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Abstract Background Immunization with meningococcal ACWY conjugate vaccine induces protective antibodies against invasive meningococcal disease (IMD) caused by serogroups A, C, W and Y. We studied MenACWY-TT vaccine immunogenicity in adolescents with a heterogenous group of primary and secondary immune deficiency including patients with systemic lupus erythematosus, mixed connective tissue disease, vasculitis, uveitis, 22Q11 syndrome, sickle cell disease, and patients who underwent stem cell transplantation for bone marrow failure. Findings We enrolled 69 individuals aged 14–18 years diagnosed with a primary or secondary immune deficiency in a prospective observational cohort study. All patients received a single dose of MenACWY-TT vaccine during the catch-up campaign 2018-19 because of the IMD-W outbreak in the Netherlands. Capsular polysaccharide-specific (PS) IgG concentrations against MenACWY were measured before and 3–6, 12, and 24 months after vaccination. Overall, geometric mean concentrations (GMCs) of MenACWY-PS-specific IgG were lower in patients compared to data from healthy, aged-matched controls (n = 75) reaching significance at 12 months postvaccination for serogroup A and W (adjusted GMC ratios 0.26 [95% CI: 0.15–0.47] and 0.22 [95% CI: 0.10–0.49], respectively). No serious adverse events were reported by study participants. Conclusions The MenACWY conjugate vaccine was less immunogenic in adolescent patients with primary or secondary immunodeficiency compared to healthy controls, urging the need for further surveillance of these patients and supporting considerations for booster MenACWY conjugate vaccinations in these patient groups.

IntroductionCommon variable immunodeficiency related interstitial lung disease (CVID-ILD, also referred to as GLILD) is generally considered a manifestation of systemic immune dysregulation occurring in up to 20% of people with CVID. There is a lack of evidence-based guidelines for the diagnosis and management of CVID-ILD.AimTo systematically review use of diagnostic tests for assessing patients with CVID for possible ILD, and to evaluate their utility and risks.MethodsEMBASE, MEDLINE, PubMed and Cochrane databases were searched. Papers reporting information on the diagnosis of ILD in patients with CVID were included.Results58 studies were included. Radiology was the investigation modality most commonly used. HRCT was the most reported test, as abnormal radiology often first raised suspicion of CVID-ILD. Lung biopsy was used in 42 (72%) of studies, and surgical lung biopsy had more conclusive results compared to trans-bronchial biopsy (TBB). Analysis of broncho-alveolar lavage was reported in 24 (41%) studies, primarily to exclude infection. Pulmonary function tests, most commonly gas transfer, were widely used. However, results varied from normal to severely impaired, typically with a restrictive pattern and reduced gas transfer.ConclusionConsensus diagnostic criteria are urgently required to support accurate assessment and monitoring in CVID-ILD. ESID and the ERS e-GLILDnet CRC have initiated a diagnostic and management guideline through international collaboration.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/, identifier CRD42022276337.

IntroductionBesides recurrent infections, a proportion of patients with Common Variable Immunodeficiency Disorders (CVID) may suffer from immune dysregulation such as granulomatous-lymphocytic interstitial lung disease (GLILD). The optimal treatment of this complication is currently unknown. Experienced-based expert opinions have been produced, but a systematic review of published treatment studies is lacking.GoalsTo summarize and synthesize the published literature on the efficacy of treatments for GLILD in CVID.MethodsWe performed a systematic review using the PRISMA guidelines. Papers describing treatment and outcomes in CVID patients with radiographic and/or histologic evidence of GLILD were included. Treatment regimens and outcomes of treatment were summarized.Results6124 papers were identified and 42, reporting information about 233 patients in total, were included for review. These papers described case series or small, uncontrolled studies of monotherapy with glucocorticoids or other immunosuppressants, rituximab monotherapy or rituximab plus azathioprine, abatacept, or hematopoietic stem cell transplantation (HSCT). Treatment response rates varied widely. Cross-study comparisons were complicated because different treatment regimens, follow-up periods, and outcome measures were used. There was a trend towards more frequent GLILD relapses in patients treated with corticosteroid monotherapy when compared to rituximab-containing treatment regimens based on qualitative endpoints. HSCT is a promising alternative to pharmacological treatment of GLILD, because it has the potential to not only contain symptoms, but also to resolve the underlying pathology. However, mortality, especially among immunocompromised patients, is high.ConclusionsWe could not draw definitive conclusions regarding optimal pharmacological treatment for GLILD in CVID from the current literature since quantitative, well-controlled evidence was lacking. While HSCT might be considered a treatment option for GLILD in CVID, the risks related to the procedure are high. Our findings highlight the need for further research with uniform, objective and quantifiable endpoints. This should include international registries with standardized data collection including regular pulmonary function tests (with carbon monoxide-diffusion), uniform high-resolution chest CT radiographic scoring, and uniform treatment regimens, to facilitate comparison of treatment outcomes and ultimately randomized clinical trials.

BackgroundGranulomatous–lymphocytic interstitial lung disease (GLILD) is a rare, potentially severe pulmonary complication of common variable immunodeficiency disorders (CVID). Informative clinical trials and consensus on management are lacking.AimsThe European GLILD network (e-GLILDnet) aims to describe how GLILD is currently managed in clinical practice and to determine the main uncertainties and unmet needs regarding diagnosis, treatment and follow-up.MethodsThe e-GLILDnet collaborators developed and conducted an online survey facilitated by the European Society for Immunodeficiencies (ESID) and the European Respiratory Society (ERS) between February–April 2020. Results were analyzed using SPSS.ResultsOne hundred and sixty-one responses from adult and pediatric pulmonologists and immunologists from 47 countries were analyzed. Respondents treated a median of 27 (interquartile range, IQR 82–maximum 500) CVID patients, of which a median of 5 (IQR 8–max 200) had GLILD. Most respondents experienced difficulties in establishing the diagnosis of GLILD and only 31 (19%) had access to a standardized protocol. There was little uniformity in diagnostic or therapeutic interventions. Fewer than 40% of respondents saw a definite need for biopsy in all cases or performed bronchoalveolar lavage for diagnostics. Sixty-six percent used glucocorticosteroids for remission-induction and 47% for maintenance therapy; azathioprine, rituximab and mycophenolate mofetil were the most frequently prescribed steroid-sparing agents. Pulmonary function tests were the preferred modality for monitoring patients during follow-up.ConclusionsThese data demonstrate an urgent need for clinical studies to provide more evidence for an international consensus regarding management of GLILD. These studies will need to address optimal procedures for definite diagnosis and a better understanding of the pathogenesis of GLILD in order to provide individualized treatment options. Non-availability of well-established standardized protocols risks endangering patients.

Abstract A wide variety of microbial and inflammatory factors induce DNA release from neutrophils as neutrophil extracellular traps (NETs). Consensus on the kinetics and mechanism of NET release has been hindered by the lack of distinctive methods to specifically quantify NET release in time. Here, we validate and refine a semi-automatic live imaging approach for quantification of NET release. Importantly, our approach is able to correct for neutrophil input and distinguishes NET release from neutrophil death by other means, aspects that are lacking in many NET quantification methods. Real time visualization shows that opsonized S. aureus rapidly induces cell death by toxins, while actual NET formation occurs after 90 minutes, similar to the kinetics of NET release by immune complexes and PMA. Inhibition of SYK, PI3K and mTORC2 attenuates NET release upon challenge with physiological stimuli but not with PMA. In contrast, neutrophils from chronic granulomatous disease patients show decreased NET release only in response to PMA. With this refined method, we conclude that NET release in primary human neutrophils is dependent on the SYK-PI3K-mTORC2 pathway and that PMA stimulation should be regarded as mechanistically distinct from NET formation induced by natural triggers.

Activated phosphoinositide 3-kinase (PI3K) δ Syndrome (APDS), caused by autosomal dominant mutations in PIK3CD (APDS1) or PIK3R1 (APDS2), is a heterogeneous primary immunodeficiency. While initial cohort-descriptions summarized the spectrum of clinical and immunological manifestations, questions about long-term disease evolution and response to therapy remain. The prospective European Society for Immunodeficiencies (ESID)-APDS registry aims to characterize the disease course, identify outcome predictors, and evaluate treatment responses. So far, 77 patients have been recruited (51 APDS1, 26 APDS2). Analysis of disease evolution in the first 68 patients pinpoints the early occurrence of recurrent respiratory infections followed by chronic lymphoproliferation, gastrointestinal manifestations, and cytopenias. Although most manifestations occur by age 15, adult-onset and asymptomatic courses were documented. Bronchiectasis was observed in 24/40 APDS1 patients who received a CT-scan compared with 4/15 APDS2 patients. By age 20, half of the patients had received at least one immunosuppressant, but 2–3 lines of immunosuppressive therapy were not unusual before age 10. Response to rapamycin was rated by physician visual analog scale as good in 10, moderate in 9, and poor in 7. Lymphoproliferation showed the best response (8 complete, 11 partial, 6 no remission), while bowel inflammation (3 complete, 3 partial, 9 no remission) and cytopenia (3 complete, 2 partial, 9 no remission) responded less well. Hence, non-lymphoproliferative manifestations should be a key target for novel therapies. This report from the ESID-APDS registry provides comprehensive baseline documentation for a growing cohort that will be followed prospectively to establish prognostic factors and identify patients for treatment studies.