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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.

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We describe the effects of polyethylene glycol-conjugated adenosine deaminase (ADA) replacement therapy on lymphocyte counts, activation, apoptosis, proliferation, and cytokine secretion in a 14-month-old girl with "delayed-onset" ADA deficiency and marked immunodysregulation. Pretreatment lymphopenia affected T cells (CD4, 150/l; CD8, 459/l), B cells (16/l), and NK cells (55/l). T cells were uniformly activated and largely apoptotic (CD4, 59%; CD8, 82%); and T-cell-dependent cytokine levels in plasma were elevated, including the levels of interleukin 2 (IL-2; 26 pg/ml), IL-4 (81 pg/ml), IL-5 (46 pg/ml), gamma interferon (1,430 pg/ml), tumor necrosis factor alpha (210 pg/ml), and IL-10 (168 pg/ml). Mitogen-stimulated peripheral blood mononuclear cells show reduced IL-2 secretion and proliferation. During the first 5 months of therapy there was clinical improvement and partial immune reconstitution, with nearly normal lymphocyte subset numbers, reduced T-cell activation and CD4-cell apoptosis, and decreased plasma cytokine levels. In parallel, IL-2 secretion and the lymphocyte mitogenic response improved. Between 4 and 7 months, immunoglobulin G antibodies to bovine ADA developed and resulted in the complete reversal of immune recovery.Adenosine deaminase (ADA) deficiency is an autosomal recessive disorder of purine metabolism which presents as severe combined immunodeficiency of infancy in 85 to 90% of patients and as delayed-or late (adult)-onset combined immunodeficiency in 10 to 15% of patients (13,15). ADA is a "housekeeping enzyme" in all tissues, resides predominantly in the cytoplasm, and is expressed at 800-to 1,000-fold higher levels in lymphoid cells than in erythrocytes. The absence of ADA causes an accumulation of toxic metabolites that impairs lymphocyte differentiation, viability, and function (17, 18). Clinically significant hepatic and neurological abnormalities also occur in some subjects.ADA-deficient patients who are not considered suitable for bone marrow or stem cell transplantation can be treated by enzyme replacement with polyethylene glycol (PEG)-conjugated bovine ADA (PEG-ADA) (16). By correcting metabolic abnormalities, PEG-ADA permits variable improvements in lymphocyte counts and immune function (17). However, in most reports of patients receiving PEG-ADA, the course of immune reconstitution has not been well characterized. We have monitored in detail the effects of PEG-ADA therapy on lymphopenia, the level of naive CD4 cells, T-cell activation, T-cell apoptosis, and the cytokine profile in a patient with a delayed-onset phenotype who manifested marked immune dysregulation as well as immunodeficiency. Immune function improved in this patient, until she developed a neutralizing antibody to PEG-ADA. CASE REPORTWe describe a 10-month-old girl who presented with recurrent infections (bronchopneumonia, viral infections, persistent otitis media); hepatopathy with elevated transaminase levels, reduced cholinesterase levels, and hepatosplenomegaly; hypoplasia of the thymus gland; skin rash; h...