Kaempferol 3-O-Rutinoside, a Flavone Derived from Tetrastigma hemsleyanum Diels et Gilg, Reduces Body Temperature through Accelerating the Elimination of IL-6 and TNF-α in a Mouse Fever Model.

Fever is a serious condition that can lead to various consequences ranging from prolonged illness to death. Tetrastigma hemsleyanum Diels et Gilg (T. hemsleyanum) has been used for centuries to treat fever, but the specific chemicals responsible for its antipyretic effects are not well understood. This study aimed to isolate and identify the chemicals with antipyretic bioactivity in T. hemsleyanum extracts and to provide an explanation for the use of T. hemsleyanum as a Chinese herbal medicine for fever treatment. Our results demonstrate that kaempferol 3-rutinoside (K3OR) could be successfully isolated and purified from the roots of T. hemsleyanum. Furthermore, K3OR exhibited a significant reduction in rectal temperature in a mouse model of fever. Notably, a 4 µM concentration of K3OR showed more effective antipyretic effects than ibuprofen and acetaminophen. To explore the underlying mechanism, we conducted an RNA sequencing analysis, which revealed that PXN may act as a key regulator in the fever process induced by lipopolysaccharide (LPS). In the mouse model of fever, K3OR significantly promoted the secretion of IL-6 and TNF-α during the early stage in the LPS-treated group. However, during the middle to late stages, K3OR facilitated the elimination of IL-6 and TNF-α in the LPS-treated group. Overall, our study successfully identified the chemicals responsible for the antipyretic bioactivity in T. hemsleyanum extracts, and it answered the question as to why T. hemsleyanum is used as a traditional Chinese herbal medicine for treating fever. These findings contribute to a better understanding of the therapeutic potential of T. hemsleyanum in managing fever, and they provide a basis for further research and development in this field.

Intranasal delivery of herbal medicine for disease treatment: A systematic review.

BACKGROUND: Intranasal administration has been adopted in traditional medicine to facilitate access to the bloodstream and central nervous system (CNS). In modern medicine, nasal drug delivery systems are valuable for disease treatment because of their noninvasiveness, good absorption, and fast-acting effects. OBJECTIVE: This study aimed to systematically organize preclinical and clinical studies on intranasal herbal medicines to highlight their potential in drug development. METHODS: A comprehensive search for literature until February 2023 was conducted on PubMed and the Web of Science. From the selected publications, we extracted key information, including the types of herbal materials, target diseases, intranasal conditions, methods of toxicity evaluation, main outcomes, and mechanisms of action, and performed quality assessments for each study. RESULTS: Of the 45 studies, 13 were clinical and 32 were preclinical; 28 studies used herbal extracts, 9 used prescriptions, and 8 used natural compounds. The target diseases were rhinosinusitis, influenza, fever, stroke, migraine, insomnia, depression, memory disorders, and lung cancer. The common intranasal volumes were 8-50 µl in mice, 20-100 µl in rats, and 100-500 µl in rabbits. Peppermint oil, Ribes nigrum folium, Melia azedarach L., Elaeocarpus sylvestris, Radix Bupleuri, Da Chuan Xiong Fang, Xingnaojing microemulsion, and Ginsenoside Rb1 emerged as potential candidates for rapid intranasal therapy. The in vivo toxicity assessments were based on mortality, body weight, behavioral changes, mucociliary activity, histopathology, and blood tests. Most intranasal treatments were safe, except for Cyclamen europaeum, Jasminum sambac, Punica granatum L., and violet oil, which caused mild adverse effects. At lower doses, intranasal herbal treatments often show greater effects than oral administration. The actions of intranasal herbal medicine mainly involve regulating inflammation and neurotransmission, with the olfactory bulb and anterior cingulate cortex to be relevant brain regions. CONCLUSION: Intranasal delivery of herbal materials holds promise for enhancing drug delivery efficacy and reducing treatment duration, offering a potential future perspective for developing intranasal therapies for various diseases.

Improving Time to Antibiotic Administration for Pediatric Oncology Patients With New-Onset Fever.

PURPOSE: Time to antibiotic administration (TTA) in <60 minutes for children with neutropenic fever presenting to an emergency room is associated with reduced incidence of sepsis and intensive care admission. As such, TTA is used as a national quality metric for pediatric oncology patients. At our center, in 2020, 19% of the hospitalized patients with a new fever encounter were receiving antibiotics in <60 minutes, prompting a multidisciplinary approach to reach a goal of >90% in all pediatric patients with cancer with a new fever. METHODS: A multidisciplinary team completed four Plan-Do-Study-Act cycles between March 2021 and September 2023. We implemented education initiatives, an updated handoff smartphrase guiding the on-call team, an antibiotic champion (AC) nursing role, a revised fever plan for handoff, a rapid-response team to address new fevers, and an algorithm for blood culture collection. Data were collected, analyzed, and reported biweekly with feedback sought for delays in TTA. RESULTS: There was a total of 639 new fevers in 329 unique oncology patients. As of September 4, 2023, average TTA decreased from 89 minutes at baseline to 46.4 minutes for more than 12 months. The percentage of patients receiving first dose of antibiotic in <60 minutes also increased from 19% to 93.7%, which was sustained as well. The most effective interventions were creation of the AC role and streamlining the blood culture collection process. CONCLUSION: This project demonstrates the importance of multidisciplinary involvement for providing optimal care. Specific implementation of targeted education, an AC role, and development of an algorithm streamlining the processes led to meaningful targeted improvements. Further analyses will explore the impact of these interventions on patient outcomes.

Metagenomic next-generation sequencing, instead of procalcitonin, could guide antibiotic usage in patients with febrile acute necrotizing pancreatitis: a multicenter, prospective cohort study.

BACKGROUNDS: The effectiveness of procalcitonin-based algorithms in guiding antibiotic usage for febrile acute necrotizing pancreatitis (ANP) remains controversial. Metagenomic next-generation sequencing (mNGS) has been applied to diagnose infectious diseases. The authors aimed to evaluate the effectiveness of blood mNGS in guiding antibiotic stewardship for febrile ANP. MATERIALS AND METHODS: The prospective multicenter clinical trial was conducted at seven hospitals in China. Blood samples were collected during fever (T ≥38.5°C) from ANP patients. The effectiveness of blood mNGS, procalcitonin, and blood culture in diagnosing pancreatic infection was evaluated and compared. Additionally, the real-world utilization of antibiotics and the potential mNGS-guided antimicrobial strategy in febrile ANP were also analyzed. RESULTS: From May 2023 to October 2023, a total of 78 patients with febrile ANP were enrolled and 30 patients (38.5%) were confirmed infected pancreatic necrosis (IPN). Compared with procalcitonin and blood culture, mNGS showed a significantly higher sensitivity rate (86.7% vs. 56.7% vs. 26.7%, P <0.001). Moreover, mNGS outperformed procalcitonin (89.5 vs. 61.4%, P <0.01) and blood culture (89.5 vs. 69.0%, P <0.01) in terms of negative predictive value. Blood mNGS exhibited the highest accuracy (85.7%) in diagnosing IPN and sterile pancreatic necrosis, significantly superior to both procalcitonin (65.7%) and blood culture (61.4%). In the multivariate analysis, positive blood mNGS (OR=60.2, P <0.001) and lower fibrinogen level (OR=2.0, P <0.05) were identified as independent predictors associated with IPN, whereas procalcitonin was not associated with IPN, but with increased mortality (Odds ratio=11.7, P =0.006). Overall, the rate of correct use of antibiotics in the cohort was only 18.6% (13/70) and would be improved to 81.4% (57/70) if adjusted according to the mNGS results. CONCLUSION: Blood mNGS represents important progress in the early diagnosis of IPN, with particular importance in guiding antibiotic usage for patients with febrile ANP.

Long-term nivolumab treatment possibly associated with aseptic meningitis.

Nivolumab is a programmed death-1 receptor blocker within the family of medications called immune checkpoint inhibitors (ICIs). Although generally well tolerated, cases of immune-related adverse events (irAEs) have been reported. We present a case of a man being treated with nivolumab for renal cell carcinoma who presented to the emergency department with problems of headache, fever and disorientation. After extensive evaluation, a diagnosis of immunotherapy-induced aseptic meningitis was considered more probable than infectious. Due to stable clinical status, no treatment was initiated, and the patient's condition improved spontaneously. The patient was discharged home. To date, only a handful of prior cases of nivolumab-induced meningitis have been reported. Our case demonstrates that irAEs can occur years after the initiation of ICIs. This was a milder presentation of a neurological irAE that resolved spontaneously with watchful waiting, showing that irAEs are likely an evolving spectrum of disease for which clinicians should be aware.

Monitoring the efficacy of antibiotic therapy in febrile pediatric oncology patients with bacteremia using infrared spectroscopy of white blood cells-based machine learning.

Bacteremia refers to the presence of bacteria in the bloodstream, which can lead to a serious and potentially life-threatening condition. In oncology patients, individuals undergoing cancer treatment have a higher risk of developing bacteremia due to a weakened immune system resulting from the disease itself or the treatments they receive. Prompt and accurate detection of bacterial infections and monitoring the effectiveness of antibiotic therapy are essential for enhancing patient outcomes and preventing the development and dissemination of multidrug-resistant bacteria. Traditional methods of infection monitoring, such as blood cultures and clinical observations, are time-consuming, labor-intensive, and often subject to limitations. This manuscript presents an innovative application of infrared spectroscopy of leucocytes of pediatric oncology patients with bacteremia combined with machine learning to diagnose the etiology of infection as bacterial and simultaneously monitor the efficacy of the antibiotic therapy in febrile pediatric oncology patients with bacteremia infections. Through the implementation of effective monitoring, it becomes possible to promptly identify any indications of treatment failure. This, in turn, indirectly serves to limit the progression of antibiotic resistance. The logistic regression (LR) classifier was able to differentiate the samples as bacterial or control within an hour, after receiving the blood samples with a success rate of over 95 %. Additionally, initial findings indicate that employing infrared spectroscopy of white blood cells (WBCs) along with machine learning is viable for monitoring the success of antibiotic therapy. Our follow up results demonstrate an accuracy of 87.5 % in assessing the effectiveness of the antibiotic treatment.

Clinical diagnosis and outcome of cervicofacial cellulitis in pyrexic rabbits: six cases (2014-2021).

OBJECTIVES: To assess the signalment, history, exam findings, diagnostics, treatment and outcome of rabbits diagnosed with pyrexia and concurrent cervicofacial cellulitis. MATERIALS AND METHODS: Retrospective evaluation of medical records of rabbits diagnosed with cervicofacial cellulitis and pyrexia based on physical exam, contrast-enhanced CT, clinicopathology and microbiology findings. RESULTS: Six out of 1588 rabbits met the study inclusion criteria. Rabbits presented with a median age of 6 years (range, 8 months to 8 years) with a presenting complaint of anorexia or hyporexia. All rabbits had a rectal temperature >40.2°C (104.4°F). Physical exam and contrast-enhanced CT revealed unilateral submandibular and ipsilateral cervical diffuse soft tissue swelling in five of six rabbits. No antemortem evidence of periodontal or dental disease was found on physical exam or CT. Leucopenia was present in five of six rabbits. A left shift with marked toxic changes was present in all four rabbits, for which blood smears were reviewed. Bacterial cultures of the aspirated subcutaneous soft tissue swelling cultured Escherichia coli, Pasteurella multocida, Granulicatella adiacens, Streptococcus species, Haemophilus species and Bacteroides species. Treatment was pursued in five rabbits, where all rabbits received supportive care and four of five rabbits received systemic antibiotics. One rabbit was euthanased following a diagnosis of cervicofacial cellulitis. Three out of five rabbits continued to decline clinically despite medical management, and thus, euthanasia was pursued within 24 hours of starting treatment. Two rabbits responded to initial treatment and developed subsequent multi-focal abscessation. One rabbit was euthanased due to client cost constraints, and one rabbit died shortly after achieving clinical resolution of cervicofacial cellulitis. CLINICAL SIGNIFICANCE: Cervicofacial cellulitis should be considered a differential diagnosis in pyrexic rabbits with facial or cervical swelling with medical and surgical management pursued for therapy.

Cleavage-resistant RIPK1-induced autoinflammatory syndrome-A report of three generations with periodic fever and clinical response to colchicine.

The clinical syndrome caused by cleavage-resistant RIPK1 is known as CRIA (Cleavage-resistant RIPK1-induced autoinflammatory) syndrome. We present a family with three generations affected by CRIA syndrome. Our index patient (P1), a boy born of a non-consanguineous marriage, developed recurrent episodes of fever after 5 months of age, with variable periodicity. His father (P2) and paternal grandmother also had periodic fever. At 23 months of age, P1 was diagnosed with renal biopsy-proven steroid-responsive nephrotic syndrome. His first visit to our center was at 2 years of age. At presentation, he had failure to thrive, microcytic hypochromic anemia, and elevated inflammatory markers and interleukin-6 levels. Amyloid A protein was elevated, serum creatinine was normal, and proteinuria resolved after addition of steroids. Next-generation sequencing showed heterozygous mutation (c.970G>A, p.Asp324His) in RIPK1. This mutation has been reported to cause CRIA syndrome. P2 and P1's asymptomatic younger brother had the same mutation. All the affected members showed variability with respect to frequency and duration of periodic fever as well as the age of onset. Both P1 and P2 had elevated amyloid A, with no evidence of renal dysfunction. P1 and P2 showed improvement in the intensity of fever spikes with colchicine treatment; however, both continue to have periodic fever.

[Neutropenia - when is GCSF support indicated?] / Neutropenie ­ wann ist eine GCSF Unterstützung notwendig?

Many systemic treatments used in genitourinary oncology negatively affect haematopoiesis, thus leading to neutropenia. Neutropenic patients are vulnerable to bacterial, and other infections. Often fever is the only symptom in these patients. Neutropenic fever is a major threat for these patients, as it may lead to life-threatening therapy complications that significantly impair the patient's quality of life, Moreover, it may also worsen the prognosis due to therapy delays or necessary dose modifications. Granulocyte colony stimulating factors (GCSF), which can improve neutrophil granulocyte formation, are used both for supportive treatment in febrile neutropenia and for its prophylaxis. The correct indication for such GCSF support depends on the general risk of febrile neutropenia of the therapy used, as well as on individual patient factors and the treatment intent (palliative vs. curative). Based on the current recommendations both of the German and international guidelines, this article aims to provide an up-to-date and practice-oriented overview of the use of GCSF in uro-oncology.

Dissecting bloodstream infections in febrile neutropenic patients with hematological malignancies, a decade-long single center retrospective observational study (2009-2019).

BACKGROUND: The use of ill-suited antibiotics is a significant risk factor behind the increase in the mortality, morbidity, and economic burden for patients who are under treatment for hematological malignancy (HM) and bloodstream infections (BSI). Such unfitting treatment choices intensify the evolution of resistant variants which is a public health concern due to possible healthcare-associated infection spread to the general population. Hence, this study aims to evaluate antibiograms of patients with BSI and risk factors associated with septicemia. METHODS: A total of 1166 febrile neutropenia episodes (FNE) among 513 patients with HM from the National Center for Cancer Care and Research (NCCCR), Qatar, during 2009-2019 were used for this study. The socio-demographic, clinical, microbial, and anti-microbial data retrieved from the patient's health records were used. RESULTS: We analyzed the sensitivity of gram-negative and gram-positive bacilli reported in HM-FN-BSI patients. Out of the total 512 microorganisms isolated, 416 (81%) were gram-negative bacteria (GNB), 76 (15%) were gram-positive bacteria (GPB) and 20 (4%) were fungi. Furthermore, in 416 GNB, 298 (71.6%) were Enterobacteriaceae sp. among which 121 (41%) were ESBL (Extended Spectrum Beta-Lactamase) resistant to Cephalosporine third generation and Piperacillin-Tazobactam, 54 (18%) were Carbapenem-resistant or multidrug-resistant organism (MDRO). It's noteworthy that the predominant infectious agents in our hospital include E. coli, Klebsiella species, and P. aeruginosa. Throughout the study period, the mortality rate due to BSI was 23%. Risk factors that show a significant correlation with death are age, disease status, mono or polymicrobial BSI and septic shock. CONCLUSION: Decision pertaining to the usage of antimicrobials for HM-FN-BSI patients is a critical task that relies on the latest pattern of prevalence, treatment resistance, and clinical outcomes. Analysis of the antibiogram of HM-FN-BSI patients in Qatar calls for a reconsideration of currently followed empirical antibiotic therapy towards better infection control and antimicrobial stewardship.

Case Report: A case of TAFRO syndrome with severe and prolonged thrombocytopenia: diagnostic pitfalls.

Thrombocytopenia, anasarca, myelofibrosis, renal dysfunction, and organomegaly (TAFRO) syndrome is a rare condition with diverse clinical and pathological characteristics related to multi-organ damage. We report a case of TAFRO syndrome complicated by immune thrombocytopenia with prolonged fever and thrombocytopenia for several weeks. A 61-year-old man was transferred with sepsis caused by Enterococcus faecalis, and developed disseminated intravascular coagulation. Antibiotics treatment was initiated: however, low-grade fever and thrombocytopenia persisted despite the adequate antimicrobial treatment. Systemic edema, pleural effusion, and ascites had developed before hospitalization, and renal and liver function had deteriorated, resulting in progressive multi-organ damage. Prednisolone 40 mg/day was initiated based on the assumption of a condition in which excessive production of inflammatory cytokines would lead to systemic deterioration and fatal organ damage. Subsequently, the fever resolved, and renal function began to normalize. However, thrombocytopenia did not show much recovery trend after Helicobacter pylori eradication therapy and initiation of thrombopoietin receptor agonists. Bone marrow biopsy results showed normal bone marrow with no malignant findings. Alternatively, significant clinical signs met the diagnostic criteria for TAFRO syndrome, and a renal biopsy revealed thrombotic microangiopathy, which is also reasonable for renal involvement in TAFRO syndrome. The use of cyclosporine remarkably corrected the thrombocytopenia. We considered this a case of TAFRO syndrome that developed after sepsis with disseminated intravascular coagulation and performed the differential diagnosis of prolonged thrombocytopenia and excluded it. Although TAFRO syndrome is a unique disease concept, diagnostic criteria may consist of nonspecific elements such as generalized edema, thrombocytopenia, persistent fever, and elevated inflammatory response, and there are many differential conditions to exclude, requiring caution in diagnosing TAFRO syndrome.

[Time to Antibiotics (TTA) - Reassessment from the German Working Group for Fever and Neutropenia in Children and Adolescents (DGPI/GPOH)]. / Time to Antibiotics (TTA) ­ Überlegungen der Arbeitsgruppe Fieber bei Granulozytopenie im Kindes- und Jugendalter (GPOH/DGPI) zu einer Neubewertung.

BACKGROUND: The current German guidance from 2016 recommends a Time to Antibiotics (TTA) of<60 min in children and adolescents with febrile neutropenia (FN). METHODS: Critical analysis of available studies and recent meta-analyses, and discussion of the practical consequences in the FN working group of the German Societies for Paediatric Oncology and Haematology and Paediatric Infectious Diseases. RESULTS: The available evidence does not support a clinically significant outcome benefit of a TTA<60 min in all paediatric patients with FN. Studies suggesting such a benefit are biased (mainly triage bias), use different TTA definitions and display further methodical limitations. In any case, a TTA<60 min remains an essential component of the 1st hour-bundle in paediatric cancer patients with septic shock or sepsis with organ dysfunction. CONCLUSION: Provided that all paediatric FN patients receive a structured medical history and physical examination (including vital signs) by experienced and trained medical personnel in a timely fashion, and provided that a sepsis triage and management bundle is established and implemented, a TTA lower than 3 hours is sufficient and reasonable in stable paediatric cancer patients with FN.

Short-Course Empiric Antibiotics in Children Undergoing Allogeneic Hematopoietic Cell Transplantation.

Fever is common in children undergoing hematopoietic cell transplantation (HCT). Empiric antibiotic (EA) therapy is initiated and often continued until neutrophil engraftment. Prolonged antibiotic exposure reduces microbiome diversity and causes overgrowth of pathogenic organisms, leading to such complications as infections from antibiotic-resistant organisms and Clostridium difficile colitis. Shorter courses of EA therapy have been studied in adults undergoing HCT without significant safety concerns, but data in children are lacking. We instituted a single-center preintervention/ postintervention quality improvement (QI) project to assess the feasibility of short-course EA therapy for first fever in patients undergoing HCT. We aimed to reduce the median duration of broad-spectrum antibiotic use in eligible patients from 20 days in 2020 to 10 days in 2021. Patients were eligible for the intervention, limiting EAs to 7 days for first fever, if they were admitted for their first allogeneic HCT, were afebrile for >24 hours, had no infection requiring systemic treatment, and were hemodynamically stable. Outcome measures included days of EA therapy for first fever and total broad-spectrum antibiotic use during the period of hospitalization, defined as the time from the start of conditioning to 30 days after HCT or hospital discharge, whichever occurred first. Balancing measures included bloodstream infection (BSI), fever, and intensive care (ICU) admission within 3 days of stopping EA therapy. Project criteria were applied retrospectively to patients who underwent HCT in 2020 to construct a preintervention short-course-eligible cohort. During the intervention period, 41 patients underwent allogeneic HCT, of whom 17 (41%) were eligible for short-course EA therapy. Among eligible patients, the median age was 5.3 years, 47% had an underlying malignancy, and 88% received myeloablative conditioning. There were no differences in demographic or HCT characteristics between patients eligible for short-course EA during the intervention and preintervention period (n = 24). The short-course EA schedule was adhered to by 14 of the 17 eligible patients (82%). The duration of EA for first fever and total broad-spectrum antibiotic use was significantly decreased in the short-course EA-eligible patients compared to the preintervention cohort, from a median of 17 days to 8 days and from 20 days to 10 days, respectively (P < .01). Of the 14 patients adhering to short-course EA, 2 experienced a balancing measure of recurrent fever requiring resumption of EA, but no infection was identified. There were no BSIs, ICU admissions, or deaths during the hospitalization period in patients who received short-course EA. In this single-center QI project, short-course EA for initial fever was successfully applied to children undergoing allogeneic HCT using strict criteria and led to a significant decrease in broad-spectrum antibiotic use during hospitalization. These results should be validated in a prospective clinical trial to include the impact of short-course EA on antibiotic-resistant organisms, the intestinal microbiome, and HCT outcomes.

Treatment of fever and associated symptoms in the emergency department: which drug to choose?

OBJECTIVE: Fever is a frequent cause of admission to the Emergency Department (ED) worldwide. Although it can be caused by a wide range of conditions, the most effective treatment based on its etiology is still undetermined. PATIENTS AND METHODS: This prospective, single-center, observational study enrolled adult patients who accessed the ED for fever. Physicians were free to administer paracetamol 1,000 mg (P), the combination paracetamol 500 mg/ibuprofen 150 mg (PI) or Ibuprofen 600 mg (I). The primary endpoint was both 1-degree and 1-point reduction in body temperature for all associated symptoms on the Numerical Rating Scale (NRS) after 1 hour (T1). The secondary endpoint was the reduction of at least 2 points on the NRS after two hours (T2). Adverse events, the need for rescue therapy, and the response based on the underlying etiology (bacterial, viral, or immune/neoplastic) were also evaluated. RESULTS: 324 patients (170 males, mean age 71±6 years) were enrolled: 187 had bacterial, 80 viral, and 57 neoplastic/inflammatory fever. Fever was treated with Paracetamol 1,000 mg (P) in 189 patients and with Paracetamol/Ibuprofen 500/150 mg (PI) in 135 subjects, while none of the patients were primarily treated with I. Based on the fever etiology P was administered to 113 patients with bacterial fever (59.8%), 48 patients with viral fever (25.4%), and 28 subjects with neoplastic/inflammatory fever (14.8%). PI was administered to 74 patients with bacterial fever (54.8%), 32 patients with viral fever (23.7%), and 29 subjects with neoplastic/inflammatory fever (21.5%). The primary endpoint was achieved by 126 patients, 70 of them (37.0%) were treated with P and 56 (41.5%) with PI (p=0.418). The secondary endpoint was achieved by 295 patients, 171 (90.5%) of them treated with P and 124 (91.9%) treated with PI (p=0.669). No significant differences were found between groups treated with P and PI concerning rescue therapy (15 vs. 6 patients; p=0.893). Interestingly, PI was more effective than P in patients with bacterial fever at T1 (P 33.6% vs. PI 48.6%; p=0.040), while efficacy of P and PI was similar at T2 for all kind of fever. CONCLUSIONS: Paracetamol 1,000 mg represents the first choice for the treatment of fever in the ED, followed by Paracetamol/Ibuprofen 500/150 mg. Interestingly, Paracetamol/Ibuprofen combination resulted in being more effective in patients with bacterial fever one hour after its administration.

Early Antibiotic Deescalation and Discontinuation in Patients with Febrile Neutropenia after Cellular Therapy: A Single-Center Prospective Unblinded Randomized Trial.

The optimal duration of empiric antimicrobial therapy of febrile neutropenia in patients after cellular therapy is unclear. Early deescalation has been suggested by some authorities; however, data are lacking for cellular therapy recipients. We performed a randomized controlled study of cellular therapy recipients with febrile neutropenia to evaluate the safety and noninferiority of an early deescalation and discontinuation antibiotic strategy (EDD arm) versus standard broad-spectrum antibiotic treatment until recovery of neutropenia (standard duration arm). The primary outcome was the fraction of antibiotic-free neutropenia days. We randomized 110 patients to the standard duration arm (n = 51) or EDD arm (n = 59). The fraction of antibiotic-free neutropenia days was higher in the EDD arm compared to the standard duration arm (median, .8 [interquartile range (IQR), .62 to .86] versus .51 [IQR, .17 to .86]; P = .016). This was true for the per-protocol, allogeneic hematopoietic cell transplantation (HCT), autologous HCT, and anti-CD19 chimeric antigen receptor T cell therapy subgroups. Treatment success rate, subsequent fever, death within 30 days, and other common cellular therapy-related toxicities were all similar between the 2 study arms. An EDD antibiotic strategy in patients after cellular therapy was safe and associated with a substantial reduction in broad-spectrum antibiotic utilization without compromising cellular therapy outcomes.

Noninfectious causes of fever in hematologic malignancies. Are antibiotics still indicated?

PURPOSE OF REVIEW: Fever is a common manifestation of both infectious and noninfectious processes in recipients of hematopoietic cell transplantation (HCT) and chimeric antigen receptor T-cell (CAR-T) therapy. Understanding the diverse causes of fever in these settings allows for accurate diagnosis and optimal use of antibiotics. RECENT FINDINGS: Herein we review common noninfectious syndromes seen in HCT and CAR-T recipients and discuss best practices in the management of these complex clinical scenarios regarding diagnosis and antibiotic use. In recent years, adverse effects of antimicrobials have highlighted the importance of antimicrobial stewardship in HCT and CAR-T patients, and an antibiotic de-escalation strategy is a safe and important tool in mitigating these adverse events, even in patients with ongoing neutropenia who become afebrile without a known infection. Common adverse events associated with antibiotics include an increased risk of Clostridiodes difficile infection (CDI), a higher incidence of multidrug-resistant organisms (MDROs), and microbiome dysbiosis. SUMMARY: Clinicians should be aware of noninfectious causes of fever in these immunocompromised patients and utilize best antibiotic practices while managing these patients.

An Update on Familial Mediterranean Fever.

(1) Background: Familial Mediterranean Fever (FMF) is the prototypal autoinflammatory disease, characterized by recurrent bursts of neutrophilic inflammation. (2) Methods: In this study we look at the most recent literature on this condition and integrate it with novel information on treatment resistance and compliance. (3) Results: The canonical clinical presentation of FMF is in children with self-limited episodes of fever and polyserositis, associated with severe long-term complications, such as renal amyloidosis. It has been described anecdotally since ancient times, however only recently it has been characterized more accurately. We propose an updated overview on the main aspects of pathophysiology, genetics, diagnosis and treatment of this intriguing disease. (4) Conclusions: Overall, this review presents the all the main aspects, including real life outcome of the latest recommendation on treatment resistance of FMF, a disease, that not only helped understanding the pathophysiology of the auto inflammatory process but also the functioning of the innate immune system itself.

A case of Robinsoniella peoriensis bacteremia during using piperacillin-tazobactam.

Infections caused by Robinsoniella peoriensis, particularly bacteremia, are rare, of which only six cases were reported R. peoriensis bloodstream infections. This case report describes an instance of R. peoriensis bacteremia arising while we treated the patient with piperacillin-tazobactam. We treated an 84-year-old female patient with peritoneal carcinoma and febrile neutropenia using piperacillin-tazobactam. The patient's fever subsided. However, she developed a fever again on the fourth day of treatment with piperacillin-tazobactam. Blood cultures taken at this time were positive for R. peoriensis. We substituted meropenem and vancomycin for piperacillin-tazobactam, after which the patient improved. We administered meropenem and vancomycin for 17 days. There is currently no appropriate established treatment for R. peoriensis. In this case, we isolated R. peoriensis from blood cultures using piperacillin-tazobactam, although it was susceptible to piperacillin-tazobactam in vitro. Therefore, monotherapy with penicillins, especially piperacillin-tazobactam, may not be sufficient for R. peoriensis infections, although it was susceptible in vitro. Carbapenem may be effective in the treatment of R. peoriensis bloodstream infections.

A Protocol for Low-Input RNA-Sequencing of Patients with Febrile Neutropenia Captures Relevant Immunological Information.

Improved methods are needed for diagnosing infectious diseases in children with cancer. Most children have fever for other reasons than bacterial infection and are exposed to unnecessary antibiotics and hospital admission. Recent research has shown that host whole blood RNA transcriptomic signatures can distinguish bacterial infection from other causes of fever. Implementation of this method in clinics could change the diagnostic approach for children with cancer and suspected infection. However, extracting sufficient mRNA to perform transcriptome profiling by standard methods is challenging due to the patient's low white blood cell (WBC) counts. In this prospective cohort study, we succeeded in sequencing 95% of samples from children with leukaemia and suspected infection by using a low-input protocol. This could be a solution to the issue of obtaining sufficient RNA for sequencing from patients with low white blood cell counts. Further studies are required to determine whether the captured immune gene signatures are clinically valid and thus useful to clinicians as a diagnostic tool for patients with cancer and suspected infection.