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1.
EClinicalMedicine ; 49: 101493, 2022 Jul.
Article in English | MEDLINE | ID: covidwho-1881936
2.
J Am Geriatr Soc ; 70(3): 650-658, 2022 03.
Article in English | MEDLINE | ID: covidwho-1731188

ABSTRACT

BACKGROUND: There is incomplete information regarding evolution of antibody titers against SARS-CoV-2 after a two-dose strategy vaccination with BNT162b2 in older adults in long-term care facilities (LTCFs) with frailty, disability, or cognitive impairment. We aimed to determine IgG antibody titer loss in older adults in LTCFs. METHODS: This is a multicenter longitudinal cohort study including 127 residents (90 females and 37 males) with a mean age of 82.7 years (range 65-99) with different frailty and disability profiles in two LTCFs in Albacete, Spain. Residents received two doses of BNT162b2 as per label, and antibody levels were determined 1 and 6 months after the second dose. Age, sex, previous history of coronavirus disease 2019 (COVID-19), comorbidity (Charlson Index), performance in activities of daily living (Barthel Index), frailty (FRAIL instrument), and cognitive status were assessed. RESULTS: The mean antibody titers 1 and 6 months after the second vaccine dose were 32,145 AU/ml (SD 41,206) and 6182 AU/ml (SD 13,316), respectively. Across all participants, the median antibody titer loss measured 77.6% (interquartile range [IQR] 23.8%). Notably, the decline of titers in individuals with pre-vaccination COVID-19 infection was significantly lower than in those without a history of SARS-CoV-2 infection (72.2% vs. 85.3%; p < 0.001). The median titer decrease per follow-up day was 0.47% (IQR 0.14%) and only pre-vaccination COVID-19 was associated with lower rate of antibody decline at 6 months (hazard ratio 0.17; 95% confidence interval 0.07-0.41; p < 0.001). Frailty, disability, older age, cognitive impairment, or comorbidity were not associated with the extent of antibody loss. CONCLUSIONS: Older adults in LTCFs experience a rapid loss of antibodies over the first 6 months after the second dose of BNT162b2 vaccine. Only pre-vaccination COVID-19 is associated with a slower rate of antibody decrease. Our data support immunization with a third dose in this vulnerable, high-risk population.


Subject(s)
/immunology , COVID-19/immunology , COVID-19/prevention & control , Disabled Persons , Frail Elderly , Aged , Aged, 80 and over , Antibody Formation , Female , Humans , Longitudinal Studies , Male , Nursing Homes , SARS-CoV-2 , Spain
3.
Lancet Reg Health West Pac ; 20: 100398, 2022 Mar.
Article in English | MEDLINE | ID: covidwho-1693129
4.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-318596

ABSTRACT

Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) has become a global pandemic. Case identification is currently made by real-time polymerase chain reaction (PCR) during the acute phase and largely restricted to healthcare laboratories. Serological assays are emerging but independent validation is urgently required to assess their utility.We evaluated five different point-of-care (POC) SARS-CoV-2 antibody test kits against PCR, finding concordance across the assays ( n= 15). We subsequently tested 200 patients using the OrientGene COVID-19 IgG/IgM Rapid Test Cassette and find a sensitivity of 74% in the early infection period (day 5-9 post symptom onset), with 100% sensitivity not seen until day 13. Specificity was 96%, but in validating the serological tests uncovered potential false-negatives from PCR testing late-presenting cases. A positive predictive value (PPV) of 37% in the general population precludes any use for general screening. Where a case definition is applied however, the PPV is substantially improved (95·4%), supporting use of serology testing in carefully targeted populations. Larger studies in specific patient cohorts, including those with mild infection are urgently required to inform on the applicability of POC serological assays to help control the spread of SARS-CoV-2 and improve case finding of patients that may experience late complications.

5.
EuropePMC;
Preprint in English | EuropePMC | ID: ppcovidwho-328605

ABSTRACT

This first of its kind study provides objective context to the potential mechanism of action of corticosteroid use in COVID-19 patients from 3 separate European medical centers by connecting inflammatory biomarkers to IgG levels for the SARS-CoV-2 spike protein antigens and neutralization of ACE2 binding within infected individuals. CXCL9 is described herein as an important COVID-19 biomarker connecting disease severity with inflammatory biomarker and serology response profiles in corticosteroid-treated patients.

6.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-322046

ABSTRACT

Baricitinib, is an oral Janus kinase (JAK)1/JAK2 inhibitor approved for the treatment of rheumatoid arthritis (RA) that was independently hypothesized, using artificial intelligence (AI)-algorithms, to be useful for the treatment of COVID-19 infection via a proposed anti-cytokine effects and as an inhibitor of host cell viral propagation 1,2 . We validated the AI-predicted biochemical inhibitory effects of baricitinib on human numb-associated kinase (hNAK) members measuring nanomolar affinities for AAK1, BIKE, and GAK. Inhibition of NAKs led to reduced viral infectivity with baricitinib using human primary liver spheroids, which express hAAK1 and hGAK. We evaluated the in vitro pharmacology of baricitinib across relevant leukocyte subpopulations coupled to its in vivo pharmacokinetics and showed it inhibited signaling of cytokines implicated in COVID-19 infection. In a case series of patients with bilateral COVID-19 pneumonia, baricitinib treatment was associated with clinical and radiologic recovery, a rapid decline in SARS-CoV-2 viral load, inflammatory markers, and IL-6 levels. This represents an important example of an AI-predicted treatment showing scientific and clinical promise during a global health crisis. Collectively, these data support further evaluation of the AI-derived hypothesis on anti-cytokine and anti-viral activity and supports its assessment in randomized trials in hospitalized COVID-19 patients.

8.
Future Virology ; 16(3):153-156, 2021.
Article in English | PMC | ID: covidwho-1389078
9.
Sci Adv ; 7(1)2021 01.
Article in English | MEDLINE | ID: covidwho-1388432

ABSTRACT

Using AI, we identified baricitinib as having antiviral and anticytokine efficacy. We now show a 71% (95% CI 0.15 to 0.58) mortality benefit in 83 patients with moderate-severe SARS-CoV-2 pneumonia with few drug-induced adverse events, including a large elderly cohort (median age, 81 years). An additional 48 cases with mild-moderate pneumonia recovered uneventfully. Using organotypic 3D cultures of primary human liver cells, we demonstrate that interferon-α2 increases ACE2 expression and SARS-CoV-2 infectivity in parenchymal cells by greater than fivefold. RNA-seq reveals gene response signatures associated with platelet activation, fully inhibited by baricitinib. Using viral load quantifications and superresolution microscopy, we found that baricitinib exerts activity rapidly through the inhibition of host proteins (numb-associated kinases), uniquely among antivirals. This reveals mechanistic actions of a Janus kinase-1/2 inhibitor targeting viral entry, replication, and the cytokine storm and is associated with beneficial outcomes including in severely ill elderly patients, data that incentivize further randomized controlled trials.


Subject(s)
Antiviral Agents/pharmacology , Azetidines/pharmacology , COVID-19/mortality , Enzyme Inhibitors/pharmacology , Janus Kinases/antagonists & inhibitors , Liver/virology , Purines/pharmacology , Pyrazoles/pharmacology , SARS-CoV-2/pathogenicity , Sulfonamides/pharmacology , Adult , Aged , Aged, 80 and over , COVID-19/drug therapy , COVID-19/metabolism , COVID-19/virology , Cytokine Release Syndrome , Cytokines/metabolism , Drug Evaluation, Preclinical , Female , Gene Expression Profiling , Humans , Interferon alpha-2/metabolism , Italy , Janus Kinases/metabolism , Liver/drug effects , Male , Middle Aged , Patient Safety , Platelet Activation , Proportional Hazards Models , RNA-Seq , Spain , Virus Internalization/drug effects
10.
N Engl J Med ; 385(5): 463-465, 2021 07 29.
Article in English | MEDLINE | ID: covidwho-1331418
11.
Journal for Immunotherapy of Cancer ; 8(Suppl 3):A854, 2020.
Article in English | ProQuest Central | ID: covidwho-1318080

ABSTRACT

BackgroundThe gut microbiome has emerged as a promising innovative therapeutic target for immune-stimulation treatment of solid tumours. MRx0518 is a novel, gut microbiome-derived oral live biotherapeutic. It has potent anti-tumorigenic efficacy in the preclinical setting including murine models of lung (LLC1), kidney (Renca) and breast (EMT6) cancer.1 In these models, a significant reduction in tumour growth has been demonstrated, including induction of immunostimulatory responses with tumour infiltration of NK cells, CD8+ and CD4+ T-cells. MRx0518 is under investigation in various oncological settings, including in combination with immune checkpoint inhibitors (NCT03637803) and radiotherapy (NCT04193904).MethodsTreatment naïve patients were recruited from April 2019 to February 2020. Patients were eligible if they received a histologically confirmed diagnosis of cancer (solid tumours) scheduled for surgical resection. Patients received 1 capsule of MRx0518 (1x1010 to 1x1011 CFU) twice daily from inclusion until the day preceding surgery (maximum 28 days therapy). The primary study outcome is to evaluate safety and tolerability of MRx0518 monotherapy in treatment naïve patients. Additional exploratory outcomes including identifying surrogate biomarkers of efficacy, microbiome analysis, effect on metabonomic markers and identification of histological and genomic alterations in paired pre-treatment (diagnostic biopsy) and post-treatment (surgical specimen) samples.ResultsIn part A, 17 patients received treatment, across tumour groups including breast (n=8), prostate (n=4), uterine (n=3), melanoma (n=1) and bladder (n=1). MRx0518 was well tolerated by all, with no grade 3/4 CTCAE toxicity reported, no severe adverse effects or treatment discontinuations. All patients proceeded to surgery, however the COVID-19 pandemic delayed surgery in 3 cases.Analysis of the first 5* patient paired samples utilising the NanoString Pan Cancer IO 360TM Gene Expression panel has demonstrated significant changes in gene expression profiles in 48 genes (pConclusionsThis study has demonstrated the safety and tolerability of the live biotherapeutic MRx0518 in treatment naïve cancer patients. Exploratory analyses of post-treatment samples has echoed preclinical observations of increased infiltration of immune cells following treatment and will undergo further validation. Part B will focus on investigating efficacy in a further 100 treatment naïve patients with a placebo-controlled arm.Trial RegistrationNCT03934827Ethics ApprovalThe study was approved by East of England - Cambridge East Research Ethics Committee approval number 18/EE/0091ReferenceLauté-Caly DL, Raftis EJ, Cowie P, et al. The flagellin of candidate live biotherapeutic Enterococcus gallinarum MRx0518 is a potent immunostimulant. Scientific Reports 2019;9(1):1-14. doi:10.1038/s41598-018-36926-8*Data analysis has been censored at 18/9/2020, further samples analysis is ongoing and will be updated.

12.
J Am Geriatr Soc ; 69(10): 2752-2758, 2021 10.
Article in English | MEDLINE | ID: covidwho-1301522

ABSTRACT

BACKGROUND: Older adults are at the highest risk of severe disease and death due to COVID-19. Randomized data have shown that baricitinib improves outcomes in these patients, but focused stratified analyses of geriatric cohorts are lacking. Our objective was to analyze the efficacy of baricitinib in older adults with COVID-19 moderate-to-severe pneumonia. METHODS: This is a propensity score [PS]-matched retrospective cohort study. Patients from the COVID-AGE and Alba-Score cohorts, hospitalized for moderate-to-severe COVID-19 pneumonia, were categorized in two age brackets of age <70 years old (86 with baricitinib and 86 PS-matched controls) or ≥70 years old (78 on baricitinib and 78 PS-matched controls). Thirty-day mortality rates were analyzed with Kaplan-Meier and Cox proportional hazard models. RESULTS: Mean age was 79.1 for those ≥70 years and 58.9 for those <70. Exactly 29.6% were female. Treatment with baricitinib resulted in a significant reduction in death from any cause by 48% in patients aged 70 or older, an 18.5% reduction in 30-day absolute mortality risk (n/N: 16/78 [20.5%] baricitinib, 30/78 [38.5%] in PS-matched controls, p < 0.001) and a lower 30-day adjusted fatality rate (HR 0.21; 95% CI 0.09-0.47; p < 0.001). Beneficial effects on mortality were also observed in the age group <70 (8.1% reduction in 30-day absolute mortality risk; HR 0.14; 95% CI 0.03-0.64; p = 0.011). CONCLUSIONS: Baricitinib is associated with an absolute mortality risk reduction of 18.5% in adults older than 70 years hospitalized with COVID-19 pneumonia.


Subject(s)
Azetidines , COVID-19 , Pneumonia, Viral , Purines , Pyrazoles , Sulfonamides , Age Factors , Aged , Aged, 80 and over , Antiviral Agents/administration & dosage , Antiviral Agents/adverse effects , Azetidines/administration & dosage , Azetidines/adverse effects , COVID-19/drug therapy , COVID-19/mortality , COVID-19/physiopathology , Female , Hospital Mortality , Humans , Janus Kinase Inhibitors/administration & dosage , Janus Kinase Inhibitors/adverse effects , Male , Mortality , Outcome and Process Assessment, Health Care , Pneumonia, Viral/diagnosis , Pneumonia, Viral/drug therapy , Purines/administration & dosage , Purines/adverse effects , Pyrazoles/administration & dosage , Pyrazoles/adverse effects , SARS-CoV-2/isolation & purification , Severity of Illness Index , Spain/epidemiology , Sulfonamides/administration & dosage , Sulfonamides/adverse effects
14.
J Am Geriatr Soc ; 69(6): 1441-1447, 2021 06.
Article in English | MEDLINE | ID: covidwho-1153546

ABSTRACT

BACKGROUND/OBJECTIVES: The safety and immunogenicity of the BNT162b2 coronavirus disease 2019 (COVID-19) vaccine in older adults with different frailty and disability profiles have not been well determined. Our objective was to analyze immunogenicity of the BNT162b2 mRNA COVID-19 vaccine in older adults across frailty and disability profiles. DESIGN: Multicenter longitudinal cohort study. SETTING AND PARTICIPANTS: A total of 134 residents aged ≥65 years with different frailty and disability profiles in five long-term care facilities (LTCFs) in Albacete, Spain. INTERVENTION AND MEASUREMENTS: Residents were administered two vaccine doses as per the label, and antibody levels were determined 21.9 days (SD 9.3) after both the first and second dose. Functional variables were assessed using activities of daily living (Barthel Index), and frailty status was determined with the FRAIL instrument. Cognitive status and comorbidity were also evaluated. RESULTS: Mean age was 82.9 years (range 65-99), and 71.6% were female. The mean antibody titers in residents with and without previous COVID-19 infection were 49,878 AU/ml and 15,274 AU/ml, respectively (mean difference 34,604; 95% confidence interval [CI]: 27,699-41,509). No severe adverse reactions were observed, after either vaccine dose. Those with prevaccination COVID-19 had an increased antibody level after the vaccine (B = 31,337; 95% CI: 22,725-39,950; p < 0.001). Frailty, disability, older age, sex, cognitive impairment, or comorbidities were not associated with different antibody titers. CONCLUSIONS: The BNT162b2 mRNA COVID-19 vaccine in older adults is safe and produces immunogenicity, independently of the frailty and disability profiles. Older adults in LTCFs should receive a COVID-19 vaccine.


Subject(s)
Antibody Formation , COVID-19 Vaccines/immunology , COVID-19 Vaccines/therapeutic use , COVID-19/prevention & control , Disabled Persons , Frail Elderly , Activities of Daily Living , Aged , Aged, 80 and over , COVID-19 Serological Testing , Comorbidity , Female , Health Status Indicators , Humans , Longitudinal Studies , Male , Nursing Homes , SARS-CoV-2 , Spain
15.
J Natl Cancer Inst ; 113(3): 344-345, 2021 03 01.
Article in English | MEDLINE | ID: covidwho-1123319
17.
Cell Rep Med ; 1(8): 100145, 2020 11 17.
Article in English | MEDLINE | ID: covidwho-1065661

ABSTRACT

A screen by Kost-Alimova et al.1 suggests that the FDA-approved SYK inhibitor fostamatinib inhibits MUC1 in the respiratory tract and has the potential to treat serious outcomes of coronavirus COVID-19, including acute respiratory distress syndrome (ARDS) and acute lung injury (ALI).


Subject(s)
Acute Lung Injury/drug therapy , Aminopyridines/therapeutic use , COVID-19/drug therapy , Drug Repositioning , Morpholines/therapeutic use , Pyrimidines/therapeutic use , SARS-CoV-2/pathogenicity , Acute Lung Injury/etiology , Acute Lung Injury/metabolism , COVID-19/complications , COVID-19/metabolism , Humans , Mucin-1/metabolism , Respiratory Distress Syndrome/drug therapy , Respiratory Distress Syndrome/etiology , Respiratory Distress Syndrome/metabolism , Syk Kinase/antagonists & inhibitors
18.
20.
J Natl Cancer Inst ; 113(4): 371-380, 2021 04 06.
Article in English | MEDLINE | ID: covidwho-1066370

ABSTRACT

BACKGROUND: Previous studies have indicated coronavirus disease 2019 (COVID-19) patients with cancer have a high fatality rate. METHODS: We conducted a systematic review of studies that reported fatalities in COVID-19 patients with cancer. A comprehensive meta-analysis that assessed the overall case fatality rate and associated risk factors was performed. Using individual patient data, univariate and multivariable logistic regression analyses were used to estimate odds ratios (OR) for each variable with outcomes. RESULTS: We included 15 studies with 3019 patients, of which 1628 were men; 41.0% were from the United Kingdom and Europe, followed by the United States and Canada (35.7%), and Asia (China, 23.3%). The overall case fatality rate of COVID-19 patients with cancer measured 22.4% (95% confidence interval [CI] = 17.3% to 28.0%). Univariate analysis revealed age (OR = 3.57, 95% CI = 1.80 to 7.06), male sex (OR = 2.10, 95% CI = 1.07 to 4.13), and comorbidity (OR = 2.00, 95% CI = 1.04 to 3.85) were associated with increased risk of severe events (defined as the individuals being admitted to the intensive care unit, or requiring invasive ventilation, or death). In multivariable analysis, only age greater than 65 years (OR = 3.16, 95% CI = 1.45 to 6.88) and being male (OR = 2.29, 95% CI = 1.07 to 4.87) were associated with increased risk of severe events. CONCLUSIONS: Our analysis demonstrated that COVID-19 patients with cancer have a higher fatality rate compared with that of COVID-19 patients without cancer. Age and sex appear to be risk factors associated with a poorer prognosis.


Subject(s)
COVID-19/epidemiology , Neoplasms/epidemiology , Asia/epidemiology , COVID-19/mortality , COVID-19/virology , Canada/epidemiology , Comorbidity , Europe/epidemiology , Female , Humans , Male , Neoplasms/mortality , Risk Factors , SARS-CoV-2/physiology , Survival Rate , United Kingdom/epidemiology , United States/epidemiology
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