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International Journal of Neonatal... Dec 2023Newborn screening (NBS) for Severe Combined Immunodeficiency (SCID) by measurement of T-cell receptor excision circles (TRECs) successfully identifies newborns with SCID...
Newborn screening (NBS) for Severe Combined Immunodeficiency (SCID) by measurement of T-cell receptor excision circles (TRECs) successfully identifies newborns with SCID and severe T-cell lymphopenia, as intended. At the same time, NBS programs face the challenge of false positive results, with a disproportionately high number in the premature newborn population. This study evaluates TREC values and SCID screening outcomes in premature newborns and elucidates evidence-based SCID screening practices that reduce unnecessary follow-up activities in this population. De-identified individual SCID newborn screening data and aggregate SCID screening data were obtained from seven states across the US for babies born between 2018 and 2020. Relevant statistics were performed on data pooled from these states to quantify screening performance metrics and clinical impact on various birth and gestational age categories of newborns. The data were normalized using multiples-of-the-median (MoM) values to allow for the aggregation of data across states. The aggregation of NBS data across a range of NBS programs highlighted the trajectory of TREC values over time, both between and within newborns, and provides evidence for improved SCID screening recommendations in the premature and low birth weight population.
PubMed: 38132827
DOI: 10.3390/ijns9040068 -
Journal of Clinical Immunology Dec 2023
Topics: Humans; Adenosine Deaminase; Intercellular Signaling Peptides and Proteins; Severe Combined Immunodeficiency
PubMed: 38129740
DOI: 10.1007/s10875-023-01638-w -
Reumatismo Dec 2023Deficiency of adenosine deaminase 2 (DADA2) is a recessively inherited autoinflammatory disease characterized by systemic inflammation and immunodeficiency. Infliximab...
Deficiency of adenosine deaminase 2 (DADA2) is a recessively inherited autoinflammatory disease characterized by systemic inflammation and immunodeficiency. Infliximab proved to be favorable in the treatment of this condition. This case report is concerned with a DADA2 deficient patient treated with infliximab. This is a rare case of DADA2 in a 32-year-old female patient. The patient was admitted with a clinical presentation of erythema, ulcers, and pruritus on both legs and ankles, accompanied by red ulcerative oral lesions, fatigue, malaise, and dizziness. The patient's genetic analysis was positive for DADA2. Treatment based on TNF-α inhibition was highly effective for this patient. We used laboratory testing and punch biopsy as differential diagnostic tools, where antinuclear antibody positivity, high prolactin levels, and high serum C-reactive protein were observed. The punch biopsy revealed both orthohyperkeratosis and parahyperkeratosis of the dermis, diffuse core fragments, plasma in the stratum corneum, and hypergranulous acanthosis. DADA2 treatment is centered on tumor necrosis factor α suppression. Although high-dose systemic glucocorticoids can reduce inflammation in the initial stages of the disease, most patients have a resistant or relapsing response to tapering attempts. The prevalence of undiagnosed cases of autoinflammatory diseases is anticipated to diminish with the growing awareness of them.
Topics: Female; Humans; Adult; Adenosine Deaminase; Infliximab; Intercellular Signaling Peptides and Proteins; Inflammation; Mutation
PubMed: 38115782
DOI: 10.4081/reumatismo.2023.1543 -
Blood Advances Apr 2024Recombination-activating genes (RAG1 and RAG2) are critical for lymphoid cell development and function by initiating the variable (V), diversity (D), and joining (J)...
Recombination-activating genes (RAG1 and RAG2) are critical for lymphoid cell development and function by initiating the variable (V), diversity (D), and joining (J) (V(D)J)-recombination process to generate polyclonal lymphocytes with broad antigen specificity. The clinical manifestations of defective RAG1/2 genes range from immune dysregulation to severe combined immunodeficiencies (SCIDs), causing life-threatening infections and death early in life without hematopoietic cell transplantation (HCT). Despite improvements, haploidentical HCT without myeloablative conditioning carries a high risk of graft failure and incomplete immune reconstitution. The RAG complex is only expressed during the G0-G1 phase of the cell cycle in the early stages of T- and B-cell development, underscoring that a direct gene correction might capture the precise temporal expression of the endogenous gene. Here, we report a feasibility study using the CRISPR/Cas9-based "universal gene-correction" approach for the RAG2 locus in human hematopoietic stem/progenitor cells (HSPCs) from healthy donors and RAG2-SCID patient. V(D)J-recombinase activity was restored after gene correction of RAG2-SCID-derived HSPCs, resulting in the development of T-cell receptor (TCR) αβ and γδ CD3+ cells and single-positive CD4+ and CD8+ lymphocytes. TCR repertoire analysis indicated a normal distribution of CDR3 length and preserved usage of the distal TRAV genes. We confirmed the in vivo rescue of B-cell development with normal immunoglobulin M surface expression and a significant decrease in CD56bright natural killer cells. Together, we provide specificity, toxicity, and efficacy data supporting the development of a gene-correction therapy to benefit RAG2-deficient patients.
Topics: Humans; DNA-Binding Proteins; Hematopoietic Stem Cells; Homeodomain Proteins; Nuclear Proteins; Receptors, Antigen, T-Cell, alpha-beta; Severe Combined Immunodeficiency; VDJ Recombinases
PubMed: 38096800
DOI: 10.1182/bloodadvances.2023011766 -
BMC Medical Genomics Dec 2023Severe combined immunodeficiency (SCID) is a group of fatal primary immunodeficiencies characterized by the severe impairment of T-cell differentiation. IL7R deficiency...
BACKGROUND
Severe combined immunodeficiency (SCID) is a group of fatal primary immunodeficiencies characterized by the severe impairment of T-cell differentiation. IL7R deficiency is a rare form of SCID that usually presents in the first months of life with severe and opportunistic infections, failure to thrive, and a high risk of mortality unless treated. Although recent improvements in early diagnosis have been achieved through newborn screening, few IL7R-related SCID patients had been reported in the Chinese population.
CASE PRESENTATION
Here, we retrospectively analyzed a case of SCID in a 5-month-old girl with symptoms, including severe T-cell depletion, recurrent fever, oral ulcers, pneumonia, hepatosplenomegaly, bone marrow hemophagocytosis, and bacterial and viral infections. Whole-exome sequencing (WES), quantitative PCR (qPCR), and chromosome microarray analysis (CMA) were performed to identify the patient's genetic etiology. We identified a 268 kb deletion and a splicing variant, c.221 + 1G > A, in the proband. These two variants of IL7R were inherited from the father and mother.
CONCLUSIONS
To our knowledge, this is the first report of whole IL7R gene deletion in combination with a pathogenic splicing variant in a patient with SCID. This deletion also expands the pathogenic variation spectrum of SCID caused by IL7R. The incorporation of exome-based copy number variant analysis makes WES a powerful molecular diagnostic technique for the clinical diagnosis of pediatric patients.
Topics: Infant, Newborn; Female; Humans; Child; Infant; Severe Combined Immunodeficiency; Retrospective Studies; Virus Diseases; Exome; China; Interleukin-7 Receptor alpha Subunit
PubMed: 38082310
DOI: 10.1186/s12920-023-01765-8 -
Journal of Thrombosis and Haemostasis :... Mar 2024A safe and efficacious hemostatic product with a long shelf-life is needed to reduce mortality from hemorrhage due to trauma and improve surgical outcomes for persons...
BACKGROUND
A safe and efficacious hemostatic product with a long shelf-life is needed to reduce mortality from hemorrhage due to trauma and improve surgical outcomes for persons with platelet deficiency or dysfunction. Thrombosomes, a trehalose-stabilized, leukoreduced, pooled blood group-O freeze-dried platelet-derived hemostatic (FPH) with a 3-year shelf-life, may satisfy this need.
OBJECTIVES
To characterize the mechanism of action of FPH.
METHODS
FPH's ability to adhere to collagen, aggregate with and without platelets, and form clots was evaluated in vitro. Nonobese diabetic-severe combined immunodeficiency mouse models were used to assess circulation persistence and hemostatic efficacy.
RESULTS
FPH displays the morphology and surface proteins of activated platelets. FPH adheres to collagen, aggregates, and promotes clots, producing an insoluble fibrin mesh. FPH is rapidly cleared from circulation, has hemostatic efficacy comparable to apheresis platelets in a murine tail-cut, and acts in a dose-dependent manner.
CONCLUSION
FPH is a first-in-class investigational treatment and shows strong potential as a hemostatic agent that is capable of binding exposed collagen, coaggregating with endogenous platelets, and promoting the coagulation cascade. These properties may be exploited to treat active platelet-related or diffuse vascular bleeding. FPH has the potential to fulfill a large unmet patient need as an acute hemostatic treatment in severe bleeding, such as surgery and trauma.
Topics: Humans; Animals; Mice; Hemostatics; Hemostasis; Blood Platelets; Blood Coagulation; Hemorrhage; Collagen; Thrombosis
PubMed: 38072376
DOI: 10.1016/j.jtha.2023.11.022 -
Journal of Clinical Medicine Dec 2023Inborn errors of immunity (IEIs) are a heterogeneous group of diverse clinical and genetic phenotypes that have an estimated combined prevalence as high as 1/1000.... (Review)
Review
Inborn errors of immunity (IEIs) are a heterogeneous group of diverse clinical and genetic phenotypes that have an estimated combined prevalence as high as 1/1000. Increased risk of frequent, severe, or opportunistic infections is a common feature of IEIs, but there are also diverse immune-mediated, non-infective complications that are associated with significant morbidity and mortality. As patient survival increases, these are becoming more apparent within the liver. Hepatic involvement of IEIs may not only manifest as infections, but also nodular regenerative hyperplasia, granulomatous disease, autoimmune hepatitis and malignancy. As therapeutic options for patients are expanding, with both pharmaceutical treatments as well as haematopoietic stem cell transplant (HSCT), iatrogenic liver injury is increasingly common and important to identify. This review article summarises the spectrum of hepatic complications seen in IEIs, and highlights the challenges of management within this patient cohort, where immunosuppression is poorly tolerated. Early recognition and prompt diagnosis of potential hepatic complications is therefore crucial in ensuring potentially reversible causes are treated, but significant uncertainty remains regarding best practice for many features of immune dysregulation with limited high-quality evidence.
PubMed: 38068532
DOI: 10.3390/jcm12237480 -
Case Reports in Pulmonology 2023Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first introduced in China in 2019, and it has rapidly spread all around the world. is the leading cause...
BACKGROUND
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first introduced in China in 2019, and it has rapidly spread all around the world. is the leading cause of fungal meningitis in human immunodeficiency virus- (HIV-) infected patients. A variety of laboratory tests have been introduced for rapid diagnosis of meningitis.
METHODS
Here, we report a case of coinfection with COVID-19 and cryptococcal meningitis in a HIV-positive patient with abnormal laboratory findings. In this case, COVID-19 was positive by polymerase chain reaction (PCR) and computerized tomography (CT) scan diagnosis. Cryptococcal antigen testing of CSF was negative, whereas India ink staining and cerebrospinal fluid (CSF) culture confirmed the presence of .
RESULTS
Although the patient was in a critical stage of illness, serum and CSF levels of procalcitonin were abnormally low, within normal limits. On the other hand, although initial lumbar puncture had showed elevated protein level, the repeat CSFs presented remarkably reduced protein levels. Our findings indicate that despite COVID-19 infection, procalcitonin level may remain normal in HIV-associated cryptococcal meningitis, and findings of an apparently normal procalcitonin level should not exclude the possibility of infection. Also, antigen testing may present false-negative result, and it should not be the sole laboratory method for diagnosis of infectious meningitis. Consequently, CSF culture and staining is recommended, even when antigen testing of organism is negative and CSF profile is unremarkable.
CONCLUSION
Laboratory information should be combined with a good understanding of clinical manifestations of patient to determine if meningitis is present and confirmed COVID-19 should not ignore possibility of other infections for consideration.
PubMed: 38034910
DOI: 10.1155/2023/2868290 -
Qatar Medical Journal 2023Severe combined immunodeficiency disease (SCID) is a rare primary immunodeficiency disease, usually manifest in the first six months of life with failure to thrive, oral...
INTRODUCTION
Severe combined immunodeficiency disease (SCID) is a rare primary immunodeficiency disease, usually manifest in the first six months of life with failure to thrive, oral thrush, recurrent respiratory infection, and chronic diarrhea.
CASE PRESENTATION
In three male patients, we describe an unusual presentation of SCID. They are an outcome of consanguineous marriage; all received the BCG vaccine at birth. All three cases presented with regional lymphadenopathy at three months, progressing to generalized lymphadenopathy treated with anti-tuberculous. The first and second cases were twins. The first had an uneventful history until 33 months when he developed multiple Suppurative Tuberculous lymphadenitis confirmed by biopsy. The second and the third cases were diagnosed with Disseminated Tuberculosis at 24 months as they developed fever, anemia, weight loss, tuberculous peritonitis, and lymphadenopathy confirmed by biopsy. After investigations, the first case was diagnosed as CD4, CD16 lymphopenic SCID, the second one as CD4, CD8, CD19, CD16 lymphopenic SCID with hypogammaglobulinemia and the third case as CD3, CD4, CD8 lymphopenic SCID with hypogammaglobulinemia. They received anti-Tuberculous medications, prophylactic Trimethoprim/Sulfamethoxazole, and Immunoglobulin infusion. When writing this abstract, the patients were alive and had no other bacterial, viral, or fungal infections. The twins are three years old, and the third case is 30 months old.
CONCLUSION
SCID may not exhibit the classical manifestation of recurrent infections. It may present only as a complication of the BCG vaccine, alarming to maintain high susceptibility in such patients, especially in a developing country, specifically in Sudan, where the BCG vaccine is usually given at birth.
PubMed: 38025336
DOI: 10.5339/qmj.2023.sqac.9 -
Open Forum Infectious Diseases Nov 2023Hemophagocytic lymphohistiocytosis triggered by disseminated Bacillus Calmette-Guerin infection is rare. Targeted next-generation sequencing for tuberculosis can rapidly...
Hemophagocytic lymphohistiocytosis triggered by disseminated Bacillus Calmette-Guerin infection is rare. Targeted next-generation sequencing for tuberculosis can rapidly identify different strains of complex as well as drug resistance genes. Herein we report 2 cases of hemophagocytic lymphohistiocytosis in whom targeted next-generation sequencing rapidly identified Bacillus Calmette-Guerin as the infectious trigger.
PubMed: 38023550
DOI: 10.1093/ofid/ofad548