Manish Butte

Home-based subcutaneous immunoglobulin therapy vs hospital-based intravenous immunoglobulin therapy: A prospective economic analysis.

Ann Allergy Asthma Immunol. 2018 Feb;120(2):195-199

Authors: Fu LW, Song C, Isaranuwatchai W, Betschel S

Abstract
BACKGROUND: Home-based subcutaneous immunoglobulin (SCIg) administration used for immunoglobulin replacement therapy for patients with primary immunodeficiency has been demonstrated to have benefits compared with hospital-based intravenous immunoglobulin (IVIg) therapy.
OBJECTIVE: To estimate the cost savings associated with treating eligible patients with primary immunodeficiency with home-based SCIg compared with hospital-based IVIg in a prospective study.
METHODS: This study was a 12-month prospective observational study that collected information from patient charts, directly from the nurse for time spent with patients and materials used, and directly from the physicians for billing. Data were collected on case report forms at each follow-up. Data were entered in a web-based REDCap database and statistical comparisons were performed.
RESULTS: The average hospital (including hospital personnel such as nurses) and physician costs were significantly lower in the SCIg group ($1,836 and $84, respectively) than in the IVIg group ($4,187 and $744, respectively), which supported the findings in the number of hospital and physician visits in each group. The total cost was reported from the hospital’s (only hospital-related costs) and the health system’s (hospital- and physician-related costs) perspectives. For the 2 perspectives, the SCIg group reported significantly lower average total costs than the IVIg group.
CONCLUSION: This is the first prospective analysis of the cost savings associated with home-based SCIG therapy compared with hospital-based IVIG therapy. These findings could help justify provision of home-based therapy training to suitable patients to lower health care costs or improve the capacity of care.

PMID: 29413344 [PubMed – in process]

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New Human Combined Immunodeficiency Due to IRF4 Deficiency Inherited by Uniparental Isodisomy.

J Allergy Clin Immunol. 2018 Feb 02;:

Authors: Bravo García-Morato M, Aracil Santos FJ, Briones AC, Blázquez Moreno A, Del Pozo Maté Á, Domínguez-Soto Á, Beato Merino MJ, Del Pino Molina L, Torres Canizales J, Marin AV, Vallespín García E, Feito Rodríguez M, Plaza López Sabando D, Jiménez-Reinoso A, Mozo Del Castillo Y, Sanz Santaeufemia FJ, de Lucas-Laguna R, Cárdenas P, Casamayor Polo L, Coronel Díaz M, Valés-Gómez M, Roldán Santiago E, Ferreira Cerdán A, Nevado Blanco J, Corbí ÁL, Reyburn HT, Regueiro JR, López-Granados E, Rodríguez Pena R

Abstract
BACKGROUND: Interferon regulatory factor 4 (IRF4) is a fundamental transcription factor in adaptive and innate immunity, due to its key role in the differentiation and functional specialization of lymphoid and myeloid lineage cells. In mouse models, IRF4 participates in bone marrow central tolerance, naïve B cell activation, germinal centre formation, plasma cell differentiation, immunoglobulin secretion, T helper subset differentiation, macrophage polarization, and dendritic cell differentiation, among other processes.
OBJECTIVE: To describe the first case of autosomal recessive human IRF4 deficiency.
METHODS: Clinical, histological, immunophenotypic and genotypic features of a patient with an autosomal recessive complete IRF4 deficiency are described.
RESULTS: We report the first case of autosomal recessive complete IRF4 deficiency in a 5-month-old Spanish girl caused by an uncommon mechanism for monogenic diseases, a maternal isodisomy of chromosome 6. The girl was homozygous for a maternal splicing mutation that abolished IRF4 expression and exhibited severe immunological as well as non-immunological abnormalities. Major clinical manifestations were severe dermatitis, gastro-intestinal and respiratory infections, failure to thrive, fever of unknown origin, hyperthyrotropinaemia, and severe fast hypoglycaemia. The immunological findings recapitulate many of the features observed in mouse models, including combined immunodeficiency with reduced total memory B and T cells, alteration of the κ/λ light chain ratio in immature B cells, absence of germinal centres in lymph nodes, absence of plasma cells and agammaglobulinaemia. Macrophage and T helper cell differentiation were also impaired. The patient died at 20 months of age of acute multiorgan failure after haematopoietic stem cell transplant.
CONCLUSIONS: This case demonstrates the relevance of IRF4 in the human immune system previously only inferred from mouse and cell models and expands our knowledge of the complexity of genetic mechanisms that lead to the appearance of primary immunodeficiencies.

PMID: 29408330 [PubMed – as supplied by publisher]

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Precision medicine in the treatment of primary immunodeficiency diseases.

Curr Opin Allergy Clin Immunol. 2018 Feb 05;:

Authors: Leiding JW, Ballow M

Abstract
PURPOSE OF THE REVIEW: Since the 1990s with the advances in molecular biology, a number of genetic defects have been described. The International Union of Immunological Sciences has recently updated the classification of genetic defects associated with primary immune deficiencies that now number 354. With the ever-expanding list of new monogenic disorders and a better understanding of the immunobiology and function of these defective genes, new therapies have emerged particularly aimed at the autoimmune and inflammatory conditions that plague these patients.
RECENT FINDINGS: Immune deficiencies associated with gain-of-function (GOF) mutations are a potential category for targeted therapies to control the GOF activities of the mutated gene. In addition to the increased susceptibility to infections these patients have autoimmune and inflammatory diseases that are difficult to control with conventional therapies. The dysregulated immune functions of the activated phospholipase-3-kinase δ syndrome, cytotoxic T lymphocyte-associated antigen-4 haploinsufficiency, lipopolysaccharide-responsive beige-like anchor deficiency, the GOF mutations of signal transducer and activator of transcription 1 and 3 immune deficiencies will be reviewed. The targeted therapies for each of these immune deficiencies using small molecule kinase inhibitors and fusion protein biologic modifiers will be described.
SUMMARY: In this review, we explore the recent advances in precision medicine treatment of several primary immunodeficiency syndromes in which immune dysregulation is a key feature. Understanding the immunobiology associated with these GOF mutations has led to the use of biologic therapies to better control the associated autoimmune and inflammatory manifestations.

PMID: 29406361 [PubMed – as supplied by publisher]

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Comprehensive review of autoantibodies in patients with hyper-IgM syndrome.

Cell Mol Immunol. 2018 Feb 05;:

Authors: Barbouche MR, Chen Q, Carbone M, Ben-Mustapha I, Shums Z, Trifa M, Malinverno F, Bernuzzi F, Zhang H, Agrebi N, Norman GL, Chang C, Gershwin ME, Invernizzi P

Abstract
Hyper-immunoglobulin M syndrome is an X-linked primary immunodeficiency disease caused by mutations in the CD40 ligand gene. The CD40 ligand has been recently highlighted as playing a key role in the pathogenesis of primary biliary cholangitis. In the present study, we assessed an extensive set of serum autoantibodies in a series of well-defined patients with hyper-immunoglobulin M syndrome. Serum, liver-related and liver-not-related autoantibodies IgG, IgM and IgA were tested by ELISA and standard indirect immunofluorescence in HEp-2 cells in 13 Tunisian patients (8 males and 5 females, aged 1-12 years) with hyper-immunoglobulin M syndrome during 1995-2012 and, as controls, 21 age- and gender-matched blood donors. The level of IgM antibody against MIT3 was significantly higher in patients than in controls (35.8 vs 10.7, P=0.002). Half of the hyperimmunoglobulin M syndrome patients were found to be anti-MIT3 IgM positive vs none of the controls (P<0.0001). Twenty-three percent of patients were found to be anti-sp100 antibody positive vs only 0.05% of controls. By immunofluorescence, 92.3% of patients were MIT3 IgM positive vs none of the controls. In conclusion, the IgM class of anti-MIT3 antibodies was shown to be present by both ELISA and immunofluorescence in most of the patients with hyper-immunoglobulin M syndrome. The presence of the hallmark of primary biliary cholangitis, a disease where the CD40 ligand is a key player, in an immunodeficiency disease caused by mutations in the CD40 ligand gene is very intriguing and opens new scenarios in understanding the immune pathogenesis of primary biliary cholangitis.Cellular and Molecular Immunology advance online publication, 5 February 2018; doi:10.1038/cmi.2017.140.

PMID: 29400703 [PubMed – as supplied by publisher]

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Sensorineural Hearing Loss in Selective Immunglobulin A Deficiency.

Turk Arch Otorhinolaryngol. 2017 Mar;55(1):31-33

Authors: Eşki E, Usta BE, Asilsoy S, Yılmaz İ

Abstract
Objective: To assess hearing functions in pediatric patients with selective immunoglobulin A (IgA) deficiency (SIGAD).
Methods: Pure-tone audiometry, acoustic impedance, otoacoustic emission, and brainstem audiometric measurements were taken during a non-infectious period in 28 patients with SIGAD and 28 healthy children with normal otoscopic examination. The results of the hearing tests were compared between the two groups.
Results: Two male patients and one female patient in the SIGAD group were found to have sensorineural hearing loss (SNHL). However, a comparison of the average pure tone cut-off values at 0.5, 1, 2, and 4 kHz did not reveal any statistically significant difference between the groups (p>0.05).
Conclusion: Pediatric patients with SIGAD may exhibit SNHL at certain frequencies and require follow-up for the potential development of hearing loss.

PMID: 29392049 [PubMed]

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Identification of IL2RG and CYBB mutations in two Chinese primary immunodeficiency patients by whole-exome sequencing.

Immunol Invest. 2018 Feb 01;:1-8

Authors: Xu S, Li Q, Wu J, Chen G, Zhu B, Gu W

Abstract
BACKGROUND: Primary immunodeficiency diseases are a group of genetic disorders that lead to increased propensity to a variety of infections, sometimes with fatal outcomes.
METHOD: In this study, whole-exome sequencing (WES) was used to identify mutations in two patients suspected of having primary immunodeficiency. Sanger sequencing was used to confirm the results in the patients and their family.
RESULT: One patient was diagnosed as X-linked severe combined immunodeficiency (X-SCID) and another patient as X-linked chronic granulomatous disease (X-CGD) by WES. Sequencing analysis of IL2RG gene revealed a novel mutation (c.794T>A, p.I265N) and CYBB gene revealed a missense mutation (c.935T>A, p.M312K).
DISCUSSION AND CONCLUSION: This study identifies one novel mutation in the IL2RG gene and another, previously described mutation in the CYBB genes. It is the first report establishing a diagnosis of X-SCID and X-CGD using WES in Chinese patients.

PMID: 29388853 [PubMed – as supplied by publisher]

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Molecular changes associated with increased TNF-α-induced apoptotis in naïve (TN) and central memory (TCM) CD8+ T cells in aged humans.

Immun Ageing. 2018;15:2

Authors: Gupta S, Su H, Agrawal S, Gollapudi S

Abstract
Background: Progressive T cell decline in aged humans is associated with a deficiency of naïve (TN) and central memory (TCM) T cells. We have previously reported increased Tumor necrosis factor-α (TNF-α)-induced apoptosis in TN and TCM T cells in aged humans; however, the molecular basis of increased apoptosis remains to be defined. Since expression of TNF receptors (TNFRs) was reported to be comparable in young and aged, we investigated signaling events downstream of TNFRs to understand the molecular basis of increased TNF-α-induced apoptosis in aged TN and TCM CD8+ cells.
Results: The expression of TRAF-2 and RIP, phosphorylation of JNK, IKKα/β, and IκBα, and activation of NF-κB activation were significantly decreased in TN and TCM CD8+ cells from aged subjects as compared to young controls. Furthermore, expression of A20, Bcl-xL, cIAP1, and FLIP-L and FLIP-S was significantly decreased in TN and TCM CD8+ cells from aged subjects.
Conclusions: These data demonstrate that an impaired expression/function of molecules downstream TNFR signaling pathway that confer survival signals contribute to increased apoptosis of TN and TCM CD8+ cells in aged humans.

PMID: 29387134 [PubMed]

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Epstein-Barr Virus Susceptibility in Activated PI3Kδ Syndrome (APDS) Immunodeficiency.

Front Immunol. 2017;8:2005

Authors: Carpier JM, Lucas CL

Abstract
Activated PI3Kδ Syndrome (APDS) is an inherited immune disorder caused by heterozygous, gain-of-function mutations in the genes encoding the phosphoinositide 3-kinase delta (PI3Kδ) subunits p110δ or p85δ. This recently described primary immunodeficiency disease (PID) is characterized by recurrent sinopulmonary infections, lymphoproliferation, and susceptibility to herpesviruses, with Epstein-Barr virus (EBV) infection being most notable. A broad range of PIDs having disparate, molecularly defined genetic etiology can cause susceptibility to EBV, lymphoproliferative disease, and lymphoma. Historically, PID patients with loss-of-function mutations causing defective cell-mediated cytotoxicity or antigen receptor signaling were found to be highly susceptible to pathological EBV infection. By contrast, the gain of function in PI3K signaling observed in APDS patients paradoxically renders these patients susceptible to EBV, though the underlying mechanisms are incompletely understood. At a cellular level, APDS patients exhibit deranged B lymphocyte development and defects in class switch recombination, which generally lead to defective immunoglobulin production. Moreover, APDS patients also demonstrate an abnormal skewing of T cells toward terminal effectors with short telomeres and senescence markers. Here, we review APDS with a particular focus on how the altered lymphocyte biology in these patients may confer EBV susceptibility.

PMID: 29387064 [PubMed]

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IL-6 receptor blockade corrects defects of XIAP-deficient regulatory T cells.

Nat Commun. 2018 Jan 31;9(1):463

Authors: Hsieh WC, Hsu TS, Chang YJ, Lai MZ

Abstract
X-linked lymphoproliferative syndrome type-2 (XLP-2) is a primary immunodeficiency disease attributed to XIAP mutation and is triggered by infection. Here, we show that mouse Xiap-/- regulatory T (Treg) cells and human XIAP-deficient Treg cells are defective in suppressive function. The Xiap-/- Treg cell defect is linked partly to decreased SOCS1 expression. XIAP binds SOCS1 and promotes SOCS1 stabilization. Foxp3 stability is reduced in Xiap-/- Treg cells. In addition, Xiap-/- Treg cells are prone to IFN-γ secretion. Transfer of wild-type Treg cells partly rescues infection-induced inflammation in Xiap-/- mice. Notably, inflammation-induced reprogramming of Xiap-/- Treg cells can be prevented by blockade of the IL-6 receptor (IL-6R), and a combination of anti-IL-6R and Xiap-/- Treg cells confers survival to inflammatory infection in Xiap-/- mice. Our results suggest that XLP-2 can be corrected by combination treatment with autologous iTreg (induced Treg) cells and anti-IL-6R antibody, bypassing the necessity to transduce Treg cells with XIAP.

PMID: 29386580 [PubMed – in process]

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