Manish Butte

Gastrointestinal Manifestations of STAT3-Deficient Hyper-IgE Syndrome.

August 15, 2017 By Manish Butte

Gastrointestinal Manifestations of STAT3-Deficient Hyper-IgE Syndrome.

J Clin Immunol. 2017 Aug 13;:

Authors: Arora M, Bagi P, Strongin A, Heimall J, Zhao X, Lawrence MG, Trivedi A, Henderson C, Hsu A, Quezado M, Kleiner DE, Venkatesan AM, Holland SM, Freeman AF, Heller T

Abstract
OBJECTIVE: STAT 3 deficiency (autosomal dominant hyper immunoglobulin E syndrome (AD-HIES)) is a primary immunodeficiency disorder with multi-organ involvement caused by dominant negative signal transducer and activator of transcription gene 3 (STAT3) mutations. We sought to describe the gastrointestinal (GI) manifestations of this disease.
METHODS: Seventy subjects aged five to 60 years with a molecular diagnosis of AD-HIES were evaluated at the National Institutes of Health (NIH). Data collection involved a GI symptom questionnaire and retrospective chart review.
RESULTS: In our cohort of 70 subjects, we found that 60% had GI symptoms (42/70). The most common manifestations were gastroesophageal reflux disease (GERD) observed in 41%, dysphagia in 31%, and abdominal pain in 24%. The most serious complications were food impaction in 13% and colonic perforation in 6%. Diffuse esophageal wall thickening in 74%, solid stool in the right colon in 50% (12/24), and hiatal hernia in 26% were the most prevalent radiologic findings. Esophagogastroduodenoscopy (EGD) demonstrated esophageal tortuosity in 35% (8/23), esophageal ulceration in 17% (4/23), esophageal strictures requiring dilation in 9% (2/23), and gastric ulceration in 17% (4/23). Esophageal eosinophilic infiltration was an unexpected histologic finding seen in 65% (11/17).
CONCLUSION: The majority of AD-HIES subjects develop GI manifestations as part of their disease. Most notable are the symptoms and radiologic findings of GI dysmotility, as well as significant eosinophilic infiltration, concerning for a secondary eosinophilic esophagitis. These findings suggest that the STAT3 pathway may be implicated in a new mechanism for the pathogenesis of several GI disorders.

PMID: 28803389 [PubMed – as supplied by publisher]

Efficacy and Safety of Subcutaneous Belimumab in Systemic Lupus Erythematosus: A Fifty-Two-Week Randomized, Double-Blind, Placebo-Controlled Study.

August 15, 2017 By Manish Butte

Efficacy and Safety of Subcutaneous Belimumab in Systemic Lupus Erythematosus: A Fifty-Two-Week Randomized, Double-Blind, Placebo-Controlled Study.

Arthritis Rheumatol. 2017 May;69(5):1016-1027

Authors: Stohl W, Schwarting A, Okada M, Scheinberg M, Doria A, Hammer AE, Kleoudis C, Groark J, Bass D, Fox NL, Roth D, Gordon D

Abstract
OBJECTIVE: To assess the efficacy and safety of subcutaneous (SC) belimumab in patients with systemic lupus erythematosus (SLE).
METHODS: Patients with moderate-to-severe SLE (score of ≥8 on the Safety of Estrogens in Lupus Erythematosus National Assessment [SELENA] version of the SLE Disease Activity Index [SLEDAI]) were randomized 2:1 to receive weekly SC belimumab 200 mg or placebo by prefilled syringe in addition to standard SLE therapy for 52 weeks. The primary end point was the SLE Responder Index (SRI4) at week 52. Secondary end points were reduction in the corticosteroid dosage and time to severe flare. Safety was assessed according to the adverse events (AEs) reported and the laboratory test results.
RESULTS: Of 839 patients randomized, 836 (556 in the belimumab group and 280 in the placebo group) received treatment. A total of 159 patients withdrew before the end of the study. At entry, mean SELENA-SLEDAI scores were 10.5 in the belimumab group and 10.3 in the placebo group. More patients who received belimumab were SRI4 responders than those who received placebo (61.4% versus 48.4%; odds ratio [OR] 1.68 [95% confidence interval (95% CI) 1.25-2.25]; P = 0.0006). In the belimumab group, both time to and risk of severe flare were improved (median 171.0 days versus 118.0 days; hazard ratio 0.51 [95% CI 0.35-0.74]; P = 0.0004), and more patients were able to reduce their corticosteroid dosage by ≥25% (to ≤7.5 mg/day) during weeks 40-52 (18.2% versus 11.9%; OR 1.65 [95% CI 0.95-2.84]; P = 0.0732), compared with placebo. AE incidence was comparable between treatment groups; serious AEs were reported by 10.8% of patients taking belimumab and 15.7% of those taking placebo. A worsening of IgG hypoglobulinemia by ≥2 grades occurred in 0.9% of patients taking belimumab and 1.4% of those taking placebo.
CONCLUSION: In patients with moderate-to-severe SLE, weekly SC doses of belimumab 200 mg plus standard SLE therapy significantly improved their SRI4 response, decreased severe disease flares as compared with placebo, and had a safety profile similar to placebo plus standard SLE therapy.

PMID: 28118533 [PubMed – indexed for MEDLINE]

Human immunity against EBV-lessons from the clinic.

August 15, 2017 By Manish Butte

Human immunity against EBV-lessons from the clinic.

J Exp Med. 2017 Feb;214(2):269-283

Authors: Tangye SG, Palendira U, Edwards ES

Abstract
The mammalian immune system has evolved over many millennia to be best equipped to protect the host from pathogen infection. In many cases, host and pathogen have coevolved, each acquiring sophisticated ways of inducing or protecting from disease. Epstein-Barr virus (EBV) is a human herpes virus that infects >90% of individuals. Despite its ubiquity, infection by EBV is often subclinical; this invariably reflects the necessity of the virus to preserve its host, balanced with sophisticated host immune mechanisms that maintain viral latency. However, EBV infection can result in various, and often fatal, clinical sequelae, including fulminant infectious mononucleosis, hemophagocytic lymphohistiocytosis, lymphoproliferative disease, organomegaly, and/or malignancy. Such clinical outcomes are typically observed in immunosuppressed individuals, with the most extreme cases being Mendelian primary immunodeficiencies (PIDs). Although these conditions are rare, they have provided critical insight into the cellular, biochemical, and molecular requirements for robust and long-lasting immunity against EBV infection. Here, we review the virology of EBV, mechanisms underlying disease pathogenesis in PIDs, and developments in immune cell-mediated therapy to treat disorders associated with or induced by EBV infection.

PMID: 28108590 [PubMed – indexed for MEDLINE]

No! When the immunologist becomes a virologist: Norovirus – an emerging infection in immune deficiency diseases.

August 15, 2017 By Manish Butte

No! When the immunologist becomes a virologist: Norovirus – an emerging infection in immune deficiency diseases.

Curr Opin Allergy Clin Immunol. 2016 Dec;16(6):557-564

Authors: Hartono S, Bhagia A, Joshi AY

Abstract
PURPOSE OF REVIEW: Norovirus infection is an emerging chronic infection in immunocompromised hosts. The aim of this review is to discuss the pathophysiology of Norovirus infection and explore mechanistic models for chronic infection/shedder state, especially in patients with immune deficiency diseases.
RECENT FINDINGS: Chronic Norovirus infection is increasingly associated with enteropathy associated with both primary and secondary immune deficiency diseases. There is an ongoing debate in the immune deficiency community whether it is truly a causative agent for the enteropathy or it is an innocent bystander.We describe the historic aspects of Norovirus infection, its immunology and viral structure and the basis for preventive and vaccination strategies.We also postulate in this review a disease model in immune deficiency subjects which creates a milieu for it to become a chronic and explore newer frontiers for disease modification and prevention.
SUMMARY: Norovirus is the most common cause of acute gastroenteritis in general population but the factors that lead to its persistence in patients with immune deficiency need further holistic studies. This should include host assessment, microbiome signatures, and viral pathogenic factors assessment.

PMID: 27755184 [PubMed – indexed for MEDLINE]

DOCK8 Drives Src-Dependent NK Cell Effector Function.

August 11, 2017 By Manish Butte

DOCK8 Drives Src-Dependent NK Cell Effector Function.

J Immunol. 2017 Aug 09;:

Authors: Kearney CJ, Vervoort SJ, Ramsbottom KM, Freeman AJ, Michie J, Peake J, Casanova JL, Picard C, Tangye SG, Ma CS, Johnstone RW, Randall KL, Oliaro J

Abstract
Mutations in the dedicator of cytokinesis 8 (DOCK8) gene cause an autosomal recessive form of hyper-IgE syndrome, characterized by chronic immunodeficiency with persistent microbial infection and increased incidence of malignancy. These manifestations suggest a defect in cytotoxic lymphocyte function and immune surveillance. However, how DOCK8 regulates NK cell-driven immune responses remains unclear. In this article, we demonstrate that DOCK8 regulates NK cell cytotoxicity and cytokine production in response to target cell engagement or receptor ligation. Genetic ablation of DOCK8 in human NK cells attenuated cytokine transcription and secretion through inhibition of Src family kinase activation, particularly Lck, downstream of target cell engagement or NKp30 ligation. PMA/Ionomycin treatment of DOCK8-deficient NK cells rescued cytokine production, indicating a defect proximal to receptor ligation. Importantly, NK cells from DOCK8-deficient patients had attenuated production of IFN-γ and TNF-α upon NKp30 stimulation. Taken together, we reveal a novel molecular mechanism by which DOCK8 regulates NK cell-driven immunity.

PMID: 28794229 [PubMed – as supplied by publisher]

Uses of Next-Generation Sequencing Technologies for the Diagnosis of Primary Immunodeficiencies.

August 10, 2017 By Manish Butte

Uses of Next-Generation Sequencing Technologies for the Diagnosis of Primary Immunodeficiencies.

Front Immunol. 2017;8:847

Authors: Seleman M, Hoyos-Bachiloglu R, Geha RS, Chou J

Abstract
Primary immunodeficiencies (PIDs) are genetic disorders impairing host immunity, leading to life-threatening infections, autoimmunity, and/or malignancies. Genomic technologies have been critical for expediting the discovery of novel genetic defects underlying PIDs, expanding our knowledge of the complex clinical phenotypes associated with PIDs, and in shifting paradigms of PID pathogenesis. Once considered Mendelian, monogenic, and completely penetrant disorders, genomic studies have redefined PIDs as a heterogeneous group of diseases found in the global population that may arise through multigenic defects, non-germline transmission, and with variable penetrance. This review examines the uses of next-generation DNA sequencing (NGS) in the diagnosis of PIDs. While whole genome sequencing identifies variants throughout the genome, whole exome sequencing sequences only the protein-coding regions within a genome, and targeted gene panels sequence only a specific cohort of genes. The advantages and limitations of each sequencing approach are compared. The complexities of variant interpretation and variant validation remain the major challenge in wide-spread implementation of these technologies. Lastly, the roles of NGS in newborn screening and precision therapeutics for individuals with PID are also addressed.

PMID: 28791010 [PubMed]

Prospective Study of a Cohort of Russian Nijmegen Breakage Syndrome Patients Demonstrating Predictive Value of Low Kappa-Deleting Recombination Excision Circle (KREC) Numbers and Beneficial Effect of Hematopoietic Stem Cell Transplantation (HSCT).

August 10, 2017 By Manish Butte

Prospective Study of a Cohort of Russian Nijmegen Breakage Syndrome Patients Demonstrating Predictive Value of Low Kappa-Deleting Recombination Excision Circle (KREC) Numbers and Beneficial Effect of Hematopoietic Stem Cell Transplantation (HSCT).

Front Immunol. 2017;8:807

Authors: Deripapa E, Balashov D, Rodina Y, Laberko A, Myakova N, Davydova NV, Gordukova MA, Abramov DS, Pay GV, Shelikhova L, Prodeus AP, Maschan MA, Maschan AA, Shcherbina A

Abstract
BACKGROUND: Nijmegen breakage syndrome (NBS) is a combined primary immunodeficiency with DNA repair defect, microcephaly, and other phenotypical features. It predominantly occurs in Slavic populations that have a high frequency of carriers with the causative NBN gene c.657_661del5 mutation. Due to the rarity of the disease in the rest of the world, studies of NBS patients are few. Here, we report a prospective study of a cohort of Russian NBS patients.
METHODS: 35 Russian NBS patients of ages 1-19 years, referred to our Center between years 2012 and 2016, were prospectively studied.
RESULTS: Despite the fact that in 80% of the patients microcephaly was diagnosed at birth or shortly thereafter, the average delay of NBS diagnosis was 6.5 years. Though 80% of the patients had laboratory signs of immunodeficiency, only 51% of the patients experienced significant infections. Autoimmune complications including interstitial lymphocytic lung disease and skin granulomas were noted in 34%, malignancies-in 57% of the patients. T-cell excision circle (TREC)/kappa-deleting recombination excision circle (KREC) levels were low in the majority of patients studied. Lower KREC levels correlated with autoimmune and oncological complications. Fifteen patients underwent hematopoietic stem cell transplantation (HSCT), 10 of them were alive and well, with good graft function. Three patients in the HSCT group and five non-transplanted patients died; tumor progression being the main cause of death. The probability of the overall survival since NBS diagnosis was 0.76 in the HSCT group and 0.3 in the non-transplanted group.
CONCLUSION: Based on our findings of low TRECs in most NBS patients, independent of their age, TREC detection can be potentially useful for detection of NBS patients during neonatal screening. KREC concentration can be used as a prognostic marker of disease severity. HSCT is a viable treatment option in NBS and should be especially considered in patients with low KREC numbers early on, before development of life-threatening complications.

PMID: 28791007 [PubMed]

Facilitated Subcutaneous Immunoglobulin (fSCIg) in Autoimmune Cytopenias Associated with Common Variable Immunodeficiency.

August 9, 2017 By Manish Butte

Facilitated Subcutaneous Immunoglobulin (fSCIg) in Autoimmune Cytopenias Associated with Common Variable Immunodeficiency.

Isr Med Assoc J. 2017 Jul;19(7):420-423

Authors: Pedini V, Savore I, Giovanna Danieli M

Abstract
BACKGROUND: Common variable immunodeficiency (CVID) is the most common symptomatic primary immune deficiency of adulthood. Besides recurrent infections, autoimmune disorders-mainly cytopenias-affect 30% of patients with CVID.
OBJECTIVES: To describe the efficacy and safety of facilitated subcutaneous immunoglobulin (fSCIg), which is a combination of 10% [human] SCIg with recombinant human hyaluronidase for the treatment of CVID-linked cytopenias.
METHODS: We describe four women (mean age 54 years) with CVID associated with idiopathic thrombocytopenic purpura (ITP) (n=3) and autoimmune hemolytic anemia (AIHA) (n=1). Diagnosis of CVID was made according to the European Society of Immune Deficiencies / Pan-American Group for Immune Deficiency criteria. All were treated with fSCIg (bi-monthly, 20 g).
RESULTS: After a median follow-up of 22 months, all patients achieved a stable remission from the cytopenias, characterized by increased platelet values in ITP (mean values 93000/mmc), and resolution of anemia. A reduction of the daily prednisone dose was documented in the patient with AIHA. No systemic adverse drug reactions were observed.
CONCLUSIONS: Our preliminary data documented the efficacy and safety of fSCIg in the treatment of CVID associated with autoimmune cytopenias, with a good tolerability. We also noted the role of fSCIg as a steroid sparing agent. It is thus possible to suppose an immunomodulatory role for fSCIg, but linked to different mechanisms than IVIg, due to the peculiar pharmacokinetic and administration route of fSCIg.

PMID: 28786256 [PubMed – in process]

Emerging Infections and Pertinent Infections Related to Travel for Patients with Primary Immunodeficiencies.

August 9, 2017 By Manish Butte

Emerging Infections and Pertinent Infections Related to Travel for Patients with Primary Immunodeficiencies.

J Clin Immunol. 2017 Aug 07;:

Authors: Sullivan KE, Bassiri H, Bousfiha AA, Costa-Carvalho BT, Freeman AF, Hagin D, Lau YL, Lionakis MS, Moreira I, Pinto JA, de Moraes-Pinto MI, Rawat A, Reda SM, Reyes SOL, Seppänen OM, Tang MLK

Abstract
In today’s global economy and affordable vacation travel, it is increasingly important that visitors to another country and their physician be familiar with emerging infections, infections unique to a specific geographic region, and risks related to the process of travel. This is never more important than for patients with primary immunodeficiency disorders (PIDD). A recent review addressing common causes of fever in travelers provides important information for the general population Thwaites and Day (N Engl J Med 376:548-560, 2017). This review covers critical infectious and management concerns specifically related to travel for patients with PIDD. This review will discuss the context of the changing landscape of infections, highlight specific infections of concern, and profile distinct infection phenotypes in patients who are immune compromised. The organization of this review will address the environment driving emerging infections and several concerns unique to patients with PIDD. The first section addresses general considerations, the second section profiles specific infections organized according to mechanism of transmission, and the third section focuses on unique phenotypes and unique susceptibilities in patients with PIDDs. This review does not address most parasitic diseases. Reference tables provide easily accessible information on a broader range of infections than is described in the text.

PMID: 28786026 [PubMed – as supplied by publisher]

Common Variable Immunodeficiency and Liver Involvement.

August 9, 2017 By Manish Butte

Common Variable Immunodeficiency and Liver Involvement.

Clin Rev Allergy Immunol. 2017 Aug 07;:

Authors: Song J, Lleo A, Yang GX, Zhang W, Bowlus CL, Eric Gershwin M, Leung PSC

Abstract
Common variable immunodeficiency (CVID) is a primary B-cell immunodeficiency disorder, characterized by remarkable hypogammaglobulinemia. The disease can develop at any age without gender predominance. The prevalence of CVID varies widely worldwide. The underlying causes of CVID remain largely unknown; primary B-cell dysfunctions, defects in T cells and antigen-presenting cells are involved. Although some monogenetic defects have been identified in some CVID patients, it is likely that CVID is polygenic. Patients with CVID develop recurrent and chronic infections (e.g., bacterial infections of the respiratory or gastrointestinal tract), autoimmune diseases, lymphoproliferation, malignancies, and granulomatous lesions. Interestingly, autoimmunity can be the only clinical manifestation of CVID at the time of diagnosis and may even develop prior to hypogammaglobulinemia. The diagnosis of CVID is largely based on the criteria established by European Society for Immunodeficiencies and Pan-American Group for Immunodeficiency (ESID/PAGID) and with some recent modifications. The disease can affect multiple organs, including the liver. Clinical features of CVID patients with liver involvement include abnormal liver biochemistries, primarily elevation of alkaline phosphatase (ALP), nodular regenerative hyperplasia (NRH), or liver cirrhosis and its complications. Replacement therapy with immunoglobulin (Ig) and anti-infection therapy are the primary treatment regimen for CVID patients. No specific therapy for liver involvement of CVID is currently available, and liver transplantation is an option only in select cases. The prognosis of CVID varies widely. Further understanding in the etiology and pathophysiology will facilitate early diagnosis and treatments to improve prognosis.

PMID: 28785926 [PubMed – as supplied by publisher]