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Pediatr Int. 2022 Sep 24:e15362. doi: 10.1111/ped.15362. Online ahead of print.

ABSTRACT

BACKGROUND: Subcutaneous immunoglobulin (SCIG) is one of the standard treatments for hypogammaglobulinemia in primary immunodeficiencies (PID) worldwide. In Japan, IgPro20 (Hizentra®; L-proline-stabilized 20% human SCIG) is approved for agammaglobulinemia or hypogammaglobulinemia due to PID or secondary immunodeficiency (SID); however, its safety and effectiveness had not been assessed in a real-world setting.

METHODS: This multicenter, open label post-marketing surveillance (PMS) study was conducted between January 2014 and March 2019. Patients who received IgPro20 due to PID or SID were included after informed consent. Physicians completed a case report form for each patient. Safety was determined from reported adverse events (AEs), adverse drug reactions (ADRs), and serious AEs (SAEs); effectiveness was assessed by infection rates after the first IgPro20 dose.

RESULTS: Among 85 patients receiving IgPro20 in the safety analysis, 39 developed AEs (45.9%; PID n=28, SID n=11). At least one ADR was observed in 27 patients (31.8%; PID n=21, SID n=6); the most common was injection site reactions (n=17, 20.0%). Four patients (PID n=3, SID n=1) reported SAEs but two were unrelated to IgPro20 administration. The infection rate decreased from 0.54 per patient during the 6 months before IgPro20 to 0.39 per patient during IgPro20 treatment. Serious bacterial infections occurred in six patients before IgPro20 (7.9%; PID n=2; SID n=4), but in only one patient with SID during IgPro20 treatment (1.2%).

CONCLUSIONS: IgPro20 was considered safe and effective among patients with agammaglobulinemia or hypogammaglobulinemia due to PID or SID in Japan.

PMID:36151913 | DOI:10.1111/ped.15362

Immunology. 2022 Sep 24. doi: 10.1111/imm.13579. Online ahead of print.

ABSTRACT

In the past few years, the spectrum of monogenic systemic auto-inflammatory diseases (MSAID) has widely expanded beyond the typical recurrent fever. Immuno-hematological features, as cytopenias, hypogammaglobulinemia, hypereosinophilia, lymphoproliferation and immunodeficiency, have been described in association of several MSAID. The objective of this review was to describe these particular MSAID. MSAID must be suspected in front of immuno-hematological features associated with non-infectious recurrent fever, chronic systemic inflammation, inflammatory cutaneous manifestations, arthritis or inflammatory bowel disease. Genes and cellular mechanisms involved are various but some of them are of special interest. Defects in actine regulation pathway are notably associated with cytopenia and immune deficiency. Because of their frequency, ADA2 deficiency and Vacuoles, E1-Enzyme, X-linked, auto-inflammatory, Somatic (VEXAS) syndrome deserves to be noticed. ADA2 deficiency results in polyarteritis nodosa-like presentation with a wide panel of manifestations including cytopenia(s), lymphoproliferation and immune deficiency. Neutrophilic dermatosis or chondritis associated with macrocytic anemia or myelodysplasia should lead to screen for VEXAS. Of note, most of MSAID are associated with inflammatory anemia. We proposed here a clinical and pragmatic approach of MSAID associated with immuno-hematological features.

PMID:36151885 | DOI:10.1111/imm.13579

Am J Gastroenterol. 2022 Sep 21. doi: 10.14309/ajg.0000000000002027. Online ahead of print.

ABSTRACT

Common variable immune deficiency (CVID) is the most common symptomatic primary immunodeficiency. It is characterized by impaired B cell differentiation. Although patients can be diagnosed with CVID anytime during their lifetime, most patients have symptoms for 5-9 years before their diagnosis. The diagnosis of CVID starts with a detailed history focusing on the infectious and noninfectious manifestations of the disease. In patients who are suspected to have CVID, quantitative immunoglobulins should be checked to confirm the diagnosis. Immunoglobulin G should be at least 2 times less than the age-specific standard deviation along with either a low immunoglobulin A or immunoglobulin M, and with evidence of impaired vaccine response. CVID is usually associated with infectious and/or noninfectious conditions, the latter of which can be inflammatory, autoimmune, lymphoproliferative, or malignant, among other manifestations. Immunoglobulin therapy has positively impacted the disease course of patients with infectious complications but has limited effect on the noninfectious manifestations since the noninfectious complications are related to immune dysregulation involving B- and T-cells rather than primarily due to antibody deficiency. When the gastrointestinal system is involved, patients with CVID may display signs and symptoms that mimic several gastrointestinal conditions like celiac disease, pernicious anemia, or inflammatory bowel diseases. The inflammatory bowel disease like condition is usually treated with steroids, 5-aminosalicylates, thiopurines, or biologics to control the inflammation. In this review, the clinical presentations, diagnostic considerations, and therapeutic options for gastrointestinal manifestations of CVID will be discussed to facilitate individualized management of these often-complex patients.

PMID:36148549 | DOI:10.14309/ajg.0000000000002027

Microorganisms. 2022 Sep 9;10(9):1812. doi: 10.3390/microorganisms10091812.

ABSTRACT

There is an ongoing need for high-precision serological assays for the quantitation of anti-SARS-CoV-2 antibodies. Here, a trimeric SARS-CoV-2 spike (S) protein was used to develop an ELISA to quantify specific IgG antibodies present in serum, plasma, and dried blood spots (DBS) collected from infected patients or vaccine recipients. The quantitative S-ELISA was calibrated with international anti-SARS-CoV-2 immunoglobulin standards to provide test results in binding antibody units per mL (BAU/mL). The assay showed excellent linearity, precision, and accuracy. A sensitivity of 100% was shown for samples collected from 54 patients with confirmed SARS-CoV-2 infection more than 14 days after symptom onset or disease confirmation by RT-PCR and 58 vaccine recipients more than 14 days after vaccination. The assay specificity was 98.3%. Furthermore, antibody responses were measured in follow-up samples from vaccine recipients and infected patients. Most mRNA vaccine recipients had a similar response, with antibody generation starting 2-3 weeks after the first vaccination and maintaining positive for at least six months after a second vaccination. For most infected patients, the antibody titers increased during the second week after PCR confirmation. This S-ELISA can be used to quantify the seroprevalence of SARS-CoV-2 in the population exposed to the virus or vaccinated.

PMID:36144414 | DOI:10.3390/microorganisms10091812

Diagnostics (Basel). 2022 Sep 9;12(9):2177. doi: 10.3390/diagnostics12092177.

ABSTRACT

Eczema is a classical characteristic not only in atopic dermatitis but also in various genodermatosis. Patients suffering from primary immunodeficiency diseases such as hyper-immunoglobulin E syndromes, Wiskott-Aldrich syndrome, immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome, STAT5B deficiency, Omenn syndrome, atypical complete DiGeorge syndrome; metabolic disorders such as acrodermatitis enteropathy, multiple carboxylase deficiency, prolidase deficiency; and other rare syndromes like severe dermatitis, multiple allergies and metabolic wasting syndrome, Netherton syndrome, and peeling skin syndrome frequently perform with eczema-like lesions. These genodermatosis may be misguided in the context of eczematous phenotype. Misdiagnosis of severe disorders unavoidably affects appropriate treatment and leads to irreversible outcomes for patients, which underlines the importance of molecular diagnosis and genetic analysis. Here we conclude clinical manifestations, molecular mechanism, diagnosis and management of several eczema-related genodermatosis and provide accessible advice to physicians.

PMID:36140582 | DOI:10.3390/diagnostics12092177

Immunol Res. 2022 Sep 21. doi: 10.1007/s12026-022-09320-w. Online ahead of print.

ABSTRACT

Glycogen storage disease type Ib (GSDIb) is an autosomal recessive disorder caused by mutations of SLC37A4 gene, which encodes glucose 6-phosphate translocase (G6PT). Malfunction of G6PT leads to excessive fat and glycogen in liver, kidney, and intestinal mucosa. The clinical manifestations of GSD1b include hepatomegaly, renomegaly, neutropenia, hypoglycemia, and lactic acidosis. Furthermore, the disorder may result in severe complications in long-term including inflammatory bowel disease (IBD), hepatocellular adenomas (HCA), short stature, and autoimmune disorders, which stem from neutropenia and neutrophil dysfunction. Here, we represent a novel mutation of SLC37A4 in a 5-month girl who has a history of hospitalizations several times due to recurrent infection and her early presentations were failure to thrive and tachypnea. Further investigations revealed mild atrial septal defect, mild arteriovenous malformation from left lung, esophageal reflux, Horseshoe kidney, and urinary reflux in this patient. Moreover, the lab tests showed neutropenia, immunoglobulin (Ig) G and IgA deficiency, as well as thrombocytosis. Whole exome sequencing revealed c.1245G > A P.W415 homozygous mutation in SLC37A4 gene and c.580G > A p.V1941 heterozygous mutation in PIK3CD gene. This study shows that manifestations of GSD1b may not be limited to what was previously known and it should be considered in a wider range of patients.

PMID:36129616 | DOI:10.1007/s12026-022-09320-w

Immunotherapy. 2022 Sep 21. doi: 10.2217/imt-2022-0097. Online ahead of print.

ABSTRACT

Aim: A novel, Investigational Wearable Infusor (IWI) was evaluated in a randomized, controlled, crossover, open-label study to determine if its delivery of subcutaneous immunoglobulin (IgPro20) achieved a comparable area under the concentration-time curve (AUC) for immunoglobulin G (IgG) versus the Crono S-PID-50 infusion pump (CP). EudraCT: 2016-003798-16. Materials & methods: Patients with primary immunodeficiency (PID) were randomized to receive IgPro20 in Sequence 1 (CP/IWI) or 2 (IWI/CP). The primary end point was AUC for IgG during the final week of each 4-week period. Results: 23 patients were enrolled. Evaluation of area under the concentration-time curve from time 0 (pre-infusion) to 7 days after infusion (AUC_{0-7 days}) (IWI: 1806 h*g/l; CP: 1829 h*g/l) and geometric mean ratio indicated comparable AUCs for IgG for both devices. Conclusion: Similar IgG exposure, indicated by AUC values, can be achieved with IgPro20 using the IWI or CP in PID.

PMID:36128795 | DOI:10.2217/imt-2022-0097

Redox Biol. 2022 Sep 13;56:102479. doi: 10.1016/j.redox.2022.102479. Online ahead of print.

ABSTRACT

The transmembrane protein p22^phox heterodimerizes with NADPH oxidase (Nox) 1-4 and is essential for the reactive oxygen species-producing capacity of oxidases. Missense mutations in the p22^phox gene prevent the formation of phagocytic Nox2-based oxidase, which contributes to host defense. This results in chronic granulomatous disease (CGD), a severe primary immunodeficiency syndrome. In this study, we characterized missense mutations in p22^phox (L51Q, L52P, E53V, and P55R) in the A22° type (wherein the p22^phox protein is undetectable) of CGD. We demonstrated that these substitutions enhanced the degradation of the p22^phox protein in the endoplasmic reticulum (ER) and the binding of p22^phox to Derlin-1, a key component of ER-associated degradation (ERAD). Therefore, the L⁵¹-L⁵²-E⁵³-P⁵⁵ sequence is responsible for protein stability in the ER. We observed that the oxidation of the thiol group of Cys-50, which is adjacent to the L⁵¹-L⁵²-E⁵³-P⁵⁵ sequence, suppressed p22^phox degradation. However, the suppression effect was markedly attenuated by the serine substitution of Cys-50. Blocking the free thiol of Cys-50 by alkylation or C50S substitution promoted the association of p22^phox with Derlin-1. Derlin-1 depletion partially suppressed the degradation of p22^phox mutant proteins. Furthermore, heterodimerization with p22^phox (C50S) induced rapid degradation of not only Nox2 but also nonphagocytic Nox4 protein, which is responsible for redox signaling. Thus, the redox-sensitive Cys-50 appears to determine whether p22^phox becomes a target for degradation by the ERAD system through its interaction with Derlin-1.

PMID:36122532 | DOI:10.1016/j.redox.2022.102479

Front Immunol. 2022 Sep 2;13:978658. doi: 10.3389/fimmu.2022.978658. eCollection 2022.

ABSTRACT

The CD3 subunits of the T-cell antigen receptor (TCR) play a central role in regulation of surface TCR expression levels. Humans who lack CD3γ (γ^–) show reduced surface TCR expression levels and abolished phorbol ester (PMA)-induced TCR down-regulation. The response to PMA is mediated by a double leucine motif in the intracellular (IC) domain of CD3γ. However, the molecular cause of the reduced TCR surface expression in γ^– lymphocytes is still not known. We used retroviral vectors carrying wild type CD3γ or CD3δ or the following chimeras (EC-extracellular, TM-transmembrane and IC): δ_ECγ_TMγ_IC (δγγ for short), γγδ, γδδ and γγ-. Expression of γγγ, γγδ, γδδ or γγ- in the γ^– T cell line JGN, which lacks surface TCR, demonstrated that cell surface TCR levels in JGN were dependent on the EC domain of CD3γ and could not be replaced by the one of CD3δ. In JGN and primary γ^– patient T cells, the tested chimeras confirmed that the response to PMA maps to the IC domain of CD3γ. Since protein homology explains these results better than domain structure, we conclude that CD3γ contributes conformational cues that improve surface TCR expression, likely at the assembly or membrane transport steps. In JGN cells all chimeric TCRs were signalling competent. However, an IC domain at CD3γ was required for TCR-induced IL-2 and TNF-α production and CD69 expression, indicating that a TCR without a CD3γ IC domain has altered signalling capabilities.

PMID:36119034 | PMC:PMC9478619 | DOI:10.3389/fimmu.2022.978658

Hematol Transfus Cell Ther. 2022 Aug 8:S2531-1379(22)00097-9. doi: 10.1016/j.htct.2022.06.009. Online ahead of print.

ABSTRACT

INTRODUCTION: Immunoglobulin represents the main therapy for patients with inborn errors of immunity (IEI) and it is a safe procedure, but adverse events (AEs) can occur with variable frequencies.

OBJECTIVE: To evaluate the frequency of immediate AEs to intravenous immunoglobulin (IVIG) regular therapy in a pediatric cohort with IEI after a pre-IVIG infusion protocol.

METHODS: This was a longitudinal study from 2011 to 2019 at a tertiary pediatric hospital in Brazil.

RESULTS: A total of 1736 infusions were studied in 70 patients with IEI, 46 (65.7%) of whom were males and whose median age was 5.8 years old (range: 6 mo – 18 yo). Seven different brands of IVIG were used with the median loading dose of 0.57g/kg (range: 0.23 – 0.88g/Kg). According to the protocol, pre-medication and step-up infusion rate, were performed in 1305 (75.2%) infusions. Immediate AEs were noted in 10 children (14.3%) and in 22 (1.2%) infusions. Skin reactions (rash or urticaria) were the most common AE with 14 episodes (0.8% of all infusions). Almost all AEs were mild (19/86.4%), with no severe ones being observed. The majority of the AEs (81.8%) was identified at a 0.04ml/kg/min infusion rate. Gender, age at first infusion, presence of infection on the infusion day and change of the IVIG brand were evaluated and none of them were associated with AEs.

CONCLUSION: The low frequency of immediate AEs in children with IEI highlights the safety and tolerability of intravenous immunoglobulin replacement with the procedures established at our center.

PMID:36114118 | DOI:10.1016/j.htct.2022.06.009