Combined therapy with IL-1 and JAK inhibitors in a patient with the NLRP1 gene mutation and a complex inflammatory phenotype.

A patient presented with overlapping clinical and laboratory features of 2 rare autoinflammatory diseases, NLRP1-associated autoinflammation with arthritis and dyskeratosis and familial multiple self-healing palmoplantar carcinoma. Her severe inflammatory attack was treated with the IL-1 receptor-α inhibitor anakinra along with the Janus kinase inhibitor ruxolitinib. Three years into the treatment, the patient's inflammatory symptoms are completely in remission.

Phase 3 randomized trial of mavorixafor, CXCR4 antagonist, in WHIM syndrome.

We investigated efficacy and safety of mavorixafor, an oral CXCR4 antagonist for participants with Warts, Hypogammaglobulinemia, Infections, and Myelokathexis (WHIM) syndrome, a rare immunodeficiency caused by CXCR4 gain-of-function variants. This randomized (1:1), double-blind, placebo-controlled, phase 3 trial enrolled participants aged ≥12 years with WHIM syndrome and absolute neutrophil count (ANC) ≤400/µL. Participants received once-daily mavorixafor or placebo for 52 weeks. Primary endpoint was time (hours) above ANC threshold ≥500/µL (TATANC; over 24 hours). Secondary endpoints included TAT absolute lymphocyte count ≥1000/µL (TATALC; defined similar to TATANC); absolute changes in white blood cell (WBC), ANC, and ALC from baseline; annualized infection rate; infection duration and total infection score (combined infection number/severity). In 31 participants (mavorixafor, n=14; placebo, n=17), mavorixafor least squares (LS) mean TATANC was 15.0 hours, placebo 2.8 hours (P<0.001). Mavorixafor LS mean TATALC was 15.8 hours, placebo 4.6 hours (P<0.001). Higher absolute WBC, ANC, and ALC levels were seen with mavorixafor than placebo at each timepoint assessed. Annualized infection rates were 60% lower with mavorixafor versus placebo (LS mean 1.7 versus 4.2; nominal P=0.007) and total infection scores were 40% lower (7.4 [95% CI, 1.6-13.2] versus 12.3 [95% CI, 7.2-17.3]). Treatment with mavorixafor reduced infection frequency, severity, duration, and antibiotic use. No discontinuations occurred due to treatment-emergent adverse events (TEAEs); no related serious TEAEs were observed. Overall, mavorixafor-treated participants showed significant increases in LS mean TATANC and TATALC, reduced infection frequency, severity/duration. Mavorixafor was well tolerated in participants with WHIM syndrome. Trial was registered at ClinicalTrials.gov NCT03995108.

Newborn Screening for Severe T and B Cell Lymphopenia Using TREC/KREC Detection: A Large-Scale Pilot Study of 202,908 Newborns.

Newborn screening (NBS) for severe inborn errors of immunity (IEI), affecting T lymphocytes, and implementing measurements of T cell receptor excision circles (TREC) has been shown to be effective in early diagnosis and improved prognosis of patients with these genetic disorders. Few studies conducted on smaller groups of newborns report results of NBS that also include measurement of kappa-deleting recombination excision circles (KREC) for IEI affecting B lymphocytes. A pilot NBS study utilizing TREC/KREC detection was conducted on 202,908 infants born in 8 regions of Russia over a 14-month period. One hundred thirty-four newborns (0.66‰) were NBS positive after the first test and subsequent retest, 41% of whom were born preterm. After lymphocyte subsets were assessed via flow cytometry, samples of 18 infants (0.09‰) were sent for whole exome sequencing. Confirmed genetic defects were consistent with autosomal recessive agammaglobulinemia in 1/18, severe combined immunodeficiency - in 7/18, 22q11.2DS syndrome - in 4/18, combined immunodeficiency - in 1/18 and trisomy 21 syndrome - in 1/18. Two patients in whom no genetic defect was found met criteria of (severe) combined immunodeficiency with syndromic features. Three patients appeared to have transient lymphopenia. Our findings demonstrate the value of implementing combined TREC/KREC NBS screening and inform the development of policies and guidelines for its integration into routine newborn screening programs.

Variants in the WDR44 WD40-repeat domain cause a spectrum of ciliopathy by impairing ciliogenesis initiation.

WDR44 prevents ciliogenesis initiation by regulating RAB11-dependent vesicle trafficking. Here, we describe male patients with missense and nonsense variants within the WD40 repeats (WDR) of WDR44, an X-linked gene product, who display ciliopathy-related developmental phenotypes that we can model in zebrafish. The patient phenotypic spectrum includes developmental delay/intellectual disability, hypotonia, distinct craniofacial features and variable presence of brain, renal, cardiac and musculoskeletal abnormalities. We demonstrate that WDR44 variants associated with more severe disease impair ciliogenesis initiation and ciliary signaling. Because WDR44 negatively regulates ciliogenesis, it was surprising that pathogenic missense variants showed reduced abundance, which we link to misfolding of WDR autonomous repeats and degradation by the proteasome. We discover that disease severity correlates with increased RAB11 binding, which we propose drives ciliogenesis initiation dysregulation. Finally, we discover interdomain interactions between the WDR and NH2-terminal region that contains the RAB11 binding domain (RBD) and show patient variants disrupt this association. This study provides new insights into WDR44 WDR structure and characterizes a new syndrome that could result from impaired ciliogenesis.

Interim analysis: Open-label extension study of leniolisib for patients with APDS.

BACKGROUND: Activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS; or p110δ-activating mutations causing senescent T cells, lymphadenopathy, and immunodeficiency) is an inborn error of immunity caused by PI3Kδ hyperactivity. Resultant immune deficiency and dysregulation lead to recurrent sinopulmonary infections, herpes viremia, autoimmunity, and lymphoproliferation. OBJECTIVE: Leniolisib, a selective PI3Kδ inhibitor, demonstrated favorable impact on immune cell subsets and lymphoproliferation over placebo in patients with APDS over 12 weeks. Here, we report results from an interim analysis of an ongoing open-label, single-arm extension study. METHODS: Patients with APDS aged 12 years or older who completed NCT02435173 or had previous exposure to PI3Kδ inhibitors were eligible. The primary end point was safety, assessed via investigator-reported adverse events (AEs) and clinical/laboratory evaluations. Secondary and exploratory end points included health-related quality of life, inflammatory markers, frequency of infections, and lymphoproliferation. RESULTS: Between September 2016 and August 2021, 37 patients (median age, 20 years; 42.3% female) were enrolled. Of these 37 patients, 26, 9, and 2 patients had previously received leniolisib, placebo, or other PI3Kδ inhibitors, respectively. At the data cutoff date (December 13, 2021), median leniolisib exposure was 102 weeks. Overall, 32 patients (87%) experienced an AE. Most AEs were grades 1 to 3; none were grade 4. One patient with severe baseline comorbidities experienced a grade 5 AE, determined as unrelated to leniolisib treatment. While on leniolisib, patients had reduced annualized infection rates (P = .004), and reductions in immunoglobulin replacement therapy occurred in 10 of 27 patients. Other observations include reduced lymphadenopathy and splenomegaly, improved cytopenias, and normalized lymphocyte subsets. CONCLUSIONS: Leniolisib was well tolerated and maintained durable outcomes with up to 5 years of exposure in 37 patients with APDS. CLINICALTRIALS: gov identifier: NCT02859727.

JAK inhibitor treatment for inborn errors of JAK/STAT signaling: An ESID/EBMT-IEWP retrospective study.

BACKGROUND: Inborn errors of immunity (IEI) with dysregulated JAK/STAT signaling present with variable manifestations of immune dysregulation and infections. Hematopoietic stem cell transplantation (HSCT) is potentially curative, but initially reported outcomes were poor. JAK inhibitors (JAKi) offer a targeted treatment option that may be an alternative or bridge to HSCT. However, data on their current use, treatment efficacy and adverse events are limited. OBJECTIVE: We evaluated the current off-label JAKi treatment experience for JAK/STAT inborn errors of immunity (IEI) among European Society for Immunodeficiencies (ESID)/European Society for Blood and Marrow Transplantation (EBMT) Inborn Errors Working Party (IEWP) centers. METHODS: We conducted a multicenter retrospective study on patients with a genetic disorder of hyperactive JAK/STAT signaling who received JAKi treatment for at least 3 months. RESULTS: Sixty-nine patients (72% children) were evaluated (45 STAT1 gain of function [GOF], 21 STAT3-GOF, 1 STAT5B-GOF, 1 suppressor of cytokine signaling 1 [aka SOCS1] loss of function, 1 JAK1-GOF). Ruxolitinib was the predominantly prescribed JAKi (80%). Overall, treatment resulted in improvement (partial or complete remission) of clinical symptoms in 87% of STAT1-GOF and in 90% of STAT3-GOF patients. We documented highly heterogeneous dosing and monitoring regimens. The response rate and time to response varied across different diseases and manifestations. Adverse events including infection and weight gain were frequent (38% of patients) but were mild (grade I-II) and transient in most patients. At last follow-up, 52 (74%) of 69 patients were still receiving JAKi treatment, and 11 patients eventually underwent HSCT after receipt of previous JAKi bridging therapy, with 91% overall survival. CONCLUSIONS: Our study suggests that JAKi may be highly effective to treat symptomatic JAK/STAT IEI patients. Prospective studies to define optimal JAKi dosing for the variable clinical presentations and age ranges should be pursued.

Documenting heritage language experience using questionnaires.

Introduction: There exists a great degree of variability in the documentation of multilingual experience across different instruments. The present paper contributes to the "methods turn" and individual differences focus in (heritage) bilingualism by proposing a comprehensive online questionnaire building on existing questionnaires and the experience of using them to document heritage bilingualism: the Heritage Language Experience (HeLEx) online questionnaire. HeLEx is validated against and contrasted to an extended version of the Language and Social Background Questionnaire designed for heritage speakers (HSs), LSBQ-H. Methods: We compare data elicited with both questionnaires in turn from a group of Turkish HSs (n = 174, mean age=32). Our validation focuses on traditional language background variables, including language exposure and use, language proficiency, language dominance, as well as a more novel measure of language entropy. The analyses are based on a subset of key questions from each questionnaire that capture language experience for up to five languages, four modalities, and five social contexts. In a subsequent set of analyses, we explore the impact of different types of response scales, response mechanisms, and manners of variable derivation on the informativity of the data they can provide, in terms of the scope, granularity and distributional properties of the derived measures. Results and Discussion: Our results show that both HeLEx and LSBQ-H are successful at detecting the important distributional patterns in the data and reveal a number of advantages of HeLEx. In the discussion, we consider the impact of methodological choices regarding question phrasing, visual format, response options, and response mechanisms. We emphasize that these choices are not trivial and can affect the derived measures and subsequent analyses on the impact of individual differences on language acquisition and processing.

Morphological transparency and markedness matter in heritage speaker gender processing: an EEG study.

The present study investigated the qualitative nature of grammatical gender knowledge and processing in heritage speakers (HSs) of Spanish living in the United States. Forty-four adult Spanish HS bilinguals participated, completing a behavioral grammatical gender assignment task and a grammaticality judgment task (GJT) while their brain activity was recorded using electroencephalography (EEG). The EEG GJT task included grammatical and ungrammatical sentences with grammatical gender violations on inanimate nouns, where transparency of the morpho(phono)logical cue and markedness were manipulated. The results of this study revealed that grammatical gender violations elicited the typical P600 effect across all relevant conditions, indicating that the grammatical representations and processing of grammatical gender in HSs are qualitatively similar to those in Spanish-dominant native speakers. Given the experimental manipulation in this study, these findings also suggest that both morphological transparency and markedness play significant roles in how grammatical gender is processed. However, the results of this study differ from those reported in previous studies with Spanish-dominant native speakers, as the P600 effect found was accompanied by a biphasic N400 effect. This pattern of results is interpreted as further evidence that the bilingual experience of HSs modulates certain aspects of morphosyntactic processing, particularly conferring a greater reliance on morphology. Additionally, the results of this study highlight the importance of incorporating neurolinguistic online processing methods to better understand what underlies HS bilingual competence and processing outcomes.

Russian heritage language development in narrative contexts: Evidence from pre- and primary-school children in Norway, Germany, and the UK.

The present study aims at obtaining a comprehensive picture of language development in Russian heritage language (RHL) by bringing together evidence from previous investigations focusing on morphosyntax and global accent as well as from a newly conducted analysis of a less-studied domain-lexical development. Our investigation is based on a narrative sample of 143 pre- and primary-school bilinguals acquiring RHL in Norway, Germany, and the United Kingdom. We performed a multiple-way analysis of lexical production in RHL across the different national contexts, across both languages (heritage and societal), also comparing bilinguals and monolinguals. The results revealed a clear and steady increase with age in narrative length and lexical diversity for all bilingual groups in both of their languages. The variation in lexical productivity as well as the differences between the bilingual groups and between bilinguals and monolinguals were attributed to input factors with language exposure in the home and age of starting preschool as the major predictors. We conclude that, overall, the results from lexical, grammatical, and phonological acquisition in RHL support the view that having longer exclusive or uninterrupted exposure to a heritage language in early childhood is beneficial for its development across domains.

A randomized, placebo-controlled phase 3 trial of the PI3Kδ inhibitor leniolisib for activated PI3Kδ syndrome.

Activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS) is an inborn error of immunity with clinical manifestations including infections, lymphoproliferation, autoimmunity, enteropathy, bronchiectasis, increased risk of lymphoma, and early mortality. Hyperactive PI3Kδ signaling causes APDS and is selectively targeted with leniolisib, an oral, small molecule inhibitor of PI3Kδ. Here, 31 patients with APDS aged ≥12 years were enrolled in a global, phase 3, triple-blinded trial and randomized 2:1 to receive 70 mg leniolisib or placebo twice daily for 12 weeks. Coprimary outcomes were differences from baseline in the index lymph node size and the percentage of naïve B cells in peripheral blood, assessed as proxies for immune dysregulation and deficiency. Both primary outcomes were met: the difference in the adjusted mean change (95% confidence interval [CI]) between leniolisib and placebo for lymph node size was -0.25 (-0.38, -0.12; P = .0006; N = 26) and for percentage of naïve B cells, was 37.30 (24.06, 50.54; P = .0002; N = 13). Leniolisib reduced spleen volume compared with placebo (adjusted mean difference in 3-dimensional volume [cm3], -186; 95% CI, -297 to -76.2; P = .0020) and improved key immune cell subsets. Fewer patients receiving leniolisib reported study treatment-related adverse events (AEs; mostly grades 1-2) than those receiving placebo (23.8% vs 30.0%). Overall, leniolisib was well tolerated and significant improvement over placebo was notable in the coprimary endpoints, reducing lymphadenopathy and increasing the percentage of naïve B cells, reflecting a favorable impact on the immune dysregulation and deficiency seen in patients with APDS. This trial was registered at www.clinicaltrials.gov as #NCT02435173.

Cancer-causing MAP2K1 mutation in a mosaic patient with cardio-facio-cutaneous syndrome and immunodeficiency.

RASopathies are disorders caused by germline mutations in genes that encode components of the RAS/mitogen-activated protein kinase (MAPK) pathway. These syndromes share features of developmental delay, facial dysmorphisms, and defects in various organs, as well as cancer predisposition. Somatic mutations of the same pathway are one of the primary causes of cancer. It is thought that germline cancer-causing mutations would be embryonic lethal, as a more severe phenotype was shown in Drosophila and zebrafish embryos with cancer MAP2K1 mutations than in those with RASopathy mutations. Here we report the case of a patient with RASopathy caused by a cancer-associated MAP2K1 p.Phe53Leu mutation. The postzygotic mosaic nature of this mutation could explain the patient's survival.

BCG Infection in Patients With Inborn Errors of Immunity Receiving the Russian BCG Strain.

BACKGROUND: Bacillus Calmette-Guierin (BCG) vaccination complications are common in inborn errors of immunity (IEI) due to the inability to clear live attenuated Mycobacterium bovis. Various BCG-vaccine strains are used worldwide, and the profile of the Russian BCG strain vaccine complications in IEI is poorly characterized. OBJECTIVE: To evaluate risks of BCG infection in a large cohort of patients with IEI vaccinated with the Russian BCG strain. METHODS: We evaluated 778 patients with IEI vaccinated with the Russian BCG strain. RESULTS: A total of 114 (15%) developed BCG infection, 41 (36%) with local, 19 (17%) with regional, and 54 with (47%) disseminated disease. BCG infection was seen in 58% of the patients with severe combined immunodeficiency (SCID), 82% with chronic granulomatous disease, 50% with innate immune defects, 5% with combined immunodeficiency, and 2% with other IEI. BCG infection presented at a median age of 4 to 5 months in SCID, chronic granulomatous disease, combined immunodeficiency, and other IEI groups versus 12 months in patients with innate immune defects (P < .005). We found no influence of specific genetic defects, CD3+ and natural killer cell numbers in SCID, or dihydrorhodamine test stimulation index values in chronic granulomatous disease on the BCG-infection risks. All patients with SCID received antimycobacterial therapy at SCID diagnosis even in the absence of active BCG infection. More antimycobacterial agents were required in disseminated relative to local or regional infection (P < .0001). Only 1 of 114 patients (with SCID) died of BCG-related complications (<1%). CONCLUSIONS: BCG infection is common in patients with IEI receiving BCG vaccination. Rational early antimycobacterial therapy, combined with anticytokine agents for posttransplant inflammatory syndrome prevention, and treatment in SCID may prevent BCG-related mortality.

Rituximab and Abatacept Are Effective in Differential Treatment of Interstitial Lymphocytic Lung Disease in Children With Primary Immunodeficiencies.

Background: Interstitial lymphocytic lung disease (ILLD), a recently recognized complication of primary immunodeficiencies (PID), is caused by immune dysregulation, abnormal bronchus-associated lymphoid tissue (BALT) hyperplasia, with subsequent progressive loss of pulmonary function. Various modes of standard immunosuppressive therapy for ILLD have been shown as only partially effective. Objectives: To retrospectively evaluate the safety and efficacy of abatacept or rituximab in treatment of ILLD in children with PID. Methods: 29 children (median age 11 years) with various forms of PID received one of the two therapy regimens predominantly based on the lesions' immunohistopathology: children with prevalent B-cell lung infiltration received rituximab (n = 16), and those with predominantly T-cell infiltration received abatacept (n = 17). Clinical and radiological symptoms were assessed using a severity scale developed for the study. Results: The targeted therapy with abatacept (A) or rituximab (R) enabled long-term control of clinical (A 3.4 ± 1.3 vs. 0.6 ± 0.1; R 2.8 ± 1 vs. 0.7 ± 0.05, p < 0.01) and radiological (A 18.4 ± 3.1 vs. 6.0 ± 2.0; R 30 ± 7.1 vs. 10 ± 1.7, p < 0.01) symptoms of ILLD in both groups and significantly improved patients' quality of life, as measured by the total scale (TS) score of 57 ± 2.1 in treatment recipients vs. 31.2 ± 1.9 before therapy (p < 0.01). Conclusions: ILLD histopathology should be considered when selecting treatment. Abatacept and rituximab are effective and safe in differential treatment of ILLD in children.

Preexisting autoantibodies to type I IFNs underlie critical COVID-19 pneumonia in patients with APS-1.

Patients with biallelic loss-of-function variants of AIRE suffer from autoimmune polyendocrine syndrome type-1 (APS-1) and produce a broad range of autoantibodies (auto-Abs), including circulating auto-Abs neutralizing most type I interferons (IFNs). These auto-Abs were recently reported to account for at least 10% of cases of life-threatening COVID-19 pneumonia in the general population. We report 22 APS-1 patients from 21 kindreds in seven countries, aged between 8 and 48 yr and infected with SARS-CoV-2 since February 2020. The 21 patients tested had auto-Abs neutralizing IFN-α subtypes and/or IFN-ω; one had anti-IFN-ß and another anti-IFN-ε, but none had anti-IFN-κ. Strikingly, 19 patients (86%) were hospitalized for COVID-19 pneumonia, including 15 (68%) admitted to an intensive care unit, 11 (50%) who required mechanical ventilation, and four (18%) who died. Ambulatory disease in three patients (14%) was possibly accounted for by prior or early specific interventions. Preexisting auto-Abs neutralizing type I IFNs in APS-1 patients confer a very high risk of life-threatening COVID-19 pneumonia at any age.

Efficacy of romiplostim in treatment of thrombocytopenia in children with Wiskott-Aldrich syndrome.

Wiskott-Aldrich syndrome (WAS) is a life-threatening primary immunodeficiency associated with bleeding of variable severity due to thrombocytopenia. Correction of the thrombocytopenia is of paramount importance for most WAS patients. We report a retrospective analysis of the safety and efficacy of romiplostim treatment in reducing thrombocytopenia and bleeding tendency in 67 children (median age 1·3 years) with genetically confirmed WAS, followed in eight months (range, 1-12 months). Complete or partial primary responses regarding platelet counts were observed in 22 (33%) and 18 (27%) subjects, respectively. Yet, even in the non-responder group, the risk of haemorrhagic events decreased significantly, to 21%, after the first month of treatment. The responses tended to be durable and stable over time, with no significant fluctuations in platelets counts. The results of this retrospective study of a large cohort of WAS patients demonstrates that romiplostim can be used to increase platelet counts and reduce the risks of life-threatening bleeding in WAS patients awaiting haematopoietic stem cell transplantation or forgoing the procedure for various reasons.

Primary Immunodeficiencies in Russia: Data From the National Registry.

Introduction: Primary immunodeficiencies (PID) are a group of rare genetic disorders with a multitude of clinical symptoms. Characterization of epidemiological and clinical data via national registries has proven to be a valuable tool of studying these diseases. Materials and Methods: The Russian PID registry was set up in 2017, by the National Association of Experts in PID (NAEPID). It is a secure, internet-based database that includes detailed clinical, laboratory, and therapeutic data on PID patients of all ages. Results: The registry contained information on 2,728 patients (60% males, 40% females), from all Federal Districts of the Russian Federation. 1,851/2,728 (68%) were alive, 1,426/1,851 (77%) were children and 425/1,851 (23%) were adults. PID was diagnosed before the age of 18 in 2,192 patients (88%). Antibody defects (699; 26%) and syndromic PID (591; 22%) were the most common groups of PID. The minimum overall PID prevalence in the Russian population was 1.3:100,000 people; the estimated PID birth rate is 5.7 per 100,000 live births. The number of newly diagnosed patients per year increased dramatically, reaching the maximum of 331 patients in 2018. The overall mortality rate was 9.8%. Genetic testing has been performed in 1,740 patients and genetic defects were identified in 1,344 of them (77.2%). The median diagnostic delay was 2 years; this varied from 4 months to 11 years, depending on the PID category. The shortest time to diagnosis was noted in the combined PIDs-in WAS, DGS, and CGD. The longest delay was observed in AT, NBS, and in the most prevalent adult PID: HAE and CVID. Of the patients, 1,622 had symptomatic treatment information: 843 (52%) received IG treatment, mainly IVIG (96%), and 414 (25%) patients were treated with biological drugs. HSCT has been performed in 342/2,728 (16%) patients, of whom 67% are currently alive, 17% deceased, and 16% lost to follow-up. Three patients underwent gene therapy for WAS; all are currently alive. Conclusions: Here, we describe our first analysis of the epidemiological features of PID in Russia, allowing us to highlight the main challenges around PID diagnosis and treatment.

The Clinical and Genetic Spectrum of 82 Patients With RAG Deficiency Including a c.256_257delAA Founder Variant in Slavic Countries.

Background: Variants in recombination-activating genes (RAG) are common genetic causes of autosomal recessive forms of combined immunodeficiencies (CID) ranging from severe combined immunodeficiency (SCID), Omenn syndrome (OS), leaky SCID, and CID with granulomas and/or autoimmunity (CID-G/AI), and even milder presentation with antibody deficiency. Objective: We aim to estimate the incidence, clinical presentation, genetic variability, and treatment outcome with geographic distribution of patients with the RAG defects in populations inhabiting South, West, and East Slavic countries. Methods: Demographic, clinical, and laboratory data were collected from RAG-deficient patients of Slavic origin via chart review, retrospectively. Recombinase activity was determined in vitro by flow cytometry-based assay. Results: Based on the clinical and immunologic phenotype, our cohort of 82 patients from 68 families represented a wide spectrum of RAG deficiencies, including SCID (n = 20), OS (n = 37), and LS/CID (n = 25) phenotypes. Sixty-seven (81.7%) patients carried RAG1 and 15 patients (18.3%) carried RAG2 biallelic variants. We estimate that the minimal annual incidence of RAG deficiency in Slavic countries varies between 1 in 180,000 and 1 in 300,000 live births, and it may vary secondary to health care disparities in these regions. In our cohort, 70% (n = 47) of patients with RAG1 variants carried p.K86Vfs*33 (c.256_257delAA) allele, either in homozygous (n = 18, 27%) or in compound heterozygous (n = 29, 43%) form. The majority (77%) of patients with homozygous RAG1 p.K86Vfs*33 variant originated from Vistula watershed area in Central and Eastern Poland, and compound heterozygote cases were distributed among all Slavic countries except Bulgaria. Clinical and immunological presentation of homozygous RAG1 p.K86Vfs*33 cases was highly diverse (SCID, OS, and AS/CID) suggestive of strong influence of additional genetic and/or epigenetic factors in shaping the final phenotype. Conclusion: We propose that RAG1 p.K86Vfs*33 is a founder variant originating from the Vistula watershed region in Poland, which may explain a high proportion of homozygous cases from Central and Eastern Poland and the presence of the variant in all Slavs. Our studies in this cohort of RAG1 founder variants confirm that clinical and immunological phenotypes only partially depend on the underlying genetic defect. As access to HSCT is improving among RAG-deficient patients in Eastern Europe, we anticipate improvements in survival.

BCG-Related Inflammatory Syndromes in Severe Combined Immunodeficiency After TCRαß+/CD19+ Depleted HSCT.

INTRODUCTION: The live-attenuated BCG vaccine is known to cause disseminated Mycobacterium bovis infection in patients with severe combined immunodeficiency (SCID). However, BCG-related post-hematopoietic stem cell transplantation (HSCT) immune reconstitution inflammatory syndromes, similar to those described in patients with HIV infections, are less-known complications of SCID. PATIENTS AND METHODS: We reported on 22 BCG-vaccinated SCID patients who had received conditioned allogeneic HSCT with TCRαß+/CD19+ graft depletion. All BCG-vaccinated patients received anti-mycobacterial therapy pre- and post-HSCT. Post-transplant immunosuppression consisted of tacrolimus in 10 patients and of 8 mg/kg tocilizumab (d-1, + 14, + 28) and 10 mg/kg abatacept (d-1, + 5, + 14, + 28) in 11 patients. RESULTS: Twelve patients, five of whom had BCG infection prior to HSCT, developed BCG-related inflammatory syndromes (BCG-IS). Five developed early BCG-IS with the median time of manifestation 11 days after HSCT, corresponding with a dramatic increase of CD3+TCRγδ+ in at least two patients. Early BCG-IS was noted in only one out of 11 patients who received tocilizumab/abatacept and 4 out of 11 patients who did not. Seven patients developed late BCG-IS which corresponded to T cell immune recovery; at the time of manifestation (median 4.2 months after HSCT), the median number of CD3+ cells was 0.42 × 109/ and CD3+CD4+ cells 0.27 × 109/l. In all patients, late BCG-IS was controlled with IL-1 or IL-6 inhibitors. CONCLUSION: BCG-vaccinated SCID patients undergoing allogeneic HSCT with TCRαß+/CD19+ graft depletion are at an increased risk of early and late BCG-IS. Anti-inflammatory therapy with IL-1 and IL-6 blockade is efficient in the prevention of early and treatment of late BCG-IS.

Efficacy and safety of octanorm (cutaquig®) in adults with primary immunodeficiencies with predominant antibody deficiency: a prospective, open-label study.

Aim: To evaluate efficacy and safety of octanorm (16.5% subcutaneous immunoglobulin) in adult patients with primary immunodeficiencies. Patients & methods: Primary immunodeficiencies patients (18-70 years) previously treated with intravenous immunoglobulin were included in this Phase III study. Octanorm was administered subcutaneously once weekly over 8 months. End points included infections, adverse events and quality of life. Results: 25 patients (mean age 35.2 years, female 60.0%) were recruited, 24 completed the study. Mean dose of octanorm was 0.11 g/kg/week. No serious bacterial infections occurred. Three patients (12.0%) had an adverse event (mild) assessed as related to octanorm. Both the mental and physical summary 36-item Short Form Health Survey scores were improved. Conclusion: Octanorm is effective, safe and improves quality of life. Clinical Trial registration number: NCT03988426.

CARMIL2 Deficiency Presenting as Very Early Onset Inflammatory Bowel Disease.

BACKGROUND: Children with very early onset inflammatory bowel diseases (VEO-IBD) often have a refractory and severe disease course. A significant number of described VEO-IBD-causing monogenic disorders can be attributed to defects in immune-related genes. The diagnosis of the underlying primary immunodeficiency (PID) often has critical implications for the treatment of patients with IBD-like phenotypes. METHODS: To identify the molecular etiology in 5 patients from 3 unrelated kindred with IBD-like symptoms, we conducted whole exome sequencing. Immune workup confirmed an underlying PID. RESULTS: Whole exome sequencing revealed 3 novel CARMIL2 loss-of-function mutations in our patients. Immunophenotyping of peripheral blood mononuclear cells showed reduction of regulatory and effector memory T cells and impaired B cell class switching. The T cell proliferation and activation assays confirmed defective responses to CD28 costimulation, consistent with CARMIL2 deficiency. CONCLUSION: Our study highlights that human CARMIL2 deficiency can manifest with IBD-like symptoms. This example illustrates that early diagnosis of underlying PID is crucial for the treatment and prognosis of children with VEO-IBD.