Research

Int J Rheum Dis. 2022 Jan 20. doi: 10.1111/1756-185X.14289. Online ahead of print.

ABSTRACT

Polyautoimmunity or multiple autoimmune syndrome (MAIS) is increasingly being recognized in pediatric clinical practice, often in conjunction with systemic lupus erythematosus (SLE). Besides multi-organ autoimmunity, children with SLE are often at a higher risk of developing infections including tuberculosis. The tendency to develop infections and multiple autoimmune diseases in childhood SLE often occurs in the absence of monogenic primary immunodeficiency disease. Conversely, children with inborn errors of immunity, of which selective IgA deficiency (sIgAD) is the most common, may develop recurrent infections and autoimmune disorders including SLE. Herein, we report a child with MAIS (including SLE) and sIgAD who developed drug-resistant tuberculosis, which was managed successfully with second-line anti-tubercular drug therapy. To the best of our knowledge, this combination of rare findings has not been reported previously in the pediatric literature. Although a majority of patients with sIgAD are either asymptomatic or have mild infections/autoimmunity, the index child had a myriad of infectious illnesses and multi-organ autoimmunity. Our case highlights the prudence of thoroughly evaluating children with SLE for other autoimmune diseases and vice versa. Given the higher probability of inherited disorders, including early complement deficiencies and monogenic interferonopathies, in childhood SLE compared with adult SLE, it may be prudent to perform a basic immunological workup (for example, immunoglobulin levels, 50% hemolytic complement) in such patients. A more extensive immunological and genetic evaluation (including next-generation sequencing) may also be required in the presence of unusual clinical or laboratory features, a positive family history, or a complicated clinical course.

PMID:35048520 | DOI:10.1111/1756-185X.14289

Intern Med J. 2022 Jan 20. doi: 10.1111/imj.15694. Online ahead of print.

ABSTRACT

BACKGROUND: Immunoglobulin is an expensive and scarce resource and usage is increasing worldwide. Immunoglobulin is used to treat a variety of clinical conditions, particularly primary and acquired immunodeficiencies and immune mediated neurological disorders. As immunoglobulin usage continues to increase, plasma collection must increase accordingly in order to sustain immunoglobulin production. The New Zealand Blood Service (NZBS) is the provider of immunoglobulin in New Zealand (NZ). Information regarding national immunoglobulin usage warrants analysis given the rise in usage.

AIMS: We set out to review immunoglobulin usage in NZ with a focus on the trend in the amount used, number of patients, clinical indications and compliance with international guidelines. A comparison with international immunoglobulin usage was performed. The impact on national plasma collection was reviewed.

METHODS: Data on immunoglobulin usage, number of patients, and plasma collection over the past decade was obtained from the NZBS Tableau database. Data from international literature was reviewed.

RESULTS: Immunoglobulin usage in NZ has been increasing over the past decade, with an annual growth rate of 6.4%. The three main indications for immunoglobulin are primary immunodeficiency disorders, chronic inflammatory demyelinating polyneuropathy (CIDP), and acquired hypogammaglobulinaemia secondary to haematological malignancies. Prominent growth in usage is evident for CIDP and acquired hypogammaglobulinaemia. Immunoglobulin usage in NZ is low compared other countries such as Australia and the United States. There has been a marked increase in plasma donations in order to keep up with immunoglobulin demand.

CONCLUSIONS: Immunoglobulin is a strategic resource and appropriate usage is critical to regulate demand. This article is protected by copyright. All rights reserved.

PMID:35049107 | DOI:10.1111/imj.15694

Front Pediatr. 2021 Dec 30;9:798959. doi: 10.3389/fped.2021.798959. eCollection 2021.

ABSTRACT

Autoimmune lymphoproliferative syndrome (ALPS) is a disorder characterized by a disruption of the lymphocyte apoptosis pathway, self-tolerance, and immune system homeostasis. Defects in genes within the first apoptosis signal (FAS)-mediated pathway cause an expansion of autoreactive double-negative T cells leading to non-malignant lymphoproliferation, autoimmune disorders, and an increased risk of lymphoma. The aim of the study was to show the diagnostic dilemmas and difficulties in the process of recognizing ALPS in the light of chronic active Epstein-Barr virus (CAEBV) infection. Clinical, immunological, flow cytometric, biomarkers, and molecular genetic approaches of a pediatric patient diagnosed with FAS-ALPS and CAEBV are presented. With the ever-expanding spectrum of molecular pathways associated with autoimmune lymphoproliferative disorders, multiple genetic defects of FAS-mediated apoptosis, primary immunodeficiencies with immune dysregulation, malignant and autoimmune disorders, and infections are included in the differential diagnosis. Further studies are needed to address the issue of the inflammatory and neoplastic role of CAEBV as a triggering and disease-modifying factor in ALPS.

PMID:35036396 | PMC:PMC8757380 | DOI:10.3389/fped.2021.798959

Med J Armed Forces India. 2022 Jan;78(1):99-102. doi: 10.1016/j.mjafi.2018.11.012. Epub 2019 Apr 15.

ABSTRACT

Chronic Granulomatous Disease (CGD) is a primary immunodeficiency disorder (PID) of phagocytic cells resulting in failure to eradicate catalase positive microorganisms like Staphylococci and fungal infections; due to deficiency or malfunction of nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase subunits in phagocytic leucocytes. We illustrate here one such case; a six year old girl who was admitted in our hospital with history of prolonged fever, non resolving bilateral otitis media and recurrent pneumonia. She was evaluated for an underlying PID and was found to have CGD based on Nitro blue Tetrazolium (NBT) Slide Test and flow cytometric Dihydrorhodamine (DHR) assay. The child was symptomatic despite initial treatment with first-line followed by second-line antibiotics. During the course of current systemic infection, she also developed infection-associated secondary Hemophagocytic Lympho Histiocytosis (HLH) as suggested by her clinical and laboratory parameters. Despite a thorough search, no microorganism could be isolated and so she was treated with empircal antibiotic therapy comprising of meropenem, linezolid and an antifungal. Fever resolved with gradual improvement of laboratory parameters and finally spontaneous resolution of HLH. We conclude that a high index of suspicion for PID is required in a child with recurrent infections. Identification of underlying infectious agent should be attempted to start targeted antimicrobial therapy; both to prevent as well as cure infection associated secondary HLH.

PMID:35035051 | PMC:PMC8737091 | DOI:10.1016/j.mjafi.2018.11.012

J Allergy Clin Immunol. 2022 Jan 11:S0091-6749(22)00039-2. doi: 10.1016/j.jaci.2021.12.790. Online ahead of print.

ABSTRACT

BACKGROUND: Non-infectious manifestations, i.e. allergy, autoimmunity/inflammation, lymphoproliferation and malignancies are known to be observed in many primary immunodeficiency diseases (PID) and to participate to their prognosis.

OBJECTIVE: In order to have a global view on their occurrence, we retrieved data from a retrospective cohort of 1375 patients included in the French national registry of PID (CEREDIH) for whom we had a 10-year follow-up since inclusion in the registry.

METHODS: These patients were followed for 10 years (2009-2018) by specialized centers in University Hospitals. This study shows that 20.1% of patients without prior curative therapy (n=1163) developed at least one manifestation (event) encompassing 277 events.

RESULTS: Autoimmune/inflammatory events (n=138) and malignancies (n=85) affected all age classes and virtually all PID diagnostic groups. They were associated with a risk of death that occurred in 14.2% of them (n=195), being found as causal in 43% of cases. Malignancies (OR: 5.62 [3.66 – 8.62]) and autoimmunity (OR: 1.9 [1.27 – 2.84]) were clearly identified as risk factors for lethality. Patients who underwent curative therapy (i.e. mostly allogeneic hematopoietic stem cell transplantation, a few cases of gene therapy or thymic transplantation) prior to the 10-year study period (n=212) had comparatively reduced but still detectable clinical manifestations (n=16) leading to death in 9.4% of them.

CONCLUSION: This study points to the frequency and severity of non-infectious manifestations in various PID groups across all age groups. These results warrant further prospective analysis to better assess their consequences and to adapt therapy, notably indication of curative therapy.

PMID:35031273 | DOI:10.1016/j.jaci.2021.12.790

IDCases. 2022 Jan 3;27:e01375. doi: 10.1016/j.idcr.2022.e01375. eCollection 2022.

ABSTRACT

Opportunistic infections are life-threatening conditions in immunocompromised patients including those with primary immunodeficiency. We describe a case of X-linked chronic granulomatous disease presenting with mesenteric abscess caused by a coinfection with Bacillus Calmette-Guérin (BCG) and Phialemonium sp. The patient received BCG vaccination at 5 months old. He developed left axillary BCG lymphadenitis at 17 months of age, and 3 months later mesenteric abscess occurred. Concomitant use of rifampicin and itraconazole at 17 months of age might have reduced serum itraconazole concentrations and led to superinfection with Phialemonium sp. in our patient, which was susceptible to itraconazole and voriconazole in vitro. The patient was successfully treated with a combination of isoniazid, rifampicin, streptomycin, ciprofloxacin, prednisolone, interferon-γ, and an increased dose of itraconazole, followed by hematopoietic stem cell transplantation. Our results suggest that clinician need to be aware of rifampicin drug interactions, and that precise detection and identification of pathogens are essential to appropriate treatment.

PMID:35028293 | PMC:PMC8739448 | DOI:10.1016/j.idcr.2022.e01375

J Clin Immunol. 2022 Jan 14. doi: 10.1007/s10875-021-01176-3. Online ahead of print.

ABSTRACT

NF-κB essential modulator (NEMO, IKK-γ) deficiency is a rare combined immunodeficiency caused by mutations in the IKBKG gene. Conventionally, patients are afflicted with life threatening recurrent microbial infections. Paradoxically, the spectrum of clinical manifestations includes severe inflammatory disorders. The mechanisms leading to autoinflammation in NEMO deficiency are currently unknown. Herein, we sought to investigate the underlying mechanisms of clinical autoinflammatory manifestations in a 12-years old male NEMO deficiency (EDA-ID, OMIM #300,291) patient by comparing the immune profile of the patient before and after hematopoietic stem cell transplantation (HSCT). Response to NF-kB activators were measured by cytokine ELISA. Neutrophil and low-density granulocyte (LDG) populations were analyzed by flow cytometry. Peripheral blood mononuclear cells (PBMC) transcriptome before and after HSCT and transcriptome of sorted normal-density neutrophils and LDGs were determined using the NanoString nCounter gene expression panels. ISG15 expression and protein ISGylation was based on Immunoblotting. Consistent with the immune deficiency, PBMCs of the patient were unresponsive to toll-like and T cell receptor-activators. Paradoxically, LDGs comprised 35% of patient PBMCs and elevated expression of genes such as MMP9, LTF, and LCN2 in the granulocytic lineage, high levels of IP-10 in the patient’s plasma, spontaneous ISG15 expression and protein ISGylation indicative of a spontaneous type I interferon (IFN) signature were observed, all of which normalized after HSCT. Collectively, our results suggest that type I IFN signature observed in the patient, dysregulated LDGs and spontaneously activated neutrophils, potentially contribute to tissue damage in NEMO deficiency.

PMID:35028801 | DOI:10.1007/s10875-021-01176-3

Turk J Pediatr. 2021;63(6):1072-1077. doi: 10.24953/turkjped.2021.06.016.

ABSTRACT

BACKGROUND: Dedicator of cytokinesis 2 (DOCK2) deficiency is a rare autosomal recessive combined immunodeficiency presenting with very early onset, severe bacterial and viral infections. In DOCK2 deficiency; T, B and NK cell numbers are decreased and functions are impaired resulting in severe atrophy of secondary lymphoid tissues. The aim of this report is to provide information on clinical and laboratory features and hematopoietic stem cell transplantation (HSCT) outcomes of a DOCK2 deficient patient. The patient was diagnosed by using a targeted next generation sequencing primary immunodeficiency (PID) panel. Lymphocyte subsets were measured by flow-cytometry.

CASE: Here, we describe a patient with DOCK2 deficiency presented with severe combined immunodeficiency. He underwent HSCT without conditioning regimen before the genetic diagnosis and developed hemophagocytic lymphohistiocytosis(HLH) due to Epstein-Barr virus (EBV) infection.

CONCLUSIONS: Genetic testing is necessery for early diagnosis of DOCK2 deficiency. The curative treatment should be HSCT soon after diagnosis.

PMID:35023658 | DOI:10.24953/turkjped.2021.06.016

Clin Exp Immunol. 2021 Nov 30:uxab019. doi: 10.1093/cei/uxab019. Online ahead of print.

ABSTRACT

This report highlights case of two siblings who developed Haemophagocytic lymphohystiocytosis (HLH) due to distinct genetic abnormalities. Though their presentation was clinically similar, the cases demonstrate that a shared genetic diagnosis among siblings cannot be assumed.

PMID:35020838 | DOI:10.1093/cei/uxab019

Clin Exp Immunol. 2021 Dec 21:uxab034. doi: 10.1093/cei/uxab034. Online ahead of print.

ABSTRACT

Primary immunodeficiency disorders comprise a rare group of mostly monogenic disorders caused by inborn errors of immunity. The majority can be identified by either Sanger sequencing or Next Generation Sequencing. Some disorders result from large insertions or deletions leading to copy number variations (CNV). Sanger sequencing may not identify these mutations. Here we present droplet digital PCR as an alternative cost-effective diagnostic method to identify CNV in these genes. The data from patients with large deletions of NFKB1, SERPING1 and SH2D1A are presented.

PMID:35020846 | DOI:10.1093/cei/uxab034