Manish Butte

Hematopoietic stem cell transplantation for pulmonary alveolar proteinosis associated with primary immunodeficiency disease.

Int J Hematol. 2017 Nov 28;:

Authors: Tanaka-Kubota M, Shinozaki K, Miyamoto S, Yanagimachi M, Okano T, Mitsuiki N, Ueki M, Yamada M, Imai K, Takagi M, Agematsu K, Kanegane H, Morio T

Abstract
Pulmonary alveolar proteinosis (PAP) is a rare disorder that is characterized by the excessive accumulation of surfactant-like materials in the alveoli, leading to hypoxemic respiratory failure. We describe two Japanese infants with PAP associated with hypogammaglobulinemia and monocytopenia. These patients may have underlying primary immunodeficiency (PID) and were successfully treated with allogeneic hematopoietic stem cell transplantation (HSCT). This report indicates that allogeneic HSCT may provide a curative treatment for PAP associated with PID.

PMID: 29185156 [PubMed – as supplied by publisher]

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New insights in the use of immunoglobulins for the management of immune deficiency (PID) patients.

Am J Clin Exp Immunol. 2017;6(5):76-83

Authors: Krivan G, Jolles S, Granados EL, Paolantonacci P, Ouaja R, Cissé OA, Bernatowska E

Abstract
Immunoglobulin replacement therapy (IRT) is standard treatment for patients with primary immunodeficiency (PID). Because most of the patients with PID will require long life-time immunoglobulin replacement therapy, the quality of the prescribed products is of utmost importance. The IRT is generally administered either intravenously (abbreviated IVIG), or subcutaneously (abbreviated SCIG). Both routes have been demonstrated to be effective. The preferred route may vary at different times during a given patient’s life. Options are therefore not fixed and the choice of route for immunoglobulin therapy will depend on several factors, including patient characteristics, clinical indication, venous access, side effects, rural or remote location, treatment compliance and patient preference. Many years ago, immunoglobulin therapy was associated with side effects which may compromise patient’s compliance and quality of life of the patients. Most of the side effects were related to impurities. Recently, major advances in the manufacturing process have been made and new processes, such as the Quality by design (QbD) approach were added into the manufacturing steps to ensure patients tolerability and safety. Due to the improved purity of the immunoglobulin products obtained by these processes, the incidence of side effects is lower, while the ways of administration of Ig therapy and the choice of the regimen has widened to suit patient’s preference and needs.

PMID: 29181272 [PubMed]

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A nine-month-old-boy with Atypical Hemophagocytic Lymphohistiocytosis.

Mediterr J Hematol Infect Dis. 2017;9(1):e2017057

Authors: Ouederni M, Ben Khaled M, Rekaya S, Ben Fraj I, Mellouli F, Bejaoui M

Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammation caused by uncontrolled proliferation of activated lymphocytes and histiocytes. Often, HLH is an acquired syndrome. We report a case of a nine month-old-boy presented with hepatosplenomegaly, severe anemia, thrombocytopenia, hypertriglyceridemia and high hyperferritinemia. These clinical features of HLH prompted a wide range of infectious and auto-immune tests to be performed. After an extensive diagnostic workup, he was referred to the immune-hematologic unit for HLH suspicion with an unknown cause. Primary HLH due to familial lymphohistiocytosis (FLH) was first evoked in front of consanguinity, probable HLH in the family, early onset, and in the absence of a causative pathology like infection or cancer. However, functional tests were normal. Atypical features like the: absence of fever, hypotonia, recurrent diarrhea since diversification, hematuria, and proteinuria suggested an inborn metabolism error with gastrointestinal involvement. Specific tests were performed to reach a final diagnosis.

PMID: 29181134 [PubMed]

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A novel de novo activating mutation in STAT3 identified in a patient with common variable immunodeficiency (CVID).

Clin Immunol. 2017 Nov 24;:

Authors: Russell MA, Pigors M, Houssen ME, Manson A, Kelsell D, Longhurst H, Morgan NG

Abstract
Common variable immunodeficiency (CVID) is characterised by repeated infection associated with primary acquired hypogammaglobulinemia. CVID frequently has a complex aetiology but, in certain cases, it has a monogenic cause. Recently, variants within the gene encoding the transcription factor STAT3 were implicated in monogenic CVID. Here, we describe a patient presenting with symptoms synonymous with CVID, who displayed reduced levels of IgG and IgA, repeated viral infections and multiple additional co-morbidities. Whole-exome sequencing revealed a de novo novel missense mutation in the coiled-coil domain of STAT3 (c.870A>T; p.K290N). Accordingly, the K290N variant of STAT3 was generated, and a STAT3 responsive dual-luciferase reporter assay revealed that the variant strongly enhances STAT3 transcriptional activity both under basal and stimulated (with IL-6) conditions. Overall, these data complement earlier studies in which CVID-associated STAT3 mutations are predicted to enhance transcriptional activity, suggesting that such patients may respond favourably to IL-6 receptor antagonists (e.g. tocilizumab).

PMID: 29180260 [PubMed – as supplied by publisher]

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Dual loss of p110δ PI3-kinase and SKAP (KNSTRN) expression leads to combined immunodeficiency and multisystem syndromic features.

J Allergy Clin Immunol. 2017 Nov 24;:

Authors: Sharfe N, Karanxha A, Dadi H, Merico D, Chitayat D, Herbrick JA, Freeman S, Grinstein S, Roifman CM

Abstract
BACKGROUND: We previously reported a novel syndrome characterized by combined immunodeficiency associated with severe developmental defects – subsequently known as Roifman-Chitayat Syndrome (RCS; OMIM 613328). Linkage analysis identified two disease-associated loci.
OBJECTIVE: To identify the genetic defect in these patients and characterize their immunological cellular abnormalities.
METHODS: Genetic, immunological, protein and cellular functional analyses were used to identify and characterize patient genetic deficiencies and aberrant patient cell behaviour.
RESULTS: Deleterious variants were found at both loci identified by linkage analysis: a homozygous stop codon in PI3-kinase p110δ (PIK3CD) and a homozygous frame shift mutation in SKAP (KNSTRN), both ablating protein expression. RCS patients display aberrant B cell development, similar to p110δ deficient mice, but also aberrant T cell spreading, cell-cell interaction and migration. Patients also display significant developmental abnormalities not seen in p110δ knockouts (e.g. optic nerve atrophy, skeletal anomalies) that we ascribe to loss of SKAP. Aberrant SKAP expression can prolong anaphase and this may contribute to developmental defects. However, we also identified MAP4 microtubule-binding protein as a novel SKAP-binding partner and show it undergoes re-localization in patient T cells, with associated areas of aberrant microtubule hyper-stabilization, likely contributing not only to the altered properties of RCS lymphoid cells but also developmental defects.
CONCLUSIONS: The complex Roifman-Chitayat Syndrome presentation, with combined developmental and immunological defects, is associated with a combined deficiency of two genes products, PI3-kinase p110δ and SKAP, both of which appear to play a significant role in the disease.

PMID: 29180244 [PubMed – as supplied by publisher]

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The Challenge of Next Generation Sequencing in a Boy With Severe Mononucleosis and EBV-related Lymphoma.

J Pediatr Hematol Oncol. 2017 Nov 23;:

Authors: Verzegnassi F, Valencic E, Kiren V, Giurici N, Bianco AM, Marcuzzi A, Vozzi D, Tommasini A, Faletra F

Abstract
A severe course of infectious mononucleosis should always lead up to the suspicion of a primary immunodeficiency. We describe the case of a boy with severe mononucleosis accompanied by the development of hemophagocytic lymphohistiocytosis and lymphoma. By whole exome sequencing, we identified a mutation of uncertain significance in CTPS2, a gene closely related to CTPS1, which is involved in a primary immune deficiency with susceptibility to herpesviruses. We discuss the challenge of a correct interpretation of data from whole exome sequencing, questioning whether the CTPS2 variant found in our patient is just an incidental finding or a mutation with variable penetrance.

PMID: 29176466 [PubMed – as supplied by publisher]

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A Review of Chronic Granulomatous Disease.

Adv Ther. 2017 Nov 22;:

Authors: Arnold DE, Heimall JR

Abstract
Chronic granulomatous disease (CGD) is a primary immunodeficiency caused by defects in any of the five subunits of the NADPH oxidase complex responsible for the respiratory burst in phagocytic leukocytes. Patients with CGD are at increased risk of life-threatening infections with catalase-positive bacteria and fungi and inflammatory complications such as CGD colitis. The implementation of routine antimicrobial prophylaxis and the advent of azole antifungals has considerably improved overall survival. Nevertheless, life expectancy remains decreased compared to the general population. Inflammatory complications are a significant contributor to morbidity in CGD, and they are often refractory to standard therapies. At present, hematopoietic stem cell transplantation (HCT) is the only curative treatment, and transplantation outcomes have improved over the last few decades with overall survival rates now > 90% in children less than 14 years of age. However, there remains debate as to the optimal conditioning regimen, and there is question as to how to manage adolescent and adult patients. The current evidence suggests that myeloablative conditioning results is more durable myeloid engraftment but with increased toxicity and high rates of graft-versus-host disease. In recent years, gene therapy has been proposed as an alternative to HCT for patients without an HLA-matched donor. However, results to date have not been encouraging. with negligible long-term engraftment of gene-corrected hematopoietic stem cells and reports of myelodysplastic syndrome due to insertional mutagenesis. Multicenter trials are currently underway in the United States and Europe using a SIN-lentiviral vector under the control of a myeloid-specific promoter, and, should the trials be successful, gene therapy may be a viable option for patients with CGD in the future.

PMID: 29168144 [PubMed – as supplied by publisher]

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First Year of Israeli Newborn Screening for Severe Combined Immunodeficiency-Clinical Achievements and Insights.

Front Immunol. 2017;8:1448

Authors: Rechavi E, Lev A, Simon AJ, Stauber T, Daas S, Saraf-Levy T, Broides A, Nahum A, Marcus N, Hanna S, Stepensky P, Toker O, Dalal I, Etzioni A, Almashanu S, Somech R

Abstract
Severe combined immunodeficiency (SCID), the most severe form of T cell immunodeficiency, is detectable through quantification of T cell receptor excision circles (TRECs) in dried blood spots obtained at birth. Herein, we describe the results of the first year of the Israeli SCID newborn screening (NBS) program. This important, life-saving screening test is available at no cost for every newborn in Israel. Eight SCID patients were diagnosed through the NBS program in its first year, revealing an incidence of 1:22,500 births in the Israeli population. Consanguine marriages and Muslim ethnic origin were found to be a risk factor in affected newborns, and a founder effect was detected for both IL7Rα and DCLRE1C deficiency SCID. Lymphocyte subset analysis and TREC quantification in the peripheral blood appear to be sufficient for confirmation of typical and leaky SCID and ruling out false positive (FP) results. Detection of secondary targets (infants with non-SCID lymphopenia) did not significantly affect the management or outcomes of these infants in our cohort. In the general, non-immunodeficient population, TREC rises along with gestational age and birth weight, and is significantly higher in females and the firstborn of twin pairs. Low TREC correlates with both gestational age and birth weight in extremely premature newborns. Additionally, the rate of TREC increase per week consistently accelerates with gestational age. Together, these findings mandate a lower cutoff or a more lenient screening algorithm for extremely premature infants, in order to reduce the high rate of FPs within this group. A significant surge in TREC values was observed between 28 and 30 weeks of gestation, where median TREC copy numbers rise by 50% over 2 weeks. These findings suggest a maturational step in T cell development around week 29 gestation, and imply moderate to late preterms should be screened with the same cutoff as term infants. The SCID NBS program is still in its infancy, but is already bearing fruit in the early detection and improved outcomes of children with SCID in Israel and other countries.

PMID: 29167666 [PubMed]

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[Atopic eczema in childhood or primary immunodeficiency – what needs to be considered?]

MMW Fortschr Med. 2017 Nov;159(20):59-63

Authors: Wollenberg A, Renner E, Hagl B

PMID: 29159616 [PubMed – in process]

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