Manish Butte

A Rare Association of Congenital Asplenia with Jejunal Arteriovenous Malformation.

Am J Case Rep. 2017 Oct 19;18:1118-1122

Authors: Arnautovic JZ, Mazhar A, Tereziu S, Gupta K

Abstract
BACKGROUND Isolated congenital asplenia is a poorly understood and rare form of primary immunodeficiency, often associated with life-threatening infections. CASE REPORT We encountered a unique case of a 22-year-old asplenic male who presented with severe iron-deficiency anemia secondary to occult gastrointestinal bleeding since age 15. Our extensive work-up confirmed jejunal arteriovenous malformations as the source of the bleed. Six months after the treatment, the patient has reported no further episodes of gastrointestinal bleeding and his hemoglobin has remained stable. CONCLUSIONS A comprehensive literature review confirmed that this is the first reported case of adult congenital asplenia associated with arteriovenous malformation in the United States. The relationship of isolated congenital asplenia and arteriovenous malformation-associated bleeding remains unknown at this time; we postulate that this may be a congenital syndrome on its own. Obscure bleeding in the presence of rare anomalies such as asplenia should be investigated as one of the important causes of unexplained intestinal arteriovenous malformations.

PMID: 29046517 [PubMed – in process]

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Lymphocytopenia is associated with anti-Beta-2 glycoprotein-1 in patients with 220 systemic lupus erythematosus.

Acta Reumatol Port. 2016 Jul-Sep;41(3):220-225

Authors: Skare T, Borba EA, Utiyama SR, Nisihara R

Abstract
BACKGROUND: Anti B2-Glicoprotein 1 (B2-GPI) is an antiphospholipid antibody that may be present in primary or secondary antiphospholipid syndrome (APS). Systemic Lupus erythematosus (SLE) is the main disease associated with secondary APS.
OBJECTIVE: To study the prevalence of anti B2-GPI in SLE patients.
METHODS: Anti B2-GPI (IgM/IgG) was studied by ELISA in 88 patients with SLE of both genders; 18.6% of which with secondary APS. Charts were reviewed for clinical and serological profile.
RESULTS: Anti B2-GPI was present in 18.6% of the whole sample and in 29.4% of those with secondary APS. At univariated analysis, the presence of anti B2-GPI was more common in patients with serositis (p=0.04), lymphocytopenia (p=0.003) and anti cardiolipin (aCl) IgM antibodies (p=0.04). In a logistic regression study, only the associations with lymphocytopenia (OR=8.2; 95%CI=2.1-39.3) and aCl IgM (p=0.04; OR=3.4; 95%CI=1.05-11.1) remained significant.
CONCLUSION: There is a 18.6% prevalence of positive anti B2-GPI in SLE population that is associated with the presence of aCl IgM and lymphocytopenia.

PMID: 27384760 [PubMed – indexed for MEDLINE]

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[Dermatomyositis-like syndrome in x-linked agammaglobulinemia].

Acta Reumatol Port. 2016 Jan-Mar;41(1):78-81

Authors: Carvalho PD, Costa C, Rodrigues M, Salvador MJ, Pereira da Silva JA, Malcata A

Abstract
Primary immunodeficiencies (PIDs) encompass more than 250 different pathological conditions. X-linked agammaglobulinemia (XLA) has been occasionally associated with cutaneous and muscular manifestations resembling dermatomyositis, often termed dermatomyositis-like syndrome (DLS). This syndrome has been associated with cutaneous, muscular and central nervous system manifestations, accompanying a persistent infection by an Echovirus. According to sixteen previously reported cases, this syndrome has a poor prognosis. We report the case of a 27-years old male, with XLA and DLS, successfully treated with 6 cycles of human immunoglobulin and methotrexate. Clinical symptoms improved dramatically with a complete resolution of the musculoskeletal manifestations. Despite this clinical response, prognosis should remain reserved. The evolution of this syndrome remains unpredictable and therapeutic options are limited. To the best of our knowledge, there are only a few reports of similar cases which have survived so many months after the diagnosis.

PMID: 27115112 [PubMed – indexed for MEDLINE]

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An update on gain-of-function mutations in primary immunodeficiency diseases.

Curr Opin Allergy Clin Immunol. 2017 Oct 16;:

Authors: Jhamnani RD, Rosenzweig SD

Abstract
PURPOSE OF REVIEW: Most primary immunodeficiencies described since 1952 were associated with loss-of-function defects. With the advent and popularization of unbiased next-generation sequencing diagnostic approaches followed by functional validation techniques, many gain-of-function mutations leading to immunodeficiency have also been identified. This review highlights the updates on pathophysiology mechanisms and new therapeutic approaches involving primary immunodeficiencies because of gain-of-function mutations.
RECENT FINDINGS: The more recent developments related to gain-of-function primary immunodeficiencies mostly involving increased infection susceptibility but also immune dysregulation and autoimmunity, were reviewed. Updates regarding pathophysiology mechanisms, different mutation types, clinical features, laboratory markers, current and potential new treatments on patients with caspase recruitment domain family member 11, signal transducer and activator of transcription 1, signal transducer and activator of transcription 3, phosphatidylinositol-4,5-biphosphate 3-kinase catalytic 110, phosphatidylinositol-4,5-biphosphate 3-kinase regulatory subunit 1, chemokine C-X-C motif receptor 4, sterile α motif domain containing 9-like, and nuclear factor κ-B subunit 2 gain-of-function mutations are reviewed for each disease.
SUMMARY: With the identification of gain-of-function mutations as a cause of immunodeficiency, new genetic pathophysiology mechanisms unveiled and new-targeted therapeutic approaches can be explored as potential rescue treatments for these diseases.

PMID: 29040208 [PubMed – as supplied by publisher]

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RI-002, an intravenous immunoglobulin containing high titer neutralizing antibody to RSV and other respiratory viruses for use in primary immunodeficiency disease and other immune compromised populations.

Expert Rev Clin Immunol. 2017 Oct 16;:1-13

Authors: Wasserman RL, Greener BN, Mond J

Abstract
INTRODUCTION: Novel immune globulin (IG) products (RI-002, RI-001) have been designed to provide protection against respiratory syncytial virus (RSV) mediated respiratory illness while at the same time meeting the manufacturing requirements established by FDA for antibody supplementation in immunocompromised subjects. Areas covered: This review covers the manufacture and development of both RI-001 and RI-002, including the selection of plasma donors for IG preparation with high-titers of anti-RSV antibody, in vitro, and preclinical data in the cotton rat model S. hispidus, and clinical trials including Phase II and compassionate use studies of RI-001 and a multi-center, pivotal Phase III study of RI-002 in PIDD patients. Expert commentary: The data demonstrate that RI-002 is efficacious in the prevention and treatment of RSV in preclinical normal and immune suppressed animal models and is safe and efficacious in the treatment of patients with various forms of primary immunodeficiency disease (PIDD). This product offers potential advantages over other available IG’s for prophylaxis in immunocompromised patients requiring polyclonal immunoglobulin supplementation because of its unique antibody composition. In addition to its enhanced neutralizing anti-RSV activity and its polyclonal IG composition, there is preclinical data to support the use of RI-002 for humoral protection against other respiratory pathogens.

PMID: 29035131 [PubMed – as supplied by publisher]

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Ataxia telangiectasia syndrome: moonlighting ATM.

Expert Rev Clin Immunol. 2017 Oct 16;:

Authors: Zaki Dizaji M, Akrami SM, Abolhassani H, Rezaei N, Aghamohammadi A

Abstract
INTRODUCTION: Ataxia-telangiectasia (A-T) a multisystem disorder primarily characterized by cerebellar degeneration, telangiectasia, immunodeficiency, cancer susceptibility and radiation sensitivity. Identification of the gene defective in this syndrome, ataxia-telangiectasia mutated gene (ATM), and further characterization of the disorder together with a greater insight into the function of the ATM protein have expanded our knowledge about the molecular pathogenesis of this disease. Area covered: In this review, we have attempted to summarize the different roles of ATM signaling that have provided new insights into the diverse clinical phenotypes exhibited by A-T patients. Expert commentary: ATM, in addition to DNA repair response, is involved in many cytoplasmic roles that explain diverse phenotypes of A-T patients. It seems accumulation of DNA damage, persistent DNA damage response signaling, and chronic oxidative stress are the main players in the pathogenesis of this disease.

PMID: 29034753 [PubMed – as supplied by publisher]

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Unexpectedly High Prevalence of Common Variable Immunodeficiency in Finland.

Front Immunol. 2017;8:1190

Authors: Selenius JS, Martelius T, Pikkarainen S, Siitonen S, Mattila E, Pietikäinen R, Suomalainen P, Aalto AH, Saarela J, Einarsdottir E, Järvinen A, Färkkilä M, Kere J, Seppänen M

Abstract
BACKGROUND: Common variable immunodeficiency (CVID) is the most common primary immunodeficiency. Prevalence varies greatly between countries and studies. Most diagnostic criteria include hypogammaglobulinemia and impaired vaccine response.
AIM: To evaluate the minimum prevalence as well as the clinical and immunological phenotypes of CVID in Southern Finland.
METHODS: We performed a cross-sectional study to assess all adult CVID patients followed up in three hospital districts in Southern and South-Eastern Finland between April 2007 and August 2015. CVID diagnosis was based, with a minor modification, on the ESID/PAGID criteria for primary CVID. Antipolysaccharide responses to Pneumovax(®) were defined as impaired only if 50% or more of the serotypes did not reach a level of 0.35 µg/mL after vaccination. We further characterized the patients’ B cell phenotypes and complications associated with CVID.
RESULTS: In total, 9 patients were excluded due to potential secondary causes before diagnosis. ESID/PAGID criteria were met by 132 patients (males 52%), of whom, 106 had “probable” and 26 “possible CVID.” Based on the population statistics in the three hospital districts, the minimum adult prevalence per 100,000 inhabitants in Finland for all CVID (“probable CVID,” respectively) patients was 6.9 (5.5). In the highest prevalence district (Helsinki and Uusimaa), the prevalence was 7.7 (6.1). CVID patients suffer from frequent complications. Ten patients died during follow-up. Of probable CVID patients, 73% had more than one clinical phenotype. Intriguingly, gradual B cell loss from peripheral blood during follow-up was seen in as many as 16% of “probable CVID” patients. Patients with possible CVID displayed somewhat milder clinical and laboratory phenotypes than probable CVID patients. We also confirm that large granular lymphocyte lymphoproliferation is a CVID-associated complication.
CONCLUSION: The prevalence of CVID in Finland appears the highest recorded, likely reflecting the genetic isolation and potential founder effects in the Finnish population. Studies to discover potential gene variants responsible for the high prevalence in Finland thus seem warranted. Increased awareness of CVID among physicians would likely lead to earlier diagnosis and improved quality of care.

PMID: 29033928 [PubMed]

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Gammaplex(®) 5 and 10% in the treatment of primary immunodeficiency and chronic immune thrombocytopenic purpura.

Immunotherapy. 2017 Oct;9(13):1071-1088

Authors: Wasserman RL

Abstract
Immunoglobulin G is used to both prevent infection in primary immunodeficiency diseases (PIDs) and prevent bleeding in immune thrombocytopenic purpura. Gammaplex is a highly purified human intravenous immunoglobulin G available as 5 and 10% liquid formulations. Gammaplex 5% has proven efficacy and safety in PID and immune thrombocytopenic purpura, protecting against serious acute bacterial infections and treating bleeding by improving platelet counts, respectively. The therapeutic effect of Gammaplex 10% is expected to be similar to that of Gammaplex 5% based on demonstrated bioequivalence in a bridging study in PID. The availability of Gammaplex 10% provides another option to individualize therapy according to patient needs, allowing a 34% reduction in infusion time without compromising safety and tolerability.

PMID: 29032734 [PubMed – in process]

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Review: Diagnosing Common Variable Immunodeficiency Disorder in the Era of Genome Sequencing.

Clin Rev Allergy Immunol. 2017 Oct 14;:

Authors: Ameratunga R, Lehnert K, Woon ST, Gillis D, Bryant VL, Slade CA, Steele R

Abstract
Common variable immunodeficiency disorders (CVID) are an enigmatic group of often heritable conditions, which may manifest for the first time in early childhood or as late as the eighth decade of life. In the last 5 years, next generation sequencing (NGS) has revolutionised identification of genetic disorders. However, despite the best efforts of researchers around the globe, CVID conditions have been slow to yield their molecular secrets. We have previously described the many clinical advantages of identifying the genetic basis of primary immunodeficiency disorders (PIDs). In a minority of CVID patients, monogenic defects have now been identified. If a causative mutation is identified, these conditions are reclassified as CVID-like disorders. Here we discuss recent advances in the genetics of CVID and discuss how NGS can be optimally deployed to identify the causal mutations responsible for the protean clinical manifestations of these conditions. Diagnostic criteria such as the Ameratunga et al. criteria will continue to play an important role in patient management as well as case selection and sequencing strategy design until the genetic conundrum of CVID is solved.

PMID: 29030829 [PubMed – as supplied by publisher]

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Patients with common variable immunodeficiency paradoxically have increased rates of autoimmune disorders.

BMJ Case Rep. 2017 Oct 13;2017:

Authors: Susheela AT, Hale A

Abstract
Common variable immunodeficiency (CVID), characterised by disordered B cell function, is one of the most common primary immunodeficiency disorders. Patients with CVID are at lifelong risk of recurrent infections, particularly of the respiratory and gastrointestinal tracts. Paradoxically, given their immunocompromised state, patients with CVID are also at significantly increased risk of autoimmune disorders, which are seen in almost 25% of cases. The authors report a 24-year-old female patient with CVID, manifested as severe hypogammaglobulinaemia with recurrent sinopulmonary infections and enterocolitis, who presented with transaminitis, chronic diarrhoea and haematemesis. No infectious aetiologies were identified. She was diagnosed with coeliac disease after a small bowel biopsy and positive response to gluten-free diet. Haematemesis was attributed to portal hypertension due to liver cirrhosis, which was confirmed via liver biopsy. Coeliac disease can be a cause of diarrhoea in patients with immunodeficiency disorders and is often underdiagnosed. It can also be the underlying source of liver disease and is an often under-recognised cause of cirrhosis. The case presented emphasises the paradoxical and challenging relationship that patients with CVID face between immunodeficiency and autoimmune disorders, and also highlights that coeliac disease is an under-recognised cause of liver disease.

PMID: 29030367 [PubMed – in process]

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