosed with post-HSCT HLH between 1998 and 2008 in Japan, 37 fulfilled our inclusion criteria; of these, 26 were classified as early-onset (onset <30 days after HSCT) and 11 were classified as late-onset (onset >30 days after HSCT). In the early-onset group, the presence of respiratory symptoms, high levels of total bilirubin, and triglycerides at onset and the lack of control of GVHD with tacrolimus were significantly associated with non-resolution of HLH (P < 0.05). The survival rate was significantly higher in patients with resolution of HLH than in those without resolution (59% vs. 14%, P < 0.05)., Conclusions: These findings suggest that early-onset post-HSCT HLH is a specific entity of HLH, and appropriate diagnosis and prompt management need to be established., (Copyright © 2011 Wiley Periodicals, Inc.)

Cytomegalovirus (CMV) reactivation was analyzed in 92 recipients of allogeneic hematopoietic stem cell transplantation (HSCT) in relation to the proportion of CD4(+) lymphocytes in blood and a microsatellite polymorphism within the first intron of the interferon-gamma (IFNG) gene. CMV reactivation was found in 50% of the HSCT recipients; in 30% of these individuals, the level of CMV copies exceeded 100 per 10(5) peripheral blood (PB) cells on at least one occasion during the 100-day post-HSCT observation period. This high CMV copy level was most frequently found between 31 and 60 days post-HSCT (P = .021). Patients with > or = 100 CMV copies/10(5) cells were characterized by poorer overall survival (OS) compared with those lacking CMV copies or having < 100 CMV copies/10(5) cells (P = .04), and they suffered from severe post-HSCT complications, including acute graft-versus-host disease (aGVHD) and relapse. Thus, patients with > or = 100 CMV copies/10(5) cells were designated as having clinically significant CMV reactivation. Patients with < 10% CD4(+) lymphocytes had a higher number of CMV DNA copies than those with higher proportions of CD4(+) lymphocytes (0.62 vs 0.21, P = .001; mean +/- SEM, 4422 +/- 1667 vs 937 +/- 662 CMV copies/10(5) cells, P < .001, for the proportion of cases with reactivation and numbers of copies, respectively). Similarly, patients carrying 2 IFNG 13-CA-repeat alleles (homozygotes) had more frequent CMV reactivation (0.50 vs 0.26; P = .039) and a higher CMV load (4111 +/- 1699 vs 950+/-591 CMV copies/10(5) cells; P = .041) compared with those with other IFNG microsatellite allele constellations. Multivariate analysis demonstrated that the IFNG 13-CA-repeat homozygous genotype (odds ratio [OR] = 0.221; P = .044), a low proportion of CD4(+) lymphocytes (OR = 0.276; P = .050), and a lack of optimal (10/10 alleles) donor-recipient HLA match (OR = 15.19; P = .006) were independent risk factors for CMV reactivation with a high number of copies.

Adoptive transfer of retrovirally transduced stem cells has recently been described for instant transgenesis in the hematopoietic compartment of mice. This method circumvents the need to manipulate the germline. However, cell type specific gene expression in this 'retrogenic' mouse model has remained tedious. Here we report a single retroviral vector-based method to rapidly generate conditional retrogenic mice. For this purpose, mutated loxP-flanked DNA segments are transduced into hematopoietic stem cells isolated from Cre recombinase transgenic mice, which are subsequently transferred into immunodeficient mice. In this way gene expression can be restricted to hematopoietic cell lineages of choice in the acquired immune system.

There is ongoing discussion whether survival improved for children requiring mechanical ventilation after hematopoietic stem cell transplantation (HSCT). We reviewed the outcomes of 150 children who received an allogeneic HSCT between January 1999 and April 2007, in a pediatric university hospital in The Netherlands. Thirty-five of the 150 patients received mechanical ventilation on 38 occasions. None of the recorded risk factors was significantly associated with the requirement of mechanical ventilation. Sixteen admissions resulted in death in the intensive care unit (ICU), giving a case fatality rate of 42% (95% confidence interval 26%-58%). ICU mortality was associated with multiorgan failure on the second day of admission and with the use of high frequency oscillatory ventilation. Patients had higher pediatric risk of mortality scores than in previous studies, reflecting higher acuity of illness on admission to the ICU. Six-month survival in patients discharged from the ICU was 82%. Compared to previous studies, we found an improvement in ICU survival and survival 6 months after ICU discharge in a recent cohort of ventilated children after allogeneic HSCT, even though our patients were more severely ill. Our results are promising, but they need to be confirmed in larger, preferably multicenter, studies.