Stability of gut microbiome after COVID-19 vaccination in healthy and immuno-compromised individuals.

Bidirectional interactions between the immune system and the gut microbiota are key contributors to various physiological functions. Immune-associated diseases such as cancer and autoimmunity, and efficacy of immunomodulatory therapies, have been linked to microbiome variation. Although COVID-19 infection has been shown to cause microbial dysbiosis, it remains understudied whether the inflammatory response associated with vaccination also impacts the microbiota. Here, we investigate the temporal impact of COVID-19 vaccination on the gut microbiome in healthy and immuno-compromised individuals; the latter included patients with primary immunodeficiency and cancer patients on immunomodulating therapies. We find that the gut microbiome remained remarkably stable post-vaccination irrespective of diverse immune status, vaccine response, and microbial composition spanned by the cohort. The stability is evident at all evaluated levels including diversity, phylum, species, and functional capacity. Our results indicate the resilience of the gut microbiome to host immune changes triggered by COVID-19 vaccination and suggest minimal, if any, impact on microbiome-mediated processes. These findings encourage vaccine acceptance, particularly when contrasted with the significant microbiome shifts observed during COVID-19 infection.

Activated phosphoinositide 3-kinase δ syndrome: Update from the ESID Registry and comparison with other autoimmune-lymphoproliferative inborn errors of immunity.

BACKGROUND: Activated phosphoinositide-3-kinase δ syndrome (APDS) is an inborn error of immunity (IEI) with infection susceptibility and immune dysregulation, clinically overlapping with other conditions. Management depends on disease evolution, but predictors of severe disease are lacking. OBJECTIVES: This study sought to report the extended spectrum of disease manifestations in APDS1 versus APDS2; compare these to CTLA4 deficiency, NFKB1 deficiency, and STAT3 gain-of-function (GOF) disease; and identify predictors of severity in APDS. METHODS: Data was collected from the ESID (European Society for Immunodeficiencies)-APDS registry and was compared with published cohorts of the other IEIs. RESULTS: The analysis of 170 patients with APDS outlines high penetrance and early onset of APDS compared to the other IEIs. The large clinical heterogeneity even in individuals with the same PIK3CD variant E1021K illustrates how poorly the genotype predicts the disease phenotype and course. The high clinical overlap between APDS and the other investigated IEIs suggests relevant pathophysiological convergence of the affected pathways. Preferentially affected organ systems indicate specific pathophysiology: bronchiectasis is typical of APDS1; interstitial lung disease and enteropathy are more common in STAT3 GOF and CTLA4 deficiency. Endocrinopathies are most frequent in STAT3 GOF, but growth impairment is also common, particularly in APDS2. Early clinical presentation is a risk factor for severe disease in APDS. CONCLUSIONS: APDS illustrates how a single genetic variant can result in a diverse autoimmune-lymphoproliferative phenotype. Overlap with other IEIs is substantial. Some specific features distinguish APDS1 from APDS2. Early onset is a risk factor for severe disease course calling for specific treatment studies in younger patients.

Age-associated B cells predict impaired humoral immunity after COVID-19 vaccination in patients receiving immune checkpoint blockade.

Age-associated B cells (ABC) accumulate with age and in individuals with different immunological disorders, including cancer patients treated with immune checkpoint blockade and those with inborn errors of immunity. Here, we investigate whether ABCs from different conditions are similar and how they impact the longitudinal level of the COVID-19 vaccine response. Single-cell RNA sequencing indicates that ABCs with distinct aetiologies have common transcriptional profiles and can be categorised according to their expression of immune genes, such as the autoimmune regulator (AIRE). Furthermore, higher baseline ABC frequency correlates with decreased levels of antigen-specific memory B cells and reduced neutralising capacity against SARS-CoV-2. ABCs express high levels of the inhibitory FcγRIIB receptor and are distinctive in their ability to bind immune complexes, which could contribute to diminish vaccine responses either directly, or indirectly via enhanced clearance of immune complexed-antigen. Expansion of ABCs may, therefore, serve as a biomarker identifying individuals at risk of suboptimal responses to vaccination.

Inborn Errors of Immunity on the Island of Ireland - a Cross-Jurisdictional UKPID/ESID Registry Report.

The epidemiology of inborn errors of immunity (IEI) in the Republic of Ireland was first published in 2005 but has not been updated since. IEI prevalence data from Northern Ireland was last published in 2018. Using data from the United Kingdom Primary Immune Deficiency (UKPID) and European Society for Immunodeficiencies (ESID) registries, we reviewed all registered cases of IEI affecting adult patients ≥ 18 years of age from the two largest immunology specialist centres in Northern Ireland and the Republic of Ireland, respectively and calculated the combined minimum adult prevalence of IEI on the island of Ireland for the first time. We also recorded data pertaining to presenting symptoms of IEI, diagnostic delay, immunoglobulin data, and genetic testing, as well as briefly reporting data pertaining to secondary immunodeficiency in both countries. As of 1 May 2020, we identified a minimum adult IEI prevalence in Ireland of 8.85/100,000 population.

Treatment of COVID-19 with remdesivir in the absence of humoral immunity: a case report.

The response to the coronavirus disease 2019 (COVID-19) pandemic has been hampered by lack of an effective severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antiviral therapy. Here we report the use of remdesivir in a patient with COVID-19 and the prototypic genetic antibody deficiency X-linked agammaglobulinaemia (XLA). Despite evidence of complement activation and a robust T cell response, the patient developed persistent SARS-CoV-2 pneumonitis, without progressing to multi-organ involvement. This unusual clinical course is consistent with a contribution of antibodies to both viral clearance and progression to severe disease. In the absence of these confounders, we take an experimental medicine approach to examine the in vivo utility of remdesivir. Over two independent courses of treatment, we observe a temporally correlated clinical and virological response, leading to clinical resolution and viral clearance, with no evidence of acquired drug resistance. We therefore provide evidence for the antiviral efficacy of remdesivir in vivo, and its potential benefit in selected patients.

Publisher Correction: Whole-genome sequencing of a sporadic primary immunodeficiency cohort.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Whole-genome sequencing of a sporadic primary immunodeficiency cohort.

Primary immunodeficiency (PID) is characterized by recurrent and often life-threatening infections, autoimmunity and cancer, and it poses major diagnostic and therapeutic challenges. Although the most severe forms of PID are identified in early childhood, most patients present in adulthood, typically with no apparent family history and a variable clinical phenotype of widespread immune dysregulation: about 25% of patients have autoimmune disease, allergy is prevalent and up to 10% develop lymphoid malignancies1-3. Consequently, in sporadic (or non-familial) PID genetic diagnosis is difficult and the role of genetics is not well defined. Here we address these challenges by performing whole-genome sequencing in a large PID cohort of 1,318 participants. An analysis of the coding regions of the genome in 886 index cases of PID found that disease-causing mutations in known genes that are implicated in monogenic PID occurred in 10.3% of these patients, and a Bayesian approach (BeviMed4) identified multiple new candidate PID-associated genes, including IVNS1ABP. We also examined the noncoding genome, and found deletions in regulatory regions that contribute to disease causation. In addition, we used a genome-wide association study to identify loci that are associated with PID, and found evidence for the colocalization of-and interplay between-novel high-penetrance monogenic variants and common variants (at the PTPN2 and SOCS1 loci). This begins to explain the contribution of common variants to the variable penetrance and phenotypic complexity that are observed in PID. Thus, using a cohort-based whole-genome-sequencing approach in the diagnosis of PID can increase diagnostic yield and further our understanding of the key pathways that influence immune responsiveness in humans.

Chronic Granulomatous Disorder-Associated Colitis Can Be Accurately Evaluated with MRI Scans and Fecal Calprotectin Level.

PURPOSE: Colitis is a common and serious complication of chronic granulomatous disorder (CGD) and requires assessment. Colonoscopy is invasive and carries risks of serious complication. We therefore assessed non-invasive monitoring via magnetic resonance imaging (MRI). We also evaluated fecal calprotectin (FCP), the Harvey-Bradshaw index (HBI) clinical score, and serum cytokines. METHODS: We recruited 10 patients with CGD (8 males, mean age 29.6 years), scored a modified HBI, and obtained stool for FCP. The following day we took blood for cytokine measurement via Luminex, performed MR enterography (scored by two independent radiologists using three systems: London score, CDMI, and MaRIA) followed by colonoscopy with disease activity measurement via ulcerative colitis endoscopic index of severity (UCEIS). We assessed patient experience after each investigation and overall preference with follow-up questionnaires. RESULTS: MRI scores correlated well with colonoscopic gold standard (for London score R2 0.91, p < 0.0001; for CDMI R2 0.83, p = 0.0006; for MaRIA R2 0.89, p = 0.0002). MRI was better tolerated and generally preferred, quicker, and visualized the entire large bowel whereas colonoscopy did not reach the terminal ileum in 3 participants. Elevated FCP accurately differentiated patients with colitis from those without, and log(calprotectin) correlated well with disease activity (R2 0.71, p = 0.009). Serum interleukin (IL)-12 concentration correlated with colitis activity but IL-1ß and TNF did not. Harvey-Bradshaw index did not correlate with colitis activity. CONCLUSIONS: MRI and fecal calprotectin are useful methods for monitoring CGD colitis and should reduce the need for colonoscopy in these patients. IL-12 may represent an appropriate target for treatment.

Absence of Persistent Hepatitis E Virus Infection in Antibody-Deficient Patients Is Associated With Transfer of Antigen-Neutralizing Antibodies From Immunoglobulin Products.

Background: Persistent hepatitis E virus (HEV) infection is described in a number of immunosuppressive conditions. We aimed to determine the risk of persistent HEV infection in patients with primary or secondary antibody deficiency. Methods: Two hundred forty-five antibody-deficient patients receiving regular immunoglobulin replacement therapy were tested for HEV RNA and anti-HEV immunoglobulin G (IgG). Immunoglobulin products and plasma specimens obtained from 9 antibody-deficient patients before and after intravenous immunoglobulin (IVIG) therapy, 5 recently treated patients with persistent HEV infection, and 5 healthy patients recovered from acute HEV infection were analyzed for anti-HEV IgG and for antibody reacting with HEV antigen. Results: No antibody-deficient patient had detectable plasma HEV RNA. Anti-HEV IgG was detected in 38.8% of patients. All 10 immunoglobulin products tested contained anti-HEV capable of neutralizing HEV antigen. Plasma samples collected following IVIG infusion therapy demonstrated a higher anti-HEV IgG level and neutralizing activity, compared with samples collected before IVIG therapy. Neutralizing activity was similar to that in healthy patients with recent acute HEV infection. Conclusion: The risk of persistent HEV infection in patients with antibody deficiency appears extremely low. This may be due to passive seroprotection afforded by the ubiquitous presence of anti-HEV in immunoglobulin replacement products.

British Lung Foundation/United Kingdom Primary Immunodeficiency Network Consensus Statement on the Definition, Diagnosis, and Management of Granulomatous-Lymphocytic Interstitial Lung Disease in Common Variable Immunodeficiency Disorders.

A proportion of people living with common variable immunodeficiency disorders develop granulomatous-lymphocytic interstitial lung disease (GLILD). We aimed to develop a consensus statement on the definition, diagnosis, and management of GLILD. All UK specialist centers were contacted and relevant physicians were invited to take part in a 3-round online Delphi process. Responses were graded as Strongly Agree, Tend to Agree, Neither Agree nor Disagree, Tend to Disagree, and Strongly Disagree, scored +1, +0.5, 0, -0.5, and -1, respectively. Agreement was defined as greater than or equal to 80% consensus. Scores are reported as mean ± SD. There was 100% agreement (score, 0.92 ± 0.19) for the following definition: "GLILD is a distinct clinico-radio-pathological ILD occurring in patients with [common variable immunodeficiency disorders], associated with a lymphocytic infiltrate and/or granuloma in the lung, and in whom other conditions have been considered and where possible excluded." There was consensus that the workup of suspected GLILD requires chest computed tomography (CT) (0.98 ± 0.01), lung function tests (eg, gas transfer, 0.94 ± 0.17), bronchoscopy to exclude infection (0.63 ± 0.50), and lung biopsy (0.58 ± 0.40). There was no consensus on whether expectant management following optimization of immunoglobulin therapy was acceptable: 67% agreed, 25% disagreed, score 0.38 ± 0.59; 90% agreed that when treatment was required, first-line treatment should be with corticosteroids alone (score, 0.55 ± 0.51).

Secondary antibody deficiency.

Secondary antibody deficiencies are defined by a quantitative or qualitative decrease in antibodies that occur most commonly as a consequence of renal or gastrointestinal immunoglobulin loss, hematological malignancies and corticosteroid, immunosuppressive or anticonvulsant medications. Patients with hematological malignancies or requiring immunosuppressive medications are known to be at increased risk of infection, but few studies directly address this relationship in the context of antibody deficiency. Immunoglobulin replacement therapy has been shown to be effective in reducing infections in primary and some secondary antibody deficiencies. The commonly encountered causes of secondary antibody deficiencies and their association with infection-related morbidity and mortality are discussed. Recommendations are made for screening and clinical management of those at risk.

Use of recombinant C1 inhibitor in patients with resistant or frequent attacks of hereditary or acquired angioedema.

BACKGROUND: Conestat alfa (Ruconest, rhC1INH) is the first recombinant human C1 inhibitor protein (C1INH) for the treatment of acute attacks of hereditary angioedema (HAE). OBJECTIVE: To assess clinical experience of the first 11 adult patients who received rhC1INH in clinical practice in the UK. METHODS: Eleven patients (nine HAE type 1, one HAE type 2 and one acquired angioedema with C1 inhibitor deficiency) received between one and six, mostly self-administered, doses of rhC1INH for acute HAE attacks. They were asked to record their time to first response and complete resolution following the treatment. This cohort included our most severely affected and difficult to treat patients. RESULTS: In most cases, time to first improvement following rhC1INH and complete resolution was recorded as comparable to their typical response to pdC1INH, although 4/11 patients reported that the time to first improvement was much quicker than their average pdC1INH response. Five of the 11 patients continued with rhC1INH as their preferred rescue treatment. Of those who chose not to continue the treatment, four reported a recurrence or early return of symptoms with rhC1INH. CONCLUSION: In our experience, rhC1INH is a beneficial treatment for patients with preference for a C1INH that is not plasma derived and it is suitable for home treatment. In some cases it demonstrates cost saving, especially for heavier patients who require higher doses. In some patients rhC1INH may result in faster resolution of symptoms. It may be associated with an early return of symptoms in patients with exceptionally frequent attacks.

An Artemis polymorphic variant reduces Artemis activity and confers cellular radiosensitivity.

Artemis is required for V(D)J recombination and the repair of a subset of radiation-induced DNA double strand breaks (DSBs). Artemis-null patients display radiosensitivity (RS) and severe combined immunodeficiency (SCID), classified as RS-SCID. Strongly impacting hypomorphic Artemis mutations confer marked infant immunodeficiency and a predisposition for EBV-associated lymphomas. Here, we provide evidence that a polymorphic Artemis variant (c.512C > G: p.171P > R), which has a world-wide prevalence of 15%, is functionally impacting. The c.512C > G mutation causes an approximately 3-fold decrease in Artemis endonuclease activity in vitro. Cells derived from a patient who expressed a single Artemis allele with the polymorphic mutational change, showed radiosensitivity and a DSB repair defect in G2 phase, with Artemis cDNA expression rescuing both phenotypes. The c.512C > G change has an additive impact on Artemis function when combined with a novel C-terminal truncating mutation (p.436C > X), which also partially inactivates Artemis activity. Collectively, our findings provide strong evidence that monoallelic expression of the c.512C > G variant impairs Artemis function causing significant radiosensitivity and a G2 phase DSB repair defect. The patient exhibiting monoallelic c.512C > G-Artemis expression showed immunodeficiency only in adulthood, developed bilateral carcinoma of the nipple and myelodysplasia raising the possibility that modestly decreased Artemis function can impact clinically.