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European Journal of Haematology Mar 2021The prevalence of obesity is increasing and progressively influencing physician-patient interactions. While there is a sizable amount of data demonstrating that obesity... (Review)
Review
The prevalence of obesity is increasing and progressively influencing physician-patient interactions. While there is a sizable amount of data demonstrating that obesity is a state of low-grade inflammation, to our knowledge, there is no single review summarizing its effects on hematologic parameters and thrombotic risk. We performed a literature search which largely surfaced observational studies, with a few systematic reviews and meta-analyses of these studies. We took care to review the mechanisms driving an inflammatory state and obesity's effect on white blood cells, red blood cells, platelets, and thrombotic risk. There is an observed relative, and sometimes absolute leukocytosis driven by this inflammatory state. Obesity is also associated with increased platelet counts and an increased risk for venous thromboembolism (VTE). Lastly, the association between obesity, iron deficiency (ID), and red blood cell counts may be present but remains uncertain. Recognizing the above associations may provide clinicians with reassurance regarding otherwise unexplained hematologic abnormalities in obese individuals. We hope this review will prompt future studies to further understand the underlying mechanisms driving these abnormalities and identify modifiable risk factors and potential therapeutic targets to prevent the development of probable obesity-associated conditions with significant morbidity and mortality, such as ID and VTE.
Topics: Adipose Tissue; Animals; Biomarkers; Cytokines; Disease Susceptibility; Humans; Inflammation; Inflammation Mediators; Leukocyte Count; Leukocytosis; Obesity; Sex Factors
PubMed: 33270290
DOI: 10.1111/ejh.13560 -
Critical Care (London, England) Jan 2022A biomarker describes a measurable indicator of a patient's clinical condition that can be measured accurately and reproducibly. Biomarkers offer utility for diagnosis,... (Review)
Review
A biomarker describes a measurable indicator of a patient's clinical condition that can be measured accurately and reproducibly. Biomarkers offer utility for diagnosis, prognosis, early disease recognition, risk stratification, appropriate treatment (theranostics), and trial enrichment for patients with sepsis or suspected sepsis. In this narrative review, we aim to answer the question, "Do biomarkers in patients with sepsis or septic shock predict mortality, multiple organ dysfunction syndrome (MODS), or organ dysfunction?" We also discuss the role of pro- and anti-inflammatory biomarkers and biomarkers associated with intestinal permeability, endothelial injury, organ dysfunction, blood-brain barrier (BBB) breakdown, brain injury, and short and long-term mortality. For sepsis, a range of biomarkers is identified, including fluid phase pattern recognition molecules (PRMs), complement system, cytokines, chemokines, damage-associated molecular patterns (DAMPs), non-coding RNAs, miRNAs, cell membrane receptors, cell proteins, metabolites, and soluble receptors. We also provide an overview of immune response biomarkers that can help identify or differentiate between systemic inflammatory response syndrome (SIRS), sepsis, septic shock, and sepsis-associated encephalopathy. However, significant work is needed to identify the optimal combinations of biomarkers that can augment diagnosis, treatment, and good patient outcomes.
Topics: Biomarkers; Humans; Leukocytosis; Sepsis; Shock, Septic; Systemic Inflammatory Response Syndrome
PubMed: 34991675
DOI: 10.1186/s13054-021-03862-5 -
Journal of Investigational Allergology... 2020Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a complex multisystemic severe drug hypersensitivity reaction whose diagnosis and management... (Review)
Review
BACKGROUND AND OBJECTIVE
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a complex multisystemic severe drug hypersensitivity reaction whose diagnosis and management are troublesome. DRESS syndrome requires management by various specialists. The correct identification of the culprit drug is essential to ensure safe future therapeutic options for the patient. There are no previous Spanish guidelines or consensus statements on DRESS syndrome. Objective: To draft a review and guidelines on the clinical diagnosis, allergy work-up, management, treatment, and prevention of DRESS syndrome in light of currently available scientific evidence and the experience of experts from multiple disciplines.
METHODS
These guidelines were drafted by a panel of allergy specialists from the Drug Allergy Committee of the Spanish Society of Allergy and Clinical Immunology (SEAIC), together with other medical specialists involved in the management of DRESS syndrome and researchers from the PIELenRed consortium. A review was conducted of scientific papers on DRESS syndrome, and the expert panel evaluated the quality of the evidence of the literature and provided grades of recommendation. Whenever evidence was lacking, a consensus was reached among the experts.
RESULTS
The first Spanish guidelines on DRESS syndrome are now being published. Important aspects have been addressed, including practical recommendations about clinical diagnosis, identification of the culprit drug through the Spanish pharmacovigilance system algorithm, and the allergy work-up. Recommendations are provided on management, treatment, and prevention. Algorithms for the management of DRESS in the acute and recovery phases have been drawn up. Expert consensus-based stepwise guidelines for the management and treatment of DRESS syndrome are provided.
Topics: Algorithms; Allopurinol; Anti-Bacterial Agents; Anticonvulsants; Comorbidity; Consensus; Drug Hypersensitivity Syndrome; Eosinophilia; Expert Testimony; Humans; Leukocytosis; Liver; Risk Factors; Skin; Spain
PubMed: 31932268
DOI: 10.18176/jiaci.0480 -
The New England Journal of Medicine Jul 2020Tofersen is an antisense oligonucleotide that mediates the degradation of superoxide dismutase 1 (SOD1) messenger RNA to reduce SOD1 protein synthesis. Intrathecal... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Tofersen is an antisense oligonucleotide that mediates the degradation of superoxide dismutase 1 (SOD1) messenger RNA to reduce SOD1 protein synthesis. Intrathecal administration of tofersen is being studied for the treatment of amyotrophic lateral sclerosis (ALS) due to mutations.
METHODS
We conducted a phase 1-2 ascending-dose trial evaluating tofersen in adults with ALS due to mutations. In each dose cohort (20, 40, 60, or 100 mg), participants were randomly assigned in a 3:1 ratio to receive five doses of tofersen or placebo, administered intrathecally for 12 weeks. The primary outcomes were safety and pharmacokinetics. The secondary outcome was the change from baseline in the cerebrospinal fluid (CSF) SOD1 concentration at day 85. Clinical function and vital capacity were measured.
RESULTS
A total of 50 participants underwent randomization and were included in the analyses; 48 participants received all five planned doses. Lumbar puncture-related adverse events were observed in most participants. Elevations in CSF white-cell count and protein were reported as adverse events in 4 and 5 participants, respectively, who received tofersen. Among participants who received tofersen, one died from pulmonary embolus on day 137, and one from respiratory failure on day 152; one participant in the placebo group died from respiratory failure on day 52. The difference at day 85 in the change from baseline in the CSF SOD1 concentration between the tofersen groups and the placebo group was 2 percentage points (95% confidence interval [CI], -18 to 27) for the 20-mg dose, -25 percentage points (95% CI, -40 to -5) for the 40-mg dose, -19 percentage points (95% CI, -35 to 2) for the 60-mg dose, and -33 percentage points (95% CI, -47 to -16) for the 100-mg dose.
CONCLUSIONS
In adults with ALS due to mutations, CSF SOD1 concentrations decreased at the highest concentration of tofersen administered intrathecally over a period of 12 weeks. CSF pleocytosis occurred in some participants receiving tofersen. Lumbar puncture-related adverse events were observed in most participants. (Funded by Biogen; ClinicalTrials.gov number, NCT02623699; EudraCT number, 2015-004098-33.).
Topics: Adult; Amyotrophic Lateral Sclerosis; Disease Progression; Dose-Response Relationship, Drug; Double-Blind Method; Female; Headache; Humans; Injections, Spinal; Intermediate Filaments; Leukocytosis; Male; Middle Aged; Mutation; Oligonucleotides; Oligonucleotides, Antisense; Superoxide Dismutase-1; Vital Capacity
PubMed: 32640130
DOI: 10.1056/NEJMoa2003715 -
Nature Medicine Nov 2019A sedentary lifestyle, chronic inflammation and leukocytosis increase atherosclerosis; however, it remains unclear whether regular physical activity influences leukocyte...
A sedentary lifestyle, chronic inflammation and leukocytosis increase atherosclerosis; however, it remains unclear whether regular physical activity influences leukocyte production. Here we show that voluntary running decreases hematopoietic activity in mice. Exercise protects mice and humans with atherosclerosis from chronic leukocytosis but does not compromise emergency hematopoiesis in mice. Mechanistically, exercise diminishes leptin production in adipose tissue, augmenting quiescence-promoting hematopoietic niche factors in leptin-receptor-positive stromal bone marrow cells. Induced deletion of the leptin receptor in Prrx1-creER; Lepr mice reveals that leptin's effect on bone marrow niche cells regulates hematopoietic stem and progenitor cell (HSPC) proliferation and leukocyte production, as well as cardiovascular inflammation and outcomes. Whereas running wheel withdrawal quickly reverses leptin levels, the impact of exercise on leukocyte production and on the HSPC epigenome and transcriptome persists for several weeks. Together, these data show that physical activity alters HSPCs via modulation of their niche, reducing hematopoietic output of inflammatory leukocytes.
Topics: Adipose Tissue; Animals; Atherosclerosis; Cardiovascular Diseases; Epigenome; Exercise; Hematopoiesis; Hematopoietic Stem Cells; Homeodomain Proteins; Humans; Inflammation; Leukocytes; Leukocytosis; Mice; Physical Conditioning, Animal; Receptors, Leptin; Sedentary Behavior; Transcriptome
PubMed: 31700184
DOI: 10.1038/s41591-019-0633-x -
American Journal of Hematology Apr 2023Atypical chronic myeloid leukemia (aCML) and myelodysplastic/myeloproliferative (MDS/MPN) neoplasms, not otherwise specified (NOS), are MDS/MPN overlap neoplasms...
DISEASE OVERVIEW
Atypical chronic myeloid leukemia (aCML) and myelodysplastic/myeloproliferative (MDS/MPN) neoplasms, not otherwise specified (NOS), are MDS/MPN overlap neoplasms characterized by leukocytosis, in the absence of monocytosis and eosinophilia, with <20% blasts in the blood and bone marrow.
DIAGNOSIS
aCML, previously known as aCML, BCR::ABL1 negative, was renamed as aCML by the ICC classification, and as MDS/MPN with neutrophilia by the 5th edition of the WHO classification. This entity is characterized by dysplastic neutrophilia with immature myeloid cells comprising ≥10% of the white blood cell count, with prominent dysgranulopoiesis. MDS/MPN-NOS consists of MDS/MPN overlap neoplasms not meeting criteria for defined categories such as chronic myelomonocytic leukemia (CMML), MDS/MPN-ring sideroblasts-thrombocytosis (MDS/MPN-RS-T), and aCML.
MUTATIONS AND KARYOTYPE
Cytogenetic abnormalities are seen in 40-50% of patients in both categories. In aCML, somatic mutations commonly encountered include ASXL1, SETBP1, ETNK1, and EZH2 whereas MDS/MPN-NOS can be further stratified by mutational profiles into CMML-like, MDS/MPN-RS-T-like, aCML-like, TP35-mutated, and "others", respectively.
RISK STRATIFICATION
The Mayo Clinic aCML model stratifies patients based on age >67 years, hemoglobin <10 g/dl, and the presence of TET2 mutations into low-risk (0-1 points) and high-risk (>2 points) groups, with median survivals of 18 and 7 months, respectively. MDS/MPN-NOS patients have traditionally been risk stratified using MDS risk models such as IPSS and IPSS-R.
TREATMENT
Leukocytosis and anemia are managed like lower risk MPN and MDS. DNMT inhibitors have been used in both entities with suboptimal response rates. Allogeneic stem cell transplant remains the only curative strategy but is associated with high morbidity and mortality.
Topics: Humans; Aged; Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative; Myelodysplastic Syndromes; Leukocytosis; Myelodysplastic-Myeloproliferative Diseases; Leukemia, Myelomonocytic, Chronic; Thrombocytosis; Mutation; Risk Assessment
PubMed: 36601682
DOI: 10.1002/ajh.26828 -
Clinical features of gingivostomatitis due to primary infection of herpes simplex virus in children.BMC Infectious Diseases Oct 2020Primary herpetic gingivostomatitis (PHGS) in children, though usually self-limited, might mimic bacterial and enteroviral pharyngitis clinically. We conducted a study to...
BACKGROUND
Primary herpetic gingivostomatitis (PHGS) in children, though usually self-limited, might mimic bacterial and enteroviral pharyngitis clinically. We conducted a study to define the clinical features of PHGS in children.
METHODS
Between January 2012 and December 2016, 282 inpatients aged less than 19 years with cell culture-confirmed herpes simplex virus (HSV) infection in a medical center were identified from the virologic laboratory logbook. Clinical data were retrospectively collected.
RESULTS
Among the 282 inpatients, 185 cases were considered as PHGS and were included for analysis. Fever was present in 99.5%. The mean duration of fever was 5.11 days (±2.24) with the longest being 17 days. Common oral manifestations included oral ulcers (84.3%), which equally resided in the anterior and posterior part of the oral cavity (65.4% vs. 63.2%), gum swelling and/or bleeding (67.6%), and exudate coated tonsils (16.8%). Leukocytosis (WBC count > 15,000/uL) was noted in 52 patients (28.1%) and a serum C-reactive protein level > 40 mg/L in 55 patients (29.7%). Fixty-five patients (35%) were diagnosed with PHGS on admission and were significantly more likely to have ulcers over the anterior oral cavity (76.1% vs. 26.7%) and gum swelling/bleeding (76.2% vs. 7.5%, p-value all < 0.001) on admission and were significantly less likely to receive antibiotic treatment (16.9 vs. 36.7%, p-value < 0.01) than others. Forty-six patients (25%) undiagnosed as PHGS on discharge were significantly more likely to have exudate coated on the tonsils, to receive antibiotic treatment and significantly less likely to have gum swelling/bleeding and oral ulcers (all p-values < 0.01).
CONCLUSIONS
Meticulously identifying specific oral manifestations of gum swelling/bleeding and ulcers over the anterior oral cavity in children can help making the diagnosis of PHGS earlier and subsequently reduce unnecessary prescription of antibiotics.
Topics: Adolescent; Anti-Bacterial Agents; C-Reactive Protein; Child; Child, Preschool; Diagnosis, Differential; Early Diagnosis; Female; Fever; Gingivitis; Herpes Simplex; Herpesvirus 1, Human; Humans; Infant; Leukocytosis; Male; Oral Ulcer; Pharyngitis; Retrospective Studies; Stomatitis, Herpetic; Tonsillitis
PubMed: 33081701
DOI: 10.1186/s12879-020-05509-2 -
American Journal of Hematology Apr 2022Chronic neutrophilic leukemia (CNL) is a rare, often aggressive myeloproliferative neoplasm (MPN) defined by persistent mature neutrophilic leukocytosis, bone marrow...
DISEASE OVERVIEW
Chronic neutrophilic leukemia (CNL) is a rare, often aggressive myeloproliferative neoplasm (MPN) defined by persistent mature neutrophilic leukocytosis, bone marrow granulocyte hyperplasia, and frequent hepatosplenomegaly. The 2013 seminal discovery of oncogenic driver mutations in colony-stimulating factor 3 receptor (CSF3R) in the majority of patients with CNL not only established its molecular pathogenesis but provided a diagnostic biomarker and rationale for pharmacological targeting.
DIAGNOSIS
In 2016, the World Health Organization (WHO) recognized activating CSF3R mutations as a central diagnostic feature of CNL. Other criteria include leukocytosis of ≥25 × 10 /L comprising >80% neutrophils with <10% circulating precursors and rare blasts, and absence of dysplasia or monocytosis, while not fulfilling criteria for other MPN.
MANAGEMENT
There is currently no standard of care for management of CNL, due in large part to the rarity of disease and dearth of formal clinical trials. Most commonly used therapeutic agents include conventional oral chemotherapy (e.g., hydroxyurea), interferon, and Janus kinase (JAK) inhibitors, while hematopoietic stem cell transplant remains the only potentially curative modality.
DISEASE UPDATES
Increasingly comprehensive genetic profiling in CNL, including new data on clonal evolution, has disclosed a complex genomic landscape with additional mutations and combinations thereof driving disease progression and drug resistance. Although accurate prognostic stratification and therapeutic decision-making remain challenging in CNL, emerging data on molecular biomarkers and the addition of newer agents, such as JAK inhibitors, to the therapeutic arsenal, are paving the way toward greater standardization and improvement of patient care.
Topics: Genomics; Humans; Leukemia, Neutrophilic, Chronic; Leukocytosis; Mutation; Prognosis
PubMed: 35089603
DOI: 10.1002/ajh.26481 -
The Journal of the American Osteopathic... Apr 2020
Topics: Biomechanical Phenomena; Humans; Lymphocytosis; Soccer
PubMed: 32227154
DOI: 10.7556/jaoa.2020.046