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Turkish Journal of Medical Sciences 2023Children with coronavirus disease 2019 (COVID-19) present milder symptoms than adults and are at lower risk of hospitalization and life-threatening complications....
BACKGROUND/AIM
Children with coronavirus disease 2019 (COVID-19) present milder symptoms than adults and are at lower risk of hospitalization and life-threatening complications. However, the kinetics of lymphocyte subsets and serum immunoglobulins in the peripheral blood during COVID-19 infection remains unclear. In this study, it was aimed to determine the changes in hematological and immunological parameters, especially in the lymphocyte subsets, in the peripheral blood of children with different COVID-19 disease severity.
MATERIALS AND METHODS
The study was planned as a prospective cohort and included 68 children aged 0-18 years who were admitted to Ege University Faculty of Medicine Department of Pediatrics and diagnosed with COVID-19 infection between May 2020 and December 2021. In addition to demographic characteristics, clinical findings, and severity criteria, hematological, biochemical, and immunological laboratory (T/B lymphocyte subgroups, serum immunoglobulins) results were noted and examined if there were some correlations between disease severity and the laboratory values.
RESULTS
In the study group, while 60.6% (n = 40) of the patients received treatment in the hospital, 10.6% (n = 7) needed intensive care treatment. Lymphopenia (35.3%) was more common than neutropenia (14.7%) in the COVID-19-infected children. CD19+ B cells were low in a very high percentage of patients (26.5%), and 16.2% had low levels of NK cells. Significant correlation between disease severity and CD19+lymphocytes, CD19+CD38+IgM lymphocytes, CD19+CD38+CD27IgM lymphocytes, CD19+CD81+ lymphocytes (p = 0.001, p = 0.008, p = 0.014, p = 0.025, and r = 0.394, r = 0.326, r = 0.303, r = 0.280, respectively), significant inverse correlation between disease severity and absolute lymphocytes counts and CD3-CD16+CD56+ lymphocytes (p = 0.004, 0.014, and r = -0.353, r = -0.304, respectively) were observed. The percentage of hospitalized patients with low CD3 levels (15%) was significantly higher than that of the outpatients with low CD3 levels.
CONCLUSION
As the severity of the disease increased, the CD19, CD19CD38IgM, CD19CD38CD27IgM, and CD19CD81 lymphocytes percentages increased, while the lymphocyte count and NK cell percentage decreased. Therefore, detecting these prognostic immunobiomarkers related to the severity of the disease may contribute considerably to management of the illness.
Topics: Humans; COVID-19; Child; Killer Cells, Natural; Male; Female; Child, Preschool; Severity of Illness Index; Infant; Adolescent; Prospective Studies; B-Lymphocytes; SARS-CoV-2; Lymphopenia; Infant, Newborn; Lymphocyte Count; Lymphocyte Subsets
PubMed: 38813014
DOI: 10.55730/1300-0144.5686 -
Frontiers in Pharmacology 2024Bendamustine was approved for treating chronic lymphocytic leukemia and indolent B-cell non-Hodgkin lymphoma. Despite its therapeutic benefits, the long-term safety of...
Bendamustine was approved for treating chronic lymphocytic leukemia and indolent B-cell non-Hodgkin lymphoma. Despite its therapeutic benefits, the long-term safety of bendamustine in a large population remains inadequately understood. This study evaluates the adverse events (AEs) associated with bendamustine, using a real-world pharmacovigilance database to support its clinical application. We conducted a post-marketing risk analysis to assess the association between bendamustine and its AEs. Data were extracted from the US FDA's Adverse Event Reporting System (FAERS), covering the period from January 2017 to September 2023. The characteristics of bendamustine-associated AEs and the onset time were further analyzed. Statistical analysis was performed using MYSQL 8.0, Navicat Premium 15, Microsoft EXCEL 2016, and Minitab 21.0. 9,461,874 reports were collected from the FAERS database, 9,131 identified bendamustine as the "primary suspected" drug. We identified 331 significant disproportionality preferred terms (PTs). Common AEs included pyrexia, neutropenia, infusion site reaction, progressive multifocal leukoencephalopathy (PML), injection site vasculitis, and pneumonia-all documented on bendamustine's label. Notably, 16 unexpected and significant AEs were discovered, including hypogammaglobulinemia, which is concerning due to its potential to increase infection susceptibility following bendamustine treatment. Other significant findings were anaphylactic reactions, PML, and cutaneous malignancies, suggesting updates to the drug's label may be necessary. Physicians should monitor for neurological and skin changes in patients and discontinue treatment if PML is suspected. Moreover, the median onset time for bendamustine-associated AEs was 13 days, with an interquartile range [IQR] of 0-59 days, predominantly occurring on the first day post-initiation. The β of bendamustine-related AEs suggested risk reduction over time. Our study uncovered some potential pharmacovigilance signals for bendamustine, providing important insights for its safe and effective clinical use.
PubMed: 38803441
DOI: 10.3389/fphar.2024.1372401 -
Andes Pediatrica : Revista Chilena de... Apr 2024Bacteremia is a major cause of morbidity and mortality in patients with cancer and episodes of high-risk febrile neutropenia (HRFN).
UNLABELLED
Bacteremia is a major cause of morbidity and mortality in patients with cancer and episodes of high-risk febrile neutropenia (HRFN).
OBJECTIVE
To identify the frequency of microorganisms isolated from blood cultures (BC) and their antimicrobial resistance (R) profile in children with HRFN, compared with the same data from previous studies of the same group.
METHOD
Prospective, multicenter, epidemiological surveillance study of microorganisms isolated from BC in patients under 18 years of age, from 7 PINDA network hospitals, between 2016 and 2021.
RESULTS
284 episodes of HRFN with positive BC were analyzed out of 1091 enrolled episodes (26%). Median age 7.2 years [3.0-12.3]. The main isolates were gram-negative bacilli (GNB) 49.2%, gram-positive cocci (GPC) 43.8%, and fungi 3.6%. The most frequently isolated microorganisms were viridans group Streptococci (VGS) (25.8%), Escherichia coli (19.8%), Pseudomonas spp. (11.2%), Klebsiella spp. (10.9%), and coagulase negative Staphylococci (CoNS) (10.9%). There was an increase in R to third-generation cephalosporins (p = 0.011) in GNB and to oxacillin in CoNS (p = 0.00), as well as a decrease in R to amikacin in non-fermenting GNB (p = 0.02) and to penicillin in VGS (p = 0.04).
CONCLUSION
VGS is the main agent isolated in BC from pediatric patients with cancer and episodes of HRFN, followed by E. coli, Pseudomonas spp., and Klebsiella spp. Having epidemiological surveillance of microorganisms isolated from BC and their antimicrobial R profile is essential to favor the rational use of antimicrobials.
Topics: Humans; Child; Neoplasms; Prospective Studies; Child, Preschool; Febrile Neutropenia; Chile; Bacteremia; Female; Male; Blood Culture; Anti-Bacterial Agents; Drug Resistance, Bacterial; Microbial Sensitivity Tests; Adolescent; Gram-Negative Bacteria
PubMed: 38801361
DOI: 10.32641/andespediatr.v95i2.5012 -
Canadian Journal of Kidney Health and... 2024Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disease characterized by excessive immune activation. It is more commonly seen in children but...
RATIONALE
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disease characterized by excessive immune activation. It is more commonly seen in children but increasingly recognized in adults. Primary HLH relies on a genetic predisposition, whereas secondary HLH develops in the context of infections, malignancies, or autoimmune diseases. Hemophagocytic lymphohistiocytosis has been rarely described in patients on immunosuppressive therapy after kidney transplant. Here, we describe a case of HLH in a patient with a remote history of kidney transplant, triggered by a viral infection.
PRESENTING CONCERNS
A 45-year-old female, with a kidney transplant in 2009 for IgA nephropathy, presented with fever, vomiting, and back pain of 1-week duration. She was on triple immunosuppression consisting of daily doses of prednisone 5 mg, azathioprine 100 mg, and tacrolimus extended release 1 mg, and a baseline creatinine of 130 µmol/L.
DIAGNOSIS
Initial investigations showed anemia, leukopenia, elevated serum creatinine, transaminitis, and markedly increased ferritin of 67 600 µg/L which prompted a bone marrow biopsy to rule out HLH. The bone marrow showed an increased proportion of CD68+ cells (macrophages) with more than 5 in 1000 hemophagocytic macrophages. Her soluble IL-2 receptor (CD25) level was 3406 pg/mL (606-2299 pg/mL) which was mildly elevated. She fulfilled 4 of the 8 criteria for HLH and with an H score was 223 which suggested a diagnosis of HLH with 96.9% probability. An extensive secondary workup for possible triggers for HLH led to a swab from genital ulcers that was positive for herpes simplex virus (HSV) type 2. The polymerase chain reaction (PCR) in the blood for HSV type 2 was also positive.
INTERVENTIONS
Given the diagnosis of HSV type 2 as the putative trigger for HLH, she was started on parenteral acyclovir for 2 weeks followed by oral valacyclovir for 2 more weeks. In the context of infection, the azathioprine was stopped while low-dose steroid and tacrolimus were continued.
OUTCOMES
With the initiation of treatment for HSV infection, leukopenia, creatinine, and transaminases improved along with ferritin levels. At her 6-month follow-up, her blood counts and liver enzymes had normalized, and ferritin was 566 µg/L.
TEACHING POINTS
Hemophagocytic lymphohistiocytosis is a rare disease in kidney transplant recipients with a high mortality rate. It can occur even in remote kidney transplant recipients so a high degree of suspicion is necessary to lead to a prompt diagnosis. Infections are common triggers for secondary HLH. Early identification and treatment of the triggering infection may improve outcomes.
PubMed: 38799982
DOI: 10.1177/20543581241253921 -
MedRxiv : the Preprint Server For... May 2024G6PC3 deficiency is a rare genetic disorder that causes syndromic congenital neutropenia. It is driven by the intracellular accumulation of a metabolite named...
BACKGROUND
G6PC3 deficiency is a rare genetic disorder that causes syndromic congenital neutropenia. It is driven by the intracellular accumulation of a metabolite named 1,5-anhydroglucitol-6-phosphate (1,5-AG6P) that inhibits glycolysis. Patients display heterogeneous extra-hematological manifestations, contributing to delayed diagnosis.
OBJECTIVE
The c.210delC variant has been identified in patients of Mexican origin. We set out to study the origin and functional consequence of this mutation. Furthermore, we sought to characterize the clinical phenotypes caused by it.
METHODS
Using whole-genome sequencing data, we conducted haplotype analysis to estimate the age of this allele and traced its ancestral origin. We examined how this mutation affected G6PC3 protein expression and performed extracellular flux assays on patient-derived cells to characterize how this mutation impacts glycolysis. Finally, we compared the clinical presentations of patients with the c.210delC mutation relative to other G6PC3 deficient patients published to date.
RESULTS
Based on the length of haplotypes shared amongst ten carriers of the c.210delC mutation, we estimated that this variant originated in a common ancestor of indigenous American origin. The mutation causes a frameshift that introduces a premature stop codon, leading to a complete loss of G6PC3 protein expression. When treated with 1,5-anhydroglucitol (1,5-AG), the precursor to 1,5-AG6P, patient-derived cells exhibited markedly reduced engagement of glycolysis. Clinically, c.210delC carriers display all the clinical features of syndromic severe congenital neutropenia type 4 observed in prior reports of G6PC3 deficiency.
CONCLUSION
The c.210delC is a loss-of-function mutation that arose from a founder effect in the indigenous Mexican population. These findings may facilitate the diagnosis of additional patients in this geographical area. Moreover, the 1,5-AG-dependent functional assay used in our study could be employed to assess the pathogenicity of additional variants.
PubMed: 38798393
DOI: 10.1101/2024.05.13.24307299 -
Vaccines Apr 2024Real-world clinical experience of using anti-programmed death-ligand 1 (PD-L1) immune checkpoint inhibitors (ICIs) combined with chemotherapy in the first-line treatment...
A Clinical Analysis of Anti-Programmed Death-Ligand 1 (PD-L1) Immune Checkpoint Inhibitor Treatments Combined with Chemotherapy in Untreated Extensive-Stage Small-Cell Lung Cancer.
Real-world clinical experience of using anti-programmed death-ligand 1 (PD-L1) immune checkpoint inhibitors (ICIs) combined with chemotherapy in the first-line treatment of extensive-stage small-cell lung cancer (SCLC) patients has rarely been reported. In this study, we aimed to perform a retrospective multicenter clinical analysis of extensive-stage SCLC patients receiving first-line therapy with anti-PD-L1 ICIs combined with chemotherapy. Between November 2018 and March 2022, 72 extensive-stage SCLC patients receiving first-line atezolizumab or durvalumab in combination with chemotherapy, according to the cancer center databases of Linkou, Chiayi, and Kaohsiung Chang Gung Memorial Hospitals, were retrospectively included in the analysis. Twenty-one patients (29.2%) received atezolizumab and fifty-one (70.8%) received durvalumab. Objective response (OR) and disease control (DC) rates of 59.7% and 73.6%, respectively, were observed with first-line ICI plus chemotherapy. The median progression-free survival (PFS) was 6.63 months (95% confidence interval (CI), 5.25-8.02), and the median overall survival (OS) was 16.07 months (95% CI, 15.12-17.0) in all study patients. A high neutrophil-to-lymphocyte ratio (NLR; >4) and a high serum lactate dehydrogenase (LDH) concentration (>260 UL) were identified as independent unfavorable factors associated with shorter OS in the multivariate analysis. Regarding safety, neutropenia was the most common grade 3 treatment-related adverse event (AE), but no treatment-related deaths occurred in the study patients. First-line anti-PD-L1 ICIs combined with chemotherapy are effective and safe for male extensive-stage SCLC patients. Further therapeutic strategies may need to be developed for patients with unfavorable outcomes (e.g., baseline high NLR and serum LDH level).
PubMed: 38793725
DOI: 10.3390/vaccines12050474 -
Cancers May 2024We performed a systematic review of studies that compared beta-lactams vs. beta-lactams plus aminoglycosides for the treatment of febrile neutropenia in cancer patients. (Review)
Review
UNLABELLED
We performed a systematic review of studies that compared beta-lactams vs. beta-lactams plus aminoglycosides for the treatment of febrile neutropenia in cancer patients.
METHOD
We searched CENTRAL, MEDLINE, and Embase for studies published up to October 2023, and randomized controlled trials (RCTs) that compared anti-Pseudomonas aeruginosa beta-lactam monotherapy with any combination of an anti-Pseudomonas aeruginosa beta-lactam and an aminoglycoside were included.
RESULT
The all-cause mortality rate of combination therapy showed no significant differences compared with that of monotherapy (RR 0.99, 95% CI 0.84 to 1.16, high certainty of evidence). Infection-related mortality rates showed that combination therapy had a small positive impact compared with the intervention with monotherapy (RR 0.83, 95% CI 0.66 to 1.05, high certainty of evidence). Regarding treatment failure, combination therapy showed no significant differences compared with monotherapy (RR 0.99, 95% CI 0.94 to 1.03, low certainty of evidence). In the sensitivity analysis, the treatment failure data published between 2010 and 2019 showed better outcomes in the same beta-lactam group (RR 1.10 [95% CI, 1.01-1.19]). Renal failure was more frequent with combination therapy of any daily dosing regimen (RR 0.46, 95% CI 0.36 to 0.60, high certainty of evidence).
CONCLUSION
We found combining aminoglycosides with a narrow-spectrum beta-lactam did not spare the use of broad-spectrum antibiotics. Few studies included antibiotic-resistant bacteria and a detailed investigation of aminoglycoside serum levels, and studies that combined the same beta-lactams showed only a minimal impact with the combination therapy. In the future, studies that include the profile of antibiotic-resistant bacteria and the monitoring of serum aminoglycoside levels will be required.
PubMed: 38792012
DOI: 10.3390/cancers16101934 -
Cancers May 2024Breast cancer (BC) incidence increases with age, particularly in HR-positive/HER2-negative subtypes. Cyclin-dependent kinase 4 and 6 inhibitors (CDK 4/6is) alongside... (Review)
Review
BACKGROUND
Breast cancer (BC) incidence increases with age, particularly in HR-positive/HER2-negative subtypes. Cyclin-dependent kinase 4 and 6 inhibitors (CDK 4/6is) alongside endocrine therapy (ET) have emerged as promising treatments for HR-positive/HER2-negative advanced and early BC. However, their efficacy, safety, and impact on quality of life (QoL) in older and frail patients remain underexplored.
METHODS
This position paper assesses the existing literature from 2015 to 2024, focusing on CDK4/6is use in patients aged 65 years and older with HR-positive/HER2-negative BC.
RESULTS
Our analysis methodically addresses critical questions regarding the utilization of CDK4/6is in the elderly BC patient population, organizing findings from the metastatic and adjuvant settings. In the metastatic setting, CDK4/6is significantly improve progression-free survival (PFS), paralleling benefits observed in younger patients, and suggest potential overall survival (OS) benefits, warranting further investigation. Despite an increased incidence of grade ≥ 3 adverse events (AEs), such as neutropenia and asthenia, CDK4/6is present a markedly lower toxicity profile compared to traditional chemotherapy, with manageable side effects. QoL analysis indicates that integrating CDK4/6is into treatment regimens does not significantly impact elderly BC patients' daily life and symptom management. Special attention is given to frail subgroups, and personalized approaches are recommended to balance efficacy and adverse effects, such as starting with ET alone and introducing CDK4/6is upon progression in patients with a low disease burden. Transitioning to the adjuvant setting, early results, particularly with abemaciclib, indicate positive effects on disease-free survival (DFS), emphasizing the need for continued analysis to validate these findings and assess long-term implications. However, data on older patients are insufficient to conclude whether they truly benefit from this treatment.
CONCLUSION
Overall, CDK4/6is present a favorable benefit-risk profile in older BC patients, at least in advanced BC; however, further research is warranted to optimize treatment strategies and improve outcomes in this population.
PubMed: 38791919
DOI: 10.3390/cancers16101838 -
Biomedicines May 2024Cancer patients face increased susceptibility to invasive infections, primarily due to ulcerative lesions on mucosal surfaces and immune suppression resulting from...
Cancer patients face increased susceptibility to invasive infections, primarily due to ulcerative lesions on mucosal surfaces and immune suppression resulting from chemotherapy. () bacteremia is notorious for its rapid progression into fatal sepsis, posing a significant threat to cancer patients, particularly those experiencing chemotherapy-induced neutropenia. This bacterial infection contributes significantly to morbidity and mortality rates among such individuals. Our latest report showed the mutually beneficial effects of postbiotic butyrate on 1,25-dihydroxyvitamin D3 (1,25D3)-controlled innate immunity during colitis. Hence, we investigated the impact of butyrate and 1,25D3 on chemotherapy-induced gut-derived sepsis in mice. The chemotherapy-induced gut-derived sepsis model was established through oral administration of 1 × 10 CFU of the wild-type strain PAO1 in C57BL/6 mice undergoing chemotherapy. Throughout the infection process, mice were orally administered butyrate and/or 1,25D3. Our observations revealed that the combined action of butyrate and 1,25D3 led to a reduction in the severity of colitis and the invasion of into the liver and spleen of the mice. This reduction was attributed to an enhancement in the expression of defensive cytokines and antimicrobial peptides within the cecum, coupled with decreased levels of zonulin and claudin-2 proteins in the mucosal lining. These effects were notably more pronounced when compared to treatments administered individually. This study unveils a promising alternative therapy that involves combining postbiotics and 1,25D3 for treating chemotherapy-induced gut-derived sepsis.
PubMed: 38790988
DOI: 10.3390/biomedicines12051026 -
Biomedicines Apr 2024Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder identified by hematological abnormalities including anemia, leukopenia, and thrombocytopenia....
Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder identified by hematological abnormalities including anemia, leukopenia, and thrombocytopenia. Complement system disturbance is implicated in the pathogenesis of SLE. In this work, we aim to study how a full assessment of the complement system, which includes the evaluation of its three pathways, relates to blood cell counts in a population of patients with SLE. New-generation functional assays of the classical, alternative, and lectin pathways of the complement system were conducted in 284 patients with SLE. Additionally, serum levels of inactive molecules (C1q, C2, C3, C4, factor D) and activated molecules (C3a), as well as regulators (C1-inhibitor and factor H), were evaluated. Complete blood cell counts were analyzed. Multivariable linear regression analysis was performed to study the relationship of hematological profiles with this full characterization of the complement system. After multivariable adjustments that included age, sex, SLICC-DI (damage), and SLEDAI (activity) scores, as well as the use of aspirin, prednisone, methotrexate, azathioprine, and mycophenolate mofetil, several relationships were observed between the C pathways and the individual products and blood cells profile. Lower values of C1q and C2 were associated with lower hemoglobin levels. Lower leukocyte counts showed significantly lower values of C4, C1 inhibitor, C3, factor D, and alternative pathway functional levels. Neutrophil counts showed significant negative relationships only with the alternative pathway and C1-inh. In the case of lymphocytes, associations were found, especially with functional tests of the classical and alternative pathways, as well as with C2, C4, C3, and C3a. On the contrary, for platelets, significance was only observed, after multivariable adjustment, with lower C2 concentrations. In conclusion, the serum complement system and hematological profile in SLE are independently linked, after adjustment for disease activity and damage. These relationships are basically negative and are predominantly found in lymphocytes.
PubMed: 38790929
DOI: 10.3390/biomedicines12050967