Manish Butte

Int Arch Allergy Immunol. 2023 Apr 25:1-10. doi: 10.1159/000528986. Online ahead of print.

ABSTRACT

INTRODUCTION: Heterogeneous clinical features of antibody deficiency (AD) may cause diagnostic delays. Calculated globulin (CG) (total protein minus albumin) has been proposed as a screening test to prevent morbidity due to diagnostic delays in AD. Our aim was to validate CG as a screening test for AD in Turkish adult patients by comparing its role with gamma globulin analysis in protein electrophoresis.

METHODS: Fifty serum samples were randomly collected for each level of CG from 15 to 25 g/L and tested for serum IgG, IgA, IgM levels and protein electrophoresis. Cut-off values predicting low IgG levels were calculated for electrophoretically determined gamma globulin and CG. Additionally, the data of 47 patients followed up in our clinic with a diagnosis of primary antibody deficiency (PAD) were retrospectively analyzed.

RESULTS: A total of 550 adult patients were included in the study. The CG value predicting patients with IgG <6 g/L as a screening test was determined as <20 g/L with 83.8% sensitivity and 74.9% specificity. The gamma globulin value which predicted patients with the same IgG value of 89.0% sensitivity and 89.4% specificity was determined as <7 g/L. In the retrospective analysis, 37 of 47 patients (78.7%) with PAD had a CG value of <20 g/L at the time of the diagnosis and all 13 patients (100%) whose gamma globulin values were measured at the time of the diagnosis had a gamma globulin value of <7 g/L.

CONCLUSION: The determined CG cut-off value of <20 g/L can be used as a screening test in Turkish adult patients.

PMID:37166344 | DOI:10.1159/000528986

Cell Mol Immunol. 2023 May 9. doi: 10.1038/s41423-023-01027-8. Online ahead of print.

ABSTRACT

As chronic antigenic stimulation from infection and autoimmunity is a feature of primary antibody deficiency (PAD), analysis of affected patients could yield insights into T-cell differentiation and explain how environmental exposures modify clinical phenotypes conferred by single-gene defects. CD57 marks dysfunctional T cells that have differentiated after antigenic stimulation. Indeed, while circulating CD57⁺ CD4⁺ T cells are normally rare, we found that they are increased in patients with PAD and markedly increased with CTLA4 haploinsufficiency or blockade. We performed single-cell RNA-seq analysis of matched CD57⁺ CD4⁺ T cells from blood and tonsil samples. Circulating CD57⁺ CD4⁺ T cells (CD4cyt) exhibited a cytotoxic transcriptome similar to that of CD8⁺ effector cells, could kill B cells, and inhibited B-cell responses. CTLA4 restrained the formation of CD4cyt. While CD57 also marked an abundant subset of follicular helper T cells, which is consistent with their antigen-driven differentiation, this subset had a pre-exhaustion transcriptomic signature marked by TCF7, TOX, and ID3 expression and constitutive expression of CTLA4 and did not become cytotoxic even after CTLA4 inhibition. Thus, CD57⁺ CD4⁺ T-cell cytotoxicity and exhaustion phenotypes are compartmentalised between blood and germinal centers. CTLA4 is a key modifier of CD4⁺ T-cell cytotoxicity, and the pathological CD4cyt phenotype is accentuated by infection.

PMID:37161048 | DOI:10.1038/s41423-023-01027-8

J Clin Immunol. 2023 May 9. doi: 10.1007/s10875-023-01509-4. Online ahead of print.

ABSTRACT

PURPOSE: To achieve reductions in infusion time, infusion sites, and frequency, a prospective, open-label, multicenter, Phase 3 study evaluated the safety, efficacy, and tolerability of subcutaneous immunoglobulin (SCIG) 16.5% (Cutaquig®, Octapharma) at enhanced infusion regimens.

METHODS: Three separate cohorts received SCIG 16.5% evaluating volume, rate, and frequency: Cohort 1) volume assessment/site: up to a maximum 100 mL/site; Cohort 2) infusion flow rate/site: up to a maximum of 100 mL/hr/site or the maximum flow rate achievable by the tubing; Cohort 3) infusion frequency: every other week at twice the patient’s weekly dose.

RESULTS: For Cohort 1 (n = 15), the maximum realized volume per site was 108 mL/site, exceeding the currently labeled (US) maximum (up to 40 mL/site for adults). In Cohort 2 (n = 15), the maximum realized infusion flow rate was 67.5 mL/hr/site which is also higher than the labeled (US) maximum (up to 52 mL/hr/site). In Cohort 3 (n = 34), the mean total trough levels for every other week dosing demonstrated equivalency to weekly dosing (p value = 0.0017). All regimens were well tolerated. There were no serious bacterial infections (SBIs). Most patients had mild (23.4%) or moderate (56.3%) adverse events. The majority of patients found the new infusion regimens to be better or somewhat better than their previous regimens and reported that switching to SCIG 16.5% was easy.

CONCLUSIONS: SCIG 16.5% (Cutaquig®), infusions are efficacious, safe, and well tolerated with reduced infusion time, fewer infusion sites, and reduced frequency. Further, the majority of patients found the new infusion regimens to be better or somewhat better than their previous regimens.

PMID:37160610 | DOI:10.1007/s10875-023-01509-4

Immunotherapy. 2023 May 9. doi: 10.2217/imt-2022-0193. Online ahead of print.

ABSTRACT

Aim: To describe development of a shared decision making (SDM) aid in treating primary immunodeficiency diseases (PID) with immunoglobulin replacement therapy (IGRT). Materials & methods: Expert engagement and qualitative formative research informed development. IGRT administration features were prioritized using object-case best-worst scaling (BWS) methodology. The aid was assessed by US adults self-reporting PID and revised following interviews/mock treatment-choice discussions with immunologists. Results: Patients participating in interviews (n = 19) and mock treatment-choice discussions (n = 5) deemed the aid useful/accessible and supported the utility of BWS, with content and BWS exercises refined following participant feedback. Conclusion: Formative research led to an improved SDM aid/BWS exercise, and illustrated how the aid may improve treatment decision making. The aid may help less-experienced patients and facilitate efficient SDM.

PMID:37158075 | DOI:10.2217/imt-2022-0193

Neurol Genet. 2023 Apr 26;9(3):e200071. doi: 10.1212/NXG.0000000000200071. eCollection 2023 Jun.

ABSTRACT

BACKGROUND AND OBJECTIVES: Owing to their extensive clinical and molecular heterogeneity, hereditary neurologic diseases in adults are difficult to diagnose. The current knowledge about the diagnostic yield and clinical utility of exome sequencing (ES) for neurologic diseases in adults is limited. This observational study assesses the diagnostic value of ES and multigene panel analysis in adult-onset neurologic disorders.

METHODS: From January 2019 through April 2022, ES-based multigene panel testing was conducted in 1,411 patients with molecularly unexplained neurologic phenotypes at the Ghent University Hospital. Gene panels were developed for ataxia and spasticity, leukoencephalopathy, movement disorders, paroxysmal episodic disorders, neurodegeneration with brain iron accumulation, progressive myoclonic epilepsy, and amyotrophic lateral sclerosis. Single nucleotide variants, small indels, and copy number variants were analyzed. Across all panels, our analysis covered a total of 725 genes associated with Mendelian inheritance.

RESULTS: A molecular diagnosis was established in 10% of the cases (144 of 1,411) representing 71 different monogenic disorders. The diagnostic yield depended significantly on the presenting phenotype with the highest yield seen in patients with ataxia or spastic paraparesis (19%). Most of the established diagnoses comprised disorders with an autosomal dominant inheritance (62%), and the most frequently mutated genes were NOTCH3 (13 patients), SPG7 (11 patients), and RFC1 (8 patients). 34% of the disease-causing variants were novel, including a unique likely pathogenic variant in APP (Ghent mutation, p.[Asn698Asp]) in a family presenting with stroke and severe cerebral white matter disease. 7% of the pathogenic variants comprised copy number variants detected in the ES data and confirmed by an independent technique.

DISCUSSION: ES and multigene panel testing is a powerful and efficient tool to diagnose patients with unexplained, adult-onset neurologic disorders.

PMID:37152446 | PMC:PMC10160959 | DOI:10.1212/NXG.0000000000200071

Clin Case Rep. 2023 May 4;11(5):e7294. doi: 10.1002/ccr3.7294. eCollection 2023 May.

ABSTRACT

KEY CLINICAL MESSAGE: Patients with COVID-19 who have undergone B-cell depletion therapy could have prolonged SARS-CoV-2 infection; therefore, even in the hospital-at-home setting, primary care physicians should carefully consider the treatment regimen and the timing of ending isolations in such cases, and should not hesitate to consult with infectious disease specialists if necessary.

ABSTRACT: We presented the first reported case of hospital-at-home care for a patient with persistent COVID-19 who had undergone B-cell depletion therapy. He received hospital-at-home care, including two courses of remdesivir; however, he ultimately failed to recover and was transferred to the hospital.

PMID:37151938 | PMC:PMC10160423 | DOI:10.1002/ccr3.7294

Trends Immunol. 2023 May 4:S1471-4906(23)00058-3. doi: 10.1016/j.it.2023.04.002. Online ahead of print.

ABSTRACT

Nucleic acid sensors survey subcellular compartments for atypical or mislocalized RNA or DNA, ultimately triggering innate immune responses. Retinoic acid-inducible gene-I (RIG-I) is part of the family of cytoplasmic RNA receptors that can detect viruses. A growing literature demonstrates that mammalian RNA polymerase III (Pol III) transcribes certain viral or cellular DNA sequences into immunostimulatory RIG-I ligands, which elicits antiviral or inflammatory responses. Dysregulation of the Pol III-RIG-I sensing axis can lead to human diseases including severe viral infection outcomes, autoimmunity, and tumor progression. Here, we summarize the newly emerging role of viral and host-derived Pol III transcripts in immunity and also highlight recent advances in understanding how mammalian cells prevent unwanted immune activation by these RNAs to maintain homeostasis.

PMID:37149405 | DOI:10.1016/j.it.2023.04.002

J Clin Immunol. 2023 May 5. doi: 10.1007/s10875-023-01507-6. Online ahead of print.

ABSTRACT

BACKGROUND AND AIMS: Subcutaneous immunoglobulin (SCIG) home infusion is widely used as an alternative to intravenous immunoglobulin (IVIG). This study aimed to determine the quality of life (QoL) of patients with primary immunodeficiency (PID) after switching to home-based SCIG.

METHODS: In this prospective open-label single-center study, QoL was determined using the validated Arabic version of the Child Health Questionnaire at baseline and 3 and 6 months after switching from IVIG to SCIG.

RESULTS: Twenty-four patients were recruited from July 2018 to August 2021, including 14 females and 10 males. The median age of the patients was 5 years (range, 0-14 years). The patients’ diagnoses included severe combined immunodeficiency, combined immunodeficiency, agammaglobulinemia, Omenn syndrome, immunodysregulation, hyper-IgE syndrome, common variable immunodeficiency, and bare lymphocyte syndrome. The median duration on IVIG before inclusion was 40 months (range, 5-125 months). The QoL score showed a significant improvement in the patients’ global health at 3 and 6 months compared with those at baseline and a significant improvement in the patients’ general health at 3 and 6 months compared with that at baseline. The mean baseline serum IgG trough level was 8.8 ± 2.1 g/L. The mean serum IgG level was significantly higher on SCIG at both 3 and 6 months (11.7 ± 2.3 and 11.7 ± 2.5 g/L, respectively).

CONCLUSIONS: This is the first study involving an Arab population to show improvement in the QoL of patients with PID after switching from hospital-based IVIG to home-based 20% SCIG.

PMID:37145392 | DOI:10.1007/s10875-023-01507-6

Turk Arch Pediatr. 2023 May;58(3):336-338. doi: 10.5152/TurkArchPediatr.2023.22312.

NO ABSTRACT

PMID:37144269 | DOI:10.5152/TurkArchPediatr.2023.22312

Clin Transl Immunology. 2023 May 2;12(5):e1448. doi: 10.1002/cti2.1448. eCollection 2023.

ABSTRACT

OBJECTIVES: Increasing evidence indicates that some germline genetic mutations that impair pathways required for robust host immune surveillance against EBV infection may result in an extremely high susceptibility to EBV-associated lymphoproliferative disease (EBV⁺ LPD). TNFRSF9 encodes a vital costimulatory molecule that enhances CD8⁺ T-cell proliferation, survival and cytolytic activity. To date, no relevant case resulting from TNFRSF9 heterozygous mutations has been identified.

METHODS: Here, we report the first case of CD137 deficiency caused by two novel biallelic heterozygous TNFRSF9 mutations [NM_001561.5: c.208 + 1->AT and c.452C>A (p.T151K)] in a patient presenting with severe EBV⁺ LPD. Immunophenotyping and in vitro assays of lymphocyte function and NK cell activity were performed.

RESULTS: Biallelic TNFRSF9 mutations resulted in markedly reduced or abrogated expression of CD137 on activated T, B and NK cells. CD8⁺ T cells from the patient had impaired activation, reduced expression/release of interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), perforin and granzyme B, and diminished cytotoxic activity. Functional experiments identified both variations were hypomorphic mutations and played a contributing role in CD137 deficiency and the development of EBV⁺ LPD.

CONCLUSION: Our study expands the genetic spectrum and clinical phenotype of patients with CD137 deficiency and provides additional evidence that the TNFRSF9 gene plays a critical role in host immune responses to EBV infection.

PMID:37144041 | PMC:PMC10153300 | DOI:10.1002/cti2.1448