Blog

Platelets. 2022 Feb 8:1-6. doi: 10.1080/09537104.2021.2002835. Online ahead of print.

ABSTRACT

Treatment of refractory autoimmune cytopenias (AICs) and Evans syndrome (ES) represent a great challenge in pediatric setting, where an underlying primary immunodeficiency is recurrent. Frequently, second or third line treatments are employed, with an increased risk of toxicity and infections. The advent of novel drugs is the object of research in order to modify the management of these patients.We report a case of successful use of bortezomib in a child with 22q11.2 deletion syndrome and CVID-like phenotype with a multi-refractory severe ES. Last flares were prolonged and dominated by severe and symptomatic ITP, refractory to different courses of high dose steroid and IVIG, mofetil mycophenolate, thrombopoietin receptor agonists, sirolimus, and rituximab. Persistence of AICs in subjects with depletion of CD20 + B-cells and IgG strengthens the hypothesis about the production of autoantibodies by terminally differentiated plasma-cells, not targetable from immunosuppressants and rituximab.In the attempt to enhance plasma-cells inhibition, the child was addressed to bortezomib, with a good response at 6 month follow-up without side effects. Nowadays, the use of bortezomib in ES/AICs is based only on small retrospective studies and case reports. Despite the lack of long term follow-up, our work highlights the potential role of bortezomib in the management of pediatric patients with multi-resistant AICs secondary to immune-system impairment.

PMID:35132908 | DOI:10.1080/09537104.2021.2002835

Immunotherapy. 2022 Feb 7. doi: 10.2217/imt-2021-0265. Online ahead of print.

ABSTRACT

Aim: Identify and describe published literature on the use of subcutaneous immunoglobulin (SCIG) as initial immunoglobulin (IG)-replacement therapy for patients with primary immunodeficiency diseases (PID). Methods: We systematically identified and summarized literature in MEDLINE, Embase, BioSciences Information Service and Cochrane Library assessing efficacy/effectiveness, safety/tolerability, health-related quality-of-life (HRQoL) and dosing regimens of SCIG for IG-naive patients with PID. Results: Sixteen studies were included. In IG-naive patients, SCIG managed/reduced infections and demonstrated similar pharmacokinetic parameters to IG-experienced patients; adverse events were mostly minor injection-site pain or discomfort. Three studies reported improvements in HRQoL. Quality of studies was difficult to assess due to limited reporting. Conclusion: Although studies were lacking, available data suggest IG-naive and IG-experienced patients initiating SCIG likely have similar outcomes.

PMID:35128932 | DOI:10.2217/imt-2021-0265

Front Immunol. 2022 Jan 20;13:801832. doi: 10.3389/fimmu.2022.801832. eCollection 2022.

ABSTRACT

BACKGROUND: STAT1 gain-of-function (GOF) is a primary immune dysregulatory disorder marked by wide infectious predisposition (most notably chronic mucocutaneous Candidiasis), autoimmunity, vascular disease and malignant predisposition. While atopic features have been described in some STAT1 GOF patients, they are not considered a predominant feature of the disease. Additionally, while eosinophilic gastrointestinal infiltration has been reported in some cases, this has always been described in the context of pre-existing oropharyngeal and/or esophageal Candidiasis.

CLINICAL CASES: Herein, we report 3 members of a multi-generational family diagnosed with STAT1 GOF caused by a novel mutation in the N-terminal domain, c.194A>C (p.D65A). The proband presented initially with a long-standing history of treatment-refractory eosinophilic esophagitis (EoE) without preceding gastrointestinal tract fungal infections, and her mother was diagnosed with esophagitis as well.

CONCLUSION: EoE has been previously associated with alterations to STAT6 and STAT3 signaling pathways. The current report expands the possible association between JAK/STAT-related disorders and EoE, suggesting that EoE could be a primary disease manifestation of STAT1 GOF, even in the absence of oropharyngeal and/or esophageal Candidiasis.

PMID:35126392 | PMC:PMC8812721 | DOI:10.3389/fimmu.2022.801832

Front Immunol. 2022 Jan 19;12:827815. doi: 10.3389/fimmu.2021.827815. eCollection 2021.

ABSTRACT

The advent of high-throughput sequencing has facilitated genotype-phenotype correlations in congenital diseases. This has provided molecular diagnosis and benefited patient management but has also revealed substantial phenotypic heterogeneity. Although distinct neuroinflammatory diseases are scarce among the several thousands of established congenital diseases, elements of neuroinflammation are increasingly recognized in a substantial proportion of inborn errors of immunity, where it may even dominate the clinical picture at initial presentation. Although each disease entity is rare, they collectively can constitute a significant proportion of neuropediatric patients in tertiary care and may occasionally also explain adult neurology patients. We focus this review on the signs and symptoms of neuroinflammation that have been reported in association with established pathogenic variants in immune genes and suggest the following subdivision based on proposed underlying mechanisms: autoinflammatory disorders, tolerance defects, and immunodeficiency disorders. The large group of autoinflammatory disorders is further subdivided into IL-1β-mediated disorders, NF-κB dysregulation, type I interferonopathies, and hemophagocytic syndromes. We delineate emerging pathogenic themes underlying neuroinflammation in monogenic diseases and describe the breadth of the clinical spectrum to support decisions to screen for a genetic diagnosis and encourage further research on a neglected phenomenon.

PMID:35126383 | PMC:PMC8807658 | DOI:10.3389/fimmu.2021.827815

Cent Eur J Immunol. 2021;46(4):531-534. doi: 10.5114/ceji.2021.111200. Epub 2021 Dec 6.

ABSTRACT

Immunoglobulin A (IgA) deficiency is the most common primary immunodeficiency in humans, with incidence depending on ethnic background and the highest frequency in Caucasians. Selective IgA deficiency may have an asymptomatic course and constitute a random laboratory finding with no clinical manifestation. There is, however, a group of patients with increased incidence of recurrent upper respiratory tract infections, allergies, asthma, atopic dermatitis and other pathologies connected with IgA deficiency. This group of patients often needs broad-spectrum antibiotic therapy with maximum doses and extended time of treatment as there is no causal treatment for IgA deficiency. An association between IgA deficiency and autoimmune diseases, such as juvenile idiopathic arthritis, has been proved before. Nonetheless, the frequency of co-occurrence of these disorders in an individual as well as the way immunodeficiency may influence the course of juvenile idiopathic arthritis is still undefined, with limited literature on this topic. This article presents case reports of three pediatric patients with confirmed co-occurrence of IgA deficiency and oligoarticular juvenile idiopathic arthritis.

PMID:35125954 | PMC:PMC8808310 | DOI:10.5114/ceji.2021.111200

Intest Res. 2022 Feb 8. doi: 10.5217/ir.2021.00029. Online ahead of print.

ABSTRACT

X-linked inhibitor of apoptosis (XIAP) deficiency is a rare primary immunodeficiency and gastrointestinal (GI) lesions in XIAP deficiency are similar to Crohn’s disease. For patients with Crohn’s disease, endoscopic balloon dilation (EBD) is known to be a standard procedure for intestinal strictures including upper GI tract. However, there are no articles which mention the efficacy of EBDs for the strictures in upper GI tract in patients with XIAP deficiency. Herein, we describe an 18-year-old male with XIAP deficiency in whom EBDs for the rectum, ileocecal valve (ICV), and duodenum were performed. Before hematopoietic stem cell transplantation (HSCT), GI endoscopy revealed strictures of the rectum, ICV and duodenum with active ulcers. Although these ulcers healed after HSCT, the strictures progressed. Therefore, we performed EBDs for the strictures of the rectum, ICV, and duodenum. In contrast studies, we did not find any other strictures in the small intestine. Throughout the patient’s clinical course, no complications of EBD occurred. He started eating after EBDs, but abdominal symptoms did not relapse without any dietary restrictions. Our case suggests that EBD could be an effective and safe procedure for intestinal strictures including upper GI tract after HSCT in patients with XIAP deficiency.

PMID:35124956 | DOI:10.5217/ir.2021.00029

Pediatr Transplant. 2022 Feb 5:e14239. doi: 10.1111/petr.14239. Online ahead of print.

ABSTRACT

BACKGROUND: Infants are subjected to hematopoietic stem cell transplantation (HSCT) due to malignant and non-malignant diseases. However, specific data concerning the outcome and transplantation-related complications in infants, as a separate age group, are limited. Our aim was to evaluate the impact of infancy on the outcome, toxicity, and complications after HSCT.

METHODS: We retrospectively analyzed data of 55 infants that underwent HSCT in our unit from May 1997 until February 2020, emphasizing on the probability of overall survival (OS) and the cumulative incidence (CI) of transplantation-related mortality (TRM) and complications.

RESULTS: We report a probability of OS of 61%, a CI of TRM at day 100 and 365 post transplantation of 22% and 30%, respectively, and additionally a CI of graft failure, acute graft-versus-host disease (GvHD), and infectious complications, 18%, 44%, and 39%, respectively. No statistically significant association was detected between the above mentioned parameters and diagnosis, the use of myeloablative or non-myeloablative/reduced toxicity conditioning regimens or the type of donor.

CONCLUSIONS: We conclude that HSCT in infancy is associated with significant mortality and morbidity. This is possibly attributed to endogenous, age-related factors. More specifically, infants may be at a higher risk of toxicities due to the immaturity of developing vital organs and the deficiency of the newly adopted immune system that predisposes them to infectious complications. The development of GvHD further augments the danger of infections, in a potential vice-versa relationship. Moreover, there are few data on pharmacokinetics of chemotherapy agents, making safe and efficacious drug administration hard.

PMID:35122456 | DOI:10.1111/petr.14239

Clin Immunol. 2022 Feb 1:108938. doi: 10.1016/j.clim.2022.108938. Online ahead of print.

ABSTRACT

Many patients with immunodeficiencies require lifelong immunoglobulin replacement therapy (IgRT). In a multicenter, randomized, open-label, crossover, non-inferiority 3-month-trial, we compared the impact of the subcutaneous immunoglobulin Gammanorm® administered via pump or syringe (rapid push). Primary endpoint was the life quality index (LQI), secondary endpoints were QoL (SF36v2), satisfaction (TSQM-11), disease and treatment burden (PRISM), incidence of infections and adverse events (AE), treatment costs, and IgG levels. 28/30 patients completed the study. Most of the endpoints were comparable. Drug administrations with rapid push were more frequent, but reduced total time expenditure and some costs. Of the TSQM-11/LQI/SF36 components only “treatment interference with daily activities” was superior with pump and two QoL domains with rapid push. Both delivery devices showed favorable safety. Rapid push was preferred by 34.5% of patients. It proved to be an efficacious and cost-effective alternative to pumps adding to patient choice and increasing flexibility during long-term IgRT.

PMID:35121105 | DOI:10.1016/j.clim.2022.108938

Eur J Pediatr. 2022 Feb 4. doi: 10.1007/s00431-022-04397-9. Online ahead of print.

ABSTRACT

Diagnosis of primary complement deficiencies requires a high index of suspicion. Thus, susceptible patients are often underdiagnosed and untreated. Here, we present a multicenter experience with two novel inborn errors of the classical complement system. This is a retrospective multicenter analysis of computerized medical records of children (<18 years) admitted in the period between 2012 and 2018 at Shaare Zedek Medical Center in Jerusalem and Edmond and Lily Safra Children’s Hospital, Tel-Hashomer Medical Center, in Ramat Gan, Israel. Patients were genetically diagnosed by a complementary immune workup. We identified 5 patients (3 males) from four different families harboring two novel mutations in the complement components C6-C8. Genetic mutations were identified by whole-exome sequencing or by sequencing of the coding exons of a single gene based on the findings in the immune workup. Clinical manifestations consisted of meningitis with or without meningococcemia. The immune workup demonstrated nearly absent levels of CH50, compatible with a complement pathway defect. Diagnosis delay ranged between 0 and 30 years.Conclusion: Awareness of risk factors for primary complement deficiencies, even at the first infectious episode, should facilitate prompt immune and genetic workup, commencing diagnosis and proper treatment for the patient and family. What is Known: • Deficiencies in the classical terminal complement components increase susceptibility to invasive meningococcal infections. • Recurrent meningococcal infections mandate a diagnostic workup of the complement system. What is New: • Genetic workup can be utilized for prompt diagnosis of complement deficiencies. • High rates of consanguinity, even in the presence of a single meningococcal infection, should promote immune and genetic workups.

PMID:35118517 | DOI:10.1007/s00431-022-04397-9

Front Immunol. 2022 Jan 17;12:805705. doi: 10.3389/fimmu.2021.805705. eCollection 2021.

ABSTRACT

BACKGROUND: Immunoglobulin (Ig) replacement therapy represents a life-saving treatment in primary antibody deficiencies. The introduction of subcutaneous Ig (SCIg) administration brings a major improvement in quality of life for patients, compared to the traditional intravenous administration. In recent years, an additional role has been proposed for Ig therapy for various inflammatory and immune-mediated diseases. Consequently, the use of SCIg has expanded from immunodeficiencies to immune-mediated diseases, such as polymyositis (PM) and dermatomyositis (DM). Given the rarity of these conditions, it is still difficult to evaluate the real impact of SCIg treatment on PM and DM, and additional data are constantly required on this topic, particularly for long-term treatments in real-life settings.

AIM: This study aimed to increase the knowledge about the anti-inflammatory and immunomodulatory effects of SCIg treatment for myositis. To this aim, a long-term evaluation of the effectiveness of 20% human SCIg treatment (20% SCIg, Hizentra^®, CSL Behring) was carried out in patients with PM/DM in care at our Center. In addition, an evaluation of the 20% SCIg therapy in CVID patients was provided. This analysis, beside adding knowledge about the use of SCIg therapy in this real-life setting, was intended as a term of comparison, regarding the safety profile.

RESULTS: Results support the beneficial effect and tolerability of long-term 20% SCIg therapy in PM/DM patients, reporting a significant improvement in creatine kinase levels, muscle strength, skin conditions, dysphagia, disease activity (MITAX score) and disability (HAQ-DI score). None of the patients reported systemic reactions. The duration of the reported local reactions was a few hours in 80% of the patients, and all resolved spontaneously. CVID patients reported an improvement in all the considered effectiveness parameters at the end of 20% SCIg therapy. The frequency of the adverse events reported by PM/DM patients was not different from what reported in CVID patients, where the use of SCIg therapy is more consolidated.

CONCLUSIONS: This study suggests that 20% SCIg treatment represents a viable and safe treatment for PM/DM patients and a valid therapeutic alternative to IVIg, with important advantages for patients’ quality of life.

PMID:35111165 | PMC:PMC8801806 | DOI:10.3389/fimmu.2021.805705