45 research outputs found
Anakinra for the treatment of COVID-19 patients: a systematic review and meta-analysis
Background
At the end of 2021, the European Medicines Agency (EMA) expanded its approval for the recombinant
human interleukinâ1 (ILâ1) receptor antagonist Anakinra for the treatment of COVIDâ19 patients with elevated soluble
urokinase plasminogen activator receptor (suPAR). However, the role of Anakinra in COVIDâ19 remains unanswered,
especially in patients receiving different forms of respiratory support. Therefore, the objective of this systematic review
is to assess the safety and effects of Anakinra compared to placebo or standard care alone on clinical outcomes in
adult hospitalized patients with SARSâCoVâ2 infection.
Methods
We searched the Cochrane COVIDâ19 Study Register (comprising MEDLINE, Embase, ClinicalTrials.gov, WHO
International Clinical Trials Registry Platform, medRxiv, and the Cochrane Central Register of Controlled Trials (CCSR))
and the WHO COVIDâ19 Global literature on coronavirus disease database to identify completed and ongoing studies
from inception of each database to December 13, 2021. Since then, we monitored new published studies weekly up
to June 30, 2022 using the CCSR. We included RCTs comparing treatment with Anakinra to placebo or standard care
alone in adult hospitalized patients with SARSâCoVâ2 infection.
Results
We included five RCTs with 1,627 patients (nAnakinra = 888, ncontrol = 739, mean age 59.63 years, 64% male).
Randomâeffects metaâanalysis was used to pool data. We found that Anakinra makes little or no difference to allâcause
mortality at up to day 28 compared to placebo or standard care alone (RR 0.96, 95% CI 0.64â1.45; RD 9 fewer per 1000,
95% CI 84 fewer to 104 more; 4 studies, 1593 participants; I2 = 49%; low certainty of evidence).
Conclusions
Anakinra has no effect on adult hospitalized patients with SARSâCoVâ2 infection regarding mortality,
clinical improvement and worsening as well as on safety outcomes compared to placebo or standard care alone.
Trial Registration: PROSPERO Registration Number: CRD42021257552.Peer Reviewe
Outpatient decolonization after recurrent skin infection with Panton-Valentine leukocidin (PVL)-producing S. aureus - The importance of treatment repetition
Background: Recurrent skin abscesses are often associated with Panton-Valentine leukocidin-producing strains of S. aureus (PVL-SA). Decolonization measures are required along with treatment of active infections to prevent re-infection and spreading. Even though most PVL-SA patients are treated as outpatients, there are few studies that assess the effectiveness of outpatient topical decolonization in PVL-SA patients.
Methods: We assessed the results of topical decolonization of PVL-SA in a retrospective review of patient files and personal interviews. Successful decolonization was defined as the absence of any skin abscesses for at least 6 months after completion of the final decolonization treatment. Clinical and demographic data was assessed. An intention-to-treat protocol was used.
Results: Our cohort consisted of 115 symptomatic patients, 66% from PVL-positive MSSA and 19% from PVL-positive MRSA. The remaining 16% consisted of symptomatic patients with close contact to PVL-SA positive index patients but without detection of PVL-SA. The majority of patients were female (66%). The median age was 29.87% of the patients lived in multiple person households. Our results showed a 48% reduction in symptomatic PVL-SA cases after the first decolonization treatment. The results also showed that the decrease continued with each repeated decolonization treatment and reached 89% following the 5th treatment. A built multivariable Cox proportional-hazards model showed that the absence of PVL-SA detection (OR 2.0) and living in single person households (OR 2.4) were associated with an independently increased chance of successful decolonization.
Conclusion: In our cohort, topical decolonization was a successful preventive measure for reducing the risk of PVL-SA skin abscesses in the outpatient setting. Special attention should be given to patients living in multiple person households because these settings could confer a risk that decolonization will not be successful
Development of a Model-Informed Dosing Tool to Optimise Initial Antibiotic Dosing - A Translational Example for Intensive Care Units
The prevalence and mortality rates of severe infections are high in intensive care units (ICUs). At the same time, the high pharmacokinetic variability observed in ICU patients increases the risk of inadequate antibiotic drug exposure. Therefore, dosing tailored to specific patient characteristics has a high potential to improve outcomes in this vulnerable patient population. This study aimed to develop a tabular dosing decision tool for initial therapy of meropenem integrating hospital-specific, thus far unexploited pathogen susceptibility information. An appropriate meropenem pharmacokinetic model was selected from the literature and evaluated using clinical data. Probability of target attainment (PTA) analysis was conducted for clinically interesting dosing regimens. To inform dosing prior to pathogen identification, the local pathogen-independent mean fraction of response (LPIFR) was calculated based on the observed minimum inhibitory concentrations distribution in the hospital. A simple, tabular, model-informed dosing decision tool was developed for initial meropenem therapy. Dosing recommendations achieving PTA > 90% or LPIFR > 90% for patients with different creatinine clearances were integrated. Based on the experiences during the development process, a generalised workflow for the development of tabular dosing decision tools was derived. The proposed workflow can support the development of model-informed dosing tools for initial therapy of various drugs and hospital-specific conditions
The geometrical shape of mesenchymal stromal cells measured by quantitative shape descriptors is determined by the stiffness of the biomaterial and by cyclic tensile forces
Controlling mesenchymal stromal cell (MSC) shape is a novel method for investigating and directing MSC behaviour in vitro. it was hypothesized that specifigc MSC shapes can be generated by using stiffnessĂą defined biomaterial surfaces and by applying cyclic tensile forces. Biomaterials used were thin and thick silicone sheets, fibronectin coating, and compacted collagen type I sheets. The MSC morphology was quantified by shape descriptors describing dimensions and membrane protrusions. Nanoscale stiffness was measured by atomic force microscopy and the expression of smooth muscle cell (SMC) marker genes (ACTA2, TAGLN, CNN1) by quantitative reverseĂą transcription polymerase chain reaction. Cyclic stretch was applied with 2.5% or 5% amplitudes. Attachment to biomaterials with a higher stiffness yielded more elongated MSCs with fewer membrane protrusions compared with biomaterials with a lower stiffness. For cyclic stretch, compacted collagen sheets were selected, which were associated with the most elongated MSC shape across all investigated biomaterials. As expected, cyclic stretch elongated MSCs during stretch. One hour after cessation of stretch, however, MSC shape was rounder again, suggesting loss of stretchĂą induced shape. Different shape descriptor values obtained by different stretch regimes correlated significantly with the expression levels of SMC marker genes. Values of approximately 0.4 for roundness and 3.4 for aspect ratio were critical for the highest expression levels of ACTA2 and CNN1. Thus, specific shape descriptor values, which can be generated using biomaterialĂą associated stiffness and tensile forces, can serve as a template for the induction of specific gene expression levels in MSC. Copyright Ă© 2017 John Wiley & Sons, Ltd.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141253/1/term2263.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/141253/2/term2263_am.pd
Corticosteroids as risk factor for COVID-19-associated pulmonary aspergillosis in intensive care patients
Purpose: Corticosteroids, in particular dexamethasone, are one of the primary treatment options for critically ill COVID-19 patients. However, there are a growing number of cases that involve COVID-19-associated pulmonary aspergillosis (CAPA), and it is unclear whether dexamethasone represents a risk factor for CAPA. Our aim was to investigate a possible association of the recommended dexamethasone therapy with a risk of CAPA.
Methods: We performed a study based on a cohort of COVID-19 patients treated in 2020 in our 13 intensive care units at Charite Universitatsmedizin Berlin. We used ECMM/ISHM criteria for the CAPA diagnosis and performed univariate and multivariable analyses of clinical parameters to identify risk factors that could result in a diagnosis of CAPA.
Results: Altogether, among the n = 522 intensive care patients analyzed, n = 47 (9%) patients developed CAPA. CAPA patients had a higher simplified acute physiology score (SAPS) (64 vs. 53, p < 0.001) and higher levels of IL-6 (1,005 vs. 461, p < 0.008). They more often had severe acute respiratory distress syndrome (ARDS) (60% vs. 41%, p = 0.024), renal replacement therapy (60% vs. 41%, p = 0.024), and they were more likely to die (64% vs. 48%, p = 0.049). The multivariable analysis showed dexamethasone (OR 3.110, CI95 1.112-8.697) and SAPS (OR 1.063, CI95 1.028-1.098) to be independent risk factors for CAPA.
Conclusion: In our study, dexamethasone therapy as recommended for COVID-19 was associated with a significant three times increase in the risk of CAPA
Severe infections of Panton-Valentine leukocidin positive Staphylococcus aureus in children
Infections caused by Panton-Valentine leukocidin-positive Staphylococcus aureus (PVL-SA) mostly present as recurrent skin abscesses and furunculosis. However, life-threatening infections (eg, necrotizing pneumonia, necrotizing fasciitis, and osteomyelitis) caused by PVL-SA have also been reported.We assessed the clinical phenotype, frequency, clinical implications (surgery, length of treatment in hospitals/intensive care units, and antibiotic treatments), and potential preventability of severe PVL-SA infections in children.Total, 75 children treated for PVL-SA infections in our in- and outpatient units from 2012 to 2017 were included in this retrospective study.Ten out of 75 children contracted severe infections (PVL-methicillin resistant S aureus nâ=â4) including necrotizing pneumonia (nâ=â4), necrotizing fasciitis (nâ=â2), pyomyositis (nâ=â2; including 1 patient who also had pneumonia), mastoiditis with cerebellitis (nâ=â1), preorbital cellulitis (nâ=â1), and recurrent deep furunculosis in an immunosuppressed patient (nâ=â1). Specific complications of PVL-SA infections were venous thrombosis (nâ=â2), sepsis (nâ=â5), respiratory failure (nâ=â5), and acute respiratory distress syndrome (nâ=â3). The median duration of hospital stay was 14 days (range 5-52 days). In 6 out of 10 patients a history suggestive for PVL-SA colonization in the patient or close family members before hospital admission was identified.PVL-SA causes severe to life-threatening infections requiring lengthy treatments in hospital in a substantial percentage of symptomatic PVL-SA colonized children. More than 50% of severe infections might be prevented by prompt testing for PVL-SA in individuals with a history of abscesses or furunculosis, followed by decolonization measures
Ivermectin for preventing and treating COVIDâ19
Background
Ivermectin, an antiparasitic agent used to treat parasitic infestations, inhibits the replication of viruses in vitro. The molecular hypothesis of ivermectin's antiviral mode of action suggests an inhibitory effect on severe acute respiratory syndrome coronavirus 2 (SARSâCoVâ2) replication in the early stages of infection. Currently, evidence on efficacy and safety of ivermectin for prevention of SARSâCoVâ2 infection and COVIDâ19 treatment is conflicting.
Objectives
To assess the efficacy and safety of ivermectin compared to no treatment, standard of care, placebo, or any other proven intervention for people with COVIDâ19 receiving treatment as inpatients or outpatients, and for prevention of an infection with SARSâCoVâ2 (postexposure prophylaxis).
Search methods
We searched the Cochrane COVIDâ19 Study Register, Web of Science (Emerging Citation Index and Science Citation Index), medRxiv, and Research Square, identifying completed and ongoing studies without language restrictions to 26 May 2021.
Selection criteria
We included randomized controlled trials (RCTs) comparing ivermectin to no treatment, standard of care, placebo, or another proven intervention for treatment of people with confirmed COVIDâ19 diagnosis, irrespective of disease severity, treated in inpatient or outpatient settings, and for prevention of SARSâCoVâ2 infection.
Coâinterventions had to be the same in both study arms.
We excluded studies comparing ivermectin to other pharmacological interventions with unproven efficacy.
Data collection and analysis
We assessed RCTs for bias, using the Cochrane risk of bias 2 tool. The primary analysis excluded studies with high risk of bias. We used GRADE to rate the certainty of evidence for the following outcomes 1. to treat inpatients with moderateâtoâsevere COVIDâ19: mortality, clinical worsening or improvement, adverse events, quality of life, duration of hospitalization, and viral clearance; 2. to treat outpatients with mild COVIDâ19: mortality, clinical worsening or improvement, admission to hospital, adverse events, quality of life, and viral clearance; (3) to prevent SARSâCoVâ2 infection: SARSâCoVâ2 infection, development of COVIDâ19 symptoms, adverse events, mortality, admission to hospital, and quality of life.
Main results
We found 14 studies with 1678 participants investigating ivermectin compared to no treatment, placebo, or standard of care. No study compared ivermectin to an intervention with proven efficacy. There were nine studies treating participants with moderate COVIDâ19 in inpatient settings and four treating mild COVIDâ19 cases in outpatient settings. One study investigated ivermectin for prevention of SARSâCoVâ2 infection. Eight studies had an openâlabel design, six were doubleâblind and placeboâcontrolled. Of the 41 study results contributed by included studies, about one third were at overall high risk of bias.
Ivermectin doses and treatment duration varied among included studies.
We identified 31 ongoing and 18 studies awaiting classification until publication of results or clarification of inconsistencies.
Ivermectin compared to placebo or standard of care for inpatient COVIDâ19 treatment
We are uncertain whether ivermectin compared to placebo or standard of care reduces or increases mortality (risk ratio (RR) 0.60, 95% confidence interval (CI) 0.14 to 2.51; 2 studies, 185 participants; very lowâcertainty evidence) and clinical worsening up to day 28 assessed as need for invasive mechanical ventilation (IMV) (RR 0.55, 95% CI 0.11 to 2.59; 2 studies, 185 participants; very lowâcertainty evidence) or need for supplemental oxygen (0 participants required supplemental oxygen; 1 study, 45 participants; very lowâcertainty evidence), adverse events within 28 days (RR 1.21, 95% CI 0.50 to 2.97; 1 study, 152 participants; very lowâcertainty evidence), and viral clearance at day seven (RR 1.82, 95% CI 0.51 to 6.48; 2 studies, 159 participants; very lowâcertainty evidence). Ivermectin may have little or no effect compared to placebo or standard of care on clinical improvement up to 28 days (RR 1.03, 95% CI 0.78 to 1.35; 1 study; 73 participants; lowâcertainty evidence) and duration of hospitalization (mean difference (MD) â0.10 days, 95% CI â2.43 to 2.23; 1 study; 45 participants; lowâcertainty evidence). No study reported quality of life up to 28 days.
Ivermectin compared to placebo or standard of care for outpatient COVIDâ19 treatment
We are uncertain whether ivermectin compared to placebo or standard of care reduces or increases mortality up to 28 days (RR 0.33, 95% CI 0.01 to 8.05; 2 studies, 422 participants; very lowâcertainty evidence) and clinical worsening up to 14 days assessed as need for IMV (RR 2.97, 95% CI 0.12 to 72.47; 1 study, 398 participants; very lowâcertainty evidence) or nonâIMV or high flow oxygen requirement (0 participants required nonâIMV or high flow; 1 study, 398 participants; very lowâcertainty evidence). We are uncertain whether ivermectin compared to placebo reduces or increases viral clearance at seven days (RR 3.00, 95% CI 0.13 to 67.06; 1 study, 24 participants; lowâcertainty evidence). Ivermectin may have little or no effect compared to placebo or standard of care on the number of participants with symptoms resolved up to 14 days (RR 1.04, 95% CI 0.89 to 1.21; 1 study, 398 participants; lowâcertainty evidence) and adverse events within 28 days (RR 0.95, 95% CI 0.86 to 1.05; 2 studies, 422 participants; lowâcertainty evidence). None of the studies reporting duration of symptoms were eligible for primary analysis. No study reported hospital admission or quality of life up to 14 days.
Ivermectin compared to no treatment for prevention of SARSâCoVâ2 infection
We found one study. Mortality up to 28 days was the only outcome eligible for primary analysis. We are uncertain whether ivermectin reduces or increases mortality compared to no treatment (0 participants died; 1 study, 304 participants; very lowâcertainty evidence). The study reported results for development of COVIDâ19 symptoms and adverse events up to 14 days that were included in a secondary analysis due to high risk of bias. No study reported SARSâCoVâ2 infection, hospital admission, and quality of life up to 14 days.
Authors' conclusions
Based on the current very lowâ to lowâcertainty evidence, we are uncertain about the efficacy and safety of ivermectin used to treat or prevent COVIDâ19. The completed studies are small and few are considered high quality. Several studies are underway that may produce clearer answers in review updates. Overall, the reliable evidence available does not support the use ivermectin for treatment or prevention of COVIDâ19 outside of wellâdesigned randomized trials
Initial Experience With SARS-CoV-2-Neutralizing Monoclonal Antibodies in Kidney or Combined Kidney-Pancreas Transplant Recipients
Background: Antiviral drugs have shown little impact in patient infected with acute respiratory coronavirus 2 (SARS-CoV-2). Especially for immunocompromised persons positive for SARS-CoV-2, novel treatments are warranted. Recently, the U.S. FDA has granted an emergency use authorization (EUA) to two monoclonal antibodies (mAb) targeting the viral spike protein: bamlanivimab and casivirimab and imdevimab. As per the EUA, all SARS-CoV-2 positive organ transplant recipients can receive mAb treatment.
Patients and methods: We queried our center's transplant registry to identify SARS-CoV-2 infected recipients treated with single doses of either Bamlanivimab or casivirimab/imdevimab up to May 31, 2021. We analyzed clinical outcomes, renal function and virus-specific antibodies. The co-primary endpoints were hospitalization due to COVID-19 and SARS-CoV-2 RT-PCR negativity.
Results: Thirteen patients at a median interval of 55 (IQR, 26-110) months from transplant were treated: 8 with bamlanivimab and 5 with casivirimab/imdevimab. In all, 4/13 (31%) patients were hospitalized at some time, while 11/13 (85%) achieved PCR negativity. 2/4 hospitalized patients received mAb as rescue treatment. Overall mortality was 23%, with one death attributable to transplant-associated lymphoma. All six patients infected with the B 1.1.7 variant were alive at last contact.
Conclusion: mAb treatment appears effective when administered early to SARS-CoV-2-infected transplant recipients
CD169/SIGLEC1 is expressed on circulating monocytes in COVID-19 and expression levels are associated with disease severity
Coronavirus disease 2019 (COVID-19) is caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Type I interferons are important in the defense of viral infections. Recently, neutralizing IgG auto-antibodies against type I interferons were found in patients with severe COVID-19 infection. Here, we analyzed expression of CD169/SIGLEC1, a well described downstream molecule in interferon signaling, and found increased monocytic CD169/SIGLEC1 expression levels in patients with mild, acute COVID-19, compared to patients with severe disease. We recommend further clinical studies to evaluate the value of CD169/SIGLEC1 expression in patients with COVID-19 with or without auto-antibodies against type I interferons