Manish Butte

Clin Exp Immunol. 2021 Jul 8. doi: 10.1111/cei.13642. Online ahead of print.

ABSTRACT

The most profound of primary immunodeficiencies, severe combined immunodeficiency (SCID), presents in infancy. Infants appear healthy at birth, but they are unable to clear pathogens, particularly viruses, and present with recurrent infection, progressive pnueumonitis and failure to thrive due to enteric viral infection, often associated with persistent vaccine-strain rotavirus. The administration of live vaccines is contraindicated in these infants, but most who are eligible receive bacillus Calmette-Guérin vaccination and the live rotavirus vaccine before the diagnosis of SCID is made, making treatment more complicated. Newborn infants with SCID can be screened using the newborn bloodspot to measure T lymphocyte receptor excision circles (TRECs), episomal DNA formed during T lymphocyte receptor development and very low or absent in SCID. Introduction of this programme in the United Kingdom will require the neonatal BCG vaccination programme to be altered, with vaccination at 28 days, once the SCID screening result is known. Although SCID newborn screening has been successfully introduced in other countries, the change in neonatal BCG vaccination requires the introduction of newborn screening to be carefully introduced. An evaluation of impact of screening on SCID diagnosis, treatment and outcomes, together with an evaluation of the technology used to detect TRECs, and the impact of screening and changes to the BCG programme on families will commence in six screening regions in England in September 2021 for 2 years – should the evaluation prove positive, it is likely that screening for this fatal disease will be introduced across the United Kingdom.

PMID:34235744 | DOI:10.1111/cei.13642

J Clin Immunol. 2021 Jul 6. doi: 10.1007/s10875-021-01065-9. Online ahead of print.

NO ABSTRACT

PMID:34231093 | DOI:10.1007/s10875-021-01065-9

Bone Marrow Transplant. 2021 Jul 5. doi: 10.1038/s41409-021-01378-8. Online ahead of print.

NO ABSTRACT

PMID:34226669 | DOI:10.1038/s41409-021-01378-8

Ann Allergy Asthma Immunol. 2021 Jul 2:S1081-1206(21)00488-9. doi: 10.1016/j.anai.2021.06.023. Online ahead of print.

NO ABSTRACT

PMID:34224864 | DOI:10.1016/j.anai.2021.06.023

Allergol Immunopathol (Madr). 2021 Jul 1;49(4):141-148. doi: 10.15586/aei.v49i4.202. eCollection 2021.

ABSTRACT

BACKGROUND: Chronic granulomatous disease (CGD) is a rare primary immunodeficiency. Infections of the lungs, skin, lymph nodes, and liver are the hallmark of CGD with frequent initial manifestations of the disease. The aim of the present study was to describe the sites of infections and their causative agents in 38 CGD pediatric patients.

METHODS: This was a retrospective single-center cohort study comprising CGD patients, and followed for over last 40 years at the Allergy and Immunology Unit of a tertiary hospital in São Paulo, Brazil. Sites of infections and their causative agents were described.

RESULTS: A total of 38 patients were included (36 males and 2 females). Median age at the onset of symptoms was 45 days (7 days-7 years) and that at the time of diagnosis was 23 months (1 month-12 years); 31.6% of the parents reported death of relatives during childhood and 21% (8 cases) had another male family member with CDG. The most common infections were pneumonia (81.6%), skin infections (50.0%), adenitis (42.1%), and liver abscess (23.7%). In all, 188 cultures were positive (85.6% for bacteria and 14.4% for fungi). The most prevalent bacterial agents were Staphylococcus sp. (12.4%), Staphylococcus aureus (11.2%), and Klebsiella pneumoniae (9.3%). Aspergillus sp. and Candida sp. were 56% and 22.2% of the isolated fungi, respectively. Mycobacterium tuberculosis was isolated in 5.6% and Mycobacterium bovis in 0.9% (only in 1 patient) of cultures.

CONCLUSION: Staphylococcus sp., Staphylococcus aureus, and Aspergillus sp. were the most frequent agents in this cohort. M. tuberculosis should be considered in endemic areas. Detection of infectious agents drives to find adequate treatment and benefits the evolution of patients with CGD.

PMID:34224228 | DOI:10.15586/aei.v49i4.202

Allergol Immunopathol (Madr). 2021 Jul 1;49(4):117-136. doi: 10.15586/aei.v49i4.200. eCollection 2021.

ABSTRACT

BACKGROUND: Syndromic immunodeficiencies are a genetically and pathophysiologically heterogeneous group of inborn errors of immunity. These are characterized by multiple extra immune clinical symptoms and a wide range of immunological phenotypes with increased susceptibility to infections, autoimmune phenomena, immune dysregulation, organ-specific pathology, and malignancy.

OBJECTIVE: To increase the pediatricians’ awareness of this multifaceted group of primary immunodeficiencies in children.

METHODS: A comprehensive review of genetic background and clinical symptomatology of syndromic immunodeficiencies as well as current diagnostic approach and treatment modalities.

RESULTS: From the pediatrician’s perspective, an early-life diagnosis of syndromic immunodeficiencies, which is frequently indispensable for successful life-saving immunocorrection, poses a diagnostic challenge. Increased pediatricians’ awareness to recognize signs and symptoms of these diseases in affected children is of paramount importance. Current advances in molecular biotechnology and immunogenetics, resulting in the implementation of newborn screening and new-generation sequencing, provide informative tools for definitive diagnosis and, in many new disease entities, for their definition and genotype-phenotype delineation and correlation.

CONCLUSIONS: A broad spectrum of clinical phenotypes in children with syndromic primary immunodeficiencies requires pediatrician’s special attention, that is, individualized multidisciplinary approach under the supervision of a clinical immunologist.

PMID:34224226 | DOI:10.15586/aei.v49i4.200

Allergol Immunopathol (Madr). 2021 Jul 1;49(4):91-97. doi: 10.15586/aei.v49i4.194. eCollection 2021.

ABSTRACT

INTRODUCTION AND OBJECTIVES: Severe combined immunodeficiency (SCID) is a subset of primary immunodeficiency diseases caused by a hereditary deficiency of the adaptive immune system. Mutation in recombination activating gene (RAG) is known as the underlying genetic cause of SCID. RAG protein plays a pivotal role in V(D)J recombination which is the main process to assemble lymphocyte antigen receptors during T- and B-cell development. The patients are characterized by recurrent infections, failure to thrive, chronic diarrhea, and fever, in early infancy. Herein, we present a case of SCID with rare neurological manifestations affected by a mutation in RAG1.

PATIENTS AND METHODS: The patient was a 15-month-old infant born to a consanguineous family. She was presented with neurological abnormalities including facial nerve palsy, seizure, and decreased consciousness. Next-generation sequencing (NGS)-based primary immunodeficiency disease (PID)-gene panel screen and Sanger sequencing were performed to identify the genetic mutation.

RESULTS: We found a novel homozygous missense mutation in RAG1, c.1210C>T,p.Arg404Trp, which was predicted to be deleterious (combined annotation dependent depletion, CADD score of 27.4). Both parents were heterozygous carriers for this mutation. According to her laboratory data, both T cell and B cell numbers were decreased and the patient was diagnosed as RAG1– SCID.

CONCLUSIONS: SCID is a pediatric emergency with a variety of manifestations in infants. Therefore, accurate diagnosis importantly in the case of rare manifestations must be considered in these patients. Our findings point toward the importance of genetic assessment for early diagnosis and timely treatment of this disorder.

PMID:34224223 | DOI:10.15586/aei.v49i4.194

Front Immunol. 2021 Jun 17;12:674226. doi: 10.3389/fimmu.2021.674226. eCollection 2021.

ABSTRACT

Severe Combined Immune Deficiency (SCID) is a primary deficiency of the immune system in which opportunistic and recurring infections are often fatal during neonatal or infant life. SCID is caused by an increasing number of genetic defects that induce an abrogation of T lymphocyte development or function in which B and NK cells might be affected as well. Because of the increased availability and usage of next-generation sequencing (NGS), many novel variants in SCID genes are being identified and cause a heterogeneous disease spectrum. However, the molecular and functional implications of these new variants, of which some are non-coding, are often not characterized in detail. Using targeted NGS, we identified a novel homozygous c.465-1G>C splice acceptor site variant in the DCLRE1C gene in a T^–B^–NK⁺ SCID patient and fully characterized the molecular and functional impact. By performing a minigene splicing reporter assay, we revealed deregulated splicing of the DCLRE1C transcript since a cryptic splice acceptor in exon 7 was employed. This induced a frameshift and the generation of a p.Arg155Serfs*15 premature termination codon (PTC) within all DCLRE1C splice variants, resulting in the absence of full-length ARTEMIS protein. Consistently, a V(D)J recombination assay and a G0 micronucleus assay demonstrated the inability of the predicted mutant ARTEMIS protein to perform V(D)J recombination and DNA damage repair, respectively. Together, these experiments molecularly and functionally clarify how a newly identified c.465-1G>C variant in the DCLRE1C gene is responsible for inducing SCID. In a clinical context, this demonstrates how the experimental validation of new gene variants, that are identified by NGS, can facilitate the diagnosis of SCID which can be vital for implementing appropriate therapies.

PMID:34220820 | PMC:PMC8248492 | DOI:10.3389/fimmu.2021.674226

J Allergy Clin Immunol Pract. 2021 Jul 1:S2213-2198(21)00759-5. doi: 10.1016/j.jaip.2021.06.031. Online ahead of print.

NO ABSTRACT

PMID:34217848 | DOI:10.1016/j.jaip.2021.06.031

Mol Immunol. 2021 Jun 30;137:57-66. doi: 10.1016/j.molimm.2021.06.018. Online ahead of print.

ABSTRACT

Patients with inborn errors of immunity (IEI) present with a heterogeneous clinical and immunological phenotype, therefore a correct molecular diagnosis is crucial for the classification and subsequent therapeutic management. On the other hand, IEI are a group of rare congenital diseases with highly diverse features and, in most cases, an as yet unknown genetic etiology. Next generation sequencing has facilitated genetic examinations of rare inherited disorders during the recent years, thus allowing a suitable molecular diagnosis in the IEI patients. This review aimed to investigate the current findings about these techniques in the field of IEI, suggesting an efficient stepwise approach to molecular diagnosis of inborn errors of immunity.

PMID:34216999 | DOI:10.1016/j.molimm.2021.06.018