Rituximab is a chimeric monoclonal antibody used to treat hematologic and autoimmune diseases by depleting CD20-expressing B cells. Patients may develop hypogammaglobulinemia following treatment, ...with some demonstrating failure of B-cell recovery. The true frequency of hypogammaglobulinemia and/or impaired B-cell reconstitution post rituximab is unknown due to the lack of prospective studies in different patient cohorts. The clinical significance remains controversial; some patients have recurrent infections while others are relatively asymptomatic. The aim of this review is to describe the prevalence of hypogammaglobulinemia and the associated risk for developing severe infection, in patients with differing underlying clinical conditions treated with rituximab. This may facilitate classification and prognostication of patients who develop these conditions and identify patients who may be at high risk of developing these complications, including those who may benefit from immunoglobulin replacement therapy.
The pathophysiology of pediatric sepsis is characterized by increased innate immune activation earlier in life. Interleukin-1 is a proinflammatory cytokine implicated in the pathophysiology of ...sepsis, and ferritin is a stable surrogate biomarker for elevated IL-1 levels. Data in adult sepsis have shown that use of anakinra, an anti-IL-1 receptor antagonist, led to improved clinical outcomes in patients with features of macrophage activation and hyperferritinemia. However, data in pediatric sepsis are lacking. Our narrative review sought to highlight the current understanding of using IL-1 inhibitors in pediatric sepsis. We identified five studies including one case report and four retrospective case series that described clinical outcomes in relation to use of anakinra for secondary hemophagocytic lymphohistiocytosis (HLH). A few patients in this pooled heterogenous cohort of 72 patients had concomitant infection meeting the criteria for sepsis. All studies measured ferritin levels and reported a decrease in ferritin after initiating anakinra. Twelve patients died after treatment initiation. There was no clear comparison in clinical outcomes between infected and noninfected patients. The pathophysiology of pediatric sepsis suggests that there is a need for blinded clinical trials using targeted immunomodulation such as IL-1 inhibitors in pediatric sepsis cohort with an immunophenotype suggesting increased innate immune activation.
Inborn errors of immunity consist of over 400 known single gene disorders that may manifest with infection susceptibility, autoimmunity, autoinflammation, hypersensitivity and cancer predisposition. ...Most patients are treated symptomatically with immunoglobulin replacement, prophylactic antimicrobials or broad immunosuppression pertaining to their disease phenotype. Other than haematopoietic stem cell transplantation, the aforementioned treatments do little to alter disease morbidity or mortality. Further, many patients may not be transplant candidates. In this review, we describe monogenic disorders affecting leucocyte migration, disorders of immune synapse formation and dysregulation of immune cell signal transduction. We highlight the use of off‐label small molecules and biologics mechanistically targeted to altered disease pathophysiology of such diseases.
•Primary Atopic Disorders are monogenic causes of allergic symptoms leading to a wide variety of phenotypes.•Many of these individual disorders vary in the presence, type, and severity of symptoms, ...such that other factors contribute to the phenotype.•Environmental modifiers such as microbiome, overt infection, diet, and stress may contribute to differences in penetrance.•Gene–environment interactions in monogenic disorders may clarify genetic and environmental effects on common allergic disease.
Environmental factors modify disease presentation and severity in allergic disorders. Primary atopic disorders (PADs) are a heterogenous group of single gene disorders that lead to significant atopic and allergic disease manifestations. However, a number of these monogenic diseases have variable penetrance suggesting that gene–gene and/or gene–environment interactions could modulate the clinical phenotype. Environmental factors such as diet, the microbiome at the epithelial–environment interface, the presence and/or extent of infection, and psychologic stress can alter disease phenotypic expression of allergic diseases, and PADs provide discrete contexts in which to understand these influences.
We outline how gene–environment interactions likely contribute to a variable penetrance and expressivity in PADs. Dietary modifications of both macronutrients and/or micronutrients alter T-cell metabolism and may influence effector T-cell function. The mucosal microbiome may affect local inflammation and may remotely influence regulatory elements, while psychologic stress can affect mast cell and other allergic effector cell function. Understanding gene–environment interactions in PADs can hopefully provide a foundation for interrogating gene–environment interactions to common allergic disorders, and also present opportunities for personalized interventions based on the altered pathways and environmental influences in affected individuals.
More than 95% of humans have been infected with Epstein–Barr virus (EBV) and develop anti-EBV IgG antibodies, conferring immunity. However, among specific populations, EBV may induce a range of ...B-cell lymphoproliferative disorders (LPDs). EBV may also contribute to T-cell and natural killer (NK)-cell lymphoproliferation. The immune system is essential to prevent infection and development of cancer. Inborn errors of immunity (IEIs) are a heterogenous group of more than 450 genetic disorders predisposing to severe and/or recurrent infection, autoimmunity, autoinflammation, or early-onset/severe neoplasia or lymphoproliferation. Monogenic disorders of T-cell and B-cell signalling are classic IEIs that predispose to EBV-associated LPDs.
We aimed to outline the various clinical manifestations of EBV-associated LPDs and the underlying IEIs associated with such presentations and discuss the recommended management and therapeutic options pertaining to these disorders.
We searched PubMed, Embase, and Web of Science Core Collection on 30 September 2021. Clinical studies, systematic reviews, narrative reviews, and case reports were identified through search strategy and cross reference from primary literature.
Effective T-cell and NK-cell cytotoxicity towards EBV-infected B cells relies on intact MAGT1-dependent NKG2D pathways and signalling lymphocyte activation molecular–associated protein-dependent signalling lymphocyte activation molecular receptors. The interaction between CD27 and CD70 is also critical to drive the expansion of EBV-specific T cells. IEIs due to T-cell and B-cell signalling defects and/or impaired T-cell and NK-cell cytotoxicity predispose to EBV-related lymphoproliferation. This includes classic disorders such as X-linked lymphoproliferative disease 1 (due to SH2D1A mutations), X-linked lymphoproliferative disease 2 (XIAP), and other genetic diseases, such as ITK, MAGT1, CD27, CD70, CTPS1, RASGRP1, and CORO1A deficiencies. EBV-driven lymphoproliferation may manifest to a lesser degree in MST1/STK4, DOCK8, STIM1, CORO1A, IL21R, PIK3CD gain-of-function, and PI3KR1 deficiencies.
Early screening for IEIs is indicated in cases of EBV-related lymphoproliferation because different forms of IEIs have specific prognostic and therapeutic implications.
Rationale End-stage renal disease (ESRD) in chronic granulomatous disease (CGD) is anecdotally attributed to use of prophylactic antimicrobials with nephrotoxic potential as well as intrinsic ...inflammatory/granulomatous complications. 10 patients had a diagnosis of ‘Renal Failure’, 2 patients had chronic kidney disease, 1 patient had acute kidney injury, 1 patient had non-specific ‘kidney disease’.
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