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BMJ Med. 2023 Oct 27;2(1):e000427. doi: 10.1136/bmjmed-2022-000427. eCollection 2023.

ABSTRACT

OBJECTIVE: To evaluate the efficacy of covid-19 convalescent plasma to treat patients admitted to hospital for moderate covid-19 disease with or without underlying immunodeficiency (CORIPLASM trial).

DESIGN: Open label, randomised clinical trial.

SETTING: CORIMUNO-19 cohort (publicly supported platform of open label, randomised controlled trials of immune modulatory drugs in patients admitted to hospital with moderate or severe covid-19 disease) based on 19 university and general hospitals across France, from 16 April 2020 to 21 April 2021.

PARTICIPANTS: 120 adults (n=60 in the covid-19 convalescent plasma group, n=60 in the usual care group) admitted to hospital with a positive SARS-CoV2 test result, duration of symptoms <9 days, and World Health Organization score of 4 or 5. 49 patients (n=22, n=27) had underlying immunosuppression.

INTERVENTIONS: Open label randomisation to usual care or four units (200-220 mL/unit, 2 units/day over two consecutive days) of covid-19 convalescent plasma with a seroneutralisation titre >40.

MAIN OUTCOME MEASURES: Primary outcomes were proportion of patients with a WHO Clinical Progression Scale score of ≥6 on the 10 point scale on day 4 (higher values indicate a worse outcome), and survival without assisted ventilation or additional immunomodulatory treatment by day 14. Secondary outcomes were changes in WHO Clinical Progression Scale scores, overall survival, time to discharge, and time to end of dependence on oxygen supply. Predefined subgroups analyses included immunosuppression status, duration of symptoms before randomisation, and use of steroids.

RESULTS: 120 patients were recruited and assigned to covid-19 convalescent plasma (n=60) or usual care (n=60), including 22 (covid-19 convalescent plasma) and 27 (usual care) patients who were immunocompromised. 13 (22%) patients who received convalescent plasma had a WHO Clinical Progression Scale score of ≥6 at day 4 versus eight (13%) patients who received usual care (adjusted odds ratio 1.88, 95% credible interval 0.71 to 5.24). By day 14, 19 (31.6%) patients in the convalescent plasma group and 20 (33.3%) patients in the usual care group needed ventilation, additional immunomodulatory treatment, or had died. For cumulative incidence of death, three (5%) patients in the convalescent plasma group and eight (13%) in the usual care group died by day 14 (adjusted hazard ratio 0.40, 95% confidence interval 0.10 to 1.53), and seven (12%) patients in the convalescent plasma group and 12 (20%) in the usual care group by day 28 (adjusted hazard ratio 0.51, 0.20 to 1.32). In a subgroup analysis performed in patients who were immunocompromised, transfusion of covid-19 convalescent plasma was associated with mortality (hazard ratio 0.39, 95% confidence interval 0.14 to 1.10).

CONCLUSIONS: In this study, covid-19 convalescent plasma did not improve early outcomes in patients with moderate covid-19 disease. The efficacy of convalescent plasma in patients who are immunocompromised should be investigated further.

TRIAL REGISTRATION: ClinicalTrials.gov NCT04345991.

PMID:37920150 | PMC:PMC10619082 | DOI:10.1136/bmjmed-2022-000427

Front Biosci (Landmark Ed). 2023 Oct 19;28(10):246. doi: 10.31083/j.fbl2810246.

ABSTRACT

BACKGROUND: Ferroptosis is a form of iron-dependent regulated cell death, and prior work has highlighted the potential utility of ferroptosis-inducing agents as tools to treat heart failure (HF). To date, however, no detailed examinations of the prognostic utility of ferroptosis-related genes (FRGs) in HF have been conducted.

METHODS: We used established genomic identification of FRGs for total samples in the gene expression omnibus (GEO) database, screened for differentially expressed FRGs, performed protein-protein interaction analysis and functional analysis of HF immune microenvironment subtypes. Subsequently, we applied tools to calculate immune cell infiltration, compare immune cell, immune response genomic and HLA gene differences between subtypes, and perform candidate drug identification. Finally, preliminary in vivo validation of the screened central genes was performed in animal models.

RESULTS: FRGs were compared between samples from HF and healthy control donors, revealing 62 of these genes to be differentially expressed as a function of HF status. HF patient-derived tissues exhibited significant changes in the expression of HLA genes, increase immune cell infiltration, and higher levels of other immune-related genes within the associated immune microenvironment. These FRGs were then leveraged to establish two different immune-related subtypes of HF based on clustering analysis results, after which these subtypes were characterized in further detail. Functional enrichment analyses revealed the identified differentially expressed genes to be enriched in key immune-related pathways including the primary immunodeficiency, natural killer cell-mediated cytotoxicity, FcϵRI signaling, and antigen processing and presentation pathways. The impact of the immune microenvironment was also explored through functional analyses, core gene analyses, and efforts to identify potential drug candidates for HF patients. Moreover, four key hub genes were identified as promising targets for therapeutic intervention in HF, including HDAC1, LNPEP, PSMA1, and PSMA6. Subsequent preclinical work in a mouse model system supported a potential role for HDAC1 as an important biomarker associated with the incidence of HF.

CONCLUSIONS: To sum up, these results emphasize the importance of ferroptosis as a regulator of the HF-related immune microenvironment, highlighting viable avenues for the further study of molecular targets amenable to pharmacological intervention with the aim of treating this debilitating disease.

PMID:37919056 | DOI:10.31083/j.fbl2810246

JAMA Netw Open. 2023 Nov 1;6(11):e2340608. doi: 10.1001/jamanetworkopen.2023.40608.

ABSTRACT

IMPORTANCE: New approaches for the prevention of acute otitis media (AOM), the most common reason for antibiotic use in children, are needed.

OBJECTIVE: To assess the efficacy of the Streptococcus salivarius K12 oral probiotics in the primary prevention of AOM.

DESIGN, SETTING, AND PARTICIPANTS: This double-blind, randomized placebo-controlled clinical trial was conducted from August 1, 2020, to May 31, 2021, at 50 day care centers in the Oulu region of Finland. A total of 827 children aged 1 to 6 years attending day care were included. The exclusion criteria consisted of ongoing antimicrobial prophylaxis or immunodeficiency. The follow-up time was 6 months and was completed on May 31, 2021. Data were analyzed from October 24, 2022, to September 16, 2023, based on intention to treat.

INTERVENTION: Eligible participants were randomly allocated to receive 1 daily dose of a S salivarius K12 product or placebo every evening for 6 months. A daily dose was defined as 1 sachet of soluble oral powder for children younger than 3 years or 1 chewable tablet for children 3 years or older containing 1 × 109 colony-forming units of S salivarius K12.

MAIN OUTCOMES AND MEASURES: The primary outcome was the proportion of children with at least 1 episode of AOM requiring antimicrobial therapy within 6 months of randomization. All physician visits and purchases of antimicrobial drugs were retrieved from the electronic national medical record and prescription register. The primary outcome was met if the legal guardian had purchased an antimicrobial prescription for AOM.

RESULTS: A total of 827 children with a mean (SD) age of 4.1 (1.6) years (433 boys [52.4%]) were randomized to S salivarius K12 oral products (n = 413) or placebo (n = 414). Thirty-four children (8.2%) in the S salivarius group and 24 children (5.8%) in the placebo group experienced at least 1 episode of AOM requiring antimicrobial therapy during the 6-month follow-up period (relative risk, 1.42 [95% CI, 0.86-2.34]; proportion difference, -2.44% [95% CI, -5.94% to 1.09%]; P = .17). Time to first AOM episode did not differ between the groups (174 [95% CI, 171-177] days in the S salivarius group vs 176 [95% CI, 173-179] days in the placebo group; P = .18).

CONCLUSIONS AND RELEVANCE: In this randomized placebo-controlled clinical trial, the daily use of the S salivarius K12 products for 6 months did not reduce the occurrence of AOM. New approaches for primary prevention of AOM among children are needed.

TRIAL REGISTRATION: ClinicalTrialsRegister.eu Identifier: 2020-001076-14.

PMID:37917062 | DOI:10.1001/jamanetworkopen.2023.40608

J Allergy Clin Immunol Glob. 2023 Sep 27;3(1):100172. doi: 10.1016/j.jacig.2023.100172. eCollection 2024 Feb.

ABSTRACT

BACKGROUND: To date, fewer than 20 patients have been identified as having germline biallelic mutations in the coronin-1A gene (CORO1A) and its protein with clinical features of combined immunodeficiency characterized by T-cell lymphopenia ranging from the severe phenotype to the mild phenotype, recurrent infections, and lymphoproliferative disorders. However, the effects of CORO1A protein disruption on actin-dependent functions in primary cells have not been fully delineated.

OBJECTIVE: We sought to characterize the underlying defects of actin-dependent cellular functions in a female patient with combined immunodeficiency caused by a novel missense variant in the CORO1A gene in combination with a de novo heterozygous microdeletion of chromosome 16p11.2 and also to provide evidence of the pathogenicity of this gene mutation.

METHODS: To identify the genetic defect, next-generation sequencing followed by Sanger confirmation and array comparative genomic hybridization were performed. Western blot and quantitative PCR tests were used to assess the effects on the protein. Flow cytometry and live microscopy were performed to investigate cellular motility and immune cell counts and function.

RESULTS: We demonstrated that the CORO1A hemizygous variant c.19C>T, p. A7C induces significant decreases in cellular levels of the CORO1A protein while leaving mRNA concentrations unaffected. The observed mutation resulted in impaired natural killer cell cytotoxicity and platelet calcium signaling. In addition, primary granulocytes and mesenchymal cells showed significant defects in motility.

CONCLUSION: Collectively, we added new data about the CORO1A gene as a key player in actin cytoskeleton dynamics and cell signaling. Our findings expand the clinical spectrum regarding CORO1A protein deficiency and confirm the importance of a personalized therapeutic approach for each patient.

PMID:37915722 | PMC:PMC10616384 | DOI:10.1016/j.jacig.2023.100172

Immun Inflamm Dis. 2023 Oct;11(10):e1049. doi: 10.1002/iid3.1049.

ABSTRACT

BACKGROUND: X-linked agammaglobulinemia (XLA) is the most common form of agammaglobulinemia and is caused by mutations in Btk, which encodes Bruton tyrosine kinase (BTK).

CASE DESCRIPTION: We describe a 36-year-old male who presented as an infant with hypogammaglobulinemia and sinopulmonary infections and was initially diagnosed with common variable immunodeficiency. Genetic testing showed he was hemizygous for Btk c.240G > A. This synonymous variant affecting the last nucleotide of exon 3 leads to aberrant splicing of most but not all mRNA transcripts.

CONCLUSION: We demonstrated reduced BTK protein expression confirming the pathogenicity of the variant and related our findings to genotype-phenotype relationship studies ina XLA caused by synonymous mutations.

PMID:37904676 | DOI:10.1002/iid3.1049

Cent Eur J Immunol. 2023;48(3):228-236. doi: 10.5114/ceji.2023.130874. Epub 2023 Sep 5.

ABSTRACT

Autosomal dominant hyper-IgE syndrome (AD-HIES) is an inborn error of immunity (IEI) caused by a dominant-negative mutation in the signal transducer and activator of transcription 3 (STAT 3). This disease is characterized by chronic eczematoid dermatitis, recurrent staphylococcal skin abscesses, pneumonia, pneumatoceles, and extremely high serum IgE levels. Loss-of-function STAT3 mutations may also result in distinct non-immunologic features such as dental, facial, skeletal, and vascular abnormalities, central nervous system malformations and an increased risk for bone fractures. Prophylactic treatment of Candida infections and prophylactic antimicrobial therapy for staphylococcal skin infections and sinopulmonary infections are essential. An awareness of the oral and maxillofacial features of HIES may facilitate early diagnosis with genetic counselling and may improve future patient care. This study describes oral, dental, and maxillofacial manifestations in 14 patients with genetically defined AD-HIES. We also review the literature and propose recommendations for the complex care of patients with this rare primary immunodeficiency.

PMID:37901871 | PMC:PMC10604639 | DOI:10.5114/ceji.2023.130874

Front Immunol. 2023 Oct 12;14:1268595. doi: 10.3389/fimmu.2023.1268595. eCollection 2023.

NO ABSTRACT

PMID:37901216 | PMC:PMC10602883 | DOI:10.3389/fimmu.2023.1268595

Front Immunol. 2023 Oct 12;14:1275892. doi: 10.3389/fimmu.2023.1275892. eCollection 2023.

ABSTRACT

INTRODUCTION: Primary antibody deficiencies (PAD) are inborn defects of the immune system that result in increased susceptibility to infections. Despite the reduced response to vaccination, PAD patients still benefit from it by reducing the risk of severe infections and complications. SARS-CoV-2 vaccines are recommended in PAD patients, but their immune effects are poorly studied. Here, we analyze virus-specific T-cell responses in PAD patients after booster vaccination against SARS-CoV-2.

PATIENTS AND METHODS: The study included 57 adult PAD patients on long-term immunoglobulin replacement therapy (IgRT) diagnosed with X-linked agammaglobulinemia (XLA; n = 4), common variable immunodeficiency (CVID; n = 33), isotype defects or IgG subclass deficiency (n = 6), and unclassified IgG deficiency (n = 14). Of those, 49 patients (86%) received vaccination against SARS-CoV-2 using mRNA vaccine (Pfizer-BioNTech). T-cell responses were assessed at a median of 21 (13 – 30) weeks after the booster dose (mainly the third dose) using commercially available interferon-gamma release assay (IGRA) with recombinant SARS-CoV-2 spike S1 protein.

RESULTS: Vaccinated PAD patients showed an increased (3.8-fold, p = 0.004) release of IFN-γ upon S1 stimulation. In this group, we also documented higher serum levels of anti-SARS-CoV-2 IgG (4.1-fold, p = 0.01), although they were not associated with IGRA results. Further subgroup analysis revealed very similar IGRA responses in CVID and unclassified IgG deficiencies that were 2.4-fold increased compared to XLA and 5.4-fold increased compared to patients with isotype defects or IgG subclass deficiencies (e.g., vs. CVID: p = 0.016). As expected, CVID and XLA patients showed decreased serum titers of anti-SARS-CoV-2 antibodies compared to other studied groups (e.g., CVID vs. unclassified IgG deficiency: 4.4-fold, p = 0.006). The results did not depend directly on IgRT mode or dose, number of vaccine doses and time from the last booster dose, and clinical manifestations of PAD. Interestingly, anti-SARS-CoV-2 titers were positively correlated with serum immunoglobulin levels before IgRT (e.g., for IgA: r = 0.45, p<0.001; for IgG: r = 0.34, p = 0.009) and the percentage of peripheral blood NK cells (r = 0.48, p<0.001).

CONCLUSIONS: Our results documented satisfactory in vitro cellular immune response in PAD patients after booster SARS-CoV-2 vaccination. Therefore, even patients with agammaglobulinemia should benefit from vaccination due to the apparent induction of cell-mediated immunity, which, together with IgRT, grants comprehensive protection against the pathogen.

PMID:37901210 | PMC:PMC10602693 | DOI:10.3389/fimmu.2023.1275892

Nat Commun. 2023 Oct 27;14(1):6771. doi: 10.1038/s41467-023-42036-5.

ABSTRACT

RAG2-SCID is a primary immunodeficiency caused by mutations in Recombination-activating gene 2 (RAG2), a gene intimately involved in the process of lymphocyte maturation and function. ex-vivo manipulation of a patient’s own hematopoietic stem and progenitor cells (HSPCs) using CRISPR-Cas9/rAAV6 gene editing could provide a therapeutic alternative to the only current treatment, allogeneic hematopoietic stem cell transplantation (HSCT). Here we show an innovative RAG2 correction strategy that replaces the entire endogenous coding sequence (CDS) for the purpose of preserving the critical endogenous spatiotemporal gene regulation and locus architecture. Expression of the corrective transgene leads to successful development into CD3⁺TCRαβ⁺ and CD3⁺TCRγδ⁺ T cells and promotes the establishment of highly diverse TRB and TRG repertoires in an in-vitro T-cell differentiation platform. Thus, our proof-of-concept study holds promise for safer gene therapy techniques of tightly regulated genes.

PMID:37891182 | DOI:10.1038/s41467-023-42036-5

Viruses. 2023 Oct 14;15(10):2091. doi: 10.3390/v15102091.

ABSTRACT

BACKGROUND: for the first time, the effect of one and two doses of adjuvanted influenza vaccines on toll-like receptors (TLRs) in patients with common variable immunodeficiency (CVID) was studied and compared (primary vaccination with one vs. two doses, primary vs. repeated vaccination).

MATERIALS AND METHODS: Six patients received one dose of quadrivalent adjuvanted influenza vaccine during the 2018-2019 and 2019-2020 influenza seasons, and nine patients with CVID received two doses of trivalent inactivated influenza vaccine during 2019-2020. Expression of TLRs was measured by flow cytometry.

RESULTS: The expression of toll-like receptors in patients with CVID was noted both with repeated (annual) administration of the influenza vaccine and in most cases was accompanied by an increase in the proportion of granulocytes (TLR3 and TLR9), lymphocytes (TLR3 and TLR8), and monocytes (TLR3 and TLR9). When carried out for the first time as a simultaneous vaccination with two doses it was accompanied by an increase in the proportion of granulocytes, lymphocytes expressing TLR9, and on monocytes-TLR3 and TLR9.

CONCLUSION: in CVID patients, the use of adjuvanted vaccines is promising, and research on the influence of the innate immunity and more effective regimens should be continued.

PMID:37896869 | DOI:10.3390/v15102091