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Emerging Infectious Diseases Jan 2021Invasive fusariosis (IF) is associated with severe neutropenia in patients with concurrent hematologic conditions. We conducted a retrospective observational study to... (Review)
Review
Invasive fusariosis (IF) is associated with severe neutropenia in patients with concurrent hematologic conditions. We conducted a retrospective observational study to characterize the epidemiology of IF in 18 Spanish hospitals during 2000-2015. In that time, the frequency of IF in nonneutropenic patients increased from 0.08 cases per 100,000 admissions in 2000-2009 to 0.22 cases per 100,000 admissions in 2010-2015. Nonneutropenic IF patients often had nonhematologic conditions, such as chronic cardiac or lung disease, rheumatoid arthritis, history of solid organ transplantation, or localized fusariosis. The 90-day death rate among nonneutropenic patients (28.6%) and patients with resolved neutropenia (38.1%) was similar. However, the death rate among patients with persistent neutropenia (91.3%) was significantly higher. We used a multivariate Cox regression analysis to characterize risk factors for death: persistent neutropenia was the only risk factor for death, regardless of antifungal therapy.
Topics: Antifungal Agents; Fusariosis; Fusarium; Humans; Neutropenia; Observational Studies as Topic; Spain
PubMed: 33352085
DOI: 10.3201/eid2701.190782 -
The Journal of Infection Sep 2023The optimisation of the use of β-lactam antibiotics (BLA) via prolonged infusions in life-threatening complications such as febrile neutropenia (FN) is still... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The optimisation of the use of β-lactam antibiotics (BLA) via prolonged infusions in life-threatening complications such as febrile neutropenia (FN) is still controversial. This systematic review and meta-analysis aim to evaluate the efficacy of this strategy in onco-haematological patients with FN.
METHODS
A systematic search was performed of PubMed, Web of Science, Cochrane, EMBASE, World Health Organization, and ClinicalTrials.gov, from database inception until December 2022. The search included randomised controlled trials (RCTs) and observational studies that compared prolonged vs short-term infusions of the same BLA. The primary outcome was all-cause mortality. Secondary outcomes were defervescence, requirement of vasoactive drugs, length of hospital stay and adverse events. Pooled risk ratios were calculated using random effects models.
RESULTS
Five studies were included, comprising 691 episodes of FN, mainly in haematological patients. Prolonged infusion was not associated with a reduction in all-cause mortality (pRR 0.83; 95% confidence interval 0.47-1.48). Nor differences were found in secondary outcomes.
CONCLUSIONS
The limited data available did not show significant differences in terms of all-cause mortality or significant secondary outcomes in patients with FN receiving BLA in prolonged vs. short-term infusion. High-quality RCTs are needed to determine whether there are subgroups of FN patients who would benefit from prolonged BLA infusion.
Topics: Humans; Anti-Bacterial Agents; Monobactams; Febrile Neutropenia
PubMed: 37423503
DOI: 10.1016/j.jinf.2023.06.023 -
Cells Oct 2022Leukocytes are essential for the function of the immune system and cell-cell interaction in the human body, but hematological diseases as well as chemotherapeutic... (Review)
Review
Leukocytes are essential for the function of the immune system and cell-cell interaction in the human body, but hematological diseases as well as chemotherapeutic treatments due to cancer lead to occasionally or even permanent leukocyte deficiency. Normally, more than 50% of leukocytes are neutrophilic granulocytes, and leukopenia is, therefore, mostly characterized by a decrease in neutrophilic granulocytes. The consequence of neutropenia is increased susceptibility to infection, but also healing disorders are suggestable due to the disturbed cell-cell interaction. While there is no surgical treatment for leucocyte disorders, patients suffering from neutropenia are sometimes in need of surgery for other reasons. Less is known about the morbidity and mortality of this patients, which is why this narrative review critically summarizes the results of recent research in this particular field. The results of this review suggest that neutropenic patients in need of emergency surgery have a higher mortality risk compared to non-neutropenic patients. In contrast, in elective surgery, there was not a clear tendency for a higher mortality risk of neutropenic patients. The role of neutrophilic granulocytes in inflammation and immunity in surgical patients is emphasized by the results, but most of the evaluated studies showed methodological flaws due to small sample sizes or risk of bias. Further research has to evaluate the risk for postoperative complications, particularly of infectious complications such as surgical site infections, in neutropenic patients undergoing elective surgery, and should address the role of neutrophilic function in postoperative morbidity and mortality.
Topics: Humans; Neutropenia; Granulocytes; Morbidity; Leukocytes; Digestive System Surgical Procedures
PubMed: 36291181
DOI: 10.3390/cells11203314 -
Cells Oct 2021Large granular lymphocyte leukemia (LGLL) is a rare lymphoproliferative disorder characterized by the clonal expansion of cytotoxic T-LGL or NK cells. Chronic isolated... (Review)
Review
Large granular lymphocyte leukemia (LGLL) is a rare lymphoproliferative disorder characterized by the clonal expansion of cytotoxic T-LGL or NK cells. Chronic isolated neutropenia represents the clinical hallmark of the disease, being present in up to 80% of cases. New advances were made in the biological characterization of neutropenia in these patients, in particular mutations and a discrete immunophenotype are now recognized as relevant features. Nevertheless, the etiology of LGLL-related neutropenia is not completely elucidated and several mechanisms, including humoral abnormalities, bone marrow infiltration/substitution and cell-mediated cytotoxicity might cooperate to its pathogenesis. As a consequence of the multifactorial nature of LGLL-related neutropenia, a targeted therapeutic approach for neutropenic patients has not been developed yet; moreover, specific guidelines based on prospective trials are still lacking, thus making the treatment of this disorder a complex and challenging task. Immunosuppressive therapy represents the current, although poorly effective, therapeutic strategy. The recent identification of a STAT3-mediated miR-146b down-regulation in neutropenic T-LGLL patients emphasized the pathogenetic role of STAT3 activation in neutropenia development. Accordingly, JAK/STAT3 axis inhibition and miR-146b restoration might represent tempting strategies and should be prospectively evaluated for the treatment of neutropenic LGLL patients.
Topics: Diagnosis, Differential; Fas Ligand Protein; Humans; Immunophenotyping; Leukemia, Large Granular Lymphocytic; Neutropenia; Prognosis
PubMed: 34685780
DOI: 10.3390/cells10102800 -
Frontiers in Immunology 2023Chimeric antigen receptor T-cell (CAR-T) therapy has shown remarkable effects in treating various hematological malignancies. However, hematotoxicity, specifically... (Review)
Review
Chimeric antigen receptor T-cell (CAR-T) therapy has shown remarkable effects in treating various hematological malignancies. However, hematotoxicity, specifically neutropenia, thrombocytopenia, and anemia, poses a serious threat to patient prognosis and remains a less focused adverse effect of CAR-T therapy. The mechanism underlying lasting or recurring late-phase hematotoxicity, long after the influence of lymphodepletion therapy and cytokine release syndrome (CRS), remains elusive. In this review, we summarize the current clinical studies on CAR-T late hematotoxicity to clarify its definition, incidence, characteristics, risk factors, and interventions. Owing to the effectiveness of transfusing hematopoietic stem cells (HSCs) in rescuing severe CAR-T late hematotoxicity and the unignorable role of inflammation in CAR-T therapy, this review also discusses possible mechanisms of the harmful influence of inflammation on HSCs, including inflammatory abrasion of the number and the function of HSCs. We also discuss chronic and acute inflammation. Cytokines, cellular immunity, and niche factors likely to be disturbed in CAR-T therapy are highlighted factors with possible contributions to post-CAR-T hematotoxicity.
Topics: Humans; Receptors, Chimeric Antigen; Immunotherapy, Adoptive; Hematopoietic Stem Cells; Inflammation; Neutropenia; Soft Tissue Injuries
PubMed: 37223096
DOI: 10.3389/fimmu.2023.1141779 -
Supportive Care in Cancer : Official... Nov 2021Multiple myeloma (MM) survival rates have been substantially increased thanks to novel agents that have improved survival outcomes and shown better tolerability than... (Review)
Review
Multiple myeloma (MM) survival rates have been substantially increased thanks to novel agents that have improved survival outcomes and shown better tolerability than treatments of earlier years. These new agents include immunomodulating imide drugs (IMiD) thalidomide and lenalidomide, the proteasome inhibitor bortezomib (PI), recently followed by new generation IMID pomalidomide, monoclonal antibodies daratumumab and elotuzumab, and next generation PI carfilzomib and ixazomib. However, even in this more promising scenario, febrile neutropenia remains a severe side effect of antineoplastic therapies and can lead to a delay and/or dose reduction in subsequent cycles. Supportive care has thus become key in helping patients to obtain the maximum benefit from novel agents. Filgrastim is a human recombinant subcutaneous preparation of G-CSF, largely adopted in hematological supportive care as "on demand" (or secondary) prophylaxis to recovery from neutropenia and its infectious consequences during anti-myeloma treatment. On the contrary, pegfilgrastim is a pegylated long-acting recombinant form of granulocyte colony-stimulating factor (G-CSF) that, given its extended half-life, can be particularly useful when adopted as "primary prophylaxis," therefore before the onset of neutropenia, along chemotherapy treatment in multiple myeloma patients. There is no direct comparison between the two G-CSF delivery modalities. In this review, we compare data on the two administrations' modality, highlighting the efficacy of the secondary prophylaxis over multiple myeloma treatment. Advantage of pegfilgrastim could be as follows: the fixed administration rather than multiple injections, reduction in neutropenia and febrile neutropenia rates, and, finally, a cost-effectiveness advantage.
Topics: Antineoplastic Combined Chemotherapy Protocols; Febrile Neutropenia; Filgrastim; Granulocyte Colony-Stimulating Factor; Humans; Multiple Myeloma; Polyethylene Glycols; Recombinant Proteins
PubMed: 33990881
DOI: 10.1007/s00520-021-06266-x -
Immunity, Inflammation and Disease Dec 2020Graves' disease (GD) is a clinical autoimmune thyroid disease. During the treatment of GD, antithyroid drug-induced agranulocytosis (TIA) is a common and even...
BACKGROUND
Graves' disease (GD) is a clinical autoimmune thyroid disease. During the treatment of GD, antithyroid drug-induced agranulocytosis (TIA) is a common and even life-threatening adverse drug reaction. Previous studies suggested that susceptibility to TIA is strongly associated with HLA-B*27:05, HLA-B*38:02, and HLA-DRB1*08:03 genetic variation and six single nucleotide polymorphisms (SNPs) in MICA genes.
AIMS
The purpose of this study is to further study the associations between TIA, HLA-B and MICA.
MATERIALS & METHODS
We genotyped MICA-STR and MICA-129 variants in 41 TIA and 308 control patients with GD and investigated the linkage effect among SNPs and short tandem repeat (STR) of MICA and HLA-B alleles.
RESULTS
The results showed that MICA*A5.1 was significantly associated with TIA (p = .007, odd ratio = 1.958, 95% confidence interval, 1.192-3.214). In addition, high linkage among MICA-129 and six SNPs MICA and HLA-B was detected, and two haplotypes (AAAACAAAAACGGCCTA and AACAAAAAAAACATTAA (p = 5.14E-07 and p = 3.42E-08, respectively)) were significantly associated with TIA. Furthermore, when we analyzed only MICA-129 and HLA-B separately, the haplotypes (AAAACAAAAAA with p = 2.49E-07 and AACAAAAAAAA with p = 2.14E-09) were identified with more significant effects. MICA-129 was completely linked to six SNPs with haplotypes ACATTACA (p = 2.05E-05) significantly associated with TIA.
CONCLUSION
These data indicated that there was a significant linkage effect between MICA-129 and other alleles, suggesting that they exert interactive effects as risk factors for the development of TIA.
Topics: Adult; Agranulocytosis; Antithyroid Agents; China; Female; HLA-B Antigens; Haplotypes; Humans; Male; Middle Aged; Young Adult
PubMed: 33017098
DOI: 10.1002/iid3.359 -
The Cochrane Database of Systematic... Nov 2022Intensive cytotoxic chemotherapy for people with cancer can cause severe and prolonged cytopenia, especially neutropenia, a critical condition that is potentially... (Review)
Review
BACKGROUND
Intensive cytotoxic chemotherapy for people with cancer can cause severe and prolonged cytopenia, especially neutropenia, a critical condition that is potentially life-threatening. When manifested by fever and neutropenia, it is called febrile neutropenia (FN). Invasive fungal disease (IFD) is one of the serious aetiologies of chemotherapy-induced FN. In pre-emptive therapy, physicians only initiate antifungal therapy when an invasive fungal infection is detected by a diagnostic test. Compared to empirical antifungal therapy, pre-emptive therapy may reduce the use of antifungal agents and associated adverse effects, but may increase mortality. The benefits and harms associated with the two treatment strategies have yet to be determined. OBJECTIVES: To assess the relative efficacy, safety, and impact on antifungal agent use of pre-emptive versus empirical antifungal therapy in people with cancer who have febrile neutropenia.
SEARCH METHODS
We searched CENTRAL, MEDLINE Ovid, Embase Ovid, and ClinicalTrials.gov to October 2021.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) that compared pre-emptive antifungal therapy with empirical antifungal therapy for people with cancer.
DATA COLLECTION AND ANALYSIS
We identified 2257 records from the databases and handsearching. After removing duplicates, screening titles and abstracts, and reviewing full-text reports, we included seven studies in the review. We evaluated the effects on all-cause mortality, mortality ascribed to fungal infection, proportion of antifungal agent use (other than prophylactic use), duration of antifungal use (days), invasive fungal infection detection, and adverse effects for the comparison of pre-emptive versus empirical antifungal therapy. We presented the overall certainty of the evidence for each outcome according to the GRADE approach.
MAIN RESULTS
This review includes 1480 participants from seven randomised controlled trials. Included studies only enroled participants at high risk of FN (e.g. people with haematological malignancy); none of them included participants at low risk (e.g. people with solid tumours). Low-certainty evidence suggests there may be little to no difference between pre-emptive and empirical antifungal treatment for all-cause mortality (risk ratio (RR) 0.97, 95% confidence interval (CI) 0.72 to 1.30; absolute effect, reduced by 3/1000); and for mortality ascribed to fungal infection (RR 0.92, 95% CI 0.45 to 1.89; absolute effect, reduced by 2/1000). Pre-emptive therapy may decrease the proportion of antifungal agent used more than empirical therapy (other than prophylactic use; RR 0.71, 95% CI 0.47 to 1.05; absolute effect, reduced by 125/1000; very low-certainty evidence). Pre-emptive therapy may reduce the duration of antifungal use more than empirical treatment (mean difference (MD) -3.52 days, 95% CI -6.99 to -0.06, very low-certainty evidence). Pre-emptive therapy may increase invasive fungal infection detection compared to empirical treatment (RR 1.70, 95% CI 0.71 to 4.05; absolute effect, increased by 43/1000; very low-certainty evidence). Although we were unable to pool adverse events in a meta-analysis, there seemed to be no apparent difference in the frequency or severity of adverse events between groups. Due to the nature of the intervention, none of the seven RCTs could blind participants and personnel related to performance bias. We identified considerable clinical and statistical heterogeneity, which reduced the certainty of the evidence for each outcome. However, the two mortality outcomes had less statistical heterogeneity than other outcomes.
AUTHORS' CONCLUSIONS
For people with cancer who are at high-risk of febrile neutropenia, pre-emptive antifungal therapy may reduce the duration and rate of use of antifungal agents compared to empirical therapy, without increasing over-all and IFD-related mortality; but the evidence regarding invasive fungal infection detection and adverse events was inconsistent and uncertain.
Topics: Humans; Antifungal Agents; Febrile Neutropenia; Invasive Fungal Infections; Neoplasms; Randomized Controlled Trials as Topic
PubMed: 36440894
DOI: 10.1002/14651858.CD013604.pub2 -
Nature Jun 2020Advances in genetics and sequencing have identified a plethora of disease-associated and disease-causing genetic alterations. To determine causality between genetics and...
Advances in genetics and sequencing have identified a plethora of disease-associated and disease-causing genetic alterations. To determine causality between genetics and disease, accurate models for molecular dissection are required; however, the rapid expansion of transcriptional populations identified through single-cell analyses presents a major challenge for accurate comparisons between mutant and wild-type cells. Here we generate mouse models of human severe congenital neutropenia (SCN) using patient-derived mutations in the GFI1 transcription factor. To determine the effects of SCN mutations, we generated single-cell references for granulopoietic genomic states with linked epitopes, aligned mutant cells to their wild-type equivalents and identified differentially expressed genes and epigenetic loci. We find that GFI1-target genes are altered sequentially, as cells go through successive states of differentiation. These insights facilitated the genetic rescue of granulocytic specification but not post-commitment defects in innate immune effector function, and underscore the importance of evaluating the effects of mutations and therapy within each relevant cell state.
Topics: Animals; Candida albicans; Cell Lineage; DNA-Binding Proteins; Disease Models, Animal; Female; Granulocyte Precursor Cells; Humans; Immunity, Innate; Male; Mice; Mice, Transgenic; Mutation; Neutropenia; Neutrophils; Transcription Factors
PubMed: 32494068
DOI: 10.1038/s41586-020-2227-7 -
Turkish Journal of Haematology :... Aug 2023Febrile neutropenia (FN) is an important complication that causes high rates of morbidity and mortality in patients with malignancies. We aimed to investigate the...
OBJECTIVE
Febrile neutropenia (FN) is an important complication that causes high rates of morbidity and mortality in patients with malignancies. We aimed to investigate the etiology, epidemiological distribution and its change over the years, clinical courses, and outcomes of FN in children with acute leukemia.
MATERIALS AND METHODS
We retrospectively analyzed the demographic data, clinical characteristics, laboratory results, severe complications, and mortality rates of pediatric patients with FN between January 2010 and December 2020.
RESULTS
In 153 patients, a total of 450 FN episodes (FNEs) occurred. Eighty-four (54.9%) of these patients were male, the median age of the patients was 6.5 (range: 3-12.2) years, and 127 patients (83%) were diagnosed with acute lymphoblastic leukemia. Fever with a focus was found in approximately half of the patients, and an etiology was identified for 38.7% of the patients. The most common fever focus was bloodstream infection (n=74, 16.5%). Etiologically, a bacterial infection was identified in 22.7% (n=102), a viral infection in 13.3% (n=60), and a fungal infection in 5.8% (n=26) of the episodes. Twenty-six (23.2%) of a total of 112 bacteria were multidrug resistant (MDR) The rate of severe complications was 7.8% (n=35) and the mortality rate was 2% (n=9). In logistic regression analysis, refractory/relapsed malignancies and high C-reactive protein (CRP) at first admission were found to be the most important independent risk factors for mortality. Prolonged neutropenia after chemotherapy, diagnosis of acute myeloid leukemia, identification of fever focus or etiological agents, invasive fungal infections, polymicrobial infections, and need for intravenous immunoglobulin treatment increased the frequency of severe complications.
CONCLUSION
We found that there was no significant change in the epidemiological distribution or frequency of resistant bacteria in our center in the last 10 years compared to previous years. Prolonged duration of fever, relapsed/refractory malignancies, presence of fever focus, and high CRP level were significant risk factors for poor clinical course and outcome.
Topics: Child; Humans; Male; Child, Preschool; Female; Retrospective Studies; Leukemia, Myeloid, Acute; Acute Disease; Risk Factors; Febrile Neutropenia; Anti-Bacterial Agents
PubMed: 37525503
DOI: 10.4274/tjh.galenos.2023.2023.0185