Research

Pediatr Allergy Immunol. 2023 Mar;34(3):e13928. doi: 10.1111/pai.13928.

NO ABSTRACT

PMID:36974644 | DOI:10.1111/pai.13928

Anticancer Res. 2023 Apr;43(4):1455-1461. doi: 10.21873/anticanres.16294.

ABSTRACT

BACKGROUND/AIM: To investigate the long-term influence of head-neutron irradiation on mice spleens, post-radiation late effects were examined in three types of mice: Balb/c and severe combined immunodeficiency (SCID) mice, which have high radio-sensitivities, and C3H mice.

MATERIALS AND METHODS: Neutron irradiation was performed with the neutron beam of the Kyoto University Research Reactor. Survival fractions and the change in spleen size after head-neutron irradiation were investigated in three different types of mice. Physical condition after neutron irradiation was observed for eighteen months.

RESULTS: The onset of primary splenic malignant lymphoma was recognized in many of the Balb/c mice 18 months after head-neutron irradiation. Eight months after head-neutron irradiation, many SCID mice developed an abscess in the part exposed to radiation and spleen swelling. The swollen spleen of SCID mice had hematopoiesis from the marrow.

CONCLUSION: Low energy head-neutron irradiation damages immune organs in radiosensitive SCID and Balb/c mice. A combination of boron neutron capture therapy and immunotherapy may be less toxic than low-energy neutron-irradiation alone.

PMID:36974803 | DOI:10.21873/anticanres.16294

Ther Adv Allergy Rhinol. 2023 Mar 14;14:27534030231156206. doi: 10.1177/27534030231156206. eCollection 2023 Jan-Dec.

ABSTRACT

Vaccinations for pathogenic organisms have been utilized for decades in both the protection and diagnosis of immunodeficiency patients. Some of these immunodeficient patients may not create an adequate response to vaccination, although some who have significant aberrancies in their immune system may surprisingly create antibodies to immunizations. We present a patient with a large Ig heavy chain deletion (severe deficiency of serum IgG1, IgG2, IgG4, and IgA1) that showed a considerable response (presumably through IgG3) after the Pfizer BioNTech COVID-19 vaccination. This finding in this unique immunodeficient patient warrants further research into alternate antibody response pathways against COVID-19.

PMID:36968252 | PMC:PMC10035523 | DOI:10.1177/27534030231156206

Front Pediatr. 2023 Mar 10;11:1108207. doi: 10.3389/fped.2023.1108207. eCollection 2023.

ABSTRACT

During recent years, the identification of monogenic mutations that cause sterile inflammation has expanded the spectrum of autoinflammatory diseases, clinical disorders characterized by uncontrolled systemic and organ-specific inflammation that, in some cases, can mirror infectious conditions. Early studies support the concept of innate immune dysregulation with a predominance of myeloid effector cell dysregulation, particularly neutrophils and macrophages, in causing tissue inflammation. However, recent discoveries have shown a complex overlap of features of autoinflammation and/or immunodeficiency contributing to severe disease phenotypes. Here, we describe the first Argentine patient with a newly described frameshift mutation in SAMD9L c.2666delT/p.F889Sfs*2 presenting with a complex phenotypic overlap of CANDLE-like features and severe infection-induced cytopenia and immunodeficiency. The patient underwent a fully matched unrelated HSCT and has since been in inflammatory remission 5 years post-HSCT.

PMID:36969289 | PMC:PMC10036571 | DOI:10.3389/fped.2023.1108207

Front Genome Ed. 2023 Mar 8;5:1141618. doi: 10.3389/fgeed.2023.1141618. eCollection 2023.

ABSTRACT

Introduction: Genome editing tools, such as CRISPR/Cas, TALE nucleases and, more recently, double-strand-break-independent editors, have been successfully used for gene therapy and reverse genetics. Among various challenges in the field, tolerable and efficient delivery of editors to target cells and sites, as well as independence from commercially available tools for flexibility and fast adoption of new editing technology are the most pressing. For many hematopoietic research applications, primary CD34⁺ cells and the human umbilical cord-derived progenitor erythroid 2 (HUDEP-2) cell line are highly informative substrates and readily accessible for in vitro manipulation. Moreover, ex vivo editing of CD34⁺ cells has immediate therapeutic relevance. Both cell types are sensitive to standard transfection procedures and reagents, such as lipofection with plasmid DNA, calling for more suitable methodology in order to achieve high efficiency and tolerability of editing with editors of choice. These challenges can be addressed by RNA delivery, either as a mixture of guide RNA and mRNA for CRISRP/Cas-based systems or as a mixture of mRNAs for TALENs. Compared to ribonucleoproteins or proteins, RNA as vector creates flexibility by removing dependence on commercial availability or laborious in-house preparations of novel editor proteins. Compared to DNA, RNA is less toxic and by obviating nuclear transcription and export of mRNA offers faster kinetics and higher editing efficiencies. Methods: Here, we detail an in vitro transcription protocol based on plasmid DNA templates with the addition of Anti-Reverse Cap Analog (ARCA) using T7 RNA polymerase, and poly (A) tailing using poly (A) polymerase, combined with nucleofection of HUDEP-2 and patient-derived CD34⁺ cells. Our protocol for RNA-based delivery employs widely available reagents and equipment and can easily be adopted for universal in vitro delivery of genome editing tools. Results and Discussion: Drawing on a common use case, we employ the protocol to target a β-globin mutation and to reactivate γ-globin expression as two potential therapies for β-hemoglobinopathies, followed by erythroid differentiation and functional analyses. Our protocol allows high editing efficiencies and unimpaired cell viability and differentiation, with scalability, suitability for functional assessment of editing outcomes and high flexibility in the application to different editors.

PMID:36969374 | PMC:PMC10030607 | DOI:10.3389/fgeed.2023.1141618

Neurooncol Pract. 2022 Dec 31;10(2):169-175. doi: 10.1093/nop/npac098. eCollection 2023 Apr.

ABSTRACT

BACKGROUND: Primary central nervous system lymphomas (PCNSLs) have historically had dismal survival rates until the advent of high-dose methotrexate (HD-MTX) based chemotherapy regimens. With increasing prevalence of autoimmune disease and development of new immunosuppressants, a genetically distinct entity known as iatrogenic immunodeficiency-associated lymphoproliferative disorder (LPD) has emerged. Many of these cases arise following methotrexate use, challenging feasibility of standard HD-MTX regimens. The aim of this study was to further characterize this disorder and determine the optimal management strategy.

METHODS: We describe a case of a 76-year-old female with iatrogenic immunodeficiency-associated PCNSL successfully treated with surgical resection followed by an antiviral and rituximab based regimen. We then performed a systematic literature review and identified 58 cases of non-transplant iatrogenic immunodeficiency-associated LPD involving the CNS. We used a linear probability statistical model to determine correlations with outcome.

RESULTS: Natalizumab was associated with EBV negative tumors (P = .023), and EBV positive tumors were associated with improved outcomes (P = .016). Surgical resection was associated with improved outcomes (P = .032), although limited by potential confounding effect. Antiviral treatment (P = .095), rituximab (P = .111), and stem cell transplant (SCT) (P = .198) showed a trend toward improved outcomes. The remaining treatments including methotrexate showed no improvement.

CONCLUSION: We propose that surgical resection, rituximab, and antiviral treatment may be considered as an alternative to standard HD-MTX based regimens when managing iatrogenic immunodeficiency-associated LPD of the CNS. Further study through prospective cohort studies or randomized clinical trials is warranted.

PMID:36970173 | PMC:PMC10037938 | DOI:10.1093/nop/npac098

Clin Immunol. 2023 Mar 24:109302. doi: 10.1016/j.clim.2023.109302. Online ahead of print.

ABSTRACT

Up to 25% of the patients with inborn errors of immunity (IEI) also exhibit immunodysregulatory features. The association of immune dysregulation and immunodeficiency may be explained by different mechanisms. The understanding of mechanisms underlying immune dysregulation in IEI has paved the way for the development of targeted treatments. In this review article, we will summarize the mechanisms of immune tolerance breakdown and the targeted therapeutic approaches to immune dysregulation in IEI.

PMID:36967025 | DOI:10.1016/j.clim.2023.109302

PLOS Glob Public Health. 2023 Feb 23;3(2):e0001572. doi: 10.1371/journal.pgph.0001572. eCollection 2023.

ABSTRACT

Reducing mortality among COVID-19 cases is a major challenge for most health systems worldwide. Estimating the risk of preexisting comorbidities on COVID-19 mortality may promote the importance of targeting at-risk populations to improve survival through primary and secondary prevention. This study was conducted to explore the contribution of exposure to some chronic diseases on the mortality of COVID-19. This was a case control study. The data were collected from the records of all patients hospitalised at Bafoussam Regional Hospital (BRH) from March 2020 to December 2021. A grid was used to extract data on patient history, case management and outcome of hospitalised patients. We estimated the frequency of each common chronic disease and assessed the association between suffering from all and each chronic disease (Diabetes or/and Hypertension, immunodeficiency condition, obesity, tuberculosis, chronic kidney disease) and fatal outcome of hospitalised patients by estimating crude and adjusted odd ratios and their corresponding 95% confidence intervals (CI) using time to symptom onset and hospital admission up to three days, age range 65 years and above, health professional worker and married status as confounder’s factors. Of 645 included patients, 120(20.23%) deaths were recorded. Among these 645 patients, 262(40.62%) were males, 128(19.84%) aged 65 years and above. The mean length of stay was 11.07. On admission, 204 (31.62%) patients presented at least one chronic disease. The most common chronic disease were hypertension (HBP) 73(11.32%), followed by diabetes + HBP 62 (9.61%), by diabetes 55(8.53%) and Immunodeficiency condition 14(2.17%). Diabetes and Diabetes + HBP were associated with a higher risk of death respectively aOR = 2.71[95%CI = 1.19-6.18] and aOR = 2.07[95% CI = 1.01-4.23] but HBP did not significantly increased the risk of death. These results suggest that health authorities should prioritize these specific group to adopt primary and secondary preventive interventions against SARS-CoV-2 infection.

PMID:36963083 | DOI:10.1371/journal.pgph.0001572

J Clin Immunol. 2023 Mar 24. doi: 10.1007/s10875-023-01474-y. Online ahead of print.

ABSTRACT

PURPOSE: Chronic sleep issues can lead to poor quality of life and increased mortality and patients with chronic health conditions often report impaired sleep quality. Higher levels of fatigue have been identified in patients diagnosed with inborn errors of immunity (or primary immunodeficiency diseases). This research sought to better understand perceived sleep quality in individuals diagnosed with IEI.

METHODS: A survey, which included the validated Sleep Quality Scale, was shared across multiple social media groups for individuals with a diagnosis of IEI.

RESULTS: Most of the participants were White/Caucasian females, between the ages of 30 and 74 years. The results of the Sleep Quality Scale suggest that this sample of individuals has moderate impairment of their sleep quality (71.8%), with a mean score of 43.0 (SD = 13.1). When comparing the results of the SQS to other patient populations and healthy control groups, the participants in this study had a poorer sleep quality score. Associations were identified between sleep quality and age, hours of sleep per night, time awake at night, times awake to urinate, attempted daytime naps, chronic pain, and mental health diagnoses.

CONCLUSION: This survey suggests that individuals with inborn errors of immunity have a moderate degree of perceived impairment in sleep quality. Healthcare providers are strongly encouraged to incorporate sleep quality screening in their routine assessments of patients with a diagnosis of Inborn Error of Immunity. Patients who are identified as having impaired sleep quality should be referred for further testing and interventions.

PMID:36959490 | DOI:10.1007/s10875-023-01474-y

Laryngoscope. 2023 Mar 24. doi: 10.1002/lary.30672. Online ahead of print.

ABSTRACT

OBJECTIVE: The objective of this study was to explore diet patterns in children with tympanostomy tube placement (TTP) complicated by postoperative tympanostomy tube otorrhea.

STUDY DESIGN: Cross-sectional survey and retrospective cohort study.

METHODS: Caregivers of children (0-12 years old), at a tertiary-care pediatric hospital who underwent TTP within 6 months to 2 years prior to enrollment were included. Children with a history of Down syndrome, cleft palate, craniofacial syndromes, known immunodeficiency, or a non-English-speaking family were excluded. Our primary outcome variable was the number of otorrhea episodes. The primary predictor was diet patterns, particularly dessert intake, which was captured through a short food questionnaire.

RESULTS: A total of 286 participants were included in this study. The median age was 1.8 years (IQR, 1.3, 2.9). A total of 174 (61%) participants reported at least one episode of otorrhea. Children who consumed dessert at least two times per week had a higher risk of otorrhea compared to children who consumed one time per week or less (odds ratio [OR], 3.22, 95% Confidence Interval [CI]: 1.69, 6.12). The odds ratio increase continued when considering more stringent criteria for otorrhea (multiple episodes or one episode occurring 4 weeks after surgery), with a 2.33 (95% CI: 1.24, 4.39) higher odds of otorrhea in children with dessert intake at least 2 times per week.

CONCLUSIONS: Our pilot data suggest that episodes of otorrhea among children with TTP were associated with more frequent dessert intake. Future studies using prospectively administered diet questionnaires are necessary to confirm these findings.

LEVEL OF EVIDENCE: 4 Laryngoscope, 2023.

PMID:36960887 | DOI:10.1002/lary.30672