Management of Atopy with Dupilumab and Omalizumab in CADINS Disease.

The caspase activation and recruitment domain 11 (CARD11) gene encodes a scaffold protein required for lymphocyte antigen receptor signaling. Dominant-negative, loss-of-function (LOF) pathogenic variants in CARD11 result in CARD11-associated atopy with dominant interference of NF-κB signaling (CADINS) disease. Patients with CADINS suffer with severe atopic manifestations including atopic dermatitis, food allergy, and chronic spontaneous urticaria in addition to recurrent infections and autoimmunity. We assessed the response of dupilumab in five patients and omalizumab in one patient with CADINS for the treatment of severe atopic symptoms. CARD11 mutations were validated for pathogenicity using a T cell transfection assay to assess the impact on activation-induced signaling to NF-κB. Three children and three adults with dominant-negative CARD11 LOF mutations were included. All developed atopic disease in infancy or early childhood. In five patients, atopic dermatitis was severe and recalcitrant to standard topical and systemic medications; one adult suffered from chronic spontaneous urticaria. Subcutaneous dupilumab was initiated to treat atopic dermatitis and omalizumab to treat chronic spontaneous urticaria. All six patients had rapid and sustained improvement in atopic symptoms with no complications during the follow-up period. Previous medications used to treat atopy were able to be decreased or discontinued. In conclusion, treatment with dupilumab and omalizumab for severe, refractory atopic disease in patients with CADINS appears to be effective and well tolerated in patients with CADINS with severe atopy.

Risk and promise: an 11-year, single-center retrospective study of severe acute GVHD in pediatric patients undergoing allogeneic HSCT for nonmalignant diseases.

Background: Hematopoietic stem cell transplantation (HSCT) is the only curative option for many nonmalignant hematopoietic-derived diseases in pediatric patients. Survival after HSCT has improved in recent years and resulted in a 90% survival rate and cure in some nonmalignant diseases. Graft-vs.-host disease (GVHD) remains a frequent and major complication of HSCT, and a leading cause of morbidity and mortality. Prognosis of patients with high-grade GVHD is dismal, with survival rates varying from 25% in the adult population to 55% in pediatric patients. Methods: The main aim of this study is to evaluate the incidence, risk factors, and outcome of severe acute GVHD (AGVHD) in pediatric patients with nonmalignant diseases, following allogeneic HSCT. Clinical and transplant data were retrospectively collected for all pediatric patients who underwent allogeneic HSCT for nonmalignant diseases at the Hadassah Medical Center between 2008 and 2019. Patients who developed severe AGVHD were compared with those who did not. Results: A total of 247 children with nonmalignant diseases underwent 266 allogeneic HSCTs at Hadassah University Hospital over an 11-year period. Seventy-two patients (29.1%) developed AGVHD, 35 of them (14.1%) severe AGVHD (grade 3-4). Significant risk factors for developing severe AGVHD were unrelated donor (p < 0.001), mismatch donor (p < 0.001), and the use of peripheral blood stem cells (PBSCs) (p < 0.001). Survival rates of pediatric patients with severe AGVHD was 71.4%, compared with 91.9% among those with mild (grade 1-2) AGVHD and 83.4% among patients without AGVHD (p = 0.067). Conclusions: These results demonstrate a high survival rate in pediatric patients with nonmalignant diseases despite severe GVHD. Significant mortality risk factors found in these patients were the source of donor PBSC (p = 0.016) and poor response to steroid treatment (p = 0.007).

Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency.

Patients with inherited CARMIL2 or CD28 deficiency have defective T cell CD28 signaling, but their immunological and clinical phenotypes remain largely unknown. We show that only one of three CARMIL2 isoforms is produced and functional across leukocyte subsets. Tested mutant CARMIL2 alleles from 89 patients and 52 families impair canonical NF-κB but not AP-1 and NFAT activation in T cells stimulated via CD28. Like CD28-deficient patients, CARMIL2-deficient patients display recalcitrant warts and low blood counts of CD4+ and CD8+ memory T cells and CD4+ TREGs. Unlike CD28-deficient patients, they have low counts of NK cells and memory B cells, and their antibody responses are weak. CARMIL2 deficiency is fully penetrant by the age of 10 yr and is characterized by numerous infections, EBV+ smooth muscle tumors, and mucocutaneous inflammation, including inflammatory bowel disease. Patients with somatic reversions of a mutant allele in CD4+ T cells have milder phenotypes. Our study suggests that CARMIL2 governs immunological pathways beyond CD28.

Vedolizumab for pediatric patients with gastrointestinal acute graft-versus-host-disease.

Vedolizumab, an anti-α4ß7 integrin monoclonal antibody, impairs homing of T-cells to the gastrointestinal (GI) endothelium and acts as a gut-selective anti-inflammatory agent. Recent reports of the efficacy of vedolizumab in treating lower GI acute graft-versus-host disease (aGVHD) are promising, but experience in children is scarce. We present a cohort of 13 pediatric patients who were treated with vedolizumab for GI aGVHD. Ten of the patients were treated for steroid-refractory disease, out of which, six suffered from severe (stage 3 or 4) GI disease before the first dose of vedolizumab. In the other three patients, vedolizumab was introduced early in the disease course. Median time between GI GVHD onset to vedolizumab treatment was 23 days (range 7-59 days), with a median of 3 doses (range 1-5) per patient. GI GVHD staging was evaluated at various time points after the first vedolizumab dose, showing improvement in nine of the 13 patients. After a median follow-up time of 13 months (range 6-34 months), eight patients completely recovered, two had ongoing chronic colitis, and three patients died. During the vedolizumab treatment period, 38 infectious episodes were noted, most of them GI related. The unique activity profile of vedolizumab makes it an appealing treatment option for lower GI aGVHD, but caution for concurrent infections is warranted.

Neurological complications following pediatric allogeneic hematopoietic stem cell transplantation: Risk factors and outcome.

Background: Allogeneic hematopoietic stem cell transplantation (HSCT) is an efficient treatment for numerous malignant and nonmalignant conditions affecting children. This procedure can result in infectious and noninfectious neurological complications (NCs). Objective: The objective of the study is to examine the incidence, risk factors, and outcomes of NCs in pediatric patients following allogeneic HSCT. Methods: We performed a retrospective study of 746 children who underwent 943 allogeneic HSCTs in two large pediatric hospitals in Israel from January 2000 to December 2019. Results: Of the pediatric patients 107 (14.3%) experienced 150 NCs. The median follow-up was 55 months. Noninfectious NCs were more common than infectious NCs (81.3% vs. 18.7%). Factors significantly associated with type of NC (infectious vs. noninfectious) were underlying disease (immunodeficiency vs. malignant and metabolic/hematologic disease) (p-value = 0.000), and use of immunosuppressive agent, either Campath or ATG (p-value = 0.041). Factors with a significant impact on developing neurological sequelae post-NC were number of HSCT >1 (p-value = 0.028), the use of alemtuzumab as an immunosuppressive agent (p-value = 0.003), and infectious type of NC (p-value = 0.046). The overall survival rate of whole NC-cohort was 44%; one-third of all mortality cases were attributed to the NC. The strongest prognostic factors associated with mortality were older age at HSCT (p-value = 0.000), the use of alemtuzumab as an immunosuppressive agent (p-value = 0.004), and the existence of neurological sequelae (p-value = 0.000). Abnormal central nervous system imaging (p-value = 0.013), the use of alemtuzumab as an immunosuppressive agent (p-value = 0.019), and neurological sequelae (p-value = 0.000) had statistically significant effects on neurological cause of death. Conclusion: Infectious and noninfectious NCs are a significant cause of morbidity and mortality following allogeneic HSCT in children. Further research is required to better understand the risk factors for different NCs and their outcomes regarding sequelae and survival.

Social determinants of health and primary immunodeficiency.

OBJECTIVE: Inborn errors of immunity (IEI) are rare genetic conditions affecting the immune system. The rate of IEI and their presentation, course, and treatment are all affected by a multitude of social determinants, eventually affecting prognosis. This review summarizes the current knowledge of the social determinants affecting infectious susceptibility, genetic predisposition, diagnosis, and treatment of IEI. DATA SOURCES: PubMed. STUDY SELECTIONS: Search terms included "consanguinity," "social determinants," and "founder effect." Further studies were selected based on relevant citations. RESULTS: Changes in climate and human behavior have modulated the spread of disease vectors and infectious organisms. Consanguinity increases the rate of autosomal recessive conditions, changes the distribution, and affects the severity of IEI. Access to sophisticated genetic and immunologic diagnostic modalities affects genetic counseling and timely diagnosis. Effective genetic counseling should address to the patient's genetic background and ethical code. Access to appropriate and timely treatment of immunodeficiencies is scarce in some regions of the world. CONCLUSION: High consanguinity rate and reduced access to prophylactic measures increase the burden of immunodeficiencies in many low- and medium-income countries. Furthermore, poor access to diagnostic and treatment modalities in these regions adversely affects patients' prognosis. Increased awareness among health care professionals and the public and increased collaboration with Western countries aid in diagnosis of these conditions. Further advancements require improved public funding to the prevention, diagnosis, and treatment of IEI.

The Clinical Aspect of Adaptor Molecules in T Cell Signaling: Lessons Learnt From Inborn Errors of Immunity.

Adaptor molecules lack enzymatic and transcriptional activities. Instead, they exert their function by linking multiple proteins into intricate complexes, allowing for transmitting and fine-tuning of signals. Many adaptor molecules play a crucial role in T-cell signaling, following engagement of the T-cell receptor (TCR). In this review, we focus on Linker of Activation of T cells (LAT) and SH2 domain-containing leukocyte protein of 76 KDa (SLP-76). Monogenic defects in these adaptor proteins, with known roles in T-cell signaling, have been described as the cause of human inborn errors of immunity (IEI). We describe the current knowledge based on defects in cell lines, murine models and human patients. Germline mutations in Adhesion and degranulation adaptor protein (ADAP), have not resulted in a T-cell defect.

Haploidentical stem cell transplantation with post-transplant cyclophosphamide for osteopetrosis and other nonmalignant diseases.

Allogeneic hematopoietic stem cell transplantation (HSCT) is curative for a variety of nonmalignant disorders including osteopetrosis, bone marrow failures, and immune deficiencies. Haploidentical HSCT is a readily available option in the absence of a matched donor, but engraftment failure and other post-transplant complications are a concern. Post-transplant cyclophosphamide (PT-Cy) regimens are gaining popularity and recent reports show promising results. We report our experience with nine pediatric patients with nonmalignant diseases who were transplanted from a haploidentical donor with PT-Cy. From 2015 to 2019, nine children with nonmalignant diseases underwent haploidentical HSCT with PT-Cy, two as a second transplant and seven as primary grafts after upfront serotherapy and busulfan-based myeloablative conditioning. Patient's diseases included osteopetrosis (n = 5), congenital amegakaryocytic thrombocytopenia (n = 2), hemophagocytic lymphohistiocytosis (n = 1), and Wiskott Aldrich syndrome (n = 1). Two patients failed to engraft following upfront PT-Cy transplants, one was salvaged with a second PT-Cy transplant, and the other with a CD34+ selected graft. None of the patients suffered from graft-versus-host disease. Three patients died from early posttransplant infectious complications and six patients are alive and well. In conclusion, haploidentical HSCT with PT-Cy is a feasible option for pediatric patients with nonmalignant diseases lacking a matched donor.

Bacillus Calmette-Guerin (BCG) Vaccine-associated Complications in Immunodeficient Patients Following Stem Cell Transplantation.

PURPOSE: Bacillus Calmette-Guerin (BCG) is a live attenuated vaccine with the potential of causing severe iatrogenic complications in patients with primary immunodeficiency diseases (PID) before and after hematopoietic stem cell transplantation (HSCT). We aim to investigate risk factors of post-HSCT BCG-related complications in PID patients. METHODS: A retrospective analysis of pediatric PID patients who had received the BCG vaccine and underwent HSCT at Hadassah-Hebrew University Medical Center, between 2007 and 2019. RESULTS: We found 15/36 (41.67%) patients who developed post-HSCT BCG-related complications. The most significant risk factor for developing BCG-related complications was T cell deficiency (47.6% of the non-complicated vs 83.3% of the BCGitis and 100% of the BCGosis groups had T cell lymphopenia, p = 0.013). None of the chronic granulomatous patients developed BCG-related manifestation post-transplant. Among T cell-deficient patients, lower NK (127 vs 698 cells/µl, p = 0.04) cell counts and NK-SCID were risk factors for ongoing post-HSCT BCGosis, as was pretransplant disseminated BCGosis (33.3% of patients with BCGosis vs none of the non-BCGosis patients, p = 0.04). Immune reconstitution inflammatory syndrome (IRIS) was observed in 3/5 patients with Omenn syndrome. Prophylactic antimycobacterial treatment was not proven effective. CONCLUSION: BCG vaccination can cause significant morbidity and mortality in the post-transplant T cell-deficient patient, especially in the presence of pre-transplant disease. Taking a detailed medical history prior to administering, the BCG vaccine is crucial for prevention of this complication.

Minor Clinical Impact of COVID-19 Pandemic on Patients With Primary Immunodeficiency in Israel.

In the last few months the world has witnessed a global pandemic due to severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection causing coronavirus disease 2019 (COVID-19). Obviously, this pandemic affected individuals differently, with a significant impact on populations considered to be at high-risk. One such population, was assumed to be patients with primary genetic defect involving components or pathways of the immune system. While human immunity against COVID-19 is not fully understood, it is, so far, well documented, that both adaptive and innate cells have a critical role in protection against SARS-CoV-2. Here, we aimed to summarize the clinical and laboratory data on primary immunodeficiency (PID) patients in Israel, who were tested positive for SARS-CoV-2, in order to estimate the impact of COVID-19 on such patients. Data was collected from mid-February to end-September. During this time Israel experienced two "waves" of COVID-19 diseases; the first, from mid-February to mid-May and the second from mid-June and still ongoing at the end of data collection. A total of 20 PID patients, aged 4 months to 60 years, were tested positive for SARS-CoV-2, all but one, were detected during the second wave. Fourteen of the patients were on routine monthly IVIG replacement therapy at the time of virus detection. None of the patients displayed severe illness and none required hospitalization; moreover, 7/20 patients were completely asymptomatic. Possible explanations for the minimal clinical impact of COVID-19 pandemic observed in our PID patients include high level of awareness, extra-precautions, and even self-isolation. It is also possible that only specific immune pathways (e.g. type I interferon signaling), may increase the risk for a more severe course of disease and these are not affected in many of the PID patients. In some cases, lack of an immune response actually may be a protective measure against the development of COVID-19 sequelae.

Successful treatment with daratumumab for post-HSCT refractory hemolytic anemia.

Autoimmune cytopenias (AIC) following allogeneic hematopoietic stem cell transplantation (HSCT) may cause significant morbidity and mortality and are often challenging to treat. We present a case of a pediatric patient with primary myelofibrosis of infancy caused by VPS45 protein deficiency, who developed severe refractory hemolytic anemia and immune-mediated thrombocytopenia 3.5 months following HSCT. After the failure of several treatments, he received daratumumab, an anti-CD38 specific antibody, and demonstrated fast and sustained response. The only side effect was delayed recovery of humoral immunity. Daratumumab, by targeting antibody-producing plasma cells, may be a valid treatment option for refractory post-HSCT AIC.

A homozygous mutation in the stem II domain of RNU4ATAC causes typical Roifman syndrome.

Roifman syndrome (OMIM# 616651) is a complex syndrome encompassing skeletal dysplasia, immunodeficiency, retinal dystrophy and developmental delay, and is caused by compound heterozygous mutations involving the Stem II region and one of the other domains of the RNU4ATAC gene. This small nuclear RNA gene is essential for minor intron splicing. The Canadian Centre for Primary Immunodeficiency Registry and Repository were used to derive patient information as well as tissues. Utilising RNA sequencing methodologies, we analysed samples from patients with Roifman syndrome and assessed intron retention. We demonstrate that a homozygous mutation in Stem II is sufficient to cause the full spectrum of features associated with typical Roifman syndrome. Further, we demonstrate the same pattern of aberration in minor intron retention as found in cases with compound heterozygous mutations.

Bone marrow transplantation for non-malignant diseases using treosulfan-based conditioning.

BACKGROUND: Treosulfan (treo) is an alkylating agent with a low acute toxicity profile that is increasingly used in hematopoietic stem cell transplantation, predominantly in non-malignant diseases. Treosulfan is usually combined with additional agents, but there is scant evidence to allow comparison between different conditioning protocols using treosulfan. We present the experience of three pediatric transplantation centers in Israel using different treosulfan-based conditioning regimens. PROCEDURE: Data were collected retrospectively on 44 children who underwent 45 hematopoietic stem cell transplantations using treosulfan in combination with either fludarabine (flu) and thiotepa (tt) (n = 20), cyclophosphamide (cy) (n = 6) or fludarabine alone (n = 19). RESULTS: Overall survival (OS) was 70.5%. Disease free survival (DFS) was 54.6%. There was no statistically significant difference between treatment groups in either OS or DFS. Overall survival in patients younger than one year was higher (88.2%). There were significantly more patients with 100% donor chimerism transplanted with flu/treo/tt compared with flu/treo or treo/cy (94.7% compared to 66.7% and 16.7%, respectively). Further prospective studies are required to determine the optimal treosulfan-based preparative regimen for children with non-malignant diseases. Pediatr Blood Cancer 2015;62:299-304. © 2014 Wiley Periodicals, Inc.

Antibiotic treatment of children with community-acquired pneumonia: comparison of penicillin or ampicillin versus cefuroxime.

OBJECTIVE: Adherence to current guidelines for treatment of non-complicated community-acquired pneumonia (CAP) in children, recommending penicillin or ampicillin as first-line treatment, has been poor. Our objective was to examine whether cefuroxime confers an advantage over penicillin or ampicillin for the treatment of children hospitalized with non-complicated CAP. PATIENTS AND METHODS: All children aged 3 months to 2 years with non-complicated CAP treated with penicillin or ampicillin or cefuroxime, admitted during 2003-2008, in the Departments of Pediatrics, Hadassah University Medical Center were included. Presenting signs, symptoms, laboratory findings at presentation, clinical parameters including number of days with IV antibiotics, oxygen treatment, length of hospital stay, change of antibiotics, and clinical course 72 hr and 1 week after admission, were compared. RESULTS: Of the 319 children admitted for non-complicated CAP, 66 were treated with IV penicillin or ampicillin, 253 with IV cefuroxime. Number of days of IV treatment, days of oxygen requirement, and days of hospitalization were similar (2.36 ± 1.6 days vs. 2.59 ± 1.6 days, 0.31 ± 1.2 days vs. 0.64 ± 1.3 days, and 2.67 ± 1.4 days vs. 2.96 ± 1.7 days, respectively). Treatment failure was not significantly different (7.6% vs. 4.7%). The number of patients who were febrile or required oxygen 72 hr after admission was similar (13.0% vs. 16.5% and 8.7% vs. 20.9%, respectively). One week after admission no difference between the two groups was seen. CONCLUSIONS: In previously healthy children, parenteral penicillin or ampicillin for treatment of non-complicated CAP in-hospital is as effective as cefuroxime, and should remain the recommended first-line therapy.