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Gene therapy for primary immunodeficiency.

July 13, 2019 By Manish Butte

Gene therapy for primary immunodeficiency.

Hum Mol Genet. 2019 Jul 11;:

Authors: Booth C, Romano R, Roncarolo MG, Thrasher AJ

Abstract
Gene therapy is now being trialled as a therapeutic option for an expanding number of conditions, based primarily on the successful treatment over the past two decades of patients with specific primary immunodeficiencies (PIDs) including severe combined immunodeficiency (SCID) and Wiskott-Aldrich syndrome (WAS) and metabolic conditions such as leukodystrophy. The field has evolved from the use of gammaretroviral vectors to more sophisticated lentiviral platforms which offer an improved biosafety profile alongside greater efficiency for HSC gene transfer. Here we review more recent developments including licensing of gene therapies, use of gene corrected autologous T cells as an alternative strategy for some PIDs and the potential of targeted gene correction using various gene editing platforms. Given the promising results of recent clinical trials it is likely that autologous gene therapies will become standard of care for a number of devastating diseases in the coming decade.

PMID: 31297531 [PubMed – as supplied by publisher]

[A clinical study of haploid hematopoietic stem cells combined with third-party umbilical cord blood transplantation in the treatment of chronic granulomatous disease].

July 12, 2019 By Manish Butte

[A clinical study of haploid hematopoietic stem cells combined with third-party umbilical cord blood transplantation in the treatment of chronic granulomatous disease].

Zhongguo Dang Dai Er Ke Za Zhi. 2019 Jun;21(6):552-557

Authors: Tang XF, Lu W, Jing YF, Huang YZ, Wu NH, Luan Z

Abstract
OBJECTIVE: To investigate the clinical efficacy of haploid hematopoietic stem cells (haplo-HSC) combined with third-party umbilical cord blood (tpCB) transplantation in the treatment of X-linked chronic granulomatous disease (X-CGD).
METHODS: The clinical data of 26 boys with X-CGD were retrospectively analyzed who were admitted to the Sixth Medical Center of PLA General Hospital between April 2014 and March 2018. All the patients were treated with haplo-HSC combined with tpCB transplantation. The median age of the patients was 3.5 years. The donor was the father in 25 cases and an aunt in 1 case. Transplantation was 5/6 HLA-matched in 9 cases, 4/6 in 12 cases, and 3/6 in 5 cases. The patients received busulfan, cyclophosphamide, fludarabine, or anti-thymocyte globulin for myeloablative preconditioning. Cyclosporine A and mycophenolate mofetil were used for prevention of acute graft-versus-host disease (aGVHD). Then the patients were treated with haploid bone marrow hematopoietic stem cells combined with tpCB transplantation on day 1 and haploid peripheral hematopoietic stem cells on day 2. The counts of median donor total nucleated cells, CD34+ cells, and CD3+ cells were 14.6×108/kg, 5.86×106/kg, and 2.13×108/kg respectively.
RESULTS: The median time to neutrophil and platelet engraftment was 12 and 23 days after transplantation respectively. Full donor hematopoietic chimerism was observed on day 30. Twenty-five cases were from haplo-HSC and 1 was from cord blood. No primary implant failure and implant dysfunction occurred, and secondary implant failure occurred in one case. The NADPH oxidase activity returned to normal one month after transplantation. The incidence of grade I-II aGVHD and grade III-IV aGVHD was 35% and 15% respectively. Chronic GVHD (cGVHD) of the skin occurred in one case, and no progression was observed after steroid administration. During the follow-up period of 6-51 months, 25 patients survived, of whom 24 were disease-free (23 patients without cGVHD and 1 with cGVHD of the skin) and NADPH oxidase activity returned to normal; one patient developed secondary implant failure but survived; one patient died of viral interstitial pneumonia 16 months after transplantation. The 5-year event-free survival rate and overall survival rate were 81%±12% and 89%±10% respectively.
CONCLUSIONS: Haplo-HSC combined with tpCB transplantation is one of the effective methods for the treatment of X-CGD in children.

PMID: 31208508 [PubMed – indexed for MEDLINE]

[Colombian Guidelines of clinical practice for the use of immunoglobulins in the treatment of replacement and immunomodulation].

July 12, 2019 By Manish Butte

[Colombian Guidelines of clinical practice for the use of immunoglobulins in the treatment of replacement and immunomodulation].

Rev Alerg Mex. 2017;64 Suppl 2:s5-s65

Authors: Olivares MM, Olmos CE, Álvarez MI, Fajardo AM, Zea-Vera AF, Ortega MC, Medina D, Pérez PM, Beltrán DG, Duque B, Álvarez CA, Lenis G, Solano JM, Gómez D, Franco JL, Díaz MC, Orrego JC, Velásquez MM, Chaparro M, Pinto JL, Izquierdo Á, Ramírez SF

Abstract
Immunoglobulins are heterodimeric proteins composed of 2 heavy chains and 2 light chains. Human immunoglobulin G (IgG) is a plasma derivative and contains more than 95% of IgG. The composition of IgG subclasses is similar to that of normal human plasma. Immunoglobulin therapy was first introduced more than 50 years ago, and its use has been described in numerous diseases. In Colombia, the importance of this immunomodulatory resource prompted the need for clinical practice guidelines to be available for its use. For this reason, a multidisciplinary group of experts was brought together and distributed in working groups, by specialties, in order to develop an initial manuscript. Systematic literature searches were undertaken; identified evidences were evaluated and classified to support a preliminary draft that was discussed, analyzed and amended. Recommendations were issued on the use of intravenous immunoglobulin in pathologies that include primary and secondary immunodeficiencies, autoimmune diseas es, neurological disorders, infections, transplants and miscellaneous conditions; grades were assigned to each one of them according to the GRADE system. The final result translated into recommendations that are put forth with the purpose to inform, guide and support on optimal use of this immunomodulatory resource.

PMID: 28863425 [PubMed – indexed for MEDLINE]

Severe Combined Immunodeficiency: A Guide for Primary Care Givers.

July 10, 2019 By Manish Butte

Severe Combined Immunodeficiency: A Guide for Primary Care Givers.

Clin Pediatr (Phila). 2019 Jul 07;:9922819859867

Authors: Seth D, Ruehle M, Kamat D

PMID: 31282184 [PubMed – as supplied by publisher]

[Inherited lymphoproliferative disorders].

July 10, 2019 By Manish Butte

[Inherited lymphoproliferative disorders].

Rinsho Ketsueki. 2019;60(6):708-715

Authors: Kanegane H, Hoshino A

Abstract
Lymphoproliferative disorders (LPDs) are caused by dysregulated lymphocyte proliferation and include polyclonal benign and monoclonal malignant diseases. LPDs frequently occur in immunocompromized patients, particularly those with primary immunodeficiency disease (PID), a monogenic disease. PID-associated LPD corresponds to inherited LPD. Here, we describe inherited LPD and focus on IKZF1-associated diseases and Epstein-Barr virus-associated LPD, such as ZAP70 deficiency and X-linked lymphoproliferative syndrome type 1 with somatic reversion mosaicism. Disclosing the pathogenesis of inherited LPDs would lead to a broad understanding of LPDs and development of new treatment strategies.

PMID: 31281164 [PubMed – in process]

[Cancer predisposition in inherited bone marrow failure syndromes and primary immunodeficiency diseases].

July 10, 2019 By Manish Butte

[Cancer predisposition in inherited bone marrow failure syndromes and primary immunodeficiency diseases].

Rinsho Ketsueki. 2019;60(6):702-707

Authors: Ishimura M, Ohga S

Abstract
Inherited bone marrow failure syndromes (IBMFS) are caused by mutations in genes associated with DNA repair and telomere maintenance. In addition, mutations in ribosome-related genes cause defective hematopoiesis. Patients with IBMFS exhibit a predisposition to developing hematological malignancy or solid tumor because of the defect in cellular and molecular hemostasis. The SAMD9 mutation causes the multisystem disorder, MIRAGE syndrome, characterized by congenital adrenal hypoplasia and loss of chromosome 7, providing a novel insight into the correlation between the germline and somatic mutations of SAMD9/SAMD9L and myelodysplastic syndrome (MDS) with monosomy 7. Primary immunodeficiency diseases (PID) are caused by inborn errors of the immune system. PID patients with inadequate tumor immunity are at an elevated risk of developing malignancies such as lymphoma, leukemia, and gastrointestinal cancer. Recently, monocytopenia and mycobacterial infection (MonoMAC) syndrome with the GATA2 gene mutation have been reported as PID related to bone marrow failure. Patients with MonoMAC syndrome often develop MDS and acute myeloid leukemia. Here, we present the pediatric-onset IBMFS and/or PID with cancer predisposition and briefly discuss the tumorigenesis in each monogenic disease.

PMID: 31281163 [PubMed – in process]

Cost-Effectiveness of a Savings-Led Economic Empowerment Intervention for AIDS-Affected Adolescents in Uganda: Implications for Scale-up in Low-Resource Communities.

July 10, 2019 By Manish Butte

Cost-Effectiveness of a Savings-Led Economic Empowerment Intervention for AIDS-Affected Adolescents in Uganda: Implications for Scale-up in Low-Resource Communities.

J Adolesc Health. 2018 01;62(1S):S29-S36

Authors: Ssewamala FM, Wang JS, Neilands TB, Bermudez LG, Garfinkel I, Waldfogel J, Brooks-Gunn J, Kirkbride G

Abstract
PURPOSE: Nearly 12 million children and adolescents in sub-Saharan Africa have lost one or both parents to AIDS. Within sub-Saharan Africa, Uganda has been greatly impacted, with an estimated 1.2 million orphaned children, nearly half of which have experienced parental loss due to the epidemic. Cost-effective and scalable interventions are needed to improve developmental outcomes for these children, most of whom are growing up in poverty. This article examines the direct impacts and cost-effectiveness of a savings-led family economic empowerment intervention, Bridges to the Future, that employed varying matched savings incentives to encourage investment in Ugandan children orphaned by AIDS.
METHODS: Using data from 48 primary schools in southwestern Uganda, we calculate per-person costs in each of the two treatment arms-Bridges (1:1 match savings) versus Bridges PLUS (1:2 match savings); estimate program effectiveness across outcomes of interest; and provide the ratios of per-person costs to their corresponding effectiveness.
RESULTS: At the 24-month postintervention initiation, children in the two treatment arms showed better results in health, mental health, and education when compared to the usual care condition; however, no statistically significant differences were found between treatment arms with the exception of school attendance rates which were higher for those in Bridges PLUS. Owing to the minimal cost difference between the Bridges and Bridges PLUS arms, we did not find substantial cost-effectiveness differences across the two treatment arms.
CONCLUSION: After 24 months, an economic intervention that incorporated matched savings yielded positive results on critical development outcomes for adolescents orphaned by AIDS in Uganda. The 1:1 and 1:2 match rates did not demonstrate variable levels of cost-effectiveness at 24-month follow-up, suggesting that governments intending to incorporate savings-led interventions within their social protection frameworks may not need to select a higher match rate to see positive developmental outcomes in the short term. Further research is required to understand intervention impacts and cost-effectiveness after a longer follow-up period.

PMID: 29273115 [PubMed – indexed for MEDLINE]

An overview of how on call consultant paediatricians can recognise and manage severe primary immunodeficiencies.

July 7, 2019 By Manish Butte

An overview of how on call consultant paediatricians can recognise and manage severe primary immunodeficiencies.

Acta Paediatr. 2019 Jul 06;:

Authors: Wekell P, Hertting O, Holmgren D, Fasth A

Abstract
Severe primary paediatric immunodeficiency syndromes are rare and potentially fatal unless suspected, diagnosed and treated early. We provide clinical guidance and support for on call consultant paediatricians working in secondary level hospitals on how to recognise and manage children with these conditions. Our paper addresses four conditions that risk the most severe outcomes if they are not adequately cared for during on call periods, such as weekends: severe combined immunodeficiency, haemophagocytic lymphohistiocytosis, severe congenital neutropaenia and chronic granulomatous disease. CONCLUSION: On call paediatricians are provided with advice on handling the most severe primary immunodeficiencies. This article is protected by copyright. All rights reserved.

PMID: 31278775 [PubMed – as supplied by publisher]

Primary Immunodeficiencies and Oncological Risk: The Experience of the Children’s Hospital of Brescia.

July 6, 2019 By Manish Butte

Primary Immunodeficiencies and Oncological Risk: The Experience of the Children’s Hospital of Brescia.

Front Pediatr. 2019;7:232

Authors: Maffeis M, Notarangelo LD, Schumacher RF, Soncini E, Soresina A, Lanfranchi A, Porta F

Abstract
Background and aims: Primary immunodeficiencies (PID) are characterized by recurrent infections and increased risk of malignancies because of the reduced immunological surveillance against cancer cells and oncogenic viruses. Methods: We report the incidence of tumors among 690 patients with PID, diagnosed from 1990 until 2017 in Brescia. Results: Out of 690 patients, 25 patients (3.6%) developed 33 tumors. Of the 25 affected patients, 8 patients suffered from common variable immunodeficiency (CVID), 5 from combined immunodeficiency (CID), 3 from Ataxia-telangectasia (AT), 2 from Hermanksy-Pudlak type 2 (HSP2), 2 from gammaglobulinemia X-linked (XLA), 2 from Wiskott-Aldrich syndrome (WAS), 2 from Hyper IgE syndrome (HIES), 1 from severe combined immunodeficiency (SCID). The age at diagnosis ranged from 1 to 52 years, with a median age of 19.6 years. The time between the diagnosis of PID and onset of tumor was short, often <1 year between diagnosis and the appearance of cancer in the case of CID. Moreover, in two cases of CID, the diagnosis of cancer was made before the diagnosis of PID, so cancer was the onset clinical manifestation. Hematological malignancies were prevalent (22/33, 66.7%) with a minority of solid tumors (11/33, 33.33%). In particular Non-Hodgkin lymphomas were the most frequent (16/33, 48.48%). In total 13 patients survived (52%) and tumor was the main cause of death (7 cases). Two patients underwent BMT once the disease was in remission. Conclusions: Therefore, the correct management of tumors that arise in patients with primitive immunodeficiency still represents a challenge in the pediatric field. For this reason now it is mandatory to collect in a unique international registry the cases of malignancies in PID that could lead to a better understanding of the etiopathogenesis and of the biological and clinical characteristics of these tumors, with the aim of defining adequate preventive measures and guaranteeing an early diagnosis which also creating a shared and specific therapeutic strategy, with the prospect of obtaining a better prognosis for these patients.

PMID: 31275905 [PubMed]

Subcutaneous immunoglobulins in patients with multiple myeloma and secondary hypogammaglobulinemia: a randomized trial.

July 6, 2019 By Manish Butte

Subcutaneous immunoglobulins in patients with multiple myeloma and secondary hypogammaglobulinemia: a randomized trial.

Clin Immunol. 2018 06;191:110-115

Authors: Vacca A, Melaccio A, Sportelli A, Solimando AG, Dammacco F, Ria R

Abstract
Multiple myeloma is commonly associated with a reduction of non-paraprotein immunoglobulins, resulting in a higher risk of infections that represent the leading cause of the patients’ death. Therefore, immunoglobulin replacement therapy appears a logical approach. A total number of 46 myeloma patients were randomly enrolled: 24 of them were assigned to receive subcutaneous immunoglobulins, and 22 were controls. The primary endpoint was the evaluation of the annual rate of severe infections in immunoglobulins-receiving patients as compared with those untreated. Subcutaneous immunoglobulins-treated patients showed a significantly lower number of severe infections per year. Adverse events were limited to the site of infusion and were easily manageable. Health-related quality of life was significantly better in subcutaneous immunoglobulins-receiving patients. By decreasing the rate of infections, the prophylactic administration of SCIg improves both adherence to chemotherapy and health-related quality of life, and is cost-effective by reducing the need of hospitalization and the use of antibiotics.

PMID: 29191714 [PubMed – indexed for MEDLINE]