Research

Cytomegalovirus Colitis in Primary Hypogammaglobulinemia With Normal CD4+ T Cells: Deficiency of CMV-Specific CD8+ T Cells.

Front Immunol. 2019;10:399

Authors: Agrawal S, Khokhar A, Gupta S

Abstract
CMV colitis has been reported in immunocompromized patients with severe deficiency of CD4+ T cells and T cell functions. In this study we present an extensive immunological analysis in a patient with primary hypogammaglobulinemia and CMV colitis who had normal numbers of CD3+T, CD4+T and CD8+T cells, and normal T cell proliferative responses to mitogens and recall antigens. Naïve (TN), central (TCM), and effector (TEM) memory subsets of CD4+ and CD8+ T cells, Granzyme+ and Perforin+ CD8+ T cells, PD-1+ T cells, CD4 Treg, CD8 Treg, and CMV tetramer specific CD8+ T cells were analyzed with specific antibodies and isotype controls using multicolor flow cytometry. CD8 TEM, Granzyme+ and Perforin+, and PD-1 CD8+T cells were increased, whereas CD8 TN and CD8 TCM cells were decreased in the patient as compared to controls. CMV tetramer+ CD8+ T cells were decreased in the patient. These data demonstrate that a deficiency of CMV-specific CD8+ T cells even in the presence of normal CD4+ T cell numbers and normal T cell functions may predispose patients with primary hypogammaglobulinemia to CMV colitis.

PMID: 30899266 [PubMed – in process]

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Disseminated and Congenital Toxoplasmosis in a Mother and Child With Activated PI3-Kinase δ Syndrome Type 2 (APDS2): Case Report and a Literature Review of Toxoplasma Infections in Primary Immunodeficiencies.

Front Immunol. 2019;10:77

Authors: Karanovic D, Michelow IC, Hayward AR, DeRavin SS, Delmonte OM, Grigg ME, Dobbs AK, Niemela JE, Stoddard J, Alhinai Z, Rybak N, Hernandez N, Pittaluga S, Rosenzweig SD, Uzel G, Notarangelo LD

Abstract
Phosphoinositide 3-kinase (PI3K) plays an integral role in lymphocyte function. Mutations in PIK3CD and PIK3R1, encoding the PI3K p110δ and p85α subunits, respectively, cause increased PI3K activity and result in immunodeficiency with immune dysregulation. We describe here the first cases of disseminated and congenital toxoplasmosis in a mother and child who share a pathogenic mutation in PIK3R1 and review the mechanisms underlying susceptibility to severe Toxoplasma gondii infection in activated PI3Kδ syndrome (APDS) and in other forms of primary immunodeficiency.

PMID: 30891027 [PubMed – in process]

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Challenges in investigating patients with isolated decreased serum IgM – The SIMcal study.

Scand J Immunol. 2019 Mar 18;:e12763

Authors: Janssen LMA, van Hout RWNM, de Vries E, SIMcal consortium

Abstract
The clinical consequences of isolated decreased serum immunoglobulin (Ig)M are not sufficiently known. Therefore, it is difficult to determine the clinical policy following such a finding. Only few reported IgM-deficient patients fulfil the European Society for Immunodeficiencies (ESID) diagnostic criteria for selective IgM deficiency (true sIgMdef), or their diagnosis is uncertain due to insufficient laboratory data (possible sIgMdef). Decreased serum IgM is often incidentally found in asymptomatic adults. The objective of our study was to further characterize true sIgMdef and to compare the European data collected through the ESID Registry community (tertiary centers) to our previously published Dutch cohort (secondary center). Fifteen centers (12 countries) participated with 98 patients. Patients were excluded if serum IgM was only determined once (n=14), had normalized (n=8), or if they also had other immunological abnormalities (n=15). Ten patients (5 adults) completely fulfilled the ESID criteria for true sIgMdef. Age-matched cut-off values varied widely between centers; when using the ESID diagnostic protocol reference values, only 6 patients (5 adults) had true sIgMdef. Because of these small numbers, further analyses were performed in patients with true or possible sIgMdef (13 adults, 48 children). Respiratory infections were commonly reported at presentation (adults 54%, children 60%). Symptomatic adults had lower serum IgM levels (mean 0.27g/l, 95%CI 0.22-0.31) than those without symptoms (mean 0.33g/l, 95%CI 0.30-0.36; p=0.02). To be able to explore the clinical consequences of true sIgMdef, we should fully analyse and accurately describe those patients in whom a decreased serum IgM is found. This article is protected by copyright. All rights reserved.

PMID: 30887554 [PubMed – as supplied by publisher]

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[Frequent infections – is it immunodeficiency?]

MMW Fortschr Med. 2019 Mar;161(5):38-40

Authors: Glück T

PMID: 30887330 [PubMed – in process]

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The First Purine Nucleoside Phosphorylase Deficiency Patient Resembling IgA Deficiency and a Review of the Literature.

Immunol Invest. 2019 Mar 19;:1-21

Authors: Fekrvand S, Yazdani R, Abolhassani H, Ghaffari J, Aghamohammadi A

Abstract
Purine nucleoside phosphorylase (PNP) deficiency is a rare autosomal recessive primary immunodeficiency disorder characterized by decreased numbers of T-cells, variable B-cell abnormalities, decreased amount of serum uric acid and PNP enzyme activity. The affected patients usually present with recurrent infections, neurological dysfunction and autoimmune phenomena. In this study, whole-exome sequencing was used to detect mutation in the case suspected of having primary immunodeficiency. We found a homozygous mutation in PNP gene in a girl who is the third case from the national Iranian registry. She had combined immunodeficiency, autoimmune hemolytic anemia and a history of recurrent infections. She developed no neurological dysfunction. She died at the age of 11 after a severe chicken pox infection. PNP deficiency should be considered in late-onset children with recurrent infections, autoimmune disorders without typical neurologic impairment.

PMID: 30885031 [PubMed – as supplied by publisher]

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Cost-utility analysis comparing hospital-based intravenous immunoglobulin with home-based subcutaneous immunoglobulin in patients with secondary immunodeficiency.

Vox Sang. 2019 Mar 18;:

Authors: Windegger TM, Nghiem S, Nguyen KH, Fung YL, Scuffham PA

Abstract
BACKGROUND AND OBJECTIVE: Immunoglobulin replacement therapy (IRT) is often used to support patients with primary immunodeficiency disease (PID) and secondary immunodeficiency disease (SID). Home-based subcutaneous immunoglobulin (SCIg) is reported to be a cheaper and more efficient option compared to hospital-based intravenous immunoglobulin (IVIg) for PID. In contrast, there is little information on the cost-effectiveness of IRT in SID. However, patients who develop hypogammaglobulinaemia secondary to other conditions (SID) have different clinical aetiology compared to PID. This study assesses whether SCIg provides a good value-for-money treatment option in patients with secondary immunodeficiency disease (SID).
METHODS: A Markov cohort simulation model with six health states was used to compare cost-effectiveness of IVIg with SCIg from a healthcare system perspective. The costs of treatment, infection and quality-adjusted life years (QALYs) for IVIg and SCIg treatment options were modelled with a time horizon of 10 years and weekly cycles. Deterministic and probabilistic sensitivity analyses were performed around key parameters.
RESULTS: The cumulative cost for IVIg was A$151 511 and for SCIg A$144 296. The QALYs with IVIg were 3·07 and with SCIg 3·51. Based on the means, SCIg is the dominant strategy with better outcomes and at lower cost. The probabilistic sensitivity analysis shows that 88·3% of the 50 000 iterations fall below the nominated willingness to pay threshold of A$50 000 per QALY. Therefore, SCIg is a cost-effective treatment option.
CONCLUSION: For SID patients in Queensland (Australia), the home-based SCIg treatment option provides better health outcomes and cost savings.

PMID: 30883804 [PubMed – as supplied by publisher]

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Lymphopenia and Severe Combined Immunodeficiency (SCID) – Think Before You Ink.

Indian J Pediatr. 2019 Mar 16;:

Authors: Aluri J, Gupta MR, Dalvi A, Mhatre S, Kulkarni M, Desai M, Shah NK, Madkaikar MR

Abstract
OBJECTIVES: Severe combined immunodeficiency (SCID) represents one of the most severe forms of Primary immunodeficiency (PID) disorders, characterized by T cell lymphopenia (TCL) and lack of cellular and humoral immune responses. However, not all patients with low T cell lymphocyte counts may have an abnormal T cell immunity and the observed TCL may be a temporary suppression resulting from transient lymphopenia secondary to severe infections. In such cases, it is necessary to estimate the severity of the observed TCL by assessing thymic capabilities.
METHODS: In this study, patients clinically suspected of SCID were evaluated for lymphocyte subsets analysis, naïve T cells and T cell receptor excision circles (TREC).
RESULTS: Patients with transient lymphopenia had detectable TREC levels and normal naïve T cells subsets. Normalization of absolute lymphocyte counts, and T cells was seen in the patients after a short duration.
CONCLUSIONS: The authors highlight the importance of detailed immunological investigations in an infant with severe infections and lymphopenia before labeling the infant as SCID.

PMID: 30879237 [PubMed – as supplied by publisher]

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Haploidentical HSCT with post-transplant CY for primary immunodeficiencies and inherited disorders in children.

Biol Blood Marrow Transplant. 2019 Mar 12;:

Authors: Neven B, Diana JS, Castelle M, Magnani A, Rosain J, Touzot F, Moreira B, Fremond ML, Briand C, Bendavid M, Romain L, Guillaume M, Vincent M, Magrin E, Bourget P, Chatenoud L, Picard C, Fischer A, Moshous D, Blanche S

Abstract
Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative treatment for some inherited disorders, including selected primary immunodeficiencies (PIDs). In the absence of a well-matched donor, HSCT from a haploidentical family donor (HIFD) may be considered. In adult recipients, high-dose, post-transplant cyclophosphamide (PTCY) is increasingly used to mitigate the risks of graft failure and graft-versus-host disease (GVHD). However, data on PTCY in children (and especially those with inherited disorders) are scarce. We reviewed the outcomes of 27 children transplanted with an HIFD and PTCY for a PID (n= 22) or osteopetrosis (n= 5) in a single center. The median (range) age was 1.5 years (0.2-17). HSCT with PTCY was a primary procedure (n=21) or a rescue procedure after graft failure (n=6). The conditioning regimen was myeloablative in most primary HSCTs and non-myeloablative in rescue procedures. After a median follow-up of 25.6 months, 24 of the 27 patients had engrafted. Twenty-one patients are alive and have been cured of the underlying disease. The two-year overall survival rate was 77.7%. The cumulative incidences of acute GVHD grade ≥ II, chronic GVHD and autoimmune disease were 45.8%, 24.2%, and 29.6%, respectively. There were two cases of grade III acute GVHD, no extensive cGVHD. The cumulative incidence of blood viral replication and life-threatening viral events were 58% and 15.6%, respectively. There was evidence of early T cell immune reconstitution. In the absence of an HLA-identical donor, HIFD HSCT with PTCY is a viable option for patients with life-threatening inherited disorders.

PMID: 30876929 [PubMed – as supplied by publisher]

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Lentiviral Vectors for the Treatment and Prevention of Cystic Fibrosis Lung Disease.

Genes (Basel). 2019 Mar 14;10(3):

Authors: Marquez Loza LI, Yuen EC, McCray PB

Abstract
Despite the continued development of cystic fibrosis transmembrane conductance regulator (CFTR) modulator drugs for the treatment of cystic fibrosis (CF), the need for mutation agnostic treatments remains. In a sub-group of CF individuals with mutations that may not respond to modulators, such as those with nonsense mutations, CFTR gene transfer to airway epithelia offers the potential for an effective treatment. Lentiviral vectors are well-suited for this purpose because they transduce nondividing cells, and provide long-term transgene expression. Studies in primary cultures of human CF airway epithelia and CF animal models demonstrate the long-term correction of CF phenotypes and low immunogenicity using lentiviral vectors. Further development of CF gene therapy requires the investigation of optimal CFTR expression in the airways. Lentiviral vectors with improved safety features have minimized insertional mutagenesis safety concerns raised in early clinical trials for severe combined immunodeficiency using γ-retroviral vectors. Recent clinical trials using improved lentiviral vectors support the feasibility and safety of lentiviral gene therapy for monogenetic diseases. While work remains to be done before CF gene therapy reaches the bedside, recent advances in lentiviral vector development reviewed here are encouraging and suggest it could be tested in clinical studies in the near future.

PMID: 30875857 [PubMed]

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