Manish Butte

Geographic Variability and Pathogen-Specific Considerations in the Diagnosis and Management of Chronic Granulomatous Disease.

Pediatric Health Med Ther. 2020;11:257-268

Authors: Prince BT, Thielen BK, Williams KW, Kellner ES, Arnold DE, Cosme-Blanco W, Redmond MT, Hartog NL, Chong HJ, Holland SM

Abstract
Chronic granulomatous disease (CGD) is a rare but serious primary immunodeficiency with varying prevalence and rates of X-linked and autosomal recessive disease worldwide. Functional defects in the phagocyte nicotinamide adenine dinucleotide phosphate oxidase complex predispose patients to a relatively narrow spectrum of bacterial and fungal infections that are sometimes fastidious and often difficult to identify. When evaluating and treating patients with CGD, it is important to consider their native country of birth, climate, and living situation, which may predispose them to types of infections that are atypical to your routine practice. In addition to recurrent and often severe infections, patients with CGD and X-linked female carriers are also susceptible to developing many non-infectious complications including tissue granuloma formation and autoimmunity. The DHR-123 oxidation assay is the gold standard for making the diagnosis and it along with genetic testing can help predict the severity and prognosis in patients with CGD. Disease management focuses on prophylaxis with antibacterial, antifungal, and immunomodulatory medications, prompt identification and treatment of acute infections, and prevention of secondary granulomatous complications. While hematopoietic stem-cell transplantation is the only widely available curative treatment for patients with CGD, recent advances in gene therapy may provide a safer, more direct alternative.

PMID: 32801991 [PubMed – as supplied by publisher]

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Beyond monogenetic rare variants: tackling the low rate of genetic diagnoses in predominantly antibody deficiency.

Cell Mol Immunol. 2020 Aug 17;:

Authors: Edwards ESJ, Bosco JJ, Ojaimi S, O’Hehir RE, van Zelm MC

Abstract
Predominantly antibody deficiency (PAD) is the most prevalent form of primary immunodeficiency, and is characterized by broad clinical, immunological and genetic heterogeneity. Utilizing the current gold standard of whole exome sequencing for diagnosis, pathogenic gene variants are only identified in less than 20% of patients. While elucidation of the causal genes underlying PAD has provided many insights into the cellular and molecular mechanisms underpinning disease pathogenesis, many other genes may remain as yet undefined to enable definitive diagnosis, prognostic monitoring and targeted therapy of patients. Considering that many patients display a relatively late onset of disease presentation in their 2nd or 3rd decade of life, it is questionable whether a single genetic lesion underlies disease in all patients. Potentially, combined effects of other gene variants and/or non-genetic factors, including specific infections can drive disease presentation. In this review, we define (1) the clinical and immunological variability of PAD, (2) consider how genetic defects identified in PAD have given insight into B-cell immunobiology, (3) address recent technological advances in genomics and the challenges associated with identifying causal variants, and (4) discuss how functional validation of variants of unknown significance could potentially be translated into increased diagnostic rates, improved prognostic monitoring and personalized medicine for PAD patients. A multidisciplinary approach will be the key to curtailing the early mortality and high morbidity rates in this immune disorder.

PMID: 32801365 [PubMed – as supplied by publisher]

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Kinetics of humoral deficiency in CART19-treated children and young adults with acute lymphoblastic leukaemia.

Bone Marrow Transplant. 2020 Aug 14;:

Authors: Deyà-Martínez A, Alonso-Saladrigues A, García AP, Faura A, Torrebadell M, Vlagea A, Català A, Esteve-Solé A, Juan M, Rives S, Alsina L

Abstract
CD19-CAR T-cell therapy (CART19) causes B-cell aplasia (BCA) and dysgammaglobulinemia but there is a lack of information about the degree of its secondary immunodeficiency. We conducted a prospective study in children and young adults with acute lymphoblastic leukaemia treated with CART19, analysing the kinetics of BCA and dysgammaglobulinemia during therapy, as well as the B-cell reconstitution in those with CART19 loss. Thirty-four patients were included (14 female) with a median age at CART19 infusion of 8.7 years (2.9-24.9). Median follow-up after infusion was 7.1 months (0.5-42). BCA was observed 7 days after infusion (3-8), with persistence at 24 months in 60% of patients. All patients developed a progressive decrease in IgM and IgA: 71% had undetectable IgM levels at 71 days (41-99) and 13% undetectable IgA levels at 185 days (11-308). Three of 12 patients had protective levels of IgA in saliva. In two of three patients who lost CART19, persistent B-cell dysfunction was observed. No severe infections occurred. In conclusion, BCA occurs soon after CART19 infusion, with a progressive decrease in IgM and IgA, and with less impairment of IgA, suggesting the possibility of an immune reservoir. A persistent B-cell dysfunction might persist after CART19 loss in this population.

PMID: 32801317 [PubMed – as supplied by publisher]

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How to investigate a suspected immune deficiency in adults.

Respir Med. 2020 Jul 29;171:106100

Authors: Grammatikos A, Bright P, Bhatnagar R, Johnston S

Abstract
Patients with immune deficiencies can present with variable clinical phenotypes. This often translates into a significant delay in their diagnosis, and resultant patient morbidity. This review summarises the most common types of immunodeficiency disorders, primary and secondary, along with their key features. It provides a structured approach for the clinician on when to suspect an immunodeficiency, the initial investigations pathway and when a specialist referral should be considered.

PMID: 32799060 [PubMed – as supplied by publisher]

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Mediating effect of soluble B-cell activation immune markers on the association between anthropometric and lifestyle factors and lymphoma development.

Sci Rep. 2020 Aug 14;10(1):13814

Authors: Saberi Hosnijeh F, Kolijn PM, Casabonne D, Nieters A, Solans M, Naudin S, Ferrari P, Mckay JD, Weiderpass E, Perduca V, Besson C, Mancini FR, Masala G, Krogh V, Ricceri F, Huerta JM, Petrova D, Sala N, Trichopoulou A, Karakatsani A, La Vecchia C, Kaaks R, Canzian F, Aune D, Boeing H, Schulze MB, Perez-Cornago A, Langerak AW, van der Velden VHJ, Vermeulen R

Abstract
Sustained B-cell activation is an important mechanism contributing to B-cell lymphoma (BCL). We aimed to validate four previously reported B-cell activation markers predictive of BCL risk (sCD23, sCD27, sCD30, and CXCL13) and to examine their possible mediating effects on the association between anthropometric and lifestyle factors and major BCL subtypes. Pre-diagnostic serum levels were measured for 517 BCL cases and 525 controls in a nested case-control study. The odds ratios of BCL were 6.2 in the highest versus lowest quartile for sCD23, 2.6 for sCD30, 4.2 for sCD27, and 2.6 for CXCL13. Higher levels of all markers were associated with increased risk of chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), and diffuse large B-cell lymphoma (DLBCL). Following mutual adjustment for the other immune markers, sCD23 remained associated with all subtypes and CXCL13 with FL and DLBCL. The associations of sCD23 with CLL and DLBCL and CXCL13 with DLBCL persisted among cases sampled > 9 years before diagnosis. sCD23 showed a good predictive ability (area under the curve = 0.80) for CLL, in particular among older, male participants. sCD23 and CXCL13 showed a mediating effect between body mass index (positive) and DLBCL risk, while CXCL13 contributed to the association between physical activity (inverse) and DLBCL. Our data suggest a role of B-cell activation in BCL development and a mediating role of the immune system for lifestyle factors.

PMID: 32796953 [PubMed – as supplied by publisher]

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The spectrum of primary immunodeficiencies at a tertiary care hospital in Pakistan.

World Allergy Organ J. 2020 Jul;13(7):100133

Authors: Qureshi S, Mir F, Junejo S, Saleem K, Zaidi S, Naveed AB, Ahmad K, Qamar FN

Abstract
Background: Primary Immunodeficiency Disorders (PIDs) are well-known disorders in the West. but the recognition and diagnosis of these disorders is challenging in developing countries. We present the spectrum of PIDs seen at a tertiary care center in Pakistan, identified using clinical case definitions and molecular methods.
Methods: A retrospective chart review of children suspected to have PID was conducted at the Aga Khan University Hospital (AKUH) Karachi, Pakistan from 2010 to 2016. Data on demographics, clinical features, family history of consanguinity, sibling death, details of laboratory workup done for PID and molecular tests targeted panel next generation sequencing (NGS) or whole exome sequencing (WES) performed at the Geha laboratory at Boston Children’s Hospital, USA was collected. The study was exempted from the Ethical Review Committee of AKUH.
Results: A total of 43 children visited the hospital with suspected PID during the study period. Genetic testing was performed in 31/43 (72.1%) children. A confirmed diagnosis of PID was established in 20/43 (46.5%) children. A pathogenic gene variant was identified in 17(85%) of the 20 confirmed cases (Table 1). Twelve (60%) of the confirmed cases of PID were male. The most common presenting symptom was recurrent diarrhea 11/20 (55%). The mean (±S.D) age of the cases at the time of diagnosis was 4.2 (±4.1) years. Chronic granulomatous disease (CGD) was the most common 6/20 (30%) disorder, followed by severe combined immunodeficiency (SCID) 3/20 (15%), leukocyte adhesion deficiency (LAD) 3/20 (15%), agammaglobulinemia/hypogammaglobulinemia 3/20 (15%), and Hermansky-Pudlak Syndrome (HPS) 2/20 (10%). Wiskott-Aldrich Syndrome, Immunodeficiency Centromeric Instability and Facial Anomalies Syndrome (ICF 2), Trichohepatoenteric syndrome (TRES), and C3 deficiency were each diagnosed once {1/20 (4.3%) each} (Table 1). Of these 20 confirmed cases, almost all 19/20 (95%) had a family history of consanguinity. Sibling death was reported in 5/20 (25%) of these cases. Five out of the 20 (25%) children died over the 7-year period for various reasons.
Conclusion: PIDs are not uncommon in Pakistan; their diagnosis may be missed or delayed due to the overlapping of clinical features of PID with other diseases and a lack of diagnostic facilities. There is a need to build capacity for early recognition and diagnosis of PIDs to decrease morbidity and mortality.

PMID: 32793328 [PubMed]

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Ataxia-telangiectasia: Epidemiology, Pathogenesis, Clinical Phenotype, Diagnosis, Prognosis and Management.

Expert Rev Clin Immunol. 2020 Aug 13;:

Authors: Amirifar P, Ranjouri MR, Lavin M, Abolhassani H, Yazdani R, Aghamohammadi A

Abstract
INTRODUCTION: Ataxia-telangiectasia (A-T) is a rare autosomal recessive syndrome characterized by progressive cerebellar ataxia, oculocutaneous telangiectasia, variable immunodeficiency, radiosensitivity, and cancer predisposition. Mutations cause A-T in the ataxia telangiectasia mutated (ATM) gene encoding a serine/threonine-protein kinase.
AREAS COVERED: The authors reviewed the literature on PubMed, Web of Science, and Scopus databases to collect comprehensive data related to A-T. This review aims to discuss various update aspects of A-T, including epidemiology, pathogenesis, clinical manifestations, diagnosis, prognosis, and management.
EXPERT OPINION: A-T as a congenital disorder has phenotypic heterogeneity, and the severity of symptoms in different patients depends on the severity of mutations. This review provides a comprehensive overview of A-T, although some relevant questions about pathogenesis remain unanswered, probably owing to the phenotypic heterogeneity of this monogenic disorder. The presence of various clinical and immunologic manifestations in A-T indicates that the identification of the role of defective ATM in phenotype can be helpful in the better management and treatment of patients in the future.

PMID: 32791865 [PubMed – as supplied by publisher]

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[Fat-soluble vitamins and immunodeficiency: mechanisms of influence and opportunities for use].

Vopr Pitan. 2020;89(3):22-32

Authors: Kinash MI, Boyarchuk OR

Abstract
The role of vitamins in the formation of the immune response, both innate and acquired immunity, is well known. At the same time, deficit of fat-soluble vitamins A, E, D leads to impaired response of the immune system to the infectious invasion and to disorders of immune system functioning. The aim of this article is to analyze the literature data on the impact of fat-soluble vitamins on the function of the human immune system and the possibilities of their use in patients with immunodeficiency. Results. Сurrently, there are enough evidences of the successful use of fat-soluble vitamins in secondary immunodeficiencies. Data on the usage of vitamins A, E, D in the treatment of primary immunodeficiencies are few. However, even reducing of antibiotics and other medicines administration in children with primary immunodeficiency indicates the feasibility of their using. The results of scientific studies on the successful use of vitamins D and A in the treatment of allergic diseases, vitamin D in the prevention and improvement of the treatment of autoimmune and oncological diseases indicate the possibility of their use as adjuvant immunomodulatory therapy in children with primary immunodeficiency. Promising may be the use of vitamins A and E, as powerful antioxidants in patients with primary immunodeficiencies with defects in DNA repair processes. Conclusion. The analysis of the literature data has shown that despite many questions need to be resolved, fat-soluble vitamins A, D, and E, and their analogues can be used in clinical settings to enhance the therapeutic effect in children with immune deficiency.

PMID: 32790255 [PubMed – as supplied by publisher]

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Targeted gene correction of human hematopoietic stem cells for the treatment of Wiskott – Aldrich Syndrome.

Nat Commun. 2020 Aug 12;11(1):4034

Authors: Rai R, Romito M, Rivers E, Turchiano G, Blattner G, Vetharoy W, Ladon D, Andrieux G, Zhang F, Zinicola M, Leon-Rico D, Santilli G, Thrasher AJ, Cavazza A

Abstract
Wiskott-Aldrich syndrome (WAS) is an X-linked primary immunodeficiency with severe platelet abnormalities and complex immunodeficiency. Although clinical gene therapy approaches using lentiviral vectors have produced encouraging results, full immune and platelet reconstitution is not always achieved. Here we show that a CRISPR/Cas9-based genome editing strategy allows the precise correction of WAS mutations in up to 60% of human hematopoietic stem and progenitor cells (HSPCs), without impairing cell viability and differentiation potential. Delivery of the editing reagents to WAS HSPCs led to full rescue of WASp expression and correction of functional defects in myeloid and lymphoid cells. Primary and secondary transplantation of corrected WAS HSPCs into immunodeficient mice showed persistence of edited cells for up to 26 weeks and efficient targeting of long-term repopulating stem cells. Finally, no major genotoxicity was associated with the gene editing process, paving the way for an alternative, yet highly efficient and safe therapy.

PMID: 32788576 [PubMed – as supplied by publisher]

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Progressive multifocal leukoencephalopathy and sarcoidosis under interleukin 7: The price of healing.

Neurol Neuroimmunol Neuroinflamm. 2020 Sep;7(5):

Authors: Guffroy A, Solis M, Gies V, Dieudonne Y, Kuhnert C, Lenormand C, Kremer L, Molitor A, Carapito R, Hansmann Y, Poindron V, Martin T, Hirschi S, Korganow AS

Abstract
OBJECTIVE: To report the association of JC virus infection of the brain (progressive multifocal encephalopathy [PML]) during the course of sarcoidosis and the challenging balance between immune reconstitution under targeted cytokine interleukin 7 (IL7) therapy for PML and immunosuppression for sarcoidosis.
METHODS: Original case report including deep sequencing (whole-exome sequencing) to exclude a primary immunodeficiency (PID) and review of the literature of cases of PML and sarcoidosis.
RESULTS: We report and discuss here a challenging case of immune reconstitution with IL7 therapy for PML in sarcoidosis in a patient without evidence for underling PID or previous immunosuppressive therapy.
CONCLUSIONS: New targeted therapies in immunology and infectiology open the doors of more specific and more specialized therapies for patients with immunodeficiencies, autoimmune diseases, or cancers. However, before instauration of these treatments, the risk of immune reconstitution inflammatory syndrome and potential exacerbation of an underlying disease must be considered. It is particularly true in case of autoimmune disease such as sarcoidosis or lupus.

PMID: 32788393 [PubMed – as supplied by publisher]

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