Manish Butte

Physiother Theory Pract. 2021 Sep 29:1-12. doi: 10.1080/09593985.2021.1983907. Online ahead of print.

ABSTRACT

PURPOSE: Individuals with a diagnosis of primary immunodeficiency disease (PID) have poorer health-related quality of life (HRQoL) compared with healthy individuals. Regular moderate exercise enhances immune function and wellbeing. Whether exercise at recommended levels for the general population is tolerated by individuals diagnosed with PID, without adverse effects, is unknown and warrants investigation.

METHODS: A prospective randomized preliminary pilot investigation with individuals diagnosed with PID was undertaken; participants were assigned to either an exercise (n = 18) or control group (n = 16). The exercise group completed an eight-week, semi-customized, home-based, moderate intensity exercise program, while the control group engaged in routine activities. Participants completed recall surveys assessing infection rates and non-routine medical care over 8 weeks prior to the eight-week intervention.

RESULTS: Given recruitment issues, the study was underpowered. Thus, as expected, no difference between groups was observed.

CONCLUSION: This preliminary pilot investigation provides the foundation for a large scale, appropriately powered, randomized controlled trial to investigate the effect of moderate exercise on infection rates and non-routine medical care for individuals with PID. Recommendations are made to strengthen the methodology of future investigations on the effects of exercise on the immune function and quality of life for individuals diagnosed with PID.

PMID:34587873 | DOI:10.1080/09593985.2021.1983907

JMIR Res Protoc. 2021 Sep 8. doi: 10.2196/32635. Online ahead of print.

ABSTRACT

BACKGROUND: Primary immunodeficiencies are a set of heterogeneous chronic disorders characterized by immune dysfunction. They are diagnostically challenging because of their clinical heterogeneity, knowledge gaps among primary care physicians, and continuing shortages of clinically trained immunologists. As a result, patients with undiagnosed primary immunodeficiencies are at increased risk for recurrent infections, cancers, and autoimmune diseases.

OBJECTIVE: This article outlines a quality improvement protocol to develop and implement a clinical decision support tool that helps reduce delays in diagnosing primary immunodeficiencies.

METHODS: We will develop and implement a clinical decision support tool for the identification of underlying primary immunodeficiencies among patients who receive primary care through a health care provider at the University of Iowa Hospitals and Clinics. The clinical decision support tool will function through an algorithm that is based on the Immune Deficiency Foundation’s 10 Warning Signs for Primary Immunodeficiency. Through the course of a year, we will use Lean Six Sigma principles and the DMAIC (Define-Measure-Analyze-Improve-Control) Framework to guide the project. The primary measure is the number of newly diagnosed primary immunodeficiency patients per month. Secondary measures include: (1) the number of new patients identified by the CDS at high risk for PI, (2) the number of new PI cases in which IVIG or rotating antibiotics are started, (3) the cost of evaluation of each patient identified by CDS tool at high risk for PIs, (4) the number of new consults not diagnosed with a PI, and (5) patient satisfaction with the process of referral to Immunology Clinic.

RESULTS: This study was determined to be non-human subjects research by the Institutional Review Board at the University of Iowa. Data collection will begin in August 2021.

CONCLUSIONS: The development and implementation of a clinical decision support tool is a promising approach to identifying patients with underlying primary immunodeficiency. This protocol assesses whether such an approach will be able to achieve its objective of reducing diagnostic delays. The disciplined approach, using Lean Six Sigma and the Define-Measure-Analyze-Improve-Control framework, will guide the implementation to maximize opportunities for success.

PMID:34587114 | DOI:10.2196/32635

J Clin Immunol. 2021 Sep 29. doi: 10.1007/s10875-021-01103-6. Online ahead of print.

ABSTRACT

X-linked inhibitor of apoptosis (XIAP) deficiency is an inherited primary immunodeficiency characterized by chronic inflammasome overactivity and associated with hemophagocytic lymphohistiocytosis (HLH) and inflammatory bowel disease (IBD). Allogeneic hematopoietic cell transplantation (HCT) with fully myeloablative conditioning may be curative but has been associated with poor outcomes. Reports of reduced-intensity conditioning (RIC) and reduced-toxicity conditioning (RTC) regimens suggest these approaches are well tolerated, but outcomes are not well established. Retrospective data were collected from an international cohort of 40 patients with XIAP deficiency who underwent HCT with RIC or RTC. Thirty-three (83%) patients had a history of HLH, and thirteen (33%) patients had IBD. Median age at HCT was 6.5 years. Grafts were from HLA-matched (n = 30, 75%) and HLA-mismatched (n = 10, 25%) donors. There were no cases of primary graft failure. Two (5%) patients experienced secondary graft failure, and three (8%) patients ultimately received a second HCT. Nine (23%) patients developed grade II-IV acute GVHD, and 3 (8%) developed extensive chronic GVHD. The estimated 2-year overall and event-free survival rates were 74% (CI 55-86%) and 64% (CI 46-77%), respectively. Recipient and donor HLA mismatch and grade II-IV acute GVHD were negatively associated with survival on multivariate analysis with hazard ratios of 5.8 (CI 1.5-23.3, p = 0.01) and 8.2 (CI 2.1-32.7, p < 0.01), respectively. These data suggest that XIAP patients tolerate RIC and RTC with survival rates similar to HCT of other genetic HLH disorders. Every effort should be made to prevent acute GVHD in XIAP-deficient patients who undergo allogeneic HCT.

PMID:34586554 | DOI:10.1007/s10875-021-01103-6

North Clin Istanb. 2021 Aug 20;8(4):405-413. doi: 10.14744/nci.2020.43420. eCollection 2021.

ABSTRACT

The normal neonate’s immune system is anatomically completed but antigenically inexperienced and shows somewhat decreased role of a number of immunological pathways. Aside from anatomic characteristics (e.g., thin skin and mucosal barriers) of newborn, weakened pro-inflammatory and T-helper cell type 1 cytokine release and lessened cell-mediated immunity predispose the neonate more susceptible to all types of infections. Furthermore, many types of primary immunodeficiency diseases (PIDs) that present in neonatal period are potentially life threatening. However, most of the newborns stand this period without sickness due to complete innate immunity with other adaptive immune system mechanisms and transferred maternal immunoglobulin G. Besides unique immunity of the preterm and normal newborns; risk factors, clinical features, and laboratory evaluation of most common PIDs in newborn are told in this article. The range of PIDs is growing, and the diagnosis and management of these disorders continues to increase in complexity. The most common PID types of the newborn including antibody deficiencies, cellular/combined immunodeficiencies, phagocytic diseases, complement deficiencies, and innate immune system and other disorders are briefly mentioned here as well.

PMID:34585079 | PMC:PMC8430363 | DOI:10.14744/nci.2020.43420

Proc Natl Acad Sci U S A. 2021 Oct 5;118(40):e2107968118. doi: 10.1073/pnas.2107968118.

ABSTRACT

Cytidine triphosphate synthase 1 (CTPS1) is necessary for an effective immune response, as revealed by severe immunodeficiency in CTPS1-deficient individuals [E. Martin et al], [Nature] [510], [288-292] ([2014]). CTPS1 expression is up-regulated in activated lymphocytes to expand CTP pools [E. Martin et al], [Nature] [510], [288-292] ([2014]), satisfying increased demand for nucleic acid and lipid synthesis [L. D. Fairbanks, M. Bofill, K. Ruckemann, H. A. Simmonds], [J. Biol. Chem. ] [270], [29682-29689] ([1995]). Demand for CTP in other tissues is met by the CTPS2 isoform and nucleoside salvage pathways [E. Martin et al], [Nature] [510], [288-292] ([2014]). Selective inhibition of the proliferative CTPS1 isoform is therefore desirable in the treatment of immune disorders and lymphocyte cancers, but little is known about differences in regulation of the isoforms or mechanisms of known inhibitors. We show that CTP regulates both isoforms by binding in two sites that clash with substrates. CTPS1 is less sensitive to CTP feedback inhibition, consistent with its role in increasing CTP levels in proliferation. We also characterize recently reported small-molecule inhibitors, both CTPS1 selective and nonselective. Cryo-electron microscopy (cryo-EM) structures reveal these inhibitors mimic CTP binding in one inhibitory site, where a single amino acid substitution explains selectivity for CTPS1. The inhibitors bind to CTPS assembled into large-scale filaments, which for CTPS1 normally represents a hyperactive form of the enzyme [E. M. Lynch et al], [Nat. Struct. Mol. Biol.] [24], [507-514] ([2017]). This highlights the utility of cryo-EM in drug discovery, particularly for cases in which targets form large multimeric assemblies not amenable to structure determination by other techniques. Both inhibitors also inhibit the proliferation of human primary T cells. The mechanisms of selective inhibition of CTPS1 lay the foundation for the design of immunosuppressive therapies.

PMID:34583994 | DOI:10.1073/pnas.2107968118

Curr Opin Allergy Clin Immunol. 2021 Sep 27. doi: 10.1097/ACI.0000000000000789. Online ahead of print.

ABSTRACT

PURPOSE OF REVIEW: In the general population, the risk of severe COVID-19 is associated with old age, male sex, hypertension, obesity and chronic diseases. Chronic lung diseases are listed as additional risk factors for hospitalization and ICU admission. The purpose of this review is to define whether chronic lung diseases, such as bronchiectasis and interstitial diseases, represent a risk for a severe SARS-CoV-2 infection in patients affected by common variable immunodeficiency (CVID), the most common symptomatic primary antibody defect.

RECENT FINDINGS: CVID patients with SARS-CoV-2 infection have been reported since the beginning of the pandemic with a wide range of clinical presentations ranging from asymptomatic to mild/moderate and severe COVID-19. The meta-analysis of 88 CVID cases described in large cohorts and case reports demonstrated that CVID patients with chronic lung involvement have an increased risk for severe COVID-19 in comparison to CVID without lung diseases (50 vs. 28%, relative risk 1.75, 95% confidence interval 1.04–2.92, P = 0.043). Differently from the general population, age and metabolic comorbidities did not represent a risk factor for severe course in this patient’s population.

SUMMARY: Underlying chronic lung diseases but not age represent a risk factor for severe COVID-19 in CVID. Prompt therapeutic intervention should be adopted in SARS-CoV-2 positive CVID patients with chronic lung diseases independently of their age.

PMID:34580250 | DOI:10.1097/ACI.0000000000000789

Cancers (Basel). 2021 Sep 8;13(18):4527. doi: 10.3390/cancers13184527.

ABSTRACT

Epstein-Barr virus (EBV) is a common pathogen infecting people primarily early in life. The virus has the ability to persist throughout a person’s life, usually in B lymphocytes. Conditions of immunodeficiency as well as the introduction of immunosuppressive therapies and the advent of transplant technologies has brought immunodeficiency-associated lymphoproliferative disorders into view, which are often driven by EBV. The group of EBV-associated lymphoproliferative disorders includes different entities, with distinct biological features, ranging from indolent disorders, which may even spontaneously regress, to aggressive lymphomas requiring prompt and adequate treatment. These disorders are often diagnostically challenging due to their overlapping morphology and immunophenotype. Both nodal and extra-nodal sites, including the gastrointestinal tract, may be involved. This review, divided in three parts, summarizes the clinical, pathological, molecular features and treatment strategies of EBV-related lymphoproliferative disorders occurring in the gastrointestinal tract and critically analyzes the major issues in the differential diagnosis. In this part of the review, we discuss plasmablastic lymphoma, extra-cavitary primary effusion lymphoma and Burkitt lymphoma.

PMID:34572754 | DOI:10.3390/cancers13184527

Pediatr Allergy Immunol. 2021 Sep 27. doi: 10.1111/pai.13671. Online ahead of print.

ABSTRACT

BACKGROUND: TYK2 deficiency is a rare Primary immunodeficiency disease caused by loss of function mutations of TYK2 gene, which is initially proposed as a subset of Hyper IgE syndrome (HIES). However, accumulating evidence suggest TYK2 deficient patients do not necessarily present with HIES characteristics, indicating a vacuum of knowledge on the exact roles of TYK2 in human immune system.

METHOD: Pathogenic effects of patients were confirmed by qRT-PCR, western blot and protein stability assays. The responses to cytokines including IFN-α/β/γ, IL-6, IL-10, IL12 and IL-23 of peripheral blood mononuclear cells (PBMCs) from these patients were detected by western blot, qRT-PCR and flow cytometry. The differentiation of T and B cells were detected by flow cytometry.

RESULTS: We described five more TYK2 deficient cases presenting with or without hyper IgE levels, atopy and distinct pathogen infection profile, which are caused by novel TYK2 mutations. These mutations were all found by high throughout sequencing and confirmed by Sanger sequencing. The patients showed heterogenous responses to various cytokine treatments, including IFN- α/β/γ, IL-6, IL-10, IL12 and IL-23. The homeostasis of lymphocytes is also disrupted.

CONCLUSION: Based on our findings, we propose that TYK2 works as a multi-tasker in orchestrating various cytokines signaling pathways, differentially combined defects of which account for the expressed clinical manifestations.

PMID:34569645 | DOI:10.1111/pai.13671

J Am Coll Emerg Physicians Open. 2021 Sep 17;2(5):e12553. doi: 10.1002/emp2.12553. eCollection 2021 Oct.

ABSTRACT

X-linked agammaglobulinemia (XLA) is a primary immunodeficiency caused by mutations in the gene for Bruton’s tyrosine kinase (Btk), with affected males most commonly presenting with recurrent bacterial infections during the first few years of life. Here we present a 17-month-old male with a chief complaint of worsening rash and fever, whose history of streptococcal pneumonia meningitis at 5 months of age prompted suspicion for an underlying immunodeficiency and subsequent diagnosis of XLA. Bacterial meningitis is a rare initial presentation of XLA, and therefore physicians may easily overlook any underlying immunodeficiency. Prompt workup for immunodeficiency should be initiated in any vaccinated patient with a history of pneumococcal meningitis outside of the newborn period. Further discussion surrounding the various presentations of XLA, their related clinical manifestations and laboratory findings, and the importance of thorough chart review may encourage earlier diagnosis and initiation of treatment of this disease.

PMID:34568871 | PMC:PMC8448482 | DOI:10.1002/emp2.12553

Front Immunol. 2021 Sep 9;12:704261. doi: 10.3389/fimmu.2021.704261. eCollection 2021.

ABSTRACT

BACKGROUND: Interstitial lymphocytic lung disease (ILLD), a recently recognized complication of primary immunodeficiencies (PID), is caused by immune dysregulation, abnormal bronchus-associated lymphoid tissue (BALT) hyperplasia, with subsequent progressive loss of pulmonary function. Various modes of standard immunosuppressive therapy for ILLD have been shown as only partially effective.

OBJECTIVES: To retrospectively evaluate the safety and efficacy of abatacept or rituximab in treatment of ILLD in children with PID.

METHODS: 29 children (median age 11 years) with various forms of PID received one of the two therapy regimens predominantly based on the lesions’ immunohistopathology: children with prevalent B-cell lung infiltration received rituximab (n = 16), and those with predominantly T-cell infiltration received abatacept (n = 17). Clinical and radiological symptoms were assessed using a severity scale developed for the study.

RESULTS: The targeted therapy with abatacept (A) or rituximab (R) enabled long-term control of clinical (A 3.4 ± 1.3 vs. 0.6 ± 0.1; R 2.8 ± 1 vs. 0.7 ± 0.05, p < 0.01) and radiological (A 18.4 ± 3.1 vs. 6.0 ± 2.0; R 30 ± 7.1 vs. 10 ± 1.7, p < 0.01) symptoms of ILLD in both groups and significantly improved patients' quality of life, as measured by the total scale (TS) score of 57 ± 2.1 in treatment recipients vs. 31.2 ± 1.9 before therapy (p < 0.01).

CONCLUSIONS: ILLD histopathology should be considered when selecting treatment. Abatacept and rituximab are effective and safe in differential treatment of ILLD in children.

PMID:34566961 | PMC:PMC8458825 | DOI:10.3389/fimmu.2021.704261