Manish Butte

Direct and Indirect Costs of Immunoglobulin Replacement Therapy in Patients with Common Variable Immunodeficiency (CVID) and X-Linked Agammaglobulinemia (XLA) in Italy.

Clin Drug Investig. 2018 Sep 06;:

Authors: Viti R, Marcellusi A, Capone A, Matucci A, Vultaggio A, Pignata C, Spadaro G, Vacca A, Marasco C, Agostini C, Mennini FS

Abstract
BACKGROUND: In Italy, there is scarce evidence on the epidemiological and economic burden induced by primary antibody deficiencies.
OBJECTIVE: The aim of this study was to elaborate the available epidemiological and cost data in order to estimate the annual expenditure induced by the management of patients affected by the common variable immunodeficiency (CVID) and X-linked agammaglobulinemia (XLA) requiring immunoglobulin (Ig) replacement therapy.
METHODS: A probabilistic cost-of-illness model was developed to estimate the number of patients with CVID and XLA, and the economic burden associated with their therapy in terms of direct or indirect costs. A systematic literature review was carried out to reveal both epidemiological and economic data. Furthermore, a probabilistic sensitivity analysis with 5000 Monte Carlo simulations was performed.
RESULTS: The epidemiological model allowed us to estimate the number of prevalent patients affected by XLA and CVID in Italy in 2017, corresponding to 1885 (95% confidence interval [CI] 944-3145) and 133 (95% CI 115-152) patients, respectively. The estimated total expenditure for the treatment and management of patients with CVID and XLA requiring Ig replacement therapy amounts to €42.68 million (95% CI €14.38-€86.1 million).
CONCLUSIONS: This information provides a comprehensive perspective of the economic issues, and facilitates better-informed public health decision making, in the management of CVID and XLA in Italy.

PMID: 30191508 [PubMed – as supplied by publisher]

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Innovation for rare diseases and bioethical concerns: A thin thread between medical progress and suffering.

World J Clin Pediatr. 2018 Aug 30;7(3):75-82

Authors: Tommasini A, Magnolato A, Bruno I

Abstract
With the development of precision medicines based on small molecules, antibodies, RNAs and gene therapy, technological innovation is providing some exciting possibilities to treat the most severe genetic diseases. However, these treatments do not always lead to a cure for the disease, and there are several factors that may hinder their overall success. Patients living during a period of great medical change and innovation may benefit from these technological advances but may also just face failures, both in terms of frustrated hopes as well as suffering. In this article, we are telling the stories of three children with rare and severe disorders, who live in an age of significant medical changes, bearing the burden of difficult scientific and ethical choices. The first two cases that are suffering respectively from severe immunodeficiency and beta thalassemia have already been described in scientific journals, as well as in popular magazines. Although similar when considering the medical challenges, the two cases had opposite outcomes, which resulted in distinct ethical implications. The third case is a baby with spinal muscular atrophy, living at a time of continued innovation in the treatment of the disease. With these cases, we discuss the challenges of providing correct information and proper counseling to families and patients that are making the bumpy journey on the road of medical innovation.

PMID: 30191136 [PubMed]

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Limited Innovations After More Than 65 Years of Immunoglobulin Replacement Therapy: Potential of IgA- and IgM-Enriched Formulations to Prevent Bacterial Respiratory Tract Infections.

Front Immunol. 2018;9:1925

Authors: Langereis JD, van der Flier M, de Jonge MI

Abstract
Patients with primary immunoglobulin deficiency have lower immunoglobulin levels or decreased immunoglobulin function, which makes these patients more susceptible to bacterial infection. Most prevalent are the selective IgA deficiencies (~1:3,000), followed by common variable immune deficiency (~1:25,000). Agammaglobulinemia is less common (~1:400,000) and is characterized by very low or no immunoglobulin production resulting in a more severe disease phenotype. Therapy for patients with agammaglobulinemia mainly relies on prophylactic antibiotics and the use of IgG replacement therapy, which successfully reduces the frequency of invasive bacterial infections. Currently used immunoglobulin preparations contain only IgG. As a result, concurrent IgA and IgM deficiency persist in a large proportion of agammaglobulinemia patients. Especially patients with IgM deficiency remain at risk for recurrent infections at mucosal surfaces, which includes the respiratory tract. IgA and IgM have multiple functions in the protection against bacterial infections at the mucosal surface. Because of their multimeric structure, both IgA and IgM are able to agglutinate bacteria efficiently. Agglutination allows for entrapment of bacteria in mucus that increases clearance from the respiratory tract. IgA is also important for blocking bacterial adhesion by interfering with bacterial adhesion receptors. IgM in its place is very well capable of activating complement, therefore, it is thought to be important in complement-mediated protection at the mucosal surface. The purpose of this Mini Review is to highlight the latest advances regarding IgA- and IgM-enriched immunoglobulin replacement therapy. We describe the different IgA- and IgM-enriched IgG formulations, their possible modes of action and potential to protect against respiratory tract infections in patients with primary immunoglobulin deficiencies.

PMID: 30190722 [PubMed – in process]

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Chronic granulomatous skin lesions leading to a diagnosis of TAP1 deficiency syndrome.

Pediatr Dermatol. 2018 Sep 06;:

Authors: Law-Ping-Man S, Toutain F, Rieux-Laucat F, Picard C, Kammerer-Jacquet S, Magérus-Chatinet A, Dupuy A, Adamski H

Abstract
Transporter associated with antigen processing (TAP) is essential for the stabilization and surface expression of major histocompatibility complex class I molecules of all nucleated cells. TAP deficiency syndrome, also known as bare lymphocyte syndrome type I, is a rare primary immunodeficiency disorder. We report a case of TAP1 deficiency revealed by skin lesions long before the occurrence of respiratory infectious manifestations.

PMID: 30189467 [PubMed – as supplied by publisher]

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What is new in HIES? Recent insights from the interface of primary immune deficiency and atopy.

Curr Opin Allergy Clin Immunol. 2018 Sep 03;:

Authors: Ponsford MJ, Rae W, Klocperk A

Abstract
PURPOSE OF REVIEW: Understanding the pathophysiology of monogenic primary immunodeficiency (PID) with atopic presentation has pivotal implications for intervention strategies and potentially wider polygenic atopic-related traits. This review will discuss advances in gene discovery arising from monogenic defects at the interface between PID and atopy, notably the hyper-IgE syndromes.
RECENT FINDINGS: Key molecular pathways underlying development of primary atopic diseases have recently been proposed. We test this classification through reviewing novel genes reported in the last 2 years and compare insights from pathway-analysis of genome-wide association studies (GWAS) of atopic-related traits.Growing access to next-generation sequencing (NGS) has resulted in a surge in gene discovery, highlighting the utility and some pitfalls of this approach in clinical practice. The variability of presenting phenotypes reveals important gene-dosage effects. This has important implications for therapeutic strategies such as protein stabilization and modulators of JAK-STAT or TH2-cytokine signalling. We also consider the therapeutic implications raised by CARD11 deficiency, and wider applications of NGS including polygenic risk score in atopy.
SUMMARY: Disorders presenting at the interface between PID and allergy are often difficult to diagnose, with serious consequences if missed. Application of NGS has already provided critical insights to pathways enabling targeted therapeutic interventions, and potential wider translation to polygenic disorders.

PMID: 30188342 [PubMed – as supplied by publisher]

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Thymus autonomy as a prelude to leukemia.

FEBS J. 2018 Sep 05;:

Authors: Paiva RA, Ramos CV, Martins VC

Abstract
Cell competition in the thymus promotes turnover and functions as a tumor suppressor by inhibiting leukemia. Using thymus transplantation experiments, we have shown that the presence of T lymphocyte precursors, recently seeding the thymus, promotes the clearance of precursors with a longer time of thymus residency. If cell competition is impaired and no cells seed the thymus, the organ is capable of sustaining T lymphocyte production, a state termed thymus autonomy. However, we observed consistently that prolonged autonomy is permissive to the emergence of T cell acute lymphoblastic leukemia (T-ALL). This resembled the onset of T-ALL in patients treated by gene therapy for X-linked severe combined immunodeficiency (SCID-X1). Following treatment, thymus activity was established, with T lymphocyte production, although no bone marrow contribution was detected. However, some patients developed T-ALL. The favored explanation for malignant transformation was considered to be genotoxicity due to integration of the retroviral vector next to oncogenes, thereby activating them ectopically. Although plausible, we consider an alternative, mutually non-exclusive explanation: that any condition enabling prolonged thymus autonomy will promote leukemogenesis. In support of this view, two independent studies have recently shown that the efficacy of reconstitution of the bone marrow in the context of SCID-X1 dramatically influences the outcome of treatment, and that lymphoid malignancies emerge following transplantation of a small number of healthy progenitors. Here, we discuss the most recent data in light of our own studies in thymopoiesis and the conditions that trigger malignant transformation of thymocytes in various experimental and clinical settings. This article is protected by copyright. All rights reserved.

PMID: 30187694 [PubMed – as supplied by publisher]

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Primary immunodeficiency diseases in a tuberculosis endemic region: challenges and opportunities.

Genes Immun. 2018 Sep 06;:

Authors: Glanzmann B, Uren C, de Villiers N, van Coller A, Glashoff RH, Urban M, Hoal EG, Esser MM, Möller M, Kinnear CJ

Abstract
While individual primary immunodeficiency diseases (PIDs) are rare, collectively they represent a significant burden of disease. Recent estimates show that about one million people in Africa suffer from a PID. However, data from African PID registries reflect only a small percentage of the estimated prevalence. This disparity is partly due to the lack of PID awareness and the masking of PIDs by the endemic pathogens. Over three million tuberculosis (TB) cases were reported in Africa in 2016, with many of these from southern Africa. Despite concerted efforts to address this high burden of disease, the underlying genetic correlates of susceptibility to TB remain poorly understood. High penetrance mutations in immune system genes can cause PIDs that selectively predispose individuals to TB and other mycobacterial diseases. Additionally, the identification of individuals at a heightened risk of developing TB or of presenting with severe or disseminated TB due to their genetic ancestry is crucial to promote a positive treatment outcome. The screening for and identification of PID mutations in TB-endemic regions by next-generation sequencing (NGS) represents a promising approach to improve the understanding of what constitutes an effective immune response to TB, as well as the range of associated PIDs and phenotypes.

PMID: 30185814 [PubMed – as supplied by publisher]

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Effects of Financial Incentives on Saving Outcomes and Material Well-Being: Evidence From a Randomized Controlled Trial in Uganda.

J Policy Anal Manage. 2018;37(3):602-629

Authors: Wang JS, Ssewamala FM, Neilands TB, Bermudez LG, Garfinkel I, Waldfogel J, Brooks-Gunn J, You J

Abstract
The use of savings products to promote financial inclusion has increasingly become a policy priority across sub-Saharan Africa, yet little is known about how families respond to varying levels of savings incentives and whether the promotion of incentivized savings in low-resource settings may encourage households to restrict expenditures on basic needs. Using data from a randomized controlled trial in Uganda, we examine: 1) whether low-income households enrolled in an economic-empowerment intervention consisting of matched savings, workshops, and mentorship reduced spending on basic needs and 2) how varied levels of matching contributions affected household savings and consumption behavior. We compared primary school-attending AIDS-affected children (N = 1,383) randomized to a control condition with two intervention arms with differing savings-match incentives: 1:1 (Bridges) and 1:2 (Bridges PLUS). We found that: 1) 24 months post-intervention initiation, children in Bridges and Bridges PLUS were more likely to have accumulated savings than children in the control condition; 2) higher match incentives (Bridges PLUS) led to higher deposit frequency but not higher savings in the bank; 3) intervention participation did not result in material hardship; and 4) in both intervention arms, participating families were more likely to start a family business and diversify their assets.

PMID: 30122799 [PubMed – indexed for MEDLINE]

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Disorders of Humoral Immunity in Children with IgG Deficiency and Recurrent Respiratory Infections.

Adv Exp Med Biol. 2018 Sep 05;:

Authors: Pasternak G, Lewandowicz-Uszyńska A, Pentoś K

Abstract
Respiratory tract infections in children are one of the most common causes for medical consultations. When the infections are of recurring nature, they are a major reason for the diagnostics for primary immunodeficiency that is in about 65% of cases underlain by disorders of humoral immunity. This study seeks to retrospectively evaluate the history of recurrent respiratory tract infections in children with humoral disorders and the associations among deficiencies in the immune system components. We evaluated 394 children aged 3 months to 18 years. We found 49.5% (195 cases) of children with IgG deficiencies, all of whom had normal IgE levels. There were 8.4% (33 cases) of IgA deficiency, 7.4% (29 cases) of IgM insufficiency, and 4.1% (16 cases) of CD19+ cells deficiency. The elevated level of CD19+ cells was found in 27.7% (109 out of the 394 children). Immunoglobulin deficiencies often coexisted with a deficiency in another immunoglobulin class above outlined. There was an interdependence between IgA abnormality and IgG, IgG3, and IgG4 abnormalities as well as between IgM abnormality and IgG and IgG1 abnormalities. We conclude that respiratory tract infections in children are often underlain by a convergence of IgG with both IgA and IgM abnormal states. The physiopathological meaning of this convergence for the infection course and resulting functional respiratory changes remains elusive.

PMID: 30182338 [PubMed – as supplied by publisher]

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