Manish Butte

Clin Endocrinol (Oxf). 2022 May 23. doi: 10.1111/cen.14782. Online ahead of print.

ABSTRACT

OBJECTIVE: Hematopoietic stem cell transplantation (HSCT) can be a curative treatment for malignant and nonmalignant diseases in children but is associated with significant late effects including growth failure. Growth hormone treatment (GHRx) is offered to improve growth, but limited data are available on its effect on adult height. We aim to evaluate the effectiveness of GHRx.

DESIGN: Single-center retrospective study.

PATIENTS: 34 patients who had received GHRx for ≥1 year were matched with two controls each, without GHRx, based on sex, indication for HSCT (malignancy, benign hematological disease or immunodeficiency), age at HSCT and conditioning with/without total body irradiation (TBI). All had reached adult height (AH).

MEASUREMENTS: The primary outcome measure was the difference between AH and predicted AH at start of GHRx or the equivalent age in controls (AH-PAH), calculated according to Bailey & Pinneau.

RESULTS: GHRx was started at age 12.0 ±2.6 years; median treatment duration was 3.8 years (range 1.7-9.2). AH-PAH SDS was significantly higher in GH treated boys (-0.5 ±0.7 SDS) than in controls (-1.5 ±1.0 SDS, p<0.001). Girls also had a higher AH-PAH after GHRx (+0.5 ±0.6 SDS) compared to controls (-0.2 SDS ±0.7, p<0.01). AH remained approximately 2 SDS below target height in treated and untreated individuals. Among GH-treated children, AH-PAH was higher in those who had received busulfan-based compared to TBI-based conditioning.

CONCLUSION: GHRx had a significant positive effect on AH compared to PAH, although AH remained far below target height. Higher AH-PAH was observed in girls and in those conditioned without TBI. This article is protected by copyright. All rights reserved.

PMID:35606687 | DOI:10.1111/cen.14782

J Clin Immunol. 2022 May 23. doi: 10.1007/s10875-022-01274-w. Online ahead of print.

ABSTRACT

The epidemiology of inborn errors of immunity (IEI) in the Republic of Ireland was first published in 2005 but has not been updated since. IEI prevalence data from Northern Ireland was last published in 2018. Using data from the United Kingdom Primary Immune Deficiency (UKPID) and European Society for Immunodeficiencies (ESID) registries, we reviewed all registered cases of IEI affecting adult patients ≥ 18 years of age from the two largest immunology specialist centres in Northern Ireland and the Republic of Ireland, respectively and calculated the combined minimum adult prevalence of IEI on the island of Ireland for the first time. We also recorded data pertaining to presenting symptoms of IEI, diagnostic delay, immunoglobulin data, and genetic testing, as well as briefly reporting data pertaining to secondary immunodeficiency in both countries. As of 1 May 2020, we identified a minimum adult IEI prevalence in Ireland of 8.85/100,000 population.

PMID:35604475 | DOI:10.1007/s10875-022-01274-w

Front Immunol. 2022 May 6;13:886117. doi: 10.3389/fimmu.2022.886117. eCollection 2022.

ABSTRACT

The transcription factor GATA2 plays a key role in the survival and self-renewal of hematopoietic stem and progenitor cells. Autosomal dominant variants in GATA2 cause a broad spectrum of heterogeneous phenotypes. Here, we present our experience with GATA2 deficiency in a retrospective multicenter analysis of computerized medical records of adult patients (age ≥18 years) treated between 2018 and 2022 at Shaare Zedek Medical Center in Jerusalem and Sheba Tel-Hashomer Medical Center in Ramat Gan, Israel. Two male and two female patients with GATA2 deficiency were identified. Three of the patients presented with symptoms in adult life and all patients were diagnosed as adults. Age at presentation was 10.5-36 years and age at diagnosis 24-47 years. Diagnosis was delayed in all patients by 1-24.5 years. The phenotypic diversity was notable. Patients presented with myelodysplastic syndrome (n=2), pulmonary alveolar proteinosis (n=1), and recurrent viral (n=1), bacterial (n=3), and mycobacterial (n=1) infections. Bone marrow biopsy revealed cytogenetic abnormalities in one patient (monosomy 7). Patients were diagnosed by exome sequencing (n=3) and Sanger sequencing of the coding exons in GATA2 (n=1). Novel heterozygous GATA2 variants (c.177C>A, p.Y59* and c.610dup, p.R204Pfs*78) were identified in two patients. Immune workup revealed B cell lymphopenia and monocytopenia in all tested patients. One patient died from overwhelming sepsis despite all patients being treated with antibiotics and anti-mycobacterials. Our cohort highlights the phenotypic diversity, late presentation, and delayed diagnosis of GATA2 deficiency. Increased awareness of this primary immune deficiency presenting in adult life is needed and should involve a high index of suspicion.

PMID:35603181 | PMC:PMC9120659 | DOI:10.3389/fimmu.2022.886117

J Allergy Clin Immunol Pract. 2022 May 19:S2213-2198(22)00490-1. doi: 10.1016/j.jaip.2022.05.004. Online ahead of print.

NO ABSTRACT

PMID:35598866 | DOI:10.1016/j.jaip.2022.05.004

J Pediatr. 2022 May 19:S0022-3476(22)00438-3. doi: 10.1016/j.jpeds.2022.05.028. Online ahead of print.

ABSTRACT

The optimal SARS-CoV-2 vaccine strategy for patients with a history of MIS-C is unclear. We performed an international survey (32 countries) and found substantial variations in vaccine policies. Respondents did not report relapses of MIS-C or other severe inflammatory side effects after SARS-CoV-2 vaccination in 273 patients with a history of MIS-C.

PMID:35598642 | DOI:10.1016/j.jpeds.2022.05.028

Brief Bioinform. 2022 May 23:bbac176. doi: 10.1093/bib/bbac176. Online ahead of print.

ABSTRACT

Distinguishing pathogenic variants from non-pathogenic ones remains a major challenge in clinical genetic testing of primary immunodeficiency (PID) patients. Most of the existing mutation pathogenicity prediction tools treat all mutations as homogeneous entities, ignoring the differences in characteristics of different genes, and use the same model for genes in different diseases. In this study, we developed a single nucleotide variant (SNV) pathogenicity prediction tool, Variant Impact Predictor for PIDs (VIPPID; https://mylab.shinyapps.io/VIPPID/), which was tailored for PIDs genes and used a specific model for each of the most prevalent PID known genes. It employed a Conditional Inference Forest model and utilized information of 85 features of SNVs and scores from 20 existing prediction tools. Evaluation of VIPPID showed that it had superior performance (area under the curve = 0.91) over non-specific conventional tools. In addition, we also showed that the gene-specific model outperformed the non-gene-specific models. Our study demonstrated that disease-specific and gene-specific models can improve SNV pathogenicity prediction performance. This observation supports the notion that each feature of mutations in the model can be potentially used, in a new algorithm, to investigate the characteristics and function of the encoded proteins.

PMID:35598327 | DOI:10.1093/bib/bbac176

J Clin Immunol. 2022 May 21. doi: 10.1007/s10875-022-01288-4. Online ahead of print.

ABSTRACT

Ras-related C3 botulinum toxin substrate 2 (RAC2) is a GTPase exclusively expressed in hematopoietic cells that acts as a pivotal regulator of several aspects of cell behavior via various cellular processes. RAC2 undergoes a tightly regulated GTP-binding/GTP-hydrolysis cycle, enabling it to function as a molecular switch. Mutations in RAC2 have been identified in 18 patients with different forms of primary immunodeficiency, ranging from phagocyte defects caused by dominant negative mutations to common variable immunodeficiency resulting from autosomal recessive loss-of-function mutations, or severe combined immunodeficiency due to dominant activating gain-of-function mutations. Here, we describe an 11-year-old girl with combined immunodeficiency presenting with recurrent respiratory infections and bronchiectasis. Immunological investigations revealed low T-cell receptor excision circle/K-deleting recombination excision circles numbers, lymphopenia, and low serum immunoglobulin G. Targeted next-generation sequencing identified a novel heterozygous mutation in RAC2, c.86C > G (p.P29R), located in the highly conserved Switch I domain. The mutation resulted in enhanced reactive oxygen species production, elevated F-actin content, and increased RAC2 protein expression in neutrophils, as well as increased cytokine production and a dysregulated phenotype in T lymphocytes. Furthermore, the dominant activating RAC2 mutation led to accelerated apoptosis with augmented intracellular active caspase 3, impaired actin polarization in lymphocytes and neutrophils, and diminished RAC2 polarization in neutrophils. We present a novel RAC2 gain-of-function mutation with implications for immunodeficiency and linked to functional dysregulation, including abnormal apoptosis and cell polarization arising from altered RAC2 expression. Thus, our findings broaden the spectrum of known RAC2 mutations and their underlying mechanisms.

PMID:35596857 | DOI:10.1007/s10875-022-01288-4

Pediatr Pulmonol. 2022 May 20. doi: 10.1002/ppul.25989. Online ahead of print.

ABSTRACT

The diagnosis of primary ciliary dyskinesia (PCD) is made through a combination of clinical features supported by a panel of diagnostic tests. Our cases highlight the similarities in the clinical presentation of patients with the specific immunodeficiency activated phosphatidylinositol 3-kinase delta syndrome 1 (APDS1 or PIK3CD-Related Disorder) and PCD. We highlight the importance of repeating nasal nitric oxide testing (nNO) when PCD has not been confirmed by genetic or ciliary electron micrograph (EM) analysis in the setting of an expanded suppurative lung disease differential that includes considerations for immunodeficiency as well as PCD. This article is protected by copyright. All rights reserved.

PMID:35596239 | DOI:10.1002/ppul.25989

Eur J Pediatr. 2022 May 20. doi: 10.1007/s00431-022-04509-5. Online ahead of print.

ABSTRACT

Bronchiectasis is a form of airway damage as a consequence of endobronchial infection and inflammation and may be present in different diseases. The underlying aetiologies include both cystic fibrosis (CF) and a group of non-cystic fibrosis diseases (NCFB) such as immunodeficiency, primary ciliary dyskinesia, or severe pulmonary infection. Although children with CF and non-cystic fibrosis bronchiectasis (NCFB) have many similar clinical features, their responses to exercise may be different. The aim of this study was to compare the efficacy of a comprehensive respiratory physiotherapy (CRP) home-program in children with CF and NCFB. Thirty children with CF and thirty children with NCFB were included in the study. Both groups performed the CRP home-program twice daily for 8 weeks. Pulmonary function, exercise capacity, and respiratory and peripheral muscle strength were assessed at baseline and after 8 weeks of training. Both groups experienced significant improvements in pulmonary function, exercise capacity, and respiratory and peripheral muscle strength (p < 0.001). Maximum expiratory pressure, exercise capacity, and peripheral muscle strength were further improved in NCFB group compared to CF (p < 0.05); however, there was a great variability in the improvements for each variable.

CONCLUSION: CRP is beneficial both for children with CF and NCFB and adherence to the program was high in both groups.

WHAT IS KNOWN: • Different physiotherapy approaches in the management of non-cystic fibrosis bronchiectasis have been based on the experience gained from the research studies performed in cystic fibrosis. • Although having similar pathophysiology, these two diseases show variation in some pulmonary and extrapulmonary features.

WHAT IS NEW: • The respiratory muscle strength and the efficacy of comprehensive respiratory physiotherapy have been compared for the first time in children with cystic fibrosis and non-cystic fibrosis bronchiectasis. • Comprehensive respiratory physiotherapy provides higher increases in children with non-cystic fibrosis bronchiectasis in exercise capacity and expiratory and peripheral muscle strength; however, there was a great variability in these improvements. Nevertheless, it can be concluded that both groups significantly benefited from the CRP program.

PMID:35595860 | DOI:10.1007/s00431-022-04509-5

Am J Health Syst Pharm. 2022 May 20:zxac139. doi: 10.1093/ajhp/zxac139. Online ahead of print.

ABSTRACT

DISCLAIMER: In an effort to expedite the publication of articles related to the COVID-19 pandemic, AJHP is posting these manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time.

PURPOSE: This report calls attention to the potential risks of diminished kidney function when administering immune globulin (IG). The goal is to increase awareness of chronic kidney disease (CKD) and kidney function impairment in patients receiving IG and provide recommendations for screening, monitoring, and management to promote risk prevention and mitigation.

SUMMARY: Human IG preparations for intravenous (IVIG) or subcutaneous (SCIG) administration are the mainstay of treatment in patients with primary immunodeficiency diseases. Increasingly, IVIG at high doses (1,000 to 2,400 mg/kg) is also used as a treatment for a variety of autoimmune and inflammatory conditions. Although some autoinflammatory disorders respond to a single course of IVIG therapy, the majority of patients require long-term, regular infusions, thereby increasing the overall risks. Often, both patients and physicians treating adults with IG are unaware of underlying CKD or kidney function impairment. This lack of awareness constitutes a major risk factor for potential worsening, particularly when using high doses of IVIG. Therefore, screening of all patients for CKD and kidney function impairment before the use of IG is essential. Identification of the cause of kidney impairment is strongly encouraged, as IG therapy may need to be modified.

CONCLUSION: As detailed here, there are potential risks to patients with impaired kidney function with administration of IG, particularly at high doses. Product selection, volume, route of administration, and rate of infusion may impact those with compromised kidney function. Therefore, screening of all patients for CKD and kidney function impairment before the use of IVIG and SCIG, as well as ongoing monitoring and management, is critical. As with all potential adverse drug reactions, the best approach is to prevent them.

PMID:35595720 | DOI:10.1093/ajhp/zxac139