The German National Registry of Primary Immunodeficiencies (2012-2017)

Introduction: The German PID-NET registry was founded in 2009, serving as the first national registry of patients with primary immunodeficiencies (PID) in Germany. It is part of the European Society for Immunodeficiencies (ESID) registry. The primary purpose of the registry is to gather data on the epidemiology, diagnostic delay, diagnosis, and treatment of PIDs. Methods: Clinical and laboratory data was collected from 2,453 patients from 36 German PID centres in an online registry. Data was analysed with the software Stata® and Excel. Results: The minimum prevalence of PID in Germany is 2.72 per 100,000 inhabitants. Among patients aged 1–25, there was a clear predominance of males. The median age of living patients ranged between 7 and 40 years, depending on the respective PID. Predominantly antibody disorders were the most prevalent group with 57% of all 2,453 PID patients (including 728 CVID patients). A gene defect was identified in 36% of patients. Familial cases were observed in 21% of patients. The age of onset for presenting symptoms ranged from birth to late adulthood (range 0–88 years). Presenting symptoms comprised infections (74%) and immune dysregulation (22%). Ninety-three patients were diagnosed without prior clinical symptoms. Regarding the general and clinical diagnostic delay, no PID had undergone a slight decrease within the last decade. However, both, SCID and hyper IgE- syndrome showed a substantial improvement in shortening the time between onset of symptoms and genetic diagnosis. Regarding treatment, 49% of all patients received immunoglobulin G (IgG) substitution (70%—subcutaneous; 29%—intravenous; 1%—unknown). Three-hundred patients underwent at least one hematopoietic stem cell transplantation (HSCT). Five patients had gene therapy. Conclusion: The German PID-NET registry is a precious tool for physicians, researchers, the pharmaceutical industry, politicians, and ultimately the patients, for whom the outcomes will eventually lead to a more timely diagnosis and better treatment

Reduced immunoglobulin (Ig) G response to Staphylococcus aureus in STAT3 Hyper-IgE Syndrome

STAT3 hyper-IgE syndrome (STAT3-HIES) patients presented with significantly lower Staphylococcus aureus-specific serum IgG compared to cystic fibrosis patients despite recurrent S. aureus infections. Immunoglobulin replacement therapy increased S. aureus-specific IgG in STAT3-HIES patients and attenuated the clinical course of disease suggesting a role of humoral immunity in S. aureus clearance

SARS-CoV-2 Saliva Mass Screening in Primary Schools: A 10-Week Sentinel Surveillance Study in Munich, Germany

Representative, actively collected surveillance data on asymptomatic SARS-CoV-2 infections in primary schoolchildren remain scarce. We evaluated the feasibility of a saliva mass screening concept and assessed infectious activity in primary schools. During a 10-week period from 3 March to 21 May 2021, schoolchildren and staff from 17 primary schools in Munich participated in the sentinel surveillance, cohort study. Participants were tested using the Salivette® system, testing was supervised by trained school staff, and samples were processed via reverse transcription quantitative polymerase chain reaction (RT-qPCR). We included 4433 participants: 3752 children (median age, 8 [range, 6–13] years; 1926 girls [51%]) and 681 staff members (median age, 41 [range, 14–71] years; 592 women [87%]). In total, 23,905 samples were processed (4640 from staff), with participants representing 8.3% of all primary schoolchildren in Munich. Only eight cases were detected: Five out of 3752 participating children (0.13%) and three out of 681 staff members (0.44%). There were no secondary cases. In conclusion, supervised Salivette® self-sampling was feasible, reliable, and safe and thus constituted an ideal method for SARS-CoV-2 mass screenings in primary schoolchildren. Our findings suggest that infectious activity among asymptomatic primary schoolchildren and staff was low. Primary schools appear to continue to play a minor role in the spread of SARS-CoV-2 despite high community incidence rates

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

Inherited CARMIL2 deficiency underlies infections, EBV+ smooth muscle tumors, and mucocutaneous inflammation. CARMIL2 deficiency impairs CD28 signaling only partially in T cells. The comparison of CARMIL2 and CD28 deficiency in humans suggests that CARMIL2 governs immunological pathways beyond CD28. 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-kappa B 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(+) T(REG)s. 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

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

International audiencePatients 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 + T REG s. 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