Human Inborn Errors of Immunity: 2019 Update of the IUIS Phenotypical Classification

Bousfiha, Aziz; Jeddane, Leïla; Pïcard, Capucine; Al‐Herz, Waleed; Ailal, Fatima; Chatila, Talal; Cunningham‐Rundles, Charlotte; Etzioni, Amos; Franco, José Luis; Holland, Steven M.; Klein, Christoph; Morio, Tomohiro; Ochs, Hans D.; Oksenhendler, Éric; Puck, Jennifer M.; Torgerson, Troy R.; Casanova, Jean‐Laurent; Sullivan, Kathleen E.; Tangye, Stuart G.

doi:10.1007/s10875-020-00758-x

Cited by 586 publications

(683 citation statements)

References 5 publications

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“…The IUIS regularly updates an extensive classification on antibody deficiencies which serves as an excellent resource (4).…”

Section: Figure 1 |mentioning

confidence: 99%

“…Patients should undergo laboratory workup to evaluate for a potential antibody deficiency when they experience sinopulmonary infections with unusual frequency, duration, or severity (3). The most profound example of a predominantly antibody deficiency is agammaglobulinemia, which has undetectable B cells (4). While X-linked agammaglobulinemia (XLA), due to absent Bruton's tyrosine kinase (BTK) was initially recognized to cause arrested B cell development, there are now at least 12 known molecular defects which lead to agammaglobulinemia (4).…”

Section: Introductionmentioning

confidence: 99%

“…The most profound example of a predominantly antibody deficiency is agammaglobulinemia, which has undetectable B cells (4). While X-linked agammaglobulinemia (XLA), due to absent Bruton's tyrosine kinase (BTK) was initially recognized to cause arrested B cell development, there are now at least 12 known molecular defects which lead to agammaglobulinemia (4). The most common clinically relevant predominantly antibody deficiency is common variable immune deficiency (CVID).…”

Section: Introductionmentioning

confidence: 99%

“…Much debate has centered on the definition and diagnostic criteria of CVID, stemming primarily from the rapidly increasing knowledge on numerous underlying molecular causes of a similar immunologic phenotype. The most recent International Union of Immunological Societies (IUIS) expert committee report lists 20 molecular defects which have been documented to cause an antibody deficiency consistent with CVID (4). If a genetic cause for the antibody deficiency is identified, the patient is diagnosed with the specific genetic immune defect, not CVID (5).…”

Section: Introductionmentioning

confidence: 99%

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Bronchiectasis in Primary Antibody Deficiencies: A Multidisciplinary Approach

2020

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Bronchiectasis, the presence of bronchial wall thickening with airway dilatation, is a particularly challenging complication of primary antibody deficiencies. While susceptibility to infections may be the primary factor leading to the development of bronchiectasis in these patients, the condition may develop in the absence of known infections. Once bronchiectasis is present, the lungs are subject to a progressive cycle involving both infectious and non-infectious factors. If bronchiectasis is not identified or not managed appropriately, the cycle proceeds unchecked and yields advanced and permanent lung damage. Severe symptoms may limit exercise tolerance, require frequent hospitalizations, profoundly impair quality of life (QOL), and lead to early death. This review article focuses on the appropriate identification and management of bronchiectasis in patients with primary antibody deficiencies. The underlying immune deficiency and the bronchiectasis need to be treated from combined immunology and pulmonary perspectives, reflected in this review by experts from both fields. An aggressive multidisciplinary approach may reduce exacerbations and slow the progression of permanent lung damage.

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“…The IUIS regularly updates an extensive classification on antibody deficiencies which serves as an excellent resource (4).…”

Section: Figure 1 |mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Bronchiectasis in Primary Antibody Deficiencies: A Multidisciplinary Approach

2020

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“…Primary immunodeficiency diseases (PIDs) are disorders associated with defects in the immune system. More than 400 different types of monogenic inherited PIDs are currently recognised; these PIDs affect different immune cells (including T cells, B cells and granulocytes) and the complement system 1–3 . Early diagnosis of PIDs is extremely difficult because these diseases do not have specific characteristic symptoms but instead have diverse clinical manifestations, particularly in early life.…”

Section: Introductionmentioning

confidence: 99%

Screening for primary immunodeficiency diseases by next‐generation sequencing in early life

Sun

Yang

et al. 2020

Clin & Trans Imm

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Objective. We aimed to use next-generation sequencing (NGS) for the early diagnosis of primary immunodeficiency diseases (PIDs) and define its effects on medical management for an infant cohort in early life. Methods. A single-centre study was conducted from November 2015 to April 2018. Infants less than 3 months old with infections or abnormal white blood cell counts were enrolled in the study. Gene variants were analysed by NGS, and once a mutation was found in a PID-associated gene, the immune functions associated with this mutation were detected. The diagnosis rate of PIDs in the cohort was the main outcome. The patients received corresponding management and follow-up treatments. Results. Among 2392 patients who were genetically tested with NGS, 51 infants were diagnosed with PIDs. Seven types of PIDs were detected, and the most common (25/51, 49%) were combined immunodeficiencies with associated or syndromic features. Thirty-five patients (68.6%) were cured or had improved outcomes after being diagnosed with PID. The NGS cost was US $280 per case. Conclusions. This study not only highlighted the potential of NGS to rapidly deliver molecular diagnoses of PIDs but also indicated that the prevalence of PIDs is underestimated. With broader use, this approach has the potential to alter clinical strategies.

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Presence of Genetic Variants Among Young Men With Severe COVID-19

Made

Simons

Schuurs-Hoeijmakers

et al. 2020

JAMA

678

623

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IMPORTANCESevere coronavirus disease 2019 (COVID-19) can occur in younger, predominantly male, patients without preexisting medical conditions. Some individuals may have primary immunodeficiencies that predispose to severe infections caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).OBJECTIVE To explore the presence of genetic variants associated with primary immunodeficiencies among young patients with COVID-19. DESIGN, SETTING, AND PARTICIPANTSCase series of pairs of brothers without medical history meeting the selection criteria of young (age <35 years) brother pairs admitted to the intensive care unit (ICU) due to severe COVID-19. Four men from 2 unrelated families were admitted to the ICUs of 4 hospitals in the Netherlands between March 23 and April 12, 2020. The final date of follow-up was May 16, 2020. Available family members were included for genetic variant segregation analysis and as controls for functional experiments.EXPOSURE Severe COVID-19. MAIN OUTCOME AND MEASURESResults of rapid clinical whole-exome sequencing, performed to identify a potential monogenic cause. Subsequently, basic genetic and immunological tests were performed in primary immune cells isolated from the patients and family members to characterize any immune defects. RESULTSThe 4 male patients had a mean age of 26 years (range, 21-32), with no history of major chronic disease. They were previously well before developing respiratory insufficiency due to severe COVID-19, requiring mechanical ventilation in the ICU. The mean duration of ventilatory support was 10 days (range, 9-11); the mean duration of ICU stay was 13 days (range, 10-16). One patient died. Rapid clinical whole-exome sequencing of the patients and segregation in available family members identified loss-of-function variants of the X-chromosomal TLR7. In members of family 1, a maternally inherited 4-nucleotide deletion was identified (c.2129_2132del; p.[Gln710Argfs*18]); the affected members of family 2 carried a missense variant (c. 2383G>T; p.[Val795Phe]). In primary peripheral blood mononuclear cells from the patients, downstream type I interferon (IFN) signaling was transcriptionally downregulated, as measured by significantly decreased mRNA expression of IRF7, IFNB1, and ISG15 on stimulation with the TLR7 agonist imiquimod as compared with family members and controls. The production of IFN-γ, a type II IFN, was decreased in patients in response to stimulation with imiquimod. CONCLUSIONS AND RELEVANCEIn this case series of 4 young male patients with severe COVID-19, rare putative loss-of-function variants of X-chromosomal TLR7 were identified that were associated with impaired type I and II IFN responses. These preliminary findings provide insights into the pathogenesis of COVID-19.

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Human Inborn Errors of Immunity: 2019 Update of the IUIS Phenotypical Classification

Cited by 586 publications

References 5 publications

Bronchiectasis in Primary Antibody Deficiencies: A Multidisciplinary Approach

Bronchiectasis in Primary Antibody Deficiencies: A Multidisciplinary Approach

Screening for primary immunodeficiency diseases by next‐generation sequencing in early life

Presence of Genetic Variants Among Young Men With Severe COVID-19

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