Manish Butte

Fourth Update on the Iranian National Registry of Primary Immunodeficiencies: Integration of Molecular Diagnosis.

October 12, 2018 By Manish Butte

Fourth Update on the Iranian National Registry of Primary Immunodeficiencies: Integration of Molecular Diagnosis.

J Clin Immunol. 2018 Oct 09;:

Authors: Abolhassani H, Kiaee F, Tavakol M, Chavoshzadeh Z, Mahdaviani SA, Momen T, Yazdani R, Azizi G, Habibi S, Gharagozlou M, Movahedi M, Hamidieh AA, Behniafard N, Nabavi M, Bemanian MH, Arshi S, Molatefi R, Sherkat R, Shirkani A, Amin R, Aleyasin S, Faridhosseini R, Jabbari-Azad F, Mohammadzadeh I, Ghaffari J, Shafiei A, Kalantari A, Mansouri M, Mesdaghi M, Babaie D, Ahanchian H, Khoshkhui M, Soheili H, Eslamian MH, Cheraghi T, Dabbaghzadeh A, Tavassoli M, Kalmarzi RN, Mortazavi SH, Kashef S, Esmaeilzadeh H, Tafaroji J, Khalili A, Zandieh F, Sadeghi-Shabestari M, Darougar S, Behmanesh F, Akbari H, Zandkarimi M, Abolnezhadian F, Fayezi A, Moghtaderi M, Ahmadiafshar A, Shakerian B, Sajedi V, Taghvaei B, Safari M, Heidarzadeh M, Ghalebaghi B, Fathi SM, Darabi B, Bazregari S, Bazargan N, Fallahpour M, Khayatzadeh A, Javahertrash N, Bashardoust B, Zamani M, Mohsenzadeh A, Ebrahimi S, Sharafian S, Vosughimotlagh A, Tafakoridelbari M, Rahimi M, Ashournia P, Razaghian A, Rezaei A, Mamishi S, Parvaneh N, Rezaei N, Hammarström L, Aghamohammadi A

Abstract
BACKGROUND: The number of inherited diseases and the spectrum of clinical manifestations of primary immunodeficiency disorders (PIDs) are ever-expanding. Molecular diagnosis using genomic approaches should be performed for all PID patients since it provides a resource to improve the management and to estimate the prognosis of patients with these rare immune disorders.
METHOD: The current update of Iranian PID registry (IPIDR) contains the clinical phenotype of newly registered patients during last 5 years (2013-2018) and the result of molecular diagnosis in patients enrolled for targeted and next-generation sequencing.
RESULTS: Considering the newly diagnosed patients (n = 1395), the total number of registered PID patients reached 3056 (1852 male and 1204 female) from 31 medical centers. The predominantly antibody deficiency was the most common subcategory of PID (29.5%). The putative causative genetic defect was identified in 1014 patients (33.1%) and an autosomal recessive pattern was found in 79.3% of these patients. Among the genetically different categories of PID patients, the diagnostic rate was highest in defects in immune dysregulation and lowest in predominantly antibody deficiencies and mutations in the MEFV gene were the most frequent genetic disorder in our cohort.
CONCLUSIONS: During a 20-year registration of Iranian PID patients, significant changes have been observed by increasing the awareness of the medical community, national PID network establishment, improving therapeutic facilities, and recently by inclusion of the molecular diagnosis. The current collective study of PID phenotypes and genotypes provides a major source for ethnic surveillance, newborn screening, and genetic consultation for prenatal and preimplantation genetic diagnosis.

PMID: 30302726 [PubMed – as supplied by publisher]

Staphylococcal scalded skin syndrome: An uncommon symptomatology revealing an immune deficiency.

October 12, 2018 By Manish Butte

Staphylococcal scalded skin syndrome: An uncommon symptomatology revealing an immune deficiency.

Arch Pediatr. 2018 Feb;25(2):126-128

Authors: Ajmi H, Jemmali N, Mabrouk S, Hassayoun S, Ben-Ali M, Barbouche MR, Mokni M, Abroug S

Abstract
Primary immune deficiencies associated with hyper-IgE syndrome are rare diseases with clinical features dominated by recurring cutaneous and visceral bacterial infections, particularly infections due to Staphylococcus species. Most of these infections are associated with milder inflammation compared to normal. We report a primary immune deficiency associated with a hyper-IgE syndrome revealed by a staphylococcal scalded skin syndrome in a 5-year-old girl. The patient presented with a severe staphylococcal infection with extensive skin lesions and disseminated intravascular coagulation. She received intravenous fluids to compensate for fluid losses and anti-staphylococcal antibiotics. Coagulopathy was also corrected. However, the progression was rapidly fatal.

PMID: 29248323 [PubMed – indexed for MEDLINE]

New primary immunodeficiency diseases: context and future.

October 10, 2018 By Manish Butte

New primary immunodeficiency diseases: context and future.

Curr Opin Pediatr. 2018 Oct 08;:

Authors: Yu JE, Orange JS, Demirdag YY

Abstract
PURPOSE OF REVIEW: Primary immunodeficiency diseases (PIDs) are genetic disorders classically characterized by impaired host defense and an increased susceptibility to infection. It is now appreciated that these conditions broadly include variations in the genetic code that cause dysregulated immune function. This review highlights the newly defined PIDs in the 2017 International Union of Immunologic Societies (IUIS) report, current approaches to diagnosing PIDs, and the implications for the future management of PIDs.
RECENT FINDINGS: With the advances in and increased commercial availability of genetic testing and the adoption of the TREC assay into the US Newborn Screening program, the number of identified PIDs has exponentially risen in the past few decades, reaching over 350 disorders. The IUIS Inborn Errors of Immunity committee acknowledged at least 50 new disorders between 2015 and 2017. Furthermore, given the greater recognition of disorders with primarily immune dysregulation, the committee proposed a more inclusive term of ‘inborn errors of immunity’ to encompass primary immunodeficiencies and immune dysregulation disorders.
SUMMARY: This latest IUIS report underscores the rapid expansion in the PID field with technologic advancements in immunogenetics and clinical screening discovering new genetic diseases, and therefore, paving the way to novel therapeutics and precision medicine.

PMID: 30300326 [PubMed – as supplied by publisher]

Epstein-Barr virus associated smooth muscle tumors in solid organ transplant recipients: Incidence over 31 years at a single institution and review of the literature.

October 10, 2018 By Manish Butte

Epstein-Barr virus associated smooth muscle tumors in solid organ transplant recipients: Incidence over 31 years at a single institution and review of the literature.

Transpl Infect Dis. 2018 Oct 09;:e13010

Authors: Stubbins RJ, Alami Laroussi N, Peters AC, Urschel S, Dicke F, Lai RL, Zhu J, Mabilangan C, Preiksaitis JK

Abstract
INTRODUCTION: Epstein-Barr virus (EBV) associated smooth muscle tumors (EBV-SMT) are a rare complication of solid organ transplantation (SOT). Incidence data related to this EBV-SMT are limited. EBV DNA is universally present in these tumors. How these cells get infected with EBV, whether this is a result of primary EBV infection versus reactivation, and how persistent active EBV infection post-transplant influences EBV-SMT pathogenesis remains unknown.
METHODS: Among 5006 SOT recipients (474 pediatric, 4532 adult) receiving SOT at our center between Jan 1984 – Dec 2015, three cases of post-transplant EBV-SMT were identified.
RESULTS: All cases were pediatric heart transplants who were EBV seronegative prior to transplant, and experienced primary EBV infection with persistently elevated EBV viral loads, despite antiviral therapy. Two are deceased at 3.2 and 0.9 years post-diagnosis, while one remains alive 6.2 years post-diagnosis. The overall local incidence of post-transplant EBV-SMT at our institution was 0.7 (95% confidence interval, 0.2 to 1.7) per 1000 patient years, and 2.6 (95% confidence interval, 0.6 to 6.7) per 1000 patient years in pediatric heart transplants. A literature review identified 36 pediatric and 51 adult cases of post-transplant EBV-SMT.
CONCLUSIONS: We hypothesize that pre-transplant EBV seronegativity, followed by primary EBV infection and persistently high EBV viral loads, represents a unique risk factor for post-transplant EBV-SMT. Pediatric heart transplant recipients were found to be disproportionately affected by post-transplant EBV-SMT at our institution. This article is protected by copyright. All rights reserved.

PMID: 30298678 [PubMed – as supplied by publisher]

The evaluation of safety and efficacy of colistin use in pediatric intensive care unit: Results from two reference hospitals and review of literature.

October 10, 2018 By Manish Butte

The evaluation of safety and efficacy of colistin use in pediatric intensive care unit: Results from two reference hospitals and review of literature.

J Infect Chemother. 2018 May;24(5):370-375

Authors: Sahbudak Bal Z, Kamit Can F, Yazici P, Berna Anil A, Duyu M, Yilmaz Ciftdogan D, Nisel Yilmaz O, Cilli F, Karapinar B

Abstract
Colistin, an old cationic polypeptide antibiotic, have been reused due to rising incidence of infections caused by multi-drug resistant (MDR) Gram-negative microorganisms and the lack of new antibiotics. Therefore, we evaluated safety and efficacy of colistin in treatment of these infections. This study included 104 critically ill children with a median age of 55,9 months between January 2011 and January 2016. Nephrotoxicity occurred in 11 (10.5%) patients. Nephrotoxicity occurred between the third and seventh day of treatment in 63% of colistin induced nephrotoxicity episodes. The subgroup analysis between the patients who developed nephrotoxicity during colistin treatment and those that did not, showed no significant difference in terms of age, underlying disease, cause for PICU admission and type of infection required colistin treatment, P values were 0.615, 0.762, 0.621, 0.803, respectively. All patients were receiving a concomitant nephrotoxic agent (P = 0,355). The majority of the patients (52%) were having primary or secondary immune deficiency in treatment failure group and the most common cause of PICU admission was sepsis in treatment failure group, P values were 0.007 and 0.045, respectively. Mortality attributed to colistin failure and crude mortality were 14.4% and 29.8%, respectively. In conclusion, colistin may have a role in the treatment of infections caused by multidrug-resistant Gram-negative bacteria in critically ill children. However, the patients have to be followed for side effects throughout colistin treatment, not for only early stage. And the clinicians should be aware of increase in the rate of nephrotoxicity in patients those have been receiving a concomitant nephrotoxic agent.

PMID: 29361414 [PubMed – indexed for MEDLINE]

How we approach: Severe congenital neutropenia and myelofibrosis due to mutations in VPS45.

October 9, 2018 By Manish Butte

How we approach: Severe congenital neutropenia and myelofibrosis due to mutations in VPS45.

Pediatr Blood Cancer. 2018 Oct 07;:e27473

Authors: Shadur B, Asherie N, Newburger PE, Stepensky P

Abstract
Mutations in the VPS45 gene lead to a severe primary immune deficiency characterized by severe congenital neutropenia and primary myelofibrosis, leading to overwhelming infection and early death. This condition is exceedingly rare with only 16 patients previously reported, including four with successful hematopoietic stem cell transplantation. We review the pathophysiology underlying this condition and detail our approach to treatment, particularly vis-à-vis bone marrow transplantation and the challenges of transplanting into a diseased bone marrow niche. We provide an update on the progress of our three previously reported patients, and two additional patients transplanted at our center.

PMID: 30294941 [PubMed – as supplied by publisher]

Targeted high-throughput sequencing technique for the molecular diagnosis of primary immunodeficiency disorders.

October 7, 2018 By Manish Butte

Targeted high-throughput sequencing technique for the molecular diagnosis of primary immunodeficiency disorders.

Medicine (Baltimore). 2018 Oct;97(40):e12695

Authors: Chi ZH, Wei W, Bu DF, Li HH, Ding F, Zhu P

Abstract
The aim of this study was to investigate the usefulness of targeted high-throughput sequencing (HTS) for the molecular diagnosis of primary immunodeficiency diseases (PID).A total of 56 clinically diagnosed or suspected PID patients were divided into 4 groups according to the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency 2015 and their chief clinical presentations. Patients and their biological family members were examined by targeted HTS, which sequenced the exons and ±10 bp flanking introns of 171 PID-related genes panel. All significant variants were confirmed by PCR-Sanger sequencing. Pathogenicity of the variants was evaluated by using bioinformatics.A total of 117 variants in 73 genes were found in 56 patients. Accurate molecular diagnosis of PID was made in 13 (23.2%) patients, and 12 novel mutations were detected in these patients. Twenty-seven patients carried heterozygous variants that are probably pathogenic in ≥2 genes; 16 patients had only 1 missense variant, or had several variants but not >1 variant was deleterious as evaluated by bioinformatics. The meaning of the targeted HTS results of these patients remains to be studied.Targeted HTS can make a precise molecular diagnosis of PID and detect more novel pathogenic mutations. More and more variations with ambiguous significance are discovered and explanation of these variations is a challenge to the clinicians.

PMID: 30290665 [PubMed – in process]

Immunoglobulin use in immune deficiency in the UK: a report of the UKPID and National Immunoglobulin Databases.

October 6, 2018 By Manish Butte

Immunoglobulin use in immune deficiency in the UK: a report of the UKPID and National Immunoglobulin Databases.

Clin Med (Lond). 2018 Oct;18(5):364-370

Authors: Shillitoe B, Hollingsworth R, Foster M, Garcez T, Guzman D, Edgar JD, Buckland M

Abstract
Supply of immunoglobulin in the UK faces pressures due to increasing demand, cost and variable supply. This paper describes immunoglobulin replacement therapy (IGRT) in primary immunodeficiency (PID) and secondary immunodeficiency (SID) to assist in the ongoing planning of UK immunoglobulin provision. A retrospective analysis of the National Immunoglobulin Database and the UKPID registry was carried out. In total, 3,222 patients are registered as receiving IGRT for immunodeficiencies. Predominately antibody disorders made up the largest diagnostic category (61% of patients). The total cost of IGRT for immunodeficiency for 2015/16 was £40,673,350; an average annual cost of £1,099,254 per centre and £12,124 per PID patient. SCIg accounted for 43.8% and 50.1% of IGRT, with home therapy accounting for 42.7% and 57.5% of place of therapy in the National Immunoglobulin Database and UKPID registry respectively. In 2015/16 use of immunoglobulin in SID increased by 24% over the previous financial year. The overall trends of increasing demand in immunology are mirrored in other specialties, most notably neurology and haematology. These data are the first national overview of IGRT for immunodeficiencies, providing a valuable resource for clinicians and policy makers in the ongoing management of UK immunoglobulin supply.

PMID: 30287427 [PubMed – in process]

Mechanisms of Regulated and Dysregulated CARD11 Signaling in Adaptive Immunity and Disease.

October 5, 2018 By Manish Butte

Mechanisms of Regulated and Dysregulated CARD11 Signaling in Adaptive Immunity and Disease.

Front Immunol. 2018;9:2105

Authors: Bedsaul JR, Carter NM, Deibel KE, Hutcherson SM, Jones TA, Wang Z, Yang C, Yang YK, Pomerantz JL

Abstract
CARD11 functions as a key signaling scaffold that controls antigen-induced lymphocyte activation during the adaptive immune response. Somatic mutations in CARD11 are frequently found in Non-Hodgkin lymphoma, and at least three classes of germline CARD11 mutations have been described as the basis for primary immunodeficiency. In this review, we summarize our current understanding of how CARD11 signals, how its activity is regulated, and how mutations bypass normal regulation to cause disease.

PMID: 30283447 [PubMed – in process]

The CBM-opathies-A Rapidly Expanding Spectrum of Human Inborn Errors of Immunity Caused by Mutations in the CARD11-BCL10-MALT1 Complex.

October 5, 2018 By Manish Butte

The CBM-opathies-A Rapidly Expanding Spectrum of Human Inborn Errors of Immunity Caused by Mutations in the CARD11-BCL10-MALT1 Complex.

Front Immunol. 2018;9:2078

Authors: Lu HY, Bauman BM, Arjunaraja S, Dorjbal B, Milner JD, Snow AL, Turvey SE

Abstract
The caspase recruitment domain family member 11 (CARD11 or CARMA1)-B cell CLL/lymphoma 10 (BCL10)-MALT1 paracaspase (MALT1) [CBM] signalosome complex serves as a molecular bridge between cell surface antigen receptor signaling and the activation of the NF-κB, JNK, and mTORC1 signaling axes. This positions the CBM complex as a critical regulator of lymphocyte activation, proliferation, survival, and metabolism. Inborn errors in each of the CBM components have now been linked to a diverse group of human primary immunodeficiency diseases termed “CBM-opathies.” Clinical manifestations range from severe combined immunodeficiency to selective B cell lymphocytosis, atopic disease, and specific humoral defects. This surprisingly broad spectrum of phenotypes underscores the importance of “tuning” CBM signaling to preserve immune homeostasis. Here, we review the distinct clinical and immunological phenotypes associated with human CBM complex mutations and introduce new avenues for targeted therapeutic intervention.

PMID: 30283440 [PubMed – in process]