Manish Butte

Primary Immunodeficiency in the NICU.

Neoreviews. 2019 Feb;20(2):e67-e78

Authors: O’Connell AE

Abstract
Primary immunodeficiency disorders (PIDs) are genetic diseases that lead to increased susceptibility to infection. Hundreds of PIDs have now been described, but a select subset commonly presents in the neonatal period. Neonates, especially premature newborns, have relative immune immaturity that makes it challenging to differentiate PIDs from intrinsic immaturity. Nonetheless, early identification and appropriate management of PIDs are critical, and the neonatal clinician should be familiar with a range of PIDs and their presentations. The neonatal clinician should also be aware of the importance of consulting with an immunologist when a PID is suspected. The role of newborn screening for severe combined immunodeficiency, as well as the initial steps of laboratory evaluation for a PID should be familiar to those caring for neonates. Finally, it is important for providers to be familiar with the initial management steps that can be taken to reduce the risk of infection in affected patients.

PMID: 31261087 [PubMed – in process]

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Transient hypogammaglobulinemia of infancy: many patients recover in adolescence and adulthood.

Clin Exp Immunol. 2019 Jul 01;:

Authors: Ameratunga R, Ahn Y, Steele R, Woon ST

Abstract
BACKGROUND: Transient hypogammaglobulinemia of infancy (THI) is a relatively rare disorder where there is an exaggeration of the physiological nadir of IgG between loss of transplacentally acquired maternal IgG and production by the infant. Patients may be vulnerable to infections during the period of hypogammaglobulinemia. The precise time to recovery in all infants is currently unknown.
OBJECTIVE: We sought to determine the clinical features and time course of recovery for patients with THI.
METHODS: We reviewed our experience with THI over the last three decades to describe clinical and laboratory features, as well as the time course of recovery.
RESULTS: Forty-seven patients were identified with THI. Only thirty-seven percent remitted by four years of age, while some patients did not recover until the third or fourth decade. In keeping with previous studies, the majority (25/47) presented with recurrent infections, nine had a family history of immunodeficiency and thirteen had adverse reactions to food as their dominant clinical manifestation. Chronic tonsillitis developed in ten patients and symptoms improved following surgery. The group with food allergies recovered sooner than those presenting with infections or with a family history immunodeficiency. Eight patients failed to respond to at least one routine childhood vaccine. Two have IgA deficiency and four individuals recovering in adolescence and adulthood continue to have borderline/low IgG levels. None have progressed to Common Variable Immunodeficiency Disorders (CVID).
CONCLUSIONS: THI is a misnomer, as the majority do not recover in infancy. Recovery from THI can extend into adulthood. THI must be considered in the differential diagnosis of adolescents or young adults presenting with primary hypogammaglobulinemia. This article is protected by copyright. All rights reserved.

PMID: 31260083 [PubMed – as supplied by publisher]

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Dysregulated Innate Lymphocytes in Patients With Primary Antibody Deficiency Treated With Intravenous Immunoglobulin.

J Investig Allergol Clin Immunol. 2017;27(6):394-396

Authors: Vigano S, Trabanelli S, Indulsi F, Salomé B, Harari A, Romero P, Helbling A, Jandus C, Jandus P

PMID: 29199969 [PubMed – indexed for MEDLINE]

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Identification of an IRF3 variant and defective antiviral interferon responses in a patient with severe influenza.

Eur J Immunol. 2019 Jun 28;:

Authors: Thomsen MM, Jørgensen SE, Storgaard M, Kristensen LS, Gjedsted J, Christiansen M, Gad HH, Hartmann R, Mogensen TH

PMID: 31250433 [PubMed – as supplied by publisher]

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Diagnostic Yield of Next Generation Sequencing in Genetically Undiagnosed Patients with Primary Immunodeficiencies: a Systematic Review.

J Clin Immunol. 2019 Jun 28;:

Authors: Yska HAF, Elsink K, Kuijpers TW, Frederix GWJ, van Gijn ME, van Montfrans JM

Abstract
BACKGROUND: As the application of next generation sequencing (NGS) is moving to earlier stages in the diagnostic pipeline for primary immunodeficiencies (PIDs), re-evaluation of its effectiveness is required. The aim of this study is to systematically review the diagnostic yield of NGS in PIDs.
METHODS: PubMed and Embase databases were searched for relevant studies. Studies were eligible when describing the use of NGS in patients that had previously been diagnosed with PID on clinical and/or laboratory findings. Relevant data on study characteristics, technological performance and diagnostic yield were extracted.
RESULTS: Fourteen studies were eligible for data extraction. Six studies described patient populations from specific PID subcategories. The remaining studies included patients with unsorted PIDs. The studies were based on populations from Italy, Iran, Turkey, Thailand, the Netherlands, Norway, Saudi Arabia, Sweden, the UK, and the USA. Eight studies used an array-based targeted gene panel, four used WES in combination with a PID filter, and two used both techniques. The mean reported reading depth ranged from 98 to 1337 times. Five studies described the sensitivity of the applied techniques, ranging from 83 to 100%, whereas specificity ranged from 45 to 99.9%. The percentage of patients who were genetically diagnosed ranged from 15 to 79%. Several studies described clinical implications of the genetic findings.
DISCUSSION: NGS has the ability to contribute significantly to the identification of molecular mechanisms in PID patients. The diagnostic yield highly depends on population and on the technical circumstances under which NGS is employed. Further research is needed to determine the exact diagnostic yield and clinical implications of NGS in patients with PID.

PMID: 31250335 [PubMed – as supplied by publisher]

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Case Report: Ocular toxoplasmosis in a WHIM syndrome immunodeficiency patient.

F1000Res. 2019;8:2

Authors: McDermott DH, Heusinkveld LE, Zein WM, Sen HN, Marquesen MM, Parta M, Rosenzweig SD, Fahle GA, Keller MD, Wiley HE, Murphy PM

Abstract
A patient with WHIM syndrome immunodeficiency presented with sudden painless right eye blindness associated with advanced retinal and optic nerve damage. Toxoplasma gondii was detected by PCR in vitreous fluid but not serum.  The patient was treated with trimethoprim-sulfamethoxazole.  Vision did not return; however, the infection did not spread to involve other sites.  Toxoplasmosis is rare in primary immunodeficiency disorders and is the first protozoan infection reported in WHIM syndrome.

PMID: 31249677 [PubMed – in process]

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Combining Mathematical Models With Experimentation to Drive Novel Mechanistic Insights Into Macrophage Function.

Front Immunol. 2019;10:1283

Authors: Jansen JE, Gaffney EA, Wagg J, Coles MC

Abstract
This perspective outlines an approach to improve mechanistic understanding of macrophages in inflammation and tissue homeostasis, with a focus on human inflammatory bowel disease (IBD). The approach integrates wet-lab and in-silico experimentation, driven by mechanistic mathematical models of relevant biological processes. Although wet-lab experimentation with genetically modified mouse models and primary human cells and tissues have provided important insights, the role of macrophages in human IBD remains poorly understood. Key open questions include: (1) To what degree hyperinflammatory processes (e.g., gain of cytokine production) and immunodeficiency (e.g., loss of bacterial killing) intersect to drive IBD pathophysiology? and (2) What are the roles of macrophage heterogeneity in IBD onset and progression? Mathematical modeling offers a synergistic approach that can be used to address such questions. Mechanistic models are useful for informing wet-lab experimental designs and provide a knowledge constrained framework for quantitative analysis and interpretation of resulting experimental data. The majority of published mathematical models of macrophage function are based either on animal models, or immortalized human cell lines. These experimental models do not recapitulate important features of human gastrointestinal pathophysiology, and, therefore are limited in the extent to which they can fully inform understanding of human IBD. Thus, we envision a future where mechanistic mathematical models are based on features relevant to human disease and parametrized by richer human datasets, including biopsy tissues taken from IBD patients, human organ-on-a-chip systems and other high-throughput clinical data derived from experimental medicine studies and/or clinical trials on IBD patients.

PMID: 31244837 [PubMed – in process]

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Application of Flow Cytometry in Primary Immunodeficiencies: Experience From India.

Front Immunol. 2019;10:1248

Authors: Madkaikar MR, Shabrish S, Kulkarni M, Aluri J, Dalvi A, Kelkar M, Gupta M

Abstract
Primary immunodeficiency diseases (PID) are a clinically and immunologically heterogeneous group of disorders of immune system. Diagnosis of these disorders is often challenging and requires identification of underlying genetic defects, complemented by a comprehensive evaluation of immune system. Flow cytometry, with its advances in the last few decades, has emerged as an indispensable tool for enumeration as well as characterization of immune cells. Flow cytometric evaluation of the immune system not only provides clues to underlying genetic defects in certain PIDs and helps in functional validation of novel genetic defects, but is also useful in monitoring immune responses following specific therapies. India has witnessed significant progress in the field of flow cytometry as well as PID over last one decade. Currently, there are seven Federation of Primary Immunodeficiency Diseases (FPID) recognized centers across India, including two Indian Council of Medical research (ICMR) funded centers of excellence for diagnosis, and management of PIDs. These centers offer comprehensive care for PIDs including flow cytometry based evaluation. The key question which always remains is how one selects from the wide array of flow cytometry based tests available, and whether all these tests should be performed before or after the identification of genetic defects. This becomes crucial, especially when resources are limited and patients have to pay for the investigations. In this review, we will share some of our experiences based on evaluation of a large cohort of hemophagocytic lymphohistiocytosis, severe combined immunodeficiency, and chronic granulomatous disease, and the lessons learned for optimum use of this powerful technology for diagnosis of these disorders.

PMID: 31244832 [PubMed – in process]

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DOCK8 mutation diagnosed using whole-exome sequencing of the dried blood spot-derived DNA: a case report of an Iraqi girl diagnosed in Japan.

BMC Med Genet. 2019 Jun 26;20(1):114

Authors: Al-Kzayer LFY, Al-Aradi HMH, Shigemura T, Sano K, Tanaka M, Hamada M, Ali KH, Aldaghir OM, Nakazawa Y, Okuno Y

Abstract
BACKGROUND: Dedicator of cytokinesis 8 (DOCK8) deficiency (MIM #243700) is a rare disease, leads to a combined primary immunodeficiency (PID), and accounts for the autosomal recessive-hyper immunoglobulin E syndrome (AR-HIES). DOCK8 deficiency status characterizes by recurrent infections, atopy, and risk of cancer. Lymphoproliferative disease complicating PID, is difficult to diagnose. Our aim is to present a rare case of PID, and to the best of our knowledge, she is the first case of DOCK8 deficiency from Iraq. The genetic diagnosis was carried out in Japan using dried blood spot-based DNA transfer and whole-exome sequencing.
CASE PRESENTATION: An 11-year-old Iraqi girl, of double first-cousin-parents, had a history of severe eczema, food allergy, and repeated infections. She presented with a jaw mass, bilateral cervical and axillary lymphadenopathy, and immunoglobulin (Ig) assays of 20, 3.3 and 1.7-fold above maximum normal level for age of IgE, IgA and IgG, respectively, along with a low IgM, eosinophilia and lymphopenia. Based on the jaw mass biopsy, non-Hodgkin lymphoma was suggested in Iraq, whereas histopathological re-evaluation in Japan revealed the diagnosis of a polyclonal reactive proliferation spectrum of lymphoproliferative disorders/plasmacytic hyperplasia, complicating PID. Whole-exome sequencing supported the diagnosis of PID by identifying a homozygous DOCK8 mutation with previously reported pathogenicity (NM_203447:c.3332delT, p.Phe1113Leufs*2), that may be attributed to consanguinity.
CONCLUSIONS: International collaboration using an effective DNA transportation technique and next-generation sequencing was the key to pinpoint the diagnosis of DOCK8 deficiency. Our case asserted that careful pathogenetic evaluation, in an advanced setting, was crucial for ruling out the neoplastic process. Pediatricians in areas with a high prevalence of consanguinity marriage should have a high index of suspicion of DOCK8 deficiency in patients with recalcitrant eczema, and frequent respiratory and skin infectious episodes.

PMID: 31242861 [PubMed – in process]

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Definition of opportunistic infections in immunocompromised children on the base of etiologies and clinical features: a summary for practical purposes.

Curr Pediatr Rev. 2019 Jun 17;:

Authors: Riccardi N, Rotulo GA, Castagnola E

Abstract
Opportunistic infections (OIs) still remain a a major cause of morbidity and death in children with either malignant or non malignant disease. OIs are defined as those due to bacteria, fungi, viruses or parasites that normally do not cause disease, but become pathogenic when the body’s defense system is impaired. OIs can also be represented by unusually severe infections caused by common pathogens. An OI could present itself at the onset of a primary immunodeficiency sindrome as a life -threatening event. More often OI is a therapy-associated complication in patients needing immunosuppressive treatment, among long-term hospitalized patients or in children undergo bone marrow or solid organ transplantation. Aim of the present review is to provide a comprehensive and ‘easy to read’ text that briefly summarises the current available knowledge about OIs in order to define when an infection should be considered as opportunistic in pediatrics as a result of an underlying congenital or acquired immune-deficit.

PMID: 31242834 [PubMed – as supplied by publisher]

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