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Annals of the American Thoracic Society Nov 2022
Topics: Humans; Neutropenia; Pleural Effusion
PubMed: 35960258
DOI: 10.1513/AnnalsATS.202204-331RL -
Revista Da Associacao Medica Brasileira... 2019Fever of undetermined origin (FUO) is a challenging entity with a striking presence in hospitals around the world. It is defined as temperature ≥ 37.8 ° C on several... (Review)
Review
Fever of undetermined origin (FUO) is a challenging entity with a striking presence in hospitals around the world. It is defined as temperature ≥ 37.8 ° C on several occasions, lasting ≥ three weeks, in the absence of diagnosis after three days of hospital investigation or 3 outpatient visits. The main etiologies are infectious, neoplastic, and non-infectious inflammatory diseases. The diagnosis is based on the detailed clinical history and physical examination of these patients, in order to direct the specific complementary tests to be performed in each case. The initial diagnostic approach of the FUO patient should include non-specific complementary exams. Empirical therapy is not recommended (with few exceptions) in patients with prolonged fever, as it may disguise and delay the diagnosis and conduct to treat the specific etiology. The prognosis encompasses mortality of 12-35%, varying according to the baseline etiology.
Topics: Cross Infection; Female; Fever of Unknown Origin; Humans; Infections; Inflammation; Male; Neoplasms; Neutropenia
PubMed: 31721964
DOI: 10.1590/1806-9282.65.10.1308 -
EMBO Molecular Medicine Jan 2024Elevated peripheral blood and tumor-infiltrating neutrophils are often associated with a poor patient prognosis. However, therapeutic strategies to target these cells...
Elevated peripheral blood and tumor-infiltrating neutrophils are often associated with a poor patient prognosis. However, therapeutic strategies to target these cells are difficult to implement due to the life-threatening risk of neutropenia. In a genetically engineered mouse model of lung adenocarcinoma, tumor-associated neutrophils (TAN) demonstrate tumor-supportive capacities and have a prolonged lifespan compared to circulating neutrophils. Here, we show that tumor cell-derived GM-CSF triggers the expression of the anti-apoptotic Bcl-xL protein and enhances neutrophil survival through JAK/STAT signaling. Targeting Bcl-xL activity with a specific BH3 mimetic, A-1331852, blocked the induced neutrophil survival without impacting their normal lifespan. Specifically, oral administration with A-1331852 decreased TAN survival and abundance, and reduced tumor growth without causing neutropenia. We also show that G-CSF, a drug used to combat neutropenia in patients receiving chemotherapy, increased the proportion of young TANs and augmented the anti-tumor effect resulting from Bcl-xL blockade. Finally, our human tumor data indicate the same role for Bcl-xL on pro-tumoral neutrophil survival. These results altogether provide preclinical evidence for safe neutrophil targeting based on their aberrant intra-tumor longevity.
Topics: Animals; Humans; Mice; Aging; Apoptosis; Apoptosis Regulatory Proteins; bcl-X Protein; Cell Line, Tumor; Lung Neoplasms; Neutropenia; Neutrophils
PubMed: 38177532
DOI: 10.1038/s44321-023-00013-x -
Current Opinion in Hematology Jan 2022Myeloid diseases are often characterized by a disturbed regulation of myeloid cell proliferation, survival, and maturation. This may either result in a severe paucity of... (Review)
Review
PURPOSE OF REVIEW
Myeloid diseases are often characterized by a disturbed regulation of myeloid cell proliferation, survival, and maturation. This may either result in a severe paucity of functional neutrophils (neutropenia), an excess production of mature cells (myeloproliferative disorders) or in clonal expansions of dysplastic or immature myeloid cells (myelodysplasia and acute myeloid leukemia). Although these conditions can be regarded as separate entities, caused by the accumulation of distinct sets of somatic gene mutations, it becomes increasingly clear that they may also evolve as the prime consequence of a congenital defect resulting in severe neutropenia. Prominent examples of such conditions include the genetically heterogeneous forms of severe congenital neutropenia (SCN) and Shwachman-Diamond Syndrome. CSF3 treatment is a successful therapy to alleviate neutropenia in the majority of these patients but does not cure the disease nor does it prevent malignant transformation. Allogeneic stem cell transplantation is currently the only therapeutic option to cure SCN, but is relatively cumbersome, e.g., hampered by treatment-related mortality and donor availability. Hence, there is a need for new therapeutic approaches.
RECENT FINDINGS
Developments in disease modeling, amongst others based on induced pluripotent stem cell and CRISPR/Cas9 based gene-editing technologies, have created new insights in disease biology and possibilities for treatment. In addition, they are fueling expectations for advanced disease monitoring to prevent malignant transformation.
SUMMARY
This review highlights the recent progress made in SCN disease modeling and discusses the challenges that are still ahead of us to gain a better understanding of the biological heterogeneity of the disease and its consequences for patient care.
Topics: Congenital Bone Marrow Failure Syndromes; Humans; Mutation; Myelodysplastic Syndromes; Neutropenia
PubMed: 34854832
DOI: 10.1097/MOH.0000000000000696 -
The Journal of Infection Jan 2023Plasma cell-free DNA Next-Generation Sequencing has been used as a non-invasive and comprehensive method for the etiological diagnosis of infectious diseases. However,...
BACKGROUND
Plasma cell-free DNA Next-Generation Sequencing has been used as a non-invasive and comprehensive method for the etiological diagnosis of infectious diseases. However, only a handful of studies have described the real-world utility of this technique in patients with hematological disorders, a cohort of patients that are distinctive due to neutropenia and weakened immune functions.
METHODS
We retrospectively analyzed the results of plasma cell-free DNA sequencing performed on 184 and 163 specimens collected from hematological patients suspected of infections with (Group I) or without (Group II) neutropenia, respectively. The diagnostic performance and the clinical impact of plasma sequencing were comparatively evaluated to conventional microbiological tests and a composite reference standard (conventional tests combined with the clinical assessment).
RESULTS
The overall positive detection rate of plasma cell-free DNA sequencing was significantly higher than that of conventional microbiological tests (72.6% vs.31.4%, P < 0.001). The positive rate of conventional microbiological tests in Group I was lower than that in Group II (25.5% vs. 38.0%, P = 0.012). Combining plasma sequencing with conventional tests yielded a positive detection rate of 75.0% and 74.8% for these two groups, respectively. Using the composite reference standard, the sensitivity and specificity of plasma sequencing were 89.1% and 65.1%, respectively. The proportions of the positive impact of cell-free DNA sequencing results in the Group I were higher than in the Group II in terms of both diagnosis and treatment (diagnosis: 54.3% vs. 40.5%, P = 0.013; treatment: 45.7% vs.30.7%, P = 0.004). A total of 73 patients (21.0%) benefited from plasma sequencing through adjustment of the antibiotic regimen.
CONCLUSIONS
The diagnostic yield of conventional microbiological tests was low in patients with neutropenia. Combining conventional tests with plasma cell-free DNA sequencing significantly improved the detection rate for pathogens and optimized antibiotic treatment. Our findings on the clinical impact warrant confirmation through larger, multicenter, randomized controlled trials. Moreover, the cost-effectiveness of this testing strategy remains unknown and requires further exploration.
Topics: Humans; Retrospective Studies; Communicable Diseases; High-Throughput Nucleotide Sequencing; Sensitivity and Specificity; Hematologic Diseases; Neutropenia; Cell-Free Nucleic Acids
PubMed: 36462587
DOI: 10.1016/j.jinf.2022.11.020 -
Nature Communications Jan 2024The limited reserves of neutrophils are implicated in the susceptibility to infection in neonates, however the regulation of neutrophil kinetics in infections in early...
The limited reserves of neutrophils are implicated in the susceptibility to infection in neonates, however the regulation of neutrophil kinetics in infections in early life remains poorly understood. Here we show that the developmental endothelial locus (DEL-1) is elevated in neonates and is critical for survival from neonatal polymicrobial sepsis, by supporting emergency granulopoiesis. Septic DEL-1 deficient neonate mice display low numbers of myeloid-biased multipotent and granulocyte-macrophage progenitors in the bone marrow, resulting in neutropenia, exaggerated bacteremia, and increased mortality; defects that are rescued by DEL-1 administration. A high IL-10/IL-17A ratio, observed in newborn sepsis, sustains tissue DEL-1 expression, as IL-10 upregulates while IL-17 downregulates DEL-1. Consistently, serum DEL-1 and blood neutrophils are elevated in septic adult and neonate patients with high serum IL-10/IL-17A ratio, and mortality is lower in septic patients with high serum DEL-1. Therefore, IL-10/DEL-1 axis supports emergency granulopoiesis, prevents neutropenia and promotes sepsis survival in early life.
Topics: Adult; Animals; Humans; Mice; Hematopoiesis; Interleukin-10; Interleukin-17; Neonatal Sepsis; Neutropenia; Sepsis; Infant, Newborn
PubMed: 38263289
DOI: 10.1038/s41467-023-44178-y -
Clinical Medicine (London, England) Jan 2023The general medical physician will often encounter patients who develop acute complications of their cancer diagnosis or anti-cancer treatment. Here we provide an...
The general medical physician will often encounter patients who develop acute complications of their cancer diagnosis or anti-cancer treatment. Here we provide an overview of emergency solid tumour oncology to guide the initial management of these patients.
Topics: Humans; Sepsis; Neutropenia; Neoplasms
PubMed: 36697019
DOI: 10.7861/clinmed.2022-0561 -
Blood Advances Oct 2023
Topics: Humans; Taste; Neutropenia; Diet; Hematopoietic Stem Cell Transplantation
PubMed: 37815817
DOI: 10.1182/bloodadvances.2023011125 -
BMJ Case Reports Jan 2021We present a case of a 75-year-old woman with Austrian syndrome: pneumonia, meningitis and endocarditis all due to Transoesophageal echocardiogram demonstrated a large...
We present a case of a 75-year-old woman with Austrian syndrome: pneumonia, meningitis and endocarditis all due to Transoesophageal echocardiogram demonstrated a large mitral valve vegetation with severe mitral regurgitation. She was treated with intravenous ceftriaxone and listed for surgical repair of her mitral valve. Preoperatively, she developed an idiosyncratic drug-induced agranulocytosis secondary to ceftriaxone, which resolved on cessation of the medication. However, while awaiting neutrophil recovery, she developed an acute deterioration, becoming critically unwell. This deterioration was multifactorial, with acute decompensated heart failure alongside COVID-19. After multidisciplinary discussion, she was considered too unwell for surgery and palliated.
Topics: Aged; Agranulocytosis; Anti-Bacterial Agents; COVID-19; Ceftriaxone; Comorbidity; Echocardiography, Transesophageal; Endocarditis, Bacterial; Female; Humans; Meningitis, Bacterial; Pandemics; Pneumococcal Infections; SARS-CoV-2; Streptococcus pneumoniae; Syndrome
PubMed: 33408111
DOI: 10.1136/bcr-2020-239355 -
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