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1.
Membrane Proteins, Vol. 128 ; CHAP: 289-324,
Article in English | Web of Science | ID: covidwho-2101587

ABSTRACT

Gangliosides are anionic lipids that form condensed membrane clusters (lipid rafts) and exert major regulatory functions on a wide range of proteins. In this review, we propose a new view of the structural features of gangliosides with special emphasis on emerging properties associated with protein binding modes. We analyze the different possibilities of molecular associations of gangliosides in lipid rafts and the role of cholesterol in this organization. We are particularly interested in amide groups of N-acetylated sugars which make it possible to neutralize the negative charge of the carboxylate group of sialic acids. We refer to this effect as "NH trick" and we demonstrate that it is operative in GM1, GD1a, GD1b and GT1b gangliosides. The NH trick is key to understand the different topologies adopted by gangliosides (chalice-like at the edge of lipid rafts, condensed clusters in central areas) and their impact on protein binding. We define three major types of ganglioside-binding domains (GBDs): alpha-helical, loop shaped, and large flat surface. We describe the mode of interaction of each GBD with typical reference proteins: synaptotagmin, 5HT1A receptor, cholera and botulinum toxins, HIV-1 surface envelope glycoprotein gp120, SARS-CoV-2 spike protein, cellular prion protein, Alzheimer's beta-amyloid peptide and Parkinson's disease associated alpha-synuclein. We discuss the common mechanisms and peculiarities of protein binding to gangliosides in the light of physiological and pathological conditions. We anticipate that innovative ganglioside-based therapies will soon show an exponential growth for the treatment of cancer, microbial infections, and neurodegenerative diseases.

2.
Journal of Pharmaceutical Negative Results ; 13:125-130, 2022.
Article in English | Web of Science | ID: covidwho-2072517

ABSTRACT

Objective: To investigate homogeneity and efficiency of applicating models of lung/bronchial organoids for SARS-COV2 infection research and evaluate the role of differentially expressed cytokine genes of interest. Methods: in this systematic review and meta-analysis of Gene Expression ombious datasets, studies of lung/bronchial organoids as models of SARS-COV2 infection were evaluated. 4 datasets of GSE160435, GSE148697, GSE150819, and GSE152060 were selected for our study. DESeq / EdgeR technique was used to identify Differential Expressed Genes (DEGs). Results: the distribution of the pooled dataset showed small variations among the 4 selected datasets. K-means cluster analysis using the KEGG Pathway database revealed activation of a cluster of genes in response to coronavirus diseases including 51 genes in the pathway of KEGG, that could verify the organoids in comparison of real COVID-19 disease specimens. proinflammatory cytokines and Granulocyte-macrophage colony-stimulating factors were selected as our genes of interest-based on the literature. We only found significant upregulation of TNF-alpha, IL23A, and IL17A genes and significant Dowiregulation of CSF2RB, IL20RB/A, IL24B. while downregulation of CSF2 was in controversy with reported literature. Conclusion: Based on the data that ultimately reached the conclusion of the interferon 1 function in COVID-19 pathology, this work may confirm the models of SARS-COV-2 infection in lung organoids;nevertheless, the contradiction to real-world studies requires more research.

3.
Vaccine X ; 12: 100211, 2022 Dec.
Article in English | MEDLINE | ID: covidwho-2004302

ABSTRACT

Background: Heterologous prime-boost SARS-CoV-2 vaccination is a widely accepted strategy during the COVID-19 pandemic, which generated a superior immune response than homologous vaccination strategy. Objective: To describe immunogenicity of heterologous prime-boost vaccination with inactivated vaccine, CoronaVac, followed by BNT162b2 and 5-month booster dose with BNT162b2 in healthy Thai adolescents. Methods: Adolescents aged 12-18 years were randomized 1:1:1:1 to receive CoronaVac (SV) followed by BNT162b2 (PZ) 30 or 20 µg at either 3- or 6-week interval (SV3w/PZ30µg, SV3w/PZ20µg, SV6w/PZ30µg or SV6w/PZ20µg). During the Omicron-predominant period, participants were offered a BNT162b2 booster dose 30, 15, or 10 µg. Immunogenicity was determined using IgG antibody against spike-receptor-binding domain of wild type(anti-S-RBD IgG) and surrogate virus neutralization test(sVNT) against Delta variant at 14 days and 5 months after the 2nd dose. Neutralization tests(sVNT and pseudovirus neutralization test; pVNT) against Omicron strain were tested pre- and 14 days post-booster dose. Results: In October 2021, 76 adolescents with a median age of 14.3 years (IQR 12.7-16.0) were enrolled: 20 in SV3w/PZ30µg; 17 in SV3w/PZ20µg; 20 in SV6w/PZ30µg; 19 in SV6w/PZ20µg. At day 14, the geometric mean(GM) of anti-S-RBD IgG in SV3w/PZ30µg was 4713 (95 %CI 4127-5382) binding-antibody unit (BAU)/ml, while geometric mean ratio(GMR) was 1.28 (1.09-1.51) in SV6w/PZ30µg. The GMs of sVNT against Delta variants at day 14 among participants in SV3w/PZ30µg and SV6wk/PZ30µg arm were 95.3 % and 99.7 %inhibition, respectively. At 5 months, GMs of sVNT against Delta variants in SV3w/PZ30µg were significantly declined to 47.8 % but remained at 89.0 % inhibition among SV6w/PZ30µg arm. In April 2022, 52 adolescents received a BNT162b2 booster dose. Proportion of participants with sVNT against Omicron strain > 80 %inhibition was significantly increased from 3.8 % pre-booster to 67 % post-booster. Proportion of participants with pVNT ID50 > 185 was 42 % at 14 days post 2nd dose and 88 % post booster, respectively. Conclusions: Heterologous prime-boost vaccination with CoronaVac followed by BNT162b2 induced high neutralizing titer against SARS-CoV-2 Delta strain. After 5-month interval, booster with BNT162b2 induced high neutralizing titer against Omicron strain.Thai Clinical Trials Registry (thaiclinicaltrials.org): TCTR20210923012.

4.
Clinicoecon Outcomes Res ; 14: 231-247, 2022.
Article in English | MEDLINE | ID: covidwho-1951748

ABSTRACT

Purpose: To estimate the clinical and economic benefits of lenzilumab plus standard of care (SOC) compared with SOC alone in the treatment of hospitalized COVID-19 patients from the National Health Service (NHS) England perspective. Methods: A cost calculator was developed to estimate the clinical benefits and costs of adding lenzilumab to SOC in newly hospitalized COVID-19 patients over 28 days. The LIVE-AIR trial results informed the clinical inputs: failure to achieve survival without ventilation (SWOV), mortality, time to recovery, intensive care unit (ICU) admission, and invasive mechanical ventilation (IMV) use. Base case costs included drug acquisition and administration for lenzilumab and remdesivir and hospital resource costs based on the level of care required. Clinical and economic benefits per weekly cohort of newly hospitalized patients were also estimated. Results: In all populations examined, specified clinical outcomes were improved with lenzilumab plus SOC over SOC treatment alone. In a base case population aged <85 years with C-reactive protein (CRP) <150 mg/L, with or without remdesivir, adding lenzilumab to SOC was estimated to result in per-patient cost savings of £1162. In a weekly cohort of 4754 newly hospitalized patients, addition of lenzilumab to SOC could result in 599 IMV uses avoided, 352 additional lives saved, and over £5.5 million in cost savings. Scenario results for per-patient cost savings included: 1) aged <85 years, CRP <150 mg/L, and receiving remdesivir (£3127); 2) Black patients with CRP <150 mg/L (£9977); and 3) Black patients from the full population (£2369). Conversely, in the full mITT population, results estimated additional cost of £4005 per patient. Conclusion: Findings support clinical benefits for SWOV, mortality, time to recovery, time in ICU, time on IMV, and ventilator use, and an economic benefit from the NHS England perspective when adding lenzilumab to SOC for hospitalized COVID-19 patients.

5.
Rev Med Interne ; 43(9): 528-536, 2022 Sep.
Article in French | MEDLINE | ID: covidwho-1931093

ABSTRACT

Anti-cytokine antibodies (ACA) are an emerging cause of acquired immunodeficiency, especially in previously healthy adults. The most frequently reported are anti-IFN-γ responsible for disseminated non-tuberculous mycobacteria infections, and anti-GM-CSF mainly in mycobacteria, cryptococcosis and nocardiosis infections. The presence of anti-IFN-α in severe COVID-19 infections has recently been described. The search for and detection of these ACAs in an unusual infection situation makes it possible to set up specific therapies in addition to the anti-infective treatment. ACAs are also frequent in various autoimmune pathologies where, in addition to being indicators of the breakdown of immune tolerance, they can modulate the activity of the disease according to their cytokine target. In this review of the literature, we will focus on the epidemiology and the clinical impact of these ACAs in healthy subjects and in infectious or dysimmune diseases.


Subject(s)
COVID-19 , Mycobacterium Infections , Adult , Autoantibodies , Cytokines , Humans , Interferon-gamma
6.
Thorax ; 2022 Jul 06.
Article in English | MEDLINE | ID: covidwho-1923310

ABSTRACT

OBJECTIVE: COVID-19 severity is correlated with granulocyte macrophage colony-stimulating factor (GM-CSF) and C reactive protein (CRP) levels. In the phase three LIVE-AIR trial, lenzilumab an anti-GM-CSF monoclonal antibody, improved the likelihood of survival without ventilation (SWOV) in COVID-19, with the greatest effect in participants having baseline CRP below a median of 79 mg/L. Herein, the utility of baseline CRP to guide lenzilumab treatment was assessed. DESIGN: A subanalysis of the randomised, blinded, controlled, LIVE-AIR trial in which lenzilumab or placebo was administered on day 0 and participants were followed through Day 28. PARTICIPANTS: Hospitalised COVID-19 participants (N=520) with SpO2 ≤94% on room air or requiring supplemental oxygen but not invasive mechanical ventilation. INTERVENTIONS: Lenzilumab (1800 mg; three divided doses, q8h, within 24 hours) or placebo infusion alongside corticosteroid and remdesivir treatments. MAIN OUTCOME MEASURES: The primary endpoint was the time-to-event analysis difference in SWOV through day 28 between lenzilumab and placebo treatments, stratified by baseline CRP. RESULTS: SWOV was achieved in 152 (90%; 95% CI 85 to 94) lenzilumab and 144 (79%; 72 to 84) placebo-treated participants with baseline CRP <150 mg/L (HR: 2.54; 95% CI 1.46 to 4.41; p=0.0009) but not with CRP ≥150 mg/L (HR: 1.04; 95% CI 0.51 to 2.14; p=0.9058). A statistically significant interaction between CRP and lenzilumab treatment was observed (p=0.044). Grade ≥3 adverse events with lenzilumab were comparable to placebo in both CRP strata. No treatment-emergent serious adverse events were attributed to lenzilumab. CONCLUSION: Hospitalised hypoxemic patients with COVID-19 with baseline CRP <150 mg/L derived the greatest clinical benefit from treatment with lenzilumab. TRIAL REGISTRATION NUMBER: NCT04351152; ClinicalTrials.gov.

7.
Vaccines (Basel) ; 10(6)2022 Jun 14.
Article in English | MEDLINE | ID: covidwho-1911693

ABSTRACT

Several approaches have produced an effective vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Since millions of people are exposed to influenza virus and SARS-CoV-2, it is of great interest to develop a two-in-one vaccine that will be able to protect against infection of both viruses. We have developed a hybrid vaccine for SARS-CoV-2 and influenza viruses using influenza virus-like particles (VLP) incorporated by protein transfer with glycosylphosphatidylinositol (GPI)-anchored SARS-CoV-2 RBD fused to GM-CSF as an adjuvant. GPI-RBD-GM-CSF fusion protein was expressed in CHO-S cells, purified and incorporated onto influenza VLPs to develop the hybrid vaccine. Our results show that the hybrid vaccine induced a strong antibody response and protected mice from both influenza virus and mouse-adapted SARS-CoV-2 challenges, with vaccinated mice having significantly lower lung viral titers compared to naive mice. These results suggest that a hybrid vaccine strategy is a promising approach for developing multivalent vaccines to prevent influenza A and SARS-CoV-2 infections.

8.
BMC Infect Dis ; 22(1): 519, 2022 Jun 04.
Article in English | MEDLINE | ID: covidwho-1879225

ABSTRACT

BACKGROUND: COVID-19 and Sexually Transmitted Diseases (STDs) are two very important diseases. However, relevant researches about how COVID-19 pandemic has impacted on the epidemiological trend of STDs are limited in China. This study aimed to analyze the impact of COVID-19 on STDs in China and proposed relevant recommendations to be used in bettering health. METHODS: The incidence of HIV infection, syphilis and gonorrhea in China from 2008 to 2020 were collected. Grey Model (1,1) were established to predict the incidence of STDs with the incidence data of these three STDs from 2013 to 2018 considering the impact of policies in China, respectively. We then calculated the predictive incidence of each STD in 2019, 2020 and 2021 by the established Model. And we estimated the extent of the impact of COVID-19 on the epidemiological changes of STDs by analyzing the difference between the absolute percentage error (APE) of the predictive incidence and actual rate in 2019 and 2020. RESULTS: The incidence of HIV infection and syphilis showed a trend of increase from 2008 to 2019 in China, but that for gonorrhea was fluctuant. Of note, the incidence of these three STDs decreased significantly in 2020 compared with that in 2019. The APE of HIV infection, syphilis and gonorrhea in 2020 (20.54%, 15.45% and 60.88%) were about 7 times, 4 times and 2 times of that in 2019 (2.94%, 4.07% and 30.41%). The incidence of HIV infection, syphilis and gonorrhea would be 5.77/100,000, 39.64/100,000 and 13.19/100,000 in 2021 based on our model. CONCLUSIONS: The epidemiological trend of STDs in China was significant influenced by COVID-19 pandemic. It is important to balance the control of COVID-19 and timely management of STDs during the COVID-19 epidemic to prevent or reduce the poor outcome among COVID-19 patients with STDs. New management strategies on STDs, such as leveraging social media, online medical care, rapid self-testing, timely diagnosis and treatment guarantee and balance of medical resources for STDs management should be adapted in the context of the long-term effects of COVID-19.


Subject(s)
COVID-19 , Gonorrhea , HIV Infections , Sexually Transmitted Diseases , Syphilis , COVID-19/epidemiology , China/epidemiology , Gonorrhea/epidemiology , Gonorrhea/prevention & control , HIV Infections/epidemiology , Humans , Pandemics , Sexually Transmitted Diseases/epidemiology , Syphilis/epidemiology , Syphilis/prevention & control
9.
Am J Respir Crit Care Med ; 205(11): 1290-1299, 2022 06 01.
Article in English | MEDLINE | ID: covidwho-1874930

ABSTRACT

Rationale: GM-CSF (granulocyte-macrophage colony-stimulating factor) has emerged as a promising target against the hyperactive host immune response associated with coronavirus disease (COVID-19). Objectives: We sought to investigate the efficacy and safety of gimsilumab, an anti-GM-CSF monoclonal antibody, for the treatment of hospitalized patients with elevated inflammatory markers and hypoxemia secondary to COVID-19. Methods: We conducted a 24-week randomized, double-blind, placebo-controlled trial, BREATHE (Better Respiratory Education and Treatment Help Empower), at 21 locations in the United States. Patients were randomized 1:1 to receive two doses of intravenous gimsilumab or placebo 1 week apart. The primary endpoint was all-cause mortality rate at Day 43. Key secondary outcomes were ventilator-free survival rate, ventilator-free days, and time to hospital discharge. Enrollment was halted early for futility based on an interim analysis. Measurements and Main Results: Of the planned 270 patients, 225 were randomized and dosed; 44.9% of patients were Hispanic or Latino. The gimsilumab and placebo groups experienced an all-cause mortality rate at Day 43 of 28.3% and 23.2%, respectively (adjusted difference = 5% vs. placebo; 95% confidence interval [-6 to 17]; P = 0.377). Overall mortality rates at 24 weeks were similar across the treatment arms. The key secondary endpoints demonstrated no significant differences between groups. Despite the high background use of corticosteroids and anticoagulants, adverse events were generally balanced between treatment groups. Conclusions: Gimsilumab did not improve mortality or other key clinical outcomes in patients with COVID-19 pneumonia and evidence of systemic inflammation. The utility of anti-GM-CSF therapy for COVID-19 remains unclear. Clinical trial registered with www.clinicaltrials.gov (NCT04351243).


Subject(s)
COVID-19 , Antibodies, Monoclonal, Humanized/therapeutic use , COVID-19/drug therapy , Double-Blind Method , Humans , Inflammation
10.
Diagnostics (Basel) ; 12(5)2022 May 12.
Article in English | MEDLINE | ID: covidwho-1855556

ABSTRACT

This research uses mathematically derived visual logistics to interpret COVID-19 molecular and rapid antigen test (RAgT) performance, determine prevalence boundaries where risk exceeds expectations, and evaluate benefits of recursive testing along home, community, and emergency spatial care paths. Mathematica and open access software helped graph relationships, compare performance patterns, and perform recursive computations. Tiered sensitivity/specificity comprise: (T1) 90%/95%; (T2) 95%/97.5%; and (T3) 100%/≥99%, respectively. In emergency medicine, median RAgT performance peaks at 13.2% prevalence, then falls below T1, generating risky prevalence boundaries. RAgTs in pediatric ERs/EDs parallel this pattern with asymptomatic worse than symptomatic performance. In communities, RAgTs display large uncertainty with median prevalence boundary of 14.8% for 1/20 missed diagnoses, and at prevalence > 33.3-36.9% risk 10% false omissions for symptomatic subjects. Recursive testing improves home RAgT performance. Home molecular tests elevate performance above T1 but lack adequate validation. Widespread RAgT availability encourages self-testing. Asymptomatic RAgT and PCR-based saliva testing present the highest chance of missed diagnoses. Home testing twice, once just before mingling, and molecular-based self-testing, help avoid false omissions. Community and ER/ED RAgTs can identify contagiousness in low prevalence. Real-world trials of performance, cost-effectiveness, and public health impact could identify home molecular diagnostics as an optimal diagnostic portal.

11.
J Med Life ; 15(2): 264-268, 2022 Feb.
Article in English | MEDLINE | ID: covidwho-1789888

ABSTRACT

There have been more than 31378143 confirmed coronavirus disease 2019 (COVID-19) cases in India. It was declared a pandemic by the World Health Organization (WHO) on March 11, 2020. Because the risk of severe COVID-19 is not consistent across all individuals, uncertainty is linked to disease development. COVID-19 results have been related to systemic inflammation as a predictor. In COVID-19, increased levels of inflammatory markers have been associated with cytokine storm, coagulopathy, and endothelial dysfunction. A significant amount of research suggests that these results have a role in the cause of death in individuals suffering from a severe form of COVID-19. We aim to show our experience of COVID-19 at GITAM Institute of Medical Sciences and Research (GIMSR), Visakhapatnam. We analyzed data on 558 patients admitted to our dedicated COVID hospital during post unlock (UL) 2.0 in India from August 2 to August 31, 2020. The mean age was 43.65 years; 69% of them were male. Using MoHFW India severity guidelines, 68.10% were mild, 18.64% were moderate, and 13.26% were severe cases. Fatigue (66.13%) was the most common complaint, followed by anosmia (63.80%), fever (57.53%), diarrhea (56.09%), shortness of breath (22.40%), and others. The most common preexisting comorbidity seen in our patients was diabetes mellitus and hypertension, respectively. Laboratory parameters revealed mean hemoglobin of 13.04±1.91 gm/dl, mean total leukocyte count of 7378.49±3229 cells/cumm, mean platelet count of 2.3±0.8 lakhs/cumm, mean erythrocyte sediment rate of 40±30 mm/hr, mean ferritin level of 335.96 ng/ml, mean D-dimer level of 794.88 ng/ml and mean CRP of 23.27 mg/l. Severity was associated with higher age, symptomatic presentation, elevated leucocytes, and elevated inflammatory markers.


Subject(s)
COVID-19 , Adult , Female , Humans , India/epidemiology , Male , Retrospective Studies , SARS-CoV-2 , Tertiary Care Centers
12.
J Clin Microbiol ; 60(4): e0229821, 2022 04 20.
Article in English | MEDLINE | ID: covidwho-1759280

ABSTRACT

Critically ill patients with coronavirus disease 2019 (COVID-19) may develop COVID-19-associated pulmonary aspergillosis (CAPA), which impacts their chances of survival. Whether positive bronchoalveolar lavage fluid (BALF) mycological tests can be used as a survival proxy remains unknown. We conducted a post hoc analysis of a previous multicenter, multinational observational study with the aim of assessing the differential prognostic impact of BALF mycological tests, namely, positive (optical density index of ≥1.0) BALF galactomannan (GM) and positive BALF Aspergillus culture alone or in combination for critically ill patients with COVID-19. Of the 592 critically ill patients with COVID-19 enrolled in the main study, 218 were included in this post hoc analysis, as they had both test results available. CAPA was diagnosed in 56/218 patients (26%). Most cases were probable CAPA (51/56 [91%]) and fewer were proven CAPA (5/56 [9%]). In the final multivariable model adjusted for between-center heterogeneity, an independent association with 90-day mortality was observed for the combination of positive BALF GM and positive BALF Aspergillus culture in comparison with both tests negative (hazard ratio, 2.53; 95% CI confidence interval [CI], 1.28 to 5.02; P = 0.008). The other independent predictors of 90-day mortality were increasing age and active malignant disease. In conclusion, the combination of positive BALF GM and positive BALF Aspergillus culture was associated with increased 90-day mortality in critically ill patients with COVID-19. Additional study is needed to explore the possible prognostic value of other BALF markers.


Subject(s)
COVID-19 , Invasive Pulmonary Aspergillosis , Pulmonary Aspergillosis , Aspergillus , Bronchoalveolar Lavage Fluid , COVID-19/complications , Critical Illness , Galactose/analogs & derivatives , Humans , Intensive Care Units , Invasive Pulmonary Aspergillosis/complications , Invasive Pulmonary Aspergillosis/diagnosis , Mannans , Mycology , Prognosis , Sensitivity and Specificity
13.
3rd International Conference on Control Systems, Mathematical Modeling, Automation and Energy Efficiency, SUMMA 2021 ; : 434-439, 2021.
Article in English | Scopus | ID: covidwho-1672881

ABSTRACT

The goal of this study is to make a comparison between chronological and biological ages across the Italian and the Russian population. To serve this purpose we employ a measure of age recently introduced in the literature by Milevski (so-called Longevity-risk-Adjusted global age, hereafter L-RaG). Data for the Italian and the Russian population, split by regions, sex, and age groups have been collected for the years 2019 and 2020. Results show that there are significant differences between the chronological and the perceived ages for females and males across Italian regions. The difference exacerbates if we make a comparison between the North and the South regions. Looking at the Russian population, the gap appears extremely high for the North Caucasian area. Finally, we compare the median values of the gaps between the years 2019 and 2020. We found that in the latter year, the median values of the gap has been decreased. This could be attributed to the consequences of the Covid-19 pandemic. © 2021 IEEE.

14.
Front Pharmacol ; 12: 804250, 2021.
Article in English | MEDLINE | ID: covidwho-1674372

ABSTRACT

Sepsis is a syndrome with high mortality, which seriously threatens human health. During the pandemic of coronavirus disease 2019 (COVID-19), some severe and critically ill COVID-19 patients with multiple organ dysfunction developed characteristics typical of sepsis and met the diagnostic criteria for sepsis. Timely detection of cytokine storm and appropriate regulation of inflammatory response may be significant in the prevention and treatment of sepsis. This study evaluated the efficacy and safety of specific interleukin (IL)-1 inhibitors, specific IL-6 inhibitors, and GM-CSF blockades in the treatment of COVID-19 (at the edge of sepsis) patients through systematic review and meta-analysis. METHODOLOGY: A literature search was conducted on PubMed, EMBASE, Clinical Key, Cochrane Library, CNKI, and Wanfang Database using proper keywords such as "SARS-CoV-2," "Corona Virus Disease 2019," "COVID-19," "anakinra," "tocilizumab," "siltuximab," "sarilumab," "mavrilimumab," "lenzilumab," and related words for publications released until August 22, 2021. Other available resources were also used to identify relevant articles. The present systematic review was performed based on PRISMA protocol. RESULTS: Based on the inclusion and exclusion criteria, 43 articles were included in the final review. The meta-analysis results showed that tocilizumab could reduce the mortality of patients with COVID-19 (at the edge of sepsis) [randomized controlled trials, RCTs: odds ratio (OR) 0.71, 95%CI: 0.52-0.97, low-certainty evidence; non-RCTs: risk ratio (RR) 0.68, 95%CI: 0.55-0.84, very low-certainty evidence) as was anakinra (non-RCTs: RR 0.47, 95%CI: 0.34-0.66, very low-certainty evidence). Sarilumab might reduce the mortality of patients with COVID-19 (at the edge of sepsis), but there was no statistical significance (OR 0.65, 95%CI: 0.36-1.2, low-certainty evidence). For safety outcomes, whether tocilizumab had an impact on serious adverse events (SAEs) was very uncertain (RCTs: OR 0.87, 95%CI: 0.38-2.0, low-certainty evidence; non-RCTs 1.18, 95%CI: 0.83-1.68, very low-certainty evidence) as was on secondary infections (RCTs: OR 0.71, 95%CI: 0.06-8.75, low-certainty evidence; non-RCTs: RR 1.15, 95%CI: 0.89-1.49, very low-certainty evidence). CONCLUSIONS: This systematic review showed that tocilizumab, sarilumab, and anakinra could reduce the mortality of people with COVID-19 (at the edge of sepsis), and tocilizumab did not significantly affect SAEs and secondary infections. The current evidence of the studies on patients treated with siltuximab, mavrilimumab, and lenzilumab is insufficient. In order to establish evidence with stronger quality, high-quality studies are needed. Systematic Review Registration: PROSPERO (https://www.crd.york.ac.uk/prospero/), identifier CRD42020226545.

15.
J Med Econ ; 25(1): 160-171, 2022.
Article in English | MEDLINE | ID: covidwho-1625356

ABSTRACT

AIMS: Estimate the clinical and economic benefits of lenzilumab plus standard of care (SOC) compared with SOC alone in the treatment of patients hospitalized with COVID-19 pneumonia from the United States (US) hospital perspective. MATERIALS AND METHODS: A per-patient cost calculator was developed to report the clinical and economic benefits associated with adding lenzilumab to SOC in newly hospitalized COVID-19 patients over 28 days. Clinical inputs were based on the LIVE-AIR trial, including failure to achieve survival without ventilation (SWOV), mortality, time to recovery, intensive care unit (ICU) admission, and invasive mechanical ventilation (IMV) use. Base case costs included the anticipated list price of lenzilumab, drug administration, and hospital resource costs based on the level of care required. A scenario analysis examined projected one-year rehospitalization costs. RESULTS: In the base case and all scenarios, lenzilumab plus SOC improved all specified clinical outcomes relative to SOC alone. Lenzilumab plus SOC resulted in estimated cost savings of $3,190 per patient in a population aged <85 years with C-reactive protein (CRP) levels <150 mg/L and receiving remdesivir (base case). Per-patient cost savings were observed in the following scenarios: (1) aged <85 years with CRP <150 mg/L, with or without remdesivir ($1,858); (2) Black and African American patients with CRP <150 mg/L ($13,154); and (3) Black and African American patients from the full population, regardless of CRP level ($2,763). In the full modified intent-to-treat population, an additional cost of $4,952 per patient was estimated. When adding rehospitalization costs to the index hospitalization, a total per-patient cost savings of $5,154 was estimated. CONCLUSIONS: The results highlight the clinical benefits for SWOV, ventilator use, time to recovery, mortality, time in ICU, and time on IMV, in addition to an economic benefit from the US hospital perspective associated with adding lenzilumab to SOC for COVID-19 patients.


Subject(s)
COVID-19 , Aged, 80 and over , Antibodies, Monoclonal, Humanized , Hospitals , Humans , SARS-CoV-2 , Standard of Care , United States
16.
J Clin Exp Hepatol ; 12(3): 1007-1011, 2022.
Article in English | MEDLINE | ID: covidwho-1561499

ABSTRACT

Liver transplant recipients are at an increased risk of opportunistic infections due to the use of immunosuppression. Coronavirus disease of 2019 (COVID-19) increases the risk of these infections further due to associated immune dysfunction and the use of high-dose steroids. We present a case of a liver transplant recipient who developed disseminated tuberculosis and invasive pulmonary aspergillosis complicated by acquired hemophagocytic lymphohistiocytosis after recovering from severe COVID-19.

17.
Clin Sci (Lond) ; 135(22): 2559-2573, 2021 11 26.
Article in English | MEDLINE | ID: covidwho-1541262

ABSTRACT

Granulocyte macrophage colony stimulating factor (GM-CSF) is a key participant in, and a clinical target for, the treatment of inflammatory diseases including rheumatoid arthritis (RA). Therapeutic inhibition of GM-CSF signalling using monoclonal antibodies to the α-subunit of the GM-CSF receptor (GMCSFRα) has shown clear benefit in patients with RA, giant cell arteritis (GCAs) and some efficacy in severe SARS-CoV-2 infection. However, GM-CSF autoantibodies are associated with the development of pulmonary alveolar proteinosis (PAP), a rare lung disease characterised by alveolar macrophage (AM) dysfunction and the accumulation of surfactant lipids. We assessed how the anti-GMCSFRα approach might impact surfactant turnover in the airway. Female C57BL/6J mice received a mouse-GMCSFRα blocking antibody (CAM-3003) twice per week for up to 24 weeks. A parallel, comparator cohort of the mouse PAP model, GM-CSF receptor ß subunit (GMCSFRß) knock-out (KO), was maintained up to 16 weeks. We assessed lung tissue histopathology alongside lung phosphatidylcholine (PC) metabolism using stable isotope lipidomics. GMCSFRß KO mice reproduced the histopathological and biochemical features of PAP, accumulating surfactant PC in both broncho-alveolar lavage fluid (BALF) and lavaged lung tissue. The incorporation pattern of methyl-D9-choline showed impaired catabolism and not enhanced synthesis. In contrast, chronic supra-pharmacological CAM-3003 exposure (100 mg/kg) over 24 weeks did not elicit a histopathological PAP phenotype despite some changes in lung PC catabolism. Lack of significant impairment of AM catabolic function supports clinical observations that therapeutic antibodies to this pathway have not been associated with PAP in clinical trials.


Subject(s)
Arthritis, Rheumatoid/metabolism , COVID-19/therapy , Pulmonary Alveolar Proteinosis/immunology , Pulmonary Surfactants/metabolism , Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/antagonists & inhibitors , Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/metabolism , Animals , Antibodies, Monoclonal, Humanized/pharmacology , Arthritis, Rheumatoid/therapy , Autoantibodies/chemistry , Bronchoalveolar Lavage Fluid , COVID-19/immunology , Choline/analogs & derivatives , Female , Granulocyte-Macrophage Colony-Stimulating Factor/chemistry , Inflammation , Interleukin-6/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Phenotype , Pulmonary Alveolar Proteinosis/genetics , SARS-CoV-2/immunology , Surface-Active Agents
18.
Vaccines (Basel) ; 9(12)2021 Nov 30.
Article in English | MEDLINE | ID: covidwho-1539981

ABSTRACT

To investigate whether oral administration of maize-produced S antigen can provide passive immunity to piglets against porcine epidemic diarrhea virus (PEDV), 16 pregnant sows were randomly assigned to one of four treatments: (1) injection of PEDV vaccine (INJ), (2) maize grain without S protein (CON), (3) maize grain containing low dose of S antigen (LOV) and (4) maize grain containing a high dose of S antigen (HOV). Vaccines were administered on days 57, 85 and 110 of gestation. Sows' serum and colostrum were collected at farrowing and milk on day 6 post-challenge to quantify neutralizing antibodies (NABs) and cytokines. Piglets were challenged with PEDV 3-5 d after farrowing, and severity of disease and mortality assessed on day 11 post-challenge. Disease severity was lower in LOV and INJ compared with HOV and CON, whereas the survival rate increased in piglets from LOV sows compared with HOV and CON (p ≤ 0.001). Higher titers of NABs and lower levels of cytokine granulocyte-macrophage colony-stimulating factor in sows' milk were positively correlated with piglet survivability (p ≤ 0.05). These data suggest that feeding S protein in corn to pregnant sows protects nursing piglets against PEDV.

20.
Int Immunopharmacol ; 101(Pt A): 108292, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1487772

ABSTRACT

Leukopenia is a common manifestation of many diseases, including global outbreak SAS-CoV-2 infection. Granulocyte-macrophage colony-stimulating factor (GM -CSF) has been proved to be effective in promoting lymphocyte regeneration, but adverse immunological effects have also emerged. This study aim to investigate the effect of GM -CSF on BCR heavy chain CDR3 repertoire while promoting lymphocyte regeneration. Cyclophosphamide (CTX) and GM -CSF were used to inhibit and stimulate bone marrow hematopoiesis, respectively. High throughput sequencing was applied to detect the characteristics of BCR CDR3 repertoire in controls, CTX group and GM -CSF group. The white blood cells (WBCs) were quickly reduced (P < 0.05) with lymphocytes decreasing causing by CTX, and the WBCs and lymphocytes returned to the level of controls after GM -CSF treatment. The diversity of BCR heavy chain CDR3 repertoire was also significantly decreased in CTX group. Although there is still a big gap from the controls, the diversity was picked up after GM -CSF treatment. The expression of IGHD01-01, IGHD02-14 and IGHJ04-01 with high-frequency usage regularly and significantly changed in three groups, and many genes with low-frequency usage lost in CTX group and did not reappear in GM -CSF group. Moreover, two shared sequences and accounted for the highest proportion in GM -CSF group have been detected in animal model of chronic lymphocytic leukemia. These results revealed that GM -CSF can partially restore changes in the BCR heavy chain CDR3 repertoire while promoting lymphocyte regeneration, but it may also lead to rearrangement, proliferation and activation of abnormal B cells, which can provide a basis for further study on the adverse immunological effects and mechanism of GM -CSF treatment.


Subject(s)
Cyclophosphamide/adverse effects , Granulocyte-Macrophage Colony-Stimulating Factor/immunology , Leukopenia/immunology , Lymphocytes/drug effects , Lymphocytes/immunology , Receptors, Antigen, B-Cell/drug effects , Receptors, Antigen, B-Cell/metabolism , Animals , Complementarity Determining Regions/drug effects , Complementarity Determining Regions/genetics , Complementarity Determining Regions/metabolism , Cyclophosphamide/therapeutic use , Female , Granulocyte-Macrophage Colony-Stimulating Factor/therapeutic use , Immunoglobulin Heavy Chains/drug effects , Immunoglobulin Heavy Chains/genetics , Immunoglobulin Heavy Chains/metabolism , Immunoglobulin Joining Region/drug effects , Immunoglobulin Joining Region/metabolism , Immunoglobulin Variable Region/drug effects , Immunoglobulin Variable Region/metabolism , Leukocytes/drug effects , Leukopenia/chemically induced , Leukopenia/drug therapy , Lymphocytes/metabolism , Mice, Inbred BALB C , Receptors, Antigen, B-Cell/immunology
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