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In patients with severe and recurrent infections, minimal diagnostic workup to test for Inborn Errors of Immunity (IEI) includes a full blood count, IgG, IgA and IgM. Vaccine antibodies against tetanus toxoid are also frequently measured, whereas testing for anti-polysaccharide IgG antibodies and IgG subclasses is not routinely performed by primary care physicians. This basic approach may cause a significant delay in diagnosing monogenic IEI that can present with an impaired IgG response to polysaccharide antigens with or without IgG subclass deficiency at an early stage. Our article reviews genetically defined IEI, that may initially present with an impaired IgG response to polysaccharide antigens, but normal or only slightly decreased IgG levels and normal responses to protein or conjugate vaccine antigens. We summarize clinical, genetic, and immunological findings characteristic for these IEI. This review may help clinicians to identify patients that require extended immunologic and genetic evaluations despite unremarkable basic immunologic findings. We recommend the inclusion of anti-polysaccharide IgG antibodies as part of the initial routine work-up for possible IEI., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (© 2024 Fasshauer, Dinges, Staudacher, Völler, Stittrich, von Bernuth, Wahn and Krüger.)

Heterozygous germline variants in human IKZF1 encoding for IKAROS define an inborn error of immunity with immunodeficiency, immune dysregulation and risk of malignancy with a broad phenotypic spectrum. Growing evidence of underlying pathophysiological genotype-phenotype correlations helps to improve our understanding of IKAROS-associated diseases. We describe 6 patients from 4 kindreds with two novel IKZF1 variants leading to haploinsufficiency from 3 centers in Germany. We also provide an overview of first symptoms to a final diagnosis including data from the literature., Competing Interests: Author AS and HB were employed by the company Labor Berlin Charité-Vivantes GmbH and author MF was employed by the company Hospital St. Georg GGmbH Leipzig. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (© 2024 Strauss, Körholz, Kuehn, Gil Silva, Taube, Trautmann-Grill, Stittrich, Pietzsch, Wiedemuth, Wahn, von Bernuth, Rosenzweig, Fasshauer, Krüger and Schuetz.)

Background: Pulmonary manifestations are the major cause of morbidity and mortality in patients with inborn errors of immunity (IEI). New and more sensitive diagnostic methods can potentially lead to earlier recognition and treatment of IEI lung disease and improve outcome. The aim of this study was to compare multiple-breath washout (MBW) and spirometry in patients with IEI and cystic fibrosis (CF) as well as healthy controls (HC) and to evaluate the sensitivity of lung clearance index (LCI) to assess lung disease in IEI., Methods: IEI patients (n=114) were recruited from our paediatric and adult immunodeficiency outpatient clinics and compared to age-matched CF patients (n=114) and HC (n=114). MBW measurements and spirometry were performed in the study participants, and MBW testing was repeated after 63-707 days in IEI patients (n=70)., Results: The LCI was significantly higher in IEI patients than in HC ( p <0.001) and significantly lower than in CF patients (p<0.001). The forced expiratory volume in 1 s (FEV 1 ) z-score was significantly lower in IEI patients than in HC (p<0.01) and significantly higher than in CF patients (p<0.01). LCI and FEV 1 z-score correlated moderately negatively in the total cohort, the IEI group and the CF group. Nineteen (20.7%) of 92 IEI patients and 35 (33.3%) of 105 CF patients had an elevated LCI but a normal FEV 1 z-score. After a median of 364 days, the median LCI of 70 IEI patients increased significantly by 0.2., Conclusion: MBW is useful to detect lung disease in IEI and is more sensitive than spirometry., Competing Interests: Conflict of interest: S. Thee declares grants to their institution from the German Innovation Fond; payment or honoraria from Chiesi (European Cystic Fibrosis Society meeting 2022) and Vertex (LEAD meeting, adherence forum); and travel expenses from Chiesi to attend the European Cystic Fibrosis Society meeting 2022. Conflict of interest: O. Staudacher declares a Travel Grant for Young Immunologists from Arbeitsgemeinschaft Pädiatrische Immunologie in the 36 months prior to manuscript submission. Conflict of interest: E. Steinke declares grants or contracts from the Clinician Scientist Program of the Berlin Institute of Health (funded by the German Federal Ministry of Education and Research); payment or honoraria for review of educational manuscripts from Vertex Pharmaceuticals Inc.; and a travel grant for conference attendance from the European Cystic Fibrosis Society, all in the 36 months prior to manuscript submission. Conflict of interest: J. Röhmel declares payment or honoraria, and support for attending meetings and/or travel from Vertex Pharmaceuticals in the 36 months prior to manuscript submission (with permission from their institution); and an unpaid role as a work package leader in BEAT-PCD, a European Research Society Clinical Research Collaboration. Conflict of interest: V. Wahn declares payment or honoraria from CSL Behring (related to www.immundefekt.de) and Pharming (related to a manuscript on APDS); and an honorarium and travel expenses from Pharming for attendance at the DGKJ congress, all in the 36 months prior to manuscript submission. Conflict of interest: H. von Bernuth declares consulting fees from Infill Healthcare Communication (2022); payment or honoraria from Deutsche Selbsthilfe Angeborene Immundefekte) (2023) and CSL Behring (2021); and payment for expert testimony from Bundessozialgericht (2023); as well as that they are a member of the Standing Comission on Vaccination at the Robert Koch Insitut, Ständige Impfkommission (STIKO). Conflict of interest: M.A. Mall declares funding to their institution in connection to the present work from the German Ministry for Education and Research (BMBF; Grant #82DZL009B1); and an unpaid role as a Fellow of the European Respiratory Society. Conflict of interest: M. Stahl declares funding to their institution (Heisenberg professorship) from the German Research Foundation (Deutsche Forschungsgemeinschaft) in connection to the present work; as well as unpaid roles as Chairman of the Forschungsgemeinschaft Mukoviszidose; Secretary of the Cystic Fibrosis Group of the European Respiratory Society; and Treasurer of the German Society of Paediatric Pulmonology. Conflict of interest: All other authors declare no competing interests., (Copyright ©The authors 2024.)

Background: Assessment of T-cell receptor excision circles (TRECs) in dried blood spots of newborns allows the detection of severe combined immunodeficiency (SCID) (T cells <300/μL at birth) with a presumed sensitivity of 100%. TREC screening also identifies patients with selected combined immunodeficiency (CID) (T cells >300/μL, yet <1500/μL at birth). Nevertheless, relevant CIDs that would benefit from early recognition and curative treatment pass undetected., Objective: We hypothesized that TREC screening at birth cannot identify CIDs that develop with age., Methods: We analyzed the number of TRECs in dried blood spots in archived Guthrie cards of 22 children who had been born in the Berlin-Brandenburg area between January 2006 and November 2018 and who had undergone hematopoietic stem-cell transplantation (HSCT) for inborn errors of immunity., Results: All patients with SCID would have been identified by TREC screening, but only 4 of 6 with CID. One of these patients had immunodeficiency, centromeric instability, and facial anomalies syndrome type 2 (ICF2). Two of 3 patients with ICF whom we have been following up at our institution had TREC numbers above the cutoff value suggestive of SCID at birth. Yet all patients with ICF had a severe clinical course that would have justified earlier HSCT., Conclusions: In ICF, naïve T cells may be present at birth, yet they decline with age. Therefore, TREC screening cannot identify these patients. Early recognition is nevertheless crucial, as patients with ICF benefit from HSCT early in life., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Activated PI3Kδ syndrome (APDS) is a rare inborn error of immunity (IEI) characterized primarily by frequent infections, lymphoproliferation and autoimmunity. Since its initial description in 2013, APDS has become part of the growing group of nearly 500 IEIs affecting various components of the immune system. The two subtypes of APDS - APDS1 and APDS2 - are caused by variants in the PIK3CD and PIK3R1 genes, respectively. Due to the rarity of the disease and the heterogeneous clinical picture, many patients are not diagnosed until years after symptom onset. Another challenge is the large number of PIK3CD and PIK3R1 variants whose functional significance for developing APDS is inconclusive. Treatment of APDS has so far been mostly symptom-oriented with immunoglobulin replacement therapy, immunosuppressive therapies and antibiotic or antiviral prophylaxes. Additionally, allogeneic stem cell transplantation as well as new targeted therapies are options targeting the root cause that may improve patients' quality of life and life expectancy. However, the clinical course of the disease is difficult to predict which complicates the choice of appropriate therapies. This review article discusses diagnostic procedures and current and future treatment options, and highlights the difficulties that physicians, patients and their caretakers face in managing this complex disease. This article is based on cohort studies, the German and US guidelines on the management of primary immunodeficiencies as well as on published experience with diagnosis and compiled treatment experience for APDS., Competing Interests: Author SV was employed by Infill Healthcare Communication. Author VW received a honorarium from Pharming Group N.V. for the supervision of the writing of this article. His homepage www.immundefekt.de is supported by CSL Behring. Author CS has declined a honorarium for her contribution to this manuscript. She was PI for Phase 3 Study CCDZ173X2201 Novartis and PI for the open extension study CCDZ173X2201E1 Novartis/Pharming. The authors declare that this study received funding from Pharming Group N.V.. The funder had the following involvement in the study: writing of the article., (Copyright © 2023 Vanselow, Wahn and Schuetz.)

Backgr Ound: T-cell receptor excision circle (TREC)-based newborn screening (NBS) for severe combined immunodeficiencies (SCID) was introduced in Germany in August 2019., Methods: Children with abnormal TREC-NBS were referred to a newly established network of Combined Immunodeficiency (CID) Clinics and Centers. The Working Group for Pediatric Immunology (API) and German Society for Newborn Screening (DGNS) performed 6-monthly surveys to assess the TREC-NBS process after 2.5 years., Results: Among 1.9 million screened newborns, 88 patients with congenital T-cell lymphocytopenia were identified (25 SCID, 17 leaky SCID/Omenn syndrome (OS)/idiopathic T-cell lymphocytopenia, and 46 syndromic disorders). A genetic diagnosis was established in 88%. Twenty-six patients underwent hematopoietic stem cell transplantation (HSCT), 23/26 within 4 months of life. Of these, 25/26 (96%) were alive at last follow-up. Two patients presented with in utero onset OS and died after birth. Five patients with syndromic disorders underwent thymus transplantation. Eight syndromic patients deceased, all from non-immunological complications. TREC-NBS missed one patient, who later presented clinically, and one tracking failure occurred after an inconclusive screening result., Conclusion: The German TREC-NBS represents the largest European SCID screening at this point. The incidence of SCID/leaky SCID/OS in Germany is approximately 1:54,000, very similar to previous observations from North American and European regions and countries where TREC-NBS was implemented. The newly founded API-CID network facilitates tracking and treatment of identified patients. Short-term HSCT outcome was excellent, but NBS and transplant registries will remain essential to evaluate the long-term outcome and to compare results across the rising numbers of TREC-NBS programs across Europe., (© 2023. The Author(s).)

Hyper-IgE syndromes and chronic mucocutaneous candidiasis constitute rare primary immunodeficiency syndromes with an overlapping clinical phenotype. In recent years, a growing number of underlying genetic defects have been identified. To characterize the underlying genetic defects in a large international cohort of 275 patients, of whom 211 had been clinically diagnosed with hyper-IgE syndrome and 64 with chronic mucocutaneous candidiasis, targeted panel sequencing was performed, relying on Agilent HaloPlex and Illumina MiSeq technologies. The targeted panel sequencing approach allowed us to identify 87 (32 novel and 55 previously described) mutations in 78 patients, which generated a diagnostic success rate of 28.4%. Specifically, mutations in DOCK8 (26 patients), STAT3 (21), STAT1 (15), CARD9 (6), AIRE (3), IL17RA (2), SPINK5 (3), ZNF341 (2), CARMIL2/RLTPR (1), IL12RB1 (1), and WAS (1) have been detected. The most common clinical findings in this cohort were elevated IgE (81.5%), eczema (71.7%), and eosinophilia (62.9%). Regarding infections, 54.7% of patients had a history of radiologically proven pneumonia, and 28.3% have had other serious infections. History of fungal infection was noted in 53% of cases and skin abscesses in 52.9%. Skeletal or dental abnormalities were observed in 46.2% of patients with a characteristic face being the most commonly reported feature (23.1%), followed by retained primary teeth in 18.9% of patients. Targeted panel sequencing provides a cost-effective first-line genetic screening method which allows for the identification of mutations also in patients with atypical clinical presentations and should be routinely implemented in referral centers., (© 2021. The Author(s).)