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Clin Lymphoma Myeloma Leuk. 2024 Apr 10:S2152-2650(24)00150-2. doi: 10.1016/j.clml.2024.04.002. Online ahead of print.

ABSTRACT

BACKGROUND: This retrospective cohort study compared patient characteristics and burden of infection in patients with mature B cell malignancies with and without secondary immunodeficiency disease (SID).

PATIENTS AND METHODS: Data were extracted from the Humedica database (H-DB) and Guardian Research Network (GRN) database from October 1, 2015 to March 10, 2020, including a 6-month pre-index period (PIP) and 12-month follow-up. Patients aged ≥18 years diagnosed with chronic lymphocytic leukemia/small lymphocytic lymphoma, multiple myeloma, or non-Hodgkin’s lymphoma in the PIP were stratified into 2 cohorts: SID (hypogammaglobulinemia [using ICD-10-CM codes] or serum IgG levels <5.0 g/L, both with signs and symptoms of SID or at least 1 infection) and no-SID. Patients with SID or primary immunodeficiency diseases in the PIP were excluded.

RESULTS: Overall, 2221 patients with SID (H-DB/GRN: n = 1959/262), and 19,141 patients without SID (n = 17,598/1543) were included. Baseline characteristics were similar across cohorts. At 12-month follow-up, significantly more patients with SID had experienced ≥1 infection and ≥1 severe bacterial infection than those without SID (both P < .001). H-DB/GRN mean (standard deviation) number of severe bacterial infections was 7.6 (9.9)/2.9 (2.7) for the SID cohort versus 5.2 (6.8)/2.4 (2.2) for the no-SID cohort.

CONCLUSION: This study confirms that patients with mature B cell malignancies and SID face a significantly higher burden of infections than those without SID.

PMID:38734499 | DOI:10.1016/j.clml.2024.04.002

J Allergy Clin Immunol Pract. 2024 May 9:S2213-2198(24)00470-7. doi: 10.1016/j.jaip.2024.05.003. Online ahead of print.

ABSTRACT

Patient registries are a mechanism for collecting data on allergic and immunologic diseases that provide important information on epidemiology and outcomes that can ultimately improve patient care. Key criteria for establishing effective registries include the use of a clearly defined purpose, identifying the target population and ensuring consistent data collection. Registries in allergic diseases include those for diseases such as inborn errors of immunity, food allergy, asthma and anaphylaxis, pharmacological interventions in vulnerable populations, and adverse effects of pharmacologic interventions including hypersensitivity reactions to drugs and vaccines. Important insights gained from patient registries in our field include contributions in phenotype and outcomes in inborn errors of immunity, the risk for adverse reactions in food-allergic patients in multiple settings, the benefits and risk of biologic medications for asthma during pregnancy, vaccine safety, and the categorization and genetic determination of risk for severe cutaneous adverse reactions to medications. Impediments to the development of clinically meaningful patient registries include the lack of funding resources for registry establishment and the quality, quantity, and consistency of available data. Despite these drawbacks, high-quality and successful registries are invaluable in informing clinical practice and improving outcomes in patients with allergic and immunological diseases.

PMID:38734373 | DOI:10.1016/j.jaip.2024.05.003

N Biotechnol. 2024 May 9:S1871-6784(24)00016-5. doi: 10.1016/j.nbt.2024.05.001. Online ahead of print.

ABSTRACT

Extracellular Vesicles (EVs) have been proposed as a promising tool for drug delivery because of their natural ability to cross biological barriers, protect their cargo, and target specific cells. Moreover, EVs are not recognized by the immune system as foreign, reducing the risk of an immune response and enhancing biocompatibility. Herein, we proposed an alternative therapeutic strategy to restore STAT3 signalling exploiting STAT3 loaded EVs. This approach could be useful in the treatment of Autosomal Dominant Hyper-IgE Syndrome (AD-HIES), a rare primary immunodeficiency and multisystem disorder due to the presence of mutations in STAT3 gene. These mutations alter the signal transduction of STAT3, thereby impeding Th17 CD4⁺ cell differentiation that leads to the failure of immune response. We set up a simple and versatile method in which EVs were loaded with fully functional STAT3 protein. Moreover, our method allows to follow the uptake of STAT3 loaded vesicles inside cells due to the presence of EGFP in the EGFP-STAT3 fusion protein construct. Taken together, the data presented in this study could provide the scientific background for the development of new therapeutic strategy aimed to restore STAT3 signalling in STAT3 misfunction associated diseases like AD-HIES. In the future, the administration of fully functional wild type STAT3 to CD4+ T cells of AD-HIES patients might compensate its loss of function and would be beneficial for these patients, lowering the risk of infections, the use of medications, and hospitalizations.

PMID:38734368 | DOI:10.1016/j.nbt.2024.05.001

Clin Immunol. 2024 May 9:110244. doi: 10.1016/j.clim.2024.110244. Online ahead of print.

ABSTRACT

Common variable immune deficiency (CVID) is a heterogenous group of disorders characterized by varying degrees of hypogammaglobulinemia, recurrent infections, and autoimmunity. Currently, pathogenic variants are identified in approximately 20-30% of CVID cases. Here we report a 3-generation family with autosomal dominant Common Variable Immunodeficiency (CVID) diagnosed in 9 affected individuals. Although primary immune deficiency panels and exome sequencing were non-diagnostic, whole genome sequencing revealed a novel, pathogenic c.499C > T: p.His167Tyr variant in IKZF1, a critical regulator of B cell development. Functional testing done through pericentromeric heterochromatin localization and light shift chemiluminescent electrophoretic mobility shift assay confirmed the variant’s deleterious effect via a haploinsufficiency mechanism. Our findings expand the spectrum of known IKZF1 mutations and contribute to a more comprehensive understanding of CVID’s genetic heterogeneity. Furthermore, this case underscores the importance of considering whole genome sequencing for comprehensive genetic diagnosis when concern for a monogenic inborn errors of immunity is high.

PMID:38734037 | DOI:10.1016/j.clim.2024.110244

J Infect Chemother. 2024 May 8:S1341-321X(24)00126-0. doi: 10.1016/j.jiac.2024.04.013. Online ahead of print.

ABSTRACT

BACKGROUND: Since the appropriate antibiotic duration for uncomplicated Staphylococcus aureus (S. aureus) bacteremia (u-SAB) in an immunocompromised state is still unclear, physicians are likely to extend antibiotic therapy from 2 weeks to 4-6 weeks. To examine the appropriate duration of antibiotic therapy for u-SAB, we performed this study.

PATIENTS AND METHODS: We reviewed all patients with u-SAB at our institute seen between January 2020 and August 2023. A total of 51 patients were enrolled, and they were divided into the following two groups by antibiotic duration: longer duration group ≥ 28 days after blood culture negativity, and shorter duration group. Then, the patients were matched by a propensity score using the covariates of age, sex, qSOFA, and CCI. The primary outcome was to identify the prognosis by duration of antibiotic treatment.

RESULTS: After propensity score matching, all-cause 30-day mortality was 0 % in both groups. Hence, there was no significant difference in all-cause 90 days mortality (19.0% vs 9.5%, p = 0.33) or recurrence (9.5%% vs 0%, p = 0.22). Before propensity-score matching, we found that a serum level of CRP 2.0mg/dL and greater after intravenous antibiotic treatment was one of the poor prognostic factors. The cut-off value of serum CRP level was 2.0mg/dL with a sensitivity of 82.1% and a specificity of 75.0%.

CONCLUSION: We suggested that 4-6 weeks of antibiotic treatment for immunodeficient u-SAB patients was unnecessary. Moreover, the serum level of CRP after completion of IV antibiotic treatment could be a prognostic marker for u-SAB.

PMID:38729565 | DOI:10.1016/j.jiac.2024.04.013

Infect Dis Ther. 2024 May 10. doi: 10.1007/s40121-024-00981-8. Online ahead of print.

ABSTRACT

INTRODUCTION: AZD7442 is a combination of two neutralizing antibodies (tixagevimab/cilgavimab) with demonstrated efficacy in reducing the risk of symptomatic coronavirus disease 2019 (COVID-19) among individuals at high risk of severe COVID-19 ≤ 6 months after administration. On February 15, 2022, the Israeli Ministry of Health (IMoH) authorized the administration of 300 mg AZD7442 as pre-exposure prophylaxis (PrEP) against severe acute respiratory syndrome coronavirus 2 infection among immunocompromised individuals aged ≥ 12 years. This study describes the real-world uptake of AZD7442 in Israel.

METHODS: This descriptive, observational study analyzed data from Israel’s largest health maintenance organization, Clalit Health Services (CHS). Individuals were assessed for AZD7442 eligibility between February 13 and December 11, 2022, and were included if they were aged ≥ 12 years, had ≥ 1 year of continuous CHS membership, had ≥ 1 moderate or severe immunocompromising condition, and were eligible for AZD7442 per IMoH recommendations during this time frame.

RESULTS: Overall, 19,161 AZD7442-eligible individuals with immunocompromising conditions were identified during the study period; 2829 (14.8%) received AZD7442. A higher proportion of individuals receiving AZD7442 were older (aged ≥ 65 years), male, not current smokers and residents in large cities; required more physician visits (> 50 visits); and had ≥ 1 COVID-19 hospitalization over 12 months, while uptake was lowest among ultra-orthodox Jewish individuals. AZD7442 uptake was also higher among individuals with multiple comorbidities (Charlson Comorbidity Index ≥ 5), including hypertension, diabetes and chronic kidney disease. In specific immunocompromised types, AZD7442 uptake was highest among individuals with lung transplantation (41%), primary immunodeficiency (32%), bone marrow transplantation (29%) and multiple myeloma (25%) or those receiving anti-CD20 therapy (26%) and was lowest in individuals with lymphoma (8%).

CONCLUSION: These results show AZD7442 uptake among the eligible population of Israel in 2022 was relatively low, at 14.8%. Uptake was generally higher among immunocompromised individuals who may be perceived to be frail or at highest risk of COVID-19 infection and complications, although at 25-41%, further improvements in uptake would be more impactful. These results also indicate there is opportunity to expand AZD7442 uptake across immunocompromised groups and ensure more equitable uptake among some other sociodemographic groups. Overall, this study will help inform and reassess future implementation strategies for vulnerable populations.

PMID:38728006 | DOI:10.1007/s40121-024-00981-8

Front Immunol. 2024 Apr 25;15:1324671. doi: 10.3389/fimmu.2024.1324671. eCollection 2024.

ABSTRACT

INTRODUCTION: Hereditary angioedema (HAE) is a rare, life-threatening autosomal dominant genetic disorder caused by a deficient and/or dysfunctional C1 esterase inhibitor (C1-INH) (type 1 and type 2) leading to recurrent episodes of edema. This study aims to explore HAE patients’ metabolomic profiles and identify novel potential diagnostic biomarkers for HAE. The study also examined distinguishing HAE from idiopathic angioedema (AE).

METHODS: Blood plasma samples from 10 HAE (types 1/2) patients, 15 patients with idiopathic AE, and 20 healthy controls were collected in Latvia and analyzed using LC-MS based targeted metabolomics workflow. T-test and fold change calculation were used to identify metabolites with significant differences between diseases and control groups. ROC analysis was performed to evaluate metabolite based classification model.

RESULTS: A total of 33 metabolites were detected and quantified. The results showed that isovalerylcarnitine, cystine, and hydroxyproline were the most significantly altered metabolites between the disease and control groups. Aspartic acid was identified as a significant metabolite that could differentiate between HAE and idiopathic AE. The mathematical combination of metabolites (hydroxyproline * cystine)/(creatinine * isovalerylcarnitine) was identified as the diagnosis signature for HAE. Furthermore, glycine/asparagine ratio could differentiate between HAE and idiopathic AE.

CONCLUSION: Our study identified isovalerylcarnitine, cystine, and hydroxyproline as potential biomarkers for HAE diagnosis. Identifying new biomarkers may offer enhanced prospects for accurate, timely, and economical diagnosis of HAE, as well as tailored treatment selection for optimal patient care.

PMID:38726011 | PMC:PMC11080650 | DOI:10.3389/fimmu.2024.1324671

Zhonghua Yu Fang Yi Xue Za Zhi. 2024 May 6;58(5):698-705. doi: 10.3760/cma.j.cn112150-20230712-00005.

ABSTRACT

The 2021 edition of the international World Allergy Organization (WAO)/European Academy of Allergy and Clinical Immunology (EAACI) guideline for the management of hereditary angioedema (HAE) is mainly based on high-quality randomized controlled trials. It provides clinical classification for HAE and offers graded recommendations for on-demand therapy, short-term prophylactic therapy, and long-term prophylactic therapy. Additionally, it provides management strategies for people with different HAE types. This article focused on the interpretation of short-term, long-term prophylactic therapy and on-demand therapy for HAE, supplemented with the latest clinical evidence, aiming to provide references for the long-term management of HAE.

PMID:38715512 | DOI:10.3760/cma.j.cn112150-20230712-00005

Cureus. 2024 Apr 6;16(4):e57697. doi: 10.7759/cureus.57697. eCollection 2024 Apr.

ABSTRACT

Adenosine deaminase (ADA) deficiency, an autosomal recessive variant, is the second most common form of severe combined immunodeficiency (SCID). We report a unique case of a three-week-old neonate who presented with prolonged and severe SARS-CoV-2 infection associated with persistent lymphopenia, subsequently revealing ADA-deficient SCID. He presented with mild and insidious symptoms, and then his clinical condition rapidly deteriorated. He required ICU admission and mechanical ventilation and developed multiple co-infections including opportunistic pathogens. Flow cytometry and whole exome sequencing diagnosed ADA-deficient SCID. This case highlights the importance of recognizing primary immunodeficiency disorders in children who consistently display lymphopenia and experience prolonged opportunistic and viral infections. Detecting lymphopenia should prompt consideration of SCID, serving as a straightforward and cost-effective screening approach, particularly in nations such as the United Arab Emirates where T-cell receptor excision circles (TRECs) are not part of newborn screening protocols.

PMID:38711702 | PMC:PMC11070899 | DOI:10.7759/cureus.57697

Sci Rep. 2024 May 6;14(1):10346. doi: 10.1038/s41598-024-61054-x.

ABSTRACT

Mammals are generally resistant to Mycobacterium avium complex (MAC) infections. We report here on a primary immunodeficiency disorder causing increased susceptibility to MAC infections in a canine breed. Adult Miniature Schnauzers developing progressive systemic MAC infections were related to a common founder, and pedigree analysis was consistent with an autosomal recessive trait. A genome-wide association study and homozygosity mapping using 8 infected, 9 non-infected relatives, and 160 control Miniature Schnauzers detected an associated region on chromosome 9. Whole genome sequencing of 2 MAC-infected dogs identified a codon deletion in the CARD9 gene (c.493_495del; p.Lys165del). Genotyping of Miniature Schnauzers revealed the presence of this mutant CARD9 allele worldwide, and all tested MAC-infected dogs were homozygous mutants. Peripheral blood mononuclear cells from a dog homozygous for the CARD9 variant exhibited a dysfunctional CARD9 protein with impaired TNF-α production upon stimulation with the fungal polysaccharide β-glucan that activates the CARD9-coupled C-type lectin receptor, Dectin-1. While CARD9-deficient knockout mice are susceptible to experimental challenges by fungi and mycobacteria, Miniature Schnauzer dogs with systemic MAC susceptibility represent the first spontaneous animal model of CARD9 deficiency, which will help to further elucidate host defense mechanisms against mycobacteria and fungi and assess potential therapies for animals and humans.

PMID:38710903 | DOI:10.1038/s41598-024-61054-x