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Background: Liver manifestations and in particular portal hypertension (PH) contribute significantly to morbidity and mortality of patients with common variable immunodeficiency disorders (CVID). Screening strategies and early detection are limited due to the lack of specific diagnostic tools., Methods: We evaluated clinical, immunological, histological, and imaging parameters in CVID patients with clinical manifestation of portal hypertension (CVID+PH)., Results: Portal hypertension was present in 5.6% of CVID patients and was associated with high clinical burden and increased mortality (18%). Longitudinal data on clinical and immunological parameters in patients before and during clinically manifest portal hypertension revealed a growing splenomegaly and increasing gamma-glutamyl transferase (GGT) and soluble interleukin 2 receptor (SIL-2R) levels with decreasing platelets over time. While ultrasound of the liver failed to detect signs of portal hypertension in most affected patients, transient elastography was elevated in all patients. All CVID+PH patients had reduced naïve CD45RA+CD4+ T-cells (mean of 6,2%). The frequency of severe B-lymphocytopenia (Euroclass B-) was higher in CVID+PH patients. The main histological findings included lymphocytic infiltration, nodular regenerative hyperplasia-like changes (NRH-LC), and porto(-septal) fibrosis., Conclusion: CVID patients with lower naïve CD45RA+CD4+ T-cells or severely reduced B-cells might be at higher risk for portal hypertension. The combination of biochemical (increasing sIL-2R, GGT, and decreasing platelets) and imaging parameters (increasing splenomegaly) should raise suspicion of the beginning of portal hypertension., 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., (Copyright © 2023 Hanitsch, Steiner, Schumann, Wittke, Kedor, Scheibenbogen and Fischer.)

Most patients with Post COVID Syndrome (PCS) present with a plethora of symptoms without clear evidence of organ dysfunction. A subset of them fulfills diagnostic criteria of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Symptom severity of ME/CFS correlates with natural regulatory autoantibody (AAB) levels targeting several G-protein coupled receptors (GPCR). In this exploratory study, we analyzed serum AAB levels against vaso- and immunoregulatory receptors, mostly GPCRs, in 80 PCS patients following mild-to-moderate COVID-19, with 40 of them fulfilling diagnostic criteria of ME/CFS. Healthy seronegative (n=38) and asymptomatic post COVID-19 controls (n=40) were also included in the study as control groups. We found lower levels for various AABs in PCS compared to at least one control group, accompanied by alterations in the correlations among AABs. Classification using random forest indicated AABs targeting ADRB2, STAB1, and ADRA2A as the strongest classifiers (AABs stratifying patients according to disease outcomes) of post COVID-19 outcomes. Several AABs correlated with symptom severity in PCS groups. Remarkably, severity of fatigue and vasomotor symptoms were associated with ADRB2 AAB levels in PCS/ME/CFS patients. Our study identified dysregulation of AAB against various receptors involved in the autonomous nervous system (ANS), vaso-, and immunoregulation and their correlation with symptom severity, pointing to their role in the pathogenesis of PCS., Competing Interests: The authors declare that HH and KS-F are managing directors of CellTrend. CellTrend holds together with Charité a patent for the diagnostic use of AABs against ADRB2. CS has a consulting agreement with CellTrend. FP reports grants from the Guthy Jackson Charitable Foundation, during the conduct of the study. 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 handling editor MD declared a past co-authorship with the author YS., (Copyright © 2022 Sotzny, Filgueiras, Kedor, Freitag, Wittke, Bauer, Sepúlveda, Mathias da Fonseca, Baiocchi, Marques, Kim, Lange, Plaça, Luebber, Paulus, De Vito, Jurisica, Schulze-Forster, Paul, Bellmann-Strobl, Rust, Hoppmann, Shoenfeld, Riemekasten, Heidecke, Cabral-Marques and Scheibenbogen.)

Morbidity and mortality of COVID-19 is increased in patients with inborn errors of immunity (IEI). Age and comorbidities and also impaired type I interferon immunity were identified as relevant risk factors. In patients with primary antibody deficiency (PAD) and lack of specific humoral immune response to SARS-CoV-2, clinical disease outcome is very heterogeneous. Despite extensive clinical reports, underlying immunological mechanisms are poorly characterized and levels of T cellular and innate immunity in severe cases remain to be determined. In the present study, we report clinical and immunological findings of 5 PAD patients with severe and fatal COVID-19 and undetectable specific humoral immune response to SARS-CoV-2. Reactive T cells to SARS-CoV-2 spike (S) and nucleocapsid (NCAP) peptide pools were analyzed comparatively by flow cytometry in PAD patients, convalescents and naïve healthy individuals. All examined PAD patients developed a robust T cell response. The presence of polyfunctional cytokine producing activated CD4 + T cells indicates a memory-like phenotype. An analysis of innate immune response revealed elevated CD169 (SIGLEC1) expression on monocytes, a surrogate marker for type I interferon response, and presence of type I interferon autoantibodies was excluded. SARS-CoV-2 RNA was detectable in peripheral blood in three severe COVID-19 patients with PAD. Viral clearance in blood was observed after treatment with COVID-19 convalescent plasma/monoclonal antibody administration. However, prolonged mucosal viral shedding was observed in all patients (median 67 days) with maximum duration of 127 days. PAD patients without specific humoral SARS-CoV-2 immunity may suffer from severe or fatal COVID-19 despite robust T cell and normal innate immune response. Intensified monitoring for long persistence of SARS-CoV-2 viral shedding and (prophylactic) convalescent plasma/specific IgG as beneficial treatment option in severe cases with RNAemia should be considered in seronegative PAD patients., Competing Interests: VC is named together with Euroimmun on a patent application filed recently regarding detection of antibodies against SARS-CoV-2. Authors CM, TM and OS are employed by Labor Berlin GmbH. 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., (Copyright © 2022 Steiner, Schwarz, Corman, Gebert, Kleinschmidt, Wald, Gläser, Kruse, Zickler, Peric, Meisel, Meyer, Staudacher, Wittke, Kedor, Bauer, Besher, Kalus, Pruß, Drosten, Volk, Scheibenbogen and Hanitsch.)

Soluble cluster of differentiation 26 (sCD26) has a wide range of enzymatic functions affecting immunological, metabolic and vascular regulation. Diminished sCD26 concentrations have been reported in various autoimmune diseases and also in Myalgic Encephalomyelitis/Chronic fatigue syndrome (ME/CFS). Here we re-evaluate sCD26 as a diagnostic marker and perform a comprehensive correlation analysis of sCD26 concentrations with clinical and paraclinical parameters in ME/CFS patients. Though this study did find significantly lower concentrations of sCD26 only in the female cohort and could not confirm diagnostic suitability, results from correlation analyses provide striking pathomechanistic insights. In patients with infection-triggered onset, the associations of low sCD26 with elevated autoantibodies (AAB) against alpha1 adrenergic (AR) and M3 muscarinic acetylcholine receptors (mAChR) point to a pathomechanism of infection-triggered autoimmune-mediated vascular and immunological dysregulation. sCD26 concentrations in infection-triggered ME/CFS were found to be associated with activated T cells, liver enzymes, creatin kinase (CK) and lactate dehydrogenase (LDH) and inversely with Interleukin-1 beta (IL-1b). Most associations are in line with the known effects of sCD26/DPP-4 inhibition. Remarkably, in non-infection-triggered ME/CFS lower sCD26 in patients with higher heart rate after orthostatic challenge and postural orthostatic tachycardia syndrome (POTS) suggest an association with orthostatic regulation. These findings provide evidence that the key enzyme sCD26 is linked to immunological alterations in infection-triggered ME/CFS and delineate a different pathomechanism in the non-infectious ME/CFS subset., Competing Interests: Author HH was employed by CellTrend GmbH. CellTrend GmbH holds a patent on the use of beta-adrenergic receptor antibodies in diagnosis of ME/CFS. CS has a consulting agreement with Celltrend. 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.​, (Copyright © 2021 Szklarski, Freitag, Lorenz, Becker, Sotzny, Bauer, Hartwig, Heidecke, Wittke, Kedor, Hanitsch, Grabowski, Sepúlveda and Scheibenbogen.)

Clinical trials on the use of COVID-19 convalescent plasma remain inconclusive. While data on safety is increasingly available, evidence for efficacy is still sparse. Subgroup analyses hint to a dose-response relationship between convalescent plasma neutralizing antibody levels and mortality. In particular, patients with primary and secondary antibody deficiency might benefit from this approach. However, testing of neutralizing antibodies is limited to specialized biosafety level 3 laboratories and is a time- and labor-intense procedure. In this single center study of 206 COVID-19 convalescent patients, clinical data, results of commercially available ELISA testing of SARS-CoV-2 spike-IgG and -IgA, and levels of neutralizing antibodies, determined by plaque reduction neutralization testing (PRNT), were analyzed. At a medium time point of 58 days after symptom onset, only 12.6% of potential plasma donors showed high levels of neutralizing antibodies (PRNT50 ≥ 1:320). Multivariable proportional odds logistic regression analysis revealed need for hospitalization due to COVID-19 (odds ratio 6.87; p -value 0.0004) and fever (odds ratio 3.00; p -value 0.0001) as leading factors affecting levels of SARS-CoV-2 neutralizing antibody titers in convalescent plasma donors. Using penalized estimation, a predictive proportional odds logistic regression model including the most important variables hospitalization, fever, age, sex, and anosmia or dysgeusia was developed. The predictive discrimination for PRNT50 ≥ 1:320 was reasonably good with AUC: 0.86 (with 95% CI: 0.79-0.92). Combining clinical and ELISA-based pre-screening, assessment of neutralizing antibodies could be spared in 75% of potential donors with a maximal loss of 10% of true positives (PRNT50 ≥ 1:320)., Competing Interests: MM and VC are named together with Euroimmun GmbH on a patent application filed recently regarding the diagnostic of SARS-CoV-2 by antibody testing. 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., (Copyright © 2021 Schlickeiser, Schwarz, Steiner, Wittke, Al Besher, Meyer, Kalus, Pruß, Kurth, Zoller, Witzenrath, Sander, Müller, Scheibenbogen, Volk, Drosten, Corman and Hanitsch.)

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.