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The American Journal of Case Reports Mar 2021BACKGROUND Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disease characterized by an intense immunologic response that results in multiorgan...
BACKGROUND Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disease characterized by an intense immunologic response that results in multiorgan dysfunction. It typically manifests as a result of a familial genetic immunodeficiency disorder or secondary to a trigger such as an infection, malignancy, or autoimmune disease. The major factors involved in the development of the disease are an individual's genetic propensity to develop HLH, such as rare associated mutations, or inflammatory processes that trigger the immune system to go haywire. CASE REPORT Before the COVID-19 pandemic, a 22-year-old woman with a history of congenital absence of the right kidney, right-sided hearing loss, and leukopenia presented with a 3-week history of generalized malaise, fever, chest pain, cough, and shortness of breath. She developed an acute systemic cytomegalovirus infection further complicated by HLH. Based on her history and clinical course, an underlying primary immunodeficiency was suspected. An immunodeficiency gene panel revealed a monoallelic mutation in GATA2, a gene that encodes zinc-transcription factors responsible for the regulation of hematopoiesis. CONCLUSIONS GATA2 deficiency encompasses a large variety of mutations in the GATA2 gene and leads to disorders associated with hematologic and immunologic manifestations of monocytopenia and B-, and natural killer-cell deficiency. Over time, affected individuals are at high risk of developing life-threatening infections and serious hematologic complications, such as myelodysplastic syndromes and/or leukemias. We aimed to illustrate the importance of identifying an underlying genetic disorder associated with secondary HLH to help guide acute and long-term management.
Topics: Cytomegalovirus Infections; Female; GATA2 Deficiency; Humans; Lymphohistiocytosis, Hemophagocytic; Young Adult
PubMed: 33684095
DOI: 10.12659/AJCR.927087 -
PloS One 2021A new respiratory virus, SARS-CoV-2, has emerged and spread worldwide since late 2019. This study aims at analysing clinical presentation on admission and the... (Observational Study)
Observational Study
INTRODUCTION
A new respiratory virus, SARS-CoV-2, has emerged and spread worldwide since late 2019. This study aims at analysing clinical presentation on admission and the determinants associated with admission in intensive care units (ICUs) in hospitalized COVID-19 patients.
PATIENTS AND METHODS
In this prospective hospital-based study, socio-demographic, clinical and biological characteristics, on admission, of adult COVID-19 hospitalized patients presenting from the community for their first admission were prospectively collected and analysed. Characteristics of patients hospitalized in medical ward to those admitted in ICU were compared using Mann-Whitney and Chi-square or Fisher exact test when appropriate. Univariate logistic regression was first used to identify variables on admission that were associated with the outcome i.e. admission to an ICU versus total hospital stay in a medical ward. Forward selection was then applied beginning with sex, age and temperature in the multivariable logistic regression model.
RESULTS
Of the 412 patients included, 325 were discharged and 87 died in hospital. Multivariable regression showed increasing odds of ICU hospitalization with temperature (OR, 1.56 [95% CI, 1.06-2.28] per degree Celsius increase), oxygen saturation <90% (OR, 12.45 [95% CI, 5.27-29.4]), abnormal lung auscultation on admission (OR, 3.58 [95% CI, 1.58-8.11]), elevated level of CRP (OR, 2.7 [95% CI, 1.29-5.66for CRP>100mg/L vs CRP<10mg/L). and monocytopenia (OR, 3.28 [95% CI, 1.4-7.68]) were also associated with increasing odds of ICU hospitalization. Older patients were less likely to be hospitalized in ICU (OR, 0.17 [95%CI, 0.05-0.51].
CONCLUSIONS
Age and delay between onset of symptoms and hospital admission were associated with the risk of hospitalisation in ICU. Age being a fixed variable, interventions that shorten this delay would improve the prognosis of Covid-19 patients.
Topics: Adult; Aged; Aged, 80 and over; COVID-19; Female; France; Hospital Mortality; Hospitalization; Humans; Intensive Care Units; Length of Stay; Male; Middle Aged; Prognosis; Prospective Studies; SARS-CoV-2
PubMed: 33503018
DOI: 10.1371/journal.pone.0243709 -
Journal of Clinical Immunology Apr 2021Germline heterozygous mutations of GATA2 underlie a variety of hematological and clinical phenotypes. The genetic, immunological, and clinical features of...
PURPOSE
Germline heterozygous mutations of GATA2 underlie a variety of hematological and clinical phenotypes. The genetic, immunological, and clinical features of GATA2-deficient patients with mycobacterial diseases in the familial context remain largely unknown.
METHODS
We enrolled 15 GATA2 index cases referred for mycobacterial disease. We describe their genetic and clinical features including their relatives.
RESULTS
We identified 12 heterozygous GATA2 mutations, two of which had not been reported. Eight of these mutations were loss-of-function, and four were hypomorphic. None was dominant-negative in vitro, and the GATA2 locus was found to be subject to purifying selection, strongly suggesting a mechanism of haploinsufficiency. Three relatives of index cases had mycobacterial disease and were also heterozygous, resulting in 18 patients in total. Mycobacterial infection was the first clinical manifestation in 11 patients, at a mean age of 22.5 years (range: 12 to 42 years). Most patients also suffered from other infections, monocytopenia, or myelodysplasia. Strikingly, the clinical penetrance was incomplete (32.9% by age 40 years), as 16 heterozygous relatives aged between 6 and 78 years, including 4 older than 60 years, were completely asymptomatic.
CONCLUSION
Clinical penetrance for mycobacterial disease was found to be similar to other GATA2 deficiency-related manifestations. These observations suggest that other mechanisms contribute to the phenotypic expression of GATA2 deficiency. A diagnosis of autosomal dominant GATA2 deficiency should be considered in patients with mycobacterial infections and/or other GATA2 deficiency-related phenotypes at any age in life. Moreover, all direct relatives should be genotyped at the GATA2 locus.
Topics: Adolescent; Adult; Alleles; Cell Line; Child; DNA Mutational Analysis; Databases, Genetic; Female; GATA2 Deficiency; Genes, Dominant; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; Germ-Line Mutation; Haploinsufficiency; Hematologic Diseases; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Mycobacterium Infections; Outcome Assessment, Health Care; Pedigree; Penetrance; Phenotype; Exome Sequencing; Young Adult
PubMed: 33417088
DOI: 10.1007/s10875-020-00930-3 -
BMJ Case Reports Dec 2020A 9-year-old girl was admitted to the paediatric intensive care unit with acute respiratory failure due to influenza. Nine months earlier, she presented with unexplained...
A 9-year-old girl was admitted to the paediatric intensive care unit with acute respiratory failure due to influenza. Nine months earlier, she presented with unexplained lymphoedema of the lower extremities and monocytopenia. She had a history of occasional finger warts and onychomycoses. During hospitalisation, the patient was diagnosed with Emberger syndrome caused by GATA2 deficiency. The admission was complicated by thromboses in the right hand, leading to amputation of multiple fingers. From then on, the patient has been in good recovery, the function of her right hand was improving and an allogeneic haematopoietic cell transplantation has now been successfully performed.
Topics: Amputation, Surgical; Anti-Bacterial Agents; Antiviral Agents; Child; Codon, Nonsense; DNA Mutational Analysis; Drug Therapy, Combination; Female; Fingers; GATA2 Deficiency; GATA2 Transcription Factor; Gangrene; Glucocorticoids; Hematopoietic Stem Cell Transplantation; Humans; Influenza A virus; Influenza, Human; Lung; Respiration, Artificial; Respiratory Distress Syndrome; Severity of Illness Index; Tomography, X-Ray Computed
PubMed: 33370941
DOI: 10.1136/bcr-2020-236521 -
Critical Care (London, England) Dec 2020COVID-19 can course with respiratory and extrapulmonary disease. SARS-CoV-2 RNA is detected in respiratory samples but also in blood, stool and urine. Severe COVID-19 is...
BACKGROUND
COVID-19 can course with respiratory and extrapulmonary disease. SARS-CoV-2 RNA is detected in respiratory samples but also in blood, stool and urine. Severe COVID-19 is characterized by a dysregulated host response to this virus. We studied whether viral RNAemia or viral RNA load in plasma is associated with severe COVID-19 and also to this dysregulated response.
METHODS
A total of 250 patients with COVID-19 were recruited (50 outpatients, 100 hospitalized ward patients and 100 critically ill). Viral RNA detection and quantification in plasma was performed using droplet digital PCR, targeting the N1 and N2 regions of the SARS-CoV-2 nucleoprotein gene. The association between SARS-CoV-2 RNAemia and viral RNA load in plasma with severity was evaluated by multivariate logistic regression. Correlations between viral RNA load and biomarkers evidencing dysregulation of host response were evaluated by calculating the Spearman correlation coefficients.
RESULTS
The frequency of viral RNAemia was higher in the critically ill patients (78%) compared to ward patients (27%) and outpatients (2%) (p < 0.001). Critical patients had higher viral RNA loads in plasma than non-critically ill patients, with non-survivors showing the highest values. When outpatients and ward patients were compared, viral RNAemia did not show significant associations in the multivariate analysis. In contrast, when ward patients were compared with ICU patients, both viral RNAemia and viral RNA load in plasma were associated with critical illness (OR [CI 95%], p): RNAemia (3.92 [1.183-12.968], 0.025), viral RNA load (N1) (1.962 [1.244-3.096], 0.004); viral RNA load (N2) (2.229 [1.382-3.595], 0.001). Viral RNA load in plasma correlated with higher levels of chemokines (CXCL10, CCL2), biomarkers indicative of a systemic inflammatory response (IL-6, CRP, ferritin), activation of NK cells (IL-15), endothelial dysfunction (VCAM-1, angiopoietin-2, ICAM-1), coagulation activation (D-Dimer and INR), tissue damage (LDH, GPT), neutrophil response (neutrophils counts, myeloperoxidase, GM-CSF) and immunodepression (PD-L1, IL-10, lymphopenia and monocytopenia).
CONCLUSIONS
SARS-CoV-2 RNAemia and viral RNA load in plasma are associated with critical illness in COVID-19. Viral RNA load in plasma correlates with key signatures of dysregulated host responses, suggesting a major role of uncontrolled viral replication in the pathogenesis of this disease.
Topics: Adult; Aged; Biomarkers; COVID-19; Chi-Square Distribution; Critical Illness; Female; Humans; Male; Middle Aged; Multivariate Analysis; Polymerase Chain Reaction; RNA, Viral; Statistics, Nonparametric; Viral Load
PubMed: 33317616
DOI: 10.1186/s13054-020-03398-0 -
Clinical & Translational Immunology 2020Chimeric antigen receptor (CAR)-T cell therapy redirected to specific antigens on tumor cells is a promising immunotherapy strategy for various cancers. Most target...
Autologous non-human primate model for safety assessment of transposon-mediated chimeric antigen receptor T cells on granulocyte-macrophage colony-stimulating factor receptor.
OBJECTIVES
Chimeric antigen receptor (CAR)-T cell therapy redirected to specific antigens on tumor cells is a promising immunotherapy strategy for various cancers. Most target antigens are also expressed on normal tissues at varying levels, and therefore, a considerable challenge in the field is determining safety profiles, including life-threatening off-tumor and off-target toxicities. The granulocyte-macrophage colony-stimulating factor receptor (hGMR) is a promising target for CAR T-cell therapy for a subset of acute myelocytic leukaemia, although it is also expressed on normal cells including monocytes, macrophages, CD34-positive haematopoietic cells and vascular endothelial cells. hGMR and other immune-related proteins are highly conserved between humans and cynomolgus macaques (). Therefore, in this study, we engineered cynomolgus T cells to express CAR molecules redirected to hGMR by (PB) transposon-based gene transfer and adoptively transferred autologous hGMR-CAR T cells into cynomolgus macaques.
METHODS
We established PB-mediated human GMR (hGMR)-specific CAR T cells using cynomolgus peripheral blood mononuclear cells and transferred them into autologous individuals, and evaluated the potential toxicity related to hGMR-CAR T cells.
RESULTS
hGMR-CAR T cells did not exert overt organ toxicities such as bone marrow suppression, monocytopenia and vasculitis, although they recognised and killed cynomolgus monocytes and macrophages .
CONCLUSION
Although our model did not simulate a tumor-bearing model, it supports the safety of hGMR-CAR T cells and demonstrates the usefulness of a non-human primate model to evaluate the safety of T-cell products by assessing off-tumor/off-target toxicity before clinical trials.
PubMed: 33251009
DOI: 10.1002/cti2.1207 -
American Journal of Blood Research 2020Aplastic anemia (AA) is a type of anemia that is caused by an intrinsic defect of hematopoietic progenitors or an extrinsic immune mediated destruction of stem cells....
Aplastic anemia (AA) is a type of anemia that is caused by an intrinsic defect of hematopoietic progenitors or an extrinsic immune mediated destruction of stem cells. Patients commonly presented with pancytopenia, particularly leukopenia that renders patient susceptible to various infections. COVID-19 is one of these infections that could be life threatening and highly contagious. Infection with COVID-19 is expected in a patient who developed fever, respiratory manifestations, leukopenia and lymphopenia together with history suggestive of exposure to infection. Furthermore COVID-19 was found associated with thrombocytopenia, agranulocytosis and monocytopenia in severe cases. Thus the relationship between COVID-19 infection and AA would be a vicious circle as both cause leukopenia and lymphopenia. This study aimed to break this circle, through proposing risk stratification of vulnerability to COVID-19 in AA patients who were admitted in our institution in the period from Mar. 2018 to Mar. 2020 followed by a strict preventive plan tailored for each risk group. 79% of AA patients were at high risk of acquiring COVID-19 infection if exposed. This group of patients have to be targeted with more aggressive preventive plan than normal healthy persons. In conclusion this study proposed next step in combating COVID-19 infection through mass survey of high risk people then application of specific precautions to them, perhaps they could be candidate for future vaccine or prophylactic treatment.
PubMed: 32923084
DOI: No ID Found -
EMBO Molecular Medicine Oct 2020Early in the COVID-19 pandemic, type 2 diabetes (T2D) was marked as a risk factor for severe disease and mortality. Inflammation is central to the aetiology of both... (Observational Study)
Observational Study
Early in the COVID-19 pandemic, type 2 diabetes (T2D) was marked as a risk factor for severe disease and mortality. Inflammation is central to the aetiology of both conditions where variations in immune responses can mitigate or aggravate disease course. Identifying at-risk groups based on immunoinflammatory signatures is valuable in directing personalised care and developing potential targets for precision therapy. This observational study characterised immunophenotypic variation associated with COVID-19 severity in T2D. Broad-spectrum immunophenotyping quantified 15 leucocyte populations in peripheral circulation from a cohort of 45 hospitalised COVID-19 patients with and without T2D. Lymphocytopenia and specific loss of cytotoxic CD8 lymphocytes were associated with severe COVID-19 and requirement for intensive care in both non-diabetic and T2D patients. A morphological anomaly of increased monocyte size and monocytopenia restricted to classical CD14 CD16 monocytes was specifically associated with severe COVID-19 in patients with T2D requiring intensive care. Increased expression of inflammatory markers reminiscent of the type 1 interferon pathway (IL6, IL8, CCL2, INFB1) underlaid the immunophenotype associated with T2D. These immunophenotypic and hyperinflammatory changes may contribute to increased voracity of COVID-19 in T2D. These findings allow precise identification of T2D patients with severe COVID-19 as well as provide evidence that the type 1 interferon pathway may be an actionable therapeutic target for future studies.
Topics: Aged; COVID-19; Chemokine CCL2; Diabetes Mellitus, Type 2; Female; Humans; Immunophenotyping; Inflammation; Interleukin-6; Leukocytes, Mononuclear; Lipopolysaccharide Receptors; Lymphopenia; Male; Middle Aged; Monocytes; Risk Factors; SARS-CoV-2; Severity of Illness Index
PubMed: 32816392
DOI: 10.15252/emmm.202013038 -
Advances in Hematology 2020Imatinib mesylate is the gold standard for the treatment of all phases of Philadelphia-positive chronic myeloid leukemia. Patients on imatinib treatment may develop...
BACKGROUND
Imatinib mesylate is the gold standard for the treatment of all phases of Philadelphia-positive chronic myeloid leukemia. Patients on imatinib treatment may develop cytopenia due to drug toxicity. This study aimed to determine the types, grades, and time course of cytopenia in CML patients on imatinib at a Nairobi hospital.
METHODS
This was a cross-sectional descriptive study of adult patients aged ≥18 years followed up at the Glivec International Patient Access Program (GIPAP) clinic from 2007 to 2015. Patients who developed cytopenia within 12 months of initiating imatinib were eligible. Clinical and hematologic data were retrieved from the patients' charts and entered into a study proforma. Measures of central tendency such as mean, median, mode, standard deviation, and variance were used for analysis.
RESULTS
Sixty three percent (63.6%) of the 94 patients developed a monocytopenia, with anemia seen in 34%, neutropenia in 27.6%, and thrombocytopenia in 8% of the 94 patients. Anemia plus neutropenia was the most common bicytopenia at 12.7%. Pancytopenia was seen in only 5 of the 94 patients. Most of the cytopenia was grades 2 and 3. Anemia was present at baseline while neutropenia and thrombocytopenia developed within 12 months of imatinib initiation. Anemia resolved during the first 12 months of therapy while neutropenia and thrombocytopenia resolved within 24-36 months of treatment.
CONCLUSION
Monocytopenia, especially anemia, was the most common type of cytopenia. The cytopenia was predominantly grade 2, developed in majority of the patients within 6 months after imatinib initiation, and had resolved by 24-36 months after imatinib initiation.
PubMed: 32454829
DOI: 10.1155/2020/7696204 -
Medicina (Kaunas, Lithuania) Jan 2020Autologous and allogeneic stem cell transplantation is used in the treatment of high-risk hematological malignancies, and monocytes are probably involved in...
Autologous and allogeneic stem cell transplantation is used in the treatment of high-risk hematological malignancies, and monocytes are probably involved in hematological reconstitution as well as posttransplant immunoregulation. The aim of our study was to investigate the levels of circulating monocyte subsets in allotransplant recipients. The levels of the classical, intermediate, and nonclassical monocyte subsets were determined by flow cytometry. Sixteen patients and 18 healthy controls were included, and the levels were analyzed during pretransplant remission ( = 13), early posttransplant during cytopenia ( = 9), and early reconstitution ( = 9). Most patients in remission showed a majority of classical monocytes. The patients showed severe early posttransplant monocytopenia, but the total peripheral blood monocyte counts normalized very early on, and before neutrophil and platelet counts. During the first 7-10 days posttransplant (i.e., during cytopenia) a majority of the circulating monocytes showed a nonclassical phenotype, but later (i.e., 12-28 days posttransplant) the majority showed a classical phenotype. However, the variation range of classical monocytes was wider for patients in remission and during regeneration than for healthy controls. The total peripheral blood monocyte levels normalize at the very early stages and before neutrophil reconstitution after stem cell transplantation, and a dominance of classical monocytes is reached within 2-4 weeks posttransplant.
Topics: Adult; Aged; Case-Control Studies; Female; Flow Cytometry; Hematologic Neoplasms; Humans; Immune Reconstitution; Leukocyte Count; Male; Middle Aged; Monocytes; Phenotype; Pilot Projects; Remission Induction; Stem Cell Transplantation; Treatment Outcome; Young Adult
PubMed: 31963675
DOI: 10.3390/medicina56010036