Manish Butte

Pre-emptive Allogeneic Hematopoietic Stem Cell Transplantation in Ataxia Telangiectasia.

Front Immunol. 2018;9:2495

Authors: Bakhtiar S, Woelke S, Huenecke S, Kieslich M, Taylor AM, Schubert R, Zielen S, Bader P

Abstract
Ataxia telangiectasia (A-T) is a primary immunodeficiency with mutations in the gene encoding the A-T mutated (ATM) protein that interacts with immune, hematopoietic, and endocrine targets resulting in broad multi-systemic clinical manifestations with a devastating outcome. Apart from a progressive neurodegenerative disorder, A-T leads to significantly increased susceptibility to malignancies. It is a matter of discussion whether pre-emptive allogeneic hematopoietic stem cell transplantation (alloHSCT) using a reduced intensity conditioning regimen would be an option to restore immune-competence and prevent malignancy, as shown in animal models, because conventional treatment protocols of malignant diseases using radio- and/or chemotherapy have a high rate of therapy-related morbidity and mortality in these patients. We present the course of the disease, including immune reconstitution and neurological outcome following pre-emptive alloHSCT in a 4-year-old boy with A-T on a 6 year follow-up. Our manuscript provides a proof-of-concept of alloHSCT as an individual pre-emptive treatment strategy from which some A-T patients might benefit.

PMID: 30420857 [PubMed – in process]

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The burden of common variable immunodeficiency disorders: a retrospective analysis of the European Society for Immunodeficiency (ESID) registry data.

Orphanet J Rare Dis. 2018 Nov 12;13(1):201

Authors: Odnoletkova I, Kindle G, Quinti I, Grimbacher B, Knerr V, Gathmann B, Ehl S, Mahlaoui N, Van Wilder P, Bogaerts K, de Vries E, Plasma Protein Therapeutics Association (PPTA) Taskforce

Abstract
BACKGROUND: Common variable immunodeficiency disorders (CVID) are a group of rare innate disorders characterized by specific antibody deficiency and increased rates of infections, comorbidities and mortality. The burden of CVID in Europe has not been previously estimated. We performed a retrospective analysis of the European Society for Immunodeficiencies (ESID) registry data on the subset of patients classified by their immunologist as CVID and treated between 2004 and 2014. The registered deaths and comorbidities were used to calculate the annual average age-standardized rates of Years of Life Lost to premature death (YLL), Years Lost to Disability (YLD) and Disability Adjusted Life Years (DALY=YLL + YLD). These outcomes were expressed as a rate per 105 of the CVID cohort (the individual disease burden), and of the general population (the societal disease burden).
RESULTS: Data of 2700 patients from 23 countries were analysed. Annual comorbidity rates: bronchiectasis, 21.9%; autoimmunity, 23.2%; digestive disorders, 15.6%; solid cancers, 5.5%; lymphoma, 3.8%, exceeded the prevalence in the general population by a factor of 34.0, 7.6, 8.1, 2.4 and 32.6, respectively. The comorbidities of CVID caused 8722 (6069; 12,363) YLD/105 in this cohort, whereas 44% of disability burden was attributable to infections and bronchiectasis. The total individual burden of CVID was 36,785 (33,078, 41,380) DALY/105. With estimated CVID prevalence of ~ 1/ 25,000, the societal burden of CVID ensued 1.5 (1.3, 1.7) DALY/105 of the general population. In exploratory analysis, increased mortality was associated with solid tumor, HR (95% CI): 2.69 (1.10; 6.57) p = 0.030, lymphoma: 5.48 (2.36; 12.71) p < .0001 and granulomatous-lymphocytic interstitial lung disease: 4.85 (1.63; 14.39) p = 0.005. Diagnostic delay (median: 4 years) was associated with a higher risk of death: 1.04 (1.02; 1.06) p = .0003, bronchiectasis: 1.03 (1.01; 1.04) p = .0001, solid tumor: 1.08 (1.04; 1.11) p < .0001 and enteropathy: 1.02 (1.00; 1.05) p = .0447 and stayed unchanged over four decades (p = .228).
CONCLUSIONS: While the societal burden of CVID may seem moderate, it is severe to the individual patient. Delay in CVID diagnosis may constitute a modifiable risk factor of serious comorbidities and death but showed no improvement. Tools supporting timely CVID diagnosis should be developed with high priority.

PMID: 30419968 [PubMed – in process]

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Primary immunodeficiency diseases in lung disease: warning signs, diagnosis and management.

Respir Res. 2018 Nov 12;19(1):219

Authors: Soler-Palacín P, de Gracia J, González-Granado LI, Martín C, Rodríguez-Gallego C, Sánchez-Ramón S, Group LI

Abstract
BACKGROUND: Pulmonary complications are common in primary immunodeficiency diseases (PID) and contribute to morbidity and mortality in these patients. However, their varied presentation and a general lack of awareness of PID in this setting make early diagnosis and treatment difficult. The aim of this study was to define the warning signs of PID in patients with respiratory manifestations, the necessary diagnostic tests, and the therapeutic management of both children and adults.
METHODS: A review of the literature was performed, and 43 PID interdisciplinary specialists were consulted.
RESULTS: This document identifies the pulmonary and extrapulmonary manifestations that should prompt a suspicion of PID, the immunological and respiratory tests that should be included in the diagnostic process according to the level of care, recommendations regarding the use of immunoglobulin replacement therapy according to the specific immunodeficiency, and the minimum recommended immunological and pulmonary monitoring in these patients.
CONCLUSIONS: This document is the first to combine scientific evidence with the opinion of a broad panel of experts specializing in the treatment of patients with immunodeficiencies. It aims to provide a useful tool for all practitioners who are regularly involved in the management of these patients.

PMID: 30419907 [PubMed – in process]

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Infectious etiology of chronic diarrhea in patients with primary immunodeficiency diseases.

Eur Ann Allergy Clin Immunol. 2018 Nov 12;:

Authors: Parvaneh L, Sharifi N, Azizi G, Sharifi L, Mohebbi A, Bahraminia E, Delavari S, Alebouyeh M, Tajeddin E, Mohebbi SR, Yazdani R, Behniafard N, Aghamohammadi A

Abstract
Summary: Background.Primary immunodeficiency diseases (PIDs) are life-threatening disorders, which manifest commonly with gastrointestinal (GI) signs, mainly as chronic diarrhea. Objective. To investigate and compare infectious etiology of chronic diarrhea in different PIDs. Patients and methods. Assessing clinical features, obtaining immunological profiles, as well as characterizing infectious etiology of diarrhea were performed in 38 PID patients with chronic diarrhea. Stool samples and/or biopsy specimens were checked using culture, microscopic examination, RT-PCR, and PCR, as appropriate. The patients were diagnosed to have common variable immunodeficiency (CVID), severe combined immunodeficiency (SCID), X-linked agammaglobulinemia (XLA), and hyper-IgM (HIgM) syndrome. Results. In 32 patients we identified 41 infectious agents including 16 parasitic (39.0%, the most common Giardia lamblia), 11 bacterial (26.8%, the most common salmonella spp), 8 viral (19.5%, the most frequent group A rotavirus), and 6 fungal organisms (14.7%, the most common Candida albicans). From 6 of the patients, no infectious agent was isolated. In CVID bacteria and parasites, in SCID bacteria and viruses, in XLA parasites, and in individuals with HIgM syndrome parasites were the leading causes of chronic diarrhea. Infection with giardia and cryptosporidium were more frequent in XLA and HIgM, respectively. Conclusion. The current study suggests considering both usual and unusual pathogens in laboratory investigation and in the empiric treatment of chronic diarrhea. Opportunistic pathogens should be taken into account when no other pathogen is identified, especially in patients on long-term treatment or prophylaxis with antifungals/antibiotics and in those from geographical locations that favor pathogenicity of these organisms.

PMID: 30417635 [PubMed – as supplied by publisher]

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Cutaneous Manifestations of Primary Immunodeficiency Diseases in Tunisian Children.

Mediterr J Hematol Infect Dis. 2018;10(1):e2018065

Authors: Dhouib NG, Ben Khaled M, Ouederni M, Ben-Mustapha I, Kouki R, Besbes H, Barbouche MR, Mellouli F, Bejaoui M

Abstract
Skin manifestations are frequent among patients with primary immunodeficiency diseases (PIDs). Their prevalence varies according to the type of immunodeficiency. This review provides the reader with an up-to-date summary of the common dermatologic manifestations of PIDs among Tunisian children. We conducted a prospective study on two hundred and ninety children with immune deficiency. Demographic details (including age, sex, and consanguinity) with personal and family history were recorded. Special attention was paid to cutaneous manifestations. Dermatological involvements were grouped according to the etiology of their most prominent sign. Cutaneous manifestations were found in 164 patients (56.5%). They revealed the diagnosis of PIDs in 71 patients (24.5 %). The mean age at presentation was 21 months. Overall the most prominent cutaneous alterations were infectious. They accounted for 106 cases (36.55%). The most prevalent causes of cutaneous infections were bacterial: 93 cases (32.06%). Immuno-allergic skin diseases were among the common findings in our study. These include eczematous dermatitis found in 62 cases (21.38%). Malignancy related PIDs was seen in a boy with Wiskott Aldrich syndrome. He developed Kaposi’s sarcoma at the age of 14 months. Cutaneous changes are common among children with PIDs. In pediatric patients with failure to thrive, chronic refractory systemic manifestations often present in other family members, recurrent cutaneous infections unresponsive to adequate therapy, atypical forms of eczematous dermatitis or unusual features should arouse the suspicion of PIDs and prompt specialized immunologic consultation should be made.

PMID: 30416697 [PubMed]

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Long-Term Efficacy and Safety of Hizentra® in Patients with Primary Immunodeficiency in Japan, Europe, and the United States: a Review of 7 Phase 3 Trials.

J Clin Immunol. 2018 Nov 10;:

Authors: Jolles S, Rojavin MA, Lawo JP, Nelson R, Wasserman RL, Borte M, Tortorici MA, Imai K, Kanegane H

Abstract
Many patients with primary immunodeficiency (PID) require immunoglobulin G (IgG) replacement therapy, delivered as intravenous IgG (IVIG) or subcutaneous IgG (SCIG). We aim to identify trends in efficacy and safety that would not be evident in individual studies of small patient numbers. Seven open-label, Phase 3, prospective, multicenter studies of the efficacy and safety of Hizentra® (a SCIG), conducted in Japan, Europe, and the US were summarized. Overall, 125 unique patients received 15,013 weekly infusions during a total observation period of 250.9 patient-years. Mean weekly doses of Hizentra® were 83.22-221.3 mg/kg body weight; infusion rates per patient (total body rate) were 25.2-49.3 mL/h across studies. The rates of infections and serious bacterial infections were 3.10 and 0.03 events per patient/year, respectively. Annualized rates of days hospitalized due to infection, out of work/school, and prophylactic antibiotic use were 0.95, 5.14, and 36.78 per patient, respectively. For the equivalent monthly dose, weekly Hizentra® SCIG administration resulted in expectedly-increased serum IgG trough levels in patients switching from IVIG, and maintained levels in patients switching from previous SCIG. Adverse events (AEs) totaled 5039 (events/infusion 0.094-0.773), almost all of which were mild/moderate. Three thousand one hundred ninety-seven were considered treatment-related, the most common of which were injection site reactions (2919 events; 0.001-0.592 AEs per infusion). Systemic AEs were very uncommon. The results from these seven studies indicate that Hizentra® therapy was both efficacious and well tolerated during long-term treatment. This is particularly important in patients with PID, who may require lifelong IgG replacement therapy.

PMID: 30415311 [PubMed – as supplied by publisher]

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Psoriasis in a cohort of patients with common variable immunodeficiency.

Br J Dermatol. 2018 Nov 10;:

Authors: Megna M, Pecoraro A, Balato N, Villani A, Crescenzi L, Balato A, Spadaro G

Abstract
Common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency in adults. CVID is characterized by reduced serum levels of IgG, IgA, and/or IgM, recurrent bacterial infections, autoimmune and inflammatory diseases and malignancies. According to literature, autoimmune diseases occur in 20-30% of CVID patients. Dermatological involvement has occasionally been reported in CVID and includes alopecia totalis, lichen planus, and vitiligo. Data regarding the frequency and features of psoriasis in CVID are scant. This article is protected by copyright. All rights reserved.

PMID: 30414274 [PubMed – as supplied by publisher]

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Hyper IgE recurrent infection syndrome in South Asia: is there a different outcome?

Allergy Asthma Clin Immunol. 2018;14:70

Authors: de Silva R, Dasanayake D, Senanayake M, Ediriweera R, Dias S, Karunatilleke C, Brocas K, Tahami F, Seneviratne S

Abstract
Background: Hyper IgE recurrent infection syndrome (HIES) is a rare immune deficiency, characterized by recurrent staphylococcal skin and lung abscesses, pneumonia and increased IgE levels. The majority of autosomal dominant HIES (AD HIGE) is due to hypomorphic mutations in the signal transducer and the activator of transcription 3 (STAT3) gene.
Case presentation: Five patients were diagnosed with HIES, based on the clinical criteria and scoring system developed at the National Institutes of Health (NIH), USA. The STAT3 gene was sequenced and previously described mutations were identified in all five patients. We compare the clinical features of our patients with those from Asia, Europe and the US.
Conclusion: Even though the number of patients is limited, there are some clinical differences in patients from South Asia compared to European and even East Asian patients. However, the mutations detected are located at hot spots seen in western and Asian patients with AD HIGE.

PMID: 30410549 [PubMed]

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LRBA in the endomembrane system.

Colomb Med (Cali). 2018 Sep 30;49(3):236-243

Authors: Martínez Jaramillo C, Trujillo-Vargas CM

Abstract
Bi-allelic mutations in LRBA (from Lipopolysaccharide-responsive and beige-like anchor protein) result in a primary immunodeficiency with clinical features ranging from hypogammaglobulinemia and lymphoproliferative syndrome to inflammatory bowel disease and heterogeneous autoimmune manifestations. LRBA deficiency has been shown to affect vesicular trafficking, autophagy and apoptosis, which may lead to alterations of several molecules and processes that play key roles for immunity. In this review, we will discuss the relationship of LRBA with the endovesicular system in the context of receptor trafficking, autophagy and apoptosis. Since these mechanisms of homeostasis are inherent to all living cells and not only limited to the immune system and also, because they are involved in physiological as well as pathological processes such as embryogenesis or tumoral transformation, we envisage advancing in the identification of potential pharmacological agents to manipulate these processes.

PMID: 30410199 [PubMed – in process]

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