Stromal interaction molecule 1 (STIM1)4 deficiency is a rare genetic disorder of store-operated Calcium entry (SOCE), associated with a complex syndrome including immunodeficiency and immune dysregulation. The link from the molecular defect to these clinical manifestations is incompletely understood. We report 2 patients with a homozygous R429C point mutation in STIM1 completely abolishing SOCE in T cells. Immunological analysis of one patient revealed that despite the expected defect of T cell proliferation and cytokine production in vitro, significant antiviral T cell populations were generated in vivo. These T cells proliferated in response to viral antigens and showed normal antiviral cytotoxicity. However, antiviral immunity was insufficient to prevent chronic CMV and EBV infections with a possible contribution of impaired NK cell function and a lack of NKT cells. Furthermore, autoimmune cytopenia, eczema and intermittent diarrhea suggested impaired immune regulation. Forkhead box protein 3 (FOXP3) positive regulatory T cells (Treg) were present but showed an abnormal phenotype. The suppressive function of STIM1 deficient Treg cells in vitro, however, was normal. Given these partial defects in cytotoxic and regulatory T cell function, impairment of other immune cell populations probably contributes more to the pathogenesis of immunodeficiency and autoimmunity in STIM1 deficiency than previously appreciated.

ZusammenfassungDie Deutsche Gesellschaft für Pneumologie hat die AWMFS1-Leitlinie Post-COVID/Long-COVID initiiert. In einem breiten interdisziplinären Ansatz wurde diese S1-Leitlinie basierend auf dem aktuellen Wissensstand gestaltet.Die klinische Empfehlung beschreibt die aktuellen Post-COVID/Long-COVID-Symptome, diagnostische Ansätze und Therapien.Neben der allgemeinen und konsentierten Einführung wurde ein fachspezifischer Zugang gewählt, der den aktuellen Wissensstand zusammenfasst.Die Leitlinie hat einen expilzit praktischen Anspruch und wird basierend auf dem aktuellen Wissenszugewinn vom Autorenteam stetig weiterentwickelt und adaptiert.

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.

The authors conclude that ETV presents an effective alternative for the treatment of obstructive hydrocephalus in infants younger than 1 year of age. Age does not present a contraindication for ETV, nor does it increase the perioperative risk. The success of ETV is determined by the cause of the hydrocephalus.

No abstract

The non-invasive tension-time index of the inspiratory muscles at rest (TTMUS) can be used for assessing respiratory muscle function in children with cystic fibrosis (CF). This study aimed to investigate how TTMUS becomes altered with increasing pulmonary impairment, and which factors determine TTMUS changes in CF. We assessed TTMUS in 47 patients with stable CF ranging in age from 9 to 26 years and in 47 controls of same age and gender. Pulmonary impairment was assessed by the pulmonary function score (PFS) according to Cropp (PFS 0-2 = no, 3-7 = mild, 8-12 = moderate, and 13-18 = severe dysfunction). Median TTMUS was significantly higher in the entire CF-group than in controls ((0.112 (0.079-0.174) vs. 0.07 (0.052-0.094), P < 0.001)). It was nearly identical in CF-patients without (0.079 (0.056-0.114)) and mild (0.080 (0.059-0.128)) pulmonary dysfunction. It was non-significantly higher in subjects with moderate (0.118 (0.103-0.173)) and grossly elevated in individuals with severe (0.232 (0.211-0.31), P < 0.001)) respiratory impairment when compared to the other PFS-groups. TTMUS was significantly related to percent predicted airway resistance (Raw%pred) (r = 0.60, P < 0.001), percent predicted Forced Expiratory Volume in 1 sec (r = -0.49, P < 0.001), percent predicted Vital Capacity (-0.57, P < 0.001), Functional Residual Capacity in percent Total Lung Capacity (r = 0.42, P = 0.003), and transcutaneous oxygen saturation (r = -0.49, P < 0.001). By contrast, Raw%pred was the only variable that had a significant effect on TTMUS (P = 0.01), when a multivariate logistic regression was applied, using the median of the entire CF-cohort to dichotomise TTMUS. These findings suggest that subjects with stable CF and severe pulmonary dysfunction are prone to respiratory muscle fatigue, and that airway obstruction is an important factor contributing to the increase of TTMUS in CF. Regular determination of TTMUS may be clinically useful during course of disease, and may aid the decision to institute therapies like respiratory muscle training or non-invasive intermittent ventilation.

SummaryTwo employees of the National Health Service (NHS) in England developed severe allergic reactions following administration of BNT162b2 vaccine against COVID-19 (coronavirus disease 2019). The British SmPC for the BNT162b2 vaccine already includes reference to a contraindication for use in individuals who have had an allergic reaction to the vaccine or any of its components. As a precautionary measure, the Medicines and Healthcare products Regulatory Agency (MHRA) has issued interim guidance to the NHS not to vaccinate in principle in “patients with severe allergies”. Allergic reactions to vaccines are very rare, but vaccine components are known to cause allergic reactions. BNT162b2 is a vaccine based on an mRNA embedded in lipid nanoparticles and blended with other substances to enable its transport into the cells. In the pivotal phase III clinical trial, the BNT162b2 vaccine was generally well tolerated, but this large clinical trial, used to support vaccine approval by the MHRA and US Food and Drug Administration, excluded individuals with a “history of a severe adverse reaction related to the vaccine and/or a severe allergic reaction (e.g., anaphylaxis) to a component of the study medication”. Vaccines are recognized as one of the most effective public health interventions. This repeated administration of a foreign protein (antigen) necessitates a careful allergological history before each application and diagnostic clarification and a risk–benefit assessment before each injection. Severe allergic reactions to vaccines are rare but can be life-threatening, and it is prudent to raise awareness of this hazard among vaccination teams and to take adequate precautions while more experience is gained with this new vaccine.

Natriuresis and polyuria are the main diagnostic criteria for CSW. The fluid balance in CSW is negative, in contrast to a positive fluid balance in SIADH. The length of the disease is self-limited and generally ceases within 2 weeks, while Na+, K+, and fluid turnover should be monitored carefully. Only a minority of our children showed elevated ANP/BNP levels. A dose/effect relationship for natriuretic peptide levels and increased Na+ turnover could not be established.