Research

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

Clin Exp Immunol. 2022 Jan 10:uxac001. doi: 10.1093/cei/uxac001. Online ahead of print.

ABSTRACT

Understanding the T cell response to SARS-CoV-2 is key in patients who lack antibody production. We demonstrate the applicability of a functional assay to measure the T cell response in a cohort of patients with immunodeficiency.

PMID:35020892 | DOI:10.1093/cei/uxac001

Clin Rev Allergy Immunol. 2022 Jan 12. doi: 10.1007/s12016-021-08916-8. Online ahead of print.

ABSTRACT

Over the past 20 years, the rapid evolution in the diagnosis and treatment of primary immunodeficiencies (PI) and the recognition of immune dysregulation as a feature in some have prompted the use of “inborn errors of immunity” (IEI) as a more encompassing term used to describe these disorders [1, 2] . This article aims to review the future of therapy of PI/IEI (referred to IEI throughout this paper). Historically, immune deficiencies have been characterized as monogenic disorders resulting in immune deficiencies affecting T cells, B cells, combination of T and B cells, or innate immune disorders. More recently, immunologists are also recognizing a variety of phenotypes associated with one genotype or similar phenotypes across genotypes and a role for incomplete penetrance or variable expressivity of some genes causing inborn errors of immunity [3]. The IUIS classification of immune deficiencies (IEIs) has evolved over time to include 10 categories, with disorders of immune dysregulation accounting for a new subset, some treatable with small molecule inhibitors or biologics. [1] Until recently, management options were limited to prompt treatment of infections, gammaglobulin replacement, and possibly bone marrow transplant depending on the defect. Available therapies have expanded to include small molecule inhibitors, biologics, gene therapy, and the use of adoptive transfer of virus-specific T cells to fight viral infections in immunocompromised patients. Several significant contributions to the field of clinical immunology have fueled the rapid advancement of therapies over the past two decades. Among these are educational efforts to recruit young immunologists to the field resulting in the growth of a world-wide community of clinicians and investigators interested in rare diseases, efforts to increase awareness of IEI globally contributing to international collaborations, along with advancements in diagnostic genetic testing, newborn screening, molecular biology techniques, gene correction, use of immune modulators, and ex vivo expansion of engineered T cells for therapeutic use. The development and widespread use of newborn screening have helped to identify severe combined immune deficiency (SCID) earlier resulting in better outcomes [4]. Continual improvements and accessibility of genetic sequencing have helped to identify new IEI diseases at an accelerated pace [5]. Advances in gene therapy and bone marrow transplant have made treatments possible in otherwise fatal diseases. Furthermore, the increased awareness of IEI across the world has driven networks of immunologists working together to improve the diagnosis and treatment of these rare diseases. These improvements in the diagnosis and treatment of IEI noted over the past 20 years bring hope for a better future for the IEI community. This paper will review future directions in a few of the newer therapies emerging for IEI. For easy reference, most of the diseases discussed in this paper are briefly described in a summary table, in the order mentioned within the paper (Appendix).

PMID:35020169 | DOI:10.1007/s12016-021-08916-8