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Purpose The FIGARO study aims to provide insights on real-world utilization and tolerability of facilitated subcutaneous immunoglobulin (fSCIG) for primary immunodeficiency disease (PID) or secondary immunodeficiency disease (SID). Methods This prospective, multicenter, observational study, evaluated medical records, charts, and diaries of patients who had received at least 1 fSCIG infusion for PID or SID. Data were analyzed by cohort (PID, SID) and age groups (pediatric [ Results The study enrolled 156 patients: 15 pediatric, 120 adult, 21 older-adult. Twelve-month follow-up data were available for 128 patients. fSCIG was mainly prescribed for PID among patients aged Conclusions FIGARO confirms the feasibility, tolerability, and good infection control of fSCIG in PID and SID patients across the age spectrum in both the home-setting and medical facility. Trial registration number ClinicalTrials.gov NCT03054181

Purpose Humoral and cellular immune responses were described after COVID-19 vaccination in patients with common variable immunodeficiency disorder (CVID). This study aimed to investigate SARS-CoV-2-specific antibody quality and memory function of B cell immunity as well as T cell responses after COVID-19 vaccination in seroresponding and non-responding CVID patients. Methods We evaluated antibody avidity and applied a memory B cell ELSPOT assay for functional B cell recall memory response to SARS-CoV-2 after COVID-19 vaccination in CVID seroresponders. We comparatively analyzed SARS-CoV-2 spike reactive polyfunctional T cell response and reactive peripheral follicular T helper cells (pTFH) by flow cytometry in seroresponding and non-seroresponding CVID patients. All CVID patients had previously failed to mount a humoral response to pneumococcal conjugate vaccine. Results SARS-CoV-2 spike antibody avidity of seroresponding CVID patients was significantly lower than in healthy controls. Only 30% of seroresponding CVID patients showed a minimal memory B cell recall response in ELISPOT assay. One hundred percent of CVID seroresponders and 83% of non-seroresponders had a detectable polyfunctional T cell response. Induction of antigen-specific CD4+CD154+CD137+CXCR5+ pTFH cells by the COVID-19 vaccine was higher in CVID seroresponder than in non-seroresponder. Levels of pTFH did not correlate with antibody response or avidity. Conclusion Reduced avidity and significantly impaired recall memory formation after COVID-19 vaccination in seroresponding CVID patients stress the importance of a more differentiated analysis of humoral immune response in CVID patients. Our observations challenge the clinical implications that follow the binary categorization into seroresponder and non-seroresponder.

BACKGROUND: Inborn errors of immunity (IEI) are rare diseases, which makes diagnosis a challenge. A better description of the initial presenting manifestations should improve awareness and avoid diagnostic delay. Although increased infection susceptibility is a well-known initial IEI manifestation, less is known about the frequency of other presenting manifestations.OBJECTIVE: We sought to analyze age-related initial presenting manifestations of IEI including different IEI disease cohorts.METHODS: We analyzed data on 16,486 patients of the European Society for Immunodeficiencies Registry. Patients with autoinflammatory diseases were excluded because of the limited number registered.RESULTS: Overall, 68% of patients initially presented with infections only, 9% with immune dysregulation only, and 9% with a combination of both. Syndromic features were the presenting feature in 12%, 4% had laboratory abnormalities only, 1.5% were diagnosed because of family history only, and 0.8% presented with malignancy. Two-third of patients with IEI presented before the age of 6 years, but a quarter of patients developed initial symptoms only as adults. Immune dysregulation was most frequently recognized as an initial IEI manifestation between age 6 and 25 years, with male predominance until age 10 years, shifting to female predominance after age 40 years. Infections were most prevalent as a first manifestation in patients presenting after age 30 years.CONCLUSIONS: An exclusive focus on infection-centered warning signs would have missed around 25% of patients with IEI who initially present with other manifestations.

SARS-CoV-2 is a single-stranded RNA virus that causes coronavirus disease 2019 (COVID-19). Given its acute and often self-limiting course, components of the innate immune system are likely central in controlling virus replication thereby determining clinical outcome. Natural killer (NK) cells are innate lymphocytes with notable activity against a broad range of viruses, including RNA viruses1,2. NK cell function may be altered during COVID-19 despite increased representation of NK cells with an activated and ‘adaptive’ phenotype3,4. Here we show that viral load decline in COVID-19 correlates with NK cell status and that NK cells can control SARS-CoV-2 replication by recognizing infected target cells. In severe COVID-19, NK cells show remarkable defects in virus control, cytokine production and cell-mediated cytotoxicity despite high expression of cytotoxic effector molecules. Single-cell RNA-sequencing (scRNA-seq) of NK cells along the time course of the entire COVID-19 disease spectrum reveals a unique gene expression signature. Transcriptional networks of interferon-driven NK cell activation are superimposed by a dominant TGFβ response signature with reduced expression of genes related to cell-cell adhesion, granule exocytosis and cell-mediated cytotoxicity. In severe COVID-19, serum levels of TGFβ peak during the first 2 weeks of infection, and serum obtained from these patients profoundly inhibits NK cell function in a TGFβ-dependent manner. Our data reveal that untimely production of TGFβ is a hallmark of severe COVID-19 and may inhibit NK cell function and early virus control.

BACKGROUND: Panton-Valentine leukocidin (PVL)–producing Staphylococcus aureus (PVL-SA) strains are frequently associated with large, recurring abscesses in otherwise healthy young individuals. The typical clinical presentation and the recommended diagnostic evaluation and treatment are not widely known. METHODS: This review is based on pertinent publications retrieved by a selective search in PubMed, with special attention to international recommendations. RESULTS: PVL-SA can cause leukocytolysis and dermatonecrosis through specific cell-wall pore formation. Unlike other types of pyoderma, such conditions caused by PVL-SA have no particular site of predilection. In Germany, the PVL gene can be detected in 61.3% (252/411) of skin and soft tissue infections with S. aureus. Skin and soft tissue infections with PVL-SA recur three times as frequently as those due to PVL-negative S. aureus. They are diagnosed by S. aureus culture from wound swabs and combined nasal/pharyngeal swabs, along with PCR for gene detection. The acute treatment of the skin abscesses consists of drainage, followed by antimicrobial therapy if needed. Important secondary preventive measures include topical cleansing with mupirocin nasal ointment and whole-body washing with chlorhexidine or octenidine. The limited evidence (level IIb) concerning PVL-SA is mainly derived from nonrandomized cohort studies and experimental analyses. CONCLUSION: PVL-SA skin infections are easily distinguished from other skin diseases with targeted history-taking and diagnostic evaluation.

Pulmonary complications are among the most frequent manifestations in patients with primary antibody deficiency (PAD), contributing significantly to morbidity and mortality. Here, we focus on recent findings in obstructive pulmonary disease and bronchiectasis in PAD. Since specific data on patients with PAD is limited and management mostly follows general recommendations, this review also aims to summarize data from the immunocompetent population.Potential risk factors for the development and progression of bronchiectasis include reduced immunoglobulins and lower CD4 cells. In addition, Pseudomonas aeruginosa and an altered microbiome might contribute to local inflammation and disease progression. Findings on the contribution of neutrophils and eosinophils in the affected immunocompetent population require confirmation in PAD. Despite its high global burden, there is an extreme paucity of data on chronic obstructive pulmonary disease in PAD. Lower IgA and IgM are associated with asthma in PAD, but the heterogeneity of prevalence among PAD groups is poorly understood. Recent observations of non-IgE-mediated pathomechanisms in asthma may be of particular interest in PAD patients.Management of PAD patients with chronic lung disease requires a multidisciplinary team approach including immunology, pulmonology, infectious disease and physiotherapy. Diagnostic processes should be harmonized to ensure a more precise perspective on prevalence and disease courses.

A subset of patients has long-lasting symptoms after mild to moderate Coronavirus disease 2019 (COVID-19). In a prospective observational cohort study, we analyze clinical and laboratory parameters in 42 post-COVID-19 syndrome patients (29 female/13 male, median age 36.5 years) with persistent moderate to severe fatigue and exertion intolerance six months following COVID-19. Further we evaluate an age- and sex-matched postinfectious non-COVID-19 myalgic encephalomyelitis/chronic fatigue syndrome cohort comparatively. Most post-COVID-19 syndrome patients are moderately to severely impaired in daily live. 19 post-COVID-19 syndrome patients fulfill the 2003 Canadian Consensus Criteria for myalgic encephalomyelitis/chronic fatigue syndrome. Disease severity and symptom burden is similar in post-COVID-19 syndrome/myalgic encephalomyelitis/chronic fatigue syndrome and non-COVID-19/myalgic encephalomyelitis/chronic fatigue syndrome patients. Hand grip strength is diminished in most patients compared to normal values in healthy. Association of hand grip strength with hemoglobin, interleukin 8 and C-reactive protein in post-COVID-19 syndrome/non-myalgic encephalomyelitis/chronic fatigue syndrome and with hemoglobin, N-terminal prohormone of brain natriuretic peptide, bilirubin, and ferritin in post-COVID-19 syndrome/myalgic encephalomyelitis/chronic fatigue syndrome may indicate low level inflammation and hypoperfusion as potential pathomechanisms.

Coronavirus disease 2019 (COVID-19) is caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Type I interferons are important in the defense of viral infections. Recently, neutralizing IgG auto-antibodies against type I interferons were found in patients with severe COVID-19 infection. Here, we analyzed expression of CD169/SIGLEC1, a well described downstream molecule in interferon signaling, and found increased monocytic CD169/SIGLEC1 expression levels in patients with mild, acute COVID-19, compared to patients with severe disease. We recommend further clinical studies to evaluate the value of CD169/SIGLEC1 expression in patients with COVID-19 with or without auto-antibodies against type I interferons.

Infections are an important warning sign for a weakened immune system. In the internal medical practice acquired (secondary), particularly drug-induced immunodeficiencies, are much more frequent than congenital (primary) immunodeficiencies. The management starts as early as the planning phase before initiation of immunosuppression. The risk of infection should be individually stratified and protective vaccinations should be completed. Depending on the immunosuppressive treatment, there can be a necessity for preventive treatment, e.g. for latent tuberculosis infection or hepatitis B. The serological results on varicella zoster virus and JC polyomavirus must also be considered. The basic immunological diagnostics include differential blood count and the determination of immunoglobulins (IgG, IgA, IgM) prior to and during immunosuppressive treatment. Relevant conspicuous laboratory results before initiation of treatment should prompt advanced immunological work-up for the identification of primary immunodeficiencies, which are often accompanied by clinical signs of immune dysregulation. Depending on the type of pathogen, localization, frequency and duration as well as the severity of the infection, prophylactic antibiotic treatment may be required. Patients with chronic severe lymphocytopenia, in particular with CD4 positive T (helper) cells 200/µl, are at increased risk for opportunistic infections so that an antibiotic prophylaxis is recommended. In patients with significantly increased proneness to infections and detection of a relevant quantitative (IgG 4 g/l) and/or qualitative antibody deficiency (impaired vaccine response), additional immunoglobulin replacement therapy may be necessary and can be administered intravenously (IVIG) or subcutaneously (SCIG) as home treatment. In accordance with the localization of the infection, multidisciplinary clarification and management is warranted.Infektionen sind ein wichtiges Warnzeichen für ein geschwächtes Immunsystem. Erworbene (sekundäre), insbesondere medikamentös induzierte Immundefekte sind in der internistischen Praxis deutlich häufiger als angeborene (primäre) Immundefekte. Das Management beginnt bereits in der Planungsphase vor Einleitung der Immunsuppression. Es sollten infektiologische Risiken individuell stratifiziert und Schutzimpfungen komplettiert werden. Je nach Immunsuppression kann die Notwendigkeit einer präventiven Therapie bestehen, etwa bei latenter Tuberkulose oder Hepatitis B. Ebenfalls müssen serologische Befunde zu Varizella-Zoster- und JC-Viren berücksichtigt werden. Als immunologische Basisdiagnostik stehen das Differenzialblutbild sowie die Bestimmung von Immunglobulinen (IgG, IgA, IgM) vor und auch während der immunsuppressiven Therapie zur Verfügung. Bei relevanten Laborauffälligkeiten vor Therapieeinleitung sollte ein angeborener Immundefekt gezielt abgeklärt werden, da dieser oft auch mit Zeichen der Immundysregulation einhergeht. Abhängig von der Art des Erregers sowie von Lokalisation, Häufigkeit, Dauer und Schweregrad der Infektion kann eine prophylaktische Antibiotikagabe erfolgen. Bei dauerhafter schwerer Lymphozytopenie, insbesondere bei CD4-positiven (Helfer‑)Zellen 200/µl, besteht ein erhöhtes Risiko opportunistischer Infektionen, sodass eine Antibiotikaprophylaxe empfohlen wird. Bei deutlich erhöhter Infektionsneigung und Nachweis einer relevanten quantitativen (IgG 4 g/l) und/oder qualitativen Antikörperstörung (eingeschränkte Impfantwort) kann eine ergänzende Immunglobulinersatztherapie erforderlich sein, die intravenös (IVIG) wie auch subkutan (SCIG) als Heimtherapie erfolgen kann. Entsprechend der Infektionslokalisation sollte eine multidisziplinäre Abklärung und Betreuung erfolgen.

Staphylococcus aureus(S. aureus) strains that produce the toxin Panton-Valentine leukocidin (PVL; PVL-SA) frequently cause recurrent skin and soft tissue infections (SSTI). PVL binds to and kills human neutrophils, resulting in the formation of neutrophil extracellular traps, but the pathomechanism has not been extensively studied. Furthermore, it is unclear why some individuals colonized with PVL-SA suffer from recurring infections whereas others are asymptomatic. We thus aimed to (a) investigate how PVL exerts its pathogenicity on neutrophils and (b) identify factors that could help to explain the predisposition of patients with recurring infections.We provide genetic and pharmacological evidence that PVL-induced NET formation is independent of NADPH-oxidase and reactive oxygen species (ROS) production. Moreover, through NET proteome analysis we identified that the protein content of PVL-induced NETs is different from NETs induced by mitogen or the microbial toxin nigericin. The abundance of the proteins cathelicidin (CAMP), elastase (NE), and proteinase 3 (PRTN3) was lower on PVL-induced NETs, and as such they were unable to killS. aureus.Furthermore, we found that neutrophils from affected patients express higher levels of CD45, one of the PVL receptors, and are more susceptible to be killed at a low PVL concentration than control neutrophils. Neutrophils from patients that suffer from recurring PVL-positive infections may thus be more sensitive to PVL-induced NET formation, which might impair their ability to combat the infection.ImportanceIndividuals colonized byStaphylococcus aureusstrains that produce Panton-Valentine leukocidin (PVL-SA) often present with recurrent skin and soft-tissue infections, whilst other individuals remain asymptomatic. PVL is a toxin that kills neutrophils, which results in the formation of neutrophil extracellular traps. Traps induced by other stimuli are known to be toxic toS. aureus.We found however that NETs specifically induced by PVL are not toxic toS. aureus. Furthermore, we show that neutrophils from individuals that suffer from recurring PVL-SA infections are more sensitive to PVL-induced NET formation compared to healthy individuals. The significance of our work is in identifying a mechanism through which PVL-SA may actively counter the engagement of neutrophils. Moreover, we identified that patients with recuring PVL-SA infections may be more sensitive to this mechanism, which may help to explain their clinical condition and might provide avenues for future treatment development.

Epidemiological data demonstrate that Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) Alpha and Delta are more transmissible, infectious, and pathogenic than previous variants. Phenotypic properties of VOC remain understudied. Here, we provide an extensive functional study of VOC Alpha replication and cell entry phenotypes assisted by reverse genetics, mutational mapping of spike in lentiviral pseudotypes, viral and cellular gene expression studies, and infectivity stability assays in an enhanced range of cell and epithelial culture models. In almost all models, VOC Alpha spread less or equally efficiently as ancestral (B.1) SARS-CoV-2. B.1. and VOC Alpha shared similar susceptibility to serum neutralization. Despite increased relative abundance of specific sgRNAs in the context of VOC Alpha infection, immune gene expression in infected cells did not differ between VOC Alpha and B.1. However, inferior spreading and entry efficiencies of VOC Alpha corresponded to lower abundance of proteolytically cleaved spike products presumably linked to the T716I mutation. In addition, we identified a bronchial cell line, NCI-H1299, which supported 24-fold increased growth of VOC Alpha and is to our knowledge the only cell line to recapitulate the fitness advantage of VOC Alpha compared to B.1. Interestingly, also VOC Delta showed a strong (595-fold) fitness advantage over B.1 in these cells. Comparative analysis of chimeric viruses expressing VOC Alpha spike in the backbone of B.1, and vice versa, showed that the specific replication phenotype of VOC Alpha in NCI-H1299 cells is largely determined by its spike protein. Despite undetectable ACE2 protein expression in NCI-H1299 cells, CRISPR/Cas9 knock-out and antibody-mediated blocking experiments revealed that multicycle spread of B.1 and VOC Alpha required ACE2 expression. Interestingly, entry of VOC Alpha, as opposed to B.1 virions, was largely unaffected by treatment with exogenous trypsin or saliva prior to infection, suggesting enhanced resistance of VOC Alpha spike to premature proteolytic cleavage in the extracellular environment of the human respiratory tract. This property may result in delayed degradation of VOC Alpha particle infectivity in conditions typical of mucosal fluids of the upper respiratory tract that may be recapitulated in NCI-H1299 cells closer than in highly ACE2-expressing cell lines and models. Our study highlights the importance of cell model evaluation and comparison for in-depth characterization of virus variant-specific phenotypes and uncovers a fine-tuned interrelationship between VOC Alpha- and host cell-specific determinants that may underlie the increased and prolonged virus shedding detected in patients infected with VOC Alpha.

Epidemiological data demonstrate that SARS-CoV-2 variants of concern (VOC) B.1.1.7 and B.1.617.2 are more transmissible and infections are associated with a higher mortality than non-VOC virus infections. Phenotypic properties underlying their enhanced spread in the human population remain unknown. B.1.1.7 virus isolates displayed inferior or equivalent spread in most cell lines and primary cells compared to an ancestral B.1 SARS-CoV-2, and were outcompeted by the latter. Lower infectivity and delayed entry kinetics of B.1.1.7 viruses were accompanied by inefficient proteolytic processing of spike. B.1.1.7 viruses failed to escape from neutralizing antibodies, but slightly dampened induction of innate immunity. The bronchial cell line NCI-H1299 supported 24- and 595-fold increased growth of B.1.1.7 and B.1.617.2 viruses, respectively, in the absence of detectable ACE2 expression and in a spike-determined fashion. Superior spread in NCI-H1299 cells suggests that VOCs employ a distinct set of cellular cofactors that may be unavailable in standard cell lines.

A subset of patients has long-lasting symptoms after mild to moderate COVID-19. In a prospective observational cohort study we analysed clinical and laboratory parameters in 42 patients (29 female/13 male, median age 36.5 years) with persistent moderate to severe fatigue and exertion intolerance six months following COVID-19 referred to as Chronic COVID-19 Syndrome (CCS). Most patients were moderately to severely impaired in daily live. 19 patients fulfilled the 2003 Canadian Consensus Criteria for myalgic encephalomyelitis/chronic fatigue syndrome referred to as CFS/CCS. Hand grip strength (HGS) was diminished in most patients. Association of several biomarker with key symptoms of physical and mental fatigue and post exertional malaise indicate low level inflammation and hypoperfusion as potential pathomechanisms.

BackgroundRecurrent skin abscesses are often associated with Panton-Valentine leukocidin-producing strains of S. aureus (PVL-SA). Decolonization measures are required along with treatment of active infections to prevent re-infection and spreading. Even though most PVL-SA patients are treated as outpatients, there are few studies that assess the effectiveness of outpatient topical decolonization in PVL-SA patients.MethodsWe assessed the results of topical decolonization of PVL-SA in a retrospective review of patient files and personal interviews. Successful decolonization was defined as the absence of any skin abscesses for at least 6 months after completion of the final decolonization treatment. Clinical and demographic data was assessed. An intention-to-treat protocol was used.ResultsOur cohort consisted of 115 symptomatic patients, 66% from PVL-positive MSSA and 19% from PVL-positive MRSA. The remaining 16% consisted of symptomatic patients with close contact to PVL-SA positive index patients but without detection of PVL-SA. The majority of patients were female (66%). The median age was 29.87% of the patients lived in multiple person households. Our results showed a 48% reduction in symptomatic PVL-SA cases after the first decolonization treatment. The results also showed that the decrease continued with each repeated decolonization treatment and reached 89% following the 5th treatment. A built multivariable Cox proportional-hazards model showed that the absence of PVL-SA detection (OR 2.0) and living in single person households (OR 2.4) were associated with an independently increased chance of successful decolonization.ConclusionIn our cohort, topical decolonization was a successful preventive measure for reducing the risk of PVL-SA skin abscesses in the outpatient setting. Special attention should be given to patients living in multiple person households because these settings could confer a risk that decolonization will not be successful.

This evidence‐based clinical guideline provides consensus‐recommendations for the treatment and care of patients with primary antibody deficiencies (PADs). The guideline group comprised 20 clinical and scientific expert associations of the German, Swiss, and Austrian healthcare system and representatives of patients. Recommendations were based on results of a systematic literature search, data extraction, and evaluation of methodology and study quality in combination with the clinical expertise of the respective representatives. Consensus‐based recommendations were determined via nominal group technique. PADs are the largest clinically relevant group of primary immunodeficiencies. Most patients with PADs present with increased susceptibility to infections, however immune dysregulation, autoimmunity, and cancer affect a significant number of patients and may precede infections. This guideline therefore covers interdisciplinary clinical and therapeutic aspects of infectious (e.g., antibiotic prophylaxis, management of bronchiectasis) and non‐infectious manifestations (e.g., management of granulomatous disease, immune cytopenia). PADs are grouped into disease entities with definitive, probable, possible, or unlikely benefit of IgG‐replacement therapy. Summary and consensus‐recommendations are provided for treatment indication, dosing, routes of administration, and adverse events of IgG‐replacement therapy. Special aspects of concomitant impaired T‐cell function are highlighted as well as clinical data on selected monogenetic inborn errors of immunity formerly classified into PADs (APDS, CTLA‐4‐, and LRBA‐deficiency).

Background A subgroup of patients with common variable immunodeficiency (CVID) experience immune dysregulation manifesting as autoimmunity, lymphoproliferation, and organ inflammation and thereby increasing morbidity and mortality. Therefore treatment of these complications demands a deeper comprehension of their cause and pathophysiology. Objectives On the basis of the identification of an interferon signature in patients with CVID with secondary complications and a skewed follicular helper T-cell differentiation in defined monogenic immunodeficiencies, we sought to determine the profile of CD4 memory T cells in blood and secondary lymphatic tissues of these patients. Methods We quantified T H 1/T H 2/T H 17 CD4 memory T cells in blood and lymph nodes of patients with CVID using flow cytometry, analyzed their function, and correlated all findings to the burden of immune dysregulation. Results Patients with CVID with immune dysregulation had a skewed memory CD4 T-cell differentiation toward a CXCR3 + CCR6 − T H 1 phenotype both in blood and lymph nodes. Consistent with our phenotypic findings, we observed a higher IFN-γ production in peripheral CD4 memory T cells and lymph node–derived follicular helper T cells of patients with CVID compared with those of healthy control subjects. Increased IFN-γ production was accompanied by a poor germinal center output, an accumulation of T-box transcription factor (T-bet) + B cells in lymph nodes, and an accumulation of T-bet + CD21 low B cells in peripheral blood of affected patients. Conclusion Identification of excessive IFN-γ production by blood and lymph node–derived T cells of patients with CVID with immune dysregulation will offer new therapeutic avenues for this subgroup. CD21 low B cells might serve as a marker of this IFN-γ–associated dysregulation.

Introduction Skin and soft tissue infections (SSTI) caused by Panton-Valentine leukocidin (PVL)-producing strains of Staphylococcus aureus (PVL-SA) are associated with recurrent skin abscesses. Secondary prevention, in conjunction with primary treatment of the infection, focuses on topical decolonization. Topical decolonization is a standard procedure in cases of recurrent PVL-SA skin infections and is recommended in international guidelines. However, this outpatient treatment is often not fully reimbursed by health insurance providers, which may interfere with successful PVL-SA decolonization. Aim Our goal was to estimate the cost effectiveness of outpatient decolonization of patients with recurrent PVL-SA skin infections. We calculated the average cost of treatment for PVL-SA per outpatient decolonization procedure as well as per in-hospital stay. Methods The study was conducted between 2014 and 2018 at a German tertiary care university hospital. The cohort analyzed was obtained from the hospital’s microbiology laboratory database. Data on medical costs, DRG-based diagnoses, and ICD-10 patient data was obtained from the hospital’s financial controlling department. We calculated the average cost of treatment for patients admitted for treatment of PVL-SA induced skin infections. The cost of outpatient treatment is based on the German regulations of drug prices for prescription drugs. Results We analyzed a total of n = 466 swabs from n = 411 patients with recurrent skin infections suspected of carrying PVL-SA. PVL-SA was detected in 61.3% of all patients included in the study. Of those isolates, 80.6% were methicillin-susceptible, 19.4% methicillin-resistant. 89.8% of all patients were treated as outpatients. In 73.0% of inpatients colonized with PVL-SA the main diagnosis was SSTI. The median length of stay was 5.5 days for inpatients colonized with PVL-SA whose main diagnosis SSTI; the average cost was €2,283. The estimated costs per decolonization procedure in outpatients ranged from €50-€110, depending on the products used. Conclusion Our data shows that outpatient decolonization offers a highly cost-effective secondary prevention strategy, which may prevent costly inpatient treatments. Therefore, health insurance companies should consider providing coverage of outpatient treatment of recurrent PVL-SA skin and soft tissue infections.

The authors regret that the author name Silvano Esposito was published incorrectly. The authors would like to apologise for any inconvenience caused.

Primary selective IgM deficiency (sIgM) is characterized by diminished serum IgM, infections and autoimmunity. Although there is some evidence of B-cell defects the pathogenesis of sIgM is poorly understood. We determined peripheral B-cell subsets and IgM-expression levels in 31 adult sIgM patients by flow cytometry. In a subset of patients B-cell subset alterations and antibody-secreting cells were determined by flow cytometry and ELISpot assay after in vitro differentiation.Patients had significantly increased transitional, decreased IgM only, switched and non-switched memory B cells and decreased membrane IgM-expression levels on memory B-cell subsets compared to healthy controls. A strongly diminished B-cell differentiation and expansion capacity was observed in 5/6 investigated patients. Severely reduced IgM-secreting capacity was detected in 2/6 patients.Taken together, our results show altered B-cell subsets and severe functional B-cell defects in sIgM. This may provide a diagnostic tool and basis for subclassification of patients to study the pathogenetic background.

Background Colonisation with Panton-Valentine Leukocidin expressing strains of Staphylococcus aureus (PVL + SA) is characterised by recurrent skin and soft tissue infections. While periorbital and orbital infections are common in children and frequently caused by S. aureus the role of PVL + SA in recurrent eye infections has not been studied. This study aimed to detect and report frequency and recurrence of periorbital or orbital infections as additional symptoms of PVL + SA colonisation in children. Methods We conducted a retrospective cohort study of pediatric patients who were treated for PVL + SA skin and soft tissue infection in our in- and outpatient clinics in Berlin, Germany from January 2012 to January 2017. We identified cases with periorbital or orbital infections in the year prior to the first PVL + SA evidence. In these cases, we conducted follow-up interviews by phone to determine recurrence of symptoms after the completion of decolonisation procedures. Results Fifty pediatric patients (age range: one week to 17 years) were evaluated and treated for PVL + SA infections in the reported time period. 19 patients (38%) reported periorbital infection or conjunctivitis, with recurrent hordeola as the most frequent finding (n = 9; 18%). Reappearance of hordeola (n = 5) was associated with recurrence of skin and soft tissue infections and/or de novo detection of PVL + SA. No further hordeola or other eye infections occurred after successful decolonisation. Conclusion Our findings suggest a frequent involvement of periorbital skin in children with PVL + SA infections. Pediatric patients with recurrent periorbital infections might benefit from PVL + SA screening and consecutive decolonisation procedures.

Vaccination against influenza in patients with primary antibody deficiency is recommended. Common variable immunodeficiency (CVID) is the most frequent and clinically relevant antibody deficiency disease and is by definition characterized by an impaired vaccination response. The purpose of this review is to present the current knowledge of humoral and cellular vaccine response to influenza in CVID patients. Studies conducted in CVID patients demonstrated an impaired humoral response upon influenza vaccination. Data on cellular immune response are in part conflicting, with two out of three studies showing responses similar to healthy controls. Available data suggest a benefit from influenza vaccination in CVID patients. Therefore, annual influenza vaccination in patients and their close household contacts is recommended.

Nontuberculous mycobacterial infections due to autoantibodies targeting interferon-γ are an emerging medical problem. However, case finding is hampered due to highly complex diagnostic procedures not available in routine laboratories. We show that QuantiFERON assays can be exploited as a simple screening tool that may facilitate adequate and timely treatment.

Objectives We report on an outbreak of skin and soft tissue infections (SSTI) among kindergarten families. We analyzed the transmission route and aimed to control the outbreak. Methods The transmission route was investigated by nasal screening for Panton-Valentine leukocidin (PVL)-producing Staphylococcus aureus (PVL-SA), subsequent microbiological investigation including whole genome sequencing and a questionnaire-based analysis of epidemiological information. The control measures included distribution of outbreak information to all individuals at risk and implementation of a Staphylococcus aureus decontamination protocol. Results Individuals from 7 of 19 families were either colonized or showed signs of SSTI such as massive abscesses or eye lid infections. We found 10 PVL-SA isolates in 9 individuals. In the WGS-analysis all isolates were found identical with a maximum of 17 allele difference. The clones were methicillin-susceptible but cotrimoxazole resistant. In comparison to PVL-SAs from an international strain collection, the outbreak clone showed close genetical relatedness to PVL-SAs from a non-European country. The questionnaire results showed frequent travels of one family to this area. The results also demonstrated likely transmission via direct contact between families. After initiation of Staphylococcus aureus decontamination no further case was detected. Conclusions Our outbreak investigation showed the introduction of a PVL-SA strain into a kindergarten likely as a result of international travel and further transmission by direct contact. The implementation of a Staphylococcus aureus decontamination protocol was able to control the outbreak.

Background Immunization against seasonal influenza with inactivated vaccine is recommended for patients with common variable immunodeficiency (CVID). However, humoral vaccine response in CVID patients is frequently impaired and current knowledge on T cell vaccine response in CVID and other patients with antibody deficiency is poor. Objective In the present study, we comparatively analyzed the antibody and T cellular immune response of patients with CVID and unclassified antibody deficiency to influenza vaccination in the season 2013–2014. Methods Eight patients with CVID, 8 patients with unclassified antibody deficiency and 9 healthy controls were vaccinated with a single dose of non-adjuvanted seasonal influenza vaccine. Before and 3 weeks after the vaccination antibody titers against the strains A/California/7/2009, A/Texas/50/2012, and B/Massachusetts/02/2012 included in the vaccine were measured by hemagglutination inhibition testing. Additionally, vaccine-specific T cell cytokine response was determined by stimulation with the complete vaccine in vitro. Results Whereas all healthy controls responded to vaccination with serum antibody titers, only 1/8 CVID patients and 4/8 patients with unclassified antibody deficiency showed a response against at least 1 of the 3 vaccine strains. However, 7/8 of the CVID and 6/8 of the patients with unclassified antibody deficiency had similar frequencies of vaccine-induced IFN-γ, TNF-α and IL-2 producing CD40L+ T cells as the control group. Conclusion Our data suggest that most CVID and unclassified antibody deficiency patients benefit from seasonal influenza vaccination by mounting a cellular response.

Introduction IgSCf est une Ig a 10 % associee avec la hyaluronidase humaine recombinante (rHuPH20) afin de faciliter la perfusion SC de l’IG, et approuvee dans l’union europeenne (UE) comme un traitement de substitution chez les adultes, enfants et adolescents (0–18 ans) atteints de PID, hypogammaglobulinemie secondaire a un myelome ou une leucemie lymphoide chronique. Cette etude a ete initiee dans l’UE en juillet 2014, afin d’acquerir des donnees supplementaires sur l’innocuite a long terme de l’IgSCf et d’evaluer les schemas therapeutiques prescrits et l‘administration dans la pratique clinique de routine. Materiels et methodes Cette etude en cours, prospective, non interventionnelle, en ouvert, non controlee, multicentrique qui vise a evaluer les effets a long terme de l‘IgSCf chez les patients adultes dans la pratique clinique de routine. Les patients adultes qui ont recu ou qui recoivent actuellement de l’IgSCf sont admissibles. Le schema therapeutique est laisse a la discretion du medecin traitant ; les patients sont suivis selon les normes pratiques cliniques et les anticorps anti-rHuPH20 sont mesures sur une base volontaire. Resultats A la date du 7 octobre 2016, le nombre des patients inclus dans l’analyse de securite etait de 62 (parmi les 86 inclus dans l’etude) qui ont recu ≥ 1 dose de l’IgSCf ; la duree de l’exposition etait de 66,7 patients-annees. Au total, 104 EI non graves (a l’exclusion des infections) ont ete signalees chez 40 patients. Aucun des 45 patients avec des donnees d’immunogenicite n‘ont developpe d’auto-anticorps anti-rHuPH20 positifs (definie comme titre ≥ 160) ou neutralisants. Les taux annuels d’hospitalisation et de visites a l’urgence ont ete, chaque, de moins de 1 par patient. La plupart des traitements ont ete administres a domicile au cours de la premiere (89,5 %) et de la deuxieme annee (91,5 %) dans l’etude. Conclusion L’analyse interimaire de ces donnees recueillies prospectivement sur l‘utilisation de l’IgSCf indique que l’IgSCf est bien toleree.

We describe the clinical course of a 2-month-old infant who was evaluated for autosomal dominant Hyper IgE Syndrome based on eczema, periorbital cellulitis, skin abscesses, increased total IgE levels and blood eosinophilia. However, scabies and nasal colonization by Panton-Valentine Leucocidin-positive S. aureus were eventually diagnosed. After specific treatment, the child was asymptomatic.

The current European Society for Immunodeficiencies (ESID) registry was established 10 years ago in 2004, when the system was moved from a paper-based to an online system. The purpose of the registry is to collect data on European patients with primary immunodeficiencies (PIDs) and their treatment, with the aim of building an easily accessible database for use by physicians and researchers. During the 10 years for which the current registry has been operational, the number of patients registered has grown substantially; after 4 years, more than 7000 patients were registered and, as of 25 June, 19 355 patients are registered in Europe as having a PID. Longitudinal data (20 or more data sets, documented every 6 months) is now available for some of the patients in the registry. Children younger than age 15 years represent two-thirds of this cohort. More than half the patients (57%) have an antibody disorder, and this is also the group with the greatest number of adult patients. Of the 19 355 registered, treatment data are available on approximately 14 000, of whom 6476 receive immunoglobulin (Ig) treatment; 4239 patients are receiving intravenous immunoglobulin (IVIg) treatment and approximately 2181 receive subcutaneous immunoglobulin (SCIg). One of the interesting comparisons arising from the registry data is the difference in minimum prevalence of PIDs between countries. In France, for example, 6·058 cases are documented per 100 000 inhabitants; much higher than in Switzerland (4·157 per 100 000) or Germany (2·105 per 100 000). This is most probably because France has a very efficient documenting system, whereby designated documenters, financed by local grants in France, visit centres to enter patients' data into the registry. Thus, the more efficient the documenting system, the higher the quality of data collected. Physicians and researchers can apply for access to the registry data by writing to ESID with details of their specific project, or with a proposal to collect new and different data on patients with specific diseases. Despite the large number of patients in the registry and the large amount of data collected, only 23 papers have been published, which is an average of more than two per year over 10 years. However, considering that more than 200 physicians and researchers have access to the database, this still means that the registry is one of the most under-used data sets of its kind in Europe. In a recent registry publication we analysed the subset of common variable immunodeficiency (CVID) subjects 1. There are more than 4000 CVID subjects in the registry, but because not all have complete data sets, the cohort described in this paper included 2212 subjects. As CVID has a variable clinical presentation, we investigated the frequencies of different disease phenotypes in the cohort 1. The most common clinical features were pneumonia (32%) and autoimmunity (29%). Other features included splenomegaly (26%), bronchiectasis (23%) and granulomatous disease (10%), and a further 10% had enteropathy. Surprisingly, 5% of patients had solid tumours and 4% had meningitis/encephalitis [conditions associated more usually with X-linked agammaglobulinaemia (XLA)]. Less frequent clinical features were lymphoma, found in 3% of the patients, splenectomy in 2% and lobectomy in 1%. With regard to how efficiently patients are being diagnosed, CVID has been described as having a bi-modal age of manifestation, with a peak in diagnoses between the ages of 5 and 10 years, a trough around the age of 20, and then another peak between 30 and 40 years. However, when patients are asked about the onset of their symptoms the reported age is lower, with most patients experiencing recurrent infections in childhood, and fewer than half manifesting after age 20 (Fig. 1). In some countries, the delay between onset of symptoms and CVID diagnosis is greater than others, the average being 4·1 years, ranging from 1·8 years in Poland to 7 years in France 1. Figure 1 (a) Age at onset of symptoms in the total cohort (n = 1914), among female patients (n = 985) and among male patients (n = 929). (b) Age at diagnosis in the total cohort (n = 2134), among ... We showed that adult CVID cases were diagnosed more promptly than paediatric cases (aged

Since we described for the first time a patient with IgG4 autoantibodies to IFN-γ more than 10 years ago, many patients with IFN-γ IgG4 autoantibodies have been described, mostly in Mongolian/ Asian patients with a particular HLA background and in association with disseminated nontuberculous mycobacterial infections. Very recently, the first Caucasian US patient was reported and we now present the case of a 65-year old Caucasian woman with severe disseminated Mycobacterium avium infection, cerebral toxoplasmosis and salmonella sepsis who was tested positive for IFN-γ deficiency due to unusual anti-IFN-γ IgG1 autoantibodies. IFN-γ production after ex vivo ConA stimulation of the patient’s whole blood and isolated peripheral blood mononuclear cells was assessed. Anti-human IFN-γ antibodies were measured by Ig/Ig-subclass-specific ELISA. In vitro physiologic relevance and blocking capacity of IFN-γ-stimulation by patient’s serum was analysed by flow cytometric assessment of cytokine-induced phosphorylation of pSTAT1Y701. Severely impaired IFN-γ production in the patient’s whole blood but normal production in peripheral blood mononuclear cells in the absence of autologous serum was observed. High titre anti-IFN-γ antibodies of the IgG1 subclass could be demonstrated in the patient’s serum by ELISA. Further, the addition of patient’s serum to IFN-γ-stimulated immune cells showed inhibition of STAT1 phosphorylation. IFN-γ autoantibodies of any IgG-isotype should be considered in patients with severe opportunistic infections independent of age at onset and ethnicity.

Background Chronic fatigue syndrome (CFS) is considered as a neuroimmunological disease but the etiology and pathophysiology is poorly understood. Patients suffer from sustained exhaustion, cognitive impairment and an increased sensitivity to pain and sensory stimuli. A subset of patients has frequent respiratory tract infections (RRTI). Dysregulation of the sympathetic nervous system and an association with genetic variations in the catechol-O-methyltransferase (COMT) and glucocorticoid receptor genes influencing sympathetic and glucocorticoid metabolism were reported in CFS. Here, we analyzed the prevalence of SNPs of COMT and glucocorticoid receptor- associated genes in CFS patients and correlated them to immunoglobulin levels and susceptibility to RRTI. Methods We analyzed blood cells of 74 CFS patients and 76 healthy controls for polymorphisms in COMT, FKBP5 and CRHR1 by allelic discrimination PCR. Serum immunoglobulins were determined by immunoturbidimetric technique, cortisol levels by ECLIA. Results Contrary to previous reports, we found no difference between CFS patients and healthy controls in the prevalence of SNPs for COMT, FKBP5 and CRHR1. In patients with the Met/Met variant of COMT rs4680 we observed enhanced cortisol levels providing evidence for its functional relevance. Both enhanced IgE and diminished IgG 3 levels and an increased susceptibility to RRTI were observed in CFS patients with the Met/Met variant. Such an association was not observed in 68 non-CFS patients with RRTI. Conclusion Our results indicate a relationship of COMT polymorphism rs4680 with immune dysregulation in CFS providing a potential link for the association between stress and infection susceptibility in CFS.

The mannose receptor (MR) is a type I membrane molecule with two lectin activities. Mannose recognition takes place through the C-type lectin-like carbohydrate recognition domains, while recognition of sulphated glycans is mediated by the cysteine-rich domain (CR). In murine spleen CR ligands are present in a subpopulation of macrophages (Mphi) placed in the marginal zone whereas MR-expressing cells consisting of Mphi and nonvascular endothelia are located in the red pulp. No colocalisation of MR with CR ligands has been observed in murine tissues. In this manuscript we describe the distribution of MR and CR ligands in human spleen. In this organ we have detected a perfect colocalisation of MR with CR ligands in Lyve-1+ cells lining venous sinuses. These cells form a physical barrier for blood cells as they need to migrate through the sinuses in order to exit the splenic parenchyma and, in this way, contribute to the unique filtration function of this organ. Furthermore, unlike murine spleen, CD68+ red pulp Mphi lack MR expression. Our results suggest an unexpected contribution of MR to splenic function through the recognition of sulphated ligands that could influence the filtering capability of this organ.

Chronic fatigue syndrome (CFS) is a severe disease characterized by various symptoms of immune dysfunction. CFS onset is typically with an infection and many patients suffer from frequently recurrent viral or bacterial infections. Immunoglobulin and mannose binding lectin (MBL) deficiency are frequent causes for increased susceptibility to infections. In this study we retrospectively analysed 300 patients with CFS for immunoglobulin and MBL levels, and B-cell subset frequencies. 25% of the CFS patients had decreased serum levels of at least one antibody class or subclass with IgG3 and IgG4 subclass deficiencies as most common phenotypes. However, we found elevated immunoglobulin levels with an excess of IgM and IgG2 in particular in another 25% of patients. No major alteration in numbers of B cells and B-cell subsets was seen. Deficiency of MBL was found in 15% of the CFS patients in contrast to 6% in a historical control group. In a 2nd cohort of 168 patients similar frequencies of IgG subclass and MBL deficiency were found. Thus, humoral immune defects are frequent in CFS patients and are associated with infections of the respiratory tract.

Epstein-Barr virus (EBV) has long been discussed as a possible cause or trigger of Chronic Fatigue Syndrome (CFS). In a subset of patients the disease starts with infectious mononucleosis and both enhanced and diminished EBV-specific antibody titers have been reported. In this study, we comprehensively analyzed the EBV-specific memory B- and T-cell response in patients with CFS. While we observed no difference in viral capsid antigen (VCA)-IgG antibodies, EBV nuclear antigen (EBNA)-IgG titers were low or absent in 10% of CFS patients. Remarkably, when analyzing the EBV-specific memory B-cell reservoir in vitro a diminished or absent number of EBNA-1- and VCA-antibody secreting cells was found in up to 76% of patients. Moreover, the ex vivo EBV-induced secretion of TNF-α and IFN-γ was significantly lower in patients. Multicolor flow cytometry revealed that the frequencies of EBNA-1-specific triple TNF-α/IFN-γ/IL-2 producing CD4(+) and CD8(+) T-cell subsets were significantly diminished whereas no difference could be detected for HCMV-specific T-cell responses. When comparing EBV load in blood immune cells, we found more frequently EBER-DNA but not BZLF-1 RNA in CFS patients compared to healthy controls suggesting more frequent latent replication. Taken together, our findings give evidence for a deficient EBV-specific B- and T-cell memory response in CFS patients and suggest an impaired ability to control early steps of EBV reactivation. In addition the diminished EBV response might be suitable to develop diagnostic marker in CFS.

Background The population of patients with common variable immunodeficiency (CVID) comprises a heterogeneous group of patients with different causes of hypogammaglobulinemia predisposing to recurrent infections, higher incidence of autoimmunity, and malignancy. Although memory B cells (memBcs) are key players in humoral defense and their numbers are commonly reduced in these patients, their functionality is not part of any current classification. Objective We established and validated a memBc enzyme-linked immunosorbent spot (ELISpot) assay that reveals the capacity of memBcs to develop into antibody-secreting cells and present an idea for a new classification based on this functional capacity. Methods The memBc ELISpot assay, combined with flow cytometry, was applied to patients with confirmed CVID in comparison with age-matched healthy control subjects. Results Ex vivo frequency of IgG-, IgM-, and IgA-secreting plasmablasts was significantly diminished by 27.2-, 2.4-, and 23.3-fold, respectively, compared with that seen in healthy control subjects. Moreover, in vitro differentiation of memBcs into antibody-secreting cells was 6.1-, 2.6-, and 3.7-fold significantly reduced for IgG-, IgM-, and IgA-secreting cells, respectively. Proliferation of memBcs correlates inversely to immunoglobulin-secreting capacity, suggesting compensatory hyperproliferation. Furthermore, patients with no serum IgA can still have a detectable IgA ELISpot assay result in vitro . Most importantly, the large heterogeneity of memBc function in patients with CVID homogenously grouped by means of fluorescence-activated cell sorting allowed additional subclassification based on memBc/plasmablast function. Conclusion These data suggest almost normal memBc/immunoglobulin-secreting plasmablast functionality in some patients if sufficient stimulatory signals are delivered, which might open up opportunities for new therapeutic approaches.