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Long term follow-up of 168 patients with X-linked agammaglobulinemia reveals increased morbidity and mortality.

J Allergy Clin Immunol. 2020 Mar 10;:

Authors: Lougaris V, Soresina A, Baronio M, Montin D, Martino S, Signa S, Volpi S, Zecca M, Marinoni M, Baselli LA, Dellepiane RM, Carrabba M, Fabio G, Putti MC, Cinetto F, Lunardi C, Gazzurelli L, Benvenuto A, Bertolini P, Conti F, Consolini R, Ricci S, Azzari C, Leonardi L, Duse M, Pulvirenti F, Milito C, Quinti I, Cancrini C, Finocchi A, Moschese V, Cirillo E, Crescenzi L, Spadaro G, Marasco C, Vacca A, Cardinale F, Martire B, Trizzino A, Licciardello M, Cossu F, Di Matteo G, Badolato R, Ferrari S, Giliani S, Pession A, Ugazio A, Pignata C, Plebani A

Abstract
BACKGROUND: X-linked agammaglobulinemia (XLA) is the prototype of primary humoral immunodeficiencies. Long-term follow-up studies regarding disease-related complications and outcome are scarse.
OBJECTIVE: To describe the natural history of X-linked agammaglobulinemia.
METHODS: A nationwide multicenter study based on the IPINet registry was established in 2000 in Italy. Affected patients were enrolled by documenting centers and patients’ laboratory, clinical and imaging data were recorded on an annual base.
RESULTS: Patients’ data (N=168) derived from a cumulative follow-up of 1370 patient years with a mean follow-up of 8.35 years per patient. Mean age at diagnosis decreased upon the establishment of the IPINet registry (84 months before versus 23 months after). Respiratory, skin and gastrointestinal manifestations were the most frequent clinical symptoms at diagnosis and during long-term follow-up. Regular immunoglobulin replacement treatment reduced the incidence of invasive infections. Affected patients developed chronic lung disease over time (47% after 40 years of follow-up) in the presence of chronic sinusitis (84%). Malignancies were documented in a minority of cases (3.7%). Overall survival for affected patients was significantly reduced when compared to the healthy male Italian population, and further deteriorated in the presence of chronic lung disease.
CONCLUSIONS: This is the first detailed long-term follow-up study for XLA patients revealing that while immunoglobulin replacement treatment reduces the incidence of invasive infections, it does not appear to influence the development of chronic lung disease. Overall survival of affected patients is reduced. Further studies are warranted in order to improve patients’ clinical management and increase awareness among physicians.

PMID: 32169379 [PubMed – as supplied by publisher]

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Neonatal Thymectomy in Children – Accelerating the Immunological Clock?

J Allergy Clin Immunol. 2020 Mar 10;:

Authors: Deya-Martinez A, Flinn AM, Gennery AR

Abstract
The thymus is critical for central tolerance and diverse T-lymphocyte repertoire development, to provide lifelong defence against pathogens, whilst maintaining self-tolerance. Peak thymic output occurs in-utero, infancy and early childhood, diminishing throughout life. Infants with congenital heart disease requiring sternotomy, often undergo thymectomy to clear the surgical field. Longterm effects of early thymectomy are just being appreciated. Many patients remain asymptomatic, despite immunological findings mirroring those of immunosenescence. Few develop increased infection or lympho-reticular malignancy risk. When considering effects of infant thymectomy, patients with partial DiGeorge syndrome or hypomorphic RAG mutations may be instructive. These patients are lymphocytopenic, with increased early onset infection and autoimmunity risk, not seen in most infant thymectomy patients. Thymic structure of partial DiGeorge syndrome or hypomorphic RAG patients is abnormal, with disrupted architecture inclining to perturbation of central tolerance. Similar findings may be seen in patients with myasthenia gravis, although disrupted peripheral tolerance may play a greater role in autoimmunity development. In conclusion, infant thymectomy may increase future risk of infection or autoimmunity with premature immunosenescence, mediated through disruption of central and peripheral tolerance mechanisms, initiated by early cessation or diminution of thymic output. Ideally, some thymic tissue should be preserved at time of surgery.

PMID: 32169378 [PubMed – as supplied by publisher]

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Clinical Implications of Experimental Analyses of AID Function on Predictive Computational Tools: Challenge of Missense Variants.

Clin Genet. 2020 Mar 11;:

Authors: Abolhassani H, Marcotte H, Fang M, Hammarström L

Abstract
Due to the increased usage of high throughput sequencing for the diagnosis of genetically inherited disorders, it is vital to evaluate the risk of new variants and novel genes before accepting them in clinical practice. However, discordant in-silico and in-vitro results, challenge estimations of the effect of an identified genetic variant. We aimed to comprehensively evaluate pathogenic and polymorphic variants using the activation-induced-cytidine-deaminase (AICDA) gene as a model. We systematically searched and identified patients with confirmed AICDA-mutations. Population-based-databases were screened for germline-polymorphic-AICDA-variants. Activity of AICDA-mutant and severity of the clinical and immunologic-phenotype were demonstrated comparing 108 population-based-variants with 48 pathogenic mutations (12 overlapping-variants). Discordant predictions of different algorithms were observed on average in 38% of the population-database variants, mainly for missense mutations. Functional activity in mutations observed only in patients was significantly lower than variants in the population databases and overlapping-variants between patients and the general-population. Surprisingly, overlapping-variants had an even higher functional activity than the most common polymorphic-variants; however, their pathogenicity was still distinguishable when their function was compared with wild-type AICDA. Classifications of genetic variants cannot readily be translated into a clinical implication. Combined databases of functional and computational assays should therefore be developed for each specific gene. This article is protected by copyright. All rights reserved.

PMID: 32162335 [PubMed – as supplied by publisher]

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Primary immunodeficiencies and their associated risk of malignancies in children: an overview.

Eur J Pediatr. 2020 Mar 11;:

Authors: Renzi S, Langenberg-Ververgaert KPS, Waespe N, Ali S, Bartram J, Michaeli O, Upton J, Cada M

Abstract
Primary immunodeficiency disorders represent a heterogeneous spectrum of diseases, predisposing to recurrent infections, allergy, and autoimmunity. While an association between primary immunodeficiency disorders and increased risk of cancer has been suggested since the 1970s, renewed attention has been given to this topic in the last decade, largely in light of the availability of large registries as well as advances in next generation sequencing. In this narrative review, we will give an insight of the primary immunodeficiencies that are commonly responsible for the greater number of cancers in the primary immunodeficiency disorders population. We will describe clinical presentations, underlying genetic lesions (if known), molecular mechanisms for carcinogenesis, as well as some management considerations. We will also comment on the future directions and challenges related to this topic.Conclusion: The awareness of the association between several primary immunodeficiencies and cancer is crucial to provide the best care for these patients.What is Known: • Patients with primary immunodeficiency have an increased risk of malignancy. The type of malignancy is highly dependent on the specific primary immunodeficiency disorder.What is New: • Survival in patients with primary immunodeficiency disorders has been improving, and conversely also their lifetime risk of malignancy. • International collaboration and multinational registries are needed to improve our knowledge and therapeutic strategies.

PMID: 32162064 [PubMed – as supplied by publisher]

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A First Case Report of DiGeorge Syndrome from Ethiopia Highlights Challenges in Identifying and Treating Children with Primary T-Cell Deficiencies in Low Resource Settings.

Case Reports Immunol. 2020;2020:8157212

Authors: Alemayehu T, Deribessa SJ

Abstract
Background: Cellular primary immunodeficiencies are rarely reported from Africa. DiGeorge syndrome is a commonly recognized form of a congenital T-cell deficiency. The disorder is characterized by hypoplastic or aplastic thymus, hypocalcemia, recurrent infections, and other associated congenital defects. Case Report. We report an eleven-month-old infant presenting with recurrent chest and diarrheal infections, failure to thrive, lymphopenia, hypocalcemia, and hypoplastic thymus on imaging. A diagnosis of DiGeorge syndrome was confirmed after determining very low CD3 and CD4 levels.
Conclusions: We describe the first case report of an Ethiopian child with a congenital T-cell immunodeficiency. We have outlined essentials for diagnosis and management of cellular primary immunodeficiency disorders in low resource settings.

PMID: 32158567 [PubMed]

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