Manish Butte

Immunoglobulin G (IgG) and IgG subclass reference intervals in children, using Optilite® reagents.

Clin Chem Lab Med. 2018 Apr 09;:

Authors: Grunewald O, Lopez B, Brabant S, Rogeau S, Deschildre A, Phrommavanh V, Lefort M, Moitrot E, Gyselinckx D, Deleplancque AS, Lefevre G, Labalette M, Dubucquoi S

Abstract
BACKGROUND: Immunoglobulin G (IgG) and IgG subclass assays are indicated in patients with suspected primary immunodeficiency (PID). Commercially available assays for IgG subclass determination are calibrated against various preparations, and so specific reference values are required for each of them. Using Optilite® reagents from The Binding Site Group Ltd., we sought to determine the pediatric IgG and IgG subclass reference intervals with respect to the ERM-DA470k certified reference material.
METHODS: Levels of IgG and IgG subclasses were analyzed in serum samples collected from a large cohort of PID-free children and adolescents. Reference intervals were calculated for previously published age groups (6-12 months, 12-18 months, 18 months-2 years, 2-3 years, 3-4 years, 4-6 years, 6-9 years, 9-12 years and 12-18 years), according to the Clinical and Laboratory Standards Institute’s C28-A3c protocol.
RESULTS: A total of 456 serum samples were analyzed. The correlation between the total IgG and the sum of the IgG subclasses was good (r2=0.96). No statistically significant gender-specific differences were observed. Our results for the changes over time in IgG and IgG subclass levels are consistent with previous reports. The differences between our lower/upper reference limits and those in the literature are probably due to variations in calibration.
CONCLUSIONS: Our present results provide a reliable basis for the diagnosis of PIDs in childhood and for the accreditation of laboratories using Optilite® immunoturbidimetric reagents for IgG subclass measurement. Laboratory scientists and clinicians should be aware of the need for manufacturer-specific IgG subclass reference intervals.

PMID: 29630506 [PubMed – as supplied by publisher]

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Gene therapy in rare diseases: the benefits and challenges of developing a patient-centric registry for Strimvelis in ADA-SCID.

Orphanet J Rare Dis. 2018 Apr 06;13(1):49

Authors: Stirnadel-Farrant H, Kudari M, Garman N, Imrie J, Chopra B, Giannelli S, Gabaldo M, Corti A, Zancan S, Aiuti A, Cicalese MP, Batta R, Appleby J, Davinelli M, Ng P

Abstract
BACKGROUND: Strimvelis (autologous CD34+ cells transduced to express adenosine deaminase [ADA]) is the first ex vivo stem cell gene therapy approved by the European Medicines Agency (EMA), indicated as a single treatment for patients with ADA-severe combined immunodeficiency (ADA-SCID) who lack a suitable matched related bone marrow donor. Existing primary immunodeficiency registries are tailored to transplantation outcomes and do not capture the breadth of safety and efficacy endpoints required by the EMA for the long-term monitoring of gene therapies. Furthermore, for extended monitoring of Strimvelis, the young age of children treated, small patient numbers, and broad geographic distribution of patients all increase the risk of loss to follow-up before sufficient data have been collected. Establishing individual investigator sites would be impractical and uneconomical owing to the small number of patients from each location receiving Strimvelis.
RESULTS: An observational registry has been established to monitor the safety and effectiveness of Strimvelis in up to 50 patients over a minimum of 15 years. To address the potential challenges highlighted above, data will be collected by a single investigator site at Ospedale San Raffaele (OSR), Milan, Italy, and entered into the registry via a central electronic platform. Patients/families and the patient’s local physician will also be able to submit healthcare information directly to the registry using a uniquely designed electronic platform. Data entry will be monitored by a Gene Therapy Registry Centre (funded by GlaxoSmithKline) who will ensure that necessary information is collected and flows between OSR, the patient/family and the patient’s local healthcare provider.
CONCLUSION: The Strimvelis registry sets a precedent for the safety monitoring of future gene therapies. A unique, patient-focused design has been implemented to address the challenges of long-term follow-up of patients treated with gene therapy for a rare disease. Strategies to ensure data completeness and patient retention in the registry will help fulfil pharmacovigilance requirements. Collaboration with partners is being sought to expand from a treatment registry into a disease registry. Using practical and cost-efficient approaches, the Strimvelis registry is hoped to encourage further innovation in registry design within orphan drug development.

PMID: 29625577 [PubMed – in process]

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Pediatric hyperimmunoglobulin E syndrome: A case series of 4 children in China.

Medicine (Baltimore). 2018 Apr;97(14):e0215

Authors: Fan H, Huang L, Yang D, Lin Y, Lu G, Xie Y, Yu J, Zhang D

Abstract
Hyperimmunoglobulin E syndromes (HIES) are rare primary immunodeficiency diseases characterized by markedly elevated serum immunoglobulin (Ig) E, recurrent pneumonia, and chronic eczema. To date, information about pediatric HIES is limited. We aimed to evaluate the spectrum of clinical and immunological features in pediatric patients with HIES in China.We retrospectively reviewed the cases of 4 pediatric patients with HIES followed at the Guangzhou Women and Children’s Medical Center from May 2013 to September 2017. We analyzed clinical presentation, laboratory data, immunological evaluations, imagenological characteristics, treatment, response to therapy, genetic and bronchoalveolar lavage fluid (BALF) findings, and prognosis.The common clinical features of the patients were recurrent respiratory and mucocutaneous infections and eczematoid skin lesions. In 3 of 4 patients, BALF and transbronchial lung biopsy (TBLB) demonstrated fungal pneumonia with organisms including invasive Aspergillus and Penicillium marneffei. Elevated serum IgG and IgM were detected in 3 and 2 cases, respectively, while CD4+ T and CD19+ B cells were slightly reduced in only 1 patient. Nitroblue tetrazolium tests (NBTs) were normal in all patients, and reduced natural killer cell counts were identified in 3 patients. A novel missense mutation in exon 17 (c.1593A>T, p.K531N) was identified in the signal transducer and activator of transcription 3 (STAT3) gene that has not been reported previously. One patient had 3 homozygous nonsynonymous variations of the complement receptor 2 (CR2) gene distributed in exons 10 (c.1916G>A, p.S639N) and 11 (c.1987T>C, p.S663P and c.2012G>A, p.R671H) with high frequency.This case series suggests that fungi are important respiratory pathogens in children with HIES and should be considered in cases of pneumonia in this population. The NIH scoring system does not allow diagnostic certainty, particularly in infants, because some of the common manifestations of HIES may not develop until the patient matures. Pulmonary complications must be identified in the early stage of the disease to treat them effectively. In addition, we report a mutation in STAT3 that has not been identified previously.

PMID: 29620631 [PubMed – in process]

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Complications Associated with Underweight Primary Immunodeficiency Patients: Prevalence and Associations Within the USIDNET Registry.

J Clin Immunol. 2018 Apr 04;:

Authors: Ruffner MA, USIDNET Body Weight Group, Sullivan KE

Abstract
PURPOSE: The point prevalence of underweight status and obesity in primary immunodeficiency disease (PID) is unknown, despite the described associations between PID and weight loss and failure to thrive. The goal of this study is to estimate the prevalence of underweight status and obesity in PID patients and to investigate the associations between abnormal body weight and complications of PID.
METHODS: Using the US Immunodeficiency Network (USIDNET), we performed a retrospective analysis of 653 pediatric (age 2 to 20 years) and 514 adult (age > 20) patient records with information on patient body mass index (BMI). Prevalence of underweight and obese status in PID patients was compared to data from the National Health and Nutrition Examination Survey (NHANES).
RESULTS: After separating BMI data by year of entry to the database, we demonstrated that both adult and pediatric patients with PID had significantly higher prevalence of underweight patients in multiple years of analysis. Further examination of underweight patients by PID diagnosis revealed that underweight status in adults with CVID was associated with granulomatous disease as well as earlier age of CVID diagnosis. In the pediatric CVID cohort, underweight status was significantly associated with lymphopenia. Examination of obesity in pediatric and adult PID patients compared to NHANES database revealed only a single year when obesity in PID patients was significantly less prevalent. In other 2-year time intervals from 2005 to 2014, the prevalence of obesity was unchanged in children and adults.
CONCLUSIONS: These results quantify the prevalence of underweight status in PID in a North American population and demonstrate that whether as a result of weight loss or poor weight gain, underweight status is more prevalent in the PID population than in the general US population. The prevalence of obesity in PID patients was similar to that seen in the general population. This highlights the need for continued education on the association of low weight and PID.
CLINICAL TRIAL REGISTRATION: NCT01953016.

PMID: 29619656 [PubMed – as supplied by publisher]

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Functional Complement Analysis Can Predict Genetic Testing Results and Long-Term Outcome in Patients With Complement Deficiencies.

Front Immunol. 2018;9:500

Authors: Blazina Š, Debeljak M, Košnik M, Simčič S, Stopinšek S, Markelj G, Toplak N, Kopač P, Zakotnik B, Pokorn M, Avčin T

Abstract
Background: Prevalence of complement deficiencies (CDs) is markedly higher in Slovenian primary immunodeficiency (PID) registry in comparison to other national and international PID registries.
Objective: The purposes of our study were to confirm CD and define complete and partial CD in registered patients in Slovenia, to evaluate frequency of clinical manifestations, and to assess the risk for characteristic infections separately for subjects with complete and partial CD.
Methods: CD was confirmed with genetic analyses in patients with C2 deficiency, C8 deficiency, and hereditary angioedema or with repeated functional complement studies and measurement of complement components in other CD. Results of genetic studies (homozygous subjects vs. heterozygous carriers) and complement functional studies were analyzed to define complete (complement below the level of heterozygous carriers) and partial CD (complement above the level of homozygous patients). Presence of characteristic infections was assessed separately for complete and partial CD.
Results: Genetic analyses confirmed markedly higher prevalence of CD in Slovenian PID registry (26% of all PID) than in other national and international PID registries (0.5-6% of all PID). Complement functional studies and complement component concentrations reliably distinguished between homozygous and heterozygous CD carriers. Subjects with partial CD had higher risk for characteristic infections than previously reported.
Conclusion: Results of our study imply under-recognition of CD worldwide. Complement functional studies and complement component concentrations reliably predicted risk for characteristic infections in patients with complete or partial CD. Vaccination against encapsulated bacteria should be advocated also for subjects with partial CD and not limited to complete CD.

PMID: 29619023 [PubMed]

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In-depth interviews of patients with primary immunodeficiency who have experienced pump and rapid push subcutaneous infusions of immunoglobulins reveal new insights on their preference and expectations.

Patient Prefer Adherence. 2018;12:423-429

Authors: Cozon GJN, Clerson P, Dokhan A, Fardini Y, Sala TP, Crave JC

Abstract
Purpose: Patients with primary immunodeficiency (PID) often receive immunoglobulin replacement therapy (IgRT). Physicians and patients have the choice between various methods of administration. For subcutaneous immunoglobulin infusions, patients may use an automated pump (P) or push the plunger of a syringe (rapid push [RP]). P infusions are performed once a week and last around 1 hour. RP decreases the duration of administration, but requires more frequent infusions.
Patients and methods: Eight out of 30 patients (coming from a single center) who had participated in the cross-over, randomized, open-label trial comparing P and RP participated in a focus group or underwent in-depth interviews. Patients had a long history of home-based subcutaneous immunoglobulin using P. The trial suggested that RP had slightly greater interference on daily life than P, but similar efficacy and better cost-effectiveness. When asked about the delivery method they had preferred, around one-third of patients pointed out RP rather than P. In-depth interviews may reveal unforeseen reasons for patients’ preferences.
Results: Interviews underlined the complexity of the relationship that the patients maintain with their disease and IgRT. Even if they recognized the genetic nature of the disease and claimed PID was a part of them, patients tried not to be overwhelmed by the disease. IgRT by P was well integrated in patients’ routine. By contrast, RP too frequently reminded the patients of their disease. In addition, some patients pointed out the difficulty of pushing the plunger due to the viscosity of the product. Coming back too frequently, RP was not perceived as time saving over a week. Long-lasting use of P could partly explain patients’ reasonable reluctance to change to RP.
Conclusion: In-depth interviews of PID patients highlighted unforeseen reasons for patients’ preference that the physician needs to explore during the shared medical decision-making process.

PMID: 29618922 [PubMed]

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Evaluation of the TLR negative regulatory network in CVID patients.

Genes Immun. 2018 Apr 05;:

Authors: Sanaei R, Rezaei N, Aghamohammadi A, Delbandi AA, Teimourian S, Yazdani R, Tavasolian P, Kiaee F, Tajik N

Abstract
Common variable immunodeficiency (CVID), a clinically symptomatic primary immunodeficiency disease (PID), is characterized by hypogammaglobulinemia leading to recurrent infections and various complications. Recently, some defects in the signaling of TLRs have been identified in CVID patients which led us to investigate the expression of TLR4 and 9 negative regulatory molecules and their upregulation status following their activation. Using TaqMan real-time PCR, SOCS1, TNFAIP3, RFN216, and IRAK-M transcripts among peripheral blood mononuclear cells (PBMCs) were measured with/without TLR4 and 9 activations. TLR4 and 9 were activated by lipopolysaccharide (LPS) and unmethylated CpG-oligodeoxynucleotide (CpG-ODN), respectively. Production of IFN-α and TNF-α cytokines, as a part of the functional response of mentioned TLRs, was also measured using ELISA. Deficient transcripts of IRAK-M and TNFAIP3 in unstimulated PBMCs and lower production of TNF-α and IFN-α after treatments were observed. Upregulation of RFN216 and TNFAIP3 after TLR9 activation was abnormal compared to healthy individuals. Significant correlations were found between abnormal IRAK-M and TNFAIP3 transcripts, and lymphadenopathy and inflammatory scenarios in patients, respectively. It seems that the transcriptional status of some negative regulatory molecules is disturbed in CVID patients, and this could be caused by the underlying pathogenesis of CVID and could involve complications like autoimmunity and inflammatory responses.

PMID: 29618830 [PubMed – as supplied by publisher]

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Allogeneic hematopoietic stem cell transplantation for severe, refractory juvenile idiopathic arthritis.

Blood Adv. 2018 Apr 10;2(7):777-786

Authors: M F Silva J, Ladomenou F, Carpenter B, Chandra S, Sedlacek P, Formankova R, Grandage V, Friswell M, Cant AJ, Nademi Z, Slatter MA, Gennery AR, Hambleton S, Flood TJ, Lucchini G, Chiesa R, Rao K, Amrolia PJ, Brogan P, Wedderburn LR, Glanville JM, Hough R, Marsh R, Abinun M, Veys P

Abstract
Patients with juvenile idiopathic arthritis (JIA) can experience a severe disease course, with progressive destructive polyarthritis refractory to conventional therapy with disease-modifying antirheumatic drugs including biologics, as well as life-threatening complications including macrophage activation syndrome (MAS). Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative immunomodulatory strategy for patients with such refractory disease. We treated 16 patients in 5 transplant centers between 2007 and 2016: 11 children with systemic JIA and 5 with rheumatoid factor-negative polyarticular JIA; all were either refractory to standard therapy, had developed secondary hemophagocytic lymphohistiocytosis/MAS poorly responsive to treatment, or had failed autologous HSCT. All children received reduced toxicity fludarabine-based conditioning regimens and serotherapy with alemtuzumab. Fourteen of 16 patients are alive with a median follow-up of 29 months (range, 2.8-96 months). All patients had hematological recovery. Three patients had grade II-IV acute graft-versus-host disease. The incidence of viral infections after HSCT was high, likely due to the use of alemtuzumab in already heavily immunosuppressed patients. All patients had significant improvement of arthritis, resolution of MAS, and improved quality of life early following allo-HSCT; most importantly, 11 children achieved complete drug-free remission at the last follow-up. Allo-HSCT using alemtuzumab and reduced toxicity conditioning is a promising therapeutic option for patients with JIA refractory to conventional therapy and/or complicated by MAS. Long-term follow-up is required to ascertain whether disease control following HSCT continues indefinitely.

PMID: 29618462 [PubMed – in process]

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Molecular Mechanisms of Human Disease Mediated by Oncogenic and Primary Immunodeficiency Mutations in Class IA Phosphoinositide 3-Kinases.

Front Immunol. 2018;9:575

Authors: Dornan GL, Burke JE

Abstract
The signaling lipid phosphatidylinositol 3,4,5, trisphosphate (PIP3) is an essential mediator of many vital cellular processes, including growth, survival, and metabolism. PIP3 is generated through the action of the class I phosphoinositide 3-kinases (PI3K), and their activity is tightly controlled through interactions with regulatory proteins and activating stimuli. The class IA PI3Ks are composed of three distinct p110 catalytic subunits (p110α, p110β, and p110δ), and they play different roles in specific tissues due to disparities in both expression and engagement downstream of cell-surface receptors. Disruption of PI3K regulation is a frequent driver of numerous human diseases. Activating mutations in the PIK3CA gene encoding the p110α catalytic subunit of class IA PI3K are frequently mutated in several cancer types, and mutations in the PIK3CD gene encoding the p110δ catalytic subunit have been identified in primary immunodeficiency patients. All class IA p110 subunits interact with p85 regulatory subunits, and mutations/deletions in different p85 regulatory subunits have been identified in both cancer and primary immunodeficiencies. In this review, we will summarize our current understanding for the molecular basis of how class IA PI3K catalytic activity is regulated by p85 regulatory subunits, and how activating mutations in the PI3K catalytic subunits PIK3CA and PIK3CD (p110α, p110δ) and regulatory subunits PIK3R1 (p85α) mediate PI3K activation and human disease.

PMID: 29616047 [PubMed]

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Adoptive T Cell Therapy for Epstein-Barr Virus Complications in Patients With Primary Immunodeficiency Disorders.

Front Immunol. 2018;9:556

Authors: McLaughlin LP, Bollard CM, Keller MD

Abstract
Patients with primary immunodeficiency disorders (PID) have an increased risk from acute and chronic Epstein-Barr Virus (EBV) viral infections and EBV-associated malignancies. Hematopoietic stem cell transplantation (HSCT) is a curative strategy for many patients with PID, but EBV-related complications are common in the immediate post-transplant period due to delayed reconstitution of T cell immunity. Adoptive T cell therapy with EBV-specific T cells is a promising therapeutic strategy for patients with PID both before and after HSCT. Here we review the methods used to manufacture EBV-specific T cells, the clinical outcomes, and the ongoing challenges for future development of the strategy.

PMID: 29616044 [PubMed]

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