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Leukemia Research Reports 2022GATA2 deficiency was first identified in 2011 and have been reported over 500 individuals with GATA2 mutations. The onset of symptoms ranges from early childhood to late...
GATA2 deficiency was first identified in 2011 and have been reported over 500 individuals with GATA2 mutations. The onset of symptoms ranges from early childhood to late adulthood but very often the diagnosis is made between adolescence and early adulthood. These patients can be relatively asymptomatic or have life threatening diseaseas (myelodysplastic syndrome, acute leukemia). We describe case of 30-years old women with GATA2 novel mutation who present by primary lymphedema, myelodysplastic changes in bone marrow, monocytopenia and history of several recurrent infections (bacterial, mycobacterial). The case illustrates the diagnostic difficulties in identifying GATA2 deficiencies.
PubMed: 36119727
DOI: 10.1016/j.lrr.2022.100346 -
Frontiers in Immunology 2022GATA-binding protein 2 () is a transcription factor responsible for the regulation of blood cell proliferation, differentiation, and maintenance in hematopoietic stem...
GATA-binding protein 2 () is a transcription factor responsible for the regulation of blood cell proliferation, differentiation, and maintenance in hematopoietic stem cells. Here, we describe successful bone marrow transplantation in a carrier of a novel GATA2 pathogenic variant who was diagnosed with immunodeficiency a few years after completion of B-cell precursor acute lymphoblastic leukemia (BCP-ALL) treatment. At the age of 4 years, the patient was diagnosed with and treated for BCP-ALL. Antileukemic therapy was complicated by pulmonary cryptococcosis. Two years after completion of the maintenance therapy, the child was consulted by an immunologist because of recurrent respiratory tract infections and an episode of sepsis. Flow cytometry revealed deep monocytopenia, lymphopenia, absence of B lymphocytes, considerably reduced NK cells, poor thymic T lymphocyte production, minor defects in T cell maturation, and absence of TCRγδ+ T cells. The presence of the likely pathogenic, heterozygous missense variant within exon 5 of (NM_032638.5: c.1047T>G, Cys349Trp) was identified in the proband and confirmed in the father of the patient, who underwent allogeneic hematopoietic stem cell transplantation (HSCT) from a matched unrelated donor due to myelodysplastic syndrome with excess blasts at the age of 22 years. An allogeneic hematopoietic stem cell transplantation with a reduced toxicity conditioning protocol was performed using a matched sibling donor. Pre-transplant conditioning included fludarabine (5 × 30 mg/m2), treosulfan (3 × 14 g/m2), and thiotepa (10 mg/kg). Complete donor chimerism was achieved on post-transplant day 17. During the 12 months of the posttransplant observation period, she remained free from symptoms of acute or chronic graft-versus-host disease, and immunosuppressive treatment was therefore stopped. This is the second reported case of BCP-ALL in a patient with deficiency, and the first successfully treated with a reduced-toxicity conditioning HSCT protocol. The co-occurrence of lymphoid malignancies and primary immunodeficiencies points to the role of genetic counseling and family screening for possible cancer predisposition syndromes prior to the selection of related HSCT donors.
Topics: Adult; Child; Child, Preschool; Female; GATA2 Transcription Factor; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Transplantation Conditioning; Young Adult
PubMed: 35983050
DOI: 10.3389/fimmu.2022.928529 -
Journal of Family Medicine and Primary... May 2022This study explored the role of various laboratory biomarkers on inflammatory indices for predicting disease progression toward severity in COVID-19 patients.
BACKGROUND AND OBJECTIVE
This study explored the role of various laboratory biomarkers on inflammatory indices for predicting disease progression toward severity in COVID-19 patients.
METHODS
This retrospective study was conducted on 1233 adults confirmed for COVID-19. The participants were grouped undermild, moderate, and severe grade disease. Serum bio-inflammatory index (SBII) and systemic inflammatory index (SII) were calculated and correlated with disease severity. The study variables, including clinical details and laboratory variables, were analyzed for impact on the inflammatory indices and severity status using a sequential multiple regression model to determine the predictors for mortality. Receiver operating characteristics defined the cut-off values for severity.
RESULTS
Among the study population, 56.2%, 20.7%, and 23.1% were categorized as mild, moderate, and severe COVID-19 cases. Diabetes with hypertension was the most prevalent comorbid condition. The odds for males to have the severe form of the disease was 1.6 times (95% CI = 1.18-2.18, = 0.002). The median (inter-quartile-range) of SBII was 549 (387.84-741.34) and SII was 2097.6 (1113.9-4153.73) in severe cases. Serum urea, electrolytes, gamma-glutamyl transferase, red-cell distribution width-to-hematocrit ratio, monocytopenia, and eosinopenia exhibited a significant influence on the SpO, SBII, and SII. Both SBII (r = -0.582, < 0.001) and SII (r = -0.52, < 0.001) strongly correlated inversely with SpO values [Figures 3a and 3b]. More than 80% of individuals admitted with severe grade COVID-19 had values of more than 50 percentile of SBII and SII. The sensitivity and specificity of SBII at 343.67 for severity were 81.4% and 70.1%, respectively. SII exhibited 77.2% sensitivity and 70.8% specificity at 998.72.
CONCLUSION
Serial monitoring of the routinely available biomarkers would provide considerable input regarding inflammatory status and severity progression in COVID-19.
PubMed: 35800567
DOI: 10.4103/jfmpc.jfmpc_2014_21 -
Heliyon Jun 2022In Covid-19, profound systemic inflammatory responses are accompanied by both metabolic risk factors for severity and, separately, metabolic mechanisms have been shown...
BACKGROUND
In Covid-19, profound systemic inflammatory responses are accompanied by both metabolic risk factors for severity and, separately, metabolic mechanisms have been shown to underly disease progression. It is unknown whether this reflects similar situations in sepsis or is a unique characteristic of Covid-19.
AIMS
Define the immunometabolic signature of Covid-19.
METHODS
65 patients with Covid-19,19 patients with sepsis and 14 healthy controls were recruited and sampled for plasma, serum and peripheral blood mononuclear cells (PBMCs) through 10 days of critical illness. Metabotyping was performed using the Biocrates p180 kit and multiplex cytokine profiling undertaken. PBMCs underwent phenotyping by flow cytometry. Immune and metabolic readouts were integrated and underwent pathway analysis.
RESULTS
Phopsphatidylcholines (PC) are reduced in Covid-19 but greater than in sepsis. Compared to controls, tryptophan is reduced in Covid-19 and inversely correlated with the severity of the disease and IFN-ɣ concentrations, conversely the kyneurine and kyneurine/tryptophan ratio increased in the most severe cases. These metabolic changes were consistent through 2 pandemic waves in our centre. PD-L1 expression in CD8+ T cells, Tregs and CD14+ monocytes was increased in Covid-19 compared to controls.
CONCLUSIONS
In our cohort, Covid-19 is associated with monocytopenia, increased CD14+ and Treg PD-L1 expression correlating with IFN-ɣ plasma concentration and disease severity (SOFA score). The latter is also associated with metabolic derangements of Tryptophan, LPC 16:0 and PCs. Lipid metabolism, in particular phosphatidylcholines and lysophosphatidylcolines, seems strictly linked to immune response in Covid-19. Our results support the hypothesis that IFN-ɣ -PD-L1 axis might be involved in the cytokine release syndrome typical of severe Covid-19 and the phenomenon persisted through multiple pandemic waves despite use of immunomodulation.
PubMed: 35774516
DOI: 10.1016/j.heliyon.2022.e09733 -
Nature Immunology Jun 2022Hypoxemia is a defining feature of acute respiratory distress syndrome (ARDS), an often-fatal complication of pulmonary or systemic inflammation, yet the resulting...
Hypoxemia is a defining feature of acute respiratory distress syndrome (ARDS), an often-fatal complication of pulmonary or systemic inflammation, yet the resulting tissue hypoxia, and its impact on immune responses, is often neglected. In the present study, we have shown that ARDS patients were hypoxemic and monocytopenic within the first 48 h of ventilation. Monocytopenia was also observed in mouse models of hypoxic acute lung injury, in which hypoxemia drove the suppression of type I interferon signaling in the bone marrow. This impaired monopoiesis resulted in reduced accumulation of monocyte-derived macrophages and enhanced neutrophil-mediated inflammation in the lung. Administration of colony-stimulating factor 1 in mice with hypoxic lung injury rescued the monocytopenia, altered the phenotype of circulating monocytes, increased monocyte-derived macrophages in the lung and limited injury. Thus, tissue hypoxia altered the dynamics of the immune response to the detriment of the host and interventions to address the aberrant response offer new therapeutic strategies for ARDS.
Topics: Animals; Humans; Hypoxia; Inflammation; Lung; Lung Injury; Mice; Respiratory Distress Syndrome
PubMed: 35624205
DOI: 10.1038/s41590-022-01216-z -
Frontiers in Immunology 2022The transcription factor GATA2 plays a key role in the survival and self-renewal of hematopoietic stem and progenitor cells. Autosomal dominant variants in cause a...
The transcription factor GATA2 plays a key role in the survival and self-renewal of hematopoietic stem and progenitor cells. Autosomal dominant variants in 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 (n=1). Novel heterozygous 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.
Topics: Bone Marrow; Delayed Diagnosis; Female; GATA2 Deficiency; GATA2 Transcription Factor; Humans; Male; Myelodysplastic Syndromes; Phenotype
PubMed: 35603181
DOI: 10.3389/fimmu.2022.886117 -
BMC Infectious Diseases May 2022Monocytes play an important role in inflammation, and monocytosis and monocyte activation are features of chronic inflammation. We aimed to investigate if HIV status was...
BACKGROUND
Monocytes play an important role in inflammation, and monocytosis and monocyte activation are features of chronic inflammation. We aimed to investigate if HIV status was associated with monocyte count and monocyte activation and to assess the relationship between monocyte count and monocyte activation markers and HIV-related factors.
METHODS
Persons living with HIV (PLWH) with measured monocyte count and sCD14 and sCD163 were included from the Copenhagen Comorbidity in HIV infection (COCOMO) study and matched 1:5 on sex and age with uninfected controls. In addition, 74 uninfected individuals from COCOMO with measured sCD14 and sCD163 were included. Identical protocols and equipment were used to determine monocyte counts and monocyte activation in PLWH and uninfected controls. Linear regression adjusted for age, sex, smoking and waist-to-hip-ratio was used to analyze the association between possible risk factors and monocyte outcomes.
RESULTS
We included 871 PLWH and 4355 uninfected controls. PLWH had - 0.021 [- 0.031 - 0.011] × 10/L) lower monocyte count than uninfected controls, and in adjusted analyses HIV status was independently associated with - 0.035 [- 0.045, - 0.025] × 10/L lower monocyte count. In contrast, PLWH had higher sCD163 and sCD14 concentrations than uninfected controls. After adjustment, HIV-status was associated with higher sCD14 and sCD163 concentrations (588 [325, 851] ng/ml, and 194 [57, 330] ng/ml, respectively).
CONCLUSION
PLWH had lower monocyte counts than controls, but the absolute difference was small, and any clinical impact is likely limited. In contrast, concentrations of monocyte activation markers, previously implicated as drivers of non-AIDS comorbidity, were higher in PLWH than in controls.
Topics: Biomarkers; HIV Infections; Humans; Inflammation; Lipopolysaccharide Receptors; Monocytes
PubMed: 35546661
DOI: 10.1186/s12879-022-07450-y -
Annals of Intensive Care May 2022The reports of an early and profound acquired immunodepression syndrome (AIDs) in ICU patients had gained sufficient credence to modify the paradigm of acute...
INTRODUCTION
The reports of an early and profound acquired immunodepression syndrome (AIDs) in ICU patients had gained sufficient credence to modify the paradigm of acute inflammation. However, despite several articles published on AIDs and its assessment by monocytic HLA-DR monitoring, several missing informations remained: 1-Which patients' are more prone to benefit from mHLA-DR measurement, 2-Is the nadir or the duration of the low mHLA-DR expression the main parameter to consider? 3-What are the compared performances of leukocytes' count analyses (lymphocyte, monocyte).
MATERIAL AND METHOD
We conducted an observational study in a surgical ICU of a French tertiary hospital. A first mHLA-DR measurement (fixed flow cytometry protocol) was performed within the first 3 days following admission and a 2nd, between day 5 and 10. The other collected parameters were: SAPS II and SOFA scores, sex, age, comorbidities, mortality and ICU-acquired infections (IAI). The associations between mHLA-DR and outcomes were tested by adjusted Fine and Gray subdistribution competing risk models.
RESULTS
1053 patients were included in the study, of whom 592 had a 2nd mHLA-DR measurement. In this cohort, 223 patients (37.7%) complicated by IAI. The initial decrement in mHLA-DR was not associated with the later occurrence of IAI, (p = 0.721), however, the persistence of a low mHLA-DR (< 8000 AB/C), measured between day 5 and day 7, was associated with the later occurrence of IAI (p = 0.01). Similarly, a negative slope between the first and the second value was significantly associated with subsequent IAI (p = 0.009). The best performance of selected markers was obtained with the combination of the second mHLA-DR measurement with SAPSII on admission. Persisting lymphopenia and monocytopenia were not associated with later occurrence of IAI.
CONCLUSION
Downregulation of mHLA-DR following admission is observed in a vast number of patients whatever the initial motif for admission. IAI mostly occurs among patients with a high severity score on admission suggesting that immune monitoring should be reserved to the most severe patients. The initial downregulation did not preclude the later development of IAI. A decreasing or a persisting low mHLA-DR expression below 8000AB/C within the first 7 days of ICU admission was independently and reliably associated with subsequent IAI among ICU patients with performances superior to leukocyte subsets count alone.
PubMed: 35526199
DOI: 10.1186/s13613-022-01010-y -
Cancers Apr 2022Hairy cell leukemia (cHCL) patients have, in most cases, a specific clinical and biological presentation with splenomegaly, anemia, leukopenia, neutropenia,...
Hairy cell leukemia (cHCL) patients have, in most cases, a specific clinical and biological presentation with splenomegaly, anemia, leukopenia, neutropenia, monocytopenia and/or thrombocytopenia, identification of hairy cells that express CD103, CD123, CD25, CD11c and identification of the V600E mutation in the B-Raf proto-oncogene () in 90% of cases. Monocytopenia is absent in vHCL and SDRPL patients and the abnormal cells do not express CD25 or CD123 and do not present the mutation. Ten percent of cHCL patients are BRAF and the distinction between cHCL and HCL-like disorders including the variant form of HCL (vHCL) and splenic diffuse red pulp lymphoma (SDRPL) can be challenging. We performed deep sequencing in a large cohort of 84 cHCL and 16 HCL-like disorders to improve insights into the pathogenesis of the diseases. mutations were detected in 76/82 patients of cHCL (93%) and additional mutations were identified in Krüppel-like Factor 2 () in 19 patients (23%) or in 6 patients (7.5%). Some genetic alterations were localized on the cytidine deaminase (AID) consensus motif, suggesting AID-induced mutations. When analyzing sequential samples, a clonal evolution was identified in half of the cHCL patients (6/12 pts). Among the 16 patients with HCL-like disorders, we observed an enrichment of mutations in vHCL/SDRPL (3/5 pts) and genes involved in the epigenetic regulation () (3/5 pts). Furthermore, mutations were associated with a bad prognosis and a shorter time to next treatment (TTNT) and progression-free survival (PFS), independently of the HCL classification.
PubMed: 35454811
DOI: 10.3390/cancers14081904 -
Journal of Fungi (Basel, Switzerland) Apr 2022The cultural recovery of Mucorales from hyphae-laden tissue is poor, and the clinical implications of culture positivity are scarcely studied. Therefore, we compared...
The cultural recovery of Mucorales from hyphae-laden tissue is poor, and the clinical implications of culture positivity are scarcely studied. Therefore, we compared clinical and histopathological characteristics of culture-positive and culture-negative histology-proven pulmonary mucormycosis cases among cancer patients. Histology specimens were blindly reviewed by a thoracic pathologist and graded on four histopathologic features: hyphal quantity, tissue necrosis, tissue invasion, and vascular invasion. Twenty cases with a corresponding fungal culture were identified; five were culture-positive, and fifteen were culture-negative. Although no statistically significant differences were found, culture-positive patients were more likely to exhibit a high burden of necrosis and have a high burden of hyphae but tended to have less vascular invasion than culture-negative patients. In terms of clinical characteristics, culture-positive patients were more likely to have acute myeloid leukemia (60% vs. 27%, = 0.19), a history of hematopoietic cell transplant (80% vs. 53%, = 0.31), severe lymphopenia (absolute lymphocyte count ≤ 500/µL, 100% vs. 73%, = 0.36), and monocytopenia (absolute monocyte count ≤100/µL, 60% vs. 20%, = 0.11). Forty-two-day all-cause mortality was comparable between culture-positive and culture-negative patients (60% and 53%, = 0.80). This pilot study represents the first comprehensive histopathological scoring method to examine the relationship between histopathologic features, culture positivity, and clinical features of pulmonary mucormycosis.
PubMed: 35448611
DOI: 10.3390/jof8040380